CA2529232A1 - Process for purifying and isolating rac-bicalutamide - Google Patents
Process for purifying and isolating rac-bicalutamide Download PDFInfo
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- CA2529232A1 CA2529232A1 CA002529232A CA2529232A CA2529232A1 CA 2529232 A1 CA2529232 A1 CA 2529232A1 CA 002529232 A CA002529232 A CA 002529232A CA 2529232 A CA2529232 A CA 2529232A CA 2529232 A1 CA2529232 A1 CA 2529232A1
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- Prior art keywords
- solvent
- bicalutamide
- crystallization
- solution
- crude
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Links
- 229960000997 bicalutamide Drugs 0.000 title claims abstract description 145
- 238000000034 method Methods 0.000 title claims abstract description 61
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 claims abstract description 134
- 238000000746 purification Methods 0.000 claims abstract description 17
- 238000002955 isolation Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims description 137
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- 238000002425 crystallisation Methods 0.000 claims description 36
- 230000008025 crystallization Effects 0.000 claims description 35
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 20
- 239000012296 anti-solvent Substances 0.000 claims description 17
- 239000013078 crystal Substances 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 15
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- 238000010992 reflux Methods 0.000 claims description 12
- 238000010899 nucleation Methods 0.000 claims description 10
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 9
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 9
- 238000009835 boiling Methods 0.000 claims description 9
- 239000011877 solvent mixture Substances 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 3
- 238000013019 agitation Methods 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 4
- 229960004592 isopropanol Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000002280 anti-androgenic effect Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- DPJHZJGAGIWXTD-UHFFFAOYSA-N 1-fluoro-4-methylsulfonylbenzene Chemical compound CS(=O)(=O)C1=CC=C(F)C=C1 DPJHZJGAGIWXTD-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 231100000721 toxic potential Toxicity 0.000 description 2
- 229940044613 1-propanol Drugs 0.000 description 1
- DRYMMXUBDRJPDS-UHFFFAOYSA-N 2-hydroxy-2-methylpropanamide Chemical compound CC(C)(O)C(N)=O DRYMMXUBDRJPDS-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- PMDYLCUKSLBUHO-UHFFFAOYSA-N 4-amino-2-(trifluoromethyl)benzonitrile Chemical compound NC1=CC=C(C#N)C(C(F)(F)F)=C1 PMDYLCUKSLBUHO-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 208000018997 giddiness Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 231100000206 health hazard Toxicity 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000000864 peroxy group Chemical group O(O*)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/06—Separation; Purification; Stabilisation; Use of additives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a new process for the isolation and purification of racemic and optically active bicalutamide.
Description
PROCESS FOR PURIFYING AND ISOLATING RAC-BICALUTAMIDE
FIELD OF THE INVENTION
The present invention relates to a process for isolating rac-bicalutamide and its intermediates.
BACKGROUND OF THE INVENTION
to Bicalutamide is also known as N-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-sulfonyl]-2-hydroxy-2-methyl-propionamide and has the following chemical formula.
OH
15 "' N
O=S=O O \ CN
~ I CF3 F
Bicalutamide Bicalutamide is an acylanilid that has anti-androgen activity. It is known to selectively decrease the testosterone level without influencing the regulation mechanisms of the hypothalamus.
The international patent No. WO 93/19770 describes both R-(-) enantiomer and S-(+) enantiomer for bicalutamide, of which the R-(-) isomer is reported to be more active and possesses lesser side-effects (e.g., headache, gynecomistia and giddiness) when used in therapy treatment.
3o U.S. Pat. No. 4,636,505 describes processes for preparing acylanilides.
The international patent No. WO 01/00608 describes a process for racemic and optically pure N-[4-cyano-3-trifluoromethylphenyl]-3-[4-fluorophenyl-sulfonyl]-
FIELD OF THE INVENTION
The present invention relates to a process for isolating rac-bicalutamide and its intermediates.
BACKGROUND OF THE INVENTION
to Bicalutamide is also known as N-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-sulfonyl]-2-hydroxy-2-methyl-propionamide and has the following chemical formula.
OH
15 "' N
O=S=O O \ CN
~ I CF3 F
Bicalutamide Bicalutamide is an acylanilid that has anti-androgen activity. It is known to selectively decrease the testosterone level without influencing the regulation mechanisms of the hypothalamus.
The international patent No. WO 93/19770 describes both R-(-) enantiomer and S-(+) enantiomer for bicalutamide, of which the R-(-) isomer is reported to be more active and possesses lesser side-effects (e.g., headache, gynecomistia and giddiness) when used in therapy treatment.
3o U.S. Pat. No. 4,636,505 describes processes for preparing acylanilides.
The international patent No. WO 01/00608 describes a process for racemic and optically pure N-[4-cyano-3-trifluoromethylphenyl]-3-[4-fluorophenyl-sulfonyl]-
2-hydroxy-2-methyl-propionamide. The process involves multiple steps including at least reacting with thionyl choride; hydrolyzing under aqueous basic conditions;
sulfonylating with sulfonyl halogenide; acid oxidizing with inorganic peroxy salt or m-chloroperbenzoic acid (MCPBA) or aqueous hydrogen peroxide. However, the synthetic pathways involve the use of substrates (such as sodium hydride) that are dangerously explosive in nature.
