Hydrochloric Acid → Cyclopropyl(2-fluoro-4-hydroxyphenyl)methanone

Temperature

0 °C

Under argon atmosphere, 4-(tert-butyldimethylsilyloxy)-2-fluorobenzonitrile (10.00 g), which can be prepared according to the method described in Reference example 1, etc., was dissolved in dehydrated THF (30 mL; manufactured by Kanto Chemical Co., Inc.). After cooling to 0° C., 1 mol/L-cyclopropylmagnesium bromide-THF solution (80 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.) was added dropwise thereto. Upon the completion of the dropwise addition, the reaction solution was stirred for 10 minutes at 0° C., and stirred for 1.5 hours at reflux. The reaction solution was cooled to 0° C., added with water (50 mL) and 5 mol/L hydrochloric acid (50 mL), and stirred at reflux overnight. After cooling to the room temperature, the reaction solution was extracted three times with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was dissolved in dehydrated THF (100 mL; manufactured by Kanto Chemical Co., Inc.), added with 1 mol/L-TBAF-THF solution (31.5 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.), and stirred for 20 minutes at room temperature. To the reaction solution, water and brine were added and extraction was carried out three times with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. N-hexane was added to the residue and the insoluble matters were suspended by ultrasonication. The insoluble matters were filtered to obtain the target compound as a crude product (6.5156 g).

1. additionUpon the completion of the dropwise addition
2. stirringstirred for 1.5 hours
3. temperatureat reflux
4. temperatureThe reaction solution was cooled to 0° C.
5. stirringstirred
6. temperatureat reflux overnight
7. temperatureAfter cooling to the room temperature
8. extractionthe reaction solution was extracted three times with ethyl acetate
9. washThe organic layer was washed with water and brine
10. dry with materialdried over anhydrous sodium sulfate
11. customAfter the solvent was evaporated under reduced pressure
12. dissolutionthe residue was dissolved in dehydrated THF (100 mL; manufactured by Kanto Chemical Co., Inc.)
13. additionadded with 1 mol/L-TBAF-THF solution (31.5 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.)
14. stirringstirred for 20 minutes at room temperature
15. additionTo the reaction solution, water and brine were added
16. extractionextraction
17. washThe organic layer was washed with water and brine
18. dry with materialdried over anhydrous sodium sulfate
19. customthe solvent was evaporated under reduced pressure
20. additionN-hexane was added to the residue
21. customthe insoluble matters were suspended by ultrasonication
22. filtrationThe insoluble matters were filtered

ORD record

ord-ffff2f1154834bf3932ee498bab9d6a2

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08304443B2