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【结 构 式】

【分子编号】46572

【品名】(1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol

【CA登记号】

【 分 子 式 】C21H32O3

【 分 子 量 】332.48328

【元素组成】C 75.86% H 9.7% O 14.44%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(XXVI)

The reduction of 2-octyn-1-ol (XII) with bis(2-methoxyethoxy)aluminum hydride in toluene/THF gives 2-octen-1-ol (XIII), which is treated with tert-butyl hydroperoxide, (+)-diethyl L-tartrate and titanium tetraisopropoxide in dichloromethane yielding epoxide (XIV). The latter is reduced with bis(2-ethoxyethoxy)aluminum hydride in toluene/THF, affording the chiral diol (XV). The selective monotosylation of (XV) with TsCl in pyridine provides the primary tosylate (XVI), which is treated with NaI in hot acetone to furnish 1-iodo-3-octanol (XVII). Protection of (XVII) with dihydropyran and pyridine hydrochloride gives the tetrahydropyranyl ether (XVIII), which is condensed with dimethyl methylphosphonate (XIX) by means of BuLi and TEA in THF to yield the phosphonate (XX). Condensation of compound (XX) with 5-methoxy-2,3,3a,4-tetrahydronaphtho[2,3-b]furan-2-one (XXI) by means of BuLi in THF affords the tricyclic adduct (XXII), which is hydrogenated with H2 over Pd/C in ethanol to provide compound (XXIII). Isomerization of (XXIII) with NaOH in refluxing ethanol gives diastereomer (XXIV). The reduction of the carbonyl group of (XXIV) with NaBH4 in methanol, followed by deprotection with HOAc in THF yields compound (XXV). The demethylation of compound (XXV) by means of BuLi and Ph2PH in THF affords the tricyclic phenol (XXVI), which is condensed with 2-chloroacetonitrile (XXVII) by means of K2CO3 in refluxing acetone to provide the precursor (XXVIII). Finally, the cyano group of (XXVIII) is hydrolyzed with KOH in refluxing water.

1 Sorbera, L.A.; Castaner, J.; Rabasseda, X.; UT-15. Drugs Fut 2001, 26, 4, 364.
2 Aristoff, P.A. (Pharmacia Corp.); Carbacyclin analogues. EP 0159784; JP 1985208936; US 4683330 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 46559 2-octyn-1-ol C8H14O 详情 详情
(XIII) 46560 (E)-2-octen-1-ol C8H16O 详情 详情
(XIV) 46561 [(2R,3S)-3-pentyloxiranyl]methanol C8H16O2 详情 详情
(XV) 46562 (3S)-1,3-octanediol C8H18O2 详情 详情
(XVI) 46563 (3S)-3-hydroxyoctyl 4-methylbenzenesulfonate C15H24O4S 详情 详情
(XVII) 46564 (3S)-1-iodo-3-octanol C8H17IO 详情 详情
(XVIII) 46565 (1S)-1-(2-iodoethyl)hexyl tetrahydro-2H-pyran-2-yl ether; 2-[[(1S)-1-(2-iodoethyl)hexyl]oxy]tetrahydro-2H-pyran C13H25IO2 详情 详情
(XIX) 13067 ethyl 5,6-difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylate C15H9F2NO4S 详情 详情
(XX) 46566 dimethyl (4S)-4-(tetrahydro-2H-pyran-2-yloxy)nonylphosphonate C16H33O5P 详情 详情
(XXI) 46567 (3aS)-5-methoxy-3a,4-dihydronaphtho[2,3-b]furan-2(3H)-one C13H12O3 详情 详情
(XXII) 46568 (9aS)-8-methoxy-3-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,4,9,9a-tetrahydro-2H-cyclopenta[b]naphthalen-2-one C27H38O4 详情 详情
(XXIII) 46569 (1S,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
(XXIV) 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
(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
(XXVI) 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
(XXVII) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(XXVIII) 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2

该中间体在本合成路线中的序号:(XV)

 

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:(XV)

 

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