iodomethyl(trimethyl)silane

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of ethyl cyanoacetate (5.34 g, 47.3 mmol) in dimethyl sulfoxide (DMSO, 20 ml) was added portionwise with sodium ethoxide (3.21 g, 47.2 mmol), and the mixture was stirred at room temperature for 4 hours with occasionally cooling the mixture on ice when temperature elevation was observed. The reaction mixture was put on an ice bath, and added dropwise with a solution of iodomethyltrimethylsilane (7.78 g, 36.4 mmol) in DMSO (5 ml), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was added with saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography [hexane/ethyl acetate (49:1)] to obtain ethyl 3-(trimethylsilyl)-2-cyanopropionate (6.06 g, 65%) mentioned in the title as colorless oil. with occasionally cooling the mixture on ice when temperature elevation The reaction mixture was put on an ice bath the mixture was stirred at room temperature for 24 hours the mixture was extracted with ethyl acetate The organic layer was washed with water dried over anhydrous sodium sulfate the solvent was evaporated The residue was purified by silica gel chromatography [hexane/ethyl acetate (49:1)]

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of ethyl cyanoacetate (5.34 g, 47.3 mmol) in dimethyl sulfoxide (DMSO, 20 ml) was added portionwise with sodium ethoxide (3.21 g, 47.2 mmol), and the mixture was stirred at room temperature for 4 hours with occasionally cooling the mixture on ice when temperature elevation was observed. The reaction mixture was put on an ice bath, and added dropwise with a solution of iodomethyltrimethylsilane (7.78 g, 36.4 mmol) in DMSO (5 ml), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was added with saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography [hexane/ethyl acetate (49:1)] to obtain ethyl 3-(trimethylsilyl)-2-cyanopropionate (6.06 g, 65%) mentioned in the title as colorless oil. with occasionally cooling the mixture on ice when temperature elevation The reaction mixture was put on an ice bath the mixture was stirred at room temperature for 24 hours the mixture was extracted with ethyl acetate The organic layer was washed with water dried over anhydrous sodium sulfate the solvent was evaporated The residue was purified by silica gel chromatography [hexane/ethyl acetate (49:1)]

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of diisopropylamine (0.7 mL, 0.005 mol) in 9 mL of dry THF was added butyllithium (BuLi) (2.83 mL of 1.62M solution in hexane, 4.6 mmol) at 0° C. The solution was stirred at this temperature for 5 minutes and cooled to -78° C. with a dry ice/isopropanol bath. A solution of 2-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (Example 46) (1.46 g, 3.8 mmol) in 12 mL of dry THF was added over 10 minutes and the reaction mixture was stirred at -78° C. for 1 hour. (Iodomethyl)trimethylsilane (1.23 g, 57 mmol) was added dropwise and the reaction mixture was warmed to room temperature and was stirred overnight. The reaction was quenched with 50 mL of 1N HCl and the aqueous phase was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by chromatography on silica gel (ethyl acetate/hexane, 65:35) to give 1.30 g of 2-methyl-3-[1-[4-[[2-(trimethylsilyl) ethyl]sulfonyl]phenyl]-4-(trifluoromethyl) -1H-imidazol-2-yl]pyridine as a white solid (74%): mp(DSC) 155°-157° C. Anal. Calc'd. for C21H24F3N3O2SSi: C, 53.94; H, 5.17; N, 8.99; S, 6.86. Found: C, 53.77; H, 4.94; N, 8.75; 6.98. the reaction mixture was stirred at -78° C. for 1 hour the reaction mixture was warmed to room temperature was stirred overnight The reaction was quenched with 50 mL of 1N HCl the aqueous phase was extracted with ethyl acetate (3×60 mL) The combined organic layers were washed with brine dried over MgSO4 filtered concentrated