PROCESSES FOR PREPARING COMPOUNDS AND COMPOUNDS

专利摘要:
trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxyamide and ({[(2s, 5r)-2-carbamoyl-7-oxo-1 ,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide, processes for their preparation, and intermediates. The present invention relates to compounds and processes for preparing compounds of formula (I) (i) including compounds such as trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane -2-carboxamide and salts thereof (eg nxl-104). The processes described provide high yielding compounds and can thus be efficient and cost-effective, as well as said processes can provide a high yield of pure intermediate compounds, thereby eliminating the need to isolate the intermediaries.
公开号:BR112013032415B1
申请号:R112013032415-5
申请日:2012-06-15
公开日:2021-07-27
发明作者:John Alistair Boyd；Janette Helen Cherryman；Michael Golden；Yuriy B. Kalyan；Graham Richard Lawton；David Milne；Andrew John Phillips；Saibaba Racha；Melanie Simone Ronsheim；Alexander Telford；Shao Hong Zhou；Mahendra G Dedhiya
申请人:Pfizer Anti-Infectives Ab；
IPC主号:

专利说明:

Cross Reference to Related Order(s)
[0001] This application claims priority under 35 U.S.C. § 119, based on U.S. Provisional Order No. Serial 61/498,522 filed June 17, 2011, which is incorporated herein by reference in its entirety. Field of Invention
[0002] The present invention relates to novel compounds and processes for preparing compounds of Formula (I), including compounds such as trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2, 1]octane-2-carboxamide and salts thereof (eg NXL-104). Background of the Invention
[0003] U.S. Patent No. 7,112,592 describes new heterocyclic compounds and their salts, processes for manufacturing the compounds, and methods of using the compounds as antibacterial agents. One such compound is trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, sodium salt. PCT application WO 2002/10172 describes the production of azabicyclic compounds and salts thereof with acids and bases, and in particular, trans-7-oxo-6-sulfoxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide and its pyridinium, tetrabutylammonium and sodium salts. PCT Application WO 2003/063864 and U.S. Patent Publication No. 2005/0020572 describe the use of compounds including trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium salt as β-lactamase inhibitors which can be administered alone or in combination with β-lactamine antibacterial agents. U.S. Patent Publication No. 2010/0197928 describes methods for preparing 2,5-disubstituted piperidine and novel intermediates. PCT Application WO 2011/042560 and US Patent Application No. 12/900,567 describe crystalline sodium salt forms of trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane- 2-carboxamide. These references are incorporated herein by reference in their entirety.
[0004] There is an existing and continuing need in the art for new and improved methods to prepare compounds of Formula (I) including trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane -2-carboxamide, related compounds and salts thereof (eg, NXL-104). The present invention provides novel compounds and processes for preparing compounds of Formula (I) including trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, related compounds and salts thereof (eg NXL-104). Invention Summary
[0005] According to some embodiments, the present invention provides processes for preparing compounds of Formula (I):
and pharmaceutically acceptable salts, solvates, hydrates, enantiomers or diastereomers thereof (eg NXL-104) using compounds of Formula (II).

[0006] According to some embodiments, the present invention provides compounds of Formula (III) and salts, solvates, hydrates, enantiomers or diastereomers thereof (for example, (2S,5R)-5-[(benzyloxy)amino []piperidine-2-carboxamide).

[0007] According to some embodiments, the present invention provides compounds of Formula (VI) or salts or analogs thereof.

[0008] According to some embodiments, the present invention provides processes for preparing a compound of Formula (IX).

[0009] According to some embodiments, the present invention provides process compounds of Formula (XIV) or salts or analogs thereof.
Detailed Description of the Invention
[00010] The present invention provides new compounds and improved methods for preparing compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, enantiomers or diastereomers thereof (for example, NXL-104).

[00011] In some embodiments, the processes comprise treating a compound of Formula (II) with a source of nitrogen or an amine to prepare a compound of Formula (III) and treating the compound of Formula (III) with a protecting group and a carbonylating agent. In other modalities, treatment is followed by lack of protection.


[00012] In some embodiments, R1, R2, R3, R4, R5, R6 and R7 include, but are not limited to, hydrogen, oxygen, nitrogen, amino, carbonyl, carbamoyl, alkyl, alkenyl, alkynyl, alkoxy, cyclo- alkyl, aryl, aralkyl, trialkylsilyl and heterocycle groups. In specific modalities, R1, R2, R3, R4, R5, R6 and R7 can be optionally substituted by one or more halogen, oxygen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino, starch, alkylamido , carbamoyl, ureido, dimethylamino, carboxyl, alkyl, allyl, halogenated alkyl, trialkylsilyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, aroyl, acyloxy, aryloxy, alkoxy cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, or a combination thereof.
[00013] In other embodiments, R1 and R2 can together form a heterocycle. The heterocycle may optionally be substituted by one or more halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino, starch, alkylamido, carbamoyl, ureido, dimethylamino, carboxyl, alkyl, halogenated alkyl, alkenyl, alkynyl 1a, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, aroyl, acyl, alkoxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkylsulfonyl, alkylsulfonyl, alkylthiosulfonyl, alkylthiosulfonyl, alkylthio , arylsulfinyl, arylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl or a combination thereof.
[00014] In still other embodiments, each of R3, R5 and R6 include COH, COB', CO-OB', CONH2, CONHB', CONHOH, CO-NHSO2B', CH2CO-OH, CH2CO-OB', CH2CONHOH, CH2CONHCN, CH2tetrazol, CH2protected tetrazole, CH2SO3H, CH2SO2B', CH2PO(OB')2, CH2PO(OB')(OH), CH2PO(B')(OH) and CH2PO(OH)2. B' includes an alkyl containing 1 to 6 carbon atoms optionally substituted by a pyridyl or carbamoyl radical, -CH 2 -alkenyl containing 3 to 9 carbon atoms, aryl containing 6 to 10 carbon atoms and aralkyl containing 7 to 11 carbon atoms carbon, wherein the nucleus of said aryl or aralkyl is optionally substituted by OH, NH 2 , NO 2 , alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms or by one or more halogen atoms.
[00015] In exemplary modalities, R3, R5 or R6 can be OR' or OP'.
[00016] R' includes SO3, SO2, SO2NHCOH, SO2NHCO, SO2NHCO-O, SO2NHCONH and SO2NHCONH2. In some embodiments, R' may be substituted by hydrogen or an alkyl group optionally substituted by a pyridyl or carbamoyl radical, -CH2-alkenyl having 3 to 9 carbon atoms, aryl having 6 to 10 carbon atoms, and aralkyl having 7 to 11 carbon atoms. The aryl or aralkyl nucleus may be replaced by OH, NH2, NO2, alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms, or one or more halogen atoms.
[00017] P' includes PO(OH)2, PO3, PO2, PO, PO(OH)(O-), PO2NHCOH, PO2NHCO, PO2NHCO-O, PO2NHCONH and PO2NHCONH2. In some embodiments, P' may be substituted by hydrogen or an alkyl group optionally substituted by a pyridyl or carbamoyl radical, -CH2 -alkenyl having 3 to 9 carbon atoms, aryl having 6 to 10 carbon atoms, and aralkyl having 7 to 11 carbon atoms. The aryl or aralkyl nucleus is optionally substituted by OH, NH 2 , NO 2 , alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms or by one or more halogen atoms.
[00018] In exemplary embodiments, R1 and R2 are hydrogen. In other embodiments, R1 is piperidinyl and R2 is hydrogen. In some examples, R3 is OSO3H.
[00019] In some embodiments, R4 is benzyloxy. In other modes, R5 is benzyloxy and R6 is hydrogen. In still other embodiments, R5 is allyl or trialkylsilyl and R6 is hydrogen. In some examples, R7 is H. In other embodiments, R7 is carbonyl, carbamoyl, or alkyl and may optionally be substituted with one or more halogen, oxygen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, arylamino, diarylamino, amido , alkylamido, carbamoyl, ureido, dimethylamino, carboxyl, alkyl, allyl, halogenated alkyl, trialkylsilyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, aroyl, alkoxy, aryloxy, heteroaryloxy, cycloalkyloxy, cycloalkylalkyloxy, arylalkyloxy, heteroarylalkyloxy, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl, arylcarbonyl, or a combination of heteroaryloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl. In specific modes, R7 is carbamoyl.
[00020] In exemplary embodiments, R4 and R5 are benzyloxy. In other embodiments, R6 and R7 are hydrogen.
[00021] The protecting group can be, for example, 9-fluorenylmethoxycarbonyl group (FMOC), tert-butoxycarbonyl group (BOC), benzyloxycarbonyl groups (CBZ), ethyl- or methyl-oxycarbonyl, phenoxycarbonyl, allyloxycarbonyl (ALOC) and equivalents known to one of skill in the art with the benefit of this description. In specific modalities, the protecting group is 9-fluorenylmethoxycarbonyl group (FMOC). In some embodiments, the carbonylating agent can include a carbonyl with two leaving groups. Leaving groups can be chloride or imidazole, for example in N,N-carbonyl diimidazole (CDI). In other embodiments, the protecting group is removed resulting in cyclization.
[00022] In exemplary embodiments, compounds formed after treatment of compounds of Formula (III) may also be treated with an SO3 complex.
[00023] Compounds of Formula (II) can be prepared using compounds of Formula (IV).

[00024] R4 is as defined above. In some examples, compounds of Formula (II) can be prepared according to Scheme I. Scheme I

[00025] R can be R4, R5 or R6 as defined above. In some embodiments, P can be a protecting group and includes 9-fluorenylmethoxycarbonyl (FMOC), tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), ethyl- or methyloxycarbonyl, phenoxycarbonyl, allyloxycarbonyl (ALOC) and groups equivalents known to one of skill in the art with the benefit of this description. In exemplary embodiments, P can be tert-butoxycarbonyl (BOC).
[00026] In exemplary embodiments, base includes bases capable of deprotonating trimethylsulfoxonium iodide, eg, sodium hydride and potassium tert-butoxide.
[00027] In exemplary embodiments, deprotection may include conditions that remove protecting group P; cyclization can include conditions that cause a 6-exo-tet cyclization to produce a piperidine ring; reduction can include conditions that cause reduction of the oxime binding to a single bond, for example, with an R configuration; selective crystallization may include conditions that allow isolation of the desired isomer, for example, an SR isomer, as a salt or as the free base. An acid, which can be monovalent or divalent, can be used to form a solid salt with the desired product.
[00028] In some embodiments, a compound of Formula IV is ring-opened with trimethylsulfoxonioylide and then converted to α-chloro-oxime in a single step. The protecting group is removed and the compound is cyclized, the oxime is selectively reduced to a hydroxylamine, and a compound of Formula V is isolated, possibly as a salt.

