DESC:A NOVEL PROCESS FOR THE PREPARATION OF HIV INHIBITORS
FIELD OF THE INVENTION
The present invention provides an improved process for the preparation of HIV inhibitor compounds of formula (I) and pharmaceutically acceptable salts thereof.

wherein m is 2 or 3; n is 0 or 1, and
when n is 0, A is methyl and B is hydrogen; or,
when n is 1, A is methyl, B is hydrogen; or,
when n is 1, A-B is -CH2-CH2- forms bicycle [3,2,1] ring structure; and
* represents chiral centre.

BACKGROUND
Polycyclic carbamoyl pyrimidines derivatives compounds of Formula (I) such as Dolutegravir, Cabotegravir and Bictegravir have been approved for treating HIV.
US8129385 B2 discloses a 16-step synthesis of Dolutegravir using Palladium on charcoal. This process is cumbersome and results in lower yields.
WO 2012018065 A1 describes an 8-step synthesis of Dolutegravir as shown in Scheme 1 using Palladium on Charcoal and column chromatography with overall yield of 33%.

Scheme 1
Further, the WO 2012018065 A1 describes synthesis of Dolutegravir as per Scheme 2 which uses pyrophoric reagent LiHMDS and silanoate reagent (KOSiMe3) resulting in overall yield of 5% Dolutegravir.
Scheme 2
WO 2011119566 A1 describes the synthesis for Cabotegravir as per Scheme 3 involving selective hydrolysis of ester using lithium hydroxide (LiOH). Further it involves time consuming demethylation reaction.

Scheme 3
CN 113816972 B describes the synthesis for Dolutegravir and its dervatives as shown in Scheme 4.

Scheme 4
Further, WO 2006/116764 A1, WO 2010/068262 A1, WO 2010/068253 A1, WO 2014/128545 A1, WO 2015/019310 A1, WO 2015/111080 A1, WO 2015/110897 A1, WO 2016/092527 A1, WO 2016/113372 A1 describes processes for preparation of HIV inhibitor and its intermediate which are incorporated herein by reference.
There is an unmet need to provide a process for the preparation of HIV inhibitors, and its intermediates which minimizes the reaction steps without compromising the yields.

OBJECT OF THE INVENTION
An object of present invention is to provide an improved process for the preparation of HIV inhibitors and pharmaceutically acceptable salts thereof, which is cost-effective and commercially feasible.
Another object of present invention is to provide an improved process for the preparation of HIV inhibitors in high yields using safer regents with minimizing the reaction process.

SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of HIV inhibitors and its pharmaceutically acceptable salts, as depicted in scheme 5:

Scheme 5
wherein m is 2 or 3; n is 0 or 1, and
when n is 0, A is methyl and B is hydrogen; or,
when n is 1, A is methyl, B is hydrogen; or,
when n is 1, A-B is -CH2-CH2- forms bicycle [3,2,1] ring structure; and * represents chiral centre.
The present invention further provides a novel intermediate methyl 3-{[2,2 (bismethyloxy)ethyl]amino}-2-[(benzyloxy)acetyl]-2-propenoate of formula (VIII) and preparation thereof as shown in scheme 5.

DETAILED DESCRIPTION OF INVENTION
The present invention provides an improved process for the preparation of HIV inhibitors and pharmaceutically acceptable salts thereof that is cost-effective and commercially feasible. Further, the present invention provides an improved process for the preparation of HIV inhibitor compounds of formula (I) in high yields using safer regents with minimizing the reaction process.
The present invention provides a process for the preparation of compound of formula (I) and pharmaceutically acceptable salts thereof,

wherein m is 2 or 3; n is 0 or 1, and
when n is 0, A is methyl and B is hydrogen; or,
when n is 1, A is methyl, B is hydrogen; or,
when n is 1, A-B is -CH2-CH2- forms bicycle [3,2,1] ring structure; and
* represents chiral centre,
comprising steps:
a) reacting a compound of formula (XI) with dimethyl acetal in presence of solvent to obtain a compound of formula (X), optionally isolating the compound of formula (X);

b) reacting the compound of formula (X) with aminoacetaldehyde dimethyl acetal in presence of solvent to obtain a compound of formula (VIII), optionally isolating the compound of formula (VIII);

c) reacting a compound of formula (VIII) with oxalate compound of formula (IX) in presence of base and solvent to obtain the compound of formula (VII);

