Title of Invention	PROCESS FOR THE PREPARATION OF IMATINIB MESYLATE
Abstract	Disclosed herein is a process for preparation of imatinib free base which comprises condensing N-(4-methyl-3-amino phenyl)-4-(4-methyl-piperazinyl-l-methyl)-benzamide with 4-methyl-(3-pyridyl)-2-pyrimidone, using polypeptide coupling agent in the presence of organic base as acid absorbing reagent in an organic solvent to form imatinib.

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FORM 2 THE PATENTS ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION: "PROCESS FOR THE PREPRATION OF IMATINIB MESYLATE" 2. APPLICANTS: (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. (a) NAME :SHANGHAI PARLING PHARMATECH CO. LTD. (b) NATIONALITY: China Company incorporated under the Chinese Companies Law (c) ADDRESS: Suite 2, No. 868 Zhenchen Road, Baoshan District, Shanghai, 200 444, China. 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. Technical Field: The present invention relates to an improved process for the preparation of imatinib involving condensing N-(4-methyl-3-amino phenyl)-4-(4-methyl- piperazinyl-1-methyl)-benzamide with 4-methyl-(3- pyridyl)-2~pyrimidone in the presence of polypeptide condensating reagent and organic base as acid absorbing reagent, to obtain imatinib. Background and Prior Art: Imatinib is known as an inhibitor of protein-tyrosine kinase and is indicated for the treatment of chronic myeloid leukemia (CML). Imatinib also has potential for the treatment of various other cancers that express these kinases including acute lymphocytic leukemia and certain solid tumors. It can also be used for the treatment of atherosclerosis, thrombosis, restenosis, or fibrosis. Thus, imatinib can also be used for the treatment of non-maligant diseases. Imatinib is usually administered orally in the form of a suitable salt, e.g., in the form of imatinib mesylate. Imatinib Mesylate is an inhibitor of signal transduction (STI571) invented by Novartis AG after 7 years of hard work; it is the first inhibitor of cancer signal transduction ratified in the whole world. It is sold by Novartis as Gleevec capsules containing imatinib mesylate in amounts equivalent to 100 mg or 400 mg of imatinib free base. Imatinib Mesylate is the rare drug in America, European Union and Japan. In May 10, 2001, it was ratified by American Food and Drug Administration (FDA) to treat the chronic myelogenous leukemia patients. Imatinib Mesylate is called as 4-(4-methyl piperazine -1- methyl) -N-4-methyl-3-[4-(3-pyridyl) pyrimidine-2-amino] - benzamide and is represented by the following structural formula: (Imatinib) There are generally two synthetic routes for synthesis of Imatinib, suitable for the industrial production. One synthetic process described in route 1 comprises using 2-methyl-5-nitroaniline as the raw material which is reacted with cyanamide to obtain guanidine; cyclization reaction with 3-dimethylamino-l-(3-pyridyl)-2-propylene-l-ketone; reduction step of nitro to amine and condensation reaction with 4-(Chloromethyl)benzoyl chloride and N-methylpiperazidine to obtain Imatinib (WO 2004/108669). Route 2 describes the successful process using 4-methyl-3-nitroanilines as the raw material. i) condensation reaction of 4-methyl-3-nitroanilines with 4-(Chloromethyl)benzoyl chloride and N-methyl piperazidine in turns; reduction step of nitro to amine; reacted with cyanamide to obtain guanidine; cyclization reaction with 3-dimethyl amino-1-(3- pyridyl)-2- propylene-1-ketone, to obtain Imatinib (WO 03/066613). The common feature of the above processes for preparing imatinib according to (WO 2004/108669) and (WO03/066613), which are described herein above, lies in the use of cyanamide as a reagent. The main difference between the two routes is that the reaction sequence of cyclization of pyrimidine chain is