Preparation method of 2-chloro-6-aminobenzoic acid

Abstract

The invention is suitable for the technical field of organic synthesis, and provides a preparation method of 2-chloro-6-aminobenzoic acid, which comprises the following steps: step (1), adding 2, 3-dichloronitrobenzene, a solvent and a strong base into a reaction flask, stirring and mixing, dropwise adding diethyl malonate at a controlled temperature, after dropwise adding is completed, keeping a constant temperature for continuous reaction, after the reaction is completed, carrying out reduced pressure distillation to recover the solvent, and obtaining 2-chloro-6-aminobenzoic acid; a compound II is obtained; step (2), adding drinking water and a solvent into the compound II, stirring and mixing, dropwise adding hydrogen peroxide at a controlled temperature, after dropwise adding is completed, keeping the constant temperature to continue the reaction, and after the reaction is completed, obtaining an intermediate III solution; and (3) carrying out nitro reduction on the compound III, after the reduction reaction is finished, extracting and washing the reaction liquid to obtain an organic layer, and carrying out reduced pressure distillation on the organic layer to obtain the compound 2-chloro-6-aminobenzoic acid. The raw materials are simple and easy to obtain, the market source is sufficient, the process cost is low, and highly toxic and dangerous materials are not involved.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing 2-chloro-6-aminobenzoic acid. Background Art

[0002] 2-Chloro-6-aminobenzoic acid has a chemical formula of C7H6ClNO2. It is an important pharmaceutical intermediate that can be used to synthesize pyrimidine salicylic acid herbicides, dicloxacillin, laquinimod, etc. It has a very wide range of applications in the field of pharmaceutical chemicals. Its chemical structure is shown in Formula III below:

[0003]

[0004] At present, there are many synthetic routes for 2-chloro-6-aminobenzoic acid. Patents US4932999 and CN1043707A report the use of 2-chloro-6-nitrotoluene through oxidation and reduction in two steps. The process yield is low, only 20% to 40%. At the same time, iron powder hydrochloric acid is used in the nitro reduction, and the process will produce a large amount of iron mud that is difficult to handle, and there are more three wastes. It is an industrial process that has been eliminated. This process route is as follows Figure 1 shown.

[0005] Chen Guoguang et al. improved the above process in the journal (Chemical Reagents, 2007, 29 (12), 761-762; 764), using 2-chloro-6-nitrotoluene through four steps of reduction, amino protection, oxidation, and deamination protection. This process also failed to avoid the high pollution process of iron powder reduction. At the same time, the process steps are cumbersome, the process cost is high, and the industrial applicability is poor. This process route is as follows Figure 2 shown.

[0006] Patent US20185527 discloses the preparation of 2-chloro-6-aminobenzoic acid using 2-chloro-6-aminobenzonitrile as raw material and a one-step hydrolysis reaction. The process route is short, but the raw material 2-cyano-3-chloroaniline needs to be made in-house, and highly toxic sodium cyanide or potassium cyanide is used in the process. The sources of raw and auxiliary materials are subject to great control, and the safety and environmental risks are also high, and the prospects for industrialization are not good. This process route is as follows Figure 3 shown.

[0007] Patent CN105801443A discloses a process for preparing 2-chloro-6-nitrobenzoic acid as a starting material by reacting with cerium chloride. The raw material cerium chloride used in this process is expensive, and auxiliary raw materials such as 4-hydroxy-3-methoxyphenylethanol are also required. The raw material sources are expensive and it is not feasible for industrialization. Figure 4 shown.

[0008] Patent CN110092727B discloses a method for preparing 2-chloro-6-aminotoluene through three steps of amino protection, oxidation and deamination protection. The methyl oxidation of this process requires the use of ferric chloride, manganese dioxide and potassium dichromate. A large amount of heavy metal waste is produced in the process, which is extremely harmful to the environment. Potassium dichromate has a long-term impact on the environment. The protective group in the first step of the process needs to use chlorobenzene or fluorobenzene as a solvent, which is highly toxic and a type of carcinogen. It is not suitable as a solvent for pharmaceutical products. The product process has great limitations and poor industrial prospects. This process route is as follows Figure 5 shown.

[0009] In view of the limitations and shortcomings of the above-mentioned synthetic routes, it is necessary to develop a new 2-chloro-6-aminobenzoic acid synthesis process to reduce the generation of a large amount of waste acid, wastewater, heavy metal solid waste, etc. in production, avoid the use of highly toxic raw materials, and ensure that the raw materials have commercial sources while ensuring the process yield, low cost, simple and easy process operating conditions and high product quality to meet the commercial needs of downstream pharmaceutical products. Summary of the invention

[0010] The present invention aims to provide a method for preparing 2-chloro-6-aminobenzoic acid to solve the problems in the above-mentioned background technology.

