Synthesis

Stimulants/Amphetamines

Michael A. Wagner – Ph.D.

Laboratory Director
Indiana State Department of Toxicology
 Abuse dosing
¾ Purity of Methamphetamine
z 60 – 90%
¾ Dosing
z 100 – 1000 mg/day
z 5000 mg/day – chronic binging
Precursors
 Charcoal lighter fluid, gasoline, kerosene, paint thinner,
rubbing alcohol, Freon, acetone, ethyl alcohol, and mineral
spirits.
 “NAZI DOPE’
AND THE BIRCH/BENKESER
REACTIONS
Lithium Source
What a difference time can make!!!
Signs and Symptoms
Pharmaceutical Speedball
Oxycodone/Amphetamine
Crank bugs
 Methamphetamine – Binge Use
High (4-16 hrs)

Rush Binge Use

(5-30 mins) (3-15 days)

~Normal
Tweaking
Normal (2-7 days)
(4-24 hrs)
Withdrawal
30-90 days

Crash
(1-3 days) after SA Stalcup
 Methamphetamine
improved reaction time
relief from fatigue light sensitivity
euphoria nervousness
headache
Symptomatology

(a) motor restlessness

tremor Blood methamphetamine concentration (m
fatigue 0.1 agitation 1 10 100
hyperactive reflexes
exhaustion
apprehensiveness
confusion
confusion
extreme fatigue
suspiciousness
drug craving
paranoia
depression
hypervigilence
hypersomnolence delusions
uncontrollable sleepiness
hallucinations
suicidal behavior irrational behavior
(b)
violence
severe hypertension/chest pains
seizures
coma
death

Logan, J For Sci 1996;41(3):457-464

 Temporal Characteristics
Methamphetamine use
¾ Events Duration
¾ Rush 5 – 30 min
¾ High 4 – 16 hours
¾ Crash 1- 3 days
¾ Normal 2- 14 days
¾ Withdrawal 30 – 90 days
¾ Injection Immediate onset
¾ Smoked 5 – 20 min
¾ Smoked Up to 8 hours high
¾ Smoked 12 – 36 hours half – life
¾ Urinary excretion Ends 3 – 5days
¾ Psychosis 1/3 of patients for 10 days
10% symptoms after 2 years
¾ Recovery 82% within a month post withdrawal
¾ Sensitivity Catecholamine agonist persist 3
months with multiple substance
¾ Tolerance 100 times increase ( 5 → 500 mg)
¾ Recovery More than 5 years in 14% of case (IV use)
¾ Psychotic relapse Single injection even after 5 years abstinence
Relapse states may persist 8 – 22years w/o
may reuse
 Amphetamines – An Update
Conclusions:
1 Sympathomimetic stimulants are now well
established throughout the US.
1 Toxicity and impairment are complex and
poorly related to quantitative blood drug
concentrations.
1 Mortality risk is increased in users.
1 Long-term cognitive effects are likely.
1 Forensic issues revolve around impairment,
psychosis, and lethality.
A good chef always samples his dishes first!!!
Time to do the dishes!!
He says to himself, after 4days with no sleep!!!!
It must have been a good patch!!
This however is my garage
This is not my yard or my car
Dangerous chemicals
the real risk - family
The Materials
“An excerpt from the
Betty Cranker
Cookbook:
Take a pinch of red
phosphorous, a
smidgen of ephedrine,
a dash
of iodine and a skosh
of lye. Add some
distilled water and
simmer
for a few hours and
hope it doesn’t
explode and kill you.”
Paul B. Johnson
Post Register, Idaho
Sympathomimetic amines

CNS stimulant
z *Amphetamine
z *Methamphetamine
z *Pemoline
z *Methylphenidate
z Metcathinone
 Methamphetamine
Synthesis
Ephedrine/Pseudoephedrine
Hydroiodic acid/red phosphorus
Lithium/anhydrous ammonia

