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【结 构 式】 
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【分子编号】31690 【品名】(2R)-2-amino-2-(4-hydroxyphenyl)ethanoic acid; (2R)-2-(4-hydroxyphenyl)glycine; D-(-)-p-Hydroxyphenylglycine; (R)-2-amino-2-(4-hydroxyphenyl)acetic acid 【CA登记号】22818-40-2 |
【 分 子 式 】C8H9NO3 【 分 子 量 】167.1644 【元素组成】C 57.48% H 5.43% N 8.38% O 28.71% |
合成路线1
该中间体在本合成路线中的序号：(IX)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2
该中间体在本合成路线中的序号：(I)Hydrogenation of D-4-hydroxyphenyl glycine (I) over Raney-Ni in NaOH affords 4-hydroxycyclohexylglycine (II), which is condensed with sulfonyl chloride (III) in dioxane in the presence of Et3N to yield derivative (IV). Carboxylic acid (IV) is converted into benzyl ester (VI) by treatment with benzyl bromide (V) by means of N,N'-dicyclohexylamine (DCHA) in DMF and (VI) is then oxidized by treatment with NaBr, 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) and NaClO2 in CH2Cl2/H2O to provide ketone (VII). Condensation of (VII) with n-propanol (VIII) by means of PhSiH3 and TFA gives a mixture of compounds from which trans-(IX) is cromatographically separated. Then ketone (IX) reacts with 4-picolyl chloride (X) and K2CO3 in DMF to furnish compound (XI). Hydrogenation of benzyl acetate (XI) over Pd/C in EtOH/HCl affords acetic acid derivative (XII), which is coupled to O-t-butylhydroxylamine hydrochloride by means of HOBt, N-methylmorpholine and N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (EDC·HCl) in CH2Cl2. Finally, removal of the t-Bu group with HCl (gas) in dichloroethane/EtOH yields the desired compound.
| 【1】 Parker, D.T. (Novartis AG); alpha-Substd. arylsulphonamido hydroxamic acids as TNF-alpha and matrix metalloproteinase inhibitors. EP 0873312; JP 2000502088; US 5770624; WO 9722587 . |
| 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) | 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 |
| (II) | 45921 | (2R)-2-amino-2-(4-hydroxycyclohexyl)ethanoic acid | C8H15NO3 | 详情 | 详情 | |
| (III) | 45922 | 4-ethoxybenzenesulfonyl chloride | C8H9ClO3S | 详情 | 详情 | |
| (IV) | 45923 | (2R)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-hydroxycyclohexyl)ethanoic acid | C16H23NO6S | 详情 | 详情 | |
| (V) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (VI) | 45924 | benzyl (2R)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-hydroxycyclohexyl)ethanoate | C23H29NO6S | 详情 | 详情 | |
| (VII) | 45925 | benzyl (2R)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-oxocyclohexyl)ethanoate | C23H27NO6S | 详情 | 详情 | |
| (VIII) | 29338 | 1-propanol | 71-23-8 | C3H8O | 详情 | 详情 |
| (IX) | 45926 | benzyl (2R)-2-[[(4-ethoxyphenyl)sulfonyl]amino]-2-(4-propoxycyclohexyl)ethanoate | C26H35NO6S | 详情 | 详情 | |
| (X) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (XI) | 45927 | benzyl (2R)-2-[[(4-ethoxyphenyl)sulfonyl](4-pyridinylmethyl)amino]-2-(4-propoxycyclohexyl)ethanoate | C32H40N2O6S | 详情 | 详情 | |
| (XII) | 45928 | (2R)-2-[[(4-ethoxyphenyl)sulfonyl](4-pyridinylmethyl)amino]-2-(4-propoxycyclohexyl)ethanoic acid | C25H34N2O6S | 详情 | 详情 |