Improved process for the preparation of Methyl imidazole benzamine intermediates thereof.
Field of Invention
The present invention relates to a process for preparation of Methyl imidazole benzamine derivatives; which are key intermediates for the preparation of substituted pyrimidinylaminobenzamides. More specifically the present invention relates to a process for the preparation of highly pure (3-(4-methyl-/#-imidazol-l-yl)-5-(trifluoromethyl) aniline of a compound of formula (I) and its pharmaceutical active compounds of substituted pyrimidinylaminobenzamides such asNilotinib (II).
Background of the Invention
Nilotinib is the compound of 4-methyl-N [3-(4-methyl-i//-imidazol-l-yl-5-(trifluoromethyl) phenyl]-3-{{4-(3-pyridinyl)-2-pyrimidinyl] amino] benzamide of Formula (II):
Nilotinib is a tyrosine kinase inhibitor used for the treatment of drug-resistant chronic myelogenous leukemia (CML), and in particular, for the treatment of chronic phase and

accelerated phase Philadelphia chromosome positive chronic myeloid leukemia (CML) in adult patients whose disease has progressed on or who cannot, tolerate other therapies that included imatinib. Nilotinib especially used as an antitumor agent.
Nilotinib was first disclosed in U.S. Patent No. 7169791. It is chemically described as 4-methyl-N-[3-(4-methyl-l//-imidazol-l-yl)-5-(trifluoromethyl) phenyl]-3- [[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide of formula (II) and is an inhibitor of the protein tyrosine kinase (TK) activity of BCR-ABL. The Schematic process described by this patent as follows.
Scheme -1 .

According to the large number of protein kinase inhibitors and the multitude of proliferative and additional PK-related diseases, there is an ever-existing need to provide novel classes of compounds that are useful as PK inhibitors and thus in the treatment of these PTK related diseases. What are required are new classes of pharmaceutical^ advantageous PK inhibiting compounds.
US7169791 describes the preparation of Nilotinib and the use thereof, and the '791 Patent describes preparation of key intermediate of compound of formula (I) and its conversion to Nilotinib and pharmaceutically acceptable salts thereof. According to the '791 patent, the preparation of compound of Formula (I) involves a four step synthetic route, starting with an aromatic substitution reaction of compound (III) with compound (IV), hydrolysis of the resulting compound (V) followed by Curtius rearrangement and deptotection reaction.
The process disclosed in the '791 patent is schematically represented by Scheme-II.

Scheme - II
The process as disclosed by the '791 application has few disadvantages like isolation of compounds V and VI involves organic solvents and chromatographic separation methods which are not feasible at large scale synthesis. Furthermore, the intermediate compound (I) obtained by this process contains impurities which are not suitable for further conversion to Nilotinib preparation.
US7781597 B2 discloses the Formula (I) synthesis from 3-bromo-5-fluoro-benzotrifluoride (X) which was reacted with compound (IV) in the presence of strong base NaH, followed by arylamination of obtained compound (XI) with (XII) in presence of Pd catalyst, phosphine ligand and finally hydrolysis of resulting compound (XIII) to yield compound (I). The process is describes by below Scheme-Ill..

Scheme - III
US '597 invention uses Pd and ligands as catalysts in the intermediate synthesis and also more purification steps are used to minimize the regiomer impurities, which comprises low yields, more expensive and commercially challenging for industrial applicability.
It is an object of the invention to provide an improved process to make the compound of formula (I) with high purity by avoiding chromatographic purification methods.
It is further an object of this invention to provide robust process which is easily scalable and provide reliably very pure compounds.
It is an object of this invention to provide alternative process to make the compound of formula (I) in high yields, more cost effective and at the same time reduce the batch cycle time at commercial scale.

Objective of the invention
It is the main object of the present invention to provide an improved process for the preparation of formula (I) with high purity, efficient and scalable process for the commercial production.
Summary of the Invention
The main aspect of the present invention is to provide a process for the preparation of pure (3-(4-methyl-7//-imidazol-l-yl)-5-(trifluoromethyl) aniline of a compound of formula (I).
This is the key intermediate for the preparation of substituted pyrimidinylaminobenzamides of formula (II)
The compound of formula (II) has been shown to inhibit one or more tyrosine kinases and can be used for the treatment of leukemia.
The process of compound of formula (I) of the present invention has depicted by the following synthetic scheme-IV.

