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Experimental

A mixture of 40 g (0.3 mole) phenylacetone, 200 ml ethanol, 200 ml 25% ammonia,


40g (1.5 mole) Al-grit and 0.3 g (1 mmol) HgCl2 is warmed with vigorous stirring
until reaction takes place, after which warming is stopped immediately. Cooling
should be applied if the reaction becomes too violent. When the violence of the
reaction has diminished, the mixture is refluxed with vigorous stirring for abo
ut 2 hr, concentrated in vacuo to 200 ml and poured into ice water, alkalinized
with 120 g KOH, and extracted with ether. The extractions are treated with 20% H
Cl, the resulting water layer alkalinized and extracted with 150 ml ether. The o
rganic layer is dried over Na2SO4, the ether evaporated, and the residue distill
ed in vacuo. Yield: 12.5 g (30%).
Preparation of amphetamine sulfate yielded 96-98% product with a purity of 99.2-
99.8% (USP grade).

Amphetamine (1) can be synthesized by the sequential alkylation of methyl acetoa


cetate (2) with dimethyl sulfate and benzyl chloride, followed by hydrolysis and
deacetylation to give 2-phenylpropionic acid (5), which through reaction with t
hionyl 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 be
nzyl chloride is of utmost importance to produce the desired dialkylacetoacetate
isomer. If methyl acetoacetate is benzylated before it is methylated, the methy
l 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 aceto
acetate (2) indicated that it was possible to get a higher yield of methyl methy
l acetoacetate (3) using methyl iodide, but its higher cost do not warrant its u
se.
Instead of using the route going through intermediates 5-6, tests indicate that
methyl benzyl methyl acetoacetate (4) will be transformed to 2-Phenylpropionamid
e (7) in 25% aqueous ammonia to the extent of approximately 50% in two weeks, st
anding 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 distilla
tion continued until the last of the methyl acetate was recovered. 1200g of dime
thyl sulfate was then added over a period of 2h at refluxing temperature. Reflux
ing was continued until reaction was neutral. The reaction mixture was then cool
ed 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 frac
tionately distilled to give 882g methyl methyl acetoacetate (3), bp 76-76.5°C/20mm
Hg. 1700g of methyl acetate was recovered as constant boiling mixture, balance w
as 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, kee
ping the temp of the solution at 50°C. The solution was then added to 657g of benz
yl 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 re
ach room temp, a test portion indicated that the reaction was 99.5% complete. Ex
cess alcohol was then distilled off until a liquid temp of 83°C was reached. The r
eaction product was then cooled to 20°C, and 1400 mL of water was added to dissolv
e 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 dis
tilled to give 855g of methyl benzyl methyl acetoacetate (4) and recovery of 165
g benzyl chloride.
2-Phenylpropionic acid (5)
855 grams of methyl benzyl methyl acetoacetate from the above run was refluxed w
ith a sodium methoxide solution (17g Na in 321mL methanol) for 3-4h, and then th
e constant boiling mixture of methyl acetate/methanol was slowly distilled off i
n the course of another 1.5h. The resulting benzyl methyl acetic acid methyl est
er was then hydrolyzed by the addition of 120g of 30% aqueous NaOH. The sodium s
alt was given two extractions, using 200 mL of xylene each time. The methyl benz
yl acetic acid was liberated from the sodium salt by the addition of 50% H2SO4 s
olution. The oil was washed with water, the water washes were combined, extracte
d with xylene, and then added to the methyl benzyl acetic acid. The xylene was d
istilled from the acid under vacuum. A yield of 567g of 2-phenylpropionic acid w
as 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. Th
e 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.
2-Phenylpropionamide (7)
420g of methyl benzyl acetyl chloride, formed as above, was converted to the ami
de 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 ammoniu
m 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-phenylpropiona
mide. Upon recrystallization from toluene there was obtained 286g of amide havin
g a mp of 108.4°C.
Phenyl-2-aminopropane (1)
230g of 2-phenylpropionamide prepared as above (mp 107-108.4°C) was added to sodiu
m hypochlorite solution, made by passing 109g of chlorine into a solution of 277
g 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. A
fter 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 to
luene, using 60 mL each time. The toluene solution was washed twice with 50 mL p
ortions of water and 148g of conc HCl slowly added to it. The aqueous solution w
as extracted with 2x30 mL toluene. The amine was then liberated with 30% NaOH. T
he water from the precipitated amine was extracted with 3x60 mL portions of tolu
ene. The toluene solution was washed with 2x100 mL water and then vacuum distill
ed. 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.