WO2013035102A1

WO2013035102A1 - Processes for the preparation of imatinib base and intermediates thereof

Info

Publication number: WO2013035102A1
Application number: PCT/IN2011/000606
Authority: WO
Inventors: Amala Kishan Kompella; Sreenivas Rachakonda; Venu Gopala Krishna Gampa; Kali Satya Bhujanga Rao Adibhatla; Venkaiah Chowdary Nannapaneni
Original assignee: Natco Pharma Limited
Priority date: 2011-09-05
Filing date: 2011-09-05
Publication date: 2013-03-14

Abstract

The invention relates to an improved process for the preparation of highly pure imatinib base (99.99% HPLC purity) of formula (I) and the pharmaceutically acceptable acid addition salts thereof. This invention also relates to processes for the preparation of the intermediates in the synthesis of imatinib base.

Description

PROCESSES FOR THE PREPARATION OF IMATINIB BASE AND

INTERMEDIATES THEREOF

BACKGROUND OF THE INVENTION

The present invention relates to the preparation of intermediates and an improved process for the preparation of imatinib employing the said intermediates. Mesylate (methane sulfonate) salt of imatinib base [(4-(4-methylpiperazin-l-ylmethyl)-N-4-[methyl-3-(4- pyridin-3-yl)pyrimidin-2-yl amino)phenyl]benzamide] (Imatinib) prepared by the process of the present invention is a protein tyrosine kinase inhibitor and has the formula (I).

The preparation of [(4-(4-methylpiperazin-l-ylmethyl)-N-4-[methyl-3-(4-pyridin-3- yl)pyrimidin-2-yl amino)phenyl]benzamide (Imatinib) of formula (I) and the use thereof especially as an antitumour agent is described in EP patent No. 0564 409, (Ciba-Geigy corp.)

Three basic synthetic routes are known for the preparation of imatinib base in Prior art (Schemes- A-C).

Scheme- A illustrates the first synthetic route for preparation of imatinib base. This method is known from EP 0564409 Al and WO 2004/074502, and comprises the condensation of two chemical moieties, N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2- pyrimidineamine(VI) and 4-(4-methylpiperazinelmethyl)benzoylchloride(VII). Scheme-A

Scheme-B:

Scheme -B illustrates the second synthetic pathway for preparation of imatinib base. This method is known from WO 03/066613, and comprises condensation of 4-(3-pyridinyl)-2- pyrimidineamine(VIII) or a precursor thereof, with N-[3-bromo-4-methylphenyl)-4-(4- methylpiperazin- 1 -ylmethyl)-benzamide(IX).

Scheme-C:

Scheme- C illustrates the third synthetic pathway for preparation of imatinib base. This method is described in WO 2004/108699 and in J. Med. Chem. 2005, 48(1), 249-255, and comprises the condensation of 4-methyl-N-3-(4-pyridin-3-yl-pyrimidin-2-yl)benzene-l,3- diamine(VI)with 4-chloromethylbenzoyl chloride(X) to yield 4-chloromethyl-N-{4- methyl-3-[(4-pyridin-3-yl)-pyrimidin-2-ylamino]-phenyl}-benzamide(XI), followed by its reaction with N-methylpiperazine.

The above prior art methods are characterized by inconveniences which make the synthesis troublesome and difficult to scale up for commercial manufacturing operations. According to EP 0233461 Bl and EP 0564409 Al, the key intermediate l-(2-methyl-5- nitrophenyl)guanidine(III) in the synthesis of imatinib by Schemes A and C, is obtained by heating 2-methyl-5-nitroaniline in the presence of an aqueous solution of cyanamide and concentrated nitric acid. The yield of the compound of the formula (III) reported in EP 0233461 and EP 0564409 is very low (20-25%). The other key intermediate in the synthesis of imatinib by Schemes-A and C is N-(5- nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine (V) which, according to EP 0564409 Al, is obtained by condensation of l-(2-methyl-5-nitrophenyl)guanidine(III) with 3-(dimethylamino)-l-(3-pyridinyl)-prop-2-en-l-one (IV). 3-(Dimethylamino)-l-(3-pyridinyl)-prop-2-en-l-one (IV) is obtained by refluxing a mixture of 3-acetylpyridine with excess of Ν,Ν-dimethyl formamide dimethyl acetal for 6-16 hours, and isolating the resultant product by concentrating the reaction mixture in vacuum, treating the residue with hexane and filtering the formed crystals (See, U.S. Pat. No. 4,281,000, EP 0025819 Bl, and U.S.Pat.No.4,374,988).

In EP 0564409 Al, the reaction of l-(2-methyl-5-nitrophenyl)guanidine (III) with 3- (dimethylamino)-l-(3-pyridinyl)-prop-2-en-l-one (IV) is carried out by prolonged heating (6-48 hours) of the reagents in a neutral solvent, in the presence of an appropriate base, if necessary. The yield of N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2- pyrimidineamine (V) did not exceed 75% according to a procedure disclosed in the experimental section of EP 0564409.

