Methyl iodide → 4-Bromo-2-fluoroanisole

2-Fluoro-4-bromophenol (1) (382.0 g, 2.0 mols) was dissolved in ethanol (1,000 ml), followed by adding potassium hydroxide (113.0 g, 2.0 mols) to the solution, sufficiently agitating the mixture, dropwise adding thereto methyl iodide (312.3 g, 2.2 mols), refluxing it for 4 hours, distilling off most of the ethanol, distilling the residue under reduced pressure and collecting a fraction of 65°-66° C. (4.5 mmHg) to obtain 2-fluoro-4-bromoanisole (2) (328.0 g). This compound was reacted with Mg (38.9 g) in diethyl ether to obtain 3-fluoro-4-methoxyphenylmagnesium bromide (3), followed by dropwise adding thereto cyclohexanone (157.0 g, 1.6 mol) at 7° C. or lower, agitating the mixture at room temperature for about 30 minutes, adding thereto 6N--HCl (350 ml), refluxing the mixture for one hour, washing the resulting organic layer with water, distilling off diethyl ether and recrystallizing the residue from ethanol to obtain (3'-fluoro-4'-methoxyphenyl)-cyclohexene-1 (4) (180.4 g) having a m.p. of 49.0°-50.0° C. This compound (112.0 g, 0.55 mol) was dissolved in xylene (700 ml), followed by adding p-chloranil (267.0 g, 1.1 mol) to the solution, refluxing the mixture for 4 hours, filtering off the resulting tetrachlorohydroquinone, washing the filtrate with 2N--NaOH aqueous solution, distilling off the solvent, subjecting the residue to column chromatography with a column filled with activated alumina and recrystallizing the resulting material from ethanol to obtain 3-fluoro-4-methoxybiphenyl (5) (69.2 g) having a m.p. of 84.5°-86.0° C.

1. additiondropwise adding
2. distillationdistilling off most of the ethanol
3. distillationdistilling the residue under reduced pressure
4. customcollecting a fraction of 65°-66° C. (4.5 mmHg)

ORD record

ord-937e1b47c3e049cfadfadc0d3c3e95ca

Source dataset

uspto-grants-1989_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04818432