Fentanyl

Fentanyl is a synthetic opioid, which is used mainly in anaesthesia. It has the elemental
formula C22H28N2O and its IUPAC-name is N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenyl-
propanamide. Its CAS-Number is: 437-38-7. Fentanyl is a piperidine derivative. In Latin it
can be found as Fentanylum. Fentanyl is – under normal conditions – a white till nearly white
polymorphic powder and has a molar mass of 336,47 g/mol. Its melting point lies at 87,5°C
(190°F) and its solubility in water is 200 mg/l at 25°C, whereas his solubility in ethanol and
methanol is nearly unlimited. The n-octanol:water partition coefficient is 860:1. The pKa is
8.4. Fentanyl was first synthesized by Dr. Paul Janssen in 1960. Depending on the position of
the substituents, some of the resulting molecules may exist as enantiomers e.g. the isomers of
3-methylfentanyl, which have differing analgesic potencies depending on which enantiomer is
used. The Dangerous Substances Directive of Fentayl is T+ (very toxic) because the lethal
dose for rats lies at 18 mg/kg (per os) and 76 mg/kg for mouse (intraperitoneal injection). The
effective dose for humans lies as an analgetic at 0,01 mg/kg, whereas the lethal dose for
human is up to date not studied. However the lethal dose of apes lies at 0,03 mg/kg, so it is
assumed, that a similar dose rate for humans can cause to death. The mass spectrum shows a
major ion at m/z =245 with other ions at m/z =146,42,189 and 44. Fentanyl in body fluids
does not respond to immunoassay screening tests for morphine-type opioids. The limit of
detection in plasma using gas chromatography is 20 ng/l.

