A kind of preparation method of 2-nitro-4-trifluoromethylbenzoic acid

Abstract

The invention discloses a method for preparing 2-nitro-4-trifluoromethylbenzoic acid, comprising: preparing pyridinium salt from pyridine or a derivative thereof, and performing a substitution reaction with 3-nitro-4-chlorobenzotrifluoride, and then further reacting with an oxidant to prepare 2-nitro-4-trifluoromethylbenzoic acid. The final product yield of the invention reaches 94%, and the purity reaches more than 98%. The preparation method has the advantages of cheap and readily available raw materials, safe reaction process, high yield and high purity.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a method for preparing 2-nitro-4-trifluoromethylbenzoic acid. Background Art

[0002] The nitro group on the benzene ring of 2-nitro-4-trifluoromethylbenzoic acid is active and can be easily replaced by other groups. It can be used to synthesize intermediates for a series of pesticides and pharmaceutical products, and therefore has important significance.

[0003] The literature reports that the synthesis of 2-nitro-4-trifluoromethylbenzoic acid mainly includes the following methods:

[0004] 1. Patent Nos. NL6500326 and US2005 / 124681 disclose a method for preparing 2-nitro-4-trifluoromethylbenzoic acid by reacting 4-trifluoromethylbenzoic acid with fuming nitric acid. The reaction route is as follows:

[0005]

[0006] This method uses fuming nitric acid as a nitration reagent to react at high temperature, which is prone to explosion; the reaction produces a lot of three wastes; the nitration product is a mixture, the separation and purification cost is high, and it is not conducive to industrial production.

[0007] 2. Patent CN108558672 discloses a method for preparing 2-nitro-4-trifluoromethylbenzoic acid by reacting 4-trifluoromethylbenzocyanide as a raw material with a nitrating agent. The reaction route is as follows:

[0008]

[0009] This method uses a mixed acid prepared from concentrated sulfuric acid and fuming nitric acid as a nitration reagent, which is highly dangerous and produces a lot of three wastes; the nitration product is a mixture, which is difficult to separate and purify, and is not conducive to industrial production.

[0010] 3. The literature Organometallics, vol. 36 (21): 4095-4098, 2017 reported a method for preparing 2-nitro-4-trifluoromethylbenzoic acid by oxidation of 2-nitro-4-trifluoromethylbenzaldehyde catalyzed by iridium (III) chloride cyclopentadiene complex. The reaction route is as follows:

[0011]

[0012] This method uses iridium (III) chloride cyclopentadiene complex as a catalyst, which has only theoretical research value and is not suitable for industrial production.

[0013] Fourth, patent US2017 / 369412 discloses a method for preparing 2-nitro-4-trifluoromethylbenzoic acid by using 4-chloro-3-nitrobenzotrifluorotoluene as a raw material, reacting with nitromethane or cyanoacetamide under base catalysis to prepare the corresponding intermediate (A) or (B), and then oxidizing under alkaline conditions. The reaction route is as follows:

[0014]

[0015] The organic solvents used in this method are all water-soluble reagents, which are difficult to recycle, resulting in a lot of three wastes, poor atom economy, high cost, and are not suitable for industrial production. Summary of the invention

[0016] Therefore, the technical problem to be solved by the present invention is to overcome the problems of using hazardous reagent raw materials, complicated operation and low yield in the preparation process of 2-nitro-4-trifluoromethylbenzoic acid in the prior art, thereby providing a preparation method of 2-nitro-4-trifluoromethylbenzoic acid, which uses 4-chloro-3-nitrotrifluorotoluene as a raw material, reacts with a pyridinium salt, and then performs an oxidation reaction under acidic conditions to obtain a target compound. The preparation method has the advantages of cheap and readily available raw materials, a safe reaction process, a high yield and high purity.

