Synthesis of Amphetamine


Synthesis of Amphetamine


A. The Leuckart Rection
This reaction can be formulated by the following scheme:
in which [a]: 180-190°C; [b]: H2SO4/HCl (dilute); [c]: 90-125 °C.
Reaction conditions can vary29. A trend15 in recent years has been to replace formamide by ammonium formate48 or a mixture of ammonia and formic acid6.
B. The Reductive Amination of Benzyl Methyl Ketone
Benzyl methyl ketone can react with ammonia in the following way:13
in which [a]: Raney Nickel, Pt, H2, Al powder in the presence of HgCl2, Nickel plated Zinc; [b]: 20-170°C, 1-130 atm, ethanol, methanol.
Reaction conditions can differ widely1,5,11,36. (Only low pressure and low temperature aminations have been encountered so far in the Netherlands.)
C. The Oxime Route
Benzyl methyl ketone reacts with hydroxylamine to give the oxime, which can be hydrogenated to give the amphetamine:14
in which [a]: Na (amalgamated), Na (absolute ethanol), LiAlH4, or H2 and Raney Nickel, nickel, iron, nickel plated zinc; [b]: 20-170°C, 1-130 atm;
Electrolytical reduction has also been reported. Great differences have been described for the reaction conditions18,27,31.
D. The Phenylnitropropene Route
Condensation of benzaldehyde with nitroethane yields 1-phenyl-2-nitropropene2,9. Hydrogenation of the double bond and subsequent reduction of the nitro group gives the amphetamine:
in which [a]: LiAlH4, H2 and Raney Nickel or Pd/C; [b]: 20-100°C, 1-80 atm, CH3OH, C2H5OH, H2O/HCOOH, C2H5OH.
Reaction conditions vary widely4,10.

Synthesis of Methamphetamine

In contrast to the western European countries, in the U.S. the illicit production of methamphetamine has preference over clandestine amphetamine production. (In The Netherlands, methamphetamine has rarely been produced up to the current time. Only once in the past 10 years has a high pressure reductive amination of benzyl methyl ketone with methylamine been found46, operating under near-professional standards.)
A. The Reductive Amination of Benzyl Methyl Ketone
Illicit methamphetamine is primarly produced in the U.S.8 by reductive amination, according to the following scheme:
in which [a]: HgCl2/Al, NaBH4 in slightly acid medium, H2/Pd, Na/ethanol, H2, Raney Nickel; [b]: 25-160 °C, 1200 atm, methanol, ethanol, ethyl ether. Reaction conditions vary widely.
B. The Leuckart Reaction
In methamphetamine preparation, the following reaction is of minor importance, compared with reductive amination. Schematically:
in which [a]: 170-190°C; [b]: H2SO4 or HCl; [c]: 120-170°C. Instead of N-methylformamide, a mixture of methylamine and formic acid is sometimes used23.
Of far lesser importance are the syntheses, in which ephedrine is used as the starting material. Several routes using ephedrine have been reported, including: (a) hydro genating ephedrine12 in acidic solutions using Pd/ BaSO4 and H2 at elevated temperatures (100°C); (b) reacting ephedrine with chlorine (from thionyl chloride or phosphorus pentachloride) and subsequent hydrogenation of the intermediate20 1-phenyl-1-chloro-2- methylaminopropane; (c) reducing of ephedrine with hydrogen iodide and red phosphorus20.
A typical example of thoughtless chemical handling is the reaction in which benzylmagnesium chloride is refluxed with the condensation product of methylamine and acetaldehyde. Due to imperfect chemical handling the efforts to produce methamphetamine were fruitless8.
A wide variety of methamphetamine syntheses are known but of lesser importance. For further details, refer to references3,32.

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