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【结 构 式】 
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【药物名称】HS-378 【化学名称】17-(Cyclopropylmethyl)-6,7-didehydro-4,5alpha-epoxy-14-ethoxy-3-hydroxy-5-methylindolo[2',3':6,7]morphinan hydrochloride 【CA登记号】173782-64-4, 188246-02-8 (free base) 【 分 子 式 】C29H33ClN2O3 【 分 子 量 】493.05096 |
【开发单位】AstraZeneca (Originator) 【药理作用】Antiarthritic Drugs, IMMUNOMODULATING AGENTS, Immunosuppressants, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, delta-Opioid Antagonists |
合成路线1
The title indolomorphinan derivative was synthesized by Fisher indole synthesis from the known 14-O-ethyl-5-methylnaltrexone (I) and phenylhydrazine hydrochloride (II) in refluxing acetic acid, followed by conversion to the corresponding hydrochloride salt.
| 【1】 Helv Chim Acta 1993, 76, 476. |
| 【2】 Schmidhammer, H. (AstraZeneca plc); New antagonist cpds.. EP 0759922; JP 1998500131; US 6136817; WO 9531463 . |
| 【3】 Monory, K.; Daurer, D.; Schmidhammer, H.; Borsodi, A.; Wieser, M.; Traynor, J.R.; Elliott, J.; Synthesis and biological evaluation of 14-alkoxymorphinans. 14. 14-Ethoxy-5-methyl substituted indolomorphinans with delta opioid receptor selectivity. Bioorg Med Chem Lett 1997, 7, 2, 151. |
合成路线2
A further procedure for the preparation of (I) from naltrexone (III) has been reported. Naltrexone (III) was O-alkylated with diethyl sulfate in the presence of NaH to give (IV). Deprotonation of (IV) using the combination potassium tert-butoxide/butyllithium, followed by methylation with dimethyl sulfate, yielded the 5-methyl derivative (V). The aryl- and enol ether groups of (V) were then cleaved by means of concentrated HBr.
| 【1】 Krassing, R.; et al.; A novel method for the introduction of a 5-beta-methyl group into 4,5-alpha-epoxymorphinan-6-ones via the enol ether. Helv Chim Acta 2000, 83, 2, 380. |
| 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) | 42229 | (1R,5R,13R,17S)-4-(cyclopropylmethyl)-17-ethoxy-10-hydroxy-13-methyl-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one | C23H29NO4 | 详情 | 详情 | |
| (III) | 42232 | (1S,5R,17S)-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one | C20H23NO4 | 详情 | 详情 | |
| (IV) | 42230 | (1S,5R,17S)-4-(cyclopropylmethyl)-10,14,17-triethoxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10,14-tetraene; (1S,5R)-4-(cyclopropylmethyl)-10,14-diethoxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10,14-tetraen-17-yl ethyl ether | C26H35NO4 | 详情 | 详情 | |
| (V) | 42231 | (1R,5R,13R,17S)-4-(cyclopropylmethyl)-10,14,17-triethoxy-13-methyl-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10,14-tetraene; (1R,5R,13R)-4-(cyclopropylmethyl)-10,14-diethoxy-13-methyl-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10,14-tetraen-17-yl ethyl ether | C27H37NO4 | 详情 | 详情 |