[0017] The present invention provides a method for preparing 2-nitro-4-trifluoromethylbenzoic acid, comprising the following steps:

[0018] a) dissolving pyridine or a derivative thereof represented by the general formula (IV) and a compound represented by the general formula (V) in a first solvent for reaction to prepare a pyridinium salt represented by the general formula (III);

[0019] b) subjecting 3-nitro-4-chlorotrifluorotoluene to a substitution reaction with a pyridinium salt represented by the general formula (III) in the presence of an acid binding agent in a second solvent to prepare an intermediate represented by the general formula (II);

[0020] c) dissolving the intermediate represented by the general formula (II) in a third solvent, and adding an oxidant to obtain the target product (I);

[0021] The reaction formula is as follows:

[0022]

[0023] Preferably, R1 represents 1 to 5 independently selected from hydrogen, cyano, nitro, fluorine, chlorine, bromine, iodine, C 1～8 Alkyl, C 2～8 Alkenyl, C 2～8an alkynyl group, a formylalkyl group, a cyanoalkyl group, an aminoalkyl group, an aminocarbonylalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a cycloalkenyl group, a cycloalkenylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, an aryl group, an arylalkyl group, an R3-(CO)-NRR5-, an R3-S(O)n-(alkyl)-, an R3-O-(alkyl)n-, an R3-(CO)-(alkyl)n-, an R3-O-(alkyl)n-(CO)-, an R3-(CO)-O-(alkyl)n-, an R3-S-(CO)-(alkyl)n-, an R3-O-(CO)-(alkyl)n- or an R3-O-(CO)-O-(alkyl)n- group;

[0024] in:

[0025] The "alkyl", "alkenyl" or "alkynyl" are independently selected from unsubstituted or substituted by at least one of halogen, alkoxy or alkoxycarbonyl.

[0026] The "aminoalkyl" or "aminocarbonylalkyl" are independently selected from unsubstituted or substituted by one or two groups selected from -R3, -OR3, -(CO)OR3, -alkyl-(CO)OR3, -(SO2)R3, -(SO2)OR3, -alkyl-(SO2)R3, -(CO)NR4R5 or -(SO2)NR4R5,

[0027] The "cycloalkyl", "cycloalkylalkyl", "aryl", "heterocyclyl", "arylalkyl" or "heterocyclylalkyl" are independently selected from unsubstituted or substituted by at least one group selected from oxo, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, cycloalkyl substituted by alkyl, -OR3, -SR3, -(CO)OR3, -(SO2)R3, -NR4R5, or -O-alkyl-(CO)OR3, or two adjacent carbon atoms on the ring form a condensed ring with unsubstituted or halogen-substituted -OCH2CH2- or -OCH2O-;

[0028] R2 is selected from hydrogen, cyano, nitro, fluorine, chlorine, bromine, iodine, C 2～8 Alkenyl, C 2～8 any one of an alkynyl group, a formylalkyl group, a cyanoalkyl group, an aminocarbonyl group, an aminocarbonylalkyl group, an aminosulfonyl group, a cycloalkenyl group, a heterocyclyl group, a heterocyclylalkyl group, an aryl group, an arylalkyl group, an R3-(CO)-NR4R5-, an R3-S(O)n-(alkyl)-, an R3-(CO)-(alkyl)n-, an R3-O-(alkyl)n-(CO)-, an R3-(CO)-O-(alkyl)n-, an R3-S-(CO)-(alkyl)n-, an R3-O-(CO)-(alkyl)n- or an R3-O-(CO)-O-(alkyl)n- group;

[0029] The X is selected from any one of fluorine, chlorine, bromine, iodine or p-toluenesulfonyloxy;

[0030] Said R3, R4, and R5 are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, formylalkyl, cyanoalkyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl or arylalkyl, wherein:

[0031] The "alkyl", "alkenyl" or "alkynyl" are independently selected from unsubstituted or substituted by at least one of halogen, alkoxy or alkoxycarbonyl.

[0032] The "amino", "aminoalkyl", "aminocarbonyl", "aminocarbonylalkyl" and "aminosulfonyl" are independently selected from unsubstituted or substituted by one or two groups selected from -R3, -OR3, -(CO)OR3, -alkyl-(CO)OR3, -(SO2)R3, -(SO2)OR3, -alkyl-(SO2)R3, -(CO)NR4R5 or -(SO2)NR4R5,

[0033] The "cycloalkyl", "cycloalkylalkyl", "aryl", "heterocyclyl", "arylalkyl" or "heterocyclylalkyl" are independently selected from unsubstituted or substituted by at least one group selected from oxo, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, cycloalkyl substituted by alkyl, -OR3, -SR3, -(CO)OR3, -(SO2)R3, -NR4R5, or -O-alkyl-(CO)OR3, or two adjacent carbon atoms on the ring form a condensed ring with unsubstituted or halogen-substituted -OCH2CH2- or -OCH2O-;

