------------------------------------------------------------------------------ Notes on the synthesis of Chloroephedrine and the reduction thereof ------------------------------------------------------------------------------ From Noggle, et al. (NARCOSWINE ALERT!) Anal-Chem, 58(8):1643, 1986: General Method for the Preparation of the 1-Phenyl-1-chloro-2-(methylamino) propanes (I). A solution of the ephedrine hydrochloride or pseudoephedrine hydrochloride (1.65 g, 10 mol) and thinyl chloride (10 mL) in chloroform (200 mL) was stirred at reflux for 3 h. The reaction solution was then cooled to room temperature and the solvent vlume reduced to approximately 50 mL. Adition of anhydrous ether (200 mL) followed by cooling (freezer) resulted in crystallization of (I) HCl. General Method for Perparation of the Methamphetamines. A mixture of the (I) HCl (500 mg, 2.3 mmol), sodium acetate trihydrate (1.22 g, 8.9 mmol), and 5% Pd-BaSO4 (250mg) in glacial acetic acid (95 mL) and water (5 mL) was shaken under a hydrogen atmosphere (intiial psi of 40-45) on a Parr apparatus for 30-60 min. After the uptake of hydrogen ceased, the catalyst was removed by filtration and washed with water (50 mL). The combined filtrate and water washings were evaportaed to dryness under reduced pressure and the remaining oil dissolved in water (50 mL), and acidified with concentrated HCl (pH 1). The acidic aqueous solution was washed with chloroform (2 x 50 mL), then made basic (pH 12) with 10% NaOH. The basic aq solution was extracted with chloroform (3 x 75 mL), and the combined extracts were washed with water (100 mL) and dried over MgSO4. Evaporation of the CHCl3 under reduced pressure yielded the product as the free base. The base was coverted to the HCl salt in ethereal HCl, and the salt was recrystallized from ethanol-ether to give a granular white solid. And not only is there a narcoswine alert, but you get to play "find the typos!" I deliberately left some easy ones in there, to make you think about if that "5 mL" should really read "50 mL", or whatever. -- Lamont Granquist (lamontg at u dot washington dot edu) ICBM: 47 39'23"N 122 18'19"W "It all comes from here, the stench and the peril."--Frodo (from Perl5/toke.c) ------------------------------------------------------------------------------ Tetrahedron: Assymmetry 9 1661-1671 (1998) Chlorination of Ephedrine and Phenylpropanolamine 1-Chloro-1-phenyl-2-aminopropane hydrochloride To 1 gram (6.61 mmol) of norephedrine, 1.43 ml (19.8 mmol) of thionyl chloride was added. After stirring for 5 hours at room temp the excess thionyl chloride was removed under vacuum. The white solid obtained was washed with acetone, filtered and recrystallized from MeOH to yield 0.76 g (74%) of 1-chloro-1-phenyl-2-aminopropane hydrochloride, mp 205-207°C. 1-Chloro-1-phenyl-2-(N-methyl)aminopropane hydrochloride (Chloroephedrine) The same general procedure as above was employed, using 3.0 g (18.1 mmol) of ephedrine and 3.9 ml (54.3 mmol) of thionyl chloride to give 3.7 g (94%) of chloroephedrine, mp 198-200°C. ------------------------------------------------------------------------------ The synthesis of methamphetamine from ephedrine derivatives was evidently first accomplished by Schmidt in 1914. Schmidt, Arch. Pharm., 252, 89, 120 (1914). Schmidt prepared 1-phenyl-1-bromo-2-methylaminopropane (bromoephedrine or bromopseudoephedrine) and reduced it to desoxyephedrine with zinc-copper and hydrochloric acid. His yield, as reported later by his student Emde, was 10%. Emde prepared 1-phenyl-1-chloro-2-methylaminopropane (chloroephedrine or chloropseudoephedrine) and catalytically hydrogenated both the chlorine compound and the bromine compound to desoxyephedrine. Gero further investigated these reactions and found that Al-Pd (palladized aluminum) gave a 44% yield in the reduction of chloroephedrine and CaH2-Pd (palladized calcium hydride) gave an 86% yield in the reduction of chloroephedrine. Emde, Concerning Diastereoisomers. I. Configuration of Ephedrine; II. Steric Inversion of Ephedrine with Hydrochloric acid; III. Chloro- and Bromo-Ephedrine. Helv. Chem. Acta., 12, 365-99 (1929); C.A. 23: 3452-4 (1929). Chloropseudoephedrine-HCl [PhChClCHMeNHMe·HCl]: (a) 60 cc. CHCl3 (chloroform) and 60 g. PCl5 (phosphorus pentachloride) are placed in a wide-mouth glass-stoppered bottle, and