2-allyl-1H-isoindole-1,3(2H)-dione -Drug Synthesis Database

【结构式】

【分子编号】46464

【品名】2-allyl-1H-isoindole-1,3(2H)-dione

【CA登记号】

【分子式】C₁₁H₉NO₂

【分子量】187.198

【元素组成】C 70.58% H 4.85% N 7.48% O 17.09%

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：(VI)

3-Bromo-4-hydroxybenzonitrile (IV) was protected as the methoxymethyl ether (V). Subsequent Heck reaction with N-allyl phthalimide (VI) produced adduct (VII). The phthaloyl group OF (VII) was then removed by hydrazinolysis to yield the primary amine (VIII), which was coupled with carboxylic acid (III) using TBTU to afford amide (IX). Pinner reaction of (IX) with concomitant methoxymethyl group deprotection gave imidate (X). Finally, ammonolysis of the imidate group of (X) furnished the title amidine.

参考文献中间体

合成目标

【1】 Pauls, H.W.; Brown, K.D.; Liang, G.; Czekaj, M.; Chu, V.; Spada, A.P.; Gong, Y.; Gao, J.; Colussi, D.J.; Amido-(propyl and allyl)-hydroxybenzamidines: Development of achiral inhibitors of factor Xa. Bioorg Med Chem Lett 2000, 10, 3, 217.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	46461	4-[2-(aminocarbonyl)-4-pyridinyl]benzoic acid		C₁₃H₁₀N₂O₃	详情	详情
(IV)	46462	3-bromo-4-hydroxybenzonitrile	2315-86-8	C₇H₄BrNO	详情	详情
(V)	46463	3-bromo-4-(methoxymethoxy)benzonitrile		C₉H₈BrNO₂	详情	详情
(VI)	46464	2-allyl-1H-isoindole-1,3(2H)-dione		C₁₁H₉NO₂	详情	详情
(VII)	46465	3-[(E)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-propenyl]-4-(methoxymethoxy)benzonitrile		C₂₀H₁₆N₂O₄	详情	详情
(VIII)	46466	3-[(E)-3-amino-1-propenyl]-4-(methoxymethoxy)benzonitrile		C₁₂H₁₄N₂O₂	详情	详情
(IX)	46467	4-[4-[([(E)-3-[5-cyano-2-(methoxymethoxy)phenyl]-2-propenyl]amino)carbonyl]phenyl]-2-pyridinecarboxamide		C₂₅H₂₂N₄O₄	详情	详情
(X)	46468	ethyl 3-[(E)-3-([4-[2-(aminocarbonyl)-4-pyridinyl]benzoyl]amino)-1-propenyl]-4-hydroxybenzenecarboximidoate		C₂₅H₂₄N₄O₄	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 reaction of 3-bromophenol (I) with 2,2,2-trichloro-1,1-dimethylethanol (II) by means of NaOH in acetone gives 2-(3-bromophenoxy)-2-methylpropionic acid (III), which is esterified with isobutylene and H2SO4, yielding the corresponding tert-butyl ester (IV). The condensation of (IV) with N-allylphthalimide (V) by means of Pd(OAc)2, tri(o-tolyl)phosphine and DIEA in acetonitrile, followed by hydrogenation with H2 over Pd/C, affords the adduct (VI). The reaction of (VI) with hydrazine in refluxing ethanol cleaves the phthalimido group to provide the amino derivative (VII), which is treated with 3,5-dinitrophenylsulfonyl chloride (VIII) and TEA in dichloromethane to give the sulfonamide (IX). The cleavage of the tert-butyl ester group of (IX) with TFA in dichloromethane yields the carboxylic acid (X), which is esterified with SASRIN resin (XI) by means of 1,3-dimethyl-2-fluoro p-toluenesulfonate (DMFPT) in dichloromethane to afford the resin-anchored polyester (XII). The N-alkylation of (XII) with 2,4-bis(trifluoromethyl)benzyl alcohol (XIII) by means of PPh3 and DIAD in THF provides the disubstituted sulfonamide (XIV). The cleavage of the sulfonamido group of (XIV) by means of mercaptoacetic acid and TEA in dichloromethane gives the resin-bound secondary amine (XV), which is acylated with 2-[4-(trifluoromethyl)phenyl]acetic acid (XVI) by means of HATU and DIEA to yield the acetamide precursor (XVII). Finally, the title product is cleaved from the resin (XVII) by treatment with TFA in dichloromethane.

参考文献中间体

合成目标

【1】 Liu, K.G.; Lambert, M.H.; Leesnitzer, L.M.; et al.; Identification of a series of PPARgamma/delta dual agonists via solid-phase parallel synthesis. Bioorg Med Chem Lett 2001, 11, 22, 2959.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X),(XII)	54445	2-[3-(3-{[(3,5-dinitrophenyl)sulfonyl]amino}propyl)phenoxy]-2-methylpropanoic acid		C₁₉H₂₁N₃O₉S	详情	详情
(I)	20704	3-bromophenol	591-20-8	C₆H₅BrO	详情	详情
(II)	25975	1,1,1-trichloro-2-methyl-2-propanol	57-15-8	C₄H₇Cl₃O	详情	详情
(III)	54439	2-(3-bromophenoxy)-2-methylpropanoic acid		C₁₀H₁₁BrO₃	详情	详情
(IV)	54440	tert-butyl 2-(3-bromophenoxy)-2-methylpropanoate		C₁₄H₁₉BrO₃	详情	详情
(V)	46464	2-allyl-1H-isoindole-1,3(2H)-dione		C₁₁H₉NO₂	详情	详情
(VI)	54441	tert-butyl 2-{3-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]phenoxy}-2-methylpropanoate		C₂₅H₂₉NO₅	详情	详情
(VII)	54442	tert-butyl 2-[3-(3-aminopropyl)phenoxy]-2-methylpropanoate		C₁₇H₂₇NO₃	详情	详情
(VIII)	54443	3,5-dinitrobenzenesulfonamide		C₆H₅N₃O₆S	详情	详情
(IX)	54444	tert-butyl 2-[3-(3-{[(3,5-dinitrophenyl)sulfonyl]amino}propyl)phenoxy]-2-methylpropanoate		C₂₃H₂₉N₃O₉S	详情	详情
(XIII)	54446	[2,4-bis(trifluoromethyl)phenyl]methanol		C₉H₆F₆O	详情	详情
(XIV)	54447	2-[3-(3-{[2,4-bis(trifluoromethyl)benzyl][(3,5-dinitrophenyl)sulfonyl]amino}propyl)phenoxy]-2-methylpropanoic acid		C₂₈H₂₅F₆N₃O₉S	详情	详情
(XV)	54448	2-[3-(3-{[2,4-bis(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoic acid		C₂₂H₂₃F₆NO₃	详情	详情
(XVI)	54449	2-[4-(trifluoromethyl)phenyl]acetic acid	32857-62-8	C₉H₇F₃O₂	详情	详情
(XVII)	54450	2-{3-[3-([2,4-bis(trifluoromethyl)benzyl]{2-[4-(trifluoromethyl)phenyl]acetyl}amino)propyl]phenoxy}-2-methylpropanoic acid		C₃₁H₂₈F₉NO₄	详情	详情

Extended Information