A preparation method and application of 3-chloro-2,4,5-trifluorobenzoic acid

Abstract

The invention discloses a preparation method of 3-chloro-2,4,5-trifluorobenzoic acid and application thereof, comprising the following steps: S1: adding bromine dropwise to 1,2,4-trifluorobenzene at 10-30°C to carry out bromination reaction; S2: adding N-chlorosuccinimide in batches to the obtained 2,4,5-trifluorobromobenzene and concentrated sulfuric acid at 5-10°C to carry out substitution reaction and purification; S3: adding magnesium chips and tetrahydrofuran to an anhydrous reaction bottle, adding the obtained 3-chloro-2,4,5-trifluorobromobenzene under stirring, heating to 35-40°C to initiate reaction, then adding bromobenzene dropwise, keeping warm and stirring for reaction for 1h, then cooling to 5-10°C, adding dry ice in batches to carry out Grignard reaction, adding ultrapure water when the system is no longer exothermic, adjusting pH=1, filtering by suction and drying; and S4: recrystallization. The invention uses 1,2,4-trifluorobenzene as a raw material, and obtains a target product through bromination, chlorination, Grignard reaction and recrystallization. The reaction process is simplified, the operation is simple, the reaction is mild, the product yield is more than 90%, the purity is more than 99.9%, the by-products in the reaction process are few, and the production cost is low.

Description

Technical Field

[0001] The invention belongs to the field of synthesis of fluoroquinolone drug intermediates, and specifically relates to a preparation method of 3-chloro-2,4,5-trifluorobenzoic acid and application thereof. Background Art

[0002] Fine aromatic fluorides have the stability, physiological activity, high fat solubility and hydrophobicity of organic compounds in structure. Therefore, many fluorine-containing medicines and pesticides have the characteristics of low dosage, low toxicity, high efficacy and strong metabolic capacity, which makes them account for an increasingly high proportion of new medicines. Therefore, domestic production enterprises must accelerate the pace of development, continuously improve the process, strive to improve product quality, and strive to provide pharmaceutical-grade fluorine-containing pharmaceutical intermediates to domestic and foreign markets. In terms of the category of fluorine-containing pharmaceutical intermediates, my country's fluorobenzene intermediates developed earlier, and the current production capacity is generally in excess; trifluorotoluene intermediates developed later, so the development speed in recent years has been faster; and for heterocyclic aromatic compounds, especially fluorine-containing pyridines, my country currently has only a few synthetic technology research units and manufacturers for fluorine-containing pyridine intermediates. Therefore, the industry generally believes that fluorine-containing pyridine intermediates will become one of the main directions of domestic fluorine-containing intermediate research and development in the next few years.

[0003] 3-Chloro-2,4,5-trifluorobenzoic acid is a key intermediate for the synthesis of new fluorinated pyridone acid (fluoroquinolone) antibacterial drugs such as sitafloxacin. At present, most domestic manufacturers are reagent manufacturers. The process routes used by these manufacturers are relatively complex, the production cost is high, and the synthesis process is unstable. A large amount of wastewater, waste gas, and waste residue will be generated, which will affect the environment. In addition, there are only a few manufacturers without large-scale production, and the production process can no longer meet market demand. For example, Zhao Jian et al. used 3,4,5,6-tetrafluorophthalic acid as the starting material to prepare 3-chloro-2,4,5-trifluorobenzoic acid product, and the reaction route is as follows:

[0004]

[0005] Another example is the invention patent with patent number CN201610044978.7, which discloses the preparation process of 3-chloro-2,4,5-trifluorobenzoic acid, and its synthesis route is as follows:

[0006]

[0007] Therefore, it is of great significance to design a process for preparing 3-chloro-2.4.5-trifluorobenzoic acid with simple procedures, stable and reasonable process and high yield. Summary of the invention

[0008] In view of the shortcomings of the prior art, the object of the present invention is to provide a preparation method of 3-chloro-2,4,5-trifluorobenzoic acid and its application.

