EP1558570A1 - Process for purifying and isolating rac-bicalutamide - Google Patents

Process for purifying and isolating rac-bicalutamide

Info

Publication number
EP1558570A1
EP1558570A1 EP03816630A EP03816630A EP1558570A1 EP 1558570 A1 EP1558570 A1 EP 1558570A1 EP 03816630 A EP03816630 A EP 03816630A EP 03816630 A EP03816630 A EP 03816630A EP 1558570 A1 EP1558570 A1 EP 1558570A1
Authority
EP
European Patent Office
Prior art keywords
solvent
bicalutamide
crystallization
solution
crude
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03816630A
Other languages
German (de)
French (fr)
Inventor
Ben-Zion Dolitzky
Ofer Reany
Jenny Shammai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Works PLC
Original Assignee
Teva Pharmaceutical Works PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Teva Pharmaceutical Works PLC filed Critical Teva Pharmaceutical Works PLC
Publication of EP1558570A1 publication Critical patent/EP1558570A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00Preparation of sulfones; Preparation of sulfoxides
    • C07C315/06Separation; Purification; Stabilisation; Use of additives

Definitions

  • the present invention relates to a process for isolating r ⁇ c-bicalutamide and its intermediates.
  • 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.
  • 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.
  • 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; and oxidizing with inorganic peroxy salt or m-chloroperbenzoic acid (MCPBA) or aqueous hydrogen peroxide.
  • MCPBA m-chloroperbenzoic acid
  • the synthetic pathways involve the use of substrates (such as sodium hydride) that are dangerously explosive in nature.
  • the present invention provides a process for the purification and crystallization of r ⁇ c-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:
  • the crude bicalutamide may or may not be substantially soluble in the solvent.
  • 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.
  • 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.
  • the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
  • the first solvent and the second solvent are the same.
  • the crude bicalutamide is dissolved in an amount of first solvent sufficient to dissolve the bicalutamide.
  • the resulting bicalutamide solution is heated to about the boiling point of the first solvent.
  • 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.
  • the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide.
  • the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
  • the first and second solvents are selected from the group consisting of ethyl acetate, acetonitrile, acetone, THF, propanol, DMF, DMSO and isobutyl methyl ketone.
  • the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
  • the crude bicalutamide is dissolved in an amount of first solvent sufficient to dissolve the bicalutamide.
  • the resulting bicalutamide solution 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 bring about an at least partially desolubilized bicalutamide.
  • a small volume of first solvent sufficient to dissolve the at least partially desolubilized bicalutamide is added to the mixture.
  • the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide.
  • the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
  • first solvent: second solvent system combinations include DMF:water and ethyl acetate:hexane.
  • the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
  • 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.
  • 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.
  • the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide.
  • the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
  • the first solvent, or anti-solvent is selected from the group consisting of toluene, ether, chloroform, water, methanol and ethanol.
  • the second solvent is selected from the group consisting of acetonitrile, acetone, THF, DMF and isobutyl methyl ketone.
  • the present invention provides a process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
  • 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.
  • 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 the racemic form of bicalutamide and any optically-active form which possesses anti- androgenic activity.
  • 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.
  • separation of optical isomers can be achieved by conventional resolution; such as fractional crystallization or flash-chromatography.
  • anti-solvent refers to a solvent in which bicalutamide has limited or no solubility.
  • crude bicalutamide refers to the product prepared by a process to prepare bicalutamide.
  • DCM dichloromethane
  • THF tetrahydrofuran
  • DABCO 1,4 dizazbicyl [2.2.2] octane
  • ACB 5-amino-2-cyano- benzotrofluoride
  • BCL rac-bicalutamide
  • 4-FPMS 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 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.
  • the crude bicalutamide is soluble in the solvent.
  • 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 hour to about 48 hours.
  • 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.
  • the agitation is carried out at room temperature.
  • 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.
  • the novel process for the purification and isolation of bicalutamide by solution crystallization comprises the steps of:
  • the first solvent and the second solvents may be the same or different.
  • the first and second solvents are the same.
  • the crude bicalutamide is dissolved in an amount of first solvent sufficient to dissolve the bicalutamide.
  • the resulting bicalutamide solution is heated to about the boiling point of the first solvent.
  • 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.
  • the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide with or without seeding.
  • the temperature sufficient to bring about crystallization of bicalutamide is about 25 °C.
  • 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 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.
  • the present invention provides a novel process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
  • the crude bicalutamide is dissolved in an amount of first solvent sufficient to dissolve the bicalutamide.
  • the the resulting bicalutamide solution 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 bring about an at least partially desolubilized bicalutamide.
  • the partial desolubilization is accompanied by the formation of a clouody appearance in the clear solution.
  • a small volume of first solvent, sufficient to dissolve the at least partially desolubilized bicalutamide is added to the mixture.
  • the crystallizing step comprises cooling the bicalutamide solution to a temperature sufficient to bring about crystallization of bicalutamide.
  • the temperature sufficient to bring about crystallization of bicalutamide is about 25°C.
  • the first solvent: second solvent systems are selected from the group consisting of DMF: water and ethyl acetate: hexane.
  • the present invention provides a novel process for the purification and isolation of bicalutamide by solution crystallization, comprising the steps of:
  • 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.
  • 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.
  • 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.
  • the first solvent, or anti-solvent is selected from the group consisting of toluene, ether, chloroform, water, methanol and ethanol.
  • the second solvent is selected from the group consisting of acetonitrile, acetone, THF, DMF and isobutyl methyl ketone.
  • the novel processes for the purification and isolation of bicalutamide by solution crystallization of the present invention are carried out using 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- butanol, butyl acetate, tert-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-l -propanol, pentane, 1- pentanol, 1 -propanol, 2-propanol, propyl acetate and tetrahydro furan.
  • 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
  • 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 crystalline bicalutamide (252.5 6 g, 94% for two steps). Purity: 99.94 % Assay: 99.4% Water: 0.11% Ethanol: 142 ppm
  • Example IB 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. The crystals were filtered off and dried in an oven at 70°C under vacuum. Solvent systems:
  • Example IC 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:
  • the crystals were filtered off and dried in an oven at 70°C under vacuum.

