Preparation method of (4 chlorphenyl) (2, 6-dichloro-4-methylphenyl) ketone and carboxamide triazole intermediates

Abstract

The invention discloses a preparation method of a carboxamide triazole intermediate, and the preparation method comprises the following steps: S1: addition reaction: introducing a p-chlorobenzene group into 2, 6-dichloro-4-methylbenzaldehyde through Grignard reaction to obtain a product 1: (4 chlorophenyl) (2, 6-dichloro-4-methylphenyl) methanol; s2, oxidation reaction: adding an oxidizing agent into the product 1, and reacting to generate a product 2: (4 chlorphenyl) (2, 6-dichloro-4-methylphenyl) ketone; s3, carrying out a halogenation reaction: adding a halide into the product 2, and carrying out a reaction to generate a product 3 (4-X methyl-2, 6-dichlorophenyl) (4-chlorphenyl) ketone; x is chlorine or bromine or iodine; the method further comprises an azidation reaction step, wherein the azidation reaction and the step S3 are a step-by-step reaction or a continuous feeding reaction; the reaction process is milder, generation of impurities in the reaction process can be reduced, and the reaction safety is improved.

Description

Technical Field

[0001] The present invention relates to the field of biological medicine technology, and particularly relates to a preparation method of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone and carboxamide triazole intermediate. Background Art

[0002] The previously authorized invention patent CN20211028077 of the applicant discloses a preparation method of 3,5-dichlorobenzyl alcohol and carboxamide triazole intermediate. The synthetic route is as follows. The core carboxamide triazole intermediate (4-chlorophenyl)-[2,6-dichloro-4-(hydroxymethyl)phenyl]methanone is prepared from tert-butyldimethylchlorosilane and 3,5-dichlorobenzyl alcohol. After the hydroxyl group of 3,5-dichlorobenzyl alcohol is protected by tert-butyldimethylchlorosilane, it is deprotonated by butyllithium and then coupled with p-chlorobenzoyl chloride, and then deprotected by concentrated hydrochloric acid to obtain the product.

[0003]

[0004] The applicant also applied for an invention patent for the synthesis method of CN 202110029565-carboxamide triazole. According to the (4-chlorophenyl)(2,6-dichloro-4-(hydroxymethyl)phenyl)methanone synthesized in the CN20211028077 patent, through halogenation and azide reaction, the important intermediate (4-chlorophenyl)(4-(azidomethyl)-2,6-dichlorophenyl)methanone of carboxamide triazole is finally obtained. The reaction formula is as follows.

[0005]

[0006] The above-mentioned existing technologies have the following problems. First, butyllithium reagent is needed for deprotonation in this reaction. Since butyllithium reagent has very high activity, a lot of impurities will be generated during the reaction process. Moreover, the shelf life of butyllithium reagent itself is short, it cannot contact air and water, and it must be kept at low temperature or even ultra-low temperature during use. Once there is a leak, the generated sparks greatly increase the risk of explosion in the production workshop. Therefore, the requirements for the production environment are very high during industrial production. Second, this reaction needs to deprotonate with butyllithium at -80 °C first and then couple with p-chlorobenzoyl chloride. The ultra-low temperature reaction process has high requirements for industrial reaction equipment. A large amount of liquid nitrogen is needed during the cooling process, and the leakage of liquid nitrogen has the production risk of suffocation. Therefore, the operation skills of production personnel are also required to be high. At the same time, the cooling process takes a long time, and the equipment cost and time cost of the whole reaction are both high, and the safety risk is also high. Third, in the existing reactions, sodium azide is used as the azide reagent, which is a highly toxic and dangerous chemical, and its purchase and use are strictly controlled, which restricts the amplification of the production capacity of the existing technology process to a certain extent. Fourth, the reaction steps of the existing technology are many, the operation is more complicated, and the industrialization cost is high. Summary of the Invention

[0007] The present invention aims to overcome at least one defect of the above-mentioned prior art, and provides (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone and a method for preparing carboxamide triazole intermediate by using (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone, so as to achieve the purpose of milder reaction, without using ultra-highly active substances such as butyllithium, and higher safety.

