Subject: Oxycodone/morphone from codeine the hard way
   From: smi@sch.tiac (Samson)

Okeley dokeley,

Here is a really roundabout way of getting from codeine to
oxycodone/oxymorphone. It starts with the method laid out by
Rappaport and Barber in J. Med Chem, 1975, 18(11) 1074-1077
(Thanks ranger....good issue) for getting thebaine from codeine:

This method goes codeine -> codeine 6-methyl ether (CME) -->
thebaine.

CME: An excess of potassium hydride (300 mol) was washed with
hexane (3 X 50 ml) and then suspennded in THF (50 ml). With
stirrng under a nitrogen atmosphere, a solution of codeine (1.00
g, 2.33 mmol) in 50 ml THF was added to the KH suspension over a
period of 2hr and stirred for an additional hour. Methyl iodide
(0.43 ml, 6.66 mmol) was added to the mixture rapidly and the
reaction was quenched after 90 sec with 20 ml of 1 N NaOC2H5 in
ethanol. Water (50 ml) was added and the solution evaporated to
remove organic solvents. The resulting aqueous mixture was
extracted with chloroform (4 X 50 ml), and the chloroform
extracts were washed witha small portion of water, dried over
MgSO4 and evaporated to give a crude solid which was crystallized
from EtOH to give 0.87g CME (Yield 83%).

Thebaine by oxidation with gamma-MnO2: A solution of CME (313 mg,
1.00 mmol) in THF (10ml) was shaken vigorously with gamma-MnO2
(440 mg, 5.0 mmol) under a nitrogen atmosphere at room
temperature. Further portions of  gamma MnO2 (440 mg, 5.0 mmol)
were added at intervals of 1, 3, 5, and 10 hr. After 24 hr, the
black mixture was filtered through a fine sintered glass funnel,
the residue was washed with THF (4 X 50 ml) and the washings were
were combined with the original filtrate to  and evaporated to
give 207 mg of crude thebaine. The MnO2 was then washed with
methanol (4 X 30 ml) to yield an additonal 119 mg of crude
thebaine. The two fractions were combined and crystallized from
ethanol to give thbaine (251 mg, 80% yield).

Now, from  the _Pharmaceutical Manufacturing Encyclopedia_
(further info on this volume by request), a procedure is given
for converting thebaine to oxymorphone with oxycodone as an
intermediate. It is a synopsis of US Pat 2,806,033 (1957):

Thebaine is dissolved in aqueous formic acid and treated with 30%
H2O2; neutralization with aqueous ammonia gives
14-hydroxycodeinone. It is hydrogenated to give oxycodone. 90 ml
of concentrated HBr are heated to 90'C. 9 grams of
14-hydroxydihihydrocodeinone (oxycodone) are then added under
stirring and the mixture is is quickly heated to 116'C and kept
at this temperature under reflux for 20 min., with continued
stirring. The resulting brown solution is diluted with about 90
ml of water and chilled with ice. Aqueous 10% NaOH is now added
to alkaline reaction and the liquid is extracted 3 times with 100
ml portions of chloroform. The layers are separated and the
aqueous phase is filtered and acidified with conc. HCl, treated
with charcoal and filtered.

The filtrate is treated with conc aqueous ammonia until the
mixture  gives a pink color on phenolpthalein paper. The liquid
is extracted 7 times with 100 ml chlorform portions, the extracts
are combined, dried with anhydrous Na2SO4 and evaporated. The
residue is dissolved in ethanol by refluxing and the ethanol
evaporated nearly to dryness. 100 ml benzene are then added, the
mixture refluxed for 1/2 hour and set aside for crystallization.
After cooling [oxymorphone] is collected by filtration. 2.3 g of
a white crystalline powder are obtained...

Notes: The _Encyclopedia_ is notoriously circumspect about the
synths it gives. For instance, the procedure given for
dextroamphetamine starts with dl-amphetamine and describes how to
resolve the isomers. Thanks! I don't know if that makes the
information therein "unreliable", but there are surely many
important blanks left to be filled in (which I don't know enough
to do). The Merck Index says of oxycodone, "Prepn by catalytic
reduction of hydroxycodeinone, its oxime, or its bromination
products or by reduction of hydroxycodeinone with sodium
hydrosulfate". This seems to be in step with the the information
given in the _Encyclopedia_. Also from the Merck, oxymorphone is
obtained from oxycodone by "boiling with concd. aq. hydrobromic
acid", the patent listed above being cited. (also see Weiss, J.
Am Chem Soc 77, 5981 (1955)).

I imagine there are ways of getting from codeine to
14-hydroxy-whatever without going through thebaine. Thebaine 
is the best starting material given its reactivity with
hydrogen peroxide. On the other hand, it is strictly controlled,
has no therapeutic use (you won't find it in any dead
grandmother's medicine cabinet...), and it one of the more scarce
opium alkaloids. Whether or not pharmaceutical manufacturers use
thebaine as a starting material on a large scale I have not been
able to verify. Older literature is rife with whining about the
scarcity of thebaine and the need for new ways to get from more
abundant alkaloids to 14-hydroxy compounds and oripavine. But
over the last 20 years or so, Papaver braectatum, a high-thebaine
poppy has increasingly been cultivated in Turkey, and the French
pharmaceutical giant Sanofi has genetically engineered a very
high thebaine variant of somniferum (up to 20% thebaine). On the
latter point, it is interesting to note that France now surpasses
Turkey in (licit) opium production (only topped by India and
Australia). Does this mean that thebaine is flooding the labs? I
don't know.

[see http://www.undcp.org for opium production numbers, and
http://www.elf.fr/us/doss/pavot/pavind.htm for info on the French thebaine
monster poppy.] 

Any corrections welcomed. I'm sure there's something not kosher in here
somewhere.

-- 
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                   Oh the humanity...
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