Case Studies

The Preparation of The Tosylate

Processing issues: The preparation of the tosylate: the protection and de-protection were used. The tBu-OPhBr formation, in the previous process, the preoxide ester and Grignard reagent were used for the transformation. The raw materials are of high cost and the conditions are unsafe. Key intermediate 6, highly flammable tBuLi was used in the old process, which was very difficult to scale-up.

Processing and Scale-up

Processing and scale-up issues: 4 Coupling reactions, all need flash column for isolation/purification. Side-chain, tedious synthesis, difficult to make it pure. One coupling reaction using DMTMM reagent, the reaction easily to be stalled, requires adding more coupling reagent multiple time. Final API, amorphous, extremely difficult to be purified, cp only 97%. Total 9 + 2 = 11 steps, overall yield ~8%.

Drug Candidate for a New Indication

Processing problems: Total 12 steps with very low overall yield (<1%). Chiral resolution only had ~13% yield, 3 recrystallization. Tetrazole synthesis, lot of tar formed, difficult isolation with low yield.