DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10, rule 13)

“A PROCESS FOR PREPARATION OF CABOTEGRAVIR OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF”

Laurus Labs Limited, an Indian company of DS-1, IKP Knowledge Park, Genome Valley, Turkapally, Shameerpet Mandal, Medchal-Malkajgiri district, Hyderabad-500 078, Telangana, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION

The present invention relates to a process for preparation of cabotegravir or its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Cabotegravir is a class of polycyclic carbamoyl pyridone compounds and is chemically known as (3S,11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide, and is approved as free acid and its sodium salt, it has the following structure:

Cabotegravir was approved as its free acid and its sodium salt and sold under the brand name Vocabria® (Cabotegravir Sodium (Tablet; Oral)) & Cabenuva® KIT (combination co-pack of Cabotegravir and Rilpivirine (Suspension, Extended Release; Intramuscular)) for treatment of human immunodeficiency virus type 1 (HIV-1) infection. Further, on December 20, 2021, U.S. FDA approved Cabotegravir free acid under the brand name Apretude® (Cabotegravir extended-release injectable suspension) for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1.

PCT application Number: 2006/116764 (“the ‘764 publication”) discloses a process for preparation of cabotegravir of Formula I and the process involves preparation of cabotegravir using an aldehyde intermediate compound. The ‘764 application disclosed process is as follows:

PCT application Number: 2010/068253 (“the ‘253 publication”) discloses a process for preparation of cabotegravir of Formula I and the process involves preparation of cabotegravir using a diol intermediate compound. The ‘253 application disclosed process is as follows:

PCT application Number: 2011/119566 (“the ‘566 publication”) discloses a process for preparation of cabotegravir of Formula I and the process involves preparation of cabotegravir using an aldehyde intermediate compound. The ‘566 application disclosed process is as follows:

PCT application Number: 2015/177537 (“the ‘537 publication”) discloses a process for preparation of cabotegravir of Formula I and the process involves preparation of cabotegravir using an aldehyde intermediate compound. The ‘537 publication disclosed process is as follows:

PCT application Number: 2016/113372 (“the ‘372 publication”) discloses a process for preparation of cabotegravir of Formula I and the process involves preparation of cabotegravir using a dimethoxy intermediate compound. The ‘372 publication disclosed process is as follows:

Cabotegravir is one of the important approved carbamoylpyridone HIV integrase inhibitors drug available in the market for the treatment of (HIV)-1 infection. Hence it is advantageous to have an alternate process for its preparation of cabotegravir, which is readily amenable to large scale production and free from its impurities.

Thus, the main objective of the present invention is to provide a process for the preparation of cabotegravir or its pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for preparation of cabotegravir or its pharmaceutically acceptable salts thereof.

In accordance with one embodiment, the present invention provides a process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:

Formula I
a) reacting a compound of Formula II with (S)-2-amino-1-propanol to provide a compound of Formula III, wherein R1 and R2 represents C1-6 alkyl or C6-12 aryl;

Formula II Formula III
b) deprotecting the compound of Formula III in presence of a suitable deprotecting agent to provide cabotegravir, and
c) optionally converting the cabotegravir into pharmaceutically acceptable salt of cabotegravir.

In accordance with another embodiment, the present invention provides a process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:
a) reacting a compound of Formula II with (S)-2-amino-1-propanol to provide a compound of Formula III;
b) deprotecting the compound of Formula III in presence of a suitable deprotecting agent to provide cabotegravir, and
c) optionally converting cabotegravir into pharmaceutically acceptable salt of cabotegravir; wherein R1 and R2 represents C1-6 alkyl selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, iso-hexyl and iso-amyl; or C6-12 aryl selected from the group comprising benzyl, benzoyl, p-methoxybenzyl, p- nitrobenzyl, o-nitrobenzyl and p-nitrobenzoyl and the like.

In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula III or its pharmaceutically acceptable salts thereof, comprising: reacting a compound of Formula II with (S)-2-amino-1-propanol to provide a compound of Formula III, wherein R1 and R2 represents C1-6 alkyl or C6-12 aryl.