The crude mixture was purified by chromatography on silica gel (ethyl acetate/hexane, 65:35)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of diisopropylamine (0.7 mL, 0.005 mol) in 9 mL of dry THF was added butyllithium (BuLi) (2.83 mL of 1.62M solution in hexane, 4.6 mmol) at 0° C. The solution was stirred at this temperature for 5 minutes and cooled to -78° C. with a dry ice/isopropanol bath. A solution of 2-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (Example 46) (1.46 g, 3.8 mmol) in 12 mL of dry THF was added over 10 minutes and the reaction mixture was stirred at -78° C. for 1 hour. (Iodomethyl)trimethylsilane (1.23 g, 57 mmol) was added dropwise and the reaction mixture was warmed to room temperature and was stirred overnight. The reaction was quenched with 50 mL of 1N HCl and the aqueous phase was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by chromatography on silica gel (ethyl acetate/hexane, 65:35) to give 1.30 g of 2-methyl-3-[1-[4-[[2-(trimethylsilyl) ethyl]sulfonyl]phenyl]-4-(trifluoromethyl) -1H-imidazol-2-yl]pyridine as a white solid (74%): mp(DSC) 155°-157° C. Anal. Calc'd. for C21H24F3N3O2SSi: C, 53.94; H, 5.17; N, 8.99; S, 6.86. Found: C, 53.77; H, 4.94; N, 8.75; 6.98. the reaction mixture was stirred at -78° C. for 1 hour the reaction mixture was warmed to room temperature was stirred overnight The reaction was quenched with 50 mL of 1N HCl the aqueous phase was extracted with ethyl acetate (3×60 mL) The combined organic layers were washed with brine dried over MgSO4 filtered concentrated The crude mixture was purified by chromatography on silica gel (ethyl acetate/hexane, 65:35)

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 60% sodium hydride in mineral oil (39 mg, 0.96 mmol, 1.3 equiv) was added to a stirred solution of benzazepine 25 (180 mg, 0.74 mmol, 1.0 equiv) in tetrahydrofuran (9.3 mL) at 25° C. The resulting brown suspension was stirred at 25° C. for 1 h. (Iodomethyl)trimethylsilane (0.55 mL, 3.7 mmol, 5.0 equiv) was added via syringe at 25° C. The reaction vessel was sealed under argon and heated to 50° C. via oil bath for 30 m. The reaction mixture was cooled to 25° C. and approximately 50% of the solvent volume was removed by sweeping with nitrogen. The crude reaction mixture was loaded directly onto a column and purified by silica gel column chromatography (5% triethylamine in ethyl acetate) to afford 31 (151 mg, 62% yield) as an off-white amorphous solid. Rf=0.41 (5% triethylamine in ethyl acetate); 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H, ArH), 6.48 (s, 1H, ArH), 5.89 (s, 2H, OCH2O), 3.56 (m, 2H, CH2), 3.02 (br s, 2H, NCH2Si), 2.91 (m, 2H, CH2), 2.59 (m, 2H, CH2), 2.49 (m, 2H, CH2), 0.13 (s, 9H, Si(CH3)3); 13C NMR (125 MHz, CDCl3) δ 200.86, 169.37, 146.18, 145.19, 132.71, 127.17, 110.46, 109.47, 108.06, 100.92, 57.78, 46.78, 36.22, 33.37, 28.08, −1.26; IR (neat film) 2953 (w, br), 1647 (w), 1556 (s), 1488 (m), 1445 (m), 1353 (w), 1248 (m), 1039 (m), 843 (m) cm−1; HRMS (EI) m/z: Calcd for C18H23NO3Si (MH+) 330.1525, observed 330.1525. was added via syringe at 25° C The reaction vessel was sealed under argon The reaction mixture was cooled to 25° C. approximately 50% of the solvent volume was removed The crude reaction mixture purified by silica gel column chromatography (5% triethylamine in ethyl acetate)

