Example 1 (Excess benzene is used in the Friedel-Craft reaction and used directly as a solvent for the methylation reaction)
Add 2 liters of reaction flask to benzene (500 ml, 5.6 mol) under anhydrous nitrogen, anhydrous aluminum trichloride (300 g, 2.25 mol), stir to reduce the temperature to 0-5 ° C, slowly within 2 hours. - Chloropropanoyl chloride (254 g, 2.0 mol) was added to the reaction flask. The reaction was continued for one hour while maintaining the reaction temperature below 10 °C. The temperature was raised to 20-30 ° C for another two hours. Gas phase analysis no longer showed the presence of 2-chloropropionyl chloride.
600 ml of ice water and 150 ml of 35% hydrochloric acid were added successively to decompose excess aluminum trichloride. The reaction solution was allowed to stand for stratification, and the upper layer of benzene was taken, washed once with water, and then allowed to stand for thorough stratification. The benzene liquid shows that the purity of the HPLC product is 98.52%, which can be directly used in the next methylation reaction.
Example 2 (toluene-substituted benzene as solvent for methylation reaction)
In a 2 liter reaction flask, benzene (350 ml, 3.94 mol) and anhydrous aluminum trichloride (300 g, 2.25 mol) were added under a nitrogen atmosphere. 2-Chloropropionyl chloride (254 g, 2.0 mol) was started to be added dropwise while stirring to 0 to 5 °C. After the completion of the dropwise addition for 30 minutes, the temperature was raised to 20-30 ° C, and the reaction was continued for three hours. The gas phase showed that 2-chloropropionyl chloride no longer remained.
600 ml of ice water and 150 ml of 35% concentrated hydrochloric acid were successively added to the reaction liquid. Stirring was continued for 15 minutes after the completion of the dropwise addition, and then the layers were allowed to stand. The upper benzene layer was washed once with water and then allowed to stand for stratification. The separated benzene layer solution distills off benzene. To about 1/3 volume, 800 ml of toluene was added to continue distillation, replacing all of the benzene. HPLC showed the content of the product (6) at 98.33%. This toluene solution can be directly reacted with the methylamine.
Example 3 (acetonitrile substituted benzene as solvent for methylation reaction)
Add 2 liters of benzene (600 ml, 6.73 mol) under anhydrous nitrogen, anhydrous aluminum trichloride (300 g, 2.25 mol), stir to reduce the temperature to 0-5 ° C, start adding 2-chloro Propionyl chloride (254 g, 2.0 mol). After 30 minutes of addition, the temperature was raised to 20-30 ° C for three hours. The gas phase showed that 2-chloropropionyl chloride was completely consumed.
400 ml of ice water was slowly added dropwise to the reaction solution, and after stirring for 10 minutes, 150 ml of 35% concentrated hydrochloric acid was added. After the dropwise addition, the mixture was further stirred for ten minutes. Wash the upper benzene layer once, then divide Floor. The separated benzene layer is concentrated under normal pressure, and 500 ml of anhydrous acetonitrile is added to the solution while it is nearly dry, and it can be directly used for the next methylation reaction. HPLC showed a product purity of 98.02%.
Second step reaction, preparation of 2-methylamino-1-phenyl-acetone (7) and its hydrochloride (10)
Example 4 (Preparation of 2-methylamino-1-phenyl-acetone under normal pressure in a benzene solution)
90 ml of the benzene solution containing 2-chloro-1-phenyl-propanone (38.6 g, 0.23 mol) obtained in the above reaction was transferred to a 0.5 liter reaction flask under a nitrogen atmosphere. After cooling to about -20 ° C, a 20% solution of methylamine in benzene (107 ml, containing 21.4 g of methylamine, 0.69 mol) was slowly added dropwise. After the completion of the dropwise addition, the temperature was slowly raised to 0 ° C for three hours, and then the temperature was raised to 10 ° C for three hours, and the temperature was further raised to 20 ° C for eight hours. The HPLC product purity after the reaction was 98.21%.
