CN111925327A - Method for preparing octahydroacridine p-toluenesulfonamide derivative by catalysis of acidic ionic liquid - Google Patents
Method for preparing octahydroacridine p-toluenesulfonamide derivative by catalysis of acidic ionic liquid Download PDFInfo
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Abstract
The invention discloses a method for preparing an octahydroacridine p-toluenesulfonamide derivative by catalyzing an acidic ionic liquid, belonging to the technical field of chemical material preparation. Adding aromatic aldehyde, p-toluenesulfonyl hydrazide, a 1, 3-cyclohexanedione compound and a Bronsted acidic ionic liquid catalyst into a reaction solvent respectively, and then reacting at a reflux temperature to obtain an octahydroacridine p-toluenesulfonamide derivative; the structural formula of the Bronsted acidic ionic liquid catalyst is as follows:
the invention adopts the Bronsted acidic ionic liquid as the catalyst, and both the selectivity and the catalytic activity of the catalyst are relatively high, so that the yield of the obtained product can be effectively improved, the generation of byproducts is reduced, the catalyst can be recycled for multiple times, the production cost is greatly saved, and the pollution to the environment is reduced.
Description
Technical Field
The invention belongs to the technical field of chemical material preparation, and particularly relates to a method for preparing an octahydroacridine p-toluenesulfonamide derivative by catalysis of an acidic ionic liquid.
Background
The sulfamide derivatives are the first synthetic drugs applied to antibacterial drugs and play an important role in the treatment process of infectious diseases. In addition, researchers have also found that they have various biological activities such as insecticidal, antifungal and antiviral activities. In addition, there are studies showing that: some tosylamide derivatives also have a wide range of biological activities against thyroid, tumors, alpha 1-adrenoceptor antagonism and HIV-1 protease inhibition. The compounds containing acridine structure also have good biological and pharmacological activity, and some of the compounds are developed into clinical medicines. The octahydroacridine p-toluenesulfonamide derivative containing both an acridine structure and a toluenesulfonamide structure has wider application in the field of medicine, and is an important medical intermediate. Thus, its preparation has received a great deal of attention from many drug synthesizers.
The multi-component reaction is that three or more than three reaction raw materials are put into a reactor to react under certain conditions to generate a single product. The multi-component reaction has the advantages of simple operation, no need of intermediate separation, high atom economy, high selectivity, small environmental pollution, easy realization of automation and the like, and is widely applied to the synthesis of the drug intermediate. A series of 1, 8-dioxo-octahydroacridine-4-toluenesulfonamide derivatives can be prepared by using Aromatic aldehyde, p-toluenesulfonyl hydrazide and 1, 3-cyclohexanedione Compounds as reaction raw materials and Glacial acetic acid as a catalyst, and the method has the advantages of few byproducts, high product yield, short reaction time and the like (Glacal acid-associated one-pot synthesis of di-responsive octahydrochridin-4-methylzelnesulfonamide derivatives [ J ], polymeric Aromatic Compounds, 2020, 40 (4): 1045-1058). However, this method also has several disadvantages: 1. the glacial acetic acid is extremely large in usage amount and cannot be recycled, and a large amount of waste acid is generated, so that the economic benefit is poor and the environmental pollution is serious; 2. the reaction temperature is high, and the reflux reaction is required to be carried out under the condition that acetic acid is used as a reaction solvent; 3. the acid corrosion is serious in the whole reaction process, and the industrial continuous production is difficult to carry out; 4. the purification of the product needs to be independently provided with a recrystallization process, and a large amount of manpower and material resources are consumed.
Disclosure of Invention
1. Problems to be solved
The invention aims to overcome the defects that the catalyst cannot be recycled, the using amount is large, the preparation process is complex, the industrial large-scale continuous production is difficult and the like in the existing preparation method of the pharmaceutical intermediate octahydroacridine p-toluenesulfonamide derivative, and provides a method for preparing the octahydroacridine p-toluenesulfonamide derivative by catalysis of an acidic ionic liquid. The technical scheme of the invention can effectively solve the problems, and the Bronsted acidic ionic liquid is used as the catalyst, so that the selectivity and the catalytic activity are relatively high, the yield of the obtained product can be effectively improved, the generation of byproducts is reduced, the catalyst can be recycled for multiple times, the production cost is greatly saved, and the pollution to the environment is reduced.