[0008] Specifically, the present invention provides a method for preparing (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone, comprising the following steps: S1: addition reaction: introducing a p-chlorophenyl group into 2,6-dichloro-4-methylbenzaldehyde through a Grignard reaction to obtain product 1: (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanol; S2: oxidation reaction: adding the product 1 to an oxidizing agent for reaction to generate product 2: (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone.

[0009] Further, in the step S1, the Grignard reagent is at least one of p-chlorophenylmagnesium bromide and p-chlorophenylmagnesium chloride.

[0010] Further, in the step S1, the molar ratio of 2,6-dichloro-4-methylbenzaldehyde to the Grignard reagent is 1:1.0 to 2.2.

[0011] Further, in the step S1, the reaction solvent for the addition reaction is at least one of diethyl ether, tetrahydrofuran, methyltetrahydrofuran, and isopropyl ether; the reaction temperature is 30 to 60 °C.

[0012] Further, in the step S2, the oxidizing agent is Dess-Martin periodinane and / or 2-iodoxybenzoic acid.

[0013] Further, in the step S2, the molar ratio of the product 1 to the oxidizing agent is: 1:1.0 to 1.5.

[0014] Further, in the step S2, the reaction solvent for the oxidation reaction is at least one of chloroform, dichloromethane, and acetonitrile.

[0015] The present invention also provides a novel method for further preparing the carboxamide triazole intermediate (4-chlorophenyl)(4-(azidomethyl)-2,6-dichlorophenyl)methanone by using the (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone prepared by the above method.

[0016] The above novel preparation method further comprises the following steps:

[0017] S3: Halogenation reaction: A halide is added to the product 2 to react to form product 3: (4-X-methyl-2,6-dichlorophenyl)(4-chlorophenyl)methanone; where X is chlorine or bromine or iodine; It further includes a step of azidation reaction: The azidation reaction and the step S3 are either a stepwise reaction or a continuous addition reaction;

[0018] The steps of the stepwise reaction are as follows: An azidation reagent is added to the product 3 to react to form a carboxamide triazole intermediate (4-chlorophenyl)(4-(azidomethyl)-2,6-dichlorophenyl)methanone;

[0019] The steps of the continuous addition reaction are as follows: An azidation reagent is added to the treatment liquid of the step S3 to react to form a carboxamide triazole intermediate (4-chlorophenyl)(4-(azidomethyl)-2,6-dichlorophenyl)methanone. The step S3 and the azidation reaction can be a continuous addition reaction, or the azidation reaction can start after the product 3 in S3 is separated, which are all within the protection scope of the present invention.

[0020] Furthermore, in the step S3, the halide is prepared by reacting with a brominating agent or a chlorinating agent or an iodinating agent.

[0021] Preferably, the step S3 further includes a step of adding a catalyst azo initiator; The azo initiator is AIBN.

[0022] Furthermore, the brominating agent is at least one of NBS, bromine, bromoacetamide, dibromohydantoin; The chlorinating agent is at least one of NCS, chlorine, dichlorohydantoin, sodium dichloroisocyanurate; The iodinating agent is at least one of NIS, iodine, diiodohydantoin.

[0023] Furthermore, in the step S3, the molar ratio of the product 2 to the azo initiator is 1:0.4 - 0.6; The molar ratio of the product 2 to the brominating agent or the chlorinating agent or the iodinating agent is 1:0.6 - 1.5.

[0024] Furthermore, in the azidation reaction step, the azidation reagent is tetrabutylammonium azide and / or potassium azide and / or sodium azide.

[0025] Furthermore, in the stepwise reaction, preferably the product 3 and the azidation reagent react at room temperature, but any adjustment of the temperature range made by those skilled in the art based on this application is within the protection scope of the present invention; The molar ratio of the product 3 to the azidation reagent is 1:1.0 - 1.5.

[0026] Furthermore, in the continuous addition reaction, the molar ratio of the product 2 to the azidation reagent is 1:0.8 - 1.5.

