CN114369021B - Preparation method and application of 2-chloro-5-bromobenzoyl chloride - Google Patents

Preparation method and application of 2-chloro-5-bromobenzoyl chloride Download PDF

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CN114369021B
CN114369021B CN202210106091.1A CN202210106091A CN114369021B CN 114369021 B CN114369021 B CN 114369021B CN 202210106091 A CN202210106091 A CN 202210106091A CN 114369021 B CN114369021 B CN 114369021B
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柴文玉
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Heilongjiang Like New Material Co ltd
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/62—Preparation of carboxylic acid halides by reactions not involving the carboxylic acid halide group
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
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    • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
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    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention provides a preparation method and application of 2-chloro-5-bromobenzoyl chloride, wherein the preparation method comprises the following steps: 1) Reacting 2-chlorobenzoic acid with thionyl chloride under the catalysis of pyridine to obtain 2-chlorobenzoyl chloride; 2) Reacting 2-chlorobenzoyl chloride with dibromohydantoin to obtain 2-chloro-5-bromobenzoyl chloride. The preparation method has the advantages of high yield, low reaction cost, low toxicity of raw materials and environmental friendliness.

Description

Preparation method and application of 2-chloro-5-bromobenzoyl chloride
Technical Field
The invention belongs to the field of organic synthesis, and relates to a preparation method and application of 2-chloro-5-bromobenzoyl chloride.
Background
Diabetes is a disorder of glucose, protein and lipid metabolism due to in vivo insulin deficiency, increased hormone antagonizing insulin or failure of insulin to exert normal physiological actions in target cells, and is mainly manifested by hyperglycemia and metabolic disorders, which can lead to chronic damage and dysfunction of various tissues and organs in the human body, especially eyes, kidneys, heart, blood vessels, nerves.
Therapeutic drugs for diabetes have been a hotspot in drug development. Dapagliflozin is a novel antidiabetic drug, is a high-selectivity human kidney sodium glucose cotransporter inhibitor, has a chemical structural formula shown in formula 1, and has the function mechanism of inhibiting the reabsorption of glucose by kidneys, and promoting the excretion of glucose through urine, so that blood sugar is reduced. Dapagliflozin can be used as a treatment for diet control and exercise assistance for first-line treatment of type 2 diabetics who are not treated with drugs, only for diet control and exercise but not for glycemic control, to improve glycemic control.
The 2-chloro-5-bromobenzoyl chloride is a key intermediate for preparing dapagliflozin, and the chemical structural formula of the intermediate is shown as formula 2. In the prior art, the method for preparing 2-chloro-5-bromobenzoyl chloride generally takes 2-chlorobenzoic acid as a starting material, wherein the first step uses thionyl chloride or oxalyl chloride to carry out acyl chlorination reaction, and the second step uses liquid bromine as a brominating agent to carry out bromination reaction. In the method, when the acylation reaction is carried out by thionyl chloride in the first step of reaction, the raw material conversion is incomplete, so that the yield of the product is low, and when the acylation reaction is carried out by oxalyl chloride in the first step of reaction, the oxalyl chloride is inconvenient to transport, and has high toxicity and high price; the liquid bromine used in the second step reaction has strong corrosiveness and toxicity, and bromine vapor can be generated in the bromine adding process, so that the environment is polluted and the physical health of people is endangered.
Therefore, the development of a preparation method of the 2-chloro-5-bromobenzoyl chloride with high yield, low cost and environmental friendliness has important significance.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of 2-chloro-5-bromobenzoyl chloride, which takes 2-chlorobenzoic acid as an initial raw material, reacts with thionyl chloride under the catalysis of pyridine to obtain 2-chlorobenzoyl chloride, and then carries out bromination reaction by using dibromo hydantoin as a brominating agent, so that the product 2-chloro-5-bromobenzoyl chloride can be obtained with high yield. The preparation method has the advantages of high yield, low reaction cost, low toxicity of raw materials and environmental friendliness. The preparation method is used for synthesizing dapagliflozin medicine, can improve the medicine synthesis yield and reduce the medicine synthesis cost.
