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【结 构 式】

【分子编号】13768

【品名】methyl 5-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate

【CA登记号】

【 分 子 式 】C27H48O5Si

【 分 子 量 】480.76062

【元素组成】C 67.45% H 10.06% O 16.64% Si 5.84%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XLV)

4) The protection of the bicyclic lactone (XXVIII) with dihydropyran and PPTS in THF gives the bistetrahydropyranyl ether (XXIX), which is reduced with DIBAL in THF to the lactol (XXX). The reaction of (XXX) with bromomagnesium acetylide in THF yields (XXXI), which is selectively benzoylated with benzoyl chloride and pyridine affording the monobenzoyl ester (XXXII). The silylation of the secondary hydroxy group of (XXXII) with TBDMS-Cl and imidazole in THF gives the fully protected compound (XXXIII), which is treated with KOH in methanol in order to eliminate the benzoyl group, yielding the hydroxymethyl derivative (XXXIV). The reaction of (XXXIV) with mesyl chloride and triethylamine in dichloromethane affords the mesylate (XXXV), which is cyclized by means of NaI, AIBN and tributyltin hydride in hot glyme giving the bicyclo[3.3.0]octane (XXXVI). The desilylation of (XXXVI) with TBAF and triethylamine in THF yields compound (XXXVII) with a secondary hydroxy group, which is acetylated with acetic anhydride to the acetate (XXXVIII). The condensation of (XXXVIII) with the copper derivative (XXXIX) affords the silylated pentanol derivative (XL), which is deprotected with TBAF and triethylamine in THF to the free pentanol derivative (XLI). The oxidation of (XLI) with SO3/Pyr in DMSO gives the corresponding aldehyde (XLII), which is further oxidized with Ag2O and NaOH in ethanol, and esterified with diazomethane yielding the methyl ester (XLIII). The deprotection of (XLIII) with PPTS in methanol, followed by selective silylation of the primary alcohol with TBDMS-Cl affords the monosilylated compound (XLIV), which is treated with dihydropyran and PPTS in order to protect the secondary hydroxy group yielding (XLV). The desilylation of (XLV) with TBAF, followed by oxidation of the primary alcohol with SO3/Pyr gives the corresponding aldehyde (XLVI), which is condensed with the previously described phosphonate (XV) by means of NaH in glyme affording the ketonic prostacycline (XLVII). Finally, this compound is deprotected with PPTS in methanol and reduced with diisobutylaluminum 2,6-di-tert-butylphenolate giving a mixture of diastereomers that is separated by column chromatography.

1 Hemmerle, H.; Gais, H.-J.; Flexible synthesen optisch aktiver isocarbacycline. Angew Chem 1989, 101, 362-5.
2 Graul, A.; Leeson, P.; Castaner, J.; Clinprost. Drugs Fut 1997, 22, 6, 608.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
51602 1-Propyne C3H4 详情 详情
(XV) 13738 dimethyl 2-oxoheptylphosphonate; Dimethyl (2-oxoheptyl)phosphonate 36969-89-8 C9H19O4P 详情 详情
(XXVIII) 13751 (3aR,4S,5R,6aS)-5-Hydroxy-4-(hydroxymethyl)hexahydro-1H-cyclopenta[c]furan-1-one C8H12O4 详情 详情
(XXIX) 13752 (3aR,4S,5R,6aS)-4-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-1H-cyclopenta[c]furan-1-one C20H32O6 详情 详情
(XXX) 13753 (1S,3aR,4R,5R,6aS)-4-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-1H-cyclopenta[c]furan-1-ol C20H34O6 详情 详情
(XXXI) 13754 (1R)-1-[(1S,2R,3R,4R)-2-(Hydroxymethyl)-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-2-propyn-1-ol C22H36O6 详情 详情
(XXXII) 13755 [(1R,2S,3R,5S)-5-[(1R)-1-hydroxy-2-propynyl]-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]methyl benzoate C29H40O7 详情 详情
(XXXIII) 13756 [(1R,2S,3R,5S)-5-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]methyl benzoate C35H54O7Si 详情 详情
(XXXIV) 13757 [(1R,2R,3R,5S)-5-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]-2-propynyl)-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]methanol C28H50O6Si 详情 详情
(XXXV) 13758 [(1R,2S,3R,5S)-5-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]methyl methanesulfonate C29H52O8SSi 详情 详情
(XXXVI) 13759 [(1R,2R,3aS,4R,6aR)-4-[[tert-Butyl(dimethyl)silyl]oxy]-5-methylene-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]octahydro-2-pentalenyl]methyl tetrahydro-2H-pyran-2-yl ether; ([(1R,3aR,4R,5R,6aS)-2-Methylene-4-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-1-pentalenyl]oxy)(tert-butyl)dimethylsilane C28H50O5Si 详情 详情
(XXXVII) 13760 (1R,3aR,4R,5R,6aS)-2-Methylene-4-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-1-pentalenol C22H36O5 详情 详情
(XXXVIII) 13761 (1R,3aR,4R,5R,6aS)-2-methylene-4-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-1-pentalenyl acetate C24H38O6 详情 详情
(XXXIX) 13762 Bis[4-(tert-butyldimethylsilyloxy)butyl] coppermagnesium chloride C21H48O2Si2 详情 详情
(XL) 13763 [(2R,3R,3aS,6aS)-5-(5-[[tert-Butyl(dimethyl)silyl]oxy]pentyl)-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,2,3,3a,4,6a-hexahydro-2-pentalenyl]methyl tetrahydro-2H-pyran-2-yl ether C32H58O5Si 详情 详情
(XLI) 13764 5-[(3aS,5R,6R,6aS)-6-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]-1-pentanol C26H44O5 详情 详情
(XLII) 13765 5-[(3aS,5R,6R,6aS)-6-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanal C26H42O5 详情 详情
(XLIII) 13766 methyl 5-[(3aS,5R,6R,6aS)-6-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate C27H44O6 详情 详情
(XLIV) 13767 methyl 5-[(3aS,5R,6S,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxy-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate C21H38O4Si 详情 详情
(XLV) 13768 methyl 5-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate C27H48O5Si 详情 详情
(XLVI) 13769 methyl 5-[(3aS,5R,6R,6aS)-6-formyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate C21H32O5 详情 详情
(XLVII) 13770 methyl 5-[(3aS,5R,6S,6aS)-6-[(E)-3-oxo-1-octenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate C28H44O5 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XLV)

