Hydrochloric Acid → Pexmetinib hydrochloride

HRID 922336Notes

Reaction equation

HRID 922336 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].[ClH:42].O1CCOCC1>>[ClH:42].[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 3

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 24765037Pexmetinib

Product 1

HCID 71712232Pexmetinib hydrochloride

Procedure

Amorphous 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea (200 mg, 0.359 mmol, 1.0 equivalent) was added to a round bottom flask that had been flame dried under a nitrogen atmosphere. THF (3.0 mL) was added and the mixture was stirred at ambient temperature until the solids were dissolved. HCl in 1,4-dioxane (4M, 135 μL, 0.54 mmol, 1.5 equivalents) was added dropwise with rapid stirring, and the mixture was stirred overnight at ambient temperature. The solids were isolated by vacuum filtration. The solids were washed with methyl tert-butyl ether (MTBE) and then with ether. The solids were dried under vacuum at 40° C. overnight to yield 150 mg 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea hydrochloride Form A (0.252 mmol, 70% theoretical yield). Methods used to characterize this material are described in Examples 1-C and 1-D.

Workup

  1. temperaturehad been flame
  2. customdried under a nitrogen atmosphere
  3. additionTHF (3.0 mL) was added
  4. dissolutionwere dissolved
  5. stirringthe mixture was stirred overnight at ambient temperature
  6. customThe solids were isolated by vacuum filtration
  7. washThe solids were washed with methyl tert-butyl ether (MTBE)
  8. customThe solids were dried under vacuum at 40° C. overnight

Sources & evidence

ORD record
ord-a538b3cd3c4147eea0305df111c20f8d
Source dataset
uspto-grants-2016_03
Patent number
US09278936B2

Reaction notes

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