wherein R1 is methoxy, ethoxy; R2 is methoxy, ethoxy, chloro, bromo;
d) reacting the compound of formula (VII) with a compound of formula (V) in the presence of an acid and solvent to obtain the compound of formula (VI), optionally isolating the compound of formula (VI);

wherein m is 2 or 3;
e) reacting the compound of formula (VI) with an acid in presence of solvent to obtain a compound of formula (III);

f) reacting the compound of formula (III) with amino reagent compound of formula (IV) in the presence of an acid and solvent to obtain a compound of formula (II);
;
wherein m is 2 or 3; n is 0 or 1, and
when n is 0, A is methyl and B is hydrogen; or,
when n is 1, A is methyl, B is hydrogen; or,
when n is 1, A-B is -CH2-CH2- forms bicycle [3,2,1] ring structure; and
* represents chiral centre;
wherein amino reagent compound of formula (IV) is
(R)-3-aminobutanol,
(S)-2-amino propanol or,
3-aminocyclopentanol;
g) reacting the compound of formula (II) with Lewis acid in presence of solvent to obtain the compound of formula (I); and
h) optionally compound of formula (I) is converted to any pharmaceutically acceptable salts.

The solvent in step (a) is selected from halogenated hydrocarbons, nitriles, amides, ethers and mixtures thereof. The halogenated hydrocarbons are selected from methylene chloride, ethylene chloride, chloroform and mixtures thereof. The amides are selected from dimethyl formamide, 1,3-Dimethyl-2-imidazolidinone, dimethyl acetamide, N-methyl pyrrolidinone and mixtures thereof. The ethers are selected from tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof. The preferred solvent is tetrahydrofuran.
Step (a) is carried out at 0 °C – 44 °C for 1 to 6 hours.
The solvent in step (b) is selected from halogenated hydrocarbons, nitriles, amides, ethers and mixtures thereof. The halogenated hydrocarbons are selected from methylene chloride, ethylene chloride, chloroform and mixtures thereof. The amides are selected from dimethyl formamide, 1,3-Dimethyl-2-imidazolidinone, dimethyl acetamide, N-methyl pyrrolidinone and mixtures thereof. The ethers are selected from tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof. The preferred solvent is toluene.
Step (b) is carried out at 20 °C – 60 °C for 1 to 4 hours.
The oxalate compound of formula (IX) in step (c) is selected from dimethyl oxalate, diethyl oxalate, methyl oxalyl chloride, methyl oxalyl bromide, ethyl oxalyl chloride, ethyl oxalyl bromide.
The base in step (c) is selected from n-butyllithium, tert-butyllithium, sodium tert- butoxide, potassium tert-butoxide, sodium tert-pentoxide, sodium methoxide, sodium ethoxide, sodium hydride, lithium diisopropylamide, and lithium bis(trimethylsilyl)amide. The preferred base is sodium tert-butoxide.
The solvent in step (c) is selected from halogenated hydrocarbons, nitriles, amides, ethers and mixtures thereof. The halogenated hydrocarbons are selected from methylene chloride, ethylene chloride, chloroform and mixtures thereof. The amides are selected from dimethyl formamide, 1,3-dimethyl-2-imidazolidinone, dimethyl acetamide, N-methyl pyrrolidinone and mixtures thereof. The ethers are selected from tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof. The preferred solvent is toluene.
Step (c) is carried out at room temperature for 1 to 8 hours.
The halo substituted benzylamine derivative of formula (V) in step (d) is selected from 2,4-diflourobenzylamine, and 2,4,6-triflourobenzylamine.
The solvent in step (d) is selected from hydrocarbons, amides, ethers and mixtures thereof. The hydrocarbons are selected from toluene, p-xylene, m-xylene, o-xylene and n-hexane, n-pentane and mixtures thereof. The amides are selected from dimethyl formamide, 1,3-dimethyl-2-imidazolidinone, dimethyl acetamide, N-methyl pyrrolidinone and mixtures thereof. The ethers are selected from tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof. The preferred solvent is toluene.

