A method for the synthesis of a cefodizime 3-position side chain

Abstract

The application discloses a synthesis method of a 3-position side chain of cefodizime, and relates to the technical field of medicine intermediates. The method comprises the following steps: taking 3-hydroxy-4-methoxybenzaldehyde as a starting material, and preparing a key intermediate 2-chloro-3,4-dipara-methoxybenzyloxy-N-(2-(1-pyrrolidine)ethyl)benzamide through five steps of reactions. First, 2-position chlorine is introduced through low-temperature chlorination, then the side chain is constructed through methylation, Pinnick oxidation to obtain a carboxylic acid, acyl chloride and amidation, demethylation through AlCl3 / pyridine, and finally, the phenolic hydroxyl group is protected through PMB. Through the sequence of chlorination-methylation / oxidation-amidation-demethylation-protection, the method fully utilizes the positioning effect, mild oxidation and selective protection strategy, realizes the advantages of high total yield, high purity, simple operation, cheap raw materials and easy industrial production, provides a high-quality side chain intermediate for subsequent synthesis of cefodizime, and has remarkable economic benefits and practical value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediates technology, and specifically to a method for synthesizing the 3-position side chain of cefdil. Background Technology

[0002] Cefiderocol is a novel siderophore cephalosporin antibiotic developed by Shionogi Pharmaceutical Co., Ltd. of Japan, and approved by the US FDA in 2019. It is the first antibiotic designed using a "Trojan horse" strategy, enhancing its penetration and antibacterial activity in multidrug-resistant Gram-negative bacteria by binding to the bacteria's iron requirements. The chemical structure of cefiderocol features a carboxypropoxyimino group on the C-7 side chain, which is not hydrolyzed by β-lactamases; it also has a pyrrolidone group on the C-3 side chain, which prevents recognition by β-lactamases. The mechanism of action of cefiderocol differs from ceftazidime and cefepime in that it contains a catechol group, which chelates ferric ions and then transports them via siderophile receptor proteins (TBDTs) of the TonB system. 2-Chloro-3,4-di-p-methoxybenzoxy-N-(2-(1-pyrrolidine)ethyl)benzamide is one of the intermediates in the synthesis of cefdil, namely the C-3 side chain.

[0003] PCT international patent WO 2016035847A1 discloses the following scheme: using 3-hydroxy-4-methoxybenzaldehyde (i.e., isovandrin) as the starting material, the process involves chlorination, demethylation, protection of catechol with p-methoxybenzyl chloride, oxidation of the aldehyde group, and then a five-step reaction involving the formation of an active anhydride from methanesulfonyl chloride and carboxylic acid, followed by nucleophilic substitution of a primary amine to synthesize an amide, ultimately yielding the C-3 side chain of cefdil. This route yields a product with relatively high purity, but the operation is cumbersome, involving multiple extractions and generating a large amount of hazardous waste. The final amidation reaction, in particular, requires low temperatures and demands sophisticated factory equipment, making it unsuitable for industrial production.

[0004] PCT international patent WO 2010050468A1 discloses the following scheme: using 2-chloro-3,4-dimethoxybenzoic acid as the starting material, the method involves demethylation, followed by the reaction of p-methoxybenzyl chloride to protect the phenolic hydroxyl group, the removal of the p-methoxybenzyl chloride-protected carboxyl group, and finally, a series of sulfonic anhydride and amidation reactions to obtain the C-3 side chain of cefdil. This route suffers from expensive starting materials, uses boron tribromide as the demethylation reagent, has a low yield, and generates a large amount of hydrogen bromide during quenching, making it unsuitable for large-scale industrial production.

[0005] Chinese patent application CN 117069638A discloses a method for preparing 2-chloro-3,4-di-p-methoxybenzyl)oxybenzaldehyde and 1-(2-aminoethyl)pyrrolidine by oxidation using a specially formulated iron-cobalt composite material as a catalyst. While this method is simple and efficient, and the catalyst can be recycled, it does not clearly specify the specific recycling method, the number of cycles, or the changes in activity after long-term use, which may affect the stability and economics of industrial production. Furthermore, using oxygen as the oxidant requires supporting safety equipment (such as a high-pressure oxygen supply system), increasing process complexity and potential safety risks.

[0006] Chinese patent application CN 117024377A discloses the following scheme: using 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzoic acid as a raw material, reacting it with 2-chloroethylamine via a sulfonating agent, and then reacting it with tetrahydropyrrole under alkaline conditions to obtain the target compound. Although this method has achieved high yield and purity on a laboratory scale, its harsh reaction conditions, complex post-processing, use of highly toxic reagents, and sensitivity to operating parameters may face multiple challenges in actual industrial production, including cost, safety, and environmental protection.

