CN103450057A - Synthesis method of p-toluene sulfonic acid pleuromutilin ester - Google Patents
Synthesis method of p-toluene sulfonic acid pleuromutilin ester Download PDFInfo
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- CN103450057A CN103450057A CN2012101698543A CN201210169854A CN103450057A CN 103450057 A CN103450057 A CN 103450057A CN 2012101698543 A CN2012101698543 A CN 2012101698543A CN 201210169854 A CN201210169854 A CN 201210169854A CN 103450057 A CN103450057 A CN 103450057A
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- pleuromutilin
- ester
- tosic acid
- sulfonic acid
- toluene sulfonic
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Abstract
The invention relates to a synthesis method of p-toluene sulfonic acid pleuromutilin ester. Especially, the method includes: under catalysis of three inorganic alkalis, i.e. sodium hydroxide, potassium hydroxide or sodium carbonate, reacting pleuromutilin with p-toluenesulfonyl chloride for 0.5-1.5h in a methyl isobutyl ketone solvent at 50-65DEG C, conducting washing and distillation of the solvent, thus obtaining the p-toluene sulfonic acid pleuromutilin ester with yield of 95-96.5% and chromatographic purity of 97-98.1%. The method has the advantages of environmental-friendliness, worker health promotion, low production cost, short synthesis reaction time and high yield.
Description
One, technical field
The invention belongs to the fine chemical technology field, relate to a kind of synthetic method of tosic acid pleuromutilin ester, especially under the catalysis of these three kinds of mineral alkalis of sodium hydroxide, potassium hydroxide or sodium carbonate, pleuromutilin and Tosyl chloride react, and obtain the method for tosic acid pleuromutilin ester.
Two. background technology
By pleuromutilin (2) and Tosyl chloride (p-TsCl) reaction, prepared by tosic acid pleuromutilin ester (1):
1 English chemical name is: 14-desoxy-14-[(tosyloxyacetyl) oxy] mutilin, the English chemical name of pleuromutilin (2) is 14-Deoxy-14-[(hydroxyacetyl) oxy] mutilin, the difference of the two is: in 1 to toluene sulphur carboxyl substituted the hydroxyl in the pleuromutilin.For the patent drafting convenience, according to the nomenclature of tosic acid derivative, by 1 called after tosic acid pleuromutilin ester.
Tosic acid pleuromutilin ester (1) is the important synthetic intermediate of Tiamulin (3):
Tiamulin is a kind of important veterinary drug, be mainly used in preventing and treating the dysentery that chronic respiratory disease of fowl (CRD), porcine mycoplasmal pneumonia, hemophilic bacterium property pleuropneumonia and pig treponema cause, with tetracycline antibiotics compatibilities such as duomycin, terramycin, can produce synergism.Low dosage also can be used for promoting growth of animals or poultry, improves efficiency of feed utilization and production performance (Huang Hexian, Zeng Zhenling, Huang Xianhui, the progress of pleuromulins microbiotic-Tiamulin, Chinese veterinary drug impurity, 2010,44 (6): 42-45).
At present, the building-up reactions of tosic acid pleuromutilin ester is mainly to adopt the organic bases triethylamine as catalyzer (Wang Liqiang, Feng Wenhua, Zhang Yue, the improvement in synthesis of pleuromulins microbiotic Retapamulin, synthetic chemistry, 2011,19 (4): 554-556).Triethylamine is poisonous, has strong and stimulating, and volatile, in air, is fuming, big for environment pollution, affects the healthy of workman.In addition, the performance of this building-up reactions of triethylamine catalysis is low, in synthetic, the input amount of triethylamine often is greater than the input amount of pleuromutilin, as Wang Li in the above wait by force people's report in the building-up reactions of tosic acid pleuromutilin ester, the input amount mol ratio of pleuromutilin and triethylamine is: 1: 1.1.In addition, also because the triethylamine catalytic performance is low, reaction times also needs very long, as Wang Li in the above wait by force people's report in the building-up reactions of tosic acid pleuromutilin ester, reaction times was up to 10 hours, this makes the production cycle of tosic acid pleuromutilin ester in industrial production long, and production efficiency is low.Under study for action, we attempt to carry out Reaction time shorten by improving temperature of reaction, but, due to triethylamine easily oxidation in air, consequently reaction solution has become brown, and reaction impurities increases.
