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Dichloromethane → Diethyl (4-{[4-({5-fluoro-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate

HRID 2279730
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HRID 2279730 반응식
Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:13]=[C:12]([NH:20][C:21]3[CH:35]=[CH:34][C:24]([CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:23][C:22]=3[O:36][CH3:37])[N:11]=2)=[C:4]([C:38](=[O:41])[NH:39][CH3:40])[CH:3]=1.CC1(C)C(C)(C)OB([C:50]2[CH:51]=[N:52][N:53]([CH2:55][CH2:56][CH2:57][OH:58])[CH:54]=2)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[F:8][C:7]1[C:2]([C:50]2[CH:51]=[N:52][N:53]([CH2:55][CH2:56][CH2:57][OH:58])[CH:54]=2)=[CH:3][C:4]([C:38](=[O:41])[NH:39][CH3:40])=[C:5]([NH:9][C:10]2[C:15]([C:16]([F:17])([F:19])[F:18])=[CH:14][N:13]=[C:12]([NH:20][C:21]3[CH:35]=[CH:34][C:24]([CH2:25][P:26](=[O:33])([O:27][CH2:28][CH3:29])[O:30][CH2:31][CH3:32])=[CH:23][C:22]=3[O:36][CH3:37])[N:11]=2)[CH:6]=1
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참가 물질

8

반응물 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 671871273-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-olHCID 86697688Diethyl (4-{[4-{[4-bromo-5-fluoro-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate2회

생성물 1

HCID 86697687
Diethyl (4-{[4-({5-fluoro-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate

시약·촉매·용매 3

HCID 178477754HCID 178477754, 화합물촉매HCID 962Water용매HCID 312751,4-Dioxane용매

실험 절차

A suspension of diethyl (4-{[4-{[4-bromo-5-fluoro-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 7C, 400 mg, 0.60 mmol), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E 258 mg, 1.02 mmol), [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (49.17 mg, 0.06 mmol), and potassium carbonate (252 mg, 1.82 mmol) in 1,4-Dioxane (2 mL) and H2O (0.5 mL) was evacuated and purged with nitrogen (3×). The sample was irradiated in the microwave at 100° C. for 1.5 hours. The reaction mixture was filtered. The filtrate was quenched with water (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a brown oil. The crude material was purified on a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→85:15) to afford the title compound as 345 mg of a yellow solid (81%). 1H NMR (DMSO-d6, 400 MHz): δ=11.84 (s, 1H), 8.94 (s, 1H), 8.80 (d, J=4.8 Hz, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 8.16 (d, J=1.5 Hz, 1H), 8.04 (d, J=8.6 Hz, 1H), 7.94 (s, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.02 (s, 1H), 6.86 (ddd, J=1.8, 2.2, 8.4 Hz, 1H), 4.62 (t, J=5.1 Hz, 1H), 4.23 (t, J=7 Hz, 2H), 3.91-4.00 (m, 4H), 3.78 (s, 3H), 3.39-3.45 (m, 2H), 3.19-3.27 (m, 2H), 2.81 (d, J=4.6 Hz, 3H), 1.96 (quin, J=6.6 Hz, 2H), 1.16 (t, J=7.1 Hz, 6H). MS (ESI): m/z 710.22 [M+H]+. UPLC: tR=1.42 min (UPLC-TOF: polar—3 min).

후처리

  1. customwas evacuated
  2. custompurged with nitrogen (3×)
  3. customThe sample was irradiated in the microwave at 100° C. for 1.5 hours
  4. filtrationThe reaction mixture was filtered
  5. customThe filtrate was quenched with water (10 mL)
  6. extractionextracted with EtOAc (20 mL)
  7. washThe organic layer was washed with brine (15 mL)
  8. dry with materialdried over anhydrous Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure to a brown oil
  11. customThe crude material was purified on a Teledyne ISCO Combiflash® Rf system

출처 및 근거

ORD 기록
ord-c6a121709e3248168cce8f8db6307705
출처 데이터셋
uspto-grants-2015_09
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US09133224B2

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