-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】(1S,3R,5Z,7E,13S,14S,17S,20S)-9,10-Secocholesta-5,7,10-triene-1,3,25-triol
　　　　　　(1S,13S,14S,17S,20S)-1,25-Dihydroxyvitamin D3

【CA登记号】

【分子式】C₂₇H₄₄O₃

【分子量】416.64993

【开发单位】Polish Academy of Science (Originator), Schering AG (Originator)

【药理作用】Bone Diseases, Treatment of, METABOLIC DRUGS, Treatment of Osteoporosis, Vitamin D Analogs

合成路线1 合成路线2

合成路线1

Asymmetric Robinson annulation of 2-methylcyclopentane-1,3-dione (II) with (phenylsulfanyl)methyl vinyl ketone (I) using R-(+)-phenylalanine as the catalyst afforded the chiral bicyclic dione (III). Oxidation of the sulfide group of (III) by means of m-chloroperbenzoic acid gave sulfone (IV). This was reduced with LiAlH4 to the trans-hydrindane derivative (V), which was further oxidized to ketone (VI) with Jones reagent. The indaneacetic ester (VII) was obtained by Horner-Emmons condensation of ketone (VI) with triethyl phosphonoacetate, followed by catalytic hydrogenation. Treatment of (VII) with bromide (VIII) in the presence of LDA provided an inseparable mixture (IX and X) of alkylated compounds at the alpha position of the ester and sulfone functions, respectively. Ester reduction of this mixture by means of DIBAL afforded the mixture of alcohols (XI) and (XII), which were separated by chromatography. The desired alcohol (XI) was reduced to the methyl derivative (XIII) via conversion to the corresponding mesylate, which was then reduced by treatment with lithium triethyl borohydride.

参考文献中间体

【1】 Marczak, S.; et al.; Synthesis and biological activity of the 1alpha,25-dihydroxyvitamin D3 diastereomer with unnatural configuration at the rings C/D side-chain moiety. Bioorg Med Chem Lett 2001, 11, 1, 63.

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)	47713	1-(phenylsulfanyl)-3-buten-2-one		C₁₀H₁₀OS	详情	详情
(II)	24232	2-methyl-1,3-cyclopentanedione	765-69-5	C₆H₈O₂	详情	详情
(III)	47714	(7aR)-7a-methyl-4-(phenylsulfanyl)-2,3,7,7a-tetrahydro-1H-indene-1,5(6H)-dione		C₁₆H₁₆O₂S	详情	详情
(IV)	47715	(7aR)-7a-methyl-4-(phenylsulfonyl)-2,3,7,7a-tetrahydro-1H-indene-1,5(6H)-dione		C₁₆H₁₆O₄S	详情	详情
(V)	47716	(3aS,4S,7aR)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-ol		C₁₆H₂₂O₃S	详情	详情
(VI)	47717	(3aS,4S,7aR)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-one		C₁₆H₂₀O₃S	详情	详情
(VII)	47718	ethyl 2-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]acetate		C₂₀H₂₈O₄S	详情	详情
(VIII)	47719	(4-bromo-1,1-dimethylbutoxy)(triethyl)silane; 4-bromo-1,1-dimethylbutyl triethylsilyl ether		C₁₂H₂₇BrOSi	详情	详情
(IX)	47720	ethyl (2S)-2-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-6-methyl-6-[(triethylsilyl)oxy]heptanoate		C₃₂H₅₄O₅SSi	详情	详情
(X)	47721	ethyl 2-[(1S,3aS,7aS)-7a-methyl-4-[4-methyl-4-[(triethylsilyl)oxy]pentyl]-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]acetate		C₃₂H₅₄O₅SSi	详情	详情
(XI)	47729	(2S)-2-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-6-methyl-6-[(triethylsilyl)oxy]-1-heptanol		C₃₀H₅₂O₄SSi	详情	详情
(XII)	47722	2-[(1S,3aS,7aS)-7a-methyl-4-[4-methyl-4-[(triethylsilyl)oxy]pentyl]-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-1-ethanol		C₃₀H₅₂O₄SSi	详情	详情
(XIII)	47723	(1S,3aS,4S,7aS)-1-[(1S)-1,5-dimethyl-5-[(triethylsilyl)oxy]hexyl]-7a-methyloctahydro-1H-inden-4-yl phenyl sulfone; ([(5S)-5-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-1,1-dimethylhexyl]oxy)(triethyl)silane		C₃₀H₅₂O₃SSi	详情	详情

合成路线2

The oxidation of the ring A precursor alcohol (XIV) with Dess-Martin reagent gave rise to a mixture of aldehyde (XV) and its cyclic tautomer, the pyran derivative (XVI). Coupling of this mixture with the lithium anion of sulfone (XIII), followed by quenching with acetyl chloride, furnished the target beta-acetoxy sulfone adduct (XVII) accompanied by the silyl-acetyl exchange product (XVIII). Reductive cleavage of the phenylsulfonyl group by means of sodium amalgam yielded the desired O-triethylsilyl triene (XIX) along with some O-acetyl byproduct. Finally, desilylation of (XIX) with tetrabutylammonium fluoride provided the title triol derivative, which was separated from its C-25 acetate byproduct by flash chromatography.

参考文献中间体

【1】 Marczak, S.; et al.; Synthesis and biological activity of the 1alpha,25-dihydroxyvitamin D3 diastereomer with unnatural configuration at the rings C/D side-chain moiety. Bioorg Med Chem Lett 2001, 11, 1, 63.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIII)	47723	(1S,3aS,4S,7aS)-1-[(1S)-1,5-dimethyl-5-[(triethylsilyl)oxy]hexyl]-7a-methyloctahydro-1H-inden-4-yl phenyl sulfone; ([(5S)-5-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-1,1-dimethylhexyl]oxy)(triethyl)silane	C₃₀H₅₂O₃SSi	详情	详情
(XIV)	47614	2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol	C₂₁H₄₂O₃Si₂	详情	详情
(XV)	47724	2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetaldehyde	C₂₁H₄₀O₃Si₂	详情	详情
(XVI)	47725	tert-butyl(dimethyl)silyl (6R,8S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5,6,7,8-tetrahydro-1H-isochromen-8-yl ether; tert-butyl[((6R,8S)-8-[[tert-butyl(dimethyl)silyl]oxy]-5,6,7,8-tetrahydro-1H-isochromen-6-yl)oxy]dimethylsilane	C₂₁H₄₀O₃Si₂	详情	详情
(XVII)	47726	1-[(1S,3aS,7aS)-1-[(1S)-1,5-dimethyl-5-[(triethylsilyl)oxy]hexyl]-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-4-yl]-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl acetate	C₅₃H₉₄O₇SSi₃	详情	详情
(XVIII)	47727	(5S)-5-[(1S,3aS,7aS)-4-[1-(acetoxy)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl]-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-1,1-dimethylhexyl acetate	C₄₉H₈₂O₈SSi₂	详情	详情
(XIX)	47728	(5S)-5-[(1S,3aS,7aS)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-4H-inden-1-yl]-1,1-dimethylhexyl triethylsilyl ether; [((1R,5S)-3-[(Z)-2-((1S,3aS,7aS)-1-[(1S)-1,5-dimethyl-5-[(triethylsilyl)oxy]hexyl]-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene]-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylenecyclohexyl)oxy](tert-butyl)dimethylsilane	C₄₅H₈₆O₃Si₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)