CN101735123A - Method for synthesizing valnemulin hydrochloride - Google Patents
Method for synthesizing valnemulin hydrochloride Download PDFInfo
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- CN101735123A CN101735123A CN200910231295A CN200910231295A CN101735123A CN 101735123 A CN101735123 A CN 101735123A CN 200910231295 A CN200910231295 A CN 200910231295A CN 200910231295 A CN200910231295 A CN 200910231295A CN 101735123 A CN101735123 A CN 101735123A
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Abstract
The invention discloses a method for synthesizing valnemulin hydrochloride. The method taking pleuromytilin a raw material comprises the following steps: synthesizing sulfonated pleurin; then, preparing 14-O-[(1-amido-2-methyl-propyl-2-yl)acetyl] mutelin by the sulfonated pleurin; synthesizing D-valine deng salt by D-valine; and finally, mixing the 14-O-[(1-amido-2-methyl-propyl-2-yl)acetyl] mutelin, the D-valine deng salt, N-methylmorpholine and allyl chloroformate by a certain sequence and a certain condition and reacting to generate mixed anhydride so as to obtain the valnemulin hydrochloride by the subsequent steps of acidylating, hydrolyzing, separating, drying and the like. The invention realizes the accurate control of the reaction by controlling the technological parameters of the reaction temperature, the drying condition, the reaction pH and the like and enhances the reaction efficiency and the quality and the purity of a product effectively. The obtained valnemulin hydrochloride can be used for medicines and meets the market requirement.
Description
Technical field
The present invention relates to a kind of synthetic method of valnemulin hydrochloride, specifically, relate to a kind of with the acetoxyl of 14-O-[(1-amino-2-methyl propyl group-2-yl)] the special woods of order and D-Xie Ansuan Deng salt is the method for the synthetic valnemulin hydrochloride of raw material.
Background technology
Valnemulin hydrochloride (Valnemulin Hydrochloride) is the semisynthetic animal specific microbiotic of pleuromutilin of new generation (pleuromutilin) class, belongs to two terpenes, belongs to same class medicine with Tiamulin.Be mainly used in mycoplasmosis and the gram positive bacteria infection of control pig, ox, sheep and poultry abroad, have wide spectrum, anti-microbial activity is strong, characteristics of pharmacokinetics is good, residual characteristics such as low, safe.Be used to prevent and treat swine dysentery that causes by the short spirochaete infection of swine dysentery and the porcine enzootic pneumonia that causes by mycoplasma pneumoniae infection by European Union approval in 1999.Infected the pig hyperplasia enteropathy (ileitis) that causes by European Union's approval prevention by hog middle spirochetosis (colitis) and treatment that the short spirochaete infection of colon pili sample causes in January, 2004 by thin lawsonia intracellularis.The producer that China can produce valnemulin at present seldom.
Disclose among the patent US4675330 with the pleuromutilin is the technology of feedstock production valnemulin; its process is: compound 2 and Xie Ansuan are at N; react in the N-dimethyl methyl phthalein amine; slough protecting group with the Pd/ gac then in methanol system and obtain the valnemulin crude product, purifying with chromatography column then obtains purer product.Technical process is as follows:
The shortcoming of this method is that gained valnemulin crude product purity generally is no more than 93%, can not be not suitable for suitability for industrialized production as drug use.
Summary of the invention
The objective of the invention is to overcome above-mentioned deficiency, the synthetic method of the valnemulin hydrochloride that can be used for medicine that a kind of production cost is low, product purity is high is provided.The present invention also aims to by processing parameters such as control reaction temperature, drying conditions, reaction pH, the accurate control of realization response makes reaction efficiency, product quality, purity all obtain effective raising.
The present invention is achieved by the following technical solutions:
The present invention is raw material with the pleuromutilin, synthetic sulfonation pleurin; Prepare the acetoxyl of 14-O-[(1-amino-2-methyl propyl group-2-yl) with the sulfonation pleurin then] the special woods of order; With the synthetic D-Xie Ansuan Deng salt of D-Xie Ansuan; At last with the acetoxyl of 14-O-[(1-amino-2-methyl propyl group-2-yl)] the special woods of order, D-Xie Ansuan Deng salt, N-methylmorpholine, allyl chlorocarbonate generate with a definite sequence, certain condition hybrid reaction and mix acid anhydride, obtains the valnemulin hydrochloride through subsequent steps such as acidylate, hydrolysis, separation, dryings.
