Hydrochloric Acid → Pexmetinib hydrochloride

HRID 922337Notes

Reaction equation

HRID 922337 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]>>[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

3

Reactant 2

HCID 313Hydrochloric AcidHCID 24765037Pexmetinib

Product 1

HCID 71712232Pexmetinib hydrochlorideYield 89.6%

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 (4.00 g, 7.19 mmol, 1.0 equivalent) was added to a round bottom flask that had been flame dried under a nitrogen atmosphere. THF (50 mL) was added and the mixture was stirred at ambient temperature until the material was dissolved. HCl (4 M in dioxane; 6.40 mL; 25.6 mmol, 3.6 equivalents) was added dropwise with rapid stirring. The mixture was stirred overnight at ambient temperature. The resulting solids were isolated by vacuum filtration and washed with MTBE and then with ether. The solids were dried under vacuum at 50° C. overnight yielding 3.82 g 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 (6.45 mmol, 90% 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 (50 mL) was added
  4. dissolutionwas dissolved
  5. stirringThe mixture was stirred overnight at ambient temperature
  6. customThe resulting solids were isolated by vacuum filtration
  7. washwashed with MTBE
  8. customThe solids were dried under vacuum at 50° C. overnight

Sources & evidence

ORD record
ord-3581ca50b79f48e8b047de1bef7f62cd
Source dataset
uspto-grants-2016_03
Patent number
US09278936B2

Reaction notes

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