CN107141324A - A kind of preparation method for removing first azithromycin - Google Patents
A kind of preparation method for removing first azithromycin Download PDFInfo
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Abstract
The invention discloses a kind of preparation method for removing first azithromycin, it is related to macrolide antibiotics preparing technical field.The imines ether of Erythromycin A 6,9 is in water, 0 DEG C of room temperature, under pH 7.0 9.0, with go back original reagent sodium borohydride or potassium borohydride reduction；Afterwards in the presence of organic solvent and water, 0 DEG C of room temperature under pH 2.0 3.5, carries out continuous hydrolysis；Continuous hydrolysis two phase reaction liquid is added in alkaline aqueous solution again, pH >=12 are adjusted, stirred, layering, aqueous phase discarded；Organic solvent is dichloromethane, chloroform, 1,2 dichloromethane, ethyl acetate or butyl acetate；After the last time hydrolysis of continuous hydrolysis terminates, layering, aqueous phase is directly added into alkaline aqueous solution, adjusts pH >=12, and first azithromycin is removed in stirring, precipitation.This method improves reducing agent utilization rate, can control the back reaction of borate, reduces unnecessary separation process, obtains high-quality removing first azithromycin.
Description
Technical field
The present invention relates to macrolide antibiotics preparing technical field, especially a kind of azithromycin procursor removes first Archie
The preparation method of mycin.
Background technology
Azithromycin is the structure of modification thing of macrolide antibiotics erythromycin, broad-spectrum antiseptic, to some tolerance β-interior
The pathogenic bacteria of amide-type antibiotic effectively, with tissue permeability is strong, concentration is high, the characteristics of long half time.Clinically use extensively
In respiratory tract, urinary system, skin soft tissue disease caused by the sensitive pathogenic infection for the treatment of, treatment for the sexually transmitted diseases is can be used for,
Prevent and treat spread of sexually transmitted diseases.It is the precursor for preparing azithromycin to remove first azithromycin, and it obtains azithromycin through methylating.
The preparation process of azithromycin includes：With azanol oximation reaction occurs for erythromycin thiocyanate A (II), obtains thiocyanic acid
Erythromycin A-9 oxime (III), handles through sulfonic acid chloride and resets, and obtains erythrocin A iminoether { Erythromycin A 6,9- imines ether (IV) and different
Structure body Erythromycin A 11,9- imines ether (V) }, by catalytic hydrogenation or with chemical reagent potassium borohydride, sodium borohydride reduction, obtain
To first azithromycin (I) is removed, methylated with formic acid, formaldehyde and obtain azithromycin.The preparation process reaction equation of azithromycin
It is as follows：
In the preparation process of azithromycin, oximate, rearrangement and methylation reaction process study are more abundant, process conditions
Simply, high income, but the reduction preparation of imines ether goes first azithromycin process complicated, is to influence the pass of azithromycin yield and quality
Key step.
Prepared by document report imines ether catalytic hydrogen reduction goes first azithromycin as follows：US：5,586,587 report for (1997)
Road, imines ether is in acetic acid, PtO2For catalyst, 50atm room temperature catalytic hydrogenation 48h obtain first azithromycin, yield
85.8%. CN：1199736A (1998) reports imines ether catalytic hydrogenation and methylated " one kettle way ", prepares azithromycin
Method, acetic acid is solvent, and 5%Rh/C is catalyst, and 70atm, 40 DEG C of hydrogenation 3h add excess formaldehyde solution, 40atm, 40
DEG C continue react 20h, directly prepare azithromycin.US：5,869,629 (1999) report 6,9- imines ether (IV) acetic acid are water-soluble
Liquid, under 75atm with 5%Pa/C be catalyst hydrogenation 12h, obtain first azithromycin.US：6,528,492B1 (2003)
The method that " one kettle way " prepares azithromycin is reset, reduced, being methylated to report oximate, using Erythromycin A as initiation material；Wherein
It is catalyst with Ni-Al, 85atm hydro-reduction imines ether prepares and removes first azithromycin.US：2005/0222052 A1 is disclosed
The imines ether phosphoric acid aqueous solution, using 5%Pt/C as catalyst, the catalytic hydrogenation 24h under 15 DEG C, 20atm obtains first Zitromax
Element.CN：103087125 A disclose imines ether methanol solution, and pH=5-6 is adjusted with perchloric acid, under Pt/C catalysis, in
First azithromycin is removed in 40--43 DEG C, hydro-reduction 4h under 8.3-8.6atm, preparation.
Prepared by chemical-agent technique reduction imines ether removes first azithromycin, is related to first azithromycin hydrogen borate and goes first with double
2 intermediate products of azithromycin hydrogen borate.Acidolysis removes borate, and distribution life can be converse in the middle part of alkalescence neutralization separation process
Should, first azithromycin hydrogen borate is changed into again, causes that yield is low, separation is difficult.Acidolysis is taken to be added when removing borate
Polyhydroxy organic additive, quickly adds alkali to neutralize, and can partly suppress reversible reaction, improves yield.
WO：03/082889 A1 discloses 6,9- imines ethers in methanol solvate, with the sodium borohydride low temperature of 6 times of molal quantitys
First azithromycin is removed in reduction preparation, and acid hemolysis process adds citric acid, yield 85.5%.US：6,703,372B1 (2004) is open
With the sodium borohydride reduction of 7.7 times of molal quantitys, obtain it is double remove first azithromycin hydrogen borate, it is sour in the presence of polyhydroxy resin
First azithromycin is removed in solution, preparation.US：6,451,990 B1 (2002) disclose 6,9- imines ethers in methanol solvate, use boron
Sodium reduction is hydrogenated, it is isolated to remove first azithromycin hydrogen borate, azithromycin hydrogen borate is changed into formaldehyde, carboxylic acid methyl,
Acidolysis, is neutralized with aqua calcis, isolated azithromycin, and yield is less than 50%.The quick grade of horse exists《Fine chemistry industry》
Reported in Vol.23, No.8 and use potassium borohydride reduction imines ether, acidolysis, neutralization extraction after directly being methylated, then are carried out
Acidolysis, prepares azithromycin.CN：101712703 A (2010) and CN：Preparation side disclosed in 102127064 A (2011)
Method is similar, and 6,9- imines ethers, with potassium borohydride reduction, are hydrolyzed in the pH=5-6 aqueous solution in the presence of polyhydroxy base auxiliary agent, plus alkali
Neutralize, dichloromethane extraction obtains first azithromycin and removes first azithromycin hydrogen borate mixed solution, methylated, then
Secondary acidolysis, neutralization are carried out, azithromycin is prepared.
