This application claims priority to Indian patent application number 341/CHE/2011 filed on Feb 07, 2011.

FIELD OF THE INVENTION

The present invention is to provide an improved process for the preparation of imatinib or pharmaceutically acceptable salt.

The present invention is also to provide a process for preparation of Imatinib mesylate polymorphic form
a.

BACK GROUND OF THE INVENTION

The compound Imatinib, chemically N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine of the formula (1)

is a pharmaceutically active compound acting as a selective inhibitor of the ABL protein tyrosine kinase. As a (mono) mesylate salt it has been used in a medicament for the treatment of various types of cancer diseases, e.g. under the brand name GLIVEC. Imatinib has been disclosed in European Patent No. 564409 (US patent no 5521184).

In European Patent No. 0564409 describes the process, wherein 2-amino-4-nitro toluene of the formula II is treated with 65% nitric acid in ethanol, followed by condensation with cyanamide solution at reflux temperature for about 25 hours to yield 2-methyl-5-nitrophenyl guanidine nitrate of the formula (III). Which is reacted with 3-dimethylamino-1- (3-pyridyl)-2-propen-1-one of the formula (IV) in the presence of isopropanol and sodium hydroxide to obtained N-(2-methyl-5-nitrophenyi)-4-(3-pyridyi)-2-pyrimidine amine of the formula (V). Reduction of compound of formula V in ethyl acetate in the presence 10% Pd/C to yield N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (VI), further condensation of compound of formula (VI) with 4- (4-methyl-piperazinomethyl) benzoyl chloride of the formula (VII) in pyridine to obtained Imatinib of formula I (scheme I).

According to above process involves column chromatography for the isolation of pure Imatinib formula I, this chromatographic purification is not suitable for commercial production. The above process also involves pyridine as a reaction solvent for the final condensation, which is not acceptable as per ICH guidelines. The obtained yield also very low thereby making the process is not economical for the commercial production.

Thus the present invention encompassed herein an improved, simple, commercially viable, eco-friendly and industrially advantageous process over the prior art for preparation of Imatinib and also novel process for the preparation of Imatinib mesylate form a.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide an improved process for tine preparation of Imatinib or pharnnaceutically acceptable salt thereof comprising the steps of:

a) reacting 2-methyl-5-nitrophenyl guanidine nitrate of formula-Ill with 3-dimethylamino-1-pyridine-3-yl-propenone of formula IV in a solvent in the presence of base to obtain N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula V,

b) reducing compound of formula V in the presence of a catalyst to obtain N-(5-amino
2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula VI,

c) condensing compound of formula VI with 4-[(methyl-1-piperizinyl)methyl]benzoyl chloride of formula VII or its salt in the presence of a solvent and base to obtain Imatinib of formula I,

d) optionally purifying Imatinib formula I, and

e) converting to pharmaceuticaiiy acceptable salt thereof.

Another aspect of present invention is to provide a novel process for the preparation of Imatinib mesylate polymorphic form a comprising the steps of:

a) suspending Imatinib base in a solvent or mixture of solvents,
b) adding methane sulfonic acid, and
c) isolating Imatinib mesylate polymorphic form a.

DETAILED DESCRIPTION OF THE INVENTION

Present invention is to provide an improved process for the preparation of Imatinib or pharmaceuticaiiy acceptable slat comprising, a) reaction of 2-methyl-5-nitrophenyl guanidine nitrate of formula III with 3-dimethylamino-1-pyridine-3-yl-propenone of formula IV in a solvent in the presence of base to yield N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula V, b) reduction of compound of formula V to yield N-(5-amino 2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula VI, followed by optionally convert to its acid addition salt thereof, c) condensation reaction of formula VI or its acid addition salt thereof with 4-[(methyl-1-piperizinyl)methyl]benzoyl chloride of formula VII in the presence solvent and base to obtain Imatinib formula I, d) optionally purifying the imatinib formula I, and e) converting to pharmaceuticaiiy acceptable salt thereof.

One embodiment of the present invention is to provide an improved process for the preparation of Imatinib or pharmaceutically acceptable salt thereof, comprising the steps of:

a) reacting 2-methyl-5-nitrophenyl guanidine nitrate of formula III with 3-dimethylamino-1-pyridine-3-yl-propenone of formula IV in a solvent in the presence of base to obtain N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula V,

b) reducing compound of formula V in the presence of a catalyst to obtain N-(5-amino 2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula VI,

c) condensing compound of formula VI with 4-[(methyl-1-piperizinyl)methyl]benzoyl
chloride of formula VII or its salt in the presence of solvent and base to obtain

Imatinib formula I, and

d) optionally purifying imatinib formula I, and

e) converting to pharmaceutically acceptable salt thereof.

