A method for catalytic synthesis of 4-methyl-2-cyanobiphenyl

Abstract

The present invention relates to a method for catalytically synthesizing 4-methyl-2-cyanobiphenyl. First, a polymer containing a phosphine ligand and a crown ether is prepared and applied to the Suzuki reaction. Adding this polymer and palladium metal to the reaction system can efficiently catalyze the reaction between 2-chlorobenzonitrile and 4-methylphenylboronic acid, and 4-methyl-2-cyanobiphenyl can be efficiently synthesized using a mixed system of water and an organic solvent as the reaction solvent. Compared with traditional ligands, the ligand catalyst in this system can effectively activate the aryl chloride bond, and together with the phosphine ligand and the phase transfer catalyst crown ether 18-crown-6, it is immobilized. This palladium catalyst is very stable, and the reaction can be carried out under the condition of extremely low catalyst dosage, and the catalytic effect loss is not obvious after being recycled multiple times. The preparation method of this catalyst is simple, the reaction efficiency is greatly improved, and it can be used to synthesize the pharmaceutical intermediate (4-methyl-2-cyanobiphenyl) of the new type of sartan antihypertensive drug, with good application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical and chemical engineering, and in particular to a method for catalytically synthesizing 4-methyl-2-cyanobiphenyl, and in particular to a process for synthesizing 4-methyl-2-cyanobiphenyl by catalyzing a Suzuki reaction of 2-chlorobenzonitrile and 4-methylphenylboronic acid using a palladium catalyst immobilized with a phosphine-containing ligand and a crown ether polymer. Background Art

[0002] 4-Methyl-2-cyanobiphenyl, a key pharmaceutical intermediate, is primarily used in the synthesis of angiotensin II antagonists and novel sartan antihypertensive drugs, such as losartan, valsartan, iprosartan, and irbesartan. Sartans have a novel mechanism of action, offer stable blood pressure reduction, few adverse reactions, significant efficacy, long-lasting effects, and good patient tolerance. They occupy a key position in the hypertension drug market and are a first-line treatment for hypertension, with broad market development prospects. 4-Methyl-2-cyanobiphenyl, a key intermediate for this class of drugs, is synthesized primarily through aromatization ring closure, multi-step synthesis, and catalytic one-step synthesis. Due to the limitation of raw materials, the aromatic ring-closure synthesis method is only of laboratory research value. The multi-step synthesis method generates a large amount of waste during the reaction and has high overall production costs. However, the Suzuki cross-coupling reaction of 2-chlorobenzonitrile and 4-methylphenylboronic acid is used to catalyze the one-step synthesis of 4-methyl-2-cyanobiphenyl. It has the advantages of fewer steps, low cost, high efficiency, good selectivity, and cheap and readily available raw materials. It is an effective method for industrial application.

[0003] However, in the Suzuki coupling reaction, the various commonly used aromatic halides primarily include iodoaryls, bromoaryls, and chloroaryls, and their reactivity decreases in descending order. The relative reactivity of leaving groups in typical halogenated aromatic substrates follows the following pattern: I->OTf->Br->Cl-. This means that compared to C-Br and Cl-C bonds, C-Cl bonds are less easily activated and less prone to Suzuki reactions. Compared to brominated and iodoaryl substrates, chloroaryl substrates are less active and require more stringent reaction conditions. However, they are also more affordable and readily available, making them ideal starting materials for coupling reactions. However, their low reactivity significantly limits their practical production and application. Therefore, the development of efficient catalysts for the Suzuki coupling reaction of chloroaryl substrates is crucial.

[0004] Crown ether 18-crown-6 is a common phase transfer catalyst, typically used in heterogeneous reactions involving potassium ions. However, 18-crown-6 is typically added all at once, resulting in large quantities and difficult recovery. Since palladium-catalyzed cross-coupling reactions require the use of aromatic halides and aromatic boronic acids, as well as inorganic bases, palladium catalysts combined with phosphine-containing ligands and crown ether 18-crown-6 are particularly effective in achieving these cross-coupling reactions.

[0005] In recent years, there have been studies on the Suzuki cross-coupling reaction and Pd-based catalysts for catalyzing haloarenes and organobenzeneboronic acid or its derivatives to form C-C bonds, as well as the synthesis of biphenyl compounds such as the key intermediate of sartan drugs, 4-methyl-2-cyanobiphenyl.