100 ml of ice water was added to the reaction flask, and the reaction solution was controlled to dropwise add concentrated hydrochloric acid in the range of 0 to 5 ° C until pH = 2-3. The aqueous layer was separated, the aqueous layer was washed twice with dichloromethane, and then dichloromethane was evaporated, and then evaporated to dryness to give 2-methylamino-1-phenyl-acetone hydrochloride (10) (41.2 g, Total step yield 90.0%)
Example 5 (Preparation of 2-methylamino-1-phenyl-acetone under a pressure reaction in a benzene solution)
Under a nitrogen atmosphere, benzene (60 g, 0.77 mol) was added to a 0.5 liter pressure reaction flask, and methylamine gas (14.2 g, 0.46 mol, methylamine solution concentration 20%) was introduced while cooling to about 5 °C. Anhydrous potassium carbonate (31.6 g, 0.23 mol) was added at the same temperature, and after stirring, 90 ml of a benzene solution containing 2-chloro-1-phenyl-propanone (38.6 g, 0.23 mol) was added. After sealing the reaction flask, the temperature was slowly raised to 20-30 ° C, the pressure reading in the reaction flask was 0.05 MPa, the reaction was kept for 10 hours, and the peak purity of the HPLC product was 98.74%.
After the completion of the reaction, 80 ml of water was added, stirred, and the temperature was lowered to about 5 ° C to neutralize with 35% concentrated hydrochloric acid to pH = 1-2, and the aqueous layer was separated. The acidified aqueous layer was washed twice with dichloromethane. After distilling off the dichloromethane, the aqueous layer was evaporated to dryness to dryness to give crystals (yield (yield) of 2-methylamino-1-phenyl-acetone (42.5 g, 2
Example 6 (Preparation of 2-methylamino-1-phenyl-acetone under a pressure reaction in an acetonitrile solution)
Under nitrogen protection, slowly introduce methylamine gas into a 0.5 liter pressure bottle pre-cooled to -20 °C The liquid methylamine (42.6 g, 1.38 mol) was collected, and 180 ml of an acetonitrile solution containing 2-chloro-1-phenyl-acetone (77.6 g, 0.46 mol) was added dropwise at the same temperature, and the closed reactor was slowly heated to 20- The reaction was carried out at 30 ° C for 6 hours, cooled to 0-5 ° C, and then acidified to pH = 1-2 by the addition of 35% concentrated hydrochloric acid.
The acetonitrile and water were concentrated under reduced pressure to give 2-methylamino-1-phenyl-acetone hydrochloride (10) (81.48 g), which was filtered and dried and collected, and the total yield of the two steps was 90.1%.
Control reaction using aqueous solution of methylamine in proton solution
Example 7 (Methylation reaction in an aqueous solution of 40% methylamine)
An aqueous solution of 200 ml of a benzene solution containing 2-chloro-1-phenyl-acetone (85.8 g, 0.51 mol) in the above Example (1) and 40% methylamine (47.3 g, 1.53 mol) was added at room temperature to 118.3 g. Mix well with stirring. The reaction was continued at room temperature for 5 hours. After the end of the reaction, HPLC showed that the product 2-methylamino-1-phenyl-acetone (7) was 45.51%, the impurity one (RT5.68) was 4.30%, the impurity two (RT9.03) was 48.14%, and the impurity three ( RT11.64) is 2.05%.
Example 8 (Methylation of 40% aqueous solution of methylamine in the presence of sodium hydroxide)
An aqueous solution of 200 ml of a benzene solution containing 2-chloro-1-phenyl-acetone (85.8 g, 0.51 mol) in the above Example (1), 40% methylamine (23.7 g, 0.76 mol), 59.2 g, at room temperature It was uniformly mixed with a 30% aqueous sodium hydroxide solution (30.6 g, 0.76 mol) with stirring. The reaction was continued at room temperature for 5 hours. After the end of the reaction, HPLC showed that the product 2-methylamino-1-phenyl-acetone (7) was 40.51%, the impurity one (RT5.4) was 4.32%, the impurity two (RT9.0) was 44.29%, and the impurity three ( RT 11.1) is 4.90%. The impurity IV (RT12.8) was 5.10%, and the impurity five (RT24.4) was 0.88%.
