DESC:FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]

PROCESS FOR SYNTHESIS OF INTERMEDIATES OF NILOTINIB AND NILOTINIB;

AARTI INDUSTRIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ADDRESS AT 71, UDYOG KSHETRA, 2ND FLOOR, MULUND GOREGAON, LINK ROAD, MULUND (W),
MUMBAI, 400080, MAHARASHTRA, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

Field of the Invention
The present invention relates to a process for the synthesis of intermediates of nilotinib, nilotinib or pharmaceutically acceptable salts thereof.
Background of the invention
Nilotinib is a synthetic aminopyrimidine, chemically known as 4-methyl-3-4-(3- pyridinyl)-2-pyrimidinylamino-N-5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenylbenzamide. It is expected to be the second-generation tyrosine kinase inhibitor and used in the treatment of chronic myelogenous leukemia (CML). Nilotinib is especially effective in imatinib-resistant patients. It is structurally represented as below.

a) Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid of formula (A) is a key intermediate required for the synthesis of Nilotinib. As a result, yield and cost of 4-methyl-3-[[4-(3-pyridyl) pyrimidin-2-yl]amino]benzoic acid ester of formula (IV), and acid addition salt of 3-guanidino-4-methyl-benzoic acid ester of formula (II) is also important, as it directly contributes to the synthesis of formula (A).

There are processes in art that disclose the preparation of compound of formulae (A), (IV) and (II). The process for the preparation of nilotinib was first reported in US 7,169,791, as shown in scheme 1 below.
Scheme 1
The process comprises reacting 3-amino-4-methylbenzoic acid ethyl ester with cyanamide in ethanol. Hydrochloric acid was added drop wise to the mixture, stirred for 15 minutes and solvent was evaporated under reduced pressure. Aqueous solution of ammonium nitrate was added to the reaction mass with cooling at 5°C-10°C to yield 3-[(Aminoiminomethyl)amino]-4-methyl-benzoic acid ethyl ester mononitrate. The salt was treated with sodium hydroxide in ethanol and refluxed for 68 hours. The solvent was evaporated to isolate 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-benzoic acid ethyl ester. The ester was hydrolyzed to 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid using aqueous sodium hydroxide in an alcoholic solvent. The intermediate was further converted to nilotinib. In case of the above disclosed process, the time required for guanidine salt preparation was about 15-16 hours. The time required for the preparation of 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-benzoic acid ethyl ester was 68 hours. Thus, overall time required for the reaction in the known processes is very high, which makes the process unsuitable on a plant scale.

WO2008058037 reports hydrolysis of 3-(4-(pyridin-3-yl) pyrimidin-2-ylamino)-4-methylbenzoic acid methyl ester using sodium hydroxide in butanol. Further, WO2010009402 discloses a process that involves reaction of 4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl] amino}benzoic acid with 5-trifluorome yl-3-[4-memyl-Hl-imidazolyl]aniline in the presence of thionyl chloride in N-methylpyrrolidine solvent to provide nilotinib. In this process, thionylchloride is highly reactive and makes it difficult to handle and difficult for a commercial scale production.

