2-(dimethylamino)ethyl(methyl)formamide -Drug Synthesis Database

【结构式】

【分子编号】54879

【品名】2-(dimethylamino)ethyl(methyl)formamide

【CA登记号】

【分子式】C₆H₁₄N₂O

【分子量】130.19004

【元素组成】C 55.35% H 10.84% N 21.52% O 12.29%

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：(XIX)

Lithiation of 2-methoxypyridine (XVIII), followed by formylation with N-formyl-N,N',N'-trimethylethylenediamine (XIX), produced the pyridine carbaldehyde (XX), which was further iodinated to (XXI) by lithiation and subsequent treatment with iodine. Reductive condensation of aldehyde (XXI) with crotyl alcohol (XXII) in the presence of triethylsilane and trifluoroacetic acid yielded the crotyl ether (XXIII). Cyclization of (XXIII) under Heck reaction conditions led to a mixture of the ethylidene pyranopyridine (XXIV) and the major isomerized analogue (XXV). Sharpless asymmetric dihydroxylation of this reaction mixture afforded the alpha-hydroxy lactol (XXVI), which was further oxidixed to hydroxy lactone (XXVII) employing iodine and CaCO3. Demethylation of ether (XXVII) under acidic conditions generated lactam (XXVIII). Mitsunobu coupling between lactam (XXVIII) and (hydroxymethyl)quinoline (XVII) furnished adduct (XXIX). The title compound was finally obtained by Heck cyclization of (XXIX) in the presence of palladium acetate and triphenylphosphine.

参考文献中间体

合成目标

【1】 Fang, F.G.; et al.; Convergent catalytic asymmetric synthesis of camptothecin analog GI147211C. Tetrahedron 1997, 53, 32, 10953.
【2】 Fang, F.G.; Xie, S.; Lowery, M.W. (GlaxoSmithKline Inc.); Intermediates in pharmaceutical camptothecin preparation. WO 9529917 .
【3】 Huie, E.M.; Fang, F.G.; Xie, S.; Comins, D.L. (GlaxoSmithKline Inc.; North Carolina State University); Preparation of a camptothecin deriv. by intramolecular cyclisation. WO 9529919 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVII)	54877	{7-iodo-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methanol		C₁₈H₂₂IN₃O₃	详情	详情
(XVIII)	54878	2-Methoxypyridine; Methyl 2-pyridyl ether	1628-89-3	C₆H₇NO	详情	详情
(XIX)	54879	2-(dimethylamino)ethyl(methyl)formamide		C₆H₁₄N₂O	详情	详情
(XX)	54880	2-methoxynicotinaldehyde		C₇H₇NO₂	详情	详情
(XXI)	54881	4-iodo-2-methoxynicotinaldehyde		C₇H₆INO₂	详情	详情
(XXII)	54882	2-Butene-1-ol; Crotyl Alcohol; trans-Propenylcarbinol	504-61-0	C₄H₈O	详情	详情
(XXIII)	54883	(E)-2-butenyl (4-iodo-2-methoxy-3-pyridinyl)methyl ether; 3-{[(E)-2-butenyloxy]methyl}-4-iodo-2-methoxypyridine		C₁₁H₁₄INO₂	详情	详情
(XXIV)	54884	4-[(E)ethylidene]-3,4-dihydro-1H-pyrano[3,4-c]pyridin-8-yl methyl ether; 4-[(E)ethylidene]-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine		C₁₁H₁₃NO₂	详情	详情
(XXV)	54885	4-ethyl-1H-pyrano[3,4-c]pyridin-8-yl methyl ether; 4-ethyl-8-methoxy-1H-pyrano[3,4-c]pyridine		C₁₁H₁₃NO₂	详情	详情
(XXVI)	54886	(4S)-4-ethyl-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-3,4-diol		C₁₁H₁₅NO₄	详情	详情
(XXVII)	54887	(4S)-4-ethyl-4-hydroxy-8-methoxy-1,4-dihydro-3H-pyrano[3,4-c]pyridin-3-one		C₁₁H₁₃NO₄	详情	详情
(XXVIII)	54888	(4S)-4-ethyl-4-hydroxy-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione		C₁₀H₁₁NO₄	详情	详情
(XXIX)	54889	(4S)-4-ethyl-4-hydroxy-7-({7-iodo-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methyl)-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione		C₂₈H₃₁IN₄O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIX)

