DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

PROCESS FOR THE PREPARATION OF NILOTINIB
INTRODUCTION
The present application provides process for the preparation of Nilotinib.
BACKGROUND OF THE INVENTION
The drug compound having the adopted name “nilotinib hydrochloride” has a chemical name 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide monohydrochloride, and is structurally represented as,

Nilotinib hydrochloride is a kinase inhibitor, approved as nilotinib hydrochloride monohydrate, sold using the trade name Tasigna®, in the form of capsule for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant to or intolerant to prior therapy that included imatinib.
US patent 7,169,791 discloses process for the preparation of nilotinib and its intermediates. The reaction scheme is depicted below

US patent 8,124,763 discloses process for the preparation of nilotinib and the reaction scheme from the patent is depicted below.

wherein R3 is lower alkyl, phenyl, phenyl-lower alkyl or substituted phenyl and base is selected from metal hydride, bulky alkyl lithium, metal alkoxide, metal bis(trimethylsilyl)amide and lithium dialkylamide.
CN103275068A discloses process for the preparation of nilotinib. The process involve reacting 3-iodo-4-methylbenzoyl chloride with 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline followed by reaction with 4-(pyridin-3-yl)pyrimidin-2-amine to give nilotinib. The reaction scheme is depicted below.

The application also discloses reaction of 4-(pyridin-3-yl)pyrimidin-2(1H)-one with 3-amino-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide to give nilotinib. The reaction scheme is depicted below.

CN103254175A discloses process for the preparation of nilotinib. The process involve reacting 4-(pyridin-3-yl)pyrimidin-2(1H)-one, ester of 3-amino-4-methylbenzoic acid and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline as per the below mentioned scheme.

US20100016590A1 discloses process for the preparation of nilotinib as per the below depicted scheme. The process involve reaction of N-(3-bromo-5-(trifluoromethyl)phenyl)-4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzamide with 4-methylimidazole in presence of base to nilotinib.

US20130210847A1 Natco discloses process for the preparation of nilotinib. The process is a reaction of 3-amino-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide with cyanamide to give 4-methyl-N-[3-(4-methyl-lFl-imidazol-l-yl-5-(trifluoromethyl)phenyl] -3-guanidino-benzamide. The guanidino-benzamide compound is reacted with 3-dimethylaminol-(3-pyridyl)-2-propen-l-one to give nilotinib. The reaction scheme is depicted below.

Despite the existence of processes for the preparation of nilotinib and its intermediates, there remains a need for providing novel solution that would decrease the consumption of time and labor and it is of particular importance to develop methods that would allow for the increase in yields and purity of particular steps, which in turn would favor an increase of the yield of the whole technology.
The present invention provides an improved process for the preparation of Nilotinib.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for the preparation of 4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzamide (Nilotinib), which is represented by formula VI,

The process of the present invention is represented in the following scheme.

DETAILED DESCRIPTION
In an aspect, the present invention provides a process for the preparation of compound of formula VI,

The schematic representation of the process for the preparation of compound of formula VI is as shown below.

The process comprises, reacting the compound II with compound III in presence of suitable solvent and base to give compound IV. The reaction is preferably carried out in the presence of a phase transfer catalyst such as tetra-n-butyl ammonium bromide.
The amount of tetra-n-butyl ammonium bromide may vary from 0.01 moles to 1 mole. The preferred range is 0.01 moles to 0.05 moles.
Suitable solvents that may be used include, but are not limited to: alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, or the like; ketones, such as for example, acetone, butanone, pentanone, methyl isobutyl ketone, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; polar aprotic solvents, such as for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, or the like; or any mixtures thereof.
Suitable base that may be used in above step include but not limited to NaOH, KOH, Na2CO3, NaHCO3 or any other suitable base known in the art.
In an embodiment, the preferred solvent is N-methylpyrrolidone and the preferred base is NaOH.
The reaction in step-1 is carried out at a suitable temperature. Suitable temperature for the reaction of step-1 may be less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -20°C, less than about -30°C or any other suitable temperatures. In a preferred embodiment, the suitable temperature is between 130 to 150 oC.
The reaction mixture obtained in step-1 may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids.
The product of step-1 may be isolated directly from the reaction mixture itself after the reaction is complete, or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
Isolation of compound may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.
Suitable solvents that may be used for isolation of compound include, but are not limited to: ketones, such as for example, acetone, methyl isobutyl ketone or the like; esters, such as for example, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, 1,2-dimethoxyethane, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitromethane; and any mixtures thereof.
The recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 150°C, less than about 120°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C or any other suitable temperatures as long as the compound is not degraded in quality, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required purity is achieved. For example, it may vary from about 1 hour to about 10 hours, or longer.
Optionally, the product of step-1 is carried to the next step without isolation.
In step-2, the compound of formula IV is reacted with thionyl chloride and compound of formula V in presence of suitable solvent.
Suitable solvent that may be used include, but are not limited to: alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, or the like; ketones, such as for example, acetone, butanone, pentanone, methyl isobutyl ketone, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; polar aprotic solvents, such as for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, or the like; or any mixtures thereof. In a preferred embodiment, the solvent used is N-methylpyrrolidone (NMP).
In an embodiment, the amount of thionyl chloride used may vary from about 1 mole to 4 moles. In a preferred embodiment, the amount of thionyl chloride used is 2-3 moles.
Suitable temperatures for the reaction of step-2 may be less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C or any other suitable temperatures. In a preferred embodiment, the temperature is from 50 to 70 oC.
The reaction mixture obtained in step-2 may optionally be filtered to remove any insoluble solids, or if any particles are present, they may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids.
The compound VIa of step-2 is precipitated by the addition of a suitable solvent to the reaction mixture followed by isolation by filtration.
Suitable solvents that may be used for precipitation include, but are not limited to: ketones, such as for example, acetone, methyl isobutyl ketone or the like; alkyl acetates such as methyl acetate, ethyl acetate, propyl acetate and butyl acetate; Halogenated hydrocarbons such as dichloromethane, chloroform, 1, 1, 2-trichloroethane, 1, 2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene or the like, and any mixtures thereof.
The compound of formula VIa is converted to compound VI by dissolving in a suitable solvent followed by basification with an aqueous alkali metal hydroxide such as NaOH, KOH or the like.
The solvent used may include a C1-C4 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, and isobutanol; or water or mixture of water and a C1-C4 alcohol.
The compound of formula VI may be further purified by slurrying in water. The slurrying is done at about 35 to 50 oC, particularly at 40-45 oC.
The compound of formula VI may further be converted to a pharmaceutically acceptable salt. In particular, the compound of formula VI is converted to its hydrochloride salt.