[0009] The technical solution of the present invention is summarized as follows:

[0010] A method for preparing 3-chloro-2,4,5-trifluorobenzoic acid comprises the following steps:

[0011] S1: At 10-30°C, add 1,2,4-trifluorobenzene to an anhydrous reaction bottle, and then drop bromine under stirring to carry out bromination reaction. Track the reaction by GC until the reaction is complete to obtain 2,4,5-trifluorobromobenzene.

[0012] S2: At 5-10°C, add 2,4,5-trifluorobromobenzene and concentrated sulfuric acid to an anhydrous reaction bottle, add N-chlorosuccinimide in batches under stirring conditions to carry out a substitution reaction, and track the reaction of the raw materials until the reaction is complete by GC. Pour the resulting reaction solution into water of equal mass, separate the organic layer, wash with water until neutral, dry, and distill to obtain 3-chloro-2,4,5-trifluorobromobenzene;

[0013] S3: Add magnesium chips and tetrahydrofuran to an anhydrous reaction bottle, add 3-chloro-2,4,5-trifluorobromobenzene under stirring, and heat to 35-40°C to initiate the reaction, then drop bromobenzene, stir and react for 1 hour, then cool to 5-10°C, add dry ice in batches to perform a Grignard reaction, and add ultrapure water when the system is no longer exothermic, adjust the pH to 1 with hydrochloric acid solution, filter and dry the obtained product to obtain a crude product;

[0014] The above reaction equation is as follows:

[0015]

[0016] S4: Add the crude product into methanol, stir and dissolve at 40-50°C, add activated carbon for decolorization, filter, cool the filtrate to 0-5°C for recrystallization, precipitate 3-chloro-2,4,5-trifluorobenzoic acid crystals, filter, dry, and obtain pure 3-chloro-2,4,5-trifluorobenzoic acid.

[0017] Furthermore, in S1-S3, the dosage ratio of 1,2,4-trifluorobenzene, bromine, concentrated sulfuric acid, N-chlorosuccinimide, magnesium chips, tetrahydrofuran, bromobenzene, dry ice, and ultrapure water is 0.1 mol: 0.1 mol: (20-25) g: 0.1 mol: 0.1 mol: 100 mL: 0.1 mol: (0.15-0.5) mol: 50 mL.

[0018] Furthermore, the dosage ratio of the 1,2,4-trifluorobenzene, bromine, concentrated sulfuric acid, N-chlorosuccinimide, magnesium chips, tetrahydrofuran, bromobenzene, dry ice, and ultrapure water is 0.1 mol: 0.1 mol: 20 g: 0.1 mol: 0.1 mol: 100 mL: 0.1 mol: 0.15 mol: 50 mL.

[0019] Furthermore, the dosage ratio of the 1,2,4-trifluorobenzene, bromine, concentrated sulfuric acid, N-chlorosuccinimide, magnesium chips, tetrahydrofuran, bromobenzene, dry ice, and ultrapure water is 0.1 mol: 0.1 mol: 22.5 g: 0.1 mol: 0.1 mol: 100 mL: 0.1 mol: 0.3 mol: 50 mL.

[0020] Furthermore, the dosage ratio of the 1,2,4-trifluorobenzene, bromine, concentrated sulfuric acid, N-chlorosuccinimide, magnesium chips, tetrahydrofuran, bromobenzene, dry ice, and ultrapure water is 0.1 mol: 0.1 mol: 25 g: 0.1 mol: 0.1 mol: 100 mL: 0.1 mol: 0.5 mol: 50 mL.

[0021] Furthermore, the mass concentration of the concentrated sulfuric acid is 98%.

[0022] Furthermore, in S4, the mass ratio of the crude product, methanol and activated carbon is 1:2:(0.05-0.1).

[0023] Furthermore, in S3 and S4, the drying temperature is 75-80°C.

[0024] Furthermore, in S3, the concentration of the hydrochloric acid solution is 2-5 mol / L.

[0025] The present invention further provides application of 3-chloro-2,4,5-trifluorobenzoic acid prepared by the preparation method in the synthesis of fluoroquinolone antibacterial drugs.

