Microchannel continuous flow preparation method for oxidizing thioether compound into sulfone compound

Abstract

The invention belongs to the field of medicines, and particularly relates to a micro-channel continuous flow preparation method for oxidizing a thioether compound into a sulfone compound. The method comprises the following steps: (1) providing an aqueous solution containing a thioether compound, alkali and a catalyst as a feed liquid A; (2) providing an aqueous solution containing hydrogen peroxide as a feed solution B; (3) respectively introducing the feed liquid A and the feed liquid B into a microreactor, and carrying out oxidation reaction on the thioether compound in the microreactor under the action of a catalyst to obtain a reaction liquid containing salts of the sulfone compound; the method also comprises a step of carrying out post-treatment by adopting continuous extraction. According to the method, the problem of intrinsic safety of hydrogen peroxide oxidation is solved by adopting a fluid chemical method. According to the method, the production efficiency is improved by adopting a liquid-liquid continuous extraction method. The method adopts water as a reaction solvent, so that the method is more environment-friendly.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to a microchannel continuous flow preparation method for oxidizing sulfide compounds into sulfone compounds. Background Art

[0002] The sulfone compounds shown in the following formula I are widely used in the fields of medicine, pesticides and veterinary drugs, and their precursor sulfide compounds have the structure shown in formula II:

[0003]

[0004] In the presence of a catalyst, using hydrogen peroxide to oxidize the compound of formula II to the compound of formula I is a general method. The method is completely and cleanly reacted, easy to post-process, high in yield, and the by-product is only water, which is very green and environmentally friendly. However, the reaction has intrinsic safety problems such as explosion and material impact under traditional batch synthesis conditions. Therefore, there is an urgent need in the art to provide a safe and efficient method for batch synthesis of compounds of formula I. Summary of the invention

[0005] The purpose of the present invention is to provide a microchannel continuous flow preparation method for oxidizing sulfide compounds into sulfone compounds.

[0006] In a first aspect of the present invention, there is provided a method for oxidizing a sulfide compound to a sulfone compound, the method comprising the steps of:

[0007] (1) providing an aqueous solution containing a sulfide compound, a base and a catalyst as a feed liquid A;

[0008] (2) providing an aqueous solution containing hydrogen peroxide as feed liquid B;

[0009] (3) respectively introducing the feed liquid A and the feed liquid B into a microreactor, so that the sulfide compound undergoes an oxidation reaction in the microreactor under the action of a catalyst to obtain a reaction liquid containing a salt of a sulfone compound;

[0010] The method further comprises the step of post-processing by continuous extraction;

[0011] The thioether compound has a structure shown in the following formula I:

[0012]

[0013] The sulfone compound has a structure shown in the following formula II:

[0014]

[0015] In Formula I and Formula II, n is selected from 0, 1, 2, 3, 4, 5 or 6, and R1 is selected from H and C1-C6 alkyl.

[0016] In one or more embodiments, the catalyst is selected from one or more of sodium tungstate, ferric chloride, manganese dioxide, and vanadium pentoxide.

[0017] In one or more embodiments, the catalyst is added in an amount of 1-20 wt % of the mass of the sulfide compound.

[0018] In one or more embodiments, the base is selected from one or more of sodium hydroxide, potassium hydroxide, and triethylamine.

[0019] In one or more embodiments, the molar ratio of the base to the thioether compound is (1-5):1.

[0020] In one or more embodiments, the concentration of the sulfide compound in the feed liquid A is 0.5-5 mol / L.

[0021] In one or more embodiments, in the microreactor, the molar ratio of hydrogen peroxide to the thioether compound is (1-3):1.

[0022] In one or more embodiments, the mass fraction of hydrogen peroxide in the feed liquid B is 10-50 wt %.

[0023] In one or more embodiments, the reaction temperature is 20-80°C.

[0024] In one or more embodiments, the residence time of the reaction is 1-6 min.

