WO2010076811A2

WO2010076811A2 - Process for the preparation of exemestane

Info

Publication number: WO2010076811A2
Application number: PCT/IN2009/000747
Authority: WO
Inventors: Ashvin Kumar Aggarwal; Anshul Kumar Jain; Venkateswaran Srinivasan Chidambaram; Lalit Wadhwa
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2008-12-30
Filing date: 2009-12-29
Publication date: 2010-07-08
Also published as: WO2010076811A3

Abstract

The present invention relates to an efficient and cost-effective process for the preparation of 6- methylenandrost-1,4-diene-3,17-dione (exemestane) by dehydrogenation of 6-methylenandrost-4- ene-3,17-dione using an dehydrogenating agent in the presence of an acid catalyst and at least one co-oxidant in an organic solvent.

Description

Process for the preparation of exemestane FIELD OF THE INVENTION

The present invention relates to an industrial advantageous process for the synthesis of aromatase inhibitor. In particular, the present invention provides an improved process for the preparation of 6- methylenandrost-l,4-diene-3,17-dione (exemestane) of formula I,

Formula I BACKGROUND OF THE INVENTION

Exemestane (trade name Aromasin) of formula I, is an oral steroidal aromatase inhibitor, used in the adjuvant treatment of hormonally-responsive breast cancer in postmenopausal women and is chemically described as 6-methylenandrosta-l,4-diene-3, 17 -dione.

Formula I

The clinical pharmacology in this exemestane product information states that the mechanism of action for breast cancer cell growth may be estrogen-dependent. Aromatase is described as the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. It is reported that the principal source of circulating, estrogens in postmenopausal women is from conversion of adrenal and "ovarian androgens (androstenedione and testosterone) to estrogens (estrone and ^~ estradiol) by the aromatase enzyme. Exemestane lowers circulating estrogen concentrations in postmenopausal women thereby providing a treatment for some postmenopausal patients with hormone-dependent breast cancer. Estrogen deprivation through aromatase inhibition is described as an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. Exemestane as an irreversible, steroidal aromatase inactivator that acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation.

US patent 4,808,616 discloses exemestane for the fust time and exemestane is prepared by dehydrogenation of 6-methylenandrost-4-ene-3,17-dione with the help of 2,3-dichloro-5,6- dicyanobenzoquinone (DDQ) using anhydrous dioxane solvent. The molar ratio of expensive and toxic DDQ used is higher (nearly one and half times) making the process costlier. 2,3-Dichloro-5,6- dicyanohydroquinone (DDHQ) is the by product in the reaction and has to be removed. As DDQ is used in excess, so formation of DDHQ is more and requires extensive purification for removal of DDHQ. In the, exemplified process exemestane is purified by column chromatography. Column chromatography is a very tedious and cumbersome process and is not advisable from industrial point of view.

CN patent application 1415624 A also discloses the dehydrogenation of 6-methylenandrost-4-ene- 3,17-dione with the help of DDQ and acid catalyst such as 3,5-dinitrobenzoic acid. The process described in this application also involve the use of the excessive molar ratio of DDQ (nearly two times) which results in the formation of more amount of DDHQ. Therefore the process requires multiple purifications to remove DDHQ and hence makes the process costlier and less production friendly.

In general, DDQ has been reported for the dehydrogenation of steroid ketones, steroid pyrrazoles, heterocyclic compounds, hydroaromatic compounds, steroid lactones, alcohols and phenols.

The methods reported in the prior art for the preparation of exemestane involves the dehydrogenation of 6-methylenandrost-4-ene-3,17-dione with the help of DDQ used in excess molar ratio. DDQ is an expensive and toxic agent and results in production of by product DDHQ, which is very difficult to remove. Therefore there is an urgent need to develop a simple and cost effective process to prepare exemestane in high purity which could minimize the amount of DDQ used- and thereby reducing the amount of DDHQ formed. Thus, the present invention provides an industrially advantageous process for the preparation of exemestane which involves the use of DDQ in fewer amounts and results in presence of undesired impurities in either acceptable limits or free from impurities. OBJECT OF THE INVENTION

The principal object of the present invention is to provide an efficient process for the preparation of exemestane.

