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【结 构 式】 
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【药物名称】Denopamine, TA-064, Kalgut 【化学名称】(R)-(-)-2'-(3,4-Dimethoxyphenyl)-2-hydroxy-2-(4-hydroxyphenyl)diethylamine 【CA登记号】71771-90-9, 64299-19-0 (HCl) 【 分 子 式 】C18H23NO4 【 分 子 量 】317.38831 |
【开发单位】Tanabe Seiyaku (Originator), Aventis Pharma (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, beta1-Adrenoceptor Agonists |
合成路线1
A new enantioselective synthesis of R-(-)-denopamine has been published: The silylation of 4-hydroxyphenacyl chloride (I) with tert-butyldimethylchlorosilane (II) and imidazole in THF gives the silylated compound (III), which is enantioselectively reduced with borane, using the (R)-oxaazaborilidine (IV) as optically active catalyst in THF, yielding (R)-2-chloro-1-[4-(tert-butyldimethylsilyloxy)phenyl]ethanol (V). The reaction of (V) with NaI in refluxing acetone affords the corresponding iodo-alcohol (VI), which is protected with triethylchlorosilane and imidazole in DMF to give the fully silylated compound (VIII). The condensation of (VIII) with 2-(3,4-dimethoxyphenyl)ethylamine (IX) by means of triethylamine in THF at 100 C in a sealed tube yields the fully silylated denopamine (X), which is finally deprotected by a treatment with KF and HCl in methanol.
| 【1】 Link, J.O.; Corey, E.J.; A catalytic enantioselective synthesis of denopamine, a useful drug for congestive heart failure. J Org Chem 1991, 56, 1, 442. |
| 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) | 10090 | 2-Chloro-1-(4-hydroxyphenyl)-1-ethanone | 6305-04-0 | C8H7ClO2 | 详情 | 详情 |
| (III) | 10092 | 1-(4-[[tert-Butyl(dimethyl)silyl]oxy]phenyl)-2-chloro-1-ethanone | C14H21ClO2Si | 详情 | 详情 | |
| (IV) | 10093 | (3aR)-1-Butyl-3-[di(2-naphthyl)methylene]tetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | C30H30BNO | 详情 | 详情 | |
| (V) | 10094 | (1R)-1-(4-[[tert-Butyl(dimethyl)silyl]oxy]phenyl)-2-chloro-1-ethanol | C14H23ClO2Si | 详情 | 详情 | |
| (VI) | 10095 | (1R)-1-(4-[[tert-Butyl(dimethyl)silyl]oxy]phenyl)-2-iodo-1-ethanol | C9H11IO | 详情 | 详情 | |
| (VIII) | 10097 | tert-Butyl(dimethyl)silyl 4-[(1R)-2-iodo-1-[(methylsilyl)oxy]ethyl]phenyl ether; tert-Butyl(4-[(1R)-2-iodo-1-[(methylsilyl)oxy]ethyl]phenoxy)dimethylsilane | C15H27IO2Si2 | 详情 | 详情 | |
| (IX) | 10098 | 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine | 120-20-7 | C10H15NO2 | 详情 | 详情 |
| (X) | 10099 | (2R)-2-(4-[[tert-Butyl(dimethyl)silyl]oxy]phenyl)-N-(3,4-dimethoxyphenethyl)-2-[(methylsilyl)oxy]-1-ethanamine; N-[(2R)-2-(4-[[tert-Butyl(dimethyl)silyl]oxy]phenyl)-2-[(methylsilyl)oxy]ethyl]-N-(3,4-dimethoxyphenethyl)amine. | C25H41NO4Si2 | 详情 | 详情 |
合成路线2
A new enantioselective synthesis for denopamine has been reported: The acylation of 1-(4-benzyloxyphenyl)-2-[2-(3,4-dimethoxyphenyl)ethylamino]ethanone (I) with benzyloxycarbonyl chloride (II) by means of NaHCO3 in dichloromethane gives the protected aminoketone (III), which is submitted to an asymmetric reduction with (R)-(+)-2-amino-3-methyl-1,1-diphenyl-1-butanol-borane complex in THF yielding the (R)-(-)-protected alcohol (V). Finally, the debenzylation of (V) by hydrogenolysis with H2 over Pd/C in methanol affords denopamine with 96% optical purity.
