CN104961785B

CN104961785B - A kind of novel acyl lactone derivative and preparation method thereof

Info

Publication number: CN104961785B
Application number: CN201510347514.9A
Authority: CN
Inventors: 梁建华; 韩煦; 郭斯阳
Original assignee: Beijing Institute of Technology BIT
Current assignee: Beijing Institute of Technology BIT
Priority date: 2015-06-19
Filing date: 2015-06-19
Publication date: 2019-01-11
Anticipated expiration: 2035-06-19
Also published as: CN104961785A

Abstract

The present invention provides a kind of novel acyl lactone derivatives, the novel acyl lactone derivative has general formula I or general formula II or the novel acyl lactone derivative is the acceptable salt or ester that the compound with the general formula I or the general formula II is formed with inorganic acid or organic acid.Novel acyl lactone derivative provided in an embodiment of the present invention has new structure, has antibacterial activity outstanding to clinical common sensitive bacteria and drug-fast bacteria, the antibacterial and bactericidal activity of part of compounds is equivalent to or better than Ketek.The present invention breaks through existing acyl lactone structure-activity relationship knowledge, provides the novel non-ketone lactone with bactericidal activity, suitable with the activity of the Ketek of listing and easy to industrialized production.And studies have shown that the target spot that acyl lactone acts on bacterial ribosome is different from the action target spot of ketone lactone.In short, many deficiencies of middle ketone lactone, acyl lactone have preferable antimicrobial agent market prospects compared with the prior art.

Description

A kind of novel acyl lactone derivative and preparation method thereof

Technical field

The present invention relates to chemical synthesis and pharmaceutical fields, more particularly to a kind of novel acyl lactone derivative, and one kind The preparation method of novel acyl lactone derivative.

Background technique

14 membered macrolide antibiotics-erythromycin (erythromycin) is very important controlling for preventing respiratory infection Drug is treated, half a century provides the approach of a highly effective and safe medication, person allergic to penicillin and mycoplasma for the mankind Patients with pneumonia plays irreplaceable role.Currently, the clinically isolated more and more displays of respiratory diseases bacteria strain With drug resistance, such as streptococcus pneumonia (S.pneumoniae), staphylococcus aureus (S.aureus) and streptococcus pyogenes (S.pyogenes) etc..Although second generation erythromycin-clarithromycin and azithromycin medicine that the eighties in last century occurs are for power It is good to learn property, but antibacterial activity is had no to the bacterium of resistance to erythromycin.It is estimated that pneumonia caused by drug tolerant bacteria in global range Caused death of child number is per year over 1800000.Therefore, the research and development of novel antimicrobial agent erythromycin have urgent and heavy Big realistic meaning.

Compared with erythromycin, clarithromycin and azithromycin etc., third generation erythromycin derivatives-ketone lactone is resistance to resisting The activity of medicine bacterium.Its structure-activity relationship shows: the induction that being introduced into of 3- carbonyl avoids 3- cladinose in original macrolide is resistance to Pharmacological property, while the aromatic side chain newly introduced on big ring produces new combination target spot to drug-fast bacteria, to obtain antimicrobial agent Activity.Therefore, 3- carbonyl and aromatic side chain constitute the important feature feature of ketolide antibiotics.Ketone lactone (ketolide) Representative drug be the listing of French HMR company 2001 Ketek.

Although the shortcomings that ketone lactone makes a breakthrough, ketone lactone is it is clear that 1) ketone lactone is to most intractable Gao Shui Flat drug-fast bacteria-composing type erm staphylococcus aureus is without antibacterial activity；2) there are new induction erm resistance mechanisms for ketone lactone； 3) with the use of Ketek, the bacterial strain of anti-ketone lactone also starts clinically to be separated to；4) hepatotoxicity wind agitation of Ketek makes It obtains FDA and limits its applicable disease.Do not understanding fully that its hepatotoxicity wind agitation is before the general character of ketone lactone is also an example, the development of ketone lactone will be located Under hepatotoxic shade

Compared with ketone lactone, the position the 3- modification of non-ketone lactone is killed two birds with one stone, and has not only avoided in-ductive drug -tolerance but also directly effect one A novel targets different from ketone lactone.The representative structure of non-ketone lactone first is that the big positive 3-O- acyl lactone of Japan in 2003 (acylide).Later, researcher reported the acyl lactone of the acyl lactone of 11- side chain derivatives, 6- side chain derivatives, 9- again The acyl lactone of side chain derivatives.But the antimicrobial agent activity of acyl lactone is disclosed at present compared with corresponding ketone lactone also less It is ideal.

Summary of the invention

Technical problem to be solved by the invention is to provide a kind of novel acyl lactone derivatives and preparation method thereof, with preferable Adaptation industrialized production, and there is preferable anti-sensitive bacteria and antimicrobial agent activity for respiratory tract germ etc..

To solve the above-mentioned problems, the invention discloses a kind of novel acyl lactone derivative, the novel acyl lactone is derivative Object has the following general formula I or general formula II or the novel acyl lactone derivative is compound and nothing with the following general formula I or II The acceptable salt or ester that machine acid or organic acid are formed；

Wherein, in the general formula I or the general formula II, R is 2- pyridyl group or 3- pyridyl group, Ar are as follows:

Wherein, when A and B are carbon atom, X represent containing there are two and more than two heteroatomic heteroaryls or Substituted heteroaryl；Either when A is nitrogen-atoms and B is carbon atom or nitrogen-atoms, X be heteroaryl, substituted heteroaryl, amino, Substituted-amino, carbamoyl, substituted-amino formoxyl, hydroxyl, substituted hydroxy, nitro, cyano, halogen or hydrogen atom.

Preferably, the virtue that the heteroaryl that the X is represented substitutes as one or more hetero atoms independently selected from O, S or N Base.

Preferably, the aryl is the virtue with 5-18,5-14,5-10,5-8,5-6 or 6 carbon atoms Race's carbocylic radical.

Preferably, the aryl is phenyl, naphthalene or anthryl.

Preferably, the heteroaryl that the X is represented is first or 5- or 6-membered as 5-18 member, 5-14 member, 5-10 member, 5-8 member, 5-6 Heteroaryl.

Preferably, the heteroaryl that the X is represented as furyl, pyrrole radicals, thienyl, imidazole radicals, triazolyl, tetrazole radical, Pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl group, pyrazinyl, pyrimidine radicals, pyridazinyl, triazine radical, benzofuranyl, Isobenzofuran-base, indyl, isoindolyl, benzo [b] thienyl, benzo [c] thienyl, benzimidazolyl, purine radicals, Yin Oxazolyl, benzoxazolyl, benzo isoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolyl, benzopyrazines base, Benzo pyridazinyl or pyridopyridine base.

Preferably, the substituted heteroaryl that the X is represented is the heteroaryl that is replaced by least one substituent group, and the X is represented Substituted-amino be the amino replaced by least one substituent group, the substituted-amino formoxyl that the X is represented is by least one The carbamoyl that substituent group replaces, the substituted hydroxy that the X is represented are the hydroxyl that is replaced by least one substituent group.

Preferably, the substituent group of the heteroaryl be selected from following at least one: aryl, heteroaryl, 5- or 6- member naphthenic base, 5- or 6- membered heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, nitro, cyano, hydroxyl, halogen Element, amino, carboxyl, sulfonic group and aldehyde radical；

The C1-C4 alkyl is the linear chain or branched chain alkyl of saturation, has 1-4 carbon atom；

The C2-C4 alkenyl is the olefinic unsaturation linear chain or branched chain alkyl containing at least one carbon-carbon double bond, has 2-4 A carbon atom；

The C2-C4 alkynyl is the acetylene series unsaturation linear chain or branched chain alkyl containing at least one triple carbon-carbon bonds, has 2-4 A carbon atom；

The C1-C4 alkoxy is group-ORa, wherein Ra is the C1-C4 alkyl；

5- the or 6- member naphthenic base is the saturated cyclic hydrocarbon group with 5 or 6 carbon atoms；

5- the or 6- membered heterocycloalkyl is the heteroatomic 5- comprising one or more independently selected from N, O and S Or 6- member naphthenic base；

The halogen is fluorine, chlorine, bromine or iodine.

Preferably, in the general formula I or the general formula II, the heteroaryl that the Ar is represented is pyridyl group, pyrimidine radicals, pyridine And pyridyl group, imidazolylphenyl, imidazolyl pyridines base and benzopyrazines base.

Preferably, in the general formula I or the general formula II, the substituted heteroaryl that the Ar is represented is at least to be taken by one The pyridyl group or pyrimidine radicals replaced for base.

Preferably, the substituent group of the pyridyl group or pyrimidine radicals is selected from following at least one: aryl, heteroaryl, 5- or 6- First naphthenic base, 5- or 6- membered heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, nitro, cyanogen Base, hydroxyl, halogen, amino, carboxyl, sulfonic group and aldehyde radical；

The C1-C4 alkoxy is group-ORa, wherein Ra is the C1-C4 alkyl；

The halogen is fluorine, chlorine, bromine or iodine.

Preferably, in the general formula I or the general formula II, the substituted heteroaryl that the Ar is represented is 5- amino -3- pyrrole Piperidinyl, 5- carbamoyl -3- pyridyl group, 5- cyano -3- pyridyl group, 5- hydroxyl -3- pyridyl group, 5- methoxyl group -3- pyridyl group, 6- nitro -3- pyridyl group, 6- amino -3- pyridyl group, 6- hydroxyl -3- pyridyl group, 6- methoxyl group -3- pyridyl group, 2- amino -3- pyrrole Piperidinyl, 4- amino -3- pyridyl group, 5- amino -2- pyridyl group, 6- amino -2- pyridyl group, 2- amino -4- pyridyl group or 2- amino - 5- pyrimidine radicals.

Preferably, in the general formula I or the general formula II, the substituted heteroaryl that the Ar is represented is in following i~xx It is any:

Preferably, the inorganic acid is hydrochloric acid, sulfuric acid, hydrobromic acid or phosphoric acid；The organic acid is acetic acid, malonic acid, first Sulfonic acid, succinic acid, p-methyl benzenesulfonic acid, citric acid, maleic acid, fumaric acid, lactic acid, benzoic acid or malic acid.

The present invention also provides the preparation methods of the novel acyl lactone derivative described in one kind, and the method includes following steps It is rapid:

To there is step 1 compound such as general formula (1) to be dissolved in acetonitrile, and aryl bromide, cuprous iodide, bis- (triphenyls is added Phosphine) after palladium chloride and triethylamine react 4h at 80 DEG C, obtain the compound such as general formula (2).

Such as the compound of general formula (2) is dissolved in methylene chloride by step 2, and 2- pyridine acetic acid hydrochloride, dicyclohexyl carbon is added After diimine, 4-dimethylaminopyridine and pyridine react 1h at 0 DEG C, the reaction was continued at 15-25 DEG C 4-24h.

The reaction product of step 2 is dissolved in methanol by step 3, and the 3h that flows back at 65 DEG C is obtained with the chemical combination such as general formula (3) Object.

Preferably, in the general formula (2) and the general formula (3),

The group that the Ar in R and the general formula (3) in the general formula (2) is represented is pyridyl group, pyrimidine radicals, pyrido pyrrole Piperidinyl, imidazolylphenyl, imidazolyl pyridines base, benzopyrazines base, 5- amino -3- pyridyl group, 5- carbamoyl -3- pyridine Base, 5- cyano -3- pyridyl group, 5- methoxyl group -3- pyridyl group, 6- nitro -3- pyridyl group, 6- amino -3- pyridyl group, 6- methoxy Base -3- pyridyl group, 2- amino -3- pyridyl group, 4- amino -3- pyridyl group, 5- amino -2- pyridyl group, 6- amino -2- pyridyl group, 2- amino -4- pyridyl group, 2- amino-5-pyrimidine base or substituted 2- pyridine acetyl derivative on amino.

Preferably, step 1, such as the compound of general formula (1) is dissolved in methylene chloride, 2- pyridine acetic acid hydrochloride, two is added After carbodicyclo hexylimide, 4-dimethylaminopyridine and pyridine react 1h at 0 DEG C, the reaction was continued at 15-25 DEG C 4-24h Afterwards, the compound such as general formula (4) is obtained.

Such as the compound of general formula (4) is dissolved in acetonitrile by step 2, and aryl bromide, cuprous iodide, bis- (triphenylphosphines) two is added Palladium chloride and triethylamine react 4h at 80 DEG C.

Preferably, in the general formula (3), the group that the Ar in the general formula (3) is represented is pyridyl group, pyrimidine radicals, pyridine And pyridyl group, imidazolylphenyl, imidazolyl pyridines base, benzopyrazines base, 5- amino -3- pyridyl group, 5- carbamoyl -3- pyrrole Piperidinyl, 5- cyano -3- pyridyl group, 5- methoxyl group -3- pyridyl group, 6- nitro -3- pyridyl group, 6- amino -3- pyridyl group, 6- methoxy Base -3- pyridyl group, 2- amino -3- pyridyl group, 4- amino -3- pyridyl group, 5- amino -2- pyridyl group, 6- amino -2- pyridyl group, 2- amino -4- pyridyl group, 2- amino-5-pyrimidine base or substituted 2- pyridine acetyl derivative on amino.

Preferably, step 1, such as the compound of general formula (5) is dissolved in acetonitrile, aryl bromide, palladium acetate, three (adjacent methyl is added Phenyl) after phosphine and triethylamine react 1h at 60 DEG C, the compound obtained for 24 hours such as general formula (6) is placed at 90 DEG C.

Such as the compound of general formula (6) is dissolved in methylene chloride by step 2, and 2- pyridine acetic acid hydrochloride, dicyclohexyl carbon is added After diimine, 4-dimethylaminopyridine and pyridine, after reacting 1h at 0 DEG C, the 6-24h that is warming up at 15-25 DEG C that the reaction was continued.

The reaction product of step 2 is dissolved in methanol by step 3, and the 3h that flows back at 65 DEG C is obtained with the chemical combination such as general formula (7) Object.

Preferably, the Ar in R and the general formula (7) in the general formula (6) and the general formula (7), in the general formula (6) The group represented is pyridyl group, pyrimidine radicals, pyridopyridine base, imidazolylphenyl, imidazolyl pyridines base, benzopyrazines base, 5- Amino -3- pyridyl group, 5- carbamoyl -3- pyridyl group, 5-Cyano- 3- pyridyl group, 5- methoxyl group -3- pyridyl group, 6- nitro - 3- pyridyl group, 6- amino -3- pyridyl group, 6- methoxyl group -3- pyridyl group, 2- amino -3- pyridyl group, 4- amino -3- pyridyl group, 5- Amino -2- pyridyl group, 6- amino -2- pyridyl group, 2- amino -4- pyridyl group, 2- amino-5-pyrimidine base or on amino it is substituted 2- pyridine acetyl derivative.

Compared with prior art, the present invention includes the following advantages:

The present invention passes through test of many times and theoretical research, optimizes the new aryl on the position 9-, the general formula provided (I) or (II) compound has new structure, has antibacterial activity outstanding to clinical common sensitive bacteria and drug-fast bacteria, such as golden yellow Portugal Grape coccus, streptococcus pneumonia, streptococcus pyogenes, bloodthirsty Bacillus influenzae, moraxelle catarrhalis etc., can individually or as active constituent it One mixes the treatment with various dosage forms or administration route for infection such as bacteriums with other medicines.

Also, with it has been reported that the compound tool compared with Ar is 3- quinolyl or 4- isoquinolyl, in the present invention There is antibacterial activity outstanding.For example, to Quality-control strains-streptococcus pneumonia ATCC 49619 of antibacterial test, the change having disclosed The minimum inhibitory concentration for closing object (being equivalent to Ar=3- quinolyl and 4- isoquinolyl in general formula I and II) is all larger than equal to 1 μ g/ ML, and reference compound Ketek MIC is 0.016 μ g/mL；And maximum 0.125 μ of ability of compound MIC prepared by the present invention G/mL, MIC are the smallest to be less than or equal to test 0.008 μ g/mL of the lowest limit.

