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【结 构 式】 
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【分子编号】51602 【品名】1-Propyne 【CA登记号】 |
【 分 子 式 】C3H4 【 分 子 量 】40.06476 【元素组成】C 89.94% H 10.06% |
合成路线1
该中间体在本合成路线中的序号：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：Racemic lometrexol has been prepared.
| 【1】 Harrington, P.M.; Shih, C.; Grindey, G.B.; Gossett, L.S.; Moran, R.G.; Taylor, S.C.; Synthesis and structure-activity relationship studies of 5,10-dideazatetrahydrofolic acid (DDATHF). Chemistry and Biology of Pteridines (1989): Pteridines and Folic Acid Derivatives. H.-C. Curtius, S. Ghisla and N. Blau (Eds.). de Gruyter, New York 1990, 1035. |
| 【2】 Taylor, E.C.; Wong, G.S.K.; Convergent and efficient palladium-effected synthesis of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF). J Org Chem 1989, 54, 15, 3618. |
| 【3】 Castaner, J.; Prous, J.; Lometrexol. Drugs Fut 1993, 18, 2, 121. |
| 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 | ||
| (I) | 14277 | 2,6-Diamino-4(3H)-pyrimidinone | C4H6N4O | 详情 | 详情 | |
| (II) | 14278 | 2-Bromomalonaldehyde | C3H3BrO2 | 详情 | 详情 | |
| (III) | 14279 | 2-Amino-6-bromopyrido[2,3-d]pyrimidin-4(3H)-one | C7H5BrN4O | 详情 | 详情 | |
| (IV) | 14280 | N-(6-Bromo-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide | C12H13BrN4O2 | 详情 | 详情 | |
| (V) | 14281 | 2,2-Dimethyl-N-[4-oxo-6-[2-(trimethylsilyl)ethynyl]-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]propanamide | C17H22N4O2Si | 详情 | 详情 | |
| (VI) | 14282 | N-(6-Ethynyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide | C14H14N4O2 | 详情 | 详情 | |
| (VII) | 14283 | diethyl (2S)-2-[(4-iodobenzoyl)amino]pentanedioate | C16H20INO5 | 详情 | 详情 | |
| (VIII) | 14284 | diethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl]ethynyl)benzoyl]amino]pentanedioate | C30H33N5O7 | 详情 | 详情 | |
| (IX) | 14285 | tert-butyl 4-ethynylbenzoate | C13H14O2 | 详情 | 详情 | |
| (X) | 14286 | tert-butyl 4-bromobenzoate | C11H13BrO2 | 详情 | 详情 | |
| (XI) | 14287 | diethyl (2S)-2-[(4-ethynylbenzoyl)amino]pentanedioate | C18H21NO5 | 详情 | 详情 | |
| (XII) | 14288 | tert-butyl 4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl]ethynyl)benzoate | C25H26N4O4 | 详情 | 详情 | |
| (XIII) | 14289 | 4-(2-[2-[(2,2-Dimethylpropanoyl)amino]-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl]ethynyl)benzoic acid | C21H18N4O4 | 详情 | 详情 | |
| (XIV) | 11013 | diethyl (2S)-2-aminopentanedioate | C9H17NO4 | 详情 | 详情 | |
| (XV) | 14291 | diethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl)benzoyl]amino]pentanedioate | C30H41N5O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The reaction of 4-methyl-4-penten-1-ol (I) with PBr3 gives the corresponding alkyl bromide (II), which is condensed with epoxide (III) and propyne (IV) by means of Mg, CuI and pentynyl lithium to yield, after silylation with Tbdms-Cl, the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by the Swern reagent to afford the ketone (VII). Alternatively, ketone (VII) can also be obtained by direct oxidation of the protected diol (V) with the Jones reagent. The Horner Emmons condensation of ketone (VII) with phosphonate (VIII) provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with the complex SO3/Pyr yields the carbaldehyde (XI). Alternatively, (XI) can also be obtained by direct oxidation of the terminal double bond of (IX) with (Ipc)2BH and pyridinium chlorochromate (PCC). The condensation of aldehyde (XI) with ketoacid (XII) by means of LDA in THF affords the heptadecadienoic acid (XIII), which is silylated with Tbdms-OTf to provide the protected linear precursor (XIV). The cyclization of (XIV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XV), which is desilylated by means of TBAF in THF to yield the unprotected precursor (XVI). Finally, this compound is epoxidated by means of dimethyldioxirane (DMDO) in acetone to afford the target epothilone B.
