U.S. patent application number 11/752728 was filed with the patent office on 2007-09-20 for preparation of oxycodone.
This patent application is currently assigned to JOHNSON MATTHEY PUBLIC LIMITED COMPANY. Invention is credited to Michael Lawrence Casner, Jen-Sen Dung, Erno M. Keskeny, Jin Luo.
Application Number | 20070219373 11/752728 |
Document ID | / |
Family ID | 33397118 |
Filed Date | 2007-09-20 |
United States Patent
Application |
20070219373 |
Kind Code |
A1 |
Casner; Michael Lawrence ;
et al. |
September 20, 2007 |
PREPARATION OF OXYCODONE
Abstract
A process for preparing oxycodone or an oxycodone salt, wherein
the oxycodone or oxycodone salt has low levels of impurities
(especially 14-hydroxycodeinone) is disclosed. The process
comprises the steps of: a) preparing a mixture comprising oxycodone
and a solvent and adjusting the pH of the mixture to less than 6;
and subsequently b) exposing the mixture to hydrogenation reagents
for a period of at least 1 hour.
Inventors: |
Casner; Michael Lawrence;
(Pitman, NJ) ; Dung; Jen-Sen; (Boothwyn, PA)
; Keskeny; Erno M.; (Wilmington, DE) ; Luo;
Jin; (Fullerton, CA) |
Correspondence
Address: |
RATNERPRESTIA
P O BOX 980
VALLEY FORGE
PA
19482-0980
US
|
Assignee: |
JOHNSON MATTHEY PUBLIC LIMITED
COMPANY
40-42 Hatton Garden
London
GB
|
Family ID: |
33397118 |
Appl. No.: |
11/752728 |
Filed: |
May 23, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11586392 |
Oct 25, 2006 |
|
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11752728 |
May 23, 2007 |
|
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11234627 |
Sep 23, 2005 |
7153966 |
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11586392 |
Oct 25, 2006 |
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Current U.S.
Class: |
546/45 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 489/08 20130101; C07D 489/04 20130101; C07D 489/02
20130101 |
Class at
Publication: |
546/045 |
International
Class: |
C07D 489/04 20060101
C07D489/04; C07D 489/02 20060101 C07D489/02 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 23, 2004 |
GB |
0421149.6 |
Claims
1. A process for preparing oxycodone or an oxycodone salt having
low levels of impurities, comprising the steps of: a) preparing a
solution comprising oxycodone or an oxycodone salt in a solvent and
maintaining said solution at a temperature of at least 55.degree.
C. for at least 1 hour, said solution having a pH less than 6; and
b) subsequently exposing the solution to hydrogenation reagents for
a period of at least 1 hour.
2. The process of claim 1, wherein the impurities include
.alpha.,.beta.-unsaturated ketones.
3. The process of claim 1, wherein the solution comprises, after
the maintaining step but before the exposing step, a level of
14-hydroxycodeinone that is higher than a level of
14-hydroxycodeinone before the maintaining step.
4. The process of claim 3, wherein the prepared oxycodone or
oxycodone salt contains less than 15 ppm of
14-hydroxycodeinone.
5. The process of claim 3, wherein the prepared oxycodone or
oxycodone salt contains less than 5 ppm of 14-hydroxycodeinone.
6. The process of claim 1, wherein the pH is less than 5.
7. The process of claim 1, wherein the pH is less than 3.
8. The process of claim 1, wherein the pH is less than or about
1.
9. The process of claim 1, wherein in step a) the temperature is at
least 60.degree. C.
10. The process of claim 1, wherein in step a) the temperature is
about 70-75.degree. C.
11. The process of claim 1, wherein in step a) the period is at
least 3 hours.
12. The process of claim 1, wherein in step a) the period is 5-10
hours.
13. The process of claims 1, wherein step b) is carried out at or
above about 40.degree. C.
14. The process of claim 1, wherein step b) is carried out at a
temperature between 40.degree. C. and 70.degree. C.
15. The process of claim 1, wherein in step b) the period is at
least 2 hours.
