CN105481913A - Method for synthesizing azithromycin - Google Patents
Method for synthesizing azithromycin Download PDFInfo
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- CN105481913A CN105481913A CN201410480463.2A CN201410480463A CN105481913A CN 105481913 A CN105481913 A CN 105481913A CN 201410480463 A CN201410480463 A CN 201410480463A CN 105481913 A CN105481913 A CN 105481913A
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Abstract
The invention relates to a method for synthesizing azithromycin. According to the invention, erythromycin thiocyanate is adopted as an initial raw material of an oximation reaction, such that erythromycin oxime thiocyanate is obtained; the next step of reaction is directly carried out; and through rearrangement, reduction and methylation reactions, azithromycin is obtained. The rearrangement and reduction reactions are carried out with a one-pot method. A reduction reaction product is not separated in a solid form, and is directly used in the methylation reaction. With the synthesizing method provided by the invention, a conversion process from erythromycin oxime thiocyanate to eythromycin oxime is eliminated, and steps that rearrangement and reduction products are separated in solid forms in an original process are also eliminated. The process is environment-friendly and simple, and has the advantages of high yield, low cost, low pollution and high product purity. The method is suitable for industrialized productions.
Description
Technical field
The present invention relates to a kind of method of synthesizing Azythromycin, belong to technical field of medicine synthesis.
Background technology
Macrolide antibiotics is with 12-16 membered macrolide for parent, the class material be connected with 1-3 sugar with glycosidic bond by hydroxyl.It has wider antimicrobial spectrum, comprises staphylococcus, suis, diphtheria corynebacterium etc.Azythromycin (Azithromycin, AZM) is applied to first 15 yuan clinical azilide class microbiotic, is the ring expansion product of erythromycin.Its synthetic route is that erythromycin obtains after erythromycin oxime through oximation reaction, carry out Beckmann rearrangement, then the rearrangement product 6 will generated, 9 one imines ether reduction, be converted into azithromycin procursor azithromycin (9 one deoxo mono-9a-aza-9a_homoerythromycinA, AZA), eventually pass methylation reaction and obtain Azythromycin.It is developed at the end of the seventies in last century by Pliva drugmaker, and within 1981, Pfizer obtains its patent right, and at sold worldwide.
The existing research to Azythromycin synthetic method mainly concentrates on rearrangement reaction step, be studied as US4328334 carries out rearrangement reaction to erythromycin oxime first, Tosyl chloride is adopted to make leavings group, acetone-water makes reaction solvent, has synthesized the rearrangement product of erythromycin oxime at low temperatures; EP0137132 have studied the impact of different solvents and alkali, finds that solvent made by acetone-water, ether, acetonitrile and toluene etc., when sodium carbonate and pyridine etc. are alkali, can obtain the rearrangement product of different isomerization body; WO00/27856 optimizes reaction conditions further, thinks that more satisfactory reaction conditions is: acetone-water is solvent, and sodium bicarbonate is that alkali can reach good productive rate and purity.
In addition, also research is had for reduction reaction and methylation reaction, as WilkeningR.R. (Tetrahedron, 1997,53 (50), 16923-16944) have studied with 1,2-ethylidene glycol is solvent, generate the precursor of Azythromycin with sodium borohydride reduction, but the method solvent is expensive, product yield is low simultaneously.27 have studied reduction reaction and the method for the treatment of different things alike that methylates, and are specially and use sodium acetate and Rh/C hydrogen reducing, then add formaldehyde reaction and obtain Azythromycin, but the expensive catalyst that the method uses, and productive rate is very low.
Above-mentioned reaction is all take erythromycin as raw material, and its price is more expensive.The report that Matachrom is starting raw material is used although existing, but be all by after Matachrom oximation reaction, be that erythromycin oxime does rearrangement reaction more further and (permitted blue and green etc. with alkali neutralization again, the novel process of one pot process (E)-erythromycin A-9 oxime, chemical reagent, 2009,31 (7), 565-567,570).And existing reaction is reacted mainly with the reaction of proceed step by step, need to be separated often walking product, complicated operation, consume a large amount of solvent, production cost is high, also can cause environmental pollution.In addition, the system using erythromycin oxime thiocyanate-to carry out rearrangement reaction in prior art is acetone and water, and this solvent system obviously exists the shortcomings such as poorly soluble, and productive rate is lower.
Therefore, need to study further Azythromycin synthetic method.
