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【结 构 式】 
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【分子编号】21229 【品名】2-(4-Aminophenyl)acetic acid 【CA登记号】5345-54-0 |
【 分 子 式 】C8H9NO2 【 分 子 量 】151.165 【元素组成】C 63.56% H 6% N 9.27% O 21.17% |
合成路线1
该中间体在本合成路线中的序号：(I)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2
该中间体在本合成路线中的序号：(I)The acetylation of 2-(4-aminophenyl)acetic acid (I) with acetic anhydride, followed by nitration with nitric acid in acetic acid and treatment with HCl in ethanol gives 2-(4-amino-3-nitrophenyl)acetic acid ethyl ester (II), which is reduced at the nitro group, and cyclized with SOCl2 yielding the benzothiadiazole (III). The condensation of (III) with 3-fluoro-4-methoxyphenacyl bromide (IV) by means of potassium tert-butoxide affords the 4-oxobutyrate (V), which is condensed with 3,4,5-trimethoxybenzaldehyde (VI) by means of sodium methopxide in methanol to provide the the dihydrofuranone (VII). Finally, this compound is treated with NaOH in methanol to promote the opening of the lactone ring yielding the target compound.
| 【1】 Mederski, W.W.K.R.; Osswald, M.; Dorsch, D.; Anzali, S.; Christadler, M.; Schmitges, C.J.; Wilm, C.; Endothelin antagonists: Evaluation of 2,1, 3-benzothiadiazole as a methylendioxyphenyl bioisoster. Bioorg Med Chem Lett 1998, 8, 1, 17. |
| 【2】 Mederski, W.W.K.R.; Dorsch, D.; Osswald, M.; Anzali, S.; Christadler, M.; Schmitges, C.J.; Schelling, P.; Wilm, C.; Fluck, M.; 3. Endothelin antagonists: Discovery of EMD 122946, a highly potent and orally active ETA selective antagonist. Bioorg Med Chem Lett 1998, 8, 13, 1771. |
| 【3】 Dorsch, D.; Osswald, M.; Mederski, W.; Wilm, C.; Schmitges, C.; Christadler, M.; Anzali, S. (Merck Patent GmbH); 2,1,3-Benzothia(oxa)diazole derivs. having an endothelin receptor antagonistic effect. DE 19607096; EP 0882030; WO 9730982 . |
| 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) | 21229 | 2-(4-Aminophenyl)acetic acid | 5345-54-0 | C8H9NO2 | 详情 | 详情 |
| (II) | 26095 | ethyl 2-(4-amino-3-nitrophenyl)acetate | C10H12N2O4 | 详情 | 详情 | |
| (III) | 26096 | ethyl 2-(2,1,3-benzothiadiazol-5-yl)acetate | C10H10N2O2S | 详情 | 详情 | |
| (IV) | 26097 | 2-bromo-1-(3-fluoro-4-methoxyphenyl)-1-ethanone | C9H8BrFO2 | 详情 | 详情 | |
| (V) | 26098 | ethyl 2-(2,1,3-benzothiadiazol-5-yl)-4-(3-fluoro-4-methoxyphenyl)-4-oxobutanoate | C19H17FN2O4S | 详情 | 详情 | |
| (VI) | 11136 | 3,4,5-Trimethoxybenzaldehyde | 86-81-7 | C10H12O4 | 详情 | 详情 |
| (VII) | 26099 | 3-(2,1,3-benzothiadiazol-5-yl)-5-(3-fluoro-4-methoxyphenyl)-5-hydroxy-4-(3,4,5-trimethoxybenzyl)-2(5H)-furanone | C27H23FN2O7S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)Condensation of o-tolyl isocyanate (XI) with 4-aminophenylacetic acid (XII) produced urea (XIII). This was coupled to tetrapeptide (X) using EDC and HOBt to give the corresponding amide (XIV). Finally, the benzyl ester groups of (XIV) were deprotected by hydrogenolysis over Pd/C.
