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【结 构 式】

【药物名称】Tiotropium bromide, BA-679-BR, Spiriva HandiHaler, Spiriva

【化学名称】(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

【CA登记号】136310-93-5, 186691-13-4 (cation), 139404-48-1 (hydrate)

【 分 子 式 】C19H22BrNO4S2

【 分 子 量 】472.42349

【开发单位】Boehringer Ingelheim (Originator), Nippon Boehringer Ingelheim (Originator), Pfizer (Marketer)

【药理作用】Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, RESPIRATORY DRUGS, Muscarinic M3 Antagonists

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6

合成路线1

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 中间体
【1】 Banholzer, R.; Bauer, R.; Reichl, R. (Boehringer Ingelheim GmbH; Boehringer Ingelheim Pharma KG); Thienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the cpds.. DE 3931041; EP 0418716; JP 1993502438; US 5610163; WO 9104252 .
【2】 Norman, P.; Rabasseda, X.; Castaner, J.; Graul, A.; Tiotropium Bromide. Drugs Fut 2000, 25, 7, 693.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 37412 methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate 553-90-2 C4H6O4 详情 详情
(II) 32082 bromo(2-thienyl)magnesium 5713-61-1 C4H3BrMgS 详情 详情
(III) 37630 methyl 2-hydroxy-2,2-di(2-thienyl)acetate 26447-85-8 C11H10O3S2 详情 详情
(IV) 37631 (1R,2S,4R,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.0(2,4)]nonan-7-ol；Scopine 498-45-3 C8H13NO2 详情 详情
(V) 37632 (1R,2S,4R,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.0(2,4)]non-7-yl 2-hydroxy-2,2-di(2-thienyl)acetate；Scopine 2,2-dithienylglycolate 136310-64-0 C18H19NO4S2 详情 详情

合成路线2

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 中间体
【1】 Banholzer, R.; Luettke, S.; Meissner, H.; Graulich, M.; Mathes, A.; Specht, P.; Broeder, W. (Boehringer Ingelheim Pharma KG); Method for producing the anticholinergic agent tiotropium bromide. DE 10064816; WO 0251840 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 37630 methyl 2-hydroxy-2,2-di(2-thienyl)acetate 26447-85-8 C11H10O3S2 详情 详情
(II) 58589 (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol C8H13NO 详情 详情
(III) 58590 (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl 2-hydroxy-2,2-di(2-thienyl)acetate C18H19NO3S2 详情 详情
(IV) 37632 (1R,2S,4R,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.0(2,4)]non-7-yl 2-hydroxy-2,2-di(2-thienyl)acetate；Scopine 2,2-dithienylglycolate 136310-64-0 C18H19NO4S2 详情 详情

合成路线3

　

参考文献 中间体
【1】 Belzer W, Harnm R, Hofmann M, et aL. 2006. New procedure for the production of tiotropiura salts from acopine methobromide. Ger Offen. DE 102004041253
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 66851 2-hydroxy-2,2-di(thiophen-2-yl)acetic acid 　 C10H8O3S2 详情 详情
(II) 66852 1-(1H-imidazol-1-yl)-2,2-di(thiophen-2-yl)-2-((trimethylsilyl)oxy)ethanone 　 C16H18N2O2S2Si 详情 详情
(III) 66853 7-hydroxy-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-9-ium bromide 　 C9H16BrNO2 详情 详情

合成路线4

　

参考文献 中间体
【1】 Issa F, Kassiou M, Chan HK, et aL. 2006. Synthesis and radiolabellolabelling of ipratropium and tiotropium for use as PET Ilgands in the study of inhaled drug deposition. Australian Journal of Chemistry , 59 (1): 53～58
【2】 Rapp AW, Sobotta R. 2003. Tecluucal synthetic method for producing tropenol from scopine esters. W0 2003002562
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 37630 methyl 2-hydroxy-2,2-di(2-thienyl)acetate 26447-85-8 C11H10O3S2 详情 详情
(I) 66854 9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-yl 3-hydroxy-2-phenylpropanoate 　 C17H21NO4 详情 详情
(II) 66855 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl 3-hydroxy-2-phenylpropanoate 　 C17H21NO3 详情 详情
(III) 58589 (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol C8H13NO 详情 详情
(V) 58590 (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl 2-hydroxy-2,2-di(2-thienyl)acetate C18H19NO3S2 详情 详情

合成路线5

　

参考文献 中间体
【1】 Banholzer R, Bodenbach G, Mathes A, et al. 2003. Technical method for producing tropenol. W0 2003101986
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 66857 6,7-dihydroxy-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-methylbut-2-enoate 　 C13H21NO4 详情 详情
(V) 58590 (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl 2-hydroxy-2,2-di(2-thienyl)acetate C18H19NO3S2 详情 详情
(II) 66858 2-(dimethylamino)-9-methylhexahydro-3aH-4,8-epiminocyclohepta[d][1,3]dioxol-6-yl 2-methylbut-2-enoate 　 C16H26N2O4 详情 详情
(IV) 37630 methyl 2-hydroxy-2,2-di(2-thienyl)acetate 26447-85-8 C11H10O3S2 详情 详情

合成路线6

　

参考文献 中间体
【1】 冉臆峰，吕良忠，许军等．2006．毫托澳饺无水钧制备方法．发明专利申请公开说明书，CN 1861598
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 37631 (1R,2S,4R,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.0(2,4)]nonan-7-ol；Scopine 498-45-3 C8H13NO2 详情 详情
(I) 13681 2-Bromothiophene 1003-09-4 C4H3BrS 详情 详情
(II) 32082 bromo(2-thienyl)magnesium 5713-61-1 C4H3BrMgS 详情 详情
(III) 37630 methyl 2-hydroxy-2,2-di(2-thienyl)acetate 26447-85-8 C11H10O3S2 详情 详情
(IV) 66859 　 　 C17H21NO4.HBr.3H2O 详情 详情
(V) 37632 (1R,2S,4R,5S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.0(2,4)]non-7-yl 2-hydroxy-2,2-di(2-thienyl)acetate；Scopine 2,2-dithienylglycolate 136310-64-0 C18H19NO4S2 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)