CN102875432B - Preparation method of high-yield tiamulinfumarate - Google Patents
Preparation method of high-yield tiamulinfumarate Download PDFInfo
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Abstract
The invention relates to a preparation method of high-yield tiamulinfumarate. The method comprises the following steps of: adding paratoluensulfonyl chloride which is 1.1-1.3 times the molar mass of truncated pleurotin ketone extract into the truncated pleurotin ketone extract; performing sulfonation reaction under a stirring state at the pH (Potential of Hydrogen) of 9-10; washing with pure water; adding quaternary ammonium salt in an amount which is 1-2 times of the molar mass of a sulfonation product and diethylaminoethylmercaptide in an amount which is 1.3-1.4 times the molar mass of the sulfonation product into the sulfonation product in sequence; performing amination reaction under the conditions of pH of 9-10 and temperature of 50-60 DEG C; adding water to extract; removing water phase; performing membrane filtration on ketone phase; performing vacuum concentration until the volume is 60-70 percent of the original volume; and adding methanol and fumaric acid to perform salt forming reaction to obtain the tiamulinfumarate. According to the process, the product yield is increased on the premise of guaranteeing product quality, so that the final product quality yield reaches 115-120 percent. The use of the diethylaminoethylmercaptide is reduced in a production process, the production cost is reduced, and preparation method has certain development prospect.
Description
Technical field
The invention belongs to bio-pharmaceuticals synthesis technical field, particularly relate to a kind of preparation method of high yield fumaric acid tiamulin.
Background technology
Fumaric acid tiamulin (Tiamulin fumarate) is to produce after pleuromutilin by fermentation, then pass through semi-synthetic, a kind of diterpenoids (pluromulin) microbiotic of the final preparation of salify.It is by suppressing the synthetic bacteriostatic action that plays of microorganism rrna interoceptive protein.This product has germicidal action under high density, and in the environment of pH8.5 ~ 9.0, germicidal action is the strongest.Tiamulin is the pleuromulins microbiotic of first animal specific, in the prospect that has a very wide range of applications aspect veterinary drug industry and livestock and poultry disease control and prevention.
The production technique of fumaric acid tiamulin is first to adopt pick up the ears bacterium fermentation of the bacterium of picking up the ears (Pleurotus mutilus) or Pa Shi to obtain pleuromutilin fermented liquid, from fermented liquid, extract pleuromutilin, take pleuromutilin as raw material is through sulfonation reaction, amination reaction again, and last salify obtains fumaric acid Yanhusuo Tiamulin.Most pharmacy corporations all adopt this technique to prepare fumaric acid tiamulin, but this technique is because synthesis step is more, and rear operation is processed loaded down with trivial details, causes product yield lower.The yield of domestic and international most of pharmacy corporation fumaric acid tiamulins is greatly about 110% left and right at present.
Summary of the invention
The object of the invention is to overcome the defect of above-mentioned prior art, provide a kind of building-up process to fumaric acid tiamulin to be optimized, determine the optimum charging ratio of building-up process, guaranteeing, under the prerequisite of quality product, to improve the preparation method of the high yield fumaric acid tiamulin of product yield.
The technical scheme taked is for achieving the above object as follows:
A kind of preparation method of high yield fumaric acid tiamulin, it is characterized in that its processing step is: first to the 1.1-1.3 that adds its molar mass in pleuromutilin ketone extraction liquid Tosyl chloride doubly, at pH9-10, under whipped state, carry out sulfonation reaction, with after pure water washing, in this sulfonated products, add its molar mass 1-2 quaternary ammonium salt and its molar mass 1.3-1.4 diethylin sulfur alcohol doubly doubly successively, at pH9-10, under 50-60 ℃ of condition, carry out amination reaction, after add water extraction, aqueous phase discarded, ketone is after membrane filtration, vacuum concentration is to the 60-70% of original volume, finally add methyl alcohol and fumaric acid to carry out obtaining fumaric acid tiamulin after salt-forming reaction.
Before sulfonation reaction, first pleuromutilin ketone extraction liquid uses membrane filtration, then under whipped state with the speed of 5 ℃/h by solution slow cooling to 15-20 ℃.
Above-mentioned membrane filtration adopts 0.2 μ m filter membrane.
Above-mentioned sulfonation reaction 30-40 minute.
Above-mentionedly with pure water washing, refer to the pure water washing of 5-6 times of volume 2 times.
Above-mentioned amination reaction 1 hour.
Above-mentionedly add water extraction and refer to the water extraction that adds 4-5 times of volume.
It is above-mentioned that to add methyl alcohol and fumaric acid to carry out salt-forming reaction be to point to 90%-95% methanol solution and the concentrated solution quality 1.2-1.5 fumaric acid doubly that adds 4-5 times of volume in concentrated solution, under agitation crystallization, and crystallization control temperature is at 0-5 ℃.
