CN112745370B - Preparation method of tulathromycin - Google Patents
Preparation method of tulathromycin Download PDFInfo
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- CN112745370B CN112745370B CN202110203010.5A CN202110203010A CN112745370B CN 112745370 B CN112745370 B CN 112745370B CN 202110203010 A CN202110203010 A CN 202110203010A CN 112745370 B CN112745370 B CN 112745370B
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- C—CHEMISTRY; METALLURGY
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- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The invention relates to a synthesis method of tulathromycin. Under the action of illumination and a specific catalytic system, the rapid, efficient and pollution-free synthesis of tulathromycin is realized, and compared with the existing synthesis method, the method has the advantages of simple operation and mild conditions, and can meet the requirements of large-scale industrial production.
Description
Technical Field
The patent relates to a preparation method of tulathromycin, belonging to the field of chemical synthesis.
Background
Tulathromycin is a macrolide semi-synthetic antibiotic which is newly developed and marketed and is specially used for animals, and can inhibit bacterial transpeptidation process by combining with 50s subunit of nucleoprotein body of sensitive bacteria and stimulating dissociation of peptidyl tRNA from ribosome during translocation, so that synthesis and elongation of peptide chain are hindered, and bacterial protein synthesis is influenced. The tulathromycin has bacteriostatic and bactericidal activity, is mainly used for preventing and treating respiratory diseases, and particularly has very obvious treatment effect on infectious diseases of respiratory systems. The tulathromycin has the characteristics of quick absorption, high bioavailability, low residue, long half-life period, lasting drug effect, capability of providing whole-course treatment by single parenteral administration and the like. The drug is listed in European Union in 2004, approved to be listed in the United states in 2005, and first approved for domestic use in No. 957 bulletin of China Ministry of agriculture in 2008.
The synthesis of tulathromycin reported at present mainly refers to a patent synthesis method (WO 9856802A 1) of the company Peucedanum, and specifically, based on erythromycin A, methyl azithromycin is synthesized by three steps, and then the methyl azithromycin is taken as a raw material, and a target product is obtained by hydroxyl protection, oxidation, epoxidation, deprotection and nucleophilic substitution. The whole synthesis process has the disadvantages of complicated steps, complex reaction conditions, high operation difficulty and high production cost.
CN103641869 is an improvement on the method, demethyl azithromycin is used as a starting material, and is directly oxidized to obtain an intermediate I by adding metal salt without carrying out hydroxyl protection, and then the intermediate I is subjected to epoxidation and nucleophilic substitution to obtain the tulathromycin. Although the method has short steps, a reagent trimethyl sulfur halide generating stink gas dimethyl sulfide is still required in the epoxidation process, and a low-boiling point reagent n-propylamine is required in the ring opening process, so that the production safety hazard is increased.
Disclosure of Invention
Aiming at the technical problems, the invention aims to provide a preparation method of tulathromycin, which has the advantages of short steps, mild conditions, high yield and wide application prospect compared with the existing literature reports.
In order to achieve the purpose, the invention is realized by the following technical scheme: taking the intermediate I as a starting material, and coupling with n-propyl glycine in a solvent by illumination in the presence of a catalyst to obtain a target product in one step.
After the reaction is finished, extracting by using an extracting agent. And washing, drying and distilling the combined organic phase under reduced pressure to obtain a crude product. And recrystallizing the crude product to obtain the telavamycin product.
The molar ratio of the intermediate I to the n-propyl glycine is 1-1.
The molar ratio of the intermediate I to the catalyst is 1.005-1.
The catalyst is Ir (ppy) 3 、[Ir(dF(CF 3 )ppy) 2 bpy]PF 6 、Ru(bpy) 3 (PF 6 ) 2 、[Ir(ppy) 2 dtbbpy]PF 6 4-CzIPN, preferably [ Ir (ppy) 2 dtbbpy]PF 6 。
The solvent is water, methanol, ethanol, propanol, n-butanol, pentanediol, dichloromethane, acetonitrile or dimethylformamide, preferably water.
The reaction temperature is 20 to 55 ℃, preferably 20 to 25 ℃.
The extractant is preferably ethyl acetate.
