Methylparaben → 4-(2-Chloroethoxy)benzoic acid

Temperature

60 °C

Potassium carbonate (7.27 g, 52.6 mmol) and commercially available 1-chloro-2-iodoethane (3.6 mL, 39.5 mmol) were added to a liquid mixture of commercially available methyl p-hydroxybenzoate (2.0 g, 13.1 mmol) and N,N-dimethylformamide (50 mL) under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 60° C. for 12 hours. The mixture was cooled to mom temperature and then a saturated aqueous ammonium chloride solution, water, and diethyl ether were added to the reaction mixture for partition. The organic layer was washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate, and then filtered and concentrated under vacuum. Tetrahydrofuran (25 mL), methanol (10 mL), and a 2 M sodium hydroxide solution (10 mL) were added to the residue at morn temperature, and the mixture was heated and stirred at 80° C. for 4 hours. The reaction mixture was cooled to 0° C., acidified with 5 M hydrochloric acid, and then the mixture was diluted with ethyl acetate for partition. The aqueous layer was extracted with ethyl acetate, the combined organic layer was washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated, the precipitate was separated by filtration with a liquid mixture of ethyl acetate and tetrahydrofuran, the resultant was washed, and the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=3:1-2:1-1:1) and the target fraction was concentrated under vacuum to obtain the title compound (278 mg, 11%).

1. temperaturethe mixture was heated
2. temperatureThe mixture was cooled to mom temperature
3. customfor partition
4. washThe organic layer was washed with water
5. dry with materiala saturated saline solution, then dried over anhydrous magnesium sulfate
6. filtrationfiltered
7. concentrationconcentrated under vacuum
8. additionTetrahydrofuran (25 mL), methanol (10 mL), and a 2 M sodium hydroxide solution (10 mL) were added to the residue at morn temperature
9. temperaturethe mixture was heated
10. stirringstirred at 80° C. for 4 hours
11. temperatureThe reaction mixture was cooled to 0° C.
12. additionthe mixture was diluted with ethyl acetate
13. customfor partition
14. extractionThe aqueous layer was extracted with ethyl acetate
15. washthe combined organic layer was washed with water
16. dry with materiala saturated saline solution, then dried over anhydrous magnesium sulfate
17. filtrationfiltered
18. customThe solvent was evaporated
19. customthe precipitate was separated by filtration with a liquid mixture of ethyl acetate and tetrahydrofuran
20. washthe resultant was washed
21. concentrationthe filtrate was concentrated under vacuum
22. customThe residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=3:1-2:1-1:1)
23. concentrationthe target fraction was concentrated under vacuum

ORD record

ord-d666d866746542b89d911bf571b55936

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08933099B2