There is a constant need to improve the synthesis process for bicalutamide which are economical and environmental safe and feasible. One approach to address this need is described in pending U.S. application serial no. 10/170,721 which describes the l0 preparation of rczc-bicalutamide, intermediates and derivatives thereof from 4-fluorophenyl methyl sulfone and 5-amino-2-cyano-benzotrifluoride precursors.
We have now found a novel, safe and effective method for the purification and isolation of bicalutamide.
OBJECTS ANI) SUMMARY OF THE INVENTION
The present invention provides a process for the purification and crystallization of sac-bicalutamide and its intermediates.
According to one object, the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
(i) combining crude bicalutamide and a solvent;
(ii) crystallizing the bicalutamide from the solvent with or without seeding;
and (iii) collecting the crystals of bicalutamide.
The crude bicalutamide may or may not be substantially soluble in the solvent.
Preferably the crude bicalutamide is soluble in the solvent. The resulting bicalutamide solution or suspension is crystallized by applying agitation for a time sufficient to bring about crystallization of the bicalutamide.
Preferably, in this embodiment, the solvent is selected from the group consisting of water, methanol, ethanol, DCM, toluene, PE, chloroform, hexane, 1,2-dichloroethane, diethyl ether, propanol and isopropanol.
According to another obj ect, the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of (i) combining crude bicalutamide and a first solvent;
(ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
to (iii) crystallizing the bicalutamide from the solvents; and (iv) collecting the crystals of bicalutamide.
In one embodiment, the first solvent and the second solvent are the same.
Preferably, in this embodiment, the crude bicalutamide is dissolved in an amount of first 15 solvent sufficient to dissolve the bicalutamide. Preferably the resulting bicalutamide solution is heated to about the boiling point of the first solvent.
Preferably, in this embodiment, the amount of second solvent added to the bicalutaxnide solution is equal to that of the first volume. The second solvent is preferably 2o added under reflux conditions.
Preferably the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide. Most preferably the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
Preferably, in this embodiment, the first and second solvents are selected from the group consisting of ethyl acetate, acetonitrile, acetone, THF, propanol, DMF, DMSO and isobutyl methyl ketone.
3o In another embodiment, the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps
sulfonylating with sulfonyl halogenide; acid oxidizing with inorganic peroxy salt or m-chloroperbenzoic acid (MCPBA) or aqueous hydrogen peroxide. However, the synthetic pathways involve the use of substrates (such as sodium hydride) that are dangerously explosive in nature.
There is a constant need to improve the synthesis process for bicalutamide which are economical and environmental safe and feasible. One approach to address this need is described in pending U.S. application serial no. 10/170,721 which describes the l0 preparation of rczc-bicalutamide, intermediates and derivatives thereof from 4-fluorophenyl methyl sulfone and 5-amino-2-cyano-benzotrifluoride precursors.
We have now found a novel, safe and effective method for the purification and isolation of bicalutamide.
OBJECTS ANI) SUMMARY OF THE INVENTION
The present invention provides a process for the purification and crystallization of sac-bicalutamide and its intermediates.
According to one object, the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
(i) combining crude bicalutamide and a solvent;
(ii) crystallizing the bicalutamide from the solvent with or without seeding;
and (iii) collecting the crystals of bicalutamide.
The crude bicalutamide may or may not be substantially soluble in the solvent.
Preferably the crude bicalutamide is soluble in the solvent. The resulting bicalutamide solution or suspension is crystallized by applying agitation for a time sufficient to bring about crystallization of the bicalutamide.
Preferably, in this embodiment, the solvent is selected from the group consisting of water, methanol, ethanol, DCM, toluene, PE, chloroform, hexane, 1,2-dichloroethane, diethyl ether, propanol and isopropanol.
According to another obj ect, the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of (i) combining crude bicalutamide and a first solvent;
(ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
to (iii) crystallizing the bicalutamide from the solvents; and (iv) collecting the crystals of bicalutamide.
In one embodiment, the first solvent and the second solvent are the same.
Preferably, in this embodiment, the crude bicalutamide is dissolved in an amount of first 15 solvent sufficient to dissolve the bicalutamide. Preferably the resulting bicalutamide solution is heated to about the boiling point of the first solvent.
Preferably, in this embodiment, the amount of second solvent added to the bicalutaxnide solution is equal to that of the first volume. The second solvent is preferably 2o added under reflux conditions.
Preferably the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide. Most preferably the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
Preferably, in this embodiment, the first and second solvents are selected from the group consisting of ethyl acetate, acetonitrile, acetone, THF, propanol, DMF, DMSO and isobutyl methyl ketone.
3o In another embodiment, the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps
3 of (r) combining crude bicalutamide and a first solvent;
(ii) adding a second solvent to the crude bicalutamide-first solvent mixture, wherein the second solvent is an anti-solvent;
(iii) crystallizing the bicalutamide from the solvents; and (iv) collecting the crystals of bicalutamide.
Preferably, in this embodiment, the crude bicalutamide is dissolved in an amount of first solvent sufficient to dissolve the bicalutamide. Preferably the resulting l0 bicalutamide solution is heated to about the boiling point of the first solvent. Preferably, in this embodiment, the addition of the second solvent, or anti-solvent, takes place under reflux conditions, with the second solvent being added in an amount sufficient to bring about an at least partially desolubilized bicalutamide.
15 \ Preferably, in this embodiment, following addition of the second solvent, a small volume of first solvent, sufficient to dissolve the at least partially desolubilized bicalutamide is added to the mixture.
