WO2004039769A1 - A process for the production of highly pure n-(4-cyano-3trifluoromethylphenyl)-3-(4-fluorophenylthio)-2-hydroxy-2methylpropanamide - Google Patents
A process for the production of highly pure n-(4-cyano-3trifluoromethylphenyl)-3-(4-fluorophenylthio)-2-hydroxy-2methylpropanamide Download PDFInfo
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- WO2004039769A1 WO2004039769A1 PCT/PL2003/000112 PL0300112W WO2004039769A1 WO 2004039769 A1 WO2004039769 A1 WO 2004039769A1 PL 0300112 W PL0300112 W PL 0300112W WO 2004039769 A1 WO2004039769 A1 WO 2004039769A1
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- Prior art keywords
- methylpropanamide
- cyano
- hydroxy
- trifluoromethylphenyl
- fluorophenylthio
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
Definitions
- the invention relates to a process for the production of highly pure N- (4-cyano-3-trifluoromethylphenyl) -3- (4- fluorophenylsulfonyl) -2-hydroxy-2-methylpropanamide by oxidation of N- (4-cyano-3-trifluoromethylphenyl) -3- (4- fluorophenylthio) -2-hydroxy-2-methylpropanamide .
- N- (4-cyano-3-trifluoromethylphenyl) -3- (4-fluorophenylsulfonyl) -2 -hydroxy-2-methylpropanamide (formula 1) is known under the name Bicalutamide . This compound displays antiandrogenic activity and is used for the therapy of prostate cancers .
- the last step of the synthesis comprises an oxidation reaction of N- (4-cyano-3- trifluoromethylphenyl) -3- ( -fluorophenylthio) -2-hydroxy-2- methylpropanamide (formula 2) , which is called therein "the sulfide” , to N- (4-cyano-3-trifluoromethylphenyl) -3- (4- fluorophenylsulfonyl) -2-hydroxy-2-methylpropanamide, that is "the sulfone” .
- the sulfone is obtained by oxidation of the sulfide with m-chloroperbenzoic acid (MCPBA) .
- MCPBA m-chloroperbenzoic acid
- This method although it proved to be reliable on a laboratory scale, it also has been associated with essential drawbacks upon scaling-up.
- the reagent used for the oxidation reaction is highly explosive. The transportation of larger amounts of this reagent is seriously hazardous, as is its handling. Moreover, it is a very expensive reagent.
- Alternative means for the oxidation of the sulfide to the sulfone are described in the application WO 01/00608.
- One group of the described methods is based on the use of a 30% aqueous solution of hydrogen peroxide as the oxidant .
- This method include carrying out the oxidation reaction in the presence of a C ⁇ - 4 -aliphatic carboxylic acid, in an aqueous alkaline medium in the presence of an organic, miscible with water solvent (C ⁇ _ -alcohol and/or acetonitrile) or in a solvent immiscible with water.
- a phase transfer catalyst has been used together with a salt of a metal from the vanadium or the chromium group.
- Bicalutamide is practically insoluble in water (5g/l000mL, at 37°C) .
- Equally slightly soluble in water is the sulfoxide formed as an intermediate during the oxidation of the sulfide to the sulfone.
- Running the oxidation reaction in a homogeneous aqueous system, at the concentrations optimal for a typical industrial process, can result in a premature precipitation of the sulfone together with the unreacted intermediate, sulfoxide.
- the sulfoxide content in the final sulfone product may reach 1-2%, which is substantially above the standard impurity level allowed for pharmaceutical substances.
- the complex of hydrogen peroxide with urea is an inexpensive and safe reagent, produced on an industrial scale.
- the known applications of this complex inter alia include its use as a detergent-improving additive.
- the optimal rate of the N- (4-cyano-3-trifluoromethyl-phenyl) -3- (4-fluorophenylthio) -2-hydroxy-2-methylpropanamide oxidation reaction is ensured not only by appropriate temperature, but also by appropriate reaction medium, which is a mixture of a C ⁇ - 4 -ca ' rboxylic acid and an organic solvent.
- reaction medium which is a mixture of a C ⁇ - 4 -ca ' rboxylic acid and an organic solvent.
- the sulfide in such medium is oxidized to the sulfone at a rate sufficient for bicalutamide to precipitate from solution only after the intermediate sulfoxide reacted completely, which affords bicalutamide containing only minimal amounts of impurities .
- a suitable reaction medium is a mixture of an organic acid and an organic solvent, in which from about 1 to about 5 parts by volume of a carboxylic acid are used for each one part by volume of the organic solvent .
