DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
PROCESS FOR PREPARATION OF DOLUTEGRAVIR OR A SALT THEREOF
INTRODUCTION
Aspects of the present application provide a process for preparation of dolutegravir of formula I or a salt thereof.
The drug compound having the adopted name Dolutegravir has chemical name 2H-Pyrido[1',2':4,5] pyrazino[2,1-b] [1,3]oxazine-9-carboxamide,N-[(2,4-difluoro phenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-(4R,12aS)”, and is represented by structure of formula I.

I
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 in adults and children aged 12 years and older. U.S. Patent No. 8,129,385 discloses dolutegravir and its pharmaceutically acceptable salts.
Process for the preparation of pyridone compound of formula II have been disclosed in U.S. Patent No. 8,129,385 and 8,669,362. The reported processes suffer from major disadvantages, including lengthy synthetic sequences, use of numerous reagents and formation of undesired compounds in large amount. Hence, there remains a need to provide an alternative processes for the preparation of pyridone compound of formula II, which is simple, economic and industrially viable.

SUMMARY
In the first embodiment, the present application provides a process for preparation of dolutegravir of formula I or a salt thereof;

I
which comprises:
(a) converting a compound of formula VIII to a compound of formula X

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl; R4 and R5 are independently C1-C8 straight or branched chain alkyl group
(b) converting a compound of formula X to a compound of formula II,

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl;
(c) converting a compound of formula II to dolutegravir of formula I or a salt
thereof.
In the second embodiment, the present application provides a process for preparation of dolutegravir or a salt thereof, which comprises:
(a) reacting a compound of formula III or a compound of formula IV

wherein P1 is an alcohol-protecting group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl; R2 and R3 are independently C1-C8 straight or branched chain alkyl group or R2 and R3 together may form a 4 to 8 member ring;
with 2,4-Difluoro benzyl amine to provide a compound of formula VI or a compound of formula VII;

(b) converting a compound of formula VI or a compound of formula VII to a compound of formula VIII

wherein P1 is an alcohol protected group; R4 and R5 are independently C1-C8 straight or branched chain alkyl group
(c) converting a compound of formula VIII to a compound of formula X;

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group;
(d) converting a compound of formula X to a compound of formula II

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl;
(e) converting a compound of formula II to dolutegravir of formula I or a salt thereof.
In the third embodiment, the present application provides a compound of formula X;

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl;

DETAILED DESCRIPTION
In the first embodiment, the present application provides a process for preparation of dolutegravir of formula I or a salt thereof;

I
which comprises:
(a) converting a compound of formula VIII to a compound of formula X

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl; R4 and R5 are independently C1-C8 straight or branched chain alkyl group
(b) converting a compound of formula X to a compound of formula II,

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl;
(c) converting a compound of formula II to dolutegravir of formula I or a salt
thereof.
Step (a) involves converting a compound of formula VIII to a compound of formula X

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl; R4 and R5 are independently C1-C8 straight or branched chain alkyl group
Conversion of compound of formula VIII to a compound of formula X may be carried out by reacting compound of formula VIII with alkyl oxalyl halide of formula IX

wherein R6 is C1-C8 straight or branched chain alkyl group; X is a halogen;
Suitable bases that may be used in step (a) include, lithium diisopropylamide (LDA), lithium diethylamide, lithium bis(trimethylsilyl)amide (LiHMDS), lithium tetramethylpiperidide (LiTMP), n-Butyllithium (n-BuLi) and the like.
Suitable solvents that may be used in step (a) include ethers, aliphatic and alicyclic hydrocarbons, aromatic hydrocarbons and any mixtures of two or more thereof.
The reaction mixture obtained from step (a) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (a) may be isolated directly from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. The mixture containing the product of stap (a) may be either directly used in step (b) without isolation or the product of step (a) may be isolated and further purified to obtain a pure product to be used in step (b). The isolation in step (a) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation. Optionally the isolated compound in step (a) may be further dried by techniques known in the art.
Step (b) involves converting a compound of formula X to a compound of formula II,

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group;
Conversion of a compound of formula X to a compound of formula II may be carried out by treating a compound of formula X with NH2–CH2-CH-(OR7)2 or NH2–CH2-CH-OP1 to provide a compound of formula XI or XII respectively.

