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Cephalosporin analog antibiotic preparation method

A cephalosporin and halogen technology, applied in the direction of medical preparations containing active ingredients, pharmaceutical formulas, active ingredients of nitro compounds, etc., can solve the problems of environmental pollution of chemical substances, low total product yield, complex reactions, etc., and achieve The effect of reducing reaction steps, high purity of raw materials, and improvement of total yield

Inactive Publication Date: 2008-01-16
ZHEJIANG ZHENYUAN PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0039] But adopt existing production method to prepare cephalosporin antibiotic and there are many shortcomings, for example, the raw material purity is not high, under alkaline conditions, hydrolysis encounters alkali-labile 7-ACA (2) and produces degradative substance, thereby influences conversion rate and Product purity; complex reactions, low total yield of final products; chemical substances used or produced pollute the environment, etc.

Method used

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  • Cephalosporin analog antibiotic preparation method
  • Cephalosporin analog antibiotic preparation method
  • Cephalosporin analog antibiotic preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Embodiment 1: the preparation of cefpodoxime axetil (6a)

[0117] This example relates to compound 6a [(6R, 7R)-7-[2-(2-aminothiazol-4-yl)-(Z)-methoxyimino-acetylamino]-3-methoxymethyl-8 -Oxo-5-thio-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid-1-(isopropylcarbonyloxy) ethyl ester], its preparation process is as follows :

[0118]

[0119] Concrete synthetic steps are as follows:

[0120] (1) (6R, 7R)-7-[2-(2-aminothiazol-4-yl)-(Z)-methoxyimino-acetylamino]-3-hydroxymethyl-8-oxo-5 - Preparation of Sodium Thio-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylate (Compound 11)

[0121] Suspend 1.15g (5mmol) of compound 8 in 0.3g (2.8mmol) Na at 5-10°C 2 CO 3 Add 1.93g (5.62mmol) of compound 10 to 18ml of acetone aqueous solution, stir for 30 minutes, then naturally warm up to room temperature, react for 5 hours, filter, remove the solid, the filtrate decompresses and recovers acetone to obtain a sticky solid, add acetone, After stirring, a loose solid was obtained, whi...

Embodiment 2

[0129] Embodiment 2: the preparation of cefuroxime axetil (6c)

[0130] This example relates to compound 6c[(6R,7R)-7-[2-(2-furyl)-(Z)-methoxyimino-acetylamino]-3-carbamate-8-oxo - the preparation of 5-thio-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid-1-acetoxyethyl ester], its preparation process is as follows:

[0131]

[0132]

[0133] Concrete synthetic steps are as follows:

[0134] (1) (6R, 7R)-7-[2-(2-furyl)-(Z)-methoxyimino-acetylamino]-3-hydroxymethyl-8-oxo-5-sulfur-1 - Preparation of sodium azabicyclo[4.2.0]-oct-2-ene-2-carboxylate (compound 15)

[0135] Suspend 3g (13mmol) of compound 8 in 6ml of water at 5-10°C, add 0.7g (6.6mmol) of Na 2 CO 3 , stirred, and added acetone 12ml. In a fume hood, another 15ml of dichloromethane was cooled to 0-5°C, and 3.8g (12.8mmol) of bis-(trichloromethyl)carbonate and 0.02ml of pyridine were added. Add 3.4g (18.2mmol) compound 13, after reacting for 1 hour, slowly raise the temperature to 30°C, continue to stir an...

Embodiment 3

[0143] Embodiment 3: the preparation of cefditoren neopentyl ester (5c)

[0144] This embodiment relates to cefditoren neopentyl ester [(6R, 7R)-{7-[2-(2-aminothiazol-4-yl)-(Z)-methoxyimino-acetylamino]-8- Oxo-5-thio-1-azabicyclo[4.2.0]-oct-2-ene-3-[(cis)-2-(4-methyl-1,3-thiazol-5-yl)ethylene base]-2-carboxylic acid-neivaloyloxymethyl ester (compound 5c)]. Its preparation process is as follows:

[0145]

[0146] The specific steps are as follows:

[0147] (1) (6R, 7R)-7-[2-(2-aminothiazol-4-yl)-(Z)-methoxyimino-acetylamino]-3-hydroxymethyl-8-oxo-5 Preparation of -thio-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid-neivaloyloxymethyl ester (compound 18)

[0148] According to the example 1 (2) method, compound (11) 2.1g (5.0mmol) was dissolved in 12 milliliters of DMF, reacted with 1.82g neovaloyloxyiodomethyl ester (compound 17) (gas phase assay content: 87.5%), After working up, 2.16 g (yield: 81.97%) of compound 18 were obtained.

[0149] 1 HNMR (DMSO d6, 400MHz)...

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Abstract

The present invention relates to new method of preparing cephalo antibiotic. The new preparation process includes first acidylating the C7 place of initial material 7-amino-3-methylol cephaloalkanoic acid, the subsequent esterifying the C2 place carboxyl radical with corresponding ester radical, and final functionating the C3 place of the product. The process of the present invention has less reaction steps, raised total synthesis efficiency, low cost and reduced environmental pollution.

Description

technical field [0001] The invention relates to a preparation method of cephalosporin antibiotics. Background technique [0002] Currently on the market, the cephalosporin antibiotics for clinical application are all semi-synthetic cephalosporins, except for 7-ADCA (1) series of oral cephalosporins such as Cefalexin (Cefalexin) (1a), Cefadroxil (Cefadroxil) ( 1b), cephradine (Cephradine) (1c), cefetamet pivoxil (Cefetamet pivoxil) (1d), etc., and cephalosporins with a methyl acetate group in the C3-position of the 7-ACA (2) series such as cephalosporins Except for Cephalothin (2a), Cefotaxime (2b), and Cefathiamidine (2c), all other cephalosporins are cephalosporins with different group substitutions at the C3-position Bacteria, which can be broadly divided into: [0003] 1. Cephalosporins substituted with a thiomethyl group at the C3-position, such as Cefazoline (3a), Cefoperazone (3b), Ceftriaxone (3c), etc.; [0004] 2. Cephalosporins substituted with a nitrogen-contai...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/48C07D501/24A61K31/546A61K31/04
Inventor 撒应福任秉钧
Owner ZHEJIANG ZHENYUAN PHARMA CO LTD
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