CN116651338A - Continuous flow reactor and gas-liquid reaction process - Google Patents
Continuous flow reactor and gas-liquid reaction process Download PDFInfo
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- CN116651338A CN116651338A CN202310404244.5A CN202310404244A CN116651338A CN 116651338 A CN116651338 A CN 116651338A CN 202310404244 A CN202310404244 A CN 202310404244A CN 116651338 A CN116651338 A CN 116651338A
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- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
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Classifications
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J10/00—Chemical processes in general for reacting liquid with gaseous media other than in the presence of solid particles, or apparatus specially adapted therefor
- B01J10/02—Chemical processes in general for reacting liquid with gaseous media other than in the presence of solid particles, or apparatus specially adapted therefor of the thin-film type
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/24—Stationary reactors without moving elements inside
- B01J19/2415—Tubular reactors
- B01J19/243—Tubular reactors spirally, concentrically or zigzag wound
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/24—Stationary reactors without moving elements inside
- B01J19/2415—Tubular reactors
- B01J19/244—Concentric tubes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/24—Stationary reactors without moving elements inside
- B01J19/2475—Membrane reactors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B45/00—Formation or introduction of functional groups containing sulfur
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/24—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfuric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00002—Chemical plants
- B01J2219/00027—Process aspects
- B01J2219/00033—Continuous processes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a continuous flow reactor and a gas-liquid reaction process. By using the continuous flow reactor, the synthesis of disulfide compounds, fluorosulfate compounds, sulfamoyl fluoride compounds and the like can be realized through efficient click chemistry reaction. The continuous flow reactor is a tubular continuous flow reactor in a tubular form, and the reactor uses the hollow fiber membrane for gas-liquid two-phase flow reaction for the first time, and the hollow fiber membrane has high permeability to a plurality of gases such as sulfuryl fluoride. The liquid reaction mixture is in the gap between the outer tube and the inner tube in the continuous flow reactor, and the gaseous reactant is in the inner tube. The gaseous reactant in the inner tube diffuses outwards through the hollow fiber membrane into the gap between the outer tube and the inner tube and reacts with the reactant solution filled in the gap. According to the invention, the click chemistry reaction using gaseous substances as reagents is realized in a flow chemistry mode, and the large-scale application of the click chemistry reaction can be realized more efficiently and conveniently.
Description
Technical Field
The invention belongs to the field of organic synthesis, and relates to a continuous flow reactor and a gas-liquid reaction process, which are used for synthesizing disulfide compounds, fluorosulfate compounds and sulfamoyl fluoride compounds.
Background
Flow chemistry has received great attention in scientific research and industrial production due to its advantages of modularity, high heat and mass transfer, automation control, and high efficiency and safety (chem.soc.rev., 2020, 49, 8910). The click chemistry reaction is easier to realize large-scale production due to the advantages of high yield, high speed, wide application range and the like. The realization of large-scale production of click chemistry reactions by using flow chemistry reactors has important practical significance for industrial application of click chemistry reactions.
The disulfide compound is widely applied to the fields of organic synthesis, medicine development, material science, peptology and the like (Top. Curr. Chem.,2018, 376,1-40). The thiol compound is used as a raw material, and the disulfide compound is synthesized through the click chemistry reaction mediated by the sulfonyl fluoride compound in the presence of alkali and solvent, so that the method has the advantages of high efficiency, high speed, high selectivity and the like. However, in practical application, the limitation of the reactor is difficult to realize large-scale production, and 100% of sulfonyl fluoride gas cannot be utilized. Similar problems are encountered in the synthesis of fluorosulfate compounds and sulfamoyl fluoride compounds based on click chemistry. Flow chemistry reactors are an important way to achieve large-scale production of such efficient click chemistry reactions.
In general, when the flow chemistry reaction involves a gas, the gas may be added to the flow reaction solution by a simple T-or Y-mixer. However, the reactor has the defects of small contact area of gas phase and liquid phase, difficulty in realizing 100% conversion rate of the gas reactant, requirement of an additional tail gas treatment device for unreacted gas reactant, and the like. The tubular flow reactor in the tube can well realize the efficient contact of the gaseous reactant and the liquid reactant, improve the reaction efficiency, simultaneously realize the full utilization of the gaseous reactant and effectively avoid the diffusion of the gaseous reactant to the environment. In an ideal tubular-in-tube tubular flow reactor, liquid passes through the outer tube-inner tube gap, while gas passes through the inner tube, the gas being able to dissolve through the inner tube wall into the liquid in the outer tube-inner tube gap, reacting with the reactants in the liquid. Hollow fiber membranes exhibit high permeability to many gases. Therefore, the invention utilizes the hollow fiber membrane as the inner tube of the reactor for the first time, and establishes a novel tube-in-tube type flow chemical reactor. Compared to the existing tube-in-tube reactors using Teflon AF-2400 as the inner tube of the reactor, the present invention uses hollow fiber membranes as the inner tube, which is cheaper and more efficient (chem.soc.rev., 2020, 49, 8910).
