A process for the synthesis of 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide

Abstract

The application discloses a synthesis method of 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide, which comprises the following steps: reacting an azido trimethylsilane compound shown in formula V with an oxidant in a solvent in the presence of a catalyst and a ligand to prepare a target product, wherein the catalyst is selected from the combination of one or more of MnCl2, manganese acetylacetone Mn(acac)2, manganese acetate Mn(OAc)2, MnBr2, MnCO3, MnF2, Mn2(CO) 10 10)CoCl2 and cobalt acetylacetone Co(acac)2. The synthesis method has the advantages of short reaction route, mild reaction condition, fast reaction rate, short reaction time, high yield, high product purity, green environmental protection, and low cost.

Description

Technical Field

[0001] This invention relates to a method for synthesizing 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide. Background Technology

[0002] Vismodegib (trade name: Erivedge) is a novel anti-tumor drug developed by Genentech Inc. and approved by the U.S. Food and Drug Administration (FDA) on January 30, 2012, for the treatment of advanced basal cell carcinoma (BCC) of the skin. Vismodegib is the first oral, highly selective small molecule inhibitor of the Hedgehog pathway, primarily used to treat patients with locally advanced basal cell carcinoma that is no longer treatable by surgery or chemotherapy, or whose basal cell carcinoma has spread to other organs. Since October 2012, Erivedge has been approved in the European Union, Switzerland, Australia, Israel, South Korea, Mexico, and Ecuador.

[0003] Vimodil (CAS No.: 879085-55-9), Chinese name: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide, English name: 2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide. Its structural formula is shown below:

[0004]

[0005] The main synthetic methods for preparing Vismodegib are as follows:

[0006] 1. The original patent WO2006028958A1 uses synthetic route 1 (as shown below) to prepare vemodigine. This route uses 3-halogen-4-chloronitrobenzene and 2-halogenpyridine as raw materials. First, 2-halogenpyridine is reacted with ZnCl2 and n-butyllithium to prepare an organozinc reagent. This reagent is then coupled with a palladium-catalyzed reaction to prepare 2-(2-chloro-5-nitrophenyl)pyridine. The nitro group is then reduced to an amino group via a reduction reaction, and finally, a condensation reaction is performed to obtain vemodigine. This synthetic route involves the preparation of an organozinc reagent. This step requires strictly anhydrous and oxygen-free reaction conditions, and the n-butyllithium used is flammable and explosive, making it dangerous for industrial production and difficult to scale up.

[0007]

[0008] 2. Chinese patent CN103910671A describes a palladium-catalyzed coupling reaction between 2-chloro-5-nitrochlorobenzene and pyridine-N-oxide to generate 2-(2-chloro-5-nitrophenyl)pyridine-N-oxide. This oxide is then deoxygenated and reduced by phosphorus oxychloride to obtain 2-(2-chloro-5-nitrophenyl)pyridine. The nitro group is then reduced with iron powder to generate 2-(2-chloro-5-aminophenyl)pyridine. Finally, it undergoes an amidation reaction with 2-chloro-4-methylsulfonylbenzoyl chloride to obtain vemodigine (reaction formula shown below). This method requires two days for the first step of the palladium-catalyzed coupling reaction, with a yield of 60%. It suffers from high raw material costs, a long reaction time, and a low yield. Furthermore, the second step uses phosphorus oxychloride, which generates a large amount of phosphorus-containing wastewater, which is detrimental to environmental protection.

[0009]

[0010] 3. Chinese patent CN104926714A describes a one-pot method for reacting 2-phenylpyridine with Ru-catalyzed bromination and copper-catalyzed chlorination to produce 2-(2-chloro-5-bromophenyl)pyridine. Then, under N2 protection, it reacts with benzamide via copper catalysis to generate 2-(2-chloro-5-benzamidophenyl)pyridine. This is followed by hydrolysis with 20% sulfuric acid to prepare 2-(2-chloro-5-aminophenyl)pyridine, which is then amidated with 2-chloro-4-methylsulfonylbenzoyl chloride to obtain vemodigine (synthetic route shown below). This method introduces the amino group through amide hydrolysis, resulting in a high yield in this step. However, the first step, the one-pot catalytic bromination and chlorination, requires 3 days, resulting in a long reaction time, slow reaction rate, and numerous chlorination and bromination reaction sites. This step is prone to side reactions, leading to low purity of the generated 2-(2-chloro-5-bromophenyl)pyridine. Furthermore, the expensive Ru catalyst makes it unsuitable for industrial production.

