Preparation method and application of NHC-Ru catalyst containing large steric hindrance functional group
By developing the N-heterocyclic carbene ruthenium complex catalyst, the problems of low yield and large catalyst usage in the olefin metathesis reaction are solved, and the catalytic effect of low amount and high yield is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202510329869.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-20
- Publication Date
- 2025-06-24
AI Technical Summary
The existing ruthenium catalysts have problems of low yield and large catalyst usage in the olefin metathesis reaction, resulting in the metal content in the target product exceeding the standard.
An N-heterocyclic carbene ruthenium complex catalyst with the structure of formula 5a, 5b, 5c and 5d was developed. A highly efficient ruthenium complex catalyst was prepared by reacting the ruthenium complex with N-heterocyclic carbenemidazole hydrochloride and 2-isopropoxystyrene under the protection of an inert gas.
The catalyst is used in the low amount in the olefin metathesis reaction, which can effectively improve the yield of the target product, reduce economic costs, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This application belongs to the field of organometallic catalysis. Specifically, it relates to a preparation method of a ruthenium complex catalyst containing a large steric hindrance functional group N-heterocyclic carbene. Background Art
[0002] The literature [Angew.Chem.Int.Ed.1995, 34(18), 2039-2041] reported the synthesis of the first-generation Grubbs catalyst containing benzylidene that can catalyze olefin metathesis reaction. The literature [J.Am.Chem.Soc.1999, 121, 791-799] reported the synthesis of the first-generation Hoveyda-Grubbs catalyst. The literature [J.Am.Chem.Soc.2000, 122, 8168-8179] reported the synthesis of the second-generation Hoveyda-Grubbs catalyst, which promoted the development of ruthenium catalysts.
[0003] The ruthenium-based metathesis catalyst catalyzing metathesis reaction is an efficient means for constructing carbon-carbon double bonds in organic synthetic chemistry and is widely used in drug synthesis. Patent WO 2010 / 011566 A1 reported the use of zhan 1B ruthenium catalyst to catalyze the preparation of an intermediate of the anti-hepatitis C drug Grazoprevir Hydrate, with a yield of 25%. Patent WO 2007 / 014926 A1 reported the use of the first-generation H-G catalyst to catalyze the preparation of an intermediate of the anti-hepatitis C drug Simeprevir Sodium, with a yield of 60%. Patent US 8299021 B2 reported the use of the second-generation H-G catalyst to catalyze the preparation of an intermediate of the anti-hepatitis C drug Danoprevir Sodium, with a yield of 52%.
[0004] The literature [Synlett.2005, 5, 765-768] reported the use of the Grubbs catalyst to reflux in dichloromethane for 72 hours to prepare the precursor (methyl 3-cyclopentene-1,1-dicarboxylate) of dolasetron mesylate for treating postoperative nausea and vomiting caused by chemotherapy and radiotherapy, with a yield of only 93%. The literature [J.Org.Chem.2012, 77, 8182-8190] reported the use of the second-generation Grubbs catalyst to react at room temperature in dichloromethane, and the catalyst dosage was as high as 0.76% mol, which easily caused the metal ruthenium content in the product to be too high.
[0005] In the above patent reports, there are problems such as low yield of the target product; or a large amount of ruthenium catalyst is used, which easily leads to the metal content in the target product exceeding the standard. Summary of the Invention
[0006] The present application provides N - heterocyclic carbene ruthenium complexes with the structural formulas of Formula 5a, 5b, 5c, and 5d:
[0007]
[0008] Among them, R1 is C2 - C 12 alkyl, C2 - C 12 alkoxy, preferably methyl, methoxy; R2 is nitro, dimethylaminosulfonyl.
[0009] The present application provides a method for synthesizing a highly efficient N - heterocyclic carbene (NHC) ruthenium complex catalyst, specifically:
[0010]
[0011] Among them, R1 is C2 - C 12 alkyl, C2 - C 12 alkoxy, preferably methyl, methoxy; R2 is nitro, dimethylaminosulfonyl.
