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With N-chloro-succinimide In acetic acid at 110℃; for 4 h;
To a solution of thiophene-3-carbaldehyde (20.0 g, 178.3 mmol) and N-chlorosuccinimide (23.8 g, 178.3 mmol) in AcOH (180 mL) was stirred at 110 °C for 4 hours. After the completion of reaction, the solution was cooled to room temperature, and then was diluted with EtOAc (120 mL), washed with H20 (100 mL x 3), saturated NaHC03 (50 mL x 2), brine, dried over anhydrous Na2S04 and concentrated to afford 5-chlorothiophene-3-carboxylic acid (8.0 g, 54.6 mmol, 31percent yield) as yellow solid, which was used directly in the next step without further purification.
Reference:
[1] Patent: WO2015/140133, 2015, A1, . Location in patent: Page/Page column 110
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 8, p. 2568 - 2578
[3] Patent: WO2015/142903, 2015, A2, . Location in patent: Page/Page column 98
With N-chloro-succinimide; In acetic acid; at 110℃; for 4h;
To a solution of thiophene-3-carbaldehyde (20.0 g, 178.3 mmol) and N-chlorosuccinimide (23.8 g, 178.3 mmol) in AcOH (180 mL) was stirred at 110 °C for 4 hours. After the completion of reaction, the solution was cooled to room temperature, and then was diluted with EtOAc (120 mL), washed with H20 (100 mL x 3), saturated NaHC03 (50 mL x 2), brine, dried over anhydrous Na2S04 and concentrated to afford 5-chlorothiophene-3-carboxylic acid (8.0 g, 54.6 mmol, 31percent yield) as yellow solid, which was used directly in the next step without further purification.
With N-chloro-succinimide; In acetic acid; at 110℃; for 4h;Inert atmosphere;
Step A: To a solution of thiophene-3-carbaldehyde (20.0 g, 178.3 mmol) and N-chlorosuccinimide (23.8 g, 178.3 mmol) in AcOH (180 mL) was stirred at 110 °C for 4 hours. After the completion of reaction, the solution was cooled to room temperature, and then was diluted with EtOAc (120 mL), washed with H20 (100 mL x 3), saturated NaHC03 (50 mL x 2), brine, dried over anhydrous Na2S04 and concentrated to afford 5-chlorothiophene-3-carboxylic acid (8.0 g, 54.6 mmol, 31percent yield) as yellow solid, which was used directly in the next step without further purification.
With sodium ethanolate; In ethanol; at 0℃; for 3.5h;
[Referential Example 343] ethyl 2-azido-3-(5-chlorothien-3-yl)acrylate: After ethanol (15 ml) was added to a 20percent ethanol solution (10.7 ml) of sodium ethoxide, and the mixture was cooled to 0°C, a mixture of the compound (1.01 g) obtained in Referential Example 342 and ethyl azidoacetate (3.55 g) was added dropwise over 30 minutes, and the resultant mixture was stirred at 0°C for 3 hours.. A cooled aqueous solution of ammonium chloride was added to the reaction mixture to conduct extraction 3 times with diethyl ether.. Organic layers were combined, and the solvent was distilled off under reduced pressure.. The residue was purified by flach column chromatagraphy on silica gel (ethyl acetate:hexane = 1:49) to obtain the title compound (1.04 g).1H-NMR (CDCl3) delta: 1.38(3H,t,J=7.1Hz), 4.34(2H,q,J=7.1Hz), 6.75(1H,s), 7.39(1H,d,J=1.7Hz), 7.54(1H,d,J=1.7Hz).
With manganese(IV) oxide; In dichloromethane; at 20℃; for 15h;
The compound (5.17 g) obtained in Referential Example 341 was dissolved in methylene chloride (400 mL), and manganese dioxide (51.3 g) was added to the solution, followed by stirring at room temperature for 15 hours. After the reaction mixture was filtered, the solvent was distilled away under reduced pressure, to thereby give the title compound (2.84 g).1H-NMR(CDCl3) delta:7.35(1H,d,J=1.7Hz), 7.88(1H,d,J=1.7Hz), 9.75(1H,s).
With manganese dioxide; In dichloromethane;
REFERENTIAL EXAMPLE 342 5-Chlorothiophene-3-carbaldehyde: The compound (5.17 g) obtained in Referential Example 341 was dissolved in methylene chloride (400 ml), and manganese dioxide (51.3 g) was added to stir the mixture at room temperature for 15 hours. After the reaction mixture was filtered, the solvent was distilled off under reduced pressure to obtain the title compound (2.84 g). 1H-NMR (CDCl3) delta: 7.35(1H,d,J=1.7 Hz), 7.88(1H,d,J=1.7 Hz), 9.75(1H,s).
With manganese(IV) oxide; In dichloromethane; at 20℃; for 15h;
[Referential Example 342] 5-Chlorothiophene-3-carbaldehyde: The compound (5.17 g) obtained in Referential Example 341 was dissolved in methylene chloride (400 ml), and manganese dioxide (51.3 g) was added to stir the mixture at room temperature for 15 hours.. After the reaction mixture was filtered, the solvent was distilled off under reduced pressure to obtain the title compound (2.84 g).1H-NMR (CDCl3) delta: 7.35(1H,d,J=1.7Hz), 7.88(1H,d,J=1.7Hz), 9.75(1H,s).
ethyl 2-azido-3-(5-chlorothien-3-yl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium ethanolate; In ethanol; at 0℃; for 3.5h;
After ethanol (15 mL) was added to a 20percent ethanol solution (10.7 mL) of sodium ethoxide, and the mixture was cooled to 0°C, a mixture of the compound (1.01 g) obtained in Referential Example 342 and ethyl azidoacetate (3.55 g) was added dropwise over 30 minutes, and the resultant mixture was stirred at 0°C for 3 hours. A cooled aqueous ammonium chloride was added to the reaction mixture, and the resultant mixture was extracted 3 times with diethyl ether. The organic layers were combined, and the solvent was distilled away under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate : hexane = 1:49), to thereby give the title compound (1.04 g).1H-NMR(CDCl3) delta:1.38(3H,t,J=7.1Hz), 4.34(2H,q,J=7.1Hz), 6.75(1H,s), 7.39(1H,d,J=1.7Hz), 7.54(1H,d,J=1.7Hz).
ethyl 2-azido-3-(5-chlorothien-3-yl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium chloride; sodium ethanolate; In ethanol;
REFERENTIAL EXAMPLE 343 Ethyl 2-azido-3-(5-chlorothien-3-yl)acrylate: After ethanol (15 ml) was added to a 20percent ethanol solution (10.7 ml) of sodium ethoxide, and the mixture was cooled to 0° C., a mixture of the compound (1.01 g) obtained in Referential Example 342 and ethyl azidoacetate (3.55 g) was added dropwise over 30 minutes, and the resultant mixture was stirred at 0° C. for 3 hours. A cooled aqueous solution of ammonium chloride was added to the reaction mixture to conduct extraction 3 times with diethyl ether. Organic layers were combined, and the solvent was distilled off under reduced pressure. The residue was purified by flach column chromatagraphy on silica gel (ethyl acetate:hexane=1:49) to obtain the title compound (1.04 g). 1H-NMR (CDCl3) delta: 1.38(3H,t,J=7.1 Hz), 4.34(2H,q,J=7.1 Hz), 6.75(1H,s), 7.39(1H,d,J=1.7 Hz), 7.54(1H,d,J=1.7 Hz).