Field of the invention
The present invention provides an improved process for preparing 4-(4-methylpiperazin-1-yl)methyl benzoic acid dihydrochloride and its reaction with N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine in presence of DCC & HOBT to give imatinib. Imatinib is converted to its oxalate salt, reconverted to imatinib and treated with methane sulphonic acid to give imatinib mesilate of high purity.
Background of the invention
N-[5-[4-(4-Methylpiperazinomethyl)- benzoyl amido)]-2-methylphenyl]-4-[3-pyridyl]-2-pyrimidineamine mesilate of formula I is commonly known as imatinib mesilate.
Imatinib mesilate is approved by U.S. FDA for treatment of Chronic Myelogenous Leukemia. It has also been approved for the treatment of patients with kit (CD 117) positive unreselectable and / or metastatic malignant Gastro Intestinal Stromal Tumors. The prior art synthesis of imatinib in EP 0564409 and its equivalent U.S Patent 55211584 comprises the steps of reactions as given in scheme - I. 2- Amino -4- nitrotoluene nitrate (2) is reacted with cyanamide solution at reflux temperature to give 2-methyl-5nitrophenyl guanidine nitrate of formula 3. Condensation of product of formula 3 with 3-dimethylamino-1-(3-pyridyl)-2-propene-1-one (4) in isopropyl alcohol and sodium hydroxide gives the product of formula 5. Reduction of N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine with Pd/C and hydrogen yielded the corresponding amino compound of formula 6, which on subsequent synthetic protocol as shown in scheme-l gave crude imatinib (8). This

In WO 2004/108699, the preparation of imatinib involves the steps of reactions as shown in scheme III.
4-Bromo methyl benzoic acid (14), obtained by the reaction of p-toluic acid with N-bromo succinimide, is hydrolyzed to give product of formula 15 which in turn is converted to 4-chloromethylbenzoyl chloride (16) using thionyl chloride. Subsequent synthetic protocol as given in scheme-Ill gives imatinib mesilate. This process involves use of thionyl chloride an obnoxious and corrosive chemical. Added to this, an additional step is involved.

Recovery of unreacted 2-amino-4-nitrotoluene is tedious. Recovery of this product is important for the process economy.
2. Diethylether is used in a preparation of product of formula 3. It is volatile and flammable.
3. Product of formula 5 is hydrogenated using 10% Pd-C making the process uneconomical.
4. 4-(4-Methylpiperazin-1-yl)methyl benzoic acid dihydrochloride is prepared by reaction of 4-(chIoromethyl) benzoic acid and N-methyl piperazine in poor yield (35%) (scheme II). Moreover, N- methyl piperzine, an expensive chemical, is used in large excess (4 moles). Further, this condensation reaction is carried out in absolute solvent for long duration (16 hrs) at reflux temperature.
5. Conversion of 4-(4-methylpiperazin--1-yl)methyl benzoic acid to benzoyi chloride derivative of formula 7 involves thionyl chloride, an obnoxious and non ecofriendly chemical.
6. Use of pyridine as solvent in the penultimate stage makes the process difficult and also environmentally unfriendly.
7. Column chromatography is applied to isolate the product of formula 8. This makes the process expensive and non-feasible on commercial scale.
8. Condensation of 4-(4-methylpiperazin-1 -yl)methyl benzoylchloride dihydrochloride (12) with N-(2-methyl-5-aminophenyl-4-(3-pyridyl)-2-pyrimidine (6) in pyridine gives poor yield of imatinib (8).
Objectives of the present invention

In view of the difficulties associated with prior art methods of synthesis, the present
invention has its objective of preparing imatinib by an efficient, economically feasible,
safe and eco-friendly process.
Another objective of the present invention is to provide a process for the preparation
of 4-(4-methylpiperazin-1-yl)methyl benzoicacid dihydrochloride (11) in good yield.
Yet another objective of the present invention is to avoid an additional step of
preparing 4-(4-methylpiperazin-1-yl)methyl benzoyl chloride dihydrochloride (12)
which involves use of thionyl chloride, a corrosive and polluting chemical.
Yet another objective of the present invention is to provide an improved process for
the preparation of imatinib, wherein nitro group of product of formula 5 is reduced
using Raney-Ni as catalyst to give product of formula 6. This will make the process
economically viable.
Still another objective of the present invention is to provide an improved process for
preparation of imatinib, wherein the unreacted product of formula 2 is recovered.
Still further objective of the present invention is to provide an improved process for
the preparation of imatinib by reacting N-(2-methyl-5-amino phenyl-4-(3-pyridyl)-2-
pyrimidine with 4-(4-methylpiperazin-1-yl)methyl benzoic acid dihydrochloride in
presence of a carbodiimide derivative,, preferably in combination with N-hydroxy
amino, or N-hydroxy amido compound for example N-hydroxy succinimide, N-
hydroxy phthalimide or 1-hydroxy benzotriazole.
Still further objective of the present invention is to provide a process for purification
of crude imatinib by converting it into salt, regenerating imatinib base and converting
into imatinib mesilate of high purity.

