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 (Будь ласка, Увійти або Реєстрація щоб переглянути вміст URL-адреси!). The general outline of this reaction is shown in Scheme 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 (Будь ласка, Увійти або Реєстрація щоб переглянути вміст URL-адреси!).
This route is generally applicable to analogs that contain a cyclic amine (such as piperidine, C-alky piperidines, pyrrolidine, C-alky pyrrolidines, morpholine and N-methylpiperazine), 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 (Будь ласка, Увійти або Реєстрація щоб переглянути вміст URL-адреси!). 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.
Scheme I, step 1. Synthesis of PCC:
Synthesis of PCC, method 1:Pyrrolidine can be substituted for piperidine in either of the two following methods for synthesis of PCC in order to make PCPy, the pyrrolidine analog of PCP. The only difference is that the nitrile product (pyrrolidinyl-cyclohexyl-carbonitrile) does not crystallize as readily as PCC does from the reaction mixtue. If the nitrile does not crystallize after 24 hr., it is extracted with hexanes, dried with sodium sulfate, and evaporated to give the crystalline product, or the dry hexanes solution can used directly in the next step for addition to the grignard reagent.
Synthesis of PCC, Method 2:The first method involves reacting cyclohexanone with the hydrochloride salt of piperidine and aqueous NaCN or KCN (Будь ласка, Увійти або Реєстрація щоб переглянути вміст URL-адреси!) . This is the most direct method, and is the one most commonly used in clandestine labs. Although it has not been reported, there appears to be some danger of evolving deadly HCN gas when following this procedure. To reduce this danger, the reaction should be done with very good ventilation, and the amount of acid carefully regulated so that the solution is in the correct pH range. If the solution becomes too acidic, the danger of 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.
The second method of PCC synthesis involves the addition of cyclohexanone to an aqueous solution of sodium bisulfite (NaHSO3), producing the bisulfite adduct. Addition of KCN or NaCN results in formation of PCC (Будь ласка, Увійти або Реєстрація щоб переглянути вміст URL-адреси!). This method is very easy and avoids the possibility of HCN evolution.
Procedure: 12.6g of sodium bisulfite is dissolved in 42 mL of H2O. 10.6 g of cyclohexanone is added with vigorous stirring. The bisulfite adduct forms immediately as a thick white slurry. The slurry is then cooled with an ice bath, and a solution of 7.86g KCN and 9.48 g piperidine is added. After stirring overnight at room temperature followed by cooling in an ice bath, the PCC will crystallize. The product is then filtered off, washed with water, and dried (in vacuo at 30 C if possible) to give 10.9 grams (86.6%) of material, mp 70-71.5 C, bp 118 C (2.5 mm Hg). Distillation is not recommended or necessary. If the PCC fails to crystallize, it can be extracted with solvent and dried, as above.
Scheme I, step 2. Reaction of PCC to give PCP:
In the last step of the traditional synthesis, a Grignard reagent (phenyl magnesium bromide) is formed by the interaction of bromobenzene and Magnesium metal. The PCC from the preceding step is then reacted with the Grignard reagent to produce the final compound. The most important factor for success of this reaction is total dryness. All of the glassware and chemicals used must be absolutely dry. The 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.
Basic preparation of 1-phenylcyclohexylpiperidine (PCP) via nitrile method:
Notes on Scheme I:Procedure: A solution of 39 g (0.203 mole) of PCC is prepared in 50:50 ether:benzene (or better solvents such as THF, hexanes/ether, or toluene/ether. This is added slowly to phenyl magnesium bromide prepared from 79 g (57 ml, 0.53 mole) of bromobenzene and 12.3 g (0.505 mole) of Mg turnings in 200 ml of dry ether. The mixture is then heated and stirred for 3 hrs and cooled. After cooling, 175 ml (0.7 equivalents) of 4 N aqueous HBr is slowly added , followed by overnight cooling in a refrigerator. Precipitated PCP hydrombromide is filtered off, air-dried, and dissolved in a minimum amount of hot ethanol. The hot solution is basified with ethanolic NaOH, which deposits a heavy yellow oil tht quickly crystallizes. After cooling, crystals of PCP base with minor amounts of inorganics are filtered off, dried and dissolved in benzene (or toluene). One third of the benzene is distilled off to remove water from the solution via azeotropic drying. After the solution has cooled, it is diluted with 2 volumes of dry ether. Saturation with dry HCl deposits PCP hydrochloride, which is filtered off to yield about 40 g (70%), mp 243-244 C.
The physical properties of the pyrrolidine analog (PCPy) prepared by ths method are bp 114-123 C at 0.14 mm, and mp 44-45 C after recrystallization from isooctane. The mp of the hydrochloride salt is 235-237 C.
Notes on reaction of PCC and the Grignard reagent:Formation of the Grignard reagent: The reaction is most conveniently carried out in a two-neck flask, but a single necked flask will work. Magnesium shavings and a magnetic stirbar are introduced into a previously dried round bottom flask. The flask is then held over a gas flame and rotated until the magnesium is quite hot. This will remove any water from its surface. A condenser and drying tube are attached to the flask and it is allowed to cool. In a second flask, bromobenzene (or equimolar amount of chlorobenzene) is mixed with THF or ether and poured into an addition funnel. 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, and the cooling water to the condenser is turned on. If the reaction does not begin within 10 min., steps are taken to initiate it (Note 1). The start of the reaction is apparent by the presence of bubbles, a grayish precipitate forming, and the solvent beginning to reflux.
Once the reaction is progressing smoothly, the ether/bromobenzene is added slowly at a rate sufficient to maintain reflux without external heating. After it has all been added, the flask is gently heated at reflux until almost all of the magnesium has disappeared.
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:
- A dry glass rod is inserted into the neck of the flask and used to crush some of the Mg chips against the bottom.
- 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.
- Stirring is stopped, a TINY crystal of Iodine is added to the flask, and the reaction allowed to stand until it starts.
- 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 quenching the reaction and isolating the final compound: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 (Будь ласка, Увійти або Реєстрація щоб переглянути вміст URL-адреси!). Primary amino analogs of PCC, such as N-ethylamino cyclohexanecarbonitrile will produce the desired PCP analogs by reaction with 3 moles of phenyllithium (Будь ласка, Увійти або Реєстрація щоб переглянути вміст URL-адреси!).
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 clandestine labs is to add the calculated amount of concentrated HCl followed by evaporation to yield the salt.
Method 2: Aqueous HBr can also be used to hydrolyze the reaction mixture. This method is illustrated above. It has the distinct advantage of allowing the separation of any unreacted PCC. It also avoids the possibility of troublesome emulsions from precipitated magnesium salts during workup. However, it may be less suitable if THF has been used as the solvent for the Grignard reaction. In this case, the THF may dissolve some of the PCP hydrobromide and reduce yields. Also, the HBr salt of PCP can be extracted from the quenched reaction mixture with chloroform.
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, followed by purification via acid/base extraction. This method has been used in large low tech clandestine PCP labs.
