CN103880903B - A kind of preparation method of tylosin class macrolide and derivant thereof - Google Patents

A kind of preparation method of tylosin class macrolide and derivant thereof Download PDF

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CN103880903B
CN103880903B CN201410108841.4A CN201410108841A CN103880903B CN 103880903 B CN103880903 B CN 103880903B CN 201410108841 A CN201410108841 A CN 201410108841A CN 103880903 B CN103880903 B CN 103880903B
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tylosin
compound
piperidyl
methyl
reaction
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CN103880903A (en
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杜体建
谷长虹
孙宝佳
吕作亮
高健
陈阳
郝飞跃
孙蕊
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YANTAI WANRUN PHARMACEUTICAL Co Ltd
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Abstract

The preparation method that the present invention relates to a kind of tylosin class macrolide and derivant thereof, comprise the following steps: under the existence of aliphatic hydrocarbon polar solvent or aromatic hydrocarbon solvents, by Tylosin A or its salt, piperidinyl compounds I together with formic acid or its aqueous solution, generate 20-piperidyl-tylosin compound; Stir with HCOOH or its aqueous solution again, generate 23-O-(6-deoxidation-2,3-bis--O-methyl D-allose base)-20-piperidyl-5-O-mycamino syl-tylono lide compound; Then again with inorganic acid reaction 3-8 hour, form 23-hydroxyl-20-piperidyl-5-O-mycamino syl-tylono lide compound; Combine oxidizer system with selectivity again and be oxidized to reactive compound; By reactive compound and piperidinyl compounds II and formic acid or its reactant aqueous solution, namely obtain described tylosin class macrolide and derivant thereof. In the preparation process of compound, the consumption that makes of mineral acid is reduced to 25～36 molar equivalents, decreases the generation of by-product and hc effluent, improve yield.

Description

Preparation method of tylosin macrolide and derivative thereof
Technical Field
The invention relates to a tylosin macrolide and a preparation method of a derivative thereof, belonging to the field of pharmacy.
Background
It has long been known that tylosin based macrolides are useful for the treatment of infectious diseases in humans, livestock, poultry and other animals. Early tylosin macrolide compounds included 16-membered tylosin macrolide compounds, e.g., tylosin a:
16-membered tylosin macrolide compounds are reported in patents US4920103, US4820695 and EP0103465B 1. In recent years, various tylosin derivatives have been developed to improve the antibacterial activity and selectivity of such compounds.
Tylosin derivatives include, for example: tylosin B (otherwise known as desmycocin), tylosin C (otherwise known as colicin) and tylosin D (otherwise known as relomycin), having the following structural formula:
as can be seen from the structural formula of tylosin B, C, D, the tylosin is obtained by reacting tylosin A through desugared ring reaction, deprotection reaction of hydroxyl on sugar ring or aldehyde group reduction reaction, and the reactions do not change the 16-membered ring structure of macrolactone and the 5-position O-carbohydramine glycosyl.
Tylosin derivatives also include, for example, the compounds discussed in patent US6514946, which correspond in structure to formula (I):
wherein:
R1and R3Each is methyl, and R2Is hydrogen; r1And R3Each is hydrogen, and R2Is methyl; or R1，R2，R3Each is hydrogen; and is
R4And R6Each is methyl, and R5Is hydrogen; r4And R6Each is hydrogen, and R5Is methyl; or R4，R5，R6Each is hydrogen.
Such compounds include, for example, 20, 23-dipiperidinyl-5-O-carbominaminoglycosyl-tylactone, which has the following structure:
these compounds and in particular 20, 23-dipiperidinyl-5-O-carbosaminyl-tylonolide are effective in the treatment of, for example, pasteurellosis, bovine respiratory disease and porcine respiratory disease and are therefore identified as having pharmacokinetic and pharmacodynamic properties. US6514946 discusses the use of these compounds in the treatment of diseases in livestock and poultry.
Various methods for preparing macrolides have been reported in the literature.
For example, in european patent EP0103465B1, debon et al discuss in great detail the various process steps involved in preparing such compounds. These processes include, for example, reduction as shown in the following formula:
wherein: r, R1，R2，R3And R4Represents various substituents. R represents in particular a nitrogen atom-containing cyclic system comprising three unsaturated or saturated rings bearing substituents. Debon et al report that the preferred reducing agent is cyanoborohydride and sodium cyanoborohydride is the selective reducing agent. Debon et al also report that the solvent for this reaction is generally an inert polar solvent, e.g., C1-C4Alkyl alcohol (see page 6, lines 7-14). In U.S. Pat. No. 4,4820695 to Debon et al, various aldehyde-based compounds (including tylosin) are discussed in depth with differencesReductive amination of the amine(s) of (a). Sodium cyanoborohydride and sodium borohydride are suitable reducing agents and anhydrous methanol is a suitable solvent (see US4820695, column 7, lines 60-68).
