Preparation method of first-generation Grubbs catalyst

Abstract

The invention relates to a first-generation Grubbs catalyst preparation method, which comprises: mixing a ruthenium-indenylene compound, a transition metal salt and a solvent, carrying out heating treatment, adding styrene in batches, and carrying out an olefin exchange reaction; and carrying out solid-liquid separation on the obtained product, and carrying out post-treatment on the obtained liquid phase to obtain the first-generation Grubbs catalyst. The transition metal salt is added as the catalyst, and styrene is added in batches, so that the use amount of styrene can be effectively reduced, the yield is improved, the post-treatment process is simple, and the method has a relatively good application prospect in the aspect of industrial amplification.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a preparation method of a first-generation Grubbs catalyst. Background Art

[0002] Olefin metathesis is one of the most important and commonly used reaction types in organic chemistry. Through metal catalysis, the carbon-carbon double bonds of two olefins can be broken and recombined into two new olefin structures. Therefore, it is widely used in natural product and drug molecule synthesis and material science. In olefin metathesis, the most widely used catalyst is the Grubbs catalyst with a ruthenium-carbene structure metal complex. Among them, the first-generation Grubbs catalyst RuCl2(=CHPh)(PCy3)2 has attracted particular attention. It not only has high catalytic activity, high water and oxygen stability, and good functional group tolerance, but also can be used to synthesize the second-generation Grubbs catalyst and Hoveyda-Grubbs catalyst, and has high practical value.

[0003] Although the first generation of Grubbs catalyst has important uses in the field of organic synthesis, its synthesis has always been a problem that restricts its application. Schwab et al. (Schwab, Peter, Grubbs, et al. Synthesis and applications ofRuCl2(=CHR')(PR3)2: The influence of the alkylidene moiety. [J]. Journal of the American Chemical Society, 1996, 118 (1): 100-100.) used RuCl2(PPh3)3 as a raw material, and first reacted with phenyldiazomethane at -78°C to generate RuCl2(=CHPh)(PPh3)2, and then replaced PPh3 with PCy3 to obtain a first generation of Grubbs catalyst. This method uses highly explosive raw materials, the reaction temperature must be strictly controlled at an extremely low temperature, the operation requirements are high, and it can only be applied to small-scale reactions.

[0004] Subsequent researchers used sulfur ylide reagents (Gandelman, M.; Rybtchinski, B.; Ashkenazi, N.; Gauvin, RM; Milstein, DJ Am. Chem. Soc. 2001, 123, 5372.) to replace phenyldiazomethane. CN111468191A discloses a method for synthesizing a ruthenium carbene catalyst, using a phosphine ylide reagent instead of phenyldiazomethane. The reaction process in the above research is relatively mild, but it is still sensitive to water and oxygen, and the operation requirements are very strict, so it is difficult to apply to industrial production.

[0005] Nolan et al. (Dorta, R.; Kelly III, RA; Nolan, SP Adv. Synth. Catal. 2004, 346, 917.) synthesized a ruthenium-indenyl compound (PCy3)2Cl2Ru (3-phenylinden-1-ylidene) from RuCl2(PPh3)3 by cyclization with an alkynol ligand, and then reacted with styrene to obtain a first-generation Grubbs catalyst. This method requires the use of a large excess of styrene for the olefin exchange reaction, which not only causes a waste of raw materials, but also makes the post-processing more complicated. Excess styrene can only be removed under heating and high vacuum, which affects the purity of the product and reduces the yield, which is not conducive to industrial production.

[0006] In summary, most of the existing first-generation Grubbs catalyst synthesis methods require the use of benzyl diazonium, ylide reagents, etc., which have problems such as harsh reaction conditions, difficult processes, and dangerousness, making them difficult to apply to industrial production, or require the use of excessive styrene, which has the defects of wasting raw materials and difficult post-processing. Summary of the invention

[0007] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a method for preparing the first generation of Grubbs catalyst, which has the characteristics of being simple and safe, high yield, convenient post-treatment, and small amount of styrene, and is suitable for industrial production.

[0008] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0009] The present invention provides a method for preparing a first-generation Grubbs catalyst, the preparation method comprising the following steps:

[0010] A ruthenium-indenyl compound, a transition metal salt and a solvent are mixed and subjected to a temperature treatment, and then styrene is added in batches to cause an olefin exchange reaction; the obtained product is subjected to solid-liquid separation, and the obtained liquid phase is post-treated to obtain the first-generation Grubbs catalyst.

