WO2018023493A1

WO2018023493A1 - Method for manufacturing aryl nitriles

Info

Publication number: WO2018023493A1
Application number: PCT/CN2016/093064
Authority: WO
Inventors: 洪浩; 詹姆斯•盖吉; 马特约•翰逊; 卢江平; 刘志清; 张恩选; 李超
Original assignee: 凯莱英医药集团（天津）股份有限公司; 凯莱英生命科学技术(天津)有限公司; 天津凯莱英制药有限公司; 凯莱英医药化学（阜新）技术有限公司; 吉林凯莱英医药化学有限公司
Priority date: 2016-08-03
Filing date: 2016-08-03
Publication date: 2018-02-08

Abstract

A method for manufacturing aryl nitriles represented by formula I. The method for manufacturing the compound represented by formula I comprises: using an aryl compound represented by formula II as a starting material; for the compound represented by formula II, n = 0 or 1, and X1, X2, X3, and X4 are independently selected from N, S, O, or C; Y is OSO₂F, OTf, or OTs; R1, R2, R3 and R4 are independently selected from any one of H, an alkyl group, an aryl group, or a halide. Nitrilization of the aryl compound is performed using a catalytic effect provided by a catalyst, a reducing agent, and a ligand to obtain the class of aryl nitrile compounds.

Description

Method for preparing aryl nitrile compound

Technical field

The present invention relates to the field of synthesis of cyanide compounds, and in particular to a process for preparing an aryl nitrile compound.

Background technique

Aryl nitriles are not only important structural components such as medicines, pesticides, dyes, functional materials, perfumes and natural products, but also important intermediates in organic synthesis. The aryl nitrile compound can be easily converted into other compounds such as aldehydes, ketones, carboxylic acids, amines, amides and heterocyclic derivatives under certain reaction conditions.

The Sandmeyer reaction and the Rosemund-Vonbraun reaction are classical methods for the synthesis of aromatic nitriles. However, these two methods usually require stoichiometric highly toxic metal cyanides such as zinc cyanide, sodium cyanide, etc., as well as harsh reaction conditions (150-250 ° C). ). Transition metal catalyzed cyanation of halogenated aromatic hydrocarbons has developed rapidly in the last decade, but there are also some problems: sensitive to air and water, expensive catalysts and complex synthesis of phosphine ligands required and low yields The aryl nitrile compound is costly to synthesize, and most of the cyanide source used is highly toxic metal cyanide, which limits its application in industrial production.

Recently, it has been reported in the literature that the use of low-toxic yellow blood salt (potassium ferrocyanide) as cyanide reagent, palladium or copper-catalyzed aromatic ring cyanation reaction to obtain a better yield (such as Chinese patent application No. 200610048481.9) , Catal.Commun.2009.10 768–771, J. Am. Chem. Soc. 2003, 125, 2890-2891, Eur. J. Org. Chem. 2007, 2401–2404, Tetrahedron Lett. 2005, 46 2585–2588) It has also been reported in the literature that the highly toxic metal cyanide is used as a cyanogen source, and copper is used to catalyze the acylation of aryl groups. In this type of reaction, the additive KI is added, but the reaction temperature is still greater than 100 ° C, and the yield is moderate. In addition, the related literature reports on the use of sodium azide in the palladium or copper catalyst conditions (Chinese Patent Application No. 200910088860 and 201510194625) to achieve aryl cyanation of various substituted aryl groups, although this type of reaction avoids the use of drama Poisonous cyanide, but using explosive sodium azide and high-cost metal palladium catalysts, is not easy to process scale production.

Recently, it has been reported in the literature that aryl mesylate substrates can be cyanide under the conditions of Ni or Pd catalysts (J. Org. Chem. 1995, 60, 6895-6903, SynLett. 2014, 25, 2938-2942). Potassium hydride is a cyanide source to achieve a moderate yield of aryl hydrogenation, but the reaction of this type of reaction to the substrate is low, and the substrate mesylate synthesis conditions are harsh, high cost, relatively low activity, need to be Realized at higher temperatures.

Summary of the invention

The main object of the present invention is to provide a process for preparing an aryl nitrile compound to solve the problem of high production cost of the aryl nitrile compound in the prior art.

In order to achieve the above object, according to one aspect of the present invention, there is provided a process for producing an aryl nitrile compound having the formula I:

Formula I, the preparation method comprises: using an aryl compound having the general formula II as a substrate,

Formula II, wherein n = 0 to 1, X ₁ , X ₂ , X ₃ and X ₄ are each independently selected from any one of N, S, O and C in a chemically acceptable structure; Is OSO ₂ F, OTf or OTs; R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from any of H, alkyl, aryl and halogen, catalyzed by a catalyst, a reducing agent and a ligand The aryl compound is cyanated with a cyan source to obtain an aryl nitrile compound.

