The invention relates to a 2-(4apos; synthesis method of-chlorphenyl) benzoic acid

Abstract

The invention discloses a synthetic method of 2-(4 '-chlorphenyl) benzoic acid. According to the invention, 2-phenylbenzoic acid is used as a raw material, 2-(4 '-chlorphenyl) benzoic acid is obtained through chlorination, 2-phenylbenzoic acid can be obtained through hydrogenation reduction of chlorinated isomers and polychlorinated byproducts generated in the reaction process, and the 2-phenylbenzoic acid is put into the next batch of chlorination reaction for re-chlorination, so that the utilization rate of the raw material 2-phenylbenzoic acid is greatly improved, and the production cost is reduced. Theoretically, the atom utilization rate can reach 100%. The method provided by the invention has the advantages of mild reaction, high conversion rate, few byproducts, high raw material utilization rate, high product yield, low process cost, environmental friendliness, simplicity in operation, suitability for industrial production and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of pesticide intermediate synthesis, and specifically relates to a method for synthesizing 2-(4'-chlorophenyl)benzoic acid. Background Art

[0002] 2-(4'-chlorophenyl)benzoic acid is a key intermediate in the synthesis of boscalid. The main synthesis methods currently include: (1) Patent CN109970571A reports that 2-(4'-chlorophenyl)benzoic acid is obtained by chlorination with 2-phenylbenzoic acid as raw material. This process requires chlorine as a chlorinating agent. The chlorinated isomers and polychlorinated products produced during the reaction are difficult to separate and purify, and the separation yield is low. The use of chlorine increases the unsafe factors such as danger and toxicity, and places high requirements on process equipment. All these lead to dangerous processes, high costs, and difficulty in industrialization.

[0003] (2) Patent CN111662184A reports that 2-phenylbenzoic acid is used as a raw material and 2-(4'-chlorophenyl)benzoic acid is obtained by chlorination with sulfuryl chloride. Although this process avoids the use of dangerous chlorine gas as a chlorinating agent, sulfuryl chloride is used as a chlorinating agent during chlorination. A large amount of by-products are generated during the reaction, and the product purification is difficult and the yield is low. At the same time, the use of sulfuryl chloride increases unsafe factors such as danger and toxicity, places high requirements on process equipment, and is difficult to industrialize.

[0004] Based on this, a new method for preparing 2-(4'-chlorophenyl)benzoic acid with low cost, high yield, simple synthesis, high purity, safety and environmental protection was developed, which has important industrial value. Summary of the invention

[0005] Aiming at the problems of low purity and yield in the prior art 2-(4'-chlorophenyl)benzoic acid synthesis process, the present invention provides a new synthesis method of 2-(4'-chlorophenyl)benzoic acid. 2-phenylbenzoic acid is used as a raw material, 2-(4'-chlorophenyl)benzoic acid is obtained by chlorination, and its crystallization mother liquor (including chlorinated isomers and polychlorinated products) is hydrogenated and reduced to obtain 2-phenylbenzoic acid, which is then put into the next batch of chlorination reaction.

[0006] The technical solution of the present invention is as follows: A new synthesis method of 2-(4'-chlorophenyl)benzoic acid comprises the following steps: (1) Chlorination: 2-phenylbenzoic acid is dissolved in a solvent and subjected to chlorination reaction in the presence of a hydrogen peroxide and concentrated hydrochloric acid system to obtain a crude 2-(4'-chlorophenyl)benzoic acid product; (2) Reduction: The crude 2-(4'-chlorophenyl)benzoic acid obtained in step (1) is recrystallized to obtain 2-(4'-chlorophenyl)benzoic acid, the recrystallization mother liquor (containing a small amount of 2-(4'-chlorophenyl)benzoic acid) is desolventized and dried, the obtained solid is dissolved in a solvent, a catalyst, a base and hydrogen are added to perform dechlorination reduction to obtain 2-phenylbenzoic acid; (3) The 2-phenylbenzoic acid obtained by hydrogenation reduction is mixed as a raw material into the next batch of chlorination reaction, i.e., the reaction of step (1), to participate in the chlorination reaction.

[0007] Furthermore, the solvent in the above chlorination reaction is chloroform, acetonitrile, dichloromethane, dichloroethane or tetrahydrofuran, preferably dichloromethane or dichloroethane.

