Overview.
Ketamine is more difficult to synthesize than the previously considered PCP derivatives. Although it is currently a popular and common drug on the illicit market, it is obtained exclusively by diversion of commercial sources rather than synthesis. This route has an overall yield of ~60%, with a difficulty rating of 2-3 out of 10 and a hazard rating of 1-2 out of 10. The general necessity of producing anhydrous methylamine in a clandestine setting, rather than purchasing it, increases the difficulty. Use of propylamine rather than methylamine would simplify this reaction, as its boiling point is above room temperature vs. methylamine, which is a gas at room temperature.
The synthesis starts with the reaction of cyclopentyl Grignard and o-chlorobenzonitrile to give o-chlorophenyl-cyclopentyl ketone, followed by alpha bromination of the ketone, and then reaction with methylamine to form an alpha-hydroxy imine (1-Hydroxycyclopentyl-(o-chlorophenyl)-ketone-N-methylimine). Heating this imine results in Ketamine via a novel alpha-hydroxyimine rearangement. Overall yields are ~60%.
Tiletamine is synthesized by an analogous process in industry, substituting 2-thiophenyl magnesium bromide for the phenyl grignard and ethylamine for methylamine. Two other ketamine analogs have been found on the black market: the compound missing the 2-chloro group on the phenyl ring, and its N-ethyl analog. Both of these compounds are most likely more potent and longer lasting than ketamine.
The synthesis starts with the reaction of cyclopentyl Grignard and o-chlorobenzonitrile to give o-chlorophenyl-cyclopentyl ketone, followed by alpha bromination of the ketone, and then reaction with methylamine to form an alpha-hydroxy imine (1-Hydroxycyclopentyl-(o-chlorophenyl)-ketone-N-methylimine). Heating this imine results in Ketamine via a novel alpha-hydroxyimine rearangement. Overall yields are ~60%.
Tiletamine is synthesized by an analogous process in industry, substituting 2-thiophenyl magnesium bromide for the phenyl grignard and ethylamine for methylamine. Two other ketamine analogs have been found on the black market: the compound missing the 2-chloro group on the phenyl ring, and its N-ethyl analog. Both of these compounds are most likely more potent and longer lasting than ketamine.
Synthetic procedure for ketamine synthesis.
Step 1: (o-chlorophenyl)-cyclopentyl ketone.119.0 g of cyclopentyl bromide and 19.4 g of magnesium are reacted in ether or THF to give a cyclopentyl Grignard reagent. The best yields are obtained if the ether solvent is distilled from the Grignard under vacuum and replaced with hydrocarbon solvent, such as benzene. 55.2 g of o-chlorobenzonitrile is then added to the reaction mixture and stirred for three days. The reaction is then hydrolyzed by pouring it onto a mixture of crushed ice and ammonium chloride, containing some ammonium hydroxide. Extraction of the mixture with organic solvent gives o-chlorophenylcyclopentylketone, bp 96-97 °C (0.3 mm Hg) (CAS# 6740-85-8).
Step 2: alpha-bromo (o-chlorophenyl)-cyclopentyl ketone.
To 21.0 g of the above ketone is added 10.0 g of bromine in 80 ml of carbon tetrachloride dropwise at 0 °C. After all the Br2 has been added, an orange suspension forms. This is washed with a dilute aqueous solution of sodium bisulfite and evaporated to give 1-bromocyclopentyl-(o-chlorophenyl)-ketone, bp 111-114 °C (0.1 mm Hg). Yield is ~66%. This bromoketone is unstable and must be used immediately. Also, attempts to distill it at 0.1 mm Hg lead to some decomposition, so it should be used without further purification.
The bromination may also be carried out with N-bromosuccinimide in somewhat higher yields (~77%).
