Synthesis method of compound 3-chloro-2, 6-difluorobenzene sulfonyl chloride

Abstract

The invention discloses a synthesis method of 3-chloro-2, 6-difluorobenzene sulfonyl chloride, which comprises the following steps: taking cheap and easily available 2, 4-difluorochlorobenzene as a raw material, and carrying out one-step reaction to obtain the target product 3-chloro-2, 6-difluorobenzene sulfonyl chloride. The synthesis method has the advantages of short steps, low cost, relatively mild reaction conditions, simple post-treatment and high product yield.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing a compound 3-chloro-2,6-difluorobenzenesulfonyl chloride. Background Art

[0002] Halogenated benzenesulfonyl chloride compounds are an important class of organic compounds with wide applications in the fields of life sciences, medicine, chemistry, etc. For example, in patent WO2017 / 201468, compounds 5-chloro-2,4-difluorobenzenesulfonyl chloride and 3-chloro-2,4-difluorobenzenesulfonyl chloride are used as key intermediates in the synthesis of benzenesulfonamide compounds, which are used as therapeutic agents for treating diseases or conditions related to voltage-gated sodium channels, such as epilepsy; in patent CN112759559A, compound 5-chloro-2,4-difluorobenzenesulfonyl chloride is used as a key intermediate in the synthesis of sulfonamide compounds, which are sodium channel blockers with dual inhibitory activity against Nav1.7 and Nav1.3, and can be used as drugs for the treatment of a wide range of pain such as neuropathic pain or inflammatory pain.

[0003] In view of the economic potential of halogenated benzenesulfonyl chloride compounds in drug synthesis, the compound 3-chloro-2,6-difluorobenzenesulfonyl chloride, as one of the compounds, also has high economic efficiency. Therefore, the synthesis method of the compound 3-chloro-2,6-difluorobenzenesulfonyl chloride needs further study. Summary of the invention

[0004] In view of the fact that there is no synthesis method of 3-chloro-2,6-difluorobenzenesulfonyl chloride in the above-mentioned prior art, the purpose of the present invention is to provide a synthesis method of 3-chloro-2,6-difluorobenzenesulfonyl chloride, the whole synthesis process is low in cost, short in steps, relatively mild in reaction conditions, and ideal in yield.

[0005] In order to achieve the above object, the present invention provides the following technical solutions:

[0006] A method for synthesizing 3-chloro-2,6-difluorobenzenesulfonyl chloride. The method uses 2,4-difluorochlorobenzene as a raw material and obtains the target product 3-chloro-2,6-difluorobenzenesulfonyl chloride through a one-step reaction.

[0007] The synthetic route of the 3-chloro-2,6-difluorobenzenesulfonyl chloride is as follows:

[0008]

[0009] Specifically, the synthesis method comprises the following steps:

[0010] (1) Adding the raw material compound 1, i.e., 2,4-difluorochlorobenzene, to the organic solvent I, and adding dropwise an n-butyl lithium solution at a low temperature of -80°C to -50°C under the protection of an inert gas;

[0011] (2) After the dropwise addition is completed, react at -80°C to -50°C for 15-30 minutes, and then introduce sulfur dioxide gas into the mixed solution until the pH value of the reaction system reaches 1-3;

[0012] (3) Concentrating to remove the solvent at 5-15°C;

[0013] (4) then adding organic solvent II, adding N-chlorosuccinimide at -5°C to 5°C, and reacting for 15-30 minutes;

[0014] (5) After the reaction is completed, the reaction solution is post-treated to obtain the target compound 2, namely 3-chloro-2,6-difluorobenzenesulfonyl chloride.

[0015] Further, in step (1), the organic solvent I comprises one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether or toluene.

[0016] Furthermore, in step (1), the inert gas is one or more of nitrogen or argon.

[0017] Furthermore, in step (4), the organic solvent II includes one or more of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or toluene.

[0018] Furthermore, in step (1), the mass volume ratio of the compound 1 to the organic solvent I is 1:5-40 g / mL.

[0019] Furthermore, in step (1), the molar ratio of compound 1 to n-butyl lithium is 1.00:(1.00-1.50).

[0020] Furthermore, in step (4), the molar ratio of compound 1 to N-chlorosuccinimide is 1.00:(1.00-1.50).

[0021] Furthermore, in step (5), the post-treatment is to add silica gel to the reaction solution, filter through diatomaceous earth, wash the filter cake with organic solvent III, collect the filtrate, spin dry to obtain a crude product, purify the crude product to obtain the target compound 2, namely 3-chloro-2,6-difluorobenzenesulfonyl chloride.

[0022] Furthermore, in step (5), the purification method includes one or more of column chromatography or distillation.

[0023] Furthermore, in step (5), the organic solvent III includes one or more of diethyl ether, methyl tert-butyl ether or petroleum ether.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The invention provides a preparation method of 3-chloro-2,6-difluorobenzenesulfonyl chloride, which uses cheap and readily available 2,4-difluorochlorobenzene as a raw material, and obtains the target product 3-chloro-2,6-difluorobenzenesulfonyl chloride by a one-step reaction. The synthesis method has the advantages of short steps, low cost, relatively mild reaction conditions, simple post-treatment, high product yield, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the H NMR spectrum of the target product 3-chloro-2,6-difluorobenzenesulfonyl chloride in Example 1. DETAILED DESCRIPTION

[0027] In order to make the technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0028] The following example provides a method for synthesizing a compound 3-chloro-2,6-difluorobenzenesulfonyl chloride, using 2,4-difluorochlorobenzene as a raw material, and obtaining the target product 3-chloro-2,6-difluorobenzenesulfonyl chloride by a one-step reaction. The synthetic route is as follows:

[0029]

[0030] The present invention will be further described below by means of specific examples.

