Novel preparation method of (4-chlorophenyl) (2, 6-dichloro-4-methylphenyl) ketone and carboxamide triazole intermediates

Abstract

The invention discloses a preparation method of (4chlorphenyl) (2, 6-dichloro-4-methyl phenyl) ketone, which comprises the following steps: sequentially carrying out halogenation reaction on 2, 5-dichloro-4-methyl benzoic acid to generate 2, 5-dichloro-4-methyl benzoyl chloride; and 2, 5-dichloro-4-methyl benzoyl chloride is subjected to a Friedel-Crafts reaction, such that the 2, 5-dichloro-4-methyl benzoyl chloride is obtained. The reaction does not need to use a butyl lithium reagent, and the whole reaction route does not have any low-temperature reaction, so that the requirement on production equipment is low. And the Friedel-Crafts reaction is a common classical reaction in production, the conditions are mild, butyl lithium is not needed, and the Grignard reagent is operated under anhydrous and anaerobic conditions. Meanwhile, highly toxic products such as sodium azide and potassium azide do not need to be used, a photochemical reaction or a heating reaction is used, a composition of 1-hydroxy-1, 2-phenyliodone-3 (1H)-ketone and azido trimethylsilane is used as an auxiliary, an azido group is directly connected to methyl, the reaction steps are few, and aftertreatment is simple.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technologies, and specifically relates to a new preparation method for (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone and carboxyamidotriazole intermediates. Background Art

[0002] The synthesis of (4-chlorophenyl)(4-(azidomethyl)-2,6-dichlorophenyl)methanone, an important intermediate of carboxyamidotriazole, can be prepared from (4-chlorophenyl)-[2,6-dichloro-4-(hydroxymethyl)phenyl]-methanone through chlorination and azidation reactions. The reaction formula is as follows:

[0003]

[0004] The following problems exist in this reaction: (4-chlorophenyl)-[2,6-dichloro-4-(hydroxymethyl)phenyl]-methanone is prepared from 3,5-dichlorobenzoyl chloride. The reaction formula is as follows:

[0005]

[0006] In the above reaction, the hydroxyl group of 3,5-dichlorobenzyl alcohol is protected by tert-butyldimethylchlorosilane, then deprotonated by butyllithium and coupled with p-chlorobenzoyl chloride, and finally deprotected by concentrated hydrochloric acid to obtain the product. When deprotonating, butyllithium reagent is required. Since the butyllithium reagent has very high activity, a lot of impurities will be generated during the reaction process. Moreover, the butyllithium reagent itself has a short shelf life, cannot contact air and water, and 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. And this reaction needs to first deprotonate with butyllithium at -80°C 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 required during the cooling process, and the leakage of liquid nitrogen has a suffocating production risk; 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.

[0007] Sodium azide is used in the azidation reaction. It is a highly toxic and dangerous chemical, and its purchase and use are strictly regulated, which restricts the amplification of the production capacity of the existing technology process to a certain extent;

[0008] Comprehensively analyzed, the reaction steps of the existing technology are numerous, the operation is more complex, and the industrialization cost is high. Summary of the Invention

[0009] The present invention aims to overcome at least one defect of the above-mentioned prior art, and provides a preparation method of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone and a preparation method of carboxamide triazole intermediate (4-chlorophenyl)(4-(azidomethyl)-2,6-dichlorophenyl)methanone comprising the said method.

[0010] Specifically, the present invention provides a preparation method of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone, which is prepared by successively carrying out a halogenation reaction on 2,5-dichloro-4-methylbenzoic acid to generate 2,5-dichloro-4-methylbenzoyl chloride, and then preparing the product by Friedel-Crafts reaction from 2,5-dichloro-4-methylbenzoyl chloride.

[0011] Preferably, the halogenation reaction is a reaction of 2,5-dichloro-4-methylbenzoic acid with a chlorinating agent, and the chlorinating agent is one or more of thionyl chloride and oxalyl chloride.

[0012] Preferably, the reaction solvent for the halogenation reaction is one or more of thionyl chloride, tetrahydrofuran, dichloromethane, chlorobenzene, chloroform, carbon tetrachloride, dichloroethane, methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, and diethyl ether. Adding or equivalently replacing relevant reaction solvents on the basis of this application are all within the protection scope of this application.