Reductive amination of tylosin B (and its derivatives) is also discussed in US6664240, Phan, et al:
wherein: r2，R4，R7And R8Represents various substituents. R7And R8In particular, each represents an independent substituent, or the two are connected to form a 3-to 7-membered heterocyclic ring. Phan et al, perform this reduction reaction with borohydride in an alcohol or acetonitrile solvent. Sodium cyanoborohydride and sodium borohydride as typical reducing agents; and methanol, ethanol, isopropanol as typical alcoholic solvents (see column 15, line 64 to column 16, line 42; column 22, lines 41-49).
In patent EP0240264B1, tao et al also discuss the reductive amination of tylosin-based macrolides:
wherein: r1，R2，R3And R4Represents various substituents. R3And R4In particular, the substituents represent independent substituents, or the substituents and the substituents are connected to form a heterocyclic ring. Tao et al found that such reduction can be achieved using formic acid as the reducing agent. In another patent to tao et al (US4921947) it is reported that the conventional solvent for the reaction is an inert polar solvent, and that amyl acetate and acetonitrile are selected among such solvents (see page 4, line 57 to page 5, line 10; column 3, line 62 to column 4, line 16).
In patent EP0103465B1, debono. et al discuss the following hydrolysis reactions:
wherein: r, R1，R2And R4Represents various substituents. Debono et al report that this hydrolysis reaction can be carried out under the action of strong inorganic acids (e.g., hydrochloric acid or sulfuric acid) or strong organic acids (e.g., p-toluenesulfonic acid) (page 7, lines 3-8). In a similar patent (US4820695) subsequent to Debono et al, the hydrolysis of tylosin derivatives, the C-20-mycaminose of colistin, is further discussed, as well as the well known DOMM procedure of the acid hydrolysis process (US4820695, column 8, lines 35-43).
In WO2008012343A2, C-20 of tylosin-like macrolides is reported to be subjected to piperidinyl derivatization by the following method:
wherein: l is a leaving group which facilitates activation of the methylene group to which it is attached, enhancing its electropositivity, and more so facilitates nucleophilic substitution of the amine with it, e.g., L is iodine, mesylate, p-toluenesulfonate, triflate, and the like.
R1And R3Each is methyl, and R2Is hydrogen; r1And R3Each is hydrogen, and R2Is methyl; or R1，R2，R3Each is hydrogen; and is
R4And R6Each is methyl, and R5Is hydrogen; r4And R6Each is hydrogen, and R5Is methyl; or R4，R5，R6Each is hydrogen.
When a hydroxyl group is substituted with an L-group, a compound capable of providing an L-group such as: iodine simple substance, methanesulfonyl chloride, paratoluensulfonyl chloride, trifluoromethanesulfonyl chloride and the like, and the compounds can generate side reaction with carbon-carbon double bonds or secondary hydroxyl with smaller steric hindrance in substrate molecules or can cause hydrolysis of lactone bonds, so that more byproducts are generated, and the purity and the yield of products are reduced.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method which is simple and convenient to operate, high in yield, low in cost and suitable for industrial production of tylosin macrolide and derivatives thereof,
the technical scheme for solving the technical problems is as follows: a preparation method of tylosin macrolide and derivatives thereof comprises the following steps:
1) in the presence of an aliphatic hydrocarbon polar solvent or an aromatic hydrocarbon solvent, mixing tylosin A or a salt thereof, a piperidyl compound I and formic acid or an aqueous solution thereof according to a molar ratio of 1.0: 1.0-4.5: 2.0-13.5, reacting for 3-10 hours at the temperature of 25-100 ℃ under normal pressure to generate a 20-piperidyl-tylosin compound; wherein,
the structural formula of the piperidyl compound I is as follows:
the structural formula of the 20-piperidyl-tylosin compound is as follows:
the R is1Is methyl, R2Is hydrogen and R3Is methyl, or said R1Is hydrogen, R2Is methyl and R3Is hydrogen, or said R1、R2And R3Are all hydrogen;
2) mixing and stirring the 20-piperidyl-tylosin compound generated in the step 1) and HCOOH or an aqueous solution thereof according to a molar ratio of 1.0: 2.0-13.5, and reacting at the temperature of 25-100 ℃ and normal pressure for 3-10 hours to generate a 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose) -20-piperidyl-5-O-mycaminose-tylosin lactone compound; wherein,
the structural formula of the 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose base) -20-piperidyl-5-O-mycaminose-tylonolide compound is as follows:
3) mixing and stirring the 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose base) -20-piperidyl-5-O-mycaminose base-tylonolide compound formed in the step 2) and inorganic acid according to the molar ratio of 1.0: 2.0-12.0, and reacting for 3-8 hours at the temperature of 25-80 ℃ under normal pressure to form a 23-hydroxy-20-piperidyl-5-O-mycaminose base-tylonolide compound; wherein,
the structural formula of the 23-hydroxy-20-piperidyl-5-O-mycaminosyl-tylonolide compound is as follows:
4) oxidizing the 23-hydroxy-20-piperidyl-5-O-mycaminosyl-tylonolide compound formed in the step 3) into an active compound by using a selective combined oxidant system under the conditions of-15 ℃ and pH of 8-10; wherein,
the structural formula of the active compound is as follows:
5) mixing the active compound formed in the step 4) with a piperidyl compound II and formic acid or an aqueous solution thereof according to a molar ratio of 1.0: 1.0-2.5: 2.0-6.5, and reacting for 3-10 hours at 25-100 ℃ under normal pressure to obtain the tylosin macrolide and the derivative thereof; wherein,
the structural formula of the piperidyl compound II is as follows:
the R is4And R6Each is methyl, and R5Is hydrogen, or said R4And R6Each is hydrogen, and R5Is methyl, or said R4、R5And R6Each is hydrogen;
the structural formula of the tylosin macrolide and the derivative thereof is as follows:
the reaction structure formula is as follows:
the selective combined oxidant system refers to an oxidant system which can selectively oxidize primary hydroxyl groups into aldehyde groups, but not carboxyl groups, and secondary hydroxyl groups are not or only little partially oxidized, wherein the selective combined oxidant system comprises a mixture consisting of NaClO and KBr and TEMPO and sodium bicarbonate, or a mixture consisting of NaClO, KBr and TEMPO derivatives and sodium bicarbonate, or a mixture consisting of silica, TEMPO and CuCl and pyridine, or a mixture consisting of silica, TEMPO and CuCl and N-methylimidazole, or a mixture consisting of silica, TEMPO, CuCl and sodium hydroxide, and the like.
