compound, pharmaceutically acceptable salt of a compound, pharmaceutical composition, and, use of a

专利摘要:
compound, pharmaceutically acceptable salt of a compound, pharmaceutical composition, method for treating or preventing disorders, and, use of a compound or salt. compounds of formula (i) and methods for treating metabolic disorders are described.
公开号:BR112012026767B1
申请号:R112012026767
申请日:2011-04-27
公开日:2020-01-21
发明作者:Joseph Aquino Christopher；John Cowan David；Loren Collins Jon；Wu Yulin
申请人:Glaxosmithkline Llc；
IPC主号:

专利说明:

“COMPOUND, PHARMACEUTICALLY ACCEPTABLE SALT FROM A COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF A COMPOUND OR SALT”
Field of the Invention
The present invention relates to compounds that are useful in the treatment and prevention of metabolic disorders, including diabetes mellitus (Type I and Type II), obesity, and related disorders, and also includes methods for preparing the compounds, pharmaceutical compositions containing the compounds , and therapeutic uses for said compounds.
Fundamentals of the Invention
More than 200 million people worldwide have diabetes. The World Health Organization estimates that 1.1 million people died of diabetes in 2005 and projects that worldwide deaths from diabetes will double between 2005 and 2030. New chemical compounds that effectively treat diabetes could save millions of human lives.
Diabetes refers to metabolic disorders that result in the body's inability to effectively regulate glucose levels. Approximately 90% of all diabetes cases are a result of type 2 diabetes diabetes while the remaining 10% are a result of type 1 diabetes, gestational diabetes, and latent autoimmune diabetes in adults (LADA). adults). All forms of diabetes result in high blood glucose levels and, if left untreated chronically, can increase the risk of macrovascular (heart disease, stroke, other forms of cardiovascular disease) and microvascular complications (kidney failure (nephropathy), blindness of diabetic retinopathy, nerve damage (diabetic neuropathy)].
Type 1 diabetes, also known as juvenile diabetes or insulin-dependent diabetes mellitus [IDDM, insulin-dependent diabetes mellitus], can occur at any age, but is most often diagnosed in children, adolescents, or young adults. Type 1 diabetes is caused by the autoimmune destruction of insulin-producing beta cells, resulting in an inability to produce enough insulin. Insulin controls blood glucose levels by promoting the transport of glucose from the blood into cells for energy use. Insufficient insulin production will lead to less glucose reabsorption in cells and result in the accumulation of glucose in the bloodstream. The lack of glucose available in cells will eventually lead to the onset of symptoms of type 1 diabetes: polyuria (frequent urination), polydipsia (thirst), constant hunger, weight loss, vision changes, and fatigue. Within 5-10 years of being diagnosed with type 1 diabetes, insulin-producing beta cells in the patient's pancreas are completely destroyed, and the body can no longer produce insulin. As a result, patients with type 1 diabetes will need daily insulin administration for the rest of their lives.
Type 2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM) or adult diabetes, occurs when the pancreas produces insufficient insulin and / or tissues become resistant to normal or elevated levels of insulin (insulin resistance), resulting in excessively high blood glucose levels. Multiple factors can lead to insulin resistance including chronically high blood glucose levels, genetics, obesity, lack of physical activity, and increasing age. Unlike type 1 diabetes, symptoms of type 2 diabetes are more silent, and as a result, the disease may not be diagnosed until several years after onset with a peak prevalence in adults close to the age of 45. Unfortunately, the incidence of type 2 diabetes in children is growing.
The primary purpose of treating type 2 diabetes is to obtain and maintain glycemic control to reduce the risk of microvascular (diabetic neuropathy, retinopathy, or nephropathy) and macrovascular complications (heart disease, stroke, other forms of cardiovascular disease). Current standards for the treatment of type 2 diabetes from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) [Diabetes Care, 2008, 31 (12), 1] outline lifestyle modification including loss weight gain and increased physical activity as a primary therapeutic approach to the control of type 2 diabetes. However, this approach alone fails in most patients within the first year, leading doctors to prescribe medications over time. ADA and EASD recommend metformin, an agent that reduces liver glucose production, as a Tier la drug; however, a significant number of patients taking metformin may experience gastrointestinal side effects and, in rare cases, potentially fatal lactic acidosis. Recommendations for the tier 1b class of drugs include sulfonylureas, which stimulate pancreatic insulin secretion via modulation of potassium channel activity, and exogenous insulin. Although both drugs quickly and effectively lower blood glucose levels, insulin requires 1 to 4 injections per day and both agents can cause unwanted weight gain and potentially fatal hypoglycemia. Tier 2a recommendations include newer agents, such as thiazolidinediones (TZDs pioglitazone and rosiglitazone), which increase insulin sensitivity by muscle, liver and fat, as well as GLP-1 analogs, which increase glucose-mediated insulin secretion postprandial from pancreatic beta cells. Although TZDs have robust, durable control of blood glucose levels, adverse effects include weight gain, edema, bone fractures in women, exacerbation of congestive heart failure, and potentially increased risk of ischemic cardiovascular events. GLP-1 analogues also effectively control blood glucose levels, however, this class of drugs requires injection and many patients complain of nausea. The most recent addition to the list of tier 2 drugs are DPP-4 inhibitors, which, like GLP-1 analogs, increase glucose-mediated insulin secretion from beta cells. Unfortunately, DPP4 inhibitors only modestly control blood glucose levels, and the long-term safety of DPP-4 inhibitors has yet to be solidly established. Other less prescribed drugs for type 2 diabetes include α-glycosidase inhibitors, glinides, and amylin analogues. Clearly, new drugs with improved profiles of efficacy, durability and side effects are needed for patients with type 2 diabetes.
GLP-1 and GIP are peptides, known as incretins, which are secreted by L and K cells, respectively, from the gastrointestinal tract into the bloodstream after ingestion of nutrients. This important physiological response serves as the primary signaling mechanism between the concentration of nutrients (glucose / fat) in the gastrointestinal tract and other peripheral organs. Upon secretion, both circulating peptides initiate signals in pancreatic beta cells to intensify glucose-stimulated insulin secretion, which in turn controls glucose concentrations in the bloodstream (for publications see: Diabetic Medicine 2007, 24 (3 ), 223; Molecular and Cellular Endocrinology 2009, 297 (1-2), 127; Experimental and Clinical Endocrinology & Diabetes 2001, 109 (Suppl. 2), S288).
The association between the incretin hormones GLP-1 and GIP and type 2 diabetes has been explored extensively. Most studies indicate that type 2 diabetes is associated with an acquired defect in GLP-1 secretion and also in the action of GIP (see Diabetes 2007, 56 (8), 1951 and Current Diabetes Reports 2006, 6 (3 ), 194). The use of exogenous GLP-1 for the treatment of patients with type 2 diabetes is severely limited due to its rapid degradation by the DPP-4 protease. Multiply modified peptides have been designed as GLP-1 mimetics that are resistant to DPP-4 and show longer half-lives than endogenous GLP-1. Agents with this profile that have been shown to be highly effective for the treatment of type 2 diabetes include exenatide and liraglutide, however, these agents require injection. Oral agents that inhibit DPP-4, such as sitagliptin vildagliptin, and saxagliptin, elevate intact GLP-1 and modestly control circulating glucose levels (see Pharmacology & Therapeutics 2010, 125 (2), 328; Diabetes Care 2007, 30 (6 ), 1335; Expert Opinion on Emerging Drugs 2008, 13 (4), 593). New oral drugs that increase GLP-1 secretion would be desirable for the treatment of type 2 diabetes.
Bile acids have been shown to increase peptide secretion from the gastrointestinal tract. Bile acids are released from the gallbladder in the small intestine after each meal to facilitate the digestion of nutrients, in particular fat, lipids, and lipid-soluble vitamins. Bile acids also function as hormones that regulate cholesterol homeostasis, energy, and glucose homeostasis via nuclear receptors (FXR, PXR, CAR, VDR) and the G protein-coupled TGR5 receptor (for publications see: Nature Drug Discovery 2008, 7 , 672; Diabetes, Obesity and Metabolism 2008, 10, 1004). TGR5 is a member of the Rhodopsin-type GPCRs (Class A) subfamily that is expressed in the intestine, gallbladder disease, adipose tissue, liver, and selected regions of the central nervous system. TGR5 is activated by multiple bile acids with lithocholic and deoxycholic acids as the most potent activators (Journal of Medicinal Chemistry 2008, 51 (6), 1831). Both deoxycholic and lithocholic acids increase the secretion of GLP-1 from an STC-1 enteroendocrine cell line, partly via TGR5 (Biochemical and Biophysical Research Communications 2005, 329, 386). A synthetic INT-777 TGR5 agonist has been shown to increase intestinal GLP-1 secretion in vivo in mice (Cell Metabolism 2009, 10, 167). Bile salts have been shown to promote secretion of GLP-1 from colonic L cells in a vascularly perfused rat neck model (Journal of Endocrinology 1995, 145 (3), 521) as well as GLP-1, YY peptide (PYY), and neurotensin in a vascularly perfused rat ileum model (Endocrinology 1998, 139 (9), 3780). In humans, the infusion of deoxycholate in the sigmoid neck produces a rapid increase in marked response to the dose of plasma concentrations of enteroglucagon and PYY (Gut 1993, 34 (9), 1219). Agents that increase colonic and ileal bile acid or bile salt concentrations will increase peptide secretion from the intestine including, but not limited to, GLP-1 and PYY.
Bile acids are synthesized from cholesterol in the liver, then undergo conjugation of the carboxylic acid with the amine functionality of taurine and glycine. Conjugated bile acids are secreted in gallbladder disease where they accumulate until the meal is consumed. When eating gallbladder disease it contracts and empties its content in the duodenum, where conjugated bile acids facilitate the absorption of cholesterol, fat, and fat-soluble vitamins in the proximal small intestine (for publications see: Frontiers in Bioscience 2009, 14, 2584; Clinical Pharmacokinetics 2002, 41 (10), 751; Journal of Pediatric Gastroenterology and Nutrition 2001, 32, 407). Conjugated bile acids continue to flow through the small intestine to the distal ileum where 90% are reabsorbed or enterocytes via the apical sodium-dependent bile acid transporter (ASBT), also known as iBAT. The remaining 10% are conjugated to bile acids by means of intestinal bacteria in the terminal ileum and colon, of which 5% are then passively reabsorbed in the colon and the remaining 5% are excreted in faeces. Bile acids that are reabsorbed by the ASBT in the ileum are then transported to the portal vein for recirculation to the liver.
This highly regulated process, called enteropathic recirculation, is important for maintaining the total volume of bile acid in the body because the amount of bile acid that is synthesized in the liver is equivalent to the amount of bile acids that are excreted in faeces. The pharmacological disruption of bile acid reabsorption with an ASBT inhibitor leads to increased concentrations of bile acids in the colon and feces, in which a physiological consequence is the increased conversion of liver cholesterol to bile acids to compensate for faecal loss of bile acids. Many pharmaceutical companies have sought this mechanism as a strategy to lower serum cholesterol in patients with dyslipidemia / hypercholesterolemia (for a publication see: Current Medicinal Chemistry 2006, 13, 997). It is important to note that the increase, mediated by an ASBT inhibitor, in the colonic concentration of bile acid / bile salt will also increase the intestinal GLP-1, PYY, GLP-2, and other peptide hormone secretion from the intestine. Thus, ASBT inhibitors could be useful for the treatment of type 2 diabetes, type 1 diabetes, dyslipidemia, obesity, short bowel syndrome, idiopathic chronic constipation, irritable bowel syndrome (IBS), Crohn's disease , and arthritis.
Certain 1,4-thiazepines are disclosed, for example in WO 94/18183 and WO 96/05188. These compounds are said to be useful as inhibitors of ileal bile acid reabsorption (ASBT).
Summary of the Invention
Briefly, in one aspect, the present invention discloses a compound of Formula I
wherein R ¹ is H, Cl, Br, N (CH ₃ ) ₂ , or methoxy;
R ² is H or OH;
cadaR ³ is independently Ci-galquila;
X is CH ₂ , C (O), or CH = CH;
Q is Co-6alkyl;
R ⁴ is OH, SO3H, CO2H, PO3H2, CONR ⁵ R ⁵ , NR ⁵ R ⁵ ; or NHC (O) CH2NR ⁵ R ⁵ ;
each R ⁵ is independently H, OH, C1-6alkyl, Co. 6alkylCO2H, C0.6alkylSO3H, Co_6alkylP03H2, C (O) C0-6alkylCO2H, C (O) C0. 6alkylSO3H, C (O) C0-6alkylPO3H2, or CH (R ⁷ ) C0. ₆ alkylCO ₂ H; and
R ⁷ is C ₀ - ₆ alkylCO ₂ H, C ₀ . ₆ alkylOH, C ₀ . ₆ alkyl SO ₃ H, or C _o . ₆ alkylPO ₃ H ₂ .
In one aspect, the present invention discloses pharmaceutically acceptable salts of the compounds of Formula I.
In one aspect, the present invention discloses pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.
In one aspect, the present invention discloses a method for treating or preventing metabolic disorders, including diabetes mellitus (Type I and Type II), obesity, and related disorders in a human, comprising administering a compound of Formula I or a pharmaceutically salt. acceptable value.
Detailed Description of the Invention
Preferably, R ¹ is methoxy.
Preferably, R is H.
Preferably, each R ³ is independently C ₂ . ₄ alkyl. Most preferably, each R ³ is independently ethyl or n-butyl.
When the R ³ groups are different, the carbon to which they are attached is chiral. In these chiral compounds, the preferred stereochemistry on that carbon atom is R.
The carbon atom to which the unsubstituted phenyl ring is attached is chiral. The preferred stereochemistry on that carbon atom is R.
Preferably, X is CH ₂ or C (O). Most preferably X is CH ₂ .
Preferably Q is C ₀ . ₂ alkyl. Most preferably Q is a Coalkyl (ie absent).
Preferably, R ⁴ is PO ₃ H ₂ or NR ⁵ R ⁵ . Most preferably R ⁴ is NR ⁵ R ⁵ .
Preferably, one R ⁵ is H and the other is OH, methyl, Cp 4 alkylCO 2 H, Co-2 alkyl S 3 H, C 2 alkyl PO 3 H 2, C (O) CO2 H, C (O) C 2 C alkyl 2 SO 3 H, C (O) Ci_ 2 alkyl PO 3 H 2, or CH (R ⁷ ) C 0 -alkylCO ₂ H. Most preferably, one R ⁵ is H and the other is CH2CO2H, CH2SO3H, CH2CH2SO3H, or CH (R ⁷ ) C0.alkylCO ₂ H.
Preferably, R ⁷ is Co-alkylC02H or C0.2alkylSO3H. Most preferably, R ⁷ is Co-alkylC02H.
As used here, "alkyl" can be straight or branched chain alkyl, unless clearly indicated otherwise.
For a review of advantageous pharmaceutically acceptable salts see, for example, Berge et al, J. Pharm, Sci., 66, 1-19, 1977. In one embodiment, acid addition salts are selected from the hydrochloride, hydrobromide, ihydrate , sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamool. In one embodiment, base addition salts include metal salts (such as sodium, potassium, aluminum, calcium, magnesium and zinc) and ammonium salts (such as isopropylamine, diethylamine, diethanolamine salts). Other salts (such as trifluoroacetates and oxalates) can be used in the manufacture of compounds of formula (I) and their pharmaceutically acceptable salts, and are included in the scope of the invention. Acid and base addition salts can be prepared by the skilled chemist by treating a compound of formula (I) with the appropriate acid or base in an advantageous solvent, followed by crystallization and filtration.
The method of treating or preventing metabolic disorders may comprise administering a compound or salt of this invention alone as monotherapy. The compounds and salts of this invention can also be used in combination with other therapeutic agents. Advantageous agents for use in combination with the compounds and salts of this invention include, for example, insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, or metformin.
Examples
The compounds of this invention can be prepared by a variety of methods, including well-known conventional synthetic methods. General illustrative synthetic methods are presented below, and then specific compounds of the invention are prepared in the working examples.
In all the schemes described below, protective groups are used for sensitive or reactive groups where necessary according to general principles of synthetic chemistry. Protective groups are manipulated according to conventional methods of organic synthesis (T.W. Green and P.G.M. Wuts, (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with respect to protective groups). These groups are removed at a convenient stage of the synthesis of the synthesis compound using methods that are easily understood by those skilled in the art. The selection of processes and also the reaction conditions and the order of their execution must be consistent with the preparation of compounds of the present invention. Compounds of the invention can be readily prepared according to Schemes 1 through 9 by those skilled in the art.
As illustrated in Scheme 1, several key intermediates can be prepared from (3Ã, 5Á) -3-butyl-3-ethyl-7,8-bis (methyloxy) -5phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepine 1,1-dioxide (Brieaddy, LE WO9605188, 1996). Lewis acid-mediated demethylation, followed by reaction with triflic anhydride provided an intermediate triflate (A). Reaction of A with carbon monoxide and palladium catalyst in MeOH resulted in intermediate ester (B). Reaction of A in the presence of cyanide and palladium catalyst resulted in intermediate nitrile (C), which was reduced with diisobutylaluminum hydride (DiBAL-H) giving the aldehyde intermediate (D) or subjected to hydrogenation in the presence of and acid resulted in origin to the aminomethyl intermediate (E).
Scheme 1: Preparation of key intermediates
Compounds of the invention can be prepared as in
Scheme 2. Subjecting the aldehyde intermediate (D) to reductive amination conditions with a substituted amine followed by, if necessary, deprotection with acid, base or functionalization (oxidation) resulted in examples of 8-aminomethyl examples (F). Alternatively, Intermediate (E) was acylated with chloroalkyl acid chlorides, then subjected to reaction with several nucleophiles including sulfite, phosphite, hydroxide, and substituted amines followed by, if required, deprotection of a protecting group giving examples of 8-aminomethyl acylated examples (F). Third and fourth procedures for preparing 8-aminomethyl compounds of the invention 5 involved reaction of Intermediate (E) with functionalized bromides in the presence of base or paraformaldehyde and triethylphosphite giving other substituted 8-aminomethyl compounds (F).
Scheme 2: Preparation of substituted aminomethyl compounds

1) R5R5NH
NaHB (OAc) ₃
2) deprotection or oxidation
1) ^CI
R ^s Br, base
2) Nucleophils [SO / ·, (EtO ^ P, -OH, HNR5R5]
3) deprotection
F
paraformaldehyde
HP (OXOEt) ₂
Compounds of the invention can be prepared as in
Scheme 3. Ester intermediate (B) was saponified under basic conditions giving carboxylic acid (G) which was then subjected to conventional amide coupling conditions in the presence of a substituted amine giving examples of amide (H). Ester intermediate (B) was also reduced with DiBAL-H to alcohol (I) which was then converted to bromide (J). 15 Bromide (J) was reacted with several nucleophiles (sulfite, phosphite, hydroxide, amines) followed, if necessary, by deprotection giving examples (K).
Scheme 3: Preparation of the intermediate ester examples (B)
Compounds of the invention can be prepared as in
Scheme 4 from the triflate intermediate (A). Subjection of intermediate (A) to a Heck reaction resulted in unsaturated ester (L) which was saponified to unsaturated acid (M). Ester (L) was subjected to conditions of hydrogenation followed by saponification giving acid (N). The formation of conventional amide with substituted amines resulted in examples of amide (O). The reduction of acid (N) with borane, followed by mesylation or formation of bromide resulted in compounds (P), which were reacted with several nucleophiles (cyanide, diethyl phosphite, hydroxide, sulphite) then, if necessary, 10 hydrolyzed, oxidized, or unprotected giving examples (Q).
Scheme 4: Preparation of examples of triflate intermediate (A)
Compounds of the invention can be prepared as in
Scheme 5. The aldehyde intermediate (D) was converted to unsaturated phosphonate (R) which was then deprotected with TMSBr giving an example of unsaturated phosphonic acid (S). Phosphonate (R) was subjected to hydrogenation, then 5 deprotected with TMSBr giving an example of saturated phosphonic acid (T).
Scheme 5: Preparation of alkylphosphonic acid derivatives

T
Compounds of the invention can be prepared as in
Scheme 6. Compound J (from Scheme 3) was oxidized to the Nhydroxyl derivative which was subjected to triethylphosphite followed by deprotection giving exemplary hydroxyl N10 (U). Intermediate Nitrile (C) was oxidized, then the nitrile was reduced to an aldehyde (V), which was then subjected to substituted amines under reductive amination conditions giving examples (W). Compound X (prepared as in Scheme 2) was oxidized, reduced, and deprotected giving an example of N-hydroxyl (Y).
Scheme 6: Preparation of N-hydroxylamine examples
J (scheme 3)

Compounds of the invention can be prepared as illustrated in Scheme 7. Intermediate nitrile (C) was oxidized to an imine, then the nitrile was reduced to an aldehyde using DiBAL-H, which was subjected to reduction with borane, reaction with triethyl phosphate, and deprotection giving the exemplary C (5) bphenyl (AA). Compound Z was oxidized with DessMartin periodinane, then subjected to substituted amines under reductive amination conditions followed, if necessary, deprotection to additional examples (BB).
Scheme 7: Preparation of C5 β epimer
Compounds of the invention can be prepared as illustrated in Scheme 8. Conversion of norleucine to an ethyl ester followed by formation of imine with benzaldehyde and alkylation with iodobutane resulted in an intermediate compound (CC). Hydrolysis of the imine followed by reduction with LAH and formation of sulfate resulted in intermediate aminosulfate (DD). Acylation of 2-bromo-1,4-bis (methyloxy) benzene with benzoyl chloride followed by selective demethylation resulted in a phenol intermediate. Acylation followed by Newman-Kwart rearrangement resulted in Intermediate (EE). 10 Deprotection of single vessel from (EE) and alkylation with aminosulfate (DD) resulted in product origin (FF). Intramolecular cyclization to an imine followed by palladium-mediated carbonylation resulted in an ester intermediate, which was reduced with LAH giving intermediate (GG). Imine reduction followed by sulfide oxidation resulted in an intermediate (HH). Conversion of (HH) to the examples of the invention (II and JJ) could be performed according to the chemistry illustrated in Schemes 2 and 3, respectively.
Scheme 8: Preparation of examples of C (3) -dibutyl
OH 3) NaH, iodobutane
1) EtOH, SOCI;
2) benzaldehyde
OEt
Ph
CC
DD
O ^ « ^Et í

II JJ
Compounds of the invention can be prepared as illustrated in Scheme 9. (3Ã, 5Ã) -3-butyl-3-ethyl-7,8-bis (methyloxy) -5phenyl-2,3,4,5-tetrahydro -1,4-benzothiazepine 1,1-dioxide (Brieaddy, LE
WO9605188, 1996) followed by triflate formation and palladium-mediated amination resulted in derivative (KK). Demethylation, triflate formation, and palladium-mediated cyanate resulted in a nitrile (LL). Reduction of nitrile with DiBAL-H to an aldehyde (MM) followed by subjection to substituted amines under conditions of reductive amination and, if necessary, exemplary deprotection (NN).
Scheme 9: Preparation of 7-N, N-dimethyl examples

1) aici ₃
2) Tip
3) Zn (CN) 2
Pd ₂ (dba) 3
DIBAL-H

Abbreviations
HATU 1,1,3,3-tetramethyl uranium hexafluorophosphate DCM dichloromethane DCE 1,2-dichloroethane DIPEA diisopropylethylamine DME 1,2-dimethoxyethane DMF ΛζΑ-dimethylformamide DMSO dimethylsulfoxide Et ₂ O diethyl ether EtOAc ethyl acetate EtOH ethanol H hour HOAc Acetic Acid MeCN acetonitrile MeOH methanol MTBE methyl t-butyl ether NMP N-methylpyrrolidinone PhH benzene PhMe toluene THF tetrahydrofuran
I. Preparation of intermediaries
Intermediates la and lb: (3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -5 phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ol- 1,1-l-dioxide (la) and (3Ã, 57 ) - 3-butyl-3-ethyl-8- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin- 7-ol 1,1dioxide (lb)

