CN111393493B - Synthetic method of tildipirosin - Google Patents
Synthetic method of tildipirosin Download PDFInfo
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- CN111393493B CN111393493B CN202010224650.XA CN202010224650A CN111393493B CN 111393493 B CN111393493 B CN 111393493B CN 202010224650 A CN202010224650 A CN 202010224650A CN 111393493 B CN111393493 B CN 111393493B
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Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthetic method of a tildipirosin intermediate. The method comprises the following steps: (1) Preparing 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide; and (2) preparing the tildipirosin. The method has the advantages of simple treatment process, small amount of waste liquid, low environmental protection treatment cost, high product yield and high purity of the obtained product.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a tildipirosin intermediate and a synthetic method of tildipirosin.
Background
Tildipirosin has a chemical formula of C 41 H 71 N 3 O 8 The chemical name of the derivative is 20, 23-dipiperidinyl-5-O-mycaminosyl-tylonolide, and the structural formula is as follows:
tylosin (tildipiriosin), a new semi-synthetic macrolide antibiotic developed by International corporation of integwort (International BV) in the netherlands, which is a special macrolide for animals, is a derivative of tylosin. Sterile injection with tildipirosin as main effective componentAgent (trade name:
) Approved for marketing in the European union countries after approval by the European pharmaceutical administration (EMA) in 2011. Can be used for preventing and treating respiratory system infectious diseases of pig and cattle caused by sensitive bacteria such as Haemophilus parasuis, actinobacillus pleuropneumoniae, pasteurella multocida and Mannheim hemolyticus. After single intramuscular injection or subcutaneous injection administration, the tildipirosin has the advantages of quick absorption, short peak reaching time, high concentration in lung tissues, high bioavailability, slow elimination, lasting drug effect, high safety, capability of providing whole-course treatment after single administration and the like, and has wide application prospect.
The antibacterial action of the tylosin is similar to that of tylosin, has strong antibacterial action on gram-positive bacteria and partial gram-negative bacteria, is particularly sensitive to pathogenic bacteria causing respiratory system diseases of pigs and cattle, such as pasteurella multocida, actinobacillus pleuropneumoniae, bordetella bronchiseptica, haemophilus parasuis, haemolytic Mannheim, histophilus somni, mycoplasma, spirochete, brucella and the like, has the same antibacterial action mechanism as macrolide medicaments such as tylosin and the like, can be combined with 50s subunits of nucleoproteins of sensitive bacteria to inhibit and prevent the synthesis and extension of nucleoprotein peptide chains, and further influence the synthesis of bacterial proteins.
The 20-piperidyl-23-iodine-5-O-mycaminosyl-tylonolide is an important intermediate for synthesizing tildipirosin, and the structural formula is as follows:
20-piperidinyl-23-iodo-5-O-mycaminosyl-tylonolide is commercially difficult to purchase and is usually synthesized by itself.
At present, the literature reports mainly include the following methods for synthesizing the intermediate of tildipirosin:
in the patent WO2008012343, tylosin is used as a raw material, and a final product is obtained by 5 steps of amination of piperidine on 20 th position, hydrolysis twice, activation on 23 th position and amination. In the method, the hydrogen bromide solution is hydrolyzed at different temperatures twice, the treatment process is complicated, the amount of waste liquid is large, and a large amount of waste liquid containing high-concentration organic solvent is generated after iodine and pyridine are used for substitution, so that the waste liquid treatment cost is greatly increased, and the yield of the method is only 12.2 percent, so that the production cost is high, and the method is not suitable for industrial production. The specific synthetic formula of the route is as follows:
patent CN102863487 reports that tylosin tartrate is used as a raw material, intermediate 23-hydroxy-5-O-mycaminosyl-tylonolide is obtained by hydrolysis, iodination is carried out, and then the intermediate and piperidine are aminated to form the final product tylosin. The method has the disadvantages that triphenylphosphine, imidazole, iodine and the like are used, anhydrous conditions are required for reaction, requirements on equipment and production conditions are high, the amount of generated high-concentration waste liquid containing imidazole and triphenylphosphine is large, the environment-friendly treatment cost is increased, the cost is not reduced, and industrial production is realized.
The specific synthetic formula of the route is as follows:
U.S. Pat. No. 6,6514946 of Japan society for the research of microbiology, uses 20,30-diiodo-5-O-mycaminose-tylonolide as raw material, reacts with piperidine in acetonitrile, and the product is obtained by column chromatography, the yield is 86.4%. The raw materials are not easy to obtain, column chromatography is utilized, the defects of the column chromatography are complex separation process, long time consumption and large solvent amount, and the method has low efficiency and is not suitable for industrial production in actual production.
