FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of carbamoylpyridone HIV integrase inhibitors and pharmaceutically acceptable salts thereof; specifically relates to the preparation of carbamoylpyridone HIV integrase inhibitors such as dolutegravir, cabotegravir and the like using novel intermediate.
BACKGROUND OF THE INVENTION:
Dolutegravir is chemically known as (4R,12aS)-9-{[(2,4-difluorophenyl)methyl] carbamoyl}-4-methyl-6,8-dioxo-3J456,8)12,12a-hexahydro-2H-pyrido[l,,2':435] pyrazino [2,l-£][l,3]oxazin-7-olate, having the following Formula I:
Dolutegravir (DTG, GSK1349572) is an integrase inhibitor being developed for the treatment of human immunodeficiency virus (HIV)-l infection. Sodium salt of dolutegravir was recently approved by FDA and marketed under the brand name of TIVICAY by ViiV Healthcare and manufactured by GlaxoSmithKIine. TIVICAY is administered orally as a tablet of 50 mg strength.
Tivicay 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.
Cabotegravir is chemically known as (3S,llaR)-N-((2,4-difluorophenyl)methyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7311,11 a-hexahydrooxazolo(3,2-a)pyrido(l ,2-d) pyrazine-8-carboxamide and represented by the following structural Formula IA. Cabotegravir is currently under Phase lib development for HIV treatment.
U.S. Patent No. 8129385 discloses carbamoylpyridone HIV integrase inhibitors and process for their preparation, including dolutegravir and cabotegravir. The disclosed

US20160108058, WO201501572, WO2015019310, WO2015177537,
WO2016092527, WO2016113372, WO2016125192, 6199/CHE/2014, 1006/MUM/ 2015, 1007/MUM/201, 247/CHE/2014 and IN201641038078.
Dolutegravir 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.
Thus, the main objective the present invention is to provide a process for the preparation of carbamoylpyridone HIV integrase inhibitors via novel intermediate compound.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a process for the preparation of carbamoylpyridone HIV integrase inhibitors and pharmaceutically acceptable salts thereof; specifically provides a process for the preparation of carbamoylpyridone HIV integrase inhibitors such as dolutegravir, cabotegravir and the like using a novel stable intermediate of Formula IX.
In one aspect, the present invention provides a process for the preparation of a compound of Formula-IX, which comprises: a) reacting a compound of Formula II, wherein R represents alkyl, aryl or aralkyl;

Formula V c) reacting the compound of Formula V with a compound of Formula VI, wherein R3 and R4 represents allcyl, aryl or aralkyl;

R40
O

OR,
O

Formula VI in presence of a suitable base and a solvent to provide a compound of Formula
VII, wherein R, Ri, R2, R3 are defined as above;
OR 0
F^ ^\ o-
R,0 ORj
Formula VII d) reacting the compound of Formula VII with a suitable acid to provide a compound of Formula VIII, wherein R and R3 are defined as above,

Formula VIII e) treating the compound of Formula VIII with ethanol to provide a compound of
Formula IX, wherein R and R3 are defined as above.
)R O

Formula IX

1 i

w w. A. T a r.
"1-4'■ 3 I
In another aspect, the present invention provides a process for the preparation of a compound of Formula IXa, which comprises:
v„i o * v;t ^ <> s. vj x ?
ij r r t L c t_ x\ t w u- H; 1

In another aspect, the present invention provides a compound of Formula IXa in crystalline form.
In another aspect, the present invention provides crystalline form of compound of Formula IXa characterized by a PXRD pattern having one or more peaks at about 5.66, 9.87, 11.40, 12.15, 12.74, 13.35, 14.09, 14.61, 15.17, 15.80, 16.11, 17.12, 18.45, 19.12, 19.48, 19.88, 20.24, 21.19, 21.72, 22.19, 23.02, 23.47, 23.61, 24.35, 24.58, 25.68, 26.28, 26.93, 27.58, 28.08, 28.34, 28.83, 29.10, 29.38, 29.86, 30.40, 30.95, 31.55, 32.57, 34.19 and 35.39 ± 0.2°29.

