CN109942653B

CN109942653B - A kind of erythromycin derivative and preparation method thereof

Info

Publication number: CN109942653B
Application number: CN201910147302.4A
Authority: CN
Inventors: 梁建华; 马聪璇
Original assignee: Beijing Institute of Technology BIT
Current assignee: Beijing Institute of Technology BIT
Priority date: 2019-02-27
Filing date: 2019-02-27
Publication date: 2021-06-25
Anticipated expiration: 2039-02-27
Also published as: CN109942653A

Abstract

The present invention provides an erythromycin derivative, characterized in that the erythromycin derivative includes a compound of general formula I, or the erythromycin derivative includes the compound of general formula I and an inorganic acid Or a pharmaceutically acceptable salt formed by an organic acid, the erythromycin derivative can be better adapted to industrial production, and can be used for clinically common erythromycin-resistant Streptococcus pneumoniae, Staphylococcus aureus, pyogenic chain Pathogenic bacteria such as cocci, catarrhalis, and Haemophilus influenzae have good anti-susceptible and anti-drug-resistant activities, and can effectively treat clinical bacterial pneumonia or other microorganisms (such as Mycoplasma, Legionella, etc.) pneumonia, and other tissue infections;

Description

Erythromycin derivative and preparation method thereof

Technical Field

The invention relates to the fields of chemical synthesis and pharmacy, in particular to an erythromycin derivative and a preparation method of the erythromycin derivative.

Background

The fourteen-element macrolide antibiotic-erythromycin (erythromycin) is a very important therapeutic drug for resisting respiratory tract infection, provides a high-efficiency safe medication way for human for half a century, and plays an irreplaceable role in penicillin allergic patients and mycoplasma pneumonia patients. Currently, clinically isolated strains of respiratory pathogens are increasingly showing resistance to such strains as streptococcus pneumoniae (s.pneumoconiae), staphylococcus aureus (s.aureus), and streptococcus pyogenes (s.pyogenenes). Particularly, at present, the clinical multi-drug resistant isolated strains are more and more, and some staphylococcus aureus strains even have drug resistance to various antibacterial drugs with different antibacterial mechanisms, such as macrolide, beta-lactam, quinolone and the like. The second generation erythromycin-clarithromycin and azithromycin which appeared in the 80's of the last century have no antibacterial activity against erythromycin resistant bacteria although the pharmacokinetic properties were good. Chinese has classified the drug-resistant bacteria infection as one of ten diseases planned by 'special item for creating new drug'. It is estimated that the number of children dying from pneumonia caused by drug-resistant bacteria worldwide exceeds 180 million per year. Research has shown that 3-O-cladinose, both erythromycin and second generation erythromycin, is a key substructure for inducing bacterial resistance. Therefore, the research and development of the novel drug-resistant bacterium erythromycin have urgent and important practical significance.

Compared with erythromycin, clarithromycin, azithromycin and the like, the third-generation ketolide derivative-telithromycin has the activity of resisting drug-resistant bacteria: the introduction of 3-carbonyl avoids the induced drug resistance of 3-O-cladinose in the original macrolide, and the newly introduced aromatic side chain at the 11-position on the macrocyclic ring generates a new combined target point-base A752 to the drug-resistant bacteria, thereby obtaining the activity of the drug-resistant bacteria. Telithromycin is the only erythromycin derivative approved for marketing by the FDA in the united states to date, but telithromycin has limited its applicability to the rare idiosyncratic but lethal hepatotoxicity that has withdrawn two indications for sinusitis, bronchitis and skin infections, leaving only community-acquired bacterial pneumonia indications. Further research shows that the terminal aryl group of the side chain structure of telithromycin, namely 'pyridylimidazole' is similar to the structure of 'nicotine' (1-methyl-2- (3-pyridyl) pyrrolidine), and off-target effect (acting on a nicotinic cholinergic receptor) caused by the degradation due to unstable metabolism of the side chain imidazole is highly related to various toxic and side effects.

Heretofore, we developed a novel 9-hydroxyketolide derivative (201010110079.5; 201010171484.8) having a structure different from telithromycin, in which quinolyl and isoquinolyl groups introduced into the 9-position allyl and propargyl termini greatly improve the activity against drug-resistant bacteria. Later, we optimized aryl groups based on this and developed novel 9-oxime ketolide derivatives (201710025471.1). The aryl of the 9-oxime ketolide is replaced by amino or carbamoyl, the 9-oxime ketolide has better antibacterial activity on pathogenic bacteria inducing drug resistance (i-erm) or efflux drug resistance (mef), but the minimum inhibitory concentration of the 9-oxime ketolide on constitutive erm streptococcus pneumoniae and the like is not lower than 32 mu g/mL. The expression of the drug resistance gene of the constitutive erm bacteria is independent of the induction of erythromycin drugs, and the MIC value of the drug resistance level is usually very high and is far higher than that of the induction erm and efflux drug-resistant bacteria. The main pathogens of community-acquired bacterial pneumonia include streptococcus pneumoniae, haemophilus influenzae and moraxella catarrhalis, and staphylococcus aureus is also one of the pathogens. Among them, constitutive streptococcus pneumoniae (c-erm) is a clinically common pathogenic bacterium with high drug resistance causing bacterial pneumonia infection at present. Therefore, a new structure is needed to be found, which is different from telithromycin with hepatotoxicity, overcomes the defect that the activity of the existing 9-oxime ketolide to the constitutive streptococcus pneumoniae is low, and has antibacterial activity to hemophilus influenza, staphylococcus aureus and the like so as to be used for clinically treating pneumonia caused by pathogenic microorganisms including the streptococcus pneumoniae.

In summary, one of the technical problems that needs to be urgently solved by those skilled in the art is: how to provide an erythromycin derivative, which can be well suitable for industrial production, has the anti-sensitive bacteria and anti-drug-resistant bacteria activity equivalent to or higher than that of marketed ketolide-telithromycin against pathogenic bacteria such as clinically common erythromycin drug-resistant streptococcus pneumoniae, staphylococcus aureus, streptococcus pyogenes, moraxella catarrhalis and hemophilus influenza bacteria, and treats clinical bacterial pneumonia or pneumonia caused by other microorganisms (such as mycoplasma, legionella and the like) and other tissue infections.

Disclosure of Invention

In order to solve the problems, the invention discloses an erythromycin derivative, wherein the erythromycin derivative is a compound with a general formula I, or the erythromycin derivative comprises a pharmaceutically acceptable salt formed by the compound with the general formula I and an inorganic acid or an organic acid;

wherein, in the general formula I, Ar comprises any one of quinolone, substituted quinolone and substituted heteroaryl containing 6-10 nitrogen atoms.

The substituted quinolone and the substituted 6-to 10-membered nitrogen atom-containing heteroaryl group refer to a quinolone containing one or more substituents and a 6-to 10-membered nitrogen atom-containing heteroaryl group.

The substituents are independently taken from one or more of the following substituents: 1-4 membered alkyl, halogen substituted 1-4 membered alkyl, 1-4 membered alkoxy, 2-4 membered alkene, 2-4 membered alkyne, 3-4 membered cycloalkyl, carboxy, carbamoyl, O- (1-4 membered alkyl, halogen substituted 1-4 membered alkyl, 2-4 membered alkene, 2-4 membered alkyne or 3-4 membered cycloalkyl) substituted oxycarbonyl, N- (1-4 membered alkyl, halogen substituted 1-4 membered alkyl, 2-4 membered alkene, 2-4 membered alkyne or 3-4 membered cycloalkyl) substituted carbamoyl, nitro, halogen, cyano, hydroxy, amino.

Alternatively, the substituted 6-to 10-membered nitrogen atom-containing heteroaryl group includes any one of a substituted pyridyl group, a substituted quinolyl group, a substituted pyridopyridyl group, and a substituted isoquinolyl group.

The substituent for substituting the 6-to 10-membered nitrogen atom-containing heteroaryl group is independently taken from one or more of the following substituents: carboxy, carbamoyl, N- (methyl) carbamoyl, N- (ethyl) carbamoyl, N- (cyclopropyl) carbamoyl, nitro, halogen, cyano, hydroxy, amino.

Optionally, the substituted quinolone has a structure represented by formula II;

x in the structure shown in the general formula II comprises any one of nitrogen atom and oxygen atom, R¹、R²Each independently selected from any one of hydrogen atom, 1-4 membered alkyl, halogen substituted 1-4 membered alkyl, 2-4 membered alkene, 2-4 membered alkyne and 3-4 membered cycloalkyl.

Alternatively, the 1-4 membered alkyl group comprises any one of methyl, ethyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

Alternatively, the halogen-substituted 1-4 membered alkyl group includes any one of a 2-fluoroethyl group, a 2, 2-difluoroethyl group and a 2,2, 2-trifluoroethyl group.

Alternatively, the 2-4 membered olefin comprises a 2-propenyl group.

Alternatively, the 2-4 membered alkyne includes a 2-propynyl group.

Alternatively, the 3-4 membered cycloalkyl group comprises any one of cyclopropyl, cyclopropylmethyl and cyclobutyl.

Optionally, the inorganic acid comprises any one of hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid.

Alternatively, the organic acid includes any one of acetic acid, malonic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, citric acid, fumaric acid, and malic acid.

The embodiment of the invention also provides a preparation method of the erythromycin derivative, which comprises the following steps:

step 1: dissolving the first compound in dichloromethane, adding acetic anhydride to obtain a mixture, ending the reaction until the thin-layer chromatography monitoring reaction is completed, spin-drying, and drying in a vacuum oven after foaming to obtain a second compound; the first compound is 3-O-descladinose-3-hydroxy-6-O-allylerythromycin A-9-oxime.

Step 2: dissolving the second compound in tetrahydrofuran, adding dimethyl sulfoxide, adding potassium hydroxide under the protection of argon, reacting at room temperature, monitoring by thin-layer chromatography that all acetyl groups at the 9-position of the second compound are removed, adding potassium hydroxide, dropwise adding methyl iodide under the protection of argon, reacting for 30-40 minutes until the reaction is completely monitored by the thin-layer chromatography, adding ethyl acetate and distilled water to extract a water phase, combining organic phases, washing the organic phase by using a saturated NaCl solution, spin-drying, foaming, and drying in a vacuum oven to obtain a third compound.

And step 3: dissolving the third compound in dichloromethane, dropwise adding pyridine under the protection of argon and at-10 ℃, dropwise adding a dichloromethane solution of triphosgene, keeping the temperature constant for reaction, transferring to room temperature for reaction till the reaction is finished, dropwise adding a saturated NaCl solution under an ice bath, stirring at normal temperature, adding distilled water and saturated NaHCO, and stirring at normal temperature₃Washing the organic phase with saturated NaCl solution, separating to obtain organic phase, spin drying and column chromatography to obtain the fourth compound.

And 4, step 4: dissolving N-chlorosuccinimide in dichloromethane, stirring at-15 ℃, dropwise adding dimethyl sulfide after the temperature is stable to generate white flocculent precipitate, dissolving the fourth compound in dichloromethane, slowly and dropwise adding the dichloromethane solution of the N-chlorosuccinimide, stirring at-15 ℃ until the conversion rate of the fourth compound is more than 95% by thin-layer chromatography, adjusting the temperature to-5 ℃, dropwise adding triethylamine, finishing the reaction after the reaction is completed, sequentially washing an organic phase by using distilled water, a saturated NaHCO3 solution and a saturated NaCl solution, separating the liquid to obtain an organic phase, and spin-drying to obtain a fifth compound.

And 5: dissolving the fifth compound in N, N-dimethylformamide at 0 ℃, adding 60% NaH under the protection of argon gas for reaction after the temperature is stable, transferring the reaction to a-5 ℃ ice salt bath, monitoring the reaction by thin-layer chromatography, and sequentially using NaOH solution and saturated NaHCO solution after the reaction is completed₃Washing the organic phase with saturated NaCl solution, separating to obtain organic phase, spin drying and column chromatography to obtain the sixth compound.

Step 6: dissolving the sixth compound, palladium acetate, tri (o-methylphenyl) phosphorus, triethylamine and halogenated compound in acetonitrile, replacing 8 times with argon in a pressure bottle, sealing, reacting at 60 ℃, heating to 90 ℃, stirring until the reaction is complete, adding ethyl acetate after the reaction is completed, washing with distilled water for 3 times, washing with saturated sodium chloride solution for 1 time, separating to obtain an organic phase, spin-drying the organic phase to obtain an intermediate product, dissolving the intermediate product in methanol, refluxing at 65 ℃ until the thin-layer chromatography monitors that the reaction is complete, spin-drying the reaction solution to obtain a crude product, and performing column chromatography to obtain the erythromycin derivative.