| 【1】 Avery, M.A. (University of Mississippi); Synthesis of epothilones and related analogs. WO 0230356 . |
| 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) | 54285 | 4-methyl-4-penten-1-ol | 22508-64-1 | C6H12O | 详情 | 详情 |
| (II) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (III) | 52578 | methyl 4-({[1-(2-oxiranyl)ethyl]oxy}methyl)phenyl ether; 2-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]oxirane | C2H5NS | 详情 | 详情 | |
| (IV) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (V) | 54286 | tert-butyl(dimethyl)silyl (1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl ether; tert-butyl[((1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl)oxy]dimethylsilane | n/a | C27H46O3Si | 详情 | 详情 |
| (VI) | 54287 | (2R,3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-6,10-dimethyl-5,10-undecadien-2-ol | n/a | C19H38O2Si | 详情 | 详情 |
| (VII) | 54288 | (3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-6,10-dimethyl-5,10-undecadien-2-one | n/a | C19H36O2Si | 详情 | 详情 |
| (VIII) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (IX) | 54289 | tert-butyl(dimethyl)silyl (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl ether; 4-((1E,3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,6,10-trimethyl-1,5,10-undecatrienyl)-2-methyl-1,3-thiazole | n/a | C24H41NOSSi | 详情 | 详情 |
| (X) | 40828 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol | C24H43NO2SSi | 详情 | 详情 | |
| (XI) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 | |
| (XII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XIII) | 46118 | (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C39H71NO6SSi2 | 详情 | 详情 | |
| (XIV) | 40834 | (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C45H85NO6SSi3 | 详情 | 详情 | |
| (XV) | 40836 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C39H69NO5SSi2 | 详情 | 详情 | |
| (XVI) | 40837 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C27H41NO5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The condensation of 3-buten-2-one (I) with the phosphonate (II) by means of LDA gives the alkylated thiazole (III), which is enantioselectively epoxidated to the chiral oxirane (V) by means of oxone and the chiral ketone (IV). Alternatively, the oxidation of the chiral epoxybutanol (VI) with CrO3 or SO3 /pyridine yields the epoxybutanone (VII), which is condensed with phosphorane (II) by means of LDA to afford the already reported chiral oxirane (V). The condensation of (V) with alkyl bromide (VIII) and propyne (IX) by means of Mg, CuBr and pentynyl lithium provides the undecatrienyl thiazole (X), which is treated with Tms-OTf in order to protect its OH group, yielding the silyl ether (XI). The oxidation of the terminal double bond of (XI) by means of (Ipc)2BH and CrO3 affords the carbaldehyde (XII), which is condensed with ketoacid (XIII) by means of LDA in THF to provide the undecadienoic acid (XIV). The cyclization of (XIV) by means of benzenesulfonyl chloride and pyridine gives the macrocyclic intermediate (XV), which is finally epoxidated by means of DMDO in acetone to furnish the target epothilone B.
| 【1】 Avery, M.A. (University of Mississippi); Synthesis of epothilones and related analogs. WO 0230356 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 54294 | 1-pentynyllithium | n/a | C5H7Li | 详情 | 详情 | |
| (I) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (II) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (III) | 54290 | 2-methyl-4-[(1E)-2-methyl-1,3-butadienyl]-1,3-thiazole | n/a | C9H11NS | 详情 | 详情 |
| (IV) | 54291 | n/a | C13H20O5 | 详情 | 详情 | |
| (V) | 54293 | 2-methyl-4-{(E)-2-[(2R)oxiranyl]-1-propenyl}-1,3-thiazole | n/a | C9H11NOS | 详情 | 详情 |
| (VI) | 52597 | 1-(2-oxiranyl)-1-ethanol | C4H8O2 | 详情 | 详情 | |
| (VII) | 54292 | 1-[(2R)oxiranyl]-1-ethanone | n/a | C4H6O2 | 详情 | 详情 |
| (VIII) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (IX) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (X) | 54295 | (1E,3S,5Z)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5,10-undecatrien-3-ol | n/a | C18H27NOS | 详情 | 详情 |
| (XI) | 54296 | 2-methyl-4-{(1E,3S,5Z)-2,6,10-trimethyl-3-[(trimethylsilyl)oxy]-1,5,10-undecatrienyl}-1,3-thiazole; (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl trimethylsilyl ether | n/a | C21H35NOSSi | 详情 | 详情 |
| (XII) | 54297 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[(trimethylsilyl)oxy]-6,10-undecadienal | n/a | C21H35NO2SSi | 详情 | 详情 |
| (XIII) | 52596 | 3-hydroxy-4,4-dimethyl-5-oxoheptanoic acid | C9H16O4 | 详情 | 详情 | |
| (XIV) | 54298 | (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-trihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | n/a | C27H43NO6S | 详情 | 详情 |
| (XV) | 40837 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C27H41NO5S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)The condensation of alkyl bromide (I) with epoxide (II) and propyne (III) by means of Mg, CuI and pentynyl lithium gives the secondary alcohol (IV), which is silylated with Sem-Cl to yield the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by means of SO3 /pyridine to afford the ketone (VII). The condensation of ketone (VII) with phosphonate (VIII) by means of BuLi in THF provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with oxalyl chloride yields the carbaldehyde (XI), which is condensed with ketoacid (XII) by means of LDA in THF to afford the heptadecadienoic acid (XIII). The protection of the free OH group of (XIII) with Troc-Cl and DMAP in dichloromethane provides the protected linear precursor (XIV), which is selectively monodeprotected with TFA in dichloromethane to furnish the linear hydroxyacid (XV). The macrocyclization of (XV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XVI), which is deprotected first with HF and pyridine (desilylation), and then with Zn and HOAc (elimination of the Troc protecting group), to yield the unprotected precursor (XVII). Finally, this compound is epoxidated by means of dimethyldioxirane (DMDO) in acetone to afford the target epothilone B.
