trimethyloxidanium;tetrafluoroborate

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 25 (25 g, 106.8 mmol), trimethyloxonium tetrafluoroborate (16.6 g, 110 mmol) and CH2Cl2 (600 mL) was stirred for 36 hours, during which the coarse suspension changed to a clear, colorless solution. Cooling of this solution of 0° C. was followed by a dropwise addition of ethylene diamine (7.00 g, 1.1 equiv) over 10 minutes. The resulting solution was warmed to room temperature, diluted with absolute ethanol (200 mL) and then evaporated to dryness. The pasty white residue was partitioned between 5% aqueous K2CO3 (200 mL) and CH2Cl2 (500 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure. Recrystallization of the residue from boiling hexanes (500 mL) afforded pure 3 as white needles that were removed by filtration and dried in air (23.52 g, 85%). 1H NMR (300 MHz, d6-DMSO) δ ppm 7.46-7.44 (m, 2H, Ar), 7.14 (t, J=7.8 Hz, 1H, Ar), 6.45 (s, 1H, NH), 4.79 (q, J=6.6 Hz, 1H), 3.43-3.37 (s, br, 4H), 1.47 (d, J=6.6 Hz, 3H). 13C NMR (75 MHz, d6-DMSO) δ ppm 166.3, 150.0, 130.0, 129.6, 129.5, 129.2, 126.6, 77.3, 50.4 (very broad), 19.2; mp=129-130° C. (hexanes); [α]23D=−80.2° (c 1.0, EtOH) (lit.4 [α]20D=−76.4° (c 1.0, EtOH). The resulting solution was warmed to room temperature evaporated to dryness The pasty white residue was partitioned between 5% aqueous K2CO3 (200 mL) and CH2Cl2 (500 mL) The organic layer was dried (Na2SO4) evaporated under reduced pressure Recrystallization of the residue

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To (R,R)-4-fluoro-2-(2-hydroxycyclohexyloxy)-nitrobenzene (0.200 g) dissolved in methylene chloride (10.0 ml) was added trimethyloxonium tetrafluoroborate (0.348 g). The mixture was stirred overnight at rt. Water was added; the organic phase was separated and evaporated to dryness to yield a brownish oil. the organic phase was separated evaporated to dryness to yield a brownish oil

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide (200 mg) in 1,2-dichloroethane (3 ml) was added trimethyloxonium tetrafluoroborate (85 mg) and the reaction mixture was stirred at room temperature for 19 hours then more trimethyloxonium tetrafluoroborate (210 mg). After 4 hours 30 minutes, more trimethyloxonium tetrafluoroborate (0.5 ml) was added and after 2 hours, the reaction mixture was heated at (85° C.) for 18 hours. The solution was then concentrated under vacuo to give a crude residue (210 mg). Part of this residue (100 mg) of the crude was extracted between AcOEt and saturated NaHCO3. The organic phases were gathered, dried over anhydrous MgSO4, filtered and evaporated to give the desired compound (54 mg). 1H-NMR (CDCl3, δ in ppm): 7.50-7.31 (m, 6H), 5.75 (bs, 2H), 5.41 (s, 1H), 2.99 (s, 3H), 2.52 (s, 3H). the reaction mixture was heated at (85° C.) for 18 hours The solution was then concentrated under vacuo to give a crude residue (210 mg) Part of this residue (100 mg) of the crude was extracted between AcOEt and saturated NaHCO3 dried over anhydrous MgSO4 filtered evaporated

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 3-(4,4-diphenylpiperidin-1-yl)propionitrile (5.00 g, 17.2 mmol, 1.00 equiv) in CH2Cl2 (40 mL) was added HCl in ether (1.0 M, 22.4 mL, 22 mmol, 1.3 equiv). After removal of the solvents, the residue and trimethyloxonium tetrafluoroborate (9.67 g, 65.4 mmol, 3.80 equiv) were stirred in refluxing anhydrous CH2Cl2 (80 mL) under argon for 44 hours. The mixture was cooled to 0° C., anhydrous MeOH (5 mL) was added, and stirring was continued for 1 hour at 0° C. The solvents were removed and the residue was dissolved in anhydrous MeOH (30 mL). Sodium borohydride (5.20 g, 138 mmol, 8.00 equiv) was added at 0° C., and stirring was continued at this temperature under argon for 2 hours. The solution was acidified to pH 1 by slow addition of 6 N aqueous HCl (40 mL) at 0° C. and stirred for 3 hours at room temperature. After removal of the solvents, water (30 mL) was added and the mixture was basified to pH 9 by addition of 6 N aqueous NaOH. The mixture was extracted with CH2Cl2 (3×100 mL), and the combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc-MeOH-isopropylamine 9:1:0 to 5:1:0.2) to give 2.18 g (41%) of yellow solid, which was characterized spectroscopically. After removal of the solvents The solvents were removed the residue was dissolved in anhydrous MeOH (30 mL) stirring was continued at this temperature under argon for 2 hours stirred for 3 hours at room temperature After removal of the solvents, water (30 mL) was added the mixture was basified to pH 9 by addition of 6 N aqueous NaOH The mixture was extracted with CH2Cl2 (3×100 mL) the combined organic solutions were dried over MgSO4 concentrated The residue was purified by flash chromatography (SiO2, EtOAc-MeOH-isopropylamine 9:1:0 to 5:1:0.2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 1-(4′-phenylsulfonylphenyl)benzimidazole (6.7 g, 20 mmol) in dichloromethane (100 ml) is admixed at −10° C. with trimethyloxonium tetrafluoroborate (3.3 g, 22 mmol) and stirred under argon for 16 h. After adding ethanol, the precipitate formed is filtered off and washed with cold petroleum ether. Yield: 80%. the precipitate formed is filtered off washed with cold petroleum ether

