Structure of 108655-63-6
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CAS No. : | 108655-63-6 |
Formula : | C4H3F3N2O |
M.W : | 152.08 |
SMILES Code : | NC1=CC(C(F)(F)F)=NO1 |
MDL No. : | MFCD04972407 |
InChI Key : | PAYOWUGPXPPRPB-UHFFFAOYSA-N |
Pubchem ID : | 13913996 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-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 |
---|---|---|
37% | In methanol; at 20℃; for 3h; | To a suspension of KCN (1.90 g, 29.1 mmol) in MeOIi (35 mL) was added drop wise Iy 3-bromo-l,l,l-trifluoropropan-2-oue oxime (5.00 g, 24.3 mmol) in MeOH (72 mL) at RT. The reaction mixture was stirred at RT for 3 hours. The solution was evaporated and then the residue was dissolved in EtOAc and stirred at RT. The solid was filtered (KBr) and the filtrate was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (Biotage: 25M, 10% to 60% EtOAc/hexane: 550 mL). Pure fractions were combined and evaporated to obtain 3-(trifluoromethyi)isoxazol-5-amine (1.38 g, 37% yield). MS (ESI) m/z: 153.0 (M-I-H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With pyridine; In dichloromethane; at 0℃; for 0.5h; | To a solution of 3- (trifluoromethyl) isoxazol-5-amine (1.0 g, 6.57 mmol) in CH2C12 (15 ml) is added dropwise, phenyl CHLOROFORMATE (1.8 ml, 14.45 mmol) and pyridine (1.0 ml, 13.14 mmol) at 0oC. The reaction mixture is stirred at 0oC for 30 min. The reaction mixture is washed with H20 and 1% HCI. To the combined organic layers are added pyridine (1.0 ml, 6.57 mmol), HA0 (1.0 ml), AND CH2CL2 (20 ml), and the mixture is stirred at RT for 3 hours. The reaction mixture is washed with 0. 1N HC1 and brine, dried (Na2SO4), and concentrated. The residue is recrystallized from n-hexanes to give phenyl 3- (trifluoromethyl) isoxazol-5-ylcarbamate as an off white solid 1.3 g (73%). MS (ESI-) for CLLH7F3N203 ONLY 271.0 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sodium hydride; In tetrahydrofuran; mineral oil; at 50℃; for 0.25h; | To a solution of phenyl 2- (2-furyl)-4-methoxyphenylcarbamate (0.250 g, 0.8 mmol) in THF (10 ml) are added 3- (trifluoromethyl) isoxazol-5-amine (0.121 g, 0.8 mmol) and NaH 60% dispersion in mineral oil (0.032 g, 0. 8 mmol). The reaction mixture is stirred at 50oC for 15MIN. The solution is concentrated under vacuum and the residue is purified by silica gel chromatography (10% ETOAC/CH2CL2) followed by trituration with CH2CL2/HEXANES to afford Example 10 as a white solid 0.143 g (48%). MS (ESI+) for CL6HL2F3N304 M/Z 366.3 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | To a solution of 3- (trifluoromethyl) isoxazol-5-amine (0.112 g, 0.735 mmol) in THF (5.0 ml) are added phenyl 4-ETHOXY-2- (1, 3-thiazol-2-yl) phenylcarbamate (0.25 g, 0.735 mmol) and TEA (0.2 ml, 1.5 mmol). The reaction mixture is stirred at 50oC for 2hr. Then NaH 60% dispersion in mineral oil (0.03 g, 0.735 mmol) is added and reaction mixture is stirred at RT for 15 min. The mixture is neutralized with 0. 1M HCI, extracted with EtOAc, and the combined organic layers are dried (MGS04), filtered, and concentrated under vacuum. The residue is triturated with CH2C12/ heptane to afford Example 18 as an orange solid 0.177 g (61%). HRMS (ESI) calcd for C16HL3N403SF3+H 399.0739, found 399. 0742. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; | EXAMPLE 1 3-Trifluoromethyl-5-hydroxyisoxazole A solution of 36% HCl (9.12 g, 15 eq.) and n-propanol (9.0 ml) was added to <strong>[108655-63-6]5-amino-3-trifluoromethylisoxazole</strong> (0.91 g, 6.0 mmole) from Preparation 1 and heated at reflux for 23 hours. The reaction mixture was cooled, extracted with methylene chloride and distilled under reduced pressure to give 0.006 g (0.7%) of the titled compound as a colorless liquid, b.p. 35-37 C./1.4 mmHg. | |
