FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"A PROCESS OF PREPARING IMATINIB"


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 describes the invention.


Field of the Invention:
The present invention relates to a novel process for the preparation of imatinib (formula I).
Background of the Invention:
Imatinib is a N- phenyl-2- pyrimidine amine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It is used in chronic myleogenous leukemia (CML), gastrointestinal stromal tumors (GIST) and a number of other malignancies. It is currently marketed by Novartis as Gleevec as its mesylate salt. Imatinib is represented by structural formula I.

The preparation of Imatinib, chemically termed as 4-(4-methylpiperazin-l-yImethyl)-N-[4-methyl -3-(4-pyridin-3-yl) pyrimidin-2-ylamino)phenyl]benzamide and the use thereof, especially as an anti-turner agent, is described in EP 0564409 & US 5521184. WO 99/03854 describes preparation of imatinib mesylate from imatinib free base, the preparation of the latter being referred to above mentioned EP0564409. WO2004/108699, US2006/0149061, US2006/0173182, WO2006071130 also describe various processes to prepare imatinib. The common feature of the processes for preparing imatinib is the condensation of amine with activated carboxylic acids as either acid chloride or ester.
Thus there is continuous need for simple, high yielding process for the preparation of imatinib which can be carried out under milder conditions to give imatinib substantially, free from impurity.

We have now found a surprisingly simple process for the preparation of imatinib, which overcomes the problems associated with the prior art method.
Objects of the Invention:
The object of the present invention is to provide an improved process for preparing
imatinib.
Another object of the present invention is to provide a process which is simple,
economical and suitable for industrial scale-up.
Brief Description of the present Invention:
The present invention provides an improved process for the preparation of imatinib base which ensures high yields in the subsequent steps, simple & economical thereof. The process is depicted below in scheme 1:
In accordance with the invention as herein described, imatinib may be prepared by a process as


wherein, L is a leaving group, preferably halo & nHHal represents an acid addition salt wherein; n represents 0,1, 2 and 3 and Hal represents bromo, chloro , fluoro or iodo; in

particular bromo or chloro, and especially chloro; (in particular a hydrobromide or hydrochloride, and more particularly a hydrochloride); which can be optionally converted to its acid addition salt.
According to the present invention, there is provided a process for preparing imatinib, either as the free base or as an acid addition salt, comprising steps of;
a) reacting compound of formula (II) with 4-halomethyl benzoic acid of formula (III) using a coupling agent in the presence of a suitable solvent, to yield amide, 4- halomethyl-N- {[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino]- phenyl}-benzamide of formula (IV);
b) condensing compound of formula (IV) with N-methyl piperazine of formula (V) in a suitable solvent to yield imatinib of formula (I) either by isolating hydrohalide salt of imatinib of formula (la) or without isolation of hydrohalide salt of imatinib of formula (la).
In a preferred embodiment, compound of formula (IV) is reacted with N-methyl piperazine of formula (V) to yield imatinib of formula (I), without isolating hydrohalide salt of imatinib of formula (la).
A suitable coupling reagent in step (a) according to the present invention can be selected from the group comprising of phenylsilane, IJ'-carbonyldiimidazole (CDI), benzotriazol-1-yloxytris (dimethylamino) phophonium hexafluorophosphate (BOP), 1-hydroxy benzotriazole hydrate (HOBt), PyBOP(Analog of the BOP), 1,3-dicyclo hexylcarbodiimide (DCC), n-Ethyl-N'-(3-dimethylaminopropyl) carbodidimide hydrochloride (EDC HC1).A particularly suitable coupling reagent for use in the above process according to the present invention is EDC HC1.
A suitable inert organic solvent in step (a) according to the present invention can be selected from the group consisting of halogenated solvent such as chloroform, dichloromethane (MDC); polar solvents such as dimethylformamide (DMF), dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone, sulfolane, diglyme, 1,4-dioxane, tetrahydrofiiran, acetonitrile, acetone and mixture thereof. In the preferred embodiment halogenated solvent is used in combination with polar solvent to

increase overall solvent power. The process is carried out at suitable temperature until no starting material is detectable. Preferably, the reaction is carried out at 10-40°C, more preferably at 25-30°C. The amide of formula (IV) is easily isolated from the reaction mixture by quenching reaction mass in water and can be optionally converted to base.
Solvents used for the condensation process in step (b), are selected from polar protic or aprotic solvents. A preferred solvent for the reaction is protic solvent, preferably alcoholic solvents. The example of alcoholic solvents include, but not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, n-pentanol and the like or mixtures thereof. The condensation may be carried out at a temperature ranging from 25°C to boiling point of the solvent, preferably at 40-60°C.
It will be appreciated that the above process steps do not require high temperature for the reaction as reported in the prior art, but is carried out under mild conditions whereby very little by-products are produced in the reaction. The isolation of imatinib as a hydrohalide salt is a method of purification of the product. Furthermore, the above process is suitable for large-scale production and is economical to operate.
The hydrohalide salt of imatinib of formula (la), especially a hydrochloride salt of imatinib of formula (la) can be treated with a suitable base to yield imatinib which is further converted to an acid addition salt of imatinib such as imatinib mesylate.
Compounds of formula (II) & (III) may be prepared by the methods known to a person skilled in the art.
The present invention also provides a method of treating a diseased state prevented, ameliorated or eliminated by the administration of an antineoplastic in patient in need of such treatment, in particular tumor disease, which method comprises administering to the patient an effective amount of imatinib or a pharmaceutically acceptable salt thereof prepared according to the present invention, substantially as hereinbefore described.

