Hydrochloric Acid → (4-(1H-Pyrazol-4-yl)-7H-pyrrolo(2,3-d)pyrimidin-7-yl)methyl pivalate

HRID 928501Notes

Reaction equation

HRID 928501 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](C(OCC)C)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.Cl.[OH-].[Na+]>COC(C)(C)C>[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][NH:21][CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 14798Sodium HydroxideHCID 57868870(4-(1-(1-Ethoxyethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

Product 1

HCID 57868869(4-(1H-Pyrazol-4-yl)-7H-pyrrolo(2,3-d)pyrimidin-7-yl)methyl pivalateYield 91%

Reagents, catalysts & solvents 1

HCID 15413tert-Butyl methyl etherSolvent

Procedure

Method A. To a 1 L round bottom flask equipped with a stir bar and nitrogen inlet was charged {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (18, theoretical amount 41.6 g, 0.112 mol) made as described above and tetrahydrofuran (THF, 610 mL, 7.5 mol) at room temperature, and the resulting mixture was treated with an 2.0 N aqueous solution of hydrochloric acid (140 mL, 0.28 mol, 2.5 equiv) at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for overnight. When the reaction was deemed complete, the reaction mixture was cooled to 0-5° C. before pH was adjusted to 9-10 with a 3 M aqueous sodium hydroxide (NaOH) solution (95 mL). The mixture was then extracted with ethyl acetate (2×300 mL) and the combined organic extracts were washed with 20% aqueous brine solution (250 mL), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure to afford the crude product as off-white to light yellow solids. The crude product was treated with methyl t-butylether (MTBE, 200 mL) and the slurry was warm to reflux for 30 minutes before being cooled to room temperature. The solids were collected by filtration and washed with MTBE (2×40 mL), dried under reduced pressure to afford [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 30.5 g, 33.52 g theoretical, 91% for two steps) as white to off-white solids. For 19: 1H NMR (DMSO-d6, 300 MHz) δ ppm 13.40 (br s, 1H), 8.75 (s, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 7.68 (d, 1H, J=3.8 Hz), 7.11 (d, 1H, J=3.8 Hz), 6.21 (s, 2H), 1.06 (s, 9H); C15H17N5O2 (MW, 299.33), LCMS (EI) m/e 300 (M++H).

Workup

  1. customTo a 1 L round bottom flask equipped with a stir bar and nitrogen inlet
  2. customat room temperature
  3. customThe resulting reaction mixture
  4. temperaturethe reaction mixture was cooled to 0-5° C. before pH
  5. extractionThe mixture was then extracted with ethyl acetate (2×300 mL)
  6. washthe combined organic extracts were washed with 20% aqueous brine solution (250 mL)
  7. dry with materialdried over magnesium sulfate (MgSO4)
  8. concentrationconcentrated under reduced pressure
  9. customto afford the crude product as off-white to light yellow solids
  10. temperaturethe slurry was warm
  11. temperatureto reflux for 30 minutes
  12. temperaturebefore being cooled to room temperature
  13. filtrationThe solids were collected by filtration
  14. washwashed with MTBE (2×40 mL)
  15. customdried under reduced pressure

Sources & evidence

ORD record
ord-23329e05cb0146e3ad1b28cf9f2d87e5
Source dataset
uspto-grants-2016_03
Patent number
US09290506B2

Reaction notes

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