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【结 构 式】 
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【分子编号】12319 【品名】(Z)-2-(2-Morpholino-2-oxoethyl)-3-(1-naphthyl)-2-propenoic acid 【CA登记号】 |
【 分 子 式 】C19H19NO4 【 分 子 量 】325.3642 【元素组成】C 70.14% H 5.89% N 4.3% O 19.67% |
合成路线1
该中间体在本合成路线中的序号：(IX)1) Synthesis of N(tau)-tert-butoxycarbonyl-N(alpha)-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine: The condensation of diethyl succinate (III) with 1-naphthaldehyde (IV) by means of sodium ethoxide in refluxing methanol gives 2-(1-naphthylmethylene)succinic acid diethyl ester (V), which is hydrolyzed to the corresponding acid (VI) with NaOH. The cyclization of (VI) with refluxing SOCl2 affords the anhydride (VII), which is treated with morpholine (VIII) in ethyl acetate, yielding 2-(morpholinocarbonylmethyl)-3-(1-naphthyl)acrylic acid (IX). Hydrogenation of (IX) with H2 over Pd/C in methanol affords the corresponding propionic acid (X), which is then condensed with histidine methyl ester (XI) by means of DCC and HONB as before, giving a racemic mixture that is submitted to optical resolution by repeated crystallization of its salycylic acid salt, thus yielding N-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine methyl ester (XII). Finally, this compound is hydrolyzed with NaOH and protected with tert-butoxycarbonyl anhydride to give (I).
| 【1】 Harada, H.; Iyobe, A.; Tsubaki, A.; Yamaguchi, T.; Kamijo, T.; Kiso, Y.; Iizuka, K.; Hirata, K.; A practical synthesis of an orally potent renin inhibitor, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-[N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naaphthyl)propionyl]-L-histidyl]aminobutyrate. J Chem Soc - Perkins Trans I 1990, 9, 2497-500. |
| 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) | 12312 | (2S)-3-[1-(tert-Butoxycarbonyl)-1H-imidazol-5-yl]-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propionic acid | C30H36N4O7 | 详情 | 详情 | |
| (III) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (IV) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (V) | 12315 | diethyl 2-[(Z)-1-naphthylmethylidene]succinate | C19H20O4 | 详情 | 详情 | |
| (VI) | 12316 | 2-[(Z)-1-Naphthylmethylidene]succinic acid | C15H12O4 | 详情 | 详情 | |
| (VII) | 12317 | 3-[(Z)-1-Naphthylmethylidene]-2,5(4H)-furandione | C15H10O3 | 详情 | 详情 | |
| (VIII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (IX) | 12319 | (Z)-2-(2-Morpholino-2-oxoethyl)-3-(1-naphthyl)-2-propenoic acid | C19H19NO4 | 详情 | 详情 | |
| (X) | 12320 | 4-Morpholino-2-(1-naphthylmethyl)-4-oxobutyric acid | C19H21NO4 | 详情 | 详情 | |
| (XI) | 12321 | methyl (2S)-2-amino-3-(1H-imidazol-5-yl)propanoate; Methyl-L-histidine | 1499-46-3 | C7H11N3O2 | 详情 | 详情 |
| (XII) | 12322 | methyl (2S)-3-(1H-imidazol-5-yl)-2-[[(2R)-4-morpholino-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propanoate | C26H30N4O5 | 详情 | 详情 |