U.S. patent application number 16/549718 was filed with the patent office on 2019-12-19 for processes for preparing morphinan-6-one products with low levels of a, -unsaturated ketone compounds.
This patent application is currently assigned to SpecGx LLC. The applicant listed for this patent is SpecGx LLC. Invention is credited to Dennis C. Aubuchon, Henry J. Buehler, William E. Dummitt, Hong Gu, Anthony Mannino.
Application Number | 20190381033 16/549718 |
Document ID | / |
Family ID | 38326629 |
Filed Date | 2019-12-19 |
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United States Patent
Application |
20190381033 |
Kind Code |
A1 |
Buehler; Henry J. ; et
al. |
December 19, 2019 |
PROCESSES FOR PREPARING MORPHINAN-6-ONE PRODUCTS WITH LOW LEVELS OF
a, -UNSATURATED KETONE COMPOUNDS
Abstract
The present invention generally relates to processes for
preparing highly pure morphinan-6-one products. The processes
involve reducing the concentration of alpha, beta unsaturated
ketone compounds present as impurities in morphinan 6 one products
or reaction mixtures including morphinan 6 one compounds by
treatment with a sulfur-containing compound.
Inventors: |
Buehler; Henry J.; (St.
Louis, MO) ; Dummitt; William E.; (St. Louis, MO)
; Mannino; Anthony; (Maryland Heights, MO) ;
Aubuchon; Dennis C.; (Arnold, MO) ; Gu; Hong;
(Oak Park, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SpecGx LLC |
Webster Groves |
MO |
US |
|
|
Assignee: |
SpecGx LLC
Webster Groves
MO
|
Family ID: |
38326629 |
Appl. No.: |
16/549718 |
Filed: |
August 23, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15710990 |
Sep 21, 2017 |
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16549718 |
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15144010 |
May 2, 2016 |
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15710990 |
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14504750 |
Oct 2, 2014 |
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15144010 |
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11915606 |
Nov 27, 2007 |
8871779 |
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PCT/US2007/005256 |
Mar 2, 2007 |
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14504750 |
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60778258 |
Mar 2, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 489/08 20130101;
A61K 31/485 20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; C07D 489/08 20060101 C07D489/08 |
Claims
1.-50. (canceled)
51. A composition comprising oxymorphone and containing about
0.001% or less, by weight of said oxymorphone, of an .alpha.,.beta.
unsaturated ketone.
52. The composition of claim 51 wherein said .alpha.,.beta.
unsaturated ketone is 14-hydroxymorphinone or
14-hydroxycodeinone.
53. The composition of claim 51 wherein said .alpha.,.beta.
unsaturated ketone is 14-hydroxymorphinone.
54. The composition of claim 51 wherein said .alpha.,.beta.
unsaturated ketone is 14-hydroxymorphinone or 14-hydroxycodeinone
and no 14-hydroxymorphinone or 14-hydroxycodeinone is detectable by
high performance liquid chromatography with mass spectrometry
detection.
55. The composition of claim 51 wherein said .alpha.,.beta.
unsaturated ketone is 14-hydroxymorphinone and said composition
comprises about 0.0005% or less, by weight of said oxymorphone, of
14-hydroxymorphinone.
56. The composition of claim 51 wherein said .alpha.,.beta.
unsaturated ketone is 14-hydroxymorphinone or 14-hydroxycodeinone
and said composition comprises about 0.0005% or less, by weight of
said oxymorphone, of 14-hydroxymorphinone or
14-hydroxycodeinone.
57. The composition of claim 51, wherein the oxymorphone is an
oxymorphone salt.
58. The composition of claim 53, wherein the oxymorphone is an
oxymorphone salt.
59. The composition of claim 55, wherein the oxymorphone is an
oxymorphone salt.
60. The composition of claim 51, wherein the oxymorphone is
oxymorphone HCl.
61. The composition of claim 53, wherein the oxymorphone is
oxymorphone HCl.
62. The composition of claim 55, wherein the oxymorphone is
oxymorphone HCl.
63. A pharmaceutical formulation comprising oxymorphone and
containing about 0.001% or less, by weight of said oxymorphone, of
an .alpha.,.beta. unsaturated ketone.
64. The pharmaceutical composition of claim 63 wherein said
.alpha.,.beta. unsaturated ketone is 14-hydroxymorphinone or
14-hydroxycodeinone.
65. The pharmaceutical composition of claim 63 wherein said
.alpha.,.beta. unsaturated ketone is 14-hydroxymorphinone.
66. The pharmaceutical composition of claim 63 comprising about
0.0005% or less, by weight of said oxymorphone, of an
.alpha.,.beta. unsaturated ketone.
67. The pharmaceutical composition of claim 63 comprising about
0.0005% or less, by weight of said oxymorphone, of
14-hydroxymorphinone.
68. The pharmaceutical composition of claim 63 wherein said
oxymorphone is oxymorphone HCl.
69. The pharmaceutical composition of claim 65 wherein said
oxymorphone is oxymorphone HCl.
70. The pharmaceutical composition of claim 67 wherein said
oxymorphone is oxymorphone HCl.
Description
FIELD OF THE INVENTION
[0001] The present invention generally relates to processes for
preparing morphinan-6-one products. The processes involve reducing
the concentration of .alpha.,.beta.-unsaturated ketone compounds
from reaction mixtures including morphinan-6-one compounds.
BACKGROUND OF THE INVENTION
[0002] The morphinan alkaloids represent a family of
structurally-related products of great medicinal importance.
Particular morphinan compounds of pharmaceutical relevance include,
for example, codeine, hydrocodone, hydromorphone, morphine,
nalbuphine, nalmefene, naloxone, naltrexone, oxycodone, and
oxymorphone. Generally, these compounds are analgesics, which are
used extensively for pain relief in the field of medicine due to
their action as opiate receptor agonists. However, nalmefene,
naloxone, naltrexone, and naltrexone methyl bromide are opiate
receptor antagonists, and are used for reversal of
narcotic/respiratory depression due to opiate receptor agonists, as
addiction therapies, and to reverse other undesirable side effects
of opiate agonist use, such as severe constipation.
[0003] Morphinan compounds and analogs thereof typically have a
ring structure generally corresponding to Formula (1):
##STR00001##
[0004] Various methods are known for the synthesis of morphinan
compounds corresponding to Formula (1). Conventional methods used
in the commercial production of morphinan compounds typically
involve the extraction of opium alkaloids from poppies (Papaver
somniferum). Generally speaking, these processes involve the
extraction of the alkaloids from opium in a liquid, precipitation
of the alkaloids, separation of the raw alkaloids (e.g., morphine
and secondary alkaloids such as papaverine, codeine, and thebaine),
and purification of the various alkaloids, optionally followed by
semi-synthesis steps to produce particular morphinan compounds.
See, for example, Barbier, A., "The Extraction of Opium,
Twenty-five years of commercial experience in the treatment of
opium," Ann. Pharm. Franc., 1947, 5, 121-40; Barbier, A., "The
Extraction of Opium Alkaloids," Bull. Narcotics, 1950, vol. 3,
22-29; Neumann, W, "The Manufacture of Alkaloids from Opium," Bull.
Narcotics, 1957, vol. 2, 34-40; Lednicer and Mitscher, Organic
Chemistry of Drug Synthesis, chapter 15, (Wiley 1977); French
Patent No. 1,000,543 to Penau et al.; British Patent No. 713,689 to
Wood et al.; and U.S. Pat. No. 2,009,181 to Kabay.
[0005] Synthetic methods for producing various morphinan compounds
are also known. These methods commonly utilize
3-methoxy-phenylethylamine as a starting material and include a
Grewe cyclization step. For example, in U.S. Pat. No. 4,368,326,
Rice discloses a process for preparing a nordihydrothebainone
(e.g., 1-bromo-N-formylnordihydrothebainone) from a
.beta.,.gamma.-hexahydroisoquinolone (e.g.,
1-(2'-bromo-4'-methoxy-5'-hydroxybenzyl)-2formyl-1,3,4,5,7,8-hexahydroqui-
nolin-6-one) by Grewe cyclization catalyzed using a super acid
catalyst alone or with a combination of an ammonium fluoride
complex and trifluoromethanesulfonic acid.
[0006] Many pharmaceutically desirable morphinan compounds and
analogs thereof have a ketone group on the C-ring of Formula (1)
and a saturated bond between the two carbon atoms positioned
.alpha. and .beta. to the ketone on the C-ring of Formula (1).
According to the common nomenclature, the ketone is present on the
C(6) carbon atom, with the .alpha. and .beta. carbon atoms being
the C(7) and C(8) positions (see, e.g., Formula (1)). Thus, these
compounds may be referred to as morphinan-6-one compounds. Various
processes for producing morphinan-6-one compounds are known, many
of which involve some form of catalytic hydrogenation of
.alpha.,.beta.-unsaturated ketone intermediate compounds at
particular points in the process. Commonly used catalysts include,
for example, palladium and platinum. For example, in U.S. Pat. No.
6,177,567 to Chiu et al., 14-hydroxycodeinone (an
.alpha.,.beta.-unsaturated ketone compound) is converted to
oxycodone by hydrogenating the .alpha.,.beta.-unsaturation using
conventional methods such as reduction by diphenylsilane and
Pd(Ph.sub.3P)/ZnCl.sub.2, or with sodium hypophosphite in
conjunction with a Pd/C catalyst in aqueous acetic acid, or by Pd/C
catalytic transfer hydrogenation.
[0007] While these and other methods of reducing or removing the
.alpha.,.beta.-unsaturation are generally effective,
.alpha.,.beta.-unsaturated ketone compounds may persist as
impurities in the final products of desirably
.alpha.,.beta.-saturated morphinan-6-one products, such as
oxycodone. Additionally, known hydrogenation methods may tend to
undesirably reduce the ketone as well as reducing or removing the
.alpha.,.beta.-unsaturation. Further, these and other hydrogenation
methods are not normally capable of efficiently and economically
reducing the levels of 7,8-unsaturation to below 10 to 100 parts
per million, or less.
[0008] Some .alpha.,.beta.-unsaturated ketone compounds show
mutagenic activity in certain tests. Therefore, a need persists for
processes for preparing highly pure morphinan-6-one products having
a relatively low concentration of .alpha.,.beta.-unsaturated ketone
compounds present as impurities therein.