| 【1】 Takeda, M.; Saito, K.; Kawaguchi, T.; Matsuki, K.; Iwakuma, T.; Asymmetric reduction of aromatic ketones. I. Enantioselective synthesis of denopamine. Chem Pharm Bull 1993, 41, 4, 639. |
| 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) | 10100 | 1-[4-(Benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanone; N-(3,4-Dimethoxyphenylethyl)-4-benzyloxyphenacylamine | C25H27NO4 | 详情 | 详情 | |
| (II) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (III) | 10102 | Benzyl 2-[4-(benzyloxy)phenyl]-2-oxoethyl(3,4-dimethoxyphenethyl)carbamate; Benzyl (4-benzyloxy)phenacyl-(3,4-dimethoxyphenethyl)carbamate | C33H33NO6 | 详情 | 详情 | |
| (IV) | 10103 | (2R)-2-Amino-3-methyl-1,1-diphenyl-1-butanol | 56755-20-5 (hydrochloride) | C17H21NO | 详情 | 详情 |
| (V) | 10104 | benzyl (2R)-2-[4-(benzyloxy)phenyl]-2-hydroxyethyl(3,4-dimethoxyphenethyl)carbamate | C33H35NO6 | 详情 | 详情 |
合成路线3
The benzylation of 4-hydroxymandelic acid (I) with benzyl alcohol (II) and K2CO3 in methanol gives 4-benzyloxymandelic acid (III), which is condensed with 2-(3,4-dimethoxyphenyl)ethylamine (IV) by means of (C2H5O)2PON3 in THF to afford N-(3,4-dimethoxyphenylethyl)-4-benzyloxymandelamide (V). The reduction of (V) with diborane in THF yields the final product protected at the phenolic hydroxyl (VI) This compound is finally deprotected by hydrogenolysis with H2 over Pd/C.
| 【1】 Noguchi, K.; Irie, K.; Preparation of optically active benzyl alcohol derivative. JP 54070231 . |
| 【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; TA-064. Drugs Fut 1982, 7, 6, 407. |
| 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) | 31684 | (2R)-4-Hydroxymandelic acid; (2R)-2-Hydroxy-2-(4-hydroxyphenyl)ethanoic acid | 7198-10-9 | C8H8O4 | 详情 | 详情 |
| (II) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
| (III) | 31685 | (2R)-2-[4-(benzyloxy)phenyl]-2-hydroxyethanoic acid; (2R)-4-benzyloxymandelic acid | C15H14O4 | 详情 | 详情 | |
| (IV) | 10098 | 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine | 120-20-7 | C10H15NO2 | 详情 | 详情 |
| (V) | 31686 | (2R)-2-[4-(benzyloxy)phenyl]-N-(3,4-dimethoxyphenethyl)-2-hydroxyethanamide | C25H27NO5 | 详情 | 详情 | |
| (VI) | 31687 | (1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol | C25H29NO4 | 详情 | 详情 |
合成路线4
The condensation of 4-benzyloxybenzaldehyde (VII) with N-(3,4-dimethoxyphenylethyl)glycine (VIII) in refluxing pyridine also gives the protected product (VI).
| 【1】 Ikezaki, M.; Umino, N.; Iwakuma, T.; Process for preparation of benzyl alcohol derivatives. JP 52051333 . |
| 【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; TA-064. Drugs Fut 1982, 7, 6, 407. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 29179 | 4-(Benzyloxy)benzaldehyde | 4397-53-9 | C14H12O2 | 详情 | 详情 |
| (VII) | 31687 | (1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol | C25H29NO4 | 详情 | 详情 | |
| (VIII) | 31688 | N-(3,4-Dimethoxyphenylethyl)glycine; 2-[(3,4-Dimethoxyphenethyl)amino]acetic acid | C12H17NO4 | 详情 | 详情 |
合成路线5
The condensation of 4-benzyloxyphenacyl chloride (XV) with the amine (IV) in refluxing CH2Cl2 gives N-(3,4-dimethoxyphenylethyl)-4-benzyloxyphenacylamine (XVI), which is reduced with NaSH4 in ethanol, also affording the protected product (VI).
