Method for continuous-flow synthesis of 1-aryl-3-alkyl-4-acyl-5-pyrazolinone

Abstract

The present invention relates to the technical field of pyrazolinone compound synthesis, and relates in particular to a method for continuous-flow synthesis of 1-aryl-3-alkyl-4-acyl-5-pyrazolinone. Specifically, an arylhydrazine compound and a dicarbonyl compound are introduced into a first set of microchannel continuous-flow reactors to carry out a first reaction. The material flowing out after the reaction is mixed with an emulsified calcium hydroxide suspension and simultaneously introduced into a second set of microchannel continuous-flow reactors to carry out a second reaction. The material flowing out after the reaction is mixed with an acyl chloride reagent and simultaneously introduced into a third set of microchannel continuous-flow reactors to carry out a third reaction. The resultant reaction solution flowing out is collected, cooled down, and then subjected to post-treatment to obtain 1-aryl-3-alkyl-4-acyl-5-pyrazolinone. The method of the present invention employs microchannel continuous-flow technology to efficiently acquire the target product in a one-step process, is simple to operate, uses simple starting materials, and provides high yield, high purity, and reduced generation of waste gas, wastewater, and solid waste.

Description

A method for continuous flow synthesis of 1-aryl-3-alkyl-4-acyl-5-pyrazolone Technical Field

[0001] This invention relates to the field of pyrazolone compound synthesis technology, and specifically to a method for continuous flow synthesis of 1-aryl-3-alkyl-4-acyl-5-pyrazolone. Background Technology

[0002] 5-Pyrazolone compounds are a class of five-membered lactam heterocyclic compounds containing multiple substitutions. They are widely found in natural products and drug molecules, exhibiting broad antibacterial and bioactive properties. Among them, 1-aryl-3-alkyl-4-acyl-5-pyrazolone compounds have wide applications in analytical chemistry, radiochemistry, biomedicine, and luminescent materials. In analytical chemistry, they are often used as chelating agents for determining the total amount of trace rare earth elements in iron, steel, and non-ferrous metals. In radiochemistry, they are commonly used as metal extractants to extract and separate radioactive metals such as uranium, plutonium, americium, neptunium, and thorium. In chemical synthesis, the metal complexes obtained after coordination with metals have anticancer, antitumor, antibacterial, and anti-inflammatory effects in pharmaceuticals. Furthermore, the chelates obtained by complexing 1-aryl-3-alkyl-4-acyl-5-pyrazolone compounds with ternary lanthanides exhibit good electroluminescent properties.

[0003] Currently, the production of 1-aryl-3-alkyl-4-acyl-5-pyrazolone compounds typically involves reacting arylhydrazine with a dicarbonyl compound at high temperature to obtain an intermediate. After separation and purification, this intermediate is then reacted with an acyl chloride compound under alkaline conditions to obtain the target product. This method requires the separation and purification of the intermediate and involves complex post-processing, resulting in high production costs, low yields, and significant waste generation. Therefore, it is difficult to scale up production on a large scale. Summary of the Invention

[0004] To address the aforementioned technical problems, a continuous flow synthesis method for 1-aryl-3-alkyl-4-acyl-5-pyrazolone is provided. This invention utilizes microchannel continuous flow technology to efficiently obtain the target product in one step. The method is simple to operate, uses simple raw materials, has high yield, high purity, and produces minimal waste.

[0005] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0006] A method for the continuous flow synthesis of 1-aryl-3-alkyl-4-acyl-5-pyrazolone includes the following steps:

[0007] The arylhydrazine compound and the dicarbonyl compound are introduced into a first group of microchannel continuous flow reactors for a first reaction. After the reaction, the material flowing out of the first group of microchannel continuous flow reactors is mixed with an emulsified calcium hydroxide emulsion and simultaneously introduced into a second group of microchannel continuous flow reactors for a second reaction. After the reaction, the material flowing out of the second group of microchannel continuous flow reactors is mixed with an acyl chloride reagent and simultaneously introduced into a third group of microchannel continuous flow reactors for a third reaction. The reaction liquid 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.

