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CN113801010A - Preparation method of 5-bromo-2-chlorobenzoic acid - Google Patents

Preparation method of 5-bromo-2-chlorobenzoic acid Download PDF

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CN113801010A
CN113801010A CN202111365309.7A CN202111365309A CN113801010A CN 113801010 A CN113801010 A CN 113801010A CN 202111365309 A CN202111365309 A CN 202111365309A CN 113801010 A CN113801010 A CN 113801010A
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acid
bromo
sodium
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吕志涛
谭光明
于华智
刘彬彬
高长彬
王士忠
陈立伟
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Shandong Chengchuang Blue Sea Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters

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Abstract

The application discloses a preparation method of 5-bromo-2-chlorobenzoic acid, belonging to the field of drug synthesis. The preparation method comprises the following steps: (1) carrying out esterification reaction on 2-nitrobenzoic acid and alcohol to obtain a first intermediate; (2) carrying out reduction reaction on the first intermediate and a first reducing agent to obtain a second intermediate; (3) carrying out halogenation reaction on the second intermediate and the first halogenated reagent, adding a second reducing agent into a reaction system after the halogenation reaction is finished, carrying out reduction reaction, and then carrying out hydrolysis reaction on the second intermediate and alkali to obtain 5-bromo-2-aminobenzoic acid; (4) the 5-bromo-2-aminobenzoic acid and a diazotization reagent undergo a diazotization reaction, and then undergo a halogenation reaction with a second halogenating reagent to obtain the 5-bromo-2-chlorobenzoic acid. The preparation method has the advantages of mild reaction conditions, safe and simple operation, short production period, cheap and easily-obtained raw materials and solvents, no explosive products and no highly toxic products, and is beneficial to environmental protection; the prepared product has higher yield and purity, and is beneficial to industrial production.

Description

Preparation method of 5-bromo-2-chlorobenzoic acid
Technical Field
The application belongs to the field of drug synthesis, and particularly relates to a preparation method of 5-bromo-2-chlorobenzoic acid.
Background
5-bromo-2-chlorobenzoic acid has important use in the synthesis of medicine, is the synthetic raw material of hypoglycemic drugs such as engelet, dapagliflozin, soagliflozin, egagliflozin, and the like, and the drug is a sodium-glucose cotransporter 2 inhibitor which can reduce the reabsorption of the kidney to glucose and is used for treating type 2 diabetes patients.
According to literature reports, there are two main methods for synthesizing 5-bromo-2-chlorobenzoic acid:
the first method comprises the following steps: toluene is used as an initial raw material and reacts with chlorine to obtain o-chlorotoluene, potassium permanganate is used for oxidizing methyl to obtain o-chlorobenzoic acid, and then bromination reaction is carried out on the o-chlorobenzoic acid and liquid bromine or NBS to obtain the 5-bromine-2-chlorobenzoic acid. However, the method is very easy to generate dichlorinated impurity in the toluene chlorination reaction, and the impurity is not easy to remove; when potassium permanganate is used for carrying out oxidation reaction on methyl, the product yield is low and is only 55 percent, and the industrial production is not facilitated. The synthetic route of the method is as follows:
Figure 50503DEST_PATH_IMAGE001
。
the second method comprises the following steps: the method comprises the steps of taking o-chlorotoluene as a starting material, reacting with chlorine by taking phosphorus pentachloride as a catalyst under the irradiation of ultraviolet light to obtain o-chlorotrifluoromethylene, hydrolyzing with glacial acetic acid to obtain o-chlorobenzoic acid, and bromizing the o-chlorobenzoic acid with liquid bromine or NBS to obtain 5-bromine-2-chlorobenzoic acid. In the method, during chlorination reaction, phosphorus pentachloride and o-chlorotoluene are solid-liquid two phases at the early stage of the reaction, so that the penetration rate of ultraviolet rays to common glass is poor, the reaction time is longer, and reduced pressure distillation purification is needed after the reaction is finished, so that the yield is lower and is only 40%. Therefore, the method has the advantages of longer production period, lower yield and higher environmental protection pressure, and is not beneficial to industrial production. The synthetic route of the method is as follows:
Figure 108589DEST_PATH_IMAGE002
。
therefore, how to provide a preparation method of 5-bromo-2-chlorobenzoic acid which is safe, high in yield, short in production period and suitable for industrial production becomes a problem to be solved urgently.