The synthetic method of a kind of valnemulin hydrochloride of the present invention may further comprise the steps:
(1) the sulfonation pleurin is synthetic: sulfonation reaction is taken place moles such as pleuromutilin and Tosyl chloride make the sulfonation pleurin;
(2) acetoxyl of 14-O-[(1-amino-2-methyl propyl group-2-yl)] the special woods of order (ATAM) synthetic: with sulfonation pleurin sulfonation pleurin in the step (1) and dimethyl Mercaptamine with 1: the molar ratio reaction of 1-1.5 makes ATAM under catalyzer and alkaline condition;
(3) D-Xie Ansuan Deng salt is synthetic: with mol ratio is that 1: 1: 1 D-Xie Ansuan, amino protecting agent, alkali is that raw material makes D-Xie Ansuan Deng salt;
(4) the valnemulin hydrochloride is synthetic: with the acetoxyl of D-Xie Ansuan Deng salt, N-methylmorpholine, allyl chlorocarbonate (MSDS), 14-O-[(1-amino-2-methyl propyl group-2-yl)] the special woods of order is with mol ratio 1-1.5: 10: 1-1.5: 1-1.5 mixes to generate and mixes acid anhydride, be hydrolyzed after having reacted and remove and deaminize, then organic phase is separated the water intaking phase, obtain the valnemulin hydrochloride with freeze dried method.
Amino protecting agent described in the step (3) is methyl aceto acetate, methyl ethyl diketone or methyl acetoacetate, and described alkali is solid sodium hydroxide or potassium hydroxide.
The synthetic method of sulfonation pleurin is: pleuromutilin is joined in its quality 4-6 organic solvent doubly, stir and make its dissolving, add equimolar Tosyl chloride, stirring reaction 15～30min under alkaline condition down at-5～5 ℃ then; After reaction finishes, reaction solution is concentrated into dried, obtains the sulfonation pleurin, molecular formula is C
29H
40O
7S.Used organic solvent is a general solvent, and reaction environment is provided, and all can as acetone, ethanol, t-butyl methyl ether.
The synthetic method of ATAM is: the heterogeneous catalyst of sulfonation pleurin, dimethyl Mercaptamine, 1-3 gram is joined in they quality 1.5-3 ethanol doubly, under 50～55 ℃, alkaline environment, be stirred to sulfonation pleurin complete reaction, utilize the TLC detection reaction whether to finish, with CHCl
3/ CH
3OH (volume)=7: 1 is a chromatographic solution, and Mercaptamine immaculate explanation reaction is finished; Reaction finishes the back and adds reaction solution 2-3 quality water doubly, and temperature of reaction is reduced to 0-5 ℃, has been stirred to precipitation and generates under this temperature, precipitates complete after-filtration, and with filter cake washing, obtain ATAM 50～55 ℃ of following vacuum-dryings, molecular formula is C
26H
43NO
4S.
Synthetic also available 2-methyl isoamyl ketone of ATAM or butylacetate are as solvent, and this moment, product can't be separated out in crystallization, after reaction finishes organic phase are directly used in the synthetic of valnemulin hydrochloride.React added heterogeneous catalyst, it mainly acts on is to strengthen speed of reaction, Tetrabutyl amonium bromide, trioctylphosphine methyl brometo de amonio, tetrabutylammonium iodide, cetyl trimethylammonium bromide and all can be used for the present invention with the approaching heterogeneous catalyst of their character.
D-Xie Ansuan Deng salt is common name, English D-VALINE DANE SALT by name, and the easy moisture absorption of D-Xie Ansuan Deng salt needs kept dry.It is synthetic by method A or method B.
