Field of the invention:
The present invention relates to an environmentally friendly and novel process for the preparation of highly pure (>99.8) (Imatinib) of formula (I)

Back ground of the invention :
Imatinib mesylate which is the methane sulfonate salt of N-{5-[4"(4-methylpiperazino-methyl)- benzoylamido]-2"methylphenyl}-4- (3-pyridyl) 2-pyrimidine-amine having the Formula I (a) I is approved under the trademark "Gleevec ®" by the US Food and Drug Administration for the treatment of Chronic Myelogenous Leukemia before and after the failure of interferon alpha. It has also been approved for the treatment of patients with kit (CD 117) positive unresectable and / or metastatic malignant Gastro Intestinal Stromal Tumors (GISTs). It has also been approved for the treatment of pediatric patients with Philadelphia chromosome positive (Ph+) Chronic Myeloid Leukemia (CML) in chronic phase.


The preparation of N-{5-[4-(4-methylpiperazino-methyl)- benzoylamido]-2-methylphenyl}-4-(3-pyridyl) 2-pyrimidine-amine (Imatinib) of Formula (I) and the use thereof especially as an antitumour agent is described in EP0564 409, (Ciba-Geigy corp.) which was published on 6th Octoberl993 and in US 55211584 (Assignee : Ciba-Geigy corp; Title : Pyrimidine derivatives and process for the preparation there of) which was published on 28 May 1996 and in equivalent applications in numerous other countries. However, the purity aspects of imatinib base are not discussed here.
The preparation of Imatinib mesylate 1(a) and the use thereof especially as an antitumour agent is described in WO99/03854, ( Assignee : Novartis). This application describes two polymorphic forms of imatinib mesylate, the form and the -form, WO 2005/075454 describes acid addition salts imatinib such as tartrate, citrate, malate, fumarate, etc., which are prepared by treatment of imatinib base with the corresponding acid.
In EP 0564409 and in its equivalent US 55211584 the following route is described


(I)
A solution of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula (II) and 4-(4-methyl-piperazinomethyl)benzoyl chloride of the formula (III) taken in pyridine are stirred under nitrogen at room temperature for 23 hours. The resulting reaction mixture is concentrated under high vacuum; water is added and the mixture is filtered. After drying at 80°C under high vacuum, the crude product is made into slurry with methylene chloride & methanol and filtered to yield Imatinib of the formula (I). Chromatographic separation is used to obtain further crop of product.

After implementing the process described in the patent mentioned as per the scheme indicated, the following are the difficulties encountered and draw backs noticed.
i) the yield of compound of formula (I) is low (50%) making the process non
economical and the purity of the product is only 97% ii) column chromatography is necessary to isolate product of formula (I) in pure form
and column chromatography technique becomes unpractical on commercial scale, iii) Usage of the obnoxious and foul smelling chemical pyridine as a solvent and its distillation for work-up makes this process to be abandoned on bulk scale.
The known intermediate of formula (III) is prepared by conventional methods and is outlined below

4-(4-methyl piperazino methyl) benzoic acid dihydro chloride of the formula (IV) on chlorination with thionyl chloride yields 4-(4-methyl piperazino methyl) benzoyl chloride dihydro chloride of the formula (III). For this acid chloride formation huge quantity of thionyl chloride i.e., 20-25 moles is required for the completion of the reaction. Further the reaction time is 20-24 hours. Thionyl chloride is very corrosive, moisture sensitive and toxic . Also during the reaction, one mole of gaseous sulfur dioxide is evolved which is toxic, corrosive and an environmental pollutant.

It is very important to examine a process of preparing the compound of the formula (I) from the point of industrial applicability whether the procedure fulfills the following requirements,
1. The starting materials for the process are easily available and as cheap as possible.
2. The use of harmful reagents are avoided during the course of the process.
3. The process should be safe from the point of environmental protection.
4. The formation of by-products and ballast materials, which caimot be used or processed further, should be minimized during the course of the process.
5. The reaction vessels generally used in pharmaceutical and chemical industry should be applicable for the carrying out the process. In other words there should not be any special or complicated or sophisticated apparatus required for carrying out the process.
6. It is also very important, that the process should result in the formation of pure final product, which does not need further expensive purification.
All of the processes described above in the prior art do not fulfill one or other of the above conditions.
Therefore we directed our R&D program to develop an improved process for the preparation of Imatinib of the formula I taking into consideration the above mentioned requirements. The aim being to provide a new environmentally protective, safe, industrially applicable process, which was devoid of the insufficiencies of the known procedures and makes possible the synthesis of pure compound of the formula I in high yields and was easily realizable industrially.
Summary of invention:
Accordingly we directed our research based on the under mentioned points
• To condense 4-(4-methyl-piperazinomethyl)benzoic acid of the formula (IV) with N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula (II) employing dicyclohexyl carbodiimide thereby avoiding the usage of Thionyl chloride(Scheme-3)
• Avoiding formation of the environmental pollutant sulfur dioxide as byproduct
• Avoiding the usage of flammable and obnoxious solvents

• Avoiding special equipments
• Reducing the number of purification steps

Imatinib base is the precursor of the salt forms of imatinib. As such, there is a need for imatinib base of high purity which may be conveniently used as a precursor in the preparation of highly pure imatinib mesylate for therapeutic application.
Summary of the invention:
The main object of the present invention is to provide an improved process for the preparation
of highly pure (>99.8%) imatinib base
Another object of the invention is to provide a process for preparation of imatinib base

