CN115872844A - Preparation method of 3-bromo-4- (trifluoromethyl) benzaldehyde - Google Patents

Abstract

The application discloses a preparation method of 3-bromo-4- (trifluoromethyl) benzaldehyde. In the application, the preparation method of the 3-bromo-4- (trifluoromethyl) benzaldehyde provided by the invention is high in yield, less in three wastes and less in environmental pollution, and is suitable for industrial large-scale production; the preparation method of the 3-bromo-4- (trifluoromethyl) benzaldehyde provided by the invention has the advantages of low price of raw materials and auxiliary materials, sufficient market supply and low preparation cost.

Description

Preparation method of 3-bromo-4-(trifluoromethyl)benzaldehyde

Technical Field

The invention relates to the field of organic synthesis, and in particular to a method for preparing 3-bromo-4-(trifluoromethyl)benzaldehyde.

Background Art

3-bromo-4-(trifluoromethyl)benzaldehyde (3-broMo-4-trifluoroMethylbenzaldehyde) is an important intermediate for the synthesis of various drugs, and the synthesis of small molecule drugs for the treatment of cancer, PD-1/PD-L1 inhibitors, is one of its important application directions. Some preparation processes for 3-bromo-4-(trifluoromethyl)benzaldehyde are disclosed in the prior art. For example, U.S. Pat. No. 6,642,222B2 discloses a preparation method such as Scheme 41, which first nitrates 4-trifluoromethylbenzoic acid, then reduces the carboxylic acid group with boric acid to obtain 3-nitro-4-trifluoromethylbenzyl alcohol, converts aniline into a halogen substituent using a Sandmeyer reaction, and oxidizes benzyl alcohol using manganese dioxide to obtain 4-trifluoromethylbenzaldehyde such as general formula 105, where X is halogen.

The inventors have found that the prior art has at least the following problems: the above-mentioned synthetic route is long, the reaction raw materials are relatively expensive, the yield is low, and manganese dioxide is a metal oxide, which has a large environmental pollution, and it is difficult to meet the pollution discharge requirements during industrial scale-up production. Therefore, the art still needs to develop a method for preparing 3-bromo-4-(trifluoromethyl)benzaldehyde with high yield and less pollution suitable for industrial production.

Summary of the invention

The object of the present invention is to provide a method for preparing 3-bromo-4-(trifluoromethyl)benzaldehyde.

In order to solve the above technical problems, the first aspect of the present invention provides a method for preparing 3-bromo-4-(trifluoromethyl)benzaldehyde, which comprises the following steps:

Compound A and compound B are reacted as shown in the following formula I:

R¹和R²分别独立地为C_1-6烷基。Among them, X is

^R1 and ^R2 are each independently _C1-6 alkyl.

In some preferred embodiments, the C _1-6 alkyl group is a C _1-4 alkyl group, and the C _1-4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group, and more preferably a methyl group or an ethyl group.

In some preferred embodiments, the compound B is N,N-dimethylformamide (DMF) or N,N-diethylformamide (DEF).

In some preferred embodiments, the method comprises the steps of:

Mixing compound A and compound B to react to obtain a reaction solution;

The reaction solution is mixed with an ice-water solution containing an acid to form a mixed solution,

Wherein, the ice-water solution containing acid is weakly acidic. Preferably, the pH value of the ice-water solution containing acid is 3-6.

In some preferred embodiments, the acid in the ice-water solution containing acid is hydrochloric acid or sulfuric acid, more preferably hydrochloric acid, such as an ice-water solution containing 7% hydrochloric acid.

In some preferred embodiments, the reaction shown in formula I is a nucleophilic addition reaction. The reaction temperature of the nucleophilic addition reaction is -10 to 10°C, preferably 0 to 5°C, for example 4°C. The reaction time of the nucleophilic addition reaction is not less than 0.5 hours, preferably not less than 0.8 hours, for example 1 hour. The reaction time of the nucleophilic addition reaction is not more than 4 hours, preferably not more than 2 hours, more preferably not more than 1.5 hours, for example 1 hour.

In some preferred embodiments, the molar ratio of compound A to compound B is 1:(1-2.5), more preferably 1:(1.5-2.0).

In some preferred embodiments, the method for preparing the compound A comprises the steps of:

In an aprotic solvent, compound C and metal magnesium are reacted as shown in the following formula II to obtain compound A;

In some preferred embodiments, the reaction shown in formula II is a Grignard reaction. The reaction temperature of the Grignard reaction is 30 to 50° C., more preferably 35 to 45° C., such as 40° C. The reaction time of the Grignard reaction is 2 to 5 hours, more preferably 2.5 to 4.5 hours, such as 3 hours or 3.5 hours.

In some preferred embodiments, the method comprises the steps of:

Metal magnesium and an initiator are added to an aprotic solvent, and then compound C is added to react to obtain compound A.

In some preferred embodiments, the aprotic solvent is selected from at least one of tetrahydrofuran, diethyl ether and toluene, such as tetrahydrofuran or a mixture of tetrahydrofuran and toluene.

In some preferred embodiments, the initiator is preferably iodine, isopropyl chloride, ethyl bromide, isopropyl bromide, and more preferably isopropyl bromide.

In some preferred embodiments, the molar ratio of the magnesium metal to the compound C is (1-3):1, more preferably (1.5-2):1, for example 1.7:1.

In some preferred embodiments, the molar ratio of the initiator to the compound C is preferably (1.5-3.5):1, and more preferably (2-2.5):1.

In some preferred embodiments, the method for preparing the compound C comprises the steps of:

In the presence of an acid and sodium nitrite, compound D is subjected to a diazotization reaction as shown in the following formula III to obtain compound C;

In some preferred embodiments, the acid is acetic acid, hydrochloric acid, sulfuric acid and/or phosphoric acid, for example, acetic acid and sulfuric acid

In some preferred embodiments, the method comprises the steps of:

Step S11, at a first temperature, adding an acid dropwise to a reaction medium containing sodium nitrite and compound D until the system becomes viscous;

Step S12 is performed after step S11, in the presence of a reducing agent, gradually heating the reaction system to a second temperature to react to obtain compound C;

Wherein, the first temperature is -10 to 0°C (preferably -7 to -4°C);

The second temperature is 45 to 70° C. (preferably 55 to 65° C.).

In some preferred schemes, in step S11, at the first temperature, acetic acid and concentrated sulfuric acid are sequentially added dropwise to a reaction medium containing sodium nitrite and compound D until the system becomes viscous.

In some preferred embodiments, the reducing agent is ethanol, an aqueous solution of hypophosphorous acid or isopropanol.

In some preferred embodiments, in step S12, an ethanol solution of sulfuric acid is gradually added dropwise to the reaction system, and the reaction system is gradually heated to a second temperature for reaction to obtain compound C;

In some preferred embodiments, in step S12, the reaction time at the second temperature is not less than 20 minutes, preferably not less than 30 minutes, for example 40-60 minutes.

In some preferred embodiments, in step S12, the time for gradually heating the reaction system to the second temperature is not less than 1 hour, preferably 1-5 hours, more preferably 1.5-3 hours, for example 2-2.5 hours.

In some preferred embodiments, the reaction medium is methanol and/or ethanol.

In some preferred embodiments, the step S12 further comprises a step S13 of separating and purifying compound C:

The reaction solution after step S12 is placed in water for stratification, and the organic phase is taken for vacuum distillation to obtain a purified compound C.

In some preferred embodiments, the organic phase is washed with an alkaline aqueous solution and an acidic aqueous solution in sequence, and after layering, the organic phase is distilled under reduced pressure to obtain a purified compound C.