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of trimethyloxonium tetrafluoroborate (5.39 mg, 0.036 mmol) and (5S,7R)—N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-7-(4-fluoro-2-methylphenyl)-N-methyl-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide (Intermediate 42, 17 mg, 0.030 mmol) in Dichloromethane (DCM) (2 ml) was stirred at rt for 3 hrs. The mixture was washed with NaHCO3 saturated solution and the aqueous layer was extracted with DCM. The organic layers were combined, filtered through a phase separator tube and concentrated. The residue was dissolved in Methanol (2 ml) and to this solution, cooled to 0° C., was added Sodium cyanoborohydride (5.73 mg, 0.091 mmol). A solution of 1.25M HCl in MeOH was added maintaining the pH around 3-4 and the reaction was left stirring at rt overnight. To the solution NaHCO3 saturated solution and DCM were added and the aqueous layer was extracted with DCM. Organic layers were combined, filtered through a phase separator tube and concentrated. The crude was purified by SP4 (12M cartridge; eluting from 90%:10% to 50%:50% Cy:EtOAc). Relevant fractions were collected obtaining the title compound (13 mg, 0.024 mmol, 78% yield); 1H NMR (500 MHz, DMSO-d6) δ ppm 8.01 (s, 1H) 7.69 (s, 2H) 7.15-7.21 (m, 1H) 6.94 (dd, 1H) 6.83 (t, 1H) 5.20-5.41 (m, 1H) 4.02-4.27 (m, 1H) 3.35-3.44 (m, 1H) 3.02-3.20 (m, 2H) 2.86 (t, 1H) 2.76 (s, 3H) 2.34 (s, 3 H) 1.59-2.19 (m, 8H) 1.47 (d, 3H); UPLC: Rt=0.68 mins, m/z=546 [M+H]+; HPLC: Rt=5.67 mins. The mixture was washed with NaHCO3 saturated solution the aqueous layer was extracted with DCM filtered through a phase separator tube concentrated The residue was dissolved in Methanol (2 ml) and to this solution maintaining the pH around 3-4 the reaction was left the aqueous layer was extracted with DCM filtered through a phase separator tube concentrated The crude was purified by SP4 (12M cartridge; eluting from 90%:10% to 50%:50% Cy:EtOAc) Relevant fractions were collected

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of Trimethyloxonium tetrafluoroborate (10.35 mg, 0.070 mmol) and methyl (5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-oxo-1,8-diazaspiro[4.5]decane-3-carboxylate (Intermediate 35, 36 mg) in Dichloromethane (DCM) (2 ml) was stirred at rt for 2 hrs. The mixture was washed with NaHCO3 saturated solution and the aqueous layer was extracted with DCM. The organic layers were combined, filtered through a phase separator tube and concentrated obtaining the intermediate methyl(5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methy)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-(methyloxy)-1,8-diazaspiro[4.5]dec-1-ene-3-carboxylate: The mixture was washed with NaHCO3 saturated solution the aqueous layer was extracted with DCM filtered through a phase separator tube concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 19-Hydroxyandrost-4-ene-3,17-dione is dissolved in methylenechloride and trimethyloxonium fluoroborate added. After stirring at room temperature for a period of two hours, water is added to the reaction mixture, the organic layer is separated, dried over magnesium sulfate and the solvent removed under vacuum. The residue is crystallized from an acetone-hexane solution to yield the desired 19-methoxyandrost-4-ene-3,17-dione. the organic layer is separated dried over magnesium sulfate the solvent removed under vacuum The residue is crystallized from an acetone-hexane solution

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 1,3,4,5-tetrahydro-6-acetoxy-2H-1-benzazepin-2-thione (235 mg, 1.0 mmol) in 25 mL of CH2Cl2 was added at 0° 295 mg (2.0 mmol) of trimethyloxonium tetrafluoroborate. After stirring at room temperature for about 30 min. water was added and the CH2Cl2 layer was separated. Drying over Na2SO4 and removal of the solvent gave 229 mg of 4,5-dihydro-6-acetoxy-2-methylthio-3H-benzazepine. was added the CH2Cl2 layer was separated Drying over Na2SO4 and removal of the solvent

