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

HRID 1775728Notes

Reaction equation

HRID 1775728 reaction equation
C(N(S(F)(F)[F:7])CC)C.CCCCC.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@:23]12[CH2:32][O:31][C@@H:30]([CH2:33]O)[CH2:29][C@H:28]1[C@@H:27]([CH3:35])[S:26][C:25]([NH:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[N:24]2>ClCCl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@:23]12[CH2:32][O:31][C@@H:30]([CH2:33][F:7])[CH2:29][C@H:28]1[C@@H:27]([CH3:35])[S:26][C:25]([NH:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[N:24]2

Participants

5

Reactant 3

HCID 8003PentaneHCID 123472(Diethylamino)sulfur trifluorideHCID 89889267N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 90089501N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(fluoromethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(Diethylamino)sulfur trifluoride (126 μL, 0.954 mmol) was added to a 0° C. solution of pentane (8 mL) and dichloromethane (5 mL). To this mixture was added N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P2) (275 mg, 0.636 mmol) drop-wise over 10 minutes. The ice bath was removed, and the reaction mixture was allowed to warm to room temperature. After 6 hours, it was diluted with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (3×35 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a white solid. Yield: 154 mg, 0.354 mmol, 56%. 1H NMR (400 MHz, CD3OD) δ 8.08-8.16 (m, 2H), 7.51-7.58 (m, 1H), 7.40-7.50 (m, 3H), 7.01-7.11 (m, 2H), 4.34-4.55 (m, 2H), 4.17 (br d, J=12 Hz, 1H), 3.92 (d, J=11.9 Hz, 1H), 3.9-4.02 (m, 1H), 3.18-3.28 (br m, 1H), 2.98-3.08 (br m, 1H), 1.73-1.81 (m, 1H), 1.55-1.67 (m, 1H), 1.26 (d, J=7.0 Hz, 3H).

Workup

  1. customThe ice bath was removed
  2. additionit was diluted with saturated aqueous sodium bicarbonate solution (20 mL)
  3. extractionextracted with dichloromethane (3×35 mL)
  4. dry with materialThe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-1ea769d2665e46409e0bfb83cb0e409e
Source dataset
uspto-grants-2016_02
Patent number
US09260455B2

Reaction notes

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