Summary of the invention
A process for preparing imatinib comprising of reacting N-(2-methyl-5-aminophenyl-4-(3-pyridyl)-2-pyrimidine of formula 6 with 4-(4-methylpiperazinomethyl) benzoic acid dihydrochloride of formula 11 in the presence of DCC and hydroxyl benzotriazole and a organic base is disclosed. It also discloses the preparation of 4-(4-methyIpiperazin-1-yl) methyl benzoic acid by acid hydrolysis of methyl-4-(4-methylpiperazino-1-yl)methyl benzoate in excellent yield. Crude imatinib was converted to its oxalate salt, preferably by treating with oxalic acid in methanol. Imatinib base is regenerated by treating the oxalate salt with a suitable base and again treated with methane sulphonic acid by a known process to give imatinib mesilate.

Description of the invention
Continued research work at our research laboratory yielded an improved, economical and ecofriendly process for the preparation of imatinib of formula 1, which is described below.
a) Condensation of 50% cyanamide solution with 2-methyl-5-nitro aniline in methanol and nitric acid at reflux temperature gave 2-methyl-5-nitro phenyl guanidine nitrate. After isolation of guanidine nitrate derivative of formula 3, it was washed with hot ethyl acetate to remove unreacted 2-methyl-5-nitro aniline. Ethyl acetate washings on concentration gave unreacted 2-methyl-5-nitro aniline.
Unreacted 2-methyl-5-nitro aniline was also recovered from the methanol mother liquor.
b) A mixture of 3-dimethylamino-1-(3-pyridyl)-2-propene-1-one and 2-methyl-5-nitro phenyl guanidine nitrate and sodium hydroxide in n-butanol was heated for
6-8 hours at reflux temperature. Then reaction mass was cooled to 0°C, to give the product of formula 5.
c) Reduction of N-(2-methyl-5-nitro phenyl)-4-(3-pyridyl)-2-pyrimidine amine (5) with Raney-Ni in alkanol yielded the product of formula 6. Preferably, reaction was conducted in methanol at a temperature of 40°C for a duration of 4 to 5 hours.
d) Methyl-4[(4-methyl piperazin-1-yl)methyl] benzoate was prepared by reacting methyl-4-bromomethyl benzoate with 1-methyl piperazine in dimethyl formamide.
e) Hydrolysis of the condensed product of formula 21 was tried with methanolic sodium hydroxide as well as hydrochloric acid. Hydrolysis using hydrochloric acid yielded 4-[(4-methyl piperazin-1-yl)methyl] benzoic acid dihydrochloride in 92% yield and >99% HPLC purity, whereas alkaline hydrolysis yielded product in lower yield and lesser purity.

f) Condensation of N-(5-aminO-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine (6) with 4-(4-methylpiperazin-1-yl)methyl benzoic acid dihydrochloride to give imatinib of formula 8 (scheme-V) was achieved by conducting the reaction in the presence of 1,3-dicyclohexylcarbodiimide, 1-hydroxy benzotriazole and an excess of triethylamine. If triethylamine was equimolar or less, the rate of
reaction was very slow or reaction was not proceeding to completion. Halogenated solvents like dichloromethane, chloroform, dichloroethane,
ethyl acetate, THF, etc., were used as solvents. Ethyl acetate was preferably the ideal solvent for the peptide type coupling.
g) Crude imatinib was treated with succinic or oxalic acid in methanol to give its corresponding succinate or oxalate salt for the purpose of purification. The salt was basified with aqueous sodium carbonate and the free base obtained, was converted to mesilate salt in methanol containing methane sulphonic acid.

Advantages of the present invention
1. 2-Methyl-5-nitro aniline can be recovered by a simple process.
2. Preparation of acid chloride 12. from product of formula 11 using thionyl chloride is avoided. This saves an additional step. This makes the process environmentally friendly.
3. Acid of formula 11 is prepared in very good yield by an improved process and used for coupling with the product of formula 6.
4. Column chromatography in the penultimate stage in the process of imatinib synthesis is avoided.
5. Use of absolute solvent in step-l (scheme-ll) for condensation of product of formula 9 with N-methyl piperazine is avoided.
6. Condensation of product of formula 11 with product of formula 6 to give imatinib is achieved in very good yield, thereby, making the process economically viable on commercial scale.
7. Imatinib base is purified by converting into an oxalate salt. The oxalate salt, on conversion back to base and reaction with methane sulphonic acid, yields imatinib mesilate in >99.8% HPLC purity.

