PROCESSES FOR THE SYNTHESIS OF DIARYLTHIOIDANTHOIN COMPOUNDS

专利摘要:
process for the synthesis of diarylthioidantoin and diarylidantoin compounds. processes are provided for the synthesis of diarylthioidantoin and diarylidantoin compounds, such as the compounds of formula: wherein x, y1, y2, r1 and r2 are as defined herein. medicinal products containing them find particular use in the treatment of prostate cancer, including castration resistant prostate cancer and/or hormone sensitive prostate cancer.
公开号:BR112012021406B1
申请号:R112012021406-3
申请日:2011-02-24
公开日:2021-08-10
发明作者:Rajendra Parasmal Jain；Remy Angelaud；Andrew Thompson；Carol LAMBERSON；Scott Greenfield
申请人:Medivation Prostate Therapeutics Llc；
IPC主号:

专利说明:

Cross Reference to Related Orders
This patent application claims priority benefit of US Provisional Patent Application No. 61/307,796, filed February 24, 2010. All contents of that application are incorporated by reference into this document. Statement on Federal Government Sponsored Research or Development Not applicable. Field of Invention
The invention is in the domain of cancer therapeutics, such as processes for the synthesis of prostate cancer therapeutics. Background of the Invention
According to the American Cancer Society, prostate cancer is the most commonly diagnosed cancer among men in the United States, except for skin cancer. The American Cancer Society estimates that approximately 186,000 new cases of prostate cancer have been diagnosed, and approximately 29,000 men have died from prostate cancer in the States
United only during 2008. Prostate cancer is thus the second leading cause of cancer death in men in the United States, after lung cancer.
Metastatic prostate cancer is cancer that has spread beyond the prostate tissues and into adjacent tissues and distant organs. Most men who die of prostate cancer die from the consequences of metastatic disease. According to the National Cancer Institute, the median survival of prostate cancer patients who have metastasized to distant organs is generally one to three years, and most of these patients will die of prostate cancer. Metastatic prostate cancer is generally divided into two states: the hormone sensitive state and the castration resistant state (also known as the hormone-refractory state).
Testosterone and other male sex hormones, collectively known as androgens, can stimulate the growth of prostate cancer cells. Androgens exert their effects on prostate cancer cells by binding to and activating the androgen receptor, which is expressed on prostate cancer cells. When they first metastasize to distant sites, most prostate cancers depend on androgens for growth. These prostate cancers are known as hormone sensitive cancers. Thus, the main therapies currently used for the treatment of metastatic prostate cancer are focused on decreasing or antagonizing the effects of androgens on prostate cancer cells. One approach uses so-called "antiandrogens," which are molecules that block the interaction of androgens with the androgen receptor. Another approach is to reduce the amount of androgens produced in the body, particularly in the testes. This can be accomplished surgically by removing both testicles (orchiectomy) or through the use of drugs known as luteinizing hormone-releasing hormone, or LHRH, agonist drugs that reduce the native production of testosterone in the testicles (sometimes called "chemical castration" ).
Most metastatic prostate cancers are initially hormone sensitive and therefore respond to hormonal therapies. However, according to a study published in the October 7, 2004 issue of The New England Journal of Medicine, virtually all hormone-sensitive metastatic prostate cancers undergo changes that convert them to the castration-resistant state by an average of 18 to 24 months after starting hormone therapy [Debes, J. et al. "Mechanisms of Androgen- Refractory Prostate Cancer." New England. J. Med. (2004), 351:1488-1490]. One of the important mechanisms by which prostate cancer cells change from the hormone-sensitive state to the castration-resistant state appears to be through overexpression of the androgen receptor. In experiments comparing gene expression in hormone-sensitive and castration-resistant prostate cancer cells, an increase in androgen receptor expression was the only genetic change consistently associated with castration-resistant disease [Chen, C. et al. "Molecular determinants of resistance to antiandrogen therapy." Nat. Med. (2004), 10(1):33-39]. Once in this state, prostate cancers generally continue to grow in an androgen-dependent manner despite reduced testosterone production to very low levels (ie, post-castration). Prostate cancer in this state is known as castration resistant prostate cancer or CRPC. The change from hormone sensitive to castration resistant state after initiation of hormone therapy is generally determined based on elevated levels of prostate specific antigen, or PSA, or based on documented disease progression as evidenced by imaging tests or clinical symptoms. Metastatic prostate cancer that has become resistant to castration is extremely aggressive; these patients have a median survival of only 10 to 16 months.
One main reason why CRPC is so deadly is that it is difficult to treat. Because therapies currently used to treat metastatic prostate cancer work by reducing the ability of androgens to stimulate prostate cancer cell growth, they are generally effective only in prostate cancers that remain sensitive to hormone by skin. dependence on androgens for growth. CRPC no longer responds to hormonal therapies that are effective in the hormone-sensitive state. To further complicate the situation, due to biological changes in prostate cancer that has entered the castration-resistant state, drugs that initially block the androgen receptor and inhibit the growth of hormone-sensitive prostate cancer may have precisely the opposite effect and start to encourage the growth of the CRPC. For example, Casodex ® (bicalutamide), sold by AstraZeneca PLC, directly blocks the interaction of androgens with the androgen receptor and is the biggest selling antiandrogen therapies. However, in an in vitro model of castration-resistant prostate cancer, in which prostate cancer cell lines were genetically engineered to overextend the androgen receptor (thus converting them from the hormone-sensitive state to the castration-resistant state ), Casodex® effectively failed to inhibit the androgen receptor in these cells, and in some cases, became an androgen receptor stimulant. These findings, which are consistent with human clinical experience published with Casodex in the CRPC, make Casodex ® an ineffective therapy for the state of castration-resistant metastatic prostate cancer.
Compounds that bind to the androgen receptor, the same target bound by Casodex® and other marketed drugs for metastatic prostate cancer, have been developed for use in the castration-resistant state of metastatic prostate cancer. These compounds bind to the androgen receptor in a way that makes them effective in treating cancers that have become refractory to currently used drugs. For example, certain compounds disclosed in U.S. Patent Application Publication Nos. 2007/0004753, 2007/0254933 (republished as 2008/0139634), and 2009/0111864 are novel small molecule androgen receptor antagonists that inhibit androgen receptor function by blocking nuclear androgen receptor translocation and DNA binding .
The synthetic route to the compounds of the invention, as described in the aforementioned U.S. Patent Applications Publications, comprises the coupling of an isocyanate with an isobutyronitrile. The main disadvantages of the process as described above include a yield of only 25% of the desired product achieved in the final step, resulting in a total yield of 15% of commercially available raw materials. Furthermore, each intermediate compound requires the use of laborious column chromatography for purification, resulting in prolonged overall production time, which is industrially disadvantageous. In comparison, the present invention described herein comprises a total yield of 50%, and any necessary purification is accomplished by means of simple precipitation or crystallization. Furthermore, the present invention avoids the use of the extremely toxic reagent acetone cyanohydrin. As a result, the process according to the present invention is a safer process, in that the amount of solvent is reduced, minimizing the residual and environmental impact, the cycle time is reduced and the result and the overall yield of the process are bigger. Invention Summary
The present invention comprises a highly efficient process for making a compound of formula (I, 2-1):
1, 2-1 where: X is S or O; Y1 and Y2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms; R1 is L1-C(=0)-NR4R5, OR L1-CN; where L1 is a single bond or C1 -C8 alkylene; and R4 and R5 are independently selected from H and C1 -C8 alkyl; and R2 is hydrogen or fluorine; said process comprising reacting the compound of formula A:
where LG is Br, I, or another good leaving group, with a compound of formula B:
to produce a compound of formula C:
reacting the compound of formula C with a compound of formula R6-LG under alkylation conditions or with a compound of formula R6-OH under esterification conditions to form the compound of formula D:
wherein R6 is C1 -C8 alkyl; and reacting the compound of formula D with the compound of formula (F, 2-F):
where X is S or O, to produce the diarylthioidantoin or diarylidantoin compound of formula (I, 2-1):