The synthesis method based on the flow chemistry of the disulfide compounds, the fluoro-sulfate compounds and the sulfamoyl fluoride compounds applies the flow chemistry to the large-scale production of click chemistry reaction, and has important practical significance for the industrialized synthesis of the disulfide compounds, the fluoro-sulfate compounds and the sulfamoyl fluoride compounds, especially for the drug synthesis and the polypeptide synthesis.
Disclosure of Invention
The invention aims to provide a tubular flow reactor in a tube, a continuous flow reactor for gas-liquid reaction and a process for synthesizing disulfide compounds, fluorosulfate compounds and sulfamoyl fluoride compounds by using the reactor. The tubular flow reactor in the tube-in-tube type adopts the hollow fiber membrane as the inner tube of the tubular flow reactor in the tube-in-tube type for the first time. In which the gaseous reactants diffuse outwards through the hollow fiber membranes. Because of the unique microstructure of the hollow fiber membrane, the gas phase and the liquid phase in the system have a large contact area. Since heterogeneous reaction occurs at the interface of two phases, the contact area of the gas phase and the liquid phase directly affects the reaction speed. Thus, the above-mentioned tube-in-tube type tubular flow reactor is capable of increasing the reaction rate of the gas-liquid reaction by increasing the contact area of the gas-liquid two phases. In addition, the reactor can realize full utilization of the gas reactant and effectively avoid diffusion of the gas reactant into the environment. Compared with the tube-in-tube reactor which uses the Teflon AF-2400 as the inner tube of the reactor in the prior art, the invention uses the hollow fiber membrane as the inner tube, which is cheaper and more efficient.
Further, the tubular flow reactor in the tube can form a continuous flow reactor for gas-liquid reaction together with a proper liquid sample injection device, a gas sample injection device, a balloon device, a three-way valve and a product collecting device. The device can realize high-efficiency and large-scale production of gas-liquid reaction, and avoid the problems that the contact area of gas and liquid phases is small, and gas reactants cannot be fully utilized in the conventional batch reaction.
Click chemistry reactions using sulfuryl fluoride gas as a reactant can be performed in this continuous flow reactor and achieve mass production of disulfide, fluorosulfate, and sulfamoyl fluoride. Compared with the click chemistry reaction synthesis process using the traditional reactor, the click chemistry reaction operation using the continuous flow reactor is simpler and more convenient, the large-scale production is easier to realize through the parallel continuous flow reactor, and the gas reactant can be fully utilized, so that the diffusion of the gas reactant into the environment is avoided.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
a tubular flow reactor in the form of a tube as described above, which can be used to construct a continuous flow reactor for gas-liquid reactions, as shown in figure 1, is characterized by:
the outer pipe wall is made of plastic, glass or metal materials with good air tightness and chemical resistance, and the inner pipe is a hollow fiber membrane;
the hollow fiber membrane is prepared from polyethersulfone, polybenzimidazole, polyvinylidene fluoride, polyacrylonitrile, polyaniline, cellulose acetate, chitosan and the like serving as raw materials;
in use, a mixed liquid formed by dissolving 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 tubular flow reactor in the tube, and simultaneously, the gaseous reactants are fed and fill the inner tube formed by the hollow fiber membranes; the gas can only permeate to the outside through the hollow fiber membrane and chemically react with the liquid filled between the outer tube and the inner tube.
