FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"A PROCESS FOR PREPARATION OF PURE EXEMESTANE'

2. APPLICANT:
(a) NAME: Mac Chem Products India Pvt. Ltd.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 304, Town Centre, Andheri-kurla Road, Andheri (E),
Mumbai-400059, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to an improved process for preparation of Exemestane having pharmaceutical acceptable purity, using inexpensive reagents.
BACKGROUND AND PRIOR ART:
Aromatase inhibitor is a class of drugs used in the treatment of breast cancer and ovarian cancer in postmenopausal women. Exemestane is an irreversible steroidal aromatase inhibitor used in the adjuvant treatment of hormonally-responsive breast cancer in postmenopausal women. Exemestane is the international commonly accepted name for 6-Methyleneandrosta-l,4-diene-3,17-dione having structural formula (I), as described below and is commercially available under brand name Aromasin.


CH2
(I)
There are several different methods for preparation of Exemestane reported in the prior art. The closest prior arts to the present invention have been disclosed in US Patent No. 4808616 and CN Patent No. 1453288. According to US4808616, method of producing Exemestane involves dehydrogenation of compound of formula (II)


CH2
(H) with dehydrogenating agent, such as 2,3-Dichloro-5,6-dicyano-l,4-quinone (hereafter
referred as DDQ), Selenium dioxide or chloranil in an inert solvent. The purification of
crude Exemestane is carried out with silica gel column. A process described in CN Patent
No. 1453288 involves dehydrogenation of compound of formula (II) with DDQ in
presence of aromatic carboxylic acid. The purification is achieved by silica gel column
chromatography followed by recrystallisation. But said prior art does not describe the
purity of final product.
Also WO2005/070951, WO01/04342, US4876045 describe different routes for the synthesis of Exemestane, but have disadvantages like use of expensive and poisonous reagents, multistep synthesis, inconvenient operations etc.
Due to the pharmaceutical use of Exemestane, it is of paramount importance to have available a process for the preparation of pure Exemestane, which minimizes or substantially eliminates the formation of the impurities and gives the final product with high purity, making large scale production possible.
OBJECT OF THE INVENTION:
The object of the present invention is to develop a process for the preparation of high purity Exemestane with individual impurity level below 0.3% and total impurity level below 1.0%, which is suitable for pharmaceutical application.

SUMMARY OF THE INVENTION:
The present invention discloses a process for the preparation of the highly pure Exemestane. Oxidation of 6-Methyleneandrost-4-ene-3,17-dione (II) using DDQ, in presence of carboxylic acid derivatives and buffer in refluxing solvent gave crude Exemestane, which was purified by column chromatography and crystallization.
DETAILED DESCRIPTION OF THE INVENTION:
Unless defined otherwise, all the technical and scientific terms used herein have same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless stated to the contrary, any of the words "including", "includes", "comprising", and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately follow it.
The term "pure" as used herein means that the "pure" substance is substantially free of impurities. As such, "pure" refers to at least 99% of the substance.
The process for preparation of Exemestane in accordance with present invention can be schematically represented as follows.


6-Methyleneandrost-4-ene-3,l 7-dione (II) was prepared by known method as described in US Patent No. 4990635, by Mannich reaction using N-methylaniline and paraformaldehyde.
The salient features of the present invention are as follows:
1. Oxidizing agent:
Oxidation of 6-Methyleneandrost-4-ene-3,l 7-dione (I/) was affected by suitable oxidizing agent, preferably quinone derivatives, more preferably DDQ. DDQ was added in the mole ratio of 1 to 3 mole; preferably 2 mole. It was observed that the entire amount of DDQ required, if added together at the beginning of the reaction led to incomplete reaction and product obtained was very difficult to purify. Therefore, the present art describes and stresses on the mode of addition of DDQ. Solution of the said oxidizing agent, in a solvent used as a reaction medium, is added in different lots over a period of time, led to complete conversion of (II) into a crude Exemestane of better color and quality, which on purification gave a pharmaceutically acceptable Exemestane.
2. Catalyst:
Organic carboxylic acid used in the present invention comprises substituted or unsubstituted benzoic acid derivatives, most preferably salicylic acid. The salicylic acid was added in the mole ratio 0.5 to 5 moles: preferably 1 to 2 moles; more preferably 1.6 to 1.7 moles.
3. Buffer:
The use of buffer to maintain pH of reaction mass during the oxidation reaction, achieve faster reaction rate, so also higher yield and better quality of product. Buffer was selected from a group comprising of sodium acetate, potassium acetate, ammonium acetate, sodium salicylate, sodium benzoate; preferably anhydrous sodium acetate. It was added in the mole ratio of 0.1 to 3 moles; preferably 0.5 to 2 mole; more preferably 1 mole.
4. Solvent:
The reaction was carried out in a suitable inert solvent. The term "inert" means stable to oxidation. It was selected from a group comprising of toluene, dioxane, benzene, xylene,

dichloromethane and mixture thereof; preferably toluene. The volume of solvent used was 10 to 100 volumes; preferably 30 to 80 volumes; more preferably 40 volumes.
5. Reaction conditions:
The reaction was carried out at temperature ranging from 30 - 110°C, preferably at the refluxing temperature of the solvent used. The time required for effective conversion of compound (II) was about 4-8 hrs; preferably 5 hrs.
6. Purification:
The product obtained after isolation from the oxidative medium, using well known method was highly colored, and simple recrystallisation technique was insufficient to achieve the desired quality of Exemestane suitable for pharmaceutical use. It was therefore necessary to develop a simple and efficient method to purify crude Exemestane to the said level of purity. A simple adsorption-desorption column chromatographic technique was developed using mixed bed of silica and alumina on which crude Exemestane was adsorbed and eluted rapidly with solvent or mixture of solvents comprising hexane, cyclohexane, ethyl acetate etc.
The product obtained thus was almost colorless and required a simple recrystallisation to achieve very high purity of Exemestane.
The recrystallisation of the isolated solid was carried out in suitable solvent. The suitable solvent is selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetone, methyl ethyl ketone, dichloromethane, dichloroethane, chloroform, petroleum ether, diethyl ether, cyclohexane; preferably methanol, isopropanol, dichloromethane and petroleum ether.
Exemestane obtained in accordance with present invention had purity greater than 99%. The purity of the obtained product was ascertained by its HPLC method.

