DESC:FIELD OF INVENTION

The present invention relates to novel process for the preparation of nilotinib and the process for the preparation of key intermediates for nilotinib viz. 4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]benzoic acid and 3-methyl-5-(4-methylimidazol-1-yl)aniline.

BACKGROUND OF THE INVENTION

Nilotinib, 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, having the following formula

is marketed under the name Tasigna® in US and Europe. Tasigna contains nilotinib monohydrate monohydrochloride salt and is available as capsules for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Tasigna is also indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib.

Nilotinib is considered a low solubility/low permeability (class IV) compound in the Biopharmaceutics Classification System (BCS). Therefore, dissolution of nilotinib can potentially be rate limiting step for in-vivo absorption. It is soluble in acidic media; being practically insoluble in buffer solutions of pH 4.5 and higher.
United States Patent No. 7,169,791 (the ‘791 patent) assigned to Novartis, discloses nilotinib and process for its preparation as depicted in the following scheme:

The ‘791 patent prepares nilotinib by coupling reaction of 4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]benzoic acid (compound of Formula II) with 3-methyl-5-(4-methylimidazol-1-yl)aniline (compound of Formula III). The preparation of compound of Formula II involves reaction of ethyl-3-amino-4-methyl benzoate (1) with cyanamide in presence of hydrochloric acid in ethanol followed by treatment with ammoniun nitrate to obtain compound 2, which on cyclization reaction with the compound of Formula IV forms ester compound 3, which on further hydrolysis afforded compound of Formula II. Process for the prepartion of the compound of Formula II as disclosed requires long reaction time and does not mention yield of the compound.

The Chinese Patent CN101928277B (the ‘277 patent) discloses process for the preparation of intermediate for nilotinib i.e. for compound of Formula II by reacting the 3-amino-4-methyl-benzoic acid with cyanamide in presence of hydrochloric acid in alcohol solvent to obtain 3-guanidino-4-methyl-benzoic acid hydrochloride which on further treatment with 3-(dimethylamino)-1-(3-pyridyl)prop-2-en-1-one (compound of Formula IV) afforded the compound of Formula II. The process disclosed requires long reaction time to afford product in low yield. In addition the starting material 3-amino-4-methyl-benzoic acid is well known irritant, which makes the process of the ‘277 patent, not suitable for commercial scale.

The United States Patent No. 8,124,763 (the ‘763 patent) assigned to Novartis, discloses preparation of nilotinib by reacting the esters of 4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]benzoic acid with 3-methyl-5-(4-methylimidazol-1-yl)aniline in presence of a base and a solvent.

The United States Patent No. 7,781,597 (the ‘597 patent) assigned to Novartis, discloses various methods for the preparation of intermediate for nilotinib i.e. 3-methyl-5-(4-methylimidazol-1-yl)aniline (the compound of Formula III), wherein in one of the processes, the compound of Formula III is prepared by reacting 1-fluoro-3,5-dimethyl-benzene with 4-methyl-1H-imidazole in presence of potassium carbonate as base and in N,N-dimethylformamide (DMF) as solvent to obtain 1-(3,5-dimethylphenyl)-4-methyl-imidazole followed by catalytic reduction using hydrogen and palladium on carbon (Pd/C).

Various other processes for the preparation of nilotinib and its intermediates are disclosed in the literature for example, United States Patent No. US 9061028, US 9187452; United States patent publication US20100016590 A1, WIPO applications WO 2013120852A1, WO 2015087343A2, WO 2016187824A1, Chinese Patent applications CN 102321073A, CN 103254175A, CN 103288804A and Indian Patent application IN 195/CHE/2015.

The present invention provides a simple, scalable and economical process for the preparation of intermediates for nilotinib viz. 4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]benzoic acid (compound of Formula II) and 3-methyl-5-(4-methylimidazol-1-yl)aniline (compound of Formula III), which on further coupling are converted to nilotinib.
SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of nilotinib,

comprising:
(a) reacting a compound of Formula VII

wherein R is C1-C3 alkyl;
with cyanamide in water in presence of an acid to form a compound of Formula VI

wherein R is C1-C3 alkyl;
(b) hydrolysing the compound of Formula VI by adding a base into the reaction mixture of step a to obtain a compound of Formula V

(c) reacting the compound of Formula V with a compound of Formula IV

in presence of a base to obtain a compound of Formula II
, and
(d) reacting the compound of Formula II with a compound of Formula III

to obtain nilotinib.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides a process for the preparation of nilotinib,

comprising:
(a) reacting a compound of Formula VII

wherein R is C1-C3 alkyl;
with cyanamide in water in presence of an acid to form a compound of Formula VI

wherein R is C1-C3 alkyl;
(b) hydrolysing the compound of Formula VI by adding a base into the reaction mixture of step a to obtain a compound of Formula V

(c) reacting the compound of Formula V with a compound of Formula IV

in presence of a base to obtain a compound of Formula II
, and
(d) reacting the compound of Formula II with a compound of Formula III

to obtain nilotinib.