Method 1: A solution of (3R, 5R) -3-butyl-3ethyl-7,8-bis (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1-dioxide , 4-benzothiazepine (200 g, 479 mmol) (prepared as in Brieaddy, LE WO9605188, 1996) in DCE (11) was saturated with HCl (g) then treated with aluminum chloride (200 g, 1.5 mol) just one time. The reaction mixture was stirred while cooling slowly to room temperature then stirred for 2.5 h. The reaction mixture was added to an ice-H ₂ O mixture with vigorous stirring. The biphasic mixture was treated with 1N HCl (-200 ml) then the phases were separated after stirring for 30 min. The organic phase was isolated, washed twice with diluted HCl (1.5 1 H ₂ 0 / ~ 200 ml 1 N HCl), dried over MgSCL, filtered, and concentrated to dryness giving a regioisomeric mixture of 7-OH and 8 products -OH (185 g, 458 mmol, 96% yield) as a white foam. N NMR indicated a 47:53 mixture of 7/8-phenols, respectively. The regioisomers were separated by means of chiral chromatography [olymeric stationary phase (CSP) -cellulose tris (3,5-dichlorophenylcarbamate) immobilized on silica (CHIRALPAK IC®, 20 microns, 20 cm x 25 cm), DCM and isopropanol (98 / 2 vol / vol) as mobile phase] giving intermediates la and lb:
Intermediate lb (fastest eluting peak): (3R, 5R) -3-butyl-3-ethyl-8- (methyloxy) -5-phenyl-2,3,4,5-tetra- hydro-1,4 benzothiazepin-7-ol (86.3 g, white solid, purity = 98.2%): NMR * H (400 MHz, DMSO-40 δ ppm 0.74 (t, .7 = 7, 0 Hz, 3 H), 0.79 (t, .7 = 7.4 Hz, 3 H), 0.94 - 1.28 (m, 4 H), 1.30 - 1.53 (m, 2 H), 1.64 - 1.81 (m, 1 H), 1.91 - 2.10 (m, 1 H), 2.45 (d, 7 = 9.8 Hz, 1 H), 3, 04 (d, .7 = 14.8 Hz, 1 H), 3.49 (d, .7 = 14.8 Hz, 1 H), 3.80 (s, 3 H), 5.85 (d, .7 = 10.0 Hz, 1 H), 6.06 (s, 1 H), 7.19 - 7.52 (m, 6 H), 9.93 (s, 1 H)
Intermediate la (peak to elute more slowly): (3Ã, 5Á) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepin-8-ol (72.5 g) as a white solid: NMR ^! H (400 MHz, DMSO-7 ₆ ) δ ppm 0.75 (t, 7 = 7.1 Hz, 3 H), 0.79 (t, .7 = 7.5 Hz, 3 H), 0.95 -1.28 (m, 4 H), 1.31-1.53 (m, 2 H), 1.64-1.76 (m, 1 H), 1.98-2.10 (m, 1 H), 2.43 (d, 7 = 9.8 Hz, 1 H), 3.06 (d, .7 = 14.8 Hz, 1 H), 3.42 (s, 3 H), 3, 49 (d, .7 = 14.8 Hz, 1 H), 5.85 (d, 7 = 9.8 Hz, 1 H), 6.04 (s, 1 H), 7.24-7.35 (m, 1 H), 7.35-7.48 (m, 5 H), 9.72 (s, 1 H).
Method 2: A stirred solution of (3R, 5R) -3-butyl-3-ethyl-7,8-bis (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-dioxide 1,4-benzothiazepine (1250 g, 2.99 mol) in 1,2-dichloroethane (6 l) was saturated with HCl gas at room temperature (the internal temperature increased to 39 ° C during this step). Bubbling of HCl gas through the solution was continued for 5 min after reaching 39 ° C. Aluminum chloride (1250 g, 9.37 mol) was added in portions over 40 min with some external cooling while maintaining the reaction temperature between 38-42 ° C. The reaction mixture was stirred for 2 h and then slowly poured over 10 kg of ice / water. Two additional batches of 1250 g and 500 g of (3Ã, 5Ã) -3-butyl-3-ethyl-7,8-bis (methyloxy) -5-phenyl-2,3,4,5-tetra- hydro1,4-benzothiazepine were processed with aluminum chloride and HCl in a similar manner. The three reaction mixtures quenched with ice / water (7.19 mol theoretical combined) were combined and the phases were separated. The aqueous phase was extracted with CH ₂ C _{1 2} (3 1) and the combined organic layers were washed with water (3 x 4 1) and concentrated until the product started to crystallize. The mixture was diluted with heptane and aged with stirring. The precipitate was collected by filtration, dried in air for 2 days and then dried in a vacuum oven at 55 ° C for 48 h giving a mixture at approx. (3Ã, 5Á) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl- 9: 8
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ol and (3Ã, 57 ) - 3-butyl-3ethyl-8- (methyloxy) -5-phenyl 1,1-dioxide -2,3,4,5-tetrahydro-1,4-benzothiazepin-7-ol (2.8 kg). Purification of the mixture according to the procedure in Method 1 resulted in 1235 grams of (3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl- 1,1-dioxide
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ol as a white solid.
Method 3: A solution of (3A, 5A) -3-butyl-3ethyl-7,8-bis (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1-dioxide , 4-benzothiazepine (11.1 kg, 26.58 mol) in DCE (69.7 kg) was treated with water (0.48 kg, 26.67 mol) then the temperature was adjusted to 35 ^o - 40 ° C . The solution was charged with oxalyl chloride (3.4 kg, 26.78 mol) and stirred for thirty minutes. Then the solution was successively loaded with aluminum trichloride (3.6 kg, 26.9 mol; 3.6 kg, 26.9 mol; 1.8 kg, 13.4 mol; 1.8 kg, 13.4 mol, 0.9 kg, 6.8 mol) allowing thirty minutes between charges. The reaction mixture was stirred at 35 ^o - 40 ° C until the reaction was complete. The reaction was quenched by slowly adding the reaction solution to water (119 kg). The organic phase was separated, then further extracted twice with water (60 kg) and once with a saturated sodium chloride solution (30 kg). The dichloroethane solution of the product mixture was concentrated to a final mass of 39 kg. This solution was used as the feed solution for preparative chromatography as described in Method 1.
Fractions with the desired product were partially concentrated to a volume of approximately 12 1. The solutions were then further concentrated by atmospheric distillation at an internal vessel temperature of 80 ° C. Upon resin, crystallization occurred. The initial slurry was diluted with water (6-12 1) and stirred for two hours. The product was collected by filtration, washed with water (4 1) then dried at 60 ° C under vacuum to a constant mass. From the above, 4.1 kg (10.22 mol) of (3Ã, 5Ã) -3-butyl-3-ethyl-8 (methyloxy) -5-phenyl-2,3 were obtained , 4,5-tetrahydro-1,4-benzothiazepin-7-ol (Intermediate 1b) and 3.9 kg (9.72 mol) of (3Ã, 5i ) - 3-butyl 1,1-dioxide -3-ethyl-7- (methyloxy) 5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ol (Intermediate la).
The recycling of intermediate 1b to (37 ', 57') 1,1-dioxide - 3butyl-3-ethyl-7,8-bis (methyloxy) -5-phenyl-2,3,4,5-tetrahydro -1,4-benzothiazepine: A solution of (37 , 5Ã) -3-butyl-3-ethyl-8- (methyloxy) -5-phenyl- 1,1-dioxide
2,3,4,5-tetrahydro-1,4-benzothiazepin-7-ol (4.1 kg 10.22 mol) in acetone (19.7 kg) was treated with potassium carbonate (3.84 kg ) and adjusted to 25 ^o 30 ° C. Methyl iodide (5.84 kg, 41.14 mol) was loaded and the reaction was maintained at 25 ° - 30 ° C until completion. The reaction was concentrated to ~ 8 l of total volume by distillation, then dichloroethane (31 kg) was loaded. The reaction was extracted twice with water (20.8 kg) and an additional charge of dichloroethane (26 kg) was carried out. The product solution was concentrated at ~ 23 1 to form an advantageous solution for re-protection to intermediates 1 and 1 as described above in Method 3.
Intermediate 2: (3A, 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4 trifluoromethanesulfonate -benzothiazepin-8-ila
Method 1: To a solution in DCM of (3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-dioxide -1, 4benzothiazepin-8-ol (105 g, 26 mmol) and pyridine (27.3 ml, 34 mmol) cooled to 0 ° C under nitrogen, trifluoromethanesulfonic anhydride (57.1 ml, mmol) was added slowly over 30 min while maintaining an internal temperature between 5-10 ° C. Once the addition was complete, the reaction was stirred by TLC and LCMS indicating complete conversion to the product. H ₂ O (250 ml) was added slowly to the mixture, and the mixture was stirred for 10 min after which the layers were separated. The aqueous was extracted once more with DCM, and the combined organics were washed with 10% HCl, brine, then dried (Na ₂ SO ₄ ), filtered, and concentrated to half volume. Hexanes were added until the solution became cloudy, and crystallization began to occur. The solids were then filtered from the solution giving the title compounds (134.6 g, 95%) as a white solid that was used without further purification: NMR Ή (400 MHz, CDCI3) δ ppm 0.76-0.96 (m , 6 H), 1.03-1.40 (m, 4 H), 1.40-1.67 (m, 4 H), 1.77-1.97 (m, 1 H), 2.10 -2.28 (m, 1 H), 3.07 (d, 7 = 14.8 Hz, 1 H), 3.48 (d, 7 = 14.9 Hz, 1 H), 3.62 (s , 3 H), 6.09 (s, 1 H), 6.34 (s, 1 H), 7.32-7.50 (m, 5 H), 7.96 (s, 1 H); ES-LCMS m / z 536 (M + H) ⁺ .
Method 2: Pyridine (441 ml, 5.45 mol) was added to a stirred suspension of (37 , 5 ) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2-dioxide , 3,4,5-tetrahydro-1,4-benzothiazepin-8-ol (1099 g, 2.72 mol) in Z-butyl methyl ether (161) with cooling at 15 ° C. Pure triflic anhydride (1076 g, 3.81 mol) was added dropwise over 45 min while maintaining the reaction temperature between 14-16 ° C. After the addition, the reaction mixture was stirred at room temperature for 2 h. Water (6 L) was added slowly and the mixture was stirred rapidly for 15 min. The layers were separated and the organic phase was washed with a 1: 1 water / brine ratio (5 l), dried over MgSO ₄ and filtered. The filtrate was concentrated to remove most of the Z-butyl methyl ether (about 13-14 l were removed). The resulting slurry was filtered and the filter cake was washed with heptane. Additional drying of the filter cake in an overnight vacuum at 40 ° C resulted in (3R, 5R) ~ trifluoromethanesulfonate ~
3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4benzothiazepin-8-yl as an off-white solid ( 1342 g). A second crop of product was obtained from the mother liquor (63 g). The combined yield was 1405 g.
Method 3: A reactor was charged with 2.75 kg (6.8 mol) of (3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5 -tetrahydro-1,4-benzothiazepin-8-ol-1,1-dioxide, 19.9 kg of 1,4-dioxane, 1.08 kg (13.6 mol) of pyridine at 25 ° C and stirred at this temperature until it dissolves. Then, the solution was cooled to about 10 ° C after which triflic anhydride 10 (2.8 kg, 9.9 mol) was added at such a rate that the internal temperature was approximately 5-15 ° C. The reaction mixture was stirred at this temperature for about 45 minutes. The jacket temperature was then raised to about 25 ° C, and the reaction was stirred at this temperature until completion. Toluene (16.3 kg) and 10% brine (8.3 1) were then added to the reactor, and the mixture was stirred for at least 5 minutes before resting for an additional 5 minutes. The aqueous layer was removed. Water (8.3 kg) was added, and the mixture was stirred for about 5 minutes before resting for at least 10 minutes. The aqueous layer was removed, and washing with water was repeated. After removing the aqueous layer, the organic layer was reduced to about 111 by means of vacuum distillation. Heptane (18.8 kg) was added, and the total volume was again reduced by vacuum distillation to about 14 ° C. An additional 4 kg of heptanes was added, and the mixture was cooled slowly to about 5 °. C overnight. The product was collected by means of filtration and washed twice with heptanes (3.6 kg and 25 4.0 kg). The cake was dried under a sheet of N ₂ then dried in vacuo (~ 60 ° C) giving 3.47 kg (95%) of (37 , 5 ) -3-butyl-3-ethyl7- (methyloxy) trifluoromethanesulfonate -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl.
Intermediate 3: methyl (3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -5phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine- 8-carboxylate
In a reaction tube containing (3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-trifluoromethanesulfonate 1,4benzothiazepin-8-yl (0.103 g, 0.192 mmol), Pd ₂ (dba) ₃ (0.011 g, 0.012 mmol), dppf (0.013 g, 0.024 mmol), and triethylamine (0.040 ml, 0.288 mmol) in DMF ( 1 ml) carbon monoxide gas was bubbled over a period of 15 min. Anhydrous MeOH (0.039 ml, 0.962 mmol) was added, and the reaction vessel was closed hermetically under a carbon monoxide atmosphere, then heated to 70 ° C overnight. The reaction was cooled to room temperature, and the contents were diluted with Et ₂ O then poured into H ₂ O. The layers were separated, the aqueous one extracted again with Et ₂ O, and the combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated. The crude material was chromatographed on silica gel using hexanes / EtOAc giving the title compound (0.080 g, 91%) as a white solid: NMR ^J H (400 MHz, CDCl ₃ ) δ ppm 0.75-0.96 (m , 6 H), 0.99-1.36 (m, 4 H), 1.36-1.59 (m, 5 H), 1.86 (ddd, .7 = 14.4, 12.0, 4.4 Hz, 1 H), 2.07-2.23 (m, 1 H), 3.02 (d, .7 = 14.8 Hz, 1 H), 3.45 (d, .7 = 14.9 Hz, 1 H), 3.57 (s, 3 H), 3.86 (s, 3 H), 6.08 (s, 1 H), 6.27 (s, 1 H), 7 , 29-7.48 (m, 5 H), 8.52 (s, 1 H); ES-LCMS m / z 446 (M + H) ⁺ .
Intermediate 4: (3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -5phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine- 1,1-dioxide 8-carboxylic
H ₂ O (0.333 ml), MeOH (0.333 ml), and THF (1 ml) were added to methyl 1,1-dioxide (3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) - 5-phenyl-
2.3.4.5- tetrahydro-1,4-benzothiazepine-8-carboxylate (0.046 g, 0.103 mmol) together with LiOH (0.013 g, 0.310 mmol), and the mixture was stirred for 2 h at room temperature to hydrolyze to acid benzoic. The mixture was concentrated to half volume, then 6N HCl was added. The mixture was extracted with EtOAc (2X), washed with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated in vacuo giving the title compound (0.039 g, 86%): 1 H NMR (400 MHz, CDCl ₃ ) δ ppm 0.67-0.99 (m, 6 H), 0.99-1.64 (m, 7 H), 1.87 ( t, J = 11.8 Hz, 1 H), 2.08-2.29 (m, 1 H), 3.09 (d, .7 = 14.8 Hz, 1 H), 3.46 (d .7 = 14.9 Hz, 1 H), 3.70 (br. S, 3 H), 6.11 (br. S, 1 H), 6.33 (br. S., 1 H ), 7.30-7.60 (m, 5 H), 8.73 (br. S., 1 H); ES-LCMS m / z 432 (M + H) ⁺ .
Intermediate 5: [(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -l, l-dioxide-5-phenyl-
2.3.4.5- tetrahydro-1,4-benzothiazepin-8-yl] methanol
HO
To a solution in DCM (2 ml) of methyl (3R, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetra 1,1-dioxide -hydro-1,4-benzothiazepine-8-carboxylate (0.275 g, 0.617 mmol) at 0 ° C under nitrogen an IM solution of DIBAL-H in toluene (1.3 ml, 1.30 mmol) was added. The reaction was warmed to room temperature and stirred for 1.5 h, then MeOH was added followed by H ₂ O. The reaction mixture was concentrated, then redissolved in EtOAc. The layers were separated, the aqueous layer was extracted again with EtOAc, then the combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated. Chromatography on silica using hexanes / EtOAc gave the title compound (0.238 g, 91%): NMR ^] H (400 MHz, CDCf) δ ppm 0.760.93 (m, 6 H), 1.04-1.36 (m, 6 H), 1.36-1.59 (m, 6 H), 1.76-1.93 (m, 1 H),
2.05-2.24 (m, 2 Η), 3.02 (d, 7 = 14.8 Hz, 1 Η), 3.42 (d, 7 = 14.8 Hz, 1 Η), 3, 54 (s, 3 Η), 4.65 (qd, 7 = 13.2, 6.3 Hz, 2 H), 6.07 (br. S., 1 H), 6.17 (s, 1 H ), 7.29-7.50 (m, 5 H), 8.03 (s, 2 H); ES-LCMS m / z 418 (M + Hf.
Intermediate 6: (3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbonitrile-1, 1-dioxide
Method 1: A mixture of trifluoromethanesulfonate (3R, 5R) ~ 3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1 , 4benzothiazepin-8-yl (0.535 g, 1.0 mmol), Pd ₂ (dba) ₃ (0.055 g, 0.06 mmol), DPPF (0.066 g, 0.12 mmol), zinc powder (0.004 g, 0.06 mmol) and Zn (CN) ₂ (0.117 g, 0.99 mmol) in DMF (10 ml) was stirred at room temperature for 15 min under a stream of nitrogen. The reaction was heated to 80 ° C and stirred for 8 h. After cooling the mixture to room temperature, DMF was removed in vacuo, Et ₂ O was added, and the organics were washed with NH 4 OH (aq) 2 N followed by brine. The organics were dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was triturated with hexanes / EtOAc, and a white solid was collected by filtration giving the title compound (0.386 g, 92%): NMR * H (400 MHz, CDCl ₃ ) δ ppm 0.73-0, 97 (m, 6 H), 0.981.62 (m, 8 H), 1.77-1.92 (m, 1 H), 2.08-2.24 (m, 1 H), 3.01 ( d, 7 = 14.9 Hz, 1 H), 3.45 (d, 7 = 14.9 Hz, 1H), 3.62 (s, 3 H), 6.08 (br. s., 1 H ), 6.26 (s, 1 H), 7.32-7.49 (m, 5 H), 8.28 (s, 1 H); ES-LCMS m / z 413 (M + Hf.
Method 2: A solution of (37 , 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro trifluoromethanesulfonate -1.4benzothiazepin-8-yl (1.346 kg, 2.51 mol) in DMF (2.5 1) was loaded with Zn (CN) ₂ (440 g, 3.75 mol) and the stirred mixture was degassed if N ₂ through the mixture for 60 min. Water (25 ml) was added and 28 degassing gas continued for 30 min. DPPF (14.5 g,
26.16 mmol) and Pd ₂ (dba) ₃ (10.5 g, 11.47 mmol) and the reaction mixture was heated to 80-85 ° C with continued degassing. The reaction was considered complete after 2 h at this temperature. After cooling the reaction mixture to 60 ° C, toluene (500 ml) was added and the mixture was stirred overnight with cooling to room temperature.
Toluene (8 1) was added and the mixture was washed with water (4x2 1). The organic phase was dried over MgSO ₄ and filtered and the filtrate was stirred over PL-BnSH resin (460 g, to agglutinate heavy metal impurities) for 3 days.
The resin was removed by filtration and the filtrate was concentrated until the product crystallized. Heptane (12 1) was added and the resulting solids were collected by filtration and washed with heptane. The white solids were dried further in vacuo giving (3Ã, 5Ã) -3-butyl-3ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-dioxide 1,4-benzothiazepine-8-carbonitrile (1,010 kg).
Method 3: (3Ã, 5Ã) -3-butyl-3ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin trifluoromethanesulfonate -8ila (2160 g, 4.05 mol) and zinc cyanide (266 g, 2.23 mol) were placed in a reactor followed by water (1084 ml) and N-methylpyrrolidinone (10830 ml).
The contents are placed under nitrogen then evacuated three times. The reaction was heated to 100 ° C and treated with a palladium acetate slurry (4.8 g, 0.02 mol) el, l'-Bis (diphenylphosphino) ferrocene (15.7 g, 0.03 mol) in NMP (50 ml). The reaction was immediately treated with polymethylhydrosiloxane (PMHS, 22 g) in NMP (50 ml) and maintained at 100 ° C for approximately one hour when HPLC analysis indicated that the reaction was complete. The reaction was cooled to approximately 35 ° C and treated with a prepared solution of water (8685 g), ammonium hydroxide (1958 g) and ethanol (17130 g) over approximately ten minutes. The resulting slurry was heated to approx. 80 ° C to dissolve. The solution was cooled to 20 ° C over approximately 60 minutes and held at 20 ° C for approximately 90 minutes. The solids were filtered, washed with a prepared solution of 50% ethanol / water (4330 ml) followed by heptane (4300 ml), and dried. The solids were dried in a vacuum oven at 50 ° C giving (3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4-1,1-dioxide, 5-tetrahydro-1,4-benzothiazepine-8-carbonitrile (1482 g, 89%).
Intermediate 7: (3Ã, 5R) -8- (bromomethyl) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide
O
Imidazole (0.153 g, 0.563 mmol) was dissolved in DCM (2 ml), and the solution was cooled to 0 ° C. Triphenylphosphine (0.295 g, 1.126 mmol) was added followed by bromine (0.058 ml, 1.126 mmol). A solution of [(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro1,4-benzothiazepin- 8-yl] methanol (0.235 g, 0.563 mmol) in DCM (1 ml) was added slowly at 0 ° C. The reaction was stirred at 0 ° C for 2 h followed by the addition of Na ₂ SO ₃ (aq), and the resulting mixture was separated. The organic layer was dried (Na ₂ SO ₄ ), filtered through a bed of silica, and concentrated giving a thick oil which solidified after resting to give the title compound (0.265 g, 84%): NMR Ή (400 MHz, CDC1 ₃ ) δ ppm 0.730.95 (m, 6 H), 1.02-1.36 (m, 5 H), 1.38-1.65 (m, 5 H), 1.76-1.92 (m , 1 H), 2.08-2.23 (m, 1 H), 3.02 (d, 7 = 14.8 Hz, 1 H), 3.43 (d, 7 = 14.8 Hz, 1 H), 3.57 (s, 3 H), 4.38-4.56 (m, 2 H), 6.06 (s, 1 H), 6.16 (s, 1 H), 7.28 -7.45 (m, 5 H), 8.05 (s, 1 H); LC-MS m / z 480 (M + Hf, LC-MS 482 (M + H + 2) ⁺ .
Intermediate 8: (3R, 5R) -3-butyl-3-ethyl-4-hydroxy-7- (methyloxy) 5-phenyl-2,3,4,5-tetrahydro-1-1,1-dioxide, 4-benzothiazepine-8-carbonitrile 1,1-dioxide
N.
^The s, ⁰ 's'-.
(3Ã, 5Á) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-
2.3.4.5- tetrahydro-1,4-benzothiazepine-8-carbonitrile (6.00 g, 14.54 mmol) dissolved in DCM (100 ml) was treated with m-CPBA (2.51 g, 11.20 mmol) with stirring at 22 ° C for 3 h. More m-CPBA (0.77 g, 3.44 mmol) was added, and the mixture was stirred for an additional 2 h. The reaction mixture was treated with 10% Na ₂ SO ₃ then vigorously stirred for 1 h. The organic layer was isolated, dried over MgSO ₄ , filtered, and concentrated to dryness. The residue was purified on 330 g silica gel eluting with 10 to 60% EtOAc / hexanes giving recovered nitrile starting material (1.33 g, 3.23 mmol, 22.2% yield) and the desired (3R, 5R) -3-butyl-3-ethyl-4-hydroxy-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-dioxide -carbonitrile (impure) (1.99 g, 31.9% yield): NMR Ή (400 MHz, DMSO-7 ₆ ) δ ppm 0.78 (t, 7 = 7.1 Hz, 3 H), 0 , 85 (t, 7 = 7.2 Hz, 3 H), 1.05-1.37 (m, 4 H), 1.38-1.51 (m, 1 H), 1.57-1, 70 (m, 1 H), 1.78-1.89 (m, 1 H), 2.01-2.12 (m, 1 H), 3.40-3.53 (m, 2 H), 3.56 (s, 3 H), 6.28 (s, 1 H), 6.39 (s, 1 H), 7.34-7.58 (m, 5 H), 8.16 (s, 1 H),
8.26 (s, 1 H).
Intermediate 9: (3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl- 1,1-dioxide
2.3.4.5- tetrahydro-1,4-benzothiazepine-8-carbaldehyde o o
Method 1: (3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) 5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine- 1,1-dioxide 8-carbonitrile (7.42 g, 17.99 mmol) dissolved in DCM (150 ml) was treated with IM DIBAL-H in toluene (36.0 ml, 36.0 mmol) at 0 ° C with stirring for 1 h after which LCMS indicated complete conversion. The reaction mixture was poured into an ice / 1N HCl mixture and stirred vigorously for 1 h. The organic phase was isolated, dried over MgSO ₄ , filtered, and concentrated to give a yellow solid. The crude product was dissolved in 80 ml of hot EtOAc to which 250 ml of hexanes were added until it became cloudy. The mixture was allowed to cool slowly to room temperature and then cooled in an ice bath. The resulting precipitate was removed by filtration, washed with 20% cold EtOAc / hexanes, and air dried to give (3Ã, 5Á) -3-butyl-3-ethyl10 7- (methyloxy) -5- 1,1-dioxide phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbaldehyde (4.00 g, 53.5% yield) as a white crystalline solid. The mother liquor was concentrated to dryness, and the residue was purified on 120 g of silica gel eluting with 20 to 40% EtOAc / hexanes giving additional product as a white solid: NMR Ή (400 MHz, DMSO-1 / g) δ ppm 0.74 (t, .7 = 7.0 Hz, 3 15 H) 0.81 (t, .7 = 7.4 Hz, 3 H) 0.96-1.29 (m, 4 H) 1.33-1.54 (m, 2 H) 1.68-1.81 (m, 1 H) 2.01-2.13 (m, 1 H) 2.80 (d, 7 = 9.8 Hz, 1 H) 3.13 (d, / = 15.0 Hz, 1 H) 3.58 (s, 3 H) 3.63 (d, .7 = 15.0 Hz, 1 H) 5.98 (d, 7 = 9.8 Hz, 1 H) 6.27 (s, 1 H) 7.32-7.40 (m, 1 H) 7.40-7.49 (m, 4 H) 8, 23 (s, 1 H) 10.27 (s, 1 H); LC-MS (ES ⁺ ) m / z 416.3 [M + H].
Method 2: A 1.5 M solution of Dibal-H in toluene (1.467
1.20 mol) was added over 50 min to a stirred solution of 1,1 (37 , 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2 , 3,4,5-tetrahydro-1,4-benzothiazepine-8-carbonitrile (673.3 g, 1.63 mol) in CTUChpA 1) while maintaining the reaction temperature below 0 ° C. The reaction mixture was stirred 25 ° C for 30 min with cooling to -10 ° C. The reaction mixture was extinguished by very slow addition of 1M HCl (8 1) over 1.25 h while maintaining the reaction temperature below + 15 ° C (caution: adding the first 500 ml of HCl is very exothermic!). Toluene (7 1) was added and the mixture was stirred for 3 h. The aqueous phase was removed and the organic layer was washed with 1M HCl (5 1). The combined aqueous layers were extracted with CH ₂ C1 ₂ (2.5 1) and the CH ₂ C1 ₂ and CH ₂ Cl ₂ / toluene layers were combined and washed with 10% Na ₂ CO ₃ (5 1), dried over MgSO ₄ , filtered and partially concentrated until a thick slurry is formed. The slurry was diluted with heptane (2-3 volumes) and aged with stirring for 15 min. The solids were collected by filtration and washed with heptane. The filter cake was air-dried for 3 h and then dried in a vacuum oven overnight at 50 ° C to (37 , 5 ) -3-butyl-3-ethyl- 1,1-dioxide 7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4benzothiazepine-8-carbaldehyde as a white solid (533 g).
Method 3: (3A, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) 5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine- 1,1-dioxide 8-carbaldehyde (2402 g, 5.82 mol) and toluene (20714g) were added in a reactor and this was stirred at 40 ° C to form a solution. Then, the solution was cooled to approximately -35 ° C and treated with a solution of DIBAL-H (1.5 M in toluene, 4472 g, 7.85 mol) while maintaining the internal temperature at less than -30 ° Ç. The reaction was stirred at approximately -30 ° C for one hour until completion and then quenched by slowly adding 1 N HCl solution (approximately 40 kg) to pH 1.0. The reaction was heated to approximately 30 ° C and stirred for one hour. Stirring was stopped and the lower aqueous layer was separated, and the organic was washed two more times with 1N HCl solution (7200 ml each) while maintaining the temperature at approximately 40 ° C. The aqueous layers were combined and backwashed with toluene (4126 g). The combined organic layers were washed with saturated aqueous sodium chloride (9000 ml) and then evaporated under reduced pressure to approximately 12 liters. The solvent was further evaporated under atmospheric pressure to a final volume of approximately 7 liters and treated with heptanes (16420 g). The contents were cooled to approximately 15 ° C and stirred for approximately two hours. The solids were manually fragmented and rinsed from the reactor with heptanes (2 x 3260 g) and collected by filtration. The collected solid material was washed with more heptanes (3180 g) then dried at 50 ° C giving (37 , 57 ) - 3-butyl-3-ethyl-7- (methyloxy) 5-phenyl 1,1-dioxide -2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbaldehyde (2128 g, 88%). Intermediate 10: dimethyl 3 - ({[(32 , 5Ã) -3-butyl-3-ethyl-4-hydroxy-7- (methyloxy) 1,1-l-dioxide-5-phenyl-2,3,4,5 -tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) pentanedioate
(37 , 57 ) - 3-butyl-3-ethyl-4-hydroxy-7- (methyloxy) -5phenyl-2,3,4,5-tetrahydro-1,4-dioxide benzothiazepine-8-carbaldehyde (298 mg, 0.691 mmol) and dimethyl 3-aminopentanedioate (181 mg, 1.036 mmol) (prepared as in Journal of the American Chemical Society 2005, 127, 247) were combined in DCM (4 ml) and stirred for 30 min. The reaction mixture was treated with NaHB (OAc) ₃ (293 mg, 1.381 mmol) and stirred at 22 ° C for 16 h after which time LCMS was shown to be complete. The mixture was diluted with DCM, washed twice with H ₂ O, dried over MgSO ₄ , filtered, and concentrated to dryness. The residue was purified on 40 g of silica gel eluting with 20 to 100% EtOAc / hexanes giving dimethyl 3 - ({[(37 , 5Ã) -3-butyl-3ethyl-4-hydroxy-7- (methyloxy ) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4benzothiazepin-8-yl] methyl} amino) pentanedioate (304 mg, 0.515 mmol, 74.5% yield ) as an amber oil: LC-MS (ES ⁺ ) m / z 591.3 [M + H]. Intermediate 11: {(E) -2 - [(3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5 -tetrahydro-1,4-benzothiazepin-8-yl] ethylene} phosphonate
Tetraethyl methanodiylbis (phosphonate) (645 mg, 2.24 mmol) dissolved in THF (7 ml) was treated with NaH (83 mg, 2.075 mmol, 60% dispersion in oil) with stirring at 22 ° C for 30 min. Added
(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-
1.4- benzothiazepine-8-carbaldehyde (300 mg, 0.722 mmol), and the mixture was stirred for 1 h at room temperature, after which LCMS indicated complete conversion. The mixture was quenched with H ₂ O, partitioned between EtOAc and brine, and the phases were separated. The organic phase was dried over MgSO ₄ , filtered, and concentrated to an oil. The residue was purified on 40 g of silica gel eluting with 40 to 100% EtOAc / hexanes giving diethyl {(E) 2 - [(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-
1.4- benzothiazepin-8-yl] ethylene} phosphonate (342 mg, 86% yield) as a clear oil: LC-MS (ES ⁺ ) m / z 550.4 [M + H].
Intermediate 12: dimethyl N - {[(37 , 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide5-phenyl-2,3,4,5-tetrahydro-1 , 4-benzothiazepin-8-yl] methyl} -L-cystinate
(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl- 1,1-dioxide
2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbaldehyde (231 mg, 0.556 mmol) and dimethyl L-cystinate (95 mg, 0.278 mmol) were combined in DCM (8 ml) and treated with TEA (0.077 ml, 0.556 mmol) at room temperature for 1 h. NaHB (OAc) ₃ (295 mg, 1.390 mmol) was added, and the reaction mixture was stirred for 16 h. The mixture was partitioned between DCM and saturated NaHCO ₃ , and the phases were separated. The aqueous phase was extracted with DCM, and the organic phases were combined, dried over MgSO ₄ , filtered and concentrated to a clear oil. The crude material was purified on 40 g of silica eluting with 20 to 100% EtOAc / hexanes giving dimethyl N {[(37 , 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -l , 1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} -L-cystinate (167 mg, 45.0% yield): NMR Ή (400 MHz, DMSO-7 ₆ ) δ ppm 0.67-0.88 (m, 12 H) 0.96-1.29 (m, 8 H) 1.32-1.53 (m, 4 H ) 1.66-1.80 (m, 2 H) 2.00-2.13 (m, 2 H) 2.54 (d, 7 = 10.0 Hz, 2 H) 2.57-2.70 (m, 2 H) 2.93-3.13 (m, 6 H) 3.42 (s, 7 H) 3.46-3.78 (m, 13 H) 5.94 (d, 7 = 9 , 6 Hz, 2 H) 6.07 (s, 2 H) 7.26-7.36 (m, 2 H) 7.37-7.46 (m, 8 H) 7.87-8.01 ( m, 2 H); LC-MS (ES ⁺ ) m / z 668.22 [M + H].
Intermediate 13: 1,1-dimethylethyl N- {[(37 , 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1dioxide-5-phenyl-2,3,4,5-tetra -hydro-1,4-benzothiazepin-8-yl] methyl} -Lmethioninate

