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 widely^1,5,11,36. (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 conditions^18,27,31.
D. The Phenylnitropropene Route
Condensation of benzaldehyde with nitroethane yields 1-phenyl-2-nitropropene^2,9. 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 widely^4,10.

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 references^3,32.