J-104870
Chemical Name: N-[3-[6-(5-Ethylthiazol-2-ylsulfanylmethyl)-4-(4-morpholinyl)pyridin-2-ylaminomethyl]-5-methoxyphenyl]carbamic acid allyl ester
CAS No. 196498-48-3
项目整合开发状态: Preclinical
项目研究机构: Banyu (Originator)
合成路线:The condensation of 4-chloro-2,6-pyridinedicarboxylic acid (I) with morpholine (II) afforded the morpholinopyridinedicarboxylic acid (III),which was further esterified with MeOH and HCl to produce diester (IV).Reduction of (IV) with NaBH4 and CaCl2 gave hydroxy ester (V).After protection of the hydroxyl group of (V) as the trimethylsilylethoxymethyl derivative (VII),the ester group was hydrolyzed under basic conditions yielding acid (VIII).This was then subjected to a Curtius rearrangement with DPPA in the presence of tert-butanol to generate the tert-butyl carbamate (IX).Alkylation of carbamate (IX) with 3-methoxy-5-nitrobenzyl bromide (X) and NaH furnished the N-benzyl carbamate derivative (XI).The nitro group of (XI) was then reduced to amine (XII) by catalytic hydrogenation over Pd/C.
合成路线:Amine (XII) was converted into allyl carbamate (XIII) by reaction with allyl chloroformate.The silylethoxymethyl protecting group of (XIII) was then removed by acidic treatment to provide alcohol (XIV),which was further activated as the corresponding mesylate (XV).Condensation of mesylate (XV) with 5-ethyl-2-mercaptothiazole (XVI) gave thioether (XVII).The N-Boc group of (XVII) was finally cleaved by treatment with trifluoroacetic acid to yield the title compound.
📌 参考资料/链接：
参考文献标题:Aminopyridine derivs.
文献作者:Fukami,T.; Mase,T.; Tsuchiya,Y.; Kanatani,A.; Fukuroda,T.(Banyu Pharmaceutical Co.,Ltd.)
参考来源:EP 0889034; US 6011039; WO 9734873
📄 详细内容
合成路线:A similar method,but using a different protection strategy,has been reported.4-Hydroxy-2,6-pyridinedicarboxylic acid (XVIII) was condensed with morpholine (II) to provide,after Fischer esterification,the morpholinopyridine diester (IV).Reduction of (IV) with calcium borohydride furnished hydroxy ester (V).Protection of (V) as the corresponding tetrahydropyranyl ether,followed by ester group saponification,afforded (XIX).Curtius rearrangement of acid (XIX) in the same conditions as above gave carbamate (XX),which was alkylated with benzyl chloride (XXI) yielding (XXII).After reduction of the nitroderivative (XXII) with iron and ammonium chloride,the resultant amine (XXIII) was acylated by allyl chloroformate to produce carbamate (XXIV).Then,acidic treatment removed the tetrahydropyranyl-protecting group to afford alcohol (XIV),which was finally processed as in the above method.
参考文献标题:Potent and selective aminopyridine NPY Y1 receptor antagonists
文献作者:Haga,Y.; Tsuchiya,Y.; Mase,T.; et al.
参考来源:21st Symp Med Chem (Nov 28 2001,Kyoto) 2001,Abst 2P-38