Hydrochloric Acid → Diethyl 2-(2,2,2-trifluoro-1-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylamino)ethyl)malonate

HRID 2193760노트

반응식

HRID 2193760 반응식
C(O[CH:4]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=4)[S:25][C:18]=23)=[C:12]([F:32])[CH:11]=1)[C:5]([F:8])([F:7])[F:6])C.[C:33]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].[H-].[Na+].Cl>O1CCCC1.CCOC(C)=O.O>[F:8][C:5]([F:6])([F:7])[CH:4]([CH:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:33]([O:41][CH2:42][CH3:43])=[O:40])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=4)[S:25][C:18]=23)=[C:12]([F:32])[CH:11]=1

참가 물질

8

반응물 4

HCID 313Hydrochloric AcidHCID 7761Diethyl MalonateHCID 24758Sodium hydrideHCID 58790399N-(1-Ethoxy-2,2,2-trifluoroethyl)-3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine

생성물 1

HCID 58790129Diethyl 2-(2,2,2-trifluoro-1-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylamino)ethyl)malonate수율 84%

시약·촉매·용매 3

HCID 962Water용매HCID 8028Tetrahydrofuran용매HCID 8857Ethyl Acetate용매

실험 절차

To a solution of 318 (470 mg, 1.01 mmol) and diethyl malonate (0.17 mL, 1.11 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was added sodium hydride (60% in oil, 89 mg, 2.22 mmol). The mixture was heated to reflux for 2 h, cooled, diluted with EtOAc and water and acidified to pH 3 using a 1N HCl solution. The organic layer was separated and the aqueous layer extracted twice with EtOAc. The extracts were combined, dried over sodium sulfate and the solvents were removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent MeOH-dichloromethane, gradient 0:100 to 20:80) to afford 319 (490 mg, 0.84 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.42 (d, J=5.2 Hz, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.24 (t, J=9.2 Hz, 1H), 6.98 (dd, J=13.6, 2.8 Hz, 1H), 6.72 (dd, J=9.2, 2.8 Hz, 1H), 6.62 (d, J=10.0 Hz, 1H), 6.46 (d, J=5.2 Hz, 1H), 5.05-4.95 (m, 1H), 4.23-4.07 (m, 4H), 3.91 (d, J=9.2 Hz, 1H), 3.72 (s, 3H), 1.18 (t, J=7.0 Hz, 3H), 1.11 (t, J=7.0 Hz, 3H). LRMS (M+1) 581.0 (100%).

후처리

  1. temperatureThe mixture was heated
  2. temperatureto reflux for 2 h
  3. temperaturecooled
  4. customThe organic layer was separated
  5. extractionthe aqueous layer extracted twice with EtOAc
  6. dry with materialdried over sodium sulfate
  7. customthe solvents were removed under reduced pressure
  8. customThe residue was purified by column chromatography on silica gel (eluent MeOH-dichloromethane, gradient 0:100 to 20:80)

출처 및 근거

ORD 기록
ord-034a87df859c4355ab501c8da0d671ab
출처 데이터셋
uspto-grants-2012_12
특허 번호
US08329726B2

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