Another object of the present invention is to prepare exemestane in high purity having undesired impurities in acceptable limit or free from impurities.

Yet another object of the present invention is to provide process for the purification of exemestane as well as intermediate.

SUMMARY OF THE INVENTION

The present invention provides an efficient and cost effective process for the preparation of highly pure exemestane of formula I,

Formula I

According to one embodiment, the present invention provides an improved process for the preparation of exemestane of formula I, which comprises the steps of: a) dehydrogenating 6-methylenandrost-4-ene-3, 17-dione of formula II,

Formula II using dehydrogenating agent such as DDQ in the presence of an acid catalyst and at least one co- oxidant in an organic solvent; b) isolating exemestane from the reaction mixture; and c) optionally, purifying exemestane using suitable solvents.

According to another embodiment, present invention provides a process for the purification of 6- methylenandrost-4-ene-3,17-dione of formula II, which comprises: a) providing a solution of 6-methylenandrost-4-ene-3,17-dione of formula II in a suitable solvent; and b) isolating 6-methylenandrost-4-ene-3, 17-dione of formula II from the mixture.

According to another embodiment the present invention provides a process for purification of exemestane which comprises dissolving exemestane in a suitable organic solvent, and isolating pure exemestane.

DETAILED DESCRIPTION OF THE INVENTION

Herein the term "DDQ" refers to 2,3-dichloro-5,6-dicyanobenzoquinone. Herein the term "DDHQ" refers to 2,3-dichloro-5,6-dicyanohydroquinone.

The present invention relates to an efficient and cost effective process for the preparation of exemestane of formula I of high purity by the dehydrogenation of 6-methylenandrost-4-ene-3,17- dione of formula II using an dehydrogenating agent such as DDQ in the presence of an acid catalyst and at least one co-oxidant in an organic solvent to form exemestane.

Generally, the reaction involves the dehydrogenation of compound of formula II in presence of a dehydrogenating agent, an acid catalyst and at least one co-oxidant in an organic solvent at room temperature to the reflux temperature of the solvent for few minutes to few hours. Preferably the reaction takes place at the reflux temperature till the completion of the reaction. The completion of the reaction may be monitored by suitable chromatographic techniques like high pressure liquid chromatography or thin layer chromatography.

An acid catalyst used in dehydrogenation reaction has marked accelerating effect on the rate of reaction. The acid -catalyst employed in the reaction can be organic acid catalyst selected from carboxylic acids such as maleic acid, oxalic acid, salicylic acid formic acid, acetic acid, trichloro acetic acid, benzoic acid, 3,5-dinitro-benzoic acid, sulfonic acids such as p-toluenesulfonic acid; picric acid, p-nitrophenol, thymoquinol; or inorganic acid selected from anhydrous hydrogen chloride, hydrochloric acid, sulfuric acid, preferably acid catalyst used is 3,5-dinitro-benzoic acid. The co-oxidant employed in the reaction can be selected from metal oxide, halide or acetate such as manganese dioxide, lead dioxide, manganese triacetate, ferric chloride, preferably manganese dioxide.

An organic solvent employed for carrying out the dehydrogenation includes aliphatic or aromatic hydrocarbons such as benzene, toluene, xylene, cyclohexane, n-hexane, heptane; nitriles such as acetonitrile; ethers such as dioxane, tetrahydrofuran, methyl tetrahydrofuran; acid solvents such as acetic acid, formic acid; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene; ketones such as acetone, methylisobutylketone and mixture thereof, preferably toluene, dioxane, and more preferably toluene.

After complete dehydrogenation reaction, the reaction mass is cooled at a temperature of ambient temperature. The reaction mass is optionally filtered to remove the undissolved impurities. Exemestane can be isolated from the reaction mass by any suitable technique known in the art such as filtration, evaporation and distillation ^nd the like.

