Synthetic method of ruthenium carbene complex

Abstract

The invention relates to a synthesis method of a ruthenium-carbene complex, which comprises the following steps: (1) reacting RuCl2 (DMSO) 4 with a carbene reagent to obtain an intermediate with a ruthenium-carbene structure; (2) carrying out complex reaction on the intermediate with the ruthenium-carbene structure obtained in the step (1) and an N-heterocyclic carbene precursor to obtain a DMSO coordinated ruthenium-carbene catalyst precursor; and (3) reacting the DMSO coordinated ruthenium carbene catalyst precursor obtained in the step (2) with a phosphine ligand to obtain the ruthenium carbene complex. The specific synthesis route of the ruthenium carbene complex provided by the invention has the characteristics of simple steps, simple operation, low raw material cost, good atom economy and the like, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing a ruthenium carbene complex. Background Art

[0002] Olefin metathesis is one of the most important and commonly used reaction types in organic chemistry. Through metal-catalyzed reactions, the carbon-carbon double bonds of two olefins can be broken and recombined into two new olefin structures. Therefore, it is widely used in the synthesis of natural products and drug molecules, and materials science.

[0003] Among the olefin metathesis catalyst systems, the most commercially available, practical, and widely used is the Grubbs catalyst, which is a metal complex with a ruthenium-carbene structure. In 1995, the first generation of Grubbs catalysts [RuCl 2 (=CHPh)(PCy 3 ) 2 ] has good stability to water and oxygen, and has good functional group tolerance to the reaction substrate. In 1999, based on the first generation of catalysts, one of the PCy 3 The ligand was replaced by an N-heterocyclic carbene ligand, and the second generation of Grubbs catalyst [(H 2 IMes)(PCy 3 )RuCl 2 (=CHPh)], which not only has the advantages of the first-generation catalyst, but also can greatly improve the reaction activity of metal catalysts. Therefore, it is widely used in the fields of medicine and material industry.

[0004] At present, the synthesis method of the second generation Grubbs catalyst is mainly obtained by subjecting the first generation Grubbs catalyst to a ligand substitution reaction. The commonly used synthesis route is shown in Route I:

[0005]

[0006] RuCl 2 (PPh 3 ) 3 Reacts with phenyldiazomethane at low temperature to generate RuCl 2 (=CHPh)(PPh 3 ) 2 , then use PCy 3 Replacement PPh 3The first generation of Grubbs catalyst was obtained; the first generation of catalyst was used to synthesize the second generation of Grubbs catalyst through ligand substitution reaction [(1) Schwab P, Grubbs RH, Ziller JW. Synthesis and Applications of RuCl 2 (dCHR')(PR 3 ) 2 :The Influence of the Alkylidene Moiety on MetathesisActivity.J.Am.Chem.Soc.1996,118(1):100-110.(2)Scho1l M,Ding S,Lee CW,GrubbsRH.Synthesis and Activity of a New Generation of Ruthenium-Based OlefinMetathesis Catalysts Coordinated with1,3-Dimesityl-4,5-dihydroimidazol-2-ylidene Ligands.Org.Lett.1999,1(6):953-956.]. In this synthetic route, phenyldiazomethane can be replaced by other reagents, such as sulfur ylide reagent (Gandelman M, Rybtchinski B, Ashkenazi N, Gauvin RM, Milstein DA New General Method for the Preparation of Metal Carbene Complexes. J. Am. Chem. Soc. 2001, 123 (22): 5372-5373.) and phosphine ylide reagent (CN111468191A).

[0007] Another widely used synthetic route was reported by Nolan et al. They prepared RuCl 2 (PPh 3 ) 3Starting from the method, an indenyl ruthenium carbene complex is synthesized by cyclization with an alkynol ligand, and then an olefin exchange reaction is carried out with styrene to obtain the first-generation Grubbs catalyst (Dorta R, Kelly III RA, Nolan SP. Cross Metathesis Allowing the Conversion of a Ruthenium Indenylidene Complex into Grubbs' Catalyst. Adv. Synth. Catal. 2004, 346, 917-920.), and then the first-generation catalyst is exchanged with the ligand to obtain the second-generation catalyst, as shown in route II:

[0008]

[0009] The starting material RuCl used in the above process route 2 (PPh 3 ) 3 It is prepared by reacting hydrated ruthenium trichloride with a large amount of triphenylphosphine. However, in the synthesis reaction, PPh 3 The ligand is lost after ligand exchange. At the same time, the above processes all require the synthesis of the first generation Grubbs catalyst and the addition of one molecule of PCy 3 The second generation catalyst is obtained by replacing the ligand. Therefore, a large amount of phosphine ligand needs to be lost, the material waste is serious, and the synthesis route is long and the process is complicated.

