DESC:
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier Indian provisional patent application No. IN201941041785, filed on October 15, 2019, the entire contents of each of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of amorphous Avatrombopag maleate, Avatrombopag maleate crystalline form B and form C.

BACKGROUND OF THE INVENTION

DOPTELET® tablets contain Avatrombopag maleate, which is indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease
who are scheduled to undergo a procedure. Avatrombopag maleate is chemically known as 1-[3-Chloro-5-[[[4-(4-chloro-2-thienyl)-5-(4-cyclohexyl-1-piperazinyl)-2-thiazolyl]amino]carbonyl]-2-pyridinyl]-4-piperidinecarboxylic acid, (2Z)-2-butenedioate (1:1) having the below structure:

Avatrombopag is first disclosed in U.S Patent No. 7,638,536. Avatrombopag maleate is specifically disclosed in Japan Patent No 4,317,818.

PCT publication No. WO2013018362A1 discloses crystalline forms A, B and C of Avatrombopag maleate, wherein Form B and Form C, are commercially suitable for industrial scaleup, but Form B has inferior oral absorption compared to Form C and Form A.

The inventors of the present invention have developed a novel process for the preparation of amorphous Avatrombopag maleate, crystalline Avatrombopag maleate form B and form C.

SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide a process for the preparation of amorphous Avatrombopag maleate, which comprises:
a) dissolving the 1-[3-Chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid ethyl ester compound of formula-1, in an organic solvent;

b) adding aqueous alkaline solution;
c) heating the solution at a temperature of 50-65°C;
d) cooling the solution to 25±5°C;
e) adding aqueous maleic acid to the reaction mass obtained in step (d) or vice-versa; and
f) removing the solvent to obtain amorphous Avatrombopag maleate.

Another aspect of the present invention is to provide a process for the preparation of Avatrombopag maleate crystalline form B, which comprises:
a) suspending amorphous Avatrombopag maleate in an alcoholic solvent or water at a temperature of 70-85°C;
b) cooling the suspension to 25±5°C; and
c) removing the solvent to obtain Avatrombopag maleate crystalline form B.

Another aspect of the present invention is to provide a process for the preparation of Avatrombopag maleate crystalline form C, which comprises:
a) treating Avatrombopag maleate in a ketone solvent; and
b) removing the solvent to obtain Avatrombopag maleate crystalline form C.

DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

The present invention relates to process for the preparation of amorphous Avatrombopag maleate, Avatrombopag maleate crystalline form B and form C.

In an embodiment, the present invention is to provide a process for the preparation of amorphous Avatrombopag maleate, which comprises:
a) dissolving the 1-[3-Chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid ethyl ester compound of formula-1, in an organic solvent;

b) adding aqueous alkaline solution;
c) heating the solution at a temperature of 50-65°C for 30-60 min under stirring;
d) cooling the solution to 25±5°C;
e) adding aqueous maleic acid to the reaction mass obtained in step (d) or vice-versa; and
f) removing the solvent to obtain amorphous Avatrombopag maleate.

Within the context of this embodiment, ester compound of formula 1 is dissolved in a solvent at 25±5°C, aqueous alkaline solution is added and heated to 50-65°C for 30 to 60 min. Suitable solvents include methanol, ethanol and isopropanol. Preferably the solvent is ethanol.

Suitable alkaline solution includes sodium hydroxide, potassium hydroxide and magnesium hydroxide. Preferably alkaline solution is sodium hydroxide.

Within the context of this embodiment, solution of aqueous maleic acid may be added at 25±5°C to Avatrombopag solution or vice-versa at 25±5°C to obtain amorphous form of Avatrombopag maleate.

Within the context of this embodiment of the present invention, the solvent can be removed using any techniques in the art such as decantation, filtration by gravity or suction and centrifugation. In particular, useful embodiments of the present invention, the solvent is removed by filtration.

Another embodiment of the present invention is to provide a process for the preparation of Avatrombopag maleate crystalline form B, which comprises:
a) suspending amorphous Avatrombopag maleate in aqueous alcoholic solvent or water at a temperature of 70-85°C;
b) cooling the suspension to 25±5°C; and
c) removing the solvent to obtain Avatrombopag maleate crystalline form B.