[0025] In one or more embodiments, the back pressure at the outlet of the microreactor is 1-5 bar.

[0026] In one or more embodiments, the feed rate of the feed liquid A is 10-30 mL / min.

[0027] In one or more embodiments, the feed rate of the feed liquid B is 1-20 mL / min.

[0028] In one or more embodiments, the method further comprises the step of quenching the hydrogen peroxide in the reaction solution with a reducing agent; preferably, the method further comprises the step of acidifying the reaction solution in which the hydrogen peroxide has been quenched with an acid.

[0029] In one or more embodiments, the method further comprises the step of: continuously extracting the acidified reaction solution; preferably, the extraction solvent is selected from one or more of ethyl acetate, isopropyl acetate, toluene and butanone; preferably, the continuous extraction is performed using a centrifugal continuous liquid-liquid extraction device.

[0030] In one or more embodiments, the continuous extraction comprises 1-4 stages of continuous extraction; preferably, in each stage of continuous extraction, the volume ratio of the aqueous phase to the extraction solvent is 1:(1-5).

[0031] In one or more embodiments, in step (3), two feed pumps are used to respectively introduce the feed liquid A and the feed liquid B into the microreactor.

[0032] In one or more embodiments, in step (3), the feed liquid A is preheated to 20-80° C. and then introduced into the microreactor.

[0033] The present invention has the following beneficial effects:

[0034] (1) The method of the present invention adopts a fluid chemical method to solve the problem of intrinsic safety of hydrogen peroxide oxidation.

[0035] (2) The method of the present invention adopts a liquid-liquid continuous extraction method to improve production efficiency.

[0036] (3) The method of the present invention uses water as the reaction solvent, which is more environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 is a process flow diagram of one or more embodiments of the present invention.

[0038] Figure 2 It is the H NMR spectrum of the methanesulfonylacetic acid obtained in Example 1.

[0039] Figure 3 This is the H NMR spectrum of 2-(methylsulfonyl)propionic acid obtained in Example 20.

[0040] Figure 4 This is the H NMR spectrum of 3-(methylsulfonyl)propionic acid obtained in Example 21. DETAILED DESCRIPTION

[0041] In order to enable those skilled in the art to understand the characteristics and effects of the present invention, the following is a general description and definition of the terms and expressions mentioned in the specification and claims. Unless otherwise specified, all technical and scientific terms used in the text are the common meanings understood by those skilled in the art for the present invention. In the event of a conflict, the definition in this specification shall prevail.

[0042] The theories or mechanisms described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, that is, the present invention can be implemented without being limited by any specific theory or mechanism.

[0043] Herein, “comprising”, “including”, “containing” and similar terms encompass the meanings of “consisting essentially of” and “consisting of”. For example, when “A comprises B and C” is disclosed herein, “A consists essentially of B and C” and “A consists of B and C” should be deemed to be disclosed herein.

[0044] In this article, all features such as values, quantities, contents and concentrations defined in the form of numerical ranges or percentage ranges are only for brevity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be considered to have included and specifically disclosed all possible secondary ranges and individual values ​​within the range (including integers and fractions).

[0045] In this document, unless otherwise specified, percentage refers to mass percentage and ratio refers to mass ratio.

[0046] Herein, when describing embodiments or examples, it should be understood that they are not used to limit the present invention to these embodiments or examples. On the contrary, all substitutes, improvements and equivalents of the methods and materials described in the present invention can be included in the scope limited by the claims.

[0047] In this document, in order to make the description concise, not all possible combinations of various technical features in various embodiments or examples are described. Therefore, as long as there is no contradiction in the combination of these technical features, the various technical features in various embodiments or examples can be combined arbitrarily, and all possible combinations should be considered to be within the scope of this specification.

[0048] To solve the safety problem, the present invention adopts a fluid chemistry method. The flow reactor used in the method of the present invention helps to quickly dissipate the heat generated during the highly exothermic reaction and obtain a higher heat transfer rate, which can prevent the generation of hot spots that may stimulate side reactions or runaway reactions. The present invention further performs post-treatment of the reaction solution through continuous extraction, which can not only improve the efficiency of the extraction but also reduce the amount of solvent used.

