Trifluoroacetic acid → (+/-)-tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-2-cyano-3-methylcyclohexylcarbamate

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To a solution of (+/−)-(1R,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate (1.0 equiv.) in DMF (0.20 M) was added NaCN (5.0 equiv.). The solution was submerged in an 85° C. oil bath and left stirring under Ar for 16 hrs. The solution was cooled to rt and left stirring under Ar overnight. The solution was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated. To a solution of the bis-Boc product (10 equiv.) in DCM (0.20 M) was added TFA (62.0 equiv.). The mixture was stirred at ambient temperature for 40 min and concentrated and neutralized with saturated aqueous sodium bicarbonate. Dioxane (0.15 M) and Boc2O (4.0 equiv.) were added. The reaction mixture was stirred vigorously at ambient temperature for 16 hrs. Volatiles were removed in vacuo. The aqueous phase was extracted with 10:1 DCM: MeOH. The combined extracts were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by ISCO chromatography over silica gel to give (+/−)-tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-2-cyano-3-methylcyclohexylcarbamate in 20% yield. LC/MS (m/z)=331.2 (MH+), Rt=0.62 min.

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