A slurry of 1,1-dimethylethyl L-methioninate (218 mg, 0.902 mmol) in DCM (3 ml) was treated with TEA (126 μΐ, 0.902 mmol) at room temperature for 15 min, after which time was added if
(3Ã, 57 ) 1,1-3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8 -carbaldehyde (250 mg, 0.602 mmol), and the mixture was stirred for 1 h. NaHB (OAc) ₃ (255 mg, 1.203 mmol) was added, and the reaction mixture was stirred overnight at room temperature where after this time LCMS indicated conversion to the desired product. The mixture was partitioned between DCM and brine, and the phases were separated. The aqueous phase was extracted with DCM, and the combined organic phases were dried over MgSO ₄ , filtered, and concentrated to a clear oil. The residue was purified on 40 g of silica eluting with 20 to 60% EtOAc / hexanes giving 1,1-dimethylethyl N- {[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -
1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} -Lmethioninate as a white solid (270 mg, 74% yield): NMR 'H (400 MHz, DMSO-7 ₆ ) δ ppm 0.75 (t, 7 = 7.0 Hz, 3 H) 0.80 (t, 7 = 7.4 Hz, 3 H) 0.98- 1.28 (m, 4 H) 1.36 (s, 9 H) 1.38-1.53 (m, 2 H) 1.65-1.85 (m, 3 H) 2.03 (s, 3 H) 2.03-2.13 (m, 1 H) 2.33-2.43 (m, 1 H) 2.53 (br. S., 2 H) 2.55 (d, 7 = 4 , 3 Hz, 1 H) 3.03 (d, 7 = 14.8 Hz, 1 H) 3.09-3.17 (m, 1 H) 3.43 (s, 3 H) 3.52 (d , 7 = 14.8 Hz, 1 H) 3.62 (br. S, 2 H) 5.93 (d, 7 = 9.6 Hz, 1 H) 6.07 (s, 1 H) 7.25 -7.36 (m, 1 H) 7.36-7.47 (m, 4 H) 7.94 (s, 1 H); LC-MS (ES ⁺ ) m / z 605.3 [M + H],
Intermediate 14: (37 , 57 ) - 3-butyl-3-ethyl-4-hydroxy-7 (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,1-dioxide 1,4-benzothiazepine-8-carbaldehyde]
(37 , 57 ) - 3-butyl-3-ethyl-4-hydroxy-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-dioxide benzothiazepine-8-carbonitrile (1.99 g, 4.64 mmol) dissolved in DCM (25 ml) was treated with DIBAL-H 1M in toluene (5.34 ml, 5.34 mmol) at 0 ° C by dripping with stirring for 1 h. A second portion of 1M DIBAL-H (5.34 ml, 5.34 mmol) was added, and the mixture was further stirred for 2 h at 0 ° C where after this time LCMS indicated conversion to the product. 1N HCl (10 ml) was added to the mixture and the mixture was stirred vigorously for 16 h. The organic phase was isolated, and the aqueous phase was extracted three times with DCM. The organic layers were combined, dried over MgSO ₄ , filtered, and concentrated to dryness. The residue was purified on 40 g of silica gel eluting with 10 to 50% EtOAc / hexanes giving (3Ã, 5Ã) -3-butyl-3-ethyl-4-hydroxy-7- (methyloxy) 1,1-dioxide -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8carbaldehyde (1.42 g, 70.9% yield) as a white foam: NMR ^! H (400 MHz, DMSO-7 _δ ) δ ppm 0.78 (t, 7 = 7.1 Hz, 3 H), 0.85 (t, 7 = 7.3 Hz, 3 H), 1.02- 1.38 (m, 4 H), 1.38-1.52 (m, 1 H), 1.56-1.73 (m, 1 H), 1.78-1.91 (m, 1 H ), 2.01-2.15 (m, 1 H), 3.39-3.51 (m, 2 H), 3.55 (s, 3 H), 6.31 (s, 1 H), 6.38 (s, 1 H), 7.32-7.75 (m, 5 H), 8.20 (s, 1 H), 8.22 (s, 1 H), 10.26 (s, 1 H). LCMS (ES ⁺ ) m / z 432.2 [M + H].
Intermediate 15: {[(37 , 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl2,3,4,5 -tetrahydro-1,4- benzothiazepin-8-yl] methyl} amine
A mixture of (3Ã, 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide -8-carbonitrile (468 mg, 1.134 mmol) and 10% palladium on carbon (60.4 mg, 0.567 mmol) in ethanol (20 ml) received hydrochloric acid (0.279 ml, 3.40 mmol) and hydrogenated to 40 psi [276 kPa] overnight, then filtered and concentrated. The residue was purified via HPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) giving the title compound (621 mg, 79%, TF A salt ) as a white solid: NMR ^] H (CDCl ₃ ) δ ppm 8.07 - 8.46 (br.s, 2H), 7.98 (s, 1H), 7.31 - 7.57 (m, 5H ), 6.27 (s, 1H), 6.17 (s, 1H), 4.12 - 4.27 (m, 1H), 3.98 - 4.12 (m, 1H), 3.55 ( s, 3H), 3.38 - 3.48 (m, 1H), 3.29 (d, J = 15.0 Hz, 1H), 2.14 - 2.38 (m, 1H), 1.80 - 1.99 (m, 1H), 1.44 - 1.75 (m, 2H), 1.14 - 1.38 (m, 3H), 0.97 - 1.15 (m, 1H), 0 , 90 (t, J = 7.2 Hz, 3H), 0.82 (t, J = 6.8 Hz, 3H); ES-LCMS m / z 417 (M + H) ⁺ ·
Intermediate 16: N - {[(3A, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl38
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} -2-chloroacetamide
To an ice-cold solution of {[(3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) - 1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro- 1,4-benzothiazepin-8-yl] methyl} amine (50 mg, 0.120 mmol) in DCM (6 ml) was added pyridine (0.097 ml, 1.20 mmol) and chloroacetyl chloride (0.048 ml, 0.60 mmol). The reaction mixture was stirred at room temperature overnight then concentrated under reduced pressure to give a light yellow oil. The crude title compound (55 mg, 92%) was used without further purification: N NMR (CDC1 ₃ ) δ ppm 7.27 - 7.45 (m, 5H), 6.91 - 7.13 (m, 1H) , 6.17 (s, 1H), 6.05 (s, 1H), 4.44 (d, J = 6.1 Hz, 2H), 4.05 (d, J = 7.0 Hz, 3H) , 3.53 (s, 3H), 3.37 (s, 1H), 3.02 (s, 2H), 2.09 - 2.24 (m, 1H), 1.69 - 1.90 (m , 1H), 0.99 - 1.60 (m, 6H), 0.86 (t, J = 7.4 Hz, 3H), 0.80 (t, J = 7.0 Hz, 3H); ES-LCMS m / z 494 (M + H) ⁺ .
Intermediate 17: (2E) -3 - [(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro- ethyl 1,4-benzothiazepin-8-yl] -2-propenoate
In a sealed tube, a solution of (3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1, dioxide-5-phenyl-2,3,4,5-tetra- trifluoromethanesulfonate hydro- 1,4-benzothiazepin-8-yl (3.5 g, 6.53 mmol) in DMF (30 ml) was treated with triethylamine (4.55 ml, 32.7 mmol), followed by ethyl acrylate (3 , 56 ml, 32.7 mmol) and bis (triphenylphosphino) palladium (II) chloride (0.459 g, 0.653 mmol). The reaction mixture was stirred at 120 ° C overnight, cooled to room temperature and partitioned between H ₂ O and EtOAc. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification on silica gel (EtOAc: hexanes = 1: 6 to 2: 1) resulted in the title compound (3.06 g, 94%) as a white solid: NMR Ή (CDC1 ₃ ): δ ppm 8.21 (s , 1H), 7.85 (d, J = 16.2 Hz, 1H), 7.30 - 7.48 (m, 5H), 6.56 (d, J = 16.0 Hz, 1H), 6 , 19 (s, 1H), 6.06 (d, J = 6.8 Hz, 1H), 4.18 - 4.30 (m, 2H), 3.55 (s, 3H), 3.44 ( d, J = 14.9 Hz, 1H), 3.02 (d, J = 14.9 Hz, 1H), 2.08 - 2.26 (m, 1H), 1.76 - 1.93 (m , 1H), 1.38 - 1.54 (m, 3H), 1.28 - 1.35 (m, 3H), 1.03-1.21 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H), 0.81 (t, J = 7.0 Hz, 3H); ES-LCMS m / z
486 (M + J /) ⁺ .
Intermediate 18: diethyl 3-aminopentanedioate
ONO
EtO OEt
To a solution of β-glutamic acid (500 mg, 3.40 mmol) in
EtOH (10 ml) was added thionyl chloride (0.992 ml, 13.59 mmol) by dropping. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was partitioned between DCM and saturated potassium carbonate solution. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure giving the title compound (702 mg, 97%) as a colorless oil: NMR Ή (CDC1 ₃ ) δ ppm 4, 04 - 4.27 (m, 4H), 3.46 - 3.74 (m, 1H), 2.24 - 2.60 (m, 4H), 1.09 - 1.29 (m, 6H).
Intermediate 19: (3Ã, 57 ) - 8- (3-bromopropyl) -3-butyl-3-ethyl-7 (methyloxy) -5-phenyl-2,3,4,5 -tetra -hydro-1,4-benzothiazepine
Br '
To a solution of 3 - [(3 / , 5R) -3-butyl-3-ethyl-7- (methyloxy) -1, 140 dioxide-5-phenyl-2,3,4,5-tetrahydro- 1,4-benzothiazepin-8-yl] -l-propanol (84.2 mg, 0.189 mmol) in THF (5 ml) was added triphenylphosphine (99 mg, 0.378 mmol) and carbon tetrabromide (125 mg, 0.378 mmol) ). The reaction mixture was stirred at room temperature overnight and partitioned between H ₂ O and DCM. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (EtOAc: hexanes = 10:90 to 50:50) resulted in the title compound (78 mg, 80%) as a clear oil: ES-LCMS m / z 508 (M + Hf.
Intermediate 20: 3 - [(3Á, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) - methanesulfonate -
1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] propyl
To an ice-cold solution of 3 - [(3Ã, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1 , 4-benzothiazepin-8-yl] -1 propanol (250 mg, 0.561 mmol) in DCM (10 ml) was added triethylamine (0.235 ml, 1.683 mmol) and methanesulfonyl chloride (0.048 ml, 0.617 mmol). The reaction mixture was stirred at room temperature overnight and partitioned between H ₂ O and DCM. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure to give the title product (280 mg, 91%) as a light yellow solid: NMR ^! H (CDC1 ₃ ) δ ppm 7.82 (s, 1H), 7.27 - 7.52 (m, 5H), 6.11 (s, 1H), 6.01 (d, J = 8.0 Hz , 1H), 4.04 - 4.26 (m, 2H), 3.47 (s, 3H), 3.31 - 3.43 (m, 1H), 2.85 - 3.07 (m, 4H ), 2.46 - 2.78 (m, 4H), 1.73 - 2.27 (m, 4H), 1.35 - 1.61 (m, 4H), 0.97 - 1.34 (m , 8H), 0.86 (t, J = 7.4 Hz, 3H), 0.80 (t, J = 6.8 Hz, 3H). Intermediate 21: 4 - [(3R, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] butanonitrile
To a solution of 3 - [(3R, 5R) -3-butyl-3ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1 methanesulfonate , 4-benzothiazepin-8il] propyl (90 mg, 0.172 mmol) in DMSO (5 ml) was added sodium cyanide (16.84 mg, 0.344 mmol). The reaction mixture was stirred at 60 ° C over the weekend and partitioned between H ₂ O and EtOAc. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (EtOAc: hexanes = 10:90 to 1: 1) resulted in the title compound (76 mg, 95%) as a white solid: NMR * H (CDCl ₃ ) δ ppm 7.81 (s, 1H ), 7.26 - 7.48 (m, 5H), 6.12 (s, 1H), 6.02 (s, 1H), 3.40 (d, J = 14.8 Hz, 1H), 3 , 01 (d, J = 14.6 Hz, 1H), 2.64 - 2.80 (m, 2H), 2.29 (t, J = 7.2 Hz, 2H), 2.08 - 2, 21 (m, 1H), 1.75 - 1.98 (m, 3H), 1.37 1.51 (m, 2H), 0.99 - 1.35 (m, 4H), 0.86 (t , J = 7.4 Hz, 3H), 0.80 (t, J = 7.0 Hz, 3H); ES-LCMS m / z 455 (M + H) ⁺ .
Intermediate 22: (3R, 5R) -8- (bromomethyl) -3-butyl-3-ethyl-7 (methyloxy) -5-phenyl-2,3-dihydro-1,4-benzothiazepin- 1,1-dioxide 4 (577) -ol
(3Ã, 5R) -8- (bromomethyl) -3-butyl-3-ethyl-7 (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-dioxide -benzothiazepine (627 mg, 1.305 mmol) dissolved in DCM (20 ml) was treated with m-CPBA (292 mg, 1.305 mmol) with stirring at 0 ° C for 1 h after which time LCMS indicated complete conversion to the product. The reaction mixture was treated with 10% Na ₂ SO ₃ with vigorous stirring for 15 min, diluted with DCM, and the organic phase was isolated, dried over MgSO ₄ , filtered, and concentrated to dryness.
The residue was purified on 40 g of silica gel eluting with DCM giving
(3R, 5Ã) -8- (bromomethyl) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3-dihydro-1,4-benzothiazepin-4 (5H) 1,1-dioxide -ol (621 mg, 96% yield) as a white foam: NMR * H (400 MHz, DMSO-Jg) δ ppm 0.79 (t, 7 = 7.1 Hz, 3 Η), 0.85 ( t, 7 = 7.3 Hz, 3 Η), 1.04-1.37 (m, 4 Η), 1.37-1.49 (m, 1 Η), 1.58-1.71 (m , 1 Η), 1.77-1.89 (m, 1 Η), 2.01-2.14 (m, 1 Η), 3.36-3.44 (m, 2 Η), 3,453.55 (m, 3 Η), 4.69 (s, 2 Η), 6.15 (s, 1 Η), 6.35 (s, 1 Η), 7.30-7.72 (m, 5 Η) , 7.98 (s, 1 Η), 8.10 (s, 1 H); LC-MS (ES ⁺ ) m / z 496.1, 498.1 [M + H], Intermediate 23: {[(3R, 5R) -3-butyl-3-ethyl-4-hydroxy-7- (methyloxy ) -1,1-dioxide5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} diethyl phosphonate
(3R, 57 ) - 8- (bromomethyl) -3-butyl-3-ethyl-7 (methyloxy) -5-phenyl-2,3-dihydro-1,4-benzothiazepin-4 ( 5H) -ol (171 mg, 0.344 mmol) dissolved in toluene (10 ml) was treated with triethyl phosphite (1.189 ml, 6.80 mmol) then heated to reflux for 16 h. The reaction mixture was washed with H ₂ O, dried over MgSO ₄ , filtered and concentrated to dryness. The residue was purified by means of RP-HPLC (30 X 150 mm, column Cl8 5um H ₂ O Sunfire Column; MeCN + 0.05% TFA & H ₂ O + 0.05% TFA were used as the solvent system ; from 15 to 100%) giving diethyl {[(3R, 5R) -3-butyl-3-ethyl-4-hydroxy-7- (methyloxy) -1, 1-dioxide-5-phenyl-2,3,4 , 5tetrahydro-1,4-benzothiazepin-8-yl] methyl} phosphonate (48.5 mg, 25.4% yield) as a clear oil: 'H NMR (400 MHz, DMSO-7 ₆ ) □ ppm 0.79 (t, 7 = 6.6 Hz, 3 H), 0.82-0.93 (m, 3 H), 1.04-1.71 (m, 12 H), 1.912.02 (m , 1 H), 2.02-2.13 (m, 1 H), 3.13-3.28 (m, 2 H), 3.29-3.40 (m, 2 H), 3.41 (s, 3 H), 3.95 (m, 7 = 7.2, 7.2, 7.2, 7.2, 2.5 Hz, 4 H), 6.12 (s, 1 H), 6.286.38 (m, 1 H), 7.31-7.39 (m, 1 H), 7.42 (t, 7 = 7.4 Hz, 2 H), 7.46-7.60 (m , 2 H),
7.82 (d, .7 = 1.8 Hz, 1 Η), 7.99-8.08 (m, 1 H); LC-MS (ES ⁺ ) m / z 554.31 [M + H]. Intermediates 24: [({[(3R, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} imino) dimethanediyl] bis (phosphonate) of tetraethyl
{[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -l, l-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} amine (155 mg, 0.37 mmol) was combined with tic acid (catalytic) in toluene (20 ml) and concentrated to aridity to azeotropically remove any residual H ₂ O. Paraformaldehyde (11.2 mg, 0.37 mmol) and toluene (5 ml) were added, and the mixture was heated to 75 ° C with vigorous stirring for 30 minutes, after which time diethyl phosphite (0.048 ml) was added. , 0.37 mmol). After 30 m in THF (20 ml) was added to the mixture, and the resulting homogeneous reaction mixture was stirred overnight at 75 ° C. The mixture was concentrated to dryness and purified by means of RP-HPLC (30 X 150 Sunfire column under acidic conditions · MeCN + 0.05% TFA and H ₂ O + 0.05% TFA were used as the solvent system; from 30% to 100% over 10 minutes, from 100% to 100% to 12 minutes) giving [({[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -l, l -dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} imino) dimethanediyl] bis (phosphonate) tetraethyl (49.7 mg, 18.6% yield) as a yellow oil: LC-MS (ES ⁺ ) m / z ΊΥ1.4 [M + H].
Intermediate 25: diethyl [({[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1, 4-benzothiazepin-8-yl] methyl} amino) methyl] phosphonate q 9
{[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -l, l-dioxide-5-phenyl-
2.3.4.5- tetrahydro-1,4-benzothiazepin-8-yl] methyl} amine (45.8 mg, 0.110 mmol) was combined with paraformaldehyde (3.47 mg, 0.110 mmol) and diethyl phosphite (0.014 ml, 0.11 mmol) in THF (4 ml) and stirred for 16 h at 75 ° C whereupon all the solvent is gone after this time, and LCMS indicated <20% conversion. The THF was replaced and more diethyl phosphite (0.043 ml, 0.330 mmol) was added, and the mixture was heated for an additional 24 h at 75 ° C where after this time LCMS indicated ~ 50% conversion. More diethyl phosphite (0.150 ml, 1.16 mmol) was added and heating was continued for 24 h after which time LCMS indicated 70% completion. More paraformaldehyde (1.651 mg, 0.055 mmol) was added and heating was continued for 24 h after which time LCMS indicated complete conversion of starting material to mono- and di-substituted products. The mixture was concentrated to dryness and purified on 24 g of silica gel eluting with 0 to 20% MeOH / DCM giving the desired diethyl [({[(3Ã, 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) methyl] phosphonate (36.3 mg, 58.3 % yield) as a clear oil: LC-MS (ES ⁺ ) m / z 567.30 [M + H].
Intermediate 26: [(3Ã, 55) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-
2.3.4.5- tetrahydro-1,4-benzothiazepin-8-yl] methanol
Step 1: To an ice-cold solution of (3R, 5R) -3butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1, 4-benzothiazepine-8 carbonitrile (2.37 g, 5.74 mmol) in DCM (50 ml) DDQ (1.956 g, 8.62 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 72 h. The reaction mixture was partitioned between H ₂ O and DCM. The organic layer was washed with saturated brine, dried, (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (EtOAc / hexanes = 1: 4 to 3: 1), followed by further purification using silica gel (MeOH: DCM = 0: 100 to 5:95) resulted in (3Ã) - 1,1-dioxide - 3-butyl-3ethyl-7- (methyloxy) -5-phenyl-2,3-dihydro-1,4-benzothiazepine-8-carbonitrile (1.42 g, 59%) as a white solid: NMR * H (CDC1 ₃ ) δ ppm 8.27 (s, 1H), 7.60 (d, J = 7.2 Hz, 2H), 7.44 - 7.54 (m, 1H), 7.35 - 7.45 ( m, 2H), 6.77 (s, 1H), 3.90 (s, 3H), 3.63 - 3.86 (m, 3H), 1.02 - 1.76 (m, 8H), 0 , 89 (t, J = 7.2 Hz, 3H), 0.83 (t, J = 6.8 Hz, 3H); ES-LCMS m / z 411 (M + Ηγ.
Step 2: To an ice-cold solution of (3Ã) -3-butyl3-ethyl-7- (methyloxy) -5-phenyl-2,3-dihydro-1,4-benzothiazepine-8-carbonitrile ( 1.32 g, 3.22 mmol) in DCM (30 ml) was added by dropping DIBAL-H (6.43 ml, 6.43 mmol) as a 1M solution in toluene. The reaction mixture was stirred at room temperature for 2 h, treated with 1N hydrochloric acid solution, and stirred for 1 h after which the layers were separated. The aqueous layer was extracted with DCM, and the combined organic layers were washed with H ₂ O, saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure giving (3Ã) -3 1,1-dioxide -butyl-3-ethyl-7 (methyloxy) -5-phenyl-2,3-dihydro-1,4-benzothiazepine-8-carbaldehyde (1.0 g, 75%) as a white solid: NMR ^] H (CDC1 ₃ ) δ ppm 10.48 (s, 1H), 8.50 (s, 1H), 7.59 - 7.68 (m, 2H), 7.43 - 7.52 (m, 1H), 7, 34 - 7.43 (m, 2H), 6.80 (s, 1H), 3.89 (s, 3H), 3.63 - 3.83 (m, 2H), 0.99 - 1.36 ( m, 5H), 0.88 (t, J = 7.0 Hz, 3H), 0.82 (t, J = 7.0 Hz, 3H); ES-LCMS m / z 414 (M + H) ⁺ .
Step 3: To a solution of (37 ) - 3-butyl-3-ethyl7- (methyloxy) -5-phenyl-2,3-dihydro-1,4-benzothiazepine-8-carbaldehyde 1,1-dioxide ( 720 mg, 1.751 mmol) in THF (20 ml) borane-THF complex (3.48 ml, 1 M solution in THF, 3.48 mmol) was added by dropping. The reaction mixture was stirred overnight, then at 40 ° C for an additional 24 h. The reaction mixture was cooled to room temperature, quenched with MeOH, stirred for 30 min, and concentrated under reduced pressure. MeOH was added several times and this was evaporated under reduced pressure. Purification using silica gel (EtOAc: hexanes = 20:80 to 50:50) resulted in the title compound (306 mg, 42%) as a white solid: NMR ^! H (CDCl3) δ ppm 8.05 (s, 1H), 7.30 - 7.53 (m, 5H), 6.18 (s, 1H), 6.08 (br. S., 1H), 4 , 53 - 4.82 (m, 2H), 3.56 (s, 3H), 3.43 (d, J = 14.9 Hz, 1H), 3.08 (d, J = 14.9 Hz, 1H), 2.38 (dd, J = 14.7, 7.4 Hz, 1H), 2.14 (t, J = 5.9 Hz, 1H), 1.71 - 1.87 (m, 1H ), 1.44 - 1.57 (m, 2H), 1.09 - 1.42 (m, 5H), 0.91 (t, J = 6.8 Hz, 3H), 0.79 (t, J = 7.2 Hz, 3H); ES-LCMS m / z 418 (M + 7 /) ⁺ ·
Intermediate 27: (3Ã, 5S) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl- 1,1-dioxide
2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbaldehyde
kJ
To a solution of [(3Ã, 5 »S) -3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetrahydro-1,4 -benzothiazepin-8-yl] methanol (460 mg, 1.102 mmol) in DCM (10 ml) Dess-Martin periodinane (491 mg, 1.157 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and filtered through a bed of silica gel. The filtrate was concentrated under reduced pressure giving the title compound (391 mg, 85% yield) as a white solid: NMR ^! H (CDCl3) δ ppm 10.35 (s, 1H), 8.55 (s, 1H), 7.33 - 7.52 (m, 5H), 6.30 (s, 1H), 6.13 ( s, 1H), 3.63 (s, 3H), 3.47 (d, J = 14.9 Hz, 1H), 3.08 (d, J = 14.9 Hz, 1H), 2.40 ( dd, J - 14.9, 7.4 Hz, 1H), 1.83 (dd, J = 14.9, 7.4 Hz, 1H), 1.11 - 1.47 (m, 5H), 0 , 91 (t, J = 6.8 Hz, 3H), 0.78 (t, J - 7.4 Hz, 3H); ES-LCMS m / z 416 (M + H) ⁺ .
Intermediate 28: 2-amino-2-butylhexanosyl hydrogen sulfate
. nh ₂ yL / 0 ^ / OH / 7 ^ Λ __ / OO
Step 1: To a stirred norleukin slurry (100 g, 762 mmol) in EtOH (715 ml) at 0 ° C was added thionyl chloride (58.4 ml, 800 mmol) over 1 h while maintaining a temperature of <5 ° C. The reaction was allowed to warm up slowly to 25 ° C and stirred overnight. The solution was heated to 65 ° C for 3 h then concentrated under reduced pressure giving ethyl norleukinate hydrochloride (149 g, 761 mmol, 100% yield) as a white solid after drying at 50 ° C under high vacuum for 15 h.
Step 2: A slurry of ethyl norleukinate hydrochloride salt (149 g, 761 mmol) in DCM (1352 ml) at 25 ° C was treated with MgSO ₄ (92 g, 761 mmol) followed by TEA (223 ml, 1599 mmol) by dripping over 1 h. After stirring for 1 h, benzaldehyde (77 ml, 761 mmol) was added via the addition funnel over 30 min followed by further MgSO ₄ , (92 g, 761 mmol). The slurry was stirred at 25 ° C for 60 h then filtered [and] washed with DCM. The filtrate was concentrated in vacuo then ground with MTBE. The mixture was filtered, and the solid was washed with MTBE. The filtrate was concentrated in vacuo giving a light yellow oil (> 95% yield).
Step 3: A mixture of NaH (16.53 g, 413 mmol) in DMF (293 ml) at 25 ° C was stirred for 10 min then cooled to 0 ° C after which a solution of ethyl N- (phenylmethylidene) was added ) norleukinate (81.8 g, 331 mmol) in DMF (58.5 ml) via drip cannula. The reaction was heated to 25 ° C and stirred for 2 h. A solution of iodobutane (44.6 ml, 364 mmol) in DMF (29.3 ml) was added via cannula, and the reaction mixture was stirred at 25 ° C for 20 h. The reaction was poured into saturated NH ₄ C1 (250 ml) and MTBE (250 ml), then stirred for 10 min. The layers were separated, and the aqueous layer was extracted with MTBE (1 x). The combined organic layers were dried (MgSO ₄ ), filtered, and concentrated in vacuo giving a yellow oil in> 95% yield.
Step 4: Pure ethyl 2-butyl-N- (phenylmethylidene) norleukinate (112.3 g, 370 mmol) was treated with 1 N HCl (444 ml, 444 mmol) and stirred at 25 ° C for 30 min. The reaction was washed with hexanes (2 x 200 ml) then the aqueous layer was cooled to 0 ° C and adjusted to pH 12 with a combination of 3N and 6N NaOH. The aqueous mixture was extracted with MTBE (4x) then the combined organic layers were washed with brine, dried (MgSO ₄ ), filtered, and concentrated in vacuo giving ethyl 2-butylnorleucinate (74 g, 93% yield) as an oil yellow.
Step 5: A solution of ethyl 2-butylnorleukinate (37 g, 172 mmol) in THF (275 ml) at 25 ° C was treated with 2M LAH (86 ml, 172 mmol) via an addition funnel over 30 min. The reaction mixture was heated to 65 ° C and stirred for 2 h, then allowed to resume at room temperature while being stirred overnight. The reaction was cooled to 0 ° C then sequentially treated with H ₂ O (7.82 ml), 15% NaOH (7.82 ml), and H ₂ O (23.5 ml). The mixture was stirred for 2 h then filtered and washed with THF. The filtrate was concentrated in vacuo giving 2-amino-2-butyl1-hexanol (29.8 g,> 95% yield) as a thick yellow oil which solidified on standing.
Step 6: A solution of 2-amino-2-butyl-1-hexanol (62.8 g, 362 mmol) in EtOAc (454 ml) at 25 ° C was treated with chlorosulfonic acid (29.1 ml, 435 mmol) . The reaction was heated to 40 ° C and stirred for 3 h, then cooled to 25 ° C. The thick mixture was placed in a refrigerator overnight, then filtered by washing with cold EtOAc. The solid was dried giving 2-amino-2-butylhexanosyl hydrogen sulfate as a white solid with> 50% yield: 'H (D ₂ O) NMR δ ppm 3.92 (s, 2H), 1.42 - 1.65 (m, 4H), 1.02 - 1.25 (m, 8H), 0.72 (t, J = 6.7 Hz, 6H).
Intermediate 29: S- [5-bromo-4- (methyloxy) -2- (phenylcarbonyl) phenyl] diethylthiocarbamate
Step 1: To a solution of 2-bromo-1,4-bis (methyloxy) benzene (203 g, 934 mmol) and benzoyl chloride (125 ml, 1074 mmol) in DCM (800 ml) at 5 ° C was added if triflic acid (83 ml, 934 mmol) over 1 h. The reaction mixture was allowed to warm to room temperature and then slowly heated to delicate reflux, and stirred for 48 h. The reaction mixture was cooled, and MeOH (20 ml) was added and continued to stir for 30 min. The reaction mixture was poured into H ₂ O and ice and stirred for 1 h. The layers were separated and the organic phase was washed with H ₂ O, dried over MgSO ₄ , and concentrated to an orange solid. MTBE (500 ml) was added and the mixture was stirred overnight. The resulting solid was filtered, rinsed with a 1: 1 ratio of MTBE / hexanes and air dried to give [4-bromo-2,5-bis (methyloxy) phenyl] (phenyl) methanone (210.6 g, 70% ) as a light gray solid: NMR * H (DMSO-d ₆ ) δ ppm 7.68 (d, J = 8.0 Hz, 2H), 7.62 (t, J = 8.0 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.42 (s, 1H), 7.07 (s, 1H), 3.76 (s, 3H), 3.59 (s, 3H ).
Step 2: A solution of [4-bromo-2,5-bis (methyloxy) phenyl] (phenyl) methanone (290 g, 0.903 mol) in DCM (1.5 1) was added by dripping over 1 h at a stirred solution of 1M BC1 ₃ in DCM (1.13 1, 1.13 mol) while maintaining the reaction temperature below 5 ° C. The reaction mixture was stirred at or below 0 ° C for 30 min and then quenched by slowly adding MeOH (500 ml) over 30 min at 10 ° C. 2N HCl (11) was added at 15 ° C over 30 min. The layers were separated, and the organic phase was concentrated by means of rotovap to approximately 500 ml diluted with hexanes. The resulting yellow crystals were collected by filtration and dried in air giving [4bromo-2-hydroxy-5- (methyloxy) phenyl] (phenyl) methanone (258 g, 93%): NMR ^! H (CDC1 ₃ ) δ ppm 11.67 (s, 1H), 7.64 - 7.72 (m, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.51 (t , J = 7.2 Hz, 2H), 7.33 (s, 1H), 7.02 (s, 1H), 3.71 (s, 3H)
Step 3: Solid potassium t-butoxide (116 g, 1.03 mol) was added fractionally to a stirred solution of [4-bromo-2-hydroxy-5- (methyloxy) phenyl] (phenyl) methanone (253.33 g, 0.825 mol) in DMF (800 ml) while maintaining the internal temperature below 20 ° C. Stirring was continued with cooling for 15 min until the internal temperature was ca. 0 ° C. The cooling bath was removed and stirring was continued for 30 min with heating to 6 ° C internal temperature. A solution of ΛζΑ-diethyl thiocarbamoyl chloride (150 g, 0.99 mol) in DMF (300 ml) was then added in a slow flow over 5 min. The resulting dark mixture was then heated to 60 ° C and maintained for 3 h. The mixture was diluted with MTBE (1.5 1) and H ₂ O (1.5 1) then quickly stirred. The layers were separated, and the aqueous phase was extracted with MTBE (1.5 1). The combined organic layers were washed with 0.2N NaOH (2 x 1.5 1) and once with brine (1 1). The dark red organic phase was dried over MgSO ₄ , filtered and concentrated to 1 l of a thick slurry, extracted with heptane. The solids were collected by filtration and washed with heptane and dried in air giving D- [5-bromo-4 (methyloxy) -2- (phenylcarbonyl) phenyl] diethylthiocarbamate (301.3 g, 86%) as an orange solid clear: NMR Ή (CDC1 ₃ ) δ ppm 7.81 (d, J = 8.0 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.36 - 7.45 ( m, 3H), 7.00 (s, 1H), 3.86 (s, 3H), 3.63 (q, J = 7.0 Hz, 2H), 3.22 (q, J = 7.2 Hz, 2H), 1.06 (q, 6H)
Step 4: A stirred mixture of D- [5-bromo-4- (methyloxy) -2 (phenylcarbonyl) phenyl] diethylthiocarbamate (301 g, 0.71 mol) in diphenyl ether (11) was gradually heated to 215 ° C of internal temperature throughout ode maintained at this temperature for 3.5 h. The dark solution was cooled to 100 ° C and treated with Darco G-60 (20 g). The mixture was further cooled to 70 ° C with stirring and filtered through celite and washing with heptane. The filtrate was diluted with heptane (4 1) with cooling to 5 ° C and aged at 0 ° C over 30 min. The supernatant was removed by decanting, and the remaining solids were ground with hexanes. The remaining solids were dissolved in DCM and concentrated in vacuo to a solid that was triturated with hexanes and collected by filtration. The material was dried under high vacuum giving * S '- [5-bromo-4 (methyloxy) -2- (phenylcarbonyl) phenyl] diethylthiocarbamate (224 g, 74%) as a dark gray solid: NMR * H (CDCl3) δ ppm 7.72 - 7.82 (m, 3H), 7.52 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 6.90 ( s, 1H), 3.87 (s, 3H), 3.15-3.29 (br. s., 2H), 3.02-3.15 (br., 2H), 0.68 - 1.09 (m, 6H).
Intermediate ______ 30: [2- [(2-amino-2-butyl-hexanosyl) thio] -4-bromo-5 (methyloxy) phenyl] (phenyl) methanone
A suspension of S- [5-bromo-4- (methyloxy) -2- (phenylcarbonyl) phenyl] diethylthiocarbamate (Intermediate 29) (15 g, 35.5 mmol) in EtOH (75 ml) was treated with 6M KOH (23 , 68 ml, 142 mmol) then heated to reflux for 3 h. The reaction was diluted with more EtOH (200 ml) then heated to 70 ° C for 15 h. The reaction was concentrated until a thick red oil [formed]. In a separate flask, the 2-amino-2-butyl-hexanesyl hydrogen sulfate (9.90 g, 39.1 mmol) was dissolved in H ₂ O (25 ml) then heated to 85 ° C after which the thiophenolate solution in H ₂ O was added via pipette. Residual thiophenolate was transferred with minimal EtOH and H ₂ O. The reaction mixture was stirred at 85 ° C for 15 h then cooled to room temperature. The reaction was poured into H ₂ O and extracted with DCM (3X). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered, and concentrated in vacuo to give a thick red oil. The residue was purified via silica gel chromatography using DCM / MeOH with 1% NHiOH (gradient 100/0% to 90:10 over 30 min) giving [2 - [(2-amino-2-butyl- hexanosyl) thio] -4-bromo-5 (methyloxy) phenyl] (phenyl) methanone (16.3 g, 96% yield) as a thick red oil: 1 H NMR (CDCl ₃ ) δ ppm 7.76 - 7 , 83 (m, 3H), 7.60 (t, J - 7.4 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 6.84 (s, 1H), 3 , 88 (s, 3H), 2.81 (s, 2H), 0.78 - 1.55 (m, 18H); LC-MS (ES ⁺ ) m / z 478.2 [M + H], 480.2 [M + H].
Intermediate _______ 31: [2 - [(2-amino-2-butylhexanosyl) thio] -4-bromo-5 (methyloxy) phenyl] (phenyl) methanone
A solution of [2 - [(2-amino-2-butylhexanosyl) thio] -4-bromo5- (methyloxy) phenyl] (phenyl) methanone (16.3 g, 34.1 mmol) in toluene (341 ml ) was treated with citric acid (0.327 g, 1.703 mmol) then heated to reflux for 15 h. The reaction was equipped with a Dean-Stark trap then heated at 130 ° C for 10 h after which more citric acid (325 mg) was added. Stirring was continued at 130 ° C for 15 h then more citric acid (100 mg) was added and stirring at 130 ° C was continued for 10 h. The reaction was concentrated in vacuo then purified by chromatography on SiO ₂ using hexanes: EtOAc (from 100: 0 to 80:20) as the eluent giving 8-bromo-3,3-dibutyl-7- (methyloxy) -5- phenyl-2,3-dihydro-1,4benzothiazepine (10 g, 63.7% yield) as an oil that solidified to a copper-colored solid when resting: NMR ^! H (CDC1 ₃ ) δ ppm 7.79 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.30 - 7.44 (m, 3H), 6.59 (s , 1H), 3.71 (s, 3H), 3.23 (s, 2H), 1.16 - 1.66 (m, 12H), 0.86 (t, J = 7.2 Hz, 6H) ; LC-MS (ES ⁺ ) m / z 460.2 [M + H], 462.2 [M + H].
Intermediate 32: methyl 3,3-dibutyl-7- (methyloxy) -5-phenyl-2,3-dihydro-1,4-
Carbon monoxide was bubbled through a mixture of 8-bromo-3,3-dibutyl-7- (methyloxy) -5-phenyl-2,3-dihydro-1,4-benzothiazepine (Intermediate 31) (10 g, 21 , 72 mmol), Pd (OAc) ₂ (0.488 g, 2.172 mmol), and dppp (0.896 g, 2.172 mmol) in DMSO (71.6 ml) for 15 min. The reaction mixture was treated with MeOH (3.51 ml, 87 mmol) and TEA (4.54 ml, 32.6 mmol) then heated to 70 ° C for 3 h, after which more MeOH ( 3.51 ml, 87 mmol). Heating under CO atmosphere was continued for 39 h. The reaction mixture was diluted with MTBE then filtered through a plug of celite and washed with MTBE. The filtrate was poured into H ₂ O then the separated aqueous layer was extracted with MTBE (1 x). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered, and concentrated in vacuo. The residue was purified via SiO ₂ chromatography signaling using hexanes: EtOAc (from 100: 0 to 60:40) as eluent giving 3,3-dibutyl-7- (methyloxy) -5-phenyl-2,3-dihydro-1, Methyl 4-benzothiazepine-8-carboxylate (86% yield) as a light orange oil: 'H NMR (CDC1 ₃ ) δ ppm 8.01 (s, 1H), 7.53 (d, J - 6.8 Hz, 2H), 7.30 - 7.44 (m, 3H), 6.69 (s, 1H), 3.93 (s, 3H), 3.72 (s, 3H), 3.22 (s , 2H), 1.14 - 1.65 (m, 12H), 0.86 (t, J = 7.2 Hz, 6H); LC-MS (ES ⁺ ) m / z 440.3 [M + H].
Intermediate 33: [3,3-dibutyl-7- (methyloxy) -5-phenyl-2,3-dihydro-1,4benzothiazepin-8-yl] methanol
HO
A solution of methyl 3,3-dibutyl-7- (methyloxy) -5-phenyl-2,3-dihydro-1,4-benzothiazepine-8-carboxylate (8.2 g, 18.65 mmol) in THF (34, 0 ml) at 25 ° C was treated with 2M LAH in THF (13.99 ml, 28.0 mmol) by drip. The reaction was stirred for 15 min then quenched with H ₂ O (1.1 ml), 15% NaOH (1.1 ml), and H ₂ O (3.4 ml). After stirring for 30 min, the reaction was filtered through a bed of celite and washed with THF. The filtrate was concentrated in vacuo giving [3,3-dibutyl-7- (methyloxy) -5-phenyl-2,3-dihydro-1,4-benzothiazepin-8-yl] methanol (7.7 g, 100% yield) : NMR 'H (CDCl ₃ ) δ ppm 7.49 - 7.59 (m, 3H), 7.30 - 7.42 (m, 3H), 6.58 (s, 1H), 3.68 (s , 3H), 3.22 (s, 2H), 1.13 - 1.65 (m, 12H), 0.86 (t, J = 7.2 Hz, 6H); LC-MS (ES ⁺ ) m / z 412.3 [M + H].
Intermediate 34: [3,3-dibutyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4benzothiazepin-8-yl] methanol
HO
A solution of [3,3-dibutyl-7- (methyloxy) -5-phenyl-2,3-dihydro-1,4-benzothiazepin-8-yl] methanol (7.7 g, 18.71 mmol) in THF (51 , 1 ml) at 25 ° C was treated with BH3.THF (20.58 ml, 20.58 mmol) by dripping then the reaction was stirred for 2 h. The reaction was quenched with MeOH (30 ml) then concentrated under reduced pressure to give a crude white foam. Purification of the residue by chromatography on SiO ₂ using a gradient of 6: 1 / hexanes: EtOAc to 2: 1 / hexanes: EtOAc resulted in a mixture of unreacted starting material and product (approximately 85.15, respectively). This material was again subjected to identical conditions and purified in a similar manner giving [3,3-dibutyl-7- (methyloxy) 5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8 -yl] methanol (6.56 g, 85% yield) containing 5-10% imine: 1 H NMR (CDCl ₃ ) δ ppm 7.50 (s, 1H), 7.24 - 7.47 (m, 5H), 6.09 (s, 1H), 5.78 (s, 1H), 4.59 (d, J = 3.1 Hz, 2H), 3.49 (s, 3H), 2.76 ( d, J = 14.2 Hz, 1H), 2.50 (d, J = 14.2 Hz, 1H), 2.01 - 2.24 (m, 2H), .08 - 1.72 (m, 10H), 0.90 (t, J = 6.9 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H); LC-MS (ES ⁺ ) m / z 414.3 [M + H],
Intermediate 35: [3,3-dibutyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methanol
A solution of [3,3-dibutyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methanol (6.56 g, 15.86 mmol) in TFA (52.4 ml) at 25 ° C was treated with 30% H ₂ O ₂ (3.24 ml, 31.7 mmol), and the reaction was stirred for 1 h. After cooling in an ice bath, H ₂ O (300 ml) and THF (120 ml) were added followed by 15% NaOH then 6N NaOH until the solution reached pH 12. After stirring for 1 h, an 10% Na ₂ SO _{3 solution} (60 ml), and the solution was stirred until bubbling ceased. The reaction was treated with DCM, and the layers were separated. The aqueous layer was extracted with DCM (2x) then the combined organic layers were washed with brine, dried (MgSO ₄ ), filtered, and concentrated in vacuo. The residue was purified by chromatography on SiO ₂ using a gradient from DCM / MeOH (from 100: 0 to 95: 5) giving [3,3dibutyl-7- (methyloxy) -1,1-dioxide-5-phenyl- 2,3,4,5-tetrahydro-1,4-benzothiazepin8-yl] methanol (6.7 g, 95% yield) as a white solid. The material contained 10-15% imine: NMR Ή (CDCl ₃ ) δ ppm 8.05 (s, 1H), 7.29 - 7.49 (m, 5H), 6.19 (s, 1H), 6 , 08 (br. S., 1H), 4.56 - 4.76 (m, 2H), 3.56 (s, 3H), 3.44 (d, J = 14.8 Hz, 1H), 3 , 07 (d, J = 14.8 Hz, 1H), 2.05 - 2.30 (m, 1H), 1.85 (m, 1H), 1.02 - 1.64 (m, 10H), 0.91 (t, J = 6.8 Hz, 3H), 0.84 (t, J = 7.0 Hz, 3H); LC-MS (ES ⁺ ) m / z 446.3 [M + H].
Intermediate 36: 3,3-dibutyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbaldefdo 1,1-dioxide
A solution of [3,3-dibutyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methanol (415 mg, 0.931 mmol) in DCM (9313 μΐ) at 25 ° C was treated with Dess-Martin periodinane (415 mg, 0.978 mmol) and stirred for 1 h. The reaction was filtered through a thin bed of SiO ₂ washing with EtOAC, then the filtrate was concentrated in vacuo to give a white solid. The residue was purified by chromatography on SiO2 using hexanes / EtOAc gradient giving 3,3-dibutyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-dioxide -1,4benzothiazepine-8-carbaldehyde (310 mg, 75% yield) as a white solid: NMR (CDC1 ₃ ) δ ppm 10.35 (s, 1H), 8.55 (s, 1H), 7.32 - 7.56 (m, 5H), 6.30 (s, 1H), 6.13 (d, J = 7.8 Hz, 1H), 3.63 (s, 3H), 3.47 (d, J = 15.0 Hz, 1H), 3.05 (d, J = 15.0 Hz, 1H), 2.12 - 2.29 (m, 1H), 1.78 - 1.92 (m, 1H ), 1.03 - 1.61 (m, 10H), 0.91 (t, J = 7.0 Hz, 3H), 0.82 (t, J = 7.1 Hz, 3H); LC-MS (ES ⁺ ) m / z 444.2 [M + H].
Intermediate 37: {[3,3-dibutyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} phosphonate of diethyl
Step 1: A solution of imidazole (306 mg, 4.49 mmol) in DCM (2.7 ml) at 0 ° C was treated with triphenylphosphmo (589 mg, 2.244 mmol) followed by Br ₂ (116 μΐ, 2.244 mmol) . After stirring for 5 min, a solution of [3,3-dibutyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-2,3,4,5-tetrahydrol, 4-benzothiazepin-8- il] methanol (Intermediate 35) (500 mg, 1.122 mmol) in DCM (2.7 ml) was added slowly, then the reaction was stirred at 0 ° C for 2 h. The reaction was treated with 10% aq. Na ₂ SO ₃ , the layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried (Na ₂ SO4), filtered through a bed of SiO ₂ , and concentrated in vacuo giving 8- (bromomethyl) -3,3-dibutyl-7 (methyloxy) -5-1,1-dioxide -phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (571 mg,> 99% yield).
Step 2: A solution of 8- (bromomethyl) -3,3dibutyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide ( 571 mg, 1.123 mmol) in toluene (5.3 ml) at 25 ° C was treated with triethyl phosphite (295 μΐ, 1.684 mmol) then heated to reflux for 18 h. The reaction was concentrated in vacuo to an oil, then purified by chromatography on SiO ₂ using 4: 1 / EtOAc: 100% EtOAc hexanes giving {[3,3-dibutyl-7- (methyloxy) -1,1 -dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4benzothiazepin-8-yl] methyl} diethyl phosphonate (285 mg, 44.9% yield): NMR ^] H (CDC1 ₃ ) δ ppm 7.99 (d, J - 2.7 Hz, 1H), 7.29 - 7.68 (m, 5H), 6.16 (s, 1H), 6.06 (br. s, 1H ), 3.95 - 4.18 (m, 4H), 3.53 (s, 3H), 3.43 (d, J = 14.8 Hz, 1H), 3.15 - 3.26 (m, 2H), 3.04 (d, J = 14.8 Hz, 1H), 2.09 2.30 (m, 1H), 1.79 - 1.94 (m, 1H), 1.04 - 1, 63 (m, 16H), 0.92 (t, J = 6.8 Hz, 3H), 0.83 (t, J = 7.1 Hz, 3H); LC-MS (ES ⁺ ) m / z 566.4 [M + H].
Intermediate 38: (3R, 5R) -3-butyl-3-ethyl-8 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4- trifluoromethanesulfonate benzothiazepin-7-ila
A solution of (3R, 5R) -3-butyl-3-ethyl-8- (methyloxy) -5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-7-ol 1,1-dioxide (9.24 g, 22.90 mmol) and pyridine dissolved in DCM (300 ml) was treated with anhydride triflic (4.64 ml, 27.5 mmol) dissolved in DCM (80 ml) by dripping with stirring and cooling in an ice bath. The reaction mixture was allowed to warm to room temperature and stirred for 1 h, after which time LCMS indicated complete conversion. The reaction mixture was washed twice with diluted HCl, dried over MgSO ₄ , filtered and concentrated to an orange foam: NMR ^! H (400 MHz, DMSO-7 ₆ ) δ ppm 0.75 (t, 7 = 7.0 Hz, 3 H), 0.81 (t, 7 = 7.3 Hz, 3 H), 0.94 - 1.29 (m, 4 H), 1.47 (q, J = 7.3 Hz, 2 H), 1.67 - 1.80 (m, 1 H), 1.95 - 2.07 (m , 1 H), 2.80 (d, 7 = 9.6 Hz, 1 H), 3.27 (d, 7—15.2 Hz, 1 H), 3.76 (d, 7 = 15.2 Hz, 1 H), 3.99 (s, 3 H), 5.86 (d, 7 = 9.6 Hz, 1 H), 6.34 (s, 1 H), 7.27 - 7.52 (m, 5 H), 7.79 (s, 1 H).
Intermediate 39: (3R, 5Ã) -3-butyl-3-ethyl-A, A-dimethyl-8 (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,1-dioxide 1,4-benzothiazepin-7-amine
(3R, 5R) -3-Butyl-3-ethyl-8 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-7 trifluoromethanesulfonate -ila (5.57 g, 10.40 mmol), Pd ₂ (dba) ₃ (0.286 g, 0.312 mmol), 2-biphenylyl-di-tbutylphosphine (0.372 g, 1.248 mmol), and K ₃ PO ₄ (2.318 g, 10.92 mmol) were combined in 1,2-dimethoxyethane (DME) (10 ml) and stirred for 10 min while purging with N ₂ . 2M dimethylamine in THF (40 ml, 80 mmol) was added, and the mixture was heated for 16 h at 100 ° C in an oil bath, where after this time LCMS indicated> 90% conversion with significant phenol formation . The reaction mixture was filtered through Celite, and the filtrate was concentrated to dryness. The residue was partitioned between DCM and NaHCO ₃ aq., And the organic phase was isolated, dried over MgSO ₄ , filtered, and concentrated to dryness. The residue was purified on 330 g of silica gel eluting with 20 to 40% EtOAc / hexanes giving (3Ã, 57 ) -3-butyl-3-ethyl-7V, A-dimethyl-8- 1,1-dioxide (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4benzothiazepin-7-amine (3.12 g, 7.25 mmol, 69.7% yield) as a white solid: NMR * H (400 MHz, DMSO-thiQ δ ppm 0.68 - 0.87 (m, 6 H), 0.96 - 1.29 (m, 4 H), 1.33 - 1.54 (m, 2 H), 1.64 - 1.83 (m, 1 H), 2.00 - 2.12 (m, 1 H), 2.46 (d, 7 = 10.0 Hz, 1 H), 2 , 53 (s, 6 H), 3.06 (d, 7 = 14.6 Hz, 1 H), 3.51 (d, 7 = 14.6 Hz, 1 H), 3.82 (s, 3 H), 5.85 (d, 7 = 9.8 Hz, 1 H), 5.94 (s, 1 H), 7.26 - 7.34 (m, 1 H), 7.34 - 7, 46 (m, 5 H); LC-MS (ES ⁺ ) m / z 431.33 [M + H] Intermediate 40: (3Ã, 5R) -3-butyl-7- (dimethylamino-dioxide ) -3-ethyl-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ol
(3R, 5R) -3-butyl-3-ethyl-A, 7V-dimethyl-8- (methyloxy) -5-phenyl-2,3,4,5tetrahydro-1,4-benzothiazepin-7-amine 1 , 1-dioxide (5.25 g, 12.19 mmol) dissolved in DCM (100 ml) was treated with aluminum chloride (6.50 g, 48.8 mmol) for 2 h at 23 ° C whereupon after this time LCMS indicated complete conversion but with significant by-product formation. The mixture was quenched with H ₂ O ice, and the mixture was stirred vigorously for 15 min. The mixture was extracted four times with DCM, and the combined organics were dried over MgSO ₄ , filtered and concentrated to dryness. The pH of the aqueous phase was adjusted to 13 with 6N NaOH, the mixture was extracted four times with DCM, and the combined organics were dried over MgSO ₄ , filtered and concentrated to dryness. The extracts with pH 1 (1.47 g) and extracts with pH 13 (1.01 g) were combined and purified on 220 g of silica gel eluting with 15 to 45% EtOAc / hexanes giving 1,1-dioxide of (3Ã, 5Ã) -3-butyl-7- (dimethylamino) -3-ethyl-5-phenyl-2,3,4,5-tetrahydro-1,4benzothiazepin-8-ol (1.76 g, 4.22 mmol, 34.7% yield) as a copper-colored glass. NMR Ή (400 MHz, DMSO-7 ₆ ) δ ppm 0.69 - 0.83 (m, 6 H), 0.96 - 1.28 (m, 4 H), 1.31 -1.54 (m , 2 H), 1.65 - 1.77 (m, 1 H), 2.00 - 2.12 (m, 1 H), 2.38 (d, 7 = 9.8 Hz, 1 H), 3.04 (d, 7 = 14.8 Hz, 1 H), 3.33 (s, 6 H), 3.45 (d, 7 = 14.8 Hz, 1 H), 5.80 (d, 7 = 9.8 Hz, 1 H), 5.89 (s, 1 H), 7.23 - 7.33 (m, 1 H), 7.33 - 7.52 (m, 5 H), 9 , 81 (s, 1 H). LC-MS (ES ') m / z 415.18 [Ml]; LCMS (ES ⁺ ) m / z 417.20 [M + H].
Intermediate 41: (3R, 5R) -3-butyl-7 (dimethylamino) -3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin- trifluoromethanesulfonate 8-ila
F
To a solution of (3R, 5R) -3-butyl-7 (dimethylamino) -3-ethyl-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin -8-ol (1.24 g, 2.98 mmol) in DCM (10 ml) at 22 ° C was added pyridine (0.602 ml, 7.44 mmol), followed by triflic anhydride (0.603 ml, 3.57 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed twice with H ₂ O, and the organic layer was isolated, dried over MgSO ₄ , filtered, and concentrated to dryness. The residue was purified on 330 g of silica eluting with DCM giving (3Ã, 5Ã) -3-butyl-7- (dimethylamino) -3-ethyl-1,1-dioxide-5-phenyl-2,3,4 trifluoromethanesulfonate , 5-tetrahydro-1,4-benzothiazepin-8-yl (1.42 g, 2.59 mmol, 87% yield) as a white foam: LC-MS (ES ⁺ ) m / z 549.17 [M + H].
Intermediate 42: (3Á, 5Ã) -3-butyl-7- (dimethylamino) -3-ethyl-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide -carbonitrile oo