The invention provides a preparation method of 2-chloro-5-bromobenzoyl chloride, which comprises the following steps:
1) Reacting 2-chlorobenzoic acid with thionyl chloride under the catalysis of pyridine to obtain 2-chlorobenzoyl chloride;
2) Reacting 2-chlorobenzoyl chloride with dibromohydantoin to obtain 2-chloro-5-bromobenzoyl chloride.
The preparation process as described above, wherein the reaction of step 2) is carried out under acid catalysis.
A process as described above wherein the acid is selected from glacial acetic acid and/or concentrated sulfuric acid.
The preparation method comprises the following steps of: (1-1.5): (0.005-0.02).
The preparation method comprises the following steps of: (1-1.3): (1-2.5).
The preparation method as described above, wherein step 1) comprises: and (3) dropwise adding sulfoxide chloride into the mixed solution of 2-chlorobenzoic acid and pyridine, wherein the dropwise adding speed is 10-12 min/g.
The preparation method as described above, wherein the reaction of step 1) is performed in a heated reflux state.
The preparation method as described above, wherein step 2) comprises: and adding dibromohydantoin into the mixed solution of 2-chlorobenzoyl chloride and the acid in batches within 20-35 min.
The preparation process as described above, wherein the reaction of step 2) is carried out at 20 to 30 ℃.
The invention also provides an application of the preparation method in the synthesis of dapagliflozin medicaments.
Compared with the prior art, the invention has at least the following beneficial effects:
1. according to the preparation method of the 2-chloro-5-bromobenzoyl chloride, in the reaction of the step 1), pyridine is added as a catalyst, so that the reaction of the 2-chlorobenzoic acid and thionyl chloride can be promoted, and the yield of the 2-chlorobenzoyl chloride is improved, so that the total yield of the 2-chloro-5-bromobenzoyl chloride is improved.
2. In the preparation method of the 2-chloro-5-bromobenzoyl chloride, in the reaction of the step 2), dibromohydantoin is used as a brominating agent for brominating, so that the preparation method has higher reaction activity and reaction yield compared with liquid bromine bromination, and has the advantages of low reaction cost, low raw material toxicity and environmental friendliness.
3. The preparation method of the 2-chloro-5-bromobenzoyl provided by the invention is applied to the synthesis of dapagliflozin medicaments, can improve the synthesis yield of the dapagliflozin medicaments and reduce the production cost of the dapagliflozin medicaments.
Drawings
FIG. 1 shows the 2-chloro-5-bromobenzoyl chloride prepared in example 1 of the present invention 1 H NMR chart.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The first aspect of the invention provides a preparation method of 2-chloro-5-bromobenzoyl chloride, which comprises the following steps:
1) Reacting 2-chlorobenzoic acid with thionyl chloride under the catalysis of pyridine to obtain 2-chlorobenzoyl chloride;
2) Reacting 2-chlorobenzoyl chloride with dibromohydantoin to obtain 2-chloro-5-bromobenzoyl chloride.
The preparation method can be represented by the following synthetic route:
in the step 1), pyridine is introduced into the reaction of 2-chlorobenzoic acid and thionyl chloride as a catalyst, lone pair electrons exist on pyridine N, and the reaction of 2-chlorobenzoic acid and thionyl chloride can be promoted by base catalysis, so that the conversion of 2-chlorobenzoic acid is more complete, the yield of 2-chlorobenzoyl chloride is higher, and the total yield of 2-chloro-5-bromobenzoyl chloride is further improved.
In step 2), dibromohydantoin (DBDMH) has a structure represented by formula 3:
wherein, the N-Br bond in the dibromohydantoin structure is more active, has higher reaction speed and higher yield when being used for bromination reaction, and can further increase the yield of the 2-chloro-5-bromobenzoyl chloride. And dibromo-sea print is a bulk chemical raw material, and has the advantages of good storage stability, low toxicity, low corrosiveness, low cost, environmental protection and the like compared with liquid bromine as a brominating agent.