The prior art methods for preparing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2- pyrimidineamine (V) consist of many steps, are time-consuming and require purification of intermediates of the synthesis which cumulatively decrease the overall yield of the product.

Both methods, A and C, require the reduction of the nitro compound (V) to N-(5-amino- 2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine (VI). In EP 0564409 Al, the reduction of a nitro group to an amino derivative in N-(substituted nitrophenyl)-4-(3- pyridinyl)-2-pyrimidineamines is carried out at room temperature and under ambient pressure of hydrogen in the presence of palladium on a solid support as a catalyst (i) for 6.5 hours in ethyl acetate (w/10% Pd/C), or (ii) for 21 hours in tetrahydrofuran (w/5% Pd/C). The yield of the product has not been disclosed in any of the examples.

The reduction of N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine to N-(5- amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine, described in WO 2004/074502 and WO 2004/108699, is carried out using tin(II) chloride -SnC12.

According to WO 2004/074502, the reaction with tin(II) chloride is carried out in tetrahydrofuran at 60° C for 4 hours or in a mixture of water and concentrated hydrochloric acid at 50° C. for 2 hours. The yield of N-(5-amino-2-methylphenyl)-4-(3- pyridinyl)-2-pyridineamine (VI), obtained after recrystallization from ethyl acetate, has not been mentioned in the examples. However, in the description of this application the authors have disclosed that the yield was 65-70%.

In WO 2004/108699, reduction with the use of tin(II) chloride was carried out in concentrated hydrochloric acid at temperature 0-5° C. for 3-4 hours and then at 25-35° C. for 1.5 hour to afford, after recrystallization from ethyl acetate, the yield of N-(5-amino- 2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (VI) in about 60% yield.

J. Med. Chem., 2005, 48(1), 249-255, describes the reduction of N-(5-nitro-2- methylphenyl)-4-(3-pyridinyl)-2-pyridineamine using SnC12.H20 in concentrated hydrochloric acid at room temperature for 30 min, where the yield of the amine after recrystallization of the crude product from methylene chloride was 81%. The yield is higher compared to that reported in WO 2004/074 502 and WO 2004/108 699. N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (VI) is the key

intermediate for imatinib mesylate. As such, there is a need for a process to generate N- (5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine of high purity which may be conveniently used as an intermediate in the preparation of highly pure Imatinib mesylate directly suitable for therapeutic use.

In the next step of Method A, N-(5-amino-2-methyIphenyl)-4-(3-pyridinyl)-2- pyridineamineis reacted with 4-(4-methylpiperazinemethyl)benzoyl chloride, in the form of a dihydrochloride. The reaction requires a large volume of an organic base, such as pyridine or triethylamine that binds the evolving as well as free hydrogen chloride.

According to Example 21 of EP 0564409 B 1 , the reaction is carried out by prolonged heating of reagents in pyridine. No reaction yield is given in the description. In practice the yield realised in this reaction is only 50-60%. Employing an obnoxious solvent like pyridine is not practical on commercial scale. Removal of pyridine by distillation and subsequent work up procedures render this process highly unpractical and unsuitable for manufacturing operations.

A modification of method A has been proposed in WO 2004/074502, wherein the condensation is carried out in a neutral organic solvent and, although a di(hydrogen halide) of the 4-(4-methylpiperazinemethyl)benzoyl chloride is used as, no hydrogen halide binding agent is used. A tri(hydrogen halide) salt of imatinib, preferably imatinib trihydrochloride in the form of a hydrate, is obtained. The salt precipitates from the solution, thereby facilitating its isolation. The yield of imatinib trihydrochloride hydrate obtained in this step is, however, a mere 53.5%; and another conversion step to liberate the imatinib free base is required, further decreasing the overall yield. In Method B, (3-pyridinyl)-2-pyrimideineamine, or a precursor thereof, is reacted with 4- methylphenyl-(4-methylpiperazin- 1 -ylmethy l)benzamide.

In one variation of Method B (Example 9 of WO 03/066613), a suspension of N-(3- guanidine-4-methylphenyl)-4-(4-methylpiperazin-l-ylmethyl)-benzamide is heated in n- butanol with a slight molar excess of 3-dimethylamino-l-pyridin-3-ylpropenone. The process requires high temperature and has to be carried out under an inert atmosphere. The product is isolated by distilling off dimethylamine and n-butanol, making up its amount in the reaction mixture during distillation, and then precipitating the product using butyl acetate.

Another variation of Method B (Example 10 of WO 03/066613) comprises the reaction of N-(3-bromo-4-methylphenyl)-4-(4-methylpiperazin-l-ylmethyl)benzamide with 4-(3- pyridinyl)-2-pyrimidineamine in the presence of sodium tert-butoxide and a catalytic amount of Pd2(dba)3-rac-BINAP. Despite a relatively high yield of the last step of condensing the key synthons of the compound, the synthesis of imatinib by this method is difficult to scale up as it requires expensive catalysts, special sonication equipment, as well as tedious purification of the product by flash chromatography on silica gel, and separating the desired from the undesired isomers using reverse-phase preparative chromatography.