| 【1】 Avery, M.A. (University of Mississippi); Synthesis of epothilones and related analogs. WO 0230356 . |
| 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) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (II) | 52578 | methyl 4-({[1-(2-oxiranyl)ethyl]oxy}methyl)phenyl ether; 2-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]oxirane | C2H5NS | 详情 | 详情 | |
| (III) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (IV) | 54286 | tert-butyl(dimethyl)silyl (1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl ether; tert-butyl[((1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl)oxy]dimethylsilane | n/a | C27H46O3Si | 详情 | 详情 |
| (V) | 54299 | (3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-1-(4-methoxyphenyl)-3,10,10-trimethyl-2,5,7-trioxa-10-silaundecane; 4-{(3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-3,10,10-trimethyl-2,5,7-trioxa-10-silaundec-1-yl}phenyl methyl ether | n/a | C27H46O4Si | 详情 | 详情 |
| (VI) | 54300 | (2R,3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-ol | n/a | C19H38O3Si | 详情 | 详情 |
| (VII) | 54301 | (3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-one | n/a | C19H36O3Si | 详情 | 详情 |
| (VIII) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (IX) | 54302 | 2-methyl-4-((1E,3S,5Z)-2,6,10-trimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-1,5,10-undecatrienyl)-1,3-thiazole; (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl [2-(trimethylsilyl)ethoxy]methyl ether | n/a | C24H41NO2SSi | 详情 | 详情 |
| (X) | 54303 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methoxy}-6,10-undecadien-1-ol | n/a | C24H43NO3SSi | 详情 | 详情 |
| (XI) | 54304 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methoxy}-6,10-undecadienal | n/a | C24H41NO3SSi | 详情 | 详情 |
| (XII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XIII) | 54305 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid | n/a | C39H71NO7SSi2 | 详情 | 详情 |
| (XIV) | 54306 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid | n/a | C42H72Cl3NO9SSi2 | 详情 | 详情 |
| (XV) | 54307 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-12,16-heptadecadienoic acid | n/a | C36H58Cl3NO8SSi | 详情 | 详情 |
| (XVI) | 52590 | 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-2,6-dioxooxa-13-cyclohexadecen-8-yl 2,2,2-trichloroethyl carbonate | C36H56Cl3NO7SSi | 详情 | 详情 | |
| (XVII) | 40837 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C27H41NO5S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIV)Synthesis of the target epothilone D. The condensation of 4-methyl-4-pentenyl bromide (XIII) with propyne (XIV) and 1-hexynyl lithium (XV) by means of CuBr in DMSO/ethyl ether gives the copper complex (XVI), which is condensed with the chiral epoxide (III) to yield the chiral unsaturated alcohol (XVII). The protection of the free OH group of (XVII) with Sem-Cl and DIEA in dichloromethane affords compound (XVIII). The selective cleavage of the Pmb-protecting group of (XVIII) by means of DDQ, followed by oxidation of the resulting alcohol with oxalyl chloride provides the methyl ketone (XIX), which is condensed with the intermediate phosphonate (X) by means of BuLi in THF to give the adduct (XX). The hydroxylation of the terminal vinylene double bond of (XX) by means of (Ipc)2BH and LiOH yields the primary alcohol (XXI), which is oxidized with (COCl)2, PTAP or DMP to afford the corresponding aldehyde (XXII). The condensation of aldehyde (XXII) with the known carboxylic acid (XXIII) by means of LDA in THF provides the linear adduct (XXIV), which is treated with Troc-Cl to protect the free OH group of (XXIV) yielding carboxylic acid (XXV).
