Preparation method and application of a pre-activated type Pd (II)-P catalyst

Abstract

The application provides a preparation method and application of a pre-activated Pd (II)-P catalyst, and belongs to the technical field of chemical catalysis. In the structure of the pre-activated Pd (II)-P catalyst, N and C are respectively coordinated with Pd (II) to construct a stable five-membered ring chelate system, ppy, X and PR3 jointly maintain the stability of the Pd (II) center in a "dormant state", and R-C-Pd-X bonds constitute the core site of the oxidative addition step in a coupling reaction, so that the oxidative addition energy barrier that needs to be overcome in the activation process of a catalytic precursor is avoided, and the activation of a new (PR3) n -Pd (0) is a key structural unit; the introduction of PR3 with large steric hindrance can enhance the "dormant state" stability of the Pd (II) center through the steric hindrance effect of ppy ligands, and can also prevent the Pd (0) generated by the reduction and activation of Pd (II) from agglomerating into palladium black, and improve the yield of a catalytic synthesis product.

Description

Technical Field

[0001] This invention belongs to the field of chemical catalysis technology, specifically relating to a method for preparing and applying a pre-activated Pd(II)-P catalyst. Background Technology

[0002] In palladium-catalyzed coupling reactions, the valence state characteristics and chemical structure of the palladium center in the catalytic precursor are the core factors determining the stability of nascent Pd(0), the controllability of the activation process, and the final catalytic performance. Pd(II) catalytic precursors with excessive stability require high temperatures and strong bases to achieve Pd(0) formation, while those with low stability are difficult to precisely control to generate Pd(0). Therefore, in the structural design of palladium catalysts, how to achieve the rapid conversion of Pd(II) catalytic precursors into nascent Pd(0) is an important technical indicator for evaluating the rationality of the palladium catalyst structural design.

[0003] Currently, the precursors for Pd(II) catalysis are all Pd(II) chloride-bridged dimers. For example, Kasahara in Japan uses palladium chloride ([PdCl4]). 2- [Pd(μ-Cl)(ppy)]2 was obtained by reacting 2-aminopyridine (ppy) with ethanol at room temperature for 48 h; another example is the synthesis of Pd[(ppy)Cl]2 by the Daria team using a water / ethanol mixed solvent system at 80 °C. This Pd(II) chloride-bridged dimer needs to be activated into a mononuclear Pd(II) compound in the catalytic CC coupling reaction, which presents problems such as a high activation energy barrier for the oxidative addition reaction and a slow conversion rate of Pd(II) species to active Pd(0), resulting in a low product yield (only about 80%). Therefore, how to improve the Pd(II) catalytic precursor to increase the yield of the catalytically synthesized product has become a pressing technical challenge in this field. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing a pre-activated Pd(II)-P catalyst and its application. The pre-activated Pd(II)-P catalyst provided by this invention can avoid the oxidative addition energy barrier that the catalytic precursor needs to overcome during the activation process, thereby improving the yield of the catalytic synthesis product.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a pre-activated Pd(II)-P catalyst with the chemical structure shown in Formula I: Formula I; In Formula I, L is chloride ion, bromide ion, acetate ion, trifluoromethanesulfonate ion or tetrafluoroborate ion, and PR3 is triphenylphosphine, tricyclohexylphosphine, di(tert-butyl)phenylphosphine, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl or 4,5-bisdiphenylphosphine-9,9-dimethyloxanethium.

[0006] This invention also provides a method for preparing the pre-activated Pd(II)-P catalyst described in the above technical solution, comprising the following steps: A coordination reaction was carried out by mixing a Pd(II) compound, a solvent, and a PR3 ligand. The system after the coordination reaction is completed is mixed with a reducing agent to carry out a reduction reaction; The system after the reduction reaction was completed was mixed with 2-(2-halo-phenyl)-pyridine and subjected to an oxidative addition reaction to obtain a pre-activated Pd(II)-P catalyst.

[0007] Preferably, the molar ratio of the Pd(II) compound to the PR3 ligand is 1:(1~1.2).

[0008] Preferably, the coordination reaction is carried out at a temperature of room temperature to 90°C for 2 to 8 hours.

[0009] Preferably, the temperature of the reduction reaction is 25~90℃, and the time of the reduction reaction is 30~60min.

[0010] Preferably, the molar ratio of the Pd(II) compound to the 2-(2-halo-phenyl)-pyridine is (1~1.2):1.

[0011] Preferably, the temperature of the oxidative addition reaction is 25~100℃, and the time of the oxidative addition reaction is 2~8h.

[0012] This invention also provides the application of the pre-activated Pd(II)-P catalyst described above in the CC coupling reaction.

[0013] Preferably, the CC coupling reaction is a Suzuki coupling reaction.

[0014] Preferably, the operation of applying the pre-activated Pd(II)-P catalyst in the CC coupling reaction includes: A pre-activated Pd(II)-P catalyst, solvent, alkaline solution, bromoary matrix and phenylboronic acid derivative were mixed and subjected to an oxidative addition reaction to obtain the target product. The alkali in the alkaline solution is sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, or an organic alkali; The oxidative addition reaction is carried out at a temperature of 40~100℃ and for a time of ≤20h.

[0015] This invention provides a pre-activated Pd(II)-P catalyst with the chemical structure shown in Formula I. The active center of this pre-activated Pd(II)-P catalyst is Pd(II), and its valence electron configuration is d. 8 via DSP 2 Hybridization forms a four-coordinate planar square structure. In this structure, the ppy ligand and its derivatives act as bidentate chelators, coordinating with Pd(II) via N and C, respectively, to construct a stable five-membered ring chelate system. ppy, X, and PR3 together maintain the stability of the Pd(II) center in its "dormant state." The RC-Pd-X bond constitutes the core site for the oxidative addition step in the coupling reaction, avoiding the oxidative addition energy barrier that the catalytic precursor needs to overcome during activation, thus activating the nascent (PR3) ligand. n The key structural unit of Pd(0) is the PR3 ligand, which, through its steric hindrance, not only enhances the "dormant state" stability of the Pd(II) center in synergy with the ppy ligand, but also prevents the Pd(0) generated by the reduction and activation of Pd(II) from agglomerating into palladium black, thereby avoiding irreversible deactivation of the catalyst and improving the yield of the catalytically synthesized product. The results of the examples show that the yield of the target product reaches 98% when the pre-activated Pd(II)-P catalyst provided by this invention is used in the CC coupling reaction. Attached Figure Description

[0016] Figure 1 The schematic diagram shows the principle of activating the pre-activated Pd(II)-P catalyst provided by the present invention to generate nascent (PR3)n-Pd(0). Detailed Implementation

[0017] This invention provides a pre-activated Pd(II)-P catalyst with the chemical structure shown in Formula I: Formula I.

[0018] In this invention, in Formula I, L is chloride ion, bromide ion, acetate ion, trifluoromethanesulfonate ion or tetrafluoroborate ion, and PR3 is triphenylphosphine, tricyclohexylphosphine, di(tert-butyl)phenylphosphine, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl or 4,5-bisdiphenylphosphine-9,9-dimethyloxanethium.

[0019] The pre-activated Pd(II)-P catalyst provided by this invention has Pd(II) as its active center and its valence electron configuration as d. 8 via DSP 2Hybridization forms a four-coordinate planar square structure. In this structure, the ppy ligand and its derivatives act as bidentate chelators, coordinating with Pd(II) via N and C, respectively, to construct a stable five-membered ring chelate system. ppy, X, and PR3 together maintain the stability of the Pd(II) center in its "dormant state." The RC-Pd-X bond constitutes the core site for the oxidative addition step in the coupling reaction, avoiding the oxidative addition energy barrier that the catalytic precursor needs to overcome during activation, thus activating the nascent (PR3) ligand. n - The key structural unit of Pd(0); the introduction of PR3 with large steric hindrance into the structure can not only enhance the "dormant state" stability of the Pd(II) center through the steric hindrance effect in conjunction with the ppy ligand, but also prevent the Pd(0) generated by the reduction and activation of Pd(II) from agglomerating into palladium black, thereby avoiding irreversible deactivation of the catalyst and thus improving the yield of the catalytic synthesis product.

