Continuous flow reactor and gas-liquid reaction process

Abstract

The present application relates to a kind of continuous flow reactor and gas-liquid reaction process.Utilizing the continuous flow reactor, the synthesis of disulfide compound, fluorosulfate compound, amine sulfuryl fluoride compound etc.can be realized by efficient click chemistry reaction.The continuous flow reactor is tubular continuous flow reactor of pipe-in-pipe type, the hollow fiber membrane is used for gas-liquid two-phase flow reaction for the first time in the reactor, and the hollow fiber membrane shows high permeability to many gases such as sulfuric fluoride.The liquid reaction mixture in the continuous flow reactor is in the gap between outer tube and inner tube, and the gaseous reactant is in the inner tube.The gaseous reactant in the inner tube diffuses outward through the hollow fiber membrane to the gap between the outer tube and the inner tube, and reacts with the reactant solution filled in the gap.The present application realizes the click chemistry reaction using gaseous substance as reagent by the way of flow chemistry, and can more efficiently and conveniently realize the scale application of click chemistry reaction.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and relates to a continuous flow reactor and a gas-liquid reaction process for synthesizing dithio compounds, fluorosulfate compounds and aminosulfonyl fluoride compounds. BACKGROUND

[0002] Flow chemistry has attracted great attention in scientific research and industrial production due to its advantages of modularity, high heat and mass transfer, automatic control and high efficiency and safety (Chem. Soc. Rev., 2020, 49, 8910). Click chemistry reactions are more likely to achieve large-scale production due to their high yield, fast rate and wide application range. It is of great practical significance to realize large-scale production of click chemistry reactions by using flow chemistry reactors.

[0003] Dithio compounds are widely used in the fields of organic synthesis, pharmaceutical development, material science and peptidomimetics (Top. Curr. Chem., 2018, 376, 1-40). Using thiol compounds as raw materials, dithio compounds can be synthesized by click chemistry reaction mediated by sulfonyl fluoride compounds in the presence of base and solvent, which has the advantages of high efficiency, rapidness and high selectivity. However, such reactions face problems in practical application, such as difficulty in achieving large-scale production due to the limitation of the reactor, and the fact that sulfonyl fluoride gas cannot be fully utilized. The synthesis processes of fluorosulfate compounds and aminosulfonyl fluoride compounds based on click chemistry reactions also encounter similar problems. Flow chemistry reactors become an important way to realize large-scale production of such efficient click chemistry reactions.

[0004] Generally, when a flow chemistry reaction involves a gas, the gas can be added to the flow reaction solution through a simple T- or Y-mixer. However, such reactors have the disadvantages of small contact area between gas and liquid phases, difficulty in achieving 100% conversion of the gaseous reactant, and the need for additional exhaust gas treatment devices for unreacted gaseous reactants. A pipe-in-pipe tubular flow reactor can achieve efficient contact between gaseous and liquid reactants, improve reaction efficiency, and fully utilize gaseous reactants while effectively preventing the diffusion of gaseous reactants into the environment. In an ideal pipe-in-pipe tubular flow reactor, liquid passes through the gap between the outer pipe and the inner pipe, while gas passes through the inner pipe. The gas can dissolve into the liquid in the gap between the outer pipe and the inner pipe through the inner pipe wall and react with the reactants in the liquid. Hollow fiber membranes exhibit high permeability to many gases. Therefore, the present application first uses a hollow fiber membrane as the inner pipe of the reactor to establish a new type of pipe-in-pipe flow chemistry reactor. Compared with the existing pipe-in-pipe reactor using Teflon AF-2400 as the inner pipe of the reactor, the present application uses a hollow fiber membrane as the inner pipe, which is more economical and more efficient (Chem. Soc. Rev., 2020, 49, 8910).

[0005] The synthesis method of dithio compounds, fluorosulfate compounds and aminosulfonyl fluoride compounds based on flow chemistry applies flow chemistry to the large-scale production of click chemistry reactions, and has important practical significance for the industrial synthesis of dithio compounds, fluorosulfate compounds and aminosulfonyl fluoride compounds, especially for drug synthesis and polypeptide synthesis. SUMMARY

