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

HRID 1775715Notes

Reaction equation

HRID 1775715 reaction equation
B(Cl)(Cl)Cl.C([O:12][CH2:13][C@@H:14]1[O:32][CH2:31][C@:17]2([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[F:40])[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20][CH2:21][C@@H:16]2[CH2:15]1)C1C=CC=CC=1.CO>ClCCl>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[C@:17]12[CH2:31][O:32][C@@H:14]([CH2:13][OH:12])[CH2:15][C@H:16]1[CH2:21][S:20][C:19]([NH:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[N:18]2

Participants

5

Reactant 3

HCID 887MethanolHCID 25135Boron TrichlorideHCID 86729526N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 86729527N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Boron trichloride (1 M solution in heptane, 89.7 mL, 89.7 mmol) was added to a 0° C. solution of N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C8) (15.20 g, 29.89 mmol) in dichloromethane (150 mL). After 15 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. Methanol (50 mL) was then added, first drop-wise {Caution: violent reaction} and then at a steady rate, while the interior of the flask was flushed with nitrogen gas. The mixture was heated at reflux for 30 minutes, cooled to room temperature and concentrated in vacuo. The residue was again dissolved in methanol, stirred, and concentrated in vacuo. The resulting material was taken up in dichloromethane and washed sequentially with 1 M aqueous sodium hydroxide solution, water, and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Chromatographic purification on silica gel (Gradient: 0% to 3% methanol in ethyl acetate) provided the product as a yellow foam. Yield: 11.97 g, 28.60 mmol, 96%. LCMS m/z 419.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.13 (d, J=7.4 Hz, 2H), 7.50-7.56 (m, 1H), 7.41-7.49 (m, 3H), 7.02-7.11 (m, 2H), 4.13 (dd, J=11.9, 1.8 Hz, 1H), 3.90 (d, J=12.1 Hz, 1H), 3.72-3.80 (m, 1H), 3.59 (d, J=5.1 Hz, 2H), 3.14-3.24 (br m, 1H), 2.96 (dd, half of ABX pattern, J=13.1, 4.1 Hz, 1H), 2.75 (dd, half of ABX pattern, J=13.1, 2.7 Hz, 1H), 1.80-1.92 (m, 1H), 1.70 (ddd, J=13.4, 4.2, 2.4 Hz, 1H).

Workup

  1. customfirst drop-wise {Caution: violent reaction}
  2. customat a steady rate, while the interior of the flask was flushed with nitrogen gas
  3. temperatureThe mixture was heated
  4. temperatureat reflux for 30 minutes
  5. temperaturecooled to room temperature
  6. concentrationconcentrated in vacuo
  7. dissolutionThe residue was again dissolved in methanol
  8. stirringstirred
  9. concentrationconcentrated in vacuo
  10. washwashed sequentially with 1 M aqueous sodium hydroxide solution, water, and saturated aqueous sodium chloride solution
  11. dry with materialThe organic layer was dried over magnesium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure
  14. customChromatographic purification on silica gel (Gradient: 0% to 3% methanol in ethyl acetate)

Sources & evidence

ORD record
ord-0674351c5aa946129dc13a39409057e3
Source dataset
uspto-grants-2016_02
Patent number
US09260455B2

Reaction notes

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