Wherein TEMPO is 2,2,6, 6-tetramethylpiperidine-N-oxide.
The TEMPO structural formula is as follows:
the derivative of TEMPO is 4-methylsulfonyl-TEMPO or 4-acetamido-TEMPO, wherein the structural formula of the 4-methylsulfonyl-TEMPO is as follows:
the structural formula of 4-acetamido-TEMPO is as follows:
the invention has the beneficial effects that: in the preparation process of the compound V, the using amount of the inorganic acid is reduced to 25-36 molar equivalents (the using amount of the inorganic acid is 72 molar equivalents in a synthesis method reported in documents), the generation of byproducts and high-concentration wastewater is reduced, the yield is improved (the yield is 65-70% in terms of tylosin A; the yield is 45-50% reported in documents), and the synthesis cost is reduced; when a compound V is converted into a tylosin macrolide and a derivative thereof, the compound V is activated by hydroxymethyl iodo or active ester in the molecule of the compound V, and then reacts with amine to generate a target product, a large amount of iodine or environmentally unfriendly substances such as methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic chloride and the like are used in the method, the hydroxymethyl group in the compound V is oxidized into an aldehyde group, and then the target product is synthesized by utilizing the reducing amine of formic acid, and the used oxidant is mainly an inorganic substance (such as sodium hypochlorite, potassium bromide and the like), so that the method is environmentally friendly, stable in process operation and more beneficial to industrial production.
A. The tylosin macrolide compound prepared by the method described in the invention has the following structural formula (I)
Wherein:
R1and R3Each is methyl, and R2Is hydrogen;
R1and R3Each is hydrogen, and R2Is methyl or R1，R2，R3Each is hydrogen;
and is
R4And R6Each is methyl, and R5Is hydrogen;
R4and R6Each is hydrogen, and R5Is methyl or R4，R5，R6Each is hydrogen.
In some embodiments, the substituted piperidinyl groups in formula (i) are the same, i.e.:
are the same.
In some embodiments, both of the substituted piperidinyl groups are piperidines (e.g., R1, R2, R3, R4, R5, R6 are each hydrogen), such as compound 20, 23-dipiperidinyl-5-O-mycaminosyl-tylonolide:
other compounds having the same substituted piperidinyl group include:
in some embodiments, the substituted piperidinyl groups in formula (i) are not the same, i.e.:
are not identical.
Other compounds having differently substituted piperidinyl groups include:
B. synthesis of tylosin macrolides
The present invention can be used to synthesize tylosin-type macrolides from materials generally available in the art.
B-1.23-O- (6-deoxy-2, 3-di-O-methyl-D-allose base) -20-piperidyl-5-O-mycaminose base-tylonolide compound.
In some embodiments, the tylosin-based macrolide synthesis starts with or includes the step of preparing a 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose yl) -20-piperidinyl-5-O-mycaminosyl-tylonolide compound, especially a compound corresponding in structure to formula (iv):
in some embodiments, R1And R3Each is methyl, and R2Is hydrogen; or R1And R3Each is hydrogen, and R2Is methyl. In other embodiments, R1、R2、R3Each is hydrogen, then the structure of the compound is:
the 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose yl) -20-piperidinyl-5-O-mycaminosyl-tylonolide compound can be prepared from tylosin a and a piperidinyl compound via a reductive amination reaction using a reducing agent comprising formic acid (or "HCOOH") and a reaction of the 20-piperidinyl tylosin compound and formic acid (one pot run):
when R is1、R2And R3When each is hydrogen, the reaction is as follows:
tylosin a, piperidine, formic acid are commercially available.
Tylosin a may be pure (or substantially pure) tylosin a. Alternatively, tylosin a may be a mixture, e.g. comprising tylosin a and one or more tylosin a derivatives, such as tylosin B, tylosin C and/or tylosin D.
