CN105646617A - Method for preparing tulathromycin - Google Patents
Method for preparing tulathromycin Download PDFInfo
- Publication number
- CN105646617A CN105646617A CN201610043716.9A CN201610043716A CN105646617A CN 105646617 A CN105646617 A CN 105646617A CN 201610043716 A CN201610043716 A CN 201610043716A CN 105646617 A CN105646617 A CN 105646617A
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- CN
- China
- Prior art keywords
- reaction
- tulathromycin
- method preparing
- propylamine
- stirring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The invention relates to large-loop type veterinary medicine antibiotics, in particular to a method for preparing tulathromycin. The method mainly solves the problem that in the prior art, the dosage of n-propylamine is large, and also solves the technical problems that due to the large dosage of n-propylamine, a crude product is not high in content and poor in character, and phosphate needs to be formed, neutralized and purified. The method comprises the steps that an epoxy intermediate, ethyl alcohol or isopropanol and N-benzyl propylamine are added into a reactor and stirred fully and evenly, and then heating and stirring are carried out for a reaction; after the reaction is finished, a solvent is removed, acetone is added, and the mixture is evenly stirred and then transferred into a pressure reactor; a palladium carbon catalyst is added in the pressure reactor, hydrogen is introduced, a reaction is carried out under stirring, the catalyst is recycled through filtering after the reaction is finished, concentration is carried out to remove the solvent, then water is added, filtering is carried out, separated-out solids are collected and subjected to vacuum drying, a tulathromycin crude product is obtained, and a fine tulathromycin product is obtained after recrystallization.
Description
Technical field
The present invention relates to a kind of big lopps veterinary drug antibiotic, especially relate to a kind of method preparing Tulathromycin.
Background technology
In recent years, Tulathromycin is as a kind of important big lopps veterinary drug antibiotic, it is possible to as antibacterial and the antiprotozoal of mammal and fish and birds, market acceptance and utilization rate in recent years are greatly improved.
Tulathromycin is currently mainly by Pfizer Inc.'s production and sales, its main production process has also applied for corresponding patent (CN1297564), it adopts n-propylamine directly as ring opening agent after having prepared epoxy intermediate in the method, it is obtained by reacting Tulathromycin crude product, passing through to be formed in after phosphate and purifying, obtain Tulathromycin fine work.
The product appearance shape that the method prepares is better, and content is higher. But in order to be formed without two substitution products, ring opening agent n-propylamine make consumption very huge, therefore also need to after obtaining crude product by formed phosphate, finally again neutralize obtain fine work. The not only consumption big (and cannot reclaim) of n-propylamine, and too increase processing step.
Summary of the invention
The present invention is to provide a kind of method preparing Tulathromycin, and it mainly solves the problem that the n-propylamine consumption existing for prior art is big; This invention also solves the content in crude product brought greatly because of n-propylamine consumption not high, character is bad, it is necessary to forms phosphate and neutralizes the technical problem of purification again.
The above-mentioned technical problem of the present invention is addressed mainly by following technical proposals:
A kind of method preparing Tulathromycin of the present invention, it is characterised in that described method includes:
A. add epoxy intermediate in the reactor, ethanol or isopropanol, N-benzyl propylamine stir, wherein epoxy intermediate with the mass ratio of ethanol or isopropanol, N-benzyl propylamine is: 1: 5��8: 0.19��0.24, is then heated to 50-60 DEG C of stirring reaction;
B. after completion of the reaction, concentration removes major part solvent, adds acetone, is transferred in pressure reactor after stirring;
C. in pressure reactor, add palladium-carbon catalyst, pass into hydrogen, keep reactant liquor 20-30 DEG C, stirring reaction under 45-55psi pressure, reaction is recovered by filtration catalyst after terminating, concentration removes major part solvent, it is subsequently adding water, collect by filtration the solid of precipitation, after vacuum drying, obtain Tulathromycin crude product, after recrystallization, obtain Tulathromycin fine work.
The reaction equation of the present invention is:
Reactor is the three-necked bottle equipped with reflux condensing tube, thermometer and mechanical stirring device; Pressure reactor is hydrogenation special purpose reactor, and allowable stress is 100psi at least. Reaction condition of the present invention is relatively mild and technique simple, each step reaction is more conventional operation, it is to avoid the environmental problem that a large amount of use n-propylamines (cannot reclaim) bring.
