U.S. patent application number 09/793024 was filed with the patent office on 2001-06-28 for method for preparing oxycodone.
Invention is credited to Chiu, Fang-Ting, Lo, Young S..
Application Number | 20010005754 09/793024 |
Document ID | / |
Family ID | 23662141 |
Filed Date | 2001-06-28 |
United States Patent
Application |
20010005754 |
Kind Code |
A1 |
Chiu, Fang-Ting ; et
al. |
June 28, 2001 |
Method for preparing oxycodone
Abstract
A method for the preparation of oxycodone, and salts thereof,
from codeine comprising oxidation of codeine to codeinone,
formation of an dienolsilyl ether congener of codeinone in strong
amine base, oxidation of the dienolsilyl ether congener using
peracetic acid, and hydrogenation of the resulting
14-hydroxycodeinone product.
Inventors: |
Chiu, Fang-Ting;
(Chesterfield, VA) ; Lo, Young S.; (Chester,
VA) |
Correspondence
Address: |
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P O BOX 368
RIDGEFIELD
CT
06877
US
|
Family ID: |
23662141 |
Appl. No.: |
09/793024 |
Filed: |
February 26, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09793024 |
Feb 26, 2001 |
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09667997 |
Sep 22, 2000 |
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09667997 |
Sep 22, 2000 |
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09419409 |
Oct 15, 1999 |
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6177567 |
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Current U.S.
Class: |
546/45 |
Current CPC
Class: |
C07D 489/06 20130101;
A61P 25/04 20180101 |
Class at
Publication: |
546/45 |
International
Class: |
C07D 471/00; C07D
489/00; C07D 491/00; C07D 498/00 |
Claims
What is claimed is:
1. A method of producing oxycodone from codeinone which comprises
the steps of: (a) producing a dienol organosilyl ether at position
6 of the C-ring of codeinone thereby forming a dienol organosilyl
ether congener of codeinone; (b) oxidizing the dienol organosilyl
ether to form 14-hydroxycodeinone; and (c) hydrogenating the
unsaturation in the C-ring of 14-hydroxycodeinone to produce
oxycodone.
2. The method of claim 1 wherein the dienol organosilyl ether
congener of codeinone is formed by reacting an organosilyl compound
with codeinone.
3. The method of claim 2 wherein the organosilyl compound has the
formula: R.sub.3.sup.3SiX wherein R.sup.3 is an alkyl or aryl group
and the three R.sup.3 groups are the same or different, and X is a
leaving group selected from imidazole, mesylate, tosylate or
halogen.
4. The method of claim 3 wherein R.sup.3 is selected from the group
consisting of C.sub.1-C.sub.4 alkyl or phenyl and X is chloro.
5. The method of claim 2 wherein the organosilyl halide is reacted
with codeinone in the presence of a strong amine base.
6. The method of claim 5 wherein the strong amine base is DBU
(1,8-Diazabicyclo[ 5.4.0.]undec-7-ene) or DBN
(1,5-Diazabicyclo[4.3.0]non- -5-ene).
7. The method of claim 1 wherein the oxidation of the dienol
organosilyl ether is performed by treating the dienol organosilyl
ether congener of codeinone with peracetic acid.
8. The method of claim 7 wherein the treatment with peracetic acid
is carried out in the presence of an organic solvent.
9. The method of claim 8 wherein the organic solvent is
toluene.
10. A process of producing 14-hydroxycodeinone from codeinone
comprising reacting an organosilyl halide in the presence of a
strong amine base and oxidizing the resulting product with
peracetic acid.
11. The process of claim 10 wherein the strong amine base is a
diazobicyclo-base.
12. The process of claim 11 wherein the strong amine base is
selected from the group consisting of: DBU
(1,8-Diazabicyclo[5.4.0.]undec-7-ene) and DBN
(1,5-Diazabicyclo[4.3.0]non-5-ene).
13. A method for oxidizing a dienol silyl ether selected from the
group having the formula: 12wherein R.sup.1 is alkyl or acyl,
R.sub.2 is lower alkyl, allyl, or lower alkyl substituted by
cycloalkyl, and R.sup.3 is an alkyl or aryl group and the three
R.sup.3 groups are the same or different which comprises the steps
of: (a) reacting the dienol silyl ether compound with peracetic
acid and (b) thereafter isolating the product as a free base.
14. A method for forming a dienol silyl ether selected from the
group having the formula: 13wherein R.sup.1 is of alkyl or acyl,
R.sub.2 is lower alkyl, allyl, or lower alkyl substituted by
cycloalkyl, and R.sup.3 is an alkyl or aryl group and the three
R.sup.3 groups are the same or different which comprises the steps
of: reacting an morphinan-6-one selected from the group having the
formula: 14 with an organosilyl compound having the formula
R.sub.3.sup.3SiX wherein R.sup.3 is as defined above and X is a
leaving group selected from imidazole, mesylate, tosylate or
halogen, in the presence of a strong amine base and an aprotic
solvent.