In another aspect, the present invention provides crystalline form of compound of Formula IXa characterized by PXRD pattern shown in Figure-1.
In another aspect, the present invention provides crystalline form of compound of Formula IXa characterized by a differential scanning calorimetry (DSC) shown in Figure-2.
In another aspect, the present invention provides use of compound of Formula IX or Formula IXa in the preparation of carbamoyl pyri done HIV integrase inhibitors such as dolutegravir, cabotegravir and the like.
In another aspect, the present invention provides a process for the preparation of dolutegravir of Formula I or pharmaceutic ally acceptable salts thereof, which comprise of converting the compound of Formula IX into dolutegravir of Formula I, wherein R and R3 are defined as above.
In another aspect, the present invention provides a process for the preparation of dolutegravir of Formula I or pharmaceutic ally acceptable salts thereof, which comprises:
a) reacting a compound of Formula II, wherein R represents alkyl, aryl or aralkyl; with N,N-dimethylformamide dimethyl acetal (DMF-DMA) in a suitable solvent to provide a compound of Formula III, wherein is R is defined as above;
b) reacting the compound of Formula III with amine compound of Formula IV, wherein R[ and R2 represents alkyl; in a suitable solvent to provide a compound of Formula V, wherein R, R| and R2 are defined as above;
c) reacting the compound of Formula V with a compound of Formula VI, wherein R3 and R4 represents alkyl, aryl or aralkyl; in presence of a suitable base and a solvent to provide a compound of Formula VII, wherein R, Ri, R2, R3 are defined as above;
d) reacting the compound of Formula VII with a suitable acid to provide a compound of Formula VIII, wherein R and R3 are defined as above;
e) treating the compound of Formula VIII with ethanol to provide a compound of Formula IX, wherein R and R3 are defined as above;
f) reacting the compound of Formula IX with (R)-3-amino-l-butanol to provide a compound of Formula X, wherein R is defined as above;

g) deprotecting the compound of Formula X to provide dolutegravir, and h) optionally converting dolutegravir into pharmaceutically acceptable salt of dolutegravir.
In another aspect, the present invention provides a process for the preparation of dolutegravir of Formula I or pharmaceutically acceptable salts thereof, which comprises:
a) reacting a compound of Formula Ha with N,N-dimethylformamide dimethyl acetal (DMF-DMA) in a suitable solvent to provide a compound of Formula Ilia,
b) reacting the compound of Formula Ilia with amine compound of Formula IVa in a suitable solvent to provide a compound of Formula Va,
c) reacting the compound of Formula Va with a compound of Formula Via in presence of a suitable base and a solvent to provide a compound of Formula Vila,
d) reacting the compound of Formula Vila with a suitable acid to provide ae compound of Formula Villa,
e) treating the compound of Formula Villa with ethanol to provide a compound of Formula IXa,
f) reacting the compound of Formula IXa with (R)-3-amino-l-butanol to provide a compound of Formula Xa,
g) deprotecting the compound of Formula Xa to provide dolutegravir, and
h) converting dolutegravir into pharmaceutically acceptable salt of dolutegravir.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure-1 is the characteristic PXRD pattern of compound of formula IXa. Figure-2 is the characteristic DSC thermogram of compound of formula IXa.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a process for the preparation of carbamoylpyridone HIV integrase inhibitors and pharmaceutically acceptable salts thereof; specifically provides a process for the preparation of carbamoylpyridone HIV integrase inhibitors such as dolutegravir, cabotegravir and the like using a novel stable intermediate of Formula IX.
In one embodiment, the present invention provides a process for the preparation of compound of Formula IX, which comprises: a) reacting a compound of Formula II, wherein R represents alkyl, aryl or aralkyl;

