Ketone compound as well as preparation method and application thereof
Through the anicyclic carbene and photoco-catalysis technology, the insufficient antioxidant activity and industrial production problems of ketone compounds in the existing technology have been solved, and efficient and environmentally friendly preparation of ketone compounds has been achieved, with broad market application prospects.
Patent Information
- Application Number
- CN202510351347.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-24
- Publication Date
- 2025-06-27
AI Technical Summary
It is difficult to easily and greenly prepare ketone compounds with higher antioxidant activity in the prior art, especially in industrial production, with long synthetic routes and severe reaction conditions.
Ketone compounds are constructed through azohexycyclocarbene and photo-coordinated catalysis, using shorter synthesis routes and mild reaction conditions, avoiding the use of metal catalysts and oxidants, thereby achieving an environmentally friendly and efficient preparation method.
The prepared ketone compounds have stronger antioxidant activity and can eliminate DPPH radicals up to 81.6%, which is suitable for industrial production, and the preparation method is environmentally friendly and easy to operate.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of medicinal chemistry, and particularly relates to a ketone compound constructed based on the synergistic catalysis of N-heterocyclic carbene and light, a preparation method thereof, and an application thereof. Background Art
[0002] Ketone compounds are widely present in a wide range of natural products and drugs. Relevant research shows that the functions of ketones significantly affect the pharmacodynamic and pharmacokinetic properties of drug molecules, improving their efficacy and specificity. The modification of such compounds, especially the modification of drug skeletons and further re-evaluation of biological activities, has become a research hotspot.
[0003] In recent years, the known harmful effects of free radicals on human metabolism and the food safety problems caused by free radicals in food have made people more and more interested in antioxidants. How to simply and greenly prepare ketone compounds with higher antioxidant activity is challenging. Summary of the Invention
[0004] The purpose of the present invention is to provide a ketone compound constructed based on the synergistic catalysis of N-heterocyclic carbene and light. Such ketone compounds have stronger antioxidant activity, can effectively scavenge free radicals, and can be prepared under milder reaction conditions and shorter synthetic routes, which is conducive to industrial scale-up production.
[0005] The present invention is achieved by the following technical solutions:
[0006] A ketone compound has a structural formula shown in Formula I:
[0007]
[0008] In Formula I, R 1 is selected from an optionally substituted saturated chain alkyl, an optionally substituted unsaturated alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; R 2 is selected from an optionally substituted benzyl or an optionally substituted azacycloalkyl.
[0009] In this technical solution, the R 1 group can be a substituted or unsubstituted saturated chain alkyl. In some embodiments, the R 1 group is selected from a substituted or unsubstituted C1-C6 saturated chain alkyl. In one or more embodiments, the R 1 group is selected from an unsubstituted C1-C6 saturated chain alkyl. In one or more embodiments, the R 1 group is selected from a C1-C4 straight-chain alkyl or a C1-C4 branched-chain alkyl. In some preferred embodiments, the R 1 group is methyl, ethyl, propyl, isopropyl, tert-butyl, or n-butyl.
[0010] In this technical solution, the R 1 group can be a substituted or unsubstituted unsaturated alkyl group. In some embodiments, the R 1 group is selected from C4-C 20 unsaturated alkyl groups. In one or more embodiments, the R 1 group is selected from unsubstituted C 10 -C 18 unsaturated alkyl groups. In some preferred embodiments, the R 1 group is selected from unsubstituted C 12 -C 18 unsaturated alkyl groups.
[0011] In this technical solution, the R 1 group can be a substituted or unsubstituted aryl group. In some embodiments, the aryl group can be a monocyclic aryl group or a fused-ring aryl group. The number of carbon atoms of the aryl group is preferably C6-C 24 , more preferably C6-C 18 , even more preferably C6-C 12 . In some preferred embodiments, the aryl group is phenyl, naphthyl or biphenyl. In some embodiments, the aryl group is preferably a substituted phenyl or naphthyl. Specifically, in some preferred embodiments, the substituents of the phenyl group are selected from substituted or unsubstituted phenyl groups, straight-chain alkyl groups with 1-6 carbon atoms, or sulfonamide groups. In some preferred embodiments, the substituents of the naphthyl group are selected from substituted or unsubstituted phenyl groups, straight-chain alkyl groups with 1-6 carbon atoms, or sulfonamide groups.
