CN110330539B - Azithromycin compound and preparation method and application thereof - Google Patents
Azithromycin compound and preparation method and application thereof Download PDFInfo
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- CN110330539B CN110330539B CN201910790164.1A CN201910790164A CN110330539B CN 110330539 B CN110330539 B CN 110330539B CN 201910790164 A CN201910790164 A CN 201910790164A CN 110330539 B CN110330539 B CN 110330539B
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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
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
Abstract
The present invention discloses an azithromycin compound, a preparation method and an application thereof, wherein the chemical structural formula of the azithromycin compound is shown as a formula I
Description
Technical Field
The disclosure relates to the technical field of organic compounds and medicines, and relates to an azithromycin compound, a preparation method and application thereof.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
In 1928, the British bacteriologist Fleming discovered penicillin, the first antibiotic in the world. Subsequently, various classes of natural or semi-synthetic antibiotics were subsequently introduced, including β -lactams, aminoglycosides, tetracyclines, chloramphenicols, macrolide antibiotics. In addition, quinolone chemotherapeutic drugs represented by ciprofloxacin and norfloxacin are also introduced into the market. The vigorous development of 20 th century antibacterial drugs, especially antibiotic drugs, provides rich treatment schemes for various bacterial infectious diseases, and powerfully promotes the progress of human beings and social development. However, in recent years, the phenomenon of resistance to bacteria has been unprecedentedly abused due to abuse of antibiotics. The spread of methicillin-resistant staphylococcus aureus, vancomycin-resistant enterococci, multidrug-resistant streptococcus pneumoniae, and multidrug-resistant mycobacterium tuberculosis severely restricts the selection of clinical treatment schemes for infectious diseases, and even may cause treatment failure for patients with immune function deficiency. Therefore, the discovery of novel antibiotic against drug-resistant bacteria is a hotspot in the field of research and development of new drugs at present.
Macrolides, as a class of natural or semi-synthetic antibiotics, have not only excellent antibacterial activity but also good tolerance in clinical administration and very little allergic reaction of penicillin drugs, and thus have an important position in clinical treatment of respiratory tract infection and soft tissue infection. In recent years, with the development of molecular biology, the modification of the semi-synthetic structure of the macrolide parent nucleus has emerged remarkably, has attracted global attention and has become one of the leading forces in the research and development of antibiotics against drug-resistant bacteria.
Disclosure of Invention
The purpose of the disclosure is to provide an azithromycin compound, a preparation method and an application thereof, and the compound is beneficial to enhancing the combination with action sites and has better activity of resisting sensitive bacteria and drug-resistant bacteria.
In order to achieve the purpose, the technical scheme of the disclosure is as follows:
in a first aspect, the disclosure provides azithromycin compounds with a chemical structural formula shown as a formula I
Wherein R is triazole, substituted triazole, oxyphenyl or substituted oxyphenyl.
In a second aspect, the disclosure provides a preparation method of the azithromycin compound, which comprises the following steps of preparing the compound shown in the formula I by taking the starting material 1 as a starting material according to the following reaction route:
the substituted raw material is phenol, substituted phenol, a combination of sodium azide and phenylacetylene or a combination of sodium azide and substituted phenylacetylene, and R is triazole, substituted triazole, oxyphenyl or substituted oxyphenyl.
In a third aspect, the disclosure provides a pharmaceutical composition containing the azithromycin compound or the pharmaceutically acceptable salt thereof.
In a fourth aspect, the present disclosure provides a pharmaceutical preparation, which comprises the azithromycin compound or the pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the azithromycin compound or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant and/or carrier.
In a fifth aspect, the disclosure provides an application of the azithromycin compound or the pharmaceutically acceptable salt, the pharmaceutical composition or the pharmaceutical preparation thereof in preparing antibacterial drugs.
The beneficial effect of this disclosure does:
1. the C-2 'and C-3' in the azithromycin compound disclosed by the invention respectively reserve hydroxyl and dimethylamino, so that the anti-sensitive bacteria activity of the compound is ensured.
2. The azithromycin compound disclosed by the invention introduces aryl carbamate group into C-4', so that the combination of the structural fragment and the action site is enhanced, and the anti-drug-resistant activity of the compound is enhanced.
3. The azithromycin compound disclosed by the invention introduces a cyclic carbonate structure at C-11 and 12 positions so as to improve the stability of AZM mother nucleus and improve the in vivo antibacterial activity of a target compound.
4. The azithromycin compound disclosed by the invention has good activity of resisting sensitive bacteria and drug-resistant bacteria. For example, compound B13 showed a 64-fold increase in activity against c.albicans ATCC10231 over the control drugs azithromycin and clarithromycin.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present disclosure. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As the introduction of the background art shows, the phenomenon that the abuse of antibiotics leads to the unprecedented flooding of the drug resistance phenomenon of bacteria is provided, and the disclosure provides an azithromycin compound, a preparation method and application thereof.
The typical embodiment of the disclosure provides an azithromycin compound with a chemical structural formula shown as a formula I
Wherein R is triazole, substituted triazole, oxyphenyl or substituted oxyphenyl.
In one or more embodiments of this embodiment, R isWherein R is1Is H, halogen or C1-C4 alkyl, R2Is phenyl or substituted phenyl.
In this series of examples, R1Is F.
In this series of examples, R2Is composed ofWherein R is3Is H, halogen, amino, alkoxy or C1-C5 alkyl.
In this series of embodiments, R is selected from:
in another embodiment of the disclosure, a preparation method of the azithromycin compound is provided, which comprises the following steps of preparing the compound shown in the formula I by using the starting material 1 as a starting material according to the following reaction route:
the substituted raw material is phenol, substituted phenol, a combination of sodium azide and phenylacetylene or a combination of sodium azide and substituted phenylacetylene, and R is triazole, substituted triazole, oxyphenyl or substituted oxyphenyl.
