Introduction
In this method, imiеation of (1) was carried out by the reaction of this compound with methylamine. The reaction was carried out in the presence of 0.04 g of potassium carbonate and in the dark and solvent-free conditions. Finally, thermal rearrangement of (2) produced ketamine (3). This step was done in two different high boiling point solvents: decaline and diphenyl ether. The results showed that when the rearrangement was carried out in diphenyl ether, the yield of this step was 50%, but the use of decaline as a solvent in this step improved the yield up to 72.5%, thus decaline was used as a solvent for the rearrangement step and the temperature was elevated to its reflux temperature (170 °C) to obtain the best result.
Equipment and glassware:
- 250 mL Round bottom flask (RBF);
- Retort stand and clamp for securing apparatus;
- Magnetic stirrer;
- 100 mL x4; 50 mL x2 Beakers;
- 1 L Separatory funnel;
- Glass rod and spatula;
- Rotovap machine;
- Flash chromatography kit (middle column and silica gel 60 ± 120 mesh);
- Vacuum source;
- Measuring cylinder 150 mL;
- Laboratory scale (0.01-100 g is suitable) [depends on synthesis load];
- Reflux condenser;
- pH indicator paper;
- Boiling chips;
- Buchner flask and funnel [Schott filter may be used for small quantities];
- Pasteur pipette.
Reagents:
- 11.20 g, 50 mmol 2-(2-Chlorophenyl)-2-hydroxycyclohexane-1-one (1) [CAS 1823362-29-3];
- 2.05 g, 15 mmol Potassium carbonate (K2CO3);
- 50 mL Methylamine (CH3NH2);
- ~300 mL Tetrahydrofuran (THF) dry;
- ~870 mL Hexane;
- ~130 mL Ethyl acetate
- 120 mL Decaline;
- ~225 mL Hydrochloric acid aq. solution (HCl) 0.1 M;
- ~150 mL Sodium hydroxide aq. NaOH 0.1 M;
- ~225 mL Dichloromethane.
2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone:
Boiling Point: 363.8 °C at 760 mm Hg (HCl salt);
Melting Point: 92.5 °C (free base), 262 - 263 °C (HCl salt);
Molecular Weight: 237.73 g/mol;
Density: 1.17 g/mL (HCl salt);
CAS Number: 6740-88-1.
Procedure
Synthesis of 2-hydroxy-2-(2-chlorophenyl)-1-cyclohexane-N-methylimine (2)
In a 250 mL round bottom flask, 2-(2-chlorophenyl)-2-hydroxycyclohexane-1-one (1) (11.20 g, 50 mmol), K2CO3 (2.05 g, 15 mmol) and 50 mL methylamine were poured, and kept in dark and stirred for 48 h at room temperature. Further, the reaction mixture was washed with dry THF (3 x 100 mL) in separatory funnel, filtered and the solvent was evaporated by rotary evaporator. Finally, purification of the product by a silica gel column chromatography (20:3 hexane/ethyl acetate) produced 2-hydroxy-2-(2-chlorophenyl)-1-cyclohexane-N-methylimine (2) as a white liquid (yield 91 %).
In a 250 mL round bottom flask, 2-(2-chlorophenyl)-2-hydroxycyclohexane-1-one (1) (11.20 g, 50 mmol), K2CO3 (2.05 g, 15 mmol) and 50 mL methylamine were poured, and kept in dark and stirred for 48 h at room temperature. Further, the reaction mixture was washed with dry THF (3 x 100 mL) in separatory funnel, filtered and the solvent was evaporated by rotary evaporator. Finally, purification of the product by a silica gel column chromatography (20:3 hexane/ethyl acetate) produced 2-hydroxy-2-(2-chlorophenyl)-1-cyclohexane-N-methylimine (2) as a white liquid (yield 91 %).
Synthesis of Ketamine (3)
In a 250 mL round bottom flask, 2-hydroxy-2-(2-chlorophenyl)-1-cyclohexane-N-methylimine (2) (5.90 g, 25 mmol) was added to 120 mL of decaline. The mixture was stirred at 170 °C for 4 h with reflux condenser. The organic product was extracted with aq. HCl (0.1 M) (3 x 75 mL). Then the reaction mixture was neutralized with aq. NaOH (0.1 M) to pH 6-7. The product was extracted with dichloromethane (3 x 75 mL). After evaporation of the solvent, Ketamine (3) was obtained as a colorless oil (yield, 72.5 %).
In a 250 mL round bottom flask, 2-hydroxy-2-(2-chlorophenyl)-1-cyclohexane-N-methylimine (2) (5.90 g, 25 mmol) was added to 120 mL of decaline. The mixture was stirred at 170 °C for 4 h with reflux condenser. The organic product was extracted with aq. HCl (0.1 M) (3 x 75 mL). Then the reaction mixture was neutralized with aq. NaOH (0.1 M) to pH 6-7. The product was extracted with dichloromethane (3 x 75 mL). After evaporation of the solvent, Ketamine (3) was obtained as a colorless oil (yield, 72.5 %).
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