Preparation of Optically Active Succinic Acid Derivatives. II. Efficient and Practical Synthesis of KAD-1229.

Abstract

For large-scale synthesis of monocalcium bis[(2S)-2-benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl)propionate]dihydrate (1, KAD-1229), we investigated regioselective reactions of (S)-2-benzylsuccinic acid (2) with cis-hexahydroisoindoline (4). It was difficult to obtain a half amide regioselectively through coupling reaction of the (S)-acid 2 with the amine 4. Therefore, the succinic acid 2 was converted to bis-activated esters 3a-c and these were reacted with 4 to give the amides 5a-c in good yields, regioselectively. The amides 5a-c were derived to KAD-1229, which has a potent hypoglycemic effect, in good yields.