[0008] The R of the dicarbonyl compound 1 Selected from one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl, tert-butyl, and phenyl; the R of the arylhydrazine compound... 2 Selected from one of hydrogen atom, methyl, ethyl, n-butyl, tert-butyl, benzyl, methoxy; R in the acyl chloride reagent 3 It is selected from one of the following: C1-C10 normal alkyl, C1-C10 isoalkyl, C1-C10 isoalkyl containing cycloalkyl, and C1-C10 straight-chain alkyl containing cycloalkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl, cyclobutyl, methylene tert-butyl, ethylcyclopentyl, phenyl, furanyl, etc.

[0009] Furthermore, the temperature of the first reaction is 60-100℃, and the retention time of the first reaction in the first group of microchannel continuous flow reactors is 85-300 seconds;

[0010] The temperature of the second reaction is 60-100℃, and the retention time of the second reaction in the second group of microchannel continuous flow reactors is 25-50 seconds;

[0011] The temperature of the third reaction is 60-100℃, and the retention time of the third reaction in the second group of microchannel continuous flow reactors is 12-50 seconds.

[0012] Furthermore, the molar ratio of the arylhydrazine compound, the dicarbonyl compound, calcium hydroxide, and the acyl chloride reagent is 1:1:4:2.

[0013] Furthermore, the flow rate of the arylhydrazine compound is 10-30 mL / min;

[0014] The flow rate of the dicarbonyl compound is 12-40 mL / min;

[0015] The flow rate of the calcium hydroxide emulsion is 50-150 mL / min;

[0016] The flow rate of the acyl chloride reagent is 25-100 mL / min.

[0017] Furthermore, the emulsified calcium hydroxide emulsion is formed by mixing calcium hydroxide with anhydrous ethanol, emulsifying the mixture, and then ultrasonically treating it. The molar concentration of the calcium hydroxide emulsion is 5-15 mol / L.

[0018] Further, the post-treatment involves sequentially adding a 1.5-5 mol / L hydrochloric acid aqueous solution at below 5°C for acidification, chloroform extraction, drying, concentration, and recrystallization.

[0019] Beneficial technical effects:

[0020] This invention emulsifies and sonicates a calcium hydroxide ethanol solution before introducing it into a microchannel reactor to mix with the materials from the first reaction. This solves the problem that current microchannel reactors cannot accept solid materials, and for the first time achieves continuous solid-liquid two-phase reaction in a microchannel. The synthesis is carried out in one step in a microchannel continuous flow reactor, and the intermediate products do not need to be separated. After the reaction, only simple quenching, extraction, and recrystallization are needed to obtain 1-aryl-3-alkyl-4-acyl-5-pyrazolone. The continuous flow synthesis method of 1-aryl-3-alkyl-4-acyl-5-pyrazolone of this invention is a one-step synthesis, which is simple to operate, uses simple raw materials, has relatively mild reaction conditions, high yield, high purity, and produces less waste. Post-processing is also relatively easy, making it green and environmentally friendly, and suitable for large-scale industrial production. Attached Figure Description

[0021] Figure 1 is a schematic diagram of the continuous flow synthesis of 1-aryl-3-alkyl-4-acyl-5-pyrazolone according to the present invention, wherein 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. Detailed Implementation

[0022] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments and accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0023] Unless otherwise specifically stated, the numerical values ​​set forth in these embodiments do not limit the scope of the invention. Techniques and methods known to those skilled in the art may not be discussed in detail, but where appropriate, such techniques and methods should be considered part of the specification. In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.

[0024] Furthermore, it should be noted that the use of terms such as "first" and "second" to define the reaction is merely for the purpose of distinguishing each reaction step. Unless otherwise stated, the above terms have no special meaning and therefore should not be construed as limiting the scope of protection of this invention.

[0025] Experimental methods not specified in the following examples are generally performed according to national standards; if there is no corresponding national standard, they are performed according to general standard requirements or general methods.

[0026] The microchannel continuous flow reactor consists of three groups: 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. Each glass chip holds 20 mL of liquid.

[0027] Retention time refers to the time required for material to pass through a continuous flow reactor. The specific calculation method is: retention time = liquid holding volume × (60s / min) / total volumetric flow rate; the liquid holding volume is the capacity of the continuous flow reactor, and the value for a single chip is a fixed value of 20mL; the total volumetric flow rate is equal to the sum of the flow rates of each injection pump.