[0008] Furthermore, the temperature of the chlorination reaction is -15°C to 80°C, preferably 25°C to 60°C.

[0009] Furthermore, the chlorination reaction time is 5 to 15 h.

[0010] Furthermore, in the above chlorination reaction, the molar ratio of 2-phenylbenzoic acid to the hydrogen peroxide concentrated hydrochloric acid system is 2-phenylbenzoic acid: hydrogen peroxide concentrated hydrochloric acid system = 1: 1-10, preferably 2-phenylbenzoic acid: hydrogen peroxide concentrated hydrochloric acid system = 1: 1.5-5.

[0011] Furthermore, in the above reduction reaction, the solvent used is ethanol, methanol or isopropanol, preferably methanol.

[0012] Furthermore, in the above reduction reaction, the base used is sodium carbonate, potassium carbonate, triethylamine or diisopropylethylamine, preferably triethylamine.

[0013] Furthermore, in the above reduction reaction, the catalyst used is platinum-carbon, palladium-carbon or nickel, preferably a palladium-carbon catalyst.

[0014] Furthermore, the temperature of the reduction reaction is 25°C to 100°C, preferably 50°C to 70°C.

[0015] Furthermore, the reduction reaction time is 8 to 15 h.

[0016] Furthermore, in the above reduction reaction, the mass ratio of solid to alkali is solid: alkali = 1: 0.45-0.85, preferably solid: alkali = 1: 0.5-0.8.

[0017] Furthermore, in the above reduction reaction, the mass ratio of solid to catalyst is solid:catalyst=1:0.01-0.5, preferably solid:catalyst=1:0.03-0.2.

[0018] The present invention uses 2-formic acid biphenyl as a raw material, and chlorinates through a hydrogen peroxide / HCl system to obtain 2-(4'-chlorophenyl)benzoic acid. The process avoids the use of chlorination reagents such as chlorine gas and sulfuryl chloride, and solves the problems of strict chlorine gas control, high toxicity, high danger, high equipment requirements, and difficulty in industrialization. The present invention performs hydrogenation reduction on the chlorinated isomers and polychlorinated products produced by chlorination to 2-formic acid biphenyl, and then further applies them to the next batch of chlorination reactions, thereby solving the problem of low total yield, greatly improving the comprehensive utilization efficiency of raw materials, and greatly reducing process costs.

[0019] The specific reaction mechanism is as follows: 1) In concentrated hydrochloric acid, hydrogen peroxide (H 2 O 2 ) as an oxidant to convert Cl - Oxidized to Cl 2 , Cl 2 Further dissociation under acidic conditions generates electrophilic Cl - :

[0020] 2) Since the formic acid group (-COOH) is a strong electron-withdrawing group, the ring A where it is located is passivated, and the electrophilic substitution mainly occurs on the unsubstituted ring B. The conjugated effect of biphenyl makes the electron density of the 4th position of ring B (relative to the para position of the connection point) higher, becoming Cl - Target of attack.

[0021]

[0022] 3) The intermediate restores the aromaticity of the benzene ring by removing a proton (usually provided by an adjacent hydrogen atom) to produce the final product 4-chloro-2-carboxylic acid biphenyl.

[0023]

[0024] The content of 2-(4'-chlorophenyl)benzoic acid prepared by the synthesis process of the invention reaches more than 99%, and the total yield reaches more than 97%.

[0025] Compared with the prior art, the present invention has the following advantages: The method for synthesizing the boscalid intermediate 2-(4'-chlorophenyl)benzoic acid provided by the present invention has the advantages of no need to use dangerous chlorine gas, thionyl chloride and other chlorination reagents, mild reaction, high conversion rate, less by-products and high yield.

[0026] The by-products produced by the chlorination reaction of the present invention can be converted back into the raw material 2-biphenyl formate by hydrogenation reduction, thereby improving the comprehensive utilization rate of the raw materials, reducing the process cost, and having important industrial value. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is a schematic diagram of the process flow of the present invention. DETAILED DESCRIPTION

[0028] The present invention is further described below in conjunction with specific embodiments and drawings of the specification, but the protection scope of the present invention is not limited thereto.