Disclosure of Invention
In order to solve the problems, the application provides a preparation method of 5-bromo-2-chlorobenzoic acid, which has mild reaction conditions, safe and simple operation, short production period, cheap and easily obtained raw materials and solvents, no explosive product and no toxic product, and is beneficial to environmental protection; the prepared product has higher yield and purity, and is beneficial to industrial production.
The application provides a preparation method of 5-bromo-2-chlorobenzoic acid, which comprises the following steps:
(1) carrying out esterification reaction on 2-nitrobenzoic acid and alcohol to obtain a first intermediate;
(2) carrying out reduction reaction on the first intermediate obtained in the step (1) and a first reducing agent to obtain a second intermediate;
(3) performing halogenation reaction on the second intermediate obtained in the step (2) and a first halogenated reagent, adding a second reducing agent into a reaction system after the halogenation reaction is completed, performing reduction reaction, and performing hydrolysis reaction on the second intermediate and alkali to obtain 5-bromo-2-aminobenzoic acid;
(4) and (4) carrying out diazotization reaction on the 5-bromo-2-aminobenzoic acid obtained in the step (3) and a diazotization reagent, and then carrying out halogenation reaction on the diazotization reagent and a second halogenating reagent to obtain the 5-bromo-2-chlorobenzoic acid.
The reaction scheme of the present application is as follows:
Figure 419484DEST_PATH_IMAGE003
。
r1 and R2 are independently selected from C1-C6 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, more preferably methyl, ethyl, isopropyl or n-butyl.
Preferably, the molar ratio of 2-nitrobenzoic acid to alcohol in step (1) is 1: (1 to 3), more preferably 1: (1.5-2).
Preferably, the alcohol in step (1) is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, n-pentanol, n-hexanol, ethylene glycol, glycerol, propylene glycol, pentaerythritol, propylene alcohol or vinyl alcohol, more preferably methanol, ethanol, isopropanol, n-butanol or t-butanol.
Preferably, the solvent for the esterification reaction in step (1) is dichloromethane, toluene, xylene or alcohol in step (1).
Preferably, the first reducing agent used in the reduction reaction in step (2) is selected from hydrogen, formic acid, ammonium formate, iron powder, zinc powder, sodium sulfide, sodium disulfide, lithium aluminum hydride or sodium borohydride, more preferably hydrogen, formic acid, ammonium formate, iron powder or zinc powder; when the first reducing agent is hydrogen, formic acid or ammonium formate, adding a metal catalyst; the metal catalyst is selected from palladium carbon, platinum carbon or Raney nickel.
Preferably, the solvent for the reduction reaction of step (2) is one or more of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate and toluene, more preferably one or more of water, methanol, ethanol and ethyl acetate.
Preferably, the reaction temperature of the reduction reaction in the step (2) is 0-90 ℃, and more preferably 20-70 ℃.
Preferably, the molar ratio of the second intermediate to the first halogenating agent in step (3) is 1: (0.8 to 2), more preferably 1: (0.8 to 1.5).
Preferably, the first halogen reagent in step (3) is selected from elemental bromine, N-bromosuccinimide (NBS), pyridinium Perbromide Hydrobromide (PHP), dibromohydantoin (DBDMH), pyridinium tribromide (PBP), tetrabromocycloketone, phosphorus tribromide, more preferably elemental bromine, N-bromosuccinimide.
