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Review of synthetic methods

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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:

with a difficulty rating of 2 out of 10. The PCC intermediate can be synthesized through several routes. A typical clandestine batch operation might be run on a 3 to 5 molar scale. and a hazard rating of 4 out of 10 (ref. 64).The most commonly used method for PCP production in clandestine labs is based on the Bruylants reaction. and reaction of this intermediate with a grignard reagent. 4). The general outline of this reaction is shown inScheme I. . two of which are illustrated here. This route has an overall yield of ~60%. that is displacement of an alpha-amino nitrile by an organometallic reagent (ref. There are two steps: preparation of a nitrile intermediate (PCC). and is usually limited by the amount of piperidine to be employed (usually a maximum of 500 gm).

in one study up to 20% of street samples of PCP contained measurable amounts of PCC. It is also somewhat difficult to separate from the final product if the reaction is not carried out to completion. 11). Handling of the material may also cause dizziness. method 1: The first method involves reacting cyclohexanone with the hydrochloride salt of piperidine and aqueous NaCN or KCN (ref 11) . the reaction should be done with very good ventilation. Although it has not been reported. dried with sodium sulfate. halophenyl. and evaporated to give the crystalline product. Larger amounts cause more severe symptoms. and use of the bisulfite adduct of cyclohexanone. the danger of . The only difference is that the nitrile product (pyrrolidinyl-cyclohexyl-carbonitrile) does not crystallize as readily as PCC does from the reaction mixtue. C-alky piperidines. Ingestion of PCC in small amounts can cause toxic symptoms. and the amount of acid carefully regulated so that the solution is in the correct pH range. and thienyl). C-alky pyrrolidines. pyrrolidine. Synthesis of PCC: Pyrrolidine can be substituted for piperidine in either of the two following methods for synthesis of PCC in order to make PCPy. and is the one most commonly used in clandestine labs. Thus. toluyl. and vomiting. it is extracted with hexanes. 10. the pyrrolidine analog of PCP. This is the most direct method. step 1. It should be born in mind that the PCC intermediate is toxic. such as headache and hangover. If the nitrile does not crystallize after 24 hr. anisyl. Additionally. morpholine and Nmethylpiperazine). faintness. trifluorotoluyl.. repeated exposure to PCC may cause an aggravated psychosis and result in sensitization. Scheme I. in which an individual may experience contact dermatitis from trace amounts of the substance.This route is generally applicable to analogs that contain a cyclic amine (such as piperidine. or the dry hexanes solution can used directly in the next step for addition to the grignard reagent. there appears to be some danger of evolving deadly HCN gas when following this procedure. It also has been applied successfully to non-cyclic secondary and primary amines such as dimethylamine and ethylamine (ref. If the solution becomes too acidic. and is also generally applicable for aromatic Grignard reagents (phenyl. There are two equally acceptable methods for preparation of the PCC intermediate: use of the hydrochloride salt of piperidine. To reduce this danger. 7. Synthesis of PCC.

and the pH is adjusted to 3-4.6 g of cyclohexanone is added with vigorous stirring. the PCC will crystallize. After 2 hr.0 mole) of KCN in 150 ml of H2O (or 116 ml of 40% aqueous NaCN) without external cooling but with efficient stirring. washed with water. The product is then filtered off. The PCC from the preceding step is then reacted with the Grignard reagent to produce the final compound. 85 g (99 ml. All of the glassware and chemicals used must be absolutely dry. as above. a Grignard reagent (phenyl magnesium bromide) is formed by the interaction of bromobenzene and Magnesium metal. Method 2: The second method of PCC synthesis involves the addition of cyclohexanone to an aqueous solution of sodium bisulfite (NaHSO3). This solution of PCC in solvent may now be used directly in the next step for addition to the phenyl magnesium bromide. mp 70-71. step 2. 98 g (104 ml. HCl and 200 g of ice-water. producing the bisulfite adduct. After the solution has been allowed to stand overnight.9 grams (86. Reaction of PCC to give PCP: In the last step of the traditional synthesis. and dry the solution by the addition of an anhydrous salt such as magnesium sulfate. The slurry is then cooled with an ice bath. 1 mole) is carefully mixed with 84 ml of conc.6%) of material. Procedure: 12. washed with cold water and dried. Addition of KCN or NaCN results in formation of PCC (ref. Distillation is not recommended or necessary. and a solution of 7. To this solution. The bisulfite adduct forms immediately as a thick white slurry. 10. The yield of PCC sufficiently pure for the next step is 169-182 g. If the PCC has not crystallized after standing overnight. or potassium carbonate. If the PCC fails to crystallize. bp 118 C (2. followed by 68 g (1.HCN evolution will increase.6g of sodium bisulfite is dissolved in 42 mL of H2O. Procedure: Piperidine. The .48 g piperidine is added. 1 mole) of cyclohexanone is added. 10). This method is very easy and avoids the possibility of HCN evolution. Scheme I.5 mm Hg).86g KCN and 9. the solution is allowed to stand overnight. The most important factor for success of this reaction is total dryness. it can be extracted with solvent and dried. the common procedure in clandestine labs is to extract the solution with white gasoline (Coleman's fuel) or benzene. After stirring overnight at room temperature followed by cooling in an ice bath. the crystalline precipitate is collected. the PCC will generally crystallize in beautiful ice-like forms. Synthesis of PCC.5 C. (88-95%) mp 63-68 C. calcium chloride. and dried (in vacuo at 30 C if possible) to give 10.

