JP2007521224A - Method for purification and isolation of RAC-bicalutamide - Google Patents

Abstract

  The present invention discloses a novel method for the isolation and purification of racemic and optically active bicalutamide.

Description

  The present invention relates to rac-bicalutamide and a method for isolating the intermediate.

Bicalutamide, also known as N- [4-cyano-3-trifluoromethyl-phenyl] -3- [4-fluorophenyl-sulfonyl] -2-hydroxy-2-methyl-propionamide, has the following chemical formula: Have

  Bicalutamide is an acylanilide having antiandrogenic activity. This is known to selectively reduce testosterone without affecting the hypothalamic control mechanism.

  International Patent No. WO 93/19770 describes both the R-(-) and S-(+) enantiomers of bicalutamide, of which the R-(-) isomer is more potent when used in therapeutic treatment. It has been reported to be active and have fewer side effects (eg, headache, gynecomastia, and dizziness).

  US Pat. No. 4,636,505 describes a process for preparing acylanilides.

  International Patent No. WO 01/00608 describes racemic and optically pure N- [4-cyano-3-trifluoromethylphenyl] -3- [4-fluorophenyl-sulfonyl] -2-hydroxy-2- The method of methyl-propionamide will be described. The method comprises reacting at least with thionyl chloride; hydrolyzing under aqueous basic conditions; sulfonylating with a sulfonyl halide; and oxidizing with an inorganic peroxide salt or m-chloroperbenzoic acid (MCPBA). Including a plurality of steps including. However, the synthetic route involves the use of hazardous substrates that are explosive in nature (eg, sodium hydride).

  There remains a need for improved methods of synthesizing bicalutamide that are economically and environmentally safe and feasible. One approach that illustrates this need is described in pending US patent application Ser. No. 10 / 170,721, where rac-bicalutamide from 4-fluorophenylethylsulfone and 5-amino-2-cyano-benzotrifluoride precursors. And the preparation of intermediates and derivatives thereof.

  We have now discovered a new, safe and effective method for the purification and isolation of bicalutamide.

Objects and Summary of the Invention The present invention provides methods for the purification and crystallization of rac-bicalutamide and its intermediates.

In accordance with one object, the present invention provides a method for the purification and isolation of bicalutamide by crystallization of a solution comprising the following steps:
(I) mixing the crude bicalutamide and the solvent;
(Ii) crystallization of bicalutamide from the solvent with or without seed addition; and
(Iii) A step of recovering the bicalutamide crystals.

  The crude bicalutamide may or may not be substantially soluble in the solvent. Preferably the bicalutamide is soluble in the solvent. The resulting bicalutamide solution or suspension crystallizes by stirring for a time sufficient to effect crystallization of 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 method for the purification and isolation of bicalutamide by crystallization of a solution comprising the following steps:
(I) mixing the crude bicalutamide and the first solvent;
(Ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(Iii) crystallizing bicalutamide from the solvent; and
(Iv) A step of recovering the bicalutamide crystals.

  In some embodiments, the first solvent and the second solvent are the same. Preferably, in this embodiment, the crude bicalutamide is dissolved in a sufficient amount of the first solvent to dissolve bicalutamide. Preferably, the resulting bicalutamide solution is heated to approximately the boiling point of the first solvent.

  Preferably, in this embodiment, the amount of the second solvent added to the bicalutamide solution is the same as the first volume. The second solvent is preferably added under reflux conditions.

  Preferably, the crystallization step comprises cooling the bicalutamide solution to a temperature sufficient to effect crystallization of bicalutamide. Most preferably, the temperature sufficient to effect 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 aspect, the present invention provides a method for the purification and isolation of bicalutamide by crystallization of a solution comprising the following steps:
(I) mixing the crude bicalutamide and the first solvent;
(Ii) adding a second solvent to the crude bicalutamide-first solvent mixture, wherein the second solvent is a poor solvent;
(Iii) crystallizing bicalutamide from the solvent; and
(Iv) A step of recovering the bicalutamide crystals.