To 21.0 g of the above ketone is added 10.0 g of bromine in 80 ml of carbon tetrachloride dropwise at 0 °C. After all the Br2 has been added, an orange suspension forms. This is washed with a dilute aqueous solution of sodium bisulfite and evaporated to give 1-bromocyclopentyl-(o-chlorophenyl)-ketone, bp 111-114 °C (0.1 mm Hg). Yield is ~66%. This bromoketone is unstable and must be used immediately. Also, attempts to distill it at 0.1 mm Hg lead to some decomposition, so it should be used without further purification.
The bromination may also be carried out with N-bromosuccinimide in somewhat higher yields (~77%).
Step 3: 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone-N-methylimine.
29.0 g of above bromoketone is dissolved in 50 ml of liquid methylamine freebase. Benzene may also be used as solvent. After one hour, the excess liquid methylamine is allowed to evaporate, although increasing the reaction time to 4-5 days may increase yield. The residue is then dissolved in pentane and filtered. The solvent is evaporated to yield 1-hydroxy-cyclopentyl-(o-chlorophenyl)-ketone N-methylimine, mp 62 °C (yield ~84%).
29.0 g of above bromoketone is dissolved in 50 ml of liquid methylamine freebase. Benzene may also be used as solvent. After one hour, the excess liquid methylamine is allowed to evaporate, although increasing the reaction time to 4-5 days may increase yield. The residue is then dissolved in pentane and filtered. The solvent is evaporated to yield 1-hydroxy-cyclopentyl-(o-chlorophenyl)-ketone N-methylimine, mp 62 °C (yield ~84%).
Step 4: 2-Methylamino-2-(o-chlorophenyl)-cyclohexanone (Ketamine).
The final step is a thermal rearrangement, and gives almost quantitative yield after 180 °C for 30 min. An alternative to the use of decalin as solvent in this step is to use a pressure bomb. 2.0 g of the preceeding N-methylimine is dissolved in 15 ml of decalin and refluxed for 2.5 h. After evaporation of the solvent under reduced pressure, the residue is extracted with dilute hydrochloric acid, the solution treated with decolorizing charcoal, and the resulting acidic solution is made basic. The liberated product, 2-methylamino-2-(o-chlorophenyl)-cyclohexanone (Ketamine), after recrystallization from pentane-ether, has a mp of 92-93 °C. The hydrochloride has a mp of 262-263 °C.
The final step is a thermal rearrangement, and gives almost quantitative yield after 180 °C for 30 min. An alternative to the use of decalin as solvent in this step is to use a pressure bomb. 2.0 g of the preceeding N-methylimine is dissolved in 15 ml of decalin and refluxed for 2.5 h. After evaporation of the solvent under reduced pressure, the residue is extracted with dilute hydrochloric acid, the solution treated with decolorizing charcoal, and the resulting acidic solution is made basic. The liberated product, 2-methylamino-2-(o-chlorophenyl)-cyclohexanone (Ketamine), after recrystallization from pentane-ether, has a mp of 92-93 °C. The hydrochloride has a mp of 262-263 °C.
As with PCE, the freebase is too caustic to be smoked, and must be converted into the HCl salt to be consumed in this manner.
In this video, you can watch syntheses manual of deschloro-ketamine, which has similar syntheses route with ketamine. I think it would be helpful for a beginner synthetic chemist.
Total synthesis of ketamine (advanced).
While there are 11 steps in the synthesis, its longitude is explained by the fact that all the precursors and even some reagents are made from scratch, employing user-friendly techniques and equipment (in fact, a need for vacuum is mentioned only once, and even that is for the removal of solvent); as well as only easy-to-get reactants. Still, the synth is obviously for the skilled only; for one thing, it involves making a Grignard. There is a potential possibility to use zinc-organic compounds instead (discussed in detail below) which is much cheaper and easier technically.
1. o-Chlorobenzoic acid.
1. o-Chlorobenzoic acid.
- Anthranilic acid 13,7 g,
- HCl (conc., d=1,19),
- NaNO2 8 g,
- CuCl 10 g.