[0020] This invention also provides a method for preparing the pre-activated Pd(II)-P catalyst described in the above technical solution, comprising the following steps: A coordination reaction was carried out by mixing a Pd(II) compound, a solvent, and a PR3 ligand. The system after the coordination reaction is completed is mixed with a reducing agent to carry out a reduction reaction; The system after the reduction reaction was completed was mixed with 2-(2-halo-phenyl)-pyridine and subjected to an oxidative addition reaction to obtain a pre-activated Pd(II)-P catalyst.

[0021] Unless otherwise specified, the present invention does not have any special limitations on the source of the raw materials, and commercially available products well known to those skilled in the art can be used.

[0022] This invention involves mixing a Pd(II) compound, a solvent, and a PR3 ligand to perform a coordination reaction. In this invention, the Pd(II) compound undergoes a coordination reaction with the PR3 ligand in the solvent to generate a compound containing [Pd(II)(PR3). n ] 2- The system.

[0023] In this invention, the Pd(II) compound is preferably at least one of Pd(II) halogen salts, palladium acetate (Pd(OAc)2), palladium trifluoromethanesulfonate (Pd(CF3SO3)2), and palladium tetrafluoroborate (Pd(BF4)2); the Pd(II) halogen salt is preferably at least one of tetrachloropalladium salt, palladium dichloride (PdCl2), tetrabromopalladium salt, and palladium dibromide (PdBr2).

[0024] In this invention, when the Pd(II) compound is a Pd(II) halide salt, it is preferable to add a salt with the same anion as the Pd(II) halide salt during mixing; the molar ratio of the Pd(II) halide salt to the salt with the same anion as the Pd(II) halide salt is preferably 1:(1~3), more preferably 1:2. In this invention, Pd(II) halide salts have low solubility in solvents and easily form inert substances. Adding an excess of halide ions will coordinate with Pd(II) to form soluble anionic complexes. These complexes are more stable and more active in solution, and are more likely to participate in subsequent reduction reactions and oxidative addition steps.

[0025] This invention does not specifically limit the type of salt that is identical to the Pd(II) halide anion; any inorganic salt well-known to those skilled in the art can be used. As one embodiment, the salt that is identical to the Pd(II) halide anion can be sodium chloride, sodium bromide, or sodium iodide.

[0026] In this invention, the solvent is preferably at least one of ethanol, acetonitrile, dimethylformamide (DMF), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), and water, more preferably ethanol and water. As one embodiment, the water may be distilled water.

[0027] The present invention does not have a special limitation on the amount of solvent used, as long as all raw materials are completely dissolved.

[0028] In this invention, when the solvent is ethanol and water, the volume ratio of ethanol to water is preferably 8:5, 1:1 or 5:6.

[0029] In this invention, the PR3 ligand is preferably triphenylphosphine (PPh3), tricyclohexylphosphine (PCy3), bis(tert-butyl)phenylphosphine ((t-Bu)2PPh), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (XPhos), 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl (SPhos), or 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (XantPhos). In this invention, the PR3 ligand can prevent Pd(0) aggregation and deactivation through steric hindrance.

[0030] In this invention, the preferred molar ratio of the Pd(II) compound to the PR3 ligand is 1:(1~1.2). As one embodiment, the molar ratio of the Pd(II) compound to the PR3 ligand can be 1:1.1. By limiting the molar ratio of the Pd(II) compound to the PR3 ligand to the above range, this invention ensures an excess of the PR3 ligand, which promotes the complete reduction of Pd(II) to Pd(0) during subsequent reduction reactions.

[0031] The present invention does not have any special limitations on the operation of mixing the Pd(II) compound, solvent and PR3 ligand, and any technical solution for preparing the mixture well known to those skilled in the art can be used.

[0032] In this invention, the temperature of the coordination reaction is preferably room temperature to 90°C; the time of the coordination reaction is preferably 2 to 8 hours. As one embodiment, the temperature of the coordination reaction can be 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, or 85°C; the time of the coordination reaction can be 3 hours, 4 hours, 5 hours, 6 hours, or 7 hours.

[0033] After obtaining the system following the completion of the coordination reaction, this invention mixes the system with a reducing agent to carry out a reduction reaction. Under the action of the reducing agent, this invention reduces Pd(II) to Pd(0), generating Pd(0)-containing (PR3). m The system.

[0034] In this invention, the reducing agent is preferably at least one of hydrazine hydrate, carbon monoxide (CO), ethanol, formaldehyde, formic acid and borohydride, more preferably hydrazine hydrate or CO.

[0035] In this invention, when the reducing agent is at least one of hydrazine hydrate, ethanol, formaldehyde, formic acid, and borohydride, the molar ratio of the Pd(II) compound to the reducing agent is preferably 1:(1~3); when the reducing agent is CO, the CO is preferably introduced into the system after the coordination reaction is completed; the CO gas flow rate is preferably 10~100 mL / min; and the introduction time is preferably 30~80 min. By limiting the ratio of the Pd(II) compound to the reducing agent within the above range, this invention can improve the degree of reduction reaction, thereby further promoting the complete reduction of Pd(II) to Pd(0).

[0036] In one embodiment, the molar ratio of the Pd(II) compound to the reducing agent can be 1:2; the gas flow rate of CO can be 20 mL / min, 30 mL / min, 40 mL / min, 50 mL / min, 60 mL / min, 70 mL / min, 80 mL / min or 90 mL / min; and the introduction time can be 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, 65 min, 70 min or 75 min.

[0037] The present invention does not have any special limitations on the operation of mixing the system and the reducing agent after the coordination reaction is completed. The reducing agent can be selected according to its actual form and mixed evenly.

[0038] In this invention, the preferred temperature for the reduction reaction is 25-90°C; the preferred time for the reduction reaction is 30-60 min. As one embodiment, the temperature for the reduction reaction can be 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, or 85°C; the preferred time for the reduction reaction can be 35 min, 40 min, 45 min, 50 min, or 55 min. By limiting the temperature and time of the reduction reaction to the above ranges, this invention can further improve the degree of reduction.

[0039] In this invention, the reduction reaction is preferably carried out under stirring conditions. The stirring rate is not particularly limited in this invention; any operation well-known to those skilled in the art can be used.

[0040] In this invention, the reduction reaction is preferably carried out in an inert atmosphere. As one embodiment, the inert atmosphere may be nitrogen.

[0041] After obtaining the system after the reduction reaction, the present invention mixes the system after the reduction reaction with 2-(2-halo-phenyl)-pyridine and carries out an oxidative addition reaction to obtain a pre-activated Pd(II)-P catalyst.

[0042] In this invention, the halogen in the 2-(2-halo-phenyl)-pyridine (2-X-ppy) is preferably bromine or chlorine; the molar ratio of the Pd(II) compound to the 2-(2-halo-phenyl)-pyridine is preferably (1~1.2):1. As one embodiment, the molar ratio of the Pd(II) compound to the 2-(2-halo-phenyl)-pyridine can be 1.1:1. Limiting the molar ratio of the Pd(II) compound to the 2-(2-halo-phenyl)-pyridine within the above range in this invention can improve the degree of oxidative addition reaction.

[0043] The present invention does not have any special limitations on the operation of mixing the system with 2-(2-halo-phenyl)-pyridine after the reduction reaction is completed, and any technical solution for preparing the mixture well known to those skilled in the art can be used.

[0044] In this invention, the preferred temperature for the oxidative addition reaction is 25-100°C; the preferred time for the oxidative addition reaction is 2-8 hours. As one embodiment, the temperature for the oxidative addition reaction can be 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, or 95°C; the preferred time for the oxidative addition reaction can be 3 hours, 4 hours, 5 hours, 6 hours, or 7 hours. By limiting the temperature and time of the oxidative addition reaction to the above ranges, this invention can further improve the degree of oxidative addition reaction.

