N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide → rel-N-[(4S,4aR,6R,8aS)-6-cyclopropyl-8a-(2,4-difluorophenyl)-4-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

HRID 1478736Notes

Reaction equation

[CH:1]1([C@@H:4]2[O:9][CH2:8][C@@:7]([NH:18][C:19]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[S:20])([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])[C@H:6]([C@@H:30](O)[CH2:31][O:32][CH3:33])[CH2:5]2)[CH2:3][CH2:2]1.C(OC[C@@H]1OC[C@]2(C3C=CC(F)=CC=3F)N=C(NC(=O)C3C=CC=CC=3)SC[C@@H]2C1)C1C=CC=CC=1>>[CH:1]1([C@@H:4]2[O:9][CH2:8][C@:7]3([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=4[F:17])[N:18]=[C:19]([NH:21][C:22](=[O:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[S:20][C@H:30]([CH2:31][O:32][CH3:33])[C@@H:6]3[CH2:5]2)[CH2:2][CH2:3]1

Participants

Reactant 2

HCID 86729526N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

HCID 90253553rel-N-({(3S,4R,6R)-6-cyclopropyl-3-(2,4-difluorophenyl)-4-[(1R)-1-hydroxy-2-methoxyethyl]tetrahydro-2H-pyran-3-yl}carbamothioyl)benzamide

Product 1

HCID 90253558rel-N-[(4S,4aR,6R,8aS)-6-cyclopropyl-8a-(2,4-difluorophenyl)-4-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Procedure

rel-N-({(3S,4R,6R)-6-Cyclopropyl-3-(2,4-difluorophenyl)-4-[(1R)-1-hydroxy-2-methoxyethyl]tetrahydro-2H-pyran-3-yl}carbamothioyl)benzamide (C41) was converted to the product using the method described for synthesis of N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C8) in Preparation P1, except that the reaction was warmed to room temperature and allowed to proceed for 18 hours before work-up. The product was obtained as a solid. Yield: 17 mg, 36 μmol, 51%. LCMS m/z 473.3 [M+H+]. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 8.24 (br d, J=7 Hz, 2H), 7.49-7.54 (m, 1H), 7.36-7.48 (m, 3H), 6.83-6.95 (m, 2H), 4.09 (br d, J=12 Hz, 1H), 3.82 (d, J=12.1 Hz, 1H), 3.62-3.69 (m, 1H), 3.37-3.45 (m, 2H), 3.34 (s, 3H), 3.09-3.16 (m, 1H), 2.94 (ddd, J=10.9, 8.2, 2.3 Hz, 1H), 1.80-1.92 (m, 1H), 1.68-1.76 (m, 1H), 0.50-0.61 (m, 2H), 0.40-0.47 (m, 1H), 0.24-0.31 (m, 1H).

Workup

customThe product was obtained as a solid

Sources & evidence

ORD record: ord-febe4ecbceb14b99bdcf03a2de336fc3
Source dataset: uspto-grants-2016_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09403846B2

Reaction notes

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