[0034] Said n is 0, 1, 2, 3 or 4;

[0035] Preferably, the first solvent is selected from at least one of dichloromethane, dichloroethane, ether, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, petroleum ether, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitromethane, nitrobenzene, ethyl acetate, dimethyl sulfoxide, N-methylpyrrolidone, benzocyanate or sulfolane;

[0036] The second solvent is selected from at least one of water, dichloromethane, dichloroethane, ether, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitromethane, nitrobenzene, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethylimidazolidinone, N-methylpyrrolidone, benzocyanate or sulfolane;

[0037] The acid binding agent is selected from at least one of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal acetates, alkali metal phosphates, alkali metal hydrogen phosphates, alkali metal alkoxides, triethylamine, diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU);

[0038] The third solvent is selected from at least one of water, dichloromethane, dichloroethane, ether, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitromethane, nitrobenzene, ethyl acetate, formic acid, acetic acid, propionic acid, n-butyric acid or isobutyric acid;

[0039] The oxidant is selected from any one of oxygen, ozone, hydrogen peroxide, peroxy acid and its salt, hypochlorous acid and its metal salt.

[0040] Preferably, the reaction temperature in step a) is -10°C to 120°C, the reaction temperature in step b) is -10°C to 120°C, and the reaction temperature in step c) is 10°C to 60°C.

[0041] Preferably, the reaction time in step a) is 2 to 16 hours, the reaction time in step b) is 2 to 10 hours, and the reaction time in step c) is 0.5 to 8 hours.

[0042] Preferably, the molar ratio of the pyridine or its derivative represented by the general formula (IV) to the compound represented by the general formula (V) is 0.8 to 1.2:1;

[0043] The molar ratio of the 3-nitro-4-chlorobenzotrifluoride to the pyridinium salt represented by the general formula (III) is 0.8 to 1.2:1.

[0044] The technical solution of the present invention has the following advantages:

[0045] 1. A method for preparing 2-nitro-4-trifluoromethylbenzoic acid of the present invention, using 4-chloro-3-nitrotrifluorotoluene as a raw material, reacting with a pyridinium salt, and then performing an oxidation reaction under acidic conditions to obtain a target compound, the final product yield reaches 94%, and the purity reaches more than 98%. The preparation method has the advantages of cheap and readily available raw materials, safe reaction process, high yield and high purity.

[0046] 2. The method for preparing 2-nitro-4-trifluoromethylbenzoic acid of the present invention has mild and rapid reaction conditions, high conversion rate, easy control, easy availability of reaction raw materials, simple reaction operation, few reaction steps, little three wastes, and avoids harm to the environment and operators. It has good industrial prospects and provides a new idea suitable for large-scale industrial production. DETAILED DESCRIPTION

[0047] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0048] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0049] Example 1

[0050] Preparation of 2-nitro-4-trifluoromethylbenzoic acid:

[0051]

[0052] 1) Preparation of pyridinium salt (A3)

[0053] 15.1g of chloroacetonitrile, 16.5g of pyridine and 50mL of toluene were mixed, stirred and refluxed for 4h, then cooled to 10°C, filtered, the filter cake was washed with a small amount of toluene, and dried to obtain 29.3g of off-white solid, with a yield of 94.8%, HPLC>99%. The filtrate was recycled without purification.

[0054] 2) Preparation of intermediate (A2)

[0055] 22.6 g of 3-nitro-4-chlorotrifluorotoluene and 18.5 g of pyridinium salt (A3) were added to 60 mL of toluene, cooled to 0°C, and 34 g of DBU was slowly added dropwise with stirring. After the addition was completed, the temperature was raised to room temperature and stirred for 6 h. The reaction solution was washed with dilute hydrochloric acid and water in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 30 g of a light yellow solid with a yield of 97.7%, HPLC>96%.

[0056] 3) Preparation of 2-nitro-4-trifluoromethylbenzoic acid

[0057] 10g intermediate (A2), 2g sodium hydroxide and 45mL N,N-dimethylformamide were mixed, the temperature was raised to 45℃, and 30mL 30% hydrogen peroxide was slowly added dropwise while stirring. The dropping speed was controlled so that the reaction temperature did not exceed 55℃. After the dropping was completed, stirring was continued for 2h, and the solvent was recovered under reduced pressure. The residue was diluted with water, acidified with hydrochloric acid, and a solid was precipitated. The filter cake was washed with water and dried to obtain 6.8g of yellow solid, with a yield of 88.8%, HPLC>98%. HNMR[DMSO-d6,300MHz]δppm:14.41(br s,1H),8.48(s,1H),8.24(d,J=9.0Hz,1H),8.11(d,J=9.0Hz,1H).