Preferably the crystallizing step comprises cooling the bicalutamide solution to a 2o temperature sufficient to bring about crystallization of bicalutamide. Most preferably the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
Preferably, in this embodiment, first solvent: second solvent system combinations include DMF:water and ethyl acetate:hexane.
In another embodiment, the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
(r) combining crude bicalutamide and a first solvent, wherein the first solvent is an anti-solvent;
(ii) adding a second solvent to the crude bicalutamide-first solvent mixture, wherein the second solvent is an anti-solvent;
(iii) crystallizing the bicalutamide from the solvents; and (iv) collecting the crystals of bicalutamide.
Preferably, in this embodiment, the crude bicalutamide is dissolved in an amount of first solvent sufficient to dissolve the bicalutamide. Preferably the resulting l0 bicalutamide solution is heated to about the boiling point of the first solvent. Preferably, in this embodiment, the addition of the second solvent, or anti-solvent, takes place under reflux conditions, with the second solvent being added in an amount sufficient to bring about an at least partially desolubilized bicalutamide.
15 \ Preferably, in this embodiment, following addition of the second solvent, a small volume of first solvent, sufficient to dissolve the at least partially desolubilized bicalutamide is added to the mixture.
Preferably the crystallizing step comprises cooling the bicalutamide solution to a 2o temperature sufficient to bring about crystallization of bicalutamide. Most preferably the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
Preferably, in this embodiment, first solvent: second solvent system combinations include DMF:water and ethyl acetate:hexane.
In another embodiment, the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
(r) combining crude bicalutamide and a first solvent, wherein the first solvent is an anti-solvent;
4 (ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(iii) crystallizing the bicalutamide from the solvents; and (iv) collecting the crystals of bicalutamide.
Preferably, in this embodiment, the crude bicalutamide is adedd to the first solvent, or anti-solvent, and the resulting bicalutamide suspension is heated to about the boiling point of the first solvent. Preferably, in this embodiment, the addition of the second solvent, or anti-solvent, takes place under reflux conditions, with the second solvent being added in an amount sufficient to dissolve the bicalutamide.
to Preferably the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide. Most preferably the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
15 Preferably, in this embodiment, the first solvent, or anti-solvent is selected from the group consisting of toluene, ether, chloroform, water, methanol and ethanol.
Preferably, in this embodiment, the second solvent is selected from the group consisting of acetonitrile, acetone, THF, DMF and isobutyl methyl ketone.
According to another object, the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
(i) combining bicalutamide and a first solvent;
(ii) adding a second solvent to the bicalutamide-first solvent mixture;
(iii) crystallizing the bicalutamide from the solvents with or without seeding; and (iv) collecting the crystals of bicalutamide.
According to another object, the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, wherein the solvents utilized have low toxic potential.
The present invention also provides rac-bicalutamide and its intermediates prepared and isolated by the processes described above.
DETAILED DESCRIPTION OF THE INVENTION
Definitions:
As used herein, rac-bicalutamide refers to both the R-(-) enantiomer and S-(+) enantiomer of bicalutamide. Rac-bicalutamide is the racemic and optically pure R-(-) and S-(+) isomers of N-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-sulfonyl]-2-hydroxy-2-methyl-propionamide. It is to be understood that this invention encompasses 1o the racemic form of bicalutamide and any optically-active form which possesses anti-androgenic activity. It is a matter of common general knowledge how a racemic compound may be resolved into its optically-active forms and how any anti-androgenic activity present in any of these forms may be determined. One skilled in the art will appreciate that the separation of optical isomers can be achieved by conventional i5 resolution; such as fractional crystallization or flash-chromatography.
As used herein, the term "anti-solvent" refers to a solvent in which bicalutamide has limited or no solubility.
20 As used herein, the term "crude bicalutamide" refers to the product prepared by a process to prepare bicalutamide.
The following abbreviations are used herein: DCM is dichloromethane. THF is tetrahydrofuran. DABCO is 1,4 dizazbicyl [2.2.2] octane. ACB is 5-amino-2-cyano-25 benzotrofluoride. BCL is rac-bicalutamide. 4-FPMS is 4-fluorophenyl methyl sulfone.
DMF is N,N dimethyl formamide. DMSO is dimethyl sulfoxide.
The present invention provides a process for the purification and isolation of bicalutamide. The crude cicalutamide may be prepared by any method, including, for 3o example, the methods disclosed in pending U.S. application serial no.
10/170,271.
The process of the invention comprises the steps of (i) combining crude bicalutamide and a solvent;
(ii) crystallizing the bicalutamide from the solvent with or without seeding;
and (iii) collecting the crystals of bicalutamide.
The crude bicalutamide may or may not be substantially soluble in the solvent.
Preferably the crude bicalutamide is soluble in the solvent. Preferably the crude bicalutamide is dissolved in the solvent and the resulting bicalutamide solution or suspension is crystallized by applying agitation for a time sufficient to bring about crystallization of the bicalutamide. The duration of the agitation may be from about 1 to hour to about 48 hours. Preferably the duration of the agitation is from about 8 hours to about 15 hours. The agitation may be brought about by any means known to the skilled artisan. The agitation may be accompanied by heating of the reaction mixture.
Preferably, the agitation is carned out at room temperature.
