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Method of synthesizing cefepime intermediate in mixed solvent

A synthesis method and mixed solvent technology, which is applied in the synthesis of intermediates and the field of synthesis of -7-amino-3-[methyl]ceph-3-ene-4-carboxylate hydrochloride, can solve the problem of long reaction time , Affect product quality and yield, product color and poor quality and other issues, to achieve high quality, high yield effect

Inactive Publication Date: 2007-10-17
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

More importantly, it replaces the CFCS substances that are harmful to the atmosphere as a solvent for the reaction, but the experiment found that: using C 5 -C 8 The cycloalkane replaces Freon TF as the solvent. This type of solvent has a small solubility for the reaction product, resulting in a longer reaction time, poorer color and quality of the product, and affecting the quality and yield of the final product.

Method used

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  • Method of synthesizing cefepime intermediate in mixed solvent
  • Method of synthesizing cefepime intermediate in mixed solvent
  • Method of synthesizing cefepime intermediate in mixed solvent

Examples

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Effect test

Embodiment 1

[0030] Example 1: (6R, 7R)-7-amino-3-[(1-methyl-1-pyrrolidine)methyl]ceph-3-ene-4-carboxylate hydrochloride (1)(7- ACP) preparation

[0031]In a 500mL four-neck flask equipped with a stirrer, condenser, thermometer and dropping funnel, add 40g (0.147mol) of 7-ACA and 200mL of dichloromethane, and add 36mL (0.170mol) of hexamethyldisilamine at room temperature 20°C Alkanes (HMDS) and 0.2mL trimethyl iodosilane (TMSI), heated to reflux for 8-12hrs under the protection of nitrogen, after checking that no ammonia gas is released, cool the solution to 0-5°C, and add it slowly under the protection of nitrogen 26.3 mL (0.183 mol) of iodotrimethylsilane (TMSI), kept at a temperature not exceeding 10-25°C, and reacted for 2 hours while stirring and keeping warm. HPLC detection 7-ACA iodide has been completed. Dichloromethane was recovered under reduced pressure, 130-150 mL was distilled, and the distillation temperature was lower than 20°C. The reaction solution was cooled to -30°C,...

Embodiment 2

[0034] Example 2: (6R, 7R)-7-amino-3-[(1-methyl-1-pyrrolidine) methyl] ceph-3-ene-4-carboxylic acid iodate (7-ACP) preparation

[0035] In a 500mL four-neck flask equipped with a stirrer, condenser, thermometer and dropping funnel, add 40g (0.147mol) of 7-ACA and 200mL of dichloromethane, and add 36mL (0.170mol) of hexamethyldisilamine at room temperature 20°C Alkanes (HMDS) and 0.2mL trimethyl iodosilane (TMSI), heated to reflux for 8-12hrs under the protection of nitrogen, after detecting that no ammonia gas is released, cool the solution to 0-5°C, and under the protection of nitrogen, slowly add 26.3 mL (0.183 mol) of iodotrimethylsilane (TMSI), kept at a temperature not exceeding 10-25°C, and reacted for 2 hours while stirring and keeping warm. HPLC detection 7-ACA iodide has been completed. Dichloromethane was recovered under reduced pressure, and 130-150 mL was distilled out, and the distillation temperature was lower than 20°C. The reaction solution was cooled to -30...

Embodiment 3

[0037] Example 3: (6R, 7R)-7-amino-3-[(1-methyl-1-pyrrolidine)methyl]ceph-3-ene-4-carboxylate hydrochloride (1)(7- ACP) preparation

[0038] In a 500mL four-neck flask equipped with a stirrer, condenser, thermometer and dropping funnel, add 40g (0.147mol) of 7-ACA and 200mL of dichloromethane, and add 36mL (0.170mol) of hexamethyldisilazol at room temperature 20°C Amane (HMDS) and 0.2mL trimethyl iodosilane (TMSI), heated to reflux for 8-12hr under the protection of nitrogen, after detecting that no ammonia gas is released, cool the solution to 0-5°C, under the protection of nitrogen, stir slowly Add 26.3 mL (0.183 mol) of iodotrimethylsilane (TMSI), keep the temperature not exceeding 10-25° C., and react for 2 h under stirring and heat preservation. HPLC detection 7-ACA iodide has been completed. Dichloromethane was recovered under reduced pressure, 130-150 mL was distilled, and the distillation temperature was lower than 20°C. The reaction solution was cooled to -30°C, an...

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Abstract

The present invention provides a method for synthesizing cefepime intermidiate in mixed solvent. The method is : using 7-ACA as material, generating 3-iodo intermediate and reacting with N-methyl pyrrolidine in mixed solution of methylene chloride and N,N-dimethyl formamide etc, high quality, high yield, delta2 isomer-free cefepime intermidiate 7-amido-3-[(1-methyldihydropyrrole)methyl]-3-cepha-4- carboxylate hydrochloride (7-ACP) 7-ACP yield amounts to 80% (mol yield) and is higher than existing technology. Tone grade of 7-ACP is less than 3,and purity is larger than 99.5%.

Description

technical field [0001] The invention belongs to the field of pharmaceutical intermediates, and relates to a method for synthesizing intermediates of cephalosporin antibiotics, in particular to (6R, 7R)-7-amino-3-[(1-methyl-1-pyrrolidine) formazan Base] the synthetic method of cephalosporin-3-ene-4-carboxylic acid hydrochloride (7-ACP). Background technique [0002] Cefepime hydrochloride is the fourth-generation cephalosporin for injection, developed by Boomer-Squibb Company, it has a broad antibacterial spectrum, strong antibacterial effect, high stability to β-lactamase, and good drug tolerance, so It is a promising antibiotic, and the key intermediate for its synthesis is (6R,7R)-7-amino-3-[(1-methyl-1-pyrrolidine)methyl]ceph-3-ene- 4-Acid salts of carboxylic acids (7-ACP), where HX is HCl, HI and H 2 SO 4 , as shown in the following formula (I). [0003] [0004] U.S. Patent No. 4,868,294 and U.S. No. 4,714,760 etc. disclose the preparation method of cefepime hydr...

Claims

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Application Information

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IPC IPC(8): C07D501/18
CPCY02P20/55
Inventor 郑庚修王秋芬高国庆侯乐伟张淑芳
Owner UNIV OF JINAN
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