after cooling with ice 40 g. of powdered (-)-ephedrine hydrochloride is added in 0.5 g. portions in about 10 minutes, shaking vigorously after each addition. The bottle is then shaken mechanically for 2 hours. The reaction mass is then decanted into a 750 cc. beaker, leaving the excess PCl5 in the bottle. After rinsing with 20ml chloroform, 500 cc. diethyl ether is added and the product allowed to stand. The product crystallizes out, is filtered under suction, washed with acetone and dried in a vacuum desiccator. Yield, 99.4%. A few recrystallizations from ethanol yields optically pure product. (b) Similarly, using 20 cc. thionyl chloride (SOCl2), 20 cc. chloroform and 10 g. of (-)-ephedrine hydrochloride. The reaction is slower, and after 30 minutes 100 cc. diethyl ether is added and the crystallized chloroephedrine is treated as above. Yield 93%. (c) Similarly from 2 g. of (+)-pseudoephedrine hydrochloride, 5 cc. of chloroform and 4 cc. SOCl2. The addition of 100 cc. diethyl ether precipitates 2.15 g. of yellowish chloropseudoephedrine HCl product. Free (+)-chloropseudoephedrine is a yellow oil with a strong odor similar to that of pseudoephedrine, too unstable to be purified for analysis. (+)-Bromopseudoephedrine-HBr: (+)-Bromopseudoephedrine-HBr was obtained from 12.9 g. of (-)-ephedrine hydrobromide, 50 g. PBr5 and 60 cc. chloroform. After 3 hours of shaking, the product is decanted off and treated with 500 cc. of ether and filtered off. Yield, 98% of pure product. (+) Desoxyephedrine: A solution of 3 g. sodium acetate in 40 cc. water is made neutral to litmus with a few drops of acetic acid. 2 g. of Pd-BaSO4 (palladium-barium sulfate) catalyst is added, with 9.8 g. of (+)-bromopseudoephedrine hydrobromide (or 7.2 g. of (+)-chloropseudoephedrine hydrochloride), and agitated under hydrogen at room temperature. About 90% of the theoretical H2 is absorbed in 2-3 hours, the catalyst is filtered off, and the product is steam distilled from the filtrate after addition of sodium hydroxide. There remains a small residue of (+)-didesoxyephedrine (probably 2,5-bis-methylamino- 3,4-diphenylhexane, b.p.0.6 165°. The steam distillate is neutralized with HCl (to methyl red) and crystallized from absolute ethanol (solubility 1:4). Yield, 80-90%. Purification was achieved by extraction of the base from the steam distillate with diethyl ether, drying and distillation under a high vacuum. The hydrochloride salt had m.p. 172°. Gero, Some Reactions of 1-Phenyl-1-chloro-2-(methylamino)propane. I. Reactions with Metals and with Hydrogen. J. Org. Chem., 16, 1731-5 (1951); C.A. 46: 6606g (1952). 1-Phenyl-1-chloro-2-methylaminopropane was reduced to methamphetamine. Propenylbenzene was formed in a side reaction in amounts ranging from a trace (reduction with calcium hydride-palladium and hydrochloric acid) to 77% (reduction with zinc and hydrochloric acid). Whether the propenylbenzene was further reduced to propylbenzene was not investigated. Hydrogenation with palladized aluminum and hydrochloric acid: Aluminum powder (9 g.) was washed successively with benzene, methanol, water, then immersed in 30 ml. of 0.1% sodium hydroxide solution. After two minutes, 100 ml. of water was added and the aluminum filtered and washed with water. A solution of 0.2 g. palladous chloride in 200 ml. hot water was then poured on the aluminum and left overnight. The palladized aluminum was filtered and washed with water and added to a solution of 22 g. of 1- phenyl-1-chloro-2-methylamino- propane in a mixture of 200 ml. of concentrated hydrochloric acid and 200 ml. water. The reaction was slow to start but became gradually quite vigorous and had to be moderated by outside cooling. When the reaction stopped, the unreacted aluminum was dissolved in concentrated hydrochloric acid and the mixture distilled with steam as long as propenylbenzene came over. The solution was then made alkaline and the steam distillation continued as long as the distillate was alkaline. The alkaline distillate was extracted with diethyl ether, the ether dried with sodium sulfate and saturated with hydrogen chloride gas. The precipitated desoxyephedrine hydrochloride was washed with ether and dried. Desoxyephedrine hydrochloride was obtained in 44% yield. Hydrogenation with calcium hydride and hydrochloric acid in the presence of palladium: 11 