A method for preparing a high-quality, stable cefixime side-chain acid active ester

Abstract

This invention relates to the field of pharmaceutical chemical synthesis technology, specifically disclosing a method for preparing a stable cefixime side-chain acid active ester. The invention involves adding dibenzothiazole disulfide, cefixime side-chain acid, an organic amine, and triethyl phosphite to a reaction solvent for a condensation reaction; then adding a crystallization solvent to the reaction system, cooling to allow crystallization, separating the solid and liquid phases, and washing the resulting solid with a phosphate buffer to obtain the cefixime side-chain acid active ester; the particle size of the dibenzothiazole disulfide is D90 = 20 μm~45 μm; the pH of the phosphate buffer is neutral. This invention couples the condensation reaction and crystallization process into one step, synergistically adding an organic amine and triethyl phosphite, purifying with a specific neutral phosphate buffer, and controlling the particle size of the raw material DM, achieving product quality assurance throughout the entire process from reaction source to purification. Accelerated testing has confirmed that the sample exhibits high stability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, and in particular to a method for preparing a stable cefixime side-chain acid active ester. Background Technology

[0002] Cefixime is a third-generation oral cephalosporin. Its side-chain acid active ester (MICA active ester, structural formula shown in Formula 1) has the molecular formula C. 15 H 12 N4S3, chemically named (S)-2-benzothiazolyl-(Z)-2-(2-aminothiazolyl-4-yl)-2-methoxycarbonylmethoxyiminothioacetic acid ester, is a key intermediate in the synthesis of cefixime. The quality of the MICA active ester directly affects the purity, yield, and stability of the final active pharmaceutical ingredient, cefixime.

[0003]

[0004] Formula 1

[0005] Formula 2 Currently, the industrial process commonly uses cefixime side-chain acid (MICA, structural formula shown in Formula 2) and dibenzothiazole disulfide (DM) as raw materials to prepare MICA active esters through a condensation reaction in the presence of triphenylphosphine (TPP) and a catalyst. However, this traditional process has the following problems: First, the product is prone to degradation during storage, resulting in increased content of related substances and poor chemical stability; second, the selectivity of the condensation reaction needs to be improved, and byproducts such as diesterization are easily generated; third, the raw material DM is a solid, which is unevenly dispersed in the reaction system, easily agglomerates, and is encapsulated by the generated product, leading to incomplete reaction, large yield fluctuations, and the potential for side reactions due to excessively high local concentrations.

[0006] To address the aforementioned issues, existing technologies typically employ solvent replacement or post-treatment modifications, but these methods fail to fundamentally improve the product's intrinsic stability, optimize reaction selectivity, or enhance raw material utilization efficiency. Therefore, there is an urgent need to develop a method for preparing high-quality, stable cefixime side-chain acid active esters suitable for industrial production. Summary of the Invention

[0007] To address the above problems, this invention provides a method for preparing a stable cefixime side-chain acid active ester, which has a short process flow, high selectivity of condensation reaction, high product yield, and high stability.

[0008] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows: A method for preparing a high-quality, stable cefixime side-chain acid active ester includes the following steps: Dibenzothiazole disulfide, cefixime side-chain acid, organic amine and triethyl phosphite were added to the reaction solvent to carry out a condensation reaction; then a crystallization solvent was added to the reaction system, the temperature was lowered to crystallize, solid and liquid were separated, and the obtained solid was washed with phosphate buffer to obtain the active cefixime side-chain acid ester. The particle size of the dibenzothiazole disulfide is D90 = 20 μm to 45 μm; the pH of the phosphate buffer is neutral.

[0009] Compared to existing technologies, this invention provides a method for preparing a high-quality, stable cefixime side-chain acid active ester. Using cefixime side-chain acid (MICA) and dibenzothiazole disulfide (DM) as raw materials, a one-step condensation-crystallization process followed by washing and purification with neutral phosphate buffer yields a highly stable MICA active ester. This invention combines the condensation reaction and crystallization process into a single step, and adds an organic amine and triethyl phosphite as catalysts in this step, improving the stability of the complex and the selectivity of the substrate. This invention uses a phosphate buffer with a specific pH to wash the organic phase of the crude solid product, effectively removing impurities and significantly improving the chemical stability of the product. This invention improves the dispersibility of the raw material DM in the reaction system by limiting its ultrafine particle size, avoiding encapsulation and improving reaction efficiency and yield.

[0010] The method for preparing stable cefixime side-chain acid active esters provided by this invention is simple, requires no special experimental equipment, and produces products with high purity and good stability, suitable for industrial production and with high market application value.

[0011] For example, dibenzothiazole disulfide can be pulverized by air jet milling or ball milling, so that the particle size of DM can be precisely controlled to D90=20μm~45μm.

[0012] Preferably, the organic amine includes at least one of 1,2-propanediamine, diethylenetriamine, or piperazine.

