A method for continuous flow electrochemical synthesis of rifamycin S from rifamycin SV at microscale

Abstract

The application discloses a method for continuously electrochemically synthesizing rifamycin S from rifamycin SV at a microscale, wherein filtrate containing rifamycin SV is pumped into a micro-flow field electrochemical reactor for reaction, and rifamycin S is obtained after acidification and crystallization of the reaction solution. The micro-flow field electrochemical reactor uses a modified graphite comb structure as an anode and an iron comb structure as a cathode, and the modified graphite comb structure and the iron comb structure are crossed to form an electrochemical micro-reaction channel. The surface of the modified graphite comb electrode is obtained by modification on the surface of a common graphite comb electrode. The method can avoid the use of exogenous oxidants and organic extraction reagents, effectively improve the reaction conversion rate, greatly shorten the reaction time, and is simple, safe and stable, and can save the post-treatment cost and is more green and efficient.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and relates to a method for continuously preparing rifamycin S, and in particular to a method for continuously preparing rifamycin S by oxidizing rifamycin SV using a micro-flow field electrochemical technology. Background Art

[0002] Rifamycin S is a broad-spectrum antibiotic and a key intermediate in 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 the bacteria. Rifamycin S is usually used in conjunction with other anti-tuberculosis drugs (such as isoniazid, pyrazinamide, etc.) to reduce the development 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 current rifamycin S production process involves filtering the filtrate of rifamycin SV to obtain a filtrate, oxidizing the filtrate to obtain rifamycin S, and then separating the rifamycin S from the filtrate through steps such as acid-base adjustment and organic solvent extraction. Finally, the rifamycin S is refined, impurities removed, and crystallized and dried. However, the oxidation process often requires the addition of large amounts of low-concentration sodium hypochlorite or hydrogen peroxide as an oxidizing agent, introducing large amounts of aqueous solution. Even after acidification, rifamycin S is difficult to precipitate, requiring extraction with large amounts of butyl acetate. This method is highly hazardous during production and generates significant amounts of wastewater, increasing production costs and hindering environmental protection.

[0004] Electrosynthesis uses electrons to drive redox reactions, eliminating 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, enabling efficient and controllable reactions, and can even produce compounds that are difficult to obtain using traditional methods. In addition, electrosynthesis can easily achieve high conversion rates, high yields, and high selectivity under mild reaction conditions, and both the reaction rate and reaction limit are 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 applications. Effectively improving the specific surface area, mass transfer / heat efficiency, and achieving precise control of the electrode spacing are the keys 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 the mass transfer and heat transfer efficiency and reaction rate by 2-3 orders of magnitude, reduce the online reaction volume several times, and improve the reaction selectivity and reduce side reactions through continuous flow and low back mixing, thereby effectively realizing the green and industrial application of electrosynthesis. In addition, the use of microchannels as flow units in 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 a key component of flow chemistry systems, has enormous potential for application in the chemical industry. Advantages of electrosynthesis microreactors include high atom economy, environmental friendliness, safety, and ease of scale-up, making them considered a versatile technology for pharmaceutical processing and chemical engineering. Reducing the distance between electrodes and increasing the electrode area effectively lowers ion transport resistance, enabling controllable electrosynthesis. This overcomes the shortcomings of traditional batch reactors and has the potential to 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 address the deficiencies of the existing technology and provide a method for the continuous flow electrochemical synthesis of rifamycin S from rifamycin SV at a microscale, so as to solve the problems of poor safety, serious pollution, large amount of wastewater, and high cost in the existing technology.

[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 liquid is collected, acidified, and crystallized to obtain rifamycin S;

[0009] In which, the micro-flow field 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 micro-reaction channel; preferably, the two comb tooth structures intersect evenly so that the formed channel size is consistent.

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

[0011]

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

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

[0014]

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

[0016] (1) After washing, ordinary graphite comb electrodes are used as the positive and negative electrodes of the electrochemical microreactor, and a 4-(carboxymethyl)benzenediazonium salt aqueous solution is prepared. Concentrated sulfuric acid is added as an electrolyte. After applying a voltage at a certain temperature, the electrolyte is pumped into the electrochemical microreactor at a certain flow rate and continuously flows 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 continuously flowing for a certain period of time.

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

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

[0021] In step (2), a 0.02-0.03M solution of SOCl2 in anhydrous dichloromethane is prepared and 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 solution of dihydrophenazine compound in anhydrous dichloromethane is prepared and 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 0.025M solution of SOCl2 in anhydrous dichloromethane is prepared and pumped into the electrochemical microreactor at a flow rate of 0.5mL / min at a temperature of 25°C, and the flow is continuous for 20min; in step (3), a 0.025M solution of dihydrophenazine compound in anhydrous dichloromethane is prepared and pumped into the electrochemical microreactor at a flow rate of 0.5mL / min at a temperature of 25°C, and the flow is continuous for 30min.

