2-Hydroxy-1,2,3-propanetricarboxylic acid hydrate (1:1) → Tofacitinib Citrate

HRID 1775126Notes

Reaction equation

[CH3:1][C@H:2]1[C@@H:7]([N:8]([C:10]2[N:18]=[CH:17][N:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)[CH3:9])[CH2:6][N:5]([C:19]([CH2:21][C:22]#[N:23])=[O:20])[CH2:4][CH2:3]1.Cl.O.[C:26]([OH:38])(=[O:37])[CH2:27][C:28]([CH2:33][C:34]([OH:36])=[O:35])([C:30]([OH:32])=[O:31])[OH:29].O.[OH-].[Li+]>O>[CH3:1][C@H:2]1[C@@H:7]([N:8]([C:10]2[N:18]=[CH:17][N:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)[CH3:9])[CH2:6][N:5]([C:19]([CH2:21][C:22]#[N:23])=[O:20])[CH2:4][CH2:3]1.[CH2:33]([C:28]([OH:29])([C:30]([OH:32])=[O:31])[CH2:27][C:26]([OH:38])=[O:37])[C:34]([OH:36])=[O:35]

Participants

Conditions

Temperature: 24 °C

Procedure

Water (0.5 mL) was added to amorphous tofacitinib hydrochloride (650 mg, 1.863 mmol). Complete dissolution was observed. A solution of citric acid monohydrate (590 mg, 2.795 mmol) and lithium hydroxide monohydrate (95 mg, 2.236 mmol) in water (10 mL) was added. A white suspension was formed in approximately 1 to 2 minutes. The suspension was stirred at 23 to 25° C. for 12 hours, filtered, washed with water (2×10 mL) and acetone (5 mL). The damp cake was dried under vacuum (5 torr) at 23 to 25° C. for 4 hours to yield tofacitinib citrate (820 mg; 87%).

Workup

dissolutionComplete dissolution
customA white suspension was formed in approximately 1 to 2 minutes
filtrationfiltered
washwashed with water (2×10 mL) and acetone (5 mL)
customThe damp cake was dried under vacuum (5 torr) at 23 to 25° C. for 4 hours

Sources & evidence

ORD record: ord-247ac153d9ca4c9ca888e4e126d87e36
Source dataset: uspto-grants-2016_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09260438B2

Reaction notes

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