[0006] The purpose of the present application is to provide a pipe-in-pipe tubular flow reactor, a continuous flow reactor for gas-liquid reactions, and a process for synthesizing dithio compounds, fluorosulfate compounds and aminosulfonyl fluoride compounds using the reactor. The pipe-in-pipe tubular flow reactor of the present application first uses a hollow fiber membrane as the inner pipe of the pipe-in-pipe tubular flow reactor. In this reactor, the gaseous reactant diffuses outward through the hollow fiber membrane. Due to the unique microstructure of the hollow fiber membrane, the gas-liquid two phases in the system have a large contact area. Since heterogeneous reactions occur at the interface between the two phases, the contact area between the gas-liquid two phases directly affects the reaction rate. Therefore, the above-mentioned pipe-in-pipe tubular flow reactor can improve the reaction rate of gas-liquid reactions by increasing the contact area between the gas-liquid two phases. In addition, the above-mentioned reactor can fully utilize the gaseous reactant and effectively prevent the diffusion of the gaseous reactant into the environment. Compared with the existing pipe-in-pipe reactor using Teflon AF-2400 as the inner pipe of the reactor, the present application uses a hollow fiber membrane as the inner pipe, which is more economical and more efficient.

[0007] Further, the pipe-in-pipe tubular flow reactor can be combined with a suitable liquid feeding device, a gas feeding device, a balloon device, a three-way valve and a product collecting device to form a continuous flow reactor for gas-liquid reaction. This device can realize efficient and large-scale production of gas-liquid reaction, avoiding the problems of small gas-liquid contact area and insufficient utilization of gas reactants in conventional batch reaction.

[0008] The click chemistry reaction using sulfuric fluoride gas as a reactant can be carried out in the continuous flow reactor, and a large amount of production of disulfide compounds, fluorosulfate compounds and amine sulfuryl fluoride compounds can be realized. Compared with the click chemistry reaction synthesis process using a traditional reactor, the click chemistry reaction operation using a continuous flow reactor is more simple, the large-scale production can be more easily realized by parallel continuous flow reactors, and the gas reactants can be fully utilized and prevented from diffusing into the environment.

[0009] To achieve the above object, the technical scheme of the present application is as follows:

[0010] The pipe-in-pipe tubular flow reactor can be used to construct a continuous flow reactor for gas-liquid reaction, as shown in Figure 1 The pipe-in-pipe tubular flow reactor has the following characteristics:

[0011] The outer tube wall is made of plastic, glass or metal material with good airtightness and chemical resistance, and the inner tube is a hollow fiber membrane;

[0012] The hollow fiber membrane is a hollow fiber membrane prepared from polyether sulfone, polybenzimidazole, polyvinylidene fluoride, polyacrylonitrile, polyaniline, cellulose acetate, chitosan, etc.

[0013] In use, the mixed liquid formed by dissolving the reactants and other non-gaseous reagents in a solvent is fed and flows into the gap between the outer tube and the inner tube of the pipe-in-pipe tubular flow reactor, at the same time, the gaseous reactant is fed and fills the inner tube composed of the hollow fiber membrane; the gas can only permeate to the outside through the hollow fiber membrane, and chemically reacts with the liquid filled in the gap between the outer tube and the inner tube.

[0014] The continuous flow reactor for gas-liquid reaction, as shown in Figure 2 The continuous flow reactor for gas-liquid reaction comprises:

[0015] The pipe-in-pipe tubular flow reactor;

[0016] A liquid feeding device, the liquid feeding device comprising a liquid conduit and a peristaltic pump upstream of the pipe-in-pipe tubular flow reactor, the peristaltic pump being capable of controlling the flow rate of the mixed liquid between the inner tube and the outer tube;

[0017] The gas inlet device comprises a double-layer gas conduit upstream of the pipe-in-pipe tubular flow reactor and a one-way valve which can prevent the backflow of liquid reactants into the gas inlet device; the inner tube of the double-layer gas conduit is a hollow fiber membrane which, together with the hollow fiber membrane in the inner tube of the pipe-in-pipe tubular flow reactor, forms a continuous tubular structure; the outer tube of the double-layer gas conduit is a tube made of a material which does not chemically react with gas and has good airtightness;

[0018] The continuous flow reactor comprises two balloon devices; one is located at the connection between the gas cylinder and the gas inlet device; the other is located between the three-way valve in the product collection device and the product collection bottle; the balloons are connected into the system through an adapter with good airtightness; when the two balloons are gradually filled with gas and expand, it indicates that the gas has completely filled the inner tube of the entire pipe-in-pipe tubular reactor, and the gas pressure in the system is slightly higher than atmospheric pressure;

[0019] The continuous flow reactor comprises two three-way valves; one is a three-way valve connecting the liquid inlet device, the gas inlet device and the pipe-in-pipe tubular flow reactor; the other is a three-way valve connecting the product collection device, the balloon device at the end of the gas inner tube and the pipe-in-pipe tubular flow reactor;

[0020] The product collection device comprises a product collection bottle and a pipeline connecting the outer tube of the pipe-in-pipe tubular flow reactor and the collection bottle.

