PREPARATION OF 4-BROMO-2-(4'-ETHOXYPHENYL)-1-CHLOROBENZENE

Abstract

A more environmentally friendly synthesis method of 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene with simplified steps provides a more effective synthetic strategy for producing key intermediates of SGLT-2 inhibitors such as dapagliflozin, sotagliflozin, and ertugliflozin. In the presence of trifluoroacetic anhydride, 5-bromo-2-chlorobenzoic acid and phenetole are selected to complete a direct acylation reaction under the catalysis of boron trifluoride diethyl etherate, and triethylsilane is added thereinto without treatment for one-pot reaction to obtain a target compound 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene.

Claims

1. A one-pot synthesis method of 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene, comprising: preparing the 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene by the following reaction formula: ##STR00007## wherein after 5-bromo-2-chlorobenzoic acid reacts with phenetole in the presence of trifluoroacetic anhydride (TFAA) and a catalytic amount of boron trifluoride diethyl etherate (BF.sub.3.EtOEt) to obtain a reaction product, triethylsilane is directly added into the reaction product without treatment for one-pot reaction to obtain the 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0012] The present disclosure can be more specifically understood from the following example, but the following example is exemplary and does not limit the scope of the present disclosure. All simple substitutions and improvements of the present disclosure made by those skilled in the art are included in the technical solution claimed by the present disclosure.

EXAMPLE 1: Synthesisof 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene

[0013] TFAA (84.0 g, 400 mmol), phenetole (14.7 g, 120 mmol), and boron trifluoride diethyl etherate (1.42 g, 10 mmol) were successively added into a 250 mL four-neck flask, 5-bromo-2-chlorobenzoic acid (23.5 g, 100 mmol) was introduced in portions, and a mixture was heated to 30±5° C. under stirring and held for reaction for 6 h to obtain a dark brown solution. After cooling to room temperature, triethylsilane (34.9 g, 300 mmol) was added into the mixture; the mixture was reheated to 55-60° C. and held for reaction for 18 h. After cooling, low boiling-point solvent was removed by vacuum concentration; residues were washed with dichloromethane (150 mL) and saturated sodium bicarbonate solution (60 mL) and separated; the organic layer was collected, washed with water (60 mL×2) twice, and concentrated. Residues were recrystallized with ethanol, filtered, and blow-dried at 40° C. to obtain a white target compound (24.3 g, yield 74.5%).