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CAS No. : | 38222-83-2 |
Formula : | C14H23N |
M.W : | 205.34 |
SMILES Code : | CC1=CC(C(C)(C)C)=NC(C(C)(C)C)=C1 |
MDL No. : | MFCD00006305 |
InChI Key : | HVHZEKKZMFRULH-UHFFFAOYSA-N |
Pubchem ID : | 98898 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; | 4-Bromomethyl-2,6-di-t-butylpyridine (Compound A3) To a mixture of 2,6-di-t-butyl-4-methylpyridine (Aldrich, 2.0 g, 9.73 mmol) in 25 ml of dry CCl4 was added benzoyl peroxide (24 mg, 0.097 mmol) and NBS (1.9 g, 10.7 mmol). The reaction mixture was refluxed for 16 hours. After it cooled to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography (silica gel, hexane) to give an oil (1.957 g) which contained 82percent of the desired product and 18percent of the starting material. 1 H NMR delta 7.09 (s, 2H), 4.39 (s, 2H), 1.35 (s, 18H). | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; | 4-Bromomethyl-2,6-di-t-butylpyridine (Compound A) To a mixture of 2,6-di-t-butyl-4-methylpyridine (Aldrich, 2.0 g, 9.73 mmol) in 25 ml of dry CCl4 was added benzoyl peroxide (24 mg, 0.097 mmol) and NBS (1.9 g, 10.7 mmol). The reaction mixture was refluxed for 16 hours. After it cooled to room temperature, the solvent was removed in vacuo and the residue was purified by column chromatography (silica gel, hexane) to give an oil (1.957 g) which contained 82percent of the desired product and 18percent of the starting material. 1 H NMR delta 7.09 (s, 2H), 4.39 (s, 2H), 1.35 (s, 18H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic anhydride; In dichloromethane; water; | Example 6B 2,2,2-Trifluoro-N-(2-iodophenyl)acetamide 2-Iodo-phenylamine (Aldrich, 1.09 g, 5 mmol) was treated with trifluoroacetic anhydride (Aldrich, 1.26 g, 6 mmol) and 2,6-di-tert-butyl-4-methyl-pyridine (Aldrich, 1.23 g, 6 mmol) in CH2Cl2 (10 mL)at room temperature overnight. It was then quenched with with water (5 mL) and extracted with EtOAc (3*10 mL). The extracts were combined and washed with brine (5 mL). The organic solution was concentrated and the title compound was purified by flash chromatography (SiO2, Hexanes/EtOAc, 80:20, Rf. 0.50) as a solid (1.1 g, yield, 70percent). 1H NMR (300 MHz, CD3OD) delta 7.07-7.12 (m, 1H), 7.39-7.47 (m, 2H), 7.95 (dd, J=7.8, 1.3 Hz, 1H) ppm. MS (DCI): m/z 316 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluorormethanesulfonic acid; In dichloromethane; at 25℃; | (1) To a solution of 4-oxocyclohexanecarboxylic acid ethyl ester (8.0 g) and 2,6-di(tert-butyl)-4-methylpyridine (14.4 g) in dichloromethane (200 ml) is added trifluoromethanesulfonic anhydride (8.73 ml) at -78°C, and the mixture is gradually warmed to 25°C, and the mixture is stirred at the same temperature overnight.. The reaction solution is poured into aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate.. The organic layer is washed with saturated brine, and the solvent is evaporated under reduced pressure to give 4-trifluoromethanesulfonyloxy-3-cyclohexenecarboxylic acid ethyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In dichloromethane; ethyl acetate; | Dimethyl-phosphinic acid C-43 rapamycin ester To a cooled (0° C.) solution of rapamycin (0.1 g, 0.109 mmol) in 