Further study of oxazolidines derived from mefloquine and arenealdehydes: diastereoisomers and polymorphs

Abstract

Abstract The reaction between racemic erythro [(R*,S*)-2,8-bis(trifluoromethyl)quinolin-4-yl]-(2-piperidyl)methanol] and 2-formyl-5-nitrothiene in toluene generates a reaction mixture containing two diastereoisomers of 4-[3-(5-nitrothien-2-yl)-hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline, 6, – namely (2S*,3R*,4S*5R*)-6 (6a) and (2R*,3S*,4S*,5R*)-6 (6b) in a ratio of 5:1 as indicated by 1H NMR spectroscopy (using the 1,3-oxazolidine ring numbering scheme for the chiral centres). Isolation of each product from the mefloquine/2-formyl-5-nitrothiene reaction mixture was achieved by fractional crystallisation of an ethanol solution, but not by column chromatography on silica, which led to the destruction of the minor product, 6b. A second polymorphic form, [monoclinic, P21/c] of (2S*,3R*,4S*,5R*)-4-[3-(2-hydroxyphenyl-hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinoline (monoclinic-7) has been isolated from MeOH solution: the previously reported orthorhombic form, space group Fdd2, had been isolated from an ethanolic solution.