The invention can obtain 2-chloro-5-bromobenzoyl chloride with higher yield by firstly carrying out the reaction of the step 1) to convert the 2-chlorobenzoic acid into the 2-chlorobenzoyl chloride, wherein the 2-chlorobenzoyl chloride has higher bromination activity than carboxylic acid with the same mother nucleus.
According to the preparation method of the 2-chloro-5-bromobenzoyl chloride, pyridine is introduced into the reaction of the 2-chlorobenzoic acid and the thionyl chloride to serve as a catalyst, and dibromo-sea print is used as a brominating agent in the bromination reaction of the 2-chlorobenzoyl chloride, so that the yield of the 2-chloro-5-bromobenzoyl chloride is remarkably improved, and meanwhile, the preparation method has the advantages of low cost, mild reaction conditions and environmental friendliness.
Further, step 1) includes: and (3) dropwise adding sulfoxide chloride into the mixed solution of 2-chlorobenzoic acid and pyridine, wherein the dropwise adding speed is 10-12 min/g. By adding dropwise and controlling the dropping speed within the above range, the reaction process can be prevented from being too severe, and the occurrence of side reactions can be suppressed.
After the 2-chlorobenzoic acid, pyridine and thionyl chloride are completely mixed, the reaction system is heated to a reflux state for reaction, and the reflux state can accelerate the reaction process.
In order to make the reaction of step 1) more thorough and not to waste the reaction raw materials, the molar ratio of 2-chlorobenzoic acid, thionyl chloride and pyridine can be controlled to be 1: (1-1.5): (0.005-0.02).
After the reaction of the step 1) is completed, a crude product of the 2-chlorobenzoyl chloride can be obtained, the purity of the crude product can reach more than 95 percent, and the bromination reaction in the step 2) can be carried out without further purification.
Furthermore, as the benzene ring of the 2-chlorobenzoyl chloride is connected with two electron withdrawing groups of chlorine and chloroformyl, the 2-chlorobenzoyl chloride has lower activity of continuing the bromination reaction, and the reaction of the 2-chlorobenzoyl chloride and dibromohydantoin can be carried out under the catalysis of acid in order to improve the activity of the bromination reaction.
Specifically, the acid in the acid catalysis is selected from glacial acetic acid and/or concentrated sulfuric acid.
In the bromination reaction of the step 2), in order to allow the reaction to proceed under mild conditions, dibromohydantoin may be added to a mixed solution of 2-chlorobenzoyl chloride and an acid in batches within 20 to 35 minutes to achieve control of the reaction rate.
Further, the bromination reaction temperature in step 2) is 20 to 30 ℃.
To make the bromination reaction of step 2) proceed more completely, the molar ratio of 2-chlorobenzoyl chloride, dibromohydantoin to acid can be controlled to be 1: (1-1.3): (1-2.5).
It will be appreciated that the reactions of step 1) and step 2) are carried out in a solvent system. The solvent used in the reaction of step 1) and step 2) is not particularly limited as long as it can dissolve the reaction substrate and does not participate in the reaction, and may be selected from, for example, methylene chloride.
The reaction progress of step 1) and step 2) may be monitored by conventional test methods in the art, such as TLC, HPLC or NMR, and the reaction time of step 1) is usually 3 to 5 hours and the reaction time of step 2) is usually 2 to 4 hours.
The second aspect of the invention provides an application of the preparation method in the synthesis of dapagliflozin medicaments. The preparation method of the 2-chloro-5-bromobenzoyl chloride provided by the first aspect of the invention has the advantages of high yield, low cost and environmental friendliness, so that when the preparation method is applied to the synthesis of dapagliflozin medicaments, the yield of dapagliflozin can be further improved, the medicament synthesis cost is reduced, and the preparation method is expected to be applied to the industrial production of Yu Dage column of net medicaments.
Hereinafter, the preparation method of 2-chloro-5-bromobenzoyl chloride provided by the present invention will be described in detail with reference to specific examples.
In the examples which follow, all starting materials, unless otherwise specified, are prepared by commercial or conventional methods.
