CN109438527A - A method of recycling Gentamicin C1a from Etimicin sulfate intermediate synthesising by-product - Google Patents
A method of recycling Gentamicin C1a from Etimicin sulfate intermediate synthesising by-product Download PDFInfo
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- CN109438527A CN109438527A CN201811103417.5A CN201811103417A CN109438527A CN 109438527 A CN109438527 A CN 109438527A CN 201811103417 A CN201811103417 A CN 201811103417A CN 109438527 A CN109438527 A CN 109438527A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
- C07H15/236—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2 a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin
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Abstract
The method that the present invention relates to a kind of to recycle Gentamicin C1a from Etimicin sulfate intermediate synthesising by-product, the present invention is by the way that synthesising by-product to be concentrated, certain density sodium hydroxide heating hydrolysis is added, it is adsorbed again with macroporous absorbent resin, macroreticular resin after absorption is rinsed with deionized water, it is eluted again with certain density Diluted Alcohol, after eluent concentration, is dried to obtain Etimicin Sulfate synthesis material Gentamicin C1a powder.
Description
Technical field
The present invention relates to a kind of conjunctions generated from semi-synthetic aminoglycoside antibiotics Etimicin Sulfate production process
At the new method for recycling Gentamicin C1a in by-product.
Background technique
Etimicin Sulfate (Etimicin sulfate) is that China scientific research personnel voluntarily develops, and possesses independent intellectual production
Efficient, less toxic, antimicrobial agent the semi-synthetic aminoglycoside antibiotics of a new generation of power is that unique first class national new drug that obtains is demonstrate,proved
The anti-infectives of book.
Currently, Etimicin Sulfate preparation method mainly includes following documents:
The technique that industrialized production Etimicin Sulfate uses is Chinese Patent Application No.: the work of 93112412.3 reports
Skill.First step synthetic reaction is to be dissolved using Gentamicin C1a ground caustic as raw material using methanol, and transition metal salt is added to target
After group carries out protectiveness complexing, under triethylamine adjusting, adds acetic anhydride to carry out acetylization reaction, make three free amino wholes
Realize that acetylation, final synthesis obtain 3,2 ', 6 '-three-N- acetyl group Gentamicin C1a of intermediate (referred to as: P1).
Synthetic route is as follows:
In the synthesis process, to guarantee conversion completely, acetic anhydride mostly uses Excess quantities, therefore has because of acetic anhydride excess
And four acetyl objects, element pentaacetylate are generated, can also there are endless fully synthetic diacetyl object and an acetylate, these all belong to conjunction
At by-product.In prior art, after the product of first step synthetic reaction being concentrated, being sloughed the transition metal ions of complexing,
Again by macroporous resin adsorption, ethanol gradient elution is come out, and collects the higher product of its moderate purity, then concentrated, spray drying
Obtain intermediate products P1.In production process, during with ethanol gradient elution after macroporous resin adsorption, by-product is largely synthesized
Object is directly discarded as impurity, not only causes environmental pollution, also wastes vast resources.
It is the structural formula of the by-product generated in synthesis process below, only lists the higher by-product of moiety content below
Structural formula:
1, four acetylation Gentamicin C1a
2, five acetylation Gentamicin C1a
3, diacetylation Gentamicin C1a
4, an acetylation Gentamicin C1a
The present invention is concentrated to a certain concentration by collecting synthesising by-product, and certain density sodium hydroxide is added and is heated to
Hydrolysis completely, then is adsorbed with macroporous absorbent resin, and the macroreticular resin after absorption is rinsed with deionized water, then with certain density dilute
Ethanol elution is dried to obtain Etimicin Sulfate synthesis material Gentamicin C1a powder after eluent concentration.Originally directly discarded
By-product using technology provided by the invention recycling after, it is repeatable to put into production use, generate apparent environmental protection and economic effect
Benefit.
Summary of the invention
The by-product generated in Etimicin Sulfate synthetic intermediate P1 synthesis of the present invention is after the completion of P1 is synthesized
Reaction solution afford the part P1 with macroporous resin adsorption except other parts eluent.
In view of background technique there are the problem of, detected by the present inventor, in the by-product of P1 mainly containing four acetylations celebrate
Big mycin C1a, five acetylation Gentamicin C1as, diacetylation Gentamicin C1a, an acetylation Gentamicin C1a, celebrating are big
Mycin C1a etc..The present inventor wishes to recycle Gentamicin C1a from the by-product of P1, to economize on resources, reduces pollution.