A continuous flow reactor for gas-liquid reactions as described above, as shown in fig. 2, comprising:
a tubular-in-tube tubular flow reactor as described above;
the liquid sample injection device comprises a liquid conduit and a peristaltic pump which are arranged at the upstream of the tubular flow reactor in the tube, and the peristaltic pump can control the flow rate of mixed liquid between the inner tube and the outer tube;
the gas sample injection device comprises a double-layer gas conduit and a one-way valve, wherein the double-layer gas conduit and the one-way valve are arranged at the upstream of the tubular flow reactor in the tube, and the one-way valve can prevent liquid reactants from flowing back into the gas sample injection device; the inner tube of the double-layer gas conduit is a hollow fiber membrane, and the hollow fiber membrane of the inner tube of the tubular flow reactor form a continuous tubular structure together; the outer tube of the double-layer gas conduit is a tube made of a material which does not react with gas chemically and has good air tightness;
balloon means, said continuous flow reactor comprising two balloon means; the gas sampling device is positioned at the joint of the gas cylinder and the gas sampling device; the other three-way valve is positioned between the product collecting device and the product collecting bottle; the balloon is connected with the access system through a switching port with good air tightness; when the two balloons are gradually overflowed and inflated by the gas, the gas is completely overflowed in the inner tube of the tubular reactor in the whole tube, and the pressure of the gas in the system is slightly higher than the atmospheric pressure;
a three-way valve, the continuous flow reactor comprising two three-way valves; one is a three-way valve connecting the liquid sample injection device, the gas sample injection device and the tubular flow reactor in the tube; the other is a three-way valve for connecting the product collecting device, the balloon device at the tail end of the gas inner tube and the tubular flow reactor in the tube;
and the product collecting device comprises a product collecting bottle and an outer tube of the tubular flow reactor in the communicating tube and a pipeline of the collecting bottle.
The synthesis process of the disulfide compound by using the continuous flow reactor for gas-liquid reaction comprises the following steps:
a) A mercaptan compound shown in a general formula (1) and alkali form mixed liquid in a solvent, the mixed liquid is fed and flows into a gap between an outer pipe and an inner pipe of the continuous flow reactor through a liquid sample injection device, and simultaneously, a gaseous reactant is fed and fills the inner pipe formed by the hollow fiber membranes through a gas sample injection device;
b) In the continuous flow reactor, the gas in the inner tube is diffused 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 disulfide compound shown in the general formula (2);
c) The generated solution of the product is collected by a product collecting device;
the gaseous reactant is sulfuryl fluoride (SO) 2 F 2 ) A gas;
the alkali is selected from one or more of triethylamine, methanolamine, ethanolamine, triethanolamine, 1, 8-diazabicyclo undec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, 4-dimethylaminopyridine and 2-tertiary butyl-1, 3-tetramethylguanidine;
preferably, the base is triethylamine;
the solvent is selected from one or more of acetonitrile, ethyl acetate, dichloromethane, normal hexane, ethanol, water, borax buffer solution and serum;
preferably, the solvent is acetonitrile or acetonitrile/borax buffer solution (1:1).
The synthesis process of the disulfide compound is characterized by comprising the following steps of:
the outer tube of the continuous flow reactor for gas-liquid reaction is made of polytetrafluoroethylene, the inner diameter is 4.0 mm, and the length is 1.5 m; the inner tube is made of polyvinylidene fluoride hollow fiber membrane, the outer diameter is 2.6 mm, and the length is 1.5 m;
the concentration of the reactants in the reaction solution is as follows: 1/6mol/L;
the concentration of the alkali in the reaction solution is as follows: 1/3 or 1/6mol/L;
the peristaltic pump has a speed of: 1mL/min;
the hourly yield is: 10mmol.
The synthesis process of the disulfide compound is characterized by comprising the following steps of:
the derivatization of the drug captopril and the oxidation of the reduced glutathione can be realized with high efficiency, and the drug captopril can be converted into corresponding disulfide.
The above-mentioned synthetic process of the fluoro sulfate compound by using the continuous flow reactor for gas-liquid reaction comprises the following steps:
a) Forming mixed liquid of the phenolic compound shown in the general formula (3) and alkali in a solvent, feeding and flowing the mixed liquid into a gap between an outer tube and an inner tube of the continuous flow reactor through a liquid sample injection device, and simultaneously feeding a gaseous reactant through a gas sample injection device and filling the inner tube formed by the hollow fiber membranes;
b) In the continuous flow reactor, the gas in the inner tube is diffused 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 fluoro sulfate compound shown in the general formula (4);
c) The generated solution of the product is collected by a product collecting device;
the gaseous reactant is sulfuryl fluoride (SO) 2 F 2 ) A gas;
the alkali is selected from one or more of triethylamine, methanolamine, ethanolamine, triethanolamine, 1, 8-diazabicyclo undec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, 4-dimethylaminopyridine and 2-tertiary butyl-1, 3-tetramethylguanidine;
preferably, the base is triethylamine;
the solvent is selected from one or more of acetonitrile, ethyl acetate, dichloromethane, normal hexane, ethanol, water, borax buffer solution and serum;
preferably, the solvent is dichloromethane.