The third step (split 2-Methylamino-1-phenyl-acetone (±)-7 resolution)
Example 9
Mixing 2-methylamino-1-phenyl-acetone hydrochloride (±)-10 (192 g, 0.96 mol) was carried out according to the method disclosed in the literature, and the desired (-)-7 was collected by filtration. (-)-DBTA composite salt, dried under reduced pressure under nitrogen to obtain 233.2 g of a white solid, yield 71.0%
The fourth step reaction (preparation of ephedrine (1))
Example 10
(S)-(-)-2-Methylamino-1-phenyl-acetone-DBTA complex salt (233.2 g, 0.34 mol) was placed in a reaction flask under nitrogen. A 50% by volume aqueous solution of methanol (700 ml) was added and stirred at room temperature to form a clear solution. Cool down to between -10 and -5 ° C and add potassium borohydride powder and maintain the same low temperature reaction for 30 to 60 minutes. The disappearance of the starting material by HPLC showed that the reaction mixture was evaporated to dryness, evaporated, evaporated, and evaporated. The precipitated (-)-DBTA was extracted twice with ethyl acetate. A 10 N aqueous sodium hydroxide solution was added dropwise to an acidic aqueous solution which had been cooled to 0 to 5 ° C until pH = 12. The precipitated oil was extracted three times with toluene. The combined organic phases were washed once with water and once with saturated brine. 5N hydrochloric acid was added dropwise to the toluene solution until pH = 5-6, and the mixture was further stirred for 15 minutes and then layered. The aqueous layer was separated and concentrated to dryness under reduced pressure to give ephedrine (1) hydrochloride (124.6 g, 91.1%, specific rotation -34.5).
In the examples of the present invention, all the obtained intermediates or final products can be detected by the existing structure detection method. The structural detection of the intermediate or final product obtained by the present invention is consistent with the known reported detection data.
Add 2 liters of reaction flask to benzene (500 ml, 5.6 mol) under anhydrous nitrogen, anhydrous aluminum trichloride (300 g, 2.25 mol), stir to reduce the temperature to 0-5 ° C, slowly within 2 hours. - Chloropropanoyl chloride (254 g, 2.0 mol) was added to the reaction flask. The reaction was continued for one hour while maintaining the reaction temperature below 10 °C. The temperature was raised to 20-30 ° C for another two hours. Gas phase analysis no longer showed the presence of 2-chloropropionyl chloride.
600 ml of ice water and 150 ml of 35% hydrochloric acid were added successively to decompose excess aluminum trichloride. The reaction solution was allowed to stand for stratification, and the upper layer of benzene was taken, washed once with water, and then allowed to stand for thorough stratification. The benzene liquid shows that the purity of the HPLC product is 98.52%, which can be directly used in the next methylation reaction.
Example 2 (toluene-substituted benzene as solvent for methylation reaction)
In a 2 liter reaction flask, benzene (350 ml, 3.94 mol) and anhydrous aluminum trichloride (300 g, 2.25 mol) were added under a nitrogen atmosphere. 2-Chloropropionyl chloride (254 g, 2.0 mol) was started to be added dropwise while stirring to 0 to 5 °C. After the completion of the dropwise addition for 30 minutes, the temperature was raised to 20-30 ° C, and the reaction was continued for three hours. The gas phase showed that 2-chloropropionyl chloride no longer remained.
600 ml of ice water and 150 ml of 35% concentrated hydrochloric acid were successively added to the reaction liquid. Stirring was continued for 15 minutes after the completion of the dropwise addition, and then the layers were allowed to stand. The upper benzene layer was washed once with water and then allowed to stand for stratification. The separated benzene layer solution distills off benzene. To about 1/3 volume, 800 ml of toluene was added to continue distillation, replacing all of the benzene. HPLC showed the content of the product (6) at 98.33%. This toluene solution can be directly reacted with the methylamine.
