WO2021114424A1 - 三氟烃基砜类化合物的制备方法 - Google Patents

三氟烃基砜类化合物的制备方法 Download PDF

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WO2021114424A1
WO2021114424A1 PCT/CN2019/129412 CN2019129412W WO2021114424A1 WO 2021114424 A1 WO2021114424 A1 WO 2021114424A1 CN 2019129412 W CN2019129412 W CN 2019129412W WO 2021114424 A1 WO2021114424 A1 WO 2021114424A1
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preparation
trifluoroalkyl
continuous reactor
temperature
group
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French (fr)
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洪浩
卢江平
包登辉
王学智
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凯莱英生命科学技术(天津)有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
    • C07D307/64—Sulfur atoms
    • 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
    • B01J19/0006—Controlling or regulating processes
    • B01J19/004—Multifunctional apparatus for automatic manufacturing of various chemical products
    • 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
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • 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
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/16—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
    • B01J23/24—Chromium, molybdenum or tungsten
    • B01J23/30—Tungsten
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—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 two 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
    • C07D207/36—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • 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
    • B01J2219/00049—Controlling or regulating processes
    • B01J2219/00051—Controlling the temperature
    • B01J2219/00054—Controlling or regulating the heat exchange system
    • B01J2219/00056—Controlling or regulating the heat exchange system involving measured parameters
    • B01J2219/00058—Temperature measurement
    • 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
    • B01J2219/00049—Controlling or regulating processes
    • B01J2219/00162—Controlling or regulating processes controlling the pressure
    • 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
    • B01J2219/00049—Controlling or regulating processes
    • B01J2219/00186—Controlling or regulating processes controlling the composition of the reactive mixture
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to the technical field of synthesis of trifluoroalkyl sulfone compounds, in particular to a method for preparing trifluoroalkyl sulfone compounds.
  • trifluoromethyl sulfone compounds is mainly obtained by oxidation of trifluoromethyl sulfide.
  • the most commonly used oxidants for the oxidation of trifluoromethyl sulfide are potassium permanganate and chromium trioxide.
  • the large number of by-products manganese and chromium salts generated by the reaction not only cause difficulty in post-processing, and low separation yield (60 ⁇ 70%), and heavy metals are difficult to recycle, which causes great environmental pollution.
  • the cost of treatment of the three wastes of enterprises is high, which does not meet the requirements of the development of green chemistry.
  • WO2015035223(A1) discloses an oxidation method using sodium periodate as an oxidant and ruthenium trichloride as a catalyst.
  • the oxidation of trifluoromethyl sulfide can be achieved at room temperature, and the separation yield is 85%.
  • the oxidation method is relatively mild, but the ruthenium catalyst is expensive, and the reaction produces a large amount of halogen-containing three wastes, the atom utilization rate is low, and the production cost is high.
  • potassium permanganate, chromium trioxide, and sodium periodate are used as traditional oxidants for the oxidation of trifluoromethyl sulfide to synthesize trifluoromethyl.
  • the production cost is high, and a large amount of halogen-containing or heavy metal-containing wastes will be generated.
  • the environment causes a lot of pollution, which is not in line with the development direction of green chemistry; in addition, using sodium periodate as the oxidant, the ruthenium trichloride catalyst used is expensive and difficult to recycle, resulting in high production costs and also limiting its application.
  • the main purpose of the present invention is to provide a method for preparing trifluorohydrocarbyl sulfone compounds, so as to solve the problem of decomposition of hydrogen peroxide when preparing trifluorohydrocarbyl sulfone compounds by using hydrogen peroxide as an oxidant in the prior art.
  • a method for preparing a trifluoroalkyl sulfone compound includes continuously feeding trifluoroalkyl sulfide compounds, sodium tungstate dihydrate and hydrogen peroxide solution into a continuous reactor through a feeding device to cause oxidation reaction of trifluoroalkyl sulfide compounds to obtain trifluoroalkyl sulfide compounds.
  • R is any one of the following groups: linear alkyl, branched alkyl, substituted aryl, unsubstituted aryl, substituted heterocyclic aryl, unsubstituted heterocyclic aryl, unsubstituted
  • the oxidation reaction temperature is 25-50°C.
  • R is any one of the following groups: C 1 ⁇ C 10 linear alkyl group, C 1 ⁇ C 10 branched chain alkyl group, C 3 ⁇ C 6 cycloalkyl group, C 6 ⁇ C 18 substituted or unsubstituted aryl, substituted or unsubstituted C 3 to C 10 heterocyclic aryl group.
  • the aforementioned aryl group is phenyl, naphthyl, biphenyl, anthracenyl
  • the aforementioned heterocyclic aryl group is pyridyl, furyl, pyrrolyl, furyl, thienyl, pyrrolyl, thiazolyl, and imidazolyl.
  • the above-mentioned substituent is any one or more of methyl, ethyl, -F, -Cl, and -OH.
  • the temperature of the above-mentioned oxidation reaction is 40-50°C.
  • the mass concentration of the above-mentioned hydrogen peroxide solution is 10-50%.
  • the molar ratio of the sodium tungstate dihydrate to the trifluoroalkyl sulfide compound is 0.1:100-20:100.
  • the molar ratio of the above-mentioned trifluoroalkyl sulfide compound and hydrogen peroxide is 1:20 to 1:2.
  • the above preparation method includes continuously feeding the first solution containing the trifluoroalkyl sulfide compound, the aqueous solution containing sodium tungstate dihydrate, and the hydrogen peroxide solution into a continuous reactor, respectively.
  • the solvent of the first solution is selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, Acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, dimethylsulfoxide, methanol, ethanol, Isopropanol, dichloromethane, biphenyl, ethylene glycol, hexamethyltriamine phosphate, phenol, pyridine, m-xylene, o-xylene, diphenyl ether, cyclohexanone, cyclohexanol, o-cresol, One or more of the group consisting of diethyl carbonate, diethyl oxalate morpholine,
  • the amount of the above-mentioned solvent relative to the trifluoroalkyl sulfide compound is 1-50 mL/g.
  • the retention time of the continuous reactor is 30-100 min.
  • the retention time of the continuous reactor is 55-65 min.
  • the above-mentioned continuous reactor is a tubular continuous reactor or a columnar reactor.
  • the above-mentioned continuous reactor is a continuous coil reactor.
  • the above-mentioned continuous reactor is equipped with heat exchange equipment for adjusting the temperature of the continuous reactor; temperature detection equipment for monitoring the reaction temperature of the continuous reactor; pressure detection equipment for monitoring the continuous reactor The pressure; online PAT equipment, used to detect the product composition of the continuous reactor; the automatic control system, the automatic control system is electrically connected with various feeding equipment, heat exchange equipment, temperature detection equipment, pressure detection equipment and online PAT equipment.
  • hydrogen peroxide is used as an oxidant to oxidize trifluoroalkyl sulfide compounds to generate a product system containing trifluoroalkyl sulfone compounds.
  • sodium tungstate dihydrate is used as a catalyst to improve the efficiency of the oxidation reaction, thereby increasing the yield of trifluoroalkyl sulfone compounds and shortening the reaction time.
  • This application adopts the above-mentioned continuous reaction equipment, that is, at one end of the continuous reactor, the reaction materials are continuously fed in, and at the same time, the product is continuously separated at the other end of the continuous reactor.
  • continuous production process greatly reduces the amount of materials that react in real time in the actual production process, and the direct contact of materials is more efficient, and because the molecular weight of hydrogen peroxide is small, it is easier to act on the sulfide of trifluoroalkyl sulfide compounds.
  • the above-mentioned oxidation reaction can take place at a lower temperature, which reduces the temperature of the oxidation reaction and avoids the long-term stay of hydrogen peroxide in the equipment, which can effectively reduce the high-temperature decomposition of hydrogen peroxide.
  • the application also reduces the requirements for the pressure and temperature resistance of the equipment, and further reduces the synthesis cost of trifluoroalkyl sulfone compounds.
  • the above-mentioned preparation method of the present application utilizes continuous feeding to improve the material contact effect, thereby enabling the oxidation reaction of sulfide to proceed at a lower temperature; and the oxidation reaction temperature is reduced It effectively reduces the decomposition of hydrogen peroxide, improves the oxidation utilization rate of hydrogen peroxide, and reduces the pressure requirements for continuous reactors.
  • reaction process has wide substrate adaptability and good functional group compatibility, and has a wide range of applications.
  • the prior art has the problem of decomposition of hydrogen peroxide when preparing trifluoroalkyl sulfone compounds using hydrogen peroxide as the oxidant.
  • the inventor of the present application has tried to change the amount of hydrogen peroxide and increase the reaction pressure.
  • increasing the amount of hydrogen peroxide does not improve the oxidation efficiency of sulfide. Therefore, the oxidation reaction temperature cannot be lowered, and the decomposition of hydrogen peroxide cannot be avoided.
  • the reaction pressure can alleviate the decomposition of hydrogen peroxide at the same temperature, the oxidation reaction Reduced efficiency has led to an increase in overall economic costs.