Further, the above cyanogenic source is selected from one or both of the group consisting of K ₄ Fe(CN) ₆ , Zn(CN) ₂ , KCN and NaCN.

Further, the above catalyst is a non-noble metal salt, and preferably the non-noble metal salt is selected from the group consisting of CuI, CuBr, CuCl, Cu(OAc) ₂ , Cu(acac) ₂ , Cu(OTf) ₂ , CuI ₂ , CuCl ₂ , CuSO ₄ , NiX. ₂ , any one or more of the group consisting of Ni(OAc) ₂ , NiX ₂ (dppf), NiX ₂ (dppe), NiX ₂ (dppp), Ni(PCy3)X ₂ and Ni(Py) ₂ Cl ₂ , wherein X represents a halogen.

Further, the above ligand is an amino ligand or a phosphine ligand, preferably the amino ligand is tetramethylethylenediamine, N-N'dimethylethylenediamine or ethylenediamine, and preferably the phosphine ligand is triphenyl. Phosphine, 1,1-bis(diphenylphosphino)ferrocene, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane or tricyclohexylphosphine.

Further, the above cyanation reaction is carried out in a solvent, preferably a solvent of dimethylformamide, N-methylpyrrolidone, N,N-diethylformamide, dimethyl sulfoxide, toluene, 1,4- Dioxane or acetonitrile preferably has a volume ratio of solvent to aryl compound of from 5 to 10:1.

Further, the above cyanation reaction is carried out in the range of 60 to 100 °C.

Further, the molar ratio of the cyanide to the aryl compound in the cyanogen source is 1:1 to 1.6:1.

Further, the molar ratio of the above catalyst to the aryl compound is from 0.005:1 to 0.2:1, preferably from 0.02:1 to 0.1:1.

Further, the molar ratio of the above catalyst to the ligand is from 1:1 to 1:10, preferably from 1:1 to 1:3.

Further, the reducing agent is zinc powder, and the molar ratio of the zinc powder to the aryl compound is 0.05:1 to 1:1, preferably 0.1:1 to 0.5:1.

According to the technical solution of the present invention, the above preparation method adopts an aryl compound having the general formula II as a substrate, and the preparation of the material is relatively easy with respect to the aryl halide, thereby reducing the cost of preparing the aryl nitrile compound; The activity of the substance is higher than that of the aryl substrate commonly used in the prior art, so the required reaction temperature is lower during the cyanation reaction. The step reduces the energy consumption of the preparation method, and also reduces the synthesis cost from this aspect; in addition, since the activity of the substance is relatively high, the requirement for the catalyst is relatively lowered, making the use of some non-precious metal catalysts possible, thereby further reducing The synthesis cost; further, since the substance has higher activity, the conversion rate is higher, thereby reducing the complexity and complexity of the product separation and recovery process, and further reducing the synthesis cost. Meanwhile, when the aryl group having the general formula II has various aromatic heterocyclic rings, its reactivity is comparable to that of the phenyl group, and therefore it is universal for the synthesis of an aryl nitrile compound. That is, the preparation method of the present application is highly versatile, and a high yield can be obtained for an aryl or heteroaryl substrate containing an electron-rich or electron-deficient substituent.

DRAWINGS

The accompanying drawings, which are incorporated in the claims of the claims In the drawing:

1 shows a ¹ H NMR spectrum of a target product obtained in the ^first step of Example 1 of the present invention;

2 shows a ¹³ C NMR spectrum of a target product obtained in the first step of Example 1 of the present invention;

Figure 3 shows a ¹ H NMR spectrum of the product according to Example 2 of the present invention;

Figure 4 shows a ¹ H NMR spectrum of the product according to Example 8 of the present invention;

Figure 5 shows a ¹³ C NMR spectrum of the product according to Example 8 of the present invention;

Figure 6 shows a ¹ H NMR spectrum of the product according to Example 9 of the present invention;

Figure 7 shows a ¹³ C NMR spectrum of the product according to Example 9 of the present invention;

Figure 8 shows a ¹ H NMR spectrum of the product according to Example 21 of the present patent;

Figure 9 shows a ¹ H NMR spectrum of the product according to Example 22 of the present patent.

detailed description

It should be noted that the embodiments in the present application and the features in the embodiments may be combined with each other without conflict. The invention will be described in detail below with reference to the drawings in conjunction with the embodiments.

