Method for continuous flow electrochemical synthesis of rifamycin S from rifamycin SV under microscale

Abstract

The invention discloses a method for performing continuous flow electrochemical synthesis on rifamycin SV under a microscale. The method comprises the following steps: pumping filtrate containing the rifamycin SV into a microflow field electrochemical reactor for reaction, collecting reaction liquid, acidifying and crystallizing to obtain the rifamycin S. According to the micro-flow field electrochemical reactor, a modified graphite comb tooth structure is used as an anode, an iron comb tooth structure is used as a cathode, and the modified graphite comb tooth structure and the iron comb tooth structure intersect with each other to form an electrochemical micro-reaction channel; the surface of the modified graphite comb tooth electrode is obtained by modifying the surface of a common graphite comb tooth electrode. The method provided by the invention can avoid the use of an exogenous oxidant and an organic extraction reagent, effectively improves the reaction conversion rate, greatly shortens the reaction time, is simple to operate, is safe and stable, saves the post-treatment cost, and is greener and more efficient.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical technology and relates to a method for continuously preparing rifamycin S, and specifically relates to a method for continuously preparing rifamycin S by oxidizing rifamycin SV using a microflow field electrochemical technology. Background Art

[0002] Rifamycin S is a broad-spectrum antibiotic and a key intermediate for the synthesis of rifamycin anti-tuberculosis drugs. It is the main raw material for the synthesis of rifampicin, rifadin, rifabutin, rifaximin, rifapentine, etc. It has high activity against Mycobacterium tuberculosis and can be used to treat tuberculosis and other diseases caused by drug-resistant mycobacteria. Rifamycin S exerts its antibacterial effect by inhibiting the activity of bacterial RNA polymerase, thereby preventing bacterial RNA synthesis, and then blocking protein synthesis, ultimately leading to the death of bacteria. Rifamycin S is usually used in conjunction with other anti-tuberculosis drugs (such as isoniazid, pyrazinamide, etc.) to reduce the production of drug-resistant strains and improve the treatment effect. Due to its broad-spectrum antibacterial effect, rifamycin S is sometimes also used to treat other infections, such as brucellosis and lymphoma virus infection.

[0003] The existing rifamycin S production process is as follows: the filtrate of rifamycin SV is filtered to obtain a filtrate, the filtrate is oxidized to obtain rifamycin S, and then rifamycin S is separated from the filtrate by acid-base adjustment, organic solvent extraction and other steps, and finally refined, impurities removed, crystallized and dried. However, during the oxidation process, a large amount of low-concentration sodium hypochlorite or hydrogen peroxide oxidation agent is often required to be added, and a large amount of aqueous solution is introduced. After that, acidified rifamycin S is difficult to precipitate, and can only be extracted with a large amount of butyl acetate. The above method is highly dangerous during the production process and generates a large amount of wastewater, which increases the production cost of the enterprise and is not conducive to green environmental protection.

[0004] Electrosynthesis uses electrons to drive redox reactions without the need for exogenous redox reagents. It is fundamentally a green synthesis technology and a new direction for the transformation and upgrading of pharmaceutical processes and fine chemicals. It has a wide range of applications in both organic and inorganic synthesis, can achieve efficient and controllable reactions, and can even prepare compounds that are difficult to obtain by traditional methods. In addition, electrosynthesis can easily achieve high conversion rates, high yields, and high selectivity under mild reaction conditions, and the reaction rate and reaction limit are both controllable. However, kettle electrosynthesis often has problems such as high overvoltage, low Faraday efficiency, small specific surface area, low reaction efficiency, and difficulty in engineering application. Effectively improving the specific surface area, mass transfer / heat efficiency, and achieving precise control of the electrode spacing are the key to solving the above problems.

