FIELD OF INVENTION

The present invention relates to an improved process for the preparation of Dolutegravir (I) or pharmaceutical^ acceptable salts thereof.

BACKGROUND OF THE INVENTION

Dolutegravir (I) is chemically known as (4/?,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2//-pyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxamide. Dolutegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Dolutegravir is being marketed under the trade name Tivicay®. US 8,129,385 disclosed Dolutegravir or its pharmaceutically acceptable salts thereof. US '385 also discloses a process for the preparation of Dolutegravir (I). The process involves the condensation of 5-benzyloxy-4-hydroxy-6-hydroxymethyl nicotinic acid (II) with 2,4-difluorobenzylamine (III) to produce 5-benzyloxy-N-(2,4-difluorobenzyl)-4-hydroxy-6-hydroxymethyl nicotinic acid amide (IV), which is further under goes oxidation using manganese dioxide (Mn02) to produce 5-benzyloxy-N-(2,4-difluorobenzyl)-6-formyl-4-hydroxy-nicotinic acid amide (V). This amide compound (V) is reacted with sodium chlorite (NaClCh) to produce 3-benzyloxy-5-(2,4-difluorobenzylcarbamoyl)-4- hydroxy-pyridine-2-carboxylic acid (VI), which is further treated with methanol (MeOH) to produce 3-benzyloxy-5-(2,4-difluorobenzyl)-4-hydroxy-pyridine-2-carboxylic acid methyl ester (VII).

The methyl ester compound (VII) is reacted with 3-bromopropene to produce l-allyl-3-benzyloxy-5-(2,4-difluorobenzyl)-4-oxo-l,4-dihydro-pyridine-2- carboxylic acid methyl ester (VIII), which is further reacted with potassium osmate dihydrate (K2OSO4.2H2O) to produce 3-benzyloxy-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-l-(2-oxo-ethyl)-l,4-dihydropyridine-2-carboxylic acid methyl ester (IX). The compound (IX) is reacted with (R)-3-amino-l-butanol (X) to produce benzyloxy Dolutegravir (XI), which is deprotected by treating with TFA to produce Dolutegravir (I). The process is as shown in scheme-I below: The major disadvantage with the above prior-art process is that it involves large no of steps and tedious work-up procedures to isolate the required product. This results a longer period of time cycle is required to produce Dolutegravir (I), which in turn renders the process more costly and less eco friendly. Further the above processes are low yielding and with less purity. US 8,217,034 discloses variant process for the preparation of Dolutegravir.

This process involves the reaction of methyl l-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-l,4-dihydro-2-pyridine carboxylate (XII) with (R)-3-amino-l-butanol (X) to produce (4R, 12o5)-4-methyl-7-[(phenylmethyl)oxy]-3,4,12,12a-tetrahydro-2//-pyrido[ 1 \2',4,5] pyrazino[2,l-b][l,3]oxazine-6,8-dione (XIII), which is further undergoes bromination using NBS to produce (4R,12aS)-9-bromo-4-methyl-7-[(phenylmethyl)oxy]-3,4,12,12a-tetrahydro-2H-pyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazine-6,8-dione (XIV). The bromo Compound (XIV) is condensed with 2,4-difluorobenzylamine (III) in the presence of Tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) to produce benzyloxy Dolutegravir (XI), which is hydrogenated in the presence of Pd/C to produce Dolutegravir (I). The process is as shown in Scheme-II below: The major disadvantage with the above prior art process of preparing Dolutegravir is the use of expensive reagent tetrakis(triphenylphosphine)palladium (Pd(PPh3)4> in coupling step. Use of this reagent on industrial scale is not preferred, which makes the process more expensive. WO 2011/119566 discloses another variant process for the preparation of Dolutegravir.

This process involves the reaction of l-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-l,4-dihydropyridine-3-carboxylic acid (XV) with acetic acid in presence of methane sulfonic acid to produce 5-methoxy-6-(methoxycarbonyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydropyridine-3-carboxylic acid (XVI), which is further condensed with (R)-3-amino-l-butanol (X) to produce (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2//-pyrido[ 1 ',2':4,5]pyrazino[2,1 -b] [ 1,3]-oxazine-9-carboxylic acid (XVII). This acid Compound XVII is acylated with 2,4-difluorobenzylamine (III) in the presence of carbonyldiimidazole (CDI) to produce methoxy Dolutegravir (XVIII), which is demethylated in the presence of lithium bromide (LiBr) to produce Dolutegravir (I).

