DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN 202041003192 filed on January 24, 2020.
FIELD OF THE INVENTION
The present disclosure relates to a process for the preparation of amorphous bictegravir sodium.

BACKGROUND OF THE INVENTION

Bictegravir (formerly known as GS-9883) also referred to as bictegravir free acid is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor that was discovered by Gilead Sciences.

Bictegravir sodium is approved as part of a single tablet regimen in combination with tenofovir alafenamide (TAF) and emtricitabine (FTC) for the treatment of HIV-1 infection under the brand name of BIKTARVY®, marketed by Gilead Sciences. Bictegravir sodium is chemically known as (2R,5S,13aR)- 2,5-Methanopyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, 2,3,4,5,7,9, 13,13a-octahydro-8-hydroxy-7,9-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-, sodium salt (1:1), having the structure below:

Formula-I

Bictegravir is disclosed in U.S Patent No. 9,216,996 B2, which is hereby incorporated by reference. Bictegravir sodium and crystalline Form I of bictegravir sodium is disclosed in U.S Patent No. 9,708,342 B2, which is hereby incorporated by reference.

The inventors of the present disclosure have developed a process for the preparation of amorphous bictegravir sodium.

SUMMARY OF THE INVENTION
One aspect of the present invention is to provide a process for the preparation of amorphous bictegravir sodium, which comprises:
a) dissolving bictegravir in a solvent;
b) adding source of sodium; and
c) isolating amorphous bictegravir sodium.

Another aspect of the present invention is to provide a process for the preparation of amorphous bictegravir sodium, which comprises:
a) providing bictegravir in a solvent;
b) optionally heating the suspension of step (a) to get clear solution;
c) adding a source of sodium at the same temperature; and
d) spray drying the clear solution of step (c) to get amorphous bictegravir sodium.

In another aspect the present invention is to provide a process for the preparation of bictegravir sodium by salt exchange method, which comprises:
a) dissolving bictegravir salt in a solvent;
b) adding source of sodium; and
c) isolating bictegravir sodium.

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.

In one embodiment the present invention is to provides a process for the preparation of amorphous bictegravir sodium, which comprises:
a) dissolving bictegravir in a solvent;
b) adding source of sodium; and
c) isolating amorphous bictegravir sodium.

According to the present invention, bictegravir is dissolved in a solvent at a temperature of 25±5 °C and added sodium source. The reaction mixture is stirred at a temperature of 80±5 °C to obtain a clear solution. The solvent was removed and dried to get amorphous bictegravir sodium.

Within the context of this embodiment of the present invention, the input bictegravir may be any crystalline form known in the art for example as disclosed in WO2015196137A1 and as disclosed in WO20190207602A1.

Within the context of this embodiment of the present invention, the solvent employed may include, water and water miscible organic solvents such as methanol, ethanol, isopropanol, trifluoroethanol, hexafluoro-2-propanol or mixtures thereof. In particular useful embodiments of the present invention mixture of water and methanol is used.

Within the context of this embodiment of the present invention, sodium source employed may include, sodium hydroxide, sodium t-butoxide, sodium methoxide, sodium ethoxide, sodium bicarbonate, sodium carbonate and the like mixtures thereof. The source of sodium can be added as a solution in suitable solvent or it may be added as a solid. In particular useful embodiments of the present invention sodium hydroxide is used as sodium source.

Within the context of this embodiment of the present invention, isolation of amorphous bictegravir sodium involves removing the solvent from a reaction mixture. Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying (e.g., agitated thin-film drying (ATFD)), agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer (RVPD) or any other suitable technique known in the art. In particular useful embodiments of the present invention the solvent is removed by spray drying.

Another embodiment of the present invention is to provide a process for the preparation of amorphous bictegravir sodium, which comprises:
a) providing bictegravir in a solvent;
b) optionally heating the suspension of step (a) to get clear solution;
c) adding a source of sodium at the same temperature; and
d) spray drying the clear solution of step (c) to get amorphous bictegravir sodium.

