Preparation method of 3, 5-dichloro-4-alkylbenzoic acid

Abstract

The invention relates to the field of organic synthesis, in particular to a preparation method of 3, 5-dichloro-4-alkylbenzoic acid. The preparation method comprises the following steps: carrying out substitution reaction on p-alkyl benzoic acid and trichloroisocyanuric acid in a mixed solvent containing sulfuric acid and acetic acid to prepare 3, 5-dichloro-4-alkyl benzoic acid; according to the preparation method, a mixed solvent of sulfuric acid and acetic acid is adopted, more reaction products of p-alkylbenzoic acid and trichloroisocyanuric acid can stay in a dichloro substitution stage, namely more 3, 5-dichloro-4-alkylbenzoic acid products can be obtained, and the separation yield can reach 65% or above. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly relates to a method for preparing 3,5-dichloro-4-alkylbenzoic acid. Background Art

[0002] 3,5-Dichloro-4-alkylbenzoic acid has important applications in the fields of pesticides, pharmaceuticals, and organic synthesis. For example, 3,5-dichloro-4-methylbenzoic acid can be used to synthesize the intermediate 3,5-dichlorobenzyl chloride of the herbicide oxaziclomefone.

[0003] In the prior art, US5254584A discloses the following method for preparing 3,5-dichloro-4-methylbenzoic acid: p-methylbenzoic acid reacts with aluminum chloride and chlorine gas to obtain 3,5-dichloro-4-methylbenzoic acid with a yield of 81%. However, this reaction is highly sensitive to conditions such as the rate of chlorine gas introduction and the reaction temperature. When these conditions change slightly, it will have a great impact on the yield.

[0004]

[0005] Oxidative chlorination, desulphonation, or decarboxylation to synthesize pharmaceutical intermediates: 2,6-Dichlorotoluene, 2,6-dichloroaniline, and 2,6-dichlorophenol (Organic Process Research and Development, 1999, 3, 1, 10-16) discloses that p-methylbenzoic acid reacts with hydrochloric acid and hydrogen peroxide in acetic acid and water to prepare 3,5-dichloro-4-methylbenzoic acid. This document also clearly records that this preparation method is highly sensitive to the ratio of hydrogen peroxide to the raw material and the dropping rate of hydrogen peroxide. Slight differences will have a great impact on the yield. At the same time, for substrates such as p-methylbenzoic acid, even under optimal conditions, the target product can only be obtained with a yield of 50%.

[0006] Therefore, there is a lack of a suitable method for preparing 3,5-dichloro-4-alkylbenzoic acid for industrial production in the prior art. Summary of the Invention

[0007] The present invention is made to solve the above problems, and the purpose is to provide a method for preparing 3,5-dichloro-4-alkylbenzoic acid. This preparation method uses p-alkylbenzoic acid as the raw material and can highly selectively obtain 3,5-dichloro-4-alkylbenzoic acid.

[0008] The present invention provides a method for preparing 3,5-dichloro-4-alkylbenzoic acid, which comprises the following steps:

[0009] In a mixed solvent containing sulfuric acid and acetic acid, a substitution reaction occurs between alkylbenzoic acid and trichloroisocyanuric acid to obtain 3,5-dichloro-4-alkylbenzoic acid;

[0010]

[0011] wherein, R 1 is a C 1-6 alkyl group.

[0012] In one embodiment, R 1 is preferably a C 1-4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0013] In one embodiment, is preferably is preferably

[0014] In one embodiment, the mixed solvent is preferably sulfuric acid and acetic acid.

[0015] In the substitution reaction, the sulfuric acid is preferably an aqueous sulfuric acid solution of 60 wt%-98 wt%, preferably an aqueous sulfuric acid solution of 98 wt%.

[0016] In the substitution reaction, the volume ratio of the sulfuric acid to the acetic acid can be (1-5):1, preferably (2-3):1, such as 7:3.

[0017] In the substitution reaction, the mass-volume ratio of the alkylbenzoic acid to the mixed solvent can be 1 g:(5-20) mL, preferably 1 g:(8-12) mL, such as 1 g:10 mL.

[0018] In the substitution reaction, the molar ratio of the trichloroisocyanuric acid to the alkylbenzoic acid can be (0.8-1.2):1, such as 0.9:1 or 1.0:1.

[0019] In the substitution reaction, the reaction temperature can be 90-100 °C.

[0020] In the substitution reaction, the reaction time can be 0.5-2 h.

[0021] In one embodiment, after the reaction is completed, the following post-treatment is further included: quenching the reaction, taking the solid for pulping, taking the filtrate for concentration, and column chromatography.

