Process for the preparation of dolutegravir

A process for the preparation of dolutegravir, comprising the steps of:

• a) reacting a compound of formula 8 with 1,1-dimethoxy-N,N-dimethyl methanamine to obtain a compound of formula 7;
• b) treating the compound of formula 7 with an alkenyl amine of the formula H2N—R3 in the presence of a solvent to obtain a compound of formula 6, wherein the solvent is selected from the group consisting of alcohol solvent, ester solvent, ether solvent, aromatic hydrocarbon solvent, and mixtures thereof;
• c) cyclizing the compound of formula 6 with dimethyl oxalate in the presence of a base and a solvent to obtain a compound of formula 5, wherein the base is selected from the group consisting of an alkali metal hydroxide, an alkali metal hydride, an alkali metal alkoxide, and mixtures thereof, and the solvent is an alcohol;
• d) converting the compound of formula 5 to a compound of formula 5a and then converting the compound of formula 5a to the compound of formula 4,
• wherein converting the compound of formula 5 to the compound of formula 5a comprises mixing boric acid with acetic anhydride which is then reacted with the compound of formula 5 to result in the compound of formula 5a, and
• wherein converting the compound of formula 5a to the compound of formula 4 is performed in the presence of a base or an acid and a solvent, wherein the base is an alkali metal hydroxide base;
• e) condensing the compound of formula 4 with 2,4-difluorobenzylamine in the presence of a base and a coupling agent in a solvent to obtain a compound of formula 3, wherein the base is selected from the group consisting of N-methylmorpholine (NMM), diisopropylethylamine, trimethylamine, N,N′-dimethylpiperazine, N-methylpiperidine, pyridine, and mixtures thereof;
• f) oxidizing the compound of formula 3 by reacting the compound of formula 3 with an oxidizing agent to obtain a compound of formula 2, wherein the oxidizing agent is selected from the group consisting of ozone, ozonized oxygen, periodic acid, osmium tetroxide-periodate, ruthenium trichloride-periodate, sodium metaperiodate, sodium orthoperiodate, ruthenium trichloride/potassium peroxymonosulfate, bis(acetonitrile)dichloropalladium (II), bis(benzonitrile)palladium (II) chloride, osmium tetroxide, sodium metaperiodate, ruthenium trichloride/potassium peroxymonosulfate, and mixtures thereof;
• g) reacting the compound of formula 2 with (R)-3-aminobutanol in the presence of an acid and a solvent to obtain a compound of formula 1, wherein the acid is selected from the group consisting of acetic acid, methane sulfonic acid, p-toluenesulfonic acid, and mixtures thereof;
• and
• h) converting the compound of formula 1 in the presence of a metal bromide to dolutegravir;
• wherein R1 and R2 are independently a C1-C6 alkyl, a C6-C10 aryl, or a C6-C10 aralkyl, and R4 the alkenyl amine of the formula H2N—R3 is allyamine, and X is O-Acyl.