[0007] In her 2020 master's thesis, Xu Jingjing reported an optimized synthetic route. This synthetic route was optimized based on the original synthetic route reported by the Japanese Patent Office. The main improvements were made to the first step of chlorination and the last step of amidation. For the last step of amidation, several condensing agents such as EDCI, p-toluenesulfonyl chloride, and methanesulfonyl chloride were tried, but the yields were not ideal.

[0008] In Qi Zhiyuan's master's thesis published in 2022, the route mainly adopted the route in patent WO 2016035847 written by Mayu Fukuda et al., and deeply optimized various parameters, but the final product purity and yield did not change significantly.

[0009] Chinese patent application CN 118063409A discloses the following scheme: using 2-chloro-3,4-dihydroxybenzoic acid as the starting material, it is first condensed with 1-(2-aminoethyl)pyrrolidine in a mixed solution of polyethylene glycol and water using EDCI, and then a hydroxyl protecting group (p-methoxybenzyl) is added to synthesize the target product. Although this process has a short synthesis step, the starting materials are expensive, resulting in high costs, which is not conducive to industrial production. Summary of the Invention

[0010] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a method for synthesizing the 3-position side chain of cefdil.

[0011] To achieve the above objectives, the present invention provides the following technical solution: A method for synthesizing the 3-side chain of cefdinir, comprising the following steps: (1) Using 3-hydroxy-4-methoxybenzaldehyde as a raw material, react with a chlorination reagent in a solvent to obtain 2-chloro-3-hydroxy-4-methoxybenzaldehyde; (2) 2-Chloro-3-hydroxy-4-methoxybenzaldehyde is methylated with a methylating agent in a solvent and under alkaline conditions to give 2-chloro-3,4-dimethoxybenzaldehyde; 2-Chloro-3,4-dimethoxybenzaldehyde reacts with sodium chlorite in the presence of a solvent, sodium dihydrogen phosphate, and hypochlorous acid scavenger to yield 2-chloro-3,4-dimethoxybenzoic acid. (3) 2-Chloro-3,4-dimethoxybenzoic acid is activated in a solvent by an acyl chloride reagent and then undergoes a condensation reaction with 1-(2-aminoethyl)pyrrolidine to give 2-chloro-3,4-dimethoxy-N-(2-(1-pyrrolidine)ethyl)benzamide; (4) 2-Chloro-3,4-dimethoxy-N-(2-(1-pyrrolidine)ethyl)benzamide undergoes a demethylation reaction in the presence of a solvent, Lewis acid and pyridine to give 2-chloro-3,4-dihydroxy-N-(2-(1-pyrrolidine)ethyl)benzamide; (5) 2-Chloro-3,4-dihydroxy-N-(2-(1-pyrrolidine)ethyl)benzamide reacts with PMBCl in the presence of a solvent, base, and catalyst to yield the target compound. The reaction equation for the above synthetic method is shown below:

[0012] The chlorination reagent mentioned in step (1) is one of sodium hypochlorite and N-chlorosuccinimide; the solvent is one of anhydrous methanol, anhydrous ethanol and anhydrous n-propanol.

[0013] The methylating agent in step (2) is one of dimethyl sulfate, dimethyl carbonate, and iodomethane; the base is one of potassium carbonate and sodium carbonate.

[0014] The hypochlorous acid scavenging agent mentioned in step (2) is one of hydrogen peroxide aqueous solution and aminosulfonic acid.

[0015] The acyl chloride reagent mentioned in step (3) is one of oxalyl chloride, thionyl chloride, phosphorus trichloride, and phosphorus oxychloride.

[0016] The Lewis acid mentioned in step (4) is one of anhydrous aluminum trichloride, anhydrous zinc chloride, and boron trifluoride.

[0017] The catalyst mentioned in step (5) is potassium iodide; the base is one of potassium carbonate, sodium carbonate, and cesium carbonate.