15. The method of claim 14 wherein the strong amine base is a
diazabicylco-base.
16. The method of claim 15 wherein the diazabicyclo-base is
selected from the group consisting of: DBU
(1,8-Diazabicyclo[5.4.0.]undec-7-ene) and DBN
(1,5-Diazabicyclo[4.3.0]non-5-ene).
17. The method of claim 14 wherein R.sup.3 is C.sub.1-C.sub.4 alkyl
or phenyl.
18. The method of claim 14 wherein X is chloride.
19. A method of producing oxycodone from codeine which comprises
the steps of: (a) oxidizing codeine to codeinone; (b) producing a
dienol organosilyl ether at position 6 of the C-ring of codeinone
thereby forming a dienol organosilyl ether congener of codeinone;
(c) oxidizing the dienol organosilyl ether to form
14-hydroxycodeinone; and (d) hydrogenating the unsaturation in the
C-ring of 14-hydroxycodeinone to produce oxycodone.
20. The method of claim 19 wherein the dienol organosilyl ether
congener of codeinone is formed by reacting an organosilyl halide
with codeinone.
21. The method of claim 20 wherein the organosilyl halide has the
formula: R.sub.3.sup.3SiCl wherein R.sup.3 is C.sub.1-C.sub.4 alkyl
or phenyl.
22. The method of claim 20 wherein the organosilyl halide is
reacted with codeinone in the presence of a strong amine base.
23. The method of claim 22 wherein the strong amine base is DBU
(1,8-Diazabicyclo[5.4.0.]undec-7-ene) or DBN
(1,5-Diazabicyclo[4.3.0]non-- 5-ene).
24. The method of claim 19 wherein the oxidation of the dienol
organosilyl ether is performed by treating the dienol organosilyl
ether congener of codeinone with peracetic acid.
25. The method of claim 24 wherein the treatment with peracetic
acid is carried out in the presence of an organic solvent.
26. The method of claim 25 wherein the organic solvent is toluene.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of Invention
[0002] The present invention relates to an improved method for
preparing oxycodone. More particularly, the present invention sets
forth a method for preparing oxycodone in high yields that does not
require the employment, or synthesis, of thebaine in the reaction
scheme.
[0003] 2. Background of the Related Art
[0004] The analgesic activity of Papaver somniferum has been known
since antiquity. It has long been understood that the milky juice
derived from the unripe seed capsules of this poppy plant possesses
potent pharmacological properties. The dried and powdered form of
the juice is referred to as opium. Opium comprises about 10% of the
juice obtained from the unripe seed capsules of Papaver
somniferum.
[0005] Early in the nineteenth century it was recognized that opium
contains numerous alkaloid compounds. The first of these alkaloids
to be isolated was morphine, described by Serturner in 1805. The
isolation of other alkaloids, including codeine (Robiquet 1832),
papaverine (Merck 1848), thebaine, oripavine and noscapine followed
in short order. By the middle of the nineteenth century, the use of
pure alkaloids rather than crude opium preparations was established
medical practice. It is now known that opium contains more than
twenty distinct alkaloids.
[0006] In general, the opium alkaloids can be divided into five
distinct chemical classes: phenanthrene, benzylisoquinoline,
tetrahydroisoquinoline, cryptopine and miscellaneous (Remington's
Pharmaceutical Sciences 433, 1975). Therapeutically useful drugs
are primarily isolated from the phenanthrene and benzylisoquinoline
classes. The principal phenanthrenes are morphine (.apprxeq.10% of
opium), codeine (.apprxeq.0.5% of opium) and thebaine
(.apprxeq.0.2% of opium). The principal benzylisoquinolines are
papaverine (.apprxeq.1.0% of opium) and noscapine (.apprxeq.6.0% of
opium).
[0007] Morphine itself comprises a 5-ring structure, incorporating
a partially hydrogenated phenanthrene ring system. Each ring of
morphine is designated as set forth below: 1
[0008] Morphine includes what is referred to in the art as a
morphinan ring structure, comprising rings A, B, C and E, as set
forth below: 2
[0009] The substituent numbering of morphine derivatives follows
two common conventions as shown: 3 4
[0010] It is the second (Chemical Abstracts) numbering system that
shall be made reference to hereinafter.
