(1R,2R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol -Drug Synthesis Database

【结构式】

【分子编号】46585

【品名】(1R,2R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol

【CA登记号】

【分子式】C₂₇H₄₂O₄

【分子量】430.62808

【元素组成】C 75.31% H 9.83% O 14.86%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(XLII)

Reaction of 3-methoxybenzyl alcohol (XXIX) with TBDMS-Cl and imidazole in dichloromethane gives the silyl ether (XXX), which is condensed with allyl bromide (XXXI) by means of BuLi in hexane to yield the 2-allyl derivative (XXXII). Deprotection of (XXXII) by means of TBAF in THF affords the benzyl alcohol (XXXIII), which is oxidized with oxalyl chloride and TEA in DMSO/dichloromethane to provide 2-allyl-3-methoxybenzaldehyde (XXXIV). Condensation of compound (XXXIV) with the chiral 1-decyne (XXXV) by means of ethylmagnesium bromide in THF gives the secondary alcohol (XXXVI), which is oxidized with pyridinium chlorochromate (PCC) in dichloromethane yielding ketone (XXXVII). The enantioselective reduction of ketone (XXXVII) by means of trimethylboroxine (TMBO), BH3/Me2S and (R)-(2-pyrrolidinyl)diphenylmethanol in toluene affords the chiral secondary alcohol (XXXVIII) as a single diastereomer. Silylation of alcohol (XXXVIII) with TBDMS-Cl and imidazole yields the corresponding ether (XXXIX), which is submitted to cyclization catalyzed by Co2(CO)8 in refluxing acetonitrile affording the tricyclic ketone (XL). Hydrogenation of the conjugated double bond of (XL) with H2 over Pd/C in ethanol provides the saturated ketone (XLI), which is reduced with NaBH4 in ethanol to give the tricyclic alcohol (XLII). Elimination of the tetrahydropyranyl-protecting group of (XLII) with p-toluensulfonic acid in methanol provides diol (XXV) already described.

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Castaner, J.; Rabasseda, X.; UT-15. Drugs Fut 2001, 26, 4, 364.
【2】 Rao, M.S.; Staszewski, J.P.; Guo, L.; Penmasta, R.; Moriarty, R.M. (United Therapeutics Corp.); Process for stereoselective synthesis of prostacyclin derivs.. WO 9921830 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	20632	diphenyl[(2R)pyrrolidinyl]methanol		C₁₇H₁₉NO	详情	详情
(XXV)	46571	(1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol		C₂₂H₃₄O₃	详情	详情
(XXIX)	46574	3-Anisylalcohol; (3-methoxyphenyl)methanol; m-Anisyl alcohol; m-methoxybenzyl alcohol; 3-Anisic alcohol; 3-Anise Alcohol; 3-methoxybenzyl alcohol; 3-methoxybenzene methanol	6971-51-3	C₈H₁₀O₂	详情	详情
(XXX)	46575	tert-butyl(dimethyl)silyl 3-methoxybenzyl ether; tert-butyl[(3-methoxybenzyl)oxy]dimethylsilane		C₁₄H₂₄O₂Si	详情	详情
(XXXI)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(XXXII)	46576	2-allyl-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl methyl ether; [(2-allyl-3-methoxybenzyl)oxy](tert-butyl)dimethylsilane		C₁₇H₂₈O₂Si	详情	详情
(XXXIII)	46577	(2-allyl-3-methoxyphenyl)methanol		C₁₁H₁₄O₂	详情	详情
(XXXIV)	46578	2-allyl-3-methoxybenzaldehyde		C₁₁H₁₂O₂	详情	详情
(XXXV)	46579	(1S)-1-pentyl-4-pentynyl tetrahydro-2H-pyran-2-yl ether; 2-[[(1S)-1-pentyl-4-pentynyl]oxy]tetrahydro-2H-pyran		C₁₅H₂₆O₂	详情	详情
(XXXVI)	46580	(6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-ol		C₂₆H₃₈O₄	详情	详情
(XXXVII)	46581	(6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-one		C₂₆H₃₆O₄	详情	详情
(XXXVIII)	46582	(1S,6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-ol		C₂₆H₃₈O₄	详情	详情
(XXXIX)	46583	[[(1S,6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecynyl]oxy](tert-butyl)dimethylsilane; 2-allyl-3-[(1S,6S)-1-[[tert-butyl(dimethyl)silyl]oxy]-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecynyl]phenyl methyl ether		C₃₂H₅₂O₄Si	详情	详情
(XL)	46584	(4R,9aS)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-methoxy-3-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,4,9,9a-tetrahydro-2H-cyclopenta[b]naphthalen-2-one		C₃₃H₅₂O₅Si	详情	详情
(XLI)	46570	(1R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,3,3a,4,9,9a-hexahydro-2H-cyclopenta[b]naphthalen-2-one		C₂₇H₄₀O₄	详情	详情
(XLII)	46585	(1R,2R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol		C₂₇H₄₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIII)