[0018] In step (1), the molar ratio of 3-hydroxy-4-methoxybenzaldehyde to the chlorinated reagent is 1:(1.05~1.5); In step (2), the molar ratio of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, methylating agent and base is 1:(1.05~1.5):(1.5~2.2); In step (2), the molar ratio of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, sodium chlorite, and hypochlorous acid scavenger is 1:(1.05~1.5):(1.5~2.5); In step (3), the molar ratio of 2-chloro-3,4-dimethoxybenzoic acid, acyl chloride reagent and 1-(2-aminoethyl)pyrrolidine is 1:(2~4):(1~2); In step (4), the molar ratio of 2-chloro-3,4-dimethoxy-N-(2-(1-pyrrolidine)ethyl)benzamide, Lewis acid and pyridine is 1:(1.05~1.5):(2.1~3); In step (5), the molar ratio of 2-chloro-3,4-dihydroxy-N-(2-(1-pyrrolidine)ethyl)benzamide, catalyst, base and PMBCl is 1:(0.1~0.3):(2~3):(2~3).

[0019] In step (2), the solvent used in the methylation reaction is one of acetonitrile, DMF, and DMAc; In step (2), the solvent used is one of tetrahydrofuran, acetonitrile, and DMF; In step (3), the solvent used is either toluene or dioxane; In step (4), the solvent used is acetonitrile; In step (5), the solvent used is acetonitrile.

[0020] In step (1), the reaction temperature is -5℃ to 10℃; In step (2), the methylation reaction is carried out at a temperature of 45°C to 55°C, and the reaction with sodium chlorite is carried out at a temperature of 25°C to 35°C. In step (3), the activation temperature is 95°C to 105°C, and the condensation reaction temperature is 5°C to 15°C. In step (4), the demethylation reaction temperature is 70°C to reflux; In step (5), the reaction temperature is 40°C to 50°C.

[0021] Due to the adoption of the above technical solutions, the beneficial effects of the present invention include: This invention uses 3-hydroxy-4-methoxybenzaldehyde as a starting material and prepares the key intermediate 2-chloro-3,4-di-p-methoxybenzoxy-N-(2-(1-pyrrolidine)ethyl)benzamide through a five-step reaction. First, at low temperature, the strong ortho- and para-position directing effect of the phenolic hydroxyl group is utilized to selectively introduce an electrophilic aromatic substitution at the 2-position using sodium hypochlorite as a chlorine source. Subsequently, the 3-position phenolic hydroxyl group is protected by potassium carbonate catalysis and dimethyl sulfate methylation. Then, a mild Pinnick oxidation (sodium chlorite / hydrogen peroxide system) efficiently converts the aldehyde group to a carboxylic acid, avoiding chlorination or peroxidation side reactions. The first two steps of this process exhibit high yields and purity, strong selectivity, and mild conditions. The intermediate can be directly reused as a wet product, significantly reducing separation losses and material consumption, providing an efficient foundation for industrial scale-up. Next, the carboxylic acid was converted to an acyl chloride using thionyl chloride, which then underwent a nucleophilic amidation reaction with 1-(2-aminoethyl)pyrrolidine to construct the target amide structure. This stage of the reaction was carried out under mild conditions with high selectivity and a yield of 97.51%. Subsequently, two methoxy groups were efficiently removed using Lewis acid (AlCl3 / pyridine) to generate a catechol structure, providing an active site for subsequent protection. This part of the operation was simple, with thorough acyl chlorination and complete demethylation, resulting in high purity intermediates and avoiding positional isomers and multi-substituted impurities, thus ensuring quality stability during subsequent coupling. Finally, under potassium carbonate / KI catalysis, the two phenolic hydroxyl groups were protected by Williamson etherification with p-methoxybenzyl chloride (PMBCl) to generate a double PMB ether protecting group. After concentration under reduced pressure, water precipitation, and recrystallization from ethyl acetate, a high-purity target product was obtained.

[0022] The entire process follows a sequence of "chlorination-methylation / oxidation-amidation-demethylation-protection," fully utilizing the positioning effect, mild oxidation, and selective protection strategies to achieve advantages such as high overall yield, excellent purity, simple operation, inexpensive raw materials, and ease of industrial production. It provides high-quality side-chain intermediates for the subsequent synthesis of cefdil, demonstrating significant economic benefits and practical value. Attached Figure Description

[0023] Figure 1 The liquid chromatogram of 2-chloro-3-hydroxy-4-methoxybenzaldehyde prepared in Example 2; Figure 2 The liquid chromatogram of the wet product of 2-chloro-3,4-dimethoxybenzaldehyde prepared in Example 2; Figure 3 The liquid chromatogram of 2-chloro-3,4-dimethoxybenzoic acid prepared in Example 2; Figure 4 The liquid chromatogram of 2-chloro-3,4-dimethoxy-N-(2-(1-pyrrolidine)ethyl)benzamide prepared in Example 2; Figure 5The liquid chromatogram of 2-chloro-3,4-dihydroxy-N-(2-(1-pyrrolidine)ethyl)benzamide prepared in Example 2; Figure 6 The liquid chromatogram of 2-chloro-3,4-di-p-methoxybenzoxy-N-(2-(1-pyrrolidine)ethyl)benzamide prepared in Example 2; Figure 7 The 1H NMR spectrum of 2-chloro-3,4-di-p-methoxybenzoxy-N-(2-(1-pyrrolidine)ethyl)benzamide prepared in Example 2. Detailed Implementation

[0024] The following description, in conjunction with specific embodiments, provides further details, but the present invention is not limited to these embodiments.

