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【结 构 式】 
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【分子编号】11975 【品名】Ethyl (E)-3-amino-2-butenoate 【CA登记号】7318-00-5 |
【 分 子 式 】C6H11NO2 【 分 子 量 】129.15888 【元素组成】C 55.8% H 8.58% N 10.84% O 24.77% |
合成路线1
该中间体在本合成路线中的序号：(II)By cyclization of methyl 2,3-dichlorobenzyldeneacetoacetate (I) with ethyl 3-aminocrotonate (II) in tert-butanol at room temperature.
| 【1】 Carter, R.E.; Berntsson, P.; Determination of te conformation of felodipine by 1H NMR-spinlattice relaxation time measurements. Acta Pharm Suec 1981, 18, 221-226. |
| 【2】 Bernston, P.B.; Carlsson, S.A.I.; Gaarder, J.O.; Ljung, B.R. (AstraZeneca AB); 2,6-Dimethyl-4-2,3-disubstituted phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid-3,5-asymmetric diesters having hypotensive properties, as well as method for treating hypertensive conditions and pharmaceutical preparations containing same. CA 1117530; EP 0007293; JP 55009083; US 4264611 . |
| 【3】 Blancafort, P.; Serradell, M.N.; Sneddon, J.M.; Castaner, J.; Felodipine. Drugs Fut 1982, 7, 3, 160. |
合成路线2
该中间体在本合成路线中的序号：(II)By cyclization of 2,3-dichlorobenzaldehyde (I) with 3-aminocrotonic acid ethyl ester (II) and acetylacetic acid methyl ester (III) in refluxing ethanol.
| 【1】 Bernston, P.B.; Carlsson, S.A.I.; Gaarder, J.O.; Ljung, B.R. (AstraZeneca AB); 2,6-Dimethyl-4-2,3-disubstituted phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid-3,5-asymmetric diesters having hypotensive properties, as well as method for treating hypertensive conditions and pharmaceutical preparations containing same. CA 1117530; EP 0007293; JP 55009083; US 4264611 . |
合成路线3
该中间体在本合成路线中的序号：(IV)The Wittig condensation of o-phthalaldehyde (I) with tert-butyl triphenylphosphoranylideneacetate (II) in methylene chloride gives tert-butyl 3-(2-formylphenyl)-2(E)-propenoate (III), which is then cyclized with ethyl 3-aminocrotonate (IV) in acetic acid.
| 【1】 Borthwick, A.D.; Pierccioli, D.; Micheli, D.; Semeraro, C.; Gaviraghi, G. (Glaxo SpA); 1,4-dihydropyridines.. ES 8703839; ES 8703839; US 4801599; US 5011848 . |
| 【2】 Prous, J.; Castaner, J.; LACIDIPINE < Rec INN; BAN; USAN >. Drugs Fut 1989, 14, 4, 317. |
| 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) | 19472 | o-phthalaldehyde; o-phthaldialdehyde; phthalaldehyde | 643-79-8 | C8H6O2 | 详情 | 详情 |
| (II) | 11335 | tert-butyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (tert-Butoxycarbonylmethylene)triphenylphosphorane | 35000-38-5 | C24H25O2P | 详情 | 详情 |
| (III) | 19474 | tert-butyl (E)-3-(2-formylphenyl)-2-propenoate | C14H16O3 | 详情 | 详情 | |
| (IV) | 11975 | Ethyl (E)-3-amino-2-butenoate | 7318-00-5 | C6H11NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The reaction between acetaldehyde (I), ethyl 3-aminocrotonate (II) and acetoacetate (III) in ethanolic medium yields the corresponding 1,4-dihydropyridine.
| 【1】 Sunkel, C.; Fau de Casa-Juana, M.; Dorrego, F.; Priego, J.; Ortega, P.; Cillero, J. (Alter SA); 1,4-Dihydropyridines, processes for their preparation and their use as antithrombotic drugs. DE 3617976; EP 0253092; US 4782069 . |
| 【2】 Ortega, M.P.; Priego, J.G.; Fau de Casa-Juana, M.; Cillero, F.J.; Sunkel, C.E.; Trombodipine. Drugs Fut 1992, 17, 6, 465. |
合成路线5
该中间体在本合成路线中的序号：The protection of the amino group of L-(2-naphthyl)alanine (I) with di-tert-butyl dicarbonate and triethylamine gives N-tert-butoxycarbonyl-L-(2-naphthyl)alanine (II), which is amidated with benzylmethylamine by means of hydroxybenzotriazole (HOBT) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (WSC) in dichloromethane yielding N-tert-butoxycarbonyl-L-(2-naphthyl)alanine N-benzyl-N-methylamide (III). Elimination of the tert-butoxycarbonyl group of (III) with HCl in dioxane affords L-(2-naphthyl)alanine N-benzyl-N-methylamide (IV), which is condensed with N-(tert-butoxycarbonyl)-[4(R)-hydroxy]-L-proline (V) by means of HOBT an WSC as before giving the protected dipeptide (VI). Elimination of the protecting group of (VI) with HCl in dioxane as before yields the dipeptide (VII) with the free amino group, which is finally acylated with 1-methylindole-3-carboxylic acid (VIII) by means of HOBT and WSC as before.
| 【1】 Leeson, P.A.; Rabasseda, X.; Castaner, J.; FK-888. Drugs Fut 1997, 22, 4, 353. |
| 【2】 Matsuo, M.; Hagiwara, D.; Miyake, H. (Fujisawa Pharmaceutical Co., Ltd.); Peptides having tachykinin antagonist activity, a process for preparation thereof and pharmaceutical compsns. comprising the same. EP 0443132; JP 1992210996; US 5468731 . |
| 【3】 Hagiwara, D.; Miyake, H.; Igari, N.; Karino, M.; Maeda, Y.; Fujii, T.; Matsuo, M.; Studies on neurokinin antagonists. 4. Synthesis and structure-activity relationships of novel dipeptide substance P antagonists. J Med Chem 1994, 37, 13, 2090-9. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11975 | Ethyl (E)-3-amino-2-butenoate | 7318-00-5 | C6H11NO2 | 详情 | 详情 | |
| (I) | 15060 | L-3-(2-Naphthyl)alanine; (S)-2-amino-3-(2-naphthyl)propionic acid | 58438-03-2 | C13H13NO2 | 详情 | 详情 |
| (II) | 15061 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid; N-T-BOC-L-3-(2-NAPHTHYL)ALANINE | 58438-04-3 | C18H21NO4 | 详情 | 详情 |
| (III) | 15062 | tert-butyl N-[(1S)-2-[benzyl(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl]carbamate | C26H30N2O3 | 详情 | 详情 | |
| (IV) | 15063 | (2S)-2-amino-N-benzyl-N-methyl-3-(2-naphthyl)propanamide | C21H22N2O | 详情 | 详情 | |
| (V) | 16094 | (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid | 16094 | C10H17NO5 | 详情 | 详情 |
| (VI) | 15065 | tert-butyl (2S,4R)-2-([[(1S)-2-[benzyl(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl]amino]carbonyl)-4-hydroxy-1-pyrrolidinecarboxylate | C31H37N3O5 | 详情 | 详情 | |
| (VII) | 15066 | (2S,4R)-N-[(1S)-2-[benzyl(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl]-4-hydroxytetrahydro-1H-pyrrole-2-carboxamide | C26H29N3O3 | 详情 | 详情 | |
| (VIII) | 15067 | 1-methyl-1H-indole-3-carboxylic acid; N-Methylindole-3-carboxylic acid | 32387-21-6 | C10H9NO2 | 详情 | 详情 |