CN104558075A - Method for directly synthesizing tilmicosin by adopting tylosin yeast filtrate - Google Patents
Method for directly synthesizing tilmicosin by adopting tylosin yeast filtrate Download PDFInfo
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- CN104558075A CN104558075A CN201310494322.1A CN201310494322A CN104558075A CN 104558075 A CN104558075 A CN 104558075A CN 201310494322 A CN201310494322 A CN 201310494322A CN 104558075 A CN104558075 A CN 104558075A
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Abstract
The invention provides a method for directly synthesizing tilmicosin by adopting tylosin yeast filtrate. The method comprises the following steps: using the tylosin yeast filtrate as the raw material; carrying out the treatment processes of fermentation liquor pre-treating, impurity eliminating, concentrating, phase conversing, ammoniation reaction, hydrolysis reaction, crystallizing, centrifuging and the like to obtain tilmicosin. The method is good in synthesis effect, high in product purity and high in yield, can greatly reduce the use of organic solvents, reduces the preparation cost, relieves environmental protection pressure, and is suitable for scale industrial production.
Description
Technical field
The present invention relates to a kind of method of directly being synthesized tilmicosin by tylosin fermented product filtrate, belong to technological field of biochemistry.
Background technology
Tilmicosin (Tilmicosin) is a kind of newer for the special microbiotic of tylosin semisynthetic Macrolide livestock and poultry, and the eighties is succeeded in developing by Elanco Animal Health Care Products Corporation of Britain.The anti-microbial activity special due to it and characteristics of pharmacokinetics, this medicine has gone through the clinical control for animal infectious diseases such as ox, goat, sheep, milk cow, pig, chickens, particularly livestock and birds respiratory disease, as the treatment of domestic animal actinobacillus property pleuropneumonia, Bacillus pasteurii disease and gallisepticum chicken disease etc. and lactating mammal mastitis.But traditional synthesis is synthesized by Webel Tylan Premix, and production cost is higher.
Summary of the invention
Technical problem to be solved by this invention is to overcome the weak point in the existing technique of tilmicosin, designs a kind of extract yield high, synthetic method low in the pollution of the environment and with low cost.
The invention provides a kind of method of directly being synthesized tilmicosin by tylosin fermented product filtrate, the method comprises the following steps:
(1) fermentation liquor pretreatment
1. after fermented liquid adds 1% silicon polymerize aluminum chloride process, Plate Filtration, when filtrate less outflow, top washing filter cake in sheet frame.
2. top is washed till activity in filtrate 500, stops top washing.
3. squeezing is to substantially not having filtrate to flow out.
(2) removal of impurities
1. carry out except miscellaneous operation with the ceramic membrane of molecular weight cut-off 20000.
2., when filtrate remains 10% of former filtrate volume, in residual filtrate, add the clear water of former filtrate 10%
3. continue except miscellaneous operation
4. when filtrate remains again 10% of former filtrate volume, then in residual filtrate, add the clear water of former filtrate 10%
5. continue except miscellaneous operation
6. when filtrate remains again 10% of former filtrate volume, then in residual filtrate, add the clear water of former filtrate 10%
7. continue removal of impurities be operated to consider fluid tire lower than 500.
8. bleed off remaining residue impurity
9. cleaning ceramic membranous system.
(3) concentrated
1. carry out concentration operation by the nanofiltration membrane of molecular weight cut-off 300 ~ 500.
2, open material feeding valve, feed liquid to be separated enters material pot, enables feed liquid in tank meet flux values when being continuously separated and buffer volumes.Open all valves on material separating pipe, enable that liquid flows through valve, pump, suspended body flowmeter flow to concentration tank.Low frequency starts security personnel's pump and dehvery pump (if having), and regulating frequency control magnetic flow meter meets set(ting)value, and material flows through feed-pipe to concentrated flow container (now should be intrasystem water).
3, after Flow of Goods and Materials is stable, opens the valve entering assembly step by step, make material enter membrane module, simultaneously low frequency start assembly recycle pump.Under the prerequisite meeting inner-outer circulation flow, regulate each pump frequency and relief valve, filtrate is appeared from penetrating fluid pipe, flows through suspended body flowmeter and transforming valve, flow to filtrate tank.Need when material tank level declines to supplement in time and keep liquid level, until material to be separated all adds.
4, solution starts to concentrate, and continues to regulate each pump frequency and relief valve, makes flow of filtrate meet set(ting)value (when flow of filtrate does not reach when pressure reaches design load, taking force value as operating point).
