DESC:Field Of The Invention
The present invention relates to a process for preparation of nintedanib and pharmaceutically acceptable salts thereof.

Background Of The Invention
Nintedanib is chemically denoted as Methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate.

Nintedanib is a combined inhibitor of the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR). Hence it is used as a selective antagonist of the protein tyrosine kinase receptor and designed for the treatment of idiopathic pulmonary fibrosis (IFF) and in combination with other active ingredients it is also used for the treatment of certain types of cancer. It is structurally represented as shown below compound of Formula (I).

It is known that Nintedanib is prepared by reacting 1-acetyl-3-(1-methoxy-1-phenylmethylene)-6-methoxycarbonyl-2-]indolinone with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide in dimethylformamide and stirred for 1 hour at 80°C. After cooling, piperidine is added and the mixture is stirred for another three hours at room temperature. The solvent is removed, and the residue is purified over aluminium oxide column with MDC/methanol eluant. The process is carried out in dimethylformamide, which is not feasible on plant scale. The process involves use of column purification for obtaining pure compound, which is also troublesome for high scale production.

Accordingly, there is a need of a process for preparation of Nintedanib, which is plant feasible, easy to operate and does not require any special technique for obtaining Nintedanib of desired purity.

Summary Of The Invention
An aspect of the invention discloses a process for preparing Nintedanib of Formula (I).

The process comprises the steps of reacting a compound of Formula (II) with a compound of Formula (III) to form an intermediate compound of Formula (IV). Compound of Formula (IV) is heated in the presence of a solvent to form nintedanib of Formula (I).

wherein, R1 is a protecting group selected from acetyl, propanyl, 3-methylbutanyl, methane sulfonyl, p-toluene sulfonyl, benzoyl, ethoxycarbonyl, tert-butoxy carbonyl and benzyloxycarbonyl. R2 is selected from halogen such as fluoro, chloro bromo and iodo, hydroxy group, alkoxy group such as methoxy, ethoxy, isopropoxy, n-propoxy, or arylalkoxy group such as phenyl-(C1-C4)-alkoxy, 1-naphtyl-(C1-C4)-alkoxy group; and 2-naphthyl-(C1-C4)-alkoxy group.

Description Of The Invention
In an embodiment of the present invention, a process to prepare Nintedanib of Formula (I) is disclosed. The process comprises of reacting a compound of Formula (II) with a compound of Formula (III) to form an intermediate compound of Formula (IV). Compound of Formula (IV) is further heated in the presence of a solvent to obtain nintedanib of Formula (I).

Compounds of Formula (II), Formula (III), Formula (IV) and Formula (I) are represented as:

In Formula (II) and Formula (IV), R1 is a protecting group selected from acetyl, propanyl, 3-methylbutanyl, methane sulfonyl, p-toluene sulfonyl, benzoyl, ethoxycarbonyl, tert-butoxy carbonyl and benzyloxycarbonyl.

R2 is selected from halogen such as fluoro, chloro bromo and iodo, hydroxy group, alkoxy group such as methoxy, ethoxy, isopropoxy, n-propoxy, or arylalkoxy group such as phenyl-(C1-C4)-alkoxy, 1-naphthyl-(C1-C4)-alkoxy group; and 2-naphtyl-(C1-C4)-alkoxy group.

In an embodiment of the present invention, compound of Formula (II) and compound of Formula (III) are reacted in the presence of a solvent. The reaction is carried out at 50°C to 90°C, preferably at a temperature of 60°C to 80°C and more preferably at 65°C to 75°C.

The solvent used in the aforesaid reaction(s) is preferably an alcohol selected from the group comprising of (1-4) C alcohol such as methanol, ethanol, iso-propanol, n-propanol, butanol, iso-butanol, and the like.

Heating of compound of Formula (IV) in the presence of a solvent is carried out at a temperature of 50°C to 90°C, preferably at a temperature of 60°C to 80°C and more preferably at 65°C to 75°C.

In an embodiment, compound of Formula (I) is formed without isolation of compound of Formula (IV). This enables a one-pot synthesis method, which has economical benefits. As the isolation of the intermediate is avoided, an additional step from the reaction is reduced thereby avoiding loss in the yield of the final product.

In another embodiment of the invention, compound of Formula (I) is prepared by isolating the intermediate compound of Formula (IV) by distillation of the solvent, dissolving the isolated compound of Formula (IV) in a solvent such as (1-4)C alcohol and heating without addition of an alkali to obtain nintedanib of Formula (I). Heating is carried out at a temperature of 50°C to 90°C, preferably at a temperature of 60°C to 80°C and more preferably at 65°C to 75°C.