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

[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 to 100 mL / min, preferably 10 to 50 mL / min.

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

[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. At the microscale, modified graphite electrodes are used to continuously electrooxidize rifamycin SV to prepare rifamycin S, avoiding the use of exogenous oxidants and organic extraction reagents, effectively improving the reaction conversion rate, significantly 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, saving post-processing costs and being more green and efficient.

[0033] (2) The method can effectively avoid side reactions, compared with the traditional chemical oxidation method, continuous flow, low back mixing, and the target product can be separated in time to avoid 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 application has excellent scale-up results and can realize continuous production, having good industrial utilization value.

[0035] (4) The present application uses a modified graphite electrode, and the catalyst is connected to the graphite electrode in the form of a covalent bond, and the electrolysis conditions are relatively mild. No reaction effect decline and catalyst shedding phenomenon are observed after continuous sampling for 24 hours. The catalytic efficiency is higher, the catalyst can be reused, and the process stability is better. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1 CV diagram of comb-shaped graphite electrode C-1;

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

[0038] Figure 3 Liquid phase diagram of crystallized product 2 of Example 1;

[0039] Figure 4 Schematic diagram of reaction flow;

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

[0041] Figure 6 Assembled schematic diagram of the electrochemical reactor. DETAILED DESCRIPTION

[0042] The above and / or other aspects of the present application will become more apparent by describing in detail the following embodiments with reference to the attached drawings.

[0043] In the following examples, the experimental methods described are conventional methods unless otherwise specified; and the reagents and materials described are commercially available unless otherwise specified.

[0044] In the following examples, the filtrate containing rifamycin SV is obtained by filtering the fermentation broth from the fermentation workshop after adding zinc sulfate, and 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 represents rifamycin SV, compound 2 represents rifamycin S, and c-1 to c-4 represent modified comb-tooth graphite electrode structures. 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 examples, a microfluidic electrochemical reactor was constructed using a modified graphite comb structure as the anode and an iron comb structure as the cathode. The modified graphite comb structure and the iron comb structure intersected in the same plane to form an electrochemical microreaction channel. The spacing between adjacent modified graphite comb teeth and iron comb teeth was 0.5 to 8 mm, and the thickness of the modified graphite comb and iron comb electrodes was 2 to 6 mm. The electrochemical microreaction channel had a length of 500 to 2000 mm and a volume of 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 the microflow field electrochemical reactor, in which two comb-tooth electrodes, a modified graphite comb-tooth structure and an iron comb-tooth structure, are arranged in the electrolytic cell. A cover plate is provided on the electrolytic cell and fixed by a base. Figure 6 This is an assembly diagram. 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. The electrode spacing is 1 mm, the cell path height is 4 mm, the cell path length is 1260 mm, and the residence volume is 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 later use. Using an electrochemical microreactor (V = 5.5 mL) with the comb-tooth graphite electrode as the positive and negative electrodes, prepare a 0.025 M aqueous solution of 4-(carboxymethyl)benzenediazonium salt and add 8 equivalents of concentrated sulfuric acid as the electrolyte. At a temperature of 25°C, apply a voltage of 0.2 V and pump the solution into the electrochemical microreactor at a flow rate of 0.5 mL / min. Continue flowing for 20 minutes.

[0055] Step 2: The electrochemical microreactor was then flushed with deionized water, ethanol, and anhydrous dichloromethane at a flow rate of 0.5 mL / min at 25°C for approximately 30 minutes. A 0.025 M solution of SOCl2 in anhydrous dichloromethane was prepared and pumped into the electrochemical microreactor at a flow rate of 0.5 mL / min at 25°C for 20 minutes.

[0056] Step 3: Prepare a 0.025M solution of N-phenyldihydrophenazine in anhydrous dichloromethane and pump it into the electrochemical microreactor at a flow rate of 0.5 mL / min at a temperature of 25°C. Continue flowing for 30 minutes to obtain the modified comb-tooth graphite electrode C-1. The CV graph of the modified comb-tooth graphite electrode C-1 is shown in Figure 2. Figure 1 As shown, it proves 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. 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 800 mA current 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 wt% dilute hydrochloric acid and allowed to stand for crystallization to obtain the target product 2 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 having a modified comb-tooth graphite electrode structure of c-1 was used to pump a 0.5% mass fraction of rifamycin SV fermentation broth 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 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 allowed to stand for crystallization to obtain the target product 2 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 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 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 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 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 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 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, a 0.5% 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 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 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 the 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 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 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 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 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, 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 5 mL / min. At a temperature of 25°C, a current of 100 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 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 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 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 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 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 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 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 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 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 allowed to stand for crystallization to obtain the target product 2 with a yield of 90%. Comparative Example 1:

[0082] At 25°C, 20 mL of the 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 at 10 mA and the reaction time was 2 h. The product was identified by TLC. The pH was adjusted to 3 by adding 10% dilute hydrochloric acid. The mixture was extracted with butyl acetate, concentrated, and recrystallized to obtain the desired product, rifamycin S, in a 39% yield.

