WO2009087666A2

WO2009087666A2 - An improved process for production of bicalutamide useful in the treatment of prostate cancer

Info

Publication number: WO2009087666A2
Application number: PCT/IN2008/000820
Authority: WO
Inventors: Raja Rao Kudaravalli; Muralidhar Rambathri
Original assignee: Kekule Pharma
Priority date: 2008-01-04
Filing date: 2008-12-08
Publication date: 2009-07-16
Also published as: WO2009087666A3

Abstract

The invention relates to an improved process for production of Bicalutamide useful in the treatment of prostate cancer by oxidizing N[4-Cyano-3-trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydroxy-2-methyl propanamide with Hydrogenperoxide in the presence of ethylacetate as solvent, methanesulfonic acid and sodiumtungstate as catalysts, washing the reaction mixture with sodiumthiosulphate solution or sodium metabisulphite solution, charcolising and evaporating the reaction mixture adding hydrocarbon solvent, cooling to room temperature and filtering.

Description

COMPLETE SPECIFICATION

AN IMPROVED PROCESS FOR PRODUCTION OF BICALUTAMJDE USEFUL IN THE TREATMENT OF PROSTATE CANCER

KEKULE PHARMA LIMITED, a company registered under the Indian Company's Act 1956, having its registered office located at A-4, Madhura Nagar Colony, S. R. Nagar Post, Hyderabad - 500038, Andhra Pradesh, India.

The following specification particularly describes the nature of this invention and the manner in which it is to be performed.

Field of the invention

The present invention relates to an improved process for production of Bicalutamide. The Bicalutamide prepared by the process of the present invention is, a Propanamide derivative namely N-[4-Cyano-3-(trifluoroniethyl)phenyl]-3-[(4-fluorophenyl)sulphonyl] -2-hydroxy-2- methyl propanamide represented by the formula [I] given below

I

Bicalutamide is pharmaceutically active compound possessing anti androgenic activity useful in the treatment of prostrate cancer. Bicalutamide, the pharmaceutical product is approved worldwide under the brand name Casodex (Astra Zeneca).

Background of the invention

Bicalutamide is the generic name for the compound N-[4-Cyano-3-{trifluoromethyJ) phenyJJ-3- [(4-fluorophenyl)sulphonyl]-2~hydroxy-2-methyl propanamide represented by the formula [I].

Bicalutamide and related acylanilides have been disclosed in EP 100172 and corresponding US 4636505 as pharmaceutically active compounds possessing anti androgenic activity useful in the treatment of prostrate cancer. Bicalutamide the pharmaceutical product is approved worldwide under the brand name Casodex (Astra Zeneca).

Several methods are known in the art for making Bicalutamide from its precursor N-[4-

Cyano-3-(trifluoromethyl)phenyl]-3-f(4-fluorophenyl)thio]-2-hydroxy-2-methyl propanamide i.e. Formula (H) given below, using different oxidizing agents.

rr

Bicalutamide has been reported to be useful as a compound having an anti androgenic action ( U.S.Pat.No.4,636,505). As a synthetic method of the compound of Bicalutamide, for example, a method comprising a reaction of Formula (II) in methylene chloride solution with m- chloroperbenzoic acid is known (Howard Tucker et al, J.Med. Chem., Vol.31, 954-959 (1988). In this method, methylene chloride is used as a solvent. Halogenated organic solvents such as methylene chloride and the /ike are generally harmful for human body, and the possibility of carcinogenicity thereof has been suggested. Furthermore, they may produce dioxin during waste treatments. Halogenated organic solvents such as methylene chloride and the like are associated with the problems of economic burden for the cost of waste treatment after use, and of corrosion of incinerator used for the waste treatment.

WO035392Q claims oxidation process of Formula (If) using H₂U₂ / Sodium tungstate / Phenyl phosphoric acid / TBAB / Ethyl acetate. When aqueous hydrogen peroxide is employed as oxidizing agent, the oxidation reaction requires that it be carried out in the presence of sodium tungstate, phenyl phosphonic acid and phase transfer catalyst with at least up to 20 fold excess of hydrogen peroxide employed at reflux temparature. Use of such large excess of hydrogen peroxide at reflux temparature makes the process not particularly safe.