Preferably, the base in step (3) is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, pyridine, triethylamine, N-diisopropylethylamine and 1, 8-diazabicycloundec-7-ene (DBU), more preferably sodium hydroxide or sodium carbonate;
preferably, the solvent for the halogenation reaction in the step (3) is one or more of ethyl acetate, methyl acetate, carbon tetrachloride, dichloromethane, acetonitrile, N-Dimethylformamide (DFM), dimethyl sulfoxide (DMSO), toluene, xylene, N-hexane and cyclohexane, and more preferably one or more of dichloromethane, ethyl acetate, xylene and toluene.
Preferably, the reaction temperature of the halogenation reaction in the step (3) is-20 to 50 ℃, and more preferably-10 to 30 ℃.
Preferably, the second reducing agent in step (3) is selected from sodium sulfite, sodium bisulfite, sodium thiosulfate or sodium dithionite (sodium hydrosulfite). After the halogenation reaction in the step (3) is finished, a second reducing agent is added to remove the excessive halogenating reagent, so that the generation of byproducts can be effectively controlled.
Preferably, the reaction temperature of the diazotization reaction in the step (4) is-20-50 ℃, and more preferably-10 ℃.
Preferably, the molar ratio of the 5-bromo-2-aminobenzoic acid, the diazotizing agent and the second halogenating agent in step (4) is 1: (0.9-2): (1.1 to 3), more preferably 1: (1.2-2): (1.5-2.5).
Preferably, the diazotizing agent in step (4) is selected from the group consisting of a combination of sodium nitrite and hydrochloric acid, nitrous acid, n-butyl nitrite or isoamyl nitrite, more preferably a combination of sodium nitrite and hydrochloric acid or n-butyl nitrite.
In the step (4), the second halogenated reagent is one or more of potassium chloride, copper chloride, cuprous chloride, N-chlorosuccinimide, phosphorus oxychloride, trichloroisocyanuric acid and chloramine T, and potassium chloride or cuprous chloride is more preferable.
The solvent for the diazotization reaction and the halogenation reaction in the step (4) is one or more of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile and toluene, and more preferably one or more of water, methanol and acetonitrile.
The application also provides the application of the preparation method of the 5-bromo-2-chlorobenzoic acid in preparing hypoglycemic drugs.
Benefits of the present application include, but are not limited to:
the preparation method of 5-bromo-2-chlorobenzoic acid provided by the application has the advantages of mild reaction conditions, safe and simple operation, short production period, cheap and easily-obtained raw materials and solvents, no explosive products and no highly toxic products, and is beneficial to environmental protection; the prepared product has higher yield and purity, and is beneficial to industrial production.
Detailed Description
The present application will be described in detail with reference to examples, but the present application is not limited to these examples.
The raw materials, solvents and reagents in the examples of the present application were all purchased commercially unless otherwise specified.
Example 1
Adding 2-nitrobenzoic acid (50 g, 0.299 mol) into dichloromethane (200 mL), stirring, adding thionyl chloride (42.7 g, 0.359 mol), heating to reflux temperature, refluxing for 5 hours, and stopping the reaction, wherein the raw material is less than 1% remained; cooling to below 5 ℃, dropwise adding methanol (15 g, 0.469 mol), controlling the temperature below 10 ℃ in the dropwise adding process, stirring for 30 minutes after the dropwise adding is finished, and concentrating under reduced pressure at 40 ℃ to obtain 48.8g of 2-nitrobenzoic acid methyl ester (first intermediate) in a light yellow liquid state, wherein the yield is 90% and the purity is 99.2%.
Example 2
Adding 2-nitrobenzoic acid (50 g, 0.299 mol) into methanol (200 mL), stirring, cooling to 0-5 ℃, dropwise adding thionyl chloride (42.7 g, 0.359 mol), reacting for 1 hour at the temperature of 0-5 ℃ after dropwise adding, slowly heating to reflux temperature after reaction, refluxing for 2 hours until the raw material residue is less than 1%, stopping reaction, and concentrating under reduced pressure at 40 ℃ to obtain 49.3g of yellow liquid methyl 2-nitrobenzoate (first intermediate), wherein the yield is 91% and the purity is 99.3%.
