WO2011039782A1 - Processes for preparing imatinib and pharmaceutically acceptable salts thereof - Google Patents

Abstract

The processes for preparing imatinib and its pharmaceutically acceptable salts, specifically imatinib mesylate, are disclosed.

Description

PROCESSES FOR PREPARING IMATINIB AND PHARMACEUTICALLY

ACCEPTABLE SALTS THEREOF

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of imatinib of formula I,

FORMULA I

and its pharmaceutically acceptable salts thereof.

The present invention also relates to processes for the preparation of β-crystalline form of imatinib mesylate.

BACKGROUND OF THE INVENTION

Imatinib of formula I, is chemically known as N-{5-[4-(4-methyl-piperazinomethyl)-benzoylamido]-2- methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine

FORMULA I

It is indicated for the treatment of chronic myeloid leukemia (CML), Philadelphia chromosome positive leukemia, for patients in chronic phase and in blast crisis, accelerated phase and also for malignant gastrointestinal stromal tumors. It selectively inhibits activation of target proteins involved in cellular proliferation. Imatinib also has potential for the treatment of other cancers that express these kinases, including acute lymphocytic leukemia and certain solid tumors. Imatinib is sold in the U.S. by Novartis as Gleevec^{I M} capsules containing imatinib mesylate equivalent to 100 or 400 mg of imatinib free base.

Imatinib and other related compounds were first disclosed in US Patent 5,521 , 184. According to this patent, imatinib is prepared by the reaction of 2-amino-4-nitrotoluene with 65% nitric acid to form its nitrate salt which is condensed with aqueous solution of cyanamide to give guanidine nitrate intermediate followed by condensation with the 3-dimethylamino-l -(3-pyridyl)-2-propen-l -one in the presence of sodium hydroxide solution in isopropanol to form a nitro pyrimi ne, intermediate. This above intermediate is then reduced 50 times the volume of ethyl acetate as solvent ι sing palladium on carbon and condensed with 4-(4-methyl- piperazinomethyl)-benzoyl chloride in pyridihe to give crude imatinib, which is then purified by column chromatography. The patent is silent about ir e yield and purity of the intermediates. We have found the process described in the above patent to be u- satisfactory, where the yield of nitro intermediate was found to be only 50%. The nitro intermediate is als found to be contaminated with inorganic impurities and use of that impure material leads to a very low yield of the final compound i.e. imatinib. Usage of pyridine as a solvent and purification of the final product by column chromatography are added disadvantages of the process described in the patent.

US patent 6,894,05 1 discloses the crystalline forms of imatinib mesylate namely a- and β forms. The process for the generation of β-crystalline form of imatinib mesylate involves the reaction of imatinib base in alcoholic solvent with methane sulfonic acid. The process requires the seeding of the reaction mixture with the desired crystalline form. Use of alcoholic solvents makes the process unsuitable as this result in the formation of sulfonic esters of alcohols, which are known to be genotoxic in mammalian cell system.

US patent application 2004/0248918 discloses the preparation of amino pyrimidine intermediate which can be further converted to imatinib. The preparation of amino pyrimidine intermediate involves the reaction of 2-methyl-5-nitroaniline with an aqueous solution of cyanamide in the presence of concentrated nitric acid in ethanol to form guanidine nitrate which is then condensed with 3-dimethylamino-l-(3-pyridyl)-2-propene- 1 -one in presence of isopropanol and sodium hydroxide to give nitro pyrimidine derivative. The nitro pyrimidine intermediate is then reduced using stannous chloride and approximately 9 volumes of solvent followed by condensation to give amine pyrimidine intermediate. The process described here involves the guanidine nitrate intermediate for the further reaction.

PCT publication WO 2004/108699 discloses a process for the preparation of imatinib and its analogues by the reaction of 2-methyl-5-nitroaniline with nitric acid in n-butanol to form its nitrate salt and then reaction with an aqueous solution of cyanamide followed by washing with methanol and ether to give guanidine nitrate. The guanidine nitrate then undergoes condensation with 3-dimethylamino- l-(3-pyridyl)-2-propen-l - one to form nitro pyrimidine intermediate which is then reduced in the presence of hydrochloric acid and stannous chloride to give corresponding amino compound. The amino intermediate is then condensed with the 4-chloromethylbenzoyl chloride in the presence of triethylamine and chloroform to give benzamide intermediate, which is reacted with N-methylpiperazine to give imatinib. The yield of the nitro pyrimidine intermediate is reported around 88%, and purity is reported only by thin layer chromatography (TLC). This nitro pyrimidine intermediate is found to be contaminated with some inorganic salt impurities, which may be the reason for such a high yield. The contamination of the nitro intermediate with inorganic salt impurities is also reflected during the reduction of nitro intermediate, as it yields amine intermediate in low yield i.e. 61 .5% due to presence of inorganic salt impurities which are washed out during the workup of amine intermediate.

US patent application 2006/0149061 discloses the synthesis of imatinib starting from 2-chloro-4-(3- pyridy])-pyrimidine which is reacted with 2-amino-4-nitrotoluene in presence of catalyst to give N-(2- methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine which is purified by slurrying in a suitable solvent. The nitro pyrimidine intermediate is then reduced using catalyst in a solvent to give corresponding amine intermediate which is then condensed with 4-(4-methyl-piperazin- l-ylmethyl)-benzoyl chloride in the presence of organic solvent to give imatinib. The obtained product is then purified with a suitable solvent. The reduction reaction requires approximately 15 times solvent with respect to nitro pyrimidine intermediate, which makes the process unattractive.

US patent application 2006/173 182 discloses the preparation of imatinib by the reduction of nitro pyrimidine intermediate in the presence of stannous chloride to form the corresponding amino compound which undergoes coupling reaction with 4-(4-methyl-piperazin- l -ylmethyl)-benzoyl chloride dihydrochloride in presence of dimethylformamide as a solvent to give imatinib trihydrochloride monohydrate, which is converted to imatinib base. Imatinib thus prepared is suspended in isopropanol followed by reaction with methane sulfonic acid to give imatinib mesylate. Coupling reaction described in this patent application produces the hydrohalide salt of imatinib, which has to be treated with a base in order to afford the imatinib base, thus an extra step is required which makes the process unattractive on commercial scale.

