CN116462724A - Preparation method of tulathromycin intermediate epoxide - Google Patents

Preparation method of tulathromycin intermediate epoxide Download PDF

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CN116462724A
CN116462724A CN202310239316.5A CN202310239316A CN116462724A CN 116462724 A CN116462724 A CN 116462724A CN 202310239316 A CN202310239316 A CN 202310239316A CN 116462724 A CN116462724 A CN 116462724A
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demethylazithromycin
tulathromycin
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epoxide
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聂媛媛
战余铭
周立山
王成威
于璐坤
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Xinfa Pharmaceutical Co Ltd
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Xinfa Pharmaceutical Co Ltd
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    • 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
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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    • Y02P20/00—Technologies relating to chemical industry
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Abstract

The invention provides a preparation method of a tulathromycin intermediate epoxide. The method of the invention comprises the steps of: reacting the demethylazithromycin with trifluoroacetic anhydride serving as an oxidation protective agent, and protecting the hydroxy group at the 2' -position and the amino group at the 6-position of the demethylazithromycin to obtain double-protected demethylazithromycin; double-protected demethylazithromycin is oxidized by Swern, and 4 '-position hydroxyl is oxidized into carbonyl, so that a ketonic intermediate, namely 4' -position carbonyl demethylazithromycin trifluoroacetate, is obtained; the ketonic intermediate is subjected to sulfoylide epoxidation to obtain the tulathromycin intermediate epoxide. The method has the advantages of cheap and easily available raw materials, environment friendliness, safety, environmental protection, easy realization of process conditions, few side reactions, simple purification, high purity and yield of target products and suitability for industrial production.

Description

Preparation method of tulathromycin intermediate epoxide
Technical Field
The invention provides a preparation method of a tulathromycin intermediate epoxide, belonging to the technical field of drug synthesis.
Background
Talarmycin, a macrolide semisynthetic antibiotic special for animals, is also called tularemia, developed by the American-type-of-Chinese-patent-Buddha company, and is sold in the United states and European Union in 2004 under the trade name of Ruikexin, and is allowed to be used in animal production for the first time in 2008 publication No. 957 in China. Talarmycin has a molecular formula of C 41 H 79 N 3 O 12 The relative molecular mass was 806.08.
The tulathromycin is mainly used for treating respiratory diseases of pigs and cattle caused by actinobacillus, mycoplasma, pasteurella and haemophilus parasuis, and has the advantages of small dosage, one-time administration, low residue, special use for animals and the like. In China, the macrolide medicines are widely used, namely tylosin and tilmicosin, and although the 2 medicines have good effects in production, with the extension of the use time, different degrees of medicine resistance appear in a plurality of areas of China, the dosage is continuously increased, the treatment effect is gradually reduced, and the medicine effects of the tylosin are higher than those of the macrolide medicines widely used in markets such as tylosin, tilmicosin and the like. Therefore, the tulathromycin has very wide application prospect in livestock and poultry production, and is prepared mainly by taking azithromycin A as a raw material at home and abroad, and the difference is mainly represented by different protecting modes of the epoxide precursor groups of the preparation intermediates.
Patent document CN103073603a takes demethylazithromycin as a raw material, acetic anhydride protects 2 '-hydroxyl, potassium dichromate oxidizes 4' -hydroxyl, cyano is introduced through sodium cyanide addition reaction, lithium aluminum hydride is reduced, and the reaction is condensed with n-bromopropane to prepare tulathromycin. The method uses sodium cyanide, and has serious environmental pollution; lithium aluminum hydride is used as a reducing reagent, and can reduce cyano and ester groups at the same time; and the final step uses n-bromopropane, the reaction is difficult to control in the secondary amine stage, and the product is difficult to purify as a whole.
The methyl methacrylate is used for protecting the 2' -hydroxyl of the demethylazithromycin by the American-type-self company, the 4 ' -hydroxyl is oxidized and epoxidized, the benzyl acyl is removed by palladium-carbon hydrogenation, and finally the nucleophilic addition of the 4 ' -epoxy is carried out by the n-propylamine to prepare the tulathromycin. (US 6420536, US6472371, CN1793155A, EP 1253153). The method for protecting hydroxyl by benzyl chloroformate and removing the protecting group by palladium-carbon hydrogenation is adopted in the synthetic route, and the benzyl chloroformate has high toxicity, the palladium-carbon cost and the high hydrogenation risk coefficient of the palladium-carbon, and is not beneficial to industrial production.