DDQ is a well known dehydrogenating agent and is known to oxidize various substrates such as chromans, steroidal and hindered alcohols as well as simple benzhydrols. Dehydrogenation of Δ⁴-3- ketones to Δ^1-4-3-ketones using DDQ is known in the art. Mechanism of dehydrogenation using DDQ involves the hydride transfer from the reactant resulting in the conversion of DDQ to its quinhydrol DDHQ.

Removal of the resulting DDHQ is a very difficult process. It is envisaged that the regeneration of DDQ in situ, by the oxidation of its reduced form DDHQ, would make the protocol catalytic with respect to DDQ. Thus, minimize the amount of DDQ required and would also solve the problem of removal of DDHQ from the reaction mixture, as in situ DDHQ is oxidized to DDQ. It is highly advantageous to use co-oxidant in dehydrogenation reaction for the oxidation of DDHQ to DDQ which is regenerated in situ. Use of the co oxidants in the dehydrogenation reaction avoids the extensive purification process required to remove DDHQ from the reaction mixture and make the process cost effective.

The starting compound, 6-methylenandrost-4-ene-3,17-dione of formula II can be prepared by the methods well known in the prior art. Specifically, the process involves the reaction of androst-4-ene- 3,17-dione of formula III

Formula III with triethyl orthoformate in a suitable solvent in the presence of an acid to give corresponding 3,5 dienol ether, which is, in situ, further reacted with N-methylaniline and aqueous formaldehyde in the presence of an acid. Suitable solvents include aliphatic or aromatic hydrocarbon, ethers, halogenated solvents, nitriles, ketones, acid solvents, and mixture thereof. Preferably the solvent can be selected from but is not limited to benzene, toluene, xylene, dioxane, acetonitrile, acetic acid, formic acid, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, methylisobutylketone, chlorobenzene, dichlorobenzene and mixture thereof, most preferably tetrahydrofuran. Acids involved in the process can be organic acid selected from carboxylic acids such as benzoic acid, 3,5- dinitrobenzoic acid, salicylic acid, acetic acid, maleic acid, oxalic acid, trichloroacetic acid, formic acid; sulfonic acids such as p-toluenesulfonic acid; p-nitrophenol, thymoquinol, picric acid; or inorganic acid selected from anhydrous hydrogen chloride or sulfuric acid, and their derivatives, preferably p-toluenesulfonic acid. 6-methylenandrost-4-ene-3,17-dione so formed, can be optionally recrystallized using water, alcohol or mixture thereof, preferably mixture of ethanol and water.

Like any synthetic compound, exemestane or its intermediates can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in exemestane, its intermediates or any active pharmaceutical ingredient are undesirable and must be present in permissible limits. Thus present invention provides processes for the purification of exemestane as well as 6-methylenandrost-4-ene-3,17-dione of formula II, a key intermediate for exemestane.

According to another embodiment, present invention provides a process for the purification of 6- methylenandrost-4-ene-3,17-dione of formula II, an intermediate for exemestane. The intermediate, if desired, is purified to remove certain identified and unidentified impurities to make the intermediate suitable for the preparation of highly pure exemestane. 6-Methylenandrost-4-ene-3,17- dione of formula II may be purified by using suitable organic solvents.

Generally, 6-methylenandrost-4-ene-3,17-dione of formula II in organic solvent is heated at a temperature of 40 ⁰C to reflux temperature of the solvent. Organic solvents include but not limited to alcohols, ketones, nitriles, ester, aliphatic or aromatic hydrocarbon, halogenated solvents, amide solvents, or mixtures thereof in suitable proportions. Preferably organic solvent is selected from isopropanol, ethanol, acetone, methyl isobutyl ketone, acetonitrile, ethylacetate, toluene, dimethyl formamide, dichloromethane and the like or mixtures thereof in any suitable proportions.

The purified compound of formula II can be precipitated from the reaction mixture by any of the two methods described in the present invention. The compound of formula II can be precipitated by cooling at a temperature of 0 ⁰C to the ambient temperature followed by stirring. Alternatively, the product can be precipitated by adding a suitable anti solvent to the reaction mixture in which the compound of formula II has lower solubility. The anti solvent includes but not limited to water, hydrocarbon solvent such as cyclohexane, hexane, heptane and the like or mixture thereof. The 6- methylenandrost-4-ene-3,17-dione of formula II can be isolated from the reaction mass after precipitation by suitable techniques such as filtration and the like.