US patent application 2008/0194819 discloses a process for the preparation of imatinib by the reaction of 2- methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to give guanidine hydrochloride intermediate which is then converted to its nitrate salt and then condensed with 3-dimethylamino-l -(3- pyridyl)-2-propene-l -one to give nitro pyrimidine derivative. The nitro pyrimidine intermediate is then reduced with Raney nickel using hydrazine hydrate, followed by condensation with 4-chloromethy (benzoyl chloride in the presence of inorganic base and finally with N-methylpiperazine to give imatinib. The process discloses the synthesis of guanidine intermediate, which is two-step reaction; firstly the hydrochloride salt is prepared which is then converted to nitrate salt. The reaction involves 99% cyanamide for the generation of guanidine nitrate, which is very difficult to handle 99% and highly toxic. Cyanamide of this much purity is also difficult to procure commercially. Even after the two step process and using highly toxic cyanamide, the condensation reaction yields nitro intermediate of low purity which on reduction with Raney nickel also requires more volume of solvent even in the presence of hydrazine hydrate. All the above shortcomings of the process make it unattractive and economically inefficient at the industrial level.

PCT publication WO 2008/ 1 17298 discloses a process for the preparation of imatinib by the reduction of N- (2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine using sodium disulfide or sodium polysulfide in ethanol to give corresponding amine intermediate which is then condensed with 4-(4-methyl-piperazin- l - ylmethyl)-benzoyl chloride in presence of potassium carbonate in alcoholic solvent to give imatinib. Use of

J sodium sulfide or sodium polysulfide is not advisable on commercial scale because of their toxicity and unpleasant smell of sulfur.

PCT publication WO 2008/136010 discloses a process for the preparation of imatinib base by the condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine with 4-(4-methyl- piperazin- l -ylmethyl)-benzoyl chloride in the presence of potassium hydroxide in chloroform to give imatinib which is further purified by converting to maleic acid salt, this requires the conversion of imatinib maleate in to the imatinib base of very high purity. The process adds an extra step for the preparation of imatinib mesylate. In addition, the process involves chloroform, which is carcinogenic and not suitable to use for the commercial production as the national toxicology programmer's report on carcinogens implicates that chloroform is reasonably anticipated to be a human carcinogen. Therefore, use of chloroform makes the process unviable.

US patent application 2008/103305 exemplified the preparation of imatinib mesylate by the treatment of imatinib free base in ethanol with methansulfonic acid. The major drawback in the reported process is the use of ethanol during mesylate salt preparation that may results in the formation of ethyl mesylate, which is proven genotoxic.

Most of the prior art processes involve the condensation of the guanidine nitrate with 3-dimethylamino- l - (3-pyridyl)-2-propene-l-one in the presence of base, to generate in situ the guanidine free base, gives nitro pyrimidine intermediate which is found to be of low purity. This may be due to the generation of inorganic salt impurities and needs purification. It is found that such inorganic salt impurities are generated during the hydrolysis of the guanidine nitrate with a base. As the guanidine nitrate intermediate is hydrolysed in situ with a base and then further reacted to give nitro intermediate. The impurities generated during the hydrolysis are carried over to nitro pyrimidine intermediate. Also during reduction of the nitro pyrimidine intermediate use of large volumes of solvent is reported, in the prior art processes which is not advisable for the commercial production of an API.

Further most of the prior art processes involve the preparation of imatinib mesylate by the treatment of imatinib in alcoholic solvent with methane sulfonic acid which can result in sulfonic acid esters of lower alcohols that are generally considered as potential alkylating agent and may exert genotoxic effects in bacterial and mammalian cell systems. These are having possible carcinogenic effects in vivo (Eder et al., 2005a, b). The need for limits on these mesylate esters in active substances has also been discussed in European Pharmacopoeia Commission. These sulfonic acid esters are highly toxic and assurance is needed that they are either absent in the final API or present in acceptable limits. Alcohols such as methanol, ethanol, isopropanol, butanol and their esters results in the formation of genotoxic impurities like methyl mesylate, ethyl mesylate, isopropyl mesylate, butyl mesylate and the like. The presence of these impurities in final API makes it not suitable for use as a drug substance.

Keeping in view of the difficulties in commercialization of the process for the preparation of imatinib described in the prior art references and considering the importance of the drug for the society, the present invention aims to solve the problems associated with the prior art. Thus, present invention provides an efficient, industrially feasible and cost effective process for the preparation of imatinib which improves the economics by providing the intermediate as well as final product in high yield as well as purity and also free from the genotoxic impurities. The process of present invention is convenient to operate on a commercial scale and gives the desired product in good yield and quality. The process of the present invention avoids the use of alcoholic solvent during the synthesis of imatinib mesylate from imatinib free base.

OBJECT OF THE INVENTION

The principal and foremost object of the present invention is to provide an improved process for the preparation of imatinib and pharmaceutically acceptable salts thereof in good yield and quality, which is efficient, industrially advantageous and convenient to operate on industrial scale.

Another object of the present invention is to provide an improved process for the preparation of imatinib wherein isolated free base of guanidine intermediate is used in place of nitrate salt of guanidine intermediate to remove the inorganic salts and other undesirable impurities prior to the reduction.

Another object of the present invention is to provide an improved process for the preparation of imatinib wherein the use of large volume of solvent during the reduction reaction and use of pyridine as a solvent at the penultimate stage is avoided.

Another object of the present invention is to provide a process for the preparation of β-crystalline form of imatinib mesylate using non-alcoholic solvent to avoid the formation of genotoxic impurities.

SUMMARY OF THE INVENTION

Accordingly, present invention provides an improved process for the preparation of imatinib of formula I,

FORMULA I

and its pharmaceutically acceptable salts thereof , which comprises the steps of:

a), reacting the compound of formula II,

FORMULA II with cyanamide in the presence of nitric acid in a suitable solvent to form guanidine nitrate intermediate of formula III;

FORMULA III b) . optionally, isolating guanidine nitrate intermediate of formula III;

c) . neutralizing the guanidine nitrate intermediate of formula III with a suitable base to form guanidine intermediate of formula IV;

FORMULA IV d). condensing isolated guanidine intermediate of formula IV with enaminoketone of formula V,

FORMULA V

in the presence of a suitable solvent to form nitro pyrimidine intermediate of formula VI;

FORMULA VI e). reducing the nitro pyrimidine intermediate of formula VI by cataiytically transfer hydrogenation in the presence of a suitable hydrogen donor over a noble metal catalyst to form amino pyrimidine intermediate of formula VII,

FORMULA VII f) . condensing the amino pyrimidine intermediate of formula VII with an intermediate of formula VIII,

FORMULA VIII wherein X is halogen or a good leaving group

in the presence of a suitable base in an organic solvent to give imatinib of formula I; and

g) . optional ly, purifying imatinib with a suitai !e solvent. According to another aspect, present invention provides a process for the preparation of β-crystalline form of imatinib mesylate, comprises the steps of:

a) , providing a solution of imatinib free base in first solvent;

b) . treating with methansulfonic acid to obtain clear solution;

c) . adding second solvent to precipitate β-crystalline form of imatinib mesylate; and

d) . isolating β-crystalline form of imatinib mesylate therefrom.