In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula III or its pharmaceutically acceptable salts thereof, comprising: reacting a compound of Formula II with (S)-2-amino-1-propanol to provide a compound of Formula III, wherein R1 and R2 represents C1-6 alkyl selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, iso-hexyl and iso-amyl; or C6-12 aryl selected from the group comprising benzyl, benzoyl, p-methoxybenzyl, p- nitrobenzyl, o-nitrobenzyl and p-nitrobenzoyl and the like.

In accordance with another embodiment, the present invention provides a process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:

Formula I
a) reacting a compound of Formula IIa with (S)-2-amino-1-propanol to provide a compound of Formula IIIa; and

Formula IIa Formula IIIa
b) converting the compound of Formula IIIa in to cabotegravir or its pharmaceutically acceptable salt of cabotegravir.

In accordance with another embodiment, the present invention provides crystalline compound of Formula IIIa.

Formula IIIa

In accordance with another embodiment, the present invention provides crystalline compound of Formula IIIa characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 1.

In accordance with another embodiment, the present invention provides a crystalline compound of Formula IIIa characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.2, 6.8, 8.7, 10.2, 10.5, 11.4, 13.7, 14.1, 14.9, 15.5, 15.8, 16.3, 16.8, 17.1, 17.2, 17.5, 18.1, 18.3, 18.6, 19.3, 19.8, 20.6, 20.8, 21.2, 21.5, 22.2, 22.6, 23.0, 23.4, 24.4, 24.7, 26.6, 27.0, 27.6, 27.7, 28.5, 28.8, 29.1, 30.2, 30.6, 31.3, 31.9, 32.4, 32.8, 33.8, 34.6 and 35.1 ±0.2° 2?.

In accordance with another embodiment, the present invention provides a crystalline compound of Formula IIIa characterized by a thermogravimetric analysis (TGA) substantially in accordance with Figure 2.

In accordance with another embodiment, the present invention provides a process for preparation of crystalline compound of Formula IIIa, comprising:

Formula IIIa
a) suspending or dissolving a compound of Formula IIIa in a suitable solvent at a suitable temperature,
b) optionally, cooling the reaction mass to below 25°C, and
c) isolating the crystalline compound of Formula IIIa.

In accordance with another embodiment, the present invention provides crystalline cabotegravir.

In accordance with another embodiment, the present invention provides crystalline cabotegravir characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 3.

In accordance with another embodiment, the present invention provides a crystalline cabotegravir characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.5, 10.9, 12.2, 12.4, 13.1, 13.3, 14.5, 14.7, 16.4, 17.0, 17.3, 17.9, 18.2, 18.9, 20.3, 21.9, 22.8, 24.2, 24.4, 24.6, 25.0, 25.8, 26.8, 27.4, 27.7, 28.2, 28.5, 29.5, 30.1, 31.1, 31.7, 32.7, 33.1, 33.5, 35.0 and 35.3 ±0.2° 2?.

In accordance with another embodiment, the present invention provides a crystalline cabotegravir characterized by a thermogravimetric analysis (TGA) substantially in accordance with Figure 4.

In accordance with another embodiment, the present invention provides a process for preparation of crystalline cabotegravir of Formula I, comprising:

Formula I
a) suspending or dissolving cabotegravir of Formula I in a suitable solvent at a suitable temperature,
b) optionally, cooling the reaction mass to below 25°C, and
c) isolating the crystalline cabotegravir of Formula I.

In accordance with another embodiment, the present invention provides a pharmaceutical composition, comprising cabotegravir or its pharmaceutically acceptable salts thereof prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

Figure 1 is the characteristic powder X-ray diffraction (PXRD) pattern of a crystalline compound of Formula IIIa.

Figure 2 is the characteristic thermogravimetric analysis (TGA) of a crystalline compound of Formula IIIa.

Figure 3 is the characteristic powder X-ray diffraction (PXRD) pattern of a crystalline cabotegravir.