dried and dissolved in benzene (or toluene). it is much easier to initiate on larger scale.3 g (0. One third of the benzene is distilled off to remove water from the solution via azeotropic drying. THF is somewhat better for small scale reactions because the reagent forms more readily in it and PCC is soluble in it. 175 ml (0. This is added slowly to phenyl magnesium bromide prepared from 79 g (57 ml. Saturation with dry HCl deposits PCP hydrochloride. The mixture is then heated and stirred for 3 hrs and cooled. In this case. which is filtered off to yield about 40 g (70%). mp 243-244 C. or toluene/ether. Notes on Scheme I: . After cooling.glassware can be conveniently dried by baking it in an oven for some time before use.505 mole) of Mg turnings in 200 ml of dry ether. which deposits a heavy yellow oil tht quickly crystallizes. crystals of PCP base with minor amounts of inorganics are filtered off. followed by overnight cooling in a refrigerator.53 mole) of bromobenzene and 12. it is diluted with 2 volumes of dry ether. The mp of the hydrochloride salt is 235-237 C. Although formation of the Grignard reagent is powerfully inhibited by traces of water on the scale normally encountered in an experimental laboratory. there seems to be a critical mass in regards to initiation of the reaction. in production-sized clandestine operations. The physical properties of the pyrrolidine analog (PCPy) prepared by ths method are bp 114-123 C at 0. whereas it is almost entirely insoluble in ether. and 2-methoxy bromobenzene results in 2-methoxy PCP. For instance. The hot solution is basified with ethanolic NaOH. hexanes/ether. Various analogs of PCP can be synthesized by this method by substituting another aryl halide for bromobenzene. After the solution has cooled. the entire reaction has been carried out in plastic garbage cans without any great care being taken to ensure dryness. Basic preparation of 1-phenylcyclohexylpiperidine (PCP) via nitrile method: Procedure: A solution of 39 g (0. Precipitated PCP hydrombromide is filtered off. After cooling. air-dried.7 equivalents) of 4 N aqueous HBr is slowly added . 0.14 mm. use of 2-bromothiophene results in TCP. and mp 44-45 C after recrystallization from isooctane.203 mole) of PCC is prepared in 50:50 ether:benzene (or better solvents such as THF. and dissolved in a minimum amount of hot ethanol. Either anhydrous tetrahydrofuran (THF) or ethyl ether can be used as solvent for this reaction. Thus.

and the reaction allowed to stand until it starts. 3. 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. bromobenzene (or equimolar amount of chlorobenzene) is mixed with THF or ether and poured into an addition funnel. Different techniques used to initiate the reaction: 1. The heat is then removed and the flask is watched for signs of reaction. Note 1. The flask is heated gently until the solvent begins to reflux. The start of the reaction is apparent by the presence of bubbles. Once it is underway.. the flask is gently heated at reflux until almost all of the magnesium has disappeared. Initiation of Grignard reaction: If the reaction does not begin within 10 min. a TINY crystal of Iodine is added to the flask. If the reaction does not begin within 10 min. a grayish precipitate forming. but a single necked flask will work. and possibly ignite. A dishpan full of ice water should be on hand to cool the flask in case this happens. The flask is then held over a gas flame and rotated until the magnesium is quite hot. A condenser and drying tube are attached to the flask and it is allowed to cool.Formation of the Grignard reagent: The reaction is most conveniently carried out in a two-neck flask. Several grams of Mg shavings are added to a flame dried test tube followed by several mL each of ether and bromobenzene. This will remove any water from its surface. 4. there are a number of ways to initiate it. the ether/bromobenzene is added slowly at a rate sufficient to maintain reflux without external heating. It should also be noted that the reagent can react violently with water once formed. A dry glass rod is then inserted into the tube and some of the Mg chips are crushed against its bottom. Otherwise the reaction may suddenly start and become violently out of control. Enough solvent is added to the flask to cover the Mg shavings. Approximately one quarter of the bromobenzene solution is added to the flask with stirring. Magnesium shavings and a magnetic stirbar are introduced into a previously dried round bottom flask. and the cooling water to the condenser is turned on. This small scale reaction should start almost immediately. If the flask were to break inside the water bath. Notes on reaction of PCC and the Grignard reagent: . the contents are poured into the reaction vessel. steps are taken to initiate it (Note 1). the results could be disastrous. Once the reaction is progressing smoothly. Stirring is stopped. and the solvent beginning to reflux. In a second flask. After it has all been added. It is important not to add more bromobenzene until the reaction has begun.

