Introduction
The main goal of this topic is to the present a research on the development of ketamine derivatives. The target molecule was a fluoro derivative of ketamine, for which a multistep synthesis has been reported. This novel ketamine derivative, 2-(2-fluorophenyl)-2-methylamino-cyclohexanone, has been called fluoroketamine.
Difficulty rating: 8/10
Reagents:
- Magnesium turnings 2.48 g;
- Iodine crystals 0.05 g;
- Bromocyclopentane 0.09 mol, 9.67 mL;
- Dry THF 210 mL;
- 2-Fluorobenzonitrile 0.075 mol, 8 mL;
- Copper(I) bromide dimethyl sulfide complex (CuBr*Me2S) 0.154 g;
- Distilled water 100 mL;
- H2SO4 15% 150 mL;
- Hexane 280 mL;
- Hydrobromic acid aq HBr 47% 10.18 mL, 1.1 mol equiv.;
- LiCl 0.03 mol, 1.26 g;
- H2O2 30% aqueous solution 12.30 mL, 2 mol equiv.;
- Methylamine 35 mL;
- Methanol 60 mL;
- Decalin 85 mL;
- PdCl2 0.25 g;
- Hydrochloric acid (Hcl aq) 10 %, 160 mL;
- Sodium hydroxide (NaOH) 50 % aq. 80 mL;
- Chloroform 170 mL;
- Dichloromethane (DCM) 50 ml;
- HCl aqueous solution 2.9 mL 37%;
Equipment and glassware:
- Three neck flask 250 mL;
- Dropping funnel with pressure equalization 200 mL;
- Reflux condenser;
- Gas inlet drying tube;
- Retort stand and clamp for securing apparatus;
- Beakers (1 L; 500 mL; 250 mL x4, 100 mL x 5);
- Heating plate with magnetic stirrer;
- Laboratory scale (0.01-200 g is suitable);
- Glass rod and spatula;
- Measuring cylinder;
- Separating funnel 500 ml;
- Rotary evaporator;
- Aluminum foil;
- Funnel;
- Filter paper;
- Column chromatography (SiO2, n-hexane: EtOAc 8:2) kit [optional];
- Buchner flask and funnel;
- Vacuum pump;
Procedures
Synthesis Of Cyclopentyl-(2-Fluorophenyl)-Ketone (2)
In a dry and nitrogen-flushed 250 mL three neck flask equipped with a 200 mL dropping funnel with pressure balance, reflux condenser with DCM drying tube and gas inlet tube, 2.48 g of magnesium turnings was charged. Then, 0.05 g iodine crystals were added and the flask was heated while stirring until violet fumes were formed. The flask was cooled to room temperature and 0.09 mol (9.67 mL) of bromocyclopentane in dry THF (70 mL) was added to the mixture without stirring. When the mixture started to boiling, the remaining bromocyclopentane was added via a dropping funnel during 1 h while stirring. To this solution 0.075 mol (8 mL) of 2-Fluorobenzonitrile in 140 mL THF was added followed by the addition of 0.154 g CuBr*Me2S (1 mol %). The mixture was refluxed under nitrogen for 4 h. After cooling to 25 °C, 30 mL of H2O was cautiously added, followed by 150 mL of 15% H2SO4. After stirring for 4 h, 50 mL of hexane was added, the organic layer was separated, and the aqueous layer was extracted twice with 30 mL portions of hexane. The combined organic phase was dried on MgSO4 and was washed with 25 mL of cooled hexane and concentrated by solvent removal under reduced pressure to afford 13 g (90%) of light yellow 2 oil .
