DESC:RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Patent Application No. 201741039806 filed on November 08, 2017; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Nintedanib esylate.

BACKGROUND OF THE INVENTION

Nintedanib esylate is a kinase inhibitor indicated for the treatment of idiopathic pulmonary fibrosis and is chemically known as 1H-Indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-,methylester, (3Z)-, ethanesulfonate (1:1) and has the formula-I as mentioned below.

Formula I

The Patent US 6762180 assigned to Boehringer Ingelheim Pharma discloses the preparation of Nintedanib as mentioned below.

The process discloses the reaction of methyl (Z)-1-acetyl-3-(ethoxyphenylmethylene)-oxindole-6-carboxylate with N-(4-aminophenyl)-N,4-dimethyl-1-piperazine acetamide in dimethylformamide, followed by the treatment with piperidine to obtain Nintedanib free base. The use of dimethyl formamide and piperidine in this reaction makes the handling and work-up difficult. The patent further discloses the use of other organic bases such as trimethylamine, N-ethyl-diisopropylamine, butylamine, dimethylamine and piperidine for this reaction.

The PCT publication WO2017016530 assigned to Zentiva discloses the use of alkali hydroxides such as potassium hydroxide; and alkali alkoxides such as potassium tert-butoxide and sodium ethoxide; for the reaction of methyl (Z)-1-acetyl-3-(ethoxyphenylmethylene)-oxindole-6-carboxylate with N-(4-aminophenyl)-N,4-dimethyl-1-piperazine acetamide to obtain Nintedanib.

Therefore, there exists a need for an improved process for Nintedanib esylate that is simple and commercially significant.

OBJECT OF THE INVENTION

The object of the present invention is to provide an improved process for the preparation of Nintedanib esylate.

Another object of the present invention is to provide an improved process for the preparation of Nintedanib free base.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an improved process for the preparation of Nintedanib esylate.

In one aspect of the invention, there is provided a process for preparing Nintedanib esylate of formula-I


Formula I
comprising the steps of:
(a) reacting a compound of formula-II as mentioned below,

Formula-II

with a compound of formula III as mentioned below,

Formula-III

in the presence of base selected from a group consisting of alkali metal and alkaline earth metal carbonates thereof to obtain Nintedanib free base; and

(b) converting the Nintedanib free base to Nintedanib esylate of formula-I.

In some embodiment, Nintedanib free base is prepared by reacting a compound of formula II with a compound of formula III in presence of a base selected from the group consisting of sodium carbonate, potassium carbonate, calcium carbonate and magnesium carbonate. In some other embodiment, the base employed is potassium carbonate.

Another aspect of the invention is to provide a process for preparing Nintedanib free base comprising the steps of:
(a) reacting a compound of formula-II as mentioned below,

Formula-II

with a compound of formula III as mentioned below,

Formula-III

in the presence of base selected from a group of alkali metal and alkaline earth metal carbonates thereof to obtain Nintedanib free base.

Another aspect of the present invention is to provide a process for preparing Nintedanib esylate of formula-I

Formula I
comprising the steps of:

(a) reacting a compound of formula-II as mentioned below,

Formula-II

with a compound of formula III as mentioned below,

Formula-III

in the absence of base to obtain a compound of formula-IV as mentioned below,

Formula-IV

(b) treating the compound of formula-IV obtained in step (a) with ethane sulfonic acid to Nintedanib esylate of formula-I; and

(c) optionally purifying the Nintedanib esylate of formula-I obtained in step (b) with suitable solvent(s).

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention is to provide a process for preparing Nintedanib esylate of formula-I comprising the steps of:

Formula I

(a) reacting a compound of formula-II,
Formula-II

with a compound of formula III,
Formula-III

in the presence of base selected from a group of alkali metal and alkaline earth metal carbonates thereof to obtain Nintedanib free base; and

(b) converting the Nintedanib free base to Nintedanib esylate of formula-I.

In some embodiment, the said alkali metal carbonates employed in the present inventions include sodium carbonate, potassium carbonate and the likes; and said alkaline earth metal carbonates employed in the present inventions include calcium carbonate, magnesium carbonate and the likes. Preferably compound of formula-II is reacted with a compound of formula-III in presence of potassium carbonate to provide Nintedanib free base.

In some other embodiment, step (a) of the present invention is carried out in presence of suitable solvent selected from a group comprising of C1-C4 alcohols such as ethanol, methanol, isopropanol; ethers such as tetrahydrofuran, dioxan; aliphatic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as methylene chloride; acetonitrile or mixtures thereof. Preferably the solvent employed in step (a) is alcohol, more preferably methanol.

