Phenylacetaldehyde to Methamphetamine synthesis

by Labrat
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Grignard reagents add to aldimines/Schiff bases to give amines, in which the hydrocarbon residue of the Grignard is attached to the carbon atom. In case of methamphetamine, this means that that methyl Grignard reagent adds to the Schiff base between phenylacetaldehyde and methamphetamine. The first step in the synthesis is the preparation of the Schiff base, which is exemplified below:

1a) JACS 69, 1792 (1947)

A solution of 45,7 g (0.38 mole) of freshly distilled (Note 1) phenylacetaldehyde in 100 ml benzene was cooled to 0°C and a solution of 15.5 g (0.5 mole) of anhydrous methylamine in benzene (Note 2) was added. An exothermic reaction occured with separation of water; start refluxing with a Dean-Stark trap attached to the reflux condenser to collect the water that is generated in the reaction. When no more water separates, distill off the solvent and distill the aldimine. Yield ~47 g (~90%)

Note 1: The phenylacetaldehyde will polymerise on standing. This polymer is degraded to the monomer on distillation.

Note 2: According to the Merck Index, a saturated solution of methylamine in benzene is 10.5 g MeNH2 in 100 ml benzene at room temp. Prepare the benzene/methylamine solution by bubbling methylamine gas into benzene at 0°C.

1b) (alternative) JACS 70, 3868 (1948)

Distill methylamine gas (prepared by dripping 50% NaOH in water over methylamine hydrochloride crystals) onto cooled phenylacetaldehyde (45.7 g, 0.38 mole) while stirring until the solution has gained about 15 g (0.5 mole) of methylamine. Let stand for 1-2 hrs under cooling and stirring. Extract the mixture with dry ether, dry the ether and evaporate the solvent to get about 80-90% yield of aldimine.

With the aldimine in hand, it's important to proceed directly to the next step: the preparation of a methyl Grignard solution in ether.

2) Same references as the above steps.

Methyl Grignard reagent is prepared by adding 71 g (0.5 mole) of methyl iodide to a suspension of 12.2 g (0.5 mole) of Mg turnings in 150 ml dry ether. Adding a crystal of iodine speeds up the reaction. After about 1/2 hour standing, cool the Grignard reagent to 0°C and add dropwise the aldimine obtained in the previous step (this better be ~0.32 mole!) dissolved in the minimum amount of dry ether. After the addition, remove the ice-bath and start refluxing the solution (I guess for about 2 hours). Afterwards, decompose the excess Grignard reagent by adding dilute (15%) ice cold HCl until the pH<2. Separate the ether layer and discard this. Bring the pH of the aqeous solution to >10, extract with 3 x 250 ml ether and dry the ether. Bubble HCl gas through the solution to get an unspecified yield of methamphetamine hydrochloride.

[Note by Rhodium: The synthesis is a complete rework and improvement of an idea originating from Gazz. Chim. Ital. 77; 320,323 (1947).]