4-amino-3-(methylamino)benzoic acid -Drug Synthesis Database

【结构式】

【分子编号】14729

【品名】4-amino-3-(methylamino)benzoic acid

【CA登记号】

【分子式】C₈H₁₀N₂O₂

【分子量】166.17968

【元素组成】C 57.82% H 6.07% N 16.86% O 19.26%

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：(III)

The reaction of 3-chloro-4-nitrobenzoic acid (I) with methylamine gives 3-(methylamino)-4-nitrobenzoic acid (II), which is hydrogenated in the presence of Raney Nickel to yield 4-amino-3-(methylamino)benzoic acid (III). Treatment of compound (III) with sodium nitrite affords 1-methyl-1H-benzotriazole-6-carboxylic acid (IV), which is reduced with lithium aluminum hydride in THF to give 6-(hydroxymethyl)-1-methyl-1H-benzotriazole (V). Oxidation of (V) with potassium permanganate in dichloroethane yields 1-methyl-1H-benzotriazole-6-carboxaldehyde (VI), which on treatment with the Grignard reagent derived from 1-bromo-4-chlorobenzene (VII) gives 6-(4-chloro-alpha-hydroxybenzyl)-1-methyl-1H-benzotriazole (VIII). Treatment of compound (VIII) with thionyl chloride in THF yields 6-(alpha,4-dichlorobenzyl)-1-methyl-1H-benzotriazole (IX), which is finally condensed with 1,2,4-triazole (X) and sodium hydride in DMF.

参考文献中间体

合成目标

【1】 Raeymaekers, A.H.M.; Freyne, E.J.E.; Van Gelder, J.L.H.; Vener, M.G. (Janssen Pharmaceutica NV); (1H-Arol-1-ylmethyl)substd. Benzotriazole derivatives. AU 8816537; EP 0293978; JP 1988316775 .
【2】 Graul, A.; Prous, J.; Castaner, J.; Vorozole. Drugs Fut 1994, 19, 5, 457.

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)	14727	3-chloro-4-nitrobenzoic acid		C₇H₄ClNO₄	详情	详情
(II)	14728	3-(methylamino)-4-nitrobenzoic acid		C₈H₈N₂O₄	详情	详情
(III)	14729	4-amino-3-(methylamino)benzoic acid		C₈H₁₀N₂O₂	详情	详情
(IV)	14730	1-methyl-1H-1,2,3-benzotriazole-6-carboxylic acid		C₈H₇N₃O₂	详情	详情
(V)	14731	(1-methyl-1H-1,2,3-benzotriazol-6-yl)methanol		C₈H₉N₃O	详情	详情
(VI)	14732	1-methyl-1H-1,2,3-benzotriazole-6-carbaldehyde		C₈H₇N₃O	详情	详情
(VII)	14733	4-Bromochlorobenzene; 1-bromo-4-chlorobenzene	106-39-8	C₆H₄BrCl	详情	详情
(VIII)	14734	(4-chlorophenyl)(1-methyl-1H-1,2,3-benzotriazol-6-yl)methanol		C₁₄H₁₂ClN₃O	详情	详情
(IX)	14735	6-[chloro(4-chlorophenyl)methyl]-1-methyl-1H-1,2,3-benzotriazole		C₁₄H₁₁Cl₂N₃	详情	详情
(X)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	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 reduction of 3,4-dinitrobenzoic acid amide (I) with H2 over Pd/C in methanol gives 3,4-diaminobenzoic acid (II), which is cyclized with 3-ethoxy-3-iminopropionic acid ethyl ester (IV) (obtained by reaction of cyanacetic acid ethyl ester (III) with ethanolic HCl) in hot acetic acid to yield 2-(5-carbamoyl-1H-benzimidazol-2-yl)acetic acid ethyl ester (V). The reaction of 3-methoxy-4-nitrobenzoic acid (VII) with aqueous methylamine in a sealed tube at 100 C gives 3-(methylamino)-4-nitrobenzoic acid (VIII), which is reduced with H2 over Pd/C in methanol/THF to yield 4-amino-3-(methylamino)benzoic acid (VI). The cyclization of (VI) with (V) by means of 1,3-dimethylperhydropyrimidin-2-one (DMPU) at 190 C affords the substituted bis-benzimidazolylmethyl (IX). The reaction of (IX) with 2-amino-3-phosponopropionic acid tris-trimethylsilyl ester (X) (prepared by esterification of 2-amino-3-phosphonopropionic acid (XI) with N-methyl-N-(trimethylsilyl)trifluoroacetamide (XII)) by means of (PyBroP) in DMF provides the carboxamide (XIII). Finally, the cleavage of the trimethylsilyl ester groups by means of TFA furnishes the target phosphonic acid.

参考文献中间体

合成目标

【1】 Rice, K.; Wang, V.R.; Hataye, J.M.; Shelton, E.J.; Spender, J.R. (Celera Genomics); Novel cpds. and compsns. for treating hepatitis C infections. WO 0020400 .

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)	55559	3,4-dinitrobenzamide		C₇H₅N₃O₅	详情	详情
(II)	55560	3,4-diaminobenzamide		C₇H₉N₃O	详情	详情
(III)	11877	Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate	105-56-6	C₅H₇NO₂	详情	详情
(IV)	17929	ethyl 3-ethoxy-3-iminopropanoate	2318-25-4	C₇H₁₃NO₃	详情	详情
(V)	55561	ethyl 2-[5-(aminocarbonyl)-1H-benzimidazol-2-yl]acetate		C₁₂H₁₃N₃O₃	详情	详情
(VI)	14729	4-amino-3-(methylamino)benzoic acid		C₈H₁₀N₂O₂	详情	详情
(VII)	21085	3-methoxy-4-nitrobenzoic acid；4-Nitro-3-methoxybenzoic acid	5081-36-7	C₈H₇NO₅	详情	详情
(VIII)	14728	3-(methylamino)-4-nitrobenzoic acid		C₈H₈N₂O₄	详情	详情
(IX)	55562	2-{[5-(aminocarbonyl)-1H-benzimidazol-2-yl]methyl}-1-methyl-1H-benzimidazole-6-carboxylic acid		C₁₈H₁₅N₅O₃	详情	详情
(X)	55563	3-{bis[(trimethylsilyl)oxy]phosphoryl}alanine		C₉H₂₄NO₅PSi₂	详情	详情
(XI)	55565	DL-2-Amino-3-phosphonopropionic acid; 2-Amino-3-phosphonopropionic acid	20263-06-3	C₃H₈NO₅P	详情	详情
(XII)	21859	2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide		C₆H₁₂F₃NOSi	详情	详情
(XIII)	55564	N-[(2-{[5-(aminocarbonyl)-1H-benzimidazol-2-yl]methyl}-1-methyl-1H-benzimidazol-6-yl)carbonyl]-3-{bis[(trimethylsilyl)oxy]phosphoryl}alanine		C₂₇H₃₇N₆O₇PSi₂	详情	详情

Extended Information