CN105481913B - A method of synthesis azithromycin - Google Patents
A method of synthesis azithromycin Download PDFInfo
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- CN105481913B CN105481913B CN201410480463.2A CN201410480463A CN105481913B CN 105481913 B CN105481913 B CN 105481913B CN 201410480463 A CN201410480463 A CN 201410480463A CN 105481913 B CN105481913 B CN 105481913B
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Abstract
The present invention relates to a kind of methods for synthesizing azithromycin, and erythromycin thiocyanate is used to obtain erythromycin oxime rhodanate as oximation reaction starting material, and directly progress next step reaction, rearranged reaction, reduction reaction and methylation reaction obtain azithromycin.Wherein rearrangement reaction, reduction reaction one kettle way carry out, and reduction reaction product does not separate in solid form and is directly used in methylation reaction.Synthetic method of the invention eliminates the conversion process that erythromycin oxime is transformed into from erythromycin oxime rhodanate, also eliminate the step of rearrangement product and reduzate must being separated in solid form in original technical process, its is environmental friendly simply, high income, at low cost, pollution is small, product purity is high, is suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of methods for synthesizing azithromycin, belong to technical field of medicine synthesis.
Background technique
Macrolide antibiotics is using 12-16 membered macrolide as parent, by hydroxyl with glycosidic bond and 1-3 sugar connection
A substance.It has wider antimicrobial spectrum, including staphylococcus, streptococcus, corynebacterium diphtheriae etc..Azithromycin
(Azithromycin, AZM) is applied to first clinical 15 yuan of azilide class antibiotic, is the ring expansion of erythromycin
Product.Its synthetic route is erythromycin after oximation reaction obtains erythromycin oxime, carries out Beckmann rearrangement, will then be generated
6,9 one imines ether of rearrangement product reduction, be converted into azithromycin procursor azithromycin (9 one deoxo, mono- 9a-aza-9a_
HomoerythromycinA, AZA), finally azithromycin is obtained by methylation reaction.It is by Pliva drugmaker upper
The exploitation of century 70 end, Pfizer obtains its patent right within 1981, and in sold worldwide.
The existing research to azithromycin synthetic method is concentrated mainly on rearrangement reaction step, for the first time such as US4328334
Rearrangement reaction is carried out to erythromycin oxime to be studied, and leaving group is made using paratoluensulfonyl chloride, it is molten that acetone-water makees reaction
Agent has synthesized the rearrangement product of erythromycin oxime at low temperature；EP0137132 has studied the influence of different solvents and alkali, discovery third
Ketone-water, ether, acetonitrile and toluene etc. make solvent, and when sodium carbonate and pyridine etc. are alkali, the rearrangement of available different isomer is produced
Object；WO00/27856 has advanced optimized reaction condition, it is believed that more satisfactory reaction condition is: acetone-water is solvent, carbonic acid
Hydrogen sodium is that alkali can achieve preferable yield and purity.
In addition, also have research for reduction reaction and methylation reaction, as Wilkening R.R. (Tetrahedron,
1997,53 (50), 16923-16944) have studied with 1,2- ethylidene glycol be solvent, with sodium borohydride reduction generate Zitromax
The precursor of element, but this method solvent is expensive, while product yield is low.27 have studied reduction reaction and the side to treat different things alike that methylates
Method specially uses sodium acetate and Rh/C hydrogen reducing, and formaldehyde is then added and reacts to obtain azithromycin, but this method uses
Expensive catalyst, and yield is very low.
Above-mentioned reaction is all using erythromycin as raw material, and price is more expensive.Although having using erythromycin thiocyanate is starting
The report of raw material, but be all by after erythromycin thiocyanate oximation reaction, then with alkali neutralization be that erythromycin oxime is further reset
Reaction (perhaps blue and green etc., one pot process (E)-erythromycin A-9 oxime new process, chemical reagent, 2009,31 (7), 565-567,
570).And existing reaction is mostly reacted with the reaction that substep carries out, and needs to separate every step product, and it is complicated for operation,
A large amount of solvents are consumed, high production cost will also result in environmental pollution.In addition, using erythromycin oxime rhodanate in the prior art
The system for carrying out rearrangement reaction is acetone and water, and the dicyandiamide solution is clearly present the disadvantages of dissolubility is poor, and yield is lower.
