DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10, rule 13)

“PROCESS FOR PREPARATION OF CABOTEGRAVIR”

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 cabotegravir and its intermediates thereof. The present invention further relates to a process for purification cabotegravir and its pharmaceutical composition 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 (s): 2006/116764 (“the ‘764 publication”), 2010/068253 (“the ‘253 publication”), 2010/011814 (“the ‘814 publication”) and 2015/177537 (“the ‘537 publication”) discloses a processes for preparation of cabotegravir by deprotection of protected cabotegravir and the process involves isolation of cabotegravir either from a mixture of methanol and methylene chloride or ethanol or from a mixture of water and tetrahydrofuran. The disclosed deprotection process is as follows:

PCT application Number: 2011/119566 (“the ‘566 publication”) discloses a process for preparation of cabotegravir by coupling of compound of Formula XIa with 2,4-difluorobenzylamine in presence of carbonyldiimidazole (CDI) and dimethoxyethane (DME) to obtain methyl protected cabotegravir of Formula XII followed by deprotection of Formula XII to obtain cabotegravir. The ‘566 application process involves isolation of cabotegravir from a mixture of water and tetrahydrofuran. The ‘566 application disclosed process is as follows:

PCT application Number: 2016/113372 (“the ‘372 publication”) discloses a process for preparation of cabotegravir and the process involves isolation of cabotegravir from methyl tert-butyl ether. The ‘372 application disclosed process is as follows:

PCT application Number: 2018/109786 (“the ‘786 publication”) discloses crystalline cabotegravir Form C-I and cabotegravir Form C-II and its process.

Cabotegravir or its pharmaceutically acceptable salts is one of the important approved carbamoylpyridone HIV integrase inhibitors drug available in the market for the treatment of (HIV)-1 infection. Cabotegravir prepared according to the reported methods always involves contamination with unreacted starting materials, by-products generated from the coupling agents used and process impurities and all these must be controlled at the source level itself otherwise the same may carry forward to further stage of the synthesis and leads to burden at final stage of the process as the purification to remove these impurities at final stage is always compromise the valuable product yield.

Hence, there exists a need in the art to develop a process for preparation and purification of cabotegravir API consistently, which is readily amenable to large scale production and free from its starting material and impurities. Thus, the main objective of the present invention is to provide an improved and effective process for preparation of cabotegravir, which is commercially feasible on large scale production with greater yield and with higher purity.

SUMMARY OF THE INVENTION

The present invention encompasses a process for preparation of cabotegravir and its intermediates thereof. The present invention further encompasses a process for purification of cabotegravir and its pharmaceutical composition thereof.

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

Formula I
a) reacting a compound of Formula XI’ with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent to obtain a compound of Formula XII’; wherein the “P” represents an alkyl, aryl or aralkyl, and

Formula XI’ Formula XII’
b) deprotecting the compound of Formula XII’ in presence of a suitable deprotecting agent to obtain cabotegravir; wherein the step a) and/or step b) comprises use of an acid prior to isolation of the corresponding product.

In accordance with another embodiment, the present invention provides process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:
a) reacting a compound of Formula XI’ with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent to obtain a compound of Formula XII’; wherein the “P” represents an alkyl, aryl or aralkyl, and
b) deprotecting the compound of Formula XII’ in presence of a suitable deprotecting agent to obtain cabotegravir;
wherein the step a) comprises use of an acid to obtain a compound of Formula XII’ contain less than 0.5% by HPLC of at least one of 2,4-difluorobenzylamine and by-products of coupling agent; and/or wherein the step b) comprises use of an acid to obtain cabotegravir contain less than 0.5% by HPLC of an open chain impurity of cabotegravir.

Open chain impurity of cabotegravir

In accordance with another embodiment, the present invention provides process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:
a) reacting a compound of Formula XI’ with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent to obtain a compound of Formula XII’; wherein the “P” represents an alkyl, aryl or aralkyl, and
b) deprotecting the compound of Formula XII’ in presence of a suitable deprotecting agent to obtain cabotegravir;
wherein the step a) comprises use of an acid to obtain a compound of Formula XII’ contain less than 0.5% by HPLC of at least one of 2,4-difluorobenzylamine and by-products of coupling agent; and/or wherein the step b) comprises use of an acid to obtain cabotegravir contain less than 0.5% by HPLC of an open chain impurity of cabotegravir;
wherein the acid is either organic acid or inorganic acid with the proviso that wherein said organic acid or inorganic acid excludes hydrochloric acid and sulfuric acid.

In accordance with another embodiment, the present invention provides process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:
a) reacting a compound of Formula XI’ with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent; wherein the “P” represents an alkyl, aryl or aralkyl,
b) treating the step a) reaction mass with an acid,
c) isolating the compound of Formula XII’ contain less than 0.5% by HPLC of at least one of 2,4-difluorobenzylamine and by-products of coupling agent,
d) deprotecting the compound of Formula XII’ obtained in step c) in presence of a suitable deprotecting agent,
e) treating the step d) reaction mass with an acid, and
f) isolating the cabotegravir contain less than 0.5% by HPLC of an open chain impurity of cabotegravir.

In accordance with another embodiment, the present invention provides process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:
a) reacting a compound of Formula XI’ with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent; wherein the “P” represents an alkyl, aryl or aralkyl,
b) treating the step a) reaction mass with an acid,
c) isolating the compound of Formula XII’ contain less than 0.5% by HPLC of at least one of 2,4-difluorobenzylamine and by-products of coupling agent, and
d) converting the compound of Formula XII’ in to cabotegravir or its pharmaceutically acceptable salts thereof.