The advantage that imines ether changes into first azithromycin is that reduction process does not go first using catalytic hydrogenation technology
Azithromycin hydrogen borate intermediate product is generated.Weak point equipment investment is big, and using noble metal catalyst, reactant processing is not
It is good, easily there is catalyst poisoning, cause production cost high.In addition, in experimentation, this seminar finds, removes first azithromycin
It is unstable in acid water, methanol, acetonitrile, under conditions of room temperature, there is impurity, purity declines；Therefore, imines ether is in faintly acid
Catalytic hydrogenation is prepared and gone during first azithromycin in water or acetic acid, side reaction unavoidably occurs, and it is low yield occur, and influence is most
Whole azithromycin product quality.
Prepared using chemical reagent reduction imines ether and remove first azithromycin, normal pressure is reacted, and equipment investment is small；But due to
There is part reversible reaction in acidolysis, N-process, generation goes first azithromycin hydrogen borate to remove first azithromycin hydrogen borate 2 with double
Intermediate product, causes separating step cumbersome, it is necessary to carry out multiple organic solvent extraction, production efficiency is low.Other document is disclosed
Sodium borohydride be reducing agent, it is necessary to which methanol is solvent, low-temperature operation, sodium borohydride consumption is big, and production cost is high.
In view of the shortcomings of the prior art first azithromycin is removed, it is necessary to develop simple to operate, high income imines ether and prepare
Method, solves the key technical problem of azithromycin production process.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method for removing first azithromycin, it the method increase also
The utilization rate of former agent, can control the back reaction of borate, simple to operate, reduce unnecessary separation process, obtain high-quality
Remove first azithromycin.
In order to solve the above technical problems, the technical solution used in the present invention is：A kind of preparation side for removing first azithromycin
Method, comprises the following steps：
(1) reduce：Erythromycin A 6,9- imines ether (IV) is in water, 0 DEG C-room temperature, under pH=7.0-9.0, is tried with reduction
Agent sodium borohydride or potassium borohydride reduction；
(2) hydrolyze：Afterwards in the presence of organic solvent and water, 0 DEG C-room temperature, under pH=2.0-3.5, continuous hydrolysis is carried out；
Continuous hydrolysis two phase reaction liquid is directly added into alkaline aqueous solution again, pH >=12 are adjusted, stirred, layering, aqueous phase discarded；
Wherein, organic solvent is dichloromethane, chloroform, 1,2- dichloromethane, ethyl acetate or butyl acetate；
(3) after the last time hydrolysis of continuous hydrolysis terminates, layering, aqueous phase is directly added into alkaline aqueous solution, is adjusted
PH >=12 are saved, first azithromycin (I) is removed in stirring, precipitation, and reaction equation is as follows：
It is preferred that, in step (1), reaction temperature is 0-5 DEG C, and go back original reagent is potassium borohydride.
It is preferred that, in step (1), Erythromycin A 6,9- imines ether (IV) is by Erythromycin A or erythromycin thiocyanate A (II)
Through oximate, reset what is obtained.
It is preferred that, in step (1), sodium borohydride or potassium borohydride molal quantity are Erythromycin A 6,9- imines ether (IV) mole
Several 1.2-1.5 times.
It is preferred that, in step (2), organic solvent is dichloromethane or chloroform.
It is preferred that, in step (2), reaction temperature is 0-5 DEG C, under pH=2.5-3.0, carries out continuous hydrolysis.
It is preferred that, in step (2), continuous hydrolysis 2-3 times is hydrolyzed into hydrolysis material≤1wt% every time.
It is preferred that, in step (2), acid used in continuous hydrolysis regulation pH=2.0-3.5 is hydrochloric acid, sulfuric acid, phosphoric acid；Step
(2) and in (3), alkaline aqueous solution is sodium hydrate aqueous solution, potassium hydroxide aqueous solution, calcium hydroxide aqueous solution, sodium carbonate
Solution or ammoniacal liquor.
It is further preferred that in step (2), acid used in continuous hydrolysis regulation pH=2.0-3.5 is 10wt%-20wt% salt
Acid；In step (2) and (3), alkaline aqueous solution is sodium hydrate aqueous solution.
It is preferred that, the preparation method of first azithromycin is gone, is comprised the following steps：
(1) reduce：By Erythromycin A 6,9- imines ether (IV) is suspended in the water of 3-8 times of quality, stirring, is cooled 0-5 DEG C,
Hydrochloric acid, sulfuric acid or phosphoric acid are added, pH=7-0-7.5 is adjusted, 5-10wt% sodium borohydride or the potassium borohydride aqueous solution is added dropwise, when
During pH=9.0, stop being added dropwise 5-10wt% sodium borohydride or the potassium borohydride aqueous solution, continue stirring reaction 1-2h, TLC monitoring
Reaction, if any Erythromycin A 6,9- imines ether (IV) raw material point is present, then hydrochloric acid, sulfuric acid or phosphoric acid is added dropwise, and adjusts pH=7.0-
After 7.5, continue that 5-10wt% sodium borohydride or the potassium borohydride aqueous solution is added dropwise, it is complete to reacting；PH=6- is neutralized to acid
7, stirring without gas untill releasing；Add Erythromycin A 6, the organic solvent of the 5-15 times of quality of 9- imines ether (IV) mass number
Dichloromethane, chloroform, 1,2- dichloromethane, ethyl acetate or butyl acetate, pH is adjusted with 10-20wt% sodium hydrate aqueous solutions
>=11, stirring, stratification；Aqueous phase is discarded；
(2) hydrolyze：Erythromycin A 6 is added in organic phase, the water of the 3-6 times of quality of 9- imines ether (IV) mass number is stirred,
0-5 DEG C of cooling, adds hydrochloric acid, sulfuric acid or phosphoric acid, adjusts pH=2.5-3.0, carries out the 1st hydrolysis, and TLC monitors former to borate
Shots disappear；Two phase reaction liquid will be hydrolyzed to add in 10-20wt% sodium hydrate aqueous solutions, pH >=12 are adjusted, stirring stands and divided
Layer, aqueous phase discarded；Erythromycin A 6 is continuously added in organic phase, the water of the 4-6 times of quality of 9- imines ether (IV) mass number is stirred,
0-5 DEG C of cooling, adds hydrochloric acid, sulfuric acid or phosphoric acid, adjusts pH=2.5-3.0, carries out the 2nd hydrolysis, and TLC is monitored to borate
Raw material point disappears；Hydrolysis two phase reaction liquid is added to 10-20wt% sodium hydrate aqueous solutions, pH >=12 are adjusted, stirring is quiet
Layering is put, again aqueous phase discarded；Erythromycin A 6 is added in organic phase, the 3-6 times of quality of 9- imines ether (IV) mass number
Water, stirring cools 0-5 DEG C, adds hydrochloric acid, sulfuric acid or phosphoric acid, adjusts pH=2.5-3.0, carries out the 3rd hydrolysis, TLC monitorings
Disappeared to borate raw material point；
(3) it is layered, organic phase, which retains, applies mechanically；20 DEG C -30 DEG C, aqueous phase is added in 5% sodium hydrate aqueous solution, and insulation is stirred
Mix, adjust pH >=12, continue to stir, first azithromycin (I) is removed in precipitation, filter, filter cake washing obtains content 85wt% with up
First azithromycin (I) crude product, directly carries out methylation reaction, obtains azithromycin.