  Preferably, in this embodiment, the crude bicalutamide is dissolved in a sufficient amount of the first solvent to dissolve bicalutamide. Preferably, the resulting bicalutamide solution is heated to approximately the boiling point of the first solvent. Preferably, in this embodiment, the addition of the second solvent or antisolvent is performed under reflux conditions, and the second solvent is added in an amount sufficient to provide at least partially non-solubilized bicalutamide. The

  Preferably, in this embodiment, after the addition of the second solvent, a small amount of the first solvent sufficient to dissolve at least partially unsolubilized bicalutamide is added to the mixture.

  Preferably, the crystallization step comprises cooling the bicalutamide solution to a temperature sufficient to effect crystallization of bicalutamide. Most preferably, the temperature sufficient to effect crystallization of bicalutamide is approximately 25 ° C.

  Preferably, in this embodiment, the first solvent: second solvent system combination comprises DMF: water and ethyl acetate: hexane.

In another aspect, the present invention provides a method for the purification and isolation of bicalutamide by crystallization of a solution comprising the following steps:
(I) mixing the crude bicalutamide and the first solvent, wherein the first solvent is a poor solvent;
(Ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(Iii) crystallizing bicalutamide from the solvent; and
(Iv) A step of recovering the bicalutamide crystals.

  Preferably, in this embodiment, the crude bicalutamide is added to the first solvent, or anti-solvent, and the resulting bicalutamide suspension is heated to approximately the boiling point of the first solvent. Preferably, in this embodiment, the second solvent or antisolvent is added under reflux conditions, and the second solvent is added in an amount sufficient to dissolve bicalutamide.

  Preferably, the crystallization step comprises cooling the bicalutamide solution to a temperature sufficient to effect crystallization of bicalutamide. Most preferably, the temperature sufficient to effect crystallization of bicalutamide is about 25 ° C.

  Preferably, in this embodiment, the first solvent or antisolvent 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 method for the purification and isolation of bicalutamide by crystallization of a solution comprising the following steps:
(I) mixing the crude bicalutamide and the first solvent;
(Ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(Iii) crystallizing bicalutamide from the solvent with or without seed addition; and
(Iv) A step of recovering the bicalutamide crystals.

  In accordance with another object, the invention provides a method for the purification and isolation of bicalutamide by crystallization of a solution. The solution utilized here has a low toxicity potential.

  The present invention also provides rac-bicalutamide prepared and isolated by the method described above, and intermediates thereof.

Detailed Description of the Invention
Definition:
As used herein, rac-bicalutamide refers to both the R-(-) and S-(+) enantiomers of bicalutamide. Rac-bicalutamide is a racemic and optically pure N- [4-cyano-3-trifluoromethyl-phenyl] -3- [4-fluorophenyl-sulfonyl] -2-hydroxy-2-methyl-propionamide. R-(-) and S-(+) isomers. It is understood that the invention encompasses racemic forms of bicalutamide and any optically active form having antiandrogenic activity. It is usually a matter of general knowledge how the racemate can be separated into its optical form and how any antiandrogenic activity present in any form can be determined. One skilled in the art will recognize that separation of optical isomers can be achieved by conventional resolution; for example, fractional recrystallization, or flash-chromatography.

  As used herein, the term “antisolvent” means a solvent in which bicalutamide has limited or no solubility.

  As used herein, the term “crude bicalutamide” means a product prepared by a method for preparing bicalutamide.

  The following abbreviations are used herein: DCM is dichloromethane. THF is tetrahydrofuran. DABCO is 1,4 dizazubicil [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 dimethylformamide. DMSO is dimethyl sulfoxide.

  The present invention provides a method for purification and isolation of bicalutamide. Crude bicalutamide can be prepared by any method, for example, the method disclosed in pending US patent application Ser. No. 10 / 170,271.

