Hydrochloric Acid → Pexmetinib hydrochloride

HRID 922338Notes

Reaction equation

HRID 922338 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>C(OCC)(=O)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

5

Reactant 3

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 24765037Pexmetinib

Product 1

HCID 71712232Pexmetinib hydrochloride

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

A round bottom was charged with 500 mL ethyl acetate and 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 (50.0 g, 89.8 mmol, 1.0 equivalent). After 10 minutes of stirring at ambient temperature a clear solution was obtained. 4 M HCl in 1,4-dioxane (23.6 mL, 94.3 mmol, 1.05 eq.) was added dropwise. A cloudy solution immediately resulted. The thick suspension was allowed to stir overnight at ambient temperature. The solids were isolated by vacuum filtration and washed with two 50 mL aliquots of ethyl acetate. The solids were suspended in 500 mL THF. The suspension was allowed to stir overnight and vacuum filtered. The solids were dried under vacuum at 50° C. overnight yielding 48.2 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 (81.4 mmol, 91% theoretical yield). Methods used to characterize this material are described in Examples 2-F and 2-G.

Workup

  1. customwas obtained
  2. customA cloudy solution immediately resulted
  3. stirringto stir overnight at ambient temperature
  4. customThe solids were isolated by vacuum filtration
  5. washwashed with two 50 mL aliquots of ethyl acetate
  6. stirringto stir overnight
  7. filtrationvacuum filtered
  8. customThe solids were dried under vacuum at 50° C. overnight
  9. customyielding

Sources & evidence

ORD record
ord-198ae18e4d604ed5aa2e881c08d82e23
Source dataset
uspto-grants-2016_03
Patent number
US09278936B2

Reaction notes

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