The process is as shown in Scheme-IH below: The major disadvantage of the above prior art process of preparing Dolutegravir is the use of expensive and highly moisture sensitive reagent, 1,1-carbonyldiimidazole (CDI), during acylation. Use of this reagent on industrial scale is not preferred due to anhydrous conditions required in the process. However, there is always a need for alternative preparative routes, which for example, involve fewer steps, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity. Hence, there is a need to develop cost effective and commercially viable process for the preparation of Dolutegravir of formula (I). The present invention is related to a process for the preparation of pure Dolutegravir of formula (I), wherein optically active acid addition salt of (R)-3-amino-l-butanol (X) is directly condensed with 5-methoxy-6-(methoxycarbonyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydropyridine-3-carboxylic acid (XVI) instead of condensing with free base of (R)-3-amino-1-butanol (X). The present invention is also related to a process for the preparation of pure Dolutegravir of formula (I), wherein, inexpensive and easily handling condensing reagents in the condensation of (4R, 12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2//-pyrido[l',2':4,5]pyrazino [2,l-b][l,3]oxazine-9-carboxylic acid (XVII) with 2,4-difluorobenzylamine (III).

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple, cost effective process for the preparation of Dolutegravir (I) with high purity and good yield on commercial scale.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an improved process for the preparation of Dolutegravir (I) or pharmaceutically acceptable salts thereof, which comprises:

(i) reacting 5-methoxy-6-(methoxycarbonyl)-4-oxo-1 -(2-oxoethyl)-1,4-dihydro pyridine-3-carboxylic acid (XVI), with an optically active acid addition salt of (7?)-3-amino-l-butanol (Xa), wherein, OA refers optically active acid, to produce (4R, 12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro- 2/f-pyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxylic acid (XVII),

(ii) converting the compound (XVII) to Dolutegravir (I) or pharmaceutically acceptable salts thereof.

In another embodiment, the present invention provides a process for the preparation of Dolutegravir (I) or pharmaceutically acceptable salts thereof, which comprises:

(i) condensing (4R, 12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexa hydro-2//-pyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxylic acid (XVII), with 2,4-difluorobenzylamine (IV), in the presence of a coupling agent to produce methoxy Dolutegravir (XVIII),

(iii) de-methylating the compound (XVIII) to produce Dolutegravir (I), or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, a process for the preparation of Dolutegravir (I) comprises: condensing 5-methoxy-6-(methoxycarbonyl)-4-oxo-1 -(2-oxoethyl)-1,4-dihydropyridine-3-carboxylic acid (XVI) with optically active acid addition salt of (/?)-3-amino-l-butanol (Xa) in the presence of a base to produce (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxylic acid (XVII). The optically active acid addition salt of (i?)-3-amino-l-butanol (Xa) is selected from the group comprising tartaric acid, dibenzoyltartaric acid, mandelic acid, camphoric acid, camphorsulfonic acid, p-hydroxymandelic acid, p-Cl-mandelic acid, phenoxypropionic acid,/J-hydroxyphenoxypropionic acid or lactic acid. Preferably D-tartaric acid can be used as optically active acid. The base is alkali salt of C1-C6 carboxylic acid selected from the group comprising sodium formate, potassium formate, sodium acetate, potassium acetate or mixtures thereof; inorganic base comprising sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate or mixtures thereof.

After completion of the reaction, reaction mass is concentrated and acidified with inorganic acid or organic acid selected from the group comprising hydrochloric acid, sulfuric acid, formic acid, acetic acid, methane sulfonic acid or mixtures thereof; and extracted with an organic solvent comprising methylene chloride, toluene and ethyl acetate. The said organic layer is concentrated and treated with an organic solvent which is alcohol, ester, ether, hydrocarbon, ketone or mixtures thereof selected from the group comprising methanol, ethanol, isopropanol, ethyl acetate, acetone, toluene, tetrahydrofuran. The obtained compound (XVII) is isolated from the reaction mass by conventional methods. The compound (XVII) obtained by the above invention is used as such without isolation in the reaction to prepare Dolutegravir (I). The compound (XVII) obtained by the above invention is isolated by conventional methods. In another embodiment, the process comprises: condensing (4R,12aS)-7-methoxy-4- methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2//-pyrido[r,2':4,5]pyrazino[2,l-b][l,3] oxazine-9-carboxylic acid (XVII) with 2,4-difluorobenzylamine (III) in presence of a coupling agent to produce methoxy Dolutegravir (XVIII).

