WO2017124222A1 - 一种泰拉霉素的制备方法及其中间体 - Google Patents

一种泰拉霉素的制备方法及其中间体 Download PDF

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WO2017124222A1
WO2017124222A1 PCT/CN2016/071198 CN2016071198W WO2017124222A1 WO 2017124222 A1 WO2017124222 A1 WO 2017124222A1 CN 2016071198 W CN2016071198 W CN 2016071198W WO 2017124222 A1 WO2017124222 A1 WO 2017124222A1
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solvent
formula
compound
crystallization
reaction
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French (fr)
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尹明星
吴冬冬
温伟江
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Zhejiang Hisun Pharmaceutical Co Ltd
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Zhejiang Hisun Pharmaceutical Co Ltd
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Priority to CN201680078823.3A priority Critical patent/CN108473524B/zh
Priority to ES16885495T priority patent/ES2858585T3/es
Priority to PCT/CN2016/071198 priority patent/WO2017124222A1/zh
Priority to EP16885495.8A priority patent/EP3406619B1/en
Priority to BR112018014534-3A priority patent/BR112018014534B1/pt
Priority to US16/070,658 priority patent/US10414746B2/en
Publication of WO2017124222A1 publication Critical patent/WO2017124222A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D315/00—Heterocyclic compounds containing rings having one oxygen atom as the only ring hetero atom according to more than one of groups C07D303/00 - C07D313/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • 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
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • the invention belongs to the field of veterinary medicine, and particularly relates to a preparation method of telamycin and an intermediate thereof.
  • Respiratory tract infection is one of the most difficult infectious diseases in animal husbandry, and it is a serious hazard to animal husbandry. When respiratory infections are prevalent, they will cause huge economic losses to livestock production. Therefore, how to prevent respiratory infections in pigs, cattle and other livestock is an important research topic for veterinarians and veterinary medicine workers. Because respiratory infections are generally multiple infections, many pathogenic factors, and complex conditions, there is currently no effective prevention. In the respiratory tract infection of animals, while seeking biological control and environmental blocking, drug control is still the main way at present. The search for new antibacterial drugs that are effective, safe, broad-spectrum, high-efficiency and low-residue to respiratory infections is an important direction for the research and development of veterinary drugs.
  • Tulathromycin is a synthetic macrolide derivative semi-synthetic antibiotic developed by Pfizer Animal Health Products of the United States. Its chemical structure is shown in Formula I. Teramycin is mainly used for the prevention and treatment of respiratory diseases of pigs and cattle caused by Actinobacillus pleuropneumoniae, Mycoplasma, Pasteurella, Haemophilus parasuis, etc., especially for bovine respiratory diseases. effect. Since there are three amine groups in the structure of telamycin, it has many advantages such as fast absorption, low dosage, long-lasting effect, and full treatment in a single administration. Since its introduction, it has been treated by domestic and foreign veterinary medicine. extensive attention.
  • Taramycin commercial-Ricox consists of two isomers in equilibrium in aqueous solution, one is 15 azalide lactone ring-tyramycin A (formula I) and the other is 13 yuan Azalide ring-Taramycin B (Formula I'), both of which are 90% and 10%, respectively. Since the solution of telamycin in the solution (ie, the telamycin solution, the solute is tyranol, the solvent is water, the organic solvent or a mixed solvent of water and an organic solvent), the two isomers are balanced with each other. Changes in the environment and pH will greatly affect the ratio of the two components in the telamycin, which puts higher requirements on the formulation.
  • the technical problem to be solved by the present invention is to overcome the defects of low purity, low yield, complicated operation, and unfavorable industrial production, etc., which are obtained by the preparation method of the existing telamycin.
  • the preparation method of the present invention has high purity of the tyanomycin, and the HPLC purity thereof is usually above 95%, and the highest is 99% or more, which can meet the purity requirement of preparing the pharmaceutical preparation, and is beneficial to improving the biological activity thereof.
  • the invention has the advantages of high yield, simple operation and more suitable for industrial production.
  • the present invention mainly solves the above technical problems by the following technical solutions.
  • the present invention provides a process for the preparation of taramycin as shown in Formula I, which comprises the steps of: subjecting a compound of the formula II to n-propylamine to a ring-opening addition reaction as shown below in an organic solvent; , producing a telamycin as shown in Formula I; wherein the organic solvent is 1,2-propanediol;
  • the method for preparing telamycin as shown in Formula I preferably comprises the steps of: mixing a mixed solution of a compound of the formula II and an organic solvent with n-propylamine to carry out the ring-opening addition. Into the reaction, you can.
  • the amount of the organic solvent to be used may not be specifically limited as long as it does not affect the progress of the reaction.
  • the temperature of the ring-opening addition reaction may be a conventional temperature for such a reaction in the art, preferably from 30 ° C to 90 ° C, more preferably from 40 ° C to 65 ° C, most preferably from 45 ° C to 55 ° C. .
  • the progress of the ring-opening addition reaction can generally be monitored by conventional detection methods in the art (for example, TLC and/or HPLC), generally by HPLC, and the content of the compound as shown in Formula II is ⁇ 2%.
  • the end of the reaction may be a conventional time for such a reaction in the art, preferably from 15 to 40 hours, more preferably from 16 to 20 hours.
  • the ring opening addition reaction is preferably carried out in gas protection.
  • the gas in the gas protection may be a gas conventional in the art, preferably nitrogen.
  • the post-treatment operation may be further included.
  • the methods and conditions for the post-treatment described can be routine methods and conditions for such reactions in the art.
  • the post-treatment operation preferably comprises the following steps: after the ring-opening addition reaction is completed, the n-propylamine and the organic solvent are removed to obtain a crude product of the telamycin as shown in Formula I; after recrystallization That is, telamycin as shown in Formula I.
  • the method of removing n-propylamine and an organic solvent may be a method conventional in the art, preferably concentrated under reduced pressure.
  • the recrystallization operation may be a conventional operation for recrystallization of such compounds in the art, and the present invention preferably comprises the following steps: the crude telamycin as shown in Formula I Mixing with solvent A, then adding an anti-solvent, and crystallization to obtain a telamycin product as shown in Formula I; wherein the solvent A is a mixed solvent of acetone and a C1-3 alcohol solvent; The anti-solvent is water or a mixed solvent of water and acetone.
  • the C 1-3 alcohol solvent is preferably 1,2-propylene glycol.
  • the amount of the solvent A used may be not particularly limited as long as the crude telamycin as shown in Formula I can be dissolved to obtain a clear and transparent solution, preferably,
  • the volume-to-mass ratio of the solvent A to the crude telamycin as shown in Formula I is from 2 ml/g to 50 ml/g, more preferably from 2 ml/g to 30 ml/g.
  • the relationship between the acetone and the C1-3 alcohol solvent may not be specifically limited.
  • the operation of adding an anti-solvent may be a conventional operation in the art, preferably a dropping.
  • the temperature at which the anti-solvent is added may be a temperature conventional in the art, preferably from 35 ° C to 45 ° C.
  • the amount of the anti-solvent may be not particularly limited as long as the tyanomycin of the formula I can be precipitated; preferably, the anti-solvent and the typhine as shown in the formula I
  • the volume-to-mass ratio of the crude crude product is from 2 ml/g to 60 ml/g.
  • the anti-solvent is a mixed solvent of water and acetone
  • the volume of the water and the acetone is preferably from 0.5:1 to 3:1.
  • the addition is stopped. After stirring for 10-30 minutes, the remaining anti-solvent is added.
  • the temperature of the crystallization may be a temperature conventional in the art, preferably from 0 °C to 45 °C.
  • the crystallization time may be a period of time conventional in the art, preferably from 1 to 6 hours, more preferably from 1 to 3 hours (e.g., 2 hours).
  • the crystallization in the recrystallization operation, includes pre-crystallization and post-crystallization, wherein the pre-stage crystallization is preferably between 35 ° C and 45 ° C.
  • the crystallization is carried out for 0.5 to 3 hours (for example, 1 hour), and the subsequent crystallization is preferably crystallization at 0 ° C to 35 ° C (for example, 0 ° C to 10 ° C) for 0.5 to 3 hours (for example, 1 hour).
  • the post-treatment operation preferably comprises the steps of: after the ring-opening addition reaction is completed, the n-propylamine is removed, then mixed with acetone, an anti-solvent is added, and crystallization is performed. That is, telamycin as shown in Formula I. Among them, the operation of removing n-propylamine, the amount of acetone, the kind and amount of anti-solvent, and the operation of crystallization are the same as described above.
  • the method for preparing the telamycin as shown in Formula I preferably further comprises the following Process A or Method B:
  • the method A preferably comprises the steps of: performing a deprotection reaction of the compound of the formula III under the action of a catalyst and a hydrogen source under the action of a catalyst and a hydrogen source as follows, to obtain the formula II as described below.
  • the method B preferably comprises the steps of: acid-base neutralization reaction of the salt IIa of the compound of the formula II with a base in a mixed solvent of water and a non-polar organic solvent, to obtain a formula II Compound shown;
  • X is an organic acid or a mineral acid
  • n is 1, 2 or 3.
  • the preparation method of the compound represented by the formula II preferably comprises the steps of: mixing a mixed solution of the compound of the formula III and an organic solvent with a hydrogen source and a catalyst to carry out the deprotection. reaction.
  • the organic solvent is preferably a C 1-3 alcohol-based solvent and / or a ketone solvent.
  • the C 1-3 alcohol solvent is preferably one or more of methanol, ethanol and isopropyl alcohol.
  • the ketone solvent is preferably acetone.