In one embodiment, with respect to compounds of formula A, LG is Br or I. In a particular embodiment, LG is Br.
Another aspect of the present invention provides an efficient method for making an acidic compound of formula (I, 2-Ia):
wherein: Y1 and Y2 are independently methyl or, with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms; R7 is L1-C(=O)-OH; where L1 is a single bond or C1 -C8 alkylene; and R2 is hydrogen or fluorine; said process comprising hydrolysis of a compound of Formula I, 2-1:
I, 2-1 wherein R1 is L1-C(=0)-NR4R5; where L1 is a single bond or C1 -C8 alkylene; and R4 and R5 are independently selected from H and C1 -C10 alkyl.
In a particular embodiment, with respect to the compound of Formula I, 2-Ia, L1 is a single bond; and R7 is -C(=O)-OH.
In a particular embodiment, with respect to the compound of Formula I, 2-Ia, Y1 and Y2 are both methyl, R7 is -C(=O)-OH and R2 is F.
In one embodiment, the above hydrolysis is carried out in the presence of concentrated HCl.
In one embodiment, the above hydrolysis is carried out at 80-140 °C or at about 80-140 °C.
In a particular embodiment, the above hydrolysis is carried out at 120°C or at about 120°C.
In one embodiment, the above hydrolysis is carried out for 10-60 h or for about 10 h to about 60 h.
In a particular embodiment, the above hydrolysis is carried out for 48 h or for about 48 h.
In a particular embodiment, with respect to the compound of Formula I, 2-Ia, X is S.
In a particular embodiment, with respect to the compound of Formula I, 2-Ia, X is O.
In a particular embodiment, with respect to the compound of Formula I, 2-Ia, Y1 and Y2 are both methyl, R7 is -C(=O)-OH and R2 is F, and X is S.
In a particular embodiment, with respect to the compound of Formula I, 2-Ia, Y1 and Y2 are both methyl, R7 is -C(=O)-OH and R2 is F, and X is O.
In a particular embodiment, the present invention comprises a highly efficient process for making a compound of formula (I):
wherein: Y1 and Y2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms; R1 is L1-C(=0)-NR4R5, OR LX-CN; where L1 is a single bond or C1 -C8 alkylene; and R4 and R5 are independently selected from H and C1 -C6 alkyl; and R2 is hydrogen or fluorine; said process comprising the following steps: reacting a compound of formula A:
where LG and Br, I or another good output group, with a formula B compound:
to form a compound of formula C:
reacting the compound of formula C with a compound of formula R6-OH under esterification conditions, or alternatively reacting the compound of formula C with a compound of formula R'-LG, where R6 is C1 -C8 alkyl and LG is Br, I or another good leaving group, to form a compound of formula D:
reacting the compound of formula D with the compound of formula F, 4-isothiocyanato-2-(trifluoromethyl)benzonitrile,
to form the compound of formula (I):
In one embodiment, relative to compounds of formula A, LG is Br or I. In a particular embodiment, LG is Br.
In a particular embodiment, the present invention comprises a highly efficient process for making a compound of formula (I):
wherein: Y1 and Y2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms; R1 is L1-C(=0)-NR4R5, OR LX-CN; where L1 is a single bond or C1 -C8 alkylene; and R4 and R5 are independently selected from H and C10-C11 alkyl; and R2 is hydrogen or fluorine; said process comprising reacting the compound of formula A:
with the formula B compound:
to produce a compound of formula C:
reacting the compound of formula C with a compound of formula E:
to form the compound of formula (G):
and reacting the compound of formula G with thiophosgene: to produce the compound diarylthioidantoin of formula
(I):.
In a particular embodiment, with respect to the compound of Formulas I, 2-Ia, L1 is a single bond.
In a particular embodiment, with respect to the compound of Formulas I, or I, 2-1, L1 is -CH2-, -CH2-CH2- or CH2-CH2-CH2-,
In a particular embodiment, with respect to the compound of Formulas I, 2-1, L1 is a single bond; and R1 is -C(=O)-NHCH3.
In a particular embodiment, with respect to the compound of Formulas I, or 2-1, L1 is a single bond; and R1 is -C(=O)-NH2.
In a particular embodiment, with respect to the compound of Formulas I, or I, 2-1, R2 is F.
In a particular embodiment, with respect to the compound of Formulas I, or I, 2-1, Y1 and Y2 are both methyl, R3 is -C(=O)-NHCH3 and R2 is F.
In a particular embodiment, with respect to the compound of Formulas I, or I, 2-1, Y1 and Y2 are both methyl, R1 is -C(=0)-NH2 and R2 is F.
In a particular embodiment, with respect to the compound of Formulas I, or I, 2-1, the compound is according to formula II:
The general scheme for one modality of the reaction, illustrated in the route proceeding A -> C -> D -> I below, is summarized below in Scheme 1:
where a) an optional synthesis of a) compound F from 4-amino-2-(trifluoromethyl)benzonitrile (compound E) and thiophosgene, and b) the optional hydrolysis of the R1 substituent of compound I to a carboxylic acid group, to synthesis when a carboxylic acid is desired at the R1 position are illustrated. In the optional hydrolysis of the R1 substituent of compound I to a carboxylic acid group, R1 is limited to -L1-(C=O)NH2 , -L1-(C=O)NHR4 and -L1-(C=O)NR4R5, a since the hydrolysis of R1 when R1 is -L1-CN could result in the hydrolysis of the other nitrile group present on the other benzene ring. In the hydrolysis shown in Scheme 1, L1 is a non-entity (i.e., a single bond), since hydrolysis is shown to result in a -COOH group, but in other embodiments, L1 may also be C1 -C8 alkylene .
In an alternative procedure, the compound of formula C is treated with compound E, under amide bond formation conditions to produce the compound of formula G, which is followed by treatment with a reagent such as thiophosgene to form the compound of Formula I ( that is, the route C -> G -> I in the above scheme).
In one embodiment, a compound of formula A is mixed with a compound of formula B in the presence of a catalytic amount of a copper(I) catalyst and a beta-dione ligand such as 2-acetylcyclohexanone, in a polar solvent and with heating to a temperature of about 90-120°C, about 100-110°C, or about 105°C. The copper(I) catalyst may be copper(I) chloride or copper(I) iodide. The copper(I) catalyst, such as CuCl, may be present in an amount of about 0.05-0.35 equivalent with respect to compound A, of about 0.15-0.25 equivalent with respect to compound A, or of about 0.2 equivalent relative to compound A. The linker, such as 2-acetylcyclohexanone, may be present in an amount of about 0.05-0.35 equivalent relative to compound A, of about of 0.15-0.25 equivalent relative to compound A, or about 0.2 equivalent relative to compound A. In another embodiment, the linker, such as 2-acetylcyclohexanone, is present in an amount approximately equal to the amount of the copper(I) catalyst such as copper(I) chloride used. Compound B can be added in an amount of about 1-2 equivalents with respect to compound A, of about 1.25-1.75 equivalent with respect to compound A, or about 1.5 equivalent with respect to compound A. A choice of beta-dione ligands will be known to those skilled in the art, such as 2,4-pentanedione, 2,4-hexanedione, 1-phenyl-1,3-butanedione, 2-acetylcyclohexanone and the like. The polar solvent can be selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylacetamide (DMA), isopropyl acetate (IPAc), isopropyl alcohol (IPA) and the like; in another embodiment, the polar solvent is DMF, water, or a mixture of DMF and water. In another embodiment, after reacting for about 6-24 h, about 8-20 h, or about 12-14 h, or after analysis shows that about 90% or more of a compound A has been consumed, the reaction mixture it is then cooled to about 15-25 °C, such as to about 25 °C or to room temperature. In another embodiment, water is added to the cooled reaction mixture, followed by washing with a water-immiscible organic solvent, such as isopropyl acetate; the mixture is then separated into organic and aqueous layers. In another embodiment, the watery layer is acidified to isolate compound C by precipitation, filtration and drying.
In one embodiment, compound C is reacted with an alkylating agent of formula R6-LG, where R6 is C1 -C8 alkyl and LG is Br, I, or other good leaving group, to form the compound of formula D. Compounds of formula R6-LG include compounds such as methyl iodide. The reaction can be carried out in the presence of an inorganic base such as K2CO3, KHCO3, Na2CO3 or NaHCO3 in a polar solvent such as DMSO, DMF, NMP, DMA or IPAc, and with a catalytic amount of water. The catalytic amount of water can be about 5-25%, 10-20% or 14% equivalents of compound C, or about 0.05-0.25%, 0.10-0.20% or 0.14% of the polar solvent volume. The reaction mixture can be heated to about 35-50°C, or about 40-46°C, for about 5-60 min, or until analysis shows more than about 90% or about 95% or about 99% conversion of compound C to compound D. After the reaction, the mixture can be cooled to about 5-25 °C or about 15-25 °C. The reaction mixture containing compound D can be combined with water to precipitate product D from solution. Product D can be isolated by filtration and drying. In one embodiment, the amount of inorganic base used, such as K2CO3, is approximately 2 equivalents or less than about 2 equivalents relative to compound C. In another embodiment, the amount of inorganic base used, such as K2CO3, is about 1.5 equivalent or less than about 1.5 equivalent relative to compound C. In another embodiment, the amount of inorganic base used, such as K2CO3, is about 1.2 equivalent or less than about 1.2 equivalent to compound C. In another embodiment, the amount of inorganic base used, such as K2CO3, is equivalent to compound C. In another embodiment, the amount of inorganic base used, such as K2CO3, is about 1.0 equivalent or less than about 1.0 equivalent relative to compound C. In another embodiment, the amount of inorganic base used, such as K2CO3, is about 0.9 equivalent or less than about 0.9 equivalent relative to compound C. In another modality, the amount of inorganic base used, such as K2CO3, is about 0.8 equivalent or less than about 0.8 equivalent relative to compound C. In another embodiment, the amount of inorganic base used, such as K2CO3, is about 0 .7 equivalent or less than about 0.7 equivalent relative to compound C. In another embodiment, the amount of inorganic base used, such as K2CO3, is about 0.6 equivalent or less than about 0.6 equivalent in in relation to compound C.
In another embodiment, when CH3I is used to generate D (where R6 = CH3), excess CH3I is quenched with acetic acid. CH3I can be used in about 1-1.5 equivalent with respect to compound C, as in an amount of about 1.2 equivalent with respect to compound C, and an amount of AcOH can be added in an approximate amount of, or slightly greater than the excess amount of methyl iodide (eg when 1.2 equivalent of methyl iodide is used, where methyl iodide is used in excess of 0.2 equivalent relative to compound C, then about of 0.21-0.25 equivalent, or about 0.23 equivalent of AcOH relative to compound C can be used) to suppress unreacted CH3I. Alternative methylating agents known to those skilled in the art, such as dimethylsulfate, can also be used for this step.
In another embodiment, the step of combining the reaction mixture containing compound D with water is carried out by gradually adding water to the hot reaction mixture over a period of about 0.5 hour to about 3.5 hours, from about 0 .6 hour to 3.4 hours, from about 1 hour to 2 hours, or in a time period of about 0.5, 0.6, 1, 2, 3, 3.4 or 3.5 hours, up to about 1-5 volumes of water, or up to about 1-3 volumes of water, or up to about 2 volumes of water are added (relative to the volume of the original reaction mixture), in order to precipitate compound D from a slower form and reduce the amount of base and inorganic cation such as K+ and CCh2- from the inorganic base such as K2CO3, which is used in the reaction. In one embodiment, the added water is at a temperature of 50°C to about 80°C, from about 50°C to about 70°C, from about 55°C to about 75°C, from about from 55 °C to about 65 °C, from about 57 °C to about 63 °C, from about 48 °C to about 53 °C, or from about 68 °C to about 71 °C, or about 57 °C or about 70 °C. In another embodiment, the precipitated compound D is resuspended or refluidified in water and then the water is removed by filtration in order to further reduce the amount of inorganic cations present. In another embodiment, the volume of water for resuspension or refluidification is about 5-15 volumes, or about 10 volumes. In another embodiment, resuspension or refluidification is carried out for about 0.5 hour to about 3 hours, for about 1.0 to about 2.0 hours, for about 1 hour, for about 1.5 hours or about 2 hours. In another embodiment, the temperature of the resuspension or refluidification water is from about 15°C to about 35°C, from about 20°C to about 30°C, from about 20°C to about 25°C C or from about 20 °C to about 23hi Va °C.
