CN102180818A - Preparation method of fumaric acid valnemulin - Google Patents
Preparation method of fumaric acid valnemulin Download PDFInfo
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- CN102180818A CN102180818A CN2011100569127A CN201110056912A CN102180818A CN 102180818 A CN102180818 A CN 102180818A CN 2011100569127 A CN2011100569127 A CN 2011100569127A CN 201110056912 A CN201110056912 A CN 201110056912A CN 102180818 A CN102180818 A CN 102180818A
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- Prior art keywords
- valnemulin
- fumaric acid
- preparation
- mibk
- add
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- LLYYNOVSVPBRGV-MVNKZKPCSA-N valnemulin Chemical compound CC(C)[C@@H](N)C(=O)NCC(C)(C)SCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 LLYYNOVSVPBRGV-MVNKZKPCSA-N 0.000 title claims abstract description 41
- 229950008166 valnemulin Drugs 0.000 title claims abstract description 39
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000001530 fumaric acid Substances 0.000 title claims abstract description 15
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 15
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims abstract description 26
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims abstract description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 8
- 238000005406 washing Methods 0.000 claims abstract description 7
- 239000013078 crystal Substances 0.000 claims abstract description 4
- 239000012065 filter cake Substances 0.000 claims abstract description 3
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 24
- 150000001735 carboxylic acids Chemical class 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000013019 agitation Methods 0.000 claims description 4
- 238000005352 clarification Methods 0.000 claims description 4
- 238000009413 insulation Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 2
- 230000002035 prolonged effect Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 238000002844 melting Methods 0.000 abstract 1
- 230000008018 melting Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 6
- 239000003814 drug Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 241000282898 Sus scrofa Species 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 244000000010 microbial pathogen Species 0.000 description 3
- 235000019629 palatability Nutrition 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- -1 carboxylate salt Chemical class 0.000 description 2
- 208000001848 dysentery Diseases 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- UURAUHCOJAIIRQ-QGLSALSOSA-N tiamulin Chemical compound CCN(CC)CCSCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 UURAUHCOJAIIRQ-QGLSALSOSA-N 0.000 description 2
- 229960004885 tiamulin Drugs 0.000 description 2
- 239000000273 veterinary drug Substances 0.000 description 2
- 102000003916 Arrestin Human genes 0.000 description 1
- 108090000328 Arrestin Proteins 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 208000001572 Mycoplasma Pneumonia Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108090000279 Peptidyltransferases Proteins 0.000 description 1
- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000589973 Spirochaeta Species 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical compound C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000004804 winding Methods 0.000 description 1
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- Fodder In General (AREA)
Abstract
The invention relates to a preparation method of fumaric acid valnemulin. The preparation method comprises the following steps: firstly adding valnemulin in a methyl isobutyl ketone solution, then heating and stirring; after dissolving, adding absolute ethanol, adding fumaric acid until a reaction solution is clear; reducing the temperature with ice bath so as to separate out crystal; filtering, and washing filter cake with methyl isobutyl ketone; and drying so as to obtain the fumaric acid valnemulin, wherein the melting point of the fumaric acid valnemulin is larger than 130 DEG C, and the yield of the fumaric acid valnemulin reaches 85%.
Description
Technical field
The present invention relates to the preparation method of drug chemical, specifically, is a kind of preparation method of fumaric acid valnemulin.
Background technology
Valnemulin is a pleuromulins semisynthetic antibiotics of new generation, belongs to two terpenes, is the animal specific microbiotic.1984 at first utilize pleuromutilin by the Berner H of Sandoz company etc. is that raw material is synthetic.Thereafter, as pre-mixture, commodity are called Econor with it in Norvatis company, now in the listing of a plurality of countries.Valnemulin is mainly used in mycoplasmosis and the gram positive bacteria infection of control pig, ox, sheep and poultry.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 Community approval in 1999.It is the veterinary drug pre-mixture of first all Europe approval, is listed in prescription drugs for animals.
The antibiotic mechanism of valnemulin is similar to Tiamulin, promptly combines arrestin matter synthetic with 50S subunit on the pathogenic micro-organism rrna.Promptly interact, stoped peptidyl transferase correctly to be positioned the CCA-end of t RNA, thereby it is proteinic synthetic to have suppressed pathogenic micro-organism, causes its death by v district with pathogenic micro-organism rrna 23S RNA.
When valnemulin exists with water miscible hydrochloride form, can at an easy rate it be added in the tap water.Yet true the proof is difficult to these microbiotic are applied to the animal that need treat by feed, because the composition in the feed can make it inactivation with its active destruction very soon.When producing the mixture of feed and medicine, must obtain package stability to a certain degree, otherwise can't reach the exact dosage desired of medication.
