| Mitiglinide is a new kind of oral hypoglycemic drug which was marketed inJapanese in 2004. Its excellent clinical performance has been attracting great attentionsince then.Due to short time for market, the production technology of Mitiglinide needsfurther improvement. Therefore in this paper some synthetic methods of Mitiglinideintroduced, compared, screened and optimized. And finally a applicable industrialprocess was established.Taking succinic acid dimethyl ester as starting materials,through stobbe condensation, hydrolysis, hydrogenation, chiral separation,(S)-2-benzylsuccinid acid is attained, which is then converted into bis-activated estersof (S)-2-benzylsuccinic acid and reacted with cis-hexahudroisoindoline in lowtemperature to acquire (2S)-2-ben zyl-3-(cis-hexahydroisoindolin-2-ylcarbon yl)propionic acid in high regioselectivity, and through treatment by sodium hydroxideand calcium chloride in aqueous solution, the products of mitiglinide was obtained atthe end. The overall yield of Mitiglinide is about 8.0%, and the quality of finalproducts conforms"Pharmacopoeia of the People's Republic of China".Based on the above study, the regioselectivity of ammonolysis of bis-activatedesters, with theoretical importance, is further explored via computational chemistry inthis paper. It is observed thatπ-πstacking interaction in the molecule of bis-activatedesters may play a crucial role in enhancing regioselectivity.In addition, the problems contained in current asymmetric synthesis of mitiglinideare analyzed, and a new method introducing chiral center through Michael additioncatalyzed by small chiral melocule is proposed and studied fundamentally. A arrangeof L-proline derivatives are prepared and their catalytic performance in modelreaction is investigated, then some discipline about structure-activity of catalysts isput forward, advancing further design and synthesis of chiral molecule of asymmetricMichael addition. |
PDF Full Text Request