[0021] The above-mentioned process for synthesizing a disulfide compound using the continuous flow reactor for gas-liquid reaction comprises the following steps:

[0022] A) mixing a thiol compound represented by general formula (1) and a base in a solvent to form a mixed liquid, feeding the mixed liquid into the gap between the outer tube and the inner tube of the continuous flow reactor through the liquid inlet device, and feeding gaseous reactants into the inner tube filled with hollow fiber membranes through the gas inlet device;

[0023] B) in the continuous flow reactor, the gas in the inner tube diffuses into the continuously flowing mixed liquid in the gap between the inner tube and the outer tube, and reacts with the mixed liquid to obtain a disulfide compound represented by general formula (2);

[0024]

[0025] C) the solution of the generated product is collected by the product collection device;

[0026] The gaseous reactant is sulfuric fluoride (SO2F2) gas;

[0027] said base is selected from one or more of triethylamine, methanolamine, ethanolamine, triethanolamine, 1,8-diazabicycloundec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, 4-dimethylaminopyridine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, in any proportion;

[0028] Preferably, said base is triethylamine;

[0029] said solvent is selected from one or more of acetonitrile, ethyl acetate, dichloromethane, n-hexane, ethanol, water, borate buffer solution, serum, in any proportion;

[0030] Preferably, said solvent is acetonitrile or acetonitrile / borate buffer solution (1:1).

[0031] The synthesis process of the above-mentioned disulfide compound is characterized in that:

[0032] The outer tube material of the continuous flow reactor for gas-liquid reaction is polytetrafluoroethylene, with an inner diameter of 4.0 mm and a length of 1.5 m; the inner tube material is polyvinylidene fluoride hollow fiber membrane, with an outer diameter of 2.6 mm and a length of 1.5 m;

[0033] The concentration of the reactant in the reaction solution is 1 / 6 mol / L;

[0034] The concentration of the base in the reaction solution is 1 / 3 or 1 / 6 mol / L;

[0035] The speed of the peristaltic pump is 1 mL / min;

[0036] The hourly output is 10 mmol.

[0037] The synthesis process of the above-mentioned disulfide compound is characterized in that:

[0038] Efficient derivatization of the drug captopril and oxidation of reduced glutathione can be achieved, which is converted into the corresponding disulfide.

[0039] The synthesis process of the above-mentioned fluorosulfate compound using the continuous flow reactor for gas-liquid reaction includes the following steps:

[0040] A) Form a mixed liquid of a phenolic compound represented by general formula (3) and a base in a solvent, which is fed by a liquid feeding device and flows into the gap between the outer tube and the inner tube of the continuous flow reactor, at the same time, a gaseous reactant is fed by a gas feeding device and fills the inner tube composed of hollow fiber membrane;

[0041] B) in the continuous flow reactor, the gas in the inner tube diffuses into the continuously flowing mixed liquid in the gap between the inner tube and the outer tube and reacts with it to obtain a fluorosulfate compound represented by general formula (4);

[0042]

[0043] C) the solution of the generated product is collected by a product collection device;

[0044] The gaseous reactant is sulfur oxyfluoride (SO2F2) gas;

[0045] The base is selected from one or more of triethylamine, methanolamine, ethanolamine, triethanolamine, 1,8-diazabicycloundec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, 4-dimethylaminopyridine, 2-tert-butyl-1,1,3,3-tetramethylguanidine, or a mixture of any proportion thereof;

[0046] Preferably, the base is triethylamine;

[0047] The solvent is selected from one or more of acetonitrile, ethyl acetate, dichloromethane, n-hexane, ethanol, water, borax buffer solution, serum, or a mixture of any proportion thereof;

[0048] Preferably, the solvent is dichloromethane.

[0049] The above-mentioned synthesis process of a fluorosulfate compound is characterized in that:

[0050] The material of the outer tube of the continuous flow reactor for gas-liquid reaction is polytetrafluoroethylene, the inner diameter is 4.0 mm, and the length is 1.5 m; the material of the inner tube is polyvinylidene fluoride hollow fiber membrane, the outer diameter is 2.6 mm, and the length is 1.5 m;

[0051] The concentration of the reactant in the reaction solution is 1 / 6 mol / L;

[0052] The concentration of the base in the reaction solution is 1 / 3 mol / L;

[0053] The speed of the peristaltic pump is 5 mL / min;

[0054] If the reaction mixture in the collection bottle contains unreacted reactants, the mixture is re-injected into the continuous flow reactor until a satisfactory yield is obtained, and the continuous flow reactor has a production capacity of 1 mmol per hour.

