Preparation method of cefprozil EP impurity E
The four-step synthesis method for preparing cefprozil EP impurity E fills the gap in preparation methods, realizes a simple and efficient synthesis and high-purity product, and provides a foundation for cefprozil drug quality research.
Patent Information
- Application Number
- CN202411126487.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-16
- Publication Date
- 2026-03-03
AI Technical Summary
The lack of a preparation method for cefprozil EP impurity E currently affects drug quality research and control.
A four-step synthetic method was adopted, including intermolecular dimerization in organic solvents, carboxyl protection, condensation reaction and deprotection under acidic conditions, using specific solvents and catalysts, and optimizing reaction conditions to prepare cefprozil E impurity E.
The preparation route is concise and simple to operate, and the product has high purity. It provides high-purity cefprozil EP impurity E as a quality study control.
Smart Images
Figure CN121591755A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing cefprozil EP impurity E. Background Technology
[0002] Cefprozil is a second-generation cephalosporin antibiotic, developed by Bristol-Myers Squibb in 1983 and approved by the FDA on December 24, 1991. It is characterized by high efficacy, low toxicity, enzyme resistance, and broad spectrum. It was also the first oral cephalosporin antibiotic approved by the FDA for the treatment of otitis media and sinusitis in children. Cefprozil exhibits strong antibacterial activity against β-lactamase-producing strains of Staphylococcus aureus, Haemophilus influenzae, and Moraxella catarrhalis. Clinically, it is mainly used for respiratory, skin, and soft tissue infections caused by susceptible bacteria, and is one of the most in-demand antibacterial drugs both domestically and internationally.
[0003] Impurity research is a key research area in drug development and commercial production, and it is conducted throughout the entire drug lifecycle. The presence of impurities directly affects the safety, efficacy, and quality control of drugs.
[0004] Impurity E in cefprozil EP is an impurity listed in the European Pharmacopoeia. It is an essential impurity to be studied in the quality research of cefprozil raw materials and preparations. Its content seriously affects the quality of the drug. Therefore, the synthesis research of cefprozil EP impurity E is very necessary and has important practical significance.
[0005] Currently, there are no literature reports on the preparation method of cefprozil EP impurity E.
[0006] This invention provides a method for preparing cefprozil EP impurity E. The preparation method involved in this invention has a short route, simple operation, convenient purification, and high product purity. Summary of the Invention
[0007] The purpose of this invention is to provide a method for preparing cefprozil EP impurity E.
[0008] This invention provides cefprozil EP impurity E (compound of formula VI), the structural formula of which is as follows:
[0009] This invention also provides a method for preparing cefprozil EP impurity E (compound of formula VI), comprising the following steps: (1) Compound I is prepared by intermolecular dimerization of compound I in at least one organic solvent in the presence of a condensing agent to obtain compound II; (2) Compound of Formula IV is prepared by attaching a carboxyl protecting group to compound of Formula III in at least one organic solvent; (3) In at least one organic solvent, in the presence of a condensing agent, compound II and compound IV undergo a condensation reaction to prepare compound V; (4) In at least one organic solvent under acidic conditions, compound V is deprotected to prepare cefprozil EP impurity E (compound VI).
[0010] The organic solvent in step (1) is selected from tetrahydrofuran, dichloromethane, and N,N-dimethylformamide, preferably tetrahydrofuran, and the volume of the organic solvent is 5-50 times (mL / g) of the mass of the compound of formula I, preferably 10 times.
[0011] In step (1), the condensing agent is selected from N,N'-dicyclohexylcarbodiimide, and the molar ratio of the condensing agent to the compound of formula I is 0.5:1.
[0012] The catalyst in step (1) is selected from 4-dimethylaminopyridine, and the molar ratio of the catalyst to the compound of formula I is 0.05:1.
[0013] In step (1), the reaction temperature is 0°C to 60°C, preferably 25°C. The reaction time is 2 to 48 hours, preferably 18 hours.
[0014] In step (2), the carboxyl protecting group is selected from benzophenone tracer, and the molar ratio of benzophenone tracer to compound III is 1 to 5:1, preferably 2:1.
[0015] In step (2), the oxidant is selected from manganese dioxide, and the molar ratio of manganese dioxide to compound III is 2 to 10:1, preferably 6:1.
[0016] The organic solvent in step (2) is selected from tetrahydrofuran, dichloromethane, trichloromethane, and methanol, preferably dichloromethane, and the volume of the organic solvent is 5-50 times (mL / g) of the mass of the compound of formula III, preferably 20 times.