  • the inventor unexpectedly discovered that when the continuous process is used to prepare the trifluoroalkyl sulfone compound, the oxidation reaction temperature of the trifluoroalkyl ether compound can be significantly reduced, and the oxidation reaction temperature of the trifluoroalkyl ether compound can be guaranteed. Yield of trifluoroalkyl sulfone compounds. Based on this, this application provides a method for preparing trifluoroalkyl sulfone compounds.
  • a method for preparing trifluoroalkyl sulfone compounds includes continuously feeding trifluoroalkyl sulfide compounds, sodium tungstate dihydrate and hydrogen peroxide solution through a feeding device It is sent to a continuous reactor to cause the trifluoroalkyl sulfide compound to undergo oxidation reaction to obtain a product system containing trifluoroalkyl sulfone compound, wherein the trifluoroalkyl sulfide compound has the structural formula In the structure shown, R is any one of the following groups: linear alkyl, branched alkyl, substituted aryl, unsubstituted aryl, substituted heterocyclic aryl, unsubstituted heterocyclic aryl, unsubstituted For cycloalkyl and substituted cycloalkyl, the oxidation reaction temperature is 25-50°C.
  • This application uses hydrogen peroxide as an oxidant to oxidize trifluoroalkyl sulfide compounds to generate a product system containing trifluoroalkyl sulfone compounds.
  • sodium tungstate dihydrate is used as a catalyst to improve the efficiency of the oxidation reaction, thereby increasing the yield of trifluoroalkyl sulfone compounds and shortening the reaction time.
  • This application uses continuous reaction equipment, that is, at one end of the continuous reactor, the reaction materials are continuously fed in, and at the same time, the product is continuously separated out at the other end of the continuous reactor, which is compared with the traditional tank process
  • the continuous production process greatly reduces the amount of materials that react in real time, and the direct contact of the materials is more efficient, and because the molecular weight of hydrogen peroxide is small, it is easier to act on the thioether bond of trifluoroalkyl sulfide compounds .
  • the above-mentioned oxidation reaction can take place at a relatively low temperature, thereby reducing the temperature of the oxidation reaction and avoiding the long-term residence of hydrogen peroxide in the equipment, thereby effectively reducing the high-temperature decomposition of hydrogen peroxide.
  • this application It also reduces the requirements for the pressure and temperature resistance of the equipment, and further reduces the synthesis cost of trifluoroalkyl sulfone compounds.
  • the above-mentioned preparation method of the present application utilizes continuous feeding to improve the material contact effect, thereby enabling the oxidation reaction of sulfide to proceed at a lower temperature; and the oxidation reaction temperature is reduced It effectively reduces the decomposition of hydrogen peroxide, improves the oxidation utilization rate of hydrogen peroxide, and reduces the pressure requirements for continuous reactors.
  • reaction process has wide substrate adaptability and good functional group compatibility, and has a wide range of applications.
  • the above-mentioned R is any one of the following groups: C 1 ⁇ C 10 linear alkyl, C 1 ⁇ C 10 branched alkyl, C 3 ⁇ C 6 Cycloalkyl, C 6 to C 18 substituted or unsubstituted aryl, substituted or unsubstituted C 3 to C 10 heterocyclic aryl, preferably aryl is phenyl, naphthyl, biphenyl, anthracenyl
  • the heterocyclic aryl group is pyridyl, furyl, pyrrolyl, furyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyridyl, pyrazinyl, indolyl and quinolinyl, when the group has In the case of a substituent, the substituent is any one or more of methyl, ethyl, -F, -Cl, and -OH.
  • the continuous production process of the present application has high reaction efficiency, and the universality of the reaction substrate is better.
  • R is the above-mentioned group.
  • the preparation method of the present application can reduce the temperature of the oxidation reaction under the premise of ensuring high oxidation efficiency.
  • the mass concentration of the above-mentioned hydrogen peroxide solution is 10-50%.
  • the concentration of hydrogen peroxide should not be too low, but not too high. If the concentration of hydrogen peroxide is too low, the oxidizing property of hydrogen peroxide is too weak, and the volume of hydrogen peroxide required increases accordingly, which may cause the reaction solution to be diluted, thereby reducing the reaction efficiency. If the concentration of hydrogen peroxide is too high, on the one hand, it is easy to cause side reactions caused by excessive oxidation. On the other hand, if the concentration of hydrogen peroxide is too high, its corrosiveness is relatively high, and long-term use is likely to cause corrosion of reaction equipment.
  • sodium tungstate dihydrate can promote the above-mentioned oxidation reaction.
  • the amount of the catalyst is too small, the catalytic effect is not obvious, and if the amount of the catalyst is too much, it is easy to waste the catalyst. Therefore, the molar ratio of the sodium tungstate dihydrate and the trifluoroalkyl sulfide compound of the present application is controlled to be 0.1:100-20:100.
  • the molar ratio of the above-mentioned trifluoroalkyl sulfide compound and hydrogen peroxide is 1:20 to 1:2.
  • the purpose of this application is to oxidize trifluoroalkyl sulfide compounds into trifluoroalkyl sulfone compounds.
  • the amount of hydrogen peroxide is too small relative to the amount of trifluoroalkyl sulfide compounds, the trifluoroalkyl sulfide compounds will be excessive and wasted, and the purity of the trifluoroalkyl sulfone compounds in the resulting product system will be too low to increase purification Difficulty and cost; if the amount of hydrogen peroxide is too large relative to the amount of trifluoroalkyl sulfide compounds, on the one hand, it may lead to waste of hydrogen peroxide, and on the other hand, increase the probability of oxygen generation.
  • the above preparation method includes: the first solution containing the trifluoroalkyl sulfide compound, the aqueous solution containing sodium tungstate dihydrate, and the hydrogen peroxide solution are respectively continuously fed into the continuous reactor .
  • the above-mentioned trifluoroalkyl sulfide compounds and sodium tungstate dihydrate are respectively prepared in the form of solutions in advance, and then they are respectively fed into the continuous reactor, which is beneficial to the trifluoroalkyl sulfide compounds and tungsten Sodium dihydrate is uniformly dissolved in the solution respectively to form a homogeneous reaction system in a continuous reactor.
  • it helps the above three materials to be more uniformly dispersed under the same reaction conditions, thereby increasing the probability of collision between the reaction materials molecules, thereby improving the efficiency of the reaction; on the other hand, it is preferable to mix the three materials during the reaction. , It helps to reduce the probability of side reactions caused by mixing the above three materials in advance, thereby affecting the efficiency of the reaction and the purity of the product.
  • the solvent of the first solution is selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, Glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N,N- Diethylformamide, N-methylpyrrolidone, dimethylsulfoxide, methanol, ethanol, isopropanol, dichloromethane, biphenyl, ethylene glycol, hexamethylphosphoric triamine, phenol, pyridine, m-di Toluene, o-xylene, diphenyl ether, cyclohexanone, cyclohexanol,
  • the retention time of the continuous reactor is 30-100 min, more preferably 55-65 min.
  • the above-mentioned reaction can be carried out in a variety of continuous reactors.
  • the above-mentioned continuous reactor is a tubular continuous reactor or a columnar reactor, preferably a continuous coil reactor.
  • the above-mentioned continuous reactor is configured with heat exchange equipment, temperature detection equipment, pressure detection equipment, online PAT equipment, and an automated control system.
  • the heat exchange equipment is used to adjust the temperature of the continuous reactor;
  • the temperature detection equipment is used to monitor the reaction temperature of the continuous reactor;
  • the pressure detection equipment is used to monitor the pressure of the continuous reactor;
  • the online PAT equipment is used to detect the continuous reactor.
  • the automatic control system is electrically connected with various feeding equipment, heat exchange equipment, temperature detection equipment, pressure detection equipment and online PAT equipment.
  • reaction residence time reaction temperature
  • reaction pressure reaction pressure
  • feed flow rate reaction materials
  • This application adopts the above-mentioned automatic control system, which is helpful for precise control and real-time feedback of reaction related parameters such as reaction residence time, reaction temperature, reaction pressure, and feed flow rate of reaction materials, thereby greatly improving the degree of equipment integration.
  • This application uses hydrogen peroxide to oxidize trifluoroalkyl sulfide compounds to generate trifluoroalkyl sulfone compounds, and the general reaction formula is as follows:
  • the temperature of the coil Before feeding, control the temperature of the coil at 50°C, and use a plunger pump to continuously drive the above-mentioned material 1, material 2 and material 3 into the coil in proportion.
  • the feeding speed of material 1 is 4.06g/min
  • the feeding speed of material 2 is 0.18g/min
  • the feeding speed of material 3 is 1.36g/min.
  • Three materials are fed at the same time, sampling at the outlet and HPLC tracking reaction . After the feeding is finished, the system in the coil is replaced with pure acetonitrile at the same flow rate as above.
  • the temperature of the coil Before feeding, control the temperature of the coil at 50°C, and use a plunger pump to continuously drive the above-mentioned material 1, material 2 and material 3 into the coil in proportion.
  • the feeding speed of material 1 is 4.87g/min
  • the feeding speed of material 2 is 0.19g/min
  • the feeding speed of material 3 is 1.36g/min.
  • Three materials are fed at the same time, sampling at the outlet and HPLC tracking reaction . After the feeding is finished, the system in the coil is replaced with pure acetonitrile at the same flow rate as above.