CN103288804 discloses a process for the preparation of nilotinib, which involves the condensation of 4-methyl-3-{[4-(pyridin-3-yl) pyrimidin- 2-yl] amino} benzoic acid with 5-trifluoromethyl-3-[4-methyl-Hl-imidazolyl] aniline in the presence of (Benzotriazol-l-yloxy)tris(dimethylamino) phosphonium hexafluoro phosphate (BOP) and l,8-Diazabicyclo[5.4.0]undec-7-ene in dimethylformamide. However, the use of BOP reagent is not recommended because of the coupling reactions that uses BOP thereby liberating HMPA (Hexamethylphosphoramide) which is carcinogenic and therefore not suitable for industrial scale operations.
Further, Organic & Biomolecular Chemistry,7(24), 5129-5136; 2009 reports hydrolysis of 3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylbenzoic acid methyl ester using lithium hydroxide in methanol and water. Medicinal Chemistry, 8(5), 985-989; 2012 reports coupling of 3-guanidino-4-methyl nitrate ethyl benzoate with 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in presence of sodium hydroxide in n-butanol to form 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl] amino] benzoic acid ethyl ester. Hydrolysis of 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl] amino] benzoic acid ethyl ester using aqueous sodium hydroxide in 1,2-dimethoxyethane is reported.
Further problems that can be involved in the conventionally known processes include number of operations like extraction, azeotropic distillation and washings for isolation of intermediates, usage of expensive reagent like diethylcyanophosphonate; and yields and purity of nilotinib obtained by said processes are low and inconsistent and requires repeated extractions for isolation of the same, thereby making the processes unsuitable for commercial scale production. Most of the known processes report coupling of 3-guanidino-4-methyl nitrate ethyl benzoate with 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in presence of alkali metal hydroxide in an alcoholic solvent. The reaction is particularly carried out in the presence of sodium hydroxide in ethanol or n-butanol. The time required for the reaction is around 24 hours and yield is around 60%.
Most of the known processes report hydrolysis step in alcoholic solvent. It is observed that use of alcohol in the process results in the formation of the product 4-methyl-3-[[4-(3-pyridyl) -2-pyrim idinyl]amino]benzoic acid with very fine particle size. This poses problem during work up, resulting in much higher time required for filtration hence isolation of acid becomes troublesome at a higher scale.
Accordingly, there exists a need for an improved process for the preparation of intermediates of nilotinib that involves a reduced reaction time, that avoids usage of alcoholic solvent in hydrolysis and provides better yield with higher purity.
Summary of the invention
An aspect of the invention discloses a process for preparation of an intermediate of nilotinib, 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]benzoic acid of formula (A). The process comprises of reacting an amine of formula (I) with cyanamide in the presence of an acid to obtain an acid addition salt of 3-guanidino-4-methyl-benzoic acid ester of formula (II), which is coupled with 3-(dimethylamino)-1-(3-pyridyl)prop-2-en-1-one of Formula (III) in the presence of a first base and a solvent to obtain a compound of formula (IV). Compound of Formula IV on hydrolysis in the presence of a second base in an aqueous medium results in compound of Formula (A).


An aspect of the present invention discloses a process to prepare compounds of Formula (II) and Formula (IV).
Another aspect of the invention encompasses a process to prepare nilotinib or its pharmaceutically acceptable salts.
Detailed description of the invention
All materials used herein were commercially purchased or prepared from commercially purchased materials as described herein.
As used in the specification the singular forms "a" "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a solvent" includes mixtures of solvents, reference to "a reagent" includes mixtures of two or more such reagents, and the like.
As used in the specification, the phrase “alternate lots” means cyanamide and acid are added in at least two alternate lots.
An embodiment of the present invention provides a process for the preparation of 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]benzoic acid of formula (A) or pharmaceutically acceptable salts thereof.

The process comprises the steps of:
reacting an amine of formula (I) with cyanamide in presence of an acid to obtain an acid addition salt of 3-guanidino-4-methyl-benzoic acid ester of formula (II);

wherein R1 is substituted or unsubstituted lower alkyl such as methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, t-butyl, phenyl, preferably alkyl group is substituted by phenyl, substituted or unsubstituted phenyl, preferably the phenyl group is substituted by a halo, nitro, lower alkyl group such as methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, t-butyl, X is -NO3-, -SO4- and -Cl-,
coupling compound of formula (II) with 3-(dimethylamino)-1-(3-pyridyl)prop-2-en-1-one of Formula (III) in the presence of a first base and a solvent to obtain compound of formula (IV); and

hydrolyzing the compound of formula (IV) in the presence of a second base in an aqueous medium to obtain compound of formula (A).