| 【1】 Jung, J.-K.; Kache, R.; Vines, K.K.; Zheng, Y.-S.; Avery, M.A.; Total synthesis of epothilones B and D amenable to large-scale preparation. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 121. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 52578 | methyl 4-({[1-(2-oxiranyl)ethyl]oxy}methyl)phenyl ether; 2-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]oxirane | C2H5NS | 详情 | 详情 | |
| (X) | 52614 | dimethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C7H12NO3PS | 详情 | 详情 | |
| (XIII) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (XIV) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (XV) | 63910 | 1-hexynyllithium | C6H9Li | 详情 | 详情 | |
| (XVI) | 52576 | (2,6-dimethyl-1,6-heptadienyl)(1-hexynyl)copper | C15H24Cu | 详情 | 详情 | |
| (XVII) | 52579 | 6,10-dimethyl-2-({[4-(methyloxy)phenyl]methyl}oxy)-5,10-undecadien-3-ol | C21H32O3 | 详情 | 详情 | |
| (XVIII) | 54299 | (3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-1-(4-methoxyphenyl)-3,10,10-trimethyl-2,5,7-trioxa-10-silaundecane; 4-{(3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-3,10,10-trimethyl-2,5,7-trioxa-10-silaundec-1-yl}phenyl methyl ether | n/a | C27H46O4Si | 详情 | 详情 |
| (XIX) | 54301 | (3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-one | n/a | C19H36O3Si | 详情 | 详情 |
| (XX) | 54302 | 2-methyl-4-((1E,3S,5Z)-2,6,10-trimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-1,5,10-undecatrienyl)-1,3-thiazole; (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl [2-(trimethylsilyl)ethoxy]methyl ether | n/a | C24H41NO2SSi | 详情 | 详情 |
| (XXI) | 54303 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methoxy}-6,10-undecadien-1-ol | n/a | C24H43NO3SSi | 详情 | 详情 |
| (XXII) | 34304 | (2S)-3-[3-[bis(2-chloroethyl)amino]phenyl]-2-[[(2S)-3-(4-fluorophenyl)-2-(formylamino)propanoyl]amino]propionic acid | C23H26Cl2FN3O4 | 详情 | 详情 | |
| (XXIII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XXIV) | 54305 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid | n/a | C39H71NO7SSi2 | 详情 | 详情 |
| (XXV) | 54306 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid | n/a | C42H72Cl3NO9SSi2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IX)The condensation of 3-buten-2-one (I) with the phosphonate (II) by means of LDA gives the alkylated thiazole (III), which is enantioselectively epoxidated to the chiral oxirane (V) by means of oxone and the chiral ketone (IV). Alternatively, the oxidation of the chiral epoxybutanol (VI) with CrO3 or SO3 /pyridine yields the epoxybutanone (VII), which is condensed with phosphorane (II) by means of LDA to afford the already reported chiral oxirane (V). The condensation of (V) with alkyl bromide (VIII) and propyne (IX) by means of Mg, CuBr and pentynyl lithium provides the undecatrienyl thiazole (X), which is treated with Tms-OTf in order to protect its OH group, yielding the silyl ether (XI). The oxidation of the terminal double bond of (XI) by means of (Ipc)2BH and CrO3 affords the carbaldehyde (XII), which is condensed with ketoacid (XIII) by means of LDA in THF to provide the undecadienoic acid (XIV). Finally, the cyclization of (XIV) by means of benzenesulfonyl chloride and pyridine gives the target epothilone D.
