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The clandestine chemistry of PCP has been previously reviewed in two excellent
articles (ref. 9, 64). In one of these, each method was rated by yield, difficulty, and
hazard on a scale of one to ten (ref 64). These ratings are included in this review at
the beginning of each section, although in some cases they are open to debate.
There are three fairly direct methods for synthesis of PCP and its derivatives: those
employing a nitrile intermediate (Scheme I), those employing an enamine
intermediate (Scheme II), and those employing a imine intermediate (Scheme III).
The method of choice depends on which particular analog is desired, as well as
what reagents are available.
There are five other promising routes to PCP analogs that have appeared in the
literature but not received as much attention by clandestine chemists. Routes IV, V,
and VI yield 1-phenyl-1-cyclohexylamine (PCA), which is an active drug itself,
and can also be used as an intermediate in synthesis of PCP and other more potent
analogs.
Schemes IV and V involve the use of 1-phenyl-1-cyclohexanol (PCOH) as an
intermediate. In Scheme IV, the PCOH is transformed to PCA through an azide
intermediate. In Scheme V, the PCOH is reacted with NaCN and H2SO4 to give Nformyl PCA (Ritter reaction), which can then be hydrolyzed to PCA with acid or
base. The PCOH used for these reactions can be prepared from cyclohexanone and
phenylmagnesium bromide or phenyllithium or obtained commercially.
Another synthesis that used PCA as an intermediate is Scheme VI. This method
starts with phenylacetonitrile, reacts it with 1,5-dibromopentane to give 1-phenyl
cyclohexanecarbonitrile, and hydrolyzes to the nitrile to 1-phenyl
cyclohexanecarboxamide. The amide can then undergo Beckmann rearrangement,
yielding N-formyl PCA, which is hydrolyzed to PCA. The PCA can be alkylated to
PCP with 1,5-dibromopentane as in the previous methods .
Probably the most promising alternative method of synthesis is shown in Scheme
VII. In this method, N-benzoyl piperidine is reacted with the lithium or magnesium
derivative of 1,5-dibromopentane to give PCP in one step.
The final method reviewed here is applicable to analogs in which there is a ketone
group at the 2-position of the cyclohexane ring, and is illustrated for the synthesis
of ketamine.
Scheme I. Overview:
The most commonly used method for PCP production in clandestine labs is based
on the Bruylants reaction, that is displacement of an alpha-amino nitrile by an
organometallic reagent (ref. 4). The general outline of this reaction is shown
inScheme I. There are two steps: preparation of a nitrile intermediate (PCC), and
reaction of this intermediate with a grignard reagent. The PCC intermediate can be
synthesized through several routes, two of which are illustrated here. A typical
clandestine batch operation might be run on a 3 to 5 molar scale, and is usually
limited by the amount of piperidine to be employed (usually a maximum of 500
gm).
This route has an overall yield of ~60%, with a difficulty rating of 2 out of 10, and
a hazard rating of 4 out of 10 (ref. 64).
This route is generally applicable to analogs that contain a cyclic amine (such as
piperidine, C-alky piperidines, pyrrolidine, C-alky pyrrolidines, morpholine and Nmethylpiperazine), and is also generally applicable for aromatic Grignard reagents
(phenyl, halophenyl, toluyl, anisyl, trifluorotoluyl, and thienyl). It also has been
applied successfully to non-cyclic secondary and primary amines such as
dimethylamine and ethylamine (ref. 7, 10, 11). There are two equally acceptable
methods for preparation of the PCC intermediate: use of the hydrochloride salt of
piperidine, and use of the bisulfite adduct of cyclohexanone.
It should be born in mind that the PCC intermediate is toxic. It is also somewhat
difficult to separate from the final product if the reaction is not carried out to
completion. Thus, in one study up to 20% of street samples of PCP contained
measurable amounts of PCC. Ingestion of PCC in small amounts can cause toxic
symptoms, such as headache and hangover. Larger amounts cause more severe
symptoms. Handling of the material may also cause dizziness, faintness, and
vomiting. Additionally, repeated exposure to PCC may cause an aggravated
psychosis and result in sensitization, in which an individual may experience contact
dermatitis from trace amounts of the substance.
HCN evolution will increase. After the solution has been allowed to stand
overnight, the PCC will generally crystallize in beautiful ice-like forms. If the PCC
has not crystallized after standing overnight, the common procedure in clandestine
labs is to extract the solution with white gasoline (Coleman's fuel) or benzene, and
dry the solution by the addition of an anhydrous salt such as magnesium sulfate,
calcium chloride, or potassium carbonate. This solution of PCC in solvent may now
be used directly in the next step for addition to the phenyl magnesium bromide.
Procedure: Piperidine, 85 g (99 ml, 1 mole) is carefully mixed with 84 ml of conc.