[0012] (1) Prepare the compound shown in Formula 4a or 4b or 4c or 4d: Under the protection of an inert gas, take the ruthenium complex shown in Formula 1 and N - heterocyclic carbene imidazole hydrochloride (NHC·HCl) to prepare the ruthenium complex shown in Formula 4a or 4b or 4c or 4d;
[0013] (2) Prepare the ruthenium complex catalyst shown in Formula 5a or 5b or 5c or 5d: Under the protection of an inert gas, take the ruthenium complex shown in Formula 4a or 4b or 4c or 4d and 2 - isopropoxystyrene shown in Formula 2 to prepare the ruthenium complex catalyst shown in Formula 5a or 5b or 5c or 5d; Among them, the structure of N - heterocyclic carbene imidazole hydrochloride (NHC·HCl) is as follows:
[0014]
[0015] R1 is C2 - C 12 alkyl, C2 - C 12 alkoxy, preferably methyl, methoxy.
[0016] Among them, in the preparation of compound 4a or 4b or 4c or 4d, the solvent is an aprotic solvent, such as: n - hexane, n - heptane, toluene, etc., preferably, the solvent is cyclohexane.
[0017] Among them, the reaction temperature is 40°C - 100°C, preferably, the temperature is 70°C.
[0018] In the preparation of compound 5a or 5b or 5c or 5d, the solvent is an aprotic solvent, such as: n - hexane, n - heptane, toluene, etc., preferably, the solvent is dichloromethane.
[0019] Among them, the reaction temperature is 40°C - 100°C. Preferably, the temperature is 40°C.
[0020] Use of the above-mentioned N-heterocyclic carbene ruthenium complex catalyst in olefin metathesis ring-closing reaction.
[0021] When using the above-synthesized N-heterocyclic carbene ruthenium complex catalyst 5a or 5b or 5c or 5d to catalyze the ring-closing metathesis reaction for preparing pharmaceutical intermediates, the catalyst dosage is low, and it can effectively improve the yield of the target product, reducing the economic cost.
[0022] This application provides a method for synthesizing the key intermediate methyl 3-cyclopentene-1,1-dicarboxylate of the antiemetic drug dolasetron mesylate by using the above-synthesized N-heterocyclic carbene ruthenium complex catalyst (5a or 5b or 5c or 5d) to catalyze the olefin ring-closing metathesis reaction.
[0023] Specifically:
[0024]
[0025] Under the protection of inert gas, take the compound shown in Formula 6 and the N-heterocyclic carbene ruthenium complex catalyst (5a or 5b or 5c or 5d), add the reaction solvent, and heat the reaction to obtain the compound shown in Formula 7.
[0026] Among them, the reaction solvent is an aprotic solvent, such as: tetrahydrofuran, toluene, n-hexane, n-heptane, etc. Preferably, the solvent is n-heptane;
[0027] Among them, the reaction temperature is 60°C - 110°C. Preferably, the temperature is 100°C;
[0028] Among them, the reaction time is 60 minutes - 210 minutes. Preferably, the time is 120 minutes;
[0029] Among them, the molar ratio of the compound 6 to the catalyst 5a or 5b or 5c or 5d is 1:0.0001 - 0.0005. Preferably, the molar ratio of the compound 6 to the catalyst 5a or 5b or 5c or 5d is 1:0.0002.
[0030] This application provides a method for using the above-synthesized N-heterocyclic carbene ruthenium complex catalyst (5a or 5b or 5c or 5d) to catalyze the olefin ring-closing metathesis reaction to prepare the key intermediate (as shown in 9) of the anti-HCV drug Danoprevir. Specifically:
[0031]
[0032] Under the protection of inert gas, the compound shown in Formula 8 and an N-heterocyclic carbene ruthenium complex catalyst (5a or 5b or 5c or 5d) are taken, a reaction solvent is added, and the reaction is heated to obtain the compound shown in Formula 9.
[0033] Among them, the reaction solvent is an aprotic solvent, such as: tetrahydrofuran, toluene, dichloromethane, etc. Preferably, the reaction solvent is toluene;
[0034] Among them, the reaction temperature is 40°C - 110°C. Preferably, the reaction temperature is 70°C;
[0035] Among them, the reaction time is 8 hours - 12 hours. Preferably, the reaction time is 10 hours;
[0036] Among them, the molar ratio of the compound 8 to the catalyst 5a or 5b or 5c or 5d is 1:0.001 - 1:0.01. Preferably, the molar ratio of the compound 8 to the catalyst 5a or 5b or 5c or 5d is 1:0.005. Detailed implementation mode
[0037] The beneficial effects achieved by this application: A method for preparing the key intermediate methyl 3-cyclopentene-1,1-dicarboxylate of the antiemetic drug dolasetron mesylate and the key intermediate of the anti-HCV drug Danoprevir by catalytic ring-closing metathesis reaction of olefins with a class of highly efficient N-heterocyclic carbene ruthenium complex catalysts provided by the present invention. The catalyst dosage is low, the operation is simple, the yield is high, and the cost is low, which is suitable for industrial production.