SUMMARY OF THE INVENTION
[0009] Among the various aspects of the present invention is the
provision of a process for the preparation of morphinan-6-one
products. The process involves reducing the concentration of
.alpha.,.beta.-unsaturated ketone compounds which are present as
impurities in reaction mixtures including morphinan-6-one
compounds. The process generally involves forming a reaction
mixture including a morphinan-6-one compound and an
.alpha.,.beta.-unsaturated ketone compound and treating the
reaction mixture with a sulfur-containing compound. In one
embodiment, the sulfur-containing compound is a sulfur-containing
inorganic acid or salt thereof.
[0010] Briefly, therefore, the present invention is directed to a
process for the preparation of a morphinan-6-one product, the
process comprising:
[0011] forming a reaction mixture comprising a morphinan-6-one
compound and an .alpha.,.beta.-unsaturated ketone compound;
[0012] treating the reaction mixture with a sulfur-containing
compound to reduce the concentration of the
.alpha.,.beta.-unsaturated ketone compound in the reaction mixture;
and
[0013] recovering the morphinan-6-one compound to produce the
morphinan-6-one product;
wherein
[0014] the morphinan-6-one compound corresponds to Formula (2):
##STR00002##
[0015] the .alpha.,.beta.-unsaturated ketone compound corresponds
to Formula (3):
##STR00003##
[0016] X is --N(R.sub.17)-- or --N.sup.+(R.sub.17aR.sub.17b)--;
[0017] R.sub.1 and R.sub.2 are independently selected from
hydrogen, substituted and unsubstituted acyl, acyloxy, alkenyl,
alkoxy, alkoxyaryl, alkyl, alkylamino, alkylthio, alkynyl, amino,
aryl, arylalkoxy, carboalkoxy, carbonyl, carboxyalkenyl,
carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkylether, halo, haloalkoxy, haloalkyl,
heteroaryl, heterocyclic, hydroxyalkyl, hydroxyl, or nitro;
[0018] R.sub.3 is hydrogen, hydroxy, protected hydroxy, alkoxy, or
acyloxy;
[0019] R.sub.10 is hydrogen, hydroxy, protected hydroxy, halo,
keto, tosyl, mesyl, or trifluoromesyl;
[0020] R.sub.14 is hydrogen, hydroxy, or protected hydroxy;
[0021] R.sub.17 is hydrogen, alkyl, cycloalkyl, alkylcarboxy,
alkylenecycloalkyl, alkoxycarbonyl, allyl, alkenyl, acyl, aryl,
formyl, formyl ester, formamide, benzyl, or an amino protecting
group; and
[0022] R.sub.17a and R.sub.17b are independently selected from
hydrogen, alkyl, alkenyl, allyl, cycloalkyl, aryl, or benzylyl,
and
[0023] the morphinan-6-one compound comprises less than about 0.1%
(by weight) morphinan-6-one product of the
.alpha.,.beta.-unsaturated ketone compound.
[0024] The present invention is also directed to a process for
preparing a morphinan-6-one product, the process comprising:
[0025] forming a reaction mixture comprising an
.alpha.,.beta.-unsaturated ketone compound;
[0026] treating the reaction mixture with a sulfur-containing
compound to reduce the .alpha.,.beta.-unsaturated ketone compound
to form a morphinan-6-one compound; and
[0027] recovering the morphinan-6-one compound to form the
morphinan-6-one product,
wherein
[0028] the morphinan-6-one compound corresponds to Formula (2):
##STR00004##
[0029] the .alpha.,.beta.-unsaturated ketone compound corresponds
to Formula (3):
##STR00005##
[0030] X is --N(R.sub.17)-- or --N.sup.+(R.sub.17aR.sub.17b)--;
[0031] R.sub.1 and R.sub.2 are independently selected from
hydrogen, substituted and unsubstituted acyl, acyloxy, alkenyl,
alkoxy, alkoxyaryl, alkyl, alkylamino, alkylthio, alkynyl, amino,
aryl, arylalkoxy, carboalkoxy, carbonyl, carboxyalkenyl,
carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkylether, halo, haloalkoxy, haloalkyl,
heteroaryl, heterocyclic, hydroxyalkyl, hydroxyl, or nitro;
[0032] R.sub.3 is hydrogen, hydroxy, protected hydroxy, alkoxy, or
acyloxy;
[0033] R.sub.10 is hydrogen, hydroxy, protected hydroxy, halo,
keto, tosyl, mesyl, or trifluoromesyl;
[0034] R.sub.14 is hydrogen, hydroxy, or protected hydroxy;
[0035] R.sub.17 is hydrogen, alkyl, cycloalkyl, alkylcarboxy,
alkylenecycloalkyl, alkoxycarbonyl, allyl, alkenyl, acyl, aryl,
formyl, formyl ester, formamide, benzyl, or an amino protecting
group; and
[0036] R.sub.17a and R.sub.17b are independently selected from
hydrogen, alkyl, alkenyl, allyl, cycloalkyl, aryl, or benzylyl.
[0037] Other objects and features will be in part apparent and in
part pointed out hereinafter.
DETAILED DESCRIPTION OF THE INVENTION
[0038] The present invention is generally directed to processes for
preparing highly pure morphinan-6-one products. The processes
generally involve treating a reaction mixture including a
morphinan-6-one compound and an .alpha.,.beta.-unsaturated ketone
compound with a sulfur-containing compound. Advantageously, the
process effectively reduces the concentration of undesirable
.alpha.,.beta.-unsaturated ketone compounds to acceptable levels
without removing or otherwise affecting other more desirable
compounds or substituent groups or unsaturation thereon. Moreover,
the sulfur-containing compound may be utilized to reduce the
concentration of .alpha.,.beta.-unsaturated ketone compounds
present in the reaction mixture from levels of about 0.5% (by
weight) or more to levels of not more than about 0.1% (by weight),
or lower (e.g., about 0.01% (by weight), about 0.001% (by weight),
or lower), with minimal side reactions, ketone reduction, and/or
any other undesirable effects.
Morphinan Products and Processes for Preparing the Same
[0039] Generally speaking, the morphinan-6-one products of interest
in the process of the present invention include morphinan compounds
having a keto group at the C(6) carbon atom on the C-ring and a
saturated bond between the C(7) and C(8) carbon atoms on the C-ring
(i.e., morphinan-6-one compounds). More specifically, the
morphinan-6-one compounds are opiate receptor agonists or
antagonists generally corresponding to Formula (2):
##STR00006##
wherein
[0040] X is --N(R.sub.17)-- or --N.sup.+(R.sub.17aR.sub.17b)--;
[0041] R.sub.1 and R.sub.2 are independently selected from
hydrogen, substituted and unsubstituted acyl, acyloxy, alkenyl,
alkoxy, alkoxyaryl, alkyl, alkylamino, alkylthio, alkynyl, amino,
aryl, arylalkoxy, carboalkoxy, carbonyl, carboxyalkenyl,
carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkylether, halo, haloalkoxy, haloalkyl,
heteroaryl, heterocyclic, hydroxyalkyl, hydroxyl, or nitro;
[0042] R.sub.3 is hydrogen, hydroxy, protected hydroxy, alkoxy, or
acyloxy;
[0043] R.sub.10 is hydrogen, hydroxy, protected hydroxy, halo,
keto, tosyl, mesyl, or trifluoromesyl;
[0044] R.sub.14 is hydrogen, hydroxy, or protected hydroxy;
[0045] R.sub.17 is hydrogen, alkyl, cycloalkyl, alkylcarboxy,
alkylenecycloalkyl, alkoxycarbonyl, allyl, alkenyl, acyl, aryl,
formyl, formyl ester, formamide, benzyl, or an amino protecting
group; and
[0046] R.sub.17a and R.sub.17b are independently selected from
hydrogen, alkyl, alkenyl, allyl, cycloalkyl, aryl, or benzyl.
[0047] When R.sub.17 is hydrogen, alkyl, alkenyl, cycloalkyl, aryl,
or benzyl, salts of the secondary or tertiary amine can be formed
wherein the anion is chloride, bromide, acetate, formate, sulfate,
bisulfate, bisulfite, oxalate, citrate, malate, tartrate, triflate,
trifluoroacetate, methane sulfonate, and the like. When X is
--N.sup.+(R.sub.17aR.sub.17b)--, the counter-ion can be chloride,
bromide, iodide, trifluoroacetate, trifluoromethanesulfonate,
methane sulfonate, acetate, p-toluenesulfonate, sulfate, bisulfate,
bisulfite, phosphate, hydrogen phosphate, dihydrogen phosphate,
fumarate, oxalate, formate, tartrate, benzoate, and the like.
[0048] In one preferred embodiment, R.sub.14 is hydroxy or
protected hydroxy. In another preferred embodiment, R.sub.14 is
hydrogen.
[0049] In either of the embodiments described above (i.e., when
R.sub.14 is hydroxy or protected hydroxy or R.sub.14 is hydrogen),
R.sub.3 is either alkoxy, hydroxy, or protected hydroxy. In one
particular embodiment, R.sub.3 is methoxy.
[0050] In any one of the embodiments described above, X is
--N(R.sub.17)-- or --N.sup.+(R.sub.17aR.sub.17b)--, wherein
R.sub.17, R.sub.17a, and R.sub.17b are defined as above. Where X is
--N(R.sub.17)--, in one particularly preferred embodiment R.sub.17
is hydrogen, alkyl, alkenyl, alkylcarboxy, or cycloalkyl. Where X
is --N.sup.+(R.sub.17aR.sub.17b)--, in one particularly preferred
embodiment R.sub.17a and R.sub.17b are independently hydrogen,
alkyl, alkenyl, or cycloalkyl.
[0051] Representative morphinan-6-one compounds corresponding to
Formula (2) (and the various preferred substituent group
definitions described above) which can be treated according to the
process described herein include, for example, oxymorphone,
naloxone, naltrexone, naltrexone methylbromide, nalbuphone,
noroxymorphone, hydromorphone, hydrocodone, oxycodone,
diethoxycarbonyl-noroxymorphone, salts thereof, and the like.
Additionally, derivatives of the above morphinan-6-one compounds
which can be treated according to the process described herein
include, for example, N-demethylated-, 10-hydroxy-, 10-halo, and
10-keto-morphinan-6-one derivatives, their protected analogs, and
the like.
