Ketamine (C13H16ClNO)

Ketamine

General Facts

Molecular formular: C13H16ClNO

Systematic name: 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one (IUPAC name)

Alternatenames:

a. In medical jargon: Ketaject, Ketanest, dl-Ketamine, Ketalar, CI 581 base, CLSTA 20,
Ketolar
b. In drug jargon: special K, green, jet, K, and super C

Molar mass: 237.092042 g/mol

Appearance: white powder, colorless liquid

History and Discovery

Initial genesis: finding a substitude for Morphin as a anaesthetic

initially: Heroin, however too addicting

temporary substitute: phencyclidine (PCP)

Phencyclidine

 strong analgesic properties, hallucinogenic effects leading to an introduction in

drug world as „angel dust“

1962: Ketamine as drug with milder side-effects but similar structure

1964: experiments on paid prisoners, first suspicion on effects on psyche

1966: patent by Clarke-Davis

1970: officially in use

proven as safe and very effective anaesthetic and painkiller for humans and animals

effects strike quickly and does not cause depression or collapse of airways

 Used for casualties of traffic accidents or battlefield victims

 Historical usage: Vietnam war as anaesthetic

however, still with psychic side effects

Synthesis (following the mechanism developed by Calvin L. Stevens)

Initial reagent: cyclopentyl Grignard

Step 0: Producing cyclopentyl Grignard

Reacting cyclopentyl bromide with magnesium in solvent (ether or THF)

Best results: distill solvent from Grignard under vacuum and replace with hydrocarbon

solvent (e.g. benzene)

Step 1: processing to (o-chlorophenyl)-cyclopentyl ketone

Adding o-chlorobenzonitrile to cyclopentyl Grignard in solvent, stirring for long period of time

(typically three days)

Hydrolyzing reaction with mixture containing crushed ice, ammonium chloride and some

ammonium hydroxide

Extraction with organic solvent gives (o-chlorophenyl)-cyclopentyl ketone

Step 2: processing to alpha-bromo (o-chlorophenyl)-cyclopentyl ketone

ketone processed with bromine in carbon tetrachloride at low temperature (typical T = 0°C),

addition of bromine dropwise forming orange suspension

Suspension washed in dilute aquerous solution of sodium bisufide and evaporated giving

1-bromocyclopentyl-(o-chlorophenyl)-ketone

Note: bromoketone is unstable, immeadiate usage. Bromination carried out with N-

Bromosuccinimide result higher yield (roughly 77%)

Step 3: processing to 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone-N-methylimine

Dissolving bromoketone in liquid methylamine freebase (or benzene as possible solvent)

After time lapse (1h): excess methylamine evaporated, residue dissolved in pentane and

filtered

evaporation of solvent yields 1-hydroxy-cyclopentyl-(o-chlorophenyl)-ketone N-methylimine

Note: longer time span (4-5d) for evaporation of methylaminemay increase yield

Step 4: processing to 2-Methylamino-2-(o-chlorophenyl)-cyclohexanone (Ketamine)

Method: Thermal rearragement (qualitative yield after 30min in 180°C)

N-methylimine dissolved in 15ml decalin, refluxed for 2.5h

Evaporation of solvent under reduced temperature followed by extraction of residue with

dilute hydrochloric acid

Treatment with decolorizing charcoal (solution: acidic => basic)

Recrystallization from pentane-ether

Note - alternative to use of decalin: pressure bomb

Properties of chemical structure

Arylcyclohexylamine derivative

racemic compound, in pharmaceutical preparation racemic

more active enantiomere esketamine (S-Ketamine) available as Ketanest S, but

Arketamine (R-Ketamine) never marketed for clinical use

 R-Ketamine S-Ketamine

Optical rotation: varies between salt and free base form

free base form: (S)-Ketamine dextrorotation  (S)-(+)-ketamine

hydrochloridesalt: levorotation(S)-(-)-ketamine

 Reason found in molecular level: different orientation of substituents:

freebase: o-chlorophenyl equatorial, methylamino axial
salt: o-chlorophenyl axial, methylamino equatorial

Usage of ketamine

a. Medical usage

injectionin I.V. systems in hydrochloric form, direct input in

bloodstream

normally used as anesthectic in veterinary medicine for small mammals, sometimes

used on humans

 on humans: limited use as anaesthetic due to side effects

 anesthetic for diagnostic and surgical procedures that do not require skeletal
muscle relaxation (dose number increasing with length of precedure as dose last
for short periods of time)

b. Drug abuse

Consumption in combination with other drugs (e.g. cocaine, ecstasy, alcohol)

consumption typically by injection or snorting, smoking and as pill also possible

In form of liquid: date rape drug since colorless and odorless

Medical aspect – effects on body and mind

a. General sideeffects
Reduce or eliminate pain
Bad hallucinations if used to escape unpleasant thoughts/emotions
Disorientation, confusion
Drowsiness, amnesia
 Nausea, may progress to vomiting
Difficulty in movements, may progress to numbness and temporary unable to
move
Higher heart rate and blood pressure
(in high doses) „K-Hole“: intense, unpleasant hallucinations (visual and auditory),
derealization, detachment from reality

b. Short-Term sideeffects
Aprupt high, starting 2-5mins. if smoked/swallowed or 30s if injected, lasting for
one hour
Relaxation in full body
Detachments from body (higher doses)
Hallucinations

c. Long-Term sideeffects
Addiction
Severe abdominal pain
Kidney problems

Sources:

http://creationwiki.org/Ketamine#Synthesis

http://www.lycaeum.org/rhodium/chemistry/pcp/ketamine.html

https://pubchem.ncbi.nlm.nih.gov/compound/ketamine

https://pubchem.ncbi.nlm.nih.gov/compound/ketamine#section=Drug-Warning

http://www.rsc.org/chemistryworld/2014/02/ketamine-special-k-drugs-podcast

http://drugabuse.com/library/the-effects-of-ketamine-use/

http://www.drugfreeworld.org/drugfacts/prescription/ketamine.html

http://onlinelibrary.wiley.com/doi/10.1002/1615-9314(20021101)25:15/17%3C1155::AID-JSSC1155%3E3.0.CO;2-M/pdf