In some preferred embodiments, the method for preparing the compound D comprises the steps of:

Compound E and N-iodosuccinimide (NIS) are reacted as shown in the following formula IV to obtain compound D;

In some preferred embodiments, the reaction is an electrophilic substitution reaction. The reaction temperature is 60 to 90°C, more preferably 65 to 85°C, such as 75°C.

In some preferred embodiments, the reaction is carried out in a polar organic medium, such as DMF or DMSO.

In some preferred embodiments, the reaction is carried out in the presence of an acid. Preferably, the reaction is carried out in the presence of glacial acetic acid.

In some preferred embodiments, the molar ratio of the compound E to the N-iodosuccinimide is (0.8-1.2):(0.8-1.2) such as 1:1.

In some preferred embodiments, the method for preparing the compound E comprises the steps of:

3-(trifluoromethyl)aniline and a brominating agent are reacted as shown in the following formula V to obtain compound E;

Wherein, the bromination reagent is dibromohydantoin (DBDMH) or N-bromosuccinimide (NBS).

In some preferred embodiments, the reaction is carried out in a polar organic medium, such as DMF or DMSO.

In some preferred embodiments, the molar ratio of the 3-(trifluoromethyl)aniline to the brominating agent is (1.5-2):1, for example, 1.7:1.

In some preferred embodiments, the reaction temperature is -5-0°C.

Compared with the prior art, the present invention has at least the following advantages:

(1) The method for preparing 3-bromo-4-(trifluoromethyl)benzaldehyde provided by the present invention has a high yield, less waste, less environmental pollution, and is suitable for industrialized scale-up production;

(2) The method for preparing 3-bromo-4-(trifluoromethyl)benzaldehyde provided by the present invention has low raw and auxiliary materials, sufficient market supply, and low preparation cost.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

DETAILED DESCRIPTION

After extensive and in-depth research, the inventors have developed a method for preparing 3-bromo-4-(trifluoromethyl)benzaldehyde suitable for industrial production. The method has a high yield and less environmental pollution, and is suitable for large-scale production.

The preparation method of 3-bromo-4-(trifluoromethyl)benzaldehyde provided by the present invention comprises the steps of:

Compound A and compound B are reacted as shown in the following formula I:

The reaction shown in the above formula I is a nucleophilic addition reaction. The aldehyde can be prepared by using a Grignard reagent and an amide compound to undergo a nucleophilic addition reaction. The nucleophilic addition reaction includes steps S1-S2,

In step S1, compound A and compound B are mixed and reacted to obtain a reaction solution, in which a relatively stable tetrahedral intermediate exists;

In step S2, the reaction solution is mixed with an ice-water solution containing an acid to form a mixed solution, and the relatively stable tetrahedral intermediate present in the reaction solution forms the target product 3-bromo-4-(trifluoromethyl)benzaldehyde under the action of the acid. In a preferred embodiment of the present invention, the acid in the ice-water solution containing an acid is hydrochloric acid or sulfuric acid, more preferably hydrochloric acid. The ice-water solution containing an acid is preferably weakly acidic. In some embodiments of the present invention, an ice-water solution containing 7% hydrochloric acid is used. When 7% hydrochloric acid is used as an acidifier to treat the tetrahedral intermediate, side reactions can be reduced and a higher yield can be obtained.

Step S1 and/or S2 is preferably carried out at a temperature below room temperature. In some embodiments of the present invention, the nucleophilic addition reaction is carried out at a reaction temperature of -10 to 10°C, preferably 0 to 5°C.

The reaction time of step S1 and/or S2 can be adjusted with the reaction progress monitoring. The method of reaction progress monitoring is carried out with reference to the method well known to those skilled in the art, such as using thin layer chromatography (TLC), sampling at intervals, monitoring the presence and size (depth) of product points, intermediate product points and raw material points, so as to obtain the optimal reaction time. In some embodiments of the present invention, the reaction time of the nucleophilic addition reaction is not less than 0.5 hours, preferably not less than 0.8 hours, for example, 1 hour. The reaction time of the nucleophilic addition reaction is not more than 4 hours, preferably not more than 2 hours, more preferably not more than 1.5 hours, for example, 1 hour.

After step S2, the target product is present in the mixed solution, but preferably, step S3 of separating and purifying 3-bromo-4-(trifluoromethyl)benzaldehyde is further included, wherein the mixed solution is subjected to extraction and reduced pressure distillation. In some embodiments of the present invention, the extractant used for extraction is petroleum ether, and the organic phase extracted is subjected to reduced pressure distillation to obtain purified 3-bromo-4-(trifluoromethyl)benzaldehyde.

In the present invention, the term "Grignard reagent" refers to an organometallic compound containing magnesium halide, which can be used as a nucleophilic reagent due to the presence of carbon anions. In some embodiments of the present invention, the Grignard reagent is compound A.

R¹和R²分别独立地为C_1-6烷基。C_1-6烷基更优选为C_1-4烷基。C_1-4烷基优选为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基，更优选为甲基或乙基。在本发明的一些实施方式中，化合物B为N,N-二甲基甲酰胺(DMF)或N,N-二乙基甲酰胺(DEF)。当使用N,N-二甲基甲酰胺(DMF)作为反应物时，得到的收率较高。In the present invention, compound B is an amide compound. In compound B, X is

R ¹ and R ² are independently C _1-6 alkyl. C _1-6 alkyl is more preferably C _1-4 alkyl. C _1-4 alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, more preferably methyl or ethyl. In some embodiments of the present invention, compound B is N,N-dimethylformamide (DMF) or N,N-diethylformamide (DEF). When N,N-dimethylformamide (DMF) is used as a reactant, a higher yield is obtained.

As the amount of the reaction raw material, preferably, the compound B is slightly excessive relative to the reaction equivalent of compound A to ensure sufficient reaction. In a preferred embodiment of the present invention, the molar ratio of compound A to compound B is 1: (1-2.5), more preferably 1: (1.5-2.0).

As compound A, it can be prepared by Grignard reaction. In the present invention, "Grignard reaction" and "Grignard reaction" are used interchangeably, which refers to the process of using halogen-containing organic matter (such as halogenated hydrocarbons) and metallic magnesium to react in an anhydrous aprotic solvent to generate an organic magnesium halide. The reaction conditions of the Grignard reaction are carried out with reference to common knowledge in the art. In some preferred embodiments of the present invention, the method for preparing the compound A comprises the steps of: in an aprotic solvent, allowing compound C and metallic magnesium to react as shown in the following formula II to obtain compound A;

In the present invention, the terms "aprotic solvent" and "aprotic solvent" are used interchangeably, and refer to a solvent with extremely weak or no proton self-transfer reaction. In some embodiments of the present invention, the aprotic solvent is selected from at least one of tetrahydrofuran, ether, and toluene, such as tetrahydrofuran, a mixture of tetrahydrofuran and toluene. When tetrahydrofuran is selected as the aprotic solvent, a better yield can be obtained.

The above-mentioned reaction of formula II is preferably carried out in the presence of an initiator. The addition of an initiator can promote the occurrence of the Grignard reaction. Usually, magnesium metal and an initiator are added to an anhydrous aprotic solvent at the same time, and then an organic matter containing a halogen is added to react. The initiator here can use an initiator commonly used in the Grignard reaction. In some embodiments of the present invention, the initiator is iodine, isopropyl chloride, ethyl bromide, isopropyl bromide, and more preferably isopropyl bromide. When isopropyl bromide is used as an initiator, a better yield can be obtained. In the present invention, the use equivalent of the initiator is preferably slightly excessive relative to the compound. In some embodiments, the molar ratio of the initiator to the compound C is preferably (1.5-3.5): 1, and more preferably (2-2.5): 1. If the amount of initiator is too small, the initiation effect is not obvious, but too much is likely to aggravate the occurrence of side reactions.

