Synthesis of 2-chloro-5-phenoxyaniline

Abstract

The present application discloses a kind of synthetic method of 2-chloro-5-phenoxyaniline, including adding 4-chloro-3-nitroanisole, acid, the first organic solvent and metal in a reaction vessel, heating the reaction system to the first target temperature, then insulation reaction, cooling, filtering, drying in turn after the reaction is completed, and obtaining an intermediate product; intermediate product, the second organic solvent, phenol and alkali are added in a reaction vessel, the reaction system is heated to the second target temperature, then insulation reaction, after the reaction is completed, recovery obtains 2-chloro-5-phenoxyaniline. The present application uses 4-chloro-3-nitroanisole as raw material, 4-chloro-3-nitroanisole is subjected to reduction reaction with metal under acidic environment, generates intermediate product 2-chloro-5-methoxyaniline, and then the intermediate product 2-chloro-5-methoxyaniline is subjected to substitution reaction with phenol under alkaline conditions, obtains 2-chloro-5-phenoxyaniline, reaction conditions are mild, organic solvent consumption is less, yield is higher and reaches 86%, process operation is simple, green and environmentally friendly.

Description

Technical Field

[0001] The present application belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing 2-chloro-5-phenoxyaniline. Background Art

[0002] The new drug BET family protein has become one of the new targets for the development of innovative cancer therapies. The BET protein family consists of four proteins: BRD2, BRD3, BRD4 and BRDT. Studies have shown that BET proteins are widely expressed in human tissues and are involved in the regulation of gene transcription. Among them, bromodomain protein 4 (BRD4) is the most important functional protein in the BET family, which can regulate DNA replication and gene expression through histone acetylation, thereby affecting the cell cycle process. In recent years, studies have found that the dysfunction of the BET family is also closely related to the occurrence, infiltration, and metastasis of tumors.

[0003] BET inhibitors are a new class of anticancer drugs that have great promise in treating blood cancers such as leukemia and lymphoma. BET inhibitors can inhibit tumor growth by blocking the function of BET proteins. The development of BET protein selective inhibitors is a new direction.

[0004] 2-Chloro-5-phenoxyaniline is an important intermediate of the new drug BET inhibitor, with the molecular formula At present, there are two main methods for synthesizing 2-chloro-5-phenoxyaniline: the phenyl ether method and the 4-chloro-3-nitrophenol method.

[0005] The phenyl ether method uses phenyl ether as raw material and obtains 2-chloro-5-phenoxyaniline through a three-step process of chlorination, nitration and reduction. The process route is long, the pollution is high, the total yield is low, and the industrial value is not great.

[0006] 4-chloro-3-nitrophenol method uses 4-chloro-3-nitrophenol as raw material and adopts coupling reaction to prepare 2-chloro-5-phenoxyaniline. The reaction solvents used in the coupling reaction are dimethyl sulfoxide, 2-pyridine carboxylic acid, etc., respectively, and a large amount of organic solvents are used, which is costly. And the reaction temperature is relatively single, which is only one reaction stage, and the yield is low. In addition, the purification of the final product adopts column chromatography, which is not suitable for industrial production. Summary of the invention

[0007] The purpose of the present application is to provide a method for synthesizing 2-chloro-5-phenoxyaniline to solve the technical problems of low yield, excessive use of organic solvent, high cost and poor environmental friendliness in the prior art method for synthesizing 2-chloro-5-phenoxyaniline.

[0008] To achieve the above object, the present application provides a method for synthesizing 2-chloro-5-phenoxyaniline, comprising:

[0009] Adding 4-chloro-3-nitroanisole, an acid, a first organic solvent and a metal into a reaction container, heating the reaction system to a first target temperature, then keeping the temperature for reaction, and cooling, filtering and drying in sequence after the reaction is completed to obtain an intermediate product;

[0010] The intermediate product, the second organic solvent, phenol and the base are added into the reaction container, the reaction system is heated to the second target temperature, and then the temperature is kept for reaction, and after the reaction is completed, 2-chloro-5-phenoxyaniline is recovered.

