Synthesis process of cefotaxime sodium

Abstract

The invention relates to the field of cephalosporin drugs, and particularly discloses a cefotaxime sodium synthesis process which comprises the following steps: mixing cefotaxime sodium, purified water and isopropanol, adding activated carbon, filtering for the first time, then adding dichloromethane, isopropanol and cefotaxime sodium seed crystals, waiting for the solution to separate out crystals, and finally filtering. According to the scheme, research is carried out aiming at the problem of yield fluctuation in industrial production of the cefotaxime sodium, and three key factors, namely the salt-forming agent proportion, the reaction temperature and the solvating-out agent isopropanol (dosage), which have the most obvious influence on the quality of the cefotaxime sodium are selected for optimization. Through response surface method research, a reasonable process parameter range is defined, the yield of the cefotaxime sodium is stably increased and maintained at 91.30%, and a scientific and reliable basis is provided for process adjustment in subsequent industrial production.

Description

Technical Field

[0001] The invention belongs to the field of cephalosporin drugs, and particularly relates to a synthesis process of ceftriaxone sodium. Background Art

[0002] As a third-generation cephalosporin antibiotic, ceftriaxone sodium holds a crucial position in clinical treatment due to its broad-spectrum antimicrobial activity and low toxicity. With the continued growth of global medical demand, the market for ceftriaxone sodium continues to expand, placing higher demands on optimizing its synthesis process. Several mature process routes have been developed for ceftriaxone sodium, primarily involving the condensation reaction of ampicillin with sodium sulfate, the cyclization reaction of the condensation product with thiamine, and the bromoacetylation reaction of the cyclization product. The product is ultimately obtained through hydrolysis, acidification, crystallization, separation, and drying. However, compared with developed countries, my country's ceftriaxone sodium crystallization process is imperfect, resulting in large, unevenly distributed, and easily agglomerated crystals produced domestically, reducing efficacy and shelf life. Studies have shown that solvent content significantly influences the crystallization process, and improper solvent ratios can lead to decreased crystal purity and impurity entrapment. Concerning environmental and safety concerns, the toxic oxazine catalysts used in traditional processes pose a threat to the environment and the health of operators. Organic solvents such as ethanol and methanol are flammable and explosive, posing safety risks. Furthermore, traditional processes suffer from high reaction temperatures, long reaction times, high energy consumption, and numerous side reactions. These inadequately controlled reaction conditions directly impact yield and product purity.

[0003] Therefore, this application will focus on the preparation process of cefotaxime acid to cefotaxime sodium, and optimize the reaction parameters such as reaction temperature, amount of solvent added, and ratio of mixed salt-forming agent through response surface methodology design to examine the effects of these factors on product yield. Summary of the Invention

[0004] The object of the present invention is to provide a synthesis process of ceftriaxone sodium with reasonable process parameters.

[0005] To achieve the above objectives, the present invention provides a process for synthesizing ceftriaxone sodium, comprising the following steps: a. preparing a container, mixing 10 g of cefotaxime acid, 10 ml of purified water, and 25 ml of isopropanol, stirring and dissolving the mixture at a temperature of 15-20° C., gradually adding a salt-forming agent during stirring, and adjusting the pH value to 5.5-6.5; b. adding 0.2 g of activated carbon for decolorization for 30-40 minutes, and filtering to obtain a carbon cake and a filtrate;

[0006] c. The filtrate mentioned in step b was transferred to the reaction flask, the temperature of the filtrate was raised to 15-20 ℃, and then 5g of dichloromethane was added and stirred for 10-15min;

[0007] d. Add 25-30 ml of isopropanol dropwise to the filtrate until the filtrate becomes turbid, then add 0.1 g of cefotaxime sodium seed crystals and grow the crystals for 30-35 min;

[0008] e. Continue to add 100-130ml of isopropanol dropwise. After the addition is complete, cool the solution to 5-10°C and allow the crystals to grow for 1-1.2h. f. Filter the solution mentioned in step e and wash the filter cake with isopropanol. Dry the filter cake in vacuum at 60-70°C.

[0009] The obtained white crystalline powder is the improved ceftriaxone sodium.

[0010] As an improvement of the above solution, in step a, the salt-forming agent includes sodium acetate and sodium isooctanoate, and the ratio of the two is 1:2.

[0011] As an improvement of the above scheme, in step c, the temperature of the filtrate is raised to 15°C.

[0012] As an improvement of the above scheme, in step e, 125 ml of isopropyl alcohol is added dropwise.

