CN114380874A - Macrolide antibiotics and preparation method and application thereof - Google Patents
Macrolide antibiotics and preparation method and application thereof Download PDFInfo
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- CN114380874A CN114380874A CN202111545813.5A CN202111545813A CN114380874A CN 114380874 A CN114380874 A CN 114380874A CN 202111545813 A CN202111545813 A CN 202111545813A CN 114380874 A CN114380874 A CN 114380874A
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- compound
- reaction
- isocyanate
- macrolide antibiotic
- heterocyclic group
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- 239000003120 macrolide antibiotic agent Substances 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 40
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 28
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention provides a macrolide antibiotic and a preparation method and application thereof, belonging to the technical field of medicines. The macrolide antibiotic provided by the invention has a structure shown in a formula I, wherein in the formula I, R comprises phenyl, naphthyl, heterocyclic group, substituted phenyl or substituted heterocyclic group. The 2-site in the macrolide antibiotic provided by the invention is a fluorine atom, and an 11-N- [3- [ [ (N-R) carbamate ] propyl ] ] group is introduced into the 11-site N, so that the inhibitory activity on macrolide drug-resistant bacteria is improved; in addition, the macrolide antibiotic provided by the invention has low cytotoxicity, hepatotoxicity and other side effects, and can be used for preparing anti-infective drugs.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to macrolide antibiotics and a preparation method and application thereof.
Background
Since 1952, the first macrolide antibiotic erythromycin A (ertyrromycinA) developed by Lilly (Lilly) has been marketed to date, and the macrolide antibiotic has been clinically used for nearly seventy years. The action mechanism of macrolide antibiotics is to inhibit protein synthesis, bind irreversibly to bacterial ribosome 50S subunit, and selectively inhibit protein synthesis by blocking transpeptidation and mRNA translocation.
Currently, macrolide antibiotics include first generation macrolide antibiotics, second generation macrolide antibiotics, and third generation macrolide-ketolide antibiotics. Among them, the marketed third-generation macrolide antibiotic-ketolide is only Telithromycin (HMR-3647, Telithromycin), and its structural formula is as follows:
it has strong activity on Mef-type streptococcus pneumoniae, Erm-type streptococcus pneumoniae, staphylococcus aureus, enterococcus faecalis and the like. However, telithromycin has been found to have severe hepatotoxicity in clinical IV studies, limiting its clinical use.
The structural formula of the subsequent research and development of Solithromycin (CEM-101, Solithromycin) is as above, the 2-site is fluorinated on the basis of the structure of the telithromycin, the interaction of halogen is increased, the antibacterial activity similar to that of the telithromycin is kept, and the 4-metanilino-1H-1, 2, 3-triazole side chain is connected with the Solithromycin to replace the pyridine part of the telithromycin imidazole, so that the Solithromycin has no obvious inhibition effect on an alpha 7 nicotinic acetylcholine receptor, the hepatotoxicity of the Solithromycin is lower, and the pharmacokinetic property of the Solithromycin is also improved. However, telithromycin is marketed with 3 reported serious hepatotoxic events, 1 of which leads to death and 1 of which leads to liver transplantation, the potential risk of hepatotoxicity of which has not been fully characterized. Therefore, the development of macrolide antibiotics having excellent inhibitory activity against drug-resistant bacteria and little side effects such as hepatotoxicity is in the spotlight.
Disclosure of Invention
In view of the above, an object of the present invention is to provide a macrolide antibiotic, which has high antibacterial activity and little side effects such as hepatotoxicity, and a method for producing the same and use thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a macrolide antibiotic which has a structure shown in a formula I:
in the formula I, R comprises phenyl, naphthyl, heterocyclic group, substituted phenyl or substituted heterocyclic group.
Preferably, the substituent on the benzene ring in the substituted phenyl group comprises C1～6Alkyl radical, C1～6Alkoxy, halogen, halogeno C1～6Alkyl, halo C1～6Alkoxy radicalPhenyl, naphthyl, C1～6One or two of alkylthio, cyano, nitro and pyrimidinyl;
the heterocyclic group includes pyridyl, pyrimidyl, thienyl or furyl;
said substituted heterocyclic group includes benzofuranyl, benzothienyl, benzothiadiazolyl, benzmethylenedioxy, C1～6Alkyl-substituted isoxazolyl or C1～6Alkyl substituted furyl.
The invention provides a preparation method of the macrolide antibiotic in the technical scheme, which comprises the following steps:
mixing a compound II, R-isocyanate, a catalyst and a soluble compound II solvent for an acylation reaction to obtain a compound III; r in the R-isocyanate comprises phenyl, naphthyl, heterocyclic group, substituted phenyl or substituted heterocyclic group;
carrying out hydrolysis reaction or alcoholysis reaction on the compound III to obtain the macrolide antibiotic;
preferably, the molar ratio of the compound II to the R-isocyanate is 1: (1.1-3).
Preferably, the temperature of the acylation reaction is-5-30 ℃ and the time is 5-40 h.
Preferably, the hydrolysis reaction is carried out under a protective atmosphere;
the temperature of the hydrolysis reaction is 40-100 ℃, and the time is 3-24 h.
Preferably, the alcoholysis reaction is carried out under a protective atmosphere; the alcoholysis reaction is carried out at the temperature of 40-70 ℃ for 3-24 hours.
Preferably, the compound II is obtained by performing Maillard addition reaction on the compound IV and 1-aminopropanol;
the invention provides the application of the macrolide antibiotic in the technical scheme or the macrolide antibiotic obtained by the preparation method in the technical scheme in the preparation of anti-infective drugs.
The invention provides a macrolide antibiotic which has a structure shown in a formula I, wherein in the formula I, R comprises phenyl, naphthyl, heterocyclic group, substituted phenyl or substituted heterocyclic group. The 2-site in the macrolide antibiotic provided by the invention is a fluorine atom, and an 11-N- [3- [ [ (N-R) carbamate ] propyl ] ] group is introduced into the 11-site N, so that the inhibitory activity on macrolide drug-resistant bacteria is improved; in addition, the macrolide antibiotic provided by the invention has low cytotoxicity, hepatotoxicity and other side effects, and can be used for preparing anti-infective drugs.