g. 1-phenyl-1-chloro-2-methylaminopropane was dissolved in 100 ml. methanol. To this solution was added a solution of 0.25 g. of palladium chloride in 7.5 ml. hot concentrated hydrochloric acid (Solution A). Calcium hydride (11 g.) was covered with 100 ml. of methanol and Solution A was added at such a rate that the temperature of the reaction mixture stayed at 35-40°, with outside cooling if necessary. When the initially vigorous hydrogen development subsided, enough concentrated hydrochloric acid was added to bring the pH to about 3 and the mixture was stirred for 30 minutes. The clear solution was filtered from the palladium black and washed with 200 ml. of water. Then 250 ml. was distilled off to remove the methanol and whatever propenylbenzene might have been formed (no more than a trace was ever found). The residue was made alkaline and steam distillation continued as long as the distillate was alkaline. The alkaline distillate was extracted with diethyl ether, the ether dried with sodium sulfate and saturated with hydrogen chloride gas. The precipitated desoxyephedrine hydrochloride was washed with ether and dried (yield 86%). Note that the Gero procedure utilizing an internal source of hydrogen (a metal hydride in acidic solution is a source of molecular hydrogen) and palladium gave a yield comparable to those obtained by catalytic hydrogenation utilizing an external source of hydrogen. Note also the use of steam distillation under acidic conditions to remove side reactants and the use of steam distillation under basic conditions to separate the desoxyephedrine instead of the usual vacuum distillation. ------------------------------------------------------------------------------ On Chloroephedrine [ Drug and Alcohol Dependence 64 (2001) 299–307 ] Many methods have been used to synthesize methamphetamine, but the most common current method involves the conversion of (-)-ephedrine or (+)-pseudoephedrine to S- (+)-methamphetamine. The common products or intermediates in this synthesis are the beta-halogenated amines. Synthesis from (-)-ephedrine yields almost exclusively the (+) isomer of chloroephedrine. In contrast, synthesis from (+)-pseudoephedrine yields both the (-) and (+) isomers in a 40:60 ratio. These compounds have been shown to cyclize to cis- or trans- 1,2-dimethyl-3-phenylaziridines. These intermediates, including the aziridines, are present in clandestinely synthesized methamphetamine, but no quantitative data is included in those reports. However, in one of the reports the chromatogram of a forensic sample showed that similar amounts of methamphetamine and chloroephedrine were present. The (+) and (-) isomers of chloroephedrine are contaminants that can be produced during the illicit manufacture of (+)-methamphetamine when (+)-pseudoephedrine or (-)-ephedrine are used as precursors. Chloroephedrine has been reported to be present in varying levels in clandestinely synthesized methamphetamine and has been observed in some forensic samples. An anecdotal report suggests that chloroephedrine impurities can be present in methamphetamine manufactured by `unscrupulous and/or unskilled' chemists and that these impurities `ruin the finer aspects of the meth high' (Fester, 1999). The actual amounts of impurities in samples of clandestinely synthesized methamphetamine have not been reported. This lack of knowledge is most likely due to methodological difficulties encountered in extracting and quantifying the impurities (Lekskulchai et al., in press). Noggle and colleagues (1986) provided chromatographic evidence suggesting that some forensic samples contained equal amounts of methamphetamine and chloroephedrine. Based on our experience with the synthetic pathways used in the clandestine manufacture of methamphetamine, an impurity content of 0-40% or higher is possible, especially if an unskilled chemist manufactures the drug. Since some methamphetamine abusers administer doses as large as 1000mg, it is possible that 400 mg or greater of chloroephedrine may be consumed. Since rats may be less sensitive than humans to the cardiovascular actions of chloroephedrine, our dose-response and combination studies employed doses of chloroephedrine that were similar to- and exceeded potential human doses. ------------------------------------------------------------------------------