Method for continuously preparing benzenesulfonic acid compound through electrochemical-enzymatic coupling

Abstract

The invention belongs to the field of organic synthesis, and relates to a method for continuously preparing benzenesulfonic acid compounds through electrochemical-enzymatic coupling. Dissolving a compound 1 and a compound 2 in a first solvent to obtain a solution A; pumping the solution A into a first micro-reactor of a micro-channel reaction device, carrying out an electric cyclization reaction, and obtaining a first reaction solution after the reaction is finished; dissolving an oxidizing agent in a second solvent to obtain a solution B; respectively and simultaneously pumping the first reaction solution and the solution B into a second microreactor of the microchannel reaction device to carry out enzymatic transesterification, and obtaining a benzenesulfonic acid compound 4 after the reaction is finished; wherein the second microreactor is filled with lipase. The novel synthesis method provided by the invention adopts a strategy of combining electro-catalysis and enzyme catalysis, and compared with a traditional chemical synthesis method, the synthesis route provided by the invention does not use reagents with strong corrosivity, high toxicity and serious pollution, such as fuming sulfuric acid, hydrochloric acid, sulfur trioxide and the like, and is greener and safer.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and relates to a method for continuously preparing benzenesulfonic acid compounds by electrochemical-enzymatic coupling. Background Art

[0002] The benzenesulfonic acid skeleton is the core structural unit of a series of biologically active compounds (J.Org.Chem.2022,87,11,7136-7149). It is one of the important structures commonly found in natural substances and is widely present in various drugs and chemical materials. The benzenesulfonic acid skeleton has strong hydrophilicity and can significantly improve the water solubility of the molecule, which is very important for the absorption, distribution and metabolism of drugs. Benzenesulfonic acid structures exist in many types of drugs, such as the anti-tumor drug niraparib tosylate: used to treat platinum-sensitive recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer, the introduction of the benzenesulfonic acid skeleton improves the water solubility and stability of the drug (JAMA.Oncol.2019;5(8):1103-1105); the anti-inflammatory drug celecoxib: used to treat inflammatory diseases such as arthritis, the introduction of the benzenesulfonic acid skeleton improves the water solubility and selectivity of the drug, reduces the nonspecific inhibition of COX-1 enzyme, and thus reduces the risk of gastrointestinal side effects (Pharmaceutics.2020,12,11,1043-1055). In addition, the benzenesulfonic acid structure can also participate in the polymerization reaction as a functional monomer. For example, in the process of preparing phenolic aerogel composite materials, 4-hydroxybenzenesulfonic acid can act as an acid catalyzer to accelerate the condensation reaction between phenols and aldehydes (Chem.Eng.J.2024,497,147856-147865).

[0003] Traditional methods for synthesizing aromatic sulfonic acid compounds, including fuming sulfuric acid sulfonation, chlorosulfonic acid sulfonation, sulfur trioxide sulfonation, and solid superacid catalytic sulfonation, have been widely used in industry. However, these methods also have some obvious shortcomings and limitations. Specifically, the catalyst used is highly corrosive, highly toxic, has harsh reaction conditions, and causes significant pollution to the environment. These problems limit the further development and application of these methods. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a method for continuously preparing benzenesulfonic acid compounds by electrochemical-enzymatic coupling in view of the deficiencies in the prior art.

[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0006] The present invention discloses a method for continuously preparing benzenesulfonic acid compounds by electrochemical-enzymatic coupling, comprising the following steps:

[0007] (1) dissolving compound 1 and compound 2 in a first solvent to obtain solution A; pumping solution A into a first microreactor of a microchannel reaction device to perform an electrocyclization reaction, and obtaining a first reaction solution after the reaction is completed;

[0008] (2) dissolving the oxidant in the second solvent to obtain a solution B; pumping the first reaction solution obtained in step (1) and the solution B into the second microreactor of the microchannel reaction device to perform an enzymatic transesterification reaction, and obtaining a benzenesulfonic acid compound 4 after the reaction is completed;

[0009] Wherein, the second microreactor is filled with lipase;

[0010] The compound 1 is shown in Formula 1, the compound 2 is shown in Formula 2, and the compound 4 is shown in Formula 4:

[0011]

[0012] in,

[0013] R is selected from C1-C6 alkyl or C1-C6 alkoxy;

[0014] n is an integer from 0 to 5.