The compound of formula II obtained after the purification process of the present invention is found to have purity more than 97% by HPLC, preferably more than 98.5 % by HPLC, more preferably more than 99.2 % by HPLC. One of the impurity that may be present in the 6-methylenandrost-4- ene-3,17-dione of formula II is its precursor of formula III. The purification process of the present invention is highly advantageous to remove starting material of formula III from intermediate .of formula II. Preferably, after the purification process of the present invention the compound of formula II is found to contain its precursor less than 0.5 % or preferably free from compound of formula III.

The preparation of exemestane from this purified compound of formula II is highly advantageous as it avoids the formation of an identified impurity of formula IV, which may be formed during the synthesis of exemestane.

Formula IV

This impurity is formed during the dehydrogenation of 6-methylenandrost-4-ene-3,17-dione of formula II, containing small amount of its precursor i.e androst-4-ene-3,17-dione of formula III. Unreacted androst-4-ene-3,17-dione of formula III present in compound of formula II may also get dehydrogenated to form undesired impurity of formula IV. Hence purification of 6-methylenandrost- 4-ene-3,17-dione of formula II, optionally, is carried out before dehydrogenation in order to minimize the amount of unreacted androst-4-ene-3,17-dione of formula III which could further result in the generation of impurity of formula FV.

According to another embodiment, the present invention provides a process for obtaining exemestane in high chemical purity. The exemestane of formula I, if desired, is purified using suitable organic solvents to remove certain identified and unidentified impurities.

Generally, exemestane of formula I in organic solvent is heated at a temperature of 50 ⁰C to reflux temperature of the solvent. Preferably exemestane is heated at a temperature of 60 to 85 ⁰C till complete dissolution. Organic solvent include esters, nitriles, ethers, ketones and mixture thereof in any suitable proportion. Preferably acetonitrile, methylacetate, ethylacetate, propylacetate, butylacetate, isopropylacetate, methyl isopropylacetate, acetone, mixture of ethylacetate and isopropyl ether, mixture of ethylacetate and methyl tertiary butyl ether, mixture of ethylacetate and acetone or mixture of acetonitrile and ethylacetate, mixture of n-butylacetate and diisopropyl ether, mixture of acetonitrile and acetone, mixture of organic solvents with water.

Exemestane can be precipitated out from the mixture by cooling the mixture at a temperature of 0 ⁰C to the ambient temperature, followed by stirring. Alternatively exemestane can be precipitated from the reaction solution by adding an anti solvent in which exemestane is less soluble. An anti-solvent may be selected from water, ketones such as acetone; esters such as ethylacetate; hydrocarbon such as cyclohexane, n-hexane or heptane; or mixture thereof. Exemestane can be isolated from the reaction mass by suitable techniques such as filtration and the like.

Exemestane obtained after the purification process of the present invention is found to contain identified and unidentified impurity less than 0.15 % by HPLC, preferably less than 0.1 %. One of the impurities that is removed along with another identified and unidentified impurities is chloro derivative of exemestane.

This chloro impurity may form during the dehydrogenation of 6-methylenandrost-4-ene-3,17-dione using DDQ. In this process, DDQ is reduced to its quinhydrol DDHQ which is a good -source of chloride ion. The presence of DDHQ in the reaction mixture results in the chlorination of exemestane to give its chloro derivative of exemestane, an impurity of exemestane. The exact position of . attachment of the chlorine atom has not been fixed as yet. Since, it is known that DDQ/DDHQ is a source of the chloride ion, the position of the chlorine atom must be one of the possible carbocation centre with or without rearrangement following hydride removal by DDQ, Since the impurity is foπned in very less quantity and difficult to isolate so its exact structure could not be ascertained. The presence of chloro impurity is confirmed by mass analysis. Hence the purification of exemestane becomes essentialif chloro impurity is present in the product.

