(2Z,4Z)-2,4-heptadienamide -Drug Synthesis Database

【结构式】

【分子编号】47499

【品名】(2Z,4Z)-2,4-heptadienamide

【CA登记号】

【分子式】C₇H₁₁NO

【分子量】125.17048

【元素组成】C 67.17% H 8.86% N 11.19% O 12.78%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XXI)

The oxidation of the primary alcohol of (XIX) with TPAP and NMO in dichloromethane gives the corresponding aldehyde (XX), which is condensed with (Z,Z)-2,4-heptadienamide (XXI) by means of Tms-OTf in dichloroethane to yield the N,N-acylated aminal (XXII). This compound undergoes elimination when treated with NaH in hot trifluoromethylbenzene affording enamide (XXIII) as a mixture of (Z) and (E) isomers, which is treated with TBAF in THF undergoing elimination of the Tips protecting group only and providing the monosilylated compound (XXIV). Removal of the remaining silyl group requires more drastic conditions (TBAF in THF/HMPA) that cause isomerization of the enamide double bond yielding a mixture of the target compound Salicylhalamide A along with its isomer Salicylhalamide B that are separated by HPLC chromatography. The intermediate (Z,Z)-2,4-heptadienamide (XXI) has been obtained as follows: The oxidation of (Z)-2-penten-1-ol (XXV) with TPAP and NMO in dichloromethane gives the corresponding aldehyde (XXVI), which is condensed with phosphonate (XXVII) by means of KH in THF to yield methyl (Z,Z)-2,4-heptadienoate (XXVIII). The hydrolysis of (XXVIII) with Ba(OH)2 in methanol/water affords (Z,Z)-2,4-heptadienoic acid (XXIX), which is finally treated with ethyl chloroformate and ammonia to provide the target amide (XXI).

参考文献中间体

合成目标

【1】 Labrecque, D.; et al.; Enantioselective total synthesis of salicylihalamides A and B. Tetrahedron Lett 2001, 42, 14, 2645.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXIIIa)	47502	(2Z,4Z)-N-((E)-3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-propenyl)-2,4-heptadienamide		C₅₁H₇₁NO₅Si₂	详情	详情
(XXIIIb)	47503	(2Z,4Z)-N-((Z)-3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-propenyl)-2,4-heptadienamide		C₅₁H₇₁NO₅Si₂	详情	详情
(XXIVa)	47504	(2Z,4Z)-N-[(E)-3-((3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl]-2,4-heptadienamide		C₄₂H₅₁NO₅Si	详情	详情
(XXIVb)	47505	(2Z,4Z)-N-[(Z)-3-((3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl]-2,4-heptadienamide		C₄₂H₅₁NO₅Si	详情	详情
(XIX)	47494	(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-3-(3-hydroxypropyl)-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one		C₃₅H₄₄O₅Si	详情	详情
(XX)	47500			C₄₄H₆₂O₅Si₂	详情	详情
(XXI)	47499	(2Z,4Z)-2,4-heptadienamide		C₇H₁₁NO	详情	详情
(XXII)	47501	(2Z,4Z)-N-[3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-[(2Z,4Z)-2,4-heptadienoylamino]propyl]-2,4-heptadienamide		C₅₈H₈₂N₂O₆Si₂	详情	详情
(XXV)	47495	cis-2-pentenol; (Z)-2-penten-1-ol	1576-95-0	C₅H₁₀O	详情	详情
(XXVI)	47496	(Z)-2-pentenal		C₅H₈O	详情	详情
(XXVII)	41856	methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate	88738-78-7	C₇H₉F₆O₅P	详情	详情
(XXVIII)	47497	methyl (2Z,4Z)-2,4-heptadienoate		C₈H₁₂O₂	详情	详情
(XXIX)	47498	(2Z,4Z)-2,4-heptadienoic acid		C₇H₁₀O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXI)