Therefore, need to improve the synthetic method of current tosic acid pleuromutilin ester, find and a kind ofly can substitute triethylamine, have nontoxic, not volatile, environmental pollution is little, do not affect workman's healthy, stable in the air, catalyzer that catalytic performance is high, for the reaction of catalysis pleuromutilin and Tosyl chloride, can synthesize expeditiously tosic acid pleuromutilin ester.
Three, summary of the invention
In order to overcome the shortcoming in existing tosic acid pleuromutilin ester synthesis reaction, the purpose of patent of the present invention be find a kind of nontoxic, not volatile, environmental pollution is little, do not affect the healthy, stable in the air of workman, and the catalyzer that catalytic performance is high can, for pleuromutilin and Tosyl chloride reaction, can synthesize tosic acid pleuromutilin ester expeditiously.
Through research, this patent finds that sodium hydroxide, potassium hydroxide or these three kinds of mineral alkalis of sodium carbonate can, for the reaction of catalysis pleuromutilin and Tosyl chloride, can synthesize tosic acid pleuromutilin ester expeditiously.Above-mentioned three kinds of mineral alkalis itself are nontoxic, not volatile, and environmental pollution is little, do not affect the healthy, stable in the air of workman; In the process of synthetic tosic acid pleuromutilin ester, catalytic activity is high, the reaction times is short, reaction is easily gone by washing after finishing.In addition, above-mentioned three kinds of mineral alkalis also have low price as the catalyzer of synthetic tosic acid pleuromutilin ester, and consumption is low, can reduce the advantage of tosic acid pleuromutilin ester production cost.
With the synthetic method of current tosic acid pleuromutilin ester relatively, the synthetic method of this patent invention has advantages of following: 1. in synthetic method, eliminated poisonous, the impact of the strong and triethylamine that volatility is large of pungency, have advantages of environmental friendliness and be conducive to workers ' health; 2. the price of three kinds of mineral alkalis used cheap than triethylamine all in synthetic method, consumption is low, has advantages of and reduces production costs; 3. in synthetic method, the catalytic activity of three kinds of mineral alkalis used is all stablized, is had under high, normal temperature and high temperature and can shorten synthesising reacting time, improves the advantage of combined coefficient and productive rate.
Four, embodiment
The present invention is described in further detail in conjunction with the following examples:
Embodiment 1
The pleuromutilin of 378.5 grams (1mol) is joined in the methyl iso-butyl ketone (MIBK) of 1500 milliliters, then under agitation adding successively the Tosyl chloride of 209.4 grams (1.1mol) and content is the aqueous sodium hydroxide solution that 40 grams (1mol), concentration are 30%.After dripping, be warmed up under 60 ℃ and react 0.5 hour.After the reaction solution cool to room temperature, isolate organic layer, after water (800 milliliters * 3) washing, anhydrous magnesium sulfate drying, after solvent is fallen in underpressure distillation, obtain the tosic acid pleuromutilin ester solid of the white of 506.6 grams, productive rate 95.1%, it is 97% that high pressure liquid chromatograph is analyzed its chromatographic purity.
Embodiment 2
The pleuromutilin of 378.5 grams (1mol) is joined in the methyl iso-butyl ketone (MIBK) of 1500 milliliters, then under agitation adding the Tosyl chloride of 209.4 grams (1.1mol) and content is the potassium hydroxide aqueous solution that 56 grams (1mol), concentration are 25%.After dripping, be warmed up under 50 ℃ and react 0.5 hour.After the reaction solution cool to room temperature, isolate organic layer, after water (800 milliliters * 3) washing, anhydrous magnesium sulfate drying, after solvent is fallen in underpressure distillation, obtain the tosic acid pleuromutilin solid of the white of 514.0 grams, productive rate 96.5%, it is 97.2% that high pressure liquid chromatograph is analyzed its chromatographic purity.
