The Synthesis, Dergradation Kinetics And Pharmacokinetics Of L-dopa Isopentyl Ester Hydrochloride In Rats

Objective: The processing route for levodopa isopentyl ester hydrochloride (LIPE) synthesis was formed by utilizing the principle of prodrug. To confirm the chemical structure of LIPE and study the dynamics of its degradation and the pharmacokinetics of LIPE in rats.Methods: LIPE was prepared with Levodopa and isoamyl alcohol as raw materials,and Thionyl Chloride as catalyst. The influence factors such as raw material ratio,amount of catalyst,reaction temperature and reaction time were investigated,then purification process was carried out in this article.The structure of the compound was confirmed by MS, IR, UV, 1H-NMR, 13C-NMR.The dynamics of its aqueous solutions were studied under the following conditions: pH 1.3, pH 5.0, pH 7.4 (temperature:37℃). An HPLC-FD method had been developed and validated for the simultaneous determination of L-dopa and its prodrug LIPE in rat plasma. The method was used to study the pharmacokinetics of L-dopa and LIPE in rats. Results: It showed that the optimun reaction conditions was as follow: n(Levodopa):n(isoamyl alcohol)=1:9,the amount of catalyst was 21% of the whole raw materials,reaction time was 6h ,and reaction temperature was 80℃. The mixture was followed by crystallization in ethanol and petroleum ether (v:v=3:2)to yield LIPE, the crystalline product was while with a purity exceeding 98%.The structure is (S)-isopentyl 2-amino-3-(3,4-dihydroxyphen -yl)propanoate hydrochloride. The half lives of LIPE aqueous solutions at pH 1.3, pH 5.0, pH 7.4 (temperature:37℃) are 6930, 433, 48h, respectively. The HPLC-FD method is fast,sensitive, accurate and is able to determinate the content of L-dopa and its prodrug LIPE. The parameters (T1/2 Ke,AUC) of L-dopa after administration of LIPE are larger significantly than after administration of L-dopa.Conclusion: The process is easy to operate and the structure of the product is consistent with the design one. The aqueous solutions of LIPE is stable under the condition of pH1.3, pH 5.0, pH 7.4 (temperature:37℃), it shows that it is stable before entering the internal circulation. L-dopa prodrug LIPE is able to increase the bioavailability and lengthen the half life of L-dopa.