Hydrochloric Acid → (E)-Methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate

HRID 1959881Notes

Reaction equation

HRID 1959881 reaction equation
[NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23]1([C:28]#[C:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(#N)C.N12CCCN=C1CCCCC2.Cl>>[CH:23]1(/[C:28](/[N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)=[CH:29]\[C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1

Participants

6

Reactant 5

HCID 313Hydrochloric AcidHCID 6342AcetonitrileHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 426313464-(1H-Pyrazol-4-yl)-7-(2-(trimethylsilyl)ethoxy)methyl-7 H-pyrrolo(2,3-d)-pyrimidineHCID 59420162Methyl 3-cyclopentylprop-2-ynoate

Product 1

HCID 59420182(E)-Methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylateYield 38.2%

Procedure

To a stirred suspension of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (17, 12.08 g, 38.31 mmol) and methyl 3-cyclopentylprop-2-ynoate (18, 8.970 g, 45.97 mmol, 1.2 equiv) in acetonitrile (76 mL, 1400 mmol) at room temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.92 mL, 19.2 mmol, 0.5 equiv). The resulting reaction mixture was stirred at room temperature for 2 h. When LCMS showed the reaction was deemed complete, the reaction mixture was quenched with water (50 mL) and 1 N aqueous HCl solution (20 mL). The quenched reaction mixture was adjusted to pH 4 after treatment with 1 N aqueous HCl solution. The mixture was then extracted with EtOAc (2×100 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2, 0-50% EtOAc/hexane gradient elution) to afford (E)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21, 6.838 g, 17.92 g theoretical, 38% in yield) as a colorless, very viscous oil. For 19: 1H NMR (CDCl3, 400 MHz) δ ppm 8.93 (s, 1H), 8.55 (bs, 1H), 8.44 (s, 1H), 7.49 (d, 1H, J=3.5 Hz), 6.86 (d, 1H, J=3.5 Hz), 6.34 (s, 1H), 5.74 (s, 2H), 4.56 (m, 1H), 3.84 (s, 3H), 3.60 (t, 2H, J=8.2 Hz), 2.01 (m, 2H), 1.96 (m, 4H), 1.77 (m, 2H), 0.98 (t, 2H, J=8.2 Hz), 0.00 (s, 9H); C24H33N5O3Si (MW, 467.64), LCMS (EI) m/e 468.2 (M++H).

Workup

  1. customThe resulting reaction mixture
  2. customthe reaction mixture was quenched with water (50 mL) and 1 N aqueous HCl solution (20 mL)
  3. customThe quenched reaction mixture
  4. extractionThe mixture was then extracted with EtOAc (2×100 mL)
  5. washthe combined organic layers were washed with brine
  6. dry with materialdried over magnesium sulfate (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by Combiflash (SiO2, 0-50% EtOAc/hexane gradient elution)

Sources & evidence

ORD record
ord-3e69c88be664410f827d834b71704003
Source dataset
uspto-grants-2013_04
Patent number
US08410265B2

Reaction notes

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