N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine -Drug Synthesis Database

【结构式】

【分子编号】44460

【品名】N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine

【CA登记号】

【分子式】C₈H₁₆N₂O

【分子量】156.22792

【元素组成】C 61.51% H 10.32% N 17.93% O 10.24%

与该中间体有关的原料药合成路线共 7 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6 合成路线7

合成路线1

该中间体在本合成路线中的序号：(XVII)

Assembly of the final product: The condensation of SAMP hydrazone (XVII) with 4-(benzyloxy)butyl iodide (XVIII) by means of LDA in THF gives the chiral 2-methylhexanal hydrazone (XIX), which is ozonolyzed in dichloromethane, yielding the free aldehyde (XX). The reduction of (XX) with NaBH4 in methanol affords the corresponding alcohol (XXI), which is protected with Tbdms-Cl and TEA in dichloromethane, providing the silyl ether (XXII). The hydrogenolysis of (XXII) with H2 over Pd/C in THF furnishes the alcohol (XXIII), which is oxidized to the aldehyde (XXIV) with oxalyl chloride, DMSO and TEA in dichloromethane. The condensation of aldehyde (XXIV) with the intermediate phosphonium salt (XVI) by means of NaHMDS in THF gives the silylated diol (XXV), which is selectively monodesilylated with CSA in dichloromethane/methanol to yield the primary alcohol (XXVI). The oxidation of (XXVI) with SO3/pyridine, DMSO and TEA in dichloromethane affords the corresponding aldehyde (XXVII), which is condensed with the oxoacid intermediate (VI) by means of LDA in THF to provide the linear heptadecadienoic acid (XXVIII) as a diastereomeric mixture.

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid	C₁₅H₃₀O₄Si	详情	详情
(XVI)	44459	[(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide	C₃₄H₄₃INOPSSi	详情	详情
(XVII)	44460	N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine	C₈H₁₆N₂O	详情	详情
(XVIII)	44461	benzyl 4-iodobutyl ether; 1-[(4-iodobutoxy)methyl]benzene	C₁₁H₁₅IO	详情	详情
(XIX)	44462	N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine; (2R)-N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-2-methoxy-1-pyrrolidinamine	C₁₉H₃₀N₂O₂	详情	详情
(XX)	44463	(2S)-6-(benzyloxy)-2-methylhexanal	C₁₄H₂₀O₂	详情	详情
(XXI)	44464	(2S)-6-(benzyloxy)-2-methyl-1-hexanol	C₁₄H₂₂O₂	详情	详情
(XXII)	44465	benzyl (5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexyl ether; [[(2S)-6-(benzyloxy)-2-methylhexyl]oxy](tert-butyl)dimethylsilane	C₂₀H₃₆O₂Si	详情	详情
(XXIII)	44466	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-1-hexanol	C₁₃H₃₀O₂Si	详情	详情
(XXIV)	43163	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal	C₁₃H₂₈O₂Si	详情	详情
(XXV)	44467	4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienyl ether	C₂₉H₅₅NO₂SSi₂	详情	详情
(XXVI)	44468	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol	C₂₃H₄₁NO₂SSi	详情	详情
(XXVII)	44469	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal	C₂₃H₃₉NO₂SSi	详情	详情
(XXVIII)	44470	(3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid	C₃₈H₆₉NO₆SSi₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XV)

The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II), which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV). The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI), which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII). The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is reduced by reaction with CCl4 and PPh3, followed by a reductive dechlorination with LiBHEt3, to furnish the dimethylated olefin (XII). Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII), which is treated with I2 and PPh3 in ethyl ether/CH3CN to yield the iodo derivative (XIV). The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI), which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in MeOH. Finally this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.