13.7 g anthranilic acid is stirred in a glass beaker in 40 mls water, 28 mls HCl and 20 g ice. With constant stirring and cooling, there's added 8 g NaNO2 in 40 mls water. Thus obtained, clear solution of diazonium salt is very slowly added with stirring into a soln. of 10 g CuCl in 25 g HCl conc. A vigorous evolution of nitrogen is observed.
When the rxn ends, the ppt is filtered, washed with cold water and reprecipitated from aq. Na2CO3. The product represents fine crystals and melts at 140-141 °C. o-Bromobenzoic acid can be obtained in an analogous manner, substituting CuCl for CuBr.
2. o-Chlorobenzonitrile.
Preparation A.
(RCOO)2Zn + Pb(SCN)2 = 2 RCN + ZnS + PbS + 2 CO2
The best results are obtained when a zinc salt is employed instead of free acid. This rxn is unsuitable for amino-, nitro- and oxy- acids, but can be used for bromo- and chlorobenzoic acids.
To a hot soln of 50 g NaOH in 40.0 mls water there's added 195 g o-chlorobenzoic acid. Carefully neutralize with NH3 or NaHCO3 and add with heating 105 g (~5% excess) ZnSO4 in 400 mls water. The precipitated salt is dried for prolonged time at 200 °C and mixed intimately with 205 g Pb(SCN)2. The mixture is coffee ground and dried at 120-140 °C for a prolonged time, then heated on open flame - the mixture melts and gases are evolved.
Distilled nitrile is treated with NH4OH, steam-distilled and salted out. Yield 137 g (80%), mp 43-46 °C, bp 232 °C. The rxn usually takes place within 30-60 mins, but the duration of drying makes the method quite time-consuming.
Preparation B.
This one doesn't require a prolonged drying. Sulfaminic acid is dirt cheap and can be acquired without causing any suspicion.
o-Bromobenzonitrile.
50 g o-Bromobenzamide and 35 g (25 g=theory) sulfaminic (sulfamic) acid is thoroughly mixed and heated in a Wurtz flask. At 250-255 °C distillation begins, which is over at 285-295 °C (takes approx. 1.5-2 hrs). The collected product is redistilled, yield 36 g (80% of theory). mp 53-57 °C, bp 251-253 °C.
3. Cyclopentanone.
100 g adipic acid and 10 g Ba(OH)2 is intimately mixed and placed into a flask with a thermometer. The rxn is heated to 280 °C, the mixture initially melts, and then the distillation takes place, which lasts about 1-2 hrs. The hot distillate is saturated with NaCl, the upper layer is decanted and distilled, collecting the fraction boiling at 128-130 °C. Dry with MgSO4. Yield: 51 g (89% of theory).
Notes:
When the rxn ends, the ppt is filtered, washed with cold water and reprecipitated from aq. Na2CO3. The product represents fine crystals and melts at 140-141 °C. o-Bromobenzoic acid can be obtained in an analogous manner, substituting CuCl for CuBr.
2. o-Chlorobenzonitrile.
Preparation A.
(RCOO)2Zn + Pb(SCN)2 = 2 RCN + ZnS + PbS + 2 CO2
The best results are obtained when a zinc salt is employed instead of free acid. This rxn is unsuitable for amino-, nitro- and oxy- acids, but can be used for bromo- and chlorobenzoic acids.
To a hot soln of 50 g NaOH in 40.0 mls water there's added 195 g o-chlorobenzoic acid. Carefully neutralize with NH3 or NaHCO3 and add with heating 105 g (~5% excess) ZnSO4 in 400 mls water. The precipitated salt is dried for prolonged time at 200 °C and mixed intimately with 205 g Pb(SCN)2. The mixture is coffee ground and dried at 120-140 °C for a prolonged time, then heated on open flame - the mixture melts and gases are evolved.