The variation of Method C described in J. Med. Chem. 2005, 48(1), 249-255 is not of much practical significance. It uses expensive analytical-grade reagents and the yields obtained in subsequent steps are rather poor. For example, the yield of the reaction of 4- methyl-N-3-[(4-pyridin-3-yl)pyrimidin-2-yl]benzene-l,3-diamine with 4-chloromethyl benzoyl chloride in dimethylformamide is 61% after recrystallization of the product from ethyl acetate, and the yield of the reaction of 4-chloromethyl-N-{[4-methyl-3-(4-pyridin- 3-yl)pyrimidin-2-ylamino]-phenyl}-benzamide with N-methylpiperazine is 68%, after recrystallizing the product from acetonitrile. In Method A, N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine is reacted with 4-(4-methylpiperazinemethyl)benzoyl chloride(VII) in the form of a dihydrochloride. This acid chloride (VII) is prepared by the reaction of 4-(4- methylpiperazinomethyl)benzoic acid dihydrochloride with thionyl chloride

The preparation of 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride is described in US4,623,486 (Pfizer Inc.)

a-chloro-p-toluic acid in absolute ethanol was treated with N-methyl piperazine. The resulting solution was refluxed for a period of 16 hours and then cooled to room temperature. The cooled reaction mixture was concentrated in vacuum and the thus obtained residue partitioned between diethyl ether and 3N aqueous sodium hydroxide. The separated aqueous layer was then washed three times with diethyl ether, cooled in ice bath and acidified with concentrated HC1. The resulting solid was filtered to yield 4-(4- methylpiperazinomethyl)benzoic acid dihydrochloride

a-chloro-p-toluic acid 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride

This process is beset with the following difficulties.

i. The reaction monitoring during condensation of α-chloro-p-toluic acid with N-methyl piperazine revealed an impurity to the extent of 30-40%.

ii. About four moles of N-methyl piperazine is used thus making the process un economical. iii. The reaction time is very lengthy (16 hours), which could be problematic for commercial scale production.

iv. Use of diethylether is not safe for commercial scale production because of its highly flammable nature, volatility and hazardous peroxide forming properties.

v. The final product is only 70% pure necessitating additional purification.

JP20031 1918 discloses preparation of 4-(4-Methylpiperazino)methylbenzoic acid dihydrochloride of purity 98% by the reaction of p-(chloromethyl)benzoic acid and excess of l-methylpiperazine(greater than 5moles). In this process use of excess moles of N-methyl piperazine affects the cost economics.

JP 2002338558 discloses three step process for the preparation of 4-(4-methylpiperazino) methyl benzoic acid dihydrochloride. The reaction of 1-methylpiperazine with 4- chloromethylbenzonitrile in xylene in the presence of K2C03 gave, after hydrolysis with concentrated hydrochloric acid 4-[(4-methyl-l-piperazinyl)methyl]benzoic acid dihydrochloride.

Further JP 20031 19185 discloses the reaction of alpha-halomethylbenzoic acid with excess moles of N-methylpiperazine followed by the recovery of the unreacted N- methylpiperazine.

4-(4-Methylpiperazino)methylbenzoic acid dihydrochloride is the key intermediate for imatinib mesylate. As such, there is a need for a process to generate 4-(4- Methylpiperazino)methylbenzoic acid dihydrochloride of high purity which may be conveniently used as an intermediate in the preparation of highly pure Imatinib mesylate directly suitable for therapeutic use. SUMMARY OF THE INVENTION

The invention provides, in a first aspect, a process for the preparation of imatinib base (I) comprising:

(a) condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (VI): with 4-(4-methylpiperazinomethyl) benzoyl chloride dihydrochloride (VII) in the presence of an inorganic base.

In a second aspect, the present invention provides a process for producing 4-(4- methylpiperazinomethyl) benzoyl chloride dihydrochloride (VII) which comprises:

(b) condensing 4-bromomethylbenzonitrile with N-methyl piperazine to produce 4- (4-methyl piperazinomethyl)benzonitrile (XII) and

(c) hydrolysis of 4-(4-methyl piperazinomethyl)benzonitrile (XII) in the presence of concentrated hydrochloric acid. In a third aspect, the present invention provides a process for producing N-(5-amino-2- methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (VI), which comprises:

(d) reducing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (V) by catalytic hydrogenation in the presence of Raney nickel. In a fourth aspect, the present invention provides a process for producing N-(5-nitro-2- methyIphenyl)-4-(3-pyridinyI)-2-pyridineamine (V) which comprises:

(e) forming a reaction mixture comprising l-(2-methyl-5-nitrophenyl)guanidine base (III) and 3-(dimethylamino)-l-(3-pyridinyl)-prop-2-en-l-one (IV), wherein the reaction mixture is free from sodium hydroxide, and

(i) isolating N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (V) from the reaction mixture.