[00029] The compound of Formula (V) can be used to prepare trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide and pharmaceutically acceptable salts thereof (for example, NXL-104) according to Scheme II below. R4, R5 and R6 are as defined above. Scheme II
Scheme Legend - Protection - Unprotection
[00030] In Scheme II, each of R1 and R2 can be hydrogen or alkyl group.
[00031] In exemplary embodiments, the piperidine nitrogen is protected, a phosgenizing agent or carbonylating agent is used to install a carbonyl, and the protecting group is removed resulting in cyclization. Hydroxylamine is deprotected, sulfated and converted to a tetra-alkylammonium salt.
[00032] In some embodiments, the present invention provides compounds of Formula (III) or salts, solvates, hydrates, enantiomers, diastereomers or analogs thereof.
(III)
[00033] The groups R1, R2, R3, R4, R5, R6 and R7 are as described above. In some embodiments, R1, R2, R6, and R7 are H and R5 is benzyloxy. For example, the present invention provides compounds of Formula (VI) or salts or analogues thereof.

[00034] In exemplary embodiments, the present invention provides compounds of Formula (VII):

[00035] R1, R2, R3, R4, R5, R6 and R7 can be any combination of the groups as described above.
[00036] In exemplary embodiments, R1, R2 and R6 are hydrogen, R5 is OSO3H and R7 is carbamoyl. In other examples, R1 is piperidinyl, R2 and R6 are hydrogen, R5 is OSO3H, and R7 is carbamoyl.
[00037] In another aspect, the present invention provides processes for preparing trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide and salts thereof (for example , NXL-104).
[00038] In specific embodiments, the present invention provides methods for preparing compounds of Formula (VIII) or pharmaceutically acceptable salts thereof (eg, NXL-104).

[00039] NXL-104 may also be referred to as the monosodium salt of (1R,2S,5R)-7-oxo-6-sulfoxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, avibactam or sodium {[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide. The structure of NXL-104 is depicted below (Formula IX).

[00040] In one aspect, the present invention provides methods for preparing trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide and pharmaceutically acceptable salts thereof ( for example NXL-104) using compounds according to Scheme III below. Scheme III
Scheme legend - base - Step 1 - Step 2 - Deprotection - cyclization - Reduction - selective crystallization
[00041] R8 and R9 include any of the groups in any combination as defined for groups R1 to R7 above.
[00042] In some embodiments, a compound of Formula (X) is ring-opened with trimethylsulfoxonioylide and converted to α-chloro-oxime in a single step.

[00043] The protecting group is removed and the compound is cyclized, the oxime is selectively reduced to a hydroxylamine, and a compound of Formula (XI) is isolated, possibly as a salt.

[00044] In some embodiments, R8 includes alkyl, allyl, aryl, heteroaryl, benzyl, alkoxyalkyl, arylalkoxyalkyl or combinations thereof, and equivalent groups known to one of skill in the art with the benefit of this description. R8 can be a substituted or unsubstituted alkyl group, which can be straight or branched. For example, R8 can be a methyl, ethyl, propyl, isopropyl, butyl, pentyl or hexyl group. In other embodiments, R8 can be an aryl or an aromatic group. For example, R8 can be a phenyl, naphthyl or furyl group. In exemplary embodiments, R8 can be a benzyl or a substituted benzyl.
[00045] In some embodiments, R9 may be a protecting group including alkyl, allyl, acyl, benzyl, H or silyl protecting groups or combinations thereof and equivalent groups known to one of skill in the art with the benefit of this description. For example, R9 can be an allyl, trialkylsilyl or benzyl group. In exemplary embodiments, R9 can be a benzyl group.
[00046] In some embodiments, P may be a protecting group and may include 9-fluorenylmethoxycarbonyl (FMOC), tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), ethyl- or methyloxycarbonyl, phenoxycarbonyl, allyloxycarbonyl (ALOC) and equivalent groups known to one of skill in the art with the benefit of this description. In exemplary embodiments, P can be tert-butoxycarbonyl (BOC).
[00047] In exemplary embodiments, base includes bases capable of deprotonating trimethylsulfoxonium iodide, eg, sodium hydride and potassium tert-butoxide.
[00048] In exemplary embodiments, deprotection includes conditions that remove protecting group P; cyclization includes conditions that cause a 6-exo-tet cyclization to produce a piperidine ring; reduction includes conditions that cause reduction of the oxime bond to a single bond, preferably with an R configuration; selective crystallization includes conditions that allow isolation of the desired isomer, for example, an SR isomer, either as a salt or as the free base. An acid, which can be monovalent or divalent, can be used to form a solid salt with the desired product.
[00049] One of skill in the art will understand with the benefit of this disclosure that those compounds of Formula (X) can be used to prepare compounds of Formula (XI) using conditions and reagents that can produce alternative compounds as intermediates. For example, chlorooxime can be prepared from compounds of Formula (XII) and (XIII) including free base, salts and enantiomers thereof.

[00050] In exemplary embodiments, chloro-oxime can be prepared according to Scheme IV below. Scheme IV

[00051] In exemplary embodiments, compounds of Formula (XI) can be used to prepare trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide and pharmaceutically acceptable salts acceptable thereof (eg NXL-104) according to Schematic V below. Scheme V
Scheme legend - Protection - Deprotection - Deprotection, 'complex SO3' - '(R10)4N+ source' - ion exchange
[00052] In some embodiments, a compound of Formula (XI) is converted to a compound of Formula (XIV) using an ammonia source.

[00053] Piperidine nitrogen is protected, a phosgenizing or carbonylation agent is used to install a carbonyl, and the protecting group is removed resulting in cyclization. Hydroxylamine is deprotected, sulfated and converted to a tetra-alkylammonium salt. The tetra-alkylammonium salt undergoes ion exchange to provide a pharmaceutically acceptable salt of (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
[00054] In some embodiments, R8 includes alkyl, allyl, aryl, heteroaryl, benzyl, alkoxyalkyl, arylalkoxyalkyl or combinations thereof, and equivalent groups known to one of skill in the art with the benefit of this description. R8 can be a substituted or unsubstituted alkyl group which can be straight or branched. For example, R8 can be a methyl, ethyl, propyl, isopropyl, butyl, pentyl or hexyl group. In other embodiments, R8 can be an aryl or an aromatic group. For example, R8 can be a phenyl, naphthyl or furyl group. In exemplary embodiments, R8 can be a benzyl or a substituted benzyl.
[00055] In some embodiments, R9 may be a suitable functional group for the protection of hydroxylamines. Examples of suitable R9 groups include alkyl, allyl, acyl, benzyl, H or silyl protecting groups or combinations thereof and equivalent groups known to one of skill in the art having the benefit of this description. In some embodiments, R9 can be an allyl, trialkylsilyl or benzyl group. In exemplary embodiments, R9 can be a benzyl group.
[00056] In exemplary embodiments, NH3 can be ammonia, a source of ammonia, or a propoxy ammonia. For example, propoxy ammonia can be formamidine and a base. In some embodiments, ammonia can be dissolved in a polar solvent such as methanol, water, isopropanol and dioxane.
[00057] In exemplary embodiments, PG includes a protection group, LG includes an output group; deprotection includes conditions for removal of the protecting group; SO3 complex includes a sulfur trioxide complex; and (R10)4N+ source includes an n-alkylammonium ion source.
[00058] The protecting group can be, for example, 9-fluorenylmethoxycarbonyl group (FMOC), tert-butoxycarbonyl group (BOC), benzyloxycarbonyl groups (CBZ), ethyl- or methyl-oxycarbonyl, phenoxycarbonyl, allyloxycarbonyl (ALOC) and equivalents known to one of skill in the art with the benefit of this description. In specific modalities, the protecting group is 9-fluorenylmethoxycarbonyl group (FMOC).
[00059] The leaving group can be an imidazole, for example, in N,N-carbonyl diimidazole (CDI).
[00060] Deprotection includes conditions for the removal of the R9 protecting group, eg hydrogenation if R9 is benzyl. The SO3 complex can be sulfur trioxide complex such as SO3 pyridine, SO3 dimethylformamide, SO3 triethylamine, SO3 trimethylamine, chlorosulfonic acid and oil.
[00061] The source of (R10)4N+ can be a source of tetra n-alkylammonium ion, such as tetraethylammonium chloride, tetramethylammonium hydroxide, tetrabutylammonium acetate and tetrabutylammonium bisulfate.
[00062] The ion exchange step converts the tetraalkylammonium salt into a pharmaceutically acceptable salt, for example, sodium, potassium, calcium and magnesium. This can be accomplished by crystallizing the salt, eg the sodium salt using a source of sodium which can be any salt or form of sodium that allows ion exchange with tetra-alkylammonium. The sodium source can be a sodium carboxylate salt, or an ion exchange resin containing sodium. In exemplary embodiments, the sodium source is sodium 2-ethylhexanoate.
[00063] Alternatively, other pharmaceutically acceptable salts of (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide can be prepared in an analogous manner. For example, the potassium salt can be prepared using potassium-soluble salts.
[00064] In specific embodiments, (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium salt is prepared using (2S,5R) benzyl )-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) using Scheme VI. Scheme VI
Figure legend - protection - deprotection - hydrogenation - SO3 source - Bu4N source - ion exchange
[00065] In exemplary embodiments, compounds described herein, for example, benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate (1:1) ethanedioate can be treated with ammonia dissolved in a polar solvent such as methanol, water, isopropanol or dioxane. After removing any by-products, the mixture can be crystallized from a non-polar solvent. Examples of suitable solvents are toluene, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), and isohexane. (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide (amide) can be protected on the piperidine nitrogen with a protecting group prior to addition of a phosgenizing or carbonylating agent, prior to deprotection of piperidine nitrogen, cyclization under basic conditions and isolation of the product by crystallization. The protecting group can be FMOC, BOC or CBZ and can be supplied in an organic solvent such as toluene, chlorobenzene or fluorobenzene. Examples of suitable phosgenizing or carbonylating agents are CDI, phosgene and triphosgene. For the deprotection of an FMOC protecting group, examples of suitable reagents are diethylamine, piperidine, and morpholine. Deprotection of other protecting groups can be carried out using methods known to those skilled in the art with the benefit of this description. Examples of bases for cyclization include diethylamine, piperidine, morpholine triethylamine, diisopropylethylamine and aqueous bases such as sodium bicarbonate solution.
[00066] (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide can also be debenzylated by treatment with hydrogen in the presence of a catalyst ( such as palladium, platinum, rhodium, nickel) and in the presence of a base (such as triethylamine, diisopropylethylamine) and a source of SO3 (such as SO3 pyridine, SO3 dimethylformamide, SO3 triethylamine, SO3 ). trimethylamine) and a solvent (such as methanol, ethanol, isopropanol, propanol, butanol, water or mixtures thereof). The product can then be treated with a tetrabutylammonium ion source (such as tetrabutylammonium acetate, tetrabutylammonium bisulfate), extracted into an organic solvent and crystallized from an organic solvent (such as methyl isobutyl ketone (MIBK) , acetone, isopropyl acetate).
[00067] ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}-sulfonyl]oxidanide of tetrabutylammonium is then dissolved in a solvent (such as ethanol, isopropanol, propanol, water or mixtures thereof) and treated with a sodium carboxylate salt (such as sodium-2-ethylhexanoate).
[00068] In another aspect, (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide sodium salt can be prepared using compounds according to the Scheme VII. Scheme VII
Scheme legend - base - carbonylation - hydrolysis, amidation - deprotection - sulfation - salt formation - ion exchange
[00069] In the presence of base, compounds of Formula (XI) react with a phosgenizing or carbonylating agent to produce the cyclic urea. The ester protecting group is removed and the resulting acid is converted to a carboxamide. Hydroxylamine is deprotected, sulfated and converted to a tetra-alkylammonium salt. The tetraalkylammonium salt undergoes ion exchange to provide a pharmaceutically acceptable salt of (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.
[00070] R8 and R9 can represent groups as described above. In specific embodiments, base includes a base for the deprotonation of benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate (1:1) ethanedioate, e.g., an inorganic base, such as KHCO3 or an organic base such as triethylamine, 3-picoline, pyridine and lutidine; carbonylation includes an addition of a carbonyl group using a single reagent (eg triphosgene, N,N-carbonyl diimidazole (CDI), C(O)(SMe)2) or a combination of reagents (eg provided in the scheme discussed above, or use of CO2 and chlorotrimethylsilane, followed by SOCl2 and pyridine); hydrolysis includes selective cleavage of the CO bond to release R7O-, eg using tetrabutylammonium hydroxide (TBAOH), LiOH, NaOH, iodotrimethylsilane (TMSI). Alternatively, this step can be replaced by other deprotection conditions, for example, when R8 = CH2C6H5, hydrogenation, or if R8 = allyl, isomerization with Pd; amidation includes activation of acidic functionality followed by quenching with an ammonia source, sequentially or simultaneously. For example, the acid can be activated using such reagents as alkyl chloroformates, trimethylacetyl chloride, thionyl chloride, diethylchlorophosphate, CDI. The resulting activated acid can be quenched with ammonia or ammonium solutions, salts, or sources, or with an ammonia propoxy such as hexamethyldisilazane (HMDS). Alternatively, activation and quenching can be simultaneous using such reagent combinations as di-imides, for example, N,N'-dicyclohexylcarbodiimide (DCC) and N-(3-dimethylaminopropyl)-N' hydrochloride -ethylcarbodiimide (EDC) or cyclic anhydride of 1-propanephosphonic acid with HMDS; deprotection includes removal of the R9 protecting group to produce the free hydroxylamine; sulfation includes addition of an SO3 group to a hydroxy group using an SO3 source, for example, SO3.DMF, SO3.NMe3 and ClSO3H; salt formation includes adding a source of tetra n-alkylammonium ion, eg, tetra n-butylammonium acetate, and isolating the resulting salt.
[00071] In some embodiments, deprotection can be achieved using methods known to those skilled in the art with the benefit of this description. For example, hydrogenation using a palladium catalyst can be used if R9 is benzyl.
[00072] In another aspect of the invention, (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide can be prepared using a compound of Formula (XV ).