[0058] Example 2

[0059] Preparation of 2-nitro-4-trifluoromethylbenzoic acid:

[0060]

[0061] 1) Preparation of pyridinium salt (B3)

[0062] 12.2g of ethyl chloroacetate, 12.8g of 3,5-dimethylpyridine and 50mL of petroleum ether (boiling range 90-120°C) were mixed, stirred and refluxed for 4h, then cooled to 10°C, filtered, the filter cake was washed with a small amount of petroleum ether, and dried to obtain 21.7g of off-white solid, with a yield of 94.4%, HPLC>99%. The filtrate was recycled without purification.

[0063] 2) Preparation of intermediate (B2)

[0064] 17 g of 3-nitro-4-chlorotrifluorotoluene and 20.8 g of pyridinium salt (B3) were added to 60 mL of N,N-dimethylformamide, and 15 g of sodium acetate was added under stirring at room temperature. After the addition, the temperature was raised to 50°C and stirred for 2 h. The reaction solution was decompressed to recover the solvent, the residue was diluted with water, extracted with ethyl acetate, and the organic phase was washed with dilute hydrochloric acid and water in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 27.9 g of a light yellow solid with a yield of 97.3%, and HPLC>96%.

[0065] 3) Preparation of 2-nitro-4-trifluoromethylbenzoic acid

[0066] 15g of intermediate (B2) was dissolved in 15mL of glacial acetic acid, and the temperature was raised to 45°C. 50mL of 30% hydrogen peroxide was slowly added dropwise and stirred for reaction. The addition rate was controlled so that the reaction temperature did not exceed 55°C. After the addition, stirring was continued for 2h, and the solvent was recovered under reduced pressure. The residue was diluted with water to precipitate solid. Filtered with suction, the filter cake was washed with water, and dried to obtain 8.1g of yellow solid, with a yield of 87.8%, HPLC>98%.

[0067] Example 3

[0068] Preparation of 2-nitro-4-trifluoromethylbenzoic acid:

[0069]

[0070] 1) Preparation of pyridinium salt (C3)

[0071] 13.8g of bromoacetamide, 17.7g of 2-methoxy-5-trifluoromethylpyridine and 50mL of ethyl acetate were mixed, stirred and refluxed for 16h, then cooled to 10°C, filtered, the filter cake was washed with a small amount of ethyl acetate, and dried to obtain 30g of off-white solid, with a yield of 95.2%, HPLC>99%. The filtrate was recycled without purification.

[0072] 2) Preparation of intermediate (C2)

[0073] 15.0 g of 3-nitro-4-chlorotrifluorotoluene and 25 g of pyridinium salt (C3) were added to 100 mL of ethyl acetate, and 0.5 mL of water was added. 33 g of powdered potassium carbonate was added in batches under stirring at room temperature. After the addition, the temperature was raised to 50 ° C and stirred for 8 h. The reaction solution was cooled to room temperature and filtered. The filtrate was washed with 2% dilute hydrochloric acid and water in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 28 g of a light yellow solid with a yield of 99.2%, HPLC>96%.

[0074] 3) Preparation of 2-nitro-4-trifluoromethylbenzoic acid

[0075] 28g of intermediate (C2) was dissolved in 60mL of glacial acetic acid, and ozone was slowly introduced under stirring at room temperature until the reaction was complete. The solvent was recovered under reduced pressure. The residue was diluted with water to precipitate solid. The filter cake was filtered, washed with water, and dried to obtain 13.8g of yellow solid, with a yield of 88.8%, HPLC>98%.

[0076] Example 4

[0077] Preparation of 2-nitro-4-trifluoromethylbenzoic acid:

[0078]

[0079] 1) Preparation of pyridinium salt (D3)

[0080] 15.1 g of chloroacetonitrile, 19.0 g of pyridine and 50 mL of toluene were mixed, stirred and refluxed for 4 h, then cooled to 10°C, filtered, the filter cake was washed with a small amount of toluene, and dried to obtain 30.0 g of off-white solid, with a yield of 88.9%, HPLC>99%. The filtrate was recycled without purification.