[0011] To achieve the above object, the present invention provides the following technical scheme: a method for preparing 2-chloro-6-aminobenzoic acid, wherein the 2-chloro-6-aminobenzoic acid is prepared from 2,3-dichloronitrobenzene by substitution to obtain compound II, compound II is oxidized to obtain compound III, and compound III is reduced to obtain the target product 2-chloro-6-aminobenzoic acid.

[0012] Preferably, the preparation method of 2-chloro-6-aminobenzoic acid comprises the following steps:

[0013] Step (1), add 2,3-dichloronitrobenzene, a solvent, and a strong base into a reaction bottle, stir and mix, and add diethyl malonate dropwise at a controlled temperature. After the addition is complete, the temperature is maintained to continue the reaction. After the reaction is complete, the solvent is recovered by distillation under reduced pressure to obtain compound II;

[0014] Step (2), adding drinking water and solvent to compound II, stirring and mixing, adding hydrogen peroxide dropwise at a controlled temperature, and after the addition is complete, maintaining a constant temperature to continue the reaction, and completing the reaction to obtain an intermediate III solution;

[0015] Step (3), performing nitro reduction on compound III, after the reduction reaction is completed, extracting and washing the reaction solution to obtain an organic layer, and then distilling the organic layer under reduced pressure to obtain compound 2-chloro-6-aminobenzoic acid.

[0016] Preferably, the solvent in step (1) is one or more of DMF, DMA, DMSO and 1,4-dioxane.

[0017] Preferably, in step (1), the strong base is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium carbonate, and the molar ratio of the strong base to the raw material 2,3-dichloronitrobenzene is 1.5-4.0:1.

[0018] Preferably, in step (1), the molar ratio of diethyl malonate to the raw material 2,3-dichloronitrobenzene is 1.0-2.0:1.

[0019] Preferably, the reaction temperature in step (1) is 30-130°C.

[0020] Preferably, the solvent in step (2) is methanol, ethanol or isopropanol.

[0021] Preferably, the reducing agent in step (3) is palladium carbon, the palladium content of the palladium carbon is 5 to 20%, and the weight ratio of the palladium carbon to 2,3-dichloronitrobenzene is 0.001 to 0.10:1.

[0022] Preferably, the solvent used for extraction in step (3) is an ester, halogenated alkane or aromatic hydrocarbon solvent.

[0023] The present invention has at least the following beneficial effects:

[0024] (1) The raw materials used in the present invention are simple and easy to obtain, with sufficient market sources, low process costs, and no highly toxic or hazardous materials are involved;

[0025] (2) The route of the present invention does not produce a large amount of waste acid, wastewater and heavy metal solid waste, and the organic solvent and palladium carbon in the process can be recycled and reused, making the process green and environmentally friendly;

[0026] (3) The process of the present invention is simple to operate, has a high reaction conversion rate, a total yield of more than 73.0%, and an average yield of more than 90% per step, which has industrial advantages;

[0027] (4) The final product 2-chloro-6-aminobenzoic acid obtained by the present invention has a high purity, which can reach more than 98.0%. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The reaction route for preparing 2-chloro-6-aminobenzoic acid in patent US4932999 and CN1043707A;

[0029] Figure 2 The reaction route for preparing 2-chloro-6-aminobenzoic acid in the journal (Chemical Reagents, 2007, 29(12), 761-762; 764) by Chen Guoguang et al.

[0030] Figure 3 The reaction route for preparing 2-chloro-6-aminobenzoic acid according to patent US20185527;

[0031] Figure 4 The reaction route for preparing 2-chloro-6-aminobenzoic acid in patent CN105801443A;

[0032] Figure 5 The reaction route for preparing 2-chloro-6-aminobenzoic acid in patent CN110092727B;

[0033] Figure 6 The reaction scheme for preparing 2-chloro-6-aminobenzoic acid according to the present invention is as follows;

[0034] Figure 7 It is the liquid phase detection spectrum of the product 2-chloro-6-aminobenzoic acid in Example 1 of the present invention;

[0035] Figure 8 is the infrared spectrum of the product 2-chloro-6-aminobenzoic acid in Example 1 of the present invention;

[0036] Fig. 9 The MS spectrum of the product 2-chloro-6-aminobenzoic acid in Example 1 of the present invention. DETAILED DESCRIPTION

[0037] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0038] The invention uses 2,3-dichloronitrobenzene as a raw material, and obtains 2-chloro-6-aminobenzoic acid through three-step reactions of substitution, oxidation and reduction. Various raw and auxiliary materials used in the invention are safe and environmentally friendly, have sufficient market sources, a simple synthesis route, a high reaction conversion rate, simple and easy process operation, and the route has industrialization advantages.

