Preparation of Optically Active Succinic Acid Derivatives. III. Regioselective Condensation Reactions of Optically Active 2-Substituted Succinic Acids with Diimidazolide

• Published in: YAKUGAKU ZASSHI Vol. 118; no. 6; pp. 248 - 255
• Main Authors: YAMAGUCHI, Toshiaki, YANAGI, Takashi, HOKARI, Hiroshi, MUKAIYAMA, Yuko, KAMIJO, Tetsuhide, YAMAMOTO, Iwao
• Format: Journal Article
• Language: Japanese
• Published: Japan The Pharmaceutical Society of Japan 01-06-1998
• Subjects: (2S)-2-benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl) propionic acid; Chemical Phenomena; Chemistry; Hypoglycemic Agents - chemical synthesis; Imidazoles; Indoles - chemical synthesis; Isoindoles; KAD-1229; potent hypoglycemic effect; Stereoisomerism
• ISSN: 0031-6903; 1347-5231
• DOI: 10.1248/yakushi1947.118.6_248

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 2N NaOH, followed by the treatment with calcium chloride to give KAD-1229 in 91% yield.