Oda S.,Chemical Development Center |
Manaka K.,Chemical Development Center |
Kakiya K.,Chemical Development Center |
Hozumi Y.,Chemical Development Center |
And 6 more authors.
Organic Process Research and Development | Year: 2015
We developed a simple synthetic route to S-2367 (Velneperit) (1) using trans-1-ethoxycarbonyl-4-aminocyclohexane hydrochloride salt (12) as a starting material. The key step was Na2WO4/H2O2 oxidation, and we found that it was accelerated in weakly basic conditions. The finding was useful to control one of the critical impurities: 14 in 10. The new process was more efficient than the early process from the viewpoint of the number of reactions, yield, throughput, and EHS (environment, health, and safety) but a quality deviation occurred in the pilot manufacturing: 10 content in 1 was over the upper limit. The cause was presumed to be hydrolysis of 1 during the recrystallization step. After finding it, we developed two reliable purification processes. The first was slurry washing including clever polymorphic control using only acetone and water. The second was salt formation of 10 and rational building of the recrystallization procedure based on solubility to improve removal rate. © 2015 American Chemical Society.