The coupling agent other than carbonyldiimidazole (CDI) selected from the group comprising isobutyl chloroformate, pivaloyl chloride, o-benzotriazoIe-l-yl-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium (HBTU), benzotriazole-1 -yl-oxy-tris(dimethylamino)phosphonium (BOP), benzotriazole- l-yl-oxy-tris-(pyrrolidino)phosphonum (PyBOP), bromo-tris-pyrrolidino-phosphoniumhexaflurophosphate (PyBrOP), tris(pyroolidino)phosphonium hexaflurophosphate (pyCOP), ethyl cyanoglyoxylate-2-oxime (Oxyma Pure), 0-(6-chloro-l-hydrocibenzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TCTU), 2-(lH-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate (HATU) or 1-cyano-2-ethoxy-2-oxoethydenminooxy)dimethylamino-morpholion-carbenium hexafluorophosphate (COMU) or mixtures thereof. The reaction is carried out in presence of an organic base selected from the group comprising N-methylmorpholine, triethylamine, diisopropylethylamine, N,N'-dimethylpiperazine, N-methylpiperidine, pyridine or mixtures thereof; in an organic solvent selected from the group comprising methylene chloride, ethyl acetate, tetrahydrofuran, dimethyl formamide, toluene, acetonitrile, acetone or mixtures thereof.

The reaction is carried out at a temperature of -30 to 80°C. After completion of the condensation reaction the reaction mass comprising methoxy Dolutegravir (XVIII) is treated with an organic acid or inorganic acid selected from the group comprising acetic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid and toluene sulfonic acid or mixtures thereof; followed by treating with aqueous alkali base comprising sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate. The methoxy Dolutegravir (XVIII) obtained by the above invention is used as such without isolation in the reaction to prepare Dolutegravir (I). The methoxy Dolutegravir (XVIII) obtained by the above invention is isolated by conventional methods. In another embodiment, the process comprises: de-methylating methoxy Dolutegravir (XVIII) using a Lewis acid to produce Dolutegravir (I). The Lewis acid is selected from the group comprising slat of magnesium selected from magnesium chloride, magnesium bromide or magnesium iodide; a salt of lithium selected from lithium chloride, lithium bromide or lithium iodide in an organic solvent, which is selected from the group comprising acetonitrile, isopropanol, ethanol, tetrahydrofuran, dimethylformamide (DMF), dimethylsulfoxide (DMSO) or mixtures thereof.

The reaction is carried out at a temperature of 10°C to about 75°C, preferably in the range of 30°C to 65°C. After completion of the reaction, the reaction mass is acidified with an organic acid or an inorganic acid to produce Dolutegravir (I), which is isolated by conventional methods. Dolutegravir (I) is purified by known methods, for example by dissolving in a solvent selected from the group comprising methanol, ethanol, isopropanol, ethyl acetate, methylene chloride, hexane, heptane, cyclohexane, acetone, THF, water or mixtures thereof; and precipitating pure Dolutegravir by cooling the solution or by adding an anti solvent. In another embodiment, Dolutegravir (I) is converted to its pharmaceutically acceptable salt by treating Dolutegravir (I) with an appropriate acid or base in presence of a solvent selected from the group comprising methanol, ethanol, isopropanol, THF, ethyl acetate, acetone, acetonitrile hexane, heptane, cyclohexane, methylene chloride or mixtures thereof. Pharmaceutical ly acceptable salts of Dolutegravir (I) include basic salt selected from the group comprising alkali metal salts selected from sodium, Lithium, potassium salts; alkaline-earth metal salts selected from calcium, magnesium salts; ammonium salts; aliphatic amine salts selected from trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine or procaine salts; aralkyl amine salts selected from N,N-dibenzylethylenediamine salts; heterocyclic aromatic amine salts selected from pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts selected from tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctyiammonium salts or tetrabutylammonium salts, and basic amino acid salts selected from arginine salts or lysine salts.

Acid salt selected from the group comprising mineral acid salts selected from hydrochloride, sulfates salts, nitrate salts, phosphates salts, carbonates salts, hydrogencarbonates or perchlorate; organic acid salts selected from acetates, propionates, lactates, maleates, fumarates, tararic acid salts, malates, citrates salts, ascorbates, formic acid; sulfonates such as methanesulfonates, isethionates, benzenesulfonates, or p-toluenesulfonates; and acidic amino acid salts selected from aspartates or glutamates. The base is alkali metal hydroxide selected from the group comprising lithium hydroxide, sodium hydroxide, potassium hydroxide, alkaline-earth metal hydroxide selected from the group comprising calcium hydroxide, magnesium hydroxide; ammonium hydroxide; aliphatic amine base selected from the group comprising trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine or procaine salts; aralkyl amine selected from the group comprising N,N-dibenzylethylenediamine; heterocyclic aromatic amine selected from the group comprising pyridine, picoline, quinoline or isoquinoline; quaternary ammonium base comprising tetramethylammonium chloride, tetraethylammonium bromide, benzyltrimethylammonium bromide, benzyltriethylammonium bromide, benzyltributylammonium bromide, methyltrioctylammonium bromide or tetrabutylammonium bromide, and basic amino acid selected from the group comprising arginine, lysine or mixtures thereof.

The acid is mineral acid selected from the group comprising hydrochloride, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, or perchloric acid; organic acid selected from the group comprising acetic acid, propionic acid, lactatic acid, maleic acid, fumaric acid, tartaric acid, malic acid, citric acid, ascorbic acid; sulfonic acid selected from the group comprising methanesulfonic acid, benzenesulfonic aid, or p-toluenesulfonates; and acidic amino acid selected from the group comprising aspartatic acid or glutamic acid or mixtures thereof. In another embodiment, 5-methoxy-6-(methoxycarbonyl)-4-oxo-l-(2-oxoethyl)-l,4- dihydropyridine-3-carboxylic acid (XVI) used in the present invention is prepared by reacting 4-methoxyacetoacetate (XIX) with N,N-dimethyl-l,l- bis(methyloxy)methanamine (DMF-DMA) (XX) to produce methyl-2- (dimethylaminomethylene)-4-methoxy-3-oxo-butanoate(methyl-3-(dimethylamino)-2 [(methyloxy)acetyl]-2-propenoate) (XXI), which is reacted with aminoacetaldehyde dimethyl acetal (XXII) to produce methyl-2-(2,2-dimethoxyethylaminomethylene)-4-methoxy-3-oxo-butanoate(methyl-3-{[2,2-bis(methyloxy)ethyl]amino}-2-[(methyloxy) acetyl]-2-propenoate) (XXIII).

The compound (XXIII) is contacted with dimethyl ethanedioate in presence of alkali metal alkoxide to produce dimethyl-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-l ,4-dihydropyridine-2,5-dicarboxylate (XXIV), which is selectively hydrolyzed with a base to produce l-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-l ,4-dihydro-3-pyridinecarboxylic acid (XV). The compound (XV) is treated with a catalytic amount of a strong protic acid in the presence of acetic acid in an organic solvent to produce a reaction mixture containing 5- methoxy-6-(methoxycarbonyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydropyridine-3-carboxylic acid (XVI), The process is as shown in Scheme-IV below: The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

Example-1:

EXAMPLES: Example-1: Process for the preparation of Dolutegravir

Step-i: Preparation of (/?)-3-amino-l-butanol tartarate salt: D-(+) Tartaric acid (12.7 g, 0.085 mol) was added in to a solution of (i?,5)-3-amino-l-butnaol (7.5 g, 0.084 mol) in methanol (100 ml) at 40 °C. The reaction mixture was stirred for about 1 hour at 35-40 °C and the reaction mass was cooled to 0-5°C and maintained for 30-40 minutes. The obtained solid was filtered and washed with chilled methanol (10 ml) at 0-5 °C. The solid was dried to get (i?)-3-amino-l-butanol tartarate salt (8.0 g, 40%).