Compared with prior art, beneficial effect of the present invention is as follows:
1, improved reaction yield: the present invention has changed the feed ratio of sulfonation reaction and amination reaction, by optimizing reaction ratio, determined optimum charging ratio example, made the mass yield of final fumaric acid tiamulin reach 115%-120%.Compare with most pharmaceutical factory existing technique, in stabilized product quality, make reaction yield improve 5%-15%, thereby increased certain output value.
2, in production process, reduce the use of diethylin sulfur alcohol, extracted and extract the methyl alcohol and the ketone that adopt and all can recycle, reduced the harm to environment.
3, reduced production cost: by change, react feed ratio, reduced the usage quantity of raw material and diethylin sulfur alcohol, make production cost reduce 15-20 unit/kg.
In sum, the invention solves the low problem of product yield in existing production, guaranteeing, under the prerequisite of quality product, to have improved product yield, make end product quality yield reach 115%-120%.. in production process, reduce the use of diethylin sulfur alcohol, reduced production cost, there is certain development prospect.
Embodiment
With example, be explained the present invention below, 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.
Following pleuromutilin ketone extraction liquid is
by higher fungi basidiomycetes pleurotus
pleurotus mutilusthrough excellent kind of seed selection, three grade fermemtation, make pleuromutilin fermented liquid,
fermented liquid after pretreatment, filters to obtain the dry mycelia of pleuromutilin, then uses acetone extraction, obtains pleuromutilin ketone extraction liquid.
Embodiment 1
1, sulfonation reaction
Get pleuromutilin ketone extraction liquid, after 0.2 μ m membrane filtration, under the state stirring with the speed of 5 ℃/h by solution slow cooling to 15 ℃.To the Tosyl chloride that adds 1.1 times of molar masss in solution, inwardly add 40% NaOH solution simultaneously, make its pH be controlled at 9.0.Fully stir after 30 minutes, solution is washed 2 times with the pure water of 5-6 times of volume.
2, amination reaction
To ketone, add successively quaternary ammonium salt and diethylin sulfur alcohol in mutually, the molar mass that adds quaternary ammonium salt is 1 times of sulfonated products molar mass, adds the molar mass of diethylin sulfur alcohol to be 1.3 times for sulfonated products.The NaOH solution that adds 2 times 40% of liquor capacity, controls pH and is 9.0, temperature of reaction is 50 ℃, fully reacts 1h.After reacting completely, add the water extraction of 4 times of volumes, aqueous phase discarded, ketone is after 0.2 μ m membrane filtration, and vacuum concentration is to 60% of original volume.
3, salt-forming reaction
To the methanol solution that adds 4 times of volumes in concentrated solution, add the fumaric acid of 1.2 times of concentrated solution quality, under agitation crystallization, crystallization control temperature is at 5 ℃.
Final fumaric acid tiamulin mass yield is 116.1%.
Embodiment 2
1, sulfonation reaction
Get pleuromutilin ketone extraction liquid, after 0.2 μ m membrane filtration, under the state stirring with the speed of 5 ℃/h by solution slow cooling to 17 ℃.To the Tosyl chloride that adds 1.2 times of molar masss in solution, inwardly add 40% NaOH solution simultaneously, make its pH be controlled at 9.5.Fully stirring reaction, after 35 minutes, washs solution 2 times with the pure water of 5 times of volumes.
2, amination reaction
To ketone, add successively quaternary ammonium salt and diethylin sulfur alcohol in mutually, the molar mass that adds quaternary ammonium salt is 1.5 times of sulfonated products molar mass, adds the molar mass of diethylin sulfur alcohol to be 1.35 times for sulfonated products.The NaOH solution that adds 2.5 times 40% of liquor capacity, control pH9.5, temperature of reaction are 55 ℃, fully react 1h.After reacting completely, add the water extraction of 4.5 times of volumes, aqueous phase discarded, ketone is after 0.2 μ m membrane filtration, and vacuum concentration is to 65% of original volume.
3, salt-forming reaction
To the methanol solution that adds 4.5 times of volumes in concentrated solution, add the fumaric acid of 1.35 times of concentrated solution quality, under agitation crystallization, crystallization control temperature is at 5 ℃.
Final fumaric acid tiamulin mass yield is 120.8%.
Embodiment 3
1, sulfonation reaction
Get pleuromutilin ketone extraction liquid, after 0.2 μ m membrane filtration, under the state stirring with the speed of 5 ℃/h by solution slow cooling to 20 ℃.To the Tosyl chloride that adds 1.3 times of molar masss in solution, inwardly add 40% NaOH solution simultaneously, make its pH be controlled at 10.0.Fully stir after 40 minutes, solution is washed 2 times with the pure water of 6 times of volumes.