  • the catalyst is preferably palladium carbon.
  • the mass fraction of palladium in the palladium carbon is preferably from 3% to 20%, more preferably from 5% to 15%, and the percentage refers to the mass of palladium as a percentage of the total mass of palladium carbon.
  • the hydrogen source is preferably ammonium formate.
  • the amount of the catalyst used may be a conventional amount for such a reaction in the art.
  • the catalyst is from 5% to 15%, more preferably from 5% to 10% by mass of the compound of the formula III.
  • the hydrogen source is generally used in an amount of more than one time the molar amount of the compound represented by the formula II.
  • the temperature of the deprotection reaction may be a conventional temperature for such a reaction in the art, preferably from 20 ° C to 25 ° C.
  • the progress of the deprotection reaction can generally be monitored by conventional detection methods in the art (e.g., HPLC), generally as the end of the reaction when the compound as shown in Formula III disappears.
  • the time for the deprotection reaction is preferably from 1 to 6 hours, more preferably from 2 to 3 hours.
  • the deprotection reaction is preferably carried out under gas protection.
  • the gas in the gas protection may be a conventional gas of this type in the art, preferably nitrogen.
  • a post-treatment operation may be further included.
  • the post-treatment operation may be a routine operation of such a reaction in the art, and preferably includes the following steps: the reaction solution after the end of the deprotection reaction is filtered (generally using diatomaceous earth to aid filtration), and washed (usually used)
  • the alcohol solvent of C 1-3 is washed), the solvent is removed (for example, concentrated under reduced pressure), and then mixed with water and an organic solvent for extraction (for example, a halogenated hydrocarbon solvent such as dichloromethane), and a base (for example, potassium carbonate, One or more of sodium carbonate, sodium hydroxide and potassium hydroxide) are adjusted to a pH between 9 and 10, layered, and the aqueous layer is extracted with an organic solvent (for example, a halogenated hydrocarbon solvent such as dichloromethane). The organic layer is extracted, washed (for example, washed with saturated brine), dried (for example
  • the organic acid may be a conventional organic acid in the art, and may not be specifically limited as long as it can form a salt with the compound of the formula II, preferably trifluoroacetic acid.
  • the inorganic acid may be a conventional inorganic acid in the art, and may not be specifically limited as long as it can form a salt with the compound of the formula II.
  • the non-polar organic solvent is preferably a halogenated hydrocarbon solvent.
  • the halogenated hydrocarbon solvent is preferably dichloromethane and/or chloroform.
  • the base may be a base conventional in the art, preferably an inorganic base.
  • the inorganic base is preferably one or more of potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide.
  • the amount of the mixed solvent to be used may not be specifically limited as long as it does not affect the progress of the reaction.
  • the amount of the base to be used is not particularly limited, and the pH of the reaction liquid is generally controlled to be between 9 and 10, which is sufficient.
  • the temperature of the acid-base neutralization reaction can be a conventional temperature for such reactions in the art.
  • the acid-base neutralization reaction time is preferably 30 minutes.
  • the post-treatment operation may be further included.
  • the post-treatment operation may be a conventional operation of such a reaction in the art, and preferably includes the following steps: after the acid-base neutralization reaction is completed, the water layer and the organic layer are separated, and the water layer is made of a non-polar organic Solvent extraction (non-polar organic solvent is preferably a halogenated hydrocarbon solvent), the organic layer is combined, washed (for example, washed with saturated brine), dried (for example, dried over anhydrous sodium sulfate), filtered, and solvent is removed (for example, reduced pressure) Concentrate).
  • non-polar organic solvent is preferably a halogenated hydrocarbon solvent
  • the preparation method of the compound of the formula II may preferably further comprise the steps of: using an alkali as a base, a trimethylphosphonium halide and a formula as shown in formula IV
  • the compound is subjected to an epoxidation reaction as shown below to obtain the compound of the formula III;
  • the method for preparing the compound of the formula III preferably comprises the steps of: mixing a mixed solution of a trimethylphosphonium halide and an organic solvent with a base, and then adding an organic solution of the compound of the formula IV, Said epoxidation reaction.
  • the trimethylphosphonium halide is preferably trimethylsulfonium bromide.
  • the organic solvent is preferably an ether solvent.
  • the ether solvent is preferably tetrahydrofuran (THF).
  • the base is preferably potassium t-butoxide.
  • the molar ratio of the trimethylphosphonium halide to the compound of formula IV is preferably from 2:1 to 10:1, more preferably from 3:1 to 4:1.
  • the molar ratio of the trimethylphosphonium halide to the base is preferably from 1:1 to 1.2:1.
  • the amount of the organic solvent to be used may not be specifically limited as long as it does not affect the progress of the reaction.
  • the temperature of the epoxidation reaction may be a conventional temperature for such a reaction in the art, preferably from -75 ° C to -65 ° C.
  • the progress of the epoxidation reaction can generally be monitored by conventional detection methods in the art (e.g., TLC, HPLC or GC), generally as the end of the reaction when the compound as shown in Formula IV disappears.
  • the epoxidation reaction time is preferably from 0.5 to 5 hours, more preferably from 1 to 2 hours.
  • the temperature at which the mixed solution of the trimethylphosphonium halide and the organic solvent is mixed with the base may be a temperature conventional in the art, preferably from -15 ° C to -5 ° C.
  • the resulting mixture is preferably stirred at -15 ° C to -5 ° C for 0.5 to 3 hours (for example, 1 hour).
  • the temperature of the reaction system is controlled to be between -75 ° C and -65 ° C, and an organic solution of the compound of the formula IV is added. .
  • the solvent is preferably a halogenated hydrocarbon solvent.
  • the halogenated hydrocarbon solvent is preferably dichloromethane.
  • the amount of the organic solvent to be used may be not particularly limited as long as the compound of the formula IV can be completely dissolved.
  • the epoxidation reaction is preferably carried out under gas protection.
  • the gas in the gas protection may be a gas conventional in the art, preferably nitrogen.
  • the post-treatment operation may be a conventional operation of such a reaction in the art, and preferably includes the following steps: after the epoxidation reaction is finished, the reaction solution is mixed with an aqueous solution of ammonium chloride, and the reaction is quenched and separated.
  • the aqueous layer and the organic layer, the aqueous layer is extracted with an organic solvent (the organic solvent is preferably a halogenated hydrocarbon solvent such as dichloromethane), all the organic layers are combined, washed (for example, washed with saturated brine), and dried (for example, Water magnesium sulfate and/or anhydrous sodium sulfate), filtered, and the solvent is removed (for example, concentrated under reduced pressure).
  • the organic solvent is preferably a halogenated hydrocarbon solvent such as dichloromethane
  • the preparation method of the compound IV can be carried out by a conventional preparation method in the art, for example, by subjecting a compound represented by the formula V to an oxidation reaction, as shown in detail in the first embodiment of the present invention, or in the example 2 of US Pat. No. 6,825,327 B2.
  • the formula is as follows:
  • the preparation method of the compound of the formula II may further comprise the step of: removing the salt IIIa of the compound of the formula III by the action of a catalyst and a hydrogen source in an organic solvent. Protecting the reaction to produce the salt IIa of the compound of formula II;
  • the method for preparing the salt IIa of the compound of the formula II preferably further comprises the steps of: forming a salt reaction of the compound of the formula III with an acid in a halogenated hydrocarbon solvent. a salt IIIa of the compound of formula III;
  • the salt IIIa of the compound of formula III is preferably a trifluoroacetate salt IIIa1 of the compound of formula III:
  • the method for preparing the trifluoroacetate salt IIIa1 of the compound of the formula III preferably comprises the steps of: mixing a mixture of the compound of the formula III and a halogenated hydrocarbon solvent with trifluoroacetic acid , the salt formation reaction can be carried out;
  • the halogenated hydrocarbon solvent is preferably dichloromethane.
  • the amount of the halogenated hydrocarbon solvent to be used is not particularly limited as long as the compound of the formula III can be dissolved to obtain a clear and transparent solution, preferably, the halogenated hydrocarbon solvent and the like.
  • the volume ratio by mass of the compound of the formula III is from 2 ml/g to 20 ml/g, more preferably from 3 ml/g to 10 ml/g.
  • the molar ratio of the compound shown to trifluoroacetic acid is preferably from 1:2 to 1:3, more preferably from 1:2.05 to 1:2.25.
  • the temperature of the mixing may be a temperature conventional in the art, preferably from 0 ° C to 40 ° C, more preferably from 25 ° C to 40 ° C, most preferably from 30 ° C to 40 ° C.
  • the temperature and time of the salt formation reaction can be the temperature and time conventional for such reactions in the art.
  • the temperature of the salt-forming reaction and the mixed solution of the compound of the formula III and the halogenated hydrocarbon solvent are the same as the mixing temperature of the trifluoroacetic acid.
  • the method for producing the trifluoroacetate salt IIIa1 of the compound of the formula III may further comprise a post-treatment operation.
  • the method and conditions for the post-treatment may be conventional methods and conditions for such reactions in the art, and preferably include the following steps: adding the reaction solution after the completion of the salt formation reaction, adding an anti-solvent, and crystallization.
  • the anti-solvent is preferably isopropyl ether.
  • the volume of the halogenated hydrocarbon solvent and the anti-solvent is preferably from 1:0.8 to 1:2, more preferably from 1:1:1 to 1:1.5.
  • the operation of adding an anti-solvent can be a routine operation in the art, preferably by dropwise addition.
  • the temperature at which the anti-solvent is added dropwise is preferably from 0 ° C to 40 ° C, more preferably from 25 ° C to 40 ° C, most preferably from 30 ° C to 40 ° C.
