1-(bromomethyl)-3-nitrobenzene -Drug Synthesis Database

【结构式】

【分子编号】19636

【品名】1-(bromomethyl)-3-nitrobenzene

【CA登记号】3958-57-4

【分子式】C₇H₆BrNO₂

【分子量】216.03418

【元素组成】C 38.92% H 2.8% Br 36.99% N 6.48% O 14.81%

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：(VIII)

Alkylation of diazepinone (VII) with m-nitrobenzyl bromide (VIII) in the presence of NaH gave the bis-nitrobenzyl derivative (IX). The silylethoxymethyl protecting groups of (IX) were then removed by means of HCl in dioxan to afford diol (X). The nitro groups of (X) were finally reduced by catalytic hydrogenation to the target diamino compound, which was finally converted to the bis-methanesulfonate salt.

参考文献中间体

合成目标

【3】 Lam, P.Y.; Eyermann, C.J.; Hodge, C.N.; Jadhav, P.K.; DeLucca, G.V. (DuPont Pharmaceuticals Co.); Cyclic ureas and analogues useful as retroviral protease inhibitors. EP 0607334; EP 0686151; EP 0765873; JP 1995500324; JP 1996509700; US 5610294; WO 9307128; WO 9419329 .
【1】 Hodge, C.N.; et al.; Improved cyclic urea inhibitors of the HIV-1 protease: Synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450. Chem Biol 1996, 3, 4, 301.
【2】 Lam, P.Y.S.; et al.; Cyclic HIV protease inhibitors. Synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas. J Med Chem 1996, 39, 18, 3514.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	19922	(4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis[[2-(trimethylsilyl)ethoxy]methoxy]-1,3-diazepan-2-one		C₃₁H₅₀N₂O₅Si₂	详情	详情
(VIII)	19636	1-(bromomethyl)-3-nitrobenzene	3958-57-4	C₇H₆BrNO₂	详情	详情
(IX)	59259	(4R,5S,6S,7R)-4,7-dibenzyl-1,3-bis(3-nitrobenzyl)-5,6-bis{[2-(trimethylsilyl)ethoxy]methoxy}-1,3-diazepan-2-one		C₄₅H₆₀N₄O₉Si₂	详情	详情
(X)	59260	(4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-bis(3-nitrobenzyl)-1,3-diazepan-2-one		C₃₃H₃₂N₄O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

Diol (I) was protected as the bis(methoxymethyl) ether (III) by reaction with methoxymethyl bromide (II) in the presence of diisopropyl ethylamine in DMF, and then, the carbobenzoxy groups of (III) were removed by hydrogenolysis in the presence of Pd/C to afford diamine (IV). Subsequent treatment of (IV) with carbonyl diimidazole (CDI) and pyridine provided the cyclic urea (V). Monoalkylation of (V) with m-iodobenzyl bromide (VI) in the presence KOH and polyethylene glycol in toluene provided the (iodobenzyl)diazepinone (VII). Suzuki coupling of (VII) with the protected pyrazolylboronic acid (VIII) in the presence of Pd(PPh3)4 and K2CO3 afforded the (pyrazolylbenzyl) derivative (IX). Further alkylation of (IX) with m-nitrobenzyl bromide (X) and NaH gave (XI). After deprotection of the methoxymethyl and the (trimethylsilyl)ethoxymethyl groups of (XI) upon treatment with HCl in dioxan-methanol, the title compound was obtained by hydrogenation of the nitro group in the presence of Pd/C.

参考文献中间体

合成目标

【1】 Han, Q.; Lam, P.Y.S.; Li, R.; Jadhav, P.K.; Chang, C.-H.; Ru, Y.; Cyclic HIV protease inhibitors: Design and synthesis of orally bioavailable, pyrazole P2/P2' cyclic ureas with improved potency. J Med Chem 1998, 41, 12, 2019.
【2】 Lam, P.Y.; Eyermann, C.J.; Hodge, C.N.; Jadhav, P.K.; DeLucca, G.V. (DuPont Pharmaceuticals Co.); Cyclic ureas and analogues useful as retroviral protease inhibitors. EP 0607334; EP 0686151; EP 0765873; JP 1995500324; JP 1996509700; US 5610294; WO 9307128; WO 9419329 .

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)	19618	benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate		C₃₄H₃₆N₂O₆	详情	详情
(II)	19619	bromo(methoxy)methane; bromomethyl methyl ether	13057-17-5	C₂H₅BrO	详情	详情
(III)	19620	benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-bis(methoxymethoxy)-5-phenylpentylcarbamate		C₃₈H₄₄N₂O₈	详情	详情
(IV)	19621	(2R,3S,4S,5R)-3,4-bis(methoxymethoxy)-1,6-diphenyl-2,5-hexanediamine; (1R,2S,3S,4R)-4-amino-1-benzyl-2,3-bis(methoxymethoxy)-5-phenylpentylamine		C₂₂H₃₂N₂O₄	详情	详情
(V)	19622	(4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis(methoxymethoxy)-1,3-diazepan-2-one		C₂₃H₃₀N₂O₅	详情	详情
(VI)	19623	1-(bromomethyl)-3-iodobenzene	49617-83-6	C₇H₆BrI	详情	详情
(VII)	19633	(4R,5S,6S,7R)-4,7-dibenzyl-1-(3-iodobenzyl)-5,6-bis(methoxymethoxy)-1,3-diazepan-2-one		C₃₀H₃₅IN₂O₅	详情	详情
(VIII)	19625	1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-ylboronic acid		C₉H₁₉BN₂O₃Si	详情	详情
(IX)	19635	(4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis(methoxymethoxy)-1-[3-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-yl)benzyl]-1,3-diazepan-2-one		C₃₉H₅₂N₄O₆Si	详情	详情
(X)	19636	1-(bromomethyl)-3-nitrobenzene	3958-57-4	C₇H₆BrNO₂	详情	详情
(XI)	19637	(4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis(methoxymethoxy)-1-(3-nitrobenzyl)-3-[3-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-yl)benzyl]-1,3-diazepan-2-one		C₄₆H₅₇N₅O₈Si	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

