Continuous flow preparation method of polysubstituted propargyl alcohol

Abstract

The invention discloses a continuous flow preparation method of polysubstituted propargyl alcohol, which uses a microtube continuous flow reaction device and comprises the following specific steps: simultaneously conveying acetylene gas or terminal alkyne compound and an organic alkali solution into a mixer for premixing; simultaneously conveying the keto-carbonyl substrate and the flowing-out reaction liquid to a reactor to carry out an alkyne hydrogenation reaction; and carrying out gas-liquid separation on the outflowing reaction liquid, and rectifying in a rectifying tower to obtain a target propargyl alcohol product. According to the method for continuously preparing the polysubstituted propargyl alcohol by using the continuous flow reaction system, full mixing of reaction materials of each reaction unit and accurate control of the reaction can be realized by regulating and controlling pipeline parameters, the automation degree is greatly improved, the manual operation is reduced, the energy consumption cost is reduced, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and particularly relates to a continuous flow preparation method of polysubstituted propargyl alcohol. Background Art

[0002] Propargyl alcohol compounds are important chemical intermediates and raw materials. They are the core skeletons of many natural products and physiologically active compounds. They also have important applications in the fields of medicine, chemicals, electroplating, pesticides, steel, etc. The development of such products is of great significance to promoting the development of the pharmaceutical and chemical industries, the oil and gas industries, and other industries.

[0003] Currently, there are several mature methods for synthesizing propargyl alcohol: First, solid potassium hydroxide-catalyzed acetylation or potassium alcoholate-catalyzed acetylation: Chinese patents CN113880691B, CN110467519B, and CN113666803B disclose methods for producing propargyl alcohol using solid potassium hydroxide or potassium alcoholate as a reaction catalyst, ether, toluene, or the like as a solvent, acetylene, and a ketone solution. The acetylation reaction proceeds at near room temperature and slight pressure, but the reaction operation is cumbersome. Second, liquid ammonia-mediated acetylation: U.S. Patent US2012053353 and Chinese Patent CN107827711A disclose methods for producing propargyl alcohol by dissolving acetylene in liquid ammonia, adding a ketone and a small amount of KOH aqueous solution, and then passing acetylene under pressure and at a suitable temperature. This method is widely used in the industrial production of methyl butargyl alcohol, but requires pressurized operation, which poses problems such as high energy consumption and high risks. Summary of the Invention

[0004] The purpose of this section is to summarize some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of this application to avoid obscuring the purpose of this section, the abstract and the title of the invention, and such simplifications or omissions should not be used to limit the scope of the present invention.

[0005] In view of the above-mentioned and / or existing problems in the prior art of the traditional intermittent reactor synthesis method, such as long reaction time, great safety hazards, high energy consumption, etc., the present invention is proposed.

[0006] One of the objectives of the present invention is to provide a continuous flow preparation method for polysubstituted propargyl alcohol, which significantly improves the degree of process automation, greatly reduces energy consumption, greatly improves process safety, and is easy to industrialize and apply.

[0007] To solve the above technical problems, the present invention provides the following technical solution: a continuous flow method for preparing polysubstituted propargyl alcohol, comprising using a microtubule continuous flow reaction device, wherein the method comprises the following specific steps:

[0008] (1) acetylene gas or a terminal alkyne compound represented by formula I and an organic base solution are simultaneously conveyed into a mixer for premixing;

[0009] (2) the ketone carbonyl substrate represented by formula II and the reaction solution discharged from step (1) are simultaneously transported to a reactor for alkyne hydrogenation reaction;

[0010] (3) The reaction liquid discharged from step (2) is subjected to gas-liquid separation and then enters a distillation tower for distillation to obtain the target propargyl alcohol product represented by formula III;

[0011]

[0012]

[0013]