[0011] The preparation method of the first-generation Grubbs catalyst provided by the present invention can effectively reduce the amount of styrene used and improve the yield by adding a transition metal salt as a catalyst and adding styrene in batches in the reaction of olefin exchange between a ruthenium-indenyl compound (PCy3)2Cl2Ru (3-phenylinden-1-ylidene) and styrene to synthesize the first-generation Grubbs catalyst, and has good application prospects in industrial scale-up.

[0012] Preferably, the transition metal salt includes any one of cuprous chloride, cuprous bromide, cupric chloride, cupric bromide, cuprous iodide, cobalt dichloride, cobalt dibromide, cobalt acetate, ferrous chloride or ferrous bromide.

[0013] Preferably, the amount of the transition metal salt is 1-20 mol% of the amount of the ruthenium-indenyl compound, for example, it can be 1 mol%, 2 mol%, 10 mol%, 15 mol% or 20 mol%, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0014] Preferably, the 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. Typical but non-limiting combinations include a combination of dichloromethane and 1,2-dichloroethane, a combination of 1,4-dioxane, tetrahydrofuran and methyltetrahydrofuran, a combination of 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene and xylene, or a combination of dichloromethane, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, toluene and xylene.

[0015] Preferably, the amount of the solvent used is such that the concentration of the ruthenium-indenyl compound in the mixed solution is 0.05-0.5 mol / L, for example, it can be 0.05 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L or 0.5 mol / L, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0016] Preferably, the molar amount of styrene added in each batch is 1-2 times the molar amount of the ruthenium-indenyl compound, for example, it can be 1 times, 1.2 times, 1.5 times, 1.8 times or 2 times, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0017] Preferably, the time interval between adjacent batches of styrene is 0.25-1 h, for example, 0.25 h, 0.5 h, 0.6 h, 0.8 h or 1 h, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0018] Preferably, after the last batch of styrene is added, the reaction is continued for 0.25-1 h, for example, 0.25 h, 0.5 h, 0.6 h, 0.8 h or 1 h, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0019] Preferably, the styrene is added in batches of 3-5 times, for example, 3 times, 4 times or 5 times.

[0020] Preferably, the molar ratio of the total amount of styrene added to the total amount of ruthenium-indenyl compounds is (3-10):1, for example, 3:1, 5:1, 6:1, 8:1 or 10:1, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0021] Preferably, the temperature end point of the temperature raising treatment is 40-100°C, for example, 40°C, 50°C, 70°C, 80°C or 100°C, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0022] Preferably, the olefin exchange reaction is carried out in a protective atmosphere.

[0023] Preferably, the protective atmosphere includes any one of nitrogen, helium or argon.

[0024] Preferably, a cooling step is included before the solid-liquid separation.

[0025] Preferably, the cooling temperature is 20-30°C, for example, 20°C, 22°C, 25°C, 28°C or 30°C, but is not limited to the listed values, and other unlisted values ​​within the numerical range are also applicable.

[0026] Preferably, the post-treatment comprises rotary evaporation, washing and drying performed in sequence.

[0027] In the present invention, the catalyst can be removed by the solid-liquid separation, and the volatile solvent can be removed by rotary evaporation. The solid after rotary evaporation is washed and dried to obtain a purple microcrystalline solid powder, which is the first generation Grubbs catalyst.

[0028] Preferably, the washing reagent includes any one of diethyl ether, methyl tert-butyl ether, methanol, acetone or n-hexane, or a combination of at least two of them. Typical but non-limiting combinations include a combination of diethyl ether and methyl tert-butyl ether, a combination of methanol, acetone and n-hexane, or a combination of diethyl ether, methyl tert-butyl ether, methanol, acetone and n-hexane.

[0029] As a preferred technical solution of the preparation method of the present invention, the preparation method comprises the following steps:

[0030] The ruthenium-indenyl compound, transition metal salt and solvent are mixed and heated to 40-100°C, and then styrene is added in batches to cause an olefin exchange reaction in a protective atmosphere; the obtained product is cooled to 20-30°C and then solid-liquid separation is performed, and the obtained liquid phase is successively subjected to rotary evaporation, washing and drying to obtain the first-generation Grubbs catalyst;