[0045] In this invention, the oxidative addition reaction is preferably carried out in an inert atmosphere; the oxidative addition reaction is preferably carried out under stirring conditions.

[0046] The present invention does not specifically limit the type of inert atmosphere; any inert atmosphere well known in the art can be used. As one embodiment, the inert atmosphere can be nitrogen.

[0047] The present invention does not impose any special limitation on the stirring rate; any operation known to those skilled in the art can be used to stir until uniform.

[0048] After the oxidative addition reaction is completed, the present invention preferably performs post-treatment on the product obtained by the oxidative addition reaction to obtain a pre-activated Pd(II)-P catalyst.

[0049] In this invention, the post-processing preferably includes sequentially performing cooling, quenching, purification, washing, and drying.

[0050] The present invention does not impose any special limitations on the cooling operation; any operation known to those skilled in the art can be used to cool to room temperature.

[0051] In this invention, the quenching is preferably carried out at room temperature; the quenching is preferably carried out under acidic conditions; the pH value of the acidic conditions is preferably 5.8 to 6.2, more preferably 6.0.

[0052] In this invention, the acidic conditions are preferably adjusted by adding dilute acid; the anion of the dilute acid is preferably the same as L in the pre-activated Pd(II)-P catalyst; the dilute acid is preferably one of hydrochloric acid, sulfuric acid, nitric acid, trifluorosulfonic acid, and tetrafluoroboric acid. This invention does not have a specific limitation on the concentration of the dilute acid, as long as the pH value for crystallization meets the required requirements. As one embodiment, the concentration of the dilute acid can be 0.5~1 mol / L.

[0053] In this invention, the purification is preferably performed by recrystallization and / or filtration. This invention does not impose any particular limitation on the recrystallization operation; any operation well-known to those skilled in the art can be used. Similarly, this invention does not impose any particular limitation on the filtration operation; any operation well-known to those skilled in the art can be used to obtain a filter cake.

[0054] The present invention does not impose any special limitations on the washing operation; any operation well known to those skilled in the art can be used. As one embodiment, the detergent used for washing can be ethanol or deionized water.

[0055] The present invention does not impose any particular limitation on the drying operation; any operation well known to those skilled in the art can be used to dry to constant weight. As one embodiment, the drying can be vacuum drying; the drying temperature can be 50°C; and the drying time can be 4–10 hours.

[0056] The preparation method provided by this invention employs a one-pot synthesis approach, with the feed added in stages according to the sequence of Pd(II) compound → PR3 ligand → 2-(2-halo-phenyl)-pyridine. This avoids competition from side reactions, resulting in mild conditions and high yields. The core of this method lies in achieving valence state regulation and ligand reconstruction of Pd through a stepwise coordination-reduction-oxidative addition process. Specifically, using Pd(II) compound as the starting material, it first undergoes a coordination reaction with the PR3 ligand to generate [Pd(II)(PR3). n ] 2- Intermediate; then, under the action of excess PR3 and reducing agent, Pd(II) is gradually reduced to Pd(0); finally, 2-(2-halo-phenyl)-pyridine is introduced into the system, triggering only the oxidative addition process of the CC coupling process, and then a small amount of dilute acid is added for crystallization to obtain the target product; through strict staged feeding sequence and precise temperature control, high selective coupling is achieved, and the yield is significantly better than the traditional multi-step method.

[0057] The present invention also provides the application of the pre-activated Pd(II)-P catalyst described in the above technical solution or the pre-activated Pd(II)-P catalyst prepared by the preparation method described in the above technical solution in CC coupling reaction.

[0058] In this invention, the CC coupling reaction is preferably a Suzuki coupling reaction. The pre-activated Pd(II)-P catalyst of this invention is used to catalyze the coupling of bromoaryl groups and phenylboronic acid derivatives to generate diaryl compounds.

[0059] In this invention, the preferred operation for using the pre-activated Pd(II)-P catalyst in the CC coupling reaction includes: A pre-activated Pd(II)-P catalyst, solvent, alkaline solution, bromoary matrix and phenylboronic acid derivative were mixed and subjected to an oxidative addition reaction to obtain the target product. The alkali in the alkaline solution is sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, or an organic alkali; The oxidative addition reaction is carried out at a temperature of 40~100℃ and for a time of ≤20h.

[0060] In this invention, the amount of the pre-activated Pd(II)-P catalyst is 1 to 2% of the phenylboronic acid derivative, more preferably 1%.

[0061] In this invention, the solvent is preferably a polar solvent or a non-polar solvent; when PR3 in the pre-activated Pd(II)-P catalyst is triphenylphosphine or tricyclohexylphosphine, the solvent is a polar solvent; the polar solvent is preferably ethanol or acetonitrile; when PR3 in the pre-activated Pd(II)-P catalyst is bis(tert-butyl)phenylphosphine, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, or 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene, the solvent is a non-polar solvent; the non-polar solvent is preferably tetrahydrofuran or toluene. In this invention, the type of solvent is selected based on the steric hindrance of PR3.

[0062] The present invention does not have a special limitation on the amount of solvent used, as long as the raw materials are completely dissolved.

[0063] In this invention, the solvent of the alkaline solution is preferably water; the alkali in the alkaline solution is sodium carbonate, potassium carbonate, cesium carbonate (Cs₂CO₃), potassium phosphate, sodium hydroxide, or an organic base, preferably sodium carbonate. This invention does not impose a specific limitation on the concentration of the alkaline solution; it can be adjusted according to the actual required amount of alkali.

[0064] In this invention, the molar ratio of the base to the bromoaryl base is preferably (2~4):1, more preferably 3:1.

[0065] This invention does not specifically limit the type of organic base, as long as the required amount is met. As one embodiment, the organic base can be triethylamine (Et3N) or potassium tert-butoxide (t-BuOK).

[0066] In this invention, the brominated aromatic base is preferably 2-bromo-5-(trifluoromethyl)pyridine; the phenylboronic acid derivative is preferably 2,4-difluorophenylboronic acid. This invention does not impose a particular limitation on the ratio of the brominated aromatic base to the phenylboronic acid derivative; a ratio well-known to those skilled in the art can be used. As one embodiment, the molar ratio of the brominated aromatic base to the phenylboronic acid derivative can be 1:1.1.

[0067] The present invention does not have any special limitations on the operation of mixing the pre-activated Pd(II)-P catalyst, solvent, alkaline solution, brominated aromatic substrate and phenylboronic acid derivative, and any technical solution for preparing the mixture known to those skilled in the art can be used.

[0068] In this invention, the temperature of the oxidative addition reaction is 40~100℃; the time of the oxidative addition reaction is ≤20h. As one embodiment, the temperature of the oxidative addition reaction can be 50℃, 60℃, 70℃, 80℃, or 90℃; the time of the oxidative addition reaction can be 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 8.5h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, or 19h. By limiting the temperature and time of the oxidative addition reaction within the above ranges, this invention can further improve the degree of the oxidative addition reaction, thereby increasing the product yield, and can avoid the situation where the pre-catalyst cannot be completely activated due to excessively low reaction temperatures.

[0069] In this invention, the oxidative addition reaction is preferably carried out in an inert atmosphere. As one embodiment, the inert atmosphere may be nitrogen.

[0070] In this invention, the oxidative addition reaction is preferably carried out under stirring conditions. This invention does not impose a particular limitation on the stirring rate; any stirring rate well known to those skilled in the art can be used.

[0071] In this invention, the equation for the oxidative addition reaction is as follows: .

[0072] After the oxidative addition reaction is completed, the present invention preferably performs post-processing on the product obtained by the oxidative addition reaction to obtain the target product.

[0073] In this invention, the post-processing preferably includes sequentially performing cooling, rotary evaporation, extraction, washing, drying, vacuum rotary evaporation, and purification.