In the present invention, as a raw material for the Grignard reaction, the use amount of magnesium metal is preferably slightly excessive relative to compound C. In some embodiments of the present invention, the molar ratio of magnesium metal to compound C is (1-3):1, more preferably (1.5-2):1, for example 1.7:1. When the molar ratio of magnesium metal to compound C is 1.7:1, the best yield can be obtained.

As compound C, it can be prepared by diazotization reaction. In the present invention, the term "diazotization reaction (Diazotisation)" refers to the reaction of aromatic primary amine and nitrous acid (in a strong acid medium) to generate a diazonium salt, and the diazotization reaction is generally carried out at low temperature. The detailed reaction principle and conditions can be referred to the textbook Organic Chemistry (Second Edition, Jonathan Clayden, Nick Greeves, and Stuart Warren). In some preferred embodiments of the present invention, the method for preparing the compound C comprises the steps of: in the presence of acid and sodium nitrite, subjecting compound D to a diazotization reaction as shown in the following formula III to obtain compound C;

In the above reaction of formula II, the acid used is preferably a strong acid or a medium-strong acid, and more preferably the acid is selected from any one of hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid or a mixture of several thereof. For example, a mixture of acetic acid and sulfuric acid, when the acid used is a mixture of acetic acid and sulfuric acid, preferably, acetic acid and concentrated sulfuric acid (a sulfuric acid aqueous solution with a mass fraction greater than or equal to 70%) are added in sequence, that is, acetic acid is first added to the reaction system, and then concentrated sulfuric acid is added, the reaction yield is higher.

More specifically, the method for preparing compound C includes steps S11 and S12. In step S11, in a reaction medium containing an acid, an aromatic amine compound (compound D) is dissolved and reacted with nitrous acid to generate a diazonium salt. In this step, nitrous acid is obtained by reacting sodium nitrite in an acidic medium. Specifically, in step S11, at a first temperature, acid is added dropwise to a reaction medium containing sodium nitrite and compound D until the system becomes viscous. It should be noted that the reaction process of step S11 should maintain the acidity of the reaction medium to reduce side reactions and increase the yield. In some embodiments, multiple sampling and determination of pH during the reaction can be achieved by continuously adding acid. Step S11 is preferably carried out at low temperature, preferably at -10 to 0°C. In the case of insufficient acid, low temperature can avoid the occurrence of side reactions.

The reaction medium for the diazotization reaction is preferably a polar organic solvent, such as methanol, ethanol or a mixture thereof. In some preferred embodiments of the present invention, ethanol is used as the reaction medium to obtain a higher yield.

In step S12, the diazo group of the obtained diazonium salt is replaced by hydrogen in the presence of a reducing agent (deamination of the aromatic amine compound) to obtain compound C. Specifically, in the presence of a reducing agent, the reaction system is gradually heated to 5 to 70°C (preferably 55 to 65°C) to react to obtain compound C. In this step, the reducing agent is preferably ethanol, propanol or hypophosphorous acid solution (H ₃ PO ₂ +H ₂ O). For lower cost, ethanol can be selected as the reducing agent. In a more preferred embodiment of the present invention, an ethanol solution of sulfuric acid is used to control the reaction rate in the scaled-up production to avoid excessive reaction and damage to the reaction vessel.

In the present invention, after step S12, preferably, step S13 of separating and purifying compound C is further included: placing the reaction solution after step S12 in water for stratification, and distilling the organic phase layer under reduced pressure to obtain purified compound C. Preferably, the organic phase is washed with an alkaline aqueous solution and an acidic aqueous solution in sequence, and after stratification, the organic phase layer is distilled under reduced pressure to obtain purified compound C.

In the present invention, compound D can be prepared by the following method: Compound E and N-iodosuccinimide (NIS) are reacted as shown in the following formula IV to obtain compound D;

The reaction shown in the above formula IV is an electrophilic substitution reaction. Preferably, in order to accelerate the reaction rate, the reaction is carried out in the presence of an acid, for example, in the presence of glacial acetic acid. The reaction temperature is 60 to 90° C., more preferably 65 to 85° C., for example, 75° C. The reaction is carried out in a polar organic medium, for example, DMF or DMSO.

In the present invention, compound D can be prepared by the following method: 3-(trifluoromethyl)aniline and a brominating agent are reacted as shown in the following formula V to obtain compound D;

Wherein, the bromination reagent is dibromohydantoin (DBDMH) or N-bromosuccinimide (NBS).

The reaction represented by formula V is preferably carried out in a polar organic medium, such as DMF or DMSO. The reaction temperature is preferably -5-0°C.

To make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts. The experimental materials and reagents used in the following examples can be obtained from commercial channels unless otherwise specified.

Unless otherwise specified, the technical and scientific terms used herein have the same meaning as commonly understood by ordinary technicians in the technical field to which the application belongs. It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments of the present application.

Example 1

1) Preparation of Compound 1

The preparation of compound 1 refers to the following reaction formula.

Add 16g DMF and 16.1g 3-(trifluoromethyl)aniline to a 100ml three-necked flask at room temperature, stir and cool to -5°C; dissolve 14.2g dibromohydantoin in 24g DMF, add dropwise to the reaction system at -5--3°C, stir at -5-0°C for 1h after the addition is completed; pour the feed solution into water and stir until solid gradually appears, centrifuge to obtain pink solid, and obtain 18.5g of product. (GC purity: 99.93%; yield: 77.12%).

2) Preparation of Compound 2

The preparation of compound 1 refers to the following reaction formula.

In a 100ml three-necked flask, add 40g of glacial acetic acid, 14.6g of compound, and 13g of NIS at room temperature, stir and heat to 75°C, until all the solids are dissolved, keep warm for 0.5h; cool to below 65°C, pour the feed liquid into water, stir until solids precipitate, centrifuge to obtain 20.1g of product (GC purity: 99.87%; yield: 90.3%).

3) Preparation of Compound 3

The preparation of compound 3 refers to the following reaction formula.

35g of anhydrous ethanol, 8.5g of compound 2 and 2.1g of sodium nitrite were added into a 250ml three-necked flask, stirred and cooled to -5°C; 8.35g of acetic acid was dissolved in 10g of anhydrous ethanol and added dropwise to the -5°C reaction system; 4.54g of concentrated sulfuric acid was added dropwise to 5g of anhydrous ethanol, keeping the temperature not exceeding 45°C, and after the addition was completed, the sulfuric acid ethanol solution was cooled to 10°C, the system temperature was maintained at -5-0°C, and the sulfuric acid ethanol solution was added dropwise, the system gradually became viscous, and after the addition was completed, stirred for 10min; the temperature was slowly raised to 55-65°C within 2-2.5h, and kept warm for 10min; the temperature was quickly raised to reflux state, and refluxed for 30min; the temperature was lowered to 40-45°C, poured into water, stirred and layered, the oil layer was extracted with DCM, washed with sodium hydroxide aqueous solution and layered; the organic phase was washed with hydrochloric acid and layered; the organic phase was distilled under reduced pressure to obtain 6.51g of the product (GC purity: 98.35%; yield: 79.88%).

4) Preparation of 3-bromo-4-(trifluoromethyl)benzaldehyde

The preparation of 3-bromo-4-(trifluoromethyl)benzaldehyde refers to the following reaction formula.

