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Complete Synthesis of Cocaine by Naviori Method

Complete synthesis of cocaine by Naviori method

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167 views7 pages

Complete Synthesis of Cocaine by Naviori Method

Complete synthesis of cocaine by Naviori method

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elahemohajer06
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© © All Rights Reserved
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" eee Si ven Sioeom cs Gas ‘Armonia odor pretnt at aus ‘very ow ove. Seo Said ‘lo inarta, coroatvos, ‘SOURCE: Oregon Department of Human Resources 1988 468 NOTICE: THI BY CoPyRigy IS MATERIAL MAY ff $88 eyes, eyes, yee HT LAW (TITLE 47, 5 PAOTecTED US. Cope| Heavy Metal and Organic Contaminants Associated With Iicit Methamphetamine Production Brent T. Burton INTRODUCTION Methamphetamine isa power stimulant drug commonly known an the street ‘as ‘crank’ or “speed.” It is currently the most popular and widespread amphetamine that's Wegally manufactured, distributed, and abused. Itt methamphetamine 's produced n clandestine laboratories that ‘widespread in the United States. The profit motive forthe clandestine chemist is enormous, with some laboratories producing In excess of $300,000 per week In street value. Although several other lic drugs of abuse are occasionally ‘manufactured in clandestine leboratories, methamphetamine accounts for almost 95 percent ofall clandestine laboratory selzures. The frequency of laboratory seizures has been increasing nationwide over the past decade (Anon 1988). The States of California, Texas, Oregon, and Washington have shown the greatest incroase in clandestine laboratory activity. ‘Adverse health effects to the sbusor are not limited to toxic effects of the drug. iit drugs produced In clandestine laboratories by unskilled chemists are lkaly to contain potentially toxic contaminants due to unintended reaction by-products ‘and reagent residuals. Process errors In the production of clandestine dru previously have resulted in severe health effects, including acute Parkinson's disease from attempted production of 1-methy!-4-phenyi-4-proplonaxy- piperidine (MPPP) and acute lead poisoning from injection of methamphetamine (Alcott et al. 1987; Ballard et al. 1985; Norton etal. 1989). ‘The average concentration of methamphetamine street samples is ‘approximately 40 to 50 percent (Hall etal. 1988). Most contaminants found in lett drugs are Intentionally added by the distributor to dilute or “cut” the product, to Increase profits. Such substances include lactose, mannitol, idocaine, procaine, caffeine, quinine, and sodium bicarbonate and may account for as 47 ‘much as 94 percent ofthe fnished produet (Grinspoon and Bakalar 1985). In the case of drugs produced by the clandestine chemist, additonal contaminants ‘may be Introduced by the production process. One can predict such potential Contaminants due to unreacted substances or unintended reaction products, {rom known production methods available to the clandestine chemist. Though ‘unintended contaminants may be Introduced into the fished drug by the Clandestine chemist, the extent and types of substances as a result of the Production process have not yet been adequately studied. HISTORY Methamphetamine was developed in 1919 as an amphetamine derivative by A. Ogeta, a Japanese pharmacologist. However, it was not until the 1930s that the pharmacciogic properties of amphetamines became known. The ‘sympathomimetic properties of amphetamines initialy made them useful as vasoconstrictor agents, and they ware frst introduced into the marketplace In 1932 as Benzodrino, an inhaler designed for celle of nasal congestion, Users ‘of these nonprescription inhalers soon noted that the ammohetarmine contents ‘Were powerful central nervous system stimulants. This property subsequently ‘made amphetamines useful drugs In the treatment of narcolepsy and some forms of depression but also made them desirable as drugs of abuse, ‘The abuse of amphetamine began almost as soon as it was avaliable as an ‘over-the-counter medication, Shortly after the Benzodrine nasal inhaler became available in 1931, abusers wore taking apart the spray botte to retrieve ‘the paper inside containing 250 mg of amphetamine. These strips of paper then were consumed in chewing gum or stirred into a beverage for ts ‘stimulating and euphoric effect (Grinspoon and Hedblom 1975). ‘By 1962 the legal production of amphetamines was estimated by the Food and Drug Administration to be more than 8 billon tablets per year, with output Increasing every year. Much of the amphetamine abuse of the 1950s and 1960s occurred as a result of prescription abuse by individual patients obtaining ‘drugs from thelr private physician, many of whom knowingly were writing Prescriptions for proft. ‘The drug culture of the 19608 braught a dangerous new route of administration for amphetamines. An injectable form of pharmaceutical methamphetamine rapidly became responsible forthe amphetamine sbuse ifestyle known as the “speed freak.” The dangerously addictive nature of injectabie emphetamines became obvious with the advent of the amphetamine-tolerant freak whe would Inject as much as 15 g of amphetamine