Hydroxyamine hydrochloride → N-[4-[(1R,3R,4Z,5S)-3-amino-4-hydroxyimino-5-methylcyclohexyl]-3-pyridinyl]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

HRID 705286Notes

Reaction equation

HRID 705286 reaction equation
Cl.[NH2:2][OH:3].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[N:17]=[C:16]([C:18]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:26]=2[C@H:27]2[CH2:32][C@@H:31]([NH:33]C(=O)OC(C)(C)C)[C:30](=O)[C@@H:29]([CH3:42])[CH2:28]2)=[O:19])[CH:15]=[CH:14][C:13]=1[F:43]>CCO.N1C=CC=CC=1>[NH2:33][C@@H:31]1[CH2:32][C@H:27]([C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[NH:20][C:18](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([F:43])=[C:12]([C:6]3[C:5]([F:4])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])[N:17]=2)[CH2:28][C@H:29]([CH3:42])/[C:30]/1=[N:2]/[OH:3]

Participants

4

Reactant 2

HCID 443297Hydroxyamine hydrochlorideHCID 86705245tert-butyl (1R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-oxocyclohexylcarbamate

Product 1

HCID 72548916N-[4-[(1R,3R,4Z,5S)-3-amino-4-hydroxyimino-5-methylcyclohexyl]-3-pyridinyl]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamideYield 14%

Reagents, catalysts & solvents 1

HCID 21975839Pyridine ethanolSolvent

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-97855a5ea5a748b3b0d90696715a5004
Source dataset
uspto-grants-2015_11
Patent number
US09173883B2

Reaction notes

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