Preparation method of high-selectivity 5-bromo-2-chlorobenzoic acid

Abstract

The invention provides a novel method for preparing 5-bromine-2-chlorobenzoic acid with high selectivity, and particularly relates to a method for preparing 5-bromine-2-chlorobenzoic acid with high selectivity by taking dibrominated amino silica gel as a brominating reagent, iron trifluoromethanesulfonate as a catalyst and halogenated hydrocarbon as a solvent. According to the novel method, dibrominated amino silica gel can be recycled, wherein the 6-time recovery rate reaches 98%; and the method is environment-friendly in process, simple and convenient to operate, low in EHS risk, high in product yield (more than or equal to 95%) and good in quality (more than or equal to 99.8%), is a process suitable for industrial production, greatly reduces the production cost of 5-bromo-2-chlorobenzoic acid, and remarkably reduces environmental pollution and resource consumption in the production process.

Description

technical field

[0001] The invention belongs to the technical field of organic synthesis chemistry and relates to a preparation method of highly selective 5-bromo-2-chlorobenzoic acid. More specifically, the present invention relates to a method for preparing 5-bromo-2-chlorobenzoic acid with high regioselectivity using brominated amino silica gel as a bromination reagent and ferric trifluoromethanesulfonate as a catalyst. Background technique

[0002] 5-Bromo-2-chlorobenzoic acid is an important class of pharmaceutical and chemical raw materials, which can be used to synthesize sodium-glucose cotransporter 2 (SGLT-2) inhibitors for diabetes treatment drugs, such as dapagliflozin and empagliflozin , Egeliejing, etc. SGLT-2 inhibitors reduce blood glucose concentration by selectively inhibiting SGLT-2, reducing proximal tubular glucose reabsorption, and increasing urinary glucose excretion. This unique non-insulin-dependent mechanism of action can promote the "escape" of gl...

Examples

Embodiment 1

[0041] Embodiment 1: the preparation of dibromoamine-based silica gel described in the present invention

[0042] Add 100g (1.31mol) of amino silica gel to a 2L three-necked flask, add 500mL of dichloromethane, start stirring, and then add 363g (2.63mol) of K 2 CO 3 After stirring evenly, add 461g (2.88mol) of bromine, heat to 40-45°C and stir under reflux for 5-6 hours. After filtration, the resulting solid is dibromoamino silica gel, dried under reduced pressure at room temperature for 8 hours, and set aside.

Embodiment 2

[0043] Embodiment 2: technical scheme described in the present invention

[0044] Add 20g 2-chlorobenzoic acid (0.128mol), 32.9g dibromoamino silica gel (0.141mol, 1.1eq) and 0.96g iron trifluoromethanesulfonate (1.9mmol, 0.015eq) respectively in a 1L three-necked flask , and then add 160mL of 1-chlorobutane to the three-neck flask, stir and suspend, and heat the suspension to 60-70°C and stir for 10-12 hours.

[0045] After the reaction, 1-chlorobutane was concentrated to dryness under reduced pressure at 40-50°C, then 100 mL of toluene was added and heated to 70-80°C and stirred for 2-3 hours to dissolve the product 5-bromo-2-chlorobenzoic acid. Silica gel was filtered off while hot, and a small amount of filtrate was taken to analyze the reaction selectivity by HPLC. The HPLC results showed that the target product 5-bromo-2-chlorobenzoic acid was 99.3%, and 3-bromo-2-chlorobenzoic acid was 0.35%. The remaining filtrate was naturally cooled to 0-10°C and stirred for 1-2 hou...

Embodiment 3

[0046] Embodiment 3: technical scheme described in the present invention

[0047] Add 20g 2-chlorobenzoic acid (0.128mol), 38.9g dibromoamino silica gel (0.166mol, 1.3eq) and 1.3g iron trifluoromethanesulfonate (2.56mmol, 0.02eq) respectively in a 1L three-necked flask , and then add 160mL of 1-chlorobutane to the three-necked flask and stir to suspend, heat the suspension to 60-70°C and stir for 8-10 hours.

