WO2012004801A1

WO2012004801A1 - Process for imatinib mesylate

Info

Publication number: WO2012004801A1
Application number: PCT/IN2010/000453
Authority: WO
Inventors: Bandi Parthasaradhi Reddy; Kura Rathnakar Reddy; Dasari Muralidhara Reddy; Rapolu Raji Reddy; Bandi Vamsi Krishna; Bhimireddy Srinivasa Reddy
Original assignee: Hetero Research Foundation
Priority date: 2010-07-07
Filing date: 2010-07-07
Publication date: 2012-01-12
Also published as: BRPI1003375A2

Abstract

The present invention provides a process for the preparation of imatinib mesylate in high purity. Thus, for example, a solution of methanesulfonic acid in isopropanol was added to the suspension of imatinib free base in isopropanol at 70 to 750C, the reaction mass was maintained at reflux for 2 hours 30 minutes and highly pure imatinib mesylate was isolated.

Description

PROCESS FOR IMATINIB MESYLATE

Field of the Invention

The present invention provides a process for the preparation of imatinib mesylate in high purity.

Background of the Invention

Imatinib mesylate, chemically 4-[(4-methyl-l-piperazinyl)methyl]-N-[4-methyl- 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide mesylate and has the structural formula:

Imatinib mesylate is known as an inhibitor of tyrosine kinases and 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 mesylate also has potential for the treatment of other cancers that express these kinases, including acute lymphocytic leukemia and certain solid tumors. Imatinib mesylate is approved under the trademark "Gleevec^®" under marketed by Novartis.

Imatinib mesylate and process for its preparation was disclosed in US patent no. 5,521 ,184.

PCT publication no. WO 99/03854 disclosed alpha crystal form and beta crystal form of imatinib mesylate. According to the publication, imatinib mesylate alpha crystal form can be prepared by suspending imatinib in ethanol and adding methanesulfonic acid, heating under reflux and isolating. PCT publication no. WO 2005/077933 described a process for preparing alpha 2 crystalline form of imatinib mesylate, which comprises suspending imatinib in isopropanol and adding methanesulfonic acid, heating under reflux and isolating.

U.S. patent publication no. 2006/0223816 described a process for preparing stable, free flowing imatinib mesylate alpha form which is substantially free of the beta form. According to the patent application, alpha form was prepared by:

a. mixing imatinib with methyl ethyl ketone or methyl isobutyl ketone or acetonitrile or 4-methylcyclohexanone;

b. heating to dissolve;

c. adding methanesulfonic acid in methyl ethyl ketone;

d. allowing the crystals to precipitate; and

e. isolating the precipitated crystal of imatinib mesylate alpha form.

U.S. patent publication no. 2007/0265288 described a method of preparing crystalline imatinib mesylate alpha form, which comprises suspending imatinib in isopropyl alcohol and adding methanesulfonic acid.

PCT publication no. WO 2009/151899 described a process for the preparation of crystalline imatinib mesylate alpha form, which comprises providing a solution or suspension of imatinib in tetrahydrofuran and adding methanesulfonic acid in tetrahydrofuran.

4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride and N-(2-methyl-5- aminophenyl)-4-(3-pyridyl)-2-pyrimidine-amine are potential genotoxic impurities in imatinib mesylate. No process was described in the prior art to reduce the potential genotoxic impurities of imatinib mesylate.

The present invention is intended to enhance the purity of imatinib mesylate. In particular, the present invention is directed to reduce or remove genotoxic impurities from imatinib mesylate.

We have discovered a process for the preparation of imatinib mesylate in high purity.

