Study On The Synthesis Of Caspofungin

Caspofungin, developed by Merck, was the first echinocandin drugs. It was approved by FDA for invasive aspergillosis in patients who were intolerant or cannot be cured of standard therapy. Owing to the unique mechanism of sterilization, broad spectrum, safer and better tolerated, Caspofungin was proved to be the most valuable antifungal drug.Poor stability, purification difficulty limited the laboratory synthesis. Based on the reported literature, this paper used pneumocandin Bo as raw materials, and focused on the attempts to explore the availability of reported routes and find the best synthetic route for preparing Caspofungin in laboratory. Five routes are as following:Route 1:Through dehydration, B1 was obtained. It was then carried out using thiophenol substituted to give compound B2. Via ethylene diamine nucleophilic substitution, B3 was yiel ded. The final reduction in hydrogen atmosphere translated B3 into Caspofungin;Route 2:Similar to Route 1, the intermediate B1 was firstly obtained. The following redu ction by hydrogen gave the intermediate 4. The next successive substitutions of thiophenol an d ethylene diamine finally yielded Caspofungin;Route 3:This route was extremely similar to Route 3, except the production of the inter mediate 4. It was yielded through the direct reduction through borane from B0. The following reactions were as Route 3 described.Route 4:We adjusted the orders of reaction sequences in Route 4. Intermediate 7 was pr-eferentially obtained via the thiophenol substitution, and then reduced by borane to yield the intermediate 10. The final substitution by ethylene diamine yielded Caspofungin.The experimental verification proved that the dehydration reaction was the key point of Route 1 and 2, which had low conversion rate and could generate epimer in the process. Moreover, the separation is difficult and noneconomic. The direct reduction reaction product of Bo in Route 3 was not stable, with a low conversion rate. The best synthetic route was Route 4, with appropriate yield of each step. Obtain the Caspofungin with the yield was 41% finally. We worked out a suitable method for preparation and separation. Ultimately we got the double acetate salt of Caspofungin as the stable compound for storage.