In one or more embodiments of this embodiment, the hydroxyl group of C-2 'of starting material 1 is esterified with an acetic acid derivative to obtain intermediate 2, intermediate 2 is reacted with N, N' -Carbonyldiimidazole (CDI) to obtain intermediate 3, intermediate 3 is reacted with hydrazine to obtain intermediate 4, intermediate 4 is substituted with chloroacetyl chloride to obtain intermediate 5, and intermediate 5 is reacted with a substituent to obtain the compound of formula i.
In the series of examples, the intermediate 5 and phenol or substituted phenol are subjected to substitution reaction to obtain a compound 6;
In the series of embodiments, the intermediate 5 and sodium azide perform substitution reaction to obtain an intermediate 7, and the intermediate 7 and phenylacetylene or substituted phenylacetylene perform cycloaddition reaction to obtain a compound 8;
Specifically, the process for preparing the intermediate 2 from the starting material 1 comprises the following steps: dissolving the starting material 1 (azithromycin) in anhydrous DCM, adding acetic anhydride and anhydrous triethylamine, reacting for 24h at room temperature, and adding a proper amount of saturated NaHCO after the reaction is finished3The solution was extracted with DCM, the organic layers were combined, washed with brine and anhydrous Na2SO4Drying, filtering, spin-drying under reduced pressure, Me2CO-H2And recrystallizing the O (2:1) to obtain an intermediate 2.
Specifically, the process for preparing the intermediate 3 from the intermediate 2 comprises the following steps: dissolving the intermediate 2 in anhydrous toluene, and adding anhydrous trisEthylamine and CDI were reacted at 55 ℃ for 72 h. After the reaction is finished, concentrating under reduced pressure, and adding a proper amount of saturated NaHCO3Solution, DCM extraction. The organic layers were combined, washed with brine and anhydrous Na2SO4Drying, filtering, spin-drying under reduced pressure, and performing column chromatography (DCM/CH)3OH 15:1) to give intermediate 3.
Specifically, the process for preparing the intermediate 4 from the intermediate 3 comprises the following steps: dissolving the intermediate 3 in DMF, adding 85% hydrazine hydrate, stirring at room temperature for 0.5h, after the reaction is finished, adding water and EtOAc for liquid separation and extraction, washing the organic layer with saturated saline solution, and adding anhydrous Na2SO4Drying, filtering, spin-drying under reduced pressure, and performing column chromatography (DCM/CH)3OH/NH4OH 10:1:0.1) to give intermediate 4.
Specifically, the process for preparing the intermediate 5 from the intermediate 4 comprises the following steps: dissolving the intermediate 4 in anhydrous DCM, adding triethylamine, slowly dropwise adding chloroacetyl chloride into the reaction solution under ice bath, stirring at room temperature for 4h after dropwise adding, performing aqueous-liquid extraction after the reaction is finished, performing DCM extraction, combining organic layers, washing with saturated saline solution, and washing with anhydrous Na2SO4Drying, filtering, spin-drying under reduced pressure, and performing column chromatography (DCM/CH)3OH/NH4OH 20:1:0.1) to give intermediate 5.
Specifically, the process for preparing the compound 6 from the intermediate 5 comprises the following steps: dissolving 5 in acetonitrile, adding phenol or substituted phenol, taking potassium carbonate as a deacidification agent, and stirring at 60 ℃ for 0.5 h. After the reaction was completed, the reaction solution was concentrated. Separating water and DCM for extraction, extracting DCM, combining organic layers, washing with saturated brine, and anhydrous Na2SO4Drying, filtering, spin-drying under reduced pressure, and performing column chromatography (DCM/CH)3OH/NH4OH 20:1:0.1) to give a pale yellow solid. Dissolving in methanol, stirring at 55 deg.C for 12 hr, concentrating the reaction solution, and performing column chromatography (DCM/CH)3OH/NH4OH 10:1:0.1) to give compound 6.
Specifically, the process for preparing the intermediate 7 from the intermediate 5 comprises the following steps: dissolving the intermediate 5 in DMF and water, adding sodium azide, stirring at 80 ℃ for 48h, separating and extracting water and EtOAc, washing the organic layer with saturated saline solution, and adding anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure to obtain the final productAnd (7) an intermediate.
Specifically, the process for preparing the compound 8 from the intermediate 7 comprises the following steps: dissolving intermediate 7 in 75% methanol, and adding CuSO4Reacting sodium ascorbate with phenylacetylene or substituted phenylacetylene at 55 deg.C for 24 hr, concentrating the reaction solution under reduced pressure, extracting with dichloromethane and dichloromethane for 2 times, mixing the organic phases, drying with anhydrous sodium sulfate, vacuum filtering, concentrating under reduced pressure, and performing column chromatography (DCM/CH)3OH/NH4OH 10:1:0.1) to give compound 8.
In a third embodiment of the disclosure, a pharmaceutical composition is provided, which contains the azithromycin compound or the pharmaceutically acceptable salt thereof.
Such as hydrochloride, phosphate, sulfate, citrate, and the like.
The fourth embodiment of the disclosure provides a pharmaceutical preparation, which comprises the azithromycin compound or the pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the azithromycin compound or the pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials and/or carriers.
The medicament dosage form disclosed by the disclosure can be oral liquid, capsules, tablets, injections and the like.
Adjuvants described in this disclosure, such as binders, fillers, disintegrants, lubricants in tablets, preservatives in liquid formulations, antioxidants, flavoring agents, fragrances, cosolvents, emulsifiers, solubilizers, tonicity adjusting agents, colorants, and the like.
Carriers described in this disclosure, such as ion exchangers, alumina, aluminum stearate, lecithin, serum albumin, glycerol, sorbitol, water, salts, and the like.
