Title of Invention

PROCESS FOR PREPARATION OF BICALUTAMIDE

Abstract

An improved process for preparation of high purity (99.8%) bicalutamide of Formula comprising a) reacting a compound, 2-cyano-5 -amino benzotrifluoride of the formula with methacryloyl chloride of the formula in a solvent selected from N, N-dimethyl formamide, N, N dimethyl acetamide or CN HN O 'CF, II N-methyl pyrrolidone, wherein, the process step is characterized by isolating the product by slow quenching of the said reaction mass with water for 2 to 15 hrs to give a compound of the formula II as a crystalline solid directly; b) reacting the compound of formula II with m-chloroperbenzoic acid; wherein the process step is characterized by stirring the said reaction mass with a chilled solvent, such as isopropanol and isolating the compound of formula III by filtration directly; c) reacting the compound of formula III with 4-fluoro thiophenol in presence of a base, selected from alkali metal alkoxides, such as sodium t-butoxide to give a compound of formula IV and IV d) reacting the compound of formula IV with peracetic acid of a strength of 10 to 16% in a chlorinated solvent such as dichloromethane to obtain compound of the formula I with desired purity.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "PROCESS FOR PREPARATION OF BICALUTAMIDE' (a) CIPLALTD. (b) 289, Bellasis Road, Mumbai Central, Mumbai -400 008, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of the invention and the manner in which it is to be performed: 10-02-2006 Field of Invention This invention relates to a process for the manufacture of (+)-N-[4 Cyano-3(trifiuoromethyl)phenyl]-3[(4 fluoro phenyl)sulfonyl]-2 hydroxy-2 methyl propanamide (I) which is also known as bicalutamide and which is useful in the treatment of prostrate cancer. Background of the invention Preparation of Bicalutamide is mentioned in the patent No. US 4,636,505, its brief process is as shown in Scheme 1 : 2 SCHEME 1 The process disclosed in US 4636505 makes use of column chromatography in almost all stages of manufacture of bicalutamide, uses highly flammable solvents like Diethyl ether for isolation of bicalutamide and its intermediates. It also makes use of reagents like sodium hydride, which is highly hazardous on industrial scale. Use of column chromatography for bulk manufacture requires large amounts of solvents and the stationary phase is discarded after use, thus is disadvantageous in production cost. In addition, the used solvent is evaporated in large amounts into atmosphere and therefore, the column chromatography is preferably not used if possible from the viewpoint of working environment or environmental protection. Furthermore, patents US 6,479,692, US 2002/0165406AI, WO 02/088070 disclose processes that make use of n-Butylithium for the condensation step (c) of scheme 1 which is extremely reactive and a fire hazard making it disadvantageous to operate on large scale. 3 Summary of the invention The present invention discloses a process that was developed by making improvements in the reaction conditions and isolation procedures, also the use of hazardous reagents like Sodium hydride; n-Butylithium is avoided, making the process safe and operable for large-scale commercial manufacture. The invention also discloses a process that gives a product having high purity levels essentially free of the 2-cyano isomer impurity (V) and low levels of side reaction products and precursors. The product manufactured by the process of the present invention has a better intrinsic dissolution profile when compared to the product prepared from the prior art patent process. The process involves 4 steps. In the first step, 2-Cyano-5-amino benzotrifluoride is reacted with Methacryloyl chloride in N,N-Dimethyl acetamide as solvent. The product is then isolated after quenching the reaction mass in water. In the second step, N-(4-Cyano-3-trifluoromethylphenyl)-2-methyl prop-3-ene amide is reacted with m-chloro perbenzoic acid in chloroform to get N-(4-Cyano-3-trifluoromethylphenyl)-2 methyl 2,3-epoxy propionamide. In the third step, N-(4-Cyano-3-trifluoromethylphenyl) - 2-methyl-2,3-epoxy propionamide is reacted with 4-fluoro thiophenol in toluene and THF to get N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluoro phenyl) thio] - 2- hydroxy-2- methyl