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【结 构 式】

【分子编号】19008

【品名】benzyl 8-(2,3-dihydroxypropyl)-1,4-dioxaspiro[4.5]dec-8-ylcarbamate

【CA登记号】

【 分 子 式 】C19H27NO6

【 分 子 量 】365.42652

【元素组成】C 62.45% H 7.45% N 3.83% O 26.27%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(IV)

Alkylation of acid (I) with allyl bromide in the presence of two equivalents of lithium diisopropylamide (LDA) in THF gave (II). Curtius rearrangement of acid (II) using diphenylphosphoryl azide (DPPA), followed by treatment of the intermediate isocyanate with benzyl alcohol afforded benzyl carbamate (III). Dihydroxylation of (III) with N-methylmorpholine-N-oxide (NMO) and a catalytic amount OsO4 provided diol (IV), which was selectively tosylated at the primary hydroxyl group with p-toluenesulfonyl chloride in the presence of dimethylaminopyridine (DMAP). Protection of secondary hydroxyl group of the resulting tosylate (V) was effected with tert-butyldimethylsilyl chloride in the presence of imidazole, affording silyl ether (VI). Then, benzyl carbamate was removed by hydrogenolysis using palladium on carbon in methanol to give free amine (VII), and further cyclization in the presence of 1,8-diazabicycloundec-7-ene (DBU) in refluxing benzene afforded azaspiro compound (VIII). This was alkylated with ethyl bromoacetate in the presence of K2CO3, followed by deprotection of the silyl ether with tetrabutylammonium fluoride to give (IX). Alcohol (IX) was then converted into azide (X) under Mitsunobu's conditions, and subsequently reduced to primary amine (XI) by catalytic hydrogenation. Hydrolysis of ester (XI) with LiOH gave acid (XII), which was cyclized by treatment with diphenylphosphoryl azide and triethylamine to give rise to the tetracyclic system (XIII). Treatment of (XIII) with iodomethane in the presence of sodium hydride provided the N-methylated compound (XIV). Condensation of (XIV) with aldehyde (XV) was performed using LDA as a base in THF at -78 C to form two separable aldol adducts (XVI), which were determined to be epimeric at the benzylic position.

1 Nagumo, S.; et al.; Total synthesis of antimuscarinic alkaloid, (±)-TAN1251A. Tetrahedron 2002, 58, 24, 4917.
2 Nagumo, S.; et al.; Total synthesis of (±)-TAN1251A. Tetrahedron Lett 1998, 39, 25, 4493.
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) 19005 1,4-dioxaspiro[4.5]decane-8-carboxylic acid C9H14O4 详情 详情
(II) 19006 8-allyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid C12H18O4 详情 详情
(III) 19007 benzyl 8-allyl-1,4-dioxaspiro[4.5]dec-8-ylcarbamate C12H18O4 详情 详情
(IV) 19008 benzyl 8-(2,3-dihydroxypropyl)-1,4-dioxaspiro[4.5]dec-8-ylcarbamate C19H27NO6 详情 详情
(V) 19009 3-(8-[[(benzyloxy)carbonyl]amino]-1,4-dioxaspiro[4.5]dec-8-yl)-2-hydroxypropyl 4-methylbenzenesulfonate C26H33NO8S 详情 详情
(VI) 19010 3-(8-[[(benzyloxy)carbonyl]amino]-1,4-dioxaspiro[4.5]dec-8-yl)-2-[[tert-butyl(dimethyl)silyl]oxy]propyl 4-methylbenzenesulfonate C32H47NO8SSi 详情 详情
(VII) 19011 3-(8-amino-1,4-dioxaspiro[4.5]dec-8-yl)-2-[[tert-butyl(dimethyl)silyl]oxy]propyl 4-methylbenzenesulfonate C24H41NO6SSi 详情 详情
(VIII) 19012 tert-butyl(dimethyl)silyl 1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-11-yl ether; 11-[[tert-butyl(dimethyl)silyl]oxy]-1,4-dioxa-9-azadispiro[4.2.4.2]tetradecane C17H33NO3Si 详情 详情
(IX) 19013 ethyl 2-(11-hydroxy-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl)acetate C15H25NO5 详情 详情
(X) 19014 ethyl 2-(11-azido-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl)acetate C15H24N4O4 详情 详情
(XI) 19015 ethyl 2-(11-amino-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl)acetate C15H26N2O4 详情 详情
(XII) 19016 2-(11-amino-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl)acetic acid C13H22N2O4 详情 详情
(XIII) 19017 Dispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one C13H20N2O3 详情 详情
(XIV) 19018 2-Methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one C14H22N2O3 详情 详情
(XV) 19019 4-[(3-methyl-2-butenyl)oxy]benzaldehyde C12H14O2 详情 详情
(XVI) 19020 (1R,4S)-4-[1-Hydroxy-1-[4-(3-methyl-2-butenyloxy)phenyl]methyl]-2-methyldispiro[2,5-diazabicyclo[3,2,1]octane-6,1'-cyclohexane-4',2''-[1,3]-dioxolan]-3-one C26H36N2O5 详情 详情
Extended Information