Alternatively, the halogenated compound includes a bromide or an iodide of any one of a quinolone, a substituted quinolone, and a substituted 6-to 10-membered nitrogen atom-containing heteroaryl.

Alternatively, the substituted quinolone and the substituted 6-to 10-membered nitrogen atom-containing heteroaryl group refer to a quinolone comprising one or more substituents and a 6-to 10-membered nitrogen atom-containing heteroaryl group.

Alternatively, the substituents for the substituted 6-to 10-membered nitrogen atom-containing heteroaryl group are independently taken from one or more of the following substituents: carboxy, carbamoyl, N- (methyl) carbamoyl, N- (ethyl) carbamoyl, N- (cyclopropyl) carbamoyl, nitro, halogen, cyano, hydroxy and amino.

Alternatively, the 2-4 membered olefin comprises a 2-propenyl group.

Alternatively, the 2-4 membered alkyne includes a 2-propynyl group.

Compared with the prior art, the invention has the following advantages:

the embodiment of the invention provides an erythromycin derivative, which can be well suitable for industrial production, has good anti-sensitive and anti-drug-resistant activity for clinically common erythromycin drug-resistant pathogenic bacteria such as streptococcus pneumoniae, staphylococcus aureus, streptococcus pyogenes, moraxella catarrhalis and hemophilus, and can effectively treat clinical bacterial pneumonia or pneumonia caused by other microorganisms (such as mycoplasma and legionella) and other tissue infections.

Drawings

FIG. 1 is a flow chart of a process for the preparation of an erythromycin derivative according to an embodiment of the present invention;

FIG. 2 is a flow chart of another method for preparing an erythromycin derivative according to an embodiment of the present invention.

Detailed Description

In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in further detail below.

Example one

The invention provides an erythromycin derivative, which is a compound with a general formula I, or comprises a pharmaceutically acceptable salt formed by the compound with the general formula I and an inorganic acid or an organic acid, wherein the salt is metabolized or converted into a compound with a general formula structure under in-vivo physiological conditions as a prodrug (produgs) and plays a pharmacological action as an active ingredient. In the present example, various pharmaceutically acceptable acids can form salts at the nitrogen of the dimethylamino group of 5-O-desosamine in formula I, which are esterified at the 2 '-OH group, and the 2' -OH group can be released again by hydrolysis of the ester group in vivo, similarly as ethyl succinate ester of erythromycin. Conventional methods for the preparation of Prodrugs are described in Design of Prodrugs (H.Bundgaad, Elseyier, 1985).

The term "aryl" as used in the examples of the present invention means an aromatic carbocyclic group having a single ring or two or more fused rings. The aryl group preferably has 5 to 18, 5 to 14, 5 to 10, 5 to 8, 5 to 6 or 6 carbon atoms. Typical examples of the "aryl group" include, but are not limited to, phenyl, naphthyl, anthryl and the like. The "aryl" groups are most preferably phenyl and naphthyl.

The term "heteroaryl" as used in the present embodiments denotes aryl as defined in the present embodiments wherein one or two or more carbon atoms are replaced by one or two or more heteroatoms independently selected from O, S or N. Heteroaryl groups containing N atoms are preferred. The heteroaryl group is preferably a 5-18 membered, 5-14 membered, 5-10 membered, 5-8 membered, 5-6 membered, or 5-or 6-membered heteroaryl group. The "heteroaryl" is preferably pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, phenylpyrimidinyl or pyridylpyridinyl. The various heteroaryl groups are provided by way of example only, and other non-recited heteroaryl groups have similar properties and are not described herein in detail based on space limitations.

The term "quinolone" used in the examples of the present invention means the structure shown below:

the term "a-b membered alkyl" (a, b are numbers) as used in the examples herein refers to a saturated straight or branched chain hydrocarbon group having a-b carbon atoms, e.g., 1-6 membered alkyl, 1-4 membered alkyl. Preferred 1-6 membered alkyl groups are methyl, ethyl, n-propyl, isopropyl, sec-butyl, tert-pentyl or neopentyl. Preferred 1-to 4-membered alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl groups, and further preferred are methyl, ethyl, n-propyl or isopropyl groups. The above alkyl groups are only used for illustration, and other non-illustrated alkyl groups have similar properties, and are not described herein for brevity.

The 1-4 membered alkoxy group is the group-ORa, wherein Ra is the 1-4 membered alkyl group, such as methoxy, ethoxy or isopropoxy.

The term "a-b membered heteroalkyl" (a, b being a number) as used in the present examples means an a-b membered alkyl as defined in the present examples, e.g. 1-6 membered heteroalkyl, 3-5 membered heteroalkyl, containing one or more heteroatoms independently selected from N, O and S. The preferred number of heteroatoms N, O and S is 1-2. Preferred heteroalkyl groups are N- (1-4 membered alkyl, halogen substituted 1-4 membered alkyl, 2-4 membered alkene, 2-4 membered alkyne or 3-4 membered cycloalkyl) substituted carbamoyl, O- (1-4 membered alkyl, halogen substituted 1-4 membered alkyl, 2-4 membered alkene, 2-4 membered alkyne or 3-4 membered cycloalkyl) substituted oxycarbonyl, N-dimethylamino, N-methyl-N-ethylamino, N-dimethylaminomethyl, N-diethylamino, methoxy, ethoxy, isopropoxy or tert-butoxy. The above-mentioned various heteroalkyl groups are only used as examples, and other non-recited heteroalkyl groups have similar properties, and are not described herein again based on space limitations.

The term "a-b membered cycloalkyl" as used in the embodiments of the present invention means a saturated cyclic hydrocarbon group or an alkyl-substituted saturated cyclic hydrocarbon group having a-b carbon atoms. Preferred cycloalkyl groups are cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl, and further preferred is cyclopropyl, cyclopropylmethyl or cyclobutyl.

The term "a-b membered heterocycloalkyl" as used in the present embodiments means an a-b membered cycloalkyl group as defined in the present embodiments comprising one or more heteroatoms independently selected from N, O and S. Preferred heterocycloalkyl groups are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or N- (3-4 membered cycloalkyl substituted) carbamoyl. The various cycloalkyl groups are given by way of example only, and other non-recited cycloalkyl groups have similar properties and are not described herein in detail based on space limitations.

The term "a-b membered alkenyl" as used in embodiments of the present invention refers to an ethylenically unsaturated straight or branched chain hydrocarbon group containing at least one carbon-carbon double bond (-C ═ C —), having a to b carbon atoms. Preferred alkenyl groups are ethenyl, propenyl. The term "a-b-membered alkynyl" as used in the examples herein refers to an acetylenically unsaturated straight or branched chain hydrocarbon radical containing at least one carbon-carbon triple bond (-C.ident.C-) having a-b carbon atoms. Preferred alkynyl groups are ethynyl or propynyl. The above alkenyl and alkynyl groups are only used for examples, and other non-enumerated alkenyl and alkynyl groups have similar properties, and are not described herein based on space limitations.

The term "halogen" as used in the examples of the present invention means fluorine, chlorine, bromine or iodine. Preferred halogens are fluorine and chlorine.

The term "substituted" as used in the embodiments of the present invention means that a compound or group is substituted with one or two or more substituents independently selected from the group consisting of: a-b membered alkyl, halo-substituted a-b membered alkyl, a-b membered heteroalkyl, a-b membered cycloalkyl, a-b membered heterocycloalkyl, aryl, heteroaryl, a-b membered alkenyl, a-b membered alkynyl, nitro, halo, cyano, hydroxy, amino and the like. Preferred substituents in this application are 1-4 membered alkyl, halogen substituted 1-4 membered alkyl, 3-4 membered alkene or alkyne, 3-4 membered cyclic hydrocarbon, carboxy, carbamoyl, O- (1-4 membered alkyl, halogen substituted 1-4 membered alkyl, 2-4 membered alkene, 2-4 membered alkyne or 3-4 membered cyclic alkyl) substituted oxycarbonyl, N- (1-4 membered alkyl, halogen substituted 1-4 membered alkyl, 2-4 membered alkene, 2-4 membered alkyne or 3-4 membered cyclic alkyl) substituted carbamoyl. The preferred number of substituents is 1-2.

Preferably, the substituted 6-to 10-membered nitrogen atom-containing heteroaryl group includes any one of a substituted pyridyl group, a substituted quinolyl group, a substituted pyridopyridyl group and a substituted isoquinolyl group.

Preferably, the substituents for said 6-to 10-membered nitrogen atom-containing heteroaryl group are independently taken from one or more of the following substituents: carboxy, carbamoyl, N- (methyl) carbamoyl, N- (ethyl) carbamoyl, N- (cyclopropyl) carbamoyl, nitro, halogen, cyano, hydroxy, amino.

The substituted position of the substituted quinolone can be 1-position, 3-position, 5-position, 7-position and 8-position. Preferably, the substituted quinolone has a structure represented by formula II;

Preferably, the 1-4 membered alkyl group includes any one of methyl, ethyl, isopropyl, n-butyl, isobutyl and tert-butyl.

Preferably, the halogen-substituted 1-4 membered alkyl group includes any one of a 2-fluoroethyl group, a 2, 2-difluoroethyl group and a 2,2, 2-trifluoroethyl group.

Preferably, the 2-4 membered olefin comprises a 2-propenyl group.

Preferably, the 2-4 membered alkyne includes a 2-propynyl group.

Preferably, the 3-4 membered cycloalkyl group includes any one of cyclopropyl, cyclopropylmethyl and cyclobutyl.

Preferably, the inorganic acid includes any one of hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid.

Preferably, the organic acid includes any one of acetic acid, malonic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, citric acid, fumaric acid, and malic acid.

The above-mentioned various substituted compounds are only used as examples, and other non-enumerated substituted compounds have similar properties in the same category, and are not repeated herein based on the limitation of the text.

Through a plurality of tests and theoretical researches, the compound shown in the general formula I has 9-methoxy oxime, 11-12 cyclic carbonate, and 2-fluorination, 3-carbonyl and 6-O- (3-aryl-2 propenyl) side chains which jointly form a novel structure, so that the erythromycin derivative has excellent antibacterial activity according to the novel structure.

The present invention also provides a method for preparing an erythromycin derivative, and specifically, fig. 1 is a flow chart of a method for preparing an erythromycin derivative according to an embodiment of the present invention, and referring to fig. 1, the method for preparing the compound of formula I may include:

And step 3: dissolving the third compound in dichloromethane, dropwise adding pyridine under the protection of argon and at-10 ℃, dropwise adding a dichloromethane solution of triphosgene, keeping the temperature unchanged for reaction, transferring to room temperature for reaction until the reaction is finished, and coolingAdding saturated NaCl solution dropwise in the bath, stirring at normal temperature, adding distilled water and saturated NaHCO₃Washing the organic phase with saturated NaCl solution, separating to obtain organic phase, spin drying and column chromatography to obtain the fourth compound.

In the embodiment of the present invention, different halogenated compounds may be used to react according to the structural requirements of different derivatives, and different erythromycin derivatives may be synthesized by obtaining different Ar groups, where the Ar group may include a group having a structure shown as follows:

wherein a-c, u-w are substituted heteroaryl, d is quinolone, e-t, x-y are substituted quinolone, the above structures are only used for illustration, and other similar structures can be used as the Ar group of the erythromycin derivative in the classification, which is not limited by the invention. Wherein, the halogen substitution position of the halogenated compound comprises the position of the connection bond between the Ar group and the mother nucleus structure.

Alternatively, the substituted quinolone has a structure represented by formula II below;

Alternatively, the 2-4 membered olefin comprises a 2-propenyl group.

Alternatively, the 2-4 membered alkyne includes a 2-propynyl group.

FIG. 2 is a flow chart of another method for preparing an erythromycin derivative according to an embodiment of the present invention, as shown in FIG. 2, the method further comprising:

and 7: adding an inorganic acid or an organic acid to the obtained seventh compound to obtain the erythromycin derivative.

Preferably, the inorganic acid is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, or phosphoric acid.

Preferably, the organic acid is acetic acid, malonic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, citric acid, maleic acid, fumaric acid, or malic acid.

Example two

The reaction route of an erythromycin derivative in the embodiment of the invention is shown as follows, the erythromycin derivative is a compound with a general formula I, and the method for preparing the erythromycin derivative specifically comprises the following steps:

in order to make the present invention more understandable to those skilled in the art, the preparation method of the erythromycin derivative of the present invention is described below by a plurality of specific examples.

