PREPARATION OF OPTICALLY-ACTIVE SUCCINIC ACID-DERIVATIVES - II - EFFICIENT AND PRACTICAL SYNTHESIS OF KAD-1229

For large-scale synthesis of monocalcium ahydroisoindolin-2-ylcarbonyl )propionate]dihydrate (1, KAD-1229), we investigated regioselective re actions of (S)-2-benzylsuccinic acid (2),vith 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 his-activated esters 3a-c and these w ere reacted with 4 to give the amides 5a-c in good yields, regioselect ively. The amides 5a-c were derived to KAD-1229, which has a potent hy poglycemic effect, in good yields.