Phosphoric Acid → Povorcitinib Phosphate

HRID 1049153Notes

Reaction equation

HRID 1049153 reaction equation
[C:1]([CH2:3][C:4]1([N:25]2[CH:29]=[C:28]([C:30]3[C:31]([CH3:36])=[N:32][NH:33][C:34]=3[CH3:35])[CH:27]=[N:26]2)[CH2:7][N:6]([C:8]2[C:22]([F:23])=[CH:21][C:11]([C:12]([NH:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:13])=[C:10]([F:24])[CH:9]=2)[CH2:5]1)#[N:2].[P:37](=[O:41])([OH:40])([OH:39])[OH:38].CCCCCCC>CO.C(O)(C)C>[P:37](=[O:38])([OH:41])([OH:40])[OH:39].[C:1]([CH2:3][C:4]1([N:25]2[CH:29]=[C:28]([C:30]3[C:34]([CH3:35])=[N:33][NH:32][C:31]=3[CH3:36])[CH:27]=[N:26]2)[CH2:7][N:6]([C:8]2[C:22]([F:23])=[CH:21][C:11]([C:12]([NH:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:13])=[C:10]([F:24])[CH:9]=2)[CH2:5]1)#[N:2]

Participants

6

Reactant 3

HCID 1004Phosphoric AcidHCID 8900Heptane2×HCID 86280672Povorcitinib

Product 1

HCID 86280671Povorcitinib PhosphateYield 89.9%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 3776IsopropanolSolvent2×

Conditions

Temperature
49.5 °C

Procedure

To a clear solution of 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (405.0 g, 798.1 mmol) in methanol (520.0 mL) and isopropanol (2550.0 mL) at 50° C. was added an aqueous solution of 85% phosphoric acid (119.65 g, 1037.8 mmol) in isopropanol (120.0 mL) over 18 minutes to form a slurry. The resulting slurry was stirred at 50° C. for 1 h. n-Heptane (4050.0 mL) was then added to the slurry over 40 min, while maintaining the internal temperature of the slurry between 46 to 53° C. After the addition of n-heptane, the slurry was gradually cooled to room temperature and stirred at room temperature for 19 h. The solids were then collected by filtration, washed with a mixture of isopropanol and n-heptane (3:10 by volume, 2×700 mL) followed by n-heptane (3×550 mL), and dried under vacuum at room temperature to afford crude 4-[3-(cyanomethyl)-3-(3′,5′-dimethyl-1H,1′H-4,4′-bipyrazol-1-yl)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide phosphoric acid salt (434.6 g, 89.9% yield).

Workup

  1. customto form a slurry
  2. additionwas then added to the slurry over 40 min
  3. temperaturethe slurry was gradually cooled to room temperature
  4. filtrationThe solids were then collected by filtration
  5. washwashed with a mixture of isopropanol and n-heptane (3:10 by volume, 2×700 mL)
  6. customdried under vacuum at room temperature

Sources & evidence

ORD record
ord-7d6991458f584ded96afc79b636f9a94
Source dataset
uspto-grants-2016_07
Patent number
US09382231B2

Reaction notes

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