[00073] These compounds of Formula (XV) can be prepared according to Scheme VIII. Scheme VIII
Scheme legend - base - Step 1 - Step 2 - Deprotection - cyclization - reduction - selective crystallization
[00074] A compound of Formula (XVI) is ring-opened with trimethylsulfoxonium ylide and converted to α-chloro-oxime.

[00075] The protecting group is removed and the compound is cyclized, the oxime is selectively reduced to a hydroxylamine, and the final compound is isolated, possibly as a salt. In some embodiments, R8 includes any alkyl, allyl, aryl, benzyl, heterocyclic and equivalent groups for the protection of carboxamides known to one of skill in the art with the benefit of this disclosure. In specific embodiments, R8 can be a tert-butyl, benzyl, allyl, methoxymethyl, silyl, tetrahydropyran or siloxyalkyl group. In exemplary embodiments, R8 can be a benzyl or a substituted benzyl.
[00076] In some embodiments, R9 may be a protecting group including alkyl, allyl, acyl, benzyl, H or silyl protecting groups and equivalent groups known to one of skill in the art with the benefit of this description. For example, R9 can be an allyl, trialkylsilyl, or preferably a benzyl group.
[00077] In exemplary embodiments, P can be a protecting group, for example, a carbamate protecting group such as tert-butoxycarbonyl (BOC) or benzyloxycarbonyl.
[00078] In exemplary embodiments, base n Step 1 includes bases capable of deprotonating trimethylsulfoxonium iodide, eg, sodium hydride and potassium tert-butoxide.
[00079] In exemplary embodiments, deprotection includes conditions that remove protecting group P; cyclization includes conditions that cause a 6-exo-tet cyclization to produce a piperidine ring; reduction includes conditions that cause reduction of the oxime bond to a single bond, preferably with an R configuration; selective crystallization includes conditions that allow isolation of the desired SR isomer, either as a salt or as the free base. An acid, which can be monovalent or divalent, can be used to form a solid salt with the desired product.
[00080] The compounds obtained using the scheme discussed above can be used to prepare (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-sodium salt carboxamide according to Scheme IX. Scheme IX
Scheme legend - Phosgenation - Deprotection, 'SO3 complex' - 'Source of (R10)4N+ - ion exchange
[00081] A compound of Formula (XV) is converted to urea, which is then deprotected, sulfated and converted to the tetra-alkylammonium salt. The tetra-alkylammonium salt is ion-exchanged to provide a pharmaceutically acceptable salt of (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide. Groups R7 and R9 are as defined above. Phosgenation or carbonylation is the addition of a carbonyl using a single reagent, for example, triphosgene, CDI, or combination of reagents such as those described in the Schemes above. Deprotection includes the removal of R8 and R9, simultaneously or sequentially. Other steps have been described elsewhere.
[00082] In some embodiments, trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide and salts thereof (eg, NXL-104) may be prepared using enzymes. For example, the processes may involve making a compound of Formula (XVII).

[00083] The compound (Formula XVII) can be prepared according to Scheme o X. Scheme X

[00084] In some embodiments, includes R8, but is not limited to, alkyl groups, aryl groups, and benzyl groups. In exemplary embodiments, R8 can be an alkyl group. For example, R8 can be methyl or ethyl.
[00085] In some embodiments, R9 may be a suitable functional group for the protection of hydroxylamines. For example, R9 can be an allyl, trialkylsilyl, or benzyl group.
[00086] In exemplary embodiments, phosgenization or carbonylation can be performed with a phosgenating agent such as triphosgene.
[00087] In exemplary embodiments, enzymatic amidation is performed using an enzyme. For example Candida antarctica Lipase A or Candida antarctica Lipase B, in the presence of an ammonia source such as ammonium carbamate, ammonia, ammonium chloride or hexamethyldisilazane and a solvent such as acetonitrile, dioxane or chlorobutane.
[00088] The processes described herein may be useful to prepare compounds in sufficient purity without isolation. For example, the use of a base (such as potassium tert-butoxide) can produce sufficiently pure beta-keto sulfoxonium (BKS) that it could be used in subsequent steps without a need for isolation. In some embodiments, processes may involve a single conversion step using a single solvent and a single reagent. For example, beta-keto sulfoxonium can be converted to chloroxime in a single solvent with a single reagent. In other embodiments, the processes can use improved reduction conditions that can produce a higher ratio of a desired SR isomer to an unwanted SS isomer. For example, the ratio can be more than 1. In some embodiments, the ratio of the desired SR isomer to the unwanted SS isomer can range from 1 to 10. In exemplary embodiments, the ratio can be 4. In still other embodiments, the processes can provide improved crystallization conditions that can allow selective isolation of the desired SR isomer in high purity. In some embodiments, the processes can provide a high yield of pure intermediate compounds, thereby eliminating the need to isolate the intermediates. For example, the processes described herein can provide a very high yield of pure benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1). In such cases, isolation of intermediaries may not be necessary.
[00089] The processes described here can provide compounds in unexpectedly high yields and can thus be efficient and cost-effective.
[00090] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one skilled in the art to which this invention belongs.
[00091] "NXL-104" refers to the monosodium salt of (1R,2S,5R)-7-oxo-6-sulfooxy-1,6-diazabicyclo[3.2.1]octane-2-carboxamide or alter- natively, sodium {[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide or avibactam, and is represented by the structure shown below.