Therefore, it is necessary to further study azithromycin synthetic method.
Summary of the invention
Simple, high income that the object of the present invention is to provide a kind of process safety environmental protection, at low cost, the small, product quality of pollution
Good, small investment is suitble to the synthetic method of the azithromycin of industrialized production.
In order to solve the above technical problems, the invention adopts the following technical scheme:
(1) rearrangement reaction is directly carried out with erythromycin oxime rhodanate, then is successively obtained through reduction reaction, methylation reaction
Azithromycin.Reaction route is as follows:
(2) technical solution of the present invention comprises the steps of:
The present invention directly obtains erythromycin oxime rhodanate as oximation reaction starting material by erythromycin thiocyanate, directly
Carry out next step reaction.
Erythromycin oxime rhodanate dissolves in organic solvent, and rearrangement reaction reagent is added until fully reacting, then directly
It connects and reduction reaction reagent is added, obtain azithromycin and its derivative, then carry out methylation reaction again and obtain azithromycin.
The organic solvent herein referred to can be halogenated alkane (preferably dichloromethane or chloroform), monohydric alcohol or polyalcohol
(methanol or ethyl alcohol etc.), ethyl acetate etc., preferred alcohol.Rearrangement reaction reagent can be p-methyl benzenesulfonic acid and its salt, to toluene
Sulfonic acid chloride, preferably paratoluensulfonyl chloride.
Rearrangement reaction temperature can be -10-40 DEG C, preferably room temperature.
The dosage of rearrangement reaction reagent be erythromycin oxime rhodanate 0.2-1.5 times of equivalent, preferably 0.6 times.Reduction is anti-
Reagent is answered to can be sodium borohydride, potassium borohydride, preferably potassium borohydride.
Reduction reaction temperature can be -10-40 DEG C, preferably room temperature.The dosage of reduction reaction reagent is erythromycin oxime sulphur cyanogen
0.2-1.2 times of equivalent of hydrochlorate, preferably 0.5 times.
Reduzate azithromycin and its derivative do not need to separate in solid form.
The preferred halogenated alkane of methylation reaction solvent, more preferable dichloromethane or chloroform；The preferred first of methylating reagent
Aldehyde and formic acid.
The present invention directly carries out rearrangement reaction, reduction reaction with erythromycin oxime rhodanate, again successively through methylation reaction
Obtain azithromycin.Rearrangement product is obtained compared to rearrangement reaction is carried out with erythromycin oxime with previous production technology, then successively through restoring
Reaction, methylation reaction obtain azithromycin.
It has the advantage that
(1) present invention directly obtains erythromycin oxime rhodanate as oximation reaction starting material by erythromycin thiocyanate,
Next step reaction is directly carried out, the conversion process for being transformed into erythromycin oxime from erythromycin oxime rhodanate is eliminated, saves simultaneously
Alkali neutralization needed for this step reaction process such as reacts, feeds intake, extracting, washing, being centrifuged, dries at the units operation, also saves this
Raw and auxiliary material (methanol, methylene chloride, ammonium hydroxide, liquid alkaline etc.) needed for portion's reaction simplifies unit operation, reduces discharge and dirt
Dye, reduces the investment (centrifuge, double-cone dryer etc.) of fixed assets and equipment, eventually reduces the production cost of product.
(2) rearrangement reaction is directly carried out with erythromycin oxime rhodanate, reduction reaction, is successively obtained again through methylation reaction
Azithromycin realizes rearrangement reduction in the same reaction system while carrying out, and eliminating must be by weight in original technical process
Row object and reduzate separate in solid form, while eliminate alkali neutralization needed for this two-step reaction process reaction,
The units operation such as extraction, washing, centrifugation, dry, raw and auxiliary material (acetone, methylene chloride, liquid needed for also saving this two reactions
Alkali etc.), unit operation is simplified, reduces discharge and pollution, reduces investment (reaction kettle, centrifugation of fixed assets and equipment
Machine, double-cone dryer etc.), eventually reduce the production cost of product.
