FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"Process for preparation of Imatinib mesylate"
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.

Technical field of the invention:
The present invention relates to a novel process for the synthesis of imatinib either as a free base or acid addition salts thereof, and also such imatinib free base and imatinib acid addition salts prepared by the process of the present invention.
Background and detailed description:
Imatinib is a 2- phenylpropylamine 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.

(I)
EP 0564409, equivalent of US 5521184 describes the preparation of imatinib and the use thereof, as an antitumor agent. The process involves reduction of N-(2-methyl-5-nitrophenyl)-6-pyridinre -3-yl-l,6-dihydropyrimidine-2-yl)-amine to yield N-(2-methyl-5-aminophenyl)-6-pyridinre -3-yl-l,6-dihydropyrimidine-2-yl)-amine, followed by amidation with 4-(4-methyl-piperazino methyl)benzoyl chloride to yield imatinib. In the prior art processes the reduction is carried out in the presence of palladium catalyst under hydrogenation conditions. The condensation is carried out in the presence of a base like pyridine, triethylamine or the like. 4-(4-methyl-piperazino methyl)benzoyl chloride is obtained as dihydrochloride and is used as such for amidation step, and further an equivalent amount of acid is released during condensation. Hence, the person skilled in the art would be expected to use base as an acid scavenger to neutralize 4-(4-methyl-


piperazino methyl)benzoyl chloride and for the acid released during the reaction prior to reaction with N-(2-methyl-5-aminophenyl)-6-pyridinre-3-yl-l,6-dihydropyrimidine-2-yl)-amine. The condensation reaction was slow, gave rise to undesirable side products, such as Impurity A and Impurity C as shown below:
H


N-(5-amino -2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidine amine (Impurity A)

N-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-yl amino)-phenyl]-4-chloromethyl benzamide (Impurity C)
These impurities A and C are said to be genotoxic and hence, it is desirable to reduce these limits below 20 ppm in the final product. Use of pyridine as a solvent in the final step was found to be undesirable since, removal of residual traces of the pyridine from the final product was difficult. As a result, additional purification steps are required to remove the impurities formed, and thereby, resulting low yielding of the imatinib.
The synthesis of imatinib mesylate is described in WO 99/03854, WO03/066613, WO2004/108699, US2006/0149061, US2006/0173182 and WO206071130. WO99/03854 describes preparation of imatinb mesylate from imatinib free base, the preparation of the latter being referred to above mentioned EP0564409.
WO03/066613 describes several synthetic routes for preparation of imatinib. Among those several processes, one of the process describes reacting 4-(4-methyl-pipearzyn-l-


ylmethyl)-benzoic acid with thionyl chloride in toluene to yield 4-(4-methyl-pipearzyn-l-ylmethyl)-benzoyl chloride, which is further condensed with 4-methyl-3-nitro aniline in the presence of pyridine and toluene at 45°C to yield N-(4-methyl-3-nitro-phenyl)-4-(4-methyl-piperazin-l-ylmethyl)-benzamide. The benzamide is further reduced to nitro & reacted with cyanamide in butanol to N-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-l-ylmethyl)-benzamide, which on further reaction with 3-dimethylamino-l-pyridin-3-yl-propenone yields imatinib.
However, there is no example disclosing the direct condensation of carboxylic acids with amine to yield amide. Further, direct conversion of carboxylic acids to amides is difficult and typically requires high reaction temperature, e.g. of about 200°C, or use of strong bases, such as sodium methoxide, sodium amide, n-butyl lithium, sodium hydride or Grignard reagent as reported in the WO03/066613.
WO2004/108699, US2006/0149061, US2006/0173182, WO206071130 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. All these processes result in the formation of genotoxic Impurities A and C to an extent of 100 to 300 ppm, which are difficult to remove by known purification techniques.
Thus, the prior art processes for the preparation of imatinib base have several disadvantages such as low yield, low purity due to the formation of impurity A and impurity C. Also, process involves use of undesirable solvents which can not removed easily so further purification is required to remove such a solvent thereby resulting in a low yield . Thus, there is need in the art for simple, high yielding process for the preparation of imatinib which can be carried out mild under mild reaction conditions to give highly purified imatinib substantially, free from impurity.
We have now found a surprisingly simple process for the preparation of imatinib, which provides an improved amidation step by condensing amine of formula (II) with carboxylic acids of formula (III), which overcomes the problems associated with the prior art method.