[0010] CN101775043A reports a method for synthesizing a second-generation Grubbs catalyst. First, a zero-valent ruthenium compound Ru(p-Cymene)(COD) is synthesized, and then the ruthenium compound is reacted with a nitrogen heterocyclic carbene ligand, PCy 3 , benzyl dichloride reacts in toluene to directly obtain the second-generation Grubb catalyst. The synthesis steps of this route are relatively simple, but the preparation of zero-valent ruthenium compounds is relatively difficult, and the yield of the second-generation Grubb catalyst is low, only 50%, which is not conducive to large-scale production. The synthesis route is shown in Route III:

[0011]

[0012] CN114149467A introduces a method of using hydrated ruthenium chloride, hydrogen, PCy 3 The invention discloses a method for synthesizing a first-generation Grubbs catalyst from hexene, hexene and benzylene, and the first-generation Grubbs catalyst can be directly ligand-exchanged with imidazole salt under the action of base without separation to obtain a second-generation Grubbs catalyst product. The disadvantage of this method is that it needs to use relatively dangerous hydrogen, which has potential safety hazards, and the feeding and reaction procedures are complicated, and the large-scale production is difficult. The synthesis route is shown in Route IV:

[0013]

[0014] In summary, most of the current ruthenium carbene complex synthesis processes have problems such as long routes, complex processes, harsh reaction conditions, and high prices of reaction materials. In particular, there are a large number of phosphine ligands (PPh 3 , PCy 3 ), resulting in the process route being difficult to scale up industrially or the cost being too high after the scale-up, limiting the application of the catalyst. At the same time, the excess phosphine ligand is difficult to separate and recover from the system, which not only increases the technical difficulty for the subsequent catalyst purification, but also reduces the yield of the target catalyst, resulting in an increase in the cost of the catalyst. Summary of the invention

[0015] In order to solve the above technical problems, the present invention provides a method for synthesizing a ruthenium carbene complex, which has the advantages of a simple synthesis route, easy availability of raw materials, no waste of phosphine ligands, etc., low raw material cost and processing cost, and is suitable for industrial scale-up production.

[0016] To achieve this object, the present invention adopts the following technical solutions:

[0017] In a first aspect, the present invention provides a method for synthesizing a ruthenium carbene complex, the method comprising the following steps:

[0018] (1) RuCl 2 (DMSO) 4 reacting with a carbene reagent to obtain an intermediate having a ruthenium-carbene structure;

[0019] (2) the intermediate having a ruthenium-carbene structure obtained in step (1) is subjected to a complexation reaction with a nitrogen heterocyclic carbene precursor to obtain a DMSO-coordinated ruthenium carbene catalyst precursor;

[0020] (3) The DMSO-coordinated ruthenium carbene catalyst precursor obtained in step (2) reacts with a phosphine ligand to obtain the ruthenium carbene complex.

[0021] The present invention adopts RuCl 2 (DMSO) 4 As a starting material, it is not only economical and readily available, but also RuCl 2 (DMSO) 4 DMSO is used as a new ligand, which is miscible with water and common organic solvents and can be easily removed by washing, thereby improving the yield and purity of the target product. The present invention designs a specific synthetic route so that the phosphine ligand is added to the reaction last, which can effectively avoid the addition of a large amount of phosphine ligand (PPh 3 , PCy 3), which not only saves raw materials and reduces economic costs; but also reduces the difficulty of post-processing, which is conducive to the purification and separation of the target product, thereby improving its yield and purity. The synthetic method has the characteristics of simple steps, simple operation, low raw material cost, good atom economy, etc., and has great application prospects in industrial scale-up.

[0022] Preferably, the carbene reagent in step (1) comprises phenyldiazomethane (PhCH=N 2 ), any one of benzylidenephosphine ylide reagents or benzylidenesulfonium ylide reagents, or a combination of at least two thereof.

[0023] In the present invention, the benzylidenephosphine ylide reagent is preferably benzylidenetriphenylphosphine (PhCH=PPh 3 ); the benzylidene sulfide reagent is preferably benzylidene diphenyl sulfide (PhCH=SPh 2 ).

[0024] Preferably, the carbene reagent in step (1) is reacted with RuCl 2 (DMSO) 4 The feeding molar ratio is (1-10):1, for example, it can be 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1, and more preferably (1.5-2.5):1.

[0025] Preferably, the reaction in step (1) is carried out in an organic solvent, and the organic solvent includes any one of dichloromethane, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene or xylene, or a combination of at least two thereof.

[0026] Preferably, the amount of the organic solvent used is such that the RuCl 2 (DMSO) 4 The initial concentration is 0.1-0.5 mol / L, for example, it can be 0.1 mol / L, 0.15 mol / L, 0.2 mol / L, 0.25 mol / L, 0.3 mol / L, 0.35 mol / L, 0.4 mol / L, 0.45 mol / L or 0.5 mol / L.

[0027] Preferably, the reaction temperature in step (1) is -78°C to 0°C, for example, -78°C, -60°C, -50°C, -40°C, -30°C, -28°C, -26°C, -24°C, -22°C, -20°C, -10°C or 0°C, and more preferably -30°C to -20°C.

[0028] Preferably, the reaction time of step (1) is 0.5 to 20 h, for example, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 10 h, 15 h or 20 h.

[0029] Preferably, the nitrogen heterocyclic carbene precursor in step (2) comprises a nitrogen heterocyclic carbene-chloroform adduct and / or a heterocyclic carbene-pentafluorobenzene adduct.

[0030] Preferably, the nitrogen heterocyclic carbene-chloroform adduct is SIMes-CCl 3 .

[0031] Preferably, the nitrogen heterocyclic carbene-pentafluorobenzene adduct is SIMes-C 6 F 5 .

[0032] Preferably, the nitrogen heterocyclic carbene precursor in step (2) and the RuCl in step (1) 2 (DMSO) 4 The feeding molar ratio is (1-10):1, for example, it can be 1:1, 1.4:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1, and more preferably (1.4-2):1.