[0074] The present invention does not impose any special limitations on the cooling operation; any operation known to those skilled in the art can be used to cool to room temperature.

[0075] The present invention does not have any special limitations on the rotary evaporation operation; the solvent need to be removed.

[0076] The present invention does not impose any particular limitation on the extraction operation; any operation well known to those skilled in the art can be used. As one embodiment, the extractant used in the extraction can be ethyl acetate.

[0077] The present invention does not impose any special limitations on the washing operation; the goal is simply to remove impurities. As one embodiment, the detergent used for washing can be saturated saline solution.

[0078] The present invention does not impose any particular limitations on the drying operation; drying to a constant weight is sufficient. As one embodiment, the drying agent used may be anhydrous sodium sulfate.

[0079] The present invention does not impose any special limitations on the operation of the reduced pressure rotary evaporation; any operation known to those skilled in the art can be used to remove the solvent.

[0080] In this invention, the purification is preferably performed using silica gel column chromatography. This invention does not impose any specific limitations on the specific purification procedures, as long as the target product can be obtained.

[0081] In CC coupling, the pre-activated Pd(II)-P catalyst provided by this invention efficiently catalyzes the coupling of brominated aromatic bases with phenylboronic acid derivatives, is compatible with a variety of solvents and ligands, and is suitable for the synthesis of high-value-added compounds such as pharmaceutical intermediates.

[0082] The pre-activated Pd(II)-P catalyst provided by this invention is activated to generate nascent (PR3). n The schematic diagram of -Pd(0) is as follows: Figure 1 As shown.

[0083] from Figure 1 It can be seen that this catalytic precursor directly utilizes the substrate of the CC coupling reaction (phenylboronic acid derivative, R2-B(OH)2) to act on the RC-Pd-L bond in its own molecule, thereby activating (PR3). n The formation of -Pd(0); upon addition of base (Base), L is stripped to form Base·L byproduct, forming an electron-deficient Pd intermediate; subsequently, phenylboronic acid is converted into B(OH)3 - The form undergoes ligand exchange with Pd, and through transmetalation, the central valence state of Pd changes from II to 0, and the ligand environment is reconstructed, simultaneously obtaining (PR3). n -Pd(0) active material and byproduct (1,2-difluorophenyl-2-pyridyl-phenylmethane) are fundamentally different from those of previously reported palladium-based catalysts.

[0084] In this invention, when the pre-activated Pd(II)-P catalyst is used to catalyze the reaction of 2-bromo-5-(trifluoromethyl)pyridine and 2,4-difluorophenylboronic acid, the reaction equation for the pre-activated Pd(II)-P catalyst and the phenylboronic acid derivative 2,4-difluorophenylboronic acid is as follows: .

[0085] The pre-activated Pd(II)-P catalyst designed and synthesized in this invention achieves substrate capture, assembly and release through Pd(II) / Pd(0) valence state cycling. This type of catalytic precursor has been successfully applied to the coupling of complex substrates such as bromoaryl and trifluoromethylpyridine. It is compatible with a variety of phosphine ligands and solvents. The core metallization step is temperature-controlled to avoid damage to sensitive functional groups by high temperature. It is suitable for the synthesis of high-value-added compounds such as pharmaceutical intermediates.

[0086] The pre-activated Pd(II)-P catalyst provided by this invention can improve the yield of catalytic synthesis products compared with existing catalytic precursors (e.g., PR3 is trimethylphosphine).

[0087] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0088] Example 1 The chemical structure of the pre-activated Pd(II)-P catalyst is shown in Formula I: Formula I; In Formula I, L represents chloride ion and PR3 represents triphenylphosphine. The preparation method of the pre-activated Pd(II)-P catalyst is as follows: Weigh 1.77 g PdCl2 (10 mmol) and 1.17 g NaCl (20 mmol) and place them in a 250 mL round-bottom flask. Add 50 mL of distilled water and stir until completely dissolved. Then, slowly add 80 mL of an ethanol solution containing 2.62 g PPh3 (10 mmol) and allow the complexation reaction to proceed at room temperature for 5 h, until the system becomes a yellow suspension. Then, heat the solution in an oil bath to 80 °C and purge with high-purity CO at a flow rate of 10 mL / min under nitrogen protection for 45 min until the solution color gradually changes from yellow to bright yellow-green. Stop the gas flow and continue reflux and stirring for 30 min to carry out the reduction reaction. Finally, add 2.34 g PdCl2. 2-(2-bromo-phenyl)-pyridine (10 mmol) was heated to 100 °C and refluxed under nitrogen atmosphere for 3 h for an oxidative addition reaction. During the reaction, the mixture was kept homogeneous by magnetic stirring, and the reaction endpoint was confirmed by TLC monitoring. After the reaction was completed, the mixture was cooled to room temperature, and 1 mol / L hydrochloric acid was slowly added dropwise to adjust the pH of the system to 6.0, resulting in the precipitation of a pale yellow crystalline solid. The solid was filtered using a Buchner funnel, and the filter cake was collected. The solid was washed twice each with 50 mL of ethanol and 50 mL of deionized water, and then dried under vacuum at 50 °C for 4 h to obtain 4.79 g of pre-activated Pd(II)-P catalyst, with a yield of 86% (calculated based on the molar amount of Pd).

[0089] The pre-activated Pd(II)-P catalyst prepared in Example 1 was characterized, and the characterization data are as follows: ① Elemental analysis: Measured values: Pd 19.02%, C 62.46%, Cl 6.34%; Theoretical values ​​(C 29 H23 The measured values ​​of NClPPd) Pd 19.02%, C 62.47%, and Cl 6.36% are basically consistent with the theoretical values.

[0090] ② 1 H NMR (500 MHz, Chloroform-d) δ 7.59 (dt, J = 7.2, 2.1 Hz, 1H), 7.32 (pd, J = 7.3, 1.7 Hz, 2H), 7.14 (ddd, J = 7.5, 3.8, 2.1 Hz, 1H), 6.99(s, 2H), 2.92 (hept, J = 7.0 Hz, 1H), 2.40 (hept, J = 6.7 Hz, 2H), 1.85 (d, J= 6.5 Hz, 2H), 1.72 (tt, J = 11.8, 3.2 Hz, 4H), 1.67 – 1.62 (m, 4H), 1.58(ddt, J = 12.8, 4.7, 2.4 Hz, 4H), 1.30 (d, J = 6.9 Hz, 7H), 1.20 (d, J = 6.8Hz, 13H), 1.10 (dtd, J = 16.5, 12.6, 3.2 Hz, 3H), 0.96 (d, J = 6.7 Hz, 6H).

[0091] ③ 13 C NMR (126 MHz, Chloroform-d) δ 164.84, 155.20, 150.70, 147.37,139.32, 139.02, 135.48 (d, J = 12.0 Hz), 131.66, 131.26, 130.72 (d, J = 2.6Hz), 128.83, 128.11 (d, J = 10.9 Hz), 124.36, 123.78, 122.17, 118.23.

[0092] ④MS(ESI(+)):m / z=521 (calcd.557 for [C 29 H 23 [NClPPd], [M-Cl] - ).

[0093] ⑤IR (KBr, ν / cm -1): 3448 (m, br, ν-OH), 3055, 3044 (ν-=CH), 2956,2921, 2898 (ν-CH, -CH2CH2-), 1620 (ν-C=N), 1601, 1585, 1482 (ν-C=C), 1435 (ν-P-C6H5), 1312 (ν-CO), 1265, 1099, 1071 (δ-=CH), 747, 692 (γ-=CH), 532, 509 (ν-Pd-P / ν-Pd-N / ν-Pd-O).