Tylosin a (or a derivative thereof) may be in its free form or in the form of a salt. Salts of various tylosines (or derivatives thereof) are preferred. In some embodiments, the salt comprises a phosphate salt. In other embodiments, the salt comprises tartrate. In still other embodiments, the salt comprises citrate or sulfate.
The solvent may be a single or a mixture of solvents. While the solvent may comprise one or more polar solvents, in some embodiments, the solvent preferably instead comprises one or more non-polar solvents. "non-polar solvent" refers to a solvent that is not sufficiently ionized to be sufficiently conductive, and that is not (or substantially not) capable of dissolving polar compounds (e.g., various inorganic salts), but is capable of dissolving non-polar compounds (e.g., hydrocarbons and resins). In general, solvents which do not react with the reaction substrates, products and any other components in the reaction mixture and which have good solubility for the substrates are preferred. For example, the aliphatic hydrocarbon polar solvent may include chloroform (or "CHCl)3"); tetrahydrofuran (or "THF"); methylene chloride (or CHCl)2"or" DCM "or" methylene chloride "); dichloroethane (or CH)2Cl2CH2Cl2) (ii) a Carbon tetrachloride (or "CCl)4"); ethyl acetate (or "CH)3COOC2H5"); or aromatic hydrocarbon solvents, e.g. toluene (or "C6H5CH3"), xylene (or" C ")6H4(CH3)2") or dimethylbenzenes (including 1, 3-dimethylbenzene (or" meta-xylene "), 1, 2-dimethylbenzene (or" ortho-xylene "), 1, 4-dimethylbenzene (or" para-xylene "), ethylbenzene, or mixtures thereof (e.g., mixtures of meta-xylene, ortho-xylene, para-xylene, and/or ethylbenzene). In some embodiments, the solvent comprises dichloroethane, chloroform, or ethyl acetate. In other embodiments, the solvent comprises xylene. In some further embodiments, the solvent comprises ethylene dichloride. In some such embodiments, dichloroethane is particularly preferred because it is readily used at typical reaction temperatures.
In some embodiments, the solvent is a mixed solvent. In some such embodiments, the solvent is a mixed solvent of toluene and dichloromethane. Herein, the toluene/dichloroethane ratio may be about 1:1 to about 1:100, or about 1:5 to about 1:8 (V/V). In some of these embodiments, the ratio is 7:1 (V/V). In other embodiments, the ratio is 6.3: 1.
Tylosin a, the piperidinyl compound, formic acid (or a source of formic acid) and the solvent may generally be added to the reaction vessel in any order.
Glass and glass-lined reactors are generally preferred.
In general, molar equivalents of tylosin a, piperidinyl compound and formic acid may be used. However, an excess of piperidinyl compound and formic acid is usually used relative to the moles of tylosin a.
In some embodiments, 1 to about 1.5 equivalents (or 1.05 to about 1.4 equivalents) of the piperidinyl compound is added to the reactor. In some such embodiments, 1.05 to about 1.2 equivalents of the piperidinyl compound are added to the reactor. In other such embodiments, about 1.07 to about 1.5 equivalents of piperidinyl compound are added to the reactor.
In some embodiments, 1 to about 5 equivalents (or 1.05 to about 14 equivalents, about 2 to about 5 equivalents, or about 2.5 to about 3.5 equivalents) of formic acid are used. In some such embodiments, about 4.5 equivalents of formic acid are used. In other such embodiments, about 2.5 to about 4 equivalents of formic acid are used. For example, in some such embodiments, about 3.0 equivalents of formic acid are used.
Generally, the amount of solvent is sufficient to prevent (or substantially prevent) the reactants, products and other components of the reaction mixture from sticking to the reactor and to promote uniform distribution of the reactants.
At least a portion of the reaction (or the entire reaction) is typically conducted at greater than about 30 ℃, greater than about 40 ℃, or greater than about 60 ℃. Generally, at least a portion of the reaction (or the entire reaction) is carried out at a temperature no greater than the boiling point of the solvent, and more typically, less than the boiling point. For example, when the solvent is dichloroethane, at least a portion of the reaction (or all of the reaction) is typically conducted at less than 83 ℃. Generally, at least a portion of the reaction (or the entire reaction) is carried out at about 60 to about 95 ℃, about 70 to about 85 ℃, about 70 to about 80 ℃, or about 75 to about 80 ℃. In some embodiments, the reaction temperature of at least a portion of the reaction (or the entire reaction) is about 80 ℃. In other embodiments, the reaction temperature of at least a portion of the reaction (or the entire reaction) is about 76 ℃. Although temperatures less than the above ranges may be used, such reaction temperatures tend to be accompanied by slower reaction rates. Also, while temperatures greater than the above ranges may be used, such temperatures tend to be accompanied by more by-products.
The reaction is preferably carried out at atmospheric pressure. In a preferred embodiment, the reaction is carried out in an inert gas (e.g., N)2) The process is carried out as follows.