  • the temperature of the coil Before feeding, control the temperature of the coil at 50°C, and use a plunger pump to continuously drive the above-mentioned material 1, material 2 and material 3 into the coil in proportion.
  • the feeding speed of material 1 is 5.62g/min
  • the feeding speed of material 2 is 0.21g/min
  • the feeding speed of material 3 is 1.36g/min.
  • the three materials are fed at the same time, and the outlet is sampled and the HPLC tracking reaction is carried out. .
  • the system in the coil is replaced with pure acetonitrile at the same flow rate as above.
  • the temperature of the coil Before feeding, control the temperature of the coil at 50°C, and use a plunger pump to continuously drive the above-mentioned material 1, material 2 and material 3 into the coil in proportion.
  • the feeding speed of material 1 is 5.03g/min
  • the feeding speed of material 2 is 0.20g/min
  • the feeding speed of material 3 is 1.36g/min.
  • the three materials are fed at the same time, and the outlet is sampled and the HPLC tracking reaction is carried out. .
  • the system in the coil is replaced with pure acetonitrile at the same flow rate as above.
  • the temperature of the coil Before feeding, control the temperature of the coil at 50°C, and use a plunger pump to continuously drive the above-mentioned material 1, material 2 and material 3 into the coil in proportion.
  • the feeding speed of material 1 is 4.07g/min
  • the feeding speed of material 2 is 0.18g/min
  • the feeding speed of material 3 is 1.36g/min.
  • Three materials are fed at the same time, sampling at the outlet and HPLC tracking reaction . After the feeding is finished, the system in the coil is replaced with pure acetonitrile at the same flow rate as above.
  • Example 8 The difference between Example 8 and Example 1 is that in Example 8, the temperature of the coil is controlled at 45° C., and the product is obtained after extraction with methyl tert-butyl ether and concentration.
  • the internal standard content is 94.8% and the yield is 97.2%.
  • Example 9 The difference between Example 9 and Example 1 is that in Example 9, the temperature of the coil is controlled at 40°C, and the product is obtained after extraction with methyl tert-butyl ether and concentration.
  • the internal standard content is 94.7% and the yield is 96.9%.
  • Example 10 The difference between Example 10 and Example 1 is that in Example 10, the coil temperature is controlled at 25°C, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard content is 88.7%, and the yield is 89.7%.
  • the reaction temperature is low and the yield is slightly lower, but the process does not have hydrogen peroxide decomposition, and can be safely continued or scaled up.
  • Example 11 The difference between Example 11 and Example 1 is that, in Example 11, 10% H 2 O 2 is taken as material 3, and the feeding speed of material 3 is 4.76 g/min, which is obtained after extraction with methyl tert-butyl ether and concentration.
  • the product has an internal standard content of 94.3% and a yield of 95.9%.
  • Example 12 The difference between Example 12 and Example 1 is that 50% H 2 O 2 is used as material 3 in Example 12, and the feeding speed of material 3 is 0.95 g/min, which is obtained after extraction with methyl tert-butyl ether and concentration.
  • the product has an internal standard content of 94.9% and a yield of 97.2%.
  • Example 13 The difference between Example 13 and Example 1 is that in Example 13, 8% H 2 O 2 is taken as material 3, and the feeding speed of material 3 is 5.95 g/min, which is obtained after extraction with methyl tert-butyl ether and concentration.
  • the product has an internal standard content of 92.1% and a yield of 91.9%.
  • Example 14 The difference between Example 14 and Example 1 is that in Example 14, 60% H 2 O 2 is taken as material 3, and the feeding speed of material 3 is 0.79 g/min, which is obtained after extraction with methyl tert-butyl ether and concentration.
  • the product has an internal standard content of 93.2% and a yield of 93.9%.
  • Example 15 The difference between Example 15 and Example 1 is that the amount of Na 2 WO 4 ⁇ 2H 2 O in Example 15 is 0.0168 mmol, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard content is 95.1%.
  • the rate is 96.9%.
  • Example 16 The difference between Example 16 and Example 1 is that the amount of Na 2 WO 4 ⁇ 2H 2 O in Example 16 is 0.0336 mol, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard content is 94.8%.
  • the rate is 97.2%.
  • Example 17 The difference between Example 17 and Example 1 is that the amount of Na 2 WO 4 ⁇ 2H 2 O in Example 17 is 0.0504 mol, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard content is 89.2%.
  • the rate is 91.1%.
  • Example 18 The difference between Example 18 and Example 1 is that the amount of Na 2 WO 4 ⁇ 2H 2 O in Example 18 is 1.344 mmol, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard content is 84.6%.
  • the rate is 83.9%.
  • Example 19 The difference between Example 19 and Example 1 is that in Example 19, 35% H 2 O 2 is taken as 3.36 mol, and the feeding speed of material 3 is 5.44 g/min, which is obtained after extraction with methyl tert-butyl ether and concentration.
  • the product has an internal standard content of 96.1% and a yield of 97.5%.
  • Example 20 The difference between Example 20 and Example 1 is that in Example 20, 35% H 2 O 2 is taken as 0.336 mol, and the feeding rate of material 3 is 0.54 g/min, and it is obtained after extraction and concentration with methyl tert-butyl ether.
  • the product has an internal standard content of 94.5% and a yield of 96.5%.
  • Example 21 The difference between Example 21 and Example 1 is that in Example 21, 35% H 2 O 2 is taken as 0.168 mol, and the feeding speed of material 3 is 0.27 g/min, and it is obtained after extraction and concentration with methyl tert-butyl ether.
  • the product has an internal standard content of 90.2% and a yield of 89.5%.
  • Example 22 The difference between Example 22 and Example 1 is that in Example 22, 35% H 2 O 2 is taken as 4.200 mol, and the feeding rate of material 3 is 0.27 g/min, which is obtained after extraction with methyl tert-butyl ether and concentration.
  • the product has an internal standard content of 91.5% and a yield of 89.9%.
  • Example 23 The difference between Example 23 and Example 1 is that the solvent in Example 23 is 1,4-dioxane, and the feeding speed of material 1 is 5.18 g/min, which is obtained after extraction and concentration with methyl tert-butyl ether.
  • the product has an internal standard content of 94.9% and a yield of 97.0%.
  • Example 24 The difference between Example 24 and Example 1 is that the solvent in Example 24 is toluene, the feeding speed of material 1 is 4.42 g/min, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard content is 95.1% , The yield is 96.8%.
  • Example 25 The difference between Example 25 and Example 1 is that the solvent in Example 25 is N,N-dimethylformamide, and the feeding rate of material 1 is 4.77 g/min. After extraction and concentration with methyl tert-butyl ether The product was obtained with an internal standard content of 94.7% and a yield of 97.5%.
  • Example 26 The difference between Example 26 and Example 1 is that the solvent in Example 26 is ethylene glycol, the feeding speed of material 1 is 5.54g/min, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the content of the internal standard is 94.0%, yield 96.4%.
  • Example 27 The difference between Example 27 and Example 1 is that the solvent in Example 27 is n-eicosane, the feeding speed of material 1 is 3.89 g/min, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard The content is 93.5% and the yield is 95.9%.
  • Example 28 The difference between Example 28 and Example 1 is that the solvent in Example 28 is dimethyl sulfoxide, and the feeding speed of material 1 is 5.45 g/min.
  • the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the standard content is 93.8%, and the yield is 94.9%.
  • Example 29 The difference between Example 29 and Example 1 is that the amount of acetonitrile in Example 29 is 30 mL, the feeding rate of material 1 is 0.90 g/min, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard content is 94.3% , The yield is 95.6%.
  • Example 30 The difference between Example 30 and Example 1 is that in Example 30, acetonitrile is 1500 mL, and the feeding rate of material 1 is 20.25 g/min.
  • the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard content is 93.9%. , The yield is 94.1%.
  • Example 31 The difference between Example 31 and Example 1 is that the amount of acetonitrile in Example 31 is 24 mL, the feeding rate of material 1 is 0.82 g/min, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard content is 85.9%. , The yield is 87.5%.
  • Example 32 The difference between Example 32 and Example 1 is that the amount of acetonitrile in Example 32 is 1650 mL, the feeding speed of material 1 is 22.23 g/min, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard content is 86.8%.
  • the yield is 87.9%.
  • Example 33 The difference between Example 33 and Example 1 is that the retention time in Example 33 is 55 min, in which the beating speed of material 1 is 4.42 g/min, the beating speed of material 2 is 0.19 g/min, and the beating speed of material 3 The speed is 1.48g/min, and the product is obtained after extraction with methyl tert-butyl ether and concentration.
  • the internal standard content is 94.5% and the yield is 96.7%.
  • Example 34 The difference between Example 34 and Example 1 is that the retention time in Example 34 is 65 min, where the beating speed of material 1 is 3.74 g/min, the beating speed of material 2 is 0.16 g/min, and the beating speed of material 3 The speed is 1.26g/min, and the product is obtained after extraction with methyl tert-butyl ether and concentration.
  • the internal standard content is 95.1%, and the yield is 97.3%.
