反应详情

A solution of hydroxylamine-HCl (4.0 equiv.) and tert-butyl (1R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-oxocyclohexylcarbamate (1.0 equiv.) in EtOH/pyridine (1/1, 0.01 M) was capped and left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and Na2CO3(sat.). The organic layer was washed with NaCl(sat), dried over MgSO4, filtered, concentrated. The Boc group was removed with 25% TFA/CH2Cl2. After 45 minutes, the volatiles were removed in vacuo and after pumping the residue was dissolved in DMSO and purified by RP-HPLC to yield N-(4-((1R,3R,5 S,Z)-3-amino-4-(hydroxyimino)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 14% yield. LC/MS (m/z)=470.3 (MH+), Rt=0.60 min. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.94 (s, 1H), 10.49 (s, 1H), 8.60 (s, 1H), 8.48 (d, J=4.0, 1H), 8.35 (dd, J=8.0, 4.0, 1H), 8.20 (t, J=8.0, 1 H), 8.02 (broad doublet, J=4.0, 2H), 7.67-7.74 (m, 1H), 7.42 (d, J=4.0, 1H), 7.36 (t, J=8.0, 2H), 4.24 (m, 1H), 3.82-3.86 (m, 1H), 3.21-3.27 (m, 1H), 2.50-2.55 (m, 1H), 2.24 (d, J=12.0, 1H), 1.86 (d, J=16.0, 1H), 1.68 (q, J=12.0, 1H), 1.59 (q, J=12.0, 1H), 1.40 (d, J=8.0, 3H).

1. waitleft
2. customThe volatiles were removed in vacuo
3. customthe residue was partitioned between EtOAc and Na2CO3(sat.)
4. washThe organic layer was washed with NaCl(sat)
5. dry with materialdried over MgSO4
6. filtrationfiltered
7. concentrationconcentrated
8. customThe Boc group was removed with 25% TFA/CH2Cl2
9. waitAfter 45 minutes
10. customthe volatiles were removed in vacuo
11. dissolutionwas dissolved in DMSO
12. custompurified by RP-HPLC