CN102659878B - Method for synthesizing tilmicosin and tilmicosin phosphate through using tylosin broth - Google Patents
Method for synthesizing tilmicosin and tilmicosin phosphate through using tylosin broth Download PDFInfo
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Abstract
A method for synthesizing tilmicosin and tilmicosin phosphate through using a tylosin broth is disclosed. The method is characterized in that the method comprises the following process steps: preprocessing the tylosin broth to obtain a tylosin filtrate; allowing the tylosin filtrate to undergo extraction, ammonification, reextraction, hydrolysis, acidification liquid extraction and vacuum drying to obtain tilmicosin; and allowing the obtained tilmicosin to undergo phosphorylation and spray drying to obtain tilmicosin phosphate. The method, which directly extracts the tylosin broth which is the initial raw material to synthesize the tilmicosin and the tilmicosin phosphate, allows the production procedure to be simplified, the product production time to be shortened, reaction conditions of the whole technology to be mild, the operation to be simple, the production process to be safe and reliable, and the organic solvent loss to be less, and has the advantages of energy saving and consumption reduction, high finished product yield, low production cost, high working efficiency and the like.
Description
Technical field
The invention belongs to biological medicine extraction, synthesis technical field, particularly relate to a kind of method of utilizing the synthetic tilmicosin of tylosin fermented liquid and phosphoric acid tilmicosin.
Background technology
Tilmicosin is that U.S. Elanco company is in the special-purpose microbiotic of the semi-synthetic Macrolide livestock and poultry of the 80's of 20th century exploitation, there is very strong anti-microbial activity, resistance is low, has a broad antifungal spectrum, all gram-positive microorganisms and part Gram-negative bacteria, Mycoplasma, spirochete etc. are all had to restraining effect, especially multiple mycoplasma and spirochete are also had to very strong restraining effect.This medicine is successively in the clinical application that goes through of the countries such as Australia, Brazil, France, Malaysia, Italy, Spain, the U.S., be used for the treatment of goat, milk cow, pig,
The infectious diseases of the animals such as chicken.Because tilmicosin is water insoluble, therefore by the tilmicosin phosphorylation, in the form of salt solution soluble in water, be convenient to taking of animal.
At present, the synthetic route of tilmicosin mainly contains two both at home and abroad: the one, directly with tylosin alkali, be hydrolyzed synthetic; Another is to utilize tylosin phosphoric acid salt or TYLOSIN TARTARATE BPV to be hydrolyzed, and takes off corresponding salt, more further synthetic, as Chinese patent " a kind of preparation method of tilmicosin " (application number: 200610048425.5).The common ground of above-mentioned technique is all to utilize the finished product tylosin salt or the alkali that have prepared to go and prepare tilmicosin again, causes operational path loaded down with trivial details, and the production cycle is long, and has increased the loss of intermediate, and production cost is high, and production efficiency is low, and product yield is low.
Summary of the invention
The object of the invention is to provide the defect that overcomes above-mentioned prior art, a kind of product yield that tilmicosin, phosphoric acid tilmicosin effectively are provided is provided, reduce production costs, technique is simple and direct, the method of utilizing the synthetic tilmicosin of tylosin fermented liquid easy and simple to handle, and further produce the phosphoric acid tilmicosin.
The technical scheme taked for achieving the above object is:
A kind of method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin, it is characterized in that its processing step is: at first the tylosin fermented liquid is carried out to pre-treatment, obtain tylosin filtrate, then tylosin filtrate is obtained to tilmicosin through extraction, aminating reaction, reextraction, hydrolysis reaction, acidizing fluid extraction, vacuum-drying; The gained tilmicosin obtains the phosphoric acid tilmicosin through phosphorylation reaction and spraying drying.
Described preprocessing process is: tylosin fermented liquid temperature is controlled at 20～30 ℃, add 10～20% polyaluminum sulfate aluminum solutions, regulating fermented liquid pH is 1～3, in the polyaluminium sulfate use procedure, constantly stir, after the adjusting of pH value reaches 1～3, continue to stir 10～15min, controlling after acidifying tires is 7000 μ/more than ml; Then adjust fermented liquid pH with 5～20% ammoniacal liquor, control pH 3～7, then stir 10～15min, standing 50～60min, filtered fermented liquid with flame filter press, obtains tylosin filtrate.