[0083] Comparative Example 2:

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

[0085] Comparative Example 3:

[0086] Example 1 : 20 mL of 0.5% rifamycin SV filtrate was added to a 50 mL three necked round flask equipped with a c-1 modified graphite carbon sheet (100 mm x 150 mm) anode and iron sheet (40 mm x 40 mm x 0.2 mm) cathode at 25°C. The current was controlled at 10 mA and the reaction time was 4 h. The product was identified by TLC. The pH was adjusted to 3 by adding 10% dilute hydrochloric acid and the product was extracted with butyl acetate. The target product, rifamycin S, was obtained by recrystallization after concentration and the yield was 45%.

[0087] Comparative Example 4:

[0088] Example 1 : 20 mL of 0.5% rifamycin SV filtrate was added to a 50 mL three necked round flask equipped with a c-1 modified graphite carbon sheet (100 mm x 150 mm) anode and iron sheet (40 mm x 40 mm x 0.2 mm) cathode at 25°C. The current was controlled at 10 mA and the reaction time was 4 h. The product was identified by TLC. The pH was adjusted to 3 by adding 10% dilute hydrochloric acid and the product was extracted with butyl acetate. The target product, rifamycin S, was obtained by recrystallization after concentration and the yield was 45%.

[0089] Comparative Example 5:

[0090] Example 1 : 20 mL of 0.5% rifamycin SV filtrate was added to a 50 mL three necked round flask equipped with a c-1 modified graphite carbon sheet (100 mm x 150 mm) anode and iron sheet (40 mm x 40 mm x 0.2 mm) cathode at 25°C. The current was controlled at 10 mA and the reaction time was 4 h. The product was identified by TLC. The pH was adjusted to 3 by adding 10% dilute hydrochloric acid and the product was extracted with butyl acetate. The target product, rifamycin S, was obtained by recrystallization after concentration and the yield was 45%.

[0091] The results of the above comparative tests show that the yield and Faraday efficiency are very low using a tank type electro-synthesis.

[0092] The present invention provides a concept and method for preparing rifamycin S by continuous flow electrochemical oxidation of rifamycin SV at a microscale based on a modified graphite carbon electrode. There are many methods and approaches for implementing this technical solution. The above is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within 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 at a reaction current of 20 to 2000 mA. 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)benzenediazonium salt, and then condensing the obtained carboxylic acid tail with an N-phenyl-substituted dihydrophenazine compound. The specific preparation steps of the modified graphite comb structure are: (1) After washing the ordinary graphite comb electrode, use it as the positive and negative electrodes of the electrochemical microreactor, prepare a 4-(carboxymethyl)benzenediazonium salt aqueous solution, add concentrated sulfuric acid as the electrolyte, apply voltage at a certain temperature, and pump it into the electrochemical microreactor at a certain flow rate. Continue to flow for a certain period of time, and apply a voltage of 0.2 V. (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 an anhydrous dichloromethane solution of an N-phenyl substituted dihydrophenazine compound into the electrochemical microreactor at a certain flow rate and continuously flowing for a certain period of time; Among them, the structural formula of N-phenyl substituted dihydrophenazine compounds is: ， The substituent R is any one of H, alkyl, halogen, alkoxy, phenyl, and cyano.

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

3. The method according to claim 1, characterized in that In step (2), a 0.02-0.03 M anhydrous dichloromethane solution of SOCl2 is prepared, and the solution is pumped into the electrochemical microreactor at a flow rate of 0.4-0.6 mL / min at a temperature of 20-30 ° C, and the flow is continuously allowed to flow for 20-30 min. In step (3), a 0.02-0.03 M anhydrous dichloromethane solution of N-phenyl substituted dihydrophenazine compounds is prepared, and the solution is pumped into the electrochemical microreactor at a flow rate of 0.4-0.6 mL / min at a temperature of 20-30 ° C, and the flow is continuously allowed to flow for 30-40 min.

4. The method according to claim 1, wherein 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.

5. The method according to claim 1, wherein The mass fraction of the rifamycin SV filtrate is 0.3-0.6%.

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

7. The method according to claim 1, characterized in that The current of the rifamycin SV filtrate in the microreactor is 100-800 mA.

8. 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 to 100 mL / min.

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 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 and perform solid-liquid separation to obtain rifamycin S.

Images