[0029] The process of the present invention is as follows Figure 1 As shown, 2-formic acid biphenyl is subjected to chlorination reaction and recrystallization purification to obtain the product 2-(4'-chlorophenyl)benzoic acid and a mother liquor containing a small amount of 2-(4'-chlorophenyl)benzoic acid, and the mother liquor is subjected to hydrogenation reduction treatment to obtain 2-formic acid biphenyl.

[0030] Example 1: Preparation of 2-(4'-chlorophenyl)benzoic acid In a 500 L reactor, 200 L of dichloroethane, 60 kg (dry, 300 mol) of 2-formic acid biphenyl, and 46 kg (450 mol) of 37% hydrochloric acid were added in sequence. Stirring was started and heated to 60 °C. After the solid was completely dissolved, 42.5 kg (250 mol) of 20% hydrogen peroxide was slowly added dropwise to the system. After the addition was completed, the reaction was continued at room temperature for 5 h. The content of 2-formic acid biphenyl was detected by HPLC to be <1%, the reaction was stopped, the mixture was allowed to stand for stratification, the organic layer was washed with water, desolventized by reduced pressure distillation, and dried to obtain 73.7 kg of white solid 2-(4'-chlorophenyl)benzoic acid crude product (purity 93%, yield 99%).

[0031] The solid obtained by chlorination was recrystallized and purified. In a 250 L reactor, 73.7 kg of crude 2-(4'-chlorophenyl)benzoic acid obtained by the above chlorination reaction and 145 L of dichloroethane were added in sequence, stirring was started, the temperature was increased, and the solid was completely dissolved. The temperature was lowered, filtered, and the filter residue was dried to obtain 68.5 kg of white solid 2-(4'-chlorophenyl)benzoic acid (purity 99%, yield 98%). The filtrate was subjected to reduced pressure distillation for desolventization and drying, and the solid was collected for hydrogenation reduction dechlorination.

[0032] The hydrogen spectrum data of 2-(4'-chlorophenyl)benzoic acid are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.83(s, 1H), 7.78 (dd, J = 7.7, 1.4 Hz, 1H), 7.59 (td, J = 7.5, 1.5 Hz, 1H), 7.52 –7.43 (m, 3H), 7.42 – 7.30 (m, 3H).

[0033] Example 2: Preparation of 2-(4'-chlorophenyl)benzoic acid In a 500 L reactor, add 200 L of dichloroethane, 60 kg (dry, 300 mol) 2-formic acid biphenyl, and 118 kg (1157 mol) 37% hydrochloric acid in sequence, start stirring, heat to 60 ° C, wait for the solid to dissolve completely, slowly add 109 kg (643 mol) 20% hydrogen peroxide to the system, and continue to keep warm for 5 hours. HPLC detection of 2-formic acid biphenyl content <1%, stop the reaction, let stand to separate, wash the organic layer with water, desolventize by vacuum distillation, and dry to obtain 75.5 kg of white solid 2-(4'-chlorophenyl) benzoic acid crude product (purity 85%, yield 92%).

[0034] Example 3: Preparation of 2-(4'-chlorophenyl)benzoic acid In a 500 L reactor, add 200 L of dichloroethane, 60 kg (dry, 300 mol) 2-formic acid biphenyl, and 78.8 kg (771 mol) 37% hydrochloric acid in sequence, start stirring, heat to 60 ° C, wait for the solid to completely dissolve, slowly add 72.9 kg (429 mol) 20% hydrogen peroxide to the system, and continue to keep warm for 5 hours. HPLC detection of 2-formic acid biphenyl content <1%, stop the reaction, let stand and separate, wash the organic layer with water, desolventize by vacuum distillation, and dry to obtain 75 kg of white solid 2-(4'-chlorophenyl) benzoic acid crude product (purity 92%, yield 99%).

[0035] Example 4: Hydrogenation reduction of chlorinated by-products In the reactor, 10 kg of the solid after desolventizing and drying the recrystallization filtrate of Example 1, 1 kg of palladium carbon, 4.57 kg of triethylamine and 60 L of methanol were added in sequence, nitrogen was replaced, and then hydrogen was replaced. Stirring was started, heated to 60 ° C, and the reaction was carried out for 10 hours. The reaction was stopped, the temperature was lowered, filtered, and desolventized by vacuum distillation. DCM was added, water was added, and hydrochloric acid was added while stirring until the aqueous phase was acidic. The organic phase was allowed to stand and decomposed, and 8.5 kg of 2-biphenyl formate was desolventized and dried (purity 99%, yield 99%).

