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【结 构 式】 
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【药物名称】Arbutamine hydrochloride, GP-2-121-3, GenESA 【化学名称】(R)-(-)-1-(3,4-Dihydroxyphenyl)-2-[4-(4-hydroxyphenyl)butylamino]ethanol hydrochloride 【CA登记号】125251-66-3, 128470-16-6 (free base) 【 分 子 式 】C18H24ClNO4 【 分 子 量 】353.84928 |
【开发单位】Sicor (Originator) 【药理作用】DIAGNOSTIC AGENTS, beta1-Adrenoceptor Agonists |
合成路线1
Demethylation of 4-(4-methoxyphenyl)butanol (I) by means of BBr3 gave phenol (II), which was subsequently protected as the benzyl ether (III) with benzyl bromide and K2CO3. Oxidation of the primary alcohol (III) employing pyridinium chlorochromate yielded aldehyde (IV). Finally, reductive amination of aldehyde (IV) with norepinephrine (V), with concomitant O-debenzylation, was accomplished by hydrogenation in the presence of both PtO2 and Pd/C.
| 【1】 Tuttle, R.R.; Browne III, C.E. (Sicor Inc.); Diagnosis, evaluation & treatment of coronary artery disease by exercise simulation using closed loop drug delivery of an exercise simulating agent beta agonist. EP 0329464; JP 1998276991; US 5108363 . |
| 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) | 55592 | 4-(4-methoxyphenyl)-1-butanol | C11H16O2 | 详情 | 详情 | |
| (II) | 55593 | 4-(4-hydroxybutyl)phenol | C10H14O2 | 详情 | 详情 | |
| (III) | 55594 | 4-[4-(benzyloxy)phenyl]-1-butanol | C17H20O2 | 详情 | 详情 | |
| (IV) | 55595 | 4-[4-(benzyloxy)phenyl]butanal | C17H18O2 | 详情 | 详情 | |
| (V) | 55596 | (-)-Arterenol; 3,4-Dihydroxyphenylethanolamine; L-Arterenol; L-Norepinephrine; L-Noradrenaline; Norepinephrine | 51-41-2 | C8H11NO3 | 详情 | 详情 |
合成路线2
The intermediate carboxylic acid (XIII) was prepared as follows: 2-(4-Hydroxyphenyl)ethanol (VI) was selectively protected at the phenolic hydroxyl with benzyl bromide, yielding (VII). Subsequent oxidation of the aliphatic alcohol group of (VII) with Dess-Martin periodinane reagent provided aldehyde (VIII). Wadsworth-Emmons condensation of (VIII) with the sodium derivative of phosphonate (IX) furnished adduct (X), which was further hydrogenated over Pd/C to the saturated ester (XI). The phenolic hydroxyl group of (XI), which was concomitantly debenzylated in the preceding hydrogenation step, was further reprotected as the methoxymethyl ether (XII). Acid (XIII) was then obtained by basic hydrolysis of ester (XII).
| 【1】 Takaoka, E.; et al.; Catalytic asymmetric synthesis of arbutamine. Heterocycles 1997, 46, 157. |
| 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) | 47355 | 4-(2-hydroxyethyl)phenol | 501-94-0 | C8H10O2 | 详情 | 详情 |
| (VII) | 33328 | 2-(p-Benzyloxyphenyl)ethanol; 2-[4-(Benzyloxy)phenyl]-1-ethanol | C15H16O2 | 详情 | 详情 | |
| (VIII) | 55597 | 2-[4-(benzyloxy)phenyl]acetaldehyde | C15H14O2 | 详情 | 详情 | |
| (IX) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (X) | 55598 | ethyl (E)-4-[4-(benzyloxy)phenyl]-2-butenoate | C19H20O3 | 详情 | 详情 | |
| (XI) | 55599 | ethyl 4-(4-hydroxyphenyl)butanoate | C12H16O3 | 详情 | 详情 | |
| (XII) | 55600 | ethyl 4-[4-(methoxymethoxy)phenyl]butanoate | C14H20O4 | 详情 | 详情 | |
| (XIII) | 55601 | 4-[4-(methoxymethoxy)phenyl]butanoic acid | C12H16O4 | 详情 | 详情 |
合成路线3
Protection of 3,4-dihydroxybenzaldehyde (XVI) with t-butyldimethylsilyl chloride and imidazole provided the corresponding bis-silyl ether (XVII) (2). Asymmetric nitroaldol condensation of aldehyde (XVII) with nitromethane in the presence of the chiral samarium tris(binaphthoxide) complex (XV) --prepared from (S)-6,6'-bis(trimethylsilylethynyl)-1,1'-dihydroxy-2,2'-binaphthalene (XIV) and samarium triisopropoxide in the presence of BuLi (2,3)-- gave rise to the (R)-nitro alcohol adduct (XVIII) with high optical purity. Catalytic hydrogenation of the nitro group of (XVIII) furnished the silylated norepinephrine (XIX), which was coupled with acid (XIII) in the presence of diethylphosphoryl cyanide to yield amide (XX). Reduction of amide (XX) with LiAlH4 gave amine (XXI). The silyl and methoxymethyl protecting groups were finally removed under acidic conditions to furnish the title compound.
