Gamithromycin preparation method

A technology of garamimycin and erythromycin, which is applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the problems of difficult scale-up production, high cost, and high production cost, and achieve easy scale-up production, The reaction process is mild and the effect of reducing production cost

Active Publication Date: 2014-02-05
TIANJIN ZHONGSHENG TIAOZHAN BIOTECH
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  • Abstract
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  • Application Information

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Problems solved by technology

[0010] In the literature (1), the disadvantage of this method is that the expensive 9-deoxy-8a-aza-8a-homoerythromycin A (structural formula 7) is directly used, which is expensive and difficult to scale up production
[0011] In the document (2), the disadvantage of this method is that the compound of structure 2 is 9(Z)-9-deoxy-erythromycin A oxime, and this erythromycin oxime has two isomers, and the method adopts The isomer is a thermodynamically unstable structure, which is inconvenient to store and is easy to convert into 9(E)-9-deoxy-erythromycin A oxime; and the reduction process from structure 3 to structure 7 and from structure 7 to structure 8 is palladium Carried out by carbon catalysis, the production cost is high

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0054] (1) Preparation of 9(E)-9-deoxy-erythromycin A oxime:

[0055] Add 100g of erythromycin and 300ml of MeOH (methanol) into a 1000ml three-necked flask, stir to dissolve, add 76.6g of triethylamine, heat to 50°C-60°C for 0.5h, add 43.8g of hydroxylamine hydrochloride, and heat to reflux for 1h- 3h, TLC was used to detect the completion of the reaction. After the reaction was completed, 200 ml of water was added, and the precipitate was filtered off to obtain 106 g of crude product 9(E)-9-deoxy-erythromycin A oxime. The crude product was mixed with 300ml isopropanol and 100g ammonia water (content is expressed as NH 3 Calculated as 25%) recrystallization to obtain 80.6g of the product, the molar yield was 83.3%, and the HPLC detection purity was 96.5%. The melting point (mp) is 156°C-160°C.

[0056] HPLC detection conditions: Agilent ZORBAX SB-C18, 5μm4.6*150mm, phosphate solution (take 8.7g of dipotassium hydrogen phosphate, add 1000ml of water, adjust the pH value to ...

Embodiment 2

[0066] A preparation method of gamithromycin, comprising the following steps:

[0067] (1) Synthesis of 9(E)-9-deoxy-9-hydroxyiminoerythromycin A from erythromycin A (hereinafter referred to as 9(E)-9-deoxy-erythromycin A oxime):

[0068] Under the condition of 50-70°C, triethylamine is used as an acid-binding agent, and 100g of erythromycin A is reacted with hydroxylamine hydrochloride in methanol (analytically pure) to obtain 9(E)-9-deoxy-erythromycin A, wherein the molar ratio of erythromycin to hydroxylamine hydrochloride is 1:3, and the molar ratio of triethylamine to erythromycin A is 1:3;

[0069] The reaction product is recrystallized with isopropanol and ammonia water. The volume-to-mass ratio of isopropanol to erythromycin A is 5:1 in ml / g. The ratio is 2:1;

[0070] (2) Synthesis of 9(Z)-9-deoxy-9-hydroxyiminoerythromycin A from 9(E)-9-deoxy-erythromycin A oxime (hereinafter referred to as 9(Z)-9- Deoxy-erythromycin A oxime):

[0071] Under the condition of 60℃,...

Embodiment 3

[0082] A preparation method of gamithromycin, comprising the following steps:

[0083] (1) Synthesis of 9(E)-9-deoxy-9-hydroxyiminoerythromycin A from erythromycin A (hereinafter referred to as 9(E)-9-deoxy-erythromycin A oxime):

[0084] Under the condition of 50-70°C, triethylamine is used as an acid-binding agent, and 100 g of erythromycin A is oximated with hydroxylamine hydrochloride in isopropanol to obtain 9(E)-9-deoxy-erythromycin A, Among them, the molar ratio of erythromycin to hydroxylamine hydrochloride is 1:6, and the molar ratio of triethylamine to erythromycin A is 1:7;

[0085] The reaction product is recrystallized with isopropanol and ammonia water. The volume to mass ratio of isopropanol to erythromycin A is 3:1 in ml / g. The ratio is 0.5:1;

[0086] (2) Synthesis of 9(Z)-9-deoxy-9-hydroxyiminoerythromycin A from 9(E)-9-deoxy-erythromycin A oxime (hereinafter referred to as 9(Z)-9- Deoxy-erythromycin A oxime):

[0087] 9(E)-9-deoxy-erythromycin A oxime is...

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Abstract

The invention provides a Gamithromycin preparation method. The preparation method comprises the following steps: 1, synthesizing 9(E)-9-deoxy-9-oxyiminoerythromycin A from erythromycin A; 2, synthesizing 9(Z)-9-deoxy-9-oxyiminoerythromycin A from the 9(E)-9-deoxy-9-oxyiminoerythromycin A; 3, synthesizing 9-deoxy-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A from the 9(Z)-9-deoxy-9-oxyiminoerythromycin A; 4, synthesizing 9-deoxy-8a-aza-8a-homoerythromycin A from the 9-deoxy-12-deoxy-9,12-epoxy-8a,9-didehydro-8a-aza-8a-homoerythromycin A; and 5, synthesizing the Gamithromycin from the 9-deoxy-8a-aza-8a-homoerythromycin A. The preparation method has the advantages of low cost, mild reaction processes and easy amplified production.

Description

technical field [0001] The invention relates to a preparation method of a medicinal compound, in particular to a preparation method of gamithromycin. Background technique [0002] Gamithromycin is a new type of second-generation macrolide veterinary antibiotic. The structure and efficacy of Gamithromycin have been certified by the Veterinary Drug Administration of the European Food and Drug Administration, and can be used for food animals. It has the advantages of fast absorption, wide distribution in the body, low residue, and high safety. Gamithromycin is mainly used to treat bovine infectious diseases caused by bacterial pathogens such as Pasteurella hemolytica, Pasteurella multocida, and histophilia. It is a veterinary antibiotic that can be clearly used, and has broad application prospects in veterinary clinics. [0003] Existing literature includes: [0004] (1) CN201110411660 discloses a preparation method of gamithromycin, the synthesis method is as follows: [0...

Claims

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Application Information

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IPC IPC(8): C07H17/00C07H1/00
Inventor 王建王勇董泽新程雪娇余贵菊焦晓军王猛焦伟丽
Owner TIANJIN ZHONGSHENG TIAOZHAN BIOTECH
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