The term “C1-3 alkyl” refers to a saturated hydrocarbon chain radical that includes solely carbon, 1 to 3 in number, and hydrogen atoms in the backbone, either linear or branched and which is attached to the rest of the molecule by a single bond. The examples of the C1-3alkyl include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl).

In one embodiment, R in the compound of Formula VI and VII is methyl, ethyl, n-propyl or 1-methylethyl (isopropyl). In a preferred embodiment, R in the compound of Formula VI and VII is methyl.

In another embodiment, in step a of the above process, the reaction of compound of Formula VII with cyanamide is carried in presence of an acid in water as solvent in absence of any organic solvent. The prior art processes use either an organic solvent or a mixture of organic solvents and water for this reaction, for example, alcoholic solvent such as ethanol or mixture of alcoholic solvent and water viz. n-BuOH and water. The present inventors found with surprise that the reaction of compound of Formula VII with cyanamide can proceed even in absence of any organic solvent by taking water as only solvent. The reaction was completed in very short period of time of 1-2 hours and with high yield. Absence of organic solvent makes the process environment friendly and more suitable for commercial manufacturing. Moreover, the compound of Formula VI was hydrolyzed in-situ (i.e. without isolating the compound of Formula VI from the reaction mixture) to directly obtain the compound of Formula V with short reaction time (1 -2 hours) and with high overall yield of more than 80 %. In addition, the obtained compound of Formula V was found to be more than 95 % pure.

In another embodiment, in step a of the above process, the acid used in the process is an inorganic acid selected from hydrochloric acid, sulfuric acid and the like. In a preferred embodiment, the acid is hydrochloric acid. In another embodiment, the acid is added to the reaction mixture in portions. In a preferred embodiment, the acid is added in 2 portions. In another embodiment, the acid is used in quantities of about 1 to 1.5 molar equivalents with respect to compound of Formula VII; preferably 1.2 equivalent.

In another embodiment, in step a of the above process, cyanamide can be used in quantities of about 1.5 to 2.5 molar equivalents with respect to compound of Formula VII. Preferably, cyanamide is about 2 to 2.2 molar equivalents to the compound of Formula VII.

The reaction of compound of Formula VII with cyanamide may be carried out at a temperature ranging from 80 °C to 110 °C, preferably at 100 °C to 105 °C. The reaction may be carried out for a time sufficient for the completion of reaction, for example 1 to 2 hours. After completion of reaction, the base is added to the reaction mixture without isolating the product of step a i.e. the compound of Formula VI.

Step b of the process described above involves hydrolysis of the compound of Formula VI by adding a base into the reaction mixture of step a. The in-situ hydrolysis of the compound of Formula VI not only makes the process cost effective but also efficient and time saving as it obviates need to isolate the intermediate. The base for hydrolyzing the compound of Formula VI can be selected from any suitable base used for hydrolysis of esters such as sodium hydroxide, potassium hydroxide and the like. In a preferred embodiment, the base is sodium hydroxide. The hydrolysis of the compounds of Formula VI can be carried out at a temperature ranging from 40 °C to 80 °C, preferably at 50 °C to 60 °C. The reaction can be carried out for a time sufficient for the completion of reaction for example 1 to 2 hrs. After completion of reaction, the compound of Formula V can be isolated from the reaction mixture by the techniques known in the art such as by precipitating by addition of an acid followed by filtration.

The step c of the process involves reaction of the compound of Formula V with a compound of Formula IV in presence of a base to obtain the cyclized product, a compound of Formula II. The base for the reaction can be selected from, but should not be restricted to, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert-butoxide, sodium tert-butoxide or a mixture thereof. In a preferred embodiment, the base is potassium carbonate. The suitable solvent for the cyclization reaction may be selected from a group consisting of N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMAc) or a mixture thereof. In a preferred embodiment, the solvent is DMF. The cyclization reaction can be carried out at a temperature ranging from 120 °C to 160 °C, preferably at a temperature of 140 °C to 150 °C. The cyclization reaction can be carried out for a time sufficient for the completion of reaction, for example 4 to 6 hrs. After completion of reaction, the compound of Formula II can be isolated from the reaction mixture by techniques known in the art such as evaporation of solvent or precipitation by addition of an acid, followed by filtration.