With hydrogenchloride; | Example 1 3-Trifluoromethyl-5-hydroxyisoxazole A solution of 36 % HCl (9.12 g, 15 eq.) and n-propanol (9.0 ml) was added to 5-amino-3-trifluoromethyl-isoxazole (0.91 g, 6.0 mmole) from Preparation 1 and heated at reflux for 23 hours. The reaction mixture was cooled, extracted with methylene chloride and distilled under reduced pressure to give 0.006 g (0.7 %) of the titled compound as a cololess liquid, b.p. 35 - 37C/1.4 mmHg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; n-butyllithium; hydroxylamine hydrochloride; diisopropylamine; In tetrahydrofuran; methanol; ice-water; hexane; water; acetonitrile; | PREPARATION 1 5-Amino-3-trifluoromethylisoxazole Diisopropylamine (96 ml, 0.690 mole) was dissolved in 615 ml of dry tetrahydrofuran and to this solution was added a solution of 15% n-butyllithium in n-hexane (420 ml, 0.660 mole), while maintaining the mixture below 0 C. The mixture was stirred at 0 C. for 30 minutes and then cooled to -72 C. While maintaining the mixture at the same temperature a solution of methyl trifluoroacetate (38.42 g, 0.300 mole) and acetonitrile (24.6 g, 0.600 mole) in dry tetrahydrofuran (385 ml) was added dropwise. After maintaining the mixture at -75 C. for 45 minutes, the solution was allowed to warm to room temperature over 1 hour. Ice-water was added and then tetrahydrofuran and n-hexane were evaporated under reduced pressure. The residue was extracted with diethylether to remove neutral and basic components. The aqueous layer was adjusted to about pH 2 with 36% HCl, extracted with methylene chloride to remove acetoacetonitrile and other by-products and then extracted with diethyl ether. The solvent was evaporated to give 43.15 g of crude trifluoroacetonitrile (b.p. of the pure product: 39 C./2.9 mmHg-43 C./2.5 mmHg). Methanol (540 ml) and 97% hydroxylamine hydrochloride (27.94 g, 0.490 mole) were added to the resulting product and the mixture was heated at reflux for 68 hours. Methanol was evaporated under reduced pressure and water (300 ml) was added to the residue. The solution was adjusted to pH 11 or above with 48% aqueous solution of sodium hydroxide and then extracted with methylene chloride. The solvent was evaporated under reduced pressure and then distilled under reduced pressure (78-79.5 C./3 mmHg) to give 24.00 g (52.6%) of 5-amino-3-trifluoromethylisoxazole as colorless crystals. | |
With sodium hydroxide; n-butyllithium; hydroxylamine hydrochloride; diisopropylamine; In tetrahydrofuran; methanol; ice-water; hexane; water; | Preparation 1 5-Amino-3-trifluoromethylisoxazole Diisopropylamine (96 ml, 0.690 mole) was dissolved in 615 ml of dry tetrahydrofuran and to this solution was added a solution of 15% n-butyllithium in n-hexane (420 ml, 0.660 mole), while maintaining the mixture below 0oC. The mixture was stirred at 0C for 30 minutes and then cooled to -72C. While maintaining the mixture at the same temperature a solution of methyl trifluoroacetate (38.42 g, 0.300 mole) and acetonitrle (24.6 g, 0.600 mole) in dry tetrahydrofuran (385 ml) was added dropwise. After maintaining the mixture at -75C for 45 minutes, the solution was allowed to warm to room temperature over 1 hour. Ice-water was added and then tetrahydrofuran and