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Stage #1: With water; sodium hydroxide In ethanol at 0.25 - 0.55℃; for 0.1 h; Stage #2: With hydrogenchloride In ethanol at 5℃;
In a round bottom flask, ethyl -4-(dimethylamino)crotonate (Formula IV, 120 g) and ethanol (480 mL) were added at about 25°C to about 35°C. To the solution, aqueous sodium hydroxide (30.5 g in 60 mL water) was added at about 10°C to about 20°C. The temperature of the reaction mixture was raised to about 50°C. The reaction mixture was stirred at about 50°C to about 55°C for about 1 hour. The reaction mixture was cooled to about 5°C. To the reaction mixture, concentrated hydrochloric acid (120 mL) was added to attain a pH of 1.5. The reaction mixture was filtered on Celite® and washed with ethanol (50 mL). The filtrate was recovered under vacuum at about 55°C to about 60°C to obtain a crude mass. Ethanol (240 mL) was added to the crude mass, and then the reaction mixture was stirred at about 55°C to about 60°C for about 15 minutes to obtain a solution. In the solution, sodium chloride was obtained as a byproduct. The solution was filtered to discard sodium chloride. The filtrate was recovered under vacuum at about 55°C to about 60°C to obtain a residue. To the residue, isopropanol (400 mL) was added, and then the reaction mixture was stirred at about 55°C to about 60°C to obtain a clear solution. The solution was gradually cooled to about 25°C to about 30°C. The solution was further stirred at the same temperature for about 2 hours. The solid obtained was filtered, and then washed with isopropanol (50 mL). The solid was dried under vacuum at about 55°C to about 60°C to provide 4-dimethylaminocrotonic acid hydrochloride. Yield: 63percent
Stage #1: at 0℃; for 0.5 h; Stage #2: With hydrogenchloride In water; isopropyl alcohol
Dimethylamine (83 g, 1.8 mol) was dissolved in dry THF (500 mL)Stirring at 0 ° C,A solution of compound 10b (60 g, 363.6 mmol) in dry THF (60 mL) was added dropwise.After 30 minutes the temperature was raised to room temperature,Concentrated to 1/3 volume under reduced pressure,filter,The filtrate continues to be distilled under reduced pressure,The residue was dissolved in isopropanol,Add concentrated hydrochloric acid to adjust the reaction solution pH to 2-3,The resulting mixture was distilled under reduced pressure to give a crude product,Isopropanol / acetone (1: 2) to give compound 10c (30 g, yield 36percent)
Reference：
[1] Patent: CN106432105, 2017, A, . Location in patent: Paragraph 0057; 0058; 0059
With lithium chloride; sodium hydroxide; In tetrahydrofuran; water; at 0 - 30℃;Inert atmosphere;
Under nitrogen protection,Methyl [bis(2,2,2-trifluoroethoxy)phosphinyl]acetate (3.18 g, 1 eq) was dissolved in tetrahydrofuran and lithium chloride (0.42 g, 1 eq) was added.Add sodium hydroxide in water (2.0 g, 5 eq, 1 mol/L) solution,Control temperature is 0 ° C to 30 ° C,Join again2-(Dimethylamino)acetaldehyde sulfite (3.4 g, 2 eq),Stir the reaction for 3 hours,After the reaction is completed, it is acidified,Extraction and column purification gave (2Z)-4-(dimethylamino)-2-butenoic acid hydrochloride (1.09 g).
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