This application claims the benefit of priority to Indian provisional application No. 515/CHE/2008 filed on February 29, 2008, which is incorporated herein by reference.

FIELD OF THE INVENTION

Disclosed herein is an improved, commercially viable and industrially advantageous process for the preparation of a substantially pure Imatinib intermediate, N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine or an acid addition salt thereof. The intermediate is useful for preparing Imatinib, or a pharmaceutically acceptable acid addition salt thereof, in high yield and purity.

BACKGROUND OF THE INVENTION U.S.

Patent No. 5,521,184 discloses a variety of N-phenyl-2-pyrimidine-amine derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. These compounds are useful in the treatment of tumoral diseases. Among them, Imatinib, 4-[(4-methyl-l-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide, is a protein-tyrosine kinase inhibitor, especially useful in the treatment of various types of cancers and also be used for the treatment of atherosclerosis, thrombosis, restenosis, or fibrosis. Imatinib can also be used for the treatment of non-maligant diseases. Imatinib is usually administered orally in the form of a suitable salt, e.g., in the form of Imatinib mesylate. Imatinib is sold by Novartis as Gleevec™ capsules containing Imatinib mesylate equivalent to 100 mg of Imatinib free base. Imatinib mesylate is represented by the following structural formula:

Various processes for the preparation of Imatinib and related compounds are disclosed in U.S. Patent No. 5,521,184, PCT Publication Nos. WO 2003/066613 Al, WO 2004/074502 A2, WO 2004/108699 Al, WO 2006/061332 Al, WO 2006/071130 A2 and U.S. Patent Application No. 2006/0149061 Al.

In the preparation of Imatinib, N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine of formula I:

is a key intermediate. U.S. Patent No. 5,521,184 (hereinafter referred to as the '184 patent) provides the process for the preparation of Imatinib by reaction of 2-methyl-5-nitroaniline with aqueous solution of cyanamide in the presence of nitric acid in ethanol to produce 2-methyl-5-nitrophenyl guanidine nitrate, which by reaction with 3-dimethylamino-l-(3-pyridinyl)-2-propen-l-one in the presence of sodium hydroxide in isopropanol to produce N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine, followed by reduction using hydrogen in the presence of Pd/C catalyst in ethyl acetate to produce N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine (formula I), which is then condensed with 4-(4-methyl-piperazinomethyl)benzoyl chloride in pyridine. The crude product obtained is then subjected to column chromatographic purifications using a solvent system containing chloroform and methanol to yield Imatinib.

The '184 patent involves the use of Pd/C catalyst for the reduction of N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine. However, a high cost of the catalysts and/ or the necessity of using equipment suitable for operation under pressure of hydrogen, extra purification steps to obtain the final product, multiple crystallizations and the use of explosive reagents are disadvantages of the process used in the '184 patent.

Moreover, Imatinib obtained by the process described in the ' 184 patent does not have satisfactory purity. Unacceptable amounts of impurities are formed along with Imatinib. The yield of Imatinib obtained is very poor and the process involves column chromatographic purifications. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible.

PCT Publication No. WO 2003/066613 Al (hereinafter referred to as the '613 application) describes several synthetic routes for preparing Imatinib. According to one synthetic process, Imatinib is prepared by the reaction of 4-(4-methyl-piperazin-l-ylmethyl)-benzoic acid methyl ester with 3-nitro-4-methyl-aniline to give N-(4-methyl-3-nitrophenyl)-4-(4-methyl-piperazin-l-ylmethyl)-benzamide, which is subsequently reduced to obtain N-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazin-l-ylmethyl)-benzamide followed by reaction with cyanamide in a mixture of concentrated hydrochloric acid solution and n-butanol to produce N-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-l-ylrnethyl)-benzamide, which is then reacted with 3-dimethylamino-l-pyridin-3-yl-propenone to yield Imatinib.

According to another synthetic process as described in the '613 application, Imatinib is prepared by the reaction of 3-bromo-4-methyl-aniline with 4-(4-methyl-piperazin-l-ylmethyl)-benzoic acid methyl ester to afford N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-l-ylmethyl)-benzamide, which by reaction with 4-(3-pyridyl)-2-pyrimidine amine to yield Imatinib.

The reduction of N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine to N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine by a chemical method, described in the applications WO 2004/074502 and WO 2004/108699 by using stannous chloride - SnCb in the presence of hydrochloric acid Stannous chloride is a highly corrosive chemical. Hence, the use of stannous chloride is not advisable for scale up operations due to its corrosive nature. Moreover, the use of hydrochloric acid in the processes corrodes the equipments used in the manufacture.