[0055] The above-mentioned synthesis process of a fluorosulfate compound is characterized in that:

[0056] The natural product thymol can be efficiently converted into the corresponding fluorosulfate.

[0057] The amine sulfuryl fluoride compound synthesis process using the continuous flow reactor for gas-liquid reaction comprises the following steps:

[0058] A) mixing the amine compound of general formula (5) with the base in the solvent to form a mixed liquid, feeding the mixed liquid into the gap between the outer tube and the inner tube of the continuous flow reactor through the liquid feeding device, and feeding the gaseous reactant into the inner tube filled with the hollow fiber membrane through the gas feeding device;

[0059] B) in the continuous flow reactor, the gas in the inner tube diffuses into the mixed liquid continuously flowing in the gap between the inner tube and the outer tube, and reacts with the mixed liquid to obtain the amine sulfuryl fluoride compound of general formula (6);

[0060]

[0061] C) the solution of the generated product is collected by the product collecting device;

[0062] The gaseous reactant is sulfuric fluoride (SO2F2) gas;

[0063] The base is selected from one or more of the following in any proportion: triethylamine, methanolamine, ethanolamine, triethanolamine, 1,8-diazabicycloundec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, 4-dimethylaminopyridine, 2-tert-butyl-1,1,3,3-tetramethylguanidine;

[0064] Preferably, the base is 4-dimethylaminopyridine;

[0065] The solvent is selected from one or more of the following in any proportion: acetonitrile, ethyl acetate, dichloromethane, n-hexane, ethanol, water, borax buffer solution, serum;

[0066] Preferably, the solvent is acetonitrile / water (4:1).

[0067] The amine sulfuryl fluoride compound synthesis process comprises the following characteristics:

[0068] The material of the outer tube of the continuous flow reactor for gas-liquid reaction is polytetrafluoroethylene, the inner diameter is 4.0 mm, and the length is 1.5 m; the material of the inner tube is polyvinylidene fluoride hollow fiber membrane, the outer diameter is 2.6 mm, and the length is 1.5 m;

[0069] The concentration of the reactant in the reaction liquid is 1 / 6 mol / L;

[0070] The concentration of the base in the reaction liquid is 1 / 12 mol / L;

[0071] The concentration of magnesium oxide in the reaction liquid is 5 / 12 mol / L;

[0072] The speed of the peristaltic pump is 5 mL / min.

[0073] If the reaction mixture in the collection bottle contains unreacted reactants, the mixture is re-injected into the continuous flow reactor with a production capacity of 1 mmol per hour until a satisfactory yield is obtained.

[0074] The present application has the following beneficial effects:

[0075] 1) The present application first uses hollow fiber membranes as the inner tube of the tube-in-tube tubular flow reactor. Gaseous reactants such as sulfuric fluoride can efficiently permeate through the hollow fiber membrane wall to the outside of the inner tube and react with the liquid reactants in the gap between the inner tube and the outer tube. Compared with the existing tube-in-tube tubular flow reactor using Teflon AF-2400 as the inner tube of the reactor, the present application uses hollow fiber membranes as the inner tube, which is more economical and efficient.

[0076] 2) The present application establishes a continuous flow reactor suitable for click chemistry reactions requiring gaseous reagents for the first time using a tube-in-tube tubular flow reactor. The use of this reactor can realize continuous synthesis, making the synthesis process more simple and efficient. Scale-up production of click chemistry reactions can be achieved through parallel continuous flow reactors.

[0077] 3) The synthesis process of disulfide compounds, fluorosulfate compounds and amine sulfonyl fluoride compounds established by the present application has the advantages of inexpensive reagents, simple operation and high yield.

[0078] 4) The present application provides an effective way for the scale-up production of functional compounds such as drugs, polypeptides and natural products, and has realized the efficient derivatization of a large amount of the drug captopril, the oxidation of the polypeptide reduced glutathione and the derivatization of the natural product thymol. BRIEF DESCRIPTION OF DRAWINGS

[0079] Figure 1 Schematic diagram of the tube-in-tube tubular flow reactor used in the examples

[0080] Figure 2 Schematic diagram of the continuous flow reactor used in the examples

[0081] Figure 3 Device diagram of the continuous flow reactor used in Example 1

[0082] Figure 4 Device diagram of the continuous flow reactor used in Example 2

[0083] Figure 5 Device diagram of the continuous flow reactor used in Example 3

[0084] Figure 6 Figure for continuous flow reactor device used in Example 4 DETAILED DESCRIPTION

[0085] Unless otherwise indicated, the starting materials and apparatus used in the present application are known products and are obtained by purchase of commercially available products.