[0011] The first total synthesis of morphine was published in 1952
(Gates, et al., 74 J. Amer. Chem. Soc., 1109, 1952). Because the
laboratory synthesis of morphine is difficult, however, the drug is
still obtained from opium or extracted from poppy straw (Goodman
& Gilman's The Pharmacological Basis of Therapeutics, 489,
1990). Semi-synthetic derivatives of the naturally occurring opium
alkaloids are widely employed in medicine today. Among the
important properties of opioids that may be altered by structural
modification are the affinity of the compound for various species
of opioid receptors, resistance to metabolic breakdown, lipid
solubility and agonist versus antagonist activity.
[0012] Codeine, hydrocodone, hydromorphone, oxycodone, and
oxymorphone which are found in present day analgesic prescription
drugs, are all congeners of morphine. Other structural analogs of
morphine used medically in the United States include: levorphanol,
nalmefene, naloxone, naltrexone, buprenorphine, butorphanol, and
nalbuphine. Some morphine analogs, such as levorphanol, may be
produced totally synthetically around a non-opiate morphinan
nucleus which is synthesizable from coal tar derivatives
(Remington's Pharmaceutical Sciences 1039, 1975).
[0013] Among the many morphine structural analogs used in medicine
today, widespread use is made of both codeine and oxycodone.
[0014] Codeine is 3-methylated morphine. Codeine has less than
one-seventh the analgesic potency of morphine (Foye, Medicinal
Chemistry, 254 (1975)). However, as codeine has a far better oral
bioavailability than morphine (the 3-methoxy group is believed to
protect it from rapid first-pass biotransformation--the action of
morphine orally is terminated largely by glucuronide conjugation at
the 3-hydroxyl group), codeine is only less than four times as
potent, on a weight basis, than morphine when both compounds are
administered orally (Drug Facts & Comparisons 1246, 1996).
While some codeine is obtained from opium directly, the quantity
obtainable from such extraction is not sufficient to meet the
extensive use of the alkaloid. The need for codeine is fulfilled by
partial synthesis of the compound from morphine (Remington's
Pharmaceutical Sciences 1038, 1975).
[0015] Oxycodone is a white, odorless crystalline powder of
semi-synthetic origin with multiple actions qualitatively similar
to those of morphine. 5
[0016] The principal actions of therapeutic value are analgesia and
sedation. It is similar to codeine and methadone in that it retains
at least one half of its analgesic activity when administered
orally. It is a pure agonist opioid, which produces not only
analgesia, but other therapeutic effects including anxiolysis,
depression of the cough reflex, euphoria and feelings of
relaxation. On a weight basis, oxycodone is approximately twice as
potent orally as morphine (Drug Facts & Comparisons 1246,
1996). Oxycodone is typically indicated for the relief of moderate
to moderately severe pain (Drug Facts & Comparisons 1259,
1996).
[0017] Thebaine, which also contains a morphinan-ring structure,
differs from codeine in replacing the hydroxyl group of the
morphinan C-ring with a methoxy group and the "C" ring has two
double bonds--.DELTA..sup.6,7, .DELTA..sub.8,14 (i.e., thebaine
differs from morphine in that both hydroxyl groups are methylated
and the "C" ring has two double bonds--.DELTA..sup.6,7,
.DELTA..sup.8,14). 6
[0018] The compound demonstrates the effect that minor
modifications in structure of morphinan compounds may have in
pharmacological effects, as thebaine lacks any substantial
analgesic activity (Foye, Medicinal Chemistry, 256 (1975)).
[0019] While lacking medicinal usefulness in itself, thebaine is
singularly important as a key intermediate in the synthesis of many
useful opiate-derivatives (See, Barber et al., 18 J. Med. Chem.
1074-107, 1975), including oxycodone (Freund et al., 94 J. Prak.
Chemie 135-178, 153, 1916; See Physician's Desk Reference, 2569,
54th Ed. 1999), naloxone, naltrexone and nalbuphine (See, U.S. Pat.
No. 4,795,813 at Col. 1, lines 16-21). Thebaine is the only known
.DELTA..sup.6,8-diene compound among the naturally-ocurring
morphine alkaloids (Seiki, 18 Chem. Pharm. Bull. 671-675,
1970).
[0020] Oxycodone may be prepared from thebaine by: dissolution of
the thebaine in aqueous formic acid, oxidation treatment with 30%
hydrogen peroxide (Seki, 18 Chem. Pharm. Bull. 671-676, 1970),
neutralization with aqueous ammonia to yield 14-hydroxycodeinone
and hydrogenation of the 14-hydroxycodeinone in acetic acid with
the aid of a palladium-charcoal catalyst (Remington's
Pharmaceutical Sciences 1041, 1975). Oxidation of thebaine may
alternatively be performed using potassium dichromate in acetic
acid (Freund et al., 94 J. Prakt. Chem. 135, 1916) or performic
acid (Iljima et al., 60 Helv. Chim. Acta 2135-2137, 1977). Improved
yield, however, has been reported to be obtained by oxidizing with
m-chloroperbenzoic acid in an acetic acid-trifluoroacetic acid
mixture (Hauser et al., 17 J. Med. Chem. 1117, 1974; See also, U.S.
