One-pot synthesis method for 5-bromo-2-chloro-4'-ethoxy diphenylmethane

Abstract

The invention discloses a one-pot synthesis method for 5-bromo-2-chloro-4'-ethoxy diphenylmethane. The method comprises the following continuous steps of: taking 2-chloro-5-bromobenzoic acid as a raw material, reacting it with thionyl chloride to generate 2-chloro-5-bromobenzoyl chloride, and adding an organic solvent, Lewis acid, phenetole and borohydride to undergo Friedel-Crafts acylation reaction and hydroboration reduction reaction so as to obtain the 5-bromo-2-chloro-4'-ethoxy diphenylmethane. The process involved in the invention has the advantages that the same Lewis acid is used as a catalyst in the Friedel-Crafts acylation reaction and the hydroboration reduction reaction, so that the catalyst consumption is greatly reduced, the operation is simple, and the intermediate needs no separation and purification. By effectively controlling the reaction conditions, and the charging sequence and proportion, the 5-bromo-2-chloro-4'-ethoxy diphenylmethane can be synthesized by one step, and fewer three wastes are discharged, the solvent recovery effect is good, and the production cost is low.

Description

technical field

[0001] The invention relates to a one-pot synthesis method of 5-bromo-2-chloro-4'-ethoxydiphenylmethane. Background technique

[0002] 5-Bromo-2-chloro-4'-ethoxydiphenylmethane is an important intermediate in the synthesis of the antidiabetic drug Dapagliflozin. It is reported that the synthetic method of 5-bromo-2-chloro-4'-ethoxydiphenylmethane mainly contains the following two kinds:

[0003] The synthesis route of 5-bromo-2-chloro-4'-ethoxydiphenylmethane reported in patent WO2010022313 is as follows: starting from 2-chloro-5-bromobenzoic acid, first performing Friedel-Crafts acylation with phenetole to obtain 5 -Bromo-2-chloro-4'-ethoxybenzophenone, and then hydroboration reduction to obtain the product, or use Et 3 Reduction of the carbonyl by SiH and trifluoroacetic acid system affords the product. The two-step reaction of this route uses Lewis acid AlCl at the same time 3 Catalytic, two-step reaction of AlCl 3 Both need to be separated and remove...

Examples

Embodiment 1

[0016] On the 1L four-necked flask, respectively install a mechanical stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel, under nitrogen protection, first add 100g of 2-chloro-5-bromobenzoic acid (96%, 0.41mol), 400ml di Chloromethane, stirred, and 68.3 g of thionyl chloride (0.58 mol, 1.4 eq) was added dropwise at room temperature for about 10 minutes. Then it was heated to 70° C. and refluxed for 4 hours, and the reaction was stirred; the reaction solvent and excess thionyl chloride were distilled off under reduced pressure. Add fresh 700ml of anhydrous tetrahydrofuran, 56.1g of phenetole (98%, 0.45mol, 1.1eq.) to the bottle, cool down to -5°C in a cooling bath, and slowly add 68.9g of aluminum trichloride (0.52mol, 1.26eq. ), the temperature is controlled to less than 10°C, and the feeding time is 15 minutes. The reaction was kept at 10° C. for 2 hours, and the residual 2-chloro-5-bromobenzoic acid content detected by HPLC was less than 0.5%...

Embodiment 2

[0020] 100g of 2-chloro-5-bromobenzoic acid (96%, 0.41mol), 400ml of dichloromethane were first added to a 1L four-necked flask, stirred, and 68.3g of thionyl chloride (0.58mol, 1.4 eq), about 20 minutes of time for adding. Then it was heated to 70° C. and refluxed for 3 hours, and the reaction was stirred; the reaction solvent and excess thionyl chloride were distilled off under reduced pressure. Add fresh 700ml of anhydrous tetrahydrofuran to the bottle, 51.1g of phenetole (98%, 0.41mol, 1.0eq), cool down to -5°C in a cold bath, and slowly add 65.6g of aluminum trichloride (0.49mol, 1.2eq) , the temperature is controlled to less than 10°C, and the feeding time is about 10 minutes. The reaction was kept at 10° C. for 3 hours, and the residual 2-chloro-5-bromobenzoic acid content detected by HPLC was less than 0.5%, that is, the reaction was stopped.

[0021] The reaction solution was continued to cool to -10°C, and 22.6g of potassium borohydride (98%, 0.41mol, 1.0eq) was ad...

technical field

[0001] The invention relates to a one-pot synthesis method of 5-bromo-2-chloro-4'-ethoxydiphenylmethane. Background technique

[0002] 5-Bromo-2-chloro-4'-ethoxydiphenylmethane is an important intermediate in the synthesis of the antidiabetic drug Dapagliflozin. It is reported that the synthetic method of 5-bromo-2-chloro-4'-ethoxydiphenylmethane mainly contains the following two kinds:

[0003] The synthesis route of 5-bromo-2-chloro-4'-ethoxydiphenylmethane reported in patent WO2010022313 is as follows: starting from 2-chloro-5-bromobenzoic acid, first performing Friedel-Crafts acylation with phenetole to obtain 5 -Bromo-2-chloro-4'-ethoxybenzophenone, and then hydroboration reduction to obtain the product, or use Et 3 Reduction of the carbonyl by SiH and trifluoroacetic acid system affords the product. The two-step reaction of this route uses Lewis acid AlCl at the same time 3 Catalytic, two-step reaction of AlCl 3 Both need to be separated and remove...

Examples

Embodiment 1

[0016] On the 1L four-necked flask, respectively install a mechanical stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel, under nitrogen protection, first add 100g of 2-chloro-5-bromobenzoic acid (96%, 0.41mol), 400ml di Chloromethane, stirred, and 68.3 g of thionyl chloride (0.58 mol, 1.4 eq) was added dropwise at room temperature for about 10 minutes. Then it was heated to 70° C. and refluxed for 4 hours, and the reaction was stirred; the reaction solvent and excess thionyl chloride were distilled off under reduced pressure. Add fresh 700ml of anhydrous tetrahydrofuran, 56.1g of phenetole (98%, 0.45mol, 1.1eq.) to the bottle, cool down to -5°C in a cooling bath, and slowly add 68.9g of aluminum trichloride (0.52mol, 1.26eq. ), the temperature is controlled to less than 10°C, and the feeding time is 15 minutes. The reaction was kept at 10° C. for 2 hours, and the residual 2-chloro-5-bromobenzoic acid content detected by HPLC was less than 0.5%...

Embodiment 2

[0020] 100g of 2-chloro-5-bromobenzoic acid (96%, 0.41mol), 400ml of dichloromethane were first added to a 1L four-necked flask, stirred, and 68.3g of thionyl chloride (0.58mol, 1.4 eq), about 20 minutes of time for adding. Then it was heated to 70° C. and refluxed for 3 hours, and the reaction was stirred; the reaction solvent and excess thionyl chloride were distilled off under reduced pressure. Add fresh 700ml of anhydrous tetrahydrofuran to the bottle, 51.1g of phenetole (98%, 0.41mol, 1.0eq), cool down to -5°C in a cold bath, and slowly add 65.6g of aluminum trichloride (0.49mol, 1.2eq) , the temperature is controlled to less than 10°C, and the feeding time is about 10 minutes. The reaction was kept at 10° C. for 3 hours, and the residual 2-chloro-5-bromobenzoic acid content detected by HPLC was less than 0.5%, that is, the reaction was stopped.

[0021] The reaction solution was continued to cool to -10°C, and 22.6g of potassium borohydride (98%, 0.41mol, 1.0eq) was ad...