[0039] The present invention is achieved through the following technical scheme, and the reaction formula and synthesis steps are as follows:

[0040] like Figure 6 As shown, 2,3-dichloronitrobenzene (Compound I) is substituted to obtain Compound II, Compound II is oxidized to obtain Compound III, and Compound III is reduced to obtain the target product 2-chloro-6-aminobenzoic acid (Compound IV).

[0041] The specific steps are as follows:

[0042] Step (1): Add 2,3-dichloronitrobenzene, solvent, and strong base to a reaction flask, stir and mix, add diethyl malonate dropwise under temperature control, and keep warm for reaction. After the reaction is completed, recover the solvent by vacuum distillation to obtain compound II;

[0043] Step (2): Add drinking water and solvent to compound II, stir and mix, add hydrogen peroxide dropwise at controlled temperature, keep warm for reaction after the addition is complete. After the reaction is complete, an intermediate III solution is obtained;

[0044] Step (3): Compound III is subjected to nitro reduction. After the reduction reaction is completed, the reaction solution is extracted and washed to obtain an organic layer. The organic layer is then distilled under reduced pressure to obtain compound 2-chloro-6-aminobenzoic acid.

[0045] The solvent used in step (1) is one or more of DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), DMSO (dimethyl sulfoxide), and 1,4-dioxane, preferably DMF.

[0046] The strong base used in step (1) is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, and sodium carbonate, preferably powdered potassium hydroxide. The molar ratio of the strong base to the raw material 2,3-dichloronitrobenzene is 1.5 to 4.0:1, preferably 2.0:1.

[0047] The molar ratio of diethyl malonate used in step (1) to the raw material 2,3-dichloronitrobenzene is 1.0-2.0:1, preferably 1.1:1.

[0048] Wherein, the reaction temperature of step (1) is 30-130°C, preferably 60-70°C.

[0049] Wherein, the solvent of step (2) is methanol, ethanol or isopropanol, preferably methanol.

[0050] The reducing agent in step (3) is palladium carbon, wherein the palladium content of palladium carbon is 5-20%, preferably 5%. The weight ratio of palladium carbon to 2,3-dichloronitrobenzene is 0.01-0.20:1, preferably 0.05:1.

[0051] The solvent used for extraction in step (3) is an ester, halogenated alkane or aromatic hydrocarbon solvent, preferably ethyl acetate, dichloromethane or toluene.

[0052] Based on the above technical solution, the present invention provides the following partial embodiments:

[0053] Example 1

[0054] The specific synthesis method is as follows:

[0055] (1) In a 500 mL glass reaction bottle, add 38.4 g (0.2 mol) of 2,3-dichloronitrobenzene and 200 mL of DMF, and then add 18.5 g (0.4 mol, 2 eq) of powdered potassium hydroxide. After the addition is completed, the feed liquid is heated to 60°C, and 35.2 g (0.22 mol, 1.1 eq) of diethyl malonate is added dropwise to the feed liquid. After the addition is completed, the temperature is kept to react for 4 hours. After the reaction is completed, the feed liquid is controlled to 60°C and DMF is recovered by vacuum distillation (187 mL is recovered). After the recovery is completed, an oily substance is obtained, which is Compound II.

[0056] (2) Add 180 mL of drinking water and 50 mL of methanol to the above compound II, stir and mix, control the temperature to 30°C, and drop 45.3 g (0.4 mol, 2.0 eq) of 30% hydrogen peroxide into the liquid. After the dropwise addition is completed, keep the temperature at 30°C for 6 hours. After the reaction is completed, a solution of compound III is obtained.

