4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether -Drug Synthesis Database

【结构式】

【分子编号】44526

【品名】4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether

【CA登记号】

【分子式】C₂₀H₃₅NOSSi₂

【分子量】393.74104

【元素组成】C 61.01% H 8.96% N 3.56% O 4.06% S 8.14% Si 14.27%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XXX)

Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with HF and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in CH2Cl2 to yield the target thiazole intermediate (XXXIV).

参考文献中间体

合成目标

【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	16299	Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium	54655-07-1	C₅H₉LiSi	详情	详情
(XXII)	44456	(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal		C₈H₉NOS	详情	详情
(XXIII)	44520	(2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile		C₉H₁₀N₂OS	详情	详情
(XXIV)	44521	ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate		C₁₁H₁₅NO₃S	详情	详情
(XXV)	44522	ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate		C₁₇H₂₉NO₃SSi	详情	详情
(XXVI)	44523	(2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal		C₁₅H₂₅NO₂SSi	详情	详情
(XXVII)	44524	(4R,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol		C₂₀H₃₅NO₂SSi₂	详情	详情
(XXVIII)	16993	methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate	79-22-1	C₂H₃ClO₂	详情	详情
(XXIX)	44525	(2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate		C₂₂H₃₇NO₄SSi₂	详情	详情
(XXX)	44526	4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether		C₂₀H₃₅NOSSi₂	详情	详情
(XXXI)	44527	tert-butyl(dimethyl)silyl (1S,3Z)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butenyl ether; 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1,5-hexadienyl]-2-methyl-1,3-thiazole		C₂₀H₃₇NOSSi₂	详情	详情
(XXXII)	44491	4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether		C₁₇H₂₈INOSSi	详情	详情
(XXXIII)	44492	(1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol		C₁₁H₁₄INOS	详情	详情
(XXXIV)	44493	(1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate		C₁₃H₁₆INO₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXX)

Synthesis of the thiazole intermediate (XXXIV): The reaction of 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (XXII) with trimethylsilyl cyanide and Et2AlCl catalyzed by a chiral bidentate phosphine oxide catalyst gives the chiral alpha-hydroxybutenenitrile (XXIII), which is hydrolyzed to the corresponding carboxylic ester (XXIV) by means of HCl in hot ethanol/water. The reaction of (XXIV) with Tbdms-Cl and imidazole yields the silylated hydroxyester (XXV), which is reduced with DIBAL in toluene, affording the aldehyde (XXVI). The reaction of (XXVI) with lithium trimethylsilylacetylide (A) in THF provides the adduct (XXVII), which is esterified with methyl chloroformate (XXVIII), furnishing the carbonate (XXIX). The reduction of (XXIX) by means of Pd(OAc)2, Bu3P and ammonium formate gives the protected acetylenic compound (XXX). The selective reduction of the triple bond of (XXX) by means of Ti(OiPr)4 and iPr-MgBr in ethyl ether yields the cis-silylated vinyl compound (XXXI), which is iodinated with I2 in dichloromethane to afford the cis-iodovinyl compound (XXXII). The desilylation of (XXXII) with FH and pyridine in THF gives the secondary alcohol (XXXIII), which is finally acetylated with Ac2O, TEA and DMAP in dichloromethane to yield the target thiazole intermediate (XXXIV).

参考文献中间体

合成目标

【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	16299	Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium	54655-07-1	C₅H₉LiSi	详情	详情
(XXII)	44456	(E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal		C₈H₉NOS	详情	详情
(XXIII)	44520	(2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenenitrile		C₉H₁₀N₂OS	详情	详情
(XXIV)	44521	ethyl (2R,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate		C₁₁H₁₅NO₃S	详情	详情
(XXV)	44522	ethyl (2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate		C₁₇H₂₉NO₃SSi	详情	详情
(XXVI)	44523	(2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenal		C₁₅H₂₅NO₂SSi	详情	详情
(XXVII)	44524	(4R,5E)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(2-methyl-1,3-thiazol-4-yl)-1-(trimethylsilyl)-5-hexen-1-yn-3-ol		C₂₀H₃₅NO₂SSi₂	详情	详情
(XXVIII)	16993	methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate	79-22-1	C₂H₃ClO₂	详情	详情
(XXIX)	44525	(2R,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-1-[2-(trimethylsilyl)ethynyl]-3-butenyl methyl carbonate		C₂₂H₃₇NO₄SSi₂	详情	详情
(XXX)	44526	4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether		C₂₀H₃₅NOSSi₂	详情	详情
(XXXI)	44527	tert-butyl(dimethyl)silyl (1S,3Z)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butenyl ether; 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-(trimethylsilyl)-1,5-hexadienyl]-2-methyl-1,3-thiazole		C₂₀H₃₇NOSSi₂	详情	详情
(XXXII)	44491	4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-iodo-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether		C₁₇H₂₈INOSSi	详情	详情
(XXXIII)	44492	(1E,3S,5Z)-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol		C₁₁H₁₄INOS	详情	详情
(XXXIV)	44493	(1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate		C₁₃H₁₆INO₂S	详情	详情

Extended Information