N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(2-methylprop-1-en-1-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide → N-[(4aR,6S,8aS)-8a-(2,4-difluorophenyl)-6-(2-methylpropyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

HRID 1775743Notes

Reaction equation

HRID 1775743 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH:19]=[C:20]([CH3:22])[CH3:21])[CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[N:10]2.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH:23][C:24](=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[N:10]2

Participants

5

Reactant 2

HCID 90089615N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(2-methylprop-1-en-1-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamideHCID 178418361HCID 178418361, compound

Product 1

HCID 90089508N-[(4aR,6S,8aS)-8a-(2,4-difluorophenyl)-6-(2-methylpropyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

A solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(2-methylprop-1-en-1-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C28) (42 mg, 95 μmol) in methanol (28 mL) was treated with palladium on activated carbon [10% by weight (dry), 50% water, 224 mg, 105 μmol] and hydrogenated (35 pounds per square inch of hydrogen) for 20 hours. The reaction mixture was filtered through Celite®, and the filter pad was rinsed with methanol (30 mL). The combined filtrates were concentrated in vacuo and purified via silica gel chromatography (Gradient: 0% to 30% ethyl acetate in heptane) to provide the product as an opaque semi-solid. Yield: 10.9 mg, 24.5 μmol, 26%. LCMS m/z 445.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.24 (br d, J=8 Hz, 2H), 7.48-7.54 (m, 1H), 7.37-7.48 (m, 3H), 6.84-6.96 (m, 2H), 4.11 (dd, J=12.2, 1.5 Hz, 1H), 3.77 (d, J=12.1 Hz, 1H), 3.64-3.72 (m, 1H), 3.09-3.17 (m, 1H), 3.01 (dd, J=12.7, 4.1 Hz, 1H), 2.63 (dd, J=12.7, 2.7 Hz, 1H), 1.86-1.97 (m, 1H), 1.76-1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.23-1.31 (m, 1H), 0.93 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H).

Workup

  1. filtrationThe reaction mixture was filtered through Celite®
  2. washthe filter pad was rinsed with methanol (30 mL)
  3. concentrationThe combined filtrates were concentrated in vacuo
  4. custompurified via silica gel chromatography (Gradient: 0% to 30% ethyl acetate in heptane)
  5. customto provide the product as an opaque semi-solid

Sources & evidence

ORD record
ord-976a622b2a6f4291bbd2a7b5622d3f46
Source dataset
uspto-grants-2016_02
Patent number
US09260455B2

Reaction notes

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