Add 1.31g magnesium chips and 25g THF to a 250ml three-necked flask at room temperature, heat to 40°C, drop 8.8g isopropyl bromide, stir for 30min after the dropwise addition, slowly add 11.2g compound 3 and 20g THF, and react at 40°C for 3h. Cool the reaction flask to about 5°C, add 4.1g N,N-dimethylformamide, stir for 1h after the addition, pour the reactant into 25g 7% glacial hydrochloric acid, extract three times with petroleum ether, 25g each time, combine the organic phases, and distill under reduced pressure to obtain 5.73g of 3-bromo-4-(trifluoromethyl)benzaldehyde. (GC purity: 99.89%; yield: 70.92%)

Example 2

In this example, 3-bromo-4-(trifluoromethyl)benzaldehyde was prepared by a method substantially the same as that in Example 1, except that a different solvent was used in step (3). In this example, the specific preparation method is as follows:

1) Preparation of Compound 1

Add 16g DMF and 16.1g 3-(trifluoromethyl)aniline to a 100ml three-necked flask at room temperature, stir and cool to -5°C; dissolve 14.2g dibromohydantoin in 24g DMF, add dropwise to the reaction system at -5 to -3°C, stir at -5 to 0°C for 1h after the addition is complete; pour the feed solution into water and stir until solid gradually appears, centrifuge to obtain a pink solid, and obtain 18.38g of product. (GC purity: 99.88%; yield: 76.62%)

2) Preparation of Compound 2

Add 40g of glacial acetic acid, 14.6g of compound, and 13g of NIS to a 100ml three-necked flask at room temperature, stir and heat to 75°C until all solids are dissolved, keep warm for 0.5h; cool to below 65°C, pour the liquid into water, stir until solids precipitate, centrifuge to obtain 20.32g of product. (GC purity: 99.85%; yield: 91.3%)

3) Preparation of Compound 3

Add 35g water, 8.5g compound 2, and 2.1g sodium nitrite to a 250ml three-necked flask, stir and cool to -5°C; dissolve 8.35g acetic acid in 10g methanol and drop it into the -5°C reaction system; drop 4.54g concentrated sulfuric acid into 5g methanol, keep the temperature not exceeding 45°C, and cool the sulfuric acid solution to 10°C after the addition, maintain the system temperature at -5 to 0°C, drop the sulfuric acid solution, the system gradually becomes viscous, and stir for 10min after the addition; slowly heat to 55 to 65°C within 2 to 2.5h, keep warm for 10min; quickly heat to reflux state, reflux for 30min; cool to 40 to 45°C, pour into water, stir and separate, extract the oil layer with DCM, wash with sodium hydroxide aqueous solution and separate; wash the organic phase with hydrochloric acid and separate; distill the organic phase under reduced pressure to obtain 4.55g of the product. (GC purity: 98.13%; yield: 55.88%)

4) Preparation of 3-bromo-4-(trifluoromethyl)benzaldehyde

Add 1.31g magnesium chips and 25g THF to a 250ml three-necked flask at room temperature, heat to 40°C, drop 8.8g isopropyl bromide, stir for 30min after the dropwise addition, slowly add 11.2g compound 3 and 20g THF, and react at 40°C for 3h. Cool the reaction flask to about 5°C, add 4.1g N,N-dimethylformamide, stir for 1h after the addition, pour the reactant into 25g 7% glacial hydrochloric acid, extract three times with petroleum ether, 25g each time, combine the organic phases, and distill under reduced pressure to obtain 5.81g of 3-bromo-4-(trifluoromethyl)benzaldehyde. (GC purity: 99.81%; yield: 71.91%)

Example 3

In this example, 3-bromo-4-(trifluoromethyl)benzaldehyde was prepared by a method substantially the same as that in Example 1, except that a different solvent was used in step (3). In this example, the specific preparation method is as follows:

1) Preparation of Compound 1

Add 16g DMF and 16.1g 3-(trifluoromethyl)aniline to a 100ml three-necked flask at room temperature, stir and cool to -5°C; dissolve 14.2g dibromohydantoin in 24g DMF, add dropwise to the reaction system at -5 to -3°C, stir at -5 to 0°C for 1h after the addition is complete; pour the feed solution into water and stir until solids appear, centrifuge to obtain pink solids, and obtain 18.58g of product. (GC purity: 99.95%; yield: 77.45%)

2) Preparation of Compound 2

Add 40g of glacial acetic acid, 14.6g of compound, and 13g of NIS to a 100ml three-necked flask at room temperature, stir and heat to 75°C until all solids are dissolved, keep warm for 0.5h; cool to below 65°C, pour the liquid into water, stir until solids precipitate, centrifuge to obtain 19.98g of product. (GC purity: 99.97%; yield: 89.76%)

3) Preparation of Compound 3

35g of a mixture of methanol and ethanol (m _methanol :m _ethanol =1:1), 8.5g of compound 2, and 2.1g of sodium nitrite were added to a 250ml three-necked flask, stirred and cooled to -5°C; 8.35g of acetic acid was dissolved in 10g of a mixture of ethanol and methanol, and added dropwise to the -5°C reaction system; 4.54g of concentrated sulfuric acid was added dropwise to a mixture of 5g of ethanol and methanol, keeping the temperature not exceeding 45°C, and after the addition was completed, the sulfuric acid ethanol solution was cooled to 10°C, the system temperature was maintained at -5 to 0°C, and the sulfuric acid ethanol solution was added dropwise, the system gradually became viscous, and after the addition was completed, the mixture was stirred for 10min; the temperature was slowly raised to 55 to 65°C within 2 to 2.5h, and kept warm for 10min; the temperature was quickly raised to reflux state, and refluxed for 30min; the temperature was lowered to 40 to 45°C, poured into water, stirred and layered, the oil layer was extracted with DCM, and the sodium hydroxide aqueous solution was washed and layered; the organic phase was washed with hydrochloric acid and layered; the organic phase was distilled under reduced pressure to obtain 5.62g of the product. (GC purity: 98.77%; yield: 68.96%)

4) Preparation of 3-bromo-4-(trifluoromethyl)benzaldehyde

Add 1.31g magnesium chips and 25g THF to a 250ml three-necked flask at room temperature, heat to 40°C, drop 8.8g isopropyl bromide, stir for 30min after the dropwise addition, slowly add 11.2g compound 3 and 20g THF, and react at 40°C for 3h. Cool the reaction flask to about 5°C, add 4.1g N,N-dimethylformamide, stir for 1h after the addition, pour the reactant into 25g 7% glacial hydrochloric acid, extract three times with petroleum ether, 25g each time, combine the organic phases, and distill under reduced pressure to obtain 5.85g of 3-bromo-4-(trifluoromethyl)benzaldehyde. (GC purity: 99.77%; yield: 72.40%)

Example 4

In this example, 3-bromo-4-(trifluoromethyl)benzaldehyde was prepared by a method substantially the same as that in Example 1, except that hydrochloric acid was used instead of sulfuric acid in step (3). In this example, the specific preparation method is as follows:

1) Preparation of Compound 1

Add 16g DMF and 16.1g 3-(trifluoromethyl)aniline to a 100ml three-necked flask at room temperature, stir and cool to -5°C; dissolve 14.2g dibromohydantoin in 24g DMF, add dropwise to the reaction system at -5--3°C, stir at -5-0°C for 1h after the addition is complete; pour the feed solution into water and stir until solid gradually appears, centrifuge to obtain a pink solid, and obtain 18.66g of product. (GC purity: 99.93%; yield: 77.78%)

2) Preparation of Compound 2

Add 40g of glacial acetic acid, 14.6g of compound, and 13g of NIS to a 100ml three-necked flask at room temperature, stir and heat to 75°C until all solids are dissolved, keep warm for 0.5h; cool to below 65°C, pour the liquid into water, stir until solids precipitate, centrifuge to obtain 20.21g of product. (GC purity: 99.88%; yield: 90.79%)