The synthesis of Fentanyl continues multiple intermediate levels: The precursor used is N-
Phenethyl-Piperidone (NPP) which can be easily synthesized from Piperidone and Phenethyl-
tosylate or Phenethyl-bromide through a simple SN2 mechanism. The NPP is reacting with
Aniline giving the Imine derivative which is reduced to the 4-Anilino-N-Phenethyl-Piperidine
(4-ANPP). The 4-ANPP is then reacted with Propionyl Chloride giving Fentanyl which is
then purified. N-alkylation of 4-piperidone can be done in Phenylthiocarbamide (PTC)
conditions. Add to one liter of acetonitrile 3 mole finely powdered potassium carbonate, then
add 10 g of PTC catalyst - TBAB or TEBA, or just polyethylene glycol-400. Stir this
suspension 15 min at 50-60°C, and then add in little portions your 4-piperidone
hydrochloride, watching that the CO2 evolution wasn't too vigorous. Stir another hour at 50-
60°C, and then add phenethylbromide dropwise and stir 15-20 h at mild reflux. Then cool,
and filter off inorganic salts - if filtration goes too slowly, add to suspension some (30-40 ml)
saturated sodium sulphate solution, this makes the sticky precipitate granular and filterable.
For this step the yield is almost quantitative. The result is a yellow solid with a melting point
of 60°C. 10 mmole of NPP is dissolved in a minimal volume of aniline (about 5-6 ml), then 1
gr of 4A Molecular Sieves is added. The mix is really gently stirred (so that the Molecular
Sieves aren't destroyed by the agitation) with a magnetic stirrer for about 24 h at room
temperature. The reaction mixture from the previous step is filtered from the molecular sieves
which are rinsed with 2×2ml THF, the filtrate and washings are poured into a 50 ml flask,
whereupon 20 ml dry Methanol is added, and the mix is stirred. About 1-1.5 g of Sodium
Borohydride is very slowly added to the mixture at room temperature, and the mix is stirred
for about 2 h. The conversion into ANPP is checked with any method and if not completly
reduced, add slowly another 0.5 g NaBH4 and stir for one more hour. When the conversion
into ANPP is complete (over 95%), evaporate the Methanol and THF under vacuum. The
residual mass consists of aniline, excess NaBH4 and ANPP complexed with borane. Pour 50
ml of water into the flask, then destroy the complex by the slow addition of a small quantity
of concentrated HCl (35%) until pH ~1, then the mix is well stirred for another hour. Now
50ml of a saturated NaCl solution is added to the mixture, and after about 10 min, a solid
mass precipitate. Separate the solid from the liquid with a filtration and keep the solid (this is
ANPP hydrochloride) after washing it with a little saturated NaCl solution. Add another 50ml
of saturated NaCl solution and place the mix in the fridge (at about 2°C) and wait 2-3 h. If
there is more precipitate, filter the solution and add the solid to the first crop. The solid mass
is ANPP which must be treated. Dissolve the solid in about 60ml water and 2N NaOH until
pH > 12.5, then extract with 3×15ml CH2Cl2. Wash the CH2Cl2 phase with 5 ml water, and
evaporate the solvent in vacuum. The residue is an oily yellow-orange liquid which
spontaneously crystallizes, consisting of ANPP pure enough for the next step. The overall
yield of ANPP is about 50-80%. 10 mmol ANPP is dissolved in about 8 ml of dry, pure
pyridine with stirring, and then 12 mmol of propionyl chloride is added dropwise to the
reaction mixture at room temperature. The reaction is exothermic and the temperature should
be controlled by carefully adjusting the addition rate, and it must be kept between 30-60°C at
all times. When all the propionyl chloride is added, the reaction mixture is stirred for about
one hour at room temperature. Check the conversion with any suitable method (TLC/GC) and
if not complete add another 1 mmol of propionyl chloride. The reaction mix is then poured
into 80 ml water with stirring, and concentrated HCl (~35%) is added dropwise until pH <
1.5. This operation can be done with another procedure as follows: Prepare 80 ml of 2N HCl
and simply pour the reaction mix into this solution. This results in the pyridine and the
Fentanyl turning into their respective hydrochloride salts. The solution is then stirred for
about 30 min. Pyridine·HCl is not soluble in CH2Cl2, while the nonpolar Fentanyl·HCl is.
Extract the solution with 3×20ml of CH2Cl2, then wash the pooled organic extracts with
2×10ml saturated NaCl solution. The solvent is evaporated under vacuum, and a yellow mass
is formed which consists of Fentanyl hydrochloride contaminated with a small quantity of
propionanilide, which was formed by the action of propionyl chloride on residual aniline from
step A. 10-15 mL acetone is now added, and a white powder forms, which is Fentanyl·HCl.
Filter the solid and wash it with a small quantity (2×3 mL) of acetone. The Fentanyl
Hydrochloride is now pure enough for use (>99.5%), the yield of this step exceeding 90%. If
it would still be impure it can be purified by recyrstallisation from hot acetone. Para-Fluoro-
Fentanyl can be synthetised with this procedure using Para-Fluoro-Aniline instead of plain
Aniline, but the purification process must be adapted. The very powerful Alpha-Methyl-
Fentanyl can also be synthetised with this method using N-(2-Phenylpropyl)-Piperidinone
which can be synthetised from 1-Phenyl-2-Bromopropane and Piperidinone or other methods.
The 1-Phenyl-2-Bromopropane is used in the underground manufacture of Amphetamine, and
the procedure of the synthesis of this compound can be easily adapted for the creation of N-
(2-Phenylpropyl)-Piperidinone or the NPP (N-Phenethyl- Piperidinone).