The acid is selected from nitric acid, sulfuric acid and hydrochloric acid.
Cyanamide is added in a range of 2.5 to 4 equivalent and acid is added in a range of 1 to 2.1 equivalent.
Cyanamide and acid are added in alternate lots, preferably in at least two lots such that the first lot of cyanamide is added in a range of 1 to 3 equivalent and a first lot of acid is added in a range of 0.8 to 1.3 equivalent to obtain a reaction mixture. Said reaction mixture is maintained for 3 to 5 hours at 65°C-75°C, and a second lot of cyanamide and acid is added in the same range as the first lot to the above reaction mixture. Alternatively, cyanamide (2.5-4 equivalents) is added in a single lot followed by gradual and continuous addition of 1.3 to 2.1 equivalent of the acid over a time period of 1-3 hours.
It has been found that the mode of addition of cyanamide and acid plays an important role in the complete conversion of the reaction. It has been observed that when cyanamide and acid are added in a single lot as reported in prior art, degradation of cyanamide occurs. In conventional processes, the product 3-guanidino-4-methyl-benzoic acid ester of formula (II) also degrades when in contact with cyanamide for a longer time resulting in impurity formation and yield loss. Thus, reaction does not show complete conversion even after excess addition of cyanamide. As per the present invention, addition of cyanamide and acid in alternate lots or addition of cyanamide and gradual and continuous addition of the acid over a prolonged time period results in maximum reaction conversion in lesser time thus providing high yield of the product.
The compound of Formula I is reacted with cyanamide and acid in a solvent, preferably an alcohol having 1-4 carbon atoms such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol and tert-butanol.
The reaction to form compound of Formula (II) is carried out at a temperature in a range of 50°C-85°C, preferably at 60°C-70°C.
The reaction to form compound of Formula (IV) is carried out at a temperature in a range of 100°C-140°C, preferably at 110°-130°C, most preferably at 120°C-125°C. It has been found that the choice of first base aids in the formation and subsequently isolation of pure ester of formula (IV).
The hydrolysis reaction to obtain compound of Formula (A) is carried out at 45°C-90°C, preferably at 50°-80°C, most preferably at 60°-70°C. The reaction is carried out in an aqueous medium.
The first base is selected from the group comprising of metal carbonate, metal bicarbonate and organic base.
The solvent used in the reaction to form compound of formula (IV) is selected from N, N-dimethyl acetamide, N-methyl pyrrolidone, dimethyl formamide and dimethyl sulfoxide.
The metal carbonate is selected from sodium carbonate, potassium carbonate, lithium carbonate, caesium carbonate, calcium carbonate, barium carbonate, magnesium carbonate or mixtures thereof.
The metal bicarbonate is selected from sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, caesium bicarbonate, calcium bicarbonate, barium bicarbonate, magnesium bicarbonate or mixtures thereof.
The organic base is selected from di-isopropyl ethylamine and triethylamine.
The second base is selected from the group comprising of metal hydroxide, metal alkoxide and alkali metal carbonate.
The metal hydroxide is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, caesium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide or mixtures thereof.
The metal alkoxide is selected from sodium alkoxides, potassium alkoxides, lithium alkoxides, caesium alkoxides, calcium alkoxides, barium alkoxides, magnesium alkoxides or mixtures thereof. Alkoxides such as methoxide, ethoxide, iso-propoxide, n-butoxide, tert-butoxide are used.
The metal carbonate is selected from sodium carbonate, potassium carbonate, lithium carbonate, caesium carbonate, calcium carbonate, barium carbonate, magnesium carbonate or mixtures thereof.
Preferably, the compound of formula (IV) is purified by crystallization. The solvent used for the crystallization is selected from ethyl acetate, isopropyl alcohol, acetone, isopropyl acetate, diiospropyl ether (DIPE), toluene, methanol, ethanol and acetonitrile. Traces of genotoxic impurities such as methyl-3-amino-4-methyl-benzoate and ethyl-3-amino-4-methyl-benzoate are efficiently removed by crystallization.
In an embodiment, the present invention provides a process for preparation of an acid addition salt of 3-guanidino-4-methyl-benzoic acid ester of formula (II). The process comprises of reacting an amine of formula (I) with cyanamide in the presence of an acid,

wherein R1 is substituted or unsubstituted lower alkyl such as methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, t-butyl, phenyl, preferably alkyl group is substituted by phenyl, substituted or unsubstituted phenyl, preferably the phenyl group is substituted by a halo, nitro, lower alkyl group such as methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, t-butyl, X is -NO3-, -SO4- and -Cl-,
The acid is selected from nitric acid, sulfuric acid and hydrochloric acid.
Cyanamide and acid are added in alternate lots, preferably in at least 2 lots such that the first lot of cyanamide is added in a range of 1 to 3 equivalent and a first lot of acid is added in a range of 0.8 to 1.3 equivalent to obtain a reaction mixture. Said reaction mixture is maintained for 3 to 5 hours at 65°C-75°C, and a second lot of cyanamide and acid is added in the same range as the first lot to the above reaction mixture. Alternatively, cyanamide (2.5-4 equivalents) is added in a single lot followed by gradual and continuous addition of 1.3 to 2.1 equivalent of the acid over a time period of 1-3 hours.
The compound of Formula I is reacted with cyanamide and acid in a solvent, preferably an alcohol having 1-4 carbon atoms. The reaction is carried out at a temperature in a range of 50°C-85°C, preferably at 60°C-70°C.
In an embodiment, the present invention relates to a process for preparing 4-methyl-3-[[4-(3-pyridyl) pyrimidin-2-yl]amino]benzoic acid ester of formula (IV). The process comprises of coupling an acid addition salt of 3-guanidino-4-methyl-benzoic acid ester of formula (II) with 3-(dimethylamino)-1-(3-pyridyl)prop-2-en-1-one of formula (III).
The reaction is carried out in the presence of a first base and a solvent.
The reaction is carried out at 100°C-140°C, preferably at 110°C-130°C, most preferably at 120°C-125°C.