| 【1】 Ikezaki, M.; Ito, N.; Okazaki, Y.; Hoshiyama, M.; Nagao, T. (Tanabe Seiyaku Co., Ltd.); Benzyl alcohol, amine derivatives. AT 343628B; BE 0833731; DE 2542881; FR 2326182; GB 1499345; JP 50157327; JP 53010974; JP 7795620; JP 7795621; NL 7511564; US 4032575; US 4072759 . |
| 【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; TA-064. Drugs Fut 1982, 7, 6, 407. |
| 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) | 10098 | 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine | 120-20-7 | C10H15NO2 | 详情 | 详情 |
| (VI) | 31687 | (1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol | C25H29NO4 | 详情 | 详情 | |
| (XV) | 31689 | 4-Benzyloxyphenacyl chloride; 1-[4-(Benzyloxy)phenyl]-2-chloro-1-ethanone | 39188-62-0 | C15H13ClO2 | 详情 | 详情 |
| (XVI) | 10100 | 1-[4-(Benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanone; N-(3,4-Dimethoxyphenylethyl)-4-benzyloxyphenacylamine | C25H27NO4 | 详情 | 详情 |
合成路线6
The formylation of 2-(4-hydroxyphenyl)glycine (IX) as usual gives N-formyl-2-(4-hydroxyphenyl)glycine (X), which by treatment with benzyl alcohol as before yields N-formyl-2-(4-benzyloxyphenyl)glycine (XI). The condensation of (XI) with the amine (IV) by means of butyl chloroformate affords the corresponding amide (XII), which is deformylated by treatment with HCl in methanol to give the glycinamide (XIII). The diazotation of (XIII) with NaNO2 in acetic acid affords N-(3,4-dimethoxyphenylethyl)-O-acetyl-4-benzyloxymandel-amide (XIV), which is finally reduced and deacetylated with LiAlH4 in THF yielding the protected product (VI).
| 【1】 Noguchi, K.; Irie, K.; Preparation of optically active benzyl alcohol derivative. JP 54070232 . |
| 【2】 Noguchi, K.; Irie, K.; Preparation of optically active benzyl alcohol derivative. JP 54070233 . |
| 【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; TA-064. Drugs Fut 1982, 7, 6, 407. |
| 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) | 10098 | 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine | 120-20-7 | C10H15NO2 | 详情 | 详情 |
| (VI) | 31687 | (1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol | C25H29NO4 | 详情 | 详情 | |
| (IX) | 31690 | (2R)-2-amino-2-(4-hydroxyphenyl)ethanoic acid; (2R)-2-(4-hydroxyphenyl)glycine; D-(-)-p-Hydroxyphenylglycine; (R)-2-amino-2-(4-hydroxyphenyl)acetic acid | 22818-40-2 | C8H9NO3 | 详情 | 详情 |
| (X) | 31691 | (2R)-2-(formylamino)-2-(4-hydroxyphenyl)ethanoic acid | C9H9NO4 | 详情 | 详情 | |
| (XI) | 31692 | N-formyl-2-(4-benzyloxyphenyl)glycine; (2R)-2-[4-(benzyloxy)phenyl]-2-(formylamino)ethanoic acid | C16H15NO4 | 详情 | 详情 | |
| (XII) | 31693 | (2R)-2-[4-(benzyloxy)phenyl]-N-(3,4-dimethoxyphenethyl)-2-(formylamino)ethanamide | C26H28N2O5 | 详情 | 详情 | |
| (XIII) | 31694 | (2R)-2-amino-2-[4-(benzyloxy)phenyl]-N-(3,4-dimethoxyphenethyl)ethanamide | C25H28N2O4 | 详情 | 详情 | |
| (XIV) | 31695 | (1R)-1-[4-(Benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-2-oxoethyl acetate; N-(3,4-Dimethoxyphenylethyl)-O-acetyl-4-benzyloxymandel-amide | C27H29NO6 | 详情 | 详情 |
合成路线7
The oxidation of 4-benzyloxyphenacyl chloride (XV) with KI and DMSO gives 4-benzyloxy-alpha-oxophenylacetaldehyde (XVII), which is condensed with the amine (IV) to afford the corresponding Schiff base (XVIII). Finally, this compound is reduced with NaBH4 yielding the protected product (VI), already obtained.