According to the present invention, bictegravir is dissolved in a solvent at a temperature of 25±5 °C or optionally heated to a temperature of 75±5 °C for complete dissolution and added sodium source. The obtained clear solution is filtered and the solvent was removed using spray drier to get amorphous bictegravir sodium.

Within the context of this embodiment of the present invention, the input bictegravir may be any crystalline form known in the art for example as disclosed in WO2015196137A1 and as disclosed in WO20190207602A1.

Within the context of this embodiment of the present invention, the solvent employed may include, water and water miscible organic solvents such as methanol, ethanol, isopropanol, trifluoroethanol, hexafluoro-2-propanol or mixtures thereof. In particular useful embodiments of the present invention trifluoroethanol or hexafluoro-2-propanol is used.

Within the context of the present disclosure, optional heating for complete dissolution up to reflux temperature of the solvent.

Within the context of this embodiment of the present invention, sodium source employed may include, sodium hydroxide, sodium t-butoxide, sodium methoxide, sodium bicarbonate, sodium carbonate and the like mixtures thereof. The source of sodium can be added as a solution in suitable solvent or it may be added as a solid. In particular useful embodiments of the present invention sodium hydroxide solution (dissolved sodium hydroxide in water) is used as sodium source.

In another embodiment the present invention is to provide a process for the preparation of bictegravir sodium by salt exchange method, which comprises:
a) dissolving bictegravir salt in a solvent;
b) adding source of sodium; and
c) isolating bictegravir sodium.

According to the present invention, bictegravir non-sodium salt is dissolved in a solvent at a temperature of 25±5 °C and added sodium source. The reaction mixture is stirred at a temperature of 80±5 °C to obtain a clear solution. The solvent was removed and dried to get bictegravir sodium.

Within the context of this embodiment of the present invention, the input is bictegravir non-sodium salt, which may include bictegravir ammonium salt, bictegravir diethyl amine salt, bictegravir (R) methyl benzyl amine salt, bictegravir propyl amine salt.

Within the context of this embodiment of the present invention, the solvent employed may include, water and water miscible organic solvents such as methanol, ethanol, isopropanol, trifluoroethanol, hexafluoro-2-propanol or mixtures thereof. In particular useful embodiments of the present invention mixture of water and methanol is used.

Within the context of this embodiment of the present invention, sodium source employed may include, sodium hydroxide, sodium t-butoxide, sodium methoxide, sodium bicarbonate, sodium carbonate and the like mixtures thereof. The source of sodium can be added as a solution in suitable solvent or it may be added as a solid. In particular useful embodiments of the present invention sodium hydroxide is used as sodium source.

Within the context of this embodiment of the present invention, isolation of bictegravir sodium involves removing the solvent from a reaction mixture. Suitable techniques which can be used for the removal of solvent include but not limited to filtration, centrifuge, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying (e.g., agitated thin-film drying (ATFD)), agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer (RVPD) or any other suitable technique known in the art. In particular useful embodiments of the present invention the solvent is removed by spray drying.

Yet, another embodiment the present invention is to provide a process for the preparation of bictegravir sodium, which comprises:
a) dissolving bictegravir sodium in a solvent mixture of trifluoro ethanol, dichloromethane and water; and
b) isolating amorphous bictegravir sodium.

According to the present invention, bictegravir sodium is suspended in a solvent mixture of trifluoroethanol, dichloromethane and water at a temperature of 25±5 °C. The reaction mixture is stirred to obtain a clear solution. The clear solution was filtered and solvent was removed by spray-drying to get amorphous bictegravir sodium.

Within the context of this embodiment of the present invention, the input bictegravir sodium may be any crystalline form known in the art for example as disclosed in WO2015196116A1.

