CN105315316A

CN105315316A - Preparation method for azithromycin intermediate

Info

Publication number: CN105315316A
Application number: CN201410349729.XA
Authority: CN
Inventors: 殷学治; 朱玲玲; 吴路新; 王小琴
Original assignee: CHANGZHOU PHARMACEUTICAL FACTORY Co Ltd
Current assignee: CHANGZHOU PHARMACEUTICAL FACTORY Co Ltd; Changzhou Pharmaceutical Factory
Priority date: 2014-07-21
Filing date: 2014-07-21
Publication date: 2016-02-10

Abstract

The invention belongs to the technical field of medicines, and concretely relates to a preparation method for an azithromycin intermediate. The preparation method comprises under certain conditions, adding potassium borohydride in batches for reducing erythromycin 6,9-imino ether, so as to obtain dihydro erythromycin. The preparation method is simple in operation, potassium borohydride usage amount is reduced, production cost is reduced, high pressure is not used, and the preparation method is suitable for industrialized production.

Description

A kind of preparation method of azithromycin intermediate

Technical field:

The present invention relates to a kind of preparation method of azithromycin intermediate dihydro homoerythromycin, belong to medical art.

Background technology:

Azythromycin (Azithromycin) is a kind of Macrolide Broad spectrum antibiotics obtained after modifying in erythromycin structure. its exploitation solves erythromycin because of the ketalization formation 8 of acid, 9-anhydroerythromycin-6,9-hemiketal and the problem lost efficacy, improve Plasma Concentration, enhance curative effect, extend the transformation period, decrease dosage and side effect, be put into one of the well selling medicine in Future Ten year.Although current China produces enterprise's sum of Azythromycin more than 110, due to problems such as hydrogenation gordian technique are immature, preparation is of low grade, production cost is higher and yield poorly, generally lack international competitiveness.

Azythromycin is the Representative Cultivars of s-generation erythromycin, it obtains erythromycin 6 by Erythromycin E oxime (I) through Beckmann rearrangement, 9-imines ether (II), reduction obtains dihydro homoerythromycin (IV), then carrying out methylates obtains Azithromycin monohydrate (V), obtains azithromycin dihydrate (VI) after recrystallization.In the synthesis technique of Azythromycin, the key of technology is the reduction of Beckmann rearrangement product.

1986, Djokic etc. adopted PtO ₂make catalyzer, reduced by erythromycin 6,9-imino-ether and obtain dihydro homoerythromycin, yield is 79%, and drug quality is fine, but the use of noble metal catalyst increases the cost of whole reaction, makes holding at high price of Azythromycin.1987, Kobrehel and Djokic described the method being prepared Azythromycin by electroreduction in patent AU8600536, and yield reaches 82%, but electrolyzer costly, was unsuitable for extensive, produced.1993, Yang utilized PtO2 to do catalyst reduction, and pressure slightly reduces, but the reaction times is long, and just obtain azithromycin procursor after namely reacting 2d, yield is 86%.1997, Wilkening etc. have studied the method for the rearrangement product utilizing sodium borohydride reduction different, different reductive agents is also attempted, but yield all .1998, Willian not fully up to expectations etc. utilizes Rh/C to reduce for catalyzer, and operating pressure is 70bar, room temperature reaction, time is only 4h, but catalyzer price is more expensive, and industrialization is more difficult.1999, the report such as Liao Lianan utilized NaBH4-BF ₃: OEt ₂the diborane reduction erythromycin A iminoether that system produces, productive rate 91.6%, but diborane and oxygen mix explosive, there is potential safety hazard in technique.Disclose by under the existence of rhodium, platinum, palladium or ruthenium metal or metal oxide catalyst in patent US4328334 and US6013778, the method of hydrogenation synthesis is carried out under high hydrogen pressure, owing to employing expensive noble metal catalyst and high pressure hydrogen, cost is too high, cannot carry out industrialized production.Patent US4328334 discloses with such as NaBH ₄reductive agent in the methanol solution of 4 DEG C, reduce the method for erythromycin A iminoether, this method needs greatly excessive NaBH ₄, and be hydrolyzed further with mineral acids such as the reduzate hydrochloric acid of borate complex form existence, hydrolysis reaction induction side reaction, produces a large amount of impurity, also far away apart from industrialized requirement.Patent CN1625560A discloses with a small amount of NaBH4 reduction 6, the method of 9-imido ether and the acid solution-treated reaction mixture of citric acid, higher yields dihydro homoerythromycin can be obtained after neutralization, avoid the acidic hydrolysis in reduction later stage, but Azythromycin ester cpds is not exclusively hydrolyzed, product has residual impurity, and recrystallization yield is too low, does not have prospects for commercial application.

Summary of the invention:

The technical problem that the present invention mainly solves: develop a kind of method preparing azithromycin intermediate dihydro homoerythromycin, the method cost is low, good product quality, and is applicable to suitability for industrialized production.

