Study On The Preparation Of The Mitiglinide Calcium

Diabetes as one kind of common and frequently-occurring disease has been listed asone of the three incurable diseases by the World Health Organization. Now285millionpeople are suffering from diabetea in the world, and the proportion of typeⅡdiabetespatients is up to95%. The demand for diabetes drugs is considerable with the risingnumber of diabetes patients. A series of new treating drugs have appeard. Recoverabilityof early postprandial insulin secretion and lowering blood glucose drug research hasbecome a new strategy for the treatment of type Ⅱ diabetes. Mitiglinide calcium isdevelopmented by Kissei pharmaceutical company in Japan, it is an ATP-dependentpotassium ion channel blocker, and firstly marketed in Japan in the year2004. Thesynthetic route of mitiglinide are systermatically studied in this paper.In this paper, two synthetic routes are designed for the intermedate (S)-2-benzyl succinic acid, and the best method is to use Mg/CH3OH to reduce the C=C bond, it uses diethyl succinate and benzaldehyde as the strating matrial, via stobbe condensation, using Mg/CH3OH to reduce the C=C bond, hydrolyze and resolved by(R)-α-phenylethylamine to give the (S)-2-benzylsuccinic acid. Three synthetic routes are slao designed for mitiglinide, and the best method is to use (S)-2-benzyl succinic acid as the strating matrial, via N,N’-carbonylimidazole to active carboxyl andgenerate active amide, condense with the cis-hydrogen isoindole, hydrolyzed withhydrochloric acid, reacts with calcium chloride in sodium hydroxide solution, afterrefining we obtain the tagert compound. The overall yeild is59.07%, and the purity of the mitiglinde is99.861%. We improved the process route, it is known that(2S)-2-benzyl-3-(cis-hydrogen isoindole-2-carbonyl) propionic acid is oil, it is verydifficult to preserved and purified, we us it react with benzyl chloride using KI ascatalyst to obtain (2S)-2-benzyl-3-(cis-hydrogen isoindole-2-carbonyl) propionic acidbenzyl ester.The synthetic route of mitiglinide calcium which we chose in this paper has manyadvantages, for example the cheap and available material, easy to opration et al. The sysnthetic route is suit for large-scale manufacture. The structuresare confirmedthrough IR, NRM and MS.