The Synthesis Of Eliglustat And Simeprevir's Key Intermediates

Eliglustat (trade name Cerdelga), a glucocerebroside analogue, is a treatment for Gaucher's disease developed by Sanofi and Genzyme Corp. It can reduce the glucose cerebrosides in the lysosomes by inhibiting the activity of glucose cerebrosides synthase, thus relieving patients' symptoms. Simeprevir (trade names Olysio and Sovriad) is a NS3/4A protease inhibitor developed by Janssen to fight against hepatitis C virus (HCV). Evidence shows that it interferences the replication of HCV virus in liver cells through inhibiting the activity of NS3/4A protease, which makes it a good choice for the treatment and cure of hepatitis C.Our work mainly includes three parts:the optimization of the Eliglustat's synthesis route, the design of a new route to synthesize Eliglustat, and the optimization of the synthesis of three key intermediates of Simeprevir.In the aspect of optimization of Eliglustat's synthesis route, we accomplished three different goals. First, we explored the synthetic routes to the intermediates and then established appropriate reaction conditions and treatments to obtain products with high purity. Second, we determined the structures of all the impurities during the synthesis of the intermediate 5, based on which we designed suitable recrystallization conditions to remove the impurities and in the meantime obtain the pure product 5. Finally, we obtained our target product Eliglustat after a series of chemical reactions including aminolysis reaction, hydrolysis reaction, reduction of carbonyl, hydrogenation reaction, and the connection of intermediates. The target product Eliglustat was determined by 1H NMR and MS. Overall, the whole synthesis process after optimization no longer contained column chromatography purification step and the yield was improved, which helped reduce the production cost and made it more suitable for industrial production.In addition, we designed a new route to synthesize Eliglustat. Based on the inverse synthetic analysis, we explored several reasonable routes to synthesize intermediate 7. The most suitable route included synthesis of amide, wittig reaction, bromo-hydroxylation of carbon double, substitution reaction of azide, reduction reaction, and the chiral resolution. Then intermediate 7 could be used to synthesize Eliglustat by one further connection reaction. This new synthetic route showed many advantages. The route was more concise and the conditions were milder. The starting materials were readily available and inexpensive. The new route we designed provided a new direction for the synthesis of Eliglustat.At last, we optimized the synthetic processes for three key intermediates and obtained sufficient results. First, we adjusted the two-step route to synthesize intermediate A, improving the overall yield from 56% to 87%. Then, we optimized part of the synthetic routes to the three intermediates to reduce the production of impurities of the corresponding reactions, after which the yield was improved. In the end, the post processes for the reactions were optimized. The column chromatography purification steps were no longer needed, which made the reaction more suitable for industrial production.