7-amido-3-hydroxyl methyl-3-cephalosporin-4-carboxylic acid crystal and preparing method thereof

A hydroxymethyl, cephalosporin technology, applied in organic chemistry and other directions, to achieve the effects of good stability, easy transportation and high purity

Inactive Publication Date: 2008-09-24
GUANGZHOU BAIYUNSHAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is no literature report about the purification of this compound and the method for preparing high-purity and stable crystals

Method used

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  • 7-amido-3-hydroxyl methyl-3-cephalosporin-4-carboxylic acid crystal and preparing method thereof
  • 7-amido-3-hydroxyl methyl-3-cephalosporin-4-carboxylic acid crystal and preparing method thereof
  • 7-amido-3-hydroxyl methyl-3-cephalosporin-4-carboxylic acid crystal and preparing method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1: Add 7-ACA to the mixture of water and methanol below 0°C, slowly add 1N NaOH, adjust the pH to 7-9, dissolve the solution, and maintain the reaction for 10-20 hours. After the completion of the reaction, slowly add 6N HCl to adjust the pH to 4 to 4.5 crystallization. Stir and grow the crystal for 1 hour, filter with suction, wash twice with water, wash with acetone slurry, and then dry at 40°C to obtain the crude product.

[0018] Put 10 grams of the above crude product and 200 milliliters of water into the reaction bottle, cool down to less than 5°C in an ice-water bath, add 10% NaOH solution dropwise until the solution is clear, pH=9, add 2 grams of activated carbon, stir for 30 minutes to decolorize, filter, stir the filtrate, Slowly add 3N hydrochloric acid dropwise at 25°C to make the pH of the feed liquid 3.5, filter, wash twice with water, wash with acetone slurry, and vacuum dry at 35°C to obtain 8.16 g of the product of the present invention. HPLC d...

Embodiment 2

[0022] Example 2: 10 grams of the crude product obtained by the above method, 100 milliliters of methanol and 100 milliliters of water were put into a reaction flask, the temperature was lowered to -10° C., ammonia water was added dropwise until the solution was clear, pH=7.5, 2 grams of active carbon was added, and stirred for 30 minutes to decolorize. Filter carbon, then stir the filtrate, slowly add 3N hydrochloric acid dropwise at 0°C to make the pH of the feed solution 4.0, crystallize, filter, wash with water twice, and dry in vacuum at 35°C to obtain 7.38 g of the product. X-ray powder diffraction data are the same as in Example 1.

Embodiment 3

[0023] Example 3: 10 grams of the crude product obtained by the above method, 50 milliliters of acetonitrile and 100 milliliters of water were put into a reaction flask, protected by nitrogen gas, 12% ethylenediamine solution was added dropwise until dissolved, 2 grams of activated carbon was added, stirred for 30 minutes for decolorization, and filtered , stirred the filtrate, slowly added dilute sulfuric acid dropwise at 10°C to make the pH of the feed solution = 4.5, filtered, washed twice with water, and dried in vacuum at 40°C to obtain 8.10 g of the product. X-ray powder diffraction data are the same as in Example 1.

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PUM

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Abstract

The present invention relates to a 7-amino-3-hydroxymethyl-3-cephalosporin-4-carboxylate crystal and a production method thereof and discloses the diffraction pattern of the crystal copper target X ray powder of the compound and represents each datum with a 2 Theta angle, an interplanar distance d and relative strength I / I0, and the production method includes the following steps: (1) the compound is alkalified for dissolution, pH is kept to be less than or equal to 9, and reaction temperature is between negative 10 DEG C to 35 DEG C; (2) the reaction solution is acidified, pH is kept to be larger than or equal to 3, the reaction temperature is between negative 0 DEG C to 50 DEG C, and therefore the product is crystallized in aqueous solution or the mixture system of water and organic solvent mixed with water. The purity of the crystal produced by the present invention reaches 98.5 percent or higher, the stability of the crystal is good, the crystal is not easily isomerizated or dehydrated to form a ring-closing compound, and can be stored for a long time, conveniently transported and sold, etc. under an economic condition, moreover, the method for producing the crystal is safe, the cost is low, the reaction process is simple and can be easily controlled, subsidiary products, such as ring-opening products, ring-closing products, dehydroxylated products, etc., cannot be easily formed, and meanwhile, the amount of substances related to optical isomers, double-bond migration structures, etc. is tiny or is not produced.

Description

technical field [0001] The invention relates to a stable high-purity 7-amino-3-hydroxymethyl-3-cephalosporin-4-carboxylic acid compound crystal and a production method thereof. technical background [0002] 7-Amino-3-hydroxymethyl-3-cephalosporin-4-carboxylic acid is an important intermediate in the synthesis of cephalosporin products. Its 3-position is different from the acetyloxy group of the existing market product 7-amino-cephalosporanic acid (7-ACA), but deacetylated, and the 3-position is a hydroxyl group, referred to as: deacetylated 7-amino-cephalosporanic acid (7-ACA) Acid (D-7-ACA), from a structural point of view, D-7-ACA is the product of 7-ACA deacetylation. With the development and marketing of some new cephalosporins, the D-7-ACA structure also has advantages in synthesis due to the good reactivity of the C-3 hydroxyl group, and its value has gradually emerged. D-7-ACA can be used to synthesize cefuroxime, cefcapene axetil, cefpodoxime, cefixime, cefdinir, c...

Claims

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Application Information

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IPC IPC(8): C07D501/18
Inventor 于沛陈矛白梅
Owner GUANGZHOU BAIYUNSHAN PHARM CO LTD
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