FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
THE PATENTS (AMENDMENT) RULES, 2006
COMPLETE SPECIFICATION [See Section 10; rule 13]
“A PROCESS FOR PREPARATION OF IMATINIB BY USING VILSMEIER REAGENT”
APPLICANT: SAKAR HEALTHCARE LIMITED
NATIONALITY: INDIAN
ADDRESS: 406, SILVER OAKS COMM. COMPLEX, OPP. ARUN SOCIETY,
PALDI, AHMEDABAD GUJARAT, INDIA - 380007
The following complete specification describes the invention:

A PROCESS FOR PREPARATION OF IMATINIB BY USING VILSMEIER
REAGENT
The present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib (formula 1) in presence of Vilsmeier reagent (formula 9) preferably in the presence of base solvent.
BACKGROUND OF INVENTION
Imatinib, also known as 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4 methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino]-phenyl]benzamide, is commercially available as mesylate salt. Imatinib is protein-tyrosine kinase inhibitor or BCR-ABL tyrosine kinase inhibitor used for the treatment of different type of Leukemia and Gastrointestinal Stromal Tumors. Imatinib is usually administered orally in the form of tablets or capsules. Imatinib can be represented by structural Formula I.

To date several methods for the preparation of anticancer drug Imatinib(1) and its salts are reported. The first synthetic pathway for Imatinib was described by Zimmermann in 1993 (Scheme-1) in EP564409. Scheme - 1:


The intermediates (2) and (3) were convergently synthesized and finally condensed in large volume of pyridine as solvent. The yields were less and use of large volume of pyridine was ecological challenge on commercial level. The desired product was purified using column chromatograph which is commercially not viable.
Loiseleur et al in WO2003066613A1 described the preparation of Imatinib base (Scheme - 2) where in condensation of 4-(3-pyridinyl)-2-pyrimedinamine(5) with N-(3-bromo-4-methylphenyl)-4-(4-methyl piperazine)-1yl-methyl)-benzamide(4)is described. The process involved the use of highly expensive Pd2(dba)3 CHCl3 catalyst and rac-BINAP as ligand. This method also involves use of special sonication equipment and further tedious purification of the product using flash chromatography and column chromatography which renders the process not suitable for commercial production.
Scheme - 2:

Loiseleur et al in WO2003066613A1 described the process where in the condensation 4-
methyl-N-3-(4-pyridin-3-yl-pyrimidin-2-yl)benzene-1,3-diamine(2)with 4-chloromethyl-
benzoyl chloride(6) is effected to obtained benzamide derivative (7) followed by its reaction
with N-methyl piperazine(8) to obtain Imatinib. The yield of this process is less and the process
is cumbersome to operate.
Both Zimmermann and Loiseleur disclosed a process involving the usage of cyanamide as a reagent which is a highly toxic, hazardous and may cause an explosion.

Scheme - 3:

Szczepeket et al in US7674901 reported an improved procedure for convergent synthesis of Imatinib in which the condensation was carried out in neutral organic solvent like DMF giving Imatinib trihydrochloride precipitate in lower yields. (55%), Further step to prepare Imatinib from the trihydrochloride and then purification renders the process cumbersome and less suitable for commercial scale production.
Scheme - 4:


Kompella et al in WO2004108699A1 described a kilogram scale process(Scheme-4) where in 4-(4-N-Methyl-piperazine-1-yl) benzoic acid(8) is reacted with large amount of thionyl chloride to obtain the acid chloride(3) and then acid chloride was condensed with amine (2) to obtain Imatinib base. The usage of large volume of toxic thionyl chloride and long reaction time renders this process ecologically not suitable and the procedure is cumbersome. Further, the base is obtained by taking the purification where in there is loss of yield.
The work-up involves distillation of excess thionyl chloride under vacuum and further work up and filtration of the toxic intermediate for product isolation. The operations are cumbersome and have safety and environmental issues, and very difficult to adopt on commercial level.
Drawbacks of reported processes:
• Cumbersome operation,
• Large solvent volume with recovery difficulty on commercial scale,
• Longer reaction time,
• Less yields,
• Ecologically non friendly reagent,
• Effluent generation,
• The Toxic and Hazardous Thionyl Chloride is used in much large quantities.
Therefore, there exists a need for an alternate process for the preparation of Imatinib, which is eco-friendly process and does not require large quantity thionyl chloride and base, has shorter reaction time and suitable for scale up for industrial production.
SUMMARY
The present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent preferably in the presence of base solvent. Vilsmeier reagent in the present invention is prepared by reaction of chlorinating agent and catalyst. In a preferred embodiment, chlorinating agent is thionyl chloride and catalyst is dimethyl formamide.
The present invention relates to a process for preparing Imatinib of formula-1


