Synthetic method of 5-bromo-2-chlorobenzoic acid

Abstract

The invention discloses a synthetic method of 5-bromo-2-chlorobenzoic acid. The method comprises the following steps of by taking salicylic acid as a starting material, performing bromination reactionto obtain 2-hydroxyl-5-bromo-benzoic acid, and then performing chlorination reaction to obtain the 5-bromo-2-chlorobenzoic acid, wherein a bromination system adopted by the bromination reaction is tetrabutyl ammonium bromide / oxygen / sodium metavanadate, a catalyst is aluminium tribromide, and a solvent is 1,4-dioxane; and a chlorinating agent is carbon tetrachloride, and a catalyst is molybdenum hexacarbonyl. The method provided by the invention adopts the cheap salicylic acid which is wide in source as the starting material and prepares the 5-bromo-2-chlorobenzoic acid through two-step reaction of bromination and chlorination, is novel in synthetic route, relatively low in production cost, relatively small in environmental pollution and very suitable for industrial mass production. According to the method, through the bromination reaction and the chlorination reaction, by selecting proper reagents, relatively high reaction yield and product purity can be obtained.

Description

technical field

[0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of 5-bromo-2-chlorobenzoic acid. Background technique

[0002] 5-Bromo-2-chlorobenzoic acid is a synthetic antidiabetic drug Dapagliflozin (see Chinese patent documents CN103570510A, CN104086379A, CN105061373A, CN107200683A, CN107417515A), aigeliejing (see Chinese patent documents CN103896752A, CN105153137A) and other antiviral drugs Important raw material for drugs and renin inhibitors.

[0003] At present, the synthetic route of 5-bromo-2-chlorobenzoic acid mainly contains the following kinds:

[0004] Route 1: Using 5-bromo-2-chlorobenzotrifluoride as the starting material, directly hydrolyze it under acidic conditions to obtain 5-bromo-2-chlorobenzoic acid [see Document 1].

[0005] The raw materials used in this route are very expensive and difficult to obtain, and a large amount of fluorine-containing waste water will b...

Examples

Embodiment 1）

[0052] The present embodiment is the preparation of 2-hydroxyl-5-bromo-benzoic acid, and the specific method is as follows:

[0053] Add 138.0g of salicylic acid (1.0mol), 6.68g of aluminum trichloride (0.05mol), and 1.0L of 1,2-dichloroethane into a three-necked flask, heat to 45°C, and dropwise add 176.0g of Bromine (1.1mol), the temperature was raised to reflux after dropping, and reacted for 15h.

[0054] The reaction controlled by HPLC was completed, and the ratio of 2-hydroxy-5-bromo-benzoic acid to 2-hydroxy-3-bromo-benzoic acid was about 6:1.

[0055] The reacted system was cooled to 0°C with ice water, and then saturated aqueous sodium bisulfite solution was added to the system with stirring until it was colorless, left to stand for liquid separation, the organic layer was washed with water and saturated brine successively, concentrated under reduced pressure, Then add ethanol / tetrahydrofuran mixed solvent (volume ratio 1:5), heat up to 70°C and stir to dissolve, and...

Embodiment 2）

[0057] The present embodiment is the preparation of 2-hydroxyl-5-bromo-benzoic acid, and the specific method is as follows:

[0058] Add 138.0g of salicylic acid (1.0mol) and 1.5L of acetic acid into a three-necked flask, heat to 80°C, add 300.0g of dibromohydantoin (1.05mol) in batches, and keep stirring at this temperature to react 12h.

[0059] The reaction controlled by HPLC was completed, and the ratio of 2-hydroxy-5-bromo-benzoic acid to 2-hydroxy-3-bromo-benzoic acid was about 7.5:1.

[0060] Cool the reacted system to room temperature, then pour it into 2L of ice water at one time, precipitate a yellow solid, filter, dry, then add ethanol / tetrahydrofuran mixed solvent (volume ratio 1:5), heat up to 70°C and stir to dissolve, Finally, it was slowly cooled to room temperature, stirred and crystallized, filtered and dried to obtain 156.0 g of white solid 2-hydroxy-5-bromo-benzoic acid with a yield of 71.9% and a purity of 96.5% (HPLC).

Embodiment 3）

[0062] The present embodiment is the preparation of 2-hydroxyl-5-bromo-benzoic acid, and the specific method is as follows:

[0063] Add 12.2g of sodium metavanadate (0.1mol), 26.7g of aluminum tribromide (0.1mol) and 338.0g of tetrabutylammonium bromide (1.05mol) to a 5L three-necked flask, then fill with oxygen, and then add 138.0g of salicylic acid (1.0mol), 2L of 1,4-dioxane, and 1.8g of water (0.1mol), heated to 80°C and stirred for 8h, supplemented with oxygen during the reaction.