[0011] Summary of the Invention

[0012] To address the shortcomings and deficiencies of existing technologies, this invention provides a method for synthesizing 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide (Vimidegi). This method features a short reaction route, mild reaction conditions, fast reaction rate, short reaction time, high yield, high product purity, and is environmentally friendly with low cost.

[0013] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0014] A method for synthesizing 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide, the method comprising using a compound of formula V Azide-trimethylsilane is reacted with an oxidant in the presence of a catalyst and a ligand in a solvent to prepare 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide. In the steps described, the catalyst is selected from MnCl2, manganese acetylacetone Mn(acac)2, manganese acetate Mn(OAc)2, MnBr2, MnCO3, MnF2, and Mn2(CO). 10 A combination of one or more of CoCl2 and Co(acac)2 acetylacetonate.

[0015] In the prior art, the synthesis of 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide (Vimidegi) typically uses compounds containing pyridine groups as raw materials, or introduces pyridine groups into the reaction pathway. However, this invention differs from the traditional method of introducing pyridine groups. This invention uses manganese or cobalt compounds as catalysts to catalyze the reaction of azide-trimethylsilane with an oxidant and the compound shown in Formula V. Under the action of the oxidant and catalyst, azide-trimethylsilane first generates azide free radicals. The catalyst is oxidized to the corresponding trivalent compound. The azide radical adds to the cyclopentene group in the compound shown in Formula V. After releasing nitrogen gas, the nitrogen radical portion rearranges with the cyclopentene portion to obtain an intermediate containing a pyridine group and a radical. This intermediate then reacts with the trivalent compound corresponding to the catalyst to obtain the final product. Simultaneously, the catalyst reverts to a divalent state. This reaction step, which "inserts" the nitrogen atom into the cyclopentene group in the compound shown in Formula V, represents a novel reaction route for synthesizing the target product of vemodig. This reaction route offers mild reaction conditions, uses a low-cost catalyst, and achieves a high yield. Furthermore, when using a manganese compound as the catalyst in this step, the reaction rate is faster than when using a cobalt compound.

[0016] In some embodiments, the reaction is carried out in the presence of an ammonium salt selected from one or more combinations of ammonium acetate, ammonium carbonate, ammonium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide, and tetrabutylammonium chloride.

[0017] Preferably, the ammonium salt is ammonium acetate.

[0018] Through research, the inventors discovered that by adding ammonium salts to the above reaction, the yield of the target product vemodilution can be further improved.

[0019] In some embodiments, the molar ratio of the ammonium salt to the compound represented by Formula V is 0.5-2.0:1.

[0020] In some embodiments, the ligand is selected from compounds with the following structures:

[0021] in,

[0022] Ph stands for benzene ring.

[0023] Through research, the inventors discovered that using the above-mentioned L1-L8 compounds as ligands for catalysts can significantly improve the yield of the target product.

[0024] In some embodiments, the oxidant is selected from one or more combinations of oxygen, elemental iodine, iodobenzene acetate, [bis(trifluoroacetoxy)iodo]benzene, di-tert-butyl peroxide, potassium persulfate, copper acetate, and 2-iodobenzoic acid.

[0025] Preferably, the oxidant is oxygen.

[0026] In some embodiments, the solvent is selected from one or more combinations of toluene, 1,4-dioxane, dichloromethane, ethylene glycol dimethyl ether, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, and water.

[0027] Preferably, the solvent is a mixture of ethylene glycol dimethyl ether and acetonitrile in a volume ratio of 2:1. Using this solvent, a higher yield of the target product can be achieved compared to other solvents.

[0028] In some embodiments, the molar ratio of the catalyst to the compound represented by Formula V is 0.01-0.2:1.

[0029] Preferably, the molar ratio of the catalyst to the compound represented by formula V is 0.1:1.

[0030] In some embodiments, the molar ratio of the ligand to the compound represented by Formula V is 0.1-0.5:1.

[0031] Preferably, the molar ratio of the ligand to the compound represented by formula V is 0.2:1.

[0032] In some embodiments, the molar ratio of the azidotrimethylsilane and the compound shown in Formula V is 1:1.0-3.0.

[0033] In some embodiments, the oxidant is oxygen, and the reaction is carried out in an oxygen environment.

