Study On The Synthesis Of New Hypoglycemic Agent Mitiglinide For Non-insulin-dependent Diabetes Mellitus

In the past decades the number of the people who suffered from diabetes mellitus increased very rapidly. Diabetes mellitus done harm to people seriously and has been become the third main disease after cardio-vascular & cerebral-vascular disease and tumour. The incidence of diabetes mellitus increase rapidly also, and it will reach to the peak in ten years. It costs much money to remedy diabetes mellitus, which will be a heavy burden on the family and society.This paper introduced several the main oral agents for the type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). These oral agents mainly include underlying categories such as sulphonylurea, biguanides, a-glucosidase inhibitors, thiazolidinediones and non-sulphonylurea insulin secretagogues and so on.Mitiglinide is the derivative of phenylalanine. It belongs to the non-sulfonylurea drug that can stimulate release of insulin. Compared to repaglinide, nateglinide and other sulfonylurea drugs, mitiglinide shows much more advantages such as can take the medicine flexibly, safely, work rapidly, intensively and short-acting.The methods of mitiglinide mainly include two types, asymmetry method andesolution method. The prior method has high yield but is protected by patent; and thelater method has low yield, so we design a new route to synthesize mitiglinide. Thenew route has some advantages such as simple operation, inexpensive materials andbetter yield compare to other synthesis routes.The synthesis route is showed as follows. First, (S)-2-chloro-3-phenylpropionic acid is synthesized from L-phenylalanine by diazotization. After esterification, the ethyl (S)-2-chloro-3-phenylpropionate reacts with diethyl malonate under the catalysis of sodium ethylate, and we obtain the corresponding triethyl ester. The (S)-benzylsuccinic acid is formed by the triethyl ester reacting with concentrate hydrochloric acid and taking place hydrolyzation and decarboxylation reaction at the same time. In order to avoid the formation of cinnamic acid, the sodium ethylate and diethyl malonate must be react sufficiently. The course has simple operation, inexpensive materials and better yield. The yield is up to 26.8%. The compoundstructure is verified by melting point, IR, 'H-NMR and optical rotation.Second, we prepare the (S)-benzylsuccinic anhydride from (S)-benylsuccinic acid by using acetic acid as solvent and acetic anhydride as dehydration regent. We gain (S)-2-benzyl-4-oxo-(cis-perhydorisoindole-2-yl)butyric acid by using the anhydride reacts with cis-perhydroisoindole in dichloromethane and at low temperature. After concentrating, the butyric acid reacts with sodium hydroxide and calcium chloride directly, and gives the mitiglinide. The course has simple operation and the yield is up to 30.3%. The compound structure is verified by melting point, IR, NMR, element analysis, mass spectrum and optical rotation.Cis-perhydroisoindole is prepared by using cis-hexahydrophthalimide as main material, lithium aluminum hydride as reducing regent and tetrahydrofuran as solvent. The yield is up to 40.8%.