Example 3
2-nitrobenzoic acid (50 g, 0.299 mol) was added to toluene (200 mL), stirred, anhydrous magnesium sulfate (20 g) and ethanol (22 g, 0.478 mol) were added, the temperature was raised to reflux temperature, reflux reaction was carried out for 7 hours, the reaction was stopped when <1% of the raw material remained, the filtrate was concentrated under reduced pressure, and 51.3g of 2-nitrobenzoic acid ethyl ester (first intermediate) was obtained as a pale yellow liquid, with a yield of 87.8% and a purity of 99.6%.
Example 4
Methyl 2-nitrobenzoate (40 g, 0.221 mol) prepared in example 1 or example 2 was added to a 500mL autoclave, methanol (200 mL) and 10% palladium on carbon (2 g) were then added, hydrogen was introduced, the mixture was replaced with 3 times, stirred, pressurized to 0.5MPa, heated to 60 ℃, reacted for 6 hours with <1% of the remaining starting material, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure at 50 ℃ to obtain 31.4g of methyl 2-aminobenzoate (second intermediate) as a yellow liquid in a yield of 94.1% and a purity of 99.3%.
Example 5
The ethyl 2-nitrobenzoate (40 g, 0.205 mol) prepared in example 3 was added to a 500mL autoclave, methanol (200 mL) and 10% palladium on carbon (2 g) were then added, hydrogen gas was introduced to replace 3 times, stirring was carried out, pressure was increased to 0.5MPa, the temperature was raised to 60 ℃, reaction was carried out for 6 hours, the raw material residue was <1%, temperature was reduced to room temperature, filtration was carried out, and the filtrate was concentrated under reduced pressure at 50 ℃ to obtain 32.3g of yellow liquid ethyl 2-aminobenzoate (second intermediate), yield was 95.4%, and purity was 99.2%.
Example 6
Adding methyl 2-aminobenzoate (30 g, 0.198 mol) prepared in example 4 into dichloromethane (180 mL), stirring, cooling to 10 ℃, starting to dropwise add a dichloromethane solution containing bromine (31.7 g, 0.198mol and 60mL of dichloromethane), controlling the temperature to be less than 20 ℃ in the dropwise adding process, stirring at room temperature for 1 hour after the dropwise adding is finished, dropwise adding a 10% sodium sulfite solution (200 mL) when the raw material is less than 1% left, separating, keeping an organic phase, adding water (120 g) into the organic phase, stirring, adjusting the pH value to 1 with hydrochloric acid, separating, keeping an aqueous phase, adding sodium hydroxide (8.5 g) (pH is greater than 10), stirring for 1 hour, washing the aqueous phase with dichloromethane (60 mL), discarding the organic phase, adjusting the pH value of the aqueous phase with hydrochloric acid to 6-7, precipitating a large amount of solid, filtering, drying by air blowing at 50 ℃ to obtain 37.8g of 5-bromo-2-aminobenzoic acid as a white solid, the yield was 88.2% and the purity was 99.7%.
Example 7
Adding ethyl 2-aminobenzoate (30 g, 0.182 mol) prepared in example 5 into dichloromethane (180 mL), stirring, cooling to 10 ℃, starting to dropwise add a dichloromethane solution containing bromine (29.1 g, 0.182mol and 60mL of dichloromethane), controlling the temperature to be less than 20 ℃ in the dropwise adding process, stirring at room temperature for 1 hour after the dropwise adding is finished, dropwise adding a 10% sodium sulfite solution (200 mL) when the raw material is less than 1% left, separating, keeping an organic phase, adding water (120 g) into the organic phase, stirring, adjusting the pH value to 1 with hydrochloric acid, separating, keeping an aqueous phase, adding sodium hydroxide (7.8 g) (pH is greater than 10), stirring for 2 hours, washing the aqueous phase with dichloromethane (60 mL), discarding the organic phase, adjusting the pH value of the aqueous phase with hydrochloric acid to 6-7, precipitating a large amount of solid, filtering, drying by air blowing at 50 ℃ to obtain 34g of 5-bromo-2-aminobenzoic acid as a white solid, the yield was 86.6% and the purity was 99.7%.
