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

HRID 1496754Notes

Reaction equation

HRID 1496754 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:4][C:3]=1[C@:16]12[CH2:25][O:24][C@@H:23]([CH3:26])[CH2:22][C@H:21]1[CH2:20][S:19][C:18]([NH:27]C(=O)C1C=CC=CC=1)=[N:17]2.FC1C=C(F)C(CNCC(F)(F)F)=CC=1[C@]12CO[C@@H](CF)C[C@H]1CSC(N)=N2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][NH:10][CH2:11][C:12]([F:14])([F:15])[F:13])=[CH:4][C:3]=1[C@:16]12[CH2:25][O:24][C@@H:23]([CH3:26])[CH2:22][C@H:21]1[CH2:20][S:19][C:18]([NH2:27])=[N:17]2

Participants

3

Reactant 2

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-amineHCID 86762649N-[(4aR,6S,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 86762650(4aR,6S,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine

Procedure

N-[(4aR,6S,8aS)-8a-(2,4-Difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C28) was converted to the product according to the method described for the synthesis of (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 (8) in Example 8. Purification via silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane) afforded the product as a white solid. Yield: 12 mg, 25%. LCMS m/z 410 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.39 (t, J=8.7 Hz, 1H), 7.00 (dd, J=12.3, 9.6 Hz, 1H), 4.07 (dd, J=11.3, 2.0 Hz, 1H), 3.70-3.79 (m, 2H), 3.18 (q, J=9.3 Hz, 2H), 2.91-3.02 (m, 2H), 2.73 (dd, J=12.5, 2.7 Hz, 1H), 1.58-1.73 (m, 2H), 1.24 (d, J=8.0 Hz, 3H).

Workup

  1. customPurification via silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane)

Sources & evidence

ORD record
ord-8e24cf1a2c3f4ab392f01056e00f1dc0
Source dataset
uspto-grants-2015_12
Patent number
US09198917B2

Reaction notes

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