1,8-Diazabicyclo(5.4.0)undec-7-ene → (4aS,5S,7aS)-7a-(2,4-Difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

HRID 68377Notes

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[CH2:28][O:27][C@H:26]([CH2:29][F:30])[C@H:25]1[CH2:24][S:23][C:22]([NH:31]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[CH2:28][O:27][C@H:26]([CH2:29][F:30])[C@H:25]1[CH2:24][S:23][C:22]([NH2:31])=[N:21]2

Participants

Conditions

Temperature: 65 °C

Procedure

1,8-Diazabicyclo[5.4.0]undec-7-ene (0.99 mL, 6.6 mmol) was added to a stirred suspension of N-((4aS,5S,7aS)-7a-(2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (1.34 g, 3.30 mmol) in dry MeOH (10 mL) at RT under nitrogen. The reaction was stirred and heated at 65° C. overnight, under nitrogen. The reaction was allowed to cool to RT and the volatiles were removed in vacuo. The residue was purified by column chromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mL per min, gradient 20% to 100% EtOAc in n-hexane) to give the title compound (1.04 g). 1H NMR (400 MHz, CDCl3) δ ppm: 2.78 (dd, J=13.33, 4.03 Hz, 1 H) 2.93-3.01 (m, 1 H) 3.09 (dd, J=13.39, 3.61 Hz, 1 H) 3.83 (dd, J=8.44, 2.45 Hz, 1 H) 4.44-4.56 (m, 3 H) 4.62 (d, J=4.40 Hz, 1 H) 6.75-6.92 (m, 2 H) 7.36-7.47 (m, 1 H).

Workup

temperatureto cool to RT
customthe volatiles were removed in vacuo
customThe residue was purified by column chromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mL per min, gradient 20% to 100% EtOAc in n-hexane)

Sources & evidence

ORD record: ord-9abf0d69e69e4c3ca0fb8676f31c90e7
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08822455B2

Reaction notes

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