Patent document CN102260306a uses acetyl to protect the 2' -hydroxyl and 6-amino of demethylazithromycin, oxidizes the 4 "-hydroxyl, epoxidizes, finally uses inorganic alkali alcohol solution to remove acetyl at high temperature, and uses n-propylamine to make nucleophilic addition of 4" -epoxy, so as to prepare tylosin. The synthesis route adopts a method of protecting hydroxyl and amino by acetyl and removing protecting groups under the condition of inorganic alkali alcohol solution, because the tulathromycin itself contains an ester group, the tulathromycin is easy to open the ring under the alkaline condition, the byproducts are more, the yield is low, and the product is not easy to purify.
Patent document CN102786569a uses di-tert-butyl carbonate to protect azithromycin A2' -hydroxyl and 6-amino, oxidizes 4 "-hydroxyl, uses trifluoroacetic acid to deprotect, and simultaneously generates trifluoroacetate, epoxidizes 4" -carbon group, and finally uses n-propylamine to perform nucleophilic addition of 4 "-epoxy to prepare tylosin. The synthetic route adopts a method of protecting hydroxyl and amino by tertiary Ding Yangtan groups; the double-protection intermediate has low yield, and deprotection is carried out before epoxidation, so that the epoxidation has more impurities, is difficult to purify and has low yield.
The literature relates to a method for preparing a tulathromycin intermediate by taking demethylazithromycin and azithromycin A as raw materials, and the method has the defects of expensive raw materials, high toxicity, environmental protection, easiness in side reaction generation, difficulty in purification, higher product impurities, low yield, severe process conditions, high risk coefficient, difficulty in industrial production and the like; therefore, the preparation method of the tulathromycin intermediate is very necessary, which is environment-friendly, economical, safe, easy to realize, less in side reaction, simple in purification, high in product purity and yield and suitable for industrial production.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a preparation method of a tulathromycin intermediate epoxide. The method has the advantages of cheap and easily available raw materials, environment friendliness, safety, environmental protection, easy realization of process conditions, few side reactions, simple purification, high purity and yield of target products and suitability for industrial production.
The technical scheme of the invention is as follows:
a process for preparing a tulathromycin intermediate epoxide comprising the steps of:
(1) Reacting the demethylazithromycin (I) with trifluoroacetic anhydride serving as an oxidation protective agent, and protecting the hydroxy group at the 2' -position and the amino group at the 6-position of the demethylazithromycin to obtain double-protected demethylazithromycin (II);
(2) Double-protected demethylazithromycin (II) is oxidized by Swern, and 4 '-hydroxyl is oxidized into carbonyl, so that a ketonic intermediate (III), namely 4' -carbonyl demethylazithromycin trifluoroacetate, is obtained;
(3) The ketonization intermediate (III) is subjected to sulfoylide epoxidation to obtain a tulathromycin intermediate epoxide (IV);
according to a preferred embodiment of the invention, in step (1), the reaction of the desmethylazithromycin (I) with trifluoroacetic anhydride is carried out in a solvent A.
Preferably, the solvent A is one of dichloromethane, tetrahydrofuran, chloroform or ethyl acetate; the mass of the solvent A is 5 to 20 times, preferably 10 times, the mass of the demethylazithromycin (I).
Preferably, the molar ratio of the desmethylazithromycin (I) to the trifluoroacetic anhydride is 1:1-3, preferably 1:2.
Preferably, the reaction temperature of the demethylazithromycin (I) and the trifluoroacetic anhydride is between-20 ℃ and 0 ℃. The reaction time is 20-120min.
Preferably, the trifluoroacetic anhydride is added dropwise to the system containing the desmethylazithromycin (I).
Preferably, the reaction solution obtained by reacting the demethylazithromycin (I) with the trifluoroacetic anhydride is directly subjected to the next step without treatment.
