1,8-Diazabicyclo(5.4.0)undec-7-ene → (4-(1-(2-Cyano-1-cyclopentylethyl)-1h-pyrazol-4-yl)-7h-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

HRID 1959912Notes

Reaction equation

HRID 1959912 reaction equation
[CH:1]1([CH:6]=[CH:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.[C:21]([O:27][CH2:28][N:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)[C:32]=2[CH:31]=[CH:30]1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[C:21]([O:27][CH2:28][N:29]1[C:33]2[N:34]=[CH:35][N:36]=[C:37]([C:38]3[CH:39]=[N:40][N:41]([CH:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][C:8]#[N:9])[CH:42]=3)[C:32]=2[CH:31]=[CH:30]1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]

Participants

5

Reactant 3

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 534011163-Cyclopentylprop-2-enenitrileHCID 57868869(4-(1H-Pyrazol-4-yl)-7H-pyrrolo(2,3-d)pyrimidin-7-yl)methyl pivalate

Product 1

HCID 59420158(4-(1-(2-Cyano-1-cyclopentylethyl)-1h-pyrazol-4-yl)-7h-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalateYield 30.9%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
55 °C

Procedure

Method A. 3-Cyclopentylacrylonitrile (8, 14.6 g, 0.12 mol, 1.20 equiv) and DBU (18.2 mL, 0.12 mol, 1.2 equiv) was added to a suspension of 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7yl]methyl pivalate (19, 30.0 g, 0.1 mol) in acetonitrile (45 mL) at room temperature. The resulting reaction mixture was heated to 50-60° C. for 17 hours (a clear solution developed midway through heating) then to room temperature for 8 hours. When LCMS analysis showed the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 2 L of ethyl acetate. The resulting solution was washed with water (3×200 mL), dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure to give the crude product (20) as a thick oil. The crude product was then purified by flash chromatography (SiO2, 0-50% EtOAc/hexanes gradient elution) to afford racemic (4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 13.0 g, 42.14 g theoretical, 30.8% yield) as a white solid. For 20: 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 resulting reaction mixture
  2. temperaturethrough heating) then to room temperature for 8 hours
  3. concentrationthe reaction mixture was concentrated under reduced pressure
  4. dissolutionthe residue was dissolved in 2 L of ethyl acetate
  5. washThe resulting solution was washed with water (3×200 mL)
  6. dry with materialdried over sodium sulfate (Na2SO4)
  7. concentrationconcentrated under reduced pressure
  8. customto give the crude product (20) as a thick oil
  9. customThe crude product was then purified by flash chromatography (SiO2, 0-50% EtOAc/hexanes gradient elution)

Sources & evidence

ORD record
ord-1f7994d41a214508b49eb6c3365ffcd4
Source dataset
uspto-grants-2013_04
Patent number
US08410265B2

Reaction notes

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