Figure 4 is the characteristic thermogravimetric analysis (TGA) of a crystalline cabotegravir.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparation of cabotegravir or its pharmaceutically acceptable salts thereof.

The compounds obtained by the process of the present invention are characterized by X-ray powder diffraction (XRPD) pattern and/or thermo gravimetric analysis (TGA).

The X-Ray powder diffraction data reported herein may be analyzed using PANalytical X’per3pro X-ray powder Diffractometer equipped with a Cu-anode ([?] =1.54 Angstrom), X-ray source operated at 45kV, 40 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°2?; step size=0.01°; and Time per step=50 sec.
Thermogravimetric analysis (TGA) data in the present invention was acquired using TA instruments TGA Q500 thermogravimetric analyzer with universal Analysis 2000 software using the following conditions; Heating rate: 10°C/min; Temperature range: 28±2°C - 250°C; Nitrogen flow: 60mL/minute.

Cabotegravir prepared according to the process disclosed in the known art involves use of aldehyde compound as an intermediate. The aldehyde compound reported in the literature is found unstable, which is difficult to handle and purify and utilizing the same in next steps results in lower yields and purity. The present inventors avoid the use of unstable aldehyde compound and involve use of stable compound of Formula II, which results in high purity and yields.

In accordance with one embodiment, the present invention provides a process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:

Formula I
a) reacting a compound of Formula II with (S)-2-amino-1-propanol to provide a compound of Formula III, wherein R1 and R2 represents C1-6 alkyl or C6-12 aryl;

Formula II Formula III
b) deprotecting the compound of Formula III in presence of a suitable deprotecting agent to provide cabotegravir, and
c) optionally converting cabotegravir into pharmaceutically acceptable salt of cabotegravir.

Unless otherwise specified the term “C1-6 alkyl” used herein is selected from but not limited to methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, iso-hexyl, iso-amyl and the like; preferably methyl or ethyl.

Unless otherwise specified the term “C6-12 aryl” used herein is selected from but not limited to benzyl, benzoyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, p-nitrobenzoyl and the like.

The compound of Formula II, which is used herein as a starting material is known in the art and can be prepared by any known methods. For example, may be prepared as per the process disclosed in IN201741012359.

The step a) of forgoing process involves reaction of a compound of Formula II with (S)-2-amino-1-propanol in presence of an acid and a solvent at a temperature of about 25°C to about reflux temperature; preferably at about 40°C to about 70°C, to obtain a compound of Formula III; wherein R1 and R2 represents C1-6 alkyl or C6-12 aryl; preferably methyl or ethyl.

In an embodiment, the compound of Formula II specifically represented as following Formula IIa;

Formula IIa

The acid used in reaction of a compound of Formula II with (S)-2-amino-1-propanol is selected from the group comprising but not limited to acetic acid, formic acid, trifluoroacetic acid, methane sulfonic acid, ethane sulfonic acid and benzene sulfonic acid and the like and mixture thereof; preferably acetic acid.

The suitable solvent used in reaction of a compound of Formula II with (S)-2-amino-1-propanol is selected from the group comprising but not limited to amides, sulfoxides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and the like and mixtures thereof. The amides include, but are not limited to dimethylacetamide, dimethylformamide, N-methylpyrrolidone and the like and mixtures thereof; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like and mixtures thereof; nitriles include, but are not limited to acetonitrile, propionitrile and the like and mixture thereof; ethers include, but are not limited to tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like and mixture thereof; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like and mixture thereof; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixture thereof; preferably dimethylformamide, acetonitrile, tetrahydrofuran and mixture thereof; more preferably tetrahydrofuran.

The step b) of forgoing process involves deprotection of Formula III, wherein R1 represents C1-6 alkyl or C6-12 aryl; preferably ethyl, in presence of a suitable deprotecting agent to provide the cabotegravir of Formula I. The deprotection of Formula X can be carried out by treating the compound of Formula III with a suitable deprotecting agent in a suitable solvent at a temperature of about 25°C to about reflux temperature; preferably at about 25°C to about 40°C.