wherein R1 is substituted or unsubstituted lower alkyl such as methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, t-butyl, phenyl, preferably alkyl group is substituted by phenyl, substituted or unsubstituted phenyl, preferably the phenyl group is substituted by a halo, nitro, lower alkyl group such as methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, t-butyl, X is -NO3-, -SO4- and -Cl-,
The first base is selected from metal carbonates, metal bicarbonates and organic bases.
The solvent is selected from N, N-dimethyl acetamide, N-methyl pyrrolidone, dimethyl formamide and dimethyl sulfoxide.
The metal carbonate is selected from sodium carbonate, potassium carbonate, lithium carbonate, caesium carbonate, calcium carbonate, barium carbonate, magnesium carbonate, or mixtures thereof.
The metal bicarbonate is selected from sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, caesium bicarbonate, calcium bicarbonate, barium bicarbonate, magnesium bicarbonate or mixtures thereof.
The organic base is selected from di-isopropyl ethylamine and triethylamine.
In an embodiment, the present invention relates to a process for preparing Nilotinib of formula (B) or its pharmaceutically acceptable salts. The process comprises the steps of:
charging 4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl] amino}benzoic acid of formula (A) with 3-(trifluoromethyl)-5-(4-methyl-lH-imidazol-1-yl)benzenamine and N-methyl-pyrrolidone.