As described in the background art, the preparation method of the aryl nitrile compound in the prior art has a problem of high cost due to various reasons. To solve the problem, the present application provides preparation of an aryl nitrile compound. Method, the aryl nitrile compound has the general formula I:

The above preparation method adopts an aryl compound having the general formula II as a substrate, and the preparation of the substance is relatively easy with respect to the aryl halide, thereby reducing the cost of preparing the aryl nitrile compound; and the activity of the substance is higher than that of the prior art. The commonly used aromatic substrate is high, so the required reaction temperature is lower during the cyanation reaction, further reducing the energy consumption of the preparation method, and also reducing the synthesis cost from this aspect; in addition, due to the activity of the substance Higher, so the requirements for the catalyst are relatively reduced, making the use of some non-precious metal catalysts possible, which in turn further reduces the synthesis cost; further, because of the higher activity of the material, the conversion rate is higher, then the product is reduced. The versatility and complexity of the separation and recovery process can also reduce the cost of synthesis.

Meanwhile, when the aryl group having the general formula II has various aromatic heterocyclic rings, its reactivity is comparable to that of the phenyl group, and therefore it is universal for the synthesis of an aryl nitrile compound. That is, the preparation method of the present application is highly versatile, and a high yield can be obtained for an aryl or heteroaryl substrate containing an electron-rich or electron-deficient substituent.

After the above synthesis, purification can be carried out by a conventional purification method, and the purification method will not be enumerated here.

In a preferred embodiment of the present application, the cyan source is selected from one or both of the group consisting of K ₄ Fe(CN) ₆ , Zn(CN) ₂ , KCN and NaCN. The use of the above-mentioned low-toxicity salts as a cyanogen source greatly reduces the use amount, and at the same time, greatly reduces the safety risk of the reaction, as well as the risks and costs of the post-treatment reaction and the three-waste treatment. Moreover, the cost of the above K ₄ Fe(CN) ₆ is lower than that of other metal cyanides, and the synthesis process is green and environmentally friendly. Of course, cyanogenic sources commonly used in the prior art can also be used in the present application without considering safety issues.

As described above, since the reactivity of the substrate is increased, the catalytic activity requirement of the catalyst can be appropriately lowered, for example, selecting a non-noble metal salt as a catalyst, and preferably the non-precious metal salt is selected from CuI, CuBr, CuCl, Cu(OAc) ₂ ( Copper acetate), Cu(acac) ₂ (copper acetylacetonate), Cu(OTf) ₂ (copper trifluoromethanesulfonate), CuI ₂ , CuCl ₂ , CuSO ₄ , NiX ₂ , Ni(OAc) ₂ (nickel acetate) Any one or more of the group consisting of NiX ₂ (dppf), NiX ₂ (dppe), NiX ₂ (dppp), Ni(PCy ₃ )X ₂ and Ni(Py) ₂ Cl ₂ , wherein X represents a halogen Dppf represents 1,1-bis(diphenylphosphino)ferrocene, dppe represents 1,2-bis(diphenylphosphino)ethane, dppp represents 1,3-bis(diphenylphosphino)propane, and PCy ₃ represents Tricyclohexylphosphine, Py represents pyridine. The cost of each of the above non-precious metal salts is low, so that the synthesis cost of the aryl nitrile compound can be further reduced. Of course, palladium catalysts commonly used in the prior art can also be used, such as PdCl ₂ , Pd(OAc) ₂ (palladium acetate), Pd(PPh ₃ ) ₄ (tetrakis(triphenylphosphine)palladium), Pd(dba) ₂ (tris(dibenzylideneacetone)dipalladium), Pd(dppf)Cl ₂ (1,1-bis(diphenylphosphino)ferrocene palladium dichloride), Pd(acac) ₂ (palladium acetylacetonate) .

When the above catalyst is selected, one skilled in the art can select a suitable ligand according to the prior art knowledge, preferably the above ligand is an amino ligand or a phosphine ligand, and further preferably the amino ligand is tetramethylethylenediamine (TMEDA). , N-N' dimethylethylenediamine (DMEDA) or ethylenediamine (EDA), further preferably the phosphine ligand is triphenylphosphine (PPh ₃ ), 1,1-bis(diphenylphosphine) ferrocene Iron (dppf), 1,2-bis(diphenylphosphine)ethane (dppe), 1,3-bis(diphenylphosphino)propane dppp or tricyclohexylphosphine (PCy ₃ ). The kind of the above-mentioned catalyst is selected from the above ligands to further improve the catalytic efficiency and activity.

