新产品编号:1338881
Chemical Name: (5R,6R)-3-(1-Azabicyclo[3.2.1]oct-6-yl)-4-(propylsulfanyl)-1,2,5-thiadiazole
项目整合开发状态: Preclinical
项目研究机构: Lilly (Originator), Novo Nordisk (Originator)
合成路线:Alkylation of ethyl nipecotate (I) with ethyl bromoacetate gave diester (II).Subsequent Dieckmann cyclization of (II) with t-BuOK,followed by acid decarboxylation afforded azabicyclo[3.2.1]octane-6-one (III).Knoevenagel condensation of (III) with ethyl cyanoacetate afforded unsaturated cyano ester (IV),which was hydrogenated over Pd/C to provide (V).Nitrosation of (V) with isoamyl nitrite in the presence of NaOEt gave the hydroxymino nitrile (VI).This was treated with S2Cl2 in cold DMF to generate the thiadiazole (VII).Hydrogenolysis of the 6-chloro of (VII) provided a mixture of isomers,from which the exo compound (VIII) was isolated by column chromatography.The required butyl thioether was then obtained by reaction with sodium hydrosulfide and n-butyl bromide in DMF.Finally,resolution with D-tartaric acid yielded the title (5R,6R) enantiomer.
合成路线:Alkylation of ethyl nipecotate (I) with ethyl bromoacetate gave diester (II).Subsequent Dieckmann cyclization of (II) with t-BuOK,followed by acid decarboxylation afforded azabicyclo[3.2.1]octane-6-one (III).Knoevenagel condensation of (III) with ethyl cyanoacetate afforded unsaturated cyano ester (IV),which was hydrogenated over Pd/C to provide (V).Nitrosation of (V) with isoamyl nitrite in the presence of NaOEt gave the hydroxymino nitrile (VI).This was treated with S2Cl2 in cold DMF to generate the thiadiazole (VII).Hydrogenolysis of the 6-chloro of (VII) provided a mixture of isomers,from which the exo compound (VIII) was isolated by column chromatography.The required propyl thioether was then obtained by reaction with sodium hydrosulfide and n-propyl bromide in DMF.Finally,resolution with D-tartaric acid yielded the title (5R,6R) enantiomer.
合成路线:Alkylation of ethyl nipecotate (I) with ethyl bromoacetate gave diester (II).Subsequent Dieckmann cyclization of (II) with t-BuOK,followed by acid decarboxylation afforded azabicyclo[3.2.1]octane-6-one (III).Knoevenagel condensation of (III) with ethyl cyanoacetate afforded unsaturated cyano ester (IV),which was hydrogenated over Pd/C to provide (V).Nitrosation of (V) with isoamyl nitrite in the presence of NaOEt gave the hydroxymino nitrile (VI).This was treated with S2Cl2 in cold DMF to generate the thiadiazole (VII).Hydrogenolysis of the 6-chloro of (VII) provided a mixture of isomers,from which the exo compound (VIII) was isolated by column chromatography.The required propyl thioether was then obtained by reaction with sodium hydrosulfide and n-propyl bromide in DMF.Finally,resolution with L-tartaric acid yielded the title (5S,6S) enantiomer.
📌 参考资料/链接：
参考文献标题:Heterocyclic cpds.and their preparation and use
文献作者:Sauerberg,P.; Olesen,P.H.(Novo Nordisk A/S)
参考来源:EP 0544779; JP 1994500542; US 5260314; US 5418240; US 5527813; US 5578602; WO 9203433
📄 详细内容
合成路线:Alkylation of ethyl nipecotate (I) with ethyl bromoacetate gave diester (II).Subsequent Dieckmann cyclization of (II) with t-BuOK,followed by acid decarboxylation afforded azabicyclo[3.2.1]octane-6-one (III).Knoevenagel condensation of (III) with ethyl cyanoacetate afforded unsaturated cyano ester (IV),which was hydrogenated over Pd/C to provide (V).Nitrosation of (V) with isoamyl nitrite in the presence of NaOEt gave the hydroxymino nitrile (VI).This was treated with S2Cl2 in cold DMF to generate the thiadiazole (VII).Hydrogenolysis of the 6-chloro of (VII) provided a mixture of isomers,from which the exo compound (VIII) was isolated by column chromatography.The required butyl thioether was then obtained by reaction with sodium hydrosulfide and n-butyl bromide in DMF.Finally,resolution with D-tartaric acid yielded the title (5R,6R) enantiomer.
合成路线:Alkylation of ethyl nipecotate (I) with ethyl bromoacetate gave diester (II).Subsequent Dieckmann cyclization of (II) with t-BuOK,followed by acid decarboxylation afforded azabicyclo[3.2.1]octane-6-one (III).Knoevenagel condensation of (III) with ethyl cyanoacetate afforded unsaturated cyano ester (IV),which was hydrogenated over Pd/C to provide (V).Nitrosation of (V) with isoamyl nitrite in the presence of NaOEt gave the hydroxymino nitrile (VI).This was treated with S2Cl2 in cold DMF to generate the thiadiazole (VII).Hydrogenolysis of the 6-chloro of (VII) provided a mixture of isomers,from which the exo compound (VIII) was isolated by column chromatography.The required propyl thioether was then obtained by reaction with sodium hydrosulfide and n-propyl bromide in DMF.Finally,resolution with D-tartaric acid yielded the title (5R,6R) enantiomer.
合成路线:Alkylation of ethyl nipecotate (I) with ethyl bromoacetate gave diester (II).Subsequent Dieckmann cyclization of (II) with t-BuOK,followed by acid decarboxylation afforded azabicyclo[3.2.1]octane-6-one (III).Knoevenagel condensation of (III) with ethyl cyanoacetate afforded unsaturated cyano ester (IV),which was hydrogenated over Pd/C to provide (V).Nitrosation of (V) with isoamyl nitrite in the presence of NaOEt gave the hydroxymino nitrile (VI).This was treated with S2Cl2 in cold DMF to generate the thiadiazole (VII).Hydrogenolysis of the 6-chloro of (VII) provided a mixture of isomers,from which the exo compound (VIII) was isolated by column chromatography.The required propyl thioether was then obtained by reaction with sodium hydrosulfide and n-propyl bromide in DMF.Finally,resolution with L-tartaric acid yielded the title (5S,6S) enantiomer.
参考文献标题:Muscarinic analgesics with potent and selective effects on the gastrointestinal tract: Potential application for the treatment of irritable bowel syndrome
文献作者:Mitch,C.H.; Brown,T.J.; Bymaster,F.P.; Calligaro,D.O.; Dieckman,D.; Merrit,L.; Peters,S.C.; Quimby,S.J.; Shannon,H.E.; Shipley,L.A.; Ward,J.S.; Hansen,K.; Olesen,P.H.; Sauerberg,P.; Sheardown,M.J.; Swedberg,M.D.; Suzdak,P.D.; Greenwood,B
参考来源:J Med Chem 1997,40(4),538