[0005] Microfluidic continuous flow electrochemical synthesis reaction technology has a large specific surface area through microscale effects, which can improve mass transfer and heat transfer efficiency and reaction rate by 2-3 orders of magnitude, reduce the online reaction volume several times, and improve reaction selectivity and reduce side reactions through continuous flow and low backmixing, thereby effectively realizing the greening and industrial application of electrosynthesis. In addition, the use of microchannels as flow units of electrochemical reactors greatly shortens the distance of molecular migration, reduces the Joule heat of the reaction, and is conducive to removing supporting electrolytes from the reaction system. The electric field in microchannels equipped with parallel electrodes is more uniform, and the short distance between the electrodes forms a stable internal laminar flow, thereby improving the control of the contact order of the reactants.

[0006] Microfluidic continuous flow electrochemical synthesis reaction technology, as an important component of flow chemistry system, has great application potential in the chemical industry. The advantages of electrosynthesis microreactors include high atom economy, green and safe and easy to scale up, etc., and are considered to be a general technology for pharmaceutical processes and chemical engineering. Reducing the distance between electrodes, increasing the electrode area, effectively reducing ion transport resistance, and realizing controllable electrosynthesis solves the shortcomings of traditional kettle reactors and may promote the industrialization of electrosynthesis technology. Summary of the invention

[0007] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for continuously electrochemically synthesizing rifamycin S from rifamycin SV at a microscale in view of the shortcomings of the prior art, so as to solve the problems of poor safety, serious pollution, large amount of wastewater, high cost, etc. in the prior art.

[0008] In order to solve the above technical problems, the present invention discloses a method for continuously electrochemically synthesizing rifamycin S from rifamycin SV at a microscale, wherein a filtrate containing rifamycin SV is pumped into a microflow field electrochemical reactor for reaction, and the reaction solution is collected, acidified, and crystallized to obtain rifamycin S;

[0009] Among them, the microfluidic electrochemical reactor uses a modified graphite comb tooth structure as an anode and an iron comb tooth structure as a cathode, and the channel formed by the modified graphite comb tooth structure and the iron comb tooth structure intersecting each other in the same plane serves as an electrochemical microreaction channel; preferably, the two comb tooth structures are evenly crossed to make the formed channel size consistent.

[0010] The modified graphite comb structure is prepared by reducing and coupling the surface of a common graphite comb electrode with 4-(carboxymethyl)benzene diazonium salt, and then condensing the obtained carboxylic acid tail with an N-phenyl-substituted dihydrophenazine compound after chlorination, wherein the structural formula of the N-phenyl-substituted dihydrophenazine compound is:

[0011]

[0012] The R substituent is any one of H, alkyl, halogen, alkoxy, phenyl, and cyano.

[0013] Specifically, the modification process of the common graphite comb electrode is as follows:

[0014]

[0015] More specifically, the modification process of the common graphite comb electrode includes the following steps:

[0016] (1) After washing the common graphite comb electrode, use it as the positive and negative electrodes of the electrochemical microreactor, prepare a 4-(carboxymethyl)benzene diazonium salt aqueous solution, add concentrated sulfuric acid as an electrolyte, apply a voltage at a certain temperature, and pump it into the electrochemical microreactor at a certain flow rate for a certain period of time;

[0017] (2) flushing the electrochemical microreactor, and then pumping the anhydrous dichloromethane solution of SOCl2 into the electrochemical microreactor at a certain flow rate for a certain period of time;

[0018] (3) Pumping the anhydrous dichloromethane solution of the dihydrophenazine compound into the electrochemical microreactor at a certain flow rate and allowing the solution to flow continuously for a certain period of time.

[0019] The reaction conditions in step (1) are as follows: prepare a 0.02-0.03M aqueous solution of 4-(carboxymethyl)benzenediazonium salt, add 6-9 equivalents of concentrated sulfuric acid as an electrolyte, apply a voltage of 0.2V at a temperature of 20-30°C, pump into the electrochemical microreactor at a flow rate of 0.4-0.6mL / min, and continue to flow for 20-30min.

[0020] Preferably, the reaction conditions in step (1) are as follows: prepare a 0.025M aqueous solution of 4-(carboxymethyl)benzenediazonium salt, add 8 times the equivalent of concentrated sulfuric acid as an electrolyte, apply a voltage of 0.2V at a temperature of 25°C, pump it into the electrochemical microreactor at a flow rate of 0.5mL / min, and continue flowing for 20min.