The fifth embodiment of the disclosure provides an application of the azithromycin compound or the pharmaceutically acceptable salt, the pharmaceutical composition or the pharmaceutical preparation thereof in preparing antibacterial drugs.
In order to make the technical solutions of the present disclosure more clearly understood by those skilled in the art, the technical solutions of the present disclosure will be described in detail below with reference to specific embodiments.
Example 1: and (3) synthesizing an intermediate 2.
Starting material 1 (azithromycin, 3.0g,3.30mmol) was dissolved in anhydrous DCM (30mL), acetic anhydride (0.75mL) and anhydrous triethylamine (2.22mL, 16.02mmol) were added and stirred at rt for 24 h. After the reaction is finished, adding a proper amount of saturated NaHCO3The solution was extracted with DCM (25 mL. times.2). The organic layers were combined, washed with brine and anhydrous Na2SO4Drying, filtering, spin-drying under reduced pressure, Me2CO-H2Recrystallization of O (2:1) gave intermediate 2(2.9g, 91.48%) as a white foamy solid.
Example 2: and (3) synthesizing an intermediate 3.
Intermediate 2(3.0g,3.80mmol) was dissolved in dry toluene (40mL), anhydrous triethylamine (1.20mL,8.66mmol) and CDI (2.46g,15.2mmol) were added, and the mixture was stirred at 55 ℃ for 72 h. After the reaction is finished, concentrating under reduced pressure, and adding a proper amount of saturated NaHCO3The solution was extracted with DCM (25 mL. times.2). The organic layers were combined, washed with brine and anhydrous Na2SO4Drying, filtering, spin-drying under reduced pressure, and performing column chromatography (DCM/CH)3OH 15:1) yielded intermediate 3 as a white foamy solid (3.0g, 86.71%).
Example 3: and (4) synthesizing an intermediate 4.
Intermediate 3(3.0g,3.29mmol) was dissolved in DMF (20mL), 85% hydrazine hydrate (0.29g,4.95mmol) was added and stirred at room temperature for 0.5 h. After completion of the reaction, the mixture was extracted with water (20mL) and EtOAc (25 mL). Organic layer, washed with brine, anhydrous Na2SO4Drying, filtering, spin-drying under reduced pressure, and performing column chromatography (DCM/CH)3OH/NH4OH 10:1:0.1) yielded intermediate 4 as a white foamy solid (2.33g, 80.90%). MS (ESI) m/z calcd for C42H74N4O15[M+H]+:875.52,found:875.7,[M+2H]2+/2:438.3,found:438.6.
Example 4: and (5) synthesizing an intermediate.
Intermediate 4(2.5g,2.86mmol) was dissolved in dry DCM (20mL) and triethylamine (0.58g,5.72mmol) was added. Chloroacetyl chloride (0.48g,4.29mmol) was slowly added dropwise to the reaction solution under ice bath. After dropping, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was extracted with water (20mL) and DCM (25 mL. times.2). Is combined withThe organic layer was washed with brine and anhydrous Na2SO4Drying, filtering, spin-drying under reduced pressure, and performing column chromatography (DCM/CH)3OH/NH4OH 20:1:0.1) gave intermediate 5 as a reddish brown foamy solid (2.1g, 77.21%). MS (ESI) m/z calcd for C44H75ClN4O16[M+H]+:951.49,found:951.6,[M+2H]2+/2:476.2,found:476.4.
Example 6: synthesis of a 1.
Intermediate 5(150mg,0.16mmol) was dissolved in acetonitrile (20mL) and phenol (151mg,1.6mmol) and potassium carbonate (442mg,3.2mmol) were added. Stirring at 60 ℃ for 0.5 h. After the reaction was completed, the reaction solution was concentrated. Water (20mL) and DCM (25 mL. times.2) were separated and extracted, and DCM (25 mL. times.2) was extracted. The organic layers were combined, washed with brine and anhydrous Na2SO4Drying, filtering, spin-drying under reduced pressure, and performing column chromatography (DCM/CH)3OH/NH4OH 20:1:0.1) to give a pale yellow solid 6. 6 was dissolved in methanol (20mL) and stirred at 55 ℃ for 12 h. After the reaction was completed, the reaction solution was concentrated. Column chromatography (DCM/CH)3OH/NH4OH 10:1:0.1) to give a pale yellow solid a1(43mg, 28.22% in two steps). Mp: 118-,1H NMR(600MHz,CDCl3,ppm):7.72-7.34(m,2H),7.22-7.08(m,2H),7.02-6.99(m,1H),5.09-5.02(m,1H),4.92-4.85(m,1H),4.67-4.66(m,1H),4.48-4.20(m,4H),3.74-3.71(m,1H),3.51-3.49(m,2H),3.35-3.28(m,3H),3.10(s,1H),2.83-2.77(m,2H),2.47-2.34(m,2H),2.23-2.19(m,3H),2.07-1.98(m,3H),1.91-1.81(m,2H),1.49-1.43(m,5H),1.33-1.31(m,3H),1.28-1.26(m,12H),1.21-1.17(m,6H),1.07-1.06(m,2H),1.00-0.96(m,6H),0.93-0.88(m,8H),0.69-0.65(m,3H);MS(ESI)m/z calcd for C48H78N4O16[M+H]+:967.54,found:967.7,[M+2H]2+/2:484.3,found:484.6.
example 7: synthesis of a 2.