[0033] Preferably, the reaction temperature in step (2) is 50°C to 80°C, for example, 50°C, 52°C, 54°C, 56°C, 58°C, 60°C, 65°C, 70°C, 75°C, 80°C, etc.

[0034] Preferably, the reaction time of step (2) is 0.5 to 10 h, for example, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h or 10 h.

[0035] Preferably, the phosphine ligand in step (3) comprises triphenylphosphine (PPh 3 ), tri-n-butylphosphine (PBu 3 ), tricyclohexylphosphine (PCy 3 ), tri-n-octylphosphine or triisopropylphosphine, or a combination of at least two thereof.

[0036] Preferably, the phosphine ligand in step (3) and the RuCl in step (1) 2 (DMSO) 4 The feeding molar ratio is (1-10):1, for example, it can be 1:1, 1.2:1, 1.8:1, 2:1, 3:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1, and more preferably (1.2-1.8):1.

[0037] Preferably, the reaction in step (3) is carried out in an organic solvent, and the organic solvent includes any one of dichloromethane, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene or xylene, or a combination of at least two thereof.

[0038] Preferably, the reaction temperature in step (3) is 0°C to 80°C, for example, it can be 0°C, 10°C, 20°C, 25°C, 30°C, 35°C, 40°C, 50°C, 60°C, 70°C or 80°C.

[0039] Preferably, the reaction time of step (3) is 0.5 to 10 h, for example, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h or 10 h.

[0040] Preferably, the DMSO-coordinated ruthenium carbene catalyst precursor obtained in step (2) is directly subjected to the reaction in step (3) without going through a separation step;

[0041] Alternatively, the DMSO-coordinated ruthenium carbene catalyst precursor obtained in step (2) is subjected to a separation step and then to the reaction in step (3).

[0042] Preferably, the separation step comprises concentration, filtration, washing and drying.

[0043] Preferably, the concentrating comprises distillation under reduced pressure.

[0044] Preferably, the washing detergent comprises any one of dichloromethane, 1,2-dichloroethane, diethyl ether, methyl tert-butyl ether, methanol or n-hexane, or a combination of at least two thereof.

[0045] Preferably, the drying comprises vacuum drying at 30-45°C (eg, 30°C, 32°C, 34°C, 36°C, 38°C, 40°C, 42°C or 45°C, etc.).

[0046] Preferably, the reactions in steps (1) to (3) are all carried out under protective gas.

[0047] Preferably, the protective gas comprises an inert gas.

[0048] Preferably, the inert gas includes any one of nitrogen, helium or argon, or a combination of at least two of them.

[0049] Preferably, after the reaction in step (3) is completed, a post-treatment step is also included.

[0050] Preferably, the post-treatment steps include concentration, filtration, washing and drying.

[0051] Preferably, the concentrating comprises distillation under reduced pressure.

[0052] Preferably, the washing solvent includes any one of dichloromethane, 1,2-dichloroethane, diethyl ether, methyl tert-butyl ether, methanol or n-hexane, or a combination of at least two thereof.

[0053] Preferably, the drying comprises vacuum drying at 30-45°C (eg, 30°C, 32°C, 34°C, 36°C, 38°C, 40°C, 42°C or 45°C, etc.).

[0054] Preferably, the synthesis method of the ruthenium carbene complex provided by the present invention specifically comprises the following steps:

[0055] (1) RuCl 2 (DMSO) 4 Mixing with an organic solvent, adding a carbene reagent, and reacting at -78°C to 0°C for 0.5 to 20 hours to obtain an intermediate having a ruthenium-carbene structure; the organic solvent includes any one of dichloromethane, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene or xylene, or a combination of at least two thereof;

[0056] (2) adding a nitrogen heterocyclic carbene precursor to step (1), and carrying out a complexation reaction at 50° C. to 80° C. for 0.5 to 10 hours to obtain a DMSO-coordinated ruthenium carbene catalyst precursor;

[0057] (3) mixing the DMSO-coordinated ruthenium carbene catalyst precursor obtained in step (2), the phosphine ligand and the organic solvent, and performing a ligand exchange reaction at 0° C. to 80° C. for 0.5 to 10 hours. After the reaction is completed, the ruthenium carbene complex is obtained by concentration, filtration, washing and drying; the organic solvent comprises any one of dichloromethane, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene or xylene, or a combination of at least two thereof;

[0058] The reactions in steps (1) to (3) are all carried out under protective gas;

[0059] The RuCl 2 (DMSO) 4 , the molar ratio of the carbenization reagent, the nitrogen heterocyclic carbene precursor and the phosphine ligand is 1:(1-10):(1-10):(1-10);

[0060] The carbenization reagent includes any one or a combination of at least two of phenyldiazomethane, benzylidenephosphine ylide reagent or benzylidenesulfonium ylide reagent;

[0061] The nitrogen heterocyclic carbene precursor includes a nitrogen heterocyclic carbene-chloroform adduct and / or a nitrogen heterocyclic carbene-pentafluorobenzene adduct;

[0062] The phosphine ligand includes any one of triphenylphosphine, tri-n-butylphosphine, tricyclohexylphosphine, tri-n-octylphosphine or triisopropylphosphine, or a combination of at least two thereof.

[0063] Exemplarily, the synthetic route of the present invention is as follows:

[0064]

[0065] Wherein, R is selected from phenyl, n-butyl, cyclohexyl, n-octyl or isopropyl.