In addition, the present invention also has prominent effect in drug-fast bacteria comparison, good antimicrobial agent activity, part are shown The antibacterial and bactericidal activity of compound is equivalent to or better than Ketek.Compared with the ketone lactone-Ketek listed at present, In the present invention preferred compound (such as Ar=6- amino -3- pyridyl group, 6- nitro -3- pyridyl group, 5- amino -3- pyridyl group, Either 5- carbamoyl -3- pyridyl group) there is quite or more preferably antibacterial activity.In particular, the compound in the application It also shows " characteristics of germ killing drugs ", the ratio of minimum bactericidal concentration and minimum inhibitory concentration is less than or equal to 4.

The present invention breaks through existing acyl lactone structure-activity relationship knowledge, provides the novel non-ketone lactone with bactericidal activity, It is suitable with the activity of the Ketek of listing and easy to industrialized production.And studies have shown that acyl lactone acts on bacterium ribose The target spot of body is different from the action target spot of ketone lactone.In short, many deficiencies of middle ketone lactone, acyl lactone have compared with the prior art There are preferable antimicrobial agent market prospects.

Detailed description of the invention

Fig. 1 is a kind of flow chart of the preparation method embodiment 1 of novel acyl lactone derivative of the invention；

Fig. 2 is a kind of flow chart of the preparation method embodiment 2 of novel acyl lactone derivative of the invention；

Fig. 3 is a kind of flow chart of the preparation method embodiment 3 of novel acyl lactone derivative of the invention.

Specific embodiment

In order to make the foregoing objectives, features and advantages of the present invention clearer and more comprehensible, with reference to the accompanying drawing and specific real Applying mode, the present invention is described in further detail.

The present invention provides a kind of novel acyl lactone derivative, the novel acyl lactone derivative have the following general formula I or General formula II or the novel acyl lactone derivative are that the compound with the following general formula I or II is formed with inorganic acid or organic acid Acceptable salt or ester, the salt or ester under prodrug (prodrug) in vivo physiological condition as releasing shown in general formula structure Free alkali simultaneously plays pharmacological action as active constituent.

The present invention passes through test of many times and theoretical research, optimizes the new aryl on the position 9-, the general formula provided (I) or (II) compound has new structure, experiments verify that, there is antibacterial activity outstanding to clinical common sensitive bacteria and drug-fast bacteria, Such as staphylococcus aureus, streptococcus pneumonia, streptococcus pyogenes, bloodthirsty Bacillus influenzae, moraxelle catarrhalis, can be individually or as One of active constituent mixes the treatment with various dosage forms or administration route for infection such as bacteriums with other medicines.

Also, with it has been reported that compared with Ar is 3- quinolyl or 4- isoquinolyl, to sensitive bacteria and be clinically separated Drug-fast bacteria there is inhibitory activity outstanding, and report the bactericidal activity of this kind of compound for the first time on this basis, highlight Difference with traditional erythromycin as bacteriostatic agent.Therefore, the present invention changes the existing structure-activity relationship in this field significantly Understanding provides a kind of novel non-ketone lactone with bactericidal activity, and easy to industrialized production.It is excellent in the embodiment of the present invention Selection of land, for above-mentioned preferred general formula I and general formula II, the heteroaryl that the X is represented as it is one or more independently selected from O, S or The aryl of the hetero atom substitution of N, that is to say one or two of aryl or more carbon atom by one or more independences The hetero atom that ground is selected from O, S or N substitutes.

In the embodiment of the present invention, it is preferable that the aryl can be for 5-18,5-14,5-10,5-8,5- The aromatic carbocyclyl groups of 6 or 6 carbon atoms, it is further preferred that the aryl can be specially but be not limited to phenyl, naphthalene Or anthryl, wherein most preferred aryl is phenyl.

In the embodiment of the present invention, it is preferable that the heteroaryl that the X is represented is first as 5-18,5-14 member, 5-10 is first, 5-8 is first, 5-6 member or 5- or 6-membered heteroaryl.It is further preferred that the heteroaryl that the X is represented can be furyl, pyrrole radicals, thiophene Base, triazolyl, tetrazole radical, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl group, pyrazinyl, pyrimidine radicals, is rattled away at imidazole radicals Piperazine base, triazine radical, benzofuranyl, isobenzofuran-base, indyl, isoindolyl, benzo [b] thienyl, benzo [c] thiophene Base, benzimidazolyl, purine radicals, indazolyl, benzoxazolyl, benzo isoxazolyl, benzothiazolyl, quinolyl, isoquinolin Base, quinazolyl, benzopyrazines base, benzo pyridazinyl or pyridopyridine base.

In the embodiment of the present invention, it is preferable that the substituted heteroaryl that the X is represented is miscellaneous to be replaced by least one substituent group Aryl, the substituted-amino formoxyl that the X is represented are the carbamoyl that is replaced by least one substituent group, what the X was represented Substituted-amino is the amino replaced by least one substituent group, and the substituted hydroxy that the X is represented is is taken by least one substituent group The hydroxyl in generation.

In the present invention, substituent group is defined as: the substituent group of the heteroaryl is selected from following at least one: aryl (example Such as phenyl), heteroaryl such as furyl, pyrrole radicals, thienyl, imidazole radicals, triazolyl, tetrazole radical, pyridyl group, pyrimidine radicals, pyrrole Piperazine base, pyridazinyl, triazine radical, quinolyl, isoquinolyl, quinazolyl, indyl), 5- or 6- member naphthenic base, 5- or 6- member it is miscellaneous Naphthenic base, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, nitro, cyano, hydroxyl, halogen, amino, carboxylic Base, sulfonic group and aldehyde radical.

Wherein:

The C1-C4 alkoxy is group-ORa, wherein Ra is the C1-C4 alkyl；

The halogen is fluorine, chlorine, bromine or iodine.

In the embodiment of the present invention, it is preferable that in the general formula I or the general formula II, the substituted heteroaryl of the Ar representative Base can be 5- amino -3- pyridyl group, 5- carbamoyl -3- pyridyl group, 5- cyano -3- pyridyl group, 5- hydroxyl -3- pyridine Base, 5- methoxyl group -3- pyridyl group, 6- nitro -3- pyridyl group, 6- amino -3- pyridyl group, 6- hydroxyl -3- pyridyl group, 6- methoxy Base -3- pyridyl group, 2- amino -3- pyridyl group, 4- amino -3- pyridyl group, 5- amino -2- pyridyl group, 6- amino -2- pyridyl group, 2- amino -4- pyridyl group or 2- amino-5-pyrimidine base.

The present invention can be provided for the pharmaceutical composition of antibacterial therapy, and the composition may include antimicrobial effective amount With the compound of aforementioned formula or its pharmaceutically acceptable salt or ester and pharmaceutically acceptable carrier.

In the embodiment of the present invention, it is preferable that in the general formula I or the general formula II, the heteroaryl that the Ar is represented is pyrrole Piperidinyl, pyrimidine radicals, pyridopyridine base, imidazolylphenyl, imidazolyl pyridines base, benzopyrazines base.

In the embodiment of the present invention, it is preferable that in the general formula I or the general formula II, the substituted heteroaryl of the Ar representative Base is the pyridyl group or pyrimidine radicals at least replaced by a substituent group.

In the embodiment of the present invention, it is preferable that the substituent group of the pyridyl group or pyrimidine radicals is selected from following at least one: virtue Base, heteroaryl, 5- or 6- member naphthenic base, 5- or 6- membered heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 Alkoxy, nitro, cyano, hydroxyl, halogen, amino, carboxyl, sulfonic group and aldehyde radical；

The C1-C4 alkoxy is group-ORa, wherein Ra is the C1-C4 alkyl；

The halogen is fluorine, chlorine, bromine or iodine.

In the embodiment of the present invention, it is preferable that in the general formula I or the general formula II, the substituted heteroaryl of the Ar representative Base are as follows:

In the embodiment of the present invention, it is preferable that the inorganic acid is hydrochloric acid, sulfuric acid, hydrobromic acid or phosphoric acid；The organic acid is Acetic acid, malonic acid, methanesulfonic acid, succinic acid, p-methyl benzenesulfonic acid, citric acid, maleic acid, fumaric acid, lactic acid, benzoic acid or apple Acid.

It should be noted that the heteroaryl that the Ar is represented can be for except quinolyl in the general formula I or the general formula II With the sulfur atom-containing heteroaryl or nitrogen atom heteroaryl except isoquinolyl.

The present invention also provides a kind of preparation method of novel acyl lactone derivative, specific steps include:

To there is step 1 compound such as general formula (1) to be dissolved in acetonitrile, and aryl bromide, cuprous iodide, bis- (triphenyls is added Phosphine) after palladium chloride and triethylamine react 4h at 80 DEG C, obtain the compound such as general formula (2)；

Such as the compound of general formula (2) is dissolved in methylene chloride by step 2, and 2- pyridine acetic acid hydrochloride, dicyclohexyl carbon is added After diimine, 4-dimethylaminopyridine and pyridine react 1h at 0 DEG C, the reaction was continued at 15-25 DEG C 4-24h；

The reaction product of step 2 is dissolved in methanol by step 3, and the 3h that flows back at 65 DEG C is obtained with the chemical combination such as general formula (3) Object；

In the embodiment of the present invention, it is preferable that in the general formula (2) and the general formula (3),

In the embodiment of the present invention, it is preferable that such as the compound of general formula (1) is dissolved in methylene chloride by step 1, and 2- pyrrole is added After pyridine acetic acid hydrochloride, dicyclohexylcarbodiimide, 4-dimethylaminopyridine and pyridine react 1h at 0 DEG C, at 15-25 DEG C After the reaction was continued 4-24h, the compound such as general formula (4) is obtained；

Such as the compound of general formula (4) is dissolved in acetonitrile by step 2, and aryl bromide, cuprous iodide, bis- (triphenylphosphines) two is added Palladium chloride and triethylamine react 4h at 80 DEG C；

In the embodiment of the present invention, it is preferable that in the general formula (3), the group that the Ar in the general formula (3) is represented is pyridine Base, pyrimidine radicals, pyridopyridine base, imidazolylphenyl, imidazolyl pyridines base, benzopyrazines base, 5- amino -3- pyridyl group, 5- Carbamoyl -3- pyridyl group, 5- cyano -3- pyridyl group, 5- methoxyl group -3- pyridyl group, 6- nitro -3- pyridyl group, 6- amino - 3- pyridyl group, 6- methoxyl group -3- pyridyl group, 2- amino -3- pyridyl group, 4- amino -3- pyridyl group, 5- amino -2- pyridyl group, 6- Amino -2- pyridyl group, 2- amino -4- pyridyl group, 2- amino-5-pyrimidine base or substituted 2- pyridine acetylpyridine derivative on amino Object.

In the embodiment of the present invention, it is preferable that such as the compound of general formula (5) is dissolved in acetonitrile by step 1, and aryl bromide, vinegar is added It after sour palladium, three (o-methyl-phenyl) phosphines and triethylamine react 1h at 60 DEG C, places for 24 hours, is obtained such as general formula (6) at 90 DEG C Compound；

Such as the compound of general formula (6) is dissolved in methylene chloride by step 2, and 2- pyridine acetic acid hydrochloride, dicyclohexyl carbon is added After diimine, 4-dimethylaminopyridine and pyridine, after reacting 1h at 0 DEG C, the 6-24h that is warming up at 15-25 DEG C that the reaction was continued；

The reaction product of step 2 is dissolved in methanol by step 3, and the 3h that flows back at 65 DEG C is obtained with the chemical combination such as general formula (7) Object；

In the embodiment of the present invention, it is preferable that in the general formula (6) and the general formula (7),

The group that the Ar in R and the general formula (7) in the general formula (6) is represented is pyridyl group, pyrimidine radicals, pyrido pyrrole Piperidinyl, imidazolylphenyl, imidazolyl pyridines base, benzopyrazines base, 5- amino -3- pyridyl group, 5- carbamoyl -3- pyridine Base, 5- cyano -3- pyridyl group, 5- methoxyl group -3- pyridyl group, 6- nitro -3- pyridyl group, 6- amino -3- pyridyl group, 6- methoxy Base -3- pyridyl group, 2- amino -3- pyridyl group, 4- amino -3- pyridyl group, 5- amino -2- pyridyl group, 6- amino -2- pyridyl group, 2- amino -4- pyridyl group, 2- amino-5-pyrimidine base or substituted 2- pyridine acetyl derivative on amino.

The present invention can be provided for the pharmaceutical composition of antibacterial therapy, and the composition may include antimicrobial effective amount With the compound of aforementioned formula or its pharmaceutically acceptable salt or ester and pharmaceutically acceptable carrier.The present invention It further include the prodrug of the compounds of this invention, though in human body metabolism or it is converted to certain undocumented structure administration Compound disclosed in the present invention, and pharmacological action is played as effective component.For the present invention, various medicinal acceptable acid Forming salt or ester can be formed on 2'-OH in 3'- tertiary amino on 5-O- desosamine.The preparation conventional method of prodrug is shown in 《Design of Prodrugs》(H.Bundgaad,Elsevier,1985)。

Correspondingly, the present invention also provides the preparation methods to above-mentioned novel acyl lactone derivative, referring specifically to following realities Apply example.

With reference to Fig. 1, a kind of flow chart of the preparation method embodiment 1 of novel acyl lactone derivative of the invention is shown, It can specifically include following steps:

To there is step 101 compound such as general formula (1) to be dissolved in acetonitrile, and aryl bromide, cuprous iodide, bis- (triphenyls is added Phosphine) after palladium chloride and triethylamine react 4h at 80 DEG C, obtain the compound such as general formula (2)；

Such as the compound of general formula (2) is dissolved in methylene chloride by step 102, and 2- pyridine acetic acid hydrochloride, dicyclohexyl is added After carbodiimide, 4-dimethylaminopyridine and pyridine react 1h at 0 DEG C, the reaction was continued at 15-25 DEG C 4-24h；

The reaction product of step 102 is dissolved in methanol by step 103, and the 3h that flows back at 65 DEG C obtains having such as general formula (3) Compound；

The corresponding reaction equation of above-mentioned reaction is as follows, wherein a, b and c respectively correspond step 101,102 and 103.

Wherein, if general formula (1) compound represented is known substance, preparation method is shown in document Liang J.H. etc. .Bioorg.Med.Chem.Lett.2013,23,1387-1393, details are not described herein again.

Preferably, R can be pyridyl group, substituted pyridinyl, pyrimidine radicals, substituted pyrimidyl, pyrido in the general formula (2) Pyridyl group, imidazolylphenyl, imidazolyl pyridines base or benzopyrazines base, specific correspondence are as follows:

Preferably, Ar can be pyridyl group, substituted pyridinyl, pyrimidine radicals, substituted pyrimidyl, pyridine in the general formula (3) And pyridyl group, imidazolylphenyl, imidazolyl pyridines base or benzopyrazines base, specific correspondence are as follows:

With reference to Fig. 2, a kind of flow chart of the preparation method embodiment 2 of novel acyl lactone derivative of the invention is shown, It can specifically include following steps:

Such as the compound of general formula (1) is dissolved in methylene chloride by step 201, and 2- pyridine acetic acid hydrochloride, dicyclohexyl is added After carbodiimide, 4-dimethylaminopyridine and pyridine react 1h at 0 DEG C, after the reaction was continued at 15-25 DEG C 4-24h, obtain Such as the compound of general formula (4)；

Such as the compound of general formula (4) is dissolved in acetonitrile by step 202, and aryl bromide, cuprous iodide, bis- (triphenylphosphines) is added Palladium chloride and triethylamine react 4h at 80 DEG C；

The reaction product of step 202 is dissolved in methanol by step 203, and the 3h that flows back at 65 DEG C obtains having such as general formula (3) Compound；

The corresponding reaction equation of above-mentioned reaction is as follows, wherein a, b and c respectively correspond step 201,202 and 203.