Example 1
The preparation method of the 2-chloro-5-bromobenzoyl chloride comprises the following steps:
1) Adding 2-chlorobenzoic acid (156 g,1.0 mol) into a 1L four-neck flask, adding 500mL of dichloromethane for dissolution, adding pyridine (1 g,0.01 mol) into a solution system for stirring, dropwise adding thionyl chloride (142.8 g,1.2 mol) into the reaction system at a rate of 11g/min at room temperature by using a constant pressure dropping funnel, heating the system to 40-50 ℃ after the dropwise addition, refluxing for 3h, detecting the reaction by TLC, and removing dichloromethane and excessive thionyl chloride by reduced pressure distillation to obtain 170.0g of a crude 2-chlorobenzoyl chloride product, wherein the yield is 97.1%, and the crude product is directly used as the next reaction without purification;
2) Adding the crude 2-chlorobenzoyl chloride obtained in the step 1) into a 1L four-necked flask, adding glacial acetic acid (120 g,2.0 mol), 500mL of dichloromethane, stirring uniformly, adding dibromohydantoin (300 g,1.05 mol) into the reaction system in batches at 25 ℃ for 30min, and carrying out heat preservation reaction for 2h after the addition is finished, and detecting the reaction by TLC;
200mL of water is added into the reaction system for extraction, the organic phase is dried by anhydrous sodium sulfate and filtered, and the filtrate is distilled under reduced pressure to remove methylene dichloride, thus obtaining 236.0g of 2-chloro-5-bromobenzoyl chloride, the purity is 96.7%, and the total yield is 92.9%.
Nuclear magnetic resonance Hydrogen Spectrometry was performed on the 2-chloro-5-bromobenzoyl chloride obtained in this example, FIG. 1 shows the 2-chloro-5-bromobenzoyl chloride obtained in inventive example 1 1 H NMR chart, as shown in fig. 1, 2-chloro-5-bromobenzoyl chloride is characterized as: 1 H NMR(400MHz，CDCl 3 )δ：8.17-8.18(s,1H)，7.62-7.65(d,1H)，7.36-7.38(d,1H).
example 2
The preparation method of the 2-chloro-5-bromobenzoyl chloride comprises the following steps:
1) Adding 2-chlorobenzoic acid (156 g,1.0 mol) into a 1L four-neck flask, adding 500mL of dichloromethane for dissolution, adding pyridine (1 g,0.01 mol) into a solution system for stirring, dropwise adding thionyl chloride (116.6 g,1.4 mol) into the reaction system at a rate of 11g/min by using a constant pressure dropping funnel at room temperature for 10min, heating the system to 40-50 ℃ after the dropwise addition, refluxing for 3h, detecting the reaction by TLC, and removing dichloromethane and excessive thionyl chloride by reduced pressure distillation to obtain 173.1g of a crude 2-chlorobenzoyl chloride product, wherein the yield is 98.9%, and the crude product is directly used as the next reaction without purification;
2) Adding the crude 2-chlorobenzoyl chloride obtained in the step 1) into a 1L four-necked flask, adding glacial acetic acid (120 g,2.0 mol), 500mL of dichloromethane, stirring uniformly, adding dibromohydantoin (300 g,1.05 mol) into the reaction system in batches at 25 ℃ for 30min, and carrying out heat preservation reaction for 2h after the addition is finished, and detecting the reaction by TLC;
200mL of water was added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, then filtered, the filtrate was distilled off under reduced pressure to remove methylene chloride, and the mixture was subjected to extraction with water 1 H NMR characterization confirmed that 240.3g of 2-chloro-5-bromobenzoyl chloride was obtained with a purity of 96.9% and a total yield of 94.6%.