| 【1】 Avery, M.A. (University of Mississippi); Synthesis of epothilones and related analogs. WO 0230356 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 54294 | 1-pentynyllithium | n/a | C5H7Li | 详情 | 详情 | |
| (I) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (II) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (III) | 54290 | 2-methyl-4-[(1E)-2-methyl-1,3-butadienyl]-1,3-thiazole | n/a | C9H11NS | 详情 | 详情 |
| (IV) | 54291 | n/a | C13H20O5 | 详情 | 详情 | |
| (V) | 54293 | 2-methyl-4-{(E)-2-[(2R)oxiranyl]-1-propenyl}-1,3-thiazole | n/a | C9H11NOS | 详情 | 详情 |
| (VI) | 52597 | 1-(2-oxiranyl)-1-ethanol | C4H8O2 | 详情 | 详情 | |
| (VII) | 54292 | 1-[(2R)oxiranyl]-1-ethanone | n/a | C4H6O2 | 详情 | 详情 |
| (VIII) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (IX) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (X) | 54295 | (1E,3S,5Z)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5,10-undecatrien-3-ol | n/a | C18H27NOS | 详情 | 详情 |
| (XI) | 54296 | 2-methyl-4-{(1E,3S,5Z)-2,6,10-trimethyl-3-[(trimethylsilyl)oxy]-1,5,10-undecatrienyl}-1,3-thiazole; (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl trimethylsilyl ether | n/a | C21H35NOSSi | 详情 | 详情 |
| (XII) | 54297 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-[(trimethylsilyl)oxy]-6,10-undecadienal | n/a | C21H35NO2SSi | 详情 | 详情 |
| (XIII) | 52596 | 3-hydroxy-4,4-dimethyl-5-oxoheptanoic acid | C9H16O4 | 详情 | 详情 | |
| (XIV) | 54298 | (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-trihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | n/a | C27H43NO6S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)The reaction of 4-methyl-4-penten-1-ol (I) with PBr3 gives the corresponding alkyl bromide (II), which is condensed with epoxide (III) and propyne (IV) by means of Mg, CuI and pentynyl lithium to yield, after silylation with Tbdms-Cl, the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by the Swern reagent to afford the ketone (VII). Alternatively, ketone (VII) can also be obtained by direct oxidation of the protected diol (V) with the Jones reagent. The Horner Emmons condensation of ketone (VII) with phosphonate (VIII) provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with the complex SO3/Pyr yields the carbaldehyde (XI). Alternatively, (XI) can also be obtained by direct oxidation of the terminal double bond of (IX) with (Ipc)2BH and pyridinium chlorochromate (PCC). The condensation of aldehyde (XI) with ketoacid (XII) by means of LDA in THF affords the heptadecadienoic acid (XIII), which is silylated with Tbdms-OTf to provide the protected linear precursor (XIV). The cyclization of (XIV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XV), which is finally desilylated by means of TBAF in THF to yield the target epothilone D.
| 【1】 Avery, M.A. (University of Mississippi); Synthesis of epothilones and related analogs. WO 0230356 . |
| 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) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (II) | 52578 | methyl 4-({[1-(2-oxiranyl)ethyl]oxy}methyl)phenyl ether; 2-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]oxirane | C2H5NS | 详情 | 详情 | |
| (III) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (IV) | 54286 | tert-butyl(dimethyl)silyl (1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl ether; tert-butyl[((1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl)oxy]dimethylsilane | n/a | C27H46O3Si | 详情 | 详情 |
| (V) | 54299 | (3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-1-(4-methoxyphenyl)-3,10,10-trimethyl-2,5,7-trioxa-10-silaundecane; 4-{(3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-3,10,10-trimethyl-2,5,7-trioxa-10-silaundec-1-yl}phenyl methyl ether | n/a | C27H46O4Si | 详情 | 详情 |
| (VI) | 54300 | (2R,3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-ol | n/a | C19H38O3Si | 详情 | 详情 |
| (VII) | 54301 | (3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-one | n/a | C19H36O3Si | 详情 | 详情 |
| (VIII) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (IX) | 54302 | 2-methyl-4-((1E,3S,5Z)-2,6,10-trimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-1,5,10-undecatrienyl)-1,3-thiazole; (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl [2-(trimethylsilyl)ethoxy]methyl ether | n/a | C24H41NO2SSi | 详情 | 详情 |
| (X) | 54303 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methoxy}-6,10-undecadien-1-ol | n/a | C24H43NO3SSi | 详情 | 详情 |
| (XI) | 54304 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methoxy}-6,10-undecadienal | n/a | C24H41NO3SSi | 详情 | 详情 |
| (XII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XIII) | 54305 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid | n/a | C39H71NO7SSi2 | 详情 | 详情 |
| (XIV) | 54306 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid | n/a | C42H72Cl3NO9SSi2 | 详情 | 详情 |
| (XV) | 54307 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-12,16-heptadecadienoic acid | n/a | C36H58Cl3NO8SSi | 详情 | 详情 |
| (XVI) | 52590 | 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-2,6-dioxooxa-13-cyclohexadecen-8-yl 2,2,2-trichloroethyl carbonate | C36H56Cl3NO7SSi | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IV)The condensation of alkyl bromide (I) with epoxide (II) and propyne (III) by means of Mg, CuI and pentynyl lithium gives the secondary alcohol (IV), which is silylated with Sem-Cl to yield the protected diol (V). The selective deprotection of (V) with DDQ gives the secondary alcohol (VI), which is oxidized by means of SO3 /pyridine to afford the ketone (VII). The condensation of ketone (VII) with phosphonate (VIII) by means of BuLi in THF provides the unsaturated alkyl thiazole (IX), which is treated with (Ipc)2BH and sodium formate in THF to give the secondary alcohol (X). The oxidation of (X) with oxalyl chloride yields the carbaldehyde (XI), which is condensed with ketoacid (XII) by means of LDA in THF to afford the heptadecadienoic acid (XIII). The protection of the free OH group of (XIII) with Troc-Cl and DMAP in dichloromethane provides the protected linear precursor (XIV), which is selectively monodeprotected with TFA in dichloromethane to furnish the linear hydroxyacid (XV). The macrocyclization of (XV) by means of 2,4,6-trichlorobenzoyl chloride and DMAP in pyridine gives the protected cyclic precursor (XVI), which is deprotected first with HF and pyridine (desilylation), and then with Zn and HOAc (elimination of the Troc protecting group), to finally yield the target epothilone D.