[0025] Example 1 (1) Add 15L of anhydrous methanol and 2.5kg (1.0eq, 16.43mol) of 3-hydroxy-4-methoxybenzaldehyde to a 50L reactor, cool to -5℃, add 16.06kg (1.05eq) of 8wt% sodium hypochlorite aqueous solution dropwise to the system, control the temperature not to exceed 5℃, and add the solution dropwise for 30min. After reacting for 1.5h, add 5L of 36wt% hydrochloric acid to the system, stir for 1h, centrifuge, and vacuum dry at 60℃ for 3h to obtain 2.76kg of light yellow powder solid 2-chloro-3-hydroxy-4-methoxybenzaldehyde, yield: 90.02%, liquid phase purity: 98.63%.

[0026] (2) In a 50L reactor, add 12.5L of acetonitrile, 2.6kg (1.0eq, 13.93mol) of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, and 2.89kg (1.5eq) of potassium carbonate. Heat to 45℃ and slowly add 1.85kg (1.05eq) of dimethyl sulfate to the system. The addition is completed in 30min. After reacting for 3h, add 30L of water. A large amount of white solid precipitates in the system. Stir for 2h and centrifuge to obtain 4.88kg of white 2-chloro-3,4-dimethoxybenzaldehyde wet product with a liquid phase purity of 97.21%. In a 50L reactor, 15L of tetrahydrofuran, 4.88kg of wet 2-chloro-3,4-dimethoxybenzaldehyde, 2.23kg (1.05eq) of sodium dihydrogen phosphate dihydrate, and 2.37kg (1.5eq) of 30% hydrogen peroxide were added. The temperature was controlled at 25℃. Sodium chlorite aqueous solution (5L water + 1.66kg sodium chlorite (80wt%), 1.05eq) was added dropwise over 30 minutes. After reacting for 3 hours, 35L of 2NHCl was added to the system. A large amount of white solid precipitated from the system. The mixture was stirred and allowed to crystallize for 1 hour. After centrifugation, the mixture was dried under vacuum at 60℃ for 3 hours to obtain 2.69kg of white solid 2-chloro-3,4-dimethoxybenzoic acid. The yield was 89.12%, and the liquid phase purity was 99.56%.

[0027] (3) In a 50L reactor, add 5L of toluene, 2.5kg (1.0eq, 11.54mol) of 2-chloro-3,4-dimethoxybenzoic acid, and 25g of DMF. Heat to 55℃ and add 2.75kg (2eq) of thionyl chloride dropwise to the system. After the addition is completed in 30min, heat to 95℃ and react for 3h. This is system A. In another 50L reactor, add 10L of toluene and 1.32kg (1eq) of 1-(2-aminoethyl)pyrrolidine. Cool to 15℃. This is system B. Slowly add system A to system B. A large amount of off-white solid precipitates from the system. After the addition is completed in 60min, react for 1h. Centrifuge and dry under vacuum at 65℃ for 3h to obtain 3.41kg of off-white solid 2-chloro-3,4-dimethoxy-N-(2-(1-pyrrolidine)ethyl)benzamide. Yield: 94.46kg. Liquid phase purity: 99.21%.

[0028] (4) In a 50L reactor, add 17.5L of acetonitrile, 3.5kg (1.0eq, 11.19mol) of 2-chloro-3,4-dimethoxy-N-(2-(1-pyrrolidine)ethyl)benzamide, and 1.57kg (1.05eq) of anhydrous aluminum trichloride. Slowly add 2.12kg (2.1eq) of pyridine to the system. After the addition is completed in 30min, react at 70℃ for 3h. Cool down and add 32L of 2N HCl to the system. A large amount of brown solid precipitates out of the system. Maintain the temperature at 10±5℃ and stir for 2h. Centrifuge and dry under vacuum at 60℃ for 4h to obtain 2.74kg of light brown solid 2-chloro-3,4-dihydroxy-N-(2-(1-pyrrolidine)ethyl)benzamide. Yield: 86.00%, liquid phase purity: 99.75%.