[0052] The method of producing the above-described morphinan-6-one
compounds for use in the present invention is not narrowly
critical, and various methods for producing morphinan-6-one
compounds are well known in the art. For example, commercial
processing methods for producing morphinan compounds typically
involve the extraction of an opium alkaloid (e.g., thebaine) from
poppies, followed by various conventional precipitation and
purification steps known to those of skill in the art. By way of
further example, the morphinan-6-one compound oxycodone may be
produced from thebaine in a substantially two-step process, as
illustrated in Reaction Scheme 1:
##STR00007##
[0053] Alternatively, various synthetic methods for producing the
above-described morphinan-6-one compounds are also known. In these
synthetic methods, a Grewe cyclization reaction is commonly used to
form nordihydrothebainone products such as by the processes
described in U.S. Pat. Nos. 4,368,326, 4,410,700, 4,521,601,
4,556,712, 4,613,668, 4,727,146, the entire disclosures of which
are hereby incorporated by reference herein. Additionally, various
methods useful for the semi-synthesis of morphinan compounds and
intermediates are known. For example, U.S. Pat. No. 6,177,567 to
Chiu et al. and U.S. Pat. No. 6,008,355 to Huang et al. (each of
which is hereby incorporated by reference herein) describe methods
for the synthesis of oxycodone from codeine. These and other
conventional practices are generally applicable in carrying out the
preparation of morphinan-6-one compounds and
.alpha.,.beta.-unsaturated ketone compounds that may be treated
according to the processes described herein.
[0054] As noted above, in the various conventional processes for
producing morphinan-6-one compounds described above, the resulting
morphinan product typically also includes some amount of an
.alpha.,.beta.-unsaturated ketone compound present as an impurity
in addition to the desired morphinan-6-one compound. The
.alpha.,.beta.-unsaturated ketone compounds present as impurities
generally correspond to Formula (3):
##STR00008##
wherein X, R.sub.1, R.sub.2, R.sub.3, R.sub.10, and R.sub.14 are
defined as above.
[0055] Reaction Conditions
[0056] As noted above, the morphinan products produced from
conventional processes for preparing morphinan-6-one compounds also
yield some amount of an .alpha.,.beta.-unsaturated ketone present
as an impurity; that is, both the morphinan-6-one compound
corresponding to Formula (2) and the .alpha.,.beta.-unsaturated
ketone compound corresponding to Formula (3) are present in the
morphinan product.
[0057] The morphinan products produced from conventional morphinan
processing methods typically comprise less than about 2% by weight
of an .alpha.,.beta.-unsaturated ketone compound. Preferably, the
morphinan products comprise less than about 1% by weight of an
.alpha.,.beta.-unsaturated ketone compound. More preferably, the
morphinan products comprise less than about 0.8% by weight of an
.alpha.,.beta.-unsaturated ketone compound. Still more preferably,
the morphinan products comprise less than about 0.5% by weight of
an .alpha.,.beta.-unsaturated ketone compound. As noted above,
however, it is desirable to minimize or further minimize the
concentration of .alpha.,.beta.-unsaturated ketone compounds
present in such products.
[0058] According to the present invention, a reaction mixture is
formed including a morphinan-6-one compound of Formula (2) and an
.alpha.,.beta.-unsaturated ketone compound of Formula (3). The
morphinan-6-one compound and the .alpha.,.beta.-unsaturated ketone
compound may be produced by any conventional method (such as those
described above), and the morphinan-6-one compound may exist as the
free base or as a salt, such as the hydrochloride salt. The
reaction mixture is treated with a sulfur-containing compound to
reduce the concentration of the .alpha.,.beta.-unsaturated ketone
compound (either by forming additional morphinan-6-one compound or
by facilitating the removal of the .alpha.,.beta.-unsaturated
ketone compound), and the morphinan-6-one compound is recovered to
produce the desired morphinan-6-one product. This process is
generically illustrated in Reaction Scheme 2, wherein the reaction
mixture including the morphinan-6-one compound and the
.alpha.,.beta.-unsaturated ketone compound is shown in brackets,
and X, R.sub.1, R.sub.2, R.sub.3, R.sub.10, and R.sub.14 are
defined as above.
##STR00009##
[0059] Various reaction mixtures (bracketed) including a
morphinan-6-one compound and an .alpha.,.beta.-unsaturated ketone
compound may be treated according to the processes described herein
to yield various highly pure morphinan-6-one products, as
illustrated in Reaction Schemes 3-10.
##STR00010##
##STR00011##
##STR00012##
##STR00013##
##STR00014##
##STR00015##
##STR00016##
##STR00017##
[0060] According to various embodiments, the reaction mixture is
formed by dissolving or otherwise dispersing the morphinan-6-one
compound and the .alpha.,.beta.-unsaturated ketone compound in a
media material (i.e., a morphinan product including the
morphinan-6-one compound and the .alpha.,.beta.-unsaturated ketone
compound is dispersed in the media material). The reaction mixture
is then treated with a sulfur-containing compound. Ideally, the
morphinan-6-one compound and the .alpha.,.beta.-unsaturated ketone
compound are in solution, but a heterogeneous mixture may also be
treated according to the processes described herein.
[0061] The media material is desirably an aqueous media or an
aqueous/organic solvent biphasic media. Exemplary aqueous media for
use in the process of the present invention includes, for example,
water, water/alcohol mixtures, dilute inorganic solvents such as
dilute sulfuric acid, ethereal solvents such as dioxane or
tetrahydrofuran, combinations thereof, and the like. Exemplary
organic solvents for use in aqueous/organic solvent biphasic media
includes, for example, butanone, ethyl acetate, butanol, diethyl
ether, benzene, chloroform, tetrachloroethylene, toluene,
1,1,1-trichloroethane, carbon tetrachloride, dibutyl ether,
cyclohexane, hexane, dipentyl ether, heptane, hexadecane,
combinations thereof, and the like.
[0062] Generally, a sufficient amount of media material to
substantially solubilize the morphinan-6-one compound and the
.alpha.,.beta.-unsaturated ketone compound in the reaction mixture
is desired, Higher amounts of media material may increase the costs
of manufacturing, as the more dilute reaction mixture may require
additional process cycle time, or require the removal or excess
media material during subsequent processing steps.
[0063] The weight ratio of media material to morphinan-6-one
compound in the reaction mixture is preferably from about 1:1 to
about 50:1. More preferably, the weight ratio of media material to
morphinan-6-one compound in the reaction mixture is from about 1:1
to about 25:1. For example, the weight ratio of media material to
morphinan-6-one compound in the reaction mixture may be from about
1:1 to about 5:1, from about 1:1 to about 10:1, from about 1:1 to
about 15:1, or from about 1:1 to about 20:1. Still more preferably,
the weight ratio of media material to morphinan-6-one compound in
the reaction mixture is from about 5:1 to about 25:1. For example,
the weight ratio of media material to morphinan-6-one compound in
the reaction mixture may be from about 5:1 to about 10:1, from
about 5:1 to about 15:1, or from about 5:1 to about 20:1. Still
more preferably, the weight ratio of media material to
morphinan-6-one compound in the reaction mixture is from about 5:1
to about 15:1. For example, the weight ratio of media material to
morphinan-6-one compound in the reaction mixture may be from about
5:1 to about 6:1, from about 5:1 to about 7:1, from about 5:1 to
about 8:1, from about 5:1 to about 9:1, from about 5:1 to about
10:1, from about 5:1 to about 11:1, from about 5:1 to about 12:1,
from about 5:1 to about 13:1, or from about 5:1 to about 14:1. Most
preferably, the weight ratio of media material to morphinan-6-one
compound in the reaction mixture is from about 5:1 to about 11:1.
It will be understood that some portion of the media material may
be derived from the sulfur-containing compound itself (e.g., as
water of hydration).
[0064] Optionally, a phase transfer catalyst may also be added to
the aqueous/organic solvent biphasic media. The phase transfer
catalyst is preferably any suitable composition for use in the
transfer of reactants (i.e., morphinan-6-one compounds,
.alpha.,.beta.-unsaturated ketone compounds, and/or
sulfur-containing compounds) between the aqueous and organic
solvent interface. Typically, the phase transfer catalyst is an
ammonium-based compound, such as a quaternary ammonium salt.
Suitable quaternary ammonium salts for use as phase transfer
catalysts include tetraalkylammonium salts such as, for example,
tetramethyl-, tetraethyl-, tetrabutyl-, tetrahexyl-, tetraoctyl-,
methyltriphenyl-, methyltrioctyl-, benzyltrimethyl-,
benzyltriethyl-, benzyltributyl-, hexadecyltrimethyl-ammonium
salts, and the like. Suitable salts include, for example, halide,
hydroxide, bicarbonate, bisulfate, thiocyanate, tetrafluoroborate,
and the like. Other phase transfer catalysts such as phosphonium
salts may be suitable as well.
[0065] A variety of sulfur-containing compounds may be utilized to
treat the reaction mixture and reduce the concentration of the
.alpha.,.beta.-unsaturated ketone compound according to the
processes described herein. In various embodiments, the
sulfur-containing compound is a sulfur-containing nucleophile. As
utilized herein, "nucleophile" refers to an ion or molecule that
donates a pair of electrons to an atomic nucleus to form a covalent
bond. In other embodiments, the sulfur-containing compound is a
sulfur-containing reducing agent. As utilized herein, "reducing
agent" refers to an agent having the ability to add one or more
electrons to an atom, ion or molecule. In either of the two
embodiments described above (i.e., when the sulfur-containing
compound is a sulfur-containing nucleophile or a sulfur-containing
reducing agent), the sulfur-containing compound is a compound
having the ability to effect the reduction of and/or a 1,4 addition
across the .alpha.,.beta.-unsaturated bond of the
.alpha.,.beta.-unsaturated ketone compound.