Thus, an object of the present invention is to provide a process for the preparation of imatinib mesylate in high purity. Detailed description of the Invention

According to one aspect of the present invention, there is provided a process for the preparation of imatinib mesylate in high purity, which comprises:

a) reacting 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride with thionyl chloride in an organic solvent;

b) heating the reaction mass obtained in step (a) at reflux;

c) isolating 4-(4-methylpiperazinomethyl)benzoyl chloride;

d) reacting 4-(4-methylpiperazinomethyl)benzoyl chloride obtained in step (c) with N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidine amine in the presence of dimethyl amino pyridine and pyridine;

e) maintaining the reaction mass obtained in step (d) at below 35°C; and

f) isolating imatinib;

g) suspending imatinib obtained in step (f) in isopropanol;

h) heating the contents obtained in step (g) at above 65°C;

i) adding a solution of methanesulfonic acid in isopropanol to the solution obtained in step (h) at above 65°C;

j) maintaining the solution obtained in step (i) at reflux; and

k) isolating highly pure imatinib mesylate.

The term "highly pure imatinib mesylate" refers to imatinib mesylate having the content of 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride or N-(2-methyl-5- aminophenyl)-4-(3-pyridyl)-2-pyrimidine-amine less than 10 parts per million (ppm).

The organic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide and acetonitrile, and more preferable organic solvent is dimethylformamide.

The reaction mass may preferably be maintained in step (e) at about 0 to 30°C and more preferably at about 20 to 30°C.

The contents are heated in step (h) may preferably at about 65 to 95°C and more preferably at about 70 to 80°C.

The addition of methanesulfonic acid solution in step (i) may preferably be carried out at about 65 to 95°C and more preferably at about 70 to 80°C. Highly pure imatinib mesylate may be isolated in step (k) by methods known such as filtration or centrifugation.

According to another aspect of the present invention, there is provided a process for the preparation of imatinib mesylate in high purity, which comprises:

a) suspending imatinib in isopropanol;

b) heating the contents obtained in step (a) at above 65°C;

c) adding a solution of methanesulfonic acid in isopropanol to the solution obtained in step (b) at above 65°C;

d) maintaining the solution obtained in step (c) at reflux; and

e) isolating highly pure imatinib mesylate.

The term "highly pure imatinib mesylate" refers to imatinib mesylate having the content of 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride or N-(2-methyl-5- aminophenyl)-4-(3-pyridyl)-2-pyrimidine-amine less than 10 ppm.

Step (b) may preferably be carried out at about 65 to 95°C and more preferably at about 70 to 80°C.

The addition of methanesulfonic acid solution in step (c) may preferably be carried out at about 65 to 95°C and more preferably at about 70 to 80°C.

Isolation of highly pure imatinib mesylate in step (e) may preferably be carried out by methods known such as filtration or centrifugation.

The purity of imatinib mesylate was measured by High performance liquid chromatography (HPLC).

The invention will now be further described by the following examples, which are illustrative rather than limiting.

Examples

Example 1 :

Preparation of imatinib

Thionyl chloride (700 ml) was added to 4-(4-methylpiperazinomethyl) benzoic acid dihydrochloride (100 gm) in dimethylformamide (4 ml) at room temperature. The contents were heated to reflux and stirred for 22 hours at reflux. The reaction mass was cooled to 25 to 30°C and then added n-hexane (600 ml). The reaction mass was stirred for 1 hour at 25 to 30°C and filtered. The solid obtained was dried at 25 to 30°C for 3 hours to obtain 4-(4-methylpiperazinomethyl)benzoylchloride. The solid was added to the mixture of N-(2-Methyl-5-aminophenyl)-4-(3-pyridinyl)-l-pyrimidine-amine (50 gm), pyridine (300 ml) and dimethylamino pyridine (2 gm) at 0 to 15°C slowly for 1 hour. The temperature of the reaction mass was raised to 25 to 30°C and stirred for 1 1 hours at 25 to 30°C. Water (750 ml) and dichloromethane (800 ml) were added to the reaction mass and the pH was adjusted to 9.0 to 9.8 with liquid ammonia (500 ml). The layers were separated and aqueous layer was extracted. The total organic layer was dried and the solvent was distilled off completely under vacuum at below 60°C. To the residual mass obtained was added acetone (500 ml) and cooled to 25 to 30°C. The reaction mass was stirred for 1 hour at 25 to 30°C and then cooled to 10 to 15°C. The reaction mass was stirred for 1 hour at 10 to 15°C and filtered. The wet solid obtained was suspended in methanol (750 ml). The contents were heated to reflux and stirred for 1 hour at reflux. The reaction mass was cooled to 25°C and stirred for 1 hour. The separated solid was filtered and dried at 60°C to obtain 135 gm of imatinib.