A kind of method that invention broadly provides new epoxy addition; generally it is difficult to expect that this compound is as Ring Opening Reagent; therefore contemplated by reverse thinking on target compound, add that benzyl is as protection base; the group increased can ensure the spatial selectivity of reaction, it is also possible to by last debenzylation purification reaction product.
As preferably, in described step b, epoxy intermediate is 1: 8��10 with the mass ratio of acetone.
As preferably, in described step c, epoxy intermediate is 1: 0.1 with the mass ratio of 10% palladium-carbon catalyst.
As preferably, in described step a, the stirring reaction time is 24��36 hours, and reaction temperature is 50��60 DEG C.
As preferably, in described step c, the time of stirring reaction is 20��24 hours, and reaction temperature is 20��30 DEG C.
As preferably, described vacuum drying condition is 60 DEG C/10mmHg, and the dry time is 8 hours.
Therefore, the present invention has employing N-benzyl propylamine as ring opening agent, it is available for replacing owing to atom N only having a H atom, therefore the selectivity reacted has great raising, simultaneously because do not need substantial amounts of n-propylamine in reaction system, after hydrogenation debenzylation, the Tulathromycin crude product quality of precipitation is also better, only can be purified by conventional recrystallization means, and the end product outward appearance obtained and character and content all reach domestic and international advanced level.
Detailed description of the invention
By the examples below, technical scheme is described in further detail.
Embodiment 1: a kind of method preparing Tulathromycin of this example, the steps include:
A. epoxy intermediate (III) (747g is added in the reactor, 1.0mol), isopropanol (5950g), N-benzyl propylamine (178.8g, 1.2mol) stir, be then heated to 50-60 DEG C of stirring reaction 36 hours;
B. after completion of the reaction, concentration removes major part solvent, adds acetone (7450g), is transferred in pressure reactor after stirring;
C. in pressure reactor, add 10% palladium-carbon catalyst (74.7g), pass into hydrogen, keeping reactant liquor 20-30 DEG C, stirring reaction 24 hours under 50psi pressure, reaction is recovered by filtration catalyst after terminating, concentration removes major part solvent, it is subsequently adding water (7470g), collects by filtration the solid of precipitation, after vacuum drying, obtain Tulathromycin crude product, fine work 621.7g is obtained, yield about 77.1% after recrystallization.
The content of the Tulathromycin fine work obtained more than 95%, retention time identical with standard substance (HPLC) .MS (EI), m/z807 (M+H).
Embodiment 2: a kind of method preparing Tulathromycin of this example, the steps include:
A. epoxy intermediate (III) (747g is added in the reactor, 1.0mol), isopropanol (3750g), N-benzyl propylamine (149g, 1.0mol) stir, be then heated to 50-60 DEG C of stirring reaction 24 hours;
B. after completion of the reaction, concentration removes major part solvent, adds acetone (6000g), is transferred in pressure reactor after stirring;
C. in pressure reactor, add 10% palladium-carbon catalyst (74.7g), pass into hydrogen, keeping reactant liquor 20-30 DEG C, stirring reaction 20 hours under 50psi pressure, reaction is recovered by filtration catalyst after terminating, concentration removes major part solvent, it is subsequently adding water (7470g), collects by filtration the solid of precipitation, after vacuum drying, obtain Tulathromycin crude product, fine work 435.6g is obtained, yield about 54.0% after recrystallization.
The content of the Tulathromycin fine work obtained more than 95%, retention time identical with standard substance (HPLC) .MS (EI), m/z807 (M+H).
Embodiment 3: a kind of method preparing Tulathromycin of this example, the steps include:
A. epoxy intermediate (III) (747g is added in the reactor, 1.0mol), isopropanol (4800g), N-benzyl propylamine (163.9g, 1.1mol) stir, be then heated to 50-60 DEG C of stirring reaction 30 hours;
B. after completion of the reaction, concentration removes major part solvent, adds acetone (6700g), is transferred in pressure reactor after stirring;
C. in pressure reactor, add 10% palladium-carbon catalyst (74.7g), pass into hydrogen, keeping reactant liquor 20-30 DEG C, stirring reaction 22 hours under 50psi pressure, reaction is recovered by filtration catalyst after terminating, concentration removes major part solvent, it is subsequently adding water (7470g), collects by filtration the solid of precipitation, after vacuum drying, obtain Tulathromycin crude product, fine work 503.8g is obtained, yield about 62.5% after recrystallization.