[0014] Among them, R 1 Selected from hydrogen, C1~C 10 Saturated aliphatic hydrocarbon, C2~C 10 Unsaturated aliphatic hydrocarbon group, C2~C 10 Alkoxy, C6~C 10 Aryl, -CH2-(OCH2-CH2)nOP1, -CH2-(OCH2-CH2)nNHP1, -CH2-(OCH2-CH2)nSP1 or -CH2-(SCH2-CH2)nSP1, where n is 0 to 10, P1 is H, C1 to C 10 Saturated aliphatic hydrocarbon, C2~C 10 Unsaturated aliphatic hydrocarbon group, C2~C 10 Alkoxy or C6~C 10 One of the aromatic groups;

[0015] R 2 Selected from hydrogen, C1~C 10 Saturated aliphatic hydrocarbon, C2~C 10 Unsaturated aliphatic hydrocarbon group, C2~C 10 Alkoxy, C6~C 10 Aryl, -CH2-(OCH2-CH2)nOP1, -CH2-(OCH2-CH2)nNHP1, -CH2-(OCH2-CH2)nSP1 or -CH2-(SCH2-CH2)nSP1, where n is 0 to 10, P1 is H, C1 to C 10 Saturated aliphatic hydrocarbon, C2~C 10 Unsaturated aliphatic hydrocarbon group, C2~C 10 Alkoxy or C6~C 10 One of the aromatic groups;

[0016] R 3 Selected from hydrogen, C1~C 10Saturated aliphatic hydrocarbon, C2~C 10 Unsaturated aliphatic hydrocarbon group, C2~C 10 Alkoxy, C6~C 10 One of the aromatic groups.

[0017] As a preferred embodiment of the continuous flow preparation method of the polysubstituted propargyl alcohol of the present invention, the organic base in step (1) is a quaternary ammonium salt.

[0018] As a preferred embodiment of the continuous flow preparation method of the polysubstituted propargyl alcohol of the present invention, the organic base solution in step (1) is a solution of a quaternary ammonium salt in a polar solvent selected from dimethyl sulfoxide, tetrahydrofuran, acetonitrile and ethanol.

[0019] As a preferred embodiment of the continuous flow preparation method of the polysubstituted propargyl alcohol of the present invention, the molar concentration of the organic base solution in step (1) is 0.1 to 1.0 mmol / mL.

[0020] As a preferred embodiment of the continuous flow preparation method of the polysubstituted propargyl alcohol of the present invention, wherein: if acetylene gas is used in step (1), the acetylene inlet pressure is 0.1-0.18 MPa, and the acetylene inlet speed is 5.00-10.0 mL / min;

[0021] If the terminal alkyne compound in step (1) is a liquid, the rate is adjusted according to the molar ratio of the reaction materials, and the injection rate of the organic base solution is 0.50 mL / min, so that the molar ratio of the terminal alkyne compound to the organic base is 10:1 to 4:1.

[0022] As a preferred embodiment of the continuous flow preparation method of the polysubstituted propargyl alcohol of the present invention, the injection rate of the ketone carbonyl compound in step (2) is 0.50 to 1.00 mL / min, so that the molar ratio of the terminal acetylene compound to the ketone carbonyl compound is 3:1 to 10:1.

[0023] As a preferred embodiment of the continuous flow preparation method of the polysubstituted propargyl alcohol of the present invention, the reaction temperature is 0 to 40°C.

[0024] As a preferred embodiment of the continuous flow preparation method of the polysubstituted propargyl alcohol of the present invention, wherein: the mixing residence time in step (1) is 2 to 30 minutes;

[0025] The reaction residence time of step (2) is 1.0 to 6.0 hours.

[0026] As a preferred embodiment of the continuous flow preparation method of the polysubstituted propargyl alcohol of the present invention, wherein: the mixer in step (1) is any one of a static mixer, a T-type mixer, a Y-type mixer, a cross mixer, a coaxial flow mixer or a flow focusing mixer;

[0027] The reactor in step (2) is any one of a microtubular reactor, a tubular reactor, and a microchannel reactor.

