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【结 构 式】

【分子编号】46582

【品名】(1S,6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-ol

【CA登记号】

【 分 子 式 】C26H38O4

【 分 子 量 】414.58532

【元素组成】C 75.32% H 9.24% O 15.44%

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:(XXXVIII)

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.

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:(IX)

 

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:(IX)

 

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