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 571759ノート

反応式

HRID 571759 の反応式
[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

参加物

6

反応物 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

生成物 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 hydrochloride収率 30%

試薬・触媒・溶媒 1

HCID 8857Ethyl Acetate溶媒

反応条件

温度
150 °C

実験手順

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)

後処理

  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

出典と根拠

ORDレコード
ord-bcc14db1c0404a3c915c5cc5bc3f70bc
出典データセット
uspto-grants-2015_05
特許番号
US09029367B2

反応ノート

読み込み中…