
Phenylacetaldehyde to Methamphetamine synthesis, by Labrat
----------------------------------------------------------

Grignard reagents add to aldimines/Schiff bases to give amines, in which
the hydrocarbon residue of the Grignard is attached to the carbon atom.
In case of methamphetamine, this means that that methyl Grignard reagent
adds to the Schiff base between phenylacetaldehyde and methamphetamine.
The first step in the synthesis is the preparation of the Schiff base,
which is exemplified below:

1a) JACS 69, 1792 (1947)

A solution of 45,7 g (0.38 mole) of freshly distilled (Note 1)
phenylacetaldehyde in 100 ml benzene was cooled to 0 deg C and a solution
of 15.5 g (0.5 mole) of anhydrous methylamine in benzene (Note 2) was
added. An exothermic reaction occured with separation of water; start
refluxing with a Dean-Stark trap attached to the reflux condenser to
collect the water that is generated in the reaction. When no more water
separates, distill off the solvent and distill the aldimine. Yield ~47 g
(~90%)

Note 1: The phenylacetaldehyde will polymerise on standing. This polymer is
        degraded to the monomer on distillation.

Note 2: According to the Merck Index, a saturated solution of methylamine
        in benzene is 10.5 g MeNH2 in 100 ml benzene at room temp. Prepare
        the benzene/methylamine solution by bubbling methylamine gas into
        benzene at 0 deg C.


1b) (alternative) JACS 70, 3868 (1948)

Distill methylamine gas (prepared by dripping 50% NaOH in water over
methylamine hydrochloride crystals) onto cooled phenylacetaldehyde (45.7 g,
0.38 mole) while stirring until the solution has gained about 15 g (0.5
mole) of methylamine. Let stand for 1-2 hrs under cooling and stirring.
Extract the mixture with dry ether, dry the ether and evaporate the solvent
to get about 80-90% yield of aldimine.

With the aldimine in hand, it's important to proceed directly to the
next step: the preparation of a methyl Grignard solution in ether.


2) Same references as the above steps.

Methyl Grignard reagent is prepared by adding 71 g (0.5 mole) of methyl
iodide to a suspension of 12.2 g (0.5 mole) of Mg turnings in 150 ml dry
ether. Adding a crystal of iodine speeds up the reaction. After about
1/2 hour standing, cool the Grignard reagent to 0 deg C and add dropwise
the aldimine obtained in the previous step (this better be ~0.32 mole!)
dissolved in the minimum amount of dry ether. After the addition, remove
the ice-bath and start refluxing the solution (I guess for about 2
hours). Afterwards, decompose the excess Grignard reagent by adding
dilute (15%) ice cold HCl until the pH<2. Separate the ether layer and
discard this. Bring the pH of the aqeous solution to >10, extract with
3 x 250 ml ether and dry the ether. Bubble HCl gas through the solution to
get an unspecified yield of methamphetamine hydrochloride.

[ Note by Rhodium: The synthesis is a complete rework and improvement of 
an idea originating from Gazz. Chim. Ital. 77; 320,323 (1947). ]

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Synthesis of P2P from phenylacetaldehyde and methyl iodide, written by RatHead


1) Methyl Iodide:
-----------------

Methyl Iodide is an important reagent in organic chemistry. It affords the 
organic chemist a means of adding a methyl group to compounds. It is most 
conveniently prepared by the reaction of PI3 on methanol.

31 grams (1.0 mole) of red phosphorous is placed in a 3 neck 500 ml. rb. 
flask add 40 ml (1.0 mole) of methanol. Attach fractionating column packed 
with freshly dried calcium chloride. (note: a small piece of stainless 
screen may be needed at bottom) Attach distillation head, condenser, and 
receiver adapter to a 100 ml. rb. flask submerged in ice water.

Dissolve 83.8 grams (2/3 mole.) of Iodine in 120 ml. of methanol. Pour 
into 250 ml sep. funnel attach to rb. flask. Add 42.3 grams (1/3 mole) 
Iodine to flask and swirl. Depending on ambient conditions heat may be 
required to start the reaction. If heat is used be prepared to remove and 
cool if needed to maintain slow but steady distillation. Once initial 
reaction has stabilized add more iodine/methanol solution dropwise to 
maintain a slow and steady distillation. Collect the fraction boiling at 
42 degrees C. When the reaction has subsided, do not heat flask excessively 
as Phosphine may be produced 

Notes: Maintain cold water through condenser at all times ensure all joints 
are tight and vapour secure keep receiver flask submerged and well chilled.
Yield 50~60 ml. 80-90%


