Diisopropylethylamine → tert-butyl ((4aS,5S,7aS)-5-(difluoromethyl)-7a-(2-fluoro-5-(5-methoxypyrazine-2-carboxamido)phenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate

HRID 707699ノート

反応式

HRID 707699 の反応式
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH:17]([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:9]3)[CH:7]=1.[CH3:29][O:30][C:31]1[N:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[PH4+]>C(Cl)Cl>[F:18][CH:17]([F:19])[C@@H:14]1[C@@H:13]2[C@@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:37]([C:34]4[CH:33]=[N:32][C:31]([O:30][CH3:29])=[CH:36][N:35]=4)=[O:38])[CH:3]=[CH:4][C:5]=3[F:28])([N:9]=[C:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[S:11][CH2:12]2)[CH2:16][O:15]1

参加物

6

反応物 4

HCID 81531DiisopropylethylamineHCID 21584439Phosphonium hexafluorophosphateHCID 457898115-Methoxy-2-pyrazinecarboxylic acidHCID 57827488tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate

生成物 1

HCID 86724404tert-butyl ((4aS,5S,7aS)-5-(difluoromethyl)-7a-(2-fluoro-5-(5-methoxypyrazine-2-carboxamido)phenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate収率 48.6%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

実験手順

To a stirred solution of tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (2.70 g) and 5-methoxypyrazine-2-carboxylic acid (1.25 g, described in WO2009/091016), in DCM (30 mL) was added N,N-diisopropylethylamine (3.5 mL) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophosphate (4.2 g). The reaction mixture was stirred at RT for 18 h, concentrated under vacuum to circa 20 mL, and sodium bicarbonate (sat., aq., 100 mL) was added. The mixture was extracted with EtOAc (2×150 mL), the combined organic portions were dried over MgSO4, evaporated and purified by silica gel chromatography (0% to 25% EtOAc in DCM gradient) to afford the title compound (1.74 g) as a white solid. NMR (400 MHz, CDCl3) δ ppm 1.54 (s, 9H), 2.76-2.88 (m, 1H), 2.95-3.28 (m, 1H), 3.34-3.53 (m, 1H), 3.83-3.93 (m, 1H), 4.10 (s, 3H), 4.46-4.68 (m, 2H), 5.98 (dt, J=3.6, 56.8 Hz, 1H), 7.07-7.20 (m, 1H), 7.36-7.48 (m, 1H), 7.96-8.04 (d, J=7.8 Hz, 1H), 8.20 (d, J=1.0 Hz, 1H), 9.04 (d, J=1.3 Hz, 1H), 9.53 (br. s., 1H)

後処理

  1. concentrationconcentrated under vacuum to circa 20 mL, and sodium bicarbonate (sat., aq., 100 mL)
  2. additionwas added
  3. extractionThe mixture was extracted with EtOAc (2×150 mL)
  4. dry with materialthe combined organic portions were dried over MgSO4
  5. customevaporated
  6. custompurified by silica gel chromatography (0% to 25% EtOAc in DCM gradient)

出典と根拠

ORDレコード
ord-7bbf952a837b4377a79ebf090f5ae712
出典データセット
uspto-grants-2015_11
特許番号
US09175013B2

反応ノート

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