A preparation method of cephalosporin intermediate

Abstract

The present invention relates to a method for preparing a cephalosporin intermediate, comprising the following steps: S1: adding 7-AMCA and AE-active ester to a reaction system, adjusting the pH of the reaction system to 6.5-10.5, and reacting at 5-30°C; S2: after the reaction, adjusting the pH of the reaction system, crystallizing, growing the crystals, filtering, washing, and drying to obtain the cephalosporin intermediate. The method for preparing the cephalosporin intermediate of the present invention can achieve a weight yield of over 150% and a product purity of over 98%. It has the advantages of simple process, mild conditions, easy operation, low pollution, low energy consumption, suitability for industrial production, and easy solvent recovery.

Description

Technical Field

[0001] The present invention relates to the field of drug preparation, in particular to a method for preparing a cephalosporin intermediate. Background Art

[0002] Cefpodoxime proxetil, chemically known as (6R,7R)-7-[(2Z)-(2-amino-4-thiazolyl)(methoxyimino)acetamido]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1-[[(1-methylethoxy)carbonyl]oxy]ethyl ester, is a broad-spectrum cephalosporin antibacterial prodrug developed by Sankyo Co., Ltd. of Japan. Its structural characteristics are a methoxymethyl group attached to the 3-position of the cephalosporin backbone and an ethylisopropyl carbonate group on the 4-position of the carboxylic acid. The presence of these two substituents contributes to its good oral absorption. The methoxyiminothiazolyl group at the 7-position is closely associated with its anti-Gram-negative activity and β-lactamase resistance. The ethylisopropyl carbonate group has an asymmetric carbon atom, resulting in the formation of two diastereoisomers of cefpodoxime proxetil, both of which are active ingredients. After oral administration, it is rapidly hydrolyzed by intestinal wall esterase to cefpodoxime with antibacterial activity. It was first launched in Japan in 1989 and has good therapeutic effects on various infections caused by common clinical pathogens.

[0003] The chemical name of cefpodoxime acid, a key intermediate in the synthesis of cefpodoxime proxetil, is (6R,7R)-7-[2-(2-amino-4-thiazolyl)-(Z)-2-(methoxyimino)acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. Its quality is a key factor affecting the quality of the cefpodoxime proxetil API. Currently, there is no industrial method for the production of cefpodoxime acid, a key intermediate in cefpodoxime proxetil. Summary of the Invention

[0004] Based on this, the purpose of the present invention is to provide a preparation method of cephalosporin intermediates, which has the advantages of simple process route, good product quality, less discharge of three wastes, easy recovery of organic solvents, green environmental protection, safety, and meeting the requirements of industrial production.

[0005] A method for preparing a cephalosporin intermediate comprises the following steps:

[0006] S1: adding 7-AMCA and AE-active ester to a reaction system, adjusting the pH of the reaction system to 6.5-10.5, and reacting at 5-30°C;

[0007] S2: After the reaction is completed, the pH value of the reaction system is adjusted, crystallization is performed, crystal growth is performed, filtration is performed, washing is performed, and drying is performed to obtain the cephalosporin intermediate.

[0008] The preparation method of a cephalosporin intermediate of the present invention has the advantages of simple process route and good product quality.

[0009] Furthermore, in S1, when adjusting the pH of the reaction system, the base used is one or more of methylamine, ethylamine, diisopropylethylamine, triethylamine, tripropylamine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, ammonia water, sodium carbonate, sodium carbonate, and sodium bicarbonate.

[0010] Furthermore, the reaction system is a mixed solvent of water and acetone, with the volume ratio of water to acetone ranging from 1:0.10 to 1:5.00. Compared to other reaction systems, using an acetone-water mixture as the reaction system offers advantages such as environmental friendliness, ease of recycling, low production costs, and minimal environmental pollution. A water-to-acetone volume ratio of less than 1:0.10 results in virtually no reaction. A water-to-acetone volume ratio greater than 1:5.00 results in an excessively high proportion of acetone, which can affect the reaction.