The inventors of the present invention observed that the yield of the reaction using dimethylformamide in piperidine and potassium hydroxide in methanol were 52% and 19% respectively. Surprisingly, the use of alkali metal and alkaline earth metal carbonates increased the yield significantly and decreased the reaction time.

In some embodiment, the Nintedanib free base obtained in step (a) is further converted to Nintedanib esylate. In some other embodiment, Nintedanib free base is reacted with ethane sulfonic acid to provide Nintedanib esylate. In some embodiment, ethane sulfonic acid used is aqueous ethane sulfonic acid to provide Nintedanib esylate.

The present invention provides a process for preparing Nintedanib esylate of formula-I

Formula I

comprising the steps of:
(a) reacting a compound of formula-II as mentioned below,

Formula-II

with a compound of formula III as mentioned below,
Formula-III

in the presence of potassium carbonate as base and methanol as solvent at temperature of about 65°C for about 3 hours to obtain Nintedanib free base; and

(b) converting the Nintedanib free base to Nintedanib esylate of formula-I by treating with aqueous ethane sulfonic acid.

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter.

Another aspect of the present invention is to provide a process for preparing Nintedanib free base comprising the steps of:

reacting a compound of formula-II,

Formula-II

with a compound of formula III,

Formula-III
in the presence of base selected from a group of alkali metal and alkaline earth metal carbonates thereof to obtain Nintedanib free base.

In some embodiment, the said alkali metal carbonates employed in the above described process for the preparation of Nintedanib free base include sodium carbonate, potassium carbonate and the likes. In another embodiment, the said alkaline earth metal carbonates employed in the process for the preparation of Nintedanib free base include calcium carbonate, magnesium carbonate and the likes. Preferably the base employed is potassium carbonate.

In some other embodiment, process for the preparation of Nintedanib free base is carried out in suitable solvent selected from a group comprising C1-C4 alcohols such as ethanol, methanol, isopropanol; ethers such as tetrahydrofuran, dioxan; aliphatic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as methylene chloride; acetonitrile, or mixtures thereof. Preferably solvent used is an alcohol, more preferably methanol.

In some embodiment, the process for the preparation of Nintedanib free base is carried out in the presence of phase transfer catalyst. Phase transfer catalyst is selected from a group comprising of one or more of tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium iodide (TBAI), benzyl triethyl ammonium chloride (TEBAC) or the like.

Another aspect of the present invention is to provide a process for preparing Nintedanib esylate of formula-I

Formula I

comprising the steps of:

(a) reacting a compound of formula-II as mentioned below,

Formula-II

with a compound of formula III as mentioned below,

Formula-III
in the absence of base to obtain a compound of formula-IV as mentioned below,

Formula-IV

(b) treating the compound of formula-IV obtained in step (a) with ethane sulfonic acid to provide Nintedanib esylate of formula-I; and

(c) optionally purifying the Nintedanib esylate of formula-I obtained in step (b) with suitable solvent(s).

In some embodiment, the step (a) of the above described process for the preparation of is carried out in presence of suitable solvent selected from a group comprising C1-C4 alcohols such as ethanol, methanol, isopropanol; ethers such as tetrahydrofuran, dioxan; aliphatic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as methylene chloride; acetonitrile or mixtures thereof. Preferably the solvent employed is alcohol, more preferably methanol.

In some embodiment, the present invention provides a process for preparing Nintedanib esylate of formula-I

Formula I

comprising the steps of:
(a) reacting a compound of formula-II as mentioned below,

Formula-II

with a compound of formula III as mentioned below,

Formula-III

in the absence of base to obtain a compound of formula-IV as mentioned below,

Formula-IV

in presence of methanol as solvent and at temperature of about 65°C for about 6 hours;

(b) treating the compound of formula-IV obtained in step (a) with aqueous ethane sulfonic acid, followed by addition of methyl tertiary butyl ether to provide Nintedanib esylate of formula-I; and

(c) optionally purifying the Nintedanib esylate of formula-I obtained in step (b) with suitable solvent(s).

The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

EXAMPLES

Example-1: Preparation for the compound of formula-II:

To a mixture of acetic anhydride (1 L) and methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (100 g), trimethylorthobenzoate (286 g) was added and heated to 105°C. The reaction mixture was stirred for 12 hours at 105°C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 40°C. Methanol (200 ml) was added to the cooled reaction mass. The reaction mass was then cooled to 5°C and maintained for 1 hour at the same temperature. The resultant solid was filtered, washed with methanol (200 ml) and dried to obtain compound of formula II. Yield: 59.5%.
Example-2: Preparation of Nintedanib free base:

To a mixture of methanol (100 ml), the compound of formula II obtained in example-1 (5 g) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (4.1 g) of formula-III, potassium carbonate (1.96 g) was added at 30°C and heated to 65°C. The reaction mixture was stirred for 3 hours at 65°C. The progress of the reaction was monitored by TLC. After completion of the reaction, methanol in the reaction mass was removed by distillation and the concentrated residue was cooled to 40°C. The cooled residue was mixed with water (100 ml) and stirred for 1 hour at 30°C. The contents were than cooled to 5°C. The resultant solid was filtered, washed with methanol (20 ml) and dried to obtain Nintedanib free base. Yield: 57.5%.