In step d, the compound of Formula II and compound of Formula III are coupled together to obtain nilotinib. The coupling of compound of Formula II and compound of Formula III can be carried out by the process as disclosed in the prior art, for example, as disclosed in US20100016590A1 by using thionyl chloride and N-methylpyrrolidone as solvent.

In another embodiment, the compound of Formula III is prepared by a process comprising:
(a) heating a mixture comprising a compound of Formula IX

wherein L is a leaving group, and 4-methylimidazole to obtain a compound of Formula VIII

, and
(b) reducing the compound of Formula VIII to obtain the compound of Formula III.

In one embodiment, L in the compound of Formula IX is a leaving group selected from, but not restricted to, halo, mesylate, tosylate, brosylate, nosylate, triflate and the like. In a preferred embodiment, L is halo selected from bromo, fluoro, iodo and chloro. In another preferred embodiment, L is fluoro.

In step a of the above process, the mixture of compound of Formula IX and 4-methylimidazole is heated in absence of any solvent or base, to obtain the compound of Formula VIII. The reaction can be carried out at a temperature of 100 °C to 140 °C, preferably at a temperature of 120 °C to 130 °C. The reaction can be carried out for a time sufficient for the completion of reaction, for example, 10 to 24 hours, preferably 15 to 20 hours.

Most of the prior art processes prepares the compound of Formula VIII by reacting compound of Formula IX with 4-methylimidazole in presence of a base and in a solvent. The present inventors surprisingly found that the reaction of compound of Formula IX and 4-methylimidazole can be carried out in neat condition, without any need of solvent or base, with good yield. The conditions of the present invention make the process environment friendly and cost effective.

In step b of the above process, the reduction of compound of Formula VIII may be carried out by the processes known for the reduction of nitro group, such as hydrogenation by using hydrogen and palladium on carbon (Pd/C).

The complete process for the preparation of nilotinib of the present invention can be depicted by the scheme below:

While developing the process of the present invention, the inventors found that any unreacted compound of Formula VII during first step of the route of synthesis leads to formation of an impurity of Formula X. Thus, the unreacted compound of Formula VII during the course of the synthesis is hydrolyzed, the hydrolyzed product (Formula VII’) reacts with the compound of Formula II formed in the step 3 to form impurity (compound of Formula X) which further reacts with amine intermediate (Formula III) to form impurity XI in the final product. The impurity X and XI were prepared by the process as described herein in the examples and were characterized. It was also found that in order to minimize the formation of impurity X and the corresponding impurity XI in nilotinib one have to optimize the quantity of cyanamide in step 1 of the process. This was demonstrated by the experiments with different molar equivalent of cyanamide with respect to the compound of Formula VII. Table 1 provides the quantity of hydrolyzed product of the unreacted compound of Formula VII formed when different ratios of cyanamide was used in the reaction.
Table 1
Molar equivalent of cyanamide w.r.t. the compound of Formula VII Quantity of the compound of Formula VII’ formed after hydrolysis
1.4 eq. 0.77 %
1.9 eq. 0.08 %
2.4 eq. Not detected

Thus, in another aspect, the present invention provides a compound of Formula X

In another aspect, the present invention provides a compound of Formula XI

In another embodiment, the present invention provides nilotinib obtained by the process as described above, wherein nilotinib is free of impurity of compound of Formula X

In another embodiment, the present invention provides nilotinib obtained by the process as described above, wherein nilotinib is free of impurity of compound of Formula XI

.
The term “free of impurity of compound of Formula X or XI” as used herein indicates that the impurity of the compound of Formula X or XI are not detected in nilotinib when analyzed by the HPLC method described herein in example.

Nilotinib obtained by the process of the present invention can be converted into its pharmaceutically acceptable salts like hydrochloride by the processes known in the art.

The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.