[0011] Furthermore, in S1, the pH is adjusted with a base, and the weight-to-volume ratio of 7-AMCA to the base is 1:0.10 to 1:3.5. Controlling the weight-to-volume ratio of 7-AMCA to the base within the range of 1:0.10 to 1:3.5 can further ensure that the pH of the reaction system can be controlled within the range of 6.5 to 10.5, thereby ensuring the normal progress of the reaction.

[0012] Furthermore, the weight-to-volume ratio of the 7-AMCA to the AE-active ester is 1:1.05 to 1:2.85. The weight-to-volume ratio of the AE-active ester is slightly higher than the weight-to-volume ratio of the 7-AMCA to the AE-active ester, ensuring complete reaction. Controlling the weight-to-volume ratio of the 7-AMCA to the AE-active ester to 1:1.05 to 1:2.85 can reduce costs while ensuring complete reaction.

[0013] Furthermore, in S2, when adjusting the pH of the reaction system, the reagent used is one or more of formic acid, acetic acid, propionic acid, carbonic acid, phosphoric acid, hydrochloric acid, sulfuric acid, lactic acid, boric acid, and hydrobromic acid.

[0014] Furthermore, in S2, adjusting the pH of the reaction system comprises the following steps: first adjusting the pH to 3.5-7.0, adding water and filtering, and then adjusting the pH of the filtrate to 2.0-3.0. The pH is first adjusted to 3.5-7.0 to further ensure that the reaction stops and to remove some of the acid, thereby reducing potential harm to the human body. The pH is then adjusted to 2.0-3.0 to ensure smooth crystallization of the system and the normal progress of the subsequent crystal growth step.

[0015] Furthermore, during crystallization, the temperature is 0 to 20°C.

[0016] Furthermore, the volume ratio of the water to the acetone is 1:2.50.

[0017] For better understanding and implementation, the present invention is described in detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is a chromatogram of a cephalosporin intermediate described in Example 1;

[0019] Figure 2 This is a chromatogram of a cephalosporin intermediate described in Example 2;

[0020] Figure 3 The chromatogram is a cephalosporin intermediate described in Example 3. DETAILED DESCRIPTION

[0021] Example 1

[0022] This embodiment provides a method for preparing a cephalosporin intermediate, wherein the cephalosporin intermediate is cefpodoxime (cefpodoxime acid), comprising the following steps:

[0023] To a 2L three-necked flask, 176ml of water and 307ml of acetone were added; 36g of 7-amino-3-methoxymethyl-2-cephem-2-carboxylic acid (7-AMCA) and 54g of 2-methoxyimino-2-(2-amino-4-thiazolyl)-(z)-phenylhydrazinethiazolylthioate (AE-active ester, i.e., MAEM) were added to the flask with stirring; the flask was cooled until the temperature of the reaction system dropped to just below 5°C, and 39ml of triethylamine was added dropwise to the flask over a period of 1.5 to 3.0 hours, with the pH not exceeding 8.0 during the addition; the temperature was maintained at 6°C until the reaction was complete.

[0024] After the reaction is completed, the pH value of the solution in the three-necked flask is adjusted to 4.5 with 6 mol / L hydrochloric acid solution; after adding water, filter, and adjust the pH of the filtrate to 2.5 with 6 mol / L hydrochloric acid solution at 10°C, and stir to grow crystals for 90 minutes; after growing crystals, filter, wash the resulting crystals with 100 ml of water, and then drain; then wash the resulting crystals with 100 ml of acetone, and then drain; vacuum dry at 40-50°C; 55.8 g of cephalosporin intermediate product is obtained, with a weight yield of 155% and a purity of 99.11%. The chromatogram of the cephalosporin intermediate product is as follows Figure 1 shown.