According to present invention compound of formula III is reacted with 3-dimethylamino-1-pyridine-3-yl-propenone of formula IV in a solvent and base. The reaction mixture is heated to reflux temperature, maintained the reaction about 12 to18 hours preferably about 16 hours. After completion of reaction, cooled to 25-35°C, water is added and stirred for about I hour. The obtained solid is filtered to get N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula V.

According to present invention the reduction reaction of step b) is carried out by dissolving N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula V in a solvent and metal catalyst is added under N2, in the presence of hydrogen source. The reaction mixture is heated to reflux for 4 hours preferably 2 to 6 hours. After completion of reaction, cooled to 25-35°C and remove catalyst. Concentrate the resulting solution, water is added to the residue and maintained the stirring for about 60minutes at 20-25°C. The obtained solid is filtered to get N-(5-amino 2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula VI followed by optionally convert to its acid addition salt thereof.

According to present invention condensation reaction of step c), is carried out by dissolving N-(5-amino 2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula VI or its acid addition salt in a solvent and base. The resulting suspension is cooled to 5 to 10°C and 4-[(methyl-1-piperizinyl) methyl] benzoyl chloride of formula VII is added lot wise over a period of 1 hour, maintained the reaction at the same temperature for about 2 hours and at 25 to 35 °C for 1 hour. After completion of reaction distilled out the solvent, water is added to the distilled mass and the resulting solution pH is adjusted to 10 to 11 by using base, stirred the mass and the obtained solid is filtered to get crude Imatinib of formula-l.

According to present invention Imatinib is optionally purified by dissolving the crude Imatinib in a solvent at 60 to 65°C. The clear solution is treated with charcoal. Concentrates the solution and isolated the obtained solid by filtration to get pure Imatinib formula I. Imatinib free base is optionally converted to pharmaceutically acceptable salt, preferably mesylate salt.

According to present invention the solvent used in the reaction step a) is selected from butanol, methanol, ethanol, isopropanol dimethylformamide, dimethylsulfoxide, tetrahydrofuran, preferably butanol or dimethylformamide. The base is selected from inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, organic base such as pyridine, thriethyl amine, dimethyl amino pyridine, diethyl amine, preferably potassium carbonate.

According to present invention the solvent is used in the reduction reaction of step b) is selected from methanol, ethanol, isopropanol, butanol, ethyl acetate, acetonitrile, or acetone preferably methanol. Metal catalyst is selected from Pd/C, Pt/C, and Raney/Ni, preferably Pd/C and hydrogen source is selected from hydrazine hydrate, hydrogen pressure, ammonium acetate or ammonium formate preferably the hydrogen source is hydrazine hydrate.

According to present invention the solvent used in the condensation reaction of step c) is selected from acetonitrile, acetone, methanol ethanol, propanol, butanol, dimethylformamide, tetrahydrofuran, preferably acetonitrile and base is selected from organic base such as dimethyiaminopyridine or triethylamine, inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate or potassium bicarbonate, preferably dimethyiaminopyridine

According to present invention the solvent used in the purification of Imatinib free base is selected from methanol, ethanol, propanol, butanol, acetone, acetonitrile.

According to present invention the base is used for the pH adjustment in step c) is selected from aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.

According to present invention N-(5-amino 2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula VI is optionally converting to its acid addition salt, preferably oxalate salt and this oxalate salt is reacted with 4-[(methyl-1-piperizinyl) methyl] benzoyl chloride of formula VII or its salt in a solvent in the presence of base to get Imatinib base.

Another embodiment of the present invention is to provide an improved process for the preparation of Imatinib mesylate polymorphic form a, comprising the steps of:

a) dissolving Imatinib base in a solvent or mixture of solvents,
b) adding methane sulfonic acid, and
c) isolating Imatinib mesylate polymorphic form a.

According to present invention Imatinib free base is suspending in to the mixture of isoamyl alcohol and toluene, to the obtained suspension methane sulfonic acid solution is added over a period of 1 hour at about 20 to 25°C. Maintained the reaction for about 45 to 60 minutes and filtered the obtained solid to get Imatinib mesylate polymorphic form a. The obtained solid is suspending in isopropyl alcohol and thus obtained solution is heating to 70-80°C. Maintaining the stirring for about 60min, cooled the mass to about 20-25°C and isolated the solid by filtration.

