Practical Isolation of tert-Butyl [(1S,2R)-2-Aminocyclohexyl]carbamate (R)-Mandelate through Diastereomeric Salt Formation under Thermodynamic Control

Abstract

A practical method for isolating tert-butyl [(1S,2R)-2-aminocyclohexyl]­carbamate ((1S,2R)-1) in its pure form was investigated. Two different patents from different groups have shown that (1S,2R)-1 can be isolated in the pure form using either (S)-mandelic acid or (R)-mandelic acid as a chiral resolving reagent. Our investigation revealed that both (1S,2R)-1 and (1R,2S)-1 form crystals with (S)-mandelic acid, and the latter salt has two crystal forms with different physicochemical properties including the solubilities and the crystal form transformation. The detailed physicochemical studies on the three crystal forms revealed that the patented processes proceed under kinetic control, which is not easy to manage on a large scale. Our process optimization based on the three crystal form behaviors led to the establishment of a process for manufacturing either (1S,2R)-1 (R)-mandelate or (1R,2S)-1 (S)-mandelate from commercially available cis-1,2-diaminocyclohexane. The newly developed process is considered to proceed under thermodynamic control and has been demonstrated on a large scale.