Preparation Of Related Substrates In Erythromycin Antibiotics And Methodological Studies On Correlated Reactions

Erythromycin antibiotics are widely used because of their special antibacterialmechanism and broad antibacterial spectrum. The sale of erythromycin antibiotics is thethird biggest in the antibiotic market, second only to that of carbostyril and β-lactamantibiotics. Although China’s research on erythromycin drugs started late, the processimprovement solved the problems regarding producing the second-generationerythromycins, making China the biggest producer of clathromycin and azithromycin.However, the quality control and safety evaluation of erythromycin antibiotics in China stillfall behind compared with those in western countries, which has seriously affected thesafety of Chinese medicinal herbs and the export of domestic erythromycins. To improvethe quality control of erythromycins in China, we need to do research on various impuritiesof erythromycin antibiotics. The impurity analysis, impurity limits and impuritytoxicological research of erythromycin antibiotics could be carried out only afterestablishing the database of related substrates. Performing a detailed study on the sources,control methods and preparation approaches of related substrates in erythromycinantibiotics is an urgent issue in China. The study on preparing related substrates inerythromycin antibiotics in this paper involve the major national drug item named“Analysis and Control of Microimpurities in Clathromycin and Azithromycin”, which has asignificant role in improving the quality control in Chinese erythromycins.Due to the growing drug resistance, developing and producing the third-generationerythromycin that can fight against resistant strains have received increasing attention.Telithromycin is the only third-generation erythromycin in the market. It still can’t beproduced in China because of the backward processing technique, especially the immatureside-chain’s processing. Studies on synthesis of4-(3-pyridyl)-1-H-imidazole--the keyintermediate in synthesizing telithromycin’s side-chain--is crucial to the commercialproduction of telithromycin in China.Drug synthesis is currently a global hot topic. As the concept of “green chemistry“haswon the support among the people, how to generate complex products with biologicalactivity using simple substrates, low-toxicity catalyst in short route is a great challengefacing mankind. The output of drugs is extremely huge because of commercial production.If their synthesis were too complex, the cost would be higher and the pollution would bemore serious. In this paper, four new methodologies in organic synthesis were illustrated. Their mild reaction conditions, easy operations, and low toxicity to the environment makethem very promising in drug synthesis.This paper includes three parts: preparation of related substrates in erythromycinantibiotics, synthesis of telithromycin key intermediate and methodological studies oncorrelated reactions. The erythromycin related substrates we prepared included thirty-fourcompounds relevant to erythromycin, roxithromycin, clarithromycin and azithromycin. Wemainly researched on the sources, control methods and preparation approaches of theserelated substrates. All related substrates were sorted into six groups:3’-N-demethylimpurities, azithromycin production intermediates, erythromycin homologous substances,acid degraded products, Z configuration impurities and clarithromycin impurities accordingto their different preparation approaches. When preparing these compounds, we choseorganic synthesis and purified them through recrystallization for large-scale preparation. Asto the impurities which are difficult to be prepared in large amount by organic synthesis likeerythromycin homologous substances, we separated them from production residue throughthe semi preparation HPLC system. The substrates we prepared included some domesticunique impurities like azithromycin Z. The research on telithromycin key intermediatefocused on the modification of synthesizing4-(3-pyridyl)-1-H-imidazole. We optimized thehexamethylene synthesis and Debus synthesis approach of4-(3-pyridyl)-1-H-imidazolebased on the previous achievements to avoid the potential problems in the process ofindustrial amplification.While doing the research on the telithromycin key intermediate4-(3-pyridyl)-1-H-imidazole, we discovered four new and green methodologies in organicsynthesis and delved deeper into them. The first methodology is one-pot synthesis of2-alkyl-4(5)-aryl-1H-imidazoles from1-aryl-2-bromoethanones, ammonium carbonate andaliphatic carboxylic. In this process, we synthesized thirteen2-alkyl-4(5)-aryl-1H-imidazoles that could be used as β-glucosidase inhibitors or potent Na+channel blockers.The second methodology is synthesis and characterization of phenyl(1,3,6,8-tetraaza-tricyclo[4.3.1.13,8]undecan-4-yl)-methanone and its derivatives. It was discovered when weprocessed hexamethylene synthesis of4-phenyl-1H-imidazole using α-bromo acetophenoneand hexamine. Then we optimized reaction conditions and explored the scope of thisprocedure. At last, eleven products with novel benzoyl-TATU structure were successfullysynthesized, which could be applied in organic synthesis and medicinal chemistry. The thirdmethodology is synthesis of2-aroyl-4(5)-aryl-1H-imidazoles(AAIs) and2-hydroxy-3,6- diaryl-pyrazines via a cascade process. Employing the cascade process of DMSO oxidationand Debus reaction to synthesize4-(3-pyridyl)-1-H-imidazole, we indentified the product tobe4(5)-(3-pyridyl)-2-(3-pyridinoyl)-1H-imidazole when only ammonia other than themixture of ammonia and formaldehyde was used to trigger Debus reaction. The productcould be precipitated from the solution with high purity. The main by-products of thisprocess--2-hydroxy-3,6-diaryl-pyrazines could be precipitated from the solvents24hourslater after the main products being filtered. We optimized the reaction conditions andexplored the scope of this procedure. Twenty-two AAIs and six2-hydroxy-3,6-diaryl-pyrazines were synthesized, which could be applied as human aldose reductaseinhibitor or antitumor agent. The fourth methodology is selective bromination of aromaticamines with DMSO/HBr under mild conditions. In the process of synthesizing AAIs,2-acetylpyrrole was brominated into1-(4-bromo-1H-pyrrol-2-yl)ethanone in the DMSO/HBr system. We conjectured it as an electrophilic aromatic bromination by BDMS formedin DMSO/HBr. Further investigation indicated that the DMSO/HBr system could be used tobrominate2-acetylpyrrole derivatives, carbazole and anilines. Temperature control used inthis bromination process helped to promote mono-or di-brominated products. Thirteenmono-and seven di-aromatic bromides synthesized could be used in making drugs,agricultural chemicals and so on. Thanks to the simple starting materials, mild conditions,easy operations, high bioactivity of products, these four protocols have great potential inorganic synthesis and medicinal chemistry.