[0028] It should be noted that the process flow diagram of the micro-tube continuous flow reaction device used in the present invention is shown in Figure 1 The microtubular continuous flow reactor consists of a mixer, a T-shaped mixing tube, a microtubular reactor, a gas-liquid separator, and a rectifier. The design principle of the microtubular continuous flow reactor is based on the previously reported literature Chin. J. Process Eng., 2024, 24(9): 1001-1015. The microtubular reactor is a reactor designed based on a circular tubular channel without internal fine structures, with an inner diameter ranging from 10 to 400 μm, combined with the intrinsic reaction dynamics. The gas-liquid separator is a tubular cyclone gas-liquid separator, and the rectifier is a heat pipe rectifier.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The method of the present invention uses a continuous flow reaction system to continuously prepare polysubstituted propargyl alcohols. The method can achieve sufficient mixing of the reaction materials of each reaction unit and precise control of the reaction by regulating pipeline parameters, greatly improving the degree of automation, reducing manual operations, and lowering energy consumption costs, making it suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. Those skilled in the art can also derive other drawings based on these drawings without inventive effort. Among them:

[0032] Figure 1 This is a schematic diagram of the process flow of the micro-tube continuous flow reaction device used in the present invention;

[0033] Figure 2 Methyl butyridine alcohol 1 H NMR spectrum;

[0034] Figure 3 Methyl butyridine alcohol 13 C NMR spectrum;

[0035] Figure 4 Dehydrolinalool 1 H NMR spectrum;

[0036] Figure 5 Dehydrolinalool 13 C NMR spectrum. DETAILED DESCRIPTION

[0037] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0038] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0039] Secondly, the term "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in various places throughout this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive of other embodiments.

[0040] Unless otherwise specified, the raw materials used in the examples were purchased commercially.

[0041] The process flow diagram of the micro-tube continuous flow reaction device used in the present invention is shown in FIG. Figure 1 The micro-tubular continuous flow reaction device consists of a mixer, a T-type mixing tube, a micro-tubular reactor, a gas-liquid separator and a rectifier;

[0042] The organic base solution was injected into the microtube by a plunger pump and then injected into the mixer through the first inlet. Acetylene gas was introduced into the mixer from the second inlet through a back pressure valve. The two materials stayed in the mixer for 30 minutes, and the temperature of the mixing unit was controlled at 25°C.

[0043] The prepared acetone dimethyl sulfoxide solution was pumped into the T-type mixing tube by a plunger pump. The reaction liquid flowing out of the mixer entered the T-type mixing tube. The two materials were mixed in the T-type mixing tube and then entered the micro-tubular reactor. After the reaction was completed, they entered the gas-liquid separator. After continuous reaction and gas-liquid separation, the reaction liquid was obtained. The residence time was 40 minutes. The reaction temperature of the reaction unit was controlled at 25°C.

[0044] After the reaction reaches equilibrium, the reaction solution is collected continuously for 40 minutes and passed into a rectifier for distillation to obtain 2-methyl-3-butyn-2-ol.

[0045] Example 1

[0046]

[0047] A plunger pump was used to inject the prepared tetrabutylammonium hydroxide solution in dimethyl sulfoxide (30 ml, 0.57 mmol / mL) into the microtube at a flow rate of 1.0 mL / min. Acetylene gas was introduced at a flow rate of 25.4 mL / min. The two materials were kept in the mixer for 30 minutes, and the temperature of the mixing unit was controlled at 25°C. A prepared acetone solution in dimethyl sulfoxide (20 ml, 0.85 mmol / mL) was pumped into the microtube at a flow rate of 0.50 mL / min. The mixture and the reaction liquid flowing out of the mixer were combined in a T-shaped mixing tube and entered the microtube reactor. After continuous reaction and gas-liquid separation, the reaction liquid was obtained. The residence time was 40 minutes, and the reaction temperature of the reaction unit was controlled at 25°C. After the reaction equilibrium, the reaction liquid was collected continuously for 40 minutes and distilled to obtain 2-methyl-3-butyn-2-ol as a light yellow liquid with a yield of 83%. The NMR spectrum data of the product are as follows: 1 H NMR (500MHz, DMSO-d6) δ5.26 (s, 1H), 3.03 (d, J = 1.3Hz, 1H), 1.34 (d, J = 2.3Hz, 6H).; 13 CNMR (125MHz, DMSO-d6) δ90.55, 71.46, 63.46, 31.85. H NMR spectrum Figure 2 As shown, the carbon spectrum is Figure 3 shown.