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)	44454	ethyl 2-methyl-1,3-thiazole-4-carboxylate	6436-59-5	C₇H₉NO₂S	详情	详情
(II)	44455	2-methyl-1,3-thiazole-4-carbaldehyde		C₅H₅NOS	详情	详情
(III)	39940	2-(triphenylphosphoranylidene)propanal		C₂₁H₁₉OP	详情	详情
(IV)	44456	(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal		C₈H₉NOS	详情	详情
(V)	44449	allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane		C₂₃H₃₉B	详情	详情
(VI)	43171	(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol		C₁₁H₁₅NOS	详情	详情
(VII)	44444	4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether		C₁₇H₂₉NOSSi	详情	详情
(VIII)	40822	(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal		C₁₆H₂₇NO₂SSi	详情	详情
(IX)	46110	methyl 2-(triphenylphosphoranylidene)-4-pentenoate		C₂₄H₂₃O₂P	详情	详情
(X)	46113	4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5,8-nonatrienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,6-heptadienyl ether		C₂₁H₃₅NOSSi	详情	详情
(XI)	46114	(4Z,7S,8E)-7-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-9-(2-methyl-1,3-thiazol-4-yl)-4,8-nonadien-1-ol		C₂₁H₃₇NO₂SSi	详情	详情
(XII)	46115	4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-9-iodo-2,6-dimethyl-1,5-nonadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-7-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-heptenyl ether		C₂₁H₃₆INOSSi	详情	详情
(XIII)	46116	(2R)-N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-2-methoxy-1-pyrrolidinamine; N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine		C₂₉H₅₁N₃O₂SSi	详情	详情
(XIV)	46117	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienenitrile		C₂₄H₄₀N₂OSSi	详情	详情
(XV)	44460	N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine		C₈H₁₆N₂O	详情	详情
(XVI)	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
(XVII)	46119	tert-butyl(dimethyl)silyl (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-heptadecadienoate		C₅₁H₉₉NO₆SSi₄	详情	详情
(XVIII)	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

合成路线3

该中间体在本合成路线中的序号：(XVII)

Assembly of the final product: The condensation of SAMP hydrazone (XVII) with 4-(benzyloxy)butyl iodide (XVIII) by means of LDA in THF gives the chiral 2-methylhexanal hydrazone (XIX), which is ozonolyzed in dichloromethane, yielding the free aldehyde (XX). The reduction of (XX) with NaBH4 in methanol affords the corresponding alcohol (XXI), which is protected with Tbdms-Cl and TEA in dichloromethane, providing the silyl ether (XXII). The hydrogenolysis of (XXII) with H2 over Pd/C in THF furnishes the alcohol (XXIII), which is oxidized to the aldehyde (XXIV) with oxalyl chloride, DMSO and TEA in dichloromethane. The methylation of aldehyde (XXIV) with Me-MgBr in THF gives the secondary alcohol (XXV), which is oxidized with tetrapropylammonium perruthenate (TPAP) in dichloromethane, yielding the methyl ketone (XXVI). The condensation of ketone (XXVI) with the intermediate phosphonium salt (XVI) by means of NaHMDS in THF gives the silylated diol (XXVII), which is selectively monodesilylated with CSA in dichloromethane/methanol to yield the primary alcohol (XXVIII). The oxidation of (XXVIII) with SO3/pyridine, DMSO and TEA in dichloromethane affords the corresponding aldehyde (XXIX), which is condensed with the oxoacid intermediate (VI) by means of LDA in THF to provide the linear heptadecadienoic acid (XXX) as a diastereomeric mixture that is separated at the carboxylic acid (XXXII) step.