[0015] In some embodiments, preferably, the R is selected from C1-C2 alkyl or C1-C2 alkoxy.

[0016] In some embodiments, further preferably, the R is selected from methyl, ethyl, methoxy or ethoxy.

[0017] In some embodiments, in step (1), the first solvent is any one or a combination of acetonitrile, dimethyl sulfoxide and ethyl acetate.

[0018] In some embodiments, preferably, in step (1), the first solvent is ethyl acetate.

[0019] In some embodiments, in step (1), the ratio of the molar amount of compound 1 to the volume amount of compound 2 is 1 mmol: (1-2) mL; the ratio of the molar amount of compound 1 to the volume amount of the first solvent is 1 mmol: (8-12) mL.

[0020] In some embodiments, preferably, in step (1), the ratio of the molar amount of compound 1 to the volume amount of compound 2 is 1 mmol:1.5 mL; the ratio of the molar amount of compound 1 to the volume amount of the first solvent is 1 mmol:10 mL.

[0021] In some embodiments, in step (1), the flow rate of the solution A pumped into the first microreactor of the microchannel reaction device is 0.1 mL / min to 1.2 mL / min; the reaction temperature of the electrocyclization reaction is room temperature, and the reaction current is 50 mA to 800 mA; the reaction residence time of the electrocyclization reaction in the first microreactor is 8 min to 40 min.

[0022] In some embodiments, preferably, in step (1), the flow rate at which the solution A is pumped into the first microreactor of the microchannel reaction device is 0.4 mL / min to 1.0 mL / min, and more preferably 0.4 mL / min; the reaction temperature of the electrocyclization reaction is room temperature, and the reaction current is 100 mA to 700 mA, and more preferably 300 mA; the reaction residence time of the electrocyclization reaction in the first microreactor is 10 min to 30 min, and more preferably 10 min to 25 min, and more preferably 25 min.

[0023] In some embodiments, in step (2), the oxidant is hydrogen peroxide; the second solvent is any one or a combination of acetonitrile, dimethyl sulfoxide and ethyl acetate; and the lipase is Novozyme 435.

[0024] In some embodiments, preferably, in step (2), the second solvent is ethyl acetate.

[0025] The lipase is Novozyme 435, and the enzyme activity of Novozyme 435 is 10000U / g. The enzyme activity is defined as: at 40°C and pH=7.5, 1g of solid enzyme powder or 1mL of liquid enzyme hydrolyzes the substrate for 1min to produce 1μmol of titratable fatty acid, which is 1U.

[0026] Wherein, in step (2), the second microreactor is filled with lipase, and the filling amount of lipase is calculated based on the raw material compound 1, 1 mmol of compound 1 needs to be filled with 500 mg of lipase, and the amount of lipase changes proportionally with the change of the amount of compound 1; when the amount of lipase is insufficient to catalyze the reaction completely, the second microreactor is reloaded with lipase.

[0027] In some embodiments, in step (2), the concentration of the oxidant in the solution B is 0.5-1.5 mmol / mL.

[0028] In some embodiments, preferably, in step (2), the concentration of the oxidant in the solution B is 1.0 mmol / mL.

[0029] In some embodiments, in step (2), during the enzymatic transesterification reaction, based on compound 1 in step (1), the molar ratio of compound 1 to the oxidant is 1:(0.10-0.70).

[0030] In some embodiments, preferably, in step (2), during the enzymatic transesterification reaction, based on compound 1 in step (1), the molar ratio of compound 1 to the oxidant is 1:(0.20-0.65), and more preferably 1:(0.50-0.65).