In accordance with another embodiment, the present invention provides process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:
a) deprotecting a compound of Formula XII’, wherein the “P” represents an alkyl, aryl or aralkyl, in presence of a suitable deprotecting agent,
b) treating the step a) reaction mass with an acid, and
c) isolating the cabotegravir contain less than 0.5% by HPLC of an open chain impurity of cabotegravir.

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

Formula I
a) reacting a compound of Formula XIa with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent to obtain a compound of Formula XII, and

Formula XIa Formula XII
b) deprotecting the compound of Formula XII in presence of a suitable deprotecting agent to provide cabotegravir;
wherein the step a) comprises use of an acid to obtain a compound of Formula XII contain less than 0.5% by HPLC of at least one of 2,4-difluorobenzylamine and by-products of coupling agent; and/or wherein the step b) comprises use of an acid to obtain cabotegravir contain less than 0.5% by HPLC of an open chain impurity of cabotegravir.

In accordance with another embodiment, the present invention provides process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:
a) reacting a compound of Formula XIa with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent to obtain a compound of Formula XII, and
b) deprotecting the compound of Formula XII in presence of a suitable deprotecting agent to provide cabotegravir;
wherein the step a) comprises use of an acid to obtain a compound of Formula XII contain less than 0.5% by HPLC of at least one of 2,4-difluorobenzylamine and by-products of coupling agent; and/or wherein the step b) comprises use of an acid to obtain cabotegravir contain less than 0.5% by HPLC of an open chain impurity of cabotegravir;
wherein the acid is either organic acid or inorganic acid with the proviso that wherein said organic acid or inorganic acid excludes hydrochloric acid and sulfuric acid.

In accordance with another embodiment, the present invention provides process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:
a) reacting a compound of Formula XIa with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent to obtain a compound of Formula XII,
b) treating the step a) reaction mass with an acid,
c) isolating the compound of Formula XII contain less than 0.5% by HPLC of at least one of 2,4-difluorobenzylamine and by-products of coupling agent,
d) deprotecting the compound of Formula XII in presence of a suitable deprotecting agent,
e) treating the step d) reaction mass with an acid, and
f) isolating the cabotegravir contain less than 0.5% by HPLC of an open chain impurity of cabotegravir.

In accordance with another embodiment, the present invention provides process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising: deprotecting a compound of Formula XII’ in presence of magnesium chloride to provide cabotegravir; wherein the “P” represents an alkyl, aryl or aralkyl.

Formula XII’ Formula I

In accordance with another embodiment, the present invention provides process for preparation of cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising: deprotecting a compound of Formula XII in presence of magnesium chloride to provide a cabotegravir of Formula I.

Formula XII Formula I

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

In another embodiment, the present invention provides crystalline compound of Formula XII characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 2.

In another embodiment, the present invention provides a crystalline compound of Formula XII characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.5, 6.1, 9.7, 11.4, 12.1, 13.3, 13.7, 15.1, 15.6, 15.9, 16.3, 16.9, 17.2, 17.4, 18.2, 19.2, 19.5, 19.8, 20.3, 20.4, 20.7, 22.3, 22.8, 23.0, 23.1, 23.5, 23.8, 23.9, 24.1, 24.4, 24.5, 25.4, 25.5, 26.2, 26.9, 27.0, 27.6, 28.5, 28.9, 29.1, 29.6, 29.7, 30.6, 30.7, 31.2, 31.5, 32.1, 32.6, 32.9, 33.4, 34.5 and 35.1 ±0.2° 2?.

In accordance with another embodiment, the present invention provides a process for purification of cabotegravir of Formula I, comprising:
a) suspending or dissolving cabotegravir in a suitable solvent at ambient temperature to reflux,
b) adding step a) reaction mass to an anti-solvent (or) adding an anti-solvent to step a) reaction mass at a suitable temperature,
c) optionally, cooling the step b) reaction mass to below 25°C, and
d) isolating the pure cabotegravir.

In accordance with another embodiment, the present invention provides a process for purification of cabotegravir of Formula I, comprising:
a) suspending or dissolving cabotegravir in a suitable solvent at ambient temperature to reflux,
b) adding step a) reaction mass to an anti-solvent (or) adding an anti-solvent to step a) reaction mass at a suitable temperature,
c) optionally, cooling the step b) reaction mass to below 25°C, and
d) isolating the pure cabotegravir; wherein the suitable solvent is selected from the group comprising alcohols, amides, sulfoxides, nitriles, halogenated solvents, sulfolane, acetic acid and the like and mixtures thereof; and wherein the anti-solvent is selected from the group comprising alcohols, ethers, esters, ketones, aromatic hydrocarbons and the like and water and mixtures thereof.

In accordance with another embodiment, the present invention provides process for preparation of pure cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:
a) reacting a compound of Formula XI’ with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent; wherein the “P” represents an alkyl, aryl or aralkyl,
b) treating the step a) reaction mass with an acid,
c) isolating the compound of Formula XII’ contain less than 0.5% by HPLC of at least one of 2,4-difluorobenzylamine and by-products of coupling agent,
d) deprotecting the compound of Formula XII’ obtained in step c) in presence of a suitable deprotecting agent,
e) treating the step d) reaction mass with an acid,
f) isolating the cabotegravir contain less than 0.5% by HPLC of an open chain impurity of cabotegravir,
g) suspending or dissolving cabotegravir in a suitable solvent at ambient temperature to reflux,
h) adding step g) reaction mass to an anti-solvent (or) adding an anti-solvent to step g) reaction mass at a suitable temperature,
i) optionally, cooling the step h) reaction mass to below 25°C, and
j) isolating the pure cabotegravir.