  • the temperature of the crystallization may be a temperature conventional in the art, preferably from -5 ° C to 40 ° C.
  • the trifluoroacetic acid in the preparation method of the trifluoroacetate salt IIIa1 of the compound of the formula III, is preferably a halogenated hydrocarbon solution of trifluoroacetic acid.
  • the form is added dropwise to a mixed solution of the compound of the formula III and a halogenated hydrocarbon solvent.
  • the amount of the halogenated hydrocarbon solvent may not be specifically limited.
  • the crystallization comprises pre-crystallization and post-crystallization, wherein the The pre-crystallization is preferably crystallization at 10 ° C - 40 ° C for 0.5 - 3 hours (for example, 1 hour), and the subsequent crystallization is preferably crystallization at -5 ° C - 10 ° C for 0.5 - 3 hours ( For example 1 hour).
  • the method for preparing a salt of the compound of the formula III (a salt other than the trifluoroacetate salt) can be referred to the compound represented by the above formula III.
  • Process for the preparation of trifluoroacetate salt IIIa1 is referred to the compound represented by the above formula III.
  • the present invention also provides a compound of formula IIIa1:
  • the present invention also provides a method for purifying taramycin as shown in Formula I, which comprises the steps of: mixing a crude telamycin as shown in Formula I with solvent A, then adding an anti-solvent, and crystallization.
  • a TELAmycin product as shown in Formula I wherein the crude TELAmycin as shown in Formula I has an HPLC purity of 65% or more; the solvent A is acetone and C 1-3 a mixed solvent of an alcohol solvent; the anti-solvent is water or a mixed solvent of water and acetone;
  • HPLC purity of the crude telamycin as shown in Formula I is preferably from 65% to 99.5% (e.g., 99.2%).
  • the crude taramycin is commercially available or can be prepared by a conventional preparation method in the art, as long as the HPLC purity is above 65%, preferably, the preparation method of the present invention as described above is used. Prepared or prepared by the method of US Pat. No. 6,825,327 B2.
  • the C 1-3 alcohol solvent is preferably 1,2-propylene glycol.
  • the amount of the solvent A to be used is not particularly limited as long as the crude telamycin as shown in Formula I can be dissolved to obtain a clear and transparent solution.
  • the volume of the solvent A and the crude telamycin as shown in Formula I is preferably from 2 ml/g to 50 ml/g, more preferably from 2 ml/g to 30 ml/g.
  • the relationship between the acetone and the C1-3 alcohol solvent may not be specifically limited.
  • the volume of the water and the acetone is preferably 0.5:1 to 3:1.
  • the operation of adding an anti-solvent can be a routine operation in the art, preferably by dropwise addition.
  • the temperature at which the anti-solvent is added may be a temperature conventional in the art, preferably from 35 ° C to 45 ° C.
  • the amount of the anti-solvent may be not particularly limited as long as the tyanomycin of the formula I can be precipitated; preferably, the anti-solvent and the typhine as shown in the formula I
  • the volume-to-mass ratio of the crude crude product is from 2 ml/g to 60 ml/g.
  • the temperature of the crystallization may be a temperature conventional in the art, preferably 0 °C - 45 °C.
  • the crystallization time may be a period of time conventional in the art, preferably from 1 to 6 hours, more preferably from 1 to 3 hours (e.g., 2 hours).
  • the crystallization in the purification method, includes pre-crystallization and post-crystallization, wherein the pre-crystallization is preferably performed at 35 ° C - 45 ° C.
  • the subsequent crystallization is preferably crystallization at 0 °C - 35 °C (e.g., 0 °C - 10 °C) for 0.5-3 hours (e.g., 1 hour).
  • the taramycin product as shown in Formula I is obtained.
  • the tauramycin obtained by the purification method can be obtained.
  • the product is subjected to the above purification method again (once or more).
  • the reagents and starting materials used in the present invention are commercially available.
  • the room temperature refers to the ambient temperature, and is generally from 10 ° C to 30 ° C.
  • the temperature of the added material refers to the temperature of the reaction system (or the reaction liquid).
  • the method of the preparation method of the invention has high purity, and the HPLC purity thereof can reach 99% or more, which can meet the purity requirement of preparing the pharmaceutical preparation, and is beneficial to improving the biological activity and ensuring the curative effect;
  • the preparation method has high yield, simple operation and is more suitable for industrial production.
  • the HLPC content is the HPLC purity.
  • the foam of the compound of the formula V prepared in Example 1 was dissolved in 150 ml of dichloromethane, and 50 ml of DMSO was added thereto with stirring, and the mixture was purged with nitrogen, and the liquid nitrogen was cooled to -75 ° C, and 11.5 ml of trifluoro was added dropwise.
  • a mixed solution of acetic anhydride and 25 ml of CH 2 Cl 2 was kept at an internal temperature of -65 ° C to -75 ° C for 45 min.
  • the reaction was maintained at -75 to -65 ° C for 2 h.
  • the reaction was traced to completion by HPLC.
  • the reaction was then quenched with aqueous ammonium chloride.
  • the reaction mixture was warmed to room temperature, and the aqueous layer and the organic layer were separated.
  • the aqueous layer was extracted once with CH 2 Cl 2 , and the organic layer was combined and washed once with saturated brine.
  • the organic phase was dried over anhydrous sodium sulfate and filtered, 35 ° C
  • the mixture was concentrated to near dryness at 40 ° C, and the oil was pumped for 1 h to obtain 24.7 g of a blister compound of the formula III, MS (ESI) 880.53.
  • Example 3 The foam obtained compound was dissolved in 24.7g 80ml CH 2 Cl 2 was added dropwise 7.2g of trifluoroacetic acid and a mixed solution of 20ml CH 2 Cl 2 at 25 ⁇ 35 °C, then added dropwise at 30 deg.]
  • C Add 150ml of isopropyl ether, change to turbid when adding about 100ml, stop the addition, slowly stir for 0.5h, drop the remaining isopropyl ether, stir and crystallize at 30 °C for 1h, then cool the ice bath (-5 °C-0 °C) After crystallizing for 1 h, filtration, the filter cake was washed with 10 ml of CH 2 Cl 2 and 15 ml of isopropyl ether mixed solvent, and the filter cake was dried by vacuum drying at 45 ° C to obtain 26.2 g of a white solid solid, which is a compound of the formula III.
  • the oil containing the crude 1,2-propanediol telamycin prepared in Example 7 (HPLC purity: 78.3%) was added with 65 ml of acetone, placed in a water bath of about 40 ° C, and 85 ml of water was slowly added dropwise to the crystallizing solution.
  • Example 8 5.0 g of the primary crystalline product of the tyanomycin obtained in Example 8 was mixed with 25 ml of acetone and 3.0 ml of 1,2-propanediol, and dissolved in a 40 ° C water bath, and an anti-solvent of 25 ml of acetone and 60 ml of water was slowly added dropwise. After the crystallization liquid is changed, the dropping is stopped, the crystal is stirred for 10 minutes, the remaining mixed solution is dripped, and the mixture is stirred and kept in a water bath at 40 ° C for 1 h, then cooled to 0-10 ° C in an ice water bath, stirred for 1 h, filtered, and used. A 40% aqueous acetone solution was washed in an appropriate amount to obtain a typhromycin crystal wet product having an HPLC purity of 99.2% and MS (ESI) 805.57.
  • 1 indicates that the taramycin product obtained in Example 7 is dried to obtain a dried product of telamycin; 2 represents a mixed solvent and its amount; 3 represents an anti-solvent and its amount; 4 represents a crystallization process; 5 represents a recrystallization yield; and 6 represents an HPLC purity of the telamycin product obtained after recrystallization.
  • Example 7 is as shown in Formula I, 0.5 g of the telamycin product, HPLC purity 99.2%, adding 5 ml of acetone, stirring in a 35 ° C water bath, slowly adding 7.5 ml of water, after the crystal solution is changed, Stop the addition, stir the crystal for 10 minutes, drip the remaining aqueous solution, drip, and cool for 1 hour, then cool to 0-10 ° C in ice water bath, stir for 1 h, filter, wash with 40% acetone aqueous solution to obtain T.
  • the crystalline wet product was found to have a content of 92.4% by HPLC.