Organic solvent N-BUTYL ACETATE extraction tylosin solution is used in above-mentioned extraction.Extraction mode: adopt the secondary counter-current extraction.Extraction ratio: tylosin filtrate volume (L) ︰ N-BUTYL ACETATE (L)=10～11 ︰ 4～4.5.In extraction process, temperature is controlled at 40～50 ℃.Carrying out the secondary counter-current extraction with separating centrifuge, is gently the mixed solvent phase mutually, the double solvent phase of taking a sample to check in extraction process and aqueous phase separation situation, tires and aqueous pH values, controls raffinate and tires below 300u/ml, collects extraction liquid.One-level extraction pH is controlled at 7.0～10.0; Secondary extraction pH is controlled at 8.0～11.0.Tire<300u/ml of raffinate (water).Extraction finishes, and adds gac in extraction liquid, the gac additional proportion: gac (t)=extraction liquid volume (m
3) * (0.5～1) %.Start stirring system, rotating speed is controlled at 20～50r/min, stirs 10～15min, and then standing 30～40min, filter after standing end.
Above-mentioned aminating reaction process is: prepare formic acid solution, formic acid and N-BUTYL ACETATE are mixed in proportion.Formic acid consumption (kg)=tylosin ferments total hundred million * 0.075; Blending ratio: formic acid (kg) ︰ N-BUTYL ACETATE (L)=1 ︰ 5～5.2.Open and stir, rotating speed is controlled at 40～60r/min.In whipping process, adopt the stream addition, add 3,5-lupetidine in the tylosin extraction liquid, used time 20～30min.3,5-lupetidine consumption (kg)=tylosin ferments total hundred million * 0.2.Heat temperature raising, tylosin extraction liquid temperature is controlled at 70～71 ℃.Adopt the stream addition to add formic acid and N-BUTYL ACETATE mixing solutions, used time 20～30min.Insulation 150～180min.
After aminating reaction finishes, stripped: solution temperature is controlled at 15～25 ℃.Add purified water, purified water consumption (m
3)=tylosin ferments total hundred million * 0.04.Open and stir, rotating speed is controlled at 40～60r/min.Configuration 10～15% hydrochloric acid solns, adopt the stream addition slowly to add, used time 30～40min.In the dropping process, detect pH every 4～6min, until pH is adjusted to 3.5～5.0.
Then the reaction that is hydrolyzed, in hydrolysis reaction, mixing speed is controlled at 40～60r/min.Configuration 10～15% hydrochloric acid solns, adopt the stream addition slowly to add, used time 10～15min.In the dropping process, detect pH every 4～6min, until pH is adjusted to 1.2～1.5.The solution heat temperature raising, the souring soln temperature is controlled at 35～45 ℃.Insulation 120～180min.
After being hydrolyzed, extracted.Open and stir, rotating speed is controlled at 40～60r/min.The souring soln temperature is controlled at 30～40 ℃.Adding N-BUTYL ACETATE in acidizing fluid, N-BUTYL ACETATE consumption (L)=hydrolyzed solution volume * hydrolyzed solution tires * and 2 * 10
-6.Configuration 15～20% sodium hydroxide solutions, adopt the stream addition slowly to add, used time 50～60min.In the dropping process, detect pH every 9～11min, until pH is adjusted to 9～11.After pH value of solution reaches processing requirement, continue to stop stirring after stirring 10～15min, then standing 60～120min.Separated after standing end, reclaimed raffinate (water).The weighing anhydrous sodium sulphate, add in extraction liquid.Stir 15～20min, standing 20～30min.Carry out solid-liquid separation after standing end, obtain the mixing solutions of tilmicosin and N-BUTYL ACETATE.The mass content of moisture (kg/L) in anhydrous sodium sulphate consumption=N-BUTYL ACETATE * N-BUTYL ACETATE volume (L) * 7.9 kg.
