1,8-Diazabicyclo(5.4.0)undec-7-ene → (4aR,6S,8aS)-8a-(2,4-difluorophenyl)-6-(2-methylpropyl)-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-2-amine

HRID 1775744Notes

Reaction equation

HRID 1775744 reaction equation
N12CCCN=C1CCCCC2.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH:34]C(=O)C1C=CC=CC=1)=[N:21]2>CO>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH2:34])=[N:21]2

Participants

4

Reactant 2

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 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

Product 1

HCID 73388368(4aR,6S,8aS)-8a-(2,4-difluorophenyl)-6-(2-methylpropyl)-4a,5,6,8-tetrahydro-4H-pyrano[3,4-d][1,3]thiazin-2-amine

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
60 °C

Procedure

1,8-Diazabicyclo[5.4.0]undec-7-ene (3.0 μL, 20 μmol) was added to a solution of 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 (C29) (10.5 mg, 23.6 μmol) in methanol (0.4 mL) and the reaction mixture was heated at 60° C. for 18 hours in a sealed vial. Solvent was removed under a stream of nitrogen, and the residue was partitioned between water (3 mL) and ethyl acetate (5 mL). The aqueous layer was extracted with ethyl acetate (5 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification was carried out via reversed phase high-performance liquid chromatography (Column: Waters XBridge C18, 5 μm; Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 30% to 100% B). Yield: 4.2 mg, 12 μmol, 51%. LCMS m/z 341.1 [M+H+]. 1H NMR (600 MHz, DMSO-d6) δ 7.31-7.36 (m, 1H), 7.15-7.20 (m, 1H), 7.08 (ddd, J=9, 8, 2 Hz, 1H), 3.86 (dd, J=10.5, 1.8 Hz, 1H), 3.54 (d, J=10.5 Hz, 1H), 3.50-3.56 (m, 1H), 2.62-2.73 (m, 3H), 1.71-1.79 (m, 1H), 1.52-1.60 (m, 1H), 1.45-1.50 (m, 1H), 1.40 (ddd, J=14, 8, 6 Hz, 1H), 1.21 (ddd, J=14, 8, 4.5 Hz, 1H), 0.89 (d, J=6.1 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H).

Workup

  1. customSolvent was removed under a stream of nitrogen
  2. customthe residue was partitioned between water (3 mL) and ethyl acetate (5 mL)
  3. extractionThe aqueous layer was extracted with ethyl acetate (5 mL)
  4. dry with materialthe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification

Sources & evidence

ORD record
ord-dff0ac0c87eb431da1268ff0d43e4f02
Source dataset
uspto-grants-2016_02
Patent number
US09260455B2

Reaction notes

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