[0006] Early on, Carini et al. applied the Meyer reaction. Using o-methoxybenzoic acid as the raw material, 4-methyl-2-cyanobiphenyl was finally synthesized through the intermediate oxazoline (Carini DJ, Duncia JV, Aldrich PE, et al. Nonpeptide angiotensin Ⅱ receptor antagonists: the discovery of a Series of N-(biphenylylmethyl)imidazoles as potent, orally active antihypertensives[J]. J Med Chem, 1991, 34(8):2522-2547). Although the initial raw materials of this synthesis method are relatively cheap and there are no by-products of dimethylbiphenyl, this method has a long route, consumes a large amount of auxiliary materials, requires high equipment, and is not easy to industrialize.

[0007] In addition, 4-methyl-2-cyanobiphenyl was synthesized by the Grignard reaction using arylphosphine complexes of palladium and copper(I) bromide as catalysts respectively (Herrmann WA, Brossmer C, Oefele K, et al. Palladacycles as structurally defined catalysts for the Heck olefination of chloro- and bromoarenes, Angew Chem Int Ed Engl. 1995, 34(17), 1844-1847). However, the Grignard reaction in the process is highly dangerous and difficult to apply industrially; moreover, the catalyst and the product are difficult to separate and cannot be reused.

[0008] Secondly, some literature has also reported a catalytic system for Suzuki coupling in the coupling reaction of o-chlorobenzonitrile and arylboronic acid (Yu-Long Zhao, You Li, Shui-Ming Li, et al. Adv. Synth. Catal. 2011, 353, 1543-1550.) without the need for ligands. However, during the reaction process, this catalytic system faces disadvantages such as high toxicity of the reaction medium, high reaction temperature, and inability to be recycled.

[0009] 4-Methyl-2-cyanobiphenyl can also be synthesized by the Suzuki coupling method. Suzuki et al. used Pd(pph3)4 as a catalyst to catalyze the coupling of 4-methylphenylboronic acid and 2-bromobenzyl cyanide under alkaline conditions (Miyaura N., Yanggi T., Suzuki A. The palladium-catalyzed cross-coupling reaction of phenylboronic acid with halorenes in the presence of bases[J]. Synth Commumn, 1981, 11(7): 513-519). This synthetic route is short, the yield of the catalytic coupling reaction is relatively high, and the product is easy to purify. However, the raw material bromide is expensive, and affected by the catalytic activity of Pd(pph3)4, it cannot be used to catalyze the coupling of 2-chlorobenzyl cyanide with easily available and inexpensive raw materials, which limits its industrial application.

[0010] With the in-depth research, for the Suzuki coupling reaction, other metals such as Pt, Cu, Ni, and Ru can all catalyze this reaction well, but palladium catalysis is still the main one. The metal catalytic system mainly focuses on the use of various ligands, mainly phosphine ligands. For some classic catalysts: Pd(pph3)4, PdCl2, PdCl2(dppf), Pd(pph3)2Cl2, and NiCl2(dppf), etc., they have mature applications in specific reactions. In the traditional Suzuki reaction involving arylphosphine ligands such as PPh3 and dppf, generally, oxidative addition is the rate-determining step, while bulky electron-rich phosphine ligands can greatly promote oxidative addition and reductive elimination, and at the same time inhibit transmetalation, making transmetalation the rate-determining step. That is, the traditional non-bulky phosphine ligands first facilitate the preferential reaction of bromides. Therefore, developing highly efficient and inexpensive new catalysts and bulky electron-rich phosphine ligands to facilitate the preferential reaction of chlorides has very important practical value.