[0026] Beneficial effects of the present invention:

[0027] 1. The present invention adopts relatively cheap 1,2,4-trifluorobenzene as a raw material for the first time, and obtains the target product through bromination, chlorination, Grignard reaction and recrystallization (specifically: 1,2,4-trifluorobenzene is used as a raw material, bromination generates 2,4,5-trifluorobromobenzene, 2,4,5-trifluorobromobenzene is added with sulfuric acid and reacted with N-chlorosuccinimide to completely generate 3-chloro-2,4,5-trifluorobromobenzene, and then a crude product is obtained through Grignard reaction, and finally recrystallization is obtained to obtain the target product 3-chloro-2,4,5-trifluorobenzoic acid), thereby avoiding the impact of a large amount of waste water, waste residue and waste gas generated in the traditional process on the environment from the source, simplifying the reaction process, being simple to operate, having a mild reaction process, having a product yield of more than 90%, a purity of more than 99.9%, having few by-products in the reaction process and having a low production cost.

[0028] 2. The preparation method of the present invention has the advantages of non-volatility, non-combustion, good thermal stability, mild reaction conditions, etc., which lays a foundation for safety and operability for later pilot or large-scale production; in addition, compared with traditional processes, the new preparation process belongs to green synthesis technology, and the amount of wastewater, waste gas, and waste residue produced is very small, achieving the purpose of energy saving and consumption reduction and environmental friendliness.

[0029] 3. The present invention achieves maximum material conversion and minimizes production costs by scientifically regulating the feed ratio, reaction temperature, and reaction time in the process and tracking the finished product content by GC throughout the reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The present invention is a flow chart of the preparation method of 3-chloro-2,4,5-trifluorobenzoic acid. DETAILED DESCRIPTION

[0031] The present invention is further described in detail below in conjunction with embodiments so that those skilled in the art can implement the invention with reference to the description.

[0032] A method for preparing 3-chloro-2,4,5-trifluorobenzoic acid comprises the following steps:

[0033] S1: At 10-30°C, add 1,2,4-trifluorobenzene to an anhydrous reaction bottle, and then drop bromine under stirring to carry out bromination reaction. Track the reaction by GC until the reaction is complete to obtain 2,4,5-trifluorobromobenzene.

[0034] S2: 5-10°C, add 2,4,5-trifluorobromobenzene obtained in S1 and concentrated sulfuric acid to an anhydrous reaction bottle, add N-chlorosuccinimide in batches under stirring conditions, carry out substitution reaction, and track by GC until the raw material reaction is complete. Then pour the obtained reaction solution into water of equal mass, separate the organic layer, wash with water to neutrality, dry, and distill to obtain 3-chloro-2,4,5-trifluorobromobenzene;

[0035] S3: Add magnesium chips and tetrahydrofuran to an anhydrous reaction bottle, add 3-chloro-2,4,5-trifluorobromobenzene obtained in S2 under stirring, and heat to 35-40°C to initiate the reaction, then drop bromobenzene, keep stirring and react for 1 hour, then cool to 5-10°C, add dry ice in batches to carry out Grignard reaction, and add ultrapure water when the system is no longer exothermic, and adjust the pH to 1 with 2-5 mol / L hydrochloric acid solution, filter with suction, and dry the obtained product at 75-80°C to obtain a crude product;

[0036] The usage ratio of the 1,2,4-trifluorobenzene, bromine, concentrated sulfuric acid, N-chlorosuccinimide, magnesium chips, tetrahydrofuran, bromobenzene, dry ice, and ultrapure water is 0.1 mol: 0.1 mol: (20-25) g: 0.1 mol: 0.1 mol: 100 mL: 0.1 mol: (0.15-0.5) mol: 50 mL;

[0037] The above reaction equation is as follows:

[0038]

[0039] S4: Add the crude product obtained in S3 to methanol, stir and dissolve at 40-50°C, add activated carbon for decolorization, control the mass ratio of crude product, methanol and activated carbon to 1:2:(0.05-0.1), filter, cool the filtrate to 0-5°C for recrystallization, precipitate 3-chloro-2,4,5-trifluorobenzoic acid crystals, filter, dry at 75-80°C to obtain pure 3-chloro-2,4,5-trifluorobenzoic acid.

[0040] Example 1

[0041] A method for preparing 3-chloro-2,4,5-trifluorobenzoic acid comprises the following steps:

[0042] S1: At 10°C, add 0.1 mol of 1,2,4-trifluorobenzene to an anhydrous reaction bottle, and then drop 0.1 mol of bromine under stirring to carry out bromination reaction. Track the reaction by GC until the reaction is complete to obtain 2,4,5-trifluorobromobenzene.