Example-3: Preparation of Nintedanib esylate of formula-I:

A suspension of Nintedanib free base obtained in example-2 (3 g) in methanol (45 ml) was stirred for 15 minutes at 30°C and heated to 50°C. The suspension was stirred for 1 hour at 50°C. Aqueous ethane sulfonic acid (0.91 g of ethane sulfonic acid in 0.28 ml of water) was added to the suspension at 50°C and cooled to 40°C. Methyl-t-butyl-ether (24 ml) was added to the reaction mixture and cooled to 30°C. The reaction mixture was stirred for 2 hours at 30°C and then cooled to 5°C. The resultant solid was filtered, washed with methyl-t-butyl-ether (6ml) and dried to obtain Nintedanib. Yield: 50%.
Example-4: Preparation of the compound of formula-IV:

A mixture of methanol (100 ml), the compound of formula II obtained in example-1 (5 g) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (4.1 g) of formula-III was heated to 65°C and stirred for 6 hours at 65°C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 30°C. The reaction mass was further cooled to 5°C and stirred for 1 hour at the same temperature. The resultant solid was filtered, washed with methanol (20 ml) and dried to obtain a compound of formula-IV. Yield: 78%.

Example-5: Preparation of Nintedanib esylate of formula-I:

A suspension of the compound of formula-IV in example-4 (3 g) in methanol (45 ml) was stirred for 15 minutes at 30°C and heated to 50°C. The suspension was stirred for 1 hour at 50°C. Aqueous ethane sulfonic acid (0.91 g of ethane sulfonic acid in 0.28 ml of water) was added to the suspension at 50°C and cooled to 40°C. Methyl-t-butyl-ether (24 ml) was added to the reaction mixture and cooled to 30°C. The reaction mixture was stirred for 2 hours at 30°C and then cooled to 5°C. The resultant solid was filtered, washed with methyl-t-butyl-ether (6 ml) and dried to obtain the titled compound. Yield: 50%.
,CLAIMS:
1. A process for preparing Nintedanib esylate of formula-I

Formula I

comprising the steps of:
(a) reacting a compound of formula-II

Formula-II

with a compound of formula III

Formula-III

in the presence of base selected from a group consisting of alkali metal and alkaline earth metal carbonates thereof to obtain Nintedanib free base; and

(b) converting the Nintedanib free base to Nintedanib esylate of formula-I.

2. The process as claimed in claim 1, wherein the alkali metal and alkaline earth metal carbonates is selected from the group consisting of sodium carbonate, potassium carbonate, calcium carbonate and magnesium carbonate.

3. The process as claimed in claim 2, wherein the carbonate is potassium carbonate.
4. The process as claimed in claim 1, wherein the step (a) is carried in the presence of solvent selected from a group comprising C1-C4 alcohols; ethers; aliphatic hydrocarbons; aromatic hydrocarbons; chlorinated hydrocarbons; acetonitrile or mixtures thereof.

5. The process as claimed in claim 4, wherein the step (a) is carried in the presence of methanol as the solvent.

6. A process for preparing Nintedanib free base comprising the step of:
reacting a compound of formula-II

Formula-II

with a compound of formula III

Formula-III

in the presence of base selected from a group of alkali metal and alkaline earth metal carbonates thereof to obtain Nintedanib free base.

7. The process according to claim 6, wherein the alkali metal and alkaline earth metal carbonates is selected from the group consisting of sodium carbonate, potassium carbonate, calcium carbonate and magnesium carbonate.

8. A process for preparing Nintedanib esylate of formula-I comprising the steps of:

Formula I

(a) reacting a compound of formula-II

Formula-II

with a compound of formula III

Formula-III

in the absence of base to obtain a compound of formula-IV; and

Formula-IV

(b) treating the compound of formula-IV obtained in step (a) with ethane sulfonic acid to provide Nintedanib esylate of formula-I.

9. The process as claimed in claim 8, wherein step (a) is carried in presence of methanol as solvent and at temperature of about 65°C.

10. The process as claimed in claim 8, wherein the ethane sulfonic acid used in step (b) is aqueous ethane sulfonic acid.