CLIAMS:Claims:

1) An improved process for the preparation of Enzalutamide of Formula (I)

(I)
comprising the steps of:
a) reacting 4-bromo-2-fluorobenzoic acid of Formula II

(II)
with a chlorinating agent in presence of a solvent in ratio between 3-8 v/w times, followed by condensation with Methylamine to yield 4-bromo-2-fluoro-N-methyl benzamide of Fomula III

(III)
b) reacting the compound of formula (III) with 2-amino isobutyric acid in presence of ligand and a solvent to give 2-(3-Fluoro-4- methylcarbamoyl-phenylamino)-2-methyl-propionic acid of Formula IV

(IV)
c) reacting the compound of Formula IV with 2-(trifluoromethyl)-4-isothiocyanato benzonitrile of Formula (V) in presence of base and a solvent to give Enzalutamide;

(V)
d) optionally, purifying Enzalutamide.

2) A process for the preparation of Enzalutamide according to claim 1, wherein chlorinating agent is selected from Oxalyl chloride, Thionyl chloride, PCl3, PCl5, POCl3.

3) A process for the preparation of Enzalutamide according to claim 1, wherein solvent in step a) is selected from halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, chloroform or mixtures thereof, in the ratio between 3-8 v/w times.

4) A process for the preparation of Enzalutamide according to claim 1, wherein ligand in step b) is selected from 2-acetyl cyclohexanone; N,N-dimethyl glycine.HCl.

5) A process for the preparation of Enzalutamide according to claim 1, wherein solvent in step b) is selected from alcohols, such as ethanol, ethylene glycols, n-butanol, isopropanol; ethers such as tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, 1,2-dimethoxy ethane; aprotic polar solvents like acetonitrile, dimethyl formamide , dimethyl sulfoxide or mixtures thereof;

6) A process for the preparation of Enzalutamide according to claim 1, wherein base is selected from inorganic or organic bases, such as triethylamine, diisoproyl ethylamine, tributyl amine, ?,?-dimethyl aniline, pyridine, N-methyl morpholine, DBN, DBU.

7) A process for the preparation of Enzalutamide according to claim 1, wherein solvent in step c) selected from ketone solvents such as acetone, methyl isobutyl ketone; acetonitrile or mixtures.

8) A process for the preparation of Enzalutamide intermediate of Formula IV comprising the steps of:
a) reacting 4-bromo-2-fluorobenzoic acid of Formula (II) with chlorinating agent in presence of a solvent, followed by condensation with Methylamine to yield 4-bromo-2-fluoro-N-methyl benzamide of Formula (III)

b) reacting the compound of formula (III) with 2-amino isobutyric acid in presence of ligand and a solvent to give 2-(3-Fluoro-4- methylcarbamoyl-phenylamino)-2-methyl-propionic acid of Formula IV

9) A process for the preparation of Enzalutamide intermediate according to claim 8, wherein chlorinating agent is selected from Oxalyl chloride, Thionyl chloride, PCl3, PCl5, POCl3 and the solvent in step a) is selected from halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, chloroform or mixtures thereof.

10) A process for the preparation of Enzalutamide intermediate according to claim 8, wherein Ligand is selected from 2-acetyl cyclohexanone, N,N-dimethyl glycine.HCl and solvent in step b) selected from alcohols, such as ethanol, ethylene glycols, n-butanol, isopropanol; ethers such as tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, 1,2-dimethoxy ethane; aprotic polar solvents like acetonitrile, dimethyl formamide , dimethyl sulfoxide or mixtures thereof.

Dated this 11th day of July, 2014

Signature:
Dr. A.K.CHATURVEDI
,TagSPECI:FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of Enzalutamide of Formula (I).