| 【1】 Takaoka, E.; et al.; Catalytic asymmetric synthesis of arbutamine. Heterocycles 1997, 46, 157. |
| 【2】 Shibasaki, M.; Fujita, M.; Urata, Y.; Sasai, H. (Chisso Corp.); Optically active nitro alcohol derivs., optically active amino alcohol derivates, and process for preparing the same. EP 0947498; WO 9824753 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 55601 | 4-[4-(methoxymethoxy)phenyl]butanoic acid | C12H16O4 | 详情 | 详情 | |
| (XIV) | 55603 | C30H30O2Si2 | 详情 | 详情 | ||
| (XV) | 55604 | C90H84Li3O6Si6Sm | 详情 | 详情 | ||
| (XVI) | 39749 | 3,4-dihydroxybenzaldehyde | 139-85-5 | C7H6O3 | 详情 | 详情 |
| (XVII) | 55602 | 3,4-bis{[tert-butyl(dimethyl)silyl]oxy}benzaldehyde | C19H34O3Si2 | 详情 | 详情 | |
| (XVIII) | 55605 | (1R)-1-(3,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-nitro-1-ethanol | C20H37NO5Si2 | 详情 | 详情 | |
| (XIX) | 55606 | (1R)-2-amino-1-(3,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-ethanol | C20H39NO3Si2 | 详情 | 详情 | |
| (XX) | 55607 | N-[(2R)-2-(3,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-hydroxyethyl]-4-[4-(methoxymethoxy)phenyl]butanamide | C32H53NO6Si2 | 详情 | 详情 | |
| (XXI) | 55608 | (1R)-1-(3,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-({4-[4-(methoxymethoxy)phenyl]butyl}amino)-1-ethanol | C32H55NO5Si2 | 详情 | 详情 |
合成路线4
The enantioselective condensation of 3,4-bis(tert-butyldimethylsilyloxy)benzaldehyde (I) with nitromethane (II), catalyzed by the chiral Zn ligand complex (III) in THF gives the (R)-2-nitroethanol derivative (IV), which is reduced with H2 over Pd/C in methanol to yield the 2-aminoethanol derivative (V). The condensation of (V) with 4-[4-(tert-butyldimethylsilyloxy)phenyl]butyric acid (VI) by means of diphenyl chlorophosphate and DIEA in dichloromethane affords the corresponding amide (VII), which is reduced by conventional methods to the protected hydroxyamine (VIII). Finally, this compound is desilylated as usual to furnish the target tetrahydroxyamine derivative.
| 【1】 Ito, H.; Bremeyer, N.; Trost, B.M.; Yeh, V.S.C.; Effect of ligand structure on the zinc-catalyzed Henry reaction. Asymmetric syntheses of (-)-denopamine and (-)-arbutamine. Org Lett 2002, 4, 16, 2621. |
| 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) | 55602 | 3,4-bis{[tert-butyl(dimethyl)silyl]oxy}benzaldehyde | C19H34O3Si2 | 详情 | 详情 | |
| (II) | 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 |
| (III) | 57893 | C64H60O3Zn2 | 详情 | 详情 | ||
| (IV) | 55605 | (1R)-1-(3,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-nitro-1-ethanol | C20H37NO5Si2 | 详情 | 详情 | |
| (V) | 55606 | (1R)-2-amino-1-(3,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-ethanol | C20H39NO3Si2 | 详情 | 详情 | |
| (VI) | 57894 | 4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)butanoic acid | C16H26O3Si | 详情 | 详情 | |
| (VII) | 57895 | N-[(2R)-2-(3,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-hydroxyethyl]-4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)butanamide | C36H63NO5Si3 | 详情 | 详情 | |
| (VIII) | 57896 | (1R)-1-(3,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)butyl]amino}-1-ethanol | C36H65NO4Si3 | 详情 | 详情 |