The method of the present invention comprises the following steps:
(I) mixing the crude bicalutamide and the solvent;
(Ii) crystallization of bicalutamide from the solvent with or without seed addition; and
(Iii) A step of recovering the bicalutamide crystals.

  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 a solvent and the resulting bicalutamide solution, or suspension, is crystallized by stirring for a time sufficient to effect crystallization of bicalutamide. The stirring time can be about 1 hour to about 48 hours. Preferably, the stirring time is from about 8 hours to about 15 hours. The stirring can be performed by any method known to those skilled in the art. The stirring may involve heating the reaction mixture. Preferably, the stirring is performed 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.

In accordance with another aspect of the present invention, a novel method for purification and isolation of bicalutamide by solution crystallization comprises the following steps:
(I) mixing the crude bicalutamide and the first solvent;
(Ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(Iii) crystallizing bicalutamide from the solvent with or without seed addition; and
(Iv) A step of recovering the bicalutamide crystals.

  The first solvent and the second solvent may be the same or different. In some embodiments of the invention, the first and second solvents are the same. Preferably the crude bicalutamide is dissolved in a sufficient amount of the first solvent to dissolve the bicalutamide. Preferably, the multiplying bicalutamide solution is heated to approximately the boiling point of the first solvent.

  Preferably, the amount of second solvent added to bicalutamide is the same as the first volume. The second solvent is preferably added under reflux conditions.

  Preferably, the crystallization step comprises cooling the bicalutamide solution to a temperature sufficient to effect crystallization of bicalutamide with or without seeding. Most preferably, the temperature sufficient to effect crystallization of bicalutamide is about 25 ° C.

  The term “seeding” means adding product crystals to the product solution to effect crystallization, or scraping the inner surface of the crystal vessel with a glass rod. The present invention covers embodiments in which crystallization or precipitation occurs spontaneously or is induced / promoted.

  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 aspect, the present invention provides a novel method for the purification and isolation of bicalutamide by crystallization of a solution comprising the following steps:
(I) mixing the crude bicalutamide and the first solvent;
(Ii) adding a second solvent to the crude bicalutamide-first solvent mixture, wherein the solvent is a poor solvent;
(Iii) crystallizing bicalutamide from the solvent; and
(Iv) A step of recovering the bicalutamide crystals.

  Preferably, the crude bicalutamide is dissolved in a sufficient amount of the first solvent to dissolve the bicalutamide. The resulting bicalutamide solution is heated to approximately the boiling point of the first solvent. Preferably, the addition of the second solvent, or anti-solvent, is performed under reflux conditions, and the second solvent is added in an amount sufficient to provide at least partially non-solubilized bicalutamide. The partial desolubilization is accompanied by the formation of a cloudy appearance in a clear solution.

  After the addition of the second solvent, a small volume of the first solvent sufficient to dissolve at least partially unsolubilized bicalutamide is added to the mixture. When the turbid solution becomes clear, a sufficient amount of the first solvent has been added.

  Preferably, the crystallization step comprises cooling the bicalutamide solution to a temperature sufficient to effect crystallization of bicalutamide. Most preferably, the temperature sufficient to effect crystallization of bicalutamide is about 25 ° C.

  Preferably, the first solvent: second solvent system is selected from DMF: water and ethyl acetate: hexane.

In another aspect, the present invention provides a novel method for the purification and isolation of bicalutamide by crystallization of a solution comprising the following steps:
(I) mixing the crude bicalutamide and the first solvent, wherein the first solvent is a poor solvent;
(Ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(Iii) crystallizing bicalutamide from the solvent with or without seed addition; and
(Iv) A step of recovering the bicalutamide crystals.

  Preferably, the crude bicalutamide is dissolved in a first solvent or a poor solvent. The resulting bicalutamide suspension is heated to approximately the boiling point of the first solvent. The addition of the second solvent or the poor solvent is performed under reflux conditions, and the second solvent is added in an amount sufficient to dissolve bicalutamide.