The present invention is during first azithromycin is removed in chemical reagent reduction erythrocin A iminoether preparation, neutral and weak base
Under conditions of property (pH=7.0-9), sodium borohydride or potassium borohydride can smoothly reduce Erythromycin A 6,9- imines ether (IV),
When pH >=8, obtain double reactants gone based on first azithromycin hydrogen borate (VI) and first azithromycin hydrogen borate is removed in part
(VII).It is double to go first azithromycin hydrogen borate (VI) to change into first Ah under the conditions of neutral and faintly acid (pH=4.0-7.0)
Miramycin borate (VII)；Continue to increase acidity, go first azithromycin hydrogen borate (VII) hydrolysis to remove boric acid, by alkali
With, precipitation remove first azithromycin (I).Reaction equation is as follows：
After the completion of sodium borohydride or potassium borohydride reduction, gone in addition alkali with precipitation during first azithromycin, this class
Topic group, which has been surprisingly found that, double remove first azithromycin hydrogen borate (VI) and goes first azithromycin hydrogen borate (VII) to be soluble in alkaline water
In, and go first azithromycin not dissolve in alkaline water, especially as pH >=12, go first azithromycin to be practically insoluble in water.It is logical
Cross to add reaction solution to separate out in buck and remove first azithromycin (I) solid, the formation of back reaction borate, Shao Liangshuan can be reduced
Remove first azithromycin hydrogen borate (VI) and go first azithromycin hydrogen borate (VII) to be dissolved in alkaline water, can efficiently separate and obtain height
Quality removes first azithromycin (I).
It is red mould with sodium borohydride or potassium borohydride reduction using water as solvent under the conditions of neutral and weakly alkaline
Plain A 6,9- imines ether (IV)；After the completion of reaction, add organic solvent extractive reaction liquid, discard containing excess sodium borohydride or
The aqueous phase of potassium borohydride.It is organic to be added to water, acidic hydrolysis is adjusted to, aqueous slkali is added rapidly to and is neutralized to pH >=12, static point
Layer, again aqueous phase discarded.Water is added, regulation to acidity carries out secondary hydrolysis.After the completion of reaction, aqueous phase is added alkalescence by split-phase
In water, first azithromycin is removed in precipitation, through filtering, is washed, and drying, can obtain being practically free of borate removes first azithromycin
(I) first azithromycin (I) and its boride, is gone to be efficiently separated.It is a small amount of in filtrate to go first azithromycin hydrogen borate (VII) to pass through
Organic extractant phase, it is reusable.
The present invention uses sodium borohydride or potassium borohydride reduction Erythromycin A 6, and 9- imines ether (IV) is in the range of pH=7-9
Carry out.Compared with known sodium borohydride reduction, sodium borohydride consumption is reduced, without the use of methanol solvate.With known boron
Hydrofining reduction is compared, and potassium borohydride is decomposed when reducing pH=5-6, slows down the emitting rate of hydrogen, improves the peace of course of reaction
Quan Xing.Neutralized in organic phase and aqueous phase by hydrolyzing, being added to alkali lye twice；The aqueous phase of third time hydrolysis, which is added in buck, to be analysed
Go out product, reach efficiently separating for first azithromycin (I) and its borate, obtain high-quality product, can directly carry out first
Base, prepares azithromycin.
It is using the beneficial effect produced by above-mentioned technical proposal：
(1) preparation process for removing first azithromycin of the invention, is reducing agent using potassium borohydride or sodium borohydride, in
Reacted in property and alkalescent aqueous phase, reduce the acid decomposition of reducing agent, improve the utilization rate of reducing agent, slow down
The emitting rate of hydrogen, increases the security of production；
(2) process of removing borate acidic hydrolysis in the presence of organic phase, is added to alkaline aqueous solution neutralization, it is ensured that
Adition process is completed in the basic conditions all the time, and the first azithromycin that goes of precipitation is directly entered organic phase, reduces reversible reaction
Occur；
(3) by being hydrolyzed in the presence of 2 organic phases, the 3rd hydrolysis layering, aqueous phase is added directly into alkaline aqueous solution,
First azithromycin solid is removed in precipitation, goes first azithromycin and its borate to be efficiently separated, and obtains high-quality removing first Zitromax
Plain product, it is simple to operate, save production cost, organic phase recycled；What is obtained goes first azithromycin solid directly to enter
Row methylates, and produces high-quality azithromycin.