Wherein, compound shown in general formula (1) is identical as the compound of Fig. 1 embodiment.Preferably, Ar in the general formula (3) It can be pyridyl group, substituted pyridinyl, pyrimidine radicals, substituted pyrimidyl, pyridopyridine base, imidazolylphenyl, imidazolyl pyridines Base or benzopyrazines base, specific correspondence are as follows:

With reference to Fig. 3, a kind of flow chart of the preparation method embodiment 3 of novel acyl lactone derivative of the invention is shown, It can specifically include following steps:

Such as the compound of general formula (5) is dissolved in acetonitrile by step 301, and aryl bromide, palladium acetate, three (o-methyl-phenyls) is added After phosphine and triethylamine react 1h at 60 DEG C, the compound obtained for 24 hours such as general formula (6) is placed at 90 DEG C；

Such as the compound of general formula (6) is dissolved in methylene chloride by step 302, and 2- pyridine acetic acid hydrochloride, dicyclohexyl is added After carbodiimide, 4-dimethylaminopyridine and pyridine, after reacting 1h at 0 DEG C, the 6-24h that is warming up at 15-25 DEG C that the reaction was continued；

The reaction product of step 302 is dissolved in methanol by step 303, and the 3h that flows back at 65 DEG C obtains having such as general formula (7) Compound；

The corresponding reaction equation of above-mentioned reaction is as follows, wherein a, b and c respectively correspond step 301,302 and 303.

Wherein, if general formula (5) compound represented is known substance, preparation method is shown in document LiangJ.H. etc. .Bioorg.Med.Chem.Lett.2013,23,1387-1393, details are not described herein again.

Preferably, R can be pyridyl group, substituted pyridinyl, pyrimidine radicals, substituted pyrimidyl, pyrido in the general formula (6) Pyridyl group, imidazolylphenyl, imidazolyl pyridines base or benzopyrazines base, specific correspondence are as follows:

Preferably, Ar can be pyridyl group, substituted pyridinyl, pyrimidine radicals, substituted pyrimidyl, pyridine in the general formula (7) And pyridyl group, imidazolylphenyl, imidazolyl pyridines base or benzopyrazines base, specific correspondence are as follows:

In order to enable those skilled in the art to better understand the present invention, illustrate the present invention below by way of multiple specific examples In novel acyl lactone derivative preparation method.

Example 1:

It prepares first: 2'-O- acetyl group -3-O- descladinosylation -3- hydroxyl -6-O-methylerythromycin A9-O- [3- (3'- (6'- nitro) pyridyl group) -2-propynyl] oxime -11,12- cyclic carbonate ester (2a)

1.00g (1.41mmol) compound 1 is dissolved in acetonitrile (10mL), bis- (triphenylphosphine) palladium chlorides are added (51mg, 0.073mmol), cuprous iodide (27mg, 0.014mmol), triethylamine (0.30mL, 2.11mmol), 2- nitro -5- bromine Pyridine (865mg, 4.26mmol).Reaction system is replaced 8 times with argon gas, under protection of argon gas, stirs 4h in 80 DEG C of oil baths.Reaction After be added distilled water (10mL) terminate reaction, be extracted twice with ethyl acetate (20mL), upper organic phase saturated common salt Water (10mL) washing, vacuum distillation obtain dry solids.(100-200 mesh silica gel, mobile phase V (dichloromethane are chromatographed through column Alkane): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) obtain compound 2a (248mg, 0.30mmol, 21.3%).

Secondly it prepares: 3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A 9-O- [3- (3'- (6'- nitro) pyridyl group) -2-propynyl] oxime -11,12- cyclic carbonate ester (3a)

248mg (0.30mmol) compound 2a is dissolved in methylene chloride (20mL), 2- pyridine second is added with stirring in 0 DEG C Acid hydrochloride (135mg, 0.78mmol), dicyclohexylcarbodiimide (DCC) (155mg, 0.75mmol), 4-dimethylaminopyridine (DMAP) pyridine (0.10mL, 1.19mmol) is slowly added dropwise in (93mg, 0.76mmol).After stirring 1h, ice-water bath is removed, 15 4h is reacted at DEG C.Decompression, which filters, after reaction removes dicyclohexylurea (DCU), is washed with saturated sodium bicarbonate solution (25mL), lower layer Organic phase is washed twice with saturated ammonium chloride solution (25mL) respectively, and saturated sodium bicarbonate solution (25mL) washed once, distillation Water (25mL) washed once, and saturated salt solution (25mL) washed once, and be evaporated under reduced pressure later, and drying can obtain solids.Through column layer It analyses (100-200 mesh silica gel, mobile phase V (methylene chloride): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) and obtains 2'-OAc-3a (163mg, 0.17mmol, 57.6%).

163mg (0.17mmol) 2'-OAc-3a is dissolved in methanol (20mL), 65 DEG C of reflux 3h, vacuum distillation concentration obtains To dry product.Plate (mobile phase V (petroleum ether): V (acetone): V (triethylamine)=5:5:0.2) is prepared through thin-layer chromatography silica gel It obtains 3a sterling (49mg, 0.054mmol, 31.8%).

HRMS(ESI)(M+H)+m/z 910.44474,calcd for C46H64N5O14910.44443.1H NMR (CDCl3,500MHz) δ:

8.63 (d, J=1.5Hz, 1H, 3'- (6'-nitro) Pyridyl), 8.52-8.51 (m, 1H, 2'-Pyridyl), 8.22 (d, J=8.5Hz, 1H, 3'- (6'-nitro) Pyridyl), 8.06 (dd, J1=6.5Hz, J2=2.0Hz, 1H, 3'- (6'-nitro) Pyridyl), 7.69-7.66 (m, 1H, 2'-Pyridyl), 7.35 (d, J=8.0Hz, 1H, 2'-Pyridyl), 7.22-7.21 (m, 1H, 2'-Pyridyl), 5.13 (dd, J1=10.5Hz, J2=2.0Hz, 1H, H-13), 5.06 (d, J= 11.0Hz, 1H, H-3), 4.92 (d, 1H, J=16.0Hz, 9-O-CH2CH ≡ CH-Ar), 4.88 (s, 1H, H-11), 4.88 (d, 1H, J=16.0Hz, 9-O-CH2CH ≡ CH-Ar), 4.04 (d, J=7.0Hz, 1H, H-1'), 3.96 (d, J=16.5Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.91 (d, J=16.5Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.74 (d, J= 3.5Hz, 1H, H-5), 3.74-3.70 (m, 1H, H-8), 3.37-3.33 (m, 1H, H-5'), 3.20 (dd, J1=10.0Hz, J2 =7.5Hz, 1H, H-2'), 3.02 (s, 3H, 6-OCH3), 2.88-2.84 (m, 1H, H-2), 2.72-2.65 (m, 1H, H-3'), 2.52 (q, J=7.0Hz, 1H, H-10), 2.34 (s, 6H ,-N (CH3) 2), 2.08-2.06 (m, 1H, H-4), 1.92-1.89 (m, 1H,H-14eq),1.68-1.65(m,1H,H-4'eq),1.59-1.54(m,1H,H-14ax),1.49(s,3H,12-CH3), 1.48-1.45(m,1H,H-7a),1.36(s,3H,6-CH3),1.33-1.28(m,1H,H-7b),1.26(d,3H,10-CH3), 1.23-1.21 (m, 1H, H-4'ax), 1.15 (d, J=6.0Hz, 3H, 5'-CH3), 1.08-1.03 (m, 6H, 4-CH3,8- CH3), 0.97 (d, J=7.0Hz, 3H, 2-CH3), 0.86 (t, J=7.5Hz, 3H, 15-CH3) .13C NMR (CDCl3, 125MHz)δ:173.9,170.3,166.4,154.9,154.6,153.9,151.1,149.2,142.3,136.5,126.2, 124.2,122.3,117.6103.5,94.9,84.9,82.8,81.3,80.7,78.5,78.3,75.5,70.5,69.2, 65.6,61.5,49.9,43.7,43.1,40.3,37.2,36.6,33.0,28.8,26.0,22.0,21.0,19.4,18.8, 15.5,15.1,12.9,10.0,8.8.

Hydrogen spectrum and carbon spectrum combine high resolution mass spectrum to determine that compound 3a that is synthesized and purifying is following structural formula:

Example 2:

It prepares first: 2'-O- acetyl group -3-O- descladinosylation -3- hydroxyl -6-O-methylerythromycin A9-O- [3- (2'- (6'- amino) pyridyl group) -2-propynyl] oxime -11,12- cyclic carbonate ester (2b)

1.00g (1.41mmol) compound 1 is dissolved in acetonitrile (10mL), bis- (triphenylphosphine) palladium chlorides are added (51mg, 0.073mmol), cuprous iodide (27mg, 0.014mmol), triethylamine (0.30mL, 2.11mmol), 2- amino -6- bromine Pyridine (731mg, 4.22mmol).Reaction system is replaced 8 times with argon gas, under protection of argon gas, stirs 4h in 80 DEG C of oil baths.Reaction After be added distilled water (10mL) terminate reaction, be extracted twice with ethyl acetate (20mL), upper organic phase saturated common salt Water (10mL) washing, vacuum distillation obtain dry solids.(100-200 mesh silica gel, mobile phase V (dichloromethane are chromatographed through column Alkane): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) obtain compound 2b (291mg, 0.36mmol, 25.5%).

Secondly it prepares: 3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A 9-O- { 3- [2'- (6'-N- (2 "-pyridine acetyl group) amino) pyridyl group] -2-propynyl } oxime -11,12- cyclic carbonate ester (3b)

291mg (0.36mmol) compound 2b is dissolved in methylene chloride (20mL), 2- pyridine second is added with stirring in 0 DEG C Pyrrole is slowly added dropwise in acid hydrochloride (157mg, 0.90mmol), DCC (187mg, 0.91mmol), DMAP (115mg, 0.90mmol) Pyridine (0.12mL, 1.45mmol).After stirring 1h, ice-water bath is removed, reacts 6h at 25 DEG C.Decompression, which filters, after reaction removes Dicyclohexylurea (DCU) is washed with saturated sodium bicarbonate solution (25mL), and lower layer's organic phase uses saturated ammonium chloride solution (25mL) respectively It washes twice, saturated sodium bicarbonate solution (25mL) washed once, and distilled water (25mL) washed once, saturated salt solution (25mL) It washed once, be evaporated under reduced pressure later, drying can obtain solids.(100-200 mesh silica gel, mobile phase V (dichloromethane are chromatographed through column Alkane): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) obtain 2'-OAc-3b (223mg, 0.21mmol, 59.5%).

223mg (0.21mmol) 2'-OAc-3b is dissolved in methanol (20mL), 65 DEG C of reflux 3h, vacuum distillation concentration obtains To dry product.Through thin-layer chromatography silica gel prepare plate (mobile phase V (petroleum ether): V (acetone): V (triethylamine)=5:20: 0.2) 3b sterling (64mg, 0.064mmol, 30.5%) is obtained.

HRMS(ESI)(M+H)+m/z 999.50615,calcd for C53H71N6O13999.50736.1H NMR (CDCl3,500MHz), δ:

9.75(s,1H,-NH-),8.67-8.66(m,1H,2'-Pyridyl),8.52-8.51(m,1H,2”- Pyridyl), 8.17 (d, J=8.0Hz, 1H, 2'- (6'-amino) Pyridyl), 7.69-7.65 (m, 2H, 2'-Pyridyl, 2'- (6'-amino) Pyridyl), the 7.63-7.60 (- Pyridyl of m, 1H, 2 "), 7.35 (d, J=8.0Hz, 1H, 2'- ), Pyridyl the 7.28 (- Pyridyl of d, J=8.0Hz, 1H, 2 "), 7.24-7.17 (m, 2H, 2'-Pyridyl, 2 "- ), Pyridyl 7.15 (d, J=8.0Hz, 1H, 2'- (6'-amino) Pyridyl), 5.15 (dd, J1=2.5Hz, J2= 11.0Hz, 1H, H-13), 5.08 (d, J=11.0Hz, 1H, H-3), 4.92 (d, 1H, J=15.5Hz, 9-O-CH2C ≡ C-Ar), 4.90 (s, 1H, H-11), 4.84 (d, J=15.5Hz, 1H, 9-O-CH2C ≡ C-Ar), 4.03 (d, J=7.5Hz, 1H, H-1'), 3.96 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.91 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2- ), COO- 3.89 (s, 2H, 2'-Pyridyl-CH2-CONH-), 3.78-3.74 (m, 1H, H-8), 3.73 (d, J=3.0Hz, 1H, H-5),3.34-3.31(m,1H,H-5'),3.23-3.18(m,1H,H-2'),3.04(s,3H,6-OCH3),2.89-2.82(m, 1H, H-2), 2.68-2.64 (m, 1H, H-3'), 2.51 (q, J=7.0Hz, 1H, H-10), 2.33 (s, 6H ,-N (CH3) 2), 2.12-2.08(m,1H,H-4),1.94-1.87(m,1H,H-14eq),1.66-1.64(m,1H,H-4'eq),1.59-1.52 (m,1H,H-14ax),1.49(s,3H,12-CH3),1.46-1.43(m,1H,H-7a),1.36(s,3H,6-CH3),1.34- 1.31 (m, 1H, H-7b), 1.25 (d, J=14.5Hz, 3H, 10-CH3), 1.14 (d, J=6.0Hz, 3H, 5'-CH3), 1.07 (d, J=7.5Hz, 3H, 4-CH3), 1.04 (d, J=7.0Hz, 3H, 8-CH3), 0.96 (d, J=7.0Hz, 3H, 2-CH3), 0.85 (t, J=7.5Hz, 3H, 15-CH3) .13C NMR (CDCl3,125MHz) δ: 173.8,170.3,168.0,166.1, 154.6,154.5,153.9,151.3149.6,149.2,140.9,138.3,137.1,136.5,124.2,123.9,123.2, 122.3,122.2,113.8,103.6,85.8,84.9,84.6,82.9,81.6,78.5,78.4,75.6,70.5,69.2, 65.6,61.8,49.9,46.3,43.8,43.2,40.3,37.2,36.6,32.9,28.8,26.0,22.1,21.0,19.4, 18.8,15.5,15.1,12.9,10.0,8.8.

Example 3:

It prepares first: 2'-O- acetyl group -3-O- descladinosylation -3- hydroxyl -6-O-methylerythromycin A9-O- [3- (3'- (5'- amino) pyridyl group) -2-propynyl] oxime -11,12- cyclic carbonate ester (2c)

1.00g (1.41mmol) compound 1 is dissolved in acetonitrile (10mL), bis- (triphenylphosphine) palladium chlorides are added (51mg, 0.073mmol), cuprous iodide (27mg, 0.014mmol), triethylamine (0.30mL, 2.11mmol), 3- amino -5- bromine Pyridine (735mg, 4.25mmol).Reaction system is replaced 8 times with argon gas, under protection of argon gas, stirs 4h in 80 DEG C of oil baths.Reaction After be added distilled water (10mL) terminate reaction, be extracted twice with ethyl acetate (20mL), upper organic phase saturated common salt Water (10mL) washing, vacuum distillation obtain dry solids.(100-200 mesh silica gel, mobile phase V (dichloromethane are chromatographed through column Alkane): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) obtain compound 2c (186mg, 0.23mmol, 16.4%).

Secondly it prepares: 3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A 9-O- { 3- [3'- (5'-N- (2 "-pyridine acetyl group) amino) pyridyl group] -2-propynyl } oxime -11,12- cyclic carbonate ester (3c).

186mg (0.23mmol) compound 2c is dissolved in methylene chloride (20mL), 2- pyridine second is added with stirring in 0 DEG C Pyridine is slowly added dropwise in acid hydrochloride (104mg, 0.60mmol), DCC (123mg, 0.60mmol), DMAP (73mg, 0.60mmol) (0.08mL, 0.93mmol).After stirring 1h, ice-water bath is removed, reacts 12h at 20 DEG C.Decompression, which filters, after reaction removes Dicyclohexylurea (DCU) is washed with saturated sodium bicarbonate solution (25mL), and lower layer's organic phase uses saturated ammonium chloride solution (25mL) respectively It washes twice, saturated sodium bicarbonate solution (25mL) washed once, and distilled water (25mL) washed once, saturated salt solution (25mL) It washed once, be evaporated under reduced pressure later, drying can obtain solids.(100-200 mesh silica gel, mobile phase V (dichloromethane are chromatographed through column Alkane): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) obtain 2'-OAc-3c (113mg, 0.108mmol, 47.0%).