[0066] Compared with the prior art, the present invention has at least the following beneficial effects:

[0067] (1) The synthesis method of the ruthenium carbene complex provided by the present invention uses RuCl 2 (DMSO) 4 As the starting material, it replaces the starting material RuCl in the traditional route 2 (PPh 3 ) 3 , thus effectively avoiding the use of large doses of triphenylphosphine, thereby reducing the cost of raw materials; at the same time, the raw material RuCl 2 (DMSO) 4 DMSO is used as a new ligand, which is miscible with water and common organic solvents and can be easily removed by washing, thereby improving the yield and purity of the target product;

[0068] (2) The synthesis method of the ruthenium carbene complex provided by the present invention can be used to synthesize the second-generation Grubbs catalyst. Compared with the traditional route of synthesizing the second-generation Grubbs catalyst by using the first-generation Grubbs catalyst, the method avoids the excessive use of PCy by using a specific synthesis route design and using a phosphorus ligand in the last step. 3 The use of ligands, i.e., reducing the waste of phosphine ligands, further reduces the cost of raw materials;

[0069] (3) The overall synthetic route involved in the synthesis method of the ruthenium carbene complex provided by the present invention has simple steps, simple operation, low raw material cost, good atom economy, and high yield, and is suitable for industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figure 1 is the ruthenium carbene complex G-1 obtained in Example 1 31 P NMR spectrum;

[0071] Figure 2 is the ruthenium carbene complex G-2 obtained in Example 7 31 P NMR spectrum;

[0072] Figure 3is the ruthenium carbene complex G-3 obtained in Example 8 31 P NMR spectrum. DETAILED DESCRIPTION

[0073] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and through specific implementation methods. However, the following examples are only simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0074] The compounds used in the following examples were synthesized with reference to the methods described in the following literature:

[0075] RuCl 2 (DMSO) 4 : Karges J, Stokes RW, Cohen SM. Photorelease of ametal-binding pharmacophore from a Ru(ii)polypyridine complex. Dalton Transactions, 2021, 50(8): 2757–2765;

[0076] Phenyldiazomethane (PhCH 2 ):Creary

[0077] Benzylidenetriphenylphosphine (PhCH=PPh 3 ): Manoni F, Connon SJ. Catalytic AsymmetricTamura Cycloadditions. Angew. Chem. Int. Ed., 2014, 53(10): 2628-2632;

[0078] SIMes-CCl 3:Polyanskii KB,Alekseeva KA,Raspertov PV,Kumandin PA,Nikitina EV,Gurbanov AV,Zubkov FI.Hoveyda–Grubbs catalysts with an N→Rucoordinate bond in a six-membered ring.Synthesis of stable,industriallyscalable,highly efficient ruthenium metathesis catalysts and 2-vinylbenzylamine ligands as their precursors.Beilstein J.Org.Chem.2019,15,769-779;

[0079] SIMes-C 6 F 5 : Blum AP, Ritter T, Grubbs RH. Synthesis of N-heterocyliccarbene-containing metal complexes from 2-(Pentaflurophenyl)imidazolidines. Organometallics, 2007, 26(8): 2122-2124.

[0080] Example 1

[0081] In this embodiment, a ruthenium carbene complex G-1 is synthesized, and its synthesis method comprises the following steps:

[0082]

[0083] (1) Add RuCl to a 100 mL reaction bottle. 2 (DMSO) 4 (2.42 g, 5 mmol), substituted N 2 Three times, in N 2 Anhydrous 1,2-dichloroethane (30 mL) was added under protection. The reaction bottle was placed in a -20°C low temperature bath, and a petroleum ether solution of phenyldiazomethane (1.19 g, 10 mmol) was slowly added dropwise, and the reaction was stirred at this temperature for 1 h.

[0084] (2) The reaction solution in step (1) was restored to room temperature, N 2 Add SIMes-CCl under protection 3(3.39 g, 8 mmol), react at 60°C for 8 h. After the reaction, cool to room temperature, remove the solvent under reduced pressure, wash the solid with ether, filter, and dry in vacuo at 60°C to obtain a powdery ruthenium carbene complex precursor.

[0085] (3) The ruthenium carbene complex precursor and PCy 3 (1.96 g, 7 mmol) was added to a 100 mL reaction bottle to replace N 2 Three times, in N 2 Dichloromethane (30 mL) was added under protection and reacted at 40° C. for 30 min. After cooling to room temperature, the solvent was removed under reduced pressure, and the solid was washed with methanol, filtered, and dried under vacuum at 60° C. to obtain 2.25 g of reddish brown solid powder, i.e., the ruthenium carbene complex G-1.

[0086] The relevant NMR characterization data of the ruthenium carbene complex G-1 are as follows:

[0087] (1) Figure 1 The following is the NMR phosphorus spectrum of the compound: 31 P NMR (203 MHz, CDCl 3 )δ29.01ppm;

[0088] (2) 1 H NMR (500 MHz, CDCl 3 ): δ19.16(s,1H),7.37-7.05(m,9H),3.88(s,4H),2.56-0.15(m,51H).

[0089] Example 2

[0090] In this embodiment, a ruthenium carbene complex G-1 is synthesized, and its synthesis method comprises the following steps:

[0091] (1) Add RuCl to a 100 mL reaction bottle. 2 (DMSO) 4 (2.42 g, 5 mmol), substituted N 2 Three times, in N 2 Anhydrous 1,2-dichloroethane (10 mL) was added under protection. The reaction bottle was placed in a -78°C low temperature bath, and benzaltriphenylphosphine (1.76 g, 5 mmol) was slowly added dropwise, and the reaction was stirred at this temperature for 10 h.