during a single day (Grinspoon and Hedbiom 1978). \Untl the 19708 most amphetamines were obtained from pharmaceutical sources that were divarted into the black market. It has been estimated that as ‘much as 60 percent of leghimate amphetamine production was diverted by shipments to unauthorized persons, thefts, or prescription forgeries (Morgan 1981). Due to the abuse of amphetamines and othor drugs in the United States, ‘the Controlled Substance Act (CSA) was passed in 1970, which designated control schedules for drugs according to their abuse potential. This act dramatically changed the availablity of pharmaceutical amphetamines by requiring special procedures for manufacturers to register shipments and provide detailed accounting of transactions involving controlled substances. Predictions that strict controls wuld result ina shift to clandestine production ‘of methamphetamine did not materialize at that time. However, the increased avalabllty and use of cocaine in tha 1970s may have temporarily reduced market demand for methamphetamine. ‘As amphetamines became more dificult to obtain, purty of street samples began 10 decline. During the mid-1870s many street samples sold 38 amphetamine contained litle or none of t, and a varity of drugs began to show tp thet were being sold as amphetamine. Samples of street amphetamines in 41973, after the effect of the CSA was apparent, contained only about 10 percent amphetamine on average (Morgan 1981). Most often, over-the-counter drugs ‘with stimulant proparties such as caffeine, ephecrine, and phenylpropanolamino ‘ware substituted and sold as amphetamine. This practice eventually led to the drug look-alike” business, a thriving mail-order enterprise offering these legal ‘over-the-counter drugs packaged and promoted with names, tablet shapes, and Colors designed to mimic amphetamines. ‘Since the mid-1980s there has been a reemergence of the ilicit use of ‘methamphetamine, One such Indicator isthe rapid increases that have been documented in numbers of clandestine laboratories seized by law enforcement agencies. Most recently, media reports have focused on the Increasing Popularly of “ce,” a smokable form of methamphetamine (Lerner 1989). The se ofthis crystalline form of methamphetamine has been prevalent especially In Hawall, where its Imported from Paci rim countries. As this form of methamphetamine becomes more widely avalable in the United Statos, itis possible that stimulant users once again wil shit to methamphetamine. CLANDESTINE SYNTHESIS OF METHAMPHETAMINE, Ilict manufacture of methamphetamine is a simple process that does not require special knowledge or expertise In chemistry. Most methamphetamine is 49 ‘produced by relatively uneducated persons who synthesize the drug trom published or harwritian recipes. The drug subcutue provides abundant ‘opportunities forthe potential clandestine chemist o obtain recipes, or ever lation cooking lasses, for methamphetamine. Many recipes in cicultion aro” hhandwriten Instructions thet describe how to procure the needed chemicals, ‘lassware, and supplies. Those instructions often include detalled sketches {and descitions of the procedure 20 the novice can produce methamphetamin ‘without prior traning. Some underground recipes even describe the legal status of various chemicals and methods to avoid detection by law enforcement offal Several publications, avalable in bookstores or by mall arder, describe the ‘methods of drug manufacture. One such publication, Psychedelic Chemistry, ‘describes detaled recipes forthe production of several drugs. in addition, Information is provided about how to obtain chemicals and laboratory equipment Without prompting the attention of law enforcement officials (Smith 1981). The clandestine chemist need not resort to handwritten underground recipes or tty to locate tha proper reference text in a bookstore. Numerous scientific journals provide a wealth ot information regarding drug synthesis, including ‘aerate procedures for a variety of processes, thatthe chemi may select depending on chemical availabilty. The educational ievel of persons utiizing ‘such references must be more sophisticated than that ofthe typical clandestine Chemist due to the highly technical nature of the journals. An example of such fn article is a description of a currently unused but proposed method of Production, authored by chemists ofthe U.S, Drug Enforcement Administration (DEA) (Cason etal, 1984). These references usually are torn or eut out of brary journals, presumably to reduce competition from other would-bo clandestine chemists. Because the clandestine chemist usually lacks skill and training in chemistry, there are multiple opportunities for errors of misunderstanding of proper Procedure. Attempts at shortcuts, inadequate fering, salt washing, or solvent ‘erection could resut in serious contamination with reagents. Atleast one ‘clandestine chemist apparently completely misunderstood the proper procedure ‘and produced a finished product that contained 60 percent lead with pheny! ‘Propanone (P2P) butno methamphetamine (Norton etal. 1980) ‘Numerous chemicals associated with te ict production of methamphetamine. are listed below. Although only a few chemicals may be required for production, there are multiple reagents and precursors that can be substituted for those that ‘are diffcut to obtain legally. Thus, there may be many chemicals that potentially can contaminate the finished product. 