DESC:Field of the invention
The present invention relates to a process for the preparation of amorphous Idelalisib of formula-1.
Background of the Invention
The chemical name for Idelalisib is 5-Fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6- ylamino)propyl]quinazolin-4(3H)-one and characterized by the CAS registry number 870281-82-6. Idelalisib has molecular formula of C22H18FN7O and molecular weight of 415.42 gm/mol.

Idelalisib is an antineoplastic agent, which is used for the treatment of chronic lymphocytic leukemia (CLL), follicular B-cell non-Hodgkin lymphoma (FL) and small lymphocytic lymphoma (SLL). It acts as a phosphoinositide 3-kinase inhibitor and specifically blocks the delta isoform of the enzyme phosphoinositide 3-kinase.

Idelalisib was reported for the first time in US patent number 6,800,620. Various processes for the preparation of Idelalisib have been disclosed in patent applications WO2005113554, CN104130261, CN104262344 and WO2015095601.

Further, the PCT application WO2015092810 discloses process for the preparation of amorphous Idelalisib by using spray drying. Each of these references are hereby incorporated by way of reference in their entirety.

Idelalisib is an oncology product and needs to be handled in isolators or in controlled area, so the isolation techniques known in the art raise lots of safety concerns. In addition to this, handling of the rotary evaporator for the isolation of such products at plant scale is difficult unit operation.

Therefore, there is a need to develop industrially feasible alternative process for the preparation of amorphous Idelalisib. It is found that the present invention meets this objective and thus provides a process for the preparation of amorphous Idelalisib that is industrially advantageous.

Objects of the Invention

The main objective of the present invention is to provide a process for the preparation of amorphous Idelalisib.

Another objective of the present invention is to provide a process for the preparation of stable amorphous form of Idelalisib, which is substantially free from residual solvents.

Summary of the Invention

In one aspect, the present invention is directed to a process for the preparation of amorphous Idelalisib, comprising the step of precipitating amorphous Idelalisib from a solution comprising Idelalisib.

In another aspect, the present invention is directed to a process for the preparation of amorphous Idelalisib, comprising the steps of:
a) providing a solution-1 of Idelalisib in solvent-1;
b) contacting the solution-1 of step (a) with solvent-2 to obtain a reaction mixture; and
c) isolating amorphous Idelalisib from the reaction mixture obtained in the step (b).

Brief description of the drawing

Figure-1: The PXRD pattern of amorphous Idelalisib according to present invention.

Detailed Description of the Invention

The present invention relates to a process for the preparation of amorphous Idelalisib.

In first aspect, the present invention relates to a process for the preparation of amorphous Idelalisib comprising the step of precipitating amorphous Idelalisib from a solution comprising Idelalisib.

In one embodiment the solution of Idelalisib is obtained either by dissolving or suspending Idelalisib in one or more solvents. Alternatively, the solution of Idelalisib in a solvent is obtained directly from the reaction mixture obtained from the reaction of its precursors.

The term “solution” used herein interchangeably represents the solution or suspension, wherein the Idelalisib is either dissolved or suspended in the solvent.

In another aspect, the present invention relates to a process for the preparation of amorphous Idelalisib, comprising the steps of:
a) providing a solution-1 of Idelalisib in solvent-1;
b) contacting the solution-1 of step (a) with solvent-2 to obtain a reaction mixture; and
c) isolating amorphous Idelalisib from the reaction mixture obtained in the step (b).

In one embodiment, the solvent-1 of step (a) comprises one or more solvent selected from water, alcohol, ketone, tetrahydrofuran, 2-methyltetrahydrofuran or mixtures thereof.

The ketone is selected from acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone and methyl isobutyl ketone. The alcohol is selected from methanol, ethanol, isopropanol, 2- propanol, 1-butanol, t-butyl alcohol, 1-pentanol and 2-pentanol.

In the preferred embodiment, the solvent-1 is selected from acetone, methanol, tetrahydrofuran, water and a mixture thereof.

In another embodiment, the solution-1 of Idelalisib in solvent-1 is obtained either by dissolving or suspending Idelalisib in solvent-1. Alternatively, the solution-1 of Idelalisib in solvent-1 is obtained directly from the reaction, wherein the Idelalisib is synthesized from its precursors in solvent-1.

In one more embodiment, the solvent-2 of step (b) preferably comprises water.

