Dimethylformamide → Tert-butyl 4-(1-(4-cyano-2-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate

HRID 1518471노트

반응식

HRID 1518471 반응식
[O:1]=[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1.CN(C=O)C.[H-].[Na+].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1F)[C:33]#[N:34]>CCOC(C)=O.O>[C:33]([C:32]1[CH:35]=[CH:36][C:37]([N:3]2[CH:4]=[CH:5][C:6]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:7][C:2]2=[O:1])=[C:30]([F:29])[CH:31]=1)#[N:34]

참가 물질

7

반응물 4

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 5872033,4-DifluorobenzonitrileHCID 67366878Tert-butyl 4-(2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate

생성물 1

HCID 57468410Tert-butyl 4-(1-(4-cyano-2-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate수율 58.8%

시약·촉매·용매 2

HCID 962Water용매HCID 8857Ethyl Acetate용매

실험 절차

To a mixture of tert-butyl 4-(2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (730 mg, 2.480 mmol, Step A of Example 132) and DMF (12 mL) at room temperature was added sodium hydride (114 mg, 2.85 mmol). After stirring at room temperature for 1 hr, 3,4-difluorobenzonitrile (345 mg, 2.480 mmol, Aldrich) was added and the reaction mixture was heated at 100° C. for 1.5 hrs and cooled to room temperature. The resulting mixture was diluted with EtOAc and water and the aqueous layer was extracted further with EtOAc (3×). The combined organic extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound (602.4 mg, 58.7%) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.47-7.64 (m, 3 H), 7.10 (d, J=7.70 Hz, 1 H), 6.04 (dd, J=7.70, 2.20 Hz, 1 H), 5.96 (d, J=2.20 Hz, 1 H), 4.41-4.55 (m, 1 H), 3.65-3.80 (m, 2 H), 3.27-3.39 (m, 2 H), 1.91-2.04 (m, 2 H), 1.71-1.84 (m, 2H), 1.48 (s, 9 H). MS (ESI) 358 (M+H-C4 H8).

후처리

  1. temperaturethe reaction mixture was heated at 100° C. for 1.5 hrs
  2. temperaturecooled to room temperature
  3. extractionthe aqueous layer was extracted further with EtOAc (3×)
  4. washThe combined organic extracts were washed with water and brine
  5. dry with materialdried (MgSO4)
  6. customevaporated under reduced pressure
  7. customThe residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes)

출처 및 근거

ORD 기록
ord-04f05274595142868df7601d87b85e28
출처 데이터셋
uspto-grants-2012_07
특허 번호
US08232404B2

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