[0031] In some embodiments, in step (2), the flow rate of the solution B pumped into the second microreactor of the microchannel reaction device is 0.010 to 0.600 mL / min; the reaction temperature of the enzymatic ester exchange reaction is 25°C to 70°C; and the reaction residence time of the enzymatic ester exchange reaction in the second microreactor is 2.0 min to 10 min.

[0032] In some embodiments, preferably, in step (2), the flow rate at which the solution B is pumped into the second microreactor of the microchannel reaction device is 0.010 to 0.100 mL / min, more preferably 0.010 to 0.050 mL / min, and even more preferably 0.025 mmol / min; the reaction temperature of the enzymatic ester exchange reaction is 50°C to 70°C, more preferably 50°C to 60°C, and even more preferably 55°C; the reaction residence time of the enzymatic ester exchange reaction in the second microreactor is 2.5 min to 7.0 min.

[0033] In some embodiments, the microchannel reaction device includes a connecting pipe, a first feed pump, a second feed pump, a first micromixer, a first microreactor, a second microreactor, an electrical box and a receiver; the first feed pump is connected to the feed port of the first microreactor through a connecting pipe; the discharge port of the first microreactor and the second feed pump are connected in parallel to the first micromixer through a connecting pipe; the first micromixer and the second microreactor and the receiver are connected in series in turn through a connecting pipe; wherein the electrode sheets at both ends of the first microreactor are respectively connected to the positive and negative poles of the electrical box, the electrode sheet connected to the positive pole of the electrical box is a carbon electrode sheet, and the electrode sheet connected to the negative pole of the electrical box is a carbon electrode sheet.

[0034] Wherein, the first micro mixer is a Y-type micro mixer or a T-type micro mixer, preferably a T-type micro mixer.

[0035] Wherein, the volume of the first microreactor is 6-14 mL, preferably 10 mL.

[0036] Wherein, the volume of the second microreactor is 1.0-5.0 mL, preferably 2.7 mL.

[0037] Wherein, the first microreactor is a tubular reactor with a tube diameter of 0.5-1.5 mm, preferably 1.0 mm.

[0038] Wherein, the flow tube diameter of the second microreactor is 2-5 mm, preferably 3 mm.

[0039] Beneficial effects:

[0040] (1) Compared with the traditional chemical method for preparing benzenesulfonic acid compounds, the present invention uses simple chemical raw materials to start the synthesis, and uses a strategy combining electrocatalysis and enzyme catalysis, which is more in line with the current concept of "green chemistry". At the same time, the introduction of microfluidic field technology with high mass transfer and high heat transfer helps to improve the reaction efficiency, greatly shorten the reaction time, maintain the stability of the enzyme, and enable the enzyme catalyst to be recycled for multiple times, providing the possibility for subsequent industrial scale-up production. This strategy has developed an efficient, green, and scalable method for continuously preparing benzenesulfonic acid compounds through an electrochemical-enzymatic coupling, which is a powerful supplement to the existing synthesis methods.

[0041] (2) The new synthesis method provided by the present invention adopts a strategy combining electrocatalysis with enzyme catalysis. Compared with the traditional chemical synthesis method, the synthesis route provided by the present invention does not use highly corrosive, toxic and polluting reagents, such as fuming sulfuric acid, hydrochloric acid, sulfur trioxide and other substances, and is more green and safe. In addition, microfluidic field technology is used to help improve the reaction efficiency and realize the efficient synthesis of benzenesulfonic acid compounds by enzyme-chemical method.

[0042] (3) Compared with the traditional reaction device, the microchannel reactor used in the present invention has the advantages of short reaction time, high conversion efficiency, precise control of reaction conditions, high safety and easy scale-up. In addition, the Novozyme435 lipase used in the present invention has good catalytic performance, green environmental protection, energy saving and high efficiency, low production cost, low toxicity and pollution, good product quality, suitable for promotion and application, so as to effectively solve the existing problems of synthesizing aromatic sulfonic acid compounds, such as strong corrosiveness, high toxicity, harsh reaction conditions, and high environmental pollution.