The synthesis process of the fluoro sulfate compound is characterized by comprising the following steps of:
the outer tube of the continuous flow reactor for gas-liquid reaction is made of polytetrafluoroethylene, the inner diameter is 4.0 mm, and the length is 1.5 m; the inner tube is made of polyvinylidene fluoride hollow fiber membrane, the outer diameter is 2.6 mm, and the length is 1.5 m;
the concentration of the reactants in the reaction solution is as follows: 1/6mol/L;
the concentration of the alkali in the reaction solution is as follows: 1/3mol/L;
the peristaltic pump has a speed of: 5mL/min;
if the reaction mixture in the collection bottle contains unreacted reactants, the mixture is re-injected into a continuous flow reactor with a hourly throughput of: 1mmol.
The synthesis process of the fluoro sulfate compound is characterized by comprising the following steps of:
the conversion of the natural product thymol into the corresponding fluorosulfate can be efficiently achieved.
The synthesis process of the sulfamoyl fluoride compound by using the continuous flow reactor for gas-liquid reaction comprises the following steps:
a) Forming mixed liquid of an amine compound shown in a general formula (5) and alkali in a solvent, feeding and flowing the mixed liquid into a gap between an outer tube and an inner tube of the continuous flow reactor through a liquid sample injection device, and simultaneously feeding a gaseous reactant through a gas sample injection device and filling the inner tube formed by the hollow fiber membranes;
b) In the continuous flow reactor, the gas in the inner tube is diffused 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 sulfamoyl fluoride compound shown in the general formula (6);
c) The generated solution of the product is collected by a product collecting device;
the gaseous reactant is sulfuryl fluoride (SO) 2 F 2 ) A gas;
the alkali is selected from one or more of triethylamine, methanolamine, ethanolamine, triethanolamine, 1, 8-diazabicyclo undec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, 4-dimethylaminopyridine and 2-tertiary butyl-1, 3-tetramethylguanidine;
preferably, the base is 4-dimethylaminopyridine;
the solvent is selected from one or more of acetonitrile, ethyl acetate, dichloromethane, normal hexane, ethanol, water, borax buffer solution and serum;
preferably, the solvent is acetonitrile/water (4:1).
The synthesis process of the amine sulfonyl fluoride compound is characterized by comprising the following steps of:
the outer tube of the continuous flow reactor for gas-liquid reaction is made of polytetrafluoroethylene, the inner diameter is 4.0 mm, and the length is 1.5 m; the inner tube is made of polyvinylidene fluoride hollow fiber membrane, the outer diameter is 2.6 mm, and the length is 1.5 m;
the concentration of the reactants in the reaction solution is as follows: 1/6mol/L;
the concentration of the alkali in the reaction solution is as follows: 1/12mol/L;
the concentration of magnesium oxide in the reaction solution was: 5/12mol/L;
the peristaltic pump has a speed of: 5mL/min;
if the reaction mixture in the collection bottle contains unreacted reactants, the mixture is re-injected into a continuous flow reactor with a hourly throughput of: 1mmol.
The invention has the beneficial effects that:
1) According to the invention, the hollow fiber membrane is used as the inner tube of the tubular flow reactor in the tube for the first time, and gaseous reactants such as sulfuryl fluoride and the like can efficiently permeate to the outside of the inner tube through the wall of the hollow fiber membrane and react with liquid reactants in the gap between the inner tube and the outer tube. Compared with the existing tubular flow reactor in the tube-in-tube type, which uses the Teflon AF-2400 as the inner tube of the reactor, the invention uses the hollow fiber membrane as the inner tube, which is more economical and efficient.
2) The invention utilizes a tubular flow reactor in a tubular form, and establishes a continuous flow reactor suitable for click chemistry reactions requiring gaseous reagents for the first time. The reactor can realize continuous synthesis, so that the synthesis process is simpler and more convenient and efficient. The large-scale production of click chemistry reactions can be realized by parallel continuous flow reactors.
3) The synthesis process of the disulfide compound, the fluoro sulfate compound and the sulfamoyl fluoride compound by utilizing the continuous flow reactor has the advantages of low reagent cost, simple operation, high yield and the like.
4) The invention provides an effective way for the large-scale production of functional compounds such as medicines, polypeptides, natural products and the like, and realizes Gao Xiaoyan biochemistry of a large number of medicines captopril, oxidation of polypeptide reducing glutathione and derivatization of natural products thymol.