The acid in step (d) is selected from acetic acid, methane sulphonic acid, sulphuric acid, hydrochloric acid and p-toluene sulphonic acid.
Step (d) is carried out at 20 °C - 90 °C for 1 to 5 hours.
Step (e) is carried out in the presence of acid and solvent.
The acid in step (e) is selected from sulphuric acid, acetic acid and p-toluene sulphonic acid.
The solvent in step (e) is selected from formic acid, methanesulfonic acid, hydrochloric acid and acetic acid. The preferred solvent is formic acid.
Step (e) is carried out at 25 °C – 30 °C for 1 to 2.5 hours.
The acid in step (f) is selected from acetic acid, hydrochloric acid and sulphuric acid.
The solvent in step (f) is selected from halogenated hydrocarbons, nitriles, amides, ethers and mixtures thereof. The halogenated hydrocarbons are selected from methylene chloride, ethylene chloride, chloroform, and mixtures thereof. The amides are selected from dimethyl formamide, 1,3-dimethyl-2-imidazolidinone, dimethyl acetamide, N-methyl pyrrolidinone and mixtures thereof. The ethers are selected from tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof. The preferred solvent is toluene.
Step (f) is carried out at 90 °C – 100 °C for 1 to 3 hours.
Step (g) is carried out in presence of Lewis acid and solvent.
The Lewis acid in step (g) is selected from titanium chloride, boron trihalides, trialkylsilyl halides magnesium chloride, magnesium bromide, magnesium iodide, magnesium sulfide, lithium chloride, lithium bromide, lithium iodide and lithium sulphide.
The solvent in step (g) is selected from halogenated hydrocarbons, nitriles, amides, ethers and mixtures thereof. The halogenated hydrocarbons are selected from methylene chloride, ethylene chloride, chloroform and mixtures thereof. The amides are selected from dimethyl formamide, 1,3-dimethyl-2-imidazolidinone, dimethyl acetamide, N-methyl pyrrolidinone and mixtures thereof. The ethers are selected from tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof. The preferred solvent is methylene chloride.
Step (g) is carried out at 0-25 °C for 15-20 minutes.
Step (g) is carried out at lower temperatures in nitrogen atmosphere.
The obtained HIV inhibitors compound of formula (I) is optionally converted to its pharmaceutically acceptable salts, preferably sodium salt by any method known in the art.
In another aspect, the present invention provides a process for the preparation of methyl 3-{[2,2(bismethyloxy)ethyl]amino}-2-[(benzyloxy)acetyl]-2-propenoate compound of formula (VIII),

comprising steps:
a) reacting a compound of formula (XI) with dimethyl acetal in presence of solvent to obtain a compound of formula (X), optionally isolating the compound of formula (X); and

b) reacting the compound of formula (X) with aminoacetaldehyde dimethyl acetal in presence of solvent to obtain a compound of formula (VIII).
In another aspect, the present invention provides a process for the preparation of compound of formula (VII), comprising:

wherein R1 is selected from methoxy, ethoxy;
reacting a compound of formula (VIII) with oxalate compound of formula (IX) in presence of base and solvent to obtain the compound of formula (VII);

wherein R1 is same as above; R2 is selected from methoxy, ethoxy, chloro and bromo.
In another aspect, the present invention provides a process for the preparation of compound of formula (VII), comprising steps:

wherein R1 is selected from methoxy, ethoxy;
a) reacting a compound of formula (XI) with dimethyl acetal in presence of solvent to obtain a compound of formula (X) and optionally isolating the compound of formula (X);

b) reacting the compound of formula (X) with aminoacetaldehyde dimethyl acetal in presence of solvent to obtain a compound of formula (VIII), optionally isolating the compound of formula (VIII); and

c) reacting a compound of formula (VIII) with oxalate compound of formula (IX) in presence of base and solvent to obtain the compound of formula (VII).

wherein R1 is selected from methoxy, ethoxy;
R2 is selected from methoxy, ethoxy, chloro and bromo.
In another aspect, the present invention provides a process for the preparation of compound of formula (III),

wherein m can be 2 or 3;
comprising steps:
a) reacting the compound of formula (VII) with compound of formula (V) in the presence of an acid and solvent to obtain the compound of formula (VI), optionally isolating the compound of formula (VI); and

wherein m is defined above;
b) reacting the compound of formula (VI) with an acid in presence of solvent to obtain the compound of formula (III).
In another aspect, the present invention is to provide a process for the preparation of compound of formula (I),

wherein
m is 2 or 3; n is 0 or 1, and
when n is 0, A is methyl and B is hydrogen; or,
when n is 1, A is methyl, B is hydrogen; or,
when n is 1, A-B is -CH2-CH2- forms bicycle [3,2,1] ring structure; and
* represents chiral centre,
comprising, reacting a compound of formula (II)

