2-(Dimethylamino)ethanol → 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)4-(2-dimethylamino-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea

HRID 407496Notes

Reaction equation

HRID 407496 reaction equation
[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46]

Participants

6

Reactant 4

HCID 79022-(Dimethylamino)ethanolHCID 11776TriphenylphosphineHCID 75555Diisopropyl diazene-1,2-dicarboxylateHCID 1356979371-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)-urea

Product 1

HCID 231395191-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)4-(2-dimethylamino-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-ureaYield 45.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 1-[3-(4-chloro-2-methyl-2H-pyrazol-3yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)urea (see above) (0.035 g, 0.09 mmol) in THF (3 mL), triphenyl phosphine (0.071 g, 0.27 mmol) and 2-dimethylamino ethanol (27.1 μL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (52.3 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was purified via preparative HPLC. The corresponding fractions were collected, neutralized with 1N NaOH and extracted with EtOAc. A second purification by flash chromatography (SiO2, CH2Cl2/MeOH gradient elution) afforded Compound 132 as an off-white solid in 45.9% yield. LCMS m/z (%)=450 (M+H 35Cl, 100), 452 (M+H 37Cl, 32). 1H NMR (400 MHz. DMSO-d6) δ: 9.11 (s, 1H), 8.56 (s, 1H), 8.06-8.00 (m, 1H), 7.60 (s, 1H), 7.52 (d, J=8.95 Hz, 1H), 7.38 (s, 1H), 7.33-7.27 (m, 1H), 7.17 (d, J=9.04 Hz, 1H), 7.05-6.98 (m, 1H), 4.12-3.95 (m, 2H), 3.65 (s, 3H), 2.55-2.51 (m, 2H), 2.10 (s, 6H).

Workup

  1. concentrationconcentrated
  2. customto give a crude product that
  3. customwas purified via preparative HPLC
  4. customThe corresponding fractions were collected
  5. extractionextracted with EtOAc
  6. customA second purification
  7. washby flash chromatography (SiO2, CH2Cl2/MeOH gradient elution)

Sources & evidence

ORD record
ord-5a8a4ea093ea488b931a96ba1dbb466b
Source dataset
uspto-grants-2014_06
Patent number
US08754238B2

Reaction notes

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