[0086] The specific embodiments of the present application are as follows:

[0087] 1. A continuous flow reactor is built as shown in Figure (2). A continuous flow reactor for gas-liquid reaction, comprising:

[0088] A tube-in-tube type tubular flow reactor can be used to build a continuous flow reactor for gas-liquid reaction, as shown in Figure (1), characterized in that:

[0089] The outer tube is made of polytetrafluoroethylene, with an inner diameter of 4.0 mm and a length of 1.5 m; the inner tube is made of polyvinylidene fluoride hollow fiber membrane, with an outer diameter of 2.6 mm and a length of 1.5 m;

[0090] A liquid sampling device, comprising a liquid conduit and a peristaltic pump upstream of the tube-in-tube type tubular flow reactor, the peristaltic pump being capable of controlling the flow rate of the mixed liquid between the inner tube and the outer tube;

[0091] A gas sampling device, comprising a double-layer gas conduit and a one-way valve upstream of the tube-in-tube type tubular flow reactor, the one-way valve being capable of preventing liquid reactants from flowing back into the gas sampling device; the inner tube of the double-layer gas conduit is a hollow fiber membrane, which together with the hollow fiber membrane in the inner tube of the tube-in-tube type tubular flow reactor forms a continuous tubular structure; the outer tube of the double-layer gas conduit is a tube made of a material that does not chemically react with gas and has good airtightness;

[0092] Balloon devices, the continuous flow reactor includes two balloon devices; one is located at the connection between the gas cylinder and the gas sampling device; the other is located between the three-way valve in the product collection device and the product collection bottle; the balloons are connected into the system through adapter interfaces with good airtightness; when the two balloons are gradually filled with gas and swell, it indicates that the gas has completely filled the inner tube of the entire tube-in-tube type tubular reactor, and the gas pressure in the system is slightly higher than atmospheric pressure;

[0093] Three-way valves, the continuous flow reactor includes two three-way valves; one is a three-way valve connecting the liquid sampling device, the gas sampling device and the tube-in-tube type tubular flow reactor; the other is a three-way valve connecting the product collection device, the elastic membrane at the end of the gas inner tube and the tube-in-tube type tubular flow reactor;

[0094] A product collection device, comprising a product collection bottle and a connecting pipe between the outer tube of a tubular flow reactor and the collection bottle.

[0095] 2. Dissolve the reactant (10.0 mmol) in 60 mL of solvent at room temperature, add the specified amount of base (20.0, 10.0 or 5.0 mmol), and stir until completely dissolved.

[0096] 3. The reactants and alkali are mixed in a solvent to form a liquid mixture. The mixture is fed into the gap between the outer and inner tubes of the continuous flow reactor at a specified flow rate through a liquid injection device. At the same time, the gaseous reactants SO2 and F2 are fed into the inner tube, which is made of hollow fiber membrane, through a gas injection device. When the two balloons are gradually filled with gas and expand, it indicates that the gas has completely filled the inner tube of the tubular reactor and the gas pressure in the system is slightly greater than atmospheric pressure.

[0097] 4. In a continuous flow reactor, the gas in the inner tube diffuses into the continuously flowing mixed liquid in the gap between the inner and outer tubes and reacts with it;

[0098] 5. After the specified reaction time, when all liquid reactants have completely passed through the tubular flow reactor and flowed into the collection device, the liquid reaction mixture is concentrated, post-processed, and the product is obtained. The yield is calculated by weighing and the structure of the product is characterized.

[0099] Example 1: Derivatization of the drug captopril

[0100]

