AN ENVIRONMENTALLY FRIENDLY PROCESS FOR THE PREPARATION

OF IMATINIB BASE

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)

(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 (CDl 17) 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.

(Ia)

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 6 ^th Octoberl993 and in US 55211584 (Assignee : Ciba-Geigy corp; Title : Pyrimidine derivatives and process for the preparation there of) which was published on 28 ^th 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 I(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 α-form and the β-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 (Scheme-1)

CHCI ₃ /EtOAc

4-[(4-methyl-1 -piperazinyl) methyl]-N-[4-methyl-3-

[(4-(pyridinyl)-2-pyrimidinyl) amino]phenyl]benzamide

(Imatinib)

(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

Scheme-2:

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 cannot 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-pyrimidineamin e 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

Scheme -3 :

4-(4-methyl piperazinomethyl) N-(5-amino-2-methylphenyl) benzoic acid dihydrochloride -4-(3-pyridyl)-2-pyrimidineamine

(IV) (ID

Dicyclohexyl carbodiimide

3

(I)

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. Basifϊcation 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 ⁰ C. iii. Maintenance for lhour at 30-35 ⁰ C. iv. Addition of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine(II) solution in acetonitrile to the reaction mass over a period of 30-40 minutes at 30-35 ⁰ C. v. Maintenance at 30-35 ⁰ 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 p ^H 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 of the 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. 1.68kgs of dicyclohexyl carbodiimide dissolved in 50L 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 5O ⁰ 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 2x1 OL 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 30-35 ⁰ 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.