Phosphorus oxychloride → Ethyl 4-chloro-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

HRID 1675674Notes

Reaction equation

HRID 1675674 reaction equation
[NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1.C(O[C:12](=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](OCC)=O)[CH3:13])C.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:15]1[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]([CH3:13])[N:1]=[C:2]2[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=12

Participants

4

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 99520Propanedioic acid, 2-(1-ethoxyethylidene)-, 1,3-diethyl esterHCID 3373101-Ethyl-1H-pyrazol-5-amine

Product 1

HCID 13059311Ethyl 4-chloro-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Conditions

Temperature
150 °C

Procedure

A mixture of 5-amino-1-ethylpyrazole (1.614 g, 14.5 mmol) and diethyl 2-(1-ethoxyethylidene)malonate [e.g. see J. Am. Chem. Soc., 1931, 53, 1836] (3.68 g) is heated at 150° C. under Dean Stark conditions for 5 hours. Phosphorous oxychloride (25 ml) is carefully added to the mixture and the resulting solution is heated at 130° C. under reflux for 18 hours. The mixture is concentrated in vacuo and the residual oil is carefully added, with cooling, to water (100 ml). The resulting mixture is extracted with dichloromethane (3×100 ml) and the combined organic extracts are dried over anhydrous sodium sulphate and concentrated in vacuo. The residual oil is purified by Biotage chromatography (silica; 90 g) eluting with 5% ethyl acetate in petroleum ether. Fractions containing the desired product are combined and concentrated in vacuo to give ethyl 4-chloro-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate.

Workup

  1. temperaturethe resulting solution is heated at 130° C.
  2. temperatureunder reflux for 18 hours
  3. concentrationThe mixture is concentrated in vacuo
  4. additionthe residual oil is carefully added
  5. temperaturewith cooling, to water (100 ml)
  6. extractionThe resulting mixture is extracted with dichloromethane (3×100 ml)
  7. dry with materialthe combined organic extracts are dried over anhydrous sodium sulphate
  8. concentrationconcentrated in vacuo
  9. customThe residual oil is purified by Biotage chromatography (silica; 90 g)
  10. washeluting with 5% ethyl acetate in petroleum ether
  11. additionFractions containing the desired product
  12. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-42a334e01d894c1d9bb5305c11175cbb
Source dataset
uspto-grants-2011_08
Patent number
US08003663B2

Reaction notes

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