The invention provides the preparation method of the macrolide antibiotic in the technical scheme, and the preparation method provided by the invention is simple to operate and suitable for industrial production.
Drawings
Figure 1 is the stability of verapamil in human liver microsomes;
FIG. 2 is a graph of I-29 stability in human liver microsomes;
FIG. 3 is a graph of I-2 stability in human liver microsomes;
FIG. 4 is a graph showing the stability of I-50 in human liver microsomes;
figure 5 shows the stability of I-58 in human liver microsomes.
Detailed Description
The invention provides a macrolide antibiotic which has a structure shown in a formula I:
in the formula I, R comprises phenyl, naphthyl, heterocyclic group, substituted phenyl or substituted heterocyclic group.
In the present invention, the substituent on the benzene ring in the substituted phenyl group preferably includes C1～6Alkyl radical, C1～6Alkoxy, halogen, halogeno C1～6Alkyl radicalHalogen substituted C1～6Alkoxy, phenyl, naphthyl, C1～6One or two of alkylthio, cyano, nitro and pyrimidinyl. In the present invention, said C1～6The alkyl group preferably includes a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a pentyl group or a hexyl group. In the present invention, C1～6Alkoxy preferably includes methoxy, 3, 4-methylenedioxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy or hexoxy. In the present invention, the halogen preferably includes one or more of fluorine, chlorine, bromine and iodine. In the present invention, the halogen C1～6The halogen in the alkyl preferably comprises one or more of fluorine, chlorine, bromine and iodine; said halo C1～6The number of halogen atoms in the alkyl group is preferably 1,2 or 3; said halo C1～6C in alkyl1～6The kind of alkyl group is preferably the same as C1～6The alkyl groups are of the same type and are not described in detail herein. In the present invention, the heterocyclic group preferably includes a pyridyl group, a pyrimidinyl group, a thienyl group or a furyl group. In the present invention, the substituted heterocyclic group includes benzofuranyl, benzothienyl, benzothiadiazolyl, benzmethylenedioxy, C1～6Alkyl-substituted isoxazolyl or C1～6Alkyl substituted furyl.
In the present invention, the R preferably has any one of the structures represented by R-1 to R-58:
the invention provides a preparation method of the macrolide antibiotic in the technical scheme, which comprises the following steps:
mixing a compound II, R-isocyanate, a catalyst and a soluble compound II solvent for an acylation reaction to obtain a compound III; r in the R-isocyanate comprises phenyl, naphthyl, heterocyclic group, substituted phenyl or substituted heterocyclic group;
carrying out hydrolysis reaction or alcoholysis reaction on the compound III to obtain the macrolide antibiotic;
in the present invention, all the raw material components are commercially available products well known to those skilled in the art unless otherwise specified.
The compound II, R-isocyanate, a catalyst and an organic solvent are mixed for acylation reaction to obtain a compound III.
In the present invention, the compound ii is preferably obtained by performing a michaelis addition reaction between the compound iv and 1-aminopropanol, and the specific steps preferably include: dissolving a compound IV in an organic solvent to obtain a compound IV solution, mixing the compound IV solution and 1-aminopropanol, and carrying out Maifand addition reaction to obtain a compound II. In the present invention, the molar ratio of the compound IV to 1-aminopropanol is preferably 1: (1-10), more preferably 1: (3-5). In the present invention, the organic solvent preferably includes N, N-dimethylformamide and/or acetonitrile; the ratio of the amount of the substance of the compound IV to the volume of the organic solvent is preferably 1 mmol: (5-10) mL, more preferably 1 mmol: (7-8) mL. In the invention, the mixing temperature is preferably-75-5 ℃, and more preferably-50-10 ℃; the mixing time is preferably 2-24 h, and more preferably 4 h; the mixing method is preferably stirring mixing, and the speed of stirring mixing is not particularly limited in the present invention, and the raw materials may be uniformly mixed. In the invention, the temperature of the Maillard addition reaction is preferably 5-40 ℃, and more preferably room temperature; the time of the Maillard addition reaction is preferably 20-72 h, and more preferably 20-48 h; the reaction generated in the Maillard addition reaction process is shown as a formula (1).
After the Michael addition reaction, the method preferably further comprises the steps of sequentially extracting, washing, drying, concentrating and separating by column chromatography to obtain a compound II. In the invention, the extraction preferably comprises ethyl acetate extraction and water extraction which are sequentially carried out, and the times of the ethyl acetate extraction and the water extraction are independently preferably 2-3 times; the washing preferably comprises water washing and saturated salt water washing which are sequentially carried out; the drying preferably comprises anhydrous sodium sulfate drying and normal-temperature drying which are sequentially carried out, and the normal-temperature drying time is preferably 2-3 h; the concentration mode of the invention is not particularly limited, and the concentration mode known to those skilled in the art can be adopted, such as reduced pressure distillation; the eluent adopted by the column chromatography separation preferably comprises an ammonia water-petroleum ether-ethyl acetate mixed solvent or an ammonia water-petroleum ether-acetone mixed solvent, and the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate mixed solvent is preferably 1: (1-2), more preferably 1: 1.5; the volume ratio of the petroleum ether to the acetone in the petroleum ether-acetone mixed solvent is preferably 3: 1; the eluent preferably further contains ammonia water, and the volume concentration of the ammonia water in the eluent is preferably 0.25-0.5%.