[0013] Further, the halogenation reaction further includes a step of adding a catalyst, and the catalyst is N,N-dimethylformamide.

[0014] Further, the Friedel-Crafts reaction is to prepare the product by reacting 2,5-dichloro-4-methylbenzoyl chloride with chlorobenzene.

[0015] Further, the Friedel-Crafts reaction further includes a step of adding a catalyst, and the catalyst is a Lewis acid.

[0016] Further, the Lewis acid is at least one of anhydrous aluminum chloride and anhydrous ferric chloride.

[0017] The present invention also provides a new method for further preparing a carboxamide triazole intermediate from the (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone prepared by the above preparation method, and the carboxamide triazole intermediate is (4-chlorophenyl)(4-(azidomethyl)-2,6-dichlorophenyl)methanone.

[0018] Preferably, the carboxamide triazole intermediate is prepared by a photochemical reaction of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone with 1-hydroxy-1,2-benziodoxol-3(1H)-one and trimethylsilyl azide.

[0019] Further, the photochemical reaction further includes a step of adding a catalyst, and the catalyst is at least one of tris(bipyridine)ruthenium(II) chloride and copper(II) chloride(dap)2.

[0020] Preferably, the molar ratio of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone to 1-hydroxy-1,2-benziodoxol-3(1H)-one is 1:1.0 to 1.4.

[0021] Preferably, the molar ratio of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone to 1-hydroxy-1,2-benziodoxol-3(1H)-one is 1:1.0 to 1.1.

[0022] Preferably, the molar ratio of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone to trimethylsilyl azide is 1:2.0 to 3.0.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] The reaction of the present invention does not require the use of butyllithium reagent, and there is no low-temperature reaction in the whole reaction route, so the requirements for production equipment are low. Moreover, the Friedel-Crafts reaction of the present invention is a classic reaction commonly used in production, with mild conditions and does not require anhydrous and anaerobic conditions like butyllithium and Grignard reagents. At the same time, this application does not need to use highly toxic substances such as sodium azide and potassium azide. With the assistance of the combination of 1-hydroxy-1,2-benziodoxol-3(1H)-one and trimethylsilyl azide through photochemical reaction or heating reaction, the azide group is directly introduced onto the methyl group, with fewer reaction steps and simple post-treatment. Description of the Drawings

[0025] Figure 1 It is the NMR spectrum of the product of Example 5.

[0026] Figure 2 It is the mass spectrum of the product of Example 5.

[0027] Figure 3 It is the NMR spectrum of the product of Example 9.

[0028] Figure 4 It is the mass spectrum of the product of Example 9. Detailed Embodiments

[0029] 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 represent the same or similar elements or elements with the same or similar functions from beginning to end. The described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. 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 to 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.

[0030] It should be noted that if there are directional indications (such as up, down, left, right, front, back...) involved in the embodiments of this application, then such directional indications are only used to explain the relative positional relationship and movement conditions between components in a certain specific posture (as shown in the accompanying drawings). If this specific posture changes, then the directional indications will also change accordingly.

[0031] In addition, if there are descriptions involving "first", "second", etc. in the embodiments of this 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 this application.

[0032] Examples 1 to 4 provide a method for synthesizing 2,5-dichloro-4-methylbenzoyl chloride, and the reaction formula is as follows: Example 1

[0033] Add 1.0 g of 2,5-dichloro-4-methylbenzoic acid and 18 mL of thionyl chloride to the reaction flask, stir until dissolved and clear, add 0.05 g of N,N-dimethylformamide, heat to 60 °C, and keep the reaction until the middle control reaches the standard. Concentrate under reduced pressure to remove the solvent, cool, and obtain 1.0 g of a light yellow oily substance. Example 2

[0034] This example is a synthesis process without adding the catalyst N,N-dimethylformamide.

[0035] Add 5.0 g of 2,5-dichloro-4-methylbenzoic acid, 50 mL of dichloromethane, and 5.0 g of oxalyl chloride to a reaction flask. Stir to dissolve and clarify, heat to reflux, and keep the reaction at a constant temperature until the in-process control meets the standard. Concentrate under reduced pressure to remove the solvent, and cool to obtain 4.5 g of a pale yellow oily substance. Example 3

[0036] Add 25.0 g of 2,5-dichloro-4-methylbenzoic acid, 100 mL of anhydrous tetrahydrofuran, and 21.7 g of oxalyl chloride to a reaction flask. Stir to dissolve and clarify, add a few drops of N,N-dimethylformamide, heat to 60 °C, and keep the reaction at a constant temperature until the in-process control meets the standard. Concentrate under reduced pressure to remove the solvent, and cool to obtain 25.6 g of a pale yellow oily substance. Example 4

[0037] This example is the scale-up synthesis process of 2,5-dichloro-4-methylbenzoyl chloride.

