A method for synthesizing cefotaxime using a microreactor

Abstract

This invention belongs to the field of pharmaceutical synthesis technology and provides a method for synthesizing cefotaxime using a microreactor. The method utilizes a microreactor to disperse an alkaline catalyst, avoiding localized over-alkaliness and solving the problems of low mass transfer efficiency, uneven mixing, and consequently low cefotaxime yield, high impurities, and low production efficiency. The mass transfer scale of a microreactor can typically reach the micrometer level, achieving uniform and ultrafast mixing within milliseconds. Its mass transfer efficiency is more than 100 times that of a traditional stirred tank reactor. The use of a microreactor allows for precise control of the reaction process. Data from the examples show that the method provided by this invention achieves a molar yield of cefotaxime of 92.2%–96.1%.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, and in particular to a method for synthesizing cefotaxime using a microreactor. Background Technology

[0002] Cefotaxime is a third-generation cephalosporin semi-synthetic broad-spectrum antibiotic. It features a broad antibacterial spectrum, strong antibacterial activity, low toxicity, and stability against β-lactamases. It exhibits extremely high antibacterial activity against hemolytic streptococci, pneumococci, Haemophilus influenzae, and meningococci, especially against Enterobacteriaceae, and strongly inhibits most anaerobic bacteria. Clinically, it is widely used to treat sepsis, purulent meningitis, and infections of the respiratory tract, urinary tract, biliary tract, bones and joints, skin and soft tissues, abdominal cavity, digestive tract, ENT, and genitals caused by susceptible bacteria. It can also be used for infectious diseases caused by weakened immune function and decreased antibody cells.

[0003] The commonly used method for synthesizing cefotaxime acid involves dissolving 7-aminocephalosporanic acid (7-ACA) in a mixture of tetrahydrofuran and water, and then reacting it with 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-thioacetic acid phenylpyrothiazolium ester (AE-active ester) to generate cefotaxime acid. This process has been industrialized, but tetrahydrofuran is highly reactive, and industrial production is prone to safety accidents. Therefore, this method is not the optimal method for industrial production.

[0004] The existing method involves adding 7-ACA solid and AE-active lipid solid to a mixed solvent system composed of dichloromethane and a co-solvent, followed by the slow dropwise addition of an alkaline catalyst. Subsequent extraction, adsorption, crystallization, washing, and drying yield cefotaxime crystals. However, this process is currently performed in a stirred tank, resulting in low mass transfer efficiency and uneven reaction within the system. This leads to significant localized over-alkaliness during the alkaline catalyst addition process, causing degradation of both raw materials and products within the stirred tank. Consequently, the cefotaxime yield is low, and reactants are wasted. Furthermore, the degradation generates a high level of maximum unknown impurities, which are crucial quality indicators of the drug and directly impact its safety. While reducing the alkaline catalyst dropwise can mitigate the localized over-alkaliness problem to some extent, it significantly extends the reaction time by approximately three times, resulting in extremely low production efficiency. Summary of the Invention

[0005] In view of this, the object of the present invention is to provide a method for synthesizing cefotaxime using a microreactor. The method provided by the present invention achieves a high yield of cefotaxime and a short synthesis time.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides a method for synthesizing cefotaxime using a microreactor, comprising the following steps:

[0008] 7-ACA, AE-active lipids, antioxidants, cosolvents and organic solvents are mixed to obtain a suspension;

[0009] The suspension is transported as a continuous phase into the microreactor and flows through the microchannel of the microreactor. The suspension flowing through the microchannel flows back from the outlet of the microreactor to the container holding the suspension, thereby realizing the self-circulation of the suspension between the microreactor and the container holding the suspension.

[0010] At the start of the self-circulation, the alkaline catalyst is transported as the dispersed phase to the dispersion chamber of the microreactor. The alkaline catalyst is dispersed into high-speed micron-sized droplets by the dispersion membrane in the dispersion chamber and enters the microchannel. During the process of the micron-sized droplets entering the microchannel, they are sheared and strongly mass-transferred and mixed by the continuous phase suspension in the microchannel. Then, they flow out of the microreactor through the circulation pipeline and return to the container holding the suspension until the alkaline catalyst is completely added.

[0011] After the alkaline catalyst is added, the mixture in the microreactor is drained and returned to the container holding the suspension to continue the reaction and obtain the cefotaxime.