In one embodiment, the residual amount of inorganic cation, such as potassium ions, remaining in compound D is less than or equal to about 1000 parts per million (ppm). In another embodiment, the residual amount of inorganic cation, such as potassium ions, remaining in compound D is less than or equal to about 500 parts per million (ppm). In another embodiment, the residual amount of inorganic cation, such as potassium ions, remaining in compound D is less than or equal to about 300 ppm.
In one embodiment, the residual amount of base, such as bicarbonate ion, carbonate ion, or other base, remaining in compound D is less than or equal to about 1000 parts per million (ppm). In another embodiment, the residual amount of base remaining in compound D is less than or equal to about 500 ppm. In another embodiment, the residual amount of base remaining in compound D is less than or equal to about 300 ppm.
In one embodiment, compound D may be dried by blowing or suctioning dry air, dry nitrogen or argon, or other dry inert gas, onto the compound. In another embodiment, compound D can be dried by placing the compound under vacuum (such as under about 1 mmHg vacuum or less, 0.5 mmHg vacuum or less, or 0.1 mmHg vacuum or less). In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 0.5%. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 0.3%. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 0.1%. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 500 ppm. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 300 ppm. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 100 ppm.
An alternative method for forming compound D from compound C uses standard Fischer esterification conditions comprising mixing compound C in methanol and heating for about 1-16 h at about 40-100 °C (or under reflux ) with a catalytic amount of acid, such as one to five drops of sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid or other mineral acid, p-toluenesulfonic acid or an ion exchange resin containing sulfonic acid; in one mode, H2SO4 is used. Water can be removed by azeotropic distillation (such as by a Dean-Stark trap) in some modalities. After the esterification is complete (about 70%, about 80%, about 90%, about 95% or about 99% complete), isolation of compound D can be carried out as described above.
In another embodiment of the invention, the step of forming compound I comprises mixing compound D with compound F in a polar solvent, or a mixture of a first polar solvent and a second polar solvent, and heating to about 60°C. 100°C, about 80-100°C, or about 80-85°C, for a time period of about 1-48 h or about 12-24 h. In another embodiment, after the reaction, the process continues by cooling the reaction mixture to about 15-30 °C, to about 25 °C or to room temperature, and combining with water, followed by extracting the desired product with a solvent polar, or a mixture of a third polar solvent and a fourth polar solvent. Compound F can be added in an amount of about 1-3 equivalents relative to compound D, or approximately about 1.5-2.5 equivalents relative to compound D, or about 1.5 equivalents or about 2 equivalents relative to compound D, or in an amount of about 1.5 equivalent, followed by an additional portion of about 0.5 equivalent as the reaction progresses. The combined organic extract layer can be reduced in volume and seeded with crystals of the desired product I to initiate crystallization by cooling to about 0-10 °C or about 3-6 °C, followed by isolation of the crystalline product by filtration and then drying the product by air flow over the product or under vacuum. In one aspect of this embodiment, the polar solvent, or the first, second, third and fourth polar solvents, can be selected from the group consisting of DMSO, DMF, NMP, DMA, IPAc, MeCN, IPA and the like. In one embodiment, the polar solvent is DMF. In one embodiment, the polar solvent is IPAc. In another embodiment, the first polar solvent is IPAc and the second polar solvent is DMSO. In another embodiment, the third polar solvent is IPAc and the fourth polar solvent is IPA. In another embodiment, the first polar solvent is IPAc, the second polar solvent is DMSO, the third polar solvent is IPAc, and the fourth polar solvent is IPA.
In another embodiment of the invention, an alternative method for forming compound I involves two steps, described in the route C G -> I in the scheme above. The first step uses standard amide bond formation conditions, comprising, for example, treating compound C with a coupling reagent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (AOP), benzotriazol-1-yloxytris(pyrrolidine)phosphonium hexafluorophosphate (PyBOP) , 7-azabenzotriazol-1-yloxytris(pyrrolidine)phosphonium hexafluorophosphate (PyAOP), O-benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl) tetrafluoroborate -N,N,N',N'-tetramethyluronium (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(tetrafluoroborate) 7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium (TATU) and the like, with compound E, in a polar solvent, or a mixture of a first polar solvent and a second polar solvent to produce compound G. In one aspect of this embodiment, the polar solvent is either the first and second polar solvents are selected from the group consisting of DCM, DMSO, DMF, NMP, DMA, MeCN and the like. The second step comprises a ring closure reaction of compound G with a thiocarbonylation reagent such as thiophosgene, and heating the pure solution to about 60-120 °C. In another embodiment, the reaction is carried out in a sealed tube apparatus. Thiophosgene or an equivalent of thiophosgene (eg, 1,1-thiocarbonyldiimidazole) may be present in an amount of about 1-10 equivalents relative to compound G, or about 5 equivalents relative to compound G.
In another embodiment of the invention, compound I may be subjected to hydrolytic conditions when R1 is a primary or secondary amide group, to produce the corresponding carboxylic acid derivative.
In one embodiment of the above method, the R1 substituent of the compound of formula A is -C(=0)-NH-R4. In another embodiment, R1 is -C(=0)-NH-CH3. In another embodiment, the R2 substituent of the compound of formula A is fluorine. In another embodiment, R1 is -C(=0)-NH-R4 and R2 is fluorine. In another embodiment, R1 is -C(=O)-NH-CH3 and R2 is fluorine, and the compound of formula A is 4-bromo-2-fluoro-N-methylbenzamide.
In one embodiment of the above method, the compound of formula B is 2-aminoisobutyric acid (i.e. Y1 and Y2 are each CH3). In another embodiment of the above method, the compound of formula B is 1-aminocyclobutanecarboxylic acid. In another embodiment of the above method, the compound of formula B is 1-aminocyclopentanecarboxylic acid.
In another embodiment, Y1 and Y2 are each CH3, R1 is -C(=0)NHCH3 and/or R2 is F.
In another embodiment, Y1 and Y2 are each CH3, R1 is -C(=O)NH2 and/or R2 is F.
Variations of the compound of formula (I) are also provided. Compounds of formula (I) or a variation thereof, as detailed herein, or a pharmaceutically acceptable salt according to any of the above, may find particular use in the treatment of prostate cancer, including CRPC and/or prostate cancer. hormone sensitive.
In an alternative embodiment of the synthesis of compounds I, 2-Ia, where R7 is -C(=O)OH, the final product can be synthesized as follows (illustrated using the isothiocyanate):
where compound C reacts with compound F isothiocyanato-2-(trifluoromethyl)benzonitrile) to form product M. In one embodiment, Y1 and Y2 are each CH3, and/or R2 is F. The reaction can take place under basic conditions , with a trialkylamino base such as triethylamine present in about 2-5 equivalents, or about 3-4 equivalents, or about 3.4 equivalents relative to compound C. Compound F, 4-iothiocyanato-2-(trifluoromethyl )benzonitrile, may be present in amounts of from about 1.1 to 4 equivalents, or from 1.1 to 2 equivalents, or from about 1.5 equivalents relative to compound C; alternatively, about 1.5 equivalent of compound F may be added, followed by another portion of about 0.5 equivalent as the reaction progresses. The solvent can be ethanol or another alcohol. The reaction mixture can be stirred for about 4 to 16 days, about 8 to 12 days, or about 10 days, at room temperature or at elevated temperature. Thereafter, the reaction mixture can be concentrated, mixed with aqueous acid such as 1M HCl and the product extracted with an organic solvent such as ethyl acetate to obtain product M.
In a further embodiment, compound C is synthesized by reacting a compound of formula J with a 1,1-disubstituted 2,2,2-trichloroethanol:
where the 2,2,2-trichloroethanol is used at about 1.5 to 4 equivalents with respect to J, or about 2 to 3 equivalents with respect to J, about 2.5 equivalents with respect to J or about 2.6 equivalents with respect to J. The reaction is carried out in an organic solvent, preferably in an anhydrous solvent such as anhydrous acetone. The reaction can be cooled to 0 °C before adding a strong base such as NaOH, KOH or another hydroxide. The base is added in about 2 to 5 equivalents, or about 3 to 4 equivalents, or about 3.8 equivalents or about 3.9 equivalents relative to J. After addition of the base, the reaction can be allowed to warm to room temperature, and it is left to stand for about 4 to 24 h, or about 8 to 16 h, or about 12 h. The product can be purified by standard methods such as column chromatography or HPLC.
In another embodiment, the invention encompasses methods of making hydantoin compounds according to Scheme 2:
where R1 = -L1- (C=O) -NH2, -L1-(C=0) NHR4, -L1-(C=O) NR4R5 or LX-CN for compound 2-1. The reactions are analogous to the reactions in Scheme 1, with replacement of thiophosgene with phosgene and replacement of thioisocyanate F with isocyanate 2-F, resulting in the product hydantoin 2-1 instead of thioidantoin I. It should be noted that phosgene can be substituted by phosgene equivalents such as 1,1-carbonyldiimidazole (see, for example, the reagents described in Phosgenations-A Handbook, by Livius Cotarca and Heiner Eckert, Weinheim, Germany: Wiley-VCH Verlag GmbH & Co., 2003, particularly those phosgene equivalents listed in Chapter 3). Analogously to Scheme 1, an optional synthesis of a) compound 2-F from 4-amino-2-(trifluoromethyl)benzonitrile (compound E) and phosgene, and b) optional hydrolysis of the R1 substituent of compound 2-1 to a carboxylic acid group, for synthesis when a carboxylic acid is desired at the Rx position, are illustrated. In the optional hydrolysis of the R1 substituent of compound 2-1 to a carboxylic acid group, R1 is limited to -L1-(C=O) NH2, - LX-(C=O)NHR4 and -L1-(C=O) NR4R5, since the hydrolysis of R1 when R10 is -LX1-CN could result in the hydrolysis of the other nitrile group present on the benzene ring. In the hydrolysis shown in Scheme 2, Lx is a non-entity (ie, a single bond), since the hydrolysis is shown to result in a -COOH group, but in other embodiments, L1 may also be C1 -C8 alkylene .
In the hydantoin modality, the present invention comprises a highly efficient process for making a compound of formula (2-1):
wherein Y1 and Y2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms; R1 is L1-C(=0)-NR4R5, or iZ-CN; where L1 is a single bond or C1 -C6 alkylene; and R4 and R5 are independently selected from H and C1 -C8 alkyl; and R2 is hydrogen or fluorine; said process comprising the following steps: reacting a compound of formula A:
where LG is Br, I, or another good leaving group, with a compound of formula B:
to form a compound of formula C:
reacting the compound of formula C with a compound of formula R6-OH under esterification conditions, or alternatively reacting the compound of formula C with a compound of formula R6-LG, where R6 is C1-6 alkyl and LG is Br, I or another good leaving group, to form a compound of formula D:
reacting the compound of formula D with the compound of formula 2-F, 4-isothiocyanato-2-(trifluoromethyl)benzonitrile
to form the compound of formula (2-1):
The general scheme for this mode of reaction is illustrated in the route proceeding A -> C -> D -> 2-1 in Scheme 2.
In an alternative embodiment, the present invention comprises a highly efficient process for making a compound of formula (2-1):
wherein Y1 and Y2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms; R1 is L1-C(=0)-NR4R5, OR L1-CN; where L1 is a single bond or C1 -C8 alkylene; and R4 and R5 are independently selected from H and C1 -C8 alkyl; and R2 is hydrogen or fluorine; said process comprising reacting the compound of formula A:
with the compound of formula B:
to produce a compound of formula C:
reacting the compound of formula C with a compound of formula E:
to form the compound of formula G:
and reacting the compound of formula G with phosgene: to produce the diarylidantoin compound of formula (2-1):