According to the invention, in step (2), the Swern oxidation of the double-protected demethylazithromycin (II) is carried out under the action of an oxidizing agent and an acid-binding agent.
Preferably, the oxidant is one of dimethyl sulfoxide-trifluoroacetic anhydride or dimethyl sulfoxide-oxalyl chloride; the molar ratio of dimethyl sulfoxide to desmethylazithromycin (I) is 7-10:1;
preferably, the acid binding agent is triethylamine, diethylamine, diisopropylethylamine or trimethylamine; the molar ratio of the demethylazithromycin (I) to the acid binding agent is 1:5-12.
Preferably, the Swern oxidation reaction temperature is-20 ℃ to-80 ℃. The reaction time is 10-60min.
Preferably, the acid-binding agent is added dropwise to a reaction system containing the double-protected demethylazithromycin (II) and the oxidizing agent.
Preferably, the reaction solution obtained by the Swern oxidation reaction can be directly processed for the next step without treatment; or, treating the reaction solution obtained by the Swern oxidation reaction and then carrying out the next step;
further preferably, the processing method includes the steps of: the reaction liquid is extracted, the organic phase is acidified, crystallized, pumped, filtered and dried to obtain a white solid ketone intermediate (III), and then the next step is carried out.
According to a preferred embodiment of the present invention, in step (3), the process for preparing the tulathromycin intermediate epoxide by sulfolobus-ylide epoxidation of the ketonic intermediate (III) comprises the steps of: in the solvent B, under the action of active alkali, trimethyl sulfur halide reacts to obtain dimethyl methylene sulfur solution, namely a sulfur ylide solvent; dripping the ketone intermediate (III) and obtaining the tulathromycin intermediate epoxide (IV) through epoxidation reaction.
Preferably, the solvent B is one or more than two of tetrahydrofuran, methyl tertiary butyl ether, toluene, methylene dichloride, chloroform or dimethyl sulfoxide; further preferably, the solvent B is one or more of tetrahydrofuran, dichloromethane or chloroform; the mass of the solvent B is 10 to 20 times of that of the trimethyl sulfur halide.
Preferably, the active base is potassium tert-butoxide, sodium tert-butoxide or sodium methoxide; the molar ratio of the ketonic intermediate (III) to the active base is 1:5-16, preferably 1:5.5.
Preferably, the trimethyl sulfur halide is one of trimethyl sulfonium bromide or trimethyl sulfur iodide; the molar ratio of the ketonic intermediate (III) to the trimethylsulfur halide is 1:2.5-3, preferably 1:2.7.
Preferably, the reaction temperature of the trimethyl sulfur halide is-30 ℃ to-10 ℃. The reaction time is 1-6 hours.
Preferably, the ketonic intermediate (III) is added dropwise to the reaction system in the form of a solution of the ketonic intermediate (III); further preferably, the solvent used for the ketonic intermediate (III) solution is methylene chloride; the mass of methylene dichloride is 2-5 times that of the ketonic intermediate (III).
Preferably, the epoxidation reaction temperature is from-20℃to-80 ℃. The epoxidation time is 1-3 hours.
Preferably, the post-treatment method of the reaction liquid obtained by the epoxidation reaction comprises the steps of: adding the reaction solution into saturated ammonium chloride aqueous solution to quench reaction, separating the solution, evaporating the organic phase to dryness under reduced pressure, adding acetone, and removing the solvent under reduced pressure; adding acetone and water, precipitating white solid, suction filtering, and drying to obtain tulathromycin intermediate epoxide.
The preparation route of the tulathromycin intermediate epoxide is as follows:
the invention has the technical characteristics and beneficial effects that:
1. in the protection process, trifluoroacetic anhydride is used as an oxidation protective agent, 2' -hydroxyl and 6-amino are protected by the trifluoroacetic anhydride to generate trifluoroacetic acid ester and trifluoroacetamide, and the trifluoroacetic acid ester is easy to deprotect and the trifluoroacetamide is easy to deprotect under alkaline conditions. The double protection is not followed by purification, the Swern oxidation is directly carried out, the process is continuous, the method is simple and reliable, and the yield is high. The Swern oxidation process is accompanied by the removal of trifluoroacetate, and the epoxidation process is accompanied by the removal of trifluoroacetamide, so that the deprotection step is omitted, the method is simple and convenient, the side reaction is reduced, and the yield and purity of the target product are improved.