5) The unsaturated pentanoic acid methyl ester derivative (XLV) obtained in scheme 16133803a can also be obtained as follows: The reaction of lactol (II) with methyltriphenylphosphonium bromide and t-BuOK in THF, followed by oxidation with PCC in dichloromethane gives the allyl ketone (XLVIII), which is methylenated with Zn/CH2Br2/TiCl4 to yield compound (XLIX). The reaction of (XLIX) with disiamylborane (DSB) and H2O2 hydroxylates the two double bonds, affording compound (L) with two primary hydroxy groups, which are oxidized with oxalyl chloride to the corresponding (LI) with two aldehyde groups. This compound cyclizes to the bicyclic hydroxyaldehyde (LII), which is dehydrated with dibenzylammonium trifluoroacetate to the unsaturated bicyclic aldehyde (LIII). The condensation of (LIII) with 3-carboxypropyltriphenylphosphonium bromide (LIV) by means of t-BuOK in THF followed by methylation with diazomethane gives the bicyclic dienoic ester (LV), which is then selectively reduced to the previously described intermediate (XLV).

1 Sodeoka, M.; Shibasaki, M.; The highly potent carbon analog of prostacyclin. Chem Lett 1984, 4, 4, 579-82.
2 Graul, A.; Leeson, P.; Castaner, J.; Clinprost. Drugs Fut 1997, 22, 6, 608.
3 Shibasaki, M.; Mase, T.; Sodeoka, M.; Ogawa, Y. (Sagami Chemical Research Center); Bicyclo[3.3.0]octane deriv. and preparation thereof. EP 0134153 .
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) 13714 Methyl 5-chloro-2-hydroxybenzoate; Methyl 5-chlorosalicylate 4068-78-4 C8H7ClO3 详情 详情
(II) 13725 (3aR,4S,5R,6aS)-4-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol C20H38O5Si 详情 详情
(XLV) 13768 methyl 5-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate C27H48O5Si 详情 详情
(XLVIII) 13771 (2R,3S,4R)-2-Allyl-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentanone C21H38O4Si 详情 详情
(XLIX) 13772 [(1R,2R,3R)-3-Allyl-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenecyclopentyl]methyl tetrahydro-2H-pyran-2-yl ether; ([(1R,2R,5R)-2-Allyl-3-methylene-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]methoxy)(tert-butyl)dimethylsilane C22H40O3Si 详情 详情
(L) 13773 3-[(1S,2R,3R,5S)-2-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-(hydroxymethyl)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-1-propanol C22H44O5Si 详情 详情
(LI) 13774 (1S,2R,3R,4R)-3-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2-(3-oxopropyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentanecarbaldehyde C22H40O5Si 详情 详情
(LII) 13775 (1R,3aR,4R,5R,6aS)-4-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-1-hydroxy-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-2-pentalenecarbaldehyde C22H40O5Si 详情 详情
(LIII) 13776 (3aS,5R,6R,6aS)-6-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenecarbaldehyde C22H38O4Si 详情 详情
(LIV) 13777 (3-Carboxypropyl)phosphonium bromide C4H10BrO2P 详情 详情
(LV) 13778 methyl (Z)-5-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]-4-pentenoate C27H46O5Si 详情 详情
Extended Information