16. The process of claim 1, wherein in step b) the period is about
6 hours.
17. The process of claim 1, wherein in step b) the hydrogenation
reagents comprise a hydrogenation catalyst and either hydrogen or a
hydrogen transfer reagent.
18. The process of claim 1, wherein the process further comprises
in sequence the subsequent steps of c) stirring the solution in
contact with charcoal at a temperature of approximately
60-65.degree. C. for 5-10 hours, d) filtering the solution to
remove the charcoal, and e) cooling the solution.
19. A process for preparing oxycodone or an oxycodone salt having
low levels of impurities, comprising the steps of preparing a
solution comprising oxycodone or an oxycodone salt in a solvent and
maintaining, for a period of at least one hour, said solution at a
temperature in a range from ambient to 70.degree. C. while in
contact with hydrogenation reagents, said solution having a pH less
than 6.
20. The process of claim 19, wherein the impurities include
14-hydroxycodeinone.
21. The process of claim 19, wherein the pH is less than 5.
22. The process of claim 19, wherein substantially all of the
oxycodone or oxycodone salt in the solution is in solution during
the step of maintaining.
23. The process of claim 19, wherein in the period is at least 2
hours.
24. The process of claim 19, wherein the period is at least 6
hours.
25. The process of claim 19, wherein the process further comprises
in sequence the subsequent steps of stirring the solution in
contact with charcoal at a temperature of approximately
60-65.degree. C. for 5-10 hours, filtering the solution to remove
the charcoal, and cooling the solution.
26. The process of claim 19, wherein the step of maintaining is
performed at a temperature of at least 50.degree. C.
27. The process of claim 26, wherein the period is at least 5.5
hours.
28. The process of claim 19, wherein the step of maintaining
comprises maintaining at 50.degree. C. for 1.5 hours and then
further maintaining at 50-55.degree. C. for at least 4 hours.
29. The process of claim 19, wherein the prepared oxycodone or
oxycodone salt contains approximately 12 ppm of
14-hydroxycodeinone.
30. A process for preparing oxycodone or an oxycodone salt having
low levels of 14-hydroxycodeinone, comprising the steps of: a)
preparing a solution comprising oxycodone or an oxycodone salt in a
solvent and maintaining said solution at a temperature of about
75.degree. C. for about 10-12 hours, said solution having a pH less
than 6; and b) subsequently exposing the solution to hydrogenation
reagents at or above about 40.degree. C. for about 6.5 hours.
31. The process of claim 30, further comprising after step b) a
step c) of filtering the solution at a temperature of about
56.degree. C.
32. The process of claim 31, wherein the prepared oxycodone or
oxycodone salt contains approximately 0 ppm of
14-hydroxycodeinone.
33. The process of claim 30, wherein the pH is less than 5.
34. The process of claim 30, wherein the pH is less than 3.
35. The process of claim 30, wherein the pH is less than or about
1.
36. A process for preparing oxycodone or an oxycodone salt having
low levels of 14-hydroxycodeinone, comprising the steps of: a)
preparing a solution comprising oxycodone or an oxycodone salt in a
solvent and maintaining said solution at a temperature of about
75.degree. C. for about 5 hours, said solution having a pH of about
1; and b) subsequently exposing the solution to hydrogenation
reagents at about 65.degree. C. for about 6 hours.
37. The process of claim 36, wherein the prepared oxycodone or
oxycodone salt contains approximately 0 ppm of
14-hydroxycodeinone.
38. The process of claim 1, wherein said oxycodone or oxycodone
salt comprises oxycodone hydrochloride.
39. The process of claim 19, wherein said oxycodone or oxycodone
salt comprises oxycodone hydrochloride.
40. The process of claim 30, wherein said oxycodone or oxycodone
salt comprises oxycodone hydrochloride.
