Preparation method of cefepime hydrochloride

A technology of cefepime hydrochloride and acetyl chloride hydrochloride, which is applied in the field of preparation of cefepime hydrochloride, can solve the problems of unavailable raw materials, complicated process, harsh reaction conditions, etc., and avoid harsh reaction conditions and temperature, and simple operation process , the effect of mild reaction conditions

Active Publication Date: 2011-01-05
HAINAN HULUWA PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the cefepime hydrochloride synthesized by the prior art generally has the defects of inhomogeneous crystal form, poor fluidity and high content of related substances. Meanwhile, in the existing synthetic method of cefepime hydrochloride, the reaction conditions are harsh, the raw materials are not easy to obtain, and the process Complexity, low yield, low product purity, and the solvent used in the reaction is highly toxic, cannot be recycled, pollutes the environment, and costs high
[0006] Chinese patent application CN200810022542.3 discloses a method for synthesizing the antibiotic cefepime hydrochloride. The method uses

Method used

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  • Preparation method of cefepime hydrochloride
  • Preparation method of cefepime hydrochloride
  • Preparation method of cefepime hydrochloride

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Experimental program
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Embodiment 1

[0053] Intermediate I: Preparation of 2-methoxyimino-2-(2-aminothiazol-4-yl)acetyl chloride hydrochloride: Add DMF (8.76L, 113mol) and dichloromethane (375L) to a reaction flask , control the temperature at 5°C, add dropwise oxalyl chloride (9.64L, 111mol), stir for 10 minutes, cool down to -25°C, and add 2-methoxyimino-2-( 2-aminothiazol-4-yl)acetic acid hydrochloride (25kg, 104mol), stirred at this temperature for 2.5 hours, filtered under nitrogen atmosphere, and the resulting solid was washed with 80L of dichloromethane and dried in vacuum at -25°C (via P 2 o 5 ), to obtain 23.48kg (90mol) of light yellow solid, based on the mass of 2-methoxyimino-2-(2-aminothiazol-4-yl) acetic acid hydrochloride, the yield of light yellow solid is 93.92% .

Embodiment 2

[0055] Intermediate II: Preparation of hydriodated (6R,7R)-7-amino-3-[(1-methyl-1-tetrahydropyrrolidine)methyl]-3-cephem-4-carboxylic acid betaine :

[0056] (1) Preparation of silylated 7-ACA slurry: add 7-ACA (20.0kg, 73.5mol) and 140L of anhydrous cyclohexane into the reaction flask, add hexamethyldisilazane (18.6 L, 88.0mol) and trimethyliodosilane (0.4L, 2.8mol) were refluxed at 55°C for 12 hours to obtain (19.92kg, 73.21mol) silylated silylated 7-ACA, which was cooled for later use.

[0057] (2) Preparation of silylated N-methyltetrahydropyrrolidine slurry: add N-methyltetrahydropyrrole (10.68L, 102.7mol) and 40L cyclohexane into the reaction flask, and add trimethylpyrrole at a controlled temperature of 20°C Iodosilane (14.6 L, 102.7 mol) was stirred for 10 minutes to obtain (10.12 L, 97.31 mol) of silylated N-methyltetrahydropyrrolidine.

[0058] (3) Preparation of Intermediate II: Under nitrogen protection, mix the above-mentioned silylated 7-ACA slurry and silylate...

Embodiment 3

[0060] Preparation of cefepime hydrochloride: Under nitrogen atmosphere at 20°C, under stirring, hydroiodate (6R, 7R)-7-amino-3-[(1-methyl-1-tetrahydropyrrole) of intermediate II Alkyl)methyl]-3-cephem-4-formic acid betaine (18.82kg, 42.38mol) was dissolved in 300L of dichloromethane, and 5.8L of trimethylsilyl chloride and 5.8L of hexamethyldisilazane were added successively. L to obtain the reaction solution. Gradually raise the temperature of the reaction solution to 25°C and keep it warm for 1.5 hours, then cool down to -40°C, within -40 to -20°C, within 40 minutes, sequentially add intermediate I 2-methoxyimino-2-( 2-aminothiazol-4-yl) acetyl chloride hydrochloride 23.48kg and triethylamine 22.9L, the resulting slurry was stirred at a temperature of 10°C and a stirring speed of 246r / min for 45 minutes, and then added within 10 minutes 70L of water was stirred at room temperature at a stirring speed of 246.5r / min for 1 hour to dissolve the solids, and the insolubles were ...

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Abstract

The invention discloses a preparation method of cefepime hydrochloride, comprising the following steps of: reacting oxalyl chloride with 2-methoxyimino-2-(2-aminothiazole-4-yl) acetic acid hydrochloride to obtain a midbody I, i.e. 2-methoxyimino-2-(2-aminothiazole-4-yl) acetyl chloride hydrochloride; mixing silanized 7-aminoce-phalosporanic acid and silanized N-methylpyrrolidine, and reacting to obtain a midbody II, i.e. hydriodic acidification (6R, 7R)-7-amino-3-[(1-methyl-1-tetrahydro pyrrolidine) methyl]-3-cephem-4-formic betaine, in the presence of trimethyl idodine silicon hydride, isopropanol and an aqueous solution of hydrogen iodide; dissolving the midbody II into dichloromethane, sequentially adding trimethylchlorosilane and hexamethyldisilazane for reaction, and then adding the midbody I and triethylamine to react to prepare the cefepime hydrochloride. The cefepime hydrochloride prepared by the method has the advantages of uniform crystal form, good flowability and simple process and is suitable for industrialized production.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of cefepime hydrochloride. Background technique [0002] Cefepime hydrochloride, whose trade name is Maspin, was developed by Boomer-Squibb Company and launched in Switzerland in 1993; in 1998, Shanghai Bristol-Myers Squibb Company introduced it and sold it in my country. The chemical name of cefepime hydrochloride is: 1-[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)-glyoxylamide]-2-carboxy-8-oxo- 5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolium salt, 72-(Z)-(O-methyloxime) Dihydrochloride monohydrate; the structural formula is: [0003] [0004] Cefepime hydrochloride is the fourth-generation cephalosporin for injection, which is based on the molecular structure of the third-generation cephalosporin, and introduces c-3 at the c-3 position of the 7-aminocephalosporanic acid (7-ACA) nucleus 'Quaternary amino substituent compounds. Com...

Claims

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Application Information

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IPC IPC(8): C07D501/46C07D501/06
Inventor 刘全国陈克领
Owner HAINAN HULUWA PHARMA GRP CO LTD
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