1 METHODS OF ILLICIT MANUFACTURE Richard Laing John Hugel 4.0 INTRODUCTION Hallucinogenic plants and toxins have been have been exploited throughout the ages. This exploitation has been unparalleled in the twentieth century. From the pharmaceutical industry introducing new therapeutic agents as a treatment for mental illness to the popularity of drug abuse by individuals, the collective knowledge of hallucinogenic drug production has increased tremen- dously in the last 60 years. The dissemination of this knowledge has allowed individuals to cultivate and manufacture hallucinogenic compounds for illicit use. This chapter describes the common syntheses of many classes ofhallucino- gens to provide an overview of illicit manufacturing. 4.0.1 THE ERGOT ALKALOIDS The poisonous properties of ergot, Claviceps, a parasitic fungus common to edible grains, have long plagued civilized humans. Outbreaks of ergot poisoning dubbed Holy Fire or Saint Anthony's Fire have been well docu- mented in ancient cultures. The result of ingestion of the ergot alkaloids included "fire" or burning feeling of the extremities followed by gangrenous infection and blackening of the appendage as if it were consumed by fire.It was not until 1670 that ergot was proved the source of these epidemics which had raged for centuries uncontrolled. Some of ergot's medicinal properties were known prior to it being found as the source of Saint Anthony's Fire. Ergot- infected grain was used as a medicinal herb in aiding the childbirthing process. It was proven effective as an oxytoxic, inducing contractions within the womb, and shortly afterwards it was shown to cause vasoconstriction and in toxic dosages hallucinations and delirium. Its wide use as an oxr..ytoxic in the 1800s led to an increase in the number of stillbirths and in 1824 the Medical Society of New York, after an inquiry into its usage, recommended it be used for post- partum hemorrhage control only. Ergot alkaloids, however, are now 'widely used to control migraine headaches through its action as a cerebral vasocon- stricter, which decreases the amplitude of the pulsation of the cranial arteries. 140 HALLUCI aGE S The three main biogenetically related groups of ergot alkaloids all have a common ergoline moiety (Figure 4.1) (Cordell 1981) : 1. The clavine type (e.g. elymoclavine, argroclavine, and chanoclavine-I). Approximately 32 alkaloids have been characterized and have little use in the pharmaceutical industry. The clavines are characterized by not having a carbonyl functionality anchored at the C-8 carbon and the double bond may either be in the 8,9- position or the 9,10- position. 2. Water soluble lysergic acid derivatives (e.g. ergine (lysergamide), ergonovine) have a carboxylic functionality attached to the C-8 carbon with simple amide groups. 3. Water insoluble lysergic acid derivatives (e.g. ergotamine, ergocornine, and ergocryptine) consist of the largest alkaloids and are sometimes referred as peptide ergot alkaloids because of the resulting production of amino acids upon hydrolysis. For example, the hydrolysis of ergotamine gives lysergic acid, proline, pryruvic acid, and L-phenylalanine. Figure 4.1 Basic structure of the 8 ergoline moiety 13 14 2 A characteristic of the lysergic acid derivatives and peptide alkaloids is the existence of two isomeric forms based on the configuration of the C-8 carbon. The peptide alkaloids exist in nature as both C-8 diastereoisomers with the iso forms (aC-8) having names ending in -inine. (See Figure 4.2.) Figure 4.2 Normal and iso-N-substi- Luted lyse/gic acid METHODS OF ILLICIT MANCFACTURE 141 In the lysergic acid derivative series the native form is physiologically active while the iso diastereoisomer either shows little or no activity. In the synthesis of LSD and other alkylamide derivatives of lysergic acid, some synthetic routes c-L! . favor the production of one form over the other. However, the iso form can easily be converted into the active and desired form by a simple reaction. (See Figure 4.3.) Figure 4.3 Simple conversion of iso- ~_"2'I, LSD to LSD under alkali conditions Alkali [OH)- .. of N N H/ H/ Iso-Lysergic Acid Diethylamide Lysergic Acid Diethylamide 4.1 ILLICIT MANUFACTURE 4.1.1 LSD The synthesis of LSD and related amides oflysergic acid requires the condensa- tion of an organic amine with either the carboxylic acid group of lysergic acid or its derivatized intermediate forming an amide bond. Numerous synthetic -; .he routes can be employed in the formation of this amide bond and many tech- -~)n. niques have evolved with advances in peptide chemistry. Much research into _:C ;50 the discovery of new lysergamides was spurred by the pharmaceutical industry in its search for more effective agents. In order to create an amide the hydroxyl group of the acid functionality must be removed. Since this hydroxyl is a poor leaving group it is either derivatized or converted to a functionality that does make a good leaving group. Compounding this difficulty is the fact that lysergic acid is sensitive to light and oxygen and is highly sensitive to many reagents. The common synthetic routes, Figure 4.4, can be classified based on the type of intermediate compound upon which the alkylamine acts as a nucleo- phile in forming the desired amide bond: azide, mixed anhydride, acid chloride and imidazole intermediates. 