[0048] Example 2

[0049]

[0050] The hydrogenation of alkynes with acetone and acetylene gas was used as an example to investigate the base used in the reaction. A prepared base solution in dimethyl sulfoxide (30 ml, 0.57 mmol / mL) was injected into a microtube using a plunger pump at a flow rate of 1.0 mL / min. Acetylene gas was simultaneously introduced at a flow rate of 25.4 mL / min. The two materials remained in the mixer for 30 minutes, and the temperature of the mixing unit was controlled at 25°C. A prepared acetone solution in dimethyl sulfoxide (20 ml, 0.85 mmol / mL) was pumped into the microtube at a flow rate of 0.50 mL / min. The reaction liquid exiting the mixer was combined with the reaction liquid in a T-shaped mixing tube and entered the microtube reactor. After continuous reaction and gas-liquid separation, the reaction liquid remained for 40 minutes. The reaction temperature in the reaction unit was controlled at 25°C. After the reaction reached equilibrium, the reaction liquid was collected continuously for 40 minutes. The product selectivity was determined by gas chromatography, and the reaction conversion was calculated based on the acetone. The reaction results are shown in Table 1.

[0051] Table 1

[0052]

[0053] As can be seen from the data analysis in Table 1, a strong base facilitates the reaction, but it also tends to trigger acetone self-condensation, affecting reaction selectivity. Considering the practicality of subsequent distillation separation, tetrabutylammonium hydroxide and tetramethylammonium hydroxide are preferred as the reaction base due to their good conversion rate and excellent selectivity, with tetrabutylammonium hydroxide being the most preferred.

[0054] Example 3

[0055]

[0056] Taking the hydrogenation of alkynes with acetone and acetylene as an example, the solvents used in the reaction were investigated. A prepared solution of tetrabutylammonium hydroxide (30 mL, 0.57 mmol / mL) was injected into a microtube at a flow rate of 1.0 mL / min using a plunger pump. Acetylene gas was simultaneously introduced at a flow rate of 25.4 mL / min. Both materials remained in the mixer for 30 minutes, and the mixing unit temperature was controlled at 25°C. A prepared solution of acetone (20 mL, 0.85 mmol / mL) was pumped into the microtube at a flow rate of 0.50 mL / min. The reaction liquid exiting the mixer was combined with the reaction liquid in a T-shaped mixing tube and then entered the microtube reactor. After continuous reaction and gas-liquid separation, the reaction liquid remained for 40 minutes, and the reaction temperature was controlled at 25°C. After equilibrium, the reaction liquid was collected continuously for 40 minutes. Product selectivity was determined by gas chromatography, and the reaction conversion was calculated using acetone as the reaction medium. The reaction results are shown in Table 2.

[0057] Table 2

[0058]

[0059] From the data analysis results in Table 2, it can be seen that polar solvents are beneficial to the reaction conversion and have a significant impact on the reaction selectivity. Dimethyl sulfoxide and N,N-dimethylformamide are preferred, and dimethyl sulfoxide is most preferred.

[0060] Example 4

[0061]

