Title of Invention	AN IMPROVED PROCESS FOR PREPARATION OF PURE ANASTROZOLE
Abstract	Disclosed herein is a process for preparation of Anastrazole with purity greater than 99.8%, which comprises alkylation of purified 3,5-bis(2-cyanoprop-2-yl)benzylbromide with 1, 2,4 triazole, followed by isolation and purification of Anastrazole using environmental friendly solvents.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION: "An Improved Process for Preparation of Pure Anastrozole" 2. APPLICANT (a) NAME: CIPLA LTD. (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. Field of Invention The present invention relates to an improved process for preparing pure Anastrozole. Moreover the process relates to alkylation of the isolated and purified 3,5-bis(2-cyanoprop-2-yl)benzylbromide as starting material, devoid of using toxic, hazardous and environmental unfriendly solvents. Background of the Invention Anastrozole is a common name of the chemically known substance 2,2'-[5-(lH-l,2,4-triazol-l-ylmethyl)-l,3-phenylene]di(2-methylpropionitrile), represented by formula (I) : CH3 H3C Anastrozole is a selective and potent non-steroidal drug which inhibits the action of the enzyme aromatase. It is used for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Anastrozole is further recognized and granted for treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown, locally advanced or metastatic breast cancer and also for adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. The synthesis of Anastrozole is described in U.S. Pat. Nos. 4935437 and RE 36617 ( a reissue of U.S. Pat. No.4935437 assigned to AstraZeneca Pharmaceuticals), which are incorporated herein by reference. These patents describe two synthetic routes for preparing Anastrozole, one starting from methyl 3,5-dimethylbenzoate in a six-step process and the 2 other started from 3,5-bis(bromomethyl)toluene in a three-step process. The second process is preferable because it is much shorter and easier to perform, however both processes involve a benzylic bromination stage with N-bromosuccinimide (NBS) in CCI4. In the first process, Bromination of methyl 3, 5-dimethylbenzoate with N-bromosuccinimide (NBS) in CCI4 affords a 3,5-bis(bromomethyl) compound, which is subsequently treated with potassium cyanide to afford a dinitrile compound. The dinitrile compound is alkylated, then reduced to the corresponding alcohol. The alcohol is converted to an alkyl chloride intermediate, and Anastrozole is then obtained by reaction of the latter compound with sodium triazole. The final product is purified by flash column chromatography, using a repeated elution with a methanolxhloroform solvent mixture. In the second process, the starting material, 3,5-bis(bromomethyl)-toluene, is reacted with potassium cyanide in dichloromethane in the presence of a catalytic amount of tetrabutylammomum bromide (TBAB) to obtain 2,2'-(5-methyl-l,3-phenylene)diacetonitrile. The product is mixed with iodomethane and sodium hydride in DMF to thereby obtain 2,2'-(5-methyl-l,3-phenylene)di(2-methylpropionitrile), (also referred to as 3,5-bis(2-cyanoprop-2-yl)toluene) which is further brominated using benzoyl peroxide and N-bromosuccinimide (NBS) in carbon tetrachloride. The mixture is refluxed for 2 hours, cooled, filtered, and the Scheme I NBS, carbon tetrachloride 2,2'-(5-methyl-1,3-phenylene)di (2-methyl-propionitrile) or 3,5-bis(2-cyanoprop-2-yl) toluene 3,5-bis(2-cyanoprop-2-yl) benzylbromide DMF Sodium triazole CH3 H3C Anastrozole filtrate is evaporated to dryness under reduced pressure. The residue obtained is dissolved in DMF and sodium triazole is added. After completion of the reaction, anastrozole is purified by flash column chromatography, eluting with ethyl acetate. Thus, the bromomethyl intermediate in the process is not isolated, but is directly converted to anastrozole in situ. As a result of using the non-isolated intermediate, an impure final product is obtained. Further, the use of chromatographic solvent such as chloroform (being a carcinogenic), use of solvent such as carbon tetrachloride (being a carcinogenic solvent) for bromination reaction and DMF for alkylation reaction is disadvantageous with respect to industrial application. US 20060189670 describes preparation of anastrazole by reacting 3,5 bis-(l-cyano-l methyl ethyl)benzylhalide with 4-Z-l,2,4-triazole, where in Z is a protecting group like an amine. US 2006/0035950 provide novel processes (scheme II) for purifying anastrozole, avoiding the use of liquid chromatography. The purification processes are via the isolated anastrozole salt forms, either by crystallization or by selective acidic extractions, and optionally in both cases, converting the purified anastrozole salt