[0011] In one or more embodiments, the first organic solvent includes one or more combinations of methanol, ethanol, isopropanol, ethyl acetate, ethyl formate, isopropyl acetate, dichloromethane, toluene, and n-hexane.

[0012] Preferably, the first organic solvent includes one or more combinations of ethyl acetate, ethyl formate and isopropyl acetate.

[0013] In one or more embodiments, the acid includes one or more combinations of sulfuric acid, formic acid, acetic acid, hydrochloric acid, propionic acid, oxalic acid, benzoic acid, salicylic acid, tartaric acid, hydrochloric acid, and nitric acid.

[0014] Preferably, the acid comprises one or more combinations of acetic acid, hydrochloric acid, propionic acid and oxalic acid.

[0015] In one or more embodiments, the metal includes one or more combinations of aluminum, iron, and magnesium.

[0016] In one or more embodiments, the molar ratio of 4-chloro-3-nitroanisole to metal is 1:(1-10).

[0017] Preferably, the molar ratio of the 4-chloro-3-nitroanisole to the metal is 1:(2-5).

[0018] In one or more embodiments, in the step of heating the reaction system to a first target temperature and then conducting a heat preservation reaction, the first target temperature is 30 to 120° C., and the heat preservation reaction time is 1 to 15 hours.

[0019] Preferably, in the step of heating the reaction system to a first target temperature and then conducting a heat preservation reaction, the first target temperature is 60 to 90° C., and the heat preservation reaction time is 3 to 8 hours.

[0020] In one or more embodiments, the base includes one or more combinations of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and butyl lithium.

[0021] Preferably, the base includes one or more combinations of sodium methoxide, sodium ethoxide, potassium tert-butoxide, and the like.

[0022] In one or more embodiments, the second organic solvent includes dimethylformamide, and the phenol includes phenol.

[0023] In one or more embodiments, in the step of heating the reaction system to a second target temperature and then conducting a heat preservation reaction, the second target temperature is 50 to 150° C., and the heat preservation reaction time is 2 to 15 hours.

[0024] Preferably, in the step of heating the reaction system to a second target temperature and then conducting a heat preservation reaction, the second target temperature is 80-120°C and the heat preservation reaction time is 80-120°C.

[0025] In one or more embodiments, the molar ratio of the intermediate product to phenol is 1:(1-5), and the molar ratio of the intermediate product to the base is 1:(1-8).

[0026] Preferably, the molar ratio of the intermediate product to phenol is 1:(1.1-2), and the molar ratio of the intermediate product to the base is 1:(1.2-3).

[0027] In one or more embodiments, the step of recovering 2-chloro-5-phenoxyaniline after the reaction is completed is specifically: extracting with ethyl acetate, recovering, washing, concentrating, and drying to obtain 2-chloro-5-phenoxyaniline.

[0028] Different from the prior art, the beneficial effects of this application are:

[0029] The present invention uses 4-chloro-3-nitroanisole as a raw material, and performs a reduction reaction on 4-chloro-3-nitroanisole and a metal in an organic solvent under an acidic environment to generate an intermediate product, 2-chloro-5-methoxyaniline. Then, the intermediate product 2-chloro-5-methoxyaniline and phenol are subjected to a substitution reaction in an organic solvent under alkaline conditions. The reaction conditions are mild, the amount of organic solvent, acid, base, and phenol used is small, the yield is high and reaches 86%, the process operation is simple, and it is green and environmentally friendly.

[0030] The present invention maintains a relatively low temperature constant temperature reaction in the reduction reaction, effectively increases the reaction speed, reduces the occurrence of side reactions, and adopts a relatively high temperature in the substitution reaction, effectively transfers the product, and accelerates the reaction conversion rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is a schematic flow chart of an embodiment of a method for synthesizing 2-chloro-5-phenoxyaniline of the present application. DETAILED DESCRIPTION

[0032] The present application will be described in detail below in conjunction with the various embodiments shown in the accompanying drawings. However, these embodiments do not limit the present application, and any structural, methodological, or functional changes made by a person of ordinary skill in the art based on these embodiments are all within the scope of protection of the present application.

