Method for synthesizing 1-aryl-3-alkyl-4-acyl-5-pyrazolone through continuous flow
1-aryl-3-alkyl-4-acyl-5-pyrazolinone is synthesized in one step through microchannel continuous flow technology, solving the complex and cost-effective synthesis methods in the prior art, and achieving efficient and environmentally friendly compound production.
Patent Information
- Application Number
- CN202510356343.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-25
- Publication Date
- 2025-07-04
Smart Images
Figure CN120247802A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pyrazolone compound synthesis, and particularly relates to a method for continuously synthesizing 1-aryl-3-alkyl-4-acyl-5-pyrazolone. Background Art
[0002] 5-Pyrazolone compounds are a class of five-membered lactam heterocyclic compounds with multiple substitution positions, widely present in natural products and drug molecules, and have broad antibacterial and biological activities. Among them, 1-aryl-3-alkyl-4-acyl-5-pyrazolone compounds are widely used in analytical chemistry, radiochemistry, biomedicine, and luminescent materials. In analytical chemistry, it is often used as a chelating agent for the determination of the total amount of trace rare earth elements in steel and non-ferrous metals. In radiochemistry, it is often used as a metal extractant to extract and separate radioactive metals such as uranium, plutonium, americium, neptunium, and thorium. In chemical synthesis, the metal complexes obtained after its coordination with metals have anti-cancer, anti-tumor, antibacterial, and anti-inflammatory effects in medicine. In addition, the chelates obtained after the complexation of 1-aryl-3-alkyl-4-acyl-5-pyrazolone compounds with ternary lanthanide metals have good electroluminescent properties.
[0003] Currently, 1-aryl-3-alkyl-4-acyl-5-pyrazolone compounds are usually obtained by reacting arylhydrazine with dicarbonyl compounds at high temperature to obtain an intermediate. After separation and purification, the target product is obtained by reacting with an acyl chloride compound under the action of a base. This method requires the separation and purification of the intermediate, has complex post-treatment, high production cost, low yield, and a large amount of "three wastes". Therefore, it is difficult to carry out large-scale production. Summary of the Invention
[0004] In order to solve the above technical problems, a method for continuously synthesizing 1-aryl-3-alkyl-4-acyl-5-pyrazolone is provided. The method of the present invention uses microchannel continuous flow technology to efficiently obtain the target product in one step, with simple operation, simple raw materials, high yield, high purity, and less three wastes.
[0005] To achieve the above object, the present invention is realized through the following technical solutions:
[0006] A method for continuously synthesizing 1-aryl-3-alkyl-4-acyl-5-pyrazolone, comprising the following steps:
[0007]
[0008] The arylhydrazine compound and the dicarbonyl compound are fed into the first group of microchannel continuous flow reactors for the first reaction. After the reaction, the material flowing out of the first group of microchannel continuous flow reactors is mixed with the emulsified calcium hydroxide emulsion and simultaneously fed into the second group of microchannel continuous flow reactors for the second reaction. After the reaction, the material flowing out of the second group of microchannel continuous flow reactors is mixed with the acyl chloride reagent and simultaneously fed into the third group of microchannel continuous flow reactors for the third reaction. The reaction solution flowing out of the third group of microchannel continuous flow reactors is collected, cooled, and post-treated to obtain 1-aryl-3-alkyl-4-acyl-5-pyrazolone;
[0009] wherein R of the dicarbonyl compound 1 is selected from one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl, tert-butyl, phenyl; R of the arylhydrazine compound 2 is selected from one of hydrogen atom, methyl, ethyl, n-butyl, tert-butyl, benzyl, methoxy; R in the acyl chloride reagent 3 is selected from one of C1-C10 normal alkyl, C1-C10 isoalkyl, C1-C10 isoalkyl containing cycloalkyl, C1-C10 straight-chain alkyl containing cycloalkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl, cyclobutyl, methylene tert-butyl, ethyl cyclopentyl, phenyl, furyl, etc.
[0010] Furthermore, the temperature of the first reaction is 60-100 °C, and the residence time for the first reaction in the first group of microchannel continuous flow reactors is 85-300 seconds;
[0011] The temperature of the second reaction is 60-100 °C, and the residence time for the second reaction in the second group of microchannel continuous flow reactors is 25-50 seconds;
[0012] The temperature of the third reaction is 60-100 °C, and the residence time for the third reaction in the second group of microchannel continuous flow reactors is 12-50 seconds.
[0013] Still further, the molar ratio of the arylhydrazine compound, the dicarbonyl compound, calcium hydroxide, and the acyl chloride reagent is 1:1:4:2.
[0014] Still further, the flow rate of the arylhydrazine compound is 10-30 mL / min;
[0015] The flow rate of the dicarbonyl compound is 12-40 mL / min;
[0016] The flow rate of the calcium hydroxide emulsion is 50-150 mL / min;
[0017] The flow rate of the acyl chloride reagent is 25 - 100 mL / min.