[0013] In catalytic processes, triethylamine and DIPEA (N,N-diisopropylethylamine) are commonly used, primarily as acid-binding agents to neutralize acids generated during the reaction. Although they can temporarily coordinate to metals, their relatively large steric hindrance prevents them from being considered as "co-ligands" in catalyst design. Compared to triethylamine or DIPEA, the preferred organic amine in this invention is one that can modulate the properties of the metal center. This invention introduces a sterically hindrance-free organic amine as a co-ligand in the condensation-crystallization step, which can form a "phosphorus-nitrogen dual-ligand" catalytic system with triethyl phosphite, improving the stability and substrate selectivity of the complex. Simultaneously, it provides a mild alkaline environment for the reaction, effectively capturing impurities generated during the reaction, synergistically protecting the active ester structure, and inhibiting the degradation of the active ester at its source.

[0014] Preferably, the molar ratio of dibenzothiazole disulfide, cefixime side chain acid, organic amine and triethyl phosphite is (1~1.5):1:(1~1.2):(1~1.2).

[0015] Preferably, the temperature of the condensation reaction is 20℃~25℃, and the time of the condensation reaction is 2h~3h.

[0016] Through extensive experiments, this invention has found that condensation reactions have high requirements for reaction temperature; only within the range of 20℃ to 25℃ can the product have high selectivity.

[0017] Preferably, the reaction solvent includes at least one of dichloromethane, ethyl acetate, or methyl tert-butyl ether.

[0018] Preferably, the crystallization solvent includes at least one of acetone, isopropanol, or n-hexane.

[0019] Preferably, the mass-to-volume ratio of the cefixime side chain acid, the reaction solvent, and the crystallization solvent is 1 g:(20~25) mL:(10~15) mL.

[0020] Preferably, the crystallization temperature is 0℃~5℃, and the crystal growth time is 1h~2h.

[0021] Preferably, the pH of the phosphate buffer is 6.5 to 7.5, and the phosphate buffer includes at least one of sodium dihydrogen phosphate buffer containing sodium chloride or disodium hydrogen phosphate buffer containing sodium chloride.

[0022] More preferably, the sodium chloride concentration in the phosphate buffer solution is 5% to 15% by mass.

[0023] Through extensive experiments, this invention has found that if the sodium chloride concentration in the phosphate buffer is too high, it will cause inorganic salts to precipitate, which will have an adverse effect on the content index of the final product; if the sodium chloride concentration is too low, it will not be able to improve the stability of the product.

[0024] Preferably, the washing is performed 1 to 3 times, and the mass-to-volume ratio of cefixime side chain acid to phosphate buffer in each washing is 1 g:(2~3) mL.

[0025] For example, after washing, the process also includes rinsing with a crystallizing solvent, drying, and obtaining the active cefixime side-chain acid ester.

[0026] Preferably, the purity of the cefixime side-chain acid active ester decreases by ≤0.1% after an accelerated stability test at 70℃±2℃ for 15 hours.

[0027] The present invention has the following beneficial effects: This invention couples the condensation reaction and crystallization process into one step. In this key step, a specific organic amine and triethyl phosphite are added synergistically. Subsequently, a specific neutral phosphate buffer is used for washing and purification. Combined with particle size control of the raw material DM, product quality assurance is achieved throughout the entire process from the reaction source to purification.

[0028] (1) Simplified process and improved efficiency: Combining condensation and crystallization reduces material transfer and intermediate processing steps, shortens the production cycle, and reduces the risk of introducing impurities due to multiple operation steps.

[0029] (2) Significantly enhanced stability: Washing with a specific neutral phosphate buffer can thoroughly remove residual catalysts, inorganic salts and trace acid and alkali impurities, fundamentally improving the chemical stability of the product.

[0030] (3) More complete reaction and higher yield: By pre-treating DM with ultrafine grinding, the specific surface area of ​​the DM reaction is greatly increased, making it uniformly dispersed in the reaction solvent. This avoids insufficient reaction and local side reactions caused by blocky particles, and improves the selectivity of the main reaction and the repeatability of the yield. Detailed Implementation

[0031] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0032] In this embodiment of the invention, products not specifically described can be obtained through commercial channels.

[0033] Example 1 This embodiment provides a method for preparing a stable cefixime side-chain acid active ester, comprising the following steps: 450 mL of reaction solvent (dichloromethane), 30.78 g (93 mmol) of dibenzothiazole disulfide with a D90 of 30 μm and 20.0 g (77 mmol) of cefixime side chain acid were added to the reaction vessel and stirred until homogeneous. Then, 6.29 g (85 mmol) of organic amine (1,2-propanediamine) and 14.10 g (85 mmol) of triethyl phosphite were added simultaneously. The molar ratio of dibenzothiazole disulfide, cefixime side chain acid, organic amine and triethyl phosphite was 1.2:1:1.1:1.1. The condensation reaction was carried out at 20 °C to 25 °C. After stirring for 2.5 h, the reaction was monitored by TLC to indicate that the reaction was complete.