by reacting N-(5-amino-2methyl-phenyl)-4-(3-pyridine)-1-pyramidine amine of formula 2

with a 4-[(4-methyl)-1-piperazinyl)methyl]benzoyl chloride of formula 3

in the presence of optimum amount of base solvent such as di-isopropylethylamine, pyridine, picoline, triethylamine, n-methyl pyrrolidone or mixture thereof and in the presence of Vilsmeier reagent (9).


EMBODIMENTS OF THE INVENTION
The present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent.
In an another embodiment, the present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent and wherein said Vilsmeier reagent is prepared by reaction of chlorinating agent and catalyst.
In an another embodiment, the present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent and wherein said Vilsmeier reagent is prepared by reaction of thionyl chloride and dimethylformamide.
In an another embodiment, the present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent and wherein said according to present invention is carried out is prepared by reaction of thionyl chloride and dimethylformamide, and wherein thionyl chloride is in the amount of at least one (1) mole per mole of benzoic acid intermediate (formula 8) and dimethylformamide is in the amount of at least three (3) mole per mole of benzoic acid intermediate (formula 8).
In another embodiment, a process of preparation of Imatinib according to present invention is carried out in the presence of base solvent at the pH range of 7 to 11.
In another embodiment a process of preparation of Imatinib according to present invention is carried out without isolation of Vilsmeier reagent before preparation of Imatinib.
In another embodiment, the invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent, wherein said Vilsmeier reagent is formed in situ.

In an another embodiment, the invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent, wherein chlorinating agent is added into reaction mixture at temperature below 5°C.
In an another embodiment, the invention relates to a process for preparing Imatinib of formula-1, wherein said process comprises step of
a) Suspending benzoic acid intermediate formula (8) in base solvent,
b) Adding catalyst to the mixture of step (a),
c) Optionally, cooling reaction mass to less than 5°C,
d) Adding chlorinating agent to the mixture of step (c),
e) Slowly increasing temperature of reaction mass to 50°C,
f) Optionally, adding base solvent to get thin slurry,
g) Adding N-(5-amino-2methyl-phenyl)-4-(3-pyridine)-1-pyramidine amine(2) in base solvent to mixture of step (f),
h) Extracting Imatinib base,
i) Optionally further converting into suitable salt.
The skilled person will understand that all embodiments of particular aspects of the inventions may be combined with one or more other embodiments of that aspect of the invention to form further embodiments without departing from the teaching of the invention.
DESCRIPTION OF THE INVENTION
Term “Imatinib” refers to 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4 methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino]-phenyl]benzamide, represented by structural Formula I.

Term "benzoic acid intermediate" refers to benzoic acid intermediate of formula 8 as below.


Vilsmeier reagent is a versatile organic reagent useful in the synthesis of a wide variety of organic molecules. Weike Su et. al. (The new General for Organic synthesis; 2010; 42:6,503-555) reported several applications of Vilsmeier reagent.
“Vilsmeier Reaction” refers to process of preparation of carboxylic acid chloride by reaction of a chlorinating agent such as phosgene, oxalyl chloride, phosphorus trichloride, phosphorous pentachloride, thionyl chloride or the like with a carboxylic acid. During this process, when an amide is added as a catalyst in order to improve a reaction rate, the chlorinating agent reacts with the amide to form a Vilsmeier reagent (chloroiminium salt).
Vilsmeier Reagent
"Vilsmeier reagent" refers to a reagent suitable for performing the Vilsmeier reaction (also known as Vilsmeier-Haack formylation), usually formed by a reaction between an amide (typically a N,N-disubstituted amide) and an acid chloride. Formation of the Vilsmeier reagent may be performed prior to conducting the formylation reaction or may be performed in situ as part of the reaction. Alternatively, a commercially available Vilsmeier reagent may be used.
The term “in situ” used herein refer to reagent or compound being formed in the reaction vessel. The amount of the Vilsmeier reagent to be used in this reaction is about1 to 2 mole per mole of benzoic acid intermediate (formula 8). Advantages of present invention
1. Minimum amount of chlorinating agent is used