2. Technical scheme
In order to solve the problems, the technical scheme adopted by the invention is as follows:
the invention relates to a method for preparing an octahydroacridine p-toluenesulfonamide derivative under the catalysis of an acidic ionic liquid, which comprises the steps of respectively adding aromatic aldehyde, p-toluenesulfonyl hydrazide, a 1, 3-cyclohexanedione compound and a Bronsted acidic ionic liquid catalyst into a reaction solvent, and then reacting at a reflux temperature to prepare the octahydroacridine p-toluenesulfonamide derivative; the structural formula of the Bronsted acidic ionic liquid catalyst is as follows:
furthermore, the molar amount of the Bronsted acidic ionic liquid catalyst is 5-9% of the molar amount of the aromatic aldehyde.
Further, the molar ratio of the aromatic aldehyde, the p-toluenesulfonyl hydrazide and the 1, 3-cyclohexanedione compound in the reaction raw materials is 1: 1: (2-2.6).
Further, the reaction solvent is a mixed solution of isopropanol, dimethylformamide and distilled water, wherein the volume ratio of the isopropanol, the dimethylformamide and the distilled water is 8: (1-4): 1.
further, the volume amount of the reaction solvent in ml is 5 to 9 times the amount of the aromatic aldehyde substance in mmol.
Further, the reaction solution is stirred and mixed uniformly at room temperature, then is heated uniformly to the reflux temperature, the reaction is carried out at the reflux temperature, and the purification operation is carried out on the reaction solution after the reaction is finished.
Further, the chemical reaction formula of the above reaction is as follows:
furthermore, the reaction liquid is heated to the reflux temperature by adopting an oil bath, the reaction time is 7-15 min, and the reaction pressure is controlled to be one atmospheric pressure.
Further, the specific purification operation process is as follows: after the reaction is finished, cooling the reaction liquid to room temperature, grinding, standing and filtering the precipitated solid; washing and vacuum drying filter residues to obtain a purified octahydroacridine p-toluenesulfonamide derivative; the filtrate can be directly added with reaction raw materials to carry out the next reaction, and can be repeatedly used for at least 4 times.
Further, washing filter residue obtained by suction filtration after the reaction is finished by using absolute ethyl alcohol; and then drying the mixture in vacuum for 22-24 hours at 85-90 ℃.
3. Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
(1) according to the method for preparing the octahydroacridine p-toluenesulfonamide derivative by the acidic ionic liquid catalysis, the octahydroacridine p-toluenesulfonamide derivative is prepared by selecting the Bronsted acidic ionic liquid catalyst with high catalytic activity, so that the utilization rate of reaction raw materials and the yield of products can be effectively improved. Meanwhile, when the catalyst is used for preparing the octahydroacridine p-toluenesulfonamide derivative, the usage amount is small, the number of times of recycling is large, the biodegradation is easy, the environmental hazard is small, the preparation process can be further simplified by using the Bronsted acidic ionic liquid catalyst, no waste liquid is generated basically in the preparation process, and the preparation method is green and pollution-free and is convenient for industrial large-scale production.
(2) The method for preparing the octahydroacridine p-toluenesulfonamide derivative by catalyzing the acidic ionic liquid can effectively reduce the using amount and the loss amount of the catalyst in the recycling process, and the used catalyst has the advantages of more recycling times, lower toxicity, easiness in biodegradation and smaller harm to the environment. On the other hand, the specific selection of the catalyst is adopted, and the preparation cost of the catalyst is low, so that the production cost is effectively reduced, and the economic benefit is high.
(3) According to the method for preparing the octahydroacridine p-toluenesulfonamide derivative by the acidic ionic liquid catalysis, a mixed solution composed of isopropanol, dimethylformamide and distilled water is used as a reaction solvent, and the volume ratio (the ratio is 8 (1-4): 1) of the isopropanol, the dimethylformamide and the distilled water is optimally designed, so that the purification process of a product can be simplified, a catalytic system formed by the catalytic system and a Bronsted acidic ionic liquid catalyst can effectively improve the catalytic efficiency and catalytic selectivity of the catalytic system, the aim of recycling the reaction solvent is fulfilled, the production cost is greatly saved, and the pollution degree of the octahydroacridine p-toluenesulfonamide derivative preparation process to the environment is reduced.