  Preferably, the crystallization step comprises cooling the bicalutamide solution to a temperature sufficient to effect crystallization of bicalutamide. Most preferably, the temperature sufficient to effect crystallization of bicalutamide is about 25 ° C.

  Preferably, the first solvent or antisolvent 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 method for the purification and isolation of bicalutamide by crystallization of the solution of the present invention is performed using a solvent having a low toxicity potential. Suitable solvents are described as class III solvents in the ICH Harmonized Tripartite Guideline, Impurities: Guideline for Residual Solvent. Class III solvents are described as being low-toxic and low-risk in human health and free of solvents known to harm human health at levels that are usually pharmaceutically acceptable. Class III solvents are acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate Isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

  The method according to our invention is illustrated in more detail by the following examples without limitation.

Example 1
Crystallization method for the 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 slowly over 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 in a vacuum oven at 60 ° C. to yield crystalline bicalutamide (252.56 g, 94% over 2 steps).
Purity: 99.94%
Assay: 99.4%
Water: 0.11%
Ethanol: 142ppm

Example 1B
A sample of rac-bicalutamide (1.5 g, 3.45 mmol) was dissolved in a minimum amount of solvent and then boiled. Under reflux conditions, an additional amount of the same solvent was added until the solvent became clear and no precipitate was observed. After the addition of solvent, the solution was cooled to room temperature and left overnight. The crystals were filtered and dried in an oven at 70 ° C. under vacuum.
Solvent system:
1. Ethyl acetate (20 mL)
2. Acetonitrile (5 mL)
3. Acetone (7.2 mL)
4). THF (7.2 mL)
5). n-propanol (27 mL)
6). DMF (2.2 mL)
7). DMSO (2.2 mL)
8). Isobutyl methyl ketone (2.2 mL)

Example 1C
Bicalutamide was easily dissolved in a suitable solvent (minimum volume under reflux) and then the antisolvent was added until a cloudy solution was formed. A few drops of solvent was then added to the solution again, and the solution was cooled to room temperature and left overnight. The crystals were filtered and dried in an oven at 70 ° C. under vacuum.
Solvent system:
1. DMF (12 mL): Water (18 mL)
2. Ethyl acetate (33 mL): hexane (6 mL)

Example 1D
A suspension of bicalutamide in an antisolvent was prepared (under reflux, constant volume), from which a highly soluble solvent was added until a clear solution was formed and all precipitate disappeared. The solution was then cooled to room temperature and left overnight. The crystals were filtered and dried in an oven at 70 ° C. under vacuum.
Solvent system:
1. Toluene (50 mL): acetonitrile (4 mL)
2. Ether (50 mL): Acetonitrile (36 mL)
3. Chloroform (50 mL): acetonitrile (13 mL)
4). Water (10 mL): Acetonitrile (14 mL)
5). Water (10 mL): Acetone (26 mL)
6). Water (10 mL): THF (36 mL)
7). Methanol (10 mL): acetonitrile (5 mL)
8). Methanol (10 mL): Acetone (4 mL)
9. Methanol (10 mL): THF (4 mL)
10. Methanol (10 mL): DMF (12.4 mL)
11. Ethanol (10 mL): THF (6.4 mL)
12 Ethanol (10 mL): DMF (12.4 mL)
13. Ethanol (10 mL): Isobutyl methyl ketone (12.4 mL)

Example 1E
Trial Procedure A sample of rac-bicalutamide (˜1 g, 2.3 mmol) was suspended in a fixed volume (30 mL) of solvent and stirred vigorously overnight at room temperature. The crystals were filtered and dried in an oven at 70 ° C. under vacuum.
Solvent system:
1. Water (30 mL)
2. Methanol (30 mL)
3. Ethanol (30 mL)
4). DCM (30 mL)
5). Toluene (30 mL)
6). Petroleum ether (30 mL)
7). Chloroform (30 mL)
8). n-hexane (30 mL)
9.1,2-dichloroethane (30 mL)
10. Diethyl ether (30 mL)
11. n-propanol (30 mL)
12 Iso-propanol (30 mL)