- organic solvents are solvents miscible with water, preferably chosen from a group comprising, inter alia: tetrahydrofuran, dioxane, acetonitrile, C ⁇ - 4 -alcohol, acetone, butanone, formamide, N,N-dialkylformamide, piperidone, N-alkylpiperidone, pyrrolidone, and sulfolane.
- a particularly preferred reaction medium is a mixture of formic acid and tetrahydrofuran.
- the process of the present invention is not disturbed by addition of the acid' containing up to 15-20 wt . % of water.
- the degree of dilution of the reaction mixture is another important parameter of the process of the present invention.
- the reaction runs most efficiently when 1 part by weight of the substrate N- (4-cyano-3-trifluoromethylphenyl) - 3- (4-fluorophenylthio) -2-hydroxy-2-methylpropanamide is used with from about 3 to about 20 parts by volume of the solvents .
- UHP is used in an amount at least stoichiometric to the substrate sulfide, and preferably about 2-4 mol equivalents of UHP are used for one mol of N- ( -cyano-3-trifluoromethylphenyl) -3- (4-fluorophenylthio) -2-hydroxy-2- methylpropanamide .
- N- (4-cyano-3-trifluoromethylphenyl) -3- (4-fluorophenylthio) -2- hydroxy-2-methylpropanamide is dissolved in an organic solvent at room temperature, the organic acid is added, followed by the UHP complex added in one or a few portions, while maintaining the temperature of the reaction mixture at 25-40°C.
- the crude product is isolated from the reaction system simply by diluting the reaction mixture with water and filtering the product.
- the impurities present in the crude product obtained do not exceed 0.1-0.3 wt.%, and therefore the product essentially does not require further purification.
- the crude precipitate may be subjected to a single crystallization from an acetone-water mixture, in order to remove particulate impurities.
- the yields of pure product are over 90%, preferably over 95%.
- simultaneous application of the urea-hydrogen peroxide complex and a carboxylic acid for the oxidation reaction allows to eliminate the risks associated with handling explosive oxidation reagents, it is more economical and it does not generate the environmentally noxious and difficult to dispose of m-chlorobenzoic acid.
- the process of the present invention also makes it possible to eliminate the problems associated with introduction of water into the reaction system. As a consequence, the pharmaceutical substance is obtained with high degree of purity and without a need for additional purification.
- the present invention is illustrated by the following, non-limiting examples.
Abstract
N-(4-Cyano-3-trifluoromethylphenyl)-3-(4fluorophenylsulfonyl)-2-hydroxy-2-methylpropanamide of high purity is produced by oxidation of N-(4-cyano-3trifluoromethylphenyl)-3-(4-fluorophenylthio)-2-hydroxy-2methylpropanamide, using urea-hydrogen peroxide complex (UHP), in a mixture of a C1_4-carboxylic acid and an organic solvent, as the oxidizing reagent. N-(4-Cyano-3-trifluoromethylphenyl)-3-(4fluorophenylsulfonyl)-2-hydroxy-2-methylpropanamide is a known antiandrogen.
Description
A PROCESS FOR THE PRODUCTION OF HIGHLY PURE N- (4-CYANO-3- TRIFLUOROMETHYLPHENYL) -3- (4-FLUOROPHENYLSULFONYL) -2-HYDROXY- 2-METHYLPROPANAMIDE
The invention relates to a process for the production of highly pure N- (4-cyano-3-trifluoromethylphenyl) -3- (4- fluorophenylsulfonyl) -2-hydroxy-2-methylpropanamide by oxidation of N- (4-cyano-3-trifluoromethylphenyl) -3- (4- fluorophenylthio) -2-hydroxy-2-methylpropanamide . N- (4-cyano-3-trifluoromethylphenyl) -3- (4-fluorophenylsulfonyl) -2 -hydroxy-2-methylpropanamide (formula 1) is known under the name Bicalutamide . This compound displays antiandrogenic activity and is used for the therapy of prostate cancers . European patent EP 0 100 172; J". Med. Chem. 31 , 885-887 (1988) ; and International Patent Application WO 01/00608 all describe a number of methods for preparation of bicalutamide, either in the racemic form or in the form of each of the separate enatiomers. In all these methods, and independently of the substrate used, the last step of the synthesis comprises an oxidation reaction of N- (4-cyano-3- trifluoromethylphenyl) -3- ( -fluorophenylthio) -2-hydroxy-2- methylpropanamide (formula 2) , which is called therein "the sulfide" , to N- (4-cyano-3-trifluoromethylphenyl) -3- (4- fluorophenylsulfonyl) -2-hydroxy-2-methylpropanamide, that is "the sulfone" .
