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【结 构 式】 
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【分子编号】19916 【品名】2-tetrahydro-1H-pyrrolizin-7(5H)-ylethylamine; 2-tetrahydro-1H-pyrrolizin-7(5H)-yl-1-ethanamine 【CA登记号】 |
【 分 子 式 】C9H18N2 【 分 子 量 】154.2554 【元素组成】C 70.08% H 11.76% N 18.16% |
合成路线1
该中间体在本合成路线中的序号：(II)By condensation of 2-chloronitrobenzene (I) with 5-(2-aminoethyl)-1-azabicyclo[3.3.0]octane (II) in refluxing pyridine.
| 【1】 Suzuki, T.; Oka, M.; Maeda, K.; Furusawa, K.; Uesaka, H.; Kataoka, T.; Synthesis and muscarinic activity of novel aniline derivatives with a 1-azabicyclo[3.3.0]octane moiety. Chem Pharm Bull 1999, 47, 1, 28. |
| 【2】 Baba, Y.; Suzuki, T.; Suzuki, T.; Hirooka, K.; Kurono, M.; Sawai, K. (Sanwa Kagaku Kenkyusho Co., Ltd.); 1-Azabicyclo[3.3.0]octane derivs. and their use. EP 0647642; US 5530138 . |
合成路线2
该中间体在本合成路线中的序号：(XII)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 |
合成路线3
该中间体在本合成路线中的序号：(VII)The hydrolysis of 4-acetamido-2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester (I) with NaOH gives the corresponding free acid (II), which is esterified with benzyl alcohol and carbonyldiimidazole (CDI) to the benzyl ester (III). Optical resolution of (III) by chiral HPLC yielded the 2(S)-isomer (IV), which is chlorinated with N-chlorosuccinomide (NCl) affords the 5-chloro derivative (V). The treatment of (V) with NaOH provides 4-amino-5-chloro-2(S)-methyl-2,3-dihydrobenzofuran-7-carboxylic acid (VI), which is condensed with the ethylamino derivative (VII) by means of CDI to give the amide (VIII). Finally, this compound is salified with fumaric acid (IX).
| 【1】 Kakigami, T.; et al.; Serotonin 5-HT4 receptor agonistic activity of the optical isomers of (±)-4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2,3-dihydro-2-methylbenzo[b]furan-7-carboxamide. Chem Pharm Bull 1998, 46, 6, 1039. |
| 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) | 27629 | methyl 4-(acetamido)-2-methyl-2,3-dihydro-1-benzofuran-7-carboxylate | C13H15NO4 | 详情 | 详情 | |
| (II) | 27630 | 4-(acetamido)-2-methyl-2,3-dihydro-1-benzofuran-7-carboxylic acid | C12H13NO4 | 详情 | 详情 | |
| (III) | 27631 | benzyl 4-(acetamido)-2-methyl-2,3-dihydro-1-benzofuran-7-carboxylate | C19H19NO4 | 详情 | 详情 | |
| (IV) | 27632 | benzyl (2S)-4-(acetamido)-2-methyl-2,3-dihydro-1-benzofuran-7-carboxylate | C19H19NO4 | 详情 | 详情 | |
| (V) | 27633 | benzyl (2S)-4-(acetamido)-5-chloro-2-methyl-2,3-dihydro-1-benzofuran-7-carboxylate | C19H18ClNO4 | 详情 | 详情 | |
| (VI) | 27634 | (2S)-4-amino-5-chloro-2-methyl-2,3-dihydro-1-benzofuran-7-carboxylic acid | C10H10ClNO3 | 详情 | 详情 | |
| (VII) | 19916 | 2-tetrahydro-1H-pyrrolizin-7(5H)-ylethylamine; 2-tetrahydro-1H-pyrrolizin-7(5H)-yl-1-ethanamine | C9H18N2 | 详情 | 详情 | |
| (VIII) | 27635 | (2S)-4-amino-5-chloro-2-methyl-N-[2-tetrahydro-1H-pyrrolizin-7(5H)-ylethyl]-2,3-dihydro-1-benzofuran-7-carboxamide | C19H26ClN3O2 | 详情 | 详情 | |
| (IX) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)The optical resolution of 4-amino-5-chloro-2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid (I) by means of brucine in methanol gives the (+)-isomer (II), which is then condensed with the ethylamino derivative (III) by means of carbonyldiimidazole in THF to afford the amide (IV). Finally, this compound is salified with fumaric acid (V) in ethanol.
| 【1】 Baba, Y.; Usui, T.; Iwata, N. (Sanwa Kagaku Kenkyusho Co., Ltd.); Benzo[b]furancarboxamide derivs., process for their preparation and their use as gastrointestinal mobility-enhancing agents. EP 0640602; JP 1995112985; US 5442077 . |
| 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) | 27636 | 4-amino-5-chloro-2-methyl-2,3-dihydro-1-benzofuran-7-carboxylic acid | C10H10ClNO3 | 详情 | 详情 | |
| (II) | 27634 | (2S)-4-amino-5-chloro-2-methyl-2,3-dihydro-1-benzofuran-7-carboxylic acid | C10H10ClNO3 | 详情 | 详情 | |
| (III) | 19916 | 2-tetrahydro-1H-pyrrolizin-7(5H)-ylethylamine; 2-tetrahydro-1H-pyrrolizin-7(5H)-yl-1-ethanamine | C9H18N2 | 详情 | 详情 | |
| (IV) | 27635 | (2S)-4-amino-5-chloro-2-methyl-N-[2-tetrahydro-1H-pyrrolizin-7(5H)-ylethyl]-2,3-dihydro-1-benzofuran-7-carboxamide | C19H26ClN3O2 | 详情 | 详情 | |
| (V) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |