Epoxy compounds usually have stronger nucleophilic ability, because the alkyl group on the oxygen atom makes the bond angle smaller, which makes the lone pair of electrons react more dissimilarly with the electron-deficient system. Compound: (S)-1-{(S)-2-[Bis[3,5-bis(trifluoromethyl)phenyl]phosphino]-ferrocenyl}ethyldicyclohexylphosphine, is researched, Molecular C40H40F12FeP2, CAS is 849923-15-5, about Toward a Scalable Synthesis and Process for EMA401, Part I: Late Stage Process Development, Route Scouting, and ICH M7 Assessment.Recommanded Product: (S)-1-{(S)-2-[Bis[3,5-bis(trifluoromethyl)phenyl]phosphino]-ferrocenyl}ethyldicyclohexylphosphine.
We present the enantioselective synthesis of sodium (3S)-5-(benzyloxy)-2-(diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (EMA401, olodanrigan), an angiotensin II type 2 antagonist. The manuscript features the process optimizations of the end game used for late phase clin. supplies, an overview of synthetic strategies identified in a route scouting exercise to a key intermediate phenylalanine derivative, and the anal. control strategy of the potentially formed highly toxic impurity bis(chloromethyl) ether (BCME). Starting from the phenylalanine derivative, we describe the optimizations of the end game from early phase to late phase processes with consequent improvements in the PMI factor. This sequence includes a Pictet-Spengler cyclization and an amide coupling as the last bond-forming steps, and the manufacturing process was successfully implemented on a 175 kg scale in a pilot plant setup. The modified process conditions eliminated one step by in situ activation of the carboxylic acid, avoided the REACH listed solvent DMF, and resulted in a PMI improvement by a factor of 3. In the final crystallization, a new, thermodynamically more stable modification of the drug substance was found in the complex solid-state landscape of EMA401 during an extensive polymorph screening. A process suitable for large-scale production was developed to prepare the new polymorph, avoiding the need of any special equipment such as fluidized bed drying required in the early phase process. In the second section, some of the synthetic approaches investigated for the route scouting of the phenylalanine derivative key intermediate are presented. To conclude, we discuss the anal. control strategy for BCME, the formation of which, due to the simultaneous presence of HCl and CH2O in the Pictet-Spengler cyclization, could not be ruled out. The BCME purge factor calculations using the tools of ICH M7 control option 4 are compared to actual results from spiking experiments
Different reactions of this compound((S)-1-{(S)-2-[Bis[3,5-bis(trifluoromethyl)phenyl]phosphino]-ferrocenyl}ethyldicyclohexylphosphine)Recommanded Product: (S)-1-{(S)-2-[Bis[3,5-bis(trifluoromethyl)phenyl]phosphino]-ferrocenyl}ethyldicyclohexylphosphine require different conditions, so the reaction conditions are very important.