EP0100172, WO134563, WO2100339 and Tucker et al in J. Med. Chem. 954-959 disclose the oxidation of Formula (II) using m-chloroperbenzoic acid (MCPBA) in chlorinated solvent, which requires 18 hours for reaction. Thus the process disclosed in the prior art involves the used of costly reagents and chlorinated solvents. Chlorinated solvents are known to be harmful to humans with a suggested possibility of being carcinogenic and also produce dioxin during disposal. Further solvents like CH₂Cb involves higher cost of disposal due to corrosion during incineration. Further the chemical risk reduction policy, "Green Chemistry" is gaining attention and industrially feasible environment friendly chemical reactions (avoiding, as far as possible the use of harmful chemicals and developing reactions which do not as far as possible discharge these) are becoming an essential feature in research. The above mentioned reaction using CH₂Cl₂ as organic solvent is from this point of view not suited for the method of preparation of the desirable Bicalutamide.

Besides being an expensive reagent, MCPBA is a highly explosive material and therefore not desirable industrially.

Synthesis of Bicalutamide without the use of MCPBA is published in WO 0100608. According to this a solution of H₂O₂ is used as oxidizing agent and the compound is oxidized in acetic or formic acid for conversion of Formula (II) to Bicalutamide. However in this method, both polar and non-polar impurities are formed which is not reduced during purification. Further this method also has a step involving use of halogenated organic solvent (e.g. 1,1,1-trichloroethane) for the synthesis of Bicalutamide and so cannot be considered environmental friendly.

Bicalutamide synthesis is aiso reported in WO0224638. According to this method, H₂O₂ is added to compound of Formula (II) and the mixture after cooling to -55⁰C, anhydrous trifluoro acetic acid (TFA) is added to the mixture to get Bicalutamide. But in this method the use of explosive TFA as reagent and the need for cooling during the addition of TFA makes the method uneconomical. Further anhydrous TFA is corrosive and hygroscopic.

Therefore there is a need to provide an improved process for the synthesis of Bicalutamide in high purity and high yield, using inexpensive, non-hazardous and easily available oxidizing agent to make the process environmentally safe and economical .

Objectives of the Invention:

Therefore the main objective of the present invention is to provide an improved, process for the preparation of Bicalutamide useful in the treatment of prostate cancer which is industrially viable and cost effective. Another objective of the present invention is to provide an improved process for the preparation of Bicalutamide useful in the treatment of prostate cancer in a purity of 97% and yield of ~65%.

Yet another objective of the present invention is to provide an improved process for the preparation of Bicalutamide useful in the treatment of prostate cancer which is clean and neat and having less pollution, thereby making it environmentally safe.

Summary of the invention

Accordingly the present invention provides an improved^process for the preparation of of N-[4- Cyano-3-(trifluoromethyl)phenyl]-3-[(4-f!uorophenyl)su]phony^]]-2-hydroxy-2-methyl propanamide (Bicalutamide) of the formula I useful in the treatment of prostate cancer

I which comprises (i) oxidizing N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluoropheπyl)thio]- 2-hydroxy-2-methyl propanamide of the formula II

Il with Hydrogenperoxide in the presence of ethylacetate as solvent methanesulfonic acid and sodiumtungstate as catalysts at a temperature in the range of 1O⁰C to 6O⁰C, (ii) washing the reaction mixture with sodiumthiosulphate solution or sodium metabisulphite solution to neutralize unreacted Hydrogenperoxide & water , (iii) charcolising the reaction mixture , (iv) evaporating the reaction mixture adding a hydrocarbon solvent and (v) cooling to room temperature and filtering to get Bicalutamide of the formula I

Detailed Description

The present invention describes a process for preparing N-[4-Cyano-3-(trifluoromethyl)phenyl]- 3-[(4-fluorophenyl)sulphonyl]-2-hydroxy-2-methylpropanamide of formula (I), known as Bicalutamide.