Adopt vacuum dryer to carry out vacuum drying treatment to the mixing solutions of tilmicosin and N-BUTYL ACETATE, mixing speed is controlled at 20～50r/min; Vacuum tightness >=-0.08MPa; Drying temperature is controlled at 50～80 ℃.Stop vacuum-drying more than vacuum dryer operation 20h, obtain the solid tilmicosin.
Tilmicosin adds purified water.Additional proportion: purified water (L) ︰ tilmicosin (kg)=1～1.2 ︰ 1.Open and stir, rotating speed is controlled at 40～60r/min; The phosphoric acid solution of configuration 70～80%; Adopt the stream addition that phosphoric acid solution is slowly splashed in tilmicosin solution, in the dropping process, detect pH every 3～5min, until pH is adjusted to 5.0～6.5.Insulation standing 100～120min after phosphorylation completes.Solution left standstill stops after finishing stirring, and obtains the phosphoric acid tilmicosin aqueous solution.
Start spray-drier, control 120～140 ℃ of inlet temperature, 40～60 ℃ of air outlet temperatures, the charging rotating speed is 150～180r/min.Spraying drying finishes, and obtains phosphoric acid tilmicosin powder.
The present invention be take the tylosin fermented liquid as the starting raw material extraction and is synthesized the phosphoric acid tilmicosin, with common process, compares, and has following technical superiority:
First: production cost is low.In common process, produce 1 ton of phosphoric acid tilmicosin, need to consume 1.2～1.3 tons of Webel Tylan Premixs, need tylosin fermented liquid (fermentation unit is at 12500～13000u/ml) 85～90m
3.And the present invention directly adopts fermented liquid instead of starting raw material, need tylosin fermented liquid (fermentation unit is at 12500～13000u/ml) 75～80m
3.Material cost descends more than 6%.
Second: simplify production process, shorten the products production time, increase work efficiency.The tylosin refined liquid take in prior art as the synthetic tilmicosin of starting raw material, phosphoric acid tilmicosin.The tylosin refined liquid technological process of production is that fermented liquid is through extraction, reextraction, neutralization and decolouring.The present invention directly be take the tylosin fermented liquid as initial feed, and after extraction, synthetic phosphoric acid tilmicosin, simplify conventional production process, shortens the production time, reduces the loss of intermediate, reduces production costs.
The the 3rd: reduce use equipment.In prior art, production tilmicosin, phosphoric acid tilmicosin conventional equipment mainly contain head tank, synthesis reaction vessel, extractor, reextraction tank, neutralization tank, intermediate tank and recycle pump.And the present invention stops using the equipment such as reextraction tank, neutralization tank, intermediate, recycle pump by using novel process, reduce maintenance of the equipment and upkeep cost, reduce production costs.
The 4th: energy-saving and cost-reducing, reduce the pollution to environment.Common process adopts crystallization process to produce the phosphoric acid tilmicosin, and uses large-scale drying plant to carry out drying to it, and energy consumption is larger.The present invention adopts drying process with atomizing, reaches energy-saving and cost-reducing purpose." three wastes " quantity discharged is few simultaneously, is significantly less than common process, therefore, after this process implementing, can not exert an influence to environment.
The 5th, product yield is high.The yield of domestic conventional production process is lower, and as Chinese patent " a kind of preparation method of tilmicosin ", (application number: product yield 200610048425.5) is lower than 85%, and product yield of the present invention is more than 85%, the yield of high and prior art.
The 6th, reaction conditions gentleness of the present invention, simple to operate, production process is safe and reliable.
The 7th, the present invention's organic solvent used is mainly N-BUTYL ACETATE, and this solvent can be reclaimed and reuse, and loss is few, and in production process, quantity of wastewater effluent is few, and three waste discharge meets environmental requirement.