Method A: in the round-bottomed flask of reflux is housed, add solid alkali and 300-400ml Virahol, stir down alkali dissolution at 50～55 ℃, add D-Xie Ansuan and amino protecting agent then successively, be stirred to solution become faint yellow, under this temperature reflux 0.5-2 hour; Reaction finishes the back and with Rotary Evaporators reaction solution is concentrated into thickness, add 250-350ml toluene or t-butyl methyl ether in viscous fluid, slowly be cooled to room temperature under condition of stirring, 0-5 ℃ leaves standstill a night, filtration, washing, 50-60 ℃ vacuum-drying are spent the night, and obtain D-Xie Ansuan Deng salt.
Method B: in the round-bottomed flask of reflux is housed, add solid alkali and 350-450ml methyl alcohol,, add D-Xie Ansuan and amino protecting agent then successively, under this temperature reflux 0.5-1 hour 50～60 ℃ of following heated and stirred dissolvings; After finishing, reaction, obtains solid with the methyl alcohol evaporate to dryness; The solid that reaction is obtained joins in the 1200-1400ml toluene, is heated to 90-100 ℃, the suspension liquid that obtains is placed down at 0-5 ℃ spent the night, filter then, with toluene wash, drying, obtain D-Xie Ansuan Deng salt.
The synthetic of valnemulin hydrochloride may further comprise the steps:
1) generates mixed acid anhydride
D) add D-Xie Ansuan Deng's salt and 200-250ml ethanol in container, stirring is dissolved in the ethanol Deng's salt;
E) add N-methylmorpholine, cool the temperature to 0-5 ℃, add MSDS and 20-30ml ethanol after the cooling again, then at-10～-15 ℃ of following stirring reaction 0.5-1 hours;
F) in reaction system, add the acetoxyl of 14-0-[(1-amino-2-methyl propyl group-2-yl)] the special woods of order, and at 0-5 ℃ of following stirring reaction 1-2 hour, then temperature is risen to 20-25 ℃ and stirred 0.5-1 hour, utilize the TLC detection reaction whether to finish, with CHCl
3/ CH
30H (volume)=7: 1 is a chromatographic solution, and ATAM immaculate explanation reaction is finished; Reaction is carried out liquid-liquid extraction after finishing, and collects organic phase;
2) hydrolysis and remove amino
A) in organic phase, add the water of its 1-2 times volume, and with dilute hydrochloric acid with pH value modulation 3.0-3.5, reaction solution is stirred 1～2h down at 40-45 ℃, separatory collection water;
B) water is removed acetylacetic ester with the butylacetate washed twice, adds the butylacetate of 1-2 times of volume then, and with NaOH solution with pH value modulation 10.0-10.5, be stirred to the complete layering of solution, collect organic phase, and with twice of distilled water elution;
3) obtain the valnemulin hydrochloride
A) in organic phase, add its volume 1-2 distilled water doubly, and the pH value is adjusted to 3.0-3.5, be stirred to the solution layering, separatory water intaking phase with dilute hydrochloric acid;
B) water is removed the micro-acetic acid butyl ester that contains in the solution 25-30 ℃ of following vacuum-evaporation, obtains the valnemulin hydrochloride by freeze dried method then.
Alkaline environment of the present invention is regulated with alkaline matter, does not do specific requirement, as long as can reach required alkaline condition and not influence reaction normally.
Its technical process is as follows:
The present invention is with the acetoxyl of 14-O-[(1-amino-2-methyl propyl group-2-yl)] the special woods of order, D-Xie Ansuan Deng salt be the synthetic valnemulin hydrochloride of raw material, by the valnemulin hydrochloride purity height that this synthetic method obtains, yield is big, meets the need of market.
The acetoxyl of 14-O-[(1-amino-2-methyl propyl group-2-yl)] building-up process of the special woods of order and valnemulin hydrochloride uses the high solvent of boiling point to do reaction solvent, the volatility of solvent in the production process is reduced, the condensation effect of removal process is better, and loss is reduced, and cost is reduced.
The acetoxyl of 14-O-[(1-amino-2-methyl propyl group-2-yl)] the special woods building-up process of order increased reaction process selection of catalysts scope, is convenient to according to circumstances select.
In D-Xie Ansuan Deng salt building-up process, as reaction solvent, avoided the generation of amido protecting group isomerized products with methyl alcohol; And make synthesis yield, purity reach high level as solvent with Virahol.