Thus, this is an object of the invention to provide an improved process for preparation of imatinib base substantially free from impurities.
This is another object of the invention to provide improved amidation step for the preparation of imatinib base.
Summary of the invention:
The present invention provides, a process for preparing imatinib, either as the free base or as an acid addition salt, wherein the process involves reacting amine of formula (II) with carboxylic acids of formula (III) using a coupling agent in the presence of a polar aprotic solvent, so as to yield amide of formula (IV).
The amides may be prepared by a process as depicted below in scheme 1:
CH ?Hs
(ID (I") °
wherein, Ri is halogen, NO2, NH2, NHC(NH)NH2 or 4(3-pyridyl)-2-pyrmidine amine;
R2 is halomethyl, (4-methyl-piperazinyl)-methyl.
Halogen is selected from chloro, bromo, fluoro and iodo; preferably chloro and bromo.
Detailed description:
In an embodiment, the present invention provides a process for preparing an amide of formula (IV) either as the free base or as an acid addition salt, comprising reacting amine of formula (II) with carboxylic acids of formula (III) using a coupling agent in the presence of a polar aprotic solvent, so as to yield amide of formula (IV) as depicted in Scheme 1.


CH3 ?**
(II) ("I) ° (IV)
In preferred embodiment of the present invention, where Ri is 4(3-pyridyl)-2-pyrmidine amine and R2 is (4-methyl-piperazinyl)-methyl, there is provided a process of preparing imatinib, either as the free base or as an acid addition salt, which comprises, reacting N-(2-methyl-5-aminophenyl)-6-pyridine -3-yl-l,6-dihydropyrimidine-2-yl)-amine of formula (11a) with 4-(4-methyl-piperazino methyl)benzoic acid of formula (Ilia) using a coupling agent in the presence of an inert organic solvent, so as 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) as depicted below in scheme 2:


(Ha)
(nHHal)


wherein; 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.
particularly an acid addition salt is hydrobromide or hydrochloride, and more particularly
a hydrochloride; which can optionally be further converted to desired organic acid
addition salt.


In further preferred embodiment N-(2-methyl-5-arninophenyl)-6-pyridine -3-yl-l,6-dihydropyrimidine-2-yl)-amine of formula (Ha) is reacted with 4-(4-methyl-piperazino methyl)benzoic acid of formula (Ilia ) using a coupling agent in the presence of an inert organic solvent , so as to yield imatinib of formula (I) without isolating hydrohalide salt of imatinib of formula (la).
Preferably, a hydrohalide salt of formula (la), in particular a hydrobromide or hydrochloride salt of imatinib, and especially a hydrochloride salt of imatinib of formula (la), substantially as hereinbefore described can be employed as an intermediate, in the preparation of imatinib free base or a further organic acid addition salt of imatinib, such as imatinib mesylate substantially as hereinafter described in greater detail.
The coupling reagent for use in a process according to the present invention can be selected from the group comprising of phenylsilane, l,l'-carbonyldiimidazole (CDI), benzotriazol-1-yloxytris (dimethylamino) phophonium hexafluorophosphate (BOP), 1-hydroxy benzotriazole hydrate (HOBt), PyBOP (Analog of the BOP), 1,3-dicyclohexylcarbodiimide (DCC), n-Ethyl-N'-(3-dimethylaminopropyl)carbodidimide hydrochloride (EDC HCl). These agents act in situ as activating reagents and convert the carboxylic acids to more reactive intermediates. Preferably, the coupling reagent used in the above process according to the present invention is n-Ethyl-N'-(3-dimethylaminopropyl)carbodidimide hydrochloride (EDC HCl).
By "inert organic solvent" is meant an organic solvent, which under the reaction conditions of a process according to the present invention, does not react with either the reactants or the products. A suitable inert organic solvent for use in a process according to the present invention can be selected from the group consisting of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, sulfolane, diglyme; 1,4-dioxane, tetrahydrofuran, acetonitrile, acetone and other inert organic solvents known in the art. Particularly the suitable inert organic solvent for use in the above process according to the present invention is dimethylformamide.