[0064] The reaction controlled by HPLC was completed, and the ratio of 2-hydroxy-5-bromo-benzoic acid to 2-hydroxy-3-bromo-benzoic acid was about 24:1.

[0065] The reacted system was cooled to room temperature, then 1N hydrochloric acid was added, and then extracted with ethyl acetate (1L×2). The organic layers were combined and washed with water and saturated brine in turn. The solvent was evaporated under reduced pressure, and then ethanol / tetrahydrofuran was added to mix Solvent (volume ...

technical field

[0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of 5-bromo-2-chlorobenzoic acid. Background technique

[0002] 5-Bromo-2-chlorobenzoic acid is a synthetic antidiabetic drug Dapagliflozin (see Chinese patent documents CN103570510A, CN104086379A, CN105061373A, CN107200683A, CN107417515A), aigeliejing (see Chinese patent documents CN103896752A, CN105153137A) and other antiviral drugs Important raw material for drugs and renin inhibitors.

[0003] At present, the synthetic route of 5-bromo-2-chlorobenzoic acid mainly contains the following kinds:

[0004] Route 1: Using 5-bromo-2-chlorobenzotrifluoride as the starting material, directly hydrolyze it under acidic conditions to obtain 5-bromo-2-chlorobenzoic acid [see Document 1].

[0005] The raw materials used in this route are very expensive and difficult to obtain, and a large amount of fluorine-containing waste water will b...

Examples

Embodiment 1）

[0052] The present embodiment is the preparation of 2-hydroxyl-5-bromo-benzoic acid, and the specific method is as follows:

[0053] Add 138.0g of salicylic acid (1.0mol), 6.68g of aluminum trichloride (0.05mol), and 1.0L of 1,2-dichloroethane into a three-necked flask, heat to 45°C, and dropwise add 176.0g of Bromine (1.1mol), the temperature was raised to reflux after dropping, and reacted for 15h.

[0054] The reaction controlled by HPLC was completed, and the ratio of 2-hydroxy-5-bromo-benzoic acid to 2-hydroxy-3-bromo-benzoic acid was about 6:1.

[0055] The reacted system was cooled to 0°C with ice water, and then saturated aqueous sodium bisulfite solution was added to the system with stirring until it was colorless, left to stand for liquid separation, the organic layer was washed with water and saturated brine successively, concentrated under reduced pressure, Then add ethanol / tetrahydrofuran mixed solvent (volume ratio 1:5), heat up to 70°C and stir to dissolve, and...

Embodiment 2）

[0057] The present embodiment is the preparation of 2-hydroxyl-5-bromo-benzoic acid, and the specific method is as follows:

[0058] Add 138.0g of salicylic acid (1.0mol) and 1.5L of acetic acid into a three-necked flask, heat to 80°C, add 300.0g of dibromohydantoin (1.05mol) in batches, and keep stirring at this temperature to react 12h.

[0059] The reaction controlled by HPLC was completed, and the ratio of 2-hydroxy-5-bromo-benzoic acid to 2-hydroxy-3-bromo-benzoic acid was about 7.5:1.

[0060] Cool the reacted system to room temperature, then pour it into 2L of ice water at one time, precipitate a yellow solid, filter, dry, then add ethanol / tetrahydrofuran mixed solvent (volume ratio 1:5), heat up to 70°C and stir to dissolve, Finally, it was slowly cooled to room temperature, stirred and crystallized, filtered and dried to obtain 156.0 g of white solid 2-hydroxy-5-bromo-benzoic acid with a yield of 71.9% and a purity of 96.5% (HPLC).

Embodiment 3）

[0062] The present embodiment is the preparation of 2-hydroxyl-5-bromo-benzoic acid, and the specific method is as follows:

[0063] Add 12.2g of sodium metavanadate (0.1mol), 26.7g of aluminum tribromide (0.1mol) and 338.0g of tetrabutylammonium bromide (1.05mol) to a 5L three-necked flask, then fill with oxygen, and then add 138.0g of salicylic acid (1.0mol), 2L of 1,4-dioxane, and 1.8g of water (0.1mol), heated to 80°C and stirred for 8h, supplemented with oxygen during the reaction.

[0064] The reaction controlled by HPLC was completed, and the ratio of 2-hydroxy-5-bromo-benzoic acid to 2-hydroxy-3-bromo-benzoic acid was about 24:1.

[0065] The reacted system was cooled to room temperature, then 1N hydrochloric acid was added, and then extracted with ethyl acetate (1L×2). The organic layers were combined and washed with water and saturated brine in turn. The solvent was evaporated under reduced pressure, and then ethanol / tetrahydrofuran was added to mix Solvent (volume ...