Acetonitrile → N-[3-[(4aR,7aS)-2-Amino-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]oxazin-7a-yl]-4-fluoro-phenyl]-5-[(1-fluorocyclopropyl)methoxy]pyrazine-2-carboxamide hydrochloride

HRID 1754876Notes

Reaction equation

HRID 1754876 reaction equation
[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([F:28])[CH2:10][O:9][CH2:8][C@:6]2([C:11]2[CH:12]=[C:13]([NH:18][C:19]([C:21]3[CH:26]=[N:25][C:24]([Cl:27])=[CH:23][N:22]=3)=[O:20])[CH:14]=[CH:15][C:16]=2[F:17])[N:7]=1.[F:29][C:30]1([CH2:33][OH:34])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C>[ClH:27].[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([F:28])[CH2:10][O:9][CH2:8][C@:6]2([C:11]2[CH:12]=[C:13]([NH:18][C:19]([C:21]3[CH:26]=[N:25][C:24]([O:34][CH2:33][C:30]4([F:29])[CH2:32][CH2:31]4)=[CH:23][N:22]=3)=[O:20])[CH:14]=[CH:15][C:16]=2[F:17])[N:7]=1

Participants

6

Reactant 4

HCID 6342AcetonitrileHCID 11430Potassium CarbonateHCID 67149022(1-Fluorocyclopropyl)methanolHCID 117738587N-[3-[(4aR,7aS)-2-Amino-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]oxazin-7 a-yl]-4-fluoro-phenyl]-5-chloro-pyrazine-2-carboxamide

Product 1

HCID 117738365N-[3-[(4aR,7aS)-2-Amino-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]oxazin-7a-yl]-4-fluoro-phenyl]-5-[(1-fluorocyclopropyl)methoxy]pyrazine-2-carboxamide hydrochlorideYield 30%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
150 °C

Procedure

N-[3-[(4aR,7aS)-2-Amino-4a-fluoro-5,7-dihydro-4H-furo[3,4-d][1,3]oxazin-7a-yl]-4-fluoro-phenyl]-5-chloro-pyrazine-2-carboxamide (110 mg, 268. μmol), (1-fluorocyclopropyl)methanol (73 mg, 805 μmol) and potassium carbonate (111 mg, 805.31 μmol) are combined in a microwave vial. Acetonitrile (3 mL) is added and the reaction mixture is heated at 150° C. for 1.5 hours in a microwave reactor. The reaction mixture is diluted with ethyl acetate and the organic layer is washed with saturated aqueous NaHCO3 and water. The combined aqueous layers are extracted twice with ethyl acetate dried with MgSO4 and the solvent removed in vacuo to give the crude product. The crude product is purified by silica gel flash chromatography, eluting with 0-3% (7 N NH3-methanol) in dichloromethane to give the free base of the title product (37 mg, 30%). The free base is dissolved in dichloromethane (2 mL) and treated with hydrochloric acid (1 M in diethyl ether, 80 μL, 80 μmol), and concentrated under reduced pressure to give the title product (39 mg, 29%). ES/MS (m/e): 464 (M+1)

Workup

  1. washthe organic layer is washed with saturated aqueous NaHCO3 and water
  2. extractionThe combined aqueous layers are extracted twice with ethyl acetate
  3. dry with materialdried with MgSO4
  4. customthe solvent removed in vacuo
  5. customto give the crude product
  6. customThe crude product is purified by silica gel flash chromatography
  7. washeluting with 0-3% (7 N NH3-methanol) in dichloromethane

Sources & evidence

ORD record
ord-072943db4e9c4a538c90cfedcbbc93c5
Source dataset
uspto-grants-2015_10
Patent number
US09169271B2

Reaction notes

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