[0022] In another embodiment, after the reaction is completed, the following post-treatment is further included: (1) quenching the reaction, taking the solid for pulping, and taking the filtrate for concentration to obtain the crude product of 3,5-dichloro-4-alkylbenzoic acid;

[0023] (2) Esterifying the crude product of 3,5-dichloro-4-alkylbenzoic acid, and rectifying to obtain the crude product of methyl 3,5-dichloro-4-alkylbenzoate;

[0024] (3) Hydrolyzing the crude product of methyl 3,5-dichloro-4-alkylbenzoate, and recrystallizing to prepare 3,5-dichloro-4-alkylbenzoic acid.

[0025] In the step (1), the solvent used for pulping is MTBE.

[0026] In the step (2), the crude product of methyl 3,5-dichloro-4-alkylbenzoate is the fraction with a top temperature of 110-130°C.

[0027] In the step (2), the crude product of methyl 3,5-dichloro-4-alkylbenzoate is a mixture containing methyl 3,5-dichloro-4-alkylbenzoate and 3,5-dichloro-4-alkylbenzoic acid.

[0028] In the step (2), the method of esterification is as follows: in methanol, the crude product of 3,5-dichloro-4-alkylbenzoic acid reacts with thionyl chloride to obtain a reaction solution containing methyl 3,5-dichloro-4-alkylbenzoate.

[0029] In the step (3), the method of hydrolysis is as follows: in tetrahydrofuran, the crude product of methyl 3,5-dichloro-4-alkylbenzoate reacts with an aqueous solution of a base to obtain 3,5-dichloro-4-alkylbenzoic acid.

[0030] In the step (3), the solvent used for recrystallization can be ethyl acetate and acetonitrile. Preferably, the volume ratio of ethyl acetate to acetonitrile is 1:(0.5-2).

[0031] In a certain embodiment, the preparation method of the 3,5-dichloro-4-alkylbenzoic acid compound includes the following steps:

[0032] In a mixed solvent of sulfuric acid and acetic acid, p-toluic acid and trichloroisocyanuric acid undergo a substitution reaction to obtain 3,5-dichloro-4-methylbenzoic acid;

[0033]

[0034] In another embodiment, after the reaction is completed, the following post-treatment is further included: (1) quenching the reaction, taking the solid for pulping, and taking the filtrate for concentration to obtain the crude product of 3,5-dichloro-4-methylbenzoic acid;

[0035] (2) Esterify the crude 3,5-dichloro-4-methylbenzoic acid, and perform rectification to obtain the crude methyl 3,5-dichloro-4-methylbenzoate;

[0036] (3) Hydrolyze the crude methyl 3,5-dichloro-4-methylbenzoate and perform recrystallization to prepare 3,5-dichloro-4-methylbenzoic acid.

[0037] In the step (2), the crude methyl 3,5-dichloro-4-methylbenzoate is the fraction with a top temperature of 110 - 130°C.

[0038] In the step (2), the crude methyl 3,5-dichloro-4-methylbenzoate is a mixture of methyl 3,5-dichloro-4-methylbenzoate and 3,5-dichloro-4-methylbenzoic acid.

[0039] In the step (2), the esterification method is as follows: In methanol, the crude 3,5-dichloro-4-methylbenzoic acid reacts with thionyl chloride to obtain a reaction solution containing methyl 3,5-dichloro-4-methylbenzoate.

[0040] In the step (3), the hydrolysis method is as follows: In tetrahydrofuran, the crude methyl 3,5-dichloro-4-methylbenzoate reacts with an aqueous solution of a base to obtain 3,5-dichloro-4-methylbenzoic acid.

[0041] In a certain embodiment, in a mixed solvent of sulfuric acid and acetic acid, p-toluic acid and trichloroisocyanuric acid react at 90 - 100°C for 0.5 - 2 h, cool down to 60°C, pour the reaction solution into ice water to quench the reaction, filter to obtain the filter cake, the filter cake is slurried with MTBE and then filtered to obtain the filtrate, and concentrate and pass through a column to prepare 3,5-dichloro-4-methylbenzoic acid.

