NOVEL INTERMEDIATES AND AN IMPROVED PROCESS FOR THE PREPARATION OF NILOTINIB EMPLOYING THE SAID INTERMEDIATES
FIELD OF THE INVENTION
This invention relates to an improved process for the preparation of Nilotinib of formula (I)
starting from 3-amino-4-methylbenzoic acid of the formula (II) through novel intermediates
4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl-5-(trifluoromethyl)phenyl]-3-nitro-benzamide of the
formula (III), 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl-5-(trifluoromethyl)phenyl]-3-arnino- benzamide the formula (IV) and 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl-5- (trifluoromethyl)phenyl]-3-guanidino-benzamide of the formula (V). This invention also relates to processes for the preparation of the above said intermediates Nilotinib hydrochloride monohydrate is indicated for the treatment for use in the treatment of chronic phase (CP) and accelerated phase (AP) Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib.

BACKGROUND OF THE INVENTION
The present invention relates to the preparation of novel intermediates and an improved process for the preparation of Nilotinib employing the said intermediates. Hydrochloride salt of

Nilotinib[4-methyl-N[3-(4-methyl-1 H-imidazol-1 -yl-5-(trifluoromethyl)phenyl]-3-{ {4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide prepared by the process of the present invention is a protein tyrosine kinase inhibitor and has the formula (I)
The preparation of Nilotinib[4-methyl-N[3-(4-methyl-l H-imidazol-l-yl-5-
(trifluoromethyl)phenyl]-3-{{4-(3-pyridinyi)-2-pyrimidinyl]amino] benzamide (Nilotinib)of formula (I) and the use thereof especially as an antitumour agent is described in WO patent No. 2004/005281 (Assignee : Novartis Pharma.) which was published on 15'*'january2004
In WO2004/005281 the following route(Scheme-I) is described .


Step-1 : 3-amino-4-methvlbenzoic acid ethyl ester of the formula (VI) ethanol is treated with cyanamide followed by hydrochloric acid to form the hydrochloride salt at reflux temperature

for Ihours. After solvent distillation the residue is treated with water and cooled to 5-10°C. A
solution of aqueous ammonium nitrate is added followed by water. Stirred for 30minutes
filtration yielded
3-[(Aminoiminomethyl)amino]-4-methyl-benzoic acid ethyl ester mononitrate of the formula
(VII).
Step-2 ; 3-r(Aminoiminomethvnaroinol-4-methvl-benzoic acid ethyl ester mononitrate obtained instep 1 is taken in ethanol and treated with3-dimethylamino-l-(3-pyridyl)-2-propen-l-oneof the formula (VIII) and sodium hydroxide and refluxed for 68 hours. The solvent is distilled off and the residue is partitioned between ethyl acetate and water. Organic layer is separated, distilled off under vacuum and crystallized from diethyl ether to yield 4-Methyl-3[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid ethyl ester of the formula(IX)
Step-3 : A suspension of 4-Methyl-3[[4-(3-pyridinyl)-2-pyrimidinyl]amino|-benzoic acid ethyl ester of
the formula (IX) obtained in step 2 is taken in ethanol and water and treated with aqueous sodium hydroxide solution. The reaction mixture is stirred at 45-degC for 2.5hours and treated with aqueous hydrochloride. After addition of water the precipitate is filtered and is isolated from a mixture of toluene and diethyl ether to yield 4-Methyl-3[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-benzoic acid oftheformula(X)
Step-4 : A solution containing 50% of propylphosphonic anhydride in DMF is added to a stirred mixture of 4-Methyl-3[[4-(3-pyridinyl)-2-pyrimidinyl]atnino]-ben2oic acid of the formula(X) obtained in step 3,
5-(4-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)-benzeneamine of the formula (Xl)and triethylamine taken in DMF are stirred at room temperature for 24 hours. The resulting reaction mixture is treated with aqueous ammonium chloride and extracted with ethyl acetate. The solvent is distilled off under vacuum and the residue is crystallized from ethanol-ethyl acetate to yield Nilotinib of the formula I