[0033] 2-Chloro-5-phenoxyaniline is an important intermediate of the new drug BET inhibitor, with the molecular formula At present, a large amount of organic solvents are used in the synthesis process of 2-chloro-5-phenoxyaniline, which is costly. In addition, the reaction temperature is relatively single, there is only one reaction stage, and the yield is low.

[0034] In order to reduce the cost of synthesizing 2-chloro-5-phenoxyaniline and reduce the amount of organic solvent used, the applicant has developed a novel method for synthesizing 2-chloro-5-phenoxyaniline, which has mild reaction conditions, simple process operation, is green and environmentally friendly, has low cost and high yield.

[0035] Specifically, see Figure 1 , Figure 1 It is a schematic flow chart of an embodiment of a method for synthesizing 2-chloro-5-phenoxyaniline of the present application.

[0036] The synthesis method comprises:

[0037] S100, adding 4-chloro-3-nitroanisole, an acid, a first organic solvent and a metal into a reaction container, heating the reaction system to a first target temperature, then keeping the temperature for reaction, and cooling, filtering and drying in sequence after the reaction is completed to obtain an intermediate product.

[0038] Using 4-chloro-3-nitroanisole as a raw material, 4-chloro-3-nitroanisole can first be subjected to a reduction reaction with a metal in a first organic solvent under an acidic environment to generate an intermediate product, 2-chloro-5-methoxyaniline, and the chemical reaction formula is as follows:

[0039]

[0040] Specifically, in one application scenario, the first organic solvent may include one or more combinations of methanol, ethanol, isopropanol, ethyl acetate, ethyl formate, isopropyl acetate, dichloromethane, toluene, and n-hexane.

[0041] In order to reduce the amount of acid used, preferably, the first organic solvent can include one or more combinations of ethyl acetate, ethyl formate, and isopropyl acetate. It can be understood that by selecting an acid-containing organic solvent, the amount of acid used in the reaction can be reduced, thereby reducing pollution.

[0042] In one application scenario, the acid may include one or more combinations of sulfuric acid, formic acid, acetic acid, hydrochloric acid, propionic acid, oxalic acid, benzoic acid, salicylic acid, tartaric acid, hydrochloric acid, and nitric acid;

[0043] Preferably, the acid may include one or more combinations of acetic acid, hydrochloric acid, propionic acid, and oxalic acid.

[0044] In one application scenario, the molar ratio of 4-chloro-3-nitroanisole to the metal may be 1:(1-10);

[0045] Preferably, the molar ratio of 4-chloro-3-nitroanisole to metal is 1:(2-5).

[0046] In order to speed up the reduction reaction and reduce side reactions, the first target temperature may be 30 to 120° C., and the insulation reaction time may be 1 to 15 hours.

[0047] Preferably, the first target temperature may be 60 to 90° C., and the insulation reaction time may be 3 to 8 hours.

[0048] By maintaining the first target temperature for isothermal reaction, the reaction rate can be effectively increased and the occurrence of side reactions can be reduced.

[0049] S200, adding the intermediate product, the second organic solvent, phenol and the base into a reaction container, heating the reaction system to a second target temperature, then keeping the temperature to react, and recovering 2-chloro-5-phenoxyaniline after the reaction is completed.

[0050] After obtaining the intermediate product 2-chloro-5-methoxyaniline, the intermediate product can be subjected to a substitution reaction with phenol in a second organic solvent under alkaline conditions to generate the target product 2-chloro-5-phenoxyaniline. The chemical reaction formula is as follows:

[0051]

[0052] Specifically, in one application scenario, the alkali may include one or more combinations of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and butyl lithium.

[0053] Preferably, the base may include one or more combinations of sodium methoxide, sodium ethoxide, potassium tert-butoxide, and the like.

[0054] In one application scenario, the second organic solvent may include dimethylformamide, and the phenol may include phenol. In other application scenarios, the second organic solvent may also be selected from other solvents that can provide a reaction system, and the phenol may also be selected from other phenols that can undergo a substitution reaction with the intermediate product 2-chloro-5-methoxyaniline, all of which can achieve the effect of this embodiment.