[0021] In step (2), a 0.02-0.03M anhydrous dichloromethane solution of SOCl2 is prepared, and the solution is pumped into the electrochemical microreactor at a flow rate of 0.4-0.6mL / min at a temperature of 20-30°C, and the flow is continued for 20-30min. In step (3), a 0.02-0.03M anhydrous dichloromethane solution of a dihydrophenazine compound is prepared, and the solution is pumped into the electrochemical microreactor at a flow rate of 0.4-0.6mL / min at a temperature of 20-30°C, and the flow is continued for 30-40min.

[0022] Preferably, in step (2), a 0.025 M solution of SOCl2 in anhydrous dichloromethane is prepared, and the solution is pumped into the electrochemical microreactor at a flow rate of 0.5 mL / min at a temperature of 25° C., and the flow is continued for 20 min; in step (3), a 0.025 M solution of a dihydrophenazine compound in anhydrous dichloromethane is prepared, and the solution is pumped into the electrochemical microreactor at a flow rate of 0.5 mL / min at a temperature of 25° C., and the flow is continued for 30 min.

[0023] The filtrate containing rifamycin SV is prepared by adding zinc sulfate to the fermentation liquid from the fermentation workshop and then filtering the mixture through plate and frame filtration to obtain the filtrate.

[0024] Preferably, the distance between adjacent comb teeth after the modified graphite comb teeth and the iron comb teeth cross is 1-4 mm, the electrode thickness of the modified graphite comb teeth and the iron comb teeth is 2-6 mm; the length of the electrochemical micro-reaction channel is 500-1000 mm, and the volume is 2-24 mL.

[0025] The mass fraction of the rifamycin SV filtrate is 0.3-0.6%.

[0026] The reaction temperature of the reaction is 20-70°C.

[0027] The reaction current of the rifamycin SV filtrate in the microreactor is 20-2000 mA, preferably 100-800 mA.

[0028] The flow rate of the rifamycin SV filtrate flowing through the electrochemical micro-reaction channel is 1-100 mL / min, preferably 10-50 mL / min.

[0029] The acidification is to adjust the pH to 1-4 with acid, and then stand for crystallization to obtain rifamycin S through solid-liquid separation.

[0030] In one embodiment, the acid is dilute hydrochloric acid. Preferably, the dilute hydrochloric acid has a mass concentration of 10%.

[0031] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0032] (1) The present invention couples the electrosynthesis method with the microfluidic continuous flow synthesis reaction technology, and uses a modified graphite electrode at a microscale to continuously electro-oxidize rifamycin SV to prepare rifamycin S, avoiding the use of exogenous oxidants and organic extraction reagents, effectively improving the reaction conversion rate, greatly shortening the reaction time, and being simple to operate, safe and stable. Compared with traditional reaction methods, the present invention does not produce a large amount of wastewater containing organic matter, saves post-processing costs, and is more green and efficient.

[0033] (2) The method of the present invention can effectively avoid the occurrence of side reactions. Compared with the traditional chemical oxidation method, it has continuous flow, low back mixing, and can separate the target product in time, avoiding further electrolysis of the final product, thereby improving the selectivity of the reaction and the quality of the product.

[0034] (3) Compared with the traditional reaction method, the present invention has excellent amplification results, can realize continuous production, and has good industrial utilization value.