[0049] Therefore, the present invention provides a method for oxidizing a sulfide compound to a sulfone compound, the method comprising the steps of:

[0050] (1) providing an aqueous solution containing a sulfide compound, a base and a catalyst as a feed liquid A;

[0051] (2) providing an aqueous solution containing hydrogen peroxide as feed liquid B;

[0052] (3) respectively introducing the feed liquid A and the feed liquid B into a microreactor, so that the sulfide compound undergoes an oxidation reaction in the microreactor under the action of a catalyst to obtain a reaction liquid containing a salt of a sulfone compound;

[0053] The method further comprises the step of post-processing by continuous extraction;

[0054] The thioether compound has a structure shown in the following formula I:

[0055]

[0056] The sulfone compound has a structure shown in the following formula II:

[0057]

[0058] In Formula I and Formula II, n is selected from 0, 1, 2, 3, 4, 5 or 6, and R1 is selected from H and C1-C6 alkyl.

[0059] As used herein, "alkyl" refers to a straight or branched monovalent saturated hydrocarbon radical having a specified number of carbon atoms, and specific alkyl groups are those having 1 to 6 carbon atoms ("C1-C6 alkyl"), usually containing 1-5 carbon atoms (C1-C5 alkyl), preferably containing 1-4 carbon atoms (C1-C4 alkyl), and more preferably containing 1-3 carbon atoms (C1-C3 alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0060] In some embodiments, R1 is preferably a C1-C3 alkyl group, more preferably a methyl group.

[0061] In some embodiments, the catalyst is selected from one or more of sodium tungstate, ferric chloride, manganese dioxide and vanadium pentoxide; preferably one or more of sodium tungstate and manganese dioxide; more preferably sodium tungstate. The catalyst herein can be used to prepare the corresponding sulfone compounds with higher yield and higher purity.

[0062] In some embodiments, the amount of the catalyst added is 1-20wt% of the mass of the sulfide compound, preferably 5-20wt% or 5-10wt%. Controlling the amount of the catalyst added within the range defined herein can produce the corresponding sulfone compound with higher yield and higher purity.

[0063] A base is added to the feed liquid A, and the base can react with the thioether compound shown in Formula I to obtain a salt of the compound of Formula I, so that the thioether compound can be dissolved in water in the form of a salt. Therefore, the method of the present invention can be carried out efficiently in green solvent water with a higher yield and higher purity. The present invention does not specifically limit the type of base, as long as it can react with the thioether compound shown in Formula I to react with an acid-base neutralization reaction. In some embodiments, the base is selected from one or more of sodium hydroxide, potassium hydroxide and triethylamine, preferably sodium hydroxide. The molar ratio of the base to the thioether compound can be (1-5):1, for example (1-3):1 or (1-2):1.

[0064] In some embodiments, the concentration of the sulfide compound in the feed liquid A is 0.5-5 mol / L, preferably 1-2 mol / L. Controlling the concentration of the sulfide compound in the feed liquid A within the range defined herein can produce the corresponding sulfone compound with higher yield and higher purity.

[0065] In the microreactor, the molar ratio of hydrogen peroxide to the sulfide compound is (1-3):1, preferably (2-2.5):1. Controlling the molar ratio of hydrogen peroxide to the sulfide compound in the microreactor within the range defined herein can produce the corresponding sulfone compounds with a higher yield and a higher purity. Specifically, the molar ratio of hydrogen peroxide to the sulfide compound in the microreactor can be controlled within the range defined in the present invention by adjusting parameters such as the concentration of hydrogen peroxide in feed liquid B, the concentration of the sulfide compound in feed liquid A, the flow rate of feed liquid A, and the flow rate of feed liquid B. In some embodiments, in feed liquid B, the mass fraction of hydrogen peroxide is 10-50wt%, preferably 20-40wt% or 30-35wt%. Controlling the concentration of hydrogen peroxide in feed liquid B within the range defined herein can produce the corresponding sulfone compounds with a higher yield and a higher purity.