The starting compound of Formula II can be prepared by the process disclosed in . Indian patent publication number WO2015/110897.
The step a) of forgoing process involves reaction of compound of Formula II, wherein R represents alkyl, aryl or aralkyl; preferably methyl, ethyl, isopropyl, isoamyl or benzyl; more preferably ethyl, with N,N-dimethylformamide dimethylacetal in a suitable solvent to provide a compound of Formula III, wherein R is defined as above.
In an embodiment, the compound of Formula II and Formula III specifically represented as following Formula Ila and Formula Ilia respectively;

The suitable solvent used herein step a) is selected from the group consisting of esters, ethers, chloro solvents, hydrocarbons, amides and mixtures thereof; preferably ethyl acetate, tetrahydrofuran, methylene chloride, toluene, dimethyl formamide and mixtures thereof; more preferably toluene; The step a) reaction advantageously carried out at a temperature of about 20°C to about 50°C; preferably at about 35-40°C, for a sufficient period of time to complete the reaction, preferably for 2 - 6 hrs. Optionally, the reaction can be proceed to next step without isolating the compound of Formula III.
The step b) of forgoing process involves reaction of compound of Formula III, wherein R is as defined above; with an amine compound of Formula IV, wherein R] and R2 represents alkyl, such as methyl, ethyl, isopropyl, isoamyl; preferably methyl; in a suitable solvent to provide a compound of Formula V.
In an embodiment, the compound of Formula IV and Formula V specifically represented as following Formula IVa and Formula Va respectively;
The suitable solvent used herein step b) is selected from the group consisting of alcohols, ethers, hydrocarbons, amides and mixtures thereof; preferably methanol, tetrahydrofuran, toluene, dimethyl formamide and mixtures thereof; more preferably toluene; the step b) reaction advantageously carried out at a temperature ranging from about 30°C to about 65°C, preferably at about 50 to about 55°C, for sufficient period of time to complete the reaction, preferably for 15-24 hrs. Optionally the reaction can be proceed to next step without isolating the compound of Formula V.
The step c) of forgoing process involves the reaction of compound of Formula V, wherein R, Ri, R2 are defined as above; with a compound of Formula VI, wherein R3 and R4 represents alkyl, aryl or aralkyl; preferably methyl, ethyl, isopropyl, isoamyl

or benzyl; and more preferably ethyl, in presence of a suitable base and solvent, to provide a compound of Formula VII.
In an embodiment, the compound of Formula VI and Formula VII specifically represented as following Formula Via and Formula Vila respectively;
I
The suitable base used herein step c) is selected from the group consisting of alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide; alkali metal hydrides like sodium hydride, potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, lithium methoxide, lithium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide and the like; and mixtures thereof; preferably, sodium ethoxide.
The suitable solvent used herein step c) is selected from the group consisting of hydrocarbons, esters, chloro solvents and mixtures thereof; preferably toluene, xylene, ethyl acetate, methyl acetate, isopropyl acetate, methylene chloride and the like; more preferably methylene chloride. The step c) reaction can be carried out at a suitable temperature ranging from about ambient temperature to reflux temperature of the solvent used; preferably at about 35-45°C, for a sufficient period of time to complete the reaction, preferably for 10-15 hrs; Optionally the reaction can be proceed to out to next step without isolating the compound of Formula VII.
Further, the step c) reaction advantageously carried out in presence of water. The presence, of water in step c) reaction controls the formation of descarboxyl impurity having the following structure:

