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:
"PROCESS FOR THE PREPRATION OF IMATINIB"
2. APPLICANTS:
I) (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 - 400 059, Maharashtra, India.

II) (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 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine with 4~(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester in the presence of base including organic bases and inorganic bases
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 kinase including acute lymphocyte 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-malignant 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 as 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-1 -(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 Jmatinib (WO 2004/108699).

Route 2 describes the successful process for the synthesis of Imatinib using 4-methyl-3-nitroanilines as the raw material, comprising condensation reaction of 4-methyl-3-nitroani lines with 4-(Chloromethyl)benzoyl chloride and N-methyl piperazidine in turns; followed by reduction of nitro group to amino group; then reaction with cyanamide to obtain guanidine; finally cyclization reaction with 3- dimethyl amino-1-(3- pyridyl)-2-propylene-1-ketone to obtain Imatinib (WO 03/066613).


Common feature of the processes for preparing imatinib according to (WO 2004/108699) and (WO03/066613) lies in 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 disadvantages are associated with the use of cyanamide is to synthesize guanidyl side chain, 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 is an additional disadvantage. 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 may cause violent reaction. Furthermore, the workers dealing with cyanamide should use appropriate personal protective clothing to prevent skin contact with cyanamide. These safety measures complicate the production procedure and increase the production cost.
Some other experimental procedure described in example 10 in PCT International Publication no. WO 2003/066613 is even less applicable to industrial purposes. These include the reaction between N-(3-bromo-4-methyl-phenyl)-4-(4-methyI-piperazin-l-ylmethyl)-benzamide and 4-(3-pyridyl)-2-pyrimidineamine which uses a mixture of rac-


BINAP (a phosphine oxide catalyst) and Pd? (dba)3*CHCb. These catalysts are very expensive and therefore, their use is unfit for commercial production.
Chinese Patent. No. CN1630648A describes a process comprising 3- bromine-4- methyl aniline as the raw material, which reacts 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 further reacts with 2-amino-4-(3-pyridyl)- pyrimidine in presence of palladium as catalyst to obtain Imatinib finally.

The drawback of the above process involves in use of trimethyl-Aluminum, which is flammable and react severely when contact with water.
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-halogen-4-(3-pyridyl)- pyrimidine to obtain Imatinib.


In the above mentioned method, the halogenated 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 avoids the 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.
Object of the invention:
It is an object of the invention to provide a simple process for preparation of imatinib by condensing 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine with 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester in the presence of base including organic bases and inorganic bases.
Summary of the invention:
The present invention discloses a new improved process for the preparation of imatinib involving condensing 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-1,3-diamine with 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester in the presence of base including organic bases and inorganic bases to yield imatinib.
Detailed description of the invention:
In preferred embodiment of the present invention, there is provided a process for preparation of imatinib, which involves the condensation of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-lf3-diamine (I) with 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester (II) in the presence of base including organic bases and inorganic bases.



The preparation of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (I) and 4-(4-Methyl-piperazin-l-ylmethy[)-benzoic acid ester (II) may be carried out according to prior art methods.
The synthesis of (I) should be referred to patent WO2004/108699.

Compound of formula I can be synthesized by using 2-methyl-5-nitroaniline as the raw material, which is reacted with 50% aqueous solution of cyanamide to obtain N-(2-Methyl-5-nitrophenyl)-guanidinium nitrate, which further reacted with 3-dimethylamino-l-pyridin-3-yl-propenone to yield (2-methyl-5-nitrophenyl)-(4-pyridin-3-yl-pyrimidin-2-yl)-amine, finally, reduction of nitro group to obtain compound of formula (I).
The synthesis of (II) should be referred synthetic communications 2003, 3597.

Compound of formula II can be synthesized by using α-haIogen-p-toluinitrile or methanesulfonic acid 4-cyano-benzyl ester or toluene-4-sulfonic acid 4-cyano-benzyl


ester as the raw material, which reacts with N-methylpiperazine, followed by hydrolysis of the cyano to acid which formed as dihydrochloride contain half crystalline hydrate, finally reaction with alcohol to obtain compound of formula (II).
The synthetic route for preparing imatinib according to the present invention is depicted in Scheme I:
Scheme 1:

In the preferred embodiment of the present invention, the coupling reaction is carried out using base including organic bases such as sodium alkoxide (sodium methylate, sodium ethylate, sodium propoxide, sodium butoxide, sodium tert-butoxide), potassium alkoxide (potassium methylate, potassium ethylate, potassium propoxide, potassium butoxide, potassium tert-butoxide), butyllithium, s-butyllithium and tert-butyllithium; and, inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and so on.
The concentration of 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 to 100°C preferably at 25 -30°C.

