Synthetic Process Study Of Pidotimod

Pidotimod,(R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid,is a chemical synthesized immunization accelerator,it was approved in Italy for use in the body to enhance immunity in 1993.Due to the existing synthetic routes to produce large amount of waste liquid,the high costs restricted the industrial development of Pidotimod,therefore,the study of the new synthetic route of Pidotimod,with potential value and practical application prospect.In this paper,based on the existing literature,designed a route to synthesize Pidotimod with L-cysteine as a raw material by cyclization,esterification,neutralization,condensation,hydrolysation and acidification,the yield was 55.1% and the purity was 99.6%.Cyclization reaction,with relatively inexpensive L-cysteine as raw material,in the aqueous solution system,cyclization to L-thiazolidine-4-carboxylic acid with the formaldehyde,the simple filtering to get the product,and the reaction conditions were optimized,ultimately,selected reaction time was 3 h,the feed ratio of the raw material is1:1.5,recovered formaldehyde aqueous solution without any treatment can be applied twice,the optimized yield was increased from 84.1% to 92.0% and purity was 99.2%.Esterification reaction,using of ethanol and dichlorosulfoxide instead of the hydrochloric methanol or ethanol as an esterification reagent in the original literature,the yield increased from the original 85% to 93%,the purity of 99.2%,while reducing the dosage of ethanol,the discharge of waste water,after optimization of the reaction conditions,the mass ratio of L-thiazolidine-4-carboxylic acid to ethanol was determined to be 1:7,the molar ratio of L-thiazolidine-4-carboxylic acid to thionyl chloride was 1:1.1,reflow time is 4 h,recycled ethanol can be applied directly twice without treatment,improved product yield,reduce production costs.Condensation reaction,using the esterified product after neutralization of NaHCO3,after extraction with methylene chloride without distillation,condensation with L-pyroglutamic acid under the action of dehydration agent DCC,and then by hydrolysing to get the final product Pidotimod.By optimizing reaction conditions,and ultimately determine the condensation temperature gradient speed temperature control,0~5 ? heated 1 h,up to25~30 ? heated preservation 10 h,using gradient speed temperature control to reduce theby-products generated,recrystallization by water product yield was 64.5%,product purity was 99.6%.Compared with the existing synthetic route,the new process of raw material prices low,simple process,easy operation,less waste liquid treatment,is conducive to industrial production.