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Industrial Secrets of Ephedrine Production PDF
Industrial Secrets of Ephedrine Production PDF
Chapter 20 & 21
Although there are many ways of producing methylamine, this procedure for
producing L-ephedrine requires a methylamine of high purity. The standard
commercial reaction, using methanol and ammonia compressed over a zeolite
catalyst, also produces dimethylamine and trimethylamine. These compounds
will interfere with the ephedrine production unless they are fractionally distilled
beforehand.
This procedure is desirable in the sense that it does not require the use of
explosive or highly flammable substances such as nitromethane. The
disadvantage is the relatively low conversion rate, which requires much boiling,
separation through crystallization, basifying of the solution to liberate gas,
drying of the evolving gas, then finally purification by condensation of the
methylamine gas, and the remaining ammonia gas is converted back into
ammonium chloride in solution. The ingredients are very easy to acquire and
these boils are relatively safe. There is only about a 50-60% conversion to
methylamine hydrochloride in the reaction, so it is important later to remove the
ammonia gas caused by basifying the methylamine. This is relatively easy with
a condenser coil kept at -15C to -20C, as methylamine liquefies at -6C and
ammonia gas at -33.4C. This is enough of a temperature difference, that
fractional distillation probably isnt necessary. It is however believed necessary
to use dry gas during condensation, as moisture in the condensation will lead to
azeotropes with water, making the ammonia and methylamine gases more
difficult to separate. Therefore, the use of the drying tube/canister described in
FIG. 24 is necessary for a clean separation of the methylamine.
Wet methylamine gas first flows through the top center of the device and down
to the bottom of the vessel. The gas is evenly dispersed around the bottom of the
device and forced by pressure upwards and through the dry magnesium sulfate,
passing through a perforated stainless steel bottom. The dry gas now exits
through the top portion of the device after the dry magnesium sulfate has
absorbed. A stainless steel moisture meter should be welded into the top portion
of the apparatus, and extend into the magnesium sulfate. This will allow for an
external reading and estimation when desiccant requires replacement, as the
magnesium sulfate will become more conductive as it absorbs water.
Filter the solution first by decanting (pouring off) and saving the liquid without
any settled ammonium chloride, where the remaining liquid is poured through a
vacuum Buchner funnel to recover ammonium chloride crystals. The liquid
solution is again set aside and saved. Boil the liquid solution again under aspirator
vacuum until the solution is concentrated to nearly half again (1/4 the original
volume) or less.
Basifying the resulting product with sodium hydroxide (lye) solution will result
in ammonia gas being produced along with methylamine gas, as some ammonium
chloride will be present. A stainless steel pressure balancing apparatus for
liberating the gas has been shown in FIG. 23. Heating the pressure balancing
apparatus to near 90C will liberate any gas dissolved in solution and gasify any
methylamine or ammonia.
The ammonia gas will interfere with the ephedrine production during amination
and needs to be removed for decent yields. One practical way to separate the
methylamine gas from the ammonia gas is to use a custom welded stainless steel
condenser coil apparatus connected to the gas output of the drying canister, which
is connected to the pressure balancing apparatus. Anti-freeze fluid from a
refrigeration system is well circulated through the cooling coil as shown in FIG.
25. However, the evolving gas should be first dried in an in-line drying tube filled
with fresh, dry magnesium sulfate before reaching the condenser FIG. 24 to
remove water that will cause the gases to form azeotropes with the water.
Azeotropes from water will make ammonia and methylamine much more difficult
to separate.
The best option for producing relatively pure methylamine gas from the
beginning, which will yield the highest amount of ephedrine in animation, is
through the reduction of nitromethane into methylamine hydrochloride, then the
subsequent basifying of the product with sodium hydroxide (lye) solution. The
additions of a lye solution will produce much evolving methylamine gas, where a
stainless steel pressure balancing apparatus that directs a portion of the evolving
gas to the top of the dripping lye solution is described in FIG. 23. Use Teflon
seals for an access port, as methylamine is highly corrosive to most seals. The
evolving gas can be bubbled through Teflon tubing although HDPE works as well,
through an optional canister containing desiccant medium such as chunks of dry
magnesium sulfate FIG. 24, then into a cold methanol solution infused with dry
ice. The methylamine will rapidly liquefy and dissolve into the solution at these
low temperatures.
Assemble a 20L round of flat bottom glass flask with the corresponding
heating/magnetic stirring mantel, where the flask should have a 24/40 adapter for
a stainless steel temperature probe, and a separate reflux condenser perhaps 40/50
or some larger size.
Drop a stirrer magnet into the solution, then add 1050g of 40 Mesh iron filings,
2250 ml of water and 10g of Ferric Chloride. Next, add 350ml of concentrated
Hydrochloric Acid ("muriatic acid" is ok). When the bubbling ceases, add 310g
of nitromethane. Obtaining nitromethane is dsecribed in a few paragraphs.
Heat the reaction mixture to reflux with a glass condenser coil and stir at 100C
and hold the refluxfor 14 hours. Then allow the solution to cool to room
temperature.
