Synthesis Of Cenicriviroc And Selexipag

Cenicriviroc is a CCR5/CCR2 inhibitor jointly developed by Takeda and Tobira Therapeutics.It can effectively reduce the viral load in HIV-1 infected individuals and prolong the life span of infected individuals,which has a good market prospect.In the synthesis work of Cenicriviroc,we mainly carried out the foll-owing work.1.Synthesis of 2--piperidone by the Schmidt reaction using cyclopentanone,avoiding difficulties in post-proc essing,severe environme-ntal pollution,and by-products caused by the use of concentrated sulfuric acid.2.In the synthesis of 1-[(4-methoxyphenyl)methyl]-2-piper idone,a suitable base was identified as an acid-binding agent,reducing the produc-tion of impurities.The target product was obtained with a high yield of 95%.3.Synthesis of 8-bromo-l-(4-methoxyindenyl)-1,2,3,4-tetrahydro-l-benzox-anthine-5-carboxylic acid methyl ester.Through a large number of expe-riments,the appropriate solvents and bases were found to successfully carry out the Claisen-Schmidt reaction,without the alkaline being too strong leading to the hydrolysis of the product.4.In the synthesis of 5-hydroxym-ethyl-2-mer-capto-l-propylimidazole,we use 1,3-dihydroxyacetone as a ra-w material to obtain a 2,5-disubstituted imidazole ring.Compared to the conventional method of Marckwald imidazole Synthetic method,it greatly increased the yield of target product.5.In the synthesis of 5-hydroxy methyl-1-propylimidazole,we use the green pollution-free hydrogen perox-ide as an oxidant and tungstic acid as a catalyst for oxidative desulfurization.Compared with the use of strong oxidizer concentrated sulfuric acid that was usedin the original route,it reduces the production of by-products and is more in line with the concept of green chemistry.6.We successfully completed the synthetic route of Cenicriviroc and obtained the target product-Cenicriviroc.Selexipag was originally discovered and synthesized by Japan’s Shin-A-kai Pharmaceutical Co.Ltd.It is a new class of PGI2 agonists that can be orally administered,and it can be maintained in the blood for a long time,it also has a highly selective and potent PGI2 receptor agonistic effect.In the synthetic study of Selexipag,we mainly carried out the following work.1.We designed a new synthetic route for Selexipag.The biphenyl acetophenone is used as raw material.A three-membered ring was formed by the over-condensation reaction of biphenyl acetophenone with anhydrous ethylene diamine.The sublimed sulfur was oxidized to a pyrazine compound.After the Chichibabin reaction,an amino group was formed,and the isopropyl group was condensed with acetone to obtain a long-chain alcohol by hydrolysis.The final product is replaced by a one-step reaction to give the final product,Selexipag.we finnaly got the target prduct-Selexipag.The harsh reaction conditions have been avoided,and the raw,material and reagents’ prices are inexpensive.The yield of each step is basically above 80%.2.We optimize the synthesis of intermediate V in the original patent route.Compared with the higher reaction pressure of the original route,expensive raw materials and catalysts,longer reaction time,we used the cheaper y-butyrolactone as raw materials.Only normal temperature and pressure are required.3.We successfully optimized the synthesis of intermediate IV in the original patent route one.The original method needs to react at 190℃.and the yield is only 56.5%,and the post-treatment process is cumbersome.By optimization,we lowered the reaction temperature to 80℃ and the yield increased to 87%.