Summary of the invention
The object of this invention is to provide that a kind of process safety environmental protection is simple, yield is high, cost is low, it is little to pollute, good product quality, less investment are applicable to the Azythromycin of suitability for industrialized production synthetic method.
For solving the problems of the technologies described above, the present invention by the following technical solutions:
(1) directly carry out rearrangement reaction with erythromycin oxime thiocyanate-, then obtain Azythromycin through reduction reaction, methylation reaction successively.Reaction scheme is as follows:
(2) technical scheme of the present invention comprises following steps:
The present invention directly obtains erythromycin oxime thiocyanate-by Matachrom as oximation reaction starting raw material, directly carries out next step reaction.
Erythromycin oxime thiocyanate-dissolves in organic solvent, adds rearrangement reaction reagent until react completely, then directly adds reduction reaction reagent, obtain azithromycin and derivative thereof, and then carries out methylation reaction and obtain Azythromycin.
Here the organic solvent referred to can be halogenated alkane (preferred methylene dichloride or trichloromethane), monohydroxy-alcohol or polyvalent alcohol (methyl alcohol or ethanol etc.), ethyl acetate etc., preferred alcohol.Rearrangement reaction reagent can be tosic acid and salt, Tosyl chloride, preferred Tosyl chloride.
Rearrangement reaction temperature can be-10-40 DEG C, preferred room temperature.
The consumption of rearrangement reaction reagent is 0.2-1.5 times of equivalent of erythromycin oxime thiocyanate-, preferably 0.6 times.Reduction reaction reagent can be sodium borohydride, POTASSIUM BOROHYDRIDE, preferred POTASSIUM BOROHYDRIDE.
Reduction reaction temperature can be-10-40 DEG C, preferred room temperature.The consumption of reduction reaction reagent is 0.2-1.2 times of equivalent of erythromycin oxime thiocyanate-, preferably 0.5 times.
Reduzate azithromycin and derivative thereof do not need to separate in solid form.
The preferred halogenated alkane of methylation reaction solvent, more preferably methylene dichloride or trichloromethane; The preferred formaldehyde of methylating reagent and formic acid.
The present invention's erythromycin oxime thiocyanate-directly carries out rearrangement reaction, reduction reaction, obtains Azythromycin through methylation reaction successively again.Compare and carry out rearrangement reaction with previous production technique erythromycin oxime and obtain rearrangement product, then obtain Azythromycin through reduction reaction, methylation reaction successively.
There is following advantage:
(1) the present invention directly obtains erythromycin oxime thiocyanate-by Matachrom as oximation reaction starting raw material, directly carry out next step reaction, eliminate the conversion process being transformed into erythromycin oxime from erythromycin oxime thiocyanate-, eliminate alkali neutralization reaction required in this step reaction process simultaneously, feed intake, extraction, washing, centrifugal, drying waits unit operation, also raw and auxiliary material (the methyl alcohol needed for the reaction of this is saved, methylene dichloride, ammoniacal liquor, liquid caustic soda etc.), simplify unit operation, decrease discharge and pollute, decrease the investment (whizzer of fixed capital and equipment, double-cone dryer etc.), eventually reduce the production cost of product.
(2) directly rearrangement reaction is carried out with erythromycin oxime thiocyanate-, reduction reaction, Azythromycin is obtained successively again through methylation reaction, achieve to reset to reduce and carry out in same reaction system simultaneously, eliminate in original technological process and rearrangement product and reduzate must be separated in solid form, eliminate alkali neutralization reaction required in this two-step reaction process simultaneously, extraction, washing, centrifugal, drying waits unit operation, also raw and auxiliary material (the acetone needed for these two reactions is saved, methylene dichloride, liquid caustic soda etc.), simplify unit operation, decrease discharge and pollute, decrease the investment (reactor of fixed capital and equipment, whizzer, double-cone dryer etc.), eventually reduce the production cost of product.
(3) a kind of process safety environmental protection is provided, simple, yield is high, cost is low, it is little to pollute, good product quality, less investment, be applicable to the synthetic method of the Azythromycin of suitability for industrialized production.
(4) advantage of the present invention is also embodied in the common use to above each advantage, make this technique be applicable to suitability for industrialized production, and cost is very low.
(5) present invention improves over this solvent system, reach good solute effect, achieve high yield, highly purified effect.
Embodiment
Specific embodiment can understand the present invention further, but can not limit content of the present invention.
