A process for the preparation of a cefodizime intermediate

Abstract

The application discloses a preparation method of a cefodizime intermediate, and belongs to the field of drug synthesis. The application provides a synthesis method of the cefodizime intermediate, wherein an iron-cobalt-oxygen composite material is used as a catalyst to catalyze the oxidation reaction of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde and 1-(2-aminoethyl)pyrrolidine, so as to prepare 2-chloro-3,4-bis(p-methoxyphenyl)oxy-N-(2-(1-pyrrolidine)ethyl)benzamide. The synthesis process of the application directly synthesizes the amide by using the iron-cobalt-oxygen composite material as the catalyst to catalyze the aldehyde, the operation process is simple, the catalyst can be recycled, the product is easy to purify, and the obtained product has high purity.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of antibacterial drug cefiderocol, and belongs to the technical field of drug synthesis. BACKGROUND

[0002] Cefiderocol has the following structure, which is the first iron-carrier cephalosporin developed by Shionogi Company of Japan and entering the third phase of clinical trials. It is used for infections caused by G-bacteria and has the first clinical effectiveness test and in-vitro test results.

[0003]

[0004] In the patent published by Futian Mayang et al., 3-hydroxy-4-methoxybenzaldehyde (i.e. iso-eugenol) is used as a starting material, and through five-step reactions such as chlorination reaction, demethylation reaction, protection of bisphenol hydroxyl by p-methoxybenzyl chloride, oxidation of aldehyde group, and continuous reaction of sulfonic anhydride and primary amide of the compound, the intermediate of cefiderocol is finally obtained. The product has high purity, but the process is complicated, and the oxidation of aldehyde group to amide also needs two-step reactions, which is not conducive to industrial production. The synthesis route is as follows:

[0005]

[0006] In the master's graduation thesis published by Xu Jinge in 2020, an optimized synthesis process route is reported. The synthesis route is optimized on the basis of the original synthesis route reported in the Japanese patent. The route mainly optimizes the original aldehyde oxidation reaction and the continuous reaction of sulfonic anhydride and amide, but it is still a two-step reaction, which is complicated and not suitable for large-scale production. The synthesis route is as follows:

[0007]

[0008] Through market research, the starting material is relatively expensive, and the economic cost of the synthesis route is high. In the process of removing the PMB protection of the carboxyl group, the alkali strength, concentration and reaction temperature need to be controlled to prevent the phenolic hydroxyl group from being deprotected, which has high requirements for the operating personnel and is not conducive to laboratory operation. Therefore, a safe and reliable, low-cost, economic and green, and simple synthesis route needs to be found. SUMMARY

[0009] The present application is aimed at the deficiencies of the prior art, and the problem to be solved is to provide a synthesis method of cefiderocol intermediate, which is iron-cobalt oxide composite material catalyzing the reaction of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde and 1-(2-aminoethyl)pyrrolidine to prepare cefiderocol intermediate. To solve the above problems, the technical scheme of the present application is:

[0010] The intermediate of ceftibuten is obtained by heating reaction of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde and 1-(2-aminoethyl)pyrrolidine with the catalysis of iron-cobalt-oxygen composite material, and the intermediate of ceftibuten is obtained by post-treatment of centrifugation, filtration and vacuum filtration.

[0011] The intermediate of ceftibuten is obtained by heating reaction of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde and 1-(2-aminoethyl)pyrrolidine with the catalysis of iron-cobalt-oxygen composite material, and the intermediate of ceftibuten is obtained by post-treatment of centrifugation, filtration and vacuum filtration.

[0012] The intermediate of ceftibuten is obtained by heating reaction of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde and 1-(2-aminoethyl)pyrrolidine with the catalysis of iron-cobalt-oxygen composite material, and the intermediate of ceftibuten is obtained by post-treatment of centrifugation, filtration and vacuum filtration.

[0013] The intermediate of ceftibuten is obtained by heating reaction of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde and 1-(2-aminoethyl)pyrrolidine with the catalysis of iron-cobalt-oxygen composite material, and the intermediate of ceftibuten is obtained by post-treatment of centrifugation, filtration and vacuum filtration.

