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Study of Multi-Substituted Quinoline Derivatives' Synthesis

Author: ZhangLiJuan
Tutor: LvWei
School: East China Normal University
Course: Organic Chemistry
Keywords: multi-substituted quinoline SN38 AB ring 4-substituted-2-quinolinone
CLC: TQ463.5
Type: Master's thesis
Year: 2011
Downloads: 32
Quote: 0
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Abstract


Quinoline derivatives are very important compounds because members of them have wide applications in medicinal chemistry, being used as antimalarial, antiinflammatory agents, antiasthamatic, and antitumor drugs. Meanwhile, quinoline ring also exists in natural products such as antitumor drug camptothecin analogs. Therefore it’s very important to study the synthesis of quinoline compounds for pharmaceutical research. In this paper we describe our synthetic work of quinoline compounds as follows:The first part of my work is to synthesize the AB ring of7-ethyl-10-hydroxycamptothecin (SN-38). SN-38is the active metabolite of Irinotecan, which is approved by FDA for the treatment of colorectal cancer and it’s mainly produced through semisynthesis from camptothecin. Our team plans to finish SN38’s total synthesis by Comins’ approach. And as a part of the work, we take1-(3-chloro-phenyl)-propan-l-one as the starting material, complete the total synthesis of2-bromo-3-bromomethyl-4-ethyl-6-methoxy-quinoline and6-benzyloxy-2-bromo-3-bromomethyl-4-ethyl-quinoline by nine steps such as nitration by nitric acid, carbonyl acetal protection, substitution reaction, nitro reduction, deprotection, acylation, ring-closure, reduction and bromination, et al. The advantages of this route include good orientation, low cost, easy amplification and it is suitable for industrial produce.To meet the demand of camptothecin analogs’ structural alteration and the correlative pharmaceutical chemistry research, the second part of my work is to study a new approach for the synthesis of multi-substituted-2-hydroxy-quinoline compounds. Starting from2,4-dichloro-quinoline-3-carboxylic acid ethyl ester, we selectively hydrolyze2-chloro on quinoline ring and take4-chloro-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester to perform different reactions. By the efforts, an efficient method for the synthesis of4-substituted-2-quinolinone-3-carboxylic acid ethyl esters has been developed by Suzuki and Sonogashira reactions in high yields. Compared with the previous methods, this novel route is efficient for the generation of many analogs for SAR studies because it allows introducing various substituents at the C-4of the quinolinone at the last step.

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CLC: > Industrial Technology > Chemical Industry > Pharmaceutical chemical industry > Production of organic compounds in drug > Heterocyclic compounds drugs
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