-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】1alpha,24(R)-Dihydroxy-25-nitrovitamin D3

【CA登记号】

【分子式】C₂₇H₄₃NO₅

【分子量】461.64746

【开发单位】Teijin (Originator)

【药理作用】Oncolytic Drugs, Vitamin D Analogs

合成路线1 合成路线2

合成路线1

Condensation of aldehyde (I) with 2-nitropropane (II) using tert-butyldimethylsilyl chloride, tetrabutylammonium fluoride and triethylamine afforded a mixture of diastereomeric nitroaldol products (III). After separation by column chromatography, the desired isomer was protected as the tert-butyldimethylsilyl ether (IV). Deprotection of the benzoate ester of (IV) was carried out by reduction with diisobutylaluminum hydride to provide alcohol (V), which was then oxidized to the corresponding ketone (VI) with pyridinium chlorochromate. Wittig reaction of (VI) with phosphorane (VII) provided the bromomethylene compound (VIII).

参考文献中间体

【1】 Oshida, J.; et al.; Synthesis and biological evaluation of 1alpha,24-dihydroxy-25-nitrovitamin D3. Bioorg Med Chem Lett 1999, 9, 3, 381.

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)	21818	(4S,7aR)-7a-methyl-1-[(1R)-1-methyl-4-oxobutyl]octahydro-1H-inden-4-yl benzoate		C₂₂H₃₀O₃	详情	详情
(II)	21819	2-nitropropane	79-46-9	C₃H₇NO₂	详情	详情
(III)	21820	(4S,7aR)-1-[(1R)-4-hydroxy-1,5-dimethyl-5-nitrohexyl]-7a-methyloctahydro-1H-inden-4-yl benzoate		C₂₅H₃₇NO₅	详情	详情
(IV)	21821	(4S,7aR)-1-((1R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethyl-5-nitrohexyl)-7a-methyloctahydro-1H-inden-4-yl benzoate		C₃₁H₅₁NO₅Si	详情	详情
(V)	21822	(4S,7aR)-1-((1R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethyl-5-nitrohexyl)-7a-methyloctahydro-1H-inden-4-ol		C₂₄H₄₇NO₄Si	详情	详情
(VI)	21823	(7aR)-1-((1R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,5-dimethyl-5-nitrohexyl)-7a-methyloctahydro-4H-inden-4-one		C₂₄H₄₅NO₄Si	详情	详情
(VIII)	21824	[[(1R,4R)-4-[(7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-(1-methyl-1-nitroethyl)pentyl]oxy](tert-butyl)dimethylsilane; (1R,4R)-4-[(7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-(1-methyl-1-nitroethyl)pentyl tert-butyl(dimethyl)silyl ether		C₂₅H₄₆BrNO₃Si	详情	详情

合成路线2

Further exchange of the protecting group of (VIII) from tert-butyldimethylsilyl to trimethylsilyl ether (IX) was carried out by desilylation with LiBF4 and H2SO4, followed by treatment with (trimethylsilyl)imidazole. The resulting compound (IX) was cyclized with enyne (X) using Pd2(dba)3, Et3N and PPh3 to afford triene (XI), which was finally desilylated with pyridinium tosylate.

参考文献中间体

【1】 Oshida, J.; et al.; Synthesis and biological evaluation of 1alpha,24-dihydroxy-25-nitrovitamin D3. Bioorg Med Chem Lett 1999, 9, 3, 381.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	21824	[[(1R,4R)-4-[(7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-(1-methyl-1-nitroethyl)pentyl]oxy](tert-butyl)dimethylsilane; (1R,4R)-4-[(7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-(1-methyl-1-nitroethyl)pentyl tert-butyl(dimethyl)silyl ether	C₂₅H₄₆BrNO₃Si	详情	详情
(IX)	21825	(1R,4R)-4-[(7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-(1-methyl-1-nitroethyl)pentyl trimethylsilyl ether; [[(1R,4R)-4-[(7aR)-4-[(E)-bromomethylidene]-7a-methyloctahydro-1H-inden-1-yl]-1-(1-methyl-1-nitroethyl)pentyl]oxy](trimethyl)silane	C₂₂H₄₀BrNO₃Si	详情	详情
(X)	21826	(5R,7S)-3,3,9,9-tetraethyl-5-(2-propynyl)-7-vinyl-4,8-dioxa-3,9-disilaundecane; (1R,3S)-1-(2-propynyl)-3-[(triethylsilyl)oxy]-4-pentenyl triethylsilyl ether	C₂₀H₄₀O₂Si₂	详情	详情
(XI)	21827	[[(1R,4R)-4-[(7aR)-7a-methyl-4-((E)-2-[(3S,5R)-2-methylene-3,5-bis[(triethylsilyl)oxy]cyclohexylidene]ethylidene)octahydro-1H-inden-1-yl]-1-(1-methyl-1-nitroethyl)pentyl]oxy](trimethyl)silane; (1R,4R)-4-[(7aR)-7a-methyl-4-((E)-2-[(3S,5R)-2-methylene-3,5-bis[(triethylsilyl)oxy]cyclohexylidene]ethylidene)octahydro-1H-inden-1-yl]-1-(1-methyl-1-nitroethyl)pentyl trimethylsilyl ether	C₄₂H₇₉NO₅Si₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)