Study On The New Synthetic Process Of Anti-hepatitis Drug Bicyclol

Bicyclol has dual roles of protecting liver and suppressing the virus as anti-hepatitis drug,which is used ordinarily at hospital.Traditional process for the synthesis of Bicyclol is as follows:It is obtained by hydrolysis,anhydridation,reduction,ring-opening and methylation in58%yield with bifendate as raw material.The Bicyclol is also obtained with the intermediate of methyl 4-bromo-7-methoxybenzo[d][1,3]dioxole-5-carboxylate as the starting materials through hydrolyzation or reduction following by esterification,coupling,and alcoholysis.The yield of Bicyclol is 23.8%.The former process suffers from expensive raw materials,low purity,and the latter has the low yield.So it is necessary for improving the synthetic process of Bicyclol.A new method for the synthesis of Bicyclol is developed based on a large amount of literatures.The reaction is conducted with methyl4-bromo-7-methoxybenzo[d][1,3]dioxole-5-carboxylate as the starting materials for reduction.Then the coupling reaction happened to afford cyclical lactone between the reduction product and raw material.Bicyclol was obtained by hydrolyzing and methylating.The total yield was 49.3%.The novel synthestic procedure is more suitable for industrial production,which exhibited several advantages such as high yield and purity,less reaction steps and low production cost.The optimal conditions were obtained by a variety of experiments.?1?The?4-bromo-7-methoxybenzo[d][1,3]dioxol-5-yl?methanol was synthesized by methyl 4-bromo-7-methoxybenzo[d][1,3]dioxole-5-carboxylate and reductant KBH₄:the molar ratio of raw material,KBH₄and promoter CaCl₂ was 1:1.2:0.7.They reacted at 50?for 4 hours using PEG-400 as phase transfer catalyst and ethanol as the solvent.The yield and purity was 96.2%and 98.6%,repectively.The KBH₄-CaCl₂reduction system has advantages of low cost,high reactivity and yield.Simutaneously,the solvent of ethanol was easily recoverd,and the cost of production was decreased.?2?The 4,10-dimethoxy-[1,3]dioxolo[4',5':3,4]benzo[1,2-c][1,3]dio-xolo[4',5':5,6]benzo[1,2-e]oxepin-6?8H?-one was prepared by coupling by methyl 4-bromo-7-methoxybenzo[d][1,3]dioxole-5-carboxylate and?4-bromo-7-methoxybenzo[d][1,3]dioxol-5-yl?methanol as substrates.The molar ratio was 1:1.1.They reacted at 155?for 4 hours using copper powder as catalyst and DMF as solvent.The yield and the purity was 55.1%and 96.7%,respectively.?3?The 5'-?hydroxymethyl?-7,7'-dimethoxy-[4,4'-bibenzo[d][1,3]di-oxole]-5-carboxylic acid was prepared from the 4,10-dimethoxy-[1,3]dioxolo[4',5':3,4]benzo[1,2-c][1,3]dio-xolo[4',5':5,6]benzo[1,2-e]oxepin-6?8H?-one by hydrolyzing.They refluxed in the presence of 5%KOH solution for 4 hours following by the acidification using 50%sulfuric acid for 1.5 hours at room temperature and the pH was close to 3.0.The yield and the purity was 96.6%and 99.2%,respectively?4?The Bicyclol was syhthesized by methylating of the5'-?hydroxymethyl?-7,7'-di-methoxy-[4,4'-bibenzo[d][1,3]dioxole]-5-carb oxylic acid.They reacted at 55?for 4 hours in the presence of NaOH as acid binding agent,?CH₃?₂SO₄ as methylating reagent and acetone as solvent.The yield and the purity was 96.2%and 98.7%,respectively.