[0018] Furthermore, the emulsified calcium hydroxide emulsion is formed by mixing calcium hydroxide with absolute ethanol, emulsifying first and then performing ultrasonic treatment. The molar concentration of the calcium hydroxide emulsion is 5 - 15 mol / L.
[0019] Furthermore, the post-treatment is successively adding 1.5 - 5 mol / L hydrochloric acid aqueous solution for acidification at a temperature below 5°C, chloroform extraction, drying, concentration, and recrystallization.
[0020] Beneficial technical effects:
[0021] In the present invention, the ethanol solution of calcium hydroxide is emulsified, ultrasonically treated, and then introduced into a microchannel reactor to be mixed with the materials of the first reaction, solving the problem that the current microchannel reactor cannot handle solid materials and realizing for the first time the continuous reaction of solid-liquid two phases in the microchannel; one-step synthesis is carried out in the microchannel continuous flow reactor, and the intermediate product does not need to be separated; after the reaction is completed, 1-aryl-3-alkyl-4-acyl-5-pyrazolone can be obtained only by simple quenching, extraction, and recrystallization; the continuous flow synthesis method of 1-aryl-3-alkyl-4-acyl-5-pyrazolone of the present invention has one-step synthesis, simple operation, simple raw materials, relatively mild reaction conditions, high yield, high purity, less three wastes, easier post-treatment, is green and environmentally friendly, and is suitable for large-scale industrial production. Description of the Drawings
[0022] Figure 1 It is a process schematic diagram of the continuous flow synthesis of 1-aryl-3-alkyl-4-acyl-5-pyrazolone of the present invention, where ① is a plunger pump, ② is the first group of microchannel reactors, ③ is the second group of microchannel reactors, and ④ is the third group of microchannel reactors. Specific Embodiments
[0023] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the embodiments and drawings of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. The following description of at least one exemplary embodiment is actually only illustrative and in no way limits the present invention and its application or use. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.
[0024] Unless otherwise specifically stated, the numerical values set forth in these embodiments do not limit the scope of the present invention. Technologies and methods known to those of ordinary skill in the relevant art may not be discussed in detail, but where appropriate, such technologies and methods should be regarded as part of the specification. In all the examples shown and discussed herein, any specific values should be construed as merely exemplary and not as a limitation. Therefore, other examples of the exemplary embodiments may have different values.
[0025] In addition, it should be noted that the use of terms such as "first" and "second" to define reactions is only for the convenience of distinguishing each reaction step. Without additional declaration, the above terms have no special meaning and therefore cannot be construed as a limitation on the protection scope of the present invention.
[0026] For the experimental methods without specific conditions indicated in the following embodiments, they are generally determined according to national standards; if there is no corresponding national standard, they are carried out according to general standard requirements or general methods.
[0027] The microchannel continuous flow reactor, the first group of microchannel reactors ② consists of five glass chips, the second group of microchannel reactors ③ consists of three glass chips, and the third group of microchannel reactors ④ consists of two glass chips. The liquid holding capacity of each glass chip is 20 mL.
[0028] The residence time refers to the time required for the material to pass through the continuous flow reactor. The specific calculation method is: residence time = liquid holding volume × (60 s / min) / total volume flow rate; the liquid holding volume is the capacity of the continuous flow reactor, and the fixed value for a single chip is 20 mL; the total volume flow rate is equal to the sum of the flow rates of each injection pump.
[0029] Example 1
[0030] Method for continuously synthesizing 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone:
[0031] 1) Hydrazine benzene (98 mL, 1 mol) and ethyl acetoacetate (126 mL, 1 mol) were introduced into the first group of microchannel continuous flow reactors by a plunger pump, and the set flow rates were 20 mL / min and 25 mL / min respectively. The temperature of the first group of microchannel continuous flow reactors was set at 60 °C, and the residence time of the material in the first group of reactors was 133 s.
[0032] 2) Preparation of calcium hydroxide ethanol emulsion: Calcium hydroxide (160 g, 4 mol) was added to 400 mL of absolute ethanol, transferred to an emulsifier for emulsification to prepare a calcium hydroxide ethanol emulsion, and it was placed in an ultrasonic device for ultrasonic treatment.
[0033] 3) The materials flowing out from the first group of microchannel continuous flow reactors and the calcium hydroxide ethanol emulsion are simultaneously introduced into the second group of microchannel continuous flow reactors. The flow rate of the calcium hydroxide ethanol emulsion is set at 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set at 60 °C, and the residence time of the materials in the second group of reactors is 25 s.
[0034] 4) The materials flowing out from the second group of continuous flow microchannel continuous flow reactors and benzoyl chloride (230 mL, 2 mol) are simultaneously introduced into the third group of microchannel continuous flow reactors. The flow rate of benzoyl chloride is set at 50 mL / min, the temperature of the third group of microchannel continuous flow reactors is set at 60 °C, and the residence time of the materials in the third group of reactors is 12 s.