The above ligands of the present application are inexpensive, and can obtain higher system purity and yield, and the catalytic efficiency of the above catalysts in combination with the Pd catalyst can obtain a comparable or higher yield on most substrates. The copper or nickel catalyst described above is more inexpensive, greatly reduces production costs, and is easy to process.

Further, it is preferred that the above cyanation reaction is carried out in a solvent, and further preferably the solvent is dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-diethylformamide, dimethyl sulfoxide. (DMSO), toluene, 1,4-dioxane or acetonitrile. Each of the above solvents is a commonly used solvent in the art, and is safe to use and low in cost. In order to further increase the reaction rate, the volume ratio of the solvent to the aryl compound is preferably from 5 to 10:1. In order to allow the reaction substrate and the cyanogen source to be sufficiently dispersed in contact, it is ensured that the reaction efficiency is not lowered due to excessive dispersion.

In the case where the substrate of the present application has a high reactivity, the reaction temperature of the above cyanation reaction is lowered, and it is preferred that the above cyanation reaction be carried out in the range of 60 to 100 ° C, preferably 80 ° C. The temperature range is significantly lower than the reaction temperature of more than 100 ° C in the prior art, so the stability of the substrate is required to be low, and the complex functional grouping is performed (for example, the compound structure contains, for example, an ester group, a ketone carbonyl group or an aromatic ring). The substrate of the functional group having a halogen atom has better functional group compatibility, and is favorable for obtaining high separation yield and system purity; at the same time, the requirements for equipment and energy are significantly reduced, and it is more favorable for preparation of the present application. The application of the method in industry.

In a preferred embodiment of the present application, the molar ratio of cyanide to aryl compound in the cyanogen source is from 1:1 to 1.6:1.

Further, in order to reduce the amount of catalyst used to reduce the cost while ensuring catalytic efficiency, it is preferred that the molar ratio of the above catalyst to the aryl compound is from 0.005:1 to 0.2:1, preferably from 0.02:1 to 0.1:1.

Further, the molar ratio of the catalyst to the ligand is preferably from 1:1 to 1:10, preferably from 1:1 to 1:3, more preferably 1:2. The molar ratio of ligand to catalyst is 2:1 in accordance with the tetradentate coordination requirement of the catalyst. During the catalytic cycle, there is a sufficient amount of coordination and leaving of the ligand, and too much ligand will waste the ligand and increase the cost. .

Further, it is preferred that the reducing agent is zinc powder, and the molar ratio of the zinc powder to the aryl compound is from 0.05:1 to 1:1, preferably from 0.1:1 to 0.5:1. The reducing agent is used to reduce the catalyst to ensure the reaction proceeds; the use of zinc powder as the reducing agent enables the reaction to proceed stably and at a low cost; the amount of the zinc powder is controlled within the above range, preferably 0.1/1. Zinc powder is used to reduce the catalyst into a zero-valent metal, and the zero-valent metal is an active catalyst intermediate during the catalytic cycle.

Further, in order to ensure a reduction in the use cost of the solvent, it is preferred that the volume ratio of the solvent to the substrate is from 5:1 to 20:1, preferably 10:1.

The substrate in the above embodiments can be taken from the existing products in the prior art, and can also be synthesized at the time of use. The synthesis method can also refer to the prior art, and details are not described herein again.

Advantageous effects of the present application will be further described below in conjunction with the examples and comparative examples.

Example 1

The synthetic route is:

step one:

3-Hydroxypyridine (100 g, 1.05 mol) and triethylamine (160 g, 1.58 mol) were added to dichloromethane (500 mL) to form a first mixed system, and at room temperature, a sulfonyl fluoride was introduced into the reaction system. After gas (118g, 1.1equiv.) and stirring for 2~3h, the sample is traced until the disappearance of the raw materials, the reaction system is cooled to 0-5 °C, and 300g of ice water at 0 °C is added to the reaction system for quenching and DCM extraction (300mLDCM each time) After a total of three times, the organic phase was combined and concentrated, and subjected to column chromatography. The volume ratio of petroleum ether to ethyl acetate in the column was 5/1 to obtain an oily liquid of 176 g, and the target product yield was 95%.