N-Boc-Phenylalanine (I) was treated with isobutyl chloroformate and N-methylmorpholine, and the resulting mixed anhydride (II) was coupled to 2-aminobenzophenone (III) to yield the corresponding amide (IV). After Boc deprotection of (IV) with HCl in EtOAc, the intermediate aminoketone was cyclized with NaOH to the benzodiazepine (V). Alkylation of (V) with 3-nitrobenzyl bromide (VI) in the presence of t-BuOK in THF gave the (nitrobenzyl)benzodiazepine (VII). The nitro group of (VV) was subsequently reduced with SnCl2 in boiling EtOAc to affford (VIII). Then, the resulting amine (VIII) was treated with N,N'-di-Boc-thiourea (IX) in the presence of HgCl2 to provide the diprotected guanidine (X), which was finally deprotected with trifluoroacetic acid in CH2Cl2.

参考文献中间体

合成目标

【1】 Dziadulewicz, E.K.; et al.; The design of non-peptide human bradykinin B2 receptor antagonists employing the benzodiazepine peptidomimetic scaffold. Bioorg Med Chem Lett 1999, 9, 3, 463.

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)	21835	N-(tert-butoxycarbonyl)phenylalanine	4530-18-1	C₁₄H₁₉NO₄	详情	详情
(II)	21836	N-(Tert-butoxycarbonyl)-DL-phenylalanine isobutoxycarbonyl anhydride		C₁₉H₂₇NO₆	详情	详情
(IV)	21838	tert-butyl 2-(2-benzoylanilino)-1-benzyl-2-oxoethylcarbamate		C₂₇H₂₈N₂O₄	详情	详情
(V)	21839	3-benzyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one		C₂₂H₁₈N₂O	详情	详情
(VI)	19636	1-(bromomethyl)-3-nitrobenzene	3958-57-4	C₇H₆BrNO₂	详情	详情
(VII)	21841	3-benzyl-1-(3-nitrobenzyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one		C₂₉H₂₃N₃O₃	详情	详情
(VIII)	21842	1-(3-aminobenzyl)-3-benzyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one		C₂₉H₂₅N₃O	详情	详情
(IX)	21843	tert-butyl [(tert-butoxycarbonyl)amino]carbothioylcarbamate	145013-05-4	C₁₁H₂₀N₂O₄S	详情	详情
(X)	21844	tert-butyl (Z)-[3-[(3-benzyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)methyl]anilino][(tert-butoxycarbonyl)amino]methylidenecarbamate		C₄₀H₄₃N₅O₅	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IV)

Acylation of L-phenylalanine tert-butyl ester (I) with 2,4-dichlorobenzoyl chloride (II) provides the corresponding amide (III). This is then N-alkylated with 3-nitrobenzyl bromide (IV) in the presence of NaH to yield (V). The tert-butyl ester group of (V) is finally cleaved with trifluoroacetic acid to furnish the target carboxylic acid. (1-3)

参考文献中间体

合成目标

【1】 Chan, L.; Reddy, J.; Proulx, M.; Das, S.K.; Pereira, O.; Wang, W.; Siddiqui, A.; Yannopoulos, C.G.; Poisson, C.; Turcotte, N.; Drouin, A.; Alaoui-Ismaili, M.H.; Bethell, R.; Hamel, M.; L'Heureux, L.; Bilimoria, D.; Nguyen-Ba, N.; Identification of N,N-disubstituted phenylalanines as a novel class of inhibitors of hepatitis C NS5B polymerase. J Med Chem 2003, 46, 8, 1283.
【2】 Proulx, M.; Chan, L.; Reddy, T.J.; Das, S.K.; Pereira, O.Z.; Identification of a novel class of inhibitors of hepatitis C NS5B polymerase. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 40.
【3】 Pereira, O.Z.; Wang, W.; Siddiqui, M.A.; Bedard, J.; Nguyen Ba, N.; Chan, C.K.L.; Das, S.K.; Shuttleworth, S. (Shire BioChem Inc.); Cpds. and methods for the treatment or prevention of flavivirus infections. US 2003229053; WO 02100846 .

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)	60837	tert-butyl (2S)-2-amino-3-phenylpropanoate		C₁₃H₁₉NO₂	详情	详情
(II)	35131	2,4-dichlorobenzoyl chloride; 2,4-Dichlorophenacylchloride	89-75-8	C₇H₃Cl₃O	详情	详情
(III)	64057	1,1-dimethylethyl 2-{[(2,4-dichlorophenyl)carbonyl]amino}-3-phenylpropanoate		C₂₀H₂₁Cl₂NO₃	详情	详情
(IV)	19636	1-(bromomethyl)-3-nitrobenzene	3958-57-4	C₇H₆BrNO₂	详情	详情
(V)	64058	1,1-dimethylethyl 2-{[(2,4-dichlorophenyl)carbonyl][(3-nitrophenyl)methyl]amino}-3-phenylpropanoate		C₂₇H₂₆Cl₂N₂O₅	详情	详情

Extended Information