[0035] 5) Collect the reaction solution in the third group of microchannel continuous flow reactors, transfer it to a 10 L reaction kettle, cool it to room temperature, cool the reaction solution to 0 °C, slowly add 2.5 M hydrochloric acid aqueous solution (1.6 L, 4 mol HCl), extract with chloroform, collect the organic phase, dry the organic phase with anhydrous magnesium sulfate, concentrate it, and cool and crystallize to obtain 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone, with a yield of 93 wt% (purity at least 99%).
[0036] The chemical structure of the product 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone in this case is as follows:
[0037]
[0038] The 1H NMR data thereof are as follows. 1 1H NMR (CDCl3, 500 MHz, δ; ppm): 7.88 (2H, d, J = 8.1 Hz), 7.65 (2H, d, J = 7.6 Hz), 7.58 (1H, t, J = 7.5 Hz), 7.52 (2H, t, J = 7.5 Hz), 7.47 (2H, t, J = 8.1 Hz), 7.31 (1H, t, J = 7.3 Hz), 2.10 (3H, s).
[0039] Example 2
[0040] Method for continuously synthesizing 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone:
[0041] 1) Hydrazine phenyl (98 mL, 1 mol) and ethyl acetoacetate (126 mL, 1 mol) are introduced into the first group of microchannel continuous flow reactors by using a plunger pump, and the set flow rates are 20 mL / min and 25 mL / min respectively. The temperature of the first group of microchannel continuous flow reactors is set at 40 °C, and the residence time of the materials in the first group of reactors is 133 s.
[0042] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160 g, 4 mol) to 400 mL of absolute ethanol, transfer it to an emulsifier for emulsification to prepare a calcium hydroxide ethanol emulsion, and place it in an ultrasonic device for ultrasonic treatment.
[0043] 3) The materials flowing out of the first group of microchannel continuous flow reactors and the calcium hydroxide ethanol emulsion are simultaneously introduced into the second group of microchannel continuous flow reactors. The flow rate of the calcium hydroxide ethanol emulsion is set at 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set at 40 °C, and the residence time of the materials in the second group of reactors is 25 s.
[0044] 4) The materials flowing out of the second group of continuous flow microchannel reactors and benzoyl chloride (230 mL, 2 mol) are simultaneously introduced into the third group of microchannel continuous flow reactors. The flow rate of benzoyl chloride is set at 50 mL / min, the temperature of the third group of microchannel continuous flow reactors is set at 40 °C, and the residence time of the materials in the third group of reactors is 12 s.
[0045] 5) Collect the reaction solution in the third group of microchannel continuous flow reactors, transfer it to a 10 L reaction kettle, cool it to room temperature, cool the reaction solution to 0 °C, slowly add 2.5 M hydrochloric acid aqueous solution (1.6 L, 4 mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, and then cool and crystallize to obtain 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone with a yield of 76 wt% (purity at least 99%).
[0046] Example 3
[0047] Method for continuously synthesizing 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone:
[0048] 1) Hydrazobenzene (98 mL, 1 mol) and ethyl acetoacetate (126 mL, 1 mol) are introduced into the first group of microchannel continuous flow reactors by a plunger pump, and the set flow rates are 20 mL / min and 25 mL / min respectively. The temperature of the first group of microchannel continuous flow reactors is set at 80 °C, and the residence time of the materials in the first group of reactors is 133 min.
[0049] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160 g, 4 mol) to 400 mL of absolute ethanol, transfer it to an emulsifier for emulsification to prepare a calcium hydroxide ethanol emulsion, and place it in an ultrasonic device for ultrasonic treatment.
[0050] 3) The materials flowing out from the first group of microchannel continuous flow reactors and the calcium hydroxide ethanol emulsion are simultaneously introduced into the second group of microchannel continuous flow reactors. The flow rate of the calcium hydroxide ethanol emulsion is set at 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set at 80 °C, and the residence time of the materials in the second group of reactors is 25 s.
[0051] 4) The materials flowing out from the second group of continuous flow microchannel reactors and benzoyl chloride (230 mL, 2 mol) are simultaneously introduced into the third group of microchannel continuous flow reactors. The flow rate of benzoyl chloride is set at 50 mL / min, the temperature of the third group of microchannel continuous flow reactors is set at 80 °C, and the residence time of the materials in the third group of reactors is 12 s.
[0052] 5) Collect the reaction solution in the third group of microchannel continuous flow reactors, transfer it to a 10 L reaction kettle, cool it to room temperature, cool the reaction solution to 0 °C, slowly add 2.5 M hydrochloric acid aqueous solution (1.6 L, 4 mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, and cool it to crystallize to obtain 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone, with a yield of 92 wt% (purity at least 99%).
[0053] Example 4
[0054] Method for continuously synthesizing 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone:
[0055] 1) Hydrazine benzene (98 mL, 1 mol) and ethyl acetoacetate (126 mL, 1 mol) are introduced into the first group of microchannel continuous flow reactors by using a plunger pump, and the set flow rates are 20 mL / min and 25 mL / min respectively. The temperature of the first group of microchannel continuous flow reactors is set at 100 °C, and the residence time of the materials in the first group of reactors is 133 s.