final product with lower yields. The present inventors surprisingly found that use of water as solvent in step c) reaction controls the formation of descarboxyl impurity to less than 1.5%, and thereby resulting improved yields and purity.
In an embodiment, the present invention provides a process for the preparation of Formula IX, wherein the step a), step b) and step c) intermediate compounds were not isolated as a solid and carried out as a one-pot process.
The step d) of forgoing process involves reaction of compound of Formula VII, wherein R, Ri, R2 and R3 are defined as above; with a suitable acid to provide a compound of Formula VIII, wherein R and R3 is as defined above; preferably ethyl; and in step e) the compound of Formula VIII further treating with ethanol followed by isolating as stable compound of Formula IX, wherein R and R3 is as defined above; preferably ethyl.
In an embodiment, the compound of Formula VIII and Formula IX specifically represented as following Formula Villa and Formula IXa respectively;
The compound of Formula VIII reported in the literature, for example 247/CHE/2014 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 working on improving the stability of Formula VIII, found that treating the compound of Formula VIII with ethanol leads to the formation of stable compound of Formula IX, and utilizing the same in the preparation of carbamoylpyridone HIV integrase inhibitors results in high purity and yields.
The suitable acid used herein step d) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, p-toluene sulfonic acid, methane sulfonic acid, formic acid, acetic acid, trifluoroacetic acid, maleic acid, oxalic acid and the like and mixtures thereof; preferably mixture of formic acid and sulfuric acid. Further, the reaction of Formula VII with an acid advantageously carried out at a suitable temperature ranging from ambient to reflux temperature; preferably at about 25°C to about 40°C.

The treatment of compound formula VIII with ethanol in step e) to provide a compound of Formula IX advantageously carried out at a temperature ranging from about ambient to reflux temperature; preferably at about 50°C to about 65°C; further isolation of compound Formula IX can be carried out by method known in the art; for example, cooling the reaction mass to about 10°C to about 35°C; preferably about 10-15°C followed by filtration.
In another embodiment, the present invention provides a compound of Formula IX, wherein R and R3 represents alkyl, aryl or aralkyl; preferably methyl, ethyl, isopropyl, isoamyl or benzyl.
In another embodiment, the present invention provides a compound of Formula IXa in crystalline form.
In another embodiment, the present invention provides crystalline form of compound of Formula IXa characterized by a PXRD pattern having one or more peaks at about 5.66, 9.87, 11.40, 12.15, 12.74, 13.35, 14.09, 14.61, 15.17, 15.80, 16.11, 17.12, 18.45, 19.12, 19.48, 19.88, 20.24, 21.19, 21.72, 22.19, 23^02, 23.47, 23.61, 24.35, 24.58, 25.68, 26.28, 26.93, 27.58, 28.08, 28.34, 28.83, 29.10, 29.38, 29.86, 30.40, 30.95, 31.55, 32.57, 34.19 and 35.39 ± O.2°20.
In another embodiment, the present invention provides crystalline form of compound of Formula IXa characterized by PXRD pattern shown in Figure-1.

In another embodiment, the present invention provides crystalline form of compound of Formula IXa characterized by a differential scanning calorimetry (DSC) shown in Figure-2.
In another embodiment, the present invention provides use of compound of Formula IX or Formula IXa in the preparation of carbamoylpyridone HIV integrase inhibitors such as dolutegravir, cabotegravir and the like, as an intermediate or as starting material.
In another embodiment, the present invention provides a process for the preparation dolutegravir of Formula I or pharmaceutically acceptable salts thereof, which comprises;
a) reacting a compound of Formula II, wherein R represents alkyl, aryl or aralkyl; with N,N-dimethylformamide dimethyl acetal (DMF-DMA) in a suitable solvent to provide a compound of Formula III, wherein is R is defined as above;
b) reacting the compound of Formula III with amine compound of Formula IV, wherein Ri and R2 represents alkyl; in a suitable solvent to provide a compound of Formula V, wherein R, R| and R2 are defined as above;
c) reacting the compound of Formula V with a compound of Formula VI, wherein R3 and R4 represents alkyl, aryl or aralkyl; in presence of a suitable base and a solvent to provide a compound of Formula VII, wherein R, Rj, R2, R3 are defined as above;
d) reacting the compound of Formula VII with a suitable acid to provide a compound of Formula VIII, wherein R and R3 are defined as above;
e) treating the compound of Formula VIII with ethanol to provide a compound of Formula IX, wherein R and R3 are defined as above;
f) reacting the compound of Formula IX with (R)-3-amino-l-butanol to provide a compound of Formula X, wherein R is defined as above;
g) deprotecting the compound of Formula X to provide dolutegravir, and h) optionally converting dolutegravir into pharmaceutically acceptable salt of dolutegravir.
The step a) to step e) of the forgoing process of dolutegravir can be carried out in a similar manner as described above for the preparation of compound of Formula IX.
The step f) of forgoing process involves reaction of compound of Formula IX, wherein R, R3 are defined as above; preferably ethyl, with (R)-3-amino-l-butanol in