[0013] The present invention has the following beneficial effects: This application scheme investigates the yield fluctuation problem in the industrial production of ceftriaxone sodium, optimizing the three key factors that most significantly impact the quality of ceftriaxone sodium: the proportion of the salt-forming agent, the reaction temperature, and the amount of the solvent isopropyl alcohol. Through response surface methodology, a reasonable range of process parameters was identified, resulting in a stable increase in the yield of ceftriaxone sodium, which was maintained at 91.30%. This provides a scientific and reliable basis for subsequent process adjustments in industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 1 is a response surface diagram showing the effect of the amount of isopropyl alcohol and the ratio of the salt-forming agent on the yield under an embodiment;

[0015] Figure 2 1 is a contour diagram showing the effect of the amount of isopropyl alcohol and the ratio of the salt-forming agent on the yield under an embodiment;

[0016] Figure 3 1 is a response surface diagram showing the effects of reaction temperature and salt-forming agent ratio on yield under an embodiment;

[0017] Figure 4 is a contour diagram showing the effects of reaction temperature and salt-forming agent ratio on yield under an embodiment;

[0018] Figure 5 1 is a response surface diagram showing the effects of reaction temperature and isopropyl alcohol dosage on yield under an embodiment;

[0019] Figure 6 1 is a contour diagram showing the effects of reaction temperature and isopropyl alcohol dosage on yield under an embodiment. DETAILED DESCRIPTION

[0020] In the description of the present invention, it should be noted that the terms "center", "longitudinal", "lateral", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "top", "bottom", "top surface", "bottom surface", "inside", "outside", "inside", "outside" and the like to indicate orientations or positional relationships based on the orientations or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore should not be understood as limiting the present invention.

[0021] In the description of the present invention, "several" means one or more, "many" means more than two, "greater than," "less than," and "exceed" are understood to exclude the number itself, while "above," "below," and "within" are understood to include the number itself. The terms "first," "second," and "third" are used solely for descriptive purposes and to distinguish technical features. They are not to be construed as indicating or implying relative importance, or as implicitly specifying the number or order of the technical features indicated.

[0022] In the description of the present invention, it should be noted that, unless otherwise clearly specified or limited, the terms "installed," "connected," "connected," and "set" should be understood in a broad sense. For example, they can refer to fixed connections, detachable connections, or integral connections; they can refer to mechanical connections or electrical connections; they can refer to direct connections or indirect connections through an intermediate medium, or they can refer to internal connections between two components. Those skilled in the art will understand the specific meanings of the above terms in the present invention based on the specific circumstances. The following describes an embodiment of the present invention based on its overall structure.

[0023] The invention discloses a synthesis process of ceftriaxone sodium, which optimizes the ratio and process parameters and improves the yield of ceftriaxone sodium.

[0024] 1. Experimental materials are shown in the table below:

[0025] name batch number company Isopropyl alcohol 230323-1 Sichuan Xilong Science Co., Ltd. Sodium 2-ethylhexanoate S133057-259 Shanghai Aladdin Biochemical Technology Co., Ltd. Sodium acetate S81827 Shanghai MacLean Biochemical Technology Co., Ltd. acetone 180304-1 Sichuan Xilong Science Co., Ltd. dichloromethane A2423204 Shanghai Aladdin Biochemical Technology Co., Ltd. Ceftriaxone AD2311016 Guangxi Kelun Pharmaceutical Co., Ltd. Ceftriaxone sodium seed crystals SBH211201 Guangxi Kelun Pharmaceutical Co., Ltd.

[0026] Table 1 Experimental reagents 2. Experimental instruments are shown in the table below:

[0027] Instrument name model company pH meter PHS-2F Tianjin Tianma Hengji Instrument Co., Ltd. One ten-thousandth electronic balance BSA124S-CW German SARTORIUS company Electric blast drying oven DHG-9075A Shanghai Yiheng Technology Co., Ltd. vacuum drying oven DZF-250 Zhengzhou Great Wall Science, Industry and Trade Co., Ltd. Circulating water multi-purpose vacuum pump SHB-III Xi'an Taikang Biotechnology Co., Ltd. Thermal collector constant temperature heating magnetic stirrer DF-101SA Shanghai Mani Instrument Equipment Co., Ltd. Ultrasonic cleaner KQ-500E Kunshan Ultrasonic Instrument Co., Ltd. Digital constant temperature water bath HH-S1 Changzhou Huaao Instrument Manufacturing Co., Ltd.

[0028] Table 2 Experimental instruments

[0029] 3. Experimental methods:

[0030] a. Prepare a container, mix 10g of cefotaxime acid, 10ml of purified water, and 25ml of isopropanol, and stir at a temperature of 15-20℃.