0 SOLVENTS Toluene PRECURSORS 51 PRODUCTION PROCESSES 2P is the primary precursor most often used by the clandestine chemist. The ‘amalgam and Leukart processes are the most popular (figure 1), accounting for ‘about 80 percent of clandestine methamphetamine production (Frank 1983) Processes involving P2P as the precursor often utlize methylamine to provide the amine group and thus formulate methamphetamine in a simple single-step reaction procedure. The amalgam method utlzes a combination of mercuric ‘chioride and aluminum foll as catalysts (igure 1). These and all reactions require a varity of acids and solvents for extraction and purification of the finished product. F Pheny/-2-propanone Methyiamine Methamphetamine FIGURE 1. Synthesis of methamphetamine utilizing the amalgam method catalyzed by mercuric chloride and aluminum foil ‘The clandestine manufacturing and purification procedure is represented by the {olowing instructions paraphrased from a recipe obtained from a clandestine ‘chemist (Dallosta 1985): The process is Iniiated.by adding mercuric chloride, ‘aluminum fol isopropanol, and sodium hydroxide to @ reaction vessel and hheating. When the solution comes toa boll, th ‘added to the misture and heated for 4 hours. ‘passed through fter paper to remove contaminants. Excess methylamine is ‘removed by the application of heat to the reaction product. The remaining ‘misture containing “reebase amine" is purified wit a salt wash to “kil the poisonous mercuric chloride.” The product then is acidified to adjust the pH, ‘rystalzed, punted with solvent ina separatory funnel, and then recrystallized ‘and packaged for distbution, ‘Unavalabilty of P2P and legal controls of other precursors have resulted in the Increasingly popular use of ephedrine as a primary precursor. Ephedrine 82 ‘common over-the-counter decongestant cold remedy that differs in molecular structure from methamphetamine only by the presence of a hydroxyl group at the B-carbon. A single-step hydrogenation reaction of ephedrine, which ‘can be accomplished by several methods, will produce a high yield of methamphetamine. This reaction has the advantage of considerably less noticeable odor than reactions utilzing P2P (the unpleasant, lingering odor of P2P and another precursor, phenylacetic acd, has frequently been a ciue to the operation of a clandestine laboratory). To escape detection and also utilize ‘sly avaliable chemicals, clandestine chemists may resort to using hydrogenation methods of ephadrine using red phosphorous as a catalyst with hydrolodie acid, In some cases clandestine chemists are fabricating high- jeseure reaction vessels to react ephedrine with hydrogen gas. If ephedrine or P2P are not the chemist may resort to industrial chemicals, such fas benzyl chioride, as the precursor. PRECURSOR SYNTHESIS ‘Clandestine manufacture of methamphetamine became more complicated in +1980 when P2P was classified as a Schedule I! controlied substance by DEA. In addition, States with clandestine drug laboratory problems, that is, California, ‘Oregon, and Washington, have passed laws requiring that any person who purchases listed chemicals that my be used in methamphetamine production be reported to the State police. These legal restrictions on P2P, intended to curb the growth of clandestine methemphetamine, spurred the development of Clandestine laboratories specializing In the production of P2P from phenylacetic ‘acid, Legitimate P2P solls commercially for less than $100 per iter, but the ‘same amount will net more than $4,000 for the clandestine chemist. Synthesis cof P2P usually is accomplished by utiizing lead acetate as the primary reagent Ina process that requires a distilation procedure (figure 2). In the hands of the Lnskiled or careless clandestine chemist, these processes may result in the Introduction of contamination from lead and other reagents used in the production process. Inthe absence of phenylacetic acid there are several alternative reactions the clandestine chemist may choose to produce methamphetamine, utlizing easily avaliable chemicals but requring more complex and often more dangerous reactions. For example, phonylacetic acid may be synthesized from industrial chemicals such as benzyichloride, toluene, or benzene. In a possible endless ‘s0urce of potential reaction pathways, the chemist may resort to manufacturing ‘many precursors rom uncontrolled chemicals. For example, ephedrine may be synthesized from proplophenone, or methylamine may be produced in a reaction with ammonia and methanol. The increasing complexity ofthe reaction ‘sequence and the substantial numbers of chemicals required inthe production 53 O- Phenylacotic acd ; = Oo}, 3 chy Load acetate Phenyt2-propanone FIGURE 2. Synthesis of he precursor P2P hom phanylacetc acid and lead ac [process increase the risk of erors and the probabilty of toxic: n Proceet ream probabity contamination in ‘TOXICITY OF DRUG CONTAMINANTS: Atbough dug cotinaon may rut n potently serous averse heath ‘fect or ta crug ur, ho deat nstucyng sucha group of unos Inde rbloma to docu th axe tg cotarinr