In the present invention, R in the R-isocyanate includes phenyl, naphthyl, heterocyclic group, substituted phenyl or substituted heterocyclic group. In the present invention, the heterocyclic group, the substituted phenyl group or the substituted heterocyclic group is the same as the aforementioned heterocyclic group, substituted phenyl group or substituted heterocyclic group in the optional kinds, and is not described herein in detail, that is, R in R-isocyanate is the same as R in formula I. In the present invention, the R-isocyanate preferably includes 4-trifluoromethylphenyl isocyanate, 4-fluorobenzene isocyanate, 4-ethylphenyl isocyanate, 4-isopropylphenyl isocyanate, 4-methoxybenzene isocyanate, 3-methoxybenzene isocyanate, 2-naphthylphenyl isocyanate, 1-naphthylphenyl isocyanate, 4-phenylphenyl isocyanate, 3-pyridine isocyanate, 3-fluorobenzene isocyanate, 3-methylbenzene isocyanate, 4-methylbenzene isocyanate, 3-methylthiophenyl isocyanate, 3,4- (methylenedioxy) isocyanate, 3-trifluoromethyl-4-chlorobenzene isocyanate, 3, 5-dimethylbenzene isocyanate, 3-cyanobenzene isocyanate, 4-isopropylphenyl isocyanate, 4-methoxybenzene isocyanate, 2-naphthylphenyl isocyanate, 1-naphthylphenyl isocyanate, 4-phenylphenyl isocyanate, 3-pyridine isocyanate, 3-fluorobenzene isocyanate, 3-methylthio-isocyanate, 3-tolylisocyanate, 4-tolylisocyanate, 3-tolylisocyanate, and the like, 2, 4-difluorophenylisocyanate, 4-trifluoromethoxybenzylisocyanate, 4-methoxybenzylisocyanate, 3, 4-difluorophenylisocyanate, 3, 4-dichlorophenylisocyanate, 4-cyanobenzylisocyanate, 3-nitrophenylylisocyanate, 4-nitrophenylylisocyanate, 2-nitrophenylylisocyanate, 3-trifluoromethylphenylisocyanate, 2-methylphenylisocyanate, 2-fluorobenzylisocyanate, 2-methoxybenzylisocyanate, 2-chlorobenzylisocyanate, 3-chlorobenzylisocyanate, 4-chlorobenzylisocyanate, 2, 4-dimethylbenzylisocyanate, 3, 4-dimethylbenzylisocyanate, 4-ethoxyphenylisocyanate, 4-methyl-3-chlorobenzylisocyanate, 4-methylbenzylisocyanate, 4-chlorobenzylisocyanate, 4-nitrobenzylisocyanate, 4-methylbenzylisocyanate, 4-chlorobenzylisocyanate, and mixtures thereof, 5-methyl-2-chlorophenylisocyanate, 2-methyl-4-chlorophenylisocyanate, 2-methyl-6-chlorophenylisocyanate, 2-methyl-3-chlorophenylisocyanate, 4-fluoro-3-chlorophenylisocyanate, 2-methyl-3-fluorophenylisocyanate, 2, 5-difluoroisocyanate, 2, 6-dimethylphenylisocyanate, 4-cyanophenylisocyanate, 2, 3-dimethylphenylisocyanate, 2, 3-dihydro-1-benzofuran-5-isocyanate, 3-ethylphenylisocyanate, 3, 5-dimethylisoxazole-4-isocyanate, 1-benzothiophene-5-isocyanate, mixtures thereof, and mixtures thereof, 2, 5-dimethyl-furan-3-isocyanate 4- (2-pyrimidine) phenyl isocyanate, 2,1, 3-benzothiadiazole-4-isocyanate, 2-cyanobenzene isocyanate or 1-thiophene isocyanate.
In the present invention, the molar ratio of the compound II to the R-isocyanate is preferably 1: (1.1 to 3), more preferably 1: (1.5-2). In the present invention, the soluble compound ii solvent preferably includes one or more of dichloromethane, N-dimethylformamide and tetrahydrofuran. In the present invention, the ratio of the amount of the substance of the compound II to the volume of the organic solvent is preferably 1 mmol: (5-40) mL, more preferably 1 mmol: (10-30) mL. In the present invention, the catalyst preferably comprises Dicyclohexylcarbodiimide (DCC) and a pyridine-based compound; the pyridine compound preferably comprises 4-Dimethylaminopyridine (DMAP) and/or pyridine; the molar ratio of dicyclohexylcarbodiimide to the pyridine compound is preferably 1: (0.01-2, more preferably 1 (0.1-1.5), most preferably 1 (0.5-1).
In the present invention, the manner of mixing the compound ii, the R-isocyanate, the catalyst and the soluble compound ii solvent is preferably stirring mixing, and the speed and time of stirring mixing are not particularly limited in the present invention, and the raw materials may be uniformly mixed. In the present invention, the mixing is preferably performed in such a sequence that the compound ii is dissolved in the partially soluble compound ii solvent, and the mixture is mixed by adding the catalyst to obtain a mixed solution; dissolving R-isocyanate in the residual soluble compound II solvent to obtain an R-isocyanate solution; dropwise adding the R-isocyanate solution to the mixed solution. In the invention, the concentration of the compound II in the mixed solution is preferably 0.06-0.3 mol/L, and more preferably 0.15-0.2 mol/L; the concentration of the R-isocyanate solution is preferably 0.05-0.2 mol/L, and more preferably 0.09-0.1 mol/L. In the invention, the dripping is preferably carried out by using a constant-pressure dropping funnel, the dripping speed is not particularly limited, and the dripping can be carried out at a constant speed; the preferable temperature of the dropwise addition is-20-0 ℃, and the more preferable temperature is-5 ℃. In the invention, the temperature of the acylation reaction is preferably-5-30 ℃, and more preferably room temperature; the time of the acylation reaction is preferably 5-40 h, more preferably 10-20 h, and the time of the acylation reaction is timed from the end of the addition of the R-isocyanate; the acylation reaction is preferably carried out under a protective atmosphere; the protective atmosphere in the present invention is not particularly limited, and those known to those skilled in the art may be used, specifically, nitrogen or argon. In the present invention, the reaction occurring during the acylation reaction is represented by the formula (2):
after the acylation reaction, the method preferably further comprises the steps of sequentially quenching and solid-liquid separation of the reaction liquid of the acylation reaction, concentrating the obtained liquid component, and then carrying out column chromatography separation to obtain a compound III. In the present invention, the quenching agent used for the quenching preferably comprises alcohol or water, and the alcohol preferably comprises methanol or ethanol; when water is used as a quenching agent, the quenching preferably further comprises extraction and drying, and the solvent for extraction is preferably ethyl acetate; the drying is preferably anhydrous sodium sulfate drying. The solid-liquid separation method is not particularly limited, and a solid-liquid separation method known to those skilled in the art, such as filtration, may be employed. The concentration method of the present invention is not particularly limited, and a concentration method known to those skilled in the art may be used, specifically, distillation under reduced pressure. In the invention, the eluent adopted by the column chromatography separation preferably comprises a petroleum ether-acetone mixed solvent, and the volume ratio of petroleum ether to acetone in the petroleum ether-acetone mixed solvent is preferably (3-6): 1, more preferably 4: 1; the eluent preferably also contains ammonia water, and the mass percentage concentration of the ammonia water is preferably 25-28%, and more preferably 26-27%; the volume concentration of the ammonia water in the eluent is preferably 0.25-0.5%.
