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

HRID 68414Notes

Reaction equation

HRID 68414 reaction equation
[CH2:1]([O:8][CH2:9][C@@H:10]1[O:15][CH2:14][C@@:13]([NH:24][C:25]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[S:26])([C:16]2[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=2[F:23])[C@H:12]([CH2:36]O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:15][CH2:14][C@:13]2([C:16]3[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=3[F:23])[N:24]=[C:25]([NH:27][C:28](=[O:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[S:26][CH2:36][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 1049PyridineHCID 67749Trifluoromethanesulfonic anhydrideHCID 86721303N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(5-bromo-2-fluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide

Product 1

HCID 86762651N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A solution of N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(5-bromo-2-fluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C31) (9.49 g, 16.2 mmol) and pyridine (4.94 mL, 61.4 mmol) in dichloromethane (278 mL) was cooled to −50° C. Trifluoromethanesulfonic anhydride (5.44 mL, 32.3 mmol) was added drop-wise to the solution and the mixture was gradually warmed to 0° C. After 2 hours, the reaction mixture was partitioned between dichloromethane (1 L) and water (500 mL). The organic layer was washed with dichloromethane (2×250 mL) and the combined organics were then washed with brine (500 mL). The resulting organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to yield an orange oily residue. Purification via silica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane) afforded the product as an orange solid. Yield: 5.53 g, 60%. LCMS m/z 571.2 [M+H+]. 1H NMR (400 MHz, CD3OD) characteristic peaks: δ 8.12 (d, J=7.4 Hz, 2H), 7.43-5.58 (m, 5H), 7.12-7.32 (m, 6H), 4.51-4.60 (m, 2H), 4.10-4.13 (m, 1H), 3.87-3.91 (m, 1H), 3.55-3.63 (m, 2H), 3.18-3.21 (m, 1H), 2.94 (dd, J=13.2, 4.0 Hz, 1H), 2.74 (dd, J=13.1, 2.9 Hz, 1H), 1.90-1.99 (m, 1H), 1.67-1.72 (m, 1H).

Workup

  1. customthe reaction mixture was partitioned between dichloromethane (1 L) and water (500 mL)
  2. washThe organic layer was washed with dichloromethane (2×250 mL)
  3. washthe combined organics were then washed with brine (500 mL)
  4. dry with materialThe resulting organic layer was dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto yield an orange oily residue
  8. customPurification via silica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-77d95aa22b5c47968258573d61f80a62
Source dataset
uspto-grants-2014_09
Patent number
US08822456B2

Reaction notes

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