CN102659878A - 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 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; Has very strong anti-microbial activity; Resistance is low; Has a broad antifungal spectrum all has restraining effect to all gram-positive microorganisms and part Gram-negative bacteria, Mycoplasma, spirochete etc., especially multiple mycoplasma and spirochete is also had very strong restraining effect.This medicine is successively in the clinical application that goes through of countries such as Australia, Brazil, France, Malaysia, Italy, Spain, the U.S., be used to treat goat, milk cow, pig,
The infection of animals such as chicken.Because tilmicosin is water insoluble,, in the form of salt solution soluble in water, be convenient to taking of animal therefore with the tilmicosin phosphorylation.
At present, the synthetic route of tilmicosin mainly contains two both at home and abroad: the one, directly be hydrolyzed synthetic with tylosin alkali; Another is to utilize tylosin phosphoric acid salt or TYLOSIN TARTARATE BPV to be hydrolyzed, and takes off corresponding salt, and is further synthetic again, like Chinese patent " a kind of preparation method of tilmicosin " (application number: 200610048425.5).The common ground of above-mentioned technology all is to utilize finished product tylosin salt or the capable again preparation tilmicosin of alkali that has prepared, and causes operational path loaded down with trivial details, and the production cycle is long, and has increased the loss of midbody, 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 defective that overcomes above-mentioned prior art; A kind of product yield that tilmicosin, phosphoric acid tilmicosin effectively are provided is provided; Reduce production costs; Technology is simple and direct, the method for utilizing the synthetic tilmicosin of tylosin fermented liquid easy and simple to handle, and further produce the phosphoric acid tilmicosin.
For realizing that the technical scheme that above-mentioned purpose is taked is:
A kind of method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin; It is characterized in that its process step is: at first the tylosin fermented liquid is carried out pre-treatment; Obtain tylosin filtrating, then tylosin filtrating is obtained 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.
Said preprocessing process is: tylosin fermented liquid temperature is controlled at 20～30 ℃; The polyaluminum sulfate aluminum solutions of adding 10～20%; Regulating fermented liquid pH is 1～3, constantly stirs in the polyaluminium sulfate use, after the adjusting of pH value reaches 1～3; Continue to stir 10～15min, to tire after the control acidifying be 7000 μ/more than the ml; Transfer fermented liquid pH with 5～20% ammoniacal liquor then, pH is 3～7 in control, and restir 10～15min leaves standstill 50～60min, with flame filter press fermented liquid is filtered, and obtains tylosin filtrating.
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 the extraction process, temperature is controlled at 40～50 ℃.Carrying out the secondary counter-current extraction with separating centrifuge, is the mixed solvent phase mutually gently, in extraction process, take a sample to check double solvent mutually with the aqueous phase separation situation, tire and aqueous pH values, the control raffinate is tired below 300u/ml, the collection extraction liquid.One-level extraction pH is controlled at 7.0～10.0; Secondary extraction pH is controlled at 8.0～11.0.Raffinate (water) is tired＜300u/ml.Extraction finishes, and adds gac in the 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, leaves standstill 30～40min then, leaves standstill the end after-filtration.
Above-mentioned aminating reaction process is: the preparation formic acid solution, mix formic acid and N-BUTYL ACETATE 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 the whipping process, adopt the stream addition, add 3 in the tylosin extraction liquid, 5-lupetidine, time spent 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, time spent 20～30min.Insulation 150～180min.
After aminating reaction finished, strip: solution temperature was 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 time spent 30～40min.In the dropping process, whenever detect pH, transfer to 3.5～5.0 until pH at a distance from 4～6min.
The reaction that is hydrolyzed then, in the hydrolysis reaction, mixing speed is controlled at 40～60r/min.Configuration 10～15% hydrochloric acid solns adopt the stream addition slowly to add time spent 10～15min.In the dropping process, whenever detect pH, transfer to 1.2～1.5 until pH at a distance from 4～6min.Solution heat temperature raising, souring soln temperature are controlled at 35～45 ℃.Insulation 120～180min.