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Abstract

一种泰拉霉素的制备方法及其中间体，该方法包括下列步骤：有机溶剂中，将如式II所示的化合物与正丙胺进行如下所示的开环加成反应，制得如式I所示的泰拉霉素；其中，所述的有机溶剂为1,2-丙二醇。该方法得到的泰拉霉素的纯度高，HPLC纯度在95%以上，最高可达到99%以上，能够满足将其制备成药物制剂的纯度要求；该方法收率高，操作简单，更适用于工业化生产。

Description

一种泰拉霉素的制备方法及其中间体 技术领域
本发明属于兽药领域，具体涉及一种泰拉霉素的制备方法及其中间体。
背景技术
呼吸道感染是畜牧业中较难控制的传染病之一，对畜牧业生产危害严重。呼吸道感染流行时，会给畜牧业生产造成巨大的经济损失。因此，如何防治猪、牛等家畜的呼吸道感染是兽医和兽药工作者的重要研究课题。由于呼吸道感染一般为多重感染，致病因素多，病情复杂，因此目前尚无十分有效的预防手段。对动物的呼吸道感染，在寻求生物防治和环境阻断的同时，药物防治仍然是目前的主要途径。寻求对呼吸道感染有效、安全、广谱、高效、低残留的新型抗菌药物是兽药研究开发的重要方向。
泰拉霉素(Tulathromycin)是由美国辉瑞动物保健品公司合成开发，为动物专用的大环内酯类半合成抗生素，其化学结构如式I所示。泰拉霉素主要用于由胸膜肺炎放线杆菌、支原体、巴氏杆菌、副嗜血杆菌等引起的猪、牛的呼吸系统疾病的防治，尤其对牛猪呼吸系统传染病有十分明显的治疗效果。由于泰拉霉素结构中有3个胺基，其具有吸收快、用量少、药效持久、单次给药即能提供全程治疗等众多优点，自上市以来，受到了国内外兽药界的广泛关注。
Figure PCTCN2016071198-appb-000001
泰拉霉素商品-瑞可新在水溶液中达到平衡时由2个同分异构体组成，一个是15元氮杂内酯环-泰拉霉素A(式I)，另一个是13元氮杂内酯环-泰拉霉素B(式I’)，二者含量分别为90％和10％。由于泰拉霉素在溶液(即泰拉霉素溶液，溶质为泰拉霉素，溶剂为水、有机溶剂或者水和有机溶剂的混合溶剂)中存在两个异构体相互平衡的现象，溶液环境及pH值的变化会较大地影响泰拉霉素中两组分比例，这对制剂提出了较高的要求。由于两种异构体的生物活性不一样，对动物的疗效也受到一定的影响。辉瑞公司在US6825327B2中公开了由异丙醇作溶剂，环氧化中间体与正丙胺进行开环反应得到泰拉 霉素粗品，再与磷酸成盐，然后碱化重结晶得到泰拉霉素。但由于泰拉霉素粗品与磷酸成盐时在有机溶剂和水的混合溶液中进行，即重结晶过程中体系含水，且由于正丙胺的残留，磷酸的用量不易精确，加之重结晶时间长，使得泰拉霉素易发生糖苷键的断裂，导致杂质增多。另外，后续碱化后，采用二氯甲烷/正庚烷体系重结晶产物收率和纯度低，除杂效果不明显。因此本领域需要提供一种制备高纯度泰拉霉素的方法。
Figure PCTCN2016071198-appb-000002
发明内容
本发明所要解决的技术问题是为了克服现有的泰拉霉素的制备方法制得的泰拉霉素的纯度低，收率低，操作复杂，不利于工业化生产等的缺陷，而提供了一种泰拉霉素的制备方法及其中间体。本发明的制备方法得到的泰拉霉素的纯度高，其HPLC纯度通常在95％以上，最高可达到99％以上，能够满足将其制备成药物制剂的纯度要求，有利于提高其生物活性，保证疗效；同时本发明的制备方法收率高，操作简单，更适用于工业化生产。
本发明主要是通过以下技术方案解决上述技术问题的。
本发明提供了一种如式I所示的泰拉霉素的制备方法，其包括下列步骤：有机溶剂中，将如式II所示的化合物与正丙胺进行如下所示的开环加成反应，制得如式I所示的泰拉霉素；其中，所述的有机溶剂为1,2-丙二醇；
Figure PCTCN2016071198-appb-000003
所述的如式I所示的泰拉霉素的制备方法，较佳地包括下列步骤：将如式II所示的化合物和有机溶剂的混合溶液与正丙胺混合，进行所述的开环加成反应，即可。
所述的如式I所示的泰拉霉素的制备方法，所述的如式II所示的化合物与正丙胺的摩尔比可为本领域此类反应常规的摩尔比，较佳地为1:5-1:30，更佳地为1:8-1:15。所述的有机溶剂的用量可不作具体限定，只要不影响反应进行即可。所述的开环加成反应的温度可为本领域此类反应常规的温度，较佳地为30℃-90℃，更佳地为40℃-65℃，最佳地为45℃-55℃。所述的开环加成反应的进程一般可采用本领域常规的检测方法进行监测(例如TLC和/或HPLC)，一般通过HPLC检测，以如式II所示的化合物的含量<2％时作为反应的终点。所述的开环加成反应的时间可为本领域此类反应常规的时间，较佳地为15-40小时，更佳地为16-20小时。
在本发明一较佳实施例中，所述的开环加成反应较佳地在气体保护中进行。所述的气体保护中的气体可为本领域常规的气体，较佳地为氮气。
所述的开环加成反应结束后，还可进一步包含后处理的操作。所述的后处理的方法和条件可为本领域此类反应常规的方法和条件。本发明中，所述的后处理的操作较佳地包括下列步骤：上述开环加成反应结束后，除去正丙胺和有机溶剂，得如式I所示的泰拉霉素粗品；重结晶后即得如式I所示的泰拉霉素。
所述的后处理操作中，所述的除去正丙胺和有机溶剂的方法可为本领域常规的方法，较佳地为减压浓缩。
所述的后处理操作中，所述的重结晶的操作可为本领域此类化合物重结晶常规的操作，本发明优选包括下列步骤：将所述的如式I所示的泰拉霉素粗品与溶剂A混合，然后加入反溶剂，析晶，得如式I所示的泰拉霉素产品；其中，所述的溶剂A为丙酮和C1-3的醇类溶剂的混合溶剂；所述的反溶剂为水或者水和丙酮的混合溶剂。所述的溶剂A中，所述的C1-3的醇类溶剂较佳地为1,2-丙二醇。
所述的重结晶操作中，所述的溶剂A的用量可不作具体限定，只要能够使如式I所示的泰拉霉素粗品溶解，得到澄清透明的溶液，即可，较佳地，所述的溶剂A与所述的如式I所示的泰拉霉素粗品的体积质量比为2ml/g-50ml/g，更佳地为2ml/g-30ml/g。所述的溶剂A中，所述的丙酮与所述的C1-3的醇类溶剂的用量关系可不作具体限定。
所述的重结晶操作中，所述的加入反溶剂的操作可为本领域常规的操作，较佳地为滴加。所述的滴加反溶剂时的温度可为本领域常规的温度，较佳地为35℃-45℃。所述的反溶剂的用量可不作具体限定，只要能够析出如式I所示的泰拉霉素即可；较佳地，所述的反溶剂与所述的如式I所示的泰拉霉素粗品的体积质量比为2ml/g-60ml/g。当所述的反溶剂为水和丙酮的混合溶剂时，所述的水与所述的丙酮的体积比较佳地为0.5:1-3:1。在加入反溶剂时，较佳地，当含如式I所示的泰拉霉素的溶液A变浑浊时，停止加入， 搅拌养晶10-30分钟后，再加入剩余反溶剂。所述的析晶的温度可为本领域常规的温度，较佳地为0℃-45℃。
所述的重结晶操作中，所述的析晶的时间可为本领域常规的时间，较佳地为1-6小时，更佳地为1-3小时(例如2小时)。
在本发明一较佳实施例中，所述的重结晶操作中，所述的析晶包括前期析晶和后期析晶，其中，所述的前期析晶较佳地为在35℃-45℃析晶0.5-3小时(例如1小时)，所述的后期析晶较佳地为在0℃-35℃(例如0℃-10℃)析晶0.5-3小时(例如1小时)。
在本发明另一较佳实施例中，所述的重结晶操作中，所述的析晶结束后，较佳地，过滤，洗涤，干燥，即得如式I所示的泰拉霉素产品。
在本发明另一较佳实施例中，所述的后处理的操作较佳地包括下列步骤：上述开环加成反应结束后，除去正丙胺，然后与丙酮混合，加入反溶剂，析晶，即得如式I所示的泰拉霉素。其中，除去正丙胺的操作，丙酮用量、反溶剂的种类和用量以及析晶的操作均同前所述。
所述的如式I所示的泰拉霉素的制备方法较佳地还可进一步包含下列方法A或方法B：
所述的方法A较佳地包括下列步骤：有机溶剂中，在催化剂和氢源的作用下，将如式III所示的化合物进行如下所示的脱保护反应，制得所述的如式II所示的化合物；
Figure PCTCN2016071198-appb-000004
所述的方法B较佳地包括下列步骤：水和非极性有机溶剂的混合溶剂中，将如式II所示的化合物的盐IIa与碱进行酸碱中和反应，制得如式II所示的化合物；
Figure PCTCN2016071198-appb-000005
其中，化合物IIa中，X为有机酸或无机酸，n为1、2或3。
方法A中，所述的如式II所示的化合物的制备方法优选包括下列步骤：将如式III所示的化合物和有机溶剂的混合溶液，与氢源和催化剂混合，进行所述的脱保护反应。