Within the context of this embodiment of the present invention, amorphous Avatrombopag maleate is treated with aqueous alcoholic solvent at 25±5°C and the suspension is heated to 70-85°C for 30 to 60 min. Suitable alcohol solvents include methanol, ethanol and isopropanol. Preferably the solvent is ethanol.

Within the context of this embodiment, the aqueous alcohol solution is used for this invention about 50% to 90 % alcohol in water, preferably the 80% ethanol in water is used for the preparation of crystalline form B.

Within the context of this embodiment of the present invention, amorphous Avatrombopag maleate is treated with water at 25±5°C and the suspension is heated to a temperature of 70-85°C for 30 to 60 min.

Within the context of this embodiment of the present invention, the suspension of step (a) is cooled to 25±5°C and removed the solvent. The solvent can be removed using any techniques in the art such as decantation, filtration by gravity or suction and centrifugation. In particular, useful embodiments of the present invention, the solvent is removed by filtration.

Another embodiment of the present invention is to provide a process for the preparation of Avatrombopag maleate crystalline form C, which comprises:
a) treating Avatrombopag maleate in a ketone solvent; and
b) removing the solvent to obtain Avatrombopag maleate crystalline form C.

Within the context of this embodiment of the present invention, Avatrombopag maleate is treated with a ketone solvent at 25±5°C and stirred for 14-18 hours. Suitable solvents include acetone, methyl ethyl ketone and Methyl iso butyl ketone. Preferably the solvent is acetone.

Within the context of this embodiment of the present invention, the input Avatrombopag maleate may be crystalline or amorphous and may be prepared by any prior-art process.

Within the context of this embodiment of the present invention, the solvent can be removed using any techniques in the art such as decantation, filtration by gravity or suction and centrifugation. In particular, useful embodiments of the present invention, the solvent is removed by filtration.

EXAMPLES
Example 1: Preparation of amorphous Avatrombopag maleate

1-[3-Chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid ethyl ester (10g; 1.0M) was dissolved in ethanol (90mL) and sodium hydroxide (1.8g; 3.0M) in 45 mL of water was added at 25±5°C. The resulting solution was heated to 55±5°C, stirred for 1 hour and cooled to 25±5°C. Maleic acid (10g; 5.9M) in 100mL of water was added to adjust the pH at 1.0 to 2.0 to form the precipitation. The resulting solid was filtered and washed with water (50mL), suck-dried for 1h and dried at 55±5°C for 16h. The solid obtained was identified as amorphous form of Avatrombopag maleate. Yield: 10.0 g

Example 2: Preparation of amorphous Avatrombopag maleate

1-[3-Chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid ethyl ester (10g; 1.0M) was dissolved in ethanol (90mL) and sodium hydroxide (1.8g; 3.0M) in 45 mL of water was added at 25±5°C. The resulting solution was heated to 55±5°C, stirred for 1 hour and cooled to 25±5°C. Maleic acid (20g; 11.8M) in 200mL of water was added to adjust the pH at 1.0 to 2.0 to form the precipitation. The resulting solid was filtered and washed with water (50mL), suck-dried for 1h and dried at 55±5°C for 16h. The solid obtained was identified as amorphous form of Avatrombopag maleate. Yield: 9.8 g

Example 3: Preparation of amorphous Avatrombopag maleate

1-[3-Chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid ethyl ester (10g; 1.0M) was dissolved in ethanol (90mL) and sodium hydroxide (1.8g; 3.0M) in 45 mL of water was added at 25±5°C. The resulting solution was heated to 55±5°C, stirred for 1 hour and cooled to 25±5°C. This solution was added to maleic acid (10g; 5.9M) dissolved in 100mL of water to adjust the pH at 1.0 to 2.0 to form the precipitation. The resulting solid was filtered and washed with water (50mL), suck-dried for 1h and dried at 55±5°C for 16h. The solid obtained was identified as amorphous form of Avatrombopag maleate. Yield: 10.0 g