[0017] In step (2), the reaction temperature is 0 to 50 degrees, preferably 25 degrees, and the reaction time is 2 to 48 hours, preferably 18 hours.
[0018] The organic solvent in step (3) is selected from dichloromethane, tetrahydrofuran, and N,N-dimethylformamide, preferably dichloromethane, and the volume of the organic solvent is 5-50 times (mL / g) of the mass of the compound of formula III, preferably 10 times.
[0019] In step (3), the condensing agent is selected from N,N'-dicyclohexylcarbodiimide, HATU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, preferably N,N'-dicyclohexylcarbodiimide, and the molar ratio of the condensing agent to the compound of formula I is 1 to 2:1, preferably 1:1.
[0020] In step (3), the molar ratio of compound IV to compound II is 1 to 2:1, preferably 1.2:1.
[0021] In step (2), the reaction temperature is 0 to 50 degrees, preferably 25 degrees, and the reaction time is 2 to 48 hours, preferably 18 hours.
[0022] In step (4), the organic solvent is selected from dichloromethane and tetrahydrofuran, preferably dichloromethane, and the volume of the organic solvent is 5-20 times (mL / g) of the mass of compound V, preferably 5 times.
[0023] In step (4), the acid is selected from trifluoroacetic acid and hydrochloric acid, preferably trifluoroacetic acid. The volume of the acid is 5-20 times (mL / g) the mass of the compound of formula V, preferably 5 times.
[0024] In step (4), the reaction temperature is 0 to 25 degrees, preferably 0 degrees, and the reaction time is 2 to 24 hours, preferably 2 hours.
[0025] Due to the application of the above technical solutions, the present invention has the following advantages: the route is short, the operation is simple, the purification is convenient, and the product purity is high. The cefprozil EP impurity E (compound of formula VI) prepared by the present invention can be used as a reference standard for cefprozil-related substances, providing a basis for the quality research of cefprozil. Attached Figure Description
[0026] Figure 1 This is the high performance liquid chromatogram of cefprozil EP impurity E (compound of formula VI) in example step (4).
[0027] Figure 2 The mass spectrometry of cefprozil EP impurity E (formula VI compound) in example step (4) is shown.
[0028] Figure 3 The 1H NMR spectrum of cefprozil EP impurity E (compound of formula VI) in example step (4) is shown. Detailed Implementation
[0029] It should be understood that those skilled in the art can make various modifications and improvements to the present invention without departing from the spirit and scope of the invention, based on the content disclosed herein. All such modifications and improvements should fall within the patent protection scope defined by the claims of this application. Furthermore, it should be understood that the embodiments provided herein are for illustrative purposes only and should not be construed as limitations of the invention.
[0030] The present invention will be further described in detail below with reference to specific embodiments.
[0031] Example: (1) Preparation of compound II: 10g of compound I was dissolved in 100ml of tetrahydrofuran. 3.86g of N,N'-dicyclohexylcarbodiimide and 0.23g of 4-dimethylaminopyridine were added at room temperature. The reaction was carried out overnight at room temperature. TLC showed that most of the starting material had reacted. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was dried by rotary evaporation and purified by column chromatography to obtain 6g of compound II. (2) Preparation of compound IV: 16.34 g of benzophenone was dissolved in 200 ml of dichloromethane. 21.71 g of manganese dioxide was added at room temperature and the reaction was carried out for 2 h at room temperature. TLC showed that the benzophenone reaction was complete. The reaction solution was filtered, and the filter cake was washed with dichloromethane until no color was observed. The filtrate was concentrated to 200 ml, and 10 g of compound III was added. The reaction was carried out overnight at room temperature. TLC showed that compound III reaction was complete. The reaction solution was evaporated to dryness and purified by column chromatography with silica gel to obtain 16 g of compound IV. (3) Preparation of compound V: 10g of compound IV was dissolved in 100ml of dichloromethane, 15.14g of compound II was added, and then 6.05g of N,N'-dicyclohexylcarbodiimide was added. The reaction was carried out overnight at room temperature. TLC showed that the reaction of compound IV was complete. Water was added to the reaction solution, and then the mixture was extracted with dichloromethane. The organic phase was dried by rotary evaporation and purified by column chromatography to obtain 18g of compound V. (3) Preparation of cefprozil EP impurity E (compound of formula VI). 18 g of compound V was dissolved in 90 ml of dichloromethane, cooled to 0°C, and 90 ml of trifluoroacetic acid was added. The reaction was carried out at 0°C for 2 hours. TLC showed the reaction was complete. The reaction solution was evaporated to dryness and purified by preparative liquid chromatography to obtain 2 g of cefprozil EP impurity E (compound of formula VI), a white solid. Characterization data are as follows: Figure 1 High performance liquid chromatography purity: 98.98%, chromatogram 2 (mass spectrometry [M+H]) + =539.1595, [M+Na] + =561.1403,[M+K] + =577.1142, Figure 3 1H NMR spectrum (400MHz, D2O).