[0028] Example 1

[0029] A method for continuous flow synthesis of 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone:

[0030] 1) Phenylated hydrazine (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, with flow rates 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 retention time of the materials in the first group of reactors was 133 s.

[0031] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160g, 4mol) to 400mL of anhydrous ethanol, transfer to an emulsifier for emulsification to prepare calcium hydroxide ethanol emulsion, and then place it in an ultrasonicator for sonication.

[0032] 3) The material flowing out of the first microchannel continuous flow reactor and the calcium hydroxide ethanol emulsion are simultaneously introduced into the second microchannel continuous flow reactor. The flow rate of the calcium hydroxide ethanol emulsion is set to 100 mL / min, the temperature of the second microchannel continuous flow reactor is set to 60℃, and the retention time of the material in the second reactor is 25 s.

[0033] 4) The material 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 to 50 mL / min, the temperature of the third group of microchannel continuous flow reactors is set to 60 °C, and the retention time of the material in the third group of reactors is 12 s.

[0034] 5) Collect the reaction solution from the third group of microchannel continuous flow reactors, transfer it to a 10L reaction vessel, cool it to room temperature, cool the reaction solution to 0℃, slowly add 2.5M hydrochloric acid aqueous solution (1.6L, 4mol HCl), extract with chloroform, collect the organic phase, dry the organic phase with anhydrous magnesium sulfate, concentrate it, cool and crystallize to obtain 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone, yield 93wt% (purity at least 99%).

[0035] The chemical structure of the product 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone in this case is as follows:

[0036] Its 1H NMR spectrum data are as follows: 1 HNMR (CDCl3, 500MHz, δ; ppm): 7.88 (2H, d, J = 8.1Hz), 7.65 (2H, d, J = 7.6Hz), 7.58 (1H, t, J = 7.5Hz), 7.52(2H,t,J=7.5Hz), 7.47(2H,t,J=8.1Hz), 7.31(1H,t,J=7.3Hz), 2.10(3H,s).

[0037] Example 2

[0038] A method for continuous flow synthesis of 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone:

[0039] 1) Phenylated hydrazine (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, with flow rates set at 20 mL / min and 25 mL / min, respectively. The temperature of the first group of microchannel continuous flow reactors was set at 40 °C, and the retention time of the materials in the first group of reactors was 133 s.

[0040] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160g, 4mol) to 400mL of anhydrous ethanol, transfer to an emulsifier for emulsification to prepare calcium hydroxide ethanol emulsion, and then place it in an ultrasonicator for sonication.

[0041] 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 to 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set to 40℃, and the retention time of the material in the second group of reactors is 25 s.

[0042] 4) The material 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 to 50 mL / min, the temperature of the third group of microchannel continuous flow reactors is set to 40 °C, and the retention time of the material in the third group of reactors is 12 s.

[0043] 5) Collect the reaction solution from the third group of microchannel continuous flow reactors, transfer it to a 10L reaction vessel, cool it to room temperature, cool the reaction solution to 0℃, slowly add 2.5M hydrochloric acid aqueous solution (1.6L, 4mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, cool and crystallize it to obtain 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone, yield 76wt% (purity at least 99%).

[0044] Example 3

[0045] A method for continuous flow synthesis of 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone:

[0046] 1) Phenylated hydrazine (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, with flow rates set at 20 mL / min and 25 mL / min, respectively. The temperature of the first group of microchannel continuous flow reactors was set at 80 °C, and the retention time of the materials in the first group of reactors was 133 min.

[0047] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160g, 4mol) to 400mL of anhydrous ethanol, transfer to an emulsifier for emulsification to prepare calcium hydroxide ethanol emulsion, and then place it in an ultrasonicator for sonication.

[0048] 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 to 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set to 80℃, and the retention time of the material in the second group of reactors is 25 s.

[0049] 4) The material 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 to 50 mL / min, the temperature of the third group of microchannel continuous flow reactors is set to 80 °C, and the retention time of the material in the third group of reactors is 12 s.

