Isopropanol → N-{(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-4-methyl-6-[(propan-2-yloxy)methyl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl}benzamide

HRID 1775740Notes

Reaction equation

HRID 1775740 reaction equation
[CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].Br[CH2:8][C@@H:9]1[O:28][CH2:27][C@:12]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[N:13]=[C:14]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:15][C@H:16]([CH3:17])[C@@H:11]2[CH2:10]1>O1CCCC1>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[C@:12]12[CH2:27][O:28][C@@H:9]([CH2:8][O:4][CH:2]([CH3:3])[CH3:1])[CH2:10][C@H:11]1[C@@H:16]([CH3:17])[S:15][C:14]([NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N:13]2

Participants

5

Reactant 3

HCID 3776IsopropanolHCID 24758Sodium hydrideHCID 90089494N-[(4R,4aR,6R,8aS)-6-(bromomethyl)-8a-(2,4-difluorophenyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 118322866N-{(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-4-methyl-6-[(propan-2-yloxy)methyl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl}benzamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
55 °C

Procedure

2-Propanol (139 μL, 1.82 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 29 mg, 0.73 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred for 30 minutes. A solution of N-[(4R,4aR,6R,8aS)-6-(bromomethyl)-8a-(2,4-difluorophenyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C26) (90 mg, 0.18 mmol) in tetrahydrofuran (0.5 mL) was added, and the reaction mixture was heated at 55° C. for 6 hours. After cooling to room temperature, it was partitioned between saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (25 mL). The aqueous layer was extracted with ethyl acetate (2×25 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 70% ethyl acetate in heptane) provided the product as a white solid. Yield: 39.2 mg, 82.4 μmol, 46%. 1H NMR (400 MHz, CD3OD) δ 8.12 (br d, J=7 Hz, 2H), 7.51-7.57 (m, 1H), 7.39-7.49 (m, 3H), 7.01-7.11 (m, 2H), 4.14 (br d, J=12 Hz, 1H), 3.89 (d, J=11.9 Hz, 1H), 3.78-3.85 (m, 1H), 3.67 (septet, J=6.0 Hz, 1H), 3.48-3.58 (m, 2H), 3.19-3.28 (br m, 1H), 2.96-3.04 (m, 1H), 1.75-1.82 (m, 1H), 1.51-1.64 (m, 1H), 1.25 (d, J=7.0 Hz, 3H), 1.14 (d, J=6.0 Hz, 3H), 1.14 (d, J=6.0 Hz, 3H).

Workup

  1. temperatureAfter cooling to room temperature
  2. customit was partitioned between saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (25 mL)
  3. extractionThe aqueous layer was extracted with ethyl acetate (2×25 mL)
  4. dry with materialthe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-5acc13efe2384e5db67406807ca3b2db
Source dataset
uspto-grants-2016_02
Patent number
US09260455B2

Reaction notes

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