Synthetic method for Tildipirosin

A technology of tediloxine and synthetic chemistry, applied in chemical instruments and methods, preparation of sugar derivatives, sugar derivatives, etc., can solve the problems of high toxicity of triphenylphosphine oxide mixture, inability to directly discharge or bury, pollution, etc.

Active Publication Date: 2015-04-08
CHINA INST OF VETERINARY DRUG CONTROL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 1. After the reaction is over, a viscous by-product—triphenylphosphine solid precipitates out, which will wrap a certain amount of target product, affecting the yield of the product
[0007] 2. The mixture of unreacted triphenylphosphine and by-product triphenylphosphine oxide is highly toxic and cannot be discharged or buried directly, otherwise it will cause environmental pollution, and the problem of "three wastes" treatment has not yet been solved in China
At present, the treatment method of this kind of waste is to adopt the method of evaporation and precipitation, but this method will consume a lot of energy, resulting in waste of resources and environmental pollution.
[0008] 3. The triphenylphosphine oxide mixed in the product cannot be completely removed by conventional precipitation and recrystallization methods, and column chromatography is required to purify the intermediate product, otherwise it will affect the next reaction and is not suitable for large-scale production
The mai

Method used

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  • Synthetic method for Tildipirosin
  • Synthetic method for Tildipirosin
  • Synthetic method for Tildipirosin

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0105] Embodiment 1: the synthesis of tediloxine

[0106] The implementation steps of this embodiment are as follows:

[0107] A. Synthesis of 23-hydroxy-20-piperidinyl-5-O-mycaminosyl-tylonolide (II)

[0108] In an aqueous solution, 0.08 mol of tylosin (I) was reacted with 0.6 mol of sulfuric acid at pH 1.8 and a reaction temperature of 60° C. for 1.2 h, then the reaction mixture was allowed to cool, and then dissolved in 25% ammonia by volume. The pH of the reaction mixture was adjusted to pH 10. According to the volume ratio of the reaction mixture to ethyl acetate 1.0:1.0, the pH-adjusted reaction mixture was extracted 3 times with ethyl acetate under alkaline conditions, the extracts were combined, and then mixed with 0.10 Molar piperidine and 2.0 molar hydrochloric acid were reacted for 1 h under the conditions of pH 1.6 and reaction temperature of 70 °C; the reaction mixture was cooled and transferred to a separatory funnel, water was added, and the pH of the reaction ...

Example Embodiment

[0116] Embodiment 2: Synthesis of Tedirosine

[0117] The implementation steps of this embodiment are as follows:

[0118] A. Synthesis of 23-hydroxy-20-piperidinyl-5-O-mycaminosyl-tylonolide (II)

[0119] In an aqueous solution, 0.04 moles of tylosin (I) and 0.8 moles of hydrochloric acid were allowed to react at pH 1.0 and a reaction temperature of 90° C. for 0.5 h, then the reaction mixture was allowed to cool, and then dissolved in 28% ammonia by volume. The pH of the reaction mixture was adjusted to pH 9. According to the volume ratio of the reaction mixture to ethyl acetate 1.0:0.5, the pH-adjusted reaction mixture was extracted with ethyl acetate under basic conditions, and the extracts were combined and mixed with 0.05 mol. Piperidine and 0.5 moles of sulfuric acid were reacted for 4 h at pH 1.0 and reaction temperature of 60 °C; after the reaction was completed, the reaction mixture was cooled to room temperature, transferred to a separatory funnel, added water, and ...

Example Embodiment

[0127] Example 3: Synthesis of Tedirosine

[0128] The implementation steps of this embodiment are as follows:

[0129] A. Synthesis of 23-hydroxy-20-piperidinyl-5-O-mycaminosyl-tylonolide (II)

[0130] In an aqueous solution, 0.06 mol of tylosin (I) was reacted with 1.0 mol of trifluoroacetic acid at pH 2.5 and a reaction temperature of 95 °C for 0.8 h, then the reaction mixture was allowed to cool, and then used 28% by volume ammonia water The pH of the reaction mixture was adjusted to pH 10. According to the volume ratio of the reaction mixture to methyl acetate of 1.0:0.5, the pH-adjusted reaction mixture was extracted with methyl acetate under alkaline conditions, and the extracts were combined and mixed with 0.12 mol. Piperidine and 0.8 mol of formic acid were reacted for 3 h at pH 2.4 and reaction temperature of 50 °C; after the reaction was completed, the reaction mixture was cooled to room temperature, transferred to a separatory funnel, added water, and the reaction...

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Abstract

The invention relates to a synthetic method for Tildipirosin. The method comprises the synthetic steps of 23-hydroxy-20-piperidyl-5-O-mycaminoseyl-tylolactones, and 23-sulphonate-20-piperidyl-5-O-mycaminoseyl-tylolactones. The reaction yield of the method is high, and the conversion rate of each step of the reaction is up to more than 80%; and the purity of the product is high, and is up to more than 98.2%. The main raw material of the method is tylosin, the reaction reagent is the normal reagent which is easily obtained in the market and is cheap, and does not need to be stored in the ultralow temperature. The method is simple and safe in operation, does not need the devices in high temperature and high pressure, and has no risk. The method is capable of effectively solving the completeness of the reactant conversion, avoiding the column chromatography isolation for the intermediate product and the environment pollution, recovering the triphenylphosphine oxide of the byproduct, shortening the reaction period, improving the yield of the product, and reducing the production cost, and has the industrialized application value.

Description

【Technical field】 [0001] The invention belongs to the technical field of organic compound synthesis. More specifically, the present invention relates to a synthetic method of tedirosin. 【Background technique】 [0002] Tildipirosin is a new macrolide antibiotic used in veterinary medicine, and it is a semi-synthetic drug homologue of tylosin. Tedirosin has a unique chemical structure, it is replaced by two piperidines at C20 and C23, and a carbamycin lactone ring is connected at C5. Since these three nitrogen atoms are easily protonated, tedirosin is a tribasic molecule. Tedirosin is used to treat and prevent respiratory diseases in cattle and pigs, and has many advantages such as drug resistance, less dosage, one-time administration, low residue, and animal-specific use. Tedirosin not only has the advantages of macrolide antibiotics, but also has high bioavailability (78.9%), which is superior to other macrolide antibiotics with a long half-life (9Day), and it can remain ...

Claims

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Application Information

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IPC IPC(8): C07H17/08C07H1/00
Inventor 朱馨乐尹晖徐士新
Owner CHINA INST OF VETERINARY DRUG CONTROL
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