[0043] (4) Compared with the prior art, the synthesis method provided by the present invention has simple, cheap and easily available starting materials, a simple process, and can effectively reduce production costs. It is expected to be suitable for industrial production, is green, environmentally friendly, energy-saving and efficient.

[0044] (5) The 2-benzamidobenzenesulfonic acid compounds prepared by the present invention can be used as standard products. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0046] Figure 1 is the compound 2-(4-methylbenzamido)benzenesulfonic acid (4a) in the embodiment of the present invention 1 H NMR spectrum.

[0047] Figure 2 is the compound 2-(4-methylbenzamido)benzenesulfonic acid (4a) in the embodiment of the present invention 13 C NMR spectrum.

[0048] Figure 3 is the compound 2-(2-methylbenzamido)benzenesulfonic acid (4b) in the embodiment of the present invention 1 H NMR spectrum.

[0049] Figure 4 is the compound 2-(2-methylbenzamido)benzenesulfonic acid (4b) in the embodiment of the present invention 13 C NMR spectrum.

[0050] Figure 5 is the compound 2-(4-methoxybenzamido)benzenesulfonic acid (4c) in the embodiment of the present invention 1 H NMR spectrum.

[0051] Figure 6 is the compound 2-(4-methoxybenzamido)benzenesulfonic acid (4c) in the embodiment of the present invention 13 C NMR spectrum.

[0052] Figure 7 is the compound 2-benzamidobenzenesulfonic acid (4d) in the embodiment of the present invention 1 H NMR spectrum.

[0053] Figure 8 is the compound 2-benzamidobenzenesulfonic acid (4d) in the embodiment of the present invention 13 C NMR spectrum.

[0054] Fig. 9 is the compound 2-(4-ethylbenzamido)benzenesulfonic acid (4e) in the embodiment of the present invention 1 H NMR spectrum.

[0055] Fig.10 is the compound 2-(4-ethylbenzamido)benzenesulfonic acid (4e) in the embodiment of the present invention 13 C NMR spectrum.

[0056] Fig.11 The schematic diagram of the synthesis of compound 4 prepared in the embodiment of the present invention; wherein R is selected from 4-methyl, 2-methyl, 4-methoxy, hydrogen or 4-ethyl.

[0057] Fig.12 Schematic diagram of the microchannel reaction device used in an embodiment of the present invention.

[0058] Fig.13 Schematic diagram of the electrode sheet in the first microreactor used in an embodiment of the present invention. DETAILED DESCRIPTION

[0059] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0060] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0061] 1. A schematic diagram of a microchannel reaction device used in an embodiment of the present invention is shown in FIG. Fig.12 As shown, the microchannel reaction device includes a connecting pipe, a first feed pump (syringe pump 1), a second feed pump (syringe pump 2), a first micromixer, a first microreactor (electric microreactor), a second microreactor (enzyme microreactor), an electrical box and a receiver; wherein the first feed pump is connected to the feed port of the first microreactor through a connecting pipe; the discharge port of the first microreactor and the second feed pump are connected to the first micromixer in parallel through a connecting pipe; the first micromixer and the second microreactor and the receiver are connected in series through a connecting pipe in turn; wherein the first microreactor is an electrical microreactor; the electrode sheets at both ends of the first microreactor are respectively connected to the positive and negative electrodes of the electrical box, the electrode sheet connected to the positive electrode of the electrical box is a carbon electrode sheet, and the electrode sheet connected to the negative electrode of the electrical box is a carbon electrode sheet. The specific schematic diagram of the electrode sheets in the first microreactor is as shown in Fig.13 shown.

[0062] Wherein, the diameter of the connecting pipe is 3mm.

[0063] Wherein, the model of the feed pump is Leifu TYD01.

[0064] Wherein, the micro mixer is a T-shaped mixer.

[0065] The flow tube diameter of the first microreactor is 1 mm, and the first microreactor is an electrochemical synthesizer with a model of MFS-EC and a volume of 10 mL.

