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 590600노트

반응식

HRID 590600 반응식
[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]

참가 물질

5

반응물 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

생성물 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

시약·촉매·용매 1

HCID 6342Acetonitrile용매

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-f416cc35fab640d5b6c4ab63dd65a0c5
출처 데이터셋
uspto-grants-2016_01
특허 번호
US09233981B1

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