Study On The Synthesis Process Of Pimodivir

Influenza viruses are highly infectious to a large number of people and it cause huge property losses every year worldwide.Pimodivir is a new type of influenza A virus PB2 subunit inhibitor,which shows excellent therapeutic effects and has broad market prospects.After a detailed analysis of the synthesis route of Pimodivir,we found that the currently used synthesis methods have problems such as low atomic economy,many three wastes,separation of chiral intermediates using chiral preparative chromatography,high cost and low yield.This article has determined the optimized synthetic routes of its two key intermediates,5-fluoro-3-(4,4,5,5-tetra methyl-1,3,2-dioxaborane-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine and(2S,3S)-transmethyl-3-aminobicyclo[2.2.2] octane-2-carboxylic acid methyl.It has successfully optimized the synthetic process of key intermediates and developed methods for the resolution of chiral intermediates.The steps of nucleophilic substitution reaction,Suzuki reaction,removal of indole N-Tos protecting group,and hydrolysis reaction were further optimized.The optimization of the pimotivir synthesis was completed.Using 5-fluoro-2-aminopyridine as the starting material,the key intermediate5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyri dine was synthesized through the reactions of bromination,hoe coupling,cyclization,bromination,N-Tos protection and Suzuki reaction.Aiming at the problem of low yield of bromination reaction in the route,the different reaction conditions such as brominating agent,temperature and time were screened to determine better reaction conditions.The total yield of the six-step reaction of this intermediate reached 37%,which is 8% higher than the literature value.Through an in-depth analysis of the synthetic route of key intermediate(2S,3S)-trans-methyl-3-aminobicyclo[2.2.2]octane-2-carboxylic acid methyl,it was determined that cyclohexene was used as the starting material to synthesis of the racemic target compound which through bromination,elimination,Diels-Alder reaction,alcoholysis,cis-trans isomerization,Curtis rearrangement and hydrogen reduction reaction.Aiming at the problems that the alcoholysis reaction and the cis-trans isomerization process in the racemate synthesis require large excess of base,long reaction time,easy dicarboxyl hydrolysis,and low yield.The effects of different kinds of alkali,solvent,concentration,temperature and time on the reaction yield were explored,and the optimal reaction conditions were determined.The optimized total yield reached 43%,which was 18% higher than the literature value.Based on this,a method for the chemical resolution of chiral key intermediate(2S,3S)-transmethyl-3-aminobicyclo[2.2.2]octane-2-carboxylic acid methyl was developed.Then the optimal resolution conditions were determined.The enantiomeric excess and specific rotation of the resolved product were determined by high performance liquid chromatography and polarimeter,and the purity and absolute configuration of product was determined.Based on the optimization of the synthesis process of 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine and(±)-transmethyl-3-aminobicyclo[2.2.2]octane-2-carboxylic acid methyl,and the successful resolution of racemic amino esters.A new route for the synthesis of(2S,3S)-3-((2-chloro-2-fluoro-5-pyrimdin-4-yl)amino)-bicyclo-[2.2.2]octane-2-carbox ylic acid methyl ester by nucleophilic substitution reaction directly with split double salt and 2,4-dichloro-5-fluoropyrimidine was explored and its reaction conditions were optimized.The new process has simple operation,high yield,and avoids the neutralization step and large amount of waste liquid;By further screening the catalyst and ligand types in the Suzuki reaction,the reaction conditions were optimized.And the "one-step" method for removing indole N-Tos protective group and hydrolyzed carboxylic acid ester group was successfully adopted and optimized,improved product yield and reduced three waste emissions.The new Pimodivir synthesis process has low production costs,mild reaction conditions,short reaction cycles,easy separation of intermediates,simple operation,high product yield,and low three waste.The total yield reached 30%,which is 15%higher than the literature value.It is of great significance to green chemical processes and practical industrial applications.