Step a, preparation of the second Compound (2' -O-acetyl-3-O-Decaclacin-3-hydroxy-6-O-allylerythromycin A9-O-acetyl oxime)

The dried first compound (2.000g, 3.170mmol) was placed in a 100mL round bottom flask, 20mL of dried dichloromethane was added, and acetic anhydride (0.900mL, 9.510mmol) was added dropwise. The reaction was carried out for about 1-1.5h, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction was washed 5 times with saturated NaHCO3 solution for 30 minutes each time, and then washed once with saturated NaCl solution. Spin-dry, foam and dry in a vacuum oven. This gave 1.930g (2.700mmol, 85.17% yield) of the second compound as a white fluffy solid.

In the examples of the present invention, the first compound is 3-O-decladinose-3-hydroxy-6-O-allylerythromycin A-9-oxime, and the preparation method thereof can be referred to Bioorganic & Medicinal Chemistry Letters, 2017, 27 (7): 1513-1524.

Step b, preparation of the third Compound (2' -O-acetyl-3-O-decladinose-3-hydroxy-6-O-allylerythromycin A9-O-Methyloxime)

The second compound (0.546g, 0.764mmol) was added to a 100mL round bottom flask, dissolved in 5mL THF, then 5mL DMSO was added, KOH powder (0.0643g, 1.146mmol) was added under argon, and the reaction was carried out at room temperature about 20min, thin layer chromatography monitors the complete removal of acetyl at the 9-position. Additional KOH powder (0.0429g, 0.764mmol) was added and CH was added dropwise under argon protection₃I (0.0500mL, 0.764mmol), reacting for 30-45min, and monitoring the reaction completion by thin layer chromatography. After-treatment 10mL of ethyl acetate, 10mL of distilled water were added, the aqueous phase was extracted three times with 10mL of ethyl acetate each time, the organic phases were combined, washed with saturated NaCl solution, dried by rotary drying, foamed and dried in a vacuum oven. A third compound was obtained as a tan solid, 0.470g (0.684mmol, 89.63% yield).

Step c, preparation of the fourth Compound (2' -O-acetyl-3-O-decladinose-3-hydroxy-6-O-allylerythromycin A9-O-methyloxime-11, 12-cyclic carbonate)

Dissolving the third compound (0.470g, 0.684mmol) in 10mL of dichloromethane, adding pyridine (0.830mL, 8.144mmol) dropwise at-10 ℃ under the protection of argon, dissolving triphosgene (0.406g, 1.369mmol) in 10mL of dichloromethane dropwise, reacting at-10 ℃ for 4h, and transferring to room temperature for 18 h. For post-treatment, 20mL of saturated NaCl solution was added dropwise in ice bath, stirred at room temperature for 30min, and then treated with distilled water and saturated NaHCO₃And washing the organic phase with saturated NaCl solution, separating liquid, and spin drying to obtain a crude product. Column chromatography (100-mesh 200 mesh silica gel with mobile phase of 10: 0.2: 0.1V (dichloromethane): V (ethanol): V (ammonia) gave 0.221g (0.310mmol, 45.32% yield) of the fourth compound as a pale yellow solid.

Step d, preparation of the fifth Compound (2' -O-acetyl-3-O-decladinose-3-carbonyl-6-O-allylerythromycin A9-O-methyloxime-11, 12-cyclic carbonate)

N-chlorosuccinimide (0.066g, 0.496mmol) was dissolved in 10mL of dichloromethane, added to a 100mL double-necked flask, stirred at-15 deg.C, and after the temperature stabilized dimethyl sulfide (0.0500mL, 0.589mmol) was added dropwise to produce a white flocculent precipitate, which was stirred for 30 min. Dissolving the fourth compound (0.221g, 0.310mmol) in 5mL dichloromethane, slowly adding dropwise into the reaction system, keeping at-15 ℃ and stirring for reaction for about 3h, monitoring the reaction by thin layer chromatography, adjusting the temperature to-5 ℃ after more than 95% of raw materials react, adding triethylamine (0.0800mL, 0.620mmol) dropwise, and reacting for 0.5 h. Post-treatment, in turn by steamingDistilled water, saturated NaHCO₃Solution, saturated NaCl solution washing organic phase, liquid separation, spin drying to get light yellow solid fifth compound, 0.210g (0.295mmol, 95.16% yield).

Step e, preparation of the sixth compound (2' -O-acetyl-2-fluoro-3-O-descladinose-3-carbonyl-6-O-allylerythromycin A9-O-methyloxime-11, 12-cyclic carbonate)

The fifth compound (2.466g, 3.469mmol) was dissolved in 40mL of DMF at 0 deg.C, and after the temperature stabilized, 60% by mass NaH (0.278g, 6.938mmol) was added under argon and reacted for 1 h. Then the reaction was transferred to a-5 ℃ ice salt bath, N-fluorobisbenzenesulfonamide (1.203g, 3.816mmol) was added, stirring was maintained at-5 ℃ for about 3 hours, and the progress of the reaction was checked by thin layer chromatography. After the reaction was completed, 2M NaOH solution and saturated NaHCO solution were used in sequence₃And washing the organic phase by using a saturated NaCl solution, separating liquid and spin-drying. Column chromatography (100-mesh 200-mesh silica gel with mobile phase of 10: 0.1) V (dichloromethane): V (ethanol): V (ammonia) to obtain the sixth compound as white solid, 1.300g (1.784mmol, 51.42% yield).

Step f, preparation of the seventh compound shown as 7a (2-fluoro-3-O-descladinose-3-carbonyl-6-O- [3- [6 '- (3' -quinolinecarboxylate) ] -E-prop-2-enyl ] erythromycin A9-O-methyloxime-11, 12-cyclic carbonate)

The sixth compound (0.400g, 0.549mmol), palladium acetate (0.037g, 0.165mmol), tris (o-methylphenyl) phosphorus (0.100g, 0.329mmol), 6-bromo-3-quinolinecarboxylic acid (0.277g, 1.098mmol), triethylamine (8.00mL, 57.770mmol) were dissolved in 8mL of acetonitrile, placed in a pressure bottle, replaced 8 times with argon, and sealed. Reacting at 60 ℃ for 1h, then heating to 90 ℃ and stirring for 48 h. After the reaction, 20mL of ethyl acetate was added, washed with water for 3 times, once with a saturated sodium chloride solution, and the organic layer was spin-dried after liquid separation. In the reaction, 2' acetyl is partially removed, the product is dissolved in methanol, the reflux is carried out for 1 to 1.5 hours at the temperature of 65 ℃, and the crude product is obtained by spin-drying the reaction liquid after the reaction is completely monitored by thin-layer chromatography. Column chromatography (100-mesh 200 mesh silica gel with mobile phase of V (dichloromethane): V (ethanol): V (ammonia) 10: 3: 0.1) gave the seventh compound shown as 7a, 47.2mg (0.0550mmol, 10.01% yield).

HRMS(ESI)(M+H)⁺m/z 858.4195，calcd for C₄₄H₆₁FN₃O₁₃858.4183.

¹H NMR(DMSO-d₆，400MHz)δ：9.24(s，1H，2′-Ar)，8.80(s，1H，4′-Ar)，8.06-9.34(m，3H，5′-Ar，7′-Ar，8′-Ar，)，6.57(d，J＝15.8Hz，1H，6-O-CH₂CH＝CH-Ar)，6.16-6.01(m，1H，6-O-CH₂CH＝CH-Ar)，4.90(s，1H，H-11)，4.35(d，J＝7.1Hz，1H，H-1′)，4.28(br，1H，H-13)，4.04(d，J＝8.4Hz，1H，H-5)，3.77(s，3H，9-O-CH₃)，3.69-3.47(m，5H，6-O-CH₂CH＝CH-Ar，H-5′，H-4，H-8)，3.27(dd，J＝8.7Hz，1H，H-2′)，3.08-2.96(m，1H，H-3′)，2.71-2.58(m，1H，H-10)，2.50(s，6H，-N(CH₃)₂)，1.80(dd，J＝21.7Hz，3H，2-CH₃)，1.72-1.58(m，2H，H-4′a，H-14eq)，1.53(s，3H，12-CH₃)，1.52-1.48(m，1H，H-14ax)，1.46(s，3H，6-CH₃)，1.31(d，J＝7.2Hz，3H，5′-CH₃)，1.21(d，J＝7.1Hz，3H，4-CH₃)，1.11(d，J＝6.2Hz，3H，10-CH₃)，0.99(d，J＝6.8Hz，3H，15-CH₃)，0.52(t，J＝7.5Hz，3H，15-CH₃).

Alternatively, step f may be the preparation of a seventh compound shown as 7d (2-fluoro-3-O-descladinose-3-carbonyl-6-O- [3- [6 '- (1', 4 '-dihydro-4' -oxoquinolinyl) ] -E-prop-2-enyl ] erythromycin A9-O-methyloxime-11, 12-cyclic carbonate)

The sixth compound (0.300g, 0.412mmol), palladium acetate (0.0278g, 0.124mmol), tris (o-methylphenyl) phosphorus (0.0752g, 0.247mmol), 6-bromo-3-quinolinecarboxylic acid-4-ol (0.221g, 0.824mmol), triethylamine (5mL, 36.071mmol) were dissolved in 5mL of acetonitrile, placed in a pressure flask, replaced 8 times with argon, and sealed. Reacting at 60 ℃ for 1h, then heating to 90 ℃ and stirring for 48 h. After the reaction, 20ml of ethyl acetate was added, washed with water for 3 times, once with a saturated sodium chloride solution, and the organic layer was spin-dried after liquid separation. Then dissolving the product in methanol, refluxing for 1-1.5h at 65 ℃, monitoring the reaction by thin-layer chromatography, and spin-drying the reaction solution to obtain a crude product. Column chromatography (100-mesh 200-mesh silica gel with mobile phase of 10: 0.5: 0.1: V (dichloromethane): V (ethanol): V (ammonia) to obtain 29.6mg (0.0357mmol, 8.66% yield) of the seventh compound shown as 7 d.

HRMS(ESI)(M+H)⁺m/z 830.4235，calcd for C₄₃H₆₁FN₃O₁₂830.4234.

¹H NMR(CDCl₃，400MHz)δ：8.29(s，1H，5′-Ar)，7.83(d，J＝8.7Hz，1H，7′-Ar)，7.65(d，J＝7.4Hz，1H，2′-Ar)，7.38(d，J＝8.7Hz，1H，8′-Ar)，6.51(d，J＝15.7Hz，1H，6-O-CH₂CH＝CH-Ar)，6.22(d，J＝7.3Hz，1H，3-Ar)，6.07(dt，J₁＝15.3Hz，J₂＝7.0Hz，1H，6-O-CH₂CH＝CH-Ar)，5.07(s，1H，H-11)，4.62(br，1H，H-13)，4.35(d，J＝7.2Hz，1H，H-1′)，4.09(d，J＝10.1Hz，1H，H-5)，3.86-3.78(m，1H，H-5′)，3.76(s，3H，9-O-CH₃)，3.70-3.59(m，1H，H-8)，3.59-3.43(m，3H，6-O-CH₂CH＝CH-Ar，H-4)，3.20(dd，J₁＝10.1Hz，J₂＝7.3Hz，1H，H-2′)，2.59-2.41(m，2H，H-10，H-3′)，2.28(s，6H，-N(CH₃)₂)，1.89-1.63(m，6H，2-CH₃，H-4′a，H-14eq，H-7a)，1.56(s，3H，12-CH₃)，1.48(s，3H，6-CH₃)，1.44-1.38(m，1H，H-14ax)，1.33(d，J＝7.0Hz，3H，5′-CH₃)，1.30-1.14(m，8H，H-7b，4-CH₃，H-4′b，10-CH₃)，0.98(br，3H，8-CH₃)，0.82(t，J＝7.7Hz，3H，15-CH₃).¹³C NMR(CDCl₃，176MHz)δ：203.8，203.7，179.0，165.4，165.3，163.5，154.6，139.4，138.6，132.6，129.8，127.1，126.0，124.4，118.5，109.7，104.1，98.6，97.4，84.9，83.3，80.0，79.8，78.0，70.5，69.7，65.8，63.8，61.6，40.7，40.3，38.5，32.7，28.2，26.3，25.1，25.0，22.7，21.3，21.2，18.3，15.3，13.2，10.8.

Alternatively, step f may be the preparation of a seventh compound shown as 7E (2-fluoro-3-O-decladinose-3-carbonyl-6-O- [3- [6 ' - (1 ', 4 ' -dihydro-4 ' -oxo-3 ' -quinolinecarboxylate) ] -E-prop-2-enyl ] erythromycin A9-O-methyloxime-11, 12-cyclic carbonate)

Increasing the polarity of the mobile phase during column chromatography purification of the seventh compound shown in fig. 7d using V (dichloromethane): V (ethanol): V (ammonia) 10: 2: 0.1 as the mobile phase gave the seventh compound shown in fig. 7e, 56.5mg (0.0646mmol, 15.68% yield).

