CLINICAL TOXICOLOGY 9(4), pp.

553- 560 ( 1976)

Illicit Synthesis of Phencyclidine(PCP)

and Several of Its Analogs
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A. T. SHULGIN, Ph.D.

Lafayette, California

D. E. MAC LEAN

Los Angeles, California

The original chemistry laying the groundwork for the preparation

of phencyclidine (PCP, 1)was a study reported in 1926 describing

the reaction of 1-piperidinocyclohexanecarbonitrile (PCC, 2) with

Grignard reagents [ 11. It was not until some 30 years later that the
anesthetic effectiveness of ( 1) was observed in animals [2], and the
compound was made a v a i l a b 6 by P a r k e Davis and Co. under the
name of Sernyl ((21-395) f o r clinical investigation in man.
The first surgical studies described the development of complete
analgesia within a few minutes following intravenous administration

553
 554 SHULGIN AND MAC LEAN

of approximately 20 mg, but at the higher dosages required for surgi-

cal anesthesia (some 4 X this amount) there was observed an excited
state which required supplementary pentobarbital for control [3].
Other early observers of P C P use in clinical anesthesia had reported
related undesirable side reactions, both during the operative state as
well a s in recovery. Johnstone et al. [4] made comment concerning
the patient's volunteering of information suggesting experiences of
trance-like ecstatic states and, upon emergence a euphoria accom-
panied by hallucinations and visual distortions. Similarly, Riffin
reported post-operative side reactions including dizziness, s l u r r e d
speech, and manic behavior [ 51.
It was this constellation of consistent and undesirable properties
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of the drug that prompted its removal from clinical use in 1965, and
which most certainly fostered and supported i t s subsequent s t r e e t
acceptance. It was widely distributed and used in San Francisco as
"Peace Pill'' and lIHogt' in 1967 ("Peace Pill" was derived by the
pronouncing of the consonants PCP, themselves an abbreviation of
the complete chemical name for (A), phenyl-cyclohexyl-piperidine).
Since that time the drug has been consistently available, both under
i t s own name a s well a s with misrepresentation as any of a number
of other drugs which might enjoy momentary popularity.
The published preparations of P C P and its analogs may be con-
sidered in three groups: those which employ the nitrile (2), those
which depend upon the formation of a Schiffs' base a s an fitermedi-
ate, and those which invoke an enamine compound. The most impor-
tant and most frequently used route to P C P and t o its analogs which
maintain a cyclic amine function, exploit the facile displacement of
the nitrile group from the intermediate ( 3 ) with an aryl Grignard re-
agent [6]. This method is completely general f o r cyclic secondary

amines (as piperidine and C-alkylpiperidines, pyrollidine and C-

alkylpyrollidines, morpholine, and methylpiperazine) and aromatic
Grignard reactants (as phenyl, halophenyl, tolyl, anisyl, trifluoro-
tolyl, and thienyl) [6, 71.
The intermediate cyclohexanecarbonitrile can be prepared from
the bisulfite addition product of cyclohexanone by treatment with
KCN and piperidine [6], o r by the addition of cyclohexanone and
 ILLICIT SYNTHESIS 555
KCN to an aqueous solution of piperidine hydrochloride [7]. Both
procedures give excellent yields. The Grignard reaction is conven-
tional, being worked up either with HBr o r NH4C1. The use of phenyl
lithium in place of phenyl magnesium bromide results in addition to
the nitrile rather than in its displacement. Efforts to prepare the
cyclopentyl homolog (4)of P C P employing this procedure also failed
with phenyl lithium [ 8 r a n d this compound could only be made by the
construction of the piperidine ring from the primary amine (- 5 ) with
pentamethylene bromide [7].
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Analogs of P C P with a mono-substituent on the nitrogen are best

prepared through the Schiffs’ base intermediate (-6 ) formed from cyclo-
hexanone and the appropriate primary amine [6]. The introduction of
the phenyl group can be achieved with phenyl lithium. The N,N-dialkyl
derivatives are easily prepared from their monoalkyl counterparts by
methylation o r ethylation via N-formylation o r N-acetylation and re-
duction with lithium aluminum hydride [6]. In addition, the free amino
compound (- 7 ) can be employed for the synthesis of either mono- o r