According to the approach presented in EP 0 100 172 and J. Med. Chem. 31 , 954-959 (1988) , the sulfone is obtained by oxidation of the sulfide with m-chloroperbenzoic acid (MCPBA) . This method, although it proved to be reliable on a laboratory scale, it also has been associated with essential drawbacks upon scaling-up. The reagent used for the oxidation reaction is highly explosive. The transportation of larger amounts of this reagent is seriously hazardous, as is its handling. Moreover, it is a very expensive reagent. Alternative means for the oxidation of the sulfide to the sulfone are described in the application WO 01/00608.
One group of the described methods is based on the use of a 30% aqueous solution of hydrogen peroxide as the oxidant . Different variations of this method are possible, which include carrying out the oxidation reaction in the presence of a Cι-4-aliphatic carboxylic acid, in an aqueous alkaline medium in the presence of an organic, miscible with water solvent (Cι_ -alcohol and/or acetonitrile) or in a solvent immiscible with water. In the latter case, a phase transfer catalyst has been used together with a salt of a metal from the vanadium or the chromium group.
Other inorganic peroxy salts, such as Oxone" (2KHS05-KHS04-K2S04) have also been proposed. Different variations of the method comprise running the reaction in a mixture of water and a miscible with water solvent or a
solvent immiscible with water, in the presence of a phase transfer catalyst .
Even though the methods for the oxidation of the sulfide to the sulfone, as presented in the application WO 01/00608, all make it possible to avoid the difficulties associated with the use of m-chloroperbenzoic acid, they are, however, not free from drawbacks.
Bicalutamide is practically insoluble in water (5g/l000mL, at 37°C) . Equally slightly soluble in water is the sulfoxide formed as an intermediate during the oxidation of the sulfide to the sulfone. Running the oxidation reaction in a homogeneous aqueous system, at the concentrations optimal for a typical industrial process, can result in a premature precipitation of the sulfone together with the unreacted intermediate, sulfoxide. The sulfoxide content in the final sulfone product may reach 1-2%, which is substantially above the standard impurity level allowed for pharmaceutical substances. This impurity is exceptionally difficult to remove, due to similar physicochemical properties of the^ sulfoxide and the sulfone. Thus, the access to a substance of pharmaceutical purity requires repeated crystallizations of the crude product, which procedure not always is effective.
On the other hand, running the reaction in a heterogeneous system necessitates the use of phase transfer
catalysts and rapid stirring of the reaction mixture, which determines the rate of the process .
The yields reported in the examples illustrating the application WO 01/00608 only rarely exceed 85%. We have found that the above mentioned difficulties are overcome in the process of the present invention, according to which a solution of urea-hydrogen peroxide complex (UHP) in a mixture with a C1.4-carboxylic acid and an organic solvent is used as the agent oxidizing N- (4-cyano-3- trifluoromethylphenyl) -3- ( -fluorophenylthio) -2-hydroxy-2- methylpropanamide to N- (4-cyano-3-trifluoromethylphenyl) -3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methylpropanamide . The complex of hydrogen peroxide with urea [urea- hydrogen peroxide complex, H202»CO (NH2) 2] is an inexpensive and safe reagent, produced on an industrial scale. The known applications of this complex inter alia include its use as a detergent-improving additive.
According to the process of the present invention, the optimal rate of the N- (4-cyano-3-trifluoromethyl-phenyl) -3- (4-fluorophenylthio) -2-hydroxy-2-methylpropanamide oxidation reaction is ensured not only by appropriate temperature, but also by appropriate reaction medium, which is a mixture of a Cι-4-ca'rboxylic acid and an organic solvent. The sulfide in such medium is oxidized to the sulfone at a rate sufficient for bicalutamide to precipitate from solution only after the
intermediate sulfoxide reacted completely, which affords bicalutamide containing only minimal amounts of impurities .
According to the process of the present invention, a suitable reaction medium is a mixture of an organic acid and an organic solvent, in which from about 1 to about 5 parts by volume of a carboxylic acid are used for each one part by volume of the organic solvent .
According to the process of the present invention, especially suitable organic solvents are solvents miscible with water, preferably chosen from a group comprising, inter alia: tetrahydrofuran, dioxane, acetonitrile, Cι-4-alcohol, acetone, butanone, formamide, N,N-dialkylformamide, piperidone, N-alkylpiperidone, pyrrolidone, and sulfolane. A particularly preferred reaction medium is a mixture of formic acid and tetrahydrofuran.