[0092] (2) The reaction solution in step (1) was restored to room temperature, N 2 SIMes-C 6 F 5(2.37 g, 5 mmol), react at 50°C for 10 h. After the reaction, cool to room temperature, remove the solvent under reduced pressure, wash the solid with n-hexane, filter, and dry in vacuo at 60°C to obtain a powdery ruthenium carbene complex precursor.

[0093] (3) The ruthenium carbene complex precursor and PCy 3 (1.4 g, 5 mmol) was added to a 100 mL reaction bottle to replace N 2 Three times, in N 2 Tetrahydrofuran (30 mL) was added under protection and reacted at 0°C for 10 h. After cooling to room temperature, the solvent was removed under reduced pressure, and the solid was washed with methanol, filtered, and dried under vacuum at 60°C to obtain 1.95 g of reddish brown solid powder, i.e., the ruthenium carbene complex G-1.

[0094] Example 3

[0095] In this embodiment, a ruthenium carbene complex G-1 is synthesized, and its synthesis method comprises the following steps:

[0096] (1) Add RuCl to a 100 mL reaction bottle. 2 (DMSO) 4 (2.42 g, 5 mmol), substituted N 2 Three times, in N 2 Anhydrous 1,2-dichloroethane (50 mL) was added under protection. The reaction bottle was placed in a 0°C low-temperature bath, and a petroleum ether solution of phenyldiazomethane (5.95 g, 50 mmol) was slowly added dropwise, and the reaction was stirred at this temperature for 0.5 h.

[0097] (2) The reaction solution in step (1) was restored to room temperature, N 2 Add SIMes-CCl under protection 3 (21.19 g, 50 mmol), react at 80°C for 0.5 h. After the reaction, cool to room temperature, remove the solvent under reduced pressure, wash the solid with dichloromethane, filter, and dry in vacuo at 80°C to obtain a powdery ruthenium carbene complex precursor.

[0098] (3) The ruthenium carbene complex precursor and PCy 3 (14 g, 50 mmol) was added to a 100 mL reaction bottle to replace N 2 Three times, in N 2 Toluene (30 mL) was added under protection, and the mixture was reacted at 80° C. for 30 min. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The solid was washed with ether, filtered, and dried under vacuum at 80° C. to obtain 1.73 g of reddish brown solid powder, i.e., the ruthenium carbene complex G-1.

[0099] Example 4

[0100] In this embodiment, a ruthenium carbene complex G-1 (i.e., Grubbs II catalyst) is synthesized, and its synthesis method comprises the following steps:

[0101] (1) Add RuCl to a 100 mL reaction bottle. 2 (DMSO) 4 (2.42 g, 5 mmol), substituted N 2 Three times, in N 2 Anhydrous tetrahydrofuran (30 mL) was added under protection. The reaction bottle was placed in a -20°C low temperature bath, and a petroleum ether solution of phenyldiazomethane (1.19 g, 10 mmol) was slowly added dropwise, and the reaction was stirred at this temperature for 1 h.

[0102] (2) The reaction solution in step (1) was restored to room temperature, N 2 Add SIMes-CCl under protection 3 (3.39 g, 8 mmol), react at 60°C for 6 h. After the reaction, cool to room temperature, remove the solvent under reduced pressure, wash the solid with ether, filter, and dry in vacuo at 60°C to obtain a powdery ruthenium carbene complex precursor.

[0103] (3) The ruthenium carbene complex precursor and PCy 3 (1.96 g, 7 mmol) was added to a 100 mL reaction bottle to replace N 2 Three times, in N 2 Dichloromethane (30 mL) was added under protection and reacted at 40° C. for 30 min. After cooling to room temperature, the solvent was removed under reduced pressure, and the solid was washed with methanol, filtered, and dried under vacuum at 60° C. to obtain 2.84 g of reddish brown solid powder, namely the ruthenium carbene complex G-1.

[0104] Example 5

[0105] In this embodiment, a ruthenium carbene complex G-1 is synthesized, and its synthesis method comprises the following steps:

[0106] (1) Add RuCl to a 100 mL reaction bottle. 2 (DMSO) 4 (2.42 g, 5 mmol), substituted N 2 Three times, in N 2 Anhydrous toluene (30 mL) was added under protection. The reaction bottle was placed in a -20°C low temperature bath, and a petroleum ether solution of phenyldiazomethane (1.19 g, 10 mmol) was slowly added dropwise, and the reaction was stirred at this temperature for 1 h.

[0107] (2) The reaction solution in step (1) was restored to room temperature, N 2 Add SIMes-CCl under protection 3(3.39 g, 8 mmol), react at 80°C for 4 h. After the reaction, cool to room temperature, remove the solvent under reduced pressure, wash the solid with ether, filter, and dry in vacuo at 60°C to obtain a powdery ruthenium carbene complex precursor.

[0108] (3) The ruthenium carbene complex precursor and PCy 3 (1.96 g, 7 mmol) was added to a 100 mL reaction bottle to replace N 2 Three times, in N 2 Dichloromethane (30 mL) was added under protection and reacted at 40° C. for 30 min. After cooling to room temperature, the solvent was removed under reduced pressure, and the solid was washed with methanol, filtered, and dried under vacuum at 60° C. to obtain 1.90 g of reddish brown solid powder, i.e., the ruthenium carbene complex G-1.