Brief description of the drawings
The present invention is further detailed explanation with reference to the accompanying drawings and detailed description；
Fig. 1 is the high-efficient liquid phase chromatogram of obtained erythromycin A-9 oxime rhodanate in reference example 1-2 of the present invention；
Fig. 2 is the high-efficient liquid phase chromatogram of obtained erythrocin A iminoether in reference example 2 of the present invention；
Fig. 3 is the obtained high-efficient liquid phase chromatogram for removing first azithromycin in the embodiment of the present invention 2；
Fig. 4 is the high-efficient liquid phase chromatogram of obtained azithromycin in reference example 3-2 of the present invention.
Embodiment
Embodiment is intended merely to illustrate process of the present invention, is not that the content of the invention is limited.
Reference example 1-1：The preparation of erythromycin thiocyanate A oximes (III)
1000mL there-necked flasks add hydroxylamine hydrochloride (114g, 1.64mol), and methanol 300g is stirred at room temperature, and triethylamine is added dropwise and adjusts
Save pH=6.3-6.7.Erythromycin thiocyanate A (II) (200g, 0.25mol) is added, 30-35 DEG C of reaction 4h is warming up to, reacted
Triethylamine regulation pH=6.5 ± 0.2 is added dropwise in journey；50-55 DEG C is warming up to, continues insulation reaction 48h.It is cooled to 15-20 DEG C, dropwise addition
600mL deionized waters, stir 0.5h；0-5 DEG C of crystallization 2h.Filtering, is washed with 200mL deionized waters, is dried, is obtained white solid red
Mycin A oximes rhodanate (III) 180g.Yield 88.4%, 182-185 DEG C of fusing point, purity 93.7% (HPLC).
Reference example 1-2：The preparation of erythromycin thiocyanate A oximes (III)
2000mL there-necked flasks add hydroxylamine hydrochloride (228g, 3.3mol), and methanol 600g is stirred at room temperature, and triethylamine is added dropwise and adjusts
Save pH=6.3-6.7.Erythromycin thiocyanate A (II) (400g, 0.5mol) is added, 30-35 DEG C, insulation reaction 10h is warming up to；
Triethylamine regulation pH=6.5 ± 0.2 is added dropwise in course of reaction；50-55 DEG C is warming up to, continues insulation reaction 40h.It is cooled to 15-20
DEG C, 1200mL deionized waters are added dropwise, 0.5h is stirred；0-5 DEG C, crystallization 2h.Filtering, is washed with 400mL deionized waters, is dried, is obtained
White solid erythromycin A-9 oxime rhodanate (III) 348g, yield 87.0%, 182-184 DEG C of the fusing point, (HPLC of purity 93.8%
As shown in Fig. 1 and table 1).
The HPLC testing results of the erythromycin A-9 oxime rhodanate of table 1
| Peak # | Retention time | Area | Area % | Highly | Separating degree | Tailing factor | Theoretical tray # |
| 1 | 5.189 | 4515.021 | 0.309 | 196 | 0.000 | 0.000 | 1417.547 |
| 2 | 5.925 | 2320.639 | 0.159 | 145 | 1.505 | 0.000 | 3081.121 |
| 3 | 7.596 | 5082.196 | 0.347 | 347 | 4.117 | 1.109 | 6233.250 |
| 4 | 9.060 | 18683.710 | 1.277 | 847 | 3.436 | 1.471 | 6011.604 |
| 5 | 10.832 | 38186.596 | 2.609 | 1834 | 3.618 | 0.960 | 7165.879 |
| 6 | 12.999 | 18449.404 | 1.261 | 574 | 3.141 | 1.048 | 3588.149 |
| 7 | 16.197 | 1374109.695 | 93.890 | 40944 | 3.933 | 1.260 | 7307.045 |
| 8 | 24.296 | 2191.019 | 0.150 | 74 | 10.609 | 1.127 | 15975.680 |
| Amount to | 1463538.280 | 100.000 | 44960 |
In table 1, it is thiocyanic acid at erythromycin A-9 oxime rhodanate, 12.99min that the corresponding peaks of retention time 16.197min, which are,
Erythromycin A.
Reference example 2：The preparation of erythrocin A iminoether
Erythromycin A-9 oxime rhodanate (III) (180g, 0.22mol), acetone 540mL are added in 2000mL there-necked flasks, is stirred
Mix.0-10 DEG C, 10% sodium bicarbonate solution 450g is added, less than 5 DEG C, paratoluensulfonyl chloride (51g, 0.27moL), 1h is added dropwise
Drop finishes, insulation reaction 3h.1200mL deionized waters are added dropwise in reaction solution, adjusts pH=11-12 with the 10wt%NaOH aqueous solution, stirs
Mix 1h.0-5 DEG C of crystallization 1h.Washed under filtering, room temperature condition with 400mL deionized waters, dry to obtain 142g white solid Erythromycin As
Imines ether.Yield 88.3%, 134-140 DEG C of fusing point, purity 92.9% (HPLC as Fig. 2 and table 2 shown in).
The HPLC testing results of table Erycette A imines ethers
| Peak # | Retention time | Area | Area % | Highly | Separating degree | Tailing factor | Theoretical tray # |
| 1 | 2.606 | 35405.142 | 2.508 | 4299 | 0.000 | 1.419 | 2051.637 |
| 2 | 4.945 | 1317.408 | 0.093 | 131 | 9.077 | 1.101 | 4807.327 |
| 3 | 5.378 | 2546.654 | 0.180 | 218 | 1.427 | 1.085 | 4458.056 |
| 4 | 7.996 | 7476.017 | 0.530 | 311 | 5.603 | 0.000 | 2729.040 |
| 5 | 8.713 | 1087.839 | 0.077 | 57 | 1.255 | 0.000 | 4329.944 |
| 6 | 10.721 | 1311764.753 | 92.913 | 44323 | 3.344 | 1.830 | 4076.105 |
| 7 | 15.171 | 1777.773 | 0.126 | 72 | 6.835 | 0.839 | 9266.035 |
| 8 | 17.022 | 3963.593 | 0.281 | 136 | 2.689 | 1.662 | 8324.875 |
| 9 | 29.750 | 46479.687 | 3.292 | 879 | 12.109 | 0.833 | 7701.607 |
| Amount to | 1411818.866 | 100.000 | 50425 |
In table 2, the corresponding peaks of retention time 10.721min are Erythromycin A 6,9- imines ethers, the method system through the present invention
The erythrocin A iminoether obtained, the content for detecting 9,11 imines ethers through HPLC is respectively less than 1%.