different. The disadvantage in use of cyanamide to synthesize guanidyl side chain is that since the cyanamide is low boiling and easy to volatile thereby isolated yield of guanidyl is low. Consequently, the synthetic yield of pyrimidine chain is also low; moreover, longer reaction time. Therefore, the raw material cannot be consumed totally. The usage of cynamide in the pharmaceutical industry is disadvantageous, because it is highly toxic, hazardous and corrosive reagent. Contact of cyanamide with water, acid and alkali's may cause violent reaction. Furthermore, the workers dealing with cyanamide should use appropriate personal protecting clothing to prevent skin contact with cyanamide. These safety measures complicate the production procedure and increase the production cost. Some other experimental procedures described in example 10 in patent application (WO 2003/066613), are even less applicable to industrial purposes. These include the reaction between N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-l-ylmethyl)-benzamide and 4-(3'-pyridyl)-2-pyrimidineamine which uses as a reagent mixture of rac-BINAP( a phosphine oxide catalyst) and Pd2(dba)3*CHCl3. These catalysts are very expensive and therefore, their use is upfit for commercial production. Chinese Patent. No. CN1630648A describes the process which comprise using 3-bromine-4- methyl aniline as the raw material, reacted with 4-(4-methyl-piperazin-methyl) methyl benzoate in presence of trimethyl-Aluminum to obtain N-(4-methyl-3-bromobenzene)-4-(4-methyl-piperazin-l- methyl)- benzamide, which is reacted with 2-amino-4-(3-pyridyl)- pyrimidine in presence of palladium as the catalyst to obtain Imatinib finally. The drawback of the above the process involves in use of trimethyl-Aluminum, which is flammable and react severely when contact with water. There will be an impurity of isomer in an amount of 10% in the final product and it is very difficult to purify. Chinese Pat. No. CN101016293A describes another process using N- (4-methyl-3-3-aminophenyl)-4-(4-methyl-piperazin-l-methyl)- benzamide as the raw material. This raw material is reacted with 2-halogeno-4-(3-pyridyl) - pyrimidine to obtain Imatinib. In the above mentioned method, the halogenation agent, such as phosphorus oxychloride, which is used to synthesize 2-halogeno-4- methyl- (3-pyridyl) - pyridine, is lachrymator and corrosive and has great influence to the surrounding. Thus, there is a need in the art to develop novel synthetic route which overcomes the above limitations mentioned in the prior art processes and without any use of cyanamide which is highly corrosive and toxic. Further, there is a need in the art for a process for preparing imatinib which is less hazardous and more environmental friendly. Objective of this invention: It is an object of the invention to provide a simple process for preparation of imatinib mesylate by condensing N-(4-methyl-3-amino phenyl)-4-(4-methyl- piperazinyl-1-methyl)-benzamide with 4-methyl-(3-pyridyl)-2-pyrimidone in the presence of polypeptide condensating reagent It is another object of the invention to provide a process for preparation of imatinib mesylate without any use of synthetic guanidinyl and pyrimidine derivative and thereby, increasing the yield of imatinib mesylate. Summary of the invention: The present invention discloses a new improved process for the preparation of imatinib mesylate involving condensing N-(4-methyl-3-aminophenyl)-4-(4-methyl- piperazin-1-methyl)-benzamide with 4-methyl-(3-pyridyl)-2-pyrimidone using polypeptide condensating reagent as coupling reagents and organic bases as acid absorbing reagents, to yield imatinib. Detailed description of the invention: In preferred embodiment of the present invention, there is provided a process for preparation of imatinib mesylate, which involves