[0031] Example 1

[0032] In this example, the compound 3-chloro-2,6-difluorobenzenesulfonyl chloride was synthesized by the following steps:

[0033] (1) Add the raw material 1, 2,4-difluorochlorobenzene (200.00 g, 1.35 mol, 1.0 eq) to anhydrous tetrahydrofuran (2.0 L), and add n-butyl lithium solution (538.59 mL, 1.35 mol, 1.00 eq, 2.5 M in Hexane) dropwise at -60°C under the protection of inert gas nitrogen. After the addition is complete, react at -60°C for 20 minutes, and the solution turns into a white emulsion. Pass sulfur dioxide gas into the mixed solution until the reaction system is acidic and the pH is about 2. Concentrate and remove the solvent at about 10°C, then add diethyl ether (2.0 L), and add N-chlorosuccinimide (179.80 g, 1.35 mol, 1.0 eq) at 0°C, and react for 15 minutes.

[0034] (2) After the reaction is completed, silica gel (200 g) is added to the reaction solution, and the mixture is filtered through diatomaceous earth. The filter cake is washed with methyl tert-butyl ether (5.0 L), and the filtrate is collected and spin-dried to obtain a crude product. The crude product is purified by column chromatography (eluent: petroleum ether) to obtain the target compound 2, i.e., 3-chloro-2,6-difluorobenzenesulfonyl chloride (light yellow liquid, weight 321.30 g, purity 98%, yield 95%).

[0035] The H NMR spectrum of the obtained compound 3-chloro-2,6-difluorobenzenesulfonyl chloride is as follows Figure 1 The obtained characterization data are as follows:

[0036] 1 H NMR (400MHz, cdcl3) δ7.77 (ddd, J=9.1, 7.6, 5.2Hz, 1H), 7.13 (td, J=9.2, 2.0Hz, 1H).

[0037] Embodiment 2-5

[0038] Examples 2-5 are the same as Example 1, except that the amount of n-butyl lithium, the amount of N-chlorosuccinimide (NCS), organic solvent I, organic solvent II, etc. used in step (1) are adjusted, as shown in Table 1.

[0039] Through Examples 1-5, the effects of various reaction conditions on the reaction yield in the synthesis of Compound 2 (3-chloro-2,6-difluorobenzenesulfonyl chloride) were verified. The results are shown in Table 1.

[0040] Table 1: Synthesis conditions and results of the examples

[0041]

[0042] Combined with Table 1, we can see that:

[0043] Comparing Example 1-2, when the molar ratio of raw material 1 to n-butyl lithium is 1:1, the reaction effect is already better.

[0044] Comparing Examples 1 and 3, when the molar ratio of raw material 1 to N-chlorosuccinimide is 1:1, the reaction effect is already better.

[0045] Comparing Examples 1 and 4, when the organic solvent I is tetrahydrofuran, the reaction effect is better.

[0046] Comparing Examples 1 and 5, when the organic solvent II is ether, the reaction effect is better.

[0047] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit it. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for synthesizing a compound 3-chloro-2,6-difluorobenzenesulfonyl chloride, characterized in that: Its synthetic route is as follows:

2. The method for synthesizing the compound 3-chloro-2,6-difluorobenzenesulfonyl chloride according to claim 1, characterized in that: It includes the following steps: (1) Adding the raw material compound 1, i.e., compound 2,4-difluorochlorobenzene, to an organic solvent I, and adding dropwise an n-butyl lithium solution at a low temperature of -80°C to -50°C under the protection of an inert gas; (2) After the dropwise addition is completed, react at -80°C to -50°C for 15-30 minutes, and then introduce sulfur dioxide gas into the mixed solution until the pH value of the reaction system reaches 1-3; (3) then spin-drying or concentrating under reduced pressure at 5-15°C to remove the solvent; (4) adding organic solvent II, adding N-chlorosuccinimide at -5°C to 5°C, and reacting for 15-30 minutes; (5) After the reaction is completed, the reaction solution is post-treated to obtain the target compound 2, namely 3-chloro-2,6-difluorobenzenesulfonyl chloride.

3. The method for synthesizing 3-chloro-2,6-difluorobenzenesulfonyl chloride according to claim 2, characterized in that: In step (1), the organic solvent I comprises one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether or toluene.

4. The method for synthesizing the compound 3-chloro-2,6-difluorobenzenesulfonyl chloride according to claim 2, characterized in that: In step (4), the organic solvent II includes one or more of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or toluene.

5. The method for synthesizing the compound 3-chloro-2,6-difluorobenzenesulfonyl chloride according to claim 2, characterized in that: In step (1), The mass volume ratio of compound 1 to organic solvent I is 1:(5-40) g / mL; The molar ratio of compound 1 to n-butyl lithium is 1.00:(1.00-1.50); The molar ratio of compound 1 to N-chlorosuccinimide is 1.00:(1.00-1.50).

6. The method for synthesizing the compound 3-chloro-2,6-difluorobenzenesulfonyl chloride according to claim 2, characterized in that: In step (5), the post-treatment is to add silica gel to the reaction solution, filter through diatomaceous earth, wash the filter cake with organic solvent III, collect the filtrate, spin dry to obtain a crude product, and purify the crude product to obtain the target compound 2, namely 3-chloro-2,6-difluorobenzenesulfonyl chloride.

7. The method for synthesizing the compound 3-chloro-2,6-difluorobenzenesulfonyl chloride according to claim 6, characterized in that: In step (5), the purification method includes one or more of column chromatography and distillation.

8. The method for synthesizing the compound 3-chloro-2,6-difluorobenzenesulfonyl chloride according to claim 6, characterized in that: The organic solvent III includes one or more of diethyl ether, methyl tert-butyl ether or petroleum ether.

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