[0094] Example 2 The chemical structure of the pre-activated Pd(II)-P catalyst is as follows: ; The preparation method of the pre-activated Pd(II)-P catalyst is as follows: Weigh 2.66 g PdBr2 (10 mmol) and 2.04 g NaBr (20 mmol) and place them in a 500 mL round-bottom flask. Add 100 mL of distilled water and stir until completely dissolved. Then, slowly add 100 mL of an ethanol solution containing 2.81 g PCy3 (10 mmol) and allow the complexation reaction to proceed at room temperature for 5 h. The system will turn into a yellow-green suspension. Then, heat the solution in an oil bath to 80 °C and purge with high-purity CO at a flow rate of 10 mL / min under nitrogen protection for 60 min until the solution color gradually changes from yellow-green to bright yellow. Stop the gas purging and continue stirring under reflux for 30 min to carry out the reduction reaction. Then, add 2.34 g PdBr2 (10 mmol) and 10 mL of distilled water. 2-(2-bromo-phenyl)-pyridine (10 mmol) was heated to 100 °C and refluxed under nitrogen atmosphere for 3 h for an oxidative addition reaction. During the reaction, the mixture was kept homogeneous by magnetic stirring. The reaction endpoint was confirmed by TLC monitoring (electrolyte: petroleum ether and ethyl acetate in a volume ratio of 10:1). After the reaction was completed, the mixture was cooled to room temperature, and 1 mol / L hydrobromic acid was slowly added dropwise to adjust the pH of the system to 6.0, resulting in the precipitation of a yellow crystalline solid. The solid was filtered using a Buchner funnel, and the filter cake was collected. The solid was washed twice each with 50 mL of ethanol and 50 mL of deionized water, and dried under vacuum at 50 °C for 4 h to obtain 4.86 g of pre-activated Pd(II)-P catalyst, with a yield of 79% (calculated based on the molar amount of Pd).

[0095] The pre-activated Pd(II)-P catalyst prepared in Example 2 was characterized, and the characterization data are as follows: ① Elemental analysis: Measured values: Pd 17.17%, C 56.42%, Br 12.96%; Theoretical values ​​(C... 29 H 38The measured values ​​of NBrPPd) Pd were 17.18%, C was 56.41%, and Br was 12.95%, which were basically consistent with the theoretical values.

[0096] ② 1 H NMR (500 MHz, Chloroform-d) δ 9.67 (ddd, J = 5.3, 1.7, 0.8 Hz,1H), 7.78 (td, J = 7.7, 1.7 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.52 (dd, J =7.7, 1.7 Hz, 1H), 7.39 (ddd, J = 7.8, 5.7, 1.2 Hz, 1H), 7.19 (ddt, J = 7.2,5.7, 1.4 Hz, 1H), 7.12 (m, 2H), 2.65 (m, 3H), 2.10 (m, 6H), 1.83 (m, 6H),1.75 (m, 10H), 1.33 (m, 12H).

[0097] ③ 13 C NMR (126 MHz, Chloroform-d) δ 164.54 (d, J = 2.7 Hz), 155.10,150.27, 147.52, 138.50, 138.05 (d, J = 6.5 Hz), 128.57 (d, J = 4.2 Hz),124.21 (d, J = 19.8 Hz), 121.85 (d, J = 3.2 Hz), 117.96 (d, J = 1.6 Hz), 34.35, 34.18, 30.45, 27.75 (d, J = 10.9 Hz).

[0098] ④MS(ESI(+)): m / z=536 (calcd.616 for [C 29 H 38 [NBrPPd], [M-Br] - ).

[0099] ⑤IR (KBr, ν / cm -1): 3459 (br, H2O), 3101 (w, ν-Ar-H), 2929 (vs), 2895(s), 2854 (vs) (ν-CH), 1601 (m), 1577 (m), 1483 (m), 1446 (s), 1266 (m), 1005 (m), 938 (ms), 580 (m, ν-Pd-P), 518 (m, ν-Pd-N / Pd-Br).

[0100] Example 3 The chemical structure of the pre-activated Pd(II)-P catalyst is as follows: ; The preparation method of the pre-activated Pd(II)-P catalyst is as follows: Weigh 2.12 g of sponge palladium, dissolve it in 10 mL of concentrated nitric acid, add 50 mL of trifluoromethanesulfonic acid to the resulting solution and heat to boiling for 1 h. Then cool to room temperature and separate the solid product, palladium trifluoromethanesulfonate, by filtration. Wash the solid twice with 50 mL of deionized water to remove residual impurities. Transfer 20 mmol of palladium trifluoromethanesulfonate to a 250 mL round-bottom flask, add 50 mL of distilled water, and stir until completely dissolved. Then slowly add 60 mL of an ethanol solution containing 9.52 g of XPhos (20 mmol) and allow the complexation reaction to proceed at room temperature for 7 h, resulting in a yellow suspension. Then heat the solution in an oil bath to 80 °C, slowly add 40 mmol of hydrazine hydrate dropwise while stirring, and allow the reduction reaction to proceed for 60 min. Finally, add 4.68 g of... 2-(2-bromo-phenyl)-pyridine (20 mmol) was heated to 100 °C and refluxed under nitrogen atmosphere for 3 h for an oxidative addition reaction. During the reaction, the mixture was kept homogeneous by magnetic stirring. The reaction endpoint was confirmed by TLC monitoring (electrolyte: petroleum ether and ethyl acetate in a volume ratio of 10:1). After the reaction was completed, the mixture was cooled to room temperature, and 0.5 mol / L CF3SO3H was slowly added dropwise to adjust the pH of the system to 6.0, resulting in the precipitation of a deep yellow crystalline solid. The solid was filtered using a Buchner funnel, and the filter cake was collected. The solid was washed twice each with 60 mL of ethanol and 60 mL of deionized water, and dried under vacuum at 50 °C for 4 h to obtain 7.11 g of pre-activated Pd(II)-P catalyst, with a yield of 82% (calculated based on the molar amount of Pd).

[0101] The pre-activated Pd(II)-P catalyst prepared in Example 3 was characterized, and the characterization data are as follows: ① Elemental analysis: Measured values: Pd 12.22%, C 62.27%, F 6.57%, S 3.69%, O 5.55%; Theoretical values ​​(C... 45 H38 The experimental values ​​of NF3O3SPPd) are basically consistent with the theoretical values: Pd 12.23%, C 62.28%, F 6.57%, S 3.70%, O 5.54%.

[0102] ② 1 H NMR (500 MHz, Chloroform-d) δ 9.51 (d, J = 5.6 Hz, 1H), 7.82 (td, J = 7.8, 1.6 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.58 (dd, J = 7.8, 1.5Hz, 1H), 7.42 (ddd, J = 7.5, 5.6, 1.2 Hz, 1H), 7.22 (m, 1H), 7.09 (td, J =7.5, 1.2 Hz, 1H), 6.98 (td, J = 7.5, 1.3 Hz, 1H), 2.48 (m, 3H), 2.05 (m, 6H),1.87 (m, 6H), 1.76 (m, 9H), 1.45 (m, 12H).

[0103] ③ 13 C NMR (126 MHz, Chloroform-d) δ 166.82 (d, J = 4.8 Hz), 153.78,150.42, 148.65, 139.12, 136.85 (d, J = 28.4 Hz), 128.92, 125.36, 123.78,122.15, 120.84 (q, J = 321.5 Hz,), 119.68, 35.68 (d, J = 19.2 Hz), 29.88 (d,J = 10.1 Hz), 27.62 (d, J = 11.5 Hz).

[0104] ④MS(ESI(+)):m / z=718 (calcd.867 for [C 44 H 38 [NF3O3SPPd], [M-CF3SO3] - ).

[0105] ⑤IR (KBr, ν / cm -1): 3058 (w, ν-Ar-H), 2931 (vs, ν-as CH2), 2853 (vs,CH2), 1604 (m, ν-C=C / C=N), 1580 (m, ν-C=C), 1479 (m), 1448 (s, δ-CH2 / ν-P-Cy),1265 (vs, ν-as SO3), 1221 (s), 1155 (s, ν-as CF3), 1032 (vs, SO3), 1008 (m,Cy), 852 (w), 756 (m, γ-Ar-H), 638 (s, δ-SO3 / ν-SO), 573 (m, ν-Pd-P), 517(m, ν-Pd-O / δ-CF3), 460 (w, ν-Pd-N / Pd-C).