[0066] In some embodiments, the reaction temperature in the microreactor is 20-80° C., preferably 70-80° C. Controlling the method of the present invention to be carried out at the reaction temperature defined herein can produce the corresponding sulfone compounds with higher yield and higher purity.

[0067] In some embodiments, the residence time of the reaction is 1-6 min, preferably 1-3 min, 1.5-3 min or 3-4 min. Controlling the residence time of the method of the present invention within the range defined herein can produce the corresponding sulfone compounds with higher yield and higher purity.

[0068] In some embodiments, the back pressure at the outlet of the microreactor is 1-5 bar, preferably 3-4 bar. Controlling the back pressure at the outlet of the microreactor in the method of the present invention within the range defined herein can produce the corresponding sulfone compounds with higher yield and higher purity.

[0069] In some embodiments, the feed rate of the feed liquid A is 10-30 mL / min, preferably 15-20 mL / min. Controlling the flow rate of the feed liquid A within the range defined herein can produce the corresponding sulfone compounds with higher yield and higher purity.

[0070] In some embodiments, the feed rate of the feed liquid B is 1-20 mL / min, preferably 3-10 mL / min. Controlling the flow rate of the feed liquid B within the range defined herein can produce the corresponding sulfone compounds with higher yield and higher purity.

[0071] In order to ensure the safety of the method of the present invention, the method further comprises the step of: using a reducing agent to quench the hydrogen peroxide in the reaction solution. The reducing agent can be a reagent commonly used in the art for quenching hydrogen peroxide, such as sodium sulfite.

[0072] In order to finally obtain the sulfone compound, the hydrochloric acid of the sulfone compound obtained in step (3) needs to be converted into the sulfone compound. Therefore, the method further comprises the step of acidifying the reaction solution in which the hydrogen peroxide has been quenched with an acid. The acid can be an acid commonly used in the art for acidifying carboxylates, and for the convenience of post-processing, it is preferably an inorganic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, etc.

[0073] In some embodiments, the method further comprises the step of: subjecting the acidified reaction solution to continuous extraction. The extraction solvent is selected from one or more of ethyl acetate, isopropyl acetate, toluene and butanone, preferably one or more of butanone, ethyl acetate and isopropyl acetate, more preferably butanone. Post-treatment using the extraction solvent defined herein can produce the corresponding sulfone compound with a higher yield and higher purity.

[0074] In some embodiments, a centrifugal continuous liquid-liquid extraction device is used for continuous extraction. Post-treatment of the reaction solution using a centrifugal continuous liquid-liquid extraction device can improve the extraction efficiency.

[0075] In some embodiments, the continuous extraction comprises 1-4 stages (1, 2, 3 or 4) of continuous extraction; preferably 3 stages. Preferably, in each stage of continuous extraction, the volume ratio of the aqueous phase to the extraction solvent is 1:(1-5), preferably 1:(2-4) or 1:(3-4). The continuous extraction method defined in the present invention can be used for post-treatment to obtain the corresponding sulfone compounds with higher yield and higher purity.

[0076] In some embodiments, the extract is concentrated and then recrystallized to obtain the sulfone compound. The sulfone compound can be recrystallized using a conventional recrystallization solvent in the art. Preferably, the recrystallization solvent is ethyl acetate.

[0077] In some embodiments, in step (3), the feed liquid A is preheated to 20-80° C., preferably preheated to 70-80° C. before being introduced into the microreactor. Preheating the feed liquid A before feeding can strengthen the reaction conditions and promote the reaction to proceed completely. Preferably, the feed liquid A is preheated to the reaction temperature before feeding.

