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

HRID 1775729Notes

Reaction equation

[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][F:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22]C(=O)C1C=CC=CC=1)=[N:10]2.N12CCCN=C1CCCCC2>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][F:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH2:22])=[N:10]2

Participants

Conditions

Temperature: 72 °C

Procedure

N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-(fluoromethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C19) (380 mg, 0.875 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (95%, 138 μL, 0.877 mmol) were combined in methanol (15 mL) and heated at 72° C. for 18 hours. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (Gradient: 45% to 100% ethyl acetate in heptane), affording the product as a white solid. Yield: 266 mg, 0.805 mmol, 92%. LCMS m/z 331.1 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.33 (ddd, J=9.6, 8.8, 6.6 Hz, 1H), 6.92-7.00 (m, 2H), 4.42 (ddd, doublet of [half of ABX pattern], J=47.4, 10.0, 3.3 Hz, 1H), 4.38 (ddd, doublet of [half of ABX pattern], J=48.0, 10.0, 5.5 Hz, 1H), 4.13 (dd, J=11.1, 2.2 Hz, 1H), 3.81-3.93 (m, 1H), 3.74 (d, J=11.1 Hz, 1H), 3.06-3.14 (m, 1H), 2.78 (ddd, J=11.9, 4.1, 3.7 Hz, 1H), 1.43-1.61 (m, 2H), 1.17 (d, J=7.0 Hz, 3H).

Workup

concentrationThe reaction mixture was concentrated in vacuo
custompurified by silica gel chromatography (Gradient: 45% to 100% ethyl acetate in heptane)

Sources & evidence

ORD record: ord-f5567342940b4038af0d6437b447aafa
Source dataset: uspto-grants-2016_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09260455B2

Reaction notes

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