1.8 mL of dichloromethane was added 0.168 g (0.82 mmol) of 2,6-di-t-butyl-4-methyl pyridine, under a stream of N2, followed immediately by a solution of dimethylphosphinic chloride (0.062 g, 0.547 mmol) in 0.2 mL of dichloromethane. The slightly yellow reaction solution was stirred at 0° C., under an atmosphere of N2, for 3.5 h (reaction monitored by TLC). The cold (0° C.) reaction solution was diluted with ~20 mL EtOAc then transferred to a separatory funnel containing EtOAc (150 mL) and saturated NaHCO3 (100 mL). Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1*100 mL), saturated NaHCO3(1*100 mL), and brine (1*100 mL), then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 1:10:3:3 MeOH/DCM/EtOAc/hexane) to provide 0.092 g of a white solid: 1H NMR (300 MHz, CDCl3) d 4.18 (m, 1H), 4.10 (m, 1H), 3.05 (m, 1H), 1.5 (m, 6H); 31P NMR (121 MHz, CDCl3) d 53.6; 1013 m/z (M+Na). | |
With sodium hydrogencarbonate; In dichloromethane; ethyl acetate; | Dimethyl-phosphinic acid C-43 rapamycin ester To a cooled (0° C.) solution of rapamycin (0.1 g, 0.109 mmol) in 1.8 mL of dichloromethane was added 0.168 g (0.82 mmol) of 2,6-di-t-butyl-4-methyl pyridine, under a stream of N2, followed immediately by a solution of dimethylphosphinic chloride (0.062 g, 0.547 mmol) in 0.2 mL of dichloromethane. The slightly yellow reaction solution was stirred at 0° C., under an atmosphere of N2, for 3.5 h (reaction monitored by TLC). The cold (0° C.) reaction solution was diluted with ~20 mL EtOAc then transferred to a separatory funnel containing EtOAc (150 mL) and saturated NaHCO3 (100 mL). Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1*100 mL), saturated NaHCO3(1*100 mL), and brine (1*100 mL), then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 1:10:3:3 MeOH/DCM/EtOAc/hexane) to provide 0.092 g of a white solid: 1H NMR (300 MHz, CDCl3) d 4.18 (m, 1H), 4.10 (m, 1H), 3.05 (m, 1H), 1.51 (m, 6H); 31P NMR (121 MHz, CDCl3) d 53.6; 1013 m/z (M+Na). | |
With sodium hydrogencarbonate; In dichloromethane; ethyl acetate; | EXAMPLE 2Dimethyl-Phosphinic Acid C-43 Rapamycin EsterTo a cooled (0° C.) solution of rapamycin (0.1 g, 0.109 mmol) in 1.8 mL of dichloromethane was added 0.168 g (0.82 mmol) of 2,6-di-t-butyl-4-methyl pyridine, under a stream of N2, followed immediately by a solution of dimethylphosphinic chloride (0.062 g, 0.547 mmol) in 0.2 mL of dichloromethane.The slightly yellow reaction solution was stirred at 0° C., under an atmosphere of N2, for 3.5 h (reaction monitored by TLC).The cold (0° C.) reaction solution was diluted with ~20 mL EtOAc then transferred to a reparatory funnel containing EtOAc (150 mL) and saturated NaHCO3 (100 mL).Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1*100 mL), saturated NaHCO3(1*100 mL), and brine (1*100 mL), then dried over MgSO4 and concentrated.The crude product was purified by silica gel flash chromatography (eluted with 1:10:3:3 MeOH/DCM/EtOAc/hexane) to provide 0.092 g of a white solid: 1H NMR (300 MHz, CDCl3) delta4.18 (m, 1H), 4.10 (m, 1H), 3.05 (m, 1H), 1.51 (m, 6H); 31P NMR (121 MHz, CDCl3) delta 53.6; 1013 m/z (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In dichloromethane; | EXAMPLE 3 Synthesis of