and is the most common one used in clandestine labs. phenyllithium will displace the nitrile group and yield the desired product (ref. One drawback is the potential for formation of troublesome emulsions from the Mg salts precipitated at basic pH during extraction. 10-11). etc. by injection. After the bubbling has stopped and the ice has melted.25 moles of Grignard reagent to 1 mole of PCC is the minimum that should be employed. then the yield of the final product can be as high as 65% based on the amount of piperidine employed. which may crystallize slowly. If the Grignard can be increased to a 2 to1 ratio. Notes on quenching the reaction and isolating the final compound: Method 1: This is the simplest method. which helps avoid formation of an emulsion. This can especially be a problem if ether/benzene was used to dissolve the PCC in the reaction. possibly taking several days to weeks. such as N-ethylamino cyclohexanecarbonitrile will produce the desired PCP analogs by reaction with 3 moles of phenyllithium (ref. If ether is being used. the base is crystallized as the HCl salt. but it is beneficial. The contents of the reaction flask are slowly poured onto the ice/NH4Cl with stirring. For the first extraction. the compound is left as the freebase. The solution of PCC is then added via the addition funnel to the reaction slowly and with stirring. An alternative. A ratio of 1. If the compound is to be administered nasally. and approximately half as much ether is added. If the desired method of administration is smoking.If THF is used for solvent. 32). The combined organic layers are then extracted 3 times with dilute HCl. or orally. the PCC is dissolved in it in a small flask. and the solvent layers are pooled. Several hundred cm3 of crushed ice are placed in a beaker along with ~15 gm of ammonium chloride and 10 ml of ammonium hydroxide. and the product is extracted with organic solvent. naphtha. The ammonium hydroxide can be left out. Suitable solvents are dry hexanes. in the presence of a Lewis acid. benzene. However. toluene. 30. The aqueous layer is extracted two more times with solvent. The HCl salt precipitates. chloroform. Note that use of phenyl lithium instead of phenylmagnesium bromide results in failure via addition to the nitrile rather than displacement. The acid layers are basified with NaOH. a cosolvent will be necessary to dissolve the PCC. the beaker is poured into a separatory funnel along with 30 ml of solvent such as hexanes. Primary amino analogs of PCC. dichloromethane. the funnel is shaken gently. In order to do this the base is dissolved in ether and HCl gas bubbled in. Evaporation of the solvent yields the oily PCP freebase. 31. When it has all been added heat is applied to the flask. which is maintained at reflux for at least 3 hrs. and allowed to dry. or white gasoline (distilled). low tech and dirty method commonly used in . toluene. is washed with ether. White gas is a solvent commonly used in clandestine labs. Enough solvent is added to a flask to dissolve the PCC.

It has the distinct advantage of allowing the separation of any unreacted PCC. the HBr salt of PCP can be extracted from the quenched reaction mixture with chloroform. followed by purification via acid/base extraction. the THF may dissolve some of the PCP hydrobromide and reduce yields. In this case. However. This method is illustrated above. Method 3: The product may also be isolated simply by decantation of the solvent from the reaction mixture followed by addition of concentrated HCl to form the HCl salt. Method 2: Aqueous HBr can also be used to hydrolyze the reaction mixture. it may be less suitable if THF has been used as the solvent for the Grignard reaction. It also avoids the possibility of troublesome emulsions from precipitated magnesium salts during workup. This method has been used in large low tech clandestine PCP labs .clandestine labs is to add the calculated amount of concentrated HCl followed by evaporation to yield the salt. Also.