[0034] Then, 250 mL of crystallization solvent (acetone) was slowly added dropwise to the reaction system. The mass-volume ratio of cefixime side chain acid, reaction solvent and crystallization solvent was 1 g: 22.5 mL: 12.5 mL. The temperature was lowered to 0℃~5℃ for crystallization. After 2 hours of crystal growth, a large number of crystals precipitated in the system.

[0035] Solid-liquid separation was performed. The obtained solid was washed twice with 50 mL of phosphate buffer (pH 7, containing 10 wt% sodium chloride in sodium dihydrogen phosphate buffer) each time. The solid was then rinsed with cold acetone and vacuum dried at 35 °C for 6 h to obtain a white to off-white crystalline powder, namely cefixime side chain acid active ester.

[0036] Example 2 This embodiment provides a method for preparing a stable cefixime side-chain acid active ester, comprising the following steps: 400 mL of reaction solvent (ethyl acetate), 26.93 g (81 mmol) of dibenzothiazole disulfide with a D90 of 45 μm and 20.0 g (77 mmol) of cefixime side chain acid were added to a reaction vessel and stirred until homogeneous. Then, 8.36 g (81 mmol) of organic amine (diethylenetriamine) and 13.46 g (81 mmol) of triethyl phosphite were added simultaneously. The molar ratio of dibenzothiazole disulfide, cefixime side chain acid, organic amine and triethyl phosphite was 1.05:1:1.05:1.05. The condensation reaction was carried out at 20 °C to 25 °C. After stirring for 2 h, the reaction was monitored by TLC to ensure it was complete.

[0037] Then, 200 mL of crystallization solvent (isopropanol) was slowly added dropwise to the reaction system. The mass-volume ratio of cefixime side chain acid, reaction solvent and crystallization solvent was 1 g: 20 mL: 10 mL. The temperature was lowered to 0℃~5℃ for crystallization. After 1.5 h of crystal growth, a large number of crystals precipitated in the system.

[0038] Solid-liquid separation was performed. The obtained solid was washed twice with phosphate buffer (containing 7 wt% sodium chloride and disodium hydrogen phosphate buffer) at pH 6.7, with 60 mL of phosphate buffer used each time. The solid was then rinsed with cold isopropanol and dried under vacuum at 35°C for 6 h to obtain a white to off-white crystalline powder, namely cefixime side chain acid active ester.

[0039] Example 3 This embodiment provides a method for preparing a stable cefixime side-chain acid active ester, comprising the following steps: 500 mL of reaction solvent (methyl tert-butyl ether), 38.48 g (116 mmol) of dibenzothiazole disulfide with a D90 of 20 μm and 20.0 g (77 mmol) of cefixime side chain acid were added to the reaction vessel and stirred until homogeneous. Then, 7.97 g (93 mmol) of organic amine (piperazine) and 15.38 g (93 mmol) of triethyl phosphite were added simultaneously. The molar ratio of dibenzothiazole disulfide, cefixime side chain acid, organic amine and triethyl phosphite was 1.5:1:1.2:1.2. The condensation reaction was carried out at 20 °C to 25 °C. After stirring for 3 h, the reaction was monitored by TLC to ensure it was complete.

[0040] Then, 300 mL of crystallization solvent (acetone) was slowly added dropwise to the reaction system. The mass-volume ratio of cefixime side chain acid, reaction solvent and crystallization solvent was 1 g: 25 mL: 15 mL. The temperature was lowered to 0℃~5℃ for crystallization. After 2 hours of crystal growth, a large number of crystals precipitated in the system.

[0041] Solid-liquid separation was performed. The obtained solid was washed three times with phosphate buffer (sodium dihydrogen phosphate buffer containing 13 wt% sodium chloride) at pH 7.3, with 40 mL of phosphate buffer used each time. The solid was then rinsed with cold acetone and vacuum dried at 35°C for 6 h to obtain a white to off-white crystalline powder, namely cefixime side chain acid active ester.

[0042] Example 4 This embodiment provides a method for preparing cefixime side-chain acid active ester, similar to Example 1, except that the organic amine 1,2-propanediamine is replaced with an equimolar amount of triethylamine. All other operating steps and conditions are the same as in Example 1 and will not be repeated here.

[0043] Comparative Example 1 This comparative example provides a method for preparing cefixime side-chain acid active ester, similar to Example 1, except that after crystallization, solid-liquid separation is performed, and the obtained solid is washed with purified water (i.e., phosphate buffer is replaced with an equal volume of purified water). All other operating steps and conditions are the same as in Example 1 and will not be repeated here.

