Acetic Anhydride → [(4aR,8aS)-2-(benzoylamino)-8a-(2,4-difluorophenyl)-4a,5,8,8a-tetrahydropyrano[3,4-d][1,3]thiazin-6(4H)-ylidene]methyl acetate

HRID 590600Notes

Reaction equation

HRID 590600 reaction equation
[C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]12[CH2:25][O:24][C@@H](C=O)[CH2:22][C@H:21]1[CH2:20][S:19][C:18]([NH:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N:17]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:5]([O:4][CH:1]=[C:2]1[O:24][CH2:25][C@:16]2([C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[F:8])[N:17]=[C:18]([NH:28][C:29](=[O:36])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[S:19][CH2:20][C@@H:21]2[CH2:22]1)(=[O:7])[CH3:6]

Participants

5

Reactant 3

HCID 7918Acetic AnhydrideHCID 11430Potassium CarbonateHCID 89889275N-[(4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Product 1

HCID 123599379[(4aR,8aS)-2-(benzoylamino)-8a-(2,4-difluorophenyl)-4a,5,8,8a-tetrahydropyrano[3,4-d][1,3]thiazin-6(4H)-ylidene]methyl acetate

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

Acetic anhydride (1.5 mL, 16 mmol) was added to a slurry of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P3) (661 mg, 1.59 mmol) and potassium carbonate (1.34 g, 9.70 mmol) in acetonitrile (16 mL). After the flask had been flushed with nitrogen, the reaction mixture was heated at reflux for 2.5 hours, then allowed to cool to room temperature and stir for 18 hours. The slurry was diluted with ethyl acetate and filtered; the solids were washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a white solid, which was assigned as a roughly 4:1 mixture of geometric isomers from the 1H NMR. Yield: 437 mg, 0.953 mmol, 60%. LCMS m/z 459.1 [M+H+]. 1H NMR (400 MHz, CDCl3), major isomer only: δ 8.09-8.32 (br s, 2H), 7.50-7.56 (m, 1H), 7.39-7.45 (m, 3H), 6.85-6.99 (m, 2H), 6.75 (d, J=1.9 Hz, 1H), 4.31 (dd, J=11.7, 1.2 Hz, 1H), 4.02 (d, J=11.8 Hz, 1H), 3.13-3.26 (m, 1H), 2.97-3.07 (m, 1H), 2.70-2.87 (m, 2H), 2.19 (s, 3H), 2.17-2.25 (m, 1H).

Workup

  1. customAfter the flask had been flushed with nitrogen
  2. temperaturethe reaction mixture was heated
  3. temperatureat reflux for 2.5 hours
  4. additionThe slurry was diluted with ethyl acetate
  5. filtrationfiltered
  6. washthe solids were washed with ethyl acetate
  7. concentrationthe combined filtrates were concentrated in vacuo
  8. customPurification

Sources & evidence

ORD record
ord-f416cc35fab640d5b6c4ab63dd65a0c5
Source dataset
uspto-grants-2016_01
Patent number
US09233981B1

Reaction notes

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