The exemestane synthesized by the process of present invention, if required, is purified using suitable solvent to remove certain the impurities including chloro impurity, if present in the product Preferably, after the purification process of the present invention the exemestane is found to contain the chloro impurity of exemestane less than 0.15 % or preferably free from impurity.

The major advantage lies in the present invention is the use of less amount of DDQ for the dehydrogenation reaction, which result in foπnation of less amount of DDHQ and hence makes the process cost effective and industrial friendly. The present invention .further provides exemestane in high chemical purity wherein impurities like compound of formula IV and chloro impurity are either absent or present in acceptable limits.

Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.

EXAMPLES

Example-1: Preparation of 6-methylenandrost-4-ene-3,17-dione

To a solution of androst-4-ene-3,17-dione (200 g, 0.7 mol) in a mixture of tetrahydrofuran (1300 ml) and triethylorthoformate (200 ml), was added p-toluenesulphonic.acid (Hg, 0.057 . mol) at 45-50 ⁰C. After one hour, N-methylaniline (80 ml) and aqueous formaldehyde (37%, 100 ml) were added at 45-50 ⁰C and the reaction mass was allowed to stir for 3 hours at the same temperature. After the completion of the reaction, reaction mass was cooled to 10-15 ⁰C and acidified with concentrated hydrochloric acid. The reaction mass was stirred for 1 hour at 0-20 ¹¹C and diluted with demineralized water (5000 ml). The precipitated solid was filtered, washed with demineralized water (1000 ml) and dried to obtain 166 g of the title compound having purity 95.54% by HPLC. Example-2:^*Preparation of 6-methylenandrost-4-ene-3,17-dione

To a solution of androst-4-ene-3,17-dione (25 g, 0.087 mol) in a mixture of dioxane (125ml) and triethylorthoformate (30ml), was added p-toluenesulphonic acid (1.25 g, 6.5 mol) at 45-50 ⁰C. After one hour, N-methylaniline (10 ml) and aqueous formaldehyde (37%, 1 1.25 ml) were added at 40-45 ⁰C and stirred for 3 hours at the same temperature. After the completion of the reaction, reaction mass was cooled to 10-15 ⁰C and acidified with concentrated hydrochloric acid. The reaction mass was stirred for 1 hour and diluted with demineralized water (375 ml). The solid, thus precipitated out, was filtered, washed with demineralized water (200 ml) and dried under vacuum to obtain 20.2 g of 6-methylenandrost-4-ene-3,17-dione having purity 95.0 % by HPLC.

Example-3: Purification of 6-methylenandrost-4-ene-3.,17-dione

A solution of 6-methylenandrost-4-ene-3,17-dione (110 g, having purity 95.0 % HPLC) in isopropyl alcohol (550 ml) was charcoalized at reflux temperature, filtered, cooled to 0-5 ⁰C and stirred for 1 hour. The precipitated solid was filtered, washed with chilled isopropyl alcohol and dried to obtain 77 g of the title compound having purity 98.2% by HPLC.

Example-4: Purification of 6-methylenandrost-4-ene-3,17-dione

6-Methylenandrost-4-ene-3,17-dione (168 g, having purity 95.0 % HPLC) in ethanol (840 ml) was heated at reflux temperature till clear solution. The reaction mass is then cooled to 0-5 ⁰C and stirred for 2 hours. The solid was filtered, washed with chilled ethanol and dried to obtain 1 16 g of the title compound having purity 98.81 % by HPLC.

Example-5: Purification of 6-methylenandrost-4-ene-3,17-dione

6-Methylenandrost-4-ene-3,17-dione (246 g, having purity 95.0 % by HPLC) in acetone (1.2 L) was heated at reflux temperature. The reaction mass is then cooled to 0-5 ⁰C and stirred for 2 hours. The precipitated solid was filtered, washed with chilled acetone and dried to obtain 129 g of the title compound having purity 99.36% by HPLC.