[0044] Comparative Example 2 This comparative example provides a method for preparing the active ester of cefixime side chain acid, similar to Example 1, except that the particle size D90 of dibenzothiazole disulfide is 10 μm. All other operating steps and conditions are the same as in Example 1 and will not be repeated here.

[0045] The molar yields (based on cefixime side-chain acid) of the active cefixime esters prepared in Examples 1-4 and Comparative Examples 1-2 were calculated respectively, and the results are shown in Table 1.

[0046] The purity of the cefixime side chain acid active esters prepared in Examples 1-4 and Comparative Examples 1-2 was tested according to the chemical industry standard HG / T6141-2023, and the results are shown in Table 1.

[0047] HPLC chromatographic conditions include: Chromatographic column: C18 (silica gel) stainless steel column (150mm×4.6mm, particle size 5μm); Mobile phase: acetonitrile, water and glacial acetic acid in a volume ratio of 600:400:6; Detection wavelength: 254nm; Injection volume: 20 μL; Flow rate: 1.0 mL / min; Running time: 35 minutes.

[0048] Accelerated stability tests were conducted on the cefixime side-chain acid active esters prepared in Examples 1-4 and Comparative Examples 1-2 (70℃±2℃, placed in a drying oven for 15h). The purity of the samples after the accelerated stability test was tested by HPLC in accordance with the chemical industry standard HG / T6141-2023. The results are shown in Table 1.

[0049] Table 1. Comparison of product quality between the examples and comparative examples.

[0050] As can be seen from the table above, the cefixime side chain acid active esters prepared in Examples 1-3 of this invention are superior to Examples 4 and Comparative Examples 1-2 in terms of initial purity, impurity control and stability. This indicates that the technical features such as one-step condensation-crystallization, synergistic addition of catalyst and alkali, buffer brine washing and DM particle size control work together to produce a synergistic effect.

[0051] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a high-quality, stable cefixime side-chain acid active ester, characterized in that, Includes the following steps: Dibenzothiazole disulfide, cefixime side-chain acid, organic amine and triethyl phosphite were added to the reaction solvent to carry out a condensation reaction; then a crystallization solvent was added to the reaction system, the temperature was lowered to crystallize, solid and liquid were separated, and the obtained solid was washed with phosphate buffer to obtain the active cefixime side-chain acid ester. The particle size of the dibenzothiazole disulfide is D90 = 20 μm to 45 μm; the pH of the phosphate buffer is neutral.

2. The method for preparing a quality-stable cefixime side-chain acid active ester as described in claim 1, characterized in that, The organic amine includes at least one of 1,2-propanediamine, diethylenetriamine, or piperazine.

3. The method for preparing a quality-stable cefixime side-chain acid active ester as described in claim 1 or 2, characterized in that, The molar ratio of dibenzothiazole disulfide, cefixime side chain acid, organic amine and triethyl phosphite is (1~1.5):1:(1~1.2):(1~1.2).

4. The method for preparing a quality-stable cefixime side-chain acid active ester as described in claim 1, characterized in that, The pH of the phosphate buffer is 6.5 to 7.5, and the phosphate buffer includes at least one of sodium dihydrogen phosphate buffer containing sodium chloride or disodium hydrogen phosphate buffer containing sodium chloride.

5. The method for preparing a quality-stable cefixime side-chain acid active ester as described in claim 4, characterized in that, The sodium chloride concentration in the phosphate buffer solution is 5% to 15%.

6. The method for preparing a quality-stable cefixime side-chain acid active ester as described in claim 1 or 5, characterized in that, The washing is performed 1 to 3 times, and the mass-to-volume ratio of cefixime side chain acid to phosphate buffer is 1 g:(2~3) mL in each washing.

7. The method for preparing a quality-stable cefixime side-chain acid active ester as described in claim 1, characterized in that, The condensation reaction temperature is 20℃~25℃, and the condensation reaction time is 2h~3h; the crystallization temperature is 0℃~5℃, and the crystal growth time is 1h~2h.

8. The method for preparing a quality-stable cefixime side-chain acid active ester as described in claim 1, characterized in that, The reaction solvent includes at least one of dichloromethane, ethyl acetate, or methyl tert-butyl ether; the crystallization solvent includes at least one of acetone, isopropanol, or n-hexane.

9. The method for preparing a quality-stable cefixime side-chain acid active ester as described in claim 1 or 8, characterized in that, The mass-volume ratio of the cefixime side chain acid, the reaction solvent, and the crystallization solvent is 1g:(20~25)mL:(10~15)mL.

10. The method for preparing a quality-stable cefixime side-chain acid active ester as described in claim 2, 4, or 7, characterized in that, The purity of the cefixime side-chain acid active ester decreased by ≤0.1% after an accelerated stability test at 70℃±2℃ for 15 hours.

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