According to yet another aspect, present invention provides a process for the preparation of β-crystalline form of imatinib mesylate, comprises the steps of:

a) , providing a solution of imatinib free base in a suitable solvent;

b) . treating with a suitable carboxylic acid;

c) . adding methansulfonic acid to the reaction mixture; and

d) . recovering β-crystalline form of imatinib mesylate therefrom.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides an efficient, industrially advantageous process for the preparation of imatinib of formula I,

FORMULA I

or its pharmaceutically acceptable salts thereof starting from a compound of formula II,

H₃c ^ FORMULA II

The process involves the reaction of cyanamide with compound of formula I I in presence of nitric acid and suitable solvent to form guanidine nitrate intermediate of formula III,

FORMULA III

Generally, the reaction takes place at a temperature of 30 °C to reflux temperature of the solvent for 1 -20 hours. Preferably, the reaction takes place at reflux temperature for 1 to 5 hours. It is preferable to use aqueous solution of cyanamide instead of pure cyanamide as used in prior art processes, as it is very easy to handle aqueous solution of cyanamide as compared to highly toxic pure cyanamide. It is highly advantageous to use aqueous solution of cyanamide due to commercial non-availability of the pure cyanamide i.e. about 99% pure. Suitable solvent employed for the reaction includes alcohol such as methanol, ethanol, isopropanol, n-butanol and the like or mixture thereof. Preferably, methanol, ethanol or isopropanol can be employed as a solvent. After the completion of the reaction, the reaction mixture was cooled to 20 °C to -25 °C. The guanidine nitrate intermediate of formula III may optionally be isolated from the reaction mixture by suitable techniques such as filtration, centrifugation. The isolated product may be washed with a suitable solvent which includes alcohol such as methanol, ethanol; halogenated solvent such as dichloromethane and the like or mixture thereof. The guanidine nitrate intermediate of formula 111 in situ, or after isolation can be then neutralized with a suitable base at a temperature of 0 to 50 °C to form guanidine intermediate of formula IV,

FORMULA IV

Suitable base can be organic or inorganic base. Inorganic base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide and hydride thereof, preferably the base is selected from sodium hydroxide or potassium hydroxide and the like. The base employed in the reaction can be used as such or their aqueous solution. The guanidine intermediate of formula IV is then isolated from the reaction mixture using suitable techniques like filtration. It is highly beneficial to proceed further reaction with guanidine intermediate of IV as during workup of the intermediate inorganic salt impurities, generated during the hydrolysis of the guanidine nitrate intermediate of formula III with an inorganic base, along with some other undesired impurities are removed from the reaction mixture. Alternatively, the intermediate of formula IV can be synthesized directly from starting material of formula II without the isolation of the guanidine nitrate intermediate of formula III.

Intermediate compound of formula IV thus prepared is found to be obtained in overall high yield and purity. The guanidine intermediate of formula IV thus obtained may have purity more than 95% by HPLC, more preferably having purity 98 % by HPLC. The yield of the compound is found to be more than 65%, preferably more than 73 %, even after using the aqueous solution of the cyanamide, which is an added advantage.

It is found by the present inventor that compound of formula IV may contain isomeric analogues as impurity, which will result in the formation of isomeric analogue of imatinib by the subsequent reaction steps same for the imatinib. Therefore to control, the formation of isomeric analogues of imatinib, the guanidine intermediate of formula IV has been prepared free from all isomeric analogues of following formula,

or they are controlled up to 0.5%, preferable 0.2%, more preferably 0.05 %.

The guanidine intermediate of formula IV, undergoes condensation reaction with the enaminoketone of formula V,

FORMULA V in the presence of an organic solvent to form nitro pyrimidine intermediate of formula VI.

FORMULA VI

The enaminoketone of formula V can be prepared by the methods already known in the art or by the method as described here for reference Specifically, the preparation of enaminoketone of formula V involves the reaction of 3-acetylpyridine with NN-dimethylformamide dimethyl acetal in the presence of a suitable acid at a temperature of 25 to 1 10 °C for 1 -3 hours, preferably till the completion of the reaction. Suitable acid employed for the reaction includes carboxylic acid such as acetic acid and the like. It is preferable to remove the methanol from the reaction mixture, as methanol may form as by product in the reaction, so it is advantageous to perform the reaction under the condition favorable for the removal of methanol formed as by product. After the completion of the reaction, the solvent can be removed from the reaction mixture by suitable techniques like distillation, evaporation.

The enaminoketone of formula V is optionally isolated from the reaction mass or it can be used as such for further reaction. Preferably, enaminoketone of formula V can be extracted from the reaction mixture using a suitable solvent followed by recovery of the product from the resulting solution by solvent removal. Suitable solvent employed for the extraction includes halogenated solvent such as dichlo omethane; aliphatic or aromatic hydrocarbon such as toluene, benzene and the like or mixture thereof. The enaminoketone of formula V, thus obtained can optionally be purified using a suitable methods like crystallization, slurry wash and the like. Specifically, resulting product can be crystallized from a suitable solvent which includes but not limited to aliphatic hydrocarbon such as cyclohexane, n-hexane, n-heptane and the like or mixture thereof.