2. Minimum use of solvent.
3. Less toxic effluent generation
4. Faster reaction
5. High purity
6. High yield.
7. Cost effective efficient process.
8. Commercially scalable process
In one embodiment the process involve the preparation of acid chloride (3) in presence of minimum amount of base such as di-isopropylethylamine, pyridine, pecoline, triethylamine, n-methyl pyrolidone etc. and reacting the acid (8) with optimum use of thionyl chloride and optimum amount of Vilsmeier reagent. Further the acid chloride (3) prepared is reacted with amine(2) in the presence of the Vilsmeier reagent as catalyst to obtain Imatinib(1) in good yield.
The reaction converting acid (8) into acid chloride (3) is accomplished by the reacting the reactant in minimum amount of base as solvent as well as acid acceptor, and using Vilsmeier catalyst (9) prepared in situ by reacting dimethyl formamide and thionyl chloride

The progress of the reaction of the formation of acids chloride (3) is monitored by HPLC analysis by observing conversion of acid (2) into acid chloride (3) in the presence of Vilsmeier reagent After conversion of acid (2) into acid chloride(3), the amine (2) was added in the same reaction mixture and reacted in the presence of Vilsmeier reagent to obtain Imatinib(1).


The Imatinib base obtained by this method is further converted into its pharmaceutically accepted salt namely Imatinib Mesylate


The present invention relates to use of Vilsmeier reagent (9) formed in situ during the reaction for the activation of –carboxylic group in the intermediate(8) to transform it in to acid chloride(3) derivative by the reaction of optimum quantity of thionyl chloride (SOCl2) in the presence of suitable base. The Vilsmeier reagent(9) is formed in situ during the reaction by the addition of dimethyl formamide (DMF) in the presence of suitable base and reacting it with thionyl chloride to obtain(9) which is not isolated. The acid chloride(3) so formed is further reacted with the base (2) without isolating acid chloride(3) and the Vilsmeier reagent (9) from the reaction mixture. On completion of the condensation of the acid chloride(3) with the amine(2) in the presence of Vilsmeier reagent, Imatinib(1) is formed in the reaction mixture. The product is isolated, purified and further converted in to Imatinib mesylate(1M) salt in high yield and purity by reacting Imatinib with methane sulphonic acid(10) in suitable solvent.
The present invention relates to process of preparation of Imatinib using bare minimum quantity of thionyl chloride and minimum quantity of DMF to obtain complete conversion into Vilsmeier Reagent, which is not isolated and used upto condensation stage to obtain Imatinib in much lesser time.
Chlorinating agent
Examples of chlorinating agent as per invention are phosgene, oxalyl chloride, phosphorus trichloride, phosphorous pentachloride, thionyl chloride and so on. Oxalyl chloride and thionyl chloride are preferably usedon an industrial scale since they can be easily removed from a reaction system along with by-product. Preferred Chlorinating agent as per present invention is thionyl chloride.
The amount of the chlorinating agent to be used in this reaction is at least one (1) mole per mole of benzoic acid intermediate (formula 8). When the lesser amount used, a reaction does not progress sufficiently. Preferably, chlorinating agent is added into reaction mixture at temperature below 5°C.
Catalyst
Examples of catalyst used in the invention for reacting the chlorinating agent with the benzoic acid intermediate is not particularly limited, as far as it can react with the chlorinating agent to

form the Vilsmeier reagent, and includes amide type compounds such as N,N-dimethylformamide (DMF), N-methyl formanilide, N-methyl formamide, N-formylpiperidine and N-formylindoline, unsubstituted formamide, N, N-dimethyl acetamide, N-methyl acetamide, N,N-dimethyl benzamide, pentamethyl acetamide and so on. Among them, DMF is particularly preferable from a viewpoint of availability, cost and reactivity of the Vilsmeier reagent.
The amount of the catalyst used in this reaction is not particularly limited and is in the amount of at least one mole to three (3) mole per mole of benzoic acid intermediate (formula 8).When the amount used is less than the range, a reaction rate is low and thereby it takes longer time to complete the reaction.
Basic Solvents
Examples of basic solvent such as di-isopropylethylamine, pyridine, pecoline, triethylamine, n-methyl pyrolidone or mixture thereof. The pH of the reaction mixture during the process may be between 7 to 11.
The reaction of acid activation and further condensation to obtain Imatinib was studied in various solvents and surprisingly it was found that basic solvent gives better product with good yield and quality.
Having described the invention with reference to the usefulness of the process for the synthesis of Imatinib(1) and its salt Imatinib Mesylate(1M), other embodiments will become apparent to one skilled in the art from consideration of the specifications.
The innovation is further defined by reference to the following examples describing the process and composition of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of this invention and hence the examples should not be construed as limiting factors for defining the invention.