[0025] The method for preparing a cephalosporin intermediate described in this embodiment utilizes an acetone and water mixture as the reaction system. Compared to other reaction systems, this method offers advantages such as environmental friendliness, ease of recovery, and low production costs, resulting in less environmental pollution. In other systems, such as the dichloromethane system, dichloromethane has a low melting point and readily evaporates during recovery, leading to low dichloromethane recovery rates and high production costs. Furthermore, if the mother liquor is not recovered and incinerated, the dichloromethane can produce dioxins during incineration, significantly polluting the environment. However, the acetone and water mixture used in this embodiment not only allows for the recovery of approximately 90% of the acetone through simple distillation, offering advantages such as ease of recovery and low production costs, but also, even without recovery, the incineration of the acetone mother liquor does not produce pollutants such as dioxins.

[0026] In addition, the method for preparing a cephalosporin intermediate described in this embodiment has simple steps, is easy to implement, and is easy to mass produce. The raw materials are basically added during the feeding stage, and the conditions during the feeding stage are simple to control. For example, the pH can be continuously controlled by simply controlling the dripping rate of triethylamine. Frequent addition of materials can be avoided during mass production, and the quality is easy to monitor.

[0027] In general, the method for preparing a cephalosporin intermediate described in this embodiment has the advantages of a simple process route, good product quality, less discharge of three wastes, easy recovery of organic solvents, green environmental protection, safety, and ability to meet industrial production requirements.

[0028] Example 2

[0029] This embodiment provides a method for preparing a cephalosporin intermediate, comprising the following steps:

[0030] To a 2 L three-necked flask, add 150 ml of water and 300 ml of acetone. While stirring, add 30 g of 7-AMCA and 50 g of MAEM to the flask. Cool the flask until the reaction system temperature drops to just below 5°C. Add 39 mL of triethylamine dropwise to the flask over a period of 1.5 to 3.0 hours, ensuring that the pH does not exceed 8.0. Maintain the temperature at 15°C until the reaction is complete.

[0031] After the reaction is completed, the pH value of the solution in the three-necked flask is adjusted to 5.0 with 6 mol / L hydrochloric acid solution; after adding water, filter, and adjust the pH of the filtrate to 2.5 with 6 mol / L hydrochloric acid solution at 10°C, and stir to grow crystals for 90 minutes; after growing crystals, filter, wash the resulting crystals with 100 ml of water, and then drain; then wash the resulting crystals with 100 ml of acetone, and then drain; vacuum dry at 40-50°C; 45.0 g of cephalosporin intermediate product is obtained, with a weight yield of 150% and a purity of 98.93%. The chromatogram of the cephalosporin intermediate product is as follows: Figure 2shown.

[0032] Example 3

[0033] This embodiment provides a method for preparing a cephalosporin intermediate, comprising the following steps:

[0034] To a 2L three-necked flask, add 176mL of water and 307mL of acetone. While stirring, add 36g of 7-AMCA and 54g of MAEM to the flask. Cool the flask until the reaction temperature drops to just below 5°C. Rapidly add 10mL of triethylamine, followed by the slow dropwise addition of 29mL of triethylamine over a 1.5-hour period, ensuring that the pH does not exceed 8.0. Maintain the temperature at 25-30°C until the reaction is complete.

[0035] After the reaction, the pH value of the solution in the three-necked flask was adjusted to 4.3 with 6 mol / L hydrochloric acid solution; after adding water, the solution was filtered, and the pH of the filtrate was adjusted to 2.5 with 6 mol / L hydrochloric acid solution at 10°C, and the solution was stirred and crystallized for 90 minutes; after the crystallization was completed, the solution was filtered, and the resulting crystals were washed with 100 ml of water and dried; the resulting crystals were then washed with 100 ml of acetone and dried; the solution was vacuum dried at 40-50°C; 55.6 g of cephalosporin intermediate product was obtained, with a weight yield of 154.4% and a purity of 99.22%. The chromatogram of the cephalosporin intermediate product is shown in FIG. Figure 3 shown.