the condensation of N-(4-methyl-3-aminophenyl)-4-(4-methyl- piperazin-1-methyl) - benzamide (I) with 4-methyl-(3-pyridyl)-2-pyrimidone (II) by using Polypeptide condensating reagent as coupling reagent in the presence of organic base as acid absorbing reagent. (") (I") The preparation of N-(4-methyl-3-aminophenyl)-4-(4-methyl-piperazin-l-methyl)-benzamide (I) and 4-methyl-(3- pyridyl)-2-pyrimidone (II) may be carried out according to the prior art methods. The synthesis of (I) should be referred to patent US20060142580. (I) Compound of formula I can be synthesized by using 4-methyl-3-nitroaniline as the raw material, reacted with 4-(4-methyl- piperazine-methyl) benzoyl chloride to obtain N-(4-methyl-3-nitrophenyl)-4-(4-methyl-piperazine-l-methyl)-Benzamide, and then reducing the nitrogroup to obtain compound of formula (I). The synthesis of (II) should be referred to patent US2006/0149061A1. Compound of formula II can be synthesized by using 3-acetylpyridine as the raw material, reacted with dimethylacetal N, N-dimethyl formamide and then reacted with urea to obtain pyrimidinone. The synthetic route for preparing imatinib according to the present invention is depicted in Scheme 1: Scheme 1: In the preferred embodiment of the present invention the coupling reaction is carried out using polypeptide condensating agent selected from phosphonium hexafluorophosphate or 3-(diethoxy-phosphoryloxy)-l,2,3-benzotriazin-4-ketone (DEPBT). The said phosphonium hexa-fluorophosphate is selected from Bromo- tris- pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) or Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). The organic base used for coupling is selected from triethylamine, diisopropylethylamine, pyridine, piperidine, Sparteine or 1, 8-diazabicyclo [5,4,0]-undec-7-ene (DBU). The concentration of the base used in reaction solution is in the range from 0.1M to 10M. The coupling reaction is carried at a reaction temperature ranging from 20 - 60°C preferably at 25 - 30°C. The solvent is selected from tetrahydrofuran, ether, methylene chloride, 1,2- dichloroethane, acetonitrile, 1-4 carbolic sterols, toluene, ethyl acetate or dimethylbenzene. In this process N-(4-methyl-3-aminophenyl)-4-(4-methyl-piperazin-l-methyl)- benzamide (I), reacts with 4-methyl-(3- pyridyl)-2- pyrimidinone (II), under the effect of polypeptide condensating agent and organic base, to obtain Imatinib. The process of the present invention overcomes the limitation of the different drawbacks mentioned in prior art processes. The reaction is carried out under moderate conditions and is easy to operate. In the present invention, the synthetic guanidyl and pyrimidine derivatives are not used, so the yield obtained is higher. Further, the process involves in use of polypeptide condensation reagent to synthesize pyrimidine derivative which is nontoxic thereby, making the process eco-friendly. The reaction yield is high and is suitable for industrial production. The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. Example 1 To a solution of N-(4-methyl-3-aminophenyl)-4-(4-methyl-piperazine-l-methyl)-Benzamide (33.8) and 4-methyl-(3-pyridyl)-2-pyrimidin-one (17.3g) in tetrahydrofuran (250ml), cooled in ice-water bath, (benzotriazole-l-yl-oxy-tris(dimethyl-amino)-phosphonium hexafluorophosphate) (BOP) (50g) and 1,8-diazabicyclo [5,4,0]-undec-7-ene (DBU)(16g) were added dropwise. After the addition, cooling bath was removed and the reaction mixture was brought to room temperature and stirred overnight. The solution was concentrated in vacuum, to obtain a residue, which was washed with water and dried to obtain Imatinib base (45g), yield: 91%. The spectrum data is as follows: 'H NMR ( 500M , DMSO ) 5 : 10.2 (s, 1H), 9.30 (s, 1H), 8.99 (s, 1H), 8.72 (d, J=4.0 Hz, 1H), 8.57 (s, 1H), 8.53 (s, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.98 (s, 1H), 7.58-7.51 (m, 4H), 7.44 (d, J=4.3 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 3.70 (s, 2H), 3.50-3.25 (m, 2H), 3.20-2.90 (m, 4H), 2.81 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H). 