[0011] Therefore, in this field, the method of synthesizing sartan biphenyl by transition metal catalysis is still generally adopted. However, developing green and recyclable catalysts is a current hot topic, and there is an urgent need to provide a process technology with inexpensive raw materials, simple operation, concise steps, low equipment cost, and meeting the requirements of environmental friendliness to produce sartan biphenyl. Summary of the Invention

[0012] The object of the present invention is to provide a method for catalytically synthesizing 4-methyl-2-cyanobiphenyl to improve the deficiencies of the prior art. In the prior art, there are problems such as a long synthesis route, a complex process, multiple-step conversions, many by-products, expensive raw material bromides, and being unable to catalyze the coupling of 2-chlorobenzonitrile with easily available and inexpensive raw materials due to the influence of the catalytic activity of Pd(pph3)4. In view of these limitations, a method for catalytically synthesizing 4-methyl-2-cyanobiphenyl is provided. The present invention prepares a palladium catalyst containing a phosphine ligand and a crown ether polymer. The preparation process of the catalyst is simple, the initial raw materials are relatively inexpensive and easy to purchase, and it is applied to the research of the key intermediate 4-methyl-2-cyanobiphenyl of sartan drugs. The reaction is carried out under relatively mild conditions, environmentally friendly reagents are used in the process, the yield is high, and the recovery effect is stable.

[0013] The technical solution of the present invention is as follows: A method for catalytically synthesizing 4-methyl-2-cyanobiphenyl, and its specific steps are as follows:

[0014] a) Bis(dicyclohexylphosphinophenyl) ether and dibenzo-18-crown-6-ether are heated and reacted in aluminum trichloride and dimethoxymethane to obtain a polymer;

[0015] b) Catalytic synthesis of 4-methyl-2-cyanobiphenyl: Add 2-chlorobenzonitrile, 4-methylphenylboronic acid, a base and a solvent to a reaction kettle. Under a protective atmosphere, after stirring, add a palladium salt and the polymer obtained in step a) to the above reaction system,

[0016] heat and react to obtain 4-methyl-2-cyanobiphenyl.

[0017] The reaction formula is as follows:

[0018]

[0019] The step diagram is as follows:

[0020]

[0021]

[0022] Reaction mechanism of the catalytic cycle process:

[0023] It is generally considered that first, Pd(0) undergoes an oxidative addition reaction with a haloarene to generate a Pd(II) complex 1, then undergoes a transmetalation reaction with an activated boric acid to generate a Pd(II) complex 2, and finally undergoes a reductive elimination to generate the product and Pd(0).

[0024]

[0025] Preferably, in step a), the mass ratio of bis(dicyclohexylphosphinophenyl) ether to dibenzo-18-crown-6-ether is 1:(0.8 - 1.2); the addition amount of dimethoxymethane is controlled such that the volume ratio of dimethoxymethane to the mass of aluminum trichloride is 5 - 6 ml / g; the mass ratio of aluminum trichloride to bis(dicyclohexylphosphinophenyl) ether is (5 - 6):1.

[0026] Preferably, in step a), the heating temperature is 150°C - 160°C and the reaction time is 5 - 6 h. The polymer after the reaction is washed with sodium hydroxide solution to remove the excess aluminum ions, and then washed with water until neutral. The washed product is dried in a vacuum environment to obtain a phosphine ligand and crown ether polymer.

[0027] Preferably, in step b), the base is potassium phosphate or potassium carbonate; the palladium salt is palladium acetate; the solvent is water or a mixture of water and 1,4-dioxane; the protective atmosphere is nitrogen or argon.

[0028] Preferably, in step b), the molar ratio of 2-chlorobenzonitrile to 4-methylphenylboronic acid is 1:(1.0 - 1.2); the molar ratio of the base to 2-chlorobenzonitrile is (2.0 - 4.0):1; the added mass of the polymer is 14.5% - 18.2% of the mass of 2-chlorobenzonitrile; the added molar amount of the palladium salt is 0.05 - 1.0 mol% of 2-chlorobenzonitrile; in the said solvent: the mass ratio of the added amount of water to 2-chlorobenzonitrile is (1.5 - 5.5):1; the volume ratio of 1,4-dioxane to water is (0.5 - 2.0):1.

[0029] Preferably, in step b), the reaction temperature is 100 - 140°C; the reaction time is 2.0 - 10 h.

[0030] After the reaction in step b) ends, the reaction kettle is taken out and cooled to room temperature, sampled, and the conversion rate and selectivity are detected by gas chromatography. The reaction solution is filtered to separate from the catalyst, and the catalyst after the reaction separation is washed with water and dried for reuse.