Example 3
The preparation method of the 2-chloro-5-bromobenzoyl chloride comprises the following steps:
1) Adding 2-chlorobenzoic acid (156 g,1.0 mol) into a 1L four-neck flask, adding 500mL of dichloromethane for dissolution, adding pyridine (1 g,0.01 mol) into a solution system for stirring, dropwise adding thionyl chloride (116.6 g,1.4 mol) into the reaction system at a rate of 11g/min by using a constant pressure dropping funnel at room temperature for 10min, heating the system to 40-50 ℃ after the dropwise addition, refluxing for 3h, detecting the reaction by TLC, and removing dichloromethane and excessive thionyl chloride by reduced pressure distillation to obtain 173.1g of a crude 2-chlorobenzoyl chloride product, wherein the yield is 98.9%, and the crude product is directly used as the next reaction without purification;
2) Adding the crude 2-chlorobenzoyl chloride obtained in the step 1) into a 1L four-necked flask, adding glacial acetic acid (120 g,2.0 mol), 500mL of dichloromethane, stirring uniformly, adding dibromohydantoin (314.5 g,1.1 mol) into the reaction system in batches at 25 ℃ for 32min, and carrying out heat preservation reaction for 2h after the addition is finished, and detecting the reaction by TLC;
200mL of water was added to the reaction system for extraction, and the organic phase was extractedDrying with anhydrous sodium sulfate, filtering, distilling the filtrate under reduced pressure to remove dichloromethane, and collecting the filtrate 1 H NMR characterization confirmed that 240.3g of 2-chloro-5-bromobenzoyl chloride was obtained with a purity of 95.6% and a total yield of 94.6%.
Example 4
The preparation method of the 2-chloro-5-bromobenzoyl chloride comprises the following steps:
1) Adding 2-chlorobenzoic acid (156 g,1.0 mol) into a 1L four-neck flask, adding 500mL of dichloromethane for dissolution, adding pyridine (1 g,0.01 mol) into a solution system for stirring, dropwise adding thionyl chloride (116.6 g,1.4 mol) into the reaction system at a rate of 11g/min by using a constant pressure dropping funnel at room temperature for 10min, heating the system to 40-50 ℃ after the dropwise addition, refluxing for 3h, detecting the reaction by TLC, and removing dichloromethane and excessive thionyl chloride by reduced pressure distillation to obtain 173.1g of a crude 2-chlorobenzoyl chloride product, wherein the yield is 98.9%, and the crude product is directly used as the next reaction without purification;
2) Adding the 2-chlorobenzoyl chloride crude product obtained in the step 1) into a 1L four-necked flask, adding glacial acetic acid (132.1 g,2.2 mol), 500mL of dichloromethane, stirring uniformly, adding dibromohydantoin (300 g,1.05 mol) into the reaction system in batches at 25 ℃ for 30min, and carrying out heat preservation reaction for 2h after the addition is finished, and detecting the reaction by TLC;
200mL of water was added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, then filtered, the filtrate was distilled off under reduced pressure to remove methylene chloride, and the mixture was subjected to extraction with water 1 H NMR characterization confirmed that 242.7g of 2-chloro-5-bromobenzoyl chloride was obtained in a purity of 97.0% and a total yield of 95.6%.
Example 5
The preparation method of the 2-chloro-5-bromobenzoyl chloride comprises the following steps:
1) Adding 2-chlorobenzoic acid (156 g,1.0 mol) into a 1L four-neck flask, adding 500mL of dichloromethane for dissolution, adding pyridine (1 g,0.01 mol) into a solution system for stirring, dropwise adding thionyl chloride (116.6 g,1.4 mol) into the reaction system at a rate of 11g/min by using a constant pressure dropping funnel at room temperature for 10min, heating the system to 40-50 ℃ after the dropwise addition, refluxing for 3h, detecting the reaction by TLC, and removing dichloromethane and excessive thionyl chloride by reduced pressure distillation to obtain 173.1g of a crude 2-chlorobenzoyl chloride product, wherein the yield is 98.9%, and the crude product is directly used as the next reaction without purification;
2) Adding the crude product of the 2-chlorobenzoyl chloride obtained in the step 1) into a 1L four-necked flask, adding concentrated sulfuric acid (215.8 g,2.2 mol), 500mL of dichloromethane, stirring uniformly, adding dibromohydantoin (300 g,1.05 mol) into the reaction system in batches at 25 ℃ for 30min, and carrying out heat preservation reaction for 2h after the addition is finished, and detecting the reaction by TLC;
200mL of water was added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, then filtered, the filtrate was distilled off under reduced pressure to remove methylene chloride, and the mixture was subjected to extraction with water 1 H NMR characterization confirmed that 243.0g of 2-chloro-5-bromobenzoyl chloride was obtained in a purity of 96.5% and a total yield of 95.7%.