The procedure was carried out in the same manner as in example 6, using 2-fluorophenol in place of phenol to obtain A2(17mg, 10.94% in two steps) as a pale yellow solid, Mp: 124-,1H NMR(600MHz,CDCl3,ppm):7.71-7.68(m,1H),7.45-7.38(m,1H),7.19-7.16(m,1H),6.89-6.87(m,1H),5.05-5.02(m,1H),4.89-4.85(m,1H),4.69-4.66(m,1H),4.40-4.34(m,3H),4.14-4.07(m,1H),3.74-3.69(m,1H),3.54-3.52(m,2H),3.49(m,1H),3.41-3.30(m,4H),2.96-2.88(m,3H),2.84-2.77(m,3H),2.68-2.66(m,1H),2.47-2.36(m,3H),2.22(s,3H),2.08-2.07(m,3H),2.04-1.98(m,3H),1.91-1.81(m,4H),1.69-1.66(m,1H),1.44(s,3H),1.32(s,3H),1.27-1.24(m,4H),1.23-1.20(m,7H),1.17-1.14(m,4H),1.08-1.06(m,3H),0.98-0.87(m,12H);MS(ESI)m/z calcd for C48H77FN4O16[M+H]+:985.53,found:985.5,[M+2H]2+/2:493.3,found:493.6.
example 8: and (5) synthesizing an intermediate 7.
Intermediate 5(2.1g,2.21mmol) was dissolved in DMF (20mL) and water (5mL) and sodium azide (1.44g,22.1mmol) was added. Stirred for 48h at 80 ℃. After completion of the reaction, the mixture was extracted with water (20mL) and EtOAc (25 mL). Organic layer, washed with brine, anhydrous Na2SO4Drying, filtration and concentration under reduced pressure gave intermediate 7(1.8g, 84.91%) as a red-brown foamy solid which was used in the next step without further purification. MS (ESI) m/z calcd for C44H75N7O16[M+H]+:958.53,found:958.5,[M+2H]2+/2:479.8,found:480.1.
Example 9: synthesis of B1.
Intermediate 7(300mg,0.31mmol) was dissolved in 75% methanol (20mL) and CuSO4(30mg), sodium ascorbate (90mg) and phenylacetylene (158mg,1.55mmol) were added to the above solution and reacted at 55 ℃ for 24 h. After the reaction is completed, the reaction solution is concentrated under reduced pressure, dichloromethane (20mL) is added into the reaction solution for extraction for 2 times, organic phases are combined, dried by anhydrous sodium sulfate, filtered by suction, concentrated under reduced pressure, and subjected to column chromatography (DCM/CH)3OH/NH4OH 10:1:0.1) gave B1(100mg, 31.37%) as a pale yellow solid. Mp: 123-,1H NMR(600MHz,CDCl3,ppm):8.05(s,1H),7.45-7.38(m,1H),7.83-7.80(m,1H),7.43-7.40(m,2H),7.35-7.32(m,1H),5.36-5.24(m,2H),5.06-4.99(m,1H),4.91-4.86(m,1H),4.62-4.49(m,2H),4.41-4.27(m,3H),3.74-3.71(m,3H),3.56-3.54(m,1H),3.49(s,3H),3.38-3.37(m,1H),3.30-3.28(m,2H),2.88-2.72(m,7H),2.45-2.41(m,1H),2.23-2.19(m,3H),2.08-2.01(m,3H),1.90-1.89(m,2H),1.73-1.71(m,2H),1.44-1.39(m,4H),1.30-1.18(m,19H),1.08-1.07(m,3H),1.01-0.98(m,3H),0.93-0.87(m,6H).MS(ESI)m/z calcd for C50H79N7O15[M+H]+:1018.56,found:1018.5,[M+2H]2+/2:509.8,found:510.2.
example 10: synthesis of B2.
As in example 9, p-methylphenylacetylene was used in place of phenylacetylene to obtain B2(40mg, 12.55%) as a pale yellow solid, Mp: 112-,1H NMR(600MHz,CDCl3,ppm):8.02-7.99(m,1H),7.71-7.70(m,2H),7.23-7.22(m,2H),5.30(s,1H),4.91-4.87(m,2H),4.62-4.53(m,2H),4.43-4.37(m,2H),3.93-3.84(m,1H),3.74-3.72(m,1H),3.57-3.56(m,1H),3.52-3.49(m,2H),3.38(s,1H),3.32-3.28(m,2H),2.96(s,1H),2.88(s,1H),2.85-2.83(m,2H),2.44-2.41(m,2H),2.38(s,3H),2.21-2.20(m,4H),2.05-2.01(m,3H),1.92-1.90(m,2H),1.85-1.81(m,2H),1.44(s,4H),1.32-1.18(m,19H),1.07-1.06(m,4H),1.04-1.01(m,4H),0.96-0.87(m,8H);MS(ESI)m/z calcd for C51H81N7O15[M+H]+:1032.58,found:1032.6,[M+2H]2+/2:516.8,found:517.2.
example 11: synthesis of B3.
As in example 9, p-ethylphenylacetylene was substituted for phenylacetylene to give B3(60mg, 18.82%) as a pale yellow solid, Mp: 124-) -126 ℃,1H NMR(600MHz,CDCl3,ppm):8.02-7.97(m,1H),7.74-7.72(m,2H),7.25-7.22(m,2H),5.30-5.22(m,2H),5.09-5.06(m,1H),4.89-4.88(m,1H),4.55-4.54(m,1H),4.41-4.38(m,4H),3.74-3.71(m,2H),3.57-3.56(m,1H),3.49(s,2H),3.37-3.35(m,1H),3.31-3.29(m,3H),2.96(s,1H),2.88-2.83(m,2H),2.70-2.66(m,2H),2.43-2.42(m,4H),2.36-2.34(m,1H),2.21(s,3H),2.06-1.98(m,3H),1.92-1.91(m,1H),1.85-1.79(m,2H),1.44(s,3H),1.31-1.19(m,20H),1.16(s,2H),1.10-1.03(m,7H),0.96-0.88(m,7H);MS(ESI)m/z calcd for C52H83N7O15[M+2H]2+/2:523.8,found:524.2.
example 12: synthesis of B4.