[0050] 5) Collect the reaction solution from the third group of microchannel continuous flow reactors, transfer it to a 10L reaction vessel, cool it to room temperature, cool the reaction solution to 0℃, slowly add 2.5M hydrochloric acid aqueous solution (1.6L, 4mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, cool and crystallize it to obtain 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone, yield 92wt% (purity at least 99%).

[0051] Example 4

[0052] A method for continuous flow synthesis of 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone:

[0053] 1) Phenylated hydrazine (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, with flow rates set at 20 mL / min and 25 mL / min, respectively. The temperature of the first group of microchannel continuous flow reactors was set at 100 °C, and the retention time of the materials in the first group of reactors was 133 s.

[0054] 2) Preparation of calcium hydroxide ethanol emulsion: Add 160g, 4mol of calcium hydroxide to 400mL of anhydrous ethanol, transfer to an emulsifier for emulsification to prepare calcium hydroxide ethanol emulsion, and then place it in an ultrasonicator for sonication.

[0055] 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 to 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set to 100℃, and the retention time of the material in the second group of reactors is 25 s.

[0056] 4) The material 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 to 50 mL / min, the temperature of the third group of microchannel continuous flow reactors is set to 100℃, and the retention time of the material in the third group of reactors is 12 s.

[0057] 5) Collect the reaction solution from the third group of microchannel continuous flow reactors, transfer it to a 10L reaction vessel, cool it to room temperature, cool the reaction solution to 0℃, slowly add 2.5M hydrochloric acid aqueous solution (1.6L, 4mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, cool and crystallize it to obtain 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone, with a yield of 93wt% (purity of at least 99%).

[0058] Example 5

[0059] A method for continuous flow synthesis of 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone:

[0060] 1) Phenylated hydrazine (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, with flow rates 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 retention time of the materials in the first group of reactors was 266 s.

[0061] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160g, 4mol) to 400mL of anhydrous ethanol, transfer to an emulsifier for emulsification to prepare calcium hydroxide ethanol emulsion, and then place it in an ultrasonicator for sonication.

[0062] 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 to 50 mL / min, the temperature of the second group of microchannel continuous flow reactors is set to 100℃, and the retention time of the material in the second group of reactors is 50 s.

[0063] 4) The material 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 to 25 mL / min, the temperature of the third group of microchannel continuous flow reactors is set to 100℃, and the retention time of the material in the third group of reactors is 25 s.

[0064] 5) Collect the reaction solution from the third group of microchannel continuous flow reactors, transfer it to a 10L reaction vessel, cool it to room temperature, cool the reaction solution to 0℃, slowly add 2.5M hydrochloric acid aqueous solution (1.6L, 4mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, cool and crystallize it to obtain 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone, with a yield of 89wt% (purity of at least 99%).

[0065] Example 6

[0066] A method for continuous flow synthesis of 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone:

[0067] 1) Phenylated hydrazine (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, with flow rates set at 30 mL / min and 37.5 mL / min, respectively. The temperature of the first group of microchannel continuous flow reactors was set at 100 °C, and the retention time of the materials in the first group of reactors was 88 s.

[0068] 2) Preparation of calcium hydroxide ethanol emulsion: Add 160g, 4mol of calcium hydroxide to 400mL of anhydrous ethanol, transfer to an emulsifier for emulsification to prepare calcium hydroxide ethanol emulsion, and then place it in an ultrasonicator for sonication.

[0069] 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 to 150 mL / min, the temperature of the second group of microchannel continuous flow reactors is set to 100℃, and the retention time of the material in the second group of reactors is 42 s.

[0070] 4) The material 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 to 70 mL / min, the temperature of the third group of microchannel continuous flow reactors is set to 100℃, and the retention time of the material in the third group of reactors is 9 s.

[0071] 5) Collect the reaction solution from the third group of microchannel continuous flow reactors, transfer it to a 10L reaction vessel, cool it to room temperature, cool the reaction solution to 0℃, slowly add 2.5M hydrochloric acid aqueous solution (1.6L, 4mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, cool and crystallize it to obtain 1-phenyl-3-methyl-4-benzoyl-5-pyrazolone, with a yield of 81wt% (purity of at least 99%).

[0072] The process parameters for Examples 1 to 6 above are shown in Table 1 below.