presence of an acid and a solvent to obtain a compound of Formula X, wherein R is defined as above, preferably ethyl.
In an embodiment, the compound of Formula X specifically represented as following Formula Xa;
The suitable acid, used herein step f) is selected from acetic acid, formic acid, trifluoroacetic acid and methane sulfonic acid and the like and mixtures thereof; preferably acetic acid. And the suitable solvent used herein is selected from the group consisting of nitriles, ethers, hydrocarbons, esters, amides and mixtures thereof; preferably toluene, ethyl acetate, dimethylformamide; more preferably toluene;
Optionally the reaction of step f) may be carried out in the presence of alcohol solvent to improve the reaction rate. The suitable alcohol solvent used preferably is selected from methanol, ethanol, isopropanol and the like and mixtures thereof; more preferably methanol.
Optionally the compound of Formula X further purified using suitable solvents selected from the group consisting of alcohols, hydrocarbons and mixtures thereof; preferably methanol, ethanol, cyclohexane, heptane; more preferably mixture ethanol and cyclohexane.
The step g) of forgoing process involves deprotection of Formula X, wherein R represents alkyl, aryl or aralkyl; preferably methyl, ethyl, isopropyl, isoamyl or benzyl; more preferably ethyl; to provide the dolutegravir of Formula I. The deprotection of Formula X can be carried out by treating the compound of Formula X with a suitable deprotecting agent in suitable solvent. 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 consisting of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetrabutyl ammonium fluoride, borontribromide, borontrichJoride, aluminium chloride, prydinehydrochloride, trimethylsilylchloride; or acid deprotecting agent such as hydrochloric acid, trifluoroacetic acid, hydrobromic acid; or metal based deprotecting agent such as palladium on carbon, palladium hydroxide, Raney nickel, Platinum oxide, cericammoniumnitrate (CAN) in presence of hydrogen source such as ammonium formate or hydrogen gas; or base deprotecting agents such as lithium hydroxide, sodium hydroxide, potassium