According to present invention Imatinib or its mesylate salt having the N-(5-amino 2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine (formula VI) impurity is less than about 0.15%by HPLC.

According to present invention Imatinib mesylate polymorphic form a having the purity more than 99.5%, preferably more than 99.8% and more preferable more than 99.95%.

According to present invention Imatinib mesylate having at least 90% of the particles have particle size of less than about 250 microns, preferably less than 200 microns.

According to present invention micronized Imatinib mesylate having at least 90% of the particles have particle size of less than about 50 microns.

According to present invention the process for preparation of compound of formula VII is provided by known methods.

The details of the invention are provided in the Examples given below to illustrate the invention only and therefore they should not be construed to limit the scope of the invention.

Examples:
Example 1: Preparation of N-(2-Methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine (formula V).
To the solution of 3-dimethylamino-1-pyridin-3-yl-propenone of formula IV (5.0 g, 0.0283 mol) in dimethylformamide (60 ml, 12 vol), 2-Methyl-5-nitrophenyl-guanidine nitrate of formula III (7.3 g, 0.0283 mol), and potassium carbonate (2.35 g, 0.017 mol) was added. The reaction mixture was heated to reflux at 135-140°C and maintained for 16 hrs. After completion of reaction, cooled the reaction mixture to room temperature, water (75 ml, 15 vol.) was added and stirred for 1 hour. The product was isolated by filtration, washed the cake with water (20 ml, 4 vol) and suck dried. The product was dried at 70 -75°C under reduced pressure to afford N-(2-Methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine formula V (7.5 g, yield 74%, HPLC purity 98.90%).

Example 2: Preparation of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimicline-amine (formula VI).
N-(2-Methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula V (5.0 g, 0.0163 mol) was taken in methanol (50 ml). To this solution Pd/C (10%, 500 mg) was added under nitrogen atmosphere at 20-25°C and hydrazine hydrate (5.0 g, 0.1 mol) was added drop wise over a period of 10 minutes at 20-25°C. The reaction mixture was heated to reflux for 4 hours at 60-65 °C. After completion of reaction, cooled the reaction mixture to 20-25°C and filter through celite bed and washed the bed with of methanol (2 vol). The combined mother liquor was concentrated under reduced pressure to obtain slurry. To the concentrated mass water (5 vol.) was added and stirred at 20-25°C for 1 hour. The product was isolated by filtration and cake was washed with cyclohexane (2 vol). The product was dried to obtained
N-{5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-aniine of formula VI (4.0 g, yield 88%).

Example 3: One pot process for the preparation of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (formula VI).

2-Methyl-5-nitrophenyl-guanidine nitrate of formula III (306.5 g, 1.1916mol) and sodium hydroxide (49.9375 g, 1.2484 mol) are added to a solution 3-dimethylamino-1-pyridin-3-yl-propenone of formula IV (200 g 1.349 mol) in 1-butanol (2400). The reaction mixture was heated to reflux at 110-112°C and maintained for 18 hours. The reaction mass was cooled to 65-70°C, to the cooled solution Pd-activated charcoal (15 g 10%) and butanol (200 ml) was added under nitrogen atmosphere at 20-25°C. Hydrazine hydrate (300 g, 1.5 vol) was then added drop wise over a period of 1 hour at 65-70''C and maintained for 1 hour. The reaction mixture was heated to 100±10°C and maintained for 10 to 12 hours. After completion of reaction, the reaction mixture was cooled to ~ 50 " C, filters the reaction mass through celite bed and washed the bed with butanol (200 ml). The combined mother liquor was concentrated under reduced pressure at 90 to 95°C to obtain slurry. The reaction mixture was cooled to 50°C, water 2000 ml) was added and stirred for 1 hour at 20-25°C. The product was filtered and washed with water (200 ml) to pH ~7. The product was taken into toluene (600 ml, 3 vol.) and mixture was heated to reflux to remove water azeotropicaliy. After complete removal of water, cooled the mixture to 25-30°C and filtered. The product was dried at 65-70°C to get title compound (220 g, yield 70%, HPLC purity = 99.0%).