[0101] Refer to the specific implementation method, such as Figure 3 As shown, compound 1a (2.17 g, 10.0 mmol), triethylamine (20.0 mmol), and acetonitrile (60 mL) were added to a 100 mL single-necked round-bottom flask and mixed thoroughly at room temperature. Simultaneously, SO2F2 gas was introduced into the continuous flow reactor through a gas injection device. When the two balloons were gradually filled and inflated with gas, and the gas pressure in the system was slightly higher than atmospheric pressure, a peristaltic pump was started at a rate of 1 mL / min. After reacting for 1 h, all liquid reactants were collected by the product collection device after passing through a tubular flow reactor. The reaction solution was washed three times with 10 mL of hydrochloric acid aqueous solution (1 M), the organic phase was dried, and the solvent was removed by rotary evaporation. The yield was calculated to be 95%. The target product 2a obtained by the above synthesis method was analyzed by 1H and 1C NMR spectroscopy. The test results are as follows: 1H NMR (500MHz, DMSO-d6) δ4.28-4.15(m, 2H), 3.62-3.56(m, 4H), 3.02-2.83(m, 4H), 2.69 (m, 2H), 2.14 (m, 2H), 1.96-1.89 (m, 4H), 1.85 (m, 2H), 1.09 (d, J=6.7Hz, 6H); 13 C{ 1 H}NMR (126MHz, DMSO-d6) δ173.3, 172.3, 58.4, 46.5, 41.2, 36.9, 28.7, 24.4, 16.5.

[0102] Example 2: Oxidation of reduced glutathione

[0103]

[0104] Refer to the specific implementation method, such as Figure 4 As shown, compound 1b (3.07 g, 10.0 mmol), triethylamine (10.0 mmol), and an acetonitrile / borax buffer solution (1:1, 60 mL) were added to a 100 mL single-necked round-bottom flask. The mixture was thoroughly mixed at room temperature, and SO2F2 gas was simultaneously introduced into a continuous flow reactor. When the two balloons were gradually filled and inflated with gas, and the gas pressure in the system was slightly higher than atmospheric pressure, a peristaltic pump was started at a rate of 1 mL / min. After reacting for 1 hour, all liquid reactants were collected by the product collection device after passing through a tubular flow reactor. The reaction solution was adjusted to alkaline with sodium hydroxide solution (1 M), and the solvent and triethylamine were removed by rotary evaporation. The yield was calculated to be 98%. The target product 2b obtained by the above synthesis method was analyzed by 1H and 1C NMR spectroscopy. The test results are as follows: 1 H NMR (500MHz, D2O) δ4.75 (dd, J=9.6, 4.4Hz, 2H), 3.75 (m, 4H), 3.63 (t, J=6.3Hz, 2H), 3 .30 (dd, J=14.3, 4.4Hz, 2H), 2.96 (dd, J=14.3, 9.6Hz, 2H), 2.49 (m, 4H), 2.08 (m, 4H); 13 C{ 1 H}NMR (126MHz, D2O) δ176.6, 176.3, 175.4, 171.9, 54.5, 52.5, 43.5, 38.6, 31.6, 27.6.

[0105] Example 3: Derivatization of the natural product thymol

[0106]

[0107] With reference to the specific embodiments, as Figure 5 To a 100 mL single necked round bottom flask, compound 1c (1.50 g, 10.0 mmol), triethylamine (20.0 mmol), dichloromethane (60 mL) were added. The mixture was stirred at room temperature while SO2F2gas was bubbled through the continuous flow reactor at a rate of 5 mL / min when the two balloons were gradually filled with gas and expanded, and the gas pressure in the system was slightly higher than atmospheric pressure. After 5 h of reaction cycle, when all the liquid reactants passed through the tube-in-tube type tubular flow reactor and were collected by the product collection device, the solvent was rotary evaporated, and 1,1,2,2-tetrachloroethane was added as 1 The yield of target compound 2c was 42% calculated by H NMR quantitative internal standard. The target product 2c obtained by the above synthesis method was detected by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results were as follows: 1 H NMR (500 MHz, CDCI3) δ 7.15 (m, 1H), 7.02 (m, 1H), 6.99 (m, 1H), 3.14 (m, 1H), 2.20 (s, 3H), 1.11 (d, J = 7.1 Hz, 6H); 13 C{ 1 H} NMR (126 MHz, CDCI3) δ 147.9, 137.9, 137.5, 129.7, 127.7, 121.0, 26.8, 23.0, 20.7.

[0108] Example 4, Derivatization of 4-piperidone ethylene glycol

[0109]

[0110] With reference to the specific embodiments, as Figure 6As shown, to a 100 mL single necked round bottom flask, compound 1d (1.43 g, 10.0 mmol), 4-dimethylaminopyridine (5.00 mmol), magnesium oxide (25.0 mmol), acetonitrile / water (4:1, 60 mL) were added. The mixture was stirred at room temperature while SO2F2gas was bubbled through the solution in a continuous flow reactor at a rate of 5 mL / min when the two balloons were inflated and the pressure in the system was slightly higher than atmospheric pressure. After 6 h of reaction, all the liquid reagents were collected by the product collection device after passing through the tube-in-tube flow reactor. After the solvent was removed by rotary evaporation, 20.0 mL of ethyl acetate was added to dissolve the product. Then, 3 x 10.0 mL of hydrochloric acid (1.00 M) was added to wash the organic phase. The organic phase was dried and the solvent was removed by rotary evaporation to obtain 2.03 g of the target compound 2d with a yield of 90%. The target product 2d obtained by the above synthesis method was detected by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and the test results were as follows: 1 H NMR (500 MHz, CDC13) δ 3.97 (s, 4H), 3.58 (m, 4H), 1.82 (m, 4H); 13 C{ 1 H} NMR (126 MHz, CDC13) δ 105.4, 64.6, 45.7, 34.0.