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group; R7 is independently C1-C8 straight or branched chain alkyl group.
Optionally compounds of formulae XI and XII may be subjected to re-functionalization to provide a compound of formula II.
Re-functionalization of compound of formula XI to formula II may be carried out by following the methods known in the art for example by following the process reported in in U.S. Patent No. 8,669,362.
Suitable solvents that may be used in step (b) include alcohols, ethers, aliphatic and alicyclic hydrocarbons, aromatic hydrocarbons and any mixtures of two or more thereof.
The reaction mixture obtained from the conversion of a compound of formula X to a compound of formula XI or XII in step (b) may be optionally processed to remove any insoluble solids by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The reaction product may be isolated directly from the reaction mixture itself after the reaction is complete or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained product may be directly used for re-functionalization or it may be isolated and further purified to improve the purity of the product to be used for re-functionalization.
Optionally, the product obtained after re-functionalization may be directly used in step (c) or it may be isolated and further purified to improve the purity of the product to be used in step (c).
Step (c) involves converting a compound of formula II to dolutegravir of formula I or a salt thereof.
Step (c) may be carried out by following the methods known in the art for example by following the process reported in U.S. Patent No. 8,129,385.
In the second embodiment, the present application provides a process for preparation of dolutegravir or a salt thereof, which comprises:
(a) reacting a compound of formula III or a compound of formula IV

wherein P1 is an alcohol-protecting group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl; R2 and R3 are independently C1-C8 straight or branched chain alkyl group or R2 and R3 are alkyl and joined to form 4 to 8 member ring;
with 2,4-Difluoro benzyl amine to provide a compound of formula VI or a compound of formula VII;

(b) converting a compound of formula VI or a compound of formula VII to a compound of formula VIII

wherein P1 is an alcohol protected group; R4 and R5 are independently C1-C8 straight or branched chain alkyl group
(c) converting a compound of formula VIII to a compound of formula X;

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl;
(d) converting a compound of formula X to a compound of formula II

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl;
(e) converting a compound of formula II to dolutegravir of formula I or a salt thereof.
Step (a) involves reacting a compound of formula III or a compound of formula IV,

wherein P1 is an alcohol-protecting group; R1 is H or C1-C8 straight or branched chain alkyl group; R2 and R3 are independently C1-C8 straight or branched chain alkyl group or R2 and R3 are alkyl and joined to form 4 to 8 member ring;
with 2,4-Difluoro benzyl amine to provide a compound of formula VI or a compound of formula VII;

Compound of formula IV in step (a) may be prepared by protecting the compound of formula III with a carbonyl- protecting group as follows.

