phenyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate → Pexmetinib

HRID 1666003Notes

Reaction equation

HRID 1666003 reaction equation
[NH2:1][CH2:2][C:3]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]2.[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>CC(N(C)C)=O>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:1][CH2:2][C:3]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:4]=2[O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]3)=[O:34])[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]

Participants

4

Reactant 2

HCID 11057211phenyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamateHCID 445421222-(5-(2-(Aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol

Product 1

HCID 24765037Pexmetinib

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent2×

Procedure

To a 4.1° C. solution of 2-(5-(2-(aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol (71.55 g, 237 mmol) in DMA (350 mL) was added a DMA (350 mL) solution of phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (80.5 g, 230 mmol). The temperature rose to 18.4° C. and stabilized. The ice bath was removed and the reaction was stirred for 2 hours. An additional portion of 2-(5-(2-(aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol was added and the reaction was stirred for 2 hours. The reaction mixture was partitioned between isopropyl acetate (1.6 L) and water (2.4 L). The aqueous layer was removed and the organic layer was washed with 0.5 N NaOH (2×2.4 L) and then saturated brine (1×2.4 L). The organic layer was dried over Na2SO4 (300 g) and concentrated to yield 110.8 g (86.6%).

Workup

  1. customrose to 18.4° C.
  2. customThe ice bath was removed
  3. additionAn additional portion of 2-(5-(2-(aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol was added
  4. stirringthe reaction was stirred for 2 hours
  5. customThe reaction mixture was partitioned between isopropyl acetate (1.6 L) and water (2.4 L)
  6. customThe aqueous layer was removed
  7. washthe organic layer was washed with 0.5 N NaOH (2×2.4 L)
  8. dry with materialThe organic layer was dried over Na2SO4 (300 g)
  9. concentrationconcentrated
  10. customto yield 110.8 g (86.6%)

Sources & evidence

ORD record
ord-392efde8fe394eff838b32398456f646
Source dataset
uspto-grants-2011_10
Patent number
US08039639B2

Reaction notes

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