参考文献中间体

合成目标

【1】 Moriarty RM, Rani N, Enache LA, et aL. 2004. The intramolecular asymmetric pauson-khand cyclization as a novel and general stereoselective route to benzindene prostaclrclins: synthesis of UT-15(Treprostinil). J Org Chcm, 69 (6): 1890～1902

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)	46574	3-Anisylalcohol; (3-methoxyphenyl)methanol; m-Anisyl alcohol; m-methoxybenzyl alcohol; 3-Anisic alcohol; 3-Anise Alcohol; 3-methoxybenzyl alcohol; 3-methoxybenzene methanol	6971-51-3	C₈H₁₀O₂	详情	详情
(II)	46575	tert-butyl(dimethyl)silyl 3-methoxybenzyl ether; tert-butyl[(3-methoxybenzyl)oxy]dimethylsilane		C₁₄H₂₄O₂Si	详情	详情
(III)	46576	2-allyl-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl methyl ether; [(2-allyl-3-methoxybenzyl)oxy](tert-butyl)dimethylsilane		C₁₇H₂₈O₂Si	详情	详情
(IV)	46577	(2-allyl-3-methoxyphenyl)methanol		C₁₁H₁₄O₂	详情	详情
(V)	46578	2-allyl-3-methoxybenzaldehyde		C₁₁H₁₂O₂	详情	详情
(VI)	46579	(1S)-1-pentyl-4-pentynyl tetrahydro-2H-pyran-2-yl ether; 2-[[(1S)-1-pentyl-4-pentynyl]oxy]tetrahydro-2H-pyran		C₁₅H₂₆O₂	详情	详情
(VII)	46580	(6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-ol		C₂₆H₃₈O₄	详情	详情
(VIII)	46581	(6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-one		C₂₆H₃₆O₄	详情	详情
(IX)	46582	(1S,6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-ol		C₂₆H₃₈O₄	详情	详情
(X)	46583	[[(1S,6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecynyl]oxy](tert-butyl)dimethylsilane; 2-allyl-3-[(1S,6S)-1-[[tert-butyl(dimethyl)silyl]oxy]-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecynyl]phenyl methyl ether		C₃₂H₅₂O₄Si	详情	详情
(XI)	46584	(4R,9aS)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-methoxy-3-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,4,9,9a-tetrahydro-2H-cyclopenta[b]naphthalen-2-one		C₃₃H₅₂O₅Si	详情	详情
(XII)	46570	(1R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,3,3a,4,9,9a-hexahydro-2H-cyclopenta[b]naphthalen-2-one		C₂₇H₄₀O₄	详情	详情
(XIII)	46585	(1R,2R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol		C₂₇H₄₂O₄	详情	详情
(XIV)	46571	(1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol		C₂₂H₃₄O₃	详情	详情
(XV)	46572	(1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol		C₂₁H₃₂O₃	详情	详情
(XVI)	46573	2-([(1R,2R,3aS,9aS)-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl]oxy)acetonitrile		C₂₃H₃₃NO₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XII)

参考文献中间体

合成目标

【1】 Moriarty RM, Penmasta R. Guo L et al. 2002. Process for stereoselective synthesis of prostacyclin derivatives. US 6441245(本专利属于United Thenpeutics Corporation, USA)