(4) According to the method for preparing the octahydroacridine p-toluenesulfonamide derivative by the acidic ionic liquid catalysis, the usage amount of the catalyst and the process parameters in the reaction process are strictly controlled, so that the occurrence of side reactions can be effectively reduced, the catalytic activity of the catalyst is best exerted, the yield and the purity of the obtained product are further ensured, and the impurity content is reduced.
(5) According to the method for preparing the octahydroacridine p-toluenesulfonamide derivative by using the acidic ionic liquid as the catalyst, the filtrate obtained after the reaction is finished can be directly added into the reaction raw material for cyclic reaction, the catalyst system does not need to be subjected to any treatment before cyclic use, the operation is simple, and the yield of the product obtained by using the catalyst in the cyclic use is not changed greatly.
(6) According to the method for preparing the octahydroacridine p-toluenesulfonamide derivative by catalyzing the acidic ionic liquid, the reaction solvent and the catalyst can be reused, and almost zero emission of waste liquid is realized; and the whole preparation process is simple, convenient, economic and convenient to popularize and apply.
Drawings
FIG. 1 is a schematic diagram showing the effect of the number of times of recycling of the catalytic system on the purity and yield of the product in example 1;
FIG. 2 is a schematic diagram showing the effect of the number of times of recycling of the catalytic system on the purity and yield of the product in example 2;
FIG. 3 is a schematic representation of the effect of the number of catalytic system cycles on product purity and yield in example 7;
FIG. 4 is a schematic representation of the effect of the number of catalytic system cycles on product purity and yield in example 8.
Detailed Description
Aiming at the defects that in the prior art, the catalyst cannot be recycled, the usage amount is large, the product purification is complex and the industrial large-scale continuous production cannot be realized in the process of preparing the pharmaceutical intermediate octahydroacridine p-toluenesulfonamide derivative by adopting a one-pot method, the invention adopts the Bronsted acidic ionic liquid as the catalyst to prepare the octahydroacridine p-toluenesulfonamide derivative, thereby effectively solving the defect problems. The ionic liquid is a liquid composed of ions, is a liquid salt at low temperature (<100 ℃), and is composed of an anion part and a cation part. Conventional ionic compounds can be converted into a liquid state only when a certain temperature is reached, and ionic liquids are liquid states in a wide temperature range around room temperature. The ionic liquid has extremely low vapor pressure, is not easy to volatilize, is non-toxic, is not flammable and explosive, has higher thermal stability and chemical stability, and under the coexistence of the ionic association and the solvation effect, the hydrogen bond, the ions, the ion cluster and other structures in the system increase the solubility of reactants in the ionic liquid and promote the reaction. Therefore, the ionic liquid is well applied to the preparation of the drug intermediate. In addition, the acidic ionic liquid as an important functionalized ionic liquid has the advantages of good catalytic activity, high selectivity, easiness in recovery and the like, and is an environment-friendly acidic catalyst with a good application prospect.
In view of the above, the applicant develops a one-pot method for preparing a high-purity, high-yield, high-economic-benefit and environment-friendly preparation method by using a specific acidic ionic liquid as a green catalyst and using an aqueous solution of a volatile organic solvent as a reaction solvent and a recrystallization solvent according to the defects of the existing preparation technology of the octahydroacridine p-toluenesulfonamide derivative and the characteristics of the acidic ionic liquid. In particular, the invention uses the Bronsted acidic ionic liquid with high catalytic activity as the catalyst, can effectively reduce the using amount of the catalyst, and can realize the recycling of the catalyst. Meanwhile, by adopting the isopropanol-dimethylformamide-distilled water mixed solvent as the reaction solvent, the purification process of the product can be simplified, the catalytic system formed by the isopropanol-dimethylformamide-distilled water mixed solvent and the Bronsted acidic ionic liquid catalyst can effectively improve the catalytic efficiency and catalytic selectivity of the catalytic system, the aim of recycling the reaction solvent is fulfilled, the production cost is greatly saved, and the pollution degree of the octahydroacridine to the toluene sulfonamide derivative preparation process to the environment is reduced.
The invention is further described with reference to specific examples.