5, system concentrates, and discharges penetrating fluid and concentrated solution, until separated material filtering completes, shuts down out of service.
6, at the end of concentrated, open cleaning water intaking valve and start scavenging pump, stopping security personnel's pump and fresh feed pump (if having)
And close feed valve, with the pure water in CIP tank by the concentrated solution ejection system in system in material pot
7, when in system, concentrated solution is ejected system, valve proceeds to water cycle state.
8, when the concentrated solution in system not yet pushes up only, and when pure water in CIP tank is not enough, pure water to be supplemented in time, prevent air from entering in system.
(4) phase inversion
By N-BUTYL ACETATE, liquid caustic soda, concentrated solution is after mixing tank mixing, and pH, 10.5 ~ 11.0, directly enters disc separator, collects butyl ester phase, dry after washing.
(5) amination reaction
N-BUTYL ACETATE mutually in, add quantitative 3 under whipped state, 5-lupetidine and formic acid.Then keep this temperature stirring reaction 2 hours, sample and analyze through HPLC.Tylosin content≤1.5% is considered as reacting completely, and reaction solution is cooled to 22 ~ 26
oC.If tylosin content >1.5%, then continue insulation reaction, repeatedly sampling analysis, until tylosin content < 1.5%.Ammonification terminates, and adds medicinal carbon, decolours 40 minutes, through titanium rod metre filter.
(6) hydrolysis reaction
Under whipped state, the hydrochloric acid slowly dripping 15% in concentrated solution adjusts pH value, and temperature remains on 20 ~ 25
oC, after mixing up pH, be slowly warming up to 60
oc, insulation reaction 4 hours, samples through liquid phase analysis.If Tylosin B component amide content>=1.5%(peak area meter), then continue maintenance 60
oc reacts, until Tylosin B component amide content is less than 1.5% then reaction solution is dropped to 22 ~ 26
oC.
(7) crystallization is centrifugal
Keep 22 ~ 26
oC, drip sodium hydroxide solution under whipped state, adjust ph occurs to there being a small amount of crystallisate, is incubated 20 minutes, continue to drip liquid caustic soda to pH10.5 ~ 11.0, to mix up after pH insulated and stirred 60 minutes, through drum centrifuge centrifugation, then with purified water washing, dry, crystal dries rear crushing packing.
Useful benefit of the present invention is: synthetic effect is good, and product purity is high, and yield is high, can reduce the use of organic solvent in a large number, reduce production cost, alleviate environmental protection pressure, is suitable for large-scale industrial and produces.
embodiment:
one,fermentation liquor pretreatment
1. after fermented liquid adds 1% silicon polymerize aluminum chloride process, Plate Filtration, when filtrate less outflow, top washing filter cake in sheet frame.
2. top is washed till activity in filtrate 500, stops top washing.
3. squeezing is to substantially not having filtrate to flow out.
Two, removal of impurities
1. carry out except miscellaneous operation with the ceramic membrane of molecular weight cut-off 20000.
2., when filtrate remains 10% of former filtrate volume, in residual filtrate, add the clear water of former filtrate 10%
3. continue except miscellaneous operation
4. when filtrate remains again 10% of former filtrate volume, then in residual filtrate, add the clear water of former filtrate 10%
5. continue except miscellaneous operation
6. when filtrate remains again 10% of former filtrate volume, then in residual filtrate, add the clear water of former filtrate 10%
7. continue removal of impurities be operated to consider fluid tire lower than 500.
8. bleed off remaining residue impurity
9. cleaning ceramic membranous system.
Three, concentrated
1. carry out concentration operation by the nanofiltration membrane of molecular weight cut-off 300 ~ 500.
2. open material feeding valve, feed liquid to be separated enters material pot, enables feed liquid in tank meet flux values when being continuously separated and buffer volumes.Open all valves on material separating pipe, enable that liquid flows through valve, pump, suspended body flowmeter flow to concentration tank.Low frequency starts security personnel's pump and dehvery pump (if having), and regulating frequency control magnetic flow meter meets set(ting)value, and material flows through feed-pipe to concentrated flow container (now should be intrasystem water).
3. after Flow of Goods and Materials is stable, open the valve entering assembly step by step, make material enter membrane module, simultaneously low frequency start assembly recycle pump.Under the prerequisite meeting inner-outer circulation flow, regulate each pump frequency and relief valve, filtrate is appeared from penetrating fluid pipe, flows through suspended body flowmeter and transforming valve, flow to filtrate tank.Need when material tank level declines to supplement in time and keep liquid level, until material to be separated all adds.