[0081] 2) Preparation of intermediate (D2)

[0082] 22.6 g of 3-nitro-4-chlorotrifluorotoluene and 21.5 g of pyridinium salt (D3) were added to 60 mL of toluene, cooled to 0°C, and 34 g of DBU was slowly added dropwise with stirring. After the addition was completed, the temperature was raised to room temperature and stirred for 6 h. The reaction solution was washed with dilute hydrochloric acid and water in turn, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 28.8 g of a light yellow solid with a yield of 89.7%, HPLC>96%.

[0083] 3) Preparation of 2-nitro-4-trifluoromethylbenzoic acid

[0084] 10g of intermediate (D2) was mixed with 45mL of toluene, heated to 45℃, and 50mL of sodium hypochlorite solution was slowly added dropwise under stirring. The dropping speed was controlled so that the reaction temperature did not exceed 55℃. After the addition, stirring was continued for 2h, and the mixture was cooled to room temperature and separated. The aqueous phase was acidified with hydrochloric acid to precipitate solids. Filtered with suction, the filter cake was washed with water, and dried to obtain 6.6g of yellow solid, with a yield of 86%, HPLC>98%.

[0085] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A method for preparing 2-nitro-4-trifluoromethylbenzoic acid, characterized in that: The following steps are involved: a) dissolving pyridine or a derivative thereof represented by the general formula (IV) and a compound represented by the general formula (V) in a first solvent for reaction to prepare a pyridinium salt represented by the general formula (III); b) subjecting 3-nitro-4-chlorotrifluorotoluene to a substitution reaction with a pyridinium salt represented by the general formula (III) in the presence of an acid binding agent in a second solvent to prepare an intermediate represented by the general formula (II); c) dissolving the intermediate represented by the general formula (II) in a third solvent, and adding an oxidant to obtain the target product (I); The oxidant is selected from any one of oxygen, ozone, hydrogen peroxide, peroxyacid and its salt, hypochlorous acid and its metal salt; The reaction formula is as follows: in: The R1 represents 1 to 5 independently selected from hydrogen, C 1～8 Alkyl, R3-O-(alkyl)n-; The R2 is selected from any one of cyano, aminocarbonyl, and R3-O-(alkyl)n-(CO)-; The X is selected from any one of chlorine or bromine; The R3 is selected from any one of methyl and ethyl; The n is 0.

2. The method for preparing 2-nitro-4-trifluoromethylbenzoic acid according to claim 1, characterized in that: The first solvent is selected from at least one of dichloromethane, dichloroethane, ether, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, petroleum ether, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitromethane, nitrobenzene, ethyl acetate, dimethyl sulfoxide, N-methylpyrrolidone or sulfolane; The second solvent is selected from at least one of water, dichloromethane, dichloroethane, ether, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitromethane, nitrobenzene, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethylimidazolidinone, N-methylpyrrolidone or sulfolane; The acid-binding agent is selected from at least one of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal acetates, alkali metal phosphates, alkali metal hydrogen phosphates, alkali metal alkoxides, triethylamine, diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene; The third solvent is selected from at least one of water, dichloromethane, dichloroethane, ether, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitromethane, nitrobenzene, ethyl acetate, formic acid, acetic acid, propionic acid, n-butyric acid or isobutyric acid.

3. The method for preparing 2-nitro-4-trifluoromethylbenzoic acid according to claim 1, characterized in that: The reaction temperature in step a) is -10°C to 120°C, the reaction temperature in step b) is -10°C to 120°C, and the reaction temperature in step c) is 10°C to 60°C.

4. The method for preparing 2-nitro-4-trifluoromethylbenzoic acid according to claim 1 or 3, characterized in that: The reaction time in step a) is 2 to 16 hours, the reaction time in step b) is 2 to 10 hours, and the reaction time in step c) is 0.5 to 8 hours.

5. The method for preparing 2-nitro-4-trifluoromethylbenzoic acid according to claim 1, characterized in that: The molar ratio of the pyridine or its derivative represented by the general formula (IV) to the compound represented by the general formula (V) is 0.8 to 1.2:1; The molar ratio of the 3-nitro-4-chlorobenzotrifluoride to the pyridinium salt represented by the general formula (III) is 0.8 to 1.2:1.

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