[0062] A plunger pump was used to inject the prepared tetrabutylammonium hydroxide solution in dimethyl sulfoxide (30 ml, 0.57 mmol / mL) into the microtube at a flow rate of 1.0 mL / min. Acetylene gas was introduced at a flow rate of 25.4 mL / min. The two materials were kept in the mixer for 30 minutes, and the temperature of the mixing unit was controlled at 25°C. A prepared methyl heptenone solution in dimethyl sulfoxide (20 ml, 0.85 mmol / mL) was pumped into the microtube at a flow rate of 0.50 mL / min. The mixture and the reaction liquid flowing out of the mixer were combined in a T-shaped mixing tube and entered the microtube reactor. After continuous reaction and gas-liquid separation, the reaction liquid was obtained. The residence time was 40 minutes, and the reaction temperature of the reaction unit was controlled at 25°C. After the reaction equilibrium was reached, the reaction liquid was collected continuously for 40 minutes and distilled to obtain dehydrolinalool as a light yellow liquid with a yield of 91%. The NMR spectrum data of the product are as follows: 1 H NMR(500MHz,Chloroform-d6)δ5.04(t,J=6.3Hz,1H),3.23(s,1H),2.36(d,J=2.1Hz,1H),2 .10(dtt,J=48.2,13.7,6.4Hz,2H),1.71–1.54(m,5H),1.53(s,3H),1.38(d,J=2.7Hz,3H).; 13 C NMR (125MHz, Chloroform-d6) δ131.88, 131.86, 131.84, 123.74, 87.65, 71.41, 67.87, 67.85, 43.13, 29.52, 25.53, 23.40, 17.52. Figure 2 As shown, the carbon spectrum is Figure 3 shown.

[0063] Example 5

[0064]

[0065] Cyclohexanone was used as the ketone carbonyl substrate in the reaction, and the operation was the same as in Example 1. The reaction temperature in the reaction unit was controlled at 25°C. The final product was a light yellow liquid with a yield of 94%. The NMR spectrum data of the product are as follows: 1 H NMR(500MHz,Chloroform-d6)δ2.58(s,1H),2.47(s,1H),1.92–1.89(m,4H),1.58–1.52,1.27–1.18(m,6H).; 13 C NMR (125MHz, Chloroform-d6): δ88.2,72.5,68.8,40.1,25.5,23.5.

[0066] Example 6

[0067]

[0068] Acetophenone was used as the ketone carbonyl substrate in the reaction. The reaction temperature was controlled at 15°C. The final product was recrystallized to obtain pale yellow crystals with a yield of 94%. The NMR spectrum of the product is as follows: 1 H NMR (500MHz, Chloroform-d6) δ7.66–7.64(m,2H),7.37–7.34(m,2H),7.30–7.27(m,1H),2.65(s,1H),2.37(s,1H),1.77(s,3H).; 13 C NMR (125MHz, Chloroform-d6) δ145.4,128.8,128.3,125.3,87.7,73.5,70.3,33.5.

[0069] Example 7

[0070]

[0071] 4-Acetylpyridine was used as the ketocarbonyl substrate in the reaction, following the same procedures as in Example 1. The reaction temperature in the reaction unit was maintained at 25°C, and the reaction coil was extended threefold to a residence time of 2 hours. The final product was recrystallized to afford pale yellow crystals in an 85% yield. The product's NMR spectrum data are as follows: 1 H NMR(500MHz,Acetone-d6)8.54(d, 3 J=5.6Hz,2H),7.57(d, 3 J=5.6Hz,2H),3.78(s,1H),3.14(s,1H),1.69(s,3H).; 13 C NMR (125MHz, Acetone-d6) δ155.9,150.5,120.9,87.9,74.2,68.7,33.7.

[0072] Example 8

[0073]

[0074] A prepared tetrabutylammonium hydroxide solution in dimethyl sulfoxide (30 ml, 0.57 mmol / mL) was injected into the microtube at a flow rate of 0.5 mL / min using a plunger pump. Simultaneously, a dimethyl sulfoxide solution of cyclohexane acetylene (30 ml, 5.7 mmol / mL) was introduced at a flow rate of 0.5 mL / min. The two materials were retained in the mixer for 30 minutes, and the temperature of the mixing unit was controlled at 25°C. A prepared cyclohexanone solution in dimethyl sulfoxide (50.3 ml, 0.85 mmol / mL) was pumped into the microtube at a flow rate of 0.50 mL / min. The mixture and the reaction solution flowing out of the mixer were combined in a T-shaped mixing tube and entered the microtube reactor. After continuous reaction and gas-liquid separation, the reaction solution was obtained. The residence time was 100 minutes, and the reaction temperature of the reaction unit was controlled at 25°C. After the reaction equilibrium was reached, the reaction solution was continuously collected for 100 minutes, concentrated, and recrystallized to obtain a white solid product with a yield of 84%. The NMR spectrum data of the product are as follows: 1 HNMR(500MHz,Chloroform-d6)δ2.43–2.37(m,1H),2.17(s,1H),1.87–1.17(m,20H).; 13 C NMR (125MHz, Chloroform-d6) δ89.4,84.3,69.1,40.8,33.1,29.2,26.3,25.7,25.1,24.0.