Example 4: Preparation of N-(5-amino-2-methylphenyl)-4 -(3-pyridyl)-2-pyrimidine-amine oxalate.
The solution of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine of formula V (50 g) in isopropanoi (500 mi) was heated to reflux. Oxalic acid dihydrate (26.6 g) was added to the reaction mixture under reflux (75-80°C) and maintained for 1 hour. The reaction mass was slowly cooled to room temperature and stirred for 1 hour. The obtained solid was filtered and washed with isopropanoi (100 ml). Amine oxalate salt was dried under vacuum 650 mmHg for 12 hours to get title compound (50 g yield 75%).

Example 5: Preparation of 4-[(4-IVIethyl-1-piperazinyl) methyl] benzoylchloride dihydrochloride (formula VII).

The solution of 4-[(4-l\/lethyl-1-piperazinyl) methyl] benzoic acid dihydrochloride (200 g, 0.651 mol) in acetonitrile (1000 ml, 5 vol) was heated to 70-75°C and thionyl chloride (980 g, 8.24 mol) was added drop wise over a period of 1,5 hours. The reaction mixture was heated at 70-75°C for 24 hrs. The progress of reaction was monitored by TLC. After completion of reaction, the solvent was distilled under reduced pressure. To the concentrated mass toluene (500 ml, 2.5 vol.) was added and stirred at 20-25''C for 2 hours. The product was filtered and washed with toluene (200 ml, 1.0 vol). The product was dried under reduced pressure at 60-65''C to get title compound (170 g, yield 80% and HPLC purity 99.5%).

Example 6: Preparation of Imatinib base (formula I):
To the solution N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine of formula VI (75 g, 0.0721 moles) in acetonitrile (900 ml), dimethylamino pyridine (DMAP, 132 g, 1.08 mol) was added. The reaction mixture was stirred to obtain a suspension. 4-[(4-Methyl-1-piperazinyl)methyl] benzoyl chloride dihydrochloride of formula VII (132g 0.406 mol) was added lot wise over a period of 1.0 hour at 25-30°C and stirred the reaction mixture for another 2 hours. The progress of reaction was monitored by TLC. After completion of reaction, the solvent was distilled under reduced pressure below 80°C to obtain slurry. The slurry mass was cooled to 25-30°C, water (750 ml) was added and adjusted the pH of reaction mixture to 10 to 11 with aqueous sodium hydroxide solution (375ml, 10%). The reaction mixture was stirred for 1 hour at 25-30°C, filtered the solid and washed the solid with water to get pH of 7.0 (158g). The crude base was mixed with water (750ml), adjusted the pH to 3 to 4 by using aqueous hydrochloric acid (70ml, 35%) and extracted the solution with dichloromethane (3X375ml). To the aqueous solution activated charcoal (3.75g) was added at 25-30°C, stirred for 1.0 hour, the solution was filtered through celite bed and wahed with water (75ml). To the filtrate acetone (750ml) and aqueous sodium hydroxide solution (300mi, 10%) was added to obtain a pH 9 to 10. The obtained solid was filtered, washed with water to till neutral pH. The obtained wet compound was taken in methanol (1500ml) and heated to 60-65°C to get clear solution. To the solution activated charcoal (3.75g) was added and maintained the stirring for 1 hour. The mass was filtered through celite bed under hot condition and washed with methanol (75ml). The solvent was distilled at 60-65°C to 5 Volumes of methanol. The distillate was cooled to 25-30°C, stirred for 1 hour, the solid was filtered and wahed with methanol (75ml). Dried the solid at 60-65°C (94g yield 70% and HPLC purity 99.9%).

Example 7: Preparation of Imatinib free base (formula I):
To the solution of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimicline-amine of formula VI (25 g, 0.09 mol) in isopropyl alcohol (250 ml), sodium hydroxide (17g, 0.43 mol) was added at 25-30°C. To the reaction mass of 4-[(4-Methyl-1-piperazinyl) methyl] benzoyl chloride dihydrochloride of formula VII (44 g , 0.135 mol) was added in lot wise over a period of 1.0 hour, maintaining the reaction at 25-30''C for 8 hours, after each lot isopropyl alcohol was added (total 125 ml). The reaction mixture was further stirred for another 2 hours at 25-30°C. The solvent was distilled under reduced pressure below 80 °C to obtain slurry. The slurry was cooled to 25-30°C, water (375 ml) was added and followed by aqueous sodium hydroxide solution (100 ml, 10%) was added at 25-30°C to get pH ~10. Reaction mass was stirred for 1 hour at 25-30°C and filtered, washed the cake with water to get pH of ~7. Wet crude product was taken in methanol (500 ml) and heated to 60-65 °C to obtain a clear solution. Activated charcoal (0.5 g) was added at 60-65 °C and maintained for 1 hour. The reaction mixture was filtered through celite bed under hot condition and washed with methanol (75 ml). The combined mother liquor was concentrated at 60-65 °C to 5 volumes of methanol. The combined mother liquor was cooled to 25 to 30°C and stirred for 1 hour. The purified base was filtered and washed with methanol (25 ml). The wet cake was again mixed with 1-butanol (175 ml) and heated to 105-110 °C to obtain a clear solution. After getting clear solution, the reaction mixture was cooled to 25-30°C and stirred for 1 hour. Filter the reaction mass and wash the solid with 1-butanol (50 ml). The product was dried under reduced pressure at 60-65°C (31.5 g, yield 70% and HPLC purity 99.90%).

