G.Patton

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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:

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.
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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.
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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 %).
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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 %).
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woohoo

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Yields is higher than with traditional ketamine rearrangement?
How to make 2-chlorophenyl hydroxy cyclohexanone?
 

woohoo

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You can buy this reagent as legal substance

About the same, but this route has less steps
G.PattonI'm interested in total synthesis, can you give me procedure for phenyl hydroxy cyclohexanones?
 

G.Patton

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Sorry for long reply. I'll make a topic with detailed information
I'm interested in total synthesis, can you give me procedure for phenyl hydroxy cyclohexanones?
woohoo
Look at here.​
 
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ASheSChem

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2-(2-Chlorophenyl)-2-hydroxycyclohexanone :
 

Montecristo

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what? You can't find? Open google or so and put "2-chlorophenyl hydroxy cyclohexanone buy"
G.PattonI am also having difficulties finding that exact chemical, outside of it being sold as 'Esketamine impurity B' at high cost and low volume.
Maybe they have moved on to another chem? or maybe not many people want?
I can however find with ease;
- 2-(2-chlorophenyl)cyclohexanone
- 2-(2-Chlorophenyl)-2-nitrocyclohexanone
How easy is it to add that hydroxy?
 

btcboss2022

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what? You can't find? Open google or so and put "2-chlorophenyl hydroxy cyclohexanone buy"
G.PattonThat product is practically impossible to obtain and in the case you can is very expensive and low amounts available.
 

Montecristo

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would love to know the method for 2-(2-Chlorophenyl)-2-nitrocyclohexanone CAS 2079878-75-2

That is actually commercially available
 

G.Patton

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Montecristo

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is it sold as any other synonyms?
could you have a look at where you may have seen it? I cant find any on the usual chem sites ,
lots of similar compounds though, i think they may have moved to nitrocyclohexanone.
Actually I don't know, I have seen good prices from Chinese manufacturers.
G.Patton
 

btcboss2022

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In my opinion is easier this from :

1-hydroxycyclopentyl-(o-chlorophenyl)-ketone-N-methylimine


29.0g 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%).

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 92-93C. 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 in order to be consumed in this manner.
 

darkmatter7

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How difficult would this be to do with little (i.e none) starting equipment?
Honestly, do I need a rotovap? C'mon.
 

JimmyMcGill

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has anyone found synthesis route for 2-(2-Chlorophenyl)-2-nitrocyclohexanone to ketamine?
 

WillD

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simplechemistry

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Actually, I don't know, I have seen good prices from Chinese manufacturers.
G.PattonHorrible prices compared to running the synth yourself. Only problem is obtaining sodium nitrate as an individual but everything else is trivial.
Also you can one pot this whole synthesis if you employ barbier rather than grignard :)
 
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