[0043] S2: At 5°C, add 2,4,5-trifluorobromobenzene obtained in S1 and 20 g of 98 wt% concentrated sulfuric acid to an anhydrous reaction bottle, add 0.1 mol N-chlorosuccinimide in batches under stirring conditions, and perform substitution reaction. Follow GC until the raw material reaction is complete. Pour the obtained reaction solution into water of equal mass, separate the organic layer, wash with water until neutral, dry, and distill to obtain 3-chloro-2,4,5-trifluorobromobenzene;

[0044] S3: Add 0.1 mol magnesium chips and 100 mL tetrahydrofuran to an anhydrous reaction bottle, add 3-chloro-2,4,5-trifluorobromobenzene obtained in S2 under stirring conditions, and heat to 35°C to initiate the reaction, then drop 0.1 mol bromobenzene, stir and react for 1 hour, then cool to 5°C, add 0.15 mol dry ice in batches to carry out Grignard reaction, and add 50 mL ultrapure water when the system is no longer exothermic, adjust the pH to 1 with 2 mol / L hydrochloric acid solution, filter with suction, and dry the obtained product at 75°C to obtain a crude product;

[0045] The above reaction equation is as follows:

[0046]

[0047] S4: The crude product obtained in S3 is added to methanol, stirred and dissolved at 40°C, and activated carbon is added for decolorization. The mass ratio of the crude product, methanol and activated carbon is controlled to be 1:2:0.05. After filtration, the filtrate is cooled to 0°C for recrystallization to precipitate 3-chloro-2,4,5-trifluorobenzoic acid crystals. After filtration and drying at 80°C, pure 3-chloro-2,4,5-trifluorobenzoic acid is obtained. The product yield is 92.5% and the purity is 99.93%.

[0048] Example 2

[0049] A method for preparing 3-chloro-2,4,5-trifluorobenzoic acid comprises the following steps:

[0050] S1: At 20°C, add 0.1 mol of 1,2,4-trifluorobenzene to an anhydrous reaction bottle, and then dropwise add 0.1 mol of bromine under stirring to carry out bromination reaction. Track the reaction by GC until the reaction is complete to obtain 2,4,5-trifluorobromobenzene.

[0051] S2: At 10°C, add 2,4,5-trifluorobromobenzene obtained in S1 and 22.5 g of 98 wt% concentrated sulfuric acid to an anhydrous reaction bottle. Under stirring conditions, add 0.1 mol of N-chlorosuccinimide in batches to carry out substitution reaction. Track the reaction of the raw materials with GC until the reaction is complete. Pour the obtained reaction solution into water of equal mass, separate the organic layer, wash with water until neutral, dry and distill to obtain 3-chloro-2,4,5-trifluorobromobenzene.

[0052] S3: Add 0.1 mol magnesium chips and 100 mL tetrahydrofuran to an anhydrous reaction bottle, add 3-chloro-2,4,5-trifluorobromobenzene obtained in S2 under stirring conditions, and heat to 38°C to initiate the reaction, then drop 0.1 mol bromobenzene, stir and react for 1 hour, then cool to 5°C, add 0.3 mol dry ice in batches to carry out Grignard reaction, and add ultrapure water when the system is no longer exothermic, adjust pH to 1 with 3.5 mol / L hydrochloric acid solution, filter with suction, and dry the obtained product at 75°C to obtain a crude product;

[0053] The above reaction equation is as follows:

[0054]

[0055] S4: The crude product obtained in S3 is added to methanol, stirred and dissolved at 45°C, and activated carbon is added for decolorization. The mass ratio of the crude product, methanol and activated carbon is controlled to be 1:2:0.08. After filtration, the filtrate is cooled to 0°C for recrystallization to precipitate 3-chloro-2,4,5-trifluorobenzoic acid crystals. After filtration and drying at 75°C, pure 3-chloro-2,4,5-trifluorobenzoic acid is obtained. The product yield is 97.1% and the purity is 99.98%.

