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Preparation method of Gamithromycin intermediate

A technology for gamycin and intermediates, applied in the field of pharmaceutical synthesis, can solve the problems of affecting product yield and quality, high pressure, and high production costs, and achieve the effects of facilitating industrial production, reducing acid degradation products, and reducing preparation costs.

Active Publication Date: 2014-06-04
LUOYANG HUIZHONG ANIMAL MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] U.S. Patent US005985844A discloses a method for preparing gamimycin. The disadvantage of this method is that the pressure used for the hydrogen reduction of the intermediate 9-deoxy-8a-aza-8a-homoerythromycin A is too large and requires 50 Atmospheric hydrogen pressure has extremely high requirements on the reactor and operation
The key to the preparation of Gamithromycin is the reduction of imino ether, but the above method either has a low yield, or needs to use precious metals as a catalyst, or needs to use sodium borohydride or potassium borohydride as a reducing agent
Using precious metals as catalysts requires high catalyst recycling requirements, high production equipment requirements, and high production costs
Use sodium borohydride or potassium borohydride as a reducing agent to generate a boric acid ester intermediate. Under acidic conditions, hydrolysis of the boric acid ester results in the breakage of the 3-position glycosidic bond, which affects the yield and quality of the product.

Method used

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  • Preparation method of Gamithromycin intermediate
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  • Preparation method of Gamithromycin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1. Preparation of (9Z)-9-deoxy-9-hydroxyiminoerythromycin A

[0041] Add 1600mL isopropanol to a 2L three-necked reaction flask, control the temperature to 20°C, stir, add 200g (0.267mol) (9E)-9-deoxy-9-hydroxyiminoerythromycin A (Xinyu Chemical Industry), Stir until dissolved. Dissolve 25g (1.086moL) of lithium hydroxide (Chengdu Kelong Chemical Reagent Factory) in 400mL of purified water and introduce it into the above-mentioned three-necked flask. Concentrate to 400ml by rotary steaming, adjust the pH to 8 with 20wt% hydrochloric acid at 0°C, pour 1000ml of purified water, precipitate a white solid, dry it after suction filtration, then wash with 300ml of dichloromethane, and dissolve the filter cake in 500ml of isopropyl Alcohol, the filtrate was obtained by suction filtration, and 500ml of dichloromethane was added to recrystallize at 0°C to obtain 140g of (9Z)-9-deoxy-9-hydroxyiminoerythromycin A as a light white solid, yield: 70%; HPLC Assayed purity: ...

Embodiment 29

[0046] Example 2. Preparation of 9-deoxy-6-deoxy-6,9-iminoether-(8a-aza-8a)-erythromycin A

[0047] Add 1000mL acetone to a 2L three-necked reaction flask, control the temperature to -4°C, stir, add 100g (0.267mol) (9Z)-9-deoxy-9-hydroxyiminoerythromycin A, and stir until dissolved. Take 50g (1.086moL) of p-toluenesulfonyl chloride (Tianjin Damao Chemical Reagent Factory) and dissolve it in 600mL of acetone, add it dropwise at constant pressure, and finish the dropping within 20 minutes. Weigh 45g of sodium bicarbonate and dissolve it in 300mL of purified water, and add dropwise at constant pressure. The temperature was controlled at -4°C, and the reaction was carried out for 1.5 hours, and the reaction was detected by TLC. Suction filtration, the filtrate was extracted with 800ml of dichloromethane and 800ml, the organic layer was separated, dried with anhydrous sodium sulfate and evaporated to dryness to obtain a light yellow viscous liquid, which was recrystallized with ...

Embodiment 3

[0051] Example 3.9-Deoxy-8a-aza-8a-homoerythromycin A preparation

[0052] Add 500mL acetone to a 1L three-necked reaction flask, control the temperature to 0°C, stir, add 50g (0.267mol) 9-deoxy-6-deoxy-6,9-iminoether-(8a-aza-8a)-red Mycin A, stirred until dissolved. 20 g of sodium borohydride was added in three batches over 30 minutes. React at 0-5°C for 2.5h, rise to room temperature (25°C) for 8h. After the reaction was detected by TLC, add 300mL of water and 20wt% hydrochloric acid to adjust the pH to 3, extract with dichloromethane (120mL×3) to obtain the aqueous phase, slowly add 20wt% NaOH dropwise at 0-5°C to adjust the pH to 10, Extract with dichloromethane (180mL×3), combine the organic phases, wash the extract with saturated brine (120mL×3), dry over anhydrous magnesium sulfate, and evaporate to dryness to obtain 31g of crude product, yield: 62%. Purity determined by HPLC: 86.1%. (Application of WATERSACQUITY UPLC BEH C18 column (2.1×50mm, 1.7μm); mobile phase...

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Abstract

The invention relates to a preparation method of a Gamithromycin intermediate. The method includes: taking 9-deoxy-6-deoxy-6, 9-imino ether-(8a-aza-8a)-erythromycin A as the raw material, dissolving it in an organic solvent, adjusting the pH to 3-6 with acid, adopting potassium borohydride or sodium borohydride as a reducing agent to conduct reduction reaction; and then adding organic sugar acid to undergo hydrolysis reaction to obtain 9-deoxy-8a-aza-8a-homoerythromycin A. As the organic sugar acid contains hydroxyl and is conducive to hydrolysis of a Gamithromycin borate intermediate, the acid degradation product is reduced, and hydrolysis of 9-deoxy-6-deoxy-6, 9-imino ether-(8a-aza-8a)-erythromycin A can be effectively reduced, the yield of the target product is enhanced, and the preparation cost of the Gamithromycin intermediate 9-deoxy-8a-aza-8a-homoerythromycin A can be significantly reduced. Thus, the preparation method is convenient for industrial production.

Description

technical field [0001] The invention relates to a preparation method of 9-deoxy-8a-aza-8a-homoerythromycin A, which belongs to the field of drug synthesis. Background technique [0002] Gamithromycin is a new type of second-generation macrolide veterinary antibiotic drug. Like azithromycin, gamimycin is also a ring-expanded derivative obtained after ring-expansion of erythromycin A oxime, and the synthetic intermediate (9Z)-9-deoxy-9-hydroxyiminoerythromycin Erythromycin A and (9E)-9-deoxy-9-hydroxyiminoerythromycin A are isomers. At present, the injection ZACTRAN produced by MERIAL.CO of France, with gamimycin as the main active ingredient, has been approved by the Veterinary Drug Administration of the European Medicines Agency and has realized market production and sales. The structure and efficacy of Gamithromycin have been certified by the Veterinary Medicines Agency of the European Food and Drug Administration. It can be used for food animals. It has the advantages of...

Claims

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Application Information

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IPC IPC(8): C07H17/00C07H1/00
Inventor 张许科刘兴金张晓会
Owner LUOYANG HUIZHONG ANIMAL MEDICINE
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