4. solution starts to concentrate, and continues to regulate each pump frequency and relief valve, makes flow of filtrate meet set(ting)value (when flow of filtrate does not reach when pressure reaches design load, taking force value as operating point).
5. system concentrates, and discharges penetrating fluid and concentrated solution, until separated material filtering completes, shuts down out of service.
6. at the end of concentrating, open cleaning water intaking valve and start scavenging pump, stopping security personnel's pump and fresh feed pump (if having)
And close feed valve, with the pure water in CIP tank by the concentrated solution ejection system in system in material pot
7., when concentrated solution in system is ejected system, valve proceeds to water cycle state.
8. when concentrated solution in system not yet pushes up only, and during pure water deficiency in CIP tank, pure water to be supplemented in time, prevent air from entering in system.
Four, phase inversion
By N-BUTYL ACETATE, liquid caustic soda, concentrated solution is after mixing tank mixing, and pH, 10.5 ~ 11.0, directly enters disc separator, collects butyl ester phase, dry after washing.
Five, amination reaction
N-BUTYL ACETATE mutually in, add quantitative 3 under whipped state, 5-lupetidine and formic acid.Then keep this temperature stirring reaction 2 hours, sample and analyze through HPLC.Tylosin content≤1.5% is considered as reacting completely, and reaction solution is cooled to 22 ~ 26
oC.If tylosin content >1.5%, then continue insulation reaction, repeatedly sampling analysis, until tylosin content < 1.5%.Ammonification terminates, and adds medicinal carbon, decolours 40 minutes, through titanium rod metre filter.
Six, hydrolysis reaction
Under whipped state, in concentrated solution, slowly drip the hydrochloric acid adjust pH of 15%, temperature remains on 20 ~ 25
oC, after mixing up pH, be slowly warming up to 60
oc, insulation reaction 4 hours, samples through liquid phase analysis.If Tylosin B component amide content>=1.5%(peak area meter), then continue maintenance 60
oc reacts, until Tylosin B component amide content is less than 1.5% then reaction solution is dropped to 22 ~ 26
oC.
Seven, crystallization is centrifugal
Keep 22 ~ 26
oC, drip sodium hydroxide solution under whipped state, adjust ph occurs to there being a small amount of crystallisate, is incubated 20 minutes, continue to drip liquid caustic soda to pH10.5 ~ 11.0, to mix up after pH insulated and stirred 60 minutes, through drum centrifuge centrifugation, then with purified water washing, dry, crystal dries rear crushing packing.
Claims (2)
1. one kind is directly synthesized the method for tilmicosin by tylosin fermented product filtrate, it is characterized in that: with tylosin fermented product filtrate for raw material, after the art breading such as liquid pre-treatment by fermentation, removal of impurities, concentrated, phase inversion, amination reaction, hydrolysis reaction, crystallization are centrifugal, obtain tilmicosin.
2. a kind of method of directly being synthesized tilmicosin by tylosin fermented product filtrate according to claim 1, is characterized in that: the method comprises the following steps:
(1) fermentation liquor pretreatment
Fermented liquid adds 1% silicon polymerize aluminum chloride process Plate Filtration,
Top is washed till activity in filtrate 500, stops top washing;
Squeezing is to substantially not having filtrate to flow out;
(2) removal of impurities
Carry out except miscellaneous operation with ceramic membrane;
When filtrate remains 10% of former filtrate volume, in residual filtrate, add the clear water of former filtrate 10%;
Continue except miscellaneous operation;
When filtrate remains again 10% of former filtrate volume, then in residual filtrate, add the clear water of former filtrate 10%;
Continue except miscellaneous operation;
When filtrate remains again 10% of former filtrate volume, then in residual filtrate, add the clear water of former filtrate 10%;
Continuation removal of impurities is operated to worry fluid and tires lower than 500;
Bleed off remaining residue impurity;
Cleaning ceramic membranous system;
(3) concentrated
1, carry out concentration operation by nanofiltration membrane;
2, open material feeding valve, feed liquid to be separated enters material pot, enables feed liquid in tank meet flux values when being continuously separated and buffer volumes; Open all valves on material separating pipe, enable that liquid flows through valve, pump, suspended body flowmeter flow to concentration tank; Low frequency starts security personnel's pump and dehvery pump (if having), and regulating frequency control magnetic flow meter meets set(ting)value, and material flows through feed-pipe to concentrated flow container (now should be intrasystem water);