In sum, the present invention directly be take the tylosin fermented liquid and is extracted and syntheticly obtain tilmicosin and phosphoric acid tilmicosin as initial feed, has simplified production process, shortens the products production time, and whole technological reaction mild condition, simple to operate, production process is safe and reliable, and the organic solvent loss is few, have energy-saving and cost-reducing, product yield is high, and production cost is low, the advantages such as working efficiency height.
Embodiment
Below with example, be explained the present invention, it should be understood that example is for the present invention rather than limitation of the present invention are described.Scope of the present invention and core content are determined according to claims.
Embodiment 1
Tylosin fermentating liquid volume 50m
3, tire as 13210u/ml, fermenting total hundred million is 660.5.The fermented liquid temperature is controlled at 20～30 ℃, adds 10～20% polyaluminum sulfate aluminum solutions, and regulating fermented liquid pH is 1.2, continues to stir 10min, after acidifying, tires as 14697u/ml; Then adjust fermented liquid pH with 5.4% ammoniacal liquor, control pH 3.2, then stir 10min, standing 50min, filtered fermented liquid with flame filter press, obtains tylosin filtrate 40m
3, after alkalization, tire as 15819u/ml.
Use organic solvent N-BUTYL ACETATE extraction tylosin solution, the N-BUTYL ACETATE volume is 16m
3.In extraction process, temperature is controlled at 40～42 ℃.Carry out the secondary counter-current extraction with separating centrifuge, extraction finishes, and raffinate is tired as 267u/ml, and the volume of N-BUTYL ACETATE is 15.8m
3.Add gac 78kg in extraction liquid, start stirring system, rotating speed is controlled at 20r/min, stirs 10min, and then standing 30min, filter after standing end, obtains filtrate 15.7m
3, tire as 39901u/ml.
Weighing formic acid 49.5 kg, N-BUTYL ACETATE are 248L, and formic acid is dissolved in N-BUTYL ACETATE.Open and stir, rotating speed is controlled at 40r/min, adopts the stream addition, adds 3,5-lupetidine 132.1kg in the tylosin extraction liquid.Heat temperature raising, tylosin extraction liquid temperature is controlled at 70～71 ℃.Adopt the stream addition to add formic acid and N-BUTYL ACETATE mixing solutions, used time 20min.Insulation 150min.Insulation finishes, and volume is 16m
3, tire as 38291u/ml.
After aminating reaction finishes, solution temperature is controlled at 15～17 ℃.Add purified water 26.4m
3, to open and stir, rotating speed is controlled at 40r/min.Configure 10% hydrochloric acid soln, adopt the stream addition slowly to add, used time 30min.In the dropping process, detect pH every 4～6min, until pH is adjusted to 3.6.In hydrolysis reaction, mixing speed is controlled at 40r/min.Configure 10% hydrochloric acid soln, adopt the stream addition slowly to add, used time 10min.In the dropping process, detect pH every 4～6min, until pH is adjusted to 1.2.The solution heat temperature raising, the souring soln temperature is controlled at 35～37 ℃.Insulation 120min.The hydrolyzed solution volume is 27m
3, tire as 22037u/ml.
After being hydrolyzed, extracted.Open and stir, rotating speed is controlled at 40r/min.The souring soln temperature is controlled at 30～33 ℃.Add N-BUTYL ACETATE 1.2m in acidizing fluid
3, configure 15% sodium hydroxide solution, adopt the stream addition slowly to add, used time 50min.In the dropping process, detect pH every 9～11min, until pH is adjusted to 9.1.After pH value of solution reaches processing requirement, continue to stop stirring after stirring 10min, then standing 60min.Separated after standing end, reclaimed raffinate (water).Weighing 261kg anhydrous sodium sulphate, add in extraction liquid.Stir 15min, standing 20min.Carry out solid-liquid separation after standing end, obtain the mixing solutions of tilmicosin and N-BUTYL ACETATE.
Adopt vacuum dryer to carry out vacuum drying treatment to the mixing solutions of tilmicosin and N-BUTYL ACETATE, mixing speed is controlled at 20r/min; Vacuum tightness-0.08MPa; Drying temperature is controlled at 50 ℃.Vacuum dryer operation 26h stops vacuum-drying, obtains solid tilmicosin 554.8kg, product yield 85.4%.