Example 1
A50 ml three-necked flask with a spherical condenser, a thermometer and a stirrer, which contains 7ml of a mixed solvent (isopropanol-dimethylformamide-distilled water in a volume ratio of 8: 3: 1), was charged with 1.0mmol of benzaldehyde, 1.0mmol of p-toluenesulfonylhydrazide, 2.4mmol of 1, 3-cyclohexanedione, stirred at room temperature, mixed well, and then 0.08mmol of Bronsted acidic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining the reflux temperature for reaction for 13min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (4ml multiplied by 3 times) and dried for 24H under the temperature of 85 ℃, 0.39g N- (1, 8-dioxo-9-phenyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide is obtained, the purity is 99.2 percent by high performance liquid chromatography, and the calculated yield is 84 percent. Benzaldehyde, p-toluenesulfonyl hydrazide and 1, 3-cyclohexanedione are directly added into the filtrate for reuse.
Example 2
A50 ml three-necked flask with a spherical condenser, a thermometer and a stirrer, which contains 7ml of a mixed solvent (isopropanol-dimethylformamide-distilled water volume ratio is 8: 2: 1), is charged with 1.0mmol of benzaldehyde, 1.0mmol of p-toluenesulfonyl hydrazide, 2.0mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.06mmol of Bronsted acidic ionic liquid catalyst is added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining the reflux temperature for reaction for 9min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (5ml multiplied by 3 times), vacuum drying is carried out at 85 ℃ for 24H, 0.50g of 4-methyl-N- (3, 3, 6, 6-tetramethyl-1, 8-dioxo-9-phenyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) benzenesulfonamide is obtained, the purity is 98.7 percent and the calculated yield is 95 percent as determined by high performance liquid chromatography. Benzaldehyde, p-toluenesulfonyl hydrazide and 5, 5-dimethyl-1, 3-cyclohexanedione are directly added into the filtrate for reuse.
Example 3
A50 ml three-necked flask with a spherical condenser, a thermometer and a stirrer, which contains 7ml of a mixed solvent (isopropanol-dimethylformamide-distilled water in a volume ratio of 8: 3: 1), was charged with 1.0mmol of p-chlorobenzaldehyde, 1.0mmol of p-toluenesulfonyl hydrazide and 2.3mmol of 1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.07mmol of Bronsted acidic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining the reflux temperature for reaction for 12min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (4ml multiplied by 3 times), vacuum drying is carried out at 85 ℃ for 24H, then 0.43g N- (9- (4-chlorphenyl) -1, 8-dioxo-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide is obtained, the purity is 98.9 percent by high performance liquid chromatography, and the calculated yield is 86 percent. Directly adding p-chlorobenzaldehyde, p-toluenesulfonyl hydrazide and 1, 3-cyclohexanedione into the filtrate for reuse.
Example 4
A50 ml three-necked flask with a spherical condenser, a thermometer and a stirrer, which contains 7ml of a mixed solvent (isopropanol-dimethylformamide-distilled water volume ratio is 8: 2: 1), is added with 1.0mmol of p-chlorobenzaldehyde, 1.0mmol of p-toluenesulfonyl hydrazide and 2.0mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.05mmol of Bronsted acidic ionic liquid catalyst is added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining the reflux temperature for reaction for 9min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (5ml multiplied by 3 times), vacuum drying is carried out at 85 ℃ for 24H, then 0.54g N- (9- (4-chlorphenyl) -3, 3, 6, 6-tetramethyl-1, 8-dioxo-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide is obtained, the purity is 98.5 percent by high performance liquid chromatography, and the calculated yield is 96 percent. Directly adding p-chlorobenzaldehyde, p-toluenesulfonyl hydrazide and 5, 5-dimethyl-1, 3-cyclohexanedione into the filtrate for reuse.
Example 5
To a 50ml three-necked flask equipped with a spherical condenser, a thermometer and a stirrer, containing 8ml of a mixed solvent (isopropanol-dimethylformamide-distilled water in a volume ratio of 8: 1: 1) were added 1.0mmol of p-tolualdehyde, 1.0mmol of p-toluenesulfonylhydrazide and 2.4mmol of 1, 3-cyclohexanedione, and the mixture was stirred at room temperature, mixed uniformly, and then 0.07mmol of Bronsted acidic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining the reflux temperature for reaction for 14min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (5ml multiplied by 3 times), vacuum drying is carried out at 85 ℃ for 24H, then 0.41g N- (1, 8-dioxo-9- (4-methylphenyl) -1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide is obtained, the purity is 98.1 percent by high performance liquid chromatography, and the calculated yield is 84 percent. And directly adding p-methylbenzaldehyde, p-toluenesulfonyl hydrazide and 1, 3-cyclohexanedione into the filtrate for reuse.