Distilled nitrile is treated with NH4OH, steam-distilled and salted out. Yield 137 g (80%), mp 43-46 °C, bp 232 °C. The rxn usually takes place within 30-60 mins, but the duration of drying makes the method quite time-consuming.
Preparation B.
This one doesn't require a prolonged drying. Sulfaminic acid is dirt cheap and can be acquired without causing any suspicion.
o-Bromobenzonitrile.
50 g o-Bromobenzamide and 35 g (25 g=theory) sulfaminic (sulfamic) acid is thoroughly mixed and heated in a Wurtz flask. At 250-255 °C distillation begins, which is over at 285-295 °C (takes approx. 1.5-2 hrs). The collected product is redistilled, yield 36 g (80% of theory). mp 53-57 °C, bp 251-253 °C.
3. Cyclopentanone.
100 g adipic acid and 10 g Ba(OH)2 is intimately mixed and placed into a flask with a thermometer. The rxn is heated to 280 °C, the mixture initially melts, and then the distillation takes place, which lasts about 1-2 hrs. The hot distillate is saturated with NaCl, the upper layer is decanted and distilled, collecting the fraction boiling at 128-130 °C. Dry with MgSO4. Yield: 51 g (89% of theory).
Notes:
- Ca(OH)2 may be substituted for Ba(OH)2 without much loss in the yield.
- If one is to use pre-made Ca or Ba adipinate, no temp control is necessary.
4. Aluminium isopropoxide
Into a 250 ml RBF equipped with an efficient reflux condenser there's added 6 g Al foil, 70 mls (51 mls in theory) abs. IPA (commercial reagent grade IPA was used without any drying) and 0.1 g HgSO4. The mixture is heated. Al(i-PrO)3 - Bp 130-140 °C at 7 mm Hg; mp 118 °C.
At the beginning of boiling 0,5 mls CCl4 (CAREFUL! Extremely toxic!) and heating continued until H2 evolution starts, when it is stopped, sometimes even cooling's needed. After the rxn subsides, heating is continued until almost full dissolution of Al (5-7 hrs). The obtained solution is immediately used as is in the following preparation.
5. Cyclopentanol.
Into a 250 ml RBF equipped with a 15 cm Vigreux column and distilling condenser there's added 53 mls (50 g) cyclopentanone in 50 mls IPA and the soln from the previous prep'n, which contains about 40 g Al isopropoxide. The rxn is gently heated, which causes acetone with some water to distill off. The distillation is ended when the temp of the vapors rises to ~85 °C.
The ppt inside the flask is carefully decomposed with 50% H2SO4 until acidic and saturated with NaCl. The upper layer is decanted and distilled, collecting the fraction boiling at 137-140 °C. Drying with MgSO4. Yield: 47 g (94%).
6. Cyclopentylbromide
In a flask, there’s mixed 47 mls (45 g) cyclopentanol and 60 mls (90 g) 48% aq. HBr. 10 g Na2SO4 is added. The rxn is left for 24 hrs with vigorous stirring. After that, it’s diluted with 200 mls water and the lower organic phase is separated and washed with water twice. Distill, collecting the fraction between 137-138 °C. Dried with MgSO4. Yield = 58 g (74%).
7. Cyclopentyl magnesium bromide.
Into a 250 mls three-necked flask equipped with a reflux condenser, addition funnel and inert gas inlet there’s placed 50 mls THF (kept over KOH, before the rxn 150 mls refluxed over 30 g CaO for 6 hrs and distilled). 9 g of fine Mg turnings is added, followed by some iodine crystals. The apparatus is flushed with argon and a gentle stream of gas is left flowing in. Magnetic stirring is commenced. The mixture instantly becomes cloudy from MgI. From the addition funnel there’s dripped 55 g (40 mls) cyclopentyl bromide in 100 mls THF so that the soln boils smoothly. The rxn is usually over in an hour, it is accompanied by precipitation of a white jelly-like mass, and at the bottom there is maybe left some unreacted Mg as a dark-grey powder.