EXAMPLES:

Example 1: Preparation of 4-methyl 3-nitro benzoic acid
To a mixture of p-toluic acid (100 g) and sulfuric acid (150 mL) was added nitrating mixture (200 mL) at a temperature of 10 °C to 20 °C. Reaction mass was stirred for 2 hrs at 10°C to 20°C. After completion of reaction, prechilled water (1500 mL) was added to the reaction mass and stirred for 30 min. The product was filtered and dried (Yield: 129 g, Purity by HPLC > 98%).

Example 2: Preparation of methyl 3-amino-4-methylbenzoate (Formula VII)
A mixture of 4-methyl 3-nitro benzoic acid (100 g), methanol (600 mL) and sulfuric acid (10 mL) was heated to reflux for 8 hrs. After completion of reaction, methanol was distilled out under reduced pressure. Ethyl acetate (950 mL) and purified water (100 mL) was added to the residue and the pH of aqueous layer was adjusted to 7 to 8 by the addition of sodium bicarbonate. Organic layer was separated, dried over anhydrous sodium sulfate and distilled out under reduced pressure. Methanol (1 litre) was added to the crude residue and treated with activated charcoal and filtered. The clear filtrate was charged in autoclave and was added 5% Pd/C (50% wet) (5g). The resultant reaction mixture was hydrogenated at hydrogen pressure of 3 to 4 kg/cm2, at a temperature 35-45 °C. After completion of reaction, Pd/C was filtered out and the clear filtrate was concentrated under reduced pressure. Water was added to the crude product, filtered and dried under reduced pressure to obtain the title product (Yield: 78.6 g, HPLC purity > 99%).

Example 3: Preparation of 3-guanidino-4-methylbenzoic acid (Formula V)
To a mixture of methyl 3-amino-4-methylbenzoate (100 g, 605.3 mmol) and cynamide (50 % solution in water, 105 mL, 1350 mmol) was added slowly concentrated hydrochloric acid (52 mL, 605.3 mmol). Reaction mixture was heated to 100 °C to 105 °C for 1 hr. Again concentrated hydrochloric acid (10 mL, 121.06 mmol) was added to the reaction mixture and was further stirred for 1 hr at 100 °C to 105 °C. After completion of reaction, the reaction mixture was cooled to 60°C and to it was added sodium hydroxide (58.1 g, 1452 mmol) and water (500 mL). The resultant reaction mixture was stirred at the same temperature for 2-3 hrs. After completion of reaction, reaction mixture was cooled and pH was adjusted 7 to 7.5 by using conc. HCl. Then methanol (100 mL) was added and stirred for 30 min. The formed precipitate was filtered and dried to afford the title product (Yield: 100 g, HPLC purity >96 %).

Example 4: Preparation of 4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid (Formula II)
A mixture of 3-guanidino-4-methylbenzoic acid (100 g, 517.5 mmol), (Z)-3-dimethylamino-1-pyridin-3-yl-propenone (118.5 g, 672.5 mmol), potassium carbonate (90 g, 651.2 mmol) and N,N-dimethylformamide (DMF, 1500 mL) was heated for 5 to 6 hrs at 140 °C. After completion of reaction, DMF was distilled out under reduced pressure below 70 °C. The obtained mass was degassed for 1 hr and then cooled to ambient temperature. Acetone was added to the crude residue and stirred for 2 hrs at ambient temperature. Then it was cooled and the solid was filtered. The obtained solid was again dissolved in water (100 mL) and pH was adjusted 6.5 to 7 by using 2N HCl solution. The resultant suspension was cooled and filtered to obtain the solid. The solid was again washed with prechilled acetone then water and dried under vacuum to obtain the title product (Yield: 135 g, HPLC purity >99%).

Example 5: Preparation of 4-methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1H-imidazole (Formula VIII)
In three neck round bottom flask fitted with condenser were added 4-methylimidazole (100 g, 1.21 mol) and 1-fluoro-3-nitro-5-trifluoromethyl-benzene (100 g, 0.48 mol). The mixture was gradually heated at 120-130 °C for 10 to 15 hrs. After completion of reaction, the reaction mixture was cooled to 80-90 °C. Water (1000 mL) was added at the same temperature. Further the whole mass was cooled to 35-40°C and product was extracted with toluene (500 mL X 2). Combined organic layers were washed with water (300 mL X 2). Toluene layer was distilled out under reduced pressure to give the crude product (120 g, HPLC: 70.6 % desired isomer & 22.5 % undesired isomer). The crude product was purified by charcolization and recrystallization using diisopropyl ether. The obtained product was further dried in air oven to obtain 60.5 g of the title product (Yield: 46.5 % , HPLC: 98.2 % desired isomer,0.8 % undesired isomer).

