- By chuckmcgill
Thanks do you have any links with more detailed reaction conditions and reagent amounts? Thanks
Ketamine synthesis from 2-(2-Chlorophenyl)-2-hydroxycyclohexanone
- Thread starter G.Patton
- Start date
This method was developed by Russian chemist Zealot from Hyperlab.
1. o-Chlorobenzoic acid
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 bee 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 bee used for bromo- and chlorobenzoic acids.
To a hot soln of 50g NaOH in 400mls water there's added 195g o-chlorobenzoic acid. Carefully neutralize with NH3 or NaHCO3 and add with heating 105g (~5% excess) ZnSO4 in 400mls water. The precipitated salt is dried for prolonged time at 200°C and mixed intimately with 205g Pb(SCN)2. The mixture is coffeeground 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 137g (80%), mp 43-46°C, bp 232°C. The rxn usually takes place within 30-60 mins, but the duration of dryings makes the method quite time-consuming.
Preparation B.
This one doesn't require a prolonged drying. Sulfaminic acid is dirt cheap and can bee acquired without causing any suspicion.
o-Bromobenzonitrile
50g o-Bromobenzamide and 35g (25g=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 36g (80% of theory).
mp 53-57°C, bp 251-253°C
3. Cyclopentanone
100g adipic acid and 10g 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: 51g (89% of theory).
4. Aluminium isopropoxide
Al(i-PrO)3 - Bp 130-140°C at 7mmHg; mp 118°C.
Into a 250ml RBF equipped with an efficient reflux condenser there's added 6g Al foil, 70mls (51mls in theory) abs. IPA (commercial reagent grade IPA was used without any drying) and 0,1g HgSO4. The mixture is heated.
In the beginning of boiling 0,5mls 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 250ml RBF equipped with a 15cm Vigreux column and distilling condenser there's added 53mls (50g) cyclopentanone in 50mls IPA and the soln from the previous prep'n, which contains about 40g 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: 47g (94%)
6. Cyclopentylbromide
In a flask there’s mixed 47mls (45g) cyclopentanol and 60mls (90g) 48% aq. HBr. 10g Na2SO4 is added. The rxn is left for 24hrs with vigorous stirring. After that it’s diluted with 200mls water and the lower organic phase is separated and washed with water twice. Distill, collecting the fraction between 137-138°C. Dryed with MgSO4.
Yield = 58g (74%)
7. Cyclopentyl magnesium bromide
Into a 250mls three-necked flask equipped with a reflux condenser, addition funnel and inert gas inlet there’s placed 50mls THF (kept over KOH, prior to the rxn 150mls refluxed over 30g CaO for 6hrs and distilled). 9g 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 beecomes cloudy from MgI. From the addition funnel there’s dripped 55g (40mls) cyclopentyl bromide in 100mls 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 maybee 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. Beesides, THF can bee dried with CaO, while for ether,sodium metal is usually employed.
8. o-Chlorophenyl cyclopentyl ketone
To the thus obtained Grignard soln there’s added 48g 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 beelow 55%.
9. alpha-Bromo-(o-chlorophenyl)-cyclopentyl ketone
40g ketone is dissolved in 70mls CCl4 and with cooling in snow it is added into a soln of 48g dioxane dibromide in 50mls dioxane, and stirred at RT for 30mins. Then 30mls water are added and the soln is washed with Na2CO3 aq. until neutral. This may lead to some preciptation of the bromoketone, which stays in CCl4. The solvent is removed, giving 47g (85%) of the bromoketone.
10. (1-hydroxy-cyclopentyl)-(o-chlorophenyl)-N-methylketimine
45g of the above bromoketone is dissolved in 50mls benzene, add therein 50mls triethylamine (17g/23mL is required for neutralization of HBr, but a 2x excess is used). The soln is then saturated with 5g methylamine, obtained by dripping a saturated soln of 15g MeNH2·HCl onto 10g NaOH, dried thru NaOH. The rxn is left for 1 day and the solvents are removed under aspirator vacuum, giving 30g (80%) of methylketimine.
11. Ketamine
10g of methylketimine is dissolved in 100mls undecane and boiled at 195°C for 3-4hrs. 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 bee purified by recrystallization from pentane/ether or hexane/ether.
1. o-Chlorobenzoic acid
- Anthranilic acid 13,7g
- HCl (conc., d=1,19)
- NaNO2 8g
- CuCl 10g
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 bee 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 bee used for bromo- and chlorobenzoic acids.