Example 6
The preparation method of the 2-chloro-5-bromobenzoyl chloride comprises the following steps:
1) Adding 2-chlorobenzoic acid (156 g,1.0 mol) into a 1L four-neck flask, adding 500mL of dichloromethane for dissolution, adding pyridine (1 g,0.01 mol) into a solution system for stirring, dropwise adding thionyl chloride (116.6 g,1.4 mol) into the reaction system at a rate of 11g/min by using a constant pressure dropping funnel at room temperature for 10min, heating the system to 40-50 ℃ after the dropwise addition, refluxing for 3h, detecting the reaction by TLC, and removing dichloromethane and excessive thionyl chloride by reduced pressure distillation to obtain 173.1g of a crude 2-chlorobenzoyl chloride product, wherein the yield is 98.9%, and the crude product is directly used as the next reaction without purification;
2) Adding the crude 2-chlorobenzoyl chloride obtained in the step 1) into a 1L four-necked flask, adding concentrated sulfuric acid (108.0 g,1.1 mol) and 500mL of dichloromethane, stirring uniformly, adding dibromohydantoin (300 g,1.05 mol) into the reaction system in batches at 25 ℃ for 30min, and carrying out heat preservation reaction for 2h after the addition is finished, and detecting the reaction by TLC;
200mL of water was added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, then filtered, the filtrate was distilled off under reduced pressure to remove methylene chloride, and the mixture was subjected to extraction with water 1 H NMR characterization242.7g of 2-chloro-5-bromobenzoyl chloride was obtained with a purity of 96.8% and a total yield of 95.6%.
Example 7
The preparation method of the 2-chloro-5-bromobenzoyl chloride comprises the following steps:
1) Adding 2-chlorobenzoic acid (156 g,1.0 mol) into a 1L four-neck flask, adding 500mL of dichloromethane for dissolution, adding pyridine (0.5 g,0.005 mol) into a solution system, stirring, dropwise adding thionyl chloride (116.6 g,1.4 mol) into the reaction system at a rate of 11g/min at room temperature by using a constant pressure dropping funnel for 10min, heating the system to 40-50 ℃ after the dropwise addition, refluxing for 3h, detecting the reaction by TLC, and distilling under reduced pressure to remove the dichloromethane and excessive thionyl chloride to obtain 163.1g of a 2-chlorobenzoyl chloride crude product, wherein the yield is 93.2%, and the product is directly used as the next reaction without purification;
2) Adding the crude 2-chlorobenzoyl chloride obtained in the step 1) into a 1L four-necked flask, adding concentrated sulfuric acid (108.0 g,1.1 mol) and 500mL of dichloromethane, stirring uniformly, adding dibromohydantoin (300 g,1.05 mol) into the reaction system in batches at 25 ℃ for 30min, and carrying out heat preservation reaction for 2h after the addition is finished, and detecting the reaction by TLC;
200mL of water was added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, then filtered, the filtrate was distilled off under reduced pressure to remove methylene chloride, and the mixture was subjected to extraction with water 1 H NMR characterization confirmed that 228.7g of 2-chloro-5-bromobenzoyl chloride was obtained in a purity of 95.8% and a total yield of 90.1%.