| 【1】 Ateeq, H.S.; Lin, K.-C.; Hsiung, S.H.; et al.; Selective, tight-binding inhibitors of integrin alpha4beta1 that inhibit allergic airway responses. J Med Chem 1999, 42, 5, 920. |
| 【2】 Lin, K.-C.; Adams, S.P.; Castro, A.C.; Zimmerman, C.N.; Cuervo, J.H.; Lee, W.-C.; Hammond, C.E.; Carter, M.B.; Almquist, R.G.; Ensinger, C.L. (Biogen, Inc.); Cell adhesion inhibitor. EP 0842196; JP 1999511124; WO 9703094 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 27105 | benzyl (2S)-1-((2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-4-(benzyloxy)-4-oxobutanoyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate | C34H46N4O7 | 详情 | 详情 | |
| (XI) | 27106 | 1-isocyanato-2-methylbenzene | 614-68-6 | C8H7NO | 详情 | 详情 |
| (XII) | 21229 | 2-(4-Aminophenyl)acetic acid | 5345-54-0 | C8H9NO2 | 详情 | 详情 |
| (XIII) | 27107 | 2-[4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid | C16H16N2O3 | 详情 | 详情 | |
| (XIV) | 27108 | benzyl (2S)-1-((2S)-2-[[(2S)-4-(benzyloxy)-2-([(2S)-4-methyl-2-[(2-[4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]pentanoyl]amino)-4-oxobutanoyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate | C50H60N6O9 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)Coupling of p-aminophenylacetic acid (IX) with o-tolyl isocyanate (X) produces urea (XI). This is subsequently condensed with the intermediate tripeptide (VIII) in the presence of HATU to yield amide (XII). Hydrogenolysis of the N-benzyloxycarbonyl group of (XII) then gives amine (XIII). Finally, acylation of amine (XIII) with 3,5-dichlorobenzensulfonyl chloride (XIV), followed by alkaline hydrolysis of the methyl ester group furnishes the title compound.
| 【1】 Lee, W.-C.; Scott, D.; Cornebise, M.; Petter, R. (Biogen Idec Inc.); Cell adhesion inhibitors. EP 1265606; JP 2003506491; US 6630503; WO 0112186 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 64990 | phenylmethyl 2-[({3-{[4-methyl-2-(methylamino)pentanoyl]amino}-1-[(methyloxy)carbonyl]propyl}amino)carbonyl]-1-pyrrolidinecarboxylate | C25H38N4O6 | 详情 | 详情 | |
| (IX) | 21229 | 2-(4-Aminophenyl)acetic acid | 5345-54-0 | C8H9NO2 | 详情 | 详情 |
| (X) | 27106 | 1-isocyanato-2-methylbenzene | 614-68-6 | C8H7NO | 详情 | 详情 |
| (XI) | 27107 | 2-[4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid | C16H16N2O3 | 详情 | 详情 | |
| (XII) | 64991 | phenylmethyl 2-[({3-{[4-methyl-2-(methyl{2-[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}amino)pentanoyl]amino}-1-[(methyloxy)carbonyl]propyl}amino)carbonyl]-1-pyrrolidinecarboxylate | C41H52N6O8 | 详情 | 详情 | |
| (XIII) | 64992 | methyl 4-{[4-methyl-2-(methyl{2-[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}amino)pentanoyl]amino}-2-[(2-pyrrolidinylcarbonyl)amino]butanoate | C33H46N6O6 | 详情 | 详情 | |
| (XIV) | 59023 | 3,5-dichlorobenzenesulfonyl chloride | C6H3Cl3O2S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The diazotization of 2-(4-aminophenyl)acetic acid (I) by means of NaNO2 and HCl gives the diazonium salt (II), which is then condensed with 2-hydroxybenzoic acid (III) to provide the target azocompound.
| 【1】 Riggs-Sauthier, J.A.; Malson, E.; Harris, M.; Myung, S.; Liddle, R.; Ekwuribe, N.; Synthesis and activity of novel 5-aminosalicylic acid (5-ASA)-containing prodrugs for the treatment of inflammatory bowel disease. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 305. |
| 【2】 Ekwuribe, N.N.; Riggs-Sauthier, J. (Nobex Corp.); Immunoregulatory cpds. and derivs. and methods of treating diseases therewith. WO 0218324 . |