In a fifth aspect, the present invention a process for producing l-(2-methyl-5- nitrophenyl)guanidine base (III), which comprises: (g) reacting 2-methyl-5-nitroaniline (II) with cyanamide in the presence of concentrated hydrochloric acid to form l-(2-methyl-5-nitrophenyl)guanidine hydrochloride; and

(h) converting the l-(2-methyl-5-nitrophenyl)guanidine hydrochloride to l-(2- methyl-5-nitrophenyl)guanidine base (III).

DETAILED DESCRIPIPTION OF THE INVENTION

The aspects of the invention mentioned above each individually provide an improved process for producing imatinib base or an intermediate thereof. As such, each aspect may be carried out on its own, or as a step in a process for preparing imatinib base or an acid addition salt thereof which includes process steps other than those of the present invention. Alternatively, each aspect of the invention described above may be carried out in combination with one or more other aspects of the present invention. In one embodiment, the present invention provides a process for preparing imatinib base which comprises all of the aspects of the invention described above. For the avoidance of doubt, the specific embodiments and preferred features of the invention described herein apply equally to an aspect of the invention whether carried out alone or in combination with another aspect. In particular, the present invention provides a process comprising steps (a), (b) and (c) set out above. Also provided is a process comprising steps (a), (b), (c) and (d) set out above. Further, the present invention provides a process comprising steps (a), (b), (c), (d), (e) and (f) set out above. Also provided is a process comprising steps (a), (b), (c), (d), (e), (f), (g) and (h) set out above. Further, any of these processes typically further comprise the step of reacting imatinib base with an acid to form a pharmaceutically acceptable acid addition salt. Typically, the acid is methane sulfonic acid and the acid addition salt is imatinib mesylate. Typically, the condensation reaction of step (a) is carried out in the absence of pyridine, and preferably in the absence of a polar solvent.

Typically, the condensation reaction is carried out in the presence of a non-polar solvent, preferably a non-polar organic solvent, and more preferably chloroform.

Typically, the inorganic base used in step (a) is a metal hydroxide, a metal carbonate or a metal hydrogencarbonate, preferably wherein the metal is a metal of Group I or Group II of the Periodic Table, more preferably a metal of Group I of the periodic table. Preferably, the inorganic base is a metal carbonate or a metal hydrogencarbonate, more preferably a metal carbonate. Typically, the metal is potassium. Most preferably the inorganic base is potassium carbonate.

Typically, the direct product of the condensation reaction in step (a) is imatinib base. Thus, typically, no further conversion steps are required to liberate the free base.

Typically, the condensation reaction of step (b) is carried out in the presence of a non- polar solvent, preferably a non-polar organic solvent, more preferably chloroform. In one embodiment, steps (b) and (c) are carried out, and 4-(4-methylpiperazinomethyl) benzoyl chloride dihydrochloride (VII) thus obtained is used in a process for the production of imatinib base or an acid addition salt therof, preferably imatinib mesylate.

Typically, the reduction of step (d) is carried out in the absence of tin (II) chloride. Thus, typically, this aspect of the invention avoids the use of toxic tin reagents.

In one embodiment, step (d) is carried out and N-(5-amino-2-methylphenyl)-4-(3- pyridinyl)-2-pyridineamine (VI) thus obtained is used in a process for the production of imatinib base or an acid addition salt therof, preferably imatinib mesylate. Typically, the reaction mixture formed in step (e) is free from an inorganic base.

Typically, the reaction mixture formed in step (e) is heated at reflux temperature for a time in the range of 7 to 1 1 hours, preferably for about 9 hours. Typically, the reaction mixture also comprises a solvent. Thus, the reflux temperature will typically depend on the nature of the solvent used. In a preferred embodiment of the invention, the reaction mixture formed in step (e) comprises n-butanol and the reflux temperature is 1 18 to 130°C, more preferably about 120°C. Typically, after formation of the reaction mixture in step (e) and prior to isolation of N- (5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (V) in step (f), the reaction mixture is cooled to a temperature in the range of 15 to 30°C, and water added thereto. More typically, the reaction mixture having been cooled an water having been added thereto, the resulting mixture is maintained at a temperature in the range of 15 to 30°C, and stirred for a time in the range of 2 to 5 hours, preferably 3 to 4 hours.

Typically, in step (f) N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (V) is isolated by filtration. In one embodiment, steps (e) and (f are carried out, and N-(5-nitro-2-methylphenyl)-4- (3-pyridinyl)-2-pyridineamine (V) thus obtained is used in a process for the production of imatinib base or an acid addition salt therof, preferably imatinib mesylate.