[0029] (5) In a 50L reactor, add 12.5L of acetonitrile, 2.5kg (1.0 eq, 8.78 mol) of 2-chloro-3,4-dihydroxy-N-(2-(1-pyrrolidine)ethyl)benzamide, 2.43kg (2 eq) of potassium carbonate, and 0.29kg (0.2 eq) of potassium iodide. Heat to 40℃, and add 2.75kg (2 eq) of p-methoxybenzyl chloride dropwise to the system. The addition is completed in 30min. Maintain this temperature for 4h, then concentrate under reduced pressure, maintaining the pressure at -0.8℃. At MPa and a temperature of 50±10℃, when no more solvent flowed out, 20L of water was added to the system, stirred for 1h, centrifuged, and the wet product was transferred to a reaction vessel. 20L of ethyl acetate was added, the temperature was raised to reflux, stirred for 2h, cooled to 0±5℃, and crystallized for 3h. After centrifugation, the product was dried under vacuum at 60℃ for 4h to obtain 3.87kg of off-white solid 2-chloro-3,4-di-p-methoxybenzoxy-N-(2-(1-pyrrolidine)ethyl)benzamide, yield: 83.95%, liquid phase purity: 99.11%.

[0030] Example 2 (1) Add 15L of anhydrous ethanol and 2.5kg (1.0eq, 16.43mol) of 3-hydroxy-4-methoxybenzaldehyde to a 50L reactor. Cool to 0℃ and add 18.35kg (1.2eq, 19.72mol) of 8wt% sodium hypochlorite aqueous solution dropwise to the system. Control the temperature not to exceed 10℃ and add the solution dropwise for 30min. After reacting for 1h, add 5L of 36wt% hydrochloric acid to the system, stir for 1h, centrifuge, and vacuum dry at 60℃ for 3h to obtain 2.88kg of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, a light yellow powder. Yield: 93.94%, liquid phase purity: 98.94%. The liquid phase spectrum is shown below. Figure 1 As shown.

[0031] (2) In a 50L reactor, add 12.5L of acetonitrile, 2.6kg (1.0eq, 13.93mol) of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, and 3.27kg (1.7eq, 23.69mol) of potassium carbonate. Heat to 50℃, and slowly add 2.11kg (1.2eq, 16.72mol) of dimethyl sulfate dropwise over 30min. After reacting for 3h, add 30L of water. A large amount of white solid precipitates from the system. Stir for 2h, centrifuge, and obtain 4.90kg of wet 2-chloro-3,4-dimethoxybenzaldehyde, with a liquid phase purity of 97.28%. The liquid phase spectrum is shown below. Figure 2 As shown.

[0032] In a 50L reactor, add 15L of tetrahydrofuran, 4.90kg of wet 2-chloro-3,4-dimethoxybenzaldehyde (all the wet product prepared above is added here; in other embodiments, all the wet product prepared above is also added), 2.4kg of sodium dihydrogen phosphate dihydrate (1.1 eq, 15.33 mol), and 3.16kg of 30% hydrogen peroxide (2.0 eq, 27.87 mol). Maintain the temperature at 30℃, and add dropwise sodium chlorite aqueous solution (5L water + 1.89kg sodium chlorite (80wt%), 1.2 eq, 16.72 mol). The addition is completed in 30 minutes, and the reaction is allowed to proceed for 3 hours. Then, add 35L of 2N... HCl was applied, and a large amount of white solid precipitated in the system. After stirring and crystallization for 1 hour, the mixture was centrifuged and dried under vacuum at 60°C for 3 hours to obtain 2.71 kg of white solid 2-chloro-3,4-dimethoxybenzoic acid. The yield was 89.78%, and the liquid phase purity was 99.54%. The liquid phase spectrum is shown below. Figure 3 As shown.

[0033] (3) In a 50L reactor, add 5L of toluene, 2.5kg (1.0eq, 11.54mol) of 2-chloro-3,4-dimethoxybenzoic acid, and 25g of DMF. Heat to 60℃ and add 4.12kg (3eq, 34.6mol) of thionyl chloride dropwise to the system. The addition is completed in 30min. Heat to 100℃ and react for 2.5h. This is system A. In another 50L reactor, add 10L of toluene and 1-(2-aminoethyl)pyrrolidine. 1.58 kg (1.2 eq, 13.85 mol) was cooled to 10 °C; this is system B. System A was slowly added dropwise to system B, and a large amount of off-white solid precipitated. The addition was completed in 60 min, and the reaction was allowed to proceed for 1 h. After centrifugation, the mixture was dried under vacuum at 65 °C for 3 h to obtain 3.52 kg of off-white solid 2-chloro-3,4-dimethoxy-N-(2-(1-pyrrolidine)ethyl)benzamide. Yield: 97.51%, HPLC purity: 99.32%. The HPLC chromatogram is shown below. Figure 4 As shown.