HRMS(ESI)(M+H)⁺m/z 874.4146，calcd for C₄₄H₆₁FN₃O₁₄874.4132.

¹H NMR(Acetone-d₆，400MHz)δ：8.87(s，1H，2′-Ar)，8.36(s，1H，5′-Ar)，8.10(d，J＝8.8Hz，1H，7′-Ar)，7.81(d，J＝8.8Hz，1H，8′-Ar)，6.61(d，J＝15.8Hz，1H，6-O-CH₂CH＝CH-Ar)，6.21(dt，J₁＝15.2Hz，J₂＝7.0Hz，1H，6-O-CH₂CH＝CH-Ar)，5.00(s，1H，H-11)，4.52(t，J＝5.7Hz，1H，H-13)，4.43(d，J＝7.2Hz，1H，H-1′)，4.15(d，J＝10.1Hz，1H，H-5)，3.93-3.85(m，1H，H-5′)，3.86(s，3H，9-O-CH₃)，3.79-3.55(m，4H，H-8，6-O-CH₂CH＝CH-Ar，H-4)，3.22(dd，J₁＝10.2Hz，J₂＝7.2Hz，1H，H-2′)，2.83-2.59(m，2H，H-10，H-3′)，2.35(s，6H，-N(CH₃)₂)，1.87-1.65(m，6H，2-CH₃，H-4′a，H-14eq，H-7a)，1.60(s，3H，12-CH₃)，1.56(s，3H，6-CH₃)，1.52-1.41(m，1H，H-14ax)，1.38(d，J＝7.1Hz，3H，5′-CH₃)，1.31-1.15(m，8H，H-7b，4-CH₃，H-4′b，10-CH₃)，1.04(br，3H，8-CH₃)，0.73(t，J＝7.5Hz，3H，15-CH₃).¹³C NMR(Acetone-d₆，176MHz)δ：205.3，203.8，203.6，178.2，166.8，165.6，165.5，164.2，153.2，144.9，139.8，134.9，132.1，131.2，128.7，125.1，123.8，120.2，108.6，104.3，99.0，97.9，84.4，82.6，79.7，79.1，78.2，70.5，69.2，65.6，63.5，60.9，41.1，39.7，38.1，32.6，26.5，24.2，24.1，22.5，20.9，20.6，18.1，14.8，14.7，12.5，10.4.

Alternatively, step f can be the preparation of the seventh compound (2-fluoro-3-O-decladinose-3-carbonyl-6-O- [3- [6 '- (1' -cyclopropyl-1 ', 4' -dihydro-4 '-oxo-3' -quinolinecarboxylate) ] -E-prop-2-enyl ] erythromycin A9-O-methyloxime-11, 12-cyclic carbonate) as shown in 7h

The sixth compound (0.300g, 0.412mmol), palladium acetate (0.0278g, 0.124mmol), tris (o-methylphenyl) phosphorus (0.0752g, 0.247mmol), 1-cyclopropyl-1, 4-dihydro-6-iodo-4-oxo-3-quinolinecarboxylic acid (0.293g, 0.824mmol), and triethylamine (5mL, 36.071mmol) were dissolved in 5mL of acetonitrile, placed in a pressure flask, replaced with argon for 8 times, sealed, reacted at 60 ℃ for 1h, then heated to 90 ℃ and stirred for 48 h. After the reaction, 20mL of ethyl acetate was added, washed with water for 3 times, once with a saturated sodium chloride solution, and the organic layer was spin-dried after liquid separation. The 2' acetyl group has been removed during the reaction. Column chromatography (100-mesh 200-mesh silica gel with mobile phase of 10: 1: 0.1) V (dichloromethane): V (ethanol): V (ammonia) to obtain the seventh compound shown in 7h, 38.3mg (0.0419mmol, 33.79% yield).

HRMS(ESI)(M+H)⁺m/z 914.4486，calcd for C₄₇H₆₅FN₃O₁₄914.4445.

¹H NMR(Acetone-d₆，400MHz)δ：8.78(s，1H，2′-Ar)，8.40(s，1H，5′-Ar)，8.29(d，J＝8.9Hz，1H，7′-Ar)，8.18(d，J＝8.9Hz，1H，8′-Ar)，6.63(d，J＝15.9Hz，1H，6-O-CH₂CH＝CH-Ar)，6.24(dt，J₁＝15.6Hz，J₂＝7.0Hz，1H，6-O-CH₂CH＝CH-Ar)，4.97(s，1H，H-11)，4.52(t，J＝6.0Hz，1H，H-13)，4.41(d，J＝7.3Hz，1H，H-1′)，4.14(d，J＝10.0Hz，1H，H-5)，3.95-3.78(m，5H，H-5′，9-O-CH₃，H-8)，3.70-3.56(m，4H，6-O-CH₂CH＝CH-Ar，H-4，1H-cyclopropyl)，3.17(dd，J₁＝10.1Hz，J₂＝7.2Hz，1H，H-2，)，2.83-2.76(m，1H，H-10)，2.62-2.51(m，1H，H-3′)，2.29(s，6H，-N(CH₃)₂)，1.85-1.77(m，6H，2-CH₃，H-4′a，H-14eq，H-7a)，1.60(s，1H，12-CH₃)，1.57(s，1H，6-CH₃)，1.55-1.50(m，1H，H-14ax)，1.49-1.43(m，2H，2H-cyclopropyl)，1.38(d，J＝7.1Hz，3H，5′-CH₃)，1.34-1.28(m，3H，2H-cyclopropyl，H-7b)，1.27-1.23(m，7H，4-CH₃，H-4′b，10-CH₃)，1.06(d，J＝6.9Hz，3H，8-CH₃)，0.75(t，J＝7.5Hz，3H，15-CH₃).¹³C NMR (Acetone-d₆，176MHz)δ：205.3，203.8，203.6，178.5，165.8，164.3，153.2，148.1，140.7，135.1，131.7，131.4，129.2，125.9，124.3，118.5，108.3，104.4，99.1，97.9，84.4，82.7，79.8，79.2，78.2，70.5，69.3，65.6，63.5，60.9，41.1，39.8，38.1，35.7，32.6，26.3，24.2，24.1，22.5，20.9，20.6，18.1，14.8，14.7，12.5，10.4，7.6，7.5.

Alternatively, step f can be the preparation of the seventh compound (2-fluoro-3-O-decladinose-3-carbonyl-6-O- [3- [5 '- (3' -picolinato) -E-prop-2-enyl ] erythromycin A9-O-methyloxime-11, 12-cyclic carbonate) as shown in 7u

The sixth compound (0.150g, 0.206mmol), palladium acetate (0.00920g, 0.0412mmol), tris (o-methylphenyl) phosphorus (0.0251g, 0.0824mmol), 5-bromo-3-pyridinecarboxylic acid (0.170g, 1.236mmol), and triethylamine (0.0828mL, 0.412mmol) were dissolved in 5mL of acetonitrile, placed in a pressure bottle, replaced with argon for 8 times, sealed, reacted at 60 ℃ for 1h, then heated to 90 ℃ and stirred for 24 h. After the reaction, 20mL of ethyl acetate was added, washed with water for 3 times, once with a saturated sodium chloride solution, and the organic layer was spin-dried after liquid separation. Dissolving the product in methanol, refluxing at 65 deg.C for 1-1.5h, monitoring reaction by thin layer chromatography, and spin-drying the reaction solution to obtain crude product. Column chromatography (100-mesh 200-mesh silica gel with mobile phase of 10: 0.4: 0.1) V (dichloromethane): V (ethanol): V (ammonia) gave the seventh compound as shown in 7u, 28.9mg (0.0358mmol, 17.38% yield).

HRMS(ESI)(M+H)⁺m/z 808.4028，calcd for C₄₀H₅₉FN₃O₁₃808.4026.

¹H NMR(DMSO-d₆，700MHz)δ：8.88(s，1H，2′-Ar)，8.74(s，1H，4′-Ar)，8.28(d，1H，6′-Ar)，6.45(d，J＝15.9Hz，1H，6-O-CH₂CH＝CH-Ar)，6.02(br，1H，6-O-CH₂CH＝CH-Ar)，4.78(s，1H，H-11)，4.41(t，J＝5.6Hz，1H，H-13)，4.30(d，J＝7.0Hz，1H，H-1′)，4.02(d，J＝10.9Hz，1H，H-5)，3.77(s，3H，9-O-CH₃)，3.75-3.66(m，2H，H-5′，H-8)，3.65-3.45(m，3H，6-O-CH₂CH＝CH-Ar，H-4)，3.18(dd，J₁＝10.1Hz，J₂＝7.3Hz，1H，H-2′)，2.73(br，1H，H-10)，2.62(br，1H，H-3′)，2.36(s，6H，-N(CH₃)₂)，1.86-1.66(m，6H，2-CH₃，H-4′a，H-14eq，H-7a)，1.54(s，3H，12-CH₃)，1.44(s，3H，6-CH₃)，1.38-1.32(m，1H，H-14ax)，1.30(d，J＝7.1Hz，3H，5′-CH₃)，1.26-1.21(m，1H，H-7b)，1.19(d，J＝6.0Hz，3H，4-CH₃)，1.14-1.10(m，1H，H-4′b)，1.07(d，J＝7.5Hz，3H，10-CH₃)，0.98(br，3H，8-CH₃)，0.72(t，J＝7.5Hz，3H，15-CH₃).¹³C NMR(DMSO-d₆，176MHz)δ：203.8，203.6，167.2，165.8，165.7，164.6，153.4，151.0，149.5，134.1，132.1，129.8，129.5，128.5，104.1，84.8，79.8，79.0，78.5，70.4，68.7，64.9，61.6，41.1，40.3，38.0，32.5，30.6，27.7，26.4，24.9，22.6，21.4，21.2，18.7，15.6，15.2，13.3，11.2.

Alternatively, step f can be the preparation of the seventh compound (2-fluoro-3-O-decladinose-3-carbonyl-6-O- [3- (5' -nicotinamido) -E-prop-2-enyl ] erythromycin A9-O-methyloxime-11, 12-cyclic carbonate) shown as 7v

The sixth compound (0.150g, 0.206mmol), palladium acetate (0.0139g, 0.0618mmol), tris (o-methylphenyl) phosphorus (0.0376g, 0.124mmol), 5-bromonicotinamide (0.0832g, 0.412mmol), triethylamine (5mL, 36.071mmol) were dissolved in 5mL of acetonitrile, placed in a pressure bottle, replaced with argon for 8 times, sealed, reacted at 60 ℃ for 1h, then heated to 90 ℃ and stirred for 48 h. After the reaction, 20mL of ethyl acetate was added, washed with water for 3 times, once with a saturated sodium chloride solution, and the organic layer was spin-dried after liquid separation. Dissolving the product in methanol, refluxing at 65 deg.C for 1-1.5h, monitoring reaction by thin layer chromatography, and spin-drying the reaction solution to obtain crude product. Column chromatography (100-mesh 200 mesh silica gel with mobile phase of 10: 0.5: 0.1: V (dichloromethane): V (ethanol): V (ammonia) gave the seventh compound, as shown at 7V, 10.3mg (0.0128mmol, 6.21% yield).

HRMS(ESI)(M+H)⁺m/z 807.4196，calcd for C₄₀H₆₀FN₄O₁₂807.4186.

¹H NMR(CDCl₃，400MHz)δ：8.98(s，1H，2′-Ar)，8.65(s，1H，4′-Ar)，8.24(s，1H，6′-Ar)，7.35(s，1H，Ar-NH₂)，6.43(d，J＝16.0Hz，1H，6-O-CH₂CH＝CH-Ar)，6.02(dt，J₁＝15.0Hz，J₂＝6.5Hz，1H，6-O-CH₂CH＝CH-Ar)，5.65(s，1H，Ar-NH₂)，5.0(s，1H，H-11)，4.54(d，J＝4.0Hz，1H，H-13)，4.36(d，J＝7.2Hz，1H，H-1′)，4.05(d，J＝10.2Hz，1H，H-5)，3.90-3.79(m，1H，H-5′)，3.73(s，3H，9-O-CH₃)，3.68-3.39(m，4H，6-O-CH₂CH＝CH-Ar，H-4，H-8)，3.27(dd，J₁＝8.8Hz，J₂＝7.6Hz，1H，H-2′)，2.71-2.58(m，1H，H-10)，2.57-2.49(m，1H，H-3′)，2.39(s，6H，-N(CH₃)₂)，1.91-1.66(m，6H，2-CH₃，H-4′a，H-14eq，H-7a)，1.58(s，3H，12-CH₃)，1.47(s，3H，6-CH₃)，1.42-1.14(m，15H，H-14ax，H-7b，H-7a，5′-CH₃，4-CH₃，10-CH₃)，1.01(d，J＝6.8Hz，3H，8-CH₃)，0.80(t，J＝7.5Hz，3H，15-CH₃).¹³C NMR(CDCl₃，176MHz)δ：203.8，203.6，168.7，165.5，165.4，163.5，153.8，151.0，148.8，138.2，132.0，131.3，129.6，128.1，103.8，85.3，83.0，80.3，80.0，77.6，70.2，69.3，66.1，62.9，61.5，40.7，40.3，38.3，32.7，29.7，28.8，26.4，25.2，25.0，22.4，21.2，21.0，18.9，15.3，15.2，12.9，10.6.

