3-Methyl-1-nitrobutane; Isoamyl nitrite -Drug Synthesis Database

【结构式】

【分子编号】32169

【品名】3-Methyl-1-nitrobutane; Isoamyl nitrite

【CA登记号】543-87-3

【分子式】C₅H₁₁NO₂

【分子量】117.14788

【元素组成】C 51.26% H 9.46% N 11.96% O 27.31%

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：(A)

The reaction of 2,6-dichloro-3-nitropyridine (I) with N-ethoxycarbonylpiperidine (II) by means of triethylamine in CHCl gives 6-chloro-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine (III), which is treated with ethanolic NH3 at 120 C in a sealed tube to afford 6-amino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine (IV). The acetylation of (IV) with acetic anhydride - acetic acid at 90 C yields the corresponding 6-acetamido derivative (V), which is reduced with H2 over Pd/C in acetic acid giving 3-amino-6-acetamido-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine (VI). The diazotation of (VI) with isoamyl nitrite (A) and tetrafluoroboric acid in ethanol affords 6-acetylamino-2-(4-ethoxycarbonylpiperazinyl)-3-pyridine diazonium tetrafluoroborate (VII), which by heat treatment at 120 C in toluene is converted into 6-acetylamino-2-(4-ethoxycarbonylpiperazinyl)-3-fluoropyridine (VIII). The hydrolysis of (VIII) with HCl in methanol yields the corresponding 6-aminopyridine derivative (IX), which is condensed with diethyl ethoxymethylenemalonate (X) by heating at 130 C to afford diethyl N-[2-(4-ethoxycarbonyl-1-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate (XI). The cyclization of (XI) by heating at 255 C yields ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (XII), which is N-alkylated by means of ethyl iodide and K2CO3 in hot DMF to afford ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (XIII). Finally, this compound is hydrolyzed by means of NaOH in refluxing ethanol.

参考文献中间体

合成目标

【1】 Matsumoto, J.; et al. (Aventis Pharma SA; Dainippon Pharmaceutical Co., Ltd.); Novel naphthyridine derivatives, intermediates thereof, processes for preparation thereof and use thereof. EP 0009425; ES 483629; US 4359578 .
【2】 Blancafort, P.; Serradell, M.N.; Mealy, N.E.; Castaner, J.; Leeson, P.A.; AT-2266. Drugs Fut 1981, 6, 3, 129.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	32169	3-Methyl-1-nitrobutane; Isoamyl nitrite	543-87-3	C₅H₁₁NO₂	详情	详情
(I)	13574	2,6-Dichloro-3-nitropyridine	16013-85-7	C₅H₂Cl₂N₂O₂	详情	详情
(II)	24694	N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine	120-43-4	C₇H₁₄N₂O₂	详情	详情
(III)	32165	6-Chloro-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine; Ethyl 4-(6-chloro-3-nitro-2-pyridinyl)-1-piperazinecarboxylate		C₁₂H₁₅ClN₄O₄	详情	详情
(IV)	32166	Ethyl 4-(6-amino-3-nitro-2-pyridinyl)-1-piperazinecarboxylate; 6-Amino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine		C₁₂H₁₇N₅O₄	详情	详情
(V)	32167	ethyl 4-[6-(acetamido)-3-nitro-2-pyridinyl]-1-piperazinecarboxylate		C₁₄H₁₉N₅O₅	详情	详情
(VI)	32168	Ethyl 4-[6-(acetamido)-3-amino-2-pyridinyl]-1-piperazinecarboxylate; 3-Amino-6-acetamido-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine		C₁₄H₂₁N₅O₃	详情	详情
(VII)	32170	6-acetamido-2-(4-ethoxycarbonylpiperazinyl)-3-pyridine diazonium tetrafluoroborate; 6-Acetamido-2-[4-(ethoxycarbonyl)pipderazin-1-yl]pyridin-3-yldiazonium tetrafluoroborate		C₁₄H₁₉BF₄N₆O₃	详情	详情
(VIII)	32171	6-acetamido-2-(4-ethoxycarbonylpiperazinyl)-3-fluoropyridine; Ethyl 4-[6-(acetamido)-3-fluoro-2-pyridinyl]-1-piperazinecarboxylate		C₁₄H₁₉FN₄O₃	详情	详情
(IX)	32172	ethyl 4-(6-amino-3-fluoro-2-pyridinyl)-1-piperazinecarboxylate		C₁₂H₁₇FN₄O₂	详情	详情
(X)	14088	Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate	87-13-8	C₁₀H₁₆O₅	详情	详情
(XI)	32173	N-[2-(4-EthoxycarbonyI-1-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate; Diethyl 2-[([6-[4-(ethoxycarbonyl)-1-piperazinyl]-5-fluoro-2-pyridinyl]amino)methylene]malonate		C₂₀H₂₇FN₄O₆	详情	详情
(XII)	32174	Ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate; Ethyl 7-[4-(ethoxycarbonyl)-1-piperazinyl]-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate		C₁₈H₂₁FN₄O₅	详情	详情
(XIII)	32175	Ethyl 7-[4-(ethoxycarbonyl)-1-piperazinyl]-1-ethyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate; Ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate		C₂₀H₂₅FN₄O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(B)

