CN108892629A - Valnemulin hydrochloride t-butyl methyl ether solvated compounds and preparation method thereof - Google Patents
Valnemulin hydrochloride t-butyl methyl ether solvated compounds and preparation method thereof Download PDFInfo
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- CN108892629A CN108892629A CN201810648345.6A CN201810648345A CN108892629A CN 108892629 A CN108892629 A CN 108892629A CN 201810648345 A CN201810648345 A CN 201810648345A CN 108892629 A CN108892629 A CN 108892629A
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- methyl ether
- valnemulin hydrochloride
- butyl methyl
- solvated compounds
- valnemulin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
- C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
- C07C2603/82—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings having three condensed rings with in total fourteen carbon atoms and having a having a [5.4.3.0(1,8)] ring structure, e.g. pleuromutiline
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Abstract
The present invention relates to a kind of valnemulin hydrochloride t-butyl methyl ether solvated compounds and preparation method thereof.Its TGA thermogravimetric analysis figure spectrum shows the weightlessness for having 6.5%~7.2% before degrading, is 1 with valnemulin hydrochloride in valnemulin hydrochloride t-butyl methyl ether solvated compounds and t-butyl methyl ether molecular ratios：0.5, theoretical percent weight loss matches for 6.8%.The solvent-free compound of valnemulin hydrochloride can be prepared after valnemulin hydrochloride t-butyl methyl ether solvated compounds are removed solvent, resulting valnemulin hydrochloride improves purity and heap density compared with amorphous products in the market, reduces powder penetrating odor.
Description
Technical field
The invention belongs to veterinary antibiotic preparation technical fields, and in particular to valnemulin hydrochloride t-butyl methyl ether solvation
Close object and preparation method thereof.
Background technique
Valnemulin hydrochloride, molecular formula C31H52N2O5SHCl, molecular weight 601.29 are animal specific antibiotic.
Swine dysentery and mycoplasma pneumoniae sense caused by being infected by European Community's approval for prevention and treatment Brachyspira hyodysenteriae for 1999
Porcine enzootic pneumonia caused by contaminating.Thereafter Novartis of Switzerland (Norvatis) company is made into pre-mixing agent and lists in Europe, is the
The veterinary drug pre-mixing agent of one all Europe approval.It is the new beast of two classes that the Ministry of Agriculture of China in 2009, which has approved valnemulin hydrochloride,
Medicine, for preventing and treating the mycoplasma infection of pig.
Most of the product that document about valnemulin hydrochloride synthesis obtains is unformed, although stability is better than trip
The valnemulin of amorph, but since valnemulin hydrochloride exists with amorphous forms, causes its hygroscopicity especially strong, to temperature with
Illumination is more sensitive, easily decompose with contacts such as feeds, smell it is larger.And the granularity of valnemulin hydrochloride amorphous products
Small, mobility is bad, powder irritation is strong and easily disperses.
Patent CN102225906A provides a kind of valnemulin hydrochloride reverse phase Crystallization method, and being first dissolved in valnemulin has
In solvent, then be passed through dry hydrogen chloride gas or hydrogen chloride organic solution is reacted, the valnemulin hydrochloride of generation from
It is precipitated in organic solvent, gained valnemulin hydrochloride content improves 1~5% than corresponding valnemulin, but hydrochloric acid irrigates Buddhist nun
Wonderful woods is still unstable easy to moisture absorption.
The patent CN104876841A for being related to crystal state valnemulin hydrochloride reports a kind of cooling-ultrasound crystallization and prepares salt
The method of sour valnemulin, what is obtained is a kind of new valnemulin hydrochloride Crystalline Compound, but because equipment limit is difficult to advise
Modelling production.
Summary of the invention
The purpose of the present invention is to provide a kind of valnemulin hydrochloride t-butyl methyl ether solvated compounds and the solvations
Close the preparation method of object.
It is a further object to provide the purposes of valnemulin hydrochloride t-butyl methyl ether solvated compounds, can make
It is standby at purity is high, good fluidity, without the solvent-free compound of the irritating valnemulin hydrochloride of powder, solve unformed hydrochloric acid and irrigate
The disadvantages of stability existing for the wonderful woods of Buddhist nun is poor, easy to moisture absorption.
