EP3119743A2

EP3119743A2 - An improved process for the preparation of agomelatine polymorphic form-1

Info

Publication number: EP3119743A2
Application number: EP14886181.8A
Authority: EP
Inventors: Manik Reddy Pullagurla; Jagadeesh Babu Rangisetty; Mecheril Valsan Nandakumar; Bhaskar Reddy Pitta
Original assignee: Biophore India Pharmaceuticals Pvt Ltd
Current assignee: Biophore India Pharmaceuticals Pvt Ltd
Priority date: 2014-03-20
Filing date: 2014-12-29
Publication date: 2017-01-25
Also published as: EP3119743A4; WO2015140812A3; WO2015140812A2

Abstract

The invention provides a process for preparation of polymorphic form I of Agomelatine comprising dissolving Agomelatine in a water miscible organic solvent to obtain Agomelatine solution (solution A), preparing a solution of water miscible organic solvent and water (solution B) and cooling to below 0 ºC, adding solution A to solution B at below 0 ºC and precipitating Agomelatine polymorphic Form 1.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF AGOMELATINE

POLYMORPHIC FORM-1 FIELD OF THE INVENTION

The invention relates to a process for the preparation of Form-1 of Agomelatine.

BACKGROUND OF THE INVENTION

Agomelatine, represented by structural formula-I, chemically named as N-[2-(7-methoxy-l- napthalenyl) ethyl] acetamide is a melatonin receptor agonist, and is a new antidepressant and anti-anxiety drug.

Formula-I

EP 0447285 discloses Agomelatine, its preparation and use of Agomelatine as a melatonic receptor agonist. S. Yous et al. in J. Med. Chem. 1992, 35, 1484-1486 described a process for the preparation of Agomelatine in which Agomelatine is obtained from chloroform and water biphasic mixture. Bernard Tinant and Jean-Paul Declercq in Acta Cryst. (1994), C50, 907- 910, first reported detailed crystallographic investigation of Agomelatine produced by Yous et al, and designated as the polymorph form -lof Agomelatine.

EP 0447285 also discloses a process for the preparation of Agomelatine by the reaction of 2- (7-methoxynapth-l-yl)-ethylamine in pyridine with acetyl chloride and finally recrystallization from isopropyl ether. The obtained Agomelatine has a melting point of 109- 110° C, but no information is provided on the crystalline form of the molecule. Later publications consider that the Agomelatine obtained according to the EP 0447285 is the same polymorphic form obtained by Yous et al., but no experimental data is provided. WO2011/054917 Al describes a process for the preparation of crystalline form-1 of Agomelatine which entails dissolving Agomelatine in an organic solvent miscible with water and pouring the solution thus obtained into water having a temperature equal or below 30 °C. Here the minimum lowest temperature we can attain in this process is 0°C as water is used as solvent. In other words Agomelatine is dissolved in a water miscible organic solvent and the obtained solution is poured in to water having a temperature ranging from 0-30°C.

CN101704763A describes a process for the preparation of form-1 of Agomelatine which is very similar to that of WO2011/054917 Al, at a temperature ranging from 0-100°C.

CN101921205A describes a process for the preparation on form-1 of Agomelatine which comprises the steps of: dissolving Agomelatine into a mixed solvent of amide and water with heating, then reducing the temperature and separating out crystals, and drying to obtain a solid.

WO2012/172387A1 describes a process for the preparation of form- VII of Agomelatine, from a solution of Agomelatine in a solvent, characterized in that the Agomelatine is crystallized by instantaneous precipitation from said solution, at a temperature equal to or below -10 °C, said solvent having a freezing point below said temperature. The same process is applied for the preparation of crystalline form-1 of Agomelatine provided that a trigger of Agomelatine form-1 is added at the time of precipitation.

However the inventors have tried to repeat the known methods for the preparation of form- 1 of Agomelatine and found that none of the process is having sufficient reproducibility, because they produce different crystalline forms and often mixtures of different crystalline forms of Agomelatine. Further chloroform solvent which is used by Yous et al. for the preparation of form-1 of Agomelatine is a class II hazardous solvent, which is difficult to remove from the pharmaceutical product to the required limit. In view of above drawbacks, there is a need for an alternative way to prepare form-1 of Agomelatine with consistent reproducibility at an industrial scale. OBJECTS OF THE INVENTION

The main object of the present invention is to provide a process for the preparation of Form-1 of Agomelatine, which overcomes the drawbacks of the known art and is consistently reproducible.

