CN103864865A - A synthetic method of high-purity tulathromycin - Google Patents
A synthetic method of high-purity tulathromycin Download PDFInfo
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- CN103864865A CN103864865A CN201210546994.8A CN201210546994A CN103864865A CN 103864865 A CN103864865 A CN 103864865A CN 201210546994 A CN201210546994 A CN 201210546994A CN 103864865 A CN103864865 A CN 103864865A
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Abstract
The invention provides a synthetic method of high-purity tulathromycin. The method includes subjecting demethylated azithromycin adopted as a raw material to substitution, oxidation, addition, reduction, condensation, and the like, so as to obtain a target compound. According to the synthetic method, the cheaper raw material is adopted, and a traditional process employing low-temperature reaction is changed. The method has the advantages of short process route, easy-to-control reaction, high yield, and the like. The method is suitable for large-scale industrialized production.
Description
Technical field
The present invention relates to a kind of method of preparing Tulathromycin compound, belong to field of veterinary.
Background technology
Respiratory tract infection is one of transmissible disease more rambunctious in livestock industry, serious to livestock industry disserve to produce.When respiratory tract infection is popular, can produces and cause huge financial loss to livestock industry.Therefore the respiratory tract infection that, how to prevent and treat the domestic animal such as pig, ox is animal doctor and veterinary drug worker's important subject.Because respiratory tract infection is generally multiple infection, paathogenic factor is many, and therefore state of an illness complexity there is no highly effective preventive means at present.To the respiratory tract infection of animal, in seeking biological control and environment blocking-up, medical treatment remains current main path.Seek to respiratory tract infection effectively, safety, wide spectrum, efficient, novel antibacterial medicine low residue be the important directions of veterinary drug research and development.
Pfizer drugmaker has caused the generally attention of countries in the world since releasing Tulathromycin in 2002.Europe and the researchist of the U.S. have carried out in a large amount of bodies and the correlation test such as medicine in-vitro Neo-Confucianism, toxicology.Main Tulathromycin therapeutic action effect, effect feature and the generation mechanism thereof inquired into.Also carried out clinical trial widely in Europe and the U.S., for research and the application of Tulathromycin provide a large amount of authentic datas simultaneously.Within 2002, European drug evaluation is affixed one's name to approval Tulathromycin with the list marketing of trade(brand)name Draxxin injection liquid, and within 2005, U.S. FDA has also been ratified the treatment of Tulathromycin for pig and ox upper respiratory tract infection.Because Tulathromycin has that anti-microbial activity is strong, has a broad antifungal spectrum, animal specific, overlength transformation period and single-dose complete the many merits such as whole therapeutic process, now extensively accepted by western developed country, become the first-line drug that treatment pig and bovine respiratory infect.
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Summary of the invention
The object of this invention is to provide the preparation method of Tulathromycin compound.
The object of the invention is to reach by the following technical programs: obtain target compound take demethyl azithromycin as raw material through reactions such as replacement, oxidation, addition, reduction, condensations.
The described reaction formula of preparing Tulathromycin compound is as follows:
The described method of preparing Tulathromycin compound, is characterized in that: in described substitution reaction, organic bases used is pyridine, picoline, pyrroles, methylpyrrole, Pyrrolidine, morpholine, the one in piperidines.
The described method of preparing Tulathromycin compound, is characterized in that: in described oxidizing reaction, oxygenant is potassium permanganate, hydrogen peroxide, the one in clorox.
The described method of preparing Tulathromycin compound, is characterized in that: in described addition reaction, system PH span of control is 7.9-9.0.
The described method of preparing Tulathromycin compound, is characterized in that: in described reduction reaction, reductive agent is sodium borohydride or POTASSIUM BOROHYDRIDE
The described method of preparing Tulathromycin compound, is characterized in that: the described condensation reaction reaction times is 4-10 hour.