Alternatively, step f can be the preparation of the seventh compound (2-fluoro-3-O-decladinose-3-carbonyl-6-O- [6 '- (1' -cyclopropyl-1 ', 4' -dihydro-4 '-oxo-3' -quinolinecarboxamido) -E-prop-2-enyl ] erythromycin A9-O-methyloxime-11, 12-cyclic carbonate) as shown in 7i

The sixth compound (0.300g, 0.412mmol), palladium acetate (0.0278g, 0.124m mol), tris (o-methylphenyl) phosphorus (0.0750g, 0.247mmol), 1-cyclopropyl-1, 4-dihydro-6-iodo-4-oxo-3-quinolinecarboxamide (0.292g, 0.824mmol), and triethylamine (0.17mL, 1.236mmol) were dissolved in 5mL of acetonitrile, placed in a pressure flask, replaced with argon for 8 times, sealed, reacted at 60 ℃ for 1h, then warmed to 90 ℃ and stirred for 24 h. After the reaction, 20mL of ethyl acetate was added, washed with water for 3 times, once with a saturated sodium chloride solution, and the organic layer was spin-dried after liquid separation. Then dissolving the product in methanol, refluxing for 1-1.5h at 65 ℃, and monitoring the reaction by thin-layer chromatography to obtain a crude product. Column chromatography (100-mesh 200-mesh silica gel with mobile phase of 10: 0.2: 0.1: V (dichloromethane): V (ethanol): V (ammonia) to give the seventh compound shown as 7i, 50.7mg (0.0555mmol, 13.47% yield).

HRMS(ESI)(M+H)⁺m/z 913.4604，calcd for C₄₇H₆₆FN₄O₁₃913.4605.

¹H NMR(CDCl₃，400MHz)δ：9.77(d，J＝5.4Hz，1H，Ar-NH₂)，8.85(s，1H，2′-Ar)，8.38(s，1H，5′-Ar)，8.11(d，J＝7.2Hz，1H，7′-Ar)，8.00(d，J＝8.8Hz，1H，8′-Ar)，6.54(d，J＝15.8Hz，1H，6-O-CH₂CH＝CH-Ar)，6.16(dt，J₁＝15.1Hz，J₂＝6.8Hz，1H，6-O-CH₂CH＝CH-Ar)，5.78(d，J＝5.3Hz，1H，Ar-NH₂)，4.99(s，1H，H-11)，4.50(br，1H，H-13)，4.36(d，J＝7.2Hz，1H，H-1，)，4.09(d，J＝10.1Hz，1H，H-5)，3.95-3.45(m，9H，H-5′，9-O-CH₃，H-8，H-4，6-O-CH₂CH＝CH-Ar，1H-cyclopropyl)，3.24(dd，J₁＝10.1Hz，J₂＝7.0Hz，1H，H-2′)，2.62-2.46(m，2H，H-3′，H-10)，2.33(s，6H，-N(CH₃)₂)，1.80(d，J＝21.4Hz，3H，2-CH₃)，1.76-1.62(m，3H，H-4′a，H-14eq，H-7a)，1.55(s，1H，12-CH₃)，1.49(s，1H，6-CH₃)，1.43-1.11(m，16H，H-14ax，2 H-cyclopropyl，5′-CH₃，2H-cyclopropyl，H-7b，4-CH₃，H-4′b，10-CH₃)，1.01(br，3H，8-CH₃)，0.75(br，3H，15-CH₃).¹³C NMR(CDCl₃，100MHz)δ：204.0，203.7，176.6，166.9，165.4，165.2，163.5，153.9，147.2，140.1，134.3，131.9，130.4，128.5，127.4，125.8，117.3，111.5，104.0，99.1，84.5，83.0，79.9，78.1，77.3，70.4，69.5，66.0，63.5，61.5，61.5，40.8，40.3，38.5，34.8，32.8，28.5，26.3，25.2，25.0，22.6，18.9，15.3，13.2，10.8.

Alternatively, step f can be the preparation of the seventh compound (2-fluoro-3-O-decladinose-3-carbonyl-6-O- [6 '- (1' -ethyl-1 ', 4' -dihydro-4 '-oxo-3' -quinolinecarboxamido) -E-prop-2-enyl ] erythromycin A9-O-methyloxime-11, 12-cyclic carbonate) as shown in 7k

The sixth compound (0.300g, 0.412mmol), palladium acetate (0.0278g, 0.124mmol), tris (o-methylphenyl) phosphorus (0.0750g, 0.247mmol), 1-ethyl-1, 4-dihydro-6-iodo-4-oxo-3-quinolinecarboxamide (1.282g, 0.824mmol), and triethylamine (0.17mL, 1.236mmol) were dissolved in 5mL of acetonitrile, placed in a pressure flask, replaced with argon for 8 times, sealed, reacted at 60 ℃ for 1h, then heated to 90 ℃ and stirred for 24 h. After the reaction, 20mL of ethyl acetate was added, washed with water for 3 times, once with a saturated sodium chloride solution, and the organic layer was spin-dried after liquid separation. Then dissolving the product in methanol, refluxing for 1-1.5h at 65 ℃, monitoring the reaction by thin-layer chromatography, and spin-drying the reaction solution to obtain a crude product. Column chromatography (100-mesh 200-mesh silica gel with mobile phase of 10: 0.1) V (dichloromethane): V (ethanol): V (ammonia) gave 49.0mg (0.0544mmol, 13.20% yield) of the seventh compound as shown in 7 k.

HRMS(ESI)(M+H)⁺m/z 901.4609，calcd for C₄₆H₆₆FN₄O₁₃901.4605.

¹H NMR(CDCl₃，400MHz)δ：9.82(d，J＝5.2Hz，1H，Ar-NH₂)，8.75(s，1H，2′-Ar)，8.41(s，1H，5′-Ar)，8.13(d，J＝8.9Hz，1H，7′-Ar)，7.56(d，J＝9.0Hz，1H，8′-Ar)，6.53(d，J＝15.9Hz，1H，6-O-CH₂CH＝CH-Ar)，6.16(dt，J₁＝15.4Hz，J₂＝6.8Hz，1H，6-O-CH₂CH＝CH-Ar)，5.82(d，J＝5.5Hz，1H，Ar-NH₂)，5.00(s，1H，H-11)，4.48(br，1H，H-13)，4.40-4.24(m，3H，H-1′，2H-ethyl)，4.08(d，J＝10.1Hz，1H，H-5)，3.92-3.82(m，1H，6-O-CH₂CH＝CH-Ar)，3.76(s，1H，9-O-CH₃)，3.69-3.47(m，4H，H-8，H-5′，H-4，6-O-CH₂CH＝CH-Ar)，3.22(dd，J₁＝10.2Hz，J₂＝7.2Hz，1H，H-2，)，2.60-2.43(m，2H，H-3′，H-10)，2.30(s，6H，-N(CH₃)₂)，1.81(d，J＝21.4Hz，3H，2-CH₃)，1.74-1.60(m，3H，H-4′a，H-14eq，H-7a)，1.59-1.51(m，6H，2H-ethyl，12-CH₃)，1.49(s，3H，6-CH₃)，1.45-1.38(m，1H，H-14ax)，1.34(d，J＝7.1Hz，4-CH₃)，1.34-1.12(m，8H，H-7b，10-CH₃，H-4′b，5′-CH₃)，1.00(br，3H，8-CH₃)，0.73(t，J＝7.6Hz，3H，15-CH₃).¹³C NMR(CDCl₃，100MHz)δ：204.0，203.7，176.5，167.0，165.3，165.1，163.5，153.9，147.1，138.1，134.1，131.6，130.6，128.6，128.1，126.3，116.4，111.7，104.0，84.5，83.0，80.0，79.8，78.0，77.39，69.6，65.9，63.4，61.4，49.2，40.7，40.3，38.5，32.7，28.3，26.3，25.2，25.0，22.6，21.2，18.9，15.3，14.6，13.1，10.7.

Alternatively, step f can be the preparation of the seventh compound shown as 7j (2-fluoro-3-O-descladinose-3-carbonyl-6-O- [6 ' - (1 ' -cyclopropyl-1 ', 4 ' -dihydro-4 ' -oxo-3 ' -quinolinecarboxamido-N ' -methyl) -E-prop-2-enyl ] erythromycin A9-O-methyloxime-11, 12-cyclic carbonate)

The sixth compound (0.300g, 0.412mmol), palladium acetate (0.0278g, 0.124mmol), tris (o-methylphenyl) phosphorus (0.0750g, 0.247mmol), 1-cyclopropyl-1, 4-dihydro-6-iodo-4-oxo-3-quinolinecarboxamide-N-methyl (0.228g, 0.618mmol), triethylamine (0.17mL, 1.236mmol) were dissolved in 5mL of acetonitrile, placed in a pressure flask, replaced with argon for 8 times, sealed, reacted at 60 ℃ for 1h, then heated to 90 ℃ and stirred for 24 h. After the reaction, 20mL of ethyl acetate was added, washed with water for 3 times, once with a saturated sodium chloride solution, and the organic layer was spin-dried after liquid separation. Then dissolving the product in methanol, refluxing for 1-1.5h at 65 ℃, monitoring the reaction by thin-layer chromatography, and spin-drying the reaction solution to obtain a crude product. Column chromatography (100-mesh 200-mesh silica gel with mobile phase of V (petroleum ether):V (dichloromethane): V (ethanol): V (ammonia): 2: 8: 0.01: 0.05) gave the seventh compound of formula 7j, 26.5mg (0.0286mmol, 6.94%).

HRMS(ESI)(M+H)⁺m/z 927.4769，calcd for C₄₈H₆₈FN₄O₁₃927.4761.

¹H NMR(CDCl₃，400MHz)δ：9.94(d，J＝5.0Hz，1H，Ar-NH-CH₃)，8.86(s，1H，2′-Ar)，8.37(d，J＝2.1Hz，1H，5′-Ar)，8.10(d，J＝9.0Hz，1H，7′-Ar)，8.00(d，J＝8.9Hz，1H，8′-Ar)，6.54(d，J＝15.9Hz，1H，6-O-CH₂CH＝CH-Ar)，6.15(dt，J₁＝15.9Hz，J₂＝6.8Hz，1H，6-O-CH₂CH＝CH-Ar)，4.99(s，1H，H-11)，4.47(br，1H，H-13)，4.37(d，J＝7.2Hz，1H，H-1，)，4.09(d，J＝10.1Hz，1H，H-5)，3.92-3.80(m，1H，6-O-CH₂CH＝CH-Ar)，3.78(s，1H，9-O-CH₃)，3.72-3.45(m，5H，H-8，H-5′，H-4，6-O-CH₂CH＝CH-Ar，1H-cyclopropyl))，3.27(dd，J₁＝10.2Hz，J₂＝7.2Hz，1H，H-2′)，3.00(d，J＝4.8Hz，3H，Ar-NH-CH₃)，2.71-2.59(m，1H，H-3′)，2.57-2.46(m，1H，H-10)，2.39(s，6H，-N(CH₃)₂)，1.81(d，J＝21.1Hz，3H，2-CH₃)，1.76-1.59(m，3H，H-4′a，H-14eq，H-7a)，1.54(s，3H，12-CH₃)，1.48(s，1H，6-CH₃)，1.42-1.11(m，16H，H-14ax，2H-cyclopropyl，5′-CH₃，2H-cyclopropyl，H-7b，4-CH₃，H-4′b，10-CH₃)，1.01(br，3H，8-CH₃)，0.73(t，J＝7.5Hz，3H，15-CH₃).¹³C NMR(CDCl₃，100MHz)δ；204.0，203.7，176.8，165.8，163.5，153.9，146.6，140.0，134.0，132.0，130.3，128.2，127.4，125.7，117.2，111.9，103.8，84.4，83.0，79.9，78.9，70.3，69.3，66.1，63.6，61.5，40.7，40.3，38.4，34.7，32.7，28.8，26.3，25.8，25.2，25.0，22.6，21.2，18.9，15.3，13.2，10.8，8.2.

