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【结 构 式】

【药物名称】Garenoxacin mesilate, T-3811ME, BMS-284756, T-3811(free base, anhydrous), Inforce

【化学名称】1-Cyclopropyl-8-(difluoromethoxy)-7-[1(R)-methyl-2,3-dihydro-1H-isoindol-5-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid monomethanesulfonate monohydrate

【CA登记号】223652-90-2, 223652-86-6 (citrate (1:1)), 194804-75-6 (free base, anhydrous), 223652-88-8 (Mg salt), 223652-87-7 (monoacetate),

【 分 子 式 】C24H26F2N2O8S

【 分 子 量 】540.54422

【开发单位】Toyama (Originator), Schering-Plough (Licensee)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, DNA Gyrase Inhibitors, DNA Topoisomerase IV Inhibitors, Quinolones

合成路线1

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.

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

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.

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 CAS号 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

合成路线3

The chiral indolines (XIX) and (XX) have been obtained as follows: The condensation of racemic 5-bromo-2-methylindoline (XXIII) with N-(benzyloxycarbonyl)-L-phenylalanine (XXIV) by means of DIC and triethylamine in THF gives the diastereomeric mixture of indolines (XXV), which is separated by column chromatography, yielding the pure enantiomer (XXVI). The cleavage of (XXVI) with 6N HCl affords 5-bromo-1(R)-methylisoindoline (XXVII), which is treated with trityl chloride and triethylamine in dichloromethane to give indoline (XIX), or with benzyl chloroformate and triethylamine to give indoline (XX).

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
(XIX) 30634 (1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole C28H24BrN 详情 详情
(XX) 30635 benzyl (1R)-5-bromo-1-methyl-1,3-dihydro-2H-isoindole-2-carboxylate C17H16BrNO2 详情 详情
(XXIII) 30638 5-bromo-1-methylisoindoline C9H10BrN 详情 详情
(XXIV) 14505 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid; N-Carbobenzyloxy-L-phenylalanine; N-Cbz-L-Phenylalanine 1161-13-3 C17H17NO4 详情 详情
(XXV) 30639 benzyl (1S)-1-benzyl-2-(5-bromo-1-methyl-1,3-dihydro-2H-isoindol-2-yl)-2-oxoethylcarbamate C26H25BrN2O3 详情 详情
(XXVI) 30640 benzyl (1S)-1-benzyl-2-[(1R)-5-bromo-1-methyl-1,3-dihydro-2H-isoindol-2-yl]-2-oxoethylcarbamate C26H25BrN2O3 详情 详情
(XXVII) 30641 (1R)-5-bromo-1-methyl-2,3-dihydro-1H-isoindole C9H10BrN 详情 详情

合成路线4

The reaction of 5-bromo-1(R)-methyl-2-(triphenylmethyl)-2,3-dihydro-1H-isoindole (I) with; BuLi, triisopropyl borate and diethanolamine (II) gives the boronic ester (III), which is condensed with 1-cyclopropyl-7-bromo-8-(difluoromethoxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (IV) by means of PdCl2(PPh3)2 to yield the precursor (V). Finally, this compound is deprotected by a treatment with HCl in ethanol/water to provide the target Garenoxacin.

1 Hayashi, K.; Takahata, M.; Kawamura, Y.; Todo, Y.; Synthesis, antibacterial activity, and toxicity of 7-(isoindolin-5-yl)-4-oxoquinoline-3-carboxylic acids. Discovery of the novel des-F(6)-quinolone antibacterial agent garenoxacin (T-3811 or BMS-284756). Arzneim Forsch Drug Res. 2002, 52, 12, 903.
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) 30634 (1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole C28H24BrN 详情 详情
(II) 24273 2-[(2-hydroxyethyl)amino]-1-ethanol 111-42-2 C4H11NO2 详情 详情
(III) 61570 (1R)-5-(1,3,6,2-dioxazaborocan-2-yl)-1-methyl-2-trityl-2,3-dihydro-1H-isoindole C32H33BN2O2 详情 详情
(IV) 61571 ethyl 7-bromo-1-cyclopropyl-8-(2,2-difluoroethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate C17H16BrF2NO3 详情 详情
(V) 61572 ethyl 1-cyclopropyl-8-(2,2-difluoroethyl)-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-isoindol-5-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate C45H40F2N2O3 详情 详情
Extended Information