In this alternative embodiment, the compound of formula C is treated with compound E under conditions of amide bond formation to produce the compound of formula G, which is followed by treatment with a reagent such as phosgene to form the compound of Formula 2-1 (ie, the route C -> G -> 2-1 in Scheme 2).
In one embodiment, a compound of formula A is mixed with a compound of formula B in the presence of a catalytic amount of a copper(I) catalyst and a beta-dione ligand such as 2-acetylcyclohexanone, in a polar solvent and with heating to a temperature of about 90-120°C, about 100-110°C or about 105°C. The copper(I) catalyst may be copper(I) chloride or copper(I) iodide. The copper(I) catalyst, such as CuCl, may be present in an amount of about 0.05-0.35 equivalent with respect to compound A, of about 0.15-0.25 equivalent with respect to compound A, or about 0.2 equivalent relative to compound A. The linker, such as 2-acetylcyclohexanone, may be present in an amount of about 0.05-0.35 equivalent relative to compound A, of about of 0.15-0.25 equivalent relative to compound A, or about 0.2 equivalent relative to compound A. In another embodiment, the linker, such as 2-acetylcyclohexanone, is present in an amount approximately equal to the amount of the copper(I) catalyst such as copper(I) chloride used. Compound B can be added in an amount of about 1-2 equivalents relative to compound A, about 1.25-1.75 equivalents relative to compound A, or about 1.5 equivalents relative to compound A. A choice of beta-dione linkers will be known to those skilled in the art, such as 2,4-pentanedione, 2,4-hexanedione, 1-phenyl-1,3-butanedione, 2-acetylcyclohexanone, and the like. The polar solvent can be selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylacetamide (DMA), isopropyl acetate (IPAc), isopropyl alcohol (IPA) and the like; in another embodiment, the polar solvent is DMF, water, or a mixture of DMF and water. In another embodiment, after reacting for about 6-24 h, about 8-20 h, or about 12-14 h, or after analysis shows that about 90% or more of a compound A has been consumed, the reaction mixture it is then cooled to about 15-25 °C, such as to about 25 °C or to room temperature. In another embodiment, water is added to the cooled reaction mixture, followed by washing with a water-immiscible organic solvent, such as isopropyl acetate; the mixture is then separated into organic and aqueous layers. In another embodiment, the aqueous layer is acidified to isolate compound C by precipitation, filtration and drying.
In one embodiment, compound C is reacted with an alkylating agent of formula R'-LG, where R6 is C1 -C8 alkyl and LG is Br, I or other good leaving group, to form compound of formula D. Compounds of formula R' -LG include compounds such as methyl iodide. The reaction can be carried out in the presence of an inorganic base such as K2CO3, KHCO3, Na2CO3 or NaHCO3 in a polar solvent such as DMSO, DMF, NMP, DMA or IPAc, and with a catalytic amount of water. The catalytic amount of water can be about 5-25%, 10-20% or 14% equivalents of compound C, or about 0.05-0.25%, 0.10-0.20% or 0.14% of the polar solvent volume. The reaction mixture can be heated to about 35-50°C, or about 40-46°C, for about 5-60 min, or until analysis shows more than about 90% or about 95% or about 99% conversion of compound C to compound D. After the reaction, the mixture can be cooled to about 5-25 °C or about 15-25 °C. The reaction mixture containing compound D can be combined with water to precipitate product D from solution. Product D can be isolated by filtration and drying. In one embodiment, the amount of inorganic base used, such as K2CO3, is approximately 2 equivalents or less than about 2 equivalents relative to compound C. In another embodiment, the amount of inorganic base used, such as K2CO3, is about 1.5 equivalent or less than about 1.5 equivalent relative to compound C. In another embodiment, the amount of inorganic base used, such as K2CO3, is about 1.2 equivalent or less than about 1.2 equivalent in relation to compound C.
In another embodiment, when CH3I is used to generate D (where R6 = CH3), excess CH3I is quenched with acetic acid. CH3I can be used in about 1-1.5 equivalent with respect to compound C, as in an amount of about 1.2 equivalent with respect to compound C, and an amount of AcOH can be added in an approximate amount of, or slightly greater than the excess amount of methyl iodide (eg when 1.2 equivalent of methyl iodide is used, where methyl iodide is used in excess of 0.2 equivalent relative to compound C, then about of 0.21-0.25 equivalent, or about 0.23 equivalent of AcOH relative to compound C can be used) to suppress unreacted CH3I. Alternative methylating agents known to those skilled in the art, such as dimethylsulfate, can also be used for this step.
In another embodiment, the step of combining the reaction mixture containing compound D with water is carried out by gradually adding water to the hot reaction mixture over 1 to 2 h, until about 1 to 5 volumes of water, or about 1 to 3 volumes of water, or about 2 volumes of water have been added (relative to the volume of the original reaction mixture) in order to precipitate compound D more slowly and reduce the amount of base and inorganic cations such as K+ and CO32" from the inorganic base, such as K2CO3, which is used in the reaction. In another modality, the precipitated compound D is resuspended or refluidified in water and then the water is removed by filtration in order to further reduce the amount of inorganic cations present.
In one embodiment, the residual amount of inorganic cation, such as potassium ions, remaining in compound D is less than or equal to about 1000 parts per million (ppm). In another embodiment, the residual amount of inorganic cation, such as potassium ions, remaining in compound D is less than or equal to about 500 parts per million (ppm). In another embodiment, the residual amount of inorganic cation, such as potassium ions, remaining in compound D is less than or equal to about 300 ppm.
In one embodiment, the residual amount of base, such as bicarbonate ion, carbonate ion, or other base, remaining in compound D is less than or equal to about 1000 parts per million (ppm). In another embodiment, the residual amount of base remaining in compound D is less than or equal to about 500 ppm. In another embodiment, the residual amount of base remaining in compound D is less than or equal to about 300 ppm.
In one embodiment, compound D may be dried by blowing or suctioning dry air, dry nitrogen or argon, or other dry inert gas, onto the compound. In another embodiment, compound D can be dried by placing the compound under vacuum (such as under about 1 mmHg vacuum or less, 0.5 mmHg vacuum or less, or 0.1 mmHg vacuum or less). In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 0.5%. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 0.3%. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 0.1%. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 500 ppm. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 300 ppm. In one embodiment, the residual amount of water remaining in compound D is less than or equal to about 100 ppm.
An alternative method for the formation of compound D from compound C uses esterification conditions of
Standard Fischer comprising mixing compound C in methanol and heating for about 1-16 h at about 40-100 °C (or under reflux) with a catalytic amount of acid, such as one to five drops of sulfuric acid, acid hydrochloric acid, nitric acid, phosphoric acid or other mineral acid, p-toluenesulfonic acid or an ion exchange resin containing sulfonic acid; in one mode, H2SO4 is used. Water can be removed by azeotropic distillation (such as by a Dean-Stark trap) in some modalities. After the esterification is complete (about 70%, about 80%, about 90%, about 95%, or about 99% complete), isolation of compound D can be carried out as described above.
In another embodiment of the invention, the step of forming compound 2-1 comprises mixing compound D with compound 2-F in a polar solvent, or a mixture of a first polar solvent and a second polar solvent, and heating until about 60-100°C, about 80-100°C, or about 80-85°C, for a time period of about 1-48 h or about 12-24 h. In another embodiment, after the reaction, the process continues by cooling the reaction mixture to about 15-30 °C, to about 25 °C or to room temperature, and combining with water, followed by extracting the desired product with a solvent polar, or a mixture of a third polar solvent and a fourth polar solvent. Compound 2-F can be added in an amount of about 1-3 equivalents relative to compound D, or approximately about 1.5-2.5 equivalents relative to compound D, or about 1.5 equivalents or about 2 equivalents relative to compound D, or in an amount of about 1.5 equivalents, followed by an additional portion of about 0.5 equivalents as the reaction progresses. The combined organic extract layer can be reduced in volume and seeded with 2-1 desired product crystals to initiate crystallization by cooling to about 0-10 °C or about 3-6 °C, followed by isolation of the crystalline product by filtration and then drying the product by air flow over the product or under vacuum. In one aspect of this embodiment, the polar solvent, or the first, second, third and fourth polar solvents, can be selected from the group consisting of DMSO, DMF, NMP, DMA, IPAc, MeCN, IPA and the like. In one embodiment, the polar solvent is DMF. In another embodiment, the first polar solvent is IPAc and the second polar solvent is DMSO. In another embodiment, the third polar solvent is IPAc and the fourth polar solvent is IPA. In another embodiment, the first polar solvent is IPAc, the second polar solvent is DMSO, the third polar solvent is IPAc, and the fourth polar solvent is IPA.
In another embodiment of the invention, an alternative method for forming compound 2-1 involves two steps, described in the route C -> G -> I route in scheme 2. The first step uses standard amide bond formation conditions, comprising , for example, treating compound C with a coupling reagent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), benzotriazol-1-yloxytris(dimethylamino)hexafluorophosphate )phosphonium (BOP), 7-azabenzotriazol-1-yloxitris(dimethylamino)phosphonium hexafluorophosphate (AOP), benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), 7-azabenzotriazol-1-yloxitris(pyrrolidino)hexafluorophosphate phosphonium (PyAOP), O-benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O- (benzotriazol-1-yl)-N,N,N,N',N'-tetramethyluronium tetrafluoroborate ( TBTU), 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), tetrafluoro 0-(7-azabenzotriazol-1-yl)-N,N, N',N'-tetramethyluronium borate (TATU) and the like, with compound E, in a polar solvent, or a mixture of a first polar solvent and a second polar solvent to produce compound G. . In one aspect of this embodiment, the polar solvent is either the first and second polar solvents are selected from the group consisting of DCM, DMSO, DMF, NMP, DMA, MeCN and the like. The second step comprises a ring closure reaction of compound G with a carbonylation reagent such as phosgene, and heating the pure solution to about 60-120 °C. In another embodiment, the reaction is carried out in a sealed tube apparatus. Phosgene or an equivalent of phosgene (eg, carbonyldiimidazole) may be present in an amount of about 1-10 equivalents relative to compound G, or about 5 equivalents relative to compound G.
In another embodiment of the invention, compound 2-1 may be subjected to hydrolytic conditions when R1 is a primary or secondary amide group, to produce the corresponding carboxylic acid derivative.
In one embodiment of the above method, the R1 substituent of the compound of formula A is -C(=0)-NH-R4. In another embodiment, R1 is -C(=0)-NH-CH3. In another embodiment, the R2 substituent of the compound of formula A is fluorine. In another embodiment, R1 is -C(=0)-NH-R4 and R2 is fluorine. In another embodiment, R1 is -C(=O)-NH-CH3 and R2 is fluorine, and the compound of formula A is 4-bromo-2-fluoro-N-methylbenzamide.
In one embodiment of the above method, the compound of formula B is 2-aminoisobutyric acid (i.e. Y1 and Y2 are each CH3). In another embodiment of the above method, the compound of formula B is 1-aminocyclobutanecarboxylic acid. In another embodiment of the above method, the compound of formula B is 1-aminocyclopentanecarboxylic acid.
In another embodiment, Y1 and Y2 are each CH3, R1 is -C(=O)NHCH3 and/or R2 is F.
In another embodiment, Y1 and Y2 are each CH3, R1 is -C(=O)NH2 and/or R2 is F.
In another embodiment, Y1 and Y2 are each CH3, R1 is -C(=O)OH and/or R2 is F.
Variations of the compound of formula (2-1) are also provided. Compounds of formula (2-1) or a variation thereof, as detailed herein, or a pharmaceutically acceptable salt according to any of the above, may find particular use in the treatment of prostate cancer, including CRPC and/or prostate cancer. hormone sensitive prostate.
In an alternative modality, where a -C(=O) OH group has replaced the R1 group, the final product can be synthesized as follows:
where compound C reacts with compound 2-F (4-isothiocyanato-2-(trifluoromethyl)benzonitrile) to form 2-M product. The reaction can take place under basic conditions, with a trialkylamino base such as triethylamine present in about 2-5 equivalents, or about 3-4 equivalents, or about 3.4 equivalents relative to compound C. Compound 2-F , 4-isocyanato-2-(trifluoromethyl)benzonitrile, 10 may be present in amounts of from about 1.1 to 4 equivalents, or from 1.1 to 2 equivalents, or from about 1.5 equivalents relative to compound C ; alternatively, about 1.5 equivalent of compound 2-F may be added, followed by another portion of about 0.5 equivalent as the reaction progresses. The solvent can be ethanol or another alcohol. The reaction mixture can be stirred for about 4 to 16 days, about 8 to 12 days, or about 10 days, at room temperature or at elevated temperature. Thereafter, the reaction mixture can be concentrated, mixed with aqueous acid such as 1M HCl, and the product extracted with an organic solvent, such as ethyl acetate, to obtain the 2-M product.
In a further embodiment, compound C is synthesized by reacting a compound of formula J with a 1,1-disubstituted 2,2,2-trichloroethanol:
where 1,1-disubstituted 2,2,2-trichloroethanol can be used in about 1.5 to 4 equivalents with respect to J, or about 2 to 3 equivalents with respect to J, about 2.5 equivalents in to J or about 2.6 equivalents to J. The reaction is carried out in an organic solvent, preferably in an anhydrous solvent, such as anhydrous acetone. The reaction can be cooled to 0 °C before adding a strong base such as NaOH, KOH or another hydroxide. The base is added in about 2 to 5 equivalents, or about 3 to 4 equivalents, or about 3.8 equivalents or about 3.9 equivalents relative to J. After addition of the base, the reaction can be allowed to warm to room temperature, and is left to stand for about 4 to 24 h, or about 8 to 16 h, or about 12 h. The product can be purified by standard methods such as column chromatography or HPLC.
In another embodiment, the invention encompasses a process for the preparation of a compound of formula (I, 2-Ia):
where X is S or O; Y1 and Y2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms; R7 is L1-COOH, where L1 is a single bond or C1-6 alkylene; 20 and R4 and R5 are independently selected from H and C1 -C20 alkyl; and R21 is hydrogen or fluorine; said process comprising reacting the compound of formula Aa:
where LG is an output group, Br or I; with the compound of formula B:
to produce a compound of formula Ca:
reacting the compound of formula Ca with a compound of formula R6-LG under alkylation conditions or with a compound of formula R6-OH under esterification conditions to form the compound of formula Da:
Ci-Cg; and reacting the compound of formula Da with the compound of formula (F, 2-F):
where X is S or O, to produce the diarylthioidantoin or diarylidantoin compound of formula (I, 2-Ia):

