Benzene → Ethyl 6-cyclopropyl-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

HRID 1522429Notes

Reaction equation

HRID 1522429 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]([NH2:15])=[CH:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1.[CH:16]1([C:19](=O)[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1.C1C=CC=CC=1>CC(O)=O>[CH:16]1([C:19]2[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]3[CH:12]=[N:11][N:10]([CH2:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:14]=3[N:15]=2)[CH2:17][CH2:18]1

Participants

5

Reactant 3

HCID 241BenzeneHCID 31612621-((4-methoxyphenyl)methyl)-1H-pyrazol-5-amineHCID 16779961Ethyl 4-cyclopropyl-2,4-dioxobutanoate

Product 1

HCID 67124423Ethyl 6-cyclopropyl-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxylateYield 71%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Conditions

Temperature
63 °C

Procedure

A mixture of 1-{[4-(methyloxy)phenyl]methyl}-1H-pyrazol-5-amine (3 g, 14.76 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (2.72 g, 14.76 mmol) and benzene (50 mL) were heated at 63° C. for 16 h. The solvent was removed under reduced pressure. The crude residue was purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex) to afford 2.56 g of the desired cyclized product and 1.71 g of the uncyclized adduct. The uncyclized adduct was dissolved in 25 mL of AcOH and heated to reflux for 16 hours. The solvent was removed under reduced pressure and the residue purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex) to afford an additional 1.15 g of the desired cyclized product (combined yield=71%). LCMS E-S (M+H)=352.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.13 (m, 4 H) 1.38 (t, J=7.07 Hz, 3 H) 2.39 (s, 1 H) 3.67 (s, 3 H) 4.41 (q, J=7.07 Hz, 2 H) 5.51 (s, 2 H) 6.84 (d, J=8.84 Hz, 2 H) 7.21 (d, J=8.59 Hz, 2 H) 7.64 (s, 1 H) 8.23 (s, 1 H).

Workup

  1. customThe solvent was removed under reduced pressure
  2. customThe crude residue was purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex)
  3. customto afford 2.56 g of the
  4. temperatureheated
  5. temperatureto reflux for 16 hours
  6. customThe solvent was removed under reduced pressure
  7. customthe residue purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex)
  8. customto afford an additional 1.15 g of the desired cyclized product (combined yield=71%)

Sources & evidence

ORD record
ord-19a4b9fa60654d7ea53a3488dd7c40b7
Source dataset
uspto-grants-2015_07
Patent number
US09073924B2

Reaction notes

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