Example 3 (acetonitrile substituted benzene as solvent for methylation reaction)
Add 2 liters of benzene (600 ml, 6.73 mol) under anhydrous nitrogen, anhydrous aluminum trichloride (300 g, 2.25 mol), stir to reduce the temperature to 0-5 ° C, start adding 2-chloro Propionyl chloride (254 g, 2.0 mol). After 30 minutes of addition, the temperature was raised to 20-30 ° C for three hours. The gas phase showed that 2-chloropropionyl chloride was completely consumed.
400 ml of ice water was slowly added dropwise to the reaction solution, and after stirring for 10 minutes, 150 ml of 35% concentrated hydrochloric acid was added. After the dropwise addition, the mixture was further stirred for ten minutes. Wash the upper benzene layer once, then divide Floor. The separated benzene layer is concentrated under normal pressure, and 500 ml of anhydrous acetonitrile is added to the solution while it is nearly dry, and it can be directly used for the next methylation reaction. HPLC showed a product purity of 98.02%.
Second step reaction, preparation of 2-methylamino-1-phenyl-acetone (7) and its hydrochloride (10)
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Example 4 (Preparation of 2-methylamino-1-phenyl-acetone under normal pressure in a benzene solution)
90 ml of the benzene solution containing 2-chloro-1-phenyl-propanone (38.6 g, 0.23 mol) obtained in the above reaction was transferred to a 0.5 liter reaction flask under a nitrogen atmosphere. After cooling to about -20 ° C, a 20% solution of methylamine in benzene (107 ml, containing 21.4 g of methylamine, 0.69 mol) was slowly added dropwise. After the completion of the dropwise addition, the temperature was slowly raised to 0 ° C for three hours, and then the temperature was raised to 10 ° C for three hours, and the temperature was further raised to 20 ° C for eight hours. The HPLC product purity after the reaction was 98.21%.
100 ml of ice water was added to the reaction flask, and the reaction solution was controlled to dropwise add concentrated hydrochloric acid in the range of 0 to 5 ° C until pH = 2-3. The aqueous layer was separated, the aqueous layer was washed twice with dichloromethane, and then dichloromethane was evaporated, and then evaporated to dryness to give 2-methylamino-1-phenyl-acetone hydrochloride (10) (41.2 g, Total step yield 90.0%)
Example 5 (Preparation of 2-methylamino-1-phenyl-acetone under a pressure reaction in a benzene solution)
Under a nitrogen atmosphere, benzene (60 g, 0.77 mol) was added to a 0.5 liter pressure reaction flask, and methylamine gas (14.2 g, 0.46 mol, methylamine solution concentration 20%) was introduced while cooling to about 5 °C. Anhydrous potassium carbonate (31.6 g, 0.23 mol) was added at the same temperature, and after stirring, 90 ml of a benzene solution containing 2-chloro-1-phenyl-propanone (38.6 g, 0.23 mol) was added. After sealing the reaction flask, the temperature was slowly raised to 20-30 ° C, the pressure reading in the reaction flask was 0.05 MPa, the reaction was kept for 10 hours, and the peak purity of the HPLC product was 98.74%.
After the completion of the reaction, 80 ml of water was added, stirred, and the temperature was lowered to about 5 ° C to neutralize with 35% concentrated hydrochloric acid to pH = 1-2, and the aqueous layer was separated. The acidified aqueous layer was washed twice with dichloromethane. After distilling off the dichloromethane, the aqueous layer was evaporated to dryness to dryness to give crystals (yield (yield) of 2-methylamino-1-phenyl-acetone (42.5 g, 2
Example 6 (Preparation of 2-methylamino-1-phenyl-acetone under a pressure reaction in an acetonitrile solution)
Under nitrogen protection, slowly introduce methylamine gas into a 0.5 liter pressure bottle pre-cooled to -20 °C The liquid methylamine (42.6 g, 1.38 mol) was collected, and 180 ml of an acetonitrile solution containing 2-chloro-1-phenyl-acetone (77.6 g, 0.46 mol) was added dropwise at the same temperature, and the closed reactor was slowly heated to 20- The reaction was carried out at 30 ° C for 6 hours, cooled to 0-5 ° C, and then acidified to pH = 1-2 by the addition of 35% concentrated hydrochloric acid.