Example 4: Preparation of amorphous Avatrombopag maleate

1-[3-Chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid ethyl ester (10g; 1.0M) was dissolved in ethanol (90mL) and sodium hydroxide (1.8g; 3.0M) in 45 mL of water was added at 25±5°C. The resulting solution was heated to 55±5°C, stirred for 1 hour and cooled to 25±5°C. This solution was added to maleic acid (20g; 11.8M) dissolved in 100mL of water to adjust the pH at 1.0 to 2.0 to form the precipitation. The resulting solid was filtered and washed with water (50mL), suck-dried for 1h and dried at 55±5°C for 16h. The solid obtained was identified as amorphous form of Avatrombopag maleate. Yield: 10.0 g

Example 5: Preparation of Avatrombopag maleate crystalline Form B
Amorphous Avatrombopag maleate (2g) was taken in aqueous ethanol (35mL EtOH in 15mL water), heated to 75±5°C and stirred for 1 hour. Resulting suspension was cooled to 25±5°C and filtered, washed with aqueous ethanol (10mL). Suck-dried for 1h and dried at 55±5°C for 16h. The solid obtained was identified as form B of Avatrombopag maleate. Yield 1.5 g

Example 6: Preparation of Avatrombopag maleate crystalline Form B
Amorphous Avatrombopag maleate (55 g) was taken in water (550 ml), heated to 75±5 °C and stirred for 1 hour. Resulting suspension was cooled to 25±5°C and filtered, washed with water (110 ml). suck dried for 1h and dried at 55±5°C for 16 hrs. the solid obtained was identified as form B of Avatrombopag Maleate. Yield 50 g

Example 7: Preparation of Avatrombopag maleate crystalline Form C
Amorphous Avatrombopag maleate (2g) was taken in acetone (30mL) at 25±5°C and stirred for 16 hours. Resulting suspension was filtered, washed with acetone (20 mL). Suck-dried for 1h and dried at 55±5°C for 16h. The solid obtained was identified as form C of Avatrombopag maleate. Yield 1.8 g

Example 8: Preparation of Avatrombopag maleate crystalline Form C
Avatrombopag maleate crystalline Form-B (1g) was taken in acetone (15mL) at 25±5°C and stirred for 16 hours. Resulting suspension was filtered, washed with acetone (10 mL). Suck-dried for 1h and dried at 55±5°C for 16h. The solid obtained was identified as form C of Avatrombopag maleate. Yield 0.8 g
,CLAIMS:1. A process for the preparation of amorphous Avatrombopag maleate, which comprises:
a) dissolving the 1-[3-Chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid ethyl ester compound of formula-1, in an organic solvent;

b) adding aqueous alkaline solution;
c) heating the solution at a temperature of 50-65°C under stirring;
d) cooling the solution to 25±5°C;
e) adding aqueous maleic acid to the reaction mass obtained in step (d) or vice-versa; and
f) removing the solvent to obtain amorphous Avatrombopag maleate.
2. A process as claimed in claim 1, wherein the alkaline solution is selected from sodium hydroxide, potassium hydroxide and magnesium hydroxide.
3. A process as claimed in claim 1, wherein the alkaline solution is sodium hydroxide.
4. A process for the preparation of Avatrombopag maleate crystalline form B, which comprises:
a) suspending amorphous Avatrombopag maleate in aqueous alcoholic solvent or water at a temperature of 70-85°C;
b) cooling the suspension to 25±5°C; and
c) removing the solvent to obtain Avatrombopag maleate crystalline form B.
5. A process as claimed in claim 4, wherein the alcoholic solvent is selected from methanol, ethanol and isopropanol.
6. A process as claimed in claim 4, wherein the alcoholic solvent is ethanol.
7. A process for the preparation of Avatrombopag maleate crystalline form C, which comprises:
a) treating Avatrombopag maleate in a ketone solvent; and
b) removing the solvent to obtain Avatrombopag maleate crystalline form C.
8. A process as claimed in claim 7, wherein the ketone solvent is selected from acetone, methyl ethyl ketone and Methyl iso butyl ketone.
9. A process as claimed in claim 7, wherein the ketone solvent is acetone.
10. A process as claimed in claim 1, 4 and 7 wherein, Avatrombopag maleate is isolated by filtration.