with Lewis acid in presence of solvent to obtain the compound of formula (I).
The present invention provides a process for the preparation of compound of formula (I), is characterized in that,

wherein n is 1; A is methyl, B is hydrogen; m is 2 which represents 2,4-diflorobenzyl collectively representing the structural formula of the compound shown in formula (Ia):
Dolutegravir;
or,
wherein n is 1; A-B is -CH2-CH2- forms bicycle [3,2,1] ring structure; m is 3 which represents 2,4,6-trifluorobenzyl collectively representing the structural formula of the compound shown in formula (Ib):
Bictegravir;
or,
when n is 0; A is methyl and B is hydrogen; m is 2 which represents 2,4-diflourobenzyl collectively representing the structural formula of the compound shown in formula (Ic):
Cabotegravir.
In another aspect, the present invention provides a novel intermediate methyl 3-{[2,2(bismethyloxy)ethyl]amino}-2-[(benzyloxy)acetyl]-2-propenoate compound of formula (VIII).

The invention is illustrated with non-limiting examples.

Example(s):
Example-1: Methyl 4-(benzyloxy)-3-oxobutanoate
7.24 g sodium tert-butoxide was dissolved in THF (20 mL) at room temperature and benzyl alcohol (3.59 g) was added to the solution. The reaction mixture was stirred for 2 hours at 40° C. The reaction mass was cooled to 0°C and Methyl 4-(chloro)-3-oxobutanoate solution (5 g in 10 mL THF) was added to the reaction mixture drop wise within 10 minutes. The reaction mass was stirred for 3 hours at room temperature. The reaction was monitored by TLC. The reaction mixture was diluted with 2N HCl and ethyl acetate. Aqueous layer was extracted with ethyl acetate. The resultant organic layer was washed with saturated sodium bicarbonate, brine and water. The organic layer was filtered, dried over sodium sulphate and organic solvent was distilled off under reduced pressure. The residue was purified by column chromatography (ethyl acetate /hexane 10: 90) to get 6.7 g of desired product as pale-yellow oil with 90% yield.
Example-2: Methyl 4-(benzyloxy)-3-oxobutanoate
7.24 g sodium tert-butoxide was dissolved in DMF (20 mL) at room temperature and benzyl alcohol (3.59 g) was added to the solution. The reaction mixture was stirred for 2 hours at 40° C. The reaction mass was cooled to 0°C and Methyl 4-(chloro)-3-oxobutanoate solution (5 g in 10 mL DMF) was added to the reaction mixture drop wise within 10 minutes. The reaction mass was stirred for 3 hours at room temperature. The reaction was monitored by TLC. The reaction mixture was diluted with 2N HCl and ethyl acetate. Aqueous layer was extracted with ethyl acetate. The resultant organic layer was washed with saturated sodium bicarbonate, brine and water. The organic layer was filtered, dried over sodium sulphate and organic solvent was distilled off under reduced pressure. The residue was purified by column chromatography (ethyl acetate /hexane 10: 90) to get 6.5 g of desired product as pale-yellow oil with 88% yield.
Example-3: Methyl 3-{[2,2(bismethyloxy)ethyl]amino}-2-[(benzyloxy)acetyl]-2-propenoate (VIII)
1 g Methyl 4-(benzyloxy)-3-oxobutanoate is dissolved in toluene (10 mL) at room temperature and N, N- dimethylformamide dimethyl acetal (0.536 g) was added to the reaction mixture while stirring. The reaction mass was stirred for 2.5 hours at 60 °C. The solvent was distilled off completely yielding 1.35 g of intermediate (X). Aminoacetaldehyde dimethyl acetal (0.435 g) and toluene (11.5 mL) was added to 1.15 g of intermediate (X) at room temperature and stirred for 1 hour. The solvent was distilled off completely to get 1.35 g of desired product as colorless liquid with 92.76% yield.
Chemical Formula: C17H23NO6; MS-ESI: m/z 238.36 (M+H)+;
1H NMR (400 MHz, CDCl3) d 11.08 – 10.89 (m, 1H), 7.96 (d, J = 13.7 Hz, 1H), 7.44 – 7.29 (m, 5H), 4.67 (d, J = 3.6 Hz, 4H), 4.45 – 4.40 (m, 1H), 3.70 (s, 3H), 3.45 (d, J = 3.9 Hz, 2H), 3.43 (s, 6H);
13C NMR (101 MHz, CDCl3) d 197.00, 197.00, 166.98, 161.02, 138.20, 128.38, 127.94, 127.61, 102.81, 98.54, 77.42, 77.10, 76.78, 74.77, 73.18, 54.95, 51.93, 50.92, 27.58;
IR (neat) vmax : 2989, 2947, 2839, 1697, 1643, 1593, 1448, 1381, 1307, 1253, 1195, 1114, 1057, 972, 779, 698, 459.
Example-4: Dimethyl 3-(benzyloxy)-1(2,2-dimethoxyethyl)-4-oxo-1,4-dihydro pyridine-2,5-dicarboxylate
