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

HRID 1496752Notes

Reaction equation

HRID 1496752 reaction equation
N12CCCN=C1CCCCC2.[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH2:20][NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:15][C:14]=1[C@:27]12[CH2:36][O:35][C@@H:34]([CH2:37][F:38])[CH2:33][C@H:32]1[CH2:31][S:30][C:29]([NH:39]C(=O)C1C=CC=CC=1)=[N:28]2>CO>[F:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([CH2:20][NH:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[CH:15][C:14]=1[C@:27]12[CH2:36][O:35][C@@H:34]([CH2:37][F:38])[CH2:33][C@H:32]1[CH2:31][S:30][C:29]([NH2:39])=[N:28]2

Participants

4

Reactant 2

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 86762647N-[(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 86762648(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
70 °C

Procedure

1,8-Diazabicyclo[5.4.0]undec-7-ene (0.084 mL, 0.534 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C27) (0.4064 g, 0.7650 mmol) in methanol (30 mL). The resulting solution was heated to 70° C. until complete consumption of starting material. The reaction mixture was concentrated under reduced pressure to yield product as an orange oily residue. Purification via silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane) afforded the product as a white solid. Yield: 0.273 g (84%). LCMS m/z 428 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.38 (t, J=8.8 Hz, 1H), 6.98 (dd, J=12.2, 9.7 Hz, 1H), 4.42-4.48 (m, 1H), 4.30-4.37 (m, 1H), 4.09 (dd, J=11.2, 2.0 Hz, 1H), 3.86-3.90 (m, 3H), 3.72 (d, J=11.2 Hz, 1H), 3.13-3.18 (m, 2H), 2.90-2.97 (m, 2H), 2.70 (dd, J=12.4, 2.6 Hz, 1H), 1.76-1.87 (m, 1H), 1.52 (ddd, J=13.1, 4.0, 2.3 Hz, 1H).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customto yield product as an orange oily residue
  3. customPurification via silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane)

Sources & evidence

ORD record
ord-d64bf10317b543c28e62544d10a0cd22
Source dataset
uspto-grants-2015_12
Patent number
US09198917B2

Reaction notes

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