According to the present invention, the input bictegravir is prepared by any prior-art process for example PCT publication No. WO2014100323A1.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and Formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES
Example 1: Preparation of bictegravir:
To a stirred solution of (2R,5S,13aR)-8-methoxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxylic acid (10 gm,1.0 eq) in methylenene dichloride, added N-methyl morpholine(3.47 gm,1.1 eq) at -20±5 °C. Added isobutyl chloroformate(4.46 gm,1.05 eq) to the reaction mixture and stirred for 45 minute at -20±5 °C and added 2,4,6-trifluorobenzyl amine (5.53 gm,1.1eq ), stirred the reaction mixture for 30 minutes at -20±5 °C, further maintained the reaction mixture at 25±5 °C for 2 hours. Quench the reaction mixture with potassium carbonate solution and fallowed by brine washing. To separated organic layer, add lithium bromide (anhydrous) and stir the reaction mixture for 12 hours. at 38±2 °C. Upon completion of the reaction by HPLC, quench the reaction mixture at room temperature fallowed by water washing. Separated the organic layer. Distilled off organic layer atmospherically and finally apply vacuum to remove methylene dichloride traces to get bictegravir.

Example 2: Preparation of crystalline bictegravir ammonium:
Bictegravir (1 g) dissolved in 10 mL of tetrahydrofuran at 25±5°C and added ammonium hydroxide (25-30%) solution 1.5 equivalent. The product precipitated immediately after addition. Stirred the reaction mass for 120 minutes at 25±5°C. The obtained product was filtered, washed with THF (3 mL) and dried under vacuum at 50 °C for 12 hours to get crystalline bictegravir ammonium.
Yield: 0.8 g

Example 3: Preparation of amorphous bictegravir sodium:
Bictegravir ammonia salt (1 g) dissolved in 60 mL methanol and water 80 mL at 25±3°C and added sodium hydroxide 0.95 equivalent at 25±3°C. Stirred the reaction mass for 120 minutes at 80±5°C. The obtained clear solution is carried forward for spray dryer. The obtained amorphous bictegravir sodium was dried under vacuum at 50 °C for 12 hours.
Yield: 0.63 g

Example 4: Preparation of amorphous bictegravir sodium:
Bictegravir (15 g) dissolved in 900 mL methanol and water 900 mL at 25±3°C and added sodium hydroxide 1.26 g (0.95 m. eq) at 25±3°C. Stirred the reaction mass for 120 minutes at 80±5 °C. The obtained clear solution passed through 0.45µ and is carry forward for spray dryer. The product obtained amorphous bictegravir sodium was dried under vacuum at 50 °C for 12 hours.

Example 4: Preparation of amorphous bictegravir sodium:
Bictegravir (5 g) was suspended in 2,2,2-Trifluoro ethanol (150 mL) at 25±5°C and heated to 75±5°C for complete dissolution. Then slowly added sodium hydroxide solution [dissolve Sodium hydroxide (445 mg) in water (25 mL) at 25±5°C] for 15-30 minutes at 75±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates and subjected to spray-drying (during spray-drying reaction mass was maintained at 50-60°C) in a laboratory spray-dryer (Model: Buchi B-290) with feed rate of solution 5 mL/min and inlet temperature at 100°C with 100% aspiration to yield amorphous bictegravir sodium.

Example 5: Preparation of amorphous bictegravir sodium:
Bictegravir (5 g) was suspended in 2,2,2-Trifluoro ethanol (100 mL) at 25±5°C and heated to 75±5°C for complete dissolution. Then slowly added Sodium hydroxide solution [dissolve Sodium hydroxide (445 mg) in water (25 mL) at 25±5°C] for 15-30 minutes at 75±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates and subjected to spray-drying (during spray-drying reaction mass was maintained at 50-60°C) in a laboratory spray-dryer (Model: Buchi B-290) with feed rate of solution 5ml/min and inlet temperature at 100°C with 100% aspiration to yield amorphous bictegravir sodium.

