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【结 构 式】 
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【分子编号】21230 【品名】ethyl 2-(4-aminophenyl)acetate 【CA登记号】5438-70-0 |
【 分 子 式 】C10H13NO2 【 分 子 量 】179.21876 【元素组成】C 67.02% H 7.31% N 7.82% O 17.85% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The methylation of ethyl 4-nitrophenylacetate (I) with NaH - ICH3 in DMF - toluene to ethyl 2-(4-nitrophenyl)propionate (II), which was reduced with H2 over Pd/C in EtOH - H2O to ethyl 2-(4-aminophenyl)propionate (III) (HCl deriv., m.p. 137-40 C). This product was acetylated with acetic anhydride to ethyl 2-(acetylaminophenyl) propionate (IV), m.p. 88-90 C, which was chlorinated with Cl2 in acetic acid to ethyl 2-(3-chloro-4-acetylaminophenyl)propionate (V), b.p. 155-60 C/0.7 mm; this, in turn, was hydrolyzed with HCl in EtOH to ethyl 2-(3-chloro-4-aminophenyl)propionate hydrochloride (VI), m.p. 164-8 C. The last step being the reaction of the preceding intermediate with cis-1,4-dichloro (or dibromo)-2-butene (A) in DMF and Na2CO3 to ethyl 2-(3-chloro-4-(3-pyrrolinyl)phenyl)propionate (VII), b.p. 128-33 C/0.25 mm; followed by hydrolysis with KOH in EtOH - H2O. The acetylation of ethyl 4-aminophenylacetate (VIII) with acetic anhydride to ethyl 4-acetylaminophenylacetate (IX), m.p. 75-8 C, followed by methylation with ICH3 and Na in liquid NH3 to ethyl 2-(4-acetylaminophenyl)propionate (IV), already obtained.
| 【1】 Carney, R.W.J.; de Stevens, G; Tertiary amino phenyl acetic acids. CH 574926; CH 577968; CH 578523; CH 581103; CH 581104; US 3641040 . |
| 【2】 Castaner, J.; Pirprofen. Drugs Fut 1977, 1, 1, 23. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 32186 | (E)-1,4-dichloro-2-butene | 110-57-6 | C4H6Cl2 | 详情 | 详情 |
| (I) | 33982 | ethyl 2-(4-nitrophenyl)acetate | 5445-26-1 | C10H11NO4 | 详情 | 详情 |
| (II) | 33983 | ethyl 2-(4-nitrophenyl)propanoate | C11H13NO4 | 详情 | 详情 | |
| (III) | 33984 | ethyl 2-(4-aminophenyl)propanoate | C11H15NO2 | 详情 | 详情 | |
| (IV) | 33985 | ethyl 2-[4-(acetamido)phenyl]propanoate | C13H17NO3 | 详情 | 详情 | |
| (V) | 33986 | ethyl 2-[4-(acetamido)-3-chlorophenyl]propanoate | C13H16ClNO3 | 详情 | 详情 | |
| (VI) | 33987 | ethyl 2-(4-amino-3-chlorophenyl)propanoate | C11H14ClNO2 | 详情 | 详情 | |
| (VII) | 33988 | ethyl 2-[3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)phenyl]propanoate | C15H18ClNO2 | 详情 | 详情 | |
| (VIII) | 21230 | ethyl 2-(4-aminophenyl)acetate | 5438-70-0 | C10H13NO2 | 详情 | 详情 |
| (IX) | 21231 | ethyl 2-[4-(acetamido)phenyl]acetate | C12H15NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The esterification of 4-aminophenylacetic acid (I) with ethanol - HCl in the usual way gives the ethyl ester (II), which is acylated with acetic anhydride in ethyl acetate yielding ethyl 4-acetaminophenylacetate (III). Finally, this compound is hydrolyzed with aqueous NaOH.
| 【1】 Sato, S.; Tsurufuji, M.; Enomoto, H.; Sugiyama, M.; Shibata, Y.; Morita, I.; Munakata, H.; Kobayashi, M.; Wagatsuma, K. (Mitsubishi Chem. Inds. Co.; Ltd.); Immunomodulating agents. DE 3317107; US 4720506 . |
| 【2】 Prous, J.; Castaner, J.; MS-932. Drugs Fut 1989, 14, 8, 759. |
合成路线3
该中间体在本合成路线中的序号：(VII)Claisen condensation between diethyl phthalate (I) and diethyl succinate (II) in the presence of NaOEt gives rise to the naphthalenedicarboxylate (III). Alkylation of the phenolic hydroxyl groups of (III) with iodoethane under Williamsom's ether synthesis conditions furnishes the diethoxy napthalenedicarboxylate (IV). Then, alkaline hydrolysis of diester (IV) affords diacid (V), which is further converted to the cyclic anhydride (VI) upon treatment with SOCl2. Condensation of anhydride (VI) with ethyl p-aminophenylacetate (VII) in boiling AcOH leads to the cyclic imide (VIII). Partial reduction of (VIII) with Zn/AcOH produces lactam (IX). The ethyl ester group of (IX) is then selectively hydrolyzed under alkaline conditions to furnish acid (X). Finally, CDI-mediated coupling of acid (X) with benzesulfonamide yields the target N-acyl sulfonamide.
| 【1】 Giblin, G.M.P.; Foord, S.; Wilson, R.; et al.; Novel nonprostanoid prostaglandin EP4 receptor antagonist. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 306. |
| 【2】 Frye, S.V.; Giblin, G.M.P.; Roomans, S. (GlaxoSmithKline plc); Benzo(f)isoindol derivs. and their use as EP4 receptor ligands. WO 0250033 . |
| 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) | 60866 | diethyl phthalate | C12H14O4 | 详情 | 详情 | |
| (II) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (III) | 60867 | diethyl 1,4-dihydroxy-2,3-naphthalenedicarboxylate | C16H16O6 | 详情 | 详情 | |
| (IV) | 60868 | diethyl 1,4-diethoxy-2,3-naphthalenedicarboxylate | C20H24O6 | 详情 | 详情 | |
| (V) | 60869 | 1,4-diethoxy-2,3-naphthalenedicarboxylic acid | C16H16O6 | 详情 | 详情 | |
| (VI) | 60870 | 4,9-diethoxynaphtho[2,3-c]furan-1,3-dione | C16H14O5 | 详情 | 详情 | |
| (VII) | 21230 | ethyl 2-(4-aminophenyl)acetate | 5438-70-0 | C10H13NO2 | 详情 | 详情 |
| (VIII) | 60871 | ethyl 2-[4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate | C26H25NO6 | 详情 | 详情 | |
| (IX) | 60872 | ethyl 2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate | C26H27NO5 | 详情 | 详情 | |
| (X) | 60873 | 2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetic acid | C24H23NO5 | 详情 | 详情 |