Hydrogen Peroxide → HCID 57552289, compound

HRID 1666000Notes

Reaction equation

HRID 1666000 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([CH2:32][CH2:33][OH:34])[N:27]=[CH:26]3)=[O:12])[N:7]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.Cl.N1C=CN=C1.C(N(C(C)C)[P:57]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])(C)C.OO.[O-:73]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.ClCCl>[P:57]([O:34][CH2:33][CH2:32][N:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[CH2:14][NH:13][C:11]([NH:10][C:8]3[N:7]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=3)=[O:12])=[CH:31][CH:30]=2)[CH:26]=[N:27]1)([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])([O:63][C:64]([CH3:65])([CH3:66])[CH3:67])=[O:73]

Participants

9

Reactant 6

HCID 784Hydrogen PeroxideHCID 795ImidazoleHCID 24477Sodium ThiosulfateHCID 853005Di-tert-butyl N,N-DiisopropylphosphoramiditeHCID 10197644Imidazolium chlorideHCID 24765037Pexmetinib

Product 1

HCID 57552289HCID 57552289, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-((5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)phenyl)methyl)urea (1.5 g, 2.69 mmol) in DMF (0.2M, 15 mL) was treated with imidazole (183 mg, 2.69 mmol), and imidazole hydrochloride (423 mg, 4.04 mmol) at room temperature. After complete dissolution was observed, di-tert-butyl diisopropylphosphoramidite (1.28 mL, 4.04 mmol) was added. Stirring was continued at room temperature for 18 hours. Hydrogen peroxide (50% aqueous, 0.535 mL, 9.43 mmol) was added at room temperature slowly, and stirring was continued for 1 hour. The reaction was completed as detected by LC and TLC. The residue was distributed between dichloromethane and 10% aqueous Na2S2O3. The aqueous layer was extracted with EtOAc (2×). The combined organic extracts were washed with brine, filtered through 1PS paper, evaporated in vacuo to yellow oil. The oil was purified by a silica gel plug eluting with DCM, 3-5% MeOH/DCM. Desired fractions were evaporated in vacuo to provide the desired product as a white foam, 1.59 g (79%). MS (APCI+) m/z 749 (M+) was detected. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (s, 1H), 7.73 (d, 1H, J=9.1 Hz), 6.79-7.35 (m, 8H), 6.23 (s, 1H), 4.62 (t, 2H, J=4.7 Hz), 4.26 (m, 4H), 2.35 (s, 3H), 1.43, s, 9H), 1.25 (s, 18H).

Workup

  1. dissolutionAfter complete dissolution
  2. stirringstirring
  3. waitwas continued for 1 hour
  4. extractionThe aqueous layer was extracted with EtOAc (2×)
  5. washThe combined organic extracts were washed with brine
  6. filtrationfiltered through 1PS paper
  7. customevaporated in vacuo to yellow oil
  8. customThe oil was purified by a silica gel plug
  9. washeluting with DCM, 3-5% MeOH/DCM
  10. customDesired fractions were evaporated in vacuo

Sources & evidence

ORD record
ord-1cdc1d3f45e34730aa2a803d3d59ac18
Source dataset
uspto-grants-2011_10
Patent number
US08039639B2

Reaction notes

Loading…