* 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.
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 29, p. 8353 - 8357[2] Angew. Chem., 2016, vol. 128, # 29, p. 8493 - 8497,5
2
[ 63366-79-0 ]
[ 4857-42-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With sodium hydroxide; water In tetrahydrofuran; methanol at 20℃; for 18 - 20 h; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water
A round bottom flask with magnetic stirrer was charged with 3-methyl-isoxazole-5- carboxylic acid ethyl ester (900 mg, 5.8 mmol) in tetrahydrofuran (2.0 mL). To the reaction was added a solution of sodium hydroxide (465 mg, 11.6 mmol) in water (2 mL), followed by methanol (4 mL). The reaction was stirred at room temperature for 18 - 20 hours under an argon atmosphere. The reaction was transferred to a separatory funnel and the pH adjusted to 2 via addition of IN hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 35 mL) and the combined extractions were washed with brine (1 x 50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to yield S-methyl-isoxazole-S-carboxylic acid as a white solid (660 mg, 90percent). The solid was used without purification in the next reaction.
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 29, p. 8353 - 8357[2] Angew. Chem., 2016, vol. 128, # 29, p. 8493 - 8497,5
[3] Patent: WO2006/91674, 2006, A1, . Location in patent: Page/Page column 79
[4] European Journal of Medicinal Chemistry, 1992, vol. 27, # 6, p. 581 - 593
3
[ 105-37-3 ]
[ 63366-79-0 ]
Yield
Reaction Conditions
Operation in experiment
24%
Stage #1: With sodium methylate In methanol; ISOPROPYLAMIDE Stage #2: With acetyl chloride In methanol; ISOPROPYLAMIDE at 5 - 20℃; for 20 h;
To a 0.5 M methanolic solution of sodium methoxide (48 mL, 24 mmol) was added a solution of nitroethane (1.7 mL, 24 mmol) in dimethylacetamide (18 mL) under a nitrogen atmosphere. After the mixture was cooled down to 5 0C, acetyl chloride (1.7 mL, 24 mmol) and ethyl propionate (2.4 mL, 24 mmol) were added and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo and partitioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried over magnesium sulfate, and concentrated in vacuo to yield an orange oil (3.7 g). The crude material was purified by flash chromatography (10percent ethyl acetate / hexanes) to provide S-methyl-isoxazole-S-carboxylic acid ethyl ester as white crystals (900 mg, 24percent).
A round bottom flask with magnetic stirrer was charged with 3-methyl-isoxazole-5- carboxylic acid ethyl ester (900 mg, 5.8 mmol) in tetrahydrofuran (2.0 mL). To the reaction was added a solution of sodium hydroxide (465 mg, 11.6 mmol) in water (2 mL), followed by methanol (4 mL). The reaction was stirred at room temperature for 18 - 20 hours under an argon atmosphere. The reaction was transferred to a separatory funnel and the pH adjusted to 2 via addition of IN hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 35 mL) and the combined extractions were washed with brine (1 x 50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to yield S-methyl-isoxazole-S-carboxylic acid as a white solid (660 mg, 90percent). The solid was used without purification in the next reaction.
To a solution of 1 (5g) in EtOH(100mL) was added thionyl chloride(3.44mL), and the resulting solution was stirred at 50 °C. After termination of this reaction, the solution was cooled to room temp. and the volatile was removed under reduced pressure. The residue was dissolved in EtOAc and partitioned between Na2CO3 soln. and EtOAc, then extracted with EtOAc. The extraction was washed with water, brine and dried with MgSO4 and concentrated in vacuo to give ethylester(6.3g). To a solution of tetramethylammonium nitrate(6.81g) in CH2Cl2 (40mL)was added trifluoromethanesulfonic acid anhydride(8.41mL). Ethylester(5.17g) in CH2Cl2 (15ml)was added to the solution and the resulting mixture was refluxed overnight. The reaction mixture was cooled to room temp. and added sat. NaHCO3 soln., then partitioned between water and EtOAc and extracted with EtOAc. The extraction was washed with water and brine, dried with MgSO4 and concentrated in vacuo. The residue was purified by silicagel columnchromatography to give 16 (5.38g).
With trifluoromethylsulfonic anhydride; tetramethylammonium nitrate; In dichloromethane;Heating / reflux;
To a solution of 1 (5g) in EtOH(100mL) was added thionyl chloride(3.44mL), and the resulting solution was stirred at 50 C. After termination of this reaction, the solution was cooled to room temp. and the volatile was removed under reduced pressure. The residue was dissolved in EtOAc and partitioned between Na2CO3 soln. and EtOAc, then extracted with EtOAc. The extraction was washed with water, brine and dried with MgSO4 and concentrated in vacuo to give ethylester(6.3g). To a solution of tetramethylammonium nitrate(6.81g) in CH2Cl2 (40mL)was added trifluoromethanesulfonic acid anhydride(8.41mL). Ethylester(5.17g) in CH2Cl2 (15ml)was added to the solution and the resulting mixture was refluxed overnight. The reaction mixture was cooled to room temp. and added sat. NaHCO3 soln., then partitioned between water and EtOAc and extracted with EtOAc. The extraction was washed with water and brine, dried with MgSO4 and concentrated in vacuo. The residue was purified by silicagel columnchromatography to give 16 (5.38g).
To a 0.5 M methanolic solution of sodium methoxide (48 mL, 24 mmol) was added a solution of nitroethane (1.7 mL, 24 mmol) in dimethylacetamide (18 mL) under a nitrogen atmosphere. After the mixture was cooled down to 5 0C, acetyl chloride (1.7 mL, 24 mmol) and ethyl propionate (2.4 mL, 24 mmol) were added and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo and partitioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried over magnesium sulfate, and concentrated in vacuo to yield an orange oil (3.7 g). The crude material was purified by flash chromatography (10% ethyl acetate / hexanes) to provide S-methyl-isoxazole-S-carboxylic acid ethyl ester as white crystals (900 mg, 24%).
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