Synthetic study of chiral drug intermediates and chiral separation of carboxylic acids

Abstract

Chirality is a major concern in the modern pharmaceutical industry. Because of chirality, living organisms show different biological responses to enantiomeric drugs. The search for the required single enantiomer has led to the concept of chiral pool of readily available and relatively inexpensive chiral compounds. The focus of the present work is the synthesis of some of the chiral drugs/intermediates using techniques like asymmetric induction by Grignard reaction and chemical manipulation of chiral molecules. The thesis comprises of seven chapters. The first chapter deals with the introduction and scope of the work, second chapter describes the experimental procedures for the synthesis of compounds. Chapters three to chapter six delineates results and discussion. The summary and conclusion derived from the present investigation are presented in the seventh chapter. The stereochemical approach and the mechanism involved in the formation of specific diastereomer are envisaged by the application of the Cram s rule and graphic representation of flying-wedge formulae followed by chemical correlation. In the preparation of 1-phenyl-1-alkyl/arylamino-2-(1-piperidinyl)propane hydrochloride, the synthetic route involved the formation of an aziridinium intermediate with three inversions starting from (1S,2R)-(+)-1-phenyl-2-(1-piperidinyl)-1- propanol. These three inversions led to overall inversion of configuration at carbon-1 in the chiral 1,2-diamines. The formation of aziridinium intermediate was inhibited in the diamines prepared from 1-phenyl-2- tosylamino-1-propanol and the reaction proceeded with two inversions only, thus leading to overall retention of configuration at C-1. Grignard reaction of (R)-(-)-phenylacetylcarbinol has gave rise to 1-phenyl-2-alkyl/aryl-1,2-dihydroxypropanes with very high enantiomeric purity. The absolute configuration at the reaction centre was derived with the help of Cram s rule, molecular modeling and chemical analogy. newline