[0034] In some embodiments, the reaction temperature is 50-100°C.

[0035] In some embodiments, the reaction time is 3-12 hours.

[0036] In some embodiments, the synthesis method further includes using the compound represented by Formula III.

[0037] With the compound shown in Formula IV The step involves an amidation reaction under alkaline conditions in an organic solvent to generate the compound represented by formula V.

[0038] In some embodiments, the alkaline conditions are formed by adding one or two bases selected from triethylamine and potassium carbonate.

[0039] Preferably, the alkaline conditions are formed by adding potassium carbonate.

[0040] In some embodiments, the molar ratio of the compound represented by Formula III to the compound represented by Formula IV is 1:1.0-1.5:

[0041] In some embodiments, the organic solvent is selected from one or more combinations of dichloromethane, N,N-dimethylformamide, and tetrahydrofuran.

[0042] Preferably, the organic solvent is selected from dichloromethane.

[0043] In some embodiments, the amidation reaction is carried out at a temperature of 20-35°C.

[0044] In some embodiments, the amidation reaction takes 2-5 hours.

[0045] In some embodiments, the synthesis method further includes using the compound represented by Formula I. The compound shown in Formula II The step involves a coupling reaction in the presence of a palladium catalyst to generate the compound represented by Formula III, wherein in Formula I, X is bromine (Br) or iodine (I).

[0046] In the compound shown in Formula I, the X atom is located at the meta position of the amino group. The coupling reaction readily proceeds at the X position, and the reaction does not involve the meta-amino group. This step results in a high reaction yield and high selectivity for the target product III. Therefore, using the reaction route of this invention, there is no need to use the nitro group for subsequent reduction to the amino group; instead, the compound shown in Formula I, containing the amino group, can be used directly as a starting material.

[0047] In some embodiments, the palladium catalyst is selected from one or more combinations of palladium acetate, palladium chloride, tetratriphenylphosphine palladium, (1,1'-bis(diphenylphosphine)ferrocene)palladium dichloride Pd(dppf)Cl2 and bis(triphenylphosphine)palladium dichloride Pd(PPh3)2Cl2.

[0048] Preferably, the palladium catalyst is tetratriphenylphosphine palladium.

[0049] In some embodiments, the coupling reaction is carried out under alkaline conditions, which are formed by adding one or two bases selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate.

[0050] Preferably, the alkaline conditions are formed by adding potassium carbonate.

[0051] In some embodiments, the coupling reaction is carried out in a solvent selected from one or more combinations of toluene, ethanol, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, methanol, and water.

[0052] Preferably, the coupling reaction is carried out in a mixed solvent of toluene, ethanol and water in a volume ratio of 3:1:1.

[0053] In some embodiments, the molar ratio of the compound represented by Formula I to the compound represented by Formula II is 1:1.0-1.5.

[0054] In some embodiments, the molar ratio of the palladium catalyst to the compound of Formula I is 0.01-0.2:1, preferably 0.025:1.

[0055] In some embodiments, the coupling reaction is carried out at a temperature of 90-130°C.

[0056] In some embodiments, the coupling reaction takes 10-14 hours.

[0057] This invention also claims protection for a compound suitable for preparing 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide, said compound having the structure shown in Formula III or Formula V:

[0058]

[0059]

[0060] Compared with the prior art, the present invention has the following advantages:

[0061] This invention provides a novel reaction route for synthesizing 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide (Vimideg). Instead of introducing a pyridine group using traditional methods, it inserts an N atom into a compound of formula V containing a cyclopentenyl group, followed by a rearrangement reaction to generate the pyridine group. This route offers mild reaction conditions, uses a low-cost catalyst, and achieves a high yield.

[0062] In the step of preparing the target product from the compound shown in Formula V, the yield of the target product can be further improved by adding an ammonium salt. By selecting specific types of ligands, the yield of the target product can be made high.

[0063] This invention requires only three reaction steps from the starting material compound represented by Formula I to the final target product. The reaction route is simple, while existing technologies typically require at least four reaction steps. Furthermore, the reaction process of this invention does not involve raw materials or intermediates that are sensitive to water or oxygen, the reaction conditions are mild, and it does not involve phosphorus oxychloride, making the reaction route environmentally friendly.

[0064] The starting material of this invention, represented by compound I, exhibits high selectivity for coupling reaction at position X. The yield of the first step reaction is very high, reaching 94%, and the yield of the second step reaction is also 92%. The yield of the third step reaction is also relatively high, reaching 68%. Therefore, the overall yield of the target product is high.