142 HALLUCINOGENS Figure 4.4 Trifluoroacetic Anhydride Basic synthetic routes for (Pioch) the manufacture of LSD Azide(Stoll-HotmanL 1 Thionyl Chloride .. Carbonyldimidazole.. - CDI (Kenner & Stedman) (Cerny-Semonsky) Oxalyl Chloride .. (Ziegler-Stuetz) j l Phosgene(PateIIl-Bernard i) Dicyclohexylcarbodiimide Sulfur Trioxide (Garbrecht) Hydroxybenzotriazol - HOST (Losse-Mahlberg) Dicyclohexylcarbodiimide - DCC (Sheehan-Hess) Azide method ,n Stoll and Hofmann published and patented extensively their work at Sandoz Research Laboratories, Basel, Switzerland, in regard to lysergic acid amide derivatives. They first described the condensation of organic amines with lysergic acid azide at low temperature (Stoll and Hofmann, 1937). They found that numerous types of amines reacted well provided that one labile hydrogen was present on the amine. The lysergic acid azide was found to be very stable and could be recrystallized optically pure. The azide resulted from the treatment of the lysergic acid hydrazide, derived by the cleavage of ergotamine using anhydrous hydrazine resulting in a 70% yield with sodium nitrite under acidic conditions (Stoll and Hofmann, 1944). The treatment of ergotamine with hydrazine produces predominantly the iso form. They also described the ill epimerization reaction between the non-active iso form to the active lysergic form by subjecting the iso forms to an alkali environment using sodium or '!II potassium hydroxide (Stoll and Hofmann, 1937). In 1943 Stoll and Hofmann described the synthesis of dialkylamine derivatives of lysergic acid including diethylamide, dimethylamide, dipropylamide, dibutylamide, diamylamide, methyl ethylamide, ethyl allylamide, butyl amylamide (Figure 4.5). In 1944 Stoll and Hofmann applied for a US patent on the synthesis of LSD which was ----------------------------,----------- METHODS OF ILLICIT MANUFACTURE 143 1 Figure 4.5 Azide mute [rom ergota- mine by Stoll and Hofmann (1936) Hydrazine Hydrate N H' Ergotamine Lysergic Acid Hydrazide NaN02 Hel Diethylamine N H' LSD Lysergic Acid Azide awarded to Sandoz Ltd in 1948 (Stoll and Hofmann, 1948). They would go on to synthesize and characterize 46 amide derivatives (Stoll and Hofmann, 1955). _~:le This reaction produces a mixture of the normal (about 80%) and iso forms -~:h with a yield of 69% from the lysergic acid hydrazide. .r.d :~~n Mixed anhydride ..:,',Ie An anhydride is formed when two carboxylic acid groups condense losing a molecule of water. The resulting anhydride is reactive and many types are used in synthetic chemistry. In the early 1950s there was great interest in developing new synthetic routes for peptides. Boissannas (1951, 1952) and Bourne et al. (1952) described the use of mixed anhydrides in the formation of amide bonds. A mixed anhydride occurs when the second carboxylic acid group is different from the first, and the more electronegative it is in nature the better it is in leaving during nucleophilic attack. It was observed that acetic acid and tri- fluoroacetic anhydride under certain conditions produced significant amounts of n-acetylation which the authors noted useful in peptide synthesis. Pioche (1956) described this reaction on lysergic acid at temperatures less than O°C :H using trifluoroacetic anhydride. It was found that the trifluoroacetyl derivative -as of lysergic acid is unstable at room temperature and, as such, the conversion to s 144 HALLUCINOGENS the amide with the appropriate alkylamine was undertaken in situ or as soon as the mixed anhydride had formed in solution. The overall yield was reported to be 58% with the production of significant quantities of the iso form (Figure 4.6). Figure 4.6 Mixed anhydride synthesis by Pioche (1956) •. Trifluoroacetic anhydride /N H Lysergic Acid Mixed Anhydride diethylamine Sulfur trioxide-dimethylformamide complex In the continuing search for peptide coupling agents Kenner and Stedman (1952) described the mixed anhydride of sulfuric acid: sulfur trioxide in dimethylformamide. Garbrecht (1956) successfully synthesized LSD by the sulfur trioxide-dimethylformamide (S03-DMF) route. In this mixed anhydride reaction the stoichiometry of the reactants was found to be critical