New Method to Large-Scalable Preparation of the Key Chiral Cyclohexane cis-Diamine Intermediate for Edoxaban

A new synthesis of tert-butyl (1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexylcarbamate, a key intermediate of edoxaban, is disclosed. This compound is a cyclohexane cis-diamine whose structure is a synthetic challenge. The known synthetic methods suffer from drawbacks, such as low yield, long reaction times, as well as excessive use of NaN3. The new method includes a total of nine steps starting from the known compound, (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one, whose γ-butyrolactone frame is ring-opened to form trans-3-azido-4-hydroxy cyclohexane after the first two steps. Subsequent oxidation leads to the formation of a cyclohexanone, which is then transformed to cis-diamine through enzyme-catalyzed asymmetric reductive amination, acylation with CbzCl, and reduction of the azido group successively. The target, tert-butyl (1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexylcarbamate, is finally formed through acylation with (Boc)2O, followed by deprotection of the Cbz group using hydrogenation.