Condense liquid NH3 with

OH
dry ice bath, Li metal, THF
CH3
CH3
HN
HN CH3
CH3
Yield 55-85%
Methamphetamine
Metabolism t ½ = 6-15 hrs
Sympathomimetics
 Methamphetamine History
1 Amphetamine synthesized 1887 by German chemist,
1 L. Edeleano
1 Methamphetamine was first produced by Dr. Nagayoshi Nagiai of Tokyo
Imperial University in 1888 by reducing ephedrine with HI & Red
Phosphorus
1 Methamphetamine synthesized from methylamine
1 and phenyl-2-propoanone 1919 by Japanese researcher, A. Ogata
1 Early 1900s: Western civilization discovers benefits of ephedrine and
pseuodephedrine as brochodilators and nasal decongestants. Fear that ma
huang plants will run out (source for the herb ephedra).
1 1927 (USA): Researcher Gordon Alles discovers that amphetamine works
as a substitute for ephedrine. Amphetamine starts being synthesized as
substitute for ma huang.
1 1930: Amphetamine discovered to increase blood pressure.
1 Marketed in 1932 as “benzedrine” in an over-the-counter inhaler to treat
nasal congestion
1 1935: Amphetamine’s stimulant effect first recognized and used to treat
narcolepsy (compulsion to sleep)
 Meth History, cont.
1 1962: early reports of illicit domestic production by biker gangs
Amphetamine and methamphetamine become Schedule II drugs in 1971
1 Motorcycle gangs synthesized drug using phenyl-2-propanone until late
1980’s. P2P became restricted substance, so chemistry shifted to making
P2P from phenyl acetic acid or other ways
1 1987, DEA busts first HI/Red Phosphorus lab in the country in California.
This method has a higher yield and more potent methamphetamine.
Mexican nationals take over the market from biker gangs with this method.
1 1990s: Mexican “Super labs” produce pounds of meth from chemicals
obtained overseas and smuggled across border. Illegal aliens make the
meth in well-organized discreet segments in the Central Valley of CA.
1 Current methods (Iodine/Red P or Lithium/Ammonia) using
1 pseudoephedrine became popular as other chemicals became illegal
 Current Methods
Reducing
Ephedrine/pseudoephedrine to
Methamphetamine

Iodine-red phosphorus
Ammonia-lithium (Nazi method)
 Old Methods

¾ Reductive Amination of Phenyl-2-

propanone with Aluminum amalgam
¾ Reducing ephedrine/pseudoephedrine to
methamphetamine via Catalytic
hydrogenation
 Chemicals in older methods
1 Reductive Amination
1 Biker dope (aluminum amalgam)
1 – Phenyl-2-propanone (P2P)
1 – Methyl amine: smells bad!!
1 – Mercuric chloride: contamination issue
1 – Aluminum foil
 Old Methods
¾ Combine P2P, methylamine, mercuric chloride, alcohol,
¾ and aluminum foil
¾ Rinse foil with mercuric chloride first
z Exothermic; react 12-18 hrs. Mixture will separate and
form oil layer on top. Cool reaction
¾ Separate to keep oil layer. Titrate with aqueous HCl to
pH 6
¾ Evaporate to recover crystals. Wash with acetone.
¾ Mixture of d,l methamphetamine (less potent)
¾ Poorer yields; more subject to ability of chemist and quality of
¾ reagents
 BIRCH/BENKESER
REACTIONS
OH
H
CH3

H + Li + R1R2NH + (ROH)**
N
H CH3

H H **
H H
CH3 CH3

H H
N N

H CH3 H CH3

REQUIREMENTS: 1) Reducible Substrate 2) (Anhyd) Ammonia (liq) 3) Sodium 4) Alcohol

* Kaiser. E.M., “A Comparison of Methods Using Lithium/Amine and Birch Reduction
Systems”,Synthesis, pp. 391-415, No. 8, Aug. 1972
Pushing e- ‘s
Birch Reduction
aka: “Nazi Method”

Benkeser used THF and lithium instead of sodium.

Lithium is commonly substituted for sodium
Birch Reduction

1Mix ground-up pseudoephedrine (no

extraction needed) and dry lithium
(from batteries)
1Add anhydrous ammonia until all lithium
reacts
 Liquefied
ammonia
collected
in here

Fertilizer + Red Devil Lye

in here

Dry Ice + Acetone or Methanol

Ammonia Gas Generator = -77oC (-107oF)

Ammonia Condenser
1Allow to warm to room temperature
1Blue color disappears

1 Add water to react remaining lithium

1Meth “oil” collects on surface

1Add non-polar solvent to remove

methamphetamine base

1Salt-out as previously describe

Catalytic reduction

1Pseudo added to chloroform

1Add thionyl chloride and stir 1-4 hrs

1Add diethyl ether until precipitates
1Filter and dry intermediate
1 Add methanol, palladium to
hydrogenator (pressure vessel)
1Add hydrogen under pressure until
reaction stops absorbing hydrogen
Catalytic reduction hazards

Thionyl chloride
Water reactive, off-gasses
sulfur dioxide, HCl
Flammable solvents: methanol, diethyl ether

Flammable gas under pressure: hydrogen

Flammable solid: palladium

 Ephedrine

Natural Source: Ephedra sinica dried stem

1 Stereochemistry: 2 chiral centers = 4 forms
1 d, l ephedrine
1 d, l pseudoephedrine (OH and NH on the
same side
1 L – ephedrine, d-pseudoephedrine produce
d - methamphetamine
Efforts to prevent/limit access
to Ephedrine/ Pseudo

1 Place behind counter

1 Ask for id or make it a prescription
1 Limit access
1 Modify the Pseudo to make it unavailable to
convert
1 Use l-pseudo instead of d-pseudo