The improved process of the present invention for the preparation of 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]benzoic acid of formula (A) advantageously lowers the overall time required for the reaction. The process is eco-friendly, cost effective and industrially feasible. Further, said process provides easy work up, reduces the time required for isolation and hence easy to operate on a higher scale. The process also provides higher yields of the products in reduced time.
EXAMPLES
The following examples illustrate the invention and are not limiting thereof.
Comparative Example 1
Preparation of ethyl 3-guanidino-4-methyl-benzoate nitrate salt (single lot addition).
Ethyl 3-amino-4-methyl-benzoate (100 g) was added to ethanol (500 ml) at room temperature. 50% cyanamide (140.75 ml) was charged to the ester solution followed by addition of 69% nitric acid (50.72 ml). The reaction mixture was heated for 24 hours under reflux. The reaction mass was cooled to room temperature and filtered. The solid was washed with water, ether and dried to give ethyl 3-guanidino-4-methyl-benzoate nitrate salt (45 g, yield: 28.36%).
Example 2
Preparation of ethyl 3-guanidino-4-methyl-benzoate nitrate salt (lot wise addition) (Formula II).
Ethanol (150 ml) was added to ethyl 3-amino-4-methyl-benzoate (50 g) at room temperature. 50% cyanamide (47 ml) was charged to the ester solution and the reaction mixture was stirred for 15 minutes. The mass was warmed to 50°C-55°C and 69% nitric acid (28 ml) was added dropwise at 50°-55°C over 30 minutes. The reaction mass was stirred for 3 hours.
Second lot of cyanamide (23.5 ml) was added to the reaction mass followed by dropwise addition of a second lot of nitric acid (8.8 ml) at 60°C-65°C with constant stirring over 15 minutes. The mass was further stirred for 3 hours and temperature was raised to 70°C-75°C. Heating was stopped and stirring was continued for 1-2 hours at room temperature. The mass was cooled to 0°C-10°C and cyclohexane (150 ml) was added. The mixture was cooled to around 5°-10°C, the slurry was filtered and washed with cyclohexane (50 ml). The solid obtained was dried to obtain ethyl 3-guanidino-4-methyl-benzoate nitrate salt (68 gm; 85.71%).
Example 3
Preparation of ethyl 3-guanidino-4-methyl-benzoate nitrate salt (lot wise addition) (Formula II)
To a solution of ethyl 3-amino-4-methyl-benzoate (20 g) in ethanol, 69% nitric acid (10.59 ml) was added dropwise over 30 minutes. 50% cyanamide solution (30 ml) was added dropwise over 15 minutes to the reaction mixture. The temperature was raised to 60°C-65°C and stirred for 3 hours. Second lot of 69% nitric acid (10.59 ml) was added dropwise followed by addition of a second lot of cyanamide (10 ml). The mixture was further stirred for 4 hours at 60°C-65°C. The mass was cooled to 5°C-10°C and stirred for 1 hour to obtain a slurry. The slurry was filtered under reduced pressure, washed with ether (100 ml) to give the title compound as a solid (22gm, yield: 69.35%).
Example 4
Preparation of ethyl 3-guanidino-4-methyl-benzoate sulfate salt (lot wise addition) (Formula II)
To a solution of ethyl 3-amino-4-methyl-benzoate (25 g) in ethanol (75 ml), 50% cyanamide (23.44 ml) was added dropwise. 50% Sulfuric acid (7.4 ml) was slowly charged to the mixture over 15 minutes. The mixture was stirred for 6 hours and second lot of 50% cyanamide (23.44 ml) was added dropwise followed by addition of second lot of 50% sulfuric acid (7.4 ml). Reaction mixture was stirred for 2 hours at 60°C-65°C. Diisopropyl ether (75 ml) was added to the mass obtained, cooled to 0°C-5°C and stirred for 1 hour. The slurry obtained was filtered under reduced pressure, washed with Diisopropyl ether (25 ml) to give the title compound (27 g, 60% yield).
Example 5
Preparation of ethyl 3-guanidino-4-methyl-benzoate nitrate salt (Gradual, continuous and prolonged addition) (Formula II).
Ethyl 3-amino-4-methyl-benzoate (500 g) was added to methanol (1000 ml) at room temperature. The reaction mixture was then heated to around 50°C-550C, Cyanamide (784 ml) was then charged to the ester solution followed by the dropwise addition of 69% Nitric acid (300 ml) over 2-3 hours. The reaction mixture was maintained between 70°C-750C for 3-4 hours. The reaction mass was cooled to room temperature and then maintained at temperature between 0°C-5°C for 1.5-2 hours and filtered. The solid was washed with chilled methanol:water mixture, dried to afford ethyl-3-guanidino-4- methyl-benzoate nitrate salt (675 g, yield, 85.51%).
Example 6
Preparation of ethyl 3-guanidino-4-methyl-benzoate HCL salt (Gradual, continuous and prolonged addition) (Formula II)
To a solution of ethyl 3-amino-4-methyl-benzoate (25 g) in ethanol (250 ml), 50% cyanamide (35 ml) was added dropwise. 35% HCl (18 ml) was slowly charged to the reaction mixture over 15 minutes. The mixture was stirred for 12 hours at 80°C-85°C temperature. The reaction mixture was cooled to room temperature and concentrated under vacuum. The semisolid obtained was stripped using toluene (100 ml). The remaining solvent was decanted to give the title compound (20 g, 55% ).