[0078] The present invention also provides a continuous flow preparation device for preparing sulfone compounds by oxidation of sulfide compounds. The device comprises a microreactor, a feed pump and a continuous extraction device. The continuous flow preparation device also comprises a back pressure valve arranged at the outlet of the microreactor.

[0079] The microreactor can be a reaction module. The reaction module can be provided with one or more heat exchange zones according to the residence time required for the reaction.

[0080] The continuous extraction device may be a centrifugal continuous liquid-liquid extraction device. Preferably, the continuous extraction device comprises one or more stages of centrifugal extractors, such as 1-4 stages.

[0081] There are two feed pumps, which are used to pass feed liquid A and feed liquid B through the microreactor respectively.

[0082] The continuous flow preparation device defined in this article can be used to prepare sulfone compounds with higher yield and higher purity.

[0083] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0084] General Mode

[0085] 1. If Figure 1 As shown, pump B is set to a certain flow rate and started to pass solvent water into the reaction module (i.e., microreactor) and discharge ethanol (protective solvent) in the module. At the same time, slowly increase the back pressure valve pressure to 10 bar to check whether the reaction module, pump and each component are working properly, and whether there is leakage and flow deviation.

[0086] 2. After the leak detection is completed, adjust the back pressure of the back pressure valve to the working pressure (about 3 bar) and continue to let water in. Set the temperature of the heat exchanger to the working temperature of 30-80℃, and start the heat exchange to heat the working temperature of the reaction module to 30-80℃.

[0087] 3. Measure the temperature of the output end. After reaching the working temperature, pump B converts water into 1.5-2.5 equivalents of 30wt% hydrogen peroxide solution at room temperature (20-25°C), while pump A converts water into an aqueous solution of thioether compound, alkali and sodium tungstate.

[0088] 4. After 5 times the residence time, the reactor is considered to have stabilized the reaction and can receive the reaction liquid and send it to IPC (chemical reaction control).

[0089] 5. After IPC is qualified, use a quencher to quench the hydrogen peroxide in the reaction solution, and then use acid to acidify to obtain the aqueous phase to be extracted.

[0090] 6. The aqueous phase to be extracted was continuously extracted using a three-stage centrifugal continuous liquid-liquid extraction device. The volume ratio of the aqueous phase to the organic phase (extraction solvent) in the first-stage extraction was 1:3, the volume ratio of the aqueous phase to the organic phase (extraction solvent) in the second-stage extraction was 1:3, and the volume ratio of the aqueous phase to the organic phase (extraction solvent) in the third-stage extraction was 1:4. The extract was concentrated and recrystallized to obtain the product, and the yield and purity of the product were tested.

[0091] In this paper, HPLC was used to test the purity of the product. The HPLC analysis conditions were as follows:

[0092] Column model: Ultimate LP-C18, 3.5μm, 4.6x 250mm;

[0093] Flow rate: 0.8 ml / min;

[0094] Washing conditions: gradient washing;

[0095] Running time: 22 minutes

[0096] Equilibration time: 5 minutes;

[0097] Detector: UV 210 nm;

[0098] Injection: 10 μl;

[0099] Column temperature: 30℃±5℃;

[0100] Autosampler temperature: room temperature;

[0101] Mobile phase ratio:

[0102] A: water / phosphoric acid = 100:0.1 (volume ratio);

[0103] B: acetonitrile;

[0104] Sample dissolving solvent: acetonitrile / water = 1:1;

[0105] The gradient is shown in Table a below:

[0106] Table a

[0107] Time (minutes) ％A ％B 0.0 98.0 2.0 3.0 98.0 2.0 10.0 40.0 60.0 15.0 15.0 85.0 15.01 98.0 2.0 22.0 98.0 2.0

[0108] Equipment and reagents are as follows:

[0109] Scale: Mettler Toledo MT 5;

[0110] Acetonitrile: Merck LiChrosolv, HPLC grade;

[0111] Water: Merck LiChrosolv, HPLC grade;

[0112] Phosphoric acid: Alfar, HPLC grade.