[0027] Compared with the prior art, the beneficial effects of the present invention are:

[0028] (1) The reaction of the present invention does not require the use of butyllithium reagent. Instead, a mild Grignard reagent is selected as the reagent for the addition reaction. The reaction process is milder, which can reduce the generation of impurities during the reaction. At the same time, it can avoid problems such as the short shelf life and harsh storage conditions of butyllithium reagent, improving the safety of the whole reaction.

[0029] (2) The reaction temperature of the present invention is appropriate. It does not require the use of ultra-low temperature reaction conditions in the prior art, has low requirements for industrial reaction equipment, simple reaction operation, higher safety for operators, and low reaction cost.

[0030] (3) In the prior art, the synthesis of the important intermediate of carboxamide triazole, (4-chlorophenyl)(4-(azidomethyl)-2,6-dichlorophenyl)methanone, requires at least six steps of reaction. However, the method of the present invention only needs four steps to complete, with a simpler process, which can significantly save reaction time and further reduce production costs. Description of the Drawings

[0031] Figure 1 It is the nuclear magnetic resonance spectrum of product 1 obtained in Example 1.

[0032] Figure 2 It is the mass spectrum of product 1 obtained in Example 1.

[0033] Figure 3 It is the nuclear magnetic resonance spectrum of product 2 obtained in Example 5.

[0034] Figure 4 It is the mass spectrum of product 2 obtained in Example 5.

[0035] Figure 5 It is the nuclear magnetic resonance spectrum of product 3 obtained from the bromination reaction in Example 9.

[0036] Figure 6 It is the mass spectrum of product 3 obtained from the bromination reaction in Example 9.

[0037] Figure 7 It is the nuclear magnetic resonance spectrum of product 3 obtained from the chlorination reaction in Example 10.

[0038] Figure 8 It is the mass spectrum of product 3 obtained from the chlorination reaction in Example 10.

[0039] Figure 9 It is the nuclear magnetic resonance spectrum of the carboxamide triazole intermediate obtained in Example 11.

[0040] Figure 10 It is the mass spectrum of the carboxamide triazole intermediate obtained in Example 11. Detailed Embodiments

[0041] The accompanying drawings in the embodiments are used to describe the technical solutions in the embodiments of the present invention in more detail. In the drawings, the same or similar reference numerals denote the same or similar elements or elements with the same or similar functions throughout. The described embodiments are some, but not all, of the embodiments of the present invention. The embodiments described below by referring to the accompanying drawings are exemplary and are intended to explain the present invention, and should not be construed as a limitation of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention. The embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

[0042] It should be noted that if there are directional indications (such as up, down, left, right, front, back...) involved in the embodiments of the present application, then such directional indications are only used to explain the relative positional relationship, movement conditions, etc. between components in a specific posture (as shown in the accompanying drawings). If this specific posture changes, then the directional indications will also change accordingly.

[0043] In addition, if there are descriptions involving "first", "second", etc. in the embodiments of the present application, then such descriptions of "first", "second", etc. are only for descriptive purposes and should not be construed as indicating or implying their relative importance or implicitly indicating the quantity of the indicated technical features. Thus, the features defined with "first" and "second" may explicitly or implicitly include at least one such feature. In addition, the technical solutions between various embodiments can be combined with each other, but it must be based on the ability of those of ordinary skill in the art to implement. When the combination of technical solutions results in contradictions or cannot be implemented, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection required by the present application.

[0044] Examples 1 to 4 are specific embodiments of the addition reaction, and the reaction formulas are as follows. Example 1

[0045] Under nitrogen protection, 10 mL of a 1 M ethereal solution of 4-chlorophenylmagnesium bromide was added to a reaction flask, and the temperature was raised to 30 °C. A 5 mL isopropyl ether solution of 1.3 g of 2,6-dichloro-4-methylbenzaldehyde was added dropwise. After the addition was complete, the temperature was further raised to reflux, and after reacting for 3 h, a sample was taken for detection and the in-process control reached the standard. The temperature was lowered to room temperature, and dilute hydrochloric acid was added dropwise while controlling the temperature below 30 °C. After standing, phase separation was carried out. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum concentration. Silica gel column chromatography was used to obtain 1.9 g of a colorless oil.