[0056] Example 3

[0057] A method for preparing 3-chloro-2,4,5-trifluorobenzoic acid comprises the following steps:

[0058] S1: At 30°C, add 0.1 mol of 1,2,4-trifluorobenzene to an anhydrous reaction bottle, and then dropwise add 0.1 mol of bromine under stirring conditions, controlling the molar ratio of 1,2,4-trifluorobenzene to bromine to be 1:1, and perform bromination reaction. Track the reaction by GC until the reaction is complete to obtain 2,4,5-trifluorobromobenzene;

[0059] S2: At 10°C, add 2,4,5-trifluorobromobenzene obtained in S1 and 25g of 98wt% concentrated sulfuric acid to an anhydrous reaction bottle, add 0.1mol N-chlorosuccinimide in batches under stirring conditions to carry out substitution reaction, and track the reaction of the raw materials with GC until the reaction is complete. Then pour the obtained reaction solution into water of equal mass, separate the organic layer, wash with water until neutral, dry, and distill to obtain 3-chloro-2,4,5-trifluorobromobenzene;

[0060] S3: Add 0.1 mol magnesium chips and 100 mL tetrahydrofuran to an anhydrous reaction bottle, add 3-chloro-2,4,5-trifluorobromobenzene obtained in S2 under stirring conditions, and heat to 40°C to initiate the reaction, then drop 0.1 mol bromobenzene, stir and react for 1 hour, then cool to 10°C, add 0.5 mol dry ice in batches to carry out Grignard reaction, and add 50 mL ultrapure water when the system is no longer exothermic, adjust the pH to 1 with 5 mol / L hydrochloric acid solution, filter with suction, and dry the obtained product at 80°C to obtain a crude product;

[0061] The above reaction equation is as follows:

[0062]

[0063] S4: The crude product obtained in S3 is added to methanol, stirred and dissolved at 50°C, and activated carbon is added for decolorization. The mass ratio of the crude product, methanol and activated carbon is controlled to be 1:2:0.1. After filtration, the filtrate is cooled to 5°C for recrystallization to precipitate 3-chloro-2,4,5-trifluorobenzoic acid crystals. After filtration and drying at 80°C, pure 3-chloro-2,4,5-trifluorobenzoic acid is obtained. The product yield is 94.8% and the purity is 99.95%.

[0064] Embodiment 1-3 uses relatively cheap 1,2,4-trifluorobenzene as a raw material for the first time, and obtains the target product through bromination, chlorination, Grignard reaction, and recrystallization (specifically: 1,2,4-trifluorobenzene is used as a raw material, bromination generates 2,4,5-trifluorobromobenzene, 2,4,5-trifluorobromobenzene is added with sulfuric acid and reacts with N-chlorosuccinimide to completely generate 3-chloro-2,4,5-trifluorobromobenzene, and then a crude product is obtained through Grignard reaction, and finally recrystallization obtains the target product 3-chloro-2,4,5-trifluorobenzoic acid), avoids the impact of a large amount of waste water, waste residue and waste gas generated in the traditional process on the environment from the source, simplifies the reaction process, is easy to operate, has a mild reaction process, a product yield of more than 90%, a purity of more than 99.9%, few by-products in the reaction process, and has a low production cost, and is applied to the synthesis of fluoroquinolone antibiotics.

[0065] The preparation methods of Examples 1-3 have the advantages of non-volatility, non-combustion, good thermal stability, and mild reaction conditions, which lay a foundation for safety and operability for later pilot or large-scale production; in addition, compared with traditional processes, the new preparation process belongs to green synthesis technology, and the amount of wastewater, waste gas, and waste residue produced is very small, achieving the purpose of energy saving and consumption reduction and environmental friendliness.

[0066] In Examples 1-3, the material conversion is maximized and the production cost is minimized by scientifically controlling the feed ratio, reaction temperature and reaction time during the process and tracking the finished product content by GC during the entire reaction.

