DESC:IMPROVED PROCESS FOR THE PREPARATION OF PURE CRYSTALLINE FORM-I OF CRISABOROLE

FIELD OF THE INVENTION

The present invention relates to improved process for the preparation of pure crystalline Form-I of Crisaborole having purity of greater than 99.8%.

BACKGROUND OF THE INVENTION

Crisaborole (INN; trade names EUCRISA®) is a nonsteroidal topical medication used for the treatment of mild-to-moderate atopic dermatitis (eczema) in adults and children. Crisaborole is a phosphodiesterase 4 (PDE-4) inhibitor. Crisaborole is chemically known as 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole having formula (I):

Crisaborole and its synthesis route were described in patent application WO2006/089067 of Anacor Pharmaceutical Inc. The synthesis route used in WO ‘067 involves numerous steps, and the total yield is not very high, which makes the process expensive.

WO 2017/193914 of Anacor Pharmaceuticals Inc. describes four crystalline Forms (I, II, III & IV) of Crisaborole.

WO 2017/093857 describes three crystalline polymorphic Forms of Crisaborole namely Form-1, Form-2 and Form-3. WO ‘857 discloses crystalline Form-1 is obtained by Crisaborole was dissolved in acetic acid at 70°C followed by the addition water and seeded with Crisaborole.

The prior art process as disclosed in WO '857 involve crystalline Form-1 of Crisaborole method carried out at 70°C, leading to formation of desbromo alcohol impurity (I), having more than 1.15%. In addition, the prior art processes lead to formation of desbromo alcohol impurity (I) is not desirable for commercial-scale manufacturing.

Surprisingly, the present invention is found that the reaction is carried out at 45-50°C and the desbromo alcohol impurity (I) is controlled to below 0.15% level.

It is therefore essential to develop simplified and improved process for the preparation of pure crystalline Form-I of Crisaborole having purity of greater than 99.8%, the resulted product is desbromo alcohol impurity (I) is controlled to below 0.15% level.

The inventors of the present invention have developed improved process for the preparation of pure crystalline Form-I of Crisaborole. The inventors have worked towards developing a cost-effective process for preparing crystalline Form-I of Crisaborole in good yield and purity.

SUMMARY OF THE INVENTION

The present invention relates to improved process for the preparation of pure crystalline Form-I of Crisaborole having purity of greater than 99.8%.

In aspect of the present invention, provides a process for the preparation of pure crystalline Form I of Crisaborole having purity of greater than 99.8%, which comprises the steps of:
a. dissolving the Crisaborole in an acetic acid at 45-50°C,
b. optionally treating the solution obtained in step-a) with seeding material,
c. cooling the reaction mass to a suitable temperature,
d. optionally adding a water to the solution obtained in step c),
e. isolating the pure crystalline Form-I of Crisaborole.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to improved process for the preparation of pure crystalline Form-I of Crisaborole having purity of greater than 99.8%.

In aspect of the present invention, provides a process for the preparation of pure crystalline Form I of Crisaborole having purity of greater than 99.8%, which comprises the steps of:

a. dissolving the Crisaborole in an acetic acid at 45-50°C,
b. optionally treating the solution obtained in step-a) with seeding material,
c. cooling the reaction mass to a suitable temperature,
d. optionally adding a water to the solution obtained in step c),
e. isolating the pure crystalline Form-I of Crisaborole.

According to the embodiment of the present invention, Crisaborole was dissolved in an acetic acid at 45-50°C, optionally treating the solution with seeding material, cooling the reaction mass to a suitable temperature, optionally adding a water to the solution and isolating the pure crystalline Form-I of Crisaborole.

According to the embodiment of the present invention, suitable temperature ranges at 30-45°C, preferably suitable temperature ranges at 35-40°C.

According to the embodiment of the present invention, the reaction is carried out at 45-50°C and the desbromo alcohol impurity (I) is controlled to below 0.15% level, where desbromo alcohol impurity (I) is less than about 0.15% or less than about 0.05 % or less than about 0.005 % or less than about 0.009 or less than about 0.0001.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

EXAMPLES

Crystalline Form-I of Crisaborole:

Example-1:

Crisaborole (100gm) was dissolved in acetic acid (800ml) at 25-35°C, raise the reaction mass temperature at 45-50°C and stir for 10-15 min. Filter the reaction mass and wash with acetic acid (200ml). Filter the reaction mixture was allowing to cool at 35-40°C, seeded with Crisaborole Form-I (0.8% seeding) and maintained at 35-40°C for 15-30 min. The reaction mixture was allowing to cool at 30-35°C and followed by additional seeded with Crisaborole Form-I (0.8% seeding). Further the reaction mass was allowing to cool at 20-25°C, followed by add with water (1000ml). The reaction mixture was stir for 30 to 60min at same temperature. The solid were filtered and washed with water (100ml), further followed by leaching with water (400ml) to give pure crystalline Form-I of Crisaborole.
Purity: = 99.8% (By HPLC)
Yield: 95% (95gm).

Example-2:

Crisaborole (150gm) was dissolved in acetic acid (1000ml) at 25-35°C, raise the reaction mass temperature at 45-50°C and stir for 10-15 min. Filter the reaction mass and wash with acetic acid (250ml). Filter the reaction mixture was allowing to cool at 35-40°C, seeded with Crisaborole Form-I (0.8% seeding) and maintained at 35-40°C for 15-30 min. The reaction mixture was allowing to cool at 30-35°C and followed by additional seeded with Crisaborole Form-I (0.8% seeding). Further the reaction mass was allowing to cool at 20-25°C, followed by add with water (1100ml). The reaction mixture was stir for 30 to 60min at same temperature. The solid were filtered and washed with water (150ml), further followed by leaching with water (500ml) to give pure crystalline Form-I of Crisaborole.
Purity: = 99.8% (By HPLC)
Yield: 96.33% (144.5gm).

Example-3:

Crisaborole (100gm) was dissolved in acetic acid (450ml) at 70°C. The mixture was cooled to 50°C to 55°C, seeded with Crisaborole Form-I (0.8% seeding) and maintained at that temperature for approximately 15 mints. The reaction mixture was then cooled to 47-53°C. followed by addition of water (450ml) over a period of 45 to 60 minute. The obtain reaction mixture was cooled to 25°C-30°C and stir for 2 to 4 hours. The solid were filtered and washed with water (100ml) to give pure crystalline Form-I of Crisaborole.
Purity: = 99.4% (By HPLC)
Yield: 87% (87gm).
,CLAIMS:WE CLAIM:
1. A process for the preparation of pure crystalline Form I of Crisaborole having purity of greater than 99.8%, which comprises the steps of:
a. dissolving the Crisaborole in an acetic acid at 45-50°C,
b. optionally treating the solution obtained in step-a) with seeding material,
c. cooling the reaction mass to a suitable temperature,
d. optionally adding a water to the solution obtained in step c),
e. isolating the pure crystalline Form-I of Crisaborole.

2. The process as claimed in claim 1, wherein the suitable temperature ranges at 30-45°C, preferably suitable temperature ranges at 35-40°C.

3. The process as claimed in claim 1, wherein the desbromo alcohol impurity (I) is controlled to below 0.15% level, where desbromo alcohol impurity (I) is less than about 0.15% or less than about 0.05 % or less than about 0.005 % or less than about 0.009 or less than about 0.0001.