2. Compared with the method of high-toxicity benzyl chloroformate, the oxidation protective agent trifluoroacetic anhydride used in the invention has the advantages of low toxicity, safety, high yield, no need of expensive palladium-carbon reduction, and mild and safe reaction conditions. After the acetic anhydride is protected, the removal is difficult, and the process is long; compared with acetic anhydride method, the method of the invention has the advantages of simplicity, less byproducts, easy purification and high yield and purity. Compared with the di-tert-butyl carbonate method, the method has the advantages of high product purity and yield, less impurities and simple steps.
3. The double-protection demethylazithromycin (II) obtained by the reaction of the demethylazithromycin (I) and the oxidation protective agent can be directly subjected to the next step without separation; the ketone intermediate (III) obtained by Swern oxidation of the double-protected demethylazithromycin (II) can be directly subjected to the next step without purification; the reaction is continuous, the production efficiency is greatly improved, the product yield is high, the quality is good, the organic solvent can be recycled, no waste water or waste residue is generated, and the method is an environment-friendly production method.
4. The method provided by the invention is used as a whole, the used raw materials are cheap and easy to obtain, the method is safe and low in toxicity, the process conditions are easy to realize, the operation is safe and simple, the side reaction is less, the purity and the yield of the target product are high, and the method is suitable for industrial production.
Drawings
FIG. 1 is an HPLC plot of the tulathromycin intermediate epoxide prepared in example 1.
FIG. 2 is an HPLC plot of the tulathromycin intermediate epoxide prepared in example 2.
FIG. 3 is an HPLC plot of the tulathromycin intermediate epoxide prepared in example 3.
FIG. 4 is an HPLC plot of the prepared tulathromycin.
Detailed Description
The invention is further illustrated by, but not limited to, the following specific examples.
Meanwhile, the raw materials and reagents used in the examples are all commercially available or obtained according to the existing methods; the method is the conventional method unless specified.
Example 1
A process for preparing a tulathromycin intermediate epoxide comprising the steps of:
(1) 25.0g (0.035 mol) of demethylazithromycin was added into a 500ml four-necked flask, 250g of methylene dichloride was added, the mixture was stirred and dissolved, the temperature was lowered, 15.0g (0.071 mol) of trifluoroacetic anhydride was added dropwise at-10℃to react for 25 minutes, and the reaction was completed, thereby obtaining a double-protected demethylazithromycin solution.
(2) The double-protection demethylazithromycin solution is cooled, 25.0g (0.32 mol) of dimethyl sulfoxide is dripped into the solution, the temperature is kept at-70 ℃, stirring is carried out for 30min, 15.0g (0.071 mol) of trifluoroacetic anhydride is dripped, the temperature is kept at-60 ℃, 25.0g (0.25 mol) of triethylamine is dripped, extraction, acidification, crystallization, suction filtration and drying are carried out after the reaction is carried out for 30min, and 20.0g of white solid ketone is obtained with the yield of 80%.
(3) 10.0g (0.064 mol) of trimethyl sulfur bromide and 150.0g of tetrahydrofuran are added into a 500ml four-port bottle, stirred and dissolved, cooled to-15 ℃, 15.0g (0.13 mol) of potassium tert-butoxide is added, the temperature is maintained at-20 ℃ for reaction for 5 hours, a sulfur ylide reagent is prepared, cooled to-80 ℃, and a methylene dichloride solution (the mass concentration is 30%) containing 20.0g (0.024 mol) of intermediate ketone is gradually added dropwise, and HPCL detection is carried out for 3 hours to complete the reaction. And transferring the reaction solution into a saturated ammonium chloride solution for quenching, separating the solution, evaporating the organic phase under reduced pressure, adding acetone, removing dichloromethane under reduced pressure, adding 80g of acetone, dropwise adding 200g of water, precipitating a white solid, carrying out suction filtration, and drying to obtain 16.0g of white powdery solid, thereby obtaining the tulathromycin intermediate epoxide with the yield of 80%.
