Study On The Synthesis Of Several Compounds With Activity Of Anti-type 2 Dibetes

In this thesis, the Synthesis of several compounds with activity of anti-type 2 dibetes was described. The overall article consisted of the synthesis of indole derivatives, C-aryl glucosides and substituted spiroketal derivative.1. The target compound 1 was synthesized by several different raw materials, including 5-bromo-2-chlorobenzoicacid,5-bromo-2-chlorobenzylalcohol and 5-bromo-2-chloro-benzaldehyde. It was also studied on the preparation of important intermediates by Friedel-Crafts, Weinreb, Suzuki cross-coupling and grignard reactions, the synthesis of intermediates about the selectivity of the ortho-position and para-position of the reaction was solved, the overall yield was improved.It was study on the glucono lactone of protection by TMS, AC and benzyl group in coupling reaction, and it was confirmed the benzyl group was first choice. Moreover, it also solved for low yield about deprotection of benzyl group in hydrogenation, and explained the possible reason that was chlorine group of 1,2-dichlorobenzene could be reduced at first and resultant hydrochloride could gradually inhibit reduction of chlorine group of 1.In the end, the isomers of undesired ortho-products were avoided in the synthesis of intermediate. Moreover, the easy purified methods, the much higher overall yield and brief steps were obtained in improved methods.2. Compound 30 was prepared from 7-cholo-5-methyl-1H-indole as the raw material in two different synthetic routes, the first synthetic method was TS protection of indole followed by bromination in 3-indole. However, the 3-Halo, and even more so, 2-haloindoles was unstable and must be utilized as soon as they are prepared. Accordingly, it was very difficult to handle the compound 25 at multi scale up level. Moreover, the intermediate was prepared by coupling reaction in unsatisfied yield and the synthetic route needed seven steps which limited a large scale production. The facile and improved second synthetic route was only three steps, firstly, the coupling reaction of between 23 and 1-(bromomethyl)-4-ethylbenzen gave 31, then the coupling reaction of between 31 and 32 afforded 29 which was hydrogenated to produce target compound 30. It has been achieved in about 72% overall yield. Moreover, it was also obtained the satisfactory results that the derivatives of compound 30 were prepared in the same manner. 3. Compound 50 was synthesized by a new route from the 3-amino-4-methyl-benzoic acid as the raw material. It was prepared by coupling between compound 55 and ethylbenzene, and followed by coupling between compound 59 and glucono lactone to afford compound 60 which was treated by methanesulfonic acid to give compound 50. Furthermore, it was also studied on the key intermediate was prepared by Suzuki cross-coupling. They all obtained the much higher overall yield and brief steps.Moreover, Compound 50 was usually purified with silicon column because it was glass off solid which limited a large scale production. The improved purification was protection of compound 50 by AC firstly to produce compound 66 which was purified by easy recrystallization, then deprotection of compound 66 to give compound 50. It was obtained the satisfactory result in high overall yield.4. Compound 75 was synthesized from 2-chloro-5-bromomphenylmethylether as a start raw material in route one, in this procedure, the mediate compound 69 needed twice purification with silicon column because isomers of undesired ortho-products was difficult to be separated. In route two, the demethyl of compound 69 without further purification with column to give 76 which was easy purification by only twice washings of solvents, and the possible reason was intramolecular hydrogen bond was produced in the isomers of undesired ortho-products, and physical properties of ortho-position and para-position of intermediate were changed greatly.Furthermore, it was studied on the influence of stereo-hindrance effect for the coupling between compound 73/70 and glucono lactone, it was obtained the helpful results to the future industrial scale.