Embodiment 1：First azithromycin (I) is gone to prepare
1.1：Reduction
40g erythrocin A iminoethers are suspended in 160mL water, stir 10min, are cooled to 0-5 DEG C, and 10wt% hydrochloric acid is added dropwise
PH=7.0 is adjusted, the 12g 16.7wt% potassium borohydride aqueous solution is slowly added to, 1h is finished, insulated and stirred reaction 2h, pH=8.5-
9.0.10wt% hydrochloric acid is added dropwise, pH=7.0 is adjusted, the 6.2g 19wt% potassium borohydride aqueous solution is added dropwise, insulated and stirred reacts 2h,
PH=8.0-8.5.10wt% hydrochloric acid is added dropwise, pH=8.0 is adjusted, the 6.2g 19wt% potassium borohydride aqueous solution, insulation reaction is added dropwise
3h, TLC are monitored, and reaction terminates.10wt% hydrochloric acid is added dropwise, pH=5-6 is adjusted, stirring without gas untill releasing.Add 280mL
Dichloromethane, is added dropwise 10wt% sodium hydrate aqueous solutions regulation pH=11-12, stirs 0.5h, static layering.Water layer 120mL
Dichloromethane is extracted.Combined dichloromethane layer, water layer discarded.
1.2：Once hydrolyze
160mL water is added in organic phase dichloromethane layer, 0-5 DEG C is cooled to, 10wt% hydrochloric acid regulation aqueous phase pH=is added dropwise
2.5-3.0, insulated and stirred reaction 1h.TLC is monitored, and borate is { double to remove first azithromycin hydrogen borate (VI) and remove first azithromycin
Borate (VII) } basic disappearance.Reaction solution is poured into 100g 5wt% sodium hydrate aqueous solution under stirring, is stirred at room temperature
1h, static layering, water layer discarded.
1.3：Secondary hydrolysis
Upper step organic phase dichloromethane layer adds 160mL water, is cooled to 0-5 DEG C, 10% hydrochloric acid adjusts pH=2.5-3.0, protects
Warm stirring reaction 1h.TLC is monitored, and borate is { double to remove first azithromycin hydrogen borate (VI) and remove first azithromycin hydrogen borate
(VII) } disappear.Reaction solution is poured into 100g 5wt% sodium hydrate aqueous solution under stirring, 1h, static point is stirred at room temperature
Layer, water layer discarded.
1.4：Go first azithromycin (I) preparation
The dichloromethane layer of secondary hydrolysis adds 160mL water, is cooled to 0-5 DEG C, 10wt% hydrochloric acid adjusts pH=2.5-3.0,
Insulated and stirred reacts 1h.TLC monitoring borates are { double to remove first azithromycin hydrogen borate (VI) and remove first azithromycin hydrogen borate
(VII) thorough, static layering } is hydrolyzed.Water layer is quickly poured into 200g 2.5wt% sodium hydrate aqueous solutions, 0.5h is stirred.
25-30 DEG C is removed under reduced pressure remaining dichloromethane, repetition measurement pH=12-13.20-25 DEG C of stirring and crystallizing 1h, filtering, uses 40mL water washings
2 times, drying must remove first azithromycin (I) 35.6g, yield 89.0%, 126-128 DEG C of fusing point, purity 84.5%, and borate is { double
Remove first azithromycin hydrogen borate (VI) and go first azithromycin hydrogen borate (VII) sum≤1% (HPLC).
Embodiment 2：First azithromycin is gone to prepare
2.1：Reduction
80g erythrocin A iminoethers are suspended in 320mL water, stir 10min, are cooled to 0-5 DEG C, and phosphorus acid for adjusting pH is added dropwise
=7.0,16.7wt% potassium borohydride aqueous solution 20g is slowly added to, 1h is finished, insulated and stirred reaction 2h, pH=8.5-9.0.Drop
Phosphorate acid, adjusts pH=7.0, and 20wt% potassium borohydride aqueous solution 10g, insulated and stirred reaction 2h, pH=8.0-8.5 is added dropwise.Drop
Phosphorate acid, adjusts pH=8.0, continues that 20wt% potassium borohydride aqueous solution 10g, insulation reaction 3h, TLC monitoring, reaction knot is added dropwise
Beam.10wt% hydrochloric acid is added dropwise, pH=5-6 is adjusted, stirring without gas untill releasing.800mL dichloromethane is added, is added dropwise
10wt% sodium hydrate aqueous solutions adjust pH=11-12, stir 0.5h, static layering.Water layer is extracted with 200mL dichloromethane.
Combined dichloromethane layer, water layer discarded.Dichloromethane layer is equally divided into two parts.
2.2：Once hydrolyze
160mL water is added in a dichloromethane layer of step 2.1,0-5 DEG C is cooled to, 10wt% hydrochloric acid regulation water is added dropwise
Phase pH=2.5-3.0, insulated and stirred reaction 1h.TLC is monitored, borate it is double remove first azithromycin hydrogen borate (VI) and go first Ah
Miramycin borate (VII) } basic disappearance.Reaction solution is poured into 5wt% sodium hydrate aqueous solution 100g under stirring, room temperature
Stir 1h, static layering, water layer discarded.
2.3：Secondary hydrolysis
Upper step is organic to be added to 160mL water, is cooled to 0-5 DEG C, 10wt% hydrochloric acid adjusts pH=2.5-3.0, insulated and stirred is anti-
Answer 1h.TLC is monitored, and borate { double to remove first azithromycin hydrogen borate (VI) and remove first azithromycin hydrogen borate (VII) } disappears.
Reaction solution is poured into 5wt% sodium hydrate aqueous solution 100g under stirring, 1h, static layering, water layer discarded is stirred at room temperature.
