FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and ruleI3)
1. TITLE OF THE INVENTION:
"AN ENVIRONMENTALLY FRIENDLY PROCESS FOR THE PREPARATION OF IMATINIB"
2. APPLICANT:-
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

FIELD OF THE INVENTION:
The present invention relates to an environmentally friendly and improved process for the preparation of Imatinib and its pharmaceutically acceptable acid addition salts thereof
BACKGROUND OF THE INVENTION:
4-(4-methylpiperazin-l-ylmethyl)-N-[4-methyl-3-[(4-pyridin-3-yl)pyrimidin-2-yl amino) phenyl]benzamide, also referred to as imatinib, is a selective inhibitor of tyrosine kinase, disclosed in EP0564409 Al, and represented by the structural formula (I):

Methanesulfonic acid addition salt of imatinib is an active ingredient of oral compositions useful in the treatment of patients with Philadelphia chromosome positive chronic myeloid leukemia and with Kit-positive unresectable and / or metastatic malignant gastrointestinal stromal tumors.
The preparation of Imatinib as reported in EP0564409 describes a coupling reaction between N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyridine amine and 4-[(4-methyl-1-piperazinyl) methyl] benzoyl chloride dihydrochloride as illustrated by the following scheme 1:


The above reaction is carried out in the presence of pyridine. Pyridine is known to be a toxic solvent according to ICH guidelines. The work-up of the reaction is conducted by evaporation of pyridine, treatment with water and a slurring step in a dichloromethane/methanol mixture. The obtained product is then purified by chromatography, which is highly undesirable in processes on industrial scale because it is expensive and time consuming.
A similar synthetic approach is reported in patent applications, US 2006/0149061 and US 20060223817. These applications describe the use of pyridine as described in EP0564409. In addition, the process described in the above publications also reports the recovery of the obtained product by evaporation of the pyridine and subsequent extraction of the product from a basic aqueous phase with dichloromethane. The obtained product is then purified by slurring in ethyl acetate.
Imatinib base is the precursor of the salt forms of imatinib. The prior art processes provides imatinib base of only about 97% purity and the side products being N-(2-methyl-5-amino phenyl)-4-(3-pyridyl)-2-pyrimidine amine which is known for its genotoxicity and the structure is as follows :

N-(2-methyl-5-amino phenyl)-4-(3-pyridyl)-2-pyrimidine amine
Hence there is a constant need to develop an environmentally friendly and an alternative process that is suitable for industrial scale-up.
OBJECT OF THE INVENTION:
The object of the present invention is to provide an improved process for preparation of Imatinib of formula (I) or its pharmaceutically acceptable acid addition salts thereof.

Yet another object of the present invention is to provide a process which avoids large quantity of solvents, additional process steps and thus making the process environmentally friendly and yielding high purity Imatinib of formula (I) or its pharmaceutically acceptable acid addition salts thereof.
Yet another object of the present invention is to provide a process for the preparation of formula (I) or its pharmaceutically acceptable acid addition salts thereof which is simple, cost effective, non-hazardous and industrially viable.
SUMMARY OF THE INVENTION:
According to a first aspect of the present invention, there is provided an environmentally friendly and improved process for the preparation of highly pure Imatinib or its pharmaceutically acceptable acid addition salts thereof which comprises following steps; a) reacting N-(5-amino-2-methylphenyI)-4-(3-pyridyl)-2-pyrimidine amine of formula (II)


in the presence of an organic or inorganic base using suitable solvent;
with 4-(4-methyl-l-piperazinyl) methyl benzoyl chloride dihydrochloride of formula (III)

b) quenching the reaction mass by water, adjusting the pH of the solution to less than about 5.0 followed by washing aqueous solution with suitable water immiscible solvent to reduce genotoxic impurity A;
c) adjusting pH of the aqueous solution to basic pH and
d) isolating imatinib base;
As used herein, the term "environmentally friendly" refers to a process that avoids use of toxic pyridine, avoids tedious & time consuming chromatography, avoids the usage of large volume of solvents and reduces the number of purification steps.
The term " highly pure Imatinib " in the specification refers to Imatinib free base having purity (measured by HPLC) preferably above 99.5% and more preferably above about 99.7%.
According to another aspect of the present invention there is provided imatinib having less than about 20 ppm of the genotoxic impurity (A);

N-(2-methyl-5-amino phenyl)-4-(3-pyridyl)-2-pyrimidine amine
Imatinib obtained by the process of the present invention may be further converted to an acid addition salt of imatinib by treatment of imatinib with an appropriate amount of an organic acid. The preferred acid is methane sulfonic acid.
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.
The invention is hereinafter detailed in greater details, no part of which may be construed as restrictive to the scope of the instant invention.