[0113] Example 1: Preparation of Methanesulfonylacetic Acid

[0114]

[0115] The reaction module was prepared according to the general mode. 1.0 kg (9.4 mol) of raw material methyl thioether acetic acid, 377 g (9.4 mol) of sodium hydroxide and 50 g (5% by mass, based on the mass of the raw material methyl thioether acetic acid) of sodium tungstate were dissolved in 6 L of water to prepare a solution. The solution was filtered and the mixed solution was preheated to 80° C. before injection. The preheated mixed solution (20 g / min, 19.0 ml / min, density: 1.05 g / ml) was injected through metering pump A, and at the same time, 2.2 equivalents (the amount of hydrogen peroxide added relative to the raw material methyl sulfide acetic acid) of hydrogen peroxide aqueous solution (the mass fraction of hydrogen peroxide in the aqueous solution is 30wt%, 6.33 g / min, 5.7 ml / min, density: 1.11 g / ml) was injected through metering pump B (room temperature 20-25° C.), and after reacting through 5 modules (80° C., 8.2 ml / module, total retention time 1.62 minutes), the mixture flowed out of the reactor, and the reaction solution flowing out was collected. After the collected reaction solution was quenched with a saturated sodium sulfite aqueous solution (the starch potassium iodide reagent test did not develop color), the pH value was adjusted to 1-2 with concentrated hydrochloric acid. Then, the aqueous solution to be extracted was pumped into a three-stage centrifugal liquid-liquid extraction device by a peristaltic pump for continuous extraction with isopropyl acetate. After the extract was concentrated, it was recrystallized with ethyl acetate to obtain 1.11 kg of the product methylsulfonylacetic acid with a yield of 85.0% and a HPLC purity of 99.2%. The H-NMR spectrum showed Figure 2 : 1 H-NMR(DMSO-d6,ppm)δ13.4(br,1H),4.25(s,2H),3.11(s,3H).

[0116] Embodiment 2-4

[0117] The method of Example 1 was repeated, with the only difference being that the amount of hydrogen peroxide added was changed. The specific conditions are shown in Table 1.

[0118] Table 1

[0119] Example Equivalent number of hydrogen peroxide to methyl sulfide acetic acid Yield purity 2 1.5 44.1％ 86.2％ 3 2.0 66.7％ 96.5％ 4 2.5 85.1％ 99.3％

[0120] Embodiment 5-7

[0121] The method of Example 1 was repeated, the only difference being that the reaction temperature in the reactor was changed. The specific conditions are shown in Table 2.

[0122] Table 2

[0123] Example Reaction temperature Yield purity 1 80℃ 85.0％ 99.2％ 5 30℃ 16.4％ 37.5％ 6 50℃ 45.3％ 69.3％ 7 70℃ 65.4％ 98.3％

[0124] Embodiment 8-10

[0125] The method of Example 1 was repeated, with the only difference being that the residence time in the reactor was changed. The specific conditions are shown in Table 3.

[0126] Table 3

[0127] Example Total retention time Yield purity 1 1.62 minutes 85.0％ 99.2％ 8 1.0 min 66.7％ 89.4％ 9 1.50 minutes 78.6％ 95.2％ 10 2.36 minutes 84.4％ 99.1％

[0128] Examples 11-14

[0129] The method of Example 1 was repeated, with the only difference being that the type of catalyst was changed, and the amount of catalyst added was still 5 wt % of the mass of the raw material methyl sulfide acetic acid. The specific conditions are shown in Table 4.

[0130] Table 4

[0131] Example catalyst Yield purity 11 Sodium Tungstate 87.1％ 99.0％ 12 Ferric chloride 62.3％ 82.4％ 13 Manganese dioxide 80.2％ 97.3％ 14 vanadium pentoxide 47.6％ 62.4％

[0132] Examples 15-18

[0133] The method of Example 1 was repeated, the only difference being that the amount of the catalyst was changed. The specific conditions are shown in Table 5.