[0106] Example 4 The chemical structure of the pre-activated Pd(II)-P catalyst is as follows: ; The preparation method of the pre-activated Pd(II)-P catalyst is as follows: Weigh 1.06 g of sponge palladium, dissolve it in 10 mL of concentrated nitric acid, add 50 mL of tetrafluoroboric acid to the resulting solution and heat to boiling for 1 h. Then cool to room temperature and separate the solid product, palladium tetrafluoroborate, by filtration. Wash the solid twice with 50 mL of deionized water to remove residual impurities. Transfer 10 mmol of solid palladium tetrafluoroborate to a 250 mL round-bottom flask, add 50 mL of distilled water, and stir until completely dissolved. Then slowly add 60 mL of an ethanol solution containing 4.11 g of SPhos (10 mmol) at room temperature for a coordination reaction for 5 h, until the system becomes a yellow-green suspension. Then heat the system in an oil bath to 80 °C, slowly add 30 mmol of hydrazine hydrate dropwise while stirring for a reduction reaction for 60 min. Finally, add 2.34 g of... 2-(2-bromo-phenyl)-pyridine (10 mmol) was heated to 100 °C and refluxed under nitrogen atmosphere for 3 h for an oxidative addition reaction. During the reaction, the mixture was kept homogeneous by magnetic stirring. The reaction endpoint was confirmed by TLC monitoring (electrolyte: petroleum ether and ethyl acetate in a volume ratio of 10:1). After the reaction was completed, the mixture was cooled to room temperature, and 0.5 mol / L HBF4 was slowly added dropwise to adjust the pH of the system to 6.0, resulting in the precipitation of a yellow crystalline solid. The solid was filtered using a Buchner funnel, and the filter cake was collected. The solid was washed twice with 60 mL of ethanol and twice with 60 mL of deionized water. The solid was then dried under vacuum at 50 °C for 4 h to obtain 6.13 g of pre-activated Pd(II)-P catalyst, with a yield of 84% (calculated based on the molar amount of Pd).

[0107] The pre-activated Pd(II)-P catalyst prepared in Example 4 was characterized, and the characterization data are as follows: ① Elemental analysis: Measured values: Pd 15.23%, C 14.52%, C 60.77%, O 4.37%, F 10.38%; Theoretical values ​​(C 37 H 31 F4O2NBPPd) Pd 14.51%, C 60.76%, O 4.38%, F 10.39%, the experimental values ​​are basically consistent with the theoretical values.

[0108] ② 1 H NMR (500 MHz, Chloroform-d) δ 9.38 (d, J = 5.5 Hz, 1H), 7.85 (td, J = 7.8, 1.5 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 7.8, 1.5Hz, 1H), 7.36 (ddd, J = 7.5, 5.5, 1.2 Hz, 1H), 7.15 (m, 2H), 6.92 (td, J =7.5, 1.2 Hz, 1H), 6.28 (d, J = 2.2 Hz, 2H), 6.12 (t, J = 2.2 Hz, 1H), 3.69(s, 6H), 2.42(m, 3H), 1.98 (m, 6H), 1.82 (m, 6H), 1.70 (m, 9H), 1.40 (m, 12H).

[0109] ③ 13 C NMR (126 MHz, Chloroform-d) δ 169.12 (d, J = 6.2 Hz, Pd-C), 160.84 (s), 154.26, 150.78, 147.88, 139.45, 137.28 (d, J = 26.8 Hz), 128.65,124.88, 123.10, 121.45, 119.82, 104.62 (s, o), 98.45 (s, p), 55.48 (s,),36.12 (d, J = 18.5 Hz), 30.15 (d, J = 9.8 Hz), 27.88 (d, J = 11.2 Hz).

[0110] ④MS(ESI(+)):m / z=644 (calcd.730 for [C 37 H31 F4O2NBPPd], [M-BF4] - )。

[0111] ⑤IR (KBr, ν / cm -1 ): 3055 (w, ν-Ar-H), 3005 (w, ν-C-H), 2930 (vs, ν-C-H), 2852 (vs, ν-C-H), 1605 (m, ν-C=C / C=N), 1583 (m, ν-C=C), 1560 (w, ν-C=C),1490 (m, ν-C-O / δ-C-H), 1447 (s, δ-C-H / ν-P-Cy), 1425 (m, ν-C-O), 1295 (m, ν-C-O), 1205 (s, δ-C-H), 1158 (s, ν-C-O-C), 1055 (vs, br, ν-as BF4 / ν-s BF4), 1008(m, Ar-OMe), 830 (m, γ-C-H), 756 (m, γ-C-H), 580 (m, ν-Pd-P), 522 (m, δ-BF4), 480 (w, ν-Pd-C / Pd-N)。

[0112] Example 5 The chemical structure of the pre-activated Pd(II)-P catalyst is as follows: ; The preparation method of the pre-activated Pd(II)-P catalyst is: Weigh 3.60 g PdI₂ (10 mmol) and 3.00 g NaI (20 mmol), place them in a 500 mL round-bottom flask, add 100 mL of distilled water, and stir until completely dissolved. Then, slowly add 100 mL of an ethanol solution containing 5.78 g XanPhos (10 mmol) and allow the complexation reaction to proceed at room temperature for 7 h, until the system becomes a yellow suspension. Then, heat the solution in an oil bath to 80 °C, and under nitrogen protection, purge with high-purity CO at a flow rate of 10 mL / min for 60 min until the solution color gradually changes from yellow to bright yellow. Stop the gas flow and continue reflux and stirring for 30 min to carry out the reduction reaction. Then, add 2.34 g PdI₂ (10 mmol) NaI. 2-(2-bromo-phenyl)-pyridine (10 mmol) was heated to 100 °C and refluxed under nitrogen atmosphere for 3 h for an oxidative addition reaction. During the reaction, the mixture was kept homogeneous by magnetic stirring. The reaction endpoint was confirmed by TLC monitoring (electrolyte: petroleum ether and ethyl acetate in a volume ratio of 10:1). After the reaction was completed, the mixture was cooled to room temperature, and 1 mol / L hydroiodic acid was slowly added dropwise to adjust the pH of the system to 6.0, resulting in the precipitation of a yellow crystalline solid. The solid was filtered using a Buchner funnel, and the filter cake was collected. The solid was washed twice each with 50 mL of ethanol and 50 mL of deionized water, and dried under vacuum at 50 °C for 4 h to obtain 8.85 g of pre-activated Pd(II)-P catalyst, with a yield of 81% (calculated based on the molar amount of Pd).

[0113] The pre-activated Pd(II)-P catalyst prepared in Example 5 was characterized, and the characterization data are as follows: ① Elemental analysis: Measured values: Pd 10.21%, C 57.76%, P 5.95%; Theoretical values ​​(C 50 H 40 The measured values ​​of NIOP2Pd were 10.20%, C 57.75%, and P 5.96%, which were basically consistent with the theoretical values.

[0114] ② 1 H NMR (500 MHz, Chloroform-d) δ 8.65 (m, 2H), 7.82 (tt, J = 7.8,1.8 Hz, 1H), 7.55 (m, 8H), 7.40 (m, 12H), 7.25 (m, 2H), 6.95 (m, 4H), 6.60(m, 2H), 1.45(s, 18H), 1.38(s, 18H).

[0115] ③ 13C NMR (126 MHz, CDCl3) δ 163.5 (s), 153.0 (d, J = 6 Hz), 148.8 (s), 147.2 (s), 138.5 (s), 135.2 (t, J = 10 Hz), 132.8 (d, J = 17 Hz), 130.8(s), 129.5 (t, J = 10 Hz), 128.0 (d, J = 54 Hz), 126.5 (m), 35.5 (s), 34.8(s), 31.6 (s), 31.2 (s).