Example 8
The preparation method of the 2-chloro-5-bromobenzoyl chloride comprises the following steps:
1) Adding 2-chlorobenzoic acid (156 g,1.0 mol) into a 1L four-neck flask, adding 500mL of dichloromethane for dissolution, adding pyridine (1 g,0.01 mol) into a solution system for stirring, dropwise adding thionyl chloride (116.6 g,1.4 mol) into the reaction system at a rate of 11g/min by using a constant pressure dropping funnel at room temperature for 10min, heating the system to 40-50 ℃ after the dropwise addition, refluxing for 3h, detecting the reaction by TLC, and removing dichloromethane and excessive thionyl chloride by reduced pressure distillation to obtain 173.1g of a crude 2-chlorobenzoyl chloride product, wherein the yield is 98.9%, and the crude product is directly used as the next reaction without purification;
2) Adding the crude product of the 2-chlorobenzoyl chloride obtained in the step 1) into a 1L four-necked flask, stirring uniformly, adding dibromohydantoin (300 g,1.05 mol) into the reaction system in batches at 25 ℃ for 30min, and after the addition is finished, preserving heat for 2h, and detecting the reaction by TLC;
200mL of water was added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, then filtered, the filtrate was distilled off under reduced pressure to remove methylene chloride, and the mixture was subjected to extraction with water 1 H NMR characterization confirmed that 213.8g of 2-chloro-5-bromobenzoyl chloride was obtained in a purity of 90.5% and a total yield of 84.2%.
Comparative example 1
The preparation method of the 2-chloro-5-bromobenzoyl chloride comprises the following steps:
1) Adding 2-chlorobenzoic acid (156 g,1.0 mol) into a 1L four-neck flask, adding 500mL of dichloromethane for dissolution, adding glacial acetic acid (132.1 g,2.2 mol) into the solution system, stirring uniformly, adding dibromohydantoin (300 g,1.05 mol) into the reaction system in batches at 25 ℃ for 30min, and after the addition, preserving heat for 2h, and detecting the reaction by TLC;
adding 200mL of water into the reaction system for extraction, drying the organic phase by using anhydrous sodium sulfate, and filtering to obtain a dichloromethane reaction solution containing 2-chloro-5-bromobenzoic acid, wherein the next reaction is directly carried out without purification;
2) Adding the dichloromethane reaction solution containing 2-chloro-5-bromobenzoic acid obtained in the step 1) into a 1L four-neck flask, stirring, adding pyridine (1 g,0.01 mol) as a catalyst, dropwise adding thionyl chloride (116.6 g,1.4 mol) into the reaction system at a rate of 11g/min at room temperature by using a constant pressure dropping funnel for 10min, heating the system to 40-50 ℃ after dropwise adding, refluxing for 3h, detecting the reaction by TLC, removing dichloromethane and excessive thionyl chloride by reduced pressure distillation, and performing three-dimensional chromatography 1 H NMR characterization confirmed that 207.0g of 2-chloro-5-bromobenzoyl chloride was obtained in a purity of 90.2% and a total yield of 81.5%.
Comparative example 2
The preparation method of the 2-chloro-5-bromobenzoyl chloride comprises the following steps:
1) Adding 2-chlorobenzoic acid (156 g,1.0 mol) into a 1L four-neck flask, adding 500mL of dichloromethane for dissolution, dropwise adding thionyl chloride (116.6 g,1.4 mol) into the reaction system at a rate of 11g/min at room temperature by using a constant pressure dropping funnel for 10min, heating the system to 40-50 ℃ after the dropwise adding is finished for refluxing for 3h, detecting the reaction by TLC, and removing dichloromethane and excessive thionyl chloride by reduced pressure distillation to obtain 142.8g of 2-chlorobenzoyl chloride crude product, wherein the yield is 81.6%, and the crude product is directly used as the next reaction without purification;
2) Adding the crude 2-chlorobenzoyl chloride obtained in the step 1) into a 1L four-necked flask, adding glacial acetic acid (120 g,2.0 mol), 500mL of dichloromethane, stirring uniformly, adding dibromohydantoin (300 g,1.05 mol) into the reaction system in batches at 25 ℃ for 30min, and carrying out heat preservation reaction for 2h after the addition is finished, and detecting the reaction by TLC;
200mL of water was added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, then filtered, the filtrate was distilled off under reduced pressure to remove methylene chloride, and the mixture was subjected to extraction with water 1 H NMR characterization confirmed that 198.3g of 2-chloro-5-bromobenzoyl chloride was obtained in a purity of 89.9% and a total yield of 78.1%.