[0012] In this technical solution, the R 1 group can be a substituted or unsubstituted heteroaryl group. In some embodiments, the heteroaryl group can be a monocyclic or fused-ring aryl group. The heteroatoms of the heteroaryl group can be sulfur, oxygen or nitrogen. The number of carbon atoms of the heteroaryl group is preferably C4-C 12 , more preferably C4-C8, even more preferably C4-C6. In one or more embodiments, the heteroaryl group is pyridyl, furyl, thiophenyl, imidazolyl, quinolinyl, pyrazolyl or pteridinyl. In some preferred embodiments, the heteroaryl group is a substituted heteroaryl group, and its substituents are preferably substituted or unsubstituted phenyl groups, straight-chain alkyl groups with 1-6 carbon atoms, or sulfonamide groups.
[0013] In this technical solution, the R 2 group can be a substituted or unsubstituted benzyl group, wherein the substituted benzyl group is preferably a benzyl group substituted with a para-ester group. In this technical solution, the R 2 group can also be a C5-C7 azacycloalkyl group. In some preferred embodiments, the R 2 group is piperidinyl.
[0014] The ketone compounds provided in this technical solution can be prepared through the synergistic catalysis of N-heterocyclic carbene and light. The synthetic route is shorter and the reaction conditions are milder, which is conducive to industrial and large-scale production. At the same time, these ketone compounds have stronger antioxidant activity, and the scavenging rate of DPPH radicals can be as high as 81.6%, showing broad market application prospects.
[0015] Furthermore, the ketone compound has any one of the following structural formulas:
[0016]
[0017]
[0018] The present invention also provides a preparation method for any one of the foregoing ketone compounds. This preparation method uses the synergistic catalysis of N-heterocyclic carbene and light to synthesize ketone compounds. The preparation process does not require metal catalysis, which can effectively avoid the use of metal reagents and equivalent oxidants, thereby making the preparation method more environmentally friendly. Specifically, the preparation method includes the following steps:
[0019] Under an inert atmosphere, a compound represented by formula II, an acylating reagent represented by formula III, 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (4CzIPN), an inorganic base, an N-heterocyclic carbene (NHC), and a first solvent are mixed to obtain a suspension, and the suspension is reacted under light irradiation to obtain a ketone compound represented by formula I.
[0020]
[0021] In this technical solution, the reaction path of the compound represented by formula II and the acylating reagent represented by formula III under the synergistic catalysis of N-heterocyclic carbene and light is as follows:
[0022]
[0023] In this technical solution, a suspension reaction system obtained by mixing a compound represented by formula II, an acylating reagent represented by formula III, 4CzIPN, an inorganic base, NHC, and a first solvent is reacted under light irradiation to obtain a ketone compound. In some preferred embodiments, after adding the compound represented by formula II, the acylating reagent, 4CzIPN, the inorganic base, and NHC into a dry container, the oxygen in the container is replaced with an inert gas, such as argon, and the first solvent is added under an argon atmosphere to obtain a suspension. Finally, the suspension is stirred and reacted under light irradiation to obtain a ketone compound.
[0024] In one or more embodiments, the inorganic base is preferably at least one of potassium carbonate, sodium carbonate, and cesium carbonate.
[0025] In one or more embodiments, the first solvent is preferably at least one of acetonitrile, chloroform, and toluene.
[0026] In some preferred embodiments, the N-heterocyclic carbene preferably has the structural formula shown in Formula V:
[0027]
[0028] In some preferred embodiments, the suspension is stirred under irradiation of a blue LED lamp to generate the ketone compound.
[0029] As a preferred embodiment of the preparation method in the present invention, R is prepared by the following steps 2 The compound of Formula II in which the R
[0030] After adding dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate and the compound shown in Formula VI to the second solvent, the reaction is carried out at room temperature to obtain the compound of Formula II in which the R 2 group is an optionally substituted benzyl group,
[0031]
[0032] In Formula VI, R 3 is selected from H or an ester group.
[0033] In this technical solution, for the ketone compound in which the R 2 group is an optionally substituted benzyl group, in the preparation, the corresponding substrate of the R 2 group is first prepared by this step. Specifically, after adding dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate and the compound shown in Formula VI to the second solvent, the reaction is carried out at room temperature for 6 to 12 hours, and after removing the solvent and purification, the corresponding product can be obtained. The reaction path is as follows:
[0034]
[0035] In some embodiments, the second solvent is preferably at least one of dichloromethane and dichloroethane.
