Water → 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

HRID 1775714Notes

Reaction equation

HRID 1775714 reaction equation
N1C=CC=CC=1.[CH2:7]([O:14][CH2:15][C@@H:16]1[O:21][CH2:20][C@@:19]([NH:30][C:31]([NH:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[S:32])([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[C@H:18]([CH2:42]O)[CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>ClCCl>[CH2:7]([O:14][CH2:15][C@@H:16]1[O:21][CH2:20][C@:19]2([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])[N:30]=[C:31]([NH:33][C:34](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[S:32][CH2:42][C@@H:18]2[CH2:17]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1

Participants

6

Reactant 4

HCID 962WaterHCID 1049PyridineHCID 67749Trifluoromethanesulfonic anhydrideHCID 86701080N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide

Product 1

HCID 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

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-55 °C

Procedure

Pyridine (11.0 mL, 137 mmol) was added to a solution of N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C7) (19.00 g, 36.08 mmol) in dichloromethane (150 mL), and the resulting solution was cooled to −50 to −60° C. Trifluoromethanesulfonic anhydride (12.1 mL, 71.9 mmol) in dichloromethane (50 mL) was added drop-wise, and the reaction mixture was gradually warmed to −5° C. over 3 hours. Water was added, and the aqueous layer was extracted with dichloromethane; the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 20% to 40% ethyl acetate in heptane) provided the product as a yellow foam. Yield: 15.51 g, 30.50 mmol, 85%. LCMS m/z 509.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.23 (br d, J=7 Hz, 2H), 7.37-7.57 (br m, 4H), 7.24-7.36 (m, 5H), 6.85-6.97 (m, 2H), 4.58 (AB quartet, upfield signals are slightly broadened, JAB=11.9 Hz, ΔνAB=23.5 Hz, 2H), 4.17 (br d, J=12 Hz, 1H), 3.90-3.97 (m, 1H), 3.83 (br d, J=12 Hz, 1H), 3.64 (dd, half of ABX pattern, J=10.1, 6.4 Hz, 1H), 3.50 (dd, half of ABX pattern, J=10.2, 4.4 Hz, 1H), 3.11-3.21 (br m, 1H), 3.02 (dd, J=12.9, 4.1 Hz, 1H), 2.64 (br d, J=13 Hz, 1H), 1.92-2.05 (br m, 1H), 1.71 (br d, J=13 Hz, 1H).

Workup

  1. temperaturethe reaction mixture was gradually warmed to −5° C. over 3 hours
  2. extractionthe aqueous layer was extracted with dichloromethane
  3. washthe combined organic layers were washed with saturated aqueous sodium chloride solution
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification via silica gel chromatography (Gradient: 20% to 40% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-74dbcaae1aa64aa7a45714fadd78dffb
Source dataset
uspto-grants-2016_02
Patent number
US09260455B2

Reaction notes

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