Scheme - IV
Drawings
Sheet (1 of 4)
Shows the PXRD values of Form (I) of formula (I)
Sheet (2 of 4)
Shows the PXRD values of Form (II) of formula (I)
Sheet (3 of 4)
Shows the IR values of Form (I) of formula (I)
Sheet (4 of 4)
Shows the IR values of Form (II) of formula (I)
Detailed Description of the Invention
In one aspect of the present invention of pure (3-(4-methyl-7//-imidazol-l-yl)-5-(trifluoromethyl) aniline of formula (I) and their pharmaceutically acceptable salts, polymorphs and crystals thereof, with high yields and purity obtained.

In one embodiment, the present invention provides an improved process for the preparation of compound of formula (I) which in turn can be used in the preparation of substituted pyrimidinylaminobenzamides of formula (II)
Another aspect of the invention, it has been found that the compound (III) [3-Fluoro-5-(trifluoromethyl)benzonitrile] undergo aromatic substitution with compound (IV) [4-Methyl imidazole] at 135-145 °C in dimethylacetamide solvent to give intermediate compound (V) which undergo further hydrolysis with aqueous caustic solution at 80-90 °C followed by pH adjustment by using aqueous HC1 to yield compound (VI) of ( 3-(4-methyl-///-imidazol-l-yl)-5-(trifluoromethyl)benzoic acid).
In the present invention, the aromatic substitution reaction was simplified to minimize the isolation process for the intermediate (V). The intermediate compound (V) was easily isolated by adding water to the reaction mass to avoid the organic solvent extraction step and also the chromatographic purification to separate the compounds. The isolated intermediate compound (V) was as it is undergone for hydrolysis without further drying.
. In the hydrolysis reaction used an aqueous caustic solution; the reaction was completed in 7-8 hours. The hydrolysis reaction was completed without using any organic solvent. The intermediate compound (VI) was simply isolated by adjusting mild acidic pH of the reaction mass to avoid the extraction of compound (VI) with organic solvent.
During the hydrolysis of compound (V), as per reaction mechanism, first the CN group has to get converted into amide, which undergo liberation of ammonia gas to form the corresponding sodium salt of compound (VI), which got converted into corresponding acid group during pH adjustment with aqueous HC1 by forming by-product NaCl. During the work up of sodium salt of compound (VI), the inorganic salts formed during the reaction such as NaCl, HC1, NaOH, NH4OH are washed out in aqueous mother liquor and water washings.

4-methylimidazole (compound IV) is a key raw material in Nilotinib intermediate ROS. 5-Methylimidazole is a tautomer of 4-methylimidazole.
In the process, along with 4-methylimidazole, 5-methylimidazole is also reacting with other materials and convert into regiomer impurity at each stage. These regiomer impurities were prepared, identified and appropriate work up processes have been developed to reduce to below 0.1%.
The present invention discloses a process for synthesis of compound of formula (I) comprising up to 0.05 to 0.1 % of total impurities with both the ethyl impurity (compound VIII) and regiomer of compound (I) each below 0.05%.
Another embodiment of the invention is the conversion of Compound (VI) (3-(4-methyl-7//-imidazol-l-yl)-5-(trifluoromethyl) benzoic acid) to Compound (VII), {tert-butyl (3-(4-methyl-i//-imidazol-l-yl)-5-(trifluoromethyl) phenyl)carbamate. The conversion of compound (VI) to compound (VII) comprises four in-situ steps known as Curtius rearrangement. Compound (VI) reacts with Diphenylphosphoryl azide (DPPA)

under thermal conditions to form acyl azide which converts in-situ into isocyanate with the release of Nitrogen gas. The isocyanate moiety potentially reacts further with nucleophile to form Compound (VII).
Another embodiment of the present invention, Curtius reaction was optimized to complete faster in 8-9 h and the work up has been designed to isolate good quality of solid. The reaction mass was distilled and the crude was isolated in the mixture of t-. Butanol and aqueous NaHCC>3 solution to yield compound (VII) without chromatographic purification method.
One more embodiment of the invention is the compound (VII) undergoes boc-deprotection in presence of Methanolic Hydrochloride. The HC1 salt of Compound (I) (3-(4-methyl-7//-imidazol-l-yl)-5-(trifluoromethyl)aniline was isolated by adding acetone followed by neutralization by using aqueous Na2CC>3 solution to prepare crude compound (I) which was optionally purified by recrystallization in toluene to achieve highly pure material of Formula (I).
One more embodiment of the invention is the work up and purification methods were established to avoid chromatographic purification and to reduce maximum impurities such as compound (VII) regiomer and critical impurity compound (VIII) [Ethyl impurity of compound (I)].
This impurity compound (VIII) and regiomer of compound (I), being structurally similar to compound (I) can derivatize in similar fashion with compound (I) during.forward reaction steps in the preparation of compound (II) and possibly difficult to remove.