15 Preferably the solvent is selected from the group consisting of water, methanol, ethanol, DCM, toluene, PE, chloroform, hexane, 1,2-dichloroethane, diethyl ether, propanol and isopropanol.
According to another embodiment of the invention, the novel process for the 2o purification and isolation of bicalutamide by solution crystallization, comprises the steps of (i) combining crude bicalutamide and a first solvent;
(ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(iii) crystallizing the bicalutamide from the solvents with or without seeding; and 25 (iv) collecting the crystals of bicalutamide.
The first solvent and the second solvents may be the same or different. In one embodiment of the invention, the first and second solvents are the same.
Preferably the crude bicalutamide is dissolved in an amount of first solvent sufficient to dissolve the 30 bicalutamide. Preferably the resulting bicalutamide solution is heated to about the boiling point of the first solvent.
Preferably, the amount of second solvent added to the bicalutamide solution is equal to that of the first volume. The second solvent is preferably added under reflux conditions.
Preferably the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide with or without seeding. Most preferably the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
l0 The term "seeding" refer to the addition of a crystal of the product to the product solution in order to bring about crystallization, or scratching the inner surface of the crystallization vessel with a glass rod. The present invention covers embodiments where crystallization or precipitation occurs spontaneously, or is induced/accelerated 15 Preferably the first and second solvents are selected from the group consisting of water, methanol, ethanol, ethyl acetate, acetonitrile, acetone, THF, propanol, DMF, DMSO and isobutyl methyl ketone.
In another embodiment, the present invention provides a novel process for the 2o purification and isolation of bicalutamide by solution crystallization, comprising the steps of (i) combining cuude bicalutamide and a first solvent;
(ii) adding a second solvent to the crude bicalutamide-first solvent mixture, wherein the second solvent is an anti-solvent;
25 (iii) crystallizing the bicalutamide from the solvents; and (iv) collecting the crystals of bicalutamide.
Preferably the crude bicalutamide is dissolved in an amount of first solvent sufficient to dissolve the bicalutamide. The the resulting bicalutatnide solution is heated 30 to about the boiling point of the first solvent. Preferably the addition of the second solvent, or anti-solvent, takes place under reflux conditions, with the second solvent being added in an amount sufficient to bring about an at least partially desolubilized bicalutamide. The partial desolubilization is accompanied by the formation of a clouody appearance in the clear solution.
Following addition of the second solvent, a small volume of first solvent, sufficient to dissolve the at least partially desolubilized bicalutamide is added to the mixture.
Sufficient volume of the first solvent is added when the cloudy solution becomes clear.
Preferably the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide. Most preferably to the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
Preferably the first solvent: second solvent systems are selected from the group consisting of DMF: water and ethyl acetate: hexane.
15 In another embodiment, the present invention provides a novel process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of (i) combining crude bicalutamide and a first solvent, wherein the first solvent is an anti-solvent;
20 (ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(iii) crystallizing the bicalutamide from the solvents with or without seeding; and (iv) collecting the crystals of bicalutamide.
Preferably the crude bicalutamide is adedd to the first solvent, or anti-solvent, and 25 the resulting bicalutamide suspension is heated to about the boiling point of the first solvent. The addition of the second solvent, or anti-solvent, takes place under reflux conditions, with the second solvent being added in an amount sufficient to dissolve the bicalutamide.
3o Preferably the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide. Most preferably the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
Preferably the first solvent, or anti-solvent is selected from the group consisting of toluene, ether, chloroform, water, methanol and ethanol.
Preferably the second solvent is selected from the group consisting of acetonitrile, acetone, THF, I~MF and isobutyl methyl ketone.
In another embodiment, the novel processes for the purification and isolation of bicalutamide by solution crystallization of the present invention are carned out using l0 solvents having low toxic potential. Suitable solvents are described as Class III solvents in the ICH Harmonized Tripartite Guideline, Impurities: Guideline for Residual Solvents.
Class III solvents are described as being regarded as less toxic and of lower risk to human health, and include no solvent known as a human health hazard at levels normally accepted in pharmaceuticals. Class III solvents acetic acid, acetone, anisole, 1-butanol, 2-15 butanol, butyl acetate, tent-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate and tetrahydro furan.
2o The process according to our invention is described in detail by the following, but not limiting, examples.
Example 1 Crystallization Methods for Preparation of Purified bicalutamide 25 Example 1A
Crude bicalutamide (260 g) was dissolved in ethanol (5 L) at reflux temperature, and water (7.5 L) was added gradually over a period of 1.5-2 hours to precipitate the product. The slurry was cooled to 0-5°C and stirred for 2 hours. The precipitate was collected, washed with water (625 mL), and dried at 60°C in a vacuum oven to yield the 3o crystalline bicalutamide (252.5 6 g, 94% for two steps).
Purity: 99.94 Assay: 99.4%
Water: 0.11 Ethanol: 142 ppm Example 1B
A sample of rac-bicalutamide (1.5 g, 3.45 mmol) was dissolved in a minimum volume of a solvent and then boiled. Under reflux conditions, an additional volume of the same solvent was added until the solution was clear and no precipitate was observed.
Following the addition of solvent, the solution was cooled to room temperature and left to stand over-night.
to The crystals were filtered off and dried in an oven at 70°C under vacuum.