[0075] Example 9

[0076]

[0077] Phenylacetylene was used as the terminal alkyne substrate in the reaction, and the procedure was the same as in Example 6. The reaction solution was concentrated and then recrystallized to obtain a white solid product with a yield of 87%. The NMR spectrum data of the product are as follows: 1 H NMR(500MHz,Chloroform-d6)δ7.42–7.40(m,2H),7.29–7.27(m,3H),2.12–1.98(m,5H),1.75–1.58(m,4H),1.30–1.21(m,2H).; 13 C NMR (125MHz, Chloroform-d6) δ132.1,128.7,128.6,123.4,93.3,84.8,69.5,40.5,25.7,23.8.

[0078] Example 10

[0079]

[0080] The reaction was carried out using phenylacetylene as the terminal alkyne substrate and acetophenone as the ketone carbonyl substrate, following the same procedures as in Example 6. The reaction temperature in the reaction unit was maintained at 25°C, and the reaction coil was extended threefold to achieve a residence time of 2 hours. The reaction solution was concentrated and purified by recrystallization to afford a pale yellow solid product in a 91% yield. The product's NMR spectrum data are as follows: 1 H NMR(500MHz,Chloroform-d6)δ7.72–7.70(m,2H),7.47–7.44,7.38–7.34,7.30–7.26(m,8H),2.52(s,1H),1.84(s,1H).; 13 C NMR (125MHz, Chloroform-d6) δ146.1,132.1,128.9,128.8,128.7,128.2,125.4,123.0,92.9,85.4,70.8,33.7.

[0081] Example 11

[0082]

[0083] The reaction was carried out using phenylacetylene as the terminal alkyne substrate and 4-acetylpyridine as the ketocarbonyl substrate, following the same procedures as in Example 6. The reaction solution was concentrated and purified by recrystallization to obtain a pale yellow solid product in an 88% yield. The product's NMR spectrum data are as follows: 1 HNMR(500MHz,Chloroform-d6)δ8.52(m,2H),7.60(m,2H),7.42–7.40(m,2H),7.31–7.29(m,3H),4.63(s,1H),1.81(s,3H,).; 13 C NMR (125MHz, Chloroform-d6) δ155.7,149.9,132.1,129.2,128.8,122.6,120.6,91.9,85.6,69.5,33.6.

[0084] The method of the present invention uses a continuous flow reaction system to continuously prepare polysubstituted propargyl alcohols. The method can achieve sufficient mixing of the reaction materials in each reaction unit and precise control of the reaction by regulating pipeline parameters, greatly improving the degree of automation, reducing manual operations, and lowering energy consumption costs, making it suitable for industrial production.

[0085] Compared with traditional batch reactor process technology, the method proposed in the present invention uses a continuous flow reaction system including a mixer and a continuous flow reactor connected in sequence to prepare polysubstituted propargyl alcohols such as dehydrolinalool. The system has excellent mass transfer, heat transfer and material molecular mixing properties, and solves the high risk and high energy consumption problems caused by excessively high pressure and low temperature in traditional reactions.

