A method for the synthesis and post-processing of a key intermediate of cefdil

Abstract

This invention discloses a method for synthesizing a key intermediate of cefdil, belonging to the field of pharmaceutical synthesis. Specifically, the method uses 2-chloro-3,4-dihydroxybenzaldehyde and 4-methoxybenzyl chloride as raw materials, and N,N-dimethylformamide as a solvent. The reaction is carried out under heating in the presence of a catalyst and a base. After the reaction is complete, hot water is added dropwise to the reaction solution, causing a solid to precipitate. The precipitated solid is then filtered, washed with water, and dried to obtain the product 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde. This invention features a green and environmentally friendly synthesis process, simple operation, and convenient product purification. The obtained product has high yield and purity, with a liquid phase purity of 99.4% and a yield of 95.8%.

Description

Technical Field

[0001] This invention specifically relates to a method for the synthesis and post-processing of a key intermediate of cefdil, and relates to the field of drug synthesis. Background Technology

[0002] In recent years, infections caused by multidrug-resistant Gram-negative bacteria, especially in hospital settings, have resulted in thousands of deaths annually. In the United States and Europe alone, more than 50,000 people die each year from antibiotic-resistant infections, a significant concern for the medical community. According to research reports, if antibiotic resistance is not addressed quickly, tens of thousands of deaths annually from antibiotic resistance will occur from 2050 onwards, resulting in global economic losses of hundreds of millions of dollars. The growing threat posed by multidrug-resistant Gram-negative bacteria, including *Pseudomonas aeruginosa*, *Klebsiella pneumoniae*, and *Escherichia coli*, is a growing global concern. The evolution of human bacterial pathogens and their resistance to antibiotics is an ongoing process, and most available antibiotics are ineffective. Currently, there are no highly targeted treatments for infections caused by multidrug-resistant Gram-negative bacteria. Therefore, there is an urgent need for new, highly effective drugs against multidrug-resistant Gram-negative bacteria. The successful launch of cefdil provides an effective solution to the problem of antibiotic resistance.

[0003] The original patent used 2-chloro-3,4-dihydroxybenzaldehyde and 4-methoxybenzyl chloride as raw materials, added potassium carbonate and potassium iodide, and heated to react. After the reaction was complete, the mixture was cooled to room temperature, extracted with water and tetrahydrofuran, and recrystallized with isopropanol. This process yielded a product with high purity, but the post-processing was complicated, the product was soluble in isopropanol, and the yield was low.

[0004] In her paper, Xu Jingjing used 2-chloro-3,4-dihydroxybenzaldehyde and 4-methoxybenzyl chloride as raw materials, added potassium carbonate and sodium iodide, and heated the reaction. In the post-processing, DMF was distilled off under reduced pressure, followed by separation extraction, washing of the organic phase, drying, filtration, and concentration under reduced pressure to remove the organic solvent, resulting in a concentrated solution. Isopropanol was then added to the concentrated solution to obtain a precipitate, which was filtered under reduced pressure. The filter cake was washed with small amounts of isopropanol multiple times and then dried under vacuum, with a yield of 86.2%. This process has a high yield, but the post-processing is complex and DMF is difficult to remove. Summary of the Invention

[0005] This invention addresses the shortcomings of existing technologies by using 2-chloro-3,4-dihydroxybenzaldehyde and 4-methoxybenzyl chloride as raw materials, and N,N-dimethylformamide as a solvent, in the presence of a catalyst and an alkali, to react under heat to obtain the product 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde. The technical solution of this invention to solve the above problems is as follows:

[0006] Using 2-chloro-3,4-dihydroxybenzaldehyde and 4-methoxybenzyl chloride as raw materials, and N,N-dimethylformamide as solvent, the reaction was carried out under the action of a catalyst and a base. After the reaction was completed, hot water was added dropwise to the reaction solution, and a solid precipitated. The solid was filtered, washed with water, and dried to obtain the product 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde.

[0007] In the method for synthesizing and post-processing the key intermediate of cefdil, the catalyst used is one of tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, potassium iodide, and sodium iodide, and the molar ratio of 2-chloro-3,4-dihydroxybenzaldehyde to the catalyst is 1:0.01 to 0.04.

[0008] In the method for synthesizing and post-processing the key intermediate of cefdil, the base used is one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, and potassium hydroxide, and the molar ratio of 2-chloro-3,4-dihydroxybenzaldehyde to the base is 1:2.1 to 2.5.