Hydrolysis extracts after accomplishing.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 the acidizing fluid, N-BUTYL ACETATE consumption (L)=hydrolyzed solution volume * hydrolyzed solution tires * and 2 * 10
-6Configuration 15～20% sodium hydroxide solutions adopt the stream addition slowly to add time spent 50～60min.In the dropping process, whenever detect pH, transfer to 9～11 until pH at a distance from 9～11min.After pH value of solution reaches processing requirement, continue to stop to stir behind stirring 10～15min, leave standstill 60～120min then.Separate after leaving standstill end, reclaim raffinate (water).The weighing SODIUM SULPHATE ANHYDROUS 99PCT adds in the extraction liquid.Stir 15～20min, leave standstill 20～30min.Carry out solid-liquid separation after leaving standstill end, obtain the mixing solutions of tilmicosin and N-BUTYL ACETATE.The mass content of moisture (kg/L) in SODIUM SULPHATE ANHYDROUS 99PCT consumption=N-BUTYL ACETATE * N-BUTYL ACETATE volume (L) * 7.9 kg.
Adopt vacuum dryer that the mixing solutions of tilmicosin and N-BUTYL ACETATE is carried out vacuum drying treatment, mixing speed is controlled at 20～50r/min; Vacuum tightness >=-0.08MPa; Drying temperature is controlled at 50～80 ℃.Stop vacuum-drying more than the 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 the tilmicosin solution, in the dropping process, whenever detect pH, transfer to 5.0～6.5 until pH at a distance from 3～5min.Phosphorylation is incubated and leaves standstill 100～120min after accomplishing.Stop after solution left standstill finishes stirring, obtain the phosphoric acid tilmicosin aqueous solution.
Start spray-drier, 120～140 ℃ of control EATs, 40～60 ℃ of air outlet temperatures, charging rotating speed are 150～180r/min.Spraying drying finishes, and obtains phosphoric acid tilmicosin powder.
The present invention is the starting raw material extraction with the tylosin fermented liquid and synthesizes the phosphoric acid tilmicosin, compares with common process, has following technical superiority:
First: production cost is low.In the common process, produce 1 ton of phosphoric acid tilmicosin, need to consume 1.2～1.3 tons of Webel Tylan Premixs, (fermentation unit is at 12500～13000u/ml) 85～90m to need the tylosin fermented liquid
3And the present invention directly adopts fermented liquid to replace being starting raw material, and (fermentation unit is at 12500～13000u/ml) 75～80m to need the tylosin fermented liquid
3Material cost descends more than 6%.
Second: simplify production process, shorten the products production time, increase work efficiency.Be the synthetic tilmicosin of starting raw material, phosphoric acid tilmicosin with the tylosin refined liquid in the prior art.The tylosin refined liquid technological process of production is that fermented liquid is through extraction, reextraction, neutralization and decolouring.The present invention is an initial feed with the tylosin fermented liquid directly, through the synthetic phosphoric acid tilmicosin in extraction back, simplifies conventional production process, shortens the PT, reduces the loss of midbody, reduces production costs.
The the 3rd: reduce use equipment.In the prior art, production tilmicosin, phosphoric acid tilmicosin conventional equipment mainly contain head tank, synthesis reaction vessel, extractor, reextraction jar, neutralization tank, midbody jar and recycle pump.And the present invention stops using the equipment such as jar, neutralization tank, midbody, recycle pump of stripping through using novel process, reduces maintenance of the equipment and upkeep cost, reduces production costs.
The 4th: energy-saving and cost-reducing, reduce pollution to environment.Common process adopts crystallization process to produce the phosphoric acid tilmicosin, and uses large-scale drying plant that it is carried out drying, and energy consumption is bigger.The present invention adopts drying process with atomizing, reaches energy saving purposes." three wastes " quantity discharged is few simultaneously, is significantly less than common process, therefore, can not exert an influence to environment behind this process implementing.
The 5th, product yield is high.The yield of domestic conventional production process is lower, and (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 like Chinese patent " a kind of preparation method of tilmicosin ".
The 6th, reaction conditions of the present invention is gentle, and simple to operate, production process is safe and reliable.