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid	C₁₅H₃₀O₄Si	详情	详情
(XVI)	44459	[(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide	C₃₄H₄₃INOPSSi	详情	详情
(XVII)	44460	N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine	C₈H₁₆N₂O	详情	详情
(XVIII)	44461	benzyl 4-iodobutyl ether; 1-[(4-iodobutoxy)methyl]benzene	C₁₁H₁₅IO	详情	详情
(XIX)	44462	N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine; (2R)-N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-2-methoxy-1-pyrrolidinamine	C₁₉H₃₀N₂O₂	详情	详情
(XX)	44463	(2S)-6-(benzyloxy)-2-methylhexanal	C₁₄H₂₀O₂	详情	详情
(XXI)	44464	(2S)-6-(benzyloxy)-2-methyl-1-hexanol	C₁₄H₂₂O₂	详情	详情
(XXII)	44465	benzyl (5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexyl ether; [[(2S)-6-(benzyloxy)-2-methylhexyl]oxy](tert-butyl)dimethylsilane	C₂₀H₃₆O₂Si	详情	详情
(XXIII)	44466	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-1-hexanol	C₁₃H₃₀O₂Si	详情	详情
(XXIV)	43163	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal	C₁₃H₂₈O₂Si	详情	详情
(XXV)	46120	(6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanol	C₁₄H₃₂O₂Si	详情	详情
(XXVI)	46121	(6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanone	C₁₄H₃₀O₂Si	详情	详情
(XXVII)	40827	tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole	C₃₀H₅₇NO₂SSi₂	详情	详情
(XXVIII)	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
(XXIX)	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
(XXX)	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

合成路线4

该中间体在本合成路线中的序号：(XV)

The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II), which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV). The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI), which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII). The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is reduced by reaction with CCl4 and PPh3, followed by a reductive dechlorination with LiBHEt3, to furnish the dimethylated olefin (XII). Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII), which is treated with I2 and PPh3 in ethyl ether/acetonitrile to yield the iodo derivative (XIV). The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI), which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in methanol. Finally, this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.

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)	44454	ethyl 2-methyl-1,3-thiazole-4-carboxylate	6436-59-5	C₇H₉NO₂S	详情	详情
(II)	44455	2-methyl-1,3-thiazole-4-carbaldehyde		C₅H₅NOS	详情	详情
(III)	39940	2-(triphenylphosphoranylidene)propanal		C₂₁H₁₉OP	详情	详情
(IV)	44456	(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal		C₈H₉NOS	详情	详情
(V)	44449	allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane		C₂₃H₃₉B	详情	详情
(VI)	43171	(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol		C₁₁H₁₅NOS	详情	详情
(VII)	44444	4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether		C₁₇H₂₉NOSSi	详情	详情
(VIII)	40822	(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal		C₁₆H₂₇NO₂SSi	详情	详情
(IX)	46110	methyl 2-(triphenylphosphoranylidene)-4-pentenoate		C₂₄H₂₃O₂P	详情	详情
(X)	46113	4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5,8-nonatrienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,6-heptadienyl ether		C₂₁H₃₅NOSSi	详情	详情
(XI)	46114	(4Z,7S,8E)-7-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-9-(2-methyl-1,3-thiazol-4-yl)-4,8-nonadien-1-ol		C₂₁H₃₇NO₂SSi	详情	详情
(XII)	46115	4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-9-iodo-2,6-dimethyl-1,5-nonadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-7-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-heptenyl ether		C₂₁H₃₆INOSSi	详情	详情
(XIII)	46116	(2R)-N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-2-methoxy-1-pyrrolidinamine; N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine		C₂₉H₅₁N₃O₂SSi	详情	详情
(XIV)	46117	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienenitrile		C₂₄H₄₀N₂OSSi	详情	详情
(XV)	44460	N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine		C₈H₁₆N₂O	详情	详情
(XVI)	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
(XVII)	46119	tert-butyl(dimethyl)silyl (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-heptadecadienoate		C₅₁H₉₉NO₆SSi₄	详情	详情
(XVIII)	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

合成路线5

该中间体在本合成路线中的序号：(XVII)