Comparative example 3
The preparation method of the 2-chloro-5-bromobenzoyl chloride comprises the following steps:
1) Adding 2-chlorobenzoic acid (156 g,1.0 mol) into a 1L four-neck flask, adding 500mL of dichloromethane for dissolution, adding pyridine (1 g,0.01 mol) into a solution system for stirring, dropwise adding thionyl chloride (116.6 g,1.4 mol) into the reaction system at a rate of 11g/min by using a constant pressure dropping funnel at room temperature for 10min, heating the system to 40-50 ℃ after the dropwise addition, refluxing for 3h, detecting the reaction by TLC, and removing dichloromethane and excessive thionyl chloride by reduced pressure distillation to obtain 173.1g of a crude 2-chlorobenzoyl chloride product, wherein the yield is 98.9%, and the crude product is directly used as the next reaction without purification;
2) Adding the crude 2-chlorobenzoyl chloride obtained in the step 1) into a 1L four-necked flask, adding glacial acetic acid (120 g,2.0 mol), 500mL of dichloromethane, stirring uniformly, adding batch bromine (300 g,1.05 mol) into the reaction system at 25 ℃ for 30min, and carrying out heat preservation reaction for 2h after the addition is finished, and detecting the reaction by TLC;
200mL of water was added to the reaction system for extraction, the organic phase was dried over anhydrous sodium sulfate, then filtered, the filtrate was distilled off under reduced pressure to remove methylene chloride, and the mixture was subjected to extraction with water 1 H NMR characterization confirmed that 210.2g of 2-chloro-5-bromobenzoyl chloride was obtained in a purity of 90.6% and a total yield of 82.8%.
The above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims (7)

1. The preparation method of the 2-chloro-5-bromobenzoyl chloride is characterized by comprising the following steps of:
1) Reacting 2-chlorobenzoic acid with thionyl chloride under the catalysis of pyridine to obtain 2-chlorobenzoyl chloride;
wherein, the mol ratio of the 2-chlorobenzoic acid, the thionyl chloride and the pyridine is 1: (1-1.5): (0.005-0.02);
2) Reacting 2-chlorobenzoyl chloride with dibromohydantoin under the catalysis of acid to obtain 2-chloro-5-bromobenzoyl chloride;
wherein, the mol ratio of the 2-chlorobenzoyl chloride to the dibromohydantoin to the acid is 1: (1-1.3): (1-2.5); the acid is selected from glacial acetic acid;
wherein the reactions in step 1) and step 2) are both carried out in a solvent system, said solvent being selected from the group consisting of methylene chloride.
2. The method of claim 1, wherein step 1) comprises: and (3) dropwise adding sulfoxide chloride into the mixed solution of 2-chlorobenzoic acid and pyridine, wherein the dropwise adding speed is 10-12 g/min.
3. The process according to claim 1 or 2, wherein the reaction of step 1) is carried out under heated reflux.
4. The method of claim 1, wherein step 2) comprises: and adding dibromohydantoin into the mixed solution of 2-chlorobenzoyl chloride and the acid in batches within 20-35 min.
5. The method according to any one of claims 1, 2 and 4, wherein the reaction in step 2) is carried out at 20 to 30 ℃.
6. The method according to claim 3, wherein the reaction in step 2) is carried out at 20 to 30 ℃.
7. Use of the preparation method of any one of claims 1-6 in the synthesis of dapagliflozin medicament.
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US6096920A (en) * 1997-01-08 2000-08-01 Albemarle Corporation Preparation of carboxylic compounds and their derivatives
CN107417515A (en) * 2017-03-30 2017-12-01 上海常丰生物医药科技有限公司 A kind of new method for synthesizing Dapagliflozin intermediate
JP2021195344A (en) * 2020-06-16 2021-12-27 株式会社トクヤマ Method for producing 5-bromo-2-halogenated benzoic acid

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US6096920A (en) * 1997-01-08 2000-08-01 Albemarle Corporation Preparation of carboxylic compounds and their derivatives
CN107417515A (en) * 2017-03-30 2017-12-01 上海常丰生物医药科技有限公司 A kind of new method for synthesizing Dapagliflozin intermediate
JP2021195344A (en) * 2020-06-16 2021-12-27 株式会社トクヤマ Method for producing 5-bromo-2-halogenated benzoic acid

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