HPLC method:
Column : C18, 5ja 250mm X 4.6mm
Detector : 254nm
Flow : 1.0 ml/min
Injection volume : 20|jJ
Buffer solution : 6.8g of potassium dihydrogen phosphate in 1000ml
ofwater adjusted to pH 4.5 with orthophosphoric
acid.
Mobile phase : 50% buffer solution and 50% acetonitrile.
Calculation : Calculate the % of impurities by area normalization.
The following examples have been described in order to further illustration and not intended to limit the invention in any way.
EXAMPLES:
EXAMPLE 1 Part A:
A mixture of 50 gm of 6-Methyleneandrost-4-ene-3,17'dione (II), 38.65 gm of salicylic acid, 13.74 gm of anhydrous sodium acetate and 2L toluene was refluxed and water was distilled off completely. While refluxing, a solution of DDQ (76 gm dissolved in 390 ml of toluene) was added in different lots in 5 hrs. Reaction mass was cooled, filtered and washed with toluene. To the filtrate 0.6L of 10% KOH was added and stirred for 30 min. Organic layer was washed with 2 x 0.5L of brine solution and concentrated under vacuum below 60° C to obtained free solid.
PartB:
The free solid obtained in Example 1 was dissolved in dichloromethane, adsorbed on silica and subsequently chromatographed on mixed bed of silica and alumina using mixture of cyclohexane : ethyl acetate (7:3). The Eluate obtained was concentrated and

I

refluxed in dichloromethane: petroleum ether (1:1) for 30 min. It was cooled to 0-5° C for
2 hrs and then filtered to obtain pure Exemestane.
Yield: 22 gm
Color: white powder
Melting point: 193-194 °C
Purity: 99.9% (HPLC)
Individual impurity: 0.02%
Total impurity: 0.1%
Assay: 99.5% by U. V. spectrophotometry at 246 nm (c=l% m 96% Ethanol W =481)
EXAMPLE 2 Part A:
A mixture of 50 gm of 6-Methyleneandrost-4-ene-3,17-dione (II), 38.65 gm of salicylic acid, 6.85 gm of anhydrous sodium acetate and 2L toluene was refluxed in an oil bath. Water was distilled off completely and while refluxing, a solution of DDQ (76 gm dissolved in 390 ml of toluene) was added in different lots in 5 hrs. Reaction mass was cooled, filtered and washed with toluene. In filtrate, 0.6L of 10% KOH is added and stirred for 30min. Organic layer was washed with 2 x 0.5L of brine solution and concentrated under vacuum below 60° C to obtained free solid.
PartB:
Purification of obtained solid as per process described in part B of Example 1
Yield: 15 gm
Color: white powder
Melting point: 192.5-194 °C
Purity: 99.75% (HPLC)
Individual impurity: 0.05%
Total impurity: 0.25%
Assay: 99.5% by U.V. spectrophotometry at 246 nm (c=l% in 96% Ethanol W = 481)

We Claim,
1. An improved process for preparation of pure Exemestane comprising the oxidation of compound of formula (II) with oxidizing agent in presence of buffer, aromatic carboxylic acid and inert solvent.

CH2 (II)
2. The process as claimed in claim 1, wherein the buffer is used to maintain the pH of the reaction mass.
3. The process as claimed in claim 1, wherein the buffer is selected from the group comprising of sodium acetate, potassium acetate, ammonium acetate, sodium salicylate, sodium benzoate; preferably anhydrous sodium acetate.
4. The process as claimed in claim 1, wherein the aromatic carboxylic acid is substituted or non-substituted benzoic acid; more preferably salicylic acid.
5. The process as claimed in claim 1, wherein the said oxidizing agent is a quinone derivative; more preferably DDQ.
6. The process as claimed in claim 1, wherein the oxidizing agent is added in lots over a period of time.
7. The process as claimed in claim I, wherein the inert solvent is selected from the group comprising of toluene, dioxane. benzene, xylene, dichloromethane and mixture thereof; more preferably toluene.

8. The process as claimed in claim 1, comprising the purification of crude Exemestane using a technique of embedding the crude product on silica, followed by column chromatography on a silica-alumina bed.
9. The process for purification of crude Exemestane as claimed in claim 8, comprising a step of recrystallisation in suitable solvent.

10. The process as claimed in claim 9, wherein suitable solvent is selected from the group comprising of methanol, ethanol, isopropanol, ethyl acetate, acetone, methyl ethyl ketone, dichloromethane, dichloroethane, chloroform, petroleum ether, diethyl ether, cyclohexane; preferably methanol, isopropanol, dichloromethane, petroleum ether or mixtures thereof.
11. The process as claimed in any one of the preceding claim comprising Exemestane with purity at least 99%, suitable for pharmaceutical formulations.
Dated this 4th Day of December, 2008