[0038] The following further details the present invention through specific implementation modes, but it is not a limitation to the present invention. According to the above content of the present invention, other various forms of modifications, substitutions or changes can be made without departing from the above basic technical idea of the present invention by using ordinary technical knowledge and conventional means in the art.
[0039] Example 1 Preparation of ruthenium complex catalyst 5a
[0040] Under anhydrous and anaerobic conditions, 988 mg (1.2 mmol) of compound 1, 950 mg (1.0 mmol) of compound 3a and 135 mg (1.2 mmol) of potassium tert-butoxide were successively added to a 50 ml schlenk flask, and 40 ml of cyclohexane was added. The reaction was carried out at 70°C for 5 hours with stirring. The solvent was evaporated to dryness, and column chromatography was carried out using petroleum ether: ethyl acetate = 15:1 as the mobile phase to obtain 946 mg of red-brown solid powder intermediate 4a, with a yield of 65%.
[0041] Under anhydrous and anaerobic conditions, 600 mg (0.4 mmol) of the intermediate of complex 4a obtained in the previous step was dissolved in 30 mL of dichloromethane, 49 mg (0.5 mmol) of copper(I) chloride was added and stirred for 5 minutes, then 102 mg (0.5 mmol) of 2-isopropoxy-4-nitrostyrene was added to the reaction. The temperature was raised to 40 °C and the reaction was carried out for 1 hour. The reaction was stopped, and the reaction solution was directly subjected to column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1) to obtain 401 mg of brown solid powder 5a with a yield of 76%.
[0042] Example 2 Preparation of ruthenium complex catalyst 5b
[0043] Under anhydrous and anaerobic conditions, 988 mg (1.2 mmol) of compound 1, 980 mg (1.0 mmol) of compound 3b and 135 mg (1.2 mmol) of potassium tert-butoxide were successively added to a 50 mL Schlenk flask, and 40 mL of toluene was added. The reaction was carried out at 70 °C for 5 hours with stirring. The solvent was evaporated, and column chromatography was performed using petroleum ether:ethyl acetate = 20:1 as the mobile phase to obtain 982 mg of red-brown solid powder intermediate 4b with a yield of 66%.
[0044] Under anhydrous and anaerobic conditions, 600 mg (0.4 mmol) of the intermediate of complex 4b obtained in the previous step was dissolved in 30 mL of dichloromethane, 48 mg (0.5 mmol) of copper(I) chloride was added and stirred for 5 minutes, then 100 mg (0.5 mmol) of 2-isopropoxy-4-nitrostyrene was added to the reaction. The temperature was raised to 40 °C and the reaction was carried out for 1 hour. The reaction was stopped, and the reaction solution was directly subjected to column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1) to obtain 413 mg of brown solid powder 5b with a yield of 78%.
[0045] Example 3 Preparation of ruthenium complex catalyst 5c
[0046] Under anhydrous and anaerobic conditions, 988 mg (1.2 mmol) of compound 1, 950 mg (1.0 mmol) of compound 3a and 135 mg (1.2 mmol) of potassium tert-butoxide were successively added to a 50 mL Schlenk flask, and 40 mL of cyclohexane was added. The reaction was carried out at 70 °C for 5 hours with stirring. The solvent was evaporated, and column chromatography was performed using petroleum ether:ethyl acetate = 15:1 as the mobile phase to obtain 946 mg of red-brown solid powder intermediate 4a with a yield of 65%.