As in example 9, p-propylphenylacetylene was substituted for phenylacetylene to obtain B4(30mg, 9.4) as a pale yellow solid1%),Mp:126–127℃,1H NMR(600MHz,CDCl3,ppm):7.95(s,1H),7.74-7.72(m,2H),7.25-7.23(m,2H),5.21(s,2H),5.07(s,1H),4.91-4.88(m,1H),4.56-4.54(m,1H),4.41(s,3H),3.74-3.71(m,1H),3.58-3.57(m,1H),3.49(s,1H),3.34-3.27(m,4H),2.88-2.83(m,2H),2.63-2.60(m,2H),2.43-2.31(m,8H),2.21(s,3H),2.06-2.02(m,2H),1.92(s,1H),1.83-1.81(m,2H),1.70-1.65(m,4H),1.44(s,3H),1.30-1.17(m,19H),1.11-1.04(m,7H),0.97-0.90(m,10H).MS(ESI)m/z calcd for C53H85N7O15[M+H]+:1060.61,found:1060.7,[M+2H]2+/2:530.8,found:531.0.
Example 13: synthesis of B5.
As in example 9, p-butylbenzene acetylene was used in place of phenylacetylene to obtain B5(60mg, 18.82%) as a pale yellow solid, Mp: 100-,1H NMR(600MHz,CDCl3,ppm):7.95(s,1H),7.73-7.72(m,2H),7.25-7.23(m,2H),5.21(s,1H),5.07(s,1H),4.89(s,1H),4.56-4.54(m,1H),4.44-4.39(m,3H),3.57-3.56(m,1H),3.34-3.29(m,3H),2.86-2.83(m,2H),2.65-2.62(m,2H),2.43-2.42(m,7H),2.21(s,4H),2.06-1.99(m,4H),1.92(s,2H),1.85-1.81(m,3H),1.64-1.59(m,4H),1.44(s,3H),1.40-1.34(m,4H),1.30-1.17(m,18H),1.07-1.04(m,6H),0.95-0.90(m,10H).MS(ESI)m/z calcd for C54H87N7O15[M+H]+:1074.63,found:1074.5,[M+2H]2+/2:537.8,found:538.1.
example 14: synthesis of B6.
P-fluoroacetylene was used in place of phenylacetylene in the same manner as in example 9 to obtain B6(50mg, 15.68%) as a pale yellow solid, Mp: 126-,1H NMR(600MHz,CDCl3,ppm):8.02-7.89(m,1H),7.80-7.78(m,2H),7.13-7.09(m,2H),5.30-5.24(m,2H),5.09-5.06(m,1H),4.90-4.89(m,1H),4.63-4.41(m,5H),3.74-3.49(m,3H),3.35-3.29(m,3H),2.88-2.83(m,2H),2.63(s,1H),2.44-2.32(m,8H),2.23-2.21(m,4H),2.06-1.92(m,5H),1.85-1.80(m,2H),1.62-1.61(m,1H),1.44(s,3H),1.30-1.16(m,18H),1.07-1.03(m,6H),0.92-0.88(m,6H);MS(ESI)m/z calcd for C50H78N7O15[M+H]+:1036.55,found:1036.5,[M+2H]2+/2:518.8,found:519.2.
example 15: synthesis of B7.
P-chlorophenylacetylene was used in place of phenylacetylene in the same manner as in example 9 to obtain B7(40mg, 12.55%) as a pale yellow solid, Mp: 126-),1H NMR(600MHz,CDCl3,ppm):8.06-8.03(m,1H),7.77-7.75(m,2H),7.43-7.38(m,2H),5.30-5.24(m,3H),5.07-5.04(m,1H),4.91-4.88(m,1H),4.55-4.37(m,5H),3.74-3.71(m,1H),3.57-3.55(m,1H),3.49(m,1H),3.37(s,1H),3.29(s,1H),2.86-2.76(m,3H),2.54(s,4H),2.44-2.38(m,2H),2.21(s,3H),2.06-1.81(m,9H),1.67-1.65(m,1H),1.62-1.61(m,1H),1.44(s,3H),1.29-1.17(m,18H),1.07-1.00(m,6H),0.93-0.87(m,6H);MS(ESI)m/z calcd for C50H78ClN7O15[M+H]+:1052.52,found:1052.5,[M+2H]2+/2:526.8,found:527.1.
example 16: synthesis of B8.
In the same manner as in example 9, m-aminophenylacetylene was substituted for phenylacetylene to give B8(40mg, 12.55%) as a pale yellow solid, Mp: 122-,1H NMR(600MHz,CDCl3,ppm):8.04-7.99(m,1H),7.12-7.09(m,3H),6.62(s,1H),5.30(s,2H),5.05-4.99(m,1H),4.89-4.88(m,1H),4.52-4.49(m,2H),4.40-4.29(m,3H),3.74-3.70(m,1H),3.66(s,1H),3.53-3.48(m,2H),3.34-3.30(m,1H),3.24(s,2H),2.96-2.83(m,3H),2.74-2.67(m,4H),2.44-2.42(m,1H),2.33-2.29(m,1H),2.21(s,4H),2.05-2.03(m,1H),1.97(m,1H),1.90-1.89(m,1H),1.84-1.82(m,1H),1.63-1.61(m,1H),1.44(s,3H),1.28-1.19(m,19H),1.12(s,1H),1.07-1.06(m,4H),0.98-0.87(m,12H);MS(ESI)m/z calcd for C50H80N8O15[M+H]+:1033.57,found:1033.5,[M+2H]2+/2:517.3,found:517.7.
example 17: synthesis of B9.
