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2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 2-benzyl-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methylquinoline

HRID 1618653
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HRID 1618653 반응식
[CH2:1]([C:8]1[C:17]([CH3:18])=[C:16](Cl)[C:15]2[C:10](=[CH:11][C:12]([F:21])=[CH:13][C:14]=2[F:20])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[NH:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:17]([CH3:18])=[C:16]([N:25]2[C:26]3[C:27](=[N:28][CH:29]=[C:30]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH:31]=3)[C:23]([CH3:38])([CH3:22])[CH2:24]2)[C:15]2[C:10](=[CH:11][C:12]([F:21])=[CH:13][C:14]=2[F:20])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
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참가 물질

7

반응물 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596314902-Benzyl-4-chloro-5,7-difluoro-3-methylquinolineHCID 672844994-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-morpholine

생성물 1

HCID 509397332-benzyl-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methylquinoline

시약·촉매·용매 2

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 1140Toluene용매

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온도
95 °C

실험 절차

A screw cap vial was charged with 2-benzyl-4-chloro-5,7-difluoro-3-methylquinoline (37 mg, 0.122 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (36.9 mg, 0.158 mmol), Pd2dba3 (16.7 mg, 0.018 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (17.4 mg, 0.037 mmol), sodium tert-butoxide (35.1 mg, 0.365 mmol), and toluene (1.22 mL). The mixture was heated to 95° C. under N2 for 18 h. The reaction was concentrated and diluted with EtOAc, then washed with saturated aqueous sodium bicarbonate solution, water, brine, and 1M NaOH. The organic layer was dried (MgSO4) and concentrated. The crude product was purified by preparative HPLC (10-70% acetonitrile in water) to give 2-benzyl-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methylquinoline as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.60-7.68 (1H, m), 7.50 (1H, d, J=2.3 Hz), 7.27-7.31 (2H, m), 7.22-7.25 (3H, m), 6.96 (1H, ddd, J=11.9, 9.0, 2.5 Hz), 5.52 (1H, d, J=2.3 Hz), 4.42 (2H, s), 3.79-3.85 (1H, m), 3.68-3.77 (4H, m), 3.56 (1H, d, J=9.0 Hz), 2.89-2.96 (4H, m), 2.19 (3H, s), 1.51 (3H, s), 1.45 (3H, s). Mass Spectrum (ESI) m/e=512.0 (M+1).

후처리

  1. customA screw cap vial
  2. concentrationThe reaction was concentrated
  3. additiondiluted with EtOAc
  4. washwashed with saturated aqueous sodium bicarbonate solution, water, brine, and 1M NaOH
  5. dry with materialThe organic layer was dried (MgSO4)
  6. concentrationconcentrated
  7. customThe crude product was purified by preparative HPLC (10-70% acetonitrile in water)

출처 및 근거

ORD 기록
ord-6e6198e2543a47cfb3a99301ebf67e4b
출처 데이터셋
uspto-grants-2014_07
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08765940B2

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