Trifluoromethanesulfonic Acid 2,2-bis(fluoromethyl)-6-(trifluoromethyl)-2H-1-benzopyran-4-yl ester A three-necked 50-ml flask (equipped with a thermometer and a dropping funnel) was charged with 1.0 g (3.6 mmol) of 2,2-bis(fluoromethyl)-3,4-dihydro-6-(trifluoromethyl)-2H-1-benzopyran-4-one, 1.8 g (8.9 mmol) of <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong>, and 10 ml of methylene chloride. Then, 2.0 g (7.1 mmol) of trifluoromethanesulfonic acid anhydride were added in a dropwise manner by spending 5 minutes to the mixture under cooling in an iced water bath at 5-10° C., while the mixture was stirred. After completing the dropping, the temperature of the mixture was gradually increased to room temperature, followed by stirring for 140 hr at room temperature. Then, the methylene chloride was distilled off by an evaporator. The resulting residue was purified by silica gel column chromatography (developing liquid: ethyl acetate/n-hexane=1/8), thereby obtaining 1.1 g (2.7 mmol) of trifluoromethanesulfonic acid 2,2-bis(fluoromethyl)-6-(trifluoromethyl)-2H-1-benzopyran-4-yl ester (yield: 75percent). This product was found to have the following properties. 1H-NMR (standard substance: TMS; solvent: CDCl3) sigma (ppm): 4.51-4.73 (m, J=46.4 Hz, 4H), 5.78 (s, 1H), 7.04 (d, J=8.8 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.58 (dd, J=8.8, 2.0 Hz, 1H) 19F-NMR (standard substance: CCl3F; solvent: CDCl3) sigma (ppm): -62.85 (s, 3F), -73.51 (s, 3F), -232.91 (t, J=46.4 Hz, 2F) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydrogencarbonate; In dichloromethane; water; | EXAMPLE 7 Preparation of 4-[6-(4-methoxyphenyl)benzo[b]thiophen-3-yl]pyridine Anhydrous trifluoromethane sulfonic acid (Tf2O; 0.14 ml, 0.8322 mmol) was added to a suspension of 3-(4-pyridyl)benzo[b] thiophen-6-ol (164 mg, 0.7216 mmol) obtained in Example 6 and 2,6-di-t-butyl-4-methylpyridine (180 mg, 0.8766 mmol) in dichloromethane (5 ml) under cooling with ice. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate. The organic layer was washed with 5percent citric acid aqueous solution, saturated aqueous solution of sodium bicarbonate, water, and then saturated brine, sequentially, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained was submitted to silica gel column chromatography (hexane:ethyl acetate=17:3) to obtain a colorless oily product of 3-(4-pyridyl)benzo[b]thiophen-6-yl=trifluoromethane sulfonate (247 mg, 95percent). 1H-NMR(CDCl3) delta: 7.33(dd, J=2.4, 8.9 Hz, 1H), 7.46(d, J=6.0 Hz, 2H), 7.65(s, 1H), 7.85(d, J=2.2 Hz, 1H), 7.93(d, J=8.9 Hz, 1H), 8.73(d, J=6.0 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With trifluoromethanesulfonic acid anhydride; In hexane; dichloromethane; | (34a) Trifluoromethanesulfonic anhydride (1.2 mL, 7.4 mmol)was added drop wise to a stirring solution of chroman-4-one (1.0 g, 6.7 mmol), 2,6-di-t-butyl-4-methyl pyridine (1.59 g, 7.7 mmol) in dichloromethane (40 mL), under nitrogen atmosphere. The reaction was heated to reflux for 2 h, allowed to cool to room temperature and was concentrated in vacuo to give a semi solid residue. This was treated with hexane and the solids were filtered off. The filtrate was concentrated to give 