In producing the granulated feed process, valnemulin is a rather unstable, particularly when contacting the composition of feedstuff raw material, especially plant or animal-origin, will cause its heavy losses in the preparatory stage.In the granulated feed production process, the dry organic raw material in animal or plant source mixes closely with mixture, VITAMIN, trace element and other additives, to reach state extremely uniformly, optionally moistening then, make its water that contains 5% to 10% weight, press down at 60 ℃ to 100 ℃ soaking condition at last and shorten granulated feed into.Of short duration in the compression process, local temperature peak even can reach 200 ℃, this temperature can cause valnemulin part loss of activity.
Contacting of other compositions can cause 1/4th to 1/3rd activeconstituents in valnemulin and the feed, and promptly valnemulin is lost.The composition that loses activity causes animal-use drug dosage inaccurate without doubt, thus cause treating can be successful problem, and the expense that rolls up the finished product.
The fact shows that the valnemulin package stability that exists with monomer in the particle is significantly less than the stability that exists with drying or amorphous hydrochloride form.Even wrecking of also can continuing of the effective constituent in the particle at room temperature.Only after 3 months, this active component content drops to below 60 %.This relative instability has caused this fact: the activeconstituents of granulated feed only can keep its accurate dosage in 3 months.Therefore, the animal rearing people is forced to use the feed of fresh relatively production.
People have made a large amount of effort, to improve the representation compound of valnemulin and other Tiamulin classes, make them can bear the temperature and pressure that constantly raises in the particle manufacture process, and loss of activity material not, and have secular actual package stability.
We have successfully prepared the carboxylate salt application form recklessly that prolongs of valnemulin, and this form has the advantage of desirable stability and palatability, and can realize cheap production.We have prepared the carboxylate salt recklessly that prolongs of valnemulin in the present invention, because its stability increases considerably.In addition, be easier to be accepted during the crystal salt oral administration by animal.For veterinary drug, the palatability of oral way may be the important factor for the treatment of successfully or failing.Therefore, produce that to improve the palatability application form also be a target of the present invention.
Carboxylic acid reaction solves this problem to form hydrochlorate with prolonging recklessly with valnemulin in the present invention, and has obtained stem-winding high crystalline and package stability.
Summary of the invention
The purpose of this invention is to provide a kind of preparation method of carboxylic acid valnemulin recklessly that prolongs.This preparation method's yield height, technology is simple, has the good commercial prospect.
In order to achieve the above object, the present invention is by the following technical solutions:
In a kind of organic solvent, add valnemulin, then heated and stirred.The dissolving back adds solvent, and adding is prolonged Hu carboxylic acid to reaction soln and clarified.Crystal is separated out in ice bath cooling, filters, and filter cake obtains the fumaric acid valnemulin after with methyl iso-butyl ketone (MIBK) washing, drying.
Described a kind of organic solvent is a methyl iso-butyl ketone (MIBK).
Described solvent is dehydrated alcohol and methyl alcohol.
Particularly preferred solvent is a dehydrated alcohol.
The preparation method of carboxylic acid valnemulin recklessly that prolongs of the present invention more specifically, comprises following steps:
Comprise following steps:
Add methyl iso-butyl ketone (MIBK) in reaction flask, carry out water bath with thermostatic control, controlled temperature is 65-70 ℃, drops into valnemulin then, is stirred to the solution clarification.Keep temperature-resistant, continue to add an amount of dehydrated alcohol, under agitation add and prolong carboxylic acid recklessly, controlling reaction time 2 hours.After finishing, reaction carries out ice bath insulation 3 hours.Filter, the methyl iso-butyl ketone (MIBK) washing is drying to obtain and prolongs carboxylic acid valnemulin recklessly.
This preparation method's yield height, technology is simple, has the good commercial prospect.
Embodiment
Be embodiments of the invention below, described embodiment just is used for illustrating the present invention, and should not be considered to be limitation of the present invention.
Embodiment 1
Add the 7ml methyl iso-butyl ketone (MIBK) in reaction flask, carry out water bath with thermostatic control, controlled temperature is 65-70 ℃, drops into the 0.5g valnemulin then, is stirred to the solution clarification.Keep temperature-resistant, continue to add the 1.5ml dehydrated alcohol, under agitation add and prolong carboxylic acid 0.13g recklessly, controlling reaction time 2 hours.After finishing, reaction carries out ice bath insulation 3 hours.Filter, the methyl iso-butyl ketone (MIBK) washing is drying to obtain and prolongs carboxylic acid valnemulin 0.44g recklessly.