The 7th, the used organic solvent of the present invention mainly is a N-BUTYL ACETATE, and this solvent can reclaim and reuse, and loss is few, and quantity of wastewater effluent is few in the production process, the three waste discharge compliance with environmental protection requirements.
In sum, the present invention is that initial feed is extracted and syntheticly obtained tilmicosin and phosphoric acid tilmicosin with the tylosin fermented liquid directly, has simplified production process; Shorten 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, has energy-saving and cost-reducing; Product yield is high, and production cost is low, advantages such as working efficiency height.
Embodiment
With instance the present invention is described below, it should be understood that instance is to be used to explain the present invention rather than limitation of the present invention.Scope of the present invention and core content are confirmed according to claims.
Embodiment 1
Tylosin fermentating liquid volume 50m
3, tiring is 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, and tiring after the acidifying is 14697u/ml; Transfer fermented liquid pH with 5.4% ammoniacal liquor then, pH is 3.2 in control, and restir 10min leaves standstill 50min, with flame filter press fermented liquid is filtered, and obtains tylosin filtrating 40m
3, tiring after the alkalization is 15819u/ml.
Use organic solvent N-BUTYL ACETATE extraction tylosin solution, the N-BUTYL ACETATE volume is 16m
3In the extraction process, temperature is controlled at 40～42 ℃.Carry out the secondary counter-current extraction with separating centrifuge, extraction finishes, and raffinate is tired and is that 267u/ml, the volume of N-BUTYL ACETATE are 15.8m
3Add gac 78kg in the extraction liquid, start stirring system, rotating speed is controlled at 20r/min, stirs 10min, leaves standstill 30min then, leaves standstill the end after-filtration, obtains the 15.7m that filtrates
3, tiring is 39901u/ml.
Weighing formic acid 49.5 kg, N-BUTYL ACETATE are 248L, and formic acid is dissolved in the N-BUTYL ACETATE.Open and stir, rotating speed is controlled at 40r/min, adopts the stream addition, adds 3 in the tylosin extraction liquid, 5-lupetidine 132.1kg.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, time spent 20min.Insulation 150min.Insulation finishes, and volume is 16m
3, tiring is 38291u/ml.
After aminating reaction finished, solution temperature was controlled at 15～17 ℃.Add purified water 26.4m
3, to open and stir, rotating speed is controlled at 40r/min.Dispose 10% hydrochloric acid soln, adopt the stream addition slowly to add time spent 30min.In the dropping process, whenever detect pH, transfer to 3.6 until pH at a distance from 4～6min.Mixing speed is controlled at 40r/min in the hydrolysis reaction.Dispose 10% hydrochloric acid soln, adopt the stream addition slowly to add time spent 10min.In the dropping process, whenever detect pH, transfer to 1.2 until pH at a distance from 4～6min.Solution heat temperature raising, souring soln temperature are controlled at 35～37 ℃.Insulation 120min.The hydrolyzed solution volume is 27m
3, tiring is 22037u/ml.
Hydrolysis extracts after accomplishing.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 the acidizing fluid
3, dispose 15% sodium hydroxide solution, adopt the stream addition slowly to add time spent 50min.In the dropping process, whenever detect pH, transfer to 9.1 until pH at a distance from 9～11min.After pH value of solution reaches processing requirement, continue to stop to stir behind the stirring 10min, leave standstill 60min then.Separate after leaving standstill end, reclaim raffinate (water).Weighing 261kg SODIUM SULPHATE ANHYDROUS 99PCT adds in the extraction liquid.Stir 15min, leave standstill 20min.Carry out solid-liquid separation after leaving standstill end, obtain the mixing solutions of tilmicosin and N-BUTYL ACETATE.
Adopt vacuum dryer that the mixing solutions of tilmicosin and N-BUTYL ACETATE is carried out vacuum drying treatment, 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 the tilmicosin solution, in the dropping process, whenever detect pH, transfer to 5.0 until pH at a distance from 3～5min.Phosphorylation is incubated and leaves standstill 100min after accomplishing.Stop after solution left standstill finishes stirring, obtain the phosphoric acid tilmicosin aqueous solution.