The reaction time depends on various factors including the reaction temperature, the solvent, the feed ratio and the desired conversion. The reaction time is from about 2 to about 9 hours, or from about 1 to about 4 hours. In some such embodiments, the reaction time is about 3.5 hours. In other such embodiments, the reaction time may be about 5.5 hours. Although reaction times shorter than these ranges may be used, such reaction times result in low conversions. Also, although longer reaction times can be used, longer reaction times tend to produce more impurities and result in wasted labor and material.
The reductive amination reaction and the hydrolysis of carbohydrase can be carried out in two steps or in one step as described in this section (section B-1), and it is preferable that the reductive amination reaction and the hydrolysis of carbohydrase are carried out in one step since HCOOH remaining from the reductive amination can be continuously reacted with the product (20-piperidyl-tylactone compound) obtained by the reductive amination reaction. And it is worth noting that formic acid is involved in the hydrolysis of mycaminosyloxy groups, with fewer by-products and a purer product being prepared.
Purification or isolation of the product may be accomplished using various methods known in the art. Alternatively, the product can be used directly in the next step without purification and isolation.
Synthesis of B-2.23-hydroxy-20-piperidyl-5-O-mycaminosyl-tylonolide
(hydrolysis of the Di-methyl protected Carbomycinosyloxy substituent)
Included in the present invention is the preparation of 23-hydroxy-20-piperidinyl-5-O-mycaminosyl-tylonolide compounds starting from or involved in the synthesis of tylosin macrolide compounds, and in particular compounds of the formula:
wherein: r1 and R3 are each methyl, and R2 is hydrogen;
or R1 and R3 are each hydrogen, R2 is methyl
When R1, R2 and R3 are each hydrogen, the structure is as follows:
the 23-hydroxy-20-piperidyl-5-O-mycaminosyl-tylonolide compound can be prepared by the hydrolysis reaction of 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose) -20-piperidyl-5-O-mycaminosyl-tylonolide compound and acid.
When R1, R2, R3 are each hydrogen, the reaction is as follows:
the 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose yl) -20-piperidinyl-5-O-mycaminosyl-tylonolide compound used in the above reaction was prepared from the above part B-1.
The acid used in this part is a strong non-oxidizing inorganic acid such as hydrochloric acid, fluoroboric acid, phosphoric acid, dilute sulfuric acid (concentration less than 50 mass fraction), hydrobromic acid, and hydrobromic acid is more preferred because it is less by-produced in the product.
Typically, a sufficient amount of acid is mixed with 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose yl) -20-piperidinyl-5-O-mycaminosyl-tylonolide compound, heated, and hydrolyzed to remove the di-methyl protected mycaminosyl group, forming a hydroxyl group. In particular, the molar amount of the acid is 5 to 15 times, preferably 10 to 13 times of that of 23-O-mycaminosyl-20-piperidyl-5-O-mycaminosyl-tylonolide. The concentration of the acid is not more than 50 percent (mass fraction), the concentration is 10 to 49 percent, and the preferred concentration is 15 to 25 percent. The acid used in some of the examples is hydrobromic acid, preferably at a concentration of 24%. Also in the examples the acid used is sulphuric acid, preferably at a concentration of 25%.
The sequence of adding the materials into the reaction kettle has no special requirements. Acid is used in the reaction process, a stainless steel kettle is corroded, and a glass or enamel kettle is preferably used as a reaction vessel.
The reaction temperature of the mixed system is 40-75 ℃, and the temperature of the reaction system varies according to the type of the acid used, for example, when hydrobromic acid is used, the reaction temperature of the system is 40-55 ℃, and when sulfuric acid is used, the reaction temperature of the system is 55-75 ℃.
Although it is possible to use lower temperatures than in this temperature range for the reaction, lower reaction temperatures result in slower reaction rates, while higher temperatures beyond this temperature range result in more by-product formation.
When part of the acid (or all of the acid) used for hydrolyzing the di-methyl protected carbohydrase glycosyl is added into the reaction kettle, the temperature of the system is slightly lower than the expected reaction temperature.
The reaction can be carried out at normal pressure, or at a pressure higher than normal pressure, or lower than normal pressure, preferably under a nitrogen atmosphere at normal pressure.
The reaction time depends on various factors, for example, the reaction temperature, the reaction solvent, the feed ratio, the desired conversion. Although the reaction time may be below this time range, the conversion rate of the reaction may be reduced, and the reaction time above this time range may result in more impurities being produced and unnecessary waste of manpower and material resources.
The reductive amination and hydrolysis of carbohydrase glycoxy groups discussed in section B-1 and the hydrolysis of the bis-methyl protected carbohydrase glycoxy groups discussed in section B-2 can be carried out in two steps (reductive amination and hydrolysis of carbohydrase amine glycoxy groups discussed in section B-1 in one step and hydrolysis of carbohydrase glycoxy groups discussed in section B-2 in one step) or in one step (one pot). Preferably, the experiment is carried out as one step, so that the operation is simple and convenient, manpower and material resources can be saved, the industrial production of the process is more facilitated, and when the three reactions are carried out as one step in one pot, the reaction system maintains the same reaction temperature or changes (particularly reduces) the reaction temperature along with the advance of the reaction time, and preferably changes (particularly reduces) the reaction temperature. Wherein, when the reaction temperature is changed, the reaction temperature of the two reactions described in the section B-1 is consistent and higher, and the reaction temperature of the reaction described in the section B-2 is lower than that of the reaction described in the section B-1. When the system is reacted at the same reaction temperature, the selected temperature is between 35 and 70 ℃, preferably between 55 and 70 ℃. The reaction is carried out by changing the reaction temperature, the reaction temperature is reduced from 80 ℃ to 35 ℃, or from 70 ℃ to 45 ℃, or from 65 ℃ to 55 ℃, or from 70 ℃ to 54 ℃, and the reaction temperature is preferably reduced from 70 ℃ to 45 ℃. During the process of adding the acid into the reaction kettle, the temperature of the reaction system is lower than the expected reaction temperature.