[0012] Preferably, in the suspension, the concentration of 7-ACA is 0.1-10 mol / L, the concentration of AE-active lipid is 0.1-10 mol / L, the concentration of antioxidant is 0.1-10 mol / L, and the volume ratio of organic solvent to co-solvent is 1:10-10:1.

[0013] Preferably, the antioxidant includes one or more of sodium sulfide, sodium dithionite, sodium thiosulfate, and sodium sulfite;

[0014] The organic solvent includes dichloromethane;

[0015] The co-solvent includes one or more of methanol, ethanol, water, and acetone.

[0016] Preferably, the temperature of the suspension is -10 to 25°C.

[0017] Preferably, the circulation flow rate of the suspension is 10 to 1000 mL / min.

[0018] Preferably, the alkaline catalyst comprises one or more of diethylamine, triethylamine, tetramethylguanidine, methylbutyramide, and ammonia.

[0019] Preferably, the molar ratio of 7-ACA to the alkaline catalyst is 0.1 to 10:1.

[0020] Preferably, the alkaline catalyst is at room temperature.

[0021] Preferably, the flow rate of the alkaline catalyst is 0.1–100 mL / min, and the addition time is 20–90 min.

[0022] Preferably, after the reaction is completed, the method further includes: sequentially extracting, decolorizing, crystallizing, filtering, washing and drying the obtained reaction solution to obtain the cefotaxime.

[0023] This invention provides a method for synthesizing cefotaxime using a microreactor, comprising the following steps: mixing 7-ACA, AE-active lipids, an antioxidant, a co-solvent, and an organic solvent to obtain a suspension; conveying the suspension as a continuous phase into a microreactor and flowing through microchannels of the microreactor; the suspension flowing through the microchannels returning from the outlet of the microreactor to a container holding the suspension, thereby achieving self-circulation of the suspension between the microreactor and the container holding the suspension; at the start of the self-circulation, an alkaline catalyst is used as... The dispersed phase is transported to the dispersion chamber of the microreactor. The alkaline catalyst is dispersed into high-speed micron-sized droplets by a dispersion membrane in the dispersion chamber and enters the microchannel. During the process of entering the microchannel, the micron-sized droplets are sheared and strongly mass-transferred and mixed by the continuous phase suspension in the microchannel. Then, they flow out of the microreactor through the circulation pipeline and return to the container holding the suspension until the alkaline catalyst is completely added. After the alkaline catalyst is completely added, the mixed liquid in the microreactor is emptied and returned to the container holding the suspension to continue the reaction.

[0024] The method of this invention utilizes a microreactor to disperse an alkaline catalyst, avoiding localized over-alkaliness and thus improving the preparation of cefotaxime. This addresses problems such as low mass transfer efficiency, uneven mixing leading to low yield, high impurities, and low production efficiency. The mass transfer scale of a microreactor typically reaches the micrometer level, achieving uniform and ultrafast mixing within milliseconds. Its mass transfer efficiency is more than 100 times that of a traditional stirred tank reactor. The use of a microreactor allows for precise control of the reaction process. Data from the examples show that the method provided by this invention achieves a molar yield of cefotaxime of 92.2%–96.1%.

[0025] Furthermore, after the reaction is completed, the process further includes: sequentially extracting, decolorizing, crystallizing, filtering, washing, and drying the resulting reaction solution to obtain the cefotaxime. The post-processing method of this invention improves the purity of cefotaxime. Attached Figure Description

[0026] Figure 1 This is a diagram of the equipment used in the method for synthesizing cefotaxime using a microreactor provided by the present invention. Detailed Implementation

[0027] This invention provides a method for synthesizing cefotaxime using a microreactor, comprising the following steps:

[0028] 7-ACA, AE-active lipids, antioxidants, cosolvents and organic solvents are mixed to obtain a suspension;

[0029] The suspension is transported as a continuous phase into the microreactor and flows through the microchannel of the microreactor. The suspension flowing through the microchannel flows back from the outlet of the microreactor to the container holding the suspension, thereby realizing the self-circulation of the suspension between the microreactor and the container holding the suspension.

[0030] At the start of the self-circulation, the alkaline catalyst is transported as the dispersed phase to the dispersion chamber of the microreactor. The alkaline catalyst is dispersed into high-speed micron-sized droplets by the dispersion membrane in the dispersion chamber and enters the microchannel. During the process of the micron-sized droplets entering the microchannel, they are sheared and strongly mass-transferred and mixed by the continuous phase suspension in the microchannel. Then, they flow out of the microreactor through the circulation pipeline and return to the container holding the suspension until the alkaline catalyst is completely added.