Valnemulin hydrochloride t-butyl methyl ether solvated compounds of the present invention, wherein valnemulin hydrochloride and tert-butyl
The molar ratio of methyl ether molecule is 1:0.5, molecular formula C31H52N2O5S·HCl·0.5C5H12O, before TGA test degradation
There is 6.5%~7.2% weightlessness.
The preparation method of valnemulin hydrochloride t-butyl methyl ether solvated compounds of the invention is to add valnemulin hydrochloride
Enter into t-butyl methyl ether, stirring be warming up to certain temperature after keep the temperature, then with the rate of 0.5 DEG C~5 DEG C/min be cooled to 0 DEG C~
20 DEG C, filtering is dried to obtain valnemulin hydrochloride t-butyl methyl ether solvated compounds.
Valnemulin hydrochloride and the mass ratio of t-butyl methyl ether are 1：5~1：15.
Holding temperature is 40 DEG C~55 DEG C, and soaking time is 1~3 hour.
It is wonderful that valnemulin hydrochloride t-butyl methyl ether solvated compounds of the invention are used to prepare the fertile Buddhist nun of not solvent-laden hydrochloric acid
Woods.Preparation method is by valnemulin hydrochloride t-butyl methyl ether solvated compounds at 70 DEG C~100 DEG C, 0.05MPa~0.09MPa
It is 3~6 hours dry under vacuum condition, obtain the solvent-free compound of valnemulin hydrochloride.
Valnemulin hydrochloride t-butyl methyl ether solvated compounds of the present invention are placed 30 days at 55 DEG C, and thermogravimetric is bent
Significant change does not occur for line, illustrates that valnemulin hydrochloride t-butyl methyl ether solvated compounds are more stable.
Beneficial effects of the present invention：In the art, t-butyl methyl ether is in purification hydrochloric acid valnemulin salt technique
Common solvent, but t-butyl methyl ether is in the subtractive process in later period by being dried under reduced pressure, filtering, crystallizing in above-mentioned technique
Etc. series of process removed, be in obtained product do not include have t-butyl methyl ether solvent.And in the application
Provided is a kind of valnemulin hydrochloride t-butyl methyl ether solvated compounds, is currently no relevant report.And it will
The solvent-free compound of valnemulin hydrochloride, institute can be prepared after valnemulin hydrochloride t-butyl methyl ether solvated compounds removing solvent
The valnemulin hydrochloride t-butyl methyl ether solvated compounds obtained improve product stability compared with amorphous products in the market
With moisture resistance, purity and heap density are improved, reduces powder penetrating odor, domestic pig is taken more agreeable to the taste.
Detailed description of the invention
Fig. 1 is the thermogravimetric analysis map of the valnemulin hydrochloride t-butyl methyl ether solvated compounds prepared in embodiment 1.
Fig. 2 is the thermogravimetric analysis map of the solvent-free compound of valnemulin hydrochloride prepared in embodiment 1.
Specific embodiment
Detailed specific description is done to the present invention combined with specific embodiments below, the present embodiment is served only for illustrating this technique,
Protection scope of the present invention is not limited to following embodiment.
Embodiment 1
The preparation of valnemulin hydrochloride t-butyl methyl ether solvated compounds
The unformed valnemulin hydrochloride of 12g that purity is 95% is added in 60g t-butyl methyl ether, stirring is warming up to 55
DEG C, 20 DEG C are cooled to the rate of 1.5 DEG C/min after heat preservation 1 hour, filters, be dried to obtain the tertiary fourth of 11.8g valnemulin hydrochloride
Base methyl ether solvated compounds, yield 91.5%.