The N-^-Cyano-S^trifluoromethy^phenyll-S-^-fluorophenyOsulphonyll^-hydroxy-Z- methyl propanamide of formula (I) prepared by oxidation of N-[4-Cyano-3- (trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydroxy-2-methyl propanamide of Formula (II) with Hydrogen peroxide. Stoichiometric ratio of the substrate to Hydrogenperoxide may be used . P)referably 1:1.5, more preferably 1:1.25 and most preferably 1:1.15 molar ratios may be used to complete the reaction. The reaction is preferably carried out at temperature more preferably between 20⁰C to 5O⁰C and most preferably between 25⁰C to 32⁰C. Hydrogen peroxide is preferably added in about 1 hr. The reaction requires preferably 4 to 10 hrs at about 25 to 32°C for completion. The reaction is complete when unreacted N-[4-Cyano-3-

(trifluoromethyI)phenyI]-3-[(4-fluorophenyl)sulphinyl]-2-hydroxy-2-methyl propanamide in the reaction mixture is less than 0.5% by HPLC. The reaction mixture is washed with sodiumthiosulphate solution or sodium metabisulphite solution to nullify unreacted Hydrogen peroxide, water and charcolised. The resulting reaction mixture is evaporated and added Isopropyl ether or t-Butylmethyl ether or n-Hexane or Toluene, cooled to 25 to 3O⁰C and isolated the product by filtration. The obtained Bicalutamide of Formula (I) has high purity i.e. at least 99.5% as measured by HPLC.

HPLC Chromatographic conditions rLiquid Chromatography equipped with variable wavelength Detector and integrator. HPLC column: Inertsil ODS-2 Cl 8 ( 250mm x 4.6 mm x 5um), Detector wave!ength:270 ran, Flow rate :1.0 ml/ min,Buffer solution .Transfer accurately 2.72 gm of KH2PO4 into graduated glass stoppered cylinder containing 650ml of HPLC Grade water, stopper the cylinder and shake well to dissolve the substance, adjust the pH to 2.8 with H3PO4, Mobile phase :Mix 50 volume of Buffer and 50 volume of Acetonitrile (HPLC grade).

The product Bicalutamide was also obtained in good yield i.e. about 98.0% with respect to the N- [4-Cyano-(3-trifluoromethy))phenyl]-3-[(4-fl uorophenyl)thio]-2-hydroxy-2 -methyl propaπamide.

The details of the invention are given in the Examples given below which are provided to illustrate the invention only and there fore should not be construed to limit the scope of the onvention.

Example 1.

Charged Ethyl Acetate 720 It into 1.6 kl Glasslined reactor,add Methanesulfonic acid 1.2 kg,Sodiumtungstatel.2 kg and N-[4-Cyano-(3-trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]- 2-hydroxy-2-methyi propanamide 60 kg at 30±5°C. Added Hydrogen peroxide(50%) 12 It at 25- 32°C.Maintain for 6 hours at 25-32°C.Checked HPLC for Bicalutamide purity in reaction mass minimum up to 99.5%. If HPLC did not comply this condition the mixture is maintained further at 25-32°C.After completion of the reaction charged Sodium thio sulphate solution ,stirred to 30±5min,settled for 3O±5min and separated the Aq.layer. Washed with organic layer with Sodium Bicarbonate Solution,Sodium Chloride solution and DM Water .Distilled out Ethyl Acetate, mass temperature at below 8O⁰C, applied vacuum and distilled out Ethyl Acetate completely upto 8O0C.C00I to 50-55°C,charged IsoPropylEther 20 It ,cooled to 3O±5°C .Filtered the mass and washed with Isopropyl ether and dried the material at 65±5°C to get Bicalutamide 64 kg. Yield - 98%. HPLC Purity 99.8%.

Example 2.

Charged Ethyl Acetate 720 It into 1.6 kl Glasslined reactor,add Methanesulfonic acid 1.2 kg,Sodiumtungstatel.2 kg and N-[4-Cyano-(3-trifluoroinethyl)phenylJ-3-f(4-fluorophenyl)thio]- 2-hydroxy-2-methyl propanamide 60 kg at 30±5°C. Added Hydrogen peroxide(50%) 12 U at 25- 32°C.Maintained for 9 hours at 25-32⁰C. Checked HPLC for Bicalutamide purity in reaction mass minimum up to 99.5%.If HPLC did not comply this condition the mixture is maintained further at 25-32⁰C. After completion of the reaction charged Sodium thio sulphate solution .stirred to 3O±5min,settled for 30±5min and separated the Aq.layer. Washed the organic layer with Sodium Bicarbonate Solution,Sodium Chloride solution and DM Water .Distilled out Ethyl Acetate, mass temperature at below 80⁰C, applied vacuum and distilled out Ethyl Acetate completely upto SO⁰CCoOl to 50-55°C,charge Touene 20 It .cooled to 30-fc5°C .Filtered the mass and wash with t- Butyl methylether and dried the material at 65±5°C to get Bicalutamide 64 kg. Yield -9« %. HPLC Purity 99.7%.

