Continuous Flow Chiral Amine Racemization Applied to Continuously Recirculating Dynamic Diastereomeric Crystallizations

A new, dynamic diastereomeric crystallization method has been developed, in which the mother liquors are continuously separated, racemized over a fixed-bed catalyst, and recirculated to crystallizer resolution–racemization–recycle (R3) process. Separating racemization from overcomes problems of using catalysts situ, that suffer conflicting sets conditions, inhibition, separation. Continuous achieved through covalent attachment [IrCp*I2]2 SCRAM catalyst Wang resin solid support give catalyst. One tertiary variety secondary optically enriched amines have efficiently, with residence times compatible (2.25–30 min). The demonstrates lower turnover (TOF) than homogeneous analogue but reuse shows long lifetime (e.g., 40 recycles, 190 h) giving acceptable number (TON) (up 4907). slow release methylamine during N-methyl was found inactivate could be partially reactivated hydroiodic acid. Dynamic is R3 process continual removal more soluble diastereomer supply less one. solubility diastereomers determined, difference correlates rate resolution also affected by rates racemization, crystal growth, dissolution. cyclic acyclic amine salts were resolved mandelic acid (MA) ditoluoyl tartaric (DTTA) higher resolvability (S = yield × d.e.) simple alone. Comparing resolvabilities, resolutions 1.6–44 effective batch, though one case worse. Further investigation this revealed an unusual thermodynamic switching behavior: rac-N-methylphenethylamine initially as (S,S)-bis-alkylammonium tartrate time became equivalent (R,S) salt. Thermal, mixing, concentration, stoichiometry, seeding conditions all affect onset behavior only associated difunctional resolving reagents.