Methyl iodide → N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(methoxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

HRID 1775730ノート

反応式

HRID 1775730 の反応式
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][OH:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:10]2.[H-].[Na+].I[CH3:34]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH3:34])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[N:10]2

参加物

5

反応物 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 89889267N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

生成物 1

HCID 118322867N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(methoxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒2 回

実験手順

A solution of N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P2) (140 mg, 0.324 mmol) in tetrahydrofuran (2.5 mL) was added to a mixture of sodium hydride (60% in mineral oil, 31 mg, 0.78 mmol) in tetrahydrofuran (5 mL), and the reaction mixture was stirred at room temperature for 25 minutes. To this was added iodomethane (24.3 μL, 0.389 mmol), and the reaction mixture was heated at 41° C. for 6 hours, cooled back to room temperature, and quenched with saturated aqueous ammonium chloride solution (15 mL). After extraction with ethyl acetate (3×20 mL), the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product as a white solid. Yield: 110 mg, 0.246 mmol, 76%. 1H NMR (400 MHz, CD3OD) δ 8.12 (br d, J=7 Hz, 2H), 7.51-7.57 (m, 1H), 7.40-7.50 (m, 3H), 7.02-7.11 (m, 2H), 4.14 (br d, J=11.7 Hz, 1H), 3.90 (d, J=11.9 Hz, 1H), 3.83-3.9 (m, 1H), 3.44-3.54 (m, 2H), 3.37-3.38 (s, 3H), 3.18-3.28 (br m, 1H), 2.96-3.05 (br m, 1H), 1.73-1.81 (m, 1H), 1.51-1.63 (m, 1H), 1.25 (d, J=6.8 Hz, 3H).

後処理

  1. temperaturethe reaction mixture was heated at 41° C. for 6 hours
  2. temperaturecooled back to room temperature
  3. customquenched with saturated aqueous ammonium chloride solution (15 mL)
  4. extractionAfter extraction with ethyl acetate (3×20 mL)
  5. dry with materialthe combined organic layers were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo

出典と根拠

ORDレコード
ord-b3bf0778059c45c8a21d0e4d56785da6
出典データセット
uspto-grants-2016_02
特許番号
US09260455B2

反応ノート

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