Example 7
Preparation of ethyl 4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]benzoate (Formula IV).
Potassium bicarbonate (79.16 gm,1.26 mol) in N, N-Dimethylacetamide (225 ml) was added to 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (119 gm, 0.67 mol), ethyl 3-guanidino-4-methyl-benzoate nitrate salt as prepared in example 2 (150 gm, 0.57 mol) and heated at 120°C-125°C for 6 to 8 hours. Water (1200 ml) was added to the reaction mixture at 0°C-10°C. The reaction mass was cooled to room temperature and stirred for 2 hours. The mass was filtered under reduced pressure and washed with water (450 ml) to give the title compound as a solid (140 gm, yield 80.45%).
Example 8
Preparation of ethyl 4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]benzoate (Formula IV).
Potassium bicarbonate (262.5 g,2.62 mol) in N, N-Dimethylacetamide (750 ml) was added to a mixture of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (403g,2.28mol), ethyl 3-guanidino-4-methyl-benzoate nitrate salt as prepared in example 2 (500 gm, 1.75 mol) and heated to around 120°C-125°C for 6 to 8 hours. Water (7000 ml) was added to the reaction mixture between 0°C-10°C. The reaction mass was then cooled to room temperature and stirred for 2 hours. The reaction mass was filtered under reduced pressure and washed with water (500 ml) to afford the compound as a solid, followed by crystallization using acetone gave title compound (470 g, yield 79.98%).
Example 9
Preparation of 4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]benzoic acid (formula A).
Water (1.12 L) was charged to ethyl 4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino] benzoate (140 g, 0.42 mol) as isolated in example 7. 30% solution of sodium hydroxide was added dropwise over 15 minutes to the reaction mixture. The mixture was stirred and heated at 60°C-70°C for 5 to 6 hours. Conc. HCl was added to the mass and heated to about 80°C-90°C for 3 hours. The reaction mass was filtered under reduced pressure at 50°C, washed with water (280 ml) followed by washing with acetone (280 ml). The compound was dried under vacuum at 50°C to obtain title compound (120 gm, yield 93.55%, HPLC purity ~99.77%).
Example 10
Preparation of 4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]benzoic acid (formula A).
Sodium hydroxide (36 gm 0.90 mole) was added to water (1750 ml) followed by ethyl 4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino] benzoate (250 g, 0.748 mol) as isolated in example 8. The mixture was stirred and heated between 60-70°C for 5 to 6 hours. Conc. HCl was then added to the mass and heated to about 80°C-90°C for 3 hours. The reaction mass was filtered under reduced pressure at 50°C,washed with water (280 ml) followed by washing with acetone (280 ml). The compound was dried under vacuum at 70°C to obtain the title compound (220 g, yield: 96.05%).
Example 11
Preparation of Nilotinib
(trifluoromethyl)-5-(4-methyl-lH-imidazol-1-yl)benzenamine (76 g, 0.32 mol) and N-Methyl-pyrrolidone (850 ml) was charged to 4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl] amino}benzoic acid of Formula A (100g, 0.33 mol). Thionyl chloride (124.5 ml, 0.33 mol) was added dropwise to the reaction mixture over 15 minutes. The reaction mixture was stirred and heated at 90°C for 3 hours. pH of the reaction mixture was adjusted to 11-12 using 20% sodium hydroxide solution and cooled to 50°C-55°C.
Stirring was continued for 1 hour to obtain a thick slurry. The slurry was filtered, washed with water (500 ml) to obtain beige solid. The solid was again slurried in water (1 L) at 40°C-50°C and stirred for 5 hours. The compound was filtered, washed with water followed by washing with acetone. The precipitate was dried under vacuum at 50°C to obtain Nilotinib base (150 gm, yield: 86.67%). HPLC purity was 98.91%.
Example 12
Preparation of Nilotinib hydrochloride
HCl solution (4 N in ethanol, 50 ml) was added dropwise, to the solution of Nilotinib base (100 g) in absolute ethanol (1000 ml) at room temperature. The resulting slurry was heated to reflux. The mixture was maintained at reflux for 1 hour. The mixture was cooled slowly to room temperature. The solid of Nilotinib hydrochloride precipitated out was separated by filtration. The solid was washed with absolute ethanol (500ml). Nilotinib hydrochloride was suck dried and further dried overnight at 70°C under vacuum (Dry weight obtained 87g, 82% ), HPLC purity: 99.84%.
As can be seen from the above examples, the process of the present invention results in higher yield of the compounds.
The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.
,CLAIMS:We Claim:
1. A process for preparing an intermediate of nilotinib of formula A, the process comprising:
reacting an amine of formula (I) with cyanamide in presence of an acid to obtain an acid addition salt of 3-guanidino-4-methyl-benzoic acid ester of formula (II);