[00092] When used herein the term "halogen" means F, Cl, Br, and I.
[00093] The term "alkyl" means a substituted or unsubstituted hydrocarbon radical which may be straight chain or branched chain and may comprise about 1 to about 20 carbon atoms, for example 1 to 12 carbon atoms, such as 1 to 8 carbon atoms, for example 1 to 4 carbon atoms. Suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. Other examples of suitable alkyl groups include, but are not limited to, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, methyl - hexyl, dimethylpentyl, ethylpentyl, ethylmethylbutyl, dimethylbutyl, and the like.
[00094] Substituted alkyl groups are alkyl groups as described above which are substituted at one or more positions by, for example, halogen, hydroxyl, amino, carboxy, alkylamino, dialkylamino, aryl, heteroaryl, alkoxy, nitro and cyano, and combinations thereof.
[00095] The term "halogenated alkyl" means a saturated hydrocarbon radical which may be straight chain or branched chain and may comprise about 1 to about 20 carbon atoms, for example 1 to 12 carbon atoms, such as 1 to 8 carbon atoms, for example, 1 to 4 carbon atoms that are substituted by one or more halogens such as, but not limited to, -CF3, CF2CF3, CHF2, CH2F, and the like. The use of the term "halogenated alkyl" should not be interpreted to mean that a "substituted alkyl" group may not be substituted by one or more halogens.
[00096] The term "alkenyl" means a substituted or unsubstituted hydrocarbon radical which may be straight chain or branched chain containing one or more carbon-carbon double bonds and which may comprise about 1 to about 20 carbon atoms, such as as 1 to 12 carbon atoms, for example 1 to 6 carbon atoms. Suitable alkenyl groups include ethenyl, propenyl, butenyl, etc.
[00097] Substituted alkenyl groups are alkenyl groups as described above that are substituted at one or more positions by, for example, halogen, hydroxyl, amino, carboxy, alkylamino, dialkylamino, aryl, heteroaryl, alkoxy, nitro and cyano, and combinations thereof.
[00098] The term "alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated, for example, methylene , ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
[00099] The term "alkynyl" means a substituted or unsubstituted aliphatic hydrocarbon radical which may be straight chain or branched chain and which contains one or more carbon-carbon triple bonds. Preferably, the alkynyl group contains 2 to 15 carbon atoms, such as 2 to 12 carbon atoms, for example 2 to 8 carbon atoms. Suitable alkynyl groups include ethynyl, propynyl, butynyl, etc.
[000100] Substituted alkynyl groups are alkynyl groups as described above which are substituted at one or more positions by, for example, halogen, hydroxyl, amino, carboxy, alkylamino, di-alkylamino, aryl, heteroaryl, alkoxy, nitro and cyano , and combinations thereof.
[000101] The term "amino" means -NH2.
[000102] The term "alkylamino" means -NH(alkyl), wherein alkyl is as described above.
[000103] The term "dialkylamino" means -N(alkyl)2, wherein alkyl is as described above.
[000104] The term "aryl" means a substituted or unsubstituted aromatic monocyclic or bicyclic ring system comprising about 5 to about 14 carbon atoms, for example about 6 to about 10 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl.
[000105] Substituted aryl groups include the aryl groups described above which are substituted one or more times, for example, but not limited to, halogen, hydroxyl, amino, carboxy, alkylamino, dialkylamino, aryl, heteroaryl, alkoxy, nitro and cyan, and combinations thereof.
[000106] The term "arylamino" means -NH(aryl), where aryl is as described above.
[000107] The term "diarylamino" means -N(aryl)2, wherein aryl is as described above.
[000108] The term "starch" means -CONH2.
[000109] The term "arylalkyl" refers to a -(alkylene)-aryl group in which the aryl and alkylene moieties are in accordance with the previous descriptions. Suitable examples include, but are not limited to, benzyl, 1-phenethyl, 2-phenethyl, phenpropyl, phenbutyl, fenpentyl, and naptylmethyl.
[000110] The term "carboxyl" means -C(O)OH.
[000111] The term "cycloalkyl" means a monocyclic, bicyclic or tricyclic non-aromatic saturated hydrocarbon radical having 3 to 10 carbon atoms, such as 3 to 8 carbon atoms, for example 3 to 6 carbon atoms. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, 1-decalin, adamant-1-yl, and adamant-2-yl. Other suitable cycloalkyl groups include, but are not limited to, spiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[5.1.0]octyl, spiro[2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, and spiro[3.5]nonyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be substituted, for example, by one or more halogen and/or alkyl groups.
[000112] The term "cycloalkylalkyl" means a -(alkylene)-cycloalkyl wherein the cycloalkyl group is as previously described; for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl, and the like.
[000113] The term "heteroaryl" means a substituted or unsubstituted aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, preferably about 5 to about 10 ring atoms and preferably 5 or 6 ring atoms , wherein at least one of the ring atoms is an N, O, or S atom. Suitable heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, benzimidazolyl, indazolyl, indolyl, quinolinyl, isoquinolinyl, naphthyridinyl and the like.
[000114] Substituted heteroaryl groups include the heteroaryl groups described above that are substituted one or more times, for example, but not limited to, halogen, hydroxyl, amino, carboxy, alkylamino, dialkylamino, aryl, heteroaryl, alkoxy, nitro and combinations thereof.
[000115] The term "heteroarylalkyl" refers to a -(alkylene)-heteroaryl group in which the heteroaryl and alkylene moieties are in accordance with the previous descriptions. Suitable examples include, but are not limited to, pyridylmethyl, thiazolylmethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl, and isoquinolinylmethyl, and the like.
[000116] The term "heterocycle" means a substituted or unsubstituted non-aromatic mono or multicyclic ring system comprising 3 to 10 atoms, preferably 5 or 6, wherein at least one of the ring atoms is an N, O or S. Suitable heterocyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, thiomorpholinyl, morpholinyl, isoxazolinyl, and the like.
[000117] Substituted heterocycle groups include the heterocycle groups described above that are substituted one or more times, for example, halogen, amino, alkyl, hydroxy, carboxy, and combinations thereof. Heterocycle groups can similarly be substituted by, for example, aryl or heteroaryl.
[000118] The term "heterocycloalkyl" refers to a -(alkylene)-heterocycle group in which the heterocycle and alkylene moieties are in accordance with the previous discussions.
[000119] The term "aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. Suitable aroyl groups include, but are not limited to, benzoyl and 1-naphthoyl.
[000120] The term "acyl" means an HC(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, or heteroalkyl-C(O)- wherein the various groups are as previously described, for example, acetyl, propionyl, benzoyl, pyridinylcarbonyl, and the like.
[000121] The term "alkoxy" means alkyl-O- groups in which the alkyl portion conforms to the previous descriptions. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, pentoxy, hexoxy, heptoxy, octoxy, and the like. For example, the alkoxy can be methoxy or ethoxy.
[000122] The term "aryloxy" means an aryl-O- group wherein the aryl group is as previously described.
[000123] The term "heteroaryloxy" means a heteroaryl-O- group wherein the heteroaryl group is as previously described.
[000124] The term "cycloalkylalkyloxy" means an -O-(alkylene)-cycloalkyl group wherein the cycloalkyl and alkylene groups are as previously described.
[000125] The term "alkylthio" means an alkyl-S- group wherein the alkyl group is as previously described.
[000126] The term "arylthio" means an aryl-S- group wherein the aryl group is as previously described.
[000127] The term "alkylsulfinyl" means a radical of -SOR where R is alkyl as defined above, for example, methylsulfinyl, ethylsulfinyl, and the like.
[000128] The term "alkylsulfonyl" means a radical of -SO2R where R is alkyl as defined above, for example, methylsulfonyl, ethylsulfonyl, and the like.
[000129] The term "arylsulfinyl" means a radical of -SOR where R is aryl as defined above, for example, phenylsulfinyl, and the like.
[000130] The term "arylsulfonyl" means a radical of -SO2R where R is aryl as defined above, for example, phenylsulfonyl, and the like.
[000131] The term "heteroarylsulfinyl" means a radical of -SOR where R is heteroaryl as defined above.
[000132] The term "heteroarylsulfonyl" means a radical of -SO2R where R is heteroaryl as defined above.
[000133] The term "alkoxycarbonyl" means an alkyl-O-C(O)- group wherein the alkyl group is as previously described.
[000134] The term "aryloxycarbonyl" means an aryl-O-C(O)- group wherein the aryl group is as previously described.
[000135] The term "heteroaryloxycarbonyl" means a heteroaryl-O-C(O)- group wherein the heteroaryl group is as previously described.
[000136] The term "cycloalkyloxy" means an -O-cycloalkyl group wherein the cycloalkyl group is as previously described, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like
[000137] The term "arylalkyloxy" means -O-(alkylene)-aryl group wherein the aryl and alkylene groups are as previously described.
[000138] The term "heteroarylalkyloxy" means -O-(alkylene)-heteroaryl group wherein the heteroaryl and alkylene groups are as previously described.
[000139] One skilled in the art will recognize that compounds of the present invention may exist in different tautomeric and geometric isomeric forms. All of these compounds, including cisisomers, transisomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers, substantially pure enantiomers, and pure, are within the scope of the present invention. Substantially pure enantiomers contain no more than 5% w/w of the corresponding opposite enantiomer, preferably no more than 2%, preferably no more than 1%.
[000140] Optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of suitable acids are tartaric, diacetyltartaric, dibenzoyltartaric,ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known to those skilled in the art with the benefit of this description, for example, by chromatography or fractional crystallization. Optically active bases or acids are then released from the separate diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (eg chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, for example, Chiracel OD and Chiracel OJ among many others, all usually selectable. Enzymatic separations, with or without derivation, are similarly useful. The optically active compounds of the invention can also be obtained using optically active starting materials in chiral synthesis processes under reaction conditions that do not cause racemization.
[000141] Furthermore, one skilled in the art will recognize that the compounds can be used in different enriched isotopic forms, for example, enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In a particular embodiment, the compounds contain 2H. In another embodiment, the compounds contain 3H. Deuterated and triciated compounds can be prepared using methods known in the art.
[000142] For example, deuterated forms can be made using the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the efficacy and increase the duration of action of drugs.
[000143] Substituted deuterium compounds can be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] (2000), 110pp; Kabalka, George W.; Var ma, Rajender S. The synthesis of radiolabeled compounds via organ-ometallic intermediates. Tetrahedron (1989), 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981), 64(1-2), 9-32.
[000144] Where applicable, the present invention likewise refers to useful forms of the compounds as described herein, such as basic free forms, and pharmaceutically acceptable salts or prodrugs of all compounds of the present invention to which salts or prodrugs can be prepared. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Pharmaceutically acceptable salts likewise include those in which the main compound functions as an acid and is reacted with an appropriate base to form, for example, sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those of skill in the art with the benefit of this disclosure will also recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with the appropriate inorganic or organic acid by any of several known methods. Alternatively, alkali metal and alkaline earth salts can be prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
[000145] The following are other examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adiPEates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclo- pentanepropionates, dodecylsulphates, ethanesulphonates, glycoheptanoates, glycerophosphates, hemisulphates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxyethanesulphonates, lactates, maleates, methanesulphonates, nicotinates, hexanoates, 2-naphthalates sulphonates pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates.
[000146] For example, the pharmaceutically acceptable salt may be a hydrochloride, a hydrobromide, a hydroformate, or a maleate.
[000147] Preferably, the salts formed are pharmaceutically acceptable for administration to mammals. However, pharmaceutically acceptable salts of the compounds are suitable as intermediates, for example, to isolate the compound as a salt and then convert the salt back to the free base compound by treatment with an alkaline reagent. The free base can then, if desired, be converted to a pharmaceutically acceptable acid addition salt.
[000148] One of ordinary skill in the art will likewise recognize that some of the compounds of the present invention may exist in different polymorphic forms. As known in the art, polymorphism is an ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species. A polymorph is a solid crystalline phase of a compound having at least two different arrangements or polymorphic forms of that compound molecule in the solid state. Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in chemical structure as crystal structures of two different chemical compounds.
[000149] One of skill in the art will also recognize that compounds of the present invention may exist in different solvate forms. Solvates of the compounds of the invention can likewise when solvent molecules are incorporated into the crystal lattice structure of the compound molecule during the crystallization process.
[000150] The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention in any way as many variations and equivalents that are encompassed by the present invention will become apparent to those skilled in the art upon reading the present description . For example, some reactions described below can be performed under a range of conditions, such as at a different temperature (4°C, 10°C, 25°C, etc.), substitution with other reagents and different amounts or concentration of reagents . EXAMPLES EXAMPLE 1 Preparation of Benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate (1:1) ethanedioate and the like