Draw the pH scope of reaction of the present invention, drying temperature scope and hydrolysis, salification process through a large amount of experimental summaries, accomplished accurate control, product quality is effectively improved, purity is greater than 97% (butt meter), molar yield can reach 60%, is higher than yield of the prior art far away.
Use ethanol during valnemulin is synthetic, Deng's salt can directly be dissolved in the ethanol, has reduced heterogeneous operation in the reaction process, has obviously improved reaction efficiency.
Embodiment
Be specific embodiments of the invention below, present embodiment only is used to set forth this technology, the present invention is not done qualification.
Embodiment 1
In the 250ml there-necked flask that mechanical stirring and thermometer are housed, add 37.85g pleuromutilin and 150ml acetone, stir and make its dissolving.There-necked flask is placed cryostat,, be cooled to 0 ℃.The 40wt%NaOH that adds 19.06g Tosyl chloride and 15ml, stirring reaction 20min.After reaction finishes, solvent is concentrated into dried, obtains the sulfonation pleurin.
Mechanical stirring is being housed, is adding the sulfonation pleurin of 53.2g in the 500ml there-necked flask of thermometer and reflux, 14.2g dimethyl Mercaptamine, 1.2g Tetrabutyl amonium bromide, the NaOH solution of 30ml 10N and 100ml t-butyl methyl ether.At 53 ℃ of following heated and stirred 1h, utilize TLC to detect, if finishing, reaction adds 250ml water to there-necked flask.Temperature of reaction is reduced to 0 ℃, after stirring 30min under this temperature, find to have precipitation to generate, filter, and with 100ml and 100ml t-butyl methyl ether repetitive scrubbing filter cake.Collect filter cake, 50 ℃ of following vacuum-dryings, obtain ATAM, 155 ℃ of fusing points.
Add 5.8g solid KOH and 325ml Virahol in round-bottomed flask, 55 ℃ of following heated and stirred dissolvings, add 11.7gD-Xie Ansuan and 11.6ml methyl acetoacetate then successively, stir behind the 10min solution and become faint yellowly, reflux is two hours then.By the Rotary Evaporators vacuum concentration water that generates in the condensation reaction is removed, be concentrated into thickness (cooling becomes solid a little), add the 300ml t-butyl methyl ether this moment, under condition of stirring, slowly be cooled to room temperature, then in refrigerator 5 ℃ leave standstill a night, with the washing of 50ml t-butyl methyl ether.In vacuum drying oven, spend the night under 60 ℃ of oil pump vacuum-dryings, get D-Xie Ansuan dane potassium salts.
Add 12.65gD-Xie Ansuan dane potassium salts and 200ml ethanol in the there-necked flask that thermometer and agitator are housed, stirring is dissolved in the solvent dane potassium salts, and add the 0.5ml N-methylmorpholine and temperature of reaction is reduced to 0 ℃ this moment.When temperature is reduced to MSDS and the 30ml t-butyl methyl ether that adds 5.3ml after 0 ℃, then reaction solution is stirred 30min down at-10 ℃.In reaction system, add the acetoxyl of the 14-O-[(1-amino-2-methyl propyl group of 23.25g-2-yl)] the special woods of order, and stir 60min down at 0 ℃, then temperature is risen to 20 ℃ and stir 30min.Reaction finishes the back and carries out elution with 200ml water, collects water.
In organic phase, add 200ml water, and pH value modulated 3.3 with dilute hydrochloric acid, with reaction solution at 40 ℃ of following strong mixing 2h.Separatory is collected water, and with 150ml butylacetate washed twice to remove acetylacetic ester.Open and stir to add the 200ml butylacetate, and pH value is modulated 10.1 with NaOH solution, the solution layering, the collection organic phase, and with twice of 150ml distilled water elution.
In organic phase, add 150ml distilled water, and the pH value is adjusted to 3.1 with dilute hydrochloric acid, solution layering behind the stirring 5min, collect water, remove the micro-acetic acid butyl ester that contains in the solution 30 ℃ of following vacuum-evaporation, by freeze dried method to valnemulin hydrochloride, molar yield 55%, purity 98.3% (butt meter).