The enaminoketone of formula V or the reaction mass (as obtained above) can be then reacted with guanidine intermediate of formula IV in the presence of an organic solvent at a temperature of about 50°C to reflux temperature of the solvent till the completion of the reaction. Preferably, the reaction mixture is heated to reflux for 4- 16 hours. Suitable solvent includes ketones such as methyl isobutyl ketone, methyl ethyl ketone and the like or mixture thereof. After completion of the reaction, desired product can be isolated from the reaction mixture by suitable techniques like filtration or centrifugation. The isolated nitro pyrimidine intermediate of formula VI, if desired can be purified with a suitable solvent which includes, but not limited to ketone such as methyl isobutyl ketone, methyl ethyl ketone and the like or mixture thereof. It is highly advantageous to perform the condensation reaction by employing free base of guanidine intermediate of formula IV, instead of guanidine nitrate intermediate of formula III, with enaminoketone compound of formula V, as guanidine intermediate of formula IV is free from the inorganic impurities. The nitro pyrimidine intermediate thus obtained is found to be of good quality and may have purity more than 97%, preferably more than 98% by HPLC with comparable yields.

Thereafter, the nitro pyrimidine intermediate of formula VI is reduced to corresponding amino pyrimidine intermediate of formu

FORMULA VII

The process of reduction of nitro pyrimidine intermediate is accomplished by catalytical transfer hydrogenation. The reduction is carried out by hydrogenation over a suitable catalyst in the presence of hydrogen donor. Suitable catalyst includes palladium, ruthenium or platinum with or without support (carbon), and the like. Suitable hydrogen donor includes for example hydrazine hydrate or sodium hypophosphite and the like. Solvent includes alcohol such as methanol, ethanol, isopropanol; esters such as ethyl acetate and the like or mixture thereof. Preferably, the reduction is carried out by hydrogenation over a noble metal catalyst in particular, palladium with or without support (carbon), in the presence of hydrazine hydrate.

It is preferable to perform the reduction reaction catalytical ly as compared to chemically, which is cumbersome during workup and gives poor yield. Suitably the reaction can be carried out at temperature of 25°C to reflux temperature. Preferably, the reduction can be carried out by hydrogenation over a noble metal catalyst in particular, palladium on carbon, in the presence of hydrazine hydrate in methanol at 20°C to reflux temperature.

The use of hydrazine hydrate in the present reaction is highly efficient as its presence reduces the amount of solvent required for the reaction. The solvent used for the reaction is 3 to 12 times to the nitro pyrimidine intermediate as compared prior art where in 50 volumes of solvent has been used. Preferably solvent used is 5 to 10 times.

The amino pyrimidine intermediate of formula VII is finally converted to imatinib by the condensation with intermediate of form

FORMULA VIII wherein X is as defined above

in presence of a suitable base in an organic solvent.

The process involves the condensation reaction at a temperature of 0°C to reflux temperature of the solvent, preferably the reaction is carried out at a temperature of 0-5°C till the completion of the reaction. Base can be organic or inorganic base. Organic base includes amines such as triethylamine, trimethylmaine, diisopropylamine, diisopropylethylamine and the like. Inorganic base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide and hydride thereof such as potassium carbonate, sodium carbonate and the like. Solvent employed for the reaction includes alcohol such as methanol, isopropanol; amide solvent such as N,N-dimethylfotmamide, dimethylacetamide, N-methyl pyrrolidone; nitrile solvent such as acetonitrile; halogenated solvent such as dichloromethane; ketone such as acetone; ether such as tertrahydrofuran; aprotic solvents such as dimethylsulfoxide; sulfolane; hexamethylphosphoramide and the like or mixture thereof. After the completion of the reaction, imatinib can be isolated from the reaction mixture by suitable methods known in the art. Specifically, imatinib can be isolated either by precipitating the imatinib in the reaction mixture by the addition of water followed by filtration or reaction mixture may be quenched by suitable quenching agent that includes a suitable acid selected from hydrochloric acid, oxalic acid and the like along with a suitable solvent, if required, followed by layer separation. Acid employed can be used as such or in solution with water. After quenching of the reaction, aqueous layer may be optionally diluted with suitable solvent, which includes ester such as ethyl acetate, butyl acetate; ketone such as acetone, methyl ethyl ketone; ether such as tetrahydrofuran and the like or mixture thereof. The resulting reaction mixture is then neutralized with a suitable base to precipitate imatinib in the reaction mixture, which can be isolated by filtration or centrifugation and the like. Suitable base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide and hydride thereof such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate and the like. Preferably, aqueous solution of sodium hydroxide can be employed. The imatinib free base, thus obtained, can optionally be purified by the conventional methods such as precipitation, crystallization or slurrying, washing in a solvent, solvent employed for the purification includes water, ester such as ethyl acetate, n-propyl acetate; ether such as diethyl ether, tetrahydrofuran, diisopropyl ether, methyl tertiary butyl ether; alcohol such as methanol, isopropanol, ethanol; ketone such as acetone, methyl isobutyl ketone; hydrocarbon such as n-hexane, toluene, xylene, halogenated solvent such as chlorobenzene; nitrile solvent such as acetonitrile, and the like or mixture thereof. The solid product can be recovered by suitable techniques such as decantation, filtration by gravity or by suction, centrifugation and the like.

Imatinib free base may be converted to pharmaceutically acceptable salts of imatinib by methods already known in the art. Pharmaceutically acceptable acids used for the salt formation includes inorganic acid such as hydrochloric acid, hydrobromic acid; organic acid includes acetic acid, tartaric acid, formic acid, citric acid, oxalic acid, methansulfonic acid and the like. Preferably, imatinib mesylate is prepared.

Imatinib can be converted to imatinib mesylate by any method known in the art. Specifically, present invention avoids the use of alcoholic solvent to circumvent the possibility of formation of even low levels of alkyl sulfonate in imatinib mesylate. The present invention employes the use of non-alcoholic solvents that includes ketone such as acetone, methyl isobutyl ketone, nitrile such as acetonitrile, ether such as t- butylmethyl ether and tetrahydrofuran, amide such as N,N-dimethylformamide, N.N-dimethylacetamide, and others like N-methyl pyrrolidone, 1 ,4-dioxane; hydrocarbon such as toluene, heptane; either alone or in admixture thereof so that may not generate any sulfonic acid esters of alkyl or aryl sulfonic acids.

According to one aspect, present invention provides a process for the preparation of β-crystalline form of imatinib mesylate.