The acetonitrile and water were concentrated under reduced pressure to give 2-methylamino-1-phenyl-acetone hydrochloride (10) (81.48 g), which was filtered and dried and collected, and the total yield of the two steps was 90.1%.
Control reaction using aqueous solution of methylamine in proton solution
Example 7 (Methylation reaction in an aqueous solution of 40% methylamine)
An aqueous solution of 200 ml of a benzene solution containing 2-chloro-1-phenyl-acetone (85.8 g, 0.51 mol) in the above Example (1) and 40% methylamine (47.3 g, 1.53 mol) was added at room temperature to 118.3 g. Mix well with stirring. The reaction was continued at room temperature for 5 hours. After the end of the reaction, HPLC showed that the product 2-methylamino-1-phenyl-acetone (7) was 45.51%, the impurity one (RT5.68) was 4.30%, the impurity two (RT9.03) was 48.14%, and the impurity three ( RT11.64) is 2.05%.
Example 8 (Methylation of 40% aqueous solution of methylamine in the presence of sodium hydroxide)
An aqueous solution of 200 ml of a benzene solution containing 2-chloro-1-phenyl-acetone (85.8 g, 0.51 mol) in the above Example (1), 40% methylamine (23.7 g, 0.76 mol), 59.2 g, at room temperature It was uniformly mixed with a 30% aqueous sodium hydroxide solution (30.6 g, 0.76 mol) with stirring. The reaction was continued at room temperature for 5 hours. After the end of the reaction, HPLC showed that the product 2-methylamino-1-phenyl-acetone (7) was 40.51%, the impurity one (RT5.4) was 4.32%, the impurity two (RT9.0) was 44.29%, and the impurity three ( RT 11.1) is 4.90%. The impurity IV (RT12.8) was 5.10%, and the impurity five (RT24.4) was 0.88%.
The third step (split 2-Methylamino-1-phenyl-acetone (±)-7 resolution)
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Example 9
Mixing 2-methylamino-1-phenyl-acetone hydrochloride (±)-10 (192 g, 0.96 mol) was carried out according to the method disclosed in the literature, and the desired (-)-7 was collected by filtration. (-)-DBTA composite salt, dried under reduced pressure under nitrogen to obtain 233.2 g of a white solid, yield 71.0%
The fourth step reaction (preparation of ephedrine (1))
Example 10
(S)-(-)-2-Methylamino-1-phenyl-acetone-DBTA complex salt (233.2 g, 0.34 mol) was placed in a reaction flask under nitrogen. A 50% by volume aqueous solution of methanol (700 ml) was added and stirred at room temperature to form a clear solution. Cool down to between -10 and -5 ° C and add potassium borohydride powder and maintain the same low temperature reaction for 30 to 60 minutes. The disappearance of the starting material by HPLC showed that the reaction mixture was evaporated to dryness, evaporated, evaporated, and evaporated. The precipitated (-)-DBTA was extracted twice with ethyl acetate. A 10 N aqueous sodium hydroxide solution was added dropwise to an acidic aqueous solution which had been cooled to 0 to 5 ° C until pH = 12. The precipitated oil was extracted three times with toluene. The combined organic phases were washed once with water and once with saturated brine. 5N hydrochloric acid was added dropwise to the toluene solution until pH = 5-6, and the mixture was further stirred for 15 minutes and then layered. The aqueous layer was separated and concentrated to dryness under reduced pressure to give ephedrine (1) hydrochloride (124.6 g, 91.1%, specific rotation -34.5).
In the examples of the present invention, all the obtained intermediates or final products can be detected by the existing structure detection method. The structural detection of the intermediate or final product obtained by the present invention is consistent with the known reported detection data.
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