18.7.2021 https://www.erowid.org/archive/rhodium/chemistry/chloroephedrine.
txt
------------------------------------------------------------------------------
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
https://www.erowid.org/archive/rhodium/chemistry/chloroephedrine.txt 1/4
18.7.2021 https://www.erowid.org/archive/rhodium/chemistry/chloroephedrine.txt
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:
https://www.erowid.org/archive/rhodium/chemistry/chloroephedrine.txt 2/4
18.7.2021 https://www.erowid.org/archive/rhodium/chemistry/chloroephedrine.txt
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
https://www.erowid.org/archive/rhodium/chemistry/chloroephedrine.txt 3/4
18.7.2021 https://www.erowid.org/archive/rhodium/chemistry/chloroephedrine.txt
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.
------------------------------------------------------------------------------
https://www.erowid.org/archive/rhodium/chemistry/chloroephedrine.txt 4/4