Embodiment 2
In the 250ml there-necked flask that mechanical stirring and thermometer are housed, add 30.1g pleuromutilin and 180ml ethanol, stir and make its dissolving.There-necked flask is placed cryostat,, be cooled to-5 ℃.The NaOH that adds the 40wt% of 15.1g Tosyl chloride and 12ml, stirring reaction 30min.After reaction finishes, solvent is concentrated into dried, obtains the solid substance product.
Mechanical stirring is being housed, is adding sulfonation pleurin, 32g dimethyl Mercaptamine, 3g cetyl trimethylammonium bromide, the NaOH solution of 50ml 10N and the 300ml2-methyl isoamyl ketone of 100g in the 500ml there-necked flask of thermometer and reflux.At 55 ℃ of following heated and stirred 1h, utilize TLC to detect, if dimethyl Mercaptamine immaculate then react end; Reaction finishes the back organic phase and is directly used in the synthetic of valnemulin hydrochloride.
Add 8g solid NaOH and 400ml methyl alcohol in round-bottomed flask, 50 ℃ of following heated and stirred dissolvings, add 23g D-Xie Ansuan and 24ml methyl ethyl diketone then successively, reflux is 1 hour then.After finishing, reaction, obtains solid with the methyl alcohol evaporate to dryness.The solid that reaction is obtained joins in the 1300ml toluene, is heated to 100 ℃, the suspension liquid that obtains is placed down at 4 ℃ spent the night.Filtered in second day, and wash with cold toluene, drying obtains D-Xie Ansuan Deng sodium salt, and this product does not have the fusing point standard.
Add 12.65gD-Xie Ansuan Deng's sodium salt and 200ml ethanol in the there-necked flask that thermometer and agitator are housed, stirring is dissolved in the solvent Deng's salt, and add the 0.5ml N-methylmorpholine and temperature of reaction is reduced to 5 ℃ this moment.When temperature is reduced to MSDS and the 20ml ethanol that adds 5.3ml after 5 ℃, then reaction solution is stirred 60min down at-15 ℃.In reaction system, add the acetoxyl of the 14-O-[(1-amino-2-methyl propyl group of 23.25g-2-yl)] the special woods of order, and stir 2h down at 5 ℃, then temperature is risen to 25 ℃ and stir 60min.Reaction finishes the back and carries out elution with 200ml water, collects water.
In organic phase, add 250ml water, and pH value modulated 3.5 with dilute hydrochloric acid, with reaction solution at 45 ℃ of following strong mixing 1h.Separatory is collected water, and with 150ml butylacetate washed twice to remove acetylacetic ester.Open and stir to add the 150ml butylacetate, and pH value is modulated 10.5 with NaOH solution, the solution layering, the collection organic phase, and with twice of 150ml distilled water elution.
In organic phase, add 180ml distilled water, and the pH value is adjusted to 3.4 with dilute hydrochloric acid, solution layering behind the stirring 5min, collect water, remove the micro-acetic acid butyl ester that contains in the solution 25 ℃ of following vacuum-evaporation, by freeze dried method to valnemulin hydrochloride, molar yield 63%, purity 99.5% (butt meter).
Embodiment 3
Except that making the solvent of butylacetate when preparing ATAM, other are identical with embodiment 2.
The foregoing description just in order further to set forth the present invention, is not done qualification to flesh and blood of the present invention.Any equivalence of doing in flesh and blood of the present invention is replaced or is improved all within protection domain of the present invention.
