1,2-Dichloroethane → tert-butyl (1R,2R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate

HRID 705252

Reaction equation

HRID 705252 reaction equation
C([O:4][C@@H:5]1[C@@H:10]([CH3:11])[CH2:9][C@@H:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])[CH2:7][C@H:6]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)C.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[C:35]1[N:40]=[C:39]([C:41](O)=[O:42])[CH:38]=[CH:37][C:36]=1[F:44].C(Cl)CCl.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(O)C.CCOC(C)=O.CCO>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[C:35]1[N:40]=[C:39]([C:41]([NH:18][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:12]=2[C@H:8]2[CH2:7][C@@H:6]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:5]([OH:4])[C@@H:10]([CH3:11])[CH2:9]2)=[O:42])[CH:38]=[CH:37][C:36]=1[F:44]

Participants

8

Reactant 4

HCID 111,2-DichloroethaneHCID 10796Cesium carbonateHCID 592265526-(2,6-Difluorophenyl)-5-fluoropicolinic acidHCID 68555677(1R,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl acetate

Product 1

HCID 86639738tert-butyl (1R,2R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamateYield 99%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 8857Ethyl AcetateSolventHCID 19794673N,N-dimethylformamide ethanolSolvent

Procedure

To a solution of (1R,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-(tert-butoxycarbonylamino)-6-methylcyclohexyl acetate (1.0 equiv.) in DMF/Ethanol (1/5, 0.05 M) was added 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.3 equiv.), aza-HOBt (1.3 equiv.) and EDC (1.3 equiv.). The mixture was stirred at rt for 6 hrs. The solution was diluted with EtOAc, washed with H2O, 1N NaOH, NaCl (sat.), dried over MgSO4, filtered and concentrated to yield crude protected amide. The material was dissolved in EtOH (0.45 M), Cs2CO3 (1.0 equiv.) was added and the solution was submerged in a 60° C. oil bath and stirred for 90 mins. The volatiles were removed in vacuo; the residue was partitioned between with EtOAc and H2O. The organic layer was washed with NaCl(sat), dried over MgSO4, filtered, concentrated and pumped on to yield tert-butyl (1R,2R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate in 99% yield. LC/MS (m/z)=557.3 (MH+), Rt=0.80 min.

Workup

  1. washwashed with H2O, 1N NaOH, NaCl (sat.)
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customto yield crude protected amide
  6. customwas submerged in a 60° C.
  7. stirringstirred for 90 mins
  8. customThe volatiles were removed in vacuo
  9. customthe residue was partitioned between with EtOAc and H2O
  10. washThe organic layer was washed with NaCl(sat)
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-597935584a404d138d4c9ad5befc024a
Source dataset
uspto-grants-2015_11
Patent number
US09173883B2

Linked notes

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