Nintedanib of Formula (I) prepared by the process of the present invention has 99.0% to 99.9% HPLC purity and is obtained in a yield of 80% to 90 %.

In a preferred embodiment of the present invention, a process to prepare compound of Formula (I) comprises reacting methyl (3Z)-3-[methoxy(phenyl)methylene]-2-oxo-1-propanoyl-indoline-6-carboxylate (Formula II) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide (Formula III) to form methyl (3Z)-3-[[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]-phenyl-methylene]-2-oxo-1-propanoyl-indoline-6-carboxylate (Formula IV). The formation of intermediate compound of Formula (IV) is confirmed by in-process analysis. Preferably, compounds of Formula (II) and Formula (III) are reacted in the presence of a solvent such as (1-4)C alcohol selected from the group comprising of methanol, ethanol, iso-propanol, n-propanol, butanol, iso-butanol, and the like. Compound of formula (IV) is heated in the presence of a solvent without isolation to form nintedanib (Formula I). The heating of compound of Formula (IV) is carried out at a temperature of 50°C to 90°C, preferably at a temperature of 60°C to 80°C and more preferably at 65°C to 75°C. The solvent is selected from the group of (1-4)C alcohol, preferably can be selected such as methanol, ethanol, iso-propanol, n-propanol, butanol, iso-butanol and the like. Compound of Formula (I) has 99.0% to 99.9% HPLC purity and is obtained in a yield of about 80% to 90%.

Heating of the reaction is continued at a temperature of 60°C to 80°C in the same alcoholic solvent or different alcoholic solvent without isolation of intermediate compound of Formula (IV), till the reaction goes to completion. The reaction directly yields nintedanib of high purity.

Nintedanib obtained from the process of the present invention can be further converted to its salt by known procedures.

Nintedanib is used as a selective antagonist of the protein tyrosine kinase receptor and used for the treatment of idiopathic pulmonary fibrosis (IFF) and in treatment of certain types of cancer.

The process covered by the present invention is n eco-friendly and a cost-effective process. The process is feasible for higher scale production. The process involves a reduced reaction time and nintedanib is isolated in higher yields and high purity without any strenuous work up.

EXAMPLES
The following examples illustrate the invention and are not limiting thereof.
Comparative Examples
Comparative example 1: Preparation of Nintedanib (Using tetrahydrofuran (THF) as a solvent).
THF (100 ml) was charged in a mixture of methyl (3Z)-3-[methoxy(phenyl)methylene]-2-oxo-1-propanoyl-indoline-6-carboxylate (10 gm) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide under nitrogen atmosphere. The mixture was heated to 65°C-70°C. The mixture was maintained at 65°C - 70°C for 22-23 hours. The reaction mass obtained was cooled to 25°C - 30°C.
Piperidine (10 ml) was added and the mixture was maintained at 25°C- 30°C for 5-6 hours. The mass was further cooled to 0°C - 5°C and stirred for 30 minutes at 0°C -5°C. The slurry obtained was filtered and washed with methanol. The wet cake obtained was dried under vacuum at 50°C to get crude nintedanib (11.5 gm). HPLC purity: 98.63%.

The solid obtained as above was charged in methanol (80 ml) and heated at 40°C -45°C for 60 minutes. The reaction mass was cooled to 20°C - 25°C. The suspension was stirred for 30 minutes. The mass was filtered and washed with chilled with methanol. The wet cake was dried at 50°C to obtain nintedanib (8.7 gm, 53%) HPLC purity: 99.24%.
Comparative example 2: Preparation of methyl (3Z)-3-[[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]-phenyl-methylene]-2-oxo-1-propanoyl-indoline-6-carboxylate ( Formula IV).
Dimethylformamide (25 ml) was charged to the mixture of methyl (3Z)-3-[methoxy(phenyl) methylene]-2-oxo-1-propanoyl-indoline-6-carboxylate (5 gm) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (2.5 gm) under nitrogen. The mixture was heated to 60°C-65°C with constant stirring and maintained for 2-3 hours. The temperature was reduced to room temperature. Water (50 ml) was charged drop wise and the mixture was stirred for 60 minutes. The slurry obtained was filtered and the wet cake was washed with water (50 ml). The wet cake was dried under vacuum at 60°C and methyl (3Z)-3-[[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]-phenyl-methylene]-2-oxo-1-propanoyl-indoline-6-carboxylate (4 gm, 49.0% yield) was isolated. HPLC purity 72.91%)

Example 1
Preparation of methyl (3Z)-3-[[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]-phenyl-methylene]-2-oxo-1-propanoyl-indoline-6-carboxylate (Formula IV).