Typically, in step (h), the l-(2-methyl-5-nitrophenyl)guanidine hydrochloride is converted to l-(2-methyl-5-nitrophenyl)guanidine base (III) by the addition of an inorganic base, preferably aqueous inorganic base, more preferably aqueous sodium hydroxide. In one embodiment, steps (g) and (h) are carried out, and l-(2-methyl-5- nitrophenyl)guanidine base (III) thus obtained is used in a process for the production of imatinib base or an acid addition salt therof, preferably imatinib mesylate. In one preferred embodiment, the present invention provides a process for producing imatinib base which comprises

(a) condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (VI): with 4-(4-methylpiperazinomethyl) benzoyl chloride dihydrochloride (VII) in the presence of an inorganic base; wherein: said 4-(4-methylpiperazinomethyl) benzoyl chloride dihydrochloride (VII) is typically obtained by a process which comprises:

(c) hydrolysis of 4-(4-methyl piperazinomethyl)benzonitrile (XII) in the presence of concentrated hydrochloric acid; and said N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (VI) is typically obtained by a process which comprises:

(d) reducing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (V) by catalytic hydrogenation in the presence of Raney nickel; and said N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (V) is typically obtained by a process which comprises:

(f) isolating N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (V) from the reaction mixture; and said l-(2-methyl-5-nitrophenyl)guanidine base (III) is typically obtained by a process which comprises:

(g) reacting 2-methyl-5-nitroaniline (II) with cyanamide in the presence of concentrated hydrochloric acid to form l-(2-methyl-5-nitrophenyl)guanidine hydrochloride; and

A particularly preferred example of this embodiment is set out in Scheme D below. idine

2-m et

hyl -5-n itroa n iline )

Im atin ib base (75% yield , (99.99% H P LC pu rity) In certain embodiments of the invention condensation of 2-methyl-5-nitroaniline (II) with cyanamide is carried out using between about 2.0 and about 4.0 molar equivalents, and particularly about 3.0 molar equivalents of cyanamide with respect to 2-methyl-5-nitro aniline. Further the product l-(2-methyl-5-nitrophenyl) guanidine may be obtained as hydrochloride salt by the lot wise addition of concentrated hydrochloric acid. This hydrochloride salt is typically neutralized using inorganic base, preferentially aqueous sodium hydroxide to get l-(2-methyl-5-nitrophenyl) guanidine (III). The yield of the reaction is typically about 98% and purity by HPLC is typically about 99%.

In certain embodiments of the invention, condensing l-(2-methyl-5- nitrophenyl)guanidine (III) with (dimethylamino)-l-(3-pyridinyl)-prop-2-en-l-one(IV) is carried out using between about 0.8 and about 1.2 molar equivalents, and particularly about 1.1 molar equivalents, of (dimethylamino-l-(3-pyridinyl)-prop-2-en-l- (dimethylamino-l-(3-pyridinyl)-prop-2-en-l-one. The reaction is typically carried out in a C1-C4 alcohol, and particularly in n-butanol. The yield of N-(5-nitro-2-methylphenyl)- 4-(3-pyridinyl)-2- N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine (V) is typically about 82% and purity by HPLC is typically about 99.9%.

In certain embodiments of the invention, N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2- pyridineamine (V) is reduced catalytically by hydrogenation to yield N-(5-amino-2- methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine (VI)in the presence of Raney nickel.

Typically, Raney nickel is used in an amount of not less than approximately 30% by weight with respect to N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine. In certain embodiments of the invention, reducing N-(5-nitro-2-methylphenyl)-4-(3- pyridinyl)-2-pyridineamine in the presence of Raney nickel is carried out in a C1-C4 alcohol, a C1-C4 aliphatic ether, or a cyclic ether, as solvent, and preferably is carried out in methanol. The yield of the reaction is typically about 80% and HPLC purity is typically about 99%. In certain embodiments of the invention, condensing N-(5-amino-2-methylphenyl)-4-(3- pyridinyl)-2-pyrimidine-amine(VI) with 4-(4-Methylpiperazino methyl)benzoyl chloride(VII) in the presence of an inorganic base to obtain imatinib base(I) is carried out using between about 1 and about 2 molar equivalents of 4-(4-Methylpiperazino)methyl benzoyl chloride dihydrochloride with respect to N-(5-amino-2-methylphenyl)-4-(3- pyridinyl)-2-pyrimidine amine and preferably about 1.5 molar equivalents.

In certain embodiments of the invention, condensing N-(5-amino-2-methylphenyl)-4-(3- pyridinyl)-2-pyrimidine-amine with 4-(4-Methylpiperazino methyl)benzoyl chloride is carried out in the presence of excess of inorganic base using between about 2 and about 6 molar equivalents of inorganic base with respect to N-(5-N-(5-amino-2-methylphenyl)- 4-(3-pyridinyl)-2-pyrimidine-amine preferably between about 3 and about 5 molar equivalents of inorganic base, more preferably in chloroform medium. In certain embodiments of the invention, after condensing N-(5-amino-2-methylphenyl)- 4-(3-pyridinyl)-2-pyrimidine-amine with 4-(4-Methylpiperazino methyl)benzoyl chloride in the presence of excess potassium carbonate in chloroform medium, water is added to the reaction mass, followed by separation of chloroform layer distillation of solvent and isolation of imatinib base using ethyl acetate.