The content of the Tulathromycin fine work obtained more than 95%, retention time identical with standard substance (HPLC) .MS (EI), m/z807 (M+H).
Embodiment 4: a kind of method preparing Tulathromycin of this example, the steps include:
A. epoxy intermediate (III) (747g is added in the reactor, 1.0mol), ethanol (5800g), N-benzyl propylamine (178.8g, 1.2mol) stir, be then heated to 50-60 DEG C of stirring reaction 36 hours;
B. after completion of the reaction, concentration removes major part solvent, adds acetone (7200g), is transferred in pressure reactor after stirring;
C. in pressure reactor, add 10% palladium-carbon catalyst (74.7g), pass into hydrogen, keeping reactant liquor 20-30 DEG C, stirring reaction 24 hours under 50psi pressure, reaction is recovered by filtration catalyst after terminating, concentration removes major part solvent, it is subsequently adding water (7470g), collects by filtration the solid of precipitation, after vacuum drying, obtain Tulathromycin crude product, fine work 589.6g is obtained, yield about 73.2% after recrystallization.
The content of the Tulathromycin fine work obtained more than 95%, retention time identical with standard substance (HPLC) .MS (EI), m/z807 (M+H).
Embodiment 5: a kind of method preparing Tulathromycin of this example, the steps include:
A. epoxy intermediate (III) (747g is added in the reactor, 1.0mol), ethanol (4000g), N-benzyl propylamine (149g, 1.0mol) stir, be then heated to 50-60 DEG C of stirring reaction 24 hours;
B. after completion of the reaction, concentration removes major part solvent, adds acetone (6300g), is transferred in pressure reactor after stirring;
C. in pressure reactor, add 10% palladium-carbon catalyst (74.7g), pass into hydrogen, keeping reactant liquor 20-30 DEG C, stirring reaction 20 hours under 50psi pressure, reaction is recovered by filtration catalyst after terminating, concentration removes major part solvent, it is subsequently adding water (7470g), collects by filtration the solid of precipitation, after vacuum drying, obtain Tulathromycin crude product, fine work 392.4g is obtained, yield about 48.7% after recrystallization.
The content of the Tulathromycin fine work obtained more than 95%, retention time identical with standard substance (HPLC) .MS (EI), m/z807 (M+H).
Embodiment 6: a kind of method preparing Tulathromycin of this example, the steps include:
A. epoxy intermediate (III) (747g is added in the reactor, 1.0mol), ethanol (5000g), N-benzyl propylamine (163.9g, 1.1mol) stir, be then heated to 50-60 DEG C of stirring reaction 30 hours;
B. after completion of the reaction, concentration removes major part solvent, adds acetone (6600g), is transferred in pressure reactor after stirring;
C. in pressure reactor, add 10% palladium-carbon catalyst (74.7g), pass into hydrogen, keeping reactant liquor 20-30 DEG C, stirring reaction 22 hours under 50psi pressure, reaction is recovered by filtration catalyst after terminating, concentration removes major part solvent, it is subsequently adding water (7470g), collects by filtration the solid of precipitation, after vacuum drying, obtain Tulathromycin crude product, fine work 506.2g is obtained, yield about 62.8% after recrystallization.
The content of the Tulathromycin fine work obtained more than 95%, retention time identical with standard substance (HPLC) .MS (EI), m/z807 (M+H).
The foregoing is only specific embodiments of the invention, but the architectural feature of the present invention is not limited thereto, any those skilled in the art is in the field of the invention, and change or the modification made all are encompassed among the scope of the claims of the present invention.
