Practical synthesis of potent sphingosine-1-phosphate lyase inhibitors THI and LX2931

A practical and scalable synthesis of in vivo sphingosine-1-phosphate lyase inhibitor LX2931 (1) is described. The synthetic route features an improved Buchi cyclocondensation of 2-ethoxyacrylonitrile (3) with either 1-amino-1-deoxy-D-fructose acetate (4a) or D-(+)-glucosamine hydrochloride (4b) to produce 1-(4((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone (2, THI), followed by oximation of THI and acid-promoted oxime isomerization to give LX2931 (1). (C) 2013 Elsevier Ltd. All rights reserved.