When the solution has cooled, pour the solution into a HDPE plastic vessel with
an overhead, explosion proof stirrer. The vessel should have a chemical resistant
pH probe fitted into a sturdy location. Under strong stirring, the pH should be
raised with the addition of a medium concentration lye solution. The pH should
be brought up to 5-7 before pouring into the stainless steel pressure balancing
vessel shown in FIG. 23, as an acidic solution over time could cause a rupture in
the pressure balancing apparatus. This procedure will produce some methylamine
gas, so stirring will even out the pH and precipitate evolving gas back into the
methylamine salt again.
One easy way to test a questionable product that you did not manufacture, to
determine if the questionable product is methylamine hydrochloride, or at least in
portion, is to leave a sample in a humid area. After several hours, the product will
turn from a solid powder to a yellow liquid, as methylamine is highly hygroscopic
(absorbs water).
Nitromethane is easily obtained using race track fuel or fuel for remote control
model cars. Hobby stores carry volumes of these products, which are almost
always mixed with methanol. It is necessary to distill away most of the methanol
first, which boils at 64.7C while nitromethane doesnt boil until 101.1C, so it is
very easy to separate the two by distillation. It is not enough to simply distill the
methanol, as one must still distill the nitromethane after, to separate the
nitromethane from lubricants and oils which are often found in the fuel mixture.
To determine when one has achieved a 10% w/w methylamine solution through
gas bubbling, one can first observe and record the increase in liquid volume.
Second, one needs to extract 10 ml of properly mixed methanol/methylamine
solution from the bubbling apparatus and add to 100 ml of distilled or reverse
osmosis water. Perform a titration from a buret filled with analytical grade 1 N
HCL (hydrochloric acid), adding a very small amount of phenylphthalein solution
(a few drops) to the methylamine/alcohol/water solution as a pH indicator. As 1N
HCL is slowly added under stirring or swirling, the reaction will turn from pink to
clear when the neutralization point is reached (About 25.6 ml of 1 N HCL for a
10% methylamine solution).
Originally obtained from below:
Add a few drops of phenolpthalein indicator (1% in alcohol) and watch the
mixture
turn pink. Now, titrate with 1 N HCl, with lots of swirling (magnetic stir if you
have one)
to a colorless endpoint
The first component is the pressure balanced separatory funnel similar to what
is shown in FIG. 23. Again, the pressure balancer should be manufactured in
stainless steel for methylamine gas liberation or wherever possible. The
separatory funnel is not used to actually separate layers, but rather to regulate
the steady solution into a pressurized reaction vessel through a valve.
Otherwise, the solution will simply flow erratically or not at all because of the
pressure created by the evolving gas. With a pressure balancer, the pressure
on the top of the separatory funnel contents is equal to the pressure inside the
reaction vessel and therefore the fluid will flow by gravity freely.
The reaction vessel should be as large as required for your scale of operation,
where Ive found pressure welded, stainless steel cylinders with a capacity of
10-20 liters to be ideal for an average person to operate and dismantle for
cleaning. There should be a decent size stainless steel access port, sealable by
clamp, and again a Teflon gasket to ensure proper sealing. The top center of
the reaction vessel should have a welder stainless steel tube that has been
welded vertically, where to 5/8 stainless steel tubing should be used.
Stainless steel valves with pressure fittings should be used to connect the
valves to the stainless steel tubing.
An inline stainless steel check valve is absolutely necessary for the exit gas,
as back flow is a common problem with these systems. Without one, your
methylamine/methanol solution will most certainly be sucked back into the
pressure balancer or the drying tube. Again, the use of chemical resistant
valves on this apparatus is a must. If the valve is resistant to ammonia
according to a chart, it will very likely be resistant to methylamine as well.
Because we are using many chemicals, some toxic, corrosive, and poisonous
in high concentrations, it is necessary and relatively easy to exercise safe
procedure for both the workers and the environment.
Full face masks with the proper, corresponding filter cartridges, are a bare
minimum in this work environment while using hazardous chemicals. When
hazardous chemicals are not being used, particle masks should be worn at all
times to avoid contamination of the yeast cultures or fermenters.
Filter cartridges only remove the majority of the pollutants, and really never
all the pollutants, so for certain times this can present a problem. Overall, it is
healthier and sometimes a better idea to use supplied air. Working around
methylamine in particular warrants the use of supplied air, or during times of
very high bleach concentrations in the facility.
A supplied air system is shown in FIG. 26. The face mask is always positively
pressurized with air, so there is generally no possibility of breathing any of the
pollutants unless the mask isnt fitted properly.
Supplied air comes from an air compressor, where we have been quite
successful using electric air compressors intaking outside air. An Egress bottle
is a small compressed air cylinder worn on the workers belt, so that a loss of
air pressure will still allow several minutes of breathable air and time to exit a
toxic environment.
The main concern is that you avoid using a gas/fuel operated compressor, or a
compressor would have means of bringing in polluted air. Wherever the
compressor is located, clean air must be a priority. Also, wearing an Egress
bottle on the operators waste will allow for some air while he/she is walking
to the air hose, where complete protection from environmental air is a priority.
Gloves are always a concern. I prefer to have several different types of gloves
for different parts of any process.
So for example, thin neoprene gloves are the best option for tedious tasks that
dont require working with strong chemicals, such as when one is in the clean
room inoculating Petri dishes. On the other hand, thick chemical resistant
gloves that extend almost up to the elbow is necessary when dealing with some
chemicals such as solvents, acids, and bases.
FIG. 26