Process for the preparation of cyclopropyl carboxylic acid esters and derivatives
AssigneeAstraZeneca AB
InventorsAdrian Clark, Elfyn Jones, Ulf Larsson, Anna Minidis
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Abstract
The invention relates to a novel process for the preparation of certain cyclopropyl carboxylic acid esters and other cyclopropyl carboxylic acid derivatives; a novel process for the preparation of dimethylsulfoxonium methylide and dimethylsulfonium methylide; to the use of certain cyclopropyl carboxylic acid esters in a process for the preparation of intermediates that can be used in the synthesis of pharmaceutically active entities; and to certain intermediates provided by these processes.
Claims22
A process for the preparation of a compound of formula (I):
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- wherein:
- R is phenyl substituted with one or more halogen;
- Y is OR1, where R1 is a straight chain alkyl, branched alkyl, cycloalkyl, or a substituted bicycloheptyl group;
- which comprises contacting a compound of formula (II):
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- where R and Y are as defined above, with dimethylsulfoxonium methylide in the presence of a solvent at a temperature of −10° C.-90° C.
A process according to any one of the preceding claims in which YH represents L-menthol.
A process according to any one of the preceding claims in which R is phenyl substituted by one or more fluorine atoms.
A process according to any one of the preceding claims in which Y is chiral
The intermediate compounds of formulae (I), (Ia), (II), (III), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX) and (IXa) above.
The intermediate compounds;
- (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl trans-2-(3,4-difluorophenyl)cyclopropanecarboxylate;
- (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl trans-(1R, 2R)-2-(3,4-difluorophenyl)cyclopropane carboxylate;
- (1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-difluorophenyl)-2-propenoate;
- (E)-3-(3,4-difluorophenyl)-2-propenoic acid;
- (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride;
- trans-(1R, 2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid;
- trans-(1R, 2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride;
- trans-(1R, 2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide;
- trans-(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl amine;
- and trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2-phenylethanoate
Dependencies are inferred from the claim text.