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【结 构 式】 
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【药物名称】Nalbuphine hydrochloride, EN-2234A, Nubain 【化学名称】17-(Cyclobutylmethyl)-4,5alpha-epoxymorphinan-3,6alpha,14-triol hydrochloride 【CA登记号】23277-43-2, 20594-83-6 (free base) 【 分 子 式 】C21H28ClNO4 【 分 子 量 】393.91461 |
【开发单位】Bristol-Myers Squibb (Originator), Endo (Licensee) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Opioid Analgesics |
合成路线1
Compound can be prepared in three different ways all starting from 14-hydroxydihydronormorphinone (I): 1) The condensation of (I) with cyclobutanecarboxyl chloride (A) by means of triethylamine in CH2Cl2 gives the bis(cyclobutylcarbonyl) derivative (II), which is then reduced and hydrolyzed with LiAlH4 in THF. 2) The condensation of (I) with cyclobutylmethyl bromide (B) in DMF gives the N-cyclobutylmethyl derivative (III), which is then reduced with NaBH4 in ethanol. 3) The reduction of (I) with NaBH4 as before gives 14-hydroxydihydronormophine (IV), which is then alkylated with cyclobutylmethyl bromide (B) in DMF.
| 【1】 Blumberg, H.; et al.; Verfahren zur Herstellung von N-substituierten 14-Hydroxydihydronormorphinen. CH 493522; DE 1670616; DE 1795707; ES 334942; FR 6112M; GB 1119270 . |
| 【2】 Blumberg, H.; et al.; 14-Hydroxydihydronormorphinone derivatives. US 3332950 . |
| 【3】 Castaner, J.; Roberts, P.J.; Nalbuphine. Drugs Fut 1977, 2, 9, 613. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 18589 | cyclobutanecarbonyl chloride | 5006-22-4 | C5H7ClO | 详情 | 详情 |
| (B) | 33931 | 1-(bromomethyl)cyclobutane;bromomethylcyclobutane;(Bromomethyl)cyclobutane;Cyclobutylmethyl bromide | 17247-58-4 | C5H9Br | 详情 | 详情 |
| (I) | 33927 | (1S,5R,13R,17S)-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 | C16H17NO4 | 详情 | 详情 | |
| (II) | 33928 | (1S,5R,13R,17S)-4-(cyclobutylcarbonyl)-17-hydroxy-14-oxo-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-10-yl cyclobutanecarboxylate | C26H29NO6 | 详情 | 详情 | |
| (III) | 33929 | (1S,5R,13R,17S)-4-(cyclobutylmethyl)-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 | C21H25NO4 | 详情 | 详情 | |
| (IV) | 33930 | (1S,5R,13R,14S,17S)-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-triene-10,14,17-triol | C16H19NO4 | 详情 | 详情 |