[0031] Stir to dissolve, gradually add salt-forming agent during stirring, and adjust the pH value to 5.5-6.5;

[0032] b. Add 0.2 g of activated carbon for decolorization for 30-40 min, and filter to obtain a carbon cake and filtrate;

[0033] c. The filtrate mentioned in step b was transferred to the reaction flask, the temperature of the filtrate was raised to 15-20 ℃, and then 5g of dichloromethane was added and stirred for 10-15min;

[0034] d. Add 25-30 ml of isopropanol dropwise to the filtrate until the filtrate becomes turbid, then add 0.1 g of cefotaxime sodium seed crystals and grow the crystals.

[0035] 30-35min;

[0036] e. Continue to add 100-130ml of isopropanol dropwise. After the addition is complete, cool the solution to 5-10°C and grow the crystal for 1-1.2h;

[0037] f. Filter the solution mentioned in step e, wash the filter cake with isopropyl alcohol; dry the filter cake in vacuo at 60-70°C to obtain a white crystalline powder as the modified cefotaxime sodium.

[0038] The above experiments were conducted in the laboratory. For industrial production, the amounts of ceftriaxone sodium, purified water, and isopropyl alcohol can be increased proportionally, with a correspondingly slightly increased reaction time. The chemical formulas and synthesis diagrams for cefotaxime acid and ceftriaxone sodium can be found in the prior art.

[0039] 3. Single factor experiment:

[0040] Under the condition of controlling variables, the effect of the proportion of salt-forming agent on the yield of ceftriaxone sodium was investigated, and five different ratios of sodium acetate: sodium isooctanoate were designed, namely 1:0, 0:1, 1:2, 2:1, and 1:1; the optimal reaction temperature in the preparation process of ceftriaxone sodium was investigated, and the temperatures were set at 0℃, 5℃, 10℃, 15℃, and 20℃ respectively; the optimal dosage of the solvent isopropyl alcohol in the preparation process was investigated, and 60mL, 80mL, 100mL, 120mL, and 140mL of isopropyl alcohol were taken respectively.

[0041] 3.1. Effect of the proportion of salt-forming agent on yield

[0042] Salt-forming agent ratio Yield / % Sodium acetate 85.00 Sodium 2-ethylhexanoate 88.62 Sodium acetate:sodium ethyl octanoate (2:1) 90.20 Sodium acetate:sodium ethyl octanoate (1:1) 90.81 Sodium acetate:sodium ethylhexanoate (1:2) 91.64

[0043] Table 3 Effect of salt-forming agent ratio on yield

[0044] As shown in Table 3, when sodium acetate and sodium 2-ethylhexanoate were used as the salt-forming agent in a molar ratio of 1:2, the product yield of cefotaxime sodium reached a peak and then showed a slow downward trend. Therefore, a salt-forming agent ratio of 1:2 was selected for the response surface design method.

[0045] 3.2 Effect of reaction temperature on yield

[0046] serial number 1 2 3 4 5 Temperature (℃) 0 5 10 15 20 Yield % 84.62 86.24 89.21 93.14 83.53

[0047] Table 4 Effect of reaction temperature on yield

[0048] As shown in Table 4, the yield of the target product gradually increases with increasing reaction temperature, reaching its peak at 15°C. Subsequently, the yield of the target product decreases rapidly as the reaction temperature increases. The experimental results show that the yield of ceftriaxone sodium reaches its maximum at 15°C. Therefore, reaction temperatures of 10°C, 15°C, and 20°C were selected for the response surface design method.

[0049] 3.3 Effect of the amount of isopropyl alcohol used as solvent on yield

[0050] serial number 1 2 3 4 5 Isopropyl alcohol dosage (mL) 60 80 100 120 140 Yield % 75.60 78.92 80.44 91.84 84.23

[0051] Table 5 Effect of the amount of isopropyl alcohol used as solvent on yield

[0052] As shown in Table 5, the yield of ceftriaxone sodium increases with increasing amounts of isopropyl alcohol (the solvent). The yield peaks at 120 mL and then declines. While ensuring cost, the response surface experiment selected 80 mL, 100 mL, and 120 mL as the ranges for isopropyl alcohol dosage.

[0053] 4. Design response surface optimization method:

[0054] A single-factor experimental approach was used, with reaction temperature, isopropyl alcohol dosage, and salt-forming agent ratio as influencing factors. Based on the principles of response surface methodology (Box-Behnken) experimental design, with yield as the response value, a three-factor, three-level response surface methodology was established using statistical analysis software to optimize the crystallization process. The experimental factors and levels are shown in Table 6.