Example 6: Prepration of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) aniline (Formula III)
A mixture of 4-methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1H-imidazole (60 g, 0.22 mol), acetic acid (180 mL) and water (420 mL) was hydrogenated in an autoclave at 60-65 °C and 4-5 bar hydrogen pressure for 5-6 hrs in presence of palladium on carbon (6 g, 5% on carbon, 50% wet). After completion of reaction, the reaction mixture was filtered over hyflo bed and washed with water (360 mL). Aq. ammonia (240 mL) was added to the filtrate to form a suspension. The suspension was stirred for 1 hr then filtered, washed with water and dried at 50-55°C to give crude 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (45 g,Yield: 84%). The 40 g of the crude product was purified by charcolization and recrystallization from diisopropyl ether. The obtained product was further dried in air oven to obtain 31 g of the title product (HPLC purity: 99.65 %).

Example 7: Preparation of Nilotinib
In three neck round bottom flask fitted with condenser were added 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidiny]amino] benzoic acid (250 g, 0.816 mol), N-methyl-2-pyrrolidone (1250 mL) and stirred for 15 min. The mixture was heated to 60-65°C. Thionyl chloride (78 mL,1.068 mol) was added slowly at 60-70°C and stirred for 60 min. A solution of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (216.2 g, 0.896 mol) in N-methyl-2-pyrrolidone (250 mL) was then added slowly into the reaction mixture at 60-70 °C and the resultant reaction mixture was heated to 90-95 °C for 2-3 hrs. After complition of reaction, water (1875 mL) was added to reaction mixture below 90 °C. The whole content was cooled to 50 °C and caustic lye (about 370 mL) was added to achieve pH above 11 then stirred at 40-50 °C for 15-30 min. Solid formed was filtered, washed with water and dried to afford crude product. The crude product was purified by crystallization using mixture of N-methyl-2-pyrrolidone and methanol (Yield: 243 g, HPLC purity: 99.54 %; Impurity of Formula X: Not detected; Impurity of Formula XI: Not detected).

Nilotinib was analysed by the HPLC method as described below:
Mobile phase: Mobile phase A- buffer solution: acetonitrile (900:100); Mobile phase B- buffer solution: acetonitrile (300:700).

Buffer Solution: It was prepared by dissolving potassium dihydrogen orthophosphate (3.4 g) in 1000 mL of water, and adjusting the pH to 3.0 ± 0.05 with orthophosphoric acid.

Diluent: 0.1 N Hydrochloric acid in water.
Blank preparation: 1.0 mL of methanol in 10 mL and dilute upto mark with diluent.
Sample preparation:
Accurately weighted 10 mg of sample was transferred in 100 mL volumetric flask. 10 mL of methanol and 25 mL diluent was added, sonicated to dissolve and diluted up to the mark with diluent.

Instrumental conditions:
A suitable High performance liquid chromatograph (HPLC) with the following conditions.

Column YMC Pack ODS AM, (250x 4.6) mm, 5µ, 12nm
Make : YMC
Flow rate 1.0 mL/min.
Wavelength 225 nm
Column temperature 35°C
Injection volume 30 µL
Run time 60 min.
Sample temperature 10°C

Gradient Programme:

Time (Min) % Mobile phase A % Mobile phase B
0 70 30
30 45 55
50 30 70
55 30 70
55.1 70 30
60 70 30

Calculation of related substance was carried out by area normalization.