Step-ii: Preparation of (4rt,12a£)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[l',2';4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxylic acid (XVII): l-[2,2-Bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-l,4-dihydro-3-pyridinecarboxylic acid (XV) (lOOg; 0.3175 moles) was suspended in acetonitrile (800 ml) and heated to 80-82°C. A mixture of acetic acid (95.25 g), methanesulfonic acid (9.14 g; 0.09525 moles) and acetonitrile (200 ml) were added to the slurry at 80-82°C. The reaction mass was continued at 80-82°C to complete the reaction. After completion of the reaction, anhydrous sodium acetate (65 g) and (/?)-3-amino-l-butanol tartrate salt (79.68g; 0.3334 moles) were added at 20-25°C and stirred at 60-65°C to complete the reaction. The reaction mass was concentrated and acidified with IN aqueous hydrochloric acid (750 ml) and extracted with methylene chloride (1500 ml) at ice cold temperature. The organic layer was separated, concentrated, treated with hot methanol (350 ml) for 2 h, filtered, washed with methanol and dried to yield (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[ 1' ,2' :4,5]pyrazino[2,1 -b] [ 1,3]oxazine-9-carboxylic acid (XVII) (72 g; HPLC purity: 99.07%).

Step-iii: Process for the preparation of Dolutegravir (I). Method A: Triethylamine (3.61 g; 0.0357 moles) was added to the suspension of (4R,12aS)-7- methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[ 1' ,2' :4,5]pyrazino[2,1 - b][l,3]oxazine-9-carboxylic acid (XVII) (10 g; 0.0325 moles) in methylene chloride (50 ml), and cooled to 10-15°C. Pivaloyl chloride (4.3 g; 0.0357 moles) was added to the reaction mass, and stirred at 10-15°C for 1 h. Thereafter, 2,4-difiuorobenzylamine (5.58 g; 0.0389 moles) was added at 10-15°C and then warmed to 20-25°C to complete the reaction. After completion of the reaction, IN aqueous hydrochloric acid (20 ml) was added, organic layer was separated, washed with 5% w/w aqueous sodium bicarbonate solution (10 ml) followed by 15% w/w aqueous sodium chloride solution (10 ml) and concentrated. To the concentrated mass, acetonitrile (100 ml) and Lithium bromide (5.08 g; 0.0584 moles) were added and heated to 65-70°C for 3 h to complete the reaction. After completion of the reaction, the reaction mass was acidified with 5N aqueous hydrochloric acid (40 ml), concentrated to about 50 ml and DM water was added to crystallize the product at 20-25°C. The slurry was stirred for 2 h, filtered, washed with DM water and dried to yield (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a,-hexahydro-2H-pyrido[ 1' ,2' :4,5]pyrazino[2,1 -b] [ 1,3]oxazine-9-carboxamide (I) (11.5 g, HPLC purity: 99.63%).

Method B: Isobutyl chloroformate (4.65 gm, 0.03404 moles) in methylene chloride (10 ml) was added to the solution of N-methylmorpholine (3.45 gm, 0.03410 moles) and (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[ 1' ,2' :4,5]pyrazino-[2,1 -b][l,3]oxazine-9-carboxy!ic acid (XVII) (10.0 gm, 0.03245 moles) in methylene chloride (60 ml) at -10 to 0°C in about 1 h. 2,4-Difloro benzyl amine (4.88 gm, 0.03409 moles) in methylene chloride (10 ml) was added to the cold reaction mass, and stirred at 20-30°C for completion of reaction. After completion of reaction, the reaction mass was washed with 5%w/w aqueous sodium bicarbonate solution (20 ml), IN hydrochloric acid (20 ml), DM water (20 ml) and concentrated. Acetonitrile (120 ml) and lithium bromide (4.8 gm, 0.05516 moles) were added to the concentrated mass, and stirred at 70-80°C for 3 h to complete the reaction. After completion of reaction, the reaction mass was acidified with 5N aqueous hydrochloric acid (40 ml) and concentrated to about 50 ml. DM Water (100 ml) was added to the concentrated reaction mass and stirred for 2 h at 25-30°C to crystallize the product. The product was filtered, washed with DM Water (50 ml) and dried to yield Dolutegravir (I) (10.7 gm, HPLC purity: 99.60%).