[0031] The amount of the transition metal salt is 1-20 mol% of the amount of the ruthenium-indenyl compound; the amount of the solvent is such that the concentration of the ruthenium-indenyl compound in the mixed solution is 0.05-0.5 mol / L; the molar amount of styrene added in each batch is 1-2 times the molar amount of the ruthenium-indenyl compound, the time interval between adjacent batches of styrene is 0.25-1h, the batches of styrene added are 3-5 times, and the molar ratio of the total amount of styrene added to the total amount of ruthenium-indenyl compound is (3-10):1.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The preparation method of the first-generation Grubbs catalyst provided by the present invention can effectively reduce the amount of styrene used and improve the yield by adding a transition metal salt as a catalyst and adding styrene in batches in the reaction of olefin exchange between a ruthenium-indenylene compound and styrene to synthesize the first-generation Grubbs catalyst. The post-treatment process is simple and has good application prospects in industrial scale-up. DETAILED DESCRIPTION

[0034] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0035] Example 1

[0036] This embodiment provides a preparation method of the first generation Grubbs catalyst, the preparation method comprising the following steps:

[0037] A ruthenium-indenyl compound, cuprous chloride and tetrahydrofuran are mixed and heated to 70°C, and then styrene is added in batches to cause an olefin exchange reaction in a nitrogen atmosphere; the obtained product is cooled to 25°C and filtered using diatomaceous earth, and the obtained liquid phase is successively subjected to rotary evaporation, acetone washing and drying to obtain the first-generation Grubbs catalyst;

[0038] The amount of cuprous chloride used is 10 mol% of the amount of ruthenium-indenyl compound used; the amount of tetrahydrofuran used is such that the concentration of the ruthenium-indenyl compound in the mixed solution is 0.1 mol / L; the molar amount of styrene added in each batch is twice the molar amount of the ruthenium-indenyl compound, the time interval between adjacent batches of styrene is 0.5 h, the batches of styrene added are 5 times, and the reaction is continued for 0.5 h after the last addition, and the molar ratio of the total amount of styrene added to the total amount of ruthenium-indenyl compound is 10:1.

[0039] Example 2

[0040] This embodiment provides a preparation method of the first generation Grubbs catalyst, the preparation method comprising the following steps:

[0041] A ruthenium-indenyl compound, cuprous chloride and tetrahydrofuran are mixed and heated to 40°C, and then styrene is added in batches to cause an olefin exchange reaction in a nitrogen atmosphere; the obtained product is cooled to 20°C and filtered using diatomaceous earth, and the obtained liquid phase is successively subjected to rotary evaporation, acetone washing and drying to obtain the first-generation Grubbs catalyst;

[0042] The amount of cuprous chloride used is 1 mol% of the amount of ruthenium-indenyl compound used; the amount of tetrahydrofuran used is such that the concentration of the ruthenium-indenyl compound in the mixed solution is 0.05 mol / L; the molar amount of styrene added in each batch is 1.5 times the molar amount of the ruthenium-indenyl compound, the time interval between adjacent batches of styrene is 0.25 h, the batches of styrene added are 4 times, and the reaction is continued for 0.25 h after the last addition, and the molar ratio of the total amount of styrene added to the total amount of ruthenium-indenyl compound is 6:1.

[0043] Example 3

[0044] This embodiment provides a preparation method of the first generation Grubbs catalyst, the preparation method comprising the following steps:

[0045] A ruthenium-indenyl compound, cuprous chloride and tetrahydrofuran are mixed and heated to 100°C, and then styrene is added in batches to cause an olefin exchange reaction in a nitrogen atmosphere; the obtained product is cooled to 30°C and filtered using diatomaceous earth, and the obtained liquid phase is successively subjected to rotary evaporation, acetone washing and drying to obtain the first generation Grubbs catalyst;

[0046] The amount of cuprous chloride used is 20 mol% of the amount of ruthenium-indenyl compound used; the amount of tetrahydrofuran used is such that the concentration of the ruthenium-indenyl compound in the mixed solution is 0.5 mol / L; the molar amount of styrene added in each batch is 1 times the molar amount of the ruthenium-indenyl compound, the time interval between adjacent batches of styrene is 1 hour, the batches of styrene added are 3 times, and the reaction is continued for 1 hour after the last addition, and the molar ratio of the total amount of styrene added to the total amount of ruthenium-indenyl compound is 3:1.

[0047] Example 4

[0048] This embodiment provides a method for preparing the first-generation Grubbs catalyst. The difference from Example 1 is that the molar amount of styrene added in each batch is adjusted to 0.5 times the molar amount of the ruthenium-indenyl compound, and the molar ratio of the total amount of styrene added to the total amount of ruthenium-indenyl compound is adaptively adjusted to 2.5:1. The rest is the same as Example 1.

