Process for the preparation of intermediate of dolutegravir

• US 10,442,769 B2
• Filed: 01/29/2018
• Issued: 10/15/2019
• Est. Priority Date: 07/04/2013
• Status: Active Grant

• Current Assignee: Hetero Research Foundation
• Original Assignee: Hetero Research Foundation
• Inventors: Reddy, Bandi Parthasaradhi, Reddy, Kura Rathnakar, Reddy, Dsari Muralidhara, Narsingam, Mogili, Krishna, Bandi Vamsi
• Primary Examiner(s): Davis, Zinna Northington
• Application Number:
  US15/882,317
• Publication Number:
  US 20180148412A1
• Time in Patent Office: 624 Days
• Field of Search: None
• CPC Class Codes: C07C 231/02 from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
• CPC Class Codes: C07D 213/14 Preparation from compounds containing heterocyclic oxygen
• CPC Class Codes: C07D 213/69 Two or more oxygen atoms
• CPC Class Codes: C07D 213/79 Acids; Esters
• CPC Class Codes: C07D 213/80 in position 3
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 309/40 Oxygen atoms attached in positions 3 and 4, e.g. maltol
• CPC Class Codes: C07D 498/12 in which the condensed system contains three hetero rings

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.

Claims

1. A process for the preparation of Dolutegravir of formula I the process comprising:

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) brominating 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-difluorobenzyl carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid of formula XIII;

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 1-allyl-3-benzyloxy-5-(2,4-difluoro-benzyl carbamoyl)-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methyl ester;

k) oxidizing 1-allyl-3-benzyloxy-5-(2,4-difluoro-benzylcarbamoyl)-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methyl ester with osmium tetraoxide and sodium metaperiodate to give methyl 3-(benzyloxy)-5-(2,4-difluorobenzyl carbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate;

l) reacting methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate with aminobutan-1-ol and acetic acid to yield (4R,12aS)-7-(benzoyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide; and

m) hydrogenating (4R,12aS)-7-(benzoyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide to yield Dolutegravir.

2. A process for preparing of Dolutegravir of Formula I according to claim 1, the process comprising:

providing Methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate;

reacting Methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate with Aminobutane-1-ol and acetic acid to yield (4R,12aS)-7-(benzoyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide; and

hydrogenating (4R,12aS)-7-(benzoyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide to yield Dolutegravir.

3. A process for the preparation of Dolutegravir of formula I the process comprising:

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) brominating 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-(benzyloxy)-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 1-allyl-3-benzyloxy-5-(2,4-difluoro-benzylcarbamoyl)-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methyl ester;

k) oxidizing 1-allyl-3-benzyloxy-5-(2,4-difluoro-benzylcarbamoyl)-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methyl ester with osmium tetraoxide and sodium metaperiodate to give methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyiridine-2-carboxylate;

l) reacting methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate with aminobutan-1-ol and acetic acid to yield (4R,12aS)-7-(benzoyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide; and

m) hydrogenating (4R,12aS)-7-(benzoyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide to yield Dolutegravir.

4. A process for preparing of Dolutegravir of Formula I according to claim 3, the process comprising:

providing Methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate;

reacting Methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate with Aminobutane-1-ol and acetic acid to yield (4R,12aS)-7-(benzoyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide; and

hydrogenating (4R,12aS)-7-(benzoyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide to yield Dolutegravir.