Hydrochloric Acid → 1-(3-Fluorophenyl)-5-carboxymethylpyrazole

To a stirring solution of ethyl vinyl ether (340 mL, 3.55 mol) in diethyl ether (200 mL), cooled in an ice bath, is added dropwise a solution of malonyl dichloride (69 mL, 0.71 mol) in ether (20 mL). Stirring is continued at 0° C. for 2 h, then a solution of triethylamine (196 mL) and ethanol (350 mL) in ether (210 mL) is added with cooling. More ether is added to further precipitate triethylamine hydrochloride, the mixture is then filtered, and the filtrate concentrated. The residue is taken up in ethanol (710 mL), then triethyl orthoformate (177 mL, 1.07 mol) and concentrated HCl (5 mL) is added. The mixture is stirred overnight then concentrated. To the residue is added ethanol (500 mL) and 3-Fluorophenylhydrazine hydrochloride (27.6 g, 0.17 mol). The mixture is heated at reflux for 2 h, then cooled and concentrated. Ethyl acetate is added, the mixture is washed with aqueous bicarbonate, then with water, dried (Na2SO4), concentrated, and the residue purified by silica gel chromatography. Ethanol (20 mL) and 1 N NaOH (100 mL) are added, and heated at reflux for 1 h. The mixture is cooled and washed with ethyl acetate. The aqueous layer is cooled and acidified, the solid collected by filtration, rinsed well with water and dried to give 1-(3-Fluorophenyl)-5-carboxymethylpyrazole as a gold solid. 1H NMR (CDCl3): δ 7.68 (d, J=1.8 Hz, 1H), 7.41-7.48 (m, 1H), 7.10-7.26 (m, 3H), 6.44 (d, J=2.1 Hz, 1H), 3.77 (8, 2H). LCMS: 221.2 (MH+), 219.2(MH−).

1. temperaturewith cooling
2. filtrationthe mixture is then filtered
3. concentrationthe filtrate concentrated
4. stirringThe mixture is stirred overnight
5. concentrationthen concentrated
6. temperatureThe mixture is heated
7. temperatureat reflux for 2 h
8. temperaturecooled
9. concentrationconcentrated
10. additionEthyl acetate is added
11. washthe mixture is washed with aqueous bicarbonate
12. dry with materialwith water, dried (Na2SO4)
13. concentrationconcentrated
14. customthe residue purified by silica gel chromatography
15. additionEthanol (20 mL) and 1 N NaOH (100 mL) are added
16. temperatureheated
17. temperatureat reflux for 1 h
18. temperatureThe mixture is cooled
19. washwashed with ethyl acetate
20. temperatureThe aqueous layer is cooled
21. filtrationthe solid collected by filtration
22. washrinsed well with water
23. customdried

ORD record

ord-12e6b585084b40b088435d7368fefcd5

Source dataset

uspto-grants-2005_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06916819B2