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【结 构 式】 
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【药物名称】Nabilone, LY-109514, Cesamet 【化学名称】(±)-trans-6,6-Dimethyl-3-(1,1-dimethylheptyl)-1-hydroxy-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one 【CA登记号】51022-71-0 【 分 子 式 】C24H36O3 【 分 子 量 】372.55272 |
【开发单位】Lilly (Originator), Valeant (Licensee) 【药理作用】Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, Cannabinoid Receptor Agonists |
合成路线1
The condensation of diethyl 2-acetylglutarate (I) with 5-(1,1-dimethylheptyl)resorcinol (II) by means of POCl3 gives ethyl 7-(1,1-dimethylheptyl)-5-hydroxy-4-methyl-2-oxo-2H-1-benzopyran-3-propionate (III), which is cyclized by means of NaH in DMSO yielding 3-(1,1-dimethylheptyl)-7,10-dihydro-1-hydroxy-6H-dibenzo[b,d]pyran-6,9-(8H)-dione (IV). The ketalization of (IV) with ethylene glycol (A) and p-toluenesulfonic acid affords the ketal (V), which by a Grignard reaction with methylmagnesium iodide in refluxing ether is converted into dl-3-(1,1-dimethylheptyl)-6,6a,7,8-tetrahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one (VI). Finally, this compound is reduced with Li in liquid ammonia.
| 【1】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as analgesic drugs. US 3944673 . |
| 【2】 Archer, R.A.; Dihydroxyhexahydrodibenzo[b,d]pyrans. DE 2451934; ES 431674; FR 2249664; GB 1487637; JP 50071678; US 3968125 . |
| 【3】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as an anti-anxiety drug. DE 2451932; ES 431675; FR 2249663; GB 1487636; JP 50082073; NL 7414437; US 3928598 . |
| 【4】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as psychotropic, particularly anti-depressant drugs. US 3953603 . |
| 【5】 Castaner, J.; Weetman, D.F.; Nabilone. Drugs Fut 1978, 3, 3, 207. |
| 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) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (I) | 15865 | Diethyl 2-acetylglutarate; diethyl 2-acetylpentanedioate | 1501-06-0 | C11H18O5 | 详情 | 详情 |
| (II) | 20233 | 5-(1,1-dimethylheptyl)-1,3-benzenediol | C15H24O2 | 详情 | 详情 | |
| (III) | 33507 | ethyl 3-[7-(1,1-dimethylheptyl)-5-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl]propanoate | C24H34O5 | 详情 | 详情 | |
| (IV) | 33508 | 3-(1,1-dimethylheptyl)-1-hydroxy-7,10-dihydro-6H-benzo[c]chromene-6,9(8H)-dione | C22H28O4 | 详情 | 详情 | |
| (V) | 33509 | 3-(1,1-Dimethylheptyl)-9,9-(ethylenedioxy)-1-hydroxy-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one | C24H32O5 | 详情 | 详情 | |
| (VI) | 33510 | 3-(1,1-dimethylheptyl)-1-hydroxy-6,6-dimethyl-6,6a,7,8-tetrahydro-9H-benzo[c]chromen-9-one | C24H34O3 | 详情 | 详情 | |
| (VII) | 20225 | iodo(methyl)magnesium | 917-64-6 | CH3IMg | 详情 | 详情 |