In one embodiment, X is S. In another embodiment, X is O. In either embodiment, L1 can be a single bond; and R7 can be -C(=O)-OH. In either of these embodiments, Y1 and Y2 can both be methyl, R7 can be -C(=O)-OH, and R2 can be F.
In another embodiment, pharmaceutical compositions according to any of the compounds detailed herein are encompassed by this invention. Thus, the invention includes pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical compositions according to the invention may be in a form suitable for oral, buccal, parenteral, subcutaneous, intramuscular, intravenous, nasal, topical or rectal administration, or a form suitable for administration by inhalation. DETAILED DESCRIPTION OF THE INVENTION Definitions
For use in this document, unless clearly stated otherwise, use of the terms "a", "an" and the like refers to one or more.
The term "about", as used herein, refers to the usual range of variation for the respective value readily known to the person skilled in this technical field. Reference to "about" a value or parameter of the present invention includes (and describes) embodiments that are directed to that value or parameter by itself.
As used herein, by "pharmaceutically acceptable" or "pharmacologically acceptable" is meant a material that is not biologically or otherwise undesirable, for example, which material can be incorporated into a pharmaceutical composition administered to a patient without causing any biological effects. significant undesirables or interacting in a harmful way with any of the other components of the composition in which it is contained.
Pharmaceutically acceptable vehicle or excipients preferably meet required manufacturing and toxicological testing standards and/or are included in the Inactive Ingredients Guide prepared by the US FDA. "Pharmaceutically acceptable salts" are those salts which retain at least part of the biological activity of the free compound (non-salt) and which can be administered as drugs or medicines to an individual. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion such as potassium or sodium, an alkaline earth ion such as calcium, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like. Other examples of pharmaceutically acceptable salts include those listed in Berge et al, Pharmaceutical Salts, J. Pharm. Sci. January 1977; 66(1): 1-19. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with an organic or inorganic base or acid, respectively, and isolating the salt thus formed during purification. subsequent. It is to be understood that a reference to a pharmaceutically acceptable salt includes its solvent addition forms or crystal forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of a solvent and are often formed during the crystallization process. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs generally exhibit different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Various factors such as recrystallization solvent, rate of crystallization and storage temperature can cause a single crystal form to predominate.
The term "excipient", as used herein, means an inert or inactive substance which can be used in the production of a drug or medicine, such as a tablet which contains an invention compound as an active ingredient. Various substances may be encompassed by the term excipient, including, without limitation, any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, chewable tablet materials, sweeteners or flavorings , suspending/gelling agent or wet granulating agent. Binders include, for example, carbomers, povidone, xanthan gum, etc.; coatings include, for example, cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, for example, calcium carbonate, dextrose, dc fructose (dc = "directly compressible"), dc honey, lactose (anhydrous or monohydrated; optionally in combination with aspartame, cellulose or microcrystalline cellulose), starch , sucrose, etc.; disintegrants include, for example, croscamelose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet materials include, for example, dextrose, dc fructose, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, dextrose, dc fructose, sorbitol, dc sucrose, etc.; and wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc. "Alkyla" refers to and includes saturated straight, branched or cyclic hydrocarbon structures and combinations thereof. Particular alkyl groups are those with 1 to 12 carbon atoms (a "C1-C12 alkyl"). More particularly, alkyl groups are those with 1 to 8 carbon atoms (a "C1 -C8 alkyl"). When an alkyl residue with a specific number of carbons is named, it is intended that all geometric isomers having that number of carbons be encompassed and described; thus, for example, "butyl" should include n-butyl, sec-butyl, isobutyl, tert-butyl and cyclobutyl; "propyl" includes n-propyl, isopropyl and cyclopropyl. This term is exemplified by groups such as methyl, i-butyl, n-heptyl, octyl, cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset of alkyl and can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring can be fused, spiro or bridged, or combinations thereof. A preferred cycloalkyl has 3 to 12 ring carbon atoms. A more preferred cycloalkyl has from 3 to 7 ring carbon atoms (a "C3-C7 cycloalkyl"). Examples of cycloalkyl groups include adamantyl, decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl and the like. "Substituted alkyl" refers to an alkyl group having from 1 to 5 substituents including, but not limited to, such substituents as alkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy , aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted aralkyl or unsubstituted, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like. "Leaving groups" are those groups that leave with an electron pair in heterolytic bond cleavage, as occurs during nucleophilic substitution. Good leaving groups include, for example: CI, Br, I, triflates, diazonium salts, fluorosulfonates, tosylates and mesylates. Specific leaving groups include Cl, Br or I. More specific groups include Br or I.
The features and effects of the present invention will be further explained with reference to the embodiments discussed below, which, however, are not intended to restrict the scope of the present invention. Process
The present invention comprises a highly efficient process for making diarylthioidantoin compounds of formula (I):
wherein Y1 and Y2 are independently methyl or, together with the carbon to which they are attached, form a cycloalkyl group of 4 to 5 carbon atoms; R1is L1-C(=0)-NR4R5, or L1-CN; where L1 is a single bond or C1 -C8 alkylene; and R4 and R5 are independently selected from H and C1 -C8 alkyl; and R2is hydrogen or fluorine; where the process comprises the following steps:
where the synthesis of compound F from compound E is an optional part of the process, and where CH3I can be replaced by R6-LG or Rβ-OH, where R6 is C1-Cg alkyl and LG is Br, I or other good group about to leave. In one embodiment, Y1 and Y2 are each CH3, R1 is -C(=O)NHCH3 and/or R2 is F. In one embodiment, Y1 and Y2 are each CH3, R1 is -C(=O)NHCH3 and R2 is F. In another embodiment, Y1 and Y2 are each CH3, R1 is -C(=O)NH2 and/or R2 is F. In another embodiment, Y1 and Y2 are each CH3, R1 is -C(= O)NH2 and R2 is F. In another embodiment, Y1 and Y2 are each CH3, R1 is replaced by -C(=O)OH and/or R2 is F. In another embodiment, Y1 and Y2 are each CH3, R1 is replaced by -C(=O)OH and R2 is F. In another embodiment, Y1 and Y2 together with the carbon to which they are attached form a cyclobutane ring, R1 is replaced by -C(=O)OH and /or R2 is F. In another embodiment, Y1 and Y2 together with the carbon to which they are attached form a cyclobutane ring, R1 is replaced by -C(=O)OH and R2 is F. In another embodiment, Y1 and Y2 together with the carbon to which they are attached form a cyclobutane ring, R1 is -C(=O)NH2 and/or R2 is F. In another embodiment, Y1 and Y2 together with the carbon to which they are attached form a cyclobutane ring, R1 is -C (=O)NH2 and R2 is F. In another embodiment, Y1 and Y2 together with the carbon to which they are attached form a cyclobutane ring, R1 is -C(=O)NHCH3 and/or R2 is F. In another embodiment, Y1 and Y2 together with the carbon to which they are attached form a cyclobutane ring, R1 is -C(=O)NHCH3 and R2 is F.
The synthesis as described above comprises a method of synthesizing compound C, which comprises mixing a commercially available variant of compound A with compound B in the presence of a catalytic amount of a copper(I) catalyst and a ligand such as acetylcyclohexanone, in a polar solvent and heating the reaction mixture, followed by cooling, adding water and washing with organic solvent, and subsequent acidification of the aqueous layer to isolate the desired product C by precipitation, filtration and drying. Copper catalysts for use in the invention may be chosen from the group consisting of copper(I) chloride and copper(I) iodide. Copper(I) chloride is typically used (Cai et al., Synthesis (Thieme Publishing Group) 2005, No. 3, pages 496-499). Compound D can be synthesized by a method comprising mixing acid C with an alkylating agent such as methyl iodide and an inorganic base in a polar solvent and a catalytic amount of water, and heating with further cooling of the mixture and combining with water , after which product D precipitates out of solution and is isolated by filtration and drying. An alternative method for this procedure uses esterification conditions of
Standard Fischer comprising mixing acid C in methanol and heating with catalytic mineral acid, followed by isolation as described above. The inorganic base for the alkylation can be selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate, typically potassium carbonate. The mineral acid for the Fischer esterification may be chosen from the group consisting of sulfuric acid, hydrochloric acid, nitric acid and phosphoric acid, typically sulfuric acid. Initial work on the reaction indicated that the amount of inorganic cations, ie, residual metal ions, and moisture present in compound D influenced the reaction of compound D with F to form compound I. Further development showed that in fact the presence of residual base was what caused undesirable side reactions.
However, inorganic cations serve as a useful proxy for the amount of base remaining in compound D preparations. of base remaining in compound D - were implemented. These strategies included the slow and gradual precipitation of product D from its reaction mixture by adding water slowly to the hot reaction mixture, and further resuspension or refluidification of compound D in water to extract the cations. (By "resuspending" or "refluidizing" a compound we mean to reform a slurry of a compound). Moisture also adversely affected the reaction of compound D with compound F to form compound I. Moisture can be removed from compound D by blowing dry air, dry nitrogen, dry argon or other dry gas over the compound, placing the compound in a filter (such as a sintered glass funnel) and sucking air or other dry gas through the compound, or placing the compound under vacuum for a period of time. Compound I can be synthesized by mixing compound D with compound F in a mixture of a first polar solvent and a second polar solvent, and heating and then cooling the mixture and combining with water, extracting the desired product with a mixture of a third polar solvent and a fourth polar solvent. The combined organic extract layer is reduced in volume and seeded with crystals of the desired product I to initiate crystallization by means of cooling, after which the crystalline product is isolated by filtration and drying. The first, second, third and fourth polar solvents can be selected from the group consisting of dimethylsulfoxide (DMSO), dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylacetamide (DMA), isopropyl acetate (IPAc), isopropyl alcohol (IPA ) and the like. In one embodiment of the invention, the first polar solvent is IPAc, the second polar solvent is DMSO, the third polar solvent is IPAc, and the fourth polar solvent is IPA. Product I can be subjected to the crystallization process by preparing a saturated solution in an organic solvent or mixture of solvents thereof, by concentrating the solution, optionally adding a seed of product I, cooling the solution to a temperature range and keeping the solution in that temperature range for a sufficient period until the crystallization of product I is complete. This crystallization process can be carried out in a temperature range of about 0 to 80 °C, typically 0 to 10 °C. Compound I can also be synthesized by first treating compound C with a coupling reagent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and the like, with compound E, in a polar solvent or a mixture of a first polar solvent and a second polar solvent to produce compound G, which is then treated with excess thiophosgene with heating to produce compound I.
Thiophosgene may be present in an amount of about 1 to 10 equivalents relative to compound G, or about 5 equivalents relative to compound G.
The polar solvent, or the first and second polar solvents, can be selected from the group consisting of DCM, DMSO, DMF, NMP, DMA, MeCN and the like.
Compound I can be subjected to hydrolytic conditions when R1 is a primary, secondary or tertiary amide group, to produce the corresponding carboxylic acid derivative.
In an optional synthetic procedure of the method of the invention, a method for synthesizing compound F is provided which comprises mixing a commercially available variant of compound E with thiophosgene in a mixture of an organic solvent, such as a non-polar solvent, and water in at room temperature, adding water and separating the product comprising the isothiocyanate compound F. The combined organic extract layer has reduced volume and a second organic solvent, such as a non-polar solvent, is added to initiate crystallization through seeding with product crystals desired F, after which the crystalline product is isolated by filtration and drying. The organic solvent can be selected from the group consisting of dichloromethane (DCM), toluene, chloroform, hexanes, heptane and 1,4-dioxane, more preferably DCM or heptane. Thiophosgene can be used in an amount of about 1 to 1.5 mol, such as 1.1 mol per mol of aniline E. Thiophosgene can be added over a period of time of 30 min to 2 h, such as 1 h.
Product F can be subjected to the crystallization process by preparing a saturated solution in an organic solvent or mixture of solvents thereof, by concentrating the solution and cooling the solution to a temperature range and keeping the solution in that temperature range for a sufficient period of time until the crystallization of product F is completed. The crystallization process can be carried out in a temperature range from 0°C to about 50°C, from about 10°C to about 40°C, from 20°C to about 30°C, or from about from 20°C to about 25°C, or from about 25°C to about 30°C, or from about 20°C, or from about 21°C, or from about 22°C, or about 23 °C, or about 24 °C, about 25 °C, about 26 °C, about 27 °C, about 28 °C, about 29 °C or about 30 °C . The organic solvent used for crystallization can be n-heptane, or a mixture of n-heptane and IPAc. For example, about 0.11% mol to about 0.65% mol IPAc in n-heptane can be used, or about 0.20 mol% to about 0.55% mol IPAc in n-heptane can be used, or about 0.03 to about 0.06% by weight of IPAc in n-heptane can be used, or about 0.20, about 0.36, about 0. 37, about 0.38, about 0.41, about 0.54 or about 0.55% mol IPAc in n-heptane can be used. The F crystallization solution can be seeded with small amounts of previously isolated F to help induce crystallization, for example, about 0.2 to 0.5% by weight of the theoretical amount of F to be obtained. The amount of F used for seeding can range from about 0.20% to about 0.50% (% by weight) of the amount of F to be recrystallized, such as about 0.20%, about 0. 25%, about 0.30%, about 0.35%, about 0.40%, about 0.45% or about 0.50%. (For about 20 g of F to be recrystallized, about 0.20% to about 0.50% by weight corresponds to about 40 mg to 100 mg of seed crystal). After seeding, the solutions/slurries can be cooled to about 0°C to about 5°C for a period of about 0.5 to about 2 hours, or about 1 hour. The solutions can also be agitated with vigorous or slow agitation, such as from about 200 rpm to about 400 rpm, about 300 rpm to about 400 rpm, about 200 rpm to about 400 rpm, or about 200, about 300 or about 400 rpm. After crystallization, the solid can then be filtered, washed with ice-cold n-heptane (about 10 to 30 ml, or about 20 ml) and dried under vacuum at about 20°C to about 25°C.
The invention is illustrated by the following non-limiting examples. EXAMPLES Experimental
In one aspect of this invention illustrated in Scheme 1, a new and improved process for the production of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2 is provided. - thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide as described below in Examples 1 to 5. Materials were obtained from commercial suppliers and were used without further purification. Reactions sensitive to air and humidity were carried out under an argon atmosphere, using oven-dried glassware and standard syringe/septum techniques. Reactions were monitored with a silica gel TLC plate under UV light (254 nm) followed by visualization with p-anisaldehyde or ninhydrin dye solution; for large-scale experiments, reactions were monitored by reverse-phase HPLC. Column chromatography was performed on silica gel 60. 1H NMR spectra were measured at 400 MHz in CDCl3 unless otherwise indicated and data were reported as follows in ppm (δ) of the internal standard (TMS, 0, 0 ppm): chemical shift (multiplicity, integration, coupling constant in Hz). .
Example 1: Conversion of 4-bromo-2-fluorobenzoic acid to 4-bromo-2-fluoro-N-methylbenzamide.