方法A中，所述的如式II所示的化合物的制备方法中，所述的有机溶剂较佳地为C1-3的醇类溶剂和/或酮类溶剂。所述的C1-3的醇类溶剂较佳地为甲醇、乙醇和异丙醇中的一种或多种。所述的酮类溶剂较佳地为丙酮。所述的催化剂较佳地为钯碳。所述的钯碳中钯的质量分数较佳地为3％-20％，更佳地为5％-15％，所述的百分比是指钯的质量占钯碳总质量的百分比。所述的氢源较佳地为甲酸铵。所述的催化剂的用量可为本领域此类反应常规的用量，较佳地，所述的催化剂为如式III所示的化合物质量的5％-15％，更佳地为5％-10％。所述的氢源的用量一般为如式II所示的化合物摩尔量的1倍以上。所述的脱保护反应的温度可为本领域此类反应常规的温度，较佳地为20℃-25℃。所述的脱保护反应的进程一般可采用本领域常规的检测方法进行监测(例如HPLC)，一般以如式III所示的化合物消失时作为反应的终点。所述的脱保护反应的时间较佳地为1-6小时，更佳地为2-3小时。
在本发明一较佳实施例中，方法A中，所述的脱保护反应较佳地在气体保护下进行。所述的气体保护中的气体可为本领域此类反应常规的气体，较佳地为氮气。
方法A中，所述的脱保护反应结束后，较佳地，还可进一步包括后处理的操作。所述的后处理的操作可为本领域此类反应常规的操作，较佳地包括下列步骤：将脱保护反应结束后的反应液，过滤(一般使用硅藻土助滤)，洗涤(一般使用C1-3的醇类溶剂洗涤)，除去溶剂(例如减压浓缩)，再与水和萃取用有机溶剂(例如卤代烃类溶剂，如二氯甲烷)混合，用碱(例如碳酸钾、碳酸钠、氢氧化钠和氢氧化钾中的一种或多种)调节pH至9-10之间，分层，水层用萃取用有机溶剂(例如卤代烃类溶剂，如二氯甲烷)萃取，合并有机层，洗涤(例如饱和食盐水洗)，干燥(例如无水硫酸钠)，除去有机溶剂，即可。
方法B中，所述的有机酸可为本领域常规的有机酸，可不作具体限定，只要能够与如式II所示的化合物成盐即可，较佳地为三氟乙酸。所述的无机酸可为本领域常规的无机酸，可不作具体限定，只要能够与如式II所示的化合物成盐即可。所述的非极性有机溶剂较佳地为卤代烃类溶剂。所述的卤代烃类溶剂较佳地为二氯甲烷和/或三氯甲烷。所述的碱可为本领域常规的碱，较佳地为无机碱。所述的无机碱较佳地为碳酸钾、碳酸钠、氢氧化钠和氢氧化钾中的一种或多种。所述的混合溶剂的用量可不作具体限定，只要不影响反应的进行即可。所述的碱的用量可不作具体限定，一般控制反应液的pH值在9-10之间，即可。所述的酸碱中和反应的温度可为本领域此类反应的常规温度。所述的酸碱中和反应的时间较佳地为30分钟。
方法B中，所述的酸碱中和反应结束后，较佳地，还可进一步包括后处理的操作。所述的后处理的操作可为本领域此类反应常规的操作，较佳地包括下列步骤：所述的酸碱中和反应结束后，分离水层和有机层，水层用非极性有机溶剂萃取(非极性有机溶剂较佳地为卤代烃类溶剂)，合并有机层，洗涤(例如饱和食盐水洗涤)，干燥(例如无水硫酸钠干燥)，过滤，除去溶剂(例如减压浓缩)，即可。
方法A中，所述的如式II所示的化合物的制备方法，较佳地还可进一步包括下列步骤：有机溶剂中，碱的作用下，将三甲基卤化锍与如式IV所示的化合物进行如下所示的环氧化反应，制得所述的如式III所示的化合物；
Figure PCTCN2016071198-appb-000006
所述的如式III所示的化合物的制备方法较佳地包括下列步骤：将三甲基卤化锍和有机溶剂的混合溶液与碱混合，然后加入如式IV所示的化合物的有机溶液，进行所述的环氧化反应。
所述的如式III所示的化合物的制备方法中，所述的三甲基卤化锍较佳地为三甲基溴化硫。所述的有机溶剂较佳地为醚类溶剂。所述的醚类溶剂较佳地为四氢呋喃(THF)。所述的碱较佳地为叔丁醇钾。所述的三甲基卤化锍与如式IV所示的化合物的摩尔比较佳地为2:1-10:1，更佳地为3:1-4:1。所述的三甲基卤化锍与所述的碱的摩尔比较佳地为1:1-1.2:1。所述的有机溶剂的用量可不作具体限定，只要不影响反应进行，即可。所述的环氧化反应的温度可为本领域此类反应常规的温度，较佳地为-75℃～-65℃。所述的环氧化反应的进程一般可采用本领域常规的检测方法进行监测(例如TLC、HPLC或GC)，一般以如式IV所示的化合物消失时作为反应的终点。所述的环氧化反应的时间较佳地为0.5-5小时，更佳地为1-2小时。
所述的三甲基卤化锍和有机溶剂的混合溶液与碱混合的温度可为本领域常规的温度，较佳地为-15℃～-5℃。所述的三甲基卤化锍和有机溶剂的混合溶液与碱混合后，较佳地将所得混合液于-15℃～-5℃下搅拌0.5-3小时(例如1小时)。所述的三甲基卤化锍和有机溶剂的混合溶液与碱混合后，较佳地，控制反应体系的温度在-75℃～-65℃之间，加入如式IV所示的化合物的有机溶液。所述的如式IV所示的化合物的有机溶液中的有机 溶剂较佳地为卤代烃类溶剂。所述的卤代烃类溶剂较佳地为二氯甲烷。所述的如式IV所示的化合物的有机溶液中，所述的有机溶剂的用量可不作具体限定，只要能够使如式IV所示的化合物完全溶解，即可。
所述的如式III所示的化合物的制备方法中，所述的环氧化反应较佳地在气体保护下进行。所述的气体保护中的气体可为本领域常规的气体，较佳地为氮气。
所述的环氧化反应结束后，较佳地还可进一步包含后处理的操作。所述的后处理的操作可为本领域此类反应常规的操作，较佳地包括下列步骤：所述的环氧化反应结束后，将反应液与氯化铵水溶液混合，淬灭反应，分离水层和有机层，水层用有机溶剂萃取(所述的有机溶剂优选卤代烃类溶剂，例如二氯甲烷)，合并所有有机层，洗涤(例如用饱和食盐水洗涤)，干燥(例如无水硫酸镁和/或无水硫酸钠)，过滤，除去溶剂(例如减压浓缩)，即可。
其中，化合物IV的制备方法可采用本领域常规的制备方法进行制备，例如将如式V所示的化合物进行氧化反应制备得到，具体见本发明实施例1，或参见US6825327B2实施例2，其反应式如下所示：
Figure PCTCN2016071198-appb-000007
方法B中，所述的如式II所示的化合物的制备方法还可进一步包括下列步骤：有机溶剂中，在催化剂和氢源的作用下，将如式III所示的化合物的盐IIIa进行脱保护反应，制得所述的如式II所示的化合物的盐IIa；
Figure PCTCN2016071198-appb-000008
其中，X和n的定义均同前所述，所述的脱保护反应的条件均同前述如式II所示的化合物的制备方法中的方法A。
所述的如式II所示的化合物的盐IIa的制备方法，较佳地还可进一步包括下列步骤：卤代烃类溶剂中，将如式III所示的化合物与酸进行成盐反应，制得如式III所示的化合物的盐IIIa；
Figure PCTCN2016071198-appb-000009
其中，IIIa中，X和n的定义均同前所述。
所述的如式III所示的化合物的盐IIIa较佳地为如式III所示的化合物的三氟乙酸盐IIIa1：
Figure PCTCN2016071198-appb-000010
所述的如式III所示的化合物的三氟乙酸盐IIIa1的制备方法较佳地包括下列步骤：将如式III所示的化合物与卤代烃类溶剂的混合溶液，与三氟乙酸混合，进行成盐反应即可；
Figure PCTCN2016071198-appb-000011
所述的如式III所示的化合物的三氟乙酸盐IIIa1的制备方法中，所述的卤代烃类溶剂较佳地为二氯甲烷。所述的卤代烃类溶剂的用量可不作具体限定，只要能够使如式III所示的化合物溶解，得到澄清透明的溶液，即可，较佳地，所述的卤代烃类溶剂与如式III所示的化合物的体积质量比为2ml/g-20ml/g，更佳地为3ml/g-10ml/g。所述的如式III 所示的化合物与三氟乙酸的摩尔比较佳地为1:2-1:3，更佳地为1:2.05-1:2.25。所述的混合的温度可为本领域常规的温度，较佳地为0℃-40℃，更佳地为25℃-40℃，最佳地为30℃-40℃。所述的成盐反应的温度和时间可为本领域此类反应常规的温度和时间。较佳地，成盐反应的温度和如式III所示的化合物与卤代烃类溶剂的混合溶液与三氟乙酸混合温度相同。
所述的如式III所示的化合物的三氟乙酸盐IIIa1的制备方法中，还可进一步包含后处理的操作。所述的后处理的方法和条件可为本领域此类反应常规的方法和条件，较佳地包括下列步骤：将成盐反应结束后的反应液，加入反溶剂，析晶，即可。所述的反溶剂较佳地为异丙醚。所述的卤代烃类溶剂与反溶剂的体积比较佳地为1:0.8-1:2，更佳地为1:1.3-1:1.5。所述的加入反溶剂的操作可为本领域常规的操作，较佳地为滴加。所述的滴加反溶剂的温度较佳地为0℃-40℃，更佳地为25℃-40℃，最佳地为30℃-40℃。在加入反溶剂时，较佳地，当混合溶液变浑浊时，停止加入，搅拌析晶0.5-1小时后，再加入剩余反溶剂。所述的析晶的温度可为本领域常规的温度，较佳地为-5℃-40℃。
