降脂活性分子bouchardatine及其类似物的合成

Synthesis of bouchardatine and its derivatives with lipid-lowering effect

目的研究并优化天然产物bouchardatine及其类似物的合成方法,提高目标化合物的总收率。方法以邻氨基苯甲酰胺、原丙酸三乙酯为起始原料,经环合、溴代后与苯肼反应得到苯腙中间体,再经Fischer重排环合得到关键中间体2-(2-吲哚)-4(3H)喹唑啉酮,该中间体在n Bu4NI催化下,与N-甲基苯胺反应制得bouchardatine;bouchardatine经三氯氧磷氯代制得另一中间体2-(2-(4-氯喹唑啉基))-1H-吲哚-3-甲醛,该中间体与N,N-二甲基-1,3-丙二胺反应得到目标化合物。结果与结论优化后的合成路线,bouchardatine的总收率为31%,bouchardatine类似物的总收率由原来的4%提高到14%,反应总时长缩短了16 h。该路线具有操作简便、中间体易于提纯等优点。对合成过程中得到的两个副产物4-氯-2-(2-1H-吲哚)喹唑啉和4-氯-2-(2-1H-3-氯吲哚)喹唑啉的合成方法进行了优化,其中4-氯-2-(2-1H-3-氯吲哚)喹唑啉未见文献报道。关键中间体2-(2-吲哚)-4(3H)喹唑啉酮和两个副产物均具有降脂活性,可作为先导化合物进行深入研究。目标化合物及中间体的结构经核磁共振谱、质谱确证。

Bouchardatine and its derivatives have recently been reported as potential agents for treatment of obesity and related metabolic disorders（ type 2 diabetes etc.）. Bouchardatine derivative R17 is synthesized from anthranilamide and triethylorthopropionate via cyclization,bromization,Fischer indolization,formylation,chlorination and substitution described in this paper. C-3-formylation of the important intermediate 2-（ 1H-indol-2-yl） quinazolin-4（ 3H）-one is a key step in the preparation of R17,it furnished bouchardatine in with only 6% overall yield as used Vilsmeier conditions. An improved synthetic method for bouchardatine catalyzed by n Bu4NI-using N-methylaniline as a formylating reagent provided a higher yield（ 55%）,the yield of R17 then enhanced from 4% to 14% in overall. We found two by-products（ 6 and 7）,both of them have lipid-lowering effect thus have potential to be lead compounds. Compound 7 has never been reported.The structures of the target compound and key intermediates were confirmed by1H-NMR,13C-NMR and MS. The improved procedures increase the yield and also have the advantages of mild condition,less by-products,no complicated purification.