nod noes fominetanphtarin, Fortis ease net po cra ve bean enecoal cen, Edema nvestoe Problem has not yet been accomplished. sea Nestanton ito hie Thao have boon opr of contained drugs produced nc lbortre that havo reutedn sasous heal eects ne unevspacting sor. One euch major utronk of sero ness om contanaae ave cecuredin 1862 when an atompt wae made by a Gandestne chet produce he meperne congener, MPEP. Instad, de oa realy minor Aeration te racion proces, high tcne methy- phony 2a, teahycopyidne (MPTP) was ayrthesed and dented on he aes, rug users nuckyeneugh jet MPTP developed eovere an permancrt Parkinson's sees. On bya aera of colncdnoos wee re cause the Pastner lgoase raced oh contarinaed erg Slr to 198)" Mi net nown how many ober oxo aubtances maybe rato y the Sangostne Short etomping wate oer age Gg, ncudngmethoptetamine "os te eat ny ergs es aera eae Schr nse cee Siig uena Tteneant neces Sra 54 developed lines ses consistant with lead Intoxication and presented with symptoms of nausea, vomiting, constipation, numbness and tingling, weakness, and headache. Laboratory data revealed elevation of liver fenzymes, suggesting a diagnosis of infectious hepatitis. However, In view of the nonspecific clinical presentation, the possiblity of lead polsoning apparently ‘was not considered unt! basophil stipping was found on the blood smear, ‘which prompted an Investigation for lead toxicty. A bload lead level of ‘204 g/dL was measured in one of the patients (<40 g/dL is normal). A blood lead lavel was not reported for the second patient, although a free erythrocyte protoporphyrin was lavatod at 68 yg. (<50 g/L Is normal), Both patients required chelation therapy with disodium calcium edetate. A sample of ‘methamphetamine obtained later from one of the vitims was shown to contain £899 ppm of lead. This would result Inthe Injection of approximately 0.1 mg of lead per dose of drug (Allott et al. 1987). ‘The second outbreak of lead poisoning was reported in 1988 and involved 12 ‘methamphetamine abusers in a three-county area in Oregon. All cases came to medical attention between April 18 and September 15, 1988. The mean age of these patients was 27 years (range 24 to 36 years), nine males and threo females. The most common complaints were gastrointestinal, that is, nausea, ‘voriting, abdominal pain, and constipation. Although lead poisoning typically is ‘associated with neurological findings, only one patient complained of paresthesias. The physical examinations were remarkable for abdominal {enderness, but evidence of encephalopathy or neuropathy was not present. ‘Anemia was common with a mean hematocrit of 29.8 percent (range 20 to 44 percent). Basophilc tipping was present in 10 cases. Elevation of iver ‘enzymes was consistent with chemical hepatitis. The most severely poisoned patient also developed a clinical pancreatitis. The mean blood lead level was 448 ula, with a range from 49 jg/all to 513 yo/dl. the latter being the highest level yet reported in a living person. Seven patients underwent chelation treatment. Although followup was not possibie forall patients, it appeared that all mproved with treatment. It was presumed that this outbreak resulted from ‘perhaps a single source because of the close proximity ofthe cases. Although ‘the source or the responsible clandestine chemist could not be identiied, one of the victims supplied a sample ofthe drug he had allegedly injected. Analysis of ‘this drug revealed that the sample contained 60 percent lead (Norton et al. 1989). This concentration of lead would result in a dose of more than 50 mg of lead per injection. ‘The cases described above involved relatively large doses of lead that rosulted In severe acute polsoning. Although smal doses of lead in ‘methamphetamine may recut in lness, the offacts may not be readily apparent to the dinician, particulary n view of the nonspecific symptoms frequent seen, Inlead poisoning. Itis not known f methamphetamine abusers, as a group, 55 ‘may be at isk of unrecognized chronic lead toxicity due to chronic low-level ‘exposure to lead; chronic accumulation may not result in liness until large body burdens of lead have been attained. thas been suspected, but not yet documented, that drug abusers may be at "isk of developing poisoning from other reagents used In the manufacturing process. Although mercury has been considered as a possible contaminant ‘ith significant heath impact, there have not yet been any confirmed cases of ‘mercury polsoning. Howaver, It must be recognized that this may be due to the lack of case recognition in patients that have complications that are consistent, ‘with drug abuse such as hepatitis and nephritis. In an attempt to document ‘excessive mercury exposure, hair samples of 12 methamphetamine abusers ‘were measured for mercury. None of the samples showed a significant Increase in mercury concentrations compared with nonuser controls French 1985). Howavar, this exploratory study could nat avercome the difficulty of selt- selection of patients and the inherent technical problems associated with ccllection and interpretation of hair sampling for mercury. Blood or urine levels ‘were not measured, and drug samples were not assayed to determine ifthe

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