[0066] The flow tube diameter of the second microreactor is 3 mm. The second microreactor is a packed column enzyme microreactor with a volume of 2.7 mL and filled with 500 mg of lipase Novozyme 435 (Shanghai Yuanye Biotechnology Co., Ltd.).

[0067] 2. The synthesis diagram of compound 4 prepared in the embodiment of the present invention is as follows Fig.11 As shown; wherein R is selected from 4-methyl, 2-methyl, 4-methoxy, hydrogen or 4-ethyl. The mixed solution of compound 1 and compound 2 is pumped into the first microreactor through the first feed pump for electrocyclization reaction to obtain a reaction solution containing intermediate 3; the reaction solution containing intermediate 3 and hydrogen peroxide are pumped into the first micromixer at the same time, and after mixing, they are continuously pumped into the second microreactor for enzymatic ester exchange reaction to obtain compound 4. After the reaction is completed, the reaction solution is post-treated, specifically: the reaction solution is concentrated, and column chromatography is separated and purified; the eluent of the column chromatography is a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:2 to 20.

[0068] 3. The enzyme activity of the lipase Novozyme 435 used in the following examples is 10000 U / g. The enzyme activity is defined as: at 40°C and pH=7.5, 1g of solid enzyme powder or 1mL of liquid enzyme hydrolyzes the substrate in 1min to produce 1μmol of titratable fatty acid, which is 1U.

[0069] 4. The benzaldehyde compounds (1a-1e) represented by compound 1 and the benzenesulfonic acid compounds (4a-4e) represented by compound 4 used in the examples of the present invention are shown in Table 1 and Table 2, respectively.

[0070] Table 1 Reactants: Benzaldehyde compounds

[0071]

[0072] Table 2 2-Benzamidobenzenesulfonic acid compounds

[0073]

[0074]

[0075] Example 1: Synthesis of Compound 4a

[0076] (1) 1 mmol 4-methylbenzaldehyde (1a) and 1.5 mL 2-aminobenzenethiol were dissolved in 10 mL ethyl acetate to obtain solution A; solution A was pumped into a first microreactor (10 mL) of a microchannel reaction device at a flow rate of 0.4 mL / min through a first feed pump, and an electrocyclization reaction was carried out at a current of 300 mA. The reaction was carried out at room temperature with a reaction residence time of 25 min. After the reaction was completed, a first reaction solution was obtained.

[0077] (2) 0.3 mmol of hydrogen peroxide was dissolved in 0.3 mL of ethyl acetate to obtain solution B; the first reaction solution obtained in step (1) and solution B were simultaneously pumped into the second microreactor (2.7 mL, loaded with 500 mg of lipase Novozyme 435) of the microchannel reaction device, wherein solution B was pumped into the second microreactor of the microchannel reaction device by a second feed pump at a flow rate of 0.025 mL / min; then, an enzymatic transesterification reaction was carried out at 55° C., with a reaction residence time of 6.3 min; after the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (V 乙酸乙酯 :V 石油醚 =1:2~20) to obtain the target product 4a with a yield of 76.9%.

[0078] The H NMR spectrum of compound 4a is shown in Figure 1 As shown, the NMR carbon spectrum is as follows Figure 2 As shown, the specific NMR data are: 1 HNMR(400MHz,DMSO-d6)δ11.38(s,1H),8.54(d,J=8.2Hz,1H),7.88(d,J=7.9Hz,2H),7 .78(dd,J=7.8,1.6Hz,1H),7.39(d,J=7.8Hz,3H),7.12(t,J=7.5Hz,1H),2.40(s,3H). 13 CNMR(101MHz,DMSO-d6)δ164.55,142.54,135.74,135.64,132.34,130.41,129.87,127.53,127.48,123.05,120.21,21.49.

[0079] Example 2: Synthesis of Compound 4b

[0080] The preparation method is the same as that of Example 1, except that compound 1a is replaced by 2-methylbenzaldehyde (1b), and the product 4b is finally prepared with a yield of 80.7%.