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4.0 g (10.5 mmol) 1,5-diacetyl-3-[(3,4-dimethoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V) are suspended in 100 ml methylene chloride and combined with 3.1 g (21 mmol) trimethyloxonium tetrafluoroborate as well as 7.2 ml Hünig base (ethyldiisopropylamine) at ambient temperature. The solution is stirred for 3 h, then a further 1.55 g trimethyloxonium tetrafluoroborate and 3.5 ml Hünig base are added and the mixture is stirred overnight. After the same amount of reagent has been added again and the mixture has been stirred for a further 5 h, the reaction is washed three times with water, the organic phase is dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue is chromatographed through a silica gel column with methylene chloride/methanol 9:1, the corresponding fractions are combined and concentrated by rotary evaporation. at ambient temperature the mixture is stirred overnight After the same amount of reagent has been added again the mixture has been stirred for a further 5 h the reaction is washed three times with water the organic phase is dried over sodium sulphate filtered concentrated by rotary evaporation The residue is chromatographed through a silica gel column with methylene chloride/methanol 9:1 concentrated by rotary evaporation

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Dissolved commercially available ethyl 2-oxopyrrolidine-3-carboxylate (2.50 g, 15.91 mmol) in 30 mL dichloromethane in 50 mL round bottom flask. To this solution was added trimethyloxonium tetrafluoroborate (2.59 g, 17.5 mmol) as a solid and rinsed with 20 mL dichloromethane. The resulting mixture was stirred at room temperature for two h and LC/MS indicated that the intermediate methyl 5-methoxy-3,4-dihydro-2H-pyrrole-4-carboxylate had formed. At this point, acetohydrazide (1.18 g, 15.91 mmol) was introduced as a solid to the mixture and the resulting solution was stirred at room temperature for 3 h. The solution was then concentrated under vacuum to remove all dichloromethane and the residue was then taken up in 100 mL n-butanol which was heated to reflux in an oil bath set at 120° C. overnight. The solution was cooled to room temperature and concentrated under vacuum. The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane:methanol solvent system. The product was extracted from the silica gel using 85:15 dichloromethane:methanol which afforded the title compound (454 mg, 11%). 1H NMR (500 MHz DMSO-d6) δ: 4.16-4.06 (m, 1H), 4.00-3.88 (m, 1H), 2.85-2.78 (m, 1H), 2.29 (s, 3H), 1.55 (dt, J=6.7, 13.9 Hz, 2H), 1.32 (dt, J=6.7, 14.0 Hz, 2H), 0.88 (t, J=7.5 Hz, 3H). LC-MS: m/z (ES)=196 (MH)+. rinsed with 20 mL dichloromethane had formed the resulting solution was stirred at room temperature for 3 h The solution was then concentrated under vacuum to remove all dichloromethane was heated to reflux in an oil bath The solution was cooled to room temperature concentrated under vacuum The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane The product was extracted from the silica gel using 85:15 dichloromethane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Dissolved commercially available ethyl 2-oxopyrrolidine-3-carboxylate (2.50 g, 15.91 mmol) in 30 mL dichloromethane in 50 mL round bottom flask. To this solution was added trimethyloxonium tetrafluoroborate (2.59 g, 17.5 mmol) as a solid and rinsed with 20 mL dichloromethane. The resulting mixture was stirred at room temperature for two h and LC/MS indicated that the intermediate methyl 5-methoxy-3,4-dihydro-2H-pyrrole-4-carboxylate had formed. At this point, acetohydrazide (1.18 g, 15.91 mmol) was introduced as a solid to the mixture and the resulting solution was stirred at room temperature for 3 h. The solution was then concentrated under vacuum to remove all dichloromethane and the residue was then taken up in 100 mL n-butanol which was heated to reflux in an oil bath set at 120° C. overnight. The solution was cooled to room temperature and concentrated under vacuum. The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane:methanol solvent system. The product was extracted from the silica gel using 85:15 dichloromethane:methanol which afforded the title compound (454 mg, 11%). 1H NMR (500 MHz DMSO-d6) δ: 4.16-4.06 (m, 1H), 4.00-3.88 (m, 1H), 2.85-2.78 (m, 1H), 2.29 (s, 3H), 1.55 (dt, J=6.7, 13.9 Hz, 2H), 1.32 (dt, J=6.7, 14.0 Hz, 2H), 0.88 (t, J=7.5 Hz, 3H). LC-MS: m/z (ES)=196 (MH)+. rinsed with 20 mL dichloromethane had formed the resulting solution was stirred at room temperature for 3 h The solution was then concentrated under vacuum to remove all dichloromethane was heated to reflux in an oil bath The solution was cooled to room temperature concentrated under vacuum The residue was purified via sixteen 1500 μm silica gel preparative plates eluting with 90:10 dichloromethane The product was extracted from the silica gel using 85:15 dichloromethane