Drawings
FIG. 1 is a schematic view of a tubular-in-tube tubular flow reactor used in the examples
FIG. 2 is a schematic of a continuous flow reactor used in the examples
FIG. 3 is a schematic view of a continuous flow reactor apparatus used in example 1
FIG. 4 is a schematic diagram of a continuous flow reactor apparatus used in example 2
FIG. 5 is a schematic diagram of a continuous flow reactor apparatus used in example 3
FIG. 6 is a schematic diagram of a continuous flow reactor apparatus used in example 4
Detailed Description
The materials and equipment used in the present invention are known products and are obtained by purchasing commercially available products, unless otherwise specified.
The specific embodiments of the present invention are as follows:
1. as shown in FIG. 2, a continuous flow reactor was constructed. A continuous flow reactor for gas-liquid reactions, comprising:
a tubular-in-tube type tubular flow reactor which can be used to construct a continuous flow reactor for gas-liquid reactions, as shown in figure (1), characterized by:
the outer tube is made of polytetrafluoroethylene, the inner diameter is 4.0 mm, and the length is 1.5 m; the inner tube is made of polyvinylidene fluoride hollow fiber membrane, the outer diameter is 2.6 mm, and the length is 1.5 m;
the liquid sample injection device comprises a liquid conduit and a peristaltic pump which are arranged at the upstream of the tubular flow reactor in the tube, and the peristaltic pump can control the flow rate of mixed liquid between the inner tube and the outer tube;
the gas sample injection device comprises a double-layer gas conduit and a one-way valve, wherein the double-layer gas conduit and the one-way valve are arranged at the upstream of the tubular flow reactor in the tube, and the one-way valve can prevent liquid reactants from flowing back into the gas sample injection device; the inner tube of the double-layer gas conduit is a hollow fiber membrane, and the hollow fiber membrane of the inner tube of the tubular flow reactor form a continuous tubular structure together; the outer tube of the double-layer gas conduit is a tube made of a material which does not react with gas chemically and has good air tightness;
balloon means, said continuous flow reactor comprising two balloon means; the gas sampling device is positioned at the joint of the gas cylinder and the gas sampling device; the other three-way valve is positioned between the product collecting device and the product collecting bottle; the balloon is connected with the access system through a switching port with good air tightness; when the two balloons are gradually overflowed and inflated by the gas, the gas is completely overflowed in the inner tube of the tubular reactor in the whole tube, and the pressure of the gas in the system is slightly higher than the atmospheric pressure;
a three-way valve, the continuous flow reactor comprising two three-way valves; one is a three-way valve connecting the liquid sample injection device, the gas sample injection device and the tubular flow reactor in the tube; the other is a three-way valve for connecting the product collecting device, the elastic membrane at the tail end of the gas inner tube and the tubular flow reactor in the tube;
and the product collecting device comprises a product collecting bottle and an outer tube of the tubular flow reactor in the communicating tube and a pipeline of the collecting bottle.
2. The reaction (10.0 mmoL) was dissolved in 60mL of solvent at room temperature, and a specified amount of base (20.0, 10.0 or 5.0 mmoL) was added and stirred until complete dissolution.
3. Forming a mixed liquid of the reactant and the alkali in the solvent, feeding and flowing the mixed liquid into a gap between an outer tube and an inner tube of the continuous flow reactor at a specified flow rate through a liquid sample feeding device, and simultaneously, enabling the gaseous reactant SO to be 2 F 2 The inner tube formed by the hollow fiber membranes is fed and filled by the gas sampling device, and after two balloons are gradually overflowed and expanded by gas, the gas is completely overflowed in the inner tube of the tubular reactor in the whole tube, and the gas pressure in the system is slightly higher than the atmospheric pressure;
4. 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;
5. after the reaction has been completed for the specified period of time, after all the liquid reactants have passed through the tubular flow reactor in tube and have flowed into the collection device, the liquid reaction mixture is concentrated, worked up to give the product, the yields are calculated by weighing and the structure of the product is characterized.
Example 1 derivatization of the drug captopril
Referring to the specific embodiment, as shown in FIG. 3, to a 100mL single port round bottom flask, compound 1a (2.17 g,10.0 mmoL), triethylamine (20.0 mmoL), acetonitrile (60 mL) were added, and mixed well at room temperature while introducing SO through a gas injection device 2 F 2 In the continuous flow reactor, when two balloons are gradually overflowed and inflated by gas and the pressure of the gas in the system is slightly higher than the atmospheric pressure, a peristaltic pump is started to sample at the speed of 1 mL/min. After 1h of reaction, after all the liquid reactants had passed through the tubular flow reactor in tube and collected by the product collection device, the reaction solution was washed three times with 10mL of aqueous hydrochloric acid (1M), the organic phase was dried, the solvent was removed by rotary evaporation, and the yield was calculated to be 95% by weight. The target product 2a obtained by the synthesis method is subjected to nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection, and the test results are as follows: 1 H NMR(500MHz，DMSO-d 6 )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-d 6 )δ173.3，172.3，58.4，46.5，41.2，36.9，28.7，24.4，16.5.