Pat. No. 4,795,813 to Schwartz, Col. 1, Lines 22-26). Yield may
also be improved by hydrogenation of 14-hydroxycodeinone under a
pressure of about 30 psi (Kra.beta.nig et al. 329 Arch. Pharm.
Pharm. Med. Chem. 325-326, 1996).
[0021] Although particularly useful in the synthesis of numerous
pharmaceutical preparations, thebaine is among the least abundant
phenanthrene alkaloids in Papaver somniferum. Due to its scarcity,
a number of investigators have proposed methods of obtaining this
unique alkaloid using other more abundant opioid compounds as
starting materials.
[0022] Seki (18 Chem. Pharm. Bull. 671-676, 1970) discloses a
method for preparing A.sup.6,8-diene compounds, such as thebaine,
from .alpha.,.beta.-unsaturated ketones such as codeinone, which
may be obtained from the natural alkaloid codeine. Codeinone was
added to a mixture of p-toluenesulfonic acid (dehydrated prior to
reaction), absolute methanol and dried benzene, the solution
refluxed for 3 hours under azeotropic removal of water, and the
reaction mixture purified by washing with diluted sodium hydroxide,
to obtain thebaine. A reported maximum yield of 26.8% was reported
when using 1.1-0.15 molar equivalents of p-toluenesulfonic acid to
codeinone. Eppenberger et al. (51 Helv. Chim. Acta 381, 1968)
report a four step method for converting dihydrocodeinone to
thebaine which results in a similar yield of 27%. Schwartz et al.
(97 J. Am. Chem. Soc. 1239, 1975) demonstrate the total synthesis
of thebaine in which the key step is the oxidative coupling of a
reticuline derivative to a salutaridine derivative. The overall
yield of dl-thebaine, however, was only in the 1-2% range based on
isovanillin. Reaction of salutaridinol with an organic or inorganic
acid halide or acid anhydride, followed by treatment with a strong
base, is taught as a method of thebaine production in U.S. Pat. No.
3,894,026 to Sohar et al. A yield as high as 50.3% was reported
(See, Col. 4, Line 29). Barber et al. (18 J. Med. Chem. 1074-1077,
1975) report synthesizing thebaine (as well as oripavine) from
codeine and morphine. Barber et al. teach methylation of the
potassium salt of codeine to give codeine methyl ether followed by
oxidation with .gamma.-MnO.sub.2 (See also, U.S. Pat. No. 4,045,440
to Rapoport et al., 1977). These authors claim a 67% yield of
oxycodone from codeine. European Patent Application No. EP 0 889
045 A1 likewise teaches a process for the production of thebaine
from the more readily available morphinans codeine and morphine.
Such method provides for converting the starting material to an
alkali metal or quaternary ammonium cation and reacting the same
with a compound of the formula RX wherein R is an alkyl or acyl
group and X is a leaving group.
[0023] While all of the above methods have been devised to increase
the supply of thebaine by synthetic and semi-synthetic means, the
fact remains that thebaine remains relatively costly as opposed to
morphine and codeine.
[0024] The use of thebaine as a starting material to form other
therapeutically useful opioids also suffers from a disadvantage
unassociated with its relative scarcity-- thebaine is a known
convulsant, capable of causing (even in low doses) strychnine-like
convulsions (Foye, Principles of Medicinal Chemistry 255, 1975; The
Merck Index, 9203 (11th Edition), 1989). Employment of thebaine in
any synthesis scheme, therefore, entails significant risks and
requires the taking of a number of precautions. Considering the
relatively high cost of, and the toxicity potential of, thebaine,
it would be preferred if alternative synthesis methods were
developed to manufacture the many opioid congeners currently
synthesized from thebaine from cheaper and less toxic
materials.
[0025] U.S. Pat. No. 2,654,756 discloses a method for converting
codeine into codeinone, dihydrocodeinone and dihydromorphine rather
than synthesizing such compounds from thebaine. Conversion is
effectuated by way of oxidation using certain ketones in the
presence of aluminum alkoxides. Likewise, methods for producing
14-hydroxymorphinans, such as naloxone, naltrexone and nalbuphine
(opioid antagonists) from codeine, without a thebaine intermediate,
have also been disclosed (See, U.S. Pat. No. 4,472,253 to Schwarz
and Schwartz and Wallace, 24 J. Med. Chem. 1525-1528, 1981). To
date, however, no economical method has been proposed for
manufacturing oxycodone from