合成路线1

Condensation of piperonyl chloride (I) with diethyl malonate (II) by means of Na in anhydrous refluxing EtOH (NaOEt) provides 2-[3,4-(methylenedioxy)benzyl]malonic acid diethyl ester (III), which is converted into the monoethyl ester (IV) by saponification with KOH in EtOH. Treatment of (IV) with diethylamine in paraformaldehyde/H2O affords acrylic ester (V), which is then subjected to saponification with NaOH in acetone/H2O to provide [3,4-(methylenedioxy)benzyl]-2-propenoic acid (VI). Alternatively, derivative (VI) can also be obtained by following this route: treatment of piperonal (VII) with diethyl malonate (II) in refluxing toluene in the presence of piperidine and acetic acid provides diethyl piperonylidene malonate (VIII), which is then hydrogenated over Pd/C to furnish diethyl piperonylmalonate (IX). Saponification of the ethyl ester moiety of (IX) by refluxing with NaOH in H2O affords piperonylmalonic acid (X), which is finally converted into intermediate (VI) by decarboxylation by treatment with diethylamine in refluxing paraformaldehyde. Reaction of (VI) with thioacetic acid at 70 C affords a racemic mixture of propionic acid derivatives (XI), which is resolved by first formation of a chiral salt (either by reaction with (R)-alpha-methylbenzylamine or by reaction with (+)-ephedrine in ether), recrystallization of the corresponding diastereomer and finally liberation of the 2-(S)-(acetylthiomethyl)-3-[3,4-(methylenedioxy)benzyl]propionic acid [(S)-(XII)] by hydrolysis with HCl in H2O/CH2Cl2. Finally, fasidotril is obtained by condensation of (S)-(XII) with benzyl alaninate (XIII) by means of HOBt and DCC in THF/CHCl3 in the presence of Et3N.