The Synthesis And Characterization Of Rfamycin-S Derivartives

Rifamycins as a kind of antibiotics have unique antimicrobial activity with a broad-spectrum effect on Gram-positive bacteria including mycobacterium tuberculosis,leprosy bacillus,streptococcus,pneumococcus,especially methicillin-resistant staphylococcus aureus,as well as some Gram-negative bacteria.Since the mid-1980s,the controlled tuberculosis has been resurging.The existing anti-tuberculosis treatment approaches are also far from satisfication since the resistance stains are still continually emerging and the appearance of multi-drug resistance as well.In the recent years,Cumbre company has designed a series of compounds modified by C-3 morpholine and C-25 carbamic acid ester through the study of bacterial drug resistance and filed for the US patent application.These compounds have a high activity against gram-negative bacteria and effectively reduce the bacterial resistance.However,no reference has been reported for the synthetic routes of these compounds.In this paper,we have chosen three compounds with higher antimicrobial activities for synthesis route optimization including YY-a,YY-b and YY-c.We optimized the method for synthesizing intermediate 2-1 by using dioxane and morpholino.We have used relatively cheaper and easily availiable Rifamycin-S as a starting material to synthesize target compounds YY-a(total 18.8%yield for 7 steps,99.1%purity in HPLC),YY-b(total 6.3%yield for 13steps,99.1%purity in HPLC)and YY-c(total 8.1%yield for 10 steps,97.9%purity in HPLC).All the intermediates and compounds were confirmed by 1H NMR and LC-MS.We developed a better method to introduce the carbamate group for C-25 position through replacement of carbonyl imidazole quaternary ammonium salt by corresponding amine.We exploited Et3N as a alkali and propargyl alcohol as a reactant to synthesize the critical intermediate 2-12.In addition,we employed intermediate 2-5 with propargylamine for ring-closure of the product with a good yield to make YY-c successfully.