A method for recovering a palladium-phosphine catalyst from the product of a Suzuki coupling reaction

Abstract

The application discloses a method for efficiently recycling and recycling a Trans-Pd(PR3)2X2 or Cis-Pd(R2P^PR2)X2 (X=Br / Cl) type palladium-phosphine catalyst from a Suzuki coupling reaction product. By using Pd(COD)X2 as a precursor, the phosphine ligand is activated in a dry solvent to form an active cis-forming species, thereby improving the catalytic efficiency and stability; after the reaction, the catalyst is recovered by removing the solvent through rotary evaporation, extracting with diethyl ether, and performing silica gel column chromatography, the recovery rate is greater than 94%, and the purity is more than 95%. The method is economical and environmentally friendly, can significantly reduce the consumption of palladium and waste emissions, and is suitable for the fields of drug synthesis and fine chemical industry.

Description

Technical Field

[0001] This invention belongs to the field of homogeneous catalysis technology and relates to a method for recovering palladium-phosphine catalysts from Suzuki coupling reaction products, particularly a method for efficiently recovering and recycling Trans-Pd(PR3)2X2 or Cis-Pd(R2P^PR2)X2 (X=Br / Cl) catalysts from Suzuki coupling reaction systems. Background Technology

[0002] Suzuki coupling reactions are an important method for forming carbon-carbon bonds and have wide applications in drug synthesis, materials science, and fine chemicals. These reactions are typically driven by palladium catalysts, with homogeneous palladium-phosphine catalysts being the preferred choice due to their high activity and selectivity. Currently, catalyst recovery technologies mainly focus on processes that convert used complexes into metallic palladium.

[0003] Palladium is a precious metal with high cost. Recycling can effectively reduce catalyst consumption and improve economic efficiency. Recycling can also reduce the emission of palladium-containing waste, reduce environmental risks, and is in line with the principles of green chemistry.

[0004] Current recycling technologies are diversifying. Ion exchange, with its high selectivity and recyclable resin properties, has become an important extraction technology, capable of efficiently enriching palladium and removing phosphine ligands, achieving recovery rates of over 98% and purities exceeding 99.9%. In pharmaceutical synthesis and other fields, the removal technology combining activated carbon adsorption and organophosphine complexation can reduce palladium residues in products to below 2 ppm, meeting stringent quality requirements. While traditional pyrometallurgy and hydrometallurgy are widely used, they face challenges related to high energy consumption and wastewater treatment, respectively. Emerging technologies, such as lithium-mediated electrodeposition, promise efficient and clean recovery at room temperature and pressure by controlling the palladium valence state. Furthermore, technologies for directly separating catalysts from reaction products are under exploration, aiming to improve the utilization efficiency of palladium and organophosphine.

[0005] Recovery methods for palladium-phosphine catalysts have shown significant advantages in the Suzuki reaction. In 2013, Manjunatha et al. successfully recovered Pd-100, Pd-106, and Pd-118 catalysts under simple acid-base conditions, achieving a recovery rate of 70-80%, and the catalysts could be recycled three times without significant deactivation. However, this method suffered from catalyst leaching rates of 15-20% and incomplete recovery. EP3297436A4 further emphasizes its suitability for industrial production, recovering over 70% of the palladium catalyst through phase separation, reducing precious metal waste. However, it also suffers from reduced catalytic activity after recovery and requires specific functional groups to promote separation, limiting the substrate range. Nobre et al. in 2004 used a PEO / methanol solvent system, enabling the catalyst to be reused more than ten times while maintaining a high yield, highlighting the simplicity and efficiency of the operation. WO2025002969A1 recovered the palladium-phosphine complex with a yield of 94.7% through distillation and the addition of phosphine ligands. However, while distillation is highly efficient, the process is complex and requires the use of high-boiling-point solvents, which may increase operating costs and energy consumption. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the above-mentioned shortcomings and provide a method for recovering palladium-phosphine catalysts from Suzuki coupling reaction products, so as to achieve efficient recovery and recycling of Trans-Pd(PR3)2Br2 or Cis-Pd(R2P^PR2)Br2 catalysts from Suzuki coupling reaction system.