Taking demethylazithromycin as a starting material, trifluoroacetic anhydride as a protecting group and triethylamine as active base, the final tulathromycin intermediate epoxide is obtained with a total yield of 64% and a purity of 92.01% (figure 1). HPLC detection method (Talarmycin central control detection method) mobile phase is dipotassium hydrogen phosphate (11.32 g/L) -acetonitrile (volume ratio 55:45), wavelength 205nm, flow rate 1.5ml/min, column temperature 25 ℃, chromatographic column Inertsil ODS-3,4.6mmx250mm,5 μm, sample injection volume 10 μl, diluent acetonitrile, retention time: 13.425min.
Example 2
A process for preparing a tulathromycin intermediate epoxide comprising the steps of:
(1) 30.0 (0.042 mol) of demethylazithromycin is added into a 500ml four-mouth bottle, 300g of dichloromethane is added, stirring and dissolving are carried out, cooling is carried out, 15.0g (0.071 mol) of trifluoroacetic anhydride is dropwise added at-15 ℃, after the dropwise addition, the reaction is carried out for 2 hours, and the reaction is complete, thus obtaining the double-protection demethylazithromycin solution.
(2) The double-protection demethylazithromycin solution is cooled, 25.0g (0.32 mol) of dimethyl sulfoxide is dripped into the solution, the temperature is kept at-70 ℃, stirring is carried out for 30min, 15.0g (0.071 mol) of trifluoroacetic anhydride is dripped, the temperature is kept at-60 ℃, 28.0g (0.47 mol) of trimethylamine is dripped, extraction, acidification, crystallization, suction filtration and drying are carried out after the reaction is carried out for 30min, and 18.75g of white solid ketone is obtained with the yield of 75%.
(3) 10.0g (0.064 mol) of trimethyl sulfur bromide and 150.0g of tetrahydrofuran are added into a 500ml four-port bottle, stirred and dissolved, cooled to-15 ℃, 18.0g (0.19 mol) of sodium tert-butoxide is added, the temperature is maintained at-20 ℃ for reaction for 5 hours, a sulfur ylide reagent is prepared, cooled to-80 ℃, and a methylene dichloride solution (the mass concentration is 30%) containing 20.0g (0.024 mol) of intermediate ketone is gradually added dropwise, and HPCL detection is carried out for 3 hours to complete the reaction. And transferring the reaction solution into a saturated ammonium chloride aqueous solution for quenching, separating the solution, evaporating the organic phase under reduced pressure, adding acetone, removing dichloromethane under reduced pressure, adding 80g of acetone, dropwise adding 200g of water, precipitating white solid, carrying out suction filtration, and drying to obtain 13.13g of white powdery solid, thus obtaining the tulathromycin intermediate epoxide with the yield of 70%.
The final yield of the intermediate epoxide of tulathromycin is 52.5% and the purity of the intermediate epoxide of tulathromycin is 89.63% (see figure 2) by using desmethyl azithromycin as a starting material, trifluoroacetic anhydride as a protecting group and trimethylamine as an acid applying agent. HPLC detection method (tulathromycin central control detection method) comprises taking dipotassium hydrogen phosphate (11.32 g/L) -acetonitrile (volume ratio 55:45) as mobile phase, and measuring at 205nm, flow rate 1.5ml/min, column temperature 25deg.C, chromatographic column Inertsil ODS-3,4.6mmx250mm;5 μm, sample volume 10. Mu.L, diluent acetonitrile, retention time 13.445min.
Example 3
A process for preparing a tulathromycin intermediate epoxide comprising the steps of:
(1) 25.0g (0.035 mol) of demethylazithromycin is added into a 500ml four-mouth bottle, 250g of methylene dichloride is added into the bottle to be stirred and dissolved, the temperature is reduced, 15.0g (0.071 mol) of trifluoroacetic anhydride is added dropwise at the temperature of-15 ℃, the reaction is completed after the dropwise addition for 2 hours, and the double-protection demethylazithromycin solution is obtained.