Example-6: Preparation of Exemestane

A mixture of 6-methylenandrost-4-ene-3,17-dione (25 g, 0.083 mol), 3,5-dinitrobenzoic acid (7.5 g, 0.035 mol), DDQ (19 g, 0.083mol) and manganese dioxide (36.4 g, 0.418 mol) in toluene (1000 ml) was refluxed at 1 10-1 15 ⁰C. After the completion of the reaction, reaction mass was cooled to 25 ⁰C and filtered. The filtrate was washed with 10% aqueous sodium hydroxide solution followed by water and distilled to obtain 14.5 g of the title compound having purity 90.96 % by HPLC.

Example-7: Preparation of Exemestane

A mixture of 6-methylenandrost-4-enc-3,17-dione (10 g, 0.033 mol), DDQ (7.6 g, 0.033 mol) and manganese dioxide (14.57 g, 0.167 mol) in toluene (350 ml) and acetic acid (50 ml) was refluxed at 1 10-1 15 ⁰C. After the completion of the reaction, reaction mass was cooled to 27 ⁰C and filtered. The filtrate was washed with aqueous sodium hydroxide solution followed by water and distilled to obtain 5.6 g of the title compound having purity 91.20 % by HPLC.

Example-8: Preparation of Exemestane

A mixture of 6-methylenandrost-4-ene-3,17-dione (1O g, 0.033 mol), 3,5-dinitrobenzoic acid (3 g, 0.014 mol), DDQ (7.6 g, 0.033 mol) and lead oxide (40 g, 0.16 mol) in toluene (400 ml) was refluxed at 110-115 ⁰C. After completion of the reaction, the reaction mass was cooled to 30 ⁰C and filtered. The filtrate was washed with 10% aqueous sodium hydroxide solution followed by water and distilled to obtain 4.6 g of the title compound having purity 91.0 % by HPLC.

ExampIe-9: Purification of exemestane

A solution of exemestane (22.6 g, having purity 87.0 % by HPLC) in acetonitrile (1 13 ml) was charcoalized with activated carbon at 75-80⁰C .The filtrate was diluted with water (79.1 ml) and the reaction -mass was cooled to 0-5 ⁰C. The precipitated solid was filtered, washed with chilled acetonitrile and dried to obtain 12.5 g of the title compound having purity 98.90 % and its chloro derivative impurity 0.08 % by HPLC.

Example-10: Purification of exemestane

A solution of exemestane (12.5 g, HPLC purity 88.90 %) in acetonitrile (62.5ml) was refluxed for 30 minutes and cooled to 25-30 ⁰C. The reaction mass was stirred for 2.0 hours, further cooled to 0-5 ⁰C and again stirred for 2 hours. The reaction mass was filtered, washed with chilled acetonitrile and dried to obtain 1 1.2 g of the title compound having purity 99.75 % and its chloro derivative impurity 0.04 % by HPLC.

Example-11: Purification of exemestane

A solution of exemestane (2 g, having purity 88.9 % by HPLC) in ethylacetate (14 ml) and was refluxed for 30 minutes and cooled to 25-30 ⁰C. The reaction mass was stirred for 2.0 hours, further cooled to 0-5 ⁰C. The reaction mass was filtered, washed with chilled ethylacetate and dried to obtain 1.6 g of the title compound having purity 99.6 % by HPLC.

Example-12: Purification of exemestane

A solution of exemestane (2.4 g, having purity 88.9 % by HPLC) in a mixture of ethylacetate and acetonitrile (1:1) was refluxed and then cooled to 25-30 ⁰C. The reaction mass was stirred for lhour and further cooled to 0-5 ⁰C. The reaction mass was filtered and washed to obtain 2.1 g of the title compound having purity 99.76 % by HPLC.

Example-13: Purification of exemestane

A solution of exemestane (5 g, having purity 88.9 % by HPLC) in acetone (22.5 ml) was refluxed for 30 minutes, cooled to 25-30 ⁰C and stirred for 2.0 hours. The reaction mass was further cooled to 0-5 ⁰C. The reaction mass was filtered, washed with chilled acetone and dried to give 2.52 g of the title compound having purity 97.5 % by HPLC.

