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 method of synthesizing 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene in one pot, consisting of: preparing the 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene by the following reaction formula: ##STR00007## wherein 5-bromo-2-chlorobenzoic acid is heated to a first temperature and held for reaction 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 first mixture, after the first mixture is cooled to room temperature, the triethylsilane is directly added to the first mixture in the pot to obtain a second mixture, the second mixture is heated to a second temperature and held for reaction to obtain the 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene.

2. The method according to claim 1, wherein the first mixture is heated to a first temperature of from 25° C. to 35° C.

3. The method according to claim 2, wherein the first mixture is held in the first temperature for 6 h.

4. The method according to claim 1, the second mixture is heated to a second temperature of from 55° C. to 60° C.

5. The method according to claim 4, wherein the second mixture is held in the second temperature for 18 h to obtain the 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene.

6. The method according to claim 1, wherein a molar amount of the boron trifluoride diethyl etherate is one tenth of a molar amount of the 5-bromo-2-chlorobenzoic acid.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

(1) 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: Synthesis of 4-bromo-2-(4′-ethoxyphenyl)-1-chlorobenzene

(2) 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%).