Embodiment
Embodiment
The first step: substitution reaction:
58.0 kg demethyl azithromycins (I) are joined in the retort of 500 L, add 300 L trichloromethanes and 30.7 kg pyridines, chilled brine is cooled to 0 ℃.In 20 minutes, add 16.1 kg diacetyl oxides, when reinforced, keep reacting liquid temperature 0 ℃ of left and right.Stir and be warming up to room temperature after 2 hours, then stirring reaction 12 hours.In reaction solution, add 100 L saturated sodium bicarbonate aqueous solutions, the 2M NaOH aqueous solution is adjusted reaction solution pH=9.0, stirs stratification after 10 minutes, takes off a layer organic phase.Organic phase is respectively washed and is once added afterwards 1 kg anhydrous magnesium sulfate drying with 50 L water and 50 L saturated aqueous common salts, filters except magnesium sulfate.In the rearmounted lyophilize dish of filtrate concentrating under reduced pressure at 45 ℃, lyophilize obtains white solid (II) 58.9 kg about 30 hours.
Second step: oxidizing reaction:
By 58.9 kg(II) join in the retort of 500 L, add 200 L isopropyl ethers, under agitation in 15 minutes, drip the solution that 7.6 kg sodium dichromate 99s and 8.3 kg sulfuric acid and 100 L water are made into, temperature should be held in 25 ℃.Stir after two hours and adjust reaction solution pH=9.0 with the 2M NaOH aqueous solution, then stir after 10 minutes and divide and get organic phase, water is washed twice with 50 L X2 isopropyl ethers.Merge organic phase, 50 L saturated sodium bicarbonate solutions are washed and 50 L water are washed respectively organic phase once.In organic phase, add 1 kg anhydrous magnesium sulfate drying, filter except magnesium sulfate.In the rearmounted lyophilize dish of filtrate concentrating under reduced pressure at 45 ℃, lyophilize obtains white solid (III) 50.0 kg, yield 85.1% about 30 hours.
The 3rd step: addition reaction:
By 50.0 kg(III) add in the retort of 500 L, add again 200L methyl alcohol, stirring adds 5.65 kg sodium cyanides and controls temperature of reaction at 5-10 ℃, drip rare HCL, in dropping process, make the pH value of solution be controlled between 8-8.5, time for adding approximately 1 hour, drips and reacts 45 minutes again.After 45 minutes, at 35 ℃, methyl alcohol is gone out in underpressure distillation, then adds 200 L ethyl acetate and 200 L water, is point to get ethyl acetate layer under 9.0-9.3 at pH, adds 1 kg anhydrous magnesium sulfate drying in ethyl acetate layer, filters except magnesium sulfate.In the rearmounted lyophilize dish of filtrate concentrating under reduced pressure at 45 ℃, lyophilize obtains white solid (IV) 44.7 kg about 30 hours.
The 4th step: reduction reaction:
By 44.7 kg(IV) join in the retort of 500 L, add 180 L isopropyl ethers, stir and be cooled to-50 ℃, add 12.0 kg POTASSIUM BOROHYDRIDE and 30 L water, react after 5.5 hours at-50 ℃, add 150 L water, isopropyl ether is removed in decompression, then adds 200 L trichloromethanes, be 9.0 o'clock extracted organic phase at pH, by 50 LX2 water washing organic phases twice, in organic phase, add 1 kg anhydrous magnesium sulfate drying, filter except magnesium sulfate.In the rearmounted lyophilize dish of filtrate concentrating under reduced pressure at 45 ℃, lyophilize obtains faint yellow solid (V) 35.3kg about 30 hours.
The 5th step: condensation reaction:
By 35.3 kg(V) join in the retort of 500 L, add 200 L methyl alcohol and 100 L water, then add sodium bicarbonate 2.8 kg, be stirred to dissolving, add 8.1 kg N-PROPYLE BROMIDEs, reflux 5 hours.Methyl alcohol and unreacted N-PROPYLE BROMIDE are removed in underpressure distillation, add 150 L trichloromethanes in pH=9.0 extraction, divide and get organic phase, add 1 kg anhydrous magnesium sulfate drying in organic phase, filter except magnesium sulfate.In the rearmounted lyophilize dish of filtrate concentrating under reduced pressure at 45 ℃, lyophilize obtains faint yellow solid (VI) 31.1kg about 30 hours.
