Citric Acid → Tofacitinib Citrate

HRID 1853382Notes

Reaction equation

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

Participants

Conditions

Temperature: 40 °C

Procedure

Citric acid (20 mg, 0.10 mmol, 1.00 equiv.) was added to a solution of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (33 mg, 0.10 mmol, 1.00 equiv.) in water/methanol (5/0.5 mL). The resulting solution was stirred at about 40° C. for about 10 minutes, and then was cooled to ambient temperature. The solvent was then removed by using a cryofreeze-dryer to give the title compound as an off-white solid (40 mg; yield=76%). 1H NMR (300 MHz, CD3OD) δ: 8.15 (s, 1H), 7.15 (d, J=3.6 Hz, 1H), 6.70 (d, J=3.6 Hz, 1H), 4.95-5.15 (m, 1H), 3.85-4.08 (m, 4H), 3.58-3.80 (m, 1H), 3.40-3.60 (m, 4H), 2.92 (Abq, J=15.6 Hz, 2H), 2.80 (Abq, J=15.6 Hz, 2H), 2.40-2.60 (m, 1H), 1.85-2.05 (m, 1H), 1.68-1.85 (m, 1H), 1.05-1.20 (m, 3H). LC-MS: m/z=313 (MH—C6H8O7)+.

Workup

temperaturewas cooled to ambient temperature
customThe solvent was then removed

Sources & evidence

ORD record: ord-223982f7b13a421db0cefbcffad77548
Source dataset: uspto-grants-2015_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08962638B2

Reaction notes

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