3) Preparation of Compound 3

Add 35g of anhydrous ethanol, 8.5g of compound 2, and 2.1g of sodium nitrite into a 250ml three-necked flask, stir and cool to -5°C; dissolve 8.35g of acetic acid in 10g of anhydrous ethanol and drop it into the -5°C reaction system; drop 4.54g of concentrated hydrochloric acid into 5g of anhydrous ethanol, keep the temperature not exceeding 45°C, and cool the hydrochloric acid ethanol solution to 10°C after the dropwise addition, maintain the system temperature at -5-0°C, drop the hydrochloric acid ethanol solution, the system gradually becomes viscous, and stir for 10min after the dropwise addition; slowly heat to 55-65°C within 2-2.5h, keep warm for 10min; quickly heat to reflux state, reflux for 30min; cool to 40-45°C, pour into water, stir and separate, extract the oil layer with DCM, wash and separate with sodium hydroxide aqueous solution; wash and separate the organic phase with hydrochloric acid; distill the organic phase under reduced pressure to obtain 3.78g of product. (GC purity: 98.15%; yield: 46.38%)

4) Preparation of 3-bromo-4-(trifluoromethyl)benzaldehyde

Add 1.31g magnesium chips and 25g THF to a 250ml three-necked flask at room temperature, heat to 40°C, drop 8.8g isopropyl bromide, stir for 30min after the addition, slowly add 11.2g compound 3 and 20g THF, react at 40°C for 3h. Cool the reaction flask to about 5°C, add 4.1g N,N-dimethylformamide, stir for 1h after the addition, pour the reactant into 25g 7% glacial hydrochloric acid, extract three times with petroleum ether, 25g each time, combine the organic phases, and distill under reduced pressure to obtain 5.8g of 3-bromo-4-(trifluoromethyl)benzaldehyde. (GC purity: 99.89%; yield: 71.78%)

Example 5

In this embodiment, 3-bromo-4-(trifluoromethyl)benzaldehyde is prepared by a method substantially the same as that in Example 1, except that phosphoric acid is used instead of sulfuric acid in step (3). In this embodiment, the specific preparation method is as follows:

1) Preparation of Compound 1

Add 16g DMF and 16.1g 3-(trifluoromethyl)aniline to a 100ml three-necked flask at room temperature, stir and cool to -5°C; dissolve 14.2g dibromohydantoin in 24g DMF, add dropwise to the reaction system at -5 to -3°C, stir at -5 to 0°C for 1h after the addition is complete; pour the feed solution into water and stir until solids appear, centrifuge to obtain pink solids, and obtain 18.59g of product. (GC purity: 99.95%; yield: 77.49%)

2) Preparation of Compound 2

Add 40g of glacial acetic acid, 14.6g of compound, and 13g of NIS to a 100ml three-necked flask at room temperature, stir and heat to 75°C until all solids are dissolved, keep warm for 0.5h; cool to below 65°C, pour the liquid into water, stir until solids precipitate, centrifuge to obtain 19.98g of product. (GC purity: 99.77%; yield: 89.76%)

3) Preparation of Compound 3

Add 35g of anhydrous ethanol, 8.5g of compound 2, and 2.1g of sodium nitrite into a 250ml three-necked flask, stir and cool to -5°C; dissolve 8.35g of acetic acid in 10g of anhydrous ethanol and drop it into the -5°C reaction system; drop 4.54g of phosphoric acid into 5g of anhydrous ethanol, keep the temperature not exceeding 45°C, and cool the phosphoric acid ethanol solution to 10°C after the dropwise addition, maintain the system temperature at -5 to 0°C, drop the phosphoric acid ethanol solution, the system gradually becomes viscous, and stir for 10min after the dropwise addition; slowly heat to 55 to 65°C within 2 to 2.5h, keep warm for 10min; quickly heat to reflux state, reflux for 30min; cool to 40 to 45°C, pour into water, stir and separate, extract the oil layer with DCM, wash and separate with sodium hydroxide aqueous solution; wash and separate the organic phase with hydrochloric acid; distill the organic phase under reduced pressure to obtain 3.15g of product. (GC purity: 98.65%; yield: 43.07%)

4) Preparation of 3-bromo-4-(trifluoromethyl)benzaldehyde

Add 1.31g magnesium chips and 25g THF to a 250ml three-necked flask at room temperature, heat to 40°C, drop 8.8g isopropyl bromide, stir for 30min after the dropwise addition, slowly add 11.2g compound 3 and 20g THF, and react at 40°C for 3h. Cool the reaction flask to about 5°C, add 4.1g N,N-dimethylformamide, stir for 1h after the addition, pour the reactant into 25g 7% glacial hydrochloric acid, extract three times with petroleum ether, 25g each time, combine the organic phases, and distill under reduced pressure to obtain 5.79g of 3-bromo-4-(trifluoromethyl)benzaldehyde. (GC purity: 99.91%; yield: 71.66%)

Example 6

In this embodiment, 3-bromo-4-(trifluoromethyl)benzaldehyde is prepared by a method substantially the same as that in Embodiment 1, except that in step (3), the heating time is different. In this embodiment, the specific preparation method is as follows:

1) Preparation of Compound 1

Add 16g DMF and 16.1g 3-(trifluoromethyl)aniline to a 100ml three-necked flask at room temperature, stir and cool to -5°C; dissolve 14.2g dibromohydantoin in 24g DMF, add dropwise to the reaction system at -5 to -3°C, stir at -5 to 0°C for 1h after the addition is complete; pour the feed solution into water and stir until solid gradually appears, centrifuge to obtain a pink solid, and obtain 18.5g of the product. (GC purity: 99.92%; yield: 77.12%)

2) Preparation of Compound 2

Add 40g of glacial acetic acid, 14.6g of compound, and 13g of NIS to a 100ml three-necked flask at room temperature, stir and heat to 75°C until all solids are dissolved, keep warm for 0.5h; cool to below 65°C, pour the liquid into water, stir until solids precipitate, centrifuge to obtain 20.1g of product. (GC purity: 99.87%; yield: 90.3%)

3) Preparation of Compound 3

Add 35g of anhydrous ethanol, 8.5g of compound 2, and 2.1g of sodium nitrite into a 250ml three-necked flask, stir and cool to -5°C; dissolve 8.35g of acetic acid in 10g of anhydrous ethanol and drop it into the -5°C reaction system; drop 4.54g of phosphoric acid into 5g of anhydrous ethanol, keep the temperature not exceeding 45°C, and cool the phosphoric acid ethanol solution to 10°C after the dropwise addition, maintain the system temperature at -5 to 0°C, drop the phosphoric acid ethanol solution, the system gradually becomes viscous, and stir for 10min after the dropwise addition; slowly heat to 55 to 65°C within 1 to 1.5h, keep warm for 10min; quickly heat to reflux state, reflux for 30min; cool to 40 to 45°C, pour into water, stir and separate, extract the oil layer with DCM, wash and separate with sodium hydroxide aqueous solution; wash and separate the organic phase with hydrochloric acid; distill the organic phase under reduced pressure to obtain 4.66g of product. (GC purity: 98.75%; yield: 57.18%)

4) Preparation of 3-bromo-4-(trifluoromethyl)benzaldehyde

Add 1.31g magnesium chips and 25g THF to a 250ml three-necked flask at room temperature, heat to 40°C, drop 8.8g isopropyl bromide, stir for 30min after the dropwise addition, slowly add 11.2g compound 3 and 20g THF, and react at 40°C for 3h. Cool the reaction flask to about 5°C, add 4.1g N,N-dimethylformamide, stir for 1h after the addition, pour the reactant into 25g 7% glacial hydrochloric acid, extract three times with petroleum ether, 25g each time, combine the organic phases, and distill under reduced pressure to obtain 5.73g of 3-bromo-4-(trifluoromethyl)benzaldehyde. (GC purity: 99.89%; yield: 70.92%)

Table 1 below shows the effect of various factors on the yield of the deamination reaction in step (3). It can be seen that when the solvent used is ethanol, the type of acid is concentrated sulfuric acid, and the heating time is 2 to 2.5 hours, the yield is significantly improved.