Start spray-drier, 120～140 ℃ of control EATs, 40～60 ℃ of air outlet temperatures, charging rotating speed are 150～180r/min.Spraying drying finishes, and obtains phosphoric acid tilmicosin 612kg.
Embodiment 2
Tylosin fermentating liquid volume 50m
3, tiring is 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 tiring after the acidifying is 15813 u/ml; Transfer fermented liquid pH with 13.8% ammoniacal liquor then, pH is 5.2 in control, and restir 13min leaves standstill 55min, with flame filter press fermented liquid is filtered, and obtains tylosin filtrating 39.2m
3, tiring after the alkalization is 16980u/ml.
Use organic solvent N-BUTYL ACETATE extraction tylosin solution.The secondary counter-current extraction is adopted in extraction, adds N-BUTYL ACETATE 15.7m
3In the extraction process, temperature is controlled at 44～46 ℃.Extraction finishes, raffinate (water) 259u/ml that tires; The extraction liquid volume is 15.5m
3Add gac 106kg in the extraction liquid, start stirring system, rotating speed is controlled at 35r/min, stirs 13min, leaves standstill 35min then, leaves standstill the end after-filtration, obtains the 15.3m that filtrates
3, tiring is 42721u/ml.
Weighing formic acid 52kg, N-BUTYL ACETATE 267L are dissolved in formic acid in the N-BUTYL ACETATE.Open and stir, rotating speed is controlled at 50r/min.Adopt the stream addition, add 3 in the tylosin extraction liquid, 5-lupetidine 140kg, time spent 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, time spent 25min, insulation 165min.Insulation finishes, and volume is 15.6m
3, tiring is 41019u/ml.
After aminating reaction finished, solution temperature was controlled at 18～21 ℃.Add purified water, purified water consumption 28m
3Open and stir, rotating speed is controlled at 50r/min.Dispose 12.3% hydrochloric acid soln, adopt the stream addition slowly to add time spent 35min.In the dropping process, whenever detect pH, transfer to 4.1 until pH at a distance from 4～6min.
In the hydrolysis reaction, mixing speed is controlled at 50r/min.Dispose 12.3% hydrochloric acid soln, adopt the stream addition slowly to add time spent 13min.In the dropping process, whenever detect pH, transfer to 1.3 until pH at a distance from 4～6min.Solution heat temperature raising, souring soln temperature are controlled at 38～41 ℃.Insulation 150min.The hydrolyzed solution volume is 27.8m
3, tiring is 22488/ml.
Hydrolysis extracts after accomplishing.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 the acidizing fluid
3, dispose 18% sodium hydroxide solution, adopt the stream addition slowly to add time spent 55min.In the dropping process, whenever detect pH, transfer to 10.2 until pH at a distance from 9～11min.After pH value of solution reaches processing requirement, continue to stop to stir behind the stirring 12min, leave standstill 90min then.Separate after leaving standstill end, reclaim raffinate (water).Weighing 410.8kg SODIUM SULPHATE ANHYDROUS 99PCT adds in the extraction liquid.Stir 18min, leave standstill 25min.Carry out solid-liquid separation after leaving standstill end, obtain the mixing solutions of tilmicosin and N-BUTYL ACETATE.
Adopt vacuum dryer that the mixing solutions of tilmicosin and N-BUTYL ACETATE is carried out vacuum drying treatment, 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 the tilmicosin solution, in the dropping process, whenever detect pH, transfer to 5.8 until pH at a distance from 3～5min.Phosphorylation is incubated and leaves standstill 110min after accomplishing.Stop after solution left standstill finishes stirring, obtain the phosphoric acid tilmicosin aqueous solution.
Start spray-drier, 120～140 ℃ of control EATs, 40～60 ℃ of air outlet temperatures, charging rotating speed are 150～180r/min.Spraying drying finishes, and obtains phosphoric acid tilmicosin powder 677kg.