In certain embodiments of the invention purification of imatinib base is carried out using methane sulfonic acid treatment followed by neutralization with aqueous sodium hydroxide. The yield of the reaction is 75% and HPLC purity is 99.99% A preferred embodiment of the preparation of key intermediate 4-(4- Methylpiperazino)methylbenzoic acid dihydrochloride comprises condensation of 4- bromomethylbenzonitrile with N-methyl piperazine in chloroform to get 4-(4-methyl piperazinomethyl)benzonitrile followed by hydrolysis of 4-(4-methyl piperazinomethyl)benzonitrile in the presence of hydrochloric acid, preferably concentrated hydrochloric acid. This embodiment typically provides 4-[(4-methyl-l- piperazinyl)methyl]benzoic acid dihydrochloride at about 99.9% purity. This route is illustrated by the following scheme-E.

Scheme-E:

4-Brom omet

hyl benzonitrile

4-(4-methyl piperazinomethyl) benzonitrile

Coned . HCI

4-(4-m ethyl piperazinomethyl)benzoic acid dihydrochloride

In certain embodiments of the invention, condensation of 4-Bromomethyl benzonitrile is carried out with excess moles of N-methyl piperazine about 2.0 to 3.0 molar equivalents particularly 2.8 molar equivalents of N-methyl piperazine with respect to 4-Bromomethyl benzonitrile in chloroform medium. The yield of the reaction typically exceeds 95% with typical HPLC purity of 99.7%.

In particular embodiments of the invention, hydrolysis of 4-(4-methyl piperazinomethyl)benzonitrile is carried out with concentrated hydrochloric acid (35%) . The yield of the reaction is typically about 75% with typical HPLC purity 99.9%.

The total yield of imatinib base obtained by the process according to the invention wherein the five aspects of the invention are carried out in combination is typically about 50%, compared to approximately 15% reported for prior art processes. The HPLC purity of the Imatinib base prepared by this process is typically 99.99% compared to approximately 95-99% of the prior art processes.

The imatinib base produced by the process of the present invention may be converted into a pharmaceutically acceptable acid addition salt by addition of a pharmaceutically acceptable acid. Typically, the pharmaceutically acceptable acid is methane sulfonic acid and the pharmaceutically acceptable acid addition salt is imitanib mesylate. However, other pharmaceutically acceptable acid addition salts are well known in the art and include include both salts of inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid and salts of organic acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p- toluenesulphonic acid. When the imatinib base produced by the process of the present invention is converted into a pharmaceutically acceptable acid addition salt, the acid addition salt thus obtained, which us preferably imatinib mesylate, may be incorporated into a pharmaceutical composition, typically in an amount 0.001% to 99% by weight, preferably 0.01% to 90% by weight, of the composition. The pharmaceutical composition typically also comprises a pharmaceutically acceptable excipient such as a diluent or carrier. The pharmaceutically acceptable excipients which are admixed with the active compound or salts of such compound, to form the compositions of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administering the compositions. Preferably the compositions are made up in a form suitable for oral, inhalation, topical, nasal, rectal, percutaneous or injectable administration.

The following examples are provided to illustrate the invention. The examples are not meant to limit the scope of the invention as defined in the claims. EXAMPLES

Example-1: Preparation of 4-(4-Methylpiperazinomethyl) benzoyl chloride: Step-A: Preparation of 4-(4-Methyl piperazinomethyl) benzonitrile:

N-methyl piperazine(456.2g, 2.79moles) was placed in a reaction flask. 4-bromomethyl benzonitrile (320g, 1.63moles) was dissolved in chloroform(1.9L) and added slowly to the reaction mass during one hour at 20-25°C. The reaction mass was maintained at room temperature for three hours. After completion of the reaction, water (3.2L) was charged to the reaction mass and chloroform layer was separated. Chloroform layer was water washed and distilled completely under vacuum to yield 4-(4-Methyl piperazinomethyl)benzonitrile.

(350g, 99.7% percentage yield, 99.2% HPLC purity).

Step-B: Preparation of 4-(4-Methylpiperazinomethyl) benzoic acid dihydrochloride: 4-(4-Methyl piperazinomethyl)benzonitrile (1 17g, 0.542moles) and concentrated hydrochloric acid(35%, 819 ml) were placed in reaction flask and heated to 90-95°C for five hours. After completion of reaction, the reaction mass was brought to 40-45°C and filtered at the same temperature. Filter cake was washed with Isopropanol(200ml) and dried to yield 4-(4-Methylpiperazinomethyl) benzoic acid dihydrochloride.

(126g, 75% percentage yield, 99.9% HPLC purity).