Example 2:

Purification of imatinib mesylate

Imatinib (100 gm) as obtained in example 1 was suspended in isopropanol (1500 ml) at 25 to 30°C and then heated to 70 to 75°C. To the solution thus obtained was added methanesulfonic acid (20 gm) in isopropanol (40 ml) slowly for 45 minutes at 70 to

75°C. The contents were heated to reflux and stirred for 2 hours 30 minutes at reflux.

The reaction mass was cooled to 25 to 30°C and stirred for 30 minutes at 25 to 30°C. The solid obtained was collected by filtration and dried at 60°C to obtain 108 gm of highly pure imatinib mesylate.

Imatinib mesylate: 99.83%;

N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidine amine impurity: 2.0 ppm;

4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride impurity: 1.0 ppm.

Example 3:

Purification of imatinib mesylate Imatinib (5 gm) was suspended in isopropanol (70 ml) at 25 to 30 C and then heated to 70 to 75°C. To the solution thus obtained was added methanesulfonic acid (1 gm) in isopropanol (2 ml) slowly for 45 minutes at 70 to 75°C. The contents were heated to reflux and stirred for 2 hours at reflux. The reaction mass was cooled to 25 to 30°C and stirred for 30 minutes at 25 to 30°C, filtered. The solid obtained was dried at 60°C to obtain 5 gm of highly pure imatinib mesylate.

Imatinib mesylate: 99.82%;

N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidine amine impurity: 4.0 ppm; 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride impurity: 3.0 ppm.

Claims

We claim:

1. A process for the preparation of imatinib mesylate in high purity, which comprises: a) reacting 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride with thionyl chloride in an organic solvent;

b) heating the reaction mass obtained in step (a) at reflux;

c) isolating 4-(4-methylpiperazinomethyl)benzoyl chloride;

e) maintaining the reaction mass obtained in step (d) at below 35°C; and

f) isolating imatinib;

g) suspending imatinib obtained in step (f) in isopropanol;

h) heating the contents obtained in step (g) at above 65°C;

j) maintaining the solution obtained in step (i) at reflux; and

k) isolating highly pure imatinib mesylate.

2. The process according to claim 1 , wherein the organic solvent used in step (a) is a solvent or mixture of solvents selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide and acetonitrile.

3. The process according to claim 2, wherein the organic solvent is dimethylformamide.

4. The process according to claim 1, wherein the reaction mass is maintained in step (e) at about 0 to 30°C.

5. The process according to claim 4, wherein the reaction mass is maintained at about 20 to 30°C.

6. The process according to claim 1 , wherein the contents are heated in step (h) at about 65 to 95°C.

7. The process according to claim 6, wherein the contents are heated at about 70 to 80°C.

8. The process according to claim 1, wherein the addition of methanesulfonic acid solution in step (i) is carried out at about 65 to 95°C.

9. The process according to claim 8, wherein the addition is carried out at about 70 to 80°C.

10. A process for the preparation of imatinib mesylate in high purity, which comprises: a) suspending imatinib in isopropanol;

b) heating the contents obtained in step (a) at above 65°C;

d) maintaining the solution obtained in step (c) at reflux; and

e) isolating highly pure imatinib mesylate.

1 1. The process according to claim 10, wherein the contents are heated in step (b) at about 65 to 95°C.

12. The process according to claim 1 1 , wherein the contents are heated at about 70 to 80°C.

13. The process according to claim 10, wherein the addition of methanesulfonic acid solution in step (c) is carried out at about 65 to 95°C.

14. The process according to claim 13, wherein the addition is carried out at about 70 to 80°C.