Example 3.

Charged Ethyl Acetate 720 It into 1.6 kl Glasslined reactor,add Methanesulfonic acid 1.2 kg,Sodiumtungstatel.2 kg and N-[4-Cyano-(3-trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]- 2-hydroxy-2-methyl propanamide 60 kg at 30±5°C.Added Hydrogen peroxide(50%) 12 It at 25- 32°C.Maintain for 5 hours at 25-32°C.Checked HPLC for Bicalutamide purity in reaction mass minimum up to 99.5%.If HPLC did not comply this condition the mixture is maintained further at 25-32°C.After completion of the reaction charged Sodium thio sulphate solution ,stired to 30±5min,settle for 30±5min and separated the Aq.layer. Washed the organic layer with Sodium Bicarbonate Solution,Sodium Chloride solution and DM Water .Distilled out Ethyl Acetate, mass temperature at below 8O⁰C, applied vacuum and distilled out Ethyl Acetate completely upto 80°C.Cooled to 50-55°C,charged Toluene 20 It ,cool to 30±5°C .Filtered the mass and washed with n-Hexane and dried the material at 65±5°C to get Bicalutamide 64 kg. Yield -98%. HPLC Purity 99.8%.

Advantages of the Invention:

1. The process is simple, cost effective, clean and neat having less pollution thereby making it environmentally safe.

2. The reactions in the process are easily controllable and hence the process is useful for industrial scale production of Bicalutamide.

3. The process produces Bicalutamide in a purity greater than 99.5% and yield greater than 98.0%.

Claims

Claims:

1. An improved process for the preparation of of N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4- fluorophenyl)sulphonyl]-2-hydroxy-2-methyl propanamide (Bicalutamide) of the formula I

which comprises (i) oxidizing N-[4-Cyano-3-(trifluoromethyI)phenyl]-3-[(4-fluorophenyl)thio]- 2-hydroxy-2-methyl propanamide of the formula II

II with Hydrogenperoxide in the presence of ethylacetate as solvent, methanesulfonic acid and sodiumtungstate as catalysts at a temperature in the range of 1O⁰C to 60⁰C, (ii) washing the reaction mixture with sodiumthiosulphate solution or sodium metabisulphite solution to neutralize unreacted Hydrogenperoxide & water (iii), charcolising the reaction mixture, (iv) evaporating the reaction mixture adding hydrocarbon solvent and cooling to room temperature and (v) filtering to get Bicalutamide of the formula 1.

2. An improved process as claimed in claim 1 wherein Hydrogen peroxide is used in slightly excess molar equivalents with respect to Formula (II), preferably in the range 1:1.5, more preferably 1 : 1.25 and most preferably 1 :1.15 molar ratios are used.

3. An improved process as claimed in claims 1 & 2 wherein the purity of Hydrogen peroxide used preferably is of 3 - 90%,n>ore preferably 30%,most preferably 50%.

4. A process as claimed in claims 1 to 3, wherein Hydrogen peroxide is added at preferably at temperature preferably between 2O⁰C to 5O⁰C and most preferably between 25⁰C to 32⁰C.

5. A process as claimed in claim 1 to 4, wherein the amount of sodium tungstate to be used is 0.5 - 5 mol % of the compound represented by the formuia U.

6. A process as claimed in claims I to 5, wherein the amount of Methanesuffonic acid to be used is 0.5 - 5 mol % of the compound represented by the formula II.

7. A process as claimed in claims 1 to 6 wherein the hydrocarbon solvent used is selected from Isoρropyletheτ,t-Butyi methytether, n-Hexane and Toluene.

8. An improved process for the preparation of of N-[4-Cyano-3-(trifiuoromethyl)phenyI]-3-[(4- fluorophenyl)suIphonyl]-2-hydroxy-2-methyl propanamide(Bicalutamide) of the formula I useful in the treatment of prostate cancer substantially as herein described with reference to the Examples.