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WO 2008/047104 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 24 April 2008 (24.04.2008) WO 2008/047104 Al (51) International Patent Classification: 4/403 Garden Enclave, Pokharan Road 2, Thane (W) 400 C07D 249/08 (2006.01) 601, Maharashtra (IN). (21) International Application Number: (74) Agents: CURTIS, Philip, Anthony et al.; A A. THORN PCT/GB2007/003942 TON & CO., 235 High Holborn, London WClV 7LE (GB). (22) International Filing Date: 17 October 2007 (17.10.2007) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (25) Filing Language: English AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, (26) Publication Language: English ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, (30) Priority Data: LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, 1719/MUM/2006 17 October 2006 (17.10.2006) IN MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, (71) Applicant (for all designated States except US): CIPLA TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, LIMITED [IN/IN]; 289 Bellasis Road, Mumbai Central, ZM, ZW Mumbai 400 008, Maharashtra (IN). (84) Designated States (unless otherwise indicated, for every (71) Applicant (for M W only): CURTIS, Philip, Anthony kind of regional protection available): ARIPO (BW, GH, [GB/GB]; 235 High Holborn, London WClV 7LE (GB). GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (72) Inventors; and European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (75) Inventors/Applicants (for US only): SRINIVAS, Pathi, FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, Laxminarayan [IN/IN]; 2475/24, 7Th B Main, RPC Lay PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, out, Vijayanagar, Bangalore 560 040, Maharashtra (IN). GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). KANKAN, Rajendra, Narayanrao [IN/IN]; 1204, Her itage, Hiranandani Gardens, Powai, Mumbai 400 076, Ma- Published: harashra (IN). RAO, Dharmaraj, Ramachandra [IN/IN]; — with international search report (54) Title: PROCESS FOR THE PREPARATION OF PURE ANASTROZOLE (57) Abstract: A process for the preparation of anastrozole which comprises: a) brominating 3,5-bis(2-cyanoprop-2-yl)toluene (II) in an organic solvent using a brominating agent to obtain 3,5- bis(2-cyanoprop-2-yl)benzylbromide (III); b) heating the reaction mass of step a) to the reflux temperature of the organic solvent for a period of time no longer than 3 hours; c) isolating and purifying the bromo intermediate (III) using an organic solvent; d) alkylating the bromo intermediate in the presence of a base, optionally a phase transfer catalyst, a 1,2,4-triazole and an organic solvent to obtain anastrozole; and e) isolating and purifying the anastrozole from an organic solvent. Process for the Preparation of Pure Anastrozole 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, without the use of toxic, hazardous and environmentally unfriendly solvents. Background of the Invention Anastrozole is a common name for the chemically known substance 2,2'-[5-(1H-1 ,2,4- triazol-1-ylmethyl)-1 ,3-phenylene]di(2-methylpropionitrile), represented by formula (I) : I 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 anastrpzole is described in U.S. Pat. Nos. 4935437 and RE 36617 ( a re¬ issue of U.S. Pat. No.4935437 assigned to AstraZeneca Pharmaceuticals). These patents describe two synthetic routes for preparing anastrozole, one starting from methyI-3,5- dimethylbenzoate in a six-step process and the 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 CCI 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 methanokchloroform 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 tetrabutylammonium bromide (TBAB) to obtain 2,2'-(5-methyl-1 ,3-phenylene)diacetonitrile. The product is mixed with iodomethane and sodium hydride in DMF to thereby obtain 2,2'- (5-methyl-1 ,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 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. The last part of this process is shown in Scheme 1 below. Scheme I 2,2'-(5-methyl-1,3-phenylene)di 3,5-bis(2-cyanoprop-2-yl) : (2-methyl-propionitrile) ben2ylbromide Anastrozole Thus, the bromomethyl intermediate in the process is not isolated or purified in either process, but is directly converted to anastrozole in situ. As a result of using the non¬ isolated, non-purified intermediate, an impure final product is obtained. Further, the use of a chromatographic solvent such as chloroform (being a carcinogenic solvent), the use of a solvent such as carbon tetrachloride (also being a carcinogenic solvent) for the bromination reaction, and DMF for the alkylation reaction is disadvantageous with respect to industrial application. US 20060189670 describes the preparation of anastrazole by reacting 3,5 bis-(1-cyano-1 methyl ethyl)benzylhalide with 4-Z-1 ,2,4-triazole. US 2006/0035950 provides 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. A 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 Il ,5-bis(2-cyanoprop- 2-yl) 3,5-bis(2-cyanoprop-2-yl^ toluene beri2ylbromide DMF Sodium triazole Purified crude anastrozole Anastrozole The above patent describes the preparation of 3,5-bis(2-cyanoprop~2-yl)benzylbromide, which is carried out in a solvent of either dichloromethane (the yield is low), or acetonitrile (the yield is not reported) and purified (the yield reported in this process is low). There are a number of steps involved in the synthesis of anastrozole, resulting in lower yield. For example, following alkylation to produce crude anastrozole, the US'950 process involves converting the crude anastrozole to a salt of anastrozole, isolating the salt of anastrozole, optionally recrystallising the salt of anastrozole, optionally converting the salt of anastrozole to anastrozole base and isolating the product. The bromination reaction as described in '950 can be carried out in a 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)benzyl bromide, a compound of formula (IV) formed during the reaction was found to an extent of 15-20% and other problems were encountered using some of these solvents which are susceptible to bromination. IV The bromination reaction described in US '590 was followed by reflux for 4-5 hours. The US '950 inventors have found that longer reaction times cause increased levels of the impurity 3,5-bis(cyanoprop-2-yl)benzylbromide. Thus, the bromination process described in US2006/0035950 is not an efficient process to produce the product in high yield. Furthermore, the purification of the crude anastrozole involves many steps, which makes the process less suitable for industrial application and reduces yield. Because of the difficulties encountered in the process disclosed in the prior art, for example using carbon tetrachloride (CCI4) and DMF on an industrial scale, and the lower yields, it would be highly desirable to develop a process for preparing anastrozole, which does not involve the use of carcinogenic solvents like carbon tetrachloride and DMF and which results in a high yield, high purity product.
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