[0036] The hydrogen spectrum data of 2-biphenyl formate are as follows: 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.73 (s, 1H),7.73 (dd, J = 7.7, 1.4 Hz, 1H), 7.57 (td, J= 7.6, 1.5 Hz, 1H), 7.49 – 7.30 (m,7H).

[0037] Example 5: The 2-carboxylic acid biphenyl obtained by reduction is put into the chlorination reaction In a 500 L reactor, 200 L of ethylene dichloride, 60 kg (dry, 300 mol) of 2-formic acid biphenyl (including 8.5 kg of 2-formic acid biphenyl obtained by reduction), and 46 kg (450 mol) of 37% hydrochloric acid were added in sequence. Stirring was started and heated to 60°C. After the solid was completely dissolved, 42.5 kg (250 mol) of 20% hydrogen peroxide was slowly added dropwise to the system. After the addition was completed, the reaction was continued to be kept warm for 5 hours. The content of 2-formic acid biphenyl was detected by HPLC to be <1%, the reaction was stopped, the organic layer was allowed to stand for stratification, and 73.7 kg of white solid 2-(4'-chlorophenyl)benzoic acid (purity 93%, yield 99%) was obtained by vacuum distillation and drying. Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing 2-(4'-chlorophenyl)benzoic acid, characterized in that: The following steps are involved: (1) Chlorination: 2-phenylbenzoic acid is dissolved in a solvent and subjected to chlorination reaction in the presence of a hydrogen peroxide and concentrated hydrochloric acid system to obtain a crude 2-(4'-chlorophenyl)benzoic acid product; (2) Reduction: The crude 2-(4'-chlorophenyl)benzoic acid obtained in step (1) is recrystallized and purified to obtain 2-(4'-chlorophenyl)benzoic acid, and the recrystallization mother liquor containing a small amount of 2-(4'-chlorophenyl)benzoic acid is desolventized and dried, and the obtained solid is dissolved in a solvent, and a catalyst, a base and hydrogen are added to perform dechlorination reduction to obtain 2-phenylbenzoic acid; (3) The 2-phenylbenzoic acid obtained by hydrogenation reduction is mixed as a raw material into the next batch of chlorination reaction, i.e., the reaction of step (1), to participate in the chlorination reaction.

2. The method for synthesizing 2-(4'-chlorophenyl)benzoic acid according to claim 1, characterized in that: The solvent in step (1) is chloroform, acetonitrile, dichloromethane, dichloroethane or tetrahydrofuran.

3. A method for synthesizing 2-(4'-chlorophenyl)benzoic acid according to claim 1, characterized in that: The reaction temperature in step (1) is -15°C to 80°C, and the reaction time is 5 to 15 h.

4. The method for synthesizing 2-(4'-chlorophenyl)benzoic acid according to claim 1, characterized in that: The molar ratio of 2-phenylbenzoic acid to the hydrogen peroxide concentrated hydrochloric acid system in step (1) is 2-phenylbenzoic acid: hydrogen peroxide concentrated hydrochloric acid system = 1:1-10.

5. The method for synthesizing 2-(4'-chlorophenyl)benzoic acid according to claim 1, characterized in that: In step (2), the solvent is ethanol, methanol or isopropanol, and the base is sodium carbonate, potassium carbonate, triethylamine or diisopropylethylamine.

6. The method for synthesizing 2-(4'-chlorophenyl)benzoic acid according to claim 1, characterized in that: The catalyst in step (2) is platinum-carbon, palladium-carbon or nickel.

7. The method for synthesizing 2-(4'-chlorophenyl)benzoic acid according to claim 1, characterized in that: The temperature of the dechlorination reduction reaction in step (2) is 25°C to 100°C, and the reaction time is 8 to 15 hours.

8. The method for synthesizing 2-(4'-chlorophenyl)benzoic acid according to claim 1, characterized in that: The mass ratio of solid to alkali in step (2) is solid: alkali = 1: 0.45-0.

85.

9. The method for synthesizing 2-(4'-chlorophenyl)benzoic acid according to claim 1, characterized in that: The mass ratio of solid to catalyst in step (2) is solid:catalyst=1:0.01-0.5.

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