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

HRID 1775135Notes

Reaction equation

HRID 1775135 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].C([O-])(=O)C.[NH4+]>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

5

Reactant 3

HCID 222302-Hydroxy-1,2,3-propanetricarboxylic acid hydrate (1:1)HCID 517165Ammonium AcetateHCID 131734729HCID 131734729, compound

Product 1

HCID 10174505Tofacitinib CitrateYield 94.6%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Conditions

Temperature
24 °C

Procedure

Water (1 mL) was added to a sample of the product obtained in Example 24 (1.06 g, 2.62 mmol; containing 12.8 wt % of acetone and 0.69% water). Complete dissolution was observed. A solution of citric acid monohydrate (0.67 g, 3.21 mmol) and ammonium acetate (0.25 g, 3.22 mmol) in water (10 mL) was added. A suspension was formed in approximately 5 minutes. The resulting white suspension was stirred at 23 to 25° C. for 16 hours, filtered and washed with water (2×5 mL). The damp cake was dried under vacuum (34 torr) at 40 to 45° C. for 16 hours to yield tofacitinib citrate (1.25 g; 94%).

Workup

  1. dissolutionComplete dissolution
  2. customA suspension was formed in approximately 5 minutes
  3. filtrationfiltered
  4. washwashed with water (2×5 mL)
  5. customThe damp cake was dried under vacuum (34 torr) at 40 to 45° C. for 16 hours

Sources & evidence

ORD record
ord-9fd403f3292f483986383f1d2679aef2
Source dataset
uspto-grants-2016_02
Patent number
US09260438B2

Reaction notes

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