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

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.

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• 2003
  • 2003-06-25 CA CA002529232A patent/CA2529232A1/en not_active Abandoned
  • 2003-06-25 CN CN03826678.4A patent/CN1819992A/zh active Pending
  • 2003-06-25 AU AU2003247740A patent/AU2003247740A1/en not_active Abandoned
  • 2003-06-25 EP EP03816630A patent/EP1558570A1/en not_active Withdrawn
  • 2003-06-25 WO PCT/US2003/020307 patent/WO2005009946A1/en active Application Filing
  • 2003-06-25 JP JP2005504628A patent/JP2007521224A/ja active Pending

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