Claims

1. A gas-liquid reaction process using a tube-in-tube tubular continuous flow reactor, characterized in that: the gaseous reactant is sulfuryl fluoride gas, and the liquid reactant is a solution of mercaptan, phenol or amine in solvent; the continuous flow reactor comprises an outer tube and an inner tube, the outer tube is made of plastic, glass or metal material with good air tightness and chemical resistance, and the inner tube is a hollow fiber membrane; the hollow fiber membrane is made of polyether sulfone, polybenzimidazole, polyvinylidene fluoride, polyacrylonitrile, polyaniline, cellulose acetate or chitosan; in use, the mixed liquid formed by dissolving the substrate and other non-gaseous reagents in the solvent is fed and flows into the gap between the outer tube and the inner tube of the tube-in-tube tubular flow reactor, at the same time, the gaseous reactant is fed and fills the inner tube composed of hollow fiber membranes; the gas can only permeate to the outside through the hollow fiber membranes, and chemically reacts with the liquid filled in the gap between the outer tube and the inner tube.

2. The gas-liquid reaction process of claim 1, characterized in that: the tube-in-tube tubular continuous flow reactor comprises a liquid sampling device, a gas sampling device, a balloon device, a three-way valve and a product collection device; the liquid sampling device comprises a liquid conduit upstream of the tube-in-tube tubular flow reactor and a peristaltic pump, which can control the flow rate of the mixed liquid between the inner tube and the outer tube; the gas sampling device comprises a double-layer gas conduit upstream of the tube-in-tube tubular flow reactor and a one-way valve, which can prevent the liquid reactant from flowing back into the gas sampling device; the inner tube of the double-layer gas conduit is a hollow fiber membrane, which together with the hollow fiber membrane in the inner tube of the tube-in-tube tubular flow reactor forms a continuous tubular structure; the outer tube of the double-layer gas conduit is a tube made of material that does not chemically react with gas and has good air tightness; the continuous flow reactor comprises two balloon devices; one is located at the connection between the gas cylinder and the gas sampling device, and the other is located between the three-way valve in the product collection device and the product collection bottle; the balloons are connected into the system through an adapter with good air tightness; when the two balloons are gradually filled and inflated with gas, it indicates that the gas has completely filled the inner tube of the entire tube-in-tube tubular reactor, and the gas pressure in the system is slightly higher than atmospheric pressure; the continuous flow reactor comprises two three-way valves; one is a three-way valve connecting the liquid sampling device, the gas sampling device and the tube-in-tube tubular flow reactor; the other is a three-way valve connecting the product collection device, the balloon device at the end of the gas inner tube and the tube-in-tube tubular flow reactor; the product collection device comprises a product collection bottle and a pipeline connecting the outer tube of the tube-in-tube tubular flow reactor and the collection bottle.

3. A method for synthesizing disulfide compounds using the process of claim 1 or 2, comprising the following steps: ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ A) a thiol compound represented by general formula (1) is mixed with a base in a solvent to form a mixed liquid, which is fed by a liquid feeding device and flows into the gap between the outer tube and the inner tube of the continuous flow reactor, while a gaseous reactant is fed by a gas feeding device and fills the inner tube made of hollow fiber membrane; B) in the continuous flow reactor, the gas in the inner tube diffuses into the mixed liquid flowing in the gap between the inner tube and the outer tube and reacts with it, to obtain a disulfide compound represented by general formula (2); C) the solution of the generated product is collected by a product collection device; the base is selected from one or more of triethylamine, methanolamine, ethanolamine, triethanolamine, 1,8-diazabicycloundec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, 4-dimethylaminopyridine, 2-tert-butyl-1,1,3,3-tetramethylguanidine in any proportion; the solvent is selected from one or more of acetonitrile, ethyl acetate, dichloromethane, n-hexane, ethanol, water, borax buffer solution, serum in any proportion.