Example-14: Purification of exemestane

A solution of exemestane (5 g, having purity 88.9 % by HPLC) in n-butylacetate (20 ml) and) was stirred at 80 ⁰C for 30 minutes, cooled to 25-30 ⁰C and stirred for 2.0 hours. The reaction mass was further cooled to 0-5 ⁰C and stirred for 1 hour. Thereafter, the reaction mass was filtered, washed with chilled n-butylacetate and dried to give 2.6 g of the title compound having purity 95.19% by HPLC.

Example-15: Purification of exemestane

A solution of exemestane (5 g, having purity 88.9 % by HPLC) was refluxed in a mixture of ethylacetate and acetone (15ml, 1: 1), cooled to 25-30 ⁰C and stirred for 1 hour. The reaction mass was further cooled to 0-5 ⁰C and stirred for 1 hour. Thereafter, the reaction mass was filtered, washed and dried to give 2.5 g of the title compound having purity 97.35 % by HPLC.

Example-16: Purification of exemestane

A solution of exemestane (5 g, having purity 88.9 % by HPLC) was refluxed in a mixture of ethylacetate and diisopropylether (25ml, 1 :1), cooled to 25-30 ⁰C and stirred for 1 hour. The reaction mass was further cooled to 0-5 >°C, filtered and washed to give 2.6 g of the title compound having purity 96.5% by HPLC. Example-17: Purification of exemestane

A solution of exemestane (3.6 g, having purity 88.9 % by HPLC) was refluxed in a mixture of ethylacetate (10.8ml) and t-butylmethylether (7.2ml), ) cooled to 25-30 ⁰C and stirred for 1.0 hour. The reaction mass was further cooled to 0-5 ⁰C, filtered and washed to give 1.95 g of the title compound having purity 96.4% by HPLC. Example-18: Purification of exemestane

A solution of exemestane (4.1g, having purity 86 % by HPLC) was refluxed in a mixture of acetonitrile (6.15 ml) and acetone (12.3ml), cooled to 25-30 ⁰C and stirred for 2.0 hours. The reaction mass was further cooled to 0-5 ⁰C, filtered and washed to give 2.53 g of the title compound having purity 98 % by HPLC.

Example-19: Purification of exemestane

A solution of crude exemestane (4 g, having purity 88.9 % by HPLC) was refluxed in a mixture of n-butylacetate (18 ml) and diisopropylether (8 ml), cooled to 25-30 ⁰C and stirred for 1.0 hour. The reaction mass was further cooled to 0-5 ⁰C, filtered and washed to give 2 g of the title compound having purity 96.06 % by HPLC.

COMPARATIVE EXAMPLES

ExampIe-20: Preparation of Exemestane

DDQ (70 g, 0.31' mol) was added in lots to a mixture of 6-methylenandrost-4-ene-3,17-dione (50 g, 0.17 mol) and 3,5-dinitro benzoic acid (25 g, 0.12 mol) in toluene (2.0 L) at 1 10-1 15 ⁰C. After the completion of the reaction, reaction mass was cooled to 25 ⁰C and filtered. The filtrate was washed with 10% aqueous sodium hydroxide solution and distilled to obtain 22.6 g of the title compound having purity 89.0% by HPLC.

Example-21: Preparation of Exemestane

DDQ (41.7 g, 0.18 mol) was added in lots to a solution of 6-methylenandrost-4-ene-3,17-dione (30 g, 0.1 mol) in toluene(1.2 L) and salicylic acid (13.8 g, 0.1 mol) at 1 LO-1 15 ⁰C. After completion of the reaction, the reaction mass was cooled up to 30 ⁰C and filtered. The filtrate was washed with 10% aqueous sodium hydroxide solution followed by water and distilled to obtain 18 g of the title compound which was charcoalized in acetone (100 ml). The filtrate was diluted with demineralized water (250 ml). The precipitated solid was filtered, washed with water and dried to obtain 13 g of the title compound having purity 95.80 % by HPLC.