Example 6: Preparation of amorphous bictegravir sodium:
Bictegravir (5 g) was dissolved in 1,1,1,3,3,3-Hexafluoro-2-propanol (25 mL) at 25±5°C. Then slowly added Sodium hydroxide solution [dissolve Sodium hydroxide (445mg) in water (10mL) at 25±5°C] for 15-30min at 25±5°C. The resulting clear solution was filtered through hyflo to remove any undissolved particulates and subjected to spray-drying in a laboratory spray-dryer (Model: Buchi B-290) with feed rate of solution 5ml/min and inlet temperature at 100°C with 100% aspiration to yield amorphous bictegravir sodium.

Example 7: Preparation of amorphous bictegravir sodium:
Bictegravir sodium (5 g) was suspended in a mixture of 2,2,2-Trifluoro ethanol (150 mL) and water (50 mL) at 25±5°C and heated to 75±5°C for complete dissolution. The resulting clear solution was filtered through hyflo to remove any undissolved particulates and subjected to spray-drying (during spray-drying reaction mass was maintained at 50-60°C) in a laboratory spray-dryer (Model: Buchi B-290) with feed rate of solution 5ml/min and inlet temperature at 100°C with 100% aspiration to yield amorphous bictegravir sodium.

Example 8: Preparation of amorphous bictegravir sodium:
Bictegravir sodium (100 g) was suspended in a mixture of 2,2,2-Trifluoro ethanol (500 mL), dichloromethane (600 mL), water (100 mL) and was stirred at ambient temperature to obtain a clear solution. The resulting clear solution was filtered through micron filter and subsequently subjected to spray-drying with feed rate of 5-6 mL/min and inlet temperature at 100-120°C with 100% aspiration to obtain solid, which was further dried under vacuum to afford amorphous bictegravir sodium.
Yield: 80g

,CLAIMS:1. A process for the preparation of amorphous bictegravir sodium, comprising the steps of:
a) dissolving bictegravir in a solvent;
b) adding source of sodium; and
c) isolating amorphous bictegravir sodium.
2. The process as claimed in claim 1, wherein the solvent is selected from the group consisting of water and water miscible organic solvents such as methanol, ethanol, isopropanol, trifluoroethanol, hexafluoro-2-propanol or mixtures thereof.
3. The process as claimed in claim 1, wherein the sodium source is selected from the group consisting of sodium hydroxide, sodium t-butoxide, sodium methoxide, sodium ethoxide, sodium bicarbonate, sodium carbonate and the like mixtures thereof.
4. The process as claimed in claim 1, wherein the solvent is removed by spray drying, thin-film drying or freeze-drying.
5. A process for the preparation of amorphous bictegravir sodium, which comprising the steps of:
a) providing bictegravir in a solvent;
b) optionally heating the suspension of step (a) to get clear solution;
c) adding a source of sodium at the same temperature; and
d) spray drying the clear solution of step (c) to get amorphous bictegravir sodium.
6. The process as claimed in claim 5, wherein the solvent is selected from the group consisting of water and water miscible organic solvents such as methanol, ethanol, isopropanol, trifluoroethanol, hexafluoro-2-propanol or mixtures thereof.

7. The process as claimed in claim 5, wherein the sodium source is selected from the group consisting of sodium hydroxide, sodium t-butoxide, sodium methoxide, sodium ethoxide, sodium bicarbonate, sodium carbonate and the like mixtures thereof.
8. A process for the preparation of amorphous bictegravir sodium, which comprising the steps of:
a) dissolving bictegravir salt in a solvent;
b) adding source of sodium; and
c) isolating bictegravir sodium.
9. The process as claimed in claim 8, wherein bictegravir salt is non-sodium salt, which may include bictegravir ammonium salt, bictegravir diethyl amine salt, bictegravir (R) methyl benzyl amine salt, bictegravir propyl amine salt.
10. The process as claimed in claim 8, wherein the solvent is selected from the group consisting of water and water miscible organic solvents such as methanol, ethanol, isopropanol, trifluoroethanol, hexafluoro-2-propanol or mixtures thereof; and sodium source is selected from the group consisting of sodium hydroxide, sodium t-butoxide, sodium methoxide, sodium ethoxide, sodium bicarbonate, sodium carbonate and the like mixtures thereof.