[0036] The present invention also provides the application of any of the foregoing ketone compounds, and the ketone compound is used to prepare an antioxidant.
[0037] Compared with the prior art, the present invention has the following advantages and beneficial effects:
[0038] 1. The ketone compounds provided by the present invention can be prepared through the synergistic catalysis of N - heterocyclic carbene and light. The synthetic route is shorter and the reaction conditions are milder, which is conducive to industrialized and large - scale production. At the same time, these ketone compounds have stronger antioxidant activity, and the scavenging rate of DPPH free radicals can be as high as 81.6%, showing broad market application prospects.
[0039] 2. The preparation method of the ketone compounds provided by the present invention uses the synergistic catalysis of N - heterocyclic carbene and light to synthesize ketone compounds. The preparation process has no metal catalysis, which can effectively avoid the use of metal reagents and equivalent oxidants, making the preparation method more environmentally friendly. Moreover, the preparation method is easy to operate, the reaction is mild, and the yield is relatively high. Detailed implementation manners
[0040] To make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below in conjunction with embodiments. The illustrative embodiments and descriptions of the present invention are only used to explain the present invention and are not intended to limit the present invention.
[0041] There are no special restrictions on the sources of all raw materials of the present invention. They can be purchased on the market or prepared according to the conventional methods well - known to those skilled in the art. There are no special restrictions on the purity of all raw materials of the present invention. The present invention preferably uses analytical pure or the conventional purity requirements in the field of pharmaceutical chemistry. All raw materials of the present invention, their trademarks and abbreviations are all conventional trademarks and abbreviations in the art. Each trademark and abbreviation is clear and definite in the field of its relevant uses. Those skilled in the art can purchase them from the market or prepare them through conventional methods according to the trademark, abbreviation and corresponding uses.
[0042] The present invention has no special restrictions on the expression methods of the substituents, and all use the expression methods well - known to those skilled in the art. Based on common sense, those skilled in the art can correctly understand their meanings according to the expression methods.
[0043] In the present invention, the term "connection", without special explanation, can be directly connected or indirectly connected through other groups.
[0044] The "first", "second", etc. (such as the first solvent, the second solvent, etc.) used in the present invention are only used to distinguish the corresponding components clearly for the sake of description, and are not intended to limit any order or emphasize importance, etc.
[0045] I. Preparation of Ketone Compounds
[0046]
Examples 1 - 9
[0047] The ketone compounds of Examples 1 to 9 were prepared using substantially the same preparation method. Specifically, 2 mol% eq. of 4CzIPN, 20 mol% eq. of NHC, 1 eq. of substrate 1 (i.e., the compound shown in Formula II), 2 eq. of acylating reagent 2 (i.e., the acylating reagent shown in Formula III), and 2 eq. of K2CO3 were added to a dry 10 mL sealed tube. The lid was covered, evacuated, and 1 mL of dry acetonitrile was added under an argon atmosphere. The lid was tightened again, and the resulting suspension was stirred overnight under irradiation with a blue LED. The reaction was monitored by thin-layer chromatography and completed, and then the reaction mixture was directly purified by column chromatography to obtain the corresponding target product 3, which is a ketone compound.
[0048]
[0049] Among them, the structural formula of the NHC used is
[0050] Furthermore, for substrate 1 in Examples 1 to 8 where R2 is a substituted or unsubstituted benzyl group, its preparation method is as follows: Prepare a dry 250 mL round-bottom flask equipped with a magnetic stirrer. Weigh 1,2,4,5-tetrazine-3,6-dicarboxylic acid dimethyl ester (1.98 g, 10 mmol) into it, add dichloromethane (30 mL) as a solution, and then add the compound of Formula VI (11 mmol). The reaction mixture was stirred at room temperature for 7 h. After the reaction was completed by TLC detection, the solvent was removed by vacuum evaporation; the product was purified using a silica gel column eluted with petroleum ether / ethyl acetate (3:1). Among them, the structural formula of the compound of Formula VI is: The R3 group is selected from H or an ester group.
[0051] The ketone compounds of Examples 1 to 9 and their characterizations are shown in Table 1:
[0052] Table 1:
[0053]
[0054]
[0055] II. Antioxidant Activity Test of Ketone Compounds
[0056]
Example 10
[0057] In this example, the antioxidant activity of the ketone compounds synthesized in this application was determined by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging assay.