In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, this do not limit the scope of the present invention in any way Example 1
To a suspension of 2-methyl-5-nitro aniline (100 gm) in methanol (300 ml) was added 70% nitric acid (65 gm) slowly at 0-5°C. Further 50% cyanamide solution (90 gm) was added to above mass and the mixture was stirred under reflux for 20 hours. The reaction mass was then cooled to 0-5°C, solid filtered and washed with methanol and isopropyl ether. Further the crude product, was taken in ethylacetate, heated at 60-65°C for 30 minutes and filtered, to give 55% of 2-methyl-5-nitrophenyl guanidine nitrate, m.p. 215-220°C.
Unreacted 2-methyl-5-nitro aniline was recovered from methanol and ethyl acetate mother liquors.
Example 2
A mixture of 2-methyl-5-nitrophenylguanidine nitrate (50 gm) and 2-dimethylamino-1-(3-pyridyl)-2-propane-1-one (35 gm) in n-butanol (350 ml) containing sodium hydroxide (9 gms) was heated under reflux for 10 hours and then allowed to come to room temperature. To this reaction mass, iso propyl alcohol was added, cooled to 10-15°C and solid filtered to give 55 gms (91%) of N-(5-nitro-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine, m.p. 194-198°C. Example 3
A slurry of N-(5-nitro-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine (100 gm) in methanol (800 ml) and Raney Ni (15 gm) was stirred under hydrogen atmosphere for

5 hrs to give 90% of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine,
m.p. 142-145°C.
Example 4
Methyl-4-(4-methylpiperazin-1-yl)-methyl benzoate (100 gm) in 20% hydrochloric
acid (300 ml) was heated under reflux for 2 to 3 hours. The reaction mass was
allowed to come to room temperature. It was further cooled to 0-5°C and maintained
for 1 hour under stirring. Crystalline solid was collected by filtration, heated in
isopropyl alcohol (400 ml) at 70°C for 30 minutes and filtered
to give 4-(4-methyIpiperazin-1-yl)methyl benzoic acid dihydrochloride (115 gm, 92%),
m.p. 310-312°C, HPLC purity 99.9%.
Example 5
To a solution of N-(5"amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine (100
gm) in methylene chloride (4.0 L) and triethyl amine (200 ml) was added,
1-hydroxy benzotriazole (65 gm), 4-(4-methylpiperazin-1-yl)methyl benzoicacid
dihydrochloride (120 gm) and the reaction mixture was cooled to 10-15°C.
1,3-Dicyclohexylcarbodiimide (96 gm) was added to the above reaction mixture and
stirred at room temperature for 24 hours. After completion of the reaction (TLC
monitor), the solid was filtered. Methylele chloride solution was washed with 10%
sodium bicarbonate solution, dried over sodium sulphate and concentrated to give
imatinib (150 gm, 85%), m.p. 205-207°C, HPLC purity 98%.

Example 6
To a solution of imatinib (250 gm) in methanol (100 ml) was added oxalic acid (64
gm) dissolved in methanol (20 ml) and stirred for 30 minutes at room temperature.
The solid separated was filtered, washed with methanol (50 ml) to give imatinib
oxalate, 285 gm, m.p.226-227°C, HPLC purity >99.7%.
Example 7
Imatinib oxalate (150 gm) prepared as given in example 6, was dissolved in water
and basified with sodium carbonate solution. The solid was filtered and dried to give
120 gm of purified imatinib base.
Example 8
Imatinib base (100 gm) was dissolved in methanol (1 L) at temperature of 40-45°C.
To this solution was added methane sulphonic acid (20 gm) and reaction mixture
was heated to reflux for 1 hour. Carbon (10 gm) was added to reaction mass and
filtered through hyflow bed. Filtrate was concentrated to above 70%, under reduced
pressure, stirred at room temperature for 12 hours and solid separated was filtered
to give imatinib mesilate, 95 gm, m.p. 212-213°C, >99.8% HPLC purity.

We Claim:
1. A process for the preparation of imatinib mesilate comprising the steps of:
a) coupling N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimicline amine of formula 6 with 4-(4-methyl piperazin-1 -yl)methyl benzoic acid dihydrochloride using suitable coupling reagents in a suitable solvent in the presence an organic base at a temperature of 10-40°C,
b) purifying the imatinib base,
c) converting it to mesilate.

2. The process, as claimed in claim 1a, wherein the coupling reagents are preferably dicyclohexylcarbodiimide in combination with 1-hydroxy- benzotriazole.
3. The process, as claimed in claim 1a, wherein the preferred solvent is selected from the group, methylene chloride, chloroform, ethyl acetate, THF, etc.,
4. The process, as claimed in claim 1a:, wherein the organic base is triethyl amine.
5. The process, as claimed in claim 1a, wherein the coupling is preferably conducted at 10-30°C.
6. The process, as claimed in claim 2, wherein the purification comprises of

a) treating crude base with oxalic acid, preferably in methanol at reflux temperature,
b) basifying imatinib oxalate in aqueous sodium carbonate at 10-20°C to get the purified base.
7. The process, as claimed in claim 1c, wherein the purified base is treated with methane sulphonic acid in methanol to give imatinib mesilate of >99.8% HPLC purity.