In accordance with another embodiment, the present invention provides process for preparation of pure cabotegravir of Formula I or its pharmaceutically acceptable salts thereof, comprising:
a) deprotecting a compound of Formula XII’ in presence of a suitable deprotecting agent,
b) treating the step a) reaction mass with an acid,
c) isolating the cabotegravir contain less than 0.5% by HPLC of an open chain impurity of cabotegravir,
d) suspending or dissolving cabotegravir in a suitable solvent at ambient temperature to reflux,
e) adding step d) reaction mass to an anti-solvent (or) adding an anti-solvent to step d) reaction mass at a suitable temperature,
f) optionally, cooling the step e) reaction mass to below 25°C, and
g) isolating the pure cabotegravir.

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 cabotegravir prepared according to the present invention.

Figure 2 is the characteristic powder X-ray diffraction (PXRD) pattern of a crystalline compound of Formula XII prepared according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparation of cabotegravir and its intermediates thereof with high product yield and quality substantially lower level of impurities, by-products and unreacted starting materials. The present invention further provides a process for purification of cabotegravir and its pharmaceutical composition thereof.

Cabotegravir prepared according to the process disclosed under the reported publications have certain drawbacks as it involves:
a) contamination of unreacted 2,4-difluorobenzylamine and an imidazole, a by-product of coupling agent used in the preparation of compound of Formula XII;
b) formation of open chain impurity of cabotegravir in the deprotection step. This impurity may be formed under strong acidic conditions at higher temperatures by oxazole ring cleavage, and

Open chain impurity of cabotegravir
c) with the use of deprotecting agents as reported in the art there is always possibility of incomplete reaction therefore the unreacted compound of Formula XII is also isolated as an impurity with the resulted cabotegravir.

These impurities once formed along with the intermediates and if failure to apply proper removal techniques the same may carry forward through subsequent reactions and may contaminate with the final cabotegravir API. Due to less polarity differences, removal of these impurities at the intermediate stage itself is critical and it requires extensive purification processes at final stage. Purification techniques at final stage are always compromise the valuable product yield; hence all these impurities and by-products are needs to be controlled at the source level itself.

The present inventors have surprisingly found that various strategies to control or removal of these impurities and by-products at prior to isolation of the intermediates stage and this will reduces the purification burden at intermediate stage or at final stage of the process thereby getting higher yield and high pure product.

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

Formula I
a) reacting a compound of Formula XI’ with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent to obtain a compound of Formula XII’; wherein the “P” represents an alkyl, aryl or aralkyl, and

Formula XI’ Formula XII’
b) deprotecting the compound of Formula XII’ in presence of a suitable deprotecting agent to obtain cabotegravir; wherein the step a) and/or step b) comprises use of an acid prior to isolation of the corresponding product.

As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having” or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.
Unless otherwise specified the term “alkyl” used herein is selected from but not limited to methyl, ethyl, isopropyl, butyl, tert-butyl, isoamyl and the like; preferably methyl.

Unless otherwise specified the term “aryl” or “aralkyl” used herein is selected from but not limited to benzyl, benzoyl, para nitro benzyl and the like.

In a specific embodiment, wherein the “P” represents an alkyl preferably methyl or an aryl preferably benzyl.

In accordance with a specific embodiment, the compound of Formula XI’ and Formula XII’ specifically represents as following compound of Formula XIa and Formula XII:

Formula XIa Formula XII

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

Formula I
a) reacting a compound of Formula XIa with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent to obtain a compound of Formula XII, and

Formula XIa Formula XII
b) deprotecting the compound of Formula XII in presence of a suitable deprotecting agent to obtain cabotegravir;
wherein the step a) comprises use of an acid to obtain the compound of Formula XII contain less than 0.5% by HPLC of at least one of 2,4-difluorobenzylamine and by-products of coupling agent; and/or wherein the step b) comprises use of an acid to obtain the cabotegravir contain less than 0.5% by HPLC of an open chain impurity of cabotegravir.

The compound of Formula XIa, 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 WO2011/119566.

The suitable coupling agent used in reaction of a compound of Formula XIa with 2,4-difluorobenzylamine is selected from the group comprising of but not limited to 2-chloro-4,6-dimethoxy-1,3,5-triazine, carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), 1-Hhydroxy benzotriazole (HOBt), 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-l-oxide hexafluorophosphate (HBTU), O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), propylphosphonic anhydride (T3P), dicyclohexylcarbodiimide (DCC), 3-hydroxytriazolo[4,5-b]pyridine (HOAT), thionyl chloride (SOCl2), oxalyl chloride (COCl)2, phosphorus oxychloride (POCl3), pivaloyl chloride (PivCl), acetic anhydride (Ac2O), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEQD), Methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl) and the like and mixture thereof; preferably carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-Hhydroxy benzotriazole and mixture thereof; more preferably carbonyldiimidazole.

The suitable solvent used in reaction of a compound of Formula XIa with 2,4-difluorobenzylamine is selected from the group comprising but not limited to ketones, esters, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, polar aprotic solvent, water and mixtures thereof. The ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters include, but are not limited to ethyl acetate, isopropyl acetate, butyl acetate and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like; polar aprotic solvent include, but are not limited to dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and the like and mixtures thereof; preferably acetonitrile, tetrahydrofuran, methylene chloride, dimethylformamide and mixtures thereof; more preferably methylene chloride.

The reaction of a compound of Formula XIa with 2,4-difluorobenzylamine is carried out at a temperature of about 0°C to about reflux temperature; preferably at about 25°C to about 50°C.

The reaction of a compound of Formula XIa with 2,4-difluorobenzylamine in the presence of coupling agent is always possibility to contamination of unreacted starting material, 2,4-difluorobenzylamine and by-products of coupling agent such as imidazole with the product. The process disclosed under the ‘566 publication involves adding water to the reaction mass after completion of the coupling reaction, which process fails to eliminate unreacted 2,4-difluorobenzylamine and imidazole by-product completely. Hence, the product isolated from the reaction mass contains more than 0.5% by HPLC of at least one of unreacted 2,4-difluorobenzylamine and imidazole by-product.