In an embodiment, the compound of Formula III specifically represented as following Formula IIIa;

Formula IIIa

The suitable deprotecting agent selected from any one of the following deprotecting agents depends on the nature of the protecting group, which are selected from the group comprising of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetrabutyl ammonium fluoride, borontribromide, borontrichloride, aluminium chloride, prydinehydrochloride, trimethylsilylchloride; or acid deprotecting agent such as hydrochloric acid, trifluoroacetic acid, hydrobromic acid; or metal based deprotecting agent such as magnesium chloride, magnesium iodide, magnesium hydroxide, lithium chloride, lithium iodide, lithium hydroxide, palladium on carbon, palladium hydroxide, Raney nickel, Platinum oxide, Ceric ammonium nitrate in presence of hydrogen source such as ammonium formate or hydrogen gas; or base deprotecting agents such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, potassium carbonate and the like; preferably sodium hydroxide.

The suitable solvent used herein for step b) deprotection reaction is selected from the group comprising but not limited to alcohols, ethers, halogenated hydrocarbons and the like and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, propanol, butanol and the like and mixtures thereof; ethers include, but are not limited to tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like and mixture thereof; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like and mixture thereof; preferably methanol, ethanol, methylene chloride and mixture thereof; more preferably ethanol.

The step c) of forgoing process involves conversion of cabotegravir of Formula I into pharmaceutically acceptable salts such as sodium can be carried out by methods known in the art; For example, treating the compound of Formula I with suitable sodium ion source such as sodium hydroxide in a suitable alcohol solvent such as methanol, ethanol, isopropanol and the like and mixture thereof; preferably ethanol, at a suitable temperature; preferably at about 50°C to about 80°C.

In another embodiment, cabotegravir of Formula I or its pharmaceutically acceptable salt obtained by the processes described as above, having purity of at least about 99% as measured by HPLC, preferably at least about 99.5% as measured by HPLC.

In another embodiment, the present invention provides crystalline compound of Formula IIIa.

In another embodiment, the present invention provides crystalline compound of Formula IIIa characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 1.

In another embodiment, the present invention provides a crystalline compound of Formula IIIa characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.2, 6.8, 8.7, 10.2, 10.5, 11.4, 13.7, 14.1, 14.9, 15.5, 15.8, 16.3, 16.8, 17.1, 17.2, 17.5, 18.1, 18.3, 18.6, 19.3, 19.8, 20.6, 20.8, 21.2, 21.5, 22.2, 22.6, 23.0, 23.4, 24.4, 24.7, 26.6, 27.0, 27.6, 27.7, 28.5, 28.8, 29.1, 30.2, 30.6, 31.3, 31.9, 32.4, 32.8, 33.8, 34.6 and 35.1 ±0.2° 2?.

In another embodiment, the present invention provides a crystalline compound of Formula IIIa characterized by a thermogravimetric analysis (TGA) substantially in accordance with Figure 2.

In another embodiment, the present invention provides a process for preparation of crystalline compound of Formula IIIa, comprising:

Formula IIIa
a) suspending or dissolving a compound of Formula IIIa in a suitable solvent at a suitable temperature,
b) optionally, cooling the reaction mass to below 25°C, and
c) isolating the crystalline compound of Formula IIIa.

The aforementioned step a) process of formation of suspension or solution of compound of Formula IIIa in a suitable solvent selected from the group comprising alcohols include, but are not limited to methanol, ethanol, propanol, butanol, tert-butanol and the like and mixture thereof; preferably ethanol, at a suitable temperature. The suitable temperature may be at about 25°C to about reflux; preferably at about 50°C to about 75°C.

Then the reaction mass may be optionally cooled to below 25°C; preferably to below 10°C, and stirring for a sufficient period of time. Then isolating the crystalline compound of Formula IIIa by any conventional techniques, for example filtration or decantation and drying at a suitable temperature for sufficient period of time.

In another embodiment, the present invention provides crystalline cabotegravir.

In another embodiment, the present invention provides crystalline cabotegravir characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 3.

