Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FO~ PRODUCING OXYMOR?HONE
This invention relates to a process for producing
oxymorphone.
Oxymorphone is a narcotic substance. It is widely
used as an analgetic. The most frequently used method for
producing oxymorphone is described by Seki, Takamlne
Kenkyisho ~e~, 12, 52 ~1960): It involves reacting
pyridine hydrochloride with oxycodone at high
temperatures. It is disadvantageous on a commercial scale
because the reaction is difficult to control, and high
temperatures are needed. Further, this reaction produces
only moderate yields along with the formation of
substantial amounts of by-products.
It is an object of this invention to provide a
process for producing oxymorphone in good yields with
substantially no by-products.
It is a further object of the present invention to
~, selectively demethylate the oxycodone methoxy group
without affecting the other sites in the oxycodone
~ 20 molecule where ether linkages can be cleaved.
; ~ In accordance with this invention, there is provided
a process for producing oxymorphone by selectively
removing the methyl group from the methoxy group of
oxycodone compr~sing reacting oxycodone with a
demethylating amount of a demethylating agent under
demethylating conditions in the presence of an attenuating
amount of an attenuating agent to attenuate the activity
of the demethylating agent, whereby oxymorphone is
produced in good yields with substantially no by-products.
30Sui,table demethylating agents are boron compounds
capable of demethylating the methoxy group but incapable
; of forming numerous by-products. Such boron compounds
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include boron tribromide, boron trichloride or the
reaction product of such halides with alcohols, e.g.,
those containing 1 to 10 carbon atoms, preferably lower
alcohols such as those containing 1 to 6 carbon atoms,
S e.g., methanol, propanol, butanol, hexanol, etc.
Present in the reaction medium during the
demethylating reaction is an attenuating agent to
attenuate the activity of the boron compound such that
when utili~ed in the process of this invention, good
yields of oxymorphone are produced with substantially no
by-products. The attenuating agent can be a weak Lewis
base which does not chemically react with the
demethylating agent. Attenuating agents include normally
liquid aromatic solvents that do not chemically react with
the boron compound, e.g., benzene, toluene, xylene,
ethylbenzene, nitrobenzene, chlorobenzene, diphenyl ether
and mixtures thereof. Chlorobenzene is the preferred
attenuating agent. Attenuating amounts include from 25%
to 900% by weight based on the weight of the boron
compound.
It is preferred to utilize a demethylating
composition which contains a boron compound in an amount
sufficient to demethylate the methoxy group of oxycodone,
e.g. from about 5 to 20% preferably about 10% based on the
total weight of the demethylating composition and an
attenuating amount of an attenuating agent, e.g., 80 to
95% preferably about 90~ by weight, based on the total
weight of the demethylating composition.
Oxymorphone is reacted with the aforesaid
demethylating agent under demethylating conditions. This
includes using a demethylating amount of the demethylating
agent, e.g., in the case of boron trihalide, from about 2
to 8 moles, advantageously 2.5 to 3.5 moles, preferably
2.5 to 7 moles, of the boron compound per mole of
- 35 oxycodone. No significant advantage is achieved by using
more than 8 moles, although this is possible. Utilizing
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less than about 2 moles may result in an incomplete
reaction. Other demethylating conditions include suitable
reaction times, e.g., 8 to 24 hours and reaction
temperatures, e.g., from about 0 to 40C. As mentioned,
s it is preferred to react oxycodone with the aforesaid
demethylating composition. Normally, the demethylating
composition is sufficiently fluid that no further solvent
is necessary to carry out the reaction. ~owever, it may
be advantageous to add a solvent, e.g., an inert solvent
that will not react with the boron compound, e.g.,
chlorobenzene. Such a solvent is preferably the same as
but can be different from the attenuating agent employed.
Alternatively, the aemethylating agent can be added
to the reaction medium separately, provided the
attenuating agent is present in a sufficient amount to
attenuate the activity of the demethylating agent. For
example, oxycodone can be mixed with the attenuating agent
to which is added the demethylating agent.
After oxycodone demethylation has occurred to the
extent desired, the demethylation reaction is quenched by
adding to the reaction medium a quenching amount of water. -
Advantageously, water is added in an amount equal to or
greater than the volume of the anhydrous reaction medium.
