Structural basis of solid solution formation during chiral resolution

A systematic study of crystal packing in a series of structures is presented: an isostructural triplet of an optically active compound {(R)-2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-[2-hydroxy-3-(4-morpholinyl)propyl]mercaptoacetonitrile hydrochloride, C(22)H(32)ClN(3)O(4)S} 1, its racemate 2 and their achiral dehydroxy parent compound {2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-[3-(4-morpholinyl)propyl]mercaptoacetonitrile hydrochloride, C(22)H(32)ClN(3)O(3)S} 3. Based on the structures we suggest some requirements necessary for an optically active compound and its racemate to be isostructural. A generally used resolving agent D-champhor sulphonic acid was unable to provide full separation of the racemate. The crystal structure of a partially resolved product (C(32)H(47)N(3)O(8)S(2)) 4 sheds light on the possible reasons of this failure. We suggest a few criteria for solid solution formation of diastereomeric salts. (C) 2000 Elsevier Science Ltd. All rights reserved.