[0038] Add 200.0 g of 2,5-dichloro-4-methylbenzoic acid and 500 mL of thionyl chloride to a reaction flask. Stir to dissolve and clarify, add 7.0 g of N,N-dimethylformamide, heat to 60 °C, and keep the reaction at a constant temperature until the in-process control meets the standard. Concentrate under reduced pressure to remove the solvent, and cool to obtain 211.3 g of a yellow oily substance.

[0039] Examples 5 to 8 provide the synthesis process of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone from 2,5-dichloro-4-methylbenzoyl chloride. The route map is as follows:

[0040] Example 5

[0041] Add 1.0 g of 2,5-dichloro-4-methylbenzoyl chloride and 10 mL of chlorobenzene to a reaction flask. After stirring to dissolve and clarify, add 0.9 g of anhydrous ferric chloride, heat to reflux, react until the in-process control meets the standard, cool to 0 - 10 °C, add water, extract with ethyl acetate, concentrate to remove the solvent, and purify by column chromatography to obtain 0.9 g of an off-white solid.

[0042] The NMR and mass spectrometry data are as follows:

[0043] 1 H NMR (400 MHz, d6-DMSO) δ 7.76 (dd, 2H), 7.65 (dd, 2H), 7.49 (s, 2H), 2.39 (s, 3H).

[0044] [M + H] + found 301. Example 6

[0045] Add 1.0 g of 2,5-dichloro-4-methylbenzoyl chloride and 10 mL of chlorobenzene to a reaction flask. After stirring until clear, add 0.65 g of anhydrous aluminum chloride. Heat to reflux and react until the in-process control meets the standard. Cool to 0 - 10 °C, add dilute hydrochloric acid aqueous solution, extract with ethyl acetate, add anhydrous sodium sulfate, concentrate to remove the solvent, purify by column chromatography, and obtain 1.1 g of white solid. Example 7

[0046] Add 10.0 g of 2,5-dichloro-4-methylbenzoyl chloride and 50 mL of chlorobenzene to a reaction flask. After stirring until clear, add 9.0 g of anhydrous aluminum chloride. Heat to reflux and react until the in-process control meets the standard. Cool to 0 - 10 °C, add dilute hydrochloric acid aqueous solution, extract with ethyl acetate, add anhydrous sodium sulfate, concentrate to remove the solvent, recrystallize with ethyl acetate and petroleum ether, and obtain 10.3 g of off-white solid. Example 8

[0047] Example 8 is the scale-up synthesis process of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone.

[0048] Add 50.0 g of 2,5-dichloro-4-methylbenzoyl chloride and 200 mL of chlorobenzene to a reaction flask. After stirring until clear, add 40.0 g of anhydrous aluminum chloride. Heat to reflux and react until the in-process control meets the standard. Cool to 0 - 10 °C, add dilute hydrochloric acid aqueous solution, extract with ethyl acetate, add anhydrous sodium sulfate, concentrate to remove the solvent, recrystallize with ethyl acetate and petroleum ether, and obtain 53.8 g of off-white solid.

[0049] Examples 9 - 11 are the preparation methods of carboxyamidotriazole intermediates, and the process route is as follows:

[0050] Example 9

[0051] Add 5 mL of acetonitrile, 1.05 g of 1-hydroxy-1,2-benziodoxol-3(1H)-one, and 0.93 of trimethylsilyl azide to a reaction flask. Stir at room temperature until 1-hydroxy-1,2-benziodoxol-3(1H)-one disappears. Add 0.01 g of copper(II) chloride (dap) and 1.0 g of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone, and react under fluorescent lamp irradiation until the in-process control meets the standard. Concentrate and pass through a column to obtain 0.78 g of white solid.

[0052] The NMR and mass spectrometry data are as follows:

[0053] 1 H NMR(400MHz,d6-DMSO)δ7.77(d, 2H), 7.67(s, 2H), 7.65(d, 2H), 4.62(s,2H).

