Introduction
Grignard reagents (CH3I and Mg) add to aldimine (Schiff bases) to give amine, in which the hydrocarbon residue of the Grignard is attached to the carbon atom. In the case of methamphetamine, it means that that methyl Grignard reagent adds to the Schiff base between phenylacetaldehyde (1) and methamphetamine (4). The first step in the synthesis is the preparation of the Schiff base (3), which is shown below.
Equipment and glassware:
- 1000 mL x2 Round bottom flasks (RBF);
- Dean-Stark trap;
- Reflux condenser;
- Distillation setup;
- 1 L Separatory funnel;
- Magnetic stirrer;
- Water bath and ice;
- Laboratory scale (0.01-100 g is suitable);
- HCl gas source;
- 100 mL x3; 250 mL x2; 1 L x2 Beakers;
- Retort stand and clamp for securing apparatus;
- Laboratory grade thermometer (-10 °C to 100 °C);
- pH indicator paper;
- Glass rod and spatula;
- Buchner flask and funnel [Schott filter may be used for small quantities];
- Vacuum source;
- 250 mL Drip funnel.
Reagents:
- 45.7 g (0.38 mole) Phenylacetaldehyde (CAS 122-78-1) (1);
- 260 mL Benzene;
- 15.5 g (0.5 mole) Methylamine anhydrous (2);
- ~1.2 L Diethyl ether (Et2O);
- 71 g (0.5 mole) Methyl iodide (CH3I);
- 12.2 g (0.5 mole) Magnesium (Mg);
- A crystal of iodine (I2);
- Hydrochloric acid (HCl) dilute (15%);
- HCl gas.
Procedure
N-Methyl-1-phenylethane-2-imine (Method 1)
A solution of 45.7 g (0.38 mole) of freshly distilled [Phenylacetaldehyde will polymerise on standing. This polymer is degraded to the monomer on distillation] phenylacetaldehyde (1) in 100 mL benzene was cooled to 0 °C and a solution of 15.5 g (0.5 mole) of anhydrous methylamine (2) in benzene [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] was added to 1 L RBF. An exothermic reaction occurred 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 (3). Yield ~47 g (~90%).
N-Methyl-1-phenylethane-2-imine (Method 2)
Bubble methylamine gas (2) [prepared by dripping 50% aqueous NaOH on methylamine hydrochloride crystals and drying the gas by passing it through a gas wash bottle with NaOH pellets] into cooled phenylacetaldehyde (1) (45.7 g, 0.38 mole) while stirring until the solution has gained about 15.5 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 (3).
With the fresh aldimine in the flask, it's important to proceed directly to the next step: the preparation of a methyl Grignard solution in ether.
A solution of 45.7 g (0.38 mole) of freshly distilled [Phenylacetaldehyde will polymerise on standing. This polymer is degraded to the monomer on distillation] phenylacetaldehyde (1) in 100 mL benzene was cooled to 0 °C and a solution of 15.5 g (0.5 mole) of anhydrous methylamine (2) in benzene [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] was added to 1 L RBF. An exothermic reaction occurred 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 (3). Yield ~47 g (~90%).
N-Methyl-1-phenylethane-2-imine (Method 2)
Bubble methylamine gas (2) [prepared by dripping 50% aqueous NaOH on methylamine hydrochloride crystals and drying the gas by passing it through a gas wash bottle with NaOH pellets] into cooled phenylacetaldehyde (1) (45.7 g, 0.38 mole) while stirring until the solution has gained about 15.5 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 (3).
With the fresh aldimine in the flask, it's important to proceed directly to the next step: the preparation of a methyl Grignard solution in ether.
Methamphetamine by Methyl Grignard Alkylation of N-methyl-1-phenylethane-2-imine
Methyl Grignard reagent is prepared by adding 71 g (0.5 mole) of methyl iodide (CH3I) to a suspension of 12.2 g (0.5 mole) of Mg turnings in 150 mL dry ether in absolutely dry 1 L RBF. Adding a crystal of iodine speeds up the reaction. After about 30 min standing, cool the Grignard reagent to 0 °C and add dropwise via drip funnel the aldimine (3) 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 (about 2 h). 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 aqueous solution to pH >10, extract with 3 x 250 mL ether and dry the ether. Bubble HCl gas through the solution to get methamphetamine hydrochloride (4). Precipitate was filtered on Buchner funnel.
Methyl Grignard reagent is prepared by adding 71 g (0.5 mole) of methyl iodide (CH3I) to a suspension of 12.2 g (0.5 mole) of Mg turnings in 150 mL dry ether in absolutely dry 1 L RBF. Adding a crystal of iodine speeds up the reaction. After about 30 min standing, cool the Grignard reagent to 0 °C and add dropwise via drip funnel the aldimine (3) 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 (about 2 h). 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 aqueous solution to pH >10, extract with 3 x 250 mL ether and dry the ether. Bubble HCl gas through the solution to get methamphetamine hydrochloride (4). Precipitate was filtered on Buchner funnel.
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