Imatinib obtained by the process of the present invention may be employed alone or in combination with other suitable therapeutic agents useful in the treatment of protein tyrosine kinase associated disorders.
While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.
The present invention will now be further illustrated by reference to the following examples, which do not limit the scope of the invention any way.
Examples:
Example 1 :-Esterification of p-Toluicacid
A solution of 100 ml methanol and p-Toluic acid (20g, 0.147 mol) was heated to 55-60° C and maintained for 4-5 hr. The methanol was removed under reduced pressure. The reaction mass was cooled to room temperature and partitioned between water (50 ml) and dichloromethane (50 ml).The organic phase was separated, the aqueous phase was back-extracted with dichloromethane (50 ml).The organic phases were combined, washed with 10% sodium bicarbonate solution to set the pH to 7, dried over anhydrous sodium sulphate and distilled out in vacuum to give 15 g (68%)of title compound.
Example 2 >Chlorination of p-Toluic acid methyl ester
To a stirred solution of p-Toluic acid methyl ester (15 g, 0.1 mol), benzoyl peroxide (8 g, 0.033 mol) and acetonitrile (150 ml) was added acetic acid (0.5ml) at room temperature. The reaction mass was stirred for 15 minutes and heated to 50-55° C. N-chloro succinimide (29.4 g, 0.22 mol) was added in lots over a period of 2 hr. The temperature of the reaction mass was raised to 75° C before being cooled to room temperature. The

reaction mass was partitioned between water (70 ml) and dichloromethane (70 ml).The organic phase was separated; the aqueous phase was back-extracted with dichloromethane (70 ml). Separated the dichloromethane phase. The organic phases were combined, washed with 10% sodium bicarbonate solution to set the pH to 7, dried over anhydrous sodium sulphate and distilled out in vacuum to give 14 g (75.88%) of title compound.
Example 3 :-Hydrolysis of 4-Chloro methyl benzoic acid methyl ester
4-Chloro methyl benzoic acid methyl ester (14 g, 0.0758 mol) and water (100 ml) were stirred at room temperature. The pH of the reaction mass was adjusted to 2-3 with acetic acid and stirred for 15 minutes. The solid obtained was filtered, washed with water (10 ml) and dried under vacuum at 50-55° C to give 12.5 g (96.67%) of title compound.
Example 4 :- Preparation of N-{4-methyl-3-IT4-f3-pyridiny1)-2-pyrimidinyl1 amino! phenvl-4-chloromethvl benzamide
To a stirred solution of chloroform (80 ml), 4-chloromethyl benzoic acid (12.5 g, 0.0733 mol), N-(2-methyl-5-amino-phenyl)4-(3-pyridyl) -2-pyrimidine amine (10.1 g, 0.0364 mol) and EDC.HC1 (28.1 g, 0.146 mol) was added DMF (5 ml). The reaction mass was stirred for 1 hr at room temperature. Water (50 ml) was added and the pH of the reaction mass adjusted to 9-10 using liquor ammonia and stirred for 30 min. The reaction mass was filtered and washed with 10 ml of water. The solid obtained was dried under vacuum at 60-65° C to give 8.6 g (27.31%) of title compound.
Example 5 : Preparation of 4T(4-Methyl-l-piperazinyl) methyl1-N-(4-methyl-3-[[4-(3-pvridinyP-2-pyrimidinyn amino] phenyl benzamide (Imatinib base)
To a stirred solution of n-butanol (50 ml), N-(4-methyI-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino] phenyl-4-chloromethyl benzamide (4 g, 0.0093mol) was added N-methyl piperazine (2.01 g, 0.0372 mol). The reaction mass was heated to 50-55° C for 6 hr and then cooled to room temperature. The solvent was distilled off under reduced pressure. The reaction mass was partitioned between water (50 ml) and dichloromethane (50 ml) and adjusted the pH to 7-8 using acetic acid. The organic phase was separated; the aqueous phase was back-extracted with dichloromethane (50 ml). Combined

dichloromethane phases were washed with water (20 ml), dried over sodium sulphate, concentrated in vacuum at 40-45° C, and acetonitrile (5 ml) was added. The solid obtained was filtered and dried under vacuum at 50-55° C to give 2.8 g (60.86%) of title compound.
Dated this 30th day of December 2008