Solvent systems:
1. Ethyl acetate (20mL) 2. Acetonitrile (SmL) 3. Acetone (7.2mL) 4. THF (7.2mL)
(iii) crystallizing the bicalutamide from the solvents; and (iv) collecting the crystals of bicalutamide.
Preferably, in this embodiment, the crude bicalutamide is adedd to the first solvent, or anti-solvent, and the resulting bicalutamide suspension is heated to about the boiling point of the first solvent. Preferably, in this embodiment, the addition of the second solvent, or anti-solvent, takes place under reflux conditions, with the second solvent being added in an amount sufficient to dissolve the bicalutamide.
to Preferably the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide. Most preferably the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
15 Preferably, in this embodiment, the first solvent, or anti-solvent is selected from the group consisting of toluene, ether, chloroform, water, methanol and ethanol.
Preferably, in this embodiment, the second solvent is selected from the group consisting of acetonitrile, acetone, THF, DMF and isobutyl methyl ketone.
According to another object, the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
(i) combining bicalutamide and a first solvent;
(ii) adding a second solvent to the bicalutamide-first solvent mixture;
(iii) crystallizing the bicalutamide from the solvents with or without seeding; and (iv) collecting the crystals of bicalutamide.
According to another object, the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, wherein the solvents utilized have low toxic potential.
The present invention also provides rac-bicalutamide and its intermediates prepared and isolated by the processes described above.
DETAILED DESCRIPTION OF THE INVENTION
Definitions:
As used herein, rac-bicalutamide refers to both the R-(-) enantiomer and S-(+) enantiomer of bicalutamide. Rac-bicalutamide is the racemic and optically pure R-(-) and S-(+) isomers of N-[4-cyano-3-trifluoromethyl-phenyl]-3-[4-fluorophenyl-sulfonyl]-2-hydroxy-2-methyl-propionamide. It is to be understood that this invention encompasses 1o the racemic form of bicalutamide and any optically-active form which possesses anti-androgenic activity. It is a matter of common general knowledge how a racemic compound may be resolved into its optically-active forms and how any anti-androgenic activity present in any of these forms may be determined. One skilled in the art will appreciate that the separation of optical isomers can be achieved by conventional i5 resolution; such as fractional crystallization or flash-chromatography.
As used herein, the term "anti-solvent" refers to a solvent in which bicalutamide has limited or no solubility.
20 As used herein, the term "crude bicalutamide" refers to the product prepared by a process to prepare bicalutamide.
The following abbreviations are used herein: DCM is dichloromethane. THF is tetrahydrofuran. DABCO is 1,4 dizazbicyl [2.2.2] octane. ACB is 5-amino-2-cyano-25 benzotrofluoride. BCL is rac-bicalutamide. 4-FPMS is 4-fluorophenyl methyl sulfone.
DMF is N,N dimethyl formamide. DMSO is dimethyl sulfoxide.
The present invention provides a process for the purification and isolation of bicalutamide. The crude cicalutamide may be prepared by any method, including, for 3o example, the methods disclosed in pending U.S. application serial no.
10/170,271.
The process of the invention comprises the steps of (i) combining crude bicalutamide and a solvent;
(ii) crystallizing the bicalutamide from the solvent with or without seeding;
and (iii) collecting the crystals of bicalutamide.
The crude bicalutamide may or may not be substantially soluble in the solvent.
Preferably the crude bicalutamide is soluble in the solvent. Preferably the crude bicalutamide is dissolved in the solvent and the resulting bicalutamide solution or suspension is crystallized by applying agitation for a time sufficient to bring about crystallization of the bicalutamide. The duration of the agitation may be from about 1 to hour to about 48 hours. Preferably the duration of the agitation is from about 8 hours to about 15 hours. The agitation may be brought about by any means known to the skilled artisan. The agitation may be accompanied by heating of the reaction mixture.
Preferably, the agitation is carned out at room temperature.
15 Preferably the solvent is selected from the group consisting of water, methanol, ethanol, DCM, toluene, PE, chloroform, hexane, 1,2-dichloroethane, diethyl ether, propanol and isopropanol.
According to another embodiment of the invention, the novel process for the 2o purification and isolation of bicalutamide by solution crystallization, comprises the steps of (i) combining crude bicalutamide and a first solvent;
(ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(iii) crystallizing the bicalutamide from the solvents with or without seeding; and 25 (iv) collecting the crystals of bicalutamide.
The first solvent and the second solvents may be the same or different. In one embodiment of the invention, the first and second solvents are the same.
Preferably the crude bicalutamide is dissolved in an amount of first solvent sufficient to dissolve the 30 bicalutamide. Preferably the resulting bicalutamide solution is heated to about the boiling point of the first solvent.
Preferably, the amount of second solvent added to the bicalutamide solution is equal to that of the first volume. The second solvent is preferably added under reflux conditions.
Preferably the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide with or without seeding. Most preferably the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
l0 The term "seeding" refer to the addition of a crystal of the product to the product solution in order to bring about crystallization, or scratching the inner surface of the crystallization vessel with a glass rod. The present invention covers embodiments where crystallization or precipitation occurs spontaneously, or is induced/accelerated 15 Preferably the first and second solvents are selected from the group consisting of water, methanol, ethanol, ethyl acetate, acetonitrile, acetone, THF, propanol, DMF, DMSO and isobutyl methyl ketone.