Claims (8)
1. the synthetic method of a valnemulin hydrochloride is characterized in that may further comprise the steps:
(1) the sulfonation pleurin is synthetic: sulfonation reaction is taken place moles such as pleuromutilin and Tosyl chloride make the sulfonation pleurin;
(2) acetoxyl of 14-O-[(1-amino-2-methyl propyl group-2-yl)] the special woods of order (ATAM) synthetic: with sulfonation pleurin sulfonation pleurin in the step (1) and dimethyl Mercaptamine with 1: the molar ratio reaction of 1-1.5 makes ATAM under catalyzer and alkaline condition;
(3) D-Xie Ansuan Deng salt is synthetic: with mol ratio is that 1: 1: 1 D-Xie Ansuan, amino protecting agent, alkali is that raw material makes D-Xie Ansuan Deng salt;
(4) the valnemulin hydrochloride is synthetic: with the acetoxyl of D-Xie Ansuan Deng salt, N-methylmorpholine, allyl chlorocarbonate (MSDS), 14-O-[(1-amino-2-methyl propyl group-2-yl)] the special woods of order is with mol ratio 1-1.5: 10: 1-1.5: 1-1.5 mixes to generate and mixes acid anhydride, be hydrolyzed after having reacted and remove and deaminize, then organic phase is separated the water intaking phase, obtain the valnemulin hydrochloride with freeze dried method.
2. synthetic method according to claim 1 is characterized in that: the amino protecting agent described in the step (3) is methyl aceto acetate, methyl ethyl diketone or methyl acetoacetate, and described alkali is solid sodium hydroxide or potassium hydroxide.
3. synthetic method according to claim 1, the synthetic method that it is characterized in that the sulfonation pleurin is: pleuromutilin is joined in its quality 4-6 organic solvent doubly, stirring makes its dissolving, add equimolar Tosyl chloride, stirring reaction 15～30min under alkaline condition down at-5～5 ℃ then; After reaction finishes, reaction solution is concentrated into dried, obtains the sulfonation pleurin, molecular formula is C
29H
40O
7S.
4. synthetic method according to claim 1, the synthetic method that it is characterized in that ATAM is: the heterogeneous catalyst of sulfonation pleurin, dimethyl Mercaptamine, 1-3 gram is joined in they quality 1.5-3 ethanol doubly, be stirred to sulfonation pleurin complete reaction under 50～55 ℃, alkaline environment; Reaction finishes the back and adds reaction solution 2-3 quality water doubly, and temperature of reaction is reduced to 0-5 ℃, has been stirred to precipitation and generates under this temperature, precipitates complete after-filtration, and with filter cake washing, obtain ATAM 50～55 ℃ of following vacuum-dryings, molecular formula is C
26H
43NO
4S.
5. synthetic method according to claim 1, the synthetic method that it is characterized in that ATAM is: the heterogeneous catalyst of sulfonation pleurin, dimethyl Mercaptamine, 1-3 gram is joined in they quality 1.5-3 2-methyl isoamyl ketone or butylacetate doubly, be stirred to sulfonation pleurin complete reaction under 50～55 ℃, alkaline environment; Reaction finishes the back organic phase and is directly used in the synthetic of valnemulin hydrochloride.
6. synthetic method according to claim 1 and 2, the synthetic method that it is characterized in that D-Xie Ansuan Deng salt is: add solid alkali and 300-400ml Virahol in the round-bottomed flask of reflux is housed, stir down alkali dissolution at 50～55 ℃, add D-Xie Ansuan and amino protecting agent then successively, be stirred to solution become faint yellow, under this temperature reflux 0.5-2 hour; Reaction finishes the back and with Rotary Evaporators reaction solution is concentrated into thickness, add 250-350ml toluene or t-butyl methyl ether in viscous fluid, slowly be cooled to room temperature under condition of stirring, 0-5 ℃ leaves standstill a night, filtration, washing, 50-60 ℃ vacuum-drying are spent the night, and obtain D-Xie Ansuan Deng salt.
7. synthetic method according to claim 1 and 2, the synthetic method that it is characterized in that D-Xie Ansuan Deng salt is: add solid alkali and 350-450ml methyl alcohol in the round-bottomed flask of reflux is housed, 50～60 ℃ of following heated and stirred dissolvings, add D-Xie Ansuan and amino protecting agent then successively, under this temperature reflux 0.5-1 hour; After finishing, reaction, obtains solid with the methyl alcohol evaporate to dryness; The solid that reaction is obtained joins in the 1200-1400ml toluene, is heated to 90-100 ℃, the suspension liquid that obtains is placed down at 0-5 ℃ spent the night, filter then, with toluene wash, drying, obtain D-Xie Ansuan Deng salt.