Example 6
To a 50ml three-necked flask equipped with a spherical condenser, a thermometer and a stirrer, containing 8ml of a mixed solvent (isopropanol-dimethylformamide-distilled water in a volume ratio of 8: 1: 1) were added 1.0mmol of p-tolualdehyde, 1.0mmol of p-toluenesulfonylhydrazide, 2.4mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.06mmol of Bronsted acidic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent refluxes (the solvent vapor does not exceed the second ball of the spherical condenser tube), keeping the reflux temperature for reaction for 10min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (6ml multiplied by 3 times), vacuum drying is carried out at 85 ℃ for 24H, 0.51g of 4-methyl-N- (3, 3, 6, 6-tetramethyl-1, 8-dioxo-9- (4-methylphenyl) -1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) benzenesulfonamide is obtained, the purity is 98.8 percent by high performance liquid chromatography, and the calculated yield is 94 percent. P-tolualdehyde, p-toluenesulfonyl hydrazide and 5, 5-dimethyl-1, 3-cyclohexanedione are directly added to the filtrate for reuse.
Example 7
To a 50ml three-necked flask equipped with a spherical condenser, a thermometer and a stirrer, containing 8ml of a mixed solvent (isopropanol-dimethylformamide-distilled water in a volume ratio of 8: 1: 1) were added 1.0mmol of p-methoxybenzaldehyde, 1.0mmol of p-toluenesulfonylhydrazide and 2.5mmol of 1, 3-cyclohexanedione, and the mixture was stirred at room temperature, mixed uniformly, and then 0.08mmol of Bronsted acidic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining the reflux temperature for reaction for 14min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (5ml multiplied by 3 times), vacuum drying is carried out at 85 ℃ for 24H, then 0.43g N- (9- (4-methoxyphenyl) -1, 8-dioxo-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide is obtained, the purity is 98.4 percent by high performance liquid chromatography, and the calculated yield is 86 percent. Directly adding p-methoxybenzaldehyde, p-toluenesulfonyl hydrazide and 1, 3-cyclohexanedione into the filtrate for reuse.
Example 8
To a 50ml three-necked flask equipped with a spherical condenser, a thermometer and a stirrer, containing 9ml of a mixed solvent (isopropanol-dimethylformamide-distilled water in a volume ratio of 8: 1: 1) were added 1.0mmol of p-methoxybenzaldehyde, 1.0mmol of p-toluenesulfonylhydrazide, 2.2mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.07mmol of Bronsted acidic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining the reflux temperature for reaction for 11min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (6ml multiplied by 3 times), vacuum drying is carried out at 85 ℃ for 24H, then 0.52g N- (9- (4-methoxyphenyl) -3, 3, 6, 6-tetramethyl-1, 8-dioxo-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide is obtained, the purity is 98.8 percent by high performance liquid chromatography, and the calculated yield is 94 percent. Directly adding p-methoxybenzaldehyde, p-toluenesulfonyl hydrazide and 5, 5-dimethyl-1, 3-cyclohexanedione into the filtrate for reuse.
Example 9
A50 ml three-necked flask with a spherical condenser, a thermometer and a stirrer, which contains 5ml of a mixed solvent (isopropanol-dimethylformamide-distilled water in a volume ratio of 8: 4: 1), is charged with 1.0mmol of p-nitrobenzaldehyde, 1.0mmol of p-toluenesulfonyl hydrazide and 2.3mmol of 1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.07mmol of Bronsted acidic ionic liquid catalyst is added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining the reflux temperature for reaction for 13min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (4ml multiplied by 3 times), vacuum drying is carried out at 85 ℃ for 24H, 0.46g of 4-methyl-N- (9- (4-nitrophenyl) -1, 8-dioxo-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) benzenesulfonamide is obtained, the purity is 98.2 percent and the calculated yield is 89 percent by high performance liquid chromatography. Directly adding p-nitrobenzaldehyde, p-toluenesulfonyl hydrazide and 1, 3-cyclohexanedione into the filtrate for reuse.