After the compound III is obtained, the compound III is subjected to hydrolysis reaction or alcoholysis reaction to obtain the macrolide antibiotic.
In the present invention, the hydrolysis reaction is carried out under a protective atmosphere; the temperature of the hydrolysis reaction is preferably 40-100 ℃, and more preferably 55-70 ℃; the time of the hydrolysis reaction is preferably 3-24 hours, and more preferably 5-10 hours; the solvent adopted in the hydrolysis reaction is preferably water; the amount of water used in the present invention is not particularly limited, and the hydrolysis reaction can be achieved. In the present invention, the alcoholysis reaction is carried out under a protective atmosphere; the temperature of the alcoholysis reaction is preferably 40-70 ℃, and more preferably 50-65 ℃; the time of the alcoholysis reaction is preferably 3-24 hours, and more preferably 4-20 hours; the solvent adopted in the alcoholysis reaction is preferably an alcohol solvent, and the alcohol solvent preferably comprises methanol and/or ethanol; the invention has no special limit on the dosage of the alcohol solvent, and can realize alcoholysis reaction. The protective atmosphere in the present invention is not particularly limited, and those known to those skilled in the art may be used, specifically, nitrogen or argon. In the present invention, the hydrolysis reaction or the reaction occurring during the hydrolysis reaction is represented by the formula (3):
after the hydrolysis reaction, the method preferably further comprises the steps of carrying out solid-liquid separation on a system of the hydrolysis reaction, concentrating the obtained liquid component, and carrying out column chromatography separation to obtain the macrolide antibiotic. The solid-liquid separation method is not particularly limited, and a solid-liquid separation method known to those skilled in the art, such as filtration, may be employed. The concentration method of the present invention is not particularly limited, and a concentration method known to those skilled in the art may be used, specifically, distillation under reduced pressure. In the invention, the eluent adopted by the column chromatography separation preferably comprises a petroleum ether-acetone mixed solvent, and the volume ratio of petroleum ether to acetone in the petroleum ether-acetone mixed solvent is preferably (1-3): 1, more preferably 1.5: 1; the eluent preferably also contains ammonia water, and the mass percentage concentration of the ammonia water is preferably 25-28%, and more preferably 26-27%; the volume concentration of the ammonia water in the eluent is preferably 0.25-0.5%.
The invention provides the application of the macrolide antibiotic in the technical scheme or the macrolide antibiotic obtained by the preparation method in the technical scheme in the preparation of anti-infective drugs. In the present invention, the anti-infective agent preferably comprises an anti-susceptible bacterial infection agent or an anti-drug resistant bacterial infection agent. In the present invention, the anti-infective agent preferably comprises staphylococcus, haemophilus influenzae, streptococcus, moraxella catarrhalis, streptococcus pyogenes, or streptococcus agalactiae; the staphylococci preferably comprise Staphylococcus epidermidis MRSE17-8, MRSE19-5, MRSE19-6, MRSE19-7, MRSE19-8, MRSE19-9, MRSE19-10, MRSE19-11, MRSE19-12 or MRSE 19-13; the haemophilus influenzae preferably comprises HIN19-15 or HIN 19-18; the streptococcus preferably include Streptococcus pneumoniae SPN19-8, SPN19-13 or SPN 19-14; the Moraxella catarrhalis preferably comprises Moraxella tara BCA19-5, BCA19-6, BCA19-31, BCA19-32, BCA19-33 or BCA 19-34; the streptococcus pyogenes preferably includes ATCC 19615; the Streptococcus agalactiae preferably comprises 19-8 or 19-9.
The 2-site of the macrolide antibiotic provided by the invention is fluorine atom, and an 11-N- [3- [ [ (N-R) carbamate ] propyl ] ] group is introduced into the 11-site N, so that the inhibitory activity on macrolide drug-resistant bacteria is improved; in addition, the macrolide antibiotic provided by the invention has low cytotoxicity and can be applied to preparation of anti-infective drugs.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Dissolving 19mmol of compound IV in 110mLN, N-dimethylformamide, adding 21mmol of 1-aminopropanol at-5 ℃, carrying out Maifanshi addition reaction for 48h under the conditions of room temperature and stirring, adding ethyl acetate for extraction for 2 times, wherein the volume of ethyl acetate for single extraction is 500mL, combining organic phases, sequentially washing the obtained organic phases with 500mL of water, washing with 500mL of saturated saline, drying and filtering with anhydrous sodium sulfate, concentrating the obtained filtrate, and carrying out silica gel chromatography purification to obtain compound II (a white solid, 7.85g and 55.33 percent), wherein an eluent adopted for silica gel chromatography purification is an ammonia-acetone-petroleum ether mixed solvent, the volume fraction of ammonia in the mixed solvent is 0.25 percent, and the volume ratio of acetone to petroleum ether is 1: 3;
structural parameters of compound ii: ESI-MS (M/z):793.4 (M)++H)；1H NMR(600MHz,CDCl3)δ8.09–8.03(m,2H),7.60(t,J＝7.2Hz,1H),7.47(t,J＝7.8Hz,2H),5.06(s,1H),4.88(dd,J＝10.2,2.4Hz,1H),4.55(d,J＝7.2Hz,1H),4.09(dd,J＝10.8,1.2Hz,1H),3.91-3.89(m,1H),3.80-3.64(m,2H),3.64-3.52(m,2H),3.41(s,1H),3.31(m,1H),3.07(q,J＝6.6Hz,1H),2.96(s,1H),2.88(d,J＝0.6Hz,1H),2.68(dd,J＝7.8,5.4Hz,1H),2.66-2.58(m,1H),2.55(s,3H),2.32(s,6H),1.96-1.92(m,1H),1.87-1.77(m,1H),1.77-1.66(m,4H),1.61-1.56(m,2H),1.45(s,3H),1.35(s,3H),1.30(d,J＝6.0Hz,3H),1.19(d,J＝6.6Hz,3H),1.04(d,J＝7.2Hz,3H),1.01(d,J＝7.2Hz,3H),0.86(t,J＝7.2Hz,3H)。
Dissolving 0.126mmol of compound II in 5mL of dichloromethane, adding 0.126mmol of DCC and 0.126mmol of DMAP, cooling to-5 ℃, dropwise adding 2mL of 4-trifluoromethylphenyl isocyanate solution (0.189 mmol) by using a constant-pressure dropping funnel under the conditions of nitrogen protection and room temperature for acylation reaction for 10 hours, adding 1mL of methanol for quenching, filtering to remove insoluble substances, concentrating the obtained filtrate, and purifying by using a silica gel chromatography to obtain a compound III-1 (102 mg of a white solid, wherein the yield is 82.93%, an eluant used for purifying by using the silica gel chromatography is 26 wt% of ammonia water-acetone-petroleum ether mixed solvent, the volume fraction of the ammonia water in the mixed solvent is 0.25%, and the volume ratio of the petroleum ether to the acetone is 3: 17;
dissolving 0.09mmol of compound III-1 in 5mL of methanol, carrying out reflux reaction for 10h under the protection of nitrogen, filtering to remove insoluble substances, concentrating the obtained filtrate, and purifying by silica gel chromatography to obtain macrolide antibiotic I-1 (white solid, 80mg, yield of 93.2%, R in I-1 is R-1, eluent adopted in silica gel chromatography purification is 26 wt% of ammonia water-acetone-petroleum ether mixed solvent, the volume fraction of the ammonia water in the mixed solvent is 0.25%, and the volume ratio of the petroleum ether to the acetone is 3: 2;
r-isocyanate and R in I-1 are the same and are R-1, namely 4-trifluoromethylphenyl.
