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 1775735Notes

Reaction equation

HRID 1775735 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.[Cl-].[Na+].O>[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 (75.9 mL, 545 mmol) was added 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 (P1) (19 g, 45 mmol) in dichloromethane (908 mL) in an ambient temperature water bath. After 5 minutes, dimethyl sulfoxide (45.2 mL, 636 mmol) was rapidly added, immediately followed by sulfur trioxide pyridine complex (98%, 59.0 g, 363 mmol) in a single portion. The resulting solution was stirred at room temperature for 4 hours, whereupon it was diluted with a 1:1 mixture of saturated aqueous sodium chloride solution and water, and stirred for 10 minutes. The aqueous layer was extracted twice with dichloromethane; the combined organic layers were washed with water until the pH of the aqueous extract was pH 6-7, then were washed twice with 0.2 N hydrochloric acid, and once with saturated aqueous sodium chloride solution. After being dried over sodium sulfate, the organic layer was filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product as a pale yellow solid. Yield: 13.27 g, 31.86 mmol, 71%. 1H NMR (400 MHz, CDCl3) δ 9.71 (br s, 1H), 8.16-8.24 (m, 2H), 7.50-7.56 (m, 1H), 7.36-7.48 (m, 3H), 6.87-6.98 (m, 2H), 4.23 (dd, J=12.2, 1.6 Hz, 1H), 4.09-4.15 (m, 1H), 3.94 (d, J=12.1 Hz, 1H), 3.13-3.22 (m, 1H), 3.04 (dd, J=13.1, 4.0 Hz, 1H), 2.69 (dd, J=13.0, 2.9 Hz, 1H), 2.02-2.15 (m, 1H), 1.92-1.99 (m, 1H).

Workup

  1. stirringstirred for 10 minutes
  2. extractionThe aqueous layer was extracted twice with dichloromethane
  3. washthe combined organic layers were washed with water until the pH of the
  4. extractionaqueous extract
  5. washwere washed twice with 0.2 N hydrochloric acid
  6. dry with materialAfter being dried over sodium sulfate
  7. filtrationthe organic layer was filtered
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-3fbde33bf92548cd9d22780f1c6d12cc
Source dataset
uspto-grants-2016_02
Patent number
US09260455B2

Reaction notes

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