41. The process of claim 36, wherein said oxycodone or oxycodone
salt comprises oxycodone hydrochloride.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/586,392, filed Oct. 25, 2006, which is a
continuation of U.S. patent application Ser. No. 11/234,627, filed
Sep. 23, 2005, which claims priority of British Patent Application
No. 0421149.6, filed Sep. 23, 2004, the entirety of which
applications are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a process for preparing
oxycodone having low levels of impurities. In particular, the
process is useful for preparing oxycodone with low levels of
.alpha.,.beta.-unsaturated ketones.
BACKGROUND OF THE INVENTION
[0003] Oxycodone is a narcotic analgesic having the structure (I):
##STR1##
[0004] Oxycodone can be manufactured from the natural product
thebaine (II) by a well-known process as disclosed in U.S. Pat. No.
6,090,943: ##STR2## Thebaine (II) or a salt thereof is reacted with
hydrogen peroxide in isopropanol, water and formic acid, producing
14-hydroxycodeinone (III). The double bond in the
14-hydroxycodeinone (III) is reduced by reaction with hydrogen in
the presence of a Pd/BaSO.sub.4 catalyst, providing oxycodone
(I).
SUMMARY OF THE INVENTION
[0005] Recently there has been a concern about the presence of
.alpha.,.beta.unsaturated ketone impurities in pharmaceutical
products. 14-hydroxycodeinone (III) is an
.alpha.,.beta.-unsaturated ketone, and unsurprisingly, small
quantities of this compound may be found in oxycodone (I). The
present inventors have sought to provide a method for preparing
oxycodone having low levels of impurities and in particular, low
levels of .alpha.,.beta.-unsaturated ketone impurities, preferably
below 10 ppm.
[0006] Accordingly, the present invention provides a process for
preparing oxycodone or an oxycodone salt, wherein the oxycodone or
oxycodone salt has low levels of impurities, comprising the steps
of: [0007] a) preparing a mixture comprising oxycodone and a
solvent and adjusting the pH of the mixture to less than 6; and
subsequently [0008] b) exposing the mixture to hydrogenation
reagents for a period of at least 1 hour.
[0009] The inventors have found that this process surprisingly
provides oxycodone with low levels of .alpha.,.beta.-unsaturated
ketone impurities, i.e. 14-hydroxycodeinone at less than 15 ppm.
The inventors have found that in order to achieve low levels of
14-hydroxycodeinone, the pH must be adjusted before the
hydrogenation step. Suitably the mixture is heated after the pH of
the mixture is adjusted, so that the process comprises the steps
of: [0010] a) preparing a mixture comprising oxycodone and a
solvent, adjusting the pH of the mixture to less than 6 and heating
the mixture at the temperature of at least 55.degree. C. for a
period of at least 1 hour; and subsequently [0011] b) exposing the
mixture to hydrogenation reagents for a period of at least 1
hour.
[0012] This process provides oxycodone with very low levels of
.alpha.,.beta.-unsaturated ketone impurities, i.e.
14-hydroxycodeinone at less than 5 ppm.
DETAILED DESCRIPTION OF THE INVENTION
[0013] The mixture comprising oxycodone and a solvent can be
prepared by a number of methods. In a first method, oxycodone base
or a salt of oxycodone, prepared and isolated using any of the
methods known to those skilled in the art, is mixed with a solvent
to form the mixture. In a second method, 14-hydroxycodeinone is
hydrogenated in a solvent using known hydrogenation reagents,
thereby providing a mixture comprising oxycodone and a solvent. In
a third method, a mixture comprising thebaine and a solvent is
subjected to oxidation conditions (e.g. hydrogen peroxide in formic
acid and water), followed by hydrogenation conditions, thereby
providing a mixture comprising oxycodone and a solvent. Other
methods of preparing a mixture comprising oxycodone and a solvent
may be known to those skilled in the art.
[0014] The pH of the mixture is adjusted to less than 6, suitably
less than 5, more suitably less than 3 and preferably about 1. The
pH is suitably adjusted by the addition of a strong acid such as
concentrated hydrochloric acid to the mixture. Preferably at least
one equivalent of acid is added to the mixture.
[0015] The solvent in the mixture is suitably an organic solvent
such as isopropanol, ethanol or SD3A (a 95:5 mixture of
ethanol:methanol). Preferably the mixture further comprises
water.