Product validation: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 (s, 2H), 7.69 - 7.60 (m, 1H), 7.38 (dd, J = 8.5, 4.8 Hz, 1H).; ¹³ C NMR (100 MHz , CDCl ₃ ) δ149.92, 147.16, 142.68, 128.69, 124.89,

Step two

Using the target product obtained in the first step as a substrate, 10 g (56.5 mmol), catalyst Ni(dppf)Cl ₂ (1.93 g, 2.8 mmol), ligand dppf (3.13 g, 5.56 mmol), zinc powder (0.367 g, 5.65mmol), cyanide zinc cyanide (4.23g, 45.2mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the oxygen content was controlled to be less than 0.03%, and the second mixed system was heated. After stirring to 80 ° C and stirring at 80 ° C for 3 h, TLC was traced to completion of the reaction of the starting material to obtain a second product system. After the second product system was cooled to room temperature, MTBE (60 mL) and 10% aqueous ammonia (130 mL) were added and mixed. The third mixed system, the third mixed system is left to stand, and the obtained aqueous phase is again extracted with MTBE (45 mL*2), and the obtained organic phase is added to 10% aqueous ammonia (20 mL), and the organic phase is separated again to obtain the organic phase. The obtained organic phases were combined, and then the pH of the organic phase was adjusted to 1-2 with a concentration of 4 mol/L HCl, and the liquid phase was separated, and the obtained aqueous phase was adjusted to pH 7-8 with a mass fraction of 30% NaOH for 1 to 2 hours. After the test, the pH of the aqueous phase is 7-8, and the precipitated solid is directly filtered, and the solid is dried to obtain 5.0 g of a white solid. Yield was 95%.

Product validation: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C ₆ H ₅ N ₂ [ M+H] ⁺ : 105.1; found for 105.1.

Example 2

The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(dppf)Cl ₂ (1.93 g, 2.8 mmol), ligand PPh ₃ (1.46 g, 5.56 mmol), zinc Powder (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the oxygen was controlled. The content is less than 0.03%, the second mixed system is heated to 80 ° C, and stirred at 80 ° C for 3 h, and then TLC is traced to the completion of the reaction of the starting material to obtain a second product system. After the second product system is cooled to room temperature, MTBE (60 mL) is added. And 10% ammonia water (130 mL) and mixed to form a third mixed system, the third mixed system was allowed to stand, and then separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL). After the liquid separation, the organic phase was again obtained, and the organic phase obtained by the above process was combined, and then the pH of the organic phase was adjusted to 1 to 2 with a concentration of 4 mol/L of HCl, and the liquid phase was obtained by using a mass fraction of 30% NaOH. After adjusting the pH to 7-8, stirring for 1 to 2 hours, the pH of the aqueous phase is 7-8, and the precipitate is directly filtered. , Solid dried to give a white solid 5.51g, 94% yield of the product.

Example 3

The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(dppf)Cl ₂ (0.77 g, 1.13 mmol), ligand dppf (1.28 g, 2.26 mmol), zinc powder. (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The combined phases were concentrated and purified by column chromatography eluting with petroleum ether / ethyl acetate = 10/1 (volume ratio) to give an oily liquid 5.57 g, yield 95%.

Example 4

The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl ₂ (0.19 g, 0.28 mmol), ligand dppf (0.31 g, 0.565 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The phases were combined and concentrated, and then purified, mjjjjjjj

Example 5

The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), a catalyst Ni (dppp)Cl ₂ (0.15 g, 0.28 mmol), a ligand dppp (0.23 g, 0.565 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The combined phases were concentrated and purified by column chromatography eluting with petroleum ether / ethyl acetate = 10/1 (volume ratio) to give an oily liquid 5.57 g, yield 95%.

Example 6

The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(dppp)Cl ₂ (0.15 g, 0.28 mmol), ligand PPh ₃ (0.15 g, 0.565 mmol), zinc Powder (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The second mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then placed in a system of MTBE (60 mL) and 10% ammonia (130 mL). After the liquid separation, the obtained aqueous phase was again extracted with MTBE (45 mL*2), the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the above process. The organic phase was combined and concentrated, and then purified tolulululululululululululu

Example 7

The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Pd(PPh ₃ ) ₄ (1.31 g, 1.13 mmol), ligand PPh ₃ (0.592 g, 2.26 mmol), zinc Powder (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The second mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then placed in a system of MTBE (60 mL) and 10% ammonia (130 mL). After the liquid separation, the obtained aqueous phase was again extracted with MTBE (45 mL*2), the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the above process. The organic phase was combined and concentrated, and then purified tolulululululululululululululu

Example 8

Using 4-benzoylsulfuryl fluoride as a substrate, 10 g (35.7 mmol), catalyst Ni(dppf)Cl ₂ (0.488 g, 0.714 mmol), ligand dppf (0.792 g, 1.43 mmol), zinc powder (0.232) g, 3.57 mmol), cyanide zinc cyanide (3.35 g, 28.56 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%, and the second mixture was mixed. The system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the starting material, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand for separation. The obtained aqueous phase was again extracted with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to combine the organic phases obtained in the above process. After concentration and column chromatography, the eluent petroleum ether / ethyl acetate = 10/1 (volume ratio) afforded 6.6 g of white solid.