[0073] Table 1. Process parameters for Examples 1 to 6

[0074] As shown in Table 1, when the temperature of the three sets of microchannel continuous flow reactors is 60-100℃ and the retention time of the material in the three sets of microchannel continuous flow reactors is 130-280 seconds / 25-50 seconds / 12-25 seconds, the yield of the target product is above 89%.

[0075] Example 7

[0076] A method for continuous flow synthesis of 1-phenyl-3-methyl-4-furanoyl-5-pyrazolone:

[0077] 1) Phenylated hydrazine (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, with flow rates 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 retention time of the materials in the first group of reactors was 133 s.

[0078] 2) Preparation of calcium hydroxide ethanol emulsion: Add 160g, 4mol of calcium hydroxide to 400mL of anhydrous ethanol, transfer to an emulsifier for emulsification to prepare calcium hydroxide ethanol emulsion, and then place it in an ultrasonicator for sonication.

[0079] 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 to 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set to 60℃, and the retention time of the material in the second group of reactors is 25 s.

[0080] 4) The material flowing out of the second group of continuous flow microchannel 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 to 40 mL / min, the temperature of the third group of microchannel continuous flow reactors is set to 60 °C, and the retention time of the material in the third group of reactors is 13 s.

[0081] 5) Collect the reaction solution from the third group of microchannel continuous flow reactors, transfer it to a 10L reaction vessel, cool it to room temperature, cool the reaction solution to 0℃, slowly add 2.5M hydrochloric acid aqueous solution (1.6L, 4mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, cool and crystallize it to obtain 1-phenyl-3-methyl-4-furanoyl-5-pyrazolone, yield 90wt% (purity at least 99%).

[0082] The chemical structure of the product 1-phenyl-3-methyl-4-furanoyl-5-pyrazolone in this case is as follows:

[0083] Its 1H NMR spectrum data are as follows: 1 HNMR (CDCl3, 300MHz, 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).

[0084] Example 8

[0085] A method for continuous flow synthesis of 1-phenyl-3-methyl-4-pentanoyl-5-pyrazolone:

[0086] 1) Phenylated hydrazine (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, with flow rates 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 retention time of the materials in the first group of reactors was 133 s.

[0087] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160g, 4mol) to 400mL of anhydrous ethanol, transfer to an emulsifier for emulsification to prepare calcium hydroxide ethanol emulsion, and then place it in an ultrasonicator for sonication.

[0088] 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 to 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set to 60℃, and the retention time of the material in the second group of reactors is 25 s.

[0089] 4) The material flowing out of the second group of continuous flow microchannel 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 to 50 mL / min, the temperature of the third group of microchannel continuous flow reactors is set to 60 °C, and the retention time of the material in the third group of reactors is 12 s.

[0090] 5) Collect the reaction solution from the third group of microchannel continuous flow reactors, transfer it to a 10L reaction vessel, cool it to room temperature, cool the reaction solution to 0℃, slowly add 2.5M hydrochloric acid aqueous solution (1.6L, 4mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, cool and crystallize it to obtain 1-phenyl-3-methyl-4-pentayl-5-pyrazolone, yield 85wt% (purity at least 99%).

[0091] The chemical structure of the product 1-phenyl-3-methyl-4-pentanoyl-5-pyrazolone in this embodiment is as follows:

[0092] Its proton spectrum data are as follows: 1 HNMR (CDCl3, 300MHz, 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).

[0093] Example 9

[0094] A method for continuous flow synthesis of 1-phenyl-3-methyl-4-propionyl-5-pyrazolone:

[0095] 1) Phenylated hydrazine (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, with flow rates 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 retention time of the materials in the first group of reactors was 133 s.

[0096] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160g, 4mol) to 400mL of anhydrous ethanol, transfer to an emulsifier for emulsification to prepare calcium hydroxide ethanol emulsion, and then place it in an ultrasonicator for sonication.

[0097] 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 to 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set to 60℃, and the retention time of the material in the second group of reactors is 25 s.

[0098] 4) The material flowing out of 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 to 35 mL / min, the temperature of the third group of microchannel continuous flow reactors is set to 60 °C, and the retention time of the material in the third group of reactors is 13 s.