[0056] 2) Preparation of calcium hydroxide ethanol emulsion: Calcium hydroxide (160 g, 4 mol) is added to 400 mL of anhydrous ethanol, transferred to an emulsifier for emulsification to prepare a calcium hydroxide ethanol emulsion, and it is placed in an ultrasonic device for ultrasonic treatment.
[0057] 3) The materials flowing out from the first group of microchannel continuous flow reactors and the calcium hydroxide ethanol emulsion are simultaneously introduced into the second group of microchannel continuous flow reactors. The flow rate of the calcium hydroxide ethanol emulsion is set at 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set at 100 °C, and the residence time of the materials in the second group of reactors is 25 s.
[0058] 4) The materials flowing out from the second group of continuous flow microchannel continuous flow reactors and benzoyl chloride (230 mL, 2 mol) were simultaneously introduced into the third group of microchannel continuous flow reactors. The flow rate of benzoyl chloride was set at 50 mL / min, the temperature of the third group of microchannel continuous flow reactors was set at 100 °C, and the residence time of the materials in the third group of reactors was 12 s.
[0059] 5) The reaction solution in the third group of microchannel continuous flow reactors was collected, transferred to a 10 L reaction kettle, cooled to room temperature, the reaction solution was cooled to 0 °C, and 2.5 M hydrochloric acid aqueous solution (1.6 L, 4 mol HCl) was slowly added. It was extracted with chloroform, the organic phase was collected, dried over anhydrous magnesium sulfate, concentrated, and cooled to crystallize to obtain 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone, with a yield of 93 wt% (purity at least 99%).
[0060] Example 5
[0061] Method for continuously synthesizing 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone:
[0062] 1) Phenylhydrazine (98 mL, 1 mol) and ethyl acetoacetate (126 mL, 1 mol) were introduced into the first group of microchannel continuous flow reactors using a plunger pump, and the flow rates were set at 10 mL / min and 12.5 mL / min respectively. The temperature of the first group of microchannel continuous flow reactors was set at 100 °C, and the residence time of the materials in the first group of reactors was 266 s.
[0063] 2) Preparation of calcium hydroxide ethanol emulsion: Calcium hydroxide (160 g, 4 mol) was added to 400 mL of anhydrous ethanol, transferred to an emulsifier for emulsification to prepare a calcium hydroxide ethanol emulsion, and it was placed in an ultrasonic device for ultrasonic treatment.
[0064] 3) The materials flowing out from the first group of microchannel continuous flow reactors and the calcium hydroxide ethanol emulsion were simultaneously introduced into the second group of microchannel continuous flow reactors. The flow rate of the calcium hydroxide ethanol emulsion was set at 50 mL / min, the temperature of the second group of microchannel continuous flow reactors was set at 100 °C, and the residence time of the materials in the second group of reactors was 50 s.
[0065] 4) The materials flowing out from the second group of continuous flow microchannel continuous flow reactors and benzoyl chloride (230 mL, 2 mol) were simultaneously introduced into the third group of microchannel continuous flow reactors. The flow rate of benzoyl chloride was set at 25 mL / min, the temperature of the third group of microchannel continuous flow reactors was set at 100 °C, and the residence time of the materials in the third group of reactors was 25 s.
[0066] 5) Collect the reaction solution in the third group of microchannel continuous flow reactors, transfer it to a 10 L reaction kettle, cool it to room temperature, cool the reaction solution to 0 °C, slowly add 2.5 M hydrochloric acid aqueous solution (1.6 L, 4 mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, and cool it to crystallize to obtain 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone, with a yield of 89 wt% (purity at least 99%).
[0067] Example 6
[0068] Method for continuously synthesizing 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone
[0069] 1) Feed phenylhydrazine (98 mL, 1 mol) and ethyl acetoacetate (126 mL, 1 mol) into the first group of microchannel continuous flow reactors using a plunger pump, and set the flow rates to 30 mL / min and 37.5 mL / min respectively. Set the temperature of the first group of microchannel continuous flow reactors to 100 °C, and the residence time of the materials in the first group of reactors is 88 s.
[0070] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160 g, 4 mol) to 400 mL of anhydrous ethanol, transfer it to an emulsifier for emulsification to prepare a calcium hydroxide ethanol emulsion, and place it in an ultrasonic device for ultrasonic treatment.
[0071] 3) Feed the materials flowing out of the first group of microchannel continuous flow reactors and the calcium hydroxide ethanol emulsion into the second group of microchannel continuous flow reactors simultaneously. Set the flow rate of the calcium hydroxide ethanol emulsion to 150 mL / min, set the temperature of the second group of microchannel continuous flow reactors to 100 °C, and the residence time of the materials in the second group of reactors is 42 s.
