CN103214531B - A kind of preparation method of azithromycin procursor azithromycin - Google Patents
A kind of preparation method of azithromycin procursor azithromycin Download PDFInfo
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- CN103214531B CN103214531B CN201310144710.7A CN201310144710A CN103214531B CN 103214531 B CN103214531 B CN 103214531B CN 201310144710 A CN201310144710 A CN 201310144710A CN 103214531 B CN103214531 B CN 103214531B
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- azithromycin
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Abstract
The invention belongs to pharmaceutical technology field, discloses a kind of preparation method of azithromycin procursor azithromycin, and its feature is in the presence of hydrolytic reagent is promoted, in two-phase solvent, hydrolysis rate is accelerated, and moment adjusts PH, to realize being completely separated for product and boride, product quality and yield are improved, and this method technique is simple, acid degradation thing ＜ 2.0%, boride ＜ 1.0%, yield 97%, product can directly methyl be combined to azithromycin, suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to a kind of preparation method of azithromycin procursor azithromycin.
Background technology
Azithromycin（N- methyl isophthalic acid 1- azepine -10- deoxidation -10- dihydro Erythromycin As）It is a kind of macrolides
Antibiotic, is widely used in respiratory system, urinary system and skin soft-tissue infection etc., and U.S. FDA approval substitutes penicillins
First-line drug of the medicine as anti-infectives, can also treat AIDS patient's mycobacteria infections.
Its chemical synthesis mainly comprises the following steps：Using erythromycin thiocyanate A as initiation material, through oximate, Beckman weight
Row, potassium borohydride reduction, acidic hydrolysis, methylate generation azithromycin.
Document（Ma Min, Yao Guowei, Deng Yulin azithromycins synthesize research [J] fine chemistry industries of mesoboric acid ester hydrolysis,
2006,23（6）：558-587.）Report, wherein during acidic hydrolysis, the cladinose ring on azithromycin（Formula III）With
The connected key of lactonic ring is weaker, unstable in acid medium, degradable, influences yield and generation impurity, total recovery 85%.
Acidic hydrolysis is another feature is that boride and target product separate not thorough, the more presence in the form of impurity
In product, target product quality is had a strong impact on, while yield reduces.
The content of the invention
(1) goal of the invention：The purpose of the present invention is exactly to thoroughly remove boride, shortens hydrolysis time, and reduction is acid
Degraded, the generation of impurity is reduced, improve product quality, improve yield.
(2) technical scheme：The preparation method of azithromycin procursor azithromycin of the present invention, it is the effect for promoting hydrolytic reagent
Under, after fast hydrolyzing is complete in two-phase solvent, moment regulation PH, target product is quickly transferred to organic phase, boronation from aqueous phase
Thing is stored in aqueous phase, and boride and product separation are thorough, and the organic phase after split-phase directly can be combined to azithromycin by methyl, very suitable
Close industrialized production.
(3) technique effect：This method process conditions are gentle, and efficiency high, raw material is simple and easy to get, and acid degradation weakens ＜
2.0%, boride ＜ 1.0%, yield significantly improves, and up to 97%, and product does not have to separation, you can direct methyl is combined to Archie
Mycin, it is suitable for industrialized production.
The specific embodiment of the invention is as follows：
Embodiment 1.
800kg purified waters are added in reactor, adds and promotees hydrolytic reagent sorbierite 16kg, dissolved clarification, it is red 160kg nitrogen will to be contained
The chloroform phase 1000L of mycin borate is added in reactor, is cooled to -10 DEG C, adds 10% hydrochloric acid to PH=1.5,5 minutes
Afterwards, quantitative disposable 20% sodium hydroxide solution that adds stirs 5 minutes to PH=9.7-10.0, stands split-phase, the aqueous phase separated
Extracted again with 100L chloroforms, chloroform mutually merges, and divides and goes aqueous phase, takes chloroform mutually to survey analysis, detected through HPLC, sour catabolite
2.1%, boride 0.9%, yield 96.1%.
Embodiment 2.
800kg purified waters are added in reactor, adds and promotees hydrolytic reagent mannitol 16kg, dissolved clarification, 160kg nitrogen will be contained
The dichloromethane phase 1000L of erythromycin borate is added in reactor, is cooled to 0 DEG C, adds 10% hydrochloric acid to PH=1.5,8 points
Zhong Hou, quantitative disposable 20% sodium hydroxide solution that adds stir 5 minutes to PH=9.7-10.0, stand split-phase, the water separated
Mutually extracted again with 100L dichloromethane, dichloromethane mutually merges, takes dichloromethane facies analysis, detected through HPLC, sour catabolite
0.98%, boride 0.5%, yield 97.0%.
Embodiment 3.