In another embodiment, the present invention provides a crystalline cabotegravir characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.5, 10.9, 12.2, 12.4, 13.1, 13.3, 14.5, 14.7, 16.4, 17.0, 17.3, 17.9, 18.2, 18.9, 20.3, 21.9, 22.8, 24.2, 24.4, 24.6, 25.0, 25.8, 26.8, 27.4, 27.7, 28.2, 28.5, 29.5, 30.1, 31.1, 31.7, 32.7, 33.1, 33.5, 35.0 and 35.3 ±0.2° 2?.

In another embodiment, the present invention provides a crystalline cabotegravir characterized by a thermogravimetric analysis (TGA) substantially in accordance with Figure 4.

In another embodiment, the present invention provides a process for preparation of crystalline cabotegravir of Formula I, comprising:

Formula I
a) suspending or dissolving cabotegravir of Formula I in a suitable solvent at a suitable temperature,
b) optionally, cooling the reaction mass to below 25°C, and
c) isolating the crystalline cabotegravir of Formula I.

The aforementioned step a) process of formation of suspension or solution of cabotegravir of Formula I in a suitable solvent selected from the group comprising alcohols include, but are not limited to methanol, ethanol, propanol, butanol, tert-butanol and the like and mixture thereof; preferably methanol, at a suitable temperature. The suitable temperature may be at about 25°C to about reflux; preferably at about 50°C to about 65°C

Then the reaction mass may be optionally cooled to below 25°C; preferably to below 20°C, and stirring for a sufficient period of time. Then isolating the crystalline cabotegravir of Formula I by any conventional techniques, for example filtration or decantation and drying at a suitable temperature for sufficient period of time.

In another embodiment, the present invention provides a pharmaceutical composition, comprising cabotegravir or its pharmaceutically acceptable salts thereof prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

EXAMPLES

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

EXAMPLE-1:

Preparation of compound of Formula IIIa

Compound of Formula IIa (100 gm), toluene (1470 mL) and acetic acid (71 gm) were added in to a round bottom flask and heated to 50-55°C and stirred for 3-4 hrs at same temperature. To the reaction mass (S)-2-amino-1-propanol (32.1 gm) was added at 50-55°C. Reaction mass was further heated to 80-85°C and allowed to stirred for 14-15 hrs at same temperature. After completion of the reaction, reaction mass was concentrated under vacuum at below 60°C and was cooled to 25-30°C. To the reaction mass methylene chloride (600 mL) and water (200 mL) and organic and aqueous layers were separated. The organic layer was treated with sodium bicarbonate solution (500 mL) and was separated and concentrated the organic layer under vacuum at below 50°C to obtain a solid. The obtained solid was dissolved in ethanol (600 mL) at 75-80°C. Reaction mass was concentrated under atmospheric pressure at below 75-80°C. Then the reaction mass was cooled to 0-5°C and stirred for 1 hr at same temperature. Precipitated solid was filtered and washed with chilled ethanol (80 mL) and dried the wet material under vacuum at 70-75°C to obtain title compound. Wt: 101 gm; PXRD: Fig. 1; TGA: Fig. 2 and MR = 190.1-191.2°C.

EXAMPLE-2:

Preparation of Cabotegravir

Sodium hydroxide (92.5 gm), ethanol (500 mL) were added in to a round bottom flask at 25-30°C and allowed to stir for 60 min at same temperature. Reaction mass was cooled to 10-15°C and a solution of compound of Formula IIIa (100 gm) in methylene chloride (700 mL) was added. Then the reaction mass was heated to 30-35°C and stirred for 6-7 hr at same temperature. After completion of the reaction, reaction mass was coolled to 5-10°C and methylene chloride (300 mL), water (500 mL) were added and stirred for 15 min at same temperature. To the reaction mass diluted HCl (220 mL) was added at 5-10°C. Reaction mass was heated to 30-35°C and separated the organic and aqueous layers. Organic layer was washed with 5% sodium bicarbonate (5×500 mL) and water (500 mL). Then the combined organic layer was concentrated under vacuum at below 50°C to obtain a residue. The obtained residue was dissolved in methanol (300 mL) and heated to reflux for 30 min. Then the solution was cooled to 10-15°C and stirred for 1 hr at same temperature. The precipitated solids were filtered and washed with chilled methanol (50 mL) and dried the wet material under vacuum at 50-55°C for about 4 hrs to obtain title compound. Wt: 85 gm; PXRD: Fig. 3 and TGA: Fig. 4.