[0116] ④MS(ESI(+)):m / z=966 (calcd.1093 for [C 50 H 40 [P2NIOPd],[MI] - ).

[0117] ⑤IR (KBr, ν / cm -1 ): 3055 (w, ν-=CH), 2955, 2905, 2865 (m, ν-CH),1590, 1570, 1480, 1435 (ms, ν-C=C), 1360 (m, δ-CH), 1249 (m, ν-CO), 1095(s-=CH), 745, 695 (s-=CH), 517 (m, ν-Pd–P), 335 (w, ν-Pd–C), 174 (w, ν-Pd-I).

[0118] Example 6 The chemical structure of the pre-activated Pd(II)-P catalyst is as follows: ; The preparation method of the pre-activated Pd(II)-P catalyst is as follows: Weigh 17.7 g PdCl2 (100 mmol) and 11.7 g NaCl (200 mmol) and place them in a 2 L round-bottom flask. Add 500 mL of distilled water and stir until completely dissolved. Then, slowly add 500 mL of an ethanol solution containing 26.2 g PPh3 (100 mmol) and allow the complexation reaction to proceed at room temperature for 5 h, until the system becomes a yellow suspension. Then, heat the solution in an oil bath to 80 °C and purge with high-purity CO at a flow rate of 100 mL / min under nitrogen protection for 45 min until the solution color gradually changes from yellow to bright yellow-green. Stop the gas flow and continue reflux and stirring for 30 min to carry out the reduction reaction. Then, add 100 mmol of PdCl2. 2-(2-bromo-phenyl)-pyridine was heated to 100 °C and refluxed under a nitrogen atmosphere for 3 h for an oxidative addition reaction. During the reaction, the mixture was kept homogeneous by magnetic stirring. The reaction endpoint was confirmed by TLC monitoring (electrolyte: petroleum ether and ethyl acetate in a volume ratio of 10:1). After the reaction was completed, the mixture was cooled to room temperature, and 1 mol / L hydrochloric acid was slowly added dropwise to adjust the pH of the system to 6.0, resulting in the precipitation of a pale yellow crystalline solid. The solid was filtered using a Buchner funnel, and the filter cake was collected. The solid was washed twice each with 500 mL of ethanol and 500 mL of deionized water, and then dried under vacuum at 50 °C for 10 h to obtain 46.79 g of pre-activated Pd(II)-P catalyst, with a yield of 84% (calculated based on the molar amount of Pd).

[0119] Example 7 The chemical structure of the pre-activated Pd(II)-P catalyst is as follows: ; The preparation method of the pre-activated Pd(II)-P catalyst is as follows: Weigh 39.9 g PdBr2 (150 mmol) and 30.6 g NaBr (300 mmol) into a 3 L round-bottom flask, add 500 mL of distilled water, and stir until completely dissolved. Then, slowly add 800 mL of an ethanol solution containing 42.15 g PCy3 (150 mmol) to carry out a coordination reaction at room temperature for 5 h, until the system becomes a yellow-green suspension. Then, heat the solution in an oil bath to 80 °C, and under nitrogen protection, purge with high-purity CO at a flow rate of 100 mL / min for 80 min until the solution color gradually changes from yellow-green to bright yellow. Stop the gas flow and continue reflux and stirring for 30 min to carry out the reduction reaction. Finally, add 35.10 g PdBr2 (150 mmol) into the flask. 2-(2-bromo-phenyl)-pyridine (150 mmol) was heated to 100 °C and refluxed under nitrogen atmosphere for 3 h for an oxidative addition reaction. During the reaction, the mixture was kept homogeneous by magnetic stirring. The reaction endpoint was confirmed by TLC monitoring (electrolyte: petroleum ether and ethyl acetate in a volume ratio of 10:1). After the reaction was completed, the mixture was cooled to room temperature, and 1 mol / L hydrobromic acid was slowly added dropwise to adjust the pH of the system to 6.0, resulting in the precipitation of a yellow crystalline solid. The solid was filtered using a Buchner funnel, and the filter cake was collected. The solid was washed twice each with 500 mL of ethanol and 500 mL of deionized water, and dried under vacuum at 50 °C for 8 h to obtain 74.45 g of pre-activated Pd(II)-P catalyst, with a yield of 81% (calculated based on the molar amount of Pd).

[0120] Example 8 The chemical structure of the pre-activated Pd(II)-P catalyst is as follows: ; The preparation method of the pre-activated Pd(II)-P catalyst is as follows: Weigh 21.2 g of sponge palladium, dissolve it in 100 mL of concentrated nitric acid, add 500 mL of trifluoromethanesulfonic acid to the resulting solution and heat to boiling for 1 h. Then cool to room temperature and separate the solid product, palladium trifluoromethanesulfonate, by filtration. Wash the solid twice with 500 mL of deionized water to remove residual impurities. Transfer 200 mmol of solid palladium trifluoromethanesulfonate to a 2 L round-bottom flask, add 500 mL of distilled water, and stir until completely dissolved. Then slowly add 600 mL of an ethanol solution containing 95.2 g of XPhos (200 mmol) and allow the complexation reaction to proceed at room temperature for 7 h, resulting in a yellow suspension. Then heat the solution in an oil bath to 80 °C, slowly add 400 mmol of hydrazine hydrate dropwise while stirring, and allow the reduction reaction to proceed for 60 min. Finally, add 46.8 g of... 2-(2-bromo-phenyl)-pyridine (200 mmol) was heated to 100 °C and refluxed under nitrogen atmosphere for 3 h for an oxidative addition reaction. During the reaction, the mixture was kept homogeneous by magnetic stirring. The reaction endpoint was confirmed by TLC monitoring (electrolyte: petroleum ether and ethyl acetate in a volume ratio of 10:1). After the reaction was completed, the mixture was cooled to room temperature, and 0.5 mol / L CF3SO3H was slowly added dropwise to adjust the pH of the system to 6.0, resulting in the precipitation of a deep yellow crystalline solid. The solid was filtered using a Buchner funnel, and the filter cake was collected. The solid was washed twice each with 600 mL of ethanol and 600 mL of deionized water, and dried under vacuum at 50 °C for 8 h to obtain 71.96 g of pre-activated Pd(II)-P catalyst, with a yield of 82% (calculated based on the molar amount of Pd).

[0121] Example 9 The chemical structure of the pre-activated Pd(II)-P catalyst is as follows: ; The preparation method of the pre-activated Pd(II)-P catalyst is as follows: Weigh 15.9 g of sponge palladium, dissolve it in 150 mL of concentrated nitric acid, add 800 mL of tetrafluoroboric acid to the resulting solution and heat to boiling for 1 h. Then cool to room temperature and separate the solid product, palladium tetrafluoroborate, by filtration. Wash the solid twice with 800 mL of deionized water to remove residual impurities. Transfer 150 mmol of solid palladium tetrafluoroborate to a 3 L round-bottom flask, add 800 mL of distilled water, and stir until completely dissolved. Then slowly add 1000 mL of an ethanol solution containing 61.15 g of SPhos (150 mmol) and allow the complexation reaction to proceed at room temperature for 5 h, resulting in a yellow-green suspension. Then heat the solution in an oil bath to 80 °C, slowly add 300 mmol of hydrazine hydrate dropwise while stirring, and allow the reduction reaction to proceed for 60 min. Finally, add 35.10 g of... 2-(2-bromo-phenyl)-pyridine (150 mmol) was heated to 100 °C and refluxed under a nitrogen atmosphere for 3 h for an oxidative addition reaction. During the reaction, the mixture was kept homogeneous by magnetic stirring. The reaction endpoint was confirmed by TLC monitoring (electrolyte: petroleum ether and ethyl acetate in a volume ratio of 10:1). After the reaction was completed, the mixture was cooled to room temperature, and 0.5 mol / L HBF4 was slowly added dropwise to adjust the pH of the system to 6.0, resulting in the precipitation of a yellow crystalline solid. The solid was filtered using a Buchner funnel, and the filter cake was collected. The solid was washed twice each with 500 mL of ethanol and 500 mL of deionized water, and dried under vacuum at 50 °C for 4 h to obtain 93.04 g of pre-activated Pd(II)-P catalyst, with a yield of 85% (based on the molar amount of Pd).