In another embodiment, the present invention provides a novel process for the 2o purification and isolation of bicalutamide by solution crystallization, comprising the steps of (i) combining cuude bicalutamide and a first solvent;
(ii) adding a second solvent to the crude bicalutamide-first solvent mixture, wherein the second solvent is an anti-solvent;
25 (iii) crystallizing the bicalutamide from the solvents; and (iv) collecting the crystals of bicalutamide.
Preferably the crude bicalutamide is dissolved in an amount of first solvent sufficient to dissolve the bicalutamide. The the resulting bicalutatnide solution is heated 30 to about the boiling point of the first solvent. Preferably the addition of the second solvent, or anti-solvent, takes place under reflux conditions, with the second solvent being added in an amount sufficient to bring about an at least partially desolubilized bicalutamide. The partial desolubilization is accompanied by the formation of a clouody appearance in the clear solution.
Following addition of the second solvent, a small volume of first solvent, sufficient to dissolve the at least partially desolubilized bicalutamide is added to the mixture.
Sufficient volume of the first solvent is added when the cloudy solution becomes clear.
Preferably the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide. Most preferably to the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
Preferably the first solvent: second solvent systems are selected from the group consisting of DMF: water and ethyl acetate: hexane.
15 In another embodiment, the present invention provides a novel process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of (i) combining crude bicalutamide and a first solvent, wherein the first solvent is an anti-solvent;
20 (ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(iii) crystallizing the bicalutamide from the solvents with or without seeding; and (iv) collecting the crystals of bicalutamide.
Preferably the crude bicalutamide is adedd to the first solvent, or anti-solvent, and 25 the resulting bicalutamide suspension is heated to about the boiling point of the first solvent. The addition of the second solvent, or anti-solvent, takes place under reflux conditions, with the second solvent being added in an amount sufficient to dissolve the bicalutamide.
3o Preferably the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide. Most preferably the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
Preferably the first solvent, or anti-solvent is selected from the group consisting of toluene, ether, chloroform, water, methanol and ethanol.
Preferably the second solvent is selected from the group consisting of acetonitrile, acetone, THF, I~MF and isobutyl methyl ketone.
In another embodiment, the novel processes for the purification and isolation of bicalutamide by solution crystallization of the present invention are carned out using l0 solvents having low toxic potential. Suitable solvents are described as Class III solvents in the ICH Harmonized Tripartite Guideline, Impurities: Guideline for Residual Solvents.
Class III solvents are described as being regarded as less toxic and of lower risk to human health, and include no solvent known as a human health hazard at levels normally accepted in pharmaceuticals. Class III solvents acetic acid, acetone, anisole, 1-butanol, 2-15 butanol, butyl acetate, tent-butylmethyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate and tetrahydro furan.
2o The process according to our invention is described in detail by the following, but not limiting, examples.
Example 1 Crystallization Methods for Preparation of Purified bicalutamide 25 Example 1A
Crude bicalutamide (260 g) was dissolved in ethanol (5 L) at reflux temperature, and water (7.5 L) was added gradually over a period of 1.5-2 hours to precipitate the product. The slurry was cooled to 0-5°C and stirred for 2 hours. The precipitate was collected, washed with water (625 mL), and dried at 60°C in a vacuum oven to yield the 3o crystalline bicalutamide (252.5 6 g, 94% for two steps).
Purity: 99.94 Assay: 99.4%
Water: 0.11 Ethanol: 142 ppm Example 1B
A sample of rac-bicalutamide (1.5 g, 3.45 mmol) was dissolved in a minimum volume of a solvent and then boiled. Under reflux conditions, an additional volume of the same solvent was added until the solution was clear and no precipitate was observed.
Following the addition of solvent, the solution was cooled to room temperature and left to stand over-night.
to The crystals were filtered off and dried in an oven at 70°C under vacuum.
Solvent systems:
1. Ethyl acetate (20mL) 2. Acetonitrile (SmL) 3. Acetone (7.2mL) 4. THF (7.2mL)
5. n-Propanol (27mL)
6. DMF (2.2mL)
7. DMSO (2.2mL)
8. Isobutyl methyl ketone (2.2mL) Examt~le 1 C
Bicalutamide was dissolved in a suitable solvent in which it is readily soluble (minimum volume under reflux) and then an anti-solvent was added until a cloudy solution was formed. A few drops of the solvent were then added to clear the solution again and the solution was cooled to room temperature and left to stand overnight.
The crystals were filtered off and dried in an oven at 70°C under vacuum.
Solvent systems:
1. DMF (l2mL): water (l8mL) 2. Ethyl acetate (33mL): hexane (6mL) Example 1D
A suspension of bicalutamide in an anti-solvent was prepared (fixed volume under reflux) and then a highly solublizing solvent was added until a clear solution was formed and all the precipitate disappeared. The solution was then cooled to room temperature and left to stand overnight .
The crystals were filtered off and dried in an oven at 70°C under vacuum.
Solvent systems:
1. Toluene (SOmL): acetonitrile (4mL) 2. Ether (SOmL): acetonitrile (36mL) l0 3. Chloroform (SOmL): acetonitrile (l3mL) 4. Water (lOmL): acetonitrile (l4mL) 5. Water (lOmL): acetone (26mL) 6. Water (lOmL): THF (36mL) 7. Methanol (lOmL): acetonitrile (SmL) ~. Methanol (lOmL): acetone (4mL)
Bicalutamide was dissolved in a suitable solvent in which it is readily soluble (minimum volume under reflux) and then an anti-solvent was added until a cloudy solution was formed. A few drops of the solvent were then added to clear the solution again and the solution was cooled to room temperature and left to stand overnight.