Examples 2 to 58
Compounds III-2 to III-58 and macrolide antibiotics I-2 to I-58 were prepared according to the procedure of step (2) of example 1, R in R-isocyanate in examples 2 to 58 was R-2 to R-58 in the order, and the yields and structural characterization data of compounds III-2 to III-58, and the yields and structural characterization data of compounds I-2 to I-58 are shown in Table 1:
TABLE 1 yield and structural characterization data for Compounds III-1 through III-58 and I-1 through I-58 prepared in examples 1 through 58
Test example 1
Determination of antibacterial Activity
(1) Culture medium and culture conditions
And (3) staphylococcus: incubating the CAMHB culture medium at 35-37 ℃ for 20h to observe the result; staphylococcus epidermidis MRSE17-8, MRSE19-5, MRSE19-6, MRSE19-7, MRSE19-8, MRSE19-9, MRSE19-10, MRSE19-11, MRSE19-12 and MRSE 19-13;
haemophilus influenzae: HTM-MHB Medium containing 5 v/v% CO at 35 ℃2Incubating for 20h in the incubator; the tested samples are H.influenzae HIN19-15 and HIN 19-18;
streptococcus genus: CAMHB culture medium containing 2.5-5 wt% of sheep blood and 5 v/v% of CO at 35 DEG C2Incubating for 20h in the incubator; pneumonia of lungStreptococci SPN19-8, SPN19-13 and SPN 19-14;
moraxella catarrhalis: CAMHB culture medium containing 2.5-5 wt% of sheep blood and 5 v/v% of CO at 35 DEG C2Incubating for 24h in the incubator; moraxella catarrhalis BCA19-5, BCA19-6, BCA19-31, BCA19-32, BCA19-33 and BCA 19-34;
streptococcus pyogenes: CAMHB culture medium containing 2.5-5 wt% of sheep blood and 5 v/v% of CO at 35 DEG C2Incubating for 20h in the incubator; streptococcus pyogenes ATCC 19615;
streptococcus agalactiae: CAMHB culture medium containing 2.5-5 wt% of sheep blood and 5 v/v% of CO at 35 DEG C2Incubating for 20h in the incubator; streptococcus agalactiae 19-8 and 19-9.
(2) Preparation of culture Medium
Preparation of CAMHB: weighing appropriate amount of CAMHB dry powder (purchased from Qingdao Haibo biotechnology, Inc.), adding appropriate amount of pure water, stirring for dissolving, sterilizing at 121 deg.C for 20mins under high pressure, and cooling to room temperature for use.
(3) Minimum Inhibitory Concentration (MIC) determination method
MIC values for each test sample were determined for the Bacteria tested using the microbials Dilution method recommended by the American Association for Clinical and Laboratory Standards (CLSI) antibacterial drug susceptibility testing protocol (see: Methods for Dilution antibacterial susceptibility Tests for bacterial thin Grow Aerobically; Approved Standard-ElementhEdtion, M07-A11,2018).
(4) Preparation of pharmaceutical solutions
Weighing a proper amount of macrolide antibiotic I (drug) prepared in the embodiment, dissolving the drug by using sterile pure water or DMSO (dimethyl sulfoxide) according to the solubility of a sample to enable the concentration of a mother solution to be 1.28mg/mL, diluting the proper amount of the mother solution to be 0.032mg/mL by using sterile MH broth, subpackaging half of the volume of the drug solution into a 96-hole loading slot, and adding the other half of the volume of the drug solution into a deep-hole loading slot after twice dilution by using the sterile MH broth; the steps are repeated, so that the concentration of the drug solution in the sample adding groove is 32, 16, 8, 4, 2,1, 0.5, 0.25, 0.125, 0.06, 0.03 and 0.015mg/L in sequence, and the drug solution is prepared for use.
(5) Preparation of inoculum
Selecting several bacterial colonies from agar plate cultured for 18-24 hr, directly preparing into bacterial suspension in sterile physiological saline, adjusting concentration of bacterial suspension to 0.5 McLee unit, diluting corrected bacterial liquid with MH broth to (4-8) × 105CFU/ml, ready to use.
(5) Sample application and inoculation
Respectively sucking 100 μ L of the above medicinal solutions with different concentrations into the 1 st to 12 th wells of a sterile 96-well polystyrene plate, adding 100 μ L of the above inoculum into each well, wherein the final concentrations of the samples in the wells are respectively 16, 8, 4, 2,1, 0.5, 0.25, 0.125, 0.06, 0.03, 0.015 and 0.008mg/L, and the final concentrations of the inoculum are (2-4) × 105CFU/mL; additionally, growth control wells containing 100. mu.L inoculum and 100. mu.L sterile MH broth; the medicine in each hole is evenly mixed with the inoculum and then sealed.
