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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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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 main disadvantage of this method is that the reaction of hydroxyl to form aldehyde is a selective oxidation reaction, and it is not easy for people to strictly control the reaction process in the stage of forming aldehyde, and aldehyde is generally unstable.
Therefore, the reaction process is difficult to accurately control, and it is easy to cause the reaction to be incomplete, or cause the reaction to continue to generate carboxylic acid.
On the other hand, the first step described in CN 200780031395.X——the solvent used in the Leuckart-Wallach reaction is the same, the first step and the last step of the method are all using the precursor toluene as the reaction medium, and the amount of use is large , in the actual production process, it will increase management costs and cause risks. It is especially important that this reagent has cumulative toxicity to the human body and will cause irreversible damage to the blood system, which is not conducive to the labor protection of on-site operators.

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

Embodiment 1

[0105] Embodiment 1: the new synthesis of tedirol

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

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

[0108] In an aqueous solution, allow 0.08 mole of tylosin (I) and 0.6 mole of sulfuric acid to react for 1.2 h under the conditions of pH 1.8 and reaction temperature 60° C., then allow the reaction mixture to cool, and then dissolve it with 25% ammonia water 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 reaction mixture adjusted to pH was extracted 3 times with ethyl acetate under alkaline conditions, the combined extracts were then mixed with 0.10 1 mole of piperidine and 2.0 moles of hydrochloric acid were reacted at pH 1.6 and reaction temperature 70°C for 1 h; the reaction mixture was cooled and transferred to a separatory funnel, water was added, and the pH of the rea...

Embodiment 2

[0116] Embodiment 2: the new synthesis of tedrol

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

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

[0119] In aqueous solution, allow 0.04 mole tylosin (I) and 0.8 mole hydrochloric acid to react 0.5h under the condition of pH 1.0 and reaction temperature 90 ℃, allow reaction mixture to cool down then, use 28% ammoniacal liquor by volume again its 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 reaction mixture adjusted to pH was extracted with ethyl acetate under alkaline conditions, the combined extracts were mixed with 0.05 mole Piperidine and 0.5 mole of sulfuric acid were reacted for 4 hours at a pH of 1.0 and a reaction temperature of 60°C; after the reaction, the reaction mixture was cooled to room temperature, transferred to a separatory funnel, water was added, and the reaction...

Embodiment 3

[0127] Embodiment 3: the new synthesis of tedrol

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

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

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

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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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