[0109] Example 6

[0110] In this embodiment, a ruthenium carbene complex G-1 is synthesized, and its synthesis method comprises the following steps:

[0111] (1) Add RuCl to a 100 mL reaction bottle. 2 (DMSO) 4 (2.42 g, 5 mmol), substituted N 2 Three times, in N 2 Anhydrous 1,2-dichloroethane (30 mL) was added under protection. The reaction bottle was placed in a -20°C low temperature bath, and a petroleum ether solution of phenyldiazomethane (1.19 g, 10 mmol) was slowly added dropwise, and the reaction was stirred at this temperature for 1 h.

[0112] (2) The reaction solution in step (1) was restored to room temperature, N 2 Add SIMes-CCl under protection 3 (3.39 g, 8 mmol), react at 60 °C for 6 h.

[0113] (3) Add PCy to the reaction bottle in step (2) 3 (1.96 g, 7 mmol), react at 40°C for 1 h, cool to room temperature, remove the solvent under reduced pressure, wash the solid with methanol, filter, and dry in vacuo at 60°C to obtain 2.87 g of reddish brown solid powder, i.e., the ruthenium carbene complex G-1.

[0114] Example 7

[0115] This example synthesized a ruthenium carbene complex G-2:

[0116]

[0117] The only difference between this embodiment and Example 1 is that in step (3), PCy 3(1.96 g, 7 mmol) was replaced by PPh 3 (1.84 g, 7 mmol), and other raw materials, contents and synthesis methods are the same as those in Example 6, to obtain 2.11 g of reddish brown solid powder, namely the ruthenium carbene complex G-2.

[0118] The relevant NMR characterization data of the ruthenium carbene complex G-2 are as follows:

[0119] (1) Figure 2 The following is the NMR phosphorus spectrum of the compound: 31 P NMR (203 MHz, CDCl 3 )δ33.90ppm;

[0120] (2) 1 H NMR (500 MHz, CDCl 3 ): δ19.60(s,1H),7.70(d,2H,J=8Hz),7.29-6.71(m,20H),6.27(s,2H,),3.39(m,4H),2.74(s,6H),2.34(s,6H),2.23(s,3H),1.91(s,3H).

[0121] Example 8

[0122] This example synthesized a ruthenium carbene complex G-3:

[0123]

[0124] The only difference between this embodiment and Example 1 is that in step (3), PCy 3 (1.96 g, 7 mmol) was replaced by PBu 3 (1.42 g, 7 mmol), and other raw materials, contents and synthesis methods are the same as those in Example 6, to obtain 2.42 g of reddish brown solid powder, namely the ruthenium carbene complex G-3.

[0125] The relevant NMR characterization data of the ruthenium carbene complex G-3 are as follows:

[0126] (1) Figure 3 The following is the NMR phosphorus spectrum of the compound: 31 P NMR (203 MHz, CDCl 3 )δ29.00ppm;

[0127] (2) 1 H NMR (500 MHz, CDCl 3): δ19.60(s,1H),8.25(d,2H,J=8Hz),7.20-6.94(m,5H),6.29(s,2H),3.34(m ,4H),2.83(s,6H),2.42(s,6H),2.23(s,3H),1.87(s,3H),1.62-0.74(m,27H).

[0128] Example 9

[0129] In this embodiment, a ruthenium carbene complex G-1 is synthesized, and its synthesis method comprises the following steps:

[0130] (1) Add RuCl to a 100 mL reaction bottle. 2 (DMSO) 4 (2.42 g, 5 mmol), substituted N 2 Three times, in N 2 Anhydrous 1,2-dichloroethane (30 mL) was added under protection. The reaction bottle was placed in a -20°C low temperature bath, and a petroleum ether solution of phenyldiazomethane (0.89 g, 7.5 mmol) was slowly added dropwise, and the reaction was stirred at this temperature for 1 h.

[0131] (2) The reaction solution in step (1) was restored to room temperature, N 2 Add SIMes-CCl under protection 3 (2.97 g, 7 mmol), react at 60 °C for 6 h.

[0132] (3) Add PCy to the reaction bottle in step (2) 3 (1.68 g, 6 mmol), react at 40°C for 1 h, cool to room temperature, remove the solvent under reduced pressure, wash the solid with methanol, filter, and dry in vacuo at 60°C to obtain 2.67 g of reddish brown solid powder, i.e., the ruthenium carbene complex G-1.

[0133] Example 10

[0134] In this embodiment, a ruthenium carbene complex G-1 is synthesized, and its synthesis method comprises the following steps:

[0135] (1) Add RuCl to a 100 mL reaction bottle. 2 (DMSO) 4 (2.42 g, 5 mmol), substituted N 2 Three times, in N 2 Anhydrous 1,2-dichloroethane (30 mL) was added under protection. The reaction bottle was placed in a -20°C low temperature bath, and a petroleum ether solution of phenyldiazomethane (1.49 g, 12.5 mmol) was slowly added dropwise, and the reaction was stirred at this temperature for 1 h.

[0136] (2) The reaction solution in step (1) was restored to room temperature, N 2 Add SIMes-CCl under protection 3 (4.24 g, 10 mmol), react at 60 °C for 6 h.