PCT Publication No. WO 2006/071130 A2 teaches the use of Raney Ni/ Hydrazine hydrate as a reagent for the reduction of N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine to N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine. This process also suffers from drawbacks since Raney Ni is a pyrophoric and explosive reagent and the use of Raney Ni is not advisable for scale up operations.

Based on the aforementioned drawbacks, the prior art processes may be unsuitable for preparation of Imatinib in commercial scale operations.

A need remains for an improved and commercially viable process of preparing a substantially pure compound of formula I to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.

Desirable process properties include less hazardous and environmentally friendly reagents, reduced cost, and greater simplicity, increased purity and increased yield of the product, thereby enabling the production of Imatinib and its pharmaceutically acceptable acid addition salts in high purity and in high yield.

SUMMARY OF THE INVENTION

The present inventors have surprisingly found that Imatinib intermediate, N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine, can be prepared in high purity and with high yield by reducing N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine with aqueous hydrazine in the presence of a Lewis acid.

The present invention provides an efficient, convenient, commercially viable and environment friendly process for the preparation of Imatinib intermediate, N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine or an acid addition salt thereof. Advantageously, the reagents used for present invention are less hazardous and easy to handle at commercial scale and also involves less expensive reagents.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a process for the preparation of the Imatinib intermediate, N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine of formula 1:

or an acid addition salt thereof, which comprises: a) reacting 2-methyl-5-nitroaniline of formula II:

with cyanamide in the presence of p-toluenesulfonic acid in an alcohol solvent to provide 2-methyl-5-nitrophenyl guanidine p-toluenesulfonate of formula III:

b) reacting the compound of formula III with 3-dimethylamino-l-(3-pyridinyl)-2-
propen-1-one of formula IV:

in the presence of a base in an alcoholic solvent to provide N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine of formula V:

c) reducing the compound of formula V by using hydrazine in the presence of a Lewis

acid in an alcoholic solvent to provide a substantially pure compound of formula I.

The compound of formula I is optionally converted into its acid addition salts.

Exemplary alcohol solvents used in step-(a) include, but are not limited to, C\ to C6 straight or branched chain alcohol solvents such as methanol, ethanol, propanol, butanol, amyl alcohol, hexanol, and mixtures thereof. Specific alcohol solvents are methanol, ethanol, 2-propanol, and mixtures thereof, and most specific alcohol solvent is 2-propanol.

The reaction in step-(a) is carried out at a temperature of 0°C to the reflux temperature of the solvent used, specifically at a temperature of 25°C to the reflux temperature of the solvent used, more specifically at a temperature of 60°C to the reflux temperature of the solvent used, and most specifically at the reflux temperature of the solvent used.

As used herein, "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.

Usually, about 0.7 to 2 moles, specifically, about 0.9 to 1.5 moles of cyanamide is used per 1 mole of 2-methyl-5-nitroaniline.

Usually, about 0.7 to 2 moles, specifically, about 0.9 to 1.5 moles of p-toluenesulfonic acid is used per 1 mole of 2-methyl-5-nitroaniline.

Preferably, cyanamide used in step-(a) may be in the form of aqueous solution of cyanamide.

The reaction mass containing the tosylate compound of formula III obtained in step-(a) may be subjected to usual work up such as washings, extractions etc. The reaction mass may be used directly in the next step to produce the compound of formula V, or the tosylate compound of formula III may be isolated and then used in the next step.

3-Dimethylamino-l-(3-pyridinyl)-2-propen-l-one used as starting material in step-(b) may be obtained by processes described in the prior art, for example by the process described in the U.S. Patent No. 5,521,184.

Exemplary alcohol solvents used in step-(b) include, but are not limited to, C1 to C6 straight or branched chain alcohol solvents such as methanol, ethanol, propanol, butanol, amyl alcohol, hexanol, and mixtures thereof. Specific alcohol solvents are methanol, ethanol, 2-propanol, isoamyl alcohol, and mixtures thereof, and most specific alcohol solvent is isoamyl alcohol.

Exemplary bases used in step-(b) include, but are not limited to, hydroxides, carbonates, bicarbonates, alkoxides and oxides of alkali or alkaline earth metals. Specific alkali metal compounds are lithium, sodium and potassium, and more specifically sodium and potassium. Specific alkaline earth metal compounds are calcium and magnesium, and more specifically magnesium. Specific bases are sodium hydroxide, potassium hydroxide, magnesium hydroxide, magnesium oxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide and potassium tert-butoxide, and more specifically sodium hydroxide and potassium hydroxide.

The reaction in step-b) is carried out at a temperature of 10°C to the reflux temperature of the solvent used, specifically at a temperature of 50°C to the reflux temperature of the solvent used, more specifically at a temperature of 60°C to the reflux temperature of the solvent used, and most specifically at the reflux temperature of the solvent used.