[0065] The three-step reaction of this invention has a fast reaction rate and a short reaction time. Attached Figure Description

[0066] Figure 1 The 1H NMR spectrum of the compound of Formula III prepared in Example 1;

[0067] Figure 2 The carbon NMR spectrum of the compound of formula III prepared in Example 1;

[0068] Figure 3 The 1H NMR spectrum of the compound of formula V prepared in Example 1;

[0069] Figure 4 The carbon NMR spectrum of the compound of formula V prepared in Example 1;

[0070] Figure 5 The 1H NMR spectrum of the compound of formula VI prepared in Example 1;

[0071] Figure 6 The image shows the carbon NMR spectrum of the compound of formula VI prepared in Example 1. Detailed Implementation

[0072] The present invention will be further described below with reference to embodiments. However, the present invention is not limited to the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to different requirements of specific applications, and the implementation conditions not specified are conventional conditions in the industry. The technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.

[0073] Example 1

[0074] This embodiment provides a method for preparing 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide (the compound shown in Formula VI), as follows:

[0075] Step 1: Preparation of 4-chloro-3-(cyclopent-1-en-1-yl)aniline (the compound shown in Formula III)

[0076]

[0077] 10 mmol of 3-bromo-4-chloroaniline (Formula I), 12 mmol of 1-cyclopentenylboronic acid (Formula II), 0.25 mmol of tetrakis(triphenylphosphine)palladium Pd(PPh3)4, and 30 mmol of potassium carbonate were added to a 100 mL three-necked flask. 20 mL of solvent (toluene:ethanol:water = 3:1:1, volume ratio) was added. The mixture was substituted with N2 three times and reacted at 110 °C for 12 hours under N2 protection. After the reaction was completed, the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1, volume ratio) to give 4-chloro-3-(cyclopent-1-en-1-yl)aniline (Formula III) in 94% yield.

[0078] The 1H NMR spectrum of compound III is shown below. Figure 1 As shown, the 1H NMR data are: 1 ¹H NMR (400MHz, CDCl₃) δ 7.12 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.8 Hz, 1H), 6.49 (dd, J = 8.5, 2.8 Hz, 1H), 6.08 (s, 1H), 3.50 (s, 2H), 2.74–2.69 (m, 2H), 2.55–2.50 (m, 2H), 2.03–1.96 (m, 2H). The carbon NMR spectrum of compound III is shown below. Figure 2 As shown, the carbon NMR data are: 13 C NMR (101MHz, CDCl3) δ144.8,141.4,137.7,131.3,130.6,121.6,116.2,114.7,35.9,33.5,23.7.

[0079] Step 2: Preparation of 2-chloro-N-(4-chloro-3-(cyclopent-1-en-1-yl)phenyl)-4-(methylsulfonyl)benzamide (the compound shown in Formula V)

[0080]

[0081] In a 50 ml round-bottom flask, 5 mmol of 4-chloro-3-(cyclopent-1-en-1-yl)aniline (Formula III) was dissolved in 30 ml of dry dichloromethane. 10 mmol of potassium carbonate was added, and the mixture was cooled to 0 °C in an ice-water bath. 5.5 mmol of 2-chloro-4-(methylsulfonyl)benzoyl chloride was slowly added, and the reaction was allowed to proceed for 3 hours after being brought to room temperature. After the reaction was completed, 20 ml of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then slurried with dichloromethane and petroleum ether to give a white solid product, 2-chloro-N-(4-chloro-3-(cyclopent-1-en-1-yl)phenyl)-4-(methylsulfonyl)benzamide (Formula V), with a yield of 92%.

[0082] The 1H NMR spectrum of compound V is shown below. Figure 3 As shown, the 1H NMR data are: 1 ¹H NMR (400MHz, DMSO-d⁶) δ 10.79 (s, 1H), 8.13 (d, J = 1.7Hz, 1H), 8.01 (dd, J = 8.0, 1.7Hz, 1H), 7.89 (d, J = 7.9Hz, 1H), 7.76 (d, J = 2.6Hz, 1H), 7.59 (dd, J = 8.7, 2.6Hz, 1H), 7.44 (d, J = 8.7Hz, 1H), 6.24–6.04 (m, 1H), 3.35 (s, 3H), 2.72–2.67 (m, 2H), 2.55–2.50 (m, 2H), 2.00–1.94 (m, 2H). The carbon NMR spectrum of compound V is shown below. Figure 4 As shown, the carbon NMR data are: 13 C NMR(101MHz,DMSO-d6)δ164.2,143.6,141.4,140.9,137.9,137.1,132.1,131 .4,130.8,130.4,128.6,126.5,126.4,121.0,119.9,43.6,36.0,33.6,23.6.

