Process for producing simvastatin and analogs thereof
AssigneeApotex Inc.
InventorsRudolf Kubela, Jayaramaiyer Radhakrishnan
Life of this patent
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Abstract
A process is disclosed for the preparation of simvastatin and its analogs through a novel intermediate (III), which enables a selective .alpha. carbon alkylation of the C-8 acyl side chain.
Claims17
A process for the preparation of a compound of formula (III):
- ##STR5## wherein:
- R.sub.1 is selected from the group consisting of methyl or hydrogen;
- R.sub.2 represents (1) an alkyl group having 3 to 7 carbon atoms, or (2) a 3- to -7 membered cycloalkyl group, or (3) an aralkyl group having 2 to 4 carbon atoms in the alkyl moiety and a phenyl in the aryl moiety which is optionally substituted;
- R.sub.3 is selected from the group phenyl which is optionally substituted by one to four substitutents:
- halogen or lower alkyl in any combination:
- -reacting a compound of formula (I) ##STR6## with an amine, R.sub.2 --NH.sub.2, -followed by hydroxyl protection with a boronic acid, R.sub.3 --B(OH).sub.2.
N-Cyclohexyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S), 6(R)-dimethyl-8(S)-[[2(S)-methylbutanoyl]oxy]-1(S)-naphthyl]-3(R), 5(R)-[phenylborylenedioxy]-heptanoic acid amide.
N-Cyclopentyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S), 6(R)-dimethyl-8(S)-[[2(S)-methylbutanoyl]oxy]-1(S)naphthyl]-3(R), 5(R)-[phenylborylenedioxy]-heptanoic acid amide.
N-(2-Phenyl)-1-ethyl-7-[1,2,6,7,8,8a(R)-hexahydro2(S), 6(R)-dimethyl-8(S)-[[2(S)-methylbutanoyl]oxy]-1(S)naphthyl]-3(R), 5(R)-[phenylborylenedioxy]-heptanoic acid amide.
N-(3-Phenyl)-1-propyl-7-[1,2,6,7,8,8a(R)-hexahydro2(S), 6(R)-dimethyl-8(S)-[[2(S)-methylbutanoyl]oxy]-1(S)naphthyl]-3(R), 5(R)-[phenylborylenedioxy]-heptanoic acid amide.
N-n-Butyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S), 6(R)-dimethyl-8(S)-[[2(S)-methylbutanoyl)oxy]-1(S)-naphtyl]-3(R), 5(R)-[phenylborylenedioxy]-heptanoic acid amide.
N-Benzyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S), 6(R)dimethyl-8(S)-[[2(S)-methylbutanoyl)oxy]-1(S)-naphthyl]-3(R), 5(R)-[phenylborylenedioxy]-heptanoic acid amide.
N-Cyclohexyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S), 6(R)-dimethyl-8(S)-[[2(S)-[4-methylbutanoyl]oxy]-1(S)napthyl]-3(R), 5(R)-[(4-fluorophenyl)borylenedioxy]-heptanoic acid amide.
N-cyclohexyl-7-[1,2,6,7,8,8a(R)-hexahydro2(S), 6(R)-dimethyl-8(S)-[[2,2-dimethylbutanoyl]oxy]-1(S)naphthyl]-3(R), 5(R)-[phenylborylenedioxy]-heptanoic acid amide.
Dependencies are inferred from the claim text.