Generally, mesylate can be prepared by the reaction of imatinib base in a first solvent with methansulfonic acid. The reaction takes place at a temperature of 0°C to reflux temperature of the solvent till the formation of imatinib mesylate. First solvent is selected from the solvent in which imatinib mesylate has high solubility. It is highly advantageous to add a solvent to the reaction mixture like water in which imatinib mesylate has high solubility, so that clear solution can be obtained and resulting solution can be charcoal ised. First solvent includes aprotic solvents, mixture of water with suitable solvent selected from nitriles, ketones, ether, and the like. Preferably first solvent is selected from water: acetonitrile, water: acetone, water: tetrahydrofuran, NN-dimethylformamide and the like. After the completion of the reaction, a second solvent is added to the reaction mixture to precipitate the desired compound. Second solvent can be selected from the solvent in which imatinib mesylate has no solubility or very less solubility, that includes but limited to nitriles, ethers, ketones and the like or mixture thereof. Preferably, second solvent that can induce precipitation are selected from methyl tertiary butyl ether, acetone, acetonitrile, tetrahydrofuran or mixture thereof. The imatinib mesylate can be isolated from the reaction mixture by the suitable techniques such as filtration, centrifugation and the like. According to another aspect, present invention provides a process for the preparation of β-crystalline form of imatinib mesylate using a suitable carboxylic acid.

Generally, the process involves the treatment of imatinib free base in solvent with a suitable carboxylic acid at a temperature of 0° to reflux temperature of the solvent for few minutes to several hours. Preferably, reaction is carried out at a temperature of 0°C to 80°C. The reaction mixture was optionally charcoalised. Suitable solvent includes esters such as ethyl acetate; ketone; ethers such as tetrahydrofuran and the like or mixture thereof. To the reaction mixture, methansulfonic acid was added at a temperature of 0° to reflux temperature. The suitable carboxylic acid employed for the reaction is one that can be further replaced by methane sulfonic acid, preferably selected from acetic acid, formic acid and the like. The β-form of imatinib mesylate can be isolated from the reaction mixture by suitable methods such as cooling followed by filtration.

In another .aspect, the imatinib mesylate can be prepared by the reaction of imatinib base in a suitable solvent with methansulfonic acid at temperature of 0 °C to reflux temperature of solvent for few minutes to several hours. Suitable solvent includes ketones such as methyl ethyl ketone, methyl isobutyl ketone; and the like or mixture thereof. After the completion of the reaction, water was added to the reaction mixture and imatinib mesylate was isolated from the reaction mixture by suitable techniques like filtration, centrifugation.

Imatinib mesylate salt, thus obtained by the present invention is highly pure. The product is having purity more than 98%, preferably more than 99%, preferably purity 99.8%.

The starting material of formula VIII can be acid halide, inorganic or organic acid anhydride, mixed acid anhydride, cyclic carboxy-anhydride, active amide or ester. It can be prepared by the methods already known in the art. Specifically, it is prepared by the reaction of the corresponding acid derivative with a suitable activating agent which includes oxalyl chloride, phosphorous trihalide, phosphorous pentahalide, thionyl halide, organic acid halide like acetyl chloride, pivaolyl chloride, alkyl or aryl chloroformates, Lewis acid like boric acid, and the like.

Major advantages of the present invention lies in high purity of imatinib and as well as of imatinib mesylate. The process involves condensation of isolated guanidine free base intermediate of formula IV and with enaminoketone of formula V, which removes the inorganic salts and other impurities prior to reduction and hence over all purity and yields are improved. The process of the present invention minimizes the use of the solvent for the reduction process by employing the use of hydrazine hydrate in combination with catalyst. The present invention also avoids the formation of genotoxic impurities by employing non-alcoholic solvents during the conversion of imatinib in to its mesylate. The last but not the least advantage of the process is to avoid the use of pyridine which eliminate the requirement of removal of residue of pyridine from the final product.

Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples. It is intended that the specification, including the examples, is considered exemplary only, with the scope and spirit of the invention being indicated by the claims, which follow.

Example- 1 Preparation of N-(2-methyl-5-nitrophenyl)guanidine

To a solution of 2-amino-4-nitrotoluene (l OOg, 0.65mol) in ethanol (250ml), concentrated nitric acid (1 18.4g) was added slowly at 25-30°C. The reaction mass was stirred for 30 minutes at 50°C. Aqueous solution of cyanamide (221.2g, 50 %) was added to the reaction mixture and refluxed for 3 hours. After completion of reaction, the reaction mixture was slowly cooled to -10°C, filtered and washed with chilled ethanol/dichloromethane to give 132g of nitrate salt of title compound. The above intermediate was neutralized with aqueous sodium hydroxide solution (10%, 300ml) and filtered. The resulting solid was washed with water and dried to give 91g (72 %) of the title compound having purity 95.86% by HPLC.

Example-2: Preparation of 3-dimethylamino-l-pyridin-3-ylpropenone

Method A: 3-Acetylpyridine (25g, 0.20mol), NN-dimethylformamide dimethyl acetal (37g, 0.3 1 mol) and acetic acid (2.5ml) were heated at 90-95 °C for 2 hours with continuous removal of methanol. After completion of reaction, excess of methanol formed in the reaction was distilled out under vacuum. The resulting residue was diluted with water and extracted with dichloromethane ( 125 ml). The organic layer was washed with water and distilled out completely under vacuum to get 34g (92%) of the title compound having purity 99.1 % by HPLC.

Method B: 3-Acetylpyridine ( l OOg, 0.82mol), N,N-dimethylformamide dimethyl acetal ( 148g, 1.24mol) and acetic acid ( 10ml) were heated at 90-95 °C tor 2 hours with continuous removal of methanol. After completion of reaction, excess of methanol formed in the reaction was distilled out under vacuum. The resulting residue was diluted with toluene (1400ml) and stirred with silica gel (25g) for 30 minutes at 25-30 °C, filtered and washed with toluene. The solvent was distilled out completely under vacuum to give a residue which was crystallized with cyclohexane (200 ml), filtered and washed to give 128g (86.5%) of the title compound having purity 98.4 % by HPLC.

Example-3: Preparation of (2-methyl-5-nitrophenyl)-(4-pyridin-3-ylpyrimidin-2-yl)amine

Method A: A solution of N-(2-methyl-5-nitrophenyl) guanidine (88g, 0.45mol) and 3-dimethyl pyridin-3- yl-propenone (68.6g, 0.39mol as prepared above) in methyl isobutylketone (880 ml) was refluxed for 12 hours. After completion of reaction, the reaction mass was cooled and filtered. The resulting solid was washed and purified with methyl isobutylketone to give 96.8g (70%) of the title compound as yellow solid having purity 98.3% by HPLC.

