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【结 构 式】

【分子编号】30628

【品名】4-bromo-3-(difluoromethoxy)-2-fluorobenzoic acid

【CA登记号】

【 分 子 式 】C8H4BrF3O3

【 分 子 量 】285.0171696

【元素组成】C 33.71% H 1.41% Br 28.03% F 20% O 16.84%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(X)

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
Extended Information