800kg purified waters are added in reactor, adds and promotees hydrolytic reagent sorbierite 8kg, dissolved clarification, it is red 160kg nitrogen will to be contained
Mycin borate 1,2- dichloroethanes 1000L are added in reactor, are cooled to 0 DEG C, add 10% hydrochloric acid to PH=1.5,15 minutes
Afterwards, 20% sodium hydroxide solution is rapidly joined to PH=9.7-10.0, is stirred 5 minutes, is stood split-phase, aqueous phase uses 100L1,2- again
Dichloroethanes extracts, and 1,2- dichloroethanes mutually merges, takes 1,2- dichloroethanes facies analyses, detected through HPLC, sour catabolite 8%,
Boride 2%, yield 90%.
Embodiment 4.
800kg purified waters are added in reactor, adds and promotees hydrolytic reagent glucose 8kg, dissolved clarification, it is red 160kg nitrogen will to be contained
Mycin borate 1,2- dichloroethanes 1000L are added in reactor, are cooled to 0 DEG C, add 10% hydrochloric acid to PH=1.5,15 minutes
Afterwards, 20% sodium hydroxide solution is added to PH=9.7-10.0, is stirred 5 minutes, is stood split-phase, aqueous phase uses 100L1,2- dichloros again
Ethane extracts, and 1,2- dichloroethanes mutually merges, takes 1,2- dichloroethanes facies analyses, detected through HPLC, sour catabolite 8.2%, boron
Compound 3.4%, yield 88%.
Claims (1)
1. a kind of preparation method of azithromycin procursor azithromycin, it comprises the following steps：800kg purified waters are added and reacted
In kettle, add and promote hydrolytic reagent mannitol 16kg, dissolved clarification, by the dichloromethane phase 1000L containing 160kg azithromycin borates
Add in reactor, be cooled to 0 DEG C, add 10% hydrochloric acid to pH=1.5, after 8 minutes, 20% hydroxide of quantitative disposable addition
Sodium solution stirs 5 minutes to pH=9.7-10.0, stands split-phase, the aqueous phase separated is extracted with 100L dichloromethane again, dichloromethane
Alkane mutually merges, and obtains the solution of azithromycin.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310144710.7A CN103214531B (en) | 2013-04-24 | 2013-04-24 | A kind of preparation method of azithromycin procursor azithromycin |
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| CN201310144710.7A CN103214531B (en) | 2013-04-24 | 2013-04-24 | A kind of preparation method of azithromycin procursor azithromycin |
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| CN103214531A CN103214531A (en) | 2013-07-24 |
| CN103214531B true CN103214531B (en) | 2017-12-01 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817600A (en) * | 2015-04-20 | 2015-08-05 | 中国医药集团总公司四川抗菌素工业研究所 | Preparation and purification method of dihydro hyper erythrocin |
| CN106632543A (en) * | 2016-12-20 | 2017-05-10 | 宁夏启元药业有限公司 | Synthesis method of azithromycin |
| CN107141324B (en) * | 2017-05-16 | 2019-10-18 | 河北科技大学 | A kind of preparation method for removing first azithromycin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0827965A2 (en) * | 1996-07-11 | 1998-03-11 | Astur-Pharma, S.A. | Synthesis of 9-deoxo- 9a-aza 11,12-deoxy- 9a-methyl-9a-homoerythromycin A 11,12- hydrogenorthoborate dihydrate |
| CN103880899A (en) * | 2012-12-24 | 2014-06-25 | 青岛康地恩动物药业有限公司 | Demethyl azithromycin synthesis method |
-
2013
- 2013-04-24 CN CN201310144710.7A patent/CN103214531B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0827965A2 (en) * | 1996-07-11 | 1998-03-11 | Astur-Pharma, S.A. | Synthesis of 9-deoxo- 9a-aza 11,12-deoxy- 9a-methyl-9a-homoerythromycin A 11,12- hydrogenorthoborate dihydrate |
| CN103880899A (en) * | 2012-12-24 | 2014-06-25 | 青岛康地恩动物药业有限公司 | Demethyl azithromycin synthesis method |
Non-Patent Citations (4)
| Title |
|---|
| 9-脱氧-9a-氮杂-9a-同型红霉素的合成;史颖，等;《精细化工》;20040731;第21卷(第7期);第546-549页 * |
| 以水为介质一锅煮合成氮红霉素;马敏，等;《2006年第六届中国药学会学术年会论文集》;20061231;第2034-2038页 * |
| 氮红霉素的合成工艺研究;陈世坤;《安徽化工》;20130415;第39卷(第2期);第32-35页 * |
| 阿奇霉素合成工艺的改进;马敏，等;《精细化工》;20060831;第23卷(第8期);第781-783页 * |
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