Method B: A solution of 3-acetylpyridine (25g, 0.20mol) and N,N-dimethylformamide dimethylacetal (37g, 0.3 1 mol) in acetic acid (2.5 ml) was heated at 90-95 °C for 2 hours with continuous removal of methanol. After completion of reaction, the reaction mixture was concentrated under vacuum. The resulting residue was diluted with methylisobutylketone (250 ml). N-(2-Methyl-5-nitrophenyl)guanidine (46g) was added to the reaction mixture and refluxed for 12 hours. After completion of reaction, the reaction mass was cooled, filtered and purified with methyl isobutylketone to give 50g (79%) of the title compound having purity 98.1% by HPLC.

Example 4: Preparation of 4-methyl-N-3-(4-pyridin-3-ylpyriinidin-2-vI)benzene-l,3-dianiine

To a solution of (2-methyl-5-nitrophenyl)-(4-pyridin-3-ylpyrimidin-2-yl)amine ( lOOg, 0.32mol) in methanol (600 ml), 10% palladium on carbon (5g, 50% wet) and aqueous hydrazine hydrate (81.45g, 80 %) were added at 25-30 °C and reaction mixture was refluxed for 8 hours under inert atmosphere. After completion of reaction, the catalyst was removed by filtration and the solvent was distilled out completely under vacuum. The resulting residue was diluted with demineralized water (400 ml). The precipitated solid was filtered, washed with demineralized water and dried to give 88g (98%) of the title compound having purity 99.8% by HPLC.

Example-5 Preparation of imatinib

Method A: A mixture of 4-(4-methylpiperzin- l-ylmethyl)benzoic acid dihydrochloride hemihydrate (6.45g, 0.02mo.), thionyl chloride (25.8ml) and NN-dimethylformamide (1.61 ml) was refluxed for 20 hours. After completion of reaction, reaction mixture was distilled out completely under vacuum to give residue which was diluted with acetone (20 ml). The precipitated solid was filtered and washed with acetone to give 4-(4-methylpiperzin-l -ylmethyl)benzoyl chloride dihydrochloride. The above intermediate was added to a stirred suspension of 4-methyl-N-(4-pyridin-3-yl-pyridiin-2-yl)benzene- l ,3-diamine (5g, O.O l Smol) and potassium carbonate ( 14.92g, O. l l mol) in acetone (50ml) at 0-5°C. After completion of reaction, demineralized water (75ml) was added to the reaction mixture. The solid thus precipitated was filtered and washed with demineralized water to give 6.9g (77.5%)of the title compound having purity 99. 10% by HPLC.

Method B: A mixture of 4-(4-methylpiperzin- l -ylmethyl)benzoic acid dihydrochloride hemihydrate (6.45g, 0.02mol), thionyl chloride (25.8ml) and N.N-dimethylformamide ( 1.61 ml) was refluxed for 20 hours. After completion of reaction, the reaction mixture was distilled out completely under vacuum to give residue which was diluted with acetone (20 ml). The precipitated solid was filtered and washed with acetone ( 13 ml) to give 4-(4-methylpiperzin- i ylmethyl)benzoyl chloride dihydrochloride. The intermediate thus obtained was added to a stirred suspension of 4-methyl-N-(4-pyridin-3-yl-pyridiin-2-yl)benzene-l ,3- diamine (5g, 0.018mol) and potassium carbonate (14.92g, O. l l mol) in tetrahydrofuran (50ml) at 0-5°C. After completion of reaction, demineralized water (75ml) was added to the reaction mixture. The solid thus precipitated was filtered and washed with demineralized water to give 6.9g (90%) of title compound having purity 99.1% by HPLC.

Method C: A mixture of 4-(4-methylpiperzin-l-ylmethyl)benzoic acid dihydrochloride hemihydrate ( 1 l g, 0.03mol), thionyl chloride (44 ml) and N,N-dimethylformamide (3ml) was refluxed for 2 hours. After completion of reaction, reaction mixture was distilled out completely under vacuum. The resulting residue was diluted with toluene (33 ml). The solid thus precipitated was filtered and washed to give 4-(4- methylpiperzin-l-ylmethyl)benzoyl chloride dihydrochloride. Above intermediate was added to a stirred solution of 4-methyl-N-(4-pyridin-3-yl-pyridiin-2-yl)benzene-l ,3-diamine (5g, 0.018mol) and potassium carbonate (19.9g, 0.14mol) in NN-dimethylformamide (50 ml) at 0-5°C. After completion of reaction, demineralized water (250 ml) was added to the reaction mixture. The solid thus precipitated was filtered and washed with demineralized water to give 7.75g (87 %) of title compound having purity 99.4 % by HPLC.

Method D; A mixture of 4-(4-methylpiperzin- l -ylmethyl)benzoic acid dihydrochloride hemihydrate (45.6g, 0.316 mol), thionyl chloride (182.4 ml) and N,N-dimethylformamide (10.5 ml) was refluxed for 2 hours. After the completion of reaction, reaction mixture was distilled out completely under vacuum. The resulting residue was diluted with acetone (137 ml). The solid thus precipitated was filtered and washed to give 4-(4-methylpiperzin- l -ylmethyl)benzoyl chloride dihydrochloride. Above intermediate was added to a solution of 4-methyl-N-(4-pyridin-3-yl-pyridiin-2-yl)benzene- l ,3-diamine (25g, 0.09mol) and potassium carbonate (99.5g, 0.72mol) in acetone (500 ml) at 0-5 °C. After completion of reaction, ethyl acetate (250 ml) was added to the reaction mixture, acidified with aqueous hydrochloric acid and layers were separated. Aqueous layer was washed with ethyl acetate and then basified with aqueous sodium hydroxide solution (20%). The solid thus precipitated was filtered and washed with demineralized water to give 42g (94%) of title compound having purity: 99.2% by HPLC

Method E: A mixture of 4-(4-methylpiperzin- l -ylmethyl)benzoic acid dihydrochloride hemihydrate (45.6g, 0.14mol), thionyl chloride ( 182.4ml) and NN-dimethylformamide ( 10.5ml) was refluxed for 20 hours. After completion of reaction, the reaction mixture was distilled out completely under vacuum to give residue which was diluted with acetone ( 137 ml). The solid thus precipitated was filtered and washed with acetone (92 ml) to give 4-(4-methylpiperzin-l -ylmethyl)benzpyl chloride dihydrochloride. Intermediate thus obtained was added to a stirred suspension of 4-methyl-N-(4-pyridin-3-yl-pyridiin-2-yl)benzene- l ,3- diamine (25g, 0.09mol) and diisopropylethylamine ( 17.44g, 0.13 mol) in acetone (500ml) at 0-5°C. After completion of reaction, water (250 ml) was added to the reaction mixture. The precipitates were filtered and washed with demineralized water to give 42g (94%) of the title compound having purity 99.7% by HPLC.