[0066] In one embodiment, the sulfur-containing compound is a
sulfur-containing inorganic acid or salt thereof. Suitable
sulfur-containing inorganic acids include, for example,
hydrosulfuric acid (H.sub.2S); sulfurous acid (H.sub.2SO.sub.3);
persulfuric acid (H.sub.2SO.sub.5); thiosulfurous acid
(H.sub.2S.sub.2O.sub.2); dithionous acid (H.sub.2S.sub.2O.sub.4);
disulfurous acid (H.sub.2S.sub.2O.sub.5); dithionic acid
(H.sub.2S.sub.2O.sub.6); pyrosulfuric acid (H.sub.2S.sub.2O.sub.7);
peroxydisulfuric acid (H.sub.2S.sub.2O.sub.5); trithionic acid
(H.sub.2S.sub.3O.sub.6); tetrathionic acid (H.sub.2S.sub.4O.sub.6);
pentathionic acid (H.sub.2S.sub.5O.sub.6); chiorosulfonic acid
(HSO.sub.3Cl); furosulfonic acid (HSO.sub.3F); sulfamic acid
(HSO.sub.3NH.sub.2); salts thereof; and the like.
[0067] Generally, the sulfur-containing inorganic acid salt may be
an alkali metal salt or an alkaline earth metal salt. For example,
the salt may be a monovalent or divalent cation selected from
Li.sup.+, Na.sup.+, K.sup.+, Rb.sup.+, Cs.sup.+, Fr.sup.+,
Be.sup.2+, Mg.sup.2+, Ca.sup.2+, Sr.sup.2+, Ba.sup.2+, or
Ra.sup.2+. Preferably, the salt is selected from the group
consisting of Li.sup.+, Na.sup.+, K.sup.+, Mg.sup.2+, Ca.sup.2+,
and combinations thereof.
[0068] Alternatively, the sulfur-containing inorganic acid salt may
be an ammonium salt (NH.sub.4.sup.+) or a quaternary ammonium salt.
For example, the sulfur-containing inorganic acid salt may be a
tetraalkylated ammonium salt; that is, a quaternary ammonium salt
substituted with four alkyl groups preferably having from 1 to
about 18 carbon atoms. Suitable tetraalkylated ammonium salts
include, for example, tetramethylammonium salts, tetraethylammonium
salts, tetrapropylammonium salts, tetrabutylammonium salts, and the
like.
[0069] In one particular embodiment, the sulfur-containing
inorganic acid is dithionous acid (H.sub.2S.sub.2O.sub.4) or salts
thereof. By way of example, salts of dithionous acid include
MHS.sub.2O.sub.4 and M.sub.2S.sub.2O.sub.4, wherein M is selected
from alkali metal salts, alkaline earth metal salts, ammonium salt
(NH.sub.4.sup.+), and quaternary ammonium salts. According to this
embodiment, the .alpha.,.beta.-unsaturated ketone compound is
chemically reduced to form the morphinan-6-one compound upon
treatment with the sulfur-containing compound, discussed in further
detail below.
[0070] In another particular embodiment, the sulfur-containing
inorganic acid is selected from the group consisting of sulfurous
acid (H.sub.2SO.sub.3); disulfurous acid (H.sub.2S.sub.2O.sub.5);
and salts thereof. By way of example, salts of sulfurous acid and
disulfurous acid include MHSO.sub.3, M.sub.2SO.sub.3,
MHS.sub.2O.sub.5, and M.sub.2S.sub.2O.sub.5 wherein M is selected
from alkali metal salts, alkaline earth metal salts, ammonium salt
(NH.sub.4.sup.+), and quaternary ammonium salts. According to this
embodiment, the sulfur-containing inorganic acid or salt thereof is
one which dissociates into the bisulfite ion (HSO.sub.3.sup.-)
and/or the sulfite ion (SO.sub.3.sup.2-) in the reaction mixture.
It will be understood by one of ordinary skill in the art that
sulfurous acid (H.sub.2SO.sub.3) generally exists as a solution of
SO.sub.2 (commonly about 6%) in water. The pKa of sulfurous acid
(H.sub.2SO.sub.3) is about 1.78 and its ionization expression
is:
H.sub.2O+SO.sub.2H.sub.2SO.sub.3H.sup.++HSO.sub.3.sup.-H.sup.++SO.sub.3.-
sup.2-
According to this embodiment, various 1,2- and 1,4-sulfonated
addition products are formed from the morphinan-6-one compound and
the .alpha.,.beta.-unsaturated ketone compound by reaction with the
bisulfite ion and/or the sulfite ion, discussed in further detail
below.
[0071] In another particular embodiment, the sulfur-containing
compound is a thiol having the formula: R--SH, wherein R is
hydrocarbyl, substituted hydrocarbyl, or heterocyclo. For example,
R may be substituted or unsubstituted alkyl, alkenyl, alkynyl, or
aryl. Exemplary thiols having the formula R--SH, wherein R is
defined as above, include alkyl or aryl thiols such as
methanethiol, ethanethiol, benzenethiol, and the like. Other
exemplary thiols include thiocarboxylic acids and salts thereof
(e.g., thiobenzoic acid) and thiol-terminated carboxylic acids and
salts thereof (e.g., thioglycolic acid (mercaptoacetic acid),
mercaptopropionic acid, and the like). Still other exemplary thiols
include amino acids (e.g., L- or D,L-cysteine), other
thiol-containing amines and/or quaternary salts thereof (e.g.,
cysteamine HCl, thiocholine, and the like), or polymer-bound thiols
(e.g., polycysteine, polyvinylarylthiol, and the like). In one
preferred embodiment, the thiol is benzenethiol. Without being
bound to one theory, it is believed that the thiol forms various
1,2- and 1,4-sulfonated addition products from the morphinan-6-one
compound and the .alpha.,.beta.-unsaturated ketone compound.
[0072] The amount of sulfur-containing compound utilized to treat
the reaction mixture may vary considerably according to the various
reaction mixture components (such as the particular morphinan-6-one
compound, the .alpha.,.beta.-unsaturated ketone compound, and/or
the media material) and concentrations thereof, time of reaction,
temperature, pressure, and the like. Relatively high usage rates of
sulfur-containing compound generally offer no significant
advantages and tend to waste chemicals and/or reactor volume.
[0073] The molar ratio of sulfur-containing compound to
morphinan-6-one compound in the reaction mixture is typically
greater than about 0.5:1. Preferably, the molar ratio of
sulfur-containing compound to morphinan-6-one compound in the
reaction mixture is from about 0.5:1 to about 3.0:1. For example,
the molar ratio of sulfur-containing compound to morphinan-6-one
compound in the reaction mixture may be from about 0.5:1 to about
0.8:1, from about 0.5:1 to about 1.0:1, from about 0.5:1 to about
1.5:1, from about 0.5:1 to about 2.0:1, or from about 0.5:1 to
about 2.5:1. More preferably, the molar ratio of sulfur-containing
compound to morphinan-6-one compound in the reaction mixture is
from about 0.6:1 to about 2.8:1. For example, the molar ratio of
sulfur-containing compound to morphinan-6-one compound in the
reaction mixture may be from about 0.6:1 to about 0.8:1, from about
0.6:1 to about 1.0:1, from about 0.6:1 to about 1.5:1, from about
0.6:1 to about 2.0:1, or from about 0.6:1 to about 2.5:1. Most
preferably, the molar ratio of sulfur-containing compound to
morphinan-6-one compound in the reaction mixture is from about
0.8:1 to about 2.5:1. For example, the molar ratio of
sulfur-containing compound to morphinan-6-one compound in the
reaction mixture may be from about 0.8:1 to about 1.0:1, from about
0.8:1 to about 1.2:1, from about 0.8:1 to about 1.4:1, from about
0.8:1 to about 1.6:1, from about 0.8:1 to about 1.8:1, from about
0.8:1 to about 2.0:1, from about 0.8:1 to about 2.2:1, or from
about 0.8:1 to about 2.4:1.
[0074] The treatment of the reaction mixture with the
sulfur-containing compound may be carried out in ambient air or in
an oxygen-free environment. Preferably, the treatment is carried
out in an inert atmosphere such as, for example, argon or nitrogen
gas. The treatment is preferably carried out at a pressure of from
about 0.5 atm to about 2.0 atm. More preferably, the treatment is
carried out at a pressure of from about 0.75 atm to about 1.5 atm;
most preferably from about 0.9 atm to about 1.25 atm.
[0075] In various embodiments, the pH of the reaction mixture
during treatment with the sulfur-containing compound is greater
than about 3. Typically, the pH of the reaction mixture during
treatment is less than about 10, although the upper pH limit may
depend on the treatment time and/or solubility of the various
reaction mixture components. Preferably, the pH of the reaction
mixture during treatment with the sulfur-containing compound is
from about 3 to about 9; more preferably from about 6 to about 9.
For example, the pH of the reaction mixture during treatment with
the sulfur-containing compound may be about 3, about 4, about 5,
about 6, about 7, about 8, or about 9. Most preferably, the
treatment occurs at a pH of from about 6 to about 7.25. Upon the
addition of the sulfur-containing compound to the reaction mixture
including the morphinan-6-one compound and the
.alpha.,.beta.-unsaturated ketone compound, the pH may be adjusted
to the desired level (e.g. using a base such as ammonium
hydroxide). Other suitable bases include, for example, sodium
hydroxide, potassium hydroxide, and the like.
[0076] The time of reaction is generally a function of the other
variables in the reaction, such as pH, ratio of media material to
morphinan-6-one compound, amount of sulfur-containing compound, and
the like. Typically, some reduction of the concentration of
.alpha.,.beta.-unsaturated ketone compound in the reaction mixture
can be observed after about 1 hour. Preferably, the reaction
mixture is treated with the sulfur-containing compound for at least
about 1 hour. In some embodiments, the time of reaction is less
than about 24 hours. In other embodiments, the time of reaction is
from about 1 hour to about 18 hours; in still other embodiments
from about 1 hour to about 15 hours; in still other embodiments
from about 1 hour to about 10 hours. More preferably, the reaction
mixture is treated with the sulfur-containing compound for about 1
hour to about 5 hours. For example, the reaction mixture may be
treated with the sulfur-containing compound for about 1 hour, for
about 2 hours, for about 3 hours, for about 4 hours, or for about 5
hours.
[0077] The temperature of the reaction mixture during treatment
with the sulfur-containing compound is generally from about
0.degree. C. to about 100.degree. C. For example, the temperature
of the reaction mixture during treatment with the sulfur-containing
compound may be from about 10.degree. C. to about 90.degree. C.,
from about 20.degree. C. to about 80.degree. C., or from about
30.degree. C. to about 70.degree. C. Preferably, the temperature of
the reaction mixture during treatment with the sulfur-containing
compound is above room temperature. The preferred reaction
temperature may vary for each morphinan-6-one. More preferably, the
temperature of the reaction mixture during treatment with the
sulfur-containing compound is from about 30.degree. C. to about
50.degree. C. For example, the temperature of the reaction mixture
during treatment with the sulfur-containing compound may be about
30.degree. C., about 35.degree. C., about 40.degree. C., about
45.degree. C., or about 50.degree. C.