[0031] The present invention screens ligands that can efficiently catalyze haloarenes (especially chloroarenes) under relatively mild conditions, and synthesizes a palladium catalyst containing a phosphine ligand and a crown ether polymer, which can efficiently realize the Suzuki reaction of 2-chlorobenzonitrile and 4-methylphenylboronic acid to obtain 4-methyl-2-cyanobiphenyl in a reaction solvent of a mixed system of water and an organic solvent. Compared with homogeneous catalysts that cannot be recycled after the reaction, the Pd catalyst used in this reaction process can be prepared on a relatively large scale, has high catalyst activity, and can be recycled five times with no obvious loss in catalytic effect.

[0032] Beneficial effects:

[0033] 1) It avoids the problem of generating a large amount of waste during the multi-step synthesis reaction process, reduces the comprehensive production cost, the reaction does not require multi-step operations, and the product is easy to separate. 2) The raw materials avoid the use of expensive bromides, and provide a method for synthesizing 4-methyl-2-cyanobiphenyl by coupling catalytically available and inexpensive 2-chlorobenzonitrile. 3) The reaction can be efficiently achieved under relatively mild conditions in a mixed system of water and organic solvents as the reaction solvent, and can be carried out under the condition of extremely low catalyst dosage. 4) A suitable phosphine-containing ligand is selected as the ligand of palladium to catalyze the Suzuki coupling reaction of chlorinated aryl substrates with relatively low reaction activity. 5) The preparation process of the catalyst is simple, the prepared catalyst has high activity, stability, and still has high activity during multiple recycling reactions. Detailed implementation manners

[0034] Example 1:

[0035] Bis(dicyclohexylphosphinophenyl) ether and dibenzo-18-crown-6-ether were used in a mass ratio of (1:0.8) to prepare a palladium catalyst containing a phosphine ligand and a crown ether polymer. Under the protection of inert gas nitrogen, 0.50 g of the phosphine compound bis(dicyclohexylphosphinophenyl) ether and 0.40 g of the crown ether compound dibenzo-18-crown-6-ether were added to 15 ml of dimethoxymethane, and then 3.0 g of aluminum trichloride was added thereto and stirred evenly. The above mixture was transferred to a polytetrafluoroethylene inner liner and reacted in a reaction kettle at 150 °C for 5 h. The reacted polymer was washed with a sodium hydroxide solution to remove excess aluminum ions, and then washed with water until neutral. The washed product was dried in a vacuum environment to obtain a phosphine ligand and crown ether polymer P1.

[0036] Example 2:

[0037] Bis(dicyclohexylphosphinophenyl) ether and dibenzo-18-crown-6-ether were used in a mass ratio of (1:1) to prepare a palladium catalyst containing a phosphine ligand and a crown ether polymer. Under the protection of inert gas nitrogen, 0.50 g of the phosphine compound bis(dicyclohexylphosphinophenyl) ether and 0.50 g of the crown ether compound dibenzo-18-crown-6-ether were added to 15 ml of dimethoxymethane, and then 3.0 g of aluminum trichloride was added thereto and stirred evenly. The above mixture was transferred to a polytetrafluoroethylene inner liner and reacted in a reaction kettle at 150 °C for 5 h. The reacted polymer was washed with a sodium hydroxide solution to remove excess aluminum ions, and then washed with water until neutral. The washed product was dried in a vacuum environment to obtain a phosphine ligand and crown ether polymer P2.

[0038] Example 3:

[0039] Bis(dicyclohexylphosphinophenyl) ether and dibenzo-18-crown-6-ether are used in a mass ratio of (1:1.2) to prepare a palladium catalyst containing a phosphine ligand and a crown ether polymer. Under the protection of an inert gas, nitrogen, 0.50 g of the phosphine compound bis(dicyclohexylphosphinophenyl) ether and 0.60 g of the crown ether compound dibenzo-18-crown-6-ether are added to 15 ml of dimethoxymethane. Subsequently, 3.0 g of aluminum trichloride is added thereto and stirred evenly. The above-mentioned mixed solution is transferred to a polytetrafluoroethylene inner liner and reacted in a reaction kettle at 150 °C for 5 h. The reacted polymer is washed with a sodium hydroxide solution to remove excess aluminum ions, and then washed with water until neutral. The washed product is dried in a vacuum environment to obtain a phosphine ligand and crown ether polymer P3.