Alternatively, step f may be the preparation of the seventh compound (2-fluoro-3-O-descladinose-3-carbonyl-6-O- [6 ' - (1 ' -ethyl-1 ', 4 ' -dihydro-4 ' -oxo-3 ' -quinolinecarboxamido-N ' -methyl) -E-prop-2-enyl ] erythromycin A9-O-methyloxime-11, 12-cyclic carbonate) shown as 7l

The sixth compound (0.347g, 0.476mmol), palladium acetate (0.0214g, 0.0952mmol), tris (o-methylphenyl) phosphorus (0.0575g, 0.189mmol), 1-ethyl-1, 4-dihydro-6-iodo-4-oxo-3-quinolinecarboxamide-N-methyl (0.254g, 0.714mmol), triethylamine (0.20mL, 1.428mmol) were dissolved in 5mL of acetonitrile, placed in a pressure bottle, replaced with argon for 8 times, sealed, reacted at 60 ℃ for 1h, then heated to 90 ℃ and stirred for 24 h. After the reaction, 20mL of ethyl acetate was added, washed with water for 3 times, once with a saturated sodium chloride solution, and the organic layer was spin-dried after liquid separation. Then dissolving the product in methanol, refluxing for 1-1.5h at 65 ℃, monitoring the reaction by thin-layer chromatography, and spin-drying the reaction solution to obtain a crude product. Column chromatography (100-mesh 200-mesh silica gel with mobile phase of V (petroleum ether): V (dichloromethane): V (ethanol): V (ammonia): 1: 9: 0.01: 0.05) gave the seventh compound as described in 7l, 60.6mg (0.0662mmol, 13.91% yield).

HRMS(ESI)(M+H)⁺m/z 915.4760，calcd for C₄₇H₆₈FN₄O₁₃915.4761.

¹H NMR(CDCl₃，400MHz)δ：10.00(d，J＝5.0Hz，1H，Ar-NH-CH₃)，8.75(s，1H，2′-Ar)，8.41(d，J＝2.1Hz，1H，5′-Ar)，8.11(d，J＝8.9Hz，1H，7′-Ar)，7.56(d，J＝9.0Hz，1H，8′-Ar)，6.54(d，J＝15.9Hz，1H，6-O-CH₂CH＝CH-Ar)，6.15(dt，J₁＝14.8Hz，J₂＝6.7Hz，1H，6-O-CH₂CH＝CH-Ar)，4.99(s，1H，H-11)，4.45(br，1H，H-13)，4.41-4.28(m，3H，H-1′，2H-ethyl)，4.09(d，J＝10.1Hz，1H，H-5)，3.94-3.81(m，1H，6-O-CH₂CH＝CH-Ar)，3.76(s，1H，9-O-CH₃)，3.74-3.45(m，4H，H-8，H-4，H-5′6-O-CH₂CH＝CH-Ar)，3.28(dd，J₁＝10.2Hz，J₂＝7.2Hz，1H，H-2′)，3.01(d，J＝4.8Hz，1H，Ar-NH-CH₃)，2.72-2.61(m，1H，H-3′)，2.51(br，1H，H-10)，2.39(s，6H，-N(CH₃)₂)，1.80(d，J＝21.4Hz，3H，2-CH₃)，1.72-1.59(m，3H，H-4′a，H-14eq，H-7a)，1.58-1.50(m，6H，2H-ethyl，12-CH₃)，1.48(s，1H，6-CH₃)，1.42-1.37(m，1H，H-14ax)，1.34(d，J＝7.1Hz，10-CH₃)，1.31-1.19(m，8H，H-7b，4-CH₃，H-4′b，5′-CH₃)，1.00(br，3H，8-CH₃)，0.71(t，J＝7.6Hz，3H，15-CH₃).¹³C NMR(CDCl₃，100MHz)δ：204.0，203.7，176.6，165.9，163.5，153.9，146.5，138.0，133.9，131.8，130.5，128.4，128.0，126.2，116.3，112.1，103.8，84.5，83.0，79.9，79.8，78.1，66.0，63.5，61.5，61.4，49.1，40.7，40.3，38.4，32.7，28.8，26.3，25.8，25.2，25.0，22.6，21.2，18.9，15.3，14.6，13.2，10.7.

Alternatively, step f can be the preparation of the seventh compound (2-fluoro-3-O-decladinose-3-carbonyl-6-O- [6 '- (1' -isopropyl-1 ', 4' -dihydro-4 '-oxo-3' -quinolinecarboxyl) -E-prop-2-enyl ] erythromycin A9-O-methyloxime-11, 12-cyclic carbonate) as shown in 7x

In the present example, the seventh compound shown as 7x may be prepared by using the sixth compound, palladium acetate, tris (o-methylphenyl) phosphorus, triethylamine and 6 '-iodo-1' -isopropyl-1 ', 4' -dihydro-4 '-oxo-3' -quinolinecarboxyl as starting reactants in step f.

HRMS(ESI)(M+H)⁺m/z 916.4606，calcd for C₄₇H₆₇FN₃O₁₄916.4602.

Alternatively, step f can be the preparation of the seventh compound shown as 7y (2-fluoro-3-O-decladinose-3-carbonyl-6-O- [6 '- (1' -isopropyl-1 ', 4' -dihydro-4 '-oxo-3' -quinolinecarboxamido) -E-prop-2-enyl ] erythromycin A9-O-methyloxime-11, 12-cyclic carbonate)

The sixth compound (0.300g, 0.412mmol), palladium acetate (0.0278g, 0.124m mol), tris (o-methylphenyl) phosphorus (0.0750g, 0.247mmol), 1-isopropyl-1, 4-dihydro-6-iodo-4-oxo-3-quinolinecarboxamide (0.220g, 0.618mmol), and triethylamine (0.17mL, 1.236mmol) were dissolved in 5mL of acetonitrile, placed in a pressure flask, replaced with argon for 8 times, sealed, reacted at 60 ℃ for 1h, then warmed to 90 ℃ and stirred for 24 h. After the reaction, 20mL of ethyl acetate was added, washed with water for 3 times, once with a saturated sodium chloride solution, and the organic layer was spin-dried after liquid separation. Then dissolving the product in methanol, refluxing for 1-1.5h at 65 ℃, and monitoring the reaction by thin-layer chromatography to obtain a crude product. Column chromatography (100-200 mesh silica gel with mobile phase of 10: 0.1: 0.05V (dichloromethane): V (ethanol): V (ammonia) to give 70.8mg (0.0774mmol, 18.78% yield) of the seventh compound as shown in 7 y.

¹H NMR(CDCl₃，400MHz)δ：9.85(d，J＝5.4Hz，1H，Ar-NH₂)，8.91(s，1H，2′-Ar)，8.44(d，J＝2.2Hz，1H，5′-Ar)，8.13(d，J＝9.0Hz，1H，7′-Ar)，7.69(d，J＝9.1Hz，1H，8′-Ar)，6.54(d，J＝15.9Hz，1H，6-O-CH₂CH＝CH-Ar)，6.17(dt，J₁＝15.5Hz，J₂＝6.8Hz，1H，6-O-CH₂CH＝CH-Ar)，5.84(d，J＝5.4Hz，1H，Ar-NH₂)，5.08-4.88(m，2H，H-11，N-CH(CH₃)₂)，4.49(br，1H，H-13)，4.36(d，J＝7.3Hz，1H，H-1′)，4.08(d，J＝10.1Hz，1H，H-5)，3.90-3.46(m，8H，H-5′，9-O-CH₃，H-8，H-4，6-O-CH₂CH＝CH-Ar)，3.22(dd，J₁＝10.2Hz，J₂＝7.2Hz，1H，H-2′)，2.62-2.45(m，2H，H-3′，H-10)，2.31(s，6H，-N(CH₃)₂)，1.81(d，J＝21.3Hz，3H，2-CH₃)，1.76-1.66(m，3H，H-4′a，H-14eq，H-7a)，1.66-1.60(m，4H，N-CH(CH₃)₂)，1.55(s，1H，12-CH₃)，1.48(s，1H，6-CH₃)，1.39-1.18(m，12H，H-14ax，5′-CH₃，H-7b，4-CH₃，H-4′b，10-CH₃)，1.01(br，3H，8-CH₃)，0.74(br，3H，15-CH₃).

¹³C NMR(CDCl₃，100MHz)δ：203.9，203.6，176.1，167.1，165.3，165.1，163.4，153.9，142.6，138.7，134.0，131.5，130.4，128.6，128.1，126.3，115.8，111.6，104.0，99.0，84.5，83.0，80.0，79.8，78.0，70.4，69.5，65.9，63.4，61.4，51.6，40.7，40.3，38.4，32.7，28.4，26.3，25.2，25.0，22.6，22.2，22.1，18.9，15.3，13.1，10.7.

In the examples of the present invention, most of the halogenated compounds for Ar group provided can be prepared by commercially available methods, methods in the prior art references, or preparation methods in the specification. By varying the type of halogenated compound, preparations of different erythromycin derivatives similar to those described above can be carried out.

Alternatively, in the practice of the present invention, the halogenated compound for the provided Ar group may also be prepared by the synthetic route shown below:

step a1, Synthesis of ninth Compound

The eighth compound (10.000g, 37.592mmol) was dissolved in 40mL of dichloromethane and 1mL of DMF, and stirred at room temperature, oxalyl chloride (3.800mL, 45.110mmol) was dissolved in 10mL of dichloromethane, added dropwise to the reaction system, and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was spin-dried and replaced with anhydrous toluene three times to obtain an oily liquid ninth compound.

In an embodiment of the invention, the eighth compound is 2-fluoro-5-iodobenzoic acid.

Step b1, tenth Compound Synthesis

50mL of toluene and triethylamine (7.300mL, 52.629mmol) were added to the ninth compound obtained in step a1, and ethyl 3- (N, N-dimethylamino) acrylate (5.382g, 37.592mmol) was dissolved in 20mL of toluene and added dropwise to the reaction system. Stirring for 4-5h at 90 ℃, and monitoring the reaction process by thin layer chromatography. After the reaction is completed, carrying out suction filtration, and carrying out rotary drying on the filtrate and replacing the filtrate with ethanol for 2-3 times to obtain an oily liquid compound.

Step c1, eleventh Compound Synthesis

The tenth compound was dissolved in a mixture of 24mL ethanol and 16mL tetrahydrofuran, and cyclopropylamine (5.2mL, 75.184mmol) was dissolved in 10mL tetrahydrofuran and added dropwise to the reaction. Transferring to room temperature after the dropwise addition, detecting by thin-layer chromatography to complete the reaction, spin-drying the reaction solution, cooling to room temperature, adding petroleum ether for crystallization, standing for 1h, and performing suction filtration after complete crystallization to obtain 11.456g (29.437mmol, total yield from the eighth compound is 78.31%) of a white solid eleventh compound.

Alternatively, step c1 may be the synthesis of a twelfth compound

The tenth compound was dissolved in a mixture of 24mL ethanol and 16mL tetrahydrofuran, and 37.592mL of a 2mol/L ethylamine tetrahydrofuran solution was added dropwise under ice. Transferring to room temperature after the dropwise addition, detecting by thin-layer chromatography to complete the reaction, spin-drying the reaction solution, cooling to room temperature, adding petroleum ether for crystallization, standing for 1h, and performing suction filtration after complete crystallization to obtain 11.226g (28.698mmol, total yield from the eighth compound is 76.34%) of a white solid twelfth compound.

In the embodiment of the present invention, ethylamine is used as a reactant in step c1 to obtain an iodoaryl group with an ethyl group at the N1 position, i.e., a twelfth compound, methylamine can be used in step c1 to obtain an iodoaryl group with a methyl group substituted at the N1 position, or isopropylamine can be used in step c1 to obtain an iodoaryl group with an isopropyl group substituted at the N1 position.

Step d1, Synthesis of the thirteenth Compound

Dissolving an eleventh compound (11.456g, 29.437mmol) in 20mL of dry DMF, adding anhydrous potassium carbonate (8.137g, 58.874mmol), reacting at 140 ℃ for 2-3h, detecting the reaction completion by thin-layer chromatography, performing suction filtration, washing a filter cake for multiple times by using dichloromethane, spin-drying a filtrate, adding tetrahydrofuran, and crystallizing to obtain a white solid, namely a thirteenth compound, 9.9434g (26.936mmol, 91.50% yield).