[0016] After the pH is adjusted, the mixture is suitably heated to
a temperature of at least 55.degree. C., preferably at least
60.degree. C. and most preferably about 70-75.degree. C. The
temperature is suitably not higher than the boiling point of the
solvent. The mixture is suitably heated for a period of at least 1
hour, preferably at least 3 hours and most preferably between 5-10
hours.
[0017] Suitable hydrogenation reagents are well known to the
skilled person and typically include a hydrogenation catalyst and
either hydrogen or a hydrogen transfer reagent, such as sodium
hypophosphite. Preferred hydrogenation catalysts are precious metal
catalysts such as palladium or platinum dispersed on a support
material such as carbon or barium sulfate. In a preferred
embodiment, a precious metal catalyst is added to the mixture and
hydrogen is passed through the mixture at a pressure of 10 psi or
more (162 kPa or more). The hydrogenation step is suitably carried
out at a temperature of at least ambient, preferably at a
temperature between room temperature and 70.degree. C. The
temperature should be sufficient to dissolve the solids in the
mixture, thereby providing a solution. The mixture is exposed to
the hydrogenation reagents for at least 1 hour, suitably at least 2
hours and preferably about 6 hours.
[0018] The product of step (b) is a mixture comprising oxycodone
and a solvent. Hydrogenation catalysts may be removed by filtering
the mixture. A purified oxycodone salt may be obtained from the
mixture by reducing the temperature, and allowing the salt to
crystallise out. For example, if hydrochloric acid was used in step
(a), the hydrochloride salt of oxycodone will be produced.
Alternatively, oxycodone base may be provided by adding a base such
as sodium hydroxide to the mixture and allowing the mixture to
cool.
[0019] If precious metal catalysts are used in the hydrogenation
step, it is possible that unacceptable levels of the metals will
remain in the final product (desirably the heavy metal content of
the final product is less than 20 ppm). In one embodiment of the
present invention, the oxycodone or oxycodone salt produced in step
(b) is subjected to a further process wherein a mixture comprising
the oxycodone or oxycodone salt and a solvent is treated with
charcoal. Suitably the mixture is heated to a temperature of
approx. 60-65.degree. C., the charcoal is added, the mixture is
stirred at 60-65.degree. C. for 5 to 10 hours and the hot mixture
is filtered to remove the charcoal. Cooling the hot mixture
provides the oxycodone salt or oxycodone. Suitably the weight ratio
of oxycodone or oxycodone salt to charcoal is between 20:1 and 1:1,
preferably about 5:1. The charcoal is suitably a charcoal such as
Darco.RTM. G-60 (Norit, USA).
[0020] Oxycodone or an oxycodone salt produced according to the
process of the invention has low levels of
.alpha.,.beta.-unsaturated ketones and is advantageously
incorporated into pharmaceutical products.
EXAMPLES
[0021] The following examples are illustrative but not limiting of
the invention.
Preparation of Oxycodone Base: Route A
[0022] Thebaine (15.94 g) was added to a 250 ml flask. Water (18
ml) was added and the mixture was stirred at room temperature.
Formic acid (42 ml) was added over 3 minutes and then the mixture
was cooled in an ice bath. Hydrogen peroxide (30%, 6.7 g) was added
and the mixture was stirred for 1 hour. The mixture was removed
from the ice bath, allowed to warm to room temperature and then
heated to 48.degree. C. for 2 hours. The mixture was transferred to
a hydrogenation bottle. A 5 wt % palladium on carbon catalyst (2 g)
was added and hydrogen was passed through the mixture at
approximately 20 psi for 15 hours. The catalyst was removed by is
passing the mixture through a pad of celite and rinsing the
filtered solid with water/formic acid (3:1, 8 ml). The mixture was
cooled in an ice bath and 25% sodium hydroxide (109 ml) was added
dropwise over 50 minutes to increase the pH to 9-10. The mixture
was stirred for 1 hour and 15 minutes and the solid product was
filtered, rinsed with cold water and dried under vacuum pump for 3
hours. The product was oxycodone base (14.152 g, 87.7% yield) and
contained 178 ppm of the .alpha.,.beta.-unsaturated ketone
impurity, 14-hydroxycodeinone.