propionamide. In the final step N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4 fluoro phenyl)thio]-2 hydroxy-2-methyl propionamide is oxidized using Peracetic acid in methylene chloride 4 as solvent to get N-[4 Cyano-3-(trifluoromethyl)phenyl]-3 [(4 fluoro phenyl) sulfonyl]-2 hydroxy-2 methyl propionamide. Peracetic acid solution can be conveniently prepared by methods known in the art, for example by slow addition of hydrogen peroxide to acetic acid under stirring with a catalytic amount of sulfuric acid. The product is purified using acetone and hexane to give bicalutamide having uniform particle size, free-flowing powder characteristics and markedly higher intrinsic dissolution. Detailed Description of the Invention The present invention discloses a process for the manufacture of bicalutamide of a very high purity and having a dissolution profile better than that produced by processes known in the art. In a preferred aspect of the invention, a process for producing N-(4-Cyano-3-trifluoromethylphenyl)-2-methyl prop-3-ene amide (II) by the reaction of 2-cyano-5- -trifluoromethyl aniline with methacryloyl chloride is disclosed. The reaction is preferably performed in a polar aprotic solvent selected from dimethyl formamide, dimethyl acetamide or N-methyl pyrrolidone. The most preferred solvent is dimethyl acetamide and the preferred temperature for addition of methacryloyl chloride is -10 to 10°C. The improvement in the reaction is in the quenching of the reaction mass in water, preferably done slowly over a period of few hours. Depending on the scale of operation the time period required for quenching could vary from 2 hours to 15 hours. More preferably the quenching time is between 6 to 12 hours. The slow quenching of the reaction in water produces the compound (II) directly as a solid in a pure form without having to undertake cumbersome column_ purification, thus avoiding solvents such as diethyl ether and petroleum ether. In another aspect of the invention, the compound (II) is oxidized to compound of formula (III) by m-chloro perbenzoic acid. The compound (III) is initially obtained as oil. The 5 improvement consists of elimination of impurities by stirring with chilled isopropanol, for a sufficient period of time to dissolve the impurities and their removal by filtration, thus avoiding purification by column chromatography. In yet another aspect of the invention, compound (III) is reacted with 4-fluoro thiophenol in presence of a base such as an alkali metal alkoxide or hydroxide in a mixture of an ether and a hydrocarbon solvent to obtain compound (IV). The base could be selected from sodium or potassium hydroxides or t-butoxides. Preferably, sodium t-butoxide is used along with tetrahydrofuran and toluene as solvents. The compound (IV) is isolated initially as oil from which impurities are eliminated by stirring a mixture of ethyl acetate and n-hexane for a sufficient period of time to dissolve the impurities, thus avoiding purification by column chromatography. In yet another aspect of the invention, compound (IV) is oxidized to compound (I) by means of peracetic acid solution in a solvent such as dichloromethane. Peracetic acid is prepared by methods known in the art, for example, by slow addition of a 50% solution of hydrogen peroxide into a vessel containing acetic acid with a catalytic amount of sulfuric acid under stirring. The content of peracetic acid in this solution is usually between 8 to 20%, more preferably between 12 to 16%. It is surprisingly found that use of peracetic acid reduces the amount of impurity such as sulfoxide formed to very negligible extent and the reaction proceeds^ to completion, hence the content of unreacted sulfide in the product is negligible. Thus the product (I) is of sufficient purity to be obtained directly as a solid without column purification. This compares very favourably with prior art processes that yield a product having considerable amounts of the sulfide (IV) and sulfoxide (VI) impurities. Generally, in a process for making an active pharmaceutical ingredient, there are associated impurities that contaminate the product. These arise from impurities present in the starting material, or competing reactions resulting in by-products, or impurities resulting from incomplete reactions or overreacted