Study On Synthesis Of Chiral Compounds(S,S)-2,8-Diazabicyclo[4.3.0]Nonan

Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent developed by Bayer AG.It has a huge market as an ideal drug for treatment of respiratory tract infections.(S,S)-2,8-diazobicyclo[4.3.0]nonane is a crucial intermediate of moxifloxacin.Currently,it can only be produced in small-scale and the price is expensive as its synthesis is difficult and costly.Therefore,searching for new synthetic methods of(S,S)-2,8-diazobicyclo[4.3.0]nonane is an urgent need of the pharmaceutical industry.On the other hand,many small molecule chiral nitrogen-containing heterocyclic compounds are highly valued because of their physiological activities and synthesis difficulties.Carrying out the study of asymmetric hydrogenation reduction of pyridine aromatic heterocyclic ring is a challenging work with academic significance.With all above-mentioned factors taken into account,this article will conduct a research on the synthesizing method of small molecule chiral nitrogen-containing heterocyclic compound such as(S,S)-2,8-diazobicyclo[4.3.0]nonane.We hope the studies in this thesis can provide theoretical and practical reference for moxifloxacin side chain of production,but also able to provide academic reference for the asymmetric hydrogenation reduction of pyridine aromatic heterocyclic ring and the asymmetric synthesis of chiral nitrogen-containing heterocyclic small molecules.In the second chapter,the following improvements are made to the Wang route:1)Using cheap and easy operation sodium sodium borohydride/zinc chloride instead of explosive and expensive lithium aluminum hydride,and maintaining a high yield of 92%.2)Replacing the original sodium ethoxide/ethanol system by eutectic/triethylamine system to improve operational safety,and improving the yield of 80.5%to 87%.3)Completing the resolution by using much cheaper D-(-)-tartaric acid instead of the relatively expensive S-(+)-mandelic.On this basis,synthetic route one is proposed and(S.S)-2,8-diazobicyclo[4.3'0]nonane is obtained in 21%overall yield.In the third chapter,the following improvements are made to the Cai and Pallavicini routes:1)Using 1,3-Dichloro-5,5-dimethylhydantoin instead of MnO2 and NaDCC to improve the reaction efficiency and reduce industrial waste,and maintaining a high yield of 93%.2)Replacing the volatile acetone by ethanol to reduce the use of solvents and increased production safety.On this basis,synthetic route two is proposed and(S,S)-2,8-diazobicyclo[4.3.0]nonane is obtained in 46%overall yield.This method is more suitable for industrialization.But this method also has the problem of using noble metal palladium carbon,high cost and long synthetic route.Further,method three is proposed that is asymmetric synthesis of(S,S)-2,8-diazobicyclo[4.3.0]nonane.By asymmetric hydrogenation reduction of 6-benzyl-pyrrolo[3,4-b]pyridine-5;,7-dione,the chiral synthesis of target compound is developed in only 5 steps with 64%overall yield.This synthetic route is a new method which is the most simple,green chemistry and high yield.But this method also exists the problem of using expensive catalysts and ligands.In the fourth chapter,a new synthetic route of(S,S)-2,8-diazobicyclo[4.3.0]nonane is designed.The synthetic intermediate pyridine-2,3-dicarboximide is immediately reduced and resoluted without protection.Moreover,the invalid chiral isomer is recycled by racemization.This route with short steps,low cost and moderate overall yield(40%),is a more economical and feasible route.