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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。
Objective To study and optimize the synthetic method of natural product bouchardatine and its analogues and to increase the total yield of target compounds. Methods Starting from anthranilamide and triethyl propionate, the intermediate of phenylhydrazone was obtained after cyclization and bromination with phenylhydrazine, then the key intermediate 2- ( 2-indole) -4 (3H) quinazolinone, which was reacted with N-methylaniline under the catalysis of Bu4NI to obtain bouchardatine. The bouchardatine was chlorinated with phosphorous oxychloride to obtain another intermediate 2 - (2- (4-chloroquinazolinyl) -1H-indole-3-carbaldehyde, which intermediate is reacted with N, N-dimethyl-1,3-propanediamine to give the title compound. RESULTS AND CONCLUSION The optimized synthetic route showed that the overall yield of bouchardatine was 31% and the total yield of bouchardatine analogs increased from 4% to 14%. The total reaction time was shortened by 16 hours. The route has the advantages of easy operation, easy purification of intermediates and the like. Synthesis of 4-chloro-2- (2-1H-indole) quinazoline and 4-chloro-2- (2-1H-3-chloroindole) quinazoline obtained in the synthesis Method was optimized, among which 4-chloro-2- (2-1H-3-chloroindole) quinazoline was not reported in the literature. The key intermediate 2- (2-indol) -4 (3H) quinazolinone and two by-products all have lipid-lowering activity and can be further studied as lead compounds. The structures of target compounds and intermediates were confirmed by NMR and MS.