The detergent is preferably a saturated sodium bicarbonate solution and a saline solution.
The recrystallization adopts n-heptane.
Preferably, the reaction system is purged with nitrogen before the light irradiation reaction, and preferably, the number of the purging is 3.
Compared with the prior art, the synthesis method of tulathromycin provided by the invention is simple and short in route, simple to operate, mild in reaction conditions, free of peculiar smell and flammable compounds, low in pollution by taking water as a solvent, high in safety and in line with a green chemical concept.
Detailed Description
The technical solution will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention and that not all embodiments are intended to be considered as limiting. All other embodiments obtained by a person skilled in the art without making any inventive step are within the scope of protection of the present invention.
Example 1:
to a 100mL reaction flask were added water (50 mL), intermediate I (7.33g, 10mmol), n-propylglycine (2.34g, 20mmol) and [ Ir (ppy) 2 dtbbpy]PF 6 (182mg, 0.2mmol). After the nitrogen gas was replaced three times, the mixture was irradiated with a blue LED lamp at 20 to 25 ℃ for 12 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The combined organic phase is washed by saturated sodium bicarbonate solution and salt solution, dried by anhydrous sodium sulfate and distilled under reduced pressure to obtain a crude product. The crude product was recrystallized from n-heptane to yield the product tulathromycin (6.12g, 76%). 1 H NMR(CDCl 3 ，400MHz)δ0.85-0.93(m，10H)；1.06(d，6H,J＝5.6Hz)；1.12-1.26(m，16H)；1.28-1.32(m，4H)；1.33-1.40(m，1H)；1.43-1.52(m，3H)；1.66(d，1H,J＝12.8Hz)；1.72(d，2H,J＝14.2Hz)；1.85-1.90(m，2H)；1.95-1.98(m，1H)；2.10-2.22(m，2H)；2.28(s，6H)；2.46-2.63(m，4H)；2.70-2.81(m，3H)；3.03(d，1H,J＝11.5Hz)；3.22(t，1H,J＝9.5Hz)；3.34(s，3H)；3.47(s，1H)；3.57-3.61(m，1H)；3.63(d，1H,J＝6.7Hz)；4.01(brs，1H)；4.30-4.42(m，2H)；4.50(d，1H,J＝7.6Hz)；4.73-4.78(m，1H)；4.95(d，1H,J＝3.3Hz)。
Example 2:
to a 100mL reaction flask were added water (50 mL), intermediate I (7.33g, 10mmol), n-propylglycine (2.34g, 20mmol) and [ Ir (ppy) 2 dtbbpy]PF 6 (91mg, 0.1mmol). After the nitrogen gas was replaced three times, the mixture was irradiated with a blue LED lamp at 20 to 25 ℃ for 12 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The combined organic phase is washed by saturated sodium bicarbonate solution, brine, dried by anhydrous sodium sulfate and distilled under reduced pressure to obtain a crude product. The crude product was recrystallized from n-heptane to yield the product tulathromycin (5.96g, 74%).
Example 3:
to a 25mL reaction flask were added water (10 mL), intermediate I (1.46g, 2mmol), n-propylglycine (0.47g, 4mmol) and Ru (bpy) in that order 3 (PF 6 ) 2 (17mg, 0.02mmol). After the nitrogen gas was replaced three times, the mixture was irradiated with a blue LED lamp at 20 to 25 ℃ for 12 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The combined organic phase is washed by saturated sodium bicarbonate solution, brine, dried by anhydrous sodium sulfate and distilled under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give the product tulathromycin (0.5g, 31%).
Example 4:
to a 25mL reaction flask were added water (10 mL), intermediate I (1.46g, 2mmol), n-propylglycine (0.47g, 4mmol), and [ Ir (dF (CF) 3 )ppy) 2 bpy]PF 6 (20mg, 0.02mmol). After the nitrogen gas was replaced three times, the mixture was irradiated with a blue LED lamp at 20 to 25 ℃ for 12 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The combined organic phases are dissolved in saturated sodium bicarbonateWashing the solution with brine, drying with anhydrous sodium sulfate, and distilling under reduced pressure to obtain crude product. The crude product was isolated by column chromatography to give the product tulathromycin (0.23g, 14%).