[000151] Compounds of Formula (XVIII) (X=O, NH; R7=benzyl, ethyl) can be prepared as described below. Example 1a Benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) can be prepared as described below.
Figure legend - Step 1 - Step 2 - Step 3 - Step 4
[000152] Dimethylsulfoxide (DMSO; 500 ml) was added to a mixture of trimethylsulfoxonium iodide (ME3SOI; 79.2 g, 360 mmols, 1.15 eq) and potassium tert-butoxide (KOtBu; 38.6 g, 344 g .4 mmols, 1.1 eq) in tetrahydrofuran (THF; 400 ml) at room temperature. The mixture was stirred until the reaction was judged to be complete and cooled to -12°C. A solution of (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (100 g, 313.1 mmol, 1 eq) in tetrahydrofuran (THF; 300 ml) was added slowly. The mixture was stirred at -12°C until the reaction was judged to be complete. The reaction was quenched by the addition of saturated aqueous ammonium chloride (500 ml) and water (300 ml). The product was extracted with ethyl acetate (1000 ml), and the resulting organic solution was washed with aqueous sodium chloride. The organic layer was concentrated in vacuo to a final volume of 600 ml.
[000153] To this solution was added O-benzylhydroxylamine hydrochloride (BnONH2HCl; 52.5 g, 328.8 mmol, 1.05 eq) and ethyl acetate (400 ml). The mixture was stirred at reflux until the reaction was judged to be complete. The mixture was cooled and washed with water and saturated sodium chloride. The organic layer was concentrated in vacuo to provide a solution of (S)-5-Benzyloxyimino-2-tert-butoxycarbonylamino-6-chlorohexanoic acid benzyl ester in ethyl acetate.
[000154] Methane sulfonic acid (MSA; 61 ml, 939.3 mmol, 3 eq) was added to this solution. The solution was stirred at 42°C until the reaction was judged to be complete. The solution was added to a solution of potassium bicarbonate (156.7 g, 1565.5 mmol, 5 eq) in water (500 ml) and the resulting mixture was vigorously stirred at 52°C until the reaction was judged to be complete. . The organic layer was washed with aqueous sodium chloride and concentrated in vacuo to provide a solution of (S)-5-Benzyloxy-imino-piperidine-2-carboxylic acid benzyl ester in ethyl acetate.
[000155] Propanic acid (140.6 ml, 1878.6 mmols, 6 eq) was added to a suspension of sodium borohydride (23.2 g, 626.2 mmol, 2 eq) in ethyl acetate (600 ml) and held until the reaction was judged to be complete. The resulting solution was added to a solution of benzyl (2S,)-5-[(benzyloxy)imino]piperidine-2-carboxylic acid benzyl ester in ethyl acetate (600 ml total volume) and sulfuric acid (83 .4 ml, 1565 mmols, 5 eq) at -20°C and held until the reaction was judged to be complete. The reaction was quenched by the addition of water (1000 ml), then neutralized with aqueous ammonia solution. The organic layer was washed with water and concentrated in vacuo to 400 ml. The solution was heated to 45°C and kept at this temperature. Methanol (200 ml) at 40°C was added, followed by a freshly prepared solution of oxalic acid dihydrate (39.5 g, 313.1 mmol) in methanol (100 ml). The mixture was cooled and the product isolated by filtration. The solid was washed with an ethyl acetate/methanol mixture, then with ethyl acetate. The solid was dried to yield benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) as a single isomer (79.4 g, 185 mmols, 59%) . Example 1b
[000156] Benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) was prepared as a single isomer (SR) from a mixture of trans (SR) and cis (SS) isomers using the following procedure.
Figure caption - reflux
[000157] Benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) (100 g, 233 mmols, 70% SR isomer) was stirred in methanol (1 .6 L) and heated to reflux. This temperature was maintained until all solids dissolved and a clear solution formed. The solution was cooled to 25°C for 2 hours, and held at this temperature for 2 hours. The precipitated solid was isolated by filtration, washed with methanol (200 ml) and dried at 35°C under vacuum for 16 hours to yield (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate of benzyl (1:1) as a white solid (65 g, 65% wt yield).
[000158] 1H NMR (400MHz, DMSO) δ: 1.41 (1H, q), 1.69 (1H, q), 1.88 (1H, d), 2.17 (1H, dd), 2, 64 (1H, t), 3.11 (1H, m), 3.40 (1H, d), 4.00 (1H, dd), 4.58 (2H, s), 5.23 (2H, s ), 7.35 (10H, m). Example 1c
[000159] Benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) can be prepared as described in Example 1a except as described below.
[000160] Benzylhydroxylamine sulfonate methane salt is used, progressing the process through an alternative intermediate, sulfoxonium oxime. Cyclization is performed using triethylamine. Piperidine oxime is isolated as its p-toluenesulfonate (tosylate) salt. Example 1d (2S)-5-Benzyloxyamino-piperidine-2-carboxylic acid benzylamide was prepared as outlined below.
Figure legend - oxalic acid - acetone
[000161] N,N'-Dicyclohexyl carbodiimide (DCC; 8.2 g, 40 mmols) was added to a solution of pyroglutamic acid (5.16 g, 40 mmols) in dimethylformamide (DMF; 60 ml) . The mixture was stirred at room temperature for 2 hours and a precipitate formed. Benzylamine (4.8 ml, 44 mmols) was added and the mixture was stirred for 2 hours. t-butyl dicarbonate (Boc2O; 9.6 g, 44 mmols), triethylamine (TEA; 6.3 ml, 44 mmols) and 4-dimethylaminopyridine (DMAP; 488 mg, 4 mmols) were added and the mixture was stirred in at room temperature for 16 hours. DMF was removed under vacuum and the residue was taken up in water (20 ml) and extracted with dichloromethane (DCM; 3 x 20 ml). The organic layers were concentrated and the crude product was purified by silica gel chromatography to give (S)-2-benzylcarbamoyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (2.23 g, 7, 0 mmols, 17.5%).
[000162] Dimethylsulfoxide (DMSO; 20 ml) was added dropwise to a suspension of potassium tert-butoxide (1.12 g, 10 mmols) and trimethylsulfoxonium iodide (2.2 g, 10 mmols) in tetra -hydrofuran (THF; 15 ml). The mixture was stirred at room temperature for 1 hour, then cooled to -10°C. A solution of (S)-2-benzylcarbamoyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1.59 g, 5 mmols) in THF (10 ml) was added, resulting in a white precipitate. The mixture was stirred at 0°C for 1 hour. The reaction was quenched with saturated NH 4 Cl solution (20 ml), and the product was extracted with EtOAc (2 x 50 ml). The organic layers were washed with brine and concentrated in vacuo. The product was purified by silica gel chromatography (EtOAc/MeOH) to yield the beta-ketosulfoxonium as a white solid (615 mg, 1.5 mmol, 30%).
[000163] A suspension of beta-ketosulfoxonium (584 mg, 1.42 mmol) and O-benzylhydroxylamine (251 mg, 1.57 mmol) in THF (20 ml) was refluxed for 2 hours. The mixture was diluted with EtOAc (50 ml) and washed with 1N HCl (20 ml) and brine (20 ml). The product was purified by silica gel chromatography to yield the chlorooxime as a colorless oil (784 mg, quant).
[000164] The chloro-oxime oil was dissolved in EtOAc (10 ml) and methane sulfonic acid (320 µl, 4.95 mmol, 3 eq) was added. The mixture was stirred at 40°C for 3 hours. The mixture was poured into saturated sodium bicarbonate solution (10 ml) and stirred at 50°C for 2 hours. The layers were separated and the organic layer was washed with water and concentrated to 10 ml. The solution was cooled to 0°C. Sulfuric acid (447 µl, 8.4 mmols, 5 eq) was added, followed by sodium triacetoxyborohydride (712 mg, 3.36 mmols). The mixture was stirred at 0°C for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution (20 ml). The layers were separated and the organic layer was washed with water. The organic layer was concentrated to 5 ml, and a solution of oxalic acid (153 mg, 1.7 mmol) in ethyl acetate (1 ml) and acetone (1 ml) was added. The resulting solid was isolated by filtration, washed with EtOAc, and dried in vacuo at 35°C to give (2S)-5-benzyloxyamino-piperidine-2-carboxylic acid benzylamide as an off-white solid (430 mg, 1.0 mmol) , 71% BKS N(Bn)). Example 1e Benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) was isolated from a mixture of trans (SR) and cis (SS) isomers using the following procedure.
Figure caption - oxalic acid
[000165] In a suspension of benzyl 5-[(benzyloxy)amino]piperidine-2-carboxylate (1:1) ethanedioate (10 g, 23.3 mmol, 3:1, SR:SS) in ethyl acetate (70 ml) was added a solution of potassium bicarbonate (9.3 g, 93 mmols, 4 eq) in water (90 ml). The mixture was stirred until all solids dissolved. The layers were separated and the aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layers were washed with water (50 ml) and concentrated under vacuum below 40°C to a final volume of 40 ml. The solution was passed through a filter and heated to 45°C. Methanol (20 ml) at 40°C was added, followed by a freshly prepared solution of oxalic acid dihydrate (3.67 g, 29.1 mmols) in methanol (10 ml). The mixture was cooled and the product isolated by filtration. The solid was washed with an ethyl acetate/methanol mixture, then with ethyl acetate. The solid was dried to yield benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) as a single isomer (7.0 g, 16.3 mmol , 70%). Example 1f Ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) was prepared as described below.
Figure legend - oxalic acid - acetone
[000166] A suspension of benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate (1:1) ethanedioate (100 g, 232 mmols) in ethanol (2000 ml) was cooled to 0°C. A solution of sodium ethoxide in ethanol (216 ml, 580 mmol, 21 wt% solution) was added slowly and the mixture was stirred for 1 hour at 0°C. Acetic acid (13.3 ml, 232 mmols) was added and the mixture was concentrated in vacuo below 35°C to a final volume of 300 ml. Ethyl acetate (700 ml) was added and the mixture was concentrated to 300 ml. This procedure was repeated twice. Water (1800 ml) was added to the mixture followed by aqueous ammonia (variable) until the pH of the aqueous layer was 7.5 to 8. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 300 ml) . The combined organic layers were washed with water (500 ml) and concentrated to a final volume of 300 ml. The solution was filtered and diluted with ethyl acetate (700 ml) and heated to 35°C. A solution of oxalic acid dihydrate (30g, 237 mmols) in acetone (200 ml) was added and the mixture was cooled to room temperature. The solids were isolated by filtration, washed with ethyl acetate and dried under vacuum at 35°C to obtain ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) as a white solid (80.7 g, 94%). Example 1g
[000167] Ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) was prepared as described below.
Figure Legend - Step 1 - Step 2 - Step 3 - Step 4 - Oxalic Acid
[000168] DMSO (120 ml) was added to a mixture of trimethylsulfoxonium iodide (20.5 g, 93.2 mmols, 1.2 eq) and potassium tert-butoxide (10.0 g, 89.4 mmol, 1, 15 eq) in tetrahydrofuran (100 ml) at room temperature. The mixture was stirred until the reaction was judged to be complete and cooled to -12°C. A solution of (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-ethyl ester 1-tert-butyl ester (20 g, 77.7 mmol, 1 eq) in tetrahydrofuran (60 ml) was added slowly. The mixture was stirred at -12°C until the reaction was judged to be complete. The reaction was quenched by the addition of saturated aqueous ammonium chloride (100 ml) and water (60 ml). The product was extracted with ethyl acetate (200 ml), and the resulting organic solution was washed with aqueous sodium chloride. The organic layer was concentrated in vacuo to a final volume of 80 ml.
[000169] To this solution was added O-benzylhydroxylamine hydrochloride (13.0 g, 81.6 mmols, 1.05 eq) and ethyl acetate (140 ml). The mixture was stirred at reflux until the reaction was judged to be complete. The mixture was cooled and washed with water and saturated sodium chloride solution. The organic layer was concentrated in vacuo to 100 ml.
[000170] To this solution was added methane sulfonic acid (15.1 ml, 233.1 mmols, 3 eq). The solution was stirred at 42°C until the reaction was judged to be complete. The solution was added to a solution of potassium bicarbonate (38.9 g, 388.5 mmols, 5 eq) in water (120 ml) and the resulting mixture was stirred vigorously at 52°C until the reaction was judged to be complete. . The organic layer was washed with aqueous sodium chloride and concentrated in vacuo to a final volume of 120 ml.
[000171] Propanic acid (34.9 ml, 466.2 mmols, 6 eq) was added to a suspension of sodium borohydride (5.75 g, 155.4 mmol, 2 eq) in ethyl acetate (160 ml) and held until the reaction was judged to be complete. The resulting solution was added to a solution of (S)-5-Benzyloxy-imino-piperidine-2-carboxylic acid ethyl ester in ethyl acetate (120 ml total volume) and sulfuric acid (20.7 ml, 388.5 mmol, 5 eq) at -20°C and held until the reaction was judged to be complete. The reaction was quenched by the addition of water (240 ml), then neutralized with aqueous ammonia solution. The organic layer was washed with water and concentrated in vacuo to 80 ml. The solution was heated to 45°C and kept at this temperature. Ethanol (80 ml, 95%) at 40°C was added, followed by a freshly prepared solution of oxalic acid dihydrate (9.8 g, 77.7 mmols) in ethanol (40 ml). The mixture was cooled and the product isolated by filtration. The solid was washed with an ethyl acetate/ethanol mixture then extracted with ethyl acetate. The solid was dried to yield ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) as a single isomer (16.4 g, 44.5 mmols, 57.3 %).
[000172] 1H NMR (400MHz, DMSO) δ: 1.22 (3H, t), 1.41 (1H, qd), 1.68 (1H, qd), 1.88 (1H, m), 2, 13 (1H, dd), 2.65 (1H, t), 3.13 (1H, m), 3.39 (1H, d), 3.92 (1H, dd), 4.19 (2H, q ), 4.59 (2H, s), 7.34 (5H, m). EXAMPLE 2 Preparation of (2S,5R)-5-[(benzyloxy)amino]piperidine-2-Carboxamide