Embodiment 3
Tylosin fermentating liquid volume 50m
3, tiring is 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, and tiring after the control acidifying is 13089u/ml; Transfer fermented liquid pH with 20% ammoniacal liquor then, pH is 6.9 in control, and restir 15min leaves standstill 60min, with flame filter press fermented liquid is filtered, and obtains tylosin filtrating 40m
3, tiring after the alkalization is 16001u/ml.
Use organic solvent N-BUTYL ACETATE extraction tylosin solution.The N-BUTYL ACETATE volume is 18m
3In the 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 the extraction liquid, start stirring system, rotating speed is controlled at 50r/min, stirs 15min, leaves standstill 40min then, leaves standstill the end after-filtration, filtrate volume 17.8m
3Tire and be 35452u/ml.
Weighing formic acid 50kg, N-BUTYL ACETATE 262L is dissolved in formic acid in the N-BUTYL ACETATE.Open and stir, rotating speed is controlled at 60r/min.Adopt the stream addition, add 3 in the tylosin extraction liquid, 5-lupetidine 135kg, time spent 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, time spent 30min.Insulation 180min.Insulation finishes, and volume is 18.1m
3, tiring is 33889u/ml.
After aminating reaction finished, solution temperature was controlled at 23～25 ℃.Add purified water 27m
3, to open and stir, rotating speed is controlled at 60r/min.Dispose 15% hydrochloric acid soln, adopt the stream addition slowly to add time spent 40min.In the dropping process, whenever detect pH, transfer to 5.0 until pH at a distance from 4～6min.
In the hydrolysis reaction, mixing speed is controlled at 60r/min.Dispose 15% hydrochloric acid soln, adopt the stream addition slowly to add time spent 15min.In the dropping process, whenever detect pH, transfer to 1.5 until pH at a distance from 4～6min.Solution heat temperature raising, souring soln temperature are controlled at 43～45 ℃.Insulation 180min.The hydrolyzed solution volume is 27.4m
3, tiring is 21848u/ml.
Hydrolysis extracts after accomplishing.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 the acidizing fluid
3, dispose 20% sodium hydroxide solution, adopt the stream addition slowly to add time spent 60min.In the dropping process, whenever detect pH, transfer to 11 until pH at a distance from 9～11min.Stop to stir after continuing to stir 15min, leave standstill 120min then.Separate after leaving standstill end, reclaim raffinate (water).Weighing 25kg SODIUM SULPHATE ANHYDROUS 99PCT adds in the extraction liquid.Stir 20min, leave standstill 30min.Carry out solid-liquid separation after leaving standstill end, obtain the mixing solutions of tilmicosin and N-BUTYL ACETATE.
Adopt vacuum dryer that the mixing solutions of tilmicosin and N-BUTYL ACETATE is carried out vacuum drying treatment, 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 the tilmicosin solution, in the dropping process, whenever detect pH, transfer to 6.5 until pH at a distance from 3～5min.Phosphorylation is incubated and leaves standstill 20min after accomplishing.Stop after solution left standstill finishes stirring, obtain the phosphoric acid tilmicosin aqueous solution.
Start spray-drier, 120～140 ℃ of control EATs, 40～60 ℃ of air outlet temperatures, charging rotating speed are 150～180r/min.Spraying drying finishes, and obtains phosphoric acid tilmicosin powder 642kg.
Claims (14)
1. method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin; It is characterized in that its process step is: at first the tylosin fermented liquid is carried out pre-treatment; Obtain tylosin filtrating, then tylosin filtrating is obtained tilmicosin through extraction, aminating reaction, reextraction, hydrolysis reaction, acidizing fluid extraction, vacuum-drying.
2. according to the described method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin of claim 1, it is characterized in that: above-mentioned tilmicosin obtains the phosphoric acid tilmicosin through phosphorylation reaction and spraying drying.
3. according to the described method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin of claim 1; It is characterized in that above-mentioned pre-treatment is meant that under whipped state the polyaluminum sulfate aluminum solutions with 10～20% joins in 20～30 ℃ of tylosin fermented liquids, transfer pH to be 1～3 after, continue to stir; Reach 7000 μ/more than the ml to tiring; Transfer pH 3～7, restir 10～15min, leave standstill 50～60min after Plate Filtration obtain tylosin filtrating.