When the three reactions are carried out in one reaction, the total reaction time depends on various factors, for example, the reaction temperature, the solvent, the material ratio, the desired conversion, and the like. In general, the total reaction time is at least 4 hours, at most 14 hours, preferably 6 to 10 hours. In some embodiments, a reaction time of 6 hours corresponds to a reaction temperature of from 70 ℃ down to 54 ℃; in other examples, the reaction time is 10 hours, corresponding to a reaction temperature of from 70 ℃ down to 45 ℃.
The obtained product can be separated or purified by conventional chemical methods, wherein the crude product is salified, backwashed (the backwashing solvent is an organic solvent which is immiscible with water and does not react with the product, such as a single solvent of ethyl acetate, dichloromethane, dichloroethane, chloroform, toluene, methyl tert-butyl ether, isopropyl ether and the like or a mixed solvent of a plurality of the solvents, preferably ethyl acetate, dichloromethane and methyl tert-butyl ether), the crude product can be primarily purified, and refined product can be obtained by pulping or recrystallizing the crude product with organic solvent (water-insoluble organic solvent which does not react with the product, such as ethyl acetate, dichloromethane, dichloroethane, chloroform, toluene, methyl tert-butyl ether, isopropyl ether, and other single solvents or mixed solvents of several solvents, preferably one or more mixed solvents of ethyl acetate, dichloromethane, and methyl tert-butyl ether). Or the crude product is directly used for the next reaction without purification.
Preparation of the active B-3 Compound (VI)
The active compound has the following structural formula (VI):
in some embodiments, the synthesis of the tylosin-like macrolide starts or comprises the preparation of the active compound and in particular comprises compound (6) of the structure:
in some embodiments R1 and R3 are each methyl, and R2 is hydrogen; r1 and R3 are each hydrogen, and R2 is methyl. In other embodiments, R1, R2, R3 are each hydrogen, and when the compound has the structure:
the active compound (6) can be prepared by reacting 23-hydroxy-20-piperidyl-5-O-carbohydramine glycosyl-tylonolide with a selective oxidant at a specific pH value and a specific reaction temperature:
when each of R1, R2, R3 is hydrogen, the reaction is as follows:
the term "selectively combined oxidant system" in this section refers to a combined oxidant or mixture of combined oxidants that selectively oxidize primary hydroxyl groups to aldehyde groups, with secondary hydroxyl groups not (or only minimally) oxidized, in some embodiments, for example, a mixture of NaClO and KBr and TEMPO and sodium bicarbonate is used, or a mixture of NaClO and derivatives of KBr and TEMPO and sodium bicarbonate, in other embodiments, a mixture of silica, TEMPO and CuCl and pyridine is used, or a mixture of silicon dioxide and TEMPO and CuCl and N-methylimidazole, or a mixture of silica and TEMPO and CuCl and sodium hydroxide, preferably a mixture of NaClO and KBr and TEMPO and sodium bicarbonate, a mixture of NaClO and KBr and TEMPO derivatives and sodium bicarbonate, more preferably a mixture of NaClO and KBr and TEMPO and sodium bicarbonate.
Wherein TEMPO is 2,2,6, 6-tetramethylpiperidine-N-oxide.
The TEMPO structural formula is as follows:
the derivative of TEMPO is 4-methylsulfonyl-TEMPO or 4-acetamido-TEMPO, wherein the structural formula of the 4-methylsulfonyl-TEMPO is as follows:
the structural formula of 4-acetamido-TEMPO is as follows:
in some embodiments, the reaction temperature is controlled to be between-25 ℃ and 3 ℃, in other embodiments, the reaction temperature is controlled to be between-15 ℃ and 15 ℃, and in other embodiments, the reaction temperature is controlled to be between-25 ℃ and 0 ℃. The reaction temperature is lower than-25 ℃, water in the system is seriously frozen, more impurities are generated, the reaction temperature is higher than 0 ℃, and more impurities are generated, so that the yield is reduced.
The 23-hydroxy-20-piperidinyl-5-O-carbosaminyl glycosyl-tylonolide used in the above reaction was prepared from B-2 above.
Detailed Description
The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
Example 1
Preparation of 20, 23-dipiperidinyl-5-O-mycaminosyl-tylonolide from tylosin A.
Part a reductive amination and acid hydrolysis of mycaminosyloxy substituents. Preparation of 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose yl) -20-piperidinyl-5-O-mycaminosyl-tylonolide compound (2).