| 【1】 Avery, M.A. (University of Mississippi); Synthesis of epothilones and related analogs. WO 0230356 . |
| 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) | 54285 | 4-methyl-4-penten-1-ol | 22508-64-1 | C6H12O | 详情 | 详情 |
| (II) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (III) | 52578 | methyl 4-({[1-(2-oxiranyl)ethyl]oxy}methyl)phenyl ether; 2-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]oxirane | C2H5NS | 详情 | 详情 | |
| (IV) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (V) | 54286 | tert-butyl(dimethyl)silyl (1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl ether; tert-butyl[((1S,3Z)-1-{(1R)-1-[(4-methoxybenzyl)oxy]ethyl}-4,8-dimethyl-3,8-nonadienyl)oxy]dimethylsilane | n/a | C27H46O3Si | 详情 | 详情 |
| (VI) | 54287 | (2R,3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-6,10-dimethyl-5,10-undecadien-2-ol | n/a | C19H38O2Si | 详情 | 详情 |
| (VII) | 54288 | (3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-6,10-dimethyl-5,10-undecadien-2-one | n/a | C19H36O2Si | 详情 | 详情 |
| (VIII) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (IX) | 54289 | tert-butyl(dimethyl)silyl (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl ether; 4-((1E,3S,5Z)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,6,10-trimethyl-1,5,10-undecatrienyl)-2-methyl-1,3-thiazole | n/a | C24H41NOSSi | 详情 | 详情 |
| (X) | 40828 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol | C24H43NO2SSi | 详情 | 详情 | |
| (XI) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 | |
| (XII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XIII) | 46118 | (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C39H71NO6SSi2 | 详情 | 详情 | |
| (XIV) | 40834 | (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C45H85NO6SSi3 | 详情 | 详情 | |
| (XV) | 40836 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C39H69NO5SSi2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XIV)Synthesis of the target epothilone D. The condensation of 4-methyl-4-pentenyl bromide (XIII) with propyne (XIV) and 1-hexynyl lithium (XV) by means of CuBr in DMSO/ethyl ether gives the copper complex (XVI), which is condensed with the chiral epoxide (III) to yield the chiral unsaturated alcohol (XVII). The protection of the free OH group of (XVII) with Sem-Cl and DIEA in dichloromethane affords compound (XVIII). The selective cleavage of the Pmb protecting group of (XVIII) by means of DDQ, followed by oxidation of the resulting alcohol with oxalyl chloride provides the methyl ketone (XIX), which is condensed with the intermediate phosphonate (X) by means of BuLi in THF to give the adduct (XX). The hydroxylation of the terminal vinylene double bond of (XX) by means of (Ipc)2BH and LiOH yields the primary alcohol (XXI), which is oxidized with (COCl)2, PTAP or DMP to afford the corresponding aldehyde (XXII). The condensation of aldehyde (XXII) with the known carboxylic acid (XXIII) by means of LDA in THF provides the linear adduct (XXIV), which is treated with Troc-Cl to protect the free OH group of (XXIV) yielding carboxylic acid (XXV).