[0035] (4) The present invention utilizes a modified graphite electrode, by connecting the catalyst to the graphite electrode in the form of a covalent bond, and the electrolysis conditions are relatively mild. The sample is continuously injected for 24 hours, and no decrease in reaction effect and catalyst shedding are observed. The catalytic efficiency is higher, the catalyst can be reused, and the process stability is better. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 It is the CV diagram of comb-tooth graphite electrode C-1;

[0037] Figure 2 Liquid phase diagram of the reaction solution of Example 1;

[0038] Figure 3 Liquid phase diagram of product 2 obtained by crystallization of Example 1;

[0039] Figure 4 is a schematic diagram of the reaction process;

[0040] Figure 5 In the figure, a is the physical appearance of the continuous flow electrochemical microreactor; b is the exploded view of the microflow field electrochemical reactor, wherein ① and ⑧ are electrode holders; ② is the electrolytic cell; ③ is the cover plate; ④ is the comb-shaped platinum-plated electrode (iron comb tooth structure); ⑤ is the comb-shaped carbon electrode (modified graphite comb tooth structure); ⑥ is the electrode interface; ⑦ is the battery back seal;

[0041] Figure 6 Schematic diagram of the assembly of the electrochemical reactor. DETAILED DESCRIPTION

[0042] 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.

[0043] 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.

[0044] In the following examples, the filtrate containing rifamycin SV is prepared by adding zinc sulfate to the fermentation broth from the fermentation workshop and filtering the filtrate through a plate and frame filter. The content of rifamycin SV in the obtained filtrate is about 0.3% to 0.6%.

[0045] As shown in Table 1, in the following examples, compound 1 is rifamycin SV, compound 2 is rifamycin S, c-1 to c-4 are modified comb-tooth graphite electrode structures, and the reaction is as follows Figure 4 shown.

[0046] Table 1 Structure of rifamycin SV, rifamycin S and series of modified graphite electrodes

[0047]

[0048] In the following embodiment, a microfluidic electrochemical reactor is constructed by the following method: a modified graphite comb structure is used as an anode, an iron comb structure is used as a cathode, and the modified graphite comb structure and the iron comb structure are intersected with each other in the same plane to form an electrochemical micro-reaction channel. The adjacent spacing between the modified graphite comb teeth and the iron comb teeth is 0.5 to 8 mm, and the electrode thickness of the modified graphite comb teeth and the iron comb teeth is 2 to 6 mm; the length of the electrochemical micro-reaction channel is 500 to 2000 mm, and the volume is 0.5 to 96 mL.

[0049] For the electrochemical microreactor used in the following specific examples, Figure 5-Figure 6 As shown, Figure 5 a is the physical appearance of the continuous flow electrochemical microreactor; Figure 5 b is an exploded view of a microfluidic electrochemical reactor, wherein two comb-tooth electrodes, a modified graphite comb-tooth structure and an iron comb-tooth structure, are arranged in an electrolytic cell, and a cover plate is arranged on the electrolytic cell and fixed by a base; Figure 6 The figure is a schematic diagram of the assembly. The flow electrolysis reactor is a sandwich structure, consisting of two aluminum supports, an electrolytic cell, two comb electrodes and a cover plate. The two comb electrodes are interwoven in the electrolytic cell to form a reaction channel, with an electrode spacing of 1 mm, a cell path height of 4 mm, a cell path length of 1260 mm, and a residence volume of 5.5 mL.

[0050] In the following examples, the volume of the electrochemical microreactor is 5.5 mL.

[0051] The transformation process of the comb-tooth graphite electrode is as follows:

[0052]

[0053] Example 1: Preparation of modified comb-tooth graphite electrode C-1.

[0054] Step 1: First, wash the comb-tooth graphite electrode with deionized water and dry it for use. Use an electrochemical microreactor (V = 5.5mL) with comb-tooth graphite electrodes as positive and negative electrodes, prepare a 0.025M aqueous solution of 4-(carboxymethyl)benzenediazonium salt, add 8 times the equivalent of concentrated sulfuric acid as the electrolyte, apply a voltage of 0.2V at a temperature of 25°C, pump it into the electrochemical microreactor at a flow rate of 0.5mL / min, and continue to flow for 20min.

[0055] Step 2: After that, the electrochemical microreactor was rinsed with deionized water, ethanol, and anhydrous dichloromethane as solvents at a flow rate of 0.5 mL / min at a temperature of 25°C for about 30 minutes respectively. A 0.025 M SOCl2 anhydrous dichloromethane solution was prepared and pumped into the electrochemical microreactor at a flow rate of 0.5 mL / min at a temperature of 25°C for 20 minutes.