Example 5:
to a 50mL reaction flask were added acetonitrile (25 mL), intermediate I (3.66g, 5 mmol), n-propylglycine (1.17g, 10mmol), and [ Ir (ppy) 2 dtbbpy]PF 6 (46mg, 0.05mmol). After the nitrogen gas was replaced three times, the mixture was irradiated with a blue LED lamp at 20 to 25 ℃ for 12 hours. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The combined organic phase is washed by saturated sodium bicarbonate solution and salt solution, dried by anhydrous sodium sulfate and distilled under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give the product tulathromycin (2.10g, 52%).
Example 6:
to a 100mL reaction flask were added water (50 mL), intermediate I (7.33g, 10mmol), n-propylglycine (2.34g, 20mmol) and [ Ir (ppy) 2 dtbbpy]PF 6 (91mg, 0.1mmol). After the nitrogen gas was replaced three times, the mixture was irradiated with a blue LED lamp at 50 to 55 ℃ for 12 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate. The combined organic phase is washed by saturated sodium bicarbonate solution, brine, dried by anhydrous sodium sulfate and distilled under reduced pressure to obtain a crude product. The crude product was recrystallized from n-heptane to yield the product tulathromycin (5.40g, 67%).
Claims (10)
1. A preparation method of tulathromycin is characterized by comprising the following steps: reacting the intermediate I with n-propyl glycine to obtain tulathromycin;
the reaction is carried out in the presence of a catalyst selected from [ Ir (dF (CF) 3 )ppy) 2 bpy]PF 6 、Ru(bpy) 3 (PF 6 ) 2 、[Ir(ppy) 2 dtbbpy]PF 6 ；
The reaction is carried out under the illumination condition of blue LED light;
the reaction is carried out in a solvent;
replacing nitrogen with the reaction system before reaction;
the structure of the intermediate I is
2. The process for the preparation of tulathromycin of claim 1, wherein: the catalyst is [ Ir (ppy) 2 dtbbpy]PF 6 。
3. The process for the preparation of tulathromycin as claimed in claim 1, characterized in that: the molar ratio of the intermediate I to the catalyst is 1.005-1.
4. The process for the preparation of tulathromycin as claimed in claim 1, characterized in that: the molar ratio of the intermediate I to the n-propyl glycine is 1 to 1.
5. The process for the preparation of tulathromycin as claimed in claim 1, characterized in that: the solvent is water, methanol, ethanol, propanol, n-butanol, pentanediol, dichloromethane, acetonitrile, or dimethylformamide.
6. The process for the preparation of tulathromycin as claimed in claim 5, wherein: the solvent is water.
7. The process for the preparation of tulathromycin as claimed in claim 1, characterized in that: the reaction temperature was maintained at 20-55 ℃.
8. The process for the preparation of tulathromycin as claimed in claim 7, wherein: the reaction temperature is 20-25 ℃.
9. The process for the preparation of tulathromycin as claimed in claim 1, characterized in that: and after the reaction is finished, extracting by using an extracting agent, combining the extract liquor, washing, drying and distilling the combined organic phase under reduced pressure to obtain a crude product, and recrystallizing the crude product to obtain the telavamycin product.
10. The process for the preparation of tulathromycin as claimed in claim 1, characterized in that: the number of times of substitution was 3 times before the reaction.
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| CN106939029A (en) * | 2017-04-28 | 2017-07-11 | 艾美科健（中国）生物医药有限公司 | A kind of preparation method of Tulathromycin |
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| WO2015014907A1 (en) * | 2013-07-31 | 2015-02-05 | Farma Grs, D.O.O. | Process for preparation of tulathromycin |
| CN103772459A (en) * | 2014-02-10 | 2014-05-07 | 青岛蔚蓝生物股份有限公司 | Tulathromycin intermediate, preparation method of tulathromycin intermediate and preparation method of tulathromycin |
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| CN106939029A (en) * | 2017-04-28 | 2017-07-11 | 艾美科健（中国）生物医药有限公司 | A kind of preparation method of Tulathromycin |
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