Citric Acid → Tofacitinib Citrate

HRID 1063472Notes

Reaction equation

HRID 1063472 reaction equation
[CH3:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:12])[CH2:9][C:10]#[N:11])[CH2:4][C@@H:3]1[N:13]([CH3:23])[C:14]1[C:15]2[CH:22]=[CH:21][NH:20][C:16]=2[N:17]=[CH:18][N:19]=1.[C:24]([OH:36])(=[O:35])[CH2:25][C:26]([CH2:31][C:32]([OH:34])=[O:33])([C:28]([OH:30])=[O:29])[OH:27]>CC(C)=O>[C:24]([OH:36])(=[O:35])[CH2:25][C:26]([CH2:31][C:32]([OH:34])=[O:33])([C:28]([OH:30])=[O:29])[OH:27].[CH3:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:12])[CH2:9][C:10]#[N:11])[CH2:4][C@@H:3]1[N:13]([CH3:23])[C:14]1[C:15]2[CH:22]=[CH:21][NH:20][C:16]=2[N:17]=[CH:18][N:19]=1

Participants

4

Reactant 2

HCID 311Citric AcidHCID 9926791Tofacitinib

Product 1

HCID 10174505Tofacitinib CitrateYield 75%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent

Conditions

Temperature
40 °C

Procedure

A stirred solution of (3R,4R)-3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile (230 mg/0.74 mmol) dissolved in 23 mL of acetone was heated to 40° C. To this solution was added 155 mg (0.81 mmol) of finely ground citric acid. The resulting mixture stirred at 40° C. for 2 hours, then at 30° C. for 4 hours followed by stirring at room temperature for an additional 18 hours. At this point, the solids were collected by filtration, washed with acetone and dried in vacuo affording 280 mg (75%) of the title compound as a white crystalline solid.

Workup

  1. waitat 30° C. for 4 hours followed
  2. stirringby stirring at room temperature for an additional 18 hours
  3. filtrationAt this point, the solids were collected by filtration
  4. washwashed with acetone
  5. customdried in vacuo

Sources & evidence

ORD record
ord-3b0bf3ec1d0043e2b6ca030d088ef680
Source dataset
uspto-grants-2005_11
Patent number
US06965027B2

Reaction notes

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