| 【1】 Jung, J.-K.; Kache, R.; Vines, K.K.; Zheng, Y.-S.; Avery, M.A.; Total synthesis of epothilones B and D amenable to large-scale preparation. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 121. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 52578 | methyl 4-({[1-(2-oxiranyl)ethyl]oxy}methyl)phenyl ether; 2-[1-({[4-(methyloxy)phenyl]methyl}oxy)ethyl]oxirane | C2H5NS | 详情 | 详情 | |
| (X) | 52614 | dimethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C7H12NO3PS | 详情 | 详情 | |
| (XIII) | 52575 | 5-bromo-2-methyl-1-pentene | C6H11Br | 详情 | 详情 | |
| (XIV) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (XV) | 63910 | 1-hexynyllithium | C6H9Li | 详情 | 详情 | |
| (XVI) | 52576 | (2,6-dimethyl-1,6-heptadienyl)(1-hexynyl)copper | C15H24Cu | 详情 | 详情 | |
| (XVII) | 52579 | 6,10-dimethyl-2-({[4-(methyloxy)phenyl]methyl}oxy)-5,10-undecadien-3-ol | C21H32O3 | 详情 | 详情 | |
| (XVIII) | 54299 | (3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-1-(4-methoxyphenyl)-3,10,10-trimethyl-2,5,7-trioxa-10-silaundecane; 4-{(3R,4S)-4-[(2Z)-3,7-dimethyl-2,7-octadienyl]-3,10,10-trimethyl-2,5,7-trioxa-10-silaundec-1-yl}phenyl methyl ether | n/a | C27H46O4Si | 详情 | 详情 |
| (XIX) | 54301 | (3S,5Z)-6,10-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5,10-undecadien-2-one | n/a | C19H36O3Si | 详情 | 详情 |
| (XX) | 54302 | 2-methyl-4-((1E,3S,5Z)-2,6,10-trimethyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-1,5,10-undecatrienyl)-1,3-thiazole; (1S,3Z)-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,8-nonadienyl [2-(trimethylsilyl)ethoxy]methyl ether | n/a | C24H41NO2SSi | 详情 | 详情 |
| (XXI) | 54303 | (2S,6Z,9S,10E)-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-9-{[2-(trimethylsilyl)ethoxy]methoxy}-6,10-undecadien-1-ol | n/a | C24H43NO3SSi | 详情 | 详情 |
| (XXII) | 34304 | (2S)-3-[3-[bis(2-chloroethyl)amino]phenyl]-2-[[(2S)-3-(4-fluorophenyl)-2-(formylamino)propanoyl]amino]propionic acid | C23H26Cl2FN3O4 | 详情 | 详情 | |
| (XXIII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XXIV) | 54305 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid | n/a | C39H71NO7SSi2 | 详情 | 详情 |
| (XXV) | 54306 | (3S,6R,7S,8S,12Z,15S,16E)-3-{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-7-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-15-{[2-(trimethylsilyl)ethoxy]methoxy}-12,16-heptadecadienoic acid | n/a | C42H72Cl3NO9SSi2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XII)6-Methoxy-2-tetralone (I) was condensed with pyrrolidine (II) to produce enamine (III). Alkylation of (III) with benzyl bromide, followed by hydrolysis of the enamine function, furnished the 1-benzylnaphthalenone (IV). After formation of the chiral enamine (VI) with (S)-alpha-methylbenzylamine (V), enantioselective Michael addition of methyl vinyl ketone (VII) provided the (R)-diketone (VIII), which underwent ring closure to the phenanthrene derivative (IX) upon treatment with NaOMe. Methyl ether cleavage by using boron trichloride in the presence of tetrabutylammonium iodide afforded phenol (X). The conjugated ketone system of (X) was diastereoselectively reduced to the trans-phenanthrenone (XI) by means of lithium in liquid ammonia. Addition of the lithium acetylide of propyne (XII) to the ketone (XI) produced a diastereomeric mixture of carbinols from which the desired isomer (XIII) was isolated by flash chromatography. The phenol group of (XIII) was then converted to the aryl triflate (XIV) by reaction with trifluoromethanesulfonic anhydride and 2,6-lutidine.
| 【1】 Liu, K.K.-C.; Morgan, B.P.; Dow, R.L.; Swick, A.G. (Pfizer Inc.); Glucocorticoid receptor modulators. EP 1175383; WO 0066522 . |
| 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) | 47506 | 6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone | 2472-22-2 | C11H12O2 | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 47507 | methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine | C15H19NO | 详情 | 详情 | |
| (IV) | 51596 | 1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone | C18H18O2 | 详情 | 详情 | |
| (V) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (VI) | 51597 | 1-benzyl-6-methoxy-N-[(1S)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine; N-(1-benzyl-6-methoxy-3,4-dihydro-2-naphthalenyl)-N-[(1S)-1-phenylethyl]amine | C26H27NO | 详情 | 详情 | |
| (VII) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (VIII) | 51598 | (1R)-1-benzyl-6-methoxy-1-(3-oxobutyl)-3,4-dihydro-2(1H)-naphthalenone | C22H24O3 | 详情 | 详情 | |
| (IX) | 51599 | (4aS)-4a-benzyl-7-methoxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone | C22H22O2 | 详情 | 详情 | |
| (X) | 51600 | (4aS)-4a-benzyl-7-hydroxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone | C21H20O2 | 详情 | 详情 | |
| (XI) | 51601 | (4aS,10aR)-4a-benzyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-2(1H)-phenanthrenone | C21H22O2 | 详情 | 详情 | |
| (XII) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (XIII) | 51603 | (2R,4aS,10aR)-4a-benzyl-2-(1-propynyl)-1,2,3,4,4a,9,10,10a-octahydro-2,7-phenanthrenediol | C24H26O2 | 详情 | 详情 | |
| (XIV) | 51604 | (4bS,7R,8aR)-4b-benzyl-7-hydroxy-7-(1-propynyl)-4b,5,6,7,8,8a,9,10-octahydro-2-phenanthrenyl trifluoromethanesulfonate | C25H25F3O4S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(II)Palladium-catalyzed coupling of 2,4-diamino-6-iodoquinazoline (I) with trimethylsilyl acetylene (II) affords the silylethynyl quinazoline (III). Subsequent treatment of (III) with tetrabutylammonium fluoride leads to the desilylated acetylene compound (IV).
