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Structure of 85952-32-5
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 85952-32-5 |
Formula : | C8H6ClF3O2S |
M.W : | 258.65 |
SMILES Code : | FC(F)(F)C1=C(CS(Cl)(=O)=O)C=CC=C1 |
MDL No. : | MFCD04972907 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅲ |
* 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 pyridine; In tetrahydrofuran; | N-[3,5-Dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-(2-trifluoromethylphenyl)methanesulphonamide The title compound is obtained by working as in Example 2, starting with 3 g (12.28 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline, 57 ml of anhydrous tetrahydrofuran, 2 ml (24.7 mmol) of pyridine and 4.8 g (18.5 mmol) of <strong>[85952-32-5](2-trifluoromethylphenyl)methanesulphonyl chloride</strong> (prepared according to Hamer et al., J. Pharm. Sci., 1975, 64, 1961). The product obtained is recrystallized from a hexane/ethyl acetate mixture. Yield: 1.37 g (24%) m.p. 146-148 C. (hexane/ethyl acetate) Elemental analysis: C17H17F3N2O6S2 1H NMR (DMSO d6): delta=2.3 (6H, s); 4.6 (2H, s); 6.27 (2H, s, exchangeable with CF3COOD); 6.71 (2H, s); 7.4 to 7.6 (4H, m); 10.6 (1H, s, exchangeable with CF3COOD) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; at -20 - 0℃; for 5h; | To a suspension of (2-trifluoromethylphenyl)methanesulfonic acid (20.3 g, 84 mmol) in THF (1.9 L) and DMF (5.0 mL) at -20 0C was added oxalyl chloride (44.7 mL,0.5 mol) slowly dropwise over 1hr. The bath temperature was maintained below 0 0C for4 h, at which point the reaction was evaporated to a volume of ~ 250 mL and diluted with 50OmL of ethyl acetate. This solution was washed with brine in a separatory funnel and dried over magnesium sulfate. The solution was then evaporated to a brown oil. This oil was taken up in 50OmL of pet ether (30-50) and heated with a heat gun until the oil went into solution. The solution was then placed into a dry-ice acetone bath to cool resulting in formation of a white crystalline material. This material was collected via EPO <DP n="34"/>filtration and dried to afford 19 g (85%) of (2-trifluoromethylphenyl)methanesulfonyl chloride as a white solid. |
85% | With oxalyl dichloride; In tetrahydrofuran; N,N-dimethyl-formamide; at -20 - 0℃; for 5h; | Step 14: To a suspension of (2-trifluoromethylphenyl)methanesulfonic acid (20.3 g, 84 mmol) in THF (1.9 L) and DMF (5.0 mL) at -20 C. was added oxalyl chloride (44.7 mL, 0.5 mol) slowly dropwise over 1hr. The bath temperature was maintained below 0 C. for 4 h, at which point the reaction was evaporated to a volume of 250 mL and diluted with 500 mL of ethyl acetate. This solution was washed with brine in a separatory funnel and dried over magnesium sulfate. The solution was then evaporated to a brown oil. This oil was taken up in 500 mL of pet ether) (30-50) and heated with a heat gun until the oil went into solution. The solution was then placed into a dry-ice acetone bath to cool resulting in formation of a white crystalline material. This material was collected via filtration and dried to afford 19 g (85%) of (2-trifluoromethylphenyl)methanesulfonyl chloride as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73%; ~ 5%Chromat. | With ammonia; water; In tetrahydrofuran; at -20 - -10℃; | EXAMPLE 1 Synthesis of (2-Trifluoromethyl-phenyl)-methanesulfonamide A vessel of suitable size was charged with tetrahydrofuran (THF, 250 mL), water (1 mL), DMF (2 mL), and (2-trifluoromethyl-phenyl)-methanesulfonic acid, sodium salt (50 g, 0.190 mol). The mixture was stirred under a nitrogen blanket and cooled to 0-5 C. Oxalyl chloride (63 g, 0.496 mol) was added dropwise to the reaction mixture. The mixture was stirred at 0-5 C. for 16 hours. In-process analysis (HPLC) showed a 99% conversion to <strong>[85952-32-5](2-(trifluoromethyl)phenyl)methanesulfonyl chloride</strong>. The reaction mixture was concentrated to 107 g, then diluted with THF (200 mL). The mixture was stirred and cooled to -10 to -20 C. Water (3.0 mL) was added dropwise. Ammonia (gas, 13 g, 0.765 mol) was added via subsurface tubing to the reaction mixture. The reaction mixture was basic to pH paper. In-process testing (HPLC) showed complete conversion of the sulfonyl chloride to the sulfonamide with 5% of the sulfonic acid. The mixture was filtered to remove inorganic salts. Water (135 mL) was added to the filtrate. The filtrate was concentrated to 190 g. The mixture was stirred at 0-5 C. for 30 min. The solid product was collected by filtration and dried to constant weight to give 33.2 g (73%) of the title compound. 1HNMR (300 MHz, CDCl3): delta 7.81-7.52 (m, 4H, ArH), 4.60 (s, 2H, CH2), and 4.52 (br s, 2H, NH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium hydrogencarbonate; In dichloromethane; water; | Step 2: Methyl 4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate (Example 2, Step 1, 9.1 g, 17 mmol) was treated with <strong>[85952-32-5](2-(trifluoromethyl)phenyl)methanesulfonyl chloride</strong> (4.8 g, 17 mmol, obtainable according to example 1 above) and sat. NaHCO3 in CH2Cl2. The mixture was poured into saturated sodium bicarbonate and extracted with CH2Cl2. The combined organic phase was washed with brine, dried over sodium sulfate and purified by column chromatography to afford 6.1 g of 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-([2-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid methyl ester as a white foam (47% yield). 1H NMR (400 MHz, CDCl3), delta 1.88-2.00 (m, 2H), 2.64-2.77 (m, 6H), 2.83-2.95 (m, 2H), 3.90 (s, 3H), 4.05 (t, J=5.9 Hz, 1H), 4.33 (s, 2H), 6.49 (d, J=8.8 Hz, 1H), 6.70-6.88 (m, 2H), 7.04 (dd, J=6.4, 2.7 Hz, 4H), 7.24 (s, 1H), 7.28-7.35 (m, 7H), 7.36-7.49 (m, 3H), 7.55-7.71 (m, 2H), 7.95 (d, J=8.1 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99%Chromat. | With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; water; at 0 - 5℃; for 16h; | EXAMPLE 1 Synthesis of (2-Trifluoromethyl-phenyl)-methanesulfonamide A vessel of suitable size was charged with tetrahydrofuran (THF, 250 mL), water (1 mL), DMF (2 mL), and (2-trifluoromethyl-phenyl)-methanesulfonic acid, sodium salt (50 g, 0.190 mol). The mixture was stirred under a nitrogen blanket and cooled to 0-5 C. Oxalyl chloride (63 g, 0.496 mol) was added dropwise to the reaction mixture. The mixture was stirred at 0-5 C. for 16 hours. In-process analysis (HPLC) showed a 99% conversion to (2-(trifluoromethyl)phenyl)methanesulfonyl chloride. The reaction mixture was concentrated to 107 g, then diluted with THF (200 mL). The mixture was stirred and cooled to -10 to -20 C. Water (3.0 mL) was added dropwise. Ammonia (gas, 13 g, 0.765 mol) was added via subsurface tubing to the reaction mixture. The reaction mixture was basic to pH paper. In-process testing (HPLC) showed complete conversion of the sulfonyl chloride to the sulfonamide with 5% of the sulfonic acid. The mixture was filtered to remove inorganic salts. Water (135 mL) was added to the filtrate. The filtrate was concentrated to 190 g. The mixture was stirred at 0-5 C. for 30 min. The solid product was collected by filtration and dried to constant weight to give 33.2 g (73%) of the title compound. 