[0056] Step 3: Prepare a 0.025M anhydrous dichloromethane solution of N-phenyldihydrophenazine, and pump it into the electrochemical microreactor at a flow rate of 0.5 mL / min at a temperature of 25°C. Continue to flow for 30 minutes to obtain the modified comb-tooth graphite electrode C-1. The CV diagram of the modified comb-tooth graphite electrode C-1 is shown in Figure 1 As shown, it is proved that the pyrazine structure is successfully fixed on the electrode surface.

[0057] Following the same experimental conditions, only the N-phenyldihydrophenazine substituent was changed to obtain modified comb-tooth graphite electrodes C-2, C-3 and C-4, respectively.

[0058] Example 2: Synthesis of Compound 2.

[0059] A modified comb-tooth graphite electrode structure was used with C-1 as the anode and an iron comb-tooth structure as the cathode. A microflow field electrochemical reactor was constructed according to the aforementioned steps. The fermentation broth of 0.5% rifamycin SV was pumped into an electrochemical microreactor with a reaction volume of 5.5 mL at a flow rate of 40 mL / min. Under the temperature condition of 25°C, an electric current of 800 mA was applied. After continuous injection for 2 minutes, the reaction liquid flowing out of the microreactor was collected. The collected reaction liquid was adjusted to pH 3 with 10wt% dilute hydrochloric acid, and the target product 2 was obtained by standing and crystallizing with a yield of 95%. The liquid phase diagram of the reaction liquid and the product after crystallization is shown in the figure below: Figure 2 and Figure 3 shown.

[0060] Example 3: Synthesis of Compound 2.

[0061] As shown in Example 2, an electrochemical microreactor with a modified comb-tooth graphite electrode structure of c-1 was used, and a 0.5% mass fraction of rifamycin SV fermentation broth was pumped into an electrochemical microreactor with a reaction volume of 5.5 mL at a flow rate of 40 mL / min. At a temperature of 25°C, an applied current of 800 mA was applied, and the reaction liquid flowing out of the microreactor was collected after continuous sampling for 2 minutes. The collected reaction liquid was adjusted to pH 3 with 10% dilute hydrochloric acid, and the target product 2 was obtained by standing and crystallizing with a yield of 96%.

[0062] Example 4: Synthesis of Compound 2.

[0063] Using an electrochemical microreactor with a modified comb-tooth graphite electrode structure of c-2, a 0.5% mass fraction of rifamycin SV filtrate was pumped into an electrochemical microreactor with a reaction volume of 5.5 mL at a flow rate of 40 mL / min. At a temperature of 25°C, an applied current of 800 mA was applied. After continuous sampling for 2 minutes, the reaction liquid flowing out of the microreactor was collected. The collected reaction liquid was adjusted to pH 3 with 10% dilute hydrochloric acid and allowed to stand for crystallization to obtain the target product 2 with a yield of 96%.

[0064] Example 5: Synthesis of Compound 2.

[0065] Using an electrochemical microreactor with a modified comb-tooth graphite electrode structure of C-3, a 0.5% mass fraction of rifamycin SV filtrate was pumped into an electrochemical microreactor with a reaction volume of 5.5 mL at a flow rate of 40 mL / min. At a temperature of 25°C, an applied current of 800 mA was applied. After continuous sampling for 2 minutes, the reaction liquid flowing out of the microreactor was collected. The collected reaction liquid was adjusted to pH 3 with 10% dilute hydrochloric acid and allowed to stand for crystallization to obtain the target product 2 with a yield of 96%.

[0066] Example 6: Synthesis of Compound 2.

[0067] Using an electrochemical microreactor with a modified comb-tooth graphite electrode structure of C-4, 0.5% of the mass fraction of rifamycin SV filtrate was pumped into the electrochemical microreactor with a reaction volume of 5.5 mL at a flow rate of 40 mL / min. At a temperature of 25°C, an applied current of 800 mA was applied. After continuous sampling for 2 minutes, the reaction liquid flowing out of the microreactor was collected. The collected reaction liquid was adjusted to pH 3 with 10% dilute hydrochloric acid and allowed to stand for crystallization to obtain the target product 2 with a yield of 94%.