参考文献中间体

合成目标

【1】 Labrecque, D.; et al.; Enantioselective total synthesis of salicylihalamides A and B. Tetrahedron Lett 2001, 42, 14, 2645.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXIIIa)	47502	(2Z,4Z)-N-((E)-3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-propenyl)-2,4-heptadienamide		C₅₁H₇₁NO₅Si₂	详情	详情
(XXIIIb)	47503	(2Z,4Z)-N-((Z)-3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-propenyl)-2,4-heptadienamide		C₅₁H₇₁NO₅Si₂	详情	详情
(XXIVa)	47504	(2Z,4Z)-N-[(E)-3-((3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl]-2,4-heptadienamide		C₄₂H₅₁NO₅Si	详情	详情
(XXIVb)	47505	(2Z,4Z)-N-[(Z)-3-((3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl]-2,4-heptadienamide		C₄₂H₅₁NO₅Si	详情	详情
(XIX)	47494	(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-3-(3-hydroxypropyl)-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one		C₃₅H₄₄O₅Si	详情	详情
(XX)	47500			C₄₄H₆₂O₅Si₂	详情	详情
(XXI)	47499	(2Z,4Z)-2,4-heptadienamide		C₇H₁₁NO	详情	详情
(XXII)	47501	(2Z,4Z)-N-[3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-[(2Z,4Z)-2,4-heptadienoylamino]propyl]-2,4-heptadienamide		C₅₈H₈₂N₂O₆Si₂	详情	详情
(XXV)	47495	cis-2-pentenol; (Z)-2-penten-1-ol	1576-95-0	C₅H₁₀O	详情	详情
(XXVI)	47496	(Z)-2-pentenal		C₅H₈O	详情	详情
(XXVII)	41856	methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate	88738-78-7	C₇H₉F₆O₅P	详情	详情
(XXVIII)	47497	methyl (2Z,4Z)-2,4-heptadienoate		C₈H₁₂O₂	详情	详情
(XXIX)	47498	(2Z,4Z)-2,4-heptadienoic acid		C₇H₁₀O₂	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 previously reported alcohol (I) was used as the starting material for the synthesis of the title compound. Alcohol (I) was oxidized to aldehyde (II) using N-methylmorpholine-N-oxide in the presence of a catalytic amount of tetrapropylammonium perruthenate. The phenolic hydroxyl group of (II) was subsequently protected as the silyl ether (III) by treatment with triisopropylsilyl chloride. The symmetrical N,N-bis-acylated aminal (V) was synthesized by condensation of aldehyde (III) with amide (IV) in the presence of trimethylsilyl triflate. Elimination of one amide moiety of (V) with NaH in refluxing toluene produced a mixture of (E)- and (Z)-enamides, from which the desired (E)-isomer (VI) could be separated by flash chromatography either at this point or after the next step. Finally, desilylation with tetrabutylammonium fluoride in THF furnished the deprotected compound.

参考文献中间体

合成目标

【1】 Blais, C.; et al.; Synthesis of salicylihalamide A and B analogs and their in vitro cytotoxicity. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 94.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	52221	14-hydroxy-3-(3-hydroxypropyl)-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one	C₁₈H₂₄O₄	详情	详情
(II)	52222	3-(14-hydroxy-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)propanal	C₁₈H₂₂O₄	详情	详情
(III)	52223	3-{1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl}propanal	C₂₇H₄₂O₄Si	详情	详情
(IV)	47499	(2Z,4Z)-2,4-heptadienamide	C₇H₁₁NO	详情	详情
(V)	52224	(2Z,4Z)-N-(1-[(2Z,4Z)-2,4-heptadienoylamino]-3-{1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl}propyl)-2,4-heptadienamide	C₄₁H₆₂N₂O₅Si	详情	详情
(VI)	52225	(2Z,4Z)-N-((E)-3-{1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl}-1-propenyl)-2,4-heptadienamide	C₃₄H₅₁NO₄Si	详情	详情

Extended Information