Tilmicosin adds purified water 540L.Open and stir, rotating speed is controlled at 40min; The phosphoric acid solution of configuration 70%; Adopt the stream addition that phosphoric acid solution is slowly splashed in tilmicosin solution, in the dropping process, detect pH every 3～5min, until pH is adjusted to 5.0.Insulation standing 100min after phosphorylation completes.Solution left standstill stops after finishing stirring, and obtains the phosphoric acid tilmicosin aqueous solution.
Start spray-drier, control 120～140 ℃ of inlet temperature, 40～60 ℃ of air outlet temperatures, the charging rotating speed is 150～180r/min.Spraying drying finishes, and obtains phosphoric acid tilmicosin 612kg.
Embodiment 2
Tylosin fermentating liquid volume 50m
3, tire as 13953u/ml, fermenting total hundred million is 697.7.The fermented liquid temperature is controlled at 24～26 ℃, adds 15% polyaluminum sulfate aluminum solutions, and regulating fermented liquid pH is 2.1, continues to stir 12min, and after acidifying, tiring is 15813 u/ml; Then adjust fermented liquid pH with 13.8% ammoniacal liquor, control pH 5.2, then stir 13min, standing 55min, filtered fermented liquid with flame filter press, obtains tylosin filtrate 39.2m
3, after alkalization, tire as 16980u/ml.
Use organic solvent N-BUTYL ACETATE extraction tylosin solution.Extraction adopts the secondary counter-current extraction, adds N-BUTYL ACETATE 15.7m
3.In extraction process, temperature is controlled at 44～46 ℃.Extraction finishes, raffinate (water) 259u/ml that tires; The extraction liquid volume is 15.5m
3.Add gac 106kg in extraction liquid, start stirring system, rotating speed is controlled at 35r/min, stirs 13min, and then standing 35min, filter after standing end, obtains filtrate 15.3m
3, tire as 42721u/ml.
Weighing formic acid 52kg, N-BUTYL ACETATE 267L, be dissolved in formic acid in N-BUTYL ACETATE.Open and stir, rotating speed is controlled at 50r/min.Adopt the stream addition, add 3,5-lupetidine 140kg in the tylosin extraction liquid, used time 25min.Heat temperature raising, tylosin extraction liquid temperature is controlled at 70～71 ℃.Adopt the stream addition to add formic acid and N-BUTYL ACETATE mixing solutions, used time 25min, insulation 165min.Insulation finishes, and volume is 15.6m
3, tire as 41019u/ml.
After aminating reaction finishes, solution temperature is controlled at 18～21 ℃.Add purified water, purified water consumption 28m
3.Open and stir, rotating speed is controlled at 50r/min.Configure 12.3% hydrochloric acid soln, adopt the stream addition slowly to add, used time 35min.In the dropping process, detect pH every 4～6min, until pH is adjusted to 4.1.
In hydrolysis reaction, mixing speed is controlled at 50r/min.Configure 12.3% hydrochloric acid soln, adopt the stream addition slowly to add, used time 13min.In the dropping process, detect pH every 4～6min, until pH is adjusted to 1.3.The solution heat temperature raising, the souring soln temperature is controlled at 38～41 ℃.Insulation 150min.The hydrolyzed solution volume is 27.8m
3, tire as 22488/ml.
After being hydrolyzed, extracted.Open and stir, rotating speed is controlled at 50r/min.The souring soln temperature is controlled at 34～35 ℃.Add N-BUTYL ACETATE 1.3 m in acidizing fluid
3, configure 18% sodium hydroxide solution, adopt the stream addition slowly to add, used time 55min.In the dropping process, detect pH every 9～11min, until pH is adjusted to 10.2.After pH value of solution reaches processing requirement, continue to stop stirring after stirring 12min, then standing 90min.Separated after standing end, reclaimed raffinate (water).Weighing 410.8kg anhydrous sodium sulphate, add in extraction liquid.Stir 18min, standing 25min.Carry out solid-liquid separation after standing end, obtain the mixing solutions of tilmicosin and N-BUTYL ACETATE.