Method F: A mixture of 4-(4-methylpiperzin-l-ylmethyI)benzoic acid dihydrochloride hemihydrate ( 182g, 0.57mol), thionyl chloride (728ml) and N,N-dimethylformamide (45.5ml) was refluxed for 20 hours. After completion of reaction, the reaction mixture was distilled out completely under vacuum to give residue which was diluted with dichloromethane (455 ml). The solid thus precipitated was filtered and washed to give 4-(4-methylpiperzin- l -ylmethyl)benzoyl chloride dihydrochloride. The above intermediate was added to a stirred suspension of 4-methyl-N-(4-pyridin-3-yl-pyridiin-2-yl)benzene- l ,3-diamine ( l OOg, 0.36mol) and potassium carbonate (398g, 2.88mol) in dichloromethane ( 1500ml) at 0-5°C. After completion of reaction, the reaction mass was quenched with dilute hydrochloric acid (2.1 L) and layers were separated. Aqueous layer was washed with dichloromethane (200 ml), diluted with tetrahydrofuran (600ml) and basified with aqueous sodium hydroxide solution (20%, 1.0 L). The solid thus precipitated was filtered, washed with sodium hydroxide solution and demineralized water ( 1000 ml) to give title compound, which was purified from acetonitrile (1.5L) to give 152g (85%) of pure title compound having purity 99.9% by HPLC.

Example 6: Purification of imatinib

A solution of imatinib (6.5g, having purity 99.5% by HPLC) in acetonitrile (225ml) was refluxed for 30 minutes, cooled to 25-30 °C and filtered. The resulting solid was washed with acetonitrile and dried to give 5.9g (90%) of title compound having purity 99.7% by HPLC.

Example 7: Preparation of β-crvstalline form of imatinib mesylate

Method A: Acetic acid (0.82ml) was added in a suspension of imatinib (3g, 6mmol) in ethyl acetate ( 120ml) at 50-55°C, stirred for 30 minutes. The reaction mixture was charcoalised and filtered. To the resulting filtrate, methanesulfonic acid (0.6 g, 6mmol) was added at 50-55°C and stirred for 30 minutes. The resulting mass was cooled to 25-30°C, filtered, washed with ethyl acetate and dried under vacuum to give 3g (84%) of the title compound having purity 99.3% by HPLC.

Method B: Formic acid (0.82ml) was added to a suspension of imatinib (3g, 6mmol) in ethyl acetate ( 120ml) at 50-55°C, and stirred for 30 minutes The reaction mixture was charcoalised and filtered. To the resulting filtrate, methanesulfonic acid (0.6g, 0 nmol)was added at 50-55°C and stirred for 30 minutes. The resulting mass was cooled to 25-30°C, filtered washed with ethyl acetate and dried under vacuum to give 3g (84%) of the title compound having purity ' ⁾.3% by HPLC.

Method C: Acetic acid (1.66ml) was added · > a suspension of imatinib (5g, l Ommol) in tetrahydrofuran (50ml) and refluxed for 30 minutes. etha; sulfonic acid (0.97g, l Ommol) was added to the reaction mixture and stirred for 30 minutes at 50-55°C. The resulting mixture was cooled to 25-30°C, filtered, washed and dried under vacuum to give 4.3g (72%) of the title compound having purity 99.5% by HPLC.

Method D: To a stirred suspension of imatinib (5g, l Ommol) in N,N-dimethylformamide ( 15ml), methanesulphonic acid (0.97g, l Ommol) was added to get clear solution. Reaction mixture was filtered to remove any undissolved solid. t-Butylmethyl ether (75ml) was added and stirred at 60°C. to precipitate the product. The resulting mixture was stirred at 25-30°C for 1 hour, filtered, washed with t-butylmethyl ether and dried to give 5g (84%) of the title compound.

Method E: To a stirred suspension of imatinib (5g, l Ommol) in acetonitrile (20ml) and water (10ml), methanesulphonic acid (0.97g, l Ommol) was added to get clear solution. Reaction mixture was charcoalised and filtered to remove any undissolved solid. Acetonitrile (75ml) was added to the reaction mixture at 25- 30°C. The resulting mixture was filtered, washed with t-butylmethyl ether and dried to give 5 g (84%) of the title compound having purity 99.94 % by HPLC.

Method F: To a stirred suspension of imatinib (5g, l Ommol) in tetrahydrofuran (20ml) and water ( 10ml), methanesulphonic acid (0.97g, lOmmol) was added to get clear solution. Reaction mixture was charcoalised and filtered to remove any undissolved solid. Tetrahydrofuran (75ml) was added slowly to the reaction mixture at 25-30°C. The resulting mixture was filtered, washed with t-butylmethyl ether and dried to give 5. lg (86%) of the title compound having purity 99.71 % by HPLC.

Method G: To a stirred suspension of imatinib (5g, l Ommol) in methyl isobutylketone (100ml), methanesulphonic acid (l g, l Ommol) was added and reaction mixture was stirred at 50-55°C. Water (2 ml) was added to the reaction mixture, stirred and filtered. The filtered solid was washed with methyl isobutylketone and dried under vacuum to give 5.1 g (84%) of the title compound having 99.9% by HPLC.

Method H: To a stirred suspension of imatinib (5g, l Ommol) in methyl ethyl ketone ( 100ml), methanesulphonic acid (l g, l Ommol) was added and reaction mixture was stirred at 50-55°C. Water (2 ml) was added to the reaction mixture, stirred and filtered. The filtered solid was washed with methyl ethyl ketone and dried under vacuum to give 4.7 g (79%) of the title compound having purity 99.95% by HPLC.