在本发明一较佳实施例中，所述的如式III所示的化合物的三氟乙酸盐IIIa1的制备方法中，所述的三氟乙酸较佳地以三氟乙酸卤代烃溶液的形式滴加到如式III所示的化合物与卤代烃类溶剂的混合溶液中。所述的三氟乙酸卤代烃溶液中，卤代烃类溶剂的用量可不作具体限定。
在本发明一较佳实施例中，所述的如式III所示的化合物的三氟乙酸盐IIIa1的制备方法中，所述的析晶包括前期析晶和后期析晶，其中，所述的前期析晶较佳地为在10℃-40℃析晶0.5-3小时(例如1小时)，所述的后期析晶较佳地为在-5℃-10℃析晶0.5-3小时(例如1小时)。
在本发明另一较佳实施例中，所述的如式III所示的化合物的三氟乙酸盐IIIa1的制备方法中，所述的析晶结束后，较佳地，过滤，洗涤(例如用二氯甲烷和异丙醚混合溶剂洗涤)，干燥(例如45℃下真空干燥)，即得如式III所示的化合物的三氟乙酸盐IIIa1。
因此，在本发明一较佳实施例中，所述的如式III所示的化合物的盐(除三氟乙酸盐外的盐)的制备方法，均可参照上述如式III所示的化合物的三氟乙酸盐IIIa1的制备方法。
因此，本发明还提供了一种如式IIIa1所示的化合物：
Figure PCTCN2016071198-appb-000012
本发明还提供了一种如式I所示的泰拉霉素的纯化方法，其包括下列步骤：将如式I所示的泰拉霉素粗品与溶剂A混合，然后加入反溶剂，析晶，得如式I所示的泰拉霉素产品；其中，所述的如式I所示的泰拉霉素粗品的HPLC纯度为65％以上；所述的溶剂A为丙酮和C1-3的醇类溶剂的混合溶剂；所述的反溶剂为水或者水和丙酮的混合溶剂；
Figure PCTCN2016071198-appb-000013
所述的如式I所示的泰拉霉素粗品的HPLC纯度较佳地为65％-99.5％(例如99.2％)。
所述的泰拉霉素粗品市售可得，或者采用本领域常规的制备方法制备得到，只要其HPLC纯度在65％以上，即可，较佳地，采用本发明如前所述的制备方法制备得到或者采用US6825327B2实施例1-6的方法制备得到。
所述的纯化方法中，所述的C1-3的醇类溶剂较佳地为1,2-丙二醇。所述的溶剂A的用量可不作具体限定，只要能够使如式I所示的泰拉霉素粗品溶解，得到澄清透明的溶液，即可。所述的溶剂A与所述的如式I所示的泰拉霉素粗品的体积质量比较佳地为2ml/g-50ml/g，更佳地为2ml/g-30ml/g。所述的溶剂A中，所述的丙酮与所述的C1-3的醇类溶剂的用量关系可不作具体限定。
所述的纯化方法中，当所述的反溶剂为水和丙酮的混合溶剂时，所述的水与所述的丙酮的体积比较佳地为0.5:1-3:1。所述的加入反溶剂的操作可为本领域常规的操作，较佳地为滴加。所述的滴加反溶剂时的温度可为本领域常规的温度，较佳地为35℃-45℃。所述的反溶剂的用量可不作具体限定，只要能够析出如式I所示的泰拉霉素即可；较佳地，所述的反溶剂与所述的如式I所示的泰拉霉素粗品的体积质量比为2ml/g-60ml/g。在加入反溶剂时，较佳地，当含如式I所示的泰拉霉素的溶液A变浑浊时，停止加入，搅 拌养晶10-30分钟后，再加入剩余反溶剂。
所述的纯化方法中，所述的析晶的温度可为本领域常规的温度，较佳地为0℃-45℃。所述的析晶的时间可为本领域常规的时间，较佳地为1-6小时，更佳地为1-3小时(例如2小时)。
在本发明一较佳实施例中，所述的纯化方法中，所述的析晶包括前期析晶和后期析晶，其中，所述的前期析晶较佳地为在35℃-45℃析晶0.5-3小时(例如1小时)，所述的后期析晶较佳地为在0℃-35℃(例如0℃-10℃)析晶0.5-3小时(例如1小时)。
在本发明另一较佳实施例中，所述的纯化方法中，所述的析晶结束后，较佳地，过滤，洗涤，干燥，即得如式I所示的泰拉霉素产品。
在本发明一较佳实施例中，若想获得高纯度(例如HPLC纯度在99％以上)的如式I所示的泰拉霉素产品，可将进行一次纯化方法制得的泰拉霉素产品再次(一次或一次以上)进行上述纯化方法。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明中，所述的室温是指环境温度，一般为10℃-30℃。
本发明中，所述的加入物料的温度、物料混合温度等均是指反应体系(或反应液)的温度。
本发明的积极进步效果在于：
本发明的制备方法得到的泰拉霉素的纯度高，其HPLC纯度可达到99％以上，能够满足将其制备成药物制剂的纯度要求，有利于提高其生物活性高，保证疗效；同时本发明的制备方法收率高，操作简单，更适用于工业化生产。
具体实施方式
下述实施例中，HLPC含量即为HPLC纯度。
实施例1如式V所示的化合物的制备
在1L三口烧瓶中，投入25g二氢高红霉素和350ml二氯甲烷，搅拌溶解，充入氮气保护，冰盐浴降温至0-10℃，用20分钟滴加12.2ml氯甲酸苄酯和50ml二氯甲烷混合溶液，保持内温0-10℃反应，TLC+HPLC跟踪至反应完全，反应时间为3h。加入饱和NaHCO3水溶液125ml淬灭反应，分离有机层和水层，水层加入50ml二氯甲烷返提一次，合并有机层，使用100ml饱和碳酸氢钠溶液洗一次，无水硫酸钠干燥。过滤，35℃-40℃减压浓 缩，使用油泵抽干，得式V所示的泡状化合物29.1g，MS(ESI)868.53。
实施例2如式IV所示的化合物的制备
将实施例1制得的如式V所示的化合物的泡状物用150ml二氯甲烷溶解，搅拌下加入50ml DMSO，充入氮气保护，液氮冷却至-75℃，滴加11.5ml三氟乙酸酐和25ml CH2Cl2的混合溶液，保持内温在-65℃～-75℃下反应45min。再滴加25ml三乙胺和25ml CH2Cl2的混合溶液，保持内温-65℃～-75℃反应30min后加水淬灭反应。分层，分出水层，有机层用100ml饱和盐水洗一次，分层，有机层加入无水硫酸钠干燥。过滤，滤液浓缩干，使用油泵抽干，得如式IV所示的泡状化合物24.3g，MS(ESI)866.51。
实施例3如式III所示的化合物的制备
在1000ml三口烧瓶中加入17.6g(0.11mol)三甲基溴化锍，氮气保护下，机械搅拌，加入150ml THF，液氮降温至-15℃，投入叔丁醇钾12.5g(0.11mol)，保持内温-15～-5℃下搅拌反应1h。然后降温至-75℃，滴加实施例2制得24.3g(0.028mol)如式IV所示的化合物和250ml CH2Cl2溶液，保持-75～-65℃，1h滴完，滴完后保持-75～-65℃反应2h。HPLC跟踪反应至完全。然后加氯化铵水溶液淬灭反应。待反应液升温至室温，分离水层和有机层，水层用CH2Cl2返提一次，合并有机层，用饱和盐水反洗一次，有机相加入无水硫酸钠干燥，过滤，35℃-40℃浓缩至近干，油泵抽1h得如式III所示的泡状化合物24.7g，MS(ESI)880.53。
实施例4如式III所示的化合物的三氟乙酸盐的制备
将实施例3制得的泡状化合物24.7g溶解在80ml CH2Cl2中，在25～35℃下滴加7.2g三氟乙酸和20ml CH2Cl2的混合溶液，然后在30℃下滴加150ml异丙醚，滴加约100ml时变浑浊，停止滴加，缓慢搅拌0.5h，滴完剩余异丙醚搅拌于30℃析晶1h，再冰水浴(-5℃-0℃)冷却析晶1h，过滤，滤饼用10ml CH2Cl2和15ml异丙醚混合溶剂洗涤，滤饼45℃真空干燥烘干，得类白色松散固体26.2g，即为如式III所示的化合物的三氟乙酸盐，HPLC纯度88.2％，1H-NMR(400MHz,DMSO)；δ＝10.85(s,1H)；8.70(s,1H)；8.38(t,J＝9.7Hz,1H)；7.38(s,5H)；6.08(s,1H)；5.18(d,J＝12.3Hz,1H)；5.06(d,J＝12.2Hz,1H)；5.01(d,J＝3.9Hz,1H)；4.90(dd,J＝10.1Hz,2.0Hz,1H)；4.70(q,J＝6.5Hz,1H)；4.60-4.67(m,2H)；4.00(s,1H)；3.67-3.72(m,1H)；3.55-3.63(m,1H)；3.47(d,J＝6.0,1H)；3.41(s,1H)；3.23-3.30(m,4H)；3.00-3.06(m,1H)；2.67-2.76(m,10H)；2.59-2.64(m,1H)；2.39(d,J＝14.8Hz,1H)；2.13-2.15(m,1H)；1.73-1.89(m,4H)；1.58-1.67(m,1H)；1.35-1.44(m,1H)；1.24-1.31(m,8H)；1.15(d,J＝5.8Hz,3H)；1.10(d,J＝6.0,3H)；1.07(s,3H)；1.01-1.03(m,3H)；0.93-0.94(m,6H)；0.82(t,J＝7.4Hz,3H)；0.74(d,J＝7.1Hz,3H).MS(ESI)880.53。
其他反应条件的实验结果：
Figure PCTCN2016071198-appb-000014