The present inventors surprisingly found that the unreacted 2,4-difluorobenzylamine and the imidazole formed as a by-product from the coupling agent are completely removed from the reaction mass by simply treating the reaction mass which is obtained after the coupling reaction with an acid. The acid used in the process of the invention advantageously forms acid salt with the unreacted 2,4-difluorobenzylamine and the imidazole and these acid salts can easily be dissolved in the aqueous phase thereby it can easily be separated from the reaction mass by simple layer separation and the pure product can be isolated from the organic phase by the conventional techniques for example solvent crystallization.

After performing the coupling reaction, the reaction mass may be diluted with aqueous acid solution so that the reaction mass split into organic phase and aqueous phase. Then the product containing organic phase may be separated from the aqueous phase and isolated the product from the organic phase. The unwanted starting material and the byproducts formed if any are separated through aqueous phase.

The acid used for treating the step a) reaction mass is either organic acid or inorganic acid. The organic acid is selected from the group comprising of but not limited to acetic acid, formic acid, citric acid, oxalic acid, tartaric acid, maleic acid, malic acid, mandelic acid, malonic acid, succinic acid, glutaric acid, adipic acid and the like and mixture thereof. The inorganic acid is selected from the group comprising of but not limited to sulfurous acid, phosphoric acid, nitrous acid and the like and mixture thereof; preferably citric acid, oxalic acid and mixture thereof; more preferably citric acid.

In a preferred embodiment, the acid is either organic acid or inorganic acid with the proviso that wherein the said organic acid or inorganic acid excludes both hydrochloric acid and sulfuric acid.

In a preferred embodiment, wherein the acid used in the process of step a) is citric acid.

In an embodiment, the present invention provides a process for preparation of compound of Formula XII by crystallization from a suitable solvent such as alcohol solvent selected form methanol, ethanol, isopropanol and the like and mixture thereof; preferably methanol, to obtain crystalline compound of Formula XII.

The compound of Formula XII 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 and substantially free of unreacted 2,4-difluorobenzylamine and byproducts of coupling agent such as imidazole; wherein the word "substantially free" refers to compound of Formula XII having less than 0.5% of unreacted 2,4-difluorobenzylamine or by-products of coupling agent or both as measured by HPLC, preferably less than about 0.3%; more preferably less than about 0.1% as measured by HPLC.

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

In another embodiment, the present invention provides crystalline compound of Formula XII characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 2.

In another embodiment, the present invention provides a crystalline compound of Formula XII characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 5.5, 6.1, 9.7, 11.4, 12.1, 13.3, 13.7, 15.1, 15.6, 15.9, 16.3, 16.9, 17.2, 17.4, 18.2, 19.2, 19.5, 19.8, 20.3, 20.4, 20.7, 22.3, 22.8, 23.0, 23.1, 23.5, 23.8, 23.9, 24.1, 24.4, 24.5, 25.4, 25.5, 26.2, 26.9, 27.0, 27.6, 28.5, 28.9, 29.1, 29.6, 29.7, 30.6, 30.7, 31.2, 31.5, 32.1, 32.6, 32.9, 33.4, 34.5 and 35.1 ±0.2° 2?.

In another embodiment, the present invention provides a crystalline compound of Formula XII characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.1, 12.1, 13.7, 15.1, 15.6, 17.2, 17.4, 18.2, 19.5, 20.7, 25.4, 30.6 ±0.2° 2?.

In another embodiment, the present invention provides preparation of cabotegravir from the compound of Formula XII of the invention, comprises: deprotecting a compound of Formula XII, in presence of a suitable deprotecting agent, treating the reaction mass with an acid, and isolating the cabotegravir.

The suitable deprotecting agent used for the process of the above embodiments is selected from the group comprising but not limited to magnesium chloride, magnesium iodide, magnesium hydroxide, lithium chloride, lithium iodide, lithium hydroxide, lithium trisiamyl borohydride, lithium triethyl borohydride, tri-sec-butyl borohydride, boron tribromide, aluminium chloride, aluminium chloride-triethylamine complex, aluminium chloride-N,N-dimethyl aniline complex and the like and mixture thereof; preferably magnesium chloride, lithium chloride, aluminium chloride and mixture thereof; more preferably magnesium chloride.

In one preferred embodiment, the deprotection of the compound of Formula XII is carried out in presence of magnesium chloride as a deprotecting agent, it is advantage over known deprotecting agents such as magnesium bromide and lithium bromide, as the commercial availability of these compounds are very limited and highly expensive. The deprotecting agent used for the present invention specifically magnesium chloride is cheaper and commercially available when compared to known deprotecting agents.

The deprotection of the compound of Formula XII in presence of a suitable deprotecting agent may be advantageously carried out in a suitable solvent. The suitable solvent includes but is not limited to polar aprotic solvents and polar protic solvents and the like and mixture thereof. The polar aprotic solvents include, but are not limited to methylene chloride, N-methylpyrrolidone, tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide and the like and mixtures thereof. The polar protic solvents include, but are not limited to methanol, ethanol, formic acid, acetic acid and the like and mixtures thereof; preferably acetonitrile.

The deprotection of the compound of Formula XII in presence of a suitable deprotecting agent is carried out at a temperature of about 25°C to reflux temperature; preferably at about 50°C to 80°C.

Deprotection process disclosed under the reported literatures involves use of a strong acids like HCl or H2SO4 at higher temperature this will hydrolyzes the magnesium complex formed during the reaction, however with using these strong acids at higher temperature there always high possibility to formation of an open chain impurity of cabotegravir (as shown below) and this may be due to ring cleavage of the oxazole ring. The open chain impurity once formed during the deprotection step, the same may be difficult to remove from the final product under normal purification techniques as both are having close polarity characteristics and thereby necessary to perform multiple solvent purifications, which process makes commercially unviable due to loss of valuable product at each stage of the purification.

