(3aS,7S,7aR)-3-[(1R)-5-hydroxy-1,5-dimethyl-3-hexynyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol -Drug Synthesis Database

【结构式】

【分子编号】38690

【品名】(3aS,7S,7aR)-3-[(1R)-5-hydroxy-1,5-dimethyl-3-hexynyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol

【CA登记号】

【分子式】C₁₈H₂₈O₂

【分子量】276.41912

【元素组成】C 78.21% H 10.21% O 11.58%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IX)

The tosylation of the primary alcohol of the hexahydroindenepropanol (I) with TsCl in pyridine gives the tosylate (II), which is treated with NaCN in DMSO to yield the butyronitrile (II). The reduction of (III) with diisobutylaluminum hydride in dichloromethane affords the butyraldehyde (IV), which is condensed with CBr4 by means of Zn in dichloromethane providing the 1,1-dibromo-1-pentene derivative (V). The dehydrobromination of (V) with n-BuLi in THF/hexane affords the 1-pentyne derivative (VI), which is treated with 1-(trimethylsilyl)imidazole to give the silyl ether (VII). The condensation of (VII) with acetone by means of n-BuLi in THF yields the 3-heptyn-2-ol derivative (VIII), which is desilylated with TBAF in THF affording the diol (IX). The oxidation of the secondary alcohol of (IX) with bipyridinium chlorochromate (BPCC) in dichloromethane provides the corresponding ketone (X), which is protected at the tertiary alcohol with 1-(trimethylsilyl)imidazole giving the silylated ketone (XI). The condensation of (XI) with the phosphorane (XII) by means of n-BuLi in THF yields the protected intermediate (XIII), which is finally deprotected with TBAF in THF.

参考文献中间体

合成目标

【1】 Baggiolini, E.G.; Hennessy, B.M.; Shiuey, S.-J.; Truitt, G.A.; Uskokovic, M.R. (F. Hoffmann-La Roche AG); Dehydrocholecalciferol derivs.. AU 8928644; EP 0325279; JP 1990009861; US 5087619 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	38682	(3aS,7S,7aR)-3-[(1S)-2-hydroxy-1-methylethyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol	C₁₃H₂₂O₂	详情	详情
(II)	38683	(2S)-2-[(3aS,7S,7aR)-7-hydroxy-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]propyl 4-methylbenzenesulfonate	C₂₀H₂₈O₄S	详情	详情
(III)	38684	(3R)-3-[(3aS,7S,7aR)-7-hydroxy-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]butanenitrile	C₁₄H₂₁NO	详情	详情
(IV)	38685	(3R)-3-[(3aS,7S,7aR)-7-hydroxy-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]butanal	C₁₄H₂₂O₂	详情	详情
(V)	38686	(3aS,7S,7aR)-3-[(1R)-4,4-dibromo-1-methyl-3-butenyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol	C₁₅H₂₂Br₂O	详情	详情
(VI)	38687	(3aS,7S,7aR)-3a-methyl-3-[(1R)-1-methyl-3-butynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol	C₁₅H₂₂O	详情	详情
(VII)	38688	(3aS,7S,7aR)-3a-methyl-3-[(1R)-1-methyl-3-butynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl trimethylsilyl ether; ([(3aS,7S,7aR)-3a-methyl-3-[(1R)-1-methyl-3-butynyl]-3a,4,5,6,7,7a-hexahydro-1H-inden-7-yl]oxy)(trimethyl)silane	C₁₈H₃₀OSi	详情	详情
(VIII)	38689	(6R)-6-[(3aS,7S,7aR)-3a-methyl-7-[(trimethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-2-methyl-3-heptyn-2-ol	C₂₁H₃₆O₂Si	详情	详情
(IX)	38690	(3aS,7S,7aR)-3-[(1R)-5-hydroxy-1,5-dimethyl-3-hexynyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol	C₁₈H₂₈O₂	详情	详情
(X)	38691	(3aR,7aS)-1-[(1R)-5-hydroxy-1,5-dimethyl-3-hexynyl]-7a-methyl-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one	C₁₈H₂₆O₂	详情	详情
(XI)	38692	(3aR,7aS)-1-[(1R)-1,5-dimethyl-5-[(trimethylsilyl)oxy]-3-hexynyl]-7a-methyl-3,3a,5,6,7,7a-hexahydro-4H-inden-4-one	C₂₁H₃₄O₂Si	详情	详情
(XII)	38693	[2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](diphenyl)phosphine; tert-butyl(dimethyl)silyl (1R,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-[(E)-2-(diphenylphosphino)ethylidene]-4-methylenecyclohexyl ether	C₃₃H₅₁O₂PSi₂	详情	详情
(XIII)	38694	(5R)-5-[(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]-1,1-dimethyl-2-hexynyl trimethylsilyl ether; [((5R)-5-[(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]-1,1-dimethyl-2-hexynyl)oxy](trimethyl)silane	C₄₂H₇₄O₃Si₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Alternatively, the intermediate diol (IX) has been obtained as follows: The condensation of perhydroindene derivative (XIV) with the acetylenic aldehyde (XV) by means of Me3AlCl gives the acetylenic alcohol (XVI), which is esterified to the formate (XVII) or the carbonate (XVIII). The deoxygenation of (XVII) or (XVIII) by means of Pd(acac)2 and P(CH3)3 in hot toluene affords the silylated diol (XIX), which is submitted to desilylation with TBAF to afford the target diol intermediate (IX).

参考文献中间体

合成目标

【1】 Radinov, R.; Hutchings, S.D.; Selective palladium-catalyzed hydrogenolysis of a secondary propargylic alcohol in the synthesis of vitamin D analog Ro 23-7553: Substrate and ligand control. Tetrahedron Lett 1999, 40, 51, 8955.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	38690	(3aS,7S,7aR)-3-[(1R)-5-hydroxy-1,5-dimethyl-3-hexynyl]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H-inden-7-ol	C₁₈H₂₈O₂	详情	详情
(XIV)	38695	(3aR,4S,7aS)-1-[(Z)ethylidene]-7a-methyloctahydro-1H-inden-4-yl trimethylsilyl ether; ([(3aR,4S,7aS)-1-[(Z)ethylidene]-7a-methyloctahydro-1H-inden-4-yl]oxy)(trimethyl)silane	C₁₅H₂₈OSi	详情	详情
(XV)	38696	4-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-2-pentynal	C₁₂H₂₂O₂Si	详情	详情
(XVI)	38697	(2S)-2-[(3aS,7S,7aR)-3a-methyl-7-[(trimethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-6-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-4-heptyn-3-ol	C₂₇H₅₀O₃Si₂	详情	详情
(XVII)	38698	1-((1S)-1-[(3aS,7S,7aR)-3a-methyl-7-[(trimethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]ethyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-2-pentynyl formate	C₂₈H₅₀O₄Si₂	详情	详情
(XVIII)	38699	1-((1S)-1-[(3aS,7S,7aR)-3a-methyl-7-[(trimethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]ethyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-2-pentynyl methyl carbonate	C₂₉H₅₂O₅Si₂	详情	详情
(XIX)	38700	[((5R)-5-[(3aS,7S,7aR)-3a-methyl-7-[(trimethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-1,1-dimethyl-2-hexynyl)oxy](tert-butyl)dimethylsilane; (5R)-5-[(3aS,7S,7aR)-3a-methyl-7-[(trimethylsilyl)oxy]-3a,4,5,6,7,7a-hexahydro-1H-inden-3-yl]-1,1-dimethyl-2-hexynyl tert-butyl(dimethyl)silyl ether	C₂₇H₅₀O₂Si₂	详情	详情

Extended Information