[0134] Table 5

[0135] Example The mass percentage of catalyst in methyl sulfide acetic acid Yield purity 15 1％ 71.1％ 89.0％ 16 5％ 85.6％ 99.7％ 17 10％ 80.2％ 96.5％ 18 20％ 76.8％ 98.4％

[0136] Example 19: Preparation of 2-(methylsulfonyl)propionic acid

[0137]

[0138] The reaction module was prepared according to the general mode. 1.0 kg (8.3 mol) of raw material 2-(methylthioether) propionic acid, 333 g (8.3 mol) of sodium hydroxide and 50 g (5% by mass, based on the mass of raw material 2-(methylthioether) propionic acid) of sodium tungstate were dissolved in 6 L of water to prepare a solution for filtration. The mixed solution was preheated to 80°C before sampling. The preheated mixed solution (20 g / min, 18.1 ml / min, density: 1.10 g / ml) was injected through metering pump A, and at the same time, 2.2 equivalents (the amount of hydrogen peroxide added relative to the raw material 2-(methylthioether) propionic acid) of hydrogen peroxide aqueous solution (the mass fraction of hydrogen peroxide in the aqueous solution is 30 wt%, 5.62 g / min, 5.07 ml / min, density: 1.11 g / ml) was injected through metering pump B (room temperature 20-25° C.), and then the mixture was reacted in 5 modules (80° C., 8.2 ml / module, and a total retention time of 1.77 minutes) and then flowed out of the reactor, and the reaction solution was collected. The collected reaction solution was quenched with a saturated sodium sulfite aqueous solution (no color was developed in the starch potassium iodide reagent test), and then the pH value was adjusted to 1-2 with concentrated hydrochloric acid. Then, the aqueous solution to be extracted was pumped into a three-stage centrifugal liquid-liquid extraction device by a peristaltic pump for continuous extraction with isopropyl acetate. After the extract was concentrated, it was recrystallized with ethyl acetate to obtain 1.04 kg of the product 2-(methylsulfonyl)propionic acid with a yield of 82.4% and a HPLC purity of 99.5%. The H NMR spectrum of the product 2-(methylsulfonyl)propionic acid was shown in FIG. Figure 3 : 1 H-NMR(DMSO-d6,ppm)δ13.4(br,1H),4.18~4.23(m,1H),3.10(s,3H),1.41~1.43(m,3H).

[0139] Example 20: Preparation of 3-(methylsulfonyl)propionic acid

[0140]

[0141] The reaction module was prepared according to the general mode. 1.0 kg of raw material 3-(methylthioether)propionic acid, 333 g of sodium hydroxide and 50 g (5% by mass, based on the mass of the raw material 3-(methylthioether)propionic acid) of sodium tungstate were dissolved in 6 L of water to prepare a solution for filtration. The mixed solution was preheated to 80°C before sampling. The preheated mixed solution (20 g / min, 17.5 ml / min, density: 1.14 g / ml) was injected through metering pump A, and at the same time, 2.2 equivalents (the amount of hydrogen peroxide added relative to the raw material 3-(methylthioether) propionic acid) of hydrogen peroxide aqueous solution (the mass fraction of hydrogen peroxide in the aqueous solution is 30 wt%, 5.62 g / min, 5.07 ml / min, density: 1.11 g / ml) was injected through metering pump B (room temperature 20-25° C.), and then the mixture was reacted in 5 modules (80° C., 8.2 ml / module, and a total retention time of 1.81 minutes) and then flowed out of the reactor, and the reaction solution was collected. The collected reaction solution was quenched with a saturated sodium sulfite aqueous solution (no color was developed in the starch potassium iodide reagent test), and then the pH value was adjusted to 1-2 with concentrated hydrochloric acid. Then, the aqueous solution to be extracted was pumped into a three-stage centrifugal liquid-liquid extraction device by a peristaltic pump for continuous extraction with butanone. After the extract was concentrated, it was recrystallized with ethyl acetate to obtain 1.12 kg of the product 3-(methylsulfonyl)propionic acid with a yield of 88.3% and a HPLC purity of 99.6%. The H NMR spectrum of the product 3-(methylsulfonyl)propionic acid was shown in FIG. Figure 4 : 1 H-NMR (D2O, ppm) δ3.47~3.50(m,2H), 3.04(s,3H), 2.81~2.85(m,3H).

