Triethylamine → Ethyl 4-chloro-1,6-diethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

HRID 1675653Notes

Reaction equation

HRID 1675653 reaction equation
[CH2:1](N(CC)CC)[CH3:2].[Cl:8][C:9](=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10][CH3:11].[CH2:23]([N:25]1[C:29]([NH2:30])=CC=[N:26]1)[CH3:24]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([CH2:1][CH3:2])[N:30]=[C:29]2[N:25]([CH2:23][CH3:24])[N:26]=[CH:11][C:10]=12

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 3373101-Ethyl-1H-pyrazol-5-amine2×HCID 57819400Diethyl(1-chloropropylidene)propanedioate2×

Product 1

HCID 59683218Ethyl 4-chloro-1,6-diethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

Triethylamine (230 ml) was added dropwise to a mixture of diethyl (1-chloropropylidene)propanedioate (208 g, e.g. which can optionally be as prepared in Intermediate 2) and 1-ethyl-1H-pyrazol-5-amine (101 g, e.g. which can optionally be as prepared in Intermediate 1) in toluene (2.65 L). The mixture was heated under reflux for 16 hours. The reaction mixture was then cooled to room temperature, and filtered through a sintered glass funnel to remove the solid present. The filtrate was evaporated under reduced pressure. The residue was then treated with phosphorus oxychloride (POCl3, 2.65 L) and the mixture was heated under reflux for 16 hours. Excess phosphorus oxychloride was removed by distillation (e.g. under reduced pressure). The reaction mixture was then cooled and poured onto a mixture of saturated aqueous sodium hydrogen carbonate solution (4 L) and ethyl acetate (1.5 L), maintaining the temperature at 5° C. The organic layer was separated and the aqueous layer further extracted with ethyl acetate (2×1 L). The combined organic extracts were washed with aqueous sodium hydrogen carbonate solution (1×2 L, e.g. optionally a saturated solution thereof) and were dried (Na2SO4). Evaporation of solvent under reduced pressure afforded the crude product (202 g). The crude product was purified by chromatography (silica gel 60-120 mesh, 3.5 kg) eluting with 3% ethyl acetate in hexane. Fractions containing the product were pooled and evaporated to give the title compound (133 g) (which in one embodiment can be e.g. a pale yellow thick liquid or oil which may solidify on standing). 1H NMR (200 MHz, chloroform-d) δ (delta) ppm 1.37 (3H, t, J=7.1 Hz), 1.45 (3H, t, J=7.1 Hz), 1.57 (3H, t, J=7.2 Hz), 2.91 (2H, q, J=7.1 Hz), 4.48 (2H, q, J=7.2 Hz), 4.57 (2H, q, J=7.1 Hz) 8.05 (1H, s).

Workup

  1. temperatureThe mixture was heated
  2. temperatureunder reflux for 16 hours
  3. filtrationfiltered through a sintered glass funnel
  4. customto remove the solid present
  5. customThe filtrate was evaporated under reduced pressure
  6. additionThe residue was then treated with phosphorus oxychloride (POCl3, 2.65 L)
  7. temperaturethe mixture was heated
  8. temperatureunder reflux for 16 hours
  9. customExcess phosphorus oxychloride was removed by distillation (e.g. under reduced pressure)
  10. temperatureThe reaction mixture was then cooled
  11. additionpoured onto a mixture of saturated aqueous sodium hydrogen carbonate solution (4 L) and ethyl acetate (1.5 L)
  12. temperaturemaintaining the temperature at 5° C
  13. customThe organic layer was separated
  14. extractionthe aqueous layer further extracted with ethyl acetate (2×1 L)
  15. washThe combined organic extracts were washed with aqueous sodium hydrogen carbonate solution (1×2 L, e.g. optionally a saturated solution
  16. dry with material) and were dried (Na2SO4)
  17. customEvaporation of solvent under reduced pressure
  18. customafforded the crude product (202 g)
  19. customThe crude product was purified by chromatography (silica gel 60-120 mesh, 3.5 kg)
  20. washeluting with 3% ethyl acetate in hexane
  21. additionFractions containing the product
  22. customevaporated

Sources & evidence

ORD record
ord-a0b9d10d49d54d4d82ecd4a6fea18892
Source dataset
uspto-grants-2011_08
Patent number
US08003663B2

Reaction notes

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