Example-2: Process for the preparation of Dolutegravir (I) (4R, 12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a,-hexahydro-2H-pyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxamide (XVIII) (2 g, 0.0046 moles) was suspended in isopropyl alcohol (20 ml) and lithium bromide (0.8 g, 0.00924 moles) was added and stirred at 70-80°C for 15 h to complete the reaction. After completion of reaction the reaction mass was acidified with 5N aqueous hydrochloric acid (5 ml) and concentrated. DM Water (20 ml) was added to the concentrated mass and stirred at 25-30°C to crystallize the product. The product was filtered, washed with DM Water and dried to yield Dolutegravir (I) (1.5 g, HPLC purity: 97.93%).

WE CLAIM:

1. A process for the preparation of Dolutegravir (I) or its pharmaceutically acceptable salts, which comprises:

(i) reacting 5-methoxy-6-(methoxycarbonyl)-4-oxo-1 -(2-oxoethyl)-1,4-dihydro pyridine-3-carboxylic acid (XVI), with an optically active acid addition salt of (/?)-3-amino-l-butanol (Ha), wherein, OA refers optically active acid, to produce (4i?,12a5)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a- hexahydro-2//-pyrido[l',2':4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxylic acid (XVII), 1 Q

(ii) converting the compound (XVII) to Dolutegravir (I) or pharmaceutically acceptable salts thereof.

2. The process according to claim 1, wherein the optically active acid addition salt of (R)-3-amino-l-butanol (Ha) is selected from the group comprising tartaric acid, dibenzoyltartaric acid, mandelic acid, camphoric acid, camphorsulfonic acid, p-hydroxymandelic acid, /?-Cl-mandelic acid, phenoxypropionic acid, p-hydroxyphenoxypropionic acid or lactic acid.

3. The process according to claim 1, wherein, the reaction in step-(i) is carried out using a base selected from the group comprising alkali salt of C|-C6 carboxylic acids, inorganic alkali bases or mixtures thereof.

4. The process according to claim 3, wherein, the base is selected from the group comprising sodium formate, potassium formate, sodium acetate, potassium acetate, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate or mixtures thereof.

5. A process for the preparation of Dolutegravir (I) or its pharmaceutically acceptable salts, which comprises:

(i) condensing (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexa hydro-2^-pyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxylic acid (XVII) with 2,4-difluorobenzylamine (III), in the presence of a coupling agent other than carbonyldiimidazole (CDI) to produce methoxy Dolutegravir (XVIII);

(ii) de-methylating the compound (XVIII) to produce Dolutegravir (I) or its pharmaceutically acceptable salts thereof.

6. The process according to claim 5, wherein the coupling agent is selected from the group comprising isobutyl chloroformate, pivaloyl chloride o-benzotriazole-l-yl-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(lH-benzotriazole-l-yl)-1,1,3,3-tetramethyluronium (HBTU), benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonium (BOP), benzotriazole-1 -yl-oxy-tris-(pyrrolidino)phosphonum (PyBOP), bromo-tris-pyrrolidino-phosphoniumhexaflurophosphate (PyBrOP), tris(pyrooIidino)phosphonium hexaflurophosphate (pyCOP), ethyl cyanoglyoxylate-2-oxime (Oxyma Pure), 0-(6-chloro-1 -hydrocibenzotriazol-1 -yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), 2-( 1 H-7-azabenzotriazol-1 -yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU), 1 -cyano-2-ethoxy-2-oxoethydenminooxy)dimethylamino-morpholion-carbenium hexafluorophosphate (COMU).

7. The process according to claim 5, wherein the reaction in step-(i) is carried out in presence of an organic base selected from the group comprising N-methylmorpholine, triethylamine, diisopropylethylamine, N,N'-dimethylpiperazine, N-methylpiperidine, pyridine or mixtures thereof.

8. The process according to claim 5, wherein the reaction in step-(i) is carried out in presence of an organic solvent selected from the group comprising methylene chloride, ethyl acetate, tetrahydrofuran, dimethyl formamide, toluene, acetonitrile or mixtures thereof.

9. The process according to claim 5, wherein the step-(ii) methoxy Dolutegravir (XXIII) is treated with a Lewis acid selected from the group comprising magnesium salt, lithium salt or mixtures thereof.

10. The process according to claim 5, wherein the step-(ii) is carried out in presence of an organic solvent selected from the group comprising acetonitrile, isopropanol, ethanol, tetrahydrofuran, dimethylformamide or mixtures thereof.