[0083] Step 3: Preparation of Vimodil (the compound shown in Formula VI)

[0084]

[0085] In a 100 ml round-bottom flask, 3 mmol of 2-chloro-N-(4-chloro-3-(cyclopent-1-en-1-yl)phenyl)-4-(methylsulfonyl)benzamide (formula V), 7.5 mmol of trimethyl azidosilane (TMSN3), 0.3 mmol of MnCl2, 0.6 mmol of 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (ligand L4), and 3 mmol of ammonium acetate were added sequentially. 20 ml of solvent (ethylene glycol dimethyl ether: acetonitrile = 2:1, v / v) was added, and the mixture was purged three times with oxygen. The reaction was then carried out at 80 °C for 3 hours. After the reaction was complete, column purification (petroleum ether: ethyl acetate = 2:1, v / v) was performed to give a white solid, vemodig, in 68% yield.

[0086] The 1H NMR spectrum of compound VI is shown below. Figure 5 As shown, the 1H NMR data are: 1 ¹H NMR (400MHz, CDCl₃) δ 9.98 (s, 1H), 8.35 (dd, J = 5.0, 0.8Hz, 1H), 7.99 (dd, J = 8.7, 2.6Hz, 1H), 7.81 (d, J = 1.7Hz, 1H), 7.72 (td, J = 7.7, 1.8Hz, 1H), 7.69–7.63 (m, 3H), 7.50 (d, J = 7.9Hz, 1H), 7.45 (d, J = 8.8Hz, 1H), 7.20–7.16 (m, 1H), 2.97 (s, 3H). The carbon NMR spectrum of compound VI is shown below. Figure 6 As shown, the carbon NMR data are: 13 C NMR (101MHz, CDCl3) δ163.9,155.7,148.7,142.5,140.7,138.4,137.1,136.5 ,132.3,131.0,129.9,128.8,127.3,125.7,125.5,122.9,122.8,121.8,44.3.

[0087] Example 2

[0088] The process is basically the same as in Example 1, except that MnCl2 in step 3 is replaced with Mn(acac)2, resulting in a yield of 34% in step 3.

[0089] Example 3

[0090] The process is basically the same as in Example 1, except that MnCl2 in step three is replaced with Mn(OAc)2, resulting in a yield of 39% in step three.

[0091] Example 4

[0092] The process was basically the same as in Example 1, except that MnCl2 in step 3 was replaced with MnBr2, and the reaction time was changed from 3h to 24h. As a result, the yield of step 3 was 65%.

[0093] Example 5

[0094] The reaction was basically the same as in Example 1, except that MnCl2 in step three was replaced with cobalt acetylacetonate Co(acac)2, and the reaction time was changed from 3 h to 24 h. As a result, the yield of step three was 66%. It can be seen that the reaction rate of step three is faster when a manganese catalyst is used.

[0095] Example 6

[0096] Basically the same as Example 1, except that ligand L4 in step three is replaced with ligand L2. The yield of step three was 53%.

[0097] Example 7

[0098] Basically the same as Example 1, except that ligand L4 in step three is replaced with ligand L3. The yield of step three was 25%.

[0099] Example 8

[0100] Basically the same as Example 1, except that ligand L4 in step three is replaced with ligand L6. The yield for step three was 22%.

[0101] Example 9

[0102] Basically the same as Example 1, except that ligand L4 in step three is replaced with ligand L7. The yield of step three was 38%.

[0103] Example 10

[0104] Basically the same as Example 1, except that ligand L4 in step three is replaced with ligand L8.

[0105] The yield of step three was 25%.

[0106] Example 11

[0107] The results were basically the same as in Example 1, except that ammonium acetate was not added in step three, resulting in a yield of 59% in step three.

[0108] Example 12

[0109] Basically the same as Example 1, the only difference being: in step one, a method is used... replace As the initial raw material, the yield of step one was 96%.

[0110] Comparative Example 1

[0111] Basically the same as Example 1, except that: ligand L4 in step three is replaced with a ligand with the following structural formula. The yield of step three was 7%.