[000173] (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide was prepared as described below. Example 2a
Figure caption - Toluene
[000174] Benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate (1:1) ethanedioate (50 g, 113.8 mmols) was mixed with a solution of ammonium in methanol ( 7N, 700 ml) and stirred until the reaction was judged to be complete. The mixture was filtered to remove ammonium oxalate by-product, the ammonium oxalate mass was washed with methanol (2x50 ml) and the combined filtrates were concentrated to 250 ml. Toluene (500 ml) was added and the solution was concentrated to 250 ml causing the product to precipitate. Toluene (500 ml) was added, and the mixture was heated to 80°C and cooled to 0°C. The product was isolated by filtration, washed with methyl tert-butyl ether (MTBE) (100 ml), and dried to yield a white crystalline solid (26.9 g, 108 mmols, 95%).
[000175] 1H NMR (400 MHz, DMSO) δH 1.12 (1H, m), 1.27 (1H, m), 1.83 (2H, m), 2.22 (1H, dd), 2, 76 (1H, m), 2.89 (1H, dd), 3.14 (1H, dd), 4.58 (2H, s), 6.46 (1H, d), 6.91 (1H, s ), 7.09 (1H, s), 7.32 (5H, m). Example 2b
Figure caption - Toluene
[000176] Benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) (50 g, 113.8 mmol) was mixed with a solution of ammonium in methanol ( 7N, 700 ml) and stirred at room temperature until the reaction was judged to be complete. The mixture was filtered to remove ammonium oxalate by-product and washed with methanol (2 x 50 ml) before being concentrated to 250 ml. Toluene (500 ml) was added and the solution was concentrated to 250 ml causing the product to precipitate. Cyclopentyl methyl ether (CPME) (500 ml) was added and the mixture was heated to 80°C and then cooled to 0°C. The product was isolated by filtration, washed with CPME (100 ml), and dried to yield a white crystalline solid (26.9 g, 108 mmols, 95%). Example 2c

[000177] Benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) (100 g) was mixed with methanol (400 ml) and an aqueous ammonium solution ( 35%, 1 L) and stirred until the reaction was judged to be complete (18 h). The mixture was filtered to remove ammonium oxalate by-product and concentrated to 500 ml. Saturated aqueous brine solution (1.45 L) was added and mixture cooled to 0°C. The product was isolated by filtration, washed with saturated aqueous brine solution (100 ml) at 0°C, then ice water (2 x 50 ml), then tert-butyl methyl ether (MTBE) (100 ml), and dried to yield a white crystalline solid (38.6 g, 68%). 2d example