Adopt vacuum dryer to carry out vacuum drying treatment to the mixing solutions of tilmicosin and N-BUTYL ACETATE, mixing speed is controlled at 35r/min; Vacuum tightness-0.09MPa; Drying temperature is controlled at 65 ℃.Vacuum dryer operation 24h stops vacuum-drying, obtains solid tilmicosin 608kg, and yield is 87.2%.
Tilmicosin adds purified water 451L.Open and stir, rotating speed is controlled at 50r/min; The phosphoric acid solution of configuration 75.2%; Adopt the stream addition that phosphoric acid solution is slowly splashed in tilmicosin solution, in the dropping process, detect pH every 3～5min, until pH is adjusted to 5.8.Insulation standing 110min after phosphorylation completes.Solution left standstill stops after finishing stirring, and obtains the phosphoric acid tilmicosin aqueous solution.
Start spray-drier, control 120～140 ℃ of inlet temperature, 40～60 ℃ of air outlet temperatures, the charging rotating speed is 150～180r/min.Spraying drying finishes, and obtains phosphoric acid tilmicosin powder 677kg.
Embodiment 3
Tylosin fermentating liquid volume 50m
3, tire as 13457u/ml, fermenting total hundred million is 673.Tylosin fermented liquid temperature is controlled at 28～30 ℃, adds 20% polyaluminum sulfate aluminum solutions, regulates fermented liquid pH2.9, and polymerization continues to stir 15min, after the control acidifying, tires as 13089u/ml; Then adjust fermented liquid pH with 20% ammoniacal liquor, control pH 6.9, then stir 15min, standing 60min, filtered fermented liquid with flame filter press, obtains tylosin filtrate 40m
3, after alkalization, tire as 16001u/ml.
Use organic solvent N-BUTYL ACETATE extraction tylosin solution.The N-BUTYL ACETATE volume is 18m
3.In extraction process, temperature is controlled at 48～50 ℃.Carry out the secondary counter-current extraction with separating centrifuge, extraction finishes, raffinate (water) 279u/ml that tires.Add gac 180kg in extraction liquid, start stirring system, rotating speed is controlled at 50r/min, stirs 15min, and then standing 40min, filter after standing end, filtrate volume 17.8m
3.Tire as 35452u/ml.
Weighing formic acid 50kg, N-BUTYL ACETATE 262L, be dissolved in formic acid in N-BUTYL ACETATE.Open and stir, rotating speed is controlled at 60r/min.Adopt the stream addition, add 3,5-lupetidine 135kg in the tylosin extraction liquid, used time 30min.Heat temperature raising, tylosin extraction liquid temperature is controlled at 70～71 ℃.Adopt the stream addition to add formic acid and N-BUTYL ACETATE mixing solutions, used time 30min.Insulation 180min.Insulation finishes, and volume is 18.1m
3, tire as 33889u/ml.
After aminating reaction finishes, solution temperature is controlled at 23～25 ℃.Add purified water 27m
3, to open and stir, rotating speed is controlled at 60r/min.Configure 15% hydrochloric acid soln, adopt the stream addition slowly to add, used time 40min.In the dropping process, detect pH every 4～6min, until pH is adjusted to 5.0.
In hydrolysis reaction, mixing speed is controlled at 60r/min.Configure 15% hydrochloric acid soln, adopt the stream addition slowly to add, used time 15min.In the dropping process, detect pH every 4～6min, until pH is adjusted to 1.5.The solution heat temperature raising, the souring soln temperature is controlled at 43～45 ℃.Insulation 180min.The hydrolyzed solution volume is 27.4m
3, tire as 21848u/ml.
