Acetyl chloride → 2-(4-Chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane

Temperature

0 °C

To a solution of 1-bromo-4-chloro-2-fluoro-3-methoxybenzene (10.4 g, 0.043 mol) in diethyl ether (150 mL) at −78° C. was slowly added n-butyl lithium (2.5M, 19.0 mL, 0.0475 mol), and the solution was stirred for thirty minutes. A solution of triisopropyl borate (12.0 g, 0.064 mL) in THF (25 mL) was slowly added and the solution warmed to 0° C. Acetyl chloride (10.0 g, 0.13 mol) was added. After stiffing for one hour the solution was concentrated and the solid residue was partitioned between ethyl acetate (150 mL) and 1N sodium hydroxide (50 mL). Ice was added to the aqueous phase that was subsequently acidified with sufficient concentrated hydrochloric acid to obtain a pH of 2. The heterogeneous mixture was extracted with ethyl acetate (2×150 mL) and the combined organic phases were dried and concentrated. The resulting solid was slurried in toluene, propane-1,3-diol (6.6 g, 0.09 mol) was added, and the resulting mixture was heated under reflux to remove water via a Dean-Stark trap. After two hours, the mixture was allowed to cool and was concentrated under vacuum. The resulting oil was dissolved in methylene chloride (50 mL), washed with water (25 mL), dried, and concentrated to give 2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane (6.4 g, 0.062 mol): 1H NMR (CDCl3): δ 7.15 (m, 1H), 6.95 (dd, 1H), 4.05 (t, 4H), 3.8 (s, 3H), 1.95 (t, 2H).

1. customat −78° C.
2. concentrationthe solution was concentrated
3. customthe solid residue was partitioned between ethyl acetate (150 mL) and 1N sodium hydroxide (50 mL)
4. additionIce was added to the aqueous phase that
5. customto obtain a pH of 2
6. extractionThe heterogeneous mixture was extracted with ethyl acetate (2×150 mL)
7. customthe combined organic phases were dried
8. concentrationconcentrated
9. temperaturethe resulting mixture was heated
10. temperatureunder reflux
11. customto remove water via a Dean-Stark trap
12. waitAfter two hours
13. temperatureto cool
14. concentrationwas concentrated under vacuum
15. dissolutionThe resulting oil was dissolved in methylene chloride (50 mL)
16. washwashed with water (25 mL)
17. customdried
18. concentrationconcentrated

ORD record

ord-0cbf0052c706411bac62d7714975729b

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09199943B2