^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.89 (s, 1H), 7.88 (s, 1H), 7.81 (m, 2H), 7.79 (m, 2H), 7.67-7.63 (m, 1H), 7.54 ( m,2H). ¹³ C NMR (100MHz, CDCl ₃ ) δ 195.17, 141.39, 136.50, 133.48, 132.33, 130.39, 130.22, 128.80, 118.17, 115.82. ESI-MS Calcd for C ₁₄ H ₁₀ NO[M+H] ⁺ :208.1;found for208.1

Example 9

Using 8-fluorosulfonyl quinolate as a substrate, 10 g (44.1 mmol), catalyst Ni(dppf)Cl ₂ (0.60 g, 0.88 mmol), ligand dppf (0.98 g, 1.76 mmol), zinc powder ( 0.287g, 4.41mmol), cyanide zinc cyanide (4.13g, 35.3mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%, and the second The mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the starting material, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to quench the system and allowed to stand. After the liquid separation, the obtained aqueous phase was again extracted with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined and concentrated, and then subjected to column chromatography. The eluent petroleum ether / ethyl acetate = 3 / 1 (volume ratio) gave a white solid 6.2 g yield 91%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.09 (dd, J = 4.2, 1.4 Hz, 1H), 8.25 (dd, J = 8.3, 1.5 Hz, 1H), 8.12 (dd, J = 7.2, 0.7 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.56 (dd, J = 8.3, 4.3 Hz, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 152.67, 147.65, 136.66, 135.69, 133.08, 128.30, 126.04, 122.95, 117.41, 113.29; ESI-MS Calcd for C ₁₀ H ₇ N ₂ [M+H] ⁺ : 155.1; found for 155.1.

Example 10

The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl ₂ (1.93 g, 2.8 mmol), ligand dppf (3.13 g, 5.56 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), potassium cyanide (5.88 g, 90.4 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 60 ° C, and stirred at 60 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The phases were combined and concentrated, and then purified and evaporated to ethyl ether.

Example 11

The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl ₂ (1.93 g, 2.8 mmol), ligand dppf (3.13 g, 5.56 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), sodium cyanide sodium cyanide (4.43 g, 90.4 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 100 ° C, and stirred at 100 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The phases were combined and concentrated, and then purified, mjjjjjjjj

Example 12

The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Cu(acac) ₂ (0.73 g, 2.8 mmol), ligand TMEDA (0.645 g, 5.56 mmol), zinc powder ( 0.367 g, 5.65 mmol), cyanide zinc cyanide (5.28 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%, and the second The mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The obtained aqueous phase was extracted again with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic phase obtained by the above process. After combined concentration and column chromatography, eluent petroleum ether / ethyl acetate = 10/1 (volume ratio) afforded 5.16 g of oily liquid.

Example 13

The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl ₂ (1.93 g, 2.8 mmol), ligand dppf (3.13 g, 5.56 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), cyanide zinc cyanide (3.97 g, 33.9 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The combined phases were concentrated and purified by column chromatography eluting with EtOAc EtOAc EtOAc

Example 14

The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl ₂ (3.86 g, 5.6 mmol), ligand dppf (9.39 g, 16.7 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), cyanide zinc cyanide (5.28 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The phases were combined and concentrated, and then purified tolulululululululululululululu

Example 15

The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst CuBr (0.40 g, 2.8 mmol), ligand DMEDA (0.49 g, 5.6 mmol), zinc powder (0.367 g, 5.65) were taken. Ment), cyanide zinc cyanide (5.28g, 45.2mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%, and the second mixed system was heated to After stirring at 80 ° C for 3 h at 80 ° C, TLC was traced until the reaction of the starting material was completed. After the system was cooled to 15-25 ° C, MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand for separation. The phase was extracted again with MTBE (45 mL*2), the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again. The organic phase obtained by the above process was combined, and the organic phase obtained by the above process was combined and concentrated. Chromatography, eluent petroleum ether / ethyl acetate = 10/1 (volume ratio) afforded 4.93 g of oily liquid, yield 84%.