Example 8
5-bromo-2-aminobenzoic acid prepared in example 6 or example 7 (30 g, 0.139 mol) was added to water (90 g), stirred, cooled to-5 ℃ and concentrated hydrochloric acid (36 mL) was added dropwise, with the temperature controlled to be less than 0 ℃ during the dropwise addition, stirred for 30 minutes after the dropwise addition was completed, after the solid was completely dissolved, the dropwise addition of an aqueous solution of sodium nitrite (12.5 g, 0.181mol, 30g of water) was started, and stirred for 1 hour after the dropwise addition was completed. Dropwise adding a hydrochloric acid-cuprous chloride solution (21 g of cuprous chloride, 0.212mol of hydrochloric acid, 37.5mL of hydrochloric acid and 37.5g of water) into the reaction system, controlling the temperature to be less than 5 ℃ in the dropwise adding process, heating to room temperature after the dropwise adding is finished, reacting for 8 hours, extracting the residual raw material of less than 1% twice by using ethyl acetate, combining organic phases, washing once by using saturated saline solution, separating liquid, adding anhydrous sodium sulfate into the organic phase for drying, filtering, and evaporating the filtrate at 50 ℃ under reduced pressure to dryness to obtain 27.8g of 5-bromo-2-chlorobenzoic acid as a white solid, wherein the yield is 85% and the purity is 99.4%.
Example 9
5-bromo-2-aminobenzoic acid prepared in example 6 or example 7 (30 g, 0.139 mol) was added to water (90 g), stirred, cooled to 5 ℃ and concentrated hydrochloric acid (36 mL) was added dropwise, with the temperature controlled to be less than 10 ℃ during the dropwise addition, stirred for 30 minutes after the dropwise addition was completed, after the solid was completely dissolved, the dropwise addition of an aqueous solution of sodium sulfite (12.5 g, 0.181mol, water 30 g) was started, and stirred for 1 hour after the dropwise addition was completed. Dropwise adding a hydrochloric acid-cuprous chloride solution (21 g of cuprous chloride, 0.212mol of hydrochloric acid, 37.5mL of hydrochloric acid and 37.5g of water) into the reaction system, controlling the temperature to be less than 5 ℃ in the dropwise adding process, heating to room temperature after the dropwise adding is finished, reacting for 8 hours, extracting the residual raw material of less than 1% twice by using ethyl acetate, combining organic phases, washing once by using saturated saline solution, separating liquid, adding anhydrous sodium sulfate into the organic phase for drying, filtering, and evaporating the filtrate at 50 ℃ under reduced pressure to dryness to obtain 27.5g of 5-bromo-2-chlorobenzoic acid as a white solid, wherein the yield is 84.1% and the purity is 99.5%.
Examples 1 to 3 are the preparation steps of the first intermediate, the yield of which reaches 87.8% or more and the purity of which reaches 99.2% or more; examples 4 to 5 are the preparation steps of the second intermediate, the yield of the second intermediate reaches more than 94.1%, and the purity reaches 99.2%; example 6-7 is a preparation procedure of 5-bromo-2-aminobenzoic acid, the yield of 5-bromo-2-aminobenzoic acid reached over 86.6%, and the purity reached 99.7%; example 8-9 is a preparation procedure of 5-bromo-2-chlorobenzoic acid, and the yield of 5-bromo-2-chlorobenzoic acid was 84.1% or more and the purity was 99.4% or more.
According to the embodiment, the preparation method has mild reaction conditions, is safe and simple to operate, reduces the emission of acid gas, and is beneficial to environmental protection; the used raw materials and solvents are cheap and easy to obtain, and no dangerous chemical raw materials such as strong toxicity and explosive are generated; the product prepared in each step has high yield and purity, and is suitable for industrial production.
