1,8-Diazabicyclo(5.4.0)undec-7-ene → (4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(oxetan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine

HRID 1478727Notes

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]([CH:30]3[CH2:33][CH2:32][O:31]3)[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]([CH:30]3[CH2:33][CH2:32][O:31]3)[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH2:34])=[N:21]2

Participants

Conditions

Temperature: 80 °C

Procedure

1,8-Diazabicyclo[5.4.0]undec-7-ene (95%, 7.5 mg, 47 μmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(oxetan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C33) (19 mg, 43 μmol) in methanol (0.5 mL), and the reaction mixture was heated at 80° C. for 3.5 hours. After cooling and removal of solvent in vacuo, purification was carried out via reversed phase HPLC (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: 20% to 60% B), providing the product as a gum. Yield: 11.7 mg, 34.4 μmol, 73%. LCMS m/z 341.2 [M+H+]. 1H NMR (600 MHz, DMSO-d6) δ 7.35 (ddd, J=9.2, 9.2, 7.0 Hz, 1H), 7.16-7.22 (m, 1H), 7.07-7.11 (m, 1H), 4.55-4.60 (m, 1H), 4.46-4.51 (m, 1H), 4.34-4.38 (m, 1H), 3.90 (dd, J=10.5, 2.2 Hz, 1H), 3.64-3.69 (m, 1H), 3.59 (d, J=10.1 Hz, 1H), 2.46-2.75 (m, 5H), 1.54-1.62 (m, 1H), 1.36-1.41 (m, 1H).

Workup

temperatureAfter cooling
customremoval of solvent
customin vacuo, purification

Sources & evidence

ORD record: ord-5816db09cca347798d4dbcfb0ea0a970
Source dataset: uspto-grants-2016_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09403846B2

Reaction notes

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