(6) Incubation
And (5) placing the 96-well plate after sample loading and inoculation under corresponding conditions for culturing for 20 h.
(7) MIC endpoint interpretation
After the culture, the growth of bacteria in each well was observed, and the lowest concentration of the drug that completely inhibited the growth of bacteria in the wells was set as the MIC, the test results for Staphylococcus epidermidis are shown in Table 2, the test results for Haemophilus influenzae, Streptococcus pneumoniae, and Streptococcus agalactiae are shown in Table 3, and the test results for Moraxella catarrhalis and Streptococcus pyogenes are shown in Table 4.
TABLE 2 MIC for minimum inhibitory concentration of Staphylococcus epidermidis
TABLE 3 MIC for minimum inhibitory concentration for Haemophilus influenzae, Streptococcus pneumoniae and Streptococcus agalactiae
TABLE 4 MIC for the minimum inhibitory concentration for Moraxella catarrhalis and Streptococcus pyogenes
As shown in tables 2-4, in vitro antibacterial activity shows that the macrolide antibiotic I prepared by the invention has good antibacterial activity on Streptococcus pneumoniae drug-resistant strains SPN19-8 and SPN19-13, MIC of most compounds is 0.03-1 mu g/mL, and the activity is superior to or equivalent to telithromycin; the macrolide antibiotics I-2, I-7, I-8, I-11, I-12, I-13, I-14 and I-15 have higher activity on Streptococcus pneumoniae drug-resistant strains SPN19-8 and SPN19-13, the MIC of the macrolide antibiotics is lower than 0.03 mu g/mL, the activity is improved by 16 times compared with telithromycin, and the activity is obviously superior to the telithromycin. The macrolide antibiotic I prepared by the invention has good antibacterial activity on 10 strains of staphylococcus epidermidis, the MIC of most compounds is 0.03-0.25 mu g/mL, and the antibacterial activity is obviously superior to or equivalent to that of erythromycin, clarithromycin and azithromycin. The 7 strains of staphylococcus epidermidis and macrolide antibiotics I resistant to erythromycin, clarithromycin and azithromycin also show better antibacterial activity, wherein the MIC of the macrolide antibiotics I-2, I-3, I-7, I-8, I-11, I-12, I-13, I-14, I-15, I-25, I-33, I-34, I-35, I-36, I-44, I-45, I-46, I-49, I-53 and I-58 is lower than 0.03 mu g/mL, and the antibacterial activity is stronger. The macrolide antibiotic I prepared by the invention has good antibacterial activity on 6 strains of Moraxella catarrhalis, and the MIC is 0.03-0.5 mu g/mL. Most of the compounds have antibacterial activity on erythromycin, clarithromycin and azithromycin-resistant Moraxella catarrhalis BCA19-5 and BCA19-6 which are equivalent to sensitive strains, wherein the MIC of macrolide antibiotics I-2, I-3, I-7, I-8, I-11, I-12, I-13, I-14 and I-15 is less than or equal to 0.03 mu g/mL, and the activity is better. The macrolide antibiotic I prepared by the invention has good bacteriostatic activity on Streptococcus agalactiae sensitive strains 19-8, the MIC is more than 0.03-0.125 mu g/mL, the activity is equivalent to that of a contrast medicament, the antibiotic activity on the azithromycin drug-resistant Streptococcus agalactiae 19-9 is superior to that of erythromycin, clarithromycin and azithromycin, and the MIC is more than 0.06-4 mu g/mL. Wherein the MIC of macrolide antibiotics I-8, I-11, I-12, I-14 and I-15 is 0.03-0.125 mu g/mL, and the activity is equivalent to or higher than that of telithromycin. The macrolide antibiotic I prepared by the invention has good antibacterial activity on a streptococcus pyogenes standard strain ATCC19615, the MIC of the macrolide antibiotic I except the macrolide antibiotics I-5, I-16, I-20 and I-23 is less than or equal to 0.03 mu g/mL, the antibacterial activity is superior to that of azithromycin and erythromycin, and the antibacterial activity is equivalent to or better than that of telithromycin and clarithromycin. The MIC of the macrolide antibiotic I prepared by the invention to Haemophilus influenzae is mostly 2-16 mug/mL, and is equivalent to that of erythromycin, clarithromycin, azithromycin and telithromycin.
Test example 2
Cytotoxicity assays
The cytotoxicity of macrolide antibiotics against mouse normal hepatocyte AML-12 cell line was determined by MTT method and the results are shown in table 5 below:
TABLE 5 cytotoxicity test results
As is clear from Table 5, macrolide antibiotics I-2, I-5, I-10, I-15, I-26, I-29, I-30, I-31, I-41, I-46, I-48, I-50, I-57 and I-58 prepared according to the present invention have less cytotoxicity, and CC is C50> 50 μ M; wherein the cytotoxicity CC of I-10, I-29, I-46, I-50 and I-5850＞1000μM。
Test example 3
Determination of acute toxicity in mice
The acute toxicity of the macrolide antibiotics I-2, I-29, I-50 and I-58 was tested in mice after a single oral administration.
(1) Experimental methods
Male Kunming mice (with the average weight of 25g) are randomly selected and grouped into 5 groups, a control group, I-2, I-29, I-50 and I-58 groups are set, the I-2, I-29 and I-50 groups of the mice in the experimental group are all given with the dosage of 1000mg/kg in a stomach irrigation mode at one time, and the I-58 group is given with the dosage of 500 mg/kg. The mouse response was observed within two weeks after dosing to evaluate acute toxicity of the compound;
kunming mice were purchased from Peking Wittisley laboratory animals technology, Inc., male, SPF grade;
the maintenance feed for the common mouse is provided by an animal house of the institute of medical and biotechnology of Chinese academy of medical science;
animal breeding environment: the animal house of the institute of medical and biotechnology of Chinese academy of medical sciences shields the environment, is illuminated in light and shade for 12 hours respectively, is constant in temperature (20-24 ℃), constant in humidity (40-60%) and is free to drink water.