DETAILED DESCRIPTION OF THE INVENTION:
In an embodiment of the present invention, there is provided an improved process for the preparation of highly pure Imatinib as depicted below in reaction scheme 2.

Accordingly, in an embodiment, the present invention provides a process for the preparation of Imatinib of formula I, which comprises following steps of;
a) Condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula (If)

with 4-(4-methyl-l-piperazinyl) methyl benzoyl chloride dihydrochloride of formula (III)


in the presence of an organic or inorganic base using suitable solvent;
A suitable inorganic base according to the present invention is selected from the group consisting of alkali metal hydroxides, alkali metal carbonates and alkali metal alkoxides. The organic base is selected form the group consisting of diethyl amine, triethyl amine, diisopropyl ethyl amine. A particularly suitable base for use in the above process according to the present invention is triethyl amine to accelerate the reaction.
In an embodiment the condensation is carried out in an organic solvent. The suitable organic solvent is selected from the group consisting of halogenated solvent such as chloroform, dichloromethane (MDC), 1,2- dichloroethane (EDC); polar solvents such as dimethylformamide (DMF), dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl pyrrolidone, sulfolane, diglyme, 1,4-dioxane, tetrahydrofuran (THF), acetonitrile, acetone and mixture thereof. In the preferred embodiment halogenated solvent is used alone or in combination with other polar solvent to increase overall solvent power. Preferably, the condensation is carried in MDC.
The condensation is carried out at a suitable temperature, preferably at a temperature of about 0-40°C, most preferably 20-30°C.
b) quenching the reaction mass by water, adjusting the pH of the solution to
less than about 5.0 using a base and washing aqueous solution with suitable water immiscible solvent to reduce genotoxic impurity A levels less than 20 ppm.

A preferred base to adjust the pH of the solution is selected from liquor ammonia,
alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium
hydroxide, lithium hydroxide; alkali metal carbonates such as sodium
carbonate, potassium carbonate, sodium bicarbonate or alkyl amine such as methlamine, diethylamine, triethylamine. A particularly suitable base for use in the above process according to the present invention is liquor ammonia.
Preferably, pH of the reaction mass is adjusted to 3.5 to 4.0 with liquor ammonia prior to washing with water immiscible solvent.
A preferred water immiscible solvent is selected from halogenated solvent
such as chlorinated solvent, ethyl acetate, toluene, xylene, etc. Preferably
chlorinated solvent is selected from the group consisting of
chloroform,dichloromethane, ethylene chloride, most preferably dichloromethane.
c) re- adjusting pH of the aqueous solution to basic pH.
The pH of the reaction mass is adjusted to about 7.5-10.0, most preferably to about 8.0- 8.5 with a suitable base.
A preferred base is selected from liquor ammonia, alkaline metal hydroxides such as sodium hydroxide, potassium hydroxide; alkaline metal carbonates such as sodium carbonate, potassium carbonate, preferably liquor ammonia; and
d) isolating imatinib base.
In one embodiment isolation involves stirring & filtering the precipitated imatinib free base.
In an alternative embodiment isolation involves adding suitable water immiscible solvent prior to the basification.
A suitable water immiscible solvent is selected from halogenated solvent such