[0078] Once the treatment is complete or has proceeded as long as
desired, the treated morphinan-6-one compound is recovered to
produce the morphinan-6-one product. Advantageously, the
morphinan-6-one compound may be recovered from the reaction mixture
without the use of an organic solvent. The absence of the need for
organic solvents in the recovery process not only provides various
environmental and material handling benefits, but also results in a
more efficient process suitable for industrial scale applications.
Typically, the morphinan-6-one compound is precipitated from the
reaction mixture as a base (or salt if desirable) and may then be
readily converted into a generally more pharmaceutically acceptable
form, if so desired. For example, the pH of the reaction mixture is
typically adjusted to about 9-10 or greater with a suitable base
such as ammonium hydroxide, and the (desired) precipitated compound
recovered. Generally speaking, this pH is at the point wherein
opium alkaloids are not ionized. The morphinan-6-one compounds can
then be optionally converted into a form more physiologically
tolerable, such as the hydrochloride salt, e.g., oxycodone HCl,
using conventional methods known to those of skill in the art. For
example, the morphinan-6-one base can be dissolved or otherwise
dispersed in water, reacted with an acid such as HCl, heated, and
cooled to precipitate the morphinan-6-one salt. By way of an
alternative example, the morphinan-6-one base can be dissolved or
otherwise dispersed in an alcohol solvent (e.g., methanol, ethanol,
etc.) or a solvent system (i.e., a mixture of solvents), reacted
with concentrated HCl or an HCl/alcohol mixture, and cooled to
precipitate the morphinan-6-one hydrochloride salt. By way of
another example, the morphinan-6-one base can be dissolved or
otherwise dispersed in water, alcohol solvent, or a solvent system,
reacted with gaseous HCl, heated, and cooled to precipitate the
morphinan-6-one hydrochloride salt.
[0079] Treatment Reaction Mechanisms
[0080] Without being bound to one theory, it is believed that the
reduction of the concentration of .alpha.,.beta.-unsaturated ketone
compounds in the reaction mixture is performed via different
mechanisms, depending on the particular sulfur-containing compound
selected to treat the reaction mixture.
[0081] In one embodiment, the .alpha.,.beta.-unsaturated ketone
compound is reduced by the sulfur-containing compound to form the
desired .alpha.,.beta.-saturated morphinan-6-one compound. See,
e.g., Camps et al., Tetrahedron Letters, Vol. 29, No. 45, 1988,
5811-5814; Louis-Andre et al., Tetrahedron Letters, Vol. 26, No. 7,
1985, 831-832). By way of example, dithionous acid
(H.sub.2S.sub.2O.sub.4) and salts thereof (e.g., MHS.sub.2O.sub.4
or M.sub.2S.sub.2O.sub.4, wherein M is defined as above) operate
according to this mechanism; other sulfur-containing compounds,
however, may also operate according to the same or a similar
mechanism. Reaction Scheme 11 generally illustrates the reduction
of the .alpha.,.beta.-unsaturated ketone compound (3) to form the
desired morphinan-6-one compound (2) according to this embodiment,
wherein X, R.sub.1, R.sub.2, R.sub.3, R.sub.10, and R.sub.14 are
defined as above.
##STR00018##
[0082] In an alternative embodiment, various 1,2- and
1,4-sulfonated addition products are formed during treatment that
assist in the removal of the .alpha.,.beta.-unsaturated ketone
compounds from the reaction mixture. As noted above, several
sulfur-containing compounds dissociate into various
sulfur-containing species. In particular, sulfurous acid
(H.sub.2SO.sub.3), disulfurous acid (H.sub.2S.sub.2O.sub.5), and
their salts dissociate into, among other things, bisulfite
(HSO.sub.3.sup.-) and sulfite (SO.sub.3.sup.2-).
[0083] Bisulfite has been shown to add via radical initiation
across isolated double bonds (see, e.g., March, J., Advanced
Organic Chemistry, p. 688, J. Wiley & Sons, 1985, 3d. ed.)
and/or add via an ionic mechanism (see, e.g., Gilbert, E.;
Sulfonation and Related Reactions, p. 152, Interscience, N.Y. 1965;
Patai et al, The Chemistry of Alkenes, p. 478, Interscience, London
1965). Without being bound to one theory, it is believed that when
the reaction mixture is treated with sulfurous acid, disulfurous
acid, or salts thereof and the pH is adjusted to between about 3
and about 9, certain 1,2- and 1,4-addition products and adducts are
stably and/or reversibly formed from the .alpha.,.beta.-unsaturated
ketone compound and the morphinan-6-one compound. It is further
believed that the products are generally stable within the pH range
of from about 3 to about 9, and adjusting the pH outside of this
range after their formation from the .alpha.,.beta.-unsaturated
ketone compounds and the morphinan-6-one compounds facilitates the
removal of the .alpha.,.beta.-unsaturated ketone compound from the
reaction mixture, resulting in a highly pure morphinan-6-one
product.
[0084] One preferred embodiment of the present invention is
illustrated in Reaction Schemes 12A and 12B, wherein X, R.sub.1,
R.sub.2, R.sub.3, R.sub.10, and R.sub.14 are defined as above and M
is a monovalent or divalent cation. For example, M may be one or
more alkali metal or alkaline earth metal monovalent or divalent
cations from the sulfur-containing compound. Alternatively, M may
be one or more monovalent or divalent cations from the alkaline
compound (e.g., NaOH, KOH, NH.sub.4OH, etc.) used to adjust the pH
of the reaction mixture to between about 3 and about 9 after the
addition of the sulfur-containing compound to the reaction
mixture.
##STR00019##
##STR00020##
[0085] As shown in Reaction Schemes 12A and 12B, various 1,2- and
1,4-sulfonated compounds are formed from the morphinan-6-one
compound (2) (scheme 12A) and the .alpha.,.beta.-unsaturated ketone
compound (3) (scheme 12B) upon treatment of a reaction mixture
including these compounds with a sulfur-containing compound at a pH
of between about 3 and about 9. While it is understood that
sulfurous acid, disulfurous acid, and salts thereof operate
according to the mechanism illustrated in Reaction Schemes 12A,
12B, and 12C, other sulfur-containing compounds may also operate
according to the same or a similar mechanism. For example, thiols
(e.g., benzenethiol) may also operate according to the mechanism
described in connection with Reaction Schemes 12A, 12B, and
12C.
[0086] Particularly, when the reaction mixture is treated with a
sulfur-containing compound and the pH of the reaction mixture is
adjusted to between about 3 and about 9, the morphinan-6-one
compound (2) forms the reversible, water-soluble 1,2-bisulfite
adduct (2A). Once the reaction mixture is sufficiently in solution
in the media material and/or the sulfur-containing compound,
dissociated sulfur specie (such as sulfite and bisulfite) react
more readily with the .alpha.,.beta.-unsaturated ketone compound
(3) also present in the reaction mixture.
[0087] As illustrated in Reaction Scheme 12B, one reaction between
the .alpha.,.beta.-unsaturated ketone compound (3) and the
sulfur-containing compound involves the rapid and reversible
1,2-addition of the bisulfite to the carbonyl (similar to the
reaction of the sulfur-containing compound with the morphinan-6-one
compound illustrated in Reaction Scheme 12A) to form the reversible
1,2-adduct (3A) from the .alpha.,.beta.-unsaturated ketone compound
(3). Another reaction between the sulfur-containing compound and
the .alpha.,.beta.-unsaturated ketone compound (3) is the slower
1,4-addition, forming the more stable 1,4-addition product (3B).
The introduction of the sulfonate group in the .beta.-position
generally enhances the reactivity of the carbonyl group by
destroying its conjugation with the double bond, such that the
reversible product is a 1,2- and 1,4-bis adduct (3C) (see Patai et
al., The Chemistry of Alkenes, p. 478, Interscience, London
1965).
[0088] Reaction Scheme 12C illustrates the removal of certain
addition products formed in the reaction mixture according to
Reaction Schemes 12A and 12B and the resulting highly pure
morphinan-6-one product, wherein X, R.sub.1, R.sub.2, R.sub.3,
R.sub.10, R.sub.14, and M are defined as above.
##STR00021##
[0089] As illustrated in Reaction Scheme 12C, the removal of the
.alpha.,.beta.-unsaturated ketone addition products is generally
based in the differences in solubility of the 1,4-addition product
(3B) generated from the .alpha.,.beta.-unsaturated ketone compound
and the desired morphinan-6-one compound (2). Adjusting the pH
outside of the range between about 3 and about 9 (i.e., the pH is
adjusted to less than about 3 or the pH is adjusted to greater than
about 9) with an acid (e.g., sulfuric acid (H.sub.2SO.sub.4)) or a
base (e.g., ammonium hydroxide (NH.sub.4OH)) results in the
decomposition of the 1,2-addition products of each compound,
rendering the desired morphinan-6-one compound (2) insoluble in
water. The relatively more stable 1,4-addition product (3B) formed
from the .alpha.,.beta.-unsaturated ketone compound remains and is
water-soluble in the final mixture at an alkaline pH (e.g., pH
.about.9 or greater). The 1,4-addition product (38) may thus be
removed from the mixture with the mother liquor, leaving the
insoluble morphinan-6-one base (2). The desired morphinan-6-one
base may then be converted into a more physiologically-tolerable
salt form, such as the hydrochloride salt, using methods known to
those of skill in the art.
[0090] One particularly preferred embodiment of the present
invention is illustrated in Reaction Schemes 13A and 13B, wherein M
is defined as above.
##STR00022##
##STR00023##
[0091] As shown in Reaction Schemes 13A and 13B, various sulfonated
compounds are formed from oxycodone (20) (scheme 13A) and the
.alpha.,.beta.-unsaturated ketone compound 14-hydroxycodeinone (30)
(scheme 13B) upon treatment of a reaction mixture including these
compounds with a sulfur-containing compound at a pH of between
about 3 and about 9. As discussed above, while it is generally
understood that sulfurous acid, disulfurous acid, and salts thereof
operate according to the mechanism described in Reaction Schemes
13A and 13B, other sulfur-containing compounds may also operate
according to the same or a similar mechanism.