[0099] 5) Collect the reaction solution from the third group of microchannel continuous flow reactors, transfer it to a 10L reaction vessel, cool it to room temperature, cool the reaction solution to 0℃, slowly add 2.5M hydrochloric acid aqueous solution (1.6L, 4mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, cool and crystallize it to obtain 1-phenyl-3-methyl-4-propionyl-5-pyrazolone, yield 89wt% (purity at least 99%).

[0100] The chemical structure of the product 1-phenyl-3-methyl-4-propionyl-5-pyrazolone in this case is as follows:

[0101] Its 1H NMR spectrum data are as follows: 1 HNMR (CDCl3, 300MHz, δ; ppm): 12.0 (s, 1H), 7.85-7.27 (m, 5H), 2.75 (q, 2H), 2.50 (s, 3H), 1.06 (t, 3H).

[0102] Example 10

[0103] A method for continuous flow synthesis of 1-phenyl-3-methyl-4-cyclopentylpropionyl-5-pyrazolone:

[0104] 1) Phenylated hydrazine (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, with flow rates 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 retention time of the materials in the first group of reactors was 133 s.

[0105] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160g, 4mol) to 400mL of anhydrous ethanol, transfer to an emulsifier for emulsification to prepare calcium hydroxide ethanol emulsion, and then place it in an ultrasonicator for sonication.

[0106] 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 to 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set to 60℃, and the retention time of the material in the second group of reactors is 25 s.

[0107] 4) The material flowing out of the second group of continuous flow microchannel 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 to 60 mL / min, the temperature of the third group of microchannel continuous flow reactors is set to 60 °C, and the retention time of the material in the third group of reactors is 12 s.

[0108] 5) Collect the reaction solution from the third group of microchannel continuous flow reactors, transfer it to a 10L reaction vessel, cool it to room temperature, cool the reaction solution to 0℃, slowly add 2.5M hydrochloric acid aqueous solution (1.6L, 4mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, cool and crystallize it to obtain 1-phenyl-3-methyl-4-cyclopentylpropionyl-5-pyrazolone, with a yield of 90wt% (purity of at least 99%).

[0109] The product in this case is 1-phenyl-3-methyl-4-cyclopentylpropionyl-5-pyrazolone.

[0110] Its NMR data are as follows: 1 HNMR (CDCl3, 300MHz, 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).

[0111] Example 11

[0112] A method for continuous flow synthesis of 1-phenyl-3-methyl-4-tert-butylacetyl-5-pyrazolone:

[0113] 1) Phenylated hydrazine (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, with flow rates 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 retention time of the materials in the first group of reactors was 133 s.

[0114] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160g, 4mol) to 400mL of anhydrous ethanol, transfer to an emulsifier for emulsification to prepare calcium hydroxide ethanol emulsion, and then place it in an ultrasonicator for sonication.

[0115] 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 to 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set to 60℃, and the retention time of the material in the second group of reactors is 25 s.

[0116] 4) The material flowing out of the second group of continuous flow microchannel reactors and tert-butylacetyl chloride (280 mL, 2 mol) are simultaneously introduced into the third group of microchannel continuous flow reactors. The flow rate of tert-butylacetyl chloride is set to 55 mL / min, the temperature of the third group of microchannel continuous flow reactors is set to 60 °C, and the retention time of the material in the third group of reactors is 12 s.

[0117] 5) Collect the reaction solution from the third group of microchannel continuous flow reactors, transfer it to a 10L reaction vessel, cool it to room temperature, cool the reaction solution to 0℃, slowly add 2.5M hydrochloric acid aqueous solution (1.6L, 4mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, cool and crystallize it to obtain 1-phenyl-3-methyl-4-tert-butylacetyl-5-pyrazolone, with a yield of 93wt% (purity of at least 99%).

[0118] The chemical structure of the product 1-phenyl-3-methyl-4-tert-butylacetyl-5-pyrazolone in this case is as follows:

[0119] Its NMR data are as follows: 1 HNMR (CDCl3, 300MHz, δ; ppm): 11.4 (s, 1H), 7.90-7.25 (m, 5H), 2.63 (s, 2H), 2.48 (s, 3H), 1.12 (s, 9H).