In a dry and nitrogen-flushed 250 mL three neck flask equipped with a 200 mL dropping funnel with pressure balance, reflux condenser with DCM drying tube and gas inlet tube, 2.48 g of magnesium turnings was charged. Then, 0.05 g iodine crystals were added and the flask was heated while stirring until violet fumes were formed. The flask was cooled to room temperature and 0.09 mol (9.67 mL) of bromocyclopentane in dry THF (70 mL) was added to the mixture without stirring. When the mixture started to boiling, the remaining bromocyclopentane was added via a dropping funnel during 1 h while stirring. To this solution 0.075 mol (8 mL) of 2-Fluorobenzonitrile in 140 mL THF was added followed by the addition of 0.154 g CuBr*Me2S (1 mol %). The mixture was refluxed under nitrogen for 4 h. After cooling to 25 °C, 30 mL of H2O was cautiously added, followed by 150 mL of 15% H2SO4. After stirring for 4 h, 50 mL of hexane was added, the organic layer was separated, and the aqueous layer was extracted twice with 30 mL portions of hexane. The combined organic phase was dried on MgSO4 and was washed with 25 mL of cooled hexane and concentrated by solvent removal under reduced pressure to afford 13 g (90%) of light yellow 2 oil .
Synthesis Of Α-Bromocyclopentyl-(2-Fluorophenyl)-Ketone (3)
Ketone 2 (0.064 mol (12.48 g)) was placed in a flask covered with aluminum foil. A 47% aqueous solution of HBr (10.18 mL, 1.1 mol equiv.) was added to ketone. After stirring the reaction mixture for 5 min at room temperature, 0.03 mol (1.26 g) of LiCl was added to the mixture and the mixture was stirred for 1 min. Then, 30% aqueous solution of H2O2 (12.30 mL, 2 mol equiv.) was added slowly. The reaction mixture was heated at 70 ℃ for 1.5 h and 35 mL of H2O was cautiously added, followed by 45 mL of hexane. The organic layer was separated and dried over MgSO4. The insoluble material was filtered off and then the solvent was evaporated under reduced pressure to afford the crude reaction mixture (17.1 g). This oily product was purified by column chromatography (SiO2, n-hexane: EtOAc 8:2) the bromoketone 3 (15.7 g, 96%) was obtained as a pure brown oily 3 product.
Synthesis Of Α-Hydroxycyclopentyl-(2-Flourophenyl)-N-Methylamine (4)
In a sealed glass reactor containing 35 mL methylamine cooled by liq. N2 vapor was added to α-bromocyclopentyl-(2-fluorophenyl)-ketone (15.7 g, 0.06 mmol). After stirring for 6 h, the excess liquid methylamine was allowed to evaporate and 100 mL of hexane was added. The organic layer was separated and was concentrated by solvent removal under reduced pressure and the crude reaction mixture was cooled to afford brown crystals. The crystals were washed twice with 30 mL of methanol and recrystallized from hexane to obtain 10.4 g (81%) as shiny crystals 4.
Synthesis Of 2-(2-Fluorophenyl)-2-Methylamino-Cyclohexanone (5)
α-hydroxycyclophenthyl-(2-flourophenyl)-N-methylamine 0.05 mol (10.4 g) 4 was dissolved in 85 mL of decalin followed by the addition of 0.25 g PdCl2 (3 mol %) and was refluxed for 4h. The solvent was evaporated under reduced pressure and the residue was extracted with 160 ml of hydrochloric acid (10 %). To this acidic solution 80 mL NaOH (50 % aq.) was added, followed by the addition of 120 ml of chloroform. The organic layer was separated, and the aqueous layer was extracted twice with 25 mL of chloroform. The combined organic phase was dried on MgSO4. The insoluble material was filtered off and the organic solvent evaporated under reduced pressure to afford 5.5 g (53%) pure brown oily fluoro ketamine 5.
Synthesis Of 1-(2-Fluorophenyl)-N-Methyl-2-Oxo cyclohexanaminium Chloride (6)
2-(2-fluorophenyl)-2-methylamino-cyclohexanone 0.024 mol (5.5 g) 5 was dissolved in a 100 mL mixture of H2O/DCM (50:50). Then, 2.9 mL of 37% aqueous solution of HCl was added slowly. The aqueous layer was separated and water was evaporated under reduced pressure. The pure powder 1-(2-fluorophenyl)-N-methyl-2-oxocyclohexanaminium chloride 6 (5.6 g) was obtained in 90% yield.
Source
- Moghimi, Abolghasem, et al. "Synthesis of 2-(2-fluorophenyl)-2-methylamino-cyclohexanone as a new ketamine derivative." Synthetic Communications 44.14 (2014): 2021-2028. https://doi.org/10.1080/00397911.2014.885053