[0007] The method of the present invention for recovering and reusing Trans-Pd(PR3)2Br2 and Cis-Pd(R2P^PR2)Br2 type catalysts from Suzuki coupling reaction products mainly includes the following steps:

[0008] First, a certain amount of palladium precursor, PR3, and dry tetrahydrofuran solvent were added sequentially into a dry double-necked round-bottom flask. The mixture was stirred at room temperature for a certain period of time to complete the activation of the Pd precursor.

[0009] Secondly, a certain amount of inorganic base is dissolved in water, and then a certain amount of phenylboronic acid derivative and 2-bromopyridine derivative are added to the above mixture in sequence. Under gas protection, the mixture is stirred at 90°C for a certain time (hours).

[0010] Third, after the reaction is complete, the reaction system is cooled to room temperature, and a large amount of solvent is removed by rotary evaporation;

[0011] Fourth, the crude product was obtained by extraction and concentration with diethyl ether; the coupling product was purified by silica gel column chromatography by elution with petroleum ether and ethyl acetate / petroleum ether in sequence; finally, the catalyst supported in the column was recovered by elution with dichloromethane and concentrated to obtain the solid catalyst.

[0012] Furthermore:

[0013] The palladium precursor is η 2 -Pd halides, including any one of cyclooctadiene palladium halide (1,5-Pd(COD)Cl2, 1,5-Pd(COD)Br2) and norbornadiene palladium halide;

[0014] Phosphine ligand PR3 is selected from any one of triphenylphosphine (PPh3), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (XPhos), or 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (SPhos); R2P^PR2 is selected from 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene (XantPhos) or 1,2-bis(diphenylphosphine)ethane (dppe);

[0015] The inorganic base is selected from any one of sodium carbonate (Na2CO3), potassium carbonate (K2CO3), potassium phosphate (K3PO4), and cesium carbonate (Cs2CO3);

[0016] Selection of substrates for coupling reactions:

[0017] The phenylboronic acid derivatives are selected from any one of 4-fluorophenylboronic acid, 4-(trifluoromethyl)phenylboronic acid, 4-hydroxyphenylboronic acid, and 4-aminophenylboronic acid, and their chemical structural formulas are as follows:

[0018] ;

[0019] 2-Bromopyridine derivatives are selected from any one of 2-bromopyridine, 3-bromopyridine, 5-bromopyrimidine, and 3-bromothiophenothiophene, and their chemical structural formulas are as follows:

[0020] .

[0021] Furthermore, in one specific embodiment, the conditions for the Suzuki coupling reaction are as follows:

[0022] Catalytic system: The amount of the palladium precursor is 0.1% to 2.0% of the molar amount of the phenylboronic acid derivative; preferably 1.0%.

[0023] Ligand dosage: When using monodentate phosphine ligand PR3, the dosage is 1.0 molar equivalent (relative to the palladium precursor); when using bidentate phosphine ligand R2P^PR2, the dosage is 2.0 molar equivalent (relative to the palladium precursor).

[0024] Reactant ratio: The molar ratio of the (hetero)aryl bromide (e.g., 2-bromopyridine derivative) to the phenylboronic acid derivative is 1.0:1.1;

[0025] Amount of alkali: The amount of inorganic alkali added is 2.0 molar equivalents of the phenylboronic acid derivative.

[0026] Mechanism and beneficial effects of the present invention

[0027] The test results of the catalytic performance of the following reactions are shown in Table 1.

[0028] (Reaction 1)

[0029] (Reaction 2)

[0030] (Reaction 3)

[0031] (Reaction 4)

[0032] Table 1. Catalytic performance test results

[0033]

[0034] The high efficiency of the preparation process in this invention stems from the palladium-catalyzed cross-coupling reaction mechanism. Specifically, different organophosphine ligand structures significantly affect the yield of the coupling products: Pd(COD)X2 / Xantphos > Pd(COD)X2 / PPh3 > commercially available Trans-Pd(PPh3)2Cl2 > Pd(COD)X2; the catalytic performance of the brominated precursor (Pd(COD)Br2) is superior to that of the chlorinated precursor (Pd(COD)Cl2). The main reason is that the rigid framework of Xantphos continues the coordination of the palladium center, resulting in Cis-(Xantphos)-Pd(0) which exposes more active sites; the PPh3-substituted Cis-Pd(PPh3)2X2 is easily inverted to the trans configuration, forming a mixture; while the Pd-Br bond energy in Pd(COD)X2 is lower and more easily broken, leading to faster Pd(0) formation. This mechanism directly supports the high recovery rates in the examples, highlighting the innovation of this invention in improving catalytic efficiency and cycle stability.