TGA thermogravimetric analysis is carried out to valnemulin hydrochloride t-butyl methyl ether solvated compounds, protective gas is nitrogen, heating
Rate is 10 DEG C/min, and analysis result is as shown in Fig. 1, and the temperature range of weight loss on heating is 100 DEG C~153 DEG C, and desolventizing loses
Weight percentage is valnemulin hydrochloride and t-butyl methyl ether in 6.5%, with valnemulin hydrochloride t-butyl methyl ether solvated compounds
Molecular ratios are 1：0.5, theoretical percent weight loss is 6.8% relatively identical, and what is illustrated is valnemulin hydrochloride tert-butyl first
Ether solvents compound.
The preparation of solvent-free valnemulin hydrochloride
Valnemulin hydrochloride t-butyl methyl ether solvated compounds in 10g embodiment 1 are taken, are placed in 70 DEG C of vacuum ovens, very
Reciprocal of duty cycle is maintained at 0.09MPa or so, obtains within dry 6 hours 9.25g solid, and TGA thermogravimetric analysis is done in sampling, analyzes result such as attached drawing
Shown in 2, sample, almost complete absence of weightlessness, illustrates that valnemulin hydrochloride t-butyl methyl ether solvated compounds are complete before degradation
It is converted to the solvent-free compound of valnemulin hydrochloride entirely.
The solvent-free compound purity of valnemulin hydrochloride is 98.6%, does not have powder penetrating odor, and heap density is 0.3g/
Ml, originally valnemulin hydrochloride heap density are 0.095g/ml.
Embodiment 2
The preparation of valnemulin hydrochloride t-butyl methyl ether solvated compounds
The unformed valnemulin hydrochloride of 12g that purity is 95% is added in 120g t-butyl methyl ether, stirring is warming up to
20 DEG C are cooled to the rate of 1 DEG C/min after 50 DEG C, heat preservation 1.5 hours, filters, be dried to obtain 12.1g valnemulin hydrochloride uncle
Butyl methyl ether solvated compounds, yield 93.8%.Its TGA weight-loss curve is similar to attached drawing 1, percent weight loss 7.0%.
The preparation of solvent-free valnemulin hydrochloride
Valnemulin hydrochloride t-butyl methyl ether solvated compounds in 10g embodiment 2 are taken, are placed in 80 DEG C of vacuum ovens, very
Reciprocal of duty cycle is maintained at 0.09MPa or so, dries and obtains within 5 hours 9.2g solid, sampling analysis, and TGA weight-loss curve is similar to attached drawing 2.
Sample purity is 98.8%, does not have powder penetrating odor, and heap density is 0.31g/ml.
Embodiment 3
The preparation of valnemulin hydrochloride t-butyl methyl ether solvated compounds
The unformed valnemulin hydrochloride of 12g that purity is 95% is added in 180g t-butyl methyl ether, stirring is warming up to
20 DEG C are cooled to the rate of 0.5 DEG C/min after 45 DEG C, heat preservation 2 hours, filters, be dried to obtain 12.3g valnemulin hydrochloride uncle
Butyl methyl ether solvated compounds, yield 95.3%.Its TGA weight-loss curve is similar to attached drawing 1, percent weight loss 7.2%.
The preparation of solvent-free valnemulin hydrochloride
Valnemulin hydrochloride t-butyl methyl ether solvated compounds in 10g embodiment 3 are taken, are placed in 90 DEG C of vacuum ovens, very
Reciprocal of duty cycle is maintained at 0.09MPa or so, dries and obtains within 4 hours 9.17g solid, sampling analysis, and TGA weight-loss curve is similar to attached drawing 2.
Sample purity is 98.5%, does not have powder penetrating odor, and heap density is 0.305g/ml.
Claims (7)
1. a kind of valnemulin hydrochloride t-butyl methyl ether solvated compounds, it is characterised in that：The valnemulin hydrochloride and tertiary fourth
The molar ratio of base methyl ether molecule is 1:0.5, molecular formula C31H52N2O5S·HCl·0.5C5H12O, valnemulin hydrochloride tert-butyl
There is 6.5%~7.2% weightlessness in methyl ether solvated compounds thermogravimetric analysis before 150 DEG C.