1HNMR (300 MHz, CDCl3): delta 7.81-7.52 (m, 4H, ArH), 4.60 (s, 2H, CH2), and 4.52 (br s, 2H, NH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hexamethyldisilazane; In tetrahydrofuran; | Step 1 : Methyl 3-[(2,2-difluoroethyl)(2-trifluoromethylphenylmethanesulfonyl)amino]- pyridine-2-carboxylate1 .08 g (5.0 mmol) of methyl 3-(2,2-difluoroethylamino)pyridine-2-carboxylate (cf.WO2009/090401 ) and a solution of 5.0 mmol of lithium hexamethyl disilazane in THF were added to a solution of 1 .29 g (5.0 mmol) of (2-trifluoromethylphenyl)methane- sulfonyl chloride in THF. Work-up gave 1.3 g of methyl 3-[(2,2-difluoroethyl)-(2-trifluoro- methylphenylmethanesulfonyl)amino]pyridine-2-carboxylate, which was reacted further without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With pyridine;Heating; | 5-[4-(Methylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.091 mmol) mentioned above, and <strong>[85952-32-5]2-(trifluoromethyl)benzylsulfonyl chloride</strong> (35 mg, 0.137 mmol) were treated by heating in pyridine (2.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to give the title compound (25 mg, yield 50%) as white crystals. 1H NMR (DMSO-d6, 400MHz) delta: 3.17 (1H, d, J=12Hz), 3.73 (1H, d, J=12Hz), 4.69 (2H, s), 6.96 (1H, d, J=9Hz), 7.27 (2H, d, J=8Hz), 7.49 (2H, d, J=8Hz), 7.6-7.8 (6H, m), 7.79 (1H, d, J=8Hz), 7.95 (1H, d, J=8Hz), 8.27 (1H, d, J=9Hz), 10.95 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium hydrogencarbonate; In dichloromethane; for 16h; | Step 15: To ethyl 3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (Step 14, 200 mg, 0.32 mmol) and sat. NaHCO3 (0.14 M) in CH2Cl2 (0.07 M) was added <strong>[85952-32-5](2-trifluoromethylphenyl)methanesulfonyl chloride</strong> (Step 14, 110 mg, 0.42 mmol). After 16 h the mixture was poured into saturated sodium bicarbonate and extracted with CH2Cl2. The combined organic phase was washed with brine, dried over sodium sulphate and purified by column chromatography to afford 250 mg of the sulfonamide, a pale yellow foam, in 93% yield. 1HNMR (400 MHz, CDCl3) delta 1.23 (t, J=I.2 Hz, 3 H), 2.62-2.71 (m, 2 H), 2.76-2.93 (m, 4 H), 2.98-3.17 (m, 4 H), 3.27-3.38 (m, 2 H), 4.11 (q, J=7.2 Hz, 2 H), 4.35 (s, 2 H), 4.57 (t, J=5.3 Hz, 1 H), 6.43 (d, J=9.1 Hz, 1 H), 6.77 (dd, J=8.8, 2.0 Hz, 1 H), 6.81 (s, 1 H), 7.18 (d, J=2.0 Hz, 1 H), 7.24-7.35 (m, 10 H), 7.41 (d, J=8.6 Hz, 3 H), 7.49 (t, J=8.3 Hz, 1 H), 7.60-7.77 (m, 2 H), 7.88 (d, J=8.6 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With pyridine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; for 20h; | Prepared using (S)-tert-butyl 3 -((4-(2-((5-amino-2-methylnaphthalen- 1- yl)oxy)pyridin-3 -yl)pyrimidin-2-yl)amino)piperidine- 1 -carboxylate (400 mg, 0.760 mmol), pyridine (1 mL), DCM (3 mL), and <strong>[85952-32-5](2-(trifluoromethyl)phenyl)methanesulfonyl chloride</strong> (295 mg, 1.14 mmol). After 20 h, the mixture was diluted with DCM (75 mL) and washed with saturated NaHCO3(aq) (25 mL), dried (Na2504), filtered and concentrated in vacuo. The crude was purified by flash chromatography through silica gel (0 - 100% EtOAc/hexanes) to provide 392 mg (69 % yield) of the title compound as a light yellow gum. LCMS (ESI) [M+H]+ =749.1,rt=2.O2min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.341% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | A mixture of 4-chloro-5-(piperazin-1-yl)-2H-pyridazin-3-one hydrochloride (0.12 g, 0.478 mmol, 1.236 equiv.) , <strong>[85952-32-5][2-(trifluoromethyl)phenyl]methanesulfonyl chloride</strong> (0.1 g, 0.387 mmol, 1 equiv.) and Triethylamine (0.144 g, 0.2 mL, 1.423 mmol, 3.681 equiv.) in dimethyl-formamide (2 mL, 0.193 M, 20 Vols) was stirred at RT for 16 hr. Diluted with water and filtered to collect solid. Purified via flash chromatography (ISCO 12g, 0-100% EtOAc/Heptane followed by 0- 20% MeOH/EtOAc). Obtained 4-chloro-5-(4-[2- (trifluoromethyl)phenyl]methanesulfonyl}piperazin-1-yl)-2H-pyridazin-3-one (42.8 mg, 0.098 mmol, Yield 25.341%) as a white solid. Calc?d [M+H]+ for C16H17ClF3N4O3S = 437.1, found 437.2. (1429) 1H NMR (DMSO-d6 ) delta: 13.00 (s, 1H), 7.88 (s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.67-7.75 (m, 2H), 7.57-7.63 (m, 1H), 4.57 (s, 2H), 3.43-3.49 (m, 4H), 3.33-3.39 (m, 4H) |