[0048] After the reaction, 1-chlorobutane was concentrated to dryness under reduced pressure at 40-50°C, then 100 mL of toluene was added and heated to 70-80°C and stirred for 2-3 hours to dissolve the product 5-bromo-2-chlorobenzoic acid. Silica gel was filtered off while hot, and a small amount of filtrate was taken to analyze the reaction selectivity by HPLC. The HPLC results showed that the target product 5-bromo-2-chlorobenzoic acid was 99.1%, and 3-bromo-2-chlorobenzoic acid was 0.41%. The remaining filtrate was naturally cooled to 0-10°C and stirred for 1-2 hours...

technical field

[0001] The invention belongs to the technical field of organic synthesis chemistry and relates to a preparation method of highly selective 5-bromo-2-chlorobenzoic acid. More specifically, the present invention relates to a method for preparing 5-bromo-2-chlorobenzoic acid with high regioselectivity using brominated amino silica gel as a bromination reagent and ferric trifluoromethanesulfonate as a catalyst. Background technique

[0002] 5-Bromo-2-chlorobenzoic acid is an important class of pharmaceutical and chemical raw materials, which can be used to synthesize sodium-glucose cotransporter 2 (SGLT-2) inhibitors for diabetes treatment drugs, such as dapagliflozin and empagliflozin , Egeliejing, etc. SGLT-2 inhibitors reduce blood glucose concentration by selectively inhibiting SGLT-2, reducing proximal tubular glucose reabsorption, and increasing urinary glucose excretion. This unique non-insulin-dependent mechanism of action can promote the "escape" of gl...

Examples

Embodiment 1

[0041] Embodiment 1: the preparation of dibromoamine-based silica gel described in the present invention

[0042] Add 100g (1.31mol) of amino silica gel to a 2L three-necked flask, add 500mL of dichloromethane, start stirring, and then add 363g (2.63mol) of K 2 CO 3 After stirring evenly, add 461g (2.88mol) of bromine, heat to 40-45°C and stir under reflux for 5-6 hours. After filtration, the resulting solid is dibromoamino silica gel, dried under reduced pressure at room temperature for 8 hours, and set aside.

Embodiment 2

[0043] Embodiment 2: technical scheme described in the present invention

[0044] Add 20g 2-chlorobenzoic acid (0.128mol), 32.9g dibromoamino silica gel (0.141mol, 1.1eq) and 0.96g iron trifluoromethanesulfonate (1.9mmol, 0.015eq) respectively in a 1L three-necked flask , and then add 160mL of 1-chlorobutane to the three-neck flask, stir and suspend, and heat the suspension to 60-70°C and stir for 10-12 hours.

[0045] After the reaction, 1-chlorobutane was concentrated to dryness under reduced pressure at 40-50°C, then 100 mL of toluene was added and heated to 70-80°C and stirred for 2-3 hours to dissolve the product 5-bromo-2-chlorobenzoic acid. Silica gel was filtered off while hot, and a small amount of filtrate was taken to analyze the reaction selectivity by HPLC. The HPLC results showed that the target product 5-bromo-2-chlorobenzoic acid was 99.3%, and 3-bromo-2-chlorobenzoic acid was 0.35%. The remaining filtrate was naturally cooled to 0-10°C and stirred for 1-2 hou...

Embodiment 3

[0046] Embodiment 3: technical scheme described in the present invention

[0047] Add 20g 2-chlorobenzoic acid (0.128mol), 38.9g dibromoamino silica gel (0.166mol, 1.3eq) and 1.3g iron trifluoromethanesulfonate (2.56mmol, 0.02eq) respectively in a 1L three-necked flask , and then add 160mL of 1-chlorobutane to the three-necked flask and stir to suspend, heat the suspension to 60-70°C and stir for 8-10 hours.

[0048] After the reaction, 1-chlorobutane was concentrated to dryness under reduced pressure at 40-50°C, then 100 mL of toluene was added and heated to 70-80°C and stirred for 2-3 hours to dissolve the product 5-bromo-2-chlorobenzoic acid. Silica gel was filtered off while hot, and a small amount of filtrate was taken to analyze the reaction selectivity by HPLC. The HPLC results showed that the target product 5-bromo-2-chlorobenzoic acid was 99.1%, and 3-bromo-2-chlorobenzoic acid was 0.41%. The remaining filtrate was naturally cooled to 0-10°C and stirred for 1-2 hours...

Images