[0086] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A continuous flow preparation method for polysubstituted propargyl alcohol, characterized in that: include, Using a microtube continuous flow reaction device, the method specifically comprises the following steps: (1) acetylene gas or a terminal alkyne compound represented by formula I and an organic base solution are simultaneously conveyed into a mixer for premixing; (2) the ketone carbonyl substrate represented by formula II and the reaction solution discharged from step (1) are simultaneously transported to a reactor for alkyne hydrogenation reaction; (3) The reaction liquid discharged from step (2) is subjected to gas-liquid separation and then enters a distillation tower for distillation to obtain the target propargyl alcohol product represented by formula III; Among them, R 1 Selected from hydrogen, C1~C 10 Saturated aliphatic hydrocarbon, C2~C 10 Unsaturated aliphatic hydrocarbon group, C2~C 10 Alkoxy, C6~C 10 Aryl, -CH2-(OCH2-CH2)nOP1, -CH2-(OCH2-CH2)nNHP1, -CH2-(OCH2-CH2)nSP1 or -CH2-(SCH2-CH2)nSP1, where n is 0 to 10, P1 is H, C1 to C 10 Saturated aliphatic hydrocarbon, C2~C 10 Unsaturated aliphatic hydrocarbon group, C2~C 10 Alkoxy or C6~C 10 One of the aromatic groups; R 2 Selected from hydrogen, C1~C 10 Saturated aliphatic hydrocarbon, C2~C 10 Unsaturated aliphatic hydrocarbon group, C2~C 10 Alkoxy, C6~C 10 Aryl, -CH2-(OCH2-CH2)nOP1, -CH2-(OCH2-CH2)nNHP1, -CH2-(OCH2-CH2)nSP1 or -CH2-(SCH2-CH2)nSP1, where n is 0 to 10, P1 is H, C1 to C 10 Saturated aliphatic hydrocarbon, C2~C 10 Unsaturated aliphatic hydrocarbon group, C2~C 10 Alkoxy or C6~C 10 One of the aromatic groups; R 3 Selected from hydrogen, C1~C 10 Saturated aliphatic hydrocarbon, C2~C 10 Unsaturated aliphatic hydrocarbon, C2~C 10 Alkoxy, C6~C 10 One of the aromatic groups.

2. The continuous flow preparation method of polysubstituted propargyl alcohol according to claim 1, characterized in that: The organic base in step (1) is a quaternary ammonium salt.

3. The continuous flow preparation method of polysubstituted propargyl alcohol according to claim 2, characterized in that: The organic base solution in step (1) is a solution prepared by dissolving a quaternary ammonium salt in a polar solvent selected from dimethyl sulfoxide, tetrahydrofuran, acetonitrile and ethanol.

4. The continuous flow preparation method of polysubstituted propargyl alcohol according to claim 2 or 3, characterized in that: The organic base solution in step (1) has a molar concentration of 0.1 to 1.0 mmol / mL.

5. The continuous flow preparation method of polysubstituted propargyl alcohol according to claim 1, characterized in that: If acetylene gas is used in step (1), the acetylene inlet pressure is 0.1-0.18 MPa, and the acetylene inlet speed is 5.00-10.0 mL / min; If the terminal alkyne compound in step (1) is a liquid, the rate is adjusted according to the molar ratio of the reaction materials, and the injection rate of the organic base solution is 0.50 mL / min, so that the molar ratio of the terminal alkyne compound to the organic base is 10:1 to 4:

1.

6. The continuous flow preparation method of polysubstituted propargyl alcohol according to claim 1, characterized in that: The injection rate of the ketone carbonyl compound in step (2) is 0.50-1.00 mL / min, so that the molar ratio of the terminal alkyne compound to the ketone carbonyl compound is 3:1-10:

1.

7. The continuous flow preparation method of polysubstituted propargyl alcohol according to claim 1, characterized in that: The reaction temperature is 0-40°C.

8. The continuous flow preparation method of polysubstituted propargyl alcohol according to claim 7, characterized in that: The mixing residence time in step (1) is 2 to 30 minutes; The reaction residence time of step (2) is 1.0 to 6.0 hours.

9. The continuous flow preparation method of polysubstituted propargyl alcohol according to any one of claims 1 to 3 and 5 to 8, characterized in that: The mixer in step (1) is any one of a static mixer, a T-type mixer, a Y-type mixer, a cross mixer, a coaxial flow mixer or a flow focusing mixer; The reactor in step (2) is any one of a microtubular reactor, a tubular reactor, and a microchannel reactor.

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