Patent CN105254693A discloses a preparation method of 20-piperidyl-23-I-5-O-mycaminosyl-tylonolide, which comprises the following steps: (1) Preparation of 20-piperidinyl-5-O-mycaminosyl-tylonolide: dissolving 18.3g of tylosin, 4.2g of piperidine and 1.4g of formic acid in 50ml of toluene, heating to 75 ℃, reacting for 1 hour, cooling to room temperature, adding 60ml of water, heating to 35 ℃, adjusting pH =2.5 by using 60% sulfuric acid solution, and hydrolyzing for 1 hour. After the reaction, the reaction solution was cooled to room temperature, 40ml of dichloromethane was added, and pH =10 was adjusted with 10N sodium hydroxide solution, the layers were separated, the aqueous phase was washed twice with 10ml of dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate for use. (2) Preparation of 20-piperidinyl-23-I-5-O-mycaminosyl-tylonolide: adding 5.2g of hexamethyldisilazane into the dried dichloromethane solution, reacting at 30 ℃ for 2.5 hours (no ammonia gas is released), cooling the reaction solution to room temperature, adding 11.9g of N, N-diethylaniline and 10.0g of iodotrimethylsilane, reacting at 30 ℃ for 2 hours, cooling to room temperature, adding 60ml of water, stirring for 2 hours, demixing, adjusting the pH of the aqueous phase with 10N sodium hydroxide solution =10, filtering, washing, and drying to obtain 14.3g of the product. In the production process of the method, the release of a large amount of ammonia has high requirements on safety protection measures of production environment and professional literacy of workers, and has relatively special requirements on corrosion resistance of equipment, and meanwhile, the use of a large amount of N, N-diethylaniline and trimethyliodosilane causes the COD (chemical oxygen demand) in the production wastewater to be very high, so that the environmental-protection treatment cost is increased.
Patent CN104558076A relates to a preparation method of 20-piperidyl-23-iodo-5-O-mycylamine glycosyl-tylonolide, which specifically comprises the following steps:
dichloromethane (120ml, 20V), pyridine (4.8g, 61mmol, 6.0eq), triphenylphosphine (15.7g, 61mmol, 6.0eq) were added into a three-necked flask, the mixture was stirred thoroughly until the system solution became clear, the temperature was maintained at 15 ℃, the iodine simple substance (15.3g, 61mmol, 6.0eq) was added in portions, after the addition, the system was allowed to warm to room temperature naturally, the reaction mixture was stirred for 1 hour, a dichloromethane (60ml, 10V) solution of compound 3 (6.0g, 10.0mmol, 1.0eq) was added dropwise at 15 ℃, after the addition, the temperature was naturally raised to room temperature, the reaction mixture was stirred for 4 hours, and the disappearance of the starting material was detected by HPLC. The reaction was quenched by addition of sodium sulfite solution at 15 ℃, the organic phase was adjusted to PH 1-2 with hydrochloric acid (1N), extracted with dichloromethane (3 × 100 ml), the aqueous phase was adjusted to PH 8-9 with saturated sodium bicarbonate solution and then extracted with dichloromethane (3 × 100 ml), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 7.17 g of a yellow solid with 95% purity in 88% yield. According to the method, iodination reaction needs to be carried out on 2 hydroxyl groups in the reaction, the activity of the iodine is high, iodination reaction can be carried out on 4 hydroxyl groups on 20-hydroxyl-23-iodine-5-O-mycaminosyl-tylonolide at a chance, the purity of the product is low, and the post-treatment purification process is complicated.
Disclosure of Invention
In order to solve the technical problems, the invention provides a synthetic method of a tildipirosin intermediate, which has low requirements on equipment and production conditions, is simple to operate, has short reaction time, can repeatedly recycle a catalyst, has high yield, has high product purity, does not have special solvents which are difficult to treat, has little waste liquid and has low waste liquid treatment cost.
The invention is realized by the following technical scheme:
a method for synthesizing a tildipirosin intermediate, wherein the tildipirosin intermediate is 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide, is characterized by comprising the following steps:
the 20-piperidyl-5-O-mycaminosyl-tylonolide and hydroiodic acid are subjected to reflux reaction to obtain the 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide.
The reaction formula is as follows:
in the synthesis method of the tildipirosin intermediate, the reaction solvent is acetonitrile.
In the synthesis method of the tildipirosin intermediate, the weight ratio of the 20-piperidyl-5-O-mycaminosyl-tylonolide to the hydroiodic acid is 1:055-0.62.