After being hydrolyzed, extracted.Open and stir, rotating speed is controlled at 60r/min.The souring soln temperature is controlled at 38～40 ℃.Add N-BUTYL ACETATE 1.2m in acidizing fluid
3, configure 20% sodium hydroxide solution, adopt the stream addition slowly to add, used time 60min.In the dropping process, detect pH every 9～11min, until pH is adjusted to 11.After continuing to stir 15min, stop stirring, then standing 120min.Separated after standing end, reclaimed raffinate (water).Weighing 25kg anhydrous sodium sulphate, add in extraction liquid.Stir 20min, standing 30min.Carry out solid-liquid separation after standing end, obtain the mixing solutions of tilmicosin and N-BUTYL ACETATE.
Adopt vacuum dryer to carry out vacuum drying treatment to the mixing solutions of tilmicosin and N-BUTYL ACETATE, mixing speed is controlled at 50r/min; Vacuum tightness-0.10MPa; Drying temperature is controlled at 80 ℃.Vacuum dryer operation 22h stops vacuum-drying, obtains solid tilmicosin 576kg, and yield is 85.7%.
Tilmicosin adds purified water 478L.Open and stir, rotating speed is controlled at 60r/min; The phosphoric acid solution of configuration 80%; Adopt the stream addition that phosphoric acid solution is slowly splashed in tilmicosin solution, in the dropping process, detect pH every 3～5min, until pH is adjusted to 6.5.Insulation standing 20min after phosphorylation completes.Solution left standstill stops after finishing stirring, and obtains the phosphoric acid tilmicosin aqueous solution.
Start spray-drier, control 120～140 ℃ of inlet temperature, 40～60 ℃ of air outlet temperatures, the charging rotating speed is 150～180r/min.Spraying drying finishes, and obtains phosphoric acid tilmicosin powder 642kg.
Claims (8)
1. a method of utilizing the tylosin fermented liquid to produce tilmicosin, it is characterized in that its processing step is: at first the tylosin fermented liquid is carried out to pre-treatment, obtain tylosin filtrate, then tylosin filtrate is obtained to tilmicosin through extraction, aminating reaction, reextraction, hydrolysis reaction, acidizing fluid extraction, vacuum-drying;
Wherein said pre-treatment refers under whipped state 10～20% polyaluminum sulfate aluminum solutions is joined in 20～30 ℃ of tylosin fermented liquids, after adjusting pH to be 1～3, continue to stir, reach 7000 μ/more than ml to tiring, adjust pH 3～7, stir again 10～15min, Plate Filtration after standing 50～60min;
Described extraction refers to that take N-BUTYL ACETATE carries out the secondary counter-current extraction to tylosin filtrate as extraction agent, tire below 300u/ml to raffinate, collect extraction liquid, the volume ratio of above-mentioned tylosin filtrate and N-BUTYL ACETATE is 10～11 ︰ 4～4.5,40～50 ℃ of extraction temperature, one-level extraction pH is controlled at 7.0～10.0; Secondary extraction pH is controlled at 8.0～11.0;
Described aminating reaction refers under whipped state, with the stream addition, in the tylosin extraction liquid, adds 3,5-lupetidine, is warming up to 70～71 ℃, continues to add formic acid and N-BUTYL ACETATE mixed solution with the stream addition, is incubated 50～180min and gets final product, wherein
3,5-lupetidine consumption=tylosin total hundred million * 0.2 kg that ferment,
Formic acid consumption=tylosin total hundred million * 0.075 k that ferment,
Jia Suan ︰ N-BUTYL ACETATE=1 kg ︰ 5～5.2 L;
Described reextraction refers under 15～25 ℃, adds purified water, fully stirs, and then adopts the stream addition slowly to add dilute hydrochloric acid, to pH 3.5～5.0;
Described hydrolysis reaction is: under whipped state, adopt the stream addition slowly to add dilute hydrochloric acid, to pH 1.2～1.5, then be warming up to 35～45 ℃, be incubated 120～180min;
Described acidizing fluid extraction is: under whipped state, add N-BUTYL ACETATE, then adopting the stream addition slowly to add mass concentration is 15～20% sodium hydroxide solutions, to pH 9～11, continue to stir 10～15min, after standing 60～120min, separate, add anhydrous sodium sulphate in the gained extraction liquid, carry out solid-liquid separation after standing 20～30min after fully stirring, obtain the mixing solutions of tilmicosin and N-BUTYL ACETATE, wherein
Tire * 0.00002 L of N-BUTYL ACETATE consumption=hydrolyzed solution volume * hydrolyzed solution,
The mass content of moisture * N-BUTYL ACETATE volume * 7.9 kg in anhydrous sodium sulphate consumption=N-BUTYL ACETATE.