Open chain impurity of cabotegravir
The present inventors surprisingly found that the formation of open chain impurity of cabotegravir is either minimized to acceptable levels or completely avoided by the use of an acid (as listed below) of the present invention at ambient temperatures and this process advantageously circumvent the necessary purification steps at final stage thereby getting product with improved yields.

The acid used for treating the reaction mass is either organic acid or inorganic acid with the proviso that wherein said organic acid or inorganic acid. The organic acid is selected from the group comprising of but not limited to acetic acid, formic acid, citric acid, oxalic acid, tartaric acid, maleic acid, malic acid, mandelic acid, malonic acid, succinic acid, glutaric acid, adipic acid and the like and mixture thereof. The inorganic acid is selected from the group comprising of but not limited to sulfurous acid, phosphoric acid, nitrous acid and the like and mixture thereof; preferably citric acid, oxalic acid and mixture thereof; more preferably citric acid.

In a preferred embodiment, the acid is either organic acid or inorganic acid with the proviso that wherein said organic acid or inorganic acid excludes both hydrochloric acid and sulfuric acid.

In a preferred embodiment, wherein the acid used in the deprotection step is citric acid.

In a preferred embodiment, after the deprotection step the acid may be added to the reaction mass obtained after the deprotection step at a temperature of about 0°C to about reflux temperature, preferably at about 25°C to about 50°C. The acid may be advantageously used for the process of the invention is an aqueous solution. Then the product may be isolated from the reaction mass by known techniques for example, when an aqueous solution of an acid is added to the reaction mas the product may get precipitated slowly and the product may be separated by filtration.

Cabotegravir 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 and substantially free of open chain impurity of cabotegravir; wherein the word "substantially free" refers to cabotegravir having less than 0.5% of open chain impurity of cabotegravir as measured by HPLC, preferably less than about 0.3% of open chain impurity of cabotegravir as measured by HPLC; more preferably less than about 0.1% of open chain impurity of cabotegravir as measured by HPLC.

Preparation of cabotegravir reported in the known literatures involves deprotection of protected cabotegravir of Formula XII’ (compound of Formula XII, when protection with methyl) using various deprotecting agents but complete cleavage of the protecting group is always a challengeable task and possible to retain protected starting material and this will isolate along with the product as an impurity. Due to close polarity differences the unreacted starting material is difficult to separable from cabotegravir under normal solvent purifications as the both cabotegravir and protected cabotegravir having less solubility in most of the solvents for solvent purification. The present inventors have surprisingly found an effective purification to remove unwanted protected cabotegravir without losing the valuable final product with the purification.

In another embodiment, the present invention provides a process for purification of cabotegravir of Formula I using solvent purification.

In another embodiment, the present invention provides a process for purification of cabotegravir of Formula I by suspending or dissolving cabotegravir in a suitable solvent and precipitating pure cabotegravir by addition of anti-solvent or vice versa.

In another embodiment, the present invention provides a process for purification of cabotegravir of Formula I, comprising:
a) suspending or dissolving cabotegravir in a suitable solvent at an ambient temperature to reflux,
b) adding step a) reaction mass to an anti-solvent (or) adding an anti-solvent to step a) reaction mass at a suitable temperature,
c) optionally, cooling the step b) reaction mass to below 25°C, and
d) isolating the pure cabotegravir.

As used herein in this specification, unless otherwise specified, cabotegravir, which is used as a starting material is known in the art and can be prepared by any processes disclosed in art, for example cabotegravir may be synthesized according to the present process described in above embodiments. The starting cabotegravir may be in any form such as crude obtained directly from the reaction mass, crystalline, amorphous or other forms of cabotegravir, including various solvates and hydrates known in the art. Further the starting cabotegravir may contain protected cabotegravir of Formula XII’ more than 0.5% by HPLC and the present invention capable of removing the protected cabotegravir from the final cabotegravir to less than 0.5% by HPLC preferably less than 0.3% more preferably less than 0.1% by HPLC.

The aforementioned formation of suspension or dissolution of cabotegravir of Formula I in a suitable solvent selected from the group comprising alcohols, amides, sulfoxides, nitriles, halogenated solvents, sulfolane, acetic acid and the like and mixtures thereof. The alcohols include, but are not limited to 2,2,2-trifluoromethanol, 2-mercaptoethanol, 2,2,2-trifluoroethanol, glycerol, hexafluoro-2-propanol, ethylene glycol, propylene glycol and the like; amides include, but are not limited to dimethylacetamide, dimethylformamide, N-methyl pyrrolidone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; halogenated solvents include, but are not limited to methylene chloride, ethylene chloride, chloroform, chlorobenzene, and the like; acetic acid and mixtures thereof; preferably 2,2,2-trifluoroethanol.

The temperature for suspending or dissolving cabotegravir of Formula I in a suitable solvent and the step of adding reaction mass to an anti-solvent (or) adding an anti-solvent to reaction mass is advantageously carried out at a temperature of about 25°C to about reflux; preferably at about 40°C to 80°C.

The anti-solvent may be selected but are not limited to alcohols, ethers, esters, ketones, aromatic hydrocarbons and the like and water and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, Isopropyl alcohol, n-propanol, n-butanol, t-butanol, 1-pentanol and the like; ethers include, but are not limited to tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; esters include, but are not limited to ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; aromatic hydrocarbons include, but are not limited to toluene and the like; and water and mixture thereof; preferably methanol, ethanol, Isopropyl alcohol, n-butanol, t-butanol, 1-pentanol, water and mixture thereof.