n-hexane were evaporated under reduced pressure. The residue was extracted with diethylether to remove neutral and basic components. The aqueous layer was adjusted to about pH 2 with 36 % HCl, extracted with methylene chloride to remove acetoacetonitrile and other by-products and then extracted with diethyl ether. The solvent was evaporated to give 43.15 g of crude trifluoroacetonitrile (b.p. of the pure product: 39C/2.9 mmHg - 43C/2.5 mmHg). Methanol (540 ml) and 97 % hydroxylamine hydrochloride (27.94 g, 0.490 mole) were added to the resulting product and the mixture was heated at reflux for 68 hours. Methanol was evaporated under reduced pressure and water (300 ml) was added to the residue. The solution was adjusted to pH 11 or above with 48 % aqueous solution of sodium hydroxide and then extracted with methylene chloride. The solvent was evaporated under reduced pressure and then distilled under reduced pressure (78 - 79.5C/3 mmHg) to give 24.00 g (52.6 %) of 5-amino-3-trifluoromethylisoxazole as colorless crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | 2,4-Dimethoxy-5-methylaniline (0.22 g, 1.3 mmol) is added dropwise as a solution in EtOAc (25 mL) to a phosgene solution (5.6 mL, 20% solution in toluene) in EtOAc (50 mL). After complete addition, the reaction is heated under reflux for 0.5 h. The reaction is cooled to RT and the solvent is removed under reduced pressure to give 1-isocyanato-2,4-dimethoxy-5-methylbenzene as a light brown solid (0.25 g, 98% yield). Sodium hydride (44 mg, 1.1 mmol, 60% oil disp.) is added to <strong>[108655-63-6]3-(trifluoromethyl)isoxazole-5-amine</strong> (0.17 g, 1.1 mmol) in THF (5 mL) at 0 C. After 0.5 h, a THF solution (5 mL) of 1-isocyanato-2,4-dimethoxy-5-methylbenzene (0.19 g, 1.0 mmol) is added dropwise. The reaction is warmed to RT. After 2 h, concentrated HCl is added until the pH<5 and the solvent is removed. The crude material is purified by chromatography (Biotage 40S, 1:1 EtOAc:hexanes). The solid is recrystallized (EtOAc/hexanes) to give Example 200 as an off-white solid (135 mg, 39% yield). HRMS calcd for C14H14F3N3O4+H 346.1014 found 346.1016. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | To a solution of <strong>[108655-63-6]3-(trifluoromethyl)isoxazol-5-amine</strong> (0.77 g) in DMF (10 mL) is added NaH (60% oil disp.). The resulting mixture is stirred for 20 min and then 4-ethoxy-1-isothiocyanato-2-nitrobenzene (see Dyson, G. M.; George, H. J.; Hunter, R. F. J. Chem. Soc. 1927, 436-445) (0.22 g) is added. The resulting mixture is stirred for 30 min, concentrated to dryness, taken-up in EtOAc, washed with brine, and purified utilizing preparatory HPLC. Yield 9%. HRMS (EI) calcd for C13H11F3N4O4S 376.0453, found 376.0450. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Pyridine (5.4 mL, 0.067 mol) is added dropwise to 5-chloro-2,4-dimethoxyaniline (10.45 g, 0.056 mol) and phenyl chloroformate (8.4 mL, 0.067 mol) in CH2Cl2 (500 mL) at 0 C. The reaction is stirred for 1.5 h and diluted with 0.1M HCl (100 mL). The organics are separated, washed w/5% NaHCO3 (100 mL) and brine (150 mL), dried (MgSO4), and the solvent is removed. The resulting solid is recrystallized (EtOAc/hexanes) to give phenyl 5-chloro-2,4-dimethoxyphenylcarbamate (16.72 g, 97% yield) as a purple solid. Sodium hydride(1.82 g, 0.046 mol, 60% oil disp.) is added to <strong>[108655-63-6]3-(trifluoromethyl)isoxazole-5-amine</strong> (6.93 g, 0.046 mol) in DMF (350 mL) at RT. After 0.5 h, a DMF solution (100 mL) of phenyl 