example 2 oxidation of reduced glutathione
Referring to the specific embodiment, as shown in FIG. 4, to a 100mL single neck round bottom flask was added compound 1b (3.07 g,10.0 mmoL), triethylamine (10.0 mmoL), acetonitrile/borax buffer mixed solution (1:1, 60 mL). Mixing at room temperature, and introducing SO 2 F 2 In a continuous flow reactor, when two balloons are gradually inflated with gasAfter overflowing and expanding, and when the gas pressure in the system is slightly higher than atmospheric pressure, starting a peristaltic pump at a speed of 1mL/min to perform sample injection, reacting for 1h, adjusting the alkalinity of a reaction liquid by using a sodium hydroxide solution (1M) after all liquid reactants pass through a tubular flow reactor in a tube and are collected by a product collecting device, performing rotary evaporation and concentration to remove a solvent and triethylamine, weighing and calculating the yield to be 98%, and performing nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection on a target product 2b obtained by the synthesis method, wherein the test result is as follows: 1 H NMR(500MHz，D 2 O)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，D 2 O)δ176.6，176.3，175.4，171.9，54.5，52.5，43.5，38.6，31.6，27.6.
example 3 derivatization of Natural product thymol
Referring to the specific embodiment, as shown in FIG. 5, to a 100mL single neck round bottom flask was added compound 1c (1.50 g,10.0 mmoL), triethylamine (20.0 mmoL), dichloromethane (60 mL). Mixing at room temperature, and introducing SO 2 F 2 In a continuous flow reactor, when two balloons are gradually overflowed and inflated by gas and the gas pressure in the system is slightly higher than atmospheric pressure, a peristaltic pump is started to sample at the speed of 5mL/min, after reaction circulation is carried out for 5 hours, after all liquid reactants pass through a tubular flow reactor in a tube, are collected by a product collecting device, the solvent is rotationally evaporated, and 1, 2-tetrachloroethane is added as a solvent 1 H NMR quantitative internal standard calculates the yield, 42% of the target compound 2 c. And (3) detecting nuclear magnetic resonance hydrogen spectrum and carbon spectrum of the target product 2c obtained by the synthesis method, wherein the test result is as follows: 1 H NMR(500MHz，CDCl 3 )δ7.15(m，1H)，7.02(m，1H)，6.99(m，1H)，3.14(m，1H)，2.20(s，3H)，1.11(d，J＝7.1Hz，6H)； 13 C{ 1 H}NMR(126MHz，CDCl 3 )δ147.9，137.9，137.5，129.7，127.7，121.0，26.8，23.0，20.7.
example 4 derivatization of 4-piperidone ethylene glycol
Referring to the specific embodiment, as shown in FIG. 6, to a 100mL single neck round bottom flask was added compound 1d (1.43 g,10.0 mmoL), 4-dimethylaminopyridine (5.00 mmoL), magnesium oxide (25.0 mmoL), acetonitrile/water (4:1, 60 mU). Mixing at room temperature, and introducing SO 2 F 2 After two balloons are gradually overflowed and inflated by gas in a continuous flow reactor and the gas pressure in the system is slightly higher than atmospheric pressure, a peristaltic pump is started to sample at the speed of 5mL/min, after the reaction circulates for 6h, after all liquid reactants pass through a tubular flow reactor in a tube and are collected by a product collecting device, after solvent is rotationally evaporated, 20.0mL of ethyl acetate dissolved product is added, then hydrochloric acid aqueous solution (3X 10.0mL and 1.00M) is added to wash an organic phase, the organic phase is dried, and the solvent is rotationally evaporated to obtain 2.03g of target compound 2d, and the yield is 90%. And (3) detecting nuclear magnetic resonance hydrogen spectrum and carbon spectrum of the target product 2d obtained by the synthesis method, wherein the test result is as follows: 1 H NMR(500MHz，CDCl 3 )δ3.97(s，4H)，3.58(m，4H)，1.82(m，4H)； 13 C{ 1 H}NMR(126MHz，CDCl 3 )δ105.4，64.6，45.7，34.0。
Claims (10)
1. a tubular-in-tube tubular flow reactor, usable for constructing a continuous flow reactor for gas-liquid reactions, characterized by:
the outer pipe wall is made of plastic, glass or metal materials with good air tightness and chemical resistance, and the inner pipe is a hollow fiber membrane;
the hollow fiber membrane is prepared from polyethersulfone, polybenzimidazole, polyvinylidene fluoride, polyacrylonitrile, polyaniline, cellulose acetate, chitosan and the like serving as raw materials;
in use, a mixed liquid formed by dissolving 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 tubular flow reactor in the tube, and simultaneously, the gaseous reactants are fed and filled in the inner tube formed by the hollow fiber membranes; the gas can only permeate to the outside through the hollow fiber membrane and chemically react with the liquid filled between the outer tube and the inner tube.
