Synthesis Of α-Phenylethanol Imidazole Derivatives Antifungal Agents

In recent years, the frequencies of invasive and systemic fungal infections have increased dramatically in the population with altered immunity by use of immunosuppressant, cortin and antibiotics etc. Opportunistic fungal infections represent significant cause of morbidity and mortality in the immunocompromised patients, such as those with AIDS, neoplasms, and transplants. Therefore, effectively control of systemic fungal disease has clinical significance. The azole antifungal agents work by inhibiting cytochrome P-450-dependent 14α-sterol demethylase (P-450_dm), an important enzyme in ergosterol biosynthesis in fungi and cholesterol synthesis in mammalian cells. For example, as wide pedigree active antifungal azoles, miconazole, econazole and fluconazole etc. have been developed and currently used in clinical antifungal chemotherapy. With the progress in pharmacology of chiral Pharmaceuticals and the strict regulation in the application of new racemic drug in recent years, the research and development of chiral pharmaceuticals have become the new direction and focus internationally. Research and development of antifungal drugs tend to focus on optically active azoles agents in recent future for their higher efficacy and lower toxicity.In this paper, optically active antifungal agents miconazole, econazole, tioconazole and their analogues flumiconazole, flueconazole and flutioconazole (chlorine on the benzene is substituted by fluorine) have been synthesized as new designed antifungal agents.2-Chloro-1 -(2,4-dichlorophenethyl)-ketone and 2-Chloro-1 -(2,4-difluoro-phenethyl)-ketone were synthesized with high yield and purity in solvent-free system by the catalysis of aluminium trichloride via Friedel-Crafts reaction from corresponding m-dichlorobenzene and m-difluorobenzene, where acylation agent was chloroacetylchloride. In this research, as a great improvement, toxic and combustible organic solvent has been avoided.l-(2,4-dichlorophenyl)-2-chloroethanol and l-(2,4-difluorophenyl)-2-chloroetha-nol were prepared by reduction of corresponding ketone with sodium (or potassuim ) borohydride in methanol. Temperature effect on the reaction was investigated and the mechanism of forming target product and byproducts was discussed. The reaction specificity was efficiently improved by calcium chloride and lanthanum chloride etc. and the action mechanism was presented. In the presence of amberlyst-732(H+) the reaction was smoothly carried out in aprotic solvent such as THF with high yield and specificity.Enantiomerically pure secondary alcohols (R), (S) - l-(2,4-dichloro-phenyl)-2-chloro-ethanol and (/?), (SO -l-(2,4-difluorophenyl)- 2-chloroethanol, which were key chiral synthetic intermediates of optically active drugs, have been prepared by irreversible transesterification reaction catalyzed by lipase from Pseudomonas stutzeri, where vinyl acetate was used as acyl donor and organic solvent. Optimum concentration of racemic substrate was 0.4mol/L. The basicity in system dramatically affects the activity and selectivity of lipase. Increase of basicity through addition of organic alkali such as triethylamine and dimethylamine to the system could markedly enhance the activity of lipase and reaction rate. The transesterification reaction for l-(2,4-difluorophenyl)- 2-chloroethanol has higher enantioselectivity (E=19) , so that one times resolution could obtain (i?)-isomer with high e.e.s value. But enantioselectivity for l-(2, 4-dichlorophenyl)-2-chloroethanol was lower (E=7), enantiomerical purity of (/?)-isomer was enhanced by two times resolution. Remained (i?)-isomer of alcohol and produced (S)-isomer of acetate were separated by silica gel column chromatography (200-300 mesh). Total yield of (*)-l-(2, 4-dichlorophenyl)-2-chloro-ethanol and (R)-\-(2, 4-difluorophenyl) - 2-chloroethanol were 23.36% with 90% e.e.sand 37.92% with 95% e.e.s respectively.The jV-alkylation reaction between l-(2, 4-dichlorophenyl)-2-chloro-ethanol or l-(2, 4-difluorophenyl)-2-chloro-ethanol and imidazole was carried out to synthesize l-(2,4-dichlorophenyl)-2-(l-imidazol)-ethanol or l-(2, 4-difluorophenyl)-2-(l-imidazol)-ethanol in THF/solid NaOH biphasic system through solid-liquid phase transfer catalysis method. Tetrabutyl ammonium bromide (TBAB) and polyethylene glycol 400(PEG400) and poly-ethylene glycol 600(PEG600) were employed as phase transfer catalysts. NaOH was used instead of NaH, NaOR, and NaNH2 which were employed in traditional method. The effects of catalyst, organic solvent, halogen leaving group on the alkyl halide, kind of bases and their amounts, temperature and agitation on the reaction were investigated. The yields of l-(2,4-dichlorophenyl)-2-(l-imidazol)-ethanol and l-(2,4-difluorophenyl)-2-(l-imidazol)-ethanol were higher than 88% and 70% respectively at optimized conditions. The byproducts were little and the product could be easily separated.The chloromethylation reaction of 2-chloro-thiophene by phase transfer catalysis was carried out to synthesize 2-chloro-3-chloromethyl-thiophene, where the catalyst was tetrabutyl ammonium bromide (TBAB).The chloromethylation reagents are paraformaldehyde and 37% concentrated hydrochloric acid. The yield of 2-chloro-3 -chloromet-hyl-thiophene was 77.6 %.The O-alkylation reactions between compound l-(2, 4-dichloro-phenyl)-2-(l-imi-dazol)-ethanol or l-(2,4-difluoro-phenyl)-2-(l-imidazol)-ethanol and benzylchloride derivatives such as 2,4-dichloro benzyl chloride, 4-chloro benzyl chloride and 2-chloro-3-chloromethyl-thiophene were performed at liquid-liquid phase transfer catalytic condition to synthesize miconazole, econazole, tioconazole and their analogues fluoride. Effects of reaction conditions on the reaction were investigated and the optimized condition was confirmed. Tetrabutyl ammonium bromide (TBAB) was used as catalyst, THF-water system was used as reaction media, the molar ratios of NaOH to substrate l-(2, 4-dichloro-phenyl)-2-(l-imidazol)-ethaol and l-(2,4-difluorophenyl)-2-(l-imidazol)-ethanol were 2.0 and 1.5 respectively.Chiral drugs miconazole, econazole, tioconazole and their analogues fluoride were synthesized at optimized N- and O-alkylation reaction condition, where the optically active compounds 1 -(2,4-dichlorophenyl)-2-chloroethanol and 1 -(2,4-difluorophenyl)-2-chloro-ethanol was used as chiral reagent. The in vitro antifiingal activity was primarily evaluated by the methods of the agar dilution and the filter paper disc diffusion. The antifungal tests results showed that the compounds fluoride were more active than miconazole, econazole and tioconazole for several kinds of Candida, and had antifungal effect on Aspergillus, on which fruconazole has no effect;(K)-isomer was more active than the (S)-isomer and racemate in most cases.Chiral antifungal drug;Miconazole, Econazole, Tioconazole, , Enzyme-Catalyzed resolution, Friedel-Crafts acylation, Reduction with sodium borohydride, Phase transfer Catalysis, N- alkylation, O-allylation...