products. Other sources are the 6 solvents used in the process that tend to get embedded in the crystal lattice and it is difficult to remove the traces of these solvents. The starting material for bicalutamide, viz., 2-cyano-5-amino benzotrifluoride is usually contaminated with the isomeric 2-cyano-3 -amino benzotrifluoride (VII). This impurity undergoes the same reactions and is present in the final product as the 2-cyano isomer (V). Till date the only method available was column purification at various stages to successively reduce the impurity, or repeated crystallizations of the final product. It has been surprisingly found that stirring intermediate (III) with chilled isopropanol and intermediate (IV) with a mixture of ethyl acetate and hexane effectively removes the corresponding isomers at those stages to acceptable limits. Thus there is provided by the process of the present invention, bicalutamide having purity by HPLC of 99.5%, more preferablyJ99.8%, having contents of the compounds of formulae VI each less than 0.1%. In yet another aspect, the invention provides a process for producing a non-hygroscopic, free-flowing, anhydrous bicalutamide produced by crystallization from acetone and hexane. The process of the present invention is illustrated by the following examples. EXAMPLE Example 1 Preparation of N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methyl prop-3-ene amide 2-Cyano-5-amino benzotrifluoride (25g) is added to N,N-dimethyl acetamide (90ml; 3.6 vols) and the contents are chilled to -5 to 0°C. Methacryloyl chloride (24g) is added at -5 to 0°C slowly in about 2-3 hours. The reaction mass is then stirred at 25-30°C for 3 hours. The mass is quenched into water (350ml; 30 vols) slowly at 25 - 30°C over a period of 10 hours. After quenching, the reaction mass is stirred for 1 hour and filtered. The product is washed with water until the pH of washings is 6.5 - 7.0 The product is dried at 50 - 55°C to give 32 grams of the title amide. Example 2 Preparation of N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methyl 2, 3-epoxy propionamide N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methyl prop-3-ene amide (35g) is taken in chloroform (350ml; 10 vols) and heated to 40°C. To this, m-chloro perbenzoic acid (53g) is added slowly at 40 - 45° C. After addition, the contents are heated to 60 - 65°C and maintained for 6 hours. The inorganics are filtered, washed with chloroform. The chloroform layer is then washed with 10% Sodium bicarbonate and the chloroform layer is then dried, distilled under vacuum at a temperature below 50° C to an oily mass. Isopropyl alcohol is added to the oily mass and chilled to 0 - 5° C for 5 hours. The solids 8 are filtered and washed with chilled Isopropyl alcohol (5ml). The product is then dried at 40 - 45° C to give the title epoxy compound 32 g. Example 3 Preparation of N- [4-Cyano-3-(trifluoromethyl)phenyl] -3- [(4-fluorophenyl)thio] -2- hydroxy-2-methyl propionamide. N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-methyl-2,3-epoxy propionamide (20g) is taken in tetrahydrofuran (100ml; 5 vols) and this solution is added to the mixture of 4-Fluoro thiophenol (14.1g) and Sodium t-butoxide (llg) in Toluene (100 ml) at a temperature 25 - 30° C in 60 - 90 minutes. After addition, the contents are stirred at 25 - 30° C for 1 hour. The reaction mass is quenched into water and toluene layer is separated. The toluene layer is washed with water, dried over sodium sulfate and concentrated under vacuum at temperature below 55° C to an oily mass. To this oily mass, ethyl acetate (20ml; 1 vol) and hexane (60ml; 3 vol) mixture is added and stirred at 25 - 30° C for 2 hours. The product is then filtered, washed with n-Hexane. The product is dried under vacuum to get the title thio compound 23g. Example 4 Preparation of N-[4-Cyano-3-(trifluoromethyl)phenyl)-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl propionamide (Bicalutamide). N- [4-Cyano-3 -(trifluoromethyl)phenyl] -3 - [(4-fluorophenyl)thio] -2-hydroxy-2-methyl propionamide (20g) is taken in methylene dichloride (200ml; 10 vols) and the contents chilled to -5°C. Peracetic acid (120ml; 6 vols) is then added slowly at -5 to +5°C in 2-3 hours. After addition, the contents are stirred at 25 - 30°C for 10 hours. pH of the reaction mass is adjusted to 6.5 to 7.0 