as chloroform, dichloromethane, ethylene chloride, ethyl acetate, toluene or xylene. A particularly suitable solvent for use in the above process according to the present invention is dichloromethane.
The product of the process of the present invention is easily isolated by distilling dichloromethane completely under reduced pressure below 40°C and isolating imatinib base in a suitable organic solvent.
A preferred organic solvent is selected from the group consisting of C1-C4 alcohols or ethyl acetate, A particularly suitable solvent for use in the above process according to the present invention is isopropyl alcohol.
The process of the present invention further comprises stirring imatinib base in isopropyl alcohol, filtering imatinib free base and drying imatinib at about 40-60°C, preferably at about 50-55°C.
Imatinib obtained by the process of the present invention is further treated with an acid so as to yield a further acid addition salt of imatinib.
The above condensation reaction avoids use of large quantity of toxic pyridine as reported in EP0564409. This further helps to reduce tedious work up involving evaporation of pyridine at high temperature. Further, the product obtained by the prior art process as reported in EP0564409 requires further purification by chromatography. Such purification is highly undesirable on industrial scale as it consumes large quantity of solvents making the process expensive and time consuming.
The process of the present invention makes use of triethyl amine, which does not require the use of chromatography as a means of purification. The process further provides highly pure imatinib which may be conveniently used as a precursor in the preparation of highly pure imatinib mesylate having very low levels of genotoxic impurities for therapeutic application. And thus forms another aspect of the present invention.

Further, Imatinib prepared by the process of the present invention is substantially free of genotoxic impurity (A).

N-(2-methyl-5-amino phenyl)-4-(3-pyridyl)-2-pyrirnidine amine
The above processes preferably prepare imatinib having less than 20 ppm, of the genotoxic impurity (A). Thus isolation of imatinib by the process of the present invention is a method of purification of the product.
Imatinib was prepared by following the process of the present invention, using appropriate solvents, reagents and reaction conditions.
The details of the invention given in the following examples, which are provided below for illustration only, and therefore these examples should not be construed to limit the scope of the invention.
Examples:
Example 1 : Preparation of Imatinib base
N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine (lOO.Ogms, 0.36 moles), of 4-(4-methyl-l-piperazinyl) methyl benzoyl chloride dihydrochloride (150.0 gms,0.46 moles) were stirred in dichloromethane (1.0 It) under nitrogen at 25-30°C for 30 minutes. To the reaction mass was charged triethyl amine (20.0 ml, 0.143 moles) at 25-30°C over a period of 30 minutes. The temperature of the reaction mass was maintained at 25-30°C for 20 hours. After completion of the reaction, water (1.0 It) was charged and the contents were further stirred at 25-30°C for 30 minutes. The aqueous phase was separated and washed with dichloromethane (200.0 ml).

Dichloromethane (2.0 It) was charged to the reaction mass and the pH of the reaction mass was adjusted to 8.0- 8.5 using liquor ammonia at 30-35°C. The organic phase was separated. The aqueous phase was extracted with dichloromethane (500.0 ml). The organic phases were combined and distilled off completely under reduced pressure below 40°C. Isopropyl alcohol (1.0 It) was charged. The contents were heated to 50-55°C and maintained for 30 minutes. The reaction mass was cooled to 25-30°C and further stirred for 1 hour. The solid was isolated by filtration, washed with Isopropyl alcohol (100.0 ml) and dried under reduced pressure at 50-55°C for 8 hours to yield the title compound Yield:-160 gms Efficiency:- 90 % HPLC purity:-99.7% Genotoxic impurity A:- <0.15%
Example 2 : Preparation of Imatinib base
N-(5-amino-2-methylphenyI)-4-(3-pyridyl)-2-pyrirnidine amine (50.0gms, 0.18 moles), of 4-(4-methyI-l-piperazinyl) methyl benzoyl chloride dihydrochloride (75.0 gms, 0.23 moles) were stirred in dichloromethane (0.5 It) under nitrogen at 25-30°C for 30 minutes. To the reaction mass was charged triethyl amine (10.0 ml, 0.071 moles) at 25-30°C over a period of 30 minutes. The temperature of the reaction mass was maintained at 25-30°C for 20 hours. After completion of reaction, water (0.5 It) was charged and the contents were further stirred at 25-30°C for 30 minutes. The aqueous phase was separated and washed with dichloromethane (100.0 ml) by adjusting the pH to 3.5-4.0 with liquor ammonia. The pH of the reaction mass was adjusted to 1.5-2.0 using hydrochloric acid.
Dichloromethane (1.0 It) was charged to the reaction mass and the pH of the reaction mass was re-adjusted to 8.0- 8.5 using liquor ammonia at 30-35°C. The organic phase was separated. The aqueous phase was extracted with dichloromethane (250.0 ml). The organic phases were combined and distilled off completely under reduced pressure below 40°C. Isopropyl alcohol (0.5 It) was charged. The contents were heated to 50-55°C and maintained for 30 minutes. The reaction mass was cooled to 25-30°C and further stirred for 1 hour. The solid was isolated by filtration, washed with Isopropyl alcohol (50.0 ml) and dried under reduced pressure at 50-55°C for 8 hours to yield the title compound.