EXAMPLES Example:-1
To a suspension of 40ml mixed picoline (commercially available) base solvent and 10g of 4-(4-N-Methyl-piperazine-1-yl)methyl benzoic acid dihydrochloride(8)was added 10ml of DMF and stirred for 10min to get a uniform suspension. The reaction mass was cooled to 0 to 5°C and thionyl chloride 4.1g was added during period of 15 to 20 minutes. The mixture was stirred for 30 min at 0-5°C and then slowly allowed to attain a temperature of 25 to 30°C within 1Hr. The temperature of the reaction mass was slowly raised to 50°C within 2 Hrs and held for half an hour. The aliquot was withdrawn and analyzed by HPLC to observe reaction progress and found that about 3% of starting material(8) was remained. Chilling was applied and the reaction mass was chilled to obtain 0 to 5°C and 10ml of mixed picoline solvent was added to get thinner slurry. A solution of 7.3g N-(5-amino-2methyl-phenyl)-4-(3-pyridine)-1-pyramidine amine(2) in 15ml of mixed picoline solvent was added. Heating was applied within 1hr and the temperature raised to about 15°C. The mass stirred for 8 hrs and checked for Imatinib content by HPLC. The reaction mass diluted with 100ml of water and pH was adjusted to 7.5 by adding of ammonia solution and stirred for 20min Methylene chloride(MDC) 100ml was added, stirred and layers separated. Two more extracts of 60ml each of MDC where given to the aqueous phase. The combined organic phase washed with water followed by saturated solution of sodium chloride and then the Organic layer distilled under vacuum to obtain a residue. Ethyl acetate100ml was added to the residue and heated to reflux for half an hour and cooling applied to the slurry to obtain 10-15°C, Slurry was filtered and solids washed with ethyl acetate. On drying under vacuum to obtain 8.75g of Imatinb Base(I) was obtained. HPLC purity 99.1%
Example:-2
To a suspension of 40ml Di-isopropyl-ethylamine base solvent and 10g of 4-(4-N-Methyl-piperazine-1-yl)methyl benzoic acid dihydrochloride(8)was added 10ml of DMF and stirred for 10min to get a uniform suspension. The reaction mass was cooled to 0 to 5°C and thionyl chloride 4.1g was added during period of 15 to 20 minutes. The mixture was stirred for 30 min at 0-5°C and then slowly allowed to attain an a temperature of 25 to 30°C within 1Hr. The temperature of the reaction mass was slowly raised to 50°C within 2 hrs and held for half an hour. The aliquot was withdrawn and analyzed by HPLC to observe reaction progress and found

that about 3%of starting material(8) was remained. Chilling was applied and the reaction mass was chilled to obtain 0 to 5°C and 10ml of di-isopropyl-ethylamine solvent was added to get thinner slurry. A solution of 7.3g N-(5-amino-2methyl-phenyl)-4-(3-pyridine)-1-pyramidine amine(2)in 15ml of mixed picoline solvent was added. Heating was applied within 1hr and the temperature raised to about 15°C. The mass stirred for 8 hrs and checked for Imatinib content by HPLC. The reaction mass diluted with 100ml of water and pH was adjusted to 7.5 by adding of ammonia solution and stirred for 20min methylenechloride(MDC) 100ml was added, stirred and layers separated. Two more extracts of 60ml each of MDC where given to the aqueous phase. The combined organic phase washed with water followed by saturated solution of sodium chloride and then the organic layer distilled under vacuum to obtain a residue. Ethyl acetate100ml was added to the residue and heated to reflux for half an hour and cooling applied to the slurry to obtain 10-15°C. Slurry was filtered and solids washed with ethyl acetate. On drying under vacuum. The output of Imatinib 7.5g, HPLC purity 98.85%
Example:-3
To a suspension of 40ml Pyridine base solvent and 10g of 4-(4-N-Methyl-piperazine-1-yl)methyl benzoic acid dihydrochloride(8) was added 10ml of DMF and stirred for 10min to get a uniform suspension. The reaction mass was cooled to 0 to 5°C and thionyl chloride 4.1g was added during period of 15 to 20 minutes. The mixture was stirred for 30 min at 0-5°C and then slowly allowed to attain an a temperature of 25 to 30°C within 1Hr. The temperature of the reaction mass was slowly raised to 50°C within 2 hrs and held for half an hour. The aliquot was withdrawn and analyzed by HPLC to observe reaction progress and found that about 3%of starting material(8) was remained. Chilling was applied and the reaction mass was chilled to obtain 0 to 5°C and 10ml of pyridine solvent was added to get thinner slurry. A solution of 7.3g N-(5-amino-2methyl-phenyl)-4-(3-pyridine)-1-pyramidine amine(2)in 15ml of mixed pyridine solvent was added. Heating was applied within 1hr and the temperature raised to about 15°C. The mass stirred for 8 hrs and checked for Imatinib content by HPLC. The reaction mass diluted with 100ml of water and pH was adjusted to 7.5 by adding of ammonia solution and stirred for 20min methylenechloride(MDC) 100ml was added, stirred and layers separated. Two more extracts of 60ml each of MDC where given to the aqueous phase. The combined organic phase washed with water followed by saturated solution of sodium chloride and then the