Suitable reagents that may be used for protecting compound of formula III include, triethyl orthoformate, trimethyl orthoformate, ethylene glycol, propylene glycol or any suitable carbonyl protecting group known in the art.
Suitable acids that may be used for protecting compound of formula III include, formic acid, propionic acid, butyric acid, isobutyric acid, fumaric acid, oxalic acid, tartaric acid, citric acid, camphor sulfonic acid and the like;
Suitable solvents that may be used for protecting compound of formula III include alcohols, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles; and any mixtures of two or more thereof.
Suitable coupling agents that may be used in step (a) include, propylphosphonic anhydride (T3P), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), N-hydroxybenzotriazole (HOBT), 4,5-dicyanoimidazole, dicyclohexylcarbodiimide (DCC), dicyclopentylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC. HCl), 1,1’-carbonyldiimidazole, cyclohexylisopropylcarbodiimide (CIC), bis[[4-(2,2-dimethyl-1,3-dioxolyl)]methyl] carbodiimide, N,N’-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-Cl), an acid chloride, ethyl chloroformate, and the like or the any two or more reagents combination thereof or any other suitable reagents known in the art.
Suitable bases that may be used in step (a) include, organic bases, such as for example, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, and the like.
Step (a) may be optionally carried out in the presence of a suitable catalyst, such as, for example, triethylamine, pyridine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1-methylmorpholine, 1-methylpiperidine, 1,5-diazabicyclo[4.3.0]non-5-ene, N,N-dimethylpiparazine, N,N-dimethylaniline, 4-(dimethylamino)-pyridine (DMAP), hexamethylenetetramine (HMTA), tetramethylethylenediamine (TMEDA), collidine, 2,3,5,6-tetramethylpyridine (TEMP), and the like.
Suitable solvents that may be used in step (a) include alcohols, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents and any mixtures of two or more thereof.
The reaction mixture obtained from step (a) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (a) may be isolated directly from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (b) or it may be isolated and further purified to improve the purity of the product.
Optionally compound of formula VI in the step (a) may be prepared by deprotecting the carbonyl protecting group of formula VII
Suitable acids that may be used for deprotecting the carbonyl protecting group of formula VII include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
Suitable solvents that may be used for deprotecting the carbonyl protecting group of formula VII include ethers, ketones, alcohols, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents; and any mixtures of two or more thereof.
Step (b) involves converting a compound of formula VI or a compound of formula VII to a compound of formula VIII

wherein P1 is an alcohol protected group; R4 and R5 are independently C1-C8 straight or branched chain alkyl group
Suitable reagents that may be used in step (b) include N,N-Dimethyl formamide dimethyl acetal, include N,N-Dimethyl formamide diethyl acetal and the like or any other suitable reagent known in the art.
Suitable solvents that may be used in step (b) include ethers, aliphatic and alicyclic hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents; and any mixtures of two or more thereof.
The reaction mixture obtained from step (b) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (b) may be isolated directly from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (c) or it may be isolated and further purified to improve the purity of the product.
Step (c) involves converting a compound of formula VIII to a compound of formula X;

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group;
Conversion of compound of formula VIII to a compound of formula X may be carried out by following the methods described in step (a) of first embodiment as defined above.
Step (d) involves converting a compound of formula X to a compound of formula II

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group;
Conversion of compound of formula X to a compound of formula II may be
carried out by following the methods described in step (b) of first embodiment as defined above.
Step (e) involves converting a compound of formula II to dolutegravir of formula
I or a salt thereof.
Step (e) may be carried out by following the methods known in the art for example by following the process reported in U.S. Patent No. 8,129,385.
Optionally the compound obtained in steps (a) to (e) may be further purified by using purification techniques known in the art, for example using column chromatography or various types of isolation methods including recrystallization, slurry in solvent, crystallization by adding an anti-solvent to a solution and the like or any other suitable purification techniques known in the art.
Suitable solvents that may be used for the purification of the compound obtained in steps (a) to (e) include water, alcohols, ketones, esters, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane; and any mixtures of two or more thereof.
Optionally steps (a) to (e) or any two or more steps may be carried out as in-situ i.e. without isolating the intermediates in each stage.
In the third embodiment, the present application provides a compound of formula X;

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl;