[0068] Example 7: Synthesis of Compound 2.

[0069] Using an electrochemical microreactor with a modified comb-tooth graphite electrode structure of C-1, a 0.5% mass fraction of rifamycin SV filtrate was pumped into an electrochemical microreactor with a reaction volume of 5.5 mL at a flow rate of 25 mL / min. At a temperature of 25°C, a current of 500 mA was applied. After continuous sampling for 2 minutes, the reaction liquid flowing out of the microreactor was collected. The collected reaction liquid was adjusted to pH 3 with 10% dilute hydrochloric acid and allowed to stand for crystallization to obtain the target product 2 with a yield of 94%.

[0070] Example 8: Synthesis of Compound 2.

[0071] Using an electrochemical microreactor with a modified comb-tooth graphite electrode structure of c-1, a 0.5% mass fraction of rifamycin SV filtrate was pumped into an electrochemical microreactor with a reaction volume of 5.5 mL at a flow rate of 10 mL / min. At a temperature of 25°C, a current of 200 mA was applied. After continuous sampling for 2 minutes, the reaction liquid flowing out of the microreactor was collected. The collected reaction liquid was adjusted to pH 3 with 10% dilute hydrochloric acid and allowed to stand for crystallization to obtain the target product 2 with a yield of 92%.

[0072] Example 9: Synthesis of Compound 2.

[0073] Using an electrochemical microreactor with a modified comb-tooth graphite electrode structure of c-1, 0.5% of the mass fraction of rifamycin SV filtrate was pumped into the electrochemical microreactor with a reaction volume of 5.5 mL at a flow rate of 5 mL / min. At a temperature of 25°C, a current of 100 mA was applied. After continuous sampling for 2 minutes, the reaction liquid flowing out of the microreactor was collected. The collected reaction liquid was adjusted to pH 3 with 10% dilute hydrochloric acid and allowed to stand for crystallization to obtain the target product 2 with a yield of 88.

[0074] Example 10: Synthesis of Compound 2.

[0075] Using an electrochemical microreactor with a modified comb-tooth graphite electrode structure of c-1, a 0.6% mass fraction of rifamycin SV filtrate was pumped into an electrochemical microreactor with a reaction volume of 5.5 mL at a flow rate of 25 mL / min. At a temperature of 25°C, a current of 600 mA was applied. After continuous sampling for 2 minutes, the reaction liquid flowing out of the microreactor was collected. The collected reaction liquid was adjusted to pH 3 with 10% dilute hydrochloric acid and allowed to stand for crystallization to obtain the target product 2 with a yield of 94%.

[0076] Example 11: Synthesis of Compound 2.

[0077] Using an electrochemical microreactor with a modified comb-tooth graphite electrode structure of c-1, a 0.4% mass fraction of rifamycin SV filtrate was pumped into an electrochemical microreactor with a reaction volume of 5.5 mL at a flow rate of 25 mL / min. At a temperature of 25°C, a current of 400 mA was applied. After continuous sampling for 2 minutes, the reaction liquid flowing out of the microreactor was collected. The collected reaction liquid was adjusted to pH 3 with 10% dilute hydrochloric acid and allowed to stand for crystallization to obtain the target product 2 with a yield of 89%.

[0078] Example 12: Synthesis of Compound 2.

[0079] Using an electrochemical microreactor with a modified comb-tooth graphite electrode structure of c-1, a 0.5% mass fraction of rifamycin SV filtrate was pumped into an electrochemical microreactor with a reaction volume of 5.5 mL at a flow rate of 25 mL / min. At a temperature of 45°C, a current of 500 mA was applied. After continuous sampling for 2 minutes, the reaction liquid flowing out of the microreactor was collected. The collected reaction liquid was adjusted to pH 3 with 10% dilute hydrochloric acid and allowed to stand for crystallization to obtain the target product 2 with a yield of 92%.