[0057] (3) The reaction solution was transferred to a 500mL hydrogenation reactor, 1.9g of 5% palladium carbon was added to the reactor, nitrogen was replaced three times, the temperature in the reactor was controlled at 60°C, hydrogen was introduced into the reactor, and no hydrogen was absorbed after 4 hours of reaction, the introduction of hydrogen was stopped, the pressure was released, the feed liquid was cooled to 30°C, after cooling, it was filtered, and the wet filter cake was bagged and stored for next use. The feed liquid was transferred to a 1000mL reaction bottle, 400mL of ethyl acetate was added, stirred for 30 minutes, allowed to stand for 10 minutes, and the upper organic layer was retained. 200mL of ethyl acetate was added to the lower aqueous layer, stirred for 30 minutes, allowed to stand for 10 minutes, and the upper organic layer was retained, and the lower aqueous layer entered the wastewater. The organic layers were combined, washed once with 100 mL of saturated brine, separated, and the organic layer was concentrated to dryness under reduced pressure at 40° C. (542 mL of ethyl acetate was recovered) to obtain 27.7 g of yellow solid 2-chloro-6-aminobenzoic acid. The total yield was 80.7% and the product purity was 99.2%.

[0058] in, Figure 7 This is the liquid phase detection spectrum of the product 2-chloro-6-aminobenzoic acid obtained in this example;

[0059] Figure 8-9 This is a characterization test spectrum of the product obtained in this example.

[0060] Example 2

[0061] (1) In a 500 mL glass reaction bottle, add 38.4 g (0.2 mol) of 2,3-dichloronitrobenzene and 320 mL of DMA, and then add 32.0 g (0.8 mol, 4 eq) of flaky sodium hydroxide. After the addition is completed, the feed liquid is heated to 70°C, and 64.1 g (0.4 mol, 2.0 eq) of diethyl malonate is added dropwise to the feed liquid. After the addition is completed, the reaction is kept warm for 3 hours. After the reaction is completed, the feed liquid is controlled to 70°C and DMA is recovered by vacuum distillation (292 mL is recovered). After the recovery is completed, an oily substance is obtained, which is Compound II.

[0062] (2) Add 200 mL of drinking water and 60 mL of ethanol to the above compound II, stir and mix, control the temperature to 40°C, and drop 81.6 g (0.6 mol, 3.0 eq) of 25% hydrogen peroxide into the liquid. After the dropwise addition is completed, keep the temperature at 40°C for 5 hours. After the reaction is completed, a solution of compound III is obtained.

[0063] (3) The reaction solution was transferred to a 500mL hydrogenation reactor, 0.4g of 20% palladium carbon was added to the reactor, nitrogen was replaced three times, the temperature in the reactor was controlled at 60°C, hydrogen was introduced into the reactor, and no hydrogen was absorbed after 4 hours of reaction, then the introduction of hydrogen was stopped, the pressure was released, the feed liquid was cooled to 30°C, after cooling, filtered, and the wet filter cake was bagged and stored for next use. The feed liquid was transferred to a 1000mL reaction bottle, 400mL of dichloromethane was added, stirred for 30 minutes, allowed to stand for 10 minutes, and the liquid was separated, and the upper organic layer was retained. 200mL of dichloromethane was added to the lower aqueous layer, stirred for 30 minutes, allowed to stand for 10 minutes, and the liquid was separated, the upper organic layer was retained, and the lower aqueous layer entered the wastewater. The organic layers were combined, washed once with 100 mL of saturated brine, separated, and the organic layer was concentrated to dryness under reduced pressure at 35° C. (366 mL of dichloromethane was recovered) to obtain 25.3 g of yellow solid 2-chloro-6-aminobenzoic acid. The total yield was 73.7% and the product purity was 98.7%.

[0064] Example 3

[0065] (1) In a 500 mL glass reaction bottle, add 38.4 g (0.2 mol) of 2,3-dichloronitrobenzene and 250 mL of DMSO, and then add 7.2 g (0.3 mol, 1.5 eq) of lithium hydroxide. After the addition is completed, the feed liquid is heated to 130°C, and 32.0 g (0.2 mol, 1.0 eq) of diethyl malonate is added dropwise to the feed liquid. After the addition is completed, the temperature is kept to react for 6 hours. After the reaction is completed, the feed liquid is controlled to 120°C and DMSO is recovered by vacuum distillation (221 mL is recovered). After the recovery is completed, an oily substance is obtained, which is Compound II.

[0066] (2) Add 160 mL of drinking water and 45 mL of isopropanol to the above compound II, stir and mix, control the temperature to 50°C, and drop 56.7 g (0.6 mol, 3.0 eq) of 30% hydrogen peroxide into the liquid. After the dropwise addition is completed, keep the temperature at 50°C for 4 hours. After the reaction is completed, a solution of compound III is obtained.