(2) The double-protection demethylazithromycin solution is cooled, 25.0g (0.32 mol) of dimethyl sulfoxide is dripped into the solution, the temperature is kept at-70 ℃, stirring is carried out for 30min, 15.0g (0.071 mol) of trifluoroacetic anhydride is dripped, the temperature is kept at-60 ℃, 25.0g (0.19 mol) of diisopropylethylamine is dripped, extraction, acidification, crystallization, suction filtration and drying are carried out after the reaction is carried out for 30min, and 18.0g of white solid ketone is obtained with the yield of 72%.
(3) 10.0g (0.064 mol) of trimethyl sulfur bromide and 150.0g of tetrahydrofuran are added into a 500ml four-port bottle, stirred and dissolved, cooled to-15 ℃, 20.0g (0.37 mol) of sodium methoxide is added, the temperature is maintained at-20 ℃ for reaction for 5 hours, a sulfur ylide reagent is prepared, cooled to-80 ℃, and a methylene dichloride solution (the mass concentration is 30%) containing 20.0g (0.024 mol) of intermediate ketone is gradually added dropwise, and HPCL detection is completed for 3 hours. And transferring the reaction solution into a saturated ammonium chloride aqueous solution for quenching, separating the solution, evaporating the organic phase under reduced pressure, adding acetone, removing dichloromethane under reduced pressure, adding 80g of acetone, dropwise adding 200g of water, precipitating white solid, carrying out suction filtration, and drying to obtain 12.24g of white powdery solid, thus obtaining the tulathromycin intermediate epoxide with the yield of 68%.
Taking demethylazithromycin as a starting material, trifluoroacetic anhydride as a protecting group and diisopropylethylamine as an acid applying agent, the final tulathromycin intermediate epoxide is obtained with a total yield of 48.96% and a purity of 91.59% (figure 3). HPLC detection method (tulathromycin central control detection method 2): the mobile phase is potassium dihydrogen phosphate (0.05 mol/L pH 7.0) -acetonitrile-methanol (volume ratio of 30:25:45), wavelength of 205nm, flow rate of 2.0ml/min, column temperature of 35 ℃, chromatographic column of Inertsil ODS-3,4.6mmx250mm,5 μm (005), sample injection volume of 10 μl, diluent acetonitrile, retention time of 18.151min.
Comparative example 1
A process for preparing a tulathromycin intermediate epoxide comprising the steps of:
(1) 30g of azithromycin A,180ml of tetrahydrofuran and 2.4g of 4-dimethylaminopyridine are added into a 500ml four-necked flask, the temperature is controlled to be-5 ℃ and 22.2g of di-tert-butyl dicarbonate is slowly added dropwise into the flask, after the mixture is stirred for half an hour, the mixture is heated to reflux and continuously reacts for 10 hours, after the reaction is finished, water washing, an organic phase is dried and concentrated, and crystallization is carried out by using normal hexane, so that a double-protection product is obtained.
(2) 56.8g of dimethyl sulfoxide and 170mL of dichloromethane are added into a 500mL four-necked flask, 18.4g of trifluoroacetic anhydride is dripped into the flask, the temperature is kept at-65 ℃, the mixture is stirred for 1 hour, 34g of 102mL of dichloromethane solution of the product in (1) is dripped into the flask, the mixture is reacted for 1 hour after the dripping, 22.0g of triethylamine is added into the flask, the mixture is stirred for 0.5 hour, and water is added into the system after the reaction is completed, and the mixture is layered. The organic phase was washed with water, dried, concentrated, 18.6g of trifluoroacetic acid was added thereto, stirred for 5 hours, 270ml of isopropanol was added thereto, and concentrated to solid crystals to obtain a ketone product.