[0049] Example 5

[0050] This embodiment provides a method for preparing the first-generation Grubbs catalyst. The difference from Example 1 is that the molar amount of styrene added in each batch is adjusted to 3 times the molar amount of the ruthenium-indenyl compound, and the molar ratio of the total amount of styrene added to the total amount of ruthenium-indenyl compound is adaptively adjusted to 15:1. The rest is the same as Example 1.

[0051] Example 6

[0052] This embodiment provides a method for preparing a first-generation Grubbs catalyst, which is different from Example 1 in that, except that an equimolar amount of cuprous chloride is replaced by cuprous bromide, the rest is the same as Example 1.

[0053] Example 7

[0054] This embodiment provides a method for preparing a first-generation Grubbs catalyst, which is different from Example 1 in that, except that an equimolar amount of cuprous chloride is replaced by cuprous iodide, the rest is the same as Example 1.

[0055] Example 8

[0056] This embodiment provides a method for preparing a first-generation Grubbs catalyst, which is different from Embodiment 1 in that, except that the equimolar amount of cuprous chloride is replaced by cupric chloride, the rest is the same as Embodiment 1.

[0057] Example 9

[0058] This embodiment provides a method for preparing a first-generation Grubbs catalyst, which is different from Example 1 in that, except that an equimolar amount of cuprous chloride is replaced by cupric bromide, the rest is the same as Example 1.

[0059] Example 10

[0060] This embodiment provides a method for preparing a first-generation Grubbs catalyst, which is different from Embodiment 1 in that, except that the equimolar amount of cuprous chloride is replaced by cobalt dichloride, the rest is the same as Embodiment 1.

[0061] Embodiment 11

[0062] This embodiment provides a method for preparing a first-generation Grubbs catalyst, which is different from Example 1 in that, except that the equimolar amount of cuprous chloride is replaced by cobalt acetate, the rest is the same as Example 1.

[0063] Example 12

[0064] This embodiment provides a method for preparing a first-generation Grubbs catalyst, which is different from Embodiment 1 in that, except that the equimolar amount of cuprous chloride is replaced by ferrous chloride, the rest is the same as Embodiment 1.

[0065] Example 13

[0066] This embodiment provides a method for preparing a first-generation Grubbs catalyst, which is different from Embodiment 1 in that, except that an equimolar amount of cuprous chloride is replaced by ferrous bromide, the rest is the same as Embodiment 1.

[0067] Embodiment 14

[0068] This example provides a method for preparing a first-generation Grubbs catalyst, which is different from Example 1 in that, except that an equal amount of tetrahydrofuran is replaced by toluene, the rest is the same as Example 1.

[0069] Embodiment 15

[0070] This embodiment provides a method for preparing a first-generation Grubbs catalyst, which is different from Embodiment 1 in that, except that an equal amount of tetrahydrofuran is replaced by 1,4-dioxane, the rest is the same as Embodiment 1.

[0071] Example 16

[0072] This example provides a method for preparing a first-generation Grubbs catalyst, which is different from Example 1 in that, except that an equal amount of tetrahydrofuran is replaced by methyltetrahydrofuran, the rest is the same as Example 1.

[0073] Embodiment 17

[0074] This embodiment provides a method for preparing a first-generation Grubbs catalyst, which is different from Embodiment 1 in that, except that an equal amount of tetrahydrofuran is replaced by 1,2-dichloroethane, the rest is the same as Embodiment 1.

[0075] Comparative Example 1

[0076] This comparative example provides a method for preparing a first-generation Grubbs catalyst, which differs from Example 1 in that cuprous chloride is not added, and the rest is the same as Example 1.

[0077] Comparative Example 2

[0078] This comparative example provides a method for preparing the first generation Grubbs catalyst, which differs from Example 1 in that the styrene is not added in batches but all at once, and the molar amount of styrene added is 10 times the molar amount of the ruthenium-indenyl compound, and the rest is the same as Example 1.

[0079] The first generation Grubbs catalyst was prepared by the preparation methods provided in Examples 1-17 and Comparative Examples 1 and 2, wherein after the product obtained by the olefin exchange reaction was cooled, the NMR phosphine spectrum ( 31 The conversion rate of raw materials was detected by P NMR. The yield was calculated by mass of the first generation Grubbs catalyst obtained by separation and purification, and the results are shown in Table 1.