As used herein, "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.

The reaction mass containing the nitro compound of formula V obtained in step-(b) may be subjected to usual work up such as washings, extractions etc. The reaction mass may be used directly in the next step to produce the compound of formula I or the nitro compound of formula V may be isolated and then used in the next step.

Exemplary alcohol solvents used in step-(c) include, but are not limited to, C1 to C6 straight or branched chain alcohol solvents such as methanol, ethanol, propanol, butanol, amyl alcohol, hexanol, and mixtures thereof. Specific alcoholic solvents are methanol, ethanol, 2-propanol, and mixtures thereof, and most specific alcoholic solvent is methanol.

Exemplary Lewis acids used in step-(c) include, but not limited to, ferric chloride, aluminum chloride, calcium chloride, zinc chloride, and combinations comprising one or more of the foregoing Lewis acids. Preferred Lewis acid is ferric chloride.

The reaction in step-(c) is carried out at a temperature of 30°C to the reflux temperature of the solvent used, specifically at a temperature of 40°C to the reflux temperature of the solvent used, more specifically at a temperature of 50°C to the reflux temperature of the solvent used, and most specifically at the reflux temperature of the solvent used.

As used herein, "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.

In one embodiment, usually about 4 to 6 moles, and specifically 4.5 to 5 moles, of hydrazine per 1 mole of N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine of formula V is employed.

In another embodiment, the hydrazine used in step-(c) may be in the form of commercially available hydrazine hydrate or aqueous solutions thereof.

In another embodiment, the Lewis acid used in this step is less than about 0.5 moles, specifically 0.01 to 0.05 moles, per 1 mole of N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine of formula V in order to ensure a proper course of the reaction.

Hydrazine with a Lewis acid, used for the reduction, allows the product to be easily isolated and purified, thereby producing the product with greater than about 84% yield.
The use of inexpensive, non-pyrophoric, non-corrosive, readily available and easy to handle reagents allows the process disclosed herein to be suitable for preparation of imatinib at lab scale and in commercial scale operations.

In one embodiment, the compound of formula I obtained in step-(c) is isolated as solid from a suitable organic solvent by methods usually known in the art such as cooling, partial removal of the solvent from the solution, addition of precipitating solvent, or a combination thereof.

The compound of formula I obtained in step-(c) has a purity (measured by High Performance Liquid Chromatography, hereinafter referred to as 'HPLC') greater than about 98.5%, specifically greater than about 99%, and more specifically greater than about 99.5%.

The compound of formula I is an amine and forms acid addition salts with organic and inorganic acids. Example of such as salts includes hydrochloride, hydrobromide, sulfate, tartarate, fumarate, mandelate and derivatives of tartaric acid.

The term "substantially pure compound of formula I or its acid addition salts" refers to the compound of formula I or its acid addition salts having purity greater than about 98.5%, specifically greater than about 99%, and more specifically greater than about 99.5% (measures by HPLC).

Imatinib and pharmaceutically acceptable acid addition salts of imatinib can be prepared in high purity by using the substantially pure compound of formula I or its acid addition salts obtained by the methods disclosed herein, by known methods, for example as described in the U.S. Patent No. 5,521,184.

HPLC Method for measuring the chemical purity:

The HPLC purity was measured by high performance liquid chromatography by using
Shimadzu LC 2010 A with UV detector having under the following conditions:
Column : Hypersil BDS C8 or equivalent. 25 cm x 4.6 mm, 5.0 micron
Column oven temperature: 30C
Detection : 230 nm
Flow rate : lml/min
Injection volume : 10 ul
Run time : 35 min
Diluent : Buffer: solvent -Gradient
Gradient programme:

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrate the process of this invention. However, it is not intended in any way to limit the scope of the present invention.

Reference Example

3-Acetylpyridine (450 gm) was stirred with N,N-dimethylformamide dimethylacetal at 80-85°C for 3 hours. The reaction was monitored by TLC. The reaction mass was diluted with a 1:1 mixture of hexane and diisopropylether (4.5 lit) and then cooled to 0-5°C. The resulting solid was filtered and dried at 30-35°C to give 560 gm of 3-dimethylamino-l-(3-pyridinyl)-2-propen-l-one (HPLC Purity: 99%).

