Hydrochloric Acid → Pexmetinib hydrochloride

반응식

[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]

참가 물질

반응물 3

HCID 313Hydrochloric Acid

HCID 312751,4-Dioxane

HCID 24765037Pexmetinib

생성물 1

HCID 71712232Pexmetinib hydrochloride

실험 절차

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.