[Preparation of optically active succinic acid derivatives. III. Regioselective condensation reactions of optically active 2-substituted succinic acids with diimidazolide].
We investigated the large scale synthesis of monocalcium bis [(2S)-2-benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl) propionate] dihydrate (KAD-1229), which has a potent hypoglycemic effect, in a single reaction vessel. (2S)-2-Benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl) propionic acid (7) was directly obtainable from (S)-2-benzylsuccinic acid (2) and cis-hexahydroisoindoline (4), without the isolation of intermediates by the method using thionyldiimidazole (9) and/or diimidazolide of the acid 2. Sequential reaction of imidazole with thionyl chloride, 2, and 4, followed by acid catalyzed hydrolysis gave amidecarboxylic acid 7 in 86% overall yield. The acid 7 was treated with 2 N NaOH, followed by the treatment with calcium chloride to give KAD-1229 in 91% yield.
Yamaguchi
T
T
Kissei Pharmaceutical Co., Ltd., Central Research Laboratories, Nagano, Japan.
Yanagi
T
T
Hokari
H
H
Mukaiyama
Y
Y
Kamijo
T
T
Yamamoto
I
I
D055598:Chemical Phenomena; D002621:Chemistry; D007004:Hypoglycemic Agents / Q000138:chemical synthesis*; D007093:Imidazoles; D007211:Indoles / Q000138:chemical synthesis*; D054833:Isoindoles; D013237:Stereoisomerism
D007004:Hypoglycemic Agents; D007093:Imidazoles; D007211:Indoles; D054833:Isoindoles; C029899:imidazole; C087255:mitiglinide