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 1775730Notes

Reaction equation

HRID 1775730 reaction equation
[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

Participants

5

Reactant 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

Product 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

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-b3bf0778059c45c8a21d0e4d56785da6
Source dataset
uspto-grants-2016_02
Patent number
US09260455B2

Reaction notes

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