Accordingly in the present invention highly pure Imatinib and its pharmaceutically acceptable
salts are prepared by
i. preparing imatinib base by the condensation of N-(5-amino-2-methylphenyl)-4-(3-
pyridyl)-2- pyrimidine amine of the formula (II) and 4-(4-methyl-
piperazinomethyl)benzoic acid of the formula (IV) in presence of dicyclohexyl
carbodiimide and isolation of imatinib base ii. Suspension of Imatinib base into demineralized water and extraction with chloroform
to remove impurities formed during course of the reaction . iii. Basification of the aqueous layer iv. Extraction of imatinib base with suitable organic solvent V. Removal of solvent completely under vacuum vi. Isolation of highly pure imatinib base (>99.8)of formula (I)
Detailed description of the invention:
Thus in accordance with the present invention preparation of Imatinib and its pharmaceutically acceptable salts comprise the following steps.
i. Condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2"pyrimidine amine of the
formula (II) and 4-(4-methyl- piperazinomethyl)benzoic acid of the formula (IV) in
acetonitrile medium to yield crude Imatinib
ii. Suspension of Imatinib base into Demineralized water and extraction with chloroform
to remove impurities formed during course of the reaction . iii. Basification of the aqueous layer with sodium Hydroxide solution, iv. Extraction of imatinib base with chloroform or methylene chloride. V. Removal of solvent completely under vacuum vi. Isolation of highly pure imatinib base (>99.8)of formula (I) by suspending in acetone.
In a specific embodiment, the present invention provides a process for the preparation of Imatinib which involves:

i. suspending 4-(4-methyl-piperazinomethyl)benzoic acid of the formula (IV)
in acetonitrile ii. Addition of Dicyclohexyl carbodiimide solution in acetonitrile and stirring the mixture for 30-40 minutes at 30-35''C. iii. Maintenance for Ihour at 30-35°C .
iv. Addition of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine(n) solution in acetonitrile to the reaction mass over a period of 30-40 minutes at 30-35°C . V. Maintenance at 30-3S'°C for 4-6 hours, vi. Filtration of the reaction mass, vii. Suspension of wet material with demineralised water viii. Washing of aqueous layer with chloroform
ix. Adjusting the aqueous layer pH to 12.0 and extraction with chloroform . X. Carbon treatment of organic layer.
xi. Concentration of the organic layer and addition of Acetone xii. Heating and filtration to yield imatinib base of purity 99.9%
The required N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (II) and 4-(4-methyl-piperazinomethyl)benzoic acid of the formula (IV) can be prepared by the prior art processes
The details of the inventions are given in the Examples which are provided for illustration only and therefore the Examples should not be construed to limit the scope of the invention.
EXAMPLES
Example-1 : Process for the preparation of imatinib of the formula (I)
Condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (II) and 4-(4-methyl-piperazinomethyl)benzoic acid ofthe formula (IV):

Into the reactor a suspension of 25L of acetonitrile and 2.5Kgs of 4-(4-methyl-piperazinomethyl)benzoic acid (IV) is charged and stirred for 15 minutes. L68kgs of dicyclohexyl carbodiimide dissolved in SOL acetonitrile is charged slowly . It is stirred for 1-2 hours at room temperature. 1.1 Kg of amine of formula (II) is dissolved in 25L acetonitrile at 50°C and is brought to room temperature. The amine solution is added to the reaction mass slowly during 1 hour. Reaction mass is maintained four to six hours at 25-35°C. Reaction mass is filtered and washed with 5L Acetonitrle. Filtered material dissolved in 25L demineralized water. Aqueous layer is washed with 2x25L chloroform.. Aqueous layer is basified with sodium hydroxide solution to a pH of 11-12 and extracted with 2xI0L chloroform. Carbon treatment is given to the chloroform layer. Organic layer is dried over anhydrous sodium sulfate and the solvent is distilled off completely under vacuum. 5L of Acetone is charged and heated to reflux temperature. Maintained at reflux temperature for 15 minutes and brought to 3 0-35 °C. The product of the formula (I) is centrifuged and washed with 2L Acetone . It is dried in oven at 60-70°C Dry wt. : 9kg Purity by HPLC : 99.9%
Advantages of the invention:
1) The Imatinib is produced in more than 99.8% purity.
2) The toxic and corrosive reagent thionyl chloride is substituted with non-toxic
Dicyclohexyl carbodiimide
3) The process can be used for commercial preparation of Imatinib salts of pharmaceutical
grade.
4) The process does not generate the environmental pollutant sulfur dioxide as by product.

We claim :
1) Novel process for the preparation of Imatinib base comprising
. suspending 4-(4-methyl-piperazinomethyl)benzoic acid of the formula (IV)
in acetonitrile ii. Addition of Dicyclohexyl carbodiimide solution in acetonitrile and stirring the mixture for 30-40 minutes at 30-35°C iii. Maintenance for Ihour at 30-35°C
iv. Addition of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine solution in acetonitrile to the reaction mass over a period of 30-40 minutes at 30-35°C V. Maintenance at 30-3°C for 4-6 hours, vi. Filtration of the reaction mass, vii. Dissolution of wet material in demineralised water viii. Washing of aqueous layer with Chloroform
ix. Adjusting the aqueous layer PH to 12.0 and extraction with chloroform . X. Carbon treatment of organic layer.
xi. Concentration of the organic layer and addition of acetone xii. Heating and filtration to yield imatinib base of purity 99.9%
2. Imatinib base of high purity ( 99.9%)
3. A process where in use of Thionyl Chloride is eliminated during the preparation of the imatinib of the formula (I)
4. A process where in the evolution of the Sulfur dioxide pollutant as effluent is avoided.
5. A novel method of preparing highly pure ( 99.9%) Imatinib essentially as herein described
with reference to example 1 .