1 g Methyl 4-(benzyloxy)-3-oxobutanoate is dissolved in toluene (10 mL) at room temperature and N, N- dimethylformamide dimethyl acetal (0.536 g) was added to the reaction mixture while stirring. The reaction mass was stirred for 2.5 hours at 60 °C. The solvent was distilled off completely. Aminoacetaldehyde dimethyl acetal (0.435 g) and toluene (11.5 mL) was added to the resulting residue (1.15 g) at room temperature and stirred for 1 hour. The solvent was distilled off completely. Methanol (40 mL), dimethyl oxalate (1.36 g) and sodium tert-butoxide (1.11 g) were added to the reaction mass (1.35 g) and stirred for 8 hours. The reaction was monitored by TLC. Methanol was distilled off and reaction mixture was quenched by addition of 2 N HCl solution. The aqueous layer was extracted with dichloromethane. The resultant organic layer was washed with saturated sodium bicarbonate, brine and water. The organic layer was dried over sodium sulphate and filtered. The filtrate was distilled under reduced pressure. The residue was purified by column chromatography (ethyl acetate /hexane 100:30) to get 1.34 g of desired product as reddish oil with 73% yield.
Example-5: Dimethyl 3-(benzyloxy)-1(2,2-dimethoxyethyl)-4-oxo-1,4-dihydro pyridine-2,5-dicarboxylate.
1 g Methyl 4-(benzyloxy)-3-oxobutanoate is dissolved in THF (10 mL) at room temperature and N, N- dimethylformamide dimethyl acetal (0.536 g) was added to the reaction mixture while stirring. The reaction mass was stirred for 2.5 hours at 60 °C. The solvent was distilled off completely. Aminoacetaldehyde dimethyl acetal (0.435 g) and THF (11.5 mL) was added to the resulting residue (1.15 g) at room temperature and stirred for 1 hour. The solvent was distilled off completely. ethanol (40 mL), dimethyl oxalate (1.36 g) and sodium tert-butoxide (1.11 g) were added to the reaction mass (1.35 g) and stirred for 8 hours. The reaction was monitored by TLC. Methanol was distilled off and reaction mixture was quenched by addition of 2 N HCl solution. The aqueous layer was extracted with dichloromethane. The resultant organic layer was washed with saturated sodium bicarbonate, brine and water. The organic layer was dried over sodium sulphate and filtered. The filtrate was distilled under reduced pressure. The residue was purified by column chromatography (ethyl acetate /hexane 100:30) to get 1.0 g of desired product as reddish oil with 54% yield.
Example-6: Methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-di-hydropyridine-2-carboxylate
1g Dimethyl 3-(benzyloxy)-1(2, 2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate was dissolved in toluene (40 mL) at room temperature and 2,4-difluorobenzylamine (0.353 g), acetic acid (0.148 g) were added to the reaction mixture. The reaction mass was stirred for 5 hours at 90 °C. Toluene was distilled off completely. Formic acid (10 mL) and 60% sulphuric acid (0.313 g) were added to the reaction mass and stirred for 2 hours 30 minutes at room temperature. The reaction was monitored by TLC. The reaction mixture was quenched with drop wise addition of saturated sodium bicarbonate until neutral pH appeared. The aqueous layer was extracted with ethyl acetate. The resultant organic layer was washed with brine and water. The organic layer was dried over sodium sulfate, filtered. The filtrate was distilled off completely. The residue was recrystallized with methanol to obtain 1 g of desired white solid product with 84% yield.
Example-6: Methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-di-hydropyridine-2-carboxylate
1g Dimethyl 3-(benzyloxy)-1(2, 2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate was dissolved in 1,4 dioxane (40 mL) at room temperature and 2,4-difluorobenzylamine (0.353 g), acetic acid (0.148 g) were added to the reaction mixture. The reaction mass was stirred for 5 hours at 90 °C. Toluene was distilled off completely. Acetic acid (10 mL) and 60% sulphuric acid (0.313 g) were added to the reaction mass and stirred for 2 hours 30 minutes at room temperature. The reaction was monitored by TLC. The reaction mixture was quenched with drop wise addition of saturated sodium bicarbonate until neutral pH appeared. The aqueous layer was extracted with ethyl acetate. The resultant organic layer was washed with brine and water. The organic layer was dried over sodium sulfate, filtered. The filtrate was distilled off completely. The residue was recrystallized with methanol to obtained 0.6 g of desired white solid product with 51% yield.