| 【1】 Vaidya, C.M.; Wright, J.E.; Rosowsky, A.; Synthesis and in vitro antitumor activity of new deaza analogues of the nonpolyglutamatable antifolate Nalpha-(4-amino-4-deoxypteroyl)-Nalpha-hemiphtaloyl-L-ornithine (PT523). J Med Chem 2002, 45, 8, 1690. |
| 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) | 65105 | 2-amino-6-iodo-4-quinazolinylamine; 6-iodo-2,4-quinazolinediamine | C8H7IN4 | 详情 | 详情 | |
| (II) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (III) | 65103 | 2-amino-6-[2-(trimethylsilyl)ethynyl]-4-quinazolinylamine; 6-[2-(trimethylsilyl)ethynyl]-2,4-quinazolinediamine | C13H16N4Si | 详情 | 详情 | |
| (IV) | 65104 | 2-amino-6-ethynyl-4-quinazolinylamine; 6-ethynyl-2,4-quinazolinediamine | C10H8N4 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(XI)6-Methoxy-2-tetralone (I) is converted into enamine (II) by treatment with pyrrolidine in toluene by azeotropic removal of water. Alkylation of (II) with benzyl bromide, followed by hydrolysis of the enamine, provides the 1-benzyl tetralone (III). This is then condensed with (S)-alpha-methylbenzylamine (IV), and the resultant imine (V) is treated with methyl vinyl ketone (VI) to furnish, after hydrolysis of the chiral auxiliary, the tricyclic ketone (VII). Rearrangement of (VII) in the presence of NaOMe results in the phenanthrenone (VIII). Cleavage of the methyl ether of (VIII) is accomplished by treatment with boron trichloride and tetrabutylammonium iodide to form phenol (IX). Reduction of enone (IX) with lithium metal in liquid ammonia leads to the saturated ketone (X). Finally, addition of the lithium acetylide of propyne (XI) to the ketone (X) affords the title carbinol adduct.
| 【1】 Morgan, B.P.; Swick, A.G.; Hargrove, D.M.; LaFlamme, J.A.; Moynihan, M.S.; Carroll, R.S.; Martin, K.A.; Lee, E.; Decosta, D.; Bordner, J.; Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists. J Med Chem 2002, 45, 12, 2417. |
| 【2】 Liu, K.K.-C.; Morgan, B.P.; Dow, R.L.; Swick, A.G. (Pfizer Inc.); Glucocorticoid receptor modulators. EP 1175383; WO 0066522 . |
| 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) | 47506 | 6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone | 2472-22-2 | C11H12O2 | 详情 | 详情 |
| (II) | 47507 | methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine | C15H19NO | 详情 | 详情 | |
| (III) | 51596 | 1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone | C18H18O2 | 详情 | 详情 | |
| (IV) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (V) | 61649 | (1S)-N-[1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenylidene]-1-phenyl-1-ethanamine | C26H27NO | 详情 | 详情 | |
| (VI) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (VII) | 61650 | (1R)-1-benzyl-10-hydroxy-5-methoxy-10-methyltricyclo[7.3.1.0~2,7~]trideca-2,4,6-trien-13-one | C22H24O3 | 详情 | 详情 | |
| (VIII) | 51599 | (4aS)-4a-benzyl-7-methoxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone | C22H22O2 | 详情 | 详情 | |
| (IX) | 51600 | (4aS)-4a-benzyl-7-hydroxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone | C21H20O2 | 详情 | 详情 | |
| (X) | 51601 | (4aS,10aR)-4a-benzyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-2(1H)-phenanthrenone | C21H22O2 | 详情 | 详情 | |
| (XI) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(IV)Reaction of 2,5-dibromopyridine (I) with morpholine (II) yields 5-bromo-2-(4-morpholinyl)pyridine (III). Palladium-catalyzed coupling of (III) with trimethylsilyl acetylene (IV) leads to the ethynylpyridine (V)
| 【1】 Gomtsyan, A.; et al.; Design, synthesis, and structure-activity relationship of 6-alkynylpyrimidines as potent adenosine kinase inhibitors. J Med Chem 2002, 45, 17, 3639. |