Sodium borohydride → Pexmetinib

HRID 1666759Notes

Reaction equation

HRID 1666759 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][CH:33]=[O: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].[BH4-].[Na+]>CO>[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]

Participants

4

Reactant 2

HCID 4311764Sodium borohydrideHCID 575522811-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-((5-fluoro-2-(1-(2-oxoethyl)-1H-indazol-5-yloxy)phenyl)methyl)urea

Product 1

HCID 24765037PexmetinibYield 55.3%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

1-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-((5-fluoro-2-(1-(2-oxoethyl)-1H-indazol-5-yloxy)phenyl)methyl)urea (2.179 g, 3.929 mmol) was suspended in MeOH (40 mL) and treated with sodium borohydride (0.7432 g, 19.64 mmol) portionwise at room temperature. The reaction mixture was stirred at room temperature until complete conversion of the starting material to product was observed by HPLC analysis. The reaction mixture was concentrated under reduced pressure and then diluted with saturated aqueous NH4Cl and extracted into dichloromethane. The organics were dried (MgSO4) and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant 2-6% iPrOH/DCM) to provide 1.21 g (55%) of the desired compound. MS (APCI+) m/z 557 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.97 (s, 1H), 7.68 (d, 1H, J=9.1 Hz), 7.35 (s, 1H), 6.85-7.4 (m, 8H), 6.24 (s, 1H), 4.87 (t, 1H, J=5.4 Hz), 4.43 (t, 1H, J=5.6 Hz), 4.28 (d, 1H, J=5.9 Hz), 3.80 (q, 1H, J=5.5 Hz), 2.35 (s, 3H), 1.25 (s, 9H).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. additiondiluted with saturated aqueous NH4Cl
  3. extractionextracted into dichloromethane
  4. dry with materialThe organics were dried (MgSO4)
  5. concentrationconcentrated under reduced pressure
  6. customto afford the crude material, which
  7. customwas purified by flash column chromatography (eluant 2-6% iPrOH/DCM)

Sources & evidence

ORD record
ord-372c9ad0382244c1b3b8956313cad3e3
Source dataset
uspto-grants-2011_10
Patent number
US08044083B2

Reaction notes

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