合成路线1

A synthesis of S-12968 has been published: The cyclization of 4-[2-(2-phthalimidoethoxy)ethoxy]-3-oxobutyric acid ethyl ester (I) with 2-(2,3-dichlorobenzylidene)-3-oxobutyric acid 2-cyanoethyl ester (II) and ammonium formate in hot ethanol gives the protected racemic 1,4-dihydropyridine (III), which is submitted to a chiral preparative HPLC to obtain the (R)-(-)-enantiomer (IV). The deprotection of (IV) with aqueous methylamine affords (S)-(-)-2-[2-(2-aminoethoxy)ethoxymethyl]-4-(2,3-dichlorophenyl)-1,4-di hydropyridine-3,5-dicarboxylic acid 3-monoethyl ester (V). Finally, this compound is methylated with diazomethane in ethyl ether/methanol. The starting compound, the dichlorobenzylidene derivative (II) has been obtained as follows: The condensation of Meldrum's acid (X) with acetic acid (XII) by means of CDI and pyridine as before gives 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (XIII), which is submitted to ring opening with 3-hydroxypropionitrile (XIV) in refluxing toluene yielding 2-cyanoethyl acetoacetate (XV). Finally, the condensation of (XV) with 2,3-dichlorobenzaldehyde (XVI) by means of piperidine and hexanoic acid in refluxing benzene affords the dichlorobenzylidene derivative (II) used as the second starting compound.