113mg (0.108mmol) 2'-OAc-3c is dissolved in methanol (20mL), 65 DEG C of reflux 3h, vacuum distillation concentration, Obtain dry product.Through thin-layer chromatography silica gel prepare plate (mobile phase V (petroleum ether): V (acetone): V (triethylamine)=5:20: 0.2) 3c sterling (37mg, 0.036mmol, 33.3%) is obtained.

HRMS(ESI)(M+H)+m/z 999.50665,calcd for C53H71N6O13999.50736.1H NMR (CDCl3,500MHz) δ:

10.31 (s, 1H ,-NH-), 8.72 (d, J=2.5Hz, 1H, 3'- (5'-amino) Pyridyl), 8.63 (d, J= 4.0Hz, 1H, 2'-Pyridyl), the 8.52 (- Pyridyl of d, J=4.0Hz, 1H, 2 "), 7.69-7.66 (m, 1H, 2'- ), Pyridyl 8.36 (d, J=1.0Hz, 1H, 3'- (5'-amino) Pyridyl), 8.09 (t, J=2.0Hz, 1H, 3'- (5'- Amino) Pyridyl), the 7.73-7.66 (- Pyridyl of m, 2H, 2'-Pyridyl, 2 "), 7.36 (d, J=8.0Hz, 1H, 2'- ), Pyridyl the 7.30 (- Pyridyl of d, J=8.0Hz, 1H, 2 ")), 7.27-7.25 (m, 1H, 2'-Pyridyl), 7.22-7.21 (- the Pyridyl of m, 1H, 2 "), 5.16 (dd, J1=10.5Hz, J2=2.0Hz, 1H, H-13), 5.08 (d, J=11.0Hz, 1H, ), H-3 4.90 (s, 1H, H-11), 4.90 (d, J=16.0Hz, 1H, 9-O-CH2C ≡ C-Ar), 4.81 (d, J=16.0Hz, 1H, 9-O-CH2C ≡ C-Ar), 4.04 (d, J=7.5Hz, 1H, H-1'), 3.96 (d, J=16.5Hz, 1H, 2'-Pyridyl-CH2- ), COO- 3.91 (d, J=16.5Hz, 1H, 2'-Pyridyl-CH2-COO-), the 3.91 (- Pyridyl-CH2- of s, 2H, 2 " ), CONH- 3.77-3.74 (m, 1H, H-8), 3.74 (d, J=3.0Hz, 1H, H-5), 3.34-3.32 (m, 1H, H-5'), 3.20 (dd, J1=10.0Hz, J2=7.0Hz, 1H, H-2'), 3.03 (s, 3H, 6-OCH3), 2.89-2.84 (m, 1H, H-2), 2.69- 2.66 (m, 1H, H-3'), 2.51 (q, J=7.0Hz, 1H, H-10), 2.33 (s, 6H ,-N (CH3) 2), 2.10-2.07 (m, 1H, H-4),1.92-1.88(m,1H,H-14eq),1.66-1.64(m,1H,H-4'eq),1.59-1.52(m,1H,H-14ax), 1.49(s,3H,12-CH3),1.47-1.44(m,1H,H-7a),1.37(s,3H,6-CH3),1.34-1.31(m,1H,H-7b), 1.25 (d, J=6.5Hz, 3H, 10-CH3), 1.15 (d, J=6.5Hz, 3H, 5'-CH3), 1.06 (d, J=7.5Hz, 3H, 4- ), CH3 1.04 (d, J=7.0Hz, 3H, 8-CH3), 0.96 (d, J=7.0Hz, 3H, 2-CH3), 0.85 (t, J=7.5Hz, 3H, 15-CH3).13C NMR(CDCl3,125MHz)δ:173.8,170.2,167.5,166.1,154.8,154.6,153.9, 149.2,148.9,147.3,140.4,137.5,136.5,134.4,129.2,124.3,124.2,122.4,122.2, 119.9,103.6,89.2,84.9,82.9,82.3,81.5,78.5,78.4,75.5,70.5,69.2,65.6,61.8,49.8, 45.2,43.8,43.2,40.3,37.2,36.6,32.9,28.8,26.0,22.1,21.0,19.4,18.8,15.5,15.1, 12.9,10.0,8.8.

Example 4:

It prepares first: 2'-O- acetyl group -3-O- descladinosylation -3- hydroxyl -6-O-methylerythromycin A9-O- [3- (3'- (6'- amino) pyridyl group) -2-propynyl] oxime -11,12- cyclic carbonate ester (2d)

1.00g (1.41mmol) compound 1 is dissolved in acetonitrile (10mL), bis- (triphenylphosphine) palladium chlorides are added (51mg, 0.073mmol), cuprous iodide (27mg, 0.014mmol), triethylamine (0.30mL, 2.11mmol), 2- amino -5- bromine Pyridine (731mg, 4.22mmol).Reaction system is replaced 8 times with argon gas, under protection of argon gas, stirs 4h in 80 DEG C of oil baths.Reaction After be added distilled water (10mL) terminate reaction, be extracted twice with ethyl acetate (20mL), upper organic phase saturated common salt Water (10mL) washing, vacuum distillation obtain dry solids.(100-200 mesh silica gel, mobile phase V (dichloromethane are chromatographed through column Alkane): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) obtain compound 2d (155mg, 0.19mmol, 13.5%)

Secondly it prepares: 3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A 9-O- { 3- [3'- (6'-N- (2 "-pyridine acetyl group) amino) pyridyl group] -2-propynyl } oxime -11,12- cyclic carbonate ester (3d)

378mg (0.47mmol) compound 2d is dissolved in methylene chloride (20mL), 2- pyridine second is added with stirring in 0 DEG C Pyrrole is slowly added dropwise in acid hydrochloride (208mg, 1.20mmol), DMAP (144mg, 1.18mmol), DCC (246mg, 1.19mmol) Pyridine (0.15mL, 1.85mmol).After stirring 1h, ice-water bath is removed, is reacted for 24 hours at 25 DEG C.Decompression is filtered and is removed after reaction Dicyclohexylurea (DCU) is removed, is washed with saturated sodium bicarbonate solution (25mL), lower layer's organic phase uses saturated ammonium chloride solution respectively (25mL) is washed twice, and saturated sodium bicarbonate solution (25mL) washed once, and distilled water (25mL) washed once, saturated salt solution (25mL) washed once, and be evaporated under reduced pressure later, and drying can obtain solids.(100-200 mesh silica gel, mobile phase V (two are chromatographed through column Chloromethanes): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) obtain 2'-OAc-3d (276mg, 0.26mmol, 55.3%).

276mg (0.26mmol) 2'-OAc-3d is dissolved in methanol (20mL), 65 DEG C of reflux 3h, vacuum distillation concentration obtains To dry product.Through thin-layer chromatography silica gel prepare plate (mobile phase V (petroleum ether): V (acetone): V (triethylamine)=5:20: 0.2) 3d sterling (29mg, 0.029mmol, 11.2%) is obtained.

HRMS(ESI)(M+H)+m/z 999.50880,calcd for C53H71N6O13999.50736.1H NMR (CDCl3,500MHz), δ:

10.20 (s, 1H ,-NH-), 8.68 (d, J=4.5Hz, 1H, 2'-Pyridyl), 8.52 (d, J=4.5Hz, 1H, 2 "-Pyridyl), 8.34 (d, J=2.0Hz, 1H, 3'- (6'-amino) Pyridyl), 8.16 (d, J=8.5Hz, 1H, 3'- (6'-amino)Pyridyl),7.71-7.66(m,3H,2'-Pyridyl,2”-Pyridyl,3'-(6'-amino) ), Pyridyl 7.35 (d, J=7.5Hz, 1H, 2'-Pyridyl), the 7.29 (- Pyridyl of d, J=8.0Hz, 1H, 2 "), 7.25- The 7.20 (- Pyridyl of m, 2H, 2'-Pyridyl, 2 "), 5.14 (dd, J1=10.5Hz, J2=2.0Hz, 1H, H-13), 5.07 (d, J=11.0Hz, 1H, H-3), 4.90 (d, J=16.0Hz, 2H, 9-O-CH2C ≡ C-Ar), 4.88 (s, 1H, H-11), 4.81 (d, J=16.0Hz, 2H, 9-O-CH2C ≡ C-Ar), 4.04 (d, J=7.0Hz, 1H, H-1'), 3.96 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.91 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.90 (s, 2H, 2 "- Pyridyl-CH2-CONH-), 3.77-3.73 (m, 1H, H-8), 3.74 (d, J=3.5Hz, 1H, H-5), 3.36-3.32 (m, 1H, H-5'), 3.22 (dd, J1=7.5Hz, J2=10.0Hz, 1H, H-2'), 3.02 (s, 3H, 6-OCH3), 2.88-2.81 (m, 1H, H-2), 2.78-2.69 (m, 1H, H-3'), 2.50 (q, J=7.0Hz, 1H, H-10), 2.37 (s, 6H ,-N (CH3) 2), 2.10-2.07(m,1H,H-4),1.93-1.89(m,1H,H-14eq),1.71-1.68(m,1H,H-4'eq),1.58-1.52 (m,1H,H-14ax),1.48(s,3H,12-CH3),1.45-1.42(m,1H,H-7a),1.36(s,3H,6-CH3),1.33- 1.30 (m, 1H, H-7b), 1.23 (d, J=5.0Hz, 3H, 10-CH3), 1.15 (d, J=6.5Hz, 3H, 5'-CH3), 1.06 (d, J=8.0Hz, 3H, 4-CH3), 1.03 (d, J=6.5Hz, 3H, 8-CH3), 0.95 (d, J=7.0Hz, 3H, 2-CH3), 0.85 (t, J=7.5Hz, 3H, 15-CH3) .13C NMR (CDCl3,125MHz) δ: 173.8,170.3,167.6,166.0,154.6, 154.6,153.9,150.8,150.5,149.4,149.2,141.0,137.3,136.6,124.3,124.1,122.3, 122.3,115.6,113.2,103.5,88.0,84.9,82.9,82.5,81.6,78.5,75.6,70.5,69.2,65.6, 61.9,49.9,46.0,43.8,43.2,40.3,37.2,36.6,33.0,26.0,22.1,21.0,19.4,18.8,15.5, 15.1,13.0,10.1,8.8.

Example 5:

Preparation: 3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A9-O- [3- (3'- (6'- amino) pyridyl group) -2-propynyl] oxime -11,12- cyclic carbonate ester (3e)

155mg (0.19mmol) compound 2d is dissolved in methylene chloride (20mL), 2- pyridine second is added with stirring in 0 DEG C Pyridine is slowly added dropwise in acid hydrochloride (87mg, 0.50mmol), DCC (100mg, 0.48mmol), DMAP (64mg, 0.52mmol) (0.06mL, 0.77mmol).After stirring 1h, ice-water bath is removed, reacts 5h at 20 DEG C.Decompression, which filters, after reaction removes two Cyclohexyl urea is washed with saturated sodium bicarbonate solution (25mL), and lower layer's organic phase is washed with saturated ammonium chloride solution (25mL) respectively It washs twice, saturated sodium bicarbonate solution (25mL) washed once, and distilled water (25mL) washed once, and saturated salt solution (25mL) is washed It washs once, is evaporated under reduced pressure later, drying can obtain solids.Through column chromatography (100-200 mesh silica gel, mobile phase V (methylene chloride): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) obtain 2'-OAc-3e (78mg, 0.084mmol, 44.2%).

78mg (0.084mmol) 2'-OAc-3e is dissolved in methanol (20mL), 65 DEG C of reflux 3h, vacuum distillation concentration obtains To dry product.Through thin-layer chromatography silica gel prepare plate (mobile phase V (petroleum ether): V (acetone): V (triethylamine)=5:20: 0.2) 3e sterling (10mg, 0.011mmol, 13.1%) is obtained.

HRMS(ESI)(M+H)+m/z 880.47048,calcd for C46H66N5O12880.47025.1H NMR (CDCl3,500MHz), δ:

8.53 (d, J=4.0Hz, 1H, 2'-Pyridyl), 8.16 (d, J=1.5Hz, 1H, 3'- (6'-amino) ), Pyridyl 7.68 (dt, J1=1.5Hz, J2=7.5Hz, 1H, 2'-Pyridyl), 7.46 (dd, J1=8.5Hz, J2= 2.5Hz, 1H, 3'- (6'-amino) Pyridyl), 7.35 (d, J=8.0Hz, 1H, 2'-Pyridyl), 7.23-7.20 (m, 1H, 2'-Pyridyl), 6.42 (d, J=8.5Hz, 1H, 3'- (6'-amino) Pyridyl), 5.15 (dd, J1=10.5Hz, J2= 2.0Hz, 1H, H-13), 5.07 (d, J=11.0Hz, 1H, H-3), 4.89 (s, 1H, H-11), 4.88 (d, J=15.5Hz, 1H, 9-O-CH2C ≡ C-Ar), 4.80 (d, J=16.0Hz, 1H, 9-O-CH2C ≡ C-Ar), 4.58 (s, 2H ,-NH2), 4.05 (d, J =7.5Hz, 1H, H-1'), 3.97 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.91 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.76-3.70 (m, 1H, H-8), 3.74 (d, J=3.5Hz, 1H, H-5), 3.35-3.33 (m, 1H, H-5'), 3.24 (dd, J1=8.0Hz, J2=9.5Hz, 1H, H-2'), 3.02 (s, 3H, 6-OCH3), 2.86-2.81 (m, 2H, H-2, H-3'), 2.50 (q, J=7.0Hz, 1H, H-10), 2.41 (s, 6H ,-N (CH3) 2), 2.10-2.08 (m, 1H, H-4),1.92-1.89(m,1H,H-14eq),1.75-1.72(m,1H,H-4'eq),1.58-1.54(m,1H,H-14ax), 1.48(s,3H,12-CH3),1.44-1.41(m,1H,H-7a),1.36(s,3H,6-CH3),1.32-1.29(s,1H,H-7b), 1.24 (d, J=7.0Hz, 3H, 10-CH3), 1.15 (d, J=6.0Hz, 3H, 5'-CH3), 1.06-1.03 (m, 6H, 4-CH3,8- CH3), 0.95 (d, J=7.0Hz, 3H, 2-CH3), 0.85 (t, J=7.0Hz, 3H, 15-CH3) .13C NMR (CDCl3, 125MHz)δ:173.8,170.3,165.7,157.5,154.6,154.0,151.6,149.2,140.7,136.6,124.3, 122.4,109.6,107.9,103.4,86.2,84.9,83.3,83.0,81.7,78.5,75.6,70.5,69.1,65.7, 62.1,49.9,43.8,43.2,40.4,37.3,36.6,33.0,25.9,22.2,21.0,19.4,18.8,15.5,15.2, 13.0,10.1,8.8.

Hydrogen spectrum and carbon spectrum combine high resolution mass spectrum to determine that compound 3e that is synthesized and purifying is following structural formula:

Example 6:

It prepares first: 2'-O- acetyl group -3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O- methyl Erythromycin A 9-O- propargyl oxime -11,12- cyclic carbonate ester (4)

2.020g (2.84mmol) compound 1 is dissolved in methylene chloride (60mL), 2- pyridine second is added with stirring in 0 DEG C Acid hydrochloride (1.233g, 7.10mmol), DCC (1.470g, 7.12mmol), DMAP (868mg, 7.12mmol) are slowly added dropwise Pyridine (0.92mL, 11.37mmol).After stirring 1h, ice-water bath is removed, reacts 4-8h at 15 DEG C.Decompression is taken out after reaction Dicyclohexylurea (DCU) is filtered out, is washed with saturated sodium bicarbonate solution (60mL), lower layer's organic phase uses saturated ammonium chloride solution respectively (60mL) is washed twice, and saturated sodium bicarbonate solution (60mL) washed once, and distilled water (60mL) washed once, saturated salt solution (60mL) washed once, and be evaporated under reduced pressure later, and drying can obtain solids.(100-200 mesh silica gel, mobile phase V (two are chromatographed through column Chloromethanes): V (ethyl alcohol): V (ammonium hydroxide)=10:0.6:0.1) obtain compound 4 (1.010g, 1.22mmol, 42.8%).