Compound can be prepared in two different ways both starting from 2,4-difluoroaniline (I): 1) The diazotation of (I) with isoamyl nitrite (B) and condensation with anisole (A) gives 4-(2,4-difluorophenyl)anisole (II), which is hydrolyzed with HI in refluxing acetic acid yielding 4-(2,4-difluorophenyl)phenol (III). Finally, this compound is carbonated with K2CO3 and CO2 at 175 C and 1300 p.s.i. 2) The diazotation of (I) with isoamyl nitrite (B) and then condensation with benzene by means of powdered Cu gives 2,4-difluorobiphenyl (IV), which is acetylated with acetic anhydride by means of AlCl3 in CH2Cl2 yielding 4-(2,4-difluorophenyl)acetophenone (V). The oxidation of (V) with H2O2 in refluxing CH2Cl2 affords 4-(2,4-difluorophenyl)phenyl acetate (VI), which can be hydrolyzed with NaOH in refluxing water to give the phenol (III).

参考文献中间体

合成目标

【1】 Ruyle, W.V.; et al. (Merck & Co., Inc.); Phenyl benzoic acid compounds in compositions and methods for treating inflammation. US 3674870 .
【2】 Howard, J.; et al. (Merck & Co., Inc.); Chemical products. DE 2532559; FR 2288729; GB 1496231; GB 1496232; JP 51034135 .
【3】 Houser, R.W.; Jones, H. (Merck & Co., Inc.); Process for preparing 4-(2,4-difluorophenyl)-salicyclic acid. US 4225730 .
【4】 Ruyle, W.V.; et al. (Merck & Co., Inc.); Halo-substituted 5-phenylbenzoic acids and their derivatives. GB 1175212 .
【5】 Arrigoni-Martelli, E.; Castaner, J.; Diflunisal. Drugs Fut 1978, 3, 4, 28.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	23767	Methoxybenzene; Methyl phenyl ether; Anisole	100-66-3	C₇H₈O	详情	详情
(B)	32169	3-Methyl-1-nitrobutane; Isoamyl nitrite	543-87-3	C₅H₁₁NO₂	详情	详情
(I)	19462	2,4-difluoroaniline; 2,4-difluorophenylamine；2,4-Difluoro-benzenamine;1-Amino-2,4-difluorobenzene	367-25-9	C₆H₅F₂N	详情	详情
(II)	33464	2',4'-difluoro[1,1'-biphenyl]-4-yl methyl ether; 2,4-difluoro-4'-methoxy-1,1'-biphenyl		C₁₃H₁₀F₂O	详情	详情
(III)	14631	2',4'-difluoro[1,1'-biphenyl]-4-ol		C₁₂H₈F₂O	详情	详情
(IV)	33465	2,4-difluoro-1,1'-biphenyl		C₁₂H₈F₂	详情	详情
(V)	33466	1-(2',4'-difluoro[1,1'-biphenyl]-4-yl)-1-ethanone		C₁₄H₁₀F₂O	详情	详情
(VI)	33467	2',4'-difluoro[1,1'-biphenyl]-4-yl acetate		C₁₄H₁₀F₂O₂	详情	详情

Extended Information