1H-1,2,4-Triazole → tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)cyclohexylcarbamate

HRID 879181

Reaction equation

HRID 879181 reaction equation
CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][C@@H:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH:19]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=O)=O.[NH:35]1[CH:39]=[N:38][CH:37]=[N:36]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C@H:9]1[CH2:8][C@@H:7]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[C@@H:6]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[C@@H:11]([CH3:12])[CH2:10]1.[NH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C@@H:9]1[CH2:8][C@H:7]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[C@H:6]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[C@H:11]([CH3:12])[CH2:10]1

Participants

6

Reactant 3

HCID 92571H-1,2,4-TriazoleHCID 10796Cesium carbonateHCID 86705223(1R,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate

Product 2

HCID 86705225tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)cyclohexylcarbamateYield 19%HCID 86705226tert-butyl (1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)cyclohexylcarbamateYield 19%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of (+/−)-(1R,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate (1.0 equiv.), 1H-1,2,4-triazole (3.0 equiv.) and Cs2CO3 (3.0 equiv.) in DMF (0.15 M) was stirred at 80° C. for 5 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by RP HPLC, followed by free basing by partitioning between an equal volume of EtOAc and Na2CO3, separating, washing with NaCl(sat.), drying over MgSO4, filtering, concentrating. Purification was completed via SFC (20% MeOH, 100 mL/min, AD column) to yield tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)cyclohexylcarbamate (19% yield, 99% ee) and tert-butyl (1S,2R,3R,5S)-5-(3-aminopyridin-4-yl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)cyclohexylcarbamate (19% yield, 99% ee). LC/MS (m/z)=373.3 (MH+), Rt=0.54 min.

Workup

  1. customThe volatiles were removed in vacuo
  2. customthe residue was partitioned between EtOAc and H2O
  3. washThe organic layer was washed with Na2CO3(sat.), NaCl(sat.)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. custompurified by RP HPLC
  8. customby partitioning between an equal volume of EtOAc and Na2CO3
  9. customseparating
  10. washwashing with NaCl(sat.)
  11. dry with materialdrying over MgSO4
  12. filtrationfiltering
  13. concentrationconcentrating
  14. customPurification

Sources & evidence

ORD record
ord-50e7d7eefca641cbb84f14203f4f7812
Source dataset
uspto-grants-2015_03
Patent number
US08987457B2

Linked notes

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