Example 10
A50 ml three-necked flask with a spherical condenser, a thermometer and a stirrer, which contains 6ml of a mixed solvent (isopropanol-dimethylformamide-distilled water volume ratio is 8: 3: 1), is added with 1.0mmol of p-nitrobenzaldehyde, 1.0mmol of p-toluenesulfonyl hydrazide and 2.1mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.05mmol of Bronsted acidic ionic liquid catalyst is added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining the reflux temperature for reaction for 7min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (4ml multiplied by 3 times) and dried for 24H under 85 ℃ in vacuum, 0.56g of 4-methyl-N- (3, 3, 6, 6-tetramethyl-9- (4-nitrophenyl) -1, 8-dioxo-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) benzenesulfonamide is obtained, the purity is 98.0 percent and the calculated yield is 98 percent by high performance liquid chromatography. Directly adding p-nitrobenzaldehyde, p-toluenesulfonyl hydrazide and 5, 5-dimethyl-1, 3-cyclohexanedione into the filtrate for reuse.
Example 11
To a 50ml three-necked flask equipped with a spherical condenser, a thermometer and a stirrer, which was charged with 8ml of a mixed solvent (isopropanol-dimethylformamide-distilled water in a volume ratio of 8: 2: 1), 1.0mmol of p-hydroxybenzaldehyde, 1.0mmol of p-toluenesulfonylhydrazide and 2.6mmol of 1, 3-cyclohexanedione were added, and the mixture was stirred at room temperature, mixed uniformly, and then 0.09mmol of Bronsted acidic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining the reflux temperature for reaction for 15min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (5ml multiplied by 3 times), vacuum drying is carried out at 85 ℃ for 24H, then 0.41g N- (9- (4-hydroxyphenyl) -1, 8-dioxo-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide is obtained, the purity is 99.2 percent by high performance liquid chromatography, and the calculated yield is 85 percent. The filter liquor is directly added with p-hydroxybenzaldehyde, p-toluenesulfonyl hydrazide and 1, 3-cyclohexanedione for reuse.
Example 12
To a 50ml three-necked flask equipped with a spherical condenser, a thermometer and a stirrer, containing 8ml of a mixed solvent (isopropanol-dimethylformamide-distilled water in a volume ratio of 8: 1: 1) were added 1.0mmol of p-hydroxybenzaldehyde, 1.0mmol of p-toluenesulfonylhydrazide, 2.5mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.08mmol of Bronsted acidic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining the reflux temperature for reaction for 13min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (5ml multiplied by 3 times), vacuum drying is carried out at 85 ℃ for 24H, then 0.49g N- (9- (4-hydroxyphenyl) -3, 3, 6, 6-tetramethyl-1, 8-dioxo-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide is obtained, the purity is 98.4 percent by high performance liquid chromatography, and the calculated yield is 91 percent. P-hydroxybenzaldehyde, p-toluenesulfonyl hydrazide and 5, 5-dimethyl-1, 3-cyclohexanedione are directly added into the filtrate for reuse.
Example 13
To a 50ml three-necked flask equipped with a spherical condenser, a thermometer and a stirrer, containing 8ml of a mixed solvent (isopropanol-dimethylformamide-distilled water in a volume ratio of 8: 1: 1) were added 1.0mmol of p-hydroxybenzaldehyde, 1.0mmol of p-toluenesulfonylhydrazide, 2.5mmol of 5, 5-dimethyl-1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.08mmol of Bronsted acidic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining the reflux temperature for reaction for 13min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (4ml multiplied by 3 times), vacuum drying is carried out at 88 ℃ for 23H, then 0.48g N- (9- (4-hydroxyphenyl) -3, 3, 6, 6-tetramethyl-1, 8-dioxo-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridine-10 (9H) -yl) -4-toluenesulfonamide is obtained, the purity is 98.41% by high performance liquid chromatography, and the calculated yield is 88%. P-hydroxybenzaldehyde, p-toluenesulfonyl hydrazide and 5, 5-dimethyl-1, 3-cyclohexanedione are directly added into the filtrate for reuse.