[0067] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. A method for preparing 3-chloro-2,4,5-trifluorobenzoic acid, characterized in that: The following steps are involved: S1: At 10-30°C, add 1,2,4-trifluorobenzene to an anhydrous reaction bottle, and then drop bromine under stirring to carry out bromination reaction. Track the reaction by GC until the reaction is complete to obtain 2,4,5-trifluorobromobenzene. S2: At 5-10°C, add 2,4,5-trifluorobromobenzene and concentrated sulfuric acid to an anhydrous reaction bottle, add N-chlorosuccinimide in batches under stirring conditions to carry out a substitution reaction, and track the reaction of the raw materials until the reaction is complete by GC. Pour the resulting reaction solution into water of equal mass, separate the organic layer, wash with water until neutral, dry, and distill to obtain 3-chloro-2,4,5-trifluorobromobenzene; S3: Add magnesium chips and tetrahydrofuran to an anhydrous reaction bottle, add 3-chloro-2,4,5-trifluorobromobenzene under stirring, and heat to 35-40°C to initiate the reaction, then drop bromobenzene, stir and react for 1 hour, then cool to 5-10°C, add dry ice in batches to perform a Grignard reaction, and add ultrapure water when the system is no longer exothermic, adjust the pH to 1 with hydrochloric acid solution, filter and dry the obtained product to obtain a crude product; S4: Add the crude product into methanol, stir and dissolve at 40-50°C, add activated carbon for decolorization, filter, cool the filtrate to 0-5°C for recrystallization, precipitate 3-chloro-2,4,5-trifluorobenzoic acid crystals, filter, dry, and obtain pure 3-chloro-2,4,5-trifluorobenzoic acid.

2. The method for preparing 3-chloro-2,4,5-trifluorobenzoic acid according to claim 1, characterized in that: In S1-S3, the usage ratio of 1,2,4-trifluorobenzene, bromine, concentrated sulfuric acid, N-chlorosuccinimide, magnesium chips, tetrahydrofuran, bromobenzene, dry ice, and ultrapure water is 0.1 mol: 0.1 mol: (20-25) g: 0.1 mol: 0.1 mol: 100mL:0.1mol:(0.15-0.5)mol:50mL.

3. The method for preparing 3-chloro-2,4,5-trifluorobenzoic acid according to claim 2, characterized in that: The dosage ratio of the 1,2,4-trifluorobenzene, bromine, concentrated sulfuric acid, N-chlorosuccinimide, magnesium chips, tetrahydrofuran, bromobenzene, dry ice, and ultrapure water is 0.1 mol: 0.1 mol: 20 g: 0.1 mol: 0.1 mol: 100 mL: 0.1 mol: 0.15mol:50mL.

4. The method for preparing 3-chloro-2,4,5-trifluorobenzoic acid according to claim 2, characterized in that: The dosage ratio of the 1,2,4-trifluorobenzene, bromine, concentrated sulfuric acid, N-chlorosuccinimide, magnesium chips, tetrahydrofuran, bromobenzene, dry ice, and ultrapure water is 0.1 mol: 0.1 mol: 22.5 g: 0.1 mol: 0.1 mol: 100 mL: 0.1 mol: 0.3mol:50mL.

5. The method for preparing 3-chloro-2,4,5-trifluorobenzoic acid according to claim 2, characterized in that: The dosage ratio of the 1,2,4-trifluorobenzene, bromine, concentrated sulfuric acid, N-chlorosuccinimide, magnesium chips, tetrahydrofuran, bromobenzene, dry ice, and ultrapure water is 0.1 mol: 0.1 mol: 25 g: 0.1 mol: 0.1 mol: 100 mL: 0.1 mol: 0.5mol:50mL.

6. A method for preparing 3-chloro-2,4,5-trifluorobenzoic acid according to any one of claims 1 to 5, characterized in that: The mass concentration of the concentrated sulfuric acid is 98%.

7. The method for preparing 3-chloro-2,4,5-trifluorobenzoic acid according to claim 1, characterized in that: In S4, the mass ratio of the crude product, methanol and activated carbon is 1:2:(0.05-0.1).

8. The method for preparing 3-chloro-2,4,5-trifluorobenzoic acid according to claim 1, characterized in that: In S3 and S4, the drying temperature is 75-80°C.

9. The method for preparing 3-chloro-2,4,5-trifluorobenzoic acid according to claim 1, characterized in that: In S3, the concentration of the hydrochloric acid solution is 2-5 mol / L.

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