Example 16

The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), a catalyst CuSO ₄ (0.45 g, 2.8 mmol), a ligand PPy ₃ (1.56 g, 5.6 mmol), and a zinc powder (0.367 g) were taken. , 5.65 mmol), cyanide zinc cyanide (5.28 g, 45.2 mmol) was added to 50 mL of toluene to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%, and the second mixed system was obtained. The temperature was raised to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the starting material, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand for separation. The obtained aqueous phase was extracted again with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again. The organic phase obtained by the above process was combined, and the organic phase obtained by the above process was combined and concentrated. After column chromatography, the eluent petroleum ether / ethyl acetate = 10/1 (volume ratio) afforded 4.75 g of oily liquid, yield 81%.

Example 17

The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(OAc) ₂ (0.199 g, 1.13 mmol), ligand TMEDA (0.26 g, 2.3 mmol), zinc powder ( 0.367 g, 5.65 mmol), K ₄ Fe(CN) ₆ (17.93 g, 16.9 mmol) was added to 50 mL of N,N-diethylbenzamide to obtain a second mixed system. After the second mixed system was replaced by nitrogen The oxygen content is controlled to be less than 0.03%, the second mixed system is heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC is traced to the completion of the reaction of the raw materials, the system is cooled to 15-25 ° C, and MTBE (60 mL) is added. After 10% ammonia (130 mL) system was allowed to stand, the liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% ammonia water (20 mL), and the organic phase was separated again to obtain the organic phase. The organic phase was combined, and the organic phase obtained by the above procedure was combined and concentrated, and then subjected to column chromatography, eluent petroleum ether / ethyl acetate = 10/1 (volume ratio) to obtain an oily liquid 5.0 g, yield 86%.

Example 18

The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(Py) ₂ Cl ₂ (0.325 g, 1.13 mmol), ligand DMEDA (0.206 g, 2.3 mmol), zinc Powder (1.84 g, 28.3 mmol), K ₄ Fe(CN) ₆ (17.93 g, 16.9 mmol) was added to 50 mL of NMP to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the oxygen content was controlled to be less than 0.03%. The second mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added. After standing, the liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined. The obtained organic phases were combined and concentrated, and then purified, mjjjjjjj

Example 19

The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl ₂ (7.7 g, 11.3 mmol), ligand dppf (12.8 g, 22.6 mmol), zinc powder were taken. (3.67g, 56.5mmol), cyanide zinc cyanide (4.23g, 45.2mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. After the liquid separation, the obtained aqueous phase was again extracted with MTBE (45 mL*2), the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the above process. The organic phase was combined and concentrated, and then purified, mjjjjjjj

Example 20

The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(dppf)Cl ₂ (0.77 g, 1.13 mmol), ligand dppf (1.28 g, 2.26 mmol), zinc powder. (0.184 g, 2.83 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The phases were combined and concentrated, and then purified, mjjjjjjjj

Example 21

2-Acetyl-5-sulfonylfluorothiophene as a substrate, 9.9 g (44.1 mmol), catalyst Ni(dppf)Cl ₂ (0.60 g, 0.88 mmol), ligand dppf (0.98 g, 1.76 mmol), zinc powder (0.287g, 4.41mmol), cyanide zinc cyanide (4.13g, 35.3mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the starting material, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to quench the system. After the liquid separation, the obtained aqueous phase was again extracted with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and then the organic phase was separated, and the organic phase obtained by the above process was combined and concentrated. Eluent petroleum ether / ethyl acetate = 3 / 1 (volume ratio) gave a white solid 6.1 g yield of 92%.

^{1 H NMR (500MHz; CDCl3)} : δ7.63 (d, J = 4.0Hz, 1H), 7.61 (d, J = 4.0Hz, 1H), 2.60 (s, 3H); 13 C NMR (125MHz; CDCl3) : δ189.9, 149.9, 137.8, 131.3, 116.4, 113.4, 27.2

Example 22

7-sulfonyl fluoride-4-methylcoumarin as a substrate, 11.38 g (44.1 mmol), catalyst Ni(dppf)Cl ₂ (0.60 g, 0.88 mmol), ligand dppf (0.98 g, 1.76 mmol) Zinc powder (0.287g, 4.41mmol), cyanide zinc cyanide (4.13g, 35.3mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The second mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the starting material, the system was cooled to 15-25 ° C, and then quenched by adding MTBE (60 mL) and 10% ammonia water (130 mL). The system was separated, and the liquid phase was separated, and the obtained aqueous phase was extracted again with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined and concentrated. Column chromatography, eluent petroleum ether / ethyl acetate = 3 / 1 (volume ratio) afforded a white solid 7.58 g yield 93%.

