Process for the preparation of intermediate of dolutegravir

Patent metadata

Field	Value
Publication number	US-9963430-B2
Application number	US-201514968088-A
Country	US
Kind code	B2
Filing date	Dec 14, 2015
Priority date	Jul 4, 2013
Publication date	May 8, 2018
Grant date	May 8, 2018

Abstract

The present invention provides a novel processes for preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate using novel intermediates.

First claim

We claim:

1. A process for the preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine -2carboxylate, which comprises:
a) treating the 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde with trimethyl orthoformate in the presence of camphorsulfonic acid and a suitable solvent to give 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one of formula III;
b) reacting the 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one obtained in step (a) with methanolic ammonia in the presence of an alcoholic solvent to give 3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one of formula IV;
c) bromionating the 3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one obtained in step (b) with N-bromosuccinimide in the presence of a chlorinated solvent to give 3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one of formula V;
d) treating the 3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one obtained in step (c) with n-butyllithium in the presence of dimethylformamide and an ether solvent to give 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde of formula VI;
e) reacting the 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde obtained in step (d) with sulfamic acid and sodium chlorite in a suitable solvent to give 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid of formula VII;
f) condensing the 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid obtained in step (e) with 2,4-difluorobenzylamine in the presence of 1-(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride, hydroxybenzotriazole and tertiary amine in a suitable solvent to give 5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo- 1,4-dihydropyridine-3-carboxamide of formula VIII;
g) condensing the 5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide obtained in step (f) with allyl bromide in the presence of a base and dimethylformamide to give 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo- 1,4-dihydropyridine-3 -carboxamide of formula XI;
h) treating the 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide obtained in step (g) with formic acid in a ketonic solvent to give 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide of formula XII;
i) reacting the 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide obtained in step (h) with sulfamic acid and sodium chlorite in a suitable solvent to give 1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid of formula XIII; and
j) methylating the 1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid with methyl iodide in the presence of a base and dimethylformamide to give methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate.

2. A process for the preparation of methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4- dihydropyridine-2-carboxylate which comprises:
a) treating the 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde with trimethyl orthoformate in the presence of camphorsulfonic acid and a suitable solvent to give 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one of formula III;
b) reacting the 3-(benzyloxy)-2-(dimethoxymethyl)-4H-pyran-4-one obtained in step (a) with methanolic ammonia in the presence of an alcoholic solvent to give 3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one of formula IV;
c) bromionating the 3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one obtained in step (b) with N-bromosuccinimide in the presence of a chlorinated solvent to give 3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one of formula V;
d) treating the 3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one obtained in step (c) with n-butyllithium in the presence of dimethylformamide and an ether solvent to give 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde Formula VI;
e) condensing the 5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde obtained in step (d) with allyl bromide in the presence of a base and dimethylformamide to give 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde of formula IX;
f) reacting the 1 - allyl-5-(benz yloxy)-6-(dimethoxymethyl)-4-oxo- 1,4-dihydropyridine-3-carbaldehyde obtained in step (e) with sulfamic acid and sodium chlorite in a suitable solvent to give 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid of formula X;
g) condensing the 1-allyl-5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid obtained in step (f) with 2,4-difluorobenzylamine in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, hydroxybenzotriazole and tertiary amine in a suitable solvent to give 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo- 1,4-dihydropyridine-3-carboxamide of formula XI;
h) treating the 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide obtained in step (g) with formic acid in a ketonic solvent to give 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide of formula XII;
i) reacting the 1-allyl-5-(benzyloxy)-N-(2,4-difluorobenzyl)-6-formyl-4-oxo-1,4-dihydropyridine-3-carboxamide obtained in step (h) with sulfamic acid and sodium chlorite in a suitable solvent to give 1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid of formula XIII; and
j) methylating the 1-allyl-3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid with methyl iodide in the presence of a base and dimethylformamide to give methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate.

Assignees

• Hetero Research Foundation

Inventors

• Reddy Bandi Parthasaradhi
• Reddy Kura Rathnakar
• Reddy Dasari Muralidhara
• Narsingam Mogili
• Krishna Bandi Vamsi

Classifications

• C07D213/14

  Preparation from compounds containing heterocyclic oxygen · CPC title

• C07D213/79

  Acids; Esters · CPC title

• C07D213/81

  Amides; Imides · CPC title

• C07D213/82 Primary

  in position 3 · CPC title

• C07D498/12

  in which the condensed system contains three hetero rings · CPC title