(2) Results of the experiment
Within two weeks after administration of I-2, I-29, I-50 and I-58, mice in the I-2, I-29, I-50 and I-58 administration groups did not die and had other observable abnormal responses as compared to the control group, indicating LD of I-2, I-29, I-5050LD of more than 1000mg/kg, I-5850More than 500mg/kg, belonging to low toxicity compounds.
Test example 4
Pharmacokinetic Properties and liver microsome stability assay
Liver microsome stability assay
The stability of the compounds I-2, I-29, I-50 and I-58 in liver metabolism was examined by using a human liver microsome model.
(1) The reagent used
Human liver microsomes (source: Mixed, biorelevationivt, ZZQ).
Positive control drug: the verapamil is used for detecting a test system reliably and has credible data.
Phosphate buffer solution: weigh approximately 5.7gK2HPO4·3H2O to a 1000mL blue-capped glass vial, dissolved in 500mL ultrapure water. Adjusting pH to 7.4 with 1mol/L hydrochloric acid, and storing in refrigerator at 4 deg.C for 1 month.
Macrolide antibiotic I standard sample working solution preparation: a proper amount of positive control standard substance or drug to be tested is weighed, DMSO is respectively used for dissolving to prepare 10mM stock solution, 10 mu L of the stock solution is taken and placed in 990 mu L of diluent to prepare 100 mu M working solution. The concentration of the drug to be tested in the final incubation system was 1. mu.M. Placing 100 μ L of 100 μ M working solution in 900 μ L diluent to obtain 10 μ M standard sample working solution, wherein the diluent is ACN (acetonitrile): H2The volume ratio of O is 1:1.
NADPH working solution: NADPH (nicotinamide adenine dinucleotide phosphate) was dissolved in a phosphate buffer solution to prepare a 10mM working solution, and the concentration of NADPH in the final incubation system was 1 mM.
Reaction termination solution: weighing a proper amount of tolbutamide and carbamazepine, dissolving the tolbutamide and the carbamazepine into 10mM internal standard stock solutions by DMSO respectively, adding 20 mu L of the tolbutamide internal standard stock solution and 4 mu L of the carbamazepine internal standard stock solution into 400mL of acetonitrile, and preparing an internal standard working solution with the tolbutamide concentration of 500nM and the carbamazepine concentration of 100 nM.
(2) LM (liver microsome) working system:
NADPH-free control and experimental LM incubations are shown in table 6:
TABLE 6 NADPH-FREE CONTROL AND EXPERIMENTAL LM EXPLORATION SYSTEMS
(3) Experimental methods
(3.1) NADPH-free control group (n ═ 1)
Referring to the LM working system, 432.5 mu L of phosphate buffer solution is added into 12.5 mu L of liver particles, the mixture is lightly oscillated and vortexed uniformly to prepare LM working solution, the volume of the LM working solution is adjusted according to the number of samples, and the preparation process is changed according to the incubation system in equal proportion. 445. mu.L of the working solution was added to a 1.1mL microtube, followed by 50. mu.L of phosphate buffer, vortexed and preincubated in a 37 ℃ water bath for 5 min. And taking 5 mu L of the positive control drug/working solution to be tested into the 1.1mL micro-tube by using a pipette, gently oscillating and vortexing uniformly. The reaction was stopped by pipetting 50. mu.L into a prepared sample collection plate (adding 400. mu.L of the reaction stop solution in advance) using a 50. mu.L range multi-channel pipette at 0, 5, 15, 30, and 60min, respectively. After the reaction is finished, the sample is vortexed and shaken for 5min, centrifuged for 15 min at 4 ℃ and 4500rpm, 100 mu L of supernatant is taken, and 100 mu L of ultrapure water is added to dilute and inject the sample.
(3.2) Experimental group (control drug/drug to be tested, n ═ 3)
Referring to the LM working system, 432.5 μ L of phosphate buffer solution was added to 12.5 μ L of liver particles, and the mixture was gently shaken and vortexed to prepare LM working solution. The volume of the LM working solution is adjusted according to the number of samples, and the preparation process is changed according to the equal proportion of the incubation system. 445. mu.L of LM working solution were added to a 1.1mL microtube, followed by 50. mu.L of ADPH working solution, vortexed and preincubated in a 37 ℃ water bath for 5 min. And taking 5 mu L of the positive control drug/drug working solution to be detected into the 1.1mL micro-tube by using a pipettor, gently oscillating, and uniformly vortexing. The reaction was stopped by pipetting 50. mu.L into a prepared sample collection plate (adding 400. mu.L of the reaction stop solution in advance) using a 50. mu.L range multi-channel pipette at 0, 5, 15, 30, and 60min, respectively. After the reaction is finished, the sample is vortexed and shaken for 5min, and is centrifuged at 4500rpm for 15 min at the temperature of 4 ℃, 100 mu L of supernatant is taken, and 100 mu L of ultrapure water is added to dilute and sample injection.
(3.3) preparation of control sample
Blank control sample: take 437.5. mu.L of phosphate buffer solution into 1.1mL microtube with pipettor, add 12.5. mu.L of liver microsomes and 50. mu.L of ADPH working solution in sequence, vortex and homogenize.
Positive control drug/test drug control sample: 432.5 μ L of phosphate buffer was pipetted into a 1.1mL microtube, followed by 12.5 μ L of liver microsomes and 50 μ L of ADPH working solution, and vortexed. 50 μ L of sample was collected and the reaction was stopped by adding 400 μ L of reaction stop solution to the plate, followed by 5 μ L of positive control/test drug standard sample working solution. This sample served as a standard sample in the study of stability of liver microparticles.
After the reaction of the sample is finished, the sample is vortexed and oscillated for 5min, centrifuged for 15 min at 4 ℃ and 4500rpm, 100 mu L of supernatant is taken, and 100 mu L of ultrapure water is added to dilute and sample injection.