As in example 9, 3-methoxyphenylacetylene was used in place of phenylacetylene to give B9(67mg, 21.02%) as a pale yellow solid, Mp: 119-,1H NMR(600MHz,CDCl3,ppm):7.94-7.93(m,1H),7.75-7.73(m,2H),6.96-6.94(m,2H),5.30-5.22(m,2H),5.07-5.03(m,1H),4.90-4.89(m,1H),4.62-4.33(m,6H),3.84(s,3H),3.74-3.71(m,1H),3.64(s,1H),3.57-3.56(m,1H),3.49(s,1H),3.38(s,1H),3.28(s,1H),2.88-2.79(m,4H),2.54(s,2H),2.44-2.38(m,2H),2.21(s,3H),2.05-1.98(m,3H),1.92-1.91(m,2H),1.85-1.79(m,2H),1.62-1.61(m,1H),1.44(s,3H),1.29-1.16(m,20H),1.07-1.00(m,7H),0.92-0.90(m,6H);MS(ESI)m/z calcd for C51H81N7O16[M+H]+:1048.57,found:1048.8,[M+2H]2+/2:524.8,found:525.1.
example 18: synthesis of B10.
In the same manner as in example 9, 4-tert-butylacetylene was used in place of phenylacetylene to obtain B10(83mg, 26.04%) as a pale yellow solid, Mp: 119-,1H NMR(600MHz,CDCl3,ppm):7.95(s,1H),7.76-7.75(m,2H),7.46-7.43(m,2H),5.20(s,1H),4.91-4.89(m,1H),4.56-4.54(m,1H),4.41(s,4H),3.74-3.71(m,2H),3.58-3.56(m,1H),3.49(s,2H),3.32-3.25(m,3H),2.88-2.83(m,3H),2.44-2.34(m,6H),2.21(s,3H),2.06-1.99(m,3H),1.92(s,1H),1.85-1.79(m,3H),1.62-1.61(m,2H),1.44(s,3H),1.34-1.19(m,28H),1.07-1.02(m,7H),0.93-0.90(m,6H);MS(ESI)m/z calcd for C54H87N7O15[M+2H]2+/2:537.8,found:538.2.
example 19: synthesis of B11.
As in example 9, 2-methoxyphenylacetylene was used in place of phenylacetylene to give B11(72mg, 22.58%) as a pale yellow solid, Mp: 110-,1H NMR(600MHz,CDCl3,ppm):8.31-8.23(m,2H),7.08-6.96(m,3H),5.30-5.23(m,2H),5.08-5.04(m,1H),4.90-4.88(m,1H),4.55-4.36(m,5H),4.14-3.93(m,4H),3.74-3.54(m,3H),3.37(s,1H),3.27(s,2H),2.96-2.83(m,3H),2.46-2.33(m,6H),2.20(s,3H),2.06-1.90(m,6H),1.85-1.80(m,2H),1.62-1.61(m,1H),1.43(s,3H),1.34-1.16(m,18H),1.09-1.00(m,7H),0.92-0.87(m,6H);MS(ESI)m/z calcd for C51H81N7O16[M+2H]2+/2:524.8,found:525.2.
example 20: synthesis of B12.
As in example 9, p-bromophenylacetylene was used instead of phenylacetylene to obtain B12(115mg, 36.07%) as a pale yellow solid, Mp: 112-,1H NMR(600MHz,CDCl3,ppm):8.08-8.03(m,1H),7.70-7.68(m,2H),7.57-7.53(m,2H),5.30-5.23(m,2H),5.07-5.03(m,1H),4.90-4.89(m,1H),4.62-4.33(m,5H),3.76-3.49(m,3H),3.43-3.24(m,4H),2.96-2.75(m,4H),2.53-2.42(m,5H),2.39-2.34(m,1H),2.21(s,4H),2.06-1.81(m,7H),1.68-1.59(m,2H),1.44(s,3H),1.29-1.15(m,17H),1.07-1.06(m,3H),1.01-1.00(m,3H),0.93-0.90(m,6H);MS(ESI)m/z calcd for C54H87N7O15[M+2H]2+/2:548.7,found:548.7.
example 21: synthesis of B13.
As in example 9, p-pentylphenylacetylene was used in place of phenylacetylene to obtain B13(114mg, 35.76%) as a pale yellow solid, Mp: 130-,1H NMR(600MHz,CDCl3,ppm):7.97(s,1H),7.73-7.71(m,2H),7.24-7.22(m,2H),5.24-5.22(m,1H),5.08-5.04(m,1H),4.91-4.89(m,1H),4.55-4.54(m,1H),4.41-4.35(m,3H),3.63(s,1H),3.57-3.55(m,1H),3.36(s,1H),3.28(s,2H),2.86-2.83(m,2H),2.64-2.61(m,3H),2.49-2.42(m,5H),2.21(s,3H),2.06-2.02(m,2H),1.99-1.98(m,1H),1.92-1.90(m,2H),1.85-1.79(m,2H),1.66-1.61(m,4H),1.44(s,3H),1.38-1.16(m,24H),1.07-1.01(m,7H),0.92-0.88(m,10H);MS(ESI)m/z calcd for C55H89N7O15[M+2H]2+/2:544.8,found:545.2.
example 22: synthesis of B14.
As in example 9, p-ethoxyphenylacetylene was used in place of phenylacetylene to obtain B14(40mg, 12.55%) as a pale yellow solid, Mp: 122-),1H NMR(600MHz,CDCl3,ppm):7.94-7.91(m,1H),7.73-7.72(m,2H),6.95-6.93(m,2H),5.30-5.21(m,2H),5.07-5.03(m,1H),4.91-4.89(m,1H),4.62-4.34(m,5H),4.08-4.05(m,2H),3.74-3.64(m,3H),3.57-3.49(m,2H),3.38-3.28(m,3H),2.86-2.79(m,3H),2.55(s,4H),2.44-2.38(m,2H),2.21(s,3H),2.05-1.91(m,6H),1.85-1.81(m,2H),1.62-1.61(m,1H),1.44-1.42(m,6H),1.32-1.17(m,18H),1.07-1.00(m,6H),0.92-0.87(m,6H);MS(ESI)m/z calcd for C52H83N7O16[M+2H]2+/2:531.8,found:532.1.
example 23: synthesis of B15.