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

In another embodiment, cabotegravir 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 and substantially free of protected cabotegravir of Formula XII’; wherein the word "substantially free" refers to cabotegravir having less than 0.5% of protected cabotegravir of Formula XII’ as measured by HPLC, preferably less than about 0.3%, more preferably less than about 0.1%.

In another embodiment, cabotegravir prepared 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 and substantially free of at least one of 2,4-difluorobenzylamine, by-products of coupling agent, open chain impurity of cabotegravir and protected cabotegravir of Formula XII’ as measured by HPLC; wherein the word "substantially free" refers to cabotegravir having less than 0.5% of at least one of 2,4-difluorobenzylamine, by-products of coupling agent, open chain impurity of cabotegravir and protected cabotegravir of Formula XII’ as measured by HPLC, preferably less than 0.3%, more preferably less than 0.1%.

The compounds obtained by the process of the present invention are characterized by X-ray powder diffraction (XRPD) pattern. 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.

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.

The present invention provides process for preparation of compound Formula XII and Formula I, obtained by the above processes, as analyzed using the high performance liquid chromatography with Zorbax C18 column and buffer, acetonitrile and water as mobile phase with flow rate of about 1.0 mL/minute.

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.

COMPARATIVE EXAMPLE-1: Preparation of Formula XII

Compound of Formula XIa (10 g) and carbonyldiimidazole (2.47 g) was charged in 1,2-dimethoxyethane (102.0 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 80°C for 1 hr. The resulting solution was cooled to 20-25°C and 2,4-difluorobenzyl amine (4.8 mL) was added and stirred the reaction mass for 1 hr at same temperature. After completion of the reaction, water (100 mL) was added and dimethoxyethane was concentrated under vacuum. Then the product was filtration and dried at 50°C in hot air oven. Wt: 10.7 g; Purity: 97.5% by HPLC; 2,4-difluorobenzylamine: 1.2% by HPLC; Imidazole: 0.5% by HPLC.

COMPARATIVE EXAMPLE-2: Preparation of Formula XII

Variant-A (HCl)

Compound of Formula XIa (10 g), dichloromethane (120 mL) and carbonyldiimidazole (2.47 g) were added in to a round bottom flask at 25-35°C and stirred for 2-3 hr. To the reaction mass 2,4-difluorobenzyl amine (4.8 mL) was added and allowed to stir the reaction mass for 1-2 hr at 20-25°C. After completion of the reaction, to the reaction mass water (100 mL) was added and organic and aqueous layers were separated. To the organic layer dil. HCl (50 ml) was added at 25-35°C and stirred for 36 hr at same temperature. Then the organic layer was monitored by HPLC.

Formula XII by HPLC 2,4-difluorobenzylamine Imidazole Open chain impurity
92.6% 0.99% 0.84% 1.05%

Variant-B (Citric acid)

Compound of Formula XIa (10 g), dichloromethane (120 mL) and carbonyldiimidazole (2.47 g) were added in to a round bottom flask at 25-35°C and stirred for 2-3 hr. To the reaction mass 2,4-difluorobenzyl amine (4.8 mL) was added and allowed to stir the reaction mass for 1-2 hr at 20-25°C. After completion of the reaction, to the reaction mass water (100 mL) was added and organic and aqueous layers were separated. To the organic layer was added aqueous citric acid solution (15.6 g citric acid dissolved in 81.2 mL of water) at 25-35°C and allowed to stir for 36 hr at same temperature. Then the organic layer was monitored by HPLC.
Formula XII by HPLC 2,4-difluorobenzylamine Imidazole Open chain impurity
95.1% Not detected by HPLC 0.03% Not detected by HPLC

COMPARATIVE EXAMPLE-3: Preparation of Cabotegravir

Compound of Formula XII (100 g), magnesium bromide (131.6 g) and acetonitrile (1.2 lit) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 50-55°C and allowed to stir for 4 hr at same temperature. After completion of the reaction, reaction mass was cooled to 25-35°C and diluted with a mixture of methylene chloride (500 mL) and water (500 mL). Adjusted the reaction mass pH to 1.0- 2.0 with dil. HCl solution and temperature shoot up was observed and was allowed to cool and stirred for 1-2 hr at 25-35°C, filtered and dried at 60°C for 12 hrs. Wt: 85 g; Purity: 97.5% by HPLC; compound of Formula XII: 0.8% by HPLC; Open chain impurity of cabotegravir: 1.1% by HPLC.

EXAMPLE-1: Preparation of Formula XII

Compound of Formula XIa (100 g), methylene chloride (975 mL) and carbonyldiimidazole (66.1 g) were added in to a round bottom flask at 25-35°C and allowed to stir for 2-3 hr at same temperature. Reaction mass was allowed to cool to 12-18°C and 2,4-difluorobenzylamine (53.5 g) was added at same temperature. Reaction mass was heated to 25-30°C and stirred for 2-3 hr at same temperature. After completion of the reaction, to the reaction mass water was added (500 mL) and organic and aqueous layers were separated. Then to the organic layer aq citric acid solution (156 g citric acid dissolved in 812 mL water) was added and organic and aqueous layers were separated followed by washing the organic layer with sodium bicarbonate solution. The organic layer was concentrated under vacuum at below 50°C to obtain solid compound. Then the solid compound was dissolved in methanol (400 mL) at 60-65°C and stir for 45 min at same temperature. Reaction mass was allowed to cool to 2-8°C and stir for 1 min at same temperature. Filtered the solid, suck dried and washed with methanol (100 mL) and dried the wet material under vacuum at 55-65°C for about 10 hr to obtain the titled compound. Wt: 135 g; Purity: 99.1% by HPLC; PXRD: Fig.: 2; 2,4-difluorobenzylamine: not detected by HPLC; Imidazole: not detected by HPLC.

