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43.3 g of 2-fluoro-4-nitrobenzoic acid was dissolved in 600 ml of dimethylformamide, and 1,1'-carbodiimide was added to it, and stirred at room temperature for 2 hours. 11.1 g of sodium borohydride was added thereto, and further stirred for 30 minutes. Aqueous saturated ammonium chloride solution was added to it, 800 ml of water was added thereto, extracted wit 1.2 liters of ethyl acetate, and the organic layer was washed with saturated saline water. The solvent was evaporated away under reduced pressure, the residue was again diluted with ethyl acetate, and the organic layer was washed with water and saturated saline water. This was dried with anhydrous sodium sulfate, and the solvent was evaporated away to obtain 32.7 g of a brown oil. The obtained oil was dissolved in 200 ml of dimethyl sulfoxide and 60 ml of triethylamine, and 88.7 g of sulfur trioxide/pyridine complex was gradually added to it, and stirred at room temperature for 2 hours. This was diluted with ethyl acetate, and the organic layer was washed with water, aqueous 0.1 N hydrochloric acid solution and saturated saline water. The solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate) and through crystallization (methanol/diethyl ether) to obtain 14.0 g of the entitled compound as an orange solid.
With lithium aluminium tetrahydride; In diethyl ether; at 0℃; for 0.75h;Reflux;
General procedure: To a stirred suspension of LiAlH4 (3.0mmol) in ether was added dropwise a solution of 21 in ether at 0C over 15min. The mixture was refluxed for 30min, then the reaction cooled to 0C and quenched with 1N HCl. The precipitate was filtered off and washed with ether. The combined filtrate was dried over MgSO4, filtered and concentrated in vacuo. The residue was puried by column chromatography on silica gel to afford the desired product.
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20 - 40℃;
General procedure: HATU (1.2 equiv) and DIEA (1.5 equiv) were added to a solutionof 2-fluoro-4-nitrobenzoic acid (1 equiv) and R6-NH2 (1 equiv) inCH2Cl2 at rt. The resulting mixture was heated to 25e40 C andstirred until the reaction was complete. The mixture was dilutedwith ethyl acetate, and the organic layer was washed with saline,dried over anhydrous Na2SO4 and filtered. The filtrate wasconcentrated and purified using chromatography to yield the intermediates33a-g. Intermediates 33a-g (1 equiv) were dissolved inethanol, and Pd/C (0.1 equiv)was added. The flask was flushed withH2 and stirred for 6 h at 40 C. The reaction mixture was filteredthrough a Celite pad and the filtrate was concentrated to dryness,yielding intermediates 34a-g.
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20 - 40℃;
General procedure: HATU (1.2 equiv) and DIEA (1.5 equiv) were added to a solutionof 2-fluoro-4-nitrobenzoic acid (1 equiv) and R6-NH2 (1 equiv) inCH2Cl2 at rt. The resulting mixture was heated to 25e40 C andstirred until the reaction was complete. The mixture was dilutedwith ethyl acetate, and the organic layer was washed with saline,dried over anhydrous Na2SO4 and filtered. The filtrate wasconcentrated and purified using chromatography to yield the intermediates33a-g. Intermediates 33a-g (1 equiv) were dissolved inethanol, and Pd/C (0.1 equiv)was added. The flask was flushed withH2 and stirred for 6 h at 40 C. The reaction mixture was filteredthrough a Celite pad and the filtrate was concentrated to dryness,yielding intermediates 34a-g.
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