2, amination reaction
To ketone, add successively quaternary ammonium salt and diethylin sulfur alcohol in mutually, the molar mass that adds quaternary ammonium salt is 2 times of sulfonated products molar mass, adds the molar mass of diethylin sulfur alcohol to be 1.5 times for sulfonated products.The NaOH solution that adds 3 times 40% of liquor capacity, control pH10.0, temperature of reaction are 60 ℃, fully react 1h.After reacting completely, add the water extraction of 5 times of volumes, aqueous phase discarded, ketone is after 0.2 μ m membrane filtration, and vacuum concentration is to 70% of original volume.
3, salt-forming reaction
To the methanol solution that adds 5 times of volumes in concentrated solution, add the fumaric acid of 1.5 times of concentrated solution quality, under agitation crystallization, crystallization control temperature is at 5 ℃.
Final fumaric acid tiamulin mass yield is 119.3%.
Claims (3)
1. the preparation method of a high yield fumaric acid tiamulin, it is characterized in that its processing step is: first pleuromutilin ketone extraction liquid is used to membrane filtration, then under whipped state with the speed of 5 ℃/h by solution slow cooling to 15-20 ℃, then to the 1.1-1.3 that adds its mole number in pleuromutilin ketone extraction liquid Tosyl chloride doubly, at pH9-10, under whipped state, carry out sulfonation reaction 30-40 minute, with after pure water washing, in this sulfonated products, add its mole number 1-2 quaternary ammonium salt and its mole number 1.3-1.4 diethylin sulfur alcohol doubly doubly successively, at pH9-10, under 50-60 ℃ of condition, carry out amination reaction 1 hour, after add the water extraction of its 4-5 times volume, aqueous phase discarded, ketone is after membrane filtration, vacuum concentration is to the 60-70% of original volume, the 90%-95% methanol solution and the concentrated solution quality 1.2-1.5 fumaric acid doubly that in the most backward concentrated solution, add 4-5 times of volume, under agitation crystallization obtains fumaric acid tiamulin, crystallization control temperature is at 0-5 ℃.
2. according to the preparation method of high yield fumaric acid tiamulin claimed in claim 1, it is characterized in that: above-mentioned membrane filtration adopts 0.2 μ m filter membrane.
3. according to the preparation method of high yield fumaric acid tiamulin claimed in claim 1, it is characterized in that: above-mentionedly with pure water washing, refer to the pure water washing of 5-6 times of volume 2 times.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103274976A (en) * | 2013-06-28 | 2013-09-04 | 宁夏泰瑞制药股份有限公司 | Refining method of tiamulin fumarate |
| CN109384698B (en) * | 2017-08-04 | 2022-07-08 | 保定加合精细化工有限公司 | Preparation method of diterpene antibiotic for livestock and poultry |
| CN113735747B (en) * | 2020-05-29 | 2024-07-02 | 新疆上昵生物科技有限公司 | Method for producing tiamulin by diethylaminoethanethiol synthetic solution |
| CN114075110B (en) * | 2020-08-20 | 2023-10-27 | 新疆上昵生物科技有限公司 | Modification method of pleuromutilin and application of pleuromutilin in preparation of tiamulin |
Citations (4)
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|---|---|---|---|---|
| US3919290A (en) * | 1972-10-03 | 1975-11-11 | Sandoz Ltd | Substituted 14-desoxy-mutilins |
| US4086359A (en) * | 1975-09-30 | 1978-04-25 | E. R. Squibb & Sons, Inc. | Derivatives of pleuromutilin and compositions |
| IE46917B1 (en) * | 1978-06-01 | 1983-11-02 | Sandoz Ltd | Process for the production of pleuromutilin derivatives |
| 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 |
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2012
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3919290A (en) * | 1972-10-03 | 1975-11-11 | Sandoz Ltd | Substituted 14-desoxy-mutilins |
| US4086359A (en) * | 1975-09-30 | 1978-04-25 | E. R. Squibb & Sons, Inc. | Derivatives of pleuromutilin and compositions |
| IE46917B1 (en) * | 1978-06-01 | 1983-11-02 | Sandoz Ltd | Process for the production of pleuromutilin derivatives |
| 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 |
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| Title |
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| DOROTA KRASUCKA等.TIAMULIN HYDROGEN FUMARATE & * |
| DOROTA KRASUCKA等.TIAMULIN HYDROGEN FUMARATE ñ |
| Drug Research》.2010,第67卷(第6期),第682-685页. * |
| ntilde * |
| VETERINARY USES AND HPLC METHOD OF DETERMINATION IN PREMIXES AND MEDICATED FEEDING STUFFS.《Acta Poloniae Pharmaceutica & * |
| VETERINARY USES AND HPLC METHOD OF DETERMINATION IN PREMIXES AND MEDICATED FEEDING STUFFS.《Acta Poloniae Pharmaceutica ñ |
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