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-BICALUTA IDE
FIELD OF THE INVENTION The present invention relates to a process for isolating røc-bicalutamide and its intermediates.
BACKGROUND OF THE INVENTION 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.
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. 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; and 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 preparation of rac-bicalutarnide, intermediates and derivatives thereof from
4-fluorophenyl methyl sulfone and 5-amino-2-cyano-benzotrifmoride precursors.
We have now found a novel, safe and effective method for the purification and isolation of bicalutamide.
OBJECTS AND SUMMARY OF THE INVENTION The present invention provides a process for the purification and crystallization of rαc-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 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 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.
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 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 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. 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. In another embodiment, 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, 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 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. 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 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:
(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. 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.
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 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 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 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. 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- 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 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 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 carried out at room temperature. 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 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 (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 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. 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 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 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, wherein the second solvent is an anti-solvent; (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 bicalutamide solution is heated 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 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. 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; (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 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. 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, DMF 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 carried out using 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- butanol, butyl acetate, tert-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-l -propanol, pentane, 1- pentanol, 1 -propanol, 2-propanol, propyl acetate and tetrahydro furan. 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 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 crystalline bicalutamide (252.5 6 g, 94% for two steps). Purity: 99.94 % Assay: 99.4% Water: 0.11% Ethanol: 142 ppm
Example IB 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. The crystals were filtered off and dried in an oven at 70°C under vacuum. Solvent systems:
1 Ethyl acetate (20mL)
2 Acetonitrile (5mL) 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)
Example IC 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 (12mL): water (18mL)
2. Ethyl acetate (33mL): hexane (6mL) Example ID 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 (50mL): acetonitrile (4mL)
2. Ether (50mL): acetonitrile (36mL) 3. Chloroform (50mL): acetonitrile (13mL) Water (lOmL): acetonitrile (14mL) Water (lOmL): acetone (26mL) Water (lOmL): THF (36mL)
7. Methanol (lOmL) acetonitrile (5mL)
8. Methanol (lOmL) acetone (4mL)
9. Methanol (lOmL) THF (4mL)
10. Methanol (lOmL) DMF(12.4mL)
11. Ethanol (lOmL): THF (6.4mL)
12. Ethanol (lOmL): D I MF (12.4mL)
13. Ethanol (lOmL): I Isobutyl methyl ketone (12.4mL)
Example IE
Trituration procedure
A sample of rac-bicalutamide (~1 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.
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

