合成路线1

Reaction of benzaldehyde (I) with dimethyl malonate (II) in refluxing toluene in the presence of piperidine and HOAc provides dimethyl benzylidene malonate (III), which is then hydrogenated over Pd/C to afford dimethyl benzyl malonate (IV). Reduction of (IV) with LiAlH4 in refluxing THF furnishes 2-benzyl-1,3-propanediol (V), which is then subjected to reaction with vinyl acetate (VI) by means of Novozym 435 enzyme to yield diacetate (VII). Enantioselective removal of one acetyl group from (VII) by treatment with Pseudomonas fluorescens Lipase in acetone/phosphate buffer (pH = 7) at 30 C gives 3-acetoxy-2(S)-benzyl-propanol (S)-(VIII), which is then oxidized by means of Jones reagent in acetone/isopropanol to provide carboxylic acid (R)-(IX). The hydrolysis of (IX) with LiOH in THF/H2O gives 2(R)-benzyl-3-hydroxypropanoic acid (R)-(X). Alternatively, intermediate (X) can also be synthesized as follows: Condensation of benzaldehyde (I) with methyl acrylate (XV) by means of diaza-1,4-bicyclo[2.2.2.]octane affords methyl beta-hydroxy-alpha-methylene-benzenepropanoate (XVI), which is then subjected to hydrolysis with KOH in MeOH/H2O to yield carboxylic acid (XVII). Treatment of (XVII) with p-toluenesulfonic acid in refluxing HOAc gives (E)-2-(acetoxymethyl)-3-phenylpropionic acid (XVIII), which is finally converted into (X) by enantioselective hydrogenation in the presence of S-Binap and ruthenium catalyst [CodRu(all)2]. Derivative (R)-(X) is then converted into 3-(acetylsulfanyl)-2(S)-benzylpropionic acid (XI) by means of a Mitsunobu reaction with thioacetic acid, diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPh3). Compound (XI) is then subjected to optical purification by formation and isolation of the corresponding salt with (-)-ephedrine and subsequent hydrolysis with HCl to furnish enantiomerically pure (S)-(XII). Finally, carboxylic acid (S)-(XII) is converted into ecadotril by its coupling with benzyl glycinate (XIV), either by means of Et3N, DCC and HOBt in CHCl3, or by first reaction with thionyl chloride to give acid chloride (S)-(XIII) and subsequent coupling with glycinate (XIV) by means of Et3N in CH2Cl2.