Method I: To a stirred suspension of imatinib ( l Og, 20.2mmol) in a mixture of acetonitrile (20ml) and demineralized water ( 10ml), methansulfonic acid (2g, 20.2mmol) was added to get clear solution. Reaction mixture was charcoalised and filtered to remove any undissolved solid. Acetonitrile (200ml) was added to the reaction mixture at 25-30°C. The resulting mixture was filtered, washed with acetonitrile and dried to give l Og (84%) of the title compound having purity 99.8% by HPLC.

Method J: To a stirred suspension of imatinib (20g, 40mmol) in a mixture of acetone (40ml) and water (20ml), methanesulphonic acid (3.92g, 40mmol) was added to get clear solution. Reaction mixture was charcoalised and filtered to remove any undissolved solid. Acetone (340ml) was added to the reaction mixture at 25-30°C. The resulting mixture was filtered, washed with t-butylmethyl ether and dried to give 20.2g (85%) of the title compound having purity 99.9% by HPLC.

Method K: To a mixture of imatinib (25g, 50mmol) in water and acetonitrile, methanesulphonic acid (3.3ml, 34mmol) was added at 25-30°C, and stirred for 30 minutes. The reaction mixture was charcoalised and filtered. Filtrate was evaporated under vacuum completely and toluene ( 150 ml) was added to the resulting residue and distilled to remove water completely. Acetonitrile ( 125ml) was added to the reaction, refluxed, cooled to 25-30°C and filtered. The filtered solid was washed with acetonitrile and dried under vacuum to give 28g (94%) of the title compound having purity 99.8% by HPLC.

Claims

WE CLAIM

1. A process for the preparation of imatinib of formula I,

FORMULA I

a), reacting the compound of formula 11,

FORMULA II

with cyanamide in the presence of nitric acid in a suitable solvent to form guanidine nitrate intermediate of formula III;

FORMULA III b) . optionally, isolating the guanidine nitrate intermediate of formula III;

c) . neutralizing the guanidine nitrate intermediate of formula III with a suitable base to form guanidine intermediate of formula IV;

FORMULA IV d). condensing the isolated guanidine intermediate of formula IV with enaminoketone of formula V,

FORMULA V

in presence of a suitable solvent to form nitro pyrimidine intermediate of formula VI;

FORMULA VI c). reducing the nitro pyrimidine intermediate of formula VI by catalytically transfer hydrogenation in the presence of a suitable hydrogen donor over a noble metal catalyst to form amino pyrimidine intermediate of formula VII; FORMULA VII

condensing t ediate of formula VII with an intermediate of formula VIII,

FORMULA VIII wherein X is halogen or a good leaving group

in the presence of suitable base in an organic solvent to give imatinib of formula I; and

g). optionally, purifying imatinib with a suitable solvent.

2. The process according to claim I , wherein in step a) suitable solvent includes alcohol such as methanol, ethanol, isopropanol, n-butanol and the like or mixture thereof.

3. The process according to claim 1, wherein in step c) suitable base is inorganic base which includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide and hydride thereof, and the like.

4. The process according to claim 1 , wherein in step d) suitable solvent is ketone.

5. The process according to claim 4, wherein suitable solvent is selected from methyl isobutyl ketone, methyl ethyl ketone and the like or mixture thereof.

6. The process according to claim 1 , wherein in step e) suitable hydrogen donor includes hydrazine hydrate or sodium hypophosphite and the like.

7. The process according to claim 1 , wherein in step e) a noble metal catalyst such as palladium, ruthenium, platinum with or without support

8. The process according to claim I , wherein step suitable base is organic base or inorganic base.

9. The process according to claim 8, wherein organic base includes triethylamine, trimethylamine, diisopropylamine, diisopropylethylamine and the like.

10. The process according to claim 8, wherein inorganic base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide and hydride thereof such as potassium carbonate, sodium carbonate and the like.

11. The process according to claim 1 , wherein step f) suitable solvent includes alcohol such as methanol, isopropanol; amide solvent such as N,N-dimethylformamide, dimethylacetamide, N-methyl pyrrolidone; nitrile solvent such as acetonitrile; halogenated solvent such as dichloromethane; ketone such as acetone; ether such as tertrahydrofuran; sulfur containing solvent such as dimethylsulfoxide; sulfolane; hexamethylphosphoramide and the like or mixture thereof .

12. The process according to claim 1 , wherein in step g) the suitable solvent includes ester such as ethyl acetate, n-propyl acetate; ether such as diethyl ether, tetrahydrofuran, diisopropyl ether, methyl tertiary butyl ether; alcohol such as methanol, isopropanol, ethanol; ketone such as acetone, methyl isobutyl ketone; hydrocarbon such as n-hexane, toluene, xylene, halogenated solvent such as chlorobenzene; acetonitrile, water and mixture thereof.

13. The process according to claim 1 , further comprising converting free base of imatinib in to imatinib mesylate.

14. A process for the preparation of β-crystalline form of imatinib mesylate, comprises the step of:

a) , providing a solution of imatinib free base in first solvent;

b) . treating with methansulfonic acid to obtain clear solution;

c) . adding second solvent to precipitate β-crystalline form of imatinib mesylate; and;

d) . isolating β-crystalline form of imatinib mesylate there from.

15. The process according to claim 14, wherein in step a) first solvent includes aprotic solvents such N,N- dimethylformamide; mixture of water with suitable solvent selected from nitriles, ketones, ether.

16. The process according to claim 15, wherein mixture of water with suitable solvent is preferably water: acetonitrile, water: acetone, water: tetrahydrofuran, and the like.

17. The process according to claim 14, wherein in step c) second solvent includes nitriles, ethers, ketone and the like or mixture thereof.

18. The process according to claim 17, wherein second solvent is selected from acetonitrile, tetrahydrofuran, acetone and the like or mixture thereof.

19. A process for the preparation of β-cry stall ine form of imatinib mesylate, comprises the step of:

a) , providing a solution of imatinib free base in a suitable solvent;

b) . treating with a suitable carboxylic acid;

c) . adding methansulfonic acid to the reaction mixture; and

d) . recovering β-crystalline form of imat inib mesylate there from.

20. The process according to claim 19, wherein in step a) suitable solvent includes esters; ketone; ethers and the like or mixture thereof.

21. The process according to claim 20, wherein esters is preferably ethyl acetate; and ethers is tetrahydrofuran and the like.

22. The process according to claim 19, wher ein in step b) suitable carboxylic acid includes formic acid, acetic acid and the like.