【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% |
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 |