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 2279730Notes

Reaction equation

HRID 2279730 reaction equation
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

Participants

8

Reactant 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)phosphonate2×

Product 1

HCID 86697687Diethyl (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

Reagents, catalysts & solvents 3

HCID 178477754HCID 178477754, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-c6a121709e3248168cce8f8db6307705
Source dataset
uspto-grants-2015_09
Patent number
US09133224B2

Reaction notes

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