Alternatively, step d1 may be the synthesis of a fourteenth compound

The twelfth compound (11.226g, 28.698mmol) is dissolved in 20mL of dry DMF, anhydrous potassium carbonate (8.052g, 58.257mmol) is added, the reaction is carried out for 2-3h at 140 ℃, after the completion of the reaction is detected by thin-layer chromatography, suction filtration is carried out, a filter cake is washed by dichloromethane for multiple times, after filtrate is dried in a spinning mode, tetrahydrofuran is added for crystallization, and the fourteenth compound which is a white solid is obtained, wherein 6.885g (18.548mmol, yield 64.63%).

Step e1, fifteenth Compound Synthesis

The thirteenth compound (9.943g, 26.936mmol) was dissolved in a mixture of 40mL of water and 40mL of tetrahydrofuran, sodium hydroxide (4.999g, 124.983mmol) was added, the mixture was stirred at 80 ℃ for 4h, after completion of the reaction, tetrahydrofuran was dried by spinning, the pH was adjusted to 4.5 with dilute hydrochloric acid, the mixture was transferred to an ice bath, and after 1h, suction filtration was performed to obtain 7.538g (21.285mmol, 79.02% yield) of a white solid compound.

HRMS(ESI)(M+H)⁺m/z 807.3845，calcd for C₁₃H₁₁INO₃355.9778.

¹H NMR(CDCl₃，400MHz)δ：14.54(s，1H，COOH)，8.87(s，1H，H-2)，8.84(d，J＝2.0Hz，1H，H-5)，8.11(dd，J₁＝8.8Hz，J₂＝2.0Hz，1H，H-7)，7.83(d，J＝9.2Hz，1H，H-8)，3.70-3.50(m，1H，1H-cyclopropyl)，1.55-1.35(m，2H，2H-cyclopropyl)，1.36-1.16(m，2H，2H-cyclopropyl).

Alternatively, step e1 may be the synthesis of the sixteenth compound

The fourteenth compound (6.885g, 18.548mmol) was dissolved in a mixture of 40mL of water and 40mL of tetrahydrofuran, sodium hydroxide (3.443g, 86.063mmol) was added, the mixture was stirred at 80 ℃ for 4 hours, after completion of the reaction, the tetrahydrofuran was dried by spinning, the pH was adjusted to 4.5 with dilute hydrochloric acid, the mixture was transferred to an ice bath, and after 1 hour, suction filtration was performed to obtain 4.950g (14.444mmol, 77.87% yield) of a white solid, which was a sixteenth compound.

HRMS(ESI)(M+H)⁺m/z 343.9773，calcd for C₁₂H₁₁INO₃343.9778.

¹H NMR(DMSO-d₆，400MHz)δ：14.88(s，1H，COOH)，9.06(s，1H，H-2)，8.57(s，1H，H-5)，8.20(d，J＝9.0Hz，1H，H-7)，7.85(d，J＝8.4Hz，1H，H-8)，4.59(d，J＝7.6Hz，2H，2H-ethyl)，1.42(t，J＝6.4Hz，3H，3H-ethyl).

Step f1, seventeenth Synthesis of Compound

The fifteenth compound (0.500g, 1.408mmol) was dissolved in 4mL of DMF, dicarbonyl imidazole (0.457g, 2.816mmol) was added and stirred at 65 ℃ for 2h, then cooled to room temperature, 10mL of glacial ammonia water was added dropwise, stirred overnight, and filtered the next day with suction to give seventeenth compound as a white solid, 0.480g (1.355mmol, 96.23% yield).

HRMS(ESI)(M+H)⁺m/z 807.3845，calcd for C₁₃H₁₂IN₂O₂354.9938.

¹H NMR(DMSO-d₆，400MHz)δ：9.08(d，J＝4.0Hz，1H，NH₂)，8.71(s，1H，H-2)，8.57(d，J＝2.0Hz，1H，H-5)，8.16(dd，J₁＝9.2Hz，J₂＝2.0Hz，1H，H-7)，7.95(d，J＝8.8Hz，1H，H-8)，7.54(d，J＝3.6Hz，1H，NH₂)，3.80-3.65(m，1H，1H-cyclopropyl)，1.31-1.16(m，2H，2H-cyclopropyl)，1.15-1.03(m，2H，2H-cyclopropyl).

Alternatively, step f1 may be the synthesis of an eighteenth compound

The sixteenth compound (1.000g, 2.914mmol) was dissolved in 10mL of DMF and dicarbonyl imidazole (0.945g, 5.828mmol) was added and stirred at 65 ℃ for 2h, then cooled to room temperature, 20mL of ice ammonia was added dropwise, stirred overnight and filtered the next day to give 0.956g (2.794mmol, 95.88% yield) of eighteenth compound as a white solid.

HRMS(ESI)(M+H)⁺m/z 342.9931，calcd for C₁₂H₁₂IN₂O₂342.9938.

¹H NMR(CDCl₃，400MHz)δ：9.67(s，1H，NH₂)，8.88(d，J＝2.1Hz，1H，H-5)，8.81(s，1H，H-2)，8.01(dd，J₁＝8.9Hz，J₂＝2.1Hz，1H，H-7)，7.30(d，J＝8.9Hz，1H，H-8)，5.87(s，1H，NH₂)，4.32(d，J＝7.4Hz，2H，2H-ethyl)，1.56(t，J＝7.1Hz，3H，3H-ethyl).

Alternatively, step f1 may be the synthesis of the nineteenth compound

The fifteenth compound (0.500g, 1.408mmol) was dissolved in 4mL of DMF and dicarbonyl imidazole (0.457g, 2.816mmol) was added and stirred at 65 ℃ for 2h, then cooled to room temperature, 10mL of 40% aqueous methylamine was added dropwise, stirred overnight, filtered with suction the next day to give nineteenth compound as a white solid, 0.492g (1.336mmol, 94.88% yield).

HRMS(ESI)(M+H)⁺m/z 369.0097，calcd for C₁₄H₁₄IN₂O₂369.0094.

¹H NMR(CDCl₃，400MHz)δ：9.71(s，1H，NH-CH₃)，8.89(s，1H，H-2)，8.78(d，J＝2.1Hz，1H，H-5)，7.99(dd，J₁＝8.9Hz，J₂＝2.2Hz，1H，H-7)，7.74(d，J＝8.9Hz，1H，H-8)，3.51(tt，J₁＝7.1Hz，J₂＝3.8Hz，1H，1H-cyclopropyl)，3.00(d，J＝4.8Hz，1H，NH-CH₃)，1.41-1.31(m，2H，2H-cyclopropyl)，1.21-1.12(m，2H，2H-cyclopropyl).

Alternatively, step f1 may be the synthesis of the twentieth compound

The sixteenth compound (0.500g, 1.457mmol) was dissolved in 6mL of DMF, dicarbonylimidazole (0.472g, 2.914mmol) was added and stirred at 65 ℃ for 2h, then cooled to room temperature, 10mL of 40% aqueous methylamine was added dropwise, stirred overnight, filtered with suction the next day to give a white solid twentieth compound, 0.475g (1.330mmol, 91.28% yield).

HRMS(ESI)(M+H)⁺m/z 357.0097，calcd for C₁₃H₁₄IN₂O₂357.0094.

¹H NMR(CDCl₃，400MHz)δ：9.78(s，1H，NH-CH₃)，8.86(d，J＝2.2Hz，1H，H-5)，8.88(s，1H，H-2)，7.99(dd，J₁＝8.8Hz，J₂＝2.2Hz，1H，H-7)，7.29(d，J＝9.0Hz，1H，H-8)，4.31(q，J＝7.2Hz，2H，2H-ethyl)，3.02(d，J＝4.8Hz，1H，NH-CH₃)，1.54(t，J＝7.1Hz，3H，3H-ethyl).

In the examples of the present invention, in the synthesis of the halogenated compound providing Ar group, ammonia water or other various substituted amines such as isopropylamine, 2,2, 2-trifluoroethylamine or methylamine may be used in steps c1 and f1, thereby obtaining other iodo-substituted quinolones.

If methylamine and ammonia water are respectively used in the steps c1 and f1, the corresponding iodoquinolone reagent is (R)₁＝CH₃，R₂＝H)：HRMS(ESI)(M+H)⁺m/z 328.9787，calcd for C₁₁H₁₀IN₂O₂328.9781.¹H NMR(DMSO-d₆，400MHz)δ：9.16(d，J＝4.6Hz，1H，NH₂)，8.86(s，1H，H-5)，8.58(d，J＝2.2Hz，1H，H-2)，8.13(dd，J₁＝8.9Hz，J₂＝2.2Hz，1H，H-7)，7.63(d，J＝9.0Hz，1H，H-8)，7.50(d，J＝4.6Hz，1H，NH₂)，3.98(s，3H，CH₃).

Using isopropylamine and aqueous ammonia, respectively, as in steps c1 and f1, the corresponding iodoquinolone reagent is (R)₁＝N-CH(CH₃)₂，R₂＝H)：¹H NMR(DMSO-d₆，400MHz)δ：9.17(d，J＝4.5Hz，1H，NH₂)，8.85(s，1H，H-2)，8.64(d，J＝2.2Hz，1H，H-5)，8.12(dd，J₁＝9.0Hz，J₂＝2.2Hz，1H，H-7)，7.88(d，J＝9.2Hz，1H，H-8)，7.60(d，J＝4.5Hz，1H，NH₂)，5.13(p，J＝6.6Hz，1H，N-CH(CH₃)₂)，1.52(d，J＝6.5Hz，6H，N-CH(CH₃)₂).

Optionally, the invention also provides that the erythromycin derivative is an acceptable salt formed by the compound with the general formula I and an inorganic acid or an organic acid, and the inorganic acid or the organic acid is added into the obtained seventh compound to generate the erythromycin derivative with excellent antibacterial activity.

EXAMPLE III

In vitro antibacterial activity test. The experimental bacteria are sensitive streptococcus pneumoniae ATCC49619, mef type drug-resistant streptococcus pneumoniae PU-09, constitutive erm type drug-resistant streptococcus pneumoniae 07P390, erm + mef type drug-resistant streptococcus pneumoniae 05O137, induced erm type drug-resistant staphylococcus aureus PU-32, constitutive erm type drug-resistant staphylococcus aureus 15B196, induced erm type drug-resistant streptococcus pyogenes 01-968, mef type drug-resistant streptococcus pyogenes 12-207, constitutive ermA type drug-resistant streptococcus pyogenes 12-206 and haemophilus influenzae ATCC 49247.

The experimental method comprises the following steps: the in vitro antibacterial activity of some of the compounds of interest on the above-mentioned bacteria was determined by the broth dilution method according to the criteria recommended by the Clinical and Laboratory Standards Institute (CLSI, 2010), each of which was subjected to plate-transfer purification before the test, and fresh cells were used for the test. In each experiment, the standard strain is used as a quality control strain for a sensitive experiment; the bacterial liquid without antibiotic drug is used as the growth control of the test strain. Minimum Inhibitory Concentration (MIC) was determined by broth two-fold dilution. The concentration range of the antibacterial drug is 256-0.002 mug/mL, and the final concentration of the tested bacterial liquid is about 5 x 105 CFU/mL.

The results of the assay are shown in the following table:

table 1 is a control chart of the MIC (μ g/mL) minimum inhibitory concentrations of the seventh compound shown as 7i, 7k, 7j and 7l against Streptococcus pneumoniae ATCC49619, Streptococcus pneumoniae PU 09, Streptococcus pneumoniae 07P390 and Streptococcus pneumoniae 05O137, respectively.

Table 2 shows the MIC (μ g/mL) comparison table of the seventh compounds shown as 7i, 7k, 7j and 7l against the minimum inhibitory concentrations (M.sub.M.) of Staphylococcus aureus PU 32, Staphylococcus aureus 15B169, Streptococcus pyogenes 12-207, Streptococcus pyogenes 01-968 and Streptococcus pyogenes 12-206, respectively.

Table 3 is a control chart of MIC (μ g/mL) minimum inhibitory concentrations of the seventh compound as shown in 7v, 7u, 7a, 7d, 7e and 7h against Streptococcus pneumoniae ATCC49619, Streptococcus pneumoniae 07P390, Staphylococcus aureus PU 32 and Haemophilus ATCC49247, respectively.