EXAMPLE Step-I: Process for the preparation of 2-methyl-5-nitrophenyl guanidine p-toluenesulfonate

A mixture of 2-methyl-5-nitroaniline (250 gm) and 50% aqueous solution of cyanamide (151.68 gm) in 2-propanol (1750 ml) was heated to 80 - 85°C under stirring for 2 hours. This was followed by the addition of solution of p-toluenesulfonic acid (347 gm) in 2-propanol (500 ml) and maintained for 12 hours at 80 - 85°C. The reaction mass was cooled to 0 - 10°C. The resulting mass was filtered, the filtered solid was washed with 2-propanol (500 ml) and dried at 25 - 35°C to give 406 gm of 2-methyl-5-nitrophenyl guanidine p-toluenesulfonate (HPLC Purity: 97%).

Step-II: Process for the preparation of N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine 2-Methyl-5-nitrophenyl guanidine p-toluenesulfonate (100 gm) was added to a solution of potassium hydroxide (15.2 gm) in isoamyl alcohol (500 ml) at 25 - 35°C. The mixture was heated at 100 - 115°C and then slowly added a solution of 3-dimethylamino-l-(3-pyridinyl)-2-propen-l-one (48 gm) in isoamyl alcohol (100 ml) over a period of 15 minutes at 100 - 115°C. The reaction mass was further heated at 130 - 132°C and maintained for 6 hours. The reaction mass was cooled at 40°C followed by the addition of isoamyl alcohol (100 ml) and the resulting mass was further cooled at 0 - 5°C and filtered. The resulted mass was slurred with ice cold methanol (100 ml), filtered and washed with water (300 ml) and then dried at 60°C for 8 hours to give 60 gm of N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine (HPLC Purity: 99.63%).

Step-III: Process for the preparation of N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine

Ferric chloride (0.65 gm) and activated carbon (12 gm) were added to a solution of N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine (50 gm) in methanol (750 ml). The mixture was heated to reflux (65°C) for 1 hour followed by slow addition of hydrazine hydrate (3.5 gm) at reflux temperature in portion. After complete addition, the reaction mixture was refluxed (65°C) for 4 hours. The resulting solution was filtered through hyflo and then methanol was distilled out completely from the filtered solution. The residue was diluted with water (500 ml) and cooled at 0 - 5°C. The product was then filtered, washed with water and then dried for 8 hours at 60-70°C to give N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine (HPLC Purity: 99.5%, Yield: 84%).

We claim:

1. A process for the preparation of N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine of formula I:
K1

or an acid addition salt thereof, comprising:
a) reacting 2-methyl-5-nitroaniline of formula II:

with cyanamide in the presence of p-toluenesulfonic acid in an alcoholic solvent to produce 2-methyl-5-nitrophenyl guanidine p-toluenesulfonate of formula III:

b) reacting the compound of formula III with 3-dimethylamino-l-(3-pyridinyl)-2-
propen-1-one of formula IV:

in the presence of a base in an alcoholic solvent to produce N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine of formula V:

c) reducing the N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine of formula V using hydrazine in the presence of a Lewis acid in an alcoholic solvent to produce N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine; and optionally converting the amino compound into its acid addition salts thereof.

2. The process of claim 1, wherein the alcohol solvent used in steps (a), (b) and (c) is a C1 to C6 straight or branched chain alcohol, or mixtures thereof.

3. The process of claim 2, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, propanol, 2-propanol, n-butanol, t-butanol, amyl alcohol,
isoamyl alcohol, and mixtures thereof.

4. The process of claim 1, wherein the cyanamide in step-(a) is used in a molar ratio of about 0.7 to 2 moles per 1 mole of 2-methyl-5-nitroaniline; and wherein the p-toluenesulfonic acid in step-(a) is used in a molar ratio of about 0.7 to 2 moles per 1 mole of 2-methyl-5-nitroaniline.

5. The process of claim 1, wherein the hydrazine in step-(c) is used in a molar ratio of about 4 to 6 moles per 1 mole of N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine; and wherein the Lewis acid in step-(c) is used in a molar ratio of less than about 0.5 moles per 1 mole of N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine.

6. The process of claim 5, wherein the Lewis acid is used in a molar ratio of 0.01 to 0.05 moles per 1 mole of N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine.

7. The process of claim 1, wherein the Lewis acid used in step-(c) is selected from the group consisting of ferric chloride, aluminum chloride, calcium chloride and zinc chloride.

8. A process for the preparation of N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine of formula I:

or an acid addition salt thereof, comprising reducing the N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidineamine of formula V:

with hydrazine in the presence of a Lewis acid in an alcoholic solvent to produce N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine; and optionally converting the amino compound into its acid addition salts thereof.

9. Use of ethyl N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine or a salt thereof, produced according to the process of any one of claims 1-8, in the process for manufacture of Imatinib or pharmaceutically acceptable salts thereof.

10. N-(5-Amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine of formula I:

or an acid addition salt thereof having a purity of greater than about 99% as measured by HPLC.