To maximize yield of oxymorphone, the quenched
reaction mixture is advantageously hydrolyzed for a period
of time and under hydrolysis conditions sufficient to
increase the arnount of recoverable oxymorphone present in
the reaction medium. Hydrolysis serves to hydrolyze both
excess reactants and reaction products present in the
reaction medium after demethylation. Suitable hydrolysis
step reaction times include hydrolysis for from about 1/2
to 10 hours, preferably from 2 to 4 hours. Suitable
temperatures for the hydrolysis step range from about 60~C
to 120C, preferably from about 80C to 100C. It has ~
been found that hydrolyzing the reaction mixture at higher
temperatures, e.g. at the reflux temperature of the
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reaction mixture, is especially advantageous, particularly
when the preferred chlorobenzene attenuatiny agent/solvent
is employed. Without being bound by any particular
theory, it is believed that hydrolysis at higher
temperatures promotes hydrolysis of those reaction
products in the form of boron complexes such as complexes
containing a boron-nitrogen bond, thereby converting more
of such complexes into recoverable oxymorphone. Higher
hydrolysis temperatures may also serve to convert other
reaction by-products present into recoverable product.
After hydrolysis, the pH of the reaction mixture is
adjusted to about 4.5 to about 6 with acid, e.g.,
hydrochloric or sulfuric, filtered and then adjusted with
a suitable base, e.g., sodium hydroxide, to a pH of about
lO to 12 and extracted with one of the conventional inert
organic extraction solvents, e.g., toluene. The aqueous
layer is then adjusted to a pH of about 2 with acid and
then to about 8.5 with base and extracted with an inert
organic extraction solvent, e.g., methylene chloride,
which is evaporated to give oxymorphone substantially free
; of impurities. The first organic extract is evaporated to
give oxycodone suitable for recycle.
The following examples illustrate the invention. All
parts are by weight unless otherwise stated.
EXAMPLE l
A slurry of 25g of oxycodone base in 200ml of
chlorobenzene is placed in a vessel equipped for efficient
stirring and the contents are cooled to less than 10C. A
solution of 60g of borontribromide is prepared in 200ml of
chlorobenzene and this solution is added over a span of 5
minutes to the oxycodone slurry. The temperature rises to
about 35C. The cooling is removed and the mixture is
stirred for 18 hours. At this point the mixture is poured
into 250ml of water and the mixture is refluxed for 2
hours. The aqueous and organic layers are separated and
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the aqueous layer is assayed for oxycodone and
oxymorphone. The aqueous layer is adjusted to a pH of 5.5
with sodium hydroxide or ammonia and filtered. The
filtrate is adjusted to a pH of 12 with sodium hydroxide
and exhaustively extracted with methylene chloride. The
methylene chloride layer is separated and evaporated to
give oxycodone which can be recycled. The aqueous layer
is acidified with hydrochloric acid to a pH of 2.0 and
then adjusted to a pH of 8.5 with ammonia and exhaustively
extracted with methylene chloride. The organic layer is
evaporated to give substantially pure oxymorphone.
Data for this experiment are shown in the following
Table I as well as that obtained for other solvents
following substantially the same procedure.
TABLE I
Run # Solvent Mole BBr Yield
1 Chlorobenzene 3 76%
2 Toluene 3 82% (9~ oxycodone
recovered)
3 CHC13 4 66%
20 4 CH2C12 4 51%
CHC13 6 51%
6 Ethylene 4 29%
Dichloride
7 S-tetrachloro 4 65%
ethane
BXAMPLE 2
A slurry of 1.5 g of oxycodone in benzene is treated
all at once with 2.3g of boron tribromide in benzene and
the mixture stirred for 2 hours, the mixture was
hydrolyzed with an equal volume of water at reflux for 2
hours. The aqueous layer was assayed to indicate an 85
yield of oxymorphone and a 15% yield of oxycodone.
By essentially following the procedure of Example 2
the data in Table II was obtained.
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_ABLE II
Run # Solvent Moles BBr3 Yield
l CHCl3/Toluene 4 70%
1:1
2 Toluene 4 76% (15% oxycodone
recovered) :~
3 Toluene 6 50%
4 Toluene 3 85% (5~ oxycodone
recovered)
Toluene 2 62% (10~ oxycodone
recovered)
10 6 Toluene l 23% (68% oxycodone
recovered)
7 Xylene 3 81% (6% oxycodone
recovered)
8 Chlorobenzene 3(BC13) 70~
: EXAMPLE 3 ~-
Using the following general procedures, oxycodone is de-
methylated to form oxymorphone using a boron tribromide demethyla-
ting agent. Variations in boron tribromide/oxycodone ratio, type
of reaction medium organic solvent employed and hydrolysis condi-
tions are set forth in Table III:
Boron tribromide in solvent is added to a slurry of oxy-
codone in solvent for Runs 5-8, with the reaction medium tempera-
. ture being maintained below about 10C. The order of addition is ::
: reversed for Runs 1-4. After reaction times varying from l to 20 ;:
hours, the reaction mixture is quenched by addition of water. Hy- :~
drolysis of the reaction mixture then takes place either at 40C
or at reflux temperature of the reaction medium. The pH of the
reaction mixture is then adjusted to about 5.5, and the reaction
mixture is analyzed for oxymorphone conversion using liquid
chromatography techniques.
