diethyl 2-(3-chloropropyl)malonate -Drug Synthesis Database

【结构式】

【分子编号】32476

【品名】diethyl 2-(3-chloropropyl)malonate

【CA登记号】18719-43-2

【分子式】C₁₀H₁₇ClO₄

【分子量】236.69528

【元素组成】C 50.74% H 7.24% Cl 14.98% O 27.04%

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：(V)

The condensation of 2-(4-nitrophenyl)ethanol (I) with 5,5-dimethylimidazolidine-2,4-dione (II) by means of PPh3 and DIAD in THF gives 5,5-dimethyl-3-[2-(4-nitrophenyl)ethyl]imidazolidine-2,4-dione (III), which is reduced with H2 over Pd/C in ethanol yielding the 4-aminophenyl derivative (IV). The condensation of (IV) with 2-(3-chloropropyl)malonic acid diethyl ester (V) by means of NaNO2 and NaOAc in water affords the hydrazone (VI), which is isomerized and cyclized in refluxing butanol giving the indolecarboxylic ester (VII). The methylation of the free amino group of (VII) with formaldehyde and NaCNBH3 yields the dimethylamino derivative (VIII), which is transesterified with benzyl alcohol and titanium tetraisopropoxide affording the benzyl ester (IX). The debenzylation of (IX) with H2 over Pd/C gives the free acid (X), which is finally converted into the target amide with benzylamine, TBTU and DIPEA in DMF.

参考文献中间体

合成目标

【1】 Robertson, A.D.; Dodsworth, S.; Sang, P.Y.; Glen, R.; Moloney, G.P.; Mathews, N.; Martin, G.R.; MacLennan, S.; Knight, C.; A novel series of 2,5-substituted tryptamine derivatives as vascular 5HT(1B/1D) receptor antagonists. J Med Chem 1997, 40, 15, 2347-62.
【2】 Mathews, N.; Martin, G.R.; Moloney, G.P.; et al.; Synthesis and serotonergic activity of substituted 2,N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N,N-dimethyltryptamine derivatives: Novel antagonists for the vascular 5-HT1B-like receptor. J Med Chem 1999, 42, 14, 2504.

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)	32472	2-(4-nitrophenyl)-1-ethanol	100-27-6	C₈H₉NO₃	详情	详情
(II)	32473	5,5-dimethyl-2,4-imidazolidinedione	77-71-4	C₅H₈N₂O₂	详情	详情
(III)	32474	5,5-dimethyl-3-(4-nitrophenethyl)-2,4-imidazolidinedione		C₁₃H₁₅N₃O₄	详情	详情
(IV)	32475	3-(4-aminophenethyl)-5,5-dimethyl-2,4-imidazolidinedione		C₁₃H₁₇N₃O₂	详情	详情
(V)	32476	diethyl 2-(3-chloropropyl)malonate	18719-43-2	C₁₀H₁₇ClO₄	详情	详情
(VI)	32477	ethyl 5-chloro-2-((Z)-2-[4-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]phenyl]hydrazono)pentanoate		C₂₀H₂₇ClN₄O₄	详情	详情
(VII)	32478	ethyl 3-(2-aminoethyl)-5-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylate		C₂₀H₂₆N₄O₄	详情	详情
(VIII)	32479	ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylate		C₂₂H₃₀N₄O₄	详情	详情
(IX)	32480	benzyl 3-[2-(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylate		C₂₇H₃₂N₄O₄	详情	详情
(X)	32481	3-[2-(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylic acid		C₂₀H₂₆N₄O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The condensation of 2-(4-nitrophenyl)ethanol (I) with imidazolidine-2,4-dione (II) by means of PPh3 and DIAD in THF gives 3-[2-(4-nitrophenyl)ethyl]imidazolidine-2,4-dione (III), which is reduced with H2 over Pd/C in ethanol yielding the 4-aminophenyl derivative (IV). The condensation of (IV) with 2-(3-chloropropyl)malonic acid diethyl ester (V) by means of NaNO2 and NaOAc in water affords the hydrazone (VI), which is isomerized and cyclized in refluxing butanol giving the indolecarboxylic ester (VII). The methylation of the free amino group of (VII) with formaldehyde and NaCNBH3 yields the dimethylamino derivative (VIII) (1), which is transesterified with benzyl alcohol and titanium tetraisopropoxide affording the benzyl ester (IX). The debenzylation of (IX) with H2 over Pd/C gives the free acid (X), which is finally converted into the target amide with benzylamine, TBTU and DIPEA in DMF.

参考文献中间体

合成目标

【1】 Robertson, A.D.; Dodsworth, S.; Sang, P.Y.; Glen, R.; Moloney, G.P.; Mathews, N.; Martin, G.R.; MacLennan, S.; Knight, C.; A novel series of 2,5-substituted tryptamine derivatives as vascular 5HT(1B/1D) receptor antagonists. J Med Chem 1997, 40, 15, 2347-62.
【2】 Mathews, N.; Martin, G.R.; Moloney, G.P.; et al.; Synthesis and serotonergic activity of substituted 2,N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N,N-dimethyltryptamine derivatives: Novel antagonists for the vascular 5-HT1B-like receptor. J Med Chem 1999, 42, 14, 2504.

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)	32472	2-(4-nitrophenyl)-1-ethanol	100-27-6	C₈H₉NO₃	详情	详情
(II)	32482	2,4-imidazolidinedione	461-72-3	C₃H₄N₂O₂	详情	详情
(III)	32483	3-(4-nitrophenethyl)-2,4-imidazolidinedione		C₁₁H₁₁N₃O₄	详情	详情
(IV)	32484	3-(4-aminophenethyl)-2,4-imidazolidinedione		C₁₁H₁₃N₃O₂	详情	详情
(V)	32476	diethyl 2-(3-chloropropyl)malonate	18719-43-2	C₁₀H₁₇ClO₄	详情	详情
(VI)	32485	ethyl 5-chloro-2-((Z)-2-[4-[2-(2,5-dioxo-1-imidazolidinyl)ethyl]phenyl]hydrazono)pentanoate		C₁₈H₂₃ClN₄O₄	详情	详情
(VII)	32486	ethyl 3-(2-aminoethyl)-5-[2-(2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylate		C₁₈H₂₂N₄O₄	详情	详情
(VIII)	32487	ethyl 3-[2-(dimethylamino)ethyl]-5-[2-(2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylate		C₂₀H₂₆N₄O₄	详情	详情
(IX)	32488	benzyl 3-[2-(dimethylamino)ethyl]-5-[2-(2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylate		C₂₅H₂₈N₄O₄	详情	详情
(X)	32489	3-[2-(dimethylamino)ethyl]-5-[2-(2,5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxylic acid		C₁₈H₂₂N₄O₄	详情	详情

Extended Information