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【结 构 式】 
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【分子编号】16465 【品名】(2S,3S,5S,8R,9S,10S,13S,14S,16S)-3-hydroxy-10,13-dimethyl-2,16-di(1-piperidinyl)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one 【CA登记号】 |
【 分 子 式 】C29H48N2O2 【 分 子 量 】456.7124 【元素组成】C 76.27% H 10.59% N 6.13% O 7.01% |
合成路线1
该中间体在本合成路线中的序号：(V)The enol acylation of 5alpha-androst-2-en-17-one (I) with isopropenyl acetate (A) using H2SO4 as catalyst gives 17-acetoxyandrost-2,16-diene (II), which is epoxidized by treatment with m-chloroperbenzoic acid in ether yielding 2alpha,3alpha:16alpha,17alpha-diepoxy-17beta-acetoxy-5alpha-androstane (III). The hydrolytic rearrangement of (III) with KOH affords 2alpha,3alpha-epoxy-5alpha-androstan-17beta-ol-16-one (IV), which is condensed with refluxing aqueous piperidine (B) to give 2beta,16beta-dipiperidino-5alpha-androstan-3alpha-ol-17-one (V). The reduction of (V) with NaBH4 in methylene chloride - methanol yields 2beta,16beta-dipiperidino-5alpha-androstan-3alpha,17beta-diol (VI), which is acetylated by reaction with acetyl chloride as usual to afford the corresponding diacetate (VII). Finally, this compound is quaternized by reaction with methyl bromide in ether.
| 【1】 Buckett, W.R.; et al.; Pancuronium bromide and other steroidal neuromuscular blocking agents containing acetylcholine fragments. J Med Chem 1973, 16, 10, 1116-24. |
| 【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Hillier, K.; ORG-NC-45. Drugs Fut 1981, 6, 5, 287. |
| 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) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (A) | 21178 | isopropenyl acetate | 108-22-5 | C5H8O2 | 详情 | 详情 |
| (I) | 32178 | (5S,8R,9S,10S,13S,14S)-10,13-dimethyl-1,4,5,6,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H28O | 详情 | 详情 | |
| (II) | 32179 | (5S,8R,9S,10S,13S,14S)-10,13-dimethyl-4,5,6,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate | C21H30O2 | 详情 | 详情 | |
| (III) | 32180 | (1aS,2aS,2bS,4aS,5aR,6aS,6bR,8aS,9aS)-2a,4a-dimethylhexadecahydro-4bH-oxireno[2'',3'':4',5']cyclopenta[1',2':7,8]phenanthro[2,3-b]oxiren-4-yl acetate | C21H30O4 | 详情 | 详情 | |
| (IV) | 32181 | (1R,3aS,3bR,5aS,6aS,7aS,8aS,8bS,10aS)-1-hydroxy-8a,10a-dimethylhexadecahydro-2H-cyclopenta[7,8]phenanthro[2,3-b]oxiren-2-one | C19H28O3 | 详情 | 详情 | |
| (V) | 16465 | (2S,3S,5S,8R,9S,10S,13S,14S,16S)-3-hydroxy-10,13-dimethyl-2,16-di(1-piperidinyl)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one | C29H48N2O2 | 详情 | 详情 | |
| (VI) | 32182 | (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-10,13-dimethyl-2,16-di(1-piperidinyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-3,17-diol | C29H50N2O2 | 详情 | 详情 | |
| (VII) | 32183 | (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-17-(acetoxy)-10,13-dimethyl-2,16-di(1-piperidinyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C33H54N2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The acetylation of (2beta,3alpha,5alpha,16beta)-3-hydroxy-2,16-bis(piperidin-1-yl)androstan-17-one (I) with acetyl chloride in dichloromethane gives the corresponding 3-acetoxy derivative (II), which is reduced with NaBH4 in methanol - THF yielding (2beta,3alpha,5alpha,16,beta,17beta)-3-acetoxy-17-hydroxy-2,6-bis (piperidin-1-yl)androstane (III). The acylation of (III) with propionyl chloride in dichloromethane as before affords the 3-acetoxy-17-propionyloxy derivative (IV), which is finally quaternized with allyl bromide in dichloromethane.
| 【1】 Sleigh, T.; Carlyle, I.C.; Muir, A.W. (Akzo Nobel N.V.); Monoquaternary 2,16-bispiperidinylandrostane derivs. EP 0571012; JP 1995267984; US 5418226 . |
| 【2】 Graul, A.; Prous, J.; Castañer, J.; Org-9487. Drugs Fut 1994, 19, 10, 916. |
| 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) | 16465 | (2S,3S,5S,8R,9S,10S,13S,14S,16S)-3-hydroxy-10,13-dimethyl-2,16-di(1-piperidinyl)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one | C29H48N2O2 | 详情 | 详情 | |
| (II) | 16466 | (2S,3S,5S,8R,9S,10S,13S,14S,16S)-10,13-dimethyl-17-oxo-2,16-di(1-piperidinyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C31H50N2O3 | 详情 | 详情 | |
| (III) | 16467 | (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-17-hydroxy-10,13-dimethyl-2,16-di(1-piperidinyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C31H52N2O3 | 详情 | 详情 | |
| (IV) | 16468 | (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-3-(acetoxy)-10,13-dimethyl-2,16-di(1-piperidinyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl propionate | C34H56N2O4 | 详情 | 详情 |