The 9-alkene and 9-alkynone lactone derivatives are compounds which have been disclosed to have good in vitro antibacterial activity against clinically common drug-resistant bacteria and sensitive bacteria, in the embodiment of the invention, 2-aminopyridyl, 3-cyanopyridyl, 3-carboxypyridyl, 2-nitropyridyl, 3-hydroxypyridyl, 1-aminoisoquinolyl, 4-aminoisoquinolyl, 3-carbamoylpyridyl, 3- (N-methyl) carbamoylpyridyl are used for preparing 9-alkene and 9-alkynone lactone analogues, and the synthesized twenty-first compound and twenty-second compound have the following structures:

tests show that the combined type erm type drug-resistant streptococcus pneumoniae 07P390 has MIC more than or equal to 32 mug/mL and has very weak antibacterial activity. Therefore, the curative effect is limited in resisting pneumonia infection caused by erythromycin resistant bacteria.

Table 4 is a comparison table of MIC (mu g/mL) of 9-ene or 9-alkynone lactone derivatives at the minimum inhibitory concentration.

As can be seen from the data in tables 1, 2, 3 and 4, in the examples of the present invention, the novel erythromycin structure composed of 9-methoxyoxime, 11-12 cyclic carbonate, 2-fluoro, 3-carbonyl and 6-O- (3-aryl-2 propenyl) side chain has excellent antibacterial activity against high levels of constitutive erm type drug-resistant Streptococcus pneumoniae 07P390, and also has excellent antibacterial activity against other constitutive erm drug-resistant bacteria such as Staphylococcus aureus 15B196, Streptococcus pyogenes 12-206, etc., which is comparable to or superior to telithromycin. Because the resistance level of the constitutive erm to the clinical clarithromycin and the azithromycin is high (basically more than or equal to 256 mu g/mL), and the constitutive erm is very popular in Asia-Pacific region at present, the constitutive erm has better clinical application prospect for the compound with antibacterial activity of the constitutive drug-resistant bacteria.

Example four

CYP3A4(Cytochrome P4503A 4) is an important metabolic enzyme in human body, and is mainly present in liver and intestinal tract. It can oxidize exogenous organic small molecules (xenobiotics) such as toxins or drugs in order to expel them from the body. CYP3a4 is responsible for metabolizing half of the drugs currently in clinical use, so drugs with strong inhibition to CYP3a4 would have potential drug-drug interactions, and co-administration may have potential toxicity.

Mixing human liver microsome, midazolam as substrate and phosphate buffer solution (pH 7.4), heating at 37 deg.C for 5min, collecting the heated mixed solution, adding medicine or sample solution and NADPH solution, mixing, and incubating at 37 deg.C for 10 min. Preparing drug solutions with different concentrations and respectively testing. And then adding an acetonitrile solution of warfarin, mixing uniformly, centrifuging at 12000rpm for 10 minutes, and detecting the concentration of the compound in the supernatant by using LC-MS. Then data processing and calculation are carried out by Prism software to obtain IC 50.

In the embodiment of the invention, IC50 of telithromycin, 7i and a control drug ketoconazole on human liver microsome CYP3a4 is detected, as shown in table 5:

table 5 Compounds inhibit IC50 of human liver microsomal CYP3A4

Compounds and control drugs	IC50(μM)
		7i	14.90
Telithromycin	11.80
		Ketoconazole	0.06

IC50(half inhibition concentration) refers to the half inhibitory concentration of the inhibitor measured. It indicates the concentration of a drug or substance (inhibitor) at which half the catalytic activity of the enzyme is inhibited. As can be seen from the above table, the erythromycin derivative provided in the examples of the present invention has a higher concentration of IC50 and a higher semi-inhibitory concentration than other compounds, and thus has a lower inhibition rate on CYP3a 4. This is because the substituted aryl group can reduce the interaction between the lone pair of electrons of the nitrogen atom on the aryl group and the heme group of CYP3A4, thereby reducing the inhibition rate of CYP3A 4. That is, the erythromycin derivatives provided by the embodiments of the present invention have more possibilities in terms of co-administration.

The embodiment of the invention also performs oral in vivo pharmacokinetic parameter test on the compound, and the test result is shown in table 6:

TABLE 6 in vivo pharmacokinetic parameters in rats

Wherein n is the number of rats, AUC is the area under the blood curve, CL is the systemic blood clearance, t_1/2For half-life, MRT is mean residence time, C_maxAt maximum blood concentration, T_maxThe time to reach maximum blood concentration.

The drug or sample was formulated as a 1% DMF, 20% hydroxypropyl- β -cyclodextrin in saline solution. The drug was administered orally at 20mg/kg, orbital bleeds were performed for 0.25, 0.5, 1, 2, 4, 6, 8 and 24h, blood samples were processed and analyzed for plasma concentration by LC-MS, after which pharmacokinetic parameters were calculated using WinNonlin software.

As can be seen from the above table, the erythromycin derivatives provided by the embodiments of the invention have good pharmacokinetic properties such as higher AUC, slower CL, longer half-life, longer MRT, higher C_maxIn actual use, the effective components of the medicine can exert the effect more quickly and better through multiple times of administration.

For simplicity of description, the method embodiments are described as a series of operational combinations, but those skilled in the art will recognize that the invention is not limited by the order of operation, as some steps may occur in other orders or concurrently in accordance with the invention. Further, those skilled in the art will also appreciate that the embodiments described in the specification are presently preferred and that no requirement is necessarily placed on the invention for the exact operation and experimental conditions involved.

The erythromycin derivative and the preparation method of the erythromycin derivative provided by the invention are described in detail above, and the principle and the implementation mode of the invention are explained in the text by applying specific examples, and the description of the examples is only used for helping to understand the method and the core idea of the invention; meanwhile, for a person skilled in the art, according to the idea of the present invention, there may be variations in the specific embodiments and the application scope, and in summary, the content of the present specification should not be construed as a limitation to the present invention.

Claims

1. An erythromycin derivative is characterized in that the erythromycin derivative is a compound with a general formula I, or a pharmaceutically acceptable salt formed by the compound with the general formula I and an inorganic acid or an organic acid;

wherein, in the general formula I, Ar is selected from any one of quinolone, substituted quinolone and substituted 6-10-membered heteroaryl containing nitrogen atoms;

the substituted quinolone and the substituted 6-to 10-membered nitrogen atom-containing heteroaryl group refer to a quinolone containing one or more substituents and a 6-to 10-membered nitrogen atom-containing heteroaryl group;

the substituents are independently taken from one or more of the following substituents: 1-4 membered alkyl, halogen substituted 1-4 membered alkyl, 1-4 membered alkoxy, 2-4 membered alkene, 2-4 membered alkyne, 3-4 membered cycloalkyl, carboxy, carbamoyl, O- (1-4 membered alkyl, halogen substituted 1-4 membered alkyl, 2-4 membered alkene, 2-4 membered alkyne or 3-4 membered cycloalkyl) substituted oxycarbonyl, N- (1-4 membered alkyl, halogen substituted 1-4 membered alkyl, 2-4 membered alkene, 2-4 membered alkyne or 3-4 membered cycloalkyl) substituted carbamoyl, nitro, halogen, cyano, hydroxy, amino;

the substituted 6-10 membered nitrogen atom-containing heteroaryl is selected from any one of substituted pyridyl, substituted quinolyl, substituted pyridopyridyl and substituted isoquinolyl;

the substituent for substituting the 6-to 10-membered nitrogen atom-containing heteroaryl group is independently taken from one or more of the following substituents: carboxy, carbamoyl, N- (methyl) carbamoyl, N- (ethyl) carbamoyl, N- (cyclopropyl) carbamoyl, nitro, halogen, cyano, hydroxy, amino;

the substituted quinolone has a structure shown in a general formula II;

x in the structure shown in the general formula II is any one of nitrogen atom and oxygen atom, R¹、R²Each independently selected from any one of hydrogen atom, 1-4 membered alkyl, halogen substituted 1-4 membered alkyl, 2-4 membered alkene, 2-4 membered alkyne and 3-4 membered cycloalkyl;

the 1-4 membered alkyl is selected from any one of methyl, ethyl, isopropyl, n-butyl, isobutyl and tert-butyl;

the halogen-substituted 1-4-membered alkyl is selected from any one of 2-fluoroethyl, 2, 2-difluoroethyl and 2,2, 2-trifluoroethyl;

the 2-4 membered olefin is 2-propenyl;

the 2-4 membered alkyne is 2-propynyl;

the 3-4 membered cycloalkyl is selected from any one of cyclopropyl, cyclopropylmethyl and cyclobutyl.

2. The erythromycin derivative according to claim 1, characterized in that:

the inorganic acid is selected from any one of hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid and phosphoric acid;

the organic acid is selected from any one of acetic acid, malonic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, citric acid, fumaric acid and malic acid.

3. A process for the preparation of an erythromycin derivative according to any one of claims 1-2, characterized in that it comprises:

step 1: dissolving the first compound in dichloromethane, adding acetic anhydride to obtain a mixture, ending the reaction until the thin-layer chromatography monitoring reaction is completed, spin-drying, and drying in a vacuum oven after foaming to obtain a second compound; the first compound is 3-O-descladinose-3-hydroxy-6-O-allylerythromycin A-9-oxime;

step 2: dissolving the second compound in tetrahydrofuran, adding dimethyl sulfoxide, adding potassium hydroxide under the protection of argon, reacting at room temperature, monitoring by thin-layer chromatography that all acetyl groups at the 9-position of the second compound are removed, adding potassium hydroxide, dropwise adding methyl iodide under the protection of argon, reacting for 30-40 minutes until the reaction is completely monitored by the thin-layer chromatography, adding ethyl acetate and distilled water to extract a water phase, combining organic phases, washing the organic phase by using a saturated NaCl solution, spin-drying, foaming, and drying in a vacuum oven to obtain a third compound;

and step 3: dissolving the third compound in dichloromethane, dropwise adding pyridine under the protection of argon and at-10 ℃, dropwise adding a dichloromethane solution of triphosgene, keeping the temperature constant for reaction, transferring to room temperature for reaction till the reaction is finished, dropwise adding a saturated NaCl solution under an ice bath, stirring at normal temperature, adding distilled water and saturated NaHCO, and stirring at normal temperature₃Washing the organic phase with saturated NaCl solution, separating to obtain organic phase, spin drying and column chromatography to obtain the fourth compound;

and 4, step 4: dissolving N-chlorosuccinimide in dichloromethane, stirring at-15 ℃, dropwise adding dimethyl sulfide after the temperature is stable to generate white flocculent precipitate, dissolving the fourth compound in dichloromethane, slowly dropwise adding the dichloromethane solution of the N-chlorosuccinimide, stirring at-15 ℃ until the conversion rate of the fourth compound is more than 95% by thin-layer chromatography, adjusting the temperature to-5 ℃, dropwise adding triethylamine, finishing reaction after the reaction is completed, washing an organic phase by using distilled water, a saturated NaHCO3 solution and a saturated NaCl solution in sequence, separating the solution to obtain an organic phase, and spin-drying to obtain a fifth compound;

and 5: dissolving the fifth compound in N, N-dimethylformamide at 0 ℃, adding 60% NaH under the protection of argon gas for reaction after the temperature is stable, transferring the reaction to a-5 ℃ ice salt bath, adding N-fluoro-diphenylsulfonamide for reaction, monitoring the reaction by thin-layer chromatography, and sequentially using NaOH solution and saturated NaHCO₃Washing the organic phase with saturated NaCl solution, separating to obtain organic phase, spin drying and column chromatography to obtain the sixth compound;

step 6: dissolving the sixth compound, palladium acetate, tri (o-methylphenyl) phosphorus, triethylamine and halogenated compound in acetonitrile, replacing 8 times with argon in a pressure bottle, sealing, reacting at 60 ℃, heating to 90 ℃, stirring until the reaction is complete, adding ethyl acetate after the reaction is completed, washing with distilled water for 3 times, washing with saturated sodium chloride solution for 1 time, separating to obtain an organic phase, spin-drying the organic phase to obtain an intermediate product, dissolving the intermediate product in methanol, refluxing at 65 ℃ until the thin-layer chromatography monitors that the reaction is complete, spin-drying the reaction solution to obtain a crude product, and performing column chromatography to obtain the erythromycin derivative;

the halogenated compound is selected from a bromide or an iodide of any one of quinolone, substituted quinolone and substituted 6-to 10-membered nitrogen atom-containing heteroaryl;

the substituent for substituting the 6-to 10-membered nitrogen atom-containing heteroaryl group is independently taken from one or more of the following substituents: carboxy, carbamoyl, N- (methyl) carbamoyl, N- (ethyl) carbamoyl, N- (cyclopropyl) carbamoyl, nitro, halogen, cyano, hydroxy and amino;

the substituted quinolone has a structure shown in a general formula II;

the 2-4 membered olefin is 2-propenyl;

the 2-4 membered alkyne is 2-propynyl;