A 50 L nitrogen flush reactor was charged with dry benzoic acid A-1 (1.8 Kg, 8.22 mol) followed by isopropyl acetate (IPAc) (12.6 L, 7 vol) and DMF (36 mL, 0.02 equiv). To the stirred slurry was added thionyl chloride (689 mL, 9.47 mol, 1.15 equiv) over 5 min (heated batch from 21°C to 23°C). The batch was heated to 60 °C for 2.5 h, held at 60-68 °C during which it was sampled for analysis by HPLC. At this point, the batch was a thin slurry. The conversion to the acid chloride was found to be 99.9% (the acid chloride intermediate was deleted with N-propylamine prior to analysis). After stirring an additional 1 h at 70-72 °C, the batch was cooled to 10 °C for 1 h.
A 30 L reactor flushed with aqueous MeNH2 nitrogen was charged (3.6 L, 41.1 mol, 5 equiv) which was further cooled to 2 to 10 °C. IPAc (3.6 L, 2 vol) was added to the MeNH2 and the MeNH2/IPAc mixture was cooled to 2 to 10°C. The acid chloride was transferred to the MeNH2/IPAc mixture for 50 min, during which time the reaction was heated to 35 °C. The reactor containing the acid chloride was rinsed with IPAc (1.8 L, 1 vol) in the 30 L reactor. The batch was left under stirring for 15 min at 30 to 35 °C before sampling for HPLC analysis. The conversion to the product was found to be 100%.
Stirring ceased and the phases were separated for 10 min. The bottom green layer has been removed. The IPAc phase was further washed with water (3 vol followed by 1 vol). The last phase separation was allowed to separate for 14 h at 30 °C. After final separation, the IPAc phase was filtered through a pad of Celite which was rinsed with IPAc (3.6 L, 2 vol) to remove dark green material. The filtrate was then reduced in volume by distillation at 9.5 L (5.3 vol) for 5h (30 to 35 °C, 100 to 200 mbar, 1.5 to 2.9 psi). Precipitation started at 8 to 9 volumes. N-heptane (18 L, 10 vol) was added to the reactor and the mixture was distilled to 8 L (4.4 vol) for 6 h (30 to 35 °C, 100 to 200 mbar, 2.9 to 1.5 psi) . At this stage the IPAc/n-heptane ratio was 26:1. The resulting slurry was allowed to stir for 12 h at 25 °C before cooling to 5-10 °C for 1 h. The batch was stirred for 1.5 h at 5-10 °C before filtration, rinsed with n-heptane (2x1 vol) and air dried. The filter cake (1.87 kg) was vacuum dried at 55-60 °C for 141 h to yield 1.72 kg (90% yield) of the desired amide product A-2 with HPLC purity of 99.5% and 0.2% H20.
Example 2: Conversion of 4-bromo-2-fluoro-N-methylbenzamide to 2-(3-fluoro-4-(methylcarbamoyl)phenylamino)-2-methylpropanoic acid.
Bromobenzamide A-2 (10 g, 43.1 mmol), aminoisobutyric acid B1 (6.7 g, 64.6 mmol, 1.5 equiv), K2 CO3 (15 g, 2.5 equiv), CuCl 99% (0 .8 g, 8.1 mmol, 0.2 equiv), DMF (60 mL, 6 vol) and water (1.8 mL) were added to the flask and the reaction slurry was heated to 30 °C. 2-acetylcyclohexanone (1.14 mL, 8.1 mmol, 0.2 equiv) was added to the reaction slurry followed by stirring at 105 °C under nitrogen for 12 to 14 h. HPLC analysis showed 96.6% conversion to the desired product. The reaction mixture was then cooled to room temperature and extracted with water (120ml) and IPAc (60ml). The lower aqueous layer was re-extracted with IPAc (60 mL) and acidified with 180 mL of 1 M citric acid to a pH of 4.0. The product began to crystallize at room temperature and the batch was further cooled to 5-7 °C, filtered, washed with water (40 ml) and dried under vacuum at 50 °C for 12 h. The reaction produced 8.3 g of product Cl (75.4% yield) as a light brown solid with HPLC-determined purity of 99.6%.
Example 3: Conversion of 2-(3-fluoro-4-(methylcarbamoyl)phenylamino)-2-methylpropanoic acid to methyl 2-(3-fluoro-4-(methylcarbamoyl)phenylamino)-2-methylpropanoate.
A mixture of the methylpropionic acid derivative Cl (4.0 g, 15.7 mmol), potassium carbonate (2.67 g, 18.8 mmol), DMF (28 mL) and water (0.04 mL) was heated. up to 30°C. Methyl iodide (1.2 mL, 18.8 mmol) was then added in one portion, and a slight warming of the reaction mixture to 32 °C was observed within 5 min. The mixture was then heated to 40 °C for 1 h. HPLC analysis of the reaction mixture showed >99.9% conversion to the ester product. AcOH (0.3 mL) was then added and the resulting mixture was heated to 60 °C, followed by the addition of water (60 mL) over 50 min, keeping the batch temperature at 58 to 63 °C. The slurry was then cooled to 30°C, the product DI was then filtered and washed with water (2x8ml). The filter cake was refluidified in water (40 ml) and rinsed with IPAc (2x8 ml) and dried under vacuum at 45-50°C for 16 h, yielding 4 g of ester (95% yield) as a brown solid. pale, with a purity of 99.9%, < 0.1% water and 80 ppm potassium.
Example 4: Conversion of 4-amino-2-(trifluoromethyl)benzonitrile to 4-isothiocyanate-2-(trifluoromethyl)benzonitrile.
Aniline E (4.0 Kg, 21.49 mol) was charged to a 30 L pan flushed with nitrogen, followed by n-heptane (9 L, 2.25 vol) and H2O (10 L, 2.5 vol). ). The mixture was then stirred for 8 min, cooled to 5 to 10 °C and thiophosgene (1.81 L, 2.72 Kg, 23, 64 mol, 1.1 equiv) was charged for 12 min, maintaining the temperature of the batch at 10 to 16 °C, followed by a rinse with n-heptane (1 L, 0.25 vol). The resulting orange slurry was then heated to 30 to 40 °C for 1.5 h, and a slight exotherm to a maximum temperature of 46.4 °C was observed. After stirring for 15 h, the orange solution was sampled (>99% conversion). The batch was then heated to 36°C and the phases were separated. A leftover layer was observed and most of it was purged with the lower aqueous layer. In two portions, n-heptane (18 L, 4.5 vol) was then loaded into the orange heptane layer and the solution distilled to 1.5 vol (45 to 46 °C, 160 mbar). The solution was diluted one more time with n-heptane (8 L, 2 vol) and the batch distilled to 1.5 vol (45 to 46 °C, 160 mbar). The solution was then diluted with n-heptane (10L, 2.5V), cooled to 30-31°C (heptane: product F, 5.3:1) and seeded with product F (10g). Crystallization was visible within 2 to 3 min after seeding and the slurry was further cooled to 0 to 10 °C for 3 h and held at 0 to 10 °C for 2 h. The batch was then filtered, washed with filtrate and chilled n-heptane (4 L, 1 vol) and dried at 20-25°C under vacuum for 13 h to yield product F (4.51 Kg, 92% ) with an HPLC-determined purity of >99% and a moisture level of 0.04%.
Example 5: Conversion of methyl 2-(3-fluoro-4-(methylcarbamoyl)phenylamino)-2-methylpopanoate to 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl- 4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide.
To a round bottom flask was charged methyl ester D-1 (150 g), 0.56 mol, isothiocyanate F 255.6 g, 1.12 mol, DMSO (150 mL, 1 equiv) and IPAc (300 mL , 2 equiv). The mixture was then heated to 83-84°C, stirred for 17.5 h and then sampled by HPLC to reveal the conversion of 96.2% A to the desired product. The reaction mixture was then cooled to 65 to 70 °C and methanol (22.5 mL, 0.15 mol) was charged. The solution was then stirred for 45 minutes and cooled to 20 to 25°C. The solution was then diluted with IPAc (900 ml, 6 vol) and washed with DI water (450 ml, 3 vol) and IPA (225 ml, 1.5 vol) was used to break the emulsion. After extracting the aqueous phase, the organic phase was then concentrated to 4.5 volumes (675 ml) under reduced pressure at 30-35°C. The solution was then diluted with IPA (2000 ml, 13.3 vol) and heated to 75-82°C (jacket temperature 95°C). During heating, the solution became slightly cloudy, but became clear at 70-71°C. The solution was then concentrated to 8 volumes (1200 ml) under atmospheric pressure maintaining 77-82°C. 1H NMR analysis revealed 7.3% mol IPAc remaining in solution. The solution was then cooled to 77°C, seeded and cooled for 5 h to 20 to 25°C. After holding at 20-25 °C for 8 h, the batch was then cooled to 0-5 °C for 2 h. After stirring at 0-5 °C for 1 h, the slurry was then filtered, washed with IPA (2 x 225 mL), vacuum conditioned for 5 min and then dried under vacuum at 50-55 °C for 117 H. The reaction yielded product 1-1 (213.9 g, 82%) as a white powder with 0.14% moisture by KF, with HPLC determined purity of > 99.9% A.
Example 6: Conversion of 4-(3-(4-cyano-3-4-(3-(4-cyano-3-(trifluoromethyl)phenyl))-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1 -yl)-2-fluorobenzoic
4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide was suspended in concentrated HCl and heated to 120 °C in a pressurized vessel for 48 h. The reaction was monitored by thin layer chromatography (TLC). The reaction mixture was cooled to room temperature. The residue was filtered and purified by silica gel chromatography (100-200 mesh, eluent: 0 to 5% methanol-dichloromethane) to yield the desired carboxylic acid derivative 1-2. MS (m/z): 452 (M+1). HPLC: Column, YMC CDS AQ, 4.6 x 250 mm, 5 µm, Mobile Phase A: 10 mM ammonium acetate, Mobile Phase B: acetonitrile, gradient, isocratic: 55% A: 45% B, retention time, 3.804 min, purity determined by HPLC, 95.82%, flow rate 1 ml/min. 1 H NMR (CDCl 3 , free base): δ (ppm) 8.22 (t, 1H), 8.0 (d, 1H), 7.98 (s, 1H), 7.82 (d, 1H), 7 .2 (m, 2H) 1.6 (s, 6H).
Example 7: Conversion of 2-(3-fluoro-4-(methylcarbamoyl)phenylamino)-2-methylpropanoic acid to 4-(1-(4-cyano-3-(trifluoromethyl)phenylamino)-2-methyl-1-oxopropan -2-ylamino)-2-fluoro-N-methylbenzamide.
The methylpropionic acid derivative Cl (0.254 g, 1 mmol) was dissolved in DCM (15 mL) with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.380 g, 2.0 mmol), followed by the slow addition of 4 -amino-2-(trifluoromethyl)benzonitrile (0.200 g, 1.1 mmol). The mixture was stirred at room temperature for 5-6 h. After reaction analysis by LCMS and TLC, the mixture was extracted with DCM and the extracts were washed with water, dried and evaporated. The crude product was purified by chromatography to yield the desired product G1 (0.150 g, 36% yield).
Example 8: Conversion of 4-(1-(4-cyano-3-(trifluoromethyl)phenylamino)-2-methyl-1-oxopropan-2-ylamino)-2-fluoro-N-methylbenzamide to 4-(3-( 4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide.
A mixture of the amide derivative G1 (0.1 g, 0.23 mmol) in neat thiophosgene (54 mg, 0.48 mmol) was heated to 100 °C in a sealed tube for 6 h, then cooled. The mixture was dissolved in DCM, filtered and the filtrate evaporated. The crude material was purified by column chromatography to furnish the desired product I-1 (4 mg, 4% yield). Analytical data are in accordance with the compound prepared in example 5.
Example 9: Synthesis of 4-(1-Carboxy-1-methylethylamino)-2-fluorobenzoic acid Example 9A: Synthesis of 4-(1-carboxy-1-methylethylamino)-2-fluorobenzoic acid from 4-amino-2-fluorobenzoic acid fluorobenzoic
4-amino-2-fluorobenzoic acid (0.2 g, 1.29 mmol) and 1,1,1-trichloro-2-methylpropan-2-ol (0.593 g, 3.35 mmol) were dissolved in anhydrous acetone and the solution was refrigerated at 0°C. Sodium hydroxide powder (0.2 g, 5.01 mmol) was added in portions, after which the reaction mixture was warmed and stirred at room temperature for 12 h. Volatiles were removed under reduced pressure and the residue was acidified with 1M aqueous HCl. The obtained crude product was purified by reverse phase HPLC to obtain 4-(1-carboxy-1-methylethylamino)-2-fluorobenzoic acid.
Example 9B: Alternative Synthesis of 4-(1-Carboxy-1-methylethylamino)-2-fluorobenzoic bromo-2-fluorobenzoic acid
4-Bromo-2-fluorobenzoic acid (20 g, 91.3 mmol), 2-aminoisobutyric acid (14.5 g, 140 mmol), Cul (3.47 g, 18.22 mmol) and K2CO3 (31.56 g , 227.91 mmol) were mixed in DMF (200 mL), H20 (20 mL) and TEA (0.63 mL, 4.54 mmol). To the reaction mixture was then added 2-acetylcyclohexanone (2.4 g, 17.1 mmol). The reaction mixture was stirred at 90 °C for 14 h. After completion of the reaction, water was added. The aqueous layer was washed with ethyl acetate. The aqueous layer was acidified by the addition of 1 M citric acid solution (pH ~ 4). The product was extracted with ethyl acetate (3x200ml). The combined organic layer was dried over anhydrous Na2 SO4 and concentrated under reduced pressure to yield 16 g of 4-(2-carboxypropan-2-ylamino)-2-fluorobenzoic acid as crude product. This raw material was used as such in the following example.
Example 10: Synthesis of 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]-2-fluorobenzoic acid (Compound Ml)
4-(1-Carboxy-1-methylethylamino)-2-fluorobenzoic acid (241 mg, 1 mmol), 4-isothiocyanato-2-trifluoromethylbenzonitrile (342 mg, 1.5 mmol) and triethylamine (343 mg, 3.4 mmol) ) were mixed in EtOH (5 ml) and the solution was stirred for 10 days at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was acidified with 1M HCl and the product was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography eluting with ethyl acetate to obtain 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl] -2-fluorobenzoic (10 mg) as an off-white solid.
The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are incorporated herein by reference in their entirety.
Although the above invention has been described in some degree of detail by way of illustration and example for purposes of clarity and understanding, it is evident from those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples are not to be interpreted as limiting the scope of the invention.