2. the production method of a phosphoric acid tilmicosin is characterized in that: the method for utilizing the tylosin fermented liquid to produce tilmicosin according to claim 1 prepares tilmicosin, by peroxophosphoric acid reaction and spraying drying, obtains the phosphoric acid tilmicosin.
3. according to the method for utilizing the tylosin fermented liquid to produce tilmicosin claimed in claim 1, it is characterized in that adding gac in described extraction liquid, fully stir, then filter after standing 30～40min.
4. according to the method for utilizing the tylosin fermented liquid to produce tilmicosin claimed in claim 3, the add-on that it is characterized in that described gac is 0.5～1% of extraction liquid volume.
5. according to the method for utilizing the tylosin fermented liquid to produce tilmicosin claimed in claim 1, it is characterized in that described dilute hydrochloric acid mass concentration is 10～15%.
6. according to the method for utilizing the tylosin fermented liquid to produce tilmicosin claimed in claim 1, it is characterized in that described vacuum drying vacuum tightness >=-0.08MPa, drying temperature is controlled at 50～80 ℃.
7. according to the production method of phosphoric acid tilmicosin claimed in claim 2, it is characterized in that described phosphorylation reaction refers to adds water by the gained tilmicosin, then employing stream addition slowly adds 70～80% phosphoric acid solution, to pH 5.0～6.5, standing 100～120min obtains the phosphoric acid tilmicosin aqueous solution.
8. according to the production method of phosphoric acid tilmicosin claimed in claim 2, it is characterized in that in described spraying drying controlling 120～140 ℃ of inlet temperature, 40～60 ℃ of air outlet temperatures, the charging rotating speed is 150～180r/min.
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| CN2012101045138A CN102659878B (en) | 2012-04-11 | 2012-04-11 | Method for synthesizing tilmicosin and tilmicosin phosphate through using tylosin broth |
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| CN103288904B (en) * | 2013-06-28 | 2015-07-15 | 宁夏泰瑞制药股份有限公司 | Preparation method of tilmicosin phosphate crystal |
| CN103483406A (en) * | 2013-09-25 | 2014-01-01 | 宁夏泰瑞制药股份有限公司 | Preparation method for tilmicosin phosphate |
| CN104725451A (en) * | 2013-12-18 | 2015-06-24 | 菏泽市方明制药有限公司 | Preparation method of tilmicosin phosphate |
| CN105777828A (en) * | 2014-12-22 | 2016-07-20 | 菏泽市方明制药有限公司 | Method for preparing high-quality tilmicosin through low-quality tylosin |
| CN105837648B (en) * | 2015-11-02 | 2018-07-06 | 湖北龙翔药业科技股份有限公司 | A kind of preparation method of tilmicosin phosphate |
| CN106366144A (en) * | 2016-08-30 | 2017-02-01 | 河北舒凯生物科技有限公司 | Preparation method of lactic acid tylosin compound |
| CN106749458A (en) * | 2017-02-21 | 2017-05-31 | 西南大学 | The preparation method of malic acid Tilmicosin double salt |
| CN107383114A (en) * | 2017-05-27 | 2017-11-24 | 山东久隆恒信药业有限公司 | A kind of preparation method of tilmicosin phosphate |
| CN107383132A (en) * | 2017-07-13 | 2017-11-24 | 江西傲新生物科技有限公司 | A kind of water-soluble phosphoric acid Tilmicosin and preparation method and application |
| 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 |
| CN114133417A (en) * | 2021-12-17 | 2022-03-04 | 齐鲁制药（内蒙古）有限公司 | Production method for improving quality of tilmicosin phosphate |
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