  • Example 35 The difference between Example 35 and Example 1 is that the retention time in Example 35 is 30 min, where the beater speed of material 1 is 8.11 g/min, the beater speed of material 2 is 0.35 g/min, and the beater speed of material 3 The speed is 2.72g/min, and the product is obtained after extraction with methyl tert-butyl ether and concentration.
  • the internal standard content is 92.1% and the yield is 93.2%.
  • Example 36 The difference between Example 36 and Example 1 is that the retention time in Example 36 is 100 min, where the beating speed of material 1 is 2.43 g/min, the beating speed of material 2 is 0.11 g/min, and the beating speed of material 3 The speed is 0.82g/min, and the product is obtained after extraction with methyl tert-butyl ether and concentration.
  • the internal standard content is 91.4% and the yield is 92.0%.
  • Example 37 The difference between Example 37 and Example 1 is that the retention time in Example 37 is 20 min, where the beating speed of material 1 is 12.17 g/min, the beating speed of material 2 is 0.53 g/min, and the beating speed of material 3 The speed is 4.08g/min, the product is obtained after extraction with methyl tert-butyl ether and concentration. The internal standard content is 77.3% and the yield is 75.9%.
  • Example 38 The difference between Example 38 and Example 1 is that the retention time in Example 38 is 110 min, where the beating speed of material 1 is 2.21 g/min, the beating speed of material 2 is 0.10 g/min, and the beating speed of material 3 The speed is 0.74g/min, and the product is obtained after extraction with methyl tert-butyl ether and concentration.
  • the internal standard content is 84.9% and the yield is 82.1%.
  • Example 39 is a continuous column reactor, which is extracted with methyl tert-butyl ether and concentrated to obtain a product with an internal standard content of 90.5% and a yield of 91.1%.
  • the reactant A was amplified to 2.0Kg, and compound B was synthesized using the reaction conditions of Example 1 above to obtain a light yellow liquid with a yield of 97.3% and an HPLC purity of 98.4%. Because the expanded reaction was compared with the small reaction in the reaction vessel The loss on the wall is relatively reduced, so the yield and purity of compound B obtained by the expanded reaction are higher.
  • Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that in Comparative Example 1, the coil temperature is controlled at 55°C, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard content is 95.3%, and the yield is 96.5%.
  • the decomposition of hydrogen peroxide was detected, so its yield decreased, and the safety was lower after long-term continuous reaction or amplified reaction.
  • Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that in Comparative Example 2, the coil temperature is controlled at 90°C, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard content is 72.9%, and the yield is 73.4%.
  • the decomposition of a large amount of hydrogen peroxide was detected, so its yield decreased significantly.
  • Comparative Example 3 The difference between Comparative Example 3 and Example 1 is that in Comparative Example 3, the temperature of the coil is controlled at 20°C, and the product is obtained after extraction and concentration with methyl tert-butyl ether.
  • the internal standard content is 79.9% and the yield is 81.2%.
  • This application uses hydrogen peroxide as an oxidant to oxidize trifluoroalkyl sulfide compounds to generate a product system containing trifluoroalkyl sulfone compounds.
  • sodium tungstate dihydrate is used as a catalyst to improve the efficiency of the oxidation reaction, thereby increasing the yield of trifluoroalkyl sulfone compounds and shortening the reaction time.
  • This application uses continuous reaction equipment, that is, at one end of the continuous reactor, the reaction materials are continuously fed in, and at the same time, the product is continuously separated out at the other end of the continuous reactor, which is compared with the traditional kettle-type process
  • the continuous production process greatly reduces the amount of materials that react in real time, and the direct contact of the materials is more efficient, and because the molecular weight of hydrogen peroxide is small, it is easier to act on the thioether bond of trifluoroalkyl sulfide compounds ,
  • the above-mentioned oxidation reaction can occur at a lower temperature, so that the oxidation temperature is reduced and the long-term stay of hydrogen peroxide in the equipment is avoided, so that the high-temperature decomposition of hydrogen peroxide can be effectively achieved.
  • the application also reduces the The equipment requires pressure and temperature resistance, thereby reducing the synthesis cost of trifluoroalkyl sulfone compounds.