The crystals were filtered off and dried in an oven at 70°C under vacuum.
Solvent systems:
1. DMF (l2mL): water (l8mL) 2. Ethyl acetate (33mL): hexane (6mL) Example 1D
A suspension of bicalutamide in an anti-solvent was prepared (fixed volume under reflux) and then a highly solublizing solvent was added until a clear solution was formed and all the precipitate disappeared. The solution was then cooled to room temperature and left to stand overnight .
The crystals were filtered off and dried in an oven at 70°C under vacuum.
Solvent systems:
1. Toluene (SOmL): acetonitrile (4mL) 2. Ether (SOmL): acetonitrile (36mL) l0 3. Chloroform (SOmL): acetonitrile (l3mL) 4. Water (lOmL): acetonitrile (l4mL) 5. Water (lOmL): acetone (26mL) 6. Water (lOmL): THF (36mL) 7. Methanol (lOmL): acetonitrile (SmL) ~. Methanol (lOmL): acetone (4mL)
9. Methanol (lOmL): THF (4mL)
10. Methanol (lOmL): DMF(12.4mL)
11. Ethanol (lOmL): THF (6.4mL)
12. Ethanol (lOmL): DMF (12.4mL)
13. Ethanol (lOmL): Isobutyl methyl ketone (12.4mL) Example 1E
Trituration procedure A sample of rac-bicalutamide (~l g, 2.3 mmol) was suspended in a fixed volume (30 mL) of a solvent and stirred vigorously at room temperature overnight.
The crystals were filtered off and dried in an oven at 70°C under vacuum.
3o Solvent systems:
1. Water (30mL) 2. Methanol (30mL) 3. Ethanol (30mL) 4. DCM (30mL) 5. Toluene (30mL) 6. Petroleum ether (30mL) 7. Chloroform (30mL) 8. n-Hexane (30mL) 9. 1,2-Dichloroethane (30mL) 10.Diethyl ether (30mL) 11.n-Propanol (30mL) 12.Iso-propanol (30mL)
Trituration procedure A sample of rac-bicalutamide (~l g, 2.3 mmol) was suspended in a fixed volume (30 mL) of a solvent and stirred vigorously at room temperature overnight.
The crystals were filtered off and dried in an oven at 70°C under vacuum.
3o Solvent systems:
1. Water (30mL) 2. Methanol (30mL) 3. Ethanol (30mL) 4. DCM (30mL) 5. Toluene (30mL) 6. Petroleum ether (30mL) 7. Chloroform (30mL) 8. n-Hexane (30mL) 9. 1,2-Dichloroethane (30mL) 10.Diethyl ether (30mL) 11.n-Propanol (30mL) 12.Iso-propanol (30mL)
Claims (33)
1. A process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
(i) combining crude bicalutamide and a solvent;
(ii) crystallizing the bicalutamide from the solvent; and (iii) collecting the crystals of bicalutamide.
(i) combining crude bicalutamide and a solvent;
(ii) crystallizing the bicalutamide from the solvent; and (iii) collecting the crystals of bicalutamide.
2. The process of claim 1, wherein the the crystallizing step (ii) comprises seeding the bicalutamide suspension.
3. The process of claim 1, further comprising heating the resulting bicalutamide solution to about the boiling point of the solvent.
4. The process of claim 1, wherein the solvent is selected from the group consisting of water, methanol, ethanol, DCM, toluene, PE, chloroform, hexane, 1,2-dichloroethane, diethyl ether, propanol and isopropanol.
5. The process of claim 1, wherein the solvent is selected from the group consisting of ethanol, propanol and isopropanol.
6. A process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
(i) combining crude bicalutamide and a first solvent;
(ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(iii) crystallizing the bicalutamide from the solvents; and (iv) collecting the crystals of bicalutamide.
(i) combining crude bicalutamide and a first solvent;
(ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(iii) crystallizing the bicalutamide from the solvents; and (iv) collecting the crystals of bicalutamide.
7. The process of claim 6, further comprising heating the bicalutamide solution of step (i) to about the boiling point of the solvent.
The process of claim 7, wherein the addition of the second solvent takes place under reflux conditions.
9. The process of claim 6, wherein the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide.
10. The process of claim 9, wherein the the crystallizing step comprises seeding the bicalutamide suspension.
11. The process of claim 9, wherein the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
12. The process of claim 6, wherein the first and second solvents are the same or different.
13. The process of claim 12, wherein the first and second solvents are selected from the group consisting of water, methanol, ethanol, ethyl acetate, acetonitrile, acetone, THF, propanol, DMF, DMSO and isobutyl methyl ketone.
14. The process of claim 12, wherein the first and second solvents are selected from the group consisting of ethanol, ethyl acetate, acetone, THF, propanol, DMSO
and isobutyl methyl ketone.
and isobutyl methyl ketone.
15. The process of claim 13, wherein the amount of the first solvent is sufficient to dissolve the crude bicalutamide.
16. The process of claim 6, wherein the second solvent is an anti-solvent.
17. The process of claim 13, wherein the first solvent: second solvent system is DMF:
water.
water.