[0035] This invention relates to the application of palladium catalysts with Pd(COD)X2 as a catalytic precursor in cross-coupling reactions. The key lies in ensuring the effective maintenance of the cis-configured active palladium species derived from this precursor throughout the reaction process. Specifically, the substitution of the COD ligand by the PR3 ligand forms a kinetically stable cis intermediate, Cis-[Pd(PR3)2X2]. This cis configuration effectively avoids the energy consumption associated with the inversion to the trans configuration, providing a structural basis for subsequent steps.

[0036] In the catalytic cycle, the in-situ generated zero-valent palladium active center (Cis-(PR3)) n Pd(0) also maintains the cis configuration. This structural feature combines electron abundance with significant steric hindrance: electron abundance helps suppress the oxidation or agglomeration of the palladium center; while the specific steric environment can significantly promote the oxidative addition of the substrate and the reductive elimination step of the coupling product, thereby efficiently driving reactions such as Suzuki coupling.

[0037] After the reaction, the cis-zero palladium species is oxidized by oxidants such as oxygen and combines with halide ions released in the reaction system to regenerate a structurally well-defined cis-divalent palladium complex. This species is structurally similar to the initial precursor, thus enabling catalyst recycling and regeneration. Attached Figure Description

[0038] Figure 1 This is a catalytic mechanism cycle diagram. Detailed Implementation

[0039] Example 1: Preparation of Pd(PPh3)2Br2

[0040] Weigh 37.44 mg of Pd(COD)Br2 (1 mol% Pd), 52.45 mg of PPh3 (2.0 equiv), and dry tetrahydrofuran (0.1 M) into a 50 mL dry double-necked round-bottom flask. Stir the mixture at room temperature for 10 minutes to activate the Pd precursor. Dissolve 2.10 g (2.0 equiv) of sodium carbonate in water (0.4 M), then add 1.73 g (1.1 equiv) of 2,4-difluorophenylboronic acid, 2.14 g (1.0 equiv) of 2-bromo-4-tert-butylpyridine, and the sodium carbonate aqueous solution to the mixture. Exchange the solution with nitrogen three times and stir at 90 °C for 3–5 hours. Cool the reaction system to room temperature and remove a large amount of solvent by rotary evaporation. Extract the aqueous phase three times with diethyl ether (100 mL), combine the organic extracts, wash with saturated brine (500 mL), dry to anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio 10:1) to obtain the target coupling product. Finally, pure dichloromethane was used as the eluent to obtain a dichloromethane solution of the target catalyst, which was then rotary evaporated to give 67.30 mg of solid catalyst, yield: 96%. The entire process was monitored by TLC.

[0041] Structural characterization:

[0042] Elemental analysis by C 52 H 70 Calculated values ​​of Br2P2Pd (%): C 62.53, H 7.01, Br 7.10, P 6.21, Pd 10.62;

[0043] Measured values ​​(%): C 62.54, H 7.02, Br 7.11, P 6.22, Pd 10.61.

[0044] 1 H NMR (500 MHz, Chloroform-d): δ 0.90 (d, 2H), 1.04 (d, 7H), 1.41 (s, 2H), 1.53 (t, 8H), 1.64-1.69 (m, 4H), 1.86 (s, 3H), 1.99 (s, 1H), 2.26 (s, 1H), 6.57 (d, 4H), 6.94-7.01 (m, 2H), 7.30 (t, 2H), 7.32-7.40 (m, 4H), 8.11 (qd, 2H).

[0045] 13C NMR (126 MHz, Chloroform-d) :δ 26.31, 27.40 (dt), 29.02, 34.09, 55.15, 103.41, 119.45, 124.60 (h), 128.77, 129.08, 130.81 (h), 132.10 (t), 138.57-140.78 (m),

[0046] IR (cm -1 ):3056, 3003 [ν(CH) arom.]; 2841, 2803 [ν(CH)OCH3]; 1602,1591, 1579, 1500 [ν(C=C) arom.]; 1460 [ν(P-Ar)]; 1281, 1250 [ν(CO) as];1180, 1100 [ν(P-Ar) coord.]; 1030 [ν(CO)s]; 825 [γ(CH) p-subst. Ph]; 734,691 [γ(CH) monosubst. Ph]; 510, 485 [ν(Pd-P)]