[0080] Table 1

[0081]

[0082]

[0083] As can be seen from Table 1, the first generation Grubbs catalyst is prepared by the preparation method provided by the present invention, the raw material conversion rate can reach 100%, the yield can reach 90%, and it can be used for large-scale industrial production;

[0084] By comparing Example 1 with Examples 4 and 5, it can be seen that if the amount of styrene added in each batch is too low or too high, the raw material conversion rate or yield will be adversely affected; by comparing Example 1 with Examples 6-17, it can be seen that using different transition metal salts as catalysts or using different solvents have different effects on the raw material conversion rate and yield; by comparing Example 1 with Comparative Example 1, it can be seen that without adding transition metal salts, the raw material conversion rate and yield are significantly reduced; by comparing Example 1 with Comparative Example 2, it can be seen that the raw material conversion rate and yield achieved by adding styrene in batches require a higher amount of styrene for adding styrene at one time, so styrene can be added in batches to effectively reduce the amount of styrene and improve the yield.

[0085] In summary, the preparation method of the first-generation Grubbs catalyst provided by the present invention can effectively reduce the amount of styrene used and improve the yield by adding a transition metal salt as a catalyst and adding styrene in batches in the reaction of olefin exchange between a ruthenium-indenyl compound and styrene to synthesize the first-generation Grubbs catalyst. The post-treatment process is simple and has good application prospects in industrial scale-up.

[0086] 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 preparing a first generation Grubbs catalyst, characterized in that: The preparation method comprises the following steps: A ruthenium-indenyl compound, a transition metal salt and a solvent are mixed and subjected to a temperature treatment, and then styrene is added in batches to cause an olefin exchange reaction; the obtained product is subjected to solid-liquid separation, and the obtained liquid phase is post-treated to obtain the first-generation Grubbs catalyst.

2. The preparation method according to claim 1, characterized in that: The transition metal salt includes any one of cuprous chloride, cuprous bromide, cupric chloride, cupric bromide, cuprous iodide, cobalt dichloride, cobalt dibromide, cobalt acetate, ferrous chloride or ferrous bromide; Preferably, the amount of the transition metal salt used is 1-20 mol% of the amount of the ruthenium-indenyl compound used.

3. The preparation method according to claim 1 or 2, characterized in that: The 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; Preferably, the amount of the solvent used is such that the concentration of the ruthenium-indenylene compound in the mixed solution after mixing is 0.05-0.5 mol / L.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The molar amount of styrene added in each batch is 1-2 times the molar amount of the ruthenium-indenyl compound; Preferably, the time interval between adjacent batches of styrene is 0.25-1h; Preferably, the styrene is added in batches of 3-5 times; Preferably, the molar ratio of the total amount of styrene added to the total amount of the ruthenium-indenyl compound is (3-10):

1.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The temperature end point of the temperature raising treatment is 40-100°C.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The olefin exchange reaction is carried out in a protective atmosphere; Preferably, the protective atmosphere includes any one of nitrogen, helium or argon.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The solid-liquid separation includes a cooling step before the solid-liquid separation; Preferably, the cooling temperature is 20-30°C.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The post-treatment includes rotary evaporation, washing and drying in sequence.

9. The preparation method according to claim 8, characterized in that: The washing reagent includes any one of ether, methyl tert-butyl ether, methanol, acetone or n-hexane, or a combination of at least two of them.

10. The preparation method according to claim 1, characterized in that: The preparation method comprises the following steps: The ruthenium-indenyl compound, transition metal salt and solvent are mixed and heated to 40-100°C, and then styrene is added in batches to cause an olefin exchange reaction in a protective atmosphere; the obtained product is cooled to 20-30°C and then solid-liquid separation is performed, and the obtained liquid phase is successively subjected to rotary evaporation, washing and drying to obtain the first-generation Grubbs catalyst; The amount of the transition metal salt is 1-20 mol% of the amount of the ruthenium-indenyl compound; the amount of the solvent is such that the concentration of the ruthenium-indenyl compound in the mixed solution is 0.05-0.5 mol / L; the molar amount of styrene added in each batch is 1-2 times the molar amount of the ruthenium-indenyl compound, the time interval between adjacent batches of styrene is 0.25-1h, the batches of styrene added are 3-5 times, and the molar ratio of the total amount of styrene added to the total amount of ruthenium-indenyl compound is (3-10):1.

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