all the possible combinations of particular and preferred embodiments indicated herein.
EXAMPLE 1:
Preparation of ethyl 5-({[2,4-difluorophenyl)methyl]amino}carbonyl)-l-[2rhydroxy -. 2-(ethoxy)ethyl]-4-oxo-3-ethoxy-l,4-dihydro-2-pyridinecarboxylate (Formula IXa):
N,N-dimethyformamide dimethyacetal (60 g) was added to Nl-(2,4-difluorobenzyl)-4-ethoxy-3-oxobutanamide (Formula Ha, 100 g) in toluene (900 ml) at 20-30°C, then reaction mass temperature was raised to 35-40°C and stirred for 4 hrs. After reaction completion, reaction mass was cooled to 20-30°C, amino acetaldehyde dimethylacetal (54 g) was added to it at 20-30°C. The reaction mass was heated to 50-56°C and stirred for 17 hrs at the same temperature. After reaction completion, reaction mass was cooled to 25-35°C, quenched with water and stirred for 15 mins at 25-35°C. Organic and aqueous layers were separated; organic layer was washed with aqueous sodium chloride solution then distilled off completely under vacuum at below 55°C. The obtained crude was dissolved in methylene chloride (200 ml) at 25-35°C. Water (1 ml) followed by sodium ethoxide (40.1 g) was added to the above solution at 20-30°C under nitrogen atmosphere. Diethyloxalate (130 ml) was added to the reaction mass at 20-30°C, heated to 40-45°C and stirred for 13 hrs at the same temperature. After reaction completion, reaction mass was cooled to 25-35°C, IN hydrochloric acid (700 ml) was added to it and stirred for 15 mins at 25-35°C. Organic and aqueous layers were separated and aqueous layer was extracted with methylene chloride. Organic layers were combined, washed twice with saturated sodium bicarbonate solution and distilled off completely at below 50°C to obtain a residue. Descarboxyl impurity was analyzed in the resultant residue and found that 0.71% by HPLC. The resultant residue was cooled to 25-35°C, formic acid (200 ml) was added, further cooled to 10-15°C, then sulphuric acid (20 ml) was added to it. The reaction mass temperature was raised to 25-30°C and stirred for 4 hrs at the same temperature. After reaction completion, water (2000 ml) was added to reaction mass and stirred for 2 hrs at 25-35°C. The solid obtained was filtered and washed with water. Water (300 ml) was added to the wet solid and. stirred for 2 hrs at 25-35°C. The solid was filtered, washed with water and suck dried under vacuum. Ethanol (280 ml) was added to the obtained solid at 25-35°C, heated to 60-65°C and stirred for 45 mins at the same temperature. The reaction mass was gradually cooled to 20-30°C and stirred for 2 hrs. Then the reaction mass was further cooled to 10-15°C and stirred for 2 hrs. The reaction mass was filtered and the solid obtained was slurry washed with chilled ethanol and suck dried. Finally the compound dried at 55-65°C for 6 hrs to get the title compound. Yield: 100 g;
'H NMR Data: 'H NMR (300 MHz, DMSO-d6): 7.43 (m, 1H), 7.07 (m, 1H), 7.25 (m, 1H), 4.54 (d, 2H, 7=5.7 Hz), 8.48 (s, 1H)3 4.07 (d, 2H, 7=5.1 Hz), 4.78 (q, 1H, .7=5.4 Hz), 4.40 (q, 2H, .7=7.2 Hz), 1.33 (t, 3H, J=7.2 Hz), 4.14 (q, 2H, .7=6.9 Hz),