In one more embodiment, the reaction mixture obtained after contacting the solution-1 with the solvent-2 is heated to a suitable temperature, preferably at 30-100 °C, more preferably at 50-100 °C and most preferably at 50-60 °C. The reaction mass obtained after heating is further cooled to a suitable temperature to precipitate an amorphous Idelalisib.

In one more embodiment, the precipitated amorphous Idelalisib is isolated by conventional techniques known in the art.

In one more embodiment, the process of the present invention further optionally comprises one or more steps of drying. In the preferred embodiment, the obtained amorphous Idelalisib is dried under reduced pressure at suitable temperature, preferably between about 30 oC and about 80 oC.

The obtained amorphous Idelalisib is stable under normal stability conditions and is substantially free from residual solvents. There is no physical change observed from amorphous form to crystalline form during the stability. Therefore, the product obtained is a pharmaceutical grade solid form of Idelalisib and is suitable for the therapeutic use.

In one more aspect of the present invention, the amorphous Idelalisib obtained from the process described herein may be used in a pharmaceutical composition. In one embodiment, such pharmaceutical composition comprises amorphous Idelalisib obtained by the processes disclosed herein, and one or more pharmaceutically acceptable carriers or excipients.

Present invention is further illustrated with the following non-limiting examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

Examples:

Example-1: Preparation of amorphous Idelalisib
To solution of Idelalisib (20 gm) in acetone (100 ml), water (20 ml) was added. The reaction mass was heated at 50-55 °C with stirring. The reaction mass was then cooled to 25-30 °C and added to pre-chilled water (400 ml). The reaction mass was further cooled to 3-4 °C and stirred for 1-2 hours. Precipitated solid was separated by filtration, washed with chilled water (160 ml) and dried under reduced pressure at 50-55 °C to yield the title product. (17.6 gm).
Moisture content: 2.5%

Example-2: Preparation of amorphous Idelalisib
To solution of Idelalisib (20 gm) in acetone (100 ml), water (20 ml) was added. The reaction mass was heated at 50-55 °C with stirring. The reaction mass was then cooled to 25-30 °C and added to pre-chilled water (400 ml). The reaction mass was further cooled to 8-9 °C and stirred for 1-2 hours. Precipitated solid was separated by filtration, washed with chilled water (80 ml) and dried under reduced pressure at 50-55 °C to yield the title product. (15.6 gm).
Moisture content: 2.5%

Example-3: Preparation of amorphous Idelalisib
To solution of Idelalisib (20 gm) in tetrahydrofuran (60 ml), water (20 ml) was added. The reaction mass was heated at 50-55 °C with stirring. The reaction mass was then cooled to 25-30 °C and added to pre-chilled water (400 ml). The reaction mass was further cooled to 3-6 °C and stirred for 1-2 hours. Precipitated solid was separated by filtration, washed with chilled water (80 ml) and dried under reduced pressure at 50-55 °C to yield the title product. (14.0 gm).
Moisture content: 2.04%

Example-4: Preparation of amorphous Idelalisib
To solution of Idelalisib (20 gm) in acetone (100 ml) and methanol (2 ml), water (20 ml) was added. The reaction mass was heated at 50-55 °C with stirring. The reaction mass was then cooled to 25-30 °C and added to pre-chilled water (400 ml). The reaction mass was further cooled to 3-7 °C and stirred for 1-2 hours. Precipitated solid was separated by filtration, washed with chilled water (80 ml) and dried under reduced pressure at 50-55 °C to yield the title product. (14.0 gm).
Moisture content: 3.23%
,CLAIMS:1. A process for the preparation of amorphous Idelalisib, comprising the steps of:
a) providing a solution-1 of Idelalisib in solvent-1;
b) contacting the solution-1 of step (a) with solvent-2 to obtain a reaction mixture; and
c) isolating amorphous Idelalisib from the reaction mixture of step (b).

2. The process according to claim 1, wherein the solution-1 is prepared by dissolving or suspending Idelalisib in solvent-1.

3. The process according to claim 1 and 2, wherein the solvent-1 is selected from water, alcohol, ketone, tetrahydrofuran, 2-methyltetrahydrofuran and mixtures thereof.

4. The process according to claim 3, wherein the alcohol is selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol and 2-pentanol.

5. The process according to claim 3, wherein the ketone is selected from acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone and methyl isobutyl ketone.

6. The process according to claim 1, wherein the solvent-2 is water.

7. The process according to claim 1, wherein the process further comprises drying amorphous Idelalisib.

8. Amorphous Idelalisib prepared by the process according to claim 1.

9. A process for the preparation of amorphous Idelalisib substantially as described herein.