Acetoacetic Ester Synthesis of Amphetamine
Amphetamine (1) can be synthesized by the sequential alkylation of methyl acetoacetate (2) with dimethyl sulfate and benzyl chloride, followed by hydrolysis and deacetylation to give 2-phenylpropionic acid (5), which through reaction with thionyl chloride and ammonia forms 2-phenylpropionamide (7). Upon treatment with aqueous sodium hypochlorite, this amide undergoes Hofmann rearrangement to form racemic amphetamine (phenyl-2-aminopropane).
The order in which methyl acetoacetate is alkylated with dimethyl sulfate and benzyl chloride is of utmost importance to produce the desired dialkylacetoacetate isomer. If methyl acetoacetate is benzylated before it is methylated, the methyl group adds to the benzylic carbon instead of on the acetoacetate alpha-carbon. By first methylating the sodium salt of methyl acetoacetate and then benzylate the sodium salt of the formed alpha-methyl-acetetoacetic ester, the formation of the desired isomer is ensured.
Methyl acetoacetate (2) was prepared from methyl acetate in good yields. Results of experiments using dimethyl sulfate or methyl iodide to alkylate methyl acetoacetate (2) indicated that it was possible to get a higher yield of methyl methyl acetoacetate (3) using methyl iodide, but its higher cost do not warrant its use.
Instead of using the route going through intermediates 5-6, tests indicate that methyl benzyl methyl acetoacetate (4) will be transformed to 2-Phenylpropionamide (7) in 25% aqueous ammonia to the extent of approximately 50% in two weeks, standing at room temperature.
Methyl methyl acetoacetate (3)
4440 grams of methyl acetate, containing 2% methyl alcohol, was weighed into a. 12L flask provided with a reflux condenser. 230g of sodium metal in the form of small pieces (~1 cm3) was added to the methyl acetate at once. Heat was applied to bring the reaction mixture to reflux. After 11h all of the sodium dissolved. Excess methyl acetate was then distilled from the reaction mixture until all of the methanol azeotrope distilled off. 5 L of toluene was then added and distillation continued until the last of the methyl acetate was recovered. 1200g of dimethyl sulfate was then added over a period of 2h at refluxing temperature. Refluxing was continued until reaction was neutral. The reaction mixture was then cooled to room temperature, and 1400 mL of water added to dissolve the sodium methyl sulfate. The oil layer was separated, washed with 2x1000 mL water and then fractionately distilled to give 882g methyl methyl acetoacetate (3), bp 76-76.5°C/20mmHg. 1700g of methyl acetate was recovered as constant boiling mixture, balance was recovered with the toluene.
Methyl benzyl methyl acetoacetate (4)
750 grams of methyl methyl acetoacetate (3) and 1690 mL of methanol were placed in a 3 L 3-neck flask provided with å reflux. 125 g of sodium metal was added, keeping the temp of the solution at 50°C. The solution was then added to 657g of benzyl chloride in a 5-liter flask. 2 h were required for the addition, keeping the temperature between 48-53°C. After several hours standing, allowing reaction to reach room temp, a test portion indicated that the reaction was 99.5% complete. Excess alcohol was then distilled off until a liquid temp of 83°C was reached. The reaction product was then cooled to 20°C, and 1400 mL of water was added to dissolve out salt. The oil was shaken with 10% NaOH for 10 min and then washed with 500 mL portions of water until neutral. The residual oil was then fractionately distilled to give 855g of methyl benzyl methyl acetoacetate (4) and recovery of 165g benzyl chloride.
2-Phenylpropionic acid (5)
855 grams of methyl benzyl methyl acetoacetate from the above run was refluxed with a sodium methoxide solution (17g Na in 321mL methanol) for 3-4h, and then the constant boiling mixture of methyl acetate/methanol was slowly distilled off in the course of another 1.5h. The resulting benzyl methyl acetic acid methyl ester was then hydrolyzed by the addition of 120g of 30% aqueous NaOH. The sodium salt was given two extractions, using 200 mL of xylene each time. The methyl benzyl acetic acid was liberated from the sodium salt by the addition of 50% H2SO4 solution. The oil was washed with water, the water washes were combined, extracted with xylene, and then added to the methyl benzyl acetic acid. The xylene was distilled from the acid under vacuum. A yield of 567g of 2-phenylpropionic acid was obtained, bp 150-155°C/8mmHg.
2-Phenylpropionyl Chloride (6)
502g of thionyl chloride was weighed into a 2-liter 3-neck flask provided with a thermometer, agitator, dropping funnel and reflux condenser. 472g of the above described methyl benzyl acetic acid was then added over a period of one hour. The temperature during addition varied between 30-40°C. The excess thionyl chloride was then distilled off, and the acid chloride vacuum distilled. Yield 420g of 2-phenylpropionyl chloride, bp 118-120°C/15mmHg.
420g of methyl benzyl acetyl chloride, formed as above, was converted to the amide by adding the chloride slowly to 4260mL of toluene (or ether) saturated with NH3 at 20°C, the NH3 always being in excess. After all of the chloride was in the reaction product was heated on a steam bath to 62°C, and the separated out ammonium chloride filtered off. The filtrate was then cooled to 10°C, and the crystals of the 2-phenylpropionamide filtered and dried. Yield 336g methyl 2-phenylpropionamide. Upon recrystallization from toluene there was obtained 286g of amide having a mp of 108.4°C.
230g of 2-phenylpropionamide prepared as above (mp 107-108.4°C) was added to sodium hypochlorite solution, made by passing 109g of chlorine into a solution of 277g of sodium hydroxide in 453 mL of water. The reaction mixture was held at 0°C for one hour. It was then slowly heated to 18°C, at which point considerable heat was given off and the solid went into solution. The flask, at this stage, had to be immersed in a freezing bath to prevent the temperature from getting too high. After the temperature was under control, the solution was heated to 58°C, whereupon the rearrangement occurred. The heating was continued until 70°C was reached. The solution was cooled; the oil layer separated and the solution extracted with toluene, using 60 mL each time. The toluene solution was washed twice with 50 mL portions of water and 148g of conc HCl slowly added to it. The aqueous solution was extracted with 2x30 mL toluene. The amine was then liberated with 30% NaOH. The water from the precipitated amine was extracted with 3x60 mL portions of toluene. The toluene solution was washed with 2x100 mL water and then vacuum distilled. Yield: 131g (69%) of purified amine, bp 105°C/30mmHg. The bp at atmospherical pressure was 205-206°C, and the HCl salt had mp 146°-150°C.
 US Pat 2,413,493