3, after Flow of Goods and Materials is stable, opens the valve entering assembly step by step, make material enter membrane module, simultaneously low frequency start assembly recycle pump; Under the prerequisite meeting inner-outer circulation flow, regulate each pump frequency and relief valve, filtrate is appeared from penetrating fluid pipe, flows through suspended body flowmeter and transforming valve, flow to filtrate tank; Need when material tank level declines to supplement in time and keep liquid level, until material to be separated all adds;
4, solution starts to concentrate, and continues to regulate each pump frequency and relief valve, makes flow of filtrate meet set(ting)value (when flow of filtrate does not reach when pressure reaches design load, taking force value as operating point);
5, system concentrates, and discharges penetrating fluid and concentrated solution, until separated material filtering completes, shuts down out of service;
6, at the end of concentrated, open cleaning water intaking valve and start scavenging pump, stopping security personnel's pump and fresh feed pump (if having);
And close feed valve, with the pure water in CIP tank by the concentrated solution ejection system in system in material pot;
7, when in system, concentrated solution is ejected system, valve proceeds to water cycle state;
8, when the concentrated solution in system not yet pushes up only, and when pure water in CIP tank is not enough, pure water to be supplemented in time, prevent air from entering in system;
(4) phase inversion
By N-BUTYL ACETATE, liquid caustic soda, concentrated solution is after mixing tank mixing, and pH, 10.5 ~ 11.0, directly enters disc separator, collects butyl ester phase, dry after washing;
(5) amination reaction
N-BUTYL ACETATE mutually in, add quantitative 3 under whipped state, 5-lupetidine and formic acid; Then keep this temperature stirring reaction 2 hours, sample and analyze through HPLC; Tylosin content≤1.5% is considered as reacting completely, and reaction solution is cooled to 22 ~ 26
oC; If tylosin content > 1.5%, then continue insulation reaction, repeatedly sampling analysis, until tylosin content < 1.5%; Ammonification terminates, and adds medicinal carbon, decolours 40 minutes, through titanium rod metre filter;
(6) hydrolysis reaction
Under whipped state, in concentrated solution, slowly drip the hydrochloric acid adjust pH of 15%, temperature remains on 20 ~ 25
oC, after mixing up pH, be slowly warming up to 60
oc, insulation reaction 4 hours, samples through liquid phase analysis; If Tylosin B component amide content>=1.5%(peak area meter), then continue maintenance 60
oc reacts, until Tylosin B component amide content is less than 1.5% then reaction solution is dropped to 22 ~ 26
oC;
(7) crystallization is centrifugal
Keep 22 ~ 26
oC, drip sodium hydroxide solution under whipped state, adjust ph occurs to there being a small amount of crystallisate, is incubated 20 minutes, continue to drip liquid caustic soda to pH10.5 ~ 11.0, to mix up after pH insulated and stirred 60 minutes, through drum centrifuge centrifugation, then with purified water washing, dry, crystal dries rear crushing packing.
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|---|---|---|---|
| CN201310494322.1A CN104558075A (en) | 2013-10-21 | 2013-10-21 | Method for directly synthesizing tilmicosin by adopting tylosin yeast filtrate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864227A (en) * | 2018-06-07 | 2018-11-23 | 中牧实业股份有限公司 | The method for producing Tilmicosin and tilmicosin phosphate using tylosin broth |
| CN115925772A (en) * | 2022-12-20 | 2023-04-07 | 山东久隆恒信药业有限公司 | Synthesis method of tilmicosin |
-
2013
- 2013-10-21 CN CN201310494322.1A patent/CN104558075A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 王枢，等: "应用膜分离技术改进泰乐菌素提取工艺", 《食品与发酵工业》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864227A (en) * | 2018-06-07 | 2018-11-23 | 中牧实业股份有限公司 | The method for producing Tilmicosin and tilmicosin phosphate using tylosin broth |
| CN115925772A (en) * | 2022-12-20 | 2023-04-07 | 山东久隆恒信药业有限公司 | Synthesis method of tilmicosin |
| CN115925772B (en) * | 2022-12-20 | 2023-07-25 | 山东久隆恒信药业有限公司 | Synthesis method of tilmicosin |
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Application publication date: 20150429 |