(3) 11.2g of potassium tert-butoxide and 90ml of tetrahydrofuran are added into a 500ml four-necked flask, cooled to-10 to-15 ℃, 13.8g of trimethylsulfonium bromide is added in batches, and the mixture is cooled to-70 ℃ after heat preservation reaction for 1 to 1.5 hours;
(4) Adding 9.4g of potassium carbonate into 90mL of dichloromethane solution of 30g of the product of the step (2), stirring for half an hour, separating liquid, extracting, drying, concentrating, dripping into the solution obtained in the step (3), stirring for 2 hours at a constant temperature, adding 8.4g of amine chloride into 45mL of water solution, standing for layering, extracting, concentrating, adding ethanol, steaming in a rotary way, and concentrating to 120mL to obtain an ethanol solution containing epoxide.
Azithromycin A is used as an initial raw material, di-tert-butyl dicarbonate is used as a protecting group, and an acid coating agent is triethylamine, so that the tulathromycin intermediate epoxide is finally obtained, the total yield is 46%, and the purity is 92%.
Compared with a comparative example using di-tert-butyl dicarbonate as a protecting group, the method has the advantages of high yield, no precipitation of solids due to double protection, avoidance of deprotection before epoxidation, high epoxidation impurity content, difficult purification, low product yield and purity and the like, and overcomes the defects of difficult removal of the protecting group, complex process, low yield, high energy consumption, difficult treatment of waste water and the like in the prior art, and overcomes the defects of high catalyst price, poor stability, unfavorable recycling and the like in the prior art. The tulathromycin epoxide intermediate synthesized by the method has high yield and purity, the purity can reach more than 92%, and the equipment cost and the raw material cost of the subsequent tulathromycin synthesis are greatly reduced.
The epoxide obtained by the method is used for preparing the tulathromycin according to the prior method, namely, the tulathromycin phosphate is obtained by nucleophilic addition with n-propylamine, the tulathromycin is further prepared by alkali neutralization, the tulathromycin obtained is compared with a tulathromycin standard product of the pyroxene product, the carbon spectrum, the hydrogen spectrum, the infrared ray and the liquid phase peak time are consistent, and the purity can reach 98 percent (figure 4) through HPLC spectrogram. HPLC detection method (tulathromycin central control detection method 2): the mobile phase is potassium dihydrogen phosphate (0.05 mol/L pH 7.0) -acetonitrile-methanol (volume ratio of 30:25:45), the wavelength is 205nm, the flow rate is 2.0ml/min, the column temperature is 35 ℃, the chromatographic column is Inertsil ODS-3,4.6mmx250mm,5 μm (005), the sample injection volume is 10 mu L, the diluent acetonitrile and the retention time is 17.784min, and the preparation method of the tulathromycin intermediate epoxide is proved to be feasible.

Claims (10)

1. A process for preparing a tulathromycin intermediate epoxide comprising the steps of:
(1) Reacting the demethylazithromycin (I) with trifluoroacetic anhydride serving as an oxidation protective agent, and protecting the hydroxy group at the 2' -position and the amino group at the 6-position of the demethylazithromycin to obtain double-protected demethylazithromycin (II);
(2) Double-protected demethylazithromycin (II) is oxidized by Swern, and 4 '-hydroxyl is oxidized into carbonyl, so that a ketonic intermediate (III), namely 4' -carbonyl demethylazithromycin trifluoroacetate, is obtained;
(3) The ketonization intermediate (III) is subjected to sulfoylide epoxidation to obtain a tulathromycin intermediate epoxide (IV);
2. the process for the preparation of the tulathromycin intermediate epoxide according to claim 1, wherein in step (1), the reaction of the desmethylazithromycin (I) with trifluoroacetic anhydride is carried out in a solvent a.
3. A process for the preparation of a tulathromycin intermediate epoxide according to claim 2, comprising one or more of the following conditions:
i. the solvent A is one of dichloromethane, tetrahydrofuran, chloroform or ethyl acetate; the mass of the solvent A is 5-20 times, preferably 10 times of that of the demethylazithromycin (I);
ii. The molar ratio of the demethylazithromycin (I) to the trifluoroacetic anhydride is 1:1-3, preferably 1:2;
iii, the reaction temperature of the demethylazithromycin (I) and the trifluoroacetic anhydride is-20-0 ℃;
and iv, adding trifluoroacetic anhydride into a system containing the demethylazithromycin (I) in a dropwise manner.