using sodium hydroxide solution at 10 - 15°C. The product 9 is filtered and washed with water until the pH of the washings are in the range of 6.5 -7.0. The product is then dissolved in Acetone (200ml; 10 vols), charcoalised and clarified. The clear filtrate is distilled under vacuum at a temperature less than 45° C. Then n-Hexane (80 ml 4 vols) is added, stirred at 25 - 30° C for 1 hour, filtered and washed with n-Hexane. The product is then dried under vacuum at a temperature less than 40° C. The dried product is then stirred in Hexane at 40 - 45° C for 2 hours, filtered and washed with Hexane. The product is then dried under vacuum at a temperature less than 40° C. Example 5 Bacalutamide formulation Ingredients Qty per tablet (mg) Bicalutamide 50 Crospovidone 20 Sodium Lauryl Sulphate 10 Lactose monohydrate 61 Starch 29 Colloidal anhydrous Silica 2.5 Magnesium Stearate 1.5 Povidone 6 Opadry Y-l-7000 white 3 Purified Water q.s. Bicalutamide, crospovidone and lactose were co-sifted to form premix A. The said premix A and starch were granulated using a binder solution of povidone, sodium lauryl sulphate in water. The granules were lubricated with colloidal anhydrous silica, 10 crospovidone and magnesium stearate and compressed. The compressed tablets were coated with Opadry Y-1 -7000 white. Intrinsic dissolution Intrinsic dissolution studies were done on bicalutamide prepared by the process of the current invention compared with that made according to prior art process as described in US 4,636,505. The experiment was conducted on a USP Type II apparatus using a medium of 1000 ml of 0.5% sodium lauryl sulfate in 0.05M sodium dihydrogen phosphate at pH 7, maintained at 37.5°C and 75rpm. Samples of bicalutamide made by the current process and prior art (50 mg each) were loaded, aliquots were drawn every 15 minutes and assay was determined by ultraviolet absorption at 270nm after appropriate dilution. The results are as summarized below. Time Process of this invention Prior art process 15 mins 73.9% 45.0% 30 mins. 83.0% 50.2% 45 mins. 85.3% 52.7% 60 mins. 88.1% 53.3% While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by appended claims. 11 We Claim 1. An improved process for preparation of high purity (99.8%) bicalutamide of Formula comprising a) reacting a compound, 2-cyano-5 -amino benzotrifluoride of the formula with methacryloyl chloride of the formula in a solvent selected from N, N-dimethyl formamide, N, N dimethyl acetamide or CN HN O 'CF, II N-methyl pyrrolidone, wherein, the process step is characterized by isolating the product by slow quenching of the said reaction mass with water for 2 to 15 hrs to give a compound of the formula II as a crystalline solid directly; b) reacting the compound of formula II with m-chloroperbenzoic acid; wherein the process step is characterized by stirring the said reaction mass with a chilled solvent, such as isopropanol and isolating the compound of formula III by filtration directly; c) reacting the compound of formula III with 4-fluoro thiophenol in presence of a base, selected from alkali metal alkoxides, such as sodium t-butoxide to give a compound of formula IV and IV d) reacting the compound of formula IV with peracetic acid of a strength of 10 to 16% in a chlorinated solvent such as dichloromethane to obtain compound of the formula I with desired purity. 2. The process as claimed in claim 1, wherein the said reaction of methacryloyl chloride with 2-cyano-5-amino benzotrifluoride is preferably done in a solvent, N,N-dimethyl acetamide. 3. The process as claimed in claim 1 and 2, wherein methacryloyl chloride used is less than 1 mole equivalent with respect to 2-cyano-5-amino benzotrifluoride, preferably between 0.9 to 0.98 mole equivalents. 4. The process as claimed in claim 1, wherein the said quenching is done in preferably for 6 to 12 hours for obtaining the crystalline solid.. Dated this the 16th day of July 2004 Dr. GOPAKUMAR G. NAIR Agent for the Applicant

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724-mum-2003-cancelled pages(10-02-2004).pdf

724-mum-2003-claims (granted)-(10-02-2006).doc

724-mum-2003-claims(granted)-(10-02-2006).pdf

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724-mum-2003-form 26(05-04-2003).pdf

724-mum-2003-form 3(17-07-2003).pdf

724-mum-2003-form 5(16-07-2004).pdf