Methanol (200 ml) was charged to the mixture of methyl (3Z)-3-[methoxy(phenyl) methylene]-2-oxo-1-propanoyl-indoline-6-carboxylate (10 gm) (Formula II) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (6 gm) (Formula III) under nitrogen. The mixture was heated up to 65°C-70°C. The mass was heated at 65°C - 70°C for 4 hours. The temperature was reduced to 0°C-5°C and stored at the same temperature for at least 60 minutes. The slurry obtained was filtered and wet cake was washed with methanol (30 ml). The wet cake was dried under vacuum at 50°C and methyl (3Z)-3-[[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]-phenyl-methylene]-2-oxo-1-propanoyl-indoline-6-carboxylate (Formula IV) (10.3 gm, 63% yield) was isolated. HPLC purity 97.72%.

Example 2 - Preparation of Nintedanib (Formula I).
N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (20.47 gm) (Formula III) was charged to methyl (3Z)-3-[methoxy(phenyl)methylene]-2-oxo-1-propanoyl-indoline-6-carboxylate (30 gm) (Formula II) in methanol (1500 ml). The reaction mixture was heated to 65°C -70°C. The reaction mixture was heated for 40-45 hours to obtain (3Z)-3-[[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]-phenyl-methylene]-2-oxo-1-propanoyl-indoline-6-carboxylate (Formula IV). 95% of the methanol (1350 ml) was removed by distillation and slurry obtained was cooled to 30°C -35°C and stirred overnight. The mass was filtered, and wet cake was washed with chilled methanol (90 ml). The cake was dried at 55°C -60°C under vacuum to yield nintedanib (36 gm). (Yield: 81%; HPLC Purity: 99.83%)

Example 3 - Preparation of Nintedanib Esylate.
Nintedanib base (10 gm) was charged to methanol (70 ml) and the reaction mixture was heated to 40°C -45°C. Ethane sulfonic acid (1.52 ml) in methanol (10 ml) was charged slowly to the reaction mixture and stirred for 10 minutes. The mass was cooled to 27°C -30°C and stirred for 60 minutes. Iso propyl alcohol (IPA) (70 ml) was charged to the reaction mass obtained and stirred for 15 minutes. The slurry was filtered, and wet cake was washed with IPA. The wet cake obtained was dried under vacuum at 45-50°C. Nintedanib esylate salt was isolated (10.6 g, 88%) having HPLC purity 99.69%.

As can be understood from the aforesaid examples, when the process is carried out in the presence of solvents such as THF, dimethylformamide, the yield and purity of compound of Formula I and Formula IV was less than the yield and purity of compound of Formula I and Formula IV, when the process was carried out in an alcoholic solvent in accordance with the present invention.

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:
1. A process for preparing intedanib of Formula (I), the process comprising the steps:

reacting a compound of Formula (II) with a compound of Formula (III) to form an intermediate compound of Formula (IV); and

wherein, R1 is a protecting group selected from acetyl, propanyl, 3-methylbutanyl, methane sulfonyl, p-toluene sulfonyl, benzoyl, ethoxycarbonyl, tert-butoxy carbonyl and benzyloxycarbonyl, R2 is selected from halogen such as fluoro, chloro bromo and iodo, hydroxy group, alkoxy group such as methoxy, ethoxy, isopropoxy, n-propoxy, or arylalkoxy group such as phenyl-(C1-C4)-alkoxy, 1-naphthyl-(C1-C4)-alkoxy group; and 2-naphtyl-(C1-C4)-alkoxy group,
heating the compound of Formula (IV) in the presence of a solvent to obtain nintedanib of Formula (I).

2. The process as claimed in claim 1, wherein compound of Formula (II) and Formula (III) are reacted in the presence of a solvent.

3. The process as claimed in claim 1 or claim 2, wherein the solvent is (1-4)C alcohol selected from methanol, ethanol, iso-propanol, n-propanol, butanol, iso-butanol.

4. The process as claimed in claim 3, wherein the solvent is methanol.

5. The process as claimed in claim 1, wherein the compound of Formula (IV) is heated at a temperature in a range of 50°C to 90°C.

6. The process as claimed in claim 1, wherein the compound of Formula (IV) is heated at a temperature in a range of 60°C to 80°C.

7. The process as claimed in claim 1, wherein the compound of Formula (IV) is heated at a temperature in a range of 65°C to 75°C.

8. The process as claimed in claim 1, wherein the process is a one pot process.

9. The process as claimed in any one of the preceding claims, wherein the compound of Formula (IV) is heated in the absence of an alkali.

10. A process of preparing a salt of nintedanib, the process comprising of reacting nintedanib of Formula (I) as claimed in any one of the claims 1-9 with ethane sulfonic acid.