Study On The Synthetic Process For The Intermediats Of An Antifungal Agent: Ketoconazole

Ketoconazole (Nizoral, KCZ) is the first orally active broad-spectrum antifungal agent, which is discovered by Belgium Janssen Pharmaceutical CO.LTD. It went on the market in 1978 and was recorded by Pharmacopoeia of the United States (21th Edition) in 1980. Ketoconazole was approved a Type A broad-spectrum antifungal agent by US Food and Drug Administration. For its excellent curative effect, Ketoconazole was absorbed by Pharmacopoeia of China as adding species in 2000.Ketoconazole's chemical name is cis-l-acetyl-4-[4-[[2-(2,4-dichloro-phenyl)-2-( 1 H-imidazole-1 -yl-methyl)-1,3 -dioxolane-4-yl]methoxyl]phenyl] piperazine. It is condesated by cis-[2-(2,4-Dicholoro-phenyl)-2-(1H-imidazole-l-ylmethyl)-l,3-dioxolane-4-yl]methyl p-toluenesulfonate (active ester) and 1-acetyl-4-(4-hydroxyphenyl) piperazine (side chain), so the synthesis of active ester and side chain are very important to the synthesis of Ketoconazole. In this article, we have extensively explored the synthesis of active ester and side chain.Active ester is obtained from m-dichlorobenzene via Friedel-Crafts acylation, glycerol cyclization, bromination, esterification, isomeric separation, imidazole alkykation, hydrolysis and esterification again. After 8 steps the overall yield is 13.8%, which is increased by 4% than the yield literature had reported. In addition, we have successfully maken some improvements, for example, shortening the reaction time, lowering thereaction temperature and raising the yield. We have designed a new route, by which we can transform the trans -[2-(Bromomethyl)-2-(2,4-dichlorophenyl)-l,3-dioxolan-4-yl] methyl Benzoate to its cis-isomer, the latter is an important intermediate to synthesize such antifungal agents as Ketoconazole, Terconazole, Itraconazole. By this way, the producing cost of those agents is cut down and the problem of pollution is successfully solved. No literature has reported this way. Additionally, a new method to synthesize the cis-[2-(2,4-Dichlorophenyl)-2-(lH-imidazole- 1 -ylmethyl)- 1,3-dioxolan-4-yl] methyl] Benzoate Nitrate has been explored. The literature preparation is to heat the mixture of imidazole and trans- [2-(Bromomethyl) -2-(2,4-dichlorophenyl)-l,3-dioxolan-4-yl] methyl Benzoate(10) under reflux for 96h. The new way is discribed as follow: adding (10) to the salt prepared from sodium hydride and imidazole, and stirring the mixture at 110°C for 5h. The yield is increased from 49% to 53%. This method shortens the reaction time and decreases the cost. There is no literature reporting this method to synthesize (10).Furthermore, we respectively investigated three routes reported by literature about the synthesis of side chain, and have researched and optimizated the synthetic process of each route. Eventually, we choosed one as the industry route considering the cost and industrial feasibility. We use bisetholamine as the starting material, via bromo-substitution, cylclization, methyl-ether deprotection and then acetylation, (14) can be gotten after 4 steps, the total yield is 32.5%, while the reported yield is 26.4%.This research is based on the literature, but simplifies the synthesis of (6) and (14) and increases the overall yield compared to the literature. Parts of the intermediates have been identified by 'H-NMR.