Hydrochloric Acid → Tofacitinib Citrate

HRID 1775133Notes

Reaction equation

HRID 1775133 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-])[O-].[Cs+].[Cs+].Cl.O1CCOCC1>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

7

Reactant 5

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 222302-Hydroxy-1,2,3-propanetricarboxylic acid hydrate (1:1)HCID 312751,4-DioxaneHCID 131734729HCID 131734729, compound

Product 1

HCID 10174505Tofacitinib CitrateYield 86.1%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Procedure

Water (1 mL) was added to a sample of the product obtained in Example 24 (1.01 g, 2.51 mmol; containing 12.8 wt % of acetone and 0.69% water). Complete dissolution was observed. A solution of citric acid monohydrate (0.64 g, 3.07 mmol) and cesium carbonate (1.02 g, 3.13 mmol) in water (10 mL) was added. A suspension was formed in approximately 1 to 2 minutes. The suspension was then treated with 4M hydrogen chloride in 1,4-dioxane (2.60 mmol). The resulting white suspension (pH=3) 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 56 hours to yield tofacitinib citrate (1.09 g; 86%).

Workup

  1. dissolutionComplete dissolution
  2. customA suspension was formed in approximately 1 to 2 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 56 hours

Sources & evidence

ORD record
ord-6377f9ddb29c4ce09866c329aeea8332
Source dataset
uspto-grants-2016_02
Patent number
US09260438B2

Reaction notes

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