Another object of the present invention is to provide a process for the preparation of form-1 of Agomelatine, which is suitable for bulk scale production. SUMMARY OF THE INVENTION

Accordingly the invention provides a process for the preparation of Agomelatine Form-1 which comprises: i) dissolving Agomelatine in a water miscible organic solvent to obtain Agomelatine solution (solution A);

ii) preparing a solution of water miscible organic solvent and water (solution B) and cooling to below 0 °C;

iii) adding solution A to solution B at below 0 °C;

iv) precipitating Agomelatine polymorphic Form 1.

In the process, the temperature in step ii) is maintained between -10 to -30° C and the temperature in step iii) is maintained between -10 to -30° C.

The water miscible organic solvent is selected from protic solvents and aprotic solvents.

In one embodiment, the protic solvent is selected from the group comprising primary, secondary and tertiary alcohols with a straight or branched, cyclic or acyclic alkyl chain with one to five carbon atoms. In another embodiment, the protic solvent is selected from aliphatic acids.

The aprotic solvent is selected from the group comprising carbonyl compounds, ethers, amides, dimethyl sulfoxide, substituted or unsubstituted morpholines, alkyl amines, substituted or unsubstituted pyrrolidines and acetonitrile.

The ratio of water-miscible organic solvent and water in step ii) is 0.2: 1 to 1:0.2. DETAILED DESCRIPTION OF THE INVENTION

The inventors have conducted a wide range of experiments to obtain the Form-1 of Agomelatine in a reproducible and consistent manner. From the vast study of experiments, inventors have found that minus temperature is very critical for the consistent formation of the Form-1 of Agomelatine.

The present invention can be achieved by the following measures:

Agomelatine is dissolved in a water-miscible organic solvent to obtain Agomelatine solution (solution A).

Water-miscible organic solvent and water are mixed and cooled to below 0° C, preferably -10° C to -30° C, more preferably -15 to -25°C (Solution B). Solution A is added to Solution B at below 0° C, preferably -10°C to -30°C, more preferably - 15°C to -25°C, during which form-1 of Agomelatine is precipitated from the solution.

The resulting heterogeneous reaction mass can be stirred at the same temperature for 1 minute to 3 hrs, preferably 10 minutes to 1.5 hr, more preferably 20 minutes to 45 minutes.

The precipitated form-1 of Agomelatine is then isolated usually by filtration and the obtained wet cake may be washed with water, or water miscible organic solvent, or mixture of water and water miscible organic solvent. The isolated form-1 of Agomelatine is optionally dried in a conventional manner, preferably dried under reduced pressure at below70 ⁰ C, more preferably below 50 ⁰ C.

Water-miscible solvent which is used for the present invention is not particularly restricted, but it is preferred that the water-miscible solvent is pharmaceutically acceptable solvent.

The water-miscible solvents comprise protic and aprotic solvents. Protic solvent is selected from the group comprising of primary, secondary and tertiary alcohols with a straight or branched, cyclic or acyclic alkyl chain with one to five carbon atoms; aliphatic acids. The preferred protic solvents are alcohols like methanol, ethanol and Isopropyl alcohol or the like; aliphatic acids like acetic acid, propionic acid, butyric acid or the like.

Aprotic solvent is selected from the group comprising carbonyl compounds like acetone, 2-butanone, acetaldehyde or the like; ethers like THF, 1,4-dioxane or the like; amides like dimethyl formamide, dimethyl acetamide; other solvents like dimethyl sulfoxide, substituted or unsubstituted morpholines, alkyl amines, substituted or unsubstituted pyrrolidine acetonitrile or the like.

The ratio of water-miscible organic solvent and water is 0.2: 1 to 1:0.2, preferably 0.5:3.0, more preferably 1: 1.

The total amount of water and water-miscible organic solvent is less than 200 volumes, preferably less thanlOO volumes, and more preferably less than 70 volumes with respect to starting material.