[0137] (3) Add PCy to the reaction bottle in step (2) 3 (2.52 g, 9 mmol), react at 40°C for 1 h, cool to room temperature, remove the solvent under reduced pressure, wash the solid with methanol, filter, and dry in vacuo at 60°C to obtain 2.69 g of reddish brown solid powder, i.e., the ruthenium carbene complex G-1.

[0138] Embodiment 11

[0139] In this embodiment, a ruthenium carbene complex G-1 is synthesized, which differs from Example 9 only in that the petroleum ether solution of phenyldiazomethane (0.89 g, 7.5 mmol) is replaced by the petroleum ether solution of phenyldiazomethane (0.59 g, 5 mmol), and the other raw materials, contents and synthesis methods are the same as those in Example 9.

[0140] Example 12

[0141] This example synthesized a ruthenium carbene complex G-1, which differed from Example 9 only in that SIMes-CCl 3 (2.97 g, 7 mmol) was replaced by SIMes-CCl 3 (2.12 g, 5 mmol), other raw materials, contents and synthesis methods are the same as those in Example 9.

[0142] Embodiment 13

[0143] This example synthesized a ruthenium carbene complex G-1, which differed from Example 9 only in that PCy 3 (1.68 g, 6 mmol) was replaced by PCy 3 (1.4 g, 5 mmol), other raw materials, contents and synthesis methods are the same as those in Example 9.

[0144] Embodiment 14

[0145] In this embodiment, a ruthenium carbene complex G-1 is synthesized, which differs from Example 10 only in that the petroleum ether solution of phenyldiazomethane (1.49 g, 12.5 mmol) is replaced by the petroleum ether solution of phenyldiazomethane (1.78 g, 15 mmol), and the other raw materials, contents and synthesis methods are the same as those in Example 10.

[0146] Embodiment 15

[0147] This example synthesized a ruthenium carbene complex G-1, which differs from Example 10 only in that SIMes-CCl 3 (4.24 g, 10 mmol) was replaced by SIMes-CCl 3 (4.88 g, 11.5 mmol), other raw materials, contents and synthesis methods are the same as those in Example 10.

[0148] Example 16

[0149] This example synthesized a ruthenium carbene complex G-1, which differs from Example 10 only in that PCy 3 (2.52 g, 9 mmol) was replaced by PCy 3 (2.8 g, 10 mmol), other raw materials, contents and synthesis methods are the same as those in Example 10.

[0150] The yields of the ruthenium carbene complexes obtained in the above Examples 1-16 are shown in Table 1.

[0151] Table 1

[0152] Yield of ruthenium carbene complex (%) Example 1 53 Example 2 46 Example 3 41 Example 4 67 Example 5 45 Example 6 68 Example 7 51 Example 8 63 Example 9 63 Example 10 64 Embodiment 11 42 Example 12 57 Embodiment 13 53 Embodiment 14 62 Embodiment 15 65 Example 16 63

[0153] The test results show that:

[0154] The present invention sets and optimizes the synthesis method of the ruthenium carbene complex, so that the obtained new synthesis method has the advantages of simple steps, simple operation, low raw material cost, good atom economy, high yield, and is suitable for industrial scale-up production. Examples 1-16 show that the yield of the ruthenium carbene complex synthesized by the synthesis method of the ruthenium carbene complex provided by the present invention is 41-68%.

[0155] The comparison between Example 1 and Examples 4 and 5 shows that the selection of a specific reaction solvent in the synthesis method provided by the present invention is beneficial to improving the yield of the product to a certain extent.

[0156] Comparison between Example 1 and Example 6 shows that in the synthesis method provided by the present invention, the ruthenium carbene complex precursor obtained in step (2) can be directly subjected to a ligand exchange reaction with a phosphine ligand without separation, and the method can effectively reduce the loss of the ruthenium carbene complex precursor during the separation process, which not only simplifies the operation steps but also further improves the yield of the target product.

[0157] By comparing Example 9 with Examples 11-13, it can be shown that the addition of raw materials below a specific ratio reduces the yield of the target product; by comparing Example 10 with Examples 14-16, it can be shown that the addition of raw materials above a specific ratio does not significantly increase the yield of the target product, but instead causes a waste of raw materials.

[0158] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for synthesizing a ruthenium carbene complex, characterized in that: The synthesis method comprises the following steps: (1) reacting RuCl2(DMSO)4 with a carbene reagent to obtain an intermediate having a ruthenium-carbene structure; (2) the intermediate having a ruthenium-carbene structure obtained in step (1) is subjected to a complexation reaction with a nitrogen heterocyclic carbene precursor to obtain a DMSO-coordinated ruthenium carbene catalyst precursor; (3) The DMSO-coordinated ruthenium carbene catalyst precursor obtained in step (2) reacts with a phosphine ligand to obtain the ruthenium carbene complex.

2. The method for synthesizing a ruthenium carbene complex according to claim 1, characterized in that: The carbenization reagent in step (1) comprises any one of phenyldiazomethane, benzylidenephosphine ylide reagent or benzylidenesulfonium ylide reagent or a combination of at least two thereof; Preferably, the molar ratio of the carbene reagent to RuCl2(DMSO)4 in step (1) is (1-10):

1.

3. The method for synthesizing a ruthenium carbene complex according to claim 1 or 2, characterized in that: The reaction in step (1) is carried out in an organic solvent, wherein the organic solvent comprises any one of dichloromethane, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene or xylene, or a combination of at least two thereof; Preferably, the amount of the organic solvent used is such that the initial concentration of the RuCl2(DMSO)4 in step (1) is 0.1 to 0.5 mol / L; Preferably, the reaction temperature in step (1) is -78°C to 0°C, more preferably -30°C to -20°C; Preferably, the reaction time in step (1) is 0.5 to 20 hours.