[0040] Example 4:

[0041] Under the protection of an inert gas, argon, 0.50 g of the phosphine compound bis(dicyclohexylphosphinophenyl) ether and 0.50 g of the crown ether compound dibenzo-18-crown-6-ether are added to 18 ml of dimethoxymethane. Subsequently, 3.0 g of aluminum trichloride is added thereto and stirred evenly. The above-mentioned mixed solution is transferred to a polytetrafluoroethylene inner liner and reacted in a reaction kettle at 150 °C for 5 h. The reacted polymer is washed with a sodium hydroxide solution to remove excess aluminum ions, and then washed with water until neutral. The washed product is dried in a vacuum environment to obtain a phosphine ligand and crown ether polymer P4.

[0042] Example 5:

[0043] Under the protection of an inert gas, argon, 0.50 g of the phosphine compound bis(dicyclohexylphosphinophenyl) ether and 0.50 g of the crown ether compound dibenzo-18-crown-6-ether are added to 15 ml of dimethoxymethane. Subsequently, 2.5 g of aluminum trichloride is added thereto and stirred evenly. The above-mentioned mixed solution is transferred to a polytetrafluoroethylene inner liner and reacted in a reaction kettle at 150 °C for 5 h. The reacted polymer is washed with a sodium hydroxide solution to remove excess aluminum ions, and then washed with water until neutral. The washed product is dried in a vacuum environment to obtain a phosphine ligand and crown ether polymer P5.

[0044] Example 6:

[0045] Under the protection of inert gas nitrogen, 0.50 g of phosphine compound bis(dicyclohexylphosphinophenyl) ether and 0.50 g of crown ether compound dibenzo-18-crown-6-ether were added to 15 ml of dimethoxymethane. Subsequently, 3.0 g of aluminum trichloride was added thereto and stirred evenly. The above-mentioned mixed solution was transferred to a polytetrafluoroethylene inner liner and reacted in a reaction kettle at 160 °C for 5 h. The polymer after the reaction was washed with sodium hydroxide solution to remove the excess aluminum ions, and then washed with water until neutral. The washed product was dried in a vacuum environment to obtain a phosphine ligand and crown ether polymer P6.

[0046] Example 7:

[0047] Under the protection of inert gas nitrogen, 0.50 g of phosphine compound bis(dicyclohexylphosphinophenyl) ether and 0.50 g of crown ether compound dibenzo-18-crown-6-ether were added to 15 ml of dimethoxymethane. Subsequently, 3.0 g of aluminum trichloride was added thereto and stirred evenly. The above-mentioned mixed solution was transferred to a polytetrafluoroethylene inner liner and reacted in a reaction kettle at 150 °C for 6 h. The polymer after the reaction was washed with sodium hydroxide solution to remove the excess aluminum ions, and then washed with water until neutral. The washed product was dried in a vacuum environment to obtain a phosphine ligand and crown ether polymer P7.

[0048] Example 8:

[0049] 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, and 2122.66 mg (10.0 mmol) of potassium phosphate were added to the reaction kettle. 1.5 mL of water and 1.5 mL of 1,4-dioxane were added. After stirring evenly, 100 mg of P1 and 1.0 mg of palladium acetate (palladium content is 45%) were added to the above reaction kettle; the equivalent of palladium was 0.1 mol% of 2-chlorobenzonitrile; nitrogen was evacuated and replaced three times. Under a nitrogen atmosphere, the above reaction system was heated and reacted at 140 °C for 5 h. After the reaction was completed, the reaction kettle was taken out and cooled to room temperature. The reaction solution was filtered to separate the catalyst. The separated catalyst was washed with water and dried for standby. The reaction solution was sampled and detected by chromatography. The yield of 4-methyl-2-cyanobiphenyl was 92%.

[0050] Example 9:

[0051] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 1.5 mL of water and 1.5 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 100 mg of P2 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile; evacuate and replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for later use (named C1). Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 99%.

[0052] Example 10:

[0053] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 1.5 mL of water and 1.5 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 100 mg of P3 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile; evacuate and replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for later use. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 94%.

[0054] Example 11:

[0055] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 1.5 mL of water and 1.5 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 100 mg of P4 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile; evacuate and replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for later use. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 96%.