When we carried out the above process in our laboratory as per the details provided in the above said patent we observed the following difficulties in carrying out the process,.
1. In step 1
(i) The yield of compound of formula (VII) is very low (25-30%) with less purity(90%) (ii)Use of diethylether is not adoptable on conimercial scale production because it is highly flammable and very volatile
2. In step (2)
i. The yield of compound of formula (IX) is low (35%) making the process non economical ii. The Reaction time is very lengthy that is 65 hours, which could be problematic for commercial scale production
iii. Use of diethyl ether is not adoptable on commercial scale production because it is highly flammable and very volatile
3. In step (4)
i) Yield of compound of formula (I) employing the intermediate of formula (XI) is very low (20-30%) thereby making the process uneconomical for commercial production
ii) Usage of the toxic and expensive propylphosphonic anhydride as a reagent makes this process impractical for manufacturing scale operations.
Summary of invention:
Keeping in view of the difficulties in commercialization and applicability for manufacturing scale of the process for the preparation of Nilotinib base disclosed in the above mentioned prior art patent and considering the importance of the drug Nilotinib for the society and health-care industry, we aimed our research work towards developing an industrially feasible and cost effective novel process for the preparation of Nilotinib of formula (I)
Objectives of the present invention
The main objective of the present invention is to provide an improved process for the preparation of Nilotinib base overcoming the difficulties of hitherto known processes.

Accordingly the present invention provides an alternate process for the preparation of Nilotinib (I) which comprises (scheme 2)
(a) Preparing 5-(4-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)-benzeneamine of the formula (XI) by conventional methods
(b) Chlorination of 4-methyl-3-nitro benzoic acid of the formula (II) to get 4-methyl-3-mtro benzoyl chloride of the formula (IIA)
(c) Condensation 5-(4-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)-benzeneamine of the formula (XI) with 4-methyl-3-nitro benzoyl chloride of the formula (IIA) at a temperature range 30-40°C in chlorohydrocarbon solvent with aqueous alkali addition to obtain 4-methyl-N-[3-(4-methyl-lH-imidazol-1 -yl-5-(trifluoromethyl)phenyl]-3-nitro-benzamide of the formula (III)
(d) Reducing compound of formula (III) by refluxing with stannous chloride in methanol for 2 to 3 hours to obtain 4-methyl-N-[3-(4-methyM H-imidazol-1-yl-5-(trifludromethyl)phenyl]-3-amino-benzamide the formula (IV)
(e) Condensing the compound of formula (IV) with cyanamide solution at 90-95''C in n-butanol solvent to obtain 4-methyl-N-[3-(4-methyl-l H-imidazol-1-yl-5-(trifluoromethyl)phenyl]-3-guanidino-benzamide of the formula (V).
(f) Condensing the compound of formula (V) with 3-dimethylamino-l-(3-pyridyl)-2-propen-l-oneof the formula (VIII) in presence of base at reflux temperature to Nilotinib of obtain the formula (I)
According to another feature of the present invention is to provide a process for the preparation of novel 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl-5-(trifluoromethyl)phenylJ-3-nitro-benzamide of the formula (III) which comprises:
• Preparing 5-(4-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)-benzeneamine of the formula (XI) by conventional methods

• Chlorination of 4-methyl-3-nitro benzoic acid of the formula (II) to get 4-methyl-3-nitro
benzoyl chloride of the formula (IIA)
• Condensation 5-(4-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)-benzeneamine of the
formula (XI) with 4-methyl'3-nitro benzoyl chloride of the formula (II A) at a temperature
range 30-40°C in chlorohydrocarbon solvent with aqueous alkali addition to obtain 4-methyl-
N-I3-(4-methyl-lH-imidazol-l-yl-5-(trifluoromethyl)phenyl]-3-nitro-benzamide of the
formula (III)
According to yet another feature of the present invention is to provide a process for the preparation of novel 4-methyl-N-[3-(4-methyl-lH-imida2ol-l-yl-5-(trifluoromethyl)phenyl]-3-aminb-benzamide the formula (IV)
• Preparing 5-(4-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)-ben2eneamine of the formula (XI) by conventional methods
• Chlorination of4-methyl-3-nitro benzoic acid of the formula (11) to get 4-methyl-3-nitro benzoyl chloride of the formula (II A)
• Condensation 5-(4-methyMH-imida2ol-l-yl)-3-(trifluoromethyl)-benzeneamine of the formula (XI) with 4-methyl-3-nitro benzoyl chloride of the formula (IIA) at a temperature range 30-40''C in chlorohydrocarbon solvent with aqueous alkali addition to obtain 4-methyI-N-[3-(4-methyI-1 H-imidazol-1 -yl-5-(trifluoromethyl)phenyl]-3-nitro-benzamide of the formula (III)
• Reducing compound of formula (III) by refluxing with stannous chloride in methanol for 2 to 3 hours to obtain 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl-5-(trif[uoromethyI)phenyl]-3-amino-benzamide the formula (IV)
Still another objective of the present invention is to provide a process for the preparation of novel 4-methyI-N-[3-(4-methyl-lH-imidazol-l-yl-5-(trifluoromethyl)phenyl]-3-guanidino-benzamide of the formula (V). This which comprises:

• Preparing 5-(4-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)-ben2eneamine of the formula (XI) by conventional methods
• Chlorinationof4-methyl-3-nitro benzoic acid ofthe formula (11) to get 4-methyl-3-nitro benzoyl chloride ofthe formula (II A)
• Condensation 5-(4-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)-benzeneamine of the formula (XI) with 4-methyl-3-nitro benzoyl chloride of the formula (IIA) at a temperature range 30-40°C in chlorohydrocarbon solvent with aqueous alkali addition to obtain 4-methyl-N-[3-(4-methyl-1 H-imidazol-1 -yl-5-(trifluoromethyl)phenyl]-3-nitro-benzamide of the formula (III)
• Reducing compound of formula (III) by refluxing with stannous chloride in methanol for 2 to 3 hours to obtain 4-methyl-N-[3-(4-methyl-l H-imidazol-l-yl-5-(trifluoromethyl)phenyl]-3-amino-benzamide the formula (IV)
• Condensing the compound of formula (IV) with cyanamide solution at PO-PS^C in n-butanol solvent to obtain 4-methyl-N-[3-(4-methyl-l H-imidazol-l-yl-5-(trifluoromethyl)phenyl]-3-guanidino-benzamide ofthe formula (V),
The reaction scheme for the preparation of Nilotinib of formula (I) according to the present invention is shown in scheme -2
Scheme -2 Step-1;


In a preferred embodiment of the present invention in step-1 the alkali may be selected from sodium hydroxide (or) potassium hydroxide more preferably potassium hydroxide. This reaction may be conducted in a chlorinated hydrocarbon such as methylene chloride (or) chloroform, more preferably chloroform. The temperature may be in the range 30-40*'C.
The reduction in step-2 may be effected by employing 5 moles of stannous chloride in methanol medium.
The solvent used in step-3 may be n-butanol.
Step-5 of the present invention may be carried by employing sodium hydroxide in the presence
of n-butanol.
The details of the invention are provided in the Example given below which are provided to illustrate the invention only and therefore they should not be construed to limit the scope of the invention
EXAMPLE-1
(a) Preparation of 4-methyl-N-[3-(4-methyI-lH-imidazol-l-yl-5-(trifluoromethyl)phenyl]-3-nitro-benzamide of the formula (III) :
To a suspension of 100g(0,55moles) of 3-amino-4-methylbenzoic acid of the formula (II) in 1L chloroform 131 g( 1.1 Omoles) of thionyl chloride was added. The reaction mass was heated to reflux temperature and maintained at the same temperature for 3hours. Then Chloroform was distilled off completely under vacuum and again 500ml of chloroform was charged and distilled
under vacuum to remove traces of thionyl chloride. The residual 3-amino-4-methylbeiizoyl chloride of the formula (II A) was taken to the following condensation step
133g(0.55moles) of 5-(4-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)-benzeneamine the formula (XI) was dissolved in IL of chloroform. The 4-methyl-3-nitro benzoyl chloride of the formula (IIA) prepared above was added slowly to the reaction mass at 30-35°C for 60minutes. Reaction mass was maintained under stirring for 2hours and filtered. Filtered wet compound was suspended in 2L purified water and 10% aqueous sodium hydroxide was added to the reaction mass to pH 12.0. Reaction mass was filtered and washed with purified water. The filtered compound of formula (III) was dried at SO-SS^C Yield: 150g(67.2%) Purity: 98.5% (by HPLC) MR: 215-220°C IR and NMR were consistent with the proposed structure.
(b) Preparation of 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl-5-(trifluoromethyl)phenyl]-3-
amino-benzamide of the formula (IV): A suspension of 140g (0,34moles) of 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl-5-(trifluoromethyl)phenyl]-3-nitro-benzamide of the formula (III) obtained from step- (a) and 389. Ig (1.73 moles ) stannous chloride in 700ml methanol was refluxed for a period of 60 minutes. The reaction mass was brought to room temperature and poured into 1kg ice. Reaction mass was basified with 20% aqueous sodium hydroxide solution and the product was extracted into Ethyl acetate (2x IL). Ethyl acetate layer was washed with water (2 x 500ml) and distilled off under vacuum . To the residue 500ml of hexane was charged and stirred at room temperature for one hour. The compound of formula (FV) was filtered and dried at 50-60**C under vacuum Yield: 112g (86.4%) Purity: 98.6%(by HPLC) MR: 210-212°C IR and NMR were consistent with the proposed structure.