The solvent is selected from alcohols such as methanol, ethanol; ethers such as tetrahydrofuran, diethyl ether, isopropyl ether; chlorinated hydrocarbons such as methylene chloride, 1,2-dichloroethane; nitriles such as acetonitrile; hydrocarbons such as toluene, dimethylbenzene; esters such as ethyl acetate; polar aprotic solvents such as dimethyl sulfoxide, dimethylfomamide.
The ester group of 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester (II) is selected from C1-C10 carbon alkyl ester such as methyl ester, ethyl ester, propyl ester, butyl ester, tert-butyl ester, pentyl ester; or substitutive benzyl ester or substitutive phenyl ester.
In this process, 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (I), reacts with 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester (II) in the presence of 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. The aminolysis reaction of ester is easy and clean. Further, the by¬product is alcohol 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.
Examples: Example 1
To a solution of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (27.7g) and 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid methyl ester (50g) in Tetrahydrofuran (250ml), a solution of sodium methylate (lOg) in methanol (10ml)


as added. The reaction mixture was heated to reflux. After completion of the reaction solution was poured into ice-water and a large amount of solid precipitated, which was filtered and washed with water and dried to obtain Imatinib base (45g). Yield: 91%.
The spectral data is as follows:
'HNMR ( 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, IH), 8.00 (s, IH), 7.98 (s, IH), 7.58-7.51 (m, 4H), 7.44 (d, J=4.3 Hz, IH), 7.22 (d, J=8.1 Hz, IH), 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 Example 2
To a solution of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (27.7g) and 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid methyl ester (50g) in toluene (250ml), a solution of sodium ethylate (20g) in methanol (10ml) was added. The reaction mixture was heated to reflux. After completion of the reaction, solution was poured into ice-water and a large amount of solid precipitated, which was filtered and washed with water and dried to obtain Imatinib base (44g). Yield: 91%.
Example 3
To a solution of potassium butoxide (250g) in methanol (1000ml), a solution of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (277g) and 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid propyl ester (600g) in Tetrahydrofuran (2500ml) was added. The reaction mixture was stirred at room temperature. After completion of the reaction solution was poured into ice-water and a large amount of solid precipitated, which was filtered and washed with water and dried to obtain Imatinib base (450g). Yield: 91%.


Example 4
To a solution of potassium butoxide (25kg) in ethanol (100 litre), a solution of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-1,3-diam ine (27.7kg) and 4-(4-Methyl-piperazin-l-ylmethyI)-benzoic acid ethyl ester (50.0kg) in toluene (250 litre) was added. The reaction mixture was stirred at room temperature. After completion of reaction, solution was poured into ice-water and a large amount of solid precipitated, which was filtered and washed with water, and dried to obtain Imatinib base (40.0kg). Yield: 81%.


We claim,
1. A process for preparation of imatinib free base comprising condensing 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-y l)-benzene-1,3-diamine with 4-(4-Methyl-piperazin-1 -ylmethyl)-benzoic acid ester in the presence of base including organic bases and inorganic base in an organic solvent to form imatinib.
2. The process as claimed in claim 1, wherein said base is selected from including organic bases such as sodium alkoxide (sodium methylate, sodium ethylate, sodium propoxide, sodium butoxide, sodium tert-butoxide), potassium alkoxide (potassium methylate, potassium ethylate, potassium propoxide, potassium butoxide, potassium tert-butoxide), butyllithium, 5-butyllithium and tert-butyllithium; and inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide.
3. The process according to claim 1, wherein the base used in the coupling reaction is in a concentration ranging from 0.1M to 10M.
4. The process according to claim 1, wherein the reaction is carried out at a temperature ranging from 20 to 100°C, preferably at 25 - 30°C.
5. The process as claimed in claims 1 and 2, wherein solvent is selected from alcohols such as methanol, ethanol; ethers such as tetrahydrofuran, diethyl ether isopropyl ether; chlorinated hydrocarbons such as methylene chloride, 1,2-dichloroethane; nitriles such as acetonitrile; hydrocarbons such as toluene, dimethylbenzene; esters such as ethyl acetate; polar aprotic solvents such as dimethyl sulfoxide, dimethylfomamide.
6. A process for preparing imatinib free base substantially described herein with reference to foregoing examples 1 to 4.
Dated this 5th day of November 2008

Jain, Mohan Babulal
For Mac Chem Products Pvt. Ltd.

Zhan Huaxing
For Shanghai Parling Pharmatech Co. Ltd.