Preparation of Oxycodone Base: Route B
[0023] Thebaine (100.0 g dry weight) was dissolved in 85% formic
acid (252.3 g). 30% Hydrogen peroxide (43.6 g) was added over a
period of about two hours. The mixture was stirred for three hours.
Ammonium hydroxide solution was added to the mixture to increase
the pH to 8-9. The solid precipitate was filtered and washed with
water and ethanol. The solid was dried on the filter and in an
oven. The product was 14-hydroxycodeinone (150.52 g damp, 75.32 g
dry weight, 75% yield).
[0024] The 14-hydroxycodeinone (39.45 g of the damp solid) was
dissolved in water (81.13 ml) and 80% acetic acid (16.17 ml). 10 wt
% palladium on carbon catalyst (0.33 g wet weight, 0.16 g dry
weight) was added and hydrogen was passed through the mixture for
about 6 hours at about 12 psi. The mixture was filtered to remove
the catalyst. An ammonium hydroxide solution was added to the
mixture up to pH 9. The solid precipitate washed with water and
with ethanol, and was dried. The product was oxycodone (18.8 g, 79%
yield).
Comparative Example 1
Heating and Recrystallisation of Oxycodone
[0025] 13.257 g of oxycodone prepared via Route A was added to a
250 ml flask. An ethanol/methanol mixture (70 ml) was added to the
flask and the mixture was stirred at room temperature, heated to
reflux (78.degree. C.) for 1 hour, cooled to room temperature and
then stirred at room temperature. The mixture was cooled in an ice
bath for 30 minutes and the solid product was filtered and rinsed
with an ethanol/methanol mixture. The solid was dried under vacuum
for 3 hours. The product was oxycodone base (11.393 g, 85.95%) and
contained 210 ppm of the .alpha.,.beta.-unsaturated ketone
impurity, 14-hydroxycodeinone.
[0026] Dissolving the oxycodone, heating to 78.degree. C. for 1
hour and recrystallising did not reduce the amount of
14-hydroxycodeinone in the oxycodone.
Comparative Example 2
Heating and Recrystallisation of Oxycodone
[0027] 11 g of the oxycodone product from comparative example 1 was
added to a 250 ml flask. An ethanol/methanol mixture (55 ml) was
added to the flask and the mixture was stirred at room temperature,
heated to reflux (78.degree. C.) for 1 hour, cooled to room
temperature and then stirred at room temperature. The mixture was
cooled in an ice bath for 35 minutes and the solid product was
filtered and rinsed with an ethanol/methanol mixture. The solid was
dried under vacuum overnight. The product was oxycodone base
(10.682 g, 97.1%) and contained 165 ppm of the
.alpha.,.beta.-unsaturated ketone impurity,
14-hydroxycodeinone.
[0028] A second step of dissolving the oxycodone, heating to
78.degree. C. for 1 hour and recrystallising did not significantly
reduce the amount of 14-hydroxycodeinone in the oxycodone.
Example 1
Preparation of Oxycodone Hydrochloride Having Low Level of
Impurities
[0029] 5 g of oxycodone product from comparative example 2 was
added to a 100 ml flask. Water (10 ml) and isopropanol (10 ml) were
added and the mixture was stirred. Concentrated hydrochloric acid
(2.64 ml) was added. The mixture was heated to 75.degree. C. for 10
hours and stirred at ambient temperature overnight. The mixture was
transferred to a hydrogenation bottle and was heated to 45.degree.
C. 5 wt % palladium on carbon catalyst (0.5 g) was added to the
mixture and hydrogen was passed through the mixture at about 12 psi
for 6.5 hours. The mixture was warmed to 55.degree. C., passed
through a filter paper, cooled to room temperature and then placed
in an ice bath for 30 minutes. The solid product was filtered,
rinsed with cold isopropanol and dried overnight under a vacuum
pump. The product was oxycodone hydrochloride (5.533 g, 99.2%) and
contained less than 2 ppm 14-hydroxycodeinone (measured by HPLC and
MS-SIM (mass spectrometry with selected ion monitoring)).