4-[(trifluoromethyl)sulfonyl]-2H-chromene (1.78 g, 94percent) as an orange oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With Tf2O; sodium hydrogencarbonate; In dichloromethane; water; | EXAMPLE 13 Preparation of 3-[6-(4-fluorophenyl)benzo[b]thiophen-3-yl]pyridine hydrochloride Tf2O (0.97 ml, 5.766 mmol) was added to a suspension of the 3-(3-pyridyl)benzo[b]thiophen-6-ol (1.14 g, 5.016 mmol) obtained in Example 8 and 2,6-di-t-butyl-4-methylpyridine (1.25 g, 6.087 mmol) in dichloromethane (35 ml) under cooling with ice. The mixture was warmed to room temperature and stirred for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with diethyl ether, washed with water, 5percent citric acid aqueous solution, saturated aqueous solution of sodium bicarbonate, water, and then saturated brine, sequentially, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was submitted to basic silica gel column chromatography (hexane:ethyl acetate=93:7) to obtain a colorless oily product of 3-(3-pyridyl)benzo[b]thiophen-6-yl=trifluoromethane sulfonate (1.78 g, 99percent). 1H-NMR(CDCl3) delta: 7.32(dd, J=2.3, 8,9 Hz, 1H), 7.42(dd, J=4.9, 7.9 Hz, 1H), 7.57(s, 1H), 7.84-7.86(m, 3H), 8.67(dd, J=2.1, 5.5 Hz, 1H), 8.80(d, J=2.1 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With trifluoromethanesulfonic acid anhydride; In hexane; dichloromethane; | (33a) Trifluoromethanesulfonic anhydride (2.2 mL, 13.4 mmol) was added dropwise to a stirring solution of thiochroman-4-one (2.0 g, 12.2 mmol), 2,6-di-t-butyl-4-methyl pyridine (2.63 g, 12.8 mmol) in dichloromethane (100 mL), under nitrogen atmosphere. The reaction was heated to reflux for 2 h, allowed to cool to room temperature and was concentrated in vacuo to give a semi-solid residue. This was treated with hexane and the solids were filtered off. The filtrate was concentrated to give 2H-1-benzothiopyran-4-yltrifluoromethyl sulfone (1.84 g, 51percent) as a solid. MS found: (M+H)+=297. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; pentane; | Step H 2,2-Difluoro-2-(2-pyridyl)ethyl trifluoromethanesulfonate (1-8) To a stirred -78° C. solution of 50 mg (0.31 mmol) of 2,2-difluoro-2-(2-pyridyl)ethanol and 100 mg (0.49 mmol) of 2,6-di-t-butyl-4-methylpyridine in 1.0 ml of CH2Cl2 was added dropwise 79 muL (0.47 mmol) of trifluoromethansulfonic anhydride. After the addition, the cold bath was removed, and stirring continued for 0.5 h. The reaction was diluted with 2 ml of pentane, and the resulting precipitate washed with pentane. The filtrate was evaporated in vacuo to dryness to give as a yellow solid: 1H NMR (CDCl3) delta8.66 (d, 1H, 4.9 Hz), 7.89 (td,1H, 7.7, 1.7 Hz), 7.76 (d, 1H, 7.9 Hz), 7.45-7.49 (m, 1H), 5.12 (t, 2 H, 11.9 Hz). | |
In dichloromethane; pentane; | Step B 2,2-Difluoro-2-(2-pyridyl)ethyl Trifluoromethanesulfonate To a stirred -78° solution of 50 mg (0.31 mmol) of 2,2-difluoro-2-(2-pyridyl)ethanol and 100 mg (0.49 mmol) of 2,6-di-t-butyl-4-methylpyridine in 1.0 mL of CH2Cl2 was added 79 muL (0.47 mmol) of trifluoromethansulfonic anhydride dropwise under Ar. After the addition, the cold bath was removed, and stirring continued for 0.5 h. The reaction was diluted with 2 mL of pentane, and the resulting precipitate washed with pentane. The filtrate was evaporated in vacuo to dryness to give the title compound as a yellow solid: 1H NMR (CDCl3) delta 8.66 (d, 1H, 4.9 Hz), 7.89 (td, 1H, 7.7, 1.7 Hz), 7.76 (d, 1H, 7.9 Hz), 7.45-7.49 (m, 1H), 5.12 (t, 2; H, 11.