[0047] Compound 2:Pd(Xantphos)Br2 solvent

[0048] Weigh 28.55 mg of Pd(COD)Cl2 (1 mol% Pd), 57.86 mg of Xantsphos (1.0 equiv), and dry tetrahydrofuran (0.1 M) into a 50 mL dry double-necked round-bottom flask. Stir the mixture at room temperature for 10 minutes to activate the Pd precursor. Dissolve 2.10 g (2.0 equiv) of sodium carbonate in water (0.4 M), then add 1.89 g (1.1 equiv) of 4-trifluoromethylphenylboronic acid, 1.75 g (1.0 equiv) of 2-bromo-5-fluoropyridine, and the sodium carbonate aqueous solution to the mixture. Exchange the solution with nitrogen three times and stir at 90 °C for 3–5 hours. Cool the reaction system to room temperature and remove a large amount of solvent by rotary evaporation. Extract the aqueous phase three times with diethyl ether (100 mL), combine the organic extracts, wash with saturated brine (500 mL), dry to anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio 10:1) to obtain the target coupling product. Finally, pure dichloromethane was used as the eluent to obtain a dichloromethane solution of the target catalyst, which was then rotary evaporated to obtain 82.00 mg of solid catalyst Pd(Xantphos)Br2, yield: 97%. The entire process was monitored by TLC.

[0049] Characterization data:

[0050] ① Elemental analysis

[0051] Measured values: Pd 13.56%, C 59.84%, Br 20.45%, P 7.94%;

[0052] Theoretical value (C) 39 H 48 Br2P2Pd) Pd 13.55%, C 59.85%, Br 20.46%, P 7.93%;

[0053] The measured values ​​are basically consistent with the theoretical values.

[0054] ② 1 H NMR (500 MHz, Chloroform-d): δ 7.11 (dt, 1H), 7.19 (dd, 1H), 7.26 – 7.34 (m, 4H), 7.31 – 7.36 (m, 1H), 7.34 – 7.39 (m, 1H), 7.66 (dt, 4H),8.04 (dt, 1H); 13C NMR (126 MHz, Chloroform-d): δ 30.85, 35.67, 124.54, 126.39,128.71, 128.78, 130.22, 132.22, 134.37, 134.86, 135.35, 153.68.

[0055] ③MS(ESI(+)):m / z=702 (calcd.782 for [C 39 H 48 [Br2P2Pd], [M-Br] - ).

[0056] ④IR (KBr, ν / cm -1 ): 3053 (w), 3026 (w); 2962 (m), 2930 (m), 2872 (w); 1601 (m), 1584 (m); 1484 (m), 1472 (m), 1459 (m), 1436 (s); 1252 (s) [ν(C–O–C)]; 1102 (m), 1029 (w); 748 (s), 698 (s); 520–505 (w); 380–350 (w).

[0057] Example 3: Preparation of Pd(Xphos)2Br2

[0058] Weigh 37.44 mg of Pd(COD)Br2 (1 mol% Pd), 95.34 mg of Xphos (2.0 equiv), and dry tetrahydrofuran (0.1 M) into a 50 mL dry double-necked round-bottom flask. Stir the mixture at room temperature for 10 minutes to activate the Pd precursor. Dissolve 2.10 g (2.0 equiv) of sodium carbonate in water (0.4 M), then add 1.89 g (1.1 equiv) of 4-trifluoromethylphenylboronic acid, 1.75 g (1.0 equiv) of 2-bromo-5-fluoropyridine, and the sodium carbonate aqueous solution to the mixture. Exchange the solution with nitrogen three times and stir at 90 °C for 3–5 hours. Cool the reaction system to room temperature and remove a large amount of solvent by rotary evaporation. Extract the aqueous phase three times with diethyl ether (100 mL), combine the organic extracts, wash with saturated brine (500 mL), dry to anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio 10:1) to obtain the target coupling product. Finally, pure dichloromethane was used as the eluent to obtain a dichloromethane solution of the target catalyst, which was then rotary evaporated to obtain 69.81 mg of solid catalyst Pd(Xphos)Br2, yield: 94%. The entire process was monitored by TLC.

[0059] Structural characterization:

[0060] Elemental analysis by C 66 H 98 Calculated values ​​of Br2P2Pd (%): C 70.09, H 8.67, Br 6.27, P 5.49, Pd 9.38.