EXAMPLE-2: Preparation of Cabotegravir

Compound of Formula XII (100 g), magnesium chloride (68.1 g) and acetonitrile (1.1 lit) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 70-75°C and allowed to stir for 5 hr at same temperature. After completion of the reaction, reaction mass was allowed to cool to 25-35°C and dilute citric acid solution (137.4 g citric acid was dissolved in 715 mL water) was added and allowed to stir for 1-2 hr at same temperature. Filtered the solid, suck dried and washed with water (200 mL) and dried the wet material under vacuum at 55-65°C for about 10 hr to obtain the titled compound. Wt: 90 g; Purity: 99.1% by HPLC; compound of Formula XII: 0.5% by HPLC; Open chain impurity of cabotegravir: not detected by HPLC.

EXAMPLE-3: Purification of Cabotegravir

Cabotegravir (100 g; Purity: 99.1 % by HPLC; compound of Formula XII: 0.5 % by HPLC) and 2,2,2-trifluoroethanol (500 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 55-65°C and pre heated ethanol (55-65°C, 1.2 lit) was added for a period of 15-20 min at 55-65°C. Reaction mass was allowed to stir for 30-40 min at 55-65°C and then the reaction mass was allowed to cool to 25-35°C and stirred for 1-2 hr at same temperature. Filtered the solid, suck dried and washed with ethanol (100 mL) and dried the wet material under vacuum at 55-65°C for about 12 hr to obtain the titled compound. Wt: 99.5 g; Purity: 99.9% by HPLC; compound of Formula XII: not detected by HPLC. PXRD: Fig. 1.

EXAMPLE-4: Purification of Cabotegravir

Cabotegravir (10 g; Purity: 99.1 % by HPLC; compound of Formula XII: 0.5 % by HPLC) and 2,2,2-trifluoroethanol (50 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 60-65°C and water (20 mL) was added for a period of 15-20 min at 25-35°C. Reaction mass was allowed to stir for 2 hr at 25-35°C. Filtered the solid, suck dried and washed with water (2 mL) and dried the wet material under vacuum at 55-65°C for about 12 hr to obtain the titled compound. Wt: 9.7 g; Purity: 99.89% by HPLC; compound of Formula XII: not detected by HPLC. PXRD: Fig. 1.

EXAMPLE-5: Purification of Cabotegravir

Cabotegravir (2 g; Purity: 99.1 % by HPLC; compound of Formula XII: 0.5 % by HPLC) and 2,2,2-trifluoroethanol (10 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 60-65°C and methanol (24 mL) was added for a period of 15-20 min at 60-65°C and allowed to stir for 30 min at same temperature. Then the reaction mass was allowed to cool to 25-35°C and allowed to stir for 1-2 hr at same temperature. Filtered the solid, suck dried and washed with methanol (2 mL) and dried the wet material under vacuum at 55-65°C for about 8 hr to obtain the titled compound. Wt: 1.94 g; Purity: 99.9% by HPLC; compound of Formula XII: not detected by HPLC. PXRD: Fig. 1.

Purification of cabotegravir by following the example-3 process and using different solvent combinations and the results given as below:

Ex Solvent Anti-solvent Output wt Purity by HPLC Formula XII by HPLC and
open chain impurity
Ex-6 Trifluoroethanol
(5 vol) Ethanol
(12 vol) 1.88 g 99.9% Not detected
Ex-7 Trifluoroethanol
(5 vol) Isopropyl alcohol
(12 vol) 1.92 g 99.87% Not detected
Ex-8 Trifluoroethanol
(5 vol) n-butanol
(12 vol) 1.89 g 99.9% Not detected
Ex-9 Trifluoroethanol
(5 vol) n-propanol
(12 vol) 1.91 g 99.9% Not detected
Ex-10 Trifluoroethanol
(5 vol) t-butanol
(12 vol) 1.9 g 99.9% Not detected
Ex-11 Trifluoroethanol
(5 vol) 1-pentanol
(12 vol) 1.88 g 99.9% Not detected
Ex-12 Trifluoroethanol
(5 vol) water
(12 vol) 1.94 g 99.9% Not detected
Ex-13 Dimethylformamide
(12 vol) water
(24 vol) 1.82 g 99.87% Not detected
Ex-14 Dimethylformamide
(12 vol) methanol
(24 vol) 1.78 g 99.89% Not detected
Ex-15 N-Methyl pyrrolidone (10 vol) water
(20 vol) 1.84 g 99.9% Not detected
Ex-16 Dimethyl sulfoxide (10 vol) water
(24 vol) 1.87 g 99.9% Not detected

,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 XI’ with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent to obtain a compound of Formula XII’; wherein the “P” represents an alkyl, aryl or aralkyl, and

Formula XI’ Formula XII’
b) deprotecting the compound of Formula XII’ in presence of a suitable deprotecting agent in a suitable solvent to obtain cabotegravir; wherein the step a) and/or step b) comprises use of an acid prior to isolation of the corresponding product.

2. The process as claimed in claim 1, wherein the “P” represents methyl, ethyl or benzyl.

3. The process as claimed in claim 1, wherein the suitable coupling agent is selected from the group comprising 2-chloro-4,6-dimethoxy-1,3,5-triazine, carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-Hhydroxy benzotriazole, 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-l-oxide hexafluorophosphate, O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, propylphosphonic anhydride, dicyclohexylcarbodiimide, 3-hydroxytriazolo[4,5-b]pyridine, thionyl chloride, oxalyl chloride, phosphorus oxychloride, pivaloyl chloride, acetic anhydride, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, Methanesulfonyl chloride, p-toluenesulfonyl chloride and mixture thereof.

4. The process as claimed in claim 1, wherein the suitable solvent is selected from the group comprising methanol, ethanol, formic acid, acetic acid, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, propionitrile, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, methylene chloride, ethylene chloride, chloroform, toluene, xylene, dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and mixtures thereof.