(2)
(Cyclohexalarnine, CI-401)

dialkyl products; amide formation followed by reduction yields mono-

alkyl isomers, and reductive methylation (with formaldehyde and
formic acid) will provide dimethylation “71. If the Schiffs’ bases a r e
reacted with an alkyl halide, a quaternary salt results, and this,
upon reaction with phenyl lithium, will provide a mixed N,N-dialkyl
analog of PCP.
 556 SHULGIN AND MAC LEAN
Yet another scheme is known for the synthesis of this class of
compounds. An enamine is prepared by the dehydration of equimolar
quantities of piperidine and cyclohexanone. The addition of anhydrous
p-toluene sulfonic acid o r of hydrogen bromide to this system produces
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an adduct from which PCP can be obtained by displacement with a

Grignard reagent [9],
The majority of the illicitly synthesized PCP is prepared accord-
ing to the general directions of Kalir et al. [7], modified in details a s
required by the availability of chemicals and equipment. A typical
batch operation will be on a 3- to 5-mole scale, and is usually limited
by the amount of piperidine to be used (usually a maximum of 500 gm).
Of all the reagents needed in this preparation, t h i s last is the most
difficult to obtain and can command a s much a s $lOOO/kg for a clean
bottle (i.e., one which is not watched o r traceable). The procedure
given in Ref. [7] for the preparation of PCC (2) is followed religiously,
except that if the product does not crystallize spontaneously after over-
night standing the reaction mixture is extracted either with benzene o r
with white gasoline, which is then dried with an appropriate anhydrous
salt before evaporation. The most common choices a r e sodium sul-
fate, calcium chloride, and potassium carbonate.
The Grignard reagent employed in the second half of the reaction
(phenyl magnesium bromide) is inevitably prepared within the labora-
tory, a s it is felt that commercially prepared material is carefully
watched. Phenyl bromide is used, ether is the invariable solvent, and
elemental iodine is popular for initiating the reaction. The isolated
nitrile is usually dissolved in white gasoline for addition to the formed
Grignard solution, and the latter is always used in excess of stoichio-
metric requirements. A 1.25 to 1 ratio is minimum, but if the Grig-
nard can be used in an excess of 2 to 1, the yield of the final product
can be a s high a s 65%, based upon the amount of piperidine employed.
The workup is a s described in Ref. [7], except for the usual use of
white gasoline in place of ether for extraction purposes. The product
is converted to the hydrochloride salt either by the addition of a
calculated amount of concentrated aqueous HC1 followed by air evapor-
ation, o r by the passage of anhydrous HC1 into an ether solution of the
base. Recently the free base itself has appeared on the street.
 ILLICIT SYNTHESIS 557

In neither of these two work-ups is unreacted nitrile ( 2 ) satisfac-

torily removed, and its unexpected toxicity can have serious conse-
quences both to the synthetic chemist and to the eventual user. These
points a r e discussed below.
Of the many analogs of P C P which have been chemically prepared
and described, a s of the present time only a few a r e known to have
appeared in illicit street use. The thiophene analog T C P (8) was
f i r s t identified by the San Francisco Drug Enforcement Administration
laboratory in 1972 [lo]. In the illicit synthesis of TCP the precursor
2-bromothiophene is the limiting reagent (both a s to expense and
availability). Although the product is somewhat more potent than
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PCP, it is sold 1:l on a weight basis. Abuse of this isomer spread

quickly and widely, and it was entered into Schedule I of the Controlled
Substances Act in July, 1975 [ll].
The N-ethyl analog of P C P (9, PCE, cyclohexamine, CI-400 of
P a r k e Davis and Co.) first appeared in the Los Angeles a r e a about
1969. The initial samples were a wet yellow to brown gum, and were
sold and accepted as PCP. The average dose was somewhat s m a l l e r
than PCP, however, suggesting a higher human potency. This is in
keeping with reported animal data [7]. By 1971 this drug was avail-
able as a white solid, superficially indistinguishable from P C P hydro-
chloride; at no time was it identified other than a s PCP. A single
report in 1970 mentions the discovery of a clandestine laboratory
presumably synthesizing this isomer [ 121.