4. The process for preparing an epoxide as claimed in claim 2, wherein the reaction mixture obtained by reacting the desmethylazithromycin (I) with trifluoroacetic anhydride is directly subjected to the next step without treatment.
5. The process for the preparation of the intermediate epoxide of tulathromycin according to claim 1, wherein in step (2) the Swern oxidation of the double protected demethylazithromycin (II) is carried out under the action of an oxidizing agent and an acid binding agent.
6. The process for the preparation of the tulathromycin intermediate epoxide according to claim 5, comprising one or more of the following conditions:
i. the oxidant is one of dimethyl sulfoxide-trifluoroacetic anhydride or dimethyl sulfoxide-oxalyl chloride; the molar ratio of dimethyl sulfoxide to desmethylazithromycin (I) is 7-10:1;
ii. The acid binding agent is triethylamine, diethylamine, diisopropylethylamine or trimethylamine; the molar ratio of the demethylazithromycin (I) to the acid binding agent is 1:5-12;
iii, the oxidation reaction temperature of Swern is-20 ℃ to-80 ℃;
and iv, adding the acid binding agent into a reaction system containing the double-protection demethylazithromycin (II) and the oxidant in a dropwise manner.
7. The process for preparing an epoxide as claimed in claim 5, wherein the reaction mixture obtained by the Swern oxidation is directly subjected to the next step without any treatment; or, treating the reaction solution obtained by the Swern oxidation reaction and then carrying out the next step;
preferably, the processing method comprises the steps of: the reaction liquid is extracted, the organic phase is acidified, crystallized, pumped, filtered and dried to obtain a white solid ketone intermediate (III), and then the next step is carried out.
8. The process for preparing a tulathromycin intermediate epoxide in accordance with claim 1, wherein in the step (3), the ketonic intermediate (III) is prepared by sulfolobus ylide epoxidation, comprising the steps of: in the solvent B, under the action of active alkali, trimethyl sulfur halide reacts to obtain dimethyl methylene sulfur solution, namely a sulfur ylide solvent; dripping the ketone intermediate (III) and obtaining the tulathromycin intermediate epoxide (IV) through epoxidation reaction.
9. The process for the preparation of the tulathromycin intermediate epoxide of claim 8, comprising one or more of the following conditions:
i. the solvent B is one or more than two of tetrahydrofuran, methyl tertiary butyl ether, toluene, methylene dichloride, chloroform or dimethyl sulfoxide; preferably, the solvent B is one or more than two of tetrahydrofuran, dichloromethane or chloroform; the mass of the solvent B is 10-20 times of that of the trimethyl sulfur halide;
ii. The active alkali is potassium tert-butoxide, sodium tert-butoxide or sodium methoxide; the molar ratio of the ketonic intermediate (III) to the active base is 1:5-16, preferably 1:5.5;
iii, trimethyl sulfur halide is one of trimethyl sulfonium bromide or trimethyl sulfur iodide; the molar ratio of the ketonic intermediate (III) to the trimethylsulfur halide is 1:2.5-3, preferably 1:2.7;
iv, the reaction temperature of the trimethyl sulfur halide is-30 ℃ to-10 ℃.
10. The process for the preparation of the tulathromycin intermediate epoxide of claim 8, comprising one or more of the following conditions:
i. the ketonization intermediate (III) is dripped into the reaction system in the form of a ketonization intermediate (III) solution; preferably, the solvent used for the ketonic intermediate (III) solution is methylene chloride; the mass of dichloromethane is 2-5 times of that of the ketonic intermediate (III);
ii. The epoxidation reaction temperature is-20 ℃ to-80 ℃;
the post-treatment method of the reaction liquid obtained by the epoxidation reaction comprises the following steps: adding the reaction solution into saturated ammonium chloride aqueous solution to quench reaction, separating the solution, evaporating the organic phase to dryness under reduced pressure, adding acetone, and removing the solvent under reduced pressure; adding acetone and water, precipitating white solid, suction filtering, and drying to obtain tulathromycin intermediate epoxide.
CN202310239316.5A 2023-03-14 2023-03-14 Preparation method of tulathromycin intermediate epoxide Pending CN116462724A (en)

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