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Home , Arketamine, Arylcyclohexylamine, Free base

(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 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: , however too addicting

temporary substitute: (PCP)

Phencyclidine  strong 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 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 in ( or THF)

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

solvent (e.g. )

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 -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

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 (S-Ketamine) available as Ketanest S, but

Arketamine (R-Ketamine) never marketed for clinical use

R-Ketamine S-Ketamine Optical rotation: varies between 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

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 (e.g. , ecstasy, )

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

In form of liquid: 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 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