Claims
1. The structural formula of a cefprozil EP impurity E (compound of formula VI) is as follows:
2. A method for preparing cefprozil EP impurity E (compound of formula VI), characterized in that: The method includes the following steps: (1) Compound I is prepared by intermolecular dimerization of compound I in at least one organic solvent in the presence of a condensing agent to obtain compound II; (2) Compound of Formula IV is prepared by attaching a carboxyl protecting group to compound of Formula III in at least one organic solvent; (3) In at least one organic solvent, in the presence of a condensing agent, compound II and compound IV undergo a condensation reaction to prepare compound V; (4) In at least one organic solvent under acidic conditions, compound V is deprotected to prepare cefprozil EP impurity E (compound VI).
3. The method as described in claim 2, characterized in that: The organic solvent in step (1) is selected from tetrahydrofuran, dichloromethane, and N,N-dimethylformamide, preferably tetrahydrofuran. The volume of the organic solvent is 5-50 times (mL / g) the mass of the compound of formula I, preferably 10 times.
4. The method as described in claim 2, characterized in that: The condensing agent in step (1) is selected from N,N'-dicyclohexylcarbodiimide, and the molar ratio of the condensing agent to the compound of formula I is 0.5:
1.
5. The method as described in claim 2, characterized in that: The catalyst in step (1) is selected from 4-dimethylaminopyridine, and the molar ratio of the catalyst to the compound of formula I is 0.05:
1.
6. The method as described in claim 2, characterized in that: The reaction temperature in step (1) is 0 degrees to 60 degrees, preferably 25 degrees, and the reaction time is 2 to 48 hours, preferably 18 hours.
7. The method as described in claim 2, characterized in that: The carboxyl protecting group in step (2) is selected from benzophenone tracer, and the molar ratio of benzophenone tracer to compound of formula III is 1 to 5:1, preferably 2:
1.
8. The method as described in claim 2, characterized in that: The oxidant in step (2) is selected from manganese dioxide, and the molar ratio of manganese dioxide to compound III is 2 to 10:1, preferably 6:
1.
9. The method as described in claim 2, characterized in that: The organic solvent in step (2) is selected from tetrahydrofuran, dichloromethane, trichloromethane, and methanol, preferably dichloromethane. The volume of the organic solvent is 5-50 times (mL / g) the mass of the compound of formula III, preferably 20 times.
10. The method as described in claim 2, characterized in that: The reaction temperature in step (2) is 0 degrees to 50 degrees, preferably 25 degrees, and the reaction time is 2 to 48 hours, preferably 18 hours.
11. The method as described in claim 2, characterized in that: The organic solvent in step (3) is selected from dichloromethane, tetrahydrofuran, and N,N-dimethylformamide, preferably dichloromethane. The volume of the organic solvent is 5-50 times (mL / g) the mass of the compound of formula III, preferably 10 times.
12. The method as described in claim 2, characterized in that: The condensing agent in step (3) is selected from N,N'-dicyclohexylcarbodiimide, HATU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, preferably N,N'-dicyclohexylcarbodiimide, and the molar ratio of the condensing agent to the compound of formula I is 1 to 2:1, preferably 1:
1.
13. The method as described in claim 2, characterized in that: In step (3), the molar ratio of compound IV to compound II is 1 to 2:1, preferably 1.2:
1.
14. The method as described in claim 2, characterized in that: The reaction temperature in step (2) is 0 degrees to 50 degrees, preferably 25 degrees, and the reaction time is 2 to 48 hours, preferably 18 hours.
15. The method as described in claim 2, characterized in that: The organic solvent in step (4) is selected from dichloromethane and tetrahydrofuran, preferably dichloromethane, and the volume of the organic solvent is 5-20 times (mL / g) of the mass of compound V, preferably 5 times.
16. The method as described in claim 2, characterized in that: The acid in step (4) is selected from trifluoroacetic acid and hydrochloric acid, preferably trifluoroacetic acid, and the volume of the acid is 5-20 times (mL / g) of the mass of the compound of formula V, preferably 5 times.
17. The method as described in claim 2, characterized in that: The reaction temperature in step (4) is 0 degrees to 25 degrees, preferably 0 degrees, and the reaction time is 2 to 24 hours, preferably 2 hours.