(4-nitrophenyl)methanamine; 4-nitrobenzylamine -Drug Synthesis Database

【结构式】

【分子编号】31562

【品名】(4-nitrophenyl)methanamine; 4-nitrobenzylamine

【CA登记号】

【分子式】C₇H₈N₂O₂

【分子量】152.1528

【元素组成】C 55.26% H 5.3% N 18.41% O 21.03%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(X)

Reductive condensation of p-nitrobenzylamine (X) with tetrahydropyran-4-one (XI) in the presence of sodium triacetoxyborohydride gave the tetrahydropyranylamine (XII), and further reductive condensation with formaldehyde afforded the tertiary amine (XIII). Reduction of the nitro group of (XIII) with iron in acetic acid yielded aniline (XIV), which was coupled with acid chloride (IX) to give amide (XV). Quaternization of (XV) with methyl iodide in DMF produced the ammonium iodide (XVI). This was finally converted to the title chloride salt employing an ion exchange resin.

参考文献中间体

合成目标

【1】 Kitayoshi, T.; Aramaki, Y.; Oda, T.; Honda, S.; Shiraishi, M. (Takeda Chemical Industries, Ltd.); Anilide deriv., production and use thereof. JP 1999263764; WO 9932468 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	31561	2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carbonyl chloride		C₁₉H₁₇ClO	详情	详情
(X)	31562	(4-nitrophenyl)methanamine; 4-nitrobenzylamine		C₇H₈N₂O₂	详情	详情
(XI)	31563	tetrahydro-4H-pyran-4-one	29943-42-8	C₅H₈O₂	详情	详情
(XII)	31564	N-(4-nitrobenzyl)-N-tetrahydro-2H-pyran-4-ylamine; N-(4-nitrobenzyl)tetrahydro-2H-pyran-4-amine		C₁₂H₁₆N₂O₃	详情	详情
(XIII)	31565	N-methyl-N-(4-nitrobenzyl)tetrahydro-2H-pyran-4-amine; N-methyl-N-(4-nitrobenzyl)-N-tetrahydro-2H-pyran-4-ylamine		C₁₃H₁₈N₂O₃	详情	详情
(XIV)	31566	N-(4-aminobenzyl)-N-methyltetrahydro-2H-pyran-4-amine; N-(4-aminobenzyl)-N-methyl-N-tetrahydro-2H-pyran-4-ylamine		C₁₃H₂₀N₂O	详情	详情
(XV)	31567	2-(4-methylphenyl)-N-(4-[[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide		C₃₂H₃₆N₂O₂	详情	详情
(XVI)	31568	N,N-dimethyl-N-[4-([[2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cyclohepten-8-yl]carbonyl]amino)benzyl]tetrahydro-2H-pyran-4-aminium iodide		C₃₃H₃₉IN₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The reaction of the benzocycloheptanone (I) with dimethylcarbonate in the presence of NaOMe gave the beta-ketoester (II). The benzocycloheptene-8-carboxylic acid (III) was prepared by NaBH4 reduction of (II) in CH2Cl2/MeOH and subsequent dehydration by mesylation and treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in THF and alkaline hydrolysis. On the other hand, the aniline (VII) was obtained by reductive aminations of 4-nitrobenzylamine (IV) successively with tetrahydropyran-4-one (V) and formalin in 1,2-dichloroethane using NaBH(OAc)3, followed by Fe reduction in AcOH or hydrogenation in EtOH of the resulting nitrobenzylamine (VI). The carboxylic acid (III) was reacted with oxalyl chloride in CH2Cl2/cat. DMF to afford the acid chloride, which was condensed with the aniline (VII) in THF/Et3N to give the anilide derivative (VIII). Compound (VIII) was treated with iodomethane in DMF to provide the quaternary ammonium iodide, which was converted to TAK-779 using ion exchange resin (Cl-).