HCl and 200 g of ice-water, and the pH is adjusted to 3-4. To this solution, 98 g
(104 ml, 1 mole) of cyclohexanone is added, followed by 68 g (1.0 mole) of KCN
in 150 ml of H2O (or 116 ml of 40% aqueous NaCN) without external cooling but
with efficient stirring. After 2 hr. the solution is allowed to stand overnight, the
crystalline precipitate is collected, washed with cold water and dried. The yield of
PCC sufficiently pure for the next step is 169-182 g. (88-95%) mp 63-68 C.
glassware can be conveniently dried by baking it in an oven for some time before
use. Either anhydrous tetrahydrofuran (THF) or ethyl ether can be used as solvent
for this reaction. THF is somewhat better for small scale reactions because the
reagent forms more readily in it and PCC is soluble in it, whereas it is almost
entirely insoluble in ether.
Although formation of the Grignard reagent is powerfully inhibited by traces of
water on the scale normally encountered in an experimental laboratory, it is much
easier to initiate on larger scale. Thus, in production-sized clandestine operations,
the entire reaction has been carried out in plastic garbage cans without any great
care being taken to ensure dryness. In this case, there seems to be a critical mass in
regards to initiation of the reaction.
Various analogs of PCP can be synthesized by this method by substituting another
aryl halide for bromobenzene. For instance, use of 2-bromothiophene results in
TCP, and 2-methoxy bromobenzene results in 2-methoxy PCP.
Notes on Scheme I:
Note 1. Initiation of Grignard reaction: If the reaction does not begin within 10
min, there are a number of ways to initiate it. It is important not to add more
bromobenzene until the reaction has begun. Otherwise the reaction may suddenly
start and become violently out of control. A dishpan full of ice water should be on
hand to cool the flask in case this happens. It should also be noted that the reagent
can react violently with water once formed, and possibly ignite. If the flask were to
break inside the water bath, the results could be disastrous.
Different techniques used to initiate the reaction:
1. A dry glass rod is inserted into the neck of the flask and used to crush some
of the Mg chips against the bottom.
2. Several grams of Mg shavings are added to a flame dried test tube followed
by several mL each of ether and bromobenzene. A dry glass rod is then
inserted into the tube and some of the Mg chips are crushed against its
bottom. This small scale reaction should start almost immediately. Once it is
underway, the contents are poured into the reaction vessel.
3. Stirring is stopped, a TINY crystal of Iodine is added to the flask, and the
reaction allowed to stand until it starts.
4. The flask is heated gently until the solvent begins to reflux. The heat is then
removed and the flask is watched for signs of reaction.
Notes on reaction of PCC and the Grignard reagent:
If THF is used for solvent, the PCC is dissolved in it in a small flask. If ether is
being used, a cosolvent will be necessary to dissolve the PCC. Suitable solvents are
dry hexanes, toluene, benzene, naphtha, or white gasoline (distilled). White gas is a
solvent commonly used in clandestine labs. A ratio of 1.25 moles of Grignard
reagent to 1 mole of PCC is the minimum that should be employed. If the Grignard
can be increased to a 2 to1 ratio, then the yield of the final product can be as high as
65% based on the amount of piperidine employed.
Enough solvent is added to a flask to dissolve the PCC, and approximately half as
much ether is added. The solution of PCC is then added via the addition funnel to
the reaction slowly and with stirring. When it has all been added heat is applied to
the flask, which is maintained at reflux for at least 3 hrs. Note that use of phenyl
lithium instead of phenylmagnesium bromide results in failure via addition to the
nitrile rather than displacement. However, in the presence of a Lewis acid,
phenyllithium will displace the nitrile group and yield the desired product (ref. 30,
31, 32). Primary amino analogs of PCC, such as N-ethylamino
cyclohexanecarbonitrile will produce the desired PCP analogs by reaction with 3
moles of phenyllithium (ref. 10-11).
Notes on quenching the reaction and isolating the final compound:
Method 1: This is the simplest method, and is the most common one used in
clandestine labs. One drawback is the potential for formation of troublesome
emulsions from the Mg salts precipitated at basic pH during extraction. This can
especially be a problem if ether/benzene was used to dissolve the PCC in the
reaction.
Several hundred cm3 of crushed ice are placed in a beaker along with ~15 gm of
ammonium chloride and 10 ml of ammonium hydroxide. The ammonium
hydroxide can be left out, but it is beneficial. The contents of the reaction flask are
slowly poured onto the ice/NH4Cl with stirring. After the bubbling has stopped and
the ice has melted, the beaker is poured into a separatory funnel along with 30 ml
of solvent such as hexanes, toluene, chloroform, dichloromethane, etc. For the first
extraction, the funnel is shaken gently, which helps avoid formation of an emulsion.
The aqueous layer is extracted two more times with solvent, and the solvent layers
are pooled. The combined organic layers are then extracted 3 times with dilute HCl.
The acid layers are basified with NaOH, and the product is extracted with organic
solvent. Evaporation of the solvent yields the oily PCP freebase, which may
crystallize slowly, possibly taking several days to weeks.
If the desired method of administration is smoking, the compound is left as the
freebase. If the compound is to be administered nasally, by injection, or orally, the
base is crystallized as the HCl salt. In order to do this the base is dissolved in ether
and HCl gas bubbled in. The HCl salt precipitates, is washed with ether, and
allowed to dry. An alternative, low tech and dirty method commonly used in