Embodiment 1:
Erythromycin oxime thiocyanate-can method conventionally obtain, and erythromycin oxime thiocyanate-directly carries out rearrangement reaction, reduction reaction, obtains Azythromycin successively again through methylation reaction, achieves to reset to reduce and carry out a reaction system simultaneously.
Erythromycin oxime thiocyanate-60g is added in the there-necked flask of 1000ml band stirring, add 250ml methyl alcohol successively, the sodium hydrogen carbonate solution of 150ml8%, pH controls about 7.0, at room temperature add 48g Tosyl chloride again, along with Tosyl chloride to add reaction solution thinning gradually, until after clarifying completely, after insulation reaction 1.5hr, the POTASSIUM BOROHYDRIDE 200ml of 20% is dripped under normal temperature, after dropwising in 4.5 hours, add 300ml trichloromethane, liquid caustic soda with 30% adjusts pH9.5, static phase-splitting, divide and get trichloromethane phase, aqueous phase uses 50ml chloroform extraction twice again, merge trichloromethane phase, in the there-necked flask that the band putting 1000ml drying stirs, add 12ml formaldehyde successively, 7.5ml formic acid, reflux 9hr, add water for cooling, again after the aftertreatment that methylates phase inversion add methyl alcohol with 30% liquid caustic soda adjust pH9.5, crystallization, be cooled to 5 DEG C, filter, dry to obtain Azythromycin crude product 41.1g (yield 68.5%).By 2010 editions Chinese Pharmacopoeia Azythromycin detection level be: 94.5%.
Embodiment 2:
Erythromycin oxime thiocyanate-directly carries out rearrangement reaction, reduction reaction, obtains Azythromycin successively again through methylation reaction, achieves to reset to reduce and carry out a reaction system simultaneously.
Erythromycin oxime thiocyanate-60g is added in the there-necked flask of 1000ml band stirring, add 150ml ethanol successively, the sodium hydrogen carbonate solution of 120ml8%, pH controls about 6.5, at room temperature add 36g Tosyl chloride again, along with Tosyl chloride to add reaction solution thinning gradually, until after clarifying completely, after insulation reaction 1hr, the POTASSIUM BOROHYDRIDE 200ml of 15% is dripped under normal temperature, after dropwising in 4 hours, add 200ml trichloromethane, liquid caustic soda with 30% adjusts pH9.0, static phase-splitting, divide and get trichloromethane phase, aqueous phase uses 50ml chloroform extraction twice again, merge trichloromethane phase, in the there-necked flask that the band putting 1000ml drying stirs, add 9ml formaldehyde successively, 6ml formic acid, reflux 8hr, add water for cooling, again after the aftertreatment that methylates phase inversion add ethanol with 30% liquid caustic soda adjust pH9.0, crystallization, be cooled to 2 DEG C, filter, dry to obtain Azythromycin crude product 44.4g (yield 74%).By 2010 editions Chinese Pharmacopoeia Azythromycin detection level be: 96.8%.
Claims (10)
1. one kind is synthesized the method for Azythromycin, it is characterized in that: obtain erythromycin oxime thiocyanate-by Matachrom as oximation reaction starting raw material, erythromycin oxime thiocyanate-dissolves in organic solvent, add rearrangement reaction reagent until react completely, then reduction reaction reagent react is directly added, obtain reduzate azithromycin, and then carry out methylation reaction and obtain Azythromycin, its reaction scheme is as follows:
2. the method for synthesis Azythromycin according to claim 1, is characterized in that: described organic solvent is halogenated alkane, monohydroxy-alcohol or polyvalent alcohol or ethyl acetate.
3. the method for synthesis Azythromycin according to claim 2, is characterized in that: halogenated alkane is methylene dichloride or trichloromethane, and monohydroxy-alcohol is methyl alcohol or ethanol.
4. the method for synthesis Azythromycin according to claim 1, is characterized in that: rearrangement reaction temperature is-10-40 DEG C, and rearrangement reaction reagent is tosic acid and salt thereof or Tosyl chloride.
5. the method for synthesis Azythromycin according to claim 1, is characterized in that: the consumption of rearrangement reaction reagent is 0.2-1.5 times of equivalent of erythromycin oxime thiocyanate-; Reduction reaction reagent is sodium borohydride or POTASSIUM BOROHYDRIDE.