2. A continuous flow reactor for gas-liquid reactions, comprising:
a tubular-in-tube tubular flow reactor as claimed in claim 1;
the liquid sample injection device comprises a liquid conduit and a peristaltic pump which are arranged at the upstream of the tubular flow reactor in the tube, and the peristaltic pump can control the flow rate of mixed liquid between the inner tube and the outer tube;
the gas sample injection device comprises a double-layer gas conduit and a one-way valve, wherein the double-layer gas conduit and the one-way valve are arranged at the upstream of the tubular flow reactor in the tube, and the one-way valve can prevent liquid reactants from flowing back into the gas sample injection device; the inner tube of the double-layer gas conduit is a hollow fiber membrane, and the hollow fiber membrane of the inner tube of the tubular flow reactor form a continuous tubular structure together; the outer tube of the double-layer gas conduit is a tube made of a material which does not react with gas chemically and has good air tightness;
balloon means, said continuous flow reactor comprising two balloon means; the gas sampling device is positioned at the joint of the gas cylinder and the gas sampling device; the other three-way valve is positioned between the product collecting device and the product collecting bottle; the balloon is connected with the access system through a switching port with good air tightness; when the two balloons are gradually overflowed and inflated by the gas, the gas is completely overflowed in the inner tube of the tubular reactor in the whole tube, and the pressure of the gas in the system is slightly higher than the atmospheric pressure;
a three-way valve, the continuous flow reactor comprising two three-way valves; one is a three-way valve connecting the liquid sample injection device, the gas sample injection device and the tubular flow reactor in the tube; the other is a three-way valve for connecting the product collecting device, the balloon device at the tail end of the gas inner tube and the tubular flow reactor in the tube;
and the product collecting device comprises a product collecting bottle and an outer tube of the tubular flow reactor in the communicating tube and a pipeline of the collecting bottle.
3. A process for synthesizing a disulfide compound using a continuous flow reactor for gas-liquid reactions as claimed in claim 2, comprising the steps of:
a) A mercaptan compound shown in a general formula (1) and alkali form mixed liquid in a solvent, the mixed liquid is fed and flows into a gap between an outer pipe and an inner pipe of the continuous flow reactor through a liquid sample injection device, and simultaneously, a gaseous reactant is fed and fills the inner pipe formed by the hollow fiber membranes through a gas sample injection device;
b) In the continuous flow reactor, the gas in the inner tube is diffused 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 disulfide compound shown in the general formula (2);
c) The generated solution of the product is collected by a product collecting device;
the gaseous reactant is sulfuryl fluoride (SO) 2 F 2 ) A gas;
the alkali is selected from one or more of triethylamine, methanolamine, ethanolamine, triethanolamine, 1, 8-diazabicyclo undec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, 4-dimethylaminopyridine and 2-tertiary butyl-1, 3-tetramethylguanidine;
preferably, the base is triethylamine;
the solvent is selected from one or more of acetonitrile, ethyl acetate, dichloromethane, normal hexane, ethanol, water, borax buffer solution and serum;
preferably, the solvent is acetonitrile or acetonitrile/borax buffer solution (1:1).
4. A process for synthesizing fluorosulfate compounds using a continuous flow reactor for gas-liquid reactions as claimed in claim 2, comprising the steps of:
a) Forming mixed liquid of the phenolic compound shown in the general formula (3) and alkali in a solvent, feeding and flowing the mixed liquid into a gap between an outer tube and an inner tube of the continuous flow reactor through a liquid sample injection device, and feeding and filling a gaseous reactant into the inner tube formed by the hollow fiber membrane through a gas sample injection device;
b) In the continuous flow reactor, the gas in the inner tube is diffused 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 fluoro sulfate compound shown in the general formula (4);
c) The generated solution of the product is collected by a product collecting device;
the gaseous reactant is sulfuryl fluoride (SO) 2 F 2 ) A gas;
the alkali is selected from one or more of triethylamine, methanolamine, ethanolamine, triethanolamine, 1, 8-diazabicyclo undec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, 4-dimethylaminopyridine and 2-tertiary butyl-1, 3-tetramethylguanidine;
preferably, the base is triethylamine;
the solvent is selected from one or more of acetonitrile, ethyl acetate, dichloromethane, normal hexane, ethanol, water, borax buffer solution and serum;
preferably, the solvent is dichloromethane.
