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

HRID 2168266Notes

Reaction equation

HRID 2168266 reaction equation
[CH2:1]([O:8][CH2:9][C@@H:10]1[O:15][CH2:14][C@@:13]([NH:25][C:26]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[S:27])([C:16]2[CH:21]=[C:20]([Br:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[C@H:12]([CH2:37]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])[C:19]([F:23])=[CH:18][C:17]=3[F:24])[N:25]=[C:26]([NH:28][C:29](=[O:36])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[S:27][CH2:37][CH: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 86721297N-[((3S,4R,6R)-6-((benzyloxy)methyl)-3-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamothioyl]benzamide

Product 1

HCID 86762635N-[(6R)-6-[(benzyloxy)methyl]-8a-(5-bromo-2,4-difluorophenyl)-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 C8 (0.964 g, 1.59 mmol) and pyridine (0.487 ml, 6.05 mmol) in dichloromethane (27.0 mL) was cooled to −50° C. internal temperature. Trifluoromethanesulfonic anhydride (0.535 mL, 3.18 mmol) was added drop-wise to the solution and the mixture was gradually warmed to 0° C. and allowed to stir at that temperature for 3.5 hours. The reaction mixture was partitioned between dichloromethane (250 mL) and water (250 mL). The organic layer was removed and washed with water (2×300 mL) and brine (1×250 mL), then dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Gradient 0% to 50% ethyl acetate in heptane) provided the product as a white solid. Yield: 822 mg, 1.40 mmol, 88%. LCMS m/z 589.6 [M+H+], Br isotopic pattern. 1H NMR (400 MHz, CD3OD), characteristic peaks: δ 8.05-8.16 (m, 2H), 7.62 (t, J=7.9 Hz, 1H), 7.61-7.67 (m, 1H), 7.42-7.49 (m, 2H), 7.28-7.33 (m, 2H), 7.16-7.25 (m, 3H), 4.58 (d, J=11.7 Hz, 1H), 4.52 (d, J=11.7 Hz, 1H), 4.07 (dd, J=11.9, 1.6 Hz, 1H), 3.89 (br d, J=11.9 Hz, 2H), 3.54-3.62 (m, 2H), 3.11-3.18 (m, 1H), 2.96 (dd, J=13.2, 4.2 Hz, 1H), 2.74 (dd, J=13.2, 2.8 Hz, 1H), 1.88-1.98 (m, 1H), 1.69 (d, J=11.7 Hz, 1H).

Workup

  1. customThe reaction mixture was partitioned between dichloromethane (250 mL) and water (250 mL)
  2. customThe organic layer was removed
  3. washwashed with water (2×300 mL) and brine (1×250 mL)
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-294e9bb2d8be4c72aaee96b21d837500
Source dataset
uspto-grants-2015_06
Patent number
US09045498B2

Reaction notes

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