  • the above-mentioned preparation method of the present application uses continuous feeding to improve the material contact effect, thereby enabling the oxidation reaction of sulfide to proceed at a lower temperature; and the oxidation reaction temperature is reduced It effectively reduces the decomposition of hydrogen peroxide, improves the oxidation utilization rate of hydrogen peroxide, and reduces the pressure requirements for continuous reactors.
  • reaction process has wide substrate adaptability and good functional group compatibility, and has a wide range of applications.

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Abstract

本发明提供了一种三氟烃基砜类化合物的制备方法。该制备方法包括将三氟烃基硫醚类化合物、钨酸钠二水合物和双氧水溶液通过送料设备连续送入连续式反应器中，使三氟烃基硫醚类化合物发生氧化反应，得到包含三氟烃基砜类化合物的产物体系，其中，三氟烃基硫醚类化合物具有结构式（I）所示的结构，R为以下基团中的任意一种：直链烷基、支链烷基、取代芳基、非取代芳基、取代杂环芳基、非取代杂环芳基、非取代环状烷基和取代环状烷基，氧化反应的温度为25～50℃。本申请利用连续化进料，提高了物料接触效果，进而使得硫醚的氧化反应在较低的温度下即可进行；而且氧化反应温度的降低，有效减少了双氧水的分解，且降低了对连续式反应器的耐压要求。

Description

三氟烃基砜类化合物的制备方法 技术领域
本发明涉及三氟烃基砜类化合物的合成技术领域，具体而言，涉及一种三氟烃基砜类化合物的制备方法。
背景技术
近年来，由于含有三氟甲基砜基团化合物被广泛应用在药物、生物活性化合物、催化剂和功能性材料等领域，应用前景广阔，所以含有三氟甲基砜基团的化合物的合成越来越受到合成工作者的重视，开发一种高效益、低成本的合成工艺具有重要意义。
目前工业上生产制造三氟甲基砜类化合物主要是通过三氟甲基硫醚氧化得到。而三氟甲基硫醚的氧化最常用的氧化剂为高锰酸钾和三氧化铬，但由于反应生成的大量副产物锰盐和铬盐不仅导致工艺后处理困难、分离收率较低(60～70％)，而且重金属难以回收利用，对环境污染较大，企业三废处理成本高，不符合绿色化学发展的要求。
国际公开号为WO2015035223(A1)的专利申请公开了使用高碘酸钠作为氧化剂、三氯化钌作为催化剂的氧化方法，在室温下即可实现三氟甲基硫醚的氧化，分离收率为85％。该氧化方法相对温和，但其中钌催化剂价格昂贵，且反应产生了大量的含卤三废，原子利用率低，生产成本较高。
还有文献提供了使用35％双氧水作为氧化剂、钨酸钠二水合物作为催化剂的氧化方法。双氧水作为清洁绿色的氧化剂，氧化反应的副产物是水，三废量大幅降低，但由于三氟烃基具有强吸电子特性，因此在氧化过中其与硫醚的氧化形成强烈的竞争，为了满足对硫醚的氧化作用，该反应的氧化温度需要维持在80℃以上。在如此高的温度下，双氧水会迅速分解，产生大量的氧气，极大增加了釜式工艺放大生产的安全隐患。
综上，高锰酸钾、三氧化铬以及高碘酸钠作为三氟甲基硫醚氧化合成三氟甲基的传统氧化剂生产成本高，而且会产生大量含卤或含重金属的三废，会对环境造成较大污染，不符合绿色化学的发展方向；另外以高碘酸钠作为氧化剂，所用的三氯化钌催化剂昂贵，难以回收利用，导致生产成本较高，同样限制了其应用。双氧水作为可替代的清洁氧化剂虽然会避免三废对环境的污染，符合绿色化学的理念，但高温下双氧水分解产生的大量氧气，给传统釜式放大生产带来巨大的安全隐患，对设备要求也高导致设备成本高，难以实现规模化生产。
发明内容
本发明的主要目的在于提供一种三氟烃基砜类化合物的制备方法，以解决现有技术中利用双氧水为氧化剂制备三氟烃基砜类化合物时双氧水分解的问题。
为了实现上述目的，根据本发明的一个方面，提供了一种三氟烃基砜类化合物的制备方法。该制备方法包括将三氟烃基硫醚类化合物、钨酸钠二水合物和双氧水溶液通过送料设备连续送入连续式反应器中，使三氟烃基硫醚类化合物发生氧化反应，得到包含三氟烃基砜类化合物的产物体系，其中，三氟烃基硫醚类化合物具有结构式
Figure PCTCN2019129412-appb-000001
所示的结构，R为以下基团中的任意一种：直链烷基、支链烷基、取代芳基、非取代芳基、取代杂环芳基、非取代杂环芳基、非取代环烷基和取代环烷基，氧化反应的温度为25～50℃。
进一步地，上述R为以下基团中的任意一种：C 1～C 10的直链烷基、C 1～C 10的支链烷基、C 3～C 6的环烷基、C 6～C 18的取代或非取代芳基、取代或非取代的C 3～C 10的杂环芳基。
进一步地，上述芳基为苯基、萘环基、联苯基、蒽基，上述杂环芳基为吡啶基、呋喃基、吡咯基、呋喃基、噻吩基、吡咯基、噻唑基、咪唑基、吡啶基、吡嗪基、吲哚基和喹啉基。
进一步地，当基团具有取代基时，上述取代基为甲基、乙基、-F、-Cl、-OH中的任意一种或多种。
进一步地，上述氧化反应的温度为40～50℃。
进一步地，上述双氧水溶液的质量浓度为10～50％。
进一步地，上述钨酸钠二水合物与三氟烃基硫醚类化合物的摩尔比为0.1:100～20:100。
进一步地，上述三氟烃基硫醚类化合物和双氧水的摩尔比为1:20～1:2。
进一步地，上述制备方法包括将含有三氟烃基硫醚类化合物的第一溶液、含有钨酸钠二水合物的水溶液以及双氧水溶液分别连续送入连续式反应器中。
进一步地，上述第一溶液的溶剂选自四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙二醇二甲醚、二乙二醇二甲醚、苯、甲苯、二甲苯、丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜、甲醇、乙醇、异丙醇、二氯甲烷、联苯、乙二醇、六甲基磷酸三胺、苯酚、吡啶、间二甲苯、邻二甲苯、二苯醚、环己酮、环己醇、邻甲酚、碳酸二乙酯、草酸二乙酯吗啉、正十八烷烃、正二十烷、硅油、丙二酸二乙酯、二乙二醇二乙醚以及氯仿组成的组中的一种或多种。
进一步地，上述溶剂相对于三氟烃基硫醚类化合物的用量为1～50mL/g。
进一步地，上述连续式反应器的保留时间为30～100min。
进一步地，上述连续式反应器的保留时间为55～65min。
进一步地，上述连续式反应器为管式连续反应器或柱状反应器。
进一步地，上述连续式反应器为连续式盘管反应器。
进一步地，上述连续式反应器配置有换热设备，用于调节连续式反应器的温度；温度检测设备，用于监测连续式反应器的反应温度；压力检测设备，用于监测连续式反应器的压力；在线PAT设备，用于检测连续式反应器的产物组成；自动化控制系统，自动化控制系统与各送料设备、换热设备、温度检测设备、压力检测设备和在线PAT设备电连接。
应用本发明的技术方案，将双氧水作为氧化剂来氧化三氟烃基硫醚类化合物，使其生成包含三氟烃基砜类化合物的产物体系。其中的钨酸钠二水合物作为催化剂有利于提高氧化反应的效率，从而提高三氟烃基砜类化合物的产率，并缩短反应时间。
本申请采用上述连续式反应设备，即在连续式反应器的一端不断地有反应物料被投进去，同时在连续式反应器的另一端不断地有产物被分离出来，相比于传统的釜式工艺，连续化生产工艺在实际生产过程中使得实时发生反应的物料量大大减少，物料直接的接触更加高效，而且由于双氧水分子量较小，因此更容易作用于三氟烃基硫醚类化合物的硫醚键，可以使上述氧化反应在较低的温度下即可发生，从而使得既降低了氧化反应的温度又避免了双氧水在设备中的长时间停留，从而可以有效的减少双氧水的高温分解，因此本申请还降低了对设备耐压和耐温的要求，进一步地降低了三氟烃基砜类化合物的合成成本。总之与现有技术相比，本申请的上述制备方法，利用连续化进料，提高了物料接触效果，进而使得硫醚的氧化反应在较低的温度下即可进行；而且氧化反应温度的降低，有效减少了双氧水的分解，提高了双氧水的氧化利用率，且降低了对连续式反应器的耐压要求。
此外，上述反应工艺具有广泛的底物适应性及良好的官能团兼容性，应用范围较广。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。
如背景技术所分析的，现有技术中存在利用双氧水为氧化剂制备三氟烃基砜类化合物时双氧水分解的问题，为解决该技术问题，本申请发明人曾尝试改变双氧水用量，提高反应压力等方式，但是发现增加双氧水用量对硫醚的氧化效率增加没有改进作用，因此也不可以降低氧化反应温度，进而也不能避免双氧水的分解；提高反应压力虽然可以缓解同等温度下双氧水的分解，但是氧化反应效率降低，导致综合经济成本增加。在上述常规路径不能有效解决技术问题的技术上，发明人意外发现当采用连续化工艺进行三氟烃基砜类化合物的制备时，可以明显降低三氟烃基醚类化合物的氧化反应温度，而且能够保证三氟烃基砜类化合物收率。基于此本申请提供了一种三氟烃基砜类化合物的制备方法。
在本申请的一种典型的实施方式中，提供了一种三氟烃基砜类化合物的制备方法，其包括将三氟烃基硫醚类化合物、钨酸钠二水合物和双氧水溶液通过送料设备连续送入连续式反应器中，使三氟烃基硫醚类化合物发生氧化反应，得到包含三氟烃基砜类化合物的产物体系， 其中，三氟烃基硫醚类化合物具有结构式
Figure PCTCN2019129412-appb-000002
所示的结构，R为以下基团中的任意一种：直链烷基、支链烷基、取代芳基、非取代芳基、取代杂环芳基、非取代杂环芳基、非取代环烷基和取代环烷基，氧化反应的温度为25～50℃。
本申请利用双氧水作为氧化剂来氧化三氟烃基硫醚类化合物，使其生成包含三氟烃基砜类化合物的产物体系。其中的钨酸钠二水合物作为催化剂有利于提高氧化反应的效率，从而提高三氟烃基砜类化合物的产率，并缩短反应时间。
本申请采用连续式反应设备，即在连续式反应器的一端不断地有反应物料被投进去，同时在连续式反应器的另一端不断地有产物被分离出来，相比于传统的釜式工艺，连续化生产工艺在实际生产过程中使得实时发生反应的物料量大大减少，物料直接的接触更加高效，而且由于双氧水分子量较小，因此更容易作用于三氟烃基硫醚类化合物的硫醚键，可以使上述氧化反应在较低的温度下即可发生，从而使得既降低了氧化反应的温度又避免了双氧水在设备中的长时间停留，从而可以有效的减少双氧水的高温分解，因此本申请还降低了对设备耐压和耐温的要求，进一步地降低了三氟烃基砜类化合物的合成成本。总之与现有技术相比，本申请的上述制备方法，利用连续化进料，提高了物料接触效果，进而使得硫醚的氧化反应在较低的温度下即可进行；而且氧化反应温度的降低，有效减少了双氧水的分解，提高了双氧水的氧化利用率，且降低了对连续式反应器的耐压要求。