(3Ã, 5Ã) -3-butyl-7 (dimethylamino) -3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4benzothiazepin-8-yl trifluoromethanesulfonate (1.42 g, 2.59 mmol) dissolved in DMF (5 ml) was combined with dicianozinc (0.456 g, 3.88 mmol), Pd ₂ (dba) 3 (0.012 g, 0.013 mmol), and DPPF (0.016 g, 0.028 mmol) and purged with N ₂ . The mixture was heated at 80 ° C for 16 h after which time LCMS indicated ~ 25% conversion. The reaction mixture was purged for 1 h with N ₂ , more dicianozinc (0.456 g, 3.88 mmol), Pd ₂ (dba) ₃ (0.036 g, 0.039 mmol), and DPPF (0.050 g, 0.091 mmol) were added. ), and the mixture was purged another 30 min with N ₂ . The resulting mixture was heated to 80 ° C for 40 h, after which LCMS indicated significant by-product formation. The mixture was partitioned between EtOAc / H ₂ O and filtered through Celite. The organic phase was isolated, washed with H ₂ O and brine, dried over MgSO ₄ , filtered and concentrated to dryness. The residue was purified on 120 g of silica gel eluted with 20 to 100% EtOAc / hexanes giving (3Ã, 5Ã) 1,1-dioxide 3-butyl-7- (dimethylamino) -3-ethyl-5- phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine8-carbonitrile (contaminated with phenol) (340 mg, 0.799 mmol, 30.9% yield: LC-MS (ES ') m / z 424.18 [Ml], LC-MS (ES ⁺ ) m / z 426.35 [M + H].
Intermediate 43: (37 , 57 ) - 3-butyl-7- (dimethylamino) -3-ethyl-5 phenyl-2,3,4,5-tetrahydro-1,4- 1,1-dioxide benzothiazepine-8-carbaldehyde
(37 , 5Ã) -3-butyl-7- (dimethylamino) -3-ethyl-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbonitrile (340 mg, 0.799 mmol) dissolved in toluene (5 ml) was treated with DIBAL-H IM in toluene (0.919 ml, 0.919 mmol ) at 0 ° C and stirred for 1 h. The mixture was warmed to room temperature and stirred overnight where after this time LCMS indicated ~ 20% conversion. More 1M DIBAL-H (131 mg, 0.919 mmol) was added, and the reaction mixture was stirred for 2 h at room temperature where after this time LCMS indicated> 80% conversion. The reaction mixture was diluted with DCM and quenched with 1N HCl. The phases were separated, and the aqueous phase was extracted twice with DCM. The organics were combined, dried over MgSO ₄ , filtered and concentrated to dryness. The residue was purified on 40 g of silica gel eluted with 20 to 40% EtOAc / hexanes giving (3Ã, 5Ã) -3-butyl-7- (dimethylamino) -3-ethyl-5-phenyl 1,1-dioxide -2,3,4,5-tetrahydro-1,4-benzothiazepine-8carbaldehyde (40 mg, 0.093 mmol, 11.7% yield): NMR Ή (400 MHz, DMSO- <7 ₆ ) δ ppm 0 , 74 (t, .7 = 6.9 Hz, 3 H), 0.80 (t, .7 = 7.4 Hz, 3 H), 0.93 - 1.27 (m, 4 H), 1 , 29 - 1.55 (m, 2 H), 1.64 - 1.82 (m, 1 H), 2.01 - 2.21 (m, 1 H), 2.64 - 2.73 (m , 1 H), 2.75 (s, 6 H), 3.06 (d, .7 = 14.8 Hz, 1 H), 3.56 (d, .7 = 14.6 Hz, 1 H) , 5.85 - 5.93 (m, 1 H), 6.04 (s, 1 H), 7.26 - 7.52 (m, 5 H), 8.21 (s, 1 H), 9 , 94 (s, 1 H).
Intermediate 44: (3Ã, 5Ã) -3-butyl-3-ethyl-A-methyl-A, 7bis (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,1-dioxide 1,4-benzothiazepine-8-carboxamide
To a solution of (37 , 5Ã) -3-butyl-3-ethyl7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4- benzothiazepine-8-carboxylic (Intermediate 4, 174 mg, 0.403 mmol) in ΛζΑ-dimethylformamide (5 ml) N, O-dimethylhydroxylamine hydrochloride (59.0 mg, 0.605 mmol), DIEA (0.282 ml, 1.613 mmol) and HATU (307 mg, 0.806 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between H ₂ O and EtOAc. The organic layer was washed with saturated brine, dried, filtered, and concentrated under reduced pressure. Purification via SiO ₂ chromatography (EtOAc: Hex = 1: 3 to 3: 1) resulted in the title compound (168 mg, 95% pure, 83%) as a light yellow oil: ES-LCMS m / z
475 (M + Hf.
Intermediate 45: diethyl {[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5phenyl-2,3,4,5-tetrahydro-1,4 benzothiazepin-8-yl] methylidene} propanedioate
To a solution of (37 , 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-dioxide -benzothiazepine-8-carbaldehyde (Intermediate 9, 109 mg, 0.262 mmol) in toluene (3 ml) was added diethyl malonate (0.048 ml, 0.315 mmol) and piperidine (0.013 ml, 0.131 mmol). The reaction mixture was stirred at 100 ° C overnight, cooled to room temperature, and concentrated under reduced pressure. Purification via chromatography on SiO ₂ (EtOAc / Hex = 10:90 to 80:20) resulted in the title compound (146 mg, 90% pure, 90%) as a light yellow oil: ES-LCMS m / z 558 (A / + H) ⁺ .
Intermediate 46:
EtO.
EtO.
EtO.
To a solution of diethyl malonate (0.096 ml, 0.628 mmol) in ethanol (3 ml) was added sodium ethoxide (0.254 ml, 0.681 mmol). The reaction mixture was stirred at room temperature for 20 min and treated with a solution of diethyl {[(3R, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide5-phenyl-2 , 3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methylidene} propanedioate (Intermediate 45, 146 mg, 0.262 mmol) in ethanol (2 ml). The reaction mixture was stirred at room temperature overnight, acidified with acetic acid at pH 3-4 and partially concentrated under reduced pressure to remove organic solvents under reduced pressure. The residue was partitioned between water and dichloromethane. The organic layer was washed with saturated brine, dried, (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (EtOAc: Hex = 1: 5 to 2: 1) resulted in the title compound (78, 120 mg, 84% pure, 53%) as a colorless oil: NMR Ή (400 MHz, CDC1 ₃ ) δ ppm 7.97 (s, 1H), 7.26 - 7.48 (m, 5H), 6.08 (s, 1H), 5.97 (s, 1H), 4.43 (br s, 1H) , 4.04 - 4.20 (m, 6H), 3.86 - 4.03 (m, 4H), 3.37 (d, J = 14.9 Hz, 1H), 2.90 (d, J = 14.9 Hz, 1H), 2.07 - 2.23 (m, 2H), 2.04 (d, J = 14.7 Hz, 1H), 1.74 - 1.90 (m, 1H) , 1.34 - 1.54 (m, 2H), 1.17 - 1.27 (m, 8H), 0.97 - 1.10 (m, 6H), 0.66 - 0.92 (m, 6H); ES-LCMS m / z 718 (M + H) ⁺ .
Intermediate 47: dimethyl 3 - ({[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide5-phenyl-2,3,4,5-tetrahydro-1 , 4-benzothiazepin-8-yl] carbonyl} amino) pentanedioate
MeOOC
(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -5phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carboxylic acid dioxide (Intermediate 4, 100 mg, 0.232 mmol) in dichloromethane (5 ml) received the addition of DIPEA (0.202 ml, 1.159 mmol) and HATU (88 mg, 0.232 mmol). The reaction mixture was stirred at room temperature for 20 min, followed by the addition of dimethyl 3-aminopentanedioate (81 mg, 0.463 mmol), and stirred at room temperature overnight. The reaction mixture was then partitioned between water and dichloromethane. The organic layer was washed with saturated brine, dried (Na ₂ SC> 4), filtered, and concentrated under reduced pressure. Purification on silica gel using MeOH: DCM = 0: 100 to 10:90 resulted in the title compound (212 mg, 63% pure, 98%): ES-LCMS m / z 589 (M + H) +. Intermediate 48: Dimethyl 3-aminopentanedioate o nh ₂ o
Dimethyl (2Z) -3-amino-2-pentenedioate (613 g, 3.54 mol) was added in portions to TF A (3.15 1) with stirring while maintaining the reaction temperature below 30 ° C with cooling external. After most of the solids had dissolved, 1M BH ₃ -THF (1.53 1, 1.53 mol) was added by dripping over 1 h while maintaining the reaction temperature between 18-21 ° C. The reaction mixture was cooled to 10 ° C and quenched by adding dripping water (500 ml) over 5 min while maintaining the reaction temperature between 10-15 ° C. The reaction was stirred at room temperature for 30 min and then filtered. The filtrate was concentrated to remove most of the TFA, and the resulting material was dissolved in CH ₂ C _{1 2} (4 1). The CH ₂ C1 _{2 solution} was added slowly to a stirred solution of K3PO4 (3 kg) in water (3 1) at room temperature and the mixture was stirred rapidly for 10 min. The layers were separated and the aqueous phase was extracted with CH ₂ C _{1 2} (21). The combined CH ₂ C1 ₂ layers were dried over MgSO ₄ , filtered and concentrated giving dimethyl 3-aminopentanedioate (568 g) as a golden liquid: NMR Ή (DMSO-d ₆ ) δ ppm 3.56 (s, 6 H) , 3.35 (m, 1 H), 2.42 (dd, J = 16 Hz, J = 5.3 Hz, 2 H), 2.29 (dd, J = 16 Hz, J = 8 Hz, 2 H ), 1.93 (br s, 2 H). Intermediate 49: Dimethyl 3-aminopentanedioate (acetic acid salt) o nh ₃ ⁺ ch ₃ co ₂ ·
A solution of dimethyl 3-aminopentanedioate (568 g, 3.24 mol) in i-butyl methyl ether (2.3 1) was cooled in an ice bath and glacial acetic acid (195, 3.24 mol) was added by dripping while maintaining the reaction temperature at about 15 ° C. The resulting mixture was seeded with a small amount of the desired crystalline product and stirred for 90 min with cooling to 5 ° C. The resulting precipitate was collected by filtration and washed with a 1: 1 ratio of 1-butyl methyl ether / heptane. The filter cake was dried under vacuum giving the dimethyl 3-aminopentanedioate acetic acid salt as an off-white solid (640 g): NMR * H (DMSO-d ₆ ) δ ppm 5.30 (br s, 3 H ), 3.56 (s, 6 H), 3.36 (m, 1 H), 2.44 (dd, J = 16, J = 5, 2 H), 2.31 (dd, J = 16, J = 8, 2 H), 1.86 (s, 3 H).
Intermediate 50: Dimethyl 3 - ({[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1,1dioxide-5-phenyl-2,3,4,5-tetrahydro-1 , 4-benzothiazepin-8-yl] methyl} amino) pentanedioate
Glacial acetic acid (420 g, 6.99 mol) was added to a stirred mixture of (3Ã, 57 ) 1,1-dioxide - 3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbaldehyde (857 g, 2.06 mol) in iPrOAc (8 1) followed by addition of the dimethyl 3aminopentanedioate acetic acid salt (645 g , 2.74 mol). Sodium triacetoxyborohydride (656 g, 3.09 mol) was added in portions over 45 min while maintaining the reaction temperature below 22 ° C. AFTER 1 h, the reaction mixture was washed with water (8 1) and 10% Na ₂ CO ₃ (8 1). The organic phase was dried over MgSO ₄ , filtered and concentrated giving dimethyl 3 ({[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-2, 3,4,5-tetrahydrol, 4-benzothiazepin-8-yl] methyl} amino) pentanedioate as an oil (1.2 kg):
NMR Ή (DMSO-d ₆ ) δ ppm 7.90 (s, 1 H), 7.42-7.34 (m, 4 H), 7.34-7.26 (m, 1 H), 6, 04 (s, 1 H), 5.91 (d, J = 9.87 Hz, 1 H), 3.67-3.53 (m, 3 H), 3.55 (s, 3 H), 3 , 54 (s, 3 H), 3.50 (d, J = 15 Hz, 1 H), 3.40 (s, 3 H), 3.23 (m, 1 H), 3.01 (d, J = 15 Hz, 1 H), 2.58-2.39 (m, 4 H), 2.03 (m, 1 H), 2.16 (br s, 1 H), 1.76-1, 66 (m, 1 H), 1.50-1.30 (m, 2 H), 1.27-0.96 (m, 4 H), 0.77 (t, J = 7.5 Hz, 3 H), 0.73 (t, J = 7.0 Hz, 3 H).
II. Preparation of compounds of the invention
Example 1: 3 - ({[(3R, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] carbonyl} amino) -2,2-dimethylpropanoic
HO
Step 1: To a DMF solution (0.5 ml) of (3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3-1,1-dioxide, 4,5-tetrahydro-1,4-benzothiazepine-8-carboxylic (0.025 g, 0.058 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (prepared as described in US-2,370,015) (0.009 g,
0.064 mmol) at 0 ° C HATU (0.024 g, 0.064 mmol) was added followed by
DIEA (0.012 ml, 0.070 mmol). The reaction was stirred for 10 min then warmed to room temperature. After 1 h the reaction was concentrated to half volume, and H ₂ O (3 ml) was added. The precipitate was filtered and dried, then used without further purification in the next step.
Step 2: The material was dissolved in THF (0.500 ml), and H ₂ O (0.250 ml) was added together with an excess of LiOH (7 mg, 0.174 mmol). The reaction was stirred at room temperature for 3 h then concentrated. The residue was purified by chromatography on silica using DCM / MeOH giving the title compound (0.020 g, 63%): NMR * H (400 MHz, CDC1 ₃ ) δ ppm 8.71 (s, 1 H) 8.13 (br. s, 1 H) 7.27-7.52 (m, 5 H) 6.21 (br. s, 1 H) 6.08 (br. s, 1 H) 3.31 3.70 (m, 7 H) 3.11 (br. S, 1 H) 2.18 (br. S., 1 H) 1.83 (br. S, 1 H) 0.99-1, 65 (m, 12 H) 0.71-0.96 (m, 6 H); LC-MS m / z 531 (M + / 7) ⁺ .
Example 2: ({[(3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] carbonyl} amino) methanesulfonic
Prepared in an analogous manner to Example 1 step 1 via HATU amide coupling using aminomethanesulfonic acid (0.013 g, 0.116 mmol) and acid 1,1-dioxide (3Ã, 5Á) -3-butyl-3-ethyl-7- (methyloxy) -5phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carboxylic (50 mg, 0.12 mmol) giving the title compound (45 mg, 73%): NMR 'Η (400 MHz, CDC1 ₃ ) δ ppm 8.47 (s, 1 H) 8.28 (partially resolved t, 7 = 5.72 Hz, 1 H) 7.47 (d, 7 = 3.62 Hz, 5 H) 6.29 (br. S, 1 H) 6.02 (br. S, 1 H) 3.43-4.72 (m, 6 H + H ₂ O) 3.22 (br. S., 1 H) 2.14 (br., 1 H) 1.80 (br., 1 H) 1.45 (br., 2 H) 0.93-1.32 (m, 5 H) 0.63-0.93 (m, 6 H); ES-LCMS m / z 525 (M + H) ⁺ .
Example 3: 2 - ({[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) trifluoroacetate
1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] carbonyl} amino) ethanesulfonic
prepared in an analogous way to Example 1 step 1 via coupling of HATU amide using taurine (0.014 g, 0.116 mmol) and acid (3Ã, 5Á) -3-butyl-3-ethyl-7- (methyloxy) -5 -phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carboxylic (0.050 g, 0.116 mmol). Purification via RP-HPLC (30x150 H ₂ O Sunfire Cl8 Column column) using MeCN / H ₂ O 10-100% with 0.1% TFA as the mobile phase over 8 min resulted in the title compound (0.015 g, 19% ): 1 H NMR (400 MHz, MeOH-J ₄ ) δ ppm 8.74 (s, 1 H) 7.48-7.72 (m, 5 H) 6.68 (s, 1 H) 6.47 (s, 1 H) 4.02 (d, 7 = 15.83 Hz, 1 H) 3.75-3.83 (m, 2 H) 3.72 (s, 3 H) 3.55 (d, 7 = 15.83 Hz, 1 H) 2.91 - 3.02 (m, 2 H) 2.77 (br. S, 1 H) 2.13 (br., 2 H) 1.66 ( s, 1 H) 1.43 (d, 7 = 6.55 Hz, 3 H) 1.02 (partially separated t, 7 = 7.48 Hz, 4 H) 0.91 (t, 7 = 7.13 Hz, 3 H); ESLCMS m / z 539 (M + H) ⁺ .
Example 4: 2,2 '- ({[(3Á, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5- hydrochloride tetrahydro-1,4-benzothiazepin-8-yl] carbonyl} imino) diacetic
HO
Prepared analogously to Example 1 via HATU amide coupling using diethyliminoacetate (0.022 g, 0.116 mmol) and acid (37 , 5 ) -3-butyl-3-ethyl-7- (methyloxy) -5- phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carboxylic (0.050 g, 0.116 mmol) followed by
LiOH (10 mg, 0.24 mmol) hydrolysis conditions giving the title compound (0.045 g, 63%): NMR Ή (400 MHz, DMSO-7 ₆ ) δ ppm 12.76 (br. S., 2 H) 7.73 (s, 1 H) 7.22-7.60 (m, 5 H) 6.15 (s, 1 H) 5.97 (br., 1 H) 4.15 (br. S ., 2 H) 3.86 (br., 2 H) 3.01-3.53 (m, 4 H + H ₂ O) 2.08 (br., 1 H) 1.66- 1.91 (m, 1 H) 0.95-1.63 (m, 7 H) 0.64-0.92 (m, 6 H); ES-LCMS m / z 547 (M + H) ⁺ .
Example 5: [(3Ã, 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro trifluoroacetate salt -1,4-benzothiazepin-8il] methanesulfonic
HO.
To a solution of (3Ã, 5Ã) -8- (bromomethyl) -3-butyl-3-ethyl-7 (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine -1.1-dioxide (0.100 g, 0.21 mmol) in 1,4-dioxane (1 ml) was added a solution of sodium sulfite (131 mg, 1.04 mmol) in H ₂ O (1 ml ). The mixture was stirred under reflux overnight, then concentrated in vacuo, and the crude reaction mixture was washed with 1N HCl. The supernatant was decanted leaving a white rubbery solid which was triturated with DCM and hexanes giving a solid which was collected via filtration. Purification was performed using HPLC prep. Agilent (Cl 8 packaging with MeCN, H ₂ O with 0.1% TF A as the mobile phase) giving the title compound (83 mg, 66%) as a trifluoroacetate salt: NMR ^! H (400 MHz, DMSO-7 ₆ ) δ ppm 8.17 (br. S., 1 H) 7.59 (br. S., 5 H) 6.33 (br. S., 2 H) 3, 14-4.46 (m, 6 H + H ₂ O) 2.02 (br. S, 2 H) 1.60 (br. S, 1 H) 1.33 (br. S, 3 H) 0 , 62-1.13 (m, 7 H); ES-LCMS m / z 482 (M + H) ⁺ . Example 6: hydrochloride salt of {[(3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetrahydro- 1,4-benzothiazepin-8-yl] methyl} phosphonic
HO Ι-
Ό
Step 1: Prepared analogously to Example 5 via alkylation using triethyl phosphite (0.352 ml, 2.01 mmol) and (37 , 52 ) - 8- (bromomethyl) -3-butyl-3-dioxide -ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.920 g, 1.92 mmol) in toluene (10 ml).
Step 2: The phosphonate ester from the previous step was dissolved in 2 ml of 6N HCl and 1 ml of EtOH, then heated to reflux for 6 h. The reaction was cooled, then concentrated. The residue was dissolved in EtOH then concentrated giving the title compound (0.86 g, 85%) as a hydrochloride salt: NMR 'H (400 MHz, MeOH-7 ₄ ) δ ppm 8.04 (d, 7 = 2 , 34 Hz, 1 H) 7.57 (s, 5 H) 6.46 (s, 1 H) 6.36 (s, 1 H) 3.79 (d, 7 = 15.51 Hz,
H) 3.58 (s, 3 H) 3.45 (d, 7 = 15.51 Hz, 1 H) 3.16-3.25 (m, 1 H) 2.99-3.12 (m,
H) 2.68 (br. S., 1 H) 1.97 (dd, 7 = 14.15, 7.12 Hz, 2 H) 1.64 (dd, 7 = 14.15, 7.32 Hz , 1 H) 1.23-1.46 (m, 3 H) 0.98 (t, 7 = 7.41 Hz, 4 H) 0.89 (t, 7 = 6.88 Hz,
H); ES-LCMS m / z 482 (M + H) ¹ .
Example 7: hydrochloride salt of 2,2 '- ({[(37', 57 ') - 3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4 , 5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} imino) diacetic
OH
Step 1: To a MeCN solution of (37 , 57 ) - 8 (bromomethyl) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepine-1,1-dioxide (77 mg, 0.16 mmol) diethyl iminodiacetic acid (33 m, 0.18 mmol) was added. The reaction mixture was heated to 65 ° C for 4 h then concentrated and concentrated to a thick oil. Chromatography on silica using hexanes / EtOAc resulted in a clear oil.
Step 2: H ₂ O and THF were added to the product from step 1 together with LiOH (15 mg, 0.36 mmol), and the mixture was stirred for 2 h at room temperature to hydrolyze the diacetic acid. The reaction mixture was concentrated to half volume, and 1 N HCl was added to acidify the reaction content, then the organics were extracted 2x DCM. The combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was triturated (DCM / EtOAc), filtered, and dried. The material was redissolved in DCM / EtOAc / MeOH, then concentrated to a solid and kept under N ₂ overnight to dry. The title compound was obtained as a hydrochloride salt as a white solid. (45 mg, 47% in 2 steps): NMR * H (400 MHz, DMSO-7 ₆ ) δ ppm 12.36 (br. S, 2 H) 8.03 (s, 1 H) 7.16- 7.55 (m, 5 H) 6.09 (s, 1 H) 5.95 (br. S, 1 H) 3.81 (br., 2 H) 3.16-3.59 ( m, 26 H) 3.07 (d, 7 = 14.83 Hz, 1 H) 2.51 (br. s., 14 H) 2.08 (br. s., 1 H) 1.75 (br s., 1 H) 0.98-1.56 (m, 8 H) 0.62-0.90 (m, 6 H); ES-LCMS m / z 533 (M + J7) ⁺ .
Example 8: (3R, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carboxamide-1,1 -dioxide
A mixture of (37 , 5R) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbonitrile-1,1-dioxide (38 mg, 0.092 mmol) and K ₂ CO ₃ (25 mg, 0.184 mmol) in DMSO ( 1 ml) was cooled to 0 ° C, and 30% w / w H ₂ O ₂ (0.016 ml, 0.153 mmol) was added by dripping. The resulting mixture was warmed to room temperature, then stirred for 2 h. H ₂ O was added, then the resulting precipitate was filtered and dried giving the title compound (40 mg, 95%): NMR Ή (400 MHz, DMSO-7 ₆ ) δ ppm 7.81 (s, 1 H) 6 , 51-6.76 (m, 5 H) 5.58 (s, 1 H) 5.31 (s, 1 H) 2.85 (s, 3 H) 2.74 (d, 7 = 14.92 Hz, 1 H) 2.36 (d, 7 = 14.92 Hz, 1 H) 1.87 (s, 2 H) 1.41-1.55 (m, 1 H) 0.96-1.13 (m, 1 H) 0.75-0.91 (m, 1 H) 0.61-0.75 (m, 1 H) 0.25-0.59 (m, 4 H) 0.13 (t , 7 = 7.37 Hz, 3 H) 0.03 (t, 7 = 6.82 Hz, 3 H); ES-LCMS m / z 431 (M + Hf.
Example 9: (2E) -3 - [(3R, 5R) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4 ammonium salt, 5-tetrahydro-1,4-benzothiazepin-8-yl] -2propenoic
HO.
To a solution of (2 £) -3 - [(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -
Ethyl 1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] -2-propenoate (300 mg, 0.618 mmol) in a 1% mixture : 1: 1 of THF / MeOH / H ₂ O (15 ml) was added lithium hydroxide (74.0 mg, 3.09 mmol), and the resulting reaction mixture was stirred at room temperature overnight other. The reaction mixture was concentrated under reduced pressure to remove organic solvents. The resulting aqueous layer was acidified to pH 1 with 1N hydrochloric acid, then the aqueous layer was extracted with DCM. The organic layer was washed with H ₂ O, saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using HPLC (eluting with MeCN / H ₂ O with 0.5% NH ₃ -H ₂ O) resulted in the title compound (201 mg, 65%, as an ammonium salt) as a white solid: NMR ^! H (MeOH-d ₄ ): δ ppm 8.06 (s, 1H), 7.27 - 7.48 (m, 5H), 6.30 (s, 1H), 6.06 (s, 1H), 4.26 (s, 2H), 3.65 (s, 1H), 3.58 (s, 3H), 3.49 (d, J = 15.0 Hz, 1H), 3.07 (d, J = 14.8 Hz, 1H), 2.52 - 2.76 (m, 4H), 2.11 - 2.28 (m, 1H), 1.69 - 1.84 (m, 1H), 1, 56 (s, 1H), 1.42 (s, 1H), 1.04 - 1.33 (m, 4H), 0.87 (t, J = 7.4 Hz,
3H), 0.78 (t, J = 6.8 Hz, 3H); ES-LCMS m / z 458 (M + H) ⁺ .
Example 10: 3 - [(37 , 5R) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] propanoic
HO.
Step 1: A mixture of (2E) -3 - [(37 , 5R) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5 ethyl tetrahydro-1,4-benzothiazepin-8-yl] -2propenoate (0.27 g, 0.556 mmol) and 10% Pd / C (0.012 g) in EtOH (10 ml) at room temperature was hydrogenated under a hydrogen atmosphere at 1 atmosphere overnight. The reaction mixture was filtered through diatomaceous earth and washed with EtOH. The filtrate was concentrated under reduced pressure giving 3 - [(37 , 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra -hydro-1,4-benzothiazepin-8il] ethyl propanoate (182 mg, 57%) as a clear oil: ES-LCMS m / z 488 (M + H) ⁺ .
Step 2: To a solution of 3 - [(3Ã, 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra- hydroxy-1,4-benzothiazepin-8-yl] propanoate (172 mg, 0.353 mmol) in a 1: 1: 2 mixture of THF / MeOH / H ₂ O (12 ml) was added lithium hydroxide ( 84 mg, 3.53 mmol). The reaction mixture was stirred at room temperature overnight, then partially concentrated under reduced pressure to remove organic solvents. The resulting aqueous layer was then acidified to pH 12 with 1N hydrochloric acid and extracted with DCM. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure giving the title compound (149 mg, 87%) as a white solid: NMR Ή (CDC1 ₃ ): δ ppm 7 , 85 (s, 1H), 7.41 (d, J = 7.0 Hz, 5H), 5.97 6.32 (m, 2H), 3.50 (s, 3H), 3.41 (d , J = 15.0 Hz, 1H), 2.78 - 2.95 (m, 2H),
2.48 - 2.66 (m, 2H), 2.09 - 2.39 (m, 1H), 1.77 - 1.97 (m, 1H), 1.13-1.38 (m,
5H), 0.98 - 1.14 (m, 1H), 0.88 (t, J = 7.3 Hz, 3H), 0.81 (t, J = 7.0 Hz, 3H);
ES-LCMS m / z 458
Example 11: 3 - [(3R, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] -jV- (methylsulfonyl) propanamide
To a solution of 3 - [(3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -
1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] propanoic (50 mg, 0.109 mmol) in a 2: 1 mixture of DCM / THF (6 ml) was added EDC (25.03 mg, 0.131 mmol), DMAP (15.95 mg, 0.131 mmol) and methanesulfonamide (12.42 mg, 0.131 mmol). The reaction mixture was stirred at room temperature overnight and partitioned between H ₂ O and DCM. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. HPLC purification (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the title compound (25 mg, 34%, TF A salt) as a white solid: NMR 'Η (CDC1 ₃ ) δ ppm 7.84 (s, 1H), 7.44 - 7.65 (m, 5H), 6.61 (s, 2H), 6.39 (s, 1H ), 3.84 (d, J = 15.6 Hz, 1H), 3.55 (s, 3H), 3.43 (d, J = 15.6 Hz, 1H), 3.27 (s, 3H ), 3.05 - 3.20 (m, 1H), 2.73 - 2.85 (m, 1H), 2.46 - 2.67 (m, 2H), 2.25 - 2.39 (m , 1H), 2.06 - 2.20 (m, 1H), 1.69 - 1.96 (m, 2H), 1.26 - 1.48 (m, 3H), 0.94 (t, J = 7.3 Hz, 3H), 0.86 (t, J = 7.0 Hz, 3H); ES-LCMS m / z 537 (M + Hf.
Example 12: 3 - [(3R, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] -7V-hydroxypropanamide
To a solution of 3 - [(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) - acid
Added 1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] propanoic (50.1 mg, 0.109 mmol) in THF (5 ml) if EDC (41.8 mg, 0.218 mmol), DMAP (39.9 mg, 0.327 mmol) and hydroxylamine hydrochloride (37.9 mg, 0.545 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was partitioned between H ₂ O and DCM and the organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. HPLC purification (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the title compound (24 mg, 35%, TFA salt) as a solid white: NMR ^] Η (CDC1 ₃ ): δ ppm 7.74 - 7.85 (m, 1H), 7.40 - 7.68 (m, 5H), 6.60 (s, 1H), 6.39 (s, 1H), 3.84 (d, J = 15.4 Hz, 1H), 3.51 - 3.63 (m, 3H), 3.46 (d, J = 15.4 Hz, 1H) , 2.84 - 3.05 (m, 1H), 2.45 - 2.79 (m, 2H), 2.23 - 2.42 (m, 1H), 1.69 - 2.23 (m, 4H), 1.28 - 1.52 (m, 3H), 0.92 - 1.13 (m, 4H), 0.76 - 0.92 (m, 3H); ES-LCMS m / z 475 (M + Hf.
Example 13: ({3 - [(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1-acid , 4-benzothiazepin-8-yl] propanoyl} amino) methanesulfonic
O
To a solution of 3 - [(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) 1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1 acid , 4-benzothiazepin-8-yl] propanoic (50 mg, 0.109 mmol) in a 2: 1 mixture of DCM / THF (6 ml) was added EDC (62.6 mg, 0.326 mmol), DMAP (39, 9 mg, 0.326 mmol) and EDC (62.6 mg, 0.326 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between H ₂ O and DCM. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. HPLC purification (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the title compound (11.4 mg, 18%, TF A salt) as a white solid: NMR ^! H (CDC1 ₃ ) δ ppm 7.85 (s, 1H), 7.35 - 7.77 (m, 5H), 6.51 (d, J = 8.1 Hz, 2H), 3.85 (d , J = 15.2 Hz, 2H), 3.67 (s, 3H), 3.21 - 3.50 (m, 2H), 2.92 (br. S, 1H), 2.58 - 2 , 80 (m, 2H), 2.12 - 2.52 (m, 2H), 1.69 - 1.97 (m, 2H), 1.31 (m, 3H), 0.63 - 0.99 (m, 6H); ES-LCMS m / z 553 (M + H) ⁺ .
Example 14: N- {3 - [(3R, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] propanoyl} glycine
HO.
Step 1: To a solution of 3 - [(37 , 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5- tetrahydro-1,4-benzothiazepin-8-yl] propanoic (50 mg, 0.109 mmol) in DCM (4 ml) DIPEA (0.095 ml, 0.544 mmol), HATU (124 mg, 0.326 mmol) and hydrochloride were added glycine methyl ester (19.39 mg, 0.218 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between H ₂ O and DCM. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification on silica gel (MeOH: DCM - 0: 100 to 10:90) resulted in A- {3 - [(37 , 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] propanoyl} methyl glycinate (45 mg, 76%) as a clear oil: ES-LCMS m / z 531
Step 2: To a solution of N- {3 - [(3Ã, 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5 methyl tetrahydro-1,4-benzothiazepin-8-yl] propanoyl} glycinate (43 mg, 0.081 mmol) in a 2: 1: 1 mixture of THF / MeOH / H ₂ O (8 ml) was added if lithium hydroxide (1.941 mg, 0.081 mmol). The reaction mixture was stirred at room temperature overnight, then partially concentrated to remove organic solvents. The resulting aqueous layer was diluted with H ₂ O and acidified to pH 1 with 1N hydrochloric acid. The aqueous layer was extracted with DCM. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification on silica gel (MeOH: DCM = 0: 100 to 10:90) resulted in the title product (21 mg, 47%) as a white solid: NMR Ή (CDC1 ₃ ) δ ppm 7.83 (s, 1H) , 7.31 - 7.62 (m, 5H), 6.02 - 6.37 (m, 3H), 3.89 (br. S., 2H), 3.49 (s, 3H), 3, 34 - 3.44 (m, 1H), 3.14 - 3.33 (m, 1H), 3.02 (d, J = 6.8 Hz, 1H), 2.70 - 2.90 (m, 1H), 2.27 - 2.66 (m, 3H), 1.76 -
1.96 (m, 1H), 0.49 - 0.93 (m, 13H); ES-LCMS m / z 515
Example 15: 2 - ({3 - [(3Ã, 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4 trifluoroacetate salt , 5-tetrahydro-1,4-benzothiazepin-8yl] propanoyl} amino) ethanesulfonic
To a solution of 3 - [(37 , 5Ã) -3-butyl-3-ethyl-7- (methyloxy) - acid
1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] propanoic (50 mg, 0.109 mmol) in a 2: 1 mixture of DCM / THF (6 ml) was added EDC (25.03 mg, 0.131 mmol), DMAP (15.95 mg, 0.131 mmol) and taurine (16.34 mg, 0.131 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between H ₂ O and DCM. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. HPLC purification (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the title compound (4.6 mg, 7%, TF A salt) as a white solid: NMR ^] H (CDCl ₃ ) δ ppm 7.40 - 8.17 (m, 6H), 6.59 (br. s., 1H), 6.46 (br. s., 1H) , 5.79
6.18 (m, 1H), 3.05 - 4.00 (m, 7H), 1.68 - 2.97 (m, 12H), 1.34-1.38 (m, 3H), 0, 62 - 1.12 (m, 6H); ES-LCMS m / z 567 (M + Hf.
Example 16: 7V- {3 - [(37 , 5A) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] propanoyl} -2-methylalanine
HO.
Step 1: To a solution of 3 - [(37 , 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra acid -hydro-1,4-benzothiazepin-8-yl] propanoic (50 mg, 0.109 mmol) in DCM (4 ml) was added DIPEA (0.057 ml, 0.326 mmol), HATU (62.0 mg, 0.163 mmol) and methyl alfaaminoisobutyrate hydrochloride (20.05 mg, 0.131 mmol). The reaction mixture was stirred at room temperature overnight and partitioned between H ₂ O and DCM. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (MeOH: DCM = 0: 100 to 10:90) resulted in methyl N- {3 - [(3Á, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -
1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] propanoyl} -2methylalaninate (56.8 mg, 89%) as a clear oil: ES-LCMS m / z 559
