CN103113271B - Preparation method of tiamulin alkali - Google Patents
Preparation method of tiamulin alkali Download PDFInfo
- Publication number
- CN103113271B CN103113271B CN201310068656.2A CN201310068656A CN103113271B CN 103113271 B CN103113271 B CN 103113271B CN 201310068656 A CN201310068656 A CN 201310068656A CN 103113271 B CN103113271 B CN 103113271B
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- CN
- China
- Prior art keywords
- preparation
- reaction
- pleuromutilin
- tiamulin
- alkali
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000003513 alkali Substances 0.000 title claims abstract description 24
- 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 title claims abstract description 24
- 229960004885 tiamulin Drugs 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 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 claims abstract description 16
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 12
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229940013085 2-diethylaminoethanol Drugs 0.000 claims abstract description 9
- 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 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 10
- -1 pleuromutilin thiocarbamide salt Chemical class 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 238000005660 chlorination reaction Methods 0.000 claims description 5
- 239000012266 salt solution Substances 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- YBDSNEVSFQMCTL-UHFFFAOYSA-N 2-(diethylamino)ethanethiol Chemical compound CCN(CC)CCS YBDSNEVSFQMCTL-UHFFFAOYSA-N 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract description 2
- 238000001704 evaporation Methods 0.000 abstract description 2
- 230000035484 reaction time Effects 0.000 abstract description 2
- 239000012320 chlorinating reagent Substances 0.000 abstract 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 206010028470 Mycoplasma infections Diseases 0.000 description 1
- 241000204003 Mycoplasmatales Species 0.000 description 1
- 241000192085 Staphylococcus gallinarum Species 0.000 description 1
- 241000589886 Treponema Species 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003317 industrial substance Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of tiamulin alkali. The preparation method comprises the following steps of: adding pleuromutilin in a chlorinating agent in a solvent for chlorinating, and then adding thiourea for reacting to obtain a solution; chlorinating 2-diethylaminoethanol in the solvent by using the chlorinating agent to obtain a chloride solution of 2-diethylaminoethanol; and mixing two solutions together to react, controlling the reaction temperature and reaction time, dewatering and drying the obtained product, and evaporating the solvent so as to obtain tiamulin alkali. The yield of tiamulin alkali can be more than 80%. The reaction method for preparing tiamulin alkali is simple and easy to control; and 2-diethylaminoethanethiol which has fetid smell and is limited application is abolished, so that the preparation method has a good commercial prospect.
Description
Technical field
The present invention relates to the preparation method of drug chemical, specifically, is a kind of preparation method of tiamulin alkali.
Background technology
Tiamulin alkali is semisynthetic di-terpene compounds, belongs to the special microbiotic of livestock and poultry.Tiamulin alkali absorbs rapidly in animal body, and Plasma Concentration is high, and distribution in vivo is wide, and residual lower.There is good efficacy to the mycoplasma infection of pig and bird, pig treponema dysentery, Staphylococcus gallinarum synovitis, have growth promoting function again, be therefore widely used as veterinary drug and fodder additives.
The production technique that current manufacturer generally adopts is after fermentation culture obtains pleuromutilin, in a solvent control condition and 2-diethylamino ethanethiol Reactive Synthesis tiamulin alkali.
The greatest problem that this technique exists is the use of 2-diethylamino ethanethiol, and 2-diethylamino ethanethiol has foul odour, and application is restricted in the world, domesticly also will verify use.This significantly limit the production of tiamulin alkali.
In order to avoid using the 2-diethylamino ethanethiol with foul odour, have employed a kind of conventional industrial chemicals 2-diethylaminoethanol in the present invention to replace 2-diethylamino ethanethiol, surprisingly this method achieves gratifying effect.By by the hydroxyl in pleuromutilin structure with after a kind of suitable chlorizating agent chlorination and thiocarbamide be obtained by reacting a kind of solution of salt, the muriate of this solution and 2-diethylaminoethanol carries out reacting the solution that can obtain containing tiamulin alkali, can obtain the tiamulin alkali of yield more than 80% after treatment.This preparation method easy control simple to operate, has got rid of and has had the 2-diethylamino ethanethiol that foul odour is restricted application, had good Commercial Prospect.
Summary of the invention
The object of this invention is to provide a kind of preparation method of tiamulin alkali.This preparation method has good yield, easy control simple to operate, has got rid of and has had the 2-diethylamino ethanethiol that foul odour is restricted application, had good Commercial Prospect.
