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 571759노트

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HRID 571759 반응식
[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

참가 물질

6

반응물 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

생성물 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 hydrochloride수율 30%

시약·촉매·용매 1

HCID 8857Ethyl Acetate용매

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온도
150 °C

실험 절차

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)

후처리

  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

출처 및 근거

ORD 기록
ord-bcc14db1c0404a3c915c5cc5bc3f70bc
출처 데이터셋
uspto-grants-2015_05
특허 번호
US09029367B2

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