Embodiment 3
The pleuromutilin of 189.3 grams (0.5mol) is added in the methyl iso-butyl ketone (MIBK) of 800 milliliters, then under agitation adding the Tosyl chloride of 104.7 grams (0.55mol) and content is the saturated aqueous sodium carbonates of 53 grams (0.5mol).After dripping, be warmed up under 65 ℃ and react 1.5 hours.After the reaction solution cool to room temperature, isolate organic layer, after water (600 milliliters * 3) washing, anhydrous magnesium sulfate drying, after solvent is fallen in underpressure distillation, obtain the tosic acid pleuromutilin solid of the white of 253.0 grams, productive rate 95.0%, it is 98.1% that high pressure liquid chromatograph is analyzed its chromatographic purity.
Claims (1)
1. the synthetic method of a tosic acid pleuromutilin ester, especially under the catalysis of these three kinds of mineral alkalis of sodium hydroxide, potassium hydroxide or sodium carbonate, under 50-65 ℃, pleuromutilin and Tosyl chloride react 0.5-1.5 hour in methyl isobutyl ketone solvent, through washing and distilling off solvent, obtain the method for tosic acid pleuromutilin ester.
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| CN2012101698543A CN103450057A (en) | 2012-05-29 | 2012-05-29 | Synthesis method of p-toluene sulfonic acid pleuromutilin ester |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3919290A (en) * | 1972-10-03 | 1975-11-11 | Sandoz Ltd | Substituted 14-desoxy-mutilins |
| EP2014645A1 (en) * | 2007-07-13 | 2009-01-14 | Nabriva Therapeutics AG | Pleuromutilin derivatives and their use as antimicrobials |
| WO2009075776A1 (en) * | 2007-12-05 | 2009-06-18 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of retapamulin and its intermediates |
| WO2010056855A1 (en) * | 2008-11-13 | 2010-05-20 | Teva Pharmaceutical Industries Ltd. | Preparation of retapamulin via its pleuromutilin-thiol precursor |
| CN101735123A (en) * | 2009-12-22 | 2010-06-16 | 山东胜利股份有限公司 | Method for synthesizing valnemulin hydrochloride |
| CN101993400A (en) * | 2009-08-17 | 2011-03-30 | 北京中牧科技服务有限责任公司 | Valnemulin synthesis method |
| CN102229580A (en) * | 2011-05-12 | 2011-11-02 | 南通大学 | Novel pleuromutilin derivate, preparation method and medical use thereof |
-
2012
- 2012-05-29 CN CN2012101698543A patent/CN103450057A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3919290A (en) * | 1972-10-03 | 1975-11-11 | Sandoz Ltd | Substituted 14-desoxy-mutilins |
| EP2014645A1 (en) * | 2007-07-13 | 2009-01-14 | Nabriva Therapeutics AG | Pleuromutilin derivatives and their use as antimicrobials |
| WO2009075776A1 (en) * | 2007-12-05 | 2009-06-18 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of retapamulin and its intermediates |
| WO2010056855A1 (en) * | 2008-11-13 | 2010-05-20 | Teva Pharmaceutical Industries Ltd. | Preparation of retapamulin via its pleuromutilin-thiol precursor |
| CN101993400A (en) * | 2009-08-17 | 2011-03-30 | 北京中牧科技服务有限责任公司 | Valnemulin synthesis method |
| CN101735123A (en) * | 2009-12-22 | 2010-06-16 | 山东胜利股份有限公司 | Method for synthesizing valnemulin hydrochloride |
| CN102229580A (en) * | 2011-05-12 | 2011-11-02 | 南通大学 | Novel pleuromutilin derivate, preparation method and medical use thereof |
Non-Patent Citations (3)
| Title |
|---|
| 付江涛等: "沃尼妙林的合成进展", 《河北化工》 * |
| 冯德鑫等: "盐酸沃尼妙林的合成", 《中国医药工艺杂志》 * |
| 王力强等: "截短侧耳素类抗生素Retapamulin的合成工艺改进", 《合成化学》 * |
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Application publication date: 20131218 |