[0034] (4) In a 50L reactor, add 17.5L of acetonitrile, 3.5kg (1.0eq, 11.19mol) of 2-chloro-3,4-dimethoxy-N-(2-(1-pyrrolidine)ethyl)benzamide, and 1.79kg (1.2eq, 13.43mol) of anhydrous aluminum trichloride. Slowly add 2.13kg (2.4eq, 26.85mol) of pyridine to the system. After the addition is completed in 30min, react at 75℃ for 3h. Cool down and add 32L of 2N HCl to the system. A large amount of brown solid precipitates out of the system. Maintain the temperature at 10±5℃ and stir for 2h. Centrifuge and vacuum dry at 60℃ for 4h to obtain 2.79kg of light brown solid 2-chloro-3,4-dihydroxy-N-(2-(1-pyrrolidine)ethyl)benzamide. Yield: 87.57%, purity: 99.78%. Liquid chromatography spectrum is shown below. Figure 5 As shown.

[0035] (5) In a 50L reactor, add 12.5L of acetonitrile, 2.5kg (1.0eq, 8.78mol) of 2-chloro-3,4-dihydroxy-N-(2-(1-pyrrolidine)ethyl)benzamide, 3.03kg (2.5eq, 21.95mol) of potassium carbonate, and 0.145kg (0.1eq, 0.88mol) of potassium iodide. Heat to 45℃, and add 3.02kg (2.2eq, 19.32mol) of p-methoxybenzyl chloride dropwise to the system. The addition is completed in 30min. Maintain this temperature and react for 3.5h. The solution was concentrated under reduced pressure, maintained at -0.8 MPa and 50 ± 10 °C. When no more solvent flowed out, 20 L of water was added to the system, and the mixture was stirred for 1 h. After centrifugation, the wet product was transferred to a reaction vessel, and 20 L of ethyl acetate was added. The mixture was heated to reflux and stirred for 2 h. The temperature was then lowered to 0 ± 5 °C, and crystallization was allowed to occur for 3 h. After centrifugation, the product was dried under vacuum at 60 °C for 4 h to obtain 3.92 kg of a white solid, 2-chloro-3,4-di-p-methoxybenzoxy-N-(2-(1-pyrrolidine)ethyl)benzamide. The yield was 85.04%, and the liquid chromatography purity was 99.21%. The liquid chromatography chromatogram is shown below. Figure 6 As shown. Its 1H NMR spectrum is as follows. Figure 7 As shown, the signal near δ 8.21 ppm belongs to the NH proton of the amide; multiple sets of aromatic hydrogen signals in the range of δ 7.42–6.84 ppm correspond to the p-methoxybenzylbenzene ring and the parent ring of chlorobenzamide in the target molecule; two sets of peaks at δ 5.12 ppm and 4.91 ppm belong to two benzyloxymethylene groups; the single peak at δ 3.75 ppm belongs to two p-methoxy methoxy protons; and the signal in the range of δ 2.54–1.50 ppm belongs to the N-ethyl segment and the pyrrolidine ring methylene proton (the peak near δ 2.50 ppm is the residual solvent peak of DMSO). The above results indicate that the spectrum is consistent with the target structure.

[0036] Example 3 (1) Add 15L of anhydrous ethanol and 2.5kg (1.0eq, 16.43mol) of 3-hydroxy-4-methoxybenzaldehyde to a 50L reactor, cool to 5℃, add 22.94kg (1.5eq) of 8wt% sodium hypochlorite aqueous solution dropwise to the system, control the temperature not to exceed 10℃, and add the solution dropwise for 30min. After reacting for 1h, add 5L of 36wt% hydrochloric acid to the system, stir for 1h, centrifuge, and vacuum dry at 60℃ for 3h to obtain 2.91kg of light yellow powder solid 2-chloro-3-hydroxy-4-methoxybenzaldehyde, yield: 94.91%, liquid phase purity: 98.71%.