[000178] Methyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate (1:1) ethanedioate (1 g, 2.74 mmols) was mixed with a solution of ammonium in methanol ( 7N, 14 ml) and stirred at room temperature until the reaction was judged to be complete. The mixture was filtered to remove ammonium oxalate by-product and washed with methanol (2 x 1 ml) before being concentrated to dryness (0.68 g, 2.72 mmols, 99%). Example 2e
Figure caption - Toluene
[000179] Ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) (10 g, 27.15 mmol) was mixed with a solution of ammonium in methanol ( 7N, 140 ml) and stirred at room temperature until the reaction was judged to be complete. The mixture was filtered to remove ammonium oxalate by-product and washed with methanol (2 x 50 ml) before being concentrated to 50 ml. Toluene (50 ml) was added and the solution was concentrated to 50 ml causing the product to precipitate. Toluene (50 ml) was added and the mixture was heated to 80°C and then cooled to 0°C. The product was isolated by filtration, washed with methyl tert-butyl ether (MTBE) (2 x 15 ml), and dried to yield a white crystalline solid (6.29 g, 25.23 mmols, 93%). Example 2f (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide ethanedioate (1:1) was prepared as described below.
Figure caption - oxalic acid
[000180] Benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate (1:1) ethanedioate (65 g, 148.0 mmol) was mixed with a solution of ammonium in methanol ( 7N, 910 ml) and stirred at room temperature until the reaction was judged to be complete. The mixture was filtered to remove ammonium oxalate by-product and washed with methanol (2 x 65 ml) before being concentrated to 325 ml. Ethyl acetate (325 ml) was added followed by addition of a solution of oxalic acid (dihydrate) (20.52g) in ethyl acetate (325 ml) and methanol (32.5 ml) to crystallize the product. . The product was filtered and washed with ethyl acetate (2 x 195 ml), then dried to yield a white crystalline solid (49.3 g, 145.2 mmols, 98%).
[000181] 1H NMR (400 MHz, DMSO + TFA) δH 1.40 (1H, m), 1.61 (1H, m), 1.93 (1H, d), 2.22 (1H, d), 2.76 (1H, m), 3.22 (1H, m), 3.38 (1H, d), 3.70 (1H, t), 4.65 (2H, s), 7.35 (5H, , m), 7.62 (1H, s), 7.88 (1H, s). EXAMPLE 3 Preparation of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
[000182] (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide was prepared as described below. Example 3a
Figure caption - Diethylamine
[000183] (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide (102 g, 409 mmols) was mixed with diisopropylethylamine (76.2 ml, 437.6 mmols) and chlorobenzene (612 ml) at 20°C. 9-Fluorenylmethyl chloroformate (107.9 g, 417.2 mmols) as a solution in chlorobenzene (612 ml) was added to the reaction mixture, and the mixture was stirred at 30°C until the reaction was complete. Carbonyl diimidazole (86.2 g, 531.7 mmols) was added and stirring was continued until the reaction was judged to be complete. Diethylamine (105.8 ml, 1022.5 mmols) was added and stirring was continued until the reaction was judged to be complete. Aqueous hydrochloric acid (640 ml, 3N, 1920 mmols) was added and the mixture was cooled to 2°C. The solid was isolated by filtration, washed with water (2 x 200 ml) and 1-chlorobutane (2 x 200 ml) and dried to yield the title compound as a white crystalline solid (101 g, 367.2 mmol, 90%) .
[000184] 1H NMR (400 MHz, DMSO) δH 1.65 (2H, m), 1.83 (1H, m), 2.07 (1H, m), 2.91 (2H, s), 3. 63 (1H, s), 3.69 (1H, d), 4.92 (1H, d), 4.96 (1H, d), 7.38 (7H, m). Example 3b
Figure caption - triphosgene - acetone
[000185] (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide was prepared as described below.
[000186] A solution of potassium bicarbonate (47.5 g, 475 mmols) in water (250 ml) was added to a suspension of (2S,5R)-5-[(benzyloxy)amino]piperidine-ethanedioate. Benzyl 2-carboxylate (1:1) (50 g, 116 mmols) in 2-methyltetrahydrofuran (350 ml) and water (200 ml). The mixture was stirred until the reaction was judged to be complete, and the layers were separated. The aqueous layer was extracted with 2-methyltetrahydrofuran (100 ml) and the combined organic layers were washed with water (150 ml). The organic layer was concentrated in vacuo and azeotropically dried to the desired water content. The solution was diluted with 2-methyltetrahydrofuran (800 ml) and cooled to 0°C. Triethylamine (42.4 ml, 309 mmols, 2.67 eq) was added, followed by a solution of triphosgene (15.1 g, 50.8 mmols, 0.44 eq) in 2-methyltetrahydrofuran (200 ml) . The mixture was stirred until the reaction was judged to be complete. The reaction was quenched with a solution of potassium bicarbonate (24 g, 240 mmols, 2.07 eq) in water (300 ml). The layers were separated and the organic layer was washed with aqueous sodium chloride solution. The organic layer was concentrated in vacuo, acetone was added and the solution was concentrated again. The solution was diluted with acetone (final volume 900 ml), water (200 ml) was added, and the mixture was cooled to -12°C. A solution of lithium hydroxide monohydrate (7.8 g, 186 mmols, 1.6 eq) in water (450 ml) was added slowly, and the mixture was stirred until the reaction was judged to be complete. The reaction was quenched with aqueous hydrochloric acid to a final pH of 8.5. Toluene (500 ml) was added and the layers were separated. The aqueous layer was washed with toluene (2 x 250 ml). Sodium chloride (60.5 g, 1000 mmols, 8.6 eq) was added, followed by dichloromethane (450 ml). Aqueous hydrochloric acid was added until a final pH of 2.5 was obtained. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 150 ml). The combined organic layers were concentrated in vacuo and azeotropically dried. The resulting solution was diluted to 450 ml with dichloromethane and cooled to 0°C. Triethylamine (20ml, 139mmol, 1.2eq) was added, followed by trimethylacetyl chloride (14.2ml, 116mmol, 1.0eq). The mixture was stirred at 0°C until the reaction was judged to be complete. The mixture was cooled to -20°C and quenched with aqueous ammonia (31 ml, 28%, 464 mmols, 4 eq). The mixture was stirred at 0°C until the reaction was judged to be complete. Water (250 ml) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (100 ml). The combined organic layers were washed with 2% aqueous ammonium chloride solution (2 x 250 ml) and concentrated in vacuo. Chlorobutane was added and the solution was concentrated in vacuo. The resulting precipitate was collected by filtration, washed with chlorobutane and dried under vacuum to yield (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide as a white solid (11.0 g, 40 mmols, 34.5%). Example 3c
Figure caption - triphosgene - 3-picoline - dichloromethane
[000187] (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide was prepared as described below.
[000188] 3-picoline (45 ml, 464, 4 eq) was added to a suspension of benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (50 g, 116 mmols). , 1 eq) in dichloromethane (1000 ml) at 0°C, followed by a solution of triphosgene (31.0 g, 104.4 mmols, 0.9 eq) in dichloromethane (200 ml). The mixture was stirred at 0°C until the reaction was judged to be complete. The reaction was quenched with a solution of sodium bicarbonate (24.4 g, 290 mmols, 2.5 eq) in water (300 ml), and the layers were separated. The aqueous layer was extracted with dichloromethane (100 ml) and the combined organic layers were washed with water. The organic layer was concentrated in vacuo to yield (2S,5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid benzyl ester as a solution in dichloromethane.
[000189] Aqueous tetrabutylammonium hydroxide (116 ml, 1.5 M, 174 mmols, 1.5 eq) was added to this solution at room temperature. The mixture was stirred until the reaction was judged to be complete. The reaction was quenched with water and the pH was adjusted to 2.5 using HCl. The aqueous layer was extracted and the combined organic layers were washed with water. The organic layer was concentrated in vacuo. Triethylamine (32.3 ml, 232 mmols, 2 eq) and hexamethyldisilazane (72.6 ml, 348 mmols, 3 eq) were added to the resulting solution. A purchased solution of 1-propanephosphonic acid cyclic anhydride in ethyl acetate (69 ml, 116 mmols, 1 eq, 50% by weight solution) was added to this mixture. The mixture was stirred until the reaction was judged to be complete. The reaction was quenched with water and the organic layer was washed with aqueous ammonium chloride solution. The organic layer was concentrated in vacuo. Chloro-butane was added and the solution was concentrated causing the product to crystallize again. The solid was isolated by filtration, washed with chlorobutane and dried under vacuum to yield (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide as a white solid (22.3 g, 81.1 mmols, 70%). 3d example
Figure caption - triphosgene, picoline - Novozime - Ammonium carbamate
[000190] (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide can be prepared using an enzymatic approach as described below.
[000191] 3-picoline (52.6 ml, 543 mmols, 4 eq) was added to a suspension of ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1: 1) (50 g, 136 mmols, 1 eq) in dichloromethane (1000 ml) at 0°C, followed by a solution of triphosgene (36.4 g, 122.4 mmols, 0.9 eq) in dichloromethane (200 ml). The mixture was stirred at 0°C until the reaction was judged to be complete. The reaction was quenched with a solution of sodium bicarbonate (28.6 g, 340 mmols, 2.5 eq) in water (300 ml), and the layers were separated. The aqueous layer was extracted with dichloromethane (100 ml) and the combined organic layers were washed with water. The organic layer was concentrated in vacuo to yield (2S,5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid ethyl ester as a solution in dichloromethane ( solution yield: 35 g, 116 mmols, 85%). Acetonitrile was added and the solution was concentrated in vacuo to yield (2S,5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid ethyl ester as a solution in acetonitrile. This solution was diluted with acetonitrile to 700 ml. To this was added ammonium carbamate (11.3 g, 145 mmols, 1.25 eq) and Novozyme 435 (35 g, immobilized Candida antarctica lipase B). The mixture was stirred at 40°C until the reaction was judged to be complete. The reaction mixture was filtered and concentrated in vacuo. The solution was diluted with dichloromethane, washed with aqueous ammonium chloride, and concentrated in vacuo. Chlorobutane was added and the solution was concentrated in vacuo. The precipitate was isolated by filtration, washed with chlorobutane and dried to yield 2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide as a white solid (24 .3 g, 88 mmols, 65% ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate). Example 3e
[000192] (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide was prepared as described below.
Figure caption - triphosgene - Novozime - Ammonium carbamate
[000193] Saturated aqueous potassium bicarbonate (30ml) was added to a solution of (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate methyl ethanedioate (1:1) (3.0g, 8.38 mmols) in 2-methyltetrahydrofuran (25 ml). The layers were separated and the organic phase was washed with saturated aqueous sodium chloride solution (12.5 ml). The aqueous phase was again extracted with 2-methyltetrahydrofuran (8.4 ml). The combined organic phases were concentrated to dryness then reconstituted in 2-methyltetrahydrofuran (75ml). Triethylamine (3.1 ml) was added and the solution was cooled to -5°C. Triphosgene (1.1 g) in 2-methyltetrahydrofuran (16.8 ml) was added dropwise, maintaining a temperature <-3°C. The mixture was stirred for 1 hour before dimethylaminopyridine (102 mg) was added. Mixing was continued until the reaction was judged to be complete. The reaction was quenched with saturated aqueous potassium bicarbonate (21 ml). The layers were separated and the organic phase was washed with water (12.6 ml). Each aqueous layer was again extracted with 2-methyltetrahydrofuran (12.6 ml). The combined organics were evaporated to dryness (3.51 g).
[000194] (2S,5R)-6-Benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid methyl ester (0.767g) was dissolved in acetonitrile (15.5 mL) containing ammonium carbamate (200 mg), Novozyme 435 (0.770 g, immobilized Candida antarctica lipase B) and calcium dichloride (0.244 g). Ascarite II (2.4 g) was separately loaded to the free top. The mixture was stirred at 40°C until the reaction was judged to be complete. The reaction mixture was filtered and concentrated in vacuo, before adding chlorobutane. The precipitate was isolated by filtration in a centrifuge, washed with chlorobutane and dried to yield 2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazobicyclo[3.2.1]octane-2-carboxamide as a solid white (96% HPLC area). Example 3f
[000195] (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide was prepared using N,N-Carbonyl diimidazole (CDI) co- described below.
Figure legend - t-amyl alcohol
[000196] (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide (2 g) was mixed with t-amyl alcohol (60 ml) and heated to 40°C. N,N-carbonyl diimidazole (CDI) (3.9 g) was added in portions over 1 hour and then the mixture heated at 60°C for 1 hour before concentrating under vacuum to approximately half its volume. The mixture was cooled to 0°C, seeded, and held at 0°C for 1.5 hours. The mixture was then filtered and washed with MTBE (5 ml) before drying at 40°C to yield a white crystalline solid (1.25 g, 56%) Example 3g
[000197] (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide was prepared as described below.
Figure caption - toluene
[000198] (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide (291 mg, 1.17 mmol) was mixed with triethylamine (193 µl, 1.37 mmol) and toluene (2 .4 ml) at 20°C. Di-t-butyldicarbonate (310 mg, 1.42 mmol) as a solution in toluene (2.0 ml) was added to the reaction mixture, and the mixture was stirred at 40°C until the reaction was complete. The solution was diluted with toluene (3.9 mL) and carbonyl diimidazole (462 mg, 2.85 mmol) was added and stirring was continued until the reaction was judged to be complete. Methanesulfonic acid (663 L, 10.2 mmols) was added and stirring was continued until the reaction was judged to be complete. After lowering the temperature to 20°C, aqueous potassium hydrogen carbonate (10.2 ml, 1N, 10.2 mmol) was added and the mixture was stirred at 20°C until the reaction was complete. The aqueous layer was separated and the toluene layer washed with water (3ml), citric acid (1N, 3ml) and water (3ml). The four aqueous washes were extracted twice with dichloromethane (2 x 3 mL). The three organic extracts were combined to produce (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide as a solution in toluene and dichloromethane (176 mg, 0.64 mmol, 55%). EXAMPLE 4 Preparation of tetrabutylammonium ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxidanide
Example 4a
[000199] (Tetrabutylammonium {[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxidanide was prepared as described below.

[000200] (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (10 g, 36.2 mmols, 1 eq) was mixed with complex of sulfur trioxide trimethylamine (6.07 g, 43.44 mmols, 1.2 eq), triethylamine (1.3 ml, 18 mmols, 0.25 eq), palladium on carbon (0.8 g, 10% palladium, 50% water), isopropanol (50 ml) and water (50 ml). This mixture was treated with hydrogen until the reaction was judged to be complete. The catalyst was removed by filtration and washed with water (20 ml). The combined filtrates were washed with n-BuOAc (70 ml, 20 ml) before a solution of tetrabutylammonium acetate (54.5 mmols) in water (20 ml) was added. The product was extracted with dichloromethane (100ml, 50ml) and solvent exchanged into 4-methyl-2-pentanone, before filtering, washing and drying to yield a white crystalline solid (16.9g, 92%).
[000201] 1H NMR (400 MHz, CDCl 3 ) δH 1.00 (12H, t), 1.45 (8H, m), 1.67 (9H, m), 1.87 (1H, m), 2, 16 (1H, m), 2.37 (1H, dd), 2.87 (1H, d), 3.31 (9H, m), 3.91 (1H, d), 4.33 (1H, s ), 5.79 (1H, s), 6.67 (1H, s). Example 4b
[000202] (Tetrabutylammonium {[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxidanide was prepared as described below.

[000203] Palladium on carbon (400 mg, 5% Pd, 3% water) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2. 1]octane-2-carboxamide (10.0 g, 36.2 mmols) in dimethylformamide (50 ml) and dichloromethane (50 ml). The mixture was stirred under a hydrogen atmosphere (3 atm) until the reaction was judged to be complete. The catalyst was removed by filtration and washed with a mixture of dimethylformamide/dichloromethane (1:1, 40 ml). The combined filtrates were added to a solution of chlorosulfonic acid (7.26 ml, 109.2 mmols 3 eq) in dimethylformamide (20 ml) and dichloromethane (20 ml) at 20°C. The reaction mixture was stirred until the reaction was judged to be complete. The solution was added to ammonium bicarbonate (28.8 g, 364 mmols, 10 eq) in water (80 ml) maintaining a pH >6. Dichloromethane (50 ml) was added and the layers were separated. The aqueous layer was washed with dichloromethane (2 x 100 ml). A solution of ammonium bicarbonate (5.75 g, 72.8 mmols, 2 eq) in water (60 ml) was added, followed by a solution of tetrabutylammonium bisulfate (18.5 g, 54.6 mmols, 1.5 eq. ) in dichloromethane (100 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (50 ml). The combined organic layers were washed with water (50 ml) and concentrated in vacuo. 2-methylpentan-4-one was added and the solution was concentrated in vacuo. The precipitate was collected by filtration, washed with 2-methylpentan-4-one and dried under vacuum to yield ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct tetrabutylammonium -6-yl]oxy}sulfonyl]oxidanide as a white solid (11.14 g, 22 mmols, 60%). Example 4c
[000204] (Tetrabutylammonium {[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxidanide was prepared as described below.