此外，上述反应工艺具有广泛的底物适应性及良好的官能团兼容性，应用范围较广。
在本申请的一种实施例中，上述R为以下基团中的任意一种：C 1～C 10的直链烷基、C 1～C 10的支链烷基、C 3～C 6的环烷基、C 6～C 18的取代或非取代芳基、取代或非取代的C 3～C 10的杂环芳基，优选芳基为苯基、萘环基、联苯基、蒽基，优选杂环芳基为吡啶基、呋喃基、吡咯基、呋喃基、噻吩基、吡咯基、噻唑基、咪唑基、吡啶基、吡嗪基、吲哚基和喹啉基，当基团具有取代基时，所述取代基为甲基、乙基、-F、-Cl、-OH中的任意一种或多种。
如前所述，本申请的连续化生产工艺的反应效率高，且反应的底物普适性较好，为了更高效地得到更稳定的产品，优选R为上述的基团，比如通过本申请的三氟烃基砜类化合物的连续化生产工艺得到的下列砜类化合物：
Figure PCTCN2019129412-appb-000003
Figure PCTCN2019129412-appb-000004
如前所述，采用本申请制备方法在保证高氧化效率的前提下可以降低氧化反应的温度，为了提高氧化效率，优选控制上述氧化反应的温度为40～50℃。在上述温度范围内，避免了反应的温度太低导致氧化效率降低的问题。
在本申请的一种实施例中，上述双氧水溶液的质量浓度为10～50％。
理论上，双氧水的浓度越大，其具有的氧化性越强。为了提高上述氧化反应的效率，双氧水的浓度不能太低，但也不能太高。若双氧水的浓度太低，则双氧水的氧化性太弱，需要的双氧水的体积相应的增大，由此可能导致反应液被稀释，从而降低反应效率。若双氧水浓度太高，一方面容易导致过度氧化带来的副反应的发生，另一方面双氧水浓度太高，其腐蚀性较大，长时间使用容易造成对反应设备的腐蚀。
钨酸钠二水合物作为催化剂，能促进上述氧化反应的进行。但是，若催化剂的用量太少，催化效果不明显，若催化剂用量太多又容易造成催化剂的浪费。因此，控制本申请的钨酸钠二水合物与三氟烃基硫醚类化合物的摩尔比为0.1:100～20:100。
在本申请的一种实施例中，上述三氟烃基硫醚类化合物和双氧水的摩尔比为1:20～1:2。
本申请的目的是使三氟烃基硫醚类化合物经氧化生成三氟烃基砜类化合物。但是，若双氧水的量相对于三氟烃基硫醚类化合物的量太少，导致三氟烃基硫醚类化合物过量而浪费，且得到的产物体系中三氟烃基砜类化合物的纯度太低增加提纯难度和成本；若双氧水的量相对于三氟烃基硫醚类化合物的量太多一方面可能导致双氧水的浪费，另一方面增大氧气产生概率。
在本申请的一种实施例中，上述制备方法包括：将含有三氟烃基硫醚类化合物的第一溶液、含有钨酸钠二水合物的水溶液以及双氧水溶液分别连续送入连续式反应器中。
本申请分别将上述三氟烃基硫醚类化合物、钨酸钠二水合物提前配成溶液的形式，然后再分别将其送入连续式反应器中，有利于三氟烃基硫醚类化合物、钨酸钠二水合物分别均匀的溶解于溶液中，以在连续式反应器中形成均相反应体系。一方面有助于上述三种物料在同样的反应条件下更均匀的分散，从而增大反应物料分子间的碰撞几率，进而提高反应的效率；另一方面优选在反应进行时再将三者混合，有助于降低提前混合上述三种物料导致的副反应的发生几率，从而影响反应的效率和产物的纯度。
为了提高上述反应的效率，以及进一步地优化上述反应的工艺，提高上述工艺的普适性，优选上述第一溶液的溶剂选自四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙二醇二甲醚、二乙二醇二甲醚、苯、甲苯、二甲苯、丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜、甲醇、乙醇、异丙醇、二氯甲烷、联苯、乙二醇、六甲基磷酸三胺、苯酚、吡啶、间二甲苯、邻二甲苯、二苯醚、环己酮、环己醇、邻甲酚、碳酸二乙酯、草酸二乙酯吗啉、正十八烷烃、正二十烷、硅油、丙二酸二乙酯、二乙二醇二乙醚以及氯仿组成的组中的一种或多种，同时，为了进一步地平衡溶剂的利用率与反应的效率的关系，优选溶剂相对于三氟烃基硫醚类化合物的用量为1～50mL/g。
为了使上述反应物料尽可能的充分反应并避免时间过长导致副产物过度生成的发生，优选控制上述连续式反应器的保留时间为30～100min，进一步优选为55～65min。
上述反应能在多种连续反应器中进行，为了提高本申请的上述反应效率，上述连续式反应器为管式连续反应器或柱状反应器，优选为连续式盘管反应器。
在本申请的一种实施例中，上述连续式反应器配置有换热设备、温度检测设备、压力检测设备、在线PAT设备和自动化控制系统。其中，换热设备用于调节连续式反应器的温度；温度检测设备用于监测连续式反应器的反应温度；压力检测设备用于监测连续式反应器的压力；在线PAT设备用于检测连续式反应器的产物组成；自动化控制系统与各送料设备、换热设备、温度检测设备、压力检测设备和在线PAT设备电连接。
由于影响连续反应过程高效运行的因素主要有反应停留时间、反应温度、反应压力、反应物料的进料流速。本申请采用上述自动化控制系统，有助于对反应的相关参数如反应停留时间、反应温度、反应压力、反应物料的进料流速进行精准的控制和实时的反馈，从而大大提高设备集成化程度，为反应提供可靠的设备支持。
以下将结合具体实施例，对本申请的有益效果进行说明。
本申请采用双氧水氧化三氟烃基硫醚类化合物生成三氟烃基砜类化合物的反应通式如下：
Figure PCTCN2019129412-appb-000005
实施例1
控制温度为15～25℃，分别准备以下物料：即将三氟甲基苯硫醚(A，30g，0.168mol)溶解于乙腈(270mL)中搅拌澄清，记为物料1；将Na 2WO 4·2H 2O(5.10g，0.015mol)溶解于蒸馏水(5.4mL)中搅拌澄清，记为物料2；取35％H 2O 2(81.62g，0.84mol)记为物料3；连续式盘管保留体积为100mL，控制反应体系在盘管内的保留时间为60min。
打料前，先将盘管温度控制在50℃，使用柱塞泵将上述物料1、物料2和物料3按比例分别连续打入盘管中。其中物料1的打料速度为4.06g/min，物料2的打料速度为0.18g/min，物料3的打料速度为1.36g/min，三股物料同时进料，出口取样并进行HPLC跟踪反应。打料完毕，用纯乙腈分别以上述同样的流速将盘管内的体系置换出来。流出体系降温至室温后，控温15～25℃，向体系中滴加10％的亚硫酸钠水溶液淬灭，然后用甲基叔丁基醚萃取、浓缩后得到产品三氟甲基苯砜，记为B，内标含量95.0％，收率97.0％。B的数据表证：MS(EI,m/z):210(M +,3.0),140.9(M +-CF 3,43.2),124.9(M +-CF 3-O,2.7),77(C 6H 5 +,100),69(CF 3 +,2.7)； 1HNMR(400MHz,CDCl 3)δ＝8.11-8.06(m,2H),7.85-7.90(m,1H),7.69-7.65(m,2H)ppm； 13CNMR(101MHz,CDCl 3)δ＝136.5,132.8-132.3(m),130.7,130.0,119.7(q,J＝324.6Hz)ppm。
实施例2
控制温度为15～25℃，分别准备以下物料：即将对氯三氟甲基苯硫醚(A，35.72g，0.168mol)溶解于乙腈(321.5mL)中搅拌澄清，记为物料1；将Na 2WO 4·2H 2O(5.10g，0.015mol)溶解于蒸馏水(6.43mL)中搅拌澄清，记为物料2；取35％H 2O 2(81.62g，0.84mol)记为物料3；连续式盘管保留体积为100mL，控制反应体系在盘管内的保留时间为60min。
打料前，先将盘管温度控制在50℃，使用柱塞泵将上述物料1、物料2和物料3按比例分别连续打入盘管中。其中物料1的打料速度为4.83g/min，物料2的打料速度为0.19g/min，物料3的打料速度为1.36g/min，三股物料同时进料，出口取样并进行HPLC跟踪反应。打料完毕，用纯乙腈分别以上述同样的流速将盘管内的体系置换出来。流出体系降温至室温后，控温15～25℃，向体系中滴加10％的亚硫酸钠水溶液淬灭，然后用甲基叔丁基醚萃取、浓缩后得到产品三氟甲基苯砜，记为B1，内标含量94.7％，收率96％。B1的数据表证：MS(EI,m/z):111(M-SO 2CF 3 +)； 1HNMR(CDCl 3,300MHz)σ:7.66(d,J＝6.9Hz,2H),7.95(d,J＝7.1Hz,2H)ppm； 13CNMR(CDCl 3,150.9MHz)σ:119.5(q,J＝325.4Hz),129.5,130.4,132.5,144.6ppm。
实施例3
控制温度为15～25℃，分别准备以下物料：将正辛基三氟甲基硫醚(A，36.0g，0.168mol)溶解于乙腈(324mL)中搅拌澄清，记为物料1；将Na 2WO 4·2H 2O(5.10g，0.015mol)溶解于蒸馏水(6.48mL)中搅拌澄清，记为物料2；取35％H 2O 2(81.62g，0.84mol)记为物料3；连续式盘管保留体积为100mL，控制反应体系在盘管内的保留时间为60min。
打料前，先将盘管温度控制在50℃，使用柱塞泵将上述物料1、物料2和物料3按比例分别连续打入盘管中。其中物料1的打料速度为4.87g/min，物料2的打料速度为0.19g/min，物料3的打料速度为1.36g/min，三股物料同时进料，出口取样并进行HPLC跟踪反应。打料完毕，用纯乙腈分别以上述同样的流速将盘管内的体系置换出来。流出体系降温至室温后，控温15～25℃，向体系中滴加10％的亚硫酸钠水溶液淬灭，然后用甲基叔丁基醚萃取、浓缩后得到产品三氟甲基苯砜，记为B2，内标含量94.7％，收率96％。B2的数据表证：GC-MS m/z 246(M+),113(M +-SO 2CF 3,100％)； 1HNMR(400MHz,CDCl 3)δ:3.26–3.18(m,2H),1.94(dt,J＝ 15.7,7.9Hz,2H),1.54–1.44(m,2H),1.41–1.21(m,8H),0.95(t,J＝6.8Hz,3H)ppm； 13CNMR(101MHz,CDCl 3)δ:119.5(q,J＝327.2Hz),49.6(q,J＝1.0Hz),31.6(s),28.8(s),28.4(s),22.6(s),20.6(s),14.1(s)ppm。
实施例4
控制温度为15～25℃，分别准备以下物料：(S)-2-甲基-6-(三氟甲基磺基)庚烷(A，41.54g，0.168mol)溶解于乙腈(374mL)中搅拌澄清，记为物料1；将Na 2WO 4·2H 2O(5.10g，0.015mol)溶解于蒸馏水(7.48mL)中搅拌澄清，记为物料2；取35％H 2O 2(81.62g，0.84mol)记为物料3；连续式盘管保留体积为100mL，控制反应体系在盘管内的保留时间为60min。