The silylated pyranopyridine (XXXIV) was prepared by an analoguos route to that of Scheme 3 starting from 2-methoxy-6-(trimethylsilyl)pyridine (XXX). Halogenation-desilylation of (XXXIV) by means of ICl-furnished iodide (XXXV). Subsequent demethylation of (XXXV) to give lactam (XXXVI) was performed employing either aqueous HI or iodotrimethylsane. Alkylation of lactam (XXXVI) with 1,4-dichloro-2-butyne (XXXVII) to (XXXVIII), followed by reaction with piperazine (IX), yielded (XXXIX). The cascade radical cyclization of (XXXIX) with isonitrile (XL) under sunlamp irradiation in the presence of hexamethyldistannane led to an inseparable mixture of the title compound and its regioisomer (XLI).

参考文献中间体

合成目标

【1】 Josien, H.; et al.; A general synthetic approach to the (20S)-camptothecin family of antitumor agents by a regiocontrolled cascade radical cyclization of aryl isonitriles. Chemistry (Weinheim) 1998, 4, 1, 67.
【2】 Curran, D.P.; et al.; Cascade radical reactions of isonitriles: A second-generation synthesis of (20S)-camptothecin, topotecan, irinotecan, and GI-147211C. Angew Chem. Int Ed 1995, 34, 23-24, 2683.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	详情	详情
(XIX)	54879	2-(dimethylamino)ethyl(methyl)formamide		C₆H₁₄N₂O	详情	详情
(XXII)	54882	2-Butene-1-ol; Crotyl Alcohol; trans-Propenylcarbinol	504-61-0	C₄H₈O	详情	详情
(XXX)	54890	methyl 6-(trimethylsilyl)-2-pyridinyl ether; 2-methoxy-6-(trimethylsilyl)pyridine		C₉H₁₅NOSi	详情	详情
(XXXI)	54891	4-iodo-2-methoxy-6-(trimethylsilyl)nicotinaldehyde		C₁₀H₁₄INO₂Si	详情	详情
(XXXII)	54892	3-{[(E)-2-butenyloxy]methyl}-4-iodo-2-methoxy-6-(trimethylsilyl)pyridine; (E)-2-butenyl [4-iodo-2-methoxy-6-(trimethylsilyl)-3-pyridinyl]methyl ether		C₁₄H₂₂INO₂Si	详情	详情
(XXXIII)	35096	4-ethyl-6-(trimethylsilyl)-1H-pyrano[3,4-c]pyridin-8-yl methyl ether; 4-ethyl-8-methoxy-6-(trimethylsilyl)-1H-pyrano[3,4-c]pyridine		C₁₄H₂₁NO₂Si	详情	详情
(XXXIV)	54893	(4S)-4-ethyl-4-hydroxy-8-methoxy-6-(trimethylsilyl)-1,4-dihydro-3H-pyrano[3,4-c]pyridin-3-one		C₁₄H₂₁NO₄Si	详情	详情
(XXXV)	54894	(4S)-4-ethyl-4-hydroxy-6-iodo-8-methoxy-1,4-dihydro-3H-pyrano[3,4-c]pyridin-3-one		C₁₁H₁₂INO₄	详情	详情
(XXXVI)	49255	(4S)-4-ethyl-4-hydroxy-6-iodo-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione		C₁₀H₁₀INO₄	详情	详情
(XXXVII)	50923	1,4-Dichloro-2-butyne	821-10-3	C₄H₄Cl₂	详情	详情
(XXXVIII)	54895	(4S)-7-(4-chloro-2-butynyl)-4-ethyl-4-hydroxy-6-iodo-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione		C₁₄H₁₃ClINO₄	详情	详情
(XXXIX)	54886	(4S)-4-ethyl-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-3,4-diol		C₁₁H₁₅NO₄	详情	详情
(XL)	54898			C₉H₇NO₂	详情	详情
(XLI)	54897	(9S)-9-ethyl-9-hydroxy-16-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro-12H-[1,4]dioxino[2,3-f]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione		C₂₈H₃₀N₄O₆	详情	详情

Extended Information