[0067] (3) The reaction solution was transferred to a 500mL hydrogenation reactor, 7.7g of 10% palladium carbon was added to the reactor, nitrogen was replaced three times, the temperature in the reactor was controlled at 60°C, hydrogen was introduced into the reactor, and no hydrogen was absorbed after 4 hours of reaction, then the introduction of hydrogen was stopped, the pressure was released, the feed liquid was cooled to 30°C, after cooling, filtered, and the wet filter cake was bagged and stored for next use. The feed liquid was transferred to a 1000mL reaction bottle, 300mL of toluene was added, stirred for 30 minutes, allowed to stand for 10 minutes, and the liquid was separated, and the upper organic layer was retained. 150mL of toluene was added to the lower aqueous layer, stirred for 30 minutes, allowed to stand for 10 minutes, and the liquid was separated, the upper organic layer was retained, and the lower aqueous layer entered the wastewater. The organic layers were combined, washed once with 100 mL of saturated brine, separated, and the organic layer was concentrated to dryness under reduced pressure at 60° C. (414 mL of toluene was recovered) to obtain 25.6 g of yellow solid 2-chloro-6-aminobenzoic acid. The total yield was 74.6% and the product purity was 98.4%.

[0068] In summary, the technical solution provided by the present invention does not use highly toxic raw materials, does not produce a large amount of waste acid, waste water, and heavy metal solid waste. The source of raw materials is sufficient and the process operation is simple and easy.

[0069] The above shows and describes the basic principles, main features and advantages of the present invention. It is obvious to those skilled in the art that the present invention is not limited to the details of the above exemplary embodiments, and that the present invention can be implemented in other specific forms without departing from the spirit or basic features of the present invention. Therefore, no matter from which point of view, the embodiments should be regarded as exemplary and non-restrictive. The scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims are included in the present invention.

[0070] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing 2-chloro-6-aminobenzoic acid, characterized in that: The 2-chloro-6-aminobenzoic acid is prepared from 2,3-dichloronitrobenzene, which is substituted to obtain compound II, compound II is oxidized to obtain compound III, and compound III is reduced to obtain the target product 2-chloro-6-aminobenzoic acid.

2. The method for preparing 2-chloro-6-aminobenzoic acid according to claim 1, wherein The preparation method of the 2-chloro-6-aminobenzoic acid comprises the following steps: Step (1), add 2,3-dichloronitrobenzene, a solvent, and a strong base into a reaction bottle, stir and mix, and add diethyl malonate dropwise at a controlled temperature. After the addition is complete, the temperature is maintained to continue the reaction. After the reaction is complete, the solvent is recovered by distillation under reduced pressure to obtain compound II; Step (2), adding drinking water and solvent to compound II, stirring and mixing, adding hydrogen peroxide dropwise at a controlled temperature, and after the addition is complete, maintaining a constant temperature to continue the reaction, and completing the reaction to obtain an intermediate III solution; Step (3), performing nitro reduction on compound III, after the reduction reaction is completed, extracting and washing the reaction solution to obtain an organic layer, and then distilling the organic layer under reduced pressure to obtain compound 2-chloro-6-aminobenzoic acid.

3. The method for preparing 2-chloro-6-aminobenzoic acid according to claim 1, wherein The solvent in step (1) is one or more of DMF, DMA, DMSO and 1,4-dioxane.

4. The method for preparing 2-chloro-6-aminobenzoic acid according to claim 1, wherein In the step (1), the strong base is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium carbonate, and the molar ratio of the strong base to the raw material 2,3-dichloronitrobenzene is 1.5-4.0:

1.

5. The method for preparing 2-chloro-6-aminobenzoic acid according to claim 1, wherein In the step (1), the molar ratio of diethyl malonate to the raw material 2,3-dichloronitrobenzene is 1.0-2.0:

1.

6. The method for preparing 2-chloro-6-aminobenzoic acid according to claim 1, characterized in that: The reaction temperature in step (1) is 30-130°C.

7. The method for preparing 2-chloro-6-aminobenzoic acid according to claim 1, characterized in that: The solvent in step (2) is methanol, ethanol or isopropanol.

8. The method for preparing 2-chloro-6-aminobenzoic acid according to claim 1, characterized in that: In the step (3), the reducing agent is palladium carbon, the palladium content of the palladium carbon is 5-20%, and the weight ratio of the palladium carbon to 2,3-dichloronitrobenzene is 0.001-0.10:

1.

9. The method for preparing 2-chloro-6-aminobenzoic acid according to claim 1, characterized in that: The solvent used for extraction in step (3) is an ester, halogenated alkane or aromatic hydrocarbon solvent.

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