【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% |
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 |