[0061] Measured values ​​(%): C 70.08, H 8.68, Br 6.26, P 5.50, Pd 9.39.

[0062] 1H NMR (500 MHz, Chloroform-d):δ 0.66 (s, 1H), 0.74 (s, 4H), 0.78 (s,3H), 1.04 (d, 12H), 1.15 (d, 5H), 1.17 (s, 3H), 1.22 (d, 17H), 1.27 (d, 21H), 1.41(s, 3H), 1.80(s, 2H), 2.15(s, 1H), 2.50(s, 1H), 2.68(s, 1H), 2.91(p, 3H), 3.18(s, 1H), 7.01(s, 9H), 7.30(d, 3H), (d, 2H), 8.13 (s,1H).

[0063] 13 C NMR (126 MHz, chloroform-d): δ-6.32-120.23(m), 120.23-144.55(m),

[0064] IR (cm -1 ): 3475 [ν(OH)]; 3053 [ν(CH) arom.]; 2961, 2920, 2862 [ν(CH) aliph.]; 1603, 1585 [ν(C=C) arom.]; 1460 [ν(P-Ar)]; 1385, 1365 [δ(CH3)iPr]; 1180, 1100 [ν(P-Ar) coord.]; 825 [γ(CH) p-subst. Ph]; 734 [γ(CH)monosubst. Ph]; 527,500 [ν(Pd-P)]

[0065] Compound 4: Pd(Sphos)2Br2 catalyst

[0066] Weigh 28.55 mg of Pd(COD)Cl2 (1 mol% Pd), 82.00 mg of Sphos (2.0 equiv), and dry tetrahydrofuran (0.1 M) into a 50 mL dry double-necked round-bottom flask. Stir the mixture at room temperature for 10 minutes to activate the Pd precursor. Dissolve 2.10 g (2.0 equiv) of sodium carbonate in water (0.4 M), then add 1.73 g (1.1 equiv) of 2,4-difluorophenylboronic acid, 2.14 g (1.0 equiv) of 2-bromo-4-tert-butylpyridine, and the sodium carbonate aqueous solution to the mixture. Exchange the solution with nitrogen three times and stir at 90 °C for 3–5 hours. Cool the reaction system to room temperature and remove a large amount of solvent by rotary evaporation. Extract the aqueous phase three times with diethyl ether (100 mL), combine the organic extracts, wash with saturated brine (500 mL), dry to anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio 10:1) to obtain the target coupling product. Finally, pure dichloromethane was used as the eluent to obtain a dichloromethane solution of the target catalyst, which was then rotary evaporated to obtain 64.27 mg of solid catalyst Pd(Sphos)Br2, yield: 95%. The entire process was monitored by TLC.

[0067] Structural characterization:

[0068] Elemental analysis by C 52 H 70 Calculated values ​​of Br2P2Pd (%): C 62.53, H 7.01, Br 7.10, P 6.21, Pd 10.62;

[0069] Measured values ​​(%): C 62.54, H 7.02, Br 7.11, P 6.22, Pd 10.61.

[0070] 1 H NMR (500 MHz, Chloroform-d): δ 0.90 (d, 2H), 1.04 (d, 7H), 1.41 (s, 2H), 1.53 (t, 8H), 1.64-1.69 (m, 4H), 1.86 (s, 3H), 1.99 (s, 1H), 2.26 (s,1H), 6.57 (d, 4H), 6.94-7.01 (m, 2H), 7.30 (t, 2H), 7.32-7.40 (m, 4H), 8.11(qd, 2H).

[0071] 13C NMR (126 MHz, Chloroform-d): δ 26.31, 27.40 (dt), 29.02, 34.09,55.15, 103.41, 119.45, 124.60 (t), 128.77, 129.08, 130.81 (t), 132.10 (t),138.57-140.78 (m), 158.07.

[0072] IR (cm -1 ): 3056, 3003 [ν(CH) arom.]; 2841, 2803 [ν(CH) OCH3]; 1602,1591, 1579, 1500 [ν(C=C) arom.]; 1460 [ν(P-Ar)]; 1281, 1250 [ν(CO) as]; 1180, 1100 [ν(P-Ar) coord.]; 1030 [ν(CO) s]; 825 [γ(CH) p-subst. Ph]; 734,691 [γ(CH) monosubst. Ph]; 510, 485 [ν(Pd-P)].