Even though the application of anhydrous formic acid is most beneficial for high purity of the final product, the process of the present invention is not disturbed by addition of the acid' containing up to 15-20 wt . % of water. The degree of dilution of the reaction mixture is another important parameter of the process of the present invention. The reaction runs most efficiently when 1 part by weight of the substrate N- (4-cyano-3-trifluoromethylphenyl) - 3- (4-fluorophenylthio) -2-hydroxy-2-methylpropanamide is used
with from about 3 to about 20 parts by volume of the solvents .
UHP is used in an amount at least stoichiometric to the substrate sulfide, and preferably about 2-4 mol equivalents of UHP are used for one mol of N- ( -cyano-3-trifluoromethylphenyl) -3- (4-fluorophenylthio) -2-hydroxy-2- methylpropanamide .
According to the process of the present invention, N- (4-cyano-3-trifluoromethylphenyl) -3- (4-fluorophenylthio) -2- hydroxy-2-methylpropanamide is dissolved in an organic solvent at room temperature, the organic acid is added, followed by the UHP complex added in one or a few portions, while maintaining the temperature of the reaction mixture at 25-40°C. The crude product is isolated from the reaction system simply by diluting the reaction mixture with water and filtering the product.
The impurities present in the crude product obtained do not exceed 0.1-0.3 wt.%, and therefore the product essentially does not require further purification. Optionally, the crude precipitate may be subjected to a single crystallization from an acetone-water mixture, in order to remove particulate impurities. The yields of pure product are over 90%, preferably over 95%.
According to the process of the present invention, simultaneous application of the urea-hydrogen peroxide complex and a carboxylic acid for the oxidation reaction
allows to eliminate the risks associated with handling explosive oxidation reagents, it is more economical and it does not generate the environmentally noxious and difficult to dispose of m-chlorobenzoic acid. The process of the present invention also makes it possible to eliminate the problems associated with introduction of water into the reaction system. As a consequence, the pharmaceutical substance is obtained with high degree of purity and without a need for additional purification. The present invention is illustrated by the following, non-limiting examples.
EXAMPLE 1
N- (4-cyano-3-trifluoromethylphenyl) -3- (4- fluorophenylthio) -2-hydroxy-2-methylpropanamide (3.93 g,
9.86 mmol) was dissolved in tetrahydrofuran (7 mL) and 85% formic acid (33 mL) was added. UHP (3.72 g, 39.5 mmol) was then added with stirring and cooling, while the temperature was maintained at 27-35°C. After 1 hour, cooling was stopped and the reaction mixture, with continued stirring, was left at room temperature overnight. Water (450 mL) was then added, the precipitate was filtered, washed with water until the filtrate was neutral, and dried. This afforded the sulfone (4.1 g; 96%), containing 0.08% of the sulfoxide (according to HPLC) ; m.p.: 189-191°C; elemental analysis for
C18H14N2O4SF4 calc: (%) C 50.23, H 3.28, N 6.51, S 7.45, F 17.66; found: (%) C 50.24, H 3.01, N 6.70, S 7.41, F 17.82; IR (KBr) , cm"1: 3580, 3485, 3338, 3114, 2991, 2230, 1690, 1592, 1516, 1329, 1132, 1053, 841, 578; XH-NMR (200 MHz), δ: 1.42 (s, 3H) , 3.73, 3.97 (AB, 2H, 2J= 14.7 Hz), 6.43 (s,
1H) , 7.33-7.43 (m, 2H) , 7.90-8.13 (m, 2H) , 8.10 (d, 1H, Jlι 2= 8.6 Hz), 8.23 (dd, 1H, J2,ι= 8.6 Hz, J2,3<= 2 Hz), 8.44 (d, 1H, J3/2« 2 Hz), 10.40 (bs, 1H) . EXAMPLE 2 N- (4-cyano-3-trifluoromethylphenyl) -3- (4- fluorophenylthio) -2-hydroxy-2 -methylpropanamide (5 g, 12 mmol) was dissolved in ethanol (12 g) and 100% formic acid (40 g) was .added. UHP (3.0 g, 36 mmol) was then added in small portions over the period of 1 hour, while the temperature was maintained at 25-35°C. The mixture was stirred for 1 additional hour, water (60 mL) was then added, the product thus precipitated was filtered and washed with water. This gave the sulfone (4.9 g, 90%). Example 3 Following a procedure analogous to the one described in Example 2, but using instead dimethylformamide (10 mL) and 90% formic acid (40 g) , the sulfone was obtained in a 92% yield.