The amount of water-miscible organic solvent used for the dissolution of Agomelatine is less than 100 volumes, preferably less than 50 volumes, and more preferably less than 20 volumes. The resulting solution of Agomelatine may optionally include a filtration to remove any un-dissolved particles.

The temperature at which the Agomelatine is dissolved in the water-miscible organic solvent is not particularly critical, but the preferred temperature is 0-50°C.

The Agomelatine that has been used in the present invention can be prepared by any method known in the art.

The invention is further illustrated, but not limited thereto, by the following examples: Example- 1:

5L of water and 5L of methanol was charged in to a reactor and cooled to -10 °C to -20 °C. In a separate flask 1 kg of Agomelatine is dissolved in 6 L of methanol. The resulting solution is filtered to remove insoluble particles and added to the above cold solution of water and methanol in 30-45 minutes, during which white solid precipitated. The reaction mass is further stirred for 50-60 minutes. The solids are collected by filtration, and dried under reduced pressure at below 60 ⁰ C. The XRD of the sample is identical with the known polymorph form-1 of Agomelatine.

Example-2:

500 mL of water and 400 mL of methanol was charged in to RBF and cooled to -20 ⁰ C to - 25 ° C. In a separate flask 100 g of Agomelatine is dissolved in 600 ml of methanol. The resulting solution is filtered to remove insoluble particles and added to the above cold solution of water and methanol in 10-15 minutes, during which white solid precipitated. The reaction mass is further stirred for 90 minutes. The solids are collected by filtration, washed with 100 ml of water, and dried under reduced pressure at below 60° C. The XRD of the sample is identical with the known polymorph form-1 of Agomelatine.

Example-3:

500 mL of water and 500 mL of ethanol was charged in to RBF and cooled to -10° C to -15°C. In a separate flask 100 g of Agomelatine is dissolved in 550 ml of ethanol. The resulting solution is filtered to remove insoluble particles and added to the above cold solution of water and ethanol in 2 hrs, during which white solid precipitated. The solids are collected by immediate filtration, washed with a 50 ml of 1 : 1 mixture of water and ethanol, and dried under reduced pressure at below 60°C. The XRD of the sample is identical with the known polymorph form-1 of Agomelatine.

Example-4:

40 L of water and 50 L of ethanol was charged in to RBF and cooled to -15° C to -20° C. In a separate flask 10 kg of Agomelatine is dissolved in 60 L of methanol. The resulting solution is filtered to remove insoluble particles and added to the above cold solution of water and ethanol in 2 hrs, during which white solid precipitated. The reaction mass is further stirred for 20 minutes. The solids are collected by filtration, and dried under reduced pressure at below 60° C. The XRD of the sample is identical with the known polymorph form-1 of Agomelatine.

Claims

We claim:

1. A process for preparation of Agomelatine Form-1 comprising the steps of: i) dissolving Agomelatine in a water miscible organic solvent to obtain Agomelatine solution (solution A);

ii) preparing a solution of water miscible organic solvent and water (solution B) and cooling to below 0 ° C;

iii) adding solution A to solution B at below 0° C;

iv) precipitating Agomelatine polymorphic Form -1.

2. The process as claimed in claim 1, wherein the temperature in step (ii) is maintained between -10 to -30° C.

3. The process as claimed in claim 1, wherein the temperature in step (iii) is maintained between -10 to -30°C.

4. The process as claimed in claim 1, wherein the water miscible solvent is selected from protic solvents and aprotic solvents.

5. The process as claimed in claim 4, wherein the protic solvent is selected from the group comprising of primary, secondary and tertiary alcohols.

6. The process as claimed in claim 5, wherein said alcohols have straight or branched, cyclic or acyclic alkyl chain with one to five carbon atoms.

7. The process as claimed in claim 4, wherein the protic solvent is selected from aliphatic acids.

8. The process as claimed in claim 1, wherein the aprotic solvent is selected from the group comprising of carbonyl compounds, ethers, amides, dimethyl sulfoxide, substituted or unsubstituted morpholines, alkyl amines, substituted or unsubstituted pyrrolidines and acetonitrile.

9. The process as claimed in claim 1, wherein the ratio of water-miscible organic solvent and water in step (ii) is 0.2: 1 to 1:0.2.