[0072] 4) Feed the materials flowing out of the second group of continuous flow microchannel continuous flow reactors and benzoyl chloride (230 mL, 2 mol) into the third group of microchannel continuous flow reactors simultaneously. Set the flow rate of benzoyl chloride to 70 mL / min, set the temperature of the third group of microchannel continuous flow reactors to 100 °C, and the residence time of the materials in the third group of reactors is 9 s.
[0073] 5) Collect the reaction solution in the third group of microchannel continuous flow reactors, transfer it to a 10 L reaction kettle, cool it to room temperature, cool the reaction solution to 0 °C, slowly add 2.5 M hydrochloric acid aqueous solution (1.6 L, 4 mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, and cool it to crystallize to obtain 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone, with a yield of 81 wt% (purity at least 99%).
[0074] The process parameters of Examples 1 to 6 are shown in Table 1 below.
[0075] Table 1 Process Parameters of Examples 1 to 6
[0076]
[0077] As can be seen from Table 1, when the temperatures of the three groups of microchannel continuous flow reactors are all 60 - 100 °C and the residence times of the materials in the three groups of microchannel continuous flow reactors are 130 - 280 s / 25 - 50 s / 12 - 25 s, the yield of the target product is above 89%.
[0078] Example 7
[0079] Method for continuously synthesizing 1 - phenyl - 3 - methyl - 4 - furanoyl - 5 - pyrazolone:
[0080] 1) Hydrazine benzene (98 mL, 1 mol) and ethyl acetoacetate (126 mL, 1 mol) are introduced into the first group of microchannel continuous flow reactors by means of a plunger pump, and the flow rates are set at 20 mL / min and 25 mL / min respectively. The temperature of the first group of microchannel continuous flow reactors is set at 60 °C, and the residence time of the material in the first group of reactors is 133 s.
[0081] 2) Preparation of calcium hydroxide ethanol emulsion: Calcium hydroxide (160 g, 4 mol) is added to 400 mL of absolute ethanol, transferred to an emulsifier for emulsification to prepare a calcium hydroxide ethanol emulsion, and then placed in an ultrasonic device for ultrasonic treatment.
[0082] 3) The material flowing out of the first group of microchannel continuous flow reactors and the calcium hydroxide ethanol emulsion are simultaneously introduced into the second group of microchannel continuous flow reactors. The flow rate of the calcium hydroxide ethanol emulsion is set at 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set at 60 °C, and the residence time of the material in the second group of reactors is 25 s.
[0083] 4) The material flowing out of the second group of continuous flow microchannel continuous flow reactors and furanoyl chloride (200 mL, 2 mol) are simultaneously introduced into the third group of microchannel continuous flow reactors. The flow rate of furanoyl chloride is set at 40 mL / min, the temperature of the third group of microchannel continuous flow reactors is set at 60 °C, and the residence time of the material in the third group of reactors is 13 s.
[0084] 5) Collect the reaction solution in the third group of microchannel continuous flow reactors, transfer it to a 10 L reaction kettle, cool it to room temperature, cool the reaction solution to 0 °C, slowly add 2.5 M hydrochloric acid aqueous solution (1.6 L, 4 mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, and cool it to crystallize to obtain 1-phenyl-3-methyl-4-furoyl-5-pyrazolone, with a yield of 90 wt% (purity at least 99%).
[0085] The chemical structure of the product 1-phenyl-3-methyl-4-furoyl-5-pyrazolone in this case is as follows:
[0086]
[0087] The 1H NMR data thereof are as follows. 1 1H NMR (CDCl3, 300 MHz, δ; ppm): 7.85 (d, 2H), 7.69 (d, 1H), 7.42 (m, 3H), 7.25 (t, 1H), 6.62 (t, 1H), 2.59 (s, 3H).
[0088] Example 8
[0089] Method for continuously synthesizing 1-phenyl-3-methyl-4-pivaloyl-5-pyrazolone:
[0090] 1) Feed phenylhydrazine (98 mL, 1 mol) and ethyl acetoacetate (126 mL, 1 mol) into the first group of microchannel continuous flow reactors by a plunger pump, and set the flow rates to 20 mL / min and 25 mL / min respectively. The temperature of the first group of microchannel continuous flow reactors is set to 60 °C, and the residence time of the materials in the first group of reactors is 133 s.
[0091] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160 g, 4 mol) to 400 mL of anhydrous ethanol, transfer it to an emulsifier for emulsification to prepare a calcium hydroxide ethanol emulsion, and place it in an ultrasonic device for ultrasonic treatment.
[0092] 3) Feed the materials flowing out of the first group of microchannel continuous flow reactors and the calcium hydroxide ethanol emulsion into the second group of microchannel continuous flow reactors simultaneously. The flow rate of the calcium hydroxide ethanol emulsion is set to 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set to 60 °C, and the residence time of the materials in the second group of reactors is 25 s.