Same as in example 9, m-methylphenylacetylene was used instead of phenylacetylene to obtain B15 (4) as a pale yellow solid0mg,12.55%),Mp:118–120℃,1H NMR(600MHz,CDCl3,ppm):7.99-7.98(m,1H),7.67(s,1H),7.60-7.59(m,1H),7.32-7.30(m,1H),7.17-7.14(m,1H),5.30-5.22(m,2H),5.09-5.06(m,1H),4.90-4.89(m,1H),4.56-4.54(m,1H),4.41(s,2H),3.74-3.70(m,2H),3.57-3.56(m,1H),3.49(s,2H),3.36-3.29(m,3H),2.88-2.84(m,2H),2.43-2.40(m,8H),2.21(s,4H),2.06-1.99(m,3H),1.92(s,2H),1.85-1.81(m,2H),1.62-1.61(m,1H),1.44(s,3H),1.30-1.16(m,21H),1.07-1.03(m,7H),0.92-0.87(m,7H);MS(ESI)m/z calcd for C51H81N7O15[M+2H]2+/2:516.8,found:517.1.
Example 24: synthesis of B16.
As in example 9, m-chlorophenylacetylene was used in place of phenylacetylene to give B16(100mg, 31.37%) as a pale yellow solid, Mp: 102-105 ℃,1H NMR(600MHz,CDCl3,ppm):8.05-8.04(m,1H),7.83(s,1H),7.70-7.69(m,1H),7.43-7.32(m,2H),5.30-5.24(m,2H),5.09-5.06(m,1H),4.91-4.90(m,1H),4.63-4.41(m,5H),4.14-4.10(m,1H),3.74-3.56(m,3H),3.34-3.28(m,4H),2.96-2.83(m,3H),2.44-2.42(m,5H),2.38-2.34(m,1H),2.21(s,3H),2.06-1.92(m,6H),1.85-1.81(m,2H),1.62-1.61(m,1H),1.44(s,3H),1.30-1.16(m,18H),1.07-1.03(m,6H),0.92-0.87(m,6H);MS(ESI)m/z calcd for C50H78ClN7O15[M+H]+:1074.63,found:1074.5,[M+2H]2+/2:526.8,found:527.0.
example 25: synthesis of B17.
In the same manner as in example 9, m-fluoroacetylene was substituted for phenylacetylene to obtain B17(50mg, 15.68%) as a pale yellow solid, Mp: 122-,1H NMR(600MHz,CDCl3,ppm):8.02(s,1H),7.59-7.55(m,2H),7.43-7.37(m,1H),7.08-7.02(m,1H),5.30-5.22(m,2H),5.10-5.08(m,1H),4.92-4.88(m,1H),4.63-4.41(m,5H),3.74-3.70(m,2H),3.58-3.57(m,1H),3.49(s,2H),3.33-3.16(m,4H),2.88-2.83(m,2H),2.43-2.38(m,6H),2.21(s,3H),2.06-1.93(m,5H),1.85-1.81(m,2H),1.62-1.61(m,1H),1.44(s,3H),1.30-1.16(m,19H),1.07-1.04(m,6H),0.92-0.87(m,6H);MS(ESI)m/z calcd for C50H78FN7O15[M+2H]2+/2:518.8,found:519.1.
example 26: synthesis of B18.
In the same manner as in example 9, m-bromophenylacetylene was substituted for phenylacetylene to obtain B18(80mg, 25.09%) as a pale yellow solid, Mp: 122-) -124 ℃,1H NMR(600MHz,CDCl3,ppm):8.06-7.99(m,2H),7.73-7.72(m,1H),7.45-7.43(m,1H),7.30-7.27(m,1H),5.30(s,1H),5.07-5.01(m,1H),4.91-4.89(m,1H),4.62-4.30(m,6H),3.74-3.70(m,4H),3.57-3.54(m,1H),3.49(s,4H),3.37-3.25(m,3H),2.84-2.78(m,3H),2.59(s,2H),2.45-2.38(m,2H),2.21(s,3H),2.05-2.01(m,2H),1.91(s,1H),1.84-1.79(m,2H),1.62-1.61(m,1H),1.44(s,3H),1.30(s,3H),1.26-1.16(m,16H),1.07-1.06(m,3H),1.01-1.00(m,3H),0.93-0.90(m,6H);MS(ESI)m/z calcd for C50H78BrN7O15[M+1+2H]2+/2:549.7,found:549.8.
the prepared compounds A1-A2 and B1-B18 were subjected to antibacterial activity tests.
Experiment raw materials:
adding fresh nutrient broth culture medium or nutrient broth culture medium (3%, V/V) containing sheep blood into a 96-well plate (ultraviolet sterilization), sequentially adding ethanol solutions (2560 mu g/mL, m/V) of a certain amount of a compound to be detected and a control medicament into No. 1 wells of rows A-H of the 96-well plate, diluting by a two-fold dilution method, inoculating a proper amount of bacteria liquid with a certain turbidity, incubating at a constant temperature of 37 ℃ for 24H, observing the bacterial growth condition of each well, and reading the MIC of the medicament.