To a hot soln of 50g NaOH in 400mls water there's added 195g o-chlorobenzoic acid. Carefully neutralize with NH3 or NaHCO3 and add with heating 105g (~5% excess) ZnSO4 in 400mls water. The precipitated salt is dried for prolonged time at 200°C and mixed intimately with 205g Pb(SCN)2. The mixture is coffeeground 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 137g (80%), mp 43-46°C, bp 232°C. The rxn usually takes place within 30-60 mins, but the duration of dryings makes the method quite time-consuming.
Preparation B.
This one doesn't require a prolonged drying. Sulfaminic acid is dirt cheap and can bee acquired without causing any suspicion.
o-Bromobenzonitrile
50g o-Bromobenzamide and 35g (25g=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 36g (80% of theory).
mp 53-57°C, bp 251-253°C
3. Cyclopentanone
100g adipic acid and 10g 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: 51g (89% of theory).
4. Aluminium isopropoxide
Al(i-PrO)3 - Bp 130-140°C at 7mmHg; mp 118°C.
Into a 250ml RBF equipped with an efficient reflux condenser there's added 6g Al foil, 70mls (51mls in theory) abs. IPA (commercial reagent grade IPA was used without any drying) and 0,1g HgSO4. The mixture is heated.
In the beginning of boiling 0,5mls 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 250ml RBF equipped with a 15cm Vigreux column and distilling condenser there's added 53mls (50g) cyclopentanone in 50mls IPA and the soln from the previous prep'n, which contains about 40g 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: 47g (94%)
6. Cyclopentylbromide
In a flask there’s mixed 47mls (45g) cyclopentanol and 60mls (90g) 48% aq. HBr. 10g Na2SO4 is added. The rxn is left for 24hrs with vigorous stirring. After that it’s diluted with 200mls water and the lower organic phase is separated and washed with water twice. Distill, collecting the fraction between 137-138°C. Dryed with MgSO4.
Yield = 58g (74%)
7. Cyclopentyl magnesium bromide
Into a 250mls three-necked flask equipped with a reflux condenser, addition funnel and inert gas inlet there’s placed 50mls THF (kept over KOH, prior to the rxn 150mls refluxed over 30g CaO for 6hrs and distilled). 9g 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 beecomes cloudy from MgI. From the addition funnel there’s dripped 55g (40mls) cyclopentyl bromide in 100mls 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 maybee 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. Beesides, THF can bee dried with CaO, while for ether,sodium metal is usually employed.
8. o-Chlorophenyl cyclopentyl ketone
To the thus obtained Grignard soln there’s added 48g 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 beelow 55%.
9. alpha-Bromo-(o-chlorophenyl)-cyclopentyl ketone
40g ketone is dissolved in 70mls CCl4 and with cooling in snow it is added into a soln of 48g dioxane dibromide in 50mls dioxane, and stirred at RT for 30mins. Then 30mls water are added and the soln is washed with Na2CO3 aq. until neutral. This may lead to some preciptation of the bromoketone, which stays in CCl4. The solvent is removed, giving 47g (85%) of the bromoketone.
10. (1-hydroxy-cyclopentyl)-(o-chlorophenyl)-N-methylketimine
45g of the above bromoketone is dissolved in 50mls benzene, add therein 50mls triethylamine (17g/23mL is required for neutralization of HBr, but a 2x excess is used). The soln is then saturated with 5g methylamine, obtained by dripping a saturated soln of 15g MeNH2·HCl onto 10g NaOH, dried thru NaOH. The rxn is left for 1 day and the solvents are removed under aspirator vacuum, giving 30g (80%) of methylketimine.
11. Ketamine
10g of methylketimine is dissolved in 100mls undecane and boiled at 195°C for 3-4hrs. 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 bee purified by recrystallization from pentane/ether or hexane/ether.
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 %).
Mind if I ask, what kind of Methylamine is used here? 40% water solution? Or pure liquid MeNH2?
Thanks!
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 %).
Mind if I ask, what kind of Methylamine is used here? 40% water solution? Or pure liquid MeNH2?
Thanks!
- By Zan444
CAS 1823362-29-3 is not avaible anymore so it shouldnt matter.
Thanks for your reply. I have been reading an article regarding the systhesis of 1823362-29-3. Would like to take a try.
bbgate.com
Do you think it is feasible?
Ketamine precursor synthesis
Introduction 2-(2-Chlorophenyl)-2-hydroxycyclohexanone (cas 1823362-29-3) is a precursor in simple Ketamine synthesis. This synthesis has less step than classical Ketamine synthesis from cyclopentyl bromide and o-chlorobenzonitrile and a little bit bigger yield. Moreover, you can ship...
bbgate.com
Do you think it is feasible?
