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【结 构 式】

【分子编号】12322

【品名】methyl (2S)-3-(1H-imidazol-5-yl)-2-[[(2R)-4-morpholino-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propanoate

【CA登记号】

【 分 子 式 】C26H30N4O5

【 分 子 量 】478.54816

【元素组成】C 65.26% H 6.32% N 11.71% O 16.72%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XII)

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
Extended Information