[0080] Example 13: Synthesis of Compound 2.

[0081] Using an electrochemical microreactor with a modified comb-tooth graphite electrode structure of c-1, a 0.5% mass fraction of rifamycin SV filtrate was pumped into an electrochemical microreactor with a reaction volume of 5.5 mL at a flow rate of 25 mL / min. Under a temperature of 55°C, a current of 500 mA was applied. After continuous injection for 2 minutes, the reaction liquid flowing out of the microreactor was collected. The collected reaction liquid was adjusted to pH 3 with 10% dilute hydrochloric acid, and the target product 2 was crystallized by standing, with a yield of 90%. Comparative Example 1:

[0082] At 25°C, 20 mL of 0.5% rifamycin SV filtrate was added to a 50 mL three-necked round-bottom flask equipped with a c-1 modified graphite carbon sheet (100 mm x 150 mm) anode and an iron sheet (40 mm x 40 mm x 0.2 mm) cathode, the current was controlled to 10 mA, the reaction time was 2 h, and the product was identified by TLC. 10% dilute hydrochloric acid was added to adjust the pH to 3, butyl acetate was extracted, and the target product rifamycin S was obtained by concentration and recrystallization with a yield of 39%.

[0083] Comparative Example 2:

[0084] At 25°C, 20 mL of 0.5% rifamycin SV filtrate was added to a 50 mL three-necked round-bottom flask equipped with a c-1 modified graphite carbon sheet (100 mm x 150 mm) anode and an iron sheet (40 mm x 40 mm x 0.2 mm) cathode, the current was controlled to 10 mA, the reaction time was 4 h, and the product was identified by TLC. 10% dilute hydrochloric acid was added to adjust the pH to 3, butyl acetate was extracted, and the target product rifamycin S was obtained by concentration and recrystallization with a yield of 45%.

[0085] Comparative Example 3:

[0086] At 25°C, 20 mL of 0.5% rifamycin SV filtrate was added to a 50 mL three-necked round-bottom flask equipped with a c-1 modified graphite carbon sheet (100 mm x 150 mm) anode and an iron sheet (40 mm x 40 mm x 0.2 mm) cathode, the current was controlled to 10 mA, the reaction time was 6 h, and the product was identified by TLC. 10% dilute hydrochloric acid was added to adjust the pH to 3, butyl acetate was extracted, and the target product rifamycin S was obtained by concentration and recrystallization with a yield of 44%.

[0087] Comparative Example 4:

[0088] At 25°C, 20 mL of 0.5% rifamycin SV filtrate was added to a 50 mL three-necked round-bottom flask equipped with a c-1 modified graphite carbon sheet (100 mm x 150 mm) anode and an iron sheet (40 mm x 40 mm x 0.2 mm) cathode, the current was controlled to 40 mA, the reaction time was 1 h, and the product was identified by TLC. 10% dilute hydrochloric acid was added to adjust the pH to 3, butyl acetate was extracted, and the target product rifamycin S was obtained by concentration and recrystallization with a yield of 41%.

[0089] Comparative Example 5:

[0090] At 25°C, 20 mL of 0.5% rifamycin SV filtrate was added to a 50 mL three-necked round-bottom flask equipped with a c-1 modified graphite carbon sheet (100 mm x 150 mm) anode and an iron sheet (40 mm x 40 mm x 0.2 mm) cathode, the current was controlled to 80 mA, the reaction time was 0.5 h, and the product was identified by TLC. 10% dilute hydrochloric acid was added to adjust the pH to 3, extracted with butyl acetate, concentrated and recrystallized to obtain the target product rifamycin S, with a yield of 44%.

[0091] The above comparative test results show that the yield and Faraday efficiency are very low when using kettle electrosynthesis.

[0092] The present invention provides a concept and method for preparing rifamycin S by continuous flow electrochemical oxidation of rifamycin SV based on modified graphite carbon electrodes at a microscale. There are many methods and approaches to implement 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 principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention. All components not specified in this embodiment can be implemented using existing technologies.