Example-7: (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-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
2 g 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-di-hydropyridine-2-carboxylate was dissolved in toluene (20 mL), and (R)-3-amino-butan-1-ol (0.454 g), acetic acid (0.306 g) were added to the reaction mixture at room temperature. The reaction mass was heated to 100 °C and stirred for 3 hours. The reaction mass was diluted with water followed by extraction with ethyl acetate. The resultant organic layer was washed with saturated sodium bicarbonate, brine and water. The organic layer was dried over sodium sulphate and filtered. The filtrate was distilled off completely. The residue was recrystallized with methanol to obtain 1.73 g of desired white solid product with 80% yield.
Example-8: (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-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
2 g 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-di-hydropyridine-2-carboxylate was dissolved in DMF (20 mL), and (R)-3-amino-butan-1-ol (0.454 g), acetic acid (0.306 g) were added to the reaction mixture at room temperature. The reaction mass was heated to 100 °C and stirred for 3 hours. The reaction mass was diluted with water followed by extraction with ethyl acetate. The resultant organic layer was washed with saturated sodium bicarbonate, brine and water. The organic layer was dried over sodium sulphate and filtered. The filtrate was distilled off completely. The residue was recrystallized with methanol to obtain 1.00 g of desired white solid product with 46% yield.
Example-9: (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
1 g (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-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 was dissolved in dichloromethane (10 mL) at room temperature. The reaction mixture was cooled to 0 °C and titanium tetrachloride (0.232 mL) was added to the reaction mixture drop wise. The reaction mixture was slowly heated to room temperature and stirred for 15-20 min. The reaction was monitored with TLC. The reaction mixture was quenched with saturated sodium bicarbonate. Layers were separated and the aqueous layer was quenched with 2 N HCl and extracted with dichloromethane. The resultant organic layer was dried over sodium sulphate and filtered. The filtrate was distilled off completely to get 0.770 g of pure dolutegravir with 94% yield.
Example-10: (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
1 g (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-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 was dissolved in Tetrahydrofuran (10 mL) at room temperature. The reaction mixture was cooled to 0 °C and titanium tetrachloride (0.232 mL) was added to the reaction mixture drop wise. The reaction mixture was slowly heated to room temperature and stirred for 15-20 min. The reaction was monitored with TLC. The reaction mixture was quenched with saturated sodium bicarbonate. Layers were separated and the aqueous layer was quenched with 2 N HCl and extracted with dichloromethane. The resultant organic layer was dried over sodium sulphate and filtered. The filtrate was distilled off completely to get 0.60 g of pure dolutegravir with 73% yield.
,CLAIMS:We claim:
1. A process for the preparation of compound of formula (I) and pharmaceutically acceptable salts thereof,

wherein m is 2 or 3; n is 0 or 1, and
when n is 0, A is methyl and B is hydrogen;
when n is 1, A is methyl, B is hydrogen;
when n is 1, A-B is -CH2-CH2- forms bicycle [3,2,1] ring structure; and
* represents chiral centre;
comprising steps:
a) reacting a compound of formula (XI) with dimethyl acetal in presence of solvent to obtain a compound of formula (X), optionally isolating the compound of formula (X);

b) reacting the compound of formula (X) with aminoacetaldehyde dimethyl acetal in presence of solvent to obtain a compound of formula (VIII), optionally isolating the compound of formula (VIII);

c) reacting a compound of formula (VIII) with oxalate compound of formula (IX) in presence of base and a solvent to obtain the compound of formula (VII);