Claims (6)
1. the method preparing Tulathromycin, it is characterised in that described method includes:
A. add epoxy intermediate in the reactor, ethanol or isopropanol, N-benzyl propylamine stir, wherein epoxy intermediate with the mass ratio of ethanol or isopropanol, N-benzyl propylamine is: 1:5��8:0.19��0.24, is then heated to 50-60 DEG C of stirring reaction;
B. after completion of the reaction, concentration removes major part solvent, adds acetone, is transferred in pressure reactor after stirring;
C. in pressure reactor, add palladium-carbon catalyst, pass into hydrogen, keep reactant liquor 20-30 DEG C, stirring reaction under 45-55psi pressure, reaction is recovered by filtration catalyst after terminating, concentration removes major part solvent, it is subsequently adding water, collect by filtration the solid of precipitation, after vacuum drying, obtain Tulathromycin crude product, after recrystallization, obtain Tulathromycin fine work.
2. a kind of method preparing Tulathromycin according to claim 1, it is characterised in that in described step b, epoxy intermediate is 1:8��10 with the mass ratio of acetone.
3. a kind of method preparing Tulathromycin according to claim 1, it is characterised in that in described step c, epoxy intermediate is 1:0.1 with the mass ratio of 10% palladium-carbon catalyst.
4. a kind of method preparing Tulathromycin according to claim 1, it is characterised in that in described step a, the stirring reaction time is 24��36 hours, and reaction temperature is 50��60 DEG C.
5. a kind of method preparing Tulathromycin according to claim 1, it is characterised in that in described step c, the time of stirring reaction is 20��24 hours, and reaction temperature is 20��30 DEG C.
6. a kind of method preparing Tulathromycin according to claim 1, it is characterised in that described vacuum drying condition is 60 DEG C/10mmHg, and the dry time is 8 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610043716.9A CN105646617A (en) | 2016-01-21 | 2016-01-21 | Method for preparing tulathromycin |
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| CN201610043716.9A CN105646617A (en) | 2016-01-21 | 2016-01-21 | Method for preparing tulathromycin |
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| CN105646617A true CN105646617A (en) | 2016-06-08 |
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| CN201610043716.9A Pending CN105646617A (en) | 2016-01-21 | 2016-01-21 | Method for preparing tulathromycin |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN107556351A (en) * | 2017-08-29 | 2018-01-09 | 博瑞生物医药（苏州）股份有限公司 | A kind of preparation method of Tulathromycin |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1793155A (en) * | 1997-06-11 | 2006-06-28 | 辉瑞产品公司 | 4'-substituted-9-deoxo-9a-aza-9a-homoerythromycin a derivatives |
| CN102295672A (en) * | 2011-07-13 | 2011-12-28 | 武汉回盛生物科技有限公司 | Synthetic method for tylosin |
| CN102786569A (en) * | 2012-09-07 | 2012-11-21 | 安徽中升药业有限公司 | Tulathromycin intermediate and preparation method thereof, as well as preparation method of tulathromycin |
| WO2015014907A1 (en) * | 2013-07-31 | 2015-02-05 | Farma Grs, D.O.O. | Process for preparation of tulathromycin |
-
2016
- 2016-01-21 CN CN201610043716.9A patent/CN105646617A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1793155A (en) * | 1997-06-11 | 2006-06-28 | 辉瑞产品公司 | 4'-substituted-9-deoxo-9a-aza-9a-homoerythromycin a derivatives |
| CN102295672A (en) * | 2011-07-13 | 2011-12-28 | 武汉回盛生物科技有限公司 | Synthetic method for tylosin |
| CN102786569A (en) * | 2012-09-07 | 2012-11-21 | 安徽中升药业有限公司 | Tulathromycin intermediate and preparation method thereof, as well as preparation method of tulathromycin |
| WO2015014907A1 (en) * | 2013-07-31 | 2015-02-05 | Farma Grs, D.O.O. | Process for preparation of tulathromycin |
Non-Patent Citations (1)
| Title |
|---|
| E. S. C. WU，等: ""Flavones. 2. Synthesis and Structure-Activity Relationship of Flavodilol and Its Analogues, a Novel Class of Antihypertensive Agents with Catecholamine Depleting Properties"", 《J. MED. CHEM.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN107556351A (en) * | 2017-08-29 | 2018-01-09 | 博瑞生物医药（苏州）股份有限公司 | A kind of preparation method of Tulathromycin |
| CN107556351B (en) * | 2017-08-29 | 2019-10-18 | 博瑞生物医药（苏州）股份有限公司 | A kind of preparation method of Tulathromycin |
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Application publication date: 20160608 |