Methylamine → (4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(5,5-dimethyltetrahydrofuran-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine

HRID 1478767Notes

Reaction equation

HRID 1478767 reaction equation
CN.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@:11]12[CH2:20][O:19][C@@H:18]([CH:21]3[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[O:22]3)[CH2:17][C@H:16]1[CH2:15][S:14][C:13]([NH:28]C(=O)C1C=CC=CC=1)=[N:12]2>C(O)C>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@:11]12[CH2:20][O:19][C@@H:18]([CH:21]3[CH2:25][CH2:24][C:23]([CH3:26])([CH3:27])[O:22]3)[CH2:17][C@H:16]1[CH2:15][S:14][C:13]([NH2:28])=[N:12]2

Participants

4

Reactant 2

HCID 6329MethylamineHCID 90253494N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(5, 5-dimethyltetrahydrofuran-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 90253489(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(5,5-dimethyltetrahydrofuran-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

Methylamine (8.0 M in ethanol, 500 μL, 4.0 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(5, 5-dimethyltetrahydrofuran-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C78) (30 mg, 0.062 mmol) in ethanol (500 μL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated to an oil and combined with material derived from a reaction run on 0.01 mmol in a similar manner. Purification via silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane) afforded the product as a white solid. By 1H NMR analysis, this product was a single diastereomer. Yield: 19.9 mg, 72%. LCMS m/z 383.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.31-7.37 (m, 1H), 6.93-7.00 (m, 2H), 4.06 (dd, J=10.9, 2.0 Hz, 1H), 3.89 (ap. q, J=6.6 Hz, 1H), 3.69 (d, J=11.3 Hz, 1H), 3.49-3.54 (m, 1H), 2.86-2.91 (m, 2H), 2.66-2.70 (m, 1H), 1.99-2.09 (m, 2H), 1.65-1.78 (m, 4H), 1.26 (s, 3H), 1.23 (s, 3H).

Workup

  1. concentrationThe mixture was concentrated to an oil
  2. customPurification via silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane)

Sources & evidence

ORD record
ord-4452b1d8d54a4d42aa95ea9341983c17
Source dataset
uspto-grants-2016_08
Patent number
US09403846B2

Reaction notes

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