Toluene (1431g), tylosin A (1) (229 g; tylosin A. gtoreq.80% and tylosin A, B, C and D. gtoreq.95%), piperidine (25.5g) and formic acid (67.5g) were added to the reactor. Heating the mixture to 65-75 ℃ under a stirring state, and preserving heat for 4-5 hours. A small sample was taken to evaporate the solvent and the formation of 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose yl) -20-piperidinyl-5-O-mycaminosyl-tylonolide compound (2) was monitored by HPLC. After the reaction was complete (tylosin A (1) HPLC content. ltoreq.2%), the product mixture was cooled to ambient temperature.
Part B.Acidolytic hydrolysis of the 6-deoxy-2, 3-di-O-methyl-D-allose substituent and preparation of 23-hydroxy-20-piperidinyl-5-O-mycaminosyl-tylonolide (3).
24% HBr (1958.3g) was added to the product mixture obtained from part A at ambient temperature, heated to 40-50 ℃ over 20 minutes while stirring. Stirring was maintained at this temperature for 5-6 hours while monitoring the reaction using HPLC. After the reaction was completed (HPLC content of 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose) -20-piperidinyl-5-O-mycaminosyl-tylonolide compound (2) was 2% or less), the reaction system was cooled to 30 ℃ or less, the aqueous phase and the organic phase were separated, and the aqueous phase was washed with dichloromethane (286.3 g each) 2 times. The aqueous phase was cooled to 5-10 ℃ and 24% NaOH (1171.8g) was slowly added dropwise to adjust the pH to about 10. The reaction mixture was extracted with methylene chloride (572.5 g each time) at an internal temperature of < 20 ℃ 2 times, the resulting organic phases were combined, sodium sulfate (177.5g) was added, the mixture was dried and then filtered off, and the solvent was evaporated from the resulting filtrate under reduced pressure to give 3105.3g of a crude product (3) (yield: 63.2%, HPLC: 91.8624%).
Part C preparation of active Compound (4)
100g (0.15mol) of the crude product (3) obtained in part B, 1.2g (0.0075mol) of TEMPO, 1.8g (0.015mol) of KBr, 12.6g (0.15mol) of sodium hydrogencarbonate and 900g of methylene chloride were put in a 2L three-necked flask, and the flask was placed in a low-temperature bath and stirred to reduce the internal temperature to about 0 ℃. 552.8g (0.6841mol) of NaClO solution was slowly added dropwise to the flask, and the internal temperature was controlled to be less than 5 ℃ over a period of about 5 hours. After the dropwise addition, the reaction is carried out for 1h at the temperature of 0-5 ℃, and the TLC monitoring is carried out, so that the raw materials are completely reacted. To the reaction flask was added 110g of a 20% sodium thiosulfate solution, and the reaction was quenched and stirred for 20 min. The insoluble solid material was removed by suction filtration and rinsed with 50ml of dichloromethane. The filtrate was allowed to stand for liquid separation, the aqueous phase was extracted with (530 g. times.2) dichloromethane, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off (40 ℃ C., -0.085MPa) to give 77.7g of a foamy yellow solid with an HPLC purity of 87.53%.
Part d. reductive amination. Preparation of 20, 23-dipiperidinyl-5-O-mycaminosyl-tylonolide (5)
Toluene (455g), active (4) (70.0g, 0.105mol), piperidine (33.0g) and 88% aqueous formic acid (65.9g,1.26mol) were added to the reactor. Heating the mixture to 65-75 ℃ under a stirring state, and preserving heat for 4-5 hours. A small sample was evaporated to dryness and the formation of 20, 23-dipiperidinyl-5-O-mycaminosyl-tylonolide (5) was monitored by HPLC. After completion of the reaction (HPLC content of active (4) ≦ 2%), the product mixture was cooled to ambient temperature. The solvent was distilled off, the product solution was obtained by back washing and extraction, 65.5g of pale yellow foamy solid was obtained by distilling off the solvent, the purity was 91.2% and the yield was 85.06%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (4)

1. A preparation method of tylosin macrolide and derivatives thereof is characterized by comprising the following steps:
1) in the presence of an aliphatic hydrocarbon polar solvent or an aromatic hydrocarbon solvent, mixing tylosin A or a salt thereof, a piperidyl compound I and formic acid according to a molar ratio of 1.0: 1.0-4.5: 2.0-13.5, reacting for 3-10 hours at the temperature of 25-100 ℃ under normal pressure to generate a 20-piperidyl-tylosin compound; wherein,
the structural formula of the piperidyl compound I is as follows:
the structural formula of the 20-piperidyl-tylosin compound is as follows:
the R is1Is methyl, R2Is hydrogen and R3Is methyl, or said R1Is hydrogen, R2Is methyl and R3Is hydrogen, or said R1、R2And R3Are all hydrogen;