Step 2: To a solution of methyl N- {3 - [(3A, 57 ) - 3-butyl-3-ethyl7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5 -tetrahydro-1,4-benzothiazepin-8-yl] propanoyl} -2-methylalaninate (54 mg, 0.097 mmol) in a 2: 1: 1 mixture of THF / MeOH / H ₂ O (8 ml) added lithium hydroxide (23.15 mg, 0.966 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure to remove organic solvents. The resulting aqueous layer was diluted with H ₂ O and acidified to pH 1 with 1N hydrochloric acid. The aqueous layer was extracted with DCM. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (MeOH: DCM = 0: 100 to 10:90) resulted in the title compound (40 mg, 72%) as a white solid: NMR 'Η (CDC1 ₃ ) δ ppm 7.82 (s, 1H ), 7.29 7.55 (m, 5H), 6.11 (s, 1H), 6.01 (s, 1H), 5.87 (s, 1H), 3.48 (s, 3H), 3.38 (d, J = 14.8 Hz, 2H), 3.06 (d, J = 14.8 Hz, 2H), 2.84 - 2.99 (m, 3H), 2.78 (s , 1H), 2.37 - 2.55 (m, 2H), 2.17 (br. S., 1H), 1.83 (d, J = 4.0 Hz, 1H), 1.51 (s , 3H), 1.48 (s, 3H), 1.00 - 1.34 (m, 9H), 0.86 (t, J = 7.3 Hz, 3H), 0.80 (t, J = 7.1 Hz, 4H); ES-LCMS m / z 545 (M + //) ⁺ ·
Example 17: 3 - ({3 - [(3R, 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4 trifluoroacetate salt , 5-tetrahydro-1,4-benzothiazepin-8il] propanoyl} amino) pentanedioic
HO, C.
HO.
Step 1: To a solution of 3 - [(3Ã, 5J ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra -hydro-1,4-benzothiazepin-8-yl] propanoic (100 mg, 0.218 mmol) in DCM (6 ml) was added DIPEA (0.190 ml, 1.088 mmol) and ELATU (165 mg, 0.435 mmol). The reaction mixture was stirred at room temperature for 20 min, then treated with diethyl 3-aminopentanedioate (66.3 mg, 0.326 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure. Purification on silica gel (EtOAcrhexanes = 1: 3 to 3: 1) resulted in diethyl 3 - ({3 - [(37 , 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -l, 1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8yl] propanoyl} amino) pentanedioate (137 mg, 96%) as a colorless oil: ESLCMS m / z 645 (M + / 7) ⁺ .
Step 2: To a solution of diethyl 3 - ({3 - [(3Ã, 57 ) - 3-butyl-3-ethyl7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4, 5-tetrahydro-1,4-benzothiazepin-8-yl] propanoyl} amino) pentanedioate (137mg, 0.212mmol) in a mixture
1: 1: 1 THF / MeOH7H ₂ O (6 ml) was added lithium hydroxide (25.4 mg, 1.062 mmol). The reaction mixture was stirred at room temperature overnight, acidified with acetic acid at pH 3-4, and concentrated under reduced pressure. Purification by means of RP-HPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the title product (92 mg, 60%, TF salt A) as white solid: NMR ^] H (MeOH-d ₄ ) δ ppm 7.90 (s, 1H), 7.48 - 7.62 (m, 5H), 6.44 (s, 1H), 6, 37 (s, 1H), 4.33 - 4.48 (m, 1H), 3.81 (d, J = 15.6 Hz, 1H), 3.57 (s, 3H), 3.46 (d , J = 15.6 Hz, 2H), 2.78 - 3.03 (m, 2H), 2.60 - 2.75 (m, 1H), 2.48 - 2.58 (m, 4H), 2.37 - 2.46 (m, 2H), 1.86 - 2.13 (m, 2H), 1.49 - 1.67 (m, 1H), 1.33-1.39 (m, 3H ), 0.96 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.0 Hz, 3H); ES-LCMS m / z 589 (Àf + / 7) ⁺ ·
Example 18: 2,2 '- ({3 - [(3Ã, 5Á) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide5-phenyl-2,3,4,5- tetrahydro-1,4-benzothiazepin-8-yl] propanoyl} imino) diacetic
HO.
HO.
Step 1: To a solution of 3 - [(3Ã, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepin-8-yl] propanoic (50 mg, 0.109 mmol) in a 2: 1 mixture of DCM / THF (6 ml) was added DMAP (39.9 mg, 0.326 mmol), EDC (62.6 mg, 0.326 mmol) and 2,2'-iminodiacetate diethyl (41.2 mg, 0.218 mmol). The reaction mixture was stirred at room temperature overnight, then partitioned between H ₂ O and DCM. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (EtOAc: hexanes = 10:90 to 50:50) resulted in diethyl 2,2 '- ({3 [(3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-2,3,4,5-tetrahydrol, 4-benzothiazepin-8-yl] propanoyl} imino) diacetate (44.8 mg, 65%) as a clear oil: ES-LCMS m / z 631 (M + H) ⁺ .
Step 2: To a solution of diethyl 2,2 '- ({3 - [(3Ã, 57 ) - 3-butyl-3ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3 , 4,5-tetrahydro-1,4-benzothiazepin-8yl] propanoyl} imino) diacetate (44.8 mg, 0.071 mmol) in a 1: 1: 1 mixture of THF / MeOH / H ₂ O (9 ml) lithium hydroxide (85 mg, 3.55 mmol) was added. The reaction mixture was stirred at room temperature overnight, acidified with 1N hydrochloric acid at pH 1 and concentrated under reduced pressure. Purification with HPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the title product (23 mg, 53%, TF A salt) as a white solid: NMR Ή (CDC1 ₃ ) δ ppm 7.84 (s, 1H), 7.61 - 7.75 (m, 2H), 7.37 - 7.59 (m, 3H), 6.54 ( br., 1H), 6.42 (s, 1H),
3.96 - 4.25 (m, 2H), 3.72 - 3.88 (m, J = 8.6 Hz, 2H), 3.23 - 3.70 (m, 11H),
2.97 - 3.13 (m, 1H), 2.50 - 2.95 (m, 2H), 2.31 - 2.48 (m, J = 14.1 Hz, 1H), 1.69 - 2, 09 (m, 3H), 0.55 - 1.45 (m, 8H); ES-LCMS m / z 575 (M + H /.
Example 19: 3 - [(37 , 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] -1 -propanol
To an ice-cold solution of 3 - [(3Ã, 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro -1,4-benzothiazepin-8il] propanoic (100 mg, 0.218 mmol) in THF (5 ml) borane-THF complex (0.653 ml, 0.653 mmol) was added. The reaction mixture was stirred at room temperature overnight, then quenched by dropping MeOH. The reaction mixture was stirred for 30 min, then concentrated under reduced pressure. The residue was taken up with MeOH and evaporated again under reduced pressure. The residue was purified using silica gel (MeOH: DCM = 0: 100 to 10:90) resulted in the title compound (96 mg, 94%) as a colorless oil: NMR 'Ή (CDC1 ₃ ) δ ppm 7.84 ( s, 1H),
7.26 - 7.48 (m, 5H), 6.11 (s, 1H), 6.01 (s, 1H), 3.58 (t, J = 6.2 Hz, 2H), 3.48 (s, 3H), 3.40 (d, J = 14.8 Hz, 1H), 3.00 (d, J = 14.8 Hz, 1H), 2.56 - 2.75 (m, 2H) , 2.02 - 2.25 (m, 1H), 1.69 - 1.92 (m, 3H), 0.99 - 1.52 (m, 14H), 0.86 (t, J = 7, 3 Hz, 3H), 0.80 (t, J = 7.0 Hz, 3H); ES-LCMS m / z 446 (M + H) ⁺ .
Example 20: 3 - [(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] -1-propanesulfonic
To a solution of (3Ã, 57 ) - 8- (3-bromopropyl) 3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5- tetrahydro-1,4-benzothiazepine (70 mg, 0.138 mmol) in a 1: 1 mixture of EtOH / H ₂ O (10 ml) was added sodium sulfite (868 mg, 6.88 mmol). The reaction mixture was stirred at reflux overnight, cooled to room temperature, and partially concentrated under reduced pressure to remove organic solvents. Then the aqueous layer was acidified to pH 1 with 1N hydrochloric acid. The aqueous layer was extracted with DCM. The combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification on silica gel (MeOH: DCM = 0: 100 to 20:80) resulted in the title compound (27.2 mg, 38%) as a white solid: NMR ^! H (CDC1 ₃ ) δ ppm (br. S., 1H), 7.16 - 7.60 (m, 5H), 6.06 (br. S., 2H), 2.33 - 3.63 (m , 14H), 0.47 - 2.26 (m, 12H); ES-LCMS m / z 510 (M + H) ⁺ .
Example 21: {3 - [(3Ã, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra trifluoroacetate salt -hydro-1,4-benzothiazepin-8il] propyl} phosphonic
Step 1: To a solution of diethylphosphite (119 mg, 0.859 mmol) in THF (5 ml) was added sodium hydride (27.5 mg, 0.687 mmol). The reaction mixture was stirred for 30 min, followed by drip addition of 3 - [(3Ã, 5Á) -3-butyl-3-ethyl-7- (methyloxy) 1,1-dioxide-5-phenyl- methanesulfonate 2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] propyl (90 mg, 0.172 mmol) in THF (5 ml). The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure. The residue was partitioned between 1N hydrochloric acid and EtOAc. The organic layer was washed with saturated brine, dried (Na ₂ SO4), filtered, and concentrated under reduced pressure. Purification using silica gel (EtOAc: hexanes = 10:90 to 100: 0) resulted in diethyl {3 - [(37 , 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1,1 -dioxide5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] propyl} phosphonate (55 mg, 53%) as a white solid: ES-LCMS m / z 566 ( M + H) ⁺ .
Step 2: To a solution of diethyl {3 - [(3Á, 5R) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra -hydro-1,4-benzothiazepin-8iljpropyl} phosphonate (50 mg, 0.088 mmol) in DCM (5 ml) was added bromotrimethylsilane (0.115 ml, 0.884 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure. Purification by RP-HPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the title compound (25 mg, 43%, TF salt A) as a white solid: NMR 'H (MeOH-d ₄ ) δ ppm 7.90 (s, 1H), 7.39 - 7.60 (m, 5H), 6.42 (s, 1H), 6 , 32 (s, 1H), 3.79 (d, J = 15.6 Hz, 1H), 3.55 (s, 3H), 3.37 (d, J = 15.6 Hz, 1H), 2 , 73 (t, J = 7.4 Hz, 2H), 2.51 - 2.66 (m, 1H), 1.75 - 2.10 (m, 4H), 1.48 - 1.72 (m , 3H), 1.20 - 1.45 (m, 3H), 0.99 - 1.13 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H), 0.86 ( t, J = 7.0 Hz, 3H); ES-LCMS m / z 510 (M + H) ⁺ .
Example 22: 2 - ({3 - [(3Ã, 5Á) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4, trifluoroacetate salt 5-tetrahydro-1,4-benzothiazepin-8-
To a solution of 3 - [(3Ã, 5Ã) -3-butyl-3ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1 methanesulfonate , 4-benzothiazepin-8il] propyl (90 mg, 0.172 mmol) in DMF (5 ml) was added potassium carbonate (238 mg, 1.719 mmol) and taurine (108 mg, 0.859 mmol). The reaction mixture was stirred at 60 ° C overnight, cooled to room temperature, acidified with 1N hydrochloric acid at pH 1 and concentrated under reduced pressure. Purification by means of RP-HPLC (eluting with MeCN7H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the title compound (22 mg, 15%, TF A salt) as a white solid: NMR ^Γ Η (MeOH-d ₄ ) δ ppm 7.42 - 7.65 (m, 5H), 6.48 (s, 1H), 6.34 (s, 1H), 3.77 (d, J = 15.4 Hz, 1H), 3.58 (s, 3H), 3.47 (d, J = 15.6 Hz, 1H), 2.95 - 3.12 (m, 4H) , 2.51 - 2.88 (m, 3H), 1.84 - 2.11 (m, 4H), 1.54 - 1.69 (m, 7.4 Hz, 1H), 1.23 1, 45 (m, 3H), 1.00 - 1.10 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H ); ES-LCMS m / z 553 (M + //) ⁺ .Example 23: acid trifluoroacetate salt 4 - [(37 ', 57') - 3-butyl-3-ethyl-7- (methyloxy) -1, l -dioxide-5-phenyl-2,3,4,5-tetrahydrol, 4-benzothiazepin-8-yl] butanoic
A mixture of 4 - [(37 ', 57') - 3-butyl-3-ethyl-7- (methyloxy) -l, ldioxide-5-phenyl-2,3,4,5-tetrahydro-1, 4-benzothiazepin-8-yl] butanonitrile (40 mg, 0.088 mmol) and 37% hydrochloric acid (4 ml) was stirred at 100 ° C overnight, cooled to room temperature and concentrated under reduced pressure. MeOH was added to transfer the residue to a flask, and the solution was concentrated under reduced pressure. Purification by means of RPHPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFAMeCN) resulted in trace amounts of the desired acid. Most of it was the acid methyl ester, which was hydrolyzed in the presence of excess lithium hydroxide. Purification by means of RP-HPLC (MeCN / H ₂ 0 with 0.05% TF A) resulted in the title compound (10 mg, 18%, TF A salt) as a white solid: NMR Ή (CDC1 ₃ ) δ ppm 7.87 (s, 1H), 7.41 - 7.65 (m, 5H), 6.59 (s, 1H), 6.32 (s, 1H), 3.65 (d, J = 15 , 6 Hz, 1H), 3.45 (d, J = 15.4 Hz, 1H), 2.83 - 2.97 (m, 1H), 2.40 - 2.66 (m, 2H), 2 , 26 - 2.38 (m, 1H), 1.62 - 2.25 (m, 5H), 1.26 - 1.47 (m, 3H), 0.96 (t, J = 7.4 Hz , 4H), 0.86 (t, J = 7.0 Hz, 3H); ESLCMS m / z
474
Example 24: 4 - [(3Ã, 5Á) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra- trifluoroacetate salt hydro-1,4-benzothiazepin-8il] butanamide
To a solution of 4 - [(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetrahydro-1,4 -benzothiazepin-8-yl] butanonitrile (40 mg, 0.088 mmol) in DMSO (4 ml) potassium carbonate (48.6 mg, 0.352 mmol) was added. The reaction flask was immersed in a bath of H ₂ O ice cream, and hydrogen peroxide (0.449 ml, 4.40 mmol) was added by dripping. The reaction mixture was warmed to room temperature and stirred for 2 h. H ₂ O was added, and the solids collected by filtration. Purification by means of RP-HPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the title compound (32 mg, 58%, TFA salt ) as a white solid: 1 H NMR (MeOH-d ₄ ) δ ppm 7.76 (s, 1H), 7.25 - 7.51 (m, 5H), 6.17 (s, 1H), 6, 01 (s, 1H), 3.40 - 3.55 (m, 4H), 3.06 (d, J = 14.8 Hz, 1H), 2.48 - 2.69 (m, 2H), 2 , 07 - 2.29 (m, 3H), 1.67 - 1.91 (m, 3H), 1.49 - 1.64 (m, 1H), 1.35 - 1.48 (m, 1H) , 0.99 - 1.34 (m, 5H), 0.86 (t, J = 7.4 Hz, 3H), 0.78 (t, J = 6.8 Hz, 3H); ES-LCMS m / z 475 (Àf + / 7) ⁺ .
Example 25: A - {[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} glycine
Step 1: To a (3R, 5R) -3-butyl-3ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-dioxide solution -benzothiazepine-8-carbaldehyde (8.35 g, 20.09 mmol) in DCE (300 ml) 1.1-dimethylethyl glycinate (3.95 g, 30.1 mmol) and acetic acid (5.75 ml) were added , 100 mmol). The reaction mixture was stirred at room temperature for 1 h, then treated with NaHB (OAc) ₃ (10.65 g, 50.2 mmol). The reaction mixture was stirred at room temperature for 1 h, then treated with aqueous sodium carbonate solution and stirred for 1 h. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with H ₂ O, saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (EtOAc / hexanes = 20:80 to 60:40) resulted in 1,1-dimethylethyl N - {[(3R, 5Ã) -3butyl-3-ethyl-7- (methyloxy) -1.1 -dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4benzothiazepin-8-yl] methyl} glycinate (8.0 g, 71%) as a white solid; NMR Ή (CDC1 ₃ ) δ ppm 7.98 (s, 1H), 7.30 - 7.48 (m, 5H), 6.17 (s, 1H), 6.08 (s, 1H), 3, 78 (s, 2H), 3.54 (s, 3H), 3.43 (d, J = 14.9 Hz, 1H), 3.29 (d, J = 2.0 Hz, 2H), 3, 03 (d, J = 14.7 Hz, 1H), 2.10 - 2.24 (m, 1H), 1.78 - 1.92 (m, 2H),
1.39 - 1.57 (m, 12H), 1.03 - 1.38 (m, 5H), 0.90 (t, J = 7.4 Hz, 3H), 0.84 (t, J = 7.0 Hz, 3H); ES-LCMS m / z 531 (M + H /.
Step 2: To a mixture of 1,1-dimethylethyl N - {[(37 , 57 ) - 3-butyl3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3, 4,5-tetrahydro-1,4-benzothiazepin8-yl] methyl} glycinate (6.7 g, 12.62 mmol) in 1,4-dioxane (5 ml) was added 4N hydrogen chloride in 1, 4-dioxane (95 ml, 379 mmol). The reaction mixture was stirred at room temperature for 16 h, then concentrated. The residue was taken up in H ₂ O (200 ml), and the solution was adjusted to pH 4-5 with acetic acid. The white precipitate was collected via filtration. Acetonitrile was added, and the mixture was heated to reflux to dissolve all the solids, cooled to room temperature and stored for 2 days without crystals. The solution was then evaporated under reduced pressure until solids precipitated out of the solution. The mixture was then heated to dissolve all the solids, then allowed to stand for 30 min. Solids were collected by means of multiple filtrations, combined, and dried under high vacuum at 50 ° C for 3 h giving the title compound (5.0 g, 82%) as a white solid: NMR Ή (MeOH-d ₄ ) δ ppm 8.06 (s, 1H), 7.25 - 7.50 (m, 5H), 6.30 (s, 1H), 6.06 (s, 1H), 4.22 (s, 2H), 3.58 (s, 3H), 3.50 (d, J = 14.8 Hz, 1H), 3.42 (s, 2H), 3.08 (d, J = 15.0 Hz, 1H), 2.12 - 2.31 (m, 1H), 1.67 - 1.86 (m, 1H), 1.49 - 1.64 (m, 1H), 1.34 - 1.48 (m, 1H ), 1.01 - 1.34 (m, 4H), 0.87 (t, J = 7.4 Hz, 3H), 0.78 (t, J = 6.8 Hz, 3H); ES-LCMS m / z 475 (M + H) ⁺ .
Example 26: 3 - ({[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) 1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro- 1,4-benzothiazepin-8il] methyl} amino) pentanedioic ho ₂ c
Method 1, Step 1: To a solution of 1,1-dioxide (3Ã, 5Ã)
3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8carbaldehyde (683 mg, 1.644 mmol) in 1,2-dichloroethane (20 ml) diethyl 3-aminopentanedioate (501 mg, 2.465 mmol) and acetic acid (0.188 ml, 3.29 mmol) were added. The reaction mixture was stirred at room temperature for 1 h, then treated with NaHB (OAc) ₃ (697 mg, 3.29 mmol). The reaction mixture was then stirred at room temperature overnight and quenched with aqueous solution of potassium carbonate. The mixture was extracted with DCM. The combined organic layers were washed with H ₂ O, saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure giving diethyl 3 - ({[(3Ã, 57 ) - 3-butyl-3-ethyl -7- (methyloxy) -1, 1-dioxide-5phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} amino) pentanedioate (880 mg, 88%) as a light yellow oil: MS-LCMS m / z 603 (M + H) ⁺ .
Method 1, Step 2: To a solution of diethyl 3 - ({[(37 , 57 ) - 3butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3, 4,5-tetrahydro-1,4benzothiazepin-8-yl] methyl} amino) pentanedioate (880 mg, 1.460 mmol) in a 1: 1: 1 mixture of THF / MeOH / H ₂ O (30 ml) added lithium hydroxide (175 mg, 7.30 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure. H ₂ O and MeCN were added to dissolve the residue. The solution was acidified with acetic acid at pH 4-5, partially concentrated to remove MeCN under reduced pressure, and allowed to rest for 30 min. The white precipitate was collected by filtration and dried under reduced pressure at 50 ° C overnight giving the title compound (803 mg, 100%) as a white solid: NMR Ή (MeOH-d ₄ ) δ ppm 8.05 (s, 1H), 7.27 - 7.49 (m, 5H), 6.29 (s, 1H), 6.06 (s, 1H), 4.25 (s, 2H), 3 , 60 - 3.68 (m, 1H), 3.58 (s, 3H), 3.47 (d, J = 14.8 Hz, 1H), 3.09 (d, J = 14.8 Hz, 1H), 2.52 - 2.73 (m, 4H), 2.12 - 2.27 (m, 1H), 1.69 - 1.84 (m, 1H), 1.48 - 1.63 ( m, 1H), 1.05 - 1.48 (m, 5H), 0.87 (t, J = 7.4 Hz, 3H), 0.78 (t, J = 7.0 Hz, 3H); ES-LCMS m / z 547 (M + Hf.
Method 2: A solution of dimethyl 3 - ({[(3Ã, 5Ã) -3-butyl-3-ethyl90
7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) pentanedioate (~ 600 g) in THF (2 , 5 1) and MeOH (1.25 1) was cooled in an ice bath and a solution of NaOH (206 g, 5.15 mol) in water (2.5 1) was added by dripping over 20 min (10-22 ° C reaction temperature). After stirring 20 min, the solution was concentrated (to remove THF / MeOH) and acidified to pH ~ 4 with concentrated HCl. The precipitated product was aged with stirring, collected by filtration and dried in air overnight. A second batch of 600 g of dimethyl 3 - ({[(37 , 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} amino) pentanedioate was saponified in a similar manner. The combined crude products (~ 2 mol, theoretical) were suspended in CH ₃ CN (8 1) and water (4 1) and the stirred mixture was heated to 65 ° C. A solution was formed which was cooled to 10 ° C over 2 h while seeding a few times with an authentic sample of the desired crystalline product. The resulting slurry was stirred at 10 ° C for 2 h, and the solid was collected by means of filtration. The filter cake was washed with water and air dried overnight. Additional drying at constant weight in a vacuum oven at 55 ° C resulted in acid 3 ({[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5- phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} amino) crystalline pentanedioic as a white solid (790 g).
Method 3: (3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) 5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide -8-carbaldehyde (1802 grams, 4.336 mol) and dimethyl 3-aminopentanedioate (1334 grams, 5.671 mol) were taken into iPrOAc slurry (13.83 kg). A nitrogen atmosphere was applied to the reactor. Glacial acetic acid (847 ml, 14.810 mol) was added to the slurry at 20 ° C, and the mixture was stirred until complete dissolution was observed. Then solid sodium triacetoxyborohydride (1424 grams, 6.719 mol) was added to the reactions over a 7 minute period. The reaction was maintained at 20 ° C for a total of 3 hours, at which time analysis by LC of a sample indicated the complete consumption of (3Ã, 5Ã) -3-butyl-3-ethyl- 1,1-dioxide 7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbaldehyde. Then, water (20.36 kg) and brine (4.8 kg) were added to the reactor. The reactor contents were stirred for 10 minutes and then allowed to rest for 10 minutes. The aqueous bottom layer was then removed and discarded. A previously prepared 10% (w / w) aqueous sodium bicarbonate solution (22.5 l) was added to the reactor. The contents were stirred for 10 minutes and then allowed to rest for 10 minutes. The aqueous bottom layer was then removed and discarded. A second wash of 10% (weight / weight) of aqueous sodium bicarbonate (22.5 l) was added to the reactor. The reactor content was stirred for 10 minutes and allowed to rest for 10 minutes. The aqueous bottom layer was then removed and discarded. The reactor contents were then reduced to an oil under vacuum distillation. THF (7.15 kg) and MeOH (3.68 kg) were added to the oil. The reactor contents were heated to 55 ° C and stirred vigorously until complete dissolution was observed. The reactor contents were then cooled to 25 ° C after which a previously prepared aqueous NaOH solution [6.75 kg of water and 2.09 kg of NaOH (50% weight / weight solution)] was added with application of cooling on the shirt. The reactor content was kept below 42 ° C during the addition of the NaOH solution. The temperature was readjusted to 25 ° C after the addition of NaOH, and the reaction was stirred for 75 minutes before HPLC analysis to indicate that the reaction was complete. Heptane (7.66 kg) was added to the reactor, and the contents were stirred for 10 minutes and then allowed to rest for 10 minutes. The aqueous layer was collected in a bottle of clean nalgene. The heptane layer was removed from the reactor and discarded. The aqueous solution was then returned to the reactor, and the reactor was prepared for vacuum distillation. Approximately 8.5 liters of distillate was collected during vacuum distillation. The vacuum was released from the reactor, and the temperature of the contents was readjusted by 25 ° C. A 1N HCl solution (30.76 kg) was added to the reactor over a period of 40 minutes. The resulting slurry was stirred at 25 ° C for 10 hours, then cooled to 5 ° C over a period of 2 hours. The slurry was kept at 5 ° C for 4 hours before the product was collected in a filter cartridge by means of vacuum filtration. The filter cake was then washed with cold water (5 ° C) (6 kg). The product cake was air-dried in the filter cartridge under vacuum for approximately 72 hours. The product was then transferred to the three trays and dried in a vacuum oven at 50 ° C for 79 hours. The temperature of the vacuum oven was then raised to 65 ° C for an additional 85 hours. The product was refilled as a single batch giving 2568 grams (93.4% yield) of acid 3 ({[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} amino) pentanedioid of intermediate grade as an off-white solid.
3 - ({[(3Ã, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-acid benzothiazepin-8-yl] methyl} amino) intermediate grade pentanedioic was dissolved (4690 g) in a mixture of glacial acetic acid (8850 g) and purified water (4200 g) at 70 ° C. The resulting solution was transferred through a 5 micron polishing filter while maintaining the temperature above 30 ° C. The reactor and filter were rinsed with a mixture of glacial acetic acid (980 g) and purified water (470 g). The temperature of the solution was adjusted to 50 ° C. Filtered purified water (4230 g) was added to the solution. The cloudy solution was then seeded with 3 ({[(37 , 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5 -tetrahydro-1,4-benzothiazepin-8-yl] methyl} amino) crystalline pentanedioic (10 g). While maintaining the temperature at 50 ° C, purified filtered water was charged to the slurry at a controlled rate (11030 g over 130 minutes). More filtered purified water was then added to the slurry at a faster controlled rate (20740 g over 100 minutes). A final load of purified filtered water (3780 g) was carried out on the slurry. The slurry was then cooled to 10 ° C at a linear rate over 135 minutes. The solids were filtered over shark skin filter paper to remove the mother liquor. The cake was then rinsed with filtered ethyl acetate (17280 g), then the washing liquors were removed by filtration. The resulting wet cake was isolated on trays and dried under vacuum at 50 ° C for 23 hours. The temperature was then raised to 60 ° C and drying was continued for another 24 hours giving 3 - ({[(3Ã, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide- 5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) crystalline pentanedioic (3740 g, 79.7% yield) as a white solid.
A slurry of this 3 - ({[(32 , 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra acid -hydro-1,4-benzothiazepin-8yljmethyl} amino) crystalline pentanedioic (3660 g) and filtered purified water (3.6 l) filtered glacial acetic acid (7530 g) was added. The temperature was raised to 60 ° C and full dissolution was observed. The temperature was reduced to 55 ° C, filtered, and treated with purified water (3.2 l). The solution was then seeded with 3 - ({[(3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetra acid -hydro-1,4-benzothiazepin-8yl] methyl} amino) crystalline pentanedioic (18 g) giving a slurry. Filtered purified water was loaded into a slurry at a controlled rate (9 1 over 140 minutes). More filtered purified water was added, then this was added to the slurry at a faster controlled rate (181 over 190 minutes). The slurry was then cooled to 10 ° C at a linear rate for 225 minutes. The solids were filtered over shark skin filter paper to remove the mother liquor. The cake was then rinsed with filtered purified water (18 1), and the washing liquors were removed by filtration. The resulting wet cake was isolated on trays and dried under vacuum at 60 ° C for 18.5 hours giving an acid 3 ({[(37 , 5Á) -3-butyl-3-ethyl-7- (methyloxy) -1 , 1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} amino) crystalline pentanedioic (3330 g, 90.8% yield) as a white solid that was analyzed for crystallinity as summarized below.
Example 27: 2V acid trifluoroacetate salt - {[(3R, 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5- tetrahydro-1,4-benzothiazepin-8il] methyl} -L-aspartic
/
Step 1: To a solution of (3Ã, 5Ã) -3-butyl-3ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-dioxide -benzothiazepine-8-carbaldehyde (33 mg, 0.079 mmol) in 1,2-dichloroethane (3 ml) dimethyl Laspartate (12.80 mg, 0.079 mmol) and NaHB (OAc) ₃ (33.7 mg, 0.159) were added mmol). The reaction mixture was stirred at room temperature overnight, then treated with an aqueous solution of potassium carbonate. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with H ₂ O, saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification by RP-HPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) twice resulted in dimethyl N - {[(3Ã, 5Ã) -3-butyl-3-ethyl7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} -L-aspartate ( 21 mg, 46%) as a colorless oil: ES-LCMS m / z 561
Step 2: To a solution of dimethyl N - {[(37 , 5R) -3-butyl-3-ethyl
7- (methyloxy) -1, 1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} -L-aspartate (21 mg, 0.037 mmol) in a 1: 1: 1 mixture of THF / MeOH / H ₂ O (3 ml) was added lithium hydroxide (17.94 mg, 0.749 mmol). The reaction mixture was stirred at room temperature overnight, treated with trifluoroacetic acid, and concentrated to 1 ml. Purification by RP-HPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the title compound (25.4 mg, 89%, salt of TF A) as a white solid: NMR ^] H (MeOH-d ₄ ) δ ppm 8.10 (s, 1H), 7.32 - 7.56 (m, 5H), 6.40 (s, 1H) , 6.17 (s, 1H), 4.38 (d, J = 7.6 Hz, 2H), 4.19 (dd, J = 6.8, 4.3 Hz, 1H), 3.55 - 3.66 (m, 4H), 3.23 (d, J = 15.0 Hz, 1H), 2.88 - 3.13 (m, 2H), 2.38 (d, J = 4.1 Hz , 1H), 1.79 - 1.95 (m, 1H), 1.62 - 1.77 (m, 1H), 1.42 - 1.58 (m, 1H), 1.03 - 1.40 (m, 4H), 0.91 (t, J = 7.4 Hz, 3H), 0.81 (t, J = 6.8 Hz, 3H); ES-LCMS m / z 533 (M + Ηγ.
Example 28: A - {[(3Ã, 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5- trifluoroacetate salt tetrahydro-1,4-benzothiazepin-8il] methyl} -D-aspartic
Step 1: To a solution of 1,1-dioxide (37 , 57 ) - 3-butyl-3 ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro- 1,4-benzothiazepine-8-carbaldehyde (33 mg, 0.079 mmol) in 1,2-dichloroethane (3 ml) was added dimethyl Daspartate (12.80 mg, 0.079 mmol) and NaHB (OAc) ₃ (33.7 mg, 0.159 mmol). The reaction mixture was stirred at room temperature overnight, then treated with an aqueous solution of potassium carbonate. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with H ₂ O, saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification by means of RP-HPLC (MeCN / H ₂ O with 0.05% TFA) resulted in dimethyl N {[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1.1 -dioxide-5-phenyl-2,3,4,5 -tetrahydro-4-benzothiazepin-8-yl] methyl} -D-aspartate (22 mg, 48%) as a colorless oil: ES-LCMS m / z 561 (M + H) ⁺ .
Step 2: To a solution of dimethyl N - {[(3R, 5R) -3-butyl-3-ethyl7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepin-8il] methyl} -D-aspartate (22 mg, 0.039 mmol) in a 1: 1: 1 mixture of THF / MeOH / H ₂ O (3 ml) lithium hydroxide was added (18.79 mg, 0.785 mmol). The reaction mixture was stirred at room temperature overnight, treated with trifluoroacetic acid, and concentrated under reduced pressure. Purification by means of RP-HPLC (MeCN / H ₂ O with 0.05% TFA) resulted in the title compound (10.9 mg, 37%, TFA salt) as a white solid: NMR 'H (MeOH-d ₄ ) δ ppm 8.10 (s, 1H), 7.33 - 7.54 (m, 5H),
6.42 (s, 1H), 6.18 (s, 1H), 4.31 - 4.45 (m, 2H), 4.13 - 4.24 (m, 1H), 3.58 3.67 (m , 4H), 2.92 - 3.14 (m, 2H), 1.80 - 1.96 (m, 1H), 1.58 - 1.78 (m, 1H),
1.43 - 1.57 (m, 1H), 1.04 - 1.41 (m, 4H), 0.91 (t, J = 7.4 Hz, 3H), 0.83 (t, J = 6, 8 Hz, 3H); ES-LCMS m / z 533 (M + H) ⁺ .
Example 29: A - {[(3R, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra trifluoroacetate salt -hydro-1,4-benzothiazepin-8yl] methyl} -A-methyl-P-alanine ^H0 ^ oP
N
I

