Potassium Carbonate → (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

HRID 1959917Notes

Reaction equation

HRID 1959917 reaction equation
C(O[C@@H]([C@H](OC(=O)C1C=CC=CC=1)C(O)=O)C(O)=O)(=O)C1C=CC=CC=1.[C:27]([O:33][CH2:34][N:35]1[C:39]2[N:40]=[CH:41][N:42]=[C:43]([C:44]3[CH:45]=[N:46][N:47]([C@@H:49]([CH:53]4[CH2:57][CH2:56][CH2:55][CH2:54]4)[CH2:50][C:51]#[N:52])[CH:48]=3)[C:38]=2[CH:37]=[CH:36]1)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[C:27]([O:33][CH2:34][N:35]1[C:39]2[N:40]=[CH:41][N:42]=[C:43]([C:44]3[CH:45]=[N:46][N:47]([C@@H:49]([CH:53]4[CH2:57][CH2:56][CH2:55][CH2:54]4)[CH2:50][C:51]#[N:52])[CH:48]=3)[C:38]=2[CH:37]=[CH:36]1)(=[O:32])[C:28]([CH3:30])([CH3:31])[CH3:29]

Participants

5

Reactant 2

HCID 11430Potassium CarbonateHCID 68471133Ruxolitinib impurity 133

Product 1

HCID 59420145(R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalateYield 86%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

Method B. A solution of enantiomerically enhanced (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, 120 mg, 0.154 mmol) in ethyl acetate (10 mL) and water (5.0 mL) at room temperature was cooled to 12° C. before being treated with 2 N aqueous potassium carbonate solution (K2CO3, 0.39 mL, 0.77 mmol, 5.0 equiv) to adjust pH to 8-9. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (30 mL). The combined organic fractions were washed with 20% aqueous brine (20 mL), dried over magnesium sulfate, filtered and concentrate under reduced pressure to afford enantiomerically enhanced (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-21, 55.7 mg, 64.8 mg theoretical, 86% yield) as white solids, which was analyzed by chiral HPLC and found to be in a ratio of 87:13 favoring the desired R-enantiomer. For ((R)-21: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.84 (s, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 7.74 (d, 1H, J=3.7 Hz,), 7.11 (d, 1H, J=3.8 Hz), 6.23 (s, 2H), 4.53 (ddd, 1H, J=9.9, 9.6, 4.2 Hz), 3.26 (dd, 1H, J=17.4, 9.9 Hz), 3.19 (dd, 1H, J=17.2, 4.3 Hz), 2.41 (m, 1H), 1.87-1.13 (m, 8H), 1.07 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421.4 (M++H).

Workup

  1. customThe two layers were separated
  2. extractionthe aqueous layer was extracted with ethyl acetate (30 mL)
  3. washThe combined organic fractions were washed with 20% aqueous brine (20 mL)
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrate under reduced pressure

Sources & evidence

ORD record
ord-8cc988ec7dca45b8bfc46e9767fa05f3
Source dataset
uspto-grants-2013_04
Patent number
US08410265B2

Reaction notes

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