[0056] Example 12:

[0057] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 1.5 mL of water and 1.5 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 100 mg of P5 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile; evacuate and replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 8 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for later use. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 91%.

[0058] Example 13:

[0059] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 1.5 mL of water and 1.5 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 100 mg of P6 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile; evacuate and replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for later use. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 97%.

[0060] Example 14:

[0061] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 1.5 mL of water and 1.5 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 100 mg of P7 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile; evacuate and replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for later use. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 99%.

[0062] Example 15:

[0063] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate into the reaction kettle. Add 3.0 mL of water, stir evenly, then add 100 mg of P2 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile. Purge with nitrogen three times. Under a nitrogen atmosphere, heat the above reaction system at 140 °C for 10 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for standby. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 90%.

[0064] Example 16:

[0065] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 1382.06 mg (10.0 mmol) of potassium carbonate into the reaction kettle. Add 1.5 mL of water and 1.5 mL of 1,4-dioxane, stir evenly, then add 100 mg of P2 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile. Purge with nitrogen three times. Under a nitrogen atmosphere, heat the above reaction system at 140 °C for 10 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for standby. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 94%.

[0066] Example 17:

[0067] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 543.84 mg (4.0 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate into the reaction kettle. Add 1.5 mL of water and 1.5 mL of 1,4-dioxane, stir evenly, then add 100 mg of P2 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile. Purge with nitrogen three times. Under a nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for standby. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 95%.

[0068] Example 18:

[0069] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 1698.13 mg (8.0 mmol) of potassium phosphate, 1.5 mL of water and 1.5 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 100 mg of P2 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile; evacuate and replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for standby. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 96%.

[0070] Example 19:

[0071] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 2.0 mL of water and 1.0 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 100 mg of P2 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile; evacuate and replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for standby. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 95%.

[0072] Example 20:

[0073] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 1.0 mL of water and 2.0 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 100 mg of P2 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile; evacuate and replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for standby. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 93%.

[0074] Example 21:

[0075] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 1.5 mL of water and 1.5 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 80 mg of P2 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile. Replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for later use. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 86%.

[0076] Example 22:

[0077] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 1.5 mL of water and 1.5 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 100 mg of P2 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile. Replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 3 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for later use. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 97%.

[0078] Example 23:

[0079] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 1.5 mL of water and 1.5 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 100 mg of P2 and 1.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.1 mol% of 2-chlorobenzonitrile. Replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 130 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for later use. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 93%.

[0080] Example 24:

[0081] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 1.5 mL of water and 1.5 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 100 mg of P2 and 0.5 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.05 mol% of 2-chlorobenzonitrile. Replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for standby. Sample the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 88%.

[0082] Example 25:

[0083] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 1.5 mL of water and 1.5 mL of 1,4-dioxane into the reaction kettle. After stirring evenly, add 100 mg of P2 and 0.5 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.05 mol% of 2-chlorobenzonitrile. Replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 10 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for standby. Sample the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 94%.

[0084] Example 26:

[0085] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, 3.0 mL of water into the reaction kettle. After stirring evenly, add 100 mg of P2 and 5.0 mg of palladium acetate (palladium content is 45%) into the above reaction kettle; the equivalent of palladium is 0.5 mol% of 2-chlorobenzonitrile. Replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for standby. Sample the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 99%.

[0086] Example 27:

[0087] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 1382.06 mg (10.0 mmol) of potassium carbonate, add 3.0 mL of water to the reaction kettle. After stirring evenly, add 100 mg of P2 and 5.0 mg of palladium acetate (palladium content is 45%) to the above reaction kettle; the equivalent of palladium is 0.5 mol% of 2-chlorobenzonitrile; evacuate and replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for standby. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 92%.

[0088] Example 28:

[0089] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2073.09 mg (15.0 mmol) of potassium carbonate, add 3.0 mL of water to the reaction kettle. After stirring evenly, add 100 mg of P2 and 5.0 mg of palladium acetate (palladium content is 45%) to the above reaction kettle; the equivalent of palladium is 0.5 mol% of 2-chlorobenzonitrile; evacuate and replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 140 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for standby. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 98%.