wherein R1 is methoxy, ethoxy; R2 is methoxy, ethoxy, chloro, bromo;
d) reacting the compound of formula (VII) with a compound of formula (V) in the presence of an acid and solvent to obtain a compound of formula (VI), optionally isolating the compound of formula (VI);

wherein m represents 2 or 3;
e) reacting the compound of formula (VI) with an acid in presence of solvent to obtain a compound of formula (III);

f) reacting the compound of formula (III) with amino reagent compound of formula (IV) in the presence of an acid and solvent to obtain a compound of formula (II);
;
wherein m is 2 or 3; n is 0 or 1, and
when n is 0, A is methyl and B is hydrogen;
when n is 1, A is methyl, B is hydrogen;
when n is 1, A-B is -CH2-CH2- forms bicycle [3,2,1] ring structure; and
* represents chiral centre;
wherein amino reagent compound of formula (IV) is (R)-3-aminobutanol, (S)-2-amino propanol or 3-aminocyclopentanol;
g) reacting the compound of formula (II) with Lewis acid in presence of solvent to obtain the compound of formula (I); and
h) optionally compound of formula (I) is converted to any pharmaceutically acceptable salts.

2. The process as claimed in claim 1, wherein the oxalate compound in step (c) is selected from dimethyl oxalate, diethyl oxalate, methyl oxalyl chloride, methyl oxalyl bromide, ethyl oxalyl chloride and ethyl oxalyl bromide.

3. The process as claimed in claim 1, wherein the base in step (c) is selected from n-butyllithium, tert-butyllithium, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, sodium methoxide, sodium ethoxide, sodium hydride, lithium diisopropylamide and lithium bis(trimethylsilyl)amide.
4. The process as claimed in claim 1, wherein the acid in step (d) is selected from acetic acid, methane sulphonic acid, sulphuric acid, hydrochloric acid and p-toluene sulphonic acid.
5. The process as claimed in claim 1, wherein the lewis acid in step (g) is selected from titanium chloride, boron trihalides, trialkylsilyl halides magnesium chloride, magnesium bromide, magnesium iodide, magnesium sulfide, lithium chloride, lithium bromide, lithium iodide and lithium sulphide.
6. A compound Methyl 3-{[2,2-(bismethyloxy)ethyl]amino}-2-[(benzyloxy)acetyl]-2-propenoate compound of formula (VIII).

7. A process for the preparation of methyl 3-{[2,2(bismethyloxy)ethyl]amino}-2-[(benzyloxy)acetyl]-2-propenoate compound of formula (VIII),

comprising steps:
a) reacting a compound of formula (XI) with dimethyl acetal in presence of solvent to obtain a compound of formula (X), optionally isolating the compound of formula (X); and

b) reacting the compound of formula (X) with aminoacetaldehyde dimethyl acetal in presence of solvent to obtain a compound of formula (VIII).
8. A process for the preparation of compound of formula (VII),

wherein R1 is methoxy, ethoxy;
comprising, reacting a compound of formula (VIII) with oxalate compound of formula (IX) in presence of base and a solvent to obtain the compound of formula (VII).

wherein R1 is methoxy, ethoxy; R2 is methoxy, ethoxy, chloro, bromo.
9. A process for the preparation of compound of formula (VII), comprising steps:

wherein R1 is selected from methoxy, ethoxy;
a) reacting a compound of formula (XI) with dimethyl acetal in presence of solvent to obtain a compound of formula (X), optionally isolating the compound of formula (X);

b) reacting the compound of formula (X) with aminoacetaldehyde dimethyl acetal in presence of solvent to obtain a compound of formula (VIII), optionally isolating the compound of formula (VIII); and

c) reacting a compound of formula (VIII) with oxalate compound of formula (IX) in presence of base and solvent to obtain the compound of formula (VII).

wherein R1 is methoxy, ethoxy; R2 is methoxy, ethoxy, chloro and bromo.
10. A process for the preparation of compound of formula (III), comprising steps:

wherein m is 2 or 3;
a) reacting the compound of formula (VII) with compound of formula (V) in the presence of an acid and solvent to obtain the compound of formula (VI), optionally isolating the compound of formula (VI); and

wherein m is 2 or 3;
b) reacting the compound of formula (VI) with an acid in presence of solvent to obtain the compound of formula (III).