[0042] In another embodiment, in a mixed solvent of sulfuric acid and acetic acid, p-toluic acid and trichloroisocyanuric acid react at 90 - 100°C for 0.5 - 2 h, cool down to 60°C, pour the reaction solution into ice water to quench the reaction, filter to obtain the filter cake, the filter cake is slurried with MTBE and then filtered to obtain the filtrate, and concentrate to obtain the crude 3,5-dichloro-4-methylbenzoic acid; esterify the crude 3,5-dichloro-4-methylbenzoic acid and perform rectification, take the fraction with a top temperature of 110 - 130°C to obtain the crude methyl 3,5-dichloro-4-methylbenzoate; hydrolyze the crude methyl 3,5-dichloro-4-methylbenzoate and perform recrystallization with a mixed solvent of ethyl acetate and acetonitrile to prepare 3,5-dichloro-4-methylbenzoic acid.

[0043] Functions and effects of the invention

[0044] A preparation method of 3,5-dichloro-4-alkylbenzoic acid compounds provided by the present invention uses trichloroisocyanuric acid as a chlorinating reagent. Compared with chlorine gas, the reaction is safer, more reliable, and has strong repeatability, making it suitable for industrial production. Further, this method ingeniously adopts a mixed solvent of sulfuric acid and acetic acid. In the above-mentioned mixed solvent, the reaction product of alkylbenzoic acid and trichloroisocyanuric acid can stay more at the dichloro substitution stage, that is, more 3,5-dichloro-4-alkylbenzoic acid products can be obtained, and the separation yield can be as high as over 65%. Description of the Drawings

[0045] Figure 1 It is the HPLC detection spectrum of the product 3,5-dichloro-4-methylbenzoic acid in Example 1;

[0046] Figure 2 It is the HPLC detection spectrum of the crude product of methyl 3,5-dichloro-4-methylbenzoate in Example 2;

[0047] Figure 3 It is the HPLC detection spectrum of the product 3,5-dichloro-4-methylbenzoic acid in Example 2;

[0048] Figure 4 It is the HPLC detection spectrum of the product in Comparative Example 4;

[0049] Figure 5 It is the HPLC detection spectrum of the product in Comparative Example 5. Detailed Embodiments

[0050] In order to make the technical means, creative features, achieved purposes and effects of the present invention easy to understand, the present invention will be specifically described below in conjunction with embodiments.

[0051] Unless otherwise specified, the reagents and raw materials used in the present invention are all commercially available.

[0052] In the following embodiments, unless otherwise specified, concentrated sulfuric acid is a 98wt% sulfuric acid aqueous solution.

[0053] In the following embodiments, unless otherwise specified, monochloro impurities and monochloro products refer to 3-chloro-4-methylbenzoic acid, and trichloro impurities and trichloro products refer to 2,3,5-trichloro-4-methylbenzoic acid.

[0054] Example 1

[0055]

[0056] Place 100 g of p-toluic acid (0.73 mol, 1.0 eq), 700 mL of concentrated sulfuric acid, and 300 mL of acetic acid in a reaction kettle. Control the temperature below 95 °C, add 170 g of trichloroisocyanuric acid (TCCA, 0.73 mol, 1.0 eq), stir for 1.0 h, control the temperature below 60 °C, drop the reaction solution into 1 L of ice water, stir at room temperature, filter, take the filter cake, add 800 mL of tert-butyl methyl ether (MTBE) for pulping, filter, take the filtrate, concentrate, and pass through a column to obtain 106.3 g, with a yield of 71.0%. As Figure 1 shown, the HPLC purity of the obtained product is 99.2%.

[0057] Example 2

[0058]

[0059] Place 9.2 kg of p-toluic acid (67.57 mol, 1.0 eq), 58.8 L of concentrated sulfuric acid, and 27.6 L of acetic acid in a reaction kettle. Control the temperature below 95 °C and add 14.1 kg of TCCA (60.67 mol, 0.9 eq), stir for 2.0 h, control the temperature below 60 °C, drop the reaction solution into ice water, stir at room temperature, filter, take the filter cake, add MTBE for pulping, filter, take the filtrate, and concentrate to obtain 17.1 kg of crude 3,5-dichloro-4-methylbenzoic acid, in which the content of 3,5-dichloro-4-methylbenzoic acid is 60.7%.

[0060] Take 15.5 kg of the crude product and 36.3 kg of methanol and add them to a reaction kettle. Install a tail gas absorption device, slowly drop 8.79 kg of thionyl chloride, stir at 63 °C for 3 h, distill off the solvent under reduced pressure at 50 °C, and subject the remaining material to reduced pressure distillation. Use a 60 cm packing column and collect the fraction with a top temperature of 110 - 130 °C at 2 mmHg to obtain 10.21 kg of crude methyl 3,5-dichloro-4-methylbenzoate. As Figure 2 shown, in this crude product, the HPLC purity of methyl 3,5-dichloro-4-methylbenzoate is 81.5% (Rt = 13.207 min), the HPLC purity of 3,5-dichloro-4-methylbenzoic acid is 12.0% (Rt = 11.943 min), and the HPLC purity of 2,3,5-trichloro-4-methylbenzoic acid is 6.4% (Rt = 11.652 min).