Embodiment 2
Add the 14ml methyl iso-butyl ketone (MIBK) in reaction flask, carry out water bath with thermostatic control, controlled temperature is 65-70 ℃, drops into the 1g valnemulin then, is stirred to the solution clarification.Keep temperature-resistant, continue to add the 4ml anhydrous methanol, under agitation add and prolong carboxylic acid 0.27g recklessly, controlling reaction time 2 hours.After finishing, reaction carries out ice bath insulation 3 hours.Filter, the methyl iso-butyl ketone (MIBK) washing is drying to obtain and prolongs carboxylic acid valnemulin 0.86g recklessly.
More than prolong recklessly to provided by the present invention that the preparation method of carboxylic acid valnemulin is described in detail, used specific case herein principle of the present invention and embodiment are set forth, the explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof; Simultaneously, for one of ordinary skill in the art, according to thought of the present invention, the part that all can change in specific embodiments and applications, in sum, this description should not be construed as limitation of the present invention.
Claims (2)
1. the preparation method of a fumaric acid valnemulin is characterized in that, comprises following steps: add valnemulin in a kind of organic solvent, then heated and stirred.The dissolving back adds solvent, and adding is prolonged Hu carboxylic acid to reaction soln and clarified; Crystal is separated out in ice bath cooling, filters, and filter cake obtains the fumaric acid valnemulin after with methyl iso-butyl ketone (MIBK) washing, drying.
2. the preparation method of fumaric acid valnemulin as claimed in claim 1 is characterized in that, described a kind of organic solvent is a methyl iso-butyl ketone (MIBK).
3. the preparation method of fumaric acid valnemulin as claimed in claim 1 is characterized in that, described solvent is dehydrated alcohol and methyl alcohol.
4. as the preparation method of claim 1 and 3 described fumaric acid valnemulins, it is characterized in that particularly preferred solvent is a dehydrated alcohol.
5. the preparation method of fumaric acid valnemulin as claimed in claim 1 is characterized in that, comprises following steps:
Add methyl iso-butyl ketone (MIBK) in reaction flask, carry out water bath with thermostatic control, controlled temperature is 65-70 ℃, drops into valnemulin then, is stirred to the solution clarification; Keep temperature-resistant, continue to add an amount of dehydrated alcohol, under agitation add and prolong carboxylic acid recklessly, controlling reaction time 2 hours; After finishing, reaction carries out ice bath insulation 3 hours; Filter, the methyl iso-butyl ketone (MIBK) washing is drying to obtain and prolongs carboxylic acid valnemulin recklessly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100569127A CN102180818A (en) | 2011-03-10 | 2011-03-10 | Preparation method of fumaric acid valnemulin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100569127A CN102180818A (en) | 2011-03-10 | 2011-03-10 | Preparation method of fumaric acid valnemulin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102180818A true CN102180818A (en) | 2011-09-14 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100569127A Pending CN102180818A (en) | 2011-03-10 | 2011-03-10 | Preparation method of fumaric acid valnemulin |
Country Status (1)
| Country | Link |
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| CN (1) | CN102180818A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103073464A (en) * | 2013-02-04 | 2013-05-01 | 中国兽医药品监察所 | Preparation method of valnemulin fumarate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101107224A (en) * | 2005-01-26 | 2008-01-16 | 诺瓦提斯公司 | Valnemulin salts with organic acids |
| CN101597248A (en) * | 2009-07-10 | 2009-12-09 | 河北远征药业有限公司 | The preparation method of valnemulin and hydrochloride thereof |
-
2011
- 2011-03-10 CN CN2011100569127A patent/CN102180818A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101107224A (en) * | 2005-01-26 | 2008-01-16 | 诺瓦提斯公司 | Valnemulin salts with organic acids |
| EP1844008B1 (en) * | 2005-01-26 | 2010-08-04 | Novartis AG | Valnemulin crystalline salts with organic acids |
| CN101597248A (en) * | 2009-07-10 | 2009-12-09 | 河北远征药业有限公司 | The preparation method of valnemulin and hydrochloride thereof |
Non-Patent Citations (2)
| Title |
|---|
| 王其合: "《延胡索酸泰妙菌素成盐结晶工艺优化》", 《中国兽药杂志》 * |
| 远立国，张展等: "沃尼妙林的研究进展", 《中国兽医科学》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103073464A (en) * | 2013-02-04 | 2013-05-01 | 中国兽医药品监察所 | Preparation method of valnemulin fumarate |
| CN103073464B (en) * | 2013-02-04 | 2014-11-26 | 中国兽医药品监察所 | Preparation method of valnemulin fumarate |
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Application publication date: 20110914 |