Claims

1. A method for continuously electrochemically synthesizing rifamycin S from rifamycin SV at a microscale, characterized in that: The filtrate containing rifamycin SV is pumped into a microfluidic electrochemical reactor for reaction, and the reaction solution is collected, acidified, and crystallized to obtain rifamycin S; The micro-flow field electrochemical reactor uses a modified graphite comb structure as an anode and an iron comb structure as a cathode, and a channel formed by the modified graphite comb structure and the iron comb structure intersecting each other in the same plane serves as an electrochemical micro-reaction channel; The modified graphite comb structure is prepared by reducing and coupling the surface of a common graphite comb electrode with 4-(carboxymethyl)benzene diazonium salt, and then condensing the obtained carboxylic acid tail with an N-phenyl-substituted dihydrophenazine compound after chlorination, wherein the structural formula of the N-phenyl-substituted dihydrophenazine compound is: The R substituent is any one of H, alkyl, halogen, alkoxy, phenyl, and cyano.

2. The method according to claim 1, characterized in that The modification process of the common graphite comb electrode comprises the following steps: (1) After washing the common graphite comb electrode, use it as the positive and negative electrodes of the electrochemical microreactor, prepare a 4-(carboxymethyl)benzene diazonium salt aqueous solution, add concentrated sulfuric acid as an electrolyte, apply a voltage at a certain temperature, and pump it into the electrochemical microreactor at a certain flow rate for a certain period of time; (2) flushing the electrochemical microreactor, and then pumping the anhydrous dichloromethane solution of SOCl2 into the electrochemical microreactor at a certain flow rate for a certain period of time; (3) Pumping the anhydrous dichloromethane solution of the dihydrophenazine compound into the electrochemical microreactor at a certain flow rate and allowing the solution to flow continuously for a certain period of time.

3. The method according to claim 2, characterized in that The reaction conditions in step (1) are as follows: prepare a 0.02-0.03M aqueous solution of 4-(carboxymethyl)benzenediazonium salt, add 6-9 times the equivalent of concentrated sulfuric acid as an electrolyte, apply a voltage of 0.2V at a temperature of 20-30°C, pump into the electrochemical microreactor at a flow rate of 0.4-0.6mL / min, and continue flowing for 20-30min.

4. The method according to claim 2, characterized in that: In step (2), a 0.02-0.03M anhydrous dichloromethane solution of SOCl2 is prepared, and the solution is pumped into the electrochemical microreactor at a flow rate of 0.4-0.6mL / min at a temperature of 20-30°C, and the flow is continued for 20-30min. In step (3), a 0.02-0.03M anhydrous dichloromethane solution of a dihydrophenazine compound is prepared, and the solution is pumped into the electrochemical microreactor at a flow rate of 0.4-0.6mL / min at a temperature of 20-30°C, and the flow is continued for 30-40min.

5. The method according to claim 1, characterized in that The modified graphite comb teeth and the iron comb teeth have an adjacent comb teeth spacing of 1 to 4 mm after crossing, and the electrode thickness of the modified graphite comb teeth and the iron comb teeth is 2 to 6 mm; the length of the electrochemical micro-reaction channel is 500 to 1000 mm, and the volume is 2 to 24 mL.

6. The method according to claim 1, characterized in that The mass fraction of the rifamycin SV filtrate is 0.3-0.6%.

7. The method according to claim 1, characterized in that The reaction temperature of the reaction is 20-70°C.

8. The method according to claim 1, characterized in that The reaction current of the rifamycin SV filtrate in the microreactor is 20-2000 mA, preferably 100-800 mA.

9. The method according to claim 1, characterized in that: The flow rate of the rifamycin SV filtrate flowing through the electrochemical micro-reaction channel is 1-100 mL / min, preferably 10-50 mL / min.

10. The method according to claim 1, characterized in that The acidification is to adjust the pH to 1-4 with acid, and then stand for crystallization to obtain rifamycin S through solid-liquid separation.

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