[0037] (2) In a 50L reactor, add 12.5L of acetonitrile, 2.6kg (1.0eq, 13.93mol) of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, and 4.23kg (2.2eq) of potassium carbonate. Heat to 55℃ and slowly add 2.64kg (1.5eq) of dimethyl sulfate to the system. After 30min, the addition is completed. After 3h of reaction, add 30L of water. A large amount of white solid precipitates in the system. Stir for 2h and centrifuge to obtain 4.91kg of wet 2-chloro-3,4-dimethoxybenzaldehyde.

[0038] In a 50L reactor, 15L of tetrahydrofuran, 4.91kg of wet 2-chloro-3,4-dimethoxybenzaldehyde, 2.61kg (1.2eq) of sodium dihydrogen phosphate dihydrate, and 3.95kg (2.5eq) of 30% hydrogen peroxide were added. The temperature was controlled at 35℃. Sodium chlorite aqueous solution (5L water + 2.36kg sodium chlorite (80wt%), 1.5eq) was added dropwise over 30min. After reacting for 3h, 35L of 2NHCl was added to the system. A large amount of white solid precipitated from the system. The mixture was stirred and allowed to crystallize for 1h. After centrifugation, the mixture was dried under vacuum at 60℃ for 3h to obtain 2.73kg of white solid 2-chloro-3,4-dimethoxybenzoic acid. Yield: 90.45%, Liquid phase purity: 99.63%.

[0039] (3) In a 50L reactor, add 5L of toluene, 2.5kg (1.0eq, 11.54mol) of 2-chloro-3,4-dimethoxybenzoic acid, and 25g of DMF. Heat to 65℃ and add 5.49kg (4eq) of thionyl chloride dropwise to the system. After 30min, the addition is completed. Heat to 105℃ and react for 2h. This is system A. In another 50L reactor, add 10L of toluene and 2.64kg (2eq) of 1-(2-aminoethyl)pyrrolidine. Cool to 5℃. This is system B. Slowly add system A to system B. A large amount of off-white solid precipitates from the system. After 60min, the addition is completed. React for 1h. Centrifuge and vacuum dry at 65℃ for 3h to obtain 3.53kg of off-white solid 2-chloro-3,4-dimethoxy-N-(2-(1-pyrrolidine)ethyl)benzamide. Yield: 97.78%, liquid phase purity: 99.43%.

[0040] (4) In a 50L reactor, add 17.5L of acetonitrile, 3.5kg (1.0eq, 11.19mol) of 2-chloro-3,4-dimethoxy-N-(2-(1-pyrrolidine)ethyl)benzamide, and 2.24kg (1.5eq) of anhydrous aluminum trichloride. Slowly add 2.66kg (3eq) of pyridine to the system. After the addition is completed in 30min, reflux the reaction for 2.5h. Cool down and add 32L of 2N HCl to the system. A large amount of brown solid precipitates out of the system. Maintain the temperature at 10±5℃ and stir for 2h. Centrifuge and dry under vacuum at 60℃ for 4h to obtain 2.81kg of light brown solid 2-chloro-3,4-dihydroxy-N-(2-(1-pyrrolidine)ethyl)benzamide. Yield: 88.20%, liquid phase purity: 99.83%.

[0041] (5) In a 50L reactor, add 12.5L of acetonitrile, 2.5kg (1.0eq, 8.78mol) of 2-chloro-3,4-dihydroxy-N-(2-(1-pyrrolidine)ethyl)benzamide, 3.64kg (3eq) of potassium carbonate, and 0.145kg (0.1eq, 0.88mol) of potassium iodide. Heat to 50℃ and add 4.13kg (3eq) of p-methoxybenzyl chloride dropwise to the system. The addition is completed in 30min. Maintain this temperature for 3h and concentrate under reduced pressure. At -0.8 MPa and a temperature of 50±10℃, when no more solvent flowed out, 20 L of water was added to the system, stirred for 1 h, centrifuged, and the wet product was transferred to a reaction vessel. 20 L of ethyl acetate was added, the temperature was raised to reflux, stirred for 2 h, cooled to 0±5℃, and crystallized for 3 h. After centrifugation, the product was dried under vacuum at 60℃ for 4 h to obtain 4.01 kg of a white solid 2-chloro-3,4-di-p-methoxybenzoxy-N-(2-(1-pyrrolidine)ethyl)benzamide, with a yield of 86.99% and a liquid phase purity of 99.13%.

[0042] The following are examples of preparing the 3-position side chain of cefdil under different process parameters than in Example 2. The different process parameters and yields are shown in Table 1.