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred −70° C. suspension of 0.26 g (1 mmol) 2-isopropoxy-5-methanesulfonyl-benzoic acid (CAS: 845616-02-6) and 0.75 ml (5 mmol) TMEDA in 2.6 ml THF was added dropwise a LDA solution (prepared from a 1.3 ml (2.1 mmol) 1.6M n-butyllithium solution in hexane and 0.3 ml (2.1 mmol) diisopropylamine in 2.5 ml THF at 0° C.). The light yellow suspension was stirred at −70° C. for 30 minutes. A solution of 0.19 ml (1.3 mmol) (iodomethyl)trimethylsilane in 0.5 ml THF was added dropwise over a period of 5 minutes. The yellow suspension was stirred at −70° C. for 15 minutes and then allowed to warm to room temperature. The light yellow solution was stirred at room temperature for 1 hour and then quenched with 5 ml brine. The mixture was diluted with 5 ml water. The mixture was concentrated in vacuo. The aqueous layer was carefully acidified with HCl 1N and extracted 3 times with dichloromethane. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 0.21 g (63%) of the title compound as a yellow oil. MS (m/e): 343.0 [M−H]+. The yellow suspension was stirred at −70° C. for 15 minutes to warm to room temperature The light yellow solution was stirred at room temperature for 1 hour quenched with 5 ml brine The mixture was diluted with 5 ml water The mixture was concentrated in vacuo extracted 3 times with dichloromethane The combined extracts were dried over Na2SO4 filtered concentrated in vacuo The crude was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 5.58 g (25 mmol) of N-benzyloxycarbonyl glycine methyl ester in dry THF (70 ml) is added dropwise to a solution at -78° C. of lithium diisopropylamine (8.76 ml, 62.5 mmol) and tetramethylethylene diamine (9.43 ml, 62.5 mmol) in dry THF (100 ml), under nitrogen. After the addition is complete, the solution is stirred for 2 hours at -78° C., then 15 minutes at -30° C. and cooled to -78° C. A solution of 5.36 g (25 mmol) of iodomethyl-trimethylsilane in dry hexamethylphosphoramide (39 ml) is added dropwise to the resultant syrupy mixture. After the addition is complete, the reaction mixture is warmed up to -50° C., kept at this temperature for 1 hour and cooled to -78° C., just before hydrolysis. The reaction mixture is quenched by addition of water and ammonium chloride and diluted with ether. The organic layer is washed with 1N potassium hydrogen sulfate, twice with water and dried over sodium sulfate. The solvent is evaporated and the residue obtained (8.03 g) is purified by flash chromatography (silica gel,ethyl acetate/petroleum ether: 2/8). 4.30 g of the title compound are obtained (yield: 56%) (colorless oil). Rf : 0.51 (ethyl acetate/petroleum ether: 2/8). After the addition 15 minutes at -30° C. and cooled to -78° C After the addition the reaction mixture is warmed up to -50° C. kept at this temperature for 1 hour cooled to -78° C., just before hydrolysis The reaction mixture is quenched by addition of water and ammonium chloride diluted with ether The organic layer is washed with 1N potassium hydrogen sulfate, twice with water dried over sodium sulfate The solvent is evaporated the residue obtained (8.03 g) is purified by flash chromatography (silica gel,ethyl acetate/petroleum ether: 2/8)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of diisopropylamine (0.7 mL, 0.005 mol) in 9 mL of dry THF was added butyllithium (BuLi) (2.83 mL of 1.62M solution in hexane, 4.6 mmol) at 0° C. The solution was stirred at this temperature for 5 minutes and cooled to −78° C. with a dry ice/isopropanol bath. A solution of 2-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (Example 44) (1.46 g, 3.8 mmol) in 12 mL of dry THF was added over 10 minutes and the reaction mixture was stirred at −78° C. for 1 hour. (Iodomethyl)trimethylsilane (1.23 g, 57 mmol) was added dropwise and the reaction mixture was warmed to room temperature and was stirred overnight. The reaction was quenched with 50 mL of 1 N HCl and the aqueous phase was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by chromatography on silica gel (ethyl acetate/hexane, 65:35) to give 1.30 g of 2-methyl-3-[1-[4-[[2-(trimethylsilyl)ethyl]sulfonyl]phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine as a white solid (74%): mp(DSC) 155–157° C. Anal. Calc'd. for C21H24F3N3O2SSi: C, 53.94; H, 5.17; N, 8.99; S, 6.86. Found: C, 53.77; H, 4.94; N, 8.75; S, 6.98. the reaction mixture was stirred at −78° C. for 1 hour the reaction mixture was warmed to room temperature was stirred overnight The reaction was quenched with 50 mL of 1 N HCl the aqueous phase was extracted with ethyl acetate (3×60 mL) The combined organic layers were washed with brine dried over MgSO4 filtered concentrated The crude mixture was purified by chromatography on silica gel (ethyl acetate/hexane, 65:35)

