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US 2013/0172551 A1Published application
Process for Preparing Carbamolypyridone Derivatives and Intermediates
AssigneeViiV Healthcare Company
InventorsSteven N. Goodman, Huan Wang, Douglas Matthew Mans
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Abstract
The present invention relates to the preparation of carbamoylpyridone derivatives and intermediates.
Claims19
A method comprising contacting methyl 3-{[2,2-bis(methyloxy)ethyl]amino}-2-[(methyloxy)acetyl]-2-propenoate (formula I):
- with an oxalate ester of formula II:
- in the presence of M+ −OR, where R is alkyl, aryl, or benzyl;
- and M+ is an alkali metal cation;
- to form a pyridinone of formula III:
1 more element
A method comprising selectively hydrolyzing a pyridinone of formula III:
- with a selective hydrolyzing reagent to form a pyridinone carboxylic acid of formula IV where R is alkyl, aryl, or benzyl:
- with greater than 90% selectivity.
A method comprising contacting a compound of formula VII:
- with a Lewis acid to form a compound of formula VIII:
A method comprising the steps of:
- a) contacting methyl-4-methoxyacetoacetate with N,N-dimethyl-1,1-bis(methyloxy)methanamine under suitable conditions to form methyl 3-(dimethylamino)-2-[(methyloxy)acetyl]-2-propenoate;
- b) contacting the methyl 3-(dimethylamino)-2-[(methyloxy)acetyl]-2-propenoate with 2,2-bis(methyloxy)ethanamine to form methyl 3-{[2,2-bis(methyloxy)ethyl]amino}-2-[(methyloxy)acetyl]-2-propenoate;
- c) contacting the methyl 3-{[2,2-bis(methyloxy)ethyl]amino}-2-[(methyloxy)acetyl]-2-propenoate with dimethylethanedioate in the presence of lithium methoxide to form dimethyl 1-[2,2-bis(methyloxy)ethyl]-3-(methyloxy)-4-oxo-1,4-dihydro-2,5-pyridinedicarboxylate;
- d) hydrolyzing the dimethyl 1-[2,2-bis(methyloxy)ethyl]-3-(methyloxy)-4-oxo-1,4-dihydro-2,5-pyridinedicarboxylate in the presence of lithium hydroxide to form 1-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-1,4-dihydro-3-pyridinecarboxylic acid;
- e) contacting the 1-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-1,4-dihydro-3-pyridinecarboxylic acid with (2S)-2-amino-1-propanol in the presence of acetic acid and a catalytic amount of methanesulfonic acid to form a compound of formula VI:
- f) contacting the compound of formula VI with 2,4-difluorobenzylamine under coupling conditions to form a compound of formula VII:
- and
- g) contacting the compound of formula VII with magnesium bromide to form a compound of formula VIII:
5 more elements
A compound selected from the group consisting of:
A process comprising contacting a compound of formula IV where R is alkyl, aryl, or benzyl:
- with acetic acid and a catalytic amount of a strong protic acid to form a pyridinone carboxylic acid aldehyde of formula V:
- wherein R is selected from the group consisting of alkyl, aryl, and benzyl.
Dependencies are inferred from the claim text.