18. The process of claim 13, wherein the amount of the first solvent is sufficient to dissolve the crude bicalutamide.
19. The process of claim 13, wherein the amount of the second solvent is added in an amount sufficient to bring about an at least partially desolubilized bicalutamide.
20. The process of claim 19, further comprising, following addition of the second solvent, adding a volume of the first solvent sufficient to dissolve the at least partially desolubilized bicalutamide.
21. The process of claim 13, wherein the first solvent is ethanol and the second solvent is water.
22. The process of claim 21, wherein the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
23. A process for the purification and isolation of bicalutamide, comprising the steps of:
(i) combining crude bicalutamide and a first solvent; wherein the first solvent is an anti-solvent;
(ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(iii) crystallizing the bicalutamide from the solvents; and (iv) collecting the crystals of bicalutamide.
(i) combining crude bicalutamide and a first solvent; wherein the first solvent is an anti-solvent;
(ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(iii) crystallizing the bicalutamide from the solvents; and (iv) collecting the crystals of bicalutamide.
24. The process of claim 23, wherein the first solvent is selected from the group consisting of toluene, ether, chloroform, water, and methanol, and the second solvent is acetonitrile.
25. The process of claim 23, wherein the first solvent is water, and the second solvent is selected from the group consisting of acetone and THF.
26. The process of claim 23, wherein the first solvent is methanol, and the second solvent is selected from the group consisting of acetone, THF and DMF.
27. The process of claim 23, wherein the first solvent is ethanol, and the second solvent is selected from the group consisting of THF, DMF and isobutyl methyl ketone.
28. The process of claim 23, wherein the second solvent is added in an amount sufficient to dissolve the bicalutamide.
29. The process of claim 23, further comprising heating the bicalutamide solution formed in step (i) to about the boiling point of the solvent.
30. The process of claim 29, wherein the addition of the second solvent takes place under reflux conditions.
31. The process of claim 23, wherein the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide.
32. The process of claim 31, wherein the the crystallizing step comprises seeding the bicalutamide solution.
33. The process of claim 32, wherein the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2003/020307 WO2005009946A1 (en) | 2003-06-25 | 2003-06-25 | Process for purifying and isolating rac-bicalutamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2529232A1 true CA2529232A1 (en) | 2005-02-03 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002529232A Abandoned CA2529232A1 (en) | 2003-06-25 | 2003-06-25 | Process for purifying and isolating rac-bicalutamide |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1558570A1 (en) |
| JP (1) | JP2007521224A (en) |
| CN (1) | CN1819992A (en) |
| AU (1) | AU2003247740A1 (en) |
| CA (1) | CA2529232A1 (en) |
| WO (1) | WO2005009946A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080177109A1 (en) * | 2005-03-29 | 2008-07-24 | Usv Limited | Novel Process for Preparation of Bicalutamide |
| CZ299577B6 (en) * | 2005-12-20 | 2008-09-03 | Interpharma Praha, A. S. | Process for preparing extremely pure 4-cyano-3-trifluoromethyl-N-( 3-p-fluorophenylsulfonyl-2-hydroxy-2-methylpropionyl) aniline |
| CN105949095A (en) * | 2016-05-27 | 2016-09-21 | 山西振东制药股份有限公司 | Method for preparing bicalutamide of crystal form I |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE28864T1 (en) * | 1982-07-23 | 1987-08-15 | Ici Plc | AMIDE DERIVATIVES. |
| HU223950B1 (en) * | 1999-06-10 | 2005-03-29 | Richter Gedeon Vegyészeti Gyár Rt. | Process for producing racemic and r-(-)- and s-(+)-n-[4-cyano-3-(trifluoromethyl)-phenyl]-3-[(4-fluorophenyl)-sulfonyl]-2-hydroxy-2-methyl-propanecarboxamide |
| CN1501912A (en) * | 2000-09-21 | 2004-06-02 | ����˹�ж�-����˹˹������˾ | Process for the preparation of n-(substituted phenyl)-3-alkyl-,aryl- and heteroarylsulfonyl-2-hydroxy-2-alkyl- and haloalkylpropanamide compounds |
| ES2331178T3 (en) * | 2001-12-13 | 2009-12-23 | Sumitomo Chemical Company, Limited | BICALUTAMIDE CRYSTALS AND METHOD FOR YOUR PRODUCTION. |
| DE10222104A1 (en) * | 2002-05-17 | 2003-12-04 | Helm Ag | Process for the preparation of N- (4'-cyano-3'-trifluoromethyl) -3- (4 "-fluorophenylsulfonyl) -2-hydroxy-2-methylpropionamide |
-
2003
- 2003-06-25 CA CA002529232A patent/CA2529232A1/en not_active Abandoned
- 2003-06-25 WO PCT/US2003/020307 patent/WO2005009946A1/en active Application Filing
- 2003-06-25 AU AU2003247740A patent/AU2003247740A1/en not_active Abandoned
- 2003-06-25 JP JP2005504628A patent/JP2007521224A/en active Pending
- 2003-06-25 CN CN03826678.4A patent/CN1819992A/en active Pending
- 2003-06-25 EP EP03816630A patent/EP1558570A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO2005009946A1 (en) | 2005-02-03 |
| JP2007521224A (en) | 2007-08-02 |
| AU2003247740A1 (en) | 2005-02-14 |
| EP1558570A1 (en) | 2005-08-03 |
| CN1819992A (en) | 2006-08-16 |
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| FZDE | Discontinued |