Phase Transfer Catalyzed Synthesis Of Clinofibrate

Clinofibrate, also known as 2,2,-(4,4,-cyclohexylidenediphenoxy)-2,2,-dimethyldibutanoic acid, is a novel agent used as treatmenting. Hyperlipidemi which belongs to phenoxy aromatic acid derivatives, it can decrease the level of very low density lipoprotein and triglyceride and increase the level of high density lipoprotein. Clinofibrate has been researched, developed and listed into the market in Japan by Sumitomo Pharmaceutical Co.Ltd in 1981. It was also collected in the Japanese Pharmacopoeiain 16 version. As we all know, high triglyceride is the main disease in hypercholesterolemic patients. Clinofibrate can significantly reduce the very low density lipoprotein and triglycerides, and it is more suitable for the treatment of high blood cholesterol patients as a clinical drug.In this paper, we have improved the synthesis route of clinofibrate which has fewer reaction steps according to reference data. The crucial condensation reaction has been discussed using the method of phase transfer catalysis. The synthesis route of this experiment mainly have two steps:(1) the intermediate 1,1-bis-(4-hydroxyphenyl)cyclohexane is prepared with phenol and cyclohexanone through electrophilic substitution reaction. (2) Dichlorocarbene is synthesized from dichloromethane and strong sodium hydroxide solution with the presence of phase transfer catalysis, clinofibrate is synthesized froml,1-bis-(4-hydroxyphenyl)cyclohexane and 2-chloro-2-methyl butyrate which is synthesized from Dichlorocarbene and butanone through addition reaction.The synthesis route of Clinofibrate with phase transfer catalysis method shows simple, practicable, economic, safety and environmental benifits. The product quality of this synthesis route is superior as its yield becomes nearly 10%(in cycloheanone) higher than that of the ordinary synthesis route with bromine generation condensation reaction. The structure of the product has been confirmed according to the foreign literature reports by elemental analysis, MS, C-NMR and H-NMR. The main quality indicators of the product are in line with the requirements made by the Japanese Pharmacopoeia. This experiment has definited the process parameters of clinofibrate synthesis route with the method of phase transfer catalysis and provided the reference for the apply of phase transfer catalysis in mass product. It will also promote the clinical application of clinofibrate as well..