[0036] Example 4

[0037] This embodiment provides a method for preparing a cephalosporin intermediate, comprising the following steps:

[0038] To a 2L three-necked flask, 483ml of acetone was added; 36g of 7-AMCA and 54g of MAEM were added to the flask with stirring; the flask was cooled until the temperature of the reaction system dropped to just below 5°C, and 39ml of triethylamine was added dropwise to the flask. The addition time was controlled to be 1.5 to 3.0 hours, and the pH was controlled not to exceed 8.0 during the addition. The temperature was maintained at 6°C. Monitoring indicated that the system was essentially unresponsive.

[0039] Example 5

[0040] This embodiment provides a method for preparing a cephalosporin intermediate, comprising the following steps:

[0041] To a 2L three-necked flask, 483ml of water was added; 36g of 7-AMCA and 54g of MAEM were added to the flask with stirring; the flask was cooled until the temperature of the reaction system dropped to just below 5°C, and 39ml of triethylamine was added dropwise to the flask. The addition time was controlled to be 1.5 to 3.0 hours, and the pH was controlled not to exceed 8.0 during the addition. The temperature was maintained at 6°C. Monitoring indicated that the system was essentially unresponsive.

[0042] Example 6

[0043] This embodiment provides a method for preparing a cephalosporin intermediate, comprising the following steps:

[0044] To a 2 L three-necked flask, 483 ml of dichloromethane was added; 36 g of 7-AMCA and 54 g of MAEM were added to the flask with stirring; the flask was cooled until the temperature of the reaction system dropped to just below 5°C, and 39 mL of triethylamine was added dropwise to the flask. The addition time was controlled to 1.5 to 3.0 hours, and the pH was maintained at no more than 8.0 during the addition. The temperature was maintained at 6°C. Monitoring indicated that the system was essentially unresponsive.

[0045] The above-described embodiments merely represent several implementations of the present invention. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous modifications and improvements without departing from the spirit of the present invention, and the present invention is intended to encompass such modifications and variations.

Claims

1. A method for preparing a cephalosporin intermediate, characterized in that: The following steps are involved: S1: adding 7-AMCA and AE-active ester to a reaction system, and when the temperature of the reaction system drops to just below 5°C, adjusting the pH of the reaction system to 6.5-10.5 with a base, and then reacting at 5-30°C; the reaction system is a mixed solvent of water and acetone, and the volume ratio of the water to the acetone is 1:2.50; when adjusting the pH of the reaction system with a base, controlling the addition time of the base to be 1.5-3.0 hours; S2: After the reaction is completed, the pH value of the reaction system is adjusted, crystallization is performed, crystal growth is performed, filtration is performed, washing is performed, and drying is performed to obtain the cephalosporin intermediate.

2. The method for preparing a cephalosporin intermediate according to claim 1, wherein In S1, when adjusting the pH of the reaction system, the base used is one or more of methylamine, ethylamine, diisopropylethylamine, triethylamine, tripropylamine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, ammonia water, sodium carbonate, and sodium bicarbonate.

3. The method for preparing a cephalosporin intermediate according to claim 1, wherein In S1, the weight-to-volume ratio of the 7-AMCA to the base is 1:0.10 to 1:3.

5.

4. The method for preparing a cephalosporin intermediate according to claim 1, wherein The weight-to-volume ratio of the 7-AMCA to the AE-active ester is 1:1.05 to 1:2.

85.

5. The method for preparing a cephalosporin intermediate according to claim 1, wherein In S2, when adjusting the pH of the reaction system, the reagent used is one or more of formic acid, acetic acid, propionic acid, carbonic acid, phosphoric acid, hydrochloric acid, sulfuric acid, lactic acid, boric acid, and hydrobromic acid.

6. The method for preparing a cephalosporin intermediate according to claim 1, wherein In S2, adjusting the pH value of the reaction system comprises the following steps: first adjusting the pH value to 3.5-7.0, adding water and filtering, and then adjusting the pH value of the filtrate to 2.0-3.

0.

7. The method for preparing a cephalosporin intermediate according to claim 1, wherein During crystallization, the temperature is 0-20°C.

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