Example 14
To a 50ml three-necked flask equipped with a spherical condenser, a thermometer and a stirrer, containing 8ml of a mixed solvent (isopropanol-dimethylformamide-distilled water in a volume ratio of 8: 3: 1), 1.0mmol of p-hydroxybenzaldehyde, 1.0mmol of p-toluenesulfonylhydrazide, 2.5mmol of 5, 5-dimethyl-1, 3-cyclohexanedione were added, stirred at room temperature, mixed uniformly, and then 0.08mmol of a Bronsted acidic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser tube), maintaining the reflux temperature for reaction for 13min, and monitoring by TLC (thin-plate chromatography) to finish the reaction. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a large amount of yellow crystals are separated out, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (4ml multiplied by 3 times), vacuum drying is carried out at 90 ℃ for 22H, then 0.46g N- (9- (4-hydroxyphenyl) -3, 3, 6, 6-tetramethyl-1, 8-dioxo-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide is obtained, the purity is 97.49 percent by high performance liquid chromatography, and the calculated yield is 85 percent. P-hydroxybenzaldehyde, p-toluenesulfonyl hydrazide and 5, 5-dimethyl-1, 3-cyclohexanedione are directly added into the filtrate for reuse.
Comparative example 1
A50 ml three-necked flask containing 7ml of isopropyl alcohol and equipped with a spherical condenser, a thermometer and a stirrer was charged with 1.0mmol of benzaldehyde, 1.0mmol of p-toluenesulfonylhydrazide and 2.4mmol of 1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.08mmol of Bronsted acidic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser), maintaining the reflux temperature for reaction for 13min, and detecting by TLC (thin-plate chromatography) to find that the raw material point is remained. Heating and stirring are stopped, the reaction liquid is naturally cooled to room temperature, a small amount of yellow crystals are precipitated, the solid is crushed, the reaction liquid is kept stand for 24H, vacuum filtration is carried out, filter residues are washed by absolute ethyl alcohol (4ml multiplied by 3 times) and dried for 24H under 85 ℃, 0.29g of light yellow solid is obtained, according to the high performance liquid chromatography, the purity of the product N- (1, 8-dioxo-9-phenyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide is 68.1 percent, and the calculated yield is 43 percent.
Comparative example 2
A50 ml three-necked flask containing 7ml of dimethylformamide and equipped with a spherical condenser, a thermometer and a stirrer was charged with 1.0mmol of benzaldehyde, 1.0mmol of p-toluenesulfonylhydrazide and 2.4mmol of 1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.08mmol of Bronsted acidic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser), maintaining the reflux temperature for reaction for 13min, and detecting by TLC (thin-plate chromatography) to find that the raw material point is remained. The heating and the stirring are closed, the reaction liquid is naturally cooled to the room temperature, and no solid is precipitated. The purity of the product N- (1, 8-dioxo-9-phenyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide in the reaction solution was determined by high performance liquid chromatography to be 9.7%, and the calculated yield was 18%.
Comparative example 3
A50 ml three-necked flask containing 7ml of distilled water and equipped with a spherical condenser, a thermometer and a stirrer was charged with 1.0mmol of benzaldehyde, 1.0mmol of p-toluenesulfonylhydrazide and 2.4mmol of 1, 3-cyclohexanedione, stirred at room temperature, mixed uniformly, and then 0.08mmol of Bronsted acidic ionic liquid catalyst was added. Heating in oil bath, uniformly heating until the solvent reflux (the solvent vapor does not exceed the second ball of the spherical condenser), maintaining the reflux temperature for reaction for 13min, and detecting by TLC (thin-plate chromatography) to find that the raw material point is remained. The heating and the stirring are closed, the reaction liquid is naturally cooled to the room temperature, and no solid is precipitated. The purity of the product N- (1, 8-dioxo-9-phenyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide in the reaction solution was 4.2% by HPLC, calculated yield was 6%.
The influence of the number of times of using the catalyst system composed of the mixed solvent and the Bronsted acidic ionic liquid in example 1, example 2, example 7 and example 8 on the purity and yield of the product N- (1, 8-dioxo-9-phenyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide was examined, and the results are shown in FIG. 1, FIG. 2, FIG. 3 and FIG. 4, respectively.
As can be seen by combining comparative examples 1-3 and FIGS. 1-4, when the catalyst is a Bronsted acidic ionic liquid catalyst and the reaction solvent is a mixture of isopropanol, dimethylformamide and distilled water, the purity and yield of the product N- (1, 8-dioxo-9-phenyl-1, 2, 3, 4, 5, 6, 7, 8-octahydroacridin-10 (9H) -yl) -4-toluenesulfonamide can be further improved. Meanwhile, the catalyst and the reaction solvent have good recycling effect, can be reused for more than 4 times at least, and the purity and yield of the obtained product are reduced.
