Process for the preparation of halo-substituted phenylcyclopropanamines and their intermediates.

Abstract

The present invention provides a process for the prepn. of substituted phenylcyclopropylamines (I) [R1, R2, R3, R4 and R5 = independently H or halogen], their salts and intermediates, which are useful for the synthesis of ticagrelor. For example, reaction of 1,2-difluorobenzene with 3-chloropropanoyl chloride in the presence of AlCl3 followed by nitration provided 1-(3,4-difluorophenyl)-3-nitropropan-1-one, which was reduced by borane-dimethylsulfide complex in the presence of (S)-(-)-2-methyl-CBS-oxazaborolidine to afford (R)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol (II). Compd. II was cyclized using mesyl chloride and DBU to give 1,2-difluoro-4-[(1S,2R)-2-nitrocyclopropyl]benzene, which is reduced to afford (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (III), which may be further converted into ticagrelor. The method provides a new and short synthetic route for the industrial prepn. of nitrogen substituted cyclopropanes in good yields. [on SciFinder(R)]