Step-C: Preparation of 4-(4-Methylpiperazinomethyl) benzoyl chloride dihydrochloride: A mixture of 4-(4-Methylpiperazinomethyl) benzoic acid dihydrochloride (42g, 0.136moles) and thionyl chloride (384g, 3.22moles) were placed in a reaction flask and heated to 80°C for 24 hours. After completion of reaction, the reaction mass was filtered and washed with chloroform to yield 4-(4-Methylpiperazinomethyl) benzoyl chloride dihydrochloride.

(42g yield). Example-2: Preparation of-4-(3-pyridinyl)- N-(5-amino-2-methylphenyl)-2-pyrimidine amine(VI)

Step-A: Preparation of l-(2-Methyl-5-nitrophenyl)guanidine 2-Methyl-5-nitroaniline-(50g, 0.328moles.) and n-butanol (200ml) were placed in a reaction flask. 35% concentrated hydrochloric acid (19ml) was added slowly to the reaction mass for 15minutes. Reaction mass was stirred for 15minutes and 50% aqueous cyanamide solution (82.3ml, 1.978moles) was added slowly to the reaction mass for 15minutes. The reaction mixture was heated to 90-95°C and stirred at the same temperature for four hours and concentrated hydrochloric acid (19ml) was slowly added drop wise within 15 minutes. The reaction mixture was further stirred for four hours while maintaining the temperature at 90-95°C. Concentrated hydrochloric acid (29ml) was added drop wise and the reaction mixture was kept at 90°C for 4hours. Reaction mass was maintained at the same temperature for a total of 20hours. After reaction completion reaction mass was cooled down to 10°C and basified with 10% aqueous sodium hydroxide solution (400ml). The solid product was filtered off, washed with 200ml of water and dried to afford l-(2-methyl-5-nitrophenyl) guanidine.

(63g, yield 98.7%, purity by HPLC: 99%)

Melting point: 136-140°C

Step-B: Preparation of N-(5-Nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine l-(2-methyl-5-nitrophenyl)guanidine (63g, 0.324moles) obtained from step-A, 3- dimethylamino-l-(3-pyridyl)-2-propen-l-one(62.5g, 0.357) and n-butanol (560ml) were placed in reaction flask. The reaction mixture was heated to 120°C for nine hours. Reaction mass was brought to room temperature, water (450ml) was added and stirred at room temperature for 3-4 hours. The precipitated solid was isolated by filtration and dried to afford 2-(2-methyl-5-nitroanilino)-4-(3-pyridinyl)pyrimidine.

(73.7g, yield 81.9%%, purity by HPLC: 99.9%), Melting point: 195.6-195.9°G;

Step-C: Preparation of N-(5-Amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine In to a hydrogenation kettle a N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2- pyridineamine (20 g; 0.0.0651 mol) obtained from step-B and methanol (400ml) were added. Wet Raney's nickel (8g) was washed thoroughly with water and was charged into hydrogenation kettle. Hydrogenation was conducted at 60psi at 25°C for 45hours. The reaction mixture was filtered and washed with methanol (200ml). The combined filtrates were concentrated in vacuum, treated with a mixture of water (100ml) and chloroform (200 ml). The organic layer was washed with water (3x50ml) and distilled under vacuum. Residual solid was brought to room temperature and ethyl acetate (150ml) was charged. The solution was heated to reflux temperature and cooled down with stirring to 0-5°C. The crystalline solid was filtered off and washed with chilled ethyl acetate (10ml), dried to afford title compound

(15.0g, yield: 82.7%) of the title product. Purity (by HPLC): 99.40%)

Melting point: 143-147°C

Example-3:

Preparation of 4-(4-Methyl-piperazin-l-ylmethyl)-N-{4-methyl-3-[(4-pyridin-3-yl) pyrimidin-2-ylamino]-phenyl}-benzamide (Imatinib base):

N-(5-Amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine obtained from step-C, example-2 (15.0g; 0.0.05mol), potassium carbonate(45g, 0.32moles) and chloroform(200ml) were charged into a reaction flask and stirred at room temperature for 15 minutes. 4-(4-Methylpiperazinomethyl) benzoyl chloride dihydrochloride obtained from step-C, example- l(26g; 0.08mol), and chloroform (50ml) were charged to reaction mass, stirred for 15minutes at room temperature and refluxed for 8hours. Water (225ml) was added to the cooled reaction mass and the organic layer was separated and washed successively with 20% sodium hydroxide solution (2x300ml) and water (2x300ml). The organic layer was distilled under vacuum to a residual volume of 135ml and ethyl acetate (135ml) was charged at 50°C. The temperature was raised to 60°C and maintained at the same temperature for 15minutes. Reaction mass was cooled down to 50°C and the precipitated product was filtered off, washed with hot ethyl acetate(45ml) and dried in the air to afford crude title compound, imatinib base (23g, purity by HPLC : 98.7%) in the form of a cream-colored, crystalline solid.