Present invention employs following technical solutions thus:
A method of recycling Gentamicin C1a, including following step from Etimicin sulfate intermediate synthesising by-product
It is rapid:
1) by-product generated in Etimicin Sulfate synthetic intermediate P1 synthesis is taken, obtains concentrate after concentrated；
2) sodium hydroxide solution is added in concentrate, and heating hydrolysis obtains hydrolyzate；
3) ammonium hydroxide is added in hydrolyzate, is adsorbed with macroporous absorbent resin, and being eluted with water to eluent pH is neutrality；
4) ethanol elution is used again, collects the component of Gentamicin C1a in eluent；
5) it is concentrated, it is dry, obtain Gentamicin C1a.
Wherein, concentration described in step 1), is selected from: nanofiltration concentration, vacuum rising film concentration, wiped film vaporization concentration, multiple-effect
One of vacuum concentration or combination；It is concentrated into dry matter weight percentage composition 10-30% therein；
Wherein, sodium hydroxide solution described in step 2), concentration expressed in percentage by weight 10-30%；Sodium hydroxide solution is used
Amount is the 30-70% of by-product concentrate weight；Hydrolysis time is 10-24 hours；Wherein, macroporous absorption described in step 3)
Resin is selected from: one of AB-8, D101, D1300, X-5, WLD3, China's shake chromatography 1；The weights of ammonia percentage concentration
For 3-15%；The additional amount of ammonium hydroxide is the 10-30% of hydrolyzate volume；
Wherein, ethyl alcohol described in step 4), volumetric concentration 2-20%；
Wherein, concentration described in step 5), it is true selected from nanofiltration concentration, vacuum rising film concentration, wiped film vaporization concentration, multiple-effect
One of sky concentration or combination；The drying mode is selected from: one of vacuum drying, spray drying, freeze-drying.
Preferably, wherein dry matter content 20-30%, 20≤A≤30 described in step 1)；
Preferably, wherein mass percentage concentration described in step 2) is the sodium hydroxide solution of 15-25%, concentration B
For 15-25；The sodium hydroxide solution dosage is the 30-50% of by-product concentrate weight；The hydrolysis 18-24 is small
When；
Preferably, wherein the 10-20% of hydrolyzate volume described in step 3)；The mass percentage concentration is 5-
13% ammonium hydroxide；
Preferably, wherein the ethyl alcohol of 10-20% concentration described in step 4)；
More preferably, wherein dry matter content 22-28% described in step 1)；
More preferably, wherein mass percentage concentration described in step 2) is the sodium hydroxide solution of 18-22%；It is described
Sodium hydroxide solution dosage be by-product concentrate weight 40-50%；Hydrolysis 20-24 hours；
More preferably, wherein the 15-18% of hydrolyzate volume described in step 3)；The mass percentage concentration is
The ammonium hydroxide of 10-13%；
More preferably, wherein the ethyl alcohol of 12-18% concentration described in step 4)；
The collection of ethanol eluate in step 3), using Gentamicin C1a in silica gel g thin-layer plate point sample detection eluent
Component, detection method are as follows: using ammonium hydroxide: methanol: chloroform volume ratio is that the ratio of 1:1:3 takes chloroform layer as exhibition after mixing
Agent is opened, iodine colour developing detects the component of Gentamicin C1a in eluent, collects the eluent that component is more than 85%；
Method of the invention is a kind of completely new process route, has no relevant report.
The technical scheme is that obtained by screening, the condition of each step, the selection result is as follows:
The screening of step 1 condition:
During ethanol gradient elution after P1 Synthesis liquid macroporous resin adsorption extracts P1, eluted from macroreticular resin
Solution of the gained containing by-product is the very low solution of the by-product concentration containing a small amount of ethyl alcohol, under normal conditions mass percent concentration
Only 0.5% or so, therefore a large amount of solution has to pass through concentration, reduces volume and improves concentration to facilitate subsequent processing and return
It receives.
Concentration can be vacuum concentration by the way of or be received using the polyether sulfone that molecular cut off is about 250 dalton
Filter membrane concentration, the present invention were once concentrated using various ways when starting test, can reach desired effect, difference concentration
The main distinction of mode is that energy consumption and efficiency, most economical scheme are concentrated using nanofiltration.
The concentration of by-product concentrate is also by screening, and hydrogen-oxygen is then added lower than limited range of the present invention in concentration
Hydrolysis effect after changing sodium solution is poor, and reaction is not thorough；More greatly higher than viscosity if limited range of the present invention if concentration
Uneven heating even local coking decomposition yield decline is easily caused when pyrohydrolysis.
The screening of step 2 condition:
The usage amount of sodium hydroxide calculated from the amount of substance be it is remote excessive, the concentration of sodium hydroxide solution can basis
The concentration of by-product concentrate carries out small-scale adjustment, and the higher then concentration of sodium hydroxide solution of by-product concentrate can be at this
Invention limits suitably to be reduced in range, so that hydrolysis liquid is kept certain viscosity, is avoided local coking.