Claims (3)
1. a synthetic method for high purity Tulathromycin, is characterized in that the step of its preparation method is: obtain target compound take demethyl azithromycin as raw material through reactions such as replacement, oxidation, addition, reduction, condensations.
2. the method for preparing as claimed in claim 1 Tulathromycin compound, is characterized in that: described to prepare Tulathromycin structural formula of compound as follows:
The method of preparing as claimed in claim 1 Tulathromycin compound, is characterized in that: in described substitution reaction, organic bases used is pyridine, picoline, pyrroles, methylpyrrole, Pyrrolidine, morpholine, the one in piperidines.
3. the method for preparing as claimed in claim 1 Tulathromycin compound, is characterized in that: in described oxidizing reaction, oxygenant is potassium permanganate, hydrogen peroxide, the one in clorox.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201210546994.8A CN103864865A (en) | 2012-12-17 | 2012-12-17 | A synthetic method of high-purity tulathromycin |
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| CN201210546994.8A CN103864865A (en) | 2012-12-17 | 2012-12-17 | A synthetic method of high-purity tulathromycin |
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| CN103864865A true CN103864865A (en) | 2014-06-18 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104861018A (en) * | 2015-06-17 | 2015-08-26 | 瑞普（天津）生物药业有限公司 | Preparation method of draxxin |
| CN106008622A (en) * | 2016-08-02 | 2016-10-12 | 海门慧聚药业有限公司 | Tulathromycin new crystal form and preparation thereof |
| CN106146576A (en) * | 2015-03-25 | 2016-11-23 | 上海医药工业研究院 | A kind of Tulathromycin has related substance, enrichment preparation method, separation method and application |
| CN106153740A (en) * | 2015-03-25 | 2016-11-23 | 上海医药工业研究院 | A kind of Tulathromycin have related substance, its be enriched with preparation method and application |
| CN108003207A (en) * | 2017-12-19 | 2018-05-08 | 海门慧聚药业有限公司 | Method for preparing tulathromycin |
| CN111253447A (en) * | 2020-03-26 | 2020-06-09 | 苏州正永生物医药有限公司 | Preparation method of tulathromycin |
-
2012
- 2012-12-17 CN CN201210546994.8A patent/CN103864865A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146576A (en) * | 2015-03-25 | 2016-11-23 | 上海医药工业研究院 | A kind of Tulathromycin has related substance, enrichment preparation method, separation method and application |
| CN106153740A (en) * | 2015-03-25 | 2016-11-23 | 上海医药工业研究院 | A kind of Tulathromycin have related substance, its be enriched with preparation method and application |
| CN106153740B (en) * | 2015-03-25 | 2019-01-01 | 上海医药工业研究院 | A kind of related substance of Tulathromycin, its be enriched with preparation method and application |
| CN106146576B (en) * | 2015-03-25 | 2019-04-12 | 上海医药工业研究院 | A kind of related substance of Tulathromycin, enrichment preparation method, separation method and application |
| CN104861018A (en) * | 2015-06-17 | 2015-08-26 | 瑞普（天津）生物药业有限公司 | Preparation method of draxxin |
| CN106008622A (en) * | 2016-08-02 | 2016-10-12 | 海门慧聚药业有限公司 | Tulathromycin new crystal form and preparation thereof |
| CN108003207A (en) * | 2017-12-19 | 2018-05-08 | 海门慧聚药业有限公司 | Method for preparing tulathromycin |
| CN108003207B (en) * | 2017-12-19 | 2019-05-10 | 海门慧聚药业有限公司 | Method for preparing tulathromycin |
| WO2019119628A1 (en) * | 2017-12-19 | 2019-06-27 | 海门慧聚药业有限公司 | Method for preparing tulathromycin |
| US11001604B2 (en) | 2017-12-19 | 2021-05-11 | Wisdom Pharmaceutical Co., Ltd. | Method for preparing tulathromycin |
| CN111253447A (en) * | 2020-03-26 | 2020-06-09 | 苏州正永生物医药有限公司 | Preparation method of tulathromycin |
| CN111253447B (en) * | 2020-03-26 | 2021-03-02 | 苏州正永生物医药有限公司 | Preparation method of tulathromycin |
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Application publication date: 20140618 |