参考文献中间体

合成目标

【1】 Shiraishi, M.; Aramaki, Y.; Seto, M.; et al.; Discovery of small molecule CCR5 antagonists. 19th Symp Med Chem and 8th Annu Meet Div Med Chem Jpn (Nov 17-19, Tokyo) 1999, Abst 2P-06.
【2】 Shiraishi, M.; Seto, M.; Aramaki, Y.; et al.; TAK-779, a small molecule CCR5 antagonist: Design, synthesis, and in vitro activity of anilide derivatives. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F911.
【3】 Aramaki, Y.; Seto, M.; Shiraishi, M.; et al.; Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety. J Med Chem 2000, 43, 10, 2049.
【4】 Kanzaki, N.; Shiraishi, M.; Fujino, M.; Nishimura, O.; Baba, M.; Lizawa, Y.; TAK-779. Drugs Fut 2000, 25, 3, 252.
【5】 Kitayoshi, T.; Aramaki, Y.; Oda, T.; Honda, S.; Shiraishi, M. (Takeda Chemical Industries, Ltd.); Anilide deriv., production and use thereof. JP 1999263764; WO 9932468 .
【6】 Kuroshima, K.; Kanzaki, N.; Nishimura, O.; Shiraishi, M.; Sawada, H.; Baba, M.; Aramaki, Y. (Takeda Chemical Industries, Ltd.); Pharmaceutical composition for antagonizing CCR5 comprising anilide derivative. JP 2000128782; JP 2000128842; US 6096780; WO 9932100 .

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)	31555	3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one		C₁₈H₁₈O	详情	详情
(II)	33422	methyl 3-(4-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate		C₂₀H₂₀O₃	详情	详情
(III)	31560	2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxylic acid		C₁₉H₁₈O₂	详情	详情
(IV)	31562	(4-nitrophenyl)methanamine; 4-nitrobenzylamine		C₇H₈N₂O₂	详情	详情
(V)	31563	tetrahydro-4H-pyran-4-one	29943-42-8	C₅H₈O₂	详情	详情
(VI)	31566	N-(4-aminobenzyl)-N-methyltetrahydro-2H-pyran-4-amine; N-(4-aminobenzyl)-N-methyl-N-tetrahydro-2H-pyran-4-ylamine		C₁₃H₂₀N₂O	详情	详情
(VII)	31566	N-(4-aminobenzyl)-N-methyltetrahydro-2H-pyran-4-amine; N-(4-aminobenzyl)-N-methyl-N-tetrahydro-2H-pyran-4-ylamine		C₁₃H₂₀N₂O	详情	详情
(VIII)	31567	2-(4-methylphenyl)-N-(4-[[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide		C₃₂H₃₆N₂O₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

4-Nitrobenzylamine (I) is protected as the corresponding trifluoroacetamide (II) and subsequently reduced to aniline (III) by catalytic hydrogenation over Pd/C. Condensation of (III) with N,N'-di-Boc-N''-(trifluoromethanesulfonyl)guanidine (IV) furnishes the Boc-protected guanidine (V). The trifluoroacetamide function of (V) is then hydrolyzed by means of K2CO3 in aqueous MeOH to provide amine (VI). (1,2)

参考文献中间体

合成目标

【1】 Tamiz, A.P.; Weinhouse, M.I.; Ahn, J.S.; Alfaro-Lopez, J.; Gaudette, J.; Meneses, J.K.; Roberts, C.; Madison, E.L.; Semple, J.E.; Levy, O.E..; Synthesis and biological activity of non-transition state urokinase inhibitors. 28th Natl Med Chem Symp (June 8 2002, San Diego) 2002, Abst 59.
【2】 Semple, J.E.; Levy, O.E.; Tamiz, A.P.; Madison, E.L.; Weinhouse, M.I. (Corvas International, Inc.); Non-covalent inhibitors of urokinase and blood vessel formation. EP 1182207; WO 0214349 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	31562	(4-nitrophenyl)methanamine; 4-nitrobenzylamine	C₇H₈N₂O₂	详情	详情
(II)	64367	2,2,2-trifluoro-N-(4-nitrobenzyl)acetamide	C₉H₇F₃N₂O₃	详情	详情
(III)	64368	N-(4-aminobenzyl)-2,2,2-trifluoroacetamide	C₉H₉F₃N₂O	详情	详情
(IV)	64369	tert-butyl [(tert-butoxycarbonyl)amino]{[(trifluoromethyl)sulfonyl]imino}methylcarbamate	C₁₂H₂₀F₃N₃O₆S	详情	详情
(V)	64370	tert-butyl [(tert-butoxycarbonyl)amino][(4-{[(2,2,2-trifluoroacetyl)amino]methyl}phenyl)imino]methylcarbamate	C₂₀H₂₇F₃N₄O₅	详情	详情
(VI)	64374	tert-butyl {[4-(aminomethyl)phenyl]imino}[(tert-butoxycarbonyl)amino]methylcarbamate	C₁₈H₂₈N₄O₄	详情	详情

Extended Information