实施例5如式II所示的化合物的制备
将实施例4制得的式III的三氟乙酸盐15g搅拌溶解在150ml甲醇中。氮气保护下，加入7.5g甲酸铵，待溶解完全后，加入10％的Pd/C 1.1g，在20-25℃下反应，HPLC跟踪至反应完全，反应约2-3h。过滤，甲醇洗涤滤饼，滤液在40℃减压浓缩干，加入40ml水和60ml二氯甲烷搅拌溶解，用2N氢氧化钠水溶液调pH至9～10，搅拌30min，分层，上水层用40ml二氯甲烷返提一次，合并有机层，饱和食盐水洗一次，分层，有机相无水硫酸钠干燥。过滤，35℃-40℃减压浓缩干，油泵抽干得如式II所示的化合物的泡状物11.7g，HPLC纯度为86.1％，MS(ESI)746.49。
其他反应条件的实验结果：
序号 1 2 3
式III的三氟乙酸盐用量 5g 5g 5g
Pd/C用量 5％的Pd/C 0.5g 10％的Pd/C 0.5g 15％的Pd/C 0.5g
反应溶剂及用量 乙醇、50ml 异丙醇、50ml 甲醇、50ml
反应温度及时间 20-25℃、3h 20-25℃、3h 20-25℃、3h
式II化合物质量 3.7g 3.4g 3.8g
式II化合HPLC纯度 84.6％ 82.2％ 86.7％
实施例6如式II所示的化合物的制备
将实施例3制得的式III所示的化合物5g搅拌溶解在50ml甲醇中。氮气保护下， 加入2.5g甲酸铵，待溶解完全后，加入10％的Pd/C 0.4g，在20℃-25℃下反应，HPLC跟踪至反应完全，反应约2-3h。过滤，甲醇洗涤滤饼，滤液在40℃减压浓缩干，加入20ml水和50ml二氯甲烷搅拌溶解，用2N氢氧化钠水溶液调pH至9～10，搅拌30min，分层，上水层用20ml二氯甲烷返提一次，合并有机层，饱和食盐水洗一次，分层，有机相无水硫酸钠干燥。过滤，35℃-40℃减压浓缩干，油泵抽干得如式II所示的化合物的泡状物4.1g，HPLC纯度为78.9％，MS(ESI)746.49。
实施例7如式I所示的化合物的制备
将实施例5制得的如式II所示的化合物的泡状物11.7g，用1,2-丙二醇6.0ml和正丙胺12ml溶解，氮气保护下，在45℃-55℃下反应，HPLC跟踪至反应，在20h反应结束，然后在40℃下减压浓缩到不滴，得到含1,2-丙二醇泰拉霉素粗品的油状物，其中，泰拉霉素HPLC含量为78.3％。
其他反应条件的实验结果：
Figure PCTCN2016071198-appb-000015
实施例8
将实施例7制得的含1,2-丙二醇泰拉霉素粗品的油状物(HPLC纯度为78.3％)中加65ml丙酮，置于约40℃水浴中，缓慢滴加85ml水，待结晶液变浑后，停止滴加，搅拌养晶10分钟，滴完剩余水溶液，滴毕，35℃-40℃水浴搅拌1h，后冰水浴冷至0-10℃，快速搅拌1h，过滤，用40％丙酮水溶液适量洗涤，得到白色松散固体泰拉霉素一次结晶产物湿品，HPLC测得含量为95.8％，MS(ESI)805.57。
实施例9
将实施例8得到的泰拉霉素一次结晶产物5.0g，加25ml丙酮和3.0ml 1,2-丙二醇混合，置于40℃水浴中搅拌溶解，缓慢滴加25ml丙酮和60ml水的反溶剂，待结晶液变浑后，停止滴加，搅拌养晶10分钟，滴完剩余混合溶液，滴毕，40℃水浴中搅拌保温1h，后冰水浴冷至0-10℃，搅拌1h，过滤，用40％丙酮水溶液适量洗涤，得到泰拉霉素结晶湿品，HPLC纯度为99.2％，MS(ESI)805.57。
其他反应条件的实验结果：
其中，①表示实施例7得到的泰拉霉素产品进行干燥，得到泰拉霉素的烘干产品； ②表示混合溶剂及其用量；③表示反溶剂及其用量；④表示析晶过程；⑤表示重结晶收率；⑥表示重结晶后得到的泰拉霉素产品的HPLC纯度。
Figure PCTCN2016071198-appb-000016
实施例10
将实施例9得到的如式I所示的泰拉霉素产物0.5g，HPLC纯度99.2％，加2.5ml丙酮和0.3ml 1,2-丙二醇，置于40℃水浴中搅拌溶解，缓慢滴加2.5ml丙酮和6ml水的混合溶液，待结晶液变浑后，停止滴加，搅拌养晶10分钟，滴完剩余混合溶液，滴毕，40℃水浴中搅拌保温1h，后冰水浴冷至0-10℃，搅拌1h，过滤，用40％丙酮水溶液适量洗涤，得到泰拉霉素结晶湿品，HPLC测得含量为99.5％。
实施例11
如式I所示的泰拉霉素粗品1.0g，HPLC纯度68.9％(采用US6825327B2实施例1-6的方法制备得到)，加5.0ml丙酮和0.6ml 1,2-丙二醇，置于41℃水浴中搅拌溶解，缓慢滴加5ml丙酮和12ml水的混合溶液，待结晶液变浑后，停止滴加，搅拌养晶10分钟，滴完剩余混合溶液，滴毕，40℃水浴中搅拌保温1h，后冰水浴冷至0-10℃，搅拌1h，过滤，用40％丙酮水溶液适量洗涤，得到泰拉霉素结晶湿品，HPLC测得含量为95.2％， MS(ESI)805.57。
实施例12
将实施例7如式I所示的泰拉霉素产物0.5g，HPLC纯度99.2％，加5ml丙酮，置于35℃水浴中搅拌溶解，缓慢滴加7.5ml水，待结晶液变浑后，停止滴加，搅拌养晶10分钟，滴完剩余水溶液，滴毕，自然冷却搅拌1h，后冰水浴冷至0-10℃，搅拌1h，过滤，用40％丙酮水溶液适量洗涤，得到泰拉霉素结晶湿品，HPLC测得含量为92.4％。
实施例13
将实施例7如式I所示的泰拉霉素产物0.5g，HPLC纯度99.2％，加0.5ml 1,2-丙二醇和5.0ml甲醇，置于40℃水浴中搅拌溶解，缓慢滴加6.0ml水，待结晶液变浑后，停止滴加，搅拌养晶10分钟，滴完剩余水溶液，滴毕，在40℃搅拌保温1h，后冰水浴冷至0-10℃，搅拌1h，过滤，用40％丙酮水溶液适量洗涤，得到泰拉霉素结晶湿品，HPLC测得含量为94.6％。
对比实施例1
将实施例5制得的如式II所示的化合物的泡状物5.0g，用2.5ml异丙醇和5ml正丙胺溶解，氮气保护下，在45℃-55℃下反应，HPLC跟踪反应，在20h反应结束，然后在40℃下减压浓缩到不滴，得到泰拉霉素粗品油状物，其中，泰拉霉素HPLC含量为60.3％。
对比实施例2
将实施例5如式II所示的化合物的泡状物3.0g，与15ml异丙醇和6.1g正丙胺混合，将混合物在50-55℃下反应30小时，而后在50℃水浴下真空下浓缩到大约剩余8ml体积。取样HPLC检测，目标化合物泰拉霉素的HPLC纯度为68.9％。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (20)

  1. 一种如式I所示的泰拉霉素的制备方法，其特征在于，其包括下列步骤：有机溶剂中，将如式II所示的化合物与正丙胺进行如下所示的开环加成反应，制得如式I所示的泰拉霉素；其中，所述的有机溶剂为1,2-丙二醇；
    Figure PCTCN2016071198-appb-100001
  2. 如权利要求1所述的制备方法，其特征在于，所述的如式II所示的化合物与正丙胺的摩尔比较佳地为1:5-1:30，更佳地为1:8-1:15；所述的开环加成反应的温度较佳地为30℃-90℃，更佳地为40℃-65℃，最佳地为45℃-55℃；所述的开环加成反应的时间较佳地为15-40小时，更佳地为16-20小时；所述的如式I所示的泰拉霉素的制备方法较佳地包括下列步骤：将如式II所示的化合物和有机溶剂的混合溶液与正丙胺混合，进行所述的开环加成反应，即可；所述的开环加成反应较佳地在气体保护下进行；所述的气体保护中的气体较佳地为氮气。
  3. 如权利要求1-2中至少一项所述的制备方法，其特征在于，所述的开环加成反应结束后，还进一步包含后处理的操作；所述的后处理的操作包括下列步骤：所述的开环加成反应结束后，除去正丙胺和有机溶剂，得如式I所示的泰拉霉素粗品；重结晶后即得如式I所示的泰拉霉素。
  4. 如权利要求3所述的制备方法，其特征在于，所述的后处理操作中，所述的除去正丙胺和有机溶剂的方法为减压浓缩；和/或，所述的重结晶的操作包括下列步骤：将所述的如式I所示的泰拉霉素粗品与溶剂A混合，然后加入反溶剂，析晶，得如式I所示的泰拉霉素产品；其中，所述的溶剂A为丙酮和C1-3的醇类溶剂的混合溶剂；所述的反溶剂为水或者水和丙酮的混合溶剂。
  5. 如权利要求4所述的制备方法，其特征在于，所述的重结晶操作中，所述的C1-3的醇类溶剂为1,2-丙二醇；和/或，所述的溶剂A与所述的如式I所示的泰拉霉素粗品的体积质量比为2ml/g-50ml/g，较佳地为2ml/g-30ml/g；和/或，所述的加入反溶剂的操作为滴加；和/或，所述的滴加反溶剂时的温度为35℃-45℃；和/或，所述的反溶剂与所述的如式I所示的泰拉霉素粗品的体积质量比为2ml/g-60ml/g；和/或，当所述的反溶剂为 水和丙酮的混合溶剂时，所述的水与所述的丙酮的体积比为0.5:1-3:1。