[0081] The H NMR spectrum of product 4b is shown in Figure 3 As shown, the NMR carbon spectrum is as follows Figure 4 As shown, the specific NMR data are: 1HNMR(400MHz,DMSO-d6)δ10.78(s,1H),8.47(d,J=8.2Hz,1H),7.73(dd,J=7.7,1.7Hz,1H),7.61– 7.56(m,1H),7.43–7.37(m,2H),7.33(d,J=7.4Hz,2H),7.10(td,J=7.6,1.2Hz,1H),2.47(s,3H). 13 C NMR (101MHz, DMSO-d6) δ167.28,136.95,136.59,135.93,135.63,131.62,130.71,130.25,127.37,127.34,126.52,123.18,120.24,20.16.

[0082] Example 3: Synthesis of Compound 4c

[0083] The preparation method is the same as that of Example 1, except that compound 1a is replaced by 4-methoxybenzaldehyde (1c), and finally product 4c is prepared with a yield of 78.2%.

[0084] The H NMR spectrum of product 4c is shown in Figure 5 As shown, the NMR carbon spectrum is as follows Figure 6 As shown, the specific NMR data are: 1 HNMR(400MHz,DMSO-d6)δ11.30(s,1H),8.50(d,J=8.2Hz,1H),7.92(d,J=8.6Hz,2H),7 .73(d,J=1.7Hz,1H),7.38(d,J=7.2Hz,1H),7.10(dd,J=8.1,6.1Hz,3H),3.85(s,3H). 13 CNMR(101MHz,DMSO-d6)δ164.15,162.59,135.85,135.65,130.31,129.42,127.43,127.29,122.84,120.08,114.57,55.96.

[0085] Example 4: Synthesis of Compound 4d

[0086] The preparation method is the same as that of Example 1, except that compound 1a is replaced by benzaldehyde (1d), and finally product 4d is prepared with a yield of 62.2%.

[0087] The H NMR spectrum of product 4d is as follows Figure 7 As shown, the NMR carbon spectrum is as follows Figure 8 As shown, the specific NMR data are: 1HNMR (400MHz, DMSO-d6) δ11.41(s,1H),8.50(d,J=8.3Hz,1H),7.98–7.93(m,2H),7.74(dd,J=7. 7,1.7Hz,1H),7.60(ddd,J=14.5,7.9,6.1Hz,3H),7.40(d,J=1.8Hz,1H),7.12(d,J=7.6Hz,1H). 13 C NMR (101MHz, DMSO-d6) δ164.55,135.89,135.62,135.12,132.42,130.32,129.35,127.47,127.44,123.15,120.19.

[0088] Example 5: Synthesis of Compound 4e

[0089] The preparation method is the same as that of Example 1, except that compound 1a is replaced by 4-ethylbenzaldehyde (1e), and the final product 4e is prepared with a yield of 75.4%.

[0090] The H NMR spectrum of product 4e is shown in Fig. 9 As shown, the NMR carbon spectrum is as follows Fig.10 As shown, the specific NMR data are: 1 HNMR(400MHz, DMSO-d6)δ11.36(s,1H),8.51(dd,J=8.2,1.2Hz,1H),7.90–7.85(m,2H),7.74(dd, J=7.8,1.7Hz,1H),7.43–7.37(m,3H),7.10(s,1H),2.70(d,J=7.5Hz,2H),1.22(t,J=7.6Hz,3H). 13 C NMR (101MHz, DMSO-d6) δ164.56,148.63,135.75,135.73,132.65,130.32,128.70,127.61,127.43,123.01,120.14,28.53,15.80.

[0091] Example 6: Synthesis of Compound 4a

[0092] The preparation method is the same as that of Example 1, except that the current of the electrocyclization reaction is 100 mA, and the yield of the final target product 4a is 70.6%.