[0014] The intermediate of ceftibuten is obtained by heating reaction of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde and 1-(2-aminoethyl)pyrrolidine with the catalysis of iron-cobalt-oxygen composite material, and the intermediate of ceftibuten is obtained by post-treatment of centrifugation, filtration and vacuum filtration.

[0015] The intermediate of ceftibuten is obtained by heating reaction of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde and 1-(2-aminoethyl)pyrrolidine with the catalysis of iron-cobalt-oxygen composite material, and the intermediate of ceftibuten is obtained by post-treatment of centrifugation, filtration and vacuum filtration.

[0016] The intermediate of ceftibuten is obtained by heating reaction of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde and 1-(2-aminoethyl)pyrrolidine with the catalysis of iron-cobalt-oxygen composite material, and the intermediate of ceftibuten is obtained by post-treatment of centrifugation, filtration and vacuum filtration.

[0017] The intermediate of ceftibuten is obtained by heating reaction of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde and 1-(2-aminoethyl)pyrrolidine with the catalysis of iron-cobalt-oxygen composite material, and the intermediate of ceftibuten is obtained by post-treatment of centrifugation, filtration and vacuum filtration.

[0018] (1) The reaction is safe and reliable, and the cost is low.

[0019] (2) The reaction uses oxygen as an oxidant, which is economical and green.

[0020] (3) The reaction is simple to operate, and the obtained product has high yield and high purity, and has good prospects for industrial scale-up. DETAILED DESCRIPTION

[0021] For further understanding of the present application, the preferred embodiments of the present application are described below in conjunction with examples, but it should be understood that these descriptions are only for further illustrating the features and advantages of the present application, and are not limitations to the claims of the present application.

[0022] The preparation method of the iron-cobalt oxide composite material comprises the following steps:

[0023] (1) Take 0.4 g of cobalt chloride hexahydrate and 0.8 g of iron nitrate nonahydrate into a small beaker, add a magnet, add 10 ml of ultrapure water at one time, magnetically stir for 10 minutes, add 10 ml of 2 mol / l NaOH solution dropwise to the small beaker, black precipitate appears, continue to stir for five minutes after the dropwise addition is completed.

[0024] (2) The system is transferred to a 50 ml hydrothermal kettle, placed in an oven, 130℃, 6h. After the kettle is cooled to room temperature, the material is transferred to a centrifuge tube, washed by centrifugation, washed with water three times, washed with anhydrous ethanol three times, and dried to obtain the iron-cobalt oxide composite material.

[0025] Example 1

[0026] Under the condition of oxygen inlet, N,N-dimethylformamide (121.128 g) is used as the solvent, 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde (20.188 g, 0.049 mol) and 1-(2-aminoethyl)pyrrolidine (5.595 g, 0.049 mol) are added into a 250 ml three-necked flask, and 0.807 g of iron-cobalt oxide composite material is added, stirred until 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde is completely dissolved, and then the temperature is raised to 60℃ for 5 hours; after the reaction is completed, the catalyst is centrifuged and filtered, the filtrate is added with 300 ml of water, the solid precipitate is collected, the filter cake is washed with water for several times, the solid is dried, the product yield is 91.9%, and the product purity is 98.9%.

[0027] Example 2

[0028] Into a 250ml three-necked flask, 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde (20.188g, 0.049mol) and 1-(2-aminoethyl)pyrrolidine (8.392g, 0.0735mol) were added with N,N-dimethylformamide (141.316g) as solvent, and 0.403g of iron-cobalt-oxygen composite material was added. The mixture was stirred until the 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde was completely dissolved, and then the temperature was raised to 70°C for 6 hours. TLC and HPLC were used to determine the completion of the reaction. After the reaction was completed, the catalyst was centrifuged and filtered. The filtrate was added with 300ml of water, and the solid precipitate was collected. The filter cake was washed with water for several times, and the solid was dried. The product yield was 89.3%, and the product purity was 98.7%.