8. synthetic method according to claim 1 is characterized in that the synthetic of valnemulin hydrochloride may further comprise the steps:
1) generates mixed acid anhydride
A) add D-Xie Ansuan Deng's salt and 200-250ml ethanol in container, stirring is dissolved in the ethanol Deng's salt;
B) add N-methylmorpholine, cool the temperature to 0-5 ℃, add MSDS and 20-30ml ethanol after the cooling again, then at-10～-15 ℃ of following stirring reaction 0.5-1 hours;
C) in reaction system, add the acetoxyl of 14-O-[(1-amino-2-methyl propyl group-2-yl)] the special woods of order, and at 0-5 ℃ of following stirring reaction 1-2 hour, then temperature is risen to 20-25 ℃ and stirred 0.5-1 hour, reaction is carried out liquid-liquid extraction after finishing, and collects organic phase;
2) hydrolysis and remove amino
A) in organic phase, add the water of its 1-2 times volume, and with dilute hydrochloric acid with pH value modulation 3.0-3.5, reaction solution is stirred 1～2h down at 40-45 ℃, separatory collection water;
B) water is removed acetylacetic ester with the butylacetate washed twice, adds the butylacetate of 1-2 times of volume then, and with NaOH solution with pH value modulation 10.0-10.5, be stirred to the complete layering of solution, collect organic phase, and with twice of distilled water elution;
3) obtain the valnemulin hydrochloride
A) in organic phase, add its volume 1-2 distilled water doubly, and the pH value is adjusted to 3.0-3.5, be stirred to the solution layering, separatory water intaking phase with dilute hydrochloric acid;
B) water is removed the micro-acetic acid butyl ester that contains in the solution 25-30 ℃ of following vacuum-evaporation, obtains the valnemulin hydrochloride by freeze dried method then.
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| CN101880252A (en) * | 2010-06-29 | 2010-11-10 | 金河生物科技股份有限公司 | Preparation method of valnemulin hydrochloride |
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| CN101880252B (en) * | 2010-06-29 | 2013-01-23 | 金河生物科技股份有限公司 | Preparation method of valnemulin hydrochloride |
| CN102675172A (en) * | 2012-04-27 | 2012-09-19 | 宁夏泰瑞制药股份有限公司 | Preparation method of tiamulin base |
| CN102675173A (en) * | 2012-04-28 | 2012-09-19 | 湖北启达药业有限公司 | Chemical synthesis method of valnemulin hydrochloride |
| CN103450060A (en) * | 2012-05-29 | 2013-12-18 | 大英九合生物化工股份有限公司 | Synthesis method of tiamulin |
| CN103450057A (en) * | 2012-05-29 | 2013-12-18 | 大英九合生物化工股份有限公司 | Synthesis method of p-toluene sulfonic acid pleuromutilin ester |
| CN103193692A (en) * | 2013-04-23 | 2013-07-10 | 河北科技大学 | Preparation of valnemulin and hydrochloride of valnemulin |
| CN103382172A (en) * | 2013-06-20 | 2013-11-06 | 中国农业科学院兰州畜牧与兽药研究所 | Synthesis method for valnemulin hydrochloride |
| CN103483232A (en) * | 2013-09-25 | 2014-01-01 | 宁夏泰瑞制药股份有限公司 | Refining method of valnemulin hydrochloride |
| CN103483232B (en) * | 2013-09-25 | 2015-05-13 | 宁夏泰瑞制药股份有限公司 | Refining method of valnemulin hydrochloride |
| CN104230851A (en) * | 2014-09-10 | 2014-12-24 | 宁夏泰瑞制药股份有限公司 | Method for recovering N-methylmorpholine from valnemulin hydrochloride synthesis wastewater |
| CN104311464A (en) * | 2014-09-15 | 2015-01-28 | 河北威远动物药业有限公司 | Preparation method of veterinary valnemulin |
| CN106432017A (en) * | 2016-08-31 | 2017-02-22 | 河北远征药业有限公司 | Synthesis method of valnemulin hydrochloride |
| CN108892629A (en) * | 2018-06-22 | 2018-11-27 | 湖北龙翔药业科技股份有限公司 | Valnemulin hydrochloride t-butyl methyl ether solvated compounds and preparation method thereof |
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