WHAT IS CLAIMED IS:
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.
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.
7. The process of claim 6, further comprising heating the bicalutamide solution of step (i) to about the boiling point of the solvent.
8. 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.
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.
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.
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.
EP03816630A 2003-06-25 2003-06-25 Process for purifying and isolating rac-bicalutamide Withdrawn EP1558570A1 (en)

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
EP1558570A1 true EP1558570A1 (en) 2005-08-03

Family

ID=34102338

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03816630A Withdrawn EP1558570A1 (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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2005329762A1 (en) * 2005-03-29 2006-10-05 Usv Limited 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)

* Cited by examiner, † Cited by third party
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
CA2423158A1 (en) * 2000-09-21 2002-03-28 Bristol-Myers Squibb Company Process for the preparation of n-(substituted phenyl)-3-alkyl-, aryl- and heteroarylsulfonyl-2-hydroxy-2-alkyl- and haloalkylpropanamide compounds
DK1462442T3 (en) * 2001-12-13 2009-12-14 Sumitomo Chemical Co Bicalutamide crystals and process for their preparation
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

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
[Online] 5 January 2007 (2007-01-05), retrieved from HTTP://ORGCHEM.COLORADO.EDU/HNDBKSUPPORT/CRYST/CRYST.HTML *
See also references of WO2005009946A1 *

Also Published As

Publication number Publication date
CN1819992A (en) 2006-08-16
JP2007521224A (en) 2007-08-02
WO2005009946A1 (en) 2005-02-03
AU2003247740A1 (en) 2005-02-14
CA2529232A1 (en) 2005-02-03

Similar Documents

Publication Publication Date Title
CN109516943B (en) Preparation method of lactam intermediate with high chiral purity and brivaracetam
EP3490973B1 (en) Polymorphic forms of belinostat and processes for preparation thereof
CN112047888B (en) Method for synthesizing enzalutamide
EP1770084B1 (en) Method for producing (z)-1-phenyl-1-diethylaminocarbonyl-2-aminomethyl cyclopropane hydrochloride
EP2940001A1 (en) Method for producing purified form of amine compound
US11325922B2 (en) Process for the preparation of Crisaborole in a stable crystal form
CA2542788C (en) Process for producing bicalutamide and method of purifying intermediate thereof
EP1558570A1 (en) Process for purifying and isolating rac-bicalutamide
TWI826724B (en) Method for producing 1,5-benzothiazepine compounds
WO2014035107A1 (en) Method for purifying fluvoxamine free base and method for preparing highly pure fluvoxamine maleate using same
KR100371241B1 (en) Method for Purifying O, S-Dimethyl N-acetylphosphoramidothioate
US7102026B2 (en) Process for preparing and isolating rac-bicalutamide and its intermediates
JP2012020970A (en) Method for producing {3-(1-diphenylmethylazetidin-3-yl)ester-5-isopropyl ester 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate}
EP0344675B1 (en) Method for the production of selegiline hydrochloride
JP6275596B2 (en) Method for producing ammonium salt of telmisartan
AU581541B2 (en) Method of preparing 6-betahalopenicillanic acids
US20060030730A1 (en) Purification and production methods of 1-aminocyclopropanecarboxylic acid
JP3042122B2 (en) Method for producing N-cyanoacetamidine derivative
JP3291987B2 (en) Purification method of O, S-dimethyl-N-acetylphosphoramidothioate
US20050032907A1 (en) Methods for preparing sertraline hydrochloride polymorphs
CN113248450B (en) Fapila preparation method of pyrrosia lingua
AU2008298402B2 (en) Method for producing N-methacryloyl-4-cyano-3-trifluoromethylaniline
US20040106829A1 (en) Process for the synthesis of modafinil
WO2008035189A1 (en) A method for the purification of lansoprazole
JP4178343B2 (en) Process for producing 2- (2-substituted-2-propenyl) indane-1,3-diones

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20041011

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

RBV Designated contracting states (corrected)

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: TEVA GYOGYSZERGYAR ZARTKOERUEN MUKOEDO RESZVENYTAR

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20080820