to anastrozole base. An improved process for the synthesis of anastrozole, which is obtained by alkylating the isolated, purified, 3,5-bis(2-cyanoprop-2-yl)benzylbromide is also disclosed. Scheme II: 4 NBS MDC/Acetonitrile ^. Purification 3,5-bis(2-cyanoprop-2-yl) toluene 3,5-bis(2-cyanoprop-2-yl) benzylbromide DMF Sodium triazole CH3 H3C Purification NCTH3 H3C^CN Purified Anastrozole crude anastrozole The above patent describes preparation of 3,5-bis(2-cyanoprop-2-yl)benzylbromide, which is carried out in solvent dichloromethane (yield is low), acetonitrile (yield is not reported) and purified, the yield reported in this process is low and also the number of steps involved in the synthesis of anastrozole is more resulting in lower yield. The bromination reaction as described in '950 can be carried out in solvent selected from the group of ethyl acetate, acetone, dichloromethane, methyl acetate, isopropyl acetate, isopropyl acetoacetate, tert-butyl acetate and acetonitrile. However, it was found that in the presence of some solvents, the purity of the product was not high. The impurity 3,5-bis(cyanoprop-2-yl)benzal bromide, a compound of formula (IV) formed during the reaction was found to an extent of 15-20% and also other problems encountered using some of these solvents are susceptible to bromination. The reaction described in this patent process was followed by reflux for 4-5 hours. The inventors 5 .CHBr2 H3C ^^\^~^rCCH3 IV have found that longer reaction times cause increased levels of the impurity 3,5-bis(cyanoprop-2- yl)benzalbromide. Thus the process described for bromination in US2006/0035950 is not an efficient process to produce the product in high yield. Because of the difficulties encountered in the process disclosed in the prior arts like using carbon tetrachloride (CCU) and DMF on industrial scale and the lower yields, it would be highly desirable to develop a process for preparing anastrozole, devoid of using carcinogenic solvents like carbon tetrachloride and DMF. Anastrozole is administered in lmg dosage, it is a very expensive product and there is a constant need for developing new process, which provides good yield with high purity, making the process commercially viable. The process of the present invention is an inventive effort to provide Anastrozole in good yield with high purity. Object of the invention: The main object of the present invention is to provide an improved process for preparation of Anastrazole with purity greater than 99.8%. 6 Summary of the Invention: The present invention discloses an improved process for preparing pure anastrozole with purity of greater than 99.8%, comprising the steps of: a) brominating 3,5-bis(2-cyanoprop-2-yl)toluene (II) in acetonitrile using N-bromo succinamide to obtain 3,5-bis(2-cyano prop-2-yl)benzylbromide (III); NC rQ^$ 3,5-bis( 2-c }iajioprop-2-3d) toluene (ID 3,5-bis(2-cyanoprop-2-ji) benzyforomide (HI) b) purifying the bromo intermediate (III) substantially free from 3, 5-bis(cyanoprop-2-yl)benzyl bromide(IV) using suitable solvent; CH. CN " CHBr, IV c) alkylating the bromo intermediate to obtain anastrozole in suitable solvent using base and tetra butyl ammonium bromide and H,C CH, "3C (I) d) isolating and purifying the anastrozole from ethylacetate and diisopropylether. 7 The process of the present invention affords Anastrazole in high yield and high purity, the purity of the pure Anastazole obtained is measured by HPLC. The pure Anastrazole prepared by the present invention is having high purity, greater than 99.8% Detailed Description of the Invention: According to the present invention, an improved process for preparing pure Anastrozole with high purity comprises the steps of; a) brominating 3,5-bis(2-cyanoprop-2-yl)toluene (II) in acetonitrile using N- bromo succinamide to obtain 3,5-bis(2-cyano prop-2-yl)benzylbromide (HI); b) purifying the bromo intermediate (III) substantially free from 3, 5- bis(cyanoprop-2-yl)benzyl bromide(IV) using suitable solvent; c) alkylating the bromo intermediate to obtain anastrozole in suitable solvent using base and tetra butyl ammonium bromide and d) isolating and purifying the anastrozole from ethylacetate and diisopropylether. The process of the present invention is as shown in scheme III. Scheme III 8 NBS Acetonitrile CH3 H3C 3,5-bis(2-cyanoprop-2-yl) toluene (ID 3,5-bis(2-cyanoprop-2-yi) benzylbromide (III) Purification Isopropyl alcohol& n-Heptane ANASTROZOLE (I) Toluene 1,2,4-triazole f Purification Purified 3,5-bis(2-cyanoprop-2-yl) benzylbromide According to one embodiment of the present invention as depicted in scheme III, the starting material 3,5-bis(2-cyanoprop-2-yl) toluene (formula II), is brominated using N-bromosucccinimide (NBS) to the