The reaction of 2(S)-benzylsuccinic acid 1-benzyl monoester (XXIII) with cis-perhydroisoindole (V) by means of isobutyl chloroformate and NMM in THF gives the succinamic ester (XXIV), which is hydrogenated with H2 over Pd/C in ethanol, yielding the already described succinamic acid (XIII). Finally, this compound is converted into its calcium salt.
The condensation of dimethyl succinate (I) with benzaldehyde (II) by means of NaOMe in refluxing methanol followed by hydrolysis with NaOH in methanol/water gives 2-benzylidenesuccinic acid (III). Compound (III) is treated with refluxing Ac2O, yielding the corresponding anhydride (IV), which by reaction with cis-perhydroisoindole (V) in toluene affords the monoamide (VI). This amide is reduced with H2 over a chiral Rhodium catalyst and treated with (R)-1-phenylethylamine (VII) to provide the chiral salt (VIII) as a single diastereomer isolated by crystallization. Finally, this salt is treated first with aqueous NH4OH and then with aqueous CaCl2.
The optical resolution of racemic 2-benzylsuccinic acid (XV) using the chiral amines (R)-1-phenylethylamine (VII), (R)-1-(1-naphthyl)ethylamine (XIV) or (S)-1-phenyl-2-(4-tolyl)ethylamine (XVI) is carried out by fractional crystallization of the corresponding diastereomeric salts and treatment with 2N HCl, providing the desired enantiomer 2(S)-benzylsuccinic acid (XVII). Reaction of (XVII) with SOCl2 gives the corresponding acyl chloride (XVIII), which is treated with 4-nitrophenol (XIX) and TEA in dichloromethane to yield the activated diester (XX). The regioselective reaction of (XX) with cis-perhydroisoindole (V) in dichloromethane affords the monoamide (XXI), which by reaction with HCl and methanol provides the corresponding methyl ester (XXII). This ester is hydrolyzed with NaOH to the previously described chiral succinamic acid (XIII), which is finally converted into its calcium salt.
The condensation of 2(S)-benzylsuccinic acid (XVII) with cis-perhydroisoindole (V) by means of imidazole, SOCl2 and TEA in ethyl acetate gives the succinamic acid (XIII), which is esterified with benzyl bromide (XXV) and K2CO3 in ethyl acetate or with benzyl alcohol (XXVI) and DCC in the same solvent, yielding the succinamic ester (XXIV). Finally, this compound is treated with NaOH or with H2 over Pd/C and reacted with CaCl2, yielding high purity mitiglinide calcium. The one-pot sequential reaction of imidazole with SOCl2, 2(S)-benzylsuccinic acid (XVII) and cis-perhydroisoindole (V), followed by hydrolysis with HCl, gives succinamic acid (XIII), which is finally treated with 2N NaOH and CaCl2.
The condensation of diethyl succinate (IX) with benzaldehyde (II) gives 2-benzylidenesuccinic acid (III), which is treated with refluxing Ac2O to yield the corresponding anhydride (IV). Reaction of (IV) with cis-perhydroisoindole (V) in toluene affords the monoamide (VI), which is reduced with H2 over Pd/C in ethanol to provide the racemic benzylsuccinamic acid (X). Esterification of (X) with (S)-N-benzylmandelamide (XI) by means of DCC and DMAP in dichloromethane gives a mixture of diastereomeric esters, which were separated by column chromatography on silica gel to provide the desired diastereomer (XII). The hydrolysis of (XII) with NaOH in methanol yields the chiral acid (XIII), which is finally treated first with NaOH and then with CaCl2 in water. The preceding optical resolution of racemic acid (X) can also be performed with (R)-1-phenylethylamine (VII) or (R)-1-(1-naphthyl)ethylamine (XIV) by fractional crystallization of the corresponding diastereomeric salts and treatment with 2N HCl.