The Synthesis of Phosphonobaclofen, an Antagonist of Baclofen

Phosphonobaclofen, 3-amino-2-(4-chlorophenyl) propylphosphonic acid, has been synthesized in five steps from ethyl 3-(4-chloropheny1)but-2-enoate, and is a specific antagonist of baclofen . Two alternative synthetic pathways, involving conjugate addition of phosphite to 2-(4-chlorophenyl) propenenitrile and of cyanide to 2-(4-chlorophenyl) ethenylphosphonate ester, failed. Cyanide ion did add efficiently to ethyl 3-(4-chloropheny1)-2-diethoxyphosphinylprop-2- enoate, and hydrogenation followed by hydrolysis of the product gave (2S,3S)- and (2R,3R)-4-amino-3-(4-chloropheny1)-2-phosphonobutanoic acid, which is also undergoing pharmacological evaluation.