benzyl bromide intermediate 3,5-bis(2-cyanoprop-2-yl) benzylbromide (formula III) in presence of benzoyl peroxide in acetonitrile. The bromination reaction is carried out at reflux temperature for not more than 3 hours by which the impurity 3,5-bis(cyanoprop-2-yl)benzalbromide, a compound of formula (IV) is formed in substantially low percentage. ,CHBr„ r^ IV 9 In an another embodiment of the present invention, the small amount of the impurity of formula (IV) generated in the bromination step is efficiently removed by purifying the bromo intermediate using suitable solvent, which results in 3,5-bis(cyanoprop-2-yl)benzyl bromide with purity greater than 90%. The suitable solvent used for purifying the bromo compound is selected from the group comprising isopropyl alcohol, n-heptane, n-hexane, toluene and mixtures thereof preferably isopropyl alcohol and n-heptane. In yet another embodiment of the present invention, the purified bromo compound (formula (III)) is alkylated with 1,2,4,-triazole in suitable solvent using suitable base in presence of tetrabutyl ammonium bromide to obtain Anastrozole, which is further purified using column chromatography followed by precipitation / crystallization using ethyl acetate and diisopropyl ether to obtain pure Anastrozole in higher yield. Suitable solvent used for the above alkylation reaction is selected from the group consisting of toluene, DMF, acetonitrile, cyclohexane preferably toluene. Suitable base used is selected from the group comprising potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate and mixtures thereof preferably potassium carbonate and powdered potassium hydroxide The process of the present invention affords anastrazole in high yield and high purity, the purity of the pure anastazole obtained is measured by HPLC. The pure Anastrazole prepared by the present invention is having high purity, greater than 99.8% 10 The details of the invention are given in the following examples, which are provided for illustration only and therefore these should not be construed to limit the scope of the present invention in any manner. Examples Example 1 Preparation of 3,5-Bis (2-cyanoprop-2-yl) benzyl bromide, compound of formula(III): Acetonitrile(650 ml), 3,5-bis(2-cyanoprop-2-yl)toluene (50 g), benzoyl peroxide (1.15 g) and acetic acid (0.6 ml) was charged and heated to 50-55°C. To this N-bromosuccinimide (50 g) was added over a period of 3 hours, maintained for 30 minutes, then slowly raised the temperature to reflux (75-80°C) and maintained for 3 hours. After reaction completion, the mass was cooled to 25-30°C, water (1.25 ml) was added and concentrated under vacuum to residue at temperature less than 60°C. The contents were cooled to 25-30°C, methylene chloride (125 ml) was charged, chilled to 10-15°C, filtered the insolubles and washed with chilled methylene chloride (8 ml). The combined methylene chloride layer was washed with 10% of sodium sulphite solution (15 ml), followed by wash with 10% of sodium bicarbonate solution (15 ml) and 10% of sodium chloride solution (15 ml). The methylene chloride layer was finally washed with water (15 ml), dried over sodium sulphate and concentrated to residue under vacuum at 35-40°C. To this residue charged isopropyl alcohol (15.5 ml) followed by n-heptane (245 ml), heated to 50-55°C, maintained for 30 minutes then slowly cooled to 25-30°C and stirred for 1 hour. The material so obtained was filtered, washed with n-heptane (12.5 ml). Purification : To the above material isopropyl alcohol (15 ml) and n-heptane (240 ml) was charged, heated the contents to 50-55°C, maintained for 30 minutes, cooled to 25-30°C, stirred for 1 hour at 25-30°C, filtered, washed with n-heptane (12.5 ml) and dried under vacuum at 35-40°C to give 3,5-Bis (2-cyanoprop-2-yl)benzyl bromide ( 50 g, 74 % yield, 94% HPLC purity). 11 Example 2 Preparation of 3,5-Bis (2-cyanoprop-2-yl)benzylbromide, compound of formula (III): Acetonitrile(1300 ml), 3,5-bis(2-cyanoprop-2-yl) toluene (100 g), Benzoyl peroxide (2.3 g) and Acetic acid (1.2 ml) was heated to 50-55°C. To this N-bromosuccinimide (100 g) was added over a period of 3 hours, maintained for 30 minutes, then slowly raised the temperature to reflux (75-80°C) and maintained for 3 hours. After reaction completion, the mass was cooled to 25-30°C, water (2.5 ml) was added and concentrated under vacuum to residue at temperature less than 60°C. The contents were cooled to 25-30°C, methylene chloride (250 ml) was charged, chilled to 10-15°C, filtered the insolubles and washed with chilled methylene chloride (15 ml). The combined methylene chloride layer was washed with 10% of sodium sulphite solution (30 ml), followed by wash with 10% of sodium bicarbonate solution (30 