Experimental materials:
1. laboratory instruments and reagents: an ultra-clean workbench (Anhui mussel Port cleaning plant, model SXK-103), a constant-temperature biochemical incubator (Shanghai arborescent instruments and meters Co., Ltd., SHX 150C), a bacteria turbidimeter (Shanghai Xinrui instruments and meters Co., Ltd., model WGZ-2-XJ), a portable pressure steam sterilizer (Shandong Xinhua medical instruments Co., Ltd., model YXQG 02), and a inoculating loop; nutrient broth (beijing obo star biotechnology limited), blood plate (denna medical science research institute), fresh sheep blood (denna medical science research institute), 96-well plate (Nest Biotech co., Ltd), benzalkonium bromide (shandonglikang disinfection science and technology limited), absolute ethyl alcohol, and distilled water.
2. The tested strains: susceptible staphylococcus aureus (s.aureus ATCC25923), susceptible salmonella typhi (s.typhimurium ATCC14028), susceptible bacillus subtilis (b.subtilis ATCC9372), susceptible pseudomonas diminuta (p.deficiency ATCC19146), penicillin-resistant staphylococcus aureus (s.aureus ATCC31007), methicillin-resistant staphylococcus aureus (s.aureus ATCC43300), erythromycin-resistant klebsiella pneumoniae (k.pneumoconiae ATCC 700603).
Recovering, subculturing, culturing and preserving strains:
inoculating strain frozen at-80 deg.C onto blood plate culture medium by plate streaking method, culturing at 37 deg.C in constant temperature incubator for 18-24 hr, subculturing in new culture medium, and performing strain extraction test after twice subculturing at 18-24 hr interval.
Addition of culture medium, control drug or test compound solution:
adding corresponding culture medium, contrast medicine or to-be-detected compound solution into a 96-well plate according to the method shown in Table 1, and after the sample is added, sequentially diluting the contrast medicine or to-be-detected compound added into each row of the 96-well plate A-H by a microsyringe twice and progressively decreasing, wherein each row is diluted to a No. 10 well.
Table 1 experimental design table
Note: (1) when the tested bacteria are staphylococcus aureus, a nutrient broth culture medium is adopted, and the rest tested strains are nutrient broth culture medium containing sheep blood;
(2) if no turbidity is found in well 10 when the MIC is recorded, the sample to be tested in this row needs to be further diluted to accurately determine the MIC of the sample.
Preparing bacterial liquid:
the turbidity of the preparation was 0.5MCF (1 MCF. multidot.3X 10)8CFU/mL) of a physiological saline suspension of the test bacteria, diluted 10-fold with physiological saline (bacterial content about 10)7) The bacterial liquid should be inoculated within 15 min.
Inoculation and incubation:
and (3) adding the bacterial liquid from No. 11 holes of each row of the 96-hole plate to No. 1 holes in sequence by using a microsyringe, adding 5 mu l of the bacterial liquid into each hole respectively, and inserting a suction head into the liquid level to avoid contact with the culture medium. After inoculation, the 96-well plate was placed in a 37 ℃ incubator for 24 hours.
Reading of MIC:
after the incubation is finished, the No. 1 hole of each row of the 96-well plate is observed backwards in sequence, the concentration corresponding to the last hole without turbidity in the culture medium of each hole of the row is taken as the MIC of the control drug or the compound to be tested, and other MICs are recorded by the same method. The results are shown in Table 2.
MIC of the Compounds of Table 2
Note:
1: susceptible staphylococcus aureus (S.aureus ATCC25923)
2: sensitive salmonella typhi (S.typhimurium ATCC14028)
3: susceptible Bacillus subtilis ATCC9372
4: susceptible Pseudomonas defect (P.deficiency ATCC19146)
5: penicillin-resistant staphylococcus aureus (S.aureus ATCC31007)
6: methicillin-resistant staphylococcus aureus (S.aureus ATCC43300)
7: erythromycin-resistant Klebsiella pneumoniae (K.pneumoconiae ATCC700603)
Azithromycin (AZM) and Clarithromycin (CAM) were used as control drugs.
The above description is only a preferred embodiment of the present disclosure and is not intended to limit the present disclosure, and various modifications and changes may be made to the present disclosure by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present disclosure should be included in the protection scope of the present disclosure.
Claims (9)
4. A preparation method of azithromycin compounds as claimed in any one of claims 1 to 3, which is characterized by comprising the following steps of preparing the compound shown in the formula I by using the formula 1 as a starting material according to the following reaction route:
wherein the substituted raw material is the combination of sodium azide and phenylacetylene or the combination of sodium azide and substituted phenylacetylene.
5. The method for preparing azithromycin compound according to claim 4, wherein hydroxyl of C-2 'of the starting material 1 is subjected to esterification reaction with acetic acid derivative to obtain an intermediate 2, the intermediate 2 is subjected to reaction with N, N' -carbonyldiimidazole to obtain an intermediate 3, the intermediate 3 is subjected to reaction with hydrazine to obtain an intermediate 4, the intermediate 4 is subjected to substitution reaction with chloroacetyl chloride to obtain an intermediate 5, and the intermediate 5 is subjected to reaction with a substitution material to obtain the compound shown in formula I.
6. The process for preparing azithromycin compound as claimed in claim 5, wherein the intermediate 5 is subjected to substitution reaction with sodium azide to obtain intermediate 7, and the intermediate 7 is subjected to substitution reaction with phenylacetylene or R3Carrying out cycloaddition reaction on the substituted phenylacetylene to obtain a compound 8;
7. A pharmaceutical composition characterized by comprising the azithromycin compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3.
8. A pharmaceutical preparation, which is characterized by comprising the azithromycin compound or the pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 or the pharmaceutical composition as claimed in claim 7 and pharmaceutically acceptable auxiliary materials and/or carriers.
9. Use of the azithromycin compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, the pharmaceutical composition as claimed in claim 7 or the pharmaceutical preparation as claimed in claim 8 in the preparation of a medicament against penicillin-resistant staphylococcus aureus (s.aureus ATCC31007) and methicillin-resistant staphylococcus aureus (s.aureus ATCC 43300).
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