打料前，先将盘管温度控制在50℃，使用柱塞泵将上述物料1、物料2和物料3按比例分别连续打入盘管中。其中物料1的打料速度为5.62g/min，物料2的打料速度为0.21g/min，物料3的打料速度为1.36g/min，三股物料同时进料，出口取样并进行HPLC跟踪反应。打料完毕，用纯乙腈分别以上述同样的流速将盘管内的体系置换出来。流出体系降温至室温后，控温15～25℃，向体系中滴加10％的亚硫酸钠水溶液淬灭，然后用甲基叔丁基醚萃取、浓缩后得到产品三氟甲基苯砜，记为B3，内标含量95％，收率96.9％。B3的数据表证：MS(EI,m/z):246[M +]； 1HNMR(300MHz,CDCl 3):δ＝0.89(dd,J＝6.70Hz,6H),1.17-1.26(m,2H),1.31-1.46(m,1H),1.50(d,3H),1.53-1.75(m,3H),2.00-2.13(m,1H),3.36(m,1H)ppm； 13CNMR(75MHz,CDCl 3):δ＝12.6(d),22.4(d),22.58(d),24.1(u),27.8(d),28.4(u),38.3(u),120.1(q,J＝329.0Hz,u)。
实施例5
控制温度为15～25℃，分别准备以下物料：2,4,6-三甲基-3-(三氟甲基硫)吡啶(A，37.17g，0.168mol)溶解于乙腈(335mL)中搅拌澄清，记为物料1；将Na 2WO 4·2H 2O(5.10g，0.015mol)溶解于蒸馏水(6.69mL)中搅拌澄清，记为物料2；取35％H 2O 2(81.62g，0.84mol)记为物料3；连续式盘管保留体积为100mL，控制反应体系在盘管内的保留时间为60min。
打料前，先将盘管温度控制在50℃，使用柱塞泵将上述物料1、物料2和物料3按比例分别连续打入盘管中。其中物料1的打料速度为5.03g/min，物料2的打料速度为0.20g/min，物料3的打料速度为1.36g/min，三股物料同时进料，出口取样并进行HPLC跟踪反应。打料完毕，用纯乙腈分别以上述同样的流速将盘管内的体系置换出来。流出体系降温至室温后，控温15～25℃，向体系中滴加10％的亚硫酸钠水溶液淬灭，然后用甲基叔丁基醚萃取、浓缩后得到产品三氟甲基苯砜，记为B4，内标含量65％，收率60％。B4的数据表证：MS(EI,m/z):m/z(％):254[M+H +]； 1HNMR(400MHz,CDCl 3):δ:7.04(s,1H,arom),2.84(s,3H,CH 3),2.64(s,3H,CH 3),2.50(s,3H,CH 3)ppm； 13CNMR(100MHz,CDCl 3)δ＝164.73,162.56,153.18(3C–Me),126.14(C–H),123.55(C–SO 2),121.38(q,J＝325Hz,CF 3),26.50(CH 3),24.51(CH 3),22.50(CH 3)ppm。
实施例6
控制温度为15～25℃，分别准备以下物料：3-(三氟甲基硫)吡啶(A，30.10g，0.168mol)溶解于乙腈(271mL)中搅拌澄清，记为物料1；将Na 2WO 4·2H 2O(5.10g，0.015mol)溶解于蒸馏水(5.42mL)中搅拌澄清，记为物料2；取35％H 2O 2(81.62g，0.84mol)记为物料3；连续式盘管保留体积为100mL，控制反应体系在盘管内的保留时间为60min。
打料前，先将盘管温度控制在50℃，使用柱塞泵将上述物料1、物料2和物料3按比例分别连续打入盘管中。其中物料1的打料速度为4.07g/min，物料2的打料速度为0.18g/min，物料3的打料速度为1.36g/min，三股物料同时进料，出口取样并进行HPLC跟踪反应。打料完毕，用纯乙腈分别以上述同样的流速将盘管内的体系置换出来。流出体系降温至室温后，控温15～25℃，向体系中滴加10％的亚硫酸钠水溶液淬灭，然后用甲基叔丁基醚萃取、浓缩后得到产品三氟甲基苯砜，记为B5，内标含量65.4％，收率52％。B5的数据表证：MS(EI,m/z):212[M+H +]； 1HNMR(400MHz,CDCl 3)δ＝9.25(d,J＝2.4Hz,1H),9.08(dd,J＝4.8,1.8Hz,1H),8.31(m,1H),7.65(m,1H)ppm； 13CNMR(100MHz,CDCl 3)δ＝156.3(CH),151.3(CH),138.5(CH),128.1(C),124.3(CH),119.3(CF 3,J＝322Hz)ppm。
实施例7
控制温度为15～25℃，分别准备以下物料：5,5-二甲基-2-(三氟甲基硫)环己烷-1,3-二酮(A，40.36g，0.168mol)溶解于乙腈(363mL)中搅拌澄清，记为物料1；将Na 2WO 4·2H 2O(5.10g，0.015mol)溶解于蒸馏水(7.26mL)中搅拌澄清，记为物料2；取35％H 2O 2(81.62g，0.84mol)记为物料3；连续式盘管保留体积为100mL，控制反应体系在盘管内的保留时间为60min。
打料前，先将盘管温度控制在50℃，使用柱塞泵将上述物料1、物料2和物料3按比例分别连续打入盘管中。中物料1的打料速度为5.45g/min，物料2的打料速度为0.21g/min，物料3的打料速度为1.36g/min，三股物料同时进料，出口取样并进行HPLC跟踪反应。打料完毕，用纯乙腈分别以上述同样的流速将盘管内的体系置换出来。流出体系降温至室温后，控温15～25℃，向体系中滴加10％的亚硫酸钠水溶液淬灭，然后用甲基叔丁基醚萃取、浓缩后得到产品三氟甲基苯砜，记为B6，内标含量75.3％，收率74.9％。B6的数据表证：MS(EI,m/z):273.3[M+H +]； 1HNMR(400MHz,CDCl 3)δ＝1.15s(CH 3),2.63s(CH 2),9.8(OH)ppm； 13CNMR(100MHz,CDCl 3)δ＝205.3(OC),139.6(CF 3),75.6(CH),52.6(CH 2),32.2(C),28.6(CH 3)ppm。
实施例8
实施例8与实施例1的区别在于，实施例8中将盘管温度控制在45℃，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量94.8％，收率97.2％。
实施例9
实施例9与实施例1的区别在于，实施例9中将盘管温度控制在40℃，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量94.7％，收率96.9％。
实施例10
实施例10与实施例1的区别在于，实施例10中将盘管温度控制在25℃，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量88.7％，收率89.7％，由于反应温度低，收率稍低，但是该过程无双氧水分解，可以安全持续进行或进行放大生产。
实施例11
实施例11与实施例1的区别在于，实施例11中取10％H 2O 2为物料3，物料3的打料速度为4.76g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量94.3％，收率95.9％。
实施例12
实施例12与实施例1的区别在于，实施例12中取50％H 2O 2为物料3，物料3的打料速度为0.95g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量94.9％，收率97.2％。
实施例13
实施例13与实施例1的区别在于，实施例13中取8％H 2O 2为物料3，物料3的打料速度为5.95g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量92.1％，收率91.9％。
实施例14
实施例14与实施例1的区别在于，实施例14中取60％H 2O 2为物料3，物料3的打料速度为0.79g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量93.2％，收率93.9％。
实施例15
实施例15与实施例1的区别在于，实施例15中Na 2WO 4·2H 2O的用量为0.0168mmol，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量95.1％，收率96.9％。
实施例16
实施例16与实施例1的区别在于，实施例16中Na 2WO 4·2H 2O的用量为0.0336mol，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量94.8％，收率97.2％。
实施例17
实施例17与实施例1的区别在于，实施例17中Na 2WO 4·2H 2O的用量为0.0504mol，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量89.2％，收率91.1％。
实施例18
实施例18与实施例1的区别在于，实施例18中Na 2WO 4·2H 2O的用量为1.344mmol，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量84.6％，收率83.9％。
实施例19
实施例19与实施例1的区别在于，实施例19中取35％H 2O 2为3.36mol，物料3的打料速度为5.44g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量96.1％，收率97.5％。
实施例20
实施例20与实施例1的区别在于，实施例20中取35％H 2O 2为0.336mol，物料3的打料速度为0.54g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量94.5％，收率96.5％。
实施例21
实施例21与实施例1的区别在于，实施例21中取35％H 2O 2为0.168mol，物料3的打料速度为0.27g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量90.2％，收率89.5％。
实施例22
实施例22与实施例1的区别在于，实施例22中取35％H 2O 2为4.200mol，物料3的打料速度为0.27g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量91.5％，收率89.9％。
实施例23
实施例23与实施例1的区别在于，实施例23中溶剂为1,4-二氧六环，物料1的打料速度为5.18g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量94.9％，收率97.0％。
实施例24
实施例24与实施例1的区别在于，实施例24中溶剂为甲苯，物料1的打料速度为4.42g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量95.1％，收率96.8％。
实施例25
实施例25与实施例1的区别在于，实施例25中溶剂为N,N-二甲基甲酰胺，物料1的打料速度为4.77g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量94.7％，收率97.5％。
实施例26