[0046] The NMR and mass spectrometry data are as Figures 1 - 2 shown, and the data are as follows.

[0047] 1 1H NMR (400 MHz, d6-DMSO) δ 7.35 (dd, 2H), 7.28 (s, 2H), 7.25 (dd, 2H), 6.43 (d, 1H), 6.25 (d, 1H), 2.28 (s, 3H).

[0048] [M + H] + found 301。

[0049] The end product obtained in this example is an oil and can directly participate in the subsequent reaction. Example 2

[0050] Under nitrogen protection, 40 mL of a 1 M solution of 4-chlorophenylmagnesium chloride in tetrahydrofuran was added to the reaction flask, and the temperature was raised to 40 °C. A 10 mL solution of 3.4 g of 2,6-dichloro-4-methylbenzaldehyde in tetrahydrofuran was added dropwise. After the addition was complete, the temperature was further raised to reflux, and after reacting for 2 h, a sample was taken for detection and the in-process control met the standard. The temperature was lowered to room temperature, and dilute hydrochloric acid was added dropwise while controlling the temperature below 30 °C. After standing, the phases were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to remove the solvent. The resulting 5.0 g of oil was used in the next reaction without any further treatment. Example 3

[0051] Under nitrogen protection, 20 mL of a 1 M solution of p-chlorophenylmagnesium bromide in methyltetrahydrofuran was added to the reaction flask, and the temperature was raised to 60 °C. A 10 mL solution of 3.7 g of 2,6-dichloro-4-methylbenzaldehyde in methyltetrahydrofuran was added dropwise. After the addition was complete, the temperature was further raised to reflux, and after reacting for 1 h, a sample was taken for detection and the in-process control met the standard. The temperature was lowered to room temperature, and dilute hydrochloric acid was added dropwise while controlling the temperature below 30 °C. After standing, the phases were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to remove the solvent. The resulting 4.8 g of oil was used in the next reaction without any further treatment. Example 4

[0052] This example is a scale-up experiment of Example 1.

[0053] Under nitrogen protection, 200 mL of a 1 M solution of 4-chlorophenylmagnesium bromide in methyltetrahydrofuran was added to the reaction flask, and the temperature was raised to 50 °C. A 100 mL solution of 31.5 g of 2,6-dichloro-4-methylbenzaldehyde in tetrahydrofuran was added dropwise. After the addition was complete, the temperature was further raised to reflux, and after reacting for 1 h, a sample was taken for detection and the in-process control met the standard. The temperature was lowered to room temperature, and dilute hydrochloric acid was added dropwise while controlling the temperature below 30 °C. After standing, the phases were separated. The aqueous phase was extracted with THF. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to remove the solvent. The resulting 51.2 g of oil was used in the next reaction without any further treatment.

[0054] Examples 5 to 8 are specific embodiments of the oxidation reaction, and the reaction formula is as follows: Example 5

[0055] Add 10 mL of chloroform and 1.5 g of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanol to a reaction flask, stir to dissolve clearly, add 2.1 g of Dess-Martin periodinane, and react at room temperature until the in-process control meets the standard. Filter the system, and wash the filter cake with chloroform. Add saturated sodium thiosulfate solution and saturated sodium carbonate solution to the filtrate, stir for 1 h, let it stand, and separate the phases. Extract the aqueous phase with dichloromethane, combine the organic phases, wash with dilute brine and then dry over anhydrous sodium sulfate, concentrate to remove the solvent, and separate by silica gel column chromatography to obtain 1.4 g of a white solid.

[0056] The NMR and mass spectrometry data are as follows, as Figures 3 - 4 shown.

[0057] 1 H NMR(400MHz,d6-DMSO)δ7.76(dd,2H),7.66(dd,2H),7.50(s,2H),2.40(s,3H).