Claims (33)

(I) mixing the crude bicalutamide and the solvent;
(Ii) crystallizing the bicalutamide from the solvent; and
(Iii) recovering the bicalutamide crystals,
A process for the purification and isolation of bicalutamide by crystallization of a solution comprising.   The method of claim 1, wherein the crystallization step (ii) comprises seeding a bicalutamide suspension.   The method of claim 1, further comprising heating the resulting bicalutamide solution to approximately the boiling point of the solvent.   The method 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.   The method of claim 1, wherein the solvent is selected from the group consisting of ethanol, propanol, and isopropanol. (I) mixing the crude bicalutamide and the first solvent;
(Ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(Iii) crystallizing bicalutamide from the solvent; and
(Iv) recovering the bicalutamide crystals,
A process for the purification and isolation of bicalutamide by crystallization of a solution comprising.   7. The method of claim 6, further comprising heating the bicalutamide solution of step (i) to approximately the boiling point of the solvent.   The method of claim 7, wherein the addition of the second solvent is performed under reflux conditions.   The method of claim 6, wherein the crystallization step comprises cooling the bicalutamide solution to a temperature sufficient to effect crystallization of the bicalutamide solution.   The method of claim 9, wherein the crystallization step comprises seeding a bicalutamide suspension.   The method of claim 9, wherein the temperature sufficient to effect crystallization of the bicalutamide is about 25 ° C.   The method of claim 6, wherein the first and second solvents are the same or different.   13. The method 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.   13. The method 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.   14. The method of claim 13, wherein the amount of the first solvent is sufficient to dissolve the crude bicalutamide.   The method of claim 6, wherein the second solvent is a poor solvent.   14. The method of claim 13, wherein the first solvent: second solvent system is DMF: water.   14. The method of claim 13, wherein the amount of the first solvent is sufficient to dissolve the crude bicalutamide.   14. The method of claim 13, wherein the second solvent is added in an amount sufficient to provide at least partially non-solubilized bicalutamide.   20. The method of claim 19, further comprising adding an amount of the first solvent sufficient to dissolve at least the unsolubilized bicalutamide after the addition of the second solvent.   The method of claim 13, wherein the first solvent is ethanol and the second solvent is water.   The method of claim 21, wherein the temperature sufficient to effect crystallization of the bicalutamide is about 25 ° C. (I) mixing the crude bicalutamide and the first solvent; wherein the first solvent is a poor solvent;
(Ii) adding a second solvent to the crude bicalutamide-first solvent mixture;
(Iii) crystallizing bicalutamide from the solvent; and
(Iv) recovering the bicalutamide crystals,
A method for the purification and isolation of bicalutamide, comprising:   24. The method 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.   24. The method of claim 23, wherein the first solvent is water and the second solvent is selected from the group consisting of acetone and THF.   24. The method of claim 23, wherein the first is methanol and the second solvent is selected from the group consisting of acetone, THF, and DMF.   24. The method of claim 23, wherein the first is ethanol and the second solvent is selected from the group consisting of THF, DMF, and isobutyl methyl ketone.   24. The method of claim 23, wherein the second solvent is added in an amount sufficient to dissolve bicalutamide.   24. The method of claim 23, further comprising heating the bicalutamide solution formed in step (i) to approximately the boiling point of the solvent.   30. The method of claim 29, wherein the addition of the second solvent is performed under reflux conditions.   24. The method of claim 23, wherein the crystallization step comprises cooling the bicalutamide solution to a temperature sufficient for crystallization of bicalutamide to occur.   32. The method of claim 31, wherein the crystallization step comprises seeding a bicalutamide solution.   The method of claim 32, wherein the temperature sufficient to effect crystallization of bicalutamide is 25 ° C.