4. The synthesis process of a disulfide compound according to claim 3, wherein: the material of the outer tube of the continuous flow reactor for gas-liquid reaction is polytetrafluoroethylene, the inner diameter is 4.0 mm, and the length is 1.5 m; the material of the inner tube is polyvinylidene fluoride hollow fiber membrane, the outer diameter is 2.6 mm, and the length is 1.5 m; the concentration of the reactant in the reaction liquid is 1 / 6 mol / L; the concentration of the base in the reaction liquid is 1 / 3 or 1 / 6 mol / L; the speed of the peristaltic pump is 1 mL / min; the hourly output is 10 mmol.

5. A method for synthesizing a fluorosulfate compound by using the process of claim 1 or 2, comprising the following steps: A) a phenolic compound represented by general formula (3) is mixed with a base in a solvent to form a mixed liquid, which is fed by a liquid feeding device and flows into the gap between the outer tube and the inner tube of the continuous flow reactor, while a gaseous reactant is fed by a gas feeding device and fills the inner tube made of hollow fiber membrane; B) in the continuous flow reactor, the gas in the inner tube diffuses into the mixed liquid flowing in the gap between the inner tube and the outer tube and reacts with it, to obtain a fluorosulfate compound represented by general formula (4); C) the solution of the generated product is collected by a product collection device; the base is selected from one or more of triethylamine, methanolamine, ethanolamine, triethanolamine, 1,8-diazabicycloundec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, 4-dimethylaminopyridine, 2-tert-butyl-1,1,3,3-tetramethylguanidine in any proportion; the solvent is selected from one or more of acetonitrile, ethyl acetate, dichloromethane, n-hexane, ethanol, water, borax buffer solution, serum in any proportion.

6. The synthesis process of a fluorosulfate compound according to claim 5, wherein: the material of the outer tube of the continuous flow reactor for gas-liquid reaction is polytetrafluoroethylene, the inner diameter is 4.0 mm, and the length is 1.5 m; the material of the inner tube is polyvinylidene fluoride hollow fiber membrane, the outer diameter is 2.6 mm, and the length is 1.5 m; The concentration of the reactant in the reaction solution is 1 / 6 mol / L. The concentration of the base in the reaction solution is 1 / 3 mol / L. The speed of the peristaltic pump is 5 mL / min. If the reaction mixture in the collection bottle contains unreacted reactants, the mixture is re-injected into the continuous flow reactor until a satisfactory yield is obtained, and the continuous flow reactor has a production capacity of 1 mmol per hour.

7. A method for synthesizing an amine sulfuryl fluoride compound using the process of claim 1 or 2, comprising the following steps: A) mixing an amine compound represented by general formula (5) with a base in a solvent to form a mixed liquid, feeding the liquid through a liquid feeding device and flowing into the gap between the outer tube and the inner tube of the continuous flow reactor, while feeding a gaseous reactant through a gas feeding device and filling the inner tube composed of a hollow fiber membrane; B) in the continuous flow reactor, the gas in the inner tube diffuses into the continuously flowing mixed liquid in the gap between the inner tube and the outer tube and reacts with it to obtain an amine sulfuryl fluoride compound represented by general formula (6); C) the solution of the generated product is collected by a product collection device; The base is selected from one or more of the following in any proportion: triethylamine, methanolamine, ethanolamine, triethanolamine, 1,8-diazabicycloundec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, 4-dimethylaminopyridine, 2-tert-butyl-1,1,3,3-tetramethylguanidine; The solvent is selected from one or more of the following in any proportion: acetonitrile, ethyl acetate, dichloromethane, n-hexane, ethanol, water, borax buffer solution, serum.

8. The synthesis process of an amine sulfuryl fluoride compound according to claim 7, characterized in that: The material of the outer tube of the continuous flow reactor for gas-liquid reaction is polytetrafluoroethylene, with an inner diameter of 4.0 mm and a length of 1.5 m; the material of the inner tube is polyvinylidene fluoride hollow fiber membrane, with an outer diameter of 2.6 mm and a length of 1.5 m; The concentration of the reactant in the reaction solution is 1 / 6 mol / L. The concentration of the base in the reaction solution is 1 / 12 mol / L. The concentration of magnesium oxide in the reaction solution is 5 / 12 mol / L. The speed of the peristaltic pump is 5 mL / min. If the reaction mixture in the collection bottle contains unreacted reactants, the mixture is re-injected into the continuous flow reactor until a satisfactory yield is obtained, and the continuous flow reactor has a production capacity of 1 mmol per hour.

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