(3) provide a kind of environmental protection of process safety, simple, high income, at low cost, pollution is small, good product quality, small investment,
It is suitble to the synthetic method of the azithromycin of industrialized production.
(4) advantages of the present invention, which is also embodied in, is used in conjunction with above each advantage, so that this technique is suitble to industrial metaplasia
It produces, and cost is very low.
(5) present invention improves over the dicyandiamide solutions, reach preferable solute effect, achieve in high yield, high-purity
Effect.
Specific embodiment
Specific embodiment cannot limit the contents of the present invention it will be further appreciated that the present invention.
Embodiment 1:
Erythromycin oxime rhodanate can be made according to the method for the prior art, and erythromycin oxime rhodanate directly carries out weight
Row reaction, reduction reaction, again successively through methylation reaction obtain azithromycin, realize rearrangement restore it is same in a reaction system
Shi Jinhang.
Erythromycin oxime rhodanate 60g is added in three-necked flask of the 1000ml with stirring, 250ml methanol is sequentially added,
The sodium bicarbonate solution of 150ml8%, pH are controlled 7.0 or so, 48g paratoluensulfonyl chloride are added at room temperature, with to first
The addition reaction solution of benzene sulfonyl chloride is gradually thinning, until after insulation reaction 1.5hr, being added dropwise 20% under room temperature after clarification completely
Potassium borohydride 200ml, after being added dropwise in 4.5 hours, 300ml chloroform is added, it is quiet with 30% liquid alkaline tune pH9.5
Only split-phase divides and takes chloroform phase, and water phase uses 50ml chloroform to extract twice again, merges chloroform phase, and it is dry to set 1000ml
In the dry three-necked flask with stirring, 12ml formaldehyde is sequentially added, 7.5ml formic acid is heated to reflux 9hr, water is added to cool down, then through first
Phase inversion adds 30% liquid alkaline tune pH9.5 of methanol after baseization post-processing, crystallizes, is cooled to 5 DEG C, azithromycin is dried to obtain in filtering
Crude product 41.1g (yield 68.5%).By 2010 editions Chinese Pharmacopoeia azithromycin detection levels are as follows: 94.5%.
Embodiment 2:
Erythromycin oxime rhodanate directly carries out rearrangement reaction, reduction reaction, successively obtains Archie through methylation reaction again
Mycin realizes rearrangement reduction in a reaction system while carrying out.
Erythromycin oxime rhodanate 60g is added in three-necked flask of the 1000ml with stirring, 150ml ethyl alcohol is sequentially added,
The sodium bicarbonate solution of 120ml8%, pH are controlled 6.5 or so, 36g paratoluensulfonyl chloride are added at room temperature, with to first
The addition reaction solution of benzene sulfonyl chloride is gradually thinning, until after insulation reaction 1hr, 15% is added dropwise under room temperature completely after clarification
After being added dropwise in 4 hours, 200ml chloroform is added in potassium borohydride 200ml, with 30% liquid alkaline tune pH9.0, static point
Phase divides and takes chloroform phase, and water phase uses 50ml chloroform to extract twice again, merges chloroform phase, sets 1000ml drying
In three-necked flask with stirring, 9ml formaldehyde is sequentially added, 6ml formic acid is heated to reflux 8hr, water is added to cool down, then after methylating
Phase inversion adds 30% liquid alkaline tune pH9.0 of ethyl alcohol after processing, crystallizes, is cooled to 2 DEG C, azithromycin crude product is dried to obtain in filtering
44.4g (yield 74%).By 2010 editions Chinese Pharmacopoeia azithromycin detection levels are as follows: 96.8%.