Step 1: To a (37 , 5R) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1 1,1-dioxide solution, 4-benzothiazepine-8-carbaldehyde (200 mg, 0.481 mmol) in 1,2-dichloroethane (10 ml) were added 1,1dimethylethyl β-alaninate (175 mg, 0.963 mmol) and acetic acid (0.276 ml, 4.81 mmol). After 1 h of stirring, NaHB (OAc) ₃ (255 mg, 1.203 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 h, then treated with an aqueous sodium carbonate solution. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with H ₂ O, saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure giving 1,1-dimethylethyl N- {[(3R, 5R) -3-butyl-3 -ethyl-7- (methyloxy) -1,1-dioxide-5phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} -β-alaninate (210 mg, 80 %) as an oil: ES-LCMS m / z 559
Step 2: A 1,1-dimethylethyl N - {[(3Ã, 5Á) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5- tetrahydro-1,4-benzothiazepin-8il] methyl} -β-alaninate (210 mg, 0.289 mmol) 4N hydrogen chloride (3.61 ml, 4N solution in 1,4-dioxane, 14.46 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure. Purification by RP-HPLC (MeCN / H ₂ O with 0.05% TF A) resulted in the title compound (143 mg, 82%, TF A salt) as a white solid: NMR (CDC1 ₃ ) δ ppm 8.13 (s, 1H), 7.35 - 7.62 (m, 5H), 6.35 (s, 1H), 6.24 (s, 1H), 4.12 - 4.42 (m, 2H), 3.62 (s, 3H), 3.33 - 3.52 (m, 2H), 3.25 (br., 2H), 2.79 (br., 2H), 2 , 35 (br. S., 1H), 1.89 - 2.10 (m, 1H), 1.68 - 1.82 (m, 1H), 1.51 - 1.68 (m, 1H), 1.18 - 1.46 (m, 3H), 1.00 - 1.17 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 6.8 Hz, 3H); ES-LCMS m / z 503 (M + H) ⁺ .
Examples 30 and 31: 4 - ({[(3R, 5R) -3-butyl-3-ethyl7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-trifluoroacetate salt -tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) butanoic acid trifluoroacetate salt of l - {[(3R, 5R) -3butyl-3-ethyl-7- (methyloxy) -l, l- dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4benzothiazepin-8-yl] methyl} -2-pyrrolidinone
Step 1: To a solution of (37 , 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,1-dioxide , 4-benzothiazepine-8-carbaldehyde (200 mg, 0.481 mmol) in 1,2-dichloroethane (5 ml) was added methyl 4aminobutanoate (111 mg, 0.722 mmol) and acetic acid (0.276 ml, 4.81 mmol). The reaction mixture was stirred at room temperature overnight, treated with NaHB (OAc) ₃ (255 mg, 1.203 mmol), and stirred for 1 h. The reaction mixture was treated with aqueous sodium carbonate solution and extracted with DCM. The organic layer was washed with H ₂ O, saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (EtOAc: Hexanes = 20:80 to 60:40) resulted in acid 4 - ({[(3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1,1 -dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} amino) butanoic (210 mg, 83%) as a light yellow oil: ES-LCMS m / z 517 (M + H) ⁺ .
Step 2: To a solution of 4 - ({[(37 , 5Á) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5 -tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) butanoic (210 mg, 0.406 mmol) in a 1: 1: 1 mixture of THF / MeOH / H ₂ O (3 ml) was added hydroxide lithium (9.73 mg, 0.406 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure. Purification by means of RP-HPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the trifluoroacetate salt of Example 30 (45.6 mg, 44%) as a white solid: NMR * H (DMSO-d ₆ ) δ ppm 8.67 (br. S., 2H), 8.09 (s, 1H), 7.30 - 7.56 (m, 5H), 6.18 (s, 1H), 5.97 (s, 1H), 4.16 (br., 2H), 3.63 (d, J = 14.8 Hz, 1H), 3 , 49 (s, 3H), 3.09 (d, J = 15.0 Hz, 1H), 2.88 - 3.01 (m, 2H), 2.33 (t, J = 7.2 Hz, 2H), 1.99-2.15 (m, 1H), 1.67 - 1.90 (m, 3H),
1.35 - 1.61 (m, 2H), 0.96 - 1.32 (m, 4H), 0.81 (t, J = 7.2 Hz, 3H), 0.76 (t, J = 6.6 Hz, 3H); ES-LCMS m / z 503 (M + H) ⁺ and Example 31 (47.8 mg, 48%) trifluoroacetate salt as a white solid: NMR 'Η (DMSO-d ₆ ) δ ppm 7.69 (s, 1H), 7.30 - 7.61 (m, 5H), 6.22 (br. S., 1H), 6.04 (br. S., 1H), 4.23 - 4.44 (m, 2H), 3.49 (s, 3H), 2.12 - 2.34 (m, 3H), 1.75 - 2.02 (m, 3H), 1.35 - 1.74 (m, 2H) , 1.11 - 1.34 (m, 3H), 0.94 - 1.10 (m, 1H), 0.64 - 0.89 (m, 6H); ES-LCMS m / z 485
Example 32: 2V trifluoroacetate salt - {[(3R, 5R) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepin-8il] methyl} -2-methylalanine
HO.
Step 1: To a solution of (3Ã, 5J ) - 3-butyl-3ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1-dioxide, 4-benzothiazepine-8-carbaldehyde (200 mg, 0.481 mmol) in 1,2-dichloroethane (300 ml) was added methyl 2methylalaninate (113 mg, 0.963 mmol) and acetic acid (0.138 ml, 2.406 mmol). The reaction mixture was stirred at room temperature for 1 h. NaHB (OAc) ₃ (255 mg, 1.203 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. Aqueous sodium carbonate solution was added to the reaction mixture which was then extracted with DCM. The organic layer was washed with H ₂ O, saturated brine, dried, (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (EtOAc: Hexanes = 20:80 to 60:40) resulted in methyl N - {[(3R, 5R) -3-butyl-3ethyl-7- (methyloxy) -1,1-dioxide-5 -phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} -2-methylalaninate (230 mg, 91%): ES-LCMS m / z 517 (M + H) ⁺ .
Step 2: To a solution of methyl N - {[(3R, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra -hydro-1,4-benzothiazepin-8
100 yl] methyl} -2-methylalaninate (230 mg, 0.245 mmol) in a 1: 1: 1 mixture of THF / MeOH / H ₂ O (15 ml) was added lithium hydroxide (5.6 mg, 0.245 mmol). The reaction mixture was stirred at room temperature overnight, then partially concentrated under reduced pressure to remove organic solvents. The residue was acidified with trifluoroacetic acid. Purification by means of RP-HPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the title compound (102 mg, 66%, TFA salt ) as a white solid: NMR Ή (DMSO-d ₆ ) δ ppm 8.10 (s, 1H), 7.28 - 7.55 (m, 5H), 6.18 (s, 1H), 6.00 (s, 1H), 4.14 (d, J = 17.6 Hz, 2H), 3.64 (d, J = 15.0 Hz, 1H), 3.49 (s, 3H), 3.13 (d, J = 14.8 Hz, 1H), 2.46 - 2.55 (m, 1H), 2.00 - 2.23 (m, 1H), 1.70 - 1.86 (m, 1H ), 1.35 - 1.49 (m, 1H), 0.98 - 1.31 (m, 4H), 0.82 (t, J = 7.2 Hz, 3H), 0.77 (t, J = 6.8 Hz, 3H); ES-LCMS m / z 503 (M + H) ⁺ .
Example 33: acid trifluoroacetate salt [2 - ({[(37 , 5R) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4, 5-tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) ethyl] phosphonic
Step 1: To a solution of 1,1-dioxide (3R, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1, 4-benzothiazepine-8-carbaldehyde (50 mg, 0.120 mmol) in 1,2-dichloroethane (3 ml) was added diethyl (2aminoethyl) phosphonate (109 mg, 0.602 mmol). The reaction mixture was stirred for 3 h, then treated with NaHB (OAc) ₃ (128 mg, 0.602 mmol). The reaction mixture was stirred at room temperature for 2 h, then treated with H ₂ O and IN hydrochloric acid in solution. The resulting mixture was concentrated under reduced pressure. Purification by means of RP-HPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN)
101 resulted in diethyl [2 - ({[(3R, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -l, 1-dioxide-5-phenyl-2,3,4,5-tefrahydro- 1,4-benzothiazepin-8-yl] methyl} amino) ethyl] phosphonate (70 mg, 71%) as a white solid: ES-LCMS m / z 581
Step 2: To a solution of diethyl [2 - ({[(3Ã, 5Ã) -3-butyl-3-ethyl7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5- tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) ethyl] phosphonate (70 mg, 0.121 mmol) in DCM (3 ml) was added bromotrimethylsilane (0.065 ml, 0.499 mmol). The reaction mixture was stirred at room temperature overnight. More bromotrimethylsilane (0.16 ml, 1.21 mmol) was added. The reaction mixture was stirred overnight, concentrated under reduced pressure and treated with H ₂ O. Purification by RP-HPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) gave the title product (51 mg, 55%, TF A salt) as a white solid: NMR ^] H (MeOH-d ₄ ) δ ppm 8.09 (s, 1H) , 7.30 - 7.53 (m, 5H), 6.39 (s, 1H), 6.15 (s, 1H), 4.12 - 4.35 (m, 2H), 3.57 - 3 , 65 (m, 4H), 3.14 - 3.24 (m, 3H), 2.23 - 2.40 (m, 1H), 1.76 - 2.06 (m, 3H), 1.59 - 1.75 (m, 1H), 1.38 - 1.55 (m, 1H), 1.00 - 1.38 (m, 4H), 0.90 (t, J = 7.4 Hz, 3H ), 0.81 (t, J = 7.0 Hz, 3H); ES-LCMS m / z 525 (M + H) ⁺ .
Example 34: [2 - ({[(3Ã, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5- trifluoroacetate salt tetrahydro-1,4-benzothiazepin-8il] methyl} amino) ethyl] ethyl hydrogen phosphonate
To a {[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -l, ldioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin solution -8-yl] methyl} amine (50 mg, 0.120 mmol) in DMF (4 ml) potassium carbonate (49.8 mg, 0.360 mmol) and diethyl (2-bromoethyl) phosphonate (17.65 mg, 0.072 mmol). The reaction mixture was heated to 90 ° C overnight, cooled to
102 at room temperature, and concentrated under reduced pressure. Trifluoroacetic acid was added to the residue, and the solution was concentrated under reduced pressure. Purification by means of RP-HPLC (MeCN / H ₂ O with 0.05% TF A) resulted in the title product (34 mg, 95%, TF A salt) as a white solid: NMR Ή (MeOH-d ₄ ) δ ppm 8.04 (s, 1H), 7.27 - 7.59 (m, 5H), 6.38 (s, 1H), 6.04 - 6.21 (m, 2H), 3.88 - 4.24 (m, 4H), 3.50 - 3.68 (m, 4H), 3.16 - 3.35 (m, 3H), 2.20 - 2.49 (m, 1H), 1 , 78 - 1.95 (m, 1H), 1.60 - 1.75 (m, 1H), 1.41 1.58 (m, 1H), 1.01 - 1.36 (m, 7H), 0.89 (t, J = 7.6 Hz, 3H), 0.81 (t, J = 6.8 Hz, 3H); ES-LCMS m / z 553 (M + H) ⁺ .
Example 35: 2 - ({[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) 1,1-dioxide-5-phenyl-2,3,4,5- ammonium salt tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) ethanesulfonic
To a solution of {[(3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetrahydro-1,4 -benzothiazepin-8-yl] methyl} amine (100 mg, 0.240 mmol) in DMF (4 ml) 2bromoethane sulfonic acid sodium salt (25.3 mg, 0.120 mmol) was added. The reaction mixture was stirred at 70 ° C overnight, cooled to room temperature, acidified with trifluoroacetic acid, and concentrated under reduced pressure. Purification by means of RP-HPLC (MeCN / H ₂ O with 0.05% TFA), followed by further purification with RP-HPLC (eluting with MeCN / H ₂ O with 0.5% ammonium hydroxide in H ₂ O) resulted in the title compound (27.6 mg, 54%, ammonium salt) as a white solid: NMR * H (MeOH-d ₄ ) δ ppm 8.03 (s, 1H), 7.19 - 7, 54 (m, 5H), 6.30 (s, 1H), 6.06 (s, 1H), 4.20 (s, 2H), 3.58 (s, 3H), 3.49 (d, J = 15.0 Hz, 1H), 3.30 - 3.38 (m, 2H), 2.96 - 3.15 (m, 3H), 2.09 - 2.31 (m, 1H), 1, 71 - 1.88 (m, J = 5.1 Hz, 1H), 1.49 - 1.70 (m, 1H), 1.34 - 1.49 (m,
103
1H), 1.05 - 1.32 (m, 4H), 0.87 (t, J = 7.4 Hz, 3H), 0.78 (t, J = 6.6 Hz, 3H); ES-LCMS m / z 525 (M + Ηγ.
Example 36: 2,2 '- ({[(3Ã, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4 trifluoroacetate salt , 5-tetrahydro-1,4-benzothiazepin-8yl] methyl} imino) diethanesulfonic
To a solution of {[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetrahydro-1,4 benzothiazepin-8-yl] methyl} amine (25 mg, 0.060 mmol) in DMF (2 ml) sodium bromide of 2bromoethane sulfonic acid (127 mg, 0.600 mmol) was added. The reaction mixture was stirred at 70 ° C overnight, cooled to room temperature, acidified to pH 3-4 with acetic acid, and concentrated under reduced pressure. Purification using RP-HPLC (MeCN / H ₂ O with 0.05% TF A) resulted in the title product (13 mg, 24%, TF A salt) as a white solid: NMR (Moondr δ ppm 8, 23 (s, 1H), 7.42 - 7.80 (m, 5H), 6.68 (s, 1H), 6.53 (s, 1H), 4.72 (d, J = 13.3 Hz , 1H), 4.40 (d, J = 13.5 Hz, 1H), 3.95 (d, J = 15.8 Hz, 1H), 3.41 3.83 (m, 8H), 2, 60 - 2.85 (m, 1H), 1.85 - 2.27 (m, 2H), 1.57 - 1.80 (m, 1H), 1.22 - 1.53 (m, 3H), 0.71 - 1.17 (m, 7H); ES-LCMS m / z 633
Example 37: 2 - ({[(3Ã, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5phenyl-2,3,4,5-tetrahydro-1-acid , 4-benzothiazepin-8-yl] methyl} amino) -2oxoethanesulfonic
To a solution of N - {[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetrahydro-1, 4-benzothiazepin-8-yl] methyl} -2
104 chloroacetamide (55 mg, 0.112 mmol) in a 1: 1 mixture of ethanol / H ₂ O (6 ml) was added sodium sulfite (141 mg, 1.115 mmol). The reaction mixture was stirred at 80 ° C overnight, cooled to room temperature, acidified with acetic acid to pH 3-4, and concentrated under reduced pressure. Purification using silica gel (MeOH: DCM = 0: 100 to 30:70) resulted in the title compound (32 mg, 52%) as an off-white solid: 1 H NMR (MeOH-d ₄ ) δ ppm 7.94 (s, 1H), 7.16 - 7.68 (m, 5H), 6.28 (br. s, 1H), 6.06 (br. s., 1H), 4.39 (br. s ., 2H), 3.63 - 3.78 (m, 2H), 3.43 - 3.59 (m, 4H), 2.06 2.49 (m, 1H), 1.01 - 1.94 (m, 7H), 0.89 (t, J = 7.4 Hz, 3H), 0.81 (t, J = 6.6 Hz, 3H); ES-LCMS m / z 539 (M + H) ⁺ .
Example 38: acid trifluoroacetate salt [2 - ({[(3Ã, 57 ) - 3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4, 5-tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) -2-oxoethyl] phosphonic
Step 1: A mixture of A - {[(3Ã, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro -1,4-benzothiazepin-8il] methyl} -2-chloroacetamide (82 mg, 0.166 mmol) and triethyl phosphite (2.9 ml, 16.63 mmol) was stirred at 135 ° C overnight, cooled at room temperature, and concentrated under reduced pressure. Diethyl [2 - ({[(37 , 5Ã) -3-butyl3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1 Crude 4-benzothiazepin8-yl] methyl} amino) -2-oxoethyl] phosphonate (99 mg, 98%) was used in the next step without further purification: ES-LCMS m / z 595 (M + JTf.
Step 2: To a solution of diethyl [2 - ({[(3Ã, 57 ) - 3-butyl-3-ethyl7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5 -tetrahydro-1,4-benzothiazepin-8-yl] methyl} amino) -2-oxoethyl] phosphonate (99 mg, 0.166 mmol) in DCM (5 ml) bromotrimethylsilane (0.065 ml, 0.499 mmol) was added, and the mixture of
The reaction was stirred at room temperature overnight. More bromotrimethylsilane (0.216 ml, 1.66 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and treated with H ₂ O. Purification by means of RP-HPLC (MeCN / H ₂ O with 0.05% TF A) resulted in the title compound (69 mg, 63%, TF A salt) as a white-gray solid: NMR Ή (MeOH-d ₄ ) δ ppm 8.01 (s, 1H), 7.35 - 7.75 (m, 5H), 6.51 (s, 1H), 6.42 (s, 1H), 4.43 (d, J = 14.8 Hz, 1H), 4.24 (d, J = 14.1 Hz, 1H), 3.85 (d, J = 15.4 Hz, 1H), 3.66 (br. S., 1H), 3.61 (s, 3H), 2.57 - 2.87 (m, 3H), 1.96 - 2, 13 (m, 2H), 1.56 - 1.75 (m, 1H), 1.22 - 1.49 (m, 3H), 0.99 (t, J = 7.4 Hz, 3H), 0 , 89 (t, J = 6.8 Hz, 3H); ESLCMS m / z 539
Example 39: trifluoroacetate salt of JV- [2 - ({[(3Ã, 5Á) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4, 5-tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) -2-oxoethyl] glycine
Step 1: To a solution of N - {[(3Ã, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepin-8yl] methyl} -2-chloroacetamide (50 mg, 0.101 mmol) in DMF (3 ml) potassium carbonate (56.1 mg, 0.406 mmol), methyl ester hydrochloride salt glycine (63.7 mg, 0.507 mmol) and potassium iodide (67.3 mg, 0.406 mmol). The reaction mixture was stirred at 60 ° C overnight, cooled to room temperature, and partitioned between H ₂ O and EtOAc. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (MeOH: DCM = 0: 100 to 20:80) resulted in methyl N- [2 - ({[(37 , 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1 , 1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8
106 yl] methyl} amino) -2-oxoethyl] glycinate (50 mg, 90%) as a colorless oil: ESLCMS m / z 546 (M + 77) ⁺ .
Step 2: To a solution of methyl N- [2 - ({[(37 , 57 ) - 3-butyl-3ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3, 4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) -2-oxoethyl] glycinate (50 mg, 0.092 mmol) in a 1: 1: 1 mixture of THF / MeOH / H ₂ O (9 ml) lithium hydroxide (54.9 mg, 2.291 mmol) was added. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure to remove organic solvents, and acidified with trifluoroacetic acid. Purification by RP-HPLC (MeCN / H ₂ O with 0.05% TF A) resulted in the title compound (15 mg, 21%, TF A salt) as a white solid: NMR 'H (MeOH-d ₄ ) δ ppm 7.90 (s, 1H), 7.25 - 7.57 (m, 5H), 6.33 (s, 1H), 6.16 (s, 1H), 4.39 (s, 2H), 3.89 (d, J = 5.9 Hz, 3H), 3.61 (d, J = 15.2 Hz, 1H), 3.55 (s, 3H), 2.27 - 2, 49 (m, 1H), 1.79 - 1.98 (m, 1H), 1.62 - 1.79 (m, 1H), 1.42 - 1.58 (m, 1H), 1.17 - 1.38 (m, 3H), 0.99 - 1.17 (m, 1H), 0.90 (t, J = 7.4 Hz, 3H), 0.82 (t, J = 6.8 Hz , 3H); ES-LCMS m / z 532 (M + H) ⁺ .
Example 40: acid trifluoroacetate salt (2 - {[2 - ({[(37 , 5Ã) -3-butyl-3-ethyl7- (methyloxy) -1,1-dioxide-5-phenyl-2,3 , 4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) -2-oxoethyl] amino} ethyl) phosphonic
Step 1: To a solution of 7V - {[(3Ã, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepin-8il] methyl} -2-chloroacetamide (50 mg, 0.101 mmol) in DMF (3 ml) potassium carbonate (28.0 mg, 0.203 mmol) and diethyl (2aminoethyl) phosphonate (20 , 21 mg, 0.112 mmol). The reaction mixture was stirred at 60 ° C overnight. Potassium iodide (33.7 mg,
107
0.203 mmol), and the reaction mixture was stirred at 60 ° C overnight, cooled to room temperature, and partitioned between H ₂ O and EtOAc. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (MeOH: DCM = 0: 100 to 20:80) resulted in diethyl (2 - {[2 - ({[(3Ã, 5R) -3-butyl-3-ethyl-7 (methyloxy) - 1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) -2-oxoethyl] amino} ethyl) phosphonate (27 mg, 40% ) as a colorless oil: ES-LCMS m / z
638 (M + H) ⁺ .
Step 2: To a solution of diethyl (2 - {[2 - ({[(3Ã, 5Ã) -3-butyl-3ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3, 4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) -2-oxoethyl] amino} ethyl) phosphonate (25 mg, 0.039 mmol) in DCM (5 ml) bromotrimethylsilane (0.102 ml) was added , 0.784 mmol). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and acidified with 1N hydrochloric acid. The residue was concentrated under reduced pressure and purified by means of RPHPLC (MeCN / H ₂ O with 0.05% TF A resulted in the title compound (15 mg, 46%, TF A salt) as a white solid: NMR ' H (MeOH-d ₄ ) δ ppm 7.96 (s, 1H), 7.33 - 7.61 (m, 5H), 6.41 (s, 1H), 6.22 (s, 1H), 4 , 25 - 4.50 (m, 2H), 3.75 - 3.84 (m, 2H), 3.69 (d, J = 15.2 Hz, 1H), 3.58 (s, 3H), 3.34 (d, J = 15.2 Hz, 1H), 3.05 - 3.22 (m, 2H), 2.42 - 2.65 (m, 1H), 1.71 - 2.02 ( m, 4H), 1.51 1.69 (m, 1H), 1.14 - 1.44 (m, 4H), 0.97 - 1.14 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H), 0.83 (t, J = 6.8 Hz, 3H); ES-LCMS m / z 582 (M + Hf.
Example 41: 3 - {[2 - ({[(3Ã, 5R) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3-trifluoroacetate salt, 4,5-tetrahydro-1,4-benzothiazepin-8il] methyl} amino) -2-oxoethyl] amino} pentanedioic
HO.
108
Step 1: To a solution of A - {[(37 , 5R) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra -hydro-1,4-benzothiazepin-8yl] methyl} -2-chloroacetamide (55 mg, 0.112 mmol) in DMF (3 ml), potassium carbonate (61.7 mg, 0.446 mmol) and potassium iodide (74, 1 mg, 0.446 mmol). The reaction mixture was stirred at 60 ° C overnight, cooled to room temperature, and partitioned between H ₂ O and EtOAc. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (MeOH: DCM = 0: 100 to 10:90) resulted in diethyl 3 - {[2 - ({[(3Ã, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1 , 1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) -2-oxoethyl] aminoPentanedioate (75 mg, 100%) as a yellow oil : ES-LCMS m / z 660 (M + H)
Step 2: To a solution of diethyl 3 - {[2 - ({[(37 , 5Ã) -3-butyl-3ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3, 4,5-tetrahydro-1,4-benzothiazepin-8il] methyl} amino) -2-oxoethyl] aminoJpentanedioate (73.9 mg, 0.112 mmol) in a 1: 1: 1 THF / MeOH / H mixture ₂ O 6 ml) was added lithium hydroxide (134 mg, 5.60 mmol). The reaction mixture was stirred at room temperature overnight, acidified with acetic acid, and concentrated under reduced pressure. Purification by RP-HPLC (MeCN / H ₂ O with 0.05% TF A) gave the title compound (20 mg, 21%, TF A salt) as a white solid: NMR * H (MeOH-d ₄ ) δ ppm 7.95 (s, 1H), 7.34 - 7.66 (m, 5H),
6.45 (s, 1H), 6.30 (s, 1H), 4.41 (d, J = 3.3 Hz, 2H), 3.82 - 4.00 (m, 3H), 3.74 (d , J = 15.4 Hz, 1H), 3.58 (s, 3H), 3.46 (d, J = 15.4 Hz, 1H), 2.85 (d, J = 5.7 Hz, 3H ), 2.45 - 2.72 (m, 2H), 1.77 - 2.11 (m, 2H), 1.49 - 1.72 (m, 1H), 1.24 -
1.45 (m, 3H), 0.97 - 1.13 (m, 1H), 0.93 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 6.8 Hz, 3H ); ES-LCMS m / z 604 (M + H) ⁺ .
Example 42: ammonium salt of 3 - ({[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -l, ldioxide-5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepin-8-yl] methyl} amino) -3oxo-1-propanesulfonic
109
Step 1: To an ice-cold solution of {[(3Ã, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro -1,4-benzothiazepin-8yl] methyl} amine (150 mg, 0.233 mmol) in DCM (10 ml) was added pyridine (0.132 ml, 1.629 mmol) and 3-chloropropanoyl chloride (0.045 ml, 0.465 mmol). The reaction mixture was stirred at room temperature for 4 h, then partitioned between H ₂ O and DCM. Purification via silica gel (MeOH: DCM = 0: 100 to 3:97) resulted in A - {[(3Ã, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5 -phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8il] methyl} -3-chloropropanamide (105 mg, 89%) as a colorless oil: ESLCMS m / z 508
Step 2: To a solution of N - {[(3Ã, 5Á) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepin-8il] methyl} -3-chloropropanamide (150 mg, 0.296 mmol) in a 1: 1 mixture of ethanol / H ₂ O (10 ml) was added sodium sulfite (186 mg, 1.479 mmol). The reaction mixture was stirred at 60 ° C overnight, cooled to room temperature, acidified with acetic acid, and concentrated under reduced pressure. Purification by means of RP-HPLC (MeCN / H ₂ O with 0.5% NH4OH) resulted in the title compound (27 mg, 15%, NH ₃ salt) as a white solid: NMR 'H (MeOH-d ^ δ ppm 8.31 - 8.49 (m, 1H), 7.86 (s, 1H), 7.13 - 7.55 (m, 5H), 6.20 (s, 1H), 6.04 (s , 1H), 4.18 - 4.37 (m, 2H), 3.51 (s, 3H), 3.44 (d, J = 14.8 Hz, 1H), 2.95 - 3.11 ( m, 3H), 2.57 - 2.73 (m, 2H), 2.08 - 2.31 (m, 1H), 1.67 - 1.85 (m, 1H), 1.48 - 1, 66 (m, 1H), 1.32 - 1.46 (m, 1H), 1.03 - 1.32 (m, 4H), 0.86 (t, J = 7.4 Hz, 3H), 0 , 78 (t, J = 6.8 Hz, 3H); ESLCMS m / z 553 (Àf + #) ⁺ .
Example 43: acid 3 - ({[(37 , 5ό) -3-6ηΐΐ1-3-6ίϋ-7- ^ 6ίΐ1όχι) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro- 1,4-benzothiazepin-8-yl] methyl} amino) pentanedioic
110
Step 1: A (3R, 5S) -3-butyl-3-ethyl7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-dioxide solution benzothiazepine-8-carbaldehyde (100 mg, 0.241 mmol) and dimethyl 3-aminopentanedioate (63.2 mg, 0.361 mmol) in 1,2-dichloroethane (4 ml) was stirred for 30 min, then treated with acetic acid (0.069 ml , 1.203 mmol). The reaction mixture was stirred for 1 h, treated with NaHB (OAc) ₃ (102 mg, 0.481 mmol), stirred at room temperature overnight, and quenched with 2N aqueous sodium carbonate solution. After stirring for 30 min, the mixture was extracted with DCM. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (EtOAc / hexanes = 1: 4 to 1: 1) resulted in dimethyl 3 - ({[(3R, 5S) -3-butyl-3-ethyl7- (methyloxy) -1,1-dioxide- 5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) pentanedioate (92.7 mg, 67%) as a colorless oil: NMR Ή (CDC1 ₃ ) δ ppm 7.99 (s, 1H), 7.21 - 7.52 (m, 5H), 6.12 (s, 1H), 6.06 (s, 1H), 3.74 (d, J = 5 , 3 Hz, 2H), 3.66 (s, 6H), 3.50 (s, 3H), 3.23 - 3.44 (m, 2H), 3.05 (d, J = 14.6 Hz , 1H), 2.56 (d, J = 6.2 Hz, 4H), 2.26 - 2.44 (m, 1H), 1.67 1.87 (m, 2H), 1.03 - 1 , 56 (m, 7H), 0.89 (t, J = 6.6 Hz, 3H), 0.76 (t, J = 7.2 Hz, 3H); ES-LCMS m / z 575 (M + 7T) ⁺ .
Step 2: To a solution of dimethyl 3 - ({[(3R, 5S) -3-butyl-3-ethyl7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra -hydro-1,4-benzothiazepin-8yl] methyl} amino) pentanedioate (92 mg, 0.160 mmol) in a 1: 1: 1 mixture of THF / MeOH / H ₂ O (6 ml) was added hydroxide monohydrate lithium (67.2 mg, 1.601 mmol). The reaction mixture was stirred at room temperature overnight, then partially concentrated under reduced pressure to remove organic solvents. The aqueous phase was
111 adjusted to pH 5 with 1N hydrochloric acid. A white precipitate was collected by filtration and dried in air giving the title compound (42 mg, 45%) as a white solid: 1 H NMR (DMSO-dg) δ ppm 7.94 (s, 1H), 7, 41 (d, J = 4.3 Hz, 4H), 7.26 - 7.38 (m, 1H), 6.10 (s, 1H), 5.93 (br. S., 1H), 3, 80 (s, 2H), 3.55 (d, J = 14.9 Hz, 1H), 3.08 (d, J = 14.9 Hz, 1H), 2.57 - 2.76 (m, 1H ), 2.31 - 2.47 (m, 3H), 2.04 - 2.21 (m, 1H), 1.55 - 1.82 (m, 1H), 1.07 - 1.51 (m , 7H), 0.86 (t, J = 6.6 Hz, 3H), 0.66 (t, J = 7.2 Hz, 3H); ES-LCMS m / z 547 (M + Hf.
Example 44: # - {[(3R, 5S) -3-butyl-3-ethyl-7- (methyloxy) - trifluoroacetate salt
1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} glycine
Step 1: To a solution of (3R, 55) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-dioxide -benzothiazepine-8-carbaldehyde (100 mg, 0.241 mmol) in 1,2-dichloroethane (4 ml) were added 1,1-dimethylethyl glycinate (47.3 mg, 0.361 mmol) and acetic acid (0.069 ml, 1.203 mmol ). The reaction mixture was stirred at room temperature for 1 hr, treated with NaHB (OAc) ₃ (102 mg, 0.481 mmol), and stirred at room temperature overnight. The reaction mixture was added with 2M aqueous sodium carbonate solution and extracted with DCM. The combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification using silica gel (EtOAc: hexanes = 1: 4 to 1: 1) resulted in 1,1-dimethylethyl N - {[(3R, 5S) -3-butyl3-ethyl-7- (methyloxy) -l, 1 -dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin8-yl] methyl} glycinate (35.8 mg, 28.0%) as a colorless oil: NMR ^] H ( CDC1 ₃ ) δ ppm 7.97 (s, 1H), 7.30 - 7.58 (m, 6H), 6.15 (s, 1H), 6.07 (s, 1H), 3.77 (s , 2H), 3.52 (s, 3H), 3.42 (d, J = 14.7 Hz, 1H), 3.27 (s, 2H), 3.06 (d, J =
112
14.7 Hz, 1H), 2.26 - 2.48 (m, 1H), 1.72 - 1.92 (m, 2H), 1.06 - 1.41 (m, 8H), 0.90 (t, J = 6.2 Hz, 3H), 0.78 (t, J = 7.2 Hz, 3H); ES-LCMS m / z 531 (M + H) ⁺ .
Step 2: A mixture of 1,1-dimethylethyl N - {[(3R, 5S) -3-butyl-3ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5 -tetrahydro-1,4-benzothiazepin-8yl] methyl} glycinate (34.0 mg, 0.064 mmol) was treated with 4N hydrogen chloride in 1,4-dioxane (1,600 ml, 6.40 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure. Purification by means of RP-HPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the title compound (35 mg, 77%, TFA salt ) as a white solid: N NMR (DMSO-d ₆ ) δ ppm 9.01 - 9.40 (m, 2H), 8.07 (s, 1H), 7.17 - 7.56 (m, 5H) , 6.16 (s, 1H), 5.95 (br. S., 1H), 4.10 - 4.31 (m, 2H), 3.84 (br. S., 2H), 3.62 (d, J = 14.3 Hz, 1H), 3.56 - 3.72 (m, 1H), 3.48 (s, 3H), 3.11 (d, J = 14.6 Hz, 1H) , 2.09 - 2.26 (m, 1H), 2.07 (s, 1H), 1.62 - 1.84 (m, 1H), 1.00 - 1.56 (m, 6H), 0 , 86 (t, J = 6.6 Hz, 3H), 0.68 (t, J = 7.0 Hz, 3H); ES-LCMS m / z 475
Example 45: {[(3R, 5o) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-trifluoroacetate salt -1,4-benzothiazepin-8il] methyl} phosphonic
Step 1: To a cold solution of imidazole (130 mg, 1.916 mmol) in DCM (5 ml) was added triphenylphosphine (251 mg, 0.958 mmol) followed by bromine drip addition (0.049 ml, 0.958 mmol). A solution of [(3R, 5S) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5tetrahydro-1,4-benzothiazepin- 8-yl] methanol (200 mg, 0.479 mmol) in DCM (5 ml) was added slowly. The reaction mixture was stirred at 0 ° C for 2 h. Aqueous sodium sulfite solution was added, and the mixture
The resulting 113 was separated. The aqueous layer was extracted with DCM, and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. Purification using silica gel (EtOAc / hexanes = 1: 10 to 1: 2) resulted in (3Ã, 5ó) -8- (bromomethyl) -3-butyl-3-ethyl-7 (methyloxy) 1,1-dioxide -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (149 mg, 64%) as a white solid: 1 H NMR (CDCl 3) δ ppm 8.06 (s, 1H) , 7.28 - 7.54 (m, 5H), 6.17 (s, 1H), 6.07 (s, 1H), 4.38 - 4.62 (m, 2H), 3.58 (s , 3H), 3.44 (d, J = 14.9 Hz, 1H), 3.09 (d, J = 14.9 Hz, 1H), 2.38 (dd, J = 14.9, 7, 4 Hz, 1H), 1.81 (dd, J = 14.7, 7.4 Hz, 1H), 1.11 - 1.59 (m, 8H), 0.91 (t, J = 6.6 Hz, 3H), 0.78 (t, J = 7.2 Hz, 3H); ES-LCMS m / z 482 (M + Hf.
Step 2: To a solution of (37 , 5 <S) -8 (bromomethyl) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4 , 5-tetrahydro-1,4benzothiazepine (149 mg, 0.310 mmol) in toluene (10 ml) was added triethyl phosphite (0.163 ml, 0.930 mmol). The reaction mixture was heated to reflux overnight, cooled to room temperature, and concentrated under reduced pressure. Purification using silica gel (EtOAcrhexanes - 50:50 to 100: 0) resulted in diethyl {[(3R, 55) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5phenyl-2 , 3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} phosphonate (132 mg, 79%) as a clear oil: 1 H NMR (CDCl 3) δ ppm 7.97 (d, J = 2.7 Hz, 1H), 7.28 - 7.50 (m, 5H), 6.13 (s, 1H), 6.04 (s, 1H), 3.88 - 4.25 (m , 5H), 3.51 (s, 3H), 3.40 (d, J = 14.8 Hz, 1H), 3.10 - 3.27 (m, 2H), 3.03 (d, J = 14.8 Hz, 1H), 2.37 (dd, J = 14.6, 7.4 Hz, 1H), 1.79 (dd, J = 14.6, 7.4 Hz, 1H), 1, 41 1.58 (m, 2H), 1.10 - 1.40 (m, 12H), 0.89 (t, J = 6.8 Hz, 3H), 0.75 (t, J = 7.2 Hz, 3H)
Step 3: To an ice-cold solution of diethyl {[(3Ã, 5S) -3-butyl-3ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro -1,4-benzothiazepin-8yl] methylJphosphonate (132 mg, 0.246 mmol) in DCM (5 ml) was added bromotrimethylsilane (0.159 ml, 1.228 mmol). The reaction mixture was warmed to room temperature, stirred overnight, and
114 concentrated under reduced pressure. The residue was partitioned between H ₂ O and DCM. The organic layer was washed with saturated brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by means of RPHPLC (eluting with MeCN / H ₂ O with 0.05% TFA-H ₂ O and 0.05% TFAMeCN) resulted in the title compound (49 mg, 32%, TF A salt) as a white solid: N NMR (CDCl ₃ ) δ ppm 7.87 (br. s., 1H), 7.31 - 7.70 (m, 5H), 5.95 - 6.46 (m, 2H), 3 , 46 - 3.62 (m, 3H), 3.20 - 3.43 (m, 2H), 2.38 - 2.90 (m, 2H), 1.76 (br. S., 1H), 1.07 - 1.53 (m, 5H), 0.96 (t, J = 6.6 Hz, 3H), 0.81 (t, J =
7.2 Hz, 3H); ES-LCMS m / z 482 (M + Hf.
Example 46: N- {[(3R, 5R) -3-butyl-3-ethyl-4-hydroxy-7- (methyloxy) -1,1-dioxide-5phenyl-2,3,4,5-tetrahydro -1,4-benzothiazepin-8-yl] methyl} glycine
(37 , 5R) -3-Butyl-3-ethyl-4-hydroxy-7- (methyloxy) -5phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide -8-carbaldehyde (410 mg, 0.95 mmol) and 1,1-dimethylethyl glycinate (187 mg, 1.43 mmol) were combined in DCM (210 ml) and stirred for 30 min at room temperature. The mixture was treated with NaEIB (OAc) ₃ (403 mg, 1.90 mmol), and the reaction mixture was stirred for 2 days at room temperature where after this time LCMS indicated conversion to the desired product. The mixture was partitioned between DCM and brine, and the phases were separated. The aqueous phase was extracted with DCM, and the organic phases were combined, dried over MgSO ₄ , filtered, and concentrated to a clear oil. The residue was purified on 40 g of silica eluting with 20 to 60% EtOAc / hexanes giving the intermediate tbutil ester as a clear oil: LC-MS (ES ⁺ ) m / z 547.40 [M + H].
The intermediate was dissolved in diethyl ether (20 ml) and treated with 4N HCl in dioxane (20 ml, 66 mmol) at room temperature. THE
The mixture was stirred overnight where after this time the mixture was concentrated to dryness and purified by means of RP-HPLC (column 30 X 150 Sunfire; 47.5 ml / min; MeCN + 0.05% TFA & H ₂ O + 0.05% TF A) giving N- {[(3Ã, 5Ã) -3-butyl-3-ethyl-4-hydroxy-7- (methyloxy) -1,1-dioxide-5 -phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} glycine (306 mg, 65.6% yield) as a white solid: 1 H NMR (400 MHz, DMSO- Jg) 5 ppm 0.79 (t, 7 = 7.0 Hz, 3 H), 0.86 (t, J = 7.3 Hz, 3 H), 1.01-1.53 (m, 5 H ), 1.58-1.72 (m, 1 H), 1.78-1.92 (m, 1 H), 1.96-2.15 (m, 1 H), 3.28-3, 45 (m, 2 H), 3.45 (s,
H), 3.74 (s, 1 H), 3.80-4.31 (m, 4 H), 6.18 (s, 1 H), 6.38 (s, 1 H), 7.33 -7.40 (m, 1 H), 7.44 (t, 7 = 7.4 Hz, 2 H), 7.47-7.69 (m, 2 H), 8.04 (s, 1 H ), 8.14 (s, 1
H), 9.19 (br. S., 1 H), 9.34 (br. S., 1 H) (an extra proton was observed); LCMS (ES ') m / z 489.4 [Ml]; LC-MS (ES ⁺ ) m / z 491.3 [M + H].
Example 47: (20) -2- ({[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide5-phenyl-2,3,4,5-tetra acid -hydro-1,4-benzothiazepin-8-yl] methyl} amino) -4 (methylsulfonyl) butanoic