[0055] In order to improve the reaction conversion rate and effectively transfer the product, in one application scenario, the second target temperature can be 50-150° C., and the insulation reaction time can be 2-15 hours.

[0056] Preferably, the reaction system is heated to a second target temperature, and then in the step of heat preservation reaction, the second target temperature is 80-120°C, and the heat preservation reaction time is 80-120°C.

[0057] It can be understood that by setting a higher reaction temperature, the conversion rate of the reaction can be accelerated and the product can be effectively transferred.

[0058] In one application scenario, the molar ratio of the intermediate product to phenol can be 1:(1-5), and the molar ratio of the intermediate product to the base can be 1:(1-8).

[0059] Preferably, the molar ratio of the intermediate product to the phenol may be 1:(1.1-2), and the molar ratio of the intermediate product to the base may be 1:(1.2-3).

[0060] In one application scenario, the steps of recovering 2-chloro-5-phenoxyaniline after the reaction is completed are as follows: extracting with ethyl acetate, recovering, washing, concentrating, and drying to obtain 2-chloro-5-phenoxyaniline.

[0061] The final product of the synthesis method of the present application can be recovered by extraction with ethyl acetate without the need for column chromatography, and is suitable for large-scale industrial production.

[0062] The technical solution of the present application is described in detail below in conjunction with specific embodiments.

[0063] The synthetic method of 2-chloro-5-phenoxyaniline comprises:

[0064] In a four-necked flask equipped with a mechanical stirrer, a reflux condenser, and a thermometer, 4-chloro-3-nitroanisole, a first organic solvent, and an acid are added in sequence, and stirred to dissolve. Iron powder is then added, and the reaction system is subsequently heated to a first target temperature and kept warm for reaction. After the insulation reaction is completed, the reaction solution is cooled and filtered, and concentrated to obtain an intermediate product, which is directly carried out to the next step without purification.

[0065] In a four-necked flask equipped with a mechanical stirrer, a reflux condenser, and a thermometer, under nitrogen protection, the intermediate product, DMF, and phenol are added and stirred to dissolve. Then, a base is added. After the feeding is completed, the reaction system is heated to the second target temperature and kept warm for reaction. After the reaction is completed, the reaction system is cooled, water is added, and ethyl acetate is used for extraction. The organic layer is washed, concentrated, and dried to obtain the off-white target product 2-chloro-5-phenoxyaniline.

[0066] Specific reaction conditions, raw material selection and dosage are shown in the table below:

[0067]

[0068]

[0069]

[0070] Effect example 1:

[0071] The structure of 2-chloro-5-phenoxyaniline prepared in Example 1 was identified by NMR analysis. The NMR results are as follows: 1 H(400Hz CDCl3) δ7.27-7.32(m 3H), δ6.98-7.00(m 2H), δ6.88-6.98(m 3H), δ5.57-5.59(s 2H).

[0072] Based on the above NMR results, it can be determined that the prepared product is 2-chloro-5-phenoxyaniline.

[0073] Effect Example 2:

[0074] The two-step yields of the target products of Examples 1 to 12 were calculated based on the following formula to obtain the following table data:

[0075] Yield = (W1 / (M1*W2 / M2))*100%.

[0076] Wherein, W1 is the mass of the actual product 2-chloro-5-phenoxyaniline; W2 is the mass of the raw material 4-chloro-3-nitrobenzyl ether; M1 is the molecular weight of the product 2-chloro-5-phenoxyaniline; M2 is the molecular weight of the raw material 4-chloro-3-nitrobenzyl ether.

[0077]

[0078] As can be seen from the data in the above table, the two-step yields of Examples 1 to 12 all reached more than 80%, with the highest reaching 86%. The synthesis method of the present application can achieve a high yield of the target product under mild reaction conditions, while using less organic solvents, acids, phenols, and bases, which is green and environmentally friendly.

[0079] In addition, the final product synthesized in the present application can be purified by extraction with ethyl acetate without the need for column chromatography, and is suitable for large-scale industrial production.