ml) and 10% of sodium chloride solution (30 ml). The methylene chloride layer was finally washed with water (30 ml), dried over sodium sulphate and concentrated to residue at 35-40°C. To this residue charged isopropyl alcohol (30 ml) and n-heptane (490 ml), heated to 50-55°C, maintained for 30 minutes, slowly cooled to 25-30°C and stirred for 1 hour. The material so obtained was filtered, washed with n-heptane (25 ml). Purification : To the above material isopropyl alcohol (240 ml) and n-heptane (240 ml) was charged, heated the contents to 55-60°C for dissolution then allowed to cool to 40-44°C, filtered, washed with n-heptane (25 ml) and dried under vacuum at 35-40°C to give 3,5-Bis (2-cyanoprop-2-yl)benzyl bromide ( 81 g, 60 % yield, 95 % HPLC purity). Example 3 Preparation of 2,2'-[5-(lH-l,2,4 - triazol —1-yl methyl)-l,3-phenylene] di (2-methyl propionitrile), compound of formula (I) [ ANASTROZOLE ]: Toluene (1000 ml), 1,2,4-triazole ( 27 g), Potassium carbonate (110 g), powdered Potassium hydroxide (20 g), Tetrabutyl ammonium bromide ( 7 g) and 3,5-Bis (2-cyanoprop-2-yl) benzyl bromide (100 g) was charged, heated to 85-90°C and maintained for 5 hours. After 12 reaction completion, the mass was cooled to 20-25°C, water (500 ml) was charged and toluene layer was separated, extracted the aqueous layer using toluene (300 ml), combined the toluene layer, washed using water (500 ml) and dried toluene layer over sodium sulphate. The toluene layer was concentrated under vacuum to residue at 50-55°C, charged isopropyl alcohol (18.8 ml) followed n-heptane (450 ml), stirred the contents for 1 hour at 25-30°C, chilled the contents to 0-5°C, maintained for 45 minutes, filtered the material, washed with n-heptane (25 ml). Purification : The above material was loaded on Silica gel column, eluted with methylene chloride followed by increasing the polarity (to an extent of 30%) using ethyl acetate. The pure fractions containing Anastrozole was concentrated to residue at 40-45°C, cooled to 20-25°C, charged methanol (420 ml), stirred for dissolution, clarified over hyflo and concentrated to residue under vacuum at 40-45°C. The contents were cooled to 20-25°C, ethyl acetate (13.8 ml) followed by di isopropyl ether (445 ml) was charged, stirred for 30 minutes, chilled to 0-5°C, maintained for 30 minutes, filtered, washed with di isopropyl ether ( 50 ml) and dried under vacuum at 40-45°C to give the title compound Anastrozole ( 45 g, 47 % yield, 99.9% HPLC purity). 13 We claim, 1. A process for preparation of anastrozole with high purity which comprises; a) brominating 3,5-bis(2-cyanoprop-2-yl)toluene (II) in acetonitrile using N-bromo succinamide to obtain 3,5-bis(2-cyano prop-2-yl)benzylbromide (III); CH, H,C 3,5-bis( 2-c janoprop-2-3d) toluene (ID Br CH, CN NC A CH, H3C 3,5-bis(2-c 5anoprop-2-3J) benzyibromide (HI) b) purifying the bromo intermediate (III) substantially free from 3, 5-bis(cyanoprop-2-yl)benzyl bromide(IV) using suitable solvent; CH, CN' CHBr, IV c) alkylating the bromo intermediate to obtain anastrozole in suitable solvent using base and tetra butyl ammonium bromide and CH, ^C (I) d) isolating and purifying the anastrozole from ethylacetate and diisopropylether. 14 2. The process as claimed in claim 1, wherein said suitable solvent used in step b) is selected from the group comprising isopropyl alcohol, n-heptane, n-hexane, toluene and mixtures thereof preferably isopropyl alcohol and n-heptane. 3. The process as claimed in claim 1, wherein said suitable solvent used in step c) is selected from the group consisting of toluene, DMF, acetonitrile, cyclohexane preferably toluene. 4. The process as claimed in claim 1 ,wherein the bromination reaction of step a) is carried out at reflux temperature for a period not more than 3 hours. 5. The process as claimed in claim 1, wherein the base used in step c) is selected from the group comprising potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate and mixtures thereof preferably potassium carbonate and powdered potassium hydroxide. 6. The process as claimed in claim 1, wherein the pure anastrazole in step d) obtained with purity of greater than 99.8%. 7. The process of preparation of highly pure anastrazole as substantially described herein with reference to the forgoing examples 1 to 3. Dated this 17th day of October 2006 Dr. Gopakumar G. Nair Agent for the Applicant 15 Abstract Disclosed herein is a process for preparation of Anastrazole with purity greater than 99.8%, which comprises alkylation of purified 3,5-bis(2-cyanoprop-2-yl)benzylbromide with 1, 2,4 triazole, followed by isolation and purification of Anastrazole using environmental friendly solvents. 16

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