[0092] Particularly, when the reaction mixture is treated with a
sulfur-containing compound and the pH of the reaction mixture is
adjusted to between about 3 and about 9, oxycodone (20) forms the
reversible, water-soluble 1,2-bisulfite adduct (20A). Once the
reaction mixture is sufficiently in solution in the media material
and the sulfur-containing compound, dissociated sulfur specie (such
as sulfite and bisulfite) react more readily with the
14-hydroxycodeinone (30) also present in the reaction mixture.
[0093] As illustrated in Reaction Scheme 13B, one reaction between
14-hydroxycodeinone (30) and the sulfur-containing compound
involves the rapid and reversible 1,2-addition of the sulfite to
the carbonyl (similar to the reaction of the sulfur-containing
compound with oxycodone illustrated in Reaction Scheme 13A) to form
the reversible 1,2-adduct (30A) from 14-hydroxycodeinone. Another
reaction between the sulfur-containing compound and
14-hydroxycodeinone (30) is the slower 1,4-addition, forming the
more stable 1,4-addition product (30B). The introduction of the
sulfonate group in the n-position generally enhances the reactivity
of the carbonyl group by destroying its conjugation with the double
bond, such that the reversible product is a 1,2- and 1,4-bis adduct
(30C) (see Patai et al., The Chemistry of Alkenes, p. 478,
Interscience, London 1965).
[0094] Reaction Scheme 13C illustrates the removal of certain
addition products formed in the reaction mixture according to
Reaction Schemes 13A and 13B and the resulting highly pure
oxycodone, wherein M is defined as above.
##STR00024##
[0095] As illustrated in Reaction Scheme 13C, the removal of the
14-hydroxycodeinone addition products is generally based on the
differences in solubility of the 1,4-addition product (30B)
generated from 14-hydroxycodeinone and the desired oxycodone (20).
Adjusting the pH outside of the range between about 3 and about 9
(i.e., the pH is adjusted to less than about 3 or greater than
about 9) with an acid (e.g., sulfuric acid (H.sub.2SO.sub.4)) or a
base (e.g., ammonium hydroxide (NH.sub.4OH)) results in the
decomposition of the 1,2-addition products of each compound,
rendering the desired oxycodone (20) insoluble in water. The
relatively more stable 1,4-addition product (30B) formed from
14-hydroxycodeinone remains and is water soluble in the final
mixture at an alkaline pH (e.g., pH .about.9 or greater). The
1,4-addition product (30B) may thus be removed from the mixture
with the mother liquor, leaving the insoluble oxycodone base (20).
The oxycodone base may then be converted into a more
physiologically-tolerable salt form, such as the hydrochloride
salt, using methods known to those of skill in the art.
[0096] Removal of Residual Sulfur-Containing Species from the
Reaction Mixture
[0097] Using the process described herein to reduce the
concentration of .alpha.,.beta.-unsaturated ketone compounds from a
reaction mixture by treating the reaction mixture with a
sulfur-containing compound may result in the undesirable
accumulation of residual sulfur-containing species (such as
sulfites and bisulfites) in the reaction mixture and/or final
morphinan-6-one product. Accordingly, the residual
sulfur-containing species may be optionally substantially removed
from the reaction mixture following the treatment with the
sulfur-containing compound using a variety of methods known to
those of skill in the art.
[0098] As described above, in various embodiments 1,2- and
1,4-sulfonated addition products may be formed by the reaction of a
sulfur-containing compound with the morphinan-6-one compound and
the .alpha.,.beta.-unsaturated ketone compound at a pH of between
about 3 to about 9. The adjustment of the pH outside of this range
eliminates the 1,2-addition products, renders the morphinan-6-one
compound insoluble in water, and the remaining water soluble
1,4-addition product can be removed in the waste stream.
[0099] To optionally substantially remove the residual
sulfur-containing species upon completion of the reaction with the
sulfur-containing compound, the pH of the reaction mixture may be
adjusted to less than about 3 (instead of adjusting the pH to
greater than 9) with an acid (e.g., sulfuric acid
(H.sub.2SO.sub.4)) and manipulated prior to the precipitation of
the morph inan-6-one compound as described in detail above. More
preferably, the pH is adjusted to less than about 2. The reduction
in pH converts any residual sulfur species that may be present in
the reaction mixture into SO.sub.2 gas, which typically has a
limited solubility in water. In one embodiment, the SO.sub.2 gas
may then be optionally heat refluxed out of the reaction mixture by
conventional means known to those of skill in the art. Typically,
the reaction mixture is heat refluxed for about 2 hours to about 5
hours. The temperature and pressure during reflux are also
generally variable. For example, the temperature of the reaction
mixture during reflux is typically from about 20.degree. C. to
about 100.degree. C., and the reflux may be performed at a pressure
of from about 0.003 atm to about 1.0 atm. Alternatively,
substantially all of the water (and the SO.sub.2 gas) may be
optionally distilled off to a receiver tank and discarded. This
procedure is also generally known to those of skill in the art.
[0100] As discussed above, after treatment of the reaction mixture
with the sulfur-containing compound to reduce the concentration of
the .alpha.,.beta.-unsaturated ketone compound in the reaction
mixture, the morphinan-6-one compound is recovered to produce the
desired morphinan-6-one product. Generally speaking, recovery
refers to one or more of the precipitation, filtration and drying
of the morphinan-6-one base, the formation of the physiologically
acceptable morphinan-6-one salt (e.g., the hydrochloride salt), the
removal of the residual sulfur-containing species, and/or
combinations thereof, to produce a morphinan-6-one product.
[0101] The treatment of the reaction mixture with a
sulfur-containing compound according to the various processes and
embodiments described herein significantly reduces the
concentration of .alpha.,.beta.-unsaturated ketone compounds in the
reaction mixture, and a highly pure morphinan-6-one product may be
produced therefrom. Typically, the morphinan-6-one product
comprises less than about 0.1% (by weight morphinan-6-one product)
of an .alpha.,.beta.-unsaturated ketone compound. For example, the
morphinan-6-one product may comprise less than about 0.05% (by
weight morphinan-6-one product) of an .alpha.,.beta.-unsaturated
ketone compound Preferably, the morphinan-6-one product comprises
less than about 0.01% (by weight morphinan-6-one product) of an
.alpha.,.beta.-unsaturated ketone compound. For example, the
morphinan-6-one product may comprise less than about 0.005% (by
weight morphinan-6-one product) of an .alpha.,.beta.-unsaturated
ketone compound. More preferably, the morphinan-6-one product
comprises less than about 0.001% (by weight morphinan-6-one
product) of an .alpha.,.beta.-unsaturated ketone compound. For
example, the morphinan-6-one product may comprise less than about
0.0005% (by weight morphinan-6-one product) of an
.alpha.,.beta.-unsaturated ketone compound. Still more preferably,
no detectable amount of an .alpha.,.beta.-unsaturated ketone
compound is present in the morphinan-6-one product.
Abbreviations and Definitions
[0102] The following definitions and methods are provided to better
define the present invention and to guide those of ordinary skill
in the art in the practice of the present invention. Unless
otherwise noted, terms are to be understood according to
conventional usage by those of ordinary skill in the relevant
art.
[0103] The term "alkyl" as used herein describes groups which are
preferably lower alkyl containing from one to eight carbon atoms in
the principal chain and up to 20 carbon atoms. They may be straight
or branched chain or cyclic and include methyl, ethyl, propyl,
isopropyl, allyl, benzyl, hexyl and the like.
[0104] The term "alkenyl" as used herein describes groups which are
preferably lower alkenyl containing from two to eight carbon atoms
in the principal chain and up to 20 carbon atoms. They may be
straight or branched chain or cyclic and include ethenyl, propenyl,
isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
[0105] The term "alkynyl" as used herein describes groups which are
preferably lower alkynyl containing from two to eight carbon atoms
in the principal chain and up to 20 carbon atoms. They may be
straight or branched chain and include ethynyl, propynyl, butynyl,
isobutynyl, hexynyl, and the like.
[0106] The term "aromatic" as used herein alone or as part of
another group denotes optionally substituted homo- or heterocyclic
aromatic groups. These aromatic groups are preferably monocyclic,
bicyclic, or tricyclic groups containing from 6 to 14 atoms in the
ring portion. The term "aromatic" encompasses the "aryl" and
"heteroaryl" groups defined below.
[0107] The term "aryl" as used herein alone or as part of another
group denote optionally substituted homocyclic aromatic groups,
preferably monocyclic or bicyclic groups containing from 6 to 12
carbons in the ring portion, such as phenyl, biphenyl, naphthyl,
substituted phenyl, substituted biphenyl or substituted naphthyl.
Phenyl and substituted phenyl are the more preferred aryl.
[0108] The terms "halogen," "halide" or "halo" as used herein alone
or as part of another group refer to chlorine, bromine, fluorine,
and iodine.
[0109] The term "heteroatom" shall mean atoms other than carbon and
hydrogen.
[0110] The terms "heterocyclo" or "heterocyclic" as used herein
alone or as part of another group denote optionally substituted,
fully saturated or unsaturated, monocyclic or bicyclic, aromatic or
non-aromatic groups having at least one heteroatom in at least one
ring, and preferably 5 or 6 atoms in each ring. The heterocyclo
group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen
atoms in the ring, and is bonded to the remainder of the molecule
through a carbon or heteroatom. Exemplary heterocyclo groups
include heteroaromatics such as furyl, pyridyl, oxazolyl, pyrrolyl,
indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary
substituents include one or more of the following groups:
hydrocarbyl, substituted hydrocarbyl, hydroxy, protected hydroxy,
acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido,
amino, cyano, ketals, acetals, esters and ethers.
[0111] The term "heteroaromatic" as used herein alone or as part of
another group denote optionally substituted aromatic groups having
at least one heteroatom in at least one ring, and preferably 5 or 6
atoms in each ring. The heteroaromatic group preferably has 1 or 2
oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in
the ring, and may be bonded to the remainder of the molecule
through a carbon or heteroatom. Exemplary heteroaromatics include
furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl,
or isoquinolinyl and the like. Exemplary substituents include one
or more of the following groups: hydrocarbyl, substituted
hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy,
alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro,
cyano, thiol, ketals, acetals, esters and ethers.