Table 1

Group Solvents acid Heating time/h Reaction yield Example 1 Ethanol Acetic acid + concentrated sulfuric acid 2～2.5 79.88% Example 2 Methanol Acetic acid + concentrated sulfuric acid 2～2.5 55.88% Example 3 Ethanol and methanol Acetic acid + concentrated sulfuric acid 2～2.5 68.96% Example 4 Ethanol Acetic acid + concentrated hydrochloric acid 2～2.5 46.38% Example 5 Ethanol Acetic acid + phosphoric acid 2～2.5 43.07% Example 6 Ethanol Acetic acid + concentrated sulfuric acid 1～1.5 57.18%

The inventors found that in step (2), the solvent, initiator, reactant, amount of magnesium chips and post-reaction treatment steps used all have an impact on the reaction result. In the following Examples 7-12, the solvent, initiator, reactant and post-reaction treatment steps used were changed to explore their effects on the yield of 3-bromo-4-(trifluoromethyl)benzaldehyde.

Example 7

In this example, 3-bromo-4-(trifluoromethyl)benzaldehyde was prepared by a method substantially the same as that in Example 1, except that in step (4), N,N-diethylformamide was used instead of DMF. In this example, the specific preparation method is as follows:

1) Preparation of Compound 1

Add 16g DMF and 16.1g 3-(trifluoromethyl)aniline to a 100ml three-necked flask at room temperature, stir and cool to -5°C; dissolve 14.2g dibromohydantoin in 24g DMF, add dropwise to the reaction system at -5 to -3°C, stir at -5 to 0°C for 1h after the addition is complete; pour the feed solution into water and stir until solid gradually appears, centrifuge to obtain a pink solid, and obtain 18.63g of product. (GC purity: 99.94%; yield: 77.66%)

2) Preparation of Compound 2

Add 40g of glacial acetic acid, 14.6g of compound, and 13g of NIS to a 100ml three-necked flask at room temperature, stir and heat to 75°C until all solids are dissolved, keep warm for 0.5h; cool to below 65°C, pour the liquid into water, stir until solids precipitate, centrifuge to obtain 20.08g of product. (GC purity: 99.88%; yield: 90.21%)

3) Preparation of Compound 3

Add 35g of anhydrous ethanol, 8.5g of compound 2, and 2.1g of sodium nitrite into a 250ml three-necked flask, stir and cool to -5°C; dissolve 8.35g of acetic acid in 10g of anhydrous ethanol and drop it into the -5°C reaction system; drop 4.54g of phosphoric acid into 5g of anhydrous ethanol, keep the temperature not exceeding 45°C, and cool the phosphoric acid ethanol solution to 10°C after the dropwise addition, maintain the system temperature at -5 to 0°C, drop the phosphoric acid ethanol solution, the system gradually becomes viscous, and stir for 10min after the dropwise addition; slowly heat to 55 to 65°C within 2 to 2.5h, keep warm for 10min; quickly heat to reflux state, reflux for 30min; cool to 40 to 45°C, pour into water, stir and separate, extract the oil layer with DCM, wash and separate with sodium hydroxide aqueous solution; wash and separate the organic phase with hydrochloric acid; distill the organic phase under reduced pressure to obtain 6.53g of product. (GC purity: 98.65%; yield: 80.12%)

4) Preparation of 3-bromo-4-(trifluoromethyl)benzaldehyde

Add 1.31g magnesium chips and 25g THF to a 250ml three-necked flask at room temperature, heat to 40°C, drop 8.8g isopropyl bromide, stir for 30min after the dropwise addition, slowly add 11.2g compound 3 and 20g THF, and react at 40°C for 3h. Cool the reaction flask to about 5°C, add 5.67g N,N-diethylformamide, stir for 1h after the addition, pour the reactant into 25g 7% glacial hydrochloric acid, extract three times with petroleum ether, 25g each time, combine the organic phases, and distill under reduced pressure to obtain 3.37g of 3-bromo-4-(trifluoromethyl)benzaldehyde. (GC purity: 99.79%; yield: 41.67%)

Example 8

In this embodiment, 3-bromo-4-(trifluoromethyl)benzaldehyde is prepared by a method substantially the same as that in Example 1, except that ethyl bromide is used instead of isopropyl bromide in step (4). In this embodiment, the specific preparation method is as follows:

1) Preparation of Compound 1

Add 16g DMF and 16.1g 3-(trifluoromethyl)aniline to a 100ml three-necked flask at room temperature, stir and cool to -5°C; dissolve 14.2g dibromohydantoin in 24g DMF, add dropwise to the reaction system at -5 to -3°C, stir at -5 to 0°C for 1h after the addition is complete; pour the feed solution into water and stir until solids appear, centrifuge to obtain pink solids, and obtain 18.58g of product. (GC purity: 99.95%; yield: 77.45%)

2) Preparation of Compound 2

Add 40g of glacial acetic acid, 14.6g of compound, and 13g of NIS to a 100ml three-necked flask at room temperature, stir and heat to 75°C until all solids are dissolved, keep warm for 0.5h; cool to below 65°C, pour the liquid into water, stir until solids precipitate, centrifuge to obtain 19.98g of product. (GC purity: 99.97%; yield: 89.76%)

3) Preparation of Compound 3

Add 35g of anhydrous ethanol, 8.5g of compound 2, and 2.1g of sodium nitrite into a 250ml three-necked flask, stir and cool to -5°C; dissolve 8.35g of acetic acid in 10g of anhydrous ethanol and drop it into the -5°C reaction system; drop 4.54g of phosphoric acid into 5g of anhydrous ethanol, keep the temperature not exceeding 45°C, and cool the phosphoric acid ethanol solution to 10°C after the dropwise addition, maintain the system temperature at -5 to 0°C, drop the phosphoric acid ethanol solution, the system gradually becomes viscous, and stir for 10min after the dropwise addition; slowly heat to 55 to 65°C within 2 to 2.5h, keep warm for 10min; quickly heat to reflux state, reflux for 30min; cool to 40 to 45°C, pour into water, stir and separate, extract the oil layer with DCM, wash and separate with sodium hydroxide aqueous solution; wash and separate the organic phase with hydrochloric acid; distill the organic phase under reduced pressure to obtain 6.49g of product. (GC purity: 98.55%; yield: 79.63%)

4) Preparation of 3-bromo-4-(trifluoromethyl)benzaldehyde

Add 1.31g magnesium chips and 25g THF to a 250ml three-necked flask at room temperature, heat to 40°C, drop 7.8g isopropyl bromide, stir for 30min after the dropwise addition, slowly add 11.2g compound 3 and 20g THF, and react at 40°C for 3h. Cool the reaction flask to about 5°C, add 4.1g N,N-dimethylformamide, stir for 1h after the addition, pour the reactant into 25g 7% glacial hydrochloric acid, extract three times with petroleum ether, 25g each time, combine the organic phases, and distill under reduced pressure to obtain 4.27g of 3-bromo-4-(trifluoromethyl)benzaldehyde. (GC purity: 99.88%; yield: 52.85%)

Example 9

In this embodiment, 3-bromo-4-(trifluoromethyl)benzaldehyde is prepared by a method substantially the same as that in Example 1, except that in step (4), isopropyl chloride is used instead of isopropyl bromide. In this embodiment, the specific preparation method is as follows:

1) Preparation of Compound 1

Add 16g DMF and 16.1g 3-(trifluoromethyl)aniline to a 100ml three-necked flask at room temperature, stir and cool to -5°C; dissolve 14.2g dibromohydantoin in 24g DMF, add dropwise to the reaction system at -5 to -3°C, stir at -5 to 0°C for 1h after the addition is complete; pour the feed solution into water and stir until solid gradually appears, centrifuge to obtain a pink solid, and obtain 18.48g of product. (GC purity: 99.93%; yield: 77.03%)

2) Preparation of Compound 2

Add 40g of glacial acetic acid, 14.6g of compound, and 13g of NIS to a 100ml three-necked flask at room temperature, stir and heat to 75°C until all solids are dissolved, keep warm for 0.5h; cool to below 65°C, pour the liquid into water, stir until solids precipitate, centrifuge to obtain 20.13g of product. (GC purity: 99.89%; yield: 90.43%)

3) Preparation of Compound 3

Add 35g of anhydrous ethanol, 8.5g of compound 2, and 2.1g of sodium nitrite into a 250ml three-necked flask, stir and cool to -5°C; dissolve 8.35g of acetic acid in 10g of anhydrous ethanol and drop it into the -5°C reaction system; drop 4.54g of concentrated sulfuric acid into 5g of anhydrous ethanol, keep the temperature not exceeding 45°C, and cool the sulfuric acid ethanol solution to 10°C after the dropwise addition, maintain the system temperature at -5 to 0°C, drop the sulfuric acid ethanol solution, the system gradually becomes viscous, and stir for 10min after the dropwise addition; slowly heat to 55 to 65°C within 2 to 2.5h, keep warm for 10min; quickly heat to reflux state, reflux for 30min; cool to 40 to 45°C, pour into water, stir and separate, extract the oil layer with DCM, wash and separate with sodium hydroxide aqueous solution; wash and separate the organic phase with hydrochloric acid; distill the organic phase under reduced pressure to obtain 6.53g of product. (GC purity: 98.65%; yield: 80.12%)

4) Preparation of 3-bromo-4-(trifluoromethyl)benzaldehyde

Add 1.31g magnesium chips and 25g THF to a 250ml three-necked flask at room temperature, heat to 40°C, drop 5.62g isopropyl chloride, stir for 30min after the dropwise addition, slowly add 11.2g compound 3 and 20g THF, and react at 40°C for 3h. Cool the reaction flask to about 5°C, add 4.1g N,N-dimethylformamide, stir for 1h after the addition, pour the reactant into 25g 7% glacial hydrochloric acid, extract three times with petroleum ether, 25g each time, combine the organic phases, and distill under reduced pressure to obtain 3.63g of 3-bromo-4-(trifluoromethyl)benzaldehyde. (GC purity: 99.89%; yield: 44.93%)

Example 10

In this example, 3-bromo-4-(trifluoromethyl)benzaldehyde was prepared by a method substantially the same as that in Example 1, except that in step (4), a different solvent was used for the Grignard reaction. In this example, the specific preparation method is as follows:

1) Preparation of Compound 1

Add 16g DMF and 16.1g 3-(trifluoromethyl)aniline to a 100ml three-necked flask at room temperature, stir and cool to -5°C; dissolve 14.2g dibromohydantoin in 24g DMF, add dropwise to the reaction system at -5 to -3°C, stir at -5 to 0°C for 1h after the addition is complete; pour the feed solution into water and stir until solids appear, centrifuge to obtain pink solids, and obtain 18.49g of product. (GC purity: 99.95%; yield: 77.07%)

2) Preparation of Compound 2

Add 40g of glacial acetic acid, 14.6g of compound, and 13g of NIS to a 100ml three-necked flask at room temperature, stir and heat to 75°C until all solids are dissolved, keep warm for 0.5h; cool to below 65°C, pour the feed solution into water, stir until solids precipitate, centrifuge to obtain 20.05g of product. (GC purity: 99.89%; yield: 90.07%)

3) Preparation of Compound 3

Add 35g of anhydrous ethanol, 8.5g of compound 2, and 2.1g of sodium nitrite into a 250ml three-necked flask, stir and cool to -5°C; dissolve 8.35g of acetic acid in 10g of anhydrous ethanol and drop it into the -5°C reaction system; drop 4.54g of concentrated sulfuric acid into 5g of anhydrous ethanol, keep the temperature not exceeding 45°C, and cool the sulfuric acid ethanol solution to 10°C after the dropwise addition, maintain the system temperature at -5 to 0°C, drop the sulfuric acid ethanol solution, the system gradually becomes viscous, and stir for 10min after the dropwise addition; slowly heat to 55 to 65°C within 2 to 2.5h, keep warm for 10min; quickly heat to reflux state, reflux for 30min; cool to 40 to 45°C, pour into water, stir and separate, extract the oil layer with DCM, wash and separate with sodium hydroxide aqueous solution; wash and separate the organic phase with hydrochloric acid; distill the organic phase under reduced pressure to obtain 6.55g of product. (GC purity: 98.73%; yield: 80.37%)

4) Preparation of 3-bromo-4-(trifluoromethyl)benzaldehyde

In a 250ml three-necked flask, 1.31g of magnesium chips and 25g of a mixture of tetrahydrofuran and toluene (m _{tetrahydrofuran} : m _toluene = 1:1) were added at room temperature, the temperature was raised to 40°C, 8.8g of isopropyl bromide was added dropwise, and stirring was continued for 30min after the addition was completed; 11.2g of compound 3 and 20g of a mixture of tetrahydrofuran and toluene (m _{tetrahydrofuran} : m _toluene = 1:1) were slowly added, and the mixture was reacted at 40°C for 3h. The reaction flask was cooled to about 5°C, 4.1g of N,N-dimethylformamide was added, and stirring was continued for 1h after the addition was completed. The reactants were poured into 25g of 7% glacial hydrochloric acid, and extracted three times with petroleum ether, 25g each time. The organic phases were combined and distilled under reduced pressure to obtain 2.08g of 3-bromo-4-(trifluoromethyl)benzaldehyde. (GC purity: 99.71%; yield: 25.72%)

Embodiment 11

In this embodiment, 3-bromo-4-(trifluoromethyl)benzaldehyde is prepared by a method substantially the same as that in Example 1, except that in step (4), the amount of magnesium chips used is different. In this embodiment, the specific preparation method is as follows:

1) Preparation of Compound 1

Add 16g DMF and 16.1g 3-(trifluoromethyl)aniline to a 100ml three-necked flask at room temperature, stir and cool to -5°C; dissolve 14.2g dibromohydantoin in 24g DMF, add dropwise to the reaction system at -5 to -3°C, stir at -5 to 0°C for 1h after the addition is complete; pour the feed solution into water and stir until solid gradually appears, centrifuge to obtain a pink solid, and obtain 18.5g of the product. (GC purity: 99.93%; yield: 77.12%)

2) Preparation of Compound 2

Add 40g of glacial acetic acid, 14.6g of compound, and 13g of NIS to a 100ml three-necked flask at room temperature, stir and heat to 75°C until all the solids are dissolved, keep warm for 0.5h; cool to below 65°C, pour the liquid into water, stir until solids precipitate, centrifuge to obtain 20.1g of product. (GC purity: 99.87%; yield: 90.3%)