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid	C₁₅H₃₀O₄Si	详情	详情
(XVI)	44459	[(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide	C₃₄H₄₃INOPSSi	详情	详情
(XVII)	44460	N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine	C₈H₁₆N₂O	详情	详情
(XVIII)	44461	benzyl 4-iodobutyl ether; 1-[(4-iodobutoxy)methyl]benzene	C₁₁H₁₅IO	详情	详情
(XIX)	44462	N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine; (2R)-N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-2-methoxy-1-pyrrolidinamine	C₁₉H₃₀N₂O₂	详情	详情
(XX)	44463	(2S)-6-(benzyloxy)-2-methylhexanal	C₁₄H₂₀O₂	详情	详情
(XXI)	44464	(2S)-6-(benzyloxy)-2-methyl-1-hexanol	C₁₄H₂₂O₂	详情	详情
(XXII)	44465	benzyl (5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexyl ether; [[(2S)-6-(benzyloxy)-2-methylhexyl]oxy](tert-butyl)dimethylsilane	C₂₀H₃₆O₂Si	详情	详情
(XXIII)	44466	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-1-hexanol	C₁₃H₃₀O₂Si	详情	详情
(XXIV)	43163	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal	C₁₃H₂₈O₂Si	详情	详情
(XXV)	46120	(6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanol	C₁₄H₃₂O₂Si	详情	详情
(XXVI)	46121	(6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2-heptanone	C₁₄H₃₀O₂Si	详情	详情
(XXVII)	40827	tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole	C₃₀H₅₇NO₂SSi₂	详情	详情
(XXVIII)	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
(XXIX)	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
(XXX)	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

合成路线6

该中间体在本合成路线中的序号：(XV)

The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (I) with DIBAL in dichloromethane gives the corresponding carbaldehyde (II), which is condensed with phosphorane (III) in refluxing benzene to yield the propionaldehyde (IV). The diastereocontrolled condensation of (IV) with (+)-allyl-di(isopinocampheyl)borane (V) in ethyl ether affords the chiral homoallyl alcohol (VI), which is silylated with Tbdms-Cl and imidazole to provide the silyl ether (VII).The oxidation of the terminal double bond of (VII) by means of OsO4, NaIO4 and 4-methylmorpholine N-oxide gives the 4-pentenal derivative (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the methyl heptadienoate (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is protected with trityl chloride and DMAP to provide the trityl ether (XII). The Hydroxylation of the terminal double bond of (XII) with 8-BBN and H2O2 gives the primary alcohol (XIII), which is treated with I2 and PPh3 to yield the iodo compound (XIV). The condensation of (XIV) with the hydrazone (XV) by means of LDA affords the chiral undecadienylhydrazone (XVI), which is treated with monoperoxyphthalic magnesium salt (MMPP) to provide the undecadienenitrile (XVII). The reduction of (XVII) with DIBAL in toluene gives the corresponding aldehyde (XVIII).

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total synthesis of 26-hydroxy-epothilone B and related analogs via a macrolactonization based strategy. Tetrahedron 1998, 54, 25, 7127.
【2】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.
【3】 He, Y.; Yang, Z.; Nicolaou, C.K.; Ninkovic, S.; Pastor, J.; Roschangar, F.; Sarabia, F.; Vallberg, H.; Vourloumis, D.; Winssinger, N.; King, N.P.; Finlay, M.R.V. (Novartis AG; Scripps Research Institute); Epothilone analogs. JP 2001504856; WO 9825929 .