4. according to the described method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin of claim 1; It is characterized in that it is that extraction agent carries out the secondary counter-current extraction to tylosin filtrating that said extraction is meant with the N-BUTYL ACETATE; Tire below 300u/ml to raffinate, collect extraction liquid, above-mentioned tylosin filtrating is 10～11 ︰ 4～4.5 with the volume ratio of N-BUTYL ACETATE; 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.
5. according to the described method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin of claim 4, it is characterized in that in above-mentioned extraction liquid, adding gac, fully stir, leave standstill 30～40min after-filtration again.
6. according to the described method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin of claim 4, the add-on that it is characterized in that above-mentioned gac is 0.5～1% of an extraction liquid volume.
7. according to the described method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin of claim 1; It is characterized in that said aminating reaction is meant under whipped state, in the tylosin extraction liquid, add 3, the 5-lupetidine with the stream addition; Be warming up to 70～71 ℃; Continuation adds formic acid and N-BUTYL ACETATE mixed solution with the stream addition, and insulation 50～180min 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 kg that ferment
Jia Suan ︰ N-BUTYL ACETATE=1 kg ︰, 5～5.2 L.
8. according to the described method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin of claim 1; It is characterized in that said reextraction is meant under 15～25 ℃, add purified water, fully stir; Adopt the stream addition slowly to add Hydrogen chloride then, to pH 3.5～5.0.
9. according to the described method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin of claim 1; It is characterized in that said hydrolysis reaction is: under that state of stirring; Adopt the stream addition slowly to add Hydrogen chloride; To pH 1.2～1.5, be warming up to 35～45 ℃ then, insulation 120～180min.
10. according to claim 8 or the 9 described methods of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin, it is characterized in that said Hydrogen chloride mass concentration is 10～15%.
11., it is characterized in that the acidizing fluid extraction is: under whipped state, add N-BUTYL ACETATE according to the described method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin of claim 1; Adopting the stream addition slowly to add mass concentration then is 15～20% sodium hydroxide solutions; To pH 9～11, continue to stir 10～15min, separate after leaving standstill 60～120min; In the gained extraction liquid, add SODIUM SULPHATE ANHYDROUS 99PCT; Carry out solid-liquid separation after leaving standstill 20～30min after fully stirring, obtain the mixing solutions of tilmicosin and N-BUTYL ACETATE, wherein
N-BUTYL ACETATE consumption=hydrolyzed solution volume * hydrolyzed solution is tired * 0.00002 L,
The mass content of moisture * N-BUTYL ACETATE volume * 7.9 kg in SODIUM SULPHATE ANHYDROUS 99PCT consumption=N-BUTYL ACETATE.
12. according to the described method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin of claim 1, it is characterized in that said vacuum drying vacuum tightness >=-0.08MPa, drying temperature is controlled at 50～80 ℃.
13. according to the described method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin of claim 2; It is characterized in that said phosphorylation reaction is meant adds water with the gained tilmicosin; Adopt the slowly phosphoric acid solution of adding 70～80% of stream addition then; To pH 5.0～6.5, leave standstill 100～120min and obtain the phosphoric acid tilmicosin aqueous solution.
14. according to the described method of utilizing the tylosin fermented liquid to produce tilmicosin and phosphoric acid tilmicosin of claim 2; It is characterized in that controlling in the said spraying drying 120～140 ℃ of EATs; 40～60 ℃ of air outlet temperatures, charging rotating speed are 150～180r/min.
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| CN103288904A (en) * | 2013-06-28 | 2013-09-11 | 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 |
| CN105837648A (en) * | 2015-11-02 | 2016-08-10 | 湖北龙翔药业科技股份有限公司 | Tilmicosin phosphate preparation method |
| 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 |
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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 |
| CN103288904A (en) * | 2013-06-28 | 2013-09-11 | 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 |
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| CN105837648A (en) * | 2015-11-02 | 2016-08-10 | 湖北龙翔药业科技股份有限公司 | Tilmicosin phosphate preparation method |
| 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 |
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