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions or the like.
As used herein, "an alcohol protecting group" is a functional group that protects the alcohol group from participating in reactions that are occurring in other parts of the molecule. Suitable alcohol protecting groups that are used in step (a) include, acetyl, benzoyl, benzyl, ß-methoxyethoxymethyl ether, methoxymethyl ether, dimethoxytrityl, p-methoxybenzyl ether, methylthiomethyl ether, allyl ether, t-butyl ether, pivaloyl, trityl, silyl ether (e.g., trimethylsilyl (TMS), t-butyldimethylsilyl (TBMDS), t-. butyldiphenylsilyl (TBDPS), t-butyldimethylsilyloxymethyl (TOM) or triisopropylsilyl (TIPS) ether), tetrahydropyranyl (THP), methyl ether and ethoxyethyl ether (EE) or any suitable alcohol protecting group known in the art.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol and the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.” Examples of “C5-C8 aliphatic or aromatic hydrocarbons” include n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, and the like.
An “aromatic hydrocarbon solvent” refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has delocalized conjugated p system. Examples of an aromatic hydrocarbon solvent include benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C12 aromatic hydrocarbons and the like.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 esters” include ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate and the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole and the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride and the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones and the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6 Nitriles” include acetonitrile, propionitrile, butanenitrile and the like.
A “polar aprotic solvents” include N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone and the like;
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this application.

EXAMPLES
EXAMPLE 1: Preparation of ethyl 4-(benzyloxy)-3,3-dimethoxybutanoate. Ethyl 4-(benzyloxy)-3-oxobutanoate (1.0 g), methanol (10 mL), trimethyl orthoformate (1.0 mL) and camphor sulfonic acid (0.29 g) were charged into a round bottom flask at 27°C and the resultant reaction mixture was stirred at 27°C for 17 hours. Reaction mass solvent was evaporated at below 45 °C under reduced pressure. The obtained residue was dissolved in ethyl acetate (30 mL), washed with water (20 mL), brine solution (20 mL) and dried with sodium sulfate. Organic layer solvent was evaporated completely at below 45°C under reduced pressure to afford title compound.
Yield: 1.0 g
EXAMPLE 2: Preparation of 4-(benzyloxy)-3,3-dimethoxy butanoic acid. Ethyl 4-(benzyloxy)-3,3-dimethoxybutanoate (0.7 g), tetrahydrofuran (3.5 mL) and 1N sodium hydroxide (10.22 mL) were charged into a round bottom flask at 27°C and the resultant reaction mixture was stirred at 27°C for 19 hours. Reaction mixture was diluted with water (10 mL) and washed with diethyl ether (25 mL). Aqueous layer was concentrated under reduced pressure at 50 °C and co distilled with Toluene (3 x 10 mL). The obtained crude compound was diluted with water (5 mL) and acidified with citric acid solution up to PH 4.5. Aqueous layer was extracted with ethyl acetate (3 x 50 mL) and combined organic extracts were dried over anhydrous sodium sulphate. Organic layer solvent was evaporated completely at below 45°C under reduced pressure to afford title compound.
Yield: 400 mg
EXAMPLE 3: Preparation of 4-(benzyloxy)-N-(2,4-difluorobenzyl) -3,3-dimethoxybutanamide. 4-(benzyloxy)-3,3-dimethoxybutanoic acid (100 mg), dimethyl formamide (3 mL), EDC.HCl (82 mg), HOBT (79 mg), Triethyl amine (0.085 mL) and 2, 4-Difluoro benzyl amine (0.051 mL) were charged into round bottom flask at 0 °C. The resultant reaction mixture temperature was raised to 27 °C and stirred at 27 °C for 16 hours 30 minutes. Reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). Combined organic layer was washed with water (3 x10 mL), brine solution (10 mL) and dried with anhydrous sodium sulphate. Organic layer solvent was evaporated completely at below 45°C under reduced pressure and the obtained crude was purified by column chromatography to afford title compound.
Yield: 60 mg.
EXAMPLE 4: Preparation of 4-(benzyloxy)-N-(2,4-difluorobenzyl) -3-oxobutanamide. 4-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3-dimethoxy butanamide (250 mg), acetone (5.0 mL) and Conc. HCl (10 mL) were charged in to round bottom flask at 27°C. The resulting reaction mixture was heated to 50 °C and the reaction mass was stirred at 50 °C for 5 hours. Reaction mixture was concentrated under reduced pressure at below 45 °C and the obtained residue was dissolved in Ethyl acetate (50 mL). Reaction mass was washed with water (10 mL), sodium bicarbonate solution (20 mL), brine solution (20 mL) and dried with anhydrous sodium sulphate. Organic layer solvent was evaporated completely at below 45°C under reduced pressure to afford title compound.
Yield: 130 mg
EXAMPLE 5: Preparation of (E)-4-(benzyloxy)-N-(2,4-difluoro benzyl)-2-((dimethylamino)methylene)-3-oxobutanamide. 4-(benzyloxy)-N-(2,4-difluoro benzyl)-3-oxobutanamide (300 mg), toluene (1.5 mL) and N,N-Dimethyl formamide dimethyl acetal (0.179 mL) were charged into round bottom flask at 27 °C and the resultant reaction mixture was stirred at 27 °C for 16 hours. Reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). Combined organic layer was washed with water (10 mL), sodium bicarbonate solution (10 mL), brine solution (10 mL) and dried with anhydrous sodium sulphate. Organic layer solvent was evaporated completely at below 45°C under reduced pressure and the obtained crude was purified by preparative TLC method to afford title compound.
Yield: 150 mg
EXAMPLE 6: Preparation of ethyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydro pyridine-2-carboxylate. Solution of (E)-4-(benzyloxy)-N-(2,4-difluorobenzyl)-2-((dimethylamino)methylene)-3-oxobutanamide (500 mg) in tetrahydrofuran (2.0 mL) was added drop wise to the reaction mixture containing LiHMDS 20% in tetrahydrofuran (3.0 mL) and tetrahydrofuran (4.0 mL) at -78 °C. Solution of ethyl oxalyl chloride (0.175 mL) & tetrahydrofuran (1.0mL) was added to the reaction mixture at -78 °C and the resultant reaction mixture was stirred at -78 °C for 2 hours. Reaction mixture was quenched with 1N HCl and extracted with ethyl acetate (3 x 20 mL). Combined organic layer was washed with water (10 mL), sodium bicarbonate (20 mL), brine solution (20 mL) and dried with anhydrous sodium sulphate. Organic layer was concentrated at 45 °C under reduced pressure. The resultant crude compound, ethanol (1.9 mL) and amino acetaldehyde dimethyl acetal (0.165 mL) were charged into round bottom flask at 27 °C. Reaction mixture was heated to 80 °C and stirred at 80 °C for 5 hours. Reaction mixture was concentrated under reduced pressure at below 45 °C and the obtained crude compound was purified by using Preparative HPLC to afford title compound.
,CLAIMS:WE CLAIM:

1. A process for preparation of dolutegravir of formula I or a salt thereof;

I
which comprises:
(a) converting a compound of formula VIII to a compound of formula X

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain
alkyl group or alkyl aryl; R4 and R5 are independently C1-C8 straight or branched chain
alkyl group
(b) converting a compound of formula X to a compound of formula II,

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl;
(c) converting a compound of formula II to dolutegravir of formula I or a salt
thereof.

2. A process for preparation of dolutegravir of formula I or a salt thereof, which comprises:

I

(a) reacting a compound of formula III or a compound of formula IV

wherein P1 is an alcohol-protecting group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl; R2 and R3 are independently C1-C8 straight or branched chain alkyl group or R2 and R3 together may form a 4 to 8 member ring;
with 2, 4-Difluoro benzyl amine to provide a compound of formula VI or a compound of
formula VII;

(b) converting a compound of formula VI or a compound of formula VII to a compound of formula VIII

wherein P1 is an alcohol protected group; R4 and R5 are independently C1-C8 straight or branched chain alkyl group
(c) converting a compound of formula VIII to a compound of formula X;

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group;
(d) converting a compound of formula X to a compound of formula II

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl;
(e) converting a compound of formula II to dolutegravir of formula I or a salt thereof.

3. A compound of formula X;

wherein P1 is an alcohol protected group; R1 is H or C1-C8 straight or branched chain alkyl group or alkyl aryl;