Examples
Example 1: Preparation of 4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzoic acid
250 mL of N-methylpyrrolidone was charged into the round bottom flask at 25-35 oC. 50.0 g of 3-[(Aminoiminomethyl)amino]-4-methyl-benzoic acid ethyl ester mononitrate, 31.6 g of (E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one, 7.72 g of sodium hydroxide and 5.66 g of tetra butyl ammonium bromide were charged into the above flask at 25-35 oC and stirred. The contents of the flask were heated to 135-140 oC and maintained at the same temperature under stirring for 18 to 20 hours. The reaction mass was cooled to 50-60 oC and 500 mL of demineralized water was added to the reaction mass. 10.56 g of sodium hydroxide was added to the reaction mass at 40-45 oC and maintained for 2-3 hours under stirring. The reaction mass was cooled to 5-10 oC and pH of the reaction mass was adjusted to 5.5-6.5 with 360 mL of 10% HCl solution. The reaction mass was stirred at 25-35 oC for 2-3 hour. The reaction mass was filtered and washed with 250 mL of demineralized water. The compound obtained was dried under reduced pressure at 50-60 oC for 8-10 hours to get the title compound.
Yield: 48.4 g
Example 2: Preparation of Nilotinib
25.0 g of 4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzoic acid and 250 mL of N-methylpyrrolidone were taken in a round bottom flask at 27 oC. 19.4 g of thionyl chloride was slowly added to the above flask at 27 oC. The contents of the flask were heated to 55 oC and 20.6 g of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline was added. The reaction mass was maintained for 2-2.5 hours at 55-60 oC. 375 mL of ethyl acetate was added to the above reaction mixture at 48 oC. The reaction mixture was stirred for 40-60 minutes and was filtered at 45 oC using a suction pump. The obtained material was charged into a fresh RBF at 27 oC and 500 mL of methanol was added and heated to 48 oC. 8.16 g of sodium hydroxide was dissolved in 50 mL of demineralized water and added to the above flask, which was maintained at 48 oC. The reaction mixture was maintained at 48-50 oC for 3-3.5 hours. The reaction mass was filtered and washed with 50 mL of methanol at 45 oC. The material was dried on vacuum pump for 1 hour and was charged into a fresh round bottom flask with 250 mL of demineralized water. The material was slurred for 2-3 hours at 40-45 oC and filtered on vacuum pump. The material was dried for 18 hours at 65 oC under vacuum to obtain the title compound.
Yield : 82.8%
Purity : 99.87 %
,CLAIMS:1. A process for the preparation of compound of formula IV,

by reacting the compound of formula II,

with a compound of formula III,

in presence of phase transfer catalyst, a suitable base and a suitable solvent.
2. The process of claim 1 wherein, the phase transfer catalyst is tetra-n-butyl ammonium bromide.
3. The process of claim 1 wherein, the suitable base is inorganic base.
4. The process of claim 1 wherein, the suitable solvent is polar aprotic solvent.
5. A process for the preparation of compound of formula VI,

by reacting the compound of formula IV with a compound of formula V,

in the presence of suitable polar aprotic solvent.
6. The process of claim 5 wherein, the compound of formula VI is obtained via the compound of formula VIa.