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The above table III data illustrate that oxymorphone
yield is improved by utilizing the chlorobenzene solvent/
attenuating agent and by utilizing hot hydrolysis
conditions.
EXAMPLE 4
Approximately 2.68kg of oxycodone are added to a 189
liter reaction vessel furnished with a heating/cooling
jacket, said vessel containing 48kg of chlorobenzene. The
contents of the reaction vessel are rapidly stirred and
the system is purged with nitrogen. About 7.8kg of boron
tribromide are added to the mixture over a period of 20-30
minutes during which time the temperature of the reaction
mixture is kept below 25C.
Upon completion of the boron tribromide addition, the
lS contents of the reaction vessel are stirred for 6 hours at
room temperature (25-28C). At this point the reaction
mixture is pumped with stirring to a 246 liter vessel
containing 32.66kg of water which has been cooled to less
than 10C. The addition process is such that the vessel
temperature remains below 30C.
The resulting slurried mixture is pumped back into
the 189 liter reaction vessel and is heated to reflux
(96C) with slow stirring so as to prevent emulsion forma-
tion. After two hours of refluxing, the reaction vessel
contents are cooled to 60-80C and the layers are allowed
to separate. Upon separation the bottom aqueous layer is
removed and the organic layer is rinsed-with 5.67kg of
de-ionized water and slowly stirred. As the mixture
settles, the layers switch so that the aqueous layer
becomes the top layer. The aqueous layer is removed and
combined with the previous aqueous extraction.
The pH of the organic layer is adjusted to 5.5-6.0
with ammonium hydroxide. About 0.45-0.9kg of darco
- (activated carbon; Darco G-60; Darco is a registered U.S.
trademark of Atlas Powder Company for a line of activated
carbons of which "G-60" is a highly activated grade for
drug/chemical purification) are added and the resulting
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mixture is filtered and then washed with 3.8-7.6 liters of de-
ionized water. The pH is readjusted to 8.8-8.9 with ammonium
hydroxide. The resulting aqueous slurry is extracted with di-
chloromethane in a continuous Karr column extractor until the
aqueous portion contains less than 1.5 mg of oxymorphone per ml.
The dichloromethane portion is backwashed with 2 3.8 liter por-
tions of de-ionized water and is returned to a 189 liter reac-
tion vessel having a heating/cooling jacket which is maintained
at 70-80C. The dichloromethane solution is stripped to dryness
and the last of the dichloromethane and residual water is removed
under vacuum. About 30 liters of anhydrous ethanol are added to
the reaction vessel whereupon the resulting mixture is warmed
to 65-70C. The mixture is filtered if necessary and the eth-
anol mixture is then cooled with stirring to less than 10C.
The resulting crystallization product is filtered and dried at
65-75C for 2-4 hours to give 1.36-1.59 kg of oxymorphone.
The filtrate is stripped to near dryness and is repla-
ced with 7.57 liters of de-ionized water. The pH is adjusted to
less than 5.0 and ls subsequently readjusted to 8.5-8.8 with
ammonium hydroxide while maintaining the temperature of the mix-
ture at less than 30C. The mixture is cooled to 10-15C and
the resulting precipitated solid is filtered and washed with two
0.95 liter portions of water at 10-15C. The solid is dried at
70-80C for a minimum of 6 hours to give 0.36 to 0.5 kg of resi-
due as additional oxymorphone-containing product.
EXAMPLE 5
- Preparation of Oxymorphone with Recovery of Unreacted Oxycodone
Oxycodone (50 g) in 400 ml of chlorobenzene is cooled
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to 8C and treated with 120 g of BBr3 in 400 ml of chlorobenzene,
over 10 minutes. The reaction medium is stirred for one hour at
room temperature and is then added to 500 ml of ice water. The
mixture is heated to reflux. The aqueous layer is then cooled
and separated, and adjusted to a pH of 5.5 with ammonia. Acti-
vated charcoal is added, and the liquid is filtered with Celite.
The pH is then adjusted to 8.5 with ammonia. The aqueous layer
is then exhaustively extracted with methylene chloride.
The methylene chloride layer is extracted with diluted
sodium hydroxide solution. The aqueous layer is then adjusted
to a pH of 4 and then 8.5, and the precipitated oxymorphone is
collected by filtration. The methylene chloride layer is ex-
tracted with lN.HCl. The resulting aqueous layer is treated
with ammonia to give a precipitate of oxycodone.
Altogether, 27.2 g of oxymorphone and 7.1 g of oxyco-
done are recovered.
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