4-Fluoroaniline → ethyl 5-ethoxy-2-(4-fluorophenyl)-2H-1,2,3-triazole-4-carboxylate

Temperature

-15 °C

A stirred mixture of 4-fluoroaniline (11.1 g, 100 mmol) in water (50 mL) and concentrated hydrochloric acid (19 mL) was cooled to −15° C. To this mixture was added a previously cooled (0° C.) solution of sodium nitrite (7.6 g, 110 mmol) in water (25 mL) over 5 min. Ice was added directly to the reaction to maintain the temperature below 5° C. After the addition was complete, the reaction was stirred at 0° C. for 15 min. Sodium acetate (41.0 g, 500 mmol) was added followed by ethyl 3-ethoxy-3-iminopropionate (15.9 g, 100 mmol). A yellow precipitate formed immediately. The suspension was stirred at 23° C. for 30 min., and then the solid was filtered and washed with water (40 mL). The still wet hydrazone was dissolved in pyridine (150 mL). A solution of copper (II) sulfate (49.7 g, 199 mmol) in water (150 mL) was added at once. The dark mixture was heated to 90° C. for 4 h. The majority of the pyridine (˜100 mL) was removed under vacuum. The residue was diluted with ethyl acetate (200 mL), water (100 mL) and 2 M sulfuric acid (80 mL). The resulting emulsion was filtered through Celite® diatomaceaous earth filter aid. The organic layer was washed with 2 M sulfuric acid (2×100 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting crude mixture was recrystallized from ethanol (80 mL) to obtain the title compound (15.1 g) as a pale red solid.

1. additionTo this mixture was added
2. additionIce was added directly to the reaction
3. temperatureto maintain the temperature below 5° C
4. additionAfter the addition
5. customA yellow precipitate formed immediately
6. stirringThe suspension was stirred at 23° C. for 30 min.
7. filtrationthe solid was filtered
8. washwashed with water (40 mL)
9. dissolutionThe still wet hydrazone was dissolved in pyridine (150 mL)
10. temperatureThe dark mixture was heated to 90° C. for 4 h
11. customThe majority of the pyridine (˜100 mL) was removed under vacuum
12. additionThe residue was diluted with ethyl acetate (200 mL), water (100 mL) and 2 M sulfuric acid (80 mL)
13. filtrationThe resulting emulsion was filtered through Celite®
14. filtrationfilter aid
15. washThe organic layer was washed with 2 M sulfuric acid (2×100 mL)
16. dry with materialdried (MgSO4)
17. concentrationconcentrated under reduced pressure
18. customThe resulting crude mixture was recrystallized from ethanol (80 mL)

ORD record

ord-4c8bb80f9275430e8e0264c9767c083b

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09302999B2