Usage of THF instead of ether is preferred since the rxn in it proceeds better and faster (THF is a more specific solvent for Grignards), the yield is better as well. Besides, THF can be dried with CaO, while for ether, sodium metal is usually employed.
Notes on the possible usage of Zn-organics:
Into a 250 ml RBF equipped with an efficient reflux condenser there's added 6 g Al foil, 70 mls (51 mls in theory) abs. IPA (commercial reagent grade IPA was used without any drying) and 0.1 g HgSO4. The mixture is heated. Al(i-PrO)3 - Bp 130-140 °C at 7 mm Hg; mp 118 °C.
At the beginning of boiling 0,5 mls CCl4 (CAREFUL! Extremely toxic!) and heating continued until H2 evolution starts, when it is stopped, sometimes even cooling's needed. After the rxn subsides, heating is continued until almost full dissolution of Al (5-7 hrs). The obtained solution is immediately used as is in the following preparation.
5. Cyclopentanol.
Into a 250 ml RBF equipped with a 15 cm Vigreux column and distilling condenser there's added 53 mls (50 g) cyclopentanone in 50 mls IPA and the soln from the previous prep'n, which contains about 40 g Al isopropoxide. The rxn is gently heated, which causes acetone with some water to distill off. The distillation is ended when the temp of the vapors rises to ~85 °C.
The ppt inside the flask is carefully decomposed with 50% H2SO4 until acidic and saturated with NaCl. The upper layer is decanted and distilled, collecting the fraction boiling at 137-140 °C. Drying with MgSO4. Yield: 47 g (94%).
6. Cyclopentylbromide
In a flask, there’s mixed 47 mls (45 g) cyclopentanol and 60 mls (90 g) 48% aq. HBr. 10 g Na2SO4 is added. The rxn is left for 24 hrs with vigorous stirring. After that, it’s diluted with 200 mls water and the lower organic phase is separated and washed with water twice. Distill, collecting the fraction between 137-138 °C. Dried with MgSO4. Yield = 58 g (74%).
7. Cyclopentyl magnesium bromide.
Into a 250 mls three-necked flask equipped with a reflux condenser, addition funnel and inert gas inlet there’s placed 50 mls THF (kept over KOH, before the rxn 150 mls refluxed over 30 g CaO for 6 hrs and distilled). 9 g of fine Mg turnings is added, followed by some iodine crystals. The apparatus is flushed with argon and a gentle stream of gas is left flowing in. Magnetic stirring is commenced. The mixture instantly becomes cloudy from MgI. From the addition funnel there’s dripped 55 g (40 mls) cyclopentyl bromide in 100 mls THF so that the soln boils smoothly. The rxn is usually over in an hour, it is accompanied by precipitation of a white jelly-like mass, and at the bottom there is maybe left some unreacted Mg as a dark-grey powder.
Usage of THF instead of ether is preferred since the rxn in it proceeds better and faster (THF is a more specific solvent for Grignards), the yield is better as well. Besides, THF can be dried with CaO, while for ether, sodium metal is usually employed.
Notes on the possible usage of Zn-organics:
- Nitriles are not bad as electrophiles, so it is possible that despite smaller reactivity of ZnR2 compounds, they would work equally well here - esp. If the rxn conditions are made harsher (gentle reflux instead of RT?).
- What one CAN say for sure-is that the rxn with ZnR2 will go just fine if one is to use o-chlorobenzoyl chloride instead of benzonitrile. Haloanhydrides generally are the best species for coupling with metalloorganics.
- Bis-dicyclopentyl zinc is conveniently made from the corresponding bromide, no need to make iodide here. And o-chlorobenzoyl chloride can be easily prepared from o-chlorobenzoic acid (obtained in Step 1) and PCl5 or some such."
8. o-Chlorophenyl cyclopentyl ketone.
