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【结 构 式】 
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【分子编号】19908 【品名】methyl 4-(acetamido)-5-chloro-2-(2-propynyloxy)benzoate 【CA登记号】 |
【 分 子 式 】C13H12ClNO4 【 分 子 量 】281.69532 【元素组成】C 55.43% H 4.29% Cl 12.59% N 4.97% O 22.72% |
合成路线1
该中间体在本合成路线中的序号：(IV)Alkylation of methyl 4-(acetylamino)-2-hydroxybenzoate (I) with propargyl bromide (II) in the presence of K2CO3 in refluxing acetonitrile gave propargyl ether (III), and subsequent chlorination with N-chlorosuccinimide in DMF yielded (IV). Then, a Claisen-type rearrangement of (IV) in boiling diphenyl ether furnished the benzopyran (V), which was hydrogenated over Pt/C to give dihydrobenzopyran (VI). Subsequent treatment of (VI) with 4 N KOH produced the hydrolysis of both ester and amide functions, affording acid (VII). Treatment of dicyclopropyl ketone (VIII) with HCl gas provided 1,7-dichloro-4-heptanone (IX). Cyclization of (IX) with cyanoacetic acid in a two-phase system of aqueous ammonia and n-hexane gave bicyclic intermediate (X), which upon decarboxylation yielded nitrile (XI). Subsequent hydrogenation in the presence of Raney-Ni and NaOH furnished 5-(2-aminoethyl)-1-azabicyclo[3.3.0]octane (XII) (3). The title compound was then obtained by coupling of acid (VII) with amine (XII) using carbonyldiimidazole (CDI), followed by conversion to the hemifumarate salt.
| 【1】 Kakigami, T.; et al.; Synthesis and structure-activity relationship of 3-substituted benzamide, benzo[b]furan-7-carboxamide, 2,3-dihydrobenzo[b]furan-7-carboxamide, and indole-5-carboxamide derivatives as selective serotonin 5-HT4 receptor agonists. Chem Pharm Bull 1998, 46, 1, 42. |
| 【2】 Suzuki, T.; et al.; N-[2-(1-Azabicyclo[3.3.0]octan-5-yl)ethyl]-2-nitroaniline, a potent muscarinic agonist. Chem Pharm Bull 1997, 45, 7, 1218. |
| 【3】 Kakigami, T.; et al.; A 3D-quantitative structure-activity relationship study of benzamide type serotonin 5-HT4 receptor agonists based on a comparative molecular field analysis model, and the design and synthesis of potent agonists. Chem Pharm Bull 1998, 46, 12, 1881. |
| 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) | 12330 | methyl 4-(acetamido)-2-hydroxybenzoate | C10H11NO4 | 详情 | 详情 | |
| (II) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (III) | 19907 | methyl 4-(acetamido)-2-(2-propynyloxy)benzoate | C13H13NO4 | 详情 | 详情 | |
| (IV) | 19908 | methyl 4-(acetamido)-5-chloro-2-(2-propynyloxy)benzoate | C13H12ClNO4 | 详情 | 详情 | |
| (V) | 19909 | methyl 5-(acetamido)-6-chloro-2H-chromene-8-carboxylate | C13H12ClNO4 | 详情 | 详情 | |
| (VI) | 19910 | methyl 5-(acetamido)-6-chloro-8-chromanecarboxylate | C13H14ClNO4 | 详情 | 详情 | |
| (VII) | 19911 | 5-amino-6-chloro-8-chromanecarboxylic acid | C10H10ClNO3 | 详情 | 详情 | |
| (VIII) | 19912 | Dicyclopropylmethanone; Dicyclopropyl ketone | 1121-37-5 | C7H10O | 详情 | 详情 |
| (IX) | 19913 | 1,7-dichloro-4-heptanone | 40624-07-5 | C7H12Cl2O | 详情 | 详情 |
| (X) | 19914 | 2-cyano-2-tetrahydro-1H-pyrrolizin-7(5H)-ylacetic acid | C10H14N2O2 | 详情 | 详情 | |
| (XI) | 19915 | 2-tetrahydro-1H-pyrrolizin-7(5H)-ylacetonitrile | C9H14N2 | 详情 | 详情 | |
| (XII) | 19916 | 2-tetrahydro-1H-pyrrolizin-7(5H)-ylethylamine; 2-tetrahydro-1H-pyrrolizin-7(5H)-yl-1-ethanamine | C9H18N2 | 详情 | 详情 |