[0055] level A reaction temperature (℃) B. Isopropyl alcohol dosage (mL) C salt forming agent ratio -1 10 80 1：1 0 15 100 1：2 1 20 120 2：1

[0056] Table 6 Response surface design factors

[0057] The results were analyzed using Design-Expert software. All data were expressed as mean ± standard deviation (mean ± SD). The differences between the two groups were compared using the t-test. The differences between multiple groups were analyzed using the one-way ANOVA test. *P < 0.05, **P < 0.01, and ***P < 0.001 were used to indicate statistically significant differences. The effects of reaction temperature, the amount of solvent isopropanol, and the ratio of the salt-forming agent on the yield of cefotaxime sodium were investigated using Design-Expert software. The results are shown in Table 7. The regression equation model for the yield of cefotaxime sodium and the variables of each factor was obtained: Y = 93.40 - 0.3750A + 3.19B + 0.3125C + 0.1250AB + 0.1250AC - 1.0000BC - 4.70A 2 -8.33B 2 -5.57C 2 .

[0058] Serial number Temperature (℃) Amount of solvent added (mL) Salt-forming agent ratio Yield (%) 1 10 80 1:1 78 2 20 80 1:1 77 3 10 120 1:1 83.5 4 20 120 1:1 83 5 10 100 2:1 83 6 20 100 2:1 82 7 10 100 1:2 84 8 20 100 1:2 83.5 9 15 80 2:1 75 10 15 120 2:1 84 11 15 80 1:2 76.5 12 15 120 1:2 81.5 13 15 100 1:1 94 14 15 100 1:1 92.9 15 15 100 1:1 93.1 16 15 100 1:1 92.8 17 15 100 1:1 94

[0059] Table 7 Response surface experimental design results

[0060] The results of variance analysis are shown in Table 8. The model p<0.0001 and the lack-of-fit term is 0.3024 (p>0.05), indicating that the model is reliable. The significance ranking of each factor is as follows: the amount of isopropanol used as the solvent (B, p<0.0001) > temperature (A, p=0.1364) > salt-forming agent ratio (C, p=0.2037). The interaction term BC (isopropanol-salifying agent ratio) p=0.0157 indicates that a high amount of isopropanol needs to be matched with a low salt-forming agent ratio to suppress solvent waste.

[0061]

[0062]

[0063] Table 8 Analysis of variance

[0064] The 3D response surface diagram and contour map of the optimized extraction scheme of the response surface experiment are attached. Figure 1-6 According to the simulation results, the optimal process conditions are the salt-forming agent ratio of 1:2, the reaction temperature of 15℃, and the amount of solvent isopropanol of 120ml.

[0065] 5. Seed-induced crystallization method:

[0066] Two parallel control experiments were conducted. The experimental group added 0.1 g of ceftriaxone sodium seeds (particle size 50-80 μm); the control group did not add seeds and relied on spontaneous nucleation. All other control parameters remained unchanged. Under the optimal experimental conditions obtained through comprehensive response surface optimization, the yield of the reaction was significantly improved when ceftriaxone sodium seeds were added compared to when no ceftriaxone sodium seeds were added (see Table 9).

[0067] index Experimental group (with seed crystals) Control group (no seed crystal) Yield 93.00±0.8％ 80.90±2.1％

[0068] Table 9 Effect of the presence or absence of seed crystals on yield

[0069] 6. Discussion

[0070] This study optimized the synthesis parameters of ceftriaxone sodium through single-factor experiments and response surface methodology (RSM). Experimental data showed that reaction temperature, the amount of isopropyl alcohol used as the solvent, and the ratio of the salt-forming agent significantly affected the product yield, with the amount of isopropyl alcohol having the most significant effect (p < 0.0001). This result is consistent with existing literature reports on the mechanism of dissolution crystallization. Specifically, adjusting the solvent polarity can effectively reduce the solubility of the target product, thereby promoting crystal precipitation. Since the reaction solvent is a key factor affecting the quality of ceftriaxone sodium in this experiment, dichloromethane was selected as the reaction solvent, compared to the commonly used ethyl acetate solvent in the literature. Using dichloromethane as the reaction solvent further reduced the content of ceftriaxone sodium and other impurities, increased the content of ceftriaxone sodium, and effectively improved the chemical stability of the product. During the crystallization of ceftriaxone sodium, an appropriate amount of dichloromethane was first added as the reaction solvent, followed by the dropwise addition of isopropyl alcohol. This optimized the crystallization process for ceftriaxone sodium, resulting in a high-quality ceftriaxone sodium product with a uniform particle size distribution. When the reaction temperature exceeded 15°C, the yield showed a significant downward trend. This phenomenon was attributed to the high temperature accelerating the hydrolysis side reaction of the β-lactam ring, leading to product decomposition. This demonstrates the critical role of temperature control in the preparation of ceftriaxone sodium.