实施例26与实施例1的区别在于，实施例26中溶剂为乙二醇，物料1的打料速度为5.54g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量94.0％，收率96.4％。
实施例27
实施例27与实施例1的区别在于，实施例27中溶剂为正二十烷，物料1的打料速度为3.89g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量93.5％，收率95.9％。
实施例28
实施例28与实施例1的区别在于，实施例28中溶剂为二甲基亚砜，物料1的打料速度为5.45g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量93.8％，收率94.9％。
实施例29
实施例29与实施例1的区别在于，实施例29中乙腈为30mL，物料1的打料速度为0.90g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量94.3％，收率95.6％。
实施例30
实施例30与实施例1的区别在于，实施例30中乙腈为1500mL，物料1的打料速度为20.25g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量93.9％，收率94.1％。
实施例31
实施例31与实施例1的区别在于，实施例31中乙腈为24mL，物料1的打料速度为0.82g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量85.9％，收率87.5％。
实施例32
实施例32与实施例1的区别在于，实施例32中乙腈为1650mL，物料1的打料速度为22.23g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量86.8％，收率87.9％。
实施例33
实施例33与实施例1的区别在于，实施例33中保留时间为55min，其中物料1的打料速度为4.42g/min，物料2的打料速度为0.19g/min，物料3的打料速度为1.48g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量94.5％，收率96.7％。
实施例34
实施例34与实施例1的区别在于，实施例34中保留时间为65min，其中物料1的打料速度为3.74g/min，物料2的打料速度为0.16g/min，物料3的打料速度为1.26g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量95.1％，收率97.3％。
实施例35
实施例35与实施例1的区别在于，实施例35中保留时间为30min，其中物料1的打料速度为8.11g/min，物料2的打料速度为0.35g/min，物料3的打料速度为2.72g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量92.1％，收率93.2％。
实施例36
实施例36与实施例1的区别在于，实施例36中保留时间为100min，其中物料1的打料速度为2.43g/min，物料2的打料速度为0.11g/min，物料3的打料速度为0.82g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量91.4％，收率92.0％。
实施例37
实施例37与实施例1的区别在于，实施例37中保留时间为20min，其中物料1的打料速度为12.17g/min，物料2的打料速度为0.53g/min，物料3的打料速度为4.08g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量77.3％，收率75.9％。
实施例38
实施例38与实施例1的区别在于，实施例38中保留时间为110min，其中物料1的打料速度为2.21g/min，物料2的打料速度为0.10g/min，物料3的打料速度为0.74g/min，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量84.9％，收率82.1％。
实施例39
实施例39与实施例1的区别在于，实施例39中为连续式柱状反应器，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量90.5％，收率91.1％。
实施例40
扩大量反应实施例
将反应物A放大至2.0Kg，采用上述实施例1的反应条件合成化合物B，得到淡黄色液体，收率97.3％，HPLC纯度为98.4％，由于扩大量反应相比于小量反应在反应容器壁上的损失相对减少，因此扩大量反应的得到的化合物B收率和纯度更高。
对比例1
对比例1与实施例1的区别在于，对比例1中将盘管温度控制在55℃，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量95.3％，收率96.5％，在该试验中，检测到双氧水的分解，因此其收率有所下降，长时间持续反应或放大反应后安全性更低。
对比例2
对比例2与实施例1的区别在于，对比例2中将盘管温度控制在90℃，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量72.9％，收率73.4％，在该试验中，检测到大量双氧水的分解，因此其收率明显下降。
对比例3
对比例3与实施例1的区别在于，对比例3中将盘管温度控制在20℃，用甲基叔丁基醚萃取、浓缩后得到产品，内标含量79.9％，收率81.2％。
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：
本申请利用双氧水作为氧化剂来氧化三氟烃基硫醚类化合物，使其生成包含三氟烃基砜类化合物的产物体系。其中的钨酸钠二水合物作为催化剂有利于提高氧化反应的效率，从而提高三氟烃基砜类化合物的产率，并缩短反应时间。
本申请采用连续式反应设备，即在连续式反应器的一端不断地有反应物料被投进去，同时在连续式反应器的另一端不断地有产物被分离出来，相比于传统的釜式工艺，连续化生产工艺在实际生产过程中使得实时发生反应的物料量大大减少，物料直接的接触更加高效，而且由于双氧水分子量较小，因此更容易作用于三氟烃基硫醚类化合物的硫醚键，可以使上述氧化反应在较低的温度下即可发生，从而既使得氧化温度降低又避免了双氧水在设备中的长时间停留，从而可以有效地双氧水的高温分解，因此本申请还降低了对设备耐压和耐温的要求，从而降低了三氟烃基砜类化合物的合成成本。总之与现有技术相比，本申请的上述制备方法，利用连续化进料，提高了物料接触效果，进而使得硫醚的氧化反应在较低的温度下即可进行；而且氧化反应温度的降低，有效减少了双氧水的分解，提高了双氧水的氧化利用率，且降低了对连续式反应器的耐压要求。
此外，上述反应工艺具有广泛的底物适应性及良好的官能团兼容性，应用范围较广。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (16)

  1. 一种三氟烃基砜类化合物的制备方法，其特征在于，包括：
    将三氟烃基硫醚类化合物、钨酸钠二水合物和双氧水溶液通过送料设备连续送入连续式反应器中，使所述三氟烃基硫醚类化合物发生氧化反应，得到包含三氟烃基砜类化合物的产物体系，其中，所述三氟烃基硫醚类化合物具有结构式
    Figure PCTCN2019129412-appb-100001
    所示的结构，R为以下基团中的任意一种：直链烷基、支链烷基、取代芳基、非取代芳基、取代杂环芳基、非取代杂环芳基、非取代环烷基和取代环烷基，所述氧化反应的温度为25～50℃。
  2. 根据权利要求1所述的制备方法，其特征在于，所述R为以下基团中的任意一种：C 1～C 10的直链烷基、C 1～C 10的支链烷基、C 3～C 6的环烷基、C 6～C 18的取代或非取代芳基、取代或非取代的C 3～C 10的杂环芳基。
  3. 根据权利要求2所述的制备方法，其特征在于，所述芳基为苯基、萘环基、联苯基、蒽基，所述杂环芳基为吡啶基、呋喃基、吡咯基、呋喃基、噻吩基、吡咯基、噻唑基、咪唑基、吡啶基、吡嗪基、吲哚基和喹啉基。
  4. 根据权利要求2所述的制备方法，其特征在于，当所述基团具有取代基时，所述取代基为甲基、乙基、-F、-Cl、-OH中的任意一种或多种。
  5. 根据权利要求1所述的制备方法，其特征在于，所述氧化反应的温度为40～50℃。
  6. 根据权利要求1所述的制备方法，其特征在于，所述双氧水溶液的质量浓度为10～50％。
  7. 根据权利要求1所述的制备方法，其特征在于，所述钨酸钠二水合物与所述三氟烃基硫醚类化合物的摩尔比为0.1:100～20:100。
  8. 根据权利要求1所述的制备方法，其特征在于，所述三氟烃基硫醚类化合物和所述双氧水的摩尔比为1:20～1:2。
  9. 根据权利要求1所述的制备方法，其特征在于，所述制备方法包括：
    将含有所述三氟烃基硫醚类化合物的第一溶液、含有所述钨酸钠二水合物的水溶液以及所述双氧水溶液分别连续送入连续式反应器中。
  10. 根据权利要求9所述的制备方法，其特征在于，所述第一溶液的溶剂选自四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙二醇二甲醚、二乙二醇二甲醚、苯、甲苯、二甲苯、丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜、甲醇、乙醇、异丙醇、二氯甲烷、联苯、乙二醇、六甲基磷酸三胺、苯酚、吡啶、间二甲苯、邻二甲苯、二苯醚、环己酮、环己醇、邻甲酚、碳酸二乙酯、草酸二乙酯吗啉、正十八烷烃、正二十烷、硅油、丙二酸二乙酯、二乙二醇二乙醚以及氯仿组成的组中的一种或多种。
  11. 根据权利要求10所述的制备方法，其特征在于，所述溶剂相对于所述三氟烃基硫醚类化合物的用量为1～50mL/g。
  12. 根据权利要求1所述的制备方法，其特征在于，所述连续式反应器的保留时间为30～100min。
  13. 根据权利要求12所述的制备方法，其特征在于，所述连续式反应器的保留时间为55～65min。
  14. 根据权利要求1所述的制备方法，其特征在于，所述连续式反应器为管式连续反应器或柱状反应器。
  15. 根据权利要求1所述的制备方法，其特征在于，所述连续式反应器为连续式盘管反应器。
  16. 根据权利要求1所述的制备方法，其特征在于，所述连续式反应器配置有：
    换热设备，用于调节所述连续式反应器的温度；
    温度检测设备，用于监测所述连续式反应器的反应温度；
    压力检测设备，用于监测所述连续式反应器的压力；
    在线PAT设备，用于检测所述连续式反应器的产物组成；
    自动化控制系统，所述自动化控制系统与各所述送料设备、所述换热设备、所述温度检测设备、所述压力检测设备和所述在线PAT设备电连接。
PCT/CN2019/129412 2019-12-11 2019-12-27 三氟烃基砜类化合物的制备方法 WO2021114424A1 (zh)

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