Acetone → Ruxolitinib impurity 133

HRID 880573Notes

Reaction equation

HRID 880573 reaction equation
[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([CH:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.CC(C)=O.[CH:41]1[CH:46]=[CH:45][C:44]([C:47]([O:49][C@H:50]([C:64]([OH:66])=[O:65])[C@H:51]([O:55][C:56]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:57])[C:52]([OH:54])=[O:53])=[O:48])=[CH:43][CH:42]=1>C(#N)C>[C:56]([O:55][C@@H:51]([C@H:50]([O:49][C:47](=[O:48])[C:44]1[CH:43]=[CH:42][CH:41]=[CH:46][CH:45]=1)[C:64]([OH:66])=[O:65])[C:52]([OH:54])=[O:53])(=[O:57])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]

Participants

6

Reactant 4

HCID 180AcetoneHCID 8028TetrahydrofuranHCID 1550213Butanedioic acid, 2,3-bis(benzoyloxy)-, (2S,3S)-HCID 59420158(4-(1-(2-Cyano-1-cyclopentylethyl)-1h-pyrazol-4-yl)-7h-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

Product 1

HCID 68471133Ruxolitinib impurity 133Yield 79.2%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
50 °C

Procedure

A solution of racemic (4-(1-(2-Cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 200 mg, 0.47 mmol) in a mixture of acetonitrile, tetrahydrofuran, and acetone (4 mL, 6:1:1) at room temperature was warmed to 50° C. before being treated with (+)-2,3-dibenzoyl-D-tartaric acid (16, 84 mg, 0.235 mmol, 0.5 equiv) in one portion. The resulting homogeneous solution was then stirred at 50° C. for 10 minutes before being cooled gradually to room temperature and stirred at room temperature for 23 hours. The solids were then collected by filtration, rinsed with a small volume of hexane, and dried under reduced pressure to afford (2S,3S)-2,3-bis(benzoyloxy)succinic acid-(R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (1:1; 22, 145 mg, 183 mg theoretical, 79.2% yield) as white crystals. The enantiomeric purity of the isolated salt was analyzed by chiral HPLC and found to be in a ratio of 87:13 favoring the desired R-enantiomer. For 22: C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421.4 (M++H).

Workup

  1. temperaturebefore being cooled gradually to room temperature
  2. stirringstirred at room temperature for 23 hours
  3. filtrationThe solids were then collected by filtration
  4. washrinsed with a small volume of hexane
  5. customdried under reduced pressure

Sources & evidence

ORD record
ord-b32c34c2766a4d5fb92b27052d80ca68
Source dataset
uspto-grants-2015_03
Patent number
US08993582B2

Reaction notes

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