Preparation method of erythromycin A(E) oxime

A technology of erythromycin and erythromycin thiocyanate, applied in sugar derivatives, organic chemistry, etc., can solve the problems of low E/Z ratio of erythromycin oxime, unsuitable for large-scale production, poor product quality, etc. , to achieve the effect of low raw material cost, good quality and simple process

Active Publication Date: 2009-02-11
ZHEJIANG GUOBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method has the following defects: high cost, serious environmental pollution, not suitable for large-scale production
This type of method has the following defects: high cost; not suitable for large-scale production
The method has the following defects: the prepared erythromycin oxime E/Z ratio is low (≤20), and the product quality is not good
The method has the following defec

Method used

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  • Preparation method of erythromycin A(E) oxime
  • Preparation method of erythromycin A(E) oxime
  • Preparation method of erythromycin A(E) oxime

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1. A preparation method of erythromycin A(E) oxime, followed by the following steps:

[0025] 1) First add 140ml methanol, hydroxylamine hydrochloride (42.3g, 0.61mol) and diammonium hydrogen phosphate (81.1g, 0.61mol) in a 500ml four-necked flask, and react for 30min at room temperature (generally 0-40°C). Then, erythromycin thiocyanate (65g, 0.087mol) was added, and the temperature was raised to 60°C to react for 32 hours. Then, the above reaction product was cooled to 40°C and 220 ml of water was added for crystallization. After adding water, cool to 20°C and filter, and after washing with 100ml*3 water three times, 55.2g of erythromycin A(E) oxime thiocyanate is obtained. HPLC: erythromycin A(E) oxime 97.5%, erythromycin A(z) oxime 0.9%.

[0026] 2) Add 55.0g (0.068mol) of erythromycin A(E) oxime thiocyanate and 170ml of methanol in a 500ml four-necked flask. After cooling to 20℃, slowly add sodium hydroxide with a mass concentration of 25%. 21.8g (0.136mol) of ...

Embodiment 2

[0027] Example 2. A preparation method of erythromycin A(E) oxime, followed by the following steps:

[0028] 1) First, add 70ml isopropanol, hydroxylamine hydrochloride (48.4g, 0.696mol) and potassium bicarbonate (69.6g, 0.696mol) in a 500ml four-necked flask, and react for 30min at room temperature. Then erythromycin thiocyanate (65g, 0.087mol) was added and reacted at 40°C for 80h. Then, the above reaction product was cooled to 38°C and 220 ml of water was added for crystallization. After adding water, cool to 20°C and filter. After washing with 100ml*3 water three times, 53.6g of erythromycin A(E) oxime thiocyanate is obtained. HPLC is: erythromycin A(E) oxime 93.5%, erythromycin A(z) oxime 2.0%.

[0029] 2) Add 55.0g (0.068mol) of erythromycin A(E) oxime thiocyanate and 170ml of ethanol in a 500ml four-necked flask. After cooling to 20℃, slowly add 25% sodium hydroxide dropwise. Aqueous solution 30.0g (0.187mol); after dripping, stirring and reacting for 22h; then 270ml of wat...

Embodiment 3

[0030] Example 3. A preparation method of erythromycin A(E) oxime, followed by the following steps:

[0031] 1) First, add 90 ml of ethanol, hydroxylamine hydrochloride (18.1 g, 0.26 mol) and sodium monohydrogen phosphate (36.9 g, 0.26 mol) to a 500 ml four-necked flask, and react for 30 min at room temperature. Then, erythromycin thiocyanate (65g, 0.087mol) was added, and the temperature was raised to 80°C to react for 24h. Then, the above reaction product was cooled to 40°C and 220 ml of water was added for crystallization. After adding water, cool to 20°C and filter. After washing with 100ml*3 water three times, 43.8g of erythromycin A(E) oxime thiocyanate is obtained. HPLC: erythromycin A(E) oxime 94.8%, erythromycin A(z) oxime 1.8%.

[0032]2). Add 40.4g (0.05mol) of erythromycin A(E) oxime thiocyanate and 100ml of isopropanol in a 500ml four-necked flask. After cooling to 5℃, slowly add hydrogen with a mass concentration of 25%. 10.0 g (0.062 mol) of sodium oxide aqueous sol...

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PUM

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Abstract

The invention discloses a preparation method for erythromycin A (E) oxime, which comprises the following steps: 1) in an organic solvent A, hydroxylamine hydrochloride reacts with an acid attaching agent with a molecular structural formula of M Y at the room temperature; then erythromycin thiocyanate is added for reaction; then crystallization, filtering and washing are carried out, and erythromycin A (E) oxime rhodanate is obtained; 2) in an organic solvent B, the erythromycin A (E) oxime rhodanate is added with alkali to have a neutralization reaction; then crystallization, filtering and washing are carried out, and the erythromycin A (E) oxime is obtained. The erythromycin A (E) oxime prepared by the method is characterized by good quality, little environmental pollution, etc.

Description

Technical field [0001] The invention relates to a new process for the synthesis of erythromycin A(E) oxime. The erythromycin A(E) oxime is a key intermediate for the synthesis of azithromycin, clarithromycin and roxithromycin. Background technique [0002] Erythromycin A oxime is a key intermediate for the synthesis of roxithromycin, azithromycin, clarithromycin and dirithromycin, and plays an important role in the synthesis of erythromycin antibiotics. [0003] Michael B.G. et al. used pyridine as a solvent to prepare erythromycin oxime in EP10952. This process dissolves erythromycin in pyridine and adds hydroxylamine hydrochloride to react. After vacuum concentration, cooling filtration and isopropanol recrystallization, the product is obtained. This method has the following defects: high cost, serious environmental pollution, and not suitable for large-scale production. [0004] Takashi A. et al. used imidazole free hydroxylamine hydrochloride in JP62081399 to react with eryth...

Claims

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Application Information

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IPC IPC(8): C07H17/08
Inventor 王飞吴虎城王宗利
Owner ZHEJIANG GUOBANG PHARMA
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