(I)

BACKGROUND OF THE INVENTION

Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors and inhibit androgen receptor nuclear translocation and interaction with DNA. A major metabolite, N-desmethyl Enzalutamide, exhibited similar in vitroactivity to Enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer xenograft model

Enzalutamide is chemical known as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylide- neimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. The structural formula of Enzalutamide is as described in Formula (I)

(I)
Prostate cancer is the most commonly diagnosed cancer among men in the United States, other than skin cancer. Prostate cancer is thus the second-leading cause of cancer death in men in the United States, after lung cancer.

Enzalutamide is a white crystalline non-hygroscopic solid with the empirical formula C21H16F4N4O2S and a molecular weight of 464.44. It is practically insoluble in water and freely soluble in NMP and acetonitrile, sparingly soluble in absolute ethanol.

Enzalutamide is achiral, therefore no stereoisomerism is observed. The pure drug substance melts at 201°C. Enzalutamide is marketed under the brand name Xtandi® as an oral capsule.

Enzalutamide is specifically disclosed in US 7709517. This patent discloses a process for the preparation of Enzalutamide starting from 2-fluoro-4-nitrotoluene, which is as demonstrated below:

US 2013/0190507 disclose different processes for the preparation of Enzalutamide starting from N-methyl-2-fluoro-4-bromobenzamide, which is demonstrated below:

The present inventors has repeated the above process and found the following disadvantages:
? In most of the patent literature, thionyl chloride is used as a chlorinating agent, in that chlorination takes place at reflux temperature, which is not feasible and cumbersome in industrial scale.
? In most of the patent literature, methylene dichloride is used as a solvent in coupling stage of 4-bromo-2-fluoro-N-methyl benzamide with 2-amino iso butyric acid, which is lowering the yield due to decomposition of product.
? Unwanted reactions are observed during the formation of Enzalutamide, due to the use of microwave irradiation at higher temperature. Further, the use of microwave irradiation at high temperature is hazardous, and industrially not feasible
? Condensation of 2-(3-Fluoro-4- methylcarbamoyl-phenylamino)-2-methyl-propionic acid methylester with 2-(trifluoromethyl)-4-isothiocyanato benzonitrile involves the use of higher temperature i.e., around 83-84°C

In view of the above and to overcome the prior-art problems the present inventors have now developed an improved process for the preparation of Enzalutamide, using minimal steps, which is industrially feasible and viable process, with the use of industrial friendly solvents, which does not include tedious work up and hazardous steps.

OBJECTIVE OF THE INVENTION

The main objective of the invention is to provide an improved process for the preparation of Enzalutamide.

Yet another objective of the invention is to provide an improved process for the preparation of Enzalutamide intermediate.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Enzalutamide of Formula (I)

(I)
comprising the steps of:
a) reacting 4-bromo-2-fluorobenzoic acid of Formula II

(II)
with a chlorinating agent in presence of a solvent; in the ratio between 3-8 v/w times, followed by condensation with Methylamine to yield 4-bromo-2-fluoro-N-methyl benzamide of Fomula III

(III)
b) reacting the compound of formula (III) with 2-amino isobutyric acid in presence of ligand and a solvent to give 2-(3-Fluoro-4- methylcarbamoyl-phenylamino)-2-methyl-propionic acid of Formula IV

(IV)
c) reacting the compound of Formula IV with 2-(trifluoromethyl)-4-isothiocyanato benzonitrile of Formula (V) in presence of base and a solvent to give Enzalutamide;

(V)
d) optionally, purifying Enzalutamide.