[0047] Under anhydrous and anaerobic conditions, 600 mg (0.4 mmol) of the complex 4a intermediate obtained in the previous step was dissolved in 30 mL of dichloromethane. 49 mg (0.5 mmol) of copper(I) chloride was added and stirred for 5 minutes. Then, 133 mg (0.5 mmol) of 2-isopropoxy-4-(dimethylaminophenyl)styrene was added to the reaction. The temperature was raised to 40 °C and the reaction was carried out for 1 hour. The reaction was stopped, and the reaction solution was directly subjected to column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1) to obtain 404 mg of a brown solid powder 5c with a yield of 73%.
[0048] Example 4 Preparation of ruthenium complex catalyst 5d
[0049] Under anhydrous and anaerobic conditions, 988 mg (1.2 mmol) of compound 1, 980 mg (1.0 mmol) of compound 3b, and 135 mg (1.2 mmol) of potassium tert-butoxide were successively added to a 50 mL Schlenk flask, and 40 mL of toluene was added. The reaction was carried out at 70 °C for 5 hours with stirring. The solvent was evaporated, and column chromatography was performed using petroleum ether:ethyl acetate = 20:1 as the mobile phase to obtain 982 mg of a red-brown solid powder intermediate 4b with a yield of 66%.
[0050] Under anhydrous and anaerobic conditions, 600 mg (0.4 mmol) of the complex 4b intermediate obtained in the previous step was dissolved in 30 mL of dichloromethane. 48 mg (0.5 mmol) of copper(I) chloride was added and stirred for 5 minutes. Then, 130 mg (0.5 mmol) of 2-isopropoxy-4-(dimethylaminophenyl)styrene was added to the reaction. The temperature was raised to 40 °C and the reaction was carried out for 1 hour. The reaction was stopped, and the reaction solution was directly subjected to column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1) to obtain 410 mg of a brown solid powder 5b with a yield of 74%.
[0051] Example 5 Preparation of methyl 3-cyclopentene-1,1-dicarboxylate
[0052] 1 g of dimethyl diallylmalonate was weighed and 2 mL of n-heptane was added. Nitrogen was passed through and stirred at room temperature for 20 minutes. 2.0 mg of catalyst 5a was weighed, dissolved in 2 mL of n-heptane and added to the reactor. The temperature was raised to 100 °C and the reaction was carried out for 150 minutes. After the reaction was complete, the n-heptane was evaporated to obtain 842 mg of a white solid powder with a yield of 97%.
[0053] Example 6 Preparation of Danoprevir intermediate
[0054] 50 mg of compound 8 was weighed and dissolved in 5 mL of toluene. Nitrogen was passed through and stirred at room temperature for 20 minutes. 4.7 mg of catalyst 5a was weighed and added to the reactor. The temperature was raised to 70 °C and the reaction was carried out for 10 hours. After the reaction was complete, column chromatography was performed to obtain 37 mg of a white solid powder with a yield of 77%.
[0055] Weigh 500 mg of Compound 8 and dissolve it in 50 mL of toluene. Introduce nitrogen and stir at room temperature for 20 minutes. Weigh 0.47 mg of Catalyst 5a and add it to the reactor. Heat up to 70 °C and react for 10 hours until the reaction is complete. Obtain 374 mg of white solid powder by column chromatography with a yield of 78%.
[0056] The process for synthesizing the NHC-Ru catalyst by the above method is stable and feasible, and it is easy to industrialize in industry, with high product yield and good quality.
[0057] As used in the specification and claims, certain terms are used to refer to specific components or methods. Those skilled in the art should understand that different regions may use different terms to refer to the same component. The specification and claims do not use the difference in names as a way to distinguish components. As used throughout the specification and claims, the term "comprising" is an open-ended term and should be interpreted as "including but not limited to". "Substantially" means within an acceptable error range. Those skilled in the art can solve the technical problem within a certain error range and basically achieve the technical effect. The subsequent description in the specification is for the purpose of describing the preferred embodiments of the present application, but the description is for the purpose of explaining the general principles of the present application and is not intended to limit the scope of the present application. The protection scope of the present application shall be determined by the scope defined by the appended claims.
[0058] It should also be noted that the term "comprising", "including" or any other variant thereof is intended to cover non-exclusive inclusion, so that a commodity or system including a series of elements not only includes those elements, but also includes other elements not explicitly listed, or also includes elements inherent to such commodity or system. Without further limitation, an element defined by the statement "including one..." does not exclude the existence of another identical element in the commodity or system including the said element.