Example 2a
Preparation of Oxycodone Base Having Low Level of Impurities
[0030] 1.2 g of crude oxycodone prepared via Route A was added to a
50 ml flask. Water (3.6 ml), isopropanol (3.6 ml) and formic acid
(4.8 ml) were added. Concentrated hydrochloric acid (0.24 ml) was
added. The mixture was heated to 75.degree. C. and stirred at
75.degree. C. for 10 hours. The mixture was cooled to room
temperature and stirred. HPLC showed that the level of
14-hydroxycodeinone in the oxycodone increased during the heating
step. Treatment with acid and heating does not prepare oxycodone
with a low level of impurities.
[0031] The mixture was transferred to a hydrogenation bottle. 5 wt
% palladium on carbon catalyst (120 mg) was added to the mixture
and hydrogen was passed through the mixture at room temperature and
about 12 psi for 24 hours. The mixture was passed through a pad of
celite and then placed in an ice bath. 50% sodium hydroxide (5.3
ml) was added dropwise over 17 minutes to a pH of 9-10. The mixture
was stirred at 0-5.degree. C. for 1 hour and 10 minutes. The solid
product was filtered, rinsed with cold water and dried under a
vacuum pump for four hours. The product was oxycodone base (1.072
g, 89.33%) and contained approximately 3 ppm 14-hydroxycodeinone
(measured by MS-SIM).
Example 2b
Preparation of Oxycodone Hydrochloride Having Low Level of
Impurities
[0032] 0.8 g of oxycodone base produced in Example 2a was added to
a 50 ml flask. Water (1.6 ml) and isopropanol (3.76 ml) were added.
Concentrated hydrochloric acid (0.32 ml) was added and the mixture
was heated to 73.degree. C. After 5 minutes at 73.degree. C. the
mixture was cooled to room temperature and was then stirred at room
temperature for 1 hour. The mixture was placed in an ice bath and
stirred for 1.5 hours. The solid product was filtered, rinsed with
cold isopropanol and dried under a vacuum pump overnight. The
product was oxycodone hydrochloride (0.892 g) and contained
approximately 5 ppm 14-hydroxycodeinone (measured by MS-SIM).
Example 3
Preparation of Oxycodone Hydrochloride Having Low Level of
Impurities
[0033] 18.8 g oxycodone prepared via Route B was added to a flask
containing ethanol (43.9 ml) and water (10.14 ml). Ethanol (5.71
ml) and concentrated hydrochloric acid (7.37 ml) were mixed and
then added to the flask, providing a mixture with a pH of 1. The
mixture was heated at 75.degree. C. for 5 hours and was then cooled
to 65.degree. C. The mixture was hydrogenated at 10-12 psi for six
hours using a 10 wt % palladium on carbon catalyst (175.6 mg wet
weight, 88 mg dry weight). The mixture was filtered to remove the
catalyst and cooled. The solid product was filtered and washed with
ethanol. The product was oxycodone hydrochloride (20.13 g, 75.3%)
and contained approximately 0 ppm 14-hydroxycodeinone.
Comparative Example 3a
Hydrogenation of Oxycodone
[0034] 3 g of crude oxycodone prepared by essentially the same
method as route A and containing 535 ppm 14-hydroxycodeinone was
added to a hydrogenation bottle. Isopropanol (9 ml), water (9 ml)
and formic acid (12 ml) were added. The mixture was hydrogenated
for 23 hours using a 5 wt % palladium on carbon catalyst (0.3 g).