[0009] In the method for synthesizing and post-processing the key intermediate of cefdil, water is added dropwise directly to the reaction solution during post-processing.

[0010] In the method for synthesizing and post-processing the key intermediate of cefdil, the temperature of the hot water added during post-processing is 55-65℃, and the rate of water addition is 3.0-6.0 mL / min.

[0011] In the method for synthesizing and post-processing the key intermediate of cefdil, the stirring speed during post-processing is 300-400 r / min.

[0012] In the method for synthesizing and post-processing the key intermediate of cefdil, the water used in the post-processing is 2.2 to 2.5 times that of DMF.

[0013] Beneficial effects of this invention:

[0014] This invention belongs to a green process synthesis, which has the advantages of simple operation process, convenient product purification, high product yield and high purity, with product purity reaching 99.1% and yield reaching 92.9%.

[0015] In addition, the present invention is simple to operate, uses conventional process conditions, and is suitable for large-scale industrial production. Detailed Implementation

[0016] To further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims of the present invention.

[0017] 2-Chloro-3,4-Dihydroxybenzaldehyde (content ≥97%), Shandong Aikesen Biomedical Co., Ltd.; Potassium carbonate, Shanghai Aladdin Biochemical Technology Co., Ltd.; Tetrabutylammonium iodide, Shanghai Taijilin Industry Co., Ltd.; p-Methoxybenzyl chloride (content ≥98%), Shanghai Haohong Biomedical Technology Co., Ltd.; N,N-Dimethylamide (analytical grade), Tianjin Fuyu Fine Chemical Co., Ltd.

[0018] Example 1

[0019] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.215 g (0.02 eq) of tetrabutylammonium iodide and 9.23 g (2.3 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 400 r / min and add 62.5 mL of 60 °C hot water dropwise at a constant temperature of 4 mL / min. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a yellowish-brown solid. The purity of the liquid phase was 99.4%, and the yield was 95.8%.

[0020] Example 2

[0021] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.107 g (0.01 eq) of tetrabutylammonium iodide and 9.23 g (2.3 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 400 r / min and add 62.5 mL of 60 °C hot water dropwise at a constant temperature of 4 mL / min. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a yellowish-brown solid. The purity of the liquid phase was 99.1%, and the yield was 92.9%.

[0022] Example 3

[0023] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.428 g (0.04 eq) of tetrabutylammonium iodide and 9.23 g (2.3 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 400 r / min and add 62.5 mL of 60 °C hot water dropwise at a constant temperature of 4 mL / min. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a yellowish-brown solid. The purity of the liquid phase was 98.8%, and the yield was 93.1%.

[0024] Example 4

[0025] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.215 g (0.02 eq) of tetrabutylammonium iodide and 8.42 g (2.1 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 400 r / min and add 62.5 mL of 60 °C hot water dropwise at a constant temperature of 4 mL / min. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a yellowish-brown solid. The purity of the liquid phase was 99.1%, and the yield was 91.2%.

[0026] Example 5

[0027] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.215 g (0.02 eq) of tetrabutylammonium iodide and 10.01 g (2.5 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 400 r / min and add 62.5 mL of 60 °C hot water dropwise at a constant temperature of 4 mL / min. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a yellowish-brown solid. The purity of the liquid phase was 99.1%, and the yield was 92.8%.

[0028] Example 6

[0029] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.215 g (0.02 eq) of tetrabutylammonium iodide and 9.23 g (2.3 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 300 r / min and add 62.5 mL of 60 °C hot water dropwise at a constant temperature of 4 mL / min. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a yellowish-brown solid. The purity of the liquid phase was 97.2%, and the yield was 93.2%.

[0030] Example 7

[0031] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.215 g (0.02 eq) of tetrabutylammonium iodide and 9.23 g (2.3 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 400 r / min and add 62.5 mL of 60 °C hot water dropwise at a constant temperature of 3 mL / min. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a yellowish-brown solid. The purity of the liquid phase was 98.9%, and the yield was 93.4%.

[0032] Example 8

[0033] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.215 g (0.02 eq) of tetrabutylammonium iodide and 9.23 g (2.3 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 400 r / min and add 62.5 mL of 60 °C hot water dropwise at a constant temperature of 5 mL / min. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a yellowish-brown solid. The purity of the liquid phase was 98.5%, and the yield was 92.8%.