2) Dimethyl Cadmium:
--------------------

To 500 ml. 3-neck rb. DRY FLASK attach a reflux condenser. Attach 125ml 
sep. funnel, add 31.3 ml. methyl iodide either freshly prepared or dried 
overnight with calcium chloride. Add 60 ml. ANHYDROUS diethyl ether to sep. 
funnel, replace stopper.
Add 12.5 grams Magnesium turnings to flask. Add 75 ml. ANHYDROUS ether to 
flask. Allow aprox. 10 ml. of halide ether solution to enter flask. If 
cloudiness does not become apparent in 1 or 2 min stop. DO NOT ADD MORE!! 
Take a glass rod about 12 inches in length and score with a 3 corner file 
2 inches from one end using pliers and a rag to protect your hands break 
away the 2 inch piece. using the remaing 10 inch piece gently poke at the 
magnesium turnings to expose fresh metal.
If reaction starts, add halide dropwise as quickly as the reflux column 
can handle. Be prepared to stop and cool with ice water bath if needed.
When all the halide has been added and the reaction is no longer refluxing, 
add 31.2 grams of anhydrous cadmium chloride in small portions through 
side neck restoppering after each addition.
After all the Cadmium chloride has been added, the flask will have a 
tannish brown solid mass inside. This is the dimethyl cadmium, keep it 
covered and protected from air. Proceed immediately to next part if at all 
possible.

Notes: Avoid breathing the cadmium chloride dust (it needs to be finely 
ground after drying) avoid contact with the methyl iodide or ether solution 
of methyl iodide avoid breathing any vapours of the metal conversion 
reaction (it smells like garlic if you must know).

3) Phenyl-2-Propanone:
----------------------

To a clean dry sep. funnel add 64 ml. phenylacetaldehyde (needs to be as 
dry as possible) and 50 ml. ANHYDROUS ether. Add dropwise the aldehyde/ether 
solution to the dimethyl cadmium swirling occasionally to break up the clumps. 
Be prepared to stop addition and cool if needed. When reflux has subsided do 
not heat. Quickly pour into a 1000 ml. beaker containing 100 ml. distilled 
water 10 ml conc. HCl and 100 cc. of chipped ice. Neutralize with sat. sodium 
bicarb untill fizzing stops. Separate, and extract water layer with 2x50 ml 
portions of technical grade ether. Distill under reduced pressure to strip 
off excess ether. Test with bisulfite any product not forming addition is 
phenyl-2-propanol (very small amount) can be saved for later oxidation.
Hydrolyse addition product and distill if desired. bp. 100 at 13 mm.
Yield 50~55 ml aprox 85% of P2P.

Note: this is only an example of a substituted Grignard reaction. Any 
attempt to actually produce or possess this substance may be illegal in 
many countries. This is offered as information only. 


--------------------------------------------------------------------------------


Subject:      phenylacetaldehyde from phenylalanine repost
From:         ssve@aol.com (SSVE)
Date:         1996/07/09
Newsgroups:   alt.drugs.chemistry

I suppose my original post was a little glib when I claimed simply that
phenylalanine in dilute sulfuric acid would turn ino
phenylacetaldehyde,with portionwise additions of NaNO@ or lazy.  Since I
got some bad mail suggesting I' a spook and since the post has
dissappeared, I guess i"ll try again providing contions and a little
homework:

Standard organic chemistry texts that I have read give nitrosification in
acetic aqueous media as a means of deamination of aromatic amines ( the
product being the corresponding alcohol).  The same texts stane that the
reaction is of LITTLE or no utility with aliphatic amines in general,
giving mixtures of alkenes and alcohols.   Again, another reaction I want
to point out is that of DECARBONYLATION OF ALPHA HYDROXY AMINES.  Such
elementary texts describe, and I quote from Noller: CHEMISTRY OF ORGANIC
COMPOUNDS, Saunders, p 857, " When alpha hydroxy acids are boiled with
dilute sulfuric acid, carbon monoxide and water are lost with the
formation of an aldehyde, a behavior called decarbonylation.    Now,
dilute acid (aqueous albeit chilled with additions of NaNO2 are just the
mixtures used to deaminate aromatic amines) and I am claiming that the
deamination of phenylalanine that subsequently proceedes to
decarbonylation to produce phenylacetaldehyde is of very good utility
indeed under rather simple conditions, and if you follow my steps this
claim will be born out: 

TO a saturated aqueous solution of phenylalaine and some sufuric acid (
not so concentrated that the evolution of NO2 gas is too vigorous or
abrupt) I added portions of NaNO2 (noxious brown gas comes off - a fume
hood or other good ventilation is necessary although carbon monoxide
evolution is not so vigorous as to be dangerous) it is desired that the
mixture be stirred to a gentle effervescence by adding portions of NaNO2
with  gentle loving care, then gradually heating to boiling as gas (NO2)
evolution gets weaker,then cool and repeat.  After about 20 minutes a
light brownish oily residue of drops begin to separate ourt having a sweet
and candy-like smell somwhat reminiscent of cinnamaldehyde.  I continue
adding NaNO2, stirring and heating this way untill phenylalanine is spent
or I add more phenylalanineand continue as a process.  If necessary add
HCl to keep acidic when NaNO2 gas is no longer emitted.  I have by no
means perfected the process, maybe it would get better milage from the
NaNO2 if I started it chilled, but the phenylacetaldehyde is fine and
easily extracted from this mommie liquor  with trichloroethane (god have
mercy on the enviornment).