[0112] Comparative Example 2

[0113] The process is basically the same as in Example 1, except that MnCl2 in step three is replaced with FeCl2. As a result, the target product compound VI cannot be obtained in step three.

[0114] Comparative Example 3

[0115] The process was basically the same as in Example 1, except that MnCl2 in step three was replaced with nickel acetylacetonate Ni(acac)2. As a result, the target product compound VI could not be obtained in step three.

[0116] Comparative Example 4

[0117] The process was basically the same as in Example 1, except that MnCl2 in step three was replaced with palladium acetate Pd(OAc)2. As a result, the target product compound VI could not be obtained in step three.

[0118] As can be seen, by selecting specific types of catalysts and ligands in step three, the present invention can synthesize the target product in a high yield.

[0119] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

[0120] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

Claims

1. A method for synthesizing 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide, characterized in that: The synthesis method includes using the compound represented by formula V. Azide-trimethylsilane is reacted with an oxidant in the presence of a catalyst and a ligand in a solvent to prepare 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide. In the steps described, the catalyst is selected from MnCl2, manganese acetylacetone Mn(acac)2, manganese acetate Mn(OAc)2, MnBr2, MnCO3, MnF2, and Mn2(CO). 10 A combination of one or more of CoCl2 and cobalt acetylacetonate Co(acac)2; the oxidant is selected from oxygen; the ligand is selected from compounds with the following structures: , where Ph is a benzene ring.

2. The synthesis method according to claim 1, characterized in that: The reaction is carried out in the presence of an ammonium salt selected from one or more combinations of ammonium acetate, ammonium carbonate, ammonium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide, and tetrabutylammonium chloride.

3. The synthesis method according to claim 1, characterized in that: The solvent is selected from one or more combinations of toluene, 1,4-dioxane, dichloromethane, ethylene glycol dimethyl ether, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, and water.

4. The synthesis method according to claim 1, characterized in that: The molar ratio of the catalyst to the compound of formula V is 0.01-0.2:1; and / or, the molar ratio of the ligand to the compound of formula V is 0.1-0.5:1; and / or, the molar ratio of the azidetrimethylsilane to the compound of formula V is 1.0-3.0:

1.

5. The synthesis method according to claim 1, characterized in that: The reaction is carried out in an oxygen environment; and / or, the temperature of the reaction is 50-100°C; and / or, the reaction time is 3-12 hours.

6. The synthesis method according to claim 1, characterized in that: The synthesis method further includes using the compound represented by Formula III. With the compound shown in Formula IV The step involves an amidation reaction under alkaline conditions in an organic solvent to generate the compound represented by formula V.

7. The synthesis method according to claim 6, characterized in that: The alkaline conditions are formed by adding one or two bases selected from triethylamine and potassium carbonate; and / or, the molar ratio of the compound represented by Formula III to the compound represented by Formula IV is 1:1.0-1.5; and / or, the organic solvent is selected from one or more combinations of dichloromethane, N,N-dimethylformamide and tetrahydrofuran; and / or, the temperature of the amidation reaction is 20-35°C; and / or, the time of the amidation reaction is 2-5 h.

8. The synthesis method according to claim 6, characterized in that: The synthesis method further includes using the compound represented by Formula I. The compound shown in Formula II The step involves a coupling reaction in the presence of a palladium catalyst to generate the compound represented by Formula III, wherein in Formula I, X is bromine (Br) or iodine (I).

9. The synthesis method according to claim 8, characterized in that: The palladium catalyst is selected from one or more combinations of palladium acetate, palladium chloride, tetra-triphenylphosphine palladium, (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride Pd(dppf)Cl2 and bis(triphenylphosphine)palladium dichloride Pd(PPh3)2Cl2; and / or, the coupling reaction is carried out under alkaline conditions, which are formed by adding one or two bases selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate; and / or, the coupling reaction is carried out in a solvent selected from one or more combinations of toluene, ethanol, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, methanol and water; and / or, the molar ratio of the compound represented by Formula I to the compound represented by Formula II is 1:1.0-1.5; and / or, the temperature of the coupling reaction is 90-130°C; and / or, the time of the coupling reaction is 10-14 h.

10. A compound suitable for preparing 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methylsulfonyl)benzamide, characterized in that: The compound has the structure shown in Formula III or Formula V: ； 。

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