The process is carried out at a temperature ranging from 5°C to the boiling point of the reaction mass until no starting material is detectable. Preferably, the reaction is carried out at 10-40°C, more preferably at 25-30°C.
It will be appreciated that the above process step does not require high temperature for the reaction as reported in the prior art, but is carried out under mild conditions such as room temperature whereby, very little by-products such as impurities A and C 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 organic acid addition salt of imatinib by treatment of imatinib prepared as above, with an appropriate amount of an organic acid. The preferred acid is methane sulfonic acid.
Imatinib either as the free base or as an acid addition salt, according to the present invention, is particularly suitable for use as an antineoplastic as described in further detail in prior art document. There is further provided by the present invention, therefore, a pharmaceutically acceptable composition comprising an effective amount of imatinib substantially as hereinbefore described, together with a pharmaceutically acceptable carrier, diluents or excipient therefore.
The term "effective amount" as used herein means an amount of imatinib which is capable of preventing, ameliorating or eliminating a disease state, in particular tumor disease, for which administration of an antineoplastic is indicated. By, virtue of its ability, imatinib can also be used for the treatment of proliferative disease, including psoriasis and cancer.
By "pharmaceutically acceptable composition" is meant that the carrier, diluent or excipient must be compatible with imatinib and not be deleterious to a recipient thereof. Suitable pharmaceutical acceptable composition according to the present invention can be


those suitable for topical, enteral, for example oral or rectal or parentral administration and may be solid or liquid. Especially, tablets or gelatin capsules containing imatinib substantially as hereinbefore described together with adjuvants or diluents can be used for oral administration. Solutions for injection may also be prepared according to the present invention by dissolving imatinib substantially as hereinbefore described in a solvent for injection and suitable additives conventionally used in the art may be added.
It is also known from the art that imatinib mesylate can prevent the development of multidrug resistance in cancer therapy with other antitumor agents or abolishes a preexisting resistance to other antitumor agents. There is also provided by the present invention, therefore the product containing imatinib, as either the free base or an acid addition salt substantially as hereinbefore described, and a further antitumor agent, for simultaneous, separate or sequential use in the treatment of tumor disease.
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 such as PTK inhibitors, antiinflammatories, antiproliferatives, chemotherapeutic agents, immunosuppressants, anticancer agents and cytotoxic agents.
The present invention further provides imatinib, either ase free base or an acid addition salt substantially as hereinbefore described, for use in the manufacture of a medicament for the treatment of a disease state prevented, ameliorated or eliminated by the administration of an anti-neoplastic.
The present invention also provides a method of treating a disease state prevented, ameliorated or eliminated by the administration of an anti-neoplastic in an animal patient in need of such treatment, in particular tumor disease, which process comprises administering to the patient an effective amount of imatinib substantially, as hereinbefore described. In particular, such methods according to the present invention can comprise use of imatinib for treatment of tumors, such as gliomas, ovarian tumors, prostate tumors colon tumors and tumors of the lung, such as especially small cell lung carcinoma and tumors of the breast or other gynecological tumors. Depending on the species, age,


