Sodium hydride → N-[3-[(1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-(3-cyclopropylprop-2-ynoxy)pyrazine-2-carboxamide

HRID 1526645Notes

Reaction equation

HRID 1526645 reaction equation
[CH:1]1([C:4]#[C:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[NH2:10][C:11]1[O:12][C@H:13]2[C@@H:15]([C@:16]([C:21]3[CH:22]=[C:23]([NH:28][C:29]([C:31]4[CH:36]=[N:35][C:34](Cl)=[CH:33][N:32]=4)=[O:30])[CH:24]=[CH:25][C:26]=3[F:27])([CH:18]([F:20])[F:19])[N:17]=1)[CH2:14]2.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[NH2:10][C:11]1[O:12][C@H:13]2[C@@H:15]([C@:16]([C:21]3[CH:22]=[C:23]([NH:28][C:29]([C:31]4[CH:36]=[N:35][C:34]([O:7][CH2:6][C:5]#[C:4][CH:1]5[CH2:3][CH2:2]5)=[CH:33][N:32]=4)=[O:30])[CH:24]=[CH:25][C:26]=3[F:27])([CH:18]([F:20])[F:19])[N:17]=1)[CH2:14]2

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 516892Sodium BicarbonateHCID 27937573-Cyclopropylprop-2-yn-1-olHCID 90412895N-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropyrazine-2-carboxamide

Product 1

HCID 118232927N-[3-[(1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl]-5-(3-cyclopropylprop-2-ynoxy)pyrazine-2-carboxamideYield 57.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 3-cyclopropylprop-2-yn-1-ol (205 mg, 2.137 mmol) in DMF (1 mL) was added sodium hydride (60% dispersion in mineral oil; 8.6 mg, 0.214 mmol) at rt. After 15 min N-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropyrazine-2-carboxamide (Example 261, 88 mg, 0.214 mmol) was added and the reaction mixture was stirred at 60° C. for 50 min. Water (1.0 mL) and aqueous, saturated NaHCO3 solution (1 mL) were added. The resulting mixture was then extracted with EtOAc (2×10 mL). The combined organic extracts were washed with water and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (0%-20% MeOH/DCM) to give 58 mg of the title compound as an off-white solid. MS m/z=472 [M+H]+

Workup

  1. extractionThe resulting mixture was then extracted with EtOAc (2×10 mL)
  2. washThe combined organic extracts were washed with water
  3. dry with materialdried over MgSO4
  4. concentrationThe filtrate was concentrated under reduced pressure
  5. customthe residue was purified by silica gel flash column chromatography (0%-20% MeOH/DCM)

Sources & evidence

ORD record
ord-dbab56de8be24145bdcf2ac3f6a52531
Source dataset
uspto-grants-2015_07
Patent number
US09085576B2

Reaction notes

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