ethyl 7-bromo-1-cyclopropyl-8-(difluoromethoxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】30631

【品名】ethyl 7-bromo-1-cyclopropyl-8-(difluoromethoxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylate

【CA登记号】

【分子式】C₁₆H₁₄BrF₂NO₄

【分子量】402.1923064

【元素组成】C 47.78% H 3.51% Br 19.87% F 9.45% N 3.48% O 15.91%

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：(XVI)

The methylation of 2,6-difluorophenol (I) with methyl iodide and K2CO3 in DMF gives 2,6-difluoroanisole (II), which by treatment with butyllithium and CO2 yields 2,4-difluoro-3-methoxybenzoic acid (III). The methylation of (III) with diazomethane in ether affords the methyl ester (IV), which by reaction with BBr3 in dichloromethane results in 2,4-difluoro-3-hydroxybenzoic acid methyl ester (V). The alkylation of (V) with chlorodifluoromethane and K2CO3 in DMF gives 3-(difluoromethoxy)-2,4-difluorobenzoic acid methyl ester (VI), which is treated with sodium azide in DMSO, yielding the azido derivative (VII). The reduction of (VII) with H2 over Pd/C in ethanol affords 3-amino-2,4-difluorobenzoic acid methyl ester (VIII), which is hydrolyzed with NaOH in ethanol, giving the free acid (IX). The reaction of (IX) with NaNO2 and HBr yields 4-bromo-3-(difluoromethoxy)-2-fluorobenzoic acid (X), which is condensed with the magnesium salt of malonic acid monoethyl ester (XI) by means of CDI in THF, affording the 3-oxopropionate (XII). The reaction of (XII) with dimethylformamide dimethylacetal (XIII) and cyclopropylamine (XIV) by means of acetic anhydride in dichloromethane gives the 3-(cyclopropylamino)acrylate (XV), which is cyclized by means of K2CO3 in hot DMSO, yielding quinolone (XVI). The condensation of (XVI) with the isoindolylboronic acid derivative (XVII) - obtained by reaction of 5-bromo-1(R)-methyl-2-tritylisoindoline (XIX) with triisopropyl borate and butyllithium in THF - by means of bis(triphenylphosphine)palladium(II) chloride as catalyst in refluxing toluene affords the protected compound (XVIII), which is finally deprotected with HCl in ethanol.

参考文献中间体

合成目标

【1】 Castañer, J.; Rabasseda, X.; Graul, A.; T-3811ME. Drugs Fut 1999, 24, 12, 1324.
【2】 Todo, Y.; Hayashi, K.; Takahata, M.; Watanabe, Y.; Narita, H. (Toyama Chemical Co., Ltd.); Quinolonecarboxylic acid derivs. or salts thereof.. EP 0882725; US 6025370; WO 9729102 .