^{1 H NMR (500MHz; CDCl3)} : δ7.71 (d, J = 8.2Hz, 1H), 7.61 (d, J = 1.6Hz, 1H), 7.57 (dd, J = 8.1,1.6Hz, 1H), 6.43 (q, J = 1.4 Hz, 1H), 2.47 (d, J = 1.3 Hz, 3H); ¹³ C NMR (125 MHz; CDCl3): δ 159.2, 153.2, 151.0, 127.5, 125.8, 123.7, 120.9, 117.9, 117.5, 115.0, 18.8

Through the synthesis process and the results of the above various examples, it can be seen that at a lower reaction temperature, a higher conversion rate can still be obtained; and the catalyst used is a non-precious metal catalyst and can be obtained when the amount is small. The ideal catalytic effect, at the same time, a higher conversion rate; further, since the conversion rate is high, the present application can achieve a yield of 80% or more by the above conventional purification method.

From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:

The above preparation method adopts an aryl compound having the general formula II as a substrate, and the preparation of the substance is relatively easy with respect to the aryl halide, thereby reducing the cost of preparing the aryl nitrile compound; and the activity of the substance is higher than that of the prior art. The commonly used aromatic substrate is high, so the required reaction temperature is lower during the cyanation reaction, further reducing the energy consumption of the preparation method, and also reducing the synthesis cost from this aspect; in addition, due to the activity of the substance Higher, so the requirements for the catalyst are relatively reduced, making the use of some non-precious metal catalysts possible, while also reducing the amount of catalyst, thereby further reducing the synthesis cost; further, because of the higher activity of the substance, its conversion rate Higher, then reduces the complexity and complexity of the product separation and recovery process, which in turn can reduce the cost of synthesis.

The above description is only the preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes can be made to the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and scope of the present invention are intended to be included within the scope of the present invention.

Claims

A method for producing an aryl nitrile compound, characterized in that the aryl nitrile compound has the formula I:

The preparation method comprises:

Taking an aryl compound having the general formula II as a substrate,

Wherein n = 0 to 1, X 1 , X 2 , X 3 and X 4 are each independently selected from any one of N, S, O and C in a chemically acceptable structure; Y is OSO 2 F , OTf or OTs; R 1 , R 2 , R 3 and R 4 are each independently selected from any one of H, an alkyl group, an aryl group and a halogen.

The aryl compound is cyanated with a cyanogen source under the catalytic action of a catalyst, a reducing agent and a ligand to obtain the aryl nitrile compound.
The method according to claim 1, wherein the cyanogen source is one or more selected from the group consisting of K 4 Fe(CN) 6 , Zn(CN) 2 , KCN and NaCN.
The preparation method according to claim 1, wherein the catalyst is a non-noble metal salt, and preferably the non-noble metal salt is selected from the group consisting of CuI, CuBr, CuCl, Cu(OAc) 2 , Cu(acac) 2 , Cu ( OTf) 2 , CuI 2 , CuCl 2 , CuSO 4 , NiX 2 , Ni(OAc) 2 , NiX 2 (dppf), NiX 2 (dppe), NiX 2 (dppp), Ni(PCy3)X 2 and Ni (Py Any one or more of the group consisting of 2 Cl 2 wherein X represents a halogen.
The preparation method according to claim 1, wherein the ligand is an amino ligand or a phosphine ligand, and preferably the amino ligand is tetramethylethylenediamine or N-N'dimethylethylene. An amine or an ethylenediamine, preferably the phosphine ligand is triphenylphosphine, 1,1-bis(diphenylphosphino)ferrocene, 1,2-bis(diphenylphosphino)ethane, 1,3- Bis(diphenylphosphino)propane or tricyclohexylphosphine.
The process according to claim 1, wherein the cyanation reaction is carried out in a solvent, preferably the solvent is dimethylformamide, N-methylpyrrolidone, N,N-diethyl The amide, dimethyl sulfoxide, toluene, 1,4-dioxane or acetonitrile preferably has a volume ratio of the solvent to the aryl compound of from 5 to 10:1.
The process according to claim 1, wherein the cyanation reaction is carried out in the range of from 60 to 100 °C.
The preparation method according to claim 1 or 2, wherein a molar ratio of cyanogen to the aryl compound in the cyanogen source is 1:1 to 1.6:1.
The process according to claim 1 or 3, wherein the molar ratio of the catalyst to the aryl compound is from 0.005:1 to 0.2:1, preferably from 0.02:1 to 0.1:1.
The production method according to claim 1 or 4, wherein the molar ratio of the catalyst to the ligand is from 1:1 to 1:10, preferably from 1:1 to 1:3.
The preparation method according to claim 1, wherein the reducing agent is zinc powder, and the molar ratio of the zinc powder to the aryl compound is 0.05:1 to 1:1, preferably 0.1:1. 0.5:1.