[0058] [M+H] + found 299。 Example 6

[0059] Add 15 mL of dichloromethane and 4.0 g of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanol to a reaction flask, stir to dissolve clearly, add 5.6 g of 2-iodoxybenzoic acid, and react at room temperature until the in-process control meets the standard. Filter the system, and wash the filter cake with dichloromethane. Add saturated sodium thiosulfate solution and saturated sodium carbonate solution to the filtrate, stir for 1 h, let it stand, and separate the phases. Extract the aqueous phase with dichloromethane, combine the organic phases, wash with dilute brine and then dry over anhydrous sodium sulfate, concentrate to remove the solvent, and recrystallize with ethyl acetate and n-heptane. Dry to obtain 4.0 g of a white solid. Example 7

[0060] Add 30 mL of acetonitrile and 10 g of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanol to a reaction flask, stir to dissolve clearly, add 20.0 g of Dess-Martin periodinane, and react at room temperature until the in-process control meets the standard. Filter the system, and wash the filter cake with acetonitrile. Concentrate under vacuum to remove the solvent, add ethyl acetate, saturated sodium thiosulfate solution and saturated sodium carbonate solution, stir for 1 h, let it stand, and separate the phases. Extract the aqueous phase with ethyl acetate, combine the organic phases, wash with dilute brine and then dry over anhydrous sodium sulfate, concentrate to remove the solvent, and recrystallize with ethyl acetate and n-heptane. Dry to obtain 10.0 g of a white solid. Example 8

[0061] This example is an enlarged test of Examples 5 to 7.

[0062] Add 200 mL of dichloromethane and 50.0 g of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanol to the reaction flask, stir until dissolved and clear, add 77.4 g of Dess-Martin oxidant, and react at room temperature until the in-process control meets the standard. Filter the system, and wash the filter cake with dichloromethane. Add saturated sodium thiosulfate solution and saturated sodium carbonate solution to the filtrate, stir for 1 h, let stand, and separate the phases. Extract the aqueous phase with dichloromethane, combine the organic phases, wash with dilute brine, dry over anhydrous sodium sulfate, concentrate to remove the solvent, and recrystallize with ethyl acetate and n-heptane. Dry to obtain 48.7 g of a white solid. Example 9

[0063] This example is the specific method of the bromination reaction, and the reaction formula is as follows.

[0064]

[0065] Add 10 mL of dichloromethane, 1.0 g of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone, 0.3 g of AIBN, and 0.7 g of NBS to the reaction flask, heat to reflux for 4 hours. Cool to room temperature, and successively add dilute hydrochloric acid, saturated brine, aqueous sodium carbonate solution, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to remove the solvent, and separate by silica gel column to obtain 0.7 g of a white solid.

[0066] The NMR and mass spectrometry data are as follows, as shown in the appendix Figures 5 - 6 as follows.

[0067] 1 H NMR (400 MHz, d6-DMSO) δ 7.79 - 7.77 (m, 4H), 7.67 (m, 2H), 4.76 (s, 2H).

[0068] [M + H3O] + found 397. Example 10

[0069] This example is the specific method of the chlorination reaction, and the reaction formula is as follows.

[0070] Add 10 mL of chloroform and 1.0 g of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone to the reaction flask, heat to reflux, and continuously introduce chlorine gas, with the end absorbed by aqueous sodium hydroxide solution, and react until the in-process control meets the standard. Cool to room temperature, successively add saturated brine, aqueous sodium carbonate solution, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to remove the solvent, and separate by silica gel column to obtain 0.7 g of a white solid.

[0071] The NMR and mass spectrometry data are as follows, and the attached drawings are as Figures 7 - 8 shown:

[0072] 1 H NMR(400MHz,CDCl3)δ7.80 - 7.78(m,2H),7.51 - 7.49(m,4H),4.61(s,2H).

[0073] [M+Na] + found 355. Example 11

[0074] Example 11 is a azidation reaction process, and the reaction formula is as follows:

[0075] 2 mL of dimethyl sulfoxide, 0.5 g of (4 - bromomethyl - 2,6 - dichlorophenyl)(4 - chlorophenyl)methanone and 0.5 g of tetrabutylammonium azide were added to the reaction flask, and stirred until the reaction was complete by in - process control. The reaction solution was transferred into an ice - water mixture. Ethyl acetate was added and stirred, and then allowed to stand for phase separation. The aqueous phase was extracted with ethyl acetate again. The organic phases were combined, washed with brine solution, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and separated by silica gel column to obtain 0.4 g of white solid.