[0031] After the alkaline catalyst is added, the mixture in the microreactor is drained and returned to the container holding the suspension to continue the reaction and obtain the cefotaxime.

[0032] Unless otherwise specified, all raw materials used in this invention are preferably commercially available products.

[0033] This invention involves mixing 7-ACA, AE-active lipids, antioxidants, cosolvents, and organic solvents to obtain a suspension.

[0034] In this invention, the antioxidant preferably includes one or more of sodium sulfide, sodium dithionite, sodium thiosulfate, and sodium sulfite.

[0035] In this invention, the organic solvent preferably includes dichloromethane.

[0036] In this invention, the co-solvent preferably includes one or more of methanol, ethanol, water, and acetone.

[0037] In this invention, the concentration of 7-ACA in the suspension is preferably 0.1-10 mol / L, the concentration of AE-active lipid is preferably 0.1-10 mol / L, the concentration of antioxidant is preferably 0.1-10 mol / L, and the volume ratio of organic solvent to co-solvent is preferably 1:10-10:1.

[0038] The present invention does not impose specific limitations on the mixing method of the 7-ACA, AE-active lipid, antioxidant, cosolvent and organic solvent, and any operation known to those skilled in the art can be used.

[0039] In this invention, the suspension is preferably contained in a four-necked flask.

[0040] After obtaining the suspension, the present invention transports the suspension as a continuous phase into a microreactor and through the microchannel of the microreactor. The suspension flowing through the microchannel flows back from the outlet of the microreactor to the container holding the suspension, thereby realizing the self-circulation of the suspension between the microreactor and the container holding the suspension.

[0041] In this invention, the microreactor preferably includes a microchannel, a dispersion chamber, and a dispersion membrane; the dispersion membrane is used to separate the dispersion chamber and the microchannel.

[0042] In this invention, the temperature of the suspension is preferably -10 to 25°C. In this invention, the suspension is preferably pumped into the microreactor using a transfer pump.

[0043] In this invention, the circulation flow rate of the suspension is preferably 10 to 1000 mL / min.

[0044] After the suspension achieves self-circulation between the microreactor and the container holding the suspension, at the start of the self-circulation, the alkaline catalyst is transported as the dispersed phase to the dispersion chamber of the microreactor. The alkaline catalyst is dispersed into high-speed micron-sized droplets by the dispersion membrane in the dispersion chamber and enters the microchannel. During the process of the micron-sized droplets entering the microchannel, they are sheared and strongly mass-mixed by the continuous phase suspension in the microchannel, and then flow out of the microreactor through the circulation pipeline and back into the container holding the suspension until the alkaline catalyst is completely added.

[0045] In this invention, the alkaline catalyst preferably comprises one or more of diethylamine, triethylamine, tetramethylguanidine, methylbutylamide, and ammonia. In this invention, the molar ratio of 7-ACA to the alkaline catalyst is preferably 0.1 to 10:1. In this invention, the temperature of the alkaline catalyst is preferably room temperature.

[0046] In this invention, the alkaline catalyst is preferably pumped into the microreactor via a delivery pump. The flow rate of the alkaline catalyst is preferably 0.1–100 mL / min, and the addition time is preferably 20–90 min.

[0047] After the alkaline catalyst is added, the present invention drains the mixture in the microreactor and returns it to the container holding the suspension to continue the reaction.

[0048] In this invention, the reaction temperature is preferably -10 to 25°C; the reaction is preferably carried out under stirring conditions. During the reaction, the reaction time is preferably controlled by detecting 7-ACA residue; the reaction is considered complete when the 7-ACA residue in the reaction system is ≤1.0%.

[0049] After the reaction is completed, the present invention preferably further includes: extracting, decolorizing, crystallizing, filtering, washing and drying the obtained reaction solution in sequence to obtain the cefotaxime.

[0050] In this invention, the extraction reagent is preferably one or more of an ethanol solution, ethanol, and water. After extraction, the invention preferably includes collecting the organic phase.

[0051] In this invention, the decolorizing reagent is preferably one or more of activated carbon, alumina, and adsorption resin.

[0052] In this invention, the crystallization method is preferably precipitation crystallization.

