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

HRID 879168Notes

Reaction equation

HRID 879168 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@H:8]1[CH2:24][C@H:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C(=O)[O:15][C@H:11]2[C@@H:10]([CH3:25])[CH2:9]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]1[N:39]=[C:38]([C:40](O)=[O:41])[CH:37]=[CH:36][C:35]=1[F:43].C(Cl)CCl.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.CCO>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]1[N:39]=[C:38]([C:40]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C@H:8]2[CH2:24][C@@H:12]([NH:13][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C@@H:11]([OH:15])[C@@H:10]([CH3:25])[CH2:9]2)=[O:41])[CH:37]=[CH:36][C:35]=1[F:43]

Participants

8

Reactant 4

HCID 111,2-DichloroethaneHCID 10796Cesium carbonateHCID 592265526-(2,6-Difluorophenyl)-5-fluoropicolinic acidHCID 90055847(3aR,5R,7S,7aS)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate

Product 1

HCID 86705216tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamateYield 100%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (3aR,5R,7S,7aS)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate (1.0 equiv.) in DMF (0.2 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 16 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,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate in 100% yield. LC/MS (m/z)=557.3 (MH+), Rt=0.83 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-097ccc8c114645a799565b9a167e6918
Source dataset
uspto-grants-2015_03
Patent number
US08987457B2

Reaction notes

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