CN103880898A

CN103880898A - Azithromycin synthesis method

Info

Publication number: CN103880898A
Application number: CN201210564543.7A
Authority: CN
Inventors: 郝智慧; 孙亚磊; 林扬
Original assignee: QINGDAO CONLINENT ANIMAL PHARMACEUTICAL CO Ltd
Current assignee: QINGDAO CONLINENT ANIMAL PHARMACEUTICAL CO Ltd
Priority date: 2012-12-24
Filing date: 2012-12-24
Publication date: 2014-06-25

Abstract

The present invention relates to the field of compound synthesis, particularly to an azithromycin synthesis method, which comprises: adopting erythromycin A (E) oxime as a starting material, adopting a one-pot boiling method to synthesize demethyl azithromycin, carrying out methylation to obtain azithromycin monohydrate, and finally carrying out re-crystallization to obtain the azithromycin dihydrate. The method has characteristics of easily available raw materials, simple operation, high yield, low production cost and easily industrial production.

Description

A kind of method of synthetic Azythromycin

Technical field

The invention belongs to antibiotic formulations field, relate to a kind of method of synthetic Azythromycin.

Background technology

Azythromycin (azithromycin) is one the 15 nitrogenous Macrocyclolactone lactone kind medicine of ring, be novel erythromycin tool representative medicine it, Puli watt (Pliva) drugmaker by Croatia developed in the 70's Mos of 20th century, within 1981, Pfizer (Pfizer) company obtains its right of use patent, and start to sell in the whole world, commodity are called Zithromax (Zithromax).It is widely used in respiratory system, urinary system and skin soft-tissue infection etc., and U.S. FDA approval substitutes the first-line drug of penicillin medicine as anti-infectives, can also treat AIDS

Patient mycobacterium infects.Another outstanding advantages of Azythromycin is to have unique pharmacokinetic property, after absorption, can be transferred to infection site, reaches very high tissue concentration, generally can be higher 300 times than bacterium extracellular concentration.The chemical stability of Azythromycin strengthens, and reduces

Erythromycin because of acid degradation deactivated problem, improved Plasma Concentration, greatly extended the transformation period.Azythromycin preparation prospect in the application of at present domestic anti-infection drug is boundless.Azythromycin, normally take Erythromycin A as raw material, obtains through oximate, Beckmann rearrangement, reduction and methylation reaction.Thereby exploitation technique cheap, that easily produce has important research and development value.

Summary of the invention

The object of the present invention is to provide a kind of simple, cheap, safe method of synthesizing Azythromycin.The method is take Erythromycin A (E) oxime as raw material, and " one kettle way " synthesizes demethyl Azythromycin, then methylates, and recrystallization obtains Azythromycin two hydrates.

Embodiment

In the present invention, the synthetic method step of Azythromycin and reaction scheme figure are as follows:

1,, take Erythromycin A (E) oxime as raw material, " one kettle way " synthesizes demethyl Azythromycin;

2, synthetic demethyl Azythromycin is synthesized to Azythromycin monohydrate through methylating, after recrystallization, obtain Azythromycin two hydrates.Its concrete reaction scheme is as shown below.

further illustrate the present invention below in conjunction with specific examples.

embodiment 1

In 5 L round-bottomed flasks, add Erythromycin A (E) oxime (100g, 0.134 mol), methyl alcohol (500 mL), vigorous stirring under ice-water bath.Slowly add Tosyl chloride (30 g, 0.134 mol), then add water (150 mL), with the pH=6-7 of 20% sodium hydroxide solution control reaction solution.React approximately 1 h, then directly add diethylamine (100 mL), after reaction is cooled to-20 ℃, slowly splash into the POTASSIUM BOROHYDRIDE aqueous solution (40 g/100 mL), rise to 5 ℃, continue reaction 10 h.Add water (1000 mL) that insolubles is dissolved, add chloroform (1000 mL), with 20% sodium hydroxide solution tune pH=9, after layering, in organic layer, add water (1000 mL), sulfuric acid with 18% is adjusted pH=4, and layering, adds ethanol (500 mL) in water layer, adjust pH=3 with nitration mixture, hydrolysis reaction adds chloroform (1000 mL) after half an hour, adjust pH=9.5 layering with 20% sodium hydroxide solution, and chloroform layer washes with water, anhydrous magnesium sulfate drying, obtains the chloroformic solution of demethyl Azythromycin.

embodiment 2

The chloroformic solution of demethyl Azythromycin is warmed up to after 40 ℃, add formaldehyde (24 mL) and formic acid (11 mL), continue to be warming up to backflow, after reacting 6 h, stop heating, add ethanol (500 mL) cancellation reaction, add water (1000 mL), with 18% sulfuric acid tune pH=4 left and right, layering, water layer is adjusted pH=9 with 20% sodium hydroxide solution, separates out a large amount of white solids.Filter filter cake cold water washing.After dry, obtain white solid 89 g.

embodiment 3

The acetone for compound (260 mL) that upper step is obtained slowly drips water (610 mL) after dissolving, and after stirring 6 h, filters, and obtains 81 g, total recovery 81%.

Claims

1. a method for synthetic Azythromycin, is characterized in that comprising following operation: take Erythromycin A (E) oxime as starting raw material, " one kettle way " synthesizes key intermediate demethyl Azythromycin, and then methylates and can obtain Azythromycin.

2. synthetic method according to claim 1, is characterized in that " one kettle way " synthetic demethyl Azythromycin comprises Beckmann rearrangement, reduction, boric acid ester hydrolysis three-step reaction.

3. synthetic method according to claim 1, what the system that it is characterized in that methylating adopted is formaldehyde-formic acid system.

4. synthetic method according to claim 1, gained Azythromycin can synthesize high-purity Azythromycin two hydrates by recrystallization.