Considering this criticality, the compound (I) was prepared where both the ethyl impurity and regiomer of compound (I) were less than 0.05% each.
Another aspect of the invention the novel crystalline forms of compound of Formula (I), it has been found that, the PXRD pattern of Crystalline Form (I) of compound of 5-(4-methyl-7//-imidaqzol-l-yl)-3-(trifluoromethyl)-benzenamine having formula (I) shown
in Sheet (1 of 2)
Another aspect of the invention, Crystalline Form (II) of compound of Formula (I), having a powder X-ray diffraction pattern comprising shown in Sheet (2 of 2)
Another aspect of the invention the novel crystalline forms of compound of Formula (I), it has been found that, the crystalline Form (I) of Formula (I) the X-ray diffraction 29 values comprise here 6.57, 11.09, 13.22, 17.52, 19.93, 22.35 and 23.15.
And IR values of crystalline Form (I) of Formula (I) (KBr, cm"1): 3354.57, 3211.86, 3103.87, 1624.73, 1509.99, 1483.96, 1407.78, 1326.79, 1259.29, 1168.65, 931.45, and 836.45.
Another aspect of the invention, it has been found that, the crystalline Form (II) of formula (I) the X-ray diffraction 20 values comprise here 6.56, 8.40, 10.52, 12.41, 14.21, 13.19, 16.91, 19.88, 20.57, 21.16, 22.18 and 24.41.
And IR values of crystalline Form (II) of Formula (I) (KBr, cm'1]: 3416.96, 3389.95, 3215.39,3192.24, 1640.49, 1621.20, 1512.22, 1487.14, 1411.92, 1327.05, 1253.75, 1118.73, and 846.76.
The Following examples are illustrative of the present inventions and are not intended to limit the inventions.

EXAMPLES: Example: 1
3-Fluoro-5(trifluoromethyl) benzonitrile (30 g, 1 equiv.) was reacted with 4-methylimidazole (39.06 g, 3 equiv.) in the presence of dimethylacetamide (60 mL, 2.0 vol) at 135-145 °C for 20-22 hours. After the reaction was completed, water was added to the reaction mass, filtered the solids. The wet material was heated with aqueous caustic solution at 80-90°C for 7-8 hours. After the reaction was completed, the reaction mass cooled to 20-35 °C and the pH of the reaction mass adjusted to 5.0-5.5 by using aqueous HC1. The resulting mass was filtered and dried under vacuum. Yield: 75%
Example: 2
To a solution of 3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl) benzoic acid (Compound VI) (30, 1 equivalent) in tert-butanol (35 v), added triethylamine (31.2
mL, 2
equiv.) and diphenylphosphoryl azide (DPPA) ( 36.6g, 1.2 equiv.) at 30-35 °C. The resulting mass was refluxed for 9-10 hours. After the reaction was completed, the solvent was distilled under vacuum below 60 °C, added tert-butanol (4 vol) followed

by Sodium bicarbonate solution at 25-30 °C. The resulting solid was filtered and dried to obtain Compound VII. Yield: 75%.
Example: 3
re^Butyl-3-(4-methyl-7//-imidazole-lyl)-5(trifluoromethyl)phenyl)carbamate Compound VII (35 g, 1 equiv.) in Methanolic HC1 (140 mL, 4 vol) was heated at 55-65 °C for 4-5 h. Once the reaction is completed, acetone was added and the resulted solid was filtered at 25-35 °C. The wet solid was taken in water and pH was adjusted to 6.5-8.5 with Na2C03 solution. The solid was filtered and dried. The obtained dried material was recrystallized in toluene to yield Compound (I). Yield: 70%
HPLC Purity: >99.9%, Total Impurity < 0.05%, RRT 1.4 imp <0.05%, Regiomer <0.05%.
The PXRD values of crystalline form (I) of 5-(4-methyl-7//-imidaqzol-l-yl)-3-(trifluoromethyl)-benzenamine having compound of formula (I) characterized as 6.57, 11.09, 13.22, 17.52, 19.93, 22.35 and 23.15± 0.2 degrees 20. IR values of crystalline Form (II) of Formula (I) (KBr, cm"1): 3354.57, 3211.86, 3103.87, 1624.73, 1509.99, 1483.96, 1407.78, 1326.79, 1259.29, 1168.65, 931.45, and 836.45.

