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【结 构 式】 
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【药物名称】BH-1625(NOMe)TB-2 【化学名称】(+)-1alpha-Hydroxy-26-(methoxyimino)-26,26,26-trimethyl-27-norvitamin D3 【CA登记号】 【 分 子 式 】C30H47NO3 【 分 子 量 】469.71399 |
【开发单位】Johns Hopkins University (Originator), M.D. Anderson Cancer Center (Originator) 【药理作用】ONCOLYTIC DRUGS, Vitamin D Analogs |
合成路线1
Alkylation of the lithium enolate of pinacolone (II) with alkyl iodide (I) affords ketone (III), which is then condensed with O-methyl hydroxylamine to produce oxime (IV). After desilylation of (IV) by means of tetrabutylammonium fluoride, the resultant alcohol (V) is oxidized to the corresponding ketone (VI), employing N-methylmorpholine-N-oxide in the presence of a catalytic amount of tetrapropylammonium perruthenate. Wadsworth-Emmons condensation of ketone (VI) with the racemic phosphine oxide (VII) provides a diastereomeric mixture of diene adducts (VIII). After desilylation of (VIII) by means of tetrabutylammonium fluoride, the resultant mixture of diol isomers is separated by column chromatography to furnish the title compound.
| 【1】 Posner, G.H.; Kensler, T.W.; Dolan, P.; Peleg, S.; Halford, B.A.; Conceptually new low-calcemic oxime analogues of the hormone 1alpha,25-dihydroxyvitamin D3: Synthesis and biological testing. J Med Chem 2002, 45, 8, 1723. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 57655 | (7R)-7-{(3aS,7aS)-7-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl}-2,2-dimethyl-3-octanone O-methyloxime | C42H75NO3Si2 | 详情 | 详情 | |
| (VIIIb) | 57656 | (7R)-7-{(3aS,7aS)-7-[(E)-2-((3S,5S)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl}-2,2-dimethyl-3-octanone O-methyloxime | C42H75NO3Si2 | 详情 | 详情 | |
| (I) | 42570 | ([(3aS,7S,7aR)-3-[(1R)-3-iodo-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl]oxy)(triethyl)silane; (3aS,7S,7aR)-3-[(1R)-3-iodo-1-methylpropyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl triethylsilyl ether | C20H37IOSi | 详情 | 详情 | |
| (II) | 10128 | 3,3-Dimethyl-2-butanone; Pinacolin | 75-97-8 | C6H12O | 详情 | 详情 |
| (III) | 57651 | (7R)-7-{(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl}-2,2-dimethyl-3-octanone | C26H48O2Si | 详情 | 详情 | |
| (IV) | 57652 | (7R)-7-{(3aS,7S,7aR)-3a-methyl-7-[(triethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl}-2,2-dimethyl-3-octanone O-methyloxime | C27H51NO2Si | 详情 | 详情 | |
| (V) | 57653 | (7R)-7-[(3aS,7S,7aR)-7-hydroxy-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-2,2-dimethyl-3-octanone O-methyloxime | C21H37NO2 | 详情 | 详情 | |
| (VI) | 57654 | (3aR,7aS)-1-[(1R)-5-(methoxyimino)-1,6,6-trimethylheptyl]-7a-methyl-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one | C21H35NO2 | 详情 | 详情 | |
| (VII) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 |