[0073] Example 5: Preparation of Pd(PPh3)2Cl2

[0074] Weigh 37.44 mg of Pd(COD)Br2 (1 mol% Pd), 52.45 mg of PPh3 (2.0 equiv), and dry tetrahydrofuran (0.1 M) into a 50 mL dry double-necked round-bottom flask. Stir the mixture at room temperature for 10 minutes to activate the Pd precursor. Dissolve 2.10 g (2.0 equiv) of sodium carbonate in water (0.4 M), then add 1.73 g (1.1 equiv) of 2,4-difluorophenylboronic acid, 1.70 g (1.0 equiv) of 2-chloro-4-tert-butylpyridine, and the sodium carbonate aqueous solution to the mixture. Exchange the solution with nitrogen three times and stir at 90 °C for 3–5 hours. Cool the reaction system to room temperature and remove a large amount of solvent by rotary evaporation. Extract the aqueous phase three times with diethyl ether (100 mL), combine the organic extracts, wash with saturated brine (500 mL), dry to anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio 10:1) to obtain the target coupling product. Finally, pure dichloromethane was used as the eluent to obtain a dichloromethane solution of the target catalyst, which was then rotary evaporated to obtain 65.80 mg of solid catalyst, yield: 94%. The entire process was monitored by TLC.

[0075] Example 6: Preparation of Pd(Xantphos)Cl2

[0076] Weigh 28.55 mg of Pd(COD)Cl2 (1 mol% Pd), 57.86 mg of Xantsphos (1.0 equiv), and dry tetrahydrofuran (0.1 M) and add them sequentially to a dry 50 mL double-necked round-bottom flask. Stir the mixture at room temperature for 10 minutes to activate the Pd precursor. Dissolve 2.10 g (2.0 equiv) of sodium carbonate in water (0.4 M), then add 1.89 g (1.1 equiv) of 4-trifluoromethylphenylboronic acid, 1.31 g (1.0 equiv) of 2-chloro-5-fluoropyridine, and the sodium carbonate aqueous solution sequentially to the above mixture. Exchange the solution with nitrogen three times and stir at 90 °C for 3–5 hours. Cool the reaction system to room temperature and remove a large amount of solvent by rotary evaporation. Extract the aqueous phase three times with diethyl ether (100 mL), combine the organic extracts, wash with saturated brine (500 mL), dry to anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio 10:1) to obtain the target coupling product. Finally, pure dichloromethane was used as the eluent to obtain a dichloromethane solution of the target catalyst, which was then rotary evaporated to obtain 72.56 mg of solid catalyst Pd(Xantphos)Cl2, yield: 96%. The entire process was monitored by TLC.

[0077] Example 7: Preparation of Pd(Xphos)2Cl2

[0078] Weigh 37.44 mg of Pd(COD)Br2 (1 mol% Pd), 95.34 mg of Xphos (2.0 equiv), and dry tetrahydrofuran (0.1 M) and add them sequentially to a dry 50 mL double-necked round-bottom flask. Stir the mixture at room temperature for 10 minutes to activate the Pd precursor. Dissolve 2.10 g (2.0 equiv) of sodium carbonate in water (0.4 M), then add 1.89 g (1.1 equiv) of 4-trifluoromethylphenylboronic acid, 1.31 g (1.0 equiv) of 2-chloro-5-fluoropyridine, and the sodium carbonate aqueous solution sequentially to the above mixture. Exchange the solution with nitrogen three times and stir at 90 °C for 3–5 hours. Cool the reaction system to room temperature and remove a large amount of solvent by rotary evaporation. Extract the aqueous phase three times with diethyl ether (100 mL), combine the organic extracts, wash with saturated brine (500 mL), dry to anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio 10:1) to obtain the target coupling product. Finally, pure dichloromethane was used as the eluent to obtain a dichloromethane solution of the target catalyst, which was then rotary evaporated to obtain 73.80 mg of solid catalyst Pd(Xphos)Cl2, yield: 94%. The entire process was monitored by TLC.