[0061] Add 10.21 kg of the crude product of methyl 3,5-dichloro-4-methylbenzoate, 25.2 kg of tetrahydrofuran, and 27.76 kg of an aqueous sodium hydroxide solution (containing 64 mol of sodium hydroxide) to the reaction kettle. Heat up to 60 - 65 °C and stir for 30 min. After the reaction is completed, cool down to room temperature. Add 7.28 kg of hydrochloric acid to adjust the pH to 1 - 2. Let it stand for liquid separation, and take the upper tetrahydrofuran phase, then concentrate and evaporate to dryness. Add 25.2 kg of ethyl acetate to dissolve at 65 - 75 °C, add 22 kg of acetonitrile, cool down to 15 - 20 °C, filter, take the filter cake, and dry to obtain 8.49 kg of solid, with a yield of 67.6%. As Figure 3 shown, the purity of the obtained product is 99.6% (Rt = 12.048 min).

[0062] Comparative Example 1

[0063] Place 5 g of p-toluic acid (37 mmol, 1.0 eq), 50 mL of dichloromethane, and 9.9 g of aluminum trichloride (74 mmol, 2.0 eq) in a reaction flask. Control the temperature below 10 °C, and continuously introduce chlorine gas into the reaction flask at a rate of 1.0 mL / s. After the reaction for a period of time, take the reaction solution and monitor the reaction by HPLC. The content of the product in the reaction solution is shown in the following table:

[0064] Table 1. Product situation in the reaction solution monitored at different times

[0065] Reaction time Content of 3-chloro-4-methylbenzoic acid Content of 3,5-dichloro-4-methylbenzoic acid 2h 95.3％ 2.7％ 3.5h 91.9％ 5.0％ 7.0h 82.8％ 10.7％ 20h 62.9％ 18.5％

[0066] After reacting for 20 h, pour the reaction solution into ice water, extract with ethyl acetate and then concentrate. Take the ethyl acetate phase and pass it through a column to obtain 1.0 g of solid, with a yield of 13.2%.

[0067] As can be seen from Table 1, under the reaction conditions of this comparative example, the main product is 3-chloro-4-methylbenzoic acid, rather than 3,5-dichloro-4-methylbenzoic acid. Even if the reaction time is extended to 20 h, the conversion rate of the target product 3,5-dichloro-4-methylbenzoic acid is less than 20%.

[0068] Comparative Example 2

[0069] Place 1 g of p-toluic acid (7.3 mmol, 1.0 eq) and the solvent in a reaction kettle. Control the temperature below 95 °C, add trichloroisocyanuric acid, and stir for 1.0 h. Take a small amount of the reaction solution and drop it into ice water, add a small amount of methyl tert-butyl ether (MTBE) for extraction, and take the MTBE phase for HPLC detection. The reaction situation is as follows:

[0070] Table 2. In-process control of the reaction under different conditions

[0071]

[0072] As shown in the figure above, when a strong acid such as concentrated sulfuric acid is used alone as the reaction solvent, the reaction always tends to produce trichlorinated products. When acetic acid alone or highly diluted concentrated sulfuric acid is used as the reaction solvent, the chlorination reaction is inhibited and almost no chlorinated products can be obtained. In addition, the applicant also unexpectedly found that when an aqueous sodium hydroxide solution is used as the reaction solvent, the reaction is more likely to produce monochlorinated products.

[0073] Comparative Example 3

[0074] 10 g of p-methylbenzoic acid (0.073 mol, 1.0 eq), 50 mL of concentrated sulfuric acid and 50 mL of acetic acid were placed in a reaction kettle, heated to 80 °C, 29.2 g of N-chlorosuccinimide (NCS, 0.22 mol, 3.0 eq) was added, and stirred for 20 h. The reaction solution was taken for HPLC detection. The content of monochlorinated product was 86.8%, and 3,5-dichloro-4-methylbenzoic acid was not detected.

[0075] Comparative Example 4

[0076] 100 g of the crude product of 3,5-dichloro-4-methylbenzoic acid in Example 2 was taken and treated as follows:

[0077] 100 g of the crude product of 3,5-dichloro-4-methylbenzoic acid was taken, dissolved in 400 mL of ethyl acetate by heating, 400 mL of acetonitrile was added dropwise, and then cooled to room temperature. Crystals were precipitated, filtered, and dried to obtain 55 g of solid. As Figure 4 shown, the purity of the obtained product was 92.8%, and the monochlorinated impurity was 4.67% (Rt = 10.414 min).