The mixture was passed through a pad of celite and the
hydrogenation bottle was rinsed with isopropanol and water. The
mixture was cooled in an ice bath. 50% sodium hydroxide (14 ml) was
added dropwise over 22 minutes to a pH of 9-10. The mixture was
stirred at 0-5.degree. C. for 1 hour and 20 minutes. The solid
product was filtered, rinsed with cold water and dried under a
vacuum pump overnight. The product was oxycodone base (2.822 g,
94.1%) and contained approximately 26 ppm 14-hydroxycodeinone
(measured by HPLC). The hydrogenation step reduced the amount of
14-hydroxycodeinone in the oxycodone, but this method, wherein the
pH of the mixture was not adjusted before the hydrogenation, did
not afford oxycodone with an impurity level of less than 10
ppm.
Comparative Example 3b
Acidification of Oxycodone
[0035] 2 g of oxycodone base produced in Comparative Example 3a was
added to a 100 ml flask. Water (4 ml) and isopropanol (9.4 ml) were
added. Concentrated hydrochloric acid (0.8 ml) was added and the
mixture was heated to 70-72.degree. C. After 5 minutes at
70-72.degree. C. the mixture was slowly cooled to room temperature.
The mixture was placed in an ice bath and stirred for 1 hour and 20
minutes. The solid product was filtered, rinsed with cold
isopropanol and dried under a vacuum pump overnight. The product
was oxycodone hydrochloride (2.401 g) and contained approximately
38 ppm 14-hydroxycodeinone (measured by HPLC). Adjusting the pH of
the oxycodone to .about.1 and heating did not further reduce the
concentration of 14-hydroxycodone. Comparative Examples 3a and 3b
demonstrate that oxycodone with very low level of impurities (less
than 10 ppm 14-hydroxycodeinone) is not prepared by hydrogenating
the oxycodone and then treating with acid.
Example 4
Preparation of Oxycodone Hydrochloride Having Low Level of
Impurities
[0036] 4.35 g oxycodone prepared by essentially the same method as
Route B was added to a flask containing ethanol (12.5 ml) and water
(2.7 ml). Concentrated hydrochloric acid (approximately 1.5 ml) was
added to the flask, providing a mixture with a pH of about 2. The
pH of the mixture was increased to 5 by adding ammonia. The mixture
was hydrogenated at 45 psi and 50.degree. C. for 1.5 hours and then
at 10-12 psi and 50-55.degree. C. for 4 hours using a 10wt %
palladium on carbon catalyst (0.06 g). The mixture was filtered to
remove the catalyst and cooled. The solid product was filtered and
washed with ethanol. The product was oxycodone hydrochloride (3.706
g, 76.1%) and contained approximately 12 ppm
14-hydroxycodeinone.
Example 5
Preparation of Oxycodone Hydrochloride Having Low Level of
Impurities
[0037] 3 g of oxycodone product from comparative example 2 was
added to a 50 ml flask. Water (1.3 ml) and ethanol (5.58 ml) were
added and the mixture was stirred. Concentrated hydrochloric acid
(1.58 ml) was added. Further water was added so that in total 4.5
ml of water was added. The mixture was heated to 75.degree. C. for
10 hours, slowly cooled to room temperature and stirred overnight.
The mixture was heated to 40.degree. C. and transferred to a
hydrogenation bottle. 5 wt % palladium on carbon catalyst (0.3 g)
was added to the mixture and hydrogen was passed through the
mixture at between 11 and 12 psi for 6.5 hours. The mixture was
warmed to 56.degree. C. and passed through two layers of filter
paper. The bottle and filtrate were rinsed with a hot solution of 1
ml water and 5 ml ethanol, and with 20 ml of hot ethanol. The
filtrate was slowly cooled to room temperature and then placed in
an ice bath for 30 minutes. The solid product was filtered, rinsed
with cold ethanol and dried overnight under a vacuum pump. The
product was oxycodone hydrochloride (2.663 g, 79.6% yield). A
further 0.334 g of oxycodone hydrochloride was obtained by washing
the filter cake and hydrogenation bottle with water and
water/ethanol (1:1), giving a combined yield of 2.997 g and 89.5%.
Both samples of oxycodone hydrochloride contained 0 ppm
14-hydroxycodeinone (measured by HPLC and MS-SIM (mass spectrometry
with selected ion monitoring)).
* * * * *