Organic layer distilled under vacuum to obtain a residue. Ethyl acetate100ml was added to the residue and heated to reflux for half an hour and cooling applied to the slurry to obtain 10-15°C, Slurry was filtered and solids washed with ethyl acetate.. On drying under vacuum. The output of Imatinib 8.8g, HPLC purity 99.2%.
Example:-4
Isopropanol 50ml was added to a reaction flask and 5g of Imatinib base (I) obtained from above examples was charged to it to obtain the thin slurry. Slowly rise the temp. to 50°C and 0.75ml of methane sulphonic acid was added to it. The reaction mass was reflux for 1 hr and then slowly cooled and then chilled to 0to 5°C. It was stirred at this temperature for 2hrs and then filtered and washed with chilled IPA. The solid was dried under vacuum at 60° to obtain Imatinib mesylate 4.9gm. HPLC purity 99.5%, XRD analysis proves that this is alpha polymorphic form.

CLAIMS
We Claim
1. A process for preparation of Imatinib or pharmaceutically acceptable salt thereof,
wherein process comprises converting benzoic acid intermediate (formula 8) into
Imatinib in the presence of Vilsmeier reagent.

2. The process according to claim 1, wherein the process is carried out in the presence of a base solvent.
3. The process according to claim 2, wherein the base solvent is selected from group consisting of di-isopropylethylamine, pyridine, picoline, triethylamine, n-methyl pyrrolidone or mixture thereof.
4. The process according to claim 1, wherein the pharmaceutically acceptable salt is mesylate salt.
5. The process according to claim 1, wherein the Vilsmeier reagent is prepared by reaction of chlorinating agent and catalyst.
6. The process according to claim 5, wherein the chlorinating agent is thionyl chloride and the catalyst is dimethyl formamide.
7. The process according to claim 6, wherein the thionyl chloride is in the amount of at least one (1) mole per mole of benzoic acid intermediate (formula 8), and the dimethylformamide is in the amount of at least three (3) mole per mole of benzoic acid intermediate (formula 8).
8. The process according to claim 1, wherein said process is carried out at a pH between 7 and 11.
9. The process according to claim 1, wherein the Vilsmeier reagent is prepared in situ.
10. A process for preparation of Imatinib or pharmaceutically acceptable salt thereof, wherein process comprising steps of
a. suspending benzoic acid intermediate formula (8) in base solvent,

b. adding catalyst to the mixture of step (a),
c. adding chlorinating agent to the mixture of step (b),
d. adding N-(5-amino-2methyl-phenyl)-4-(3-pyridine)-1-pyramidine amine(2) in
base solvent to mixture of step (c),
e. extracting Imatinib base,
f. optionally further converting into pharmaceutically acceptable salt.
11. The process according to claim 10, wherein the base solvent is selected from group consisting of di-isopropylethylamine, pyridine, picoline, triethylamine, n-methyl pyrrolidone or mixture thereof.
12. The process according to claim 10, wherein the pharmaceutically acceptable salt is mesylate salt.
13. The process according to claim 10, wherein the Vilsmeier reagent is prepared by reaction of chlorinating agent and catalyst.
14. The process according to claim 13, wherein the chlorinating agent is thionyl chloride and the catalyst is dimethyl formamide.
15. The process according to claim 14, wherein thionyl chloride is in the amount of at least one (1) mole per mole of benzoic acid intermediate (formula 8) and dimethylformamide is in the amount of at least three (3) mole per mole of benzoic acid intermediate (formula 8).
16. The process according to claim 10, wherein process is carried out at a pH between 7 and 11.