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【结 构 式】 
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【药物名称】Ganaxolone, CCD-1042 【化学名称】3alpha-Hydroxy-3beta-methyl-5alpha-pregnan-20-one 【CA登记号】38398-32-2 【 分 子 式 】C22H36O2 【 分 子 量 】332.53102 |
【开发单位】CoCensys (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Antiepileptic Drugs, Antimigraine Drugs, NEUROLOGIC DRUGS, Drugs Acting on GABA(A) Receptors |
合成路线1
Addition of the sulfur ylide generated from trimethylsulfoxonium iodide and NaH to the 20-ethylene ketal of pregnane-3,20-dione (I) furnished the spiro oxirane derivative (II). This was reduced to the tertiary alcohol (III) by means of LiAlH4 in refluxing THF. Then, acid hydrolysis of the ethylene ketal function of (III) provided the title compound. Alternatively, the intermediate ketal (III) was prepared by addition of methylmagnesium bromide to ketone (I), followed by chromatographic separation of the resultant mixture of 3-alpha and 3-beta methyl adducts.
| 【1】 Hogenkamp, D.J.; et al.; Synthesis and in vitro activity of 3beta-substituted-3alpha-hydroxypregnan-20-ones: Allosteric modulators of the GABAA receptor. J Med Chem 1997, 40, 1, 61. |
| 【2】 Bolger, M. B.; Gee, K.W.; Lan, N.; Belelli, D.; Mirsadeghi, S.; Purdy, R.H.; Tahir, S.H. (CoCensys, Inc.); GABA receptor modulators. WO 9303732 . |
| 【3】 Stephenson, L.; Newall, C.E.; Phillipps, G.H.; Weir, N.G.; Cook, M.C.; Hunter, A.C.; Lawrence, R. (GlaxoSmithKline plc); 3alpha-Hydroxy steroids and esters thereof. GB 1380248 . |
| 【4】 Stephenson, L.; Newall, C.E.; Phillipps, G.H.; Weir, N.G.; Cook, M.C.; Hunter, A.C.; Lawrence, R. (GlaxoSmithKline plc); Anaesthetic steroids of the androstane and pregnane series. US 3953429 . |
| 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) | 56213 | (5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-17-(2-methyl-1,3-dioxolan-2-yl)hexadecahydro-3H-cyclopenta[a]phenanthren-3-one | C23H36O3 | 详情 | 详情 | |
| (II) | 56214 | C24H38O3 | 详情 | 详情 | ||
| (III) | 56215 | (3R,5S,8R,9S,10S,13S,14S,17S)-3,10,13-trimethyl-17-(2-methyl-1,3-dioxolan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol | C24H40O3 | 详情 | 详情 |
合成路线2
Starting from the unprotected diketone (IV), selective addition of dimethyloxosulfonium methylide to the 3 keto group furnished oxirane (V). This was then reduced to the title alcohol by treatment with tributylstannyl hydride and AIBN.
| 【1】 Bolger, M. B.; Gee, K.W.; Lan, N.; Belelli, D.; Mirsadeghi, S.; Purdy, R.H.; Tahir, S.H. (CoCensys, Inc.); GABA receptor modulators. WO 9303732 . |