3) Preparation of Compound 3

Add 35g of anhydrous ethanol, 8.5g of compound 2, and 2.1g of sodium nitrite into a 250ml three-necked flask, stir and cool to -5°C; dissolve 8.35g of acetic acid in 10g of anhydrous ethanol and drop it into the -5°C reaction system; drop 4.54g of concentrated sulfuric acid into 5g of anhydrous ethanol, keep the temperature not exceeding 45°C, and cool the sulfuric acid ethanol solution to 10°C after the dropwise addition, maintain the system temperature at -5 to 0°C, drop the sulfuric acid ethanol solution, the system gradually becomes viscous, and stir for 10min after the dropwise addition; slowly heat to 55 to 65°C within 2 to 2.5h, keep warm for 10min; quickly heat to reflux state, reflux for 30min; cool to 40 to 45°C, pour into water, stir and separate, extract the oil layer with DCM, wash and separate with sodium hydroxide aqueous solution; wash and separate the organic phase with hydrochloric acid; distill the organic phase under reduced pressure to obtain 6.51g of product. (GC purity: 98.35%; yield: 79.88%)

4) Preparation of 3-bromo-4-(trifluoromethyl)benzaldehyde

Add 2.3g magnesium chips and 25g THF to a 250ml three-necked flask at room temperature, heat to 40°C, drop 8.8g isopropyl bromide, stir for 30min after the dropwise addition, slowly add 11.2g compound 3 and 20g THF, and react at 40°C for 3h. Cool the reaction flask to about 5°C, add 4.1g N,N-dimethylformamide, stir for 1h after the addition, pour the reactant into 25g 7% glacial hydrochloric acid, extract three times with petroleum ether, 25g each time, combine the organic phases, and distill under reduced pressure to obtain 4.63g of 3-bromo-4-(trifluoromethyl)benzaldehyde. (GC purity: 99.93%; yield: 57.3%)

Example 12

In this example, 3-bromo-4-(trifluoromethyl)benzaldehyde was prepared by a method substantially the same as that in Example 1, except that in step (4), the treatment steps after the reaction were different. In this example, the specific preparation method was as follows:

1) Preparation of Compound 1

Add 16g DMF and 16.1g 3-(trifluoromethyl)aniline to a 100ml three-necked flask at room temperature, stir and cool to -5°C; dissolve 14.2g dibromohydantoin in 24g DMF, add dropwise to the reaction system at -5 to -3°C, stir at -5 to 0°C for 1h after the addition is complete; pour the feed solution into water and stir until solid gradually appears, centrifuge to obtain a pink solid, and obtain 18.6g of product. (GC purity: 99.95%; yield: 77.53%)

2) Preparation of Compound 2

Add 40g of glacial acetic acid, 14.6g of compound, and 13g of NIS to a 100ml three-necked flask at room temperature, stir and heat to 75°C until all solids are dissolved, keep warm for 0.5h; cool to below 65°C, pour the liquid into water, stir until solids precipitate, centrifuge to obtain 20.11g of product. (GC purity: 99.89%; yield: 90.34%)

3) Preparation of Compound 3

Add 35g of anhydrous ethanol, 8.5g of compound 2, and 2.1g of sodium nitrite into a 250ml three-necked flask, stir and cool to -5°C; dissolve 8.35g of acetic acid in 10g of anhydrous ethanol and drop it into the -5°C reaction system; drop 4.54g of concentrated sulfuric acid into 5g of anhydrous ethanol, keep the temperature not exceeding 45°C, and cool the sulfuric acid ethanol solution to 10°C after the dropwise addition, maintain the system temperature at -5 to 0°C, drop the sulfuric acid ethanol solution, the system gradually becomes viscous, and stir for 10min after the dropwise addition; slowly heat to 55 to 65°C within 2 to 2.5h, keep warm for 10min; quickly heat to reflux state, reflux for 30min; cool to 40 to 45°C, pour into water, stir and separate, extract the oil layer with DCM, wash and separate with sodium hydroxide aqueous solution; wash and separate the organic phase with hydrochloric acid; distill the organic phase under reduced pressure to obtain 6.55g of product. (GC purity: 98.35%; yield: 80.37%)

4) Preparation of 3-bromo-4-(trifluoromethyl)benzaldehyde

Add 1.31g magnesium chips and 25g THF to a 250ml three-necked flask at room temperature, heat to 40°C, drop 8.8g isopropyl bromide, stir for 30min after the addition, slowly add 11.2g compound 3 and 20g THF, react at 40°C for 3h. Cool the reaction flask to about 5°C, add 4.1g N,N-dimethylformamide, stir for 1h after the addition, pour the reactant into 25g 7% glacial sulfuric acid, extract three times with petroleum ether, 25g each time, combine the organic phases, and distill under reduced pressure to obtain 2.63g of 3-bromo-4-(trifluoromethyl)benzaldehyde. (GC purity: 99.93%; yield: 32.55%)

Table 2 below shows the effects of changing various factors on the reaction yield in step (2).

Table 2

Those skilled in the art will appreciate that the above-mentioned embodiments are specific examples for implementing the present invention, and in actual applications, various changes may be made thereto in form and detail without departing from the spirit and scope of the present invention.

Claims (10)

1. A process for preparing 3-bromo-4- (trifluoromethyl) benzaldehyde, comprising the steps of:

enabling a lower compound A and a compound B to react as shown in the following formula I to obtain 3-bromo-4- (trifluoromethyl) benzaldehyde;

wherein B is

R ¹ And R ² Are each independently C _1-6 An alkyl group.

2. The method of claim 1, wherein compound B is N, N-Dimethylformamide (DMF) or N, N-Diethylformamide (DEF).

3. The method according to claim 1, characterized in that it comprises the steps of:

mixing the compound A and the compound B for reaction to obtain a reaction solution;

mixing the reaction solution with an ice water solution containing acid to form a mixed solution,

wherein the ice water solution containing acid is weakly acidic.

4. The method according to claim 3, wherein the acid is hydrochloric acid or sulfuric acid in the ice water solution containing the acid.

5. The process according to claim 1, characterized in that the process for the preparation of said compound a comprises the steps of:

in an aprotic solvent, enabling a compound C and metal magnesium to react as shown in a formula II to obtain a compound A;

6. the process according to claim 5, characterized in that the process for the preparation of said compound C comprises the steps of:

in the presence of acid and sodium nitrite, enabling the compound D to have diazotization reaction shown as the following formula III to obtain a compound C;

7. the method according to claim 6, characterized in that it comprises the steps of:

step S11, dropwise adding acid into a reaction medium containing sodium nitrite and a compound D at a first temperature until the system is viscous;

step S12, which is carried out after step S11, gradually raising the temperature of the reaction system to a second temperature for reaction in the presence of a reducing agent to obtain a compound C;

wherein the first temperature is between-10 ℃ and 0 ℃;

the second temperature is 45-70 ℃.

8. The method according to claim 7, wherein in step S11, the reducing agent is selected from ethanol, propanol and/or phosphorous acid;

and/or in step S12, the reaction is carried out at the second temperature for not less than 20 minutes;

and/or, in the step S12, the time for gradually raising the temperature of the reaction system to the second temperature is not less than 1 hour;

and/or the reaction medium is methanol and/or ethanol;

and/or, in step S11, the acid is acetic acid, hydrochloric acid, sulfuric acid and/or phosphoric acid.

9. The method of claim 6, wherein the method of preparing said compound D comprises the steps of:

reacting the compound E with N-iodosuccinimide (NIS) as shown in the following formula IV to obtain a compound D;

10. the process according to claim 9, characterized in that the process for preparing said compound E comprises the steps of: reacting 3- (trifluoromethyl) aniline with a brominating reagent as shown in formula V below to obtain a compound D;