3.64 (m, lHa), 3.34 (m, lHb), 1.04 (t3 3H, 7=7.2 Hz), 6.75 (d, OH, J=6.6 Hz), 10.35 (t, NH, >6.0 Hz). ESI-MS (m/z): 469 (M+H)+ Purity by HPLC: 97.9%; descarboxyl impurity: 0.02%
EXAMPLE 2:
Preparation of N9-(2)4-difluorobenzyl)-(4R,12aS)-7-ethoxy-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 (Formula Xa):
R-3-amino-l-butanol (31.96 g), methanol (36.39 g) was added to the compound of Formula [Xa (160 g) in toluene (2320 ml) at 25-35°C, then cooled to 15-25°C and stirred for 15 mins. Acetic acid (113.52 g) was added to the reaction mass at 20-25°C, then heated to 80-90°C and stirred for 15 hrs at same temperature. After reaction completion, reaction mass was cooled to 25-35°C, water (1600. ml) was added to it and stirred for 15 mins at 25-35°C. Organic and aqueous layers were separated and aqueous layer was extracted with methylene chloride. Organic layers were combined, washed with saturated sodium bicarbonate solution followed by 5% sodium chloride solution. The solvent from organic layer was distilled off under vacuum at below 50°C. Ethanoi (160 ml) was added to the residue, stirred for 10 mins at below 50°C and again distilled off the solvent completely under vacuum at below 50°C. The reaction mass was cooled to 25-35°C, ethanoi (208 ml) was added to it, heated to 75-85°C and stirred for 15 mins. The reaction mass then cooled to 40-50°C and cyclohexane (208 ml) was added to it. The reaction mass was further cooled to 10-15°C and stirred for 60 mins. The solid formed was filtered off, washed with mixture of ethanoi and cyclohexane, suck dried and finally dried at 70-75°C for 4 hrs to get the title compound. Yield: 120 g; Melting range: 161-164°C Purity by HPLC: 99.6%
EXAMPLE 3:
Preparation of dolutegravir (Formula I): •
Sodium hydroxide (67.04 g) was added to .pre-coo.led ethanoi (490 ml) at 20-25°C, . stirred for 90 mins at 25-35°C and then cooled to 10-15°C. To this, solution of compound of Formula Xa (100 g) in methylene chloride (700 ml) was added at 10-15°C The reaction mass temperature was raised to 25-35°C and stirred for 13 hrs at same temperature. After reaction completion, reaction mass cooled to 5-15°C, methylene chloride (500 ml), water (500 ml) followed by 6Nhydrochloric acid (300 ml) was added to it at 5-15°C; and stirred for 10 mins at 25-35°C. Organic and aqueous layers were separated and aqueous layer was extracted with methylene chloride. Organic layers were combined, washed with saturated sodium bicarbonate solution followed by water; and then distilled off the solvent from organic layer completely under vacuum at below 50°C. The obtained residue was dissolved in methanol (240Q mil at 60-70°C and subjected to carbon treatment. The reaction mass

then filtered through hyflow and washed with methanol at 65-70°C; filtrate obtained was stirred at reflux for 10 mins and distilled off methanol from filtrate partially at 60-70°C. The reaction mass cooled to 25-35°C, stirred for 30 mins then again cooled to 10-15°C and stirred for an hour. The solid formed was filtered, washed with chilled methanol, dried under vacuum for 2 hrs at 25-35°C and finally dried at 50-55°C for 4 hrs to get the title compound. Yield: 70 grams. Purity by HPLC: 99.2%.
EXAMPLE-4:
Preparation of dolutegravir sodium:
A mixture of dolutegravir (60 g) and ethanol (220 ml) was heated to 75-85°C and stirred for 15 mins. To this, 2N sodium hydroxide solution (prepared by dissolving 6.29g of sodium hydroxide in 75.8 ml of water) was added at 75-85°C and stirred for 30 mins at the same temperature. Then reaction mass was cooled to 25-35°C and stirred for 30 mins. The obtained solid was filtered, washed with ethanol, suck dried and finally dried at 50-55°C for 12 hrs to get the title compound. Yield: 58 g.
REFERENCE EXAMPLE: Preparation of compound of Formula Vila:
A mixture of compound of Formula Va (100 g), diethyl oxalate (300 mL, 3V), sodium ethoxide (44.5 g, 2.5eq) and toluene (15V) was heated to 50-55°C and stirred for 2-3 hrs. After reaction completion, the reaction mass was cooled to room temperature and water (20V) was added to it. The organic and aqueous layers were separated.- Aqueous layer was extracted with toluene (2X5V). The organic layers were combined and washed with saturated sodium bicarbonate solution (5V) followed by water (5V) and brine (5V) solution. Organic layer was distilled off completely under vacuum to get the title compound as brown color liquid (75% yield). Descarboxyl impurity: 5.9% by HPLC.