5. The process as claimed in claim 1, wherein the suitable deprotecting agent is selected from the group comprising magnesium chloride, magnesium iodide, magnesium hydroxide, lithium chloride, lithium iodide, lithium hydroxide, lithium trisiamyl borohydride, lithium triethyl borohydride, tri-sec-butyl borohydride, boron tribromide, aluminium chloride, aluminium chloride-triethylamine complex, aluminium chloride-N,N-dimethyl aniline complex and mixture thereof.

6. The process as claimed in claim 1, wherein the acid is either organic acid or inorganic acid with the proviso that wherein said organic acid or inorganic acid excludes hydrochloric acid and sulfuric acid.

7. The process as claimed in claim 6, wherein in the acid is selected from the group comprising acetic acid, formic acid, citric acid, oxalic acid, tartaric acid, maleic acid, malic acid, mandelic acid, malonic acid, succinic acid, glutaric acid, adipic acid, sulfurous acid, phosphoric acid, nitrous acid and mixture thereof.

8. The process as claimed in claim 1, wherein the step a) comprises:
i) reacting a compound of Formula XI’ with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent,
ii) treating the step i) reaction mass with an acid, and
iii) isolating the compound of Formula XII’ contain less than 0.5% by HPLC of at least one of 2,4-difluorobenzylamine and by-products of coupling agent.

9. The process as claimed in claim 8, wherein the suitable coupling agent is carbonyldiimidazole; wherein the suitable solvent is methylene chloride; wherein the acid is citric acid and wherein the by-products of coupling agent is imidazole.

10. The process as claimed in claim 1, wherein the step b) comprises:
i) deprotecting the compound of Formula XII’ with a suitable deprotecting agent in a suitable solvent,
ii) treating the step i) reaction mass with an acid at a temperature of about 25°C to about 50°C, and
iii) isolating the cabotegravir contain less than 0.5% by HPLC of open chain impurity of cabotegravir.

11. The process as claimed in claim 10, wherein the suitable deprotecting agent is magnesium chloride and suitable solvent is acetonitrile.

12. A process for purification of cabotegravir of Formula I, comprising:

Formula I
a) suspending or dissolving cabotegravir in a suitable solvent at ambient temperature to reflux,
b) adding step a) reaction mass to an anti-solvent (or) adding an anti-solvent to step a) reaction mass at a suitable temperature,
c) optionally, cooling the step b) reaction mass to below 25°C, and
d) isolating the pure cabotegravir.

13. The process as claimed in claim 12, wherein in the suitable solvent is selected from the group comprising 2,2,2-trifluoromethanol, 2-mercaptoethanol, 2,2,2-trifluoroethanol, glycerol, hexafluoro-2-propanol, ethylene glycol, propylene glycol, dimethylacetamide, dimethylformamide, N-methyl pyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, acetonitrile, propionitrile, methylene chloride, ethylene chloride, chloroform, chlorobenzene, acetic acid and mixtures thereof.

14. The process as claimed in claim 12, wherein in the anti-solvent is selected from the group comprising methanol, ethanol, Isopropyl alcohol, n-propanol, n-butanol, t-butanol, 1-pentanol, tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, toluene, water and mixture thereof.

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

Formula I
a) reacting a compound of Formula XI’ with 2,4-difluorobenzylamine in presence of a suitable coupling agent in a suitable solvent; wherein the “P” represents an alkyl, aryl or aralkyl,

Formula XI’
b) treating the step a) reaction mass with an acid,
c) isolating the compound of Formula XII’ contain less than 0.5% by HPLC of at least one of 2,4-difluorobenzylamine and by-products of coupling agent,

Formula XII’
d) deprotecting the compound of Formula XII’ obtained in step c) in presence of a suitable deprotecting agent in a suitable solvent,
e) treating the step d) reaction mass with an acid, and
f) isolating the cabotegravir contain less than 0.5% by HPLC of an open chain impurity of cabotegravir.

16. The process as claimed in claim 15, wherein the “P” represents methyl, ethyl or benzyl;
wherein the suitable coupling agent is selected from the group comprising 2-chloro-4,6-dimethoxy-1,3,5-triazine, carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-Hhydroxy benzotriazole, 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-l-oxide hexafluorophosphate, O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, propylphosphonic anhydride, dicyclohexylcarbodiimide, 3-hydroxytriazolo[4,5-b]pyridine, thionyl chloride, oxalyl chloride, phosphorus oxychloride, pivaloyl chloride, acetic anhydride, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, Methanesulfonyl chloride, p-toluenesulfonyl chloride and mixture thereof;
wherein in the suitable solvent is selected from the group comprising methanol, ethanol, formic acid, acetic acid, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, propionitrile, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, methylene chloride, ethylene chloride, chloroform, toluene, xylene, dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and mixtures thereof;
wherein in the suitable deprotecting agent is selected from the group comprising magnesium chloride, magnesium iodide, magnesium hydroxide, lithium chloride, lithium iodide, lithium hydroxide, lithium trisiamyl borohydride, lithium triethyl borohydride, tri-sec-butyl borohydride, boron tribromide, aluminium chloride, aluminium chloride-triethylamine complex, aluminium chloride-N,N-dimethyl aniline complex and mixture thereof; and
wherein in the acid is selected from the group comprising acetic acid, formic acid, citric acid, oxalic acid, tartaric acid, maleic acid, malic acid, mandelic acid, malonic acid, succinic acid, glutaric acid, adipic acid, sulfurous acid, phosphoric acid, nitrous acid and mixture thereof.

17. Crystalline compound of Formula XII characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.1, 12.1, 13.7, 15.1, 15.6, 17.2, 17.4, 18.2, 19.5, 20.7, 25.4, 30.6 ±0.2° 2?.