  6. 如权利要求4或5所述的制备方法，其特征在于，所述的重结晶操作中，在加入反溶剂时，当含如式I所示的泰拉霉素的溶液A变浑浊时，停止加入，搅拌养晶10-30分钟后，再加入剩余反溶剂；所述的析晶的温度较佳地为0℃-45℃；所述的析晶的时间较佳地为1-6小时。
  7. 如权利要求4-6中至少一项所述的制备方法，其特征在于，所述的重结晶操作中，所述的析晶包括前期析晶和后期析晶，其中，所述的前期析晶为在35℃-45℃析晶0.5-3小时，所述的后期析晶为在0℃-35℃析晶0.5-3小时。
  8. 如权利要求1-7中至少一项所述的制备方法，其特征在于，所述的如式I所示的化合物的制备方法还进一步包含下列方法A或方法B：
    所述的方法A包括下列步骤：有机溶剂中，在催化剂和氢源的作用下，将如式III所示的化合物进行如下所示的脱保护反应，制得所述的如式II所示的化合物；
    Figure PCTCN2016071198-appb-100002
    所述的方法B包括下列步骤：水和非极性有机溶剂的混合溶剂中，将如式II所示的化合物的盐IIa与碱进行酸碱中和反应，制得如式II所示的化合物；
    Figure PCTCN2016071198-appb-100003
    其中，化合物IIa中，X为有机酸或无机酸，n为1、2或3。
  9. 如权利要求8所述的制备方法，其特征在于，
    方法A中，所述的有机溶剂较佳地为C1-3的醇类溶剂和/或酮类溶剂；所述的C1-3的醇类溶剂较佳地为甲醇、乙醇和异丙醇中的一种或多种；所述的酮类溶剂较佳地为丙酮；所述的催化剂较佳地为钯碳；所述的钯碳中钯的质量分数较佳地为3％-20％，更佳地为5％-15％；所述的百分比是指钯的质量占钯碳总质量的百分比；所述的氢源较佳地为甲酸 铵；所述的催化剂地用量为如式III所示的化合物质量的5％-15％，更佳地为5％-10％；所述的氢源的用量较佳地为如式II所示的化合物摩尔量的1倍以上；所述的脱保护反应的温度较佳地为20℃-25℃；所述的脱保护反应的时间较佳地为1-6小时，更佳地为2-3小时；所述的如式II所示的化合物的制备方法较佳地包括下列步骤：将如式III所示的化合物和有机溶剂的混合溶液与氢源和催化剂混合，进行所述的脱保护反应；所述的脱保护反应较佳地在气体保护下进行；所述的气体保护中的气体较佳地为氮气；
    和/或，方法B中，所述的有机酸较佳地为三氟乙酸；所述的非极性有机溶剂较佳地为卤代烃类溶剂；所述的卤代烃类溶剂较佳地为二氯甲烷和/或三氯甲烷；所述的碱较佳地为无机碱；所述的无机碱较佳地为碳酸钾、碳酸钠、氢氧化钠和氢氧化钾中的一种或多种。
  10. 如权利要求8或9所述的制备方法，其特征在于，方法A中，所述的如式II所示的化合物的制备方法，还进一步包括下列步骤：有机溶剂中，碱的作用下，将三甲基卤化锍与如式IV所示的化合物进行如下所示的环氧化反应，制得所述的如式III所示的化合物；
    Figure PCTCN2016071198-appb-100004
  11. 如权利要求10所述的制备方法，其特征在于，所述的如式III所示的化合物的制备方法中，所述的三甲基卤化锍较佳地为三甲基溴化硫；所述的有机溶剂较佳地为醚类溶剂；所述的醚类溶剂较佳地为四氢呋喃；所述的碱较佳地为叔丁醇钾；所述的三甲基卤化锍与如式IV所示的化合物的摩尔比较佳地为2:1-10:1，更佳地为3:1-4:1；所述的三甲基卤化锍与所述的碱的摩尔比较佳地为1:1-1.2:1；所述的三甲基卤化锍与碱混合的温度较佳地为-15℃～-5℃；所述的三甲基卤化锍与碱混合后，较佳地将所得混合液于-15℃～-5℃下搅拌0.5-3小时；所述的三甲基卤化锍和有机溶剂的混合溶液与碱混合后，较佳地控制反应体系的温度在-75℃～-65℃之间，加入如式IV所示的化合物的有机溶液；所述的如式IV所示的化合物的有机溶液中的有机溶剂较佳地为卤代烃类溶剂；所述的卤代烃类溶剂较佳地为二氯甲烷；所述的环氧化反应的温度较佳地为-75℃～-65℃；所述的如式III所示的化合物的制备方法较佳地包括下列步骤：将三甲基卤化锍和有机溶剂的混合溶 液与碱混合，然后加入如式IV所示的化合物的有机溶液，进行所述的环氧化反应；所述的环氧化反应较佳地在气体保护下进行，所述的气体保护中的气体较佳地为氮气。
  12. 如权利要求8或9所述的制备方法，其特征在于，方法B中，所述的如式II所示的化合物的制备方法还进一步包括下列步骤：有机溶剂中，在催化剂和氢源的作用下，将如式III所示的化合物的盐IIIa进行脱保护反应，制得所述的如式II所示的化合物的盐IIa；
    Figure PCTCN2016071198-appb-100005
    其中，X和n的定义如权利要求8所述；所述的脱保护反应的条件同权利要求8或9中如式II所示的化合物的制备方法中方法A。
  13. 如权利要求12所述的制备方法，其特征在于，所述的如式II所示的化合物的盐的制备方法还进一步包括下列步骤：卤代烃类溶剂中，将如式III所示的化合物与酸X进行成盐反应，制得如式III所示的化合物的盐IIIa；
    Figure PCTCN2016071198-appb-100006
    其中，X和n的定义如权利要求8所述，所述的如式III所示的化合物的盐IIIa较佳地为如式III所示的三氟乙酸盐IIIa1：
    Figure PCTCN2016071198-appb-100007
  14. 如权利要求13所述的制备方法，其特征在于，所述的如式III所示的化合物的三氟乙酸盐IIIa1的制备方法包括下列步骤：将如式III所示的化合物与卤代烃类溶剂的混合溶液与三氟乙酸混合，进行成盐反应，即可；
    Figure PCTCN2016071198-appb-100008
  15. 如权利要求14所述的制备方法，其特征在于，所述的如式III所示的化合物的三氟乙酸盐IIIa1的制备方法中，所述的卤代烃类溶剂为二氯甲烷；和/或，所述的如式III所示的化合物与三氟乙酸的摩尔比为1:2-1:3，较佳地为1:2.05-1:2.25；和/或，所述的混合的温度为0℃-40℃，较佳地为25℃-40℃，更佳地为30℃-40℃。
  16. 如权利要求14或15所述的制备方法，其特征在于，所述的如式III所示的化合物的三氟乙酸盐IIIa1的制备方法还进一步包含后处理的操作，所述的后处理的操作包括下列步骤：将成盐反应结束后的反应液，加入反溶剂混合，析晶，即可；所述的反溶剂较佳地为异丙醚；所述的卤代烃类溶剂与反溶剂的体积比较佳地为1:0.8-1:2，更佳地为1:1.3-1:1.5；所述的加入反溶剂的操作较佳地为滴加；所述的滴加反溶剂的温度较佳地为0℃-40℃，更佳地为25℃-40℃，最佳地为30℃-40℃；所述的析晶的温度较佳地为-5℃-40℃。
  17. 一种如式IIIa1所示的化合物：
    Figure PCTCN2016071198-appb-100009
  18. 一种如式I所示的泰拉霉素的纯化方法，其特征在于，其包括下列步骤：将如式I所示的泰拉霉素粗品与溶剂A混合，然后加入反溶剂，析晶，得如式I所示的泰拉霉素产品；其中，所述的如式I所示的泰拉霉素粗品的HPLC纯度为65％以上；所述的溶剂A为丙酮和C1-3的醇类溶剂的混合溶剂；所述的反溶剂为水或者水和丙酮的混合溶 剂；
    Figure PCTCN2016071198-appb-100010
  19. 如权利要求18所述的纯化方法，其特征在于，所述的如式I所示的泰拉霉素粗品的HPLC纯度为65％-99.5％；和/或，所述的C1-3的醇类溶剂为1,2-丙二醇；和/或，所述的溶剂A与所述的如式I所示的泰拉霉素粗品的体积质量比为2ml/g-50ml/g，较佳地为2ml/g-30ml/g；和/或，所述的加入反溶剂的操作为滴加；所述的滴加反溶剂时的温度较佳地为35℃-45℃；和/或，所述的反溶剂与所述的如式I所示的泰拉霉素粗品的体积质量比为2ml/g-60ml/g。
  20. 如权利要求18或19所述的纯化方法，其特征在于，当所述的反溶剂为水和丙酮的混合溶剂时，所述的水与所述的丙酮的体积比较佳地为0.5:1-3:1；在加入反溶剂时，较佳地当含如式I所示的泰拉霉素的溶液A变浑浊时，停止加入，搅拌养晶10-30分钟后，再加入剩余反溶剂；所述的析晶的温度较佳地为0℃-45℃；所述的析晶的时间较佳地为1-6小时；所述的析晶较佳地包括前期析晶和后期析晶，其中，所述的前期析晶较佳地为在35℃-45℃析晶0.5-3小时，所述的后期析晶较佳地为在0℃-35℃析晶0.5-3小时。
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