[0090] Example 29:

[0091] Add 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate, add 1.5 mL of water and 1.5 mL of 1,4-dioxane to the reaction kettle. After stirring evenly, add 100 mg of P2 and 5.0 mg of palladium acetate (palladium content is 45%) to the above reaction kettle; the equivalent of palladium is 0.5 mol% of 2-chlorobenzonitrile; evacuate and replace nitrogen three times. Under the nitrogen atmosphere, heat the above reaction system at 110 °C for 5 h. After the reaction is completed, take out the reaction kettle and cool it to room temperature. Filter the reaction solution to separate it from the catalyst. The separated catalyst is washed with water and dried for standby. Take a sample of the reaction solution and detect it by chromatography. The yield of 4-methyl-2-cyanobiphenyl is 86%.

[0092] Example 30:

[0093] 550.28 mg (4.0 mmol) of 2-chlorobenzonitrile, 652.61 mg (4.8 mmol) of 4-methylphenylboronic acid, 2122.66 mg (10.0 mmol) of potassium phosphate were added to a reaction kettle, 1.5 mL of water and 1.5 mL of 1,4-dioxane were added. After stirring evenly, 100 mg of P2 and 5.0 mg of palladium acetate (palladium content was 45%) were added to the above reaction kettle; the equivalent of palladium was 0.5 mol% of 2-chlorobenzonitrile; nitrogen was evacuated and replaced three times. Under a nitrogen atmosphere, the above reaction system was heated at 130 °C for 5 h. After the reaction was completed, the reaction kettle was taken out and cooled to room temperature. The reaction solution was filtered to separate the catalyst. The separated catalyst was washed with water and dried for standby. The reaction solution was sampled and detected by chromatography. The yield of 4-methyl-2-cyanobiphenyl was 99%.

[0094] Table:

[0095] The catalyst after washing and drying in Example 9 was reused. The process flow was the same as that of the implementation example. The recycling situation of the catalyst is as follows in the table:

[0096] Recovery times Yield of 4-methyl-2-cyanobiphenyl 1 96％ 2 94％ 3 94％ 4 93％ 5 90％

Claims

1. A method for catalytic synthesis of 4-methyl-2-cyanobiphenyl, the specific steps are as follows: a) React bis(dicyclohexylphosphinophenyl) ether and dibenzo-18-crown-6-ether by heating in aluminum trichloride and dimethoxymethane to obtain a polymer; the mass ratio of bis(dicyclohexylphosphinophenyl) ether to dibenzo-18-crown-6-ether is 1:(0.8 - 1.2); the addition amount of dimethoxymethane is controlled so that the volume ratio of dimethoxymethane to the mass of aluminum trichloride is 5 - 6 ml / g; the mass ratio of aluminum trichloride to bis(dicyclohexylphosphinophenyl) ether is (5 - 6):1; the heating temperature is 150°C - 160°C, and the reaction time is 5 - 6 h; b) Catalytic synthesis of 4-methyl-2-cyanobiphenyl: Add 2-chlorobenzonitrile, 4-methylphenylboronic acid, a base and a solvent into a reaction kettle. Under a protective atmosphere, after stirring, add a palladium salt and the polymer obtained in step a) into the above reaction system, and heat and react to obtain 4-methyl-2-cyanobiphenyl; the molar ratio of 2-chlorobenzonitrile to 4-methylphenylboronic acid is 1:(1.0 - 1.2); the molar ratio of the base to 2-chlorobenzonitrile is (2.0 - 4.0):1; the added mass of the polymer is 14.5% - 18.2% of the mass of 2-chlorobenzonitrile; the added molar amount of the palladium salt is 0.05 - 1.0 mol% of 2-chlorobenzonitrile; in the said solvent: the mass ratio of the added amount of water to 2-chlorobenzonitrile is (1.5 - 5.5):1; the solvent is water or a mixture of water and 1,4-dioxane; the volume ratio of 1,4-dioxane to water is (0.5 - 2.0):

1.

2. The method according to claim 1, wherein The base described in step b) is potassium phosphate or potassium carbonate; the palladium salt is palladium acetate; the protective atmosphere is nitrogen or argon.

3. The method according to claim 1, characterized in that In step b), the reaction temperature is 100 - 140°C; The reaction time is 2.0 - 10 h.

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