1 1/10th psychoactive

1 Modify the molecule (ex. Phenylephrine) and

prevent methamphetamine from being formed.
Still works as decongestant
 Why not make your own?
1 On-line recipe for Brewer’s yeast, molasses
and benzaldehyde
1 Industrial process use “special” yeast
1 Benzaldehyde toxicity reduces output
1 Product produced is l –
phenylacetylcarbinol
1 Still need to go through reductive
animation to become ephedrine
1 Methyl amine, aluminum amalgam
1 Then you would have to do it again to
make the meth
from http://designer-drugs.com/pte/12.162.180.114/dcd/pdf/biotransformation.ephedrine.pdf
“Biotransformation for L-Ephedrine Production”, P.L. Rogers, H.S. Shin, and B. Wang, Univ. of
New South Wales, Sidney, Australia
 Phosphorus
1Red P can only be ordered out-of-country
except as a reagent
1Get from match box strike plates
– 40% red P, 30% anitmony sufate
1Use white phosphorus
1Use hypophosphorous or phosphorous acid

1Hazards
1Flammable solid (friction)
1If heated, converts to white phosphorus
1Air reactive flammable solid
1Off gases phosphine
1Especially w heated
Phosphine
1PEL = 0.3 ppm, IDLH = 50 ppm
1LEL = 1.8%, auto-ignition @ 38oC
1 Examples of levels measured in controlled
cook situations
1Open container of red phosphorus = 1.4 ppm
1HI/RP cook: 0-13 ppm at sample port
1Making HI by mixing I2 and water, then
adding RP: 0-42 ppm
1Hypophosphorous acid cook: 0-85 ppm
1Levels measured at clan labs: 23 ppm at
opening of 22 liter
1Levels measured opening evidence containers
11-28 ppm opening kaypak
15-7.5 ppm opening evidence bucket
Iodine
1Sources
1Hydriodic acid
1Iodine crystals/prills from commercial
sources
1Feed supply (antibiotic, supplement)
1Make from iodine tincture
1Hazards
1Severe respiratory irritant
1– PEL= 0.1 ppm
1– IDLH = 2 ppm
1Corrosive
1Oxidizer
HI/Red Phosphorus
Step 1: Tablet Extraction

1Pseudoephedrine tablets ground up using

any type of grinder
1Tablets extracted with water or
polar solvent
1(MeOH, denatured alcohol)
1Filter off pill binder material
1Evaporate off solvent to leave
pseudoephedrine solid
1Fire hazard!!
HI/Red Phosphorus
Step 2: Convert to Meth

1Mix red phosphorus, water, pseudo

and iodine
1Heat generated by reaction alone; splatter
if not added slowly or in order
1Boil for extended period of time
1Phosphine gas (deadly) and iodine vapor
emitted during cook (deadly). Attach
hose to top of reaction vessel and run
into water, kitty litter.

4 hr cook yields 76-79% conversion

1 hr cook with hypo yields 83%
HI/Red Phosphorus
Step 3: Isolate

1Filter off red phosphorus

1Waste flammable solid
1Make solution basic (>pH 12)
1Lot of heat generated, volatilizing
meth base into the air
1Add non-polar solvent to extract meth
1Coleman fuel, naptha, lighter fluid,
toluene, diethyl ether, freon 11, carbon
tetrachloride
1– Except for freons and heavily
chlorinated solvents, all are very
flammable.
1Biphasic solution (meth in top layer if
solvent lighter than water)
 HI/Red Phosphorus
Step 4: Salt out
1Separate off solvent phase
1Bubble HCl through solvent mixture to
make methamphetaminehydrochloride
1Used to use commercial HCl cylinders
1Make own by mixing coarse salt and
sulfuric acid, or muriatic acid and
aluminum strips in a closed container
with a hose
1Levels measured during controlled cooks
exceed IDLH
1Evaporate off solvent to have meth
powder
1Flammability issue again!!
1Waste
1Red P/Iodine mixture: corrosive, off
gassing
1NaOH mixture: corrosive
1Organic solvents (Alcohols w
binders+Non-polar solvents)
Table 1: Common Flame Temperatures.
Fuel Oxidant Temperature Ref.
CH4 Air 1700-1900 C 11
CH4 O2 2700-2800 C 11
H2 Air 2000-2100 C 11, 12
H2 O2 2550-2700 C 11, 12
C2H2 Air 2100-2400 C 11, 12
C2H2 O2 3050-3150 C 11, 12
C2H2 NO2 2600-2800 C 11, 12
Inductively
Coupled Plasma
6,000-10,000 C 12
 Old Methods
Reductive Amination of Phenyl-2 - propanone
with Aluminum amalgam
1 Reducing ephedrine/pseudoephedrine to
methamphetamine via Catalytic Hydrogenation.