Fentanyl is not used as such but rather the Fentanyldihydrogencitrate. This has more
application possibilities: On the one hand as intravenous therapy as anaesthetic, as
transdermal patch, on the other hand as lozenge. Since short time there is Fentanyl nasal spray
and Fentanyl lozenges. The analgesic is mostly used perioperational, thus bevor, during and
after an operation, because of its painkilling and soothing values. As plaster it is used by
strong and mainly chronic pains, mostly by cancer patients. Fentanyl patches are
manufactured in five patch sizes: 12.5 micrograms/hour, 25 µg/h, 50 µg/h, 75 µg/h, and
100 µg/h. Dosage is based on the size of the patch, since the transdermal absorption rate is
generally constant at a constant skin temperature. Fentanyl lozenges (Actiq) are a solid
formulation of fentanyl citrate on a stick in the form of a lollipop that dissolves slowly in the
mouth for transmucosal absorption. These lozenges are intended for opioid-tolerant
individuals and are effective in treating breakthrough cancer pain. It is most effective when
the lozenge is consumed in 15 minutes. Fentanyl lozenges are available in six dosages, from
200 to 1600 µg in 200 µg increments (excluding 1000 µg and 1400 µg). Because Fentanyl
shows a hundred-times higher value as morphine to that effect there are low doses of the
analgesic necessarily. Furthermore Fentanyl has a fundamental higher effectivity but his
duration of effect is in comparison to morphine shorter. The half-value period lies between 5-
10 minutes. The widespread use of Fentanyl triggered the production of Fentanyl citrate
(Fentanyl combined with citrate at a 1:1 ratio), which entered the clinical practice as a general
anaesthetic under the trade name Sublimaze in the 1960s. Through the delivery method of
transdermal patches, Fentanyl is currently the most widely used synthetic opioid in clinical
practice, with several new delivery methods currently in development.

As said, Fentanyl was first synthesized by Paul Janssen under the label of his relatively newly
formed Janssen Pharmaceutica in 1959. In the 1960s, fentanyl was introduced as an
intravenous anesthetic under the trade name of Sublimaze. In the mid-1990s, Janssen
Pharmaceutica developed and introduced into clinical trials the Duragesic patch, which is a
formation of an inert alcohol gel infused with select fentanyl doses which are worn to provide
constant administration of the opioid over a period of 48 to 72 hours. After a set of successful
clinical trials, Duragesic fentanyl patches were introduced into the medical practice.

Fentanyl is quite lipophilic and it disperses fast in aliphatic tissue. It is mainly metabolized in
the liver and only 10% are eliminated trough kidney. Because of this lipophilicity Fentanyl is
incorporated with difficulty controllably in adipic. That is why Fentanyl is avoided and
similar substances like Alfentanil, Remifentanil, Carfentanil, Lofentanil and Sulfentanil are
used. United States Air Force Pararescue uses lollipops with the powerful painkiller fentanyl,
also the Royal Danish Army does. In addict to dose there can be adverse reactions, which are
similar to those of morphine. It impacts the perceptive faculty, works calming, heads to
clouding of consciousness and sleep-similarly conditions. Further adverse reactions are
retarded heart action, constricted pupils, occlusion, vomitus, sickness, euphoria and anxiety
state, which can head to bipolar disorder, lightheadedness or fainting spells, redness,
blistering, peeling or loosening of the skin, including inside the mouth, problems with
balance, talking, walking, trouble passing urine or change in the amount of urine and unusual
bleeding or bruising. Too high doses influence the respiratory centre and can lead to
hyperventilation. As consequence of this there will be coma or death. Therefore a constant
observation with a possible airway is needed. Sole exceptions are patients which use
Fentanyl-containing plasters. The constant effect and in comparison to anaesthetic used lower
doses are making a permanent observation unnecessarily. Fentanyl also increases the effects
of benzodiazepines such as diazepam (Valium) and Alprazolam (Xanax) and central nervous
system depressants such as opiates, barbiturates, tranquilizers and tricyclic antidepressants.
Fentanyl taken concurrently with Amiodarone (Cordarone) may result in heart (cardiac)
toxicity, Clonidine (Catapres, others) may result in greater than expected Fentanyl effects.
The Fentanyl dose may need to be decreased if these medicines are to be combined; MAO
inhibitors may worsen the lowering of blood pressure and depression of breathing seen with
Fentanyl, Rifabutin (Mycobutin) may decrease pain control by Fentanyl, Ritonavir (Norvir)
and perhaps other protease inhibitors can lead to major Fentanyl toxicity, Sibutramine
(Meridia) may increase risk of serotonin syndrome and Sildenafil (Viagra) may lead to
changes in Sildenafil or in Fentanyl levels. A number of emotional side effects, some quite
serious, can be caused by Fentanyl. Severe emotional side effects that usually require a
doctor's intervention include hallucinations or hearing voices, and depression that includes
suicidal thoughts. Other possible side effects include milder depression, nervousness,
depression and confusion. Fentanyl dosages very widely based upon the reason for the pain,
the duration of usage and the tolerance the patient may have to pain medications. Fentanyl is a
very potent pain medication, therefore, many patients will not qualify for the Fentanyl patch
or Actiq lollipops as they only appropriate for patients with a tolerance for Fentanyl or other
opioid pain medications.