[0058] The specific test method is as follows:
[0059] Preparation of DPPH free radical solution: Accurately weigh 0.2 mg of DPPH (1,1-diphenyl-2-picrylhydrazyl), and make up the volume to 20 mL with anhydrous methanol in a light-proof brown volumetric flask, then store it in the refrigerator.
[0060] Preparation of sample solution: Accurately weigh 1 mg of the ketone compound sample to be measured, dissolve it with 1 mL of anhydrous methanol, and prepare a sample solution of the ketone compound to be measured with a concentration of 1 mg / mL.
[0061] Determination method: The experiment is carried out in a light-proof environment. Use a pipette to suck 0.1 mL of the sample solution of the compound to be measured and 0.1 mL of the DPPH free radical solution into a 96-well plate, shake well, and measure the absorbance value at 515 nm with an enzyme-labeled instrument after reacting for 30 min at 30 °C. At the same time, measure the data of two parallel experiments, and take the average value to obtain the absorbance value A of the compound sample at this concentration. i ; Use a pipette to suck 0.1 mL of the sample solution of the compound to be measured and 0.1 mL of anhydrous methanol into a 96-well plate and mix them. Measure its absorbance value as A after 30 min. j ; Use a pipette to suck 0.1 mL of the DPPH· free radical solution and 0.1 mL of anhydrous methanol into a 96-well plate and mix them. Measure its absorbance value as A0 after 30 min. Calculate the scavenging rate S of each measured compound on the DPPH free radical according to the following scavenging rate formula. R :
[0062]
[0063] Experimental results:
[0064] The scavenging rate of the ketone compound in Example 2 on the DPPH free radical is 75.2%, and the scavenging rate of the ketone compound in Example 3 on the DPPH free radical is 81.6%, showing good antioxidant activity. Other compounds also have antioxidant activity. The experimental methods and final effects are the same. To reduce the repeated content, the experimental contents of other compounds are not listed one by one.
[0065] The specific embodiments described above further elaborate on the purpose, technical solutions, and beneficial effects of the present invention. It should be understood that the above description is only the specific embodiments of the present invention and is not used to limit the protection scope of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. A ketone compound, characterized in that It has the structural formula shown in Formula I: In Formula I, R 1 R is selected from an optionally substituted saturated chain alkyl group, an optionally substituted unsaturated alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; 2 is selected from optionally substituted benzyl or optionally substituted azacycloalkyl.
2. A ketone compound according to claim 1, characterized in that: The R 1 Selected from C1~C6 saturated chain alkyl, C4~C 20 Unsaturated alkyl, C6~C 12 Aryl, C4-C6 heteroaryl.
3. A ketone compound according to claim 2, characterized in that: The substituent of the aryl group or heteroaryl group is phenyl group, straight-chain alkyl group or sulfonamide group.
4. A ketone compound according to claim 1, characterized in that: The R 2 It is selected from unsubstituted benzyl, benzyl substituted with a para-ester group, or C5-C7 azacycloalkyl.
5. A ketone compound according to any one of claims 1 to 4, characterized in that: Has any of the following structural formulas:
6. A method for preparing a ketone compound, characterized in that: For preparing a ketone compound according to any one of claims 1 to 5, the preparation method comprises the following steps: Under an inert atmosphere, a compound represented by formula II, an acylating agent represented by formula III, 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, an inorganic base, a nitrogen heterocyclic carbene, and a first solvent are mixed to obtain a suspension, and the suspension is reacted under light to obtain a ketone compound represented by formula I. Formula II: Formula III 7. The method for preparing a ketone compound according to claim 6, characterized in that: The following steps were used to prepare R 2 The compound of formula II wherein the group is an optionally substituted benzyl group: After adding 1,2,4,5-tetrazine-3,6-dicarboxylic acid dimethyl ester and the compound represented by formula VI to the second solvent, the reaction was carried out at room temperature to obtain R 2 The compound of formula II wherein the group is an optionally substituted benzyl group, In Formula VI, R 3 Selected from H or an ester group.
8. The method for preparing a ketone compound according to claim 6 or 7, characterized in that: The nitrogen heterocyclic carbene has the structural formula shown in Formula V:
9. The method for preparing a ketone compound according to claim 6 or 7, characterized in that: The suspension is stirred under the irradiation of a blue LED light to generate the ketone compound.
10. An application of a ketone compound, characterized in that: A ketone compound as claimed in any one of claims 1 to 5 is used to prepare an antioxidant.