In the synthesis method of the tildipirosin intermediate, the concentration of hydroiodic acid is 50-60% by mass.
In the above method for synthesizing the tildipirosin intermediate, the concentration of hydroiodic acid is 57% by mass.
In the synthesis method of the tildipirosin intermediate, the reaction time is 4-5h.
In the above method for synthesizing the intermediate of tildipirosin, the reaction further comprises a post-treatment step, wherein the post-treatment step is: after the reaction is finished, concentrating under reduced pressure until no solvent exists basically, adding water, adjusting the pH to 11-12 by using a sodium hydroxide solution, stirring for 15-20min, carrying out suction filtration, and drying to obtain a product 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide.
The detailed steps of the synthesis method of the tildipirosin intermediate are as follows:
adding 20-piperidyl-5-O-mycaminosyl-tylonolide into acetonitrile, stirring, adding hydriodic acid (57%), refluxing for 4.5h, concentrating under reduced pressure until no solvent exists basically, adding water, adjusting pH to 11-12 with sodium hydroxide solution, stirring for 15-20min, performing suction filtration, and drying to obtain 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide.
The method for synthesizing the tildipirosin, which comprises the method for synthesizing the intermediate of tildipirosin, comprises the following steps:
(1) Preparation of 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide
Adding 20-piperidyl-5-O-mycaminosyl-tylonolide into acetonitrile, stirring, adding hydroiodic acid (57%), refluxing for 4.5h, concentrating under reduced pressure until no solvent exists basically, adding water, adjusting the pH to 11-12 with a sodium hydroxide solution, stirring for 15-20min, carrying out suction filtration, and drying to obtain 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide;
(2) Preparation of tildipirosin
Dissolving 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide in butyl acetate, adding piperidine and potassium carbonate, heating and refluxing for 3 hours, filtering, adding purified water into the filtrate, adjusting the pH value to 4.0 by using hydrochloric acid, separating a water phase, washing the water phase by using dichloromethane, adjusting the pH value to 10 by using 4mol/L sodium hydroxide, stirring for 1 hour, filtering, and drying a filter cake to obtain the tildipirosin.
Compared with the prior art, the invention has the following beneficial effects:
(1) The synthesis method of the tildipirosin intermediate 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide adopts hydroiodic acid for one-time hydrolysis preparation, and has the advantages of simple treatment process, small amount of generated waste liquid, environmental protection and low treatment cost.
(2) The synthesis method of the tildipirosin intermediate 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide does not involve raw materials such as triphenylphosphine, iodine, imidazole and pyridine which have special odor or generate odor after reaction, is more green in production process, does not need special harsh conditions for reaction, has lower requirements on equipment and production conditions, avoids generating a large amount of high-concentration waste liquid, is low in environmental protection treatment cost, and is beneficial to industrial production.
(3) The synthesis method of the tildipirosin intermediate 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide has the advantages of easily obtained raw materials, no need of column chromatography, simple separation process, short time consumption, small solvent amount, high production efficiency and suitability for industrial production.
(4) The synthesis method of the tildipirosin intermediate 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide has the advantages of high product yield and high purity of the obtained product.
Detailed Description
The present invention will be further described with reference to specific examples so that those skilled in the art may better understand the present invention, but the present invention is not limited thereto.
Example 1 Synthesis of 20-piperidinyl-23-iodo-5-O-mycaminosyl-tylonolide
Adding 71.5kg of 20-piperidyl-5-O-mycylamine glycosyl-tylonolide (1) and 160kg of acetonitrile into a 500L reaction kettle, stirring, adding 44.1kg of hydroiodic acid (57%), performing reflux reaction for 4.5 hours, concentrating under reduced pressure until the mixture is basically free of solvent, adding water, adjusting the pH value to 11 by using a sodium hydroxide solution, stirring for 20min, performing suction filtration and drying to obtain 63.0kg of a product 20-piperidyl-23-iodo-5-O-mycylamine glycosyl-tylonolide (2), wherein the yield is 95.4%, and the purity is 98.1%.
EXAMPLE 2 Synthesis of 20-piperidinyl-23-iodo-5-O-mycaminosyl-tylonolide
Adding 71.5kg of 20-piperidyl-5-O-mycylamine glycosyl-tylonolide (1) and 160kg of acetonitrile into a 500L reaction kettle, stirring, adding 44.1kg of hydroiodic acid (57%), performing reflux reaction for 4.5 hours, concentrating under reduced pressure until the mixture is basically free of solvent, adding water, adjusting the pH value to 12 by using a sodium hydroxide solution, stirring for 20min, performing suction filtration and drying to obtain 63.2kg of a product 20-piperidyl-23-iodo-5-O-mycylamine glycosyl-tylonolide (2), wherein the yield is 95.8% and the purity is 98.3%.
