(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-pentanol -Drug Synthesis Database

【结构式】

【分子编号】53689

【品名】(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-pentanol

【CA登记号】n/a

【分子式】C₂₉H₄₈O₃

【分子量】444.69832

【元素组成】C 78.33% H 10.88% O 10.79%

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：(III)

Protection of 3-beta-hydroxy-5-cholenic acid (I) with 2,3-dihydropyran in the presence of pyridinium p-toluenesulfonate provided the bis-tetrahydropyranyl derivative (II). Reduction of the tetrahydropyranyl ester group of (II) with LiAlH4 gave alcohol (III), which was further oxidized to aldehyde (IV) under Swern conditions. Addition of isopropylmagnesium bromide to the aldehyde (IV) yielded the secondary alcohol (V). After silylation of alcohol (V) with t-butyldimethylsilyl chloride and imidazole to (VI), the tetrahydropyranyl protecting group was removed under acidic conditions to afford alcohol (VII). This was further esterified with Ac2O in pyridine to provide acetate ester (VIII).

参考文献中间体

合成目标

【1】 Moriarty, R.M.; et al.; Synthesis of squalamine. A steroidal antibiotic from the shark. Tetrahedron Lett 1994, 35, 44, 8103.
【2】 Pechulis, A.D.; et al.; Synthesis of 24xi-squalamine, an anti-infective steroidal polyamine. J Org Chem 1995, 60, 16, 5121.
【3】 Moriarty, R.M.; Guo, L.; Tuladhar, S.M. (Genaera Corp.); Chemical synthesis of squalamine. WO 9419366 .

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)	53687	5-Cholenic acid-3beta-ol; 3beta-Hydroxy-5-cholen-24-oic acid	5255-17-4	C₂₄H₃₈O₃	详情	详情
(II)	53688	tetrahydro-2H-pyran-2-yl (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate	n/a	C₃₄H₅₄O₅	详情	详情
(III)	53689	(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-pentanol	n/a	C₂₉H₄₈O₃	详情	详情
(IV)	53690	(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanal	n/a	C₂₉H₄₆O₃	详情	详情
(V)	53691	(6R)-6-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-3-heptanol	n/a	C₃₂H₅₄O₃	详情	详情
(VI)	53692	tert-butyl(dimethyl)silyl (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl ether; tert-butyl({(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl}oxy)dimethylsilane	n/a	C₃₈H₆₈O₃Si	详情	详情
(VII)	53693	(3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol	n/a	C₃₃H₆₀O₂Si	详情	详情
(VIII)	53694	(3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1,5-dimethylhexyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate	n/a	C₃₅H₆₂O₃Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

In a different method, protection of alcohol (III) as the tert-butyldimethylsilyl ether (XXX), followed by allylic oxidation by means of CrO3 in the presence of 3,5-dimethylpyrazole (DMP), gave enone (XXXI). Hydrogenation of (XXXI) using Adams catalyst resulted in the formation of the saturated ketone (XXXII). Some undesired 7-beta alcohol byproduct was reoxidized to ketone (XXXII) by means of Collin's reagent. Stereoselective reduction of ketone (XXXII) with K-Selectride afforded the 7-alpha alcohol (XXXIII), which was protected as the benzyl ether (XXXIV) by treatment with benzyl bromide and NaH. After desilylation of (XXXIV) with Bu4NF, the deprotected alcohol was subjected to Swern oxidation to provide aldehyde (XXXV). Addition of isopropylmagnesium chloride to aldehyde (XXXV) gave alcohol (XXXVI) as a mixture of epimers.

参考文献中间体

合成目标

【1】 Pechulis, A.D.; et al.; Synthesis of 24xi-squalamine, an anti-infective steroidal polyamine. J Org Chem 1995, 60, 16, 5121.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	53689	(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-pentanol	n/a	C₂₉H₄₈O₃	详情	详情
(XXX)	53714	tert-butyl(dimethyl)silyl (4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentyl ether; tert-butyl({(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentyl}oxy)dimethylsilane	n/a	C₃₅H₆₂O₃Si	详情	详情
(XXXI)	53715	(3S,8S,9S,10R,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-methylbutyl)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4,8,9,10,11,12,13,14,15,16,17-tetradecahydro-7H-cyclopenta[a]phenanthren-7-one	n/a	C₃₅H₆₀O₄Si	详情	详情
(XXXII)	53716	(3S,5R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-methylbutyl)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-7H-cyclopenta[a]phenanthren-7-one	n/a	C₃₅H₆₂O₄Si	详情	详情
(XXXIII)	53717	(3S,5S,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-methylbutyl)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-7-ol	n/a	C₃₅H₆₄O₄Si	详情	详情
(XXXIV)	53718	benzyl (3S,5S,7R,8R,9S,10S,13R,14S,17R)-17-((1R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-methylbutyl)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-7-yl ether; ({(4R)-4-[(3S,5S,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentyl}oxy)(tert-butyl)dimethylsilane	n/a	C₄₂H₇₀O₄Si	详情	详情
(XXXV)	53719	(4R)-4-[(3S,5S,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanal	n/a	C₃₆H₅₄O₄	详情	详情
(XXXVI)	53720	(6R)-6-[(3S,5S,7R,8R,9S,10S,13R,14S,17R)-7-(benzyloxy)-10,13-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-3-heptanol	n/a	C₃₉H₆₂O₄	详情	详情

Extended Information