Hydrochloric Acid → Pexmetinib hydrochloride

HRID 922342Notes

Reaction equation

HRID 922342 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]>C(O)(C)C>[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 2

HCID 313Hydrochloric AcidHCID 24765037Pexmetinib

Product 1

HCID 71712232Pexmetinib hydrochloride

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
25 °C

Procedure

A reactor was charged with 2-(5-(2-(aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol (12.13 kg, 40.27 mol) and phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (14.00 kg, 40.07 mol). The solids were suspended in isopropanol (172.8 kg, 220 L). The suspension was heated from 20° C. to 35° C. and stirred at 35-40° C. for 5 hours to form 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea. The solution was cooled to 25° C. and subsequently polish filtered. To the filtered solution of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea in isopropanol was added HCl (4.80 kg of 32% aqueous HCl, 1.05 eq.) through a polish filter at 22-23° C., and the mixture was stirred at 18-23° C. overnight (14 hours). The bulk solution was seeded with 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 B by adding 20.0 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 B suspended in 300-400 mL of isopropanol to the bulk solution. The mixture was stirred for 3 days (convenience). Analysis showed complete crystallization, at which time 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 From B was isolated by filtration. The product was washed with isopropanol (64 kg, 81.4 L) added via polish filter in portions and dried under vacuum at 55° C. for about 28 hours to provide 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 B (92.3% yield). Methods used to characterize this material are described in Examples 2-F and 2-G. Form B prepared according to this method was anhydrous, as confirmed by single X-ray crystallography.

Workup

  1. filtrationsubsequently polish filtered
  2. filtrationfilter at 22-23° C.
  3. additionby adding 20.0 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 B
  4. stirringThe mixture was stirred for 3 days (convenience)
  5. customcrystallization

Sources & evidence

ORD record
ord-2c144b56376b4cabb12e7f02ca2c9e97
Source dataset
uspto-grants-2016_03
Patent number
US09278936B2

Reaction notes

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