[0112] The term "acyl," as used herein alone or as part of another
group, denotes the moiety formed by removal of the hydroxy group
from the group --COOH of an organic carboxylic acid, e.g., RC(O)--,
wherein R is R.sup.1, R.sup.1O--, R.sup.1R.sup.2N--, or R.sup.1S--,
R.sup.1 is hydrocarbyl, heterosubstituted hydrocarbyl, or
heterocyclo, and R.sup.2 is hydrogen, hydrocarbyl or substituted
hydrocarbyl.
[0113] The term "acyloxy," as used herein alone or as part of
another group, denotes an acyl group as described above bonded
through an oxygen linkage (--O--), e.g., RC(O)O-- wherein R is as
defined in connection with the term "acyl."
[0114] The term "heteroaryl" as used herein alone or as part of
another group denote optionally substituted aromatic groups having
at least one heteroatom in at least one ring, and preferably 5 or 6
atoms in each ring. The heteroaryl group preferably has 1 or 2
oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is
bonded to the remainder of the molecule through a carbon. Exemplary
heteroaryls include furyl, benzofuryl, oxazolyl, isoxazolyl,
oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl,
imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl,
indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl,
purinyl, quinolinyl, isoquinolinyl, imidazopyridyl and the like.
Exemplary substituents include one or more of the following groups:
hydrocarbyl, substituted hydrocarbyl, hydroxy, protected hydroxy,
acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido,
amino, cyano, ketals, acetals, esters and ethers.
[0115] The terms "hydrocarbon" and "hydrocarbyl" as used herein
describe organic compounds or radicals consisting exclusively of
the elements carbon and hydrogen. These moieties include alkyl,
alkenyl, alkynyl, and aryl moieties. These moieties also include
alkyl, alkenyl, alkynyl, and aryl moieties substituted with other
aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl
and alkynaryl. Unless otherwise indicated, these moieties
preferably comprise 1 to 20 carbon atoms.
[0116] The "substituted hydrocarbyl" moieties described herein are
hydrocarbyl moieties which are substituted with at least one atom
other than carbon, including moieties in which a carbon chain atom
is substituted with a hetero atom such as nitrogen, oxygen,
silicon, phosphorous, boron, sulfur, or a halogen atom. These
substituents include halogen, heterocyclo, alkoxy, alkenoxy,
aryloxy, hydroxy, protected hydroxy, acyl, acyloxy, nitro, amino,
amido, nitro, cyano, ketals, acetals, esters and ethers.
[0117] The term "hydroxy protecting group" refers to hydrocarbyl
and substituted hydrocarbyl moieties which bond to an hydroxy
oxygen atom in a molecule so as to protect that oxygen atom from
further reaction during synthesis. This protection allows reactions
to occur selectively at another reaction site on the same molecule.
Examples of hydroxy protecting groups include, but are not limited
to, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl,
p-nitrobenzyl, allyl, trityl, methoxymethyl, methoxyethoxymethyl,
ethoxyethyl, tetra hydropyranyl, tetrahydrothiopyranyl, and
trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl
ether, dimethylarylsilyl ether, triisopropylsilyl ether and
t-butyldimethylsilyl ether; esters such as benzoyl, acetyl,
phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as
chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and
carbonates including but not limited to alkyl carbonates having
from one to six carbon atoms such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl
carbonates having from one to six carbon atoms and substituted with
one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and
2,2,2-trichloroethyl; alkenyl carbonates having from two to six
carbon atoms such as vinyl and allyl; cycloalkyl carbonates have
from three to six carbon atoms such as cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl; and phenyl or benzyl carbonates
optionally substituted on the ring with one or more C.sub.1-8
alkoxy, or nitro.
[0118] Having described the invention in detail, it will be
apparent that modifications and variations are possible without
departing the scope of the invention defined in the appended
claims. Furthermore, it should be appreciated that all examples in
the present disclosure are provided as non-limiting examples.
Example 1
[0119] In this Example, an oxycodone HCl sample was treated with a
sulfur-containing compound according to the processes described
herein.
[0120] To a 250 ml, 3 neck round bottom flask equipped with a
mechanical stirrer, N.sub.2 inlet, and thermocouple for temperature
control was added 10 g of oxycodone HCl (0.028 moles; >0.3% by
weight 14-hydroxycodeinone (14-OHC) impurity). Next, with mixing
100 g of deoxygenated water (10 minute N.sub.2 purge) was added.
The solution pH was adjusted to about 6 with ammonium hydroxide.
Next, 5.0 g of sodium dithionite (Na.sub.2S.sub.2O.sub.4) was
added. The pH was then adjusted to about 7 with concentrated
ammonium hydroxide. The resulting mixture was stirred at 70.degree.
C. for about 16 hours.
[0121] After about 16 hours, the pH was adjusted to about 9 with
ammonium hydroxide, precipitating the oxycodone base. The mixture
was stirred for about 1 hour, and the precipitated oxycodone base
was filtered, washed with water, and dried overnight at 40.degree.
C. under reduced pressure.
[0122] The oxycodone base sample was converted to the oxycodone HCl
salt by dissolving about 14.5 g of the oxycodone base in a 100 ml,
3 neck round bottom flask equipped with a mechanical stirrer,
N.sub.2 inlet, and thermocouple for temperature control. Next, with
mixing about 29 g of H.sub.2O and about 12.6 g of concentrated HCl
was added. The resulting mixture was heated to about 65.degree.
C.-75.degree. C. until substantially all was in solution. The heat
was then removed, resulting in the precipitation of the oxycodone
HCl salt. The precipitated mixture was stirred for about 1-3 hours
at less than about 10.degree. C. and filtered to collect the
precipitated oxycodone HCl.
[0123] The 14-hydroxycodeinone (14-OHC) content was analyzed in the
oxycodone base sample and the oxycodone HCl sample using an Agilent
HPLC with MS interface capability. The results are illustrated in
Table 1.
TABLE-US-00001 TABLE 1 Initial 14- Final 14-OHC content OHC content
Oxycodone base (% Oxycodone HCl (% by wt.) by wt.) (% by wt.) 0.3
0.0005 0.0005
Examples 2A-2G
[0124] In Examples 2A-2G, an oxycodone HCl sample was treated with
a sulfur-containing compound according to the processes described
herein. The treatment was performed at various temperatures, times
of reaction, concentration of reactants, and pH.
Example 2A
[0125] To a 100 ml, 3 neck round bottom flask equipped with a
mechanical stirrer, N.sub.2 inlet, and thermocouple for temperature
control was added 9.2 g of wet oxycodone HCl (0.02 moles; 0.13% by
weight 14-hydroxycodeinone (14-OHC) impurity). Next, with mixing
36.2 g of H.sub.2O and 40.3 g of 6 wt. % SO.sub.2/H.sub.2O solution
was added. The resulting mixture was heated to about 30.degree. C.
and the solution pH was adjusted to about 6 with ammonium
hydroxide. The mixture was stirred for about 3 hours. The pH of the
mixture was then adjusted to about 8.8-9.8 with concentrated
ammonium hydroxide and stirred for about 30 minutes. The
precipitated oxycodone base was then filtered from the mother
liquor, washed with about 25.73 g of H.sub.2O, and dried. The
14-hydroxycodeinone content (14-OHC) in the oxycodone base was then
measured as described in the preceding Example.
[0126] The experiment was repeated using identical reagents,
amounts thereof, and conditions to form the oxycodone base sample.
This oxycodone base sample was converted to the oxycodone HCl salt
as described in the preceding example. The 14-hydroxycodeinone
content (14-OHC) in the oxycodone base sample and the oxycodone HCl
sample were then measured.
[0127] Results and reaction conditions for this experiment are
illustrated in Table 2.
TABLE-US-00002 TABLE 2 Concentration Molar Ratio Initial 14- Final
14-OHC content Temperature Time (g H.sub.2O per g of SO.sub.2 to
OHC content Oxycodone Oxycodone Trial (.degree. C.) (hr.) pH
Oxycodone HCl) Oxycodone HCl (% by wt.) base (% by wt.) HCl (% by
wt.) 1 30 3 6 10.2 1.8:1 0.13 0.0007 Not tested 2 30 3 6 10.2 1.8:1
0.13 0.0007 0.0007
Example 2B
[0128] This Example was performed according to the process
described in Example 2A. However, in this Example 9.4 g of wet
oxycodone HCl (0.02 moles; 0.13% by weight 14-hydroxycodeinone
(14-OHC) impurity) was mixed with about 34.6 g of H.sub.2O and
about 27.4 g of 6 wt. % SO.sub.2/H.sub.2O solution. The mixture was
heated to about 50.degree. C. Next, the pH was adjusted to about 7
using ammonium hydroxide.
[0129] The resulting mixture was allowed to react for either 1 hour
or 5 hours. At the end of the desired reaction time, the solution
was adjusted to a pH of 8.8-9.8 with about 2.0 g of concentrated
ammonium hydroxide and stirred for about 30 minutes. The solids
were filtered and washed with about 28.0 g of H.sub.2O and dried.
The 14-hydroxycodeinone (14-OHC) content in the resulting oxycodone
base was measured, as was the 14-hydroxycodeinone (14-OHC) content
in the oxycodone HCl salt formed according to the method described
in the preceding example. The results and reaction conditions in
the various trials are illustrated in Table 3.
TABLE-US-00003 TABLE 3 Concentration Molar Ratio Initial 14- Final
14-OHC content Temperature Time (g H.sub.2O per g of SO.sub.2 to
OHC content Oxycodone Oxycodone Trial (.degree. C.) (hr.) pH
Oxycodone HCl) Oxycodone HCl (% by wt.) base (% by wt.) HCl (% by
wt.) 3 50 1 7 8.2 1.2:1 0.13 None detected None detected 4 50 5 7
8.2 1.2:1 0.13 0.00005 0.0005
Example 2C
[0130] This Example was performed according to the process
described in Example 2A. However, in this Example 9.1 g of wet
oxycodone HCl (0.02 moles; 0.13-0.14% by weight 14-hydroxycodeinone
(14-OHC) impurity) was mixed with about 7.0 g of H.sub.2O and about
52.8 g of 6 wt. % SO.sub.2/H.sub.2O solution. The mixture was
heated to either 10.degree. C. or 50.degree. C. Next, the pH was
adjusted to 7 using ammonium hydroxide.