The above description is only an example of the present application, and the protection scope of the present application is not limited by these specific examples, but is defined by the claims of the present application. Various modifications and changes may occur to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the technical idea and principle of the present application should be included in the protection scope of the present application.

Claims (10)

1. A preparation method of 5-bromo-2-chlorobenzoic acid is characterized by comprising the following steps:
(1) carrying out esterification reaction on 2-nitrobenzoic acid and alcohol to obtain a first intermediate;
(2) carrying out reduction reaction on the first intermediate obtained in the step (1) and a first reducing agent to obtain a second intermediate;
(3) performing halogenation reaction on the second intermediate obtained in the step (2) and a first halogenated reagent, adding a second reducing agent into a reaction system after the halogenation reaction is completed, performing reduction reaction, and performing hydrolysis reaction on the second intermediate and alkali to obtain 5-bromo-2-aminobenzoic acid;
(4) and (4) carrying out diazotization reaction on the 5-bromo-2-aminobenzoic acid obtained in the step (3) and a diazotization reagent, and then carrying out halogenation reaction on the diazotization reagent and a second halogenating reagent to obtain the 5-bromo-2-chlorobenzoic acid.
2. The production method according to claim 1, wherein the molar ratio of 2-nitrobenzoic acid to alcohol in the step (1) is 1: (1-3).
3. The method according to claim 1, wherein the alcohol in the step (1) is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, n-pentanol, n-hexanol, ethylene glycol, glycerol, propylene glycol, pentaerythritol, allyl alcohol, and vinyl alcohol;
the solvent for the esterification reaction in the step (1) is dichloromethane, toluene, xylene or alcohol in the step (1).
4. The preparation method according to claim 1, wherein the first reducing agent used in the reduction reaction in step (2) is selected from hydrogen gas, formic acid, ammonium formate, iron powder, zinc powder, sodium sulfide, sodium disulfide, lithium aluminum hydride, or sodium borohydride; when the first reducing agent is hydrogen, formic acid or ammonium formate, adding a metal catalyst; the metal catalyst is selected from palladium carbon, platinum carbon or Raney nickel;
the solvent of the reduction reaction in the step (2) is one or more of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate and toluene;
the reaction temperature of the reduction reaction in the step (2) is 0-90 ℃.
5. The method according to claim 1, wherein the molar ratio of the second intermediate to the first halogenating agent in the step (3) is 1: (0.8-2).
6. The method of claim 1, wherein the first halogenating agent in step (3) is selected from elemental bromine, N-bromosuccinimide, pyridinium perbromide hydrobromide, dibromohydantoin, pyridinium tribromide, tetrabromocycloketone, phosphorus tribromide;
the alkali in the step (3) is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, pyridine, triethylamine, N-diisopropylethylamine and 1, 8-diazabicycloundecen-7-ene;
the solvent of the halogenation reaction in the step (3) is one or more of ethyl acetate, methyl acetate, carbon tetrachloride, dichloromethane, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, toluene, xylene, N-hexane and cyclohexane;
the reaction temperature of the halogenation reaction in the step (3) is-20-50 ℃.
7. The method according to claim 1, wherein the second reducing agent in the step (3) is selected from sodium sulfite, sodium bisulfite, sodium thiosulfate and sodium dithionite.
8. The preparation method according to claim 1, wherein the reaction temperature of the diazotization reaction in the step (4) is-20 to 50 ℃.
9. The production method according to claim 1, wherein the molar ratio of the 5-bromo-2-aminobenzoic acid, the diazotizing agent, and the second halogenating agent in the step (4) is 1: (0.9-2): (1.1-3).
10. The method according to claim 1, wherein the diazotizing agent in the step (4) is selected from the group consisting of a combination of sodium nitrite and hydrochloric acid, nitrous acid, n-butyl nitrite, isoamyl nitrite;
in the step (4), the second halogenated reagent is one or more of potassium chloride, copper chloride, cuprous chloride, N-chlorosuccinimide, phosphorus oxychloride, trichloroisocyanuric acid and chloramine T;
the solvent for diazotization and halogenation in the step (4) is one or more of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile and toluene.