Claims (2)
1. a kind of method for synthesizing azithromycin, it is characterised in that: obtained by erythromycin thiocyanate as oximation reaction starting material
To erythromycin oxime rhodanate, erythromycin oxime rhodanate dissolves in organic solvent, and rearrangement reaction reagent is added until reaction
Completely, it is then directly added into the reaction of reduction reaction reagent, reduzate azithromycin is obtained, then carries out methylation reaction again and obtain
To azithromycin, reaction route is as follows:
Specific preparation process is as follows for it: erythromycin oxime rhodanate 60g being added in three-necked flask of the 1000ml with stirring, successively
250ml methanol, the sodium bicarbonate solution of 150ml8% is added, pH is controlled 7.0 or so, adds 48g at room temperature to toluene
Sulfonic acid chloride, as the addition reaction solution of paratoluensulfonyl chloride is gradually thinning, until completely after clarification, after insulation reaction 1.5hr,
20% potassium borohydride 200ml is added dropwise under room temperature, after being added dropwise in 4.5 hours, 300ml chloroform is added, with 30%
Liquid alkaline tune pH9.5, static split-phase divide and take chloroform phase, and water phase uses 50ml chloroform to extract twice again, merge chloroform
Phase sets in the dry three-necked flask with stirring of 1000ml, sequentially adds 12ml formaldehyde, 7.5ml formic acid is heated to reflux 9hr, adds
Water cooling, then phase inversion adds 30% liquid alkaline tune pH9.5 of methanol after methylation post-processing, crystallizes, is cooled to 5 DEG C, filter, dries
Do to obtain azithromycin crude product 41.1g.
2. a kind of method for synthesizing azithromycin, it is characterised in that steps are as follows: erythromycin oxime rhodanate 60g is added
In three-necked flask of the 1000ml with stirring, 150ml ethyl alcohol, the sodium bicarbonate solution of 120ml8% are sequentially added, pH is controlled 6.5
Left and right, adds 36g paratoluensulfonyl chloride at room temperature, as the addition reaction solution of paratoluensulfonyl chloride is gradually thinning, until
Completely after clarification, after insulation reaction 1hr, the potassium borohydride 200ml of dropwise addition 15% adds after being added dropwise in 4 hours under room temperature
Enter 200ml chloroform, with 30% liquid alkaline tune pH9.0, static split-phase divides and takes chloroform phase, and water phase uses 50ml trichlorine again
Methane extracts twice, merges chloroform phase, sets in the dry three-necked flask with stirring of 1000ml, sequentially adds 9ml formaldehyde,
6ml formic acid, is heated to reflux 8hr, and water is added to cool down, then through methylation post-processing after phase inversion add ethyl alcohol with 30% liquid alkaline tune pH9.0,
Crystallization, is cooled to 2 DEG C, and azithromycin crude product 44.4g is dried to obtain in filtering.
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| CN106083954B (en) * | 2016-06-22 | 2018-12-11 | 连云港笃翔化工有限公司 | A kind of preparation method of 6,9 imines ether compound of erythromycin |
| CN110483594B (en) * | 2019-09-11 | 2021-07-16 | 杭州新桂实业有限公司 | Method for synthesizing azithromycin |
| CN112745369A (en) * | 2020-12-24 | 2021-05-04 | 宁夏启元药业有限公司 | Method for synthesizing erythromycin cyanamide by using erythromycin thiocyanate oxime |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007015265A2 (en) * | 2005-05-24 | 2007-02-08 | Kopran Research Laboratories Ltd | A process for preparing 6,9-imino ether |
| CN101712703A (en) * | 2009-11-18 | 2010-05-26 | 上海华理生物医药有限公司 | Method for preparing azithromycin and method for preparing intermediate of azithromycin |
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| GB9824580D0 (en) * | 1998-11-10 | 1999-01-06 | Biochemie Sa | Organic compounds |
| WO2009156938A2 (en) * | 2008-06-24 | 2009-12-30 | Alembic Limited | A cost effective process for preparing 6,9-imino ether |
| CN102127064B (en) * | 2010-12-29 | 2013-09-11 | 开封制药(集团)有限公司 | Preparation method of azithromycin intermediate |
| CN103772456B (en) * | 2014-01-11 | 2016-04-27 | 浙江耐司康药业有限公司 | The preparation method of dihydro homoerythromycin |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007015265A2 (en) * | 2005-05-24 | 2007-02-08 | Kopran Research Laboratories Ltd | A process for preparing 6,9-imino ether |
| CN101712703A (en) * | 2009-11-18 | 2010-05-26 | 上海华理生物医药有限公司 | Method for preparing azithromycin and method for preparing intermediate of azithromycin |
Non-Patent Citations (1)
| Title |
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| 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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