Into reaction flask crude imatinib base (21g, 0.042g), and water(420ml) water were charged under stirring. Methane sulfonic acid (6.12g, 0.063moles) was added slowly and stirred at room temperature for 30minutes. Reaction mass was washed with chloroform(3x 100ml) and separated aqueous layer was basified with 20% sodium hydroxide solution( 150ml). Aqueous layer was extracted with chloroform (1x250ml, 2x100ml). Separated organic layer , washed with water(3x300ml) and carbon treatment was given to organic layer. Organic layer was distilled off completely under vacuum and mixture of chloroform (69ml) and ethyl acetate(l 15ml) was charged . Reaction mass was heated to 60°C, maintained 30minutes, cooled down to 50°C. The separated solid was filtered, washed with hot ethyl acetate (20ml) and dried to yield imatinib base(20g, 75% yield, 99.99% HPLC purity).

Claims

We claim:

1. A process for the preparation of imatinib base (I)

comprising

(a) condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine

(VI):

with 4-(4-methylpiperazinomethyl) benzoyl chloride dihydrochloride (VII):

(VII)

in the presence of an inorganic base.

A process according to claim 1, wherein the condensation reaction is carried out in the absence of pyridine.

A process according to claim 2, wherein the condensation reaction is carried out in the absence of a polar solvent. A process according to claim 1, 2 or 3, wherein the condensation reaction is carried out in the presence of a non-polar solvent.

A process according to claim 4, wherein the non-polar solvent is chloroform.

A process according to any preceding claim, wherein the inorganic base is potassium carbonate.

A process according to any preceding claim wherein imatinib base is the direct product of the condensation reaction.

A process for producing 4-(4-methylpiperazinomethyl) benzoyl chloride dihydrochloride (VII) which comprises:

(b) condensing 4-bromomethylbenzonitrile with N-methyl piperazine to produce 4-(4-methyl piperazinomethyl)benzonitrile (XII):

and

(c) hydrolysis of 4-(4-methyl piperazinomethyl)benzonitrile (XII) in the presence of concentrated hydrochloric acid.

A process for producing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2- pyridineamine (VI), which comprises:

(d) reducing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (V):

(V)

catalytic hydrogenation in the presence of Raney nickel.

10. A process according to claim 9 wherein the reduction is carried out in the absence of tin (II) chloride.

11. A process for producing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2- pyridineamine (V) which comprises:

(e) forming a reaction mixture comprising l-(2-methyl-5-nitrophenyl)guanidine base (III) and 3-(dimethylamino)-l-(3-pyridinyl)-prop-2-en-l-one (IV), wherein the reaction mixture is free from sodium hydroxide:

and

(f) isolating N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (V) from the reaction mixture.

12. A process according to claim 11, wherein the reaction mixture is free from an inorganic base.

13. A process according to claim 1 1 or 12, wherein the reaction mixture is heated at reflux temperature for a time in the range of 7 to 1 1 hours.

14. A process according to claim 13 wherein the reaction mixture comprises n- butanol and the reflux temperature is 118 to 130°C.

15. A process according to any one of claim 13 or 14, wherein, prior to isolation of N- (5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (V), the reaction mixture is cooled to a temperature in the range of 15 to 30 °C, and water added thereto.

16. A process according to any one of claims 1 1 to 15 wherein N-(5-nitro-2- methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (V) is isolated by filtration.

17. A process for producing l -(2-methyl-5-nitrophenyl)guanidine base (III), which comprises: (g) reacting 2-methyl-5-nitroaniline (II):

with cyanamide in the presence of concentrated hydrochloric acid to form 1- (2-methyl-5-nitrophenyl)guanidine hydrochloride; and

18. A process according to any one of claims 1 to 7, which comprises producing N- (5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (VI) according to the process of claim 9 or 10, and using the N-(5-amino-2-methylphenyl)-4-(3- pyridinyl)-2-pyridineamine (VI) thus produced in step (a).

19. A process according to any one of claims 1 to 7 or 18 which comprises producing 4-(4-methylpiperazinomethyl) benzoyl chloride dihydrochloride (VII) according to the process of claim 8, and using the 4-(4-methylpiperazinomethyl) benzoyl chloride dihydrochloride (VII) thus produced in step (a).

20. A process according to claim 18, which comprises producing N-(5-nitro-2- methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (V) according to the process of any one of claims 1 1 to 16, and using the N-(5-nitro-2-methylphenyl)-4-(3- pyridinyl)-2-pyridineamine thus produced in step (d).

21. A process according to claim 20, which comprises producing l-(2-methyl-5- nitrophenyl)guanidine base (III) according to the process of claim 17, and using the l-(2-methyl-5-nitrophenyl)guanidine base thus produced in step (e).

22. A process for the production of imatinib base wherein a product obtained by a process according to any one of claims 8 to 18 is used as an intermediate.

23. A process according to any one of claims 1 to 7, or 18 to 22, which further comprises reacting imatinib base with an acid to form a pharmaceutically acceptable acid addition salt.

24. A process according to claim 23, wherein the acid is methane sulfonic acid and the acid addition salt is imatinib mesylate.

25. A process according to claim 23 or 24 which further comprises incorporating the acid addition salt into a pharmaceutical composition.