1,1-dimethylethyl N- {[(3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepin-8-yl] methyl} -Lmethioninate (270 mg, 0.45 mmol) dissolved in TFA (3.4 ml, 44.6 mmol) was cooled in an ice bath and treated by means of addition of H ₂ O ₂ by dripping (100 μΐ, 0.982 mmol). The mixture was allowed to warm to 22 ° C and was stirred overnight where after this time LCMS indicated complete conversion to the desired product with a very small amount of sulfoxide impurity. The reaction mixture was concentrated to dryness and purified by means of RP-HPLC giving (2S) -2 - ({[(37 , 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1,1 -dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8
116 il] methyl} amino) -4- (methylsulfonyl) butanoic (207 mg, 80% yield) as a white solid: NMR 'Η (400 MHz, DMSO-Tg) δ ppm 0.75 (t, 7 = 7 , 0 Hz, 3 H) 0.80 (t, 7 = 7.4 Hz, 3 H) 0.97-1.28 (m, 4 H) 1.32-1.54 (m, 2 H) 1.681 , 80 (m, 1 H) 1.88-2.13 (m, 3 H) 2.59 (d, 1 H) 2.98 (s, 3 H) 3.06 (d, 7 = 14.9 Hz, 1 H) 3.11 - 3.27 (m, 3 H) 3.44 (s, 3 H) 3.55 (d, 7 = 15.0 Hz, 1 H) 3.66-3.74 (m, 1 H) 3.76-3.86 (m, 1 H) 5.94 (d, 7 = 9.2 Hz, 1 H) 6.10 (s, 1 H) 7.27-7, 37 (m, 1 H) 7.37-7.47 (m, 4 H) 8.00 (s, 1 H) (2 protons not observed); LC-MS (ES ⁺ ) m / z 581.3 [ M + H].
Example 48: A - {[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} -7V-hydroxyglycma
1,1-dimethylethyl N- {[(37 ', 57') - 3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra -hydro-1,4-benzothiazepin-8-yl] methyl} glycinate (80 mg, 0.15 mmol) dissolved in DCM (5 ml) was treated with m-CPBA (33.8 mg, 0.15 mmol), then stirred at 22 ° C for 16 h. The mixture was diluted with DCM and stirred with 10% aqueous Na ₂ SO ₃ for 15 min. The organic phase was isolated, dried over MgSO ₄ , filtered, and concentrated to dryness. The residue was purified on 40 g of silica eluting with 30 to 100% EtOAc / hexanes giving two separate products that were not further characterized. Both products were converted separately to the title compound using the procedure below.
The first product (35 mg, 0.064 mmol) dissolved in DCM (1.5 ml) and MeOH (1.5 ml) was treated with acetic acid (0.011 ml, 0.20 mmol) and NaCNBH ₄ (12 mg, 0, 19 mmol) at 22 ° C for 2 h, after which time LCMS indicated full conversion to the intermediate t-Bu-ester. Trifluoroacetic acid (4.95 pL, 0.064 mmol) was added, and the mixture was stirred at 22 ° C for 16 h after which time LCMS indicated
117 conversion to products with MW = 474 and 490. The reaction mixture was concentrated to dryness and the residue was purified by means of RP-HPLC (column 30 X 50 Sunfire column at 55 ml / min; MeCN + 0.05% of TFA & H ₂ O + 0.05% TFA were used as the eluents; from 10% to 100% over 8 minutes) giving N- {[(3R, 5R) -3-butyl-3-ethyl-7 - (methyloxy) -1, 1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} -N-hydroxyglycine (18.9 mg, 60.0% yield): LC-MS (ES) m / z 489.2 [Ml]. LC-MS (ES ⁺ ) m / z 490.9 [M + H]. The 'H NMR of the material was not interpretable due to the physical properties of the title compound.
The second product (15 mg, 0.028 mmol) was subjected to similar conditions giving the title compound which was identical to the title compound prepared above: LC-MS (ES ') m / z 489.1 [Ml]. LC-MS (ES ⁺ ) m / z
491.2 [M + H].
Example 49: Ammonium salt of A - {[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetrahydro -1,4-benzothiazepin-8-yl] methyl} -Amethylglycine
A slurry of 1,1-dimethylethyl N-methylglycinate.HCl (164 mg, 0.902 mmol) in DCM (3 ml) was treated with TEA (0.126 ml, 0.90 mmol) at room temperature for 15 min, after which this time (3R, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5tetrahydro-1,4-benzothiazepine 1,1-dioxide was added -8-carbaldehyde (250 mg, 0.60 mmol), and the mixture was stirred for 1 h. NaHB (OAc) ₃ (255 mg, 1.20 mmol) was added, and the reaction mixture was stirred for 16 h at room temperature where after this time LCMS indicated conversion to the desired product. The mixture was partitioned between DCM and brine, and the phases were separated. THE
The aqueous phase was extracted with DCM, and the organic phases were combined, dried over MgSO ₄ , filtered, and concentrated to a clear oil. The residue was purified on 40 g of silica eluting with 20 to 60% EtOAc / hexanes giving the intermediate t-butyl ester (196 mg) as a white solid: NMR Ή (400 MHz, DMSO-7 ₆ ) δ ppm 0 .75 (t, 7 = 7.0 Hz, 3 H) 0.80 (t, 7 = 7.4 Hz, 3 H) 0.97-1.27 (m, 4 H) 1.33-1, 55 (m, 2 H) 1.42 (s, 9 H) 1.67-1.79 (m, 1 H) 2.00-2.11 (m, 1 H) 2.26 (s, 3 H ) 2.60 (d, 7 = 9.8 Hz, 1 H) 3.06 (d, 7 = 14.8 Hz, 1 H) 3.20 (s, 2 H) 3.42 (s, 3 H ) 3.53 (d, 7 = 14.8 Hz, 1 H) 3.57-3.68 (m, 2 H) 5.93 (d, 7 = 9.8 Hz, 1 H) 6.09 ( s, 1 H) 7.29-7.37 (m, 1 H) 7.41 (d, 7 = 4.3 Hz, 4 H) 7.95 (s, 1 H).
The ester was dissolved in diethyl ether (20 ml) and treated with 4N HCl in dioxane (20 ml, 80 mmol) at room temperature. The mixture was stirred overnight where after this time LCMS indicated ~ 80% conversion to acid. The reaction mixture was stirred for another 24 h, after which time LCMS indicated complete conversion. The mixture was concentrated to dryness and purified by means of RP-HPLC (column 30 X 100 XBridge; Acetonitrile + 0.2% NH ₄ OH and H ₂ O +0.2% NH ₄ OH were used as the solvent system ; from 10% to 70% over 8 minutes, from 100% to 100% to 10 minutes) giving N - {[(3Á, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -
1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} -Nomethylglycine (130 mg, 44.2% yield) ammonium salt as a white solid: NMR Ή (400 MHz, DMSO-7 ₆ ) δ ppm 0.75 (t, 7 = 7.0 Hz, 3 H) 0.80 (t, 7 = 7.4 Hz, 3 H) 0.96-1.28 (m, 4 H) 1.32-1.53 (m, 2 H) 1.68-1.80 (m, 1 H) 1.99-2.11 (m, 1 H) 2.30 (s, 3 H) 2.62 (d, 7 = 9.4 Hz, 1 H) 3.07 (d, 7 = 14.9 Hz, 1 H) 3.24 (s, 2 H) 3.42 (s, 3 H) 3.54 (d, 7 = 14.9 Hz, 1 H) 3.69 (s, 2 H) 5.93 (d, 7 = 8.2 Hz, 1 H) 6.10 (s, 1 H) 7.33 (dq, 7 = 8.5, 4.2 Hz, 1 H) 7.41 (d, 7 = 4.3 Hz, 4 H) 7.98 (s, 1 H) (COOH proton not observed); LC-MS (ES ⁺ ) m / z
489.3 [M + H].
Example 50: 3 - ({[(3Ã, 5Ã) -3-butyl-3-ethyl-4-trifluoroacetate salt
119 hydroxy-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4benzothiazepin-8-yl] methyl} amino) pentanedioic
Dimethyl 3 - ({[(3Ã, 5Ã) -3-butyl-3-ethyl-4-hydroxy-7- (methyloxy) -1,1diioxide-5-phenyl-2,3,4,5-tetrahydro- 1,4-benzothiazepin-8-yl] methyl} amino) pentanedioate (304 mg, 0.52 mmol) dissolved in THF (5 ml) was treated with 1M LiOH (5.15 ml, 5.15 mmol) at temperature then vigorously stirred for 2 h. The reaction mixture was concentrated to remove THF, and the remaining aqueous portion was treated with 1 N HCl until the material started to precipitate (pH = 5). The rubbery mixture was extracted three times with DCM, and the organics were combined, dried over MgSO ₄ , filtered, and concentrated to dryness. The residue was purified by means of RP-HPLC (column 30 X 150 Sunfire at 47.5 ml / min; MeCN + 0.05% TFA & H ₂ O + 0.05% TFA were used as the solvent system; 10% to 80% over 10 minutes) giving 3 - ({[(3Ã, 5Ã) -3-butyl-3-ethyl-4hydroxy-7- (methyloxy) -1,1-dioxide-5-phenyl acid -2,3,4,5-tetrahydro-1,4benzothiazepin-8-yl] methyl} amino) pentanedioic (273.5 mg, 94% yield) as a white solid. NMR Ή (400 MHz, DMSO-7 ₆ ) δ ppm 0.79 (t, 7 = 7.1 Hz, 3 H), 0.85 (t, 7 = 7.4 Hz, 3 H), 1.06 -1.37 (m, 4 H), 1.37-1.50 (m, 1 H), 1.58-1.71 (m, 1 H), 1.78-1.93 (m, 1 H), 2.00-2.14 (m, 1 H), 2,672.88 (m, 4 H), 3.16 (s, 1 H), 3.26-3.45 (m, 2 H) , 3.46 (s, 3 H), 3.71 - 3.85 (m, 1 H), 4.26 (br. S., 2 H), 6.16 (s, 1 H), 6, 38 (s, 1 H), 7.32-7.40 (m, 1 H), 7.44 (t, 7 = 7.5 Hz, 2 H), 7.46-7.65 (m, 2 H), 8.05 (s, 1 H), 8.16 (s, 1 H), 8.62 (br. S., 2 H), 12.92 (br. S., 2 H) (2 extra protons observed). LC-MS (ES ') m / z 561.20 [Ml],
Example 51: {2 - [(37 , 5Ã) -3-butyl-3-ethyl-7 acid bis-ammonium salt
120 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8yl] ethyl} phosphonic
Diethyl {(E) -2 - [(3R, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide5-phenyl-2,3,4,5-tetrahydro-1 , 4-benzothiazepin-8-yl] ethenyl} phosphonate (240 mg, 0.44 mmol) dissolved in EtOH (20 ml) was treated with 10% palladium on carbon (46.5 mg, 0.44 mmol) under a balloon of hydrogen gas at 23 ° C overnight. The catalyst was removed by filtration, and the filtrate was concentrated to dryness giving the intermediate phosphonate as a clear oil. The residue was dissolved in DCM (10 ml) and treated with bromotrimethylsilane (0.227 ml, 1.75 mmol) for 16 h at 23 ° C with stirring. The reaction mixture was concentrated to dryness, then purified by means of RP-HPLC (30x100 XBridge column, MeCN / H ₂ O containing 0.2% NH4OH buffer, from 10 to 80 to 100% over 8 min) {2 [(37 , 5R) -3-butyl-3-ethyl-7- (methyloxy) -1,2-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4 -benzothiazepin-8-yl] ethyl} phosphonic (88 mg, 40.7% yield) bis-ammonium salt as a white solid: NMR Ή (400 MHz, DMSO-7 ₆ ) δ ppm 0.70-0, 85 (m, 6 H) 0.97-1.30 (m, 4 H) 1.29-1.64 (m, 4 H) 1.67-1.81 (m, 1 H) 2.00- 2.12 (m, 1 H) 2.58 (d, 7 = 9.8 Hz, 1 H) 2.63-2.79 (m, 2 H) 3.05 (d, 7 = 14.9 Hz , 1 H) 3.39 (s, 3 H) 3.50 (d, 7 = 14.9 Hz, 1 H) 5.92 (d, 7 = 9.6 Hz, 1 H) 6.05 (s , 1 H) 7.26-7.36 (m, 1 H) 7.36-7.46 (m, 4 H) 7.65 (s, 1 H) (phosphonic acid protons not observed); LC-MS (ES ⁺ ) m / z 496.3 [M + H].
Example 52: Bisammonium salt of A - {[(3R, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5- tetrahydro-1,4-benzothiazepin-8-yl] methyl} -L-serine
121
A slurry of 1,1-dimethylethyl L-serinate.HCl (238 mg, 1.20 mmol) in DCM (8 ml) was treated with TEA (0.168 ml, 1.20 mmol) at room temperature for 15 min. that after this time was added
(37 , 5R) -3-Butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-dioxide -carbaldehyde (250 mg, 0.60 mmol), and the mixture was stirred for 1 h. NaHB (OAc) ₃ (319 mg, 1.504 mmol) was added, and the reaction mixture was stirred for 16 h at room temperature. The mixture was partitioned between DCM and brine, and the phases were separated. The aqueous phase was extracted with DCM, and the organic phases were combined, dried over MgSO ₄ , filtered, and concentrated to a clear oil. The residue was treated with 4N HCl in dioxane (10 ml, 40.0 mmol) at 22 ° C with stirring overnight. The reaction mixture was concentrated to dryness, then purified by means of RP-HPLC (30x100 XBridge column, MeCN / H ₂ O containing 0.2% NH ₄ OH buffer, from 10 to 70 to 100% over 8 min ) giving N - {[(3R, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} -L-serine (194 mg, 63.9% yield) bis-ammonium salt as a white solid: NMR 'H (400 MHz, DMSO-7 ₆ ) δ ppm 0.75 (t, 7 = 7.0 Hz, 3 H) 0.80 (t, 7 = 7.4 Hz, 3 H) 0.96-1 , 29 (m, 4 H) 1.32-1.54 (m, 2 H) 1.66-1.82 (m, 1 H) 1.98-2.13 (m, 1 H) 2.62 (d, 7 = 9.6 Hz, 1 H) 3.06 (d, 7 = 15.0 Hz, 1 H) 3.16 (t, 7 = 5.2 Hz, 1 H) 3.45 (s , 3 H) 3.56 (d, 7 = 14.9 Hz, 1 H) 3.65 (qd, 7 = 11.1, 5.2 Hz, 2 H) 3.79-3.94 (m, 2 H) 5.02 (br. S., 1 H) 5.94 (d, 7 = 9.6 Hz, 1 H) 6.10 (s, 1 H) 7.28-7.37 (m, 1 H) 7.37-7.47 ( _m , 4 H) 8.02 (s, 1 H) (2 replacements not observed); LC-MS (ES ⁺ ) m / z 505.3 [M + H].
Example 53: bis - ammonium salt of A - {[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1, 1
122 dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} -L-cystine
Dimethyl N- {[(3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5phenyl-2,3,4,5-tetrahydro-1,4- benzothiazepin-8-yl] methyl} -L-cystinate (167 mg, 0.25 mmol) dissolved in THF (5 ml) was treated with IM LiOH (5 ml, 5.0 mmol), then vigorously stirred for 1 h . The mixture was neutralized with 1N HCl (5 ml) and concentrated to remove THF. The residue was extracted twice with DCM, and the organic phases were combined, dried over MgSO ₄ , filtered, and concentrated to dryness. A portion of the residue was purified by means of RP-HPLC (30 X 100 XBridge column; MeCN + 0.2% NH ₄ OH and H ₂ O +0.2% NH ₄ OH were used as the solvent system; 10% to 70% over 8 minutes) giving N - {[(3Ã, 5Ã) -3-butyl3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-2,3,4 , 5-tetrahydro-1,4-benzothiazepin8-yl] methyl} -L-cystine (20.5 mg, 0.032 mmol, 12.81% yield) as a white solid: LC-MS (ES) m / z 638.25 [Ml]; LC-MS (ES ⁺ ) m / z 640.27 [M + H].
Example 54: {[(3Ã, 5Ã) -3-butyl-3-ethyl-4-hydroxy-7- (methyloxy) -1,1dioxide-5-phenyl-2,3,4,5-tetrahydro- 1,4-benzothiazepin-8-yl] methyl} phosphonic
Diethyl {[(3Ã, 5R) -3-butyl-3-ethyl-4-hydroxy-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetrahydro-1,4 -benzothiazepin-8-yl] methyl} phosphonate (48.5 mg, 0.088 mmol) dissolved in DCM (1 ml) was treated with bromine (trimethyl) silane (67.1 mg, 0.44 mmol) at room temperature for
123
H. The reaction mixture was concentrated to dryness, then purified by means of RP-HPLC (column 30 X 75 Sunfire at 55 ml / min; MeCN + 0.05% TFA & H ₂ O + 0.05% TFA were used as the solvent system; from 10% to 80% over 11 minutes) giving {[(3R, 5R) -3-butyl-3-ethyl-4-hydroxy7- (methyloxy) -1,1-dioxide-5-acid -phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8il] methyl} phosphonic (35.3 mg, 81% yield) as a white solid: NMR Ή (400 MHz, DMSO- 7 ₆ ) δ ppm 0.79 (t, 7 = 7.3 Hz, 3 H), 0.82-0.94 (m, 3 H), 1.05-1.52 (m, 5 H), 1.55-1.67 (m, 1 H), 1.77-2.02 (m, 1 H), 2.02-2.15 (m, 1 H), 2.83-3.10 ( m, 2 H), 3.26-3.43 (m, 2 H), 3.38 (s, 3 H), 3.96 (s, 0 H), 6.09 (s, 1 H), 6.33 (s, 1 H), 7.30-7.38 (m, 1 H), 7.42 (t, 7 = 7.6 Hz, 2 H), 7,457.58 (m, 2 H) , 7.84 (d, 7 = 2.5 Hz, 1 H), 8.00-8.05 (m, 1 H); LC-MS (ES ') m / z 496-38 [Ml]. LC-MS (ES ⁺ ) m / z 498.18 [M + H].
Example 55: {(£) -2 - [(3R, 5R) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3-bis-ammonium salt , 4,5-tetrahydro-1,4-benzothiazepin-8il] ethenyl} phosphonic
Diethyl {(E) -2 - [(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1,2-dioxide5-phenyl-2,3,4,5-tetrahydro-1 , 4-benzothiazepin-8-yl] ethenyl} phosphonate (95 mg, 0.173 mmol) was dissolved in DCM (4 ml) and treated with bromotrimethylsilane (0.090 ml, 0.69 mmol) at 22 ° C overnight. with agitation. The reaction mixture was concentrated to dryness, and the crude product was purified by means of RP-HPLC (30x100 XBridge column, MeCN / H ₂ O containing 0.2% NH4OH buffer, from 10 to 50 to 100% over 8 min) giving {(E) -2 - [(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-2,3,4,5-tetra acid -hydro-1,4-benzothiazepin-8-yl] ethylene} phosphonic (51 mg, 59.8% yield) bis-ammonium salt as a white solid: NMR ^J H (400 MHz, DMSO-7 ₆ ) δ ppm 0.76 (t, 7 = 7.0 Hz, 3 H) 0.81 (t, 7 = 7.4 Hz, 3 H) 0.98
124
1.30 (m, 4 Η) 1.31-1.55 (m, 2 Η) 1.67-1.81 (m, 1 Η) 2.00-2.14 (m, 1 Η) 2, 65 (d, 7 = 10.2 Hz, 1 Η) 3.08 (d, 7 = 14.9 Hz, 1 Η) 3.43 (s, 3 Η) 3.55 (d, 7 = 14.9 Hz, 1 Η) 5.94 (d, 7 = 10.0 Hz, 1 Η) 6.10 (s, 1 Η) 6.31 (dd, 7 = 17.4, 13.9 Hz, 1 H) 7.13 (dd, 7 = 19.3, 17.8 Hz, 1 H) 7.28-7.37 (m, 1 H) 7.42 (d, 7 = 4.5 Hz, 4 H) 7 , 93 (s, 1 H) (acid protons not observed). Large coupling constant (17.57 Hz) suggests E isomer; LC-MS (ES ⁺ ) m / z 494.3 [M + H]. Example 56: JV ammonium salt - {[(32 , 5R) -3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepin-8-yl] methyl} -L-threonine
HO,
A slurry of 1,1-dimethylethyl L-threoninate (255 mg, 1.20 mmol) in DCM (3 ml) was treated with TEA (0.168 ml, 1.20 mmol) at room temperature for 15 min, after which this time has been added
(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8- 1,1-dioxide carbaldehyde (250 mg, 0.602 mmol), and the mixture was stirred for 1 h. NaHB (OAc) ₃ (255 mg, 1.20 mmol) was added, and the reaction mixture was stirred for 16 h. The mixture was partitioned between DCM and brine, and the phases were separated. The aqueous phase was extracted with DCM, and the organic phases were combined, dried over MgSO ₄ , filtered, and concentrated giving the ester intermediate as a clear oil. The residue was treated with 4N HCl in 1,4-dioxane (10 ml, 40.0 mmol) at room temperature overnight. The mixture was concentrated to dryness, then purified by means of RP-HPLC (30x100 XBridge column, MeCN / H ₂ O containing 0.2% NH4OH buffer, from 10 to 70 to 100% over 10 min) giving N- {[(3Ã, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8- il] methyl} -L-threonine (188 mg, 60.2% yield) ammonium salt as a white solid: NMR 'H (400
125
MHz, DMSO-7 ₆ ) δ ppm 0.75 (t, 7 = 7.0 Hz, 3 H) 0.80 (t, 7 = 7.4 Hz, 3 H) 0.971.28 (m, 4 H) 1.16 (d, 7 = 6.4 Hz, 3 H) 1.33-1.54 (m, 2 H) 1.68-1.79 (m, 1 H) 2.00-2.12 ( m, 1 H) 2.59 (d, 7 = 9.8 Hz, 1 H) 2.96 (d, 7 = 4.7 Hz, 1 H) 3.06 (d, 7 = 14.9 Hz, 1 H) 3.44 (s, 3 H) 3.54 (d, 7 = 14.9 Hz, 1 H) 3.67-3.93 (m, 3 H) 5.94 (d, 7 = 9 , 4 Hz, 1 H) 6.09 (s, 1 H) 7.29-7.37 (m, 1 H) 7.37-7.46 (m, 4 H) 8.03 (s, 1 H ) (3 replaceable protons not observed); LC-MS (ES ⁺ ) m / z
O., OH _ _
519.3 [M + H]. _
Example 57: sàLjâíe Hç_l ^ o ^ ^^^^ - {[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1,1dióxido-5-phenyl-2,3,4, ^L 5-tetra-4-yl-4-benzothiazepin-8-yl] methyl} -D-proline
O
1,1-Dimethylethyl D-prolinate (206 mg, 1.20 mmol) and (32 , 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2-1,1-dioxide , 3,4,5-tetrahydro-1,4-benzothiazepine-8-carbaldehyde (250 mg, 0.60 mmol) was combined in DCM (5 ml), and the mixture was stirred for 1 h. NaHB (OAc) ₃ (319 mg, 1.50 mmol) was added, and the reaction mixture was stirred for 3 days at room temperature. The mixture was partitioned between DCM and H ₂ O, and the phases were separated. The aqueous phase was extracted with DCM, and the organic phases were combined, dried over MgSO ₄ , filtered, and concentrated to a clear oil.
The residue was treated with TFA (4 ml, 51.9 mmol) at room temperature for 3 h. The reaction mixture was concentrated to dryness, then purified by means of RP-HPLC (column 30 X 100 XBridge; MeCN + 0.1% NH ₄ OH and H ₂ O +0.1% NH ₄ OH were used as the system solvent; 10% to 70% over 8 minutes) giving ammonium salt of 1 {[(3Ã, 5Á) -3-butyl-3-ethyl-7- (methyloxy) -1, l-dioxide-5- phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} -D-proline (333 mg,> 99% yield) as a white solid: NMR Ή (400 MHz , DMSO-7 ₆ ) δ ppm 0.75 (t, 7 = 7.0 Hz, 3 H), 0.81 (t, 7 = 7.4 Hz, 3 H), 0.95-1.31 ( m, 4 H), 1.34-1.56 (m, 2 H), 1.67-2.14 (m, 5 H), 2.36-2.47 (m, 1 H), 2, 58-2.81 (m, 1 H), 3.06 (d, 7 = 15.0
126
Hz, 1 Η), 3.14-3.27 (m, 1 Η), 3.35-3.47 (m, 1 Η), 3.49 (s, 3 Η), 3.62 (d, 7 = 15.0 Hz, 1 Η), 4.17-4.30 (m, 1 Η), 4.36 (d, 7 = 13.1 Hz, 1 Η), 4.50 (d, 7 = 13.1 Hz, 1 Η), 5.96 (br. S., 1 Η), 6.17 (s, 1 Η), 7.31-7.55 (m, 5 Η), 8.09 ( s, 1 Η), 9.84 (br. s., 1 H); LC-MS (ES ^- ) m / z 513.6 [Ml]. LC-MS (ES ⁺ ) m / z 515.3 [M + H].
Example 58: ammonium salt of A ² - {[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepin-8-yl] methyl} -L-lysine
A 1,1-dimethylethyl # - {[(1,1-dimethylethyl) oxy] carbonyl} -L-lysinate.HCl (890 mg, 2.63 mmol) in DCM (10 ml) was treated with TEA ( 0.380 ml, 2.73 mmol) at room temperature for 15 min, after which (3R, 5R) -3-butyl-3-ethyl-7 (methyloxy) -5-phenyl 1,1-dioxide -2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbaldehyde (600 mg, 1.444 mmol), and the mixture was stirred for 1 h. NaHB (OAc) ₃ (765 mg, 3.61 mmol) was added, and the reaction mixture was stirred for 16 h at room temperature. The mixture was partitioned between DCM and brine, and the phases were separated. The aqueous phase was extracted with DCM, and the organic phases were combined, dried over MgSO ₄ , filtered, and concentrated to a clear oil. The residue was treated with 4N HCl in 1,4-dioxane (10 ml, 40.0 mmol) at 22 ° C with stirring overnight. The mixture was concentrated to dryness and purified by means of RP-HPLC (30x100 XBridge column, MeCN / H ₂ O containing 0.2% NH4OH buffer, from 10 to 80 to 100% over 10 min) giving A ² - {[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) 1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin- 8-yl] methyl} -L-lysine (297 mg, 37.7% yield) ammonium salt as a pink foam: NMR ^! H (400 MHz, DMSO-7 ₆ ) δ ppm 0.75 (t, 7 = 7.0 Hz, 3 Η) 0.80 (t, 7 = 7.4 Hz, 3
127
Η) 0.97-1.60 (m, 12 Η) 1.67-1.80 (m, 1 Η) 1.99-2.14 (m, 1 Η) 2.54 (d, 7 = 9 , 8 Hz, 1 Η) 2.64-2.78 (m, 3 Η) 3.06 (d, 7 = 14.9 Hz, 1 Η) 3.41 (s, 3 Η) 3.50 (dd , 7 = 15.0, 9.3 Hz, 2 Η) 3.65 (d, 7 = 15.0 Hz, 1 Η) 5.94 (d, 7 = 9.6 Hz, 1 Η) 6.06 (s, 1 Η) 7.32 (dq, 7 = 8.5, 4.2 Hz, 1 H) 7.41 (d, 7 = 4.5 Hz, 4 H) 7.99 (s, 1 H ) (4 proton replaceable protons not observed); LC-MS (ES) m / z 546.4 [M + H].
Example 59: 2V ammonium salt ² - {[(37 , 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -l, ldioxide-o-phenyl-l ^^^ - tetrahydro -LÚ-benzothiazepin-S-iljmetil} - #, # dimethyl-L-lysine
A slurry of A ^ X-dimethyl-L-lysine (250 mg, 1.177 mmol) in DCM (3 ml) was treated with TEA (0.165 ml, 1.19 mmol) at room temperature for 15 min, after which time was added
(3R, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8- 1,1-dioxide carbaldehyde (250 mg, 0.60 mmol) and THF (3.00 ml), and the mixture was stirred for 1 h. NaHB (OAc) ₃ (255 mg, 1.203 mmol) was added, and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was partitioned between DCM and H ₂ O, and the phases were isolated. While the organic phase showed a mix of aldehyde and alcohol through LCMS, the aqueous phase showed the presence of the desired product. The aqueous phase was isolated, and the pH was adjusted to 10 with 1M Na ₂ CO ₃ aq. The aqueous layer was extracted five times with DCM, and the organic phases were combined, dried over MgSO ₄ , filtered, and concentrated to dryness giving the crude product as a brown oil. The crude material was purified by means of RP-HPLC (30x100 XBridge column, MeCN / H ₂ O containing 0.2% NH ₄ OH buffer, from 10 to 80 to 100% over 10 min)
128 giving ammonium salt of À / ² - {[(3jR, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepin-8-yl] methyl} -A ⁶ , A ⁶ -dimethyl-Llisine (23.5 mg, 6.8% yield) as a white solid: NMR Ή (400 MHz, DMSO- 7 ₆ ) δ ppm 0.75 (t, 7 = 7.0 Hz, 3 H) 0.80 (t, 7 = 7.4 Hz, 3 H) 0.981.66 (m, 12 H) 1.68- 1.80 (m, 1 H) 1.99-2.09 (m, 1 H) 2.11 (s, 6 H) 2.14-2.23 (m, 2 H) 2.58 (d, 7 = 9.8 Hz, 1 H) 2.99-3.09 (m, 2 H) 3.43 (s, 3 H) 3.54 (d, 7 = 14.9 Hz, 1 H) 3, 59-3.83 (m, 2 H) 5.94 (d, 7 = 9.4 Hz, 1 H) 6.09 (s, 1 H) 7.28-7.38 (m, 1 H) 7 , 38-7.46 (m, 4 H) 8.02 (s, 1 H) (2 replaceable protons not observed); LC-MS (ES ⁺ ) m / z 574.4 [M + H].
Examples 60 and 61: tetra-ammonium salt of [({[(3Ã, 5Á) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4, 5-tetrahydro-1,4-benzothiazepin-8yl] methyl} imino) dimethanediyl] bis (phosphonic acid) and triamonium salt of [({[(3Ã, 5Ã) -3-butyl-3-ethyl-7-acid - (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-4-benzothiazepin-8-yl] methyl} {[(ethyloxy) (hydroxy) phosphoryl] methyl } amino) methyl] phosphonic
HO
Tetraethyl [({[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5 phenyl-2,3,4,5-tetrahydro-1,4 benzothiazepin-8-yl] methyl} imino) dimethanediyl] bis (phosphonate) (100 mg, 0.14 mmol) dissolved in DCM (5 ml) was treated with bromine (trimethyl) silane (171 mg, 1.116 mmol) at 23 ° C overnight. The mixture was concentrated to dryness, and the crude product was purified by means of RP-HPLC (column 30 X 100 XBridge under basic conditions; MeCN +0.1% NH4OH and H ₂ O +0.1% ΝΉ4ΟΗ were used as the solvent system; from 10% to 55% over 6 minutes, from 100% to 100% to 8 minutes) giving [({[(3Á, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-2,3,4,5-tetrahydro129
1,4-benzothiazepin-8-yl] methyl} imino) dimethanediyl] bis (phosphonic acid) (45.4 mg, 53.8% yield) tetra-ammonium salt: NMR (400 MHz, DMSOd ₆ ) δ ppm 0.75 (t, 7 = 6.9 Hz, 3 H) 0.80 (t, 7 = 7.5 Hz, 3 H) 0.97-1.29 (m, 4 H) 1.32-1 .55 (m, 2 H) 1.68-1.81 (m, 1 H) 1.98-2.14 (m, 1 H) 2.58-2.77 (m, 5 H) 3.09 (d, 7 = 14.8 Hz, 1 H) 3.41 (s, 3 H) 3.52 (d, 7 = 15.0 Hz, 1 H) 3.75-3.96 (m, 2 H ) 5.94 (d, 7 = 8.6 Hz, 1 H) 6.08 (s, 1 H) 7.25-7.37 (m, 1 H) 7.36-7.49 (m, 4 H) 7.90 (s, 1 H) (phosphonic acid protons not observed); LC-MS (ES ⁺ ) m / z 605.2 [M + H]) and acid [({[(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1, l-dioxide5 -phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} {[(ethyloxy) (hydroxy) phosphoryl] methyl} amino) methyl] phosphonic (10.8 mg, 12.2% yield) triamonium salt: (NMR ^! H (400 MHz, DMSO-cQ δ ppm 0.75 (t, 7 = 7.0 Hz, 3 H) 0.80 (t, 7 = 7, 4 Hz, 3 H) 0.96-1.28 (m, 4 H) 1.08 (t, 7 = 7.0 Hz, 3 H) 1.31-1.54 (m, 2 H) 1, 68-1.80 (m, 1 H) 1.99-2.11 (m, 1 H) 2.61-2.79 (m, 5 H) 3.06 (d, / = 14.9 Hz, 1 H) 3.41 (s, 3 H) 3.53 (d, 7 = 14.9 Hz, 1 H) 3.64-3.76 (m, 2 H) 3.76-3.93 (m , 2 H) 5.94 (d, 7 = 9.6 Hz, 1 H) 6.08 (s, 1 H) 7.26-7.36 (m, 1 H) 7.36-7.48 ( m, 4 H) 7.94 (s, 1 H) (phosphonic acid protons not observed); LC-MS (ES ⁺ ) m / z 633.3 [M + H]).
Example 62: [({[(37 , 5Á) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5- trifluoroacetate salt tetrahydro-1,4-benzothiazepin-8yl] methyl} amino) methyl] phosphonic
Diethyl [({[(3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4- benzothiazepin-8-yl] methyl} amino) methyl] phosphonate (36.3 mg, 0.064 mmol) dissolved in DCM (1 ml) was treated with bromine (trimethyl) silane (100 mg, 0.65 mmol) at 23 ° C for 18 h. The mixture was concentrated to dryness, and the crude product was purified by means of RP
130
HPLC (column 30 X 75, C18, 5um H ₂ O Sunfire Column at 55 ml / min; MeCN + 0.05% TFA & H ₂ O + 0.05% TFA were used as the solvent system; from 10 to 100 over 8 min., From 100 to 100 (10 min) giving acid [({[(3R, 5Á) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5- phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} amino) methyl] phosphonic (6.0 mg, 18.4% yield) trifluoroacetate salt as a white glass: NMR ^! H (400 MHz, DMSO-7 ₆ ) δ ppm 0.75 (t, 7 = 7.0 Hz, 3 H) 0.81 (t, 7 = 7.4 Hz, 3 H) 0.951.32 (m, 4 H) 1.33-1.56 (m, 2 H) 1.68-1.80 (m, 1 H) 1.98-2.12 (m, 1 H) 2.632.73 (m, 1 H ) 3.00-3.13 (m, 2 H) 3.48 (s, 3 H) 3.57-3.66 (m, 2 H) 4.14-4.30 (m, 2 H) 5 , 86-6.02 (m, 1 H) 6.15 (s, 1 H) 7.31-7.50 (m, 5 H) 8.10 (s, 1 H) (3 replaceable protons not observed) ; LC-MS (ES) m / z 509.5 [Ml]. LC-MS (ES ⁺ ) m / z 511.2 [M + H].
Example 63: ammonium salt of l - {[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -l, ldioxide-5-phenyl-2,3,4,5-tetrahydro -1,4-benzothiazepin-8-yl] methyl} -L-proline
1,1-Dimethylethyl L-prolinate.HCl (206 mg, 1.203 mmol) and (3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3, 1,1dioxide, 4,5-tetrahydro-1,4-benzothiazepine-8-carbaldehyde (250 mg, 0.60 mmol) was combined in DCM (5 ml), and the mixture was stirred for 1 h. NaHB (OAc) ₃ (319 mg, 1.504 mmol) was added, and the reaction mixture was stirred for 16 h at room temperature. The mixture was partitioned between DCM and brine, and the phases were separated. The aqueous phase was extracted with DCM, and the organic phases were combined, dried over MgSO ₄ , filtered, and concentrated to a clear oil. The residue was treated with 4N HCl in 1,4-dioxane (10 ml, 40.0 mmol) at room temperature overnight. The reaction mixture was concentrated to dryness and purified by means of RP-HPLC (column 30
131
X 100 XBridge column; MeCN + 0.2% NH ₄ OH and H ₂ O +0.2% NH4OH were used as the solvent system; from 10% to 70% over 8 minutes, from 100% to 100% to 10 minutes) giving l - {[(3Ã, 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1 - dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} -L-proline (260 mg, 84% yield) ammonium salt as a white solid: NMR 'H (400 MHz, DMSO-Jg) δ ppm 0.75 (t, 7 = 7.0 Hz, 3 H) 0.80 (t, 7 = 7.4 Hz, 3 H) 0.96-1, 29 (m, 4 H) 1.32-1.53 (m, 2 H) 1.64-1.94 (m, 4 H) 1.99-2.16 (m, 2 H) 2.62 ( d, 7 = 10.0 Hz, 1 H) 2.98-3.12 (m, 2 H) 3.26-3.37 (m, 2 H) 3.44 (s, 3 H) 3.55 (d, 7 = 15.0 Hz, 1 H) 3.82 (d, 7 = 14.1 Hz, 1 H) 3,894.00 (m, 1 H) 5.94 (d, 7 = 9.2 Hz , 1 H) 6.10 (s, 1 H) 7.27-7.37 (m, 1 H) 7.42 (d, 7 = 4.5 Hz, 4 H) 7.99 (s, 1 H ) (COOH proton not observed); LC-MS (ES ⁺ ) m / z 513.5 [M + H].
Example 64: ({[(3R, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl2,3,4,5-tetrahydro-1 acid, 4-benzothiazepin-8-yl] methyl} amino) (oxo) acetic
Step 1: A solution of {[(3Ã, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -
1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} amine (77 mg, 0.19 mmol) in DCM (924 μΐ) at 0 ° C it was treated with Et ₃ N (56.7 μΐ, 0.407 mmol) followed by methyl chlorine (oxo) acetate (18.7 μΐ, 0.203 mmol). The reaction was stirred for 30 min, then heated to 25 ° C and stirred for an additional 1 h. LCMS indicated 92: 8 / prod: SM. More acid chloride (2 µl) was added, then this was stirred at 25 ° C for 2 h. The reaction was diluted with DCM and H ₂ O, the layers were separated, and the aqueous layer extracted with DCM (3x). The combined organic layers were dried (MgSO ₄ ), filtered, and concentrated in vacuo giving methyl ({[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1.1
132 dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} amino) (oxo) acetate (93 mg, 100% yield) which was used as such which in the next step: NMR Ή (CDC1 ₃ ) δ 7.96 (s, 1H), 7.28-7.54 (m, 6H), 6.18 (s, 1H), 6.06 (s, 1H ), 4.48 (d, J = 6.0 Hz, 2H), 3.87 (s, 3H), 3.54 (s, 3H), 3.41 (d, J = 14.8 Hz, 1H ), 2.96-3.10 (m, 2H), 2.06-2.22 (m, 1H), 1.76-1.90 (m, 1H), 1.031.58 (m, 6H), 0.88 (t, J = 7.4 Hz, 3H), 0.81 (t, J = 7.0 Hz, 3H); LC-MS (ES ⁺ ) m / z 503 [M + H].
Step 2: A solution of methyl ({[(37 , 5Ã) -3-butyl-3-ethyl-7 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepin-8yl] methyl} amino) (oxo) acetate (93 mg, 0.185 mmol) in THF (694 μΐ) and H ₂ O (231 μΐ) at 0 ° C was treated with 1M aq. (204 μΐ, 0.204 mmol). The reaction was stirred at 0 ° C for 60 min, then heated to 25 ° C and stirred for 1 h. The reaction was diluted with EtOAc and acidified with diluted HCl. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered, and concentrated in vacuo. The residue was triturated with hexanes / Et ₂ O, then this was collected as a white solid by filtration. ({[(3 / , 57 ) - 3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide5-phenyl-2,3,4,5-tetrahydro- 1,4-benzothiazepin-8-yl] methyl} amino) (oxo) acetic (79 mg, 87% yield) as a white solid: Ή NMR (DMSO-d ₆ ) δ ppm 9.37 (br. s. , 1H), 7.75 (br., 1H), 7.27-7.65 (m, 5H), 6.17 (br., 1H), 5.92 (br. S., 1H), 4.16 - 4.38 (m, 2H), 3.48 (m 4H), 3.03 (br s, 1H), 1.95 - 2.26 (m, 1H), 1.62 - 1.88 (m, 1H), 0.94 - 1.61 (m, 6H), 0.46 - 0.95 (m, 6H) ^; LCMS (ES ⁺ ) m / z 489 [M + H],
Example 65: 3 - ({[3,3-dibutyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin trifluoroacetate salt -8yl] methyl} amino) pentanedioic
133
Step 1: A solution of 3,3-dibutyl-7 (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbaldehyde 1,1-dioxide (150 mg, 0.338 mmol) and dimethyl 3-aminopentanedioate (89 mg, 0.507 mmol) in
1,2-dichloroethane (DCE) (3.36 ml) was treated with acetic acid (19.36 μΐ, 0.338 mmol) and stirred at 25 ° C for 1 h. The reaction was treated with NaHB (OAc) ₃ (71.7 mg, 0.338 mmol), then stirred for 15 h. The reaction was treated with more NaHB (OAc) ₃ (71.7 mg, 0.338 mmol), then stirred for 4 h. The reaction was poured into DCM and Na ₂ CO ₃ aq. to 10% _; The layers were separated, and the aqueous layer was extracted with DCM (2x). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered, and concentrated in vacuo. The residue was purified by preparative chromatography on SiO ₂ using hexanes: EtOAc as eluent giving dimethyl 3 - ({[3,3-dibutyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-2,3 , 4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} amino) pentanedioate (142 mg, 69.7% yield).
Step 2: A solution of dimethyl 3 - ({[3,3-dibutyl-7- (methyloxy) -
1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} amino) pentanedioate (140 mg, 0.232 mmol) in THF (1.05 ml) and H ₂ O (348 μΐ) at 25 ° C was treated with LiOH IN (929 μΐ, 0.929 mmol), then stirred for 4 h. THF was removed under reduced pressure, then the residue was lipophilized to a white solid. The material was purified via RP-HPLC purification (30 X 150 mm column, Cl8 5um H ₂ O Sunfire Column; MeCN + 0.05% TFA & H ₂ O + 0.05% TFA were used as the solvent system ; from 10 to 100% over 10 min.) giving acid 3 - ({[3,3-dibutyl-7- (methyloxy) -
1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} amino)
134 pentanedioic (81 mg, 50.6% yield) trifluoroacetate salt as an amorphous white solid: NMR ^J H (DMSO-do) δ ppm 12.79 (br. S., 1H), 8.75 (br. s, 1H), 8.48 (br., 1H), 8.10 (s, 1H), 7.28 - 7.56 (m, 5H), 6.17 (s, 1H), 5, 98 (s, 1H), 4.27 (br., 2H), 3.69 - 3.80 (m, 1H), 3.62 (d, J = 14.8 Hz, 1H), 3, 49 (s, 3H), 3.10 (d, J = 14.8 Hz, 1H), 2.62 - 2.89 (m, 4H), 2.07 (br. S., 1H), 1, 76 (br. S, 1H), 0.99-1.55 (m, 10H), 0.86 (t, J = 6.6 Hz, 3H), 0.76 (t, J = 6.9 Hz , 3H); LC-MS (ES ⁺ ) m / z 575.1 [M + H].
Example 66: 7V trifluoroacetate salt - {[3,3-dibutyl-7- (methyloxy) -1, ldioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8 -il] methyl} glycine

