Trifluoroacetic acid → 5-(2,3-Dihydrobenzo[1,4]dioxin-6-ylmethyl)-4-methylimidazole-1-sulfonic acid dimethylamide

4-Methyl-1-(dimethylsulfamoyl)imidazole (1) (2.0 g, 10.6 mmol) is taken up in 42 mL of anhydrous THF and cooled to −78° C. n-BuLi (6.6 mL, 10.6 mmol) is added dropwise to the solution of (1). The resultant solution is stirred at −78° C. for 30 min. Tert-butyldimethylsilylchloride (TBSCl) (1.6 g, 10.6 mmol) in 10 mL of THF is added to the reaction. The reaction is warmed to rt and stirred overnight. The next day the reaction is cooled to −20° C. and 7.3 mL (11.6 mmol) of n-BuLi added. After stirring at −20° C. for 30 min, 1,4 -benzodioxan-6-carboxaldehyde (2) (1.92 g, 11.7 mmol) in 10 mL of THF is added to the reaction mixture. Then reaction is warmed to rt and stirred for 3 h. The reaction is quenched with water and diluted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (1:2 ethyl acetate/hexane) affords 3.9 g (8.4 mmol) of 2-(t-butyldimethylsilyl)-5-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)hydroxymethyl]-4-methylimidazole-1-sulfonic acid dimethylamide (3). (3) (1.0 g, 2.14 mmol) is taken up in 21 mL of THF. A 1M solution of tetra-n-butylammonium fluoride (TBAF) in THF (2.35 mL, 2.35 mmol) is added dropwise to the solution of (3). The reaction is stirred for 30 min at rt. The reaction is quenched with water and then extracted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography using ethyl acetate as eluant affords 0.75 g (2.12 mmol) 5-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)hydroxymethyl]-4-methylimidazole-1-sulfonic acid dimethylamide (4). (4) (0.75 g, 2.12 mmol) is taken up in 28 mL of dichloromethane, to the solution is added 2.7 mL (17.0 mmol) of triethylsilane and 5.2 mL (67.8 mmol) of trifluoroacetic acid. The reaction is stirred at rt overnight and then quenched with water and neutralized with solid sodium bicarbonate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography using a 3:1 mixture of ethyl acetate and hexane affords 0.63 g (1.87 mmol) of 5-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-4-methylimidazole-1-sulfonic acid dimethylamide (5). (5) (0.63 g, 1.87 mmol) is taken up in 10 mL of a 1.5N HCl solution and heated at reflux for. The reaction is diluted with ethyl acetate, neutralized with solid sodium bicarbonate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Crystallization from ether/hexane affords 0.33 g (1.43 mmol) of 4(5)-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-4-methyl-1H-imidazole (6) (M).

1. customquenched with water and neutralized with solid sodium bicarbonate
2. washThe organic layer is washed with water
3. dry with materialThe organic phase is dried over sodium sulfate
4. customthe solvent removed under reduced pressure
5. additiona 3:1 mixture of ethyl acetate and hexane

ORDレコード

ord-0e23d8a38e404905b09ae83fff183c68

出典データセット

uspto-grants-2001_12

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US06329369B1