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【结 构 式】

【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%

与该中间体有关的原料药合成路线共 2 条

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.
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) 42004 2,6-difluoro-4-nitrophenol 658-07-1 C6H3F2NO3 详情 详情
(III) 42005 4-amino-2,6-difluorophenol 126058-97-7 C6H5F2NO 详情 详情
(IV) 42006 3,5-difluoro-4-hydroxybenzonitrile 2967-54-6 C7H3F2NO 详情 详情
Extended Information