[0093] 4) The materials flowing out from the second group of continuous flow microchannel continuous flow reactors and pivaloyl chloride (245 mL, 2 mol) are simultaneously introduced into the third group of microchannel continuous flow reactors. The flow rate of pivaloyl chloride is set at 50 mL / min, the temperature of the third group of microchannel continuous flow reactors is set at 60 °C, and the residence time of the materials in the third group of reactors is 12 s.
[0094] 5) Collect the reaction solution in the third group of microchannel continuous flow reactors, transfer it to a 10 L reaction kettle, cool it to room temperature, cool the reaction solution to 0 °C, slowly add 2.5 M hydrochloric acid aqueous solution (1.6 L, 4 mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, and cool it to crystallize to obtain 1-phenyl-3-methyl-4-pivaloyl-5-pyrazolone, with a yield of 85 wt% (purity at least 99%).
[0095] The chemical structure of the product 1-phenyl-3-methyl-4-pivaloyl-5-pyrazolone in this example is as follows:
[0096]
[0097] Its hydrogen spectrum data is as follows, 1 HNMR(CDCl3, 300 MHz, δ; ppm): 13.0(s, 1H), 7.85(d, 2H), 7.69(d, 1H), 7.42(m, 1H), 7.25(t, 1H), 2.50(s, 3H), 1.40(s, 9H).
[0098] Example 9
[0099] Method for continuously synthesizing 1-phenyl-3-methyl-4-propionyl-5-pyrazolone:
[0100] 1) Hydrazine benzene (98 mL, 1 mol) and ethyl acetoacetate (126 mL, 1 mol) are introduced into the first group of microchannel continuous flow reactors by using a plunger pump, and the flow rates are set at 20 mL / min and 25 mL / min respectively. The temperature of the first group of microchannel continuous flow reactors is set at 60 °C, and the residence time of the materials in the first group of reactors is 133 s.
[0101] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160 g, 4 mol) to 400 mL of absolute ethanol, transfer it to an emulsifier for emulsification to prepare a calcium hydroxide ethanol emulsion, and place it in an ultrasonic device for ultrasonic treatment.
[0102] 3) The materials flowing out from the first group of microchannel continuous flow reactors and the calcium hydroxide ethanol emulsion are simultaneously introduced into the second group of microchannel continuous flow reactors. The flow rate of the calcium hydroxide ethanol emulsion is set at 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set at 60 °C, and the residence time of the materials in the second group of reactors is 25 s.
[0103] 4) The materials flowing out from the second group of continuous flow microchannel reactors and propionyl chloride (175 mL, 2 mol) are simultaneously introduced into the third group of microchannel continuous flow reactors. The flow rate of propionyl chloride is set at 35 mL / min, the temperature of the third group of microchannel continuous flow reactors is set at 60 °C, and the residence time of the materials in the third group of reactors is 13 s.
[0104] 5) Collect the reaction solution in the third group of microchannel continuous flow reactors, transfer it to a 10 L reaction kettle, cool it to room temperature, cool the reaction solution to 0 °C, slowly add 2.5 M hydrochloric acid aqueous solution (1.6 L, 4 mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, and cool it to crystallize to obtain 1-phenyl-3-methyl-4-propionyl-5-pyrazolone, with a yield of 89 wt% (purity at least 99%).
[0105] The chemical structure of the product 1-phenyl-3-methyl-4-propionyl-5-pyrazolone in this case is as follows:
[0106]
[0107] The 1H NMR data thereof are as follows. 1 1H NMR (CDCl3, 300 MHz, δ; ppm): 12.0 (s, 1H), 7.85 - 7.27 (m, 5H), 2.75 (q, 2H), 2.50 (s, 3H), 1.06 (t, 3H).
[0108] Example 10
[0109] Method for continuously synthesizing 1-phenyl-3-methyl-4-cyclopentylpropionyl-5-pyrazolone:
[0110] 1) Hydrazine benzene (98 mL, 1 mol) and ethyl acetoacetate (126 mL, 1 mol) are introduced into the first group of microchannel continuous flow reactors by using a plunger pump, and the set flow rates are 20 mL / min and 25 mL / min respectively. The temperature of the first group of microchannel continuous flow reactors is set at 60 °C, and the residence time of the materials in the first group of reactors is 133 s.
[0111] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160 g, 4 mol) to 400 mL of anhydrous ethanol, transfer it to an emulsifier for emulsification to prepare a calcium hydroxide ethanol emulsion, and place it in an ultrasonic device for ultrasonic treatment.
[0112] 3) The materials flowing out from the first group of microchannel continuous flow reactors and the calcium hydroxide ethanol emulsion are simultaneously introduced into the second group of microchannel continuous flow reactors. The flow rate of the calcium hydroxide ethanol emulsion is set at 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set at 60 °C, and the residence time of the materials in the second group of reactors is 25 s.
[0113] 4) The materials flowing out from the second group of continuous flow microchannel continuous flow reactors and cyclopentylpropionyl chloride (306 mL, 2 mol) are simultaneously introduced into the third group of microchannel continuous flow reactors. The flow rate of cyclopentylpropionyl chloride is set at 60 mL / min, the temperature of the third group of microchannel continuous flow reactors is set at 60 °C, and the residence time of the materials in the third group of reactors is 12 s.