(3.4) analytical method
The liquid phase conditions and mass spectrum conditions are shown in tables 7-8:
TABLE 7 liquid phase conditions of the analytical methods for verapamil and macrolide antibiotics I-29, I-2, I-50 and I-58
TABLE 8 Mass Spectrometry conditions for the methods of analysis of verapamil and macrolide antibiotics I-29, I-2, I-50 and I-58
(3.5) data processing and analysis
The concentration of each drug to be tested at 0min is 100%, and the concentrations at other time points are compared with the concentration at 0min to obtain the residual hundred of each drug to be testedAnd (4) dividing the ratio. The natural logarithm of the remaining percentage of each time point and the corresponding incubation time are plotted, the slope (-k) is obtained through linear regression, the T1/2(min) of the microsome metabolism of each drug to be tested is obtained through the formula (4), and the data of the microsome is extrapolated by applying the formulas (5) and (6) of the Well Stiredmodel, so that the inherent clearance rate CLint (mL. min) of each drug to be tested in the human liver can be obtained-1·kg-1) And liver clearance CLh (mL. min)-1·kg-1) The empirical values of the relevant physicochemical parameters are shown in Table 9.
T1/2 ═ -0.693/k type (4)
TABLE 9 empirical values of physicochemical parameters
(3.6) results of the experiment
In a human liver microsome incubation system with or without NADPH, I-phase metabolic elimination of macrolide antibiotic compounds I-29, I-2, I-50 and I-58 was examined, the results of stability in human liver microsome incubation system without NADPH are shown in Table 10, the stability results in the human liver microsome incubation system added with NADPH are shown in Table 11 and FIGS. 1-5, wherein, FIG. 1 is a graph showing the result of the stability of verapamil in human liver microsomes, FIG. 2 is a graph showing the result of the stability of macrolide antibiotic I-29 in human liver microsomes, FIG. 3 is a graph showing the results of stability of macrolide antibiotic I-2 in human liver microsomes, FIG. 4 is a graph showing the results of stability of macrolide antibiotic I-50 in human liver microsomes, FIG. 5 is a graph showing the results of stability of macrolide antibiotic I-58 in human liver microsomes.
TABLE 10 stability of the Compounds in NADPH-free human liver microsomes
TABLE 11 stability of the Compounds in human liver microsomes (Mean + -SD)
Note: if clearance is <0, clearance and half-life are reported as 0.00 and ∞, respectively; NC: not calculated, Not calculated.
As can be seen from FIGS. 1 to 5 and tables 10 to 11, the remaining percentages of I-29, I-2, I-50 and I-58 after incubation for 60min in the negative control group without NADPH were all 89.4% or more, indicating that the compounds were stable in this system and there was no deviation in the results of enzyme metabolism due to instability of the compounds, and that the metabolic transformation of I-29, I-2, I-50 and I-58 hardly occurred in the incubation solution without NADPH. Metabolic elimination can occur in human liver microsome incubations added with NADPH, the metabolic degrees of I-29, I-2, I-50 and I-58 in liver microsome are different, the residual percentages of 60min are respectively (73.3 +/-0.797)%, (0.366 +/-0.528)%, (0.267 +/-0.355)% and (0.0492 +/-0.016)%, the intrinsic clearance rates are respectively (4.02 +/-0.641), (183 +/-14.7), (341 +/-9.03) and (439 +/-8.00) mu L/(min. mg), which indicates that the metabolism of the compounds I-29, I-2, I-50 and I-58 in human liver microsome is dependent, the metabolic conversion rate of the compound I-29 is low, and the metabolic conversion rates of the compounds I-2, I-50 and I-58 are high.
The elimination half-life and clearance of compounds I-29, I-2, I-50 and I-58 in human liver microsome incubation system are shown in Table 12, and their elimination half-life T in human liver microsome1/2Respectively (176 + -29.9), (3.80 + -0.315), (2.03 + -0.0537) and (1.58 + -0.0290) min, and the liver clearance of human is respectively (10.11 + -61), (460 + -36.8), (855 + -22.6) and (1101 + -20.1) mL/(min-kg) obtained by extrapolation of intrinsic clearance. It shows that the metabolism of the compound I-29 is slowly eliminated in the liver, and the compounds I-2, I-50 and I-58 can be metabolized quickly in the liver.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. A macrolide antibiotic having the structure shown in formula I:
in the formula I, R comprises phenyl, naphthyl, heterocyclic group, substituted phenyl or substituted heterocyclic group.
2. Macrolide antibiotic according to claim 1, characterized in that the substituents on the phenyl ring in the substituted phenyl group include C1～6Alkyl radical, C1～6Alkoxy, halogen, halogeno C1～6Alkyl, halo C1～6Alkoxy, phenyl, naphthyl, C1～6One or two of alkylthio, cyano, nitro and pyrimidinyl;
the heterocyclic group includes pyridyl, pyrimidyl, thienyl or furyl;
said substituted heterocyclic group includes benzofuranyl, benzothienyl, benzothiadiazolyl, benzmethylenedioxy, C1～6Alkyl-substituted isoxazolyl or C1～6Alkyl substituted furyl.
3. A process for the preparation of a macrolide antibiotic according to any of claims 1 to 2, comprising the steps of:
mixing a compound II, R-isocyanate, a catalyst and a soluble compound II solvent for an acylation reaction to obtain a compound III; r in the R-isocyanate comprises phenyl, naphthyl, heterocyclic group, substituted phenyl or substituted heterocyclic group;
carrying out hydrolysis reaction or alcoholysis reaction on the compound III to obtain the macrolide antibiotic;
4. the process according to claim 3, wherein the molar ratio between the compound II and the R-isocyanate is 1: (1.1-3).
5. The method according to claim 3 or 4, wherein the acylation reaction is carried out at a temperature of-5 to 30 ℃ for 5 to 40 hours.
6. The method according to claim 3, wherein the hydrolysis reaction is carried out under a protective atmosphere;
the temperature of the hydrolysis reaction is 40-100 ℃, and the time is 3-24 h.
7. The method of claim 3, wherein the alcoholysis reaction is carried out under a protective atmosphere; the alcoholysis reaction is carried out at the temperature of 40-70 ℃ for 3-24 hours.
8. The preparation method according to claim 3, wherein the compound II is obtained by performing Maillard addition reaction on the compound IV and 1-aminopropanol;
9. use of a macrolide antibiotic according to any of claims 1 to 2 or obtained by the process according to any of claims 3 to 8 for the preparation of an anti-infective medicament.
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