Another early substitute for P C P was the pyrollidine homolog

(10). Although both mouse and primate screening have shown this
compound to be quantitatively and qualitatively similar to P C P [7],
it was found in s t r e e t use to cause a barbiturate-like sedation, and
it was not accepted. A recent report [ 131 mentions this compound
as having appeared in New Jersey, dispersed on vegetable matter
intended to be smoked. Neither the N-ethyl nor the pyrollidine
analogs of P C P are presently recognized in the Controlled Sub-
stances Act schedules.
Considering the usual methods employed in illicit manufacture
of P C P o r closely related analogs, a general picture can be drawn
of the variety of chemicals that might, taken together, suggest such
 558 SHULGIN AND MAC LEAN

purpose. At least one chemical from each of five chemical groups

must be represented, as well as the more usual chemical accessories
such as solvents and drying agents.
1. An aliphatic amine: examples would be piperidine, ethyl amine,
pyrollidine, morpholine, N-methyl piperazine.
2. An aliphatic ketone: cyclohexanone.
3. An aromatic halide: examples would be bromobenzene, bromo-
anisole, bromotoluene, bromothiophene.
4. A leaving group intermediate: examples would be potassium
cyanide, anhydrous hydrogen bromide, p-toluene sulfonic acid.
5. A metal: magnesium o r lithium.
As both the intermediate nitrile PCC ( 2 ) and the final product
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(such a s PCP) have similar basicity and solution properties, any in-
complete conversion will result in a product containing varying amounts
of PCC as a contaminant. This chemical may well be implicated in the
toxic complications associated with P C P use [ 141. Immense care is
taken during illicit manufacture at the stage where this intermediate
is collected and dried, more even than in the handling of the final prod-
uct. Chronic exposure to this compound has led to an aggravated psy-
chotic condition that has resulted in a protracted hypersensitivity to
the chemical, a s shown by skin-patch assay [15]. The extent of con-
tamination of P C P with this intermediate is difficult to determine, a s
most analytical schemes (GLC, TLC) appear to promote its decompo-
sition. A technique has recently been developed allowing estimation
of PCC in P C P and T C P [16]. A major laboratory, which has had ex-
tensive experience in the analysis of s t r e e t drugs, has found that in
all samples submitted for analysis which proved to be PCP, approxi-
mately 20% contained detectable amounts of PCC [17].
There is a defensive value in briefly reviewing the published
scientific literature that exists concerning related compounds, for it
may well be from these papers that clues can be obtained concerning
tomorrow' s pharmacologic and analytic problems. In the references
already cited, there are literally dozens of analogs described, both
chemically and pharmacologically. Implicit in the generalized direc-
tions are dozens more, many of which may reasonably be predicted
to be of similar pharmacology. A host of analogs with the aromatic
ring replaced with other functions such as benzyl, vinyl, allyl, acetyl-
enyl, and cyan0 groups have been studied as anticholinergic agents,
and appear to be similar in potency [18-201. A related class of com-
pounds that has already been clinically established as being pharma-
cologically equivalent to PCP, can be illustrated by the structure of
ketamine (11). Although somewhat less potent than PCP, it produces
at effectiveToses a depersonalization and intoxication state which,
through word of mouth, is being touted as being superior to that pro-
duced by PCP. The thiophene analog of ketamine, tiletamine (12),
is currently also in clinical study, and a large number of r e l a t a ana-
logs have been prepared.
There must also be considered the continuing flood of new com-
 ILLICIT SYNTHESIS 559

(11) (12)
(ketamine, CI-581) (tiletamine, CI-634)

pounds in the literature, chemicals which are less closely related in

structure, but which a r e described a s producing sensory disturbances,
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disorientation, and related symptoms. An arbi t rary single example of

such a compound is (13) [21]. Although such dysphoric properties are
considered a s undesirable s i de reactions and reason f o r the discontin-
uation of study of a given drug, these very properties are the ones that
attract the attention of those individuals who a r e the advocates of this
form of drug abuse. The pharmacologic literature is avidly followed,
and there a r e , apparently, an unending line of experimental subjects
who, knowingly o r unknowingly, can be called upon to determine the
properties of an unknown drug,

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