(c) Preparation of 4-methyl-N-[3-(4-methyl-lH-imida2ol-l-yl-5-(trifluoromethyl)phenyl]-3-
guanidino-benzamide nitrate of the formula (V):
To a suspension of 50g (0.133moles) of 4-me%l-N-[3-(4-methyl-lH-imidazol-l-yl-5-(trifluoromethyl)phenyl]-3-amino-benzamide of the formula (IV) obtained from step-(b) in 500ml n-butanol 8,4g(0.133moles) of concentrated nitric acid was added. A solution of 5.6g (O.133moles) of cyanamide in 6ml water was added and reaction mass was heated to 70-80'*C for 16hours, Solvent was distilled off completely under vacuum and a mixture of 300ml ethyl acetate and 100ml of Isopropyl alcohol was added. The reaction mass was maintained under stirring for 1 hour and the product was filtered. Yield : 25.6g (40%)
IR and NMR were consistent with the proposed structure.
(d) Preparation of Nilotinib of the formula (I):
A mixture of 10g(0.020moles) of 4-methyl-N-t3-(4-methyl-lH-imidazol-l-yl-5-
(trifluoromethyl)phenyl]-3-guanidino-benzamide nitrate from step- (c), 3.65g(0.02moles) of 3-
dimethylamino-l-(3-pyridyl)-2-propen-l-oneofthe formula (VIII) and 0.83g (0.020 moles )
of sodium hydroxide flakes in 100 ml n-butanol was heated at 110-120°C for 7 hours . Reaction
mass was brought to room temperature and the separated solid was filtered off. Filtrate was
concentrated voider vacuum to 30ml and stirred for 2hours at room temperature. The separated
solid of formula(I) was filtered and dried at 60-65*'C under vacuum
Yield :5.5g (55%)
MR:235-236°C
Purity : 99.0% (by HPLC)
IR and NMR were consistent with the proposed structure.

The following are the Advantages of the present invention:
1. Yields realized are fairly high in all the steps (40-87%) as compared to 20-50% realized by the process disclosed in the prior art(WO2004/005281) .
2. Reaction times are fairly low (7-13 hours) at all the steps as compared to the time 12-65 hours for most of the stages in the processes disclosed in the above mentioned patent.
3. Obnoxious and foul smelling, difficult to handle reagents are avoided making the process environmentally safe for commercial application.
4. Consequently the process is simple, economical and viable for plant scale operations.

We Claim:
1. A process for the preparation of Nilotinib of the fonnula-l which comprises the following steps:
a. Preparing 5-(4-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)-benzeneajnine of the
formula (XI) by conventional methods
b. Chlorination of 4-methyl-3-nitro benzoic acid of the formula (II) to get 4-methyl-3-
nitro benzoyl chloride of the formula (II A)
c. Condensation 5-(4-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)-benzeneamine of
the formula (XI) with 4-methyl-3-nitro benzoyl chloride of the formula (IIA) at a
temperature range 30-40°C in chlorohydrocarbon solvent with aqueous alkali addition
to obtain 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl-5-(trifluoromethyl)phenyl]-3-
nitro-benzamide of the formula (III)
d. Reducing compound of formula (III) by refluxing with stannous chloride in methanol
for 2 to 3 hoursto obtain4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl-5-
(trifluoromethyl)phenyl]-3-amino-benzamide the formula (IV)
e. Condensing the compound of formula (IV) with cyanamide solution at PO-QS^C in
n-butanol solvent to obtain 4-methyl-N-[3-(4-methyl-lH«imida2ol-l-yl-5-
(trifluoromethyl)phenyl]-3-guanidino-benzamide of the formula (V).
f. Condensing the compound of formula (V) with 3-dimethylamino-l-(3-pyridyl)-2-
propen-1-one of the formula (VIII) in presence of base at reflux temperature to
Nilotinib of obtain the formula (I)


2. The novel intermediate 4-methyl-N-[3-(4-methyl-IH-imidazol-l-yl-5-
(trifluoromethyl)phenyl]-3-nitro benzamide of formula (III)
3. A method preparing the said intermediate 4-methyI-N-[3-(4-methyl-lH-imidazol-1-yl-
5-(trifluoromethyl)phenyI]-3-nitro-benzamide of the formula (III) essentially as in
example-1
4. The novel intermediate 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl-5-
(trifluoromethyl)phenyl]-3-amino-benzamide the formula (IV)
5. A method of preparing the said intermediate 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl- 5-(trifluoromethyl)phenyl]-3-amino-benzamide the formula (IV) essentially as in
example-1
6. The novel intermediate 4-methyl-N-[3-(4-methyl-1 H-imidazol-1 -yl-5-(trifluoromethyl)phenyl]-3-guanidino-benzamide of the formula (V).
7. A method of preparing the said intermediate 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl-5-(trifluoromethyl)phenyl]-3-guanidino-benzamide of the formula (V) essentially as in' example-1
8. A method of preparing the nilotinib of formula (I) essentially as in example-1