EXAMPLE-3:

Preparation of Cabotegravir Sodium

A mixture of cabotegravir (100 g) and ethanol (366.6 ml) was heated to 75-80°C and stirred for 15 mins. To this, 2N sodium hydroxide solution (prepared by dissolving 10.5 g of sodium hydroxide in 126.6 ml of water) was added at 75-80°C and stirred for 30 mins at the same temperature. Then the reaction mass was cooled to 25-35°C and was stirred for 30 min at same temperature. Precipitated solid was filtered, washed with ethanol (400 mL), suck dried and dried at 50-55°C for 12 hrs to get the title compound. Wt: 105 gm.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.
,CLAIMS:We claim:

1. A process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:

Formula I
a) reacting a compound of Formula II with (S)-2-amino-1-propanol in presence of an acid and a solvent to provide a compound of Formula III, wherein R1 and R2 represents C1-6 alkyl or C6-12 aryl;

Formula II Formula III
b) deprotecting the compound of Formula III in presence of a suitable deprotecting agent to provide cabotegravir, and
c) optionally converting the cabotegravir into pharmaceutically acceptable salt of cabotegravir.

2. The process as claimed in claim 1, wherein the C1-6 alkyl is selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, iso-hexyl, iso-amyl; and C6-12 aryl is selected from the group comprising benzyl, benzoyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl and p-nitrobenzoyl.

3. The process as claimed in claim 1, wherein the acid is selected from the group comprising acetic acid, formic acid, trifluoroacetic acid, methane sulfonic acid, ethane sulfonic acid and benzene sulfonic acid and mixture thereof.

4. The process as claimed in claim 1, wherein the solvent is selected from the group comprising dimethylacetamide, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, acetonitrile, propionitrile, tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, methylene chloride, ethylene chloride, chloroform, toluene, xylene and mixture thereof.

5. The process as claimed in claim 1, wherein the suitable deprotecting agent is selected from the group comprising 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetrabutyl ammonium fluoride, borontribromide, borontrichloride, aluminium chloride, prydinehydrochloride, trimethylsilylchloride, hydrochloric acid, trifluoroacetic acid, hydrobromic acid, magnesium chloride, magnesium iodide, magnesium hydroxide, lithium chloride, lithium iodide, lithium hydroxide, palladium on carbon, palladium hydroxide, Raney nickel, Platinum oxide, Ceric ammonium nitrate in presence of hydrogen source, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and potassium carbonate.

6. The process as claimed in claim 1, wherein both R1 and R2 are ethyl; wherein the acid is acetic acid; wherein the solvent is toluene; and wherein the deprotecting agent is sodium hydroxide.

7. A process for preparation of crystalline compound of Formula IIIa, comprising:

Formula IIIa
a) suspending or dissolving a compound of Formula IIIa in a suitable solvent at a suitable temperature,
b) optionally, cooling the reaction mass to below 25°C, and
c) isolating the crystalline compound of Formula IIIa.

8. The process as claimed in claim 7, wherein the suitable solvent is selected from the group comprising methanol, ethanol, propanol, butanol, tert-butanol and mixture thereof.

9. A process for preparation of crystalline cabotegravir of Formula I, comprising:

Formula I
a) suspending or dissolving cabotegravir of Formula I in a suitable solvent at a suitable temperature,
b) optionally, cooling the reaction mass to below 25°C, and
c) isolating the crystalline cabotegravir of Formula I.

10. The process as claimed in claim 9, wherein the suitable solvent is selected from the group comprising methanol, ethanol, propanol, butanol and tert-butanol and mixture thereof.