4-[({4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】53515

【品名】4-[({4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid

【CA登记号】n/a

【分子式】C₂₃H₂₈N₆O₆

【分子量】484.51216

【元素组成】C 57.02% H 5.82% N 17.35% O 19.81%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(V)

The reaction of Distamycin A (I) with succinic anhydride and Na2CO3 in hot DMF gives the nitrile (II), which is treated with Boc2O and DMAP in dichloromethane to yield the monocarbamate (III). The reaction of (III) with Boc2O and DMAP in DMF affords the bis carbamate (IV), which is hydrolyzed with LiOH in THF/water to provide the carboxylic acid (V). The condensation of (V) with N-(2-aminoethyl)guanidine (VI) by means of by means of TBTU in DMF gives the guanidinoethyl amide (VII), which is deprotected by means of TFA in dichloromethane to yield the aminopyrrole derivative (VIII). Finally, this compound is condensed with the acid chloride (IX) by means of NaHCO3 in dioxane/water to provide the target brostallicin.

参考文献中间体

合成目标

【1】 Nesi, M.; Beria, I.; Syntheses of brostallicin starting from distamycin A. Tetrahedron Lett 2002, 43, 41, 7323.

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)	57197	N-(5-{[(3-amino-3-iminopropyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-({[4-(formylamino)-1-methyl-1H-pyrrol-2-yl]carbonyl}amino)-1-methyl-1H-pyrrole-2-carboxamide		C₂₂H₂₇N₉O₄	详情	详情
(II)	57198	N-(2-cyanoethyl)-4-({[4-({[4-(formylamino)-1-methyl-1H-pyrrol-2-yl]carbonyl}amino)-1-methyl-1H-pyrrol-2-yl]carbonyl}amino)-1-methyl-1H-pyrrole-2-carboxamide		C₂₂H₂₄N₈O₄	详情	详情
(III)	57199	tert-butyl 5-{[(5-{[(5-{[(2-cyanoethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl(formyl)carbamate		C₂₇H₃₂N₈O₆	详情	详情
(IV)	57200	tert-butyl 5-{[(5-{[(5-{[(tert-butoxycarbonyl)(2-cyanoethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl(formyl)carbamate		C₃₂H₄₀N₈O₈	详情	详情
(V)	53515	4-[({4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid	n/a	C₂₃H₂₈N₆O₆	详情	详情
(VI)	41437	N-(2-aminoethyl)guanidine		C₃H₁₀N₄	详情	详情
(VII)	57201	tert-butyl 5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino}ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-ylcarbamate		C₂₆H₃₆N₁₀O₅	详情	详情
(VIII)	41444	N-(2-[[amino(imino)methyl]amino]ethyl)-4-[[(4-[[(4-amino-1-methyl-1H-pyrrol-2-yl)carbonyl]amino]-1-methyl-1H-pyrrol-2-yl)carbonyl]amino]-1-methyl-1H-pyrrole-2-carboxamide		C₂₁H₂₈N₁₀O₃	详情	详情
(IX)	41441	4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carbonyl chloride		C₉H₈BrClN₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The condensation of 4-(tert-butoxycarbonylamino)-1-methyl-1H-pyrrole-2-carboxylic acid (I) with 4-amino-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (II) by means of DCC, HOBT and TEA in hot DMF gives the dimeric amide (III), which is hydrolyzed with NaOH in hot methanol/water to yield the carboxylic acid (IV). The condensation of (IV) with methyl ester (II) by means of HBTU and TEA in hot DMF affords the trimeric diamide (V), which is hydrolyzed with NaOH in methanol/water to provide the carboxylic acid (VI). The deprotection of the carbamate group of (VI) with HCl in ethyl acetate gives the trimeric amino acid (VII), which is condensed with 4,5-dichloroisothiazole-3-carboxylic acid (VIII) by means of HBTU and DIEA in DMF to yield the tetrameric carboxylic acid (IX). The condensation of (IX) with 3-aminopropionitrile (X) by means of HBTU and TEA in DMF affords the corresponding tetrameric tetraamide (XI), which is treated with gaseous HCl in methanol to provide the iminoester (XII). Finally, this compound is treated with NH3 in methanol to furnish the target carboxamidine.

参考文献中间体

合成目标

【1】 Burli, R.; et al.; HARP: A novel class of antibiotics. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1685.

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)	53510	4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid	77716-11-1	C₁₁H₁₆N₂O₄	详情	详情
(II)	53511	methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate	180258-45-1	C₇H₁₀N₂O₂	详情	详情
(III)	53512	methyl 4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylate	n/a	C₁₈H₂₄N₄O₅	详情	详情
(IV)	53513	4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid	n/a	C₁₇H₂₂N₄O₅	详情	详情
(V)	53514	methyl 4-[({4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylate	n/a	C₂₄H₃₀N₆O₆	详情	详情
(VI)	53515	4-[({4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid	n/a	C₂₃H₂₈N₆O₆	详情	详情
(VII)	53516	4-{[(4-{[(4-amino-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrole-2-carboxylic acid	n/a	C₁₈H₂₀N₆O₄	详情	详情
(VIII)	53517	4,5-Dichloroisothiazole-3-carboxylic acid	131947-13-2	C₄HCl₂NO₂S	详情	详情
(IX)	53518	4-{[(4-{[(4-{[(4,5-dichloro-3-isothiazolyl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrole-2-carboxylic acid	n/a	C₂₂H₁₉Cl₂N₇O₅S	详情	详情
(X)	38094	3-aminopropanenitrile	151-18-8	C₃H₆N₂	详情	详情
(XI)	53519	4,5-dichloro-N-(5-{[(5-{[(5-{[(2-cyanoethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-3-isothiazolecarboxamide	n/a	C₂₅H₂₃Cl₂N₉O₄S	详情	详情
(XII)	53520	methyl 3-{[(4-{[(4-{[(4-{[(4,5-dichloro-3-isothiazolyl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}propanimidoate	n/a	C₂₆H₂₇Cl₂N₉O₅S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XII)

