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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 3h; |
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With thionyl chloride |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 1h; |
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With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h; |
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With thionyl chloride In N,N-dimethyl-formamide |
1 Starting Material Preparation 1 (Synthesis of 5-(2-methoxy-4-nitrophenyl)-4-carboethoxyoxazole)
EXAMPLE 1 Starting Material Preparation 1 (Synthesis of 5-(2-methoxy-4-nitrophenyl)-4-carboethoxyoxazole) In 80 ml of N,N-dimethylformamide (hereinafter abbreviated as DMF) was dissolved 17.7 g (0.09 mol) of 2-methoxy-4-nitrobenzoic acid, and 11.9 g (0.09 mol) of thionyl chloride was added thereto dropwise over 1 hour to prepare 2-methoxy-4-nitrobenzoic acid chloride. |
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With thionyl chloride In dichloromethane for 2h; Heating / reflux; |
2-3.1
(1) Thionyl chloride (11.1 mL) was added to a dichloromethane solution (20 mL) of 2-methoxy-4-nitrobenzoic acid (500 mg) and heated under reflux for 2 hours. The solvent was evaporated off under reduced pressure from the reaction liquid, and chloroform (5 mL) was added to the residue. The chloroform solution was dropwise added to a THF solution (10 mL) of morpholine (2.2 g), and after the addition, this was stirred overnight at room temperature. The solvent was evaporated off under reduced pressure from the reaction liquid, and water was added to the resulting residue, and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate = 3/2) to obtain (2-methoxy-nitrophenyl)(morpholino)methanone (280 mg) as a white solid. ESI-MS Found: m/z 267[M+H]+. |
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With thionyl chloride In 1,2-dichloro-ethane for 1.5h; Heating / reflux; |
205 Example 205; 6-(4-Amino-2-methoxyphenyl)-3-cyclohexyl-1-ethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
Example 205 6-(4-Amino-2-methoxyphenyl)-3-cyclohexyl-1-ethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one To a 10 ml 1,2-dichloroethane suspension of 1.2 g (6.06 mmol) of 2-methoxy-4-nitrobenzoic acid, 0.88 ml (12.1 mmol) of thionyl chloride was added, and the mixture was heated under reflux for 1.5 hours.. The reaction mixture was cooled to room temperature, and then distilled under reduced pressure to obtain an acid chloride. To a 10 ml pyridine solution of the acid chloride synthesised above, 1.1 g (4.66 mmol) of the compound obtained in Production Example 57 was added.. The mixture was stirred at room temperature for 5 hours.. Then, the reaction mixture was distilled under reduced pressure, an aqueous solution of sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate.. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure.. A carboxamide intermediate was obtained by this procedure. To a 30 ml methanol/10 ml N,N-dimethylformamide mixed solution of the above carboxamide intermediate, 170 mg of 5% palladium carbon was added, and the mixture was stirred for 18 hours in an atmosphere of hydrogen at room temperature and atmospheric pressure.. Then, the catalyst was removed by filtration, and the filtrate was distilled under reduced pressure to obtain an amine intermediate. To the above amine intermediate, 19 ml of ethanol and 38 ml of a 1M aqueous solution of sodium hydroxide were added, and the mixture was heated under reflux for 24 hours.. Then, the reaction mixture was cooled to room temperature, diluted with water, and extracted with dichloromethane.. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, whereafter the solvent was distilled off under reduced pressure.. The residue was purified by silica gel column chromatography (chloroform/methanol = 30/1) to obtain 996 mg (58%) of the captioned compound. |
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With thionyl chloride; N,N-dimethyl-formamide In chloroform for 6h; Reflux; |
A19.a
A suspension of 2-methoxy-4-nitro-benzoic acid (4.0 g, 20.3 mmol), SOCl2 (4.72 ml, 64.9 mmol), CHCl3 (20 ml) and a drop of DMF was refluxed for 6 h. After cooling, the solvents were removed under reduced pressure and the crude residual oil was used in the next step without purification. Yield: 4.4 g of intermediate 37 (100 %). |
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With oxalyl dichloride In dichloromethane; 1,2-dichloro-ethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; Inert atmosphere; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; |
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With thionyl chloride for 3h; Inert atmosphere; Reflux; |
General procedure for preparation of N,N-diethylbenzamides3
General procedure: The substituted N,N-diethyl benzamides were prepared from the respective substituted benzoic acids. The acid (5 g, 32.9 mmol) was refluxed with excess thionyl chloride (50 mL) until the evolution of hydrogen chloride was ceased. The excess thionyl chloride was removed under reduced pressure and co-distilled with toluene (3x15 mL). The acid chloride was dissolved in dry CH2Cl2 (100 mL) and added drop wise diethylamine (13.6 mL, 131.5 mmol) at 0 °C and stirred at room temperature for overnight. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with water (50 mL), brine solution and dried over anhydrous MgSO4. The organic layer was removed on rotovapor to give the crude compound. The crude compound was purified by flash column chromatography to obtain the pure diethylbenzamide. |
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With chloro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.333333h; |
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With thionyl chloride at 60℃; for 1h; |
General procedure: To stirring mixtures of 53 (1eq.) in anhydrous CH2Cl2 were added the respective R2-COCl or R2-SO2Cl (1.2eq.) reagents and pyridine (1.2eq.). Note that for any analogs where the R2-CO2H starting materials were only commercially available, the acids were first converted to the acid chlorides by stirring in thionyl chloride at 60°C for 1h, then concentrating. The reactions were allowed to stir at room temperature for 18h, then were diluted with hexanes. The precipitates were filtered, rinsed with water, and collected. Flash chromatographic purification (either normal-phase with hexanes:EtOAc gradients, or reverse-phase with a water:MeOH gradients) afforded the products as solids. If necessary, products were further purified by preparatory RP-HPLC (water:CH3CN gradients), concentrated, and lyophilized. Refer to the Supporting Information for individual compound characterization data. |
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