2.4：Go first azithromycin (I) preparation
The dichloromethane layer of secondary hydrolysis adds 160mL water, is cooled to 0-5 DEG C, 10wt% hydrochloric acid adjusts pH=2.5-3.0,
Insulated and stirred reacts 1h.TLC monitoring borates are { double to remove first azithromycin hydrogen borate (VI) and remove first azithromycin hydrogen borate
(VII) } disappear, static layering.Water layer is quickly poured into 3wt% sodium hydrate aqueous solutions 200g, 0.5h is stirred.25-30℃
Remaining dichloromethane is removed under reduced pressure, pH=12-13 is controlled.20-25 DEG C of stirring and crystallizing 1h, filtering, with 50mL water washings 2 times, is dried
It is dry, first azithromycin (I) 35.3g must be removed, yield 88.3%, 127-129 DEG C of fusing point, purity 85%, borate is { double to remove first Archie
Mycin borate (VI) and remove first azithromycin hydrogen borate (VII) do not detect (HPLC).
Another dichloromethane operation of step 2.1 ibid, obtains demethyl azithromycin (I) 35.4g, yield 88.5%,
Fusing point is 127-129 DEG C, and purity 87.0%, borate is { double to remove first azithromycin hydrogen borate (VI) and remove first azithromycin boric acid
Ester (VII) sum }≤0.5% (HPLC as Fig. 3 and table 3 shown in).
The HPLC testing results of the demethyl azithromycin of table 3
| Peak # | Retention time | Area | Area accumulates % | Highly | Separating degree | Tailing factor | Theoretical tray # |
| 1 | 2.338 | 10128.803 | 0.984 | 886 | 0.000 | 1.706 | 787.836 |
| 2 | 4.467 | 6406.678 | 0.623 | 328 | 4.620 | 0.000 | 922.775 |
| 3 | 4.998 | 2576.723 | 0.250 | 139 | 0.874 | 0.000 | 1015.126 |
| 4 | 6.176 | 79631.347 | 7.738 | 4295 | 2.228 | 1.246 | 3313.019 |
| 5 | 7.661 | 22343.551 | 2.171 | 994 | 3.237 | 0.730 | 3930.765 |
| 6 | 11.390 | 896084.681 | 87.076 | 34956 | 6.872 | 1.374 | 5831.552 |
| 7 | 15.687 | 4347.906 | 0.423 | 189 | 7.196 | 0.929 | 11021.376 |
| 8 | 22.778 | 4343.199 | 0.422 | 140 | 10.171 | 1.005 | 13080.556 |
| 9 | 30.352 | 3222.797 | 0.313 | 70 | 8.159 | 1.424 | 13121.502 |
| Amount to | 1029085.684 | 100.000 | 41997 |
In table 3, the corresponding peaks of retention time 11.390min are demethyl azithromycin.
Embodiment 3：First azithromycin (I) is gone to prepare
3.1：Reduction
80g erythrocin A iminoethers are suspended in 320mL water, stir 10min, are cooled to 0-5 DEG C, and 10wt% sulfuric acid is added dropwise
PH=7.0 is adjusted, slowly plus 15wt% potassium borohydride aqueous solution 20g, 1h are finished, insulated and stirred reaction 2h, pH=8.5-9.0.
10wt% sulfuric acid is added dropwise, pH=7.0 is adjusted, 20wt% potassium borohydride aqueous solution 10g, insulated and stirred reaction 2h, pH=is added dropwise
8.0-8.5.10wt% hydrochloric acid is added dropwise again, pH=8.0 is adjusted, continues that 20wt% potassium borohydride aqueous solution 11g are added dropwise, insulation is anti-
3h is answered, TLC monitorings, reaction terminates.10wt% sulfuric acid is added dropwise, pH=5-6 is adjusted, stirring without gas untill releasing.Add
800mL dichloromethane, is added dropwise 10wt% sodium hydrate aqueous solutions regulation pH=11-12, stirs 0.5h, static layering.Water layer is used
200mL dichloromethane is extracted.Combined dichloromethane layer, water layer discarded.
3.2：Once hydrolyze
320mL water is added in organic phase dichloromethane layer, 0-5 DEG C is cooled to, 10wt% sulfuric acid regulation aqueous phase pH=is added dropwise
2.5-3.0, insulated and stirred reaction 1h.TLC is monitored, and borate is { double to remove first azithromycin hydrogen borate (VI) and remove first azithromycin
Borate (VII) } basic disappearance.Reaction solution is poured into 5wt% sodium hydrate aqueous solution 200g under stirring, is stirred at room temperature
1h, static layering, water layer discarded.
3.3：Secondary hydrolysis
Upper step is organic to be added to 320mL water, is cooled to 0-5 DEG C, and pH=2.5-3.0, insulated and stirred are adjusted with 10wt% sulfuric acid
React 1h.TLC is monitored, and borate { double to remove first azithromycin hydrogen borate (VI) and remove first azithromycin hydrogen borate (VII) } disappears
Lose.Reaction solution is poured into 5wt% sodium hydroxide solution 200g under stirring, 1h, static layering, water layer discarded is stirred at room temperature.
3.4：Go first azithromycin (I) preparation
The dichloromethane layer of secondary hydrolysis adds 320mL water, is cooled to 0-5 DEG C, 10wt% sulfuric acid adjusts pH=2.5-3.0,
Insulated and stirred reacts 1h.TLC monitoring borates are { double to remove first azithromycin hydrogen borate (VI) and remove first azithromycin hydrogen borate
(VII) thorough, static layering } is hydrolyzed.Water layer is quickly poured into 400g 2.5wt%-3wt% sodium hydrate aqueous solutions 400g
In, stir 0.5h.25-30 DEG C is removed under reduced pressure remaining dichloromethane, controls pH=12-13.20-25 DEG C of stirring and crystallizing 1h, mistake
Filter, with 120mL water washings 2 times, drying must remove first azithromycin (I) 70.5g, yield 88.0%, 128-130 DEG C of fusing point, purity
80%, borate { double to remove first azithromycin hydrogen borate (VI) and go first azithromycin hydrogen borate (VII) sum }≤0.3%
(HPLC)。
Embodiment 4：Go first azithromycin (I) preparation
4.1：Reduction
80g erythrocin A iminoethers are suspended in 320mL water, stir 10min, are cooled to 0-5 DEG C, and 50wt% acetic acid is added dropwise
PH=7.0 is adjusted, slowly plus 15wt% potassium borohydride aqueous solution 20g, 1h are finished, insulated and stirred reaction 2h, pH=8.5-9.0.