Secondly it prepares: 3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A 9-O- { 3- [5'- (2'- amino) pyrimidine radicals] -2-propynyl } oxime -11,12- cyclic carbonate ester (3f)

1.010g (1.22mmol) compound 4 is dissolved in acetonitrile (10mL), bis- (triphenylphosphine) palladium chlorides are added (45mg, 0.064mmol), cuprous iodide (23mg, 0.121mmol), triethylamine (0.26mL, 1.86mmol), 2- amino -5- bromine Pyrimidine (635mg, 3.65mmol).Reaction system is replaced 8 times with argon gas, under protection of argon gas, stirs 4h in 80 DEG C of oil baths.Reaction After be added distilled water (10mL) terminate reaction, be extracted twice with ethyl acetate (20mL), upper organic phase saturated common salt Water (10mL) washing, vacuum distillation obtain dry solids.(100-200 mesh silica gel, mobile phase V (dichloromethane are chromatographed through column Alkane): V (ethyl alcohol): V (ammonium hydroxide)=10:0.6:0.1) obtain 2'-OAc-3f (156mg, 0.17mmol, 13.9%).

156mg (0.17mmol) 2'-OAc-3f is dissolved in methanol (20mL), 65 DEG C of reflux 3h, vacuum distillation concentration obtains To dry product.Plate (mobile phase V (petroleum ether): V (acetone): V (triethylamine)=5:5:0.2) is prepared through thin-layer chromatography silica gel It obtains 3f sterling (14mg, 0.016mmol, 9.4%).

HRMS(ESI)(M+H)+m/z 881.46649,calcd for C45H65N6O12881.46550.1H NMR (CDCl3,500MHz), δ:

8.53 (d, J=4.0Hz, 1H, 2'-Pyridyl), 8.35 (s, 2H, 5'- (2'-amino)-Pyrimidinyl), 7.68 (td, J1=8.0Hz, J2=2.0Hz, 1H, 2'-Pyridyl), 7.35 (d, J=7.5Hz, 1H, 2'-Pyridyl), 7.22 (dd, J1=5.0Hz, J2=7.0Hz, 1H, 2'-Pyridyl), 5.25 (s, 2H ,-NH2), 5.14 (dd, J1= 10.5Hz, J2=2.5Hz, 1H, H-13), 5.07 (d, J=11.0Hz, 1H, H-3), 4.88 (d, J=16.0Hz, 1H, 9-O- CH2C ≡ C-Ar), 4.88 (s, 1H, H-11), 4.80 (d, J=15.5Hz, 1H, 9-O-CH2C ≡ C-Ar), 4.06 (d, J= 7.0Hz, 1H, H-1'), 3.97 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.91 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.74-3.70 (m, 1H, H-8), 3.74 (d, J=3.0Hz, 1H, H-5), 3.38-3.33 (m, 1H, H-5'), 3.27 (dd, J1=7.5Hz, J2=2.5Hz, 1H, H-2'), 3.02 (s, 3H, 6-OCH3), 2.86-2.83 (m, 2H, H-2, H-3'), 2.50 (q, J=7.0Hz, 1H, H-10), 2.45 (s, 6H ,-N (CH3) 2), 2.10-2.08 (m, 1H, H- 4),1.92-1.87(m,1H,H-14eq),1.79-1.77(m,1H,H-4'eq),1.59-1.52(m,1H,H-14ax),1.48 (s,3H,12-CH3),1.44-1.41(m,1H,H-7a),1.35(s,3H,6-CH3),1.33-1.31(m,1H,H-7b), 1.26-1.24 (m, 6H, 10-CH3,5'-CH3), 1.16 (d, J=6.0Hz, 3H, 4-CH3), 1.04 (d, J=7.0Hz, 3H, 8- CH3), 0.96 (d, J=7.0Hz, 3H, 2-CH3), 0.85 (t, J=7.5Hz, 3H, 15-CH3) .13C NMR (CDCl3, 125MHz)δ:173.8,170.3,165.9,161.2,160.8,154.6,153.9,149.2,136.6,124.3,122.4, 108.7,103.3,89.2,84.9,82.9,81.7,80.1,78.5,75.6,70.4,69.0,65.7,61.9,49.9,43.7, 43.2,40.4,37.2,36.6,33.0,25.9,22.1,21.0,19.4,18.8,15.5,15.1,13.0,10.1,8.8.

Hydrogen spectrum and carbon spectrum combine high resolution mass spectrum to determine that compound 3f that is synthesized and purifying is following structural formula:

Example 7:

Preparation: 3-O- descladinosylation -3-O- [2- (2 '-pyridine) acetyl group] -6-O-methylerythromycin A9-O- { 3- [3'- (5'- amino) pyridyl group] -2-propynyl } oxime -11,12- cyclic carbonate ester (3g)

1.000g (1.20mmol) compound 4 is dissolved in acetonitrile (10mL), bis- (triphenylphosphine) palladium chlorides are added (45mg, 0.064mmol), cuprous iodide (23mg, 0.121mmol), triethylamine (0.25mL, 1.79mmol), 3- amino -5- bromine Pyridine (625mg, 3.61mmol).Reaction system is replaced 8 times with argon gas, under protection of argon gas, stirs 4h in 80 DEG C of oil baths.Reaction After be added distilled water (10mL) terminate reaction, be extracted twice with ethyl acetate (20mL), upper organic phase saturated common salt Water (10mL) washing, vacuum distillation obtain dry solids.(100-200 mesh silica gel, mobile phase V (dichloromethane are chromatographed through column Alkane): V (ethyl alcohol): V (ammonium hydroxide)=10:0.6:0.1) obtain 2'-OAc-3g (263mg, 0.28mmol, 23.3%).

263mg (0.28mmol) 2'-OAc-3g is dissolved in methanol (20mL), 65 DEG C of reflux 3h, vacuum distillation concentration obtains To dry product.Plate (mobile phase V (petroleum ether): V (acetone): V (triethylamine)=5:5:0.2) is prepared through thin-layer chromatography silica gel It obtains 3g sterling (61mg, 0.066mmol, 23.6%).

HRMS(ESI)(M+H)+m/z 880.47102,calcd for C46H66N5O12880.47025.1H NMR (CDCl3,500MHz), δ:

8.52-8.51 (m, 1H, 2'-Pyridyl), 8.03 (d, J=1.5Hz, 1H, 3'- (5'-amino)-Pyridyl), 7.99 (d, J=3.0Hz, 1H, 3'- (5'-amino)-Pyridyl), 7.68 (td, J1=2.0Hz, J2=7.5Hz, 1H, 2'- ), Pyridyl 7.36 (d, J=7.5Hz, 1H, 2'-Pyridyl), 7.22-7.19 (m, 1H, 2'-Pyridyl), 7.07-7.06 (m, 1H, 3'- (5'-amino)-Pyridyl), 5.15 (dd, J1=11.0Hz, J2=2.5Hz, 1H, H-13), 5.07 (d, J= 11.0Hz, 1H, H-3), 4.89 (s, 1H, H-11), 4.87 (d, J=15.5Hz, 1H, 9-O-CH2C ≡ C-Ar), 4.81 (d, J= 16.0Hz, 1H, 9-O-CH2C ≡ C-Ar), 4.04 (d, J=7.0Hz, 1H, H-1'), 3.96 (d, J=16.0Hz, 1H, 2'- ), Pyridyl-CH2-COO- 3.92 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.83 (br, 2H, NH2), 3.75-3.71 (m, 1H, H-8), 3.73 (d, J=10.0Hz, 1H, H-5), 3.34-3.32 (m, 1H, H-5'), 3.19 (dd, J1 =10.0Hz, J2=7.5Hz, 1H, H-2'), 3.03 (s, 3H, 6-OCH3), 2.88-2.84 (m, 1H, H-2), 2.67-2.62 (m, 1H, H-3'), 2.52 (q, J=7.0Hz, 1H, H-10), 2.32 (s, 6H ,-N (CH3) 2), 2.10-2.08 (m, 1H, H-4), 1.92-1.88(m,1H,H-14eq),1.65-1.62(m,1H,H-4'eq),1.60-1.53(m,1H,H-14ax),1.49(s, 3H,12-CH3),1.44-1.41(m,1H,H-7a),1.36(s,3H,6-CH3),1.32-1.29(m,1H,H-7b),1.25(d, J=7.0Hz, 3H, 10-CH3), 1.15 (d, J=6.0Hz, 3H, 5'-CH3), 1.07 (d, J=7.5Hz, 3H, 4-CH3), 1.03 (d, J=7.0Hz, 3H, 8-CH3), 0.96 (d, J=7.0Hz, 3H, 2-CH3), 0.85 (t, J=7.5Hz, 3H, 15-CH3) .13C NMR(CDCl3,125MHz)δ:173.9,170.3,165.9,154.6,153.9,149.1,142.1,142.0, 136.6,136.5,124.2,123.9,122.2,119.8,103.6,88.4,84.9,82.9,82.9,81.4,78.5,78.3, 75.6,70.5,69.2,65.5,61.8,49.9,43.7,43.1,40.2,37.2,36.6,32.9,28.7,25.9,22.1, 21.0,19.3,18.7,15.5,15.1,12.9,10.0,8.8.

Hydrogen spectrum and carbon spectrum combine high resolution mass spectrum to determine that compound 3g that is synthesized and purifying is following structural formula:

Example 8:

Preparation: 3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A9-O- { 3- [3'- (5'- carbamoyl) pyridyl group] -2-propynyl } oxime -11,12- cyclic carbonate ester (3h)

628mg (0.757mmol) compound 4 is dissolved in acetonitrile (10mL), bis- (triphenylphosphine) palladium chlorides are added (30mg, 0.043mmol), cuprous iodide (23mg, 0.121mmol), triethylamine (0.26mL, 1.86mmol), 5- bromine niacinamide (456mg, 2.27mmol).Reaction system is replaced 8 times with argon gas, under protection of argon gas, stirs 4h in 80 DEG C of oil baths.Reaction terminates Distilled water (10mL) is added afterwards and terminates reaction, is extracted twice with ethyl acetate (20mL), upper organic phase saturated salt solution (10mL) washing, vacuum distillation obtain dry solids.(100-200 mesh silica gel, mobile phase V (dichloromethane are chromatographed through column Alkane): V (ethyl alcohol): V (ammonium hydroxide)=10:0.6:0.1) obtain 2'-OAc-3h (182mg, 0.13mmol, 17.2%).

182mg (0.13mmol) 2'-OAc-3h is dissolved in methanol (20mL), 65 DEG C of reflux 3h, vacuum distillation concentration obtains To dry product.Plate (mobile phase V (petroleum ether): V (acetone): V (triethylamine)=5:5:0.2) is prepared through thin-layer chromatography silica gel It obtains 3h sterling (18mg, 0.020mmol, 15.4%).

HRMS(ESI)(M+H)+m/z 908.46768,calcd for C47H66N5O13908.46516.1H NMR (CDCl3,500MHz), δ:

9.05 (d, J=2.0Hz, 3'- (5'-carbamoyl)-Pyridyl), 8.74 (d, J=2.0Hz, 1H, 3'- (5'- Carbamoyl)-Pyridyl), 8.43 (d, J=4.0Hz, 1H, 2'-Pyridyl), 8.21 (t, J=2.0Hz, 1H, 3'- (5'- Carbamoyl)-Pyridyl), 7.68 (td, J1=7.5Hz, J2=2.0Hz, 1H, 2'-Pyridyl), 7.34 (d, J= 8.0Hz, 1H, 2'-Pyridyl), 7.21 (dd, J1=5.0Hz, J2=7.0Hz, 1H, 2'-Pyridyl), 6.76 (br, 1H ,- ), NH2 5.77 (br, 1H ,-NH2), 5.12 (dd, J1=10.5Hz, J2=2.0Hz, 1H, H-13), 5.06 (d, J=11.0Hz, 1H, H-3), 4.91 (s, 1H, H-11), 4.84 (s, 2H, 9-O-CH2C ≡ C-Ar), 4.07 (d, J=7.0Hz, 1H, H-1'), 3.96 (d, J=16.5Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.92 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2- ), COO- 3.74 (d, J=10.0Hz, 1H, H-5), 3.71-3.66 (m, 1H, H-8), 3.38-3.35 (m, 1H, H-5'), 3.30- 3.26 (m, 1H, H-2'), 3.01 (s, 3H, 6-OCH3), 2.88-2.84 (m, 2H, H-2, H-3'), 2.51 (q, J=7.0Hz, 1H,H-10),2.46(s,6H,-N(CH3)2),2.07-2.05(m,1H,H-4),1.90-1.86(m,1H,H-14eq),1.80- 1.78(m,1H,H-4'eq),1.60-1.52(m,1H,H-14ax),1.50(s,3H,12-CH3),1.44-1.42(m,1H,H- 7a), 1.35 (s, 3H, 6-CH3), 1.32-1.29 (m, 1H, H-7b), 1.26 (d, J=6.5Hz, 3H, 10-CH3), 1.16 (d, J =6.5Hz, 3H, 5'-CH3), 1.04 (t, J=8.0Hz, 6H, 4-CH3,8-CH3), 0.97 (d, J=7.0Hz, 3H, 2-CH3), 0.85 (t, J=7.5Hz, 3H, 15-CH3) .13C NMR (CDCl3,125MHz) δ: 174.0,170.4,166.6,165.8, 155.0,154.5,153.9,149.2,148.3,137.6,136.7,128.3,124.4,122.4,120.0,103.2,90.6, 85.2,83.1,81.8,81.6,78.5,78.4,75.6,70.4,69.0,65.8,61.6,50.0,43.7,43.2,40.4, 37.2,36.6,33.0,26.0,22.1,21.0,19.4,18.8,15.6,15.2,12.9,10.1,8.8.

Hydrogen spectrum and carbon spectrum combine high resolution mass spectrum to determine that compound 3h that is synthesized and purifying is following structural formula:

Example 9:

Preparation: 3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A9-O- [3- (3'- pyridyl group) -2-propynyl] oxime -11,12- cyclic carbonate ester (3i)

500mg (1.20mmol) compound 4 is dissolved in acetonitrile (10mL), bis- (triphenylphosphine) palladium chlorides are added (22mg, 0.031mmol), cuprous iodide (14mg, 0.074mmol), triethylamine (0.13mL, 0.93mmol), 3- bromopyridine (0.18mL, 1.87mmol).Reaction system is replaced 8 times with argon gas, under protection of argon gas, stirs 4h in 80 DEG C of oil baths.Reaction knot Distilled water (10mL) is added after beam and terminates reaction, is extracted twice with ethyl acetate (20mL), upper organic phase saturated salt solution (10mL) washing, vacuum distillation obtain dry solids.(100-200 mesh silica gel, mobile phase V (dichloromethane are chromatographed through column Alkane): V (ethyl alcohol): V (ammonium hydroxide)=10:0.6:0.1) obtain 2'-OAc-3i (119mg, 0.13mmol, 10.8%).

119mg (0.13mmol) 2'-OAc-3i is dissolved in methanol (20mL), 65 DEG C of reflux 3h, vacuum distillation concentration obtains To dry product.Plate (mobile phase V (petroleum ether): V (acetone): V (triethylamine)=5:5:0.2) is prepared through thin-layer chromatography silica gel It obtains 3i sterling (28mg, 0.032mmol, 24.6%).

