2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 1-(7-Fluoro-3-methyl-2-(2-methyl-3-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2',3',5',6'-hexahydrospiro[indole-3,4'-pyran]

HRID 1618526노트

반응식

HRID 1618526 반응식
[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=2)[C:23]=1[CH3:40].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CCOC(C)=O>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:23]([CH3:40])[C:24]([C:33]3[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=3)=[N:25]2)=[CH:30][CH:29]=1

참가 물질

9

반응물 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 672846616-Morpholino-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]HCID 672852274-Chloro-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline

생성물 1

HCID 509390771-(7-Fluoro-3-methyl-2-(2-methyl-3-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2',3',5',6'-hexahydrospiro[indole-3,4'-pyran]

시약·촉매·용매 4

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 962Water용매HCID 1140Toluene용매HCID 8857Ethyl Acetate용매

반응 조건

온도
100 °C

실험 절차

To a stirred solution of 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (86 mg, 0.31 mmol), 4-chloro-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline (90 mg, 0.31 mmol) in toluene (1.7 mL) was added Pd2dba3 (43 mg, 0.047 mmol), XPhos (45 mg, 0.09 mmol) and sodium tert-butoxide (90 mg, 0.94 mmol) and the reaction was heated in the microwave for 1 h at 100° C. After this time the reaction was cooled to rt and treated with EtOAc (100 mL) and water (40 mL). The separated organic layer was washed with NaCl (saturated aqueous solution, 40 mL), dried over MgSO4, filtered and evaporated in vacuo. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1-(7-fluoro-3-methyl-2-(2-methyl-3-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. 1H NMR (400 MHz, chloroform-d) δ ppm 8.59-8.67 (1H, m), 7.84-7.94 (1H, m), 7.76-7.83 (1H, m), 7.59-7.69 (1H, m), 7.27-7.34 (2H, m), 7.11-7.18 (1H, m), 6.28-6.47 (1H, m), 5.48-5.70 (1H, m), 3.97-4.09 (2H, m), 3.85-3.94 (1H, m), 3.68-3.80 (4H, m), 3.48-3.63 (2H, m), 2.89-3.05 (4H, m), 2.36-2.44 (3H, m), 2.09-2.25 (2H, m), 2.05 (4H, dd, J=4.5, 2.3 Hz), 1.90 (1H, dt, J=13.7, 1.2 Hz), 1.72-1.81 (1H, m). Mass Spectrum (ESI) m/e=525 (M+1).

후처리

  1. temperatureAfter this time the reaction was cooled to rt
  2. washThe separated organic layer was washed with NaCl (saturated aqueous solution, 40 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. customevaporated in vacuo
  6. customPurification by reverse phase HPLC (10 to 60% acetonitrile in water)

출처 및 근거

ORD 기록
ord-fd0b43b6c0854ecd9f89fbb2a3702c9e
출처 데이터셋
uspto-grants-2014_07
특허 번호
US08765940B2

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