Yield :- 75 gms,
Efficiency:- 84%
HPLC purity :- 99.7%
Genotoxic impurity A :- < 20 ppm.
Example 3 : Preparation of Imatinib base
N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine (50.0gms, 0.18 moles), of 4-(4-methyl-l-piperazinyl) methyl benzoyl chloride dihydrochloride (75.0 gms, 0.23 moles) were stirred in dichloromethane (0.5 It) under nitrogen at 25-30°C for 30 minutes. To the reaction mass was charged triethyl amine (10.0 ml, 0.071 moles) at 25-30°C over a period of 30 minutes. The temperature of the reaction mass was maintained at 25-30°C for 20 hours. After completion of reaction, water (0.5 It) was charged and the contents were further stirred at 25-30°C for 30 minutes. The aqueous phase was separated and washed with dichloromethane (100.0 ml) by adjusting the pH to 3.5-4.0 with liquor ammonia. Dichloromethane (1,0 It) was charged to the reaction mass and the pH of the reaction mass was re-adjusted to 8.0- 8.5 using liquor ammonia at 30-35°C. The organic phase was separated. The aqueous phase was extracted with dichloromethane (250.0 ml). The organic phases were combined and distilled off completely under reduced pressure below 40°C. Isopropyl alcohol (0.5 It) was charged. The contents were heated to 50-55°C and maintained for 30 minutes. The reaction mass was cooled to 25-30°C and further stirred for 1 hour. The solid was isolated by filtration, washed with Isopropyl alcohol (50.0 ml) and dried under reduced pressure at 50-55°C for 8 hours to yield the title compound. Yield:- 75 gms, Efficiency:- 84% HPLC purity:-99.7% Genotoxic impurity A :- < 20 ppm.
Example 4 : Preparation of Imatinib base
N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine (l00.0gms, 0.361 moles), of 4-(4-methyI-l-piperazinyl) methyl benzoyl chloride dihydrochloride (150.0 gms, 0.46 moles) were stirred in dichloromethane (1.0 It) under nitrogen at 25-30°C for 30 minutes. To the reaction mass was charged triethyl amine (20.0 ml, 0.142 moles) at 25-

30°C over a period of 30 minutes. The temperature of the reaction mass was maintained at 25-30°C for 20 hours. After completion of reaction, water (1.0 It) was charged and the contents were further stirred at 25-30°C for 30 minutes. The aqueous phase was separated and washed with dichloromethane (100.0 ml) by adjusting the pH to 3.5-4.0 with liquor ammonia. The pH of the aqueous phase was re-adjusted to 8.0- 8.5 using liquor ammonia at 30-35°C. The precipitated solids were filtered and dried under vacuum to give the title compound.
Yield:-148 gms,
Efficiency:-83.1%
HPLC purity:-99.7%
Genotoxic impurity A :- < 20 ppm.
Example 5 :Preparation of Imatinib mesylate
Imatinib base (85 g, 0.172 moles) was stirred in isopropanol (850 ml). Methane sulphonic acid (16.75 g, 0.174 moles) was charged and the reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated to 170 ml volume and cooled to afford 93.5 g (91.58%) of the title compound as the mesylate salt.