HRMS(ESI)(M+H)+m/z 865.46097,calcd for C46H65N4O12865.45935.1H NMR (CDCl3,500MHz), δ:

8.65 (d, J=1.0Hz, 1H, 3'-Pyridyl), 8.52-8.51 (m, 2H, 3'-Pyridyl), 7.72 (dt, J1 =7.5Hz, J2=2.0Hz, 1H, 3'-Pyridyl), 7.67 (td, J1=7.5Hz, J2=1.5Hz, 1H, 2'-Pyridyl), 7.36 (d, J=8.0Hz, 1H, 2'-Pyridyl), 7.27-7.19 (m, 2H, 2'-Pyridyl, 3'-Pyridyl), 5.15 (dd, J1=11.0Hz, J2=2.5Hz, 1H, H-13), 5.07 (d, J=11.0Hz, 1H, H-3), 4.91 (d, J=16.0Hz, 1H, 9- O-CH2C ≡ C-Ar), 4.90 (s, 1H, H-11), 4.84 (d, J=15.5Hz, 1H, 9-O-CH2CH ≡ CH-Ar), 4.03 (d, J =7.5Hz, 1H, H-1'), 3.96 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.91 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.75-3.70 (m, 1H, H-8), 3.74 (d, J=3.0Hz, 1H, H-5), 3.35-3.31 (m, 1H, H-5'), 3.19 (dd, J1=10.0Hz, J2=7.0Hz, 1H, H-2'), 3.03 (s, 3H, 6-OCH3), 2.89-2.82 (m, 1H, H-2), 2.67-2.62 (m, 1H, H-3'), 2.51 (q, J=7.0Hz, 1H, H-10), 2.32 (s, 6H ,-N (CH3) 2), 2.11-2.06(m,1H,H-4),1.92-1.87(m,1H,H-14eq),1.65-1.62(m,1H,H-4'eq),1.59-1.52 (m,1H,H-14ax),1.49(s,3H,12-CH3),1.46-1.43(m,1H,H-7a),1.37(s,3H,6-CH3),1.33- 1.30 (m, 1H, H-7b), 1.25 (d, J=7.0Hz, 3H, 10-CH3), 1.15 (d, J=6.5Hz, 3H, 5'-CH3), 1.07 (d, J=7.5Hz, 3H, 4-CH3), 1.04 (d, J=7.0Hz, 3H, 8-CH3), 0.96 (d, J=7.0Hz, 3H, 2-CH3), 0.85 (t, J=7.5Hz, 3H, 15-CH3) .13C NMR (CDCl3,125MHz) δ: 173.8,170.3,166.1,154.6,153.9, 152.3,149.2,148.6,138.7,136.5,124.2,122.9,122.2,120.1,103.6,89.3,84.9,82.9, 82.4,81.5,78.5,78.4,75.6,70.5,69.3,65.6,61.8,49.9,43.8,43.2,40.3,37.2,36.6, 33.0,28.7,26.0,22.1,21.0,19.4,18.8,15.5,15.1,12.9,10.1,8.8.

Example 10:

Preparation: 3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A9-O- [3- (6'- quinoxalinyl) -2-propynyl] oxime -11,12- cyclic carbonate ester (3j)

1.010g (1.22mmol) compound 4 is dissolved in acetonitrile (10mL), bis- (triphenylphosphine) palladium chlorides are added (45mg, 0.064mmol), cuprous iodide (25mg, 0.121mmol), triethylamine (0.26mL, 1.86mmol), 6- bromine quinoxaline (755mg, 3.61mmol).Reaction system is replaced 8 times with argon gas, under protection of argon gas, stirs 4h in 80 DEG C of oil baths.Reaction terminates Distilled water (10mL) is added afterwards and terminates reaction, is extracted twice with ethyl acetate (20mL), upper organic phase saturated salt solution (10mL) washing, vacuum distillation obtain dry solids.(100-200 mesh silica gel, mobile phase V (dichloromethane are chromatographed through column Alkane): V (ethyl alcohol): V (ammonium hydroxide)=10:0.6:0.1) obtain 2'-OAc-3j (218mg, 0.23mmol, 22.8%).

218mg (0.23mmol) 2'-OAc-3j is dissolved in methanol (20mL), 65 DEG C of reflux 3h, vacuum distillation concentration obtains To dry product.Plate (mobile phase V (petroleum ether): V (acetone): V (triethylamine)=5:5:0.2) is prepared through thin-layer chromatography silica gel It obtains 3j sterling (34mg, 0.037mmol, 16.1%).

HRMS(ESI)(M+H)+m/z 916.47271,calcd for C49H66N5O12916.47025.1H NMR (CDCl3,500MHz) δ:

8.84 (d, J=1.5Hz, 1H, 6'-quinoxalyl), 8.81 (d, J=1.5Hz, 1H, 6'-quinoxalyl), 8.52 (d, J=4.0Hz, 1H, 2'-Pyridyl), 8.17 (d, J=4.0Hz, 1H, 6'-quinoxalyl), 8.03 (d, J= 9.0Hz, 1H, 6'-quinoxalyl), 7.78 (dd, J1=8.5Hz, J2=1.5Hz, 1H, 6'-quinoxalyl), 7.67 (td, J1=7.5Hz, J2=1.5Hz, 1H, 2'-Pyridyl), 7.35 (d, J=9.0Hz, 1H, 2'-Pyridyl), 7.23- 7.20 (m, 1H, 2'-Pyridyl), 5.16 (dd, J1=11.0Hz, J2=2.5Hz, 1H, H-13), 5.07 (d, J=11.0Hz, 1H, H-3), 4.98 (d, J=16.0Hz, 1H, 9-O-CH2C ≡ C-Ar), 4.92 (s, 1H, H-11), 4.90 (d, J=16.0Hz, 1H, 9-O-CH2C ≡ C-Ar), 4.04 (d, J=7.0Hz, 1H, H-1'), 3.96 (d, J=16.0Hz, 1H, 2'-Pyridyl- ), CH2-COO- 3.91 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.81-3.76 (m, 1H, H-8), 3.75 (d, J=3.0Hz, 1H, H-5), 3.34-3.32 (m, 1H, H-5'), 3.20 (dd, J1=10.0Hz, J2=7.0Hz, 1H, H- 2'), 3.06 (s, 3H, 6-OCH3), 2.87-2.84 (m, 1H, H-2), and 2.70-2.64 (m, 1H, H-3 '), 2.53 (q, J= 7.0Hz,1H,H-10),2.33(s,6H,-N(CH3)2),2.10-2.08(m,1H,H-4),1.94-1.90(m,1H,H- 14eq),1.67-1.64(m,1H,H-4'eq),1.61-1.54(m,1H,H-14ax),1.51(s,3H,12-CH3),1.50- 1.46 (m, 1H, H-7a), 1.40 (s, 3H, 6-CH3), 1.37-1.34 (m, 1H, H-7b), 1.28 (t, J=7.0Hz, 3H, 10- ), CH3 1.15 (d, J=6.5Hz, 3H, 5'-CH3), 1.07 (d, J=7.5Hz, 3H, 4-CH3), 1.04 (d, J=6.5Hz, 3H, 8-CH3), 0.98 (d, J=7.0Hz, 3H, 2-CH3), 0.86 (t, J=7.5Hz, 3H, 15-CH3) .13C NMR (CDCl3, 125MHz)δ:173.8,170.3,166.2,154.6,154.0,149.2,145.5,145.0,142.8,142.7,136.6, 133.0,132.5,129.5,125.0,124.2,122.3,103.6,89.0,84.9,84.8,82.9,81.6,78.5,78.4, 75.6,70.5,69.2,65.6,62.0,49.9,43.8,43.2,40.3,37.3,36.6,33.0,28.9,26.0,22.1, 21.0,19.4,18.8,15.6,15.1,12.9,10.1,8.8.

Example 11:

Preparation: 3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A9-O- { 3- [(4'- imidazole radicals) -1'- phenyl] -2-propynyl } oxime -11,12- cyclic carbonate ester (3k)

500mg (0.602mmol) compound 4 is dissolved in acetonitrile (10mL), bis- (triphenylphosphine) palladium chlorides are added (24mg, 0.034mmol), cuprous iodide (15mg, 0.079mmol), triethylamine (0.13mL, 0.93mmol), 1- (4- bromobenzene Base) imidazoles (400mg, 1.79mmol).Reaction system is replaced 8 times with argon gas, under protection of argon gas, stirs 4h in 80 DEG C of oil baths. Distilled water (10mL) is added after reaction and terminates reaction, is extracted twice with ethyl acetate (20mL), upper organic phase saturation Saline solution (10mL) washing, vacuum distillation obtain dry solids.(100-200 mesh silica gel, mobile phase V (two are chromatographed through column Chloromethanes): V (ethyl alcohol): V (ammonium hydroxide)=10:0.6:0.1) obtain 2'-OAc-3k (120mg, 0.12mmol, 19.9%).

120mg (0.12mmol) 2'-OAc-3k is dissolved in methanol (20mL), 65 DEG C of reflux 3h, vacuum distillation concentration obtains To dry product.Plate (mobile phase V (petroleum ether): V (acetone): V (triethylamine)=5:5:0.2) is prepared through thin-layer chromatography silica gel It obtains 3k sterling (18mg, 0.019mmol, 15.8%).

HRMS(ESI)(M+H)+m/z 930.48363,calcd for C50H68N5O12930.48590.1H NMR (CDCl3,500MHz), δ:

8.52 (d, J=3.5Hz, 1H, 2'-Pyridyl), 7.86 (s, 1H, (4'-imidazolyl) -1'-Phenyl), 7.68 (td, J1=7.5Hz, J2=2.0Hz, 1H, 2'-Pyridyl), 7.53 (d, J=8.5Hz, 2H, (4'- imidazolyl)-1'-Phenyl),7.36-7.32(m,3H,2'-Pyridyl,(4'-imidazolyl)-1'-Phenyl), 7.28(s,1H,(4'-imidazolyl)-1'-Phenyl),7.22-7.20(m,2H,2'-Pyridyl,(4'- Imidazolyl) -1'-Phenyl), 5.15 (dd, J1=11.0Hz, J2=2.5Hz, 1H, H-13), 5.07 (d, J= 11.0Hz, 1H, H-3), 4.90 (d, J=15.5Hz, 1H, 9-O-CH2C ≡ C-Ar), 4.90 (s, 1H, H-11), 4.85 (d, J= 16.0Hz, 1H, 9-O-CH2C ≡ C-Ar), 4.05 (d, J=7.0Hz, 1H, H-1'), 3.96 (d, J=16.0Hz, 1H, 2'- ), Pyridyl-CH2-COO- 3.91 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.75-3.71 (m, 1H, H- 8), 3.73 (d, J=3.0Hz, 1H, H-5), 3.37-3.34 (m, 1H, H-5'), 3.23 (dd, J1=10.0Hz, J2=7.5Hz, 1H, H-2'), 3.04 (s, 3H, 6-OCH3), 3.00-2.84 (m, 2H, H-2, H-3'), 2.50 (q, J=7.0Hz, 1H, H-10), 2.39(s,6H,-N(CH3)2),2.11-2.09(m,1H,H-4),1.91-1.88(m,1H,H-14eq),1.73-1.71(m, 1H,H-4'eq),1.58-1.53(m,1H,H-14ax),1.49(s,3H,12-CH3),1.46-1.42(m,1H,H-7a),1.37 (s, 3H, 6-CH3), 1.33-1.31 (m, 1H, H-7b), 1.24 (d, J=9.0Hz, 3H, 10-CH3), 1.15 (d, J=6.0Hz, 3H, 5'-CH3), 1.07-1.03 (m, 6H, 4-CH3,8-CH3), 0.96 (d, J=7.0Hz, 3H, 2-CH3), 0.849 (t, J= 7.5Hz,3H,15-CH3).13C NMR(CDCl3,125MHz)δ:173.9,170.4,165.8,154.6,153.9,149.2, 136.6,135.5,133.3,130.6,124.3,122.4,122.3,121.1,118.0,103.5,87.4,84.9,84.5, 82.9,81.7,78.5,78.4,75.6,70.5,69.1,65.7,61.9,49.9,43.8,43.2,40.4,37.2,36.6, 33.0,25.9,22.1,21.0,19.4,18.8,15.6,15.1,13.0,10.1,8.8.

Example 12:

Preparation: 2'-O- acetyl group -3-O- descladinosylation -3- hydroxyl -6-O-methylerythromycin A9-O- [3- (3'- (2'- Amino) pyridyl group)-E-2- acrylic] and oxime -11,12- cyclic carbonate ester synthesis (6a)

1.00g (1.40mmol) compound 5 is dissolved in acetonitrile (by degassing process) (10mL), adds three (o-tolyl) phosphines (171mg, 0.56mmol), palladium acetate (63mg, 0.28mmol), triethylamine (0.39mL, 2.80mmol), 2- amino -3- bromine pyrrole Pyridine (728mg, 4.20mmol).Reaction system is replaced 4 times with argon gas, under protection of argon gas, in 60 DEG C of stirring 1h, then in 90 DEG C Stirring is for 24 hours.Distilled water (10mL) stopped reaction is added after reaction, is extracted with ethyl acetate (20mL), upper organic phase is used Saturated salt solution (10mL) washing, concentrated by rotary evaporation, dry solids.(100-200 mesh silicagel column, mobile phase V are chromatographed through column (methylene chloride): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) obtain compound 6a (309mg, 0.38mmol, 27.1%).

3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A9-O- [3- (3'- (2'- Amino) pyridyl group)-E-2- acrylic] and oxime -11,12- cyclic carbonate ester synthesis (7a)

Compound 6a (309mg, 0.38mmol) is dissolved in CH2Cl2 (20mL), 2- pyridine second is added with stirring in 0 DEG C Acid hydrochloride (167mg, 0.95mmol), DCC (198mg, 0.95mmol), DMAP (117mg, 0.95mmol) are slowly dropped into pyrrole After 1h is stirred in pyridine (0.12mL, 1.52mmol), it is warming up to 15 DEG C of reaction 23h.It first filters after reaction and removes dicyclohexylurea, then CH2Cl2 (30mL) extraction is added, is washed with saturation NaHCO3 solution (25mL), lower layer's organic phase is respectively with saturation NH4Cl solution (25mL) wash twice, is saturated that NaHCO3 solution (25mL) washed once, semi-saturation NaCl solution (25mL) washed once, by Revolving, drying can obtain solids (351mg, 0.38mmol, 100.0%).Through column chromatography, (100-200 mesh silicagel column, mobile phase are V (methylene chloride): V (ethyl alcohol): V (ammonium hydroxide)=15:0.6:0.1) obtain 2'-OAc-7a (155mg, 0.168mmol, 44.2%).

155mg (0.168mmol) 2'-OAc-7a is dissolved in 20mL methanol, 65 DEG C of reflux 3h, concentrated by rotary evaporation, dry Product 147mg (0.167mmol, yield 99.4%).Preparing plate through thin-layer chromatography silica gel, (mobile phase is V (petroleum ether): V (third Ketone): V (triethylamine)=5:20:0.2) obtain 7a sterling (7.7mg, 0.009mmol, 5.4%).