权利要求:
Claims (18)
[0001]
1. Process for preparing a compound of formula (I,2-I):
[0002]
2. Process for preparing a compound of formula (I,2-I):
[0003]
3. Process according to claim 1, characterized in that X is S.
[0004]
4. Process according to claim 1, characterized in that Y1 and Y2 are both methyl.
[0005]
5. Process according to claim 1, characterized in that Y1 and Y2 together with the carbon to which they are attached, combine to form a cyclobutyl ring or cyclopentyl ring.
[0006]
6. Process according to claim 1, characterized in that R1 is -C(=O)-NHCH3.
[0007]
7. Process according to claim 1, characterized in that Y1 and Y2 are both methyl and R1 is -C(=O)-NHCH3.
[0008]
8. Process for preparing a compound of formula (I,2-Ia):
[0009]
9. Process according to claim 8, characterized in that X is S.
[0010]
10. Process according to claim 8, characterized in that Y1 and Y2 are both methyl, R7 is -C(=O)-OH and R2 is F.
[0011]
11. Process according to claim 2, characterized in that X is S.
[0012]
12. Process according to claim 2, characterized in that Y1 and Y2 are both methyl.
[0013]
13. Process according to claim 2, characterized in that Y1 and Y2 together with the carbon to which they are attached, combine to form a cyclobutyl ring or cyclopentyl ring.
[0014]
14. Process according to claim 2, characterized in that R1 is -C(=O)-NHCH3.
[0015]
15. Process according to claim 2, characterized in that R1 is -C(=O)-NH2.
[0016]
16. Process according to claim 2, characterized in that R2 is F.
[0017]
17. Process according to claim 2, characterized in that Y1 and Y2 are both methyl, and R1 is -C(=O)-NHCH3 and R2 is F.
[0018]
18. Process according to claim 2, characterized in that Y1 and Y2 are both methyl, and R1 is -C(=O)-NH2 and R2is FI In a particular embodiment, in relation to the compounds of Formulas I, or I, 2-1, Y1 and Y2 are both methyl. In a particular embodiment, with respect to compounds of Formulas I, or I, 2-1, Y1 and Y2, together with the carbon to which they are attached, combine to form a cyclobutyl ring. In a particular embodiment, with respect to compounds 15 of Formulas I, or I, 2-1, Y1 and Y2, together with the carbon to which they are attached, combine to form a ring

