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【结 构 式】 
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【分子编号】33914 【品名】(2R)-2-[(1S,2S,6R,14R,15S,16R)-11,15-dimethoxy-5-methyl-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-3,3-dimethyl-2-butanol 【CA登记号】 |
【 分 子 式 】C27H39NO4 【 分 子 量 】441.611 【元素组成】C 73.43% H 8.9% N 3.17% O 14.49% |
合成路线1
该中间体在本合成路线中的序号：(III)The hydrogenation of 7-acetyl-6,14-endoetheno-6,7,8,14-tetrahydrothebaine (I) with H2 over Pd/C in acetic acid gives the corresponding endo-ethano derivative (II), which by a Grignard reaction with tertbutyl-magnesium chloride (A) in ether-benzene yields 7alpha-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine (III). The reaction of III with BrCN in CH2Cl2 affords 7alpha-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-N-cyano-6,7,8,14-tetrahydronorthebaine (IV), which is treated with KOH in ethylene glycol at 170 C to give 7alpha(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine (V). This compound is treated first with cyclopropylcarbonyl chloride (B) in CH2Cl2 containing triethylamine, followed by a reduction with LiAlH4 in refluxing THF yielding N-cyclopropylmethyl-7alpha-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydro-northebaine (VI). Finally, (VI) is demethylated with KOH in diethylene glycol at 210-220 C.
| 【1】 Bentley, K.W.; Thebaine and Oripavine derivatives. CH 558362; DE 1620206; FR 6395M; GB 1136214 . |
| 【2】 Castaner, J.; Paton, D.M.; Buprenorphine. Drugs Fut 1977, 2, 9, 570. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 14061 | Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride | 4023-34-1 | C4H5ClO | 详情 | 详情 |
| (A) | 15459 | tert-butyl(chloro)magnesium | 677-22-5 | C4H9ClMg | 详情 | 详情 |
| (I) | 33912 | 1-[(1R,2S,6R,14R,15S,16S)-11,15-dimethoxy-5-methyl-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11,18-tetraen-16-yl]-1-ethanone | C23H27NO4 | 详情 | 详情 | |
| (II) | 33913 | 1-[(1S,2S,6R,14R,15S,16S)-11,15-dimethoxy-5-methyl-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-1-ethanone | C23H29NO4 | 详情 | 详情 | |
| (III) | 33914 | (2R)-2-[(1S,2S,6R,14R,15S,16R)-11,15-dimethoxy-5-methyl-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-3,3-dimethyl-2-butanol | C27H39NO4 | 详情 | 详情 | |
| (IV) | 33915 | (2R)-2-[(1S,2S,6R,14R,15S,16R)-5-cyano-11,15-dimethoxy-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-3,3-dimethyl-2-butanol | C27H36N2O4 | 详情 | 详情 | |
| (V) | 33916 | (2R)-2-[(1S,2S,6R,14R,15S,16R)-11,15-dimethoxy-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-3,3-dimethyl-2-butanol | C26H37NO4 | 详情 | 详情 | |
| (VI) | 33917 | (2R)-2-[(1S,2S,6R,14R,15S,16R)-5-(cyclopropylmethyl)-11,15-dimethoxy-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-3,3-dimethyl-2-butanol | C30H43NO4 | 详情 | 详情 |