[0029] Example 3

[0030] Into a 250ml three-necked flask, 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde (20.188g, 0.049mol) and 1-(2-aminoethyl)pyrrolidine (8.392g, 0.0735mol) were added with N,N-dimethylformamide (141.316g) as solvent, and 0.403g of iron-cobalt-oxygen composite material was added. The mixture was stirred until the 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde was completely dissolved, and then the temperature was raised to 70°C for 6 hours. TLC and HPLC were used to determine the completion of the reaction. After the reaction was completed, the catalyst was centrifuged and filtered. The filtrate was added with 300ml of water, and the solid precipitate was collected. The filter cake was washed with water for several times, and the solid was dried. The product yield was 89.3%, and the product purity was 98.7%.

[0031] Example 4

[0032] Into a 250ml three-necked flask, 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde (20.188g, 0.049mol) and 1-(2-aminoethyl)pyrrolidine (8.392g, 0.0735mol) were added with N,N-dimethylformamide (141.316g) as solvent, and 0.403g of iron-cobalt-oxygen composite material was added. The mixture was stirred until the 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde was completely dissolved, and then the temperature was raised to 70°C for 6 hours. TLC and HPLC were used to determine the completion of the reaction. After the reaction was completed, the catalyst was centrifuged and filtered. The filtrate was added with 300ml of water, and the solid precipitate was collected. The filter cake was washed with water for several times, and the solid was dried. The product yield was 89.3%, and the product purity was 98.7%.

[0033] Example 5

[0034] Into a 250ml three-necked flask, 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde (20.188g, 0.049mol) and 1-(2-aminoethyl)pyrrolidine (11.190g, 0.0980mol) were added with N,N-dimethylformamide (161.504g) as solvent, and 0.605g of iron-cobalt-oxygen composite material was added, and stirred until 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde was completely dissolved. The temperature was raised to 70°C and reacted for 7 hours. After TLC and HPLC detection confirmed that the reaction was completed, the catalyst was centrifuged and filtered, 300ml of water was added to the filtrate, the solid precipitate was collected, the filter cake was washed with a small amount of water for several times, and the solid was dried. The product yield was 87.6%, and the product purity was 98.8%.

[0035] Example 6

[0036] Into a 250ml three-necked flask, 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde (20.188g, 0.049mol) and 1-(2-aminoethyl)pyrrolidine (11.190g, 0.0980mol) were added with N,N-dimethylformamide (161.504g) as solvent, and 0.605g of iron-cobalt-oxygen composite material was added, and stirred until 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde was completely dissolved. The temperature was raised to 70°C and reacted for 7 hours. After TLC and HPLC detection confirmed that the reaction was completed, the catalyst was centrifuged and filtered, 300ml of water was added to the filtrate, the solid precipitate was collected, the filter cake was washed with a small amount of water for several times, and the solid was dried. The product yield was 87.6%, and the product purity was 98.8%.

[0037] Example 7

[0038] Into a 250ml three-necked flask, 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde (20.188g, 0.049mol) and 1-(2-aminoethyl)pyrrolidine (11.190g, 0.0980mol) were added with N,N-dimethylformamide (161.504g) as solvent, and 0.605g of iron-cobalt-oxygen composite material was added, and stirred until 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde was completely dissolved. The temperature was raised to 70°C and reacted for 7 hours. After TLC and HPLC detection confirmed that the reaction was completed, the catalyst was centrifuged and filtered, 300ml of water was added to the filtrate, the solid precipitate was collected, the filter cake was washed with a small amount of water for several times, and the solid was dried. The product yield was 87.6%, and the product purity was 98.8%.

[0039] Example 8

[0040] Under the condition of oxygen, 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde (20.188 g, 0.049 mol) and 1-(2-aminoethyl) pyrrolidine (13.988 g, 0.1225 mol) were added into a 250 ml three-necked flask with N,N-dimethylformamide (141.316 g) as solvent, and then 1.009 g of iron-cobalt-oxygen composite was added. The mixture was stirred until 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde was completely dissolved, and then the temperature was raised to 75 °C for 5 hours. After TLC and HPLC detection, it was determined that the reaction was completed. The catalyst was centrifuged and filtered, the filtrate was added with 300 ml of water, and the solid precipitate was collected. The filter cake was washed with water for several times, and the solid was dried. The product yield was 90.1%, and the product purity was 98.8%.

[0041] Comparative Example 1

[0042] Under the condition of oxygen, 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde (20.188 g, 0.049 mol) and 1-(2-aminoethyl) pyrrolidine (5.595 g, 0.0490 mol) were added into a 250 ml three-necked flask with N,N-dimethylformamide (121.128 g) as solvent, and then the mixture was stirred until 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde was completely dissolved. The temperature was raised to 75 °C for 5 hours. After TLC and HPLC detection, it was determined that the reaction was completed. The mixture was centrifuged and filtered, the filtrate was added with 300 ml of water, and the solid precipitate was collected. The filter cake was washed with water for several times, and the solid was dried. The product yield was 27.3%, and the product purity was 95.3%.

[0043] Comparative Example 2

[0044] Under the condition of oxygen, 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde (20.188 g, 0.049 mol) and 1-(2-aminoethyl) pyrrolidine (13.988 g, 0.1225 mol) were added into a 250 ml three-necked flask with N,N-dimethylformamide (9161.504 g) as solvent, and then 1.009 g of iron trichloride was added. The mixture was stirred until 2-chloro-3,4-bis((4-methoxybenzyl)oxy) benzaldehyde was completely dissolved, and then the temperature was raised to 70 °C for 6 hours. After TLC and HPLC detection, it was determined that the reaction was completed. The catalyst was centrifuged and filtered, the filtrate was added with 300 ml of water, and the solid precipitate was collected. The filter cake was washed with water for several times, and the solid was dried. The product yield was 39.8%, and the product purity was 42.5%.

[0045] The above describes the specific embodiments of the present application in combination with the embodiments, but is not a limitation on the embodiments of the present application. Various modifications or variations made by those skilled in the art on the basis of the technical solutions of the present application without creative labor are still within the protection scope of the present application.

Claims

1. A method for preparing a cefdil intermediate, characterized in that, The preparation method is as follows: using an iron-cobalt-oxygen composite material as a catalyst, catalyzes the oxidation reaction of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde with 1-(2-aminoethyl)pyrrolidine, and the reaction equation is as follows: 2-Chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde, 1-(2-aminoethyl)pyrrolidine, and an iron-cobalt-oxy composite material were added to a reaction vessel. The iron-cobalt-oxy composite material was added at a mass of 2%-5% of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde. A solvent was added, and an oxidant O2 was introduced. The mixture was stirred and dispersed, heated, and stirred to react. After the reaction was completed, the mixture was centrifuged, filtered, and the catalyst was removed. The filtrate was collected, water was added, and the mixture was filtered under vacuum. The solid was collected, washed several times with water, and then dried to obtain the product cefdil intermediate solid. The method for preparing the iron-cobalt-oxygen composite material includes the following steps: (1) Weigh 0.4g of cobalt chloride hexahydrate and 0.8g of ferric nitrate nonahydrate and put them into a small beaker. Add a magnetic stir bar and add 10ml of ultrapure water at once. Stir magnetically for 10 minutes. Add 10ml of 2mol / L NaOH solution dropwise to the small beaker. A black precipitate will appear. After the addition is complete, continue stirring for five minutes. (2) The system was transferred to a 50ml hydrothermal reactor, placed in an oven, and heated at 130℃ for 6 hours. After the reactor cooled to room temperature, the material was transferred to a centrifuge tube, centrifuged and washed, washed three times with water and three times with anhydrous ethanol, and dried to obtain the iron-cobalt-oxygen composite material.

2. The method for preparing a cefdil intermediate as described in claim 1, characterized in that, The added solvent is 6.0-8.0 times the mass of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde.

3. The method for preparing a cefdil intermediate as described in claim 1, characterized in that, The molar ratio of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde to 1-(2-aminoethyl)pyrrolidine is 1:1 to 2.

5.

4. The method for preparing a cefdil intermediate as described in claim 1, characterized in that, The solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

5. The method for preparing a cefdil intermediate as described in claim 1, characterized in that, The reaction time of 2-chloro-3,4-bis((4-methoxybenzyl)oxy)benzaldehyde with 1-(2-aminoethyl)pyrrolidine is 5-8 h, and the reaction temperature is 50-80 °C.

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