新产品编号:690261
Chemical Name: 3-(3-Hydroxy-4-methoxyphenyl)-8H-thieno[2,3-b]pyrrolizin-8-one
CAS No. 258270-07-4
项目整合开发状态: Preclinical
项目研究机构: Servier (Originator)
合成路线:The title compound has been synthesized by two closely related methods.Claisen condensation of 3,4-dimethoxyphenylacetonitrile (I) with ethyl formate produced the cyano aldehyde sodium enolate (II),which was further O-acylated with benzenesulfonyl chloride to afford (III).The aminothiophene derivative (V) was prepared by cyclization of (III) with methyl thioglycolate (IV) under basic conditions.A pyrrole ring was then introduced in (V) through a Paal-Knorr synthesis employing 2,5-dimethoxytetrahydrofuran (VI) in the presence of 4-chloropyridinium chloride,yielding (VII).Refluxing of ester (VII) in pyrrolidine (VIII) gave rise to amide (IX).The intramolecular cyclization of (IX) under Vilsmeier conditions furnished the tricyclic system (X).Finally,regioselective cleavage of the meta methoxy group of (X) by means of AlCl3 yielded the target compound.
📌 参考资料/链接：
参考文献标题:Derivs.of the 8H-(2,3-b)-pyrrolizine-8-one,process for their preparation and pharmaceutical compsns.containing them
文献作者:Caignard,D.-H.; Enghehard,C.; Robba,M.; Lancelot,J.-C.; Pierre,A.; Renard,P.; Rault,S.; Atassi,G.(ADIR et Cie.)
参考来源:EP 0982308; FR 2781482; JP 2000044572; US 6071945
📄 详细内容
合成路线:In an alternative procedure,isovanillin (XI) was protected by O-benzylation,giving (XII),and its aldehyde group was subsequently reduced to alcohol (XIII) with NaBH4.The benzylic alcohol (XIII) was chlorinated to (XIV),which was converted to nitrile (XV) by chloride displacement with tetraethylammonium cyanide.Nitrile (XV) was subjected to Claisen condensation with ethyl formate,yielding (XVI),followed by sulfonylation with benzenesulfonyl chloride to afford (XVII),which was cyclized to the amino thiophene (XVIII) by treatment with ethyl thioglycolate (IV) as above.Condensation of (XVIII) with 2,5-dimethoxytetrahydrofuran (VI) produced the corresponding pyrrole derivative (XIX).After conversion of the ester group of (XIX) to amide (XX) upon heating with pyrrolidine (VIII),its cyclization with POCl3 furnished the thienopyrrolizinone (XXI).The O-benzyl protecting group of (XXI) was finally cleaved by treatment with HBr in HOAc.
参考文献标题:Design,synthesis and antiproliferative activity of tripentones: A new series of antitubulin agents
文献作者:Lisowski,V.; Enguehard,C.; Lancelot,J.-C.; Caignard,D.H.; Lambel,S.; Leonce,S.; Pierre,A.; Atassi,G.; Renard,P.; Rault,S.
参考来源:Bioorg Med Chem Lett 2001,11(16),2205
产品链接: CAS No. 258270-07-4››