[0114] 5) Collect the reaction solution in the third group of microchannel continuous flow reactors, transfer it to a 10 L reaction kettle, cool it to room temperature, cool the reaction solution to 0 °C, slowly add 2.5 M hydrochloric acid aqueous solution (1.6 L, 4 mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, and cool it to crystallize to obtain 1-phenyl-3-methyl-4-cyclopentylpropionyl-5-pyrazolone, with a yield of 90 wt% (purity at least 99%).
[0115] The product 1-phenyl-3-methyl-4-cyclopentylpropionyl-5-pyrazolone in this case
[0116]
[0117] Its NMR data is as follows. 1 HNMR(CDCl3, 300 MHz, δ; ppm): 12.2 (s, 1H), 7.85 - 7.27 (m, 5H), 2.75 (q, 2H), 2.50 (s, 3H), 1.2 - 2.0 (m, 9H).
[0118] Example 11
[0119] Method for continuously synthesizing 1-phenyl-3-methyl-4-tert-butylacetyl-5-pyrazolone:
[0120] 1) Hydrazine benzene (98 mL, 1 mol) and ethyl acetoacetate (126 mL, 1 mol) were introduced into the first group of microchannel continuous flow reactors by a plunger pump, and the flow rates were set at 20 mL / min and 25 mL / min respectively. The temperature of the first group of microchannel continuous flow reactors was set at 60 °C, and the residence time of the materials in the first group of reactors was 133 s.
[0121] 2) Preparation of calcium hydroxide ethanol emulsion: Calcium hydroxide (160 g, 4 mol) was added to 400 mL of absolute ethanol, transferred to an emulsifier for emulsification to prepare a calcium hydroxide ethanol emulsion, and then placed in an ultrasonic device for ultrasonic treatment.
[0122] 3) The materials flowing out of the first group of microchannel continuous flow reactors and the calcium hydroxide ethanol emulsion were simultaneously introduced into the second group of microchannel continuous flow reactors. The flow rate of the calcium hydroxide ethanol emulsion was set at 100 mL / min, the temperature of the second group of microchannel continuous flow reactors was set at 60 °C, and the residence time of the materials in the second group of reactors was 25 s.
[0123] 4) The materials flowing out of the second group of continuous flow microchannel reactors and tert-butyl acetyl chloride (280 mL, 2 mol) were simultaneously introduced into the third group of microchannel continuous flow reactors. The flow rate of tert-butyl acetyl chloride was set at 55 mL / min, the temperature of the third group of microchannel continuous flow reactors was set at 60 °C, and the residence time of the materials in the third group of reactors was 12 s.
[0124] 5) The reaction solution in the third group of microchannel continuous flow reactors was collected, transferred to a 10 L reaction kettle, cooled to room temperature, and then cooled to 0 °C. 2.5 M hydrochloric acid aqueous solution (1.6 L, 4 mol HCl) was slowly added. After chloroform extraction, the organic phase was collected, dried with anhydrous magnesium sulfate, concentrated, and then cooled and crystallized to obtain 1-phenyl-3-methyl-4-tert-butylacetyl-5-pyrazolone, with a yield of 93 wt% (purity at least 99%).
[0125] The chemical structure of the product 1-phenyl-3-methyl-4-tert-butylacetyl-5-pyrazolone in this case is as follows:
[0126]
[0127] Its NMR data are as follows, 1 HNMR(CDCl3, 300 MHz, δ; ppm): 11.4(s, 1H), 7.90 - 7.25(m, 5H), 2.63(s, 2H), 2.48(s, 3H), 1.12(s, 9H).
[0128] Example 12
[0129] Method for continuous flow synthesis of 1-phenyl-3-phenyl-4-acetyl-5-pyrazolone:
[0130] 1) Hydrazine benzene (98 mL, 1 mol) and ethyl benzoylacetate (173 mL, 1 mol) were introduced into the first group of microchannel continuous flow reactors by a plunger pump, and the flow rates were set at 20 mL / min and 35 mL / min respectively. The temperature of the first group of microchannel continuous flow reactors was set at 60 °C, and the residence time of the materials in the first group of reactors was 109 s.
[0131] 2) Preparation of calcium hydroxide ethanol emulsion: Calcium hydroxide (160 g, 4 mol) was added to 400 mL of absolute ethanol, transferred to an emulsifier for emulsification to prepare a calcium hydroxide ethanol emulsion, and it was placed in an ultrasonic device for ultrasonic treatment.
[0132] 3) The materials flowing out from the first group of microchannel continuous flow reactors and the calcium hydroxide ethanol emulsion were simultaneously introduced into the second group of microchannel continuous flow reactors. The flow rate of the calcium hydroxide ethanol emulsion was set at 100 mL / min, the temperature of the second group of microchannel continuous flow reactors was set at 60 °C, and the residence time of the materials in the second group of reactors was 23 s.