HRMS(ESI)(M+H)+m/z 882.48606,calcd for C46H68N5O12882.48590.1H NMR (CDCl3,500MHz), δ:

8.53 (d, J=4.0Hz, 1H, 2'-Pyridyl), 7.97 (dd, J1=4.5, J2=1.0Hz, 1H, 3'- (2'- Amino)-Pyridyl), 7.68 (td, J1=1.5Hz, J2=7.5Hz, 1H, 2'-Pyridyl), 7.45 (dd, J1=7.5, J2 =1.5Hz, 1H, 3'- (2'-amino)-Pyridyl), 7.35 (d, J=7.5Hz, 1H, 2'-Pyridyl), 7.22 (dd, J1= 7.0, J2=5.0Hz, 1H, 2'-Pyridyl), 6.65 (dd, J1=7.0, J2=5.0Hz, 1H, 3'- (2'-amino)- ), Pyridyl 6.55 (d, J=15.5Hz, 1H, 9-O-CH2CH=CH-Ar), 6.22 (dt, J1=16.0, J2=6.0Hz, 1H, 9-O-CH2CH=CH-Ar), 5.13 (dd, J1=11.0, J2=2.5Hz, 1H, H-13), 5.06 (d, J=11.0Hz, 1H, H- 3), 4.88 (s, 1H, H-11), 4.68-4.65 (m, 4H, 9-O-CH2CH=CH-Ar ,-NH2), 4.05 (d, J=7.5Hz, 1H, ), H-1' 3.96 (d, J=16.0Hz, 1H, Pyridyl-CH2-COO-), 3.91 (d, J=16.0Hz, 1H, Pyridyl-CH2- ), COO- 3.74-3.70 (m, 1H, H-8), 3.74 (d, J=2.0Hz, 1H, H-5), 3.37-3.33 (m, 1H, H-5'), 3.25 (dd, J1=10.0, J2=7.5Hz, 1H, H-2'), 2.98 (s, 3H, 6-OCH3), 2.88-2.81 (m, 2H, H-2, H-3'), 2.49 (q, J=7.0Hz, 1H, H-10), 2.42 (s, 6H ,-N (CH3) 2), 2.10-2.05 (m, 1H, H-4), 1.92-1.87 (m, 1H,H-14eq),1.76-1.74(m,1H,H-4'eq),1.59-1.52(m,1H,H-14ax),1.49(s,3H,12-CH3), 1.43-1.40 (m, 1H, H-7a), 1.34 (s, 3H, 6-CH3), 1.22 (d, 3H, 10-CH3), 1.15 (d, J=6.0Hz, 3H, 5'-CH3), 1.06-1.03 (m, 6H, 4-CH3,8-CH3), 0.95 (d, J=7.0Hz, 3H, 2-CH3), 0.86 (t, J= 7.5Hz,3H,15-CH3).13C NMR(CDCl3,125MHz)δ:173.8,170.3,164.8,155.9,154.6,153.9, 149.2,146.9,136.6,135.1,129.7,127.6,124.3,122.4,118.0,114.4,103.4,85.0,83.0, 81.6,78.5,78.5,75.6,73.9,70.5,69.1,65.7,49.9,43.7,43.2,40.4,37.2,36.6,32.9, 25.8,22.1,21.0,19.4,18.8,15.6,15.1,12.9,10.1,8.8.

Example 13:

Preparation: 2'-O- acetyl group -3-O- descladinosylation -3- hydroxyl -6-O-methylerythromycin A9-O- [3- (4'- (2'- Amino) pyridyl group)-E-2- acrylic] and oxime -11,12- cyclic carbonate ester synthesis (6b)

1.00g (1.40mmol) compound 5 is dissolved in acetonitrile (by degassing process) (10mL), adds three (o-tolyl) phosphines (171mg, 0.56mmol), palladium acetate (63mg, 0.28mmol), triethylamine (0.39mL, 2.80mmol), 2- amino -4- bromine pyrrole Pyridine (728mg, 4.20mmol).Reaction system is replaced 4 times with argon gas, under protection of argon gas, in 60 DEG C of stirring 1h, then in 90 DEG C Stirring is for 24 hours.Distilled water (10mL) stopped reaction is added after reaction, is extracted with ethyl acetate (20mL), upper organic phase is used Saturated salt solution (10mL) washing, concentrated by rotary evaporation, dry solids.(100-200 mesh silicagel column, mobile phase V are chromatographed through column (methylene chloride): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) obtain compound 6b (227mg, 0.28mmol, 20.0%).

3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A 9-O- ﹛ 3- [4'- [2'-N- (2 "-pyridine acetyl group) amino] pyridyl group]-E-2- Bing Xi Ji ﹜ oxime -11,12- cyclic carbonate ester synthesis (7b)

Compound 6b (227mg, 0.28mmol) is dissolved in CH2Cl2 (20mL), 2- pyridine second is added with stirring in 0 DEG C Acid hydrochloride (122mg, 0.70mmol), DCC (145mg, 0.70mmol), DMAP (86mg, 0.70mmol) are slowly dropped into pyridine After (0.09mL, 1.12mmol) stirs 1h, it is warming up to 15 DEG C of reaction 23h.It first filters after reaction and removes dicyclohexylurea, then plus Enter CH2Cl2 (30mL) extraction, washed with saturation NaHCO3 solution (25mL), lower layer's organic phase is respectively with saturation NH4Cl solution (25mL) wash twice, is saturated that NaHCO3 solution (25mL) washed once, semi-saturation NaCl solution (25mL) washed once, by Revolving, drying can obtain solids (280mg, 0.27mmol, 96.4%).(100-200 mesh silicagel column, mobile phase V are chromatographed through column (methylene chloride): V (ethyl alcohol): V (ammonium hydroxide)=15:0.6:0.1) obtain 2'-OAc-7b (80mg, 0.077mmol, 28.5%).

80mg (0.077mmol) 2'-OAc-7b is dissolved in 20mL methanol, 65 DEG C of reflux 3h, concentrated by rotary evaporation, it is so dry that produce Object 74mg (0.074mmol, yield 96.1%).Preparing plate through thin-layer chromatography silica gel, (mobile phase is V (petroleum ether): V (acetone): V (triethylamine)=5:20:0.2) obtain 7b sterling (13mg, 0.013mmol, 17.6%).

HRMS(ESI)(M+H)+m/z 1001.52509,calcd for C53H73N6O131001.52301.1H NMR (CDCl3,500MHz), δ:

9.93 (s, 1H ,-NH-CO-), 8.68 (dd, J1=4.5Hz, J2=0.5Hz, 1H, 2'-Pyridyl), 8.53 (- the Pyridyl of dd, J1=5.0Hz, J2=0.5Hz, 1H, 2 "), 8.21 (d, J=5.5Hz, 1H, 4'- (2'-amino) Pyridyl),8.18(s,1H,4'-(2'-amino)Pyridyl),7.70-7.67(m,2H,2'-Pyridyl,2”- ), Pyridyl 7.35 (d, J=8.0Hz, 1H, 2'-Pyridyl), the 7.30 (- Pyridyl of d, J=7.5Hz, 1H, 2 "), 7.24- The 7.20 (- Pyridyl of m, 2H, 2'-Pyridyl, 2 "), 7.02 (dd, J1=5.5Hz, J2=1.5Hz, 1H, 4'- (2'-amino) ), Pyridyl 6.63-6.53 (m, 2H, 9-O-CH2CH=CH-Ar, 9-O-CH2CH=CH-Ar), 5.16 (dd, J1=11.0, J2=2.5Hz, 1H, H-13), 5.06 (d, J=11.0Hz, 1H, H-3), 4.89 (s, 1H, H-11), 4.75-4.65 (m, 2H, 9- ), O-CH2CH=CH-Ar 4.05 (d, J=7.0Hz, 1H, H-1'), 3.97 (d, J=16.0Hz, 1H, Pyridyl-CH2- ), COO- 3.91 (d, J=16.0Hz, 1H, Pyridyl-CH2COO), 3.90 (s, 2H, Pyridyl-CH2-CONH-), 3.77- 3.75 (m, 1H, H-8), 3.74 (d, J=3.0Hz, 1H, H-5), 3.37-3.31 (m, 1H, H-5'), 3.27-3.25 (m, 1H, H- 2'), 2.98 (s, 3H, 6-OCH3), 2.86-2.83 (m, 2H, H-2, H-3'), 2.49 (q, J=7.0Hz, 1H, H-10), 2.43 (s,6H,-N(CH3)2),2.10-2.08(m,1H,H-4),1.92-1.88(m,1H,H-14eq),1.77-1.75(m,1H,H- 4'eq),1.60-1.52(m,1H,H-14ax),1.49(s,3H,12-CH3),1.43-1.40(s,1H,H-7a),1.33(s, 3H, 6-CH3), 1.24 (d, J=6.5Hz, 3H, 10-CH3), 1.15 (d, J=6.5Hz, 3H, 5'-CH3), 1.05-1.03 (m, 6H, 4-CH3,8-CH3), 0.96 (d, J=7.0Hz, 3H, 2-CH3), 0.85 (t, J=7.0Hz, 3H, 15-CH3) .13C NMR (CDCl3,125MHz)δ:173.8,170.3,167.7,164.9,154.8,154.6,153.9,152.0,149.5,149.2, 148.0,146.8,137.2,136.7,131.4,129.7,124.4,124.1,122.4,122.3,116.9,111.6, 103.0,84.9,83.0,81.7,78.5,78.5,75.7,73.6,70.4,68.8,65.8,49.9,46.2,43.7,43.2, 37.2,36.5,32.9,25.8,22.2,20.9,19.4,18.8,15.6,15.1,13.0,10.1,8.9.

Example 14:

It prepares first: 2'-O- acetyl group -3-O- descladinosylation -3- hydroxyl -6-O-methylerythromycin A9-O- [3- (3'- (5'- amino) pyridyl group)-E-2- acrylic] oxime -11,12- cyclic carbonate ester synthesis (6c)

1.00g (1.40mmol) compound 5 is dissolved in acetonitrile (by degassing process) (10mL), adds three (o-tolyl) phosphines (171mg, 0.56mmol), palladium acetate (63mg, 0.28mmol), triamine (0.39mL, 2.80mmol), 3- amino -5- bromopyridine (728mg,4.20mmol).Reaction system is replaced 4 times with argon gas, under protection of argon gas, in 60 DEG C of stirring 1h, is then stirred in 90 DEG C It mixes for 24 hours.Distilled water (10mL) stopped reaction is added after reaction, is extracted with ethyl acetate (20mL), upper organic phase is used full It is washed with saline solution (10mL), concentrated by rotary evaporation, dry solids.(100-200 mesh silicagel column, mobile phase V are chromatographed through column (methylene chloride): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) obtain compound 6c (231mg, 0.28mmol, 20.0%).

Secondly it prepares: 3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A 9-O- ﹛ The synthesis of 3- [3'- [5'-N- (2 "-pyridine acetyl group) amino] pyridyl group]-E-2- Bing Xi Ji ﹜ oxime -11,12- cyclic carbonate ester (7c)

Compound 6c (231mg, 0.28mmol) is dissolved in CH2Cl2 (20mL), 2- pyridine second is added with stirring in 0 DEG C Acid hydrochloride (125mg, 0.70mmol), DCC (148mg, 0.70mmol), DMAP (88mg, 0.70mmol) are slowly dropped into pyridine After (0.09mL, 1.12mmol) stirs 1h, it is warming up to 15 DEG C of reaction 23h.It first filters after reaction and removes dicyclohexylurea, then plus Enter CH2Cl2 (30mL) extraction, washed with saturation NaHCO3 solution (25mL), lower layer's organic phase is respectively with saturation NH4Cl solution (25mL) wash twice, is saturated that NaHCO3 solution (25mL) washed once, semi-saturation NaCl solution (25mL) washed once, by Revolving, drying can obtain solids (280mg, 0.27mmol, 96.4%).(100-200 mesh silicagel column, mobile phase V are chromatographed through column (methylene chloride): V (ethyl alcohol): V (ammonium hydroxide)=15:0.6:0.1) obtain 2'-OAc-7c (170mg, 0.163mmol, 60.4%).

170mg (0.163mmol) 2'-OAc-7c is dissolved in 20mL methanol, 65 DEG C of reflux 3h, concentrated by rotary evaporation, dry Product 160mg (0.160mmol, yield 98.2%).Preparing plate through thin-layer chromatography silica gel, (mobile phase is V (petroleum ether): V (third Ketone): V (triethylamine)=5:20:0.2) obtain 7c sterling (35.5mg, 0.035mmol, 21.9%).

HRMS(ESI)(M+H)+m/z 1001.52346,calcd for C53H73N6O131001.52301.1H NMR (CDCl3,500MHz), δ:

10.22 (s, 1H ,-NH-CO-), 8.65 (d, J=4.5Hz, 1H, 2'-Pyridyl), 8.56 (d, J=2.5Hz, 1H, 3'- (5'-amino) Pyridyl), the 8.54 (- Pyridyl of d, J=5.0Hz, 1H, 2 "), 8.32 (d, J=1.5Hz, 1H, 3'-(5'-amino)Pyridyl),8.13(s,1H,3'-(5'-amino)Pyridyl),7.73-7.67(m,2H,2'- Pyridyl, 2 "-Pyridyl), the 7.35-7.24 (- Pyridyl of m, 4H, 2'-Pyridyl, 2 "), 6.59 (d, J=16.5Hz, 1H, 9-O-CH2CH=CH-Ar), 6.45 (dt, J1=16.5, J2=5.5Hz, 1H, 9-O-CH2CH=CH-Ar), 5.16 (dd, J1=11.0Hz, J2=2.5Hz, 1H, H-13), 5.06 (d, J=11.5Hz, 1H, H-3), 4.88 (s, 1H, H-11), 4.75- 4.64 (m, 2H, 9-O-CH2CH=CH-Ar), 4.08 (d, J=7.0Hz, 1H, H-1'), 3.97 (d, J=16.0Hz, 1H, ), Pyridyl-CH2-COO- 3.90 (d, J=16.0Hz, 1H, Pyridyl-CH2-COO-), 3.90 (s, 2H, Pyridyl- ), CH2-CONH- 3.80-3.77 (m, 1H, H-8), 3.74 (d, J=3.0Hz, 1H, H-5), 3.38-3.33 (m, 2H, H-5', H- 2'), 2.98 (s, 3H, 6-OCH3), 2.85-2.82 (m, 1H, H-2), 2.55 (s, 6H ,-N (CH3) 2), 2.49 (q, J= 7.0Hz,1H,H-10),2.11-2.09(m,1H,H-4),1.93-1.90(m,2H,H-14eq,H-4'eq),1.59-1.52(m, 1H,H-14ax),1.49(s,3H,12-CH3),1.40-1.38(m,1H,H-7a),1.33(s,3H,6-CH3),1.33-1.30 (m, 1H, H-7b), 1.23 (d, J=7.0Hz, 3H, 10-CH3), 1.16 (d, J=6.0Hz, 3H, 5'-CH3), 1.05 (d, J= 6.5Hz, 3H, 4-CH3), 1.02 (d, J=7.5Hz, 3H, 8-CH3), 0.96 (d, J=7.0Hz, 3H, 2-CH3), 0.85 (t, J =7.0Hz, 3H, 15-CH3) .13C NMR (CDCl3,125MHz) δ: 173.8,170.3,167.6,164.8,155.0, 154.6,153.9,149.2,148.9,143.6,140.2,137.6,136.7,132.8,129.0,128.3,124.4, 124.4,123.7,122.4,122.4,115.5,103.0,84.9,83.0,81.8,78.5,78.5,75.7,73.8,70.3, 68.8,65.7,49.9,45.4,43.7,43.2,40.4,37.2,36.5,32.9,25.8,22.2,20.9,19.4,18.8, 15.6,15.1,13.0,10.1,8.9.

Example 15:

It prepares first: 2'-O- acetyl group -3-O- descladinosylation -3- hydroxyl -6-O-methylerythromycin A9-O- [3- (3'- (6'- amino) pyridyl group)-E-2- acrylic] oxime -11,12- cyclic carbonate ester synthesis (6d)

1.00g (1.40mmol) compound 5 is dissolved in acetonitrile (by degassing process) (10mL), adds three (o-tolyl) phosphines (171mg, 0.56mmol), palladium acetate (63mg, 0.28mmol), triethylamine (0.39mL, 2.80mmol), 2- amino -5- bromine pyrrole Pyridine (728mg, 4.20mmol).Reaction system is replaced 4 times with argon gas, under protection of argon gas, in 60 DEG C of stirring 1h, then in 90 DEG C Stirring is for 24 hours.Distilled water (10mL) stopped reaction is added after reaction, is extracted with ethyl acetate (20mL), upper organic phase is used Saturated salt solution (10mL) washing, concentrated by rotary evaporation, dry solids.(100-200 mesh silicagel column, mobile phase V are chromatographed through column (methylene chloride): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) obtain compound 6d (369mg, 0.46mmol, 32.9%).