[0122] Example 10 The chemical structure of the pre-activated Pd(II)-P catalyst is as follows: ; The preparation method of the pre-activated Pd(II)-P catalyst is as follows: Weigh 36.0 g PdI₂ (100 mmol) and 30.00 g NaI (200 mmol), place them in a 3 L round-bottom flask, add 1000 mL of distilled water, and stir until completely dissolved. Then, slowly add 1000 mL of an ethanol solution containing 57.8 g XanPhos (100 mmol) and carry out a coordination reaction at room temperature for 7 h, until the system turns into a yellow-green suspension. Then, heat the solution in an oil bath to 80 °C, and under nitrogen protection, introduce high-purity CO at a flow rate of 80 mL / min for 60 min until the solution color gradually changes from yellow to bright yellow. Stop the gas flow and continue reflux and stirring for 30 min to carry out the reduction reaction. Then, add 23.4 g of PdI₂. 2-(2-bromo-phenyl)-pyridine (100 mmol) was heated to 100 °C and refluxed under a nitrogen atmosphere for 3 h for an oxidative addition reaction. During the reaction, the mixture was kept homogeneous by magnetic stirring. The reaction endpoint was confirmed by TLC monitoring (electrolyte: petroleum ether and ethyl acetate in a volume ratio of 10:1). After the reaction was completed, the mixture was cooled to room temperature, and 1 mol / L hydroiodic acid was slowly added dropwise to adjust the pH of the system to 6.0, resulting in the precipitation of a yellow crystalline solid. The solid was filtered using a Buchner funnel, and the filter cake was collected. The solid was washed twice each with 500 mL of ethanol and 500 mL of deionized water, and dried under vacuum at 50 °C for 4 h to obtain 86.32 g of pre-activated Pd(II)-P catalyst, with a yield of 79% (calculated based on the molar amount of Pd).

[0123] Application Example 1 To a 250 mL round-bottom flask equipped with a magnetic stirrer, 5.00 mmol of 2-bromo-5-(trifluoromethyl)pyridine, 5.50 mmol of 2,4-difluorophenylboronic acid, and 1 mol% of the pre-activated Pd(II)-P catalyst prepared in Example 1 (2,4-difluorophenylboronic acid) were added sequentially. After purging the air in the flask three times with nitrogen, 60 mL of freshly distilled tetrahydrofuran was added to completely dissolve the solid. Sodium carbonate (15.0 mmol) was dissolved in 15 mL of deoxygenated deionized water to prepare a clear solution, which was then added to the reaction system in one go using a syringe. The mixture was heated to 90 °C under nitrogen protection and refluxed with vigorous stirring for 12 h for the oxidative addition reaction. After TLC monitoring (petroleum ether to ethyl acetate volume ratio of 10:1) showed that the starting materials were completely consumed, heating was stopped, and the mixture was cooled to room temperature. The reaction solution was washed with saturated brine and then extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, dried with anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether and ethyl acetate in a volume ratio of 10:1) to give a colorless to pale yellow solid with a yield of 99.5%.

[0124] Application Example 2 Based on Application Example 1, the temperature of the oxidative addition reaction was modified to 60°C, while other conditions remained unchanged, and the yield was 98%.

[0125] Application Example 3 Based on Application Example 1, the temperature of the oxidative addition reaction was modified to 25°C, while other conditions remained unchanged. The product Trace (the content of which was extremely small and almost negligible) was obtained.

[0126] Application Example 4 Based on Example 2, the type of alkali was changed to potassium phosphate, while other conditions remained the same, and the yield was 92%.

[0127] Application Example 5 Based on Application Example 2, the type of base was changed to cesium carbonate, the time of the oxidative addition reaction was changed to 8.5 h, and other conditions remained unchanged, with a yield of 90%.

[0128] Application Example 6 Based on Application Example 2, the type of base was changed to Et3N, the time of the oxidative addition reaction was changed to 9h, and other conditions remained unchanged. The product Trace (the content is extremely small and can be almost ignored).

[0129] Application Example 7 Based on Application Example 2, the type of base was changed to t-BuOK, the time of the oxidative addition reaction was changed to 9 hours, and other conditions remained unchanged, with a yield of 12%.

[0130] As can be seen from the above application examples, using sodium carbonate and performing an oxidative addition reaction at 60°C for 20 hours can yield 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine with a yield of 98%.

[0131] Application Example 8 Based on Application Example 2, the pre-activated Pd(II)-P catalyst of Example 2 was used, with other conditions remaining unchanged.

[0132] Application Example 9 Based on Application Example 2, the pre-activated Pd(II)-P catalyst of Example 3 was used, with other conditions remaining unchanged.

[0133] Application Example 10 Based on Application Example 2, the pre-activated Pd(II)-P catalyst of Example 4 was used, with other conditions remaining unchanged.

[0134] Application Example 11 Based on Application Example 2, the pre-activated Pd(II)-P catalyst of Example 5 was used, with other conditions remaining unchanged.

[0135] The yields of applications 8-11 were all above 95%.

[0136] As can be seen from the above embodiments, the pre-activated Pd(II)-P catalyst provided by the present invention can avoid the oxidative addition energy barrier that the catalytic precursor needs to overcome during the activation process, thereby improving the yield of the catalytic synthesis product.

[0137] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A pre-activated Pd(II)-P catalyst, with a chemical structure as shown in Formula I: Formula I; In Formula I, L is chloride ion, bromide ion, acetate ion, trifluoromethanesulfonate ion or tetrafluoroborate ion, and PR3 is triphenylphosphine, tricyclohexylphosphine, di(tert-butyl)phenylphosphine, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl or 4,5-bisdiphenylphosphine-9,9-dimethyloxanethium.

2. The preparation method of the pre-activated Pd(II)-P catalyst according to claim 1, comprising the following steps: A coordination reaction was carried out by mixing a Pd(II) compound, a solvent, and a PR3 ligand. The system after the coordination reaction is completed is mixed with a reducing agent to carry out a reduction reaction; The system after the reduction reaction was completed was mixed with 2-(2-halo-phenyl)-pyridine and subjected to an oxidative addition reaction to obtain a pre-activated Pd(II)-P catalyst.

3. The preparation method according to claim 2, characterized in that, The molar ratio of the Pd(II) compound to the PR3 ligand is 1:(1~1.2).

4. The production method according to claim 2, characterized by, The coordination reaction is carried out at a temperature of room temperature to 90°C for a duration of 2 to 8 hours.

5. The preparation method according to claim 2, characterized in that, The reduction reaction is carried out at a temperature of 25~90℃ for 30~60 min.

6. The preparation method according to claim 2, characterized in that, The molar ratio of the Pd(II) compound to 2-(2-halo-phenyl)-pyridine is (1~1.2):

1.

7. The preparation method according to claim 2, characterized in that, The oxidative addition reaction is carried out at a temperature of 25~100℃ for 2~8h.

8. The application of the pre-activated Pd(II)-P catalyst according to claim 1 in CC coupling reaction.

9. The application according to claim 8, characterized in that, The CC coupling reaction is a Suzuki coupling reaction.

10. The application according to claim 8, characterized in that, The operation of applying the pre-activated Pd(II)-P catalyst in the CC coupling reaction includes: A pre-activated Pd(II)-P catalyst, solvent, alkaline solution, bromoary matrix and phenylboronic acid derivative were mixed and subjected to an oxidative addition reaction to obtain the target product. The alkali in the alkaline solution is sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, or an organic alkali; The oxidative addition reaction is carried out at a temperature of 40~100℃ and for a time of ≤20h.

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