[0079] Example 8: Preparation of Pd(Sphos)2Cl2

[0080] Weigh 28.55 mg of Pd(COD)Cl2 (1 mol% Pd), 82.00 mg of Sphos (2.0 equiv), and dry tetrahydrofuran (0.1 M) and add them sequentially to a dry 50 mL double-necked round-bottom flask. Stir the mixture at room temperature for 10 minutes to activate the Pd precursor. Dissolve 2.10 g (2.0 equiv) of sodium carbonate in water (0.4 M), then add 1.73 g (1.1 equiv) of 2,4-difluorophenylboronic acid, 1.70 g (1.0 equiv) of 2-chloro-4-tert-butylpyridine, and the sodium carbonate aqueous solution sequentially to the above mixture. Exchange the solution with nitrogen three times and stir at 90 °C for 3–5 hours. Cool the reaction system to room temperature and remove a large amount of solvent by rotary evaporation. Extract the aqueous phase three times with diethyl ether (100 mL), combine the organic extracts, wash with saturated brine (500 mL), dry to anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio 10:1) to obtain the target coupling product. Finally, pure dichloromethane was used as the eluent to obtain a dichloromethane solution of the target catalyst, which was then rotary evaporated to obtain 64.35 mg of solid catalyst Pd(Sphos)Cl2, yield: 93%. The entire process was monitored by TLC.

Claims

1. A method for recovering palladium-phosphine catalyst from Suzuki coupling reaction products, characterized in that, Includes the following steps: (a) The palladium precursor, phosphine ligand and organic solvent are mixed and stirred to activate the palladium precursor and form an active catalyst species; The phosphine ligands include PR3 or R2P^PR2; (b) An aqueous solution of an inorganic base, a phenylboronic acid derivative, and a 2-bromopyridine derivative were added to the mixture from step (a), and a Suzuki coupling reaction was carried out under a gaseous atmosphere. (c) After the reaction is complete, cool the reaction system to room temperature and remove the solvent by rotary evaporation; (d) Extract the reaction mixture with diethyl ether and concentrate to obtain the crude product; (e) Catalyst recovery and reuse via silica gel column chromatography.

2. The method according to claim 1, characterized in that, The palladium precursor is an η²-Pd halide, selected from cyclooctadiene palladium halide or norbornene palladium halide.

3. The method according to claim 1, characterized in that, The PR3 is selected from any one of triphenylphosphine, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl or 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl; the R2P^PR2 is selected from any one of 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene or 1,2-bis(diphenylphosphine)ethane.

4. The method according to claim 1, characterized in that: The organic solvent is dry tetrahydrofuran, and the amount used is 0.1 mol / L; The inorganic base is selected from any one of sodium carbonate, potassium carbonate, potassium phosphate, or cesium carbonate, and the amount used is 2.0 mol equivalent of the phenylboronic acid derivative.

5. The method according to claim 1, characterized in that, The phenylboronic acid derivative is selected from any one of 4-fluorophenylboronic acid, 4-(trifluoromethyl)phenylboronic acid, 4-hydroxyphenylboronic acid, or 4-aminophenylboronic acid.

6. The method according to claim 1, characterized in that, The 2-bromopyridine derivative is selected from 2-bromopyridine, 3-bromopyridine, 5-bromopyrimidine, or 3-bromothiophene.

7. The method according to claim 1, characterized in that, The amount of palladium precursor used in step (a) is 0.1%-2.0% of the molar amount of the phenylboronic acid derivative; when using a monodentate phosphine ligand, the amount is 1.0 molar equivalent relative to the palladium precursor; when using a bidentate phosphine ligand, the amount is 2.0 molar equivalent relative to the palladium precursor.

8. The method according to claim 1, characterized in that, The molar ratio of the (hetero)aryl bromide to the phenylboronic acid derivative in step (b) is 1.0:1.1; the Suzuki coupling reaction is carried out under gas protection and stirred at 90°C for 3-5 hours.

9. The method according to claim 1, characterized in that, Step (e) includes: (1) The crude product was separated by silica gel column chromatography and eluted sequentially with a mixed solvent of petroleum ether, ethyl acetate and petroleum ether to obtain the coupling product; (2) Finally, dichloromethane was used as the eluent to elute the palladium-phosphine catalyst supported in the chromatography column, and the solid catalyst was obtained by concentration.

10. The method according to any one of claims 1-9, characterized in that, The method is applicable to the recovery of Trans-Pd(PR3)2X2 or Cis-Pd(R2P^PR2)X2 (X=Br / Cl) type palladium-phosphine catalysts, wherein the catalyst maintains the cis configuration during the reaction and avoids inversion to the trans configuration, thereby improving catalytic efficiency and cycle stability.

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