Fentanyl takes effect as an agonist at the µ-opioid-receptors. It leads to gradual reduction of

Fentanyl is also misused, for example to elongate drugs like heroine. This is though not often
a case, because it is hard to get and so it can not get in circulation. Nevertheless there are such
cases: In April and May 2006 in the United States were several intoxications because of
Fentanyl, where some of the concerned persons came to death. In those cases Fentanyl was
produced illegal. This progression went on, so that between 2005 and 2007 over 1000 death
people were registered, mainly people in Chicago, Philadelphia and Detroit. Beside the use as
drug and in medicine Fentanyl and its derivatives are misused as warfare agent. In doing so,
Carfentanyl, a derivative, is used as aerosol, by what people come to death. Carfentanyl is
5000-7500 times higher effective as morphine, according to this more effective than Fentanyl.
On 26th October 2002 Russian special forces used Carfentanyl to end the siege of the theatre
building in Moscow where Chechen separatists have been holding hundreds of hostages. At
least 119 civilians died in the storming of the theatre, where about 50 armed Chechens were
holding almost 800 people hostage, with 245 hospitalized. By insertion of a methyl-group
1979 there was synthesized a designer-drug, Methylfentanyl. It is called “China White” in
scene-jargon (Apache, China Girl, Dance Fever, Friend, Goodfella, Jackpot, Murder 8, TNT,
as well as Tango and Cash are further names) and has a higher effect as Fentanyl, so it can
come to death if it is used in wrong dose. In October 2007 a man in Darmstadt died of mixture
consumption of alcohol and Fentanyl, after he synthesised the analgesic in his own laboratory
himself and illegal. Furthermore drug addicts cut the plasters in little pieces suck them or cock
them, so that they can get Fentanyl in a purer form. There were also studied more derivatives
like 3-Methylthiofentanyl, 3-methylfentanyl, Acetyl-Alpha-methylfentanyl, Alpha-
methylthiofentanyl, Beta-hydroxy-3-methylfentanyl, Thiofentanyl and the p-fluorofentanyl,
which hat up to date the highest effect of the Fentanylderivatives. However the cis(+) form of
3-methyl fentanyl was 6 684 times more potent and the trans(±) form approximately 500
times more potent than morphine. Because of its effect Fentanyl falls under the controlled
substances legislation in Germany and the Swiss. In Germany Fentanyl is selled under the
names: Abstral, Actiq, Durogesic, Effentora, Fentadolon and Matrifen.

Quellen: http://fentanyl.de/
http://www.nn-online.de/artikel.asp?art=1177533&kat=10
http://en.wikipedia.org/wiki/Fentanyl; http://de.wikipedia.org/wiki/Fentanyl
http://designer-drug.com/pte/12.162.180.114/dcd/chemistry/fentanyl.html
http://chemipedia.org/mediawiki/index.php/Fentanyl
http://www.nida.nih.gov/drugpages/fentanyl.html
http://www.answers.com/topic/fentanyl
http://www.herbs2000.com/medica/fentanyl.htm
http://www.emcdda.europa.eu/publications/drug-profiles/fentanyl