| 【1】 Ikezaki, M.; Umino, N.; Iwakuma, T.; Process for preparation of benzyl alcohol derivatives. JP 52051334 . |
| 【2】 Ikezaki, M.; Umino, N.; Iwakuma, T.; Process for preparation of benzyl alcohol derivatives. JP 52051335 . |
| 【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; TA-064. Drugs Fut 1982, 7, 6, 407. |
| 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) | 10098 | 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine | 120-20-7 | C10H15NO2 | 详情 | 详情 |
| (VI) | 31687 | (1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol | C25H29NO4 | 详情 | 详情 | |
| (XV) | 31689 | 4-Benzyloxyphenacyl chloride; 1-[4-(Benzyloxy)phenyl]-2-chloro-1-ethanone | 39188-62-0 | C15H13ClO2 | 详情 | 详情 |
| (XVII) | 31696 | 2-[4-(benzyloxy)phenyl]-2-oxoacetaldehyde; 4-benzyloxy-alpha-oxophenylacetaldehyde | C15H12O3 | 详情 | 详情 | |
| (XVIII) | 31697 | 1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)imino]-1-ethanone | C25H25NO4 | 详情 | 详情 |
合成路线8
By reduction of benzyl (4-benzyloxy)phenacyl-(3,4-dimethoxyphenethyl)carbamate (XIX) with sodium prolinate-borane complex (XX) and hydrogenation over 10% palladium on a carbon catalyst.
| 【1】 Iwakuma, T.; Umino, N.; Itoh, N.; Asymetric reduction of various ketones with the sodium salts of alpha-amino acid borane complex. Chem Pharm Bull 1979, 27, 6, 1479-81. |
| 【2】 Blancafort, P.; Castaner, J.; Serradell, M.N.; TA-064. Drugs Fut 1982, 7, 6, 407. |
合成路线9
The enantioselective condensation of 4-(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 ethanol to yield the 2-aminoethanol derivative (V). The condensation of (V) with carboxylic acid (VI) by means of 2,2-dimethylpropanoyl chloride and DIEA in THF affords the corresponding amide (VII), which is reduced with LiAlH4 in Et2O to yield the protected hydroxyamine (VIII). Finally, this compound is desilylated by means of HCl and KF in MeOH 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) | 57897 | 4-{[tert-butyl(dimethyl)silyl]oxy}benzaldehyde | C13H20O2Si | 详情 | 详情 | |
| (II) | 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 |
| (III) | 57893 | C64H60O3Zn2 | 详情 | 详情 | ||
| (IV) | 57898 | (1R)-1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-nitro-1-ethanol | C14H23NO4Si | 详情 | 详情 | |
| (V) | 57899 | (1R)-2-amino-1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-ethanol | C14H25NO2Si | 详情 | 详情 | |
| (VI) | 24049 | 2-(3,4-dimethoxyphenyl)acetic acid | 93-40-3 | C10H12O4 | 详情 | 详情 |
| (VII) | 57900 | N-[(2R)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-hydroxyethyl]-2-(3,4-dimethoxyphenyl)acetamide | C24H35NO5Si | 详情 | 详情 | |
| (VIII) | 57901 | (1R)-1-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol | C24H37NO4Si | 详情 | 详情 |
合成路线10
The enantioselective reduction of the phenacyl bromide (I) by means of a culture of Rhodotolule rubra in water gives the a(R)-hydroxy enantiomer (II), which is treated with K2CO3 in refluxing ethanol to yield the chiral epoxide (III). The condensation of (III) with 2-(3,4-dimethoxyphenyl)ethylamine (IV) by means of N,O-bis(trimethylsilyl)acetamide (TMSA) in hot DMSO affords the benzylated precursor (V), which is finally deprotected by means of HCl in water to provide the target Denopamine.
| 【1】 Goswami, J.; et al.; A conventient stereoselective synthesis of (R)-(-)-denopamine and (R)-(-)-salmeterol. Tetrahedron Asymmetry 2001, 12, 24, 3343. |
| 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) | 36424 | 1-[4-(benzyloxy)phenyl]-2-bromo-1-ethanone | C15H13BrO2 | 详情 | 详情 | |
| (II) | 62589 | (1R)-1-[4-(benzyloxy)phenyl]-2-bromo-1-ethanol | C15H15BrO2 | 详情 | 详情 | |
| (III) | 62590 | (2R)-2-[4-(benzyloxy)phenyl]oxirane; benzyl 4-[(2R)oxiranyl]phenyl ether | C15H14O2 | 详情 | 详情 | |
| (IV) | 10098 | 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine | 120-20-7 | C10H15NO2 | 详情 | 详情 |
| (V) | 31687 | (1R)-1-[4-(benzyloxy)phenyl]-2-[(3,4-dimethoxyphenethyl)amino]-1-ethanol | C25H29NO4 | 详情 | 详情 |