Claims
1. A process for the production of highly pure N- (4-cyano- 3-trifluoromethylphenyl) -3- (4-fluorophenyl-sulfonyl) -2- hydroxy-2-methylpropanamide by oxidation of N- (4-cyano-3- trifluoromethylphenyl) -3- (4-fluorophenylthio) -2-hydroxy-2- methylpropanamide, characterized in that the oxidizing reagent is urea-hydrogen peroxide complex (UHP) used in a mixture of a Cι-4-carboxylic acid and an organic solvent.
2. A process according to claim 1, characterized in that an organic, miscible with water solvent is used.
3. A process according to claim 2, characterized in that the organic solvent is chosen from a group comprising tetrahydrofuran, dioxane, acetonitrile, Cι-4-alcohol, acetone, butanone, formamide, N,N-dialkylformamide, piperidone, N-alkylpiperidone, pyrrolidone, and sulfolane.
4. A process according to claims 1 or 2, characterized in that from about 1 to about 5 parts by volume of said carboxylic acid are used for each one part by volume of said organic solvent .
5. A process according to claim 4, characterized in that the oxidation reaction is carried out in a mixture of formic acid and tetrahydrofuran.
6. A process according to claim 1, characterized in that from about 2 to about 4 molar equivalents of urea-hydrogen peroxide complex are used for one mol of N- (4-cyano-3- trifluoromethylphenyl) -3- ( -fluorophenylthio) -2-hydroxy-2- methylpropanamide.
7. A process according to claim 1, characterized in that 1 part by weight of N- (4-cyano-3-trifluoromethylphenyl) -3- (4- fluorophenylthio) -2-hydroxy-2-methylpropanamide is used with from about 3 to about 20 parts by volume of the solvents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003285838A AU2003285838A1 (en) | 2002-10-30 | 2003-10-28 | A process for the production of highly pure n-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylthio)-2-hydroxy-2-methylpropanamide |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL356894A PL201540B1 (en) | 2002-10-30 | 2002-10-30 | Method of manufacture of high purity N-(4-cyano-3-trifluoromethyl phenylo)-3-(4-fluorophenylosulfon ylo)-2-hydroxy-2- methyl propane amide |
| PLP-356894 | 2002-10-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2004039769A1 true WO2004039769A1 (en) | 2004-05-13 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/PL2003/000112 WO2004039769A1 (en) | 2002-10-30 | 2003-10-28 | A process for the production of highly pure n-(4-cyano-3trifluoromethylphenyl)-3-(4-fluorophenylthio)-2-hydroxy-2methylpropanamide |
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| AU (1) | AU2003285838A1 (en) |
| PL (1) | PL201540B1 (en) |
| WO (1) | WO2004039769A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007013094A2 (en) * | 2005-04-15 | 2007-02-01 | Sun Pharmaceutical Industries Limited | A process for preparation of antiandrogen compound |
| EP1919863A1 (en) * | 2005-07-26 | 2008-05-14 | Apotex Pharmachem Inc. | Process for the production 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0100172A1 (en) * | 1982-07-23 | 1984-02-08 | Imperial Chemical Industries Plc | Amide derivatives |
-
2002
- 2002-10-30 PL PL356894A patent/PL201540B1/en not_active IP Right Cessation
-
2003
- 2003-10-28 WO PCT/PL2003/000112 patent/WO2004039769A1/en not_active Application Discontinuation
- 2003-10-28 AU AU2003285838A patent/AU2003285838A1/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0100172A1 (en) * | 1982-07-23 | 1984-02-08 | Imperial Chemical Industries Plc | Amide derivatives |
Non-Patent Citations (2)
| Title |
|---|
| M.S. COOPER ET AL, SYNLETT, no. 9, 1990, pages 533 - 535, XP001147750 * |
| R. BALICKI, J. PRAKT. CHEM., vol. 341, no. 2, 1999, pages 184 - 185, XP002270694 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007013094A2 (en) * | 2005-04-15 | 2007-02-01 | Sun Pharmaceutical Industries Limited | A process for preparation of antiandrogen compound |
| WO2007013094A3 (en) * | 2005-04-15 | 2007-11-01 | Sun Pharmaceutical Ind Ltd | A process for preparation of antiandrogen compound |
| EP1919863A1 (en) * | 2005-07-26 | 2008-05-14 | Apotex Pharmachem Inc. | Process for the production of bicalutamide |
| EP1919863A4 (en) * | 2005-07-26 | 2008-09-03 | Apotex Pharmachem Inc | Process for the production 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| PL356894A1 (en) | 2004-05-04 |
| PL201540B1 (en) | 2009-04-30 |
| AU2003285838A1 (en) | 2004-05-25 |
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