6. the method for synthesis Azythromycin according to claim 1, is characterized in that: reduction reaction temperature is-10-40 DEG C, and the consumption of reduction reaction reagent is 0.2-1.2 times of equivalent of erythromycin oxime thiocyanate-.
7. the method for synthesis Azythromycin according to claim 1, is characterized in that: reduzate azithromycin is not separated in solid form.
8. the method for synthesis Azythromycin according to claim 1, is characterized in that: methylation reaction solvent is halogenated alkane; Methylating reagent is formaldehyde and formic acid.
9. one kind is synthesized the method for Azythromycin, it is characterized in that step is as follows: added by erythromycin oxime thiocyanate-60g in the there-necked flask of 1000ml band stirring, add 250ml methyl alcohol successively, the sodium hydrogen carbonate solution of 150ml8%, pH controls about 7.0, at room temperature add 48g Tosyl chloride again, along with Tosyl chloride to add reaction solution thinning gradually, until after clarifying completely, after insulation reaction 1.5hr, the POTASSIUM BOROHYDRIDE 200ml of 20% is dripped under normal temperature, after dropwising in 4.5 hours, add 300ml trichloromethane, liquid caustic soda with 30% adjusts pH9.5, static phase-splitting, divide and get trichloromethane phase, aqueous phase uses 50ml chloroform extraction twice again, merge trichloromethane phase, in the there-necked flask that the band putting 1000ml drying stirs, add 12ml formaldehyde successively, 7.5ml formic acid, reflux 9hr, add water for cooling, again after the aftertreatment that methylates phase inversion add methyl alcohol with 30% liquid caustic soda adjust pH9.5, crystallization, be cooled to 5 DEG C, filter, dry to obtain Azythromycin crude product 411g.
10. one kind is synthesized the method for Azythromycin, it is characterized in that step is as follows: added by erythromycin oxime thiocyanate-60g in the there-necked flask of 1000ml band stirring, add 150ml ethanol successively, the sodium hydrogen carbonate solution of 120ml8%, pH controls about 6.5, at room temperature add 36g Tosyl chloride again, along with Tosyl chloride to add reaction solution thinning gradually, until after clarifying completely, after insulation reaction 1hr, the POTASSIUM BOROHYDRIDE 200ml of 15% is dripped under normal temperature, after dropwising in 4 hours, add 200ml trichloromethane, liquid caustic soda with 30% adjusts pH9.0, static phase-splitting, divide and get trichloromethane phase, aqueous phase uses 50ml chloroform extraction twice again, merge trichloromethane phase, in the there-necked flask that the band putting 1000ml drying stirs, add 9ml formaldehyde successively, 6ml formic acid, reflux 8hr, add water for cooling, again after the aftertreatment that methylates phase inversion add ethanol with 30% liquid caustic soda adjust pH9.0, crystallization, be cooled to 2 DEG C, filter, dry to obtain Azythromycin crude product 44.4g.
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Cited By (5)
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| CN106083954A (en) * | 2016-06-22 | 2016-11-09 | 连云港笃翔化工有限公司 | A kind of preparation method of erythromycin 6,9 imines ether compound |
| CN110483594A (en) * | 2019-09-11 | 2019-11-22 | 杭州新桂实业有限公司 | A method of synthesis 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 |
| CN115651036A (en) * | 2022-11-10 | 2023-01-31 | 山东安信制药有限公司 | A kind of method utilizing microchannel reactor to prepare azithromycin |
| CN117417388A (en) * | 2023-10-24 | 2024-01-19 | 山东安信制药有限公司 | One-pot chemical synthesis of azithromycin |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106083954A (en) * | 2016-06-22 | 2016-11-09 | 连云港笃翔化工有限公司 | A kind of preparation method of erythromycin 6,9 imines ether compound |
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| CN110483594A (en) * | 2019-09-11 | 2019-11-22 | 杭州新桂实业有限公司 | A method of synthesis 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 |
| CN115651036A (en) * | 2022-11-10 | 2023-01-31 | 山东安信制药有限公司 | A kind of method utilizing microchannel reactor to prepare azithromycin |
| CN115651036B (en) * | 2022-11-10 | 2025-09-26 | 山东安信制药有限公司 | A method for preparing azithromycin using a microchannel reactor |
| CN117417388A (en) * | 2023-10-24 | 2024-01-19 | 山东安信制药有限公司 | One-pot chemical synthesis of azithromycin |
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