[0034] Example 9

[0035] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.215 g (0.02 eq) of tetrabutylammonium iodide and 9.23 g (2.3 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 400 r / min and add 62.5 mL of 55 °C hot water dropwise at a constant temperature of 4 mL / min. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a yellowish-brown solid. The purity of the liquid phase was 99.2%, and the yield was 92.4%.

[0036] Example 10

[0037] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.215 g (0.02 eq) of tetrabutylammonium iodide and 9.23 g (2.3 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 400 r / min and add 55 mL of 65 °C hot water dropwise at a constant temperature of 4 mL / min. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a yellowish-brown solid. The purity of the liquid phase was 95.9%, and the yield was 92.7%.

[0038] Example 11

[0039] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.215 g (0.02 eq) of tetrabutylammonium iodide and 9.23 g (2.3 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 400 r / min and add 60 mL of 65 °C hot water dropwise at a constant temperature of 4 mL / min. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a yellowish-brown solid. The purity of the liquid phase was 96.2%, and the yield was 93.2%.

[0040] Comparative Example 1

[0041] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.215 g (0.02 eq) of tetrabutylammonium iodide and 9.23 g (2.3 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 100 r / min and add 62.5 mL of 60 °C hot water dropwise at a constant temperature of 4 mL / min. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a brownish-yellow viscous solid. The purity of the liquid phase was 75.4%, and the yield was 75.2%.

[0042] Comparative Example 2

[0043] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.215 g (0.02 eq) of tetrabutylammonium iodide and 9.23 g (2.3 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 400 r / min and add 62.5 mL of 60 °C hot water dropwise at 10 mL / min at a constant temperature. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a brownish-yellow granular solid. The purity of the liquid phase was 81.2%, and the yield was 81.3%.

[0044] Comparative Example 3

[0045] Take a 100 mL three-necked flask and add 5 g (1 eq) of 2-chloro-3,4-dihydroxybenzaldehyde, followed by 25 mL of N,N-dimethylamide. Stir and dissolve at room temperature. Add 0.215 g (0.02 eq) of tetrabutylammonium iodide and 9.23 g (2.3 eq) of potassium carbonate, then add 9.53 g (2.1 eq) of PMBCl dropwise. After the addition is complete, heat to 50 °C and react for 2 h 45 min. After the reaction is complete, stir at 400 r / min and add 62.5 mL of water at 25 °C dropwise at a constant temperature. Filter the solid and recrystallize it from 70 mL of water at 40 °C for 30 min to obtain a brown spherical solid. The purity of the liquid phase was 65.9%, and the yield was 63.1%.

[0046] While the specific embodiments of the present invention have been described above, they are not intended to limit the scope of protection of the present invention. Those skilled in the art should understand that various modifications or variations that can be made by those skilled in the art without creative effort based on the technical solutions of the present invention are still within the scope of protection of the present invention.

Claims

1. A method of synthesis of a cefodizime key intermediate, characterized by, The reaction equation of the synthesis method is as follows: ； The product 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde is obtained by using 2-chloro-3,4-dihydroxybenzaldehyde and 4-methoxychlorobenzene as raw materials, using N,N-dimethylformamide as a solvent, under the action of a catalyst and a base, heating reaction, adding hot water dropwise into the reaction solution after the reaction, precipitating a solid, filtering, washing the filtered solid with water, and drying; wherein the catalyst is one of tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, and benzyltriethylammonium chloride, the molar ratio of 2-chloro-3,4-dihydroxybenzaldehyde to the catalyst is 1:0.01-0.04; the base is one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, and potassium hydroxide, and the molar ratio of 2-chloro-3,4-dihydroxybenzaldehyde to the base is 1:2.1-2.

5.

2. The method of synthesis of cefodizime key intermediate as claimed in claim 1 wherein, The temperature of the hot water dropwise added is 55-65 DEG C, and the speed of the hot water dropwise added is 3.0-6.0 mL / min.

3. The process for synthesis and work-up of Cefodizime key intermediate as claimed in claim 1 wherein, The stirring speed of the reaction solution during the process of the hot water dropwise added is 300-400 r / min.

4. The process for the synthesis of cefodizime key intermediate as claimed in claim 1, wherein, The volume of the hot water dropwise added is 2.2-2.5 times of the solvent N,N-dimethylformamide.

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