5. A process for synthesizing an amine sulfonyl fluoride compound utilizing a continuous flow reactor for gas-liquid reactions as defined in claim 2, comprising the steps of:
a) Forming mixed liquid of an amine compound shown in a general formula (5) and alkali in a solvent, feeding and flowing the mixed liquid into a gap between an outer tube and an inner tube of the continuous flow reactor through a liquid sample injection device, and feeding a gaseous reactant into the inner tube formed by hollow fiber membranes through a gas sample injection device;
b) In the continuous flow reactor, the gas in the inner tube is diffused 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 sulfamoyl fluoride compound shown in the general formula (6);
c) The generated solution of the product is collected by a product collecting device;
the gaseous reactant is sulfuryl fluoride (SO) 2 F 2 ) A gas;
the alkali is selected from one or more of triethylamine, methanolamine, ethanolamine, triethanolamine, 1, 8-diazabicyclo undec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, 4-dimethylaminopyridine and 2-tertiary butyl-1, 3-tetramethylguanidine;
preferably, the base is 4-dimethylaminopyridine;
the solvent is selected from one or more of acetonitrile, ethyl acetate, dichloromethane, normal hexane, ethanol, water, borax buffer solution and serum;
preferably, the solvent is acetonitrile/water (4:1).
6. A process for the synthesis of a disulfide compound as claimed in claim 3, wherein:
the outer tube of the continuous flow reactor for gas-liquid reaction is made of polytetrafluoroethylene, the inner diameter is 4.0 mm, and the length is 1.5 m; the inner tube is made of polyvinylidene fluoride hollow fiber membrane, the outer diameter is 2.6 mm, and the length is 1.5 m;
the concentration of the reactants in the reaction solution is as follows: 1/6mol/L;
the concentration of the alkali in the reaction solution is as follows: 1/3 or 1/6mol/L;
the peristaltic pump has a speed of: 1mL/min;
the hourly yield is: 10mmol.
7. The process for synthesizing a fluorosulfate compound as set forth in claim 4, wherein:
the outer tube of the continuous flow reactor for gas-liquid reaction is made of polytetrafluoroethylene, the inner diameter is 4.0 mm, and the length is 1.5 m; the inner tube is made of polyvinylidene fluoride hollow fiber membrane, the outer diameter is 2.6 mm, and the length is 1.5 m;
the concentration of the reactants in the reaction solution is as follows: 1/6mol/L;
the concentration of the alkali in the reaction solution is as follows: 1/3mol/L;
the peristaltic pump has a speed of: 5mL/min;
if the reaction mixture in the collection bottle contains unreacted reactants, the mixture is re-injected into a continuous flow reactor with a hourly throughput of: 1mmol.
8. The synthesis process of the sulfamoyl fluoride compound according to claim 5, wherein the synthesis process comprises the following steps:
the outer tube of the continuous flow reactor for gas-liquid reaction is made of polytetrafluoroethylene, the inner diameter is 4.0 mm, and the length is 1.5 m; the inner tube is made of polyvinylidene fluoride hollow fiber membrane, the outer diameter is 2.6 mm, and the length is 1.5 m;
the concentration of the reactants in the reaction solution is as follows: 1/6mol/L;
the concentration of the alkali in the reaction solution is as follows: 1/12mol/L;
the concentration of magnesium oxide in the reaction solution was: 5/12mol/L;
the peristaltic pump has a speed of: 5mL/min;
if the reaction mixture in the collection bottle contains unreacted reactants, the mixture is re-injected into a continuous flow reactor with a hourly throughput of: 1mmol.
9. A process for the synthesis of a disulfide compound as claimed in claim 3, wherein:
the derivatization of the drug captopril and the oxidation of the reduced glutathione can be realized with high efficiency, and the drug captopril can be converted into corresponding disulfide.
10. The process for synthesizing a fluorosulfate compound as set forth in claim 4, wherein:
the conversion of the natural product thymol into the corresponding fluorosulfate can be efficiently achieved.
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| CN202310404244.5A CN116651338A (en) | 2023-04-17 | 2023-04-17 | Continuous flow reactor and gas-liquid reaction process |
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