[0053] In this invention, the washing reagent preferably includes one or more of ethanol solution, ethanol, and water.

[0054] Figure 1 The diagram below shows the equipment used in the method for synthesizing cefotaxime using a microreactor provided by this invention. Figure 1 The method provided by the present invention will be described.

[0055] 7-ACA, AE-active lipids, antioxidants, co-solvents, and organic solvents are mixed in a four-necked flask to obtain a suspension. The suspension in the four-necked flask is pumped into the microchannel of a microreactor by a transfer pump, then flows out of the microreactor through the microchannel, and then flows back into the four-necked flask, realizing the self-circulation of the suspension between the microreactor and the four-necked flask. After self-circulation, the alkaline catalyst is pumped into the dispersion chamber of the microreactor by a transfer pump. In the dispersion chamber, the alkaline catalyst is dispersed into high-speed micron-sized droplets by a dispersion membrane and enters the microchannel. During the process of entering the microchannel, the micron-sized droplets are sheared and strongly mass-transferred and mixed by the continuous phase suspension in the microchannel, and then flow out of the microreactor and back into the four-necked flask through the circulation pipeline until the alkaline catalyst is completely added. After the alkaline catalyst is completely added, the mixture in the microreactor is emptied and returned to the four-necked flask to continue the reaction.

[0056] The following detailed description of the method for synthesizing cefotaxime using a microreactor provided by the present invention, with reference to specific embodiments, should not be construed as limiting the scope of protection of the present invention.

[0057] The conditions and yields of Examples 1-5 and Comparative Example 1 are shown in Tables 1 and 2.

[0058] Table 1 Conditions of Examples 1-5 and Comparative Example 1

[0059]

[0060]

[0061] Table 2 Conditions of Examples 1-5 and Comparative Example 1

[0062]

[0063] The post-processing steps in Examples 1-5 are as follows: the reaction solution is extracted with water and the organic phase is collected; activated carbon is added to the organic phase for decolorization to obtain a decolorized crude product; the decolorized crude product is placed in a flask for precipitation and crystallization, then filtered, the collected filter residue is washed with water three times, and then dried to obtain the final product.

[0064] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing Cefotaxime using a microreactor, characterized in that, The method comprises the following steps: mixing 7-ACA, AE-active lipid, antioxidant, cosolvent and organic solvent to obtain a suspension; feeding the suspension as a continuous phase into a microreactor and flowing through the microchannels of the microreactor, and flowing back from the outlet of the microreactor into the container containing the suspension to realize self-circulation of the suspension between the microreactor and the container containing the suspension; when the self-circulation starts, feeding a basic catalyst as a dispersed phase into the dispersion chamber of the microreactor, dispersing the basic catalyst into high-speed micron-sized droplets by a dispersion membrane in the dispersion chamber, and entering into the microchannels, in the process of entering into the microchannels, the micron-sized droplets are sheared and strongly mass-transfer-mixed by the continuous phase suspension in the microchannels, and then flow out of the microreactor through the circulation pipeline and flow back into the container containing the suspension until the basic catalyst is added up; after the basic catalyst is added up, emptying the mixed solution in the microreactor and flowing back into the container containing the suspension to continue the reaction to obtain the ceftiofur; the organic solvent is dichloromethane; the cosolvent is acetone; the antioxidant is sodium sulfite; the basic catalyst is methylbutylamide, and the temperature of the basic catalyst is normal temperature; in the suspension, the concentration of 7-ACA is 2 mol / L, the concentration of AE-active lipid is 2 mol / L, and the concentration of antioxidant is 0.8 mol / L, and the volume ratio of organic solvent to cosolvent is 2:1; the temperature of the suspension is 0℃; the circulation flow rate of the suspension is 100 mL / min; the flow rate of the basic catalyst is 1.0 mL / min, and the adding time is 50 min; the molar ratio of 7-ACA to the basic catalyst is 2:1; the temperature of the reaction is 10℃; after the reaction is completed, the obtained reaction solution is sequentially subjected to extraction, decolorization, crystallization, filtration, washing and drying to obtain the ceftiofur; the reagent for extraction is one or more of ethanol solution, ethanol and water; the reagent for decolorization is one or more of activated carbon, alumina and adsorption resin; the crystallization mode is precipitation crystallization; the reagent for washing includes one or more of ethanol solution, ethanol and water.

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