50wt% acetic acid is added dropwise, pH=7.0 is adjusted, 20wt% potassium borohydride aqueous solution 10g, insulated and stirred reaction 2h, pH=is added dropwise
8.0-8.5.50wt% acetic acid is added dropwise again, pH=8.0 is adjusted, continues that 20wt% potassium borohydride aqueous solution 11g are added dropwise, insulation is anti-
3h is answered, TLC monitorings, reaction terminates.50wt% acetic acid is added dropwise, pH=5-6 is adjusted, stirring without gas untill releasing.Add
800mL dichloromethane, is added dropwise 10wt% sodium hydrate aqueous solutions regulation pH=11-12, stirs 0.5h, static layering.Water layer is used
200mL dichloromethane is extracted.Combined dichloromethane layer, water layer discarded.
4.2：Once hydrolyze
320mL water is added in organic phase dichloromethane layer, 0-5 DEG C is cooled to, 85wt% phosphoric acid regulation aqueous phase pH=is added dropwise
2.5-3.0, insulated and stirred reaction 1h.TLC is monitored, and borate is { double to remove first azithromycin hydrogen borate (VI) and remove first azithromycin
Borate (VII) } basic disappearance.Reaction solution is poured into 5wt% sodium hydroxide solution 200g under stirring, 1h is stirred at room temperature,
Static layering, water layer discarded.
4.3：Secondary hydrolysis
Upper step organic phase dichloromethane layer adds 320mL water, is cooled to 0-5 DEG C, and pH=2.5- is adjusted with 85wt% phosphoric acid
3.0, insulated and stirred reaction 1h.TLC is monitored, and borate is { double to remove first azithromycin hydrogen borate (VI) and remove first azithromycin boric acid
Ester (VII) } disappear.Reaction solution is poured into 5wt% sodium hydrate aqueous solution 200g under stirring, 1h, static point is stirred at room temperature
Layer, water layer discarded.
4.4：Go first azithromycin (I) preparation
The dichloromethane layer of secondary hydrolysis adds 320mL water, is cooled to 0-5 DEG C, 85wt% phosphoric acid adjusts pH=2.5-3.0,
Insulated and stirred reacts 1h.TLC monitoring borates are { double to remove first azithromycin hydrogen borate (VI) and remove first azithromycin hydrogen borate
(VII) thorough, static layering } is hydrolyzed.Water layer is quickly poured into 400g 2.5wt%-3wt% sodium hydrate aqueous solutions 400g
In, stir 0.5h.25-30 DEG C is removed under reduced pressure remaining dichloromethane, controls pH=12-13.20-25 DEG C of stirring and crystallizing 1h, mistake
Filter, with 120mL water washings 2 times, drying must remove first azithromycin (I) 72.0g, yield 90.0%, 128-130 DEG C of fusing point, purity
84%, borate { double to remove first azithromycin hydrogen borate (VI) and go first azithromycin hydrogen borate (VII) sum }≤0.3%
(HPLC)。
Reference example 3-1:The preparation of azithromycin
250mL there-necked flasks add demethyl azithromycin (I) (15g, 0.02mol), and dissolving is stirred at room temperature in acetone 50mL.
30-40 DEG C, anhydrous formic acid (2.5g, 0.06mol), 37% formaldehyde (2.2g, 0.03mol) is added dropwise.It is warming up to 50-55 DEG C, insulation
4h is reacted, TLC monitoring reactions are finished.
Room temperature is down to, 50mL deionized waters are added, 50mL is added dropwise in 10wt% sodium hydrate aqueous solutions regulation pH=12-13
Deionized water, stirring and crystallizing 2h.Filtering, with 30mL water washings 2 times, drying obtains azithromycin 13.5g, yield 90%, purity
97.6% (HPLC).
Reference example 3-2:The preparation of azithromycin
500mL there-necked flasks add demethyl azithromycin (I) (50g, 0.07mol), and dissolving is stirred at room temperature in acetone 175mL.
30-40 DEG C, anhydrous formic acid (8.5g, 0.18mol), 37% formaldehyde (7.3g, 0.09mol) is added dropwise.It is warming up to 50-55 DEG C, insulation
4h is reacted, TLC monitoring reactions are finished.
Room temperature is down to, 175mL deionized waters are added, 10wt% sodium hydrate aqueous solutions regulation pH=12-13 is added dropwise
175mL deionized waters, stirring and crystallizing 2h.Filtering, with 100mL water washings 2 times, drying obtains Azithromycin 4 7.5g, yield
95%, purity 98.8% (HPLC as Fig. 4 and table 4 shown in).
The HPLC testing results of the azithromycin of table 4
| Retention time | Area | Area % | Highly | Separating degree (USP) | Tailing factor | Theoretical cam curve (USP) |
| 23.588 | 24046 | 0.065 | 714 | -- | 1.100 | 10675 |
| 25.247 | 83341 | 0.225 | 1060 | 1.218 | 1.442 | 3111 |
| 28.800 | 70928 | 0.192 | 1453 | 2.300 | 1.113 | 8104 |
| 36.294 | 18734 | 0.051 | 407 | 4.044 | -- | 3581 |
| 37.285 | 25298 | 0.068 | 545 | 0.511 | -- | 10535 |
| 41.623 | 12422 | 0.034 | 276 | 3.163 | 1.236 | 16650 |
| 49.114 | 36561015 | 98.894 | 309919 | 3.354 | 2.542 | 3827 |
| 60.578 | 31933 | 0.086 | 475 | 4.475 | -- | 15465 |
| 62.410 | 47933 | 0.130 | 822 | 1.038 | 0.939 | 24883 |
| 64.922 | 94403 | 0.255 | 1444 | 1.512 | 1.065 | 22294 |
| 36970055 | 100.000 | 317114 |
In table 4, the corresponding peaks of retention time 49.114min are azithromycin.