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	46575	tert-butyl(dimethyl)silyl 3-methoxybenzyl ether; tert-butyl[(3-methoxybenzyl)oxy]dimethylsilane		C₁₄H₂₄O₂Si	详情	详情
(I)	46574	3-Anisylalcohol; (3-methoxyphenyl)methanol; m-Anisyl alcohol; m-methoxybenzyl alcohol; 3-Anisic alcohol; 3-Anise Alcohol; 3-methoxybenzyl alcohol; 3-methoxybenzene methanol	6971-51-3	C₈H₁₀O₂	详情	详情
(III)	46576	2-allyl-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl methyl ether; [(2-allyl-3-methoxybenzyl)oxy](tert-butyl)dimethylsilane		C₁₇H₂₈O₂Si	详情	详情
(IV)	46577	(2-allyl-3-methoxyphenyl)methanol		C₁₁H₁₄O₂	详情	详情
(V)	46578	2-allyl-3-methoxybenzaldehyde		C₁₁H₁₂O₂	详情	详情
(VI)	46579	(1S)-1-pentyl-4-pentynyl tetrahydro-2H-pyran-2-yl ether; 2-[[(1S)-1-pentyl-4-pentynyl]oxy]tetrahydro-2H-pyran		C₁₅H₂₆O₂	详情	详情
(VII)	46580	(6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-ol		C₂₆H₃₈O₄	详情	详情
(VIII)	46581	(6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-one		C₂₆H₃₆O₄	详情	详情
(IX)	46582	(1S,6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-ol		C₂₆H₃₈O₄	详情	详情
(X)	46583	[[(1S,6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecynyl]oxy](tert-butyl)dimethylsilane; 2-allyl-3-[(1S,6S)-1-[[tert-butyl(dimethyl)silyl]oxy]-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecynyl]phenyl methyl ether		C₃₂H₅₂O₄Si	详情	详情
(XI)	46584	(4R,9aS)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-methoxy-3-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,4,9,9a-tetrahydro-2H-cyclopenta[b]naphthalen-2-one		C₃₃H₅₂O₅Si	详情	详情
(XII)	46585	(1R,2R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol		C₂₇H₄₂O₄	详情	详情
(XIII)	46585	(1R,2R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol		C₂₇H₄₂O₄	详情	详情
(XIV)	46571	(1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol		C₂₂H₃₄O₃	详情	详情
(XV)	46572	(1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol		C₂₁H₃₂O₃	详情	详情
(XVI)	46573	2-([(1R,2R,3aS,9aS)-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl]oxy)acetonitrile		C₂₃H₃₃NO₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XIII)

参考文献中间体

合成目标

【1】 Moriarty RM, Penmasta R. Guo L et al. 2002. Process for stereoselective synthesis of prostacyclin derivatives. US 6441245(本专利属于United Thenpeutics Corporation, USA)

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	46575	tert-butyl(dimethyl)silyl 3-methoxybenzyl ether; tert-butyl[(3-methoxybenzyl)oxy]dimethylsilane		C₁₄H₂₄O₂Si	详情	详情
(I)	46574	3-Anisylalcohol; (3-methoxyphenyl)methanol; m-Anisyl alcohol; m-methoxybenzyl alcohol; 3-Anisic alcohol; 3-Anise Alcohol; 3-methoxybenzyl alcohol; 3-methoxybenzene methanol	6971-51-3	C₈H₁₀O₂	详情	详情
(III)	46576	2-allyl-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl methyl ether; [(2-allyl-3-methoxybenzyl)oxy](tert-butyl)dimethylsilane		C₁₇H₂₈O₂Si	详情	详情
(IV)	46577	(2-allyl-3-methoxyphenyl)methanol		C₁₁H₁₄O₂	详情	详情
(V)	46578	2-allyl-3-methoxybenzaldehyde		C₁₁H₁₂O₂	详情	详情
(VI)	46579	(1S)-1-pentyl-4-pentynyl tetrahydro-2H-pyran-2-yl ether; 2-[[(1S)-1-pentyl-4-pentynyl]oxy]tetrahydro-2H-pyran		C₁₅H₂₆O₂	详情	详情
(VII)	46580	(6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-ol		C₂₆H₃₈O₄	详情	详情
(VIII)	46581	(6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-one		C₂₆H₃₆O₄	详情	详情
(IX)	46582	(1S,6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-ol		C₂₆H₃₈O₄	详情	详情
(X)	46583	[[(1S,6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecynyl]oxy](tert-butyl)dimethylsilane; 2-allyl-3-[(1S,6S)-1-[[tert-butyl(dimethyl)silyl]oxy]-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecynyl]phenyl methyl ether		C₃₂H₅₂O₄Si	详情	详情
(XI)	46584	(4R,9aS)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-methoxy-3-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,4,9,9a-tetrahydro-2H-cyclopenta[b]naphthalen-2-one		C₃₃H₅₂O₅Si	详情	详情
(XII)	46585	(1R,2R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol		C₂₇H₄₂O₄	详情	详情
(XIII)	46585	(1R,2R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol		C₂₇H₄₂O₄	详情	详情
(XIV)	46571	(1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol		C₂₂H₃₄O₃	详情	详情
(XV)	46572	(1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol		C₂₁H₃₂O₃	详情	详情
(XVI)	46573	2-([(1R,2R,3aS,9aS)-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl]oxy)acetonitrile		C₂₃H₃₃NO₃	详情	详情

Extended Information