Acetic Acid → (1R,5S,6R)-5-(5-(((5-chloropyridin-2-yl)methyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine

HRID 1526644Notes

Reaction equation

HRID 1526644 reaction equation
C(OC(=O)[NH:7][C:8]1[O:9][C@H:10]2[C@@H:12]([C@:13]([C:18]3[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=3[F:25])([CH:15]([F:17])[F:16])[N:14]=1)[CH2:11]2)(C)(C)C.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH:34]=O)=[N:32][CH:33]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCCl.CCOC(C)=O.O>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH:24][C:22]2[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C@:13]3([CH:15]([F:16])[F:17])[C@@H:12]4[C@@H:10]([CH2:11]4)[O:9][C:8]([NH2:7])=[N:14]3)[CH:23]=2)=[N:32][CH:33]=1

Participants

10

Reactant 6

HCID 176Acetic AcidHCID 6422Trifluoroacetic acidHCID 14798Sodium HydroxideHCID 5049666Sodium triacetoxyborohydrideHCID 101032675-Chloropyridine-2-carboxaldehydeHCID 131733175tert-butyl ((1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate

Product 1

HCID 118232935(1R,5S,6R)-5-(5-(((5-chloropyridin-2-yl)methyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amineYield 83%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of tert-butyl((1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (16i-B, 0.072 g, 0.194 mmol) and 5-chloropicolinaldehyde (0.028 g, 0.198 mmol) in DCE (1 mL) at RT was added HOAc (0.011 ml, 0.194 mmol) and sodium triacetoxyborohydride (0.050 g, 0.236 mmol). The reaction mixture was stirred at RT for 1.5 h. Trifluoroacetic acid (2.0 ml, 26.9 mmol) was added and after 15 min, and the reaction mixture was diluted with EtOAc and water. The pH was adjusted to 9 with 10 M NaOH. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (60% to 100% EtOAc in heptane) to give the title compound (0.064 g, 0.161 mmol, 83% yield) as a white solid.

Workup

  1. extractionThe aqueous phase was extracted with EtOAc
  2. washthe combined organic extracts were washed with brine
  3. dry with materialdried over MgSO4
  4. concentrationThe filtrate was concentrated under reduced pressure
  5. customthe residue was purified by flash column chromatography on silica gel (60% to 100% EtOAc in heptane)

Sources & evidence

ORD record
ord-a6282bbd8aab44a18f8b8dd1300e9d86
Source dataset
uspto-grants-2015_07
Patent number
US09085576B2

Reaction notes

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