Claims (10)
1. a kind of preparation method for removing first azithromycin, it is characterised in that：Comprise the following steps：
(1) reduce：Erythromycin A 6,9- imines ether (IV) is in water, 0 DEG C-room temperature, under pH=7.0-9.0, uses go back original reagent boron
Sodium hydride or potassium borohydride reduction；
(2) hydrolyze：Afterwards in the presence of organic solvent and water, 0 DEG C-room temperature, under pH=2.0-3.5, continuous hydrolysis is carried out；Again will
Continuous hydrolysis two phase reaction liquid is directly added into alkaline aqueous solution, adjusts pH >=12, is stirred, layering, aqueous phase discarded；
Wherein, organic solvent is dichloromethane, chloroform, 1,2- dichloromethane, ethyl acetate or butyl acetate；
(3) after the last time hydrolysis of continuous hydrolysis terminates, layering, aqueous phase is directly added into alkaline aqueous solution, adjusts pH
>=12, first azithromycin (I) is removed in stirring, precipitation, and reaction equation is as follows：
2. a kind of preparation method for removing first azithromycin according to claim 1, it is characterised in that in step (1), reaction
Temperature is 0-5 DEG C, and go back original reagent is potassium borohydride.
3. a kind of preparation method for removing first azithromycin according to claim 1, it is characterised in that red mould in step (1)
Plain A 6,9- imines ether (IV) is obtained by Erythromycin A or erythromycin thiocyanate A (II) through oximate, rearrangement.
4. a kind of preparation method for removing first azithromycin according to claim 1, it is characterised in that in step (1), boron hydrogen
Change that sodium or potassium borohydride molal quantity are Erythromycin A 6,9- imines ether (IV) molal quantity 1.2-1.5 times.
5. a kind of preparation method for removing first azithromycin according to claim 1, it is characterised in that organic in step (2)
Solvent is dichloromethane or chloroform.
6. a kind of preparation method for removing first azithromycin according to claim 1, it is characterised in that in step (2), reaction
Temperature is 0-5 DEG C, under pH=2.5-3.0, carries out continuous hydrolysis.
7. a kind of preparation method for removing first azithromycin according to claim 1, it is characterised in that in step (2), continuously
Hydrolysis 2-3 times, is hydrolyzed into hydrolysis material≤1wt% every time.
8. a kind of preparation method for removing first azithromycin according to claim 1, it is characterised in that in step (2), continuously
Acid used in hydrolysis regulation pH=2.0-3.5 is hydrochloric acid, sulfuric acid, phosphoric acid；In step (2) and (3), alkaline aqueous solution is sodium hydroxide
The aqueous solution, potassium hydroxide aqueous solution, calcium hydroxide aqueous solution, aqueous sodium carbonate or ammoniacal liquor.
9. a kind of preparation method for removing first azithromycin according to claim 7, it is characterised in that in step (2), continuously
Acid used in hydrolysis regulation pH=2.0-3.5 is 10wt%-20wt% hydrochloric acid；In step (2) and (3), alkaline aqueous solution is hydrogen-oxygen
Change sodium water solution.
10. a kind of preparation method for removing first azithromycin according to claim 1, it is characterised in that comprise the following steps：
(1) reduce：By Erythromycin A 6,9- imines ether (IV) is suspended in the water of 3-8 times of quality, stirring, is cooled 0-5 DEG C, is added
Hydrochloric acid, sulfuric acid or phosphoric acid, adjust pH=7-0-7.5, and 5-10wt% sodium borohydride or the potassium borohydride aqueous solution is added dropwise, works as pH=
When 9.0, stop being added dropwise 5-10wt% sodium borohydride or the potassium borohydride aqueous solution, continue stirring reaction 1-2h, TLC monitoring anti-
Should, if any Erythromycin A 6,9- imines ether (IV) raw material point is present, then hydrochloric acid, sulfuric acid or phosphoric acid is added dropwise, and adjusts pH=7.0-7.5
Afterwards, dropwise addition 5-10wt% sodium borohydride or the potassium borohydride aqueous solution is continued, it is complete to reacting；PH=6-7 is neutralized to acid, is stirred
Mix untill being released without gas；Add the organic solvent dichloro of the 5-15 times of quality of Erythromycin A 6,9- imines ether (IV) mass number
Methane, chloroform, 1,2- dichloromethane, ethyl acetate or butyl acetate, with 10-20wt% sodium hydrate aqueous solutions adjust pH >=
11, stirring, stratification；Aqueous phase is discarded；
(2) hydrolyze：Erythromycin A 6 is added in organic phase, the water of the 3-6 times of quality of 9- imines ether (IV) mass number is stirred, cooling
0-5 DEG C, hydrochloric acid, sulfuric acid or phosphoric acid are added, pH=2.5-3.0 is adjusted, the 1st hydrolysis is carried out, TLC is monitored to borate raw material point
Disappear；Hydrolysis two phase reaction liquid is added in 10-20wt% sodium hydrate aqueous solutions, pH >=12 is adjusted, stirs, stratification,
Aqueous phase discarded；Erythromycin A 6 is continuously added in organic phase, the water of the 4-6 times of quality of 9- imines ether (IV) mass number is stirred, drop
Warm 0-5 DEG C, hydrochloric acid, sulfuric acid or phosphoric acid are added, pH=2.5-3.0 is adjusted, the 2nd hydrolysis is carried out, TLC is monitored to borate raw material
Point disappears；Hydrolysis two phase reaction liquid is added to 10-20wt% sodium hydrate aqueous solutions, pH >=12 are adjusted, stirring stands and divided
Layer, again aqueous phase discarded；Erythromycin A 6 is added in organic phase, the water of the 3-6 times of quality of 9- imines ether (IV) mass number is stirred
Mix, cool 0-5 DEG C, add hydrochloric acid, sulfuric acid or phosphoric acid, adjust pH=2.5-3.0, carry out the 3rd hydrolysis, TLC is monitored to boric acid
Ester raw material point disappears；
(3) it is layered, organic phase, which retains, applies mechanically；20 DEG C -30 DEG C, aqueous phase is added in 5% sodium hydrate aqueous solution, insulated and stirred,
PH >=12 are adjusted, continues to stir, first azithromycin (I) is removed in precipitation, filters, filter cake washing obtains content 85wt% with the first that gets on
Azithromycin (I) crude product, directly carries out methylation reaction, obtains azithromycin.
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| CN110684056A (en) * | 2018-07-05 | 2020-01-14 | 青岛农业大学 | Chemical synthesis method of azithromycin intermediate |
| CN113929721A (en) * | 2021-11-03 | 2022-01-14 | 浙江耐司康药业有限公司 | Azithromycin synthesis process |
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