2,4-imidazolidinedione -Drug Synthesis Database

【结构式】

【分子编号】32482

【品名】2,4-imidazolidinedione

【CA登记号】461-72-3

【分子式】C₃H₄N₂O₂

【分子量】100.07704

【元素组成】C 36.01% H 4.03% N 27.99% O 31.97%

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：(II)

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

合成路线2

该中间体在本合成路线中的序号：(XXII)

An alternative synthetic method employed the racemic amino acid (XXIX). The phenylpyruvic acid precursor (XXVII) was prepared from benzaldehyde (XXI) by several procedures. Condensation of benzaldehyde (XXI) with hydantoin (XXII) yielded the benzylidene hydantoin (XXIV), which was converted to (XXVII) by basic hydrolysis. Alternatively, aldehyde (XXI) was condensed with N-acetyl glycine or with the phosphonoacetate reagent (XXIII) to produce (XXV) or (XXVI), respectively. Basic hydrolysis of either (XXV) or (XXVI) led to the desired phenylpyruvic acid (XXVII). Dialkylation of keto acid (XXVII) with iodomethane and NaOH furnished the dimethyl derivative (XXVIII). Then, reductive amination of (XXVIII) with methylamine yielded the racemic amino acid (XXIX). Coupling of amino acid (XXIX) with the intermediate dipeptide (XIX) gave rise to tripeptide (XXX) as an epimeric mixture. After chromatographic isolation of the desired isomer, basic hydrolysis of the ethyl ester provided the title compound.

参考文献中间体

合成目标

【1】 Zask, A.; Cheung, K.; Birnberg, G.; et al.; Synthesis and biological activity of analogs of the antimicrotubule agent HTI-286. Proc Am Assoc Cancer Res 2002, 43, Abst 3653.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIX)	55124	ethyl (E,4S)-4-[[(2S)-2-amino-3,3-dimethylbutanoyl](methyl)amino]-2,5-dimethyl-2-hexenoate		C₁₇H₃₂N₂O₃	详情	详情
(XXI)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(XXII)	32482	2,4-imidazolidinedione	461-72-3	C₃H₄N₂O₂	详情	详情
(XXIII)	55126	methyl 2-(acetyloxy)-2-(diethoxyphosphoryl)acetate		C₉H₁₇O₇P	详情	详情
(XXIV)	55127	5-[(Z)-phenylmethylidene]-2,4-imidazolidinedione		C₁₀H₈N₂O₂	详情	详情
(XXV)	55128	2-methyl-4-[(Z)-phenylmethylidene]-1,3-oxazol-5-one		C₁₁H₉NO₂	详情	详情
(XXVI)	55129	methyl (Z)-2-(acetyloxy)-3-phenyl-2-propenoate		C₁₂H₁₂O₄	详情	详情
(XXVII)	55130	2-Oxophenylpropionic acid; Alpha-keto-DL-phenylalanine; Benzylglyoxylic acid; Phenylpyruvic acid	156-06-9	C₉H₈O₃	详情	详情
(XXVIII)	55131	3-methyl-2-oxo-3-phenylbutanoic acid		C₁₁H₁₂O₃	详情	详情
(XXIX)	55132	N-methyl-3-phenylvaline		C₁₂H₁₇NO₂	详情	详情
(XXX)	55133	ethyl (E,4S)-4-[((2S)-3,3-dimethyl-2-{[3-methyl-2-(methylamino)-3-phenylbutanoyl]amino}butanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate		C₂₉H₄₇N₃O₄	详情	详情

Extended Information