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【结 构 式】 
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【分子编号】30619 【品名】2,6-difluorophenol 【CA登记号】28177-48-2 |
【 分 子 式 】C6H4F2O 【 分 子 量 】130.0939664 【元素组成】C 55.4% H 3.1% F 29.21% O 12.3% |
合成路线1
该中间体在本合成路线中的序号：(I)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
该中间体在本合成路线中的序号：(I)Nitration of 2,6-difluorophenol (I) gave 2,6-difluoro-4-nitrophenol (II), which was reduced to the corresponding aniline (III) by hydrogenation over Pd/C. Nitrile (IV) was obtained by diazotization of (III) followed by in situ displacement of the diazonium salt with CuCN and KCN. The nitrile (IV) was finally reduced to the title benzylamine employing borane in THF.
| 【1】 Qiu, J.; Stevenson, S.H.; O'Beirne, M.J.; Silverman, R.B.; 2,6-Difluorophenol as a bioisostere of a carboxylic acid: Bioisosteric analogues of gamma-aminobutyric acid. J Med Chem 1999, 42, 2, 329. |