2) mixing and stirring the 20-piperidyl-tylosin compound generated in the step 1) and HCOOH or an aqueous solution thereof according to a molar ratio of 1.0: 2.0-13.5, and reacting at the temperature of 25-100 ℃ and normal pressure for 3-10 hours to generate a 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose) -20-piperidyl-5-O-mycaminosyl-tylosin lactone compound; wherein,
the structural formula of the 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose base) -20-piperidyl-5-O-mycaminose-tylonolide compound is as follows:
3) mixing and stirring the 23-O- (6-deoxy-2, 3-di-O-methyl-D-allose base) -20-piperidyl-5-O-mycaminose base-tylonolide compound formed in the step 2) and inorganic acid according to the molar ratio of 1.0: 2.0-12.0, and reacting for 3-8 hours at the temperature of 25-80 ℃ under normal pressure to form a 23-hydroxy-20-piperidyl-5-O-mycaminose base-tylonolide compound; wherein,
the structural formula of the 23-hydroxy-20-piperidyl-5-O-mycaminosyl-tylonolide compound is as follows:
4) oxidizing the 23-hydroxy-20-piperidyl-5-O-mycaminosyl-tylonolide compound formed in the step 3) into an active compound by using a selective combined oxidant system under the conditions of-15 ℃ and pH of 8-10; wherein,
the structural formula of the active compound is as follows:
wherein the selective combined oxidant system is a mixture consisting of NaClO and KBr and TEMPO and sodium bicarbonate, or a mixture consisting of NaClO and KBr and TEMPO derivatives and sodium bicarbonate, or a mixture consisting of silica, TEMPO and CuCl and pyridine, or a mixture consisting of silica and TEMPO and CuCl and N-methylimidazole, or a mixture consisting of silica and TEMPO and CuCl and sodium hydroxide; the derivative of TEMPO is one of 4-methylsulfonyl-TEMPO or 4-acetamido-TEMPO;
5) mixing the active compound formed in the step 4) with a piperidyl compound II and formic acid or an aqueous solution thereof according to a molar ratio of 1.0: 1.0-2.5: 2.0-6.5, and reacting for 3-10 hours at 25-100 ℃ under normal pressure to obtain the tylosin macrolide and the derivative thereof; wherein,
the structural formula of the piperidyl compound II is as follows:
the R is4And R6Each is methyl, and R5Is hydrogen, or said R4And R6Each is hydrogen, and R5Is methyl, or said R4、R5And R6Each is hydrogen;
the structural formula of the tylosin macrolide and the derivative thereof is as follows:
2. the method for preparing a tylosin macrolide and derivatives thereof according to claim 1, wherein the aliphatic hydrocarbon polar solvent is any one of chloroform, tetrahydrofuran, dichloromethane, dichloroethane, carbon tetrachloride or ethyl acetate; the aromatic hydrocarbon solvent is any one or mixture of toluene, xylene or ethylbenzene.
3. The method for preparing the tylosin macrolide and the derivative thereof according to claim 2, wherein the xylene is any one or a mixture of 1, 3-dimethylbenzene, 1, 2-dimethylbenzene or 1, 4-dimethylbenzene.
4. The process for producing a tylosin macrolide and derivatives thereof according to claim 1, wherein the inorganic acid is any one of dilute sulfuric acid, hydrochloric acid, phosphoric acid or hydrobromic acid.
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CN104478974B (en) * 2014-11-28 2016-08-17 武汉回盛生物科技有限公司 A kind of 20, the synthetic method of 23-dipiperidino-5-O-mycamino syl-tylono lide
CN104497082B (en) * 2015-01-13 2017-12-12 中国兽医药品监察所 A kind of synthetic method of tylonolide
CN104558076A (en) * 2015-02-10 2015-04-29 上海皓元化学科技有限公司 Preparation method of tildipirosin and intermediate compounds of tildipirosin
CN104774223A (en) * 2015-03-26 2015-07-15 宁夏泰瑞制药股份有限公司 Method for producing tildipirosin by using tylosin alkali
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CN104892704B (en) * 2015-04-07 2017-08-08 中牧实业股份有限公司 The preparation method of the O mycaminose Ji Taile lactones of 20,23 dipiperidino 5
CN108033988A (en) * 2017-12-28 2018-05-15 山东鲁抗舍里乐药业有限公司 A kind of preparation method of tylonolide
CN114920789B (en) * 2022-07-07 2024-06-14 京山瑞生制药有限公司 Preparation method of tylosin key intermediate
CN117510561B (en) * 2023-11-30 2024-04-02 中国农业科学院饲料研究所 Tylosin derivative and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0103465A1 (en) * 1982-09-13 1984-03-21 Eli Lilly And Company 20-Amino macrolide derivatives
CN101506220A (en) * 2006-07-28 2009-08-12 英特威国际有限公司 Macrolide synthesis process
CN102382159A (en) * 2011-12-07 2012-03-21 齐鲁动物保健品有限公司 Preparation method of tilmicosin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0103465A1 (en) * 1982-09-13 1984-03-21 Eli Lilly And Company 20-Amino macrolide derivatives
CN101506220A (en) * 2006-07-28 2009-08-12 英特威国际有限公司 Macrolide synthesis process
CN102382159A (en) * 2011-12-07 2012-03-21 齐鲁动物保健品有限公司 Preparation method of tilmicosin

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