[0076] The NMR and mass spectrometry data are as follows, and the attached drawings are as shown in Figures 9 - 10.

[0077] 1 H NMR(400MHz,CDCl3)δ7.79(d,2H),7.49(d,2H),7.40(s,2H),4.47(s,2H).

[0078] [M+Na] + found 362.

[0079] Examples 12 - 14 are continuous reaction preparation methods of halogenation reaction and azidation reaction, and the reaction formula is as follows: In the reaction formula, X can be any one of halogen elements such as Cl, Br, and I. Example 12

[0080] Add 20 mL of dichloromethane, 5.0 g of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone, 1.1 g of AIBN, and 3.5 g of diiodohydantoin to the reaction flask. Heat to reflux and react until the in-process control meets the standard. Cool to room temperature, successively add dilute hydrochloric acid and saturated brine for washing. Add anhydrous sodium sulfate and sodium carbonate, mix and stir for 1 hour, then filter and concentrate to remove the solvent. When the internal temperature drops to room temperature, add 15 mL of dimethyl sulfoxide and 4.0 g of tetrabutylammonium azide, and stir until the in-process reaction is complete. Transfer the reaction solution to an ice-water mixture. Add ethyl acetate and stir, let it stand for phase separation, and extract the aqueous phase with ethyl acetate again. Combine the organic phases, wash with brine solution, dry with anhydrous sodium sulfate, concentrate to remove the solvent, and separate by silica gel column to obtain 3.6 g of white solid. Example 13

[0081] Add 30 mL of dichloromethane, 10.0 g of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone, 2.8 g of AIBN, and 5.4 g of NCS to the reaction flask. Heat to reflux and react until the in-process control meets the standard. Cool to room temperature, successively add dilute hydrochloric acid and saturated brine for washing. Add anhydrous sodium sulfate and sodium carbonate, mix and stir for 1 hour, then filter and concentrate to remove the solvent. When the internal temperature drops to room temperature, add 40 mL of dimethyl sulfoxide and 2.7 g of potassium azide, and stir until the in-process reaction is complete. Transfer the reaction solution to an ice-water mixture. Add ethyl acetate and stir, let it stand for phase separation, and extract the aqueous phase with ethyl acetate again. Combine the organic phases, wash with brine solution, dry with anhydrous sodium sulfate, concentrate to remove the solvent, and recrystallize with n-heptane and methyl tert-butyl ether. Filter and dry to obtain 8.5 g of white solid. Example 14

[0082] This example is the scale-up experiment of Examples 12 - 13.

[0083] Add 150 mL of dichloromethane, 50.0 g of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone, 14.0 g of AIBN, and 27.0 g of NCS to the reaction flask. Heat to reflux and react until the in-process control meets the standard. Cool to room temperature, successively add dilute hydrochloric acid and saturated brine for washing. Add anhydrous sodium sulfate and sodium carbonate, mix and stir for 1 hour, then filter and concentrate to remove the solvent. When the internal temperature drops to room temperature, add 200 mL of dimethyl sulfoxide and 12.0 g of sodium azide, and stir until the in-process reaction is complete. Transfer the reaction solution to an ice-water mixture. Add ethyl acetate and stir, let it stand for phase separation, and extract the aqueous phase with ethyl acetate again. Combine the organic phases, wash with brine solution, dry with anhydrous sodium sulfate, concentrate to remove the solvent, and recrystallize with n-heptane and methyl tert-butyl ether. Filter and dry to obtain 40.1 g of white solid.

[0084] The above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the above preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention. Those skilled in the art can also make other changes within the spirit of the present invention for use in the design of the present invention, as long as they do not deviate from the technical effects of the present invention. All such changes made in accordance with the spirit of the present invention should be included within the scope of protection required by the present invention.