4. The method for synthesizing a ruthenium carbene complex according to any one of claims 1 to 3, characterized in that: The nitrogen heterocyclic carbene precursor in step (2) includes a nitrogen heterocyclic carbene-chloroform adduct and / or a nitrogen heterocyclic carbene-pentafluorobenzene adduct; Preferably, the nitrogen heterocyclic carbene-chloroform adduct is SIMes-CCl3; Preferably, the nitrogen heterocyclic carbene-pentafluorobenzene adduct is SIMes-C6F5; Preferably, the molar ratio of the nitrogen heterocyclic carbene precursor in step (2) to the RuCl2(DMSO)4 in step (1) is (1-10):1; Preferably, the reaction temperature in step (2) is 50°C to 80°C; Preferably, the reaction time in step (2) is 0.5 to 10 h.

5. The method for synthesizing a ruthenium carbene complex according to any one of claims 1 to 4, characterized in that: The phosphine ligand in step (3) includes any one of triphenylphosphine, tri-n-butylphosphine, tricyclohexylphosphine, tri-n-octylphosphine or triisopropylphosphine, or a combination of at least two thereof; Preferably, the molar ratio of the phosphine ligand in step (3) to the RuCl2(DMSO)4 in step (1) is (1-10):

1.

6. The method for synthesizing a ruthenium carbene complex according to any one of claims 1 to 5, characterized in that: The reaction in step (3) is carried out in an organic solvent, wherein the organic solvent comprises any one of dichloromethane, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene or xylene, or a combination of at least two thereof; Preferably, the reaction temperature in step (3) is 0°C to 80°C; Preferably, the reaction time in step (3) is 0.5 to 10 h.

7. The method for synthesizing a ruthenium carbene complex according to any one of claims 1 to 6, characterized in that: The DMSO-coordinated ruthenium carbene catalyst precursor obtained in step (2) is directly subjected to the reaction in step (3) without going through a separation step; Alternatively, the DMSO-coordinated ruthenium carbene catalyst precursor obtained in step (2) is subjected to a separation step and then to the reaction in step (3); Preferably, the separation step comprises concentration, filtering, washing and drying; Preferably, the concentration comprises distillation under reduced pressure; Preferably, the washing detergent comprises any one of dichloromethane, 1,2-dichloroethane, diethyl ether, methyl tert-butyl ether, methanol or n-hexane, or a combination of at least two thereof; Preferably, the drying comprises vacuum drying at 30-45°C.

8. The method for synthesizing a ruthenium carbene complex according to any one of claims 1 to 7, characterized in that: The reactions in steps (1) to (3) are all carried out under protective gas; Preferably, the protective gas comprises an inert gas; Preferably, the inert gas includes any one of nitrogen, helium or argon, or a combination of at least two of them.

9. The method for synthesizing a ruthenium carbene complex according to any one of claims 1 to 8, characterized in that: After the reaction in step (3) is completed, a post-treatment step is also included; Preferably, the post-processing step comprises concentration, filtration, washing and drying; Preferably, the concentration comprises distillation under reduced pressure; Preferably, the washing solvent includes any one of dichloromethane, 1,2-dichloroethane, diethyl ether, methyl tert-butyl ether, methanol or n-hexane, or a combination of at least two thereof; Preferably, the drying comprises vacuum drying at 30-45°C.

10. The method for synthesizing a ruthenium carbene complex according to any one of claims 1 to 9, characterized in that: The synthesis method specifically comprises the following steps: (1) mixing RuCl2(DMSO)4 with an organic solvent, adding a carbene reagent, and reacting at -78°C to 0°C for 0.5 to 20 hours to obtain an intermediate having a ruthenium-carbene structure; the organic solvent comprises any one of dichloromethane, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene or xylene, or a combination of at least two thereof; (2) adding a nitrogen heterocyclic carbene precursor to step (1), and carrying out a complexation reaction at 50° C. to 80° C. for 0.5 to 10 hours to obtain a DMSO-coordinated ruthenium carbene catalyst precursor; (3) mixing the DMSO-coordinated ruthenium carbene catalyst precursor obtained in step (2), the phosphine ligand and the organic solvent, and performing a ligand exchange reaction at 0° C. to 80° C. for 0.5 to 10 hours, and obtaining the ruthenium carbene complex after concentration, filtration, washing and drying; the organic solvent comprises any one of dichloromethane, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene or xylene, or a combination of at least two thereof; The reactions in steps (1) to (3) are all carried out under protective gas; The molar ratio of RuCl2(DMSO)4, carbene reagent, nitrogen heterocyclic carbene precursor and phosphine ligand is 1:(1-10):(1-10):(1-10); The carbenization reagent includes any one or a combination of at least two of phenyldiazomethane, benzylidenephosphine ylide reagent or benzylidenesulfonium ylide reagent; The nitrogen heterocyclic carbene precursor includes a nitrogen heterocyclic carbene-chloroform adduct and / or a nitrogen heterocyclic carbene-pentafluorobenzene adduct; The phosphine ligand includes any one of triphenylphosphine, tri-n-butylphosphine, tricyclohexylphosphine, tri-n-octylphosphine or triisopropylphosphine, or a combination of at least two thereof.

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