1,4-Dichloro-2-butyne -Drug Synthesis Database

【结构式】

【分子编号】50923

【品名】1,4-Dichloro-2-butyne

【CA登记号】821-10-3

【分子式】C₄H₄Cl₂

【分子量】122.98116

【元素组成】C 39.07% H 3.28% Cl 57.66%

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：(XXXVII)

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

合成路线2

该中间体在本合成路线中的序号：(IX)

In an alternative procedure, nucleophilic displacement of the nitro group from 3-nitro-2-isoxazoline (VI) with lithium benzylate gave the benzyl ether (VII), which was converted to isoxazolidinone (VIII) by catalytic hydrogenation. Alkylation of (VIII) with 1,4-dichloro-2-butyne (IX) resulted in a 4:1 mixture of regioisomers (X) and (XI). After chromatographic isolation, the desired isomer (X) was condensed with pyrrolidine (V) to provide the title compound.

参考文献中间体

合成目标

【1】 Dallanoce, C.; et al.; Synthesis and functional characterization of novel derivatives related to oxotremorine and oxotremorine-M. Bioorg Med Chem 1999, 7, 8, 1539.
【2】 Conti, P.; et al.; Synthesis and binding affinity of new muscarinic ligands structurally related to oxotremorine. Bioorg Med Chem Lett 1997, 7, 8, 1033.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	50920	3-nitro-4,5-dihydroisoxazole		C₃H₄N₂O₃	详情	详情
(VII)	50921	benzyl 4,5-dihydro-3-isoxazolyl ether; 3-(benzyloxy)-4,5-dihydroisoxazole		C₁₀H₁₁NO₂	详情	详情
(VIII)	50922	3-isoxazolidinone		C₃H₅NO₂	详情	详情
(IX)	50923	1,4-Dichloro-2-butyne	821-10-3	C₄H₄Cl₂	详情	详情
(X)	50924	2-(4-chloro-2-butynyl)-3-isoxazolidinone		C₇H₈ClNO₂	详情	详情
(XI)	50925	3-[(4-chloro-2-butynyl)oxy]-4,5-dihydroisoxazole; 4-chloro-2-butynyl 4,5-dihydro-3-isoxazolyl ether		C₇H₈ClNO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXXV)

Alternatively, morpholine (XVIII) was alkylated with 1,4-dichloro-2-butyne (XXXV) in the presence of K2CO3 to afford the propargyl chloride (XXXVI). Displacement of the chloride of (XXXVI) with sodium azide in DMSO gave the propargylic azide (XXXVII). The title triazole was then produced via isomerization and cyclization of azide (XXXVII) upon heating with dimethylamine in a sealed tube.

参考文献中间体

合成目标

【1】 Harrison, T.; Owens, A.P.; Williams, B.J.; et al.; An orally active, water-soluble neurokinin-1 receptor antagonist suitable for both intravenous and oral clinical administration. J Med Chem 2001, 44, 24, 4296.
【2】 Baker, R.; Harrison, T.; Mcleod, A.M.; Owens, A.P.; Seward, E.M.; Swain, C.J.; Teall, M.R. (Merck Sharp & Dohme Ltd.); Substd. morpholine derivs. and their use as therapeutic agents. EP 0737192; EP 1099702; JP 1997507484; JP 2000219629; US 5612337; WO 9518124 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVIII)	18293	(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine	171482-05-6	C₂₀H₁₈F₇NO₂	详情	详情
(XXXV)	50923	1,4-Dichloro-2-butyne	821-10-3	C₄H₄Cl₂	详情	详情
(XXXVI)	53302	(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-4-(4-chloro-2-butynyl)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-chloro-2-butynyl)-3-(4-fluorophenyl)morpholine	n/a	C₂₄H₂₁ClF₇NO₂	详情	详情
(XXXVII)	53303	(2R,3S)-4-(4-azido-2-butynyl)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholine; (2R,3S)-4-(4-azido-2-butynyl)-3-(4-fluorophenyl)morpholinyl (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl ether	n/a	C₂₄H₂₁F₇N₄O₂	详情	详情

Extended Information