Detailed process is as follows:

Erythromycin 6 is added in reaction flask, 9-imines ether and methyl alcohol, at a certain temperature, gradation adds POTASSIUM BOROHYDRIDE, continue to keep thermotonus, after reaction terminates solution is slowly heated to room temperature and underpressure distillation concentrates, methylene dichloride and water is added in resistates, stratification, concentration of organic layers, add acetone and water and citric acid monohydrate compound, after citric acid dissolves, with hydrochloric acid, pH value of solution is adjusted to acidity, stirring at room temperature, solution is cooled to less than 10 DEG C, slowly add the sodium hydroxide of 20% wherein, pH value is adjusted to alkalescence, continue to stir, crystal is separated out, filter, and use cold water filter wash, dried overnight at 40 DEG C, obtain intermediate dihydro homoerythromycin.

Wherein temperature of reaction is-10 DEG C-10 DEG C;

The amount of the POTASSIUM BOROHYDRIDE needed for reaction is 2-10 times of erythromycin 6,9-imido ether;

Reaction times is 2-10h;

Hydrochloric acid conditioning solution PH is 2-5;

Acidic solution churning time is 0.5-6h;

The PH of sodium hydrate regulator solution is 10-13.

Embodiment:

Contribute to understanding the present invention by following embodiment, but do not limit content of the present invention.

Embodiment one

In 500mL single port bottle, add 200mL methyl alcohol and 18g erythromycin 6,9-imines ether, then make solution be chilled to-10 DEG C, add 6gKBH three times in 1 little time-division ₄, keep temperature of reaction at-10 DEG C of reaction 6h, solution be slowly heated to room temperature and underpressure distillation concentrates.200mL methylene dichloride and 200mL water is added, stratification, concentration of organic layers in resistates.Add 100mL acetone and 200mL water, and add 16g citric acid monohydrate compound wherein, after citric acid dissolves, with 6N hydrochloric acid, pH value of solution is adjusted to 3, and stirring at room temperature 1h, gained solution is cooled to less than 10 DEG C, slowly adds the sodium hydroxide of 20% wherein, pH value is transferred to 12, and stirs 1h at the same temperature.The crystal of filtering-depositing, and use cold water filter wash, dried overnight at 40 DEG C, obtain 16.03g solid, yield: 89%.

Embodiment two

In 500mL single port bottle, add 200mL methyl alcohol and 18g erythromycin 6,9-imines ether, then make solution be chilled to 0 DEG C, add 6gKBH three times in 1 little time-division ₄, keep temperature of reaction at 0 DEG C of reaction 4h, solution be slowly heated to room temperature and underpressure distillation concentrates.200mL methylene dichloride and 200mL water is added, stratification, concentration of organic layers in resistates.Add 100mL acetone and 200mL water, and add 16g citric acid monohydrate compound wherein, after citric acid dissolves, with 6N hydrochloric acid, pH value of solution is adjusted to 2, and stirring at room temperature 3h, gained solution is cooled to less than 10 DEG C, slowly adds the sodium hydroxide of 20% wherein, pH value is transferred to 11, and stirs 1h at the same temperature.The crystal of filtering-depositing, and use cold water filter wash, dried overnight at 40 DEG C, obtain 13.15g solid, yield: 73%.

Embodiment three

In 500mL single port bottle, add 200mL methyl alcohol and 18g erythromycin 6,9-imines ether, then make solution be chilled to-10 DEG C, add 3gKBH three times in 1 little time-division ₄, keep temperature of reaction at-10 DEG C of reaction 6h, solution be slowly heated to room temperature and underpressure distillation concentrates.200mL methylene dichloride and 200mL water is added, stratification, concentration of organic layers in resistates.Add 100mL acetone and 200mL water, and add 16g citric acid monohydrate compound wherein, after citric acid dissolves, with 6N hydrochloric acid, pH value of solution is adjusted to 3, and stirring at room temperature 1h, gained solution is cooled to less than 10 DEG C, slowly adds the sodium hydroxide of 20% wherein, pH value is transferred to 12, and stirs 1h at the same temperature.The crystal of filtering-depositing, and use cold water filter wash, dried overnight at 40 DEG C, obtain 13.73g solid, yield: 76%.

Claims

1. a preparation method for azithromycin intermediate, is characterized in that comprising the steps:

2. method according to claim 1, is characterized in that temperature of reaction is-10 DEG C-10 DEG C.

3. method according to claim 1, is characterized in that the amount of the POTASSIUM BOROHYDRIDE needed for reacting is 2-10 times of erythromycin 6,9-imido ether.

4. method according to claim 1, is characterized in that the reaction times is 2-10h.

5. method according to claim 1, is characterized in that hydrochloric acid conditioning solution PH is 2-5.

6. method according to claim 1, is characterized in that acidic solution churning time is 0.5-6h.

7. method according to claim 1, is characterized in that the PH of sodium hydrate regulator solution is 10-13.