[0093] Example 7: Synthesis of Compound 4a

[0094] The preparation method is the same as that of Example 1, except that the current of the electrocyclization reaction is 700 mA, and the yield of the final target product 4a is 61.6%.

[0095] Example 8: Synthesis of Compound 4a

[0096] The preparation method is the same as that of Example 1, except that the feed pump flow rate of solution A in the electrocyclization reaction is 1 mL / min, and the yield of the final target product 4a is 61.6%.

[0097] Example 9: Synthesis of Compound 4a

[0098] The preparation method is the same as that of Example 1, except that the feed pump flow rate of solution A in the electrocyclization reaction is 0.5 mL / min, and the yield of the final target product 4a is 66%.

[0099] Example 10: Synthesis of Compound 4a

[0100] The preparation method is the same as that of Example 1, except that the reaction temperature of the enzymatic transesterification reaction is 25° C., and the yield of the final target product 4a is 13.6%.

[0101] Example 11: Synthesis of Compound 4a

[0102] The preparation method is the same as that of Example 1, except that the reaction temperature of the enzymatic transesterification reaction is 65° C., and the yield of the final target product 4a is 23.2%.

[0103] Comparative Example 1: Reaction using a conventional reaction bottle

[0104] (1) 10 mL of ethyl acetate, 1 mmol of 4-methylbenzaldehyde (1a) and 1.5 mL of 2-aminobenzenethiol were added to an electroreaction bottle. The negative electrode of the electroreaction was inserted into a graphite electrode, and the positive electrode was inserted into a graphite electrode. The current was adjusted to 300 mA. The electrocyclization reaction was carried out at room temperature. The speed was set to 160 rpm. Samples were taken every 5 minutes, and the reaction progress was monitored by HPLC.

[0105] (2) When the reaction system of step (1) reaches equilibrium, the reaction solution is transferred to a 25 mL parallel reactor test tube, and 0.3 mmol hydrogen peroxide and 0.3 mL ethyl acetate reagent are added to the reaction solution, followed by adding 500 mg of lipase Novozyme 435, which is slowly poured into the mixed solution. The speed of the parallel reactor is set to 160 rpm and the reaction temperature is set to 55° C. The reaction progress is detected and the reaction progress is monitored by HPLC at time points such as 10 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, and 4 h after the reaction. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain a crude product, which is separated by column chromatography to obtain the target product 4a with a yield of 36%.

[0106] Comparative Example 2: No current applied

[0107] 10 mL of ethyl acetate, 1 mmol of 4-methylbenzaldehyde (1a) and 1.5 mL of 2-aminobenzenethiol were added to the electroreaction bottle, the stirring device was turned on and the speed was set to 160 rpm, no current was applied, the reaction was carried out at room temperature, samples were taken every 5 minutes, and the reaction progress was monitored by HPLC. The experimental results showed that the intermediate product 2-(p-tolyl)benzo[d]thiazole could not be obtained, proving that current is a necessary condition for the reaction.

[0108] Comparative Example 3: No lipase added

[0109] (1) 10 mL of ethyl acetate, 1 mmol of 4-methylbenzaldehyde (1a) and 1.5 mL of 2-aminobenzenethiol were added to an electroreaction bottle. The negative electrode of the electroreaction was inserted into a graphite electrode, and the positive electrode was inserted into a graphite electrode. The current was adjusted to 300 mA. The electrocyclization reaction was carried out at room temperature. The speed was set to 160 rpm. Samples were taken every 5 minutes, and the reaction progress was monitored by HPLC.

[0110] (2) When the reaction system of step (1) reaches equilibrium, the reaction solution is transferred to a 25 mL parallel reactor test tube, and 0.3 mmol hydrogen peroxide and 0.3 mL ethyl acetate reagent are added to the reaction solution, and lipase Novozyme 435 is not added. The speed of the parallel reactor is set to 160 revolutions per minute, the reaction temperature is 55° C., and the reaction progress is detected. The reaction progress is monitored by HPLC at time points such as 10 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, and 4 h after the reaction begins. The experimental results show that no reaction occurs in the reaction system, proving that lipase Novozyme 435 is a necessary condition for the reaction.