5-chloro-2,4-dimethoxyphenylcarbamate (14.0 g, 0.046 mol) is added and the reaction warmed to RT. The reaction is heated at 50 C. for 1 h, cooled to RT and the solvent is removed. The residue is dissolved in EtOAc (150 mL), washed with 1M HCl (150 mL), H2O (150 mL), and brine (150 mL). The organics are separated, dried (MgSO4) and the solvent is removed under reduced pressure. The dark solid is dissolved in EtOH (500 mL) and stirred with Darco activated carbon (15) for 4 h. The mixture is filtered over Celite and the solvent is removed to give a solid, which is recrystallized (EtOAc/hexanes) to give Example 500 as a tan solid (10.47 g, 63% yield). HRMS (ESI) calcd for C13H11ClF3N3O4+H 366.0468 found 366.0475. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | To a solution of 3- (trifluoromethyl) isoxazol-5-amine (0.152 g, 1.0 mmol) in THF (10 ML) is added NaH 60% dispersion in mineral oil (0.04 g, 1. 0 mmol). After stirring the mixture at RT for 15 min phenyl 4-ETHOXY-2- (2-FURYL) PHENYLCARBAMATE (0. 323 g, 1.0 mmol) is added and the reaction mixture is heated at 50oC for 1 hour. The mixture is neutralized with 0. 1M HCl, extracted with EtOAc, and the combined organic layers are dried (MGSO4), filtered, and concentrated under vacuum. The residue is triturated with CH2C12 to afford Example 15 as a yellow solid 0.188 g (50%). HRMS (ESI) calcd for C17HL4N304F3+H 382.1014, found 382. 1013. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | To a solution OF 3- (TRIFLUOROMETHYL) isoxazol-5-amine (0.08 g, 0.55 mmol) in DMF (10 ML) is added NaH 60% dispersion in mineral oil (0.02 g, 0.55 MMOL). After stirring the mixture at RT for 15 min phenyl 4-METHOXY-2- (1, 3-OXAZOL-2- yl) phenylcarbamate (0.17 g, 055 mmol) is added and the reaction mixture is heated at 50oC for 30 min. The mixture is neutralized with 0. 1M HCl, extracted with EtOAc, and the combined organic layers are dried (MGS04), filtered, and concentrated under vacuum. The residue is triturated with CH2CL2/N-HEXANES to afford Example 16 as a white solid 0.131 g (65%). HRMS (ESI) calcd for C15HLLN404F3+H 369. 0811, found 369.0803. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | To a solution of 3- (trifluoromethyl) isoxazol-5-amine (0.047 g, 0. 308, mmol) in DMF (6.0 ml) is added NaH 60% dispersion in mineral oil (0.012 g, 0.308 mmol). After stirring the mixture at RT for 15 min phenyl 4-ETHOXY-2- (1, 3-oxazol-2-yl) phenylcarbamate (0.1 g, 0.308 mmol) is added and the reaction mixture is heated at 50oC FOR 30 MIN. The mixture is neutralized with 0. 1M HCl, extracted with EtOAc, and the combined organic layers are dried (MGS04), filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography (40% EtOAc/heptane) followed by the trituration with CH2C12/HEPTANE to afford Example 17 as a white solid 0.103 g (87%). HRMS (ESI) calcd for C16HL3N404F3+H 383.0967, found 383.0961. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22.8% | General procedure: Heteroarylamine (1.0 mmol) was added to THF (20 mL) and cooled on a dry ice in acetone bath. To that, butyllithium (400 muL, 1.0 mmol, 2.5 M in hexane) was added dropwise over 20 min. The reaction mixture was removed from the dry ice in acetone bath and 1-adamantyl isocyanate (177 mg, 1.0 mmol) was added and stirred for 1 h. Methanol (4 mL) was then added to quench any unreacted butyllithium. The solvents were then removed under reduced pressure and the residue was purified by normal phase flash column chromatography using a hexane to ethyl acetate gradient. |