Study On The Process For The Preparation Of Sofosbuvir

Sofosbuvir is a novel anti-hepatitis C virus drug with unique pharmacological effects and therapeutic effects,a broad market space and application prospects.The reported synthetic methods in the literature generally have the problems of long synthetic route,low yield,use of highly toxic substances,and large amount of waste.The reported synthetic methods of the key intermediate(2R)-2-deoxy-2-fluoro-2-methy-D-erythrovalerate-?-lactone-3,5-dibenzoate,have the problems of low chemical yield in fluorination,poor stereoselectivity in Wittig reaction,and using highly toxic substances such as osmium tetroxide.In this paper,through the analysis of the reported synthetic methods,the synthetic route with low-cost R-glyceraldehyde acetonide as raw material was determined,and the synthesis of key intermediates for sofobuvir was explored,and the nucleophilic fluorination,Wittig reaction selectivity and dihydroxylation reaction was studied.A new synthesis method and process was put forward,the optimization of the synthesis process of the key intermediate was completed,and on this basis,the optimization of the overall synthesis process of sofosbuvir was completed.Through analyzing the mechanism of the fluorination of cyclic sulfate compound5,fluorinated reagents such as diethylaminosulfur trifluoride,tetrabutylammonium fluoride and tetraethylammonium fluoride were selected to study effect on reaction yield of different fluorinating reagents,finding that the property of the fluorination reagents have a great influence on the yield of the ring-opening fluorination of cyclic sulfate.The effect of solvent on fluorination reaction was studied,and was found that the polar protic solvent has a significant inhibitory effect on nucleophilicity,which is unfavorable for the nucleophilic substitution reaction of S_N2;the weakly polar aprotic solvent favors the nucleophilic substitution reaction of S_N2.Side effects such as the elimination reaction increased significantly when the temperature rised.Through optimizing experiments on fluorinated reagents,solvents,and temperatures,optimized process conditions were obtained.Tetraethylammonium fluoride was used as the fluorination reagent,1,4-dioxane was the solvent,and the reaction temperature was110°C,which could effectively control the occurrence of side reactions.Tetraethylammonium fluoride,as a fluorinating agent,has the characteristics of being less susceptible to hydrolysis and mild reaction conditions.After optimization,the fluorination reaction conditions were mild and the yield reached 81%.For the problems reported in the literature such as low yield of Wittig reaction and high impurity content of isomers,carbamoyl methylene triphenylphosphine was used as a stable phosphorus ylide.The reaction temperature and the effect of the solvent on the yield and isomer ratio of the Wittig reaction were studied.It was found that a stable phosphorous ylide was used to produce mainly trans-(E)-configuration products under low temperature,aprotic solvent-dichloromethane.After optimization,when the reaction temperature was-70°C,the yield of this step reached 95%,and the cis(Z)-olefin isomer was reduced to 1.2%,which greatly increased the yield of the product and reduced the isomer impurities.The literature reports the use of highly toxic osmium tetroxide for dihydroxylation.Through analyzing,low-cost and low-toxicity potassium permanganate was used as dihydroxylation oxidant.In view of the problem that potassium permanganate is not easily soluble in organic solvents and prone to excessive oxidation in aqueous phase,phase transfer catalysis was used in the dihydroxylation reaction of compound 2.By studying the influence of reaction conditions such as phase transfer catalyst,temperature,oxidant amount and solvent on the dihydroxylation reaction,it was found that benzyl triethylammonium chloride was used as the phase transfer catalyst and the problem of dihydroxylation reaction was effectively solved.Through optimizing the reaction conditions,the yield reached 79%.The yield of the key intermediate 8 reached from 18%,which is reported in the literature,to 42%.The raw materials are cheap and easy to obtain,the reaction conditions are mild,and they are safe and environmentally friendly.Based on the optimization of the synthesis of key intermediate,the synthesis of sofosbuvir was accomplished via reduction,acylation,substitution,deprotection,and substitution of tri-t-butoxy lithium aluminum hydride,and various process conditions were optimized.We successfully obtained a new synthetic route for sofobuvir.The new sofobuvir synthetic route has advantages of using cheap raw materials which is easy to obtain,easy to purify the intermediate,high product yield,safe and environmentally friendly.It has important application value and significance.