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)	30619	2,6-difluorophenol	28177-48-2	C₆H₄F₂O	详情	详情
(II)	30620	2,6-difluorophenyl methyl ether; 1,3-difluoro-2-methoxybenzene		C₇H₆F₂O	详情	详情
(III)	30621	2,4-difluoro-3-methoxybenzoic acid	178974-97-5	C₈H₆F₂O₃	详情	详情
(IV)	30622	methyl 2,4-difluoro-3-methoxybenzoate		C₉H₈F₂O₃	详情	详情
(V)	30623	methyl 2,4-difluoro-3-hydroxybenzoate		C₈H₆F₂O₃	详情	详情
(VI)	30624	methyl 3-(difluoromethoxy)-2,4-difluorobenzoate		C₉H₆F₄O₃	详情	详情
(VII)	30625	methyl 4-azido-3-(difluoromethoxy)-2-fluorobenzoate		C₉H₆F₃N₃O₃	详情	详情
(VIII)	30626	methyl 4-amino-3-(difluoromethoxy)-2-fluorobenzoate		C₉H₈F₃NO₃	详情	详情
(IX)	30627	4-amino-3-(difluoromethoxy)-2-fluorobenzoic acid		C₈H₆F₃NO₃	详情	详情
(X)	30628	4-bromo-3-(difluoromethoxy)-2-fluorobenzoic acid		C₈H₄BrF₃O₃	详情	详情
(XI)	14338	potassium 3-ethoxy-3-oxopropanoate	6148-64-7	C₅H₇KO₄	详情	详情
(XII)	30629	ethyl 3-[4-bromo-3-(difluoromethoxy)-2-fluorophenyl]-3-oxopropanoate		C₁₂H₁₀BrF₃O₄	详情	详情
(XIII)	11984	N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal	4637-24-5	C₅H₁₃NO₂	详情	详情
(XIV)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情
(XV)	30630	ethyl (Z)-2-[4-bromo-3-(difluoromethoxy)-2-fluorobenzoyl]-3-(cyclopropylamino)-2-propenoate		C₁₆H₁₅BrF₃NO₄	详情	详情
(XVI)	30631	ethyl 7-bromo-1-cyclopropyl-8-(difluoromethoxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylate		C₁₆H₁₄BrF₂NO₄	详情	详情
(XVII)	30632	(1R)-1-methyl-2-trityl-2,3-dihydro-1H-isoindol-5-ylboronic acid		C₂₈H₂₆BNO₂	详情	详情
(XVIII)	30633	ethyl 1-cyclopropyl-8-(difluoromethoxy)-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-isoindol-5-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate		C₄₄H₃₈F₂N₂O₄	详情	详情
(XIX)	30634	(1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole		C₂₈H₂₄BrN	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVI)

The reaction of 2-(benzyloxycarbonyl)-5-bromo-1(R)-methylisoindoline (XX) with hexabutyldistannane and bis(triphenylphosphine)palladium(II) chloride in toluene gives the corresponding tributyltin derivative (XXI), which is condensed with the previously described quinolone (XVI) by means of the palladium catalyst as before, yielding the protected compound (XXII), which is deprotected by hydrolysis of the ester group with NaOH, followed by hydrogenolysis with H2 over Pd/C in acetic acid.

参考文献中间体

合成目标

【1】 Yamada, M.; Takahata, M.; Ojima, K.; Todo, Y.; Kito, T.; Hayashi, H.; Watanabe, Y.; Narita, H.; Hamamoto, S.; T-3811, a novel des-F(6)-quinolone: Synthesis and in vitro activity of 7-(isoindolin-5-yl) derivatives. 37th Intersci Conf Antimicrob Agents Chemother (Sept 28-Oct 1, Toronto) 1997, Abst F-158.
【2】 Castañer, J.; Rabasseda, X.; Graul, A.; T-3811ME. Drugs Fut 1999, 24, 12, 1324.
【3】 Todo, Y.; Hayashi, K.; Takahata, M.; Watanabe, Y.; Narita, H. (Toyama Chemical Co., Ltd.); Quinolonecarboxylic acid derivs. or salts thereof.. EP 0882725; US 6025370; WO 9729102 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XVI)	30631	ethyl 7-bromo-1-cyclopropyl-8-(difluoromethoxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylate	C₁₆H₁₄BrF₂NO₄	详情	详情
(XX)	30635	benzyl (1R)-5-bromo-1-methyl-1,3-dihydro-2H-isoindole-2-carboxylate	C₁₇H₁₆BrNO₂	详情	详情
(XXI)	30636	benzyl (1R)-1-methyl-5-(tributylstannyl)-1,3-dihydro-2H-isoindole-2-carboxylate	C₂₉H₄₃NO₂Sn	详情	详情
(XXII)	30637	ethyl 7-[(1R)-2-[(benzyloxy)carbonyl]-1-methyl-2,3-dihydro-1H-isoindol-5-yl]-1-cyclopropyl-8-(difluoromethoxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylate	C₃₃H₃₀F₂N₂O₆	详情	详情

Extended Information