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)	44454	ethyl 2-methyl-1,3-thiazole-4-carboxylate	6436-59-5	C₇H₉NO₂S	详情	详情
(II)	44455	2-methyl-1,3-thiazole-4-carbaldehyde		C₅H₅NOS	详情	详情
(III)	39940	2-(triphenylphosphoranylidene)propanal		C₂₁H₁₉OP	详情	详情
(IV)	44456	(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal		C₈H₉NOS	详情	详情
(VI)	43171	(1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol		C₁₁H₁₅NOS	详情	详情
(VII)	44444	4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether		C₁₇H₂₉NOSSi	详情	详情
(VIII)	40822	(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal		C₁₆H₂₇NO₂SSi	详情	详情
(IX)	46110	methyl 2-(triphenylphosphoranylidene)-4-pentenoate		C₂₄H₂₃O₂P	详情	详情
(X)	46111	methyl (2E,5S,6E)-2-allyl-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate		C₂₂H₃₅NO₃SSi	详情	详情
(XI)	46112	(2E,5S,6E)-2-allyl-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol		C₂₁H₃₅NO₂SSi	详情	详情
(XII)	54771	(2E,5S,6E)-2-allyl-5-{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienyl trityl ether; 4-{(1E,3S,5E)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-6-[(trityloxy)methyl]-1,5,8-nonatrienyl}-2-methyl-1,3-thiazole		C₄₀H₄₉NO₂SSi	详情	详情
(XIII)	54772	(4E,7S,8E)-7-{[tert-butyl(dimethyl)silyl]oxy}-8-methyl-9-(2-methyl-1,3-thiazol-4-yl)-4-[(trityloxy)methyl]-4,8-nonadien-1-ol		C₄₀H₅₁NO₃SSi	详情	详情
(XIV)	54773	tert-butyl(dimethyl)silyl (1S,3E)-7-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-[(trityloxy)methyl]-3-heptenyl ether; 4-{(1E,3S,5E)-3-{[tert-butyl(dimethyl)silyl]oxy}-9-iodo-2-methyl-6-[(trityloxy)methyl]-1,5-nonadienyl}-2-methyl-1,3-thiazole		C₄₀H₅₀INO₂SSi	详情	详情
(XV)	44460	N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine		C₈H₁₆N₂O	详情	详情
(XVI)	54774	(2R)-N-{(Z,2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienylidene}-2-methoxy-1-pyrrolidinamine; N-{(Z,2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienylidene}-N-[(2R)-2-methoxypyrrolidinyl]amine		C₄₈H₆₅N₃O₃SSi	详情	详情
(XVII)	54775	(2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienenitrile		C₄₃H₅₄N₂O₂SSi	详情	详情
(XVIII)	54776	(2S,6E,9S,10E)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6-[(trityloxy)methyl]-6,10-undecadienal		C₄₃H₅₅NO₃SSi	详情	详情

合成路线7

该中间体在本合成路线中的序号：(XVII)

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	43166	(3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid	C₁₅H₃₀O₄Si	详情	详情
(XVI)	44459	[(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide	C₃₄H₄₃INOPSSi	详情	详情
(XVII)	44460	N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine	C₈H₁₆N₂O	详情	详情
(XVIII)	44461	benzyl 4-iodobutyl ether; 1-[(4-iodobutoxy)methyl]benzene	C₁₁H₁₅IO	详情	详情
(XIX)	44462	N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine; (2R)-N-[(E,2S)-6-(benzyloxy)-2-methylhexylidene]-2-methoxy-1-pyrrolidinamine	C₁₉H₃₀N₂O₂	详情	详情
(XX)	44463	(2S)-6-(benzyloxy)-2-methylhexanal	C₁₄H₂₀O₂	详情	详情
(XXI)	44464	(2S)-6-(benzyloxy)-2-methyl-1-hexanol	C₁₄H₂₂O₂	详情	详情
(XXII)	44465	benzyl (5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexyl ether; [[(2S)-6-(benzyloxy)-2-methylhexyl]oxy](tert-butyl)dimethylsilane	C₂₀H₃₆O₂Si	详情	详情
(XXIII)	44466	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-1-hexanol	C₁₃H₃₀O₂Si	详情	详情
(XXIV)	43163	(5S)-6-[[tert-butyl(dimethyl)silyl]oxy]-5-methylhexanal	C₁₃H₂₈O₂Si	详情	详情
(XXV)	44467	4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienyl ether	C₂₉H₅₅NO₂SSi₂	详情	详情
(XXVI)	44468	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol	C₂₃H₄₁NO₂SSi	详情	详情
(XXVII)	44469	(2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,10-dimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal	C₂₃H₃₉NO₂SSi	详情	详情
(XXVIII)	44470	(3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid	C₃₈H₆₉NO₆SSi₂	详情	详情

Extended Information