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同族专利:

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公开号 | 公开日

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SI2538785T1|2018-05-31|

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CN103108549A|2013-05-15|

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PL2538785T3|2018-08-31|

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CN103108549B|2015-09-09|

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MX2012009782A|2012-11-29|

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RU2554081C2|2015-06-27|

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SI3329775T1|2021-09-30|

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EP2538785A1|2013-01-02|

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KR20130027468A|2013-03-15|

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US20130190507A1|2013-07-25|

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EP2538785A4|2013-10-30|

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EP3329775A1|2018-06-06|

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CA2790924C|2016-08-02|

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PT3329775T|2021-07-19|

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WO2011106570A1|2011-09-01|

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US9174943B2|2015-11-03|

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RU2012140454A|2014-03-27|

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BR112012021406A2|2018-06-05|

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KR101514659B1|2015-04-23|

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HUE038637T2|2018-12-28|

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DK3329775T3|2021-07-26|

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EP3329775B1|2021-04-21|

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EP2538785B1|2018-03-21|

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HUE055051T2|2021-10-28|

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CY1120207T1|2018-12-12|

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ES2671343T3|2018-06-06|

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PT2538785T|2018-05-09|

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JP2013520519A|2013-06-06|

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JP5718372B2|2015-05-13|

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CA2790924A1|2011-09-01|

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PL3329775T3|2021-11-08|

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ES2880354T3|2021-11-24|

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DK2538785T3|2018-05-22|

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法律状态:
2018-07-17| B25G| Requested change of headquarter approved|Owner name: MEDIVATION PROSTATE THERAPEUTICS, INC. (US) |

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2018-07-31| B25D| Requested change of name of applicant approved|Owner name: MEDIVATION PROSTATE THERAPEUTICS LLC (US) |

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2019-01-29| 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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2020-07-14| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-10-13| B06G| Technical and formal requirements: other requirements [chapter 6.7 patent gazette]|

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

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2021-06-29| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-07-13| B25G| Requested change of headquarter approved|Owner name: MEDIVATION PROSTATE THERAPEUTICS LLC (US) |

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2021-08-10| 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 24/02/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |

优先权:

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申请号 | 申请日 | 专利标题

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US30779610P| true| 2010-02-24|2010-02-24|

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US61/307,796|2010-02-24|

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PCT/US2011/026135|WO2011106570A1|2010-02-24|2011-02-24|Processes for the synthesis of diarylthiohydantoin and diarylhydantoin compounds|

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