In another aspect the present invention relates to the preparation of Enzalutamide intermediate of Formula IV comprises reacting the compound of Formula II with chlorinating agent in presence of a solvent, followed by condensation with methylamine to yield 4-bromo-2-fluoro-N-methyl benzamide of Formula III, which is further reacted with 2-amino iso butyric acid in presence of ligand and a solvent to give 2-(3-Fluoro-4- methylcarbamoyl-phenylamino)-2-methyl-propionic acid of Formula IV

Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Enzalutamide of Formula (I) comprising the steps of reacting 4-bromo-2-fluorobenzoic acid of Formula II with chlorinating agent selected from Oxalyl chloride, Thionyl chloride, PCl3, PCl5, POCl3; in presence of a solvent selected from halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, chloroform; esters such as ethyl acetate, isopropyl acetate, isobutyl acetate, methyl acetate or mixtures thereof ; in the ratio between 3-8 v/w times; at a temperature ranging from 10-15°C; to obtain a residual mass. The residual mass was further condensed with methylamine at a pH ranging from 8 to 9; at a temperature ranging from10-25°C; to yield 4-bromo-2-fluoro-N-methyl benzamide of Formula III.

The present inventors found that the use of oxalyl chloride as a chlorinating agent completes the reaction at a low temperature ranging from 25-30°C, which is industrially feasible, cost effective and avoids unwanted reactions, which minimized the formation of impurity. After completion of the reaction, the removal of oxalyl chloride is quiet and does not require any cumbersome workup.

However, the prior art patents includes the use of thionyl chloride as a chlorinating agent moves the reaction at reflux temperature i.e., at 60-110°C, which is tedious and cumbersome.

The obtained compound of formula (III) is reacted with 2-amino iso butyric acid in presence of ligand selected from 2-acetyl cyclohexanone, N,N-dimethyl glycine.HCl; in a solvent selected from alcohols, such as ethanol, ethylene glycols, n-butanol, isopropanol; ethers such as tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, 1,2-dimethoxy ethane; aprotic polar solvents like acetonitrile, dimethylformamide , dimethylsulfoxide or mixtures thereof; at temperature ranging from 50 -120 °C to give 2-(3-Fluoro-4-methylcarbamoyl-phenylamino)-2-methyl-propionic acid of Formula IV.

The present invnetors found that the use of dimethyl formamide as a solvent in coupling stage of 4-bromo-2-fluoro-N-methyl benzamide with 2-amino isobutyric acid yield lower yield due to the decomposition of product. The present inventors found that the decomposition of the product is due to the distillation of solvent at high temperature. Further, the prior art patents includes the use of thiophosgene, which is highly hazardous and is very laborious for handling at large scale.

In view of this, the present inventors developed an improved process for the preparation of Enzalutamide, by using industrial friendly solvents and reagents, which leads in the formation of good yield with high purity

The obtained compound of Formula IV is reacted with 2-(trifluoromethyl)-4-isothiocyanato benzonitrile of Formula (V) in presence of base selected from inorganic or organic bases, such as triethylamine, diisoproylethylamine, tributyl amine, ?,?-dimethyl aniline, pyridine, N-methylmorpholine, DBN, DBU; in a solvent selected from ketone solvents such as acetone, methyl isobutyl ketone; acetonitrile or mixtures thereof; at a temperature ranging from 25-30°C for about 24 hours. The reaction mass was filtered and distilled off to give a residue, which is purified by column chromatography to give Enzalutamide

The present inventors developed a process for the preparation of Enzalutamide, wherein the reaction course is extremely smooth and achievable at room temperature conditions of 25-30°C, which is not only industrially feasible but also cost effective and provide pure materials/intermediates. Exceptional advantage of the said process of the present invention was that- it does not require cumbersome process such as use of microwave irradiation at an elevated temperatures i.e., around 83-84°C and prolonged hours e.g. as disclosed in US 7709517 example 56 such microwave dependent reaction was carried out upto exceeding 72 hours and resulting in poor yields and exceptional levels of impurity formation.

To overcome these serious industrially non-viable process concerns as cited above -especially use of microwave irradiation based reaction, the present inventors aimed for a process, which is not only industrially upscale process but also cost effective and least time consuming. The inventors in the present invention found that the use of base in the condensation step makes the reaction to move smoothly at ordinary lower temperatures i.e. at about 25-30°C, which was found to help in avoiding the formation of large number impurities due to unwanted parallel reactions and resulting in recovering purer material.

Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 50-60°C for time ranging from 12 to 16 hrs depending upon the physical attributes of the end product obtained i.e. Pure Enzalutamide.

The process related impurities that appear in the impurity profile of the Enzalutamide may be substantially removed by the process of the present invention resulting in the formation of highly pure material. The process of the present invention is as summarized in the Scheme-I as represented below:

Scheme-I: Process for preparation of Enzalutamide of the present invention

In another embodiment, the Enzalutamide obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising Enzalutamide obtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions derived from Enzalutamide of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES

Example 1
Preparation of 4-bromo-2-fluoro-N-methyl benzamide (III)

N,N-Dimethyl formamide (1.0 mL, 0.013) was added to the suspension of 4-bromo-2-fluorobenzoic acid (30.0 g, 0.137) in dichloromethane (300 mL) at 0 to 15 °C. To the reaction mixture oxalyl chloride (19.8 mL, 0.23) was added drop wise and stirred at 25-30°C for 2 to 3 hrs. Distill off the solvents to get residue. Dichloromethane (250 mL) was added to the residue and cooled to 10 to 15 °C. Methyl amine solution (10% Methyl amine in dichloromethane (500 ml) was added drop wise at a pH around 8 to 9. The reaction mixture was stirred at 25-30°C for 1 hr. Add DM water and stir for 30 min and separate the organic layer. The aqueous layer was extracted twice with Dichloromethane (2 × 200 ml) and combined organic layer washed with 5% citric acid solution (100 mL). The organic layer was washed with 150 ml of 5% NaHCO3 solution followed by 200 ml of DM water wash. The organic layer was concentrated to obtain title product as off-white solid.

Yield: 30.0 gm

Example 2
Preparation of 2-(3-Fluoro-4-methylcarbamoyl-phenylamino)-2-methyl-propionicacid (IV)

4-bromo-2-fluoro-N-methyl benzamide (10 gm, 0.043) and K2CO3 (14.8 gm, 0.107) was charged in to reaction flask containing 2-aminoisobutyric acid (17.2 gm, 0.166), DM water (1.8mL) and 1,4-dioxane (25mL). The reaction mixture was purged with nitrogen gas for 20 min and then charged CuCl (5.15 gm, 0.052) and 2-Acetyl cyclohexanone (4.4 mL, 0.034). Continue purging nitrogen gas for 20 min followed by refluxed for 36 hrs. The reaction mass was cooled to 10 to 15 °C and then charged DM water (20 mL). The pH of the reaction mass adjusted to 3-5 with 1 M citric acid solution. Ethyl acetate was charged under stirring for 10-20 min and separates the organic layer. The aqueous layer was extracted with Ethyl acetate (2 × 50 mL). The organic layer was distilled off and washed with methyl tert-butyl ether (100 mL) to obtain the title product.

Yield: 8.0 gm
Chromatographic Purity (By HPLC): 97.14%

Example 3
Preparation of Enzalutamide (I)

2-(trifluoromethyl)-4-isothiocyanato benzonitrile (16.6 gm, 0.072), 2-(3-Fluoro-4-methylcarbamoyl-phenylamino)-2-methyl-propionic acid (8.3 gm, 0.033) were charged in to the reaction flask containing triethylamine (8.3 mL, 0.059M), acetone (83 mL) at 25-30°C and stirred for 24 hrs. The reaction mass was filtered and filtrate was distilled off to get residue. The residue was purified through column chromatography using 60-120 mesh silica gel using 30% Ethyl acetate in hexane. The solvent fractions were collected and concentrated to obtain pure Enzalutamide.

Yield: 4.5 gm
Chromatographic Purity (By HPLC): 99.1%
Purification may be further carried out using the same solvent/s and recrystallized product obtained resulted in the purity exceeding 99.5% (by HPLC).

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the description and examples are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.