13C NMR (125M , DMSO ) 5 : 164.9, 161.3, 161.1, 159.4, 150.8, 147.7, 137.7, 137.1, 134.9, 134.3, 132.3, 129.9, 129.1, 127.7, 127.6, 123.9, 117.2, 116.8, 107.5,59.9,52.1,48.9,42.2, 17.5. MS (M++l): 494.3 10 Example 2 To a solution of N-(4-methyl-3-aminophenyl)-4-(4-methyl-piperazine-l-methyl)-Benzamide (33.8) and 4-methyl-(3-pyridyl)-2- pyrimidin- one(17.3g) in acetonitrile (250ml), cooled in ice-water bath, (benzotriazole-l-yl-oxy-tris_(dimethyl-. amino)-phosphonium hexafluorophosphate) (BOP)(50g) and 1,8-diazabicyclo [5,4,0]-undec-7-ene (DBU)(16g) were added dropwise. After the addition, the cooling bath was removed and the reaction mixture was warmed up to room temperature and stirred overnight. The solvent was concentrated to obtain residue, which is washed with water and dried to obtain Imatinib base (44g), yield: 89%. Example 3 To a solution of N- (4-methyl-3-aminophenyl)-4-(4-methyl-piperazine-l-methyl)- Benzamide (338) and 4-methyl- (3-pyridyl)-2- pyrimidin- one(173g) in toluene (2500ml), cooled in ice-water bath, Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate ( PyBrOP ) (500g) and triethylamine (160g) were added dropwise. After the addition, the cooling bath was removed, the reaction mixture was warmed to room temperature and was stirred overnight. The solvent was concentrated to obtain residue, which is washed with water and dried to obtain Imatinib base (445g), yield: 90%. Example 4 To a solution of N- (4-methyl-3-aminophenyl)-4-(4-methyl-piperazine-l-methyl)-Benzamide (3.38kg) and 4-methyl-(3-pyridyl)-2-pyrimidin-one( 1.73kg) in acetonitrile (25L), ' cooled in ice-water bath, Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate ( PyBrOP ) (5Kg) and Diisopropylethylamine (1.6Kg) were added dropwise. After the addition, the cooling bath was removed, the reaction mixture was wanned to room temperature and stirred overnight. The solvent was concentrated to obtain residue, which was washed with water and dried to obtain Imatinib base (4kg), yield:81%. 11 We claim, 1. A process for preparation of imatinib free base comprising condensing N-(4-methyl-3-amino phenyl)-4-(4-methyl-piperazinyl-l-methyl)-benzamide with 4-methyl-(3-pyridyl)-2-pyrimidone, using polypeptide coupling agent in the presence of organic base as acid absorbing reagent in an organic solvent to form imatinib. 2. The process as claimed in claim 1, wherein said polypeptide condensating agent is selected from phosphonium hexafluorophosphate or 3-(diethoxy-phosphoryloxy)-l,2,3-benzotriazin-4-ketone (DEPBT). 3. The process as claimed in claims 1 and 2, wherein Phosphonium hexafluorophosphate is selected from Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP) or Benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). 4. The process as claimed in claims 1 and 2, wherein said organic base is triethylamine, diisopropylethylamine, pyridine, piperidine, cytisine or 1,8-Diazabicycloundec-7-ene (DBU). 5. The process according claim 1, wherein the base used in the coupling reaction is at a concentration ranging from 0.1M to 10M. 6. The process according to claim 1, wherein the reaction is carried out at a temperature ranging from 20 to 60°C preferably at 25 - 30°C. 7. The process as claimed in claims 1 and 2 wherein, the solvent used is selected from tetrahydrofuran, ether, dichloromethane, 1,2-dichloroethane, acetonitrile, 1,4-carbonic sterol, toluene, ethyl acetate or dimethyl- benzene. 8. A process for preparing imatinib free base substantially described herein with reference to foregoing examples 1 to 4.

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