EXAMPLE 3 Synthesis of 20-piperidinyl-23-iodo-5-O-mycaminosyl-tylonolide
Adding 71.5kg of 20-piperidyl-5-O-mycaminosyl-tylonolide (1) and 160kg of acetonitrile into a 500L reaction kettle, stirring, adding 39.5kg of hydroiodic acid (57%), performing reflux reaction for 4.5h (the reaction kettle is connected with a tail gas absorption tank), concentrating under reduced pressure until no solvent exists basically, adding water, adjusting the pH to 12 by using a sodium hydroxide solution, stirring for 20min, performing suction filtration and drying to obtain 62.9kg of a product 20-piperidyl-23-iodine-5-O-mycaminosyl-tylonolide (2), wherein the yield is 95.3%, and the purity is 98.5%.
EXAMPLE 4 Synthesis of 20-piperidinyl-23-iodo-5-O-mycaminosyl-tylonolide
Adding 71.5kg of 20-piperidyl-5-O-mycylamine glycosyl-tylonolide (1) and 160kg of acetonitrile into a 500L reaction kettle, stirring, adding 44.5kg of hydroiodic acid (57%), performing reflux reaction for 4.5 hours, concentrating under reduced pressure until the mixture is basically free of solvent, adding water, adjusting the pH value to 12 by using a sodium hydroxide solution, stirring for 20min, performing suction filtration and drying to obtain 63.2kg of a product 20-piperidyl-23-iodo-5-O-mycylamine glycosyl-tylonolide (2), wherein the yield is 95.7%, and the purity is 98.4%.
Example 5
(1) Synthesis of 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide
Adding 71.5kg of 20-piperidyl-5-O-mycaminosyl-tylonolide (1) and 160kg of acetonitrile into a 500L reaction kettle, stirring, adding 41.7kg of hydroiodic acid (57%), performing reflux reaction for 4.5h (a tail gas absorption tank is connected to the reaction kettle), concentrating under reduced pressure until no solvent exists basically, adding water, adjusting the pH to 12 by using a sodium hydroxide solution, stirring for 20min, performing suction filtration and drying to obtain 63.2kg of a product 20-piperidyl-23-iodine-5-O-mycaminosyl-tylonolide (2), wherein the yield is 95.7%, and the purity is 98.3%.
(2) Preparation of tildipirosin
In a 500L reaction kettle, dissolving 56.6kg of 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide with 200kg of butyl acetate, adding 27kg of piperidine and 55kg of potassium carbonate, heating and refluxing for 3h, filtering, adding 200kg of purified water into the filtrate, adjusting the pH to 4.0 with hydrochloric acid, separating out an aqueous phase, washing the aqueous phase with 30kg of dichloromethane, adjusting the pH to 10 with 4mol/L of sodium hydroxide, stirring for 1h, filtering, drying a filter cake to obtain 49.2kg of tedizonew, wherein the yield is 91.9%, and the HPLC purity is 98.2%.
Claims (1)
1. A synthetic method of tildipirosin is characterized by comprising the following steps:
(1) Preparation of 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide
Adding 20-piperidyl-5-O-mycaminosyl-tylonolide into acetonitrile, stirring, adding 57% hydriodic acid, refluxing for 4.5h, connecting a reaction kettle to a tail gas absorption tank, concentrating under reduced pressure until no solvent exists basically, adding water, adjusting the pH to 11-12 by using a sodium hydroxide solution, stirring for 15-20min, carrying out suction filtration, and drying to obtain 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide;
(2) Preparation of tildipirosin
Dissolving 20-piperidyl-23-iodo-5-O-mycaminosyl-tylonolide with butyl acetate, then adding piperidine and potassium carbonate, heating and refluxing for 3h, filtering, adding purified water into filtrate, adjusting the pH value to 4.0 with hydrochloric acid, separating out a water phase, washing the water phase with dichloromethane, adjusting the pH value to 10 with 4mol/L sodium hydroxide, stirring for 1h, filtering, and drying a filter cake to obtain the tildipirosin.
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| CN111393493A (en) | 2020-07-10 |
| CN108822162A (en) | 2018-11-16 |
| CN108822162B (en) | 2020-03-17 |
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