[0071] In response surface experiments, Box-Behnken design (BBD) is used to model the 2 =0.995) deeply reveals the interaction between various factors. The overall significance of the model: F value is 184.10 (p < 0.0001), indicating that the model has a strong explanatory power for yield and is statistically significant. Residual analysis: The residual sum of squares is 2.78, and the p value of the lack of fit test is 0.3024 (not significant), indicating that the model has not omitted significant factors and has a good fit. The coefficient of determination is: R 2=658.62 / 661.40≈0.996, indicating that the model can explain 99.60% of the yield variation and has high prediction accuracy. Among them, the p value for the amount of solvent (B) is less than 0.0001, and the F value reaches 204.48, indicating that the amount of solvent has the most significant effect on the yield. The interaction effect of B and C (BC): p=0.0157 (*significant), indicating that the amount of solvent and the ratio of salt-forming agent need to be optimized synergistically. Specifically, when the amount of solvent is high and the ratio of salt-forming agent is 1:2, the yield decreases, while the yield is highest when the solvent is 100mL and the ratio is 1:1. From the contour diagram of the solvent amount and the salt-forming agent ratio, it is obtained that: the response surface diagram (A) shows that when the solvent amount is 100-120mL and the salt-forming agent ratio is 1:1, the yield is significantly increased. The contour diagram (B): the elliptical contour lines indicate that there is an interaction between the solvent amount and the salt-forming agent ratio. Excessive solvent (>120mL) may lead to low supersaturation and decreased crystallization efficiency. This discovery provides a theoretical basis for solvent recovery and recycling in industrial production, which helps to reduce production costs and reduce environmental pollution. In addition, the process parameters optimized by response surface analysis (reaction temperature 15°C, solvent isopropanol dosage 120 mL, and salt-forming agent ratio 1:2) showed stable yields (91.30% ± 0.80%) in three verification experiments, thus confirming the reliability of the established model.

[0072] In the seed-induced crystallization experiment, the yield of ceftriaxone sodium showed an upward trend with the addition of seed crystals. The reason is speculated to be that the addition of seed crystals can reduce the large number of crystal nuclei produced instantaneously in the initial stage of crystallization, improve the stability of the dissolution crystallization process, and provide powerful conditions for crystallization control.

[0073] The foregoing descriptions of specific exemplary embodiments of the present invention are for purposes of illustration and description. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that many variations and modifications are possible in light of the foregoing teachings. The exemplary embodiments have been selected and described for the purpose of explaining the specific principles of the invention and their practical application, thereby enabling those skilled in the art to realize and utilize a variety of exemplary embodiments of the invention and various options and modifications. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A process for synthesizing cefotaxime sodium, characterized in that The following steps are involved: a. Prepare a container, mix 10g of cefotaxime acid, 10ml of purified water, and 25ml of isopropanol, stir and dissolve at a temperature of 15-20 ℃, gradually add a salt-forming agent during stirring, and adjust the pH value to 5.5-6.5; b. Add 0.2 g of activated carbon for decolorization for 30-40 min, and filter to obtain a carbon cake and filtrate; c. The filtrate mentioned in step b was transferred to the reaction flask, the temperature of the filtrate was raised to 15-20 ℃, and then 5g of dichloromethane was added and stirred for 10-15min; d. Add 25-30 ml of isopropanol dropwise to the filtrate until the filtrate becomes turbid, then add 0.1 g of cefotaxime sodium seed crystals and grow the crystals for 30-35 min; e. Continue to add 100-130ml of isopropanol dropwise. After the addition is complete, cool the solution to 5-10°C and grow the crystal for 1-1.2h; f. Filter the solution mentioned in step e, wash the filter cake with isopropyl alcohol; dry the filter cake in vacuo at 60-70°C to obtain a white crystalline powder as the modified cefotaxime sodium.

2. The synthesis process of ceftriaxone sodium according to claim 1, wherein: In the step a, the salt-forming agent includes sodium acetate and sodium isooctanoate, and the ratio of the two is 1:

2.

3. The synthesis process of ceftriaxone sodium according to claim 2, wherein: In the step c, the temperature of the filtrate is raised to 15°C.

4. The synthesis process of ceftriaxone sodium according to claim 3, wherein: In the step e, 125 ml of isopropyl alcohol is added dropwise.

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