diethyl 1-diazo-2-oxopropylphosphonate -Drug Synthesis Database

【结构式】

【分子编号】35884

【品名】diethyl 1-diazo-2-oxopropylphosphonate

【CA登记号】

【分子式】C₇H₁₃N₂O₄P

【分子量】220.165062

【元素组成】C 38.19% H 5.95% N 12.72% O 29.07% P 14.07%

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：(XXVII)

The regiocontrolled condensation of (spirolactam (XVII) with the chiral borane (+)(Z)-crotyl-diisopinocampheylborane (XX) in THF gives the diol (XXI), which is silylated with TBDMS-OTf and lutidine in dichloromethane yielding the bis(silyloxy) compound (XXII). The ozonolysis of the terminal double bond of (XXII) with O3 in dichloromethane affords the aldehyde (XXIII), which is condensed with the silyl aldimine (XXIV) by means of LDA in THF giving the unsaturated aldehyde (XXV). Hydrogenation of the double bond of (XXV) yields aldehyde (XXVI), which is condensed with the diazo phosphonate (XXVII) by means of K2CO3 in methanol providing the terminal acetylenic compound (XXVIII). The reaction of (XXVIII) with TBAF in THF gives the desilylated acetylenic compound (XXIX), which is brominated with NBS and AgNO3 in acetone yielding the omega-bromoacetylenic compound (XXX). Finally, this compound is treated with tributyltin hydride, Pd2(dba)3 and PPh3 in chloroform to afford the desired tributyl stannane intermediate (I).

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total synthesis of the novel immunosuppressant Sanglifehrin A. J Am Chem Soc 2000, 122, 16, 3830.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	35874	(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S,6E)-2-hydroxy-3-methyl-7-(tributylstannyl)-6-heptenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₄H₆₅NO₄Sn	详情	详情
(XVII)	32424	2-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde	C₁₆H₂₇NO₄	详情	详情
(XXI)	35879	(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-4-pentenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₂₀H₃₅NO₄	详情	详情
(XXII)	35880	(2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-pentenyl)-9-ethyl-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₂H₆₃NO₄Si₂	详情	详情
(XXIII)	35881	(2R,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-((2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-2-methylbutanal	C₃₁H₆₁NO₅Si₂	详情	详情
(XXV)	35882	(E,4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-4-methyl-2-hexenal	C₃₃H₆₃NO₅Si₂	详情	详情
(XXVI)	35883	(4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-4-methylhexanal	C₃₃H₆₅NO₅Si₂	详情	详情
(XXVII)	35884	diethyl 1-diazo-2-oxopropylphosphonate	C₇H₁₃N₂O₄P	详情	详情
(XXVIII)	35885	(2S,3S,4S,5S,6R,9S,11S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₄H₆₅NO₄Si₂	详情	详情
(XXIX)	35886	(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-[(2S,3S)-2-hydroxy-3-methyl-6-heptynyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₂₂H₃₇NO₄	详情	详情
(XXX)	32435	(2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-2-hydroxy-3-methyl-6-heptynyl]-9-ethyl-4-hydroxy-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₂₂H₃₆BrNO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXVII)

The silylation of hydroxyester (XLVIII) with Tips-Cl and imidazole in THF gives the fully protected compound (XLIX), which is reduced with DIBAL in dichloromethane to the carbinol (L).The epoxidation of the double bond of (L) with MCPBA in dichloromethane yields the epoxide (LI), which is condensed with the Grignard reagent (LII) by means of CuI in ethyl ether/THF affording the diol (LIII). Esterification of the primary OH group of (LIII) with pivaloyl chloride gives the ester (LIV), which is desilylated with TBAF in THF providing the diol (LV). The cyclic ketalization of (LV) catalyzed by PdCl2 and benzoquinone yields the cyclic ketal (LVI), which is debenzylated as usual affording the primary alcohol (LVII). The oxidation of (LVII) with TPAP and NMO in dichloromethane gives the aldehyde (LVIII), which is condensed with diazophosphonate (XXVII) by means of K2CO3 in methanol yielding the ethynyl derivative (LIX), with simultaneous hydrolysis of the pivaloyl ester. The reaction of (LIX) with tributyltin hydride and PdCl2 in dichloromethane affords the vinyl stannane derivative (LX). Finally, the hydroxymethyl group of (LX) is oxidized with TPAP, NMO and NaClO2 to the corresponding carboxylic group of the desired tributylstannane intermediate (XXXII).

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total synthesis of the novel immunosuppressant Sanglifehrin A. J Am Chem Soc 2000, 122, 16, 3830.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXVII)	35884	diethyl 1-diazo-2-oxopropylphosphonate		C₇H₁₃N₂O₄P	详情	详情
(XXXII)	35904	(4S,6R)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]nonane-6-carboxylic acid		C₂₄H₄₄O₄Sn	详情	详情
(XLVIII)	35892	ethyl (E,4R,5R)-6-(benzyloxy)-5-hydroxy-4-methyl-2-hexenoate		C₁₆H₂₂O₄	详情	详情
(XLIX)	35893	ethyl (E,4R,5R)-6-(benzyloxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-hexenoate		C₂₅H₄₂O₄Si	详情	详情
(L)	35894	(E,4R,5R)-6-(benzyloxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-hexen-1-ol		C₂₃H₄₀O₃Si	详情	详情
(LI)	35895	((2S,3R)-3-[(1R,2R)-3-(benzyloxy)-1-methyl-2-[(triisopropylsilyl)oxy]propyl]oxiranyl)methanol		C₂₃H₄₀O₄Si	详情	详情
(LII)	35896	bromo(3-butenyl)magnesium	7103-09-5	C₄H₇BrMg	详情	详情
(LIII)	35897	(2S,3S,4R,5R)-6-(benzyloxy)-2-(3-butenyl)-4-methyl-5-[(triisopropylsilyl)oxy]-1,3-hexanediol		C₂₇H₄₈O₄Si	详情	详情
(LIV)	35898	(2S)-2-[(1S,2R,3R)-4-(benzyloxy)-1-hydroxy-2-methyl-3-[(triisopropylsilyl)oxy]butyl]-5-hexenyl pivalate		C₃₂H₅₆O₅Si	详情	详情
(LV)	35899	(2S)-2-[(1S,2R,3R)-4-(benzyloxy)-1,3-dihydroxy-2-methylbutyl]-5-hexenyl pivalate		C₂₃H₃₆O₅	详情	详情
(LVI)	35900	[(4S,6S)-3-[(benzyloxy)methyl]-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate		C₂₃H₃₄O₅	详情	详情
(LVII)	35901	[(4S,6S)-3-(hydroxymethyl)-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate		C₁₆H₂₈O₅	详情	详情
(LVIII)	35902	[(4S,6S)-3-formyl-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methyl pivalate		C₁₆H₂₆O₅	详情	详情
(LIX)	35903	[(4S,6S)-3-ethynyl-1,4-dimethyl-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol		C₁₂H₁₈O₃	详情	详情
(LX)	32448	[(3R,4S,5S,6S)-1,4-dimethyl-3-[(E)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol		C₂₄H₄₆O₃Sn	详情	详情

Extended Information