[0043] Table 1

[0044] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. However, any modifications, alterations, and variations made by those skilled in the art without departing from the scope of the present invention based on the disclosed technical content are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and variations made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the present invention.

Claims

1. A method for synthesizing the 3-position side chain of cefdil, characterized in that, Includes the following steps: (1) Using 3-hydroxy-4-methoxybenzaldehyde as a raw material, react with a chlorination reagent in a solvent to obtain 2-chloro-3-hydroxy-4-methoxybenzaldehyde; (2) 2-Chloro-3-hydroxy-4-methoxybenzaldehyde is methylated with a methylating agent in a solvent and under alkaline conditions to give 2-chloro-3,4-dimethoxybenzaldehyde; 2-Chloro-3,4-dimethoxybenzaldehyde reacts with sodium chlorite in the presence of a solvent, sodium dihydrogen phosphate, and hypochlorous acid scavenger to yield 2-chloro-3,4-dimethoxybenzoic acid. (3) 2-Chloro-3,4-dimethoxybenzoic acid is activated in a solvent by an acyl chloride reagent and then undergoes a condensation reaction with 1-(2-aminoethyl)pyrrolidine to give 2-chloro-3,4-dimethoxy-N-(2-(1-pyrrolidine)ethyl)benzamide; (4) 2-Chloro-3,4-dimethoxy-N-(2-(1-pyrrolidine)ethyl)benzamide undergoes a demethylation reaction in the presence of a solvent, Lewis acid and pyridine to give 2-chloro-3,4-dihydroxy-N-(2-(1-pyrrolidine)ethyl)benzamide; (5) 2-Chloro-3,4-dihydroxy-N-(2-(1-pyrrolidine)ethyl)benzamide reacts with PMBCl in the presence of solvent, base and catalyst to give the target compound; The chlorination reagent mentioned in step (1) is sodium hypochlorite; the solvent is one of anhydrous methanol, anhydrous ethanol, and anhydrous n-propanol; in step (1), the reaction temperature is -5℃ to 10℃; The methylating agent in step (2) is dimethyl sulfate; the base is potassium carbonate; The acyl chloride reagent mentioned in step (3) is thionyl chloride; The Lewis acid mentioned in step (4) is anhydrous aluminum trichloride; The catalyst mentioned in step (5) is potassium iodide; the base is potassium carbonate; In step (4), the molar ratio of 2-chloro-3,4-dimethoxy-N-(2-(1-pyrrolidine)ethyl)benzamide, Lewis acid and pyridine is 1:(1.05~1.5):(2.1~3).

2. The synthesis method according to claim 1, characterized in that: The hypochlorous acid scavenging agent mentioned in step (2) is one of hydrogen peroxide aqueous solution and aminosulfonic acid.

3. The synthesis method according to any one of claims 1-2, characterized in that, In step (1), the molar ratio of 3-hydroxy-4-methoxybenzaldehyde to the chlorinated reagent is 1:(1.05~1.5); In step (2), the molar ratio of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, methylating agent and base is 1:(1.05~1.5):(1.5~2.2); In step (2), the molar ratio of 2-chloro-3-hydroxy-4-methoxybenzaldehyde, sodium chlorite, and hypochlorous acid scavenger is 1:(1.05~1.5):(1.5~2.5); In step (3), the molar ratio of 2-chloro-3,4-dimethoxybenzoic acid, acyl chloride reagent and 1-(2-aminoethyl)pyrrolidine is 1:(2~4):(1~2); In step (5), the molar ratio of 2-chloro-3,4-dihydroxy-N-(2-(1-pyrrolidine)ethyl)benzamide, catalyst, base and PMBCl is 1:(0.1~0.3):(2~3):(2~3).

4. The synthesis method according to any one of claims 1-2, characterized in that, In step (2), the solvent used in the methylation reaction is one of acetonitrile, DMF, or DMAc. In step (2), the solvent used for the reaction with sodium chlorite is one of tetrahydrofuran, acetonitrile, or DMF; In step (3), the solvent used is either toluene or dioxane; In step (4), the solvent used is acetonitrile; In step (5), the solvent used is acetonitrile.

5. The synthesis method according to any one of claims 1-2, characterized in that, In step (2), the methylation reaction is carried out at a temperature of 45°C to 55°C, and the reaction with sodium chlorite is carried out at a temperature of 25°C to 35°C. In step (3), the activation temperature is 95°C to 105°C, and the condensation reaction temperature is 5°C to 15°C. In step (4), the demethylation reaction temperature is 70°C to reflux; In step (5), the reaction temperature is 40°C to 50°C.

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