Friedel-Crafts acylation of N-methylpyrrole (I) with trichloroacetyl chloride (II) affords the pyrrolyl ketone (III), which is subsequently subjected to electrophilic nitration with in situ generated acetyl nitrate, producing nitropyrrole (IV). Cleavage of the trichloroketone group of (IV) under alkaline conditions, followed by Fischer esterification leads to methyl ester (V). The nitro group of (V) is then reduced to amine (VI) by catalytic hydrogenation over Pd/C. After protection of amine (VI) as the corresponding N-Boc derivative (VII), saponification of the methyl ester group of (VII) yields acid (VIII). Coupling between the pyrrolecarboxylic acid (VIII) and amino ester (VI) provides the amide adduct (IX). After alkaline ester hydrolysis in (IX), the resultant carboxylic acid (X) is coupled with a further moiety of methyl 4-amino-1-methylpyrrole-2-carboxylate (VI) to furnish the tripyrrolyl compound (XI). Subsequent methyl ester saponification in (XI) provides acid (XII).

参考文献中间体

合成目标

【1】 Ge, Y.; Taylor, M.J.; Baird, E.E.; Moser, H.E.; Burli, R.W. (GeneSoft, Inc.); Charged cpds. comprising a nucleic acid binding moiety and uses therefor. JP 2003529609; WO 0174898 .

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)	11285	1-Methyl-1H-pyrrole; Methylpyrrole	96-54-8	C₅H₇N	详情	详情
(II)	47015	2,2,2-trichloroacetyl chloride	76-02-8	C₂Cl₄O	详情	详情
(III)	47020	2,2,2-trichloro-1-(1-methyl-1H-pyrrol-2-yl)-1-ethanone		C₇H₆Cl₃NO	详情	详情
(IV)	47021	2,2,2-trichloro-1-(1-methyl-4-nitro-1H-pyrrol-2-yl)-1-ethanone		C₇H₅Cl₃N₂O₃	详情	详情
(V)	58474	methyl 1-methyl-4-nitro-1H-pyrrole-2-carboxylate		C₇H₈N₂O₄	详情	详情
(VI)	53511	methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate	180258-45-1	C₇H₁₀N₂O₂	详情	详情
(VII)	58475	methyl 4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylate		C₁₂H₁₈N₂O₄	详情	详情
(VIII)	53510	4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid	77716-11-1	C₁₁H₁₆N₂O₄	详情	详情
(IX)	53512	methyl 4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylate	n/a	C₁₈H₂₄N₄O₅	详情	详情
(X)	53513	4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid	n/a	C₁₇H₂₂N₄O₅	详情	详情
(XI)	53514	methyl 4-[({4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylate	n/a	C₂₄H₃₀N₆O₆	详情	详情
(XII)	53515	4-[({4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid	n/a	C₂₃H₂₈N₆O₆	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XII)

The tripyrrolyl acid (XII) is coupled with N,N-dimethyl-1,3-propanediamine (XIII) to afford amide (XIV). After acidic Boc group cleavage in (XIV), the resultant amino compound (XV) is acylated by 4,5-dichloroisothiazole-3-carboxylic acid (XVI) to furnish the tetra-heterocyclic amide (XVII). Finally, selective displacement of the 5-chloro group of (XVII) with 1,4-butanediamine (XVIII) gives rise to the title compound.

参考文献中间体

合成目标

【1】 Ge, Y.; Taylor, M.J.; Baird, E.E.; Moser, H.E.; Burli, R.W. (GeneSoft, Inc.); Charged cpds. comprising a nucleic acid binding moiety and uses therefor. JP 2003529609; WO 0174898 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	53515	4-[({4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid	n/a	C₂₃H₂₈N₆O₆	详情	详情
(XIII)	25248	N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine	109-55-7	C₅H₁₄N₂	详情	详情
(XIV)	58476	tert-butyl 5-({[5-({[5-({[3-(dimethylamino)propyl]amino}carbonyl)-1-methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3-ylcarbamate		C₂₈H₄₀N₈O₅	详情	详情
(XV)	58477	4-{[(4-{[(4-amino-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-N-[3-(dimethylamino)propyl]-1-methyl-1H-pyrrole-2-carboxamide		C₂₃H₃₂N₈O₃	详情	详情
(XVI)	53577	((3aR,4R,6R,6aS)-2,2-dimethyl-6-{6-[(3R)tetrahydro-3-furanylamino]-9H-purin-9-yl}tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl methylcarbamate	n/a	C₁₉H₂₆N₆O₆	详情	详情
(XVII)	58478	4,5-dichloro-N-[5-({[5-({[5-({[3-(dimethylamino)propyl]amino}carbonyl)-1-methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3-yl]-3-isothiazolecarboxamide		C₂₇H₃₁Cl₂N₉O₄S	详情	详情
(XVIII)	42070	1,4-butanediamine; 4-aminobutylamine	110-60-1	C₄H₁₂N₂	详情	详情

Extended Information