Example-22: Preparation of Exemestane

DDQ (12 g, 0.053 mol) was added in lots to a mixture of 6-methylenandrost-4-ene-3, 17-dione (1O g, 0.033 mol) in acetic acid (250 ml) at 1 10-1 15 ⁰C in 3 hours. After completion of the reaction, the solvent was distilled and extracted with toluene. The organic layer was washed with 10% aqueous sodium hydroxide solution followed by water and distilled to obtain 6.2 g of the title compound having purity 89.40 % by HPLC.

Claims

WE CLAIM

1). A process for the preparation of exemestane of formula I,

Formula I comprising the steps of: a) dehydrogenating 6-methylenandrost-4-ene-3,17-^"dione of formula II,

Formula II using an dehydrogenating agent such as DDQ in the presence of an acid catalyst and at least one co-oxidant in an organic solvent; b) isolating exemestane of formula I from the reaction mixture; and c) optionally, purifying exemestane using suitable solvents.

2). The process according to claim 1, wherein in step a) the acid catalyst is organic acid or inorganic acid catalyst.

3). The process according to claim 2, wherein organic acid catalyst is selected from carboxylic acids such as maleic acid, oxalic acid, salicylic acid, formic acid, acetic acid, trichloro acetic acid, benzoic acid, 3,5-dinitro-benzoic acid; sulfonic acids such as p-toluenesulfonic acid; picric acid, p-nitrophenol, thymoquinol and the like.

4). The process according to claim 2, wherein inorganic acid catalyst selected from anhydrous hydrogen chloride, sulfuric acid, hydrochloric acid. 5). The process according to claim 1, wherein in step a) co-oxidant include metal oxide, halide or acetate.

6). The process according to claim 5, wherein metal is selected from manganese, lead and iron; and halide is selected from chloride and bromide.

7). The process according to claim 5, wherein co-oxidant is manganese dioxide, lead dioxide, manganese triacetate, ferric chloride.

8). The process according to claim 1, wherein in step a), an organic solvent includes aliphatic or aromatic hydrocarbons such as benzene, toluene, xylene, cyclohexane, n-hexane, heptane; nitriles such as acetonitrile; ethers such as dioxane, tetrahydrofuran, methyl tetrahydrofuran; acid solvents such as acetic acid, formic acid, trifluoroacetic acid; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene; ketones such as methylisobutylketone, acetone; and mixture thereof.

9). A process for the purification of exemestane, comprises: a) dissolving exemestane in organic solvent which include esters, nitriles, ethers, ketones and mixture thereof; b) inducing precipitation; and c) isolating pure exemestane.

10). The process according to claim 9, wherein in step a) organic solvent is selected from acetonitrile, methylacetate, ethylacetate, propylacetate, butylacetate, isopropylacetate, methyl isopropylacetate, acetone, mixture of ethylacetate and isopropyl ether, mixture of ethylacetate and methyl tertiary butyl ether, mixture of ethylacetate and acetone or mixture of acetonitrile and ethylacetate, mixture of n-butylacetate and diisopropyl ether, mixture of acetonitrile and acetone, mixture of organic solvents with water.

11). The process according to claim 9, wherein in step b) precipitation is induced t>y cooling.

12). The process according to claim 9, wherein in step b) precipitation is induced by adding an anti solvent selected from water, ketones such as acetone; esters such as ethylacetate; hydrocarbon such as eyclohexane, n-hexane or heptane; or mixture thereof 13). A process for the purification of 6-methylenandrost-4-ene-3,17-dione of formula II, which comprises: a) providing a solution of 6-methylenandrost-4-ene-3,17-dione of formula II in a suitable solvent; and b) isolating 6-methylenandrost-4-ene-3, 17-dione of formula II from the mixture.

14). The process according to claim 13, wherein in step a) suitable solvent includes alcohols such as isopropanol, ethanol; ketones such as acetone, methyl isobutyr ketone; nitriles such as acetonitrile; ester such as ethyTacetate; aliphatic or aromatic hydrocarbon such as toluene; amide solvents such as dimethyl formamide, halogenated solvents such as dichloromethane or mixtures thereof.

15). The process according to claim 13, wherein precipitation is either induced by cooling or by adding an anti solvent selected from water, hydrocarbon solvent such as cyclohexane, hexane, heptane or mixture thereof.