[0131] The resulting mixture was allowed to react for either 1 hour
or 5 hours. At the end of the desired reaction time, the solution
was adjusted to a pH of 8.8-9.8 with about 2.0-2.5 g of
concentrated ammonium hydroxide and stirred for about 30 minutes.
The solids were filtered and washed with about 28.0 g of H.sub.2O
and dried. The 14-hydroxycodeinone (14-OHC) content in the
resulting oxycodone base was measured, as was the
14-hydroxycodeinone (14-OHC) content in the oxycodone HCl salt
formed by the method described in the preceding example. The
results and reaction conditions in the various trials are
illustrated in Table 4.
TABLE-US-00004 TABLE 4 Concentration Molar Ratio Initial 14- Final
14-OHC content Temperature Time (g H.sub.2O per g of SO.sub.2 to
OHC content Oxycodone Oxycodone Trial (.degree. C.) (hr.) pH
Oxycodone HCl) Oxycodone HCl (% by wt.) base (% by wt.) HCl (% by
wt.) 5 50 1 7 8.2 2.4:1 0.13 None detected 0.0006 6 50 5 7 8.2
2.4:1 0.13 0.00015 0.0004 7 10 5 7 8.2 2.4:1 0.14 0.001 Not
tested
Example 2D
[0132] This Example was performed according to the process
described in Example 2A. However, in this Example 9.52 g of wet
oxycodone HCl (0.02 moles; 0.13% by weight 14-hydroxycodeinone
(14-OHC) impurity) was mixed with about 72.24 g of H.sub.2O and
about 27.76 g of 6 wt. % SO.sub.2/H.sub.2O solution. The mixture
was heated to about 50.degree. C. Next, the pH was adjusted to
about 7 using ammonium hydroxide.
[0133] The resulting mixture was allowed to react for either 1 hour
or 5 hours. At the end of the desired reaction time, the solution
was adjusted to a pH of 8.8-9.8 with about 2.0-2.5 g of
concentrated ammonium hydroxide and stirred for about 30 minutes.
The solids were filtered and washed with about 28.0 g of H.sub.2O
and dried. The 14-hydroxycodeinone (14-OHC) content in the
resulting oxycodone base was measured, as was the
14-hydroxycodeinone (14-OHC) content in the oxycodone HCl salt
formed by the method described in the preceding example. The
results and reaction conditions in the various trials are
illustrated in Table 5.
TABLE-US-00005 TABLE 5 Concentration Molar Ratio Initial 14- Final
14-OHC content Temperature Time (g H.sub.2O per g of SO.sub.2 to
OHC content Oxycodone Oxycodone Trial (.degree. C.) (hr.) pH
Oxycodone HCl) Oxycodone HCl (% by wt.) base (% by wt.) HCl (% by
wt.) 8 50 1 7 13.1 1.2:1 0.13 0.0002 0.0003 9 50 5 7 13.1 1.2:1
0.13 None detected 0.0004
Example 2E
[0134] This Example was performed according to the process
described in Example 2A. However, in this Example 9.5 g of wet
oxycodone HCl (0.02 moles; 0.13-0.14% by weight 14-hydroxycodeinone
(14-OHC) impurity) was mixed with about 39.7 g of H.sub.2O and
about 55.6 g of 6 wt. % SO.sub.2/H.sub.2O solution. The mixture was
heated to either 10.degree. C. or 50.degree. C. Next, the pH was
adjusted to about 7 using ammonium hydroxide.
[0135] The resulting mixture was allowed to react for either 1 hour
or 5 hours. At the end of the desired reaction time, the solution
was adjusted to a pH of 8.8-9.8 with about 2.0-2.5 g of
concentrated ammonium hydroxide and stirred for about 30 minutes.
The solids were filtered and washed with about 30.6 g of H.sub.2O
and dried. The 14-hydroxycodeinone (14-OHC) content in the
resulting oxycodone base was measured, as was the
14-hydroxycodeinone (14-OHC) content in the oxycodone HCl salt
formed by the method described in the preceding example. The
results and reaction conditions in the various trials are
illustrated in Table 6.
TABLE-US-00006 TABLE 6 Concentration Molar Ratio Initial 14- Final
14-OHC content Temperature Time (g H.sub.2O per g of SO.sub.2 to
OHC content Oxycodone Oxycodone Trial (.degree. C.) (hr.) pH
Oxycodone HCl) Oxycodone HCl (% by wt.) base (% by wt.) HCl (% by
wt.) 10 50 1 7 12.3 2.4:1 0.13 None detected 0.0004 11 50 5 7 12.3
2.4:1 0.13 None detected 0.0004 12 10 5 7 12.3 2.4:1 0.13 0.0008
Not tested
Example 2F
[0136] To a 22 L, 3 neck round bottom flask equipped with a
mechanical stirrer, N.sub.2 inlet, and thermocouple for temperature
control was added 1840 g of wet oxycodone HCl (4.27 moles: 0.13% by
weight 14-hydroxycodeinone (14-OHC) impurity). Next, with mixing
2706 g of H.sub.2O and 7717 g of 6.4 wt. % SO.sub.2/H.sub.2O
solution was added. The resulting mixture was heated to about
40.degree. C. and the solution pH was adjusted to about 7 using
concentrated ammonium hydroxide. The mixture was stirred for about
5 hours.
[0137] After about 5 hours, the solution was adjusted to a pH of
about 1.7 with the addition of 293.0 g concentrated sulfuric acid
(96-98%). The pressure was slowly reduced to about 0.26 atm to
facilitate the distillation/removal of unreacted SO.sub.2. As the
distillation progressed, 23.4 g of concentrated sulfuric acid was
added as the pressure was decreased to about 0.11 atm and the
solution temperature was increased to about 50-55.degree. C.
[0138] The solution was then cooled to about 30.degree. C. and the
solution pH adjusted to about 8.5-10 with concentrated ammonium
hydroxide. The solution was stirred for about 30 minutes and
filtered. The solids were filtered and washed with about 2000 g of
H.sub.2O and dried. The 14-hydroxycodeinone (14-OHC) content in the
resulting oxycodone base was measured, as was the
14-hydroxycodeinone (14-OHC) content in the oxycodone HCl salt
formed by the method described in the preceding example. The
results and reaction conditions are illustrated in Table 7.
TABLE-US-00007 TABLE 7 Concentration Molar Ratio Initial 14- Final
14-OHC content Temperature Time (g H.sub.2O per g of SO.sub.2 to
OHC content Oxycodone Oxycodone Trial (.degree. C.) (hr.) pH
Oxycodone HCl) Oxycodone HCl (% by wt.) base (% by wt.) HCl (% by
wt.) 13 40 5 7 6.6 1.8:1 0.13 0.0001 0.0005
Example 2G
[0139] To a 50 ml, 3 neck round bottom flask equipped with a
mechanical stirrer, N.sub.2 inlet, and thermocouple for temperature
control was added 3.33 g of oxycodone HCl (0.0095 moles; 0.2% by
weight 14-hydroxycodeinone (14-OHC) impurity). Next, with mixing
33.3 g of H.sub.2O and 0.83 g of sodium bisulfite was added. The
resulting mixture was heated to about 30.degree. C. and the
solution pH was adjusted to about 7 with ammonium hydroxide. The
mixture was stirred for about 15 hours. The pH of the mixture was
then adjusted to about 8.8-9.8 with concentrated ammonium hydroxide
and stirred for about 60 minutes. The precipitated oxycodone base
was then filtered from the mother liquor, washed with about 10.0 g
of H.sub.2O, and dried. The 14-hydroxycodeinone (14-OHC) content in
the resulting oxycodone base was measured, as was the
14-hydroxycodeinone (14-OHC) content in the oxycodone HCl salt
formed by the method described in the preceding example. The
results and reaction conditions in the various trials are
illustrated in Table 8.
TABLE-US-00008 TABLE 8 Concentration Molar Ratio Initial 14- Final
14-OHC content Temperature Time (g H.sub.2O per g of SO.sub.2 to
OHC content Oxycodone Oxycodone Trial (.degree. C.) (hr.) pH
Oxycodone HCl) Oxycodone HCl (% by wt.) base (% by wt.) HCl (% by
wt.) 14 30 15 7 10 0.84:1 0.2 0.0004 0.0004
Example 3
[0140] In this Example, an oxymorphone HCl sample was treated with
a sulfur-containing compound according to the processes described
herein.
[0141] To a 250 ml, 3 neck round bottom flask equipped with a
mechanical stirrer, N.sub.2 inlet, and thermocouple for temperature
control was added 150 g H.sub.2O and 15 g oxymorphone HCl sample
(0.044 moles; 0.3-0.5% by weight 14-hydroxymorphinone (14-OHM)
impurity). Next, 7.5 g of sodium bisulfite (NaHSO.sub.3) was added.
The pH was then adjusted to about 7 with concentrated ammonium
hydroxide, and the resulting mixture was stirred at 23.degree. C.
for about 16 hours.
[0142] After about 16 hours, the pH was adjusted to about 8.8-9.8
with ammonium hydroxide and the solution was cooled to about
20.degree. C. The precipitated oxymorphone base was filtered,
washed with water (about 45 g), and dried for 4 hours at 65.degree.
C.
[0143] The oxymorphone base sample was analyzed using the methods
described above, and the sample contained no detectable amount of
14-hydroxymorphinone or 14-hydroxycodeinone. This experiment was
repeated using a 6 wt. % SO.sub.2/H.sub.2O solution in place of
sodium bisulfite and similar results were obtained.
Example 4
[0144] In this Example, oxycodone base was treated with a thiol
according to the processes described herein.
[0145] To a 25 ml, 3 neck round bottom flask equipped with a
mechanical stirrer, N.sub.2 inlet, and thermocouple for temperature
control was added 3.0 g oxycodone base (0.01 moles; 0.3-0.5% by
weight 14-hydroxycodeinone (14-OHC) impurity). Next, 18 g of
chloroform was added, and the mixture was stirred at 70.degree. C.
until the oxycodone base was dissolved. After the mixture was
substantially homogenous, 1.5 g of benzenethiol was added to the
mixture with stirring.
[0146] After about 16 hours, a sample was analyzed using the
methods described in the preceding examples. HPLC area percent
analysis indicated a 14-hydroxycodeinone level of less than about
0.0022%.
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