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* Cited by examiner, † Cited by third party
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CN114516806A (en) * 2022-02-21 2022-05-20 阜新都创新材料科技有限公司 Preparation method of 2, 6-dibromo-4-trifluoromethoxy aniline
WO2023019849A1 (en) * 2021-08-16 2023-02-23 浙江奥翔药业股份有限公司 Method for preparing 5-bromo-2-chloro-benzoic acid as raw material in hypoglycemic drug synthesis
CN117285411A (en) * 2023-09-11 2023-12-26 扬州市普林斯医药科技有限公司 Preparation method of 2' -bromo-o-fluoro acetophenone

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103596564A (en) * 2011-06-01 2014-02-19 株式会社绿十字 Novel diphenylmethane derivatives as SGLT2 inhibitors
US20140274918A1 (en) * 2013-03-18 2014-09-18 Green Cross Corporation Method for dual inhibition of sglt1 and sglt2 using diphenylmethane derivatives
CN104744227A (en) * 2013-12-25 2015-07-01 重庆博腾制药科技股份有限公司 5-bromine-2-chlorobenzaldehyde preparation method
CN108250060A (en) * 2018-01-26 2018-07-06 江苏尚莱特医药化工材料有限公司 The synthetic method of the bromo- 2- chlorobenzoic acids of 5-
CN109311861A (en) * 2016-06-17 2019-02-05 株式会社大熊制药 The method for being used to prepare diphenylmethane derivatives
CN110002989A (en) * 2019-03-15 2019-07-12 河北合佳医药科技集团股份有限公司 A kind of preparation method of the bromo- 2- chlorobenzoic acid of highly selective 5-
CN110590541A (en) * 2019-10-16 2019-12-20 吕东 Preparation method of 5-bromo-2-chlorobenzoic acid

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103596564A (en) * 2011-06-01 2014-02-19 株式会社绿十字 Novel diphenylmethane derivatives as SGLT2 inhibitors
US20140274918A1 (en) * 2013-03-18 2014-09-18 Green Cross Corporation Method for dual inhibition of sglt1 and sglt2 using diphenylmethane derivatives
CN104744227A (en) * 2013-12-25 2015-07-01 重庆博腾制药科技股份有限公司 5-bromine-2-chlorobenzaldehyde preparation method
CN109311861A (en) * 2016-06-17 2019-02-05 株式会社大熊制药 The method for being used to prepare diphenylmethane derivatives
CN108250060A (en) * 2018-01-26 2018-07-06 江苏尚莱特医药化工材料有限公司 The synthetic method of the bromo- 2- chlorobenzoic acids of 5-
CN110002989A (en) * 2019-03-15 2019-07-12 河北合佳医药科技集团股份有限公司 A kind of preparation method of the bromo- 2- chlorobenzoic acid of highly selective 5-
CN110590541A (en) * 2019-10-16 2019-12-20 吕东 Preparation method of 5-bromo-2-chlorobenzoic acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JUN LIAO等: "Synthesis and biological evaluation of novel fluconazole analogues bearing 1,3,4-oxadiazole moiety as potent antifungal agents", 《ARCHIVES OF PHARMACAL RESEARCH》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023019849A1 (en) * 2021-08-16 2023-02-23 浙江奥翔药业股份有限公司 Method for preparing 5-bromo-2-chloro-benzoic acid as raw material in hypoglycemic drug synthesis
CN114163309A (en) * 2021-12-27 2022-03-11 甘肃皓天医药科技有限责任公司 Preparation method of dorawirin intermediate
CN114516806A (en) * 2022-02-21 2022-05-20 阜新都创新材料科技有限公司 Preparation method of 2, 6-dibromo-4-trifluoromethoxy aniline
CN117285411A (en) * 2023-09-11 2023-12-26 扬州市普林斯医药科技有限公司 Preparation method of 2' -bromo-o-fluoro acetophenone

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