[0111] The present invention provides a method and idea for the continuous preparation of benzenesulfonic acid compounds by electrochemical-enzymatic coupling. There are many methods and approaches to realize the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the protection scope of the present invention. All components not specified in this embodiment can be realized by existing technologies.

Claims

1. A method for continuously preparing benzenesulfonic acid compounds by electrochemical-enzymatic coupling, characterized in that: The steps include: (1) dissolving compound 1 and compound 2 in a first solvent to obtain solution A; pumping solution A into a first microreactor of a microchannel reaction device to perform an electrocyclization reaction, and obtaining a first reaction solution after the reaction is completed; (2) dissolving the oxidant in the second solvent to obtain a solution B; pumping the first reaction solution obtained in step (1) and the solution B into the second microreactor of the microchannel reaction device to perform an enzymatic transesterification reaction, and obtaining a benzenesulfonic acid compound 4 after the reaction is completed; Wherein, the second microreactor is filled with lipase; The compound 1 is shown in Formula 1, the compound 2 is shown in Formula 2, and the compound 4 is shown in Formula 4: in, R is selected from C1-C6 alkyl or C1-C6 alkoxy; n is an integer from 0 to 5.

2. The method according to claim 1, characterized in that The R is selected from C1-C2 alkyl or C1-C2 alkoxy.

3. The method according to claim 1, characterized in that In step (1), the first solvent is any one of acetonitrile, dimethyl sulfoxide and ethyl acetate or a combination of several of them.

4. The method according to claim 1, characterized in that: In step (1), the ratio of the molar amount of the compound 1 to the volume amount of the compound 2 is 1 mmol: (1-2) mL; the ratio of the molar amount of the compound 1 to the volume amount of the first solvent is 1 mmol: (8-12) mL.

5. The method according to claim 1, characterized in that In step (1), the flow rate of the solution A pumped into the first microreactor of the microchannel reaction device is 0.1 mL / min to 1.2 mL / min; the reaction temperature of the electrocyclization reaction is room temperature, and the reaction current is 50 mA to 800 mA; the reaction residence time of the electrocyclization reaction in the first microreactor is 8 min to 40 min.

6. The method according to claim 1, characterized in that In step (2), the oxidant is hydrogen peroxide; the second solvent is any one or a combination of acetonitrile, dimethyl sulfoxide and ethyl acetate; and the lipase is lipase Novozyme 435.

7. The method according to claim 1, characterized in that In step (2), the concentration of the oxidant in the solution B is 0.5 to 1.5 mmol / mL.

8. The method according to claim 1, characterized in that: In step (2), during the enzymatic transesterification reaction, based on compound 1 in step (1), the molar ratio of compound 1 to the oxidant is 1:(0.10-0.70).

9. The method according to claim 1, characterized in that: In step (2), the flow rate of the solution B pumped into the second microreactor of the microchannel reaction device is 0.010 to 0.600 mL / min; the reaction temperature of the enzymatic ester exchange reaction is 25°C to 70°C; and the reaction residence time of the enzymatic ester exchange reaction in the second microreactor is 2.0 min to 10 min.

10. The method according to claim 1, characterized in that The microchannel reaction device includes a connecting pipe, a first feed pump, a second feed pump, a first micromixer, a first microreactor, a second microreactor, an electrical box and a receiver; the first feed pump is connected to the feed port of the first microreactor through a connecting pipe; the discharge port of the first microreactor and the second feed pump are connected in parallel to the first micromixer through a connecting pipe; the first micromixer and the second microreactor and the receiver are connected in series in sequence through a connecting pipe; wherein the electrode sheets at both ends of the first microreactor are respectively connected to the positive and negative poles of the electrical box, the electrode sheet connected to the positive pole of the electrical box is a carbon electrode sheet, and the electrode sheet connected to the negative pole of the electrical box is a carbon electrode sheet.

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