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

HRID 1496767Notes

Reaction equation

HRID 1496767 reaction equation
C(N(CC)CC)C.CS(C)=O.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:40])=[C:17]([C@:19]23[CH2:28][O:27][C@@H:26]([CH2:29][OH:30])[CH2:25][C@H:24]2[CH2:23][S:22][C:21]([NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:20]3)[CH:18]=1>ClCCl.O.[Cl-].[Na+].O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:40])=[C:17]([C@:19]23[CH2:28][O:27][C@@H:26]([CH:29]=[O:30])[CH2:25][C@H:24]2[CH2:23][S:22][C:21]([NH:31][C:32](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:20]3)[CH:18]=1

Participants

7

Reactant 3

HCID 679Dimethyl SulfoxideHCID 8471TriethylamineHCID 86762652N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 86762661N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

Triethylamine (6.94 mL, 50.0 mmol), dimethyl sulfoxide (4.14 mL, 58.3 mmol) and pyridine-sulfur trioxide complex (5.41 g, 33.3 mmol) were added to a solution of N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C33) (2.00 g, 4.17 mmol) in dichloromethane (420 mL). The resulting solution was allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with water (200 mL) and brine (200 mL). The resulting biphasic solution was left stirring at room temperature for 10 minutes. The organic layer was then isolated and the resulting aqueous layer was back extracted with dichloromethane (3×100 mL). The combined organics were washed with water (2×200 mL), aqueous 0.2 N hydrochloric acid (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated. Purification via silica gel chromatography (Gradient: 20% to 100% ethyl acetate in heptane) afforded the product as a white solid. Yield 1.10 g, 55%. 1H NMR (400 MHz, DMSO-d6) characteristic peaks: δ 9.60 (s, 1H), 8.10 (br d, J=7.6 Hz, 2H), 7.47-7.67 (m, 5H), 7.32 (dd, J=12.1, 8.8 Hz, 1H), 4.32 (d, J=9.8 Hz, 1H), 3.07-3.11 (m, 1H), 2.67-2.88 (m, 2H), 1.96-2.00 (m, 1H), 1.67-1.74 (m, 1H).

Workup

  1. waitThe resulting biphasic solution was left
  2. stirringstirring at room temperature for 10 minutes
  3. customThe organic layer was then isolated
  4. extractionthe resulting aqueous layer was back extracted with dichloromethane (3×100 mL)
  5. washThe combined organics were washed with water (2×200 mL), aqueous 0.2 N hydrochloric acid (200 mL) and brine (200 mL)
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification via silica gel chromatography (Gradient: 20% to 100% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-ede15362e4f34bd0bdc69da55ed6cb91
Source dataset
uspto-grants-2015_12
Patent number
US09198917B2

Reaction notes

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