Dimethyl Sulfoxide → N-[(4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

HRID 1478706Notes

Reaction equation

HRID 1478706 reaction equation
C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]12[CH2:25][O:24][C@@H:23]([CH2:26][OH:27])[CH2:22][C@H:21]1[CH2:20][S:19][C:18]([NH:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N:17]2.CS(C)=O>ClCCl.O.[Cl-].[Na+]>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]12[CH2:25][O:24][C@@H:23]([CH:26]=[O:27])[CH2:22][C@H:21]1[CH2:20][S:19][C:18]([NH:28][C:29](=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[N:17]2

Participants

7

Reactant 3

HCID 679Dimethyl SulfoxideHCID 8471TriethylamineHCID 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

Product 1

HCID 89889275N-[(4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 5234Sodium ChlorideSolventHCID 6344DichloromethaneSolvent

Procedure

Triethylamine (16.7 mL, 120 mmol) was added in one portion to a solution of 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 (C9) (4.18 g, 10.0 mmol) in dichloromethane (200 mL) that was immersed in a room temperature water bath. After 5 minutes, anhydrous dimethyl sulfoxide (9.94 mL, 140 mmol) was rapidly added, followed immediately by solid sulfur trioxide pyridine complex (98%, 13.0 g, 80.0 mmol) in a single portion. The resulting solution was stirred at ambient temperature for 6.5 hours, then diluted with a 1:1 mixture of water and saturated aqueous sodium chloride solution (200 mL) and stirred for 10 minutes. The aqueous layer was extracted with dichloromethane (2×200 mL), and the combined organic layers were washed with water (100 mL), washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) gave the product as a white solid. Yield: 2.81 g, 6.75 mmol, 67%. LCMS m/z 414.9 [M−H+]. 1H NMR (400 MHz, CDCl3) δ 9.71 (s, 1H), 8.20 (br d, J=7 Hz, 2H), 7.50-7.56 (m, 1H), 7.36-7.49 (m, 3H), 6.86-6.99 (m, 2H), 4.23 (br d, J=12.1 Hz, 1H), 4.12 (dd, J=12.1, 2.9 Hz, 1H), 3.94 (d, J=12.5 Hz, 1H), 3.13-3.22 (m, 1H), 3.04 (dd, J=13.1, 4.1 Hz, 1H), 2.69 (dd, J=13.1, 2.9 Hz, 1H), 2.02-2.14 (m, 1H), 1.92-1.99 (m, 1H).

Workup

  1. customwas immersed in a room temperature
  2. stirringstirred for 10 minutes
  3. extractionThe aqueous layer was extracted with dichloromethane (2×200 mL)
  4. washthe combined organic layers were washed with water (100 mL)
  5. washwashed with saturated aqueous sodium chloride solution (100 mL)
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-ed55d1c056a94da3b4c15c94c3e1263d
Source dataset
uspto-grants-2016_08
Patent number
US09403846B2

Reaction notes

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