[0142] Examples 21-24

[0143] The method of Example 20 was repeated, with the only difference being that the type of extraction solvent was changed. The specific conditions are shown in Table 6.

[0144] Table 6

[0145] Example Extraction solvent Yield purity 21 Isopropyl acetate 84.3％ 99.2％ 22 Ethyl acetate 82.3％ 99.5％ 23 Toluene 75.0％ 99.0％ 24 Butanone 90.1％ 99.5％

Claims

1. A method for oxidizing a sulfide compound to a sulfone compound, characterized in that: The method comprises the steps of: (1) providing an aqueous solution containing a sulfide compound, a base and a catalyst as a feed liquid A; (2) providing an aqueous solution containing hydrogen peroxide as feed liquid B; (3) respectively introducing the feed liquid A and the feed liquid B into a microreactor, so that the sulfide compound undergoes an oxidation reaction in the microreactor under the action of a catalyst to obtain a reaction liquid containing a salt of a sulfone compound; The method further comprises the step of post-processing by continuous extraction; The thioether compound has a structure shown in the following formula I: The sulfone compound has a structure shown in the following formula II: In Formula I and Formula II, n is selected from 0, 1, 2, 3, 4, 5 or 6, and R1 is selected from H and C1-C6 alkyl.

2. The method according to claim 1, characterized in that: The catalyst is selected from one or more of sodium tungstate, ferric chloride, manganese dioxide and vanadium pentoxide; and / or The added amount of the catalyst is 1-20 wt % of the mass of the sulfide compound.

3. The method according to claim 1, characterized in that: The base is selected from one or more of sodium hydroxide, potassium hydroxide and triethylamine; and / or The molar ratio of the base to the sulfide compound is (1-5):

1.

4. The method according to claim 1, characterized in that The concentration of the sulfide compound in the feed liquid A is 0.5-5 mol / L.

5. The method according to claim 1, characterized in that: In the microreactor, the molar ratio of hydrogen peroxide to the sulfide compound is (1-3):1; and / or In the feed liquid B, the mass fraction of hydrogen peroxide is 10-50wt%.

6. The method according to claim 1, characterized in that The method has one or more of the following features: The reaction temperature is 20-80°C; The residence time of the reaction is 1-6min; The back pressure at the outlet of the microreactor is 1-5 bar; The feed rate of the feed liquid A is 10-30 mL / min; The feed rate of the feed liquid B is 1-20 mL / min.

7. The method according to claim 1, characterized in that The method further comprises the step of: quenching the hydrogen peroxide in the reaction solution with a reducing agent; preferably, the method further comprises the step of: acidifying the reaction solution in which the hydrogen peroxide has been quenched with an acid.

8. The method according to claim 7, characterized in that The method further comprises the steps of: continuously extracting the acidified reaction solution; preferably, the extraction solvent is selected from one or more of ethyl acetate, isopropyl acetate, toluene and butanone; preferably, the continuous extraction is performed using a centrifugal continuous liquid-liquid extraction device.

9. The method according to claim 8, characterized in that The continuous extraction includes 1-4 stages of continuous extraction; preferably, in each stage of continuous extraction, the volume ratio of the aqueous phase to the extraction solvent is 1:(1-5).

10. The method according to claim 1, characterized in that: In step (3), two feed pumps are used to respectively pass the feed liquid A and the feed liquid B into the microreactor; and / or In step (3), the feed liquid A is preheated to 20-80° C. and then introduced into the microreactor.

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