wherein, R1 is substituted or unsubstituted lower alkyl such as methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, t-butyl, phenyl, preferably alkyl group is substituted by phenyl, substituted or unsubstituted phenyl, preferably the phenyl group is substituted by a halo, nitro, lower alkyl group such as methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, t-butyl, X is -NO3-, -SO4- and -Cl-,
coupling compound of formula (II) with compound of formula (III) in presence of a first base and a solvent to obtain a compound of formula (IV);

hydrolyzing the compound of formula (IV) in presence of a second base in an aqueous medium to obtain compound of formula (A).

2. A process for preparing compound of formula (II) as claimed in claim 1, the process comprising reacting an amine of formula (I) with cyanamide in presence of an acid, wherein the cyanamide and the acid are added in alternate lots or cyanamide is added in a single lot followed by gradual and continuous addition of the acid for a prolonged time.

wherein, R1 is substituted or unsubstituted lower alkyl such as methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, t-butyl, phenyl, preferably alkyl group is substituted by phenyl, substituted or unsubstituted phenyl, preferably the phenyl group is substituted by a halo, nitro, lower alkyl group such as methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, t-butyl, X is -NO3-, -SO4- and -Cl-,
3. A process for preparing compound of formula (IV) as claimed in claim 1, the process comprising coupling compound of formula (II) with compound of formula (III) in presence of a first base and a solvent.

wherein, R1 is substituted or unsubstituted lower alkyl such as methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, t-butyl, phenyl, preferably alkyl group is substituted by phenyl, substituted or unsubstituted phenyl, preferably the phenyl group is substituted by a halo, nitro, lower alkyl group such as methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, t-butyl, X is -NO3-, -SO4- and -Cl-,
4. The process as claimed in claim 1 or 2 comprising reacting the compound of Formula I with the compound of Formula II in a solvent selected from an alcohol having 1-4 carbon atoms such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol and tert-butanol.
5. The process as claimed in claim 1 comprising adding cyanamide and acid in alternate lots or adding cyanamide in a single lot followed by gradual and continuous addition of the acid for a prolonged time.
6. The process as claimed in claim 1 or 2 comprising reacting compound of formula
I at a temperature in a range of 50°C-85°C.
7. The process as claimed in claim 1 or 2, wherein the acid is selected from nitric acid, sulfuric acid and hydrochloric acid.
8. The process as claimed in claim 1 or 2, wherein cyanamide is added in a range of 2.5 to 4 equivalent and acid is added in a range of 1.0 to 2.1 equivalent.
9. The process as claimed in claim 1 or 3, wherein the first base is selected from metal carbonate, metal bicarbonate and organic base.
10. The process as claimed in claim 9, wherein
the metal carbonate is selected from sodium carbonate, potassium carbonate, lithium carbonate, caesium carbonate, calcium carbonate, barium carbonate, magnesium carbonate or mixtures thereof,
the metal bicarbonate is selected from sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, caesium bicarbonate, calcium bicarbonate, barium bicarbonate, magnesium bicarbonate or mixtures thereof,
the organic base is selected from di-isopropyl ethylamine and triethylamine.
11. The process as claimed in claim 1 or 3 , wherein the solvent to prepare compound of formula (IV) is selected from N, N-dimethyl acetamide, N-methyl pyrrolidone, dimethyl formamide and dimethyl sulfoxide.
12. The process as claimed in claim 1 or 3 comprising reacting compound of Formula II with compound of Formula III at a temperature in a range of 100°C-140°C.
13. The process as claimed in claim 1 or 3, wherein compound of Formula IV is purified by crystallization using a solvent selected from ethyl acetate, isopropyl alcohol, acetone, isopropyl acetate, diiospropyl ether (DIPE), toluene, methanol, ethanol and acetonitrile.
14. The process as claimed in claim 1 or 3, wherein the second base is selected from a group comprising of metal hydroxide, metal alkoxide and metal carbonate.
15. The process as claimed in claim 14, wherein the metal hydroxide is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, caesium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide or mixtures thereof,
the metal alkoxide is selected from sodium alkoxides, potassium alkoxides, lithium alkoxides, caesium alkoxides, calcium alkoxides, barium alkoxides, magnesium alkoxides or mixtures thereof.
the metal carbonate is selected from sodium carbonate, potassium carbonate, lithium carbonate, caesium carbonate, calcium carbonate, barium carbonate, magnesium carbonate or mixtures thereof.
16. The process as claimed in claim 1, wherein the hydrolysis reaction is carried out at a temperature in a range of 45°C-90°C.
17. A process for preparing Nilotinib of Formula B or its pharmaceutically acceptable salts the process comprising reacting compound of formula (A) prepared by the process as claimed in claim 1 with 3-(trifluoromethyl)-5- (4-methyl-lH-imidazol-1-yl)benzenamine and N-methyl-pyrrolidone.

Dated this 21st day of February, 2019

For AARTI INDUSTRIES LIMITED
By their Agents

(GIRISH VIJAYANAND SHETH) (IN/PA 1022)
KRISHNA & SAURASTRI ASSOCIATES LLP