In order to achieve the above object, the present invention is by the following technical solutions:
First pleuromutilin is used chlorizating agent chlorination in a solvent, obtain the pleuromutilin that hydroxyl is chlorinated, then add thiocarbamide and react, obtain clear soln; 2-diethylaminoethanol with after a kind of chlorizating agent chlorination, obtains the chloride soln of 2-diethylaminoethanol in a kind of solvent; Mixed by two kinds of solution and react, control temperature of reaction and reaction times, the product obtained, through dehydrating, namely obtains tiamulin alkali after evaporating solvent, and yield reaches more than 80%;
Described solvent is the one in ethyl acetate, methylene dichloride, chloroform, acetone, methyl acetate, ethyl formate and hexone;
Described chlorizating agent is the one in chlorine, hydrogenchloride, sulfur oxychloride, phosphorus pentachloride and phosphorus trichloride;
Described a kind of solvent is the one in tetrahydrofuran (THF), ethyl acetate, methylene dichloride, chloroform, acetone, methyl acetate, ethyl formate and hexone;
Described a kind of chlorizating agent is the one in chlorine, hydrogenchloride, sulfur oxychloride, phosphorus pentachloride and phosphorus trichloride;
The preparation method of a kind of tiamulin alkali of the present invention, more specifically, comprises following steps:
(1), the preparation of pleuromutilin thiocarbamide salt
In reaction flask, add pleuromutilin and ethyl acetate, add sulfur oxychloride, controlling temperature of reaction is 30 DEG C to 50 DEG C, reacts 2 to 4 hours, then adds thiocarbamide and continues reaction 3 to 5 hours, obtain the solution containing pleuromutilin thiocarbamide salt;
(2), the preparation of tiamulin alkali
Ethyl acetate and 2-diethylaminoethanol is added in reaction flask, be added dropwise to sulfur oxychloride, room temperature reaction 30 minutes to 2 hours, the solution obtained is joined in the solution containing pleuromutilin thiocarbamide salt, 45 DEG C to 65 DEG C are reacted 3 to 5 hours, anhydrous sodium sulfate drying, solvent evaporated, obtains tiamulin alkali.
Embodiment
Here is embodiments of the invention, and described embodiment is only used to the present invention is described, and should not be considered to be limitation of the present invention.
Embodiment 1
The preparation of pleuromutilin thiocarbamide salt
In reaction flask, drop into 20g pleuromutilin, 40ml chloroform, add sulfur oxychloride 2.5ml, 35 DEG C are carried out chlorination reaction 2 hours, then add 5.4g thiocarbamide and continue reaction 3 hours, obtain pleuromutilin thiocarbamide salt solution.
Embodiment 2
The preparation of tiamulin alkali
In reaction flask, add ethyl acetate, then add 2-diethylaminoethanol 8ml and sulfur oxychloride 2ml, room temperature reaction 1 hour.Mixed with pleuromutilin thiocarbamide salt solution by the reaction solution obtained, 48 DEG C are reacted 4 hours.Anhydrous sodium sulfate drying, solvent evaporated, obtains tiamulin alkali, yield 90.9%.
Above the preparation method of a kind of tiamulin alkali provided by the present invention is described in detail, apply specific case herein to set forth principle of the present invention and embodiment, the explanation of above embodiment just understands method of the present invention and core concept thereof for helping; Meanwhile, for one of ordinary skill in the art, according to thought of the present invention, all will change in specific embodiments and applications, in sum, this description should not be construed as limitation of the present invention.
Claims (1)
1. a preparation method for tiamulin alkali, is characterized in that, comprises following steps:
(1), the preparation of pleuromutilin thiocarbamide salt
In reaction flask, drop into 20g pleuromutilin, 40ml chloroform, add sulfur oxychloride 2.5ml, 35 DEG C are carried out chlorination reaction 2 hours, then add 5.4g thiocarbamide and continue reaction 3 hours, obtain pleuromutilin thiocarbamide salt solution;
(2), the preparation of tiamulin alkali
In reaction flask, add ethyl acetate, then add 2-diethylaminoethanol 8ml and sulfur oxychloride 2ml, room temperature reaction 1 hour.Mixed with pleuromutilin thiocarbamide salt solution by the reaction solution obtained, 48 DEG C are reacted 4 hours; Anhydrous sodium sulfate drying, solvent evaporated, obtains tiamulin alkali.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310068656.2A CN103113271B (en) | 2013-03-05 | 2013-03-05 | Preparation method of tiamulin alkali |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310068656.2A CN103113271B (en) | 2013-03-05 | 2013-03-05 | Preparation method of tiamulin alkali |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103113271A CN103113271A (en) | 2013-05-22 |
| CN103113271B true CN103113271B (en) | 2015-04-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310068656.2A Expired - Fee Related CN103113271B (en) | 2013-03-05 | 2013-03-05 | Preparation method of tiamulin alkali |
Country Status (1)
| Country | Link |
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| CN (1) | CN103113271B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892476B (en) * | 2015-05-07 | 2017-05-17 | 陕西师范大学 | Synthesis method of Tiamulin |
| CN114685333B (en) * | 2020-12-30 | 2024-02-27 | 广州自远生物科技有限公司 | Synthesis method of tiamulin and intermediate thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3919290A (en) * | 1972-10-03 | 1975-11-11 | Sandoz Ltd | Substituted 14-desoxy-mutilins |
| US4032530A (en) * | 1971-10-05 | 1977-06-28 | Sandoz Ltd. | Certain pleuromutilins |
| GB2025930B (en) * | 1978-06-01 | 1983-02-09 | Sandoz Ltd | Process for the production of pleuromutilin derivatives |
| US20100184987A1 (en) * | 2008-11-13 | 2010-07-22 | Teva Pharmaceutical Industries Ltd. | Preparation of Retapamulin via its Pleuromutilin-thiol precursor |
| 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 |
-
2013
- 2013-03-05 CN CN201310068656.2A patent/CN103113271B/en not_active Expired - Fee Related
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| CN103113271A (en) | 2013-05-22 |
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Granted publication date: 20150401 Termination date: 20180305 |