Example: 4
>e^-Butyl-3-(4-methyl-;//-imidazole-lyl)-5(trifluoromethyl)phenyl)carbamate Compound VII (160 g, 1 equiv.) in IPA (800 mL, 5 vol) and IPA HC1 (800 mL, 5 vol) was heated at 55-65 °C for 4-5 h. After the reaction is completed, the resulted solid was filtered at 25-30 °C. To the wet solid water was added and pH was adjusted to 6.5-8.5 with Na2C03 solution. The mass was extracted with ethyl acetate. The EtOAc layer was distilled and the crude was isolated in hexanes to
obtain Formula (I). Yield: 50%
The PXRD values of crystalline form (I) of 5-(4-methyl-///-imidaqzol-l-yl)-3-(trifluoromethyl)-benzenamine having formula (I) characterized as 6.64, 11.17, 13.22, 17.58, 19.98, 22.42 and 23.20 ± 0.2 degrees 20.
Example: 5
ferr-Butyl-3-(4-methyl-i//-imidazole-lyl)-5(trifluoromethyl)phenyl)carbamate Compound VII (1160 g, 1 equiv.) in Methanolic HC1 (5800 mL, 5 vol) was heated at 50-60 °C for 3-4 h. Once the reaction is completed, acetone was added and the resulted solid was filtered at 25-35 °C. The wet solid was taken in water and the pH was adjusted to 6.5-7.5 with Na2C03 solution. The solid was filtered and dried to obtain Formula (I). Yield: 80%.

The PXRD values of crystalline form (II) of 5-(4-methyl-///-imidaqzol-l-yl)-3-(trifluoromethyl)-benzenamine having formula (I) characterized as 6.56, 8.40, 10.52, 12.41, 14.21, 13.19, 16.91, 19.88, 20.57, 21.16, 22.18 and 24.41± 0.2 degrees 29.
IR values of crystalline Form (II) of Formula (I) (KBr, cm"1): 3416.96, 3389.95, 3215.39, 3192.24, 1640.49, 1621.20, 1512.22, 1487.14, 1411.92, 1327.05, 1253.75, 1118.73, and 846.76.

CLAIMS:
1.A process for the preparation of highly pure compound of (3-(4-methyl-7//-
imidazol-l-yl)-5-(trifluoromethyl) aniline of formula (I) comprising,
Step a) reacting 3-fluoro-5-(trifluoromethyl)benzonitrile with a compound of 4-methyl-7//-imidazole, or a salt thereof, using an appropriate solvent to prepare 3-(4-methyl-7//-imidazol-1 -yl)-5-(trifluoromethyl)nitrile;
Step b) hydrolysis of the resulting step a) compound with a suitable base in a suitable solvent to give compound of (3-(4-methyl-7#-imidazol-1 -yl)-5-(trifluoromethyl) benzoic acid).
Step c) conversion of acid compound of step b) to corresponding carbamate in the presence of alcohols, organic azide and a suitable base.
Step d) deprotection of compound of step c) in the presence of alcohols with hydro halo acid compounds to acquire formula (I)
2.A process of claim 1, wherein the solvent used in Step a) is N, N-dimethylformamide, N,N-dimethylacetamide or l-methyl-2-pyrrolidinone.
3.A process preparation according to claim 1: step b) the hydrolysis process, the suitable base is selected from sodium hydroxide, potassium hydroxide, Lithium hydroxide, Rubidium hydroxide, Cesium hydroxide, Magnesium hydroxide, Strontium hydroxide, Barium hydroxide or mixtures thereof.
4.A process preparation according to claim 1: step b) wherein the solvent selected

from protic solvents. More preferably the protic solvent is water.
5.A process preparation according to claim 1: step c) wherein the organic azide is Diphenylphosphoryl azide (DPPA) and the step c) suitable base is Triethylamine.
6.A process preparation according to claim 1: step d) wherein the alcohols with hydro halo acid compounds selected from methanolic, ethanolic or isopropyl alcoholic hydrochloride and mixtures thereof.
7.Crystalline Form (I) of compound of Formula (I), having a powder X-ray diffraction pattern comprising one or more of peaks located at 6.57, 11.09, 13.22, 17.52, 19.93 and 22.35 ± 0.2 degrees 20
8. Crystalline Form (II) of compound of Formula (I), having a powder X-ray diffraction pattern comprising one or more of peaks located at 6.56, 8.40, 10.52, 14.21, 19.88 and 20.57 ± 0.2 degrees 20.
9.The compound of Formula (I), wherein the ethyl impurity less than 0.1%.
10.The compound of Formula (I), wherein the regiomer impurity below 0.1%