To the thus obtained Grignard soln there’s added 48 g o-chlorobenzonitrile and the mixture is stirred for 3 days at RT. It is then poured into a mixture of ice/NH4Cl, with addition of some conc. aq. NH3 and left at ambient temp until all ice melts. The ketone partially floats, partially goes to the bottom. It’s extracted with benzene. The yields fluctuate, but rarely drop below 55%.
9. alpha-Bromo-(o-chlorophenyl)-cyclopentyl ketone.
40 g ketone is dissolved in 70 mls CCl4 and with cooling in snow it is added into a soln. of 48 g dioxane dibromide in 50 mls dioxane, and stirred at RT for 30 mins. Then 30 mls water are added and the soln is washed with Na2CO3 aq. until neutral. This may lead to some precipitation of the bromoketone, which stays in CCl4. The solvent is removed, giving 47 g (85%) of the bromoketone.
10. 1-hydroxy-cyclopentyl-(o-chlorophenyl)-N-methylketimine
45 g of the above bromoketone is dissolved in 50 mls benzene, add therein 50mls triethylamine (17 g/23 mL is required for neutralization of HBr, but a 2x excess is used). The soln. is then saturated with 5 g methylamine, obtained by dripping a saturated soln of 15 g MeNH2·HCl onto 10 g NaOH, dried thru NaOH. The rxn is left for 1 day and the solvents are removed under aspirator vacuum, giving 30 g (80%) of methylketimine.
11. Ketamine
10 g of methylketimine is dissolved in 100 mls undecane and boiled at 195 °C for 3-4 hrs. Ketamine is extracted with 20% HCl. Acidic extract is basified and extracted with DCM. Solvent is removed, giving the product as an oil that quickly crystallizes. It can be purified by recrystallization from pentane/ether or hexane/ether. The yields are close to quantitative.
rxn - reaction,
soln.- solution,
bp - boiling point,
mp - melting point,
ppt - precipitation.
To the thus obtained Grignard soln there’s added 48 g o-chlorobenzonitrile and the mixture is stirred for 3 days at RT. It is then poured into a mixture of ice/NH4Cl, with addition of some conc. aq. NH3 and left at ambient temp until all ice melts. The ketone partially floats, partially goes to the bottom. It’s extracted with benzene. The yields fluctuate, but rarely drop below 55%.
9. alpha-Bromo-(o-chlorophenyl)-cyclopentyl ketone.
40 g ketone is dissolved in 70 mls CCl4 and with cooling in snow it is added into a soln. of 48 g dioxane dibromide in 50 mls dioxane, and stirred at RT for 30 mins. Then 30 mls water are added and the soln is washed with Na2CO3 aq. until neutral. This may lead to some precipitation of the bromoketone, which stays in CCl4. The solvent is removed, giving 47 g (85%) of the bromoketone.
10. 1-hydroxy-cyclopentyl-(o-chlorophenyl)-N-methylketimine
45 g of the above bromoketone is dissolved in 50 mls benzene, add therein 50mls triethylamine (17 g/23 mL is required for neutralization of HBr, but a 2x excess is used). The soln. is then saturated with 5 g methylamine, obtained by dripping a saturated soln of 15 g MeNH2·HCl onto 10 g NaOH, dried thru NaOH. The rxn is left for 1 day and the solvents are removed under aspirator vacuum, giving 30 g (80%) of methylketimine.
11. Ketamine
10 g of methylketimine is dissolved in 100 mls undecane and boiled at 195 °C for 3-4 hrs. Ketamine is extracted with 20% HCl. Acidic extract is basified and extracted with DCM. Solvent is removed, giving the product as an oil that quickly crystallizes. It can be purified by recrystallization from pentane/ether or hexane/ether. The yields are close to quantitative.
rxn - reaction,
soln.- solution,
bp - boiling point,
mp - melting point,
ppt - precipitation.
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