Example 8: Preparation of 4-methyl-3-[[4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]benzoyl]amino]benzoic acid (Impurity of Formula X)
In three neck round bottom flask fitted with condenser were added 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidiny]amino]benzoic acid (20 g, 0.652 mol), N-methyl-2-pyrrolidone ( 120 mL) and stirred for 15 min. The mixture was heated to 60-70 °C and thionyl chloride (6.9 mL, 0.094 mol) was slowly added at 60-70 °C and stirred for 60 min. Then a solution of methyl 3-amino- 4-methylbenzoate (16 g, 0.065 mol) in N-methyl-2-pyrrolidone (30 mL) was added slowly in to the reaction mixture at 60-70 °C and the resultant reaction mixture was heated to 90-95 °C for 2-3 hrs. Progress of reaction was monitored by TLC. After completion of reaction, water (160 mL) was added slowly in to reaction mixture below 70 °C. Content was cooled to 50 °C and caustic lye solution (about 24 mL) was added to adjust pH around 7 then stirred at 50-55 °C. The formed suspension was filtered, washed with water (50 mL X 2) and dried to get 21 g of methyl ester intermediate. The dried intermediate (15 g) and N-methyl-2-pyrrolidone (75 mL) were added in three neck round bottom flask fitted with condenser. A solution of sodium hydroxide (2.7 g) in water (75 mL) was added to the above suspension and the whole reaction mixture was heated to 85-90 °C for 2-3 hrs. Progress of reaction was monitored by TLC. After completion, the reaction mass was cooled to 25-30 °C and ~2N aq. HCl was added to adjust pH between 6.0-6.5 to form the precipitate. The precipitate was filtered out, washed with water and dried to get the title compound.
1H NMR (500 MHz, DMSO-d6) d 2.36 (s,3H), 2.42 (s,3H), 7.43-7.56 (m,4H), 7.79-7.83 (m,2H), 8.03 (d,1H), 8.40(d,1H), 8.47-8.49 (m,1H), 8.60 (d,1H), 8.73-8.74 (m,1H), 9.11 (s ,1H), 9.33 (d,1H), 9.96 (br s,1H).
LC-MS (Direct mass): m/z :439.88.

Example 9: Preparation of 4-methyl-N-[2-methyl-5-[[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]carbamoyl]phenyl]-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]benzamide (Impurity of Formula XI)
In three neck round bottom flask fitted with condenser were added impurity of Formula X (5 g, 0.0113 mol), N-methyl-2-pyrrolidone (25 mL) and stirred for 15 min. The mixture was heated to 50 °C and thionyl chloride (1.5 mL,0.0205 mol) was slowly added at 50-55 °C and stirred for 60 min at 60-65 °C. Then a solution of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (3 g, 0.0124 mol) in N-methyl-2-pyrrolidone (5 mL) was added slowly in to reaction mixture and the resultant reaction mixture was heated to 85-90 °C for 2 hrs. Progress of reaction was monitored by TLC. After completion of reaction, reaction mass was cooled to 50 °C. Water (75 mL) was added followed by caustic lye (about 370 mL) to achieve pH above 11 and then stirred at 40-50 °C. Solid formed was filtered, washed with water and dried to get crude product. The crude product was purified by crystallization using methanol to afford the title compound.
1H NMR (500MHz, DMSO-d6) d 2.23 (s,3H), 2.38 (s,3H), 2.41 (s,3H), 7.48 (d,1H),7.53-7.58 (m,4H),7.78 (s,1H), 7.83 (d,1H), 7.90 (d,1H), 8.07 (s,1H), 8.22 (s,1H), 8.26 (s,1H), 8.37(d,2H), 8.49 (d,1H), 8.60 (d,1H), 8.72 (d,1H), 9.22 (s,1H), 9.33 (s,1H), 10.10 (s,1H),10.72 (s,1H)
LC-MS (Direct mass): m/z: 660.78 (as M-H).

,CLAIMS:We Claim:
1. A process for the preparation of nilotinib,

comprising:
(a) reacting a compound of Formula VII

wherein R is C1-C3 alkyl;
with cyanamide in water in presence of an acid to form a compound of Formula VI

wherein R is C1-C3 alkyl;
(b) hydrolysing the compound of Formula VI by adding a base into the reaction mixture of step a to obtain a compound of Formula V

(c) reacting the compound of Formula V with a compound of Formula IV

in presence of a base to obtain a compound of Formula II
, and
(d) reacting the compound of Formula II with a compound of Formula III

to obtain nilotinib.

2. The process as claimed in claim 1, wherein the acid in step a is hydrochloric acid and the base in step b is sodium hydroxide.

3. The process as claimed in claim 1, wherein the base in step c is selected from a group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert-butoxide or sodium tert-butoxide.

4. The process as claimed in claim 1, wherein the compound of Formula III is prepared by a process comprising:
(a) heating a mixture comprising a compound of Formula IX

wherein L is a leaving group, and 4-methylimidazole to obtain a compound of Formula VIII
, and
(b) reducing the compound of Formula VIII to obtain the compound of Formula III.

5. The process as claimed in claim 4, wherein L is fluoro.

6. Nilotinib obtained by the process as claimed in claim 1, wherein nilotinib is free of impurity of compound of Formula X

7. Nilotinib obtained by the process as claimed in claim 1, wherein nilotinib is free of impurity of compound of Formula XI