Claims (9)
1. A method for preparing octahydroacridine p-toluenesulfonamide derivatives by acidic ionic liquid catalysis is characterized in that: adding aromatic aldehyde, p-toluenesulfonyl hydrazide, a 1, 3-cyclohexanedione compound and a Bronsted acidic ionic liquid catalyst into a reaction solvent respectively, and then reacting at a reflux temperature to obtain an octahydroacridine p-toluenesulfonamide derivative; the structural formula of the Bronsted acidic ionic liquid catalyst is as follows:
2. the method for preparing the octahydroacridine p-toluenesulfonamide derivative under the catalysis of the acidic ionic liquid according to claim 1, wherein the acidic ionic liquid comprises the following steps: the molar weight of the Bronsted acidic ionic liquid catalyst is 5-9% of that of the aromatic aldehyde.
3. The method for preparing the octahydroacridine p-toluenesulfonamide derivative under the catalysis of the acidic ionic liquid according to claim 1, wherein the acidic ionic liquid comprises the following steps: the molar ratio of aromatic aldehyde, p-toluenesulfonyl hydrazide and a 1, 3-cyclohexanedione compound in the reaction raw materials is 1: 1: (2-2.6).
4. The method for preparing the octahydroacridine p-toluenesulfonamide derivative under the catalysis of the acidic ionic liquid according to claim 1, wherein the acidic ionic liquid comprises the following steps: the reaction solvent is a mixed solution composed of isopropanol, dimethylformamide and distilled water, wherein the volume ratio of the isopropanol, the dimethylformamide and the distilled water is 8: (1-4): 1.
5. the method for preparing the octahydroacridine p-toluenesulfonamide derivative under the catalysis of the acidic ionic liquid according to any one of claims 1 to 4, wherein the acidic ionic liquid comprises the following steps: the volume of the reaction solvent in ml is 5 to 9 times the amount of the aromatic aldehyde substance in mmol.
6. The method for preparing the octahydroacridine p-toluenesulfonamide derivative under the catalysis of the acidic ionic liquid according to claim 5, wherein the acidic ionic liquid comprises the following steps: stirring and mixing the reaction solution uniformly at room temperature, heating uniformly to reflux temperature, reacting at the reflux temperature, and purifying the reaction solution after the reaction is finished.
7. The method for preparing the octahydroacridine p-toluenesulfonamide derivative under the catalysis of the acidic ionic liquid according to claim 6, wherein the reaction liquid is heated to the reflux temperature by adopting an oil bath, the reaction time is 7-15 min, and the reaction pressure is controlled to be one atmospheric pressure.
8. The method for preparing the octahydroacridine p-toluenesulfonamide derivative under the catalysis of the acidic ionic liquid according to claim 7, wherein the specific purification operation comprises the following steps: after the reaction is finished, cooling the reaction liquid to room temperature, grinding, standing and filtering the precipitated solid; washing and vacuum drying filter residues to obtain a purified octahydroacridine p-toluenesulfonamide derivative; the filtrate can be directly added with reaction raw materials for the next reaction.
9. The method for preparing the octahydroacridine p-toluenesulfonamide derivative under the catalysis of the acidic ionic liquid according to claim 8, wherein the acidic ionic liquid comprises the following steps: washing filter residue obtained by suction filtration after the reaction is finished by using absolute ethyl alcohol; and then drying the mixture in vacuum for 22-24 hours at 85-90 ℃.
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| CN103193707A (en) * | 2013-04-18 | 2013-07-10 | 安徽工业大学 | Method for preparing 9-aryl multi-hydrogen acridine ramification through catalysis |
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| CN103193707A (en) * | 2013-04-18 | 2013-07-10 | 安徽工业大学 | Method for preparing 9-aryl multi-hydrogen acridine ramification through catalysis |
| CN111393440A (en) * | 2020-05-08 | 2020-07-10 | 马鞍山市泰博化工科技有限公司 | Method for preparing pharmaceutical intermediate 5,10-diaryl pyrido [4,3-b ] [1,6] naphthyridine derivative |
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