Tiotropium bromide, BA-679-BR, Spiriva HandiHaler, Spiriva
噻托溴铵 噻托溴铵 噻托溴铵Chemical Name: (1R,2R,4S,5S,7S)-7-[2-Hydroxy-2,2-di(2-thienyl)acetoxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0(2,4)]nonane bromide; 6beta,7beta-Epoxy-3alpha-[2-hydroxy-2,2-di(2-thienyl)acetoxy]-8,8-dimethyl-1alphaH,5alphaH-tropanium bromide
CAS No. 136310-93-5, 186691-13-4 (cation), 139404-48-1 (hydrate)
项目整合开发状态: Launched-2002
项目研究机构: Boehringer Ingelheim (Originator), Nippon Boehringer Ingelheim (Originator), Pfizer (Marketer)
合成路线:The Grignard condensation of oxalic acid dimethyl ester (I) with 2-thienylmagnesium bromide (II) gives 2-hydroxy-2,2-bis(2-thienyl)acetic acid methyl ester (III),which is submitted to transesterification with scopine (IV) catalyzed by Na or NaOEt,providing the corresponding ester (V).Finally,(V) is quaternized with methyl bromide in dichloromethane/acetonitrile.
📌 参考资料/链接：
参考文献标题:Thienylcarboxylic acid ester of aminoalcohols,their quaternary products,their preparation and use of the cpds.
文献作者:Banholzer,R.; Bauer,R.; Reichl,R.(Boehringer Ingelheim GmbH; Boehringer Ingelheim Pharma KG)
参考来源:DE 3931041; EP 0418716; JP 1993502438; US 5610163; WO 9104252
📄 详细内容
合成路线:The transesterification of 2-hydroxy-2,2-bis(2-thienyl)acetic acid methyl ester (I) with endo-8-methyl-8-azabicyclo[3,2,1]-6-octen-3-ol (II) gives the corresponding ester (III),which is epoxidated with V2O5 and H2O2 to yield the epoxy compound (IV).Finally,this compound is quaternized with methyl bromide as usual.
参考文献标题:Method for producing the anticholinergic agent tiotropium bromide
文献作者:Banholzer,R.; Luettke,S.; Meissner,H.; Graulich,M.; Mathes,A.; Specht,P.; Broeder,W.(Boehringer Ingelheim Pharma KG)
参考来源:DE 10064816; WO 0251840
合成路线:The Grignard condensation of oxalic acid dimethyl ester (I) with 2-thienylmagnesium bromide (II) gives 2-hydroxy-2,2-bis(2-thienyl)acetic acid methyl ester (III),which is submitted to transesterification with scopine (IV) catalyzed by Na or NaOEt,providing the corresponding ester (V).Finally,(V) is quaternized with methyl bromide in dichloromethane/acetonitrile.
参考文献标题:Tiotropium Bromide
文献作者:Norman,P.; Rabasseda,X.; Castar,J.; Graul,A.
参考来源:Drugs Fut 2000,25(7),693