The amount ranges and concentration of sodium hydroxide solution provided by the present invention are obtained by test of many times in the present invention.
The screening of step 3 condition:
The hydrolyzate of by-product is in strong basicity, and due to containing a large amount of sodium hydroxides, therefore its relative density is more than macroreticular resin
Greatly, it is found in research process of the present invention, hydrolyzate directly will cause resin with macroporous resin adsorption and swim in above hydrolyzate, inhale
Attached poor effect, therefore must be added to the lower liquid of relative density to adjust its density, it is allowed to the density lower than macroreticular resin, is made
Macroreticular resin gives full play to its adsorption.
The model of macroreticular resin be also it is by screening determining, experiment sieving AB-8, D101, D1300, X-5, WLD3,
China's shake chromatographs No. 1 totally 6 kinds of macroreticular resin, can achieve the desired results.
Being eluted with water to eluent pH is neutrality, main purpose two, first is that washing away the inorganic impurities such as sodium hydroxide, is prevented
Only it remains in recycling Gentamicin C1a, recycles second is that collecting the eluent containing a large amount of ammonium hydroxide for vacuum concentration.
The screening of step 4 condition:
Resin after absorption, which uses, is washed to eluent pH to be eluted with Diluted Alcohol, concentration of alcohol after neutral
It is, according to the difference of production season, because the different ethanol concentration of room temperature can be adjusted suitably, to be mentioned in the present invention by screening
It can achieve optimal elution effect in the concentration range of confession, the too low effluent volume that will cause of concentration is excessive, and waste is a large amount of molten
Agent；It will cause impurity to be eluted together with Gentamicin C1a for excessive concentration, causes recycling Gentamicin C1a impurity residual
Allowance is excessively high, influences the production of subsequent Etimicin.
The screening of step 5 condition:
The satisfactory Gentamicin C1a eluate concentration obtained is eluted using Diluted Alcohol from macroporous resin column not
It is high, it is necessary to can be dried to after concentration as solid.
The mode of concentration of the present invention is by screening, and it is about 250 dalton that test, which uses molecular cut off,
Polyether sulfone filtering film concentration, vacuum rising film concentration, wiped film vaporization concentration, multiple-effect vacuum concentration mode, can reach expected
Effect, the main distinction of different condensing modes are that energy consumption and efficiency, most economical scheme are using nanofiltration concentration and vacuum liter
The mode that both film concentrations combine.Drying mode of the present invention is tested using vacuum drying, by spraying by screening
Dry, freeze-drying can achieve the desired results, and difference is the quality of energy consumption and product.Vacuum drying comprehensive energy consumption is medium,
But products therefrom is easy agglomeration, and equipment not easy cleaning；It is lower to be spray-dried energy consumption, but high-temperature process need to be passed through, impurity is more,
Product is in loose powders；It is higher to be freeze-dried energy consumption, product is in loose bulk, best in quality.
Specific embodiment
The present invention is further described with reference to embodiments, to make understanding in more detail to the present invention.With
Lower described only to explain the preferred embodiment of the present invention, not it is intended that the present invention is limited in any way accordingly, therefore all
It is made any form modification or change on the basis of creation spirit of the invention, all should belong to protection category of the invention.
Embodiment 1
The by-product for taking Etimicin Sulfate intermediate products P1 to extract recycles ethyl alcohol with vacuum concentration, is concentrated to dryness substance
Content about 20-30%.
Concentrate 300L is taken, 20% caustic lye of soda 120L is added, is heated with stirring to boiling reflux.After hydrolysis 20 hours,
Sampling is cooled to room temperature after the conversion completely of TLC method control test.8% ammonium hydroxide 80L is added in hydrolyzate, with macroporous absorption tree
Rouge (resin loading amount 1800L) absorption, flow control exist in 1/500 resin volume/minute, deionization washed resin, flow control
1/160 resin volume/minute, until cleaning solution pH weakly acidic pH.With 12% ethanol elution, flow control 1/360 resin volume/point
Clock, the sampling of eluent outlet per hour.With the component of TLC method detection Gentamicin C1a, elution is collected after component is more than 90%
Liquid.Stop collecting lower than 85% to the eluent component that TLC method detects Gentamicin C1a, uses deionization water rinse resin instead
Until eluent alcoholic strength is zero, the eluent vacuum concentration being collected into recycles ethyl alcohol.It is concentrated to dryness content of material about 28%,
Concentrate is spray-dried, Gentamicin C1a powder is obtained.
Embodiment 2
The by-product for taking Etimicin Sulfate intermediate products P1 to extract, nanofiltration concentration and recovery ethyl alcohol, then with being concentrated in vacuo to
Dry matter content about 20-30%.