Secondly it prepares: 3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A 9-O- ﹛ 3- [3'- [6'-N- (2 "-pyridine acetyl group) amino)] pyridyl group]-E-2- Bing Xi Ji ﹜ oxime -11,12- cyclic carbonate ester synthesis (7d)

Compound 6d (218mg, 0.27mmol) is dissolved in CH2Cl2 (20mL), 2- pyridine second is added with stirring in 0 °C Acid hydrochloride (118mg, 0.68mmol), DCC (140mg, 0.68mmol), DMAP (83mg, 0.68mmol) are slowly dropped into pyridine After (0.09mL, 1.08mmol) stirs 1h, 15 DEG C are warming up to, reacts 23h.It first filters after reaction and removes dicyclohexylurea, then CH2Cl2 (30mL) extraction is added, is washed with saturation NaHCO3 solution (25mL), lower layer's organic phase is respectively with saturation NH4Cl solution (25mL) wash twice, is saturated that NaHCO3 solution (25mL) washed once, semi-saturation NaCl solution (25mL) washed once, by Revolving, drying can obtain solids (280mg, 0.27mmol, 100.0%).Through column chromatography, (100-200 mesh silicagel column, mobile phase are V (methylene chloride): V (ethyl alcohol): V (ammonium hydroxide)=15:0.6:0.1) obtain 2'-OAc-7d (87mg, 0.083mmol, 30.7%).

87mg (0.083mmol) 2'-OAc-7d is dissolved in 20mL methanol, 65 DEG C of reflux 3h, concentrated by rotary evaporation, it is so dry that produce Object 80mg (0.080mmol, yield 96.4%).Preparing plate through thin-layer chromatography silica gel, (mobile phase is V (petroleum ether): V (acetone): V (triethylamine)=5:20:0.2) obtain 7d sterling (30mg, 0.030mmol, 37.5%).

HRMS(ESI)(M+H)+m/z 1001.51975,calcd for C53H73N6O131001.52301.1H NMR (CDCl3,500MHz), δ: 10.05 (s, 1H ,-NH-CO-), 8.68 (d, J=4.0Hz, 1H, 2'-Pyridyl), 8.52 (d, J =4.5Hz, 1H, 2 "-Pyridyl), 8.26 (d, J=2.0Hz, 1H, 3'- (6'-amino) Pyridyl), 8.16 (d, J= 8.5Hz,1H,3'-(6'-amino)Pyridyl),7.73-7.66(m,3H,2'-Pyridyl,2”-Pyridyl,3'-(6'- Amino) Pyridyl), 7.35 (d, J=7.5Hz, 1H, 2'-Pyridy), the 7.29 (- Pyridyl of d, J=7.5Hz, 1H, 2 "), The 7.25-7.20 (- Pyridyl of m, 2H, 2'-Pyridy, 2 "), 6.54 (d, J=16.0Hz, 1H, 9-O-CH2CH=CH-Ar), 6.35 (dt, J1=16.0, J2=6.0Hz, 1H, 9-O-CH2CH=CH-Ar), 5.15 (dd, J1=10.5Hz, J2=2.0Hz, 1H, H-13), 5.07 (d, J=11.0Hz, 1H, H-3), 4.89 (s, 1H, H-11), 4.72-4.63 (m, 2H, 9-O-CH2CH= ), CH-Ar 4.04 (d, J=7.0Hz, 1H, H-1'), 3.96 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.91 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), the 3.90 (- Pyridyl-CH2-CONH- of s, 2H, 2 "), 3.77- 3.73 (m, 1H, H-8), 3.73 (d, J=3.0Hz, 1H, H-5), 3.35-3.33 (m, 1H, H-5'), 3.22-3.19 (m, 1H, H- 2'), 2.98 (s, 3H, 6-OCH3), 2.88-2.81 (m, 1H, H-2), 2.79-2.75 (br, 1H, H-3'), 2.49 (q, J= 7.0Hz,1H,H-10),2.39(s,6H,-N(CH3)2),2.10-2.08(m,1H,H-4),1.91-1.88(m,1H,H- 14eq),1.72-1.70(m,1H,H-4'eq),1.57-1.54(m,1H,H-14ax),1.48(s,3H,12-CH3),1.43- 1.40 (m, 1H, H-7a), 1.33 (s, 3H, 6-CH3), 1.30-1.27 (m, 1H, H-7b), 1.23 (d, J=7.0Hz, 3H, 10- ), CH3 1.15 (d, J=6.5Hz, 3H, 5'-CH3), 1.06-1.03 (m, 6H, 4-CH3,8-CH3), 0.94 (d, J=7.0Hz, 3H, 2-CH3), 0.86 (t, J=7.5Hz, 3H, 15-CH3) .13C NMR (CDCl3,125MHz) δ: 173.8,170.3, 167.5,164.8,154.8,154.6,153.9,150.6,149.5,149.2,146.4,137.3,136.6,135.2, 128.9,128.5,126.8,124.3,124.1,122.3,113.7,103.4,84.9,83.0,81.6,78.5,78.5, 75.6,74.0,70.5,69.1,65.7,49.9,46.1,43.8,43.2,40.4,37.2,36.6,32.9,25.8,22.2, 21.0,19.4,18.8,15.6,15.1,13.0,10.1,8.8.

Example 16:

It prepares first: 3-O- descladinosylation -3-O- [2- (2'- pyridine) acetyl group] -6-O-methylerythromycin A 9-O- { 3- [3'- (6'- amino) pyridyl group] -2- acrylic } oxime -11,12- cyclic carbonate ester (7e)

244mg (0.30mmol) compound 12 is dissolved in methylene chloride (20mL), 2- pyridine second is added with stirring in 0 °C Pyridine is slowly added dropwise in acid hydrochloride (135mg, 0.78mmol), DCC (162mg, 0.79mmol), DMAP (93mg, 0.76mmol) (0.10mL, 1.21mmol).After stirring 1h, ice-water bath is removed, reacts 6h at 18 DEG C.Decompression, which filters, after reaction removes two Cyclohexyl urea is washed with saturated sodium bicarbonate solution (25mL), and lower layer's organic phase is washed with saturated ammonium chloride solution (25mL) respectively It washs twice, saturated sodium bicarbonate solution (25mL) washed once, and distilled water (25mL) washed once, and saturated salt solution (25mL) is washed It washs once, is evaporated under reduced pressure later, drying can obtain solids.Through column chromatography (100-200 mesh silica gel, mobile phase V (methylene chloride): V (ethyl alcohol): V (ammonium hydroxide)=10:0.4:0.1) obtain 2'-OAc-7e (104mg, 0.10mmol, 33.3%).

104mg (0.10mmol) 2'-OAc-7e is dissolved in respectively in methanol (20mL), 65 °C of reflux 3h, is evaporated under reduced pressure dense Contracting, obtains dry product.Plate (mobile phase V (petroleum ether): V (acetone): V (three second are prepared through thin-layer chromatography silica gel respectively again Amine)=5:20:0.2) obtain 7e sterling (29mg, 0.029mmol, 29.0%).

HRMS(ESI)(M+H)+m/z 882.48453,calcd for C46H68N5O12882.48590.1H NMR (CDCl3,500MHz), δ:

8.53-8.52 (m, 1H, 2'-Pyridyl), 8.02 (d, J=2.0Hz, 1H, 3'- (6'-amino) Pyridyl), 7.67 (td, J1=8.0Hz, J2=2.0Hz, 1H, 2'-Pyridyl), 7.55 (dd, J1=2.0Hz, J2=8.5Hz, 1H, 3'- (6'-amino) Pyridyl), 7.35 (d, J=8.0Hz, 1H, 2'-Pyridyl), 7.22-7.20 (m, 1H, 2'-Pyridyl), 6.49-6.46 (m, 2H, 3'- (6'-amino) Pyridyl, 9-O-CH2CH=CH-Ar), 6.22 (dt, J1=6.5Hz, J2= 16.0Hz, 1H, 9-O-CH2CH=CH-Ar), 5.16 (dd, J1=11.0Hz, J2=2.5Hz, 1H, H-13), 5.07 (d, J= 11.0Hz, 1H, H-3), 4.89 (s, 1H, H-11), 4.68-4.61 (m, 2H, 9-O-CH2CH=CH-Ar), 4.50 (br, 2H ,- ), NH2 4.04 (d, J=7.5Hz, 1H, H-1'), 3.96 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.91 (d, J=16.0Hz, 1H, 2'-Pyridyl-CH2-COO-), 3.76-3.71 (m, 1H, H-8), 3.73 (d, J=3.0Hz, 1H, ), H-5 3.36-3.32 (m, 1H, H-5'), 3.23 (dd, J1=10.0Hz, J2=7.5Hz, 1H, H-2'), 2.98 (s, 3H, 6- ), OCH3 2.86-2.82 (m, 1H, H-2), 2.80-2.77 (m, 1H, H-3'), 2.49 (q, J=7.0Hz, 1H, H-10), 2.38 (s,6H,-N(CH3)2),2.10-2.08(m,1H,H-4),1.93-1.88(m,1H,H-14eq),1.72-1.70(m,1H,H- 4'eq),1.59-1.52(m,1H,H-14ax),1.49(s,3H,12-CH3),1.43-1.40(m,1H,H-7a),1.33(s, 3H, 6-CH3), 1.30-1.27 (m, 1H, H-7b), 1.24 (d, J=6.5Hz, 3H, 10-CH3), 1.15 (d, J=6.0Hz, 3H, 5'-CH3), 1.06-1.03 (m, 6H, 4-CH3,8-CH3), 0.94 (d, J=7.0Hz, 3H, 2-CH3), 0.86 (t, J= 7.0Hz,3H,15-CH3).13C NMR(CDCl3,125MHz)δ:173.8,170.3,164.6,157.7,154.7,154.0, 149.2,147.0,136.6,134.9,129.3,124.3,123.8,122.3,108.7,103.5,84.9,83.1,81.6, 78.5,78.5,75.6,74.4,70.5,69.1,65.7,49.9,43.8,43.2,40.4,37.2,36.6,32.9,25.7, 22.2,21.0,19.4,18.8,15.6,15.1,13.0,10.1,8.8.

Hydrogen spectrum and carbon spectrum combine high resolution mass spectrum to determine that compound 7e that is synthesized and purifying is following structural formula:

According to Clinical and Laboratory Standards Institute (CLSI, 2010) recommend standard, Using broth dilution method determination partial target compound to sensitive streptococcus pneumonia ATCC49619, mef type drug resistance pneumonia streptococcus (methicillin-resistant is golden yellow by bacterium PU-09, erm type drug resistance streptococcus pyogenes 01-968, erm type resistant Staphylococcus aureus PU-32 Color staphylococcus MRSA) antibacterial activity in vitro.Every plant of bacterium all turns a work by plate point pure before the test, is used with new fresh thalli In test.Experiment uses reference culture as sensitive experiment Quality Control bacterium every time；With the bacterium solution without antibacterials as test organisms Strain growth control.Minimum inhibitory concentration (MIC) uses the micro meat soup doubling dilution of standard.Antibacterials measure concentration range 256/64-0.008mg/L being tested bacterium solution final concentration is about 5 × 10⁵CFU/ml。

Measurement result see the table below 1-2, and table 1 is compound 3a-3e and 7a-7e minimum inhibitory concentration MIC (μ g/mL), and table 2 is Compound 3f-3k minimum inhibitory concentration MIC (μ g/mL).

Table 1

Table 2

To Quality-control strains-streptococcus pneumonia ATCC 49619 of antibacterial test, the compound having disclosed (is equivalent to general formula Ar=3- quinoline and 4- isoquinolin in I and II) MIC to be all larger than equal to 1 μ g/mL, Ketek MIC be 0.016 μ g/mL, from As can be seen that its MIC of compound prepared by the present invention maximum ability 0.125 μ g/mL, MIC are the smallest to be less than or equal to survey in upper table 0.008 μ g/mL of the lowest limit is tried, shows antibacterial activity outstanding.

Above-mentioned data be shown in drug-fast bacteria comparison on, the present invention also has prominent effect, show good anti-sensitive bacteria and Antimicrobial agent activity.For example, compared with the ketone lactone-Ketek listed at present, preferred compound in the present invention (such as change Close object 3e and 7e, that is, Ar=6- amino -3- pyridyl group, compound 3g, that is, 5- amino -3- pyridyl group or compound 3h, that is, 5- ammonia Base formoxyl -3- pyridyl group) there is quite or more preferably antibacterial activity.

Further, 10 μ l culture solutions are taken to be coated on not antibiotic plate from 1-8 times of MIC concentration-response hole, through 35 DEG C, it is incubated within 24 hours, the minimum antibacterials concentration of clump count≤5 is minimum bactericidal concentration (MBC), is greater than 99.9% at this time Bacterium be killed, as a result see the table below 3, table 3 is compound 3f-3k minimum bactericidal concentration MBC (μ g/mL).

Table 3

Through table 3 as it can be seen that compared with clarithromycin, the compound in the embodiment of the present invention also shows very outstanding The Ketek of excellent bactericidal activity, bactericidal activity and antimicrobial agent is quite even more excellent.In addition, compound 3f-3k Minimum bactericidal concentration and the ratio of minimum inhibitory concentration are less than or equal to 4, show " characteristics of germ killing drugs ".

By above-mentioned experimental data it is found that the embodiment of the present invention changes the existing structure-activity relationship understanding in this field significantly, Many deficiencies of middle ketone lactone compared with the prior art, the present invention break through existing structure-activity relationship knowledge, and providing has sterilization Active novel non-ketone lactone is suitable with the activity of Ketek and easy to industrialized production.

For embodiment of the method, for simple description, therefore, it is stated as a series of operative combination, but this field Technical staff should be aware of, and the present invention is not limited by described operation order, because according to the present invention, certain steps can Sequentially or simultaneously to be carried out using other.Secondly, those skilled in the art should also know that, implementation described in this description Example belongs to preferred embodiment, and related operation and experiment condition are not necessarily essential to the invention.

Above to a kind of novel acyl lactone derivative provided by the present invention and a kind of system of novel acyl lactone derivative Preparation Method is described in detail, and used herein a specific example illustrates the principle and implementation of the invention, The above description of the embodiment is only used to help understand the method for the present invention and its core ideas；Meanwhile for the one of this field As technical staff, according to the thought of the present invention, there will be changes in the specific implementation manner and application range, to sum up institute It states, the contents of this specification are not to be construed as limiting the invention.

Claims

1. a kind of acyl lactone derivative, which is characterized in that the acyl lactone derivative has the following general formula I or general formula II or institute State acyl lactone derivative be acceptable salt that compound with the following general formula I or II and inorganic acid or organic acid are formed or Ester；

Wherein, A is nitrogen-atoms and B is carbon atom or nitrogen-atoms, and X is amino, carbamoyl or nitro.

2. acyl lactone derivative as described in claim 1, which is characterized in that in the general formula I or the general formula II, Ar is represented Substituted heteroaryl be the pyridyl group or pyrimidine radicals replaced by a substituent group.

3. acyl lactone derivative as claimed in claim 2, which is characterized in that in the general formula I or the general formula II, the Ar The substituted heteroaryl represented is 5- amino -3- pyridyl group, 5- carbamoyl -3- pyridyl group, 6- nitro -3- pyridyl group, 6- Amino -3- pyridyl group, 2- amino -3- pyridyl group, 4- amino -3- pyridyl group, 5- amino -2- pyridyl group, 6- amino -2- pyridine Base, 2- amino -4- pyridyl group or 2- amino-5-pyrimidine base.

4. acyl lactone derivative as described in claim 1, which is characterized in that in the general formula I or the general formula II, Ar is represented Substituted heteroaryl be following i~xi in it is any:

5. acyl lactone derivative as described in claim 1, which is characterized in that the inorganic acid be hydrochloric acid, sulfuric acid, hydrobromic acid or Phosphoric acid；The organic acid is acetic acid, malonic acid, methanesulfonic acid, succinic acid, p-methyl benzenesulfonic acid, citric acid, maleic acid, fumaric acid, cream Acid, benzoic acid or malic acid.