Claims

1. A method for preparing (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone, characterized in that, It includes the following steps: S1: Addition reaction: The 2,6-dichloro-4-methylbenzaldehyde introduces a p-chlorophenyl group through a Grignard reaction to obtain Product 1: (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanol; S2: Oxidation reaction: Add the Product 1 to an oxidizing agent for reaction to generate Product 2: (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone.

2. The preparation method according to claim 1, wherein, In the step S1, the Grignard reagent is at least one of p-chlorophenylmagnesium bromide and p-chlorophenylmagnesium chloride.

3. The preparation method according to claim 1, characterized in that, In the step S1, the molar ratio of the 2,6-dichloro-4-methylbenzaldehyde to the Grignard reagent is 1:1.0 - 2.

2.

4. The preparation method according to claim 1, wherein In the step S1, the reaction solvent for the addition reaction is at least one of ether, tetrahydrofuran, methyltetrahydrofuran, and isopropyl ether; the reaction temperature is 30 - 60 °C.

5. The preparation method according to claim 1, wherein In the step S2, the oxidizing agent is Dess-Martin periodinane and / or 2-iodoxybenzoic acid.

6. The preparation method according to claim 1, wherein In the step S2, the molar ratio of the Product 1 to the oxidizing agent is: 1:1.0 - 1.

5.

7. The preparation method according to claim 1, wherein In the step S2, the reaction solvent for the oxidation reaction is at least one of chloroform, dichloromethane, and acetonitrile.

8. A novel preparation method of a carboxamido triazole intermediate comprising the preparation method according to any one of claims 1 - 7, wherein the carboxamido triazole intermediate is (4-chlorophenyl)(4-(azidomethyl)-2,6-dichlorophenyl)methanone.

9. The novel preparation method according to claim 8, characterized in that, It further includes the following steps: S3: Halogenation reaction: Add a halogenating agent to the Product 2 for reaction to generate Product 3: (4-X-methyl-2,6-dichlorophenyl)(4-chlorophenyl)methanone; X is chlorine or bromine or iodine; It further includes a step of azidation reaction: The azidation reaction and the step S3 are carried out in a stepwise reaction or a continuous addition reaction; The steps of the stepwise reaction are as follows: Add an azidation reagent to the Product 3 for reaction to generate the carboxamido triazole intermediate (4-chlorophenyl)(4-(azidomethyl)-2,6-dichlorophenyl)methanone; The steps of the continuous addition reaction are as follows: Add an azidation reagent to the treatment solution of the step S3 for reaction to generate the carboxamido triazole intermediate (4-chlorophenyl)(4-(azidomethyl)-2,6-dichlorophenyl)methanone.

10. The preparation method according to claim 9, wherein, In the step S3, the halogenating agent is prepared by reacting with a brominating agent or a chlorinating agent or an iodinating agent.

11. The preparation method according to claim 9, wherein The step S3 further includes a step of adding a catalyst azo initiator; the azo initiator is AIBN.

12. The preparation method according to claim 9, wherein The brominating agent is at least one of NBS, bromine, bromoacetamide, and dibromohydantoin; the chlorinating agent is at least one of NCS, chlorine, dichlorohydantoin, and sodium dichloroisocyanurate; the iodinating agent is at least one of NIS, iodine, and diiodohydantoin.

13. The preparation method according to claim 11, characterized in that, In the step S3, the molar ratio of the Product 2 to the azo initiator is 1:0.4 - 0.6; the molar ratio of the Product 2 to the brominating agent or the chlorinating agent or the iodinating agent is 1:0.6 - 1.

5.

14. The preparation method according to claim 9, wherein, In the azidation reaction step, the azidation reagent is tetrabutylammonium azide and / or potassium azide and / or sodium azide.

15. The preparation method according to claim 9, wherein In the stepwise reaction, the molar ratio of the Product 3 to the azidation reagent is 1:1.0 - 1.

5.

16. The preparation method according to claim 9, wherein, In the consecutive reaction, the molar ratio of the product 2 to the azide reagent is 1:0.8 to 1.5.

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