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With lithium hydroxide; In 1,4-dioxane; water; at 20℃;
General procedure: Phenylisoxazole ester 9a and 9b or phenylpyrazole ester 9c and 9d (1 mmol) was dissolved in 40 mL 1,4-dioxane, and then 1 N LiOH (3 mL) was added, followed by stirring at room temperature overnight. Next, the mixture was concentrated, and the residue was taken up to 20 mL with water and extracted with EtOAc (30 mL). Subsequently, 2 N HCl was added to the aqueous layer to precipitate the carboxylic acid. The mixture was extracted with DCM (30 mL × 2), dried over Na2SO4 and then evaporated to produce the desired compound (10a-d) as indicated. The yields of the hydrolysis are in the range of 88% to 96%.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;
General procedure: To a solution of compound 15 (1.0 mmol) in dichloromethane (20 ml) was added EDCI·HCl (1.2 mmol) and HOBt (0.1 mmol). Then added corresponding hetroaromatic acids 10a-i, 14a-i and 12a-d (1.0 mmol) and the reaction mixture was stirred at room temperature for 10 h. The reaction was monitored by TLC. After completion of reaction, water was added to reaction mixture and extracted with dichloromethane (2 × 30 ml). The solvent was evaporated under reduced pressure to afford the crude product which was further purified by column chromatography on silica gel using ethyl acetate and hexane as solvent system to obtain the pure products as solids.
5-(4-methoxyphenyl)-N-(2-methylquinolin-8-yl)isoxazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
[00419] 5-(4-Methoxyphenyl)isoxazole-3-carboxylic acid (219 mg, 1.0 mmol) and N-(3- dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 jiL, 1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution was added 8-aminoquinaldine (158 mg, 1.0 mmol) and the mixture was stirred for 20 hrs. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layers were collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to afford compound A24. ESI-MS: m/z 360 [M+H].
5-(4-Methoxyphenyl)isoxazole-3-carboxylic acid (219 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 muL, 1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution was added 8-aminoquinaldine (158 mg, 1.0 mmol) and the mixture was stirred for 20 hrs. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layers were collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to afford compound A24. ESI-MS: m/z 360 [M+H]+.
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione; In chloroform; for 4h;Reflux; Green chemistry;
General procedure: Ketoxime 5a (0.161 g, 1 mmol), IBX (0.840 g, 3 mmol), and chloroform (5 mL) were placed in a 100 mL round-bottom flask. The reaction was refluxed for 4 h. The reaction was continuously monitored using TLC. The product 6a was purified using column chromatography with petroleum ether and ethyl acetate (9:1) as an eluent.
N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(5-(4-methoxyphenyl)isoxazole-3-carboxamide)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; dimethyl sulfoxide; at 20℃; for 24h;Cooling with ice;
General procedure: To a solution of oximic acid (4a-k, 3.6 mmol in 50 mL THF) was added HOBt (3.6 mmol) in an ice-cooled bath. Next, a mixture of cystamine dihydrochloride (1.8 mmol) and TEA (1 mL) in DMSO (6 mL) were added, followed by the addition of EDCI (4.0 mmol). After stirring for 24 h at room temperature, the reaction was quenched with water and extracted with EtOAc (60 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and then evaporated. The resulting residue was then purified by column chromatography on silica gel as indicated.
With boron tribromide; In dichloromethane; at -20 - 20℃; for 24h;Inert atmosphere;
General procedure: To a solution of phenylisoxazole acid or phenylpyrazole acid (10a, 10c and 10d) (1 mmol in 30 mL DCM)was added tribromoborane (3 mmol) dropwise under nitrogen at -20C. After the addition, the solution was stirred at room temperature for 24 h. Next, water was added dropwise to this solution until no gas was liberated. The reaction mixture was then extracted with DCM (20 mL × 2). The organic layer was washed with brine (30 mL × 2), dried over Na2SO4 and concentrated to obtain a crude demethylated product 10e-g (28% to 49% yields).
1-isopropyl-1H-pyrazolo [3, 4-d] pyrimidine-3, 4-diamine[ No CAS ]
N-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-(4-methoxyphenyl)isoxazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
General procedure: To a solution of aryl or alkyl acid (1 equiv) in CH2Cl2 (10 mL), was added oxalyl chloride (2.5 equiv) and DMF (0.01 equiv) at 0C and then stirring for 2h. To the resulting solid were added THF (10 mL) and 20 (1.2 equiv) after concentrating under reduced pressure, subsequent cooling to -10C, DIPEA (2.5 equiv) was added dropwise, and the reaction proceed for 3 h. The mixture was added H2O and extracted with chloroform. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/DCM=30/1) to afford the corresponding product.
N-(2-(1H-indol-3-yl)ethyl)-5-(4-methoxyphenyl)isoxazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
General procedure: A solution of compound 2 (1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (0.21 g, 1.1 mmol) and hydroxybenzotriazole (HOBt) (0.13 g, 1 mmol) in dry acetonitrile (10 mL) was stirred at room temperature for 30 min. Then, tryptamine 3 (0.16 g, 1 mmol) was added to the mixture and the reaction was continued at room temperature for 24 h. After completion of reaction, the solvent was reduced under vacuum at 40 C and the residue was dissolved in dichloromethane (50%) and washed with sodium carbonate (10%). The organic phase was dried over Na2SO4 and the solvent was evaporated. The obtained compound 4a-k was completely pure.
General procedure: A solution of isoxazole acid derivative 1 (1mmol), EDCI (1.1mmol), and HOBt (1mmol) in dry acetonitrile (10mL) was stirred at room temperature for 30min. Then, 3-picolylamine 2a or 4-picolylamine 2b (1mmol) was added drop wise to the mixture and the reaction was continued at room temperature for 24h. After completion of the reaction, the solvent was reduced under vacuum and the residue was dissolved in dichloromethane and washed with sodium carbonate (10%, 3×20). The organic phase was dried over Na2SO4 and the solvent was evaporated under vacuum to give compound 3 which was completely pure. Finally, the mixture of compound 3 (1mmol) and benzyl halide derivative 4 (1.2mmol) in dry acetonitrile (10mL) was heated at reflux for 10-15h. After completion of the reaction which was monitored by TLC, the mixture was allowed to be cool and the precipitates were filtered off to afford products 5a-q in good yields.
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