[0059] The above description shows and describes several preferred embodiments of the invention. However, as mentioned above, it should be understood that the invention is not limited to the forms disclosed herein, should not be regarded as excluding other embodiments, but can be used in various other combinations, modifications and environments, and can be changed within the scope of the inventive concept described herein through the above teachings or the technology or knowledge in the relevant field. And any changes and modifications made by those skilled in the art without departing from the spirit and scope of the invention shall fall within the protection scope of the appended claims of the invention.
Claims
1. A NHC-Ru catalyst containing a large steric functional group, the general structural formula of which is: in, NHC-Ru is N-heterocyclic carbene ruthenium; R1 is C2-C 12 Alkyl, C2-C 12 Alkoxy, preferably methyl, methoxy; R2 is nitro, dimethylaminosulfonyl.
2. A method for preparing the NHC-Ru catalyst as claimed in claim 1, characterized in that: Here are the steps: Where R1 is C2-C 12 Alkyl, C2-C 12 Alkoxy, preferably methyl, methoxy; R2 is nitro, dimethylaminosulfonyl; (1) preparing the compound of formula 4a or 4b or 4c or 4d: under the protection of inert gas, taking the ruthenium complex of formula 1 and N-heterocyclic carbene imidazole hydrochloride (NHC·HCl) to prepare the ruthenium complex of formula 4a or 4b or 4c or 4d; (2) preparing the ruthenium complex catalyst of formula 5a or 5b or 5c or 5d: under the protection of inert gas, taking the ruthenium complex of formula 4a or 4b or 4c or 4d and 2-isopropoxystyrene of formula 2 to prepare the ruthenium complex catalyst of formula 5a or 5b or 5c or 5d; N-heterocyclic carbene imidazole hydrochloride (NHC·HCl) has the following structure: Where R1 is C2-C 12 Alkyl, C2-C 12 Alkoxy group, preferably methyl group or methoxy group.
3. According to claim 2, the ruthenium complex of formula 4a, 4b, 4c or 4d is prepared by using an aprotic solvent such as n-hexane, n-heptane, toluene, etc., preferably cyclohexane.
4. According to claim 2, the ruthenium complex of formula 4a, 4b, 4c or 4d is prepared at a reaction temperature of 40°C to 100°C, preferably 70°C.
5. According to claim 2, the ruthenium complex catalyst 5a or 5b or 5c or 5d is prepared from the ruthenium complex represented by formula 4a or 4b or 4c or 4d, and the solvent is an aprotic solvent, such as: n-hexane, n-heptane, toluene, etc., and the preferred solvent is dichloromethane.
6. A method for preparing 3-cyclopentene-1,1-dicarboxylic acid methyl ester (as shown in 7) as a key intermediate of the antiemetic drug dolasetron mesylate by catalyzing the NHC-Ru catalyst (5a or 5b or 5c or 5d) according to any one of claims 1-2, characterized in that: Here are the steps: Under the protection of inert gas, the compound represented by Formula 6 and the N-heterocyclic carbene ruthenium complex catalyst (5a or 5b or 5c or 5d) are added with a reaction solvent, and heated to react to obtain the compound represented by Formula 7; The reaction solvent is an aprotic solvent, such as tetrahydrofuran, toluene, n-hexane, n-heptane, etc., and the preferred solvent is n-heptane; the reaction temperature is 60°C-110°C, and the preferred temperature is 100°C; the reaction time is 60 minutes-210 minutes, and the preferred time is 120 minutes.
7. A method for preparing a key intermediate (as shown in 9) of an anti-HCV drug Danoprevir by catalyzing metathesis ring closure using the N-heterocyclic carbene ruthenium complex catalyst (5a or 5b or 5c or 5d) according to any one of claims 1-2, characterized in that: Here are the steps: Under the protection of inert gas, the compound shown in Formula 8 and the N-heterocyclic carbene ruthenium complex catalyst (5a or 5b or 5c or 5d) are added with a reaction solvent, and heated to react to obtain the compound shown in Formula 9; The reaction solvent is an aprotic solvent, such as tetrahydrofuran, toluene, dichloromethane, etc., and the preferred solvent is toluene; the reaction temperature is 40°C-110°C, and the preferred temperature is 70°C; the reaction time is 8 hours-12 hours, and the preferred reaction time is 10 hours.
Citation Information
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