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【结 构 式】 
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【分子编号】38001 【品名】cyclooctanecarbaldehyde 【CA登记号】6688-11-5 |
【 分 子 式 】C9H16O 【 分 子 量 】140.22544 【元素组成】C 77.09% H 11.5% O 11.41% |
合成路线1
该中间体在本合成路线中的序号：(II)Reductive alkylation of ethyl 4-oxopiperidine-3-carboxylate (I) with cyclooctane carboxaldehyde (II) in the presence of sodium triacetoxy borohydride provided the cyclooctylmethyl piperidine (III). Treatment of (III) with ammonium acetate gave the unstable enamine (IV), which was reduced to amine (V) with NaBH3CN and subsequently coupled with 2-fluoronitrobenzene (VI) in refluxing MeOH to furnish nitroaniline (VIIa-b) as a mixture of trans- and cis-isomers. After separation by silica gel column chromatography, the desired trans-isomer was hydrogenated in the presence of Pd/C to afford phenylenediamine (VIII). Cyclization of (VIII) with carbonyldiimidazole produced benzimidazolone (IX), which was N-alkylated with ethyl iodide and NaH to give (X). Reduction of the ester group of (X) with LiAlH4 yielded the corresponding alcohol as a racemate. Optical resolution was achieved using a Chiralpak AD column.
| 【1】 Kawamoto, H.; et al.; Discovery and synthesis of the first potent and selective small molecule ORL1 receptor antagonist: J-113397. 20th Symp Med Chem (Dec 6 2000, Tokyo) 2000, Abst 1P-14. |
| 【2】 Miyaji, M.; Nakashima, H.; Arai, S.; Kawamoto, H.; Ohta, H.; Itoh, Y.; Iwasawa, Y.; Kato, T.; Ozaki, S.; Discovery of the first potent and selective small molecule opioid receptor-like (ORL1) antagonist: 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]3-ethyl-1,3-dihydro-2H-benzimidazol-2-one(J-113397). J Med Chem 1999, 42, 25, 5061. |
| 【3】 Ozaki, S.; Kawamoto, H.; Hirano, K.; Ito, Y.; Hayashi, K.; Iwasawa, Y. (Banyu Pharmaceutical Co., Ltd.); 2-Oxoimidazole derivs.. EP 0990653; WO 9854168 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 38005 | ethyl (3R,4R)-1-(cyclooctylmethyl)-4-(2-nitroanilino)-3-piperidinecarboxylate | C23H35N3O4 | 详情 | 详情 | |
| (VIIb) | 38006 | ethyl (3S,4R)-1-(cyclooctylmethyl)-4-(2-nitroanilino)-3-piperidinecarboxylate | C23H35N3O4 | 详情 | 详情 | |
| (I) | 38000 | ethyl 4-oxo-3-piperidinecarboxylate | 4644-61-5 | C8H13NO3 | 详情 | 详情 |
| (II) | 38001 | cyclooctanecarbaldehyde | 6688-11-5 | C9H16O | 详情 | 详情 |
| (III) | 38002 | ethyl 1-(cyclooctylmethyl)-4-oxo-3-piperidinecarboxylate | C17H29NO3 | 详情 | 详情 | |
| (IV) | 38003 | ethyl 4-amino-1-(cyclooctylmethyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylate | C17H30N2O2 | 详情 | 详情 | |
| (V) | 38004 | ethyl 4-amino-1-(cyclooctylmethyl)-3-piperidinecarboxylate | C17H32N2O2 | 详情 | 详情 | |
| (VI) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (VIII) | 38007 | ethyl (3R,4R)-4-(2-aminoanilino)-1-(cyclooctylmethyl)-3-piperidinecarboxylate | C23H37N3O2 | 详情 | 详情 | |
| (IX) | 38008 | ethyl (3R,4R)-1-(cyclooctylmethyl)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-3-piperidinecarboxylate | C24H35N3O3 | 详情 | 详情 | |
| (X) | 38009 | ethyl (3R,4R)-1-(cyclooctylmethyl)-4-(3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-3-piperidinecarboxylate | C26H39N3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The chloroformylation of cyclooctanone (XI) with DMF and POCl3 gives 2-chloro-1-cyclooctenecarbaldehyde (XII), which is dechlorinated and hydrogenated with H2 over Pd/C to afford the desired intermediate (II).
| 【1】 Kawamoto, H.; et al.; Synthesis of J-113397, the first potent and selective ORL1 antagonist. Tetrahedron 2001, 57, 6, 981. |