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; pentane; | Step 1 Trifluoromethanesulphonic acid 7-nitro-3,4,4a,8a-tetrahydronaphthalen-1-yl ester 9.8 ml of trifluoromethanesulphonic anhydride are poured at 0° C. into a solution of 10 g of 7-nitrotetralone and 11.8 g of <strong>[38222-83-2]2,6-di-tert-butyl-4-methylpyridine</strong> in 365 ml of dichloromethane. After 24 hours at ambient temperature, concentration to dryness and taking up the residue in 200 ml of pentane at reflux for 30 minutes, the precipitate formed is filtered off. The organic phase is washed with a 1N hydrochloric acid solution and then with water, dried over magnesium sulphate and concentrated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoromethylsulfonic anhydride; In dichloromethane; pentane; | 2,2-Difluoro-2-(2-pyridyl)ethyl trifluoromethanesulfonate (I-1-4) To a stirred solution of 5 g (31.4 mmol) of 2,2-difluoro-2-(2-pyridyl)ethanol I-1-3 and 9.69 g (47.2 mmol) of 2,6-di-t-butyl-4-methylpyridine in 110 mL of methylene chloride at -78° C. under Ar was added 7.93 mL (47.2 mmol) of triflic anhydride dropwise. After 1 h, the reaction was diluted with 100 mL of pentane and filtered. The filtrate was concentrated and treated again with pentane and filtered. Concentration of the filtrate gave I-1-4 as a brown oil, contaminated with 2,6-di-t-butyl-4-methylpyridine: 1H NMR (CDCl3) delta5.12 (t, 2H), 7.45-7.5 (m, 1H), 7.75 (d,1H), 7.86-7.94 (m, 1H), 8.65 (d, 1H). | |
With trifluoromethylsulfonic anhydride; In dichloromethane; pentane; | Step E 2,2-Difluoro-2-(2-pyridyl)ethyl trifluoromethanesulfonate (5a) To a stirred solution of 5 g (31.4 mmol) of 2,2-difluoro-2-(2-pyridyl)ethanol 5 and 9.69 g (47.2 mmol) of 2,6-di-t-butyl-4-methylpyridine in 110 mL of methylene chloride at -78° C. under Ar was added 7.93 mL (47.2 mmol) of triflic anhydride dropwise. After 1 h, the reaction was diluted with 100 mL of pentane and filtered. The filtrate was concentrated and treated again with pentane and filtered. Concentration of the filtrate gave 5a as a brown oil, contaminated with 2,6-di-t-butyl-4-methylpyridine: 1H NMR (CDCl3) delta5.12 (t, 2H), 7.45-7.5 (m, 1H), 7.75 (d, 1H), 7.86-7.94 (m, 1H), 8.65 (d, 1H). | |
With trifluoromethylsulfonic anhydride; In dichloromethane; pentane; | 2,2-Difluoro-2-(2-pyridyl)ethyl Trifluoromethanesulfonate (1-4). To a stirred solution of 5 g (31.4 mmol) of 2,2-difluoro-2-(2-pyridyl)ethanol 1-3 and 9.69 g (47.2 mmol) of 2,6-di-t-butyl-4-methylpyridine in 110 mL of methylene chloride at -78° C. under Ar was added 7.93 mL (47.2 mmol) of triflic anhydride dropwise. After 1 h, the reaction was diluted with 100 mL of pentane and filtered. The filtrate was concentrated and treated again with pentane and filtered. Concentration of the filtrate gave 1-4 as a brown oil, contaminated with 2,6-di-t-butyl-4-methylpyridine: 1H NMR (CDCl3) delta 5.12 (t, 2H), 7.45-7.5 (m, 1H), 7.75 (d, 1H), 7.86-7.94 (m, 1H), 8.65 (d, 1H). |