The Optimization On Synthetic Technology Of Scopolamine Butylbromide And Velpatasvir Intermediate

Scopolamine butylbromide is a M receptor antagonist,it has the function not only blocking ganglion and neuromuscular junction,but also relieving the smooth muscle spasm.This medication is used to treat esopHageal spasms and bladder spasms.The attachment of the butyl-bromide moiety can effectively prevent this drug crossing the blood-brain barrier,minimizing undesirable central nervous system side effects.In this thesis,the synthesis of scopolamine butylbromide was studied:1)The synthesis of 6?-hydroxy tropinone was optimized.The yield was improved from 30.0%to 49.0%,and starting material/sovent(w/v)was changed from 1:200 to 1:30;2)In the synthesis of 3a-aceoxyl-6?-hidroxy tropane,the yield was increased from 55.0%to 72.0%by means of selective hydrolysis;3)The synthesis conditions for 3a-acetoxy trop-6-ene was studied.The yield was increased from 40.0%to 61.0%;4)The resolution of tropine acid was also studied,and the optical purity(e.e)of the product can reach>95.0%.The whole process was optimized and the column chromatography purification procedure was avoided during the whole process.The total yield was increased from 1.0%to 3.8%,which was suitable for industrial production.Velpatasvir is a new anti-hepatitis C virus drug which was developed by American biopHarmaceutical company Gilead Sciences.It is an NS5A inhibitor in the treatment of hepatitis C infection of all six major genotypes.It is often used together with sofosbuvir in a two-drug combination form to treat hepatitis C patients.Once-daily sofosbuvir and velpatasvir for 12 weeks provided high rates of sustained virologic response among both previously treated and untreated patients infected with five different HCV genotypes.In the optimization of synthesis of velpatasvir,the following work was carried out:1)The synthetic routes of three key intermediates were determinated;2)In the synthesis of 1-bromide-2-(bromomethyl)-4-chlorobenzene,the yield was increased from 73.0%to 80.0%by changing the feeding way;3)In the synthesis of 7-hydroxy-1-tetralone,different methods were used to study the reduction of carbonyl group and Friedel-Crafts reaction.The total yield of four-step reaction was up to 55.3%.4)In the synthesis of tert-butyl 2-(9-chloro-1,4,5,11-tetrahydro isochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carbox ylate,it was found that the reaction can be promoted by the removal of water and the yield can be increased from 56.0%to 71.0%.A method was developed for the purification of 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one by recrystallization with toluene for two times.During the whole process,the column chromatography purification procedure was avoided,which was suitable for industrial production.