[0054] [M + H] + found 341. Example 10

[0055] Add 5 mL of acetonitrile, 1.22 g of 1-hydroxy-1,2-benziodoxol-3(1H)-one, and 1.15 g of trimethylsilyl azide into the reaction flask. Stir at room temperature until 1-hydroxy-1,2-benziodoxol-3(1H)-one disappears. Then add 0.01 g of tris(bipyridine)ruthenium(II) chloride and 1.0 g of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone. React under fluorescent lamp irradiation until the in-process control meets the standard. Concentrate and pass through a column to obtain 0.84 g of white solid. Example 11

[0056] Add 25 mL of acetonitrile, 5.2 g of 1-hydroxy-1,2-benziodoxol-3(1H)-one, and 4.8 g of trimethylsilyl azide into the reaction flask. Stir at room temperature until 1-hydroxy-1,2-benziodoxol-3(1H)-one disappears. Concentrate to dryness. Add 30 mL of acetonitrile, 0.05 g of tris(bipyridine)ruthenium(II) chloride and 5.0 g of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone. React under fluorescent lamp irradiation until the in-process control meets the standard. Concentrate and replace the solvent with ethyl acetate. Wash successively with aqueous sodium bicarbonate solution and dilute brine, then dry over anhydrous sodium sulfate. Recrystallize with n-heptane and methyl tert-butyl ether. Filter and dry to obtain 4.1 g of off-white solid.

[0057] The above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit them. 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. These changes made in accordance with the spirit of the present invention should all be included within the scope claimed by the present invention.

Claims

1. A new preparation method of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone, characterized in that, 2,5-Dichloro-4-methylbenzoyl chloride is generated from 2,5-dichloro-4-methylbenzoic acid through a halogenation reaction; and then it is prepared from 2,5-dichloro-4-methylbenzoyl chloride through a Friedel-Crafts reaction.

2. The new preparation method according to claim 1, characterized in that, The halogenation reaction is the reaction of 2,5-dichloro-4-methylbenzoic acid with a chlorinating agent, and the chlorinating agent is one or more of thionyl chloride and oxalyl chloride.

3. The new preparation method according to claim 1, characterized in that, The reaction solvent for the halogenation reaction is one or more of thionyl chloride, tetrahydrofuran, dichloromethane, chlorobenzene, chloroform, carbon tetrachloride, dichloroethane, methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, and diethyl ether.

4. The new preparation method according to claim 1, characterized in that, The halogenation reaction further includes a step of adding a catalyst, and the catalyst is N,N-dimethylformamide.

5. According to the new preparation method described in claim 1, it is characterized in that, The Friedel-Crafts reaction is the reaction of 2,5-dichloro-4-methylbenzoyl chloride with chlorobenzene to obtain the product.

6. The new preparation method according to claim 1, characterized in that, The Friedel-Crafts reaction further includes a step of adding a catalyst, and the catalyst is a Lewis acid.

7. The new preparation method according to claim 6, characterized in that, The Lewis acid is at least one of anhydrous aluminum chloride and anhydrous ferric chloride.

8. A new method for further preparing a carboxamido triazole intermediate from (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone prepared by the preparation method according to any one of claims 1 to 7, and the carboxamido triazole intermediate is (4-chlorophenyl)(4-(azidomethyl)-2,6-dichlorophenyl)methanone.

9. The new method according to claim 8, characterized in that, The carboxamido triazole intermediate is prepared from (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone, 1-hydroxy-1,2-benziodoxol-3(1H)-one, and trimethylsilyl azide through a photochemical reaction.

10. The new method according to claim 9, characterized in that, The photochemical reaction further includes a step of adding a catalyst, and the catalyst is at least one of tris(bipyridine)ruthenium(II) chloride and copper(II) chloride(dap)2.

11. The new method according to claim 9, characterized in that, The molar ratio of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone to 1-hydroxy-1,2-benziodoxol-3(1H)-one is 1:1.0 to 1.

4.

12. The new method according to claim 11, characterized in that, The molar ratio of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone to 1-hydroxy-1,2-benziodoxol-3(1H)-one is 1:1.0 to 1.

1.

13. The new method according to claim 11, wherein The molar ratio of (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone to trimethylsilyl azide is 1:2.0 to 3.0.

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