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A kind of preparation method of norazithromycin

A technology of norazithromycin and erythromycin, which is applied in the preparation of sugar derivatives, chemical instruments and methods, organic chemistry, etc., can solve the problems of reduced purity, small investment in equipment, low production efficiency, etc., to reduce acidic ineffective decomposition, The effect of slowing down the release speed and saving production costs

Active Publication Date: 2019-10-18
HEBEI GUOLONG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disadvantages: Large investment in equipment, use of precious metal catalysts, poor handling of reactants, prone to catalyst poisoning, resulting in high production costs
In addition, during the experiment, our research group found that norazithromycin was unstable in acidic water, methanol, and acetonitrile. At room temperature, impurities appeared and the purity decreased; In the process of preparing norazithromycin with hydrogen, side reactions inevitably occur, and the yield is low, which affects the quality of the final azithromycin product
[0010] Use chemical reagents to reduce imido ether to prepare norazithromycin, the reaction is carried out under normal pressure, and the equipment investment is small; but due to the acid hydrolysis and neutralization process, there are partial reversible reactions to generate norazithromycin borate and bisnorazithromycin borate 2 an intermediate product, resulting in cumbersome separation steps, multiple organic solvent extractions are required, and the production efficiency is low.
In addition, the sodium borohydride disclosed in the literature is a reducing agent, requires methanol as a solvent, and operates at low temperature. The amount of sodium borohydride is large, and the production cost is high.

Method used

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  • A kind of preparation method of norazithromycin
  • A kind of preparation method of norazithromycin
  • A kind of preparation method of norazithromycin

Examples

Experimental program
Comparison scheme
Effect test

reference example 1-1

[0046] Reference Example 1-1: Preparation of erythromycin thiocyanate A oxime (III)

[0047] Add hydroxylamine hydrochloride (114g, 1.64mol) and 300g methanol, stir at room temperature, and add triethylamine dropwise to adjust pH=6.3-6.7. Add erythromycin thiocyanate A(II) (200g, 0.25mol), increase the temperature to 30-35℃ and react for 4h, add triethylamine dropwise during the reaction to adjust pH=6.5±0.2; increase the temperature to 50-55℃, continue to keep warm Reaction for 48h. Cool to 15-20°C, add 600mL deionized water dropwise, stir for 0.5h; 0-5°C, crystallize for 2h. Filter, wash with 200 mL deionized water, and dry to obtain 180 g of white solid erythromycin A oxime thiocyanate (III). The yield was 88.4%, the melting point was 182-185°C, and the purity was 93.7% (HPLC).

reference example 1-2

[0048] Reference Example 1-2: Preparation of erythromycin thiocyanate A oxime (III)

[0049] Add hydroxylamine hydrochloride (228g, 3.3mol), 600g methanol, stir at room temperature, and add triethylamine dropwise to adjust pH=6.3-6.7. Add erythromycin thiocyanate A(II) (400g, 0.5mol), heat up to 30-35°C, keep the reaction for 10h; add triethylamine dropwise to adjust pH=6.5±0.2 during the reaction; heat up to 50-55°C, Continue the incubation reaction for 40 hours. Cool down to 15-20℃, add 1200mL deionized water dropwise, stir for 0.5h; 0-5℃, crystallize for 2h. Filter, wash with 400mL deionized water, and dry to obtain 348 g of white solid erythromycin A oxime thiocyanate (III), yield 87.0%, melting point 182-184°C, purity 93.8% (see HPLC figure 1 And shown in Table 1).

[0050] Table 1 HPLC detection results of erythromycin A oxime thiocyanate

[0051] peak# keep time area area% height Degree of separation Tailing factor Theory tray# 15.1894515.0210.3091960.0000.0001417.547 ...

reference example 2

[0053] Reference Example 2: Preparation of erythromycin A imine ether

[0054] Add erythromycin A oxime thiocyanate (III) (180 g, 0.22 mol) and 540 mL of acetone to a 2000 mL three-necked flask, and stir. At 0-10°C, add 450g of 10% sodium bicarbonate solution, below 5°C, add p-toluenesulfonyl chloride (51g, 0.27mol) dropwise for 1h, keep the temperature for 3h. Add 1200 mL of deionized water dropwise to the reaction solution, adjust the pH=11-12 with a 10wt% NaOH aqueous solution, and stir for 1 hour. Crystallize at 0-5℃ for 1h. Filter, wash with 400 mL deionized water at room temperature, and dry to obtain 142 g of white solid erythromycin A imino ether. The yield is 88.3%, the melting point is 134-140℃, and the purity is 92.9% (see HPLC figure 2 And shown in Table 2).

[0055] Table 2 HPLC test results of erythromycin A imine ether

[0056] peak# keep time area area% height Degree of separation Tailing factor Theory tray# 12.60635405.1422.50842990.0001.4192051.637 24.9451...

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Abstract

The invention discloses a preparation method of norazithromycin and relates to the technical field of macrolide antibiotics. The preparation method comprises the following steps: reducing erythrocin A 6,9-imino ether in water at 0 DEG C to room temperature under the pH of 7.0-9.0 by using a reducing agent sodium borohydride or potassium borohydride; then in the presence of an organic solvent and water, performing continuous hydrolysis at 0 DEG C to room temperature under the pH of 2.0-3.0; then adding two-phase reaction liquids after continuous hydrolysis into an alkaline aqueous solution, adjusting the pH to be greater than or equal to 12, stirring, layering and abandoning the aqueous phase, wherein the organic solvent is dichloromethane, chloroform, 1,2-dichloromethane, ethyl acetate or butyl acetate; and after the last hydrolysis reaction in continuous hydrolysis, performing layering, directly adding the aqueous phase into the alkaline aqueous solution, adjusting the pH to be greater than or equal to 12, and performing stirring and separating out norazithromycin. The method increases the utilization ratio of the reducing agent, can control reverse reactions of borate, and reduces unnecessary separating process to obtain high quality norazithromycin.

Description

Technical field [0001] The invention relates to the technical field of preparation of macrolide antibiotics, in particular to a preparation method of the azithromycin precursor norazithromycin. Background technique [0002] Azithromycin is a structural modification of the macrolide antibiotic erythromycin. It is broad-spectrum antibacterial. It is effective against certain pathogenic bacteria resistant to β-lactam antibiotics. It has the characteristics of strong tissue permeability, high concentration and long half-life. . Clinically, it is widely used in the treatment of respiratory tract, urinary system, skin and soft tissue diseases caused by sensitive pathogenic bacteria infection, and can also be used in the treatment of venereal diseases and prevention and treatment of venereal diseases. Demethylazithromycin is the precursor for the preparation of azithromycin, which is methylated to obtain azithromycin. [0003] The preparation process of azithromycin includes: oximation ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H17/00C07H1/00
Inventor 付德才李志伟刘丽星王丽云郭李珉
Owner HEBEI GUOLONG PHARMA CO LTD