[0078] Comparative Example 5

[0079] 100 g of the crude product of 3,5-dichloro-4-methylbenzoic acid in Example 2 was taken and treated as follows:

[0080] 100 g of the crude product of 3,5-dichloro-4-methylbenzoic acid was added to 400 mL of ethyl acetate and dissolved by heating, and then cooled to room temperature. Crystals were precipitated, filtered, and dried to obtain 70 g of solid. As Figure 5 shown, the purity of the obtained product was 79.7%, the monochlorinated impurity was 14.6% (Rt = 10.408 min), and the trichlorinated impurity was 4.07% (Rt = 11.780 min).

[0081] According to the preparation method of 3,5-dichloro-4-alkylbenzoic acid involved in Embodiment 1-2, trichloroisocyanuric acid is used as the chlorinating reagent in this preparation method. Compared with chlorine gas, the reaction is safer, more reliable, and has strong repeatability, making it suitable for industrial production. Further, this method also ingeniously adopts a mixed solvent of sulfuric acid and acetic acid. In the above-mentioned mixed solvent, the reaction product of alkylbenzoic acid and trichloroisocyanuric acid can stay more at the dichloro substitution stage, that is, more 3,5-dichloro-4-alkylbenzoic acid products can be obtained, and the separation yield can be as high as over 65%.

[0082] According to the preparation method of 3,5-dichloro-4-alkylbenzoic acid involved in Embodiment 2, although the yield of 3,5-dichloro-4-alkylbenzoic acid products is improved to a considerable extent by using a mixed solvent composed of sulfuric acid and acetic acid in this application, however, a small amount of monochloro products or trichloro products are always generated during the reaction process, and the monochloro products or trichloro products are quite similar to the target product in various properties and are difficult to separate by means other than column chromatography in the prior art. This application unexpectedly discovers that by first subjecting the crude product to esterification rectification, the monochloro impurities can be basically removed, and then by hydrolysis and recrystallization, the trichloro impurities can be separated, thereby obtaining a target product with high purity. And this method has small losses, a convenient large-batch production process, and is suitable for industrial production.

Claims

1. A method for preparing 3,5-dichloro-4-alkylbenzoic acid, characterized in that, It includes the following steps: In a mixed solvent containing sulfuric acid and acetic acid, a substitution reaction occurs between p-alkylbenzoic acid and trichloroisocyanuric acid to obtain 3,5-dichloro-4-alkylbenzoic acid; Among them, R 1 is C 1-6 alkyl.

2. The preparation method according to claim 1, characterized in that, The sulfuric acid is an aqueous sulfuric acid solution with a concentration of 60wt%-98wt%.

3. The preparation method according to claim 1, characterized in that, The volume ratio of the sulfuric acid to the acetic acid is (1-5):

1.

4. The preparation method according to claim 3, characterized in that, The volume ratio of the sulfuric acid to the acetic acid is (2-3):

1.

5. The preparation method according to claim 1, characterized in that, The mass-volume ratio of the p-alkylbenzoic acid to the mixed solvent is 1g:(5-20)mL.

6. The preparation method according to claim 1, wherein The molar ratio of the trichloroisocyanuric acid to the p-alkylbenzoic acid is (0.8-1.2):

1.

7. The preparation method according to claim 1, characterized in that, The reaction temperature is 90-100°C.

8. The preparation method according to claim 1, characterized in that, R 1 is C 1-4 alkyl group.

9. The preparation method according to claim 1, wherein The preparation method of the 3,5-dichloro-4-alkylbenzoic acid compound includes the following steps: In a mixed solvent of sulfuric acid and acetic acid, a substitution reaction occurs between p-methylbenzoic acid and trichloroisocyanuric acid to obtain 3,5-dichloro-4-methylbenzoic acid; 10. The preparation method according to claim 1, characterized in that, After the substitution reaction, the following post-treatment steps are further included: (1) Quench the reaction, take the solid for pulping, and take the filtrate for concentration to obtain the crude product of 3,5-dichloro-4-alkylbenzoic acid; (2) Esterify the crude product of 3,5-dichloro-4-alkylbenzoic acid and perform rectification to obtain the crude product of methyl 3,5-dichloro-4-alkylbenzoate; (3) Hydrolyze the crude product of methyl 3,5-dichloro-4-alkylbenzoate and perform recrystallization to obtain 3,5-dichloro-4-alkylbenzoic acid.

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