WE CLAIM:
Claim 1: A process for the preparation of a compound of Formula IX, which
comprises: a) reacting a compound of Formula II, wherein R represents alkyl, aryl or aralkyl;
with N,N-dimethylformamide dimethyl acetai (DMF-DMA) in a suitable solvent to provide a compound of Formula III, wherein R is defined as above;
b) reacting the compound of Formula III with amine compound of Formula IV, wherein Ri and R2 represents alkyl;
in a suitable solvent to provide a compound of Formula V, wherein R, R| and R2 are defined as above;
c) reacting the compound of Formula V with a compound of Formula VI, wherein R3 and R4 represents alkyl, aryl or aralkyl;
in presence of a suitable base and a solvent to provide a compound of Formula VII, wherein R, Ri, R2, and R3 are defined as above;

d) reacting the compound of Formula VII with a suitable acid to provide a compound of Formula VIII, wherein R and R3 are defined as above,
e) treating the compound of Formula VIII with ethanol to provide a compound of Formula IX, wherein R and R3 are defined as above.
Claim 2: The process of claim 1, wherein the R, R3 and R4 represents ethyl; and
R] and R2 represents methyl.
Claim 3: The process of claim 1, wherein in step c) the suitable base is sodium
ethoxide and the solvent is a mixture of methylene chloride and water.
Claim 4: The process of claim 1, wherein the compound of Formula III, V and
VII are not isolated as a solid.
Claim 5: A process for the preparation of a compound of Formula IX, wherein
R and R3 represents alkyl, aryl or aralkyl; comprises; a) treating a compound of Formula VIII

with ethanol to provide a compound of Formula IX, wherein R and R3 are defined as above.
Claim 6: A compound of Formula DC, wherein R and R3 represents alkyl, aryl
or aralkyl.
Claim 7: The compound of Formula IX, wherein the R and R3 represents ethyl.
Claim 8: A process for the preparation of dolutegravir of Formula I or
pharmaceutic ally acceptable salts thereof, which comprises: a) reacting a compound of Formula IX
with (R)-3-amino-l-butanol to provide a compound of Formula X, wherein R and R3 represents alkyl, aryl or aralkyl;
b) deprotecting the compound of Formula X to provide dolutegravir, and

c) optionally converting dolutegravir into pharmaceutically acceptable salt of dolutegravir.
Claim 9: A process for the preparation of dolutegravir of Formula I or
pharmaceutically acceptable salts thereof, which comprises: a) reacting a compound of Formula Ha
with N,N-dimethylformamide dimethyl acetal (DMF-DMA) in a suitable solvent to provide a compound of Formula Ilia,
b) reacting the compound of Formula Ilia with amine compound of Formula IVa
c) reacting the compound of Formula Va with a compound of Formula Via
in presence of a suitable base and a solvent to provide a compound of Formula Vila,

d) reacting the compound of Formula Vila with a suitable acid to provide a compound of Formula Villa,
e) treating the compound of Formula Villa with ethanol followed by isolating the compound of Formula IXa, and
f) converting the compound of Formula IXa in to dolutegravir or pharmaceutically acceptable salts thereof.
Claim 10: A process for the preparation of dolutegravir of Formula I or pharmaceutically acceptable salts thereof, which comprises: a) reacting a compound of Formula II, wherein R represents alkyl, aryl or aralkyl;
with N,N-dimethylformamide dimethyl acetal (DMF-DMA) in a suitable solvent to provide a compound of Formula III, wherein R is defined as above;

b) reacting the compound of Formula III with amine compound of Formula IV, wherein R\ and R2 represents aikyl;
in a suitable solvent to provide a compound of Formula V, wherein R, R[ and R2 are defined as above;
c) reacting the compound of Formula V with a compound of Formula VI, wherein R3 and R4 represents alkyl, aryl or aralkyl;
d) reacting the compound of Formula VII with a suitable acid to provide a compound of Formula VIII, wherein R and R3 are defined as above,
e) treating the compound of Formula VIII with ethanol to provide a compound of Formula IX, wherein R and R3 are defined as above.

f) converting the compound of Formula IX in to dolutegravir of Formula I or
pharmaceutically acceptable salts thereof; wherein the compound of Formula III,
Formula V and Formula VII are not isolated as a solid; and in step c) the suitable
■ base is sodium ethoxide and the solvent is a mixture of methylene chloride and
water.