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 60% sodium hydride in mineral oil (39 mg, 0.96 mmol, 1.3 equiv) was added to a stirred solution of benzazepine 25 (180 mg, 0.74 mmol, 1.0 equiv) in tetrahydrofuran (9.3 mL) at 25° C. The resulting brown suspension was stirred at 25° C. for 1 h. (Iodomethyl)trimethylsilane (0.55 mL, 3.7 mmol, 5.0 equiv) was added via syringe at 25° C. The reaction vessel was sealed under argon and heated to 50° C. via oil bath for 30 m. The reaction mixture was cooled to 25° C. and approximately 50% of the solvent volume was removed by sweeping with nitrogen. The crude reaction mixture was loaded directly onto a column and purified by silica gel column chromatography (5% triethylamine in ethyl acetate) to afford 31 (151 mg, 62% yield) as an off-white amorphous solid. Rf=0.41 (5% triethylamine in ethyl acetate); 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H, ArH), 6.48 (s, 1H, ArH), 5.89 (s, 2H, OCH2O), 3.56 (m, 2H, CH2), 3.02 (br s, 2H, NCH2Si), 2.91 (m, 2H, CH2), 2.59 (m, 2H, CH2), 2.49 (m, 2H, CH2), 0.13 (s, 9H, Si(CH3)3); 13C NMR (125 MHz, CDCl3) δ 200.86, 169.37, 146.18, 145.19, 132.71, 127.17, 110.46, 109.47, 108.06, 100.92, 57.78, 46.78, 36.22, 33.37, 28.08, −1.26; IR (neat film) 2953 (w, br), 1647 (w), 1556 (s), 1488 (m), 1445 (m), 1353 (w), 1248 (m), 1039 (m), 843 (m) cm−1; HRMS (EI) m/z: Calcd for C18H23NO3Si (MH+) 330.1525; observed 330.1525. was added via syringe at 25° C The reaction vessel was sealed under argon The reaction mixture was cooled to 25° C. approximately 50% of the solvent volume was removed The crude reaction mixture purified by silica gel column chromatography (5% triethylamine in ethyl acetate)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of diisopropylamine (0.7 mL, 0.005 mol) in 9 mL of dry THF was added butyllithium (BuLi) (2.83 mL of 1.62M solution in hexane, 4.6 mmol) at 0° C. The solution was stirred at this temperature for 5 minutes and cooled to -78° C. with a dry ice/isopropanol bath. A solution of 2-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (Example 44) (1.46 g, 3.8 mmol) in 12 mL of dry THF was added over 10 minutes and the reaction mixture was stirred at −780° C. for 1 hour. (Iodomethyl)trimethylsilane (1.23 g, 57 mmol) was added dropwise and the reaction mixture was warmed to room temperature and was stirred overnight. The reaction was quenched with 50 mL of 1 N HCl and the aqueous phase was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude mixture was purified by chromatography on silica gel (ethyl acetate/hexane, 65:35) to give 1.30 g of 2-methyl-3-[1-[4-[[2-(trimethylsilyl)ethyl]sulfonyl]phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine as a white solid (74%): mp(DSC) 155-157° C. Anal. Calc'd. for C21H24F3N3O2SSi: C, 53.94; H, 5.17; N, 8.99; S, 6.86. Found: c, 53.77; H, 4.94; N, 8.75; S, 6.98. the reaction mixture was stirred at −780° C. for 1 hour the reaction mixture was warmed to room temperature was stirred overnight The reaction was quenched with 50 mL of 1 N HCl the aqueous phase was extracted with ethyl acetate (3×60 mL) The combined organic layers were washed with brine dried over MgSO4 filtered concentrated The crude mixture was purified by chromatography on silica gel (ethyl acetate/hexane, 65:35)