individual condition, mode of administration and the clinical picture in question, effective doses, for example daily doses of about 1-250 mg, typically 1-1000 mg, more typically 5-500 mg , can be administered.
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.
Preparation of 4-[(4-Methyl-l-piperazinyl) methyl]-N-(4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino] phenyl benzamide (Imatinib base)
Example 1
N-(2-methyl-5-amino phenyl)-4-(3-pyridyl)-2-pyrimidine amine (l00g, 0.361 M ), 4-(4-methyl-1-piperazinyl) methyl benzoic acid dihydrochloride (118 g, 0.384 M) and dimethyl formamide (1000 ml) were charged in a reactor under nitrogen atmosphere. The reaction mixture cooled to 10°C. To this solution, N-Ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride (100 g, 0.522 M) was added slowly at 10-15 °C over a period of 1 hour. The reaction mixture was stirred at 10-15°C for 1 hour and then at 25-30°C for 4 hours. The reaction mixture was further cooled to 0-5°C and stirred for 1 hour. The insolubles were removed by filtration. The clear filtrate was concentrated under reduced pressure below 70°C. The residue was dissolved in 1.0 It purified water at 25-30°C. About 2.0 It methylene chloride was added to the reaction mass and pH was adjusted to 8.0- 8.5 using liquor ammonia at 30-35°C. The organic layer was separated, treated with 10 g activated charcoal and stirred for 30 minutes. The reaction mass filtered on hyflo. The clear filtrate was concentrated completely under reduced pressure below 40°C. To the residue was charged 500 ml acetonitrile and stirred at 40-45°C for 30 minutes. 'Tie reaction mass was cooled to 25-30°C and further stirred for 1 hour. The solid obtai led was isolated by filtration, washed with 100 ml acetonitrile and dried to afford 85 g (47.75 %)of title compound.
Example 2
To a solution of 4-(4-methyl-l-piperazinyl) methyl benzoic acid ( 42.12 g, 0.18M ) and N-(2-methyl-5-amino phenyl)-4-(3-pyridyl)-2-pyrimidine amine ( 50 g, 0.18 M) in DMF ( 400 ml) was added phenylsilane ( 58.43 g, 0.54 M) slowly. The reaction mixture was


stirred for 5 h at room temperature under an argon atmosphere and then the solvent was evaporated. The resulting mixture was purified to afford 45 g ( 50%) of title compound. Preparation of 4-[(4-Methyl-l-piperazinyl)methyl]-N-(4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino] phenyl benzamide hydrochloride (Imatinib Hydrochloride )
Example 3
N-(2-methyl-5-amino phenyl)-4-(3-pyridyl)-2-pyrimidine amine (200g, 0.722M ), 4-(4-methyl-1-piperazinyl) methyl benzoic acid dihydrochloride (236 g, 0.768M) and dimethyl formamide ( 2000 ml) were charged in a reactor under nitrogen atmosphere. The reaction mixture cooled to 10°C. To this solution, N-Ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride (200 g, 1.044M) was added slowly at 10-15 °C over a period of 1 hour. The reaction mixture was stirred at 10-15°C for 1 hour and then at 25-30°C for 4 hours. The reaction mixture was further cooled to 0-5°C and stirred for 1 hour. The insolubles were removed by filtration. The pH of the clear filtrate was adjusted to 1.5 -2.0 by using IPA + HC1 at 25-30°C. The contents were stirred at 25-30°C for 1 hour. The solids were filtered, washed with 100 ml dimethyl formamide and dried under vacuum at 45-50°C to give about 200 g ( 52.31%) of the title compound as the hydrochloride salt.
Preparation of 4-[(4-Methyl-l-piperazinyl)methyl]-N-(4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino] phenyl benzamide mesylate (Imatinib Mesylate)
Example 4
4-[(4-Methyl-l-piperazinyl) methyl]-N-(4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]
amino] phenyl benzamide (85 g, 0.172M) was stirred in isopropanol (850 ml). Methane sulphonic acid (16.75 g, 0.174M) was charged and the reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated to 170 ml volume and cooled to afford 93 g (91.58%) of the title compound as the mesylate salt.