[000205] Palladium on carbon (1g, 5% Pd, 3% moisture) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1 ]octane-2-carboxamide (5 g, 18.2 mmols) in dimethylformamide (25 ml) and dichloromethane (50 ml). The mixture was stirred under an atm of hydrogen (3 bar) until the reaction was judged to be complete. The catalyst was removed by filtration and washed with a mixture of dimethylformamide (5 ml) and dichloromethane (10 ml). The combined filtrates were added to a solution of SO3.DMF (5.58 g, 36.4 mmols) in acetic acid (20 ml). The mixture was stirred until the reaction was judged to be complete. Dichloromethane (100 ml) was added and the resulting precipitate was collected by filtration. The precipitate was washed with dichloromethane (2 x 10 ml). A solution of tetrabutylammonium acetate in water (23.7 ml, 1M, 23.7 mmols, 1.3 eq) was added to the precipitate. The product was extracted with dichloromethane (50 ml, 10 ml), and the combined organic layers were washed with water (10 ml). The organic layer was concentrated, diluted with 4-methyl-2-pentanone and concentrated again. The resulting precipitate was collected by filtration, washed with cold 4-methyl-2-pentanone and dried in vacuo to yield tetrabutylammonium ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2. 1]oct-6-yl]oxy}sulfonyl]oxidanide as a white solid (6.33 g, 69%). Example 4d
[000206] ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxida-nide of tetrabutylammonium was prepared as described below .

[000207] A diazabicyclo[3.2.1]octane-2-carboxamide (10 g, 36.3 mmols), Pd/C (10%, 2 g, 0.2 parts), dichloromethane (50 ml) and dimethylformamide (50 ml) is stirred in an atmosphere of hydrogen (3 bar) for 3 hours. The catalyst is removed by filtration through a cellulose pad and washed with DMF (20 ml). To the combined filtrates a solution of SO3.DMF (5.07 g, 35.6 mmols) in DMF (15 ml) is added. The mixture is stirred for 30 minutes at room temperature. The reaction mixture is analyzed by HPLC for consumption of starting material. If necessary, additional SO3.DMF in DMF is added and the mixture is stirred for an additional 30 minutes. On completion of the reaction, the mixture is quenched by adding a solution of tetrabutylammonium acetate (15 g, 49.8 mmols) in water (50 ml). The mixture is stirred for 2 hours at room temperature. Xylenes (400 ml) is added and the mixture is concentrated under vacuum below 35°C to a final volume of 50 ml. Xylenes (400 ml) is added and the mixture is concentrated to a final volume of 35 ml. Water (20 ml) is added and the mixture is allowed to settle. The organic layer is removed. The aqueous layer is extracted with DCM (3 x 50 ml) and the combined organic layers are washed with water (10 ml). The organic layer is treated with SC-40 carbon at reflux to remove palladium impurities. Carbon is removed by filtration. The organic layer is concentrated under vacuum to a final volume of 50 ml. MIBK (50 ml) is added, and the mixture is concentrated to a final volume of 50 ml. MIBK (130 ml) is added and the mixture is concentrated to a final volume of 90 ml. The mixture is cooled to 0°C and stirred for 3 hours. The crystals are collected by filtration, washed with cold MIBK (20 ml) and dried under vacuum at 45°C to give ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2. tetrabutylammonium 1]oct-6-yl]oxy}sulfonyl]oxidanide (11.2 g, 61%). Example 4e
[000208] (Tetrabutylammonium {[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxidanide was prepared as described below.

[000209] (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (60 g, 215.8 mmols, 1 eq) was mixed with complex of sulfur trioxide trimethylamine (36.0 g, 258.9 mmols, 1.2 eq), triethylamine (7.52 ml, 53.9 mmols, 0.25 eq), palladium on carbon (2.4 eq). g, 10% palladium, 50% water), isopropanol (300 ml) and water (300 ml). This mixture was then kept under hydrogen (1 bar) until the reaction was judged to be complete. The catalyst was removed by filtration and washed with isopropanol (120 ml). The combined filtrates were added to a premixed solution of tetrabutylammonium hydroxide (118 mmolS, 1.15 eq), acetic acid (15.45 mL, 270 mmols, 1.25 eq) and water (120 mL). The product solution was concentrated by distillation to remove isopropanol, and the product was extracted with dichloromethane (360 ml, 120 ml) and solvent exchanged into 4-methyl-2-pentanone, before filtering, washing and drying to yield a white crystalline solid (90.4 g, 79%). EXAMPLE 5 Preparation of sodium ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide (NXL-104)

[000210] (Sodium {[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide was prepared as described below. Example 5a
[000211] (Sodium {[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxidanide (NXL-104 Form I) was prepared as described below.
Figure legend - sodium 2-ethylhexanoate - water
[000212] A solution of sodium ethyl hexanoate (32.8 g, 197 mmols, 2 eq) in ethanol (350 ml) was added to a seeded solution of tetrabutylammonium ({[(2S,5R)-2-carbamoyl- 7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxidanide (50 g, 98.7 mmols) in ethanol (315 ml) containing water (6.25 ml, 2% by volume) The reaction mixture was held until the reaction was judged to be complete.The product was filtered, washed and dried to yield a white crystalline solid (26.6 g, 94%).
[000213] 1H NMR (400 MHz, CDCl3) δH 1.65 (2H, m), 1.84 (1H, m), 2.07 (1H, m), 2.93 (1H, d), 3. 03 (1H, d), 3.69 (1H, d), 3.99 (1H, s), 7.27 (1H, s), 7.43 (1H, s). Example 5b
[000214] (Sodium {[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxidanide (NXL-104 Form II) was prepared as described below
Figure legend - sodium 2-ethylhexanoate - water
[000215] A solution of tetrabutylammonium ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxidanide (10.1 g, 20 mmols) in isobutanol (48 ml) and water (2.5 ml) was transferred into a 500 ml reactor through a 0.2 µm filter and heated to 35°C. Sodium hexanoate (6.7 g) was dissolved in isobutanol (49.5 ml) and water (0.5 ml) at 35 DEG C. This solution was added to the solution of ({[(2S,5R)-2- tetrabutylammonium carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxidanide through a 0.2 µm filter for 1 hour.The mixture was stirred 1 hour at 35°C, 2 hours at 25°C and 2 hours at 0°C The mixture was filtered and the crystals were washed with a mixture of isobutanol (19.5 ml) and water (0.5 ml). dried under vacuum at 35°C to provide a crystalline form (5.48 g, 90%). Example 5c
[000216] (Sodium {[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxidanide (NXL-104 Form I) was prepared as described below.
Figure legend - sodium 2-ethylhexanoate - water
[000217] A solution of tetrabutylammonium ({[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxidanide (50 g, 98.7 mmols) in isobutanol (238 ml) and water (12.5 ml) was transferred to a 1-liter reactor through a 0.2 µm filter and heated to 35°C. Sodium ethylhexanoate (33.3 g) was dissolved in isobutanol (250 ml) at 35°C. This solution was added to the solution of ({[(2S,5R)-2-carbamoyl-7-oxo-1, tetrabutylammonium 6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl]oxidanide for 1 hour The mixture was stirred 1 hour at 35°C, 2 hours at 25°C and 2 hours at 0°C. The mixture was filtered and the crystals washed with a mixture of isobutanol (97.5 ml) and water (2.5 ml) The crystals were resuspended in anhydrous EtOH (250 ml) and stirred at 35°C for 4 hours. The mixture was cooled to 0°C and filtered.The crystals were washed with EtOH (25 ml) and dried at 35°C for 16 hours to yield 26.2 g (93%) of NXL-104 as a fine white powder. XRD shows Fo pure rma I. HELOS X50 = 4.6 µm.
[000218] The present invention will not be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims. It will also be understood that all values are approximate, and are provided for description.
[000219] All patents, patent applications, publications, product descriptions, and protocols are cited throughout this application, the descriptions of which are incorporated herein by reference in their entirety for all purposes.

权利要求:
Claims (24)
[0001]
1. Process for preparing a compound of Formula (I):
[0002]
2. Process according to claim 1, characterized in that R1, R2 and R7 are hydrogen and R3 is OSO3H.
[0003]
3. Process according to claim 1, characterized in that R4 is benzyloxy; and either R5 is benzyloxy and R6 and R7 are hydrogen, or R5 is allyl or trialkylsilyl and R6 is hydrogen.
[0004]
4. Process according to claim 1, characterized in that it comprises treating the compound of Formula (III) with 9-fluorenylmethoxycarbonyl, or N,N-carbonyl di-imidazole.
[0005]
5. Process according to claim 1, characterized in that it further comprises treating the compound formed after treating the compound of Formula (III) with an SO3 complex.
[0006]
6. Process according to claim 1, characterized in that the compound of Formula (I) is trans-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane- 2-carboxamide, or a pharmaceutically acceptable salt thereof.
[0007]
7. Process according to claim 1, characterized in that the compound of Formula (I) is {[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1] sodium oct-6-yl]oxy}sulfonyl)oxidanide.
[0008]
8. Process according to claim 1, characterized in that the compound of Formula (II) is benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate and the compound of Formula (III) is (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide.
[0009]
9. Compound, characterized by the fact that it has Formula (III)
[0010]
10. Compound according to claim 9, characterized in that R5 is allyl, benzyloxy or trialkylsilyl and R1, R6 and R7 are hydrogen.
[0011]
11. Compound according to claim 9, characterized in that R1, R2 and R6 are hydrogen and R5 is OSO3H.
[0012]
12. Compound, characterized by the fact that it has Formula (VI):
[0013]
13. Compound, according to claim 12, characterized in that the compound has the Formula (VII):
[0014]
14. Process, according to claim 1, for the preparation of a compound of Formula (IX), characterized in that it comprises:
[0015]
15. Process according to claim 14, characterized in that R8 is selected from the group consisting of methyl, ethyl and benzyl.
[0016]
16. Process according to claim 14, characterized by the fact that R8 is benzyl.
[0017]
17. Process according to claim 14, characterized in that R9 is selected from the group consisting of allyl and trialkylsilyl.
[0018]
18. Process according to claim 14, characterized by the fact that R9 is benzyl.
[0019]
19. Process according to claim 14, characterized in that it comprises treating the compound of Formula (XIV) with 9-fluorenylmethoxycarbonyl.
[0020]
20. Process according to claim 14, characterized in that it comprises treating the compound of Formula (XIV) with N,N-carbonyl diimidazole.
[0021]
21. Process according to claim 14, characterized in that it comprises treating the compound of Formula (XVII) with a complex of SO3.
[0022]
22. Compound according to claim 9, characterized in that it is a compound of Formula (XIV):
[0023]
23. A compound according to claim 22, characterized in that R9 is selected from the group consisting of allyl, benzyl and trialkylsilyl.
[0024]
24. Compound according to claim 22, characterized in that R9 is benzyl.

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法律状态:
2019-02-05| B25A| Requested transfer of rights approved|Owner name: PFIZER ANTI-INFECTIVES AB (SE) |

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2020-06-30| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-09-29| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-11-10| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-03-09| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2021-06-08| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2021-06-15| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-07-27| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/06/2012, 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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US201161498522P| true| 2011-06-17|2011-06-17|

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US61/498,522|2011-06-17|

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