Example 8: Preparation of Imatinib Mesylate polymorphic form a:
To the solution of isoamyl alcohol and toluene (750 ml (15 vol, 1:1 mixture), Imatinib base (50.0 g, 0.1012 mol) was added at 20-25°C and stirred for 15 minutes under nitrogen atmosphere to obtain a suspension. To the suspension methane sulfonic acid solution (250 ml, 10.32 g, 0.1063 mol, toluene: isoamyl alcohol, 1:1 mixture) was added drop wise at the same temperature over a period of 1 hour. The reaction mixture was stirred further for 1 hour. The progress of reaction was monitored by XRPD. After completion of reaction, the product was filtered under nitrogen atmosphere and cake was washed with isopropyl alcohol (100 ml,) and suck dried. The wet cake was mixed with isopropyl alcohol (500 ml) and heated the reaction mixture to 78-80°C stirred for 60 minutes. The reaction mass was cooled to 20-25°C. Filter the solid under nitrogen atmosphere and suck dry. The product was dried at 50-55°C for 30-35 hours to get Imatinib mesylate a crystalline form (50 g).

We Claim:

1. An improved process for the preparation of Imatinib or pharmaceutically acceptable salt thereof, comprising the steps of:

a) reacting 2-methyl-5-nitrophenyl guanidine nitrate of formula III with 3-dimethylamino-1-pyridine-3-yl-propenone of formula IV in a solvent in the presence of base to obtain N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2- pyrimidine amine of formula V,

b) reducing compound of formula V in presence of a catalyst to obtain N-(5-amino 2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of formula VI,

c) condensing compound of formula VI with 4-[(methyl-1-piperizinyl)methyl]benzoyl chloride of formula VII or its salt in the presence of solvent and base to obtain Imatinib formula I ,


d) optionally purifying imatinib formula I, and

e) converting to pharmaceutically acceptable salt thereof.

2. The process according to claim 1, wherein the solvent used in step a) is selected from butanol, methanol, ethanol, isopropanol dimethylformamide, dimethylsulfoxide, tetrahydrofuran, butanol dimethylformamide or mixture thereof.

3. The process according to claim 1, wherein the base used in step a) is selected from inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, organic base such as pyridine, thriethyl amine, dimethyl amino pyridine, diethyl amine, or potassium carbonate.

4. The process according to claim 1, wherein the solvent used in step b) is selected from methanol, ethanol, isopropanol, butanol, ethyl acetate, acetonitrile, acetone, methanol or mixture thereof.

5. The process according to claim 1, wherein the metal catalyst used in reduction step b)
is selected from Pd/C, Pt/C, or Raney/Ni, and hydrogen source is selected from hydrazine hydrate, hydrogen pressure, ammonium acetate or ammonium formate.

6. The process according to claim 1, wherein the solvent used in step c) is selected from acetonitrile, acetone, methanol ethanol, propanol, butanol, dimethylformamide, tetrahydrofuran or mixture thereof, and base is selected from dimethylaminopyridine, triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate or potassium bicarbonate.

7. The process according to claim 1, wherein Imatinib is obtained in step c) is optionally purified in solvent is selected from acetone, methanol, ethanol, isopropanol, butanol, acetonitrile or mixture thereof.

8. A process for the preparation of Imatinib mesylate polymorphic form a, comprising the steps of:

a) dissolving Imatinib base in a solvent or mixture of solvents,
b) adding methane sulfonic acid, and
c) isolating Imatinib mesylate polymorphic form a.

9. The process according to claim 8, wherein the solvent is selected from isoamylalcohol, toluene or mixture thereof.

10. Imatinib mesylate have N-{5-amino 2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine (formula VI) impurity less than about 0.15% by HPLC.