2. the preparation method of valnemulin hydrochloride t-butyl methyl ether solvated compounds described in claim 1, it is characterised in that：Salt
Sour valnemulin is added in t-butyl methyl ether, and solution is stirred and heated, and is cooled down after heat preservation with the rate of 0.5 DEG C~5 DEG C/min
To 0 DEG C~20 DEG C, filtering is dried to obtain valnemulin hydrochloride t-butyl methyl ether solvated compounds.
3. preparation method according to claim 2, it is characterised in that：The mass ratio of valnemulin hydrochloride and t-butyl methyl ether
It is 1：5~1：15.
4. preparation method according to claim 2, it is characterised in that：Holding temperature is 40 DEG C~55 DEG C, soaking time 1
~3 hours.
5. valnemulin hydrochloride t-butyl methyl ether solvated compounds are preparing the purposes in the solvent-free compound of valnemulin hydrochloride.
6. purposes according to claim 5, it is characterised in that：The method for preparing the solvent-free compound of valnemulin hydrochloride is：
Valnemulin hydrochloride t-butyl methyl ether solvated compounds are done under 70 DEG C~100 DEG C, 0.05MPa~0.09MPa vacuum condition
It is dry, obtain the solvent-free compound of valnemulin hydrochloride.
7. purposes according to claim 6, it is characterised in that：Vacuum drying time is 3~6 hours.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810648345.6A CN108892629A (en) | 2018-06-22 | 2018-06-22 | Valnemulin hydrochloride t-butyl methyl ether solvated compounds and preparation method thereof |
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| CN201810648345.6A CN108892629A (en) | 2018-06-22 | 2018-06-22 | Valnemulin hydrochloride t-butyl methyl ether solvated compounds and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110179758A (en) * | 2019-06-23 | 2019-08-30 | 瑞普（天津）生物药业有限公司 | It is a kind of can drinking water administration crystal state valnemulin hydrochloride soluble powder and its application |
| CN110179757A (en) * | 2019-06-23 | 2019-08-30 | 瑞普（天津）生物药业有限公司 | A kind of soluble powder of crystal state valnemulin hydrochloride and its application |
| WO2020258660A1 (en) | 2019-06-23 | 2020-12-30 | 天津瑞普生物技术股份有限公司 | Crystal form of valnemulin hydrochloride hydrate, preparation method therefor, and pharmaceutical composition containing crystal form |
Citations (3)
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| CN101735123A (en) * | 2009-12-22 | 2010-06-16 | 山东胜利股份有限公司 | Method for synthesizing valnemulin hydrochloride |
| 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 |
| CN107805226A (en) * | 2017-11-23 | 2018-03-16 | 湖北龙翔药业科技股份有限公司 | A kind of valnemulin o-benzoic sulfimide compound and preparation method thereof |
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2018
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Patent Citations (3)
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| CN101735123A (en) * | 2009-12-22 | 2010-06-16 | 山东胜利股份有限公司 | Method for synthesizing valnemulin hydrochloride |
| 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 |
| CN107805226A (en) * | 2017-11-23 | 2018-03-16 | 湖北龙翔药业科技股份有限公司 | A kind of valnemulin o-benzoic sulfimide compound and preparation method thereof |
Non-Patent Citations (1)
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| JINBO OUYANG 等: "Crystal structures and phase transformation of two novel solvates of valnemulin hydrochloride", 《CRYSTENGCOMM》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110179758A (en) * | 2019-06-23 | 2019-08-30 | 瑞普（天津）生物药业有限公司 | It is a kind of can drinking water administration crystal state valnemulin hydrochloride soluble powder and its application |
| CN110179757A (en) * | 2019-06-23 | 2019-08-30 | 瑞普（天津）生物药业有限公司 | A kind of soluble powder of crystal state valnemulin hydrochloride and its application |
| WO2020258660A1 (en) | 2019-06-23 | 2020-12-30 | 天津瑞普生物技术股份有限公司 | Crystal form of valnemulin hydrochloride hydrate, preparation method therefor, and pharmaceutical composition containing crystal form |
| CN110179758B (en) * | 2019-06-23 | 2021-06-22 | 瑞普（天津）生物药业有限公司 | Crystalline valnemulin hydrochloride soluble powder capable of being administered by drinking water and application thereof |
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