Concentrate 600L is taken, 20% caustic lye of soda 250kg is added, is heated with stirring to boiling reflux.Hydrolysis 24 hours is used
After the conversion completely of TLC method control test, it is cooled to room temperature.8% ammonium hydroxide 150L is added in hydrolyzate, with macroporous absorbent resin (tree
Rouge loading amount 1800L) absorption, flow control is in 1/500 resin volume/minute, and deionization washed resin, flow control is 1/160
Resin volume/minute, until cleaning solution pH weakly acidic pH.With 5% ethanol elution, flow control in 1/360 resin volume/minute, etc.
Oral fluid detection optically-active is higher than 0.1 out, collects sympathetic liquid, and the sampling of eluent outlet per hour detects Gentamicin C1a with TLC method
Component.When component is more than to be transferred to Gentamicin C1a liquid after 90% to collect.Gentamicin C1a is detected to eluent TLC method
Component stops Gentamicin C1a liquid lower than 90% and collects, and collects as sympathetic liquid.Use 20% ethanol elution instead, flow control exists
1/360 resin volume/minute changes deionization water rinse resin until eluent optical activity terminates lower than liquid collection sympathetic after 0.1,
Until eluent alcoholic strength is zero, recycles sympathetic liquid and be concentrated and apply.
The eluent nanofiltration concentration and recovery ethyl alcohol being collected into, then with dry matter content 28-35% is concentrated in vacuo to, will be concentrated
Liquid is spray-dried, and Gentamicin C1a powder is obtained.
Claims (8)
1. a kind of method for recycling Gentamicin C1a from Etimicin sulfate intermediate synthesising by-product, comprising the following steps:
1) by-product generated in Etimicin Sulfate synthetic intermediate P1 synthesis is taken, obtains concentrate after concentrated；
2) sodium hydroxide solution is added in concentrate, and heating hydrolysis obtains hydrolyzate；
3) ammonium hydroxide is added in hydrolyzate, is adsorbed with macroporous absorbent resin, and being eluted with water to eluent pH is neutrality；
4) ethanol elution is used again, collects the component of Gentamicin C1a in eluent；
5) it is concentrated, it is dry, obtain Gentamicin C1a.
2. the method as described in claim 1, it is characterised in that:
Concentration described in step 1), is selected from: during nanofiltration concentration, vacuum rising film concentration, wiped film vaporization concentration, multiple-effect vacuum are concentrated
One kind or combination；It is concentrated into dry matter weight percentage composition 10-30% therein.
3. the method as described in claim 1, it is characterised in that:
Sodium hydroxide solution described in step 2), concentration expressed in percentage by weight are 10~30%；Dosage is by-product concentrate weight
30~70%；Hydrolysis time is 10-24 hours.
4. the method as described in claim 1, it is characterised in that:
Macroporous absorbent resin described in step 3) is selected from: one chromatographed in No. 1 shakes in AB-8, D101, D1300, X-5, WLD3, China
Kind；The weights of ammonia percentage concentration is 3-15%；The additional amount of ammonium hydroxide is the 10-30% of hydrolyzate volume.
5. the method as described in claim 1, it is characterised in that:
Ethyl alcohol described in step 4), volumetric concentration 2-20%.
6. the method as described in claim 1, it is characterised in that:
Concentration described in step 5), in nanofiltration concentration, vacuum rising film concentration, wiped film vaporization concentration, multiple-effect vacuum concentration
One kind or combination；The drying mode is selected from: one of vacuum drying, spray drying, freeze-drying.
7. the method as described in claim 1, it is characterised in that:
The dry matter content 20-30%, 20≤A≤30 described in step 1)；
Sodium hydroxide solution dosage described in step 2) is the 30~50% of by-product concentrate weight；
Mass percentage concentration described in step 2) is the sodium hydroxide solution of 15-25%, and concentration B is 15~25；Described
Hydrolysis 18-24 hours；
The 10-20% of hydrolyzate volume described in step 3)；The mass percentage concentration is the ammonium hydroxide of 5-13%；
The ethyl alcohol of 10-20% concentration described in step 4).
8. the method as described in claim 1, it is characterised in that:
Dry matter content 22-28% described in step 1)；
Sodium hydroxide solution dosage described in step 2) is the 40~50% of by-product concentrate weight；
Mass percentage concentration described in step 2) is the sodium hydroxide solution of 18-22%；Hydrolysis 20-24 hours；
The 15-18% of hydrolyzate volume described in step 3)；The mass percentage concentration is the ammonium hydroxide of 10-13%；
The ethyl alcohol of 12-18% concentration described in step 4).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113416118A (en) * | 2021-06-24 | 2021-09-21 | 无锡济煜山禾药业股份有限公司 | Method for recovering solvent methanol in production process of bulk drugs |
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