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

Authors: Pinheiro, Alessandra C.; Kaiser, Carlos R.; LourenÇo, Maria C.S.; de Souza, Marcus V.N.; Wardell, Solange M.S.V.; Wardell, James L. Goncalves, R.S.B.; De Souza, M.V.N.; Wardell, S.M.S.V.; Wardell, J.L.


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.
Keywords: diasteromers; mefloquine derivatives, oxazolidines; polymorphs Document Type: Research Article DOI: http://dx.doi.org/10.1515/zkri-2015-1858 Publication date: 1 de Janeiro de 2016 [:en]

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.


Keywords: diasteromers; mefloquine derivatives, oxazolidines; polymorphs Document Type: Research Article DOI: http://dx.doi.org/10.1515/zkri-2015-1858 Publication date: 1 de Janeiro de 2016 [:]

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