[0133] 4) The materials flowing out from the second group of continuous flow microchannel continuous flow reactors and acetyl chloride (142 mL, 2 mol) were simultaneously introduced into the third group of microchannel continuous flow reactors. The flow rate of acetyl chloride was set at 30 mL / min, the temperature of the third group of microchannel continuous flow reactors was set at 60 °C, and the residence time of the materials in the third group of reactors was 13 s.
[0134] 5) The reaction solution in the third group of microchannel continuous flow reactors was collected, transferred to a 10 L reaction kettle, cooled to room temperature, the reaction solution was cooled to 0 °C, 2.5 M hydrochloric acid aqueous solution (1.6 L, 4 mol HCl) was slowly added, extracted with chloroform, the organic phase was collected, dried with anhydrous magnesium sulfate, concentrated and then cooled and crystallized to obtain 1-phenyl-3-phenyl-4-acetyl-5-pyrazolone, with a yield of 89 wt% (purity at least 99%).
[0135] The chemical structure of the product 1-phenyl-3-phenyl-4-acetyl-5-pyrazolone in this case is as follows:
[0136]
[0137] Its 1H NMR data are as follows, 1 1H NMR (CDCl3, 300 MHz, δ; ppm): 7.90 - 7.25 (m, 10H), 3.20 (s, 1H), 2.18 (s, 3H).
[0138] The above are only the preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes, shall be covered by the protection scope of the present invention.
Claims
1. A method for continuously synthesizing 1-aryl-3-alkyl-4-acyl-5-pyrazolone, characterized in that, It includes the following steps: Let the arylhydrazine compound and the dicarbonyl compound enter the first group of microchannel continuous flow reactors for the first reaction. After the reaction, the material flowing out of the first group of microchannel continuous flow reactors is mixed with the emulsified calcium hydroxide emulsion and simultaneously introduced into the second group of microchannel continuous flow reactors for the second reaction. After the reaction, the material flowing out of the second group of microchannel continuous flow reactors is mixed with the acyl chloride reagent and simultaneously introduced into the third group of microchannel continuous flow reactors for the third reaction. The reaction solution flowing out of the third group of microchannel continuous flow reactors is collected, cooled, and post-treated to obtain 1-aryl-3-alkyl-4-acyl-5-pyrazolone; wherein R of the dicarbonyl compound 1 is selected from one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl, tert-butyl, phenyl; R of the arylhydrazine compound 2 is selected from one of a hydrogen atom, methyl, ethyl, n-butyl, tert-butyl, benzyl, methoxy; R in the acyl chloride reagent 3 is selected from one of a C1-C10 normal alkyl group, a C1-C10 isoalkyl group, a C1-C10 isoalkyl group containing a cycloalkyl group, a C1-C10 straight-chain alkyl group containing a cycloalkyl group.
2. The method for continuously synthesizing 1-aryl-3-alkyl-4-acyl-5-pyrazolone according to claim 1, characterized in that, The temperature of the first reaction is 60 - 100 °C, and the residence time for the first reaction in the first group of microchannel continuous flow reactors is 85 - 300 seconds; The temperature of the second reaction is 60 - 100 °C, and the residence time for the second reaction in the second group of microchannel continuous flow reactors is 25 - 50 seconds; The temperature of the third reaction is 60 - 100 °C, and the residence time for the third reaction in the second group of microchannel continuous flow reactors is 12 - 50 seconds.
3. A method for continuously synthesizing 1-aryl-3-alkyl-4-acyl-5-pyrazolone according to claim 2, characterized in that, The molar ratio of the arylhydrazine compound, the dicarbonyl compound, calcium hydroxide, and the acyl chloride reagent is 1:1:4:
2.
4. A method for continuously synthesizing 1-aryl-3-alkyl-4-acyl-5-pyrazolone according to claim 3, characterized in that, The flow rate of the arylhydrazine compound is 10 - 30 mL / min; The flow rate of the dicarbonyl compound is 12 - 40 mL / min; The flow rate of the calcium hydroxide emulsion is 50 - 150 mL / min; The flow rate of the acyl chloride reagent is 25 - 100 mL / min.
5. A method for continuously synthesizing 1-aryl-3-alkyl-4-acyl-5-pyrazolone according to claim 4, characterized in that, The emulsified calcium hydroxide emulsion is formed by mixing calcium hydroxide with absolute ethanol, emulsifying first, and then ultrasonic treating. The molar concentration of the calcium hydroxide emulsion is 5 - 15 mol / L.
6. A method for continuously synthesizing 1-aryl-3-alkyl-4-acyl-5-pyrazolone according to any one of claims 1-5, characterized in that, The post-treatment is successively adding acidification with 1.5 - 5 mol / L hydrochloric acid aqueous solution at a temperature below 5 °C, chloroform extraction, drying, concentration, and recrystallization.