Step 1: A solution of 3,3-dibutyl-7 (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbaldehyde 1,1-dioxide (150 mg, 0.338 mmol) and 1,1-dimethylethyl glycinate (44.4 mg, 0.338 mmol) in 1,2dichloroethane (DCE) (3.36 ml) was treated with acetic acid (19.36 μΐ, 0.338 mmol) and stirred at 25 ° C for 1 h. The reaction was treated with NaHB (OAc) ₃ (71.7 mg, 0.338 mmol), then stirred for 5 h. More NaHB (OAc) ₃ (71.7 mg, 0.338 mmol) was added, then stirring was continued at 25 ° C for 4 h. The reaction was poured into DCM and Na ₂ CO ₃ aq. 10%, The layers were separated and the aqueous layer was extracted with DCM (2x). The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered, and concentrated in vacuo. The residue was purified by means of preparative chromatography on SiO ₂ using hexanes: EtOAc as the eluent giving 1,1-dimethylethyl N - {[3,3-dibutyl-7- (methyloxy) -1,1-dioxide-5-phenyl- 2,3,4,5tetrahydro-1,4-benzothiazepin-8-yl] methyl} glycinate (100 mg, 52.9% yield).
Step 2: A 1,1-dimethylethyl N - {[3,3-dibutyl-7 solution
135 (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8yl] methyl} glycinate (130 mg, 0.233 mmol) in DCM (2 ml ) at 25 ° C was treated with excess 4M HCl in 1,4-dioxane (3.53 ml, 116 mmol), then stirred for 15 h. The reaction was concentrated in vacuo, then the residue was triturated with Et ₂ O. A white solid was collected by filtration, then purified by means of RP-HPLC (column 30 X 150 mm, C18 5 um H ₂ O Sunfire Column ; MeCN + 0.05% TFA & H ₂ O + 0.05% TFA as the solvent system; 10 to 100% over 10 min.) Giving N - {[3,3dibutyl-7- (methyloxy ) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin8-yl] methyl} glycine (70 mg, 48.8% yield) trifluoroacetate salt as a white amorphous solid: 1 H NMR (DMSO-dg) δ ppm 13.72 (br. s., 1H), 8.76 - 9.61 (m, 2H), 8.07 (s, 1H), 7 , 26 - 7.52 (m, 5H), 6.17 (s, 1H), 5.75 - 6.04 (br s, 1H), 4.05 - 4.28 (m, 2H), 3, 84 (br., 2H), 3.63 (d, J = 14.9 Hz, 1H), 3.48 (s, 3H), 3.10 (d, J = 14.9 Hz, 1H) , 1.99 - 2.15 (m, 1H), 1.64 - 1.84 (m, 1H), 0.99 - 1.52 (m, 10H), 0.87 (t, J = 6, 6 Hz, 3H), 0.75 (t, J = 6.9 Hz, 3H); LCMS (ES ⁺ ) m / z 503.1 [M + H].
Example 67: {[3,3-dibutyl-7- (methyloxy) -1, dihydro-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8- trifluoroacetate salt il] methyl} phosphonic
A solution of diethyl {[3,3-dibutyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} phosphonate (200 mg, 0.354 mmol) in DCM (6.9 ml) at 25 ° C was treated with TMSBr (213 μΐ, 1.640 mmol), then stirred at 25 ° C for 15 h. The reaction was concentrated in vacuo, then triturated with Et ₂ O / hexanes. A white solid was collected by filtration which was purified via preparative RP-HPLC (column 30 X 150 mm, Cl8 5um H ₂ O Sunfire Column; MeCN + 0.05% TFA & H ₂ O
136 + 0.05% TFA was used as the solvent system; 10 to 80% over 12 min.) giving {[3,3-dibutyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] methyl} phosphonic (60 mg, 27.2% yield) trifluoroacetate salt as a white solid: NMR ^] H (CDC1 ₃ ) δ ppm 7.87 (br. s., 1H), 7.50-7.73 (m, 5H), 6.58 (s, 1H), 6.50 (s, 1H), 3.89 ( d, J = 15.0 Hz, 1H), 3.61 (s, 3H), 3.34-3.66 (m, 3H), 2.83 - 3.06 (m, 1H), 2.44 2.75 (m, 1H), 1.18-2.02 (m, 10H), 0.74 - 1.04 (m, 6H); LC-MS (ES ⁺ ) m / z 510.4 [M + H].
Example 68: A - ([(3Ã, 5Á) -3-butyl-7- (dimethylamino) 3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetra- trifluoroacetate salt hydro-1,4-benzothiazepin-8il] methyl} glycine
(3R, 5R) -3-Butyl-7- (dimethylamino) -3-ethyl-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbaldehyde 1,1-dioxide ( 22 mg, 0.051 mmol) and 1,1-dimethylethyl glycinate (33.7 mg, 0.257 mmol) were combined in DCM (4 ml) and stirred for 1 h at room temperature. The mixture was treated with NaHB (OAc) ₃ (76 mg, 0.359 mmol), then stirred for 2 days at room temperature. The reaction mixture was partitioned between DCM and brine, and the phases were separated. The aqueous phase was extracted with DCM, and the organic phases were combined, dried over MgSO ₄ , filtered, and concentrated to a clear oil. The residue was purified on 4 g of silica gel eluting with 30 to 100% EtOAc / hexanes giving the intermediate t-butyl ester (18 mg, 0.033 mmol, 64.2% yield) as a clear oil. LC-MS (ES ⁺ ) m / z 544.34 [M + H]. The ester was treated with 4N HCl in 1,4-dioxane (1.283 ml, 5.13 mmol) at room temperature. The mixture was stirred overnight, then concentrated to dryness. O
137 material was purified by means of RP-HPLC (column 30 X 75 Sunfire; 55 ml / min; 10% to 100% MeCN in H ₂ O with 0.05% TFA buffer over 8 minutes) giving salt trifluoroacetate N - {[(3Ã, 57 ) - 3-butyl-7 (dimethylamino) -3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1, 4benzothiazepin-8-yl] methyl} glycine (17.1 mg, 0.024 mmol, 46.5% yield) as a clear oil: NMR Ή (400 MHz, DMSO-J ₆ ) δ ppm 0.77 (t, 7 = 7.0 Hz, 3 H), 0.82 (t, J = 7.3 Bz, 3 H), 0.94 - 1.30 (m, 4 H), 1.36 - 1.63 (m , 2 H), 1.70 - 1.86 (m, 1 H), 2.02 - 2.20 (m, 1 H), 2.44 (s, 6 H), 3.16 (s, 1 H), 3.56 - 3.80 (m, 1 H), 3.91 (br. S, 2 H), 4.14 - 4.40 (m, 2 H), 5.94 (br. S ., 1 H), 6.27 (s, 1 H), 7.16 - 7.65 (m, 5 H), 8.13 (s, 1 H), 9.35 (br. S., 2 H) (amine proton not observed); LC-MS (ES ') m / z 486.4 [Ml]. LCMS (ES ⁺ ) m / z 488.3 [M + H].
Example 69: bis - ammonium salt of 3 - ({[(3Ã, 5Ã) -3-butyl-7 (dimethylamino) -3-ethyl-1,1-dioxide-5-phenyl-2,3,4, 5-tetrahydro-1,4benzothiazepin-8-yl] methyl} amino) pentanedioic
(3Ã, 5Ã) -3-butyl-7- (dimethylamino) -3-ethyl-5phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carbaldehyde 1,1-dioxide ( 22 mg, 0.051 mmol) and dimethyl 3-aminopentanedioate (45.0 mg, 0.257 mmol) were combined in DCM (4 ml) and stirred for 1 h at room temperature. The mixture was treated with NaHB (OAc) ₃ (76 mg, 0.359 mmol), then stirred for 2 days at room temperature. The mixture was partitioned between DCM and brine, and the phases were separated. The aqueous phase was extracted with DCM, and the organic phases were combined, dried over MgSO ₄ , filtered, and concentrated to a clear oil. The residue was purified on 40 g of silica eluted with 30 to 100% EtOAc / hexanes giving intermediate bis
138 methyl ester as a clear oil. LC-MS (ES ⁺ ) m / z 588.29 [M + H], The ester was dissolved in TEIF (0.5 ml) and treated with 1M LiOH (0.513 ml, 0.513 mmol) at room temperature. The mixture was stirred overnight. The mixture was concentrated to dryness and purified by means of RP-HPLC (column 30 X 100 XBridge at 55 ml / min; from 10% to 100% MeCN in H ₂ O with 0.1% NH4OH buffer over 8 minutes) giving 3 - ({[(3R, 5R) -3-butyl-7- (dimethylamino) -3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetra acid bisammonium salt -hydro-1,4-benzothiazepin-8-yl] methyl} amino) pentanedioic (11.2 mg, 0.019 mmol, 36.7% yield) as a white solid: 1 H NMR (400 MHz, DMSO-7 ₆ ) δ ppm 0.75 (t, 7 = 7.1 Hz, 3 H), 0.79 (t, 7 = 7.6 Hz, 3 H), 0.94 - 1.29 (m, 4 H) , 1.31 - 1.52 (m, 2 H), 1.65 - 1.82 (m, 1 H), 1.66 - 1.83 (m, 1 H), 1.96 - 2.15 (m, 1 H), 2.26 - 2.40 (m, 4 H), 2.47 (s, 6 H), 2.60 (d, 7 = 9.8 Hz, 1 H), 3, 06 (d, 7 = 14.9 Hz, 1 H), 3.16 (t, 7 = 6.2 Hz, 1 H), 3.52 (d, 7 = 15.0 Hz, 1 H), 3 , 78 (s, 2 H), 5.88 (d, 7 = 9.6 Hz, 1 H), 6.11 (s, 1 H), 7.26 7.35 (m, 1 H), 7 , 35 - 7.48 (m, 4 H), 7.94 (s, 1 H) (acid protons not observed); LC-MS (ES ') m / z 558.3 [Ml]. LC-MS (ES ⁺ ) m / z 560.2 [M + H].
Example 70: 3 - ({[(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1-acid , 4-benzothiazepin-8-yl] carbonyl} amino) pentanedioic
HOOC.
HOOC.
Dimethyl 3 - ({[(37 , 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5phenyl-2,3,4,5-tetrahydro-1,4 -benzothiazepin-8-yl] carbonyl} amino) pentanedioate (Intermediate 47, 212 mg, 0.227 mmol) in a 1: 1: 1 mixture of methanol / water / tetrahydrofuran (15 ml) was added with hydroxide monohydrate lithium (28.6 mg, 0.681 mmol). The reaction mixture was stirred at room temperature overnight and partially concentrated under reduced pressure. The residue was then adjusted to pH = 2 using acid
139 IN hydrochloric and partitioned between water and dichloromethane. The organic layer was washed with saturated brine, dried (Na ₂ SO4), filtered, and concentrated under reduced pressure. HPLC purification (Middle column: Gilson 845Z Prep. System; Sunfire C18 5μΜ, 30x150 mm; Method: 10-100% MeCN / H ₂ O with 0.05% TFA over 10 min, 45 ml / min , λ = 220, 254 nm) gave the title compound as a light yellow solid (61 mg, 95% pure, 38%) as a TFA salt: NMR Ή (400 MHz, DMSO-dg) δ 8.40 8, 55 (m, 1H), 8.36 (s, 1H), 7.24 - 7.55 (m, 5H), 6.17 - 6.28 (m, 1H), 5.86 6.05 (m , 1H), 4.46 - 4.63 (m, 1H), 3.47 - 3.70 (m, 4H), 3.06 - 3.20 (m, 1H), 2.52 - 2.61 (m, 4H), 1.97 - 2.23 (m, 1H), 1.66 - 1.88 (m, 1H), 1.34 - 1.61 (m, 2H), 0.95 - 1 , 34 (m, 4H), 0.68 - 0.89 (m, 6H); ES-LCMS m / z 561 (M + J7) ⁺ .
Example 71: l - [(3R, 5R) -3-butyl-3-ethyl-7- (methyloxy) -1,1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] ethanone
To an ice-cold solution of (3R, 5R) -3-butyl-3-ethylN-methyl-N, 7-bis (methyloxy) -5-phenyl-2,3,4,5-tetra- hydro-1,4-benzothiazepine-8carboxamide (Intermediate 44, 160 mg, 0.337 mmol) in tetrahydrofuran (5 ml) was added methylmagnesium bromide (0.337 ml, 1.011 mmol). The reaction mixture was stirred at room temperature for 1 h, treated with a saturated solution of ammonium hydrochloride, and extracted with EtOAc. The organic layer was washed with saturated brine, dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure. Purification via SiO ₂ chromatography (MeOH: DCM = 0: 100 to 3:97) resulted in the title compound (78 mg, 94% pure, 50%) as a white solid: H NMR (400 MHz, CDC1 ₃ ) δ ppm 8.43 (s, 1H), 7.30 - 7.51 (m, 5H), 6.25 (s, 1H), 6.09 (s, 1H), 3.57 (s, 3H), 3.43 (d, J = 14.9 Hz, 1H), 3.00 (d, J = 14.9 Hz, 1H), 2.54 (s, 2H), 2.11 - 2.26 (m , J = 4.1
140
Hz, 1H), 1.77 - 1.93 (m, 1H), 1.57 (d, J = 7.2 Hz, 1H), 1.38 - 1.51 (m, 2H), 1.01 - 1.35 (m, 5H), 0.87 (t, J = 7.4 Hz, 3H), 0.81 (t, J = 7.0 Hz, 3H); ESLCMS m / z 430 (M + H) ⁺ .
Example 72: 3 - [(3Ã, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -1, 1-dioxide-5-phenyl-
2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl] pentanedioic
A mixture of tetraethyl 2 - [(3A, 57 ) - 3-butyl-3-ethyl-7- (methyloxy) 1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1 , 4-benzothiazepin-8-yl] -1,1,3,3propanetetracarboxylate (Intermediate 46, 120 mg, 0.167 mmol) and 37% hydrochloric acid (3 ml) was stirred at reflux for 20 h. LC-MS showed that there was no starting material left, however, instead, a mixture of tri-acid and di-acid. More 37% hydrochloric acid (3 ml) was added, and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure. Purification with HPLC (eluting with MeCN / water with 0.05% TFA-H ₂ O and 0.05% TFA-MeCN) resulted in the title compound (76 mg, 95% pure, 68%) as a white solid: NMR Ή (400 MHz, DMSOd ₆ ) δ ppm 12.14 (br. S, 2H), 7.78 (br. S, 1H), 6.98 - 7.66 (m, 5H), 5.58 - 6.41 (m, 1H), 3.55 - 3.82 (m, 2H), 3.46 (s, 3H), 2.59 (d, J = 7.2 Hz, 4H), 0, 95 2.26 (m, 7H), 0.68 - 0.92 (m, 6H); ES-LCMS m / z 518 (M + H) ⁺ .
Example 73: 2 - ((3R, 5Ã) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-8-carboxamido acid )acetic
141
To a solution in DMF (1,1 , 5A) -3-butyl-3-ethyl-7- (methyloxy) -5-phenyl-2,3,4,5-tetrahydro-dioxide solution -1, 4benzothiazepine-8-carboxylic (Intermediate 4, 0.025 g, 0.058 mmol) and glycine methyl ester hydrochloride (0.008 g, 0.064 mmol) at 0 ° C was added HATU (0.024 g, 0.064 mmol) followed by DIPEA (0.009 g, 0.070 mmol). The reaction was stirred for 10 min and then heated to room temperature. After 1 h the reaction was concentrated to half volume and water (3 ml) was added. The precipitate was filtered, dried, and used without further purification. The material was dissolved in THF (0.500 ml) and H ₂ O (0.250 ml) was added followed by LiOH (0.007 g, 0.174 mmol). The reaction was stirred at room temperature for 3 h, then concentrated in vacuo. The residue was chromatographed via SiO ₂ chromatography using DCM / MeOH giving the title compound with 90% purity: NMR Ή (400 MHz, MeOH- ^ δ ppm 8.63 (s, 1 Η), 7.38 - 7, 58 (m, 5 Η), 6.46 (br. S., 1 H), 6.20 (br. S., 1 H), 4.04 - 4.21 (m, 2 H), 3, 68 (s, 3 H), 2.39 (br. S, 1 H), 1.90 (br. S, 1 H), 1.75 (br. S, 1 H), 1.52 ( br. s., 1 H), 1.05 - 1.43 (m, 6 H), 0.94 (t, 7 = 7.46 Hz, 3 H), 0.84 (t, 7 = 6, 98 Hz, 3 H); ESLCMS m / z 489 (M + //) ⁺ .
Method for determining crystallinity:
Differential scanning calorimetry analysis was performed using a TA Instruments Q1000 DSC DSC. A sample was loaded into a non-hermetically sealed aluminum pan and scanned under purging with nitrogen at 10 ° C / min. The thermogravimetric analysis was performed using a TA instruments Q5000 TGA equipment. The sample was loaded into a platinum pan and scanned from room temperature until it started to decompose at 10 ° C / min.
A sample of Final Crystalline Example 26 from Method 3 showed a start of decomposition at approximately 207 ° C. TGA confirmed that DSC's endotherm was due to decomposition rather than true fusion. No significant weight loss was observed by TGA
142 (less than 0.5% w / w) before decomposition.
A sample of Final Crystalline Example 26 of Method 3 showed significant peaks of diffraction in the X-ray diffraction pattern (PXRD) in values in two theta in degrees and spacing in Angstroms in parentheses of 4.9 (18), 5, 3 (17), 9.8 (9.0), 12.0 (7.4), 13.2 (6.7), 18.5 (4.8), 19.8 (4.5), 21.1 (4.2).
A powder X-ray diffraction scan was obtained by filling a 1 mm glass capillary with the sample. The PXRD scan was collected using a PANalytical X'Pert Pro MPD diffractometer equipped with a copper X-ray tube, an incident beam elliptical mirror and a PANalytical X'celerator detector. Silicon powder (NIST 640b) was used as an internal standard to correct, if necessary, for experimental 2-theta errors. In addition, a short-range low-angle scan was compared with a short-range low-angle positive scan to assess the 2-theta error for the lowest observed diffraction peaks (close to 5 degrees 2-theta) and also to verify whether the capillary was properly aligned on the X-ray beam. The data diffraction was collected from 3.5 to 90 degrees 2 theta. A separate scan of a capillary filled with pure sample (no internal standard) was collected from 3.5 to 50 degrees 2 theta.
Method for determining the inhibition of human iBAT:
In preparation for measuring the absorption of bile acid into cells expressing the ileal bile acid cotransporter (iBAT, ileal bile acid cotransporter), HEK293 cells were cultured in DMEM / F12 supplemented with 10% FBS. Twenty-four hours before carrying out an experiment cells were harvested at an 80-90% confluence. Cells were seeded in poly-d-lysine coated plates at 50,000 cells per well, and human Bacman iBAT virus was added in such a way that each well contains 3.67 x 10e6 pfu (73.4 pfu / cell). Each
The assay was covered with Breathe Easy Seal and placed in an incubator for 24 hours to allow expression of the carrier.
On the day of the absorption experiment, 10 mM HEPES was added to Hank's balanced salt solution, and the pH was adjusted to 7.4 with TRIS (HBSSH). The assay buffer was prepared by adding 100 pM of [ ³ H] -taurocholate and 10 μΜ of cold taurocholate at room temperature HBSSH. A separate wash buffer was prepared by adding 10 μΜ of cold taurocholate to HBSSH (—30 ml per assay) and placed on ice. Using 100% DMSO, dilution curves of 3 times, 8 points, for each test compound were prepared starting from 200 μΜ. Similarly, an 8-point dose-response curve was prepared from the control compound [(3R, 5R) -3-butyl-3-ethyl-7,8-bis (methyloxy) 1,1-dioxide 5 -phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (Brieaddy, LE WO9605188, 1996)] starting from 1.8 mM. Drug plates were created by adding 3 μΐ of each concentration to a 96-well V-bottom plate, then diluted 60 times with 177 μΐ of assay buffer. Plates were removed from the incubator and allowed to cool to room temperature. The medium was aspirated, and wells were washed once with 300 μΐ HBSSH. 50 μΐ of each dose-response curve concentration was added in triplicate per column on the assay plates, reserving column 10 for control (assay buffer + 1.67% DMSO) and columns 11 and 12 for the control compound . Plates were incubated at room temperature for 90 minutes, then the plates were aspirated, then washed IX with 300 μΐ of wash buffer. 220 μΐ of Microscint 20 was added to each well, and the plates were closed tightly. The amount of [ ³ H] taurocholate in the cell lysate was quantified using a microplate scintillation counter the following day.
The percentage of inhibition of absorption was determined using the following formula for each drug concentration: 100 * (l - ((Tl-C2) / (Cl 144
C2))); where TI is the average cpm for the test compound, Cl is the average cpm observed in the absence of any added inhibition, and C2 is the average cpm observed in the presence of a substance known to elicit 100% absorption inhibition (30 μΜ of control compound). IC50's can be generated using the formula 5, y = (Vmax * χ ^Λ η) / (Κ ^Λ η + χ ^Λ η).
The compounds of the invention were tested in the above test and the results are summarized below where each number is an average of at least 2 data points.
Compound iBAT IC ₅₀ (nM) Example 1Example 2Example 3Example 4Example 5Example 6Example 7Example 8Example 9Example 10Example 11Example 12Example 13Example 14Example 15Example 16Example 17Example 18Example 19Example 20Example 21Example 22Example 23Example 24Example 25Example 26Example 27Example 28Example 29Example 30Example 31Example 32Example 33Example 34Example 35Example 36Example 37Example 38Example 39 32112 2540423145733172068167276504731333072862245124402736434755367128740719026982790543659249619
145
Example 40
Example 41
Example 42
Example 43
Example 44
Example 45
Example 46
Example 47
Example 48
Example 49
Example 50
Example 51
Example 52
Example 53
Example 54
Example 55
Example 56
Example 57
Example 58
Example 59
Example 60
Example 61
Example 62
Example 63
Example 64
Example 65
Example 66
Example 67
Example 68
Example 69
Example 70
Example 71
Example 72
Example 73
4670
3330
128
7679
648
1950
124
131
425
751
1458
3326
3330
3360
3900
8992
337
100
100> 3000 not tested

权利要求:
Claims (6)
[1]
1. Composite, characterized by the fact of understanding

[2]
2. Composite, characterized by the fact of understanding

[3]
Compound according to claim 2, characterized by the fact that said compound is crystalline.
[4]
Pharmaceutically acceptable salt of a compound, characterized in that said compound is as defined in any one of claims 1 to 3.
[5]
Pharmaceutical composition, characterized in that it comprises a compound or a salt as defined in any one of claims 1 to 4.
[6]
6. Use of a compound or a salt as defined in any of claims 1 to 4, characterized by the fact that it is in the manufacture of a medicament for the treatment or prevention of diabetes mellitus (Type I and Type II) or obesity.

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法律状态:
2016-03-01| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law|

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2019-01-29| B07E| Notice of approval relating to section 229 industrial property law|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-04-24| B06T| Formal requirements before examination|

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2019-09-03| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application according art. 36 industrial patent law|

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2019-12-24| B09A| Decision: intention to grant|

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2020-01-21| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 27/04/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US32821210P| true| 2010-04-27|2010-04-27|

---

US32922510P| true| 2010-04-29|2010-04-29|

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PCT/US2011/034024|WO2011137135A1|2010-04-27|2011-04-27|Chemical compounds|

---