[0120] Example 12

[0121] A method for continuous flow synthesis of 1-phenyl-3-phenyl-4-acetyl-5-pyrazolone:

[0122] 1) Phenylated hydrazine (98 mL, 1 mol) and ethyl benzoate (173 mL, 1 mol) were introduced into the first group of microchannel continuous flow reactors using a plunger pump, with flow rates 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 retention time of the materials in the first group of reactors was 109 s.

[0123] 2) Preparation of calcium hydroxide ethanol emulsion: Add calcium hydroxide (160g, 4mol) to 400mL of anhydrous ethanol, transfer to an emulsifier for emulsification to prepare calcium hydroxide ethanol emulsion, and then place it in an ultrasonicator for sonication.

[0124] 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 to 100 mL / min, the temperature of the second group of microchannel continuous flow reactors is set to 60℃, and the retention time of the material in the second group of reactors is 23 s.

[0125] 4) The material flowing out of the second group of continuous flow microchannel reactors and acetyl chloride (142 mL, 2 mol) are simultaneously introduced into the third group of microchannel continuous flow reactors. The flow rate of acetyl chloride is set to 30 mL / min, the temperature of the third group of microchannel continuous flow reactors is set to 60 °C, and the retention time of the material in the third group of reactors is 13 s.

[0126] 5) Collect the reaction solution from the third group of microchannel continuous flow reactors, transfer it to a 10L reaction vessel, cool it to room temperature, cool the reaction solution to 0℃, slowly add 2.5M hydrochloric acid aqueous solution (1.6L, 4mol HCl), extract with chloroform, collect the organic phase, dry it with anhydrous magnesium sulfate, concentrate it, cool and crystallize it to obtain 1-phenyl-3-phenyl-4-acetyl-5-pyrazolone, with a yield of 89wt% (purity of at least 99%).

[0127] The chemical structure of the product 1-phenyl-3-phenyl-4-acetyl-5-pyrazolone in this case is as follows:

[0128] Its 1H NMR spectrum data are as follows: 1 HNMR (CDCl3, 300MHz, δ; ppm): 7.90-7.25 (m, 10H), 3.20 (s, 1H), 2.18 (s, 3H).

[0129] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for continuous flow synthesis of 1-aryl-3-alkyl-4-acyl-5-pyrazolone, characterized in that, Includes the following steps: The arylhydrazine compound and the dicarbonyl compound are introduced into a first group of microchannel continuous flow reactors for a first reaction. After the reaction, the material flowing out of the first group of microchannel continuous flow reactors is mixed with an emulsified calcium hydroxide emulsion and simultaneously introduced into a second group of microchannel continuous flow reactors for a second reaction. After the reaction, the material flowing out of the second group of microchannel continuous flow reactors is mixed with an acyl chloride reagent and simultaneously introduced into a third group of microchannel continuous flow reactors for a third reaction. The reaction liquid 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. The R of the dicarbonyl compound 1 Selected from one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl, tert-butyl, and phenyl; the R of the arylhydrazine compound... 2 Selected from one of hydrogen atom, methyl, ethyl, n-butyl, tert-butyl, benzyl, methoxy; R in the acyl chloride reagent 3 It is selected from one of the following: C1-C10 normal alkyl, C1-C10 isoalkyl, C1-C10 isoalkyl containing cycloalkyl, and C1-C10 straight-chain alkyl containing cycloalkyl.

2. The method for continuous flow synthesis of 1-aryl-3-alkyl-4-acyl-5-pyrazolone according to claim 1, characterized in that, The temperature of the first reaction is 60-100℃, and the retention time of 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℃, and the retention time of 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℃, and the retention time of the third reaction in the second group of microchannel continuous flow reactors is 12-50 seconds.

3. The method for continuous flow synthesis of 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. The method for continuous flow synthesis of 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. The method for continuous flow synthesis of 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 anhydrous ethanol, emulsifying the mixture, and then ultrasonically treating it. The molar concentration of the calcium hydroxide emulsion is 5-15 mol / L.

6. A method for continuous flow synthesis of 1-aryl-3-alkyl-4-acyl-5-pyrazolone according to any one of claims 1-5, characterized in that, The post-treatment process involves adding a 1.5-5 mol / L hydrochloric acid aqueous solution at a temperature below 5°C for acidification, chloroform extraction, drying, concentration, and recrystallization.

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