We claim,
1. An environmentally friendly and improved process for the preparation of highly pure Imatinib of formula (I) or its pharmaceutically acceptable acid addition salts thereof

which comprises following steps;
a) condensing N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula (II)

with 4-(4-methyl-l-piperazinyl) methyl benzoyl chloride dihydrochloride of formula (III)

in the presence of an organic or inorganic base using suitable solvent;
b) quenching the reaction mass by water, adjusting the pH of the solution to less than about 5.0 followed by washing aqueous solution with suitable water immiscible solvent to reduce genotoxic impurity A;
c) re-adjusting pH of the aqueous solution to basic pH and

d) isolating imatinib base.
2. The process according to claim 1, wherein the imatinib base contains less than about 20 ppm of the genotoxic impurity (A).

N-(2-methyl-5-amino phenyl)-4-(3-pyridyl)-2-pyrimidine amine
The process according to claim 1, wherein in step a, the organic base selected from the group consisting of diethyl amine, triethyl amine, diisopropyl ethyl amine and the inorganic base is selected from the group consisting of alkali metal hydroxides, alkali metal carbonates and alkali metal alkoxides, preferably triethyl amine.
The process according to claim 1, wherein in step a, the solvent is selected from halogenated solvent selected from the group consisting of chloroform, MDC or EDC; polar solvent selected from the group consisting of DMF, dimethylacetamide, DMSO, N-methyl pyrrolidone, sulfolane, diglyme, 1,4-dioxane, THF, acetonitrile, acetone or mixture thereof; preferably, MDC.
The process according to claim 1, wherein in step a, the condensation is carried out at a temperature of about 0-40°C.
The process according to claim 5, wherein the reaction mass is stirred at 25-30°C for 20 hrs.
The process according to claim 1, wherein in step b, the pH of the solution is adjusted with alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide or lithium hydroxide; alkali metal carbonates such

as sodium carbonate, potassium carbonate or sodium bicarbonate or alkyl amines such as methylamine, diethylamine or triethylamine, preferably liquor ammonia.
8. The process according to claim 7, wherein, the pH of the reaction mass is adjusted to 3.5 to 4.0 with liquor ammonia.
9. The process according to claim 1, wherein in step b, a water immiscible solvent is selected from the group consisting of chlorinated solvent, ethyl acetate, toluene or xylene.
10. The process according to claim 9, wherein the preferred chlorinated solvent is selected from the group consisting of chloroform, dichloromethane or ethylene chloride; most preferably dichloromethane.
11. The process according to claim 1, wherein in step c, the pH of the reaction mass is re-adjusted to about 7.5-10.0, most preferably to about 8.0- 8.5 with a suitable base.
12. The process according to claim 11, wherein the preferred base is selected from liquor ammonia, alkaline metal hydroxides such as sodium hydroxide, potassium hydroxide; alkaline metal carbonates such as sodium carbonate, potassium carbonate; preferably liquor ammonia.
13. The process according to claim 1, wherein in step d, isolation involves stirring & filtering precipitated imatinib free base.
14. The process according to claim 1, wherein in step d, isolation involves adding a suitable water immiscible solvent prior to the basification.

15. The process according to claim 14, wherein the suitable water immiscible solvent is selected from as the group consisting of chloroform, dichloromethane, ethylene chloride, ethyl acetate, toluene, xylene, preferably dichloromethane.
16. The process according to claim 15, wherein dichloromethane is distilled of completely under reduced pressure below 40°C.
17. The process according to claim 16, further comprises isolating imatinib base in a suitable organic solvent selected from the group consisting of C1-C4 alcohols or ethyl acetate; preferably isopropyl alcohol.
18. The process according to claim 17, further comprises stirring imatinib base in isopropyl alcohol and filtering imatinib free base.
19. The process according to any of the claim 13 or 18, wherein said imatinib free base is treated with an acid so as to yield a further acid addition salt of imatinib.
20. The process according to claim 1, wherein the imatinib base is having purity above 99.5% and more preferably about 99.7%.

21. A process according to claim 1, wherein use of pyridine and purification by chromatography are eliminated during the preparation of the Imatinib of formula (I) or its pharmaceutically acceptable acid addition salts thereof.
22. An improved process for the preparation of highly pure Imatinib of formula (I) or its pharmaceutically acceptable acid addition salts thereof is substantially as herein described and exemplified.