[0080] The above description of the disclosure is provided to enable any person of ordinary skill in the art to implement or use the disclosure. Various modifications to the disclosure will be apparent to those of ordinary skill in the art, and the general principles corresponding to the disclosure may be applied to other variations without departing from the scope of protection of the disclosure. Therefore, the disclosure is not limited to the examples and designs described herein, but is consistent with the widest range of principles and novel features disclosed herein.

Claims

1. A method for synthesizing 2-chloro-5-phenoxyaniline, characterized in that: include: Adding 4-chloro-3-nitroanisole, an acid, a first organic solvent and a metal into a reaction container, heating the reaction system to a first target temperature, then keeping the temperature for reaction, and cooling, filtering and drying in sequence after the reaction is completed to obtain an intermediate product, 2-chloro-5-methoxyaniline; Add the intermediate product, the second organic solvent, phenol and the base into the reaction container, heat the reaction system to the second target temperature, then keep the temperature for reaction, and after the reaction is completed, recover 2-chloro-5-phenoxyaniline, wherein the second target temperature is 80-150° C., and the keeping temperature for reaction is 2-15 hours; Wherein, the metal is selected from one or more combinations of aluminum, iron, and magnesium; the base is selected from one or more combinations of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and butyl lithium; and the phenol is phenol.

2. The synthesis method according to claim 1, characterized in that The first organic solvent is selected from one or more combinations of methanol, ethanol, isopropanol, ethyl acetate, ethyl formate, isopropyl acetate, dichloromethane, toluene, and n-hexane.

3. The synthesis method according to claim 2, characterized in that The first organic solvent is selected from one or more combinations of ethyl acetate, ethyl formate and isopropyl acetate.

4. The synthesis method according to claim 1, characterized in that The acid is selected from one or more combinations of sulfuric acid, formic acid, acetic acid, hydrochloric acid, propionic acid, oxalic acid, benzoic acid, salicylic acid, tartaric acid, hydrochloric acid, and nitric acid.

5. The synthesis method according to claim 4, characterized in that The acid is selected from one or more combinations of acetic acid, hydrochloric acid, propionic acid and oxalic acid.

6. The synthesis method according to claim 1, characterized in that The molar ratio of the 4-chloro-3-nitroanisole to the metal is 1:(1-10).

7. The synthesis method according to claim 6, characterized in that The molar ratio of the 4-chloro-3-nitroanisole to the metal is 1:(2-5).

8. The synthesis method according to claim 1, characterized in that In the step of heating the reaction system to a first target temperature and then maintaining the temperature for reaction, the first target temperature is 30-120° C. and the time for maintaining the temperature for reaction is 1-15 hours.

9. The synthesis method according to claim 8, characterized in that In the step of heating the reaction system to a first target temperature and then maintaining the temperature for reaction, the first target temperature is 60-90° C. and the time for maintaining the temperature for reaction is 3-8 hours.

10. The synthesis method according to claim 1, characterized in that The base is selected from one or more combinations of sodium methoxide, sodium ethoxide and potassium tert-butoxide.

11. The synthesis method according to claim 1, characterized in that: The second organic solvent is dimethylformamide.

12. The synthesis method according to claim 1, characterized in that: In the step of heating the reaction system to a second target temperature and then maintaining the temperature for reaction, the second target temperature is 80-120° C. and the time for maintaining the temperature for reaction is 2-15 hours.

13. The synthesis method according to claim 1, characterized in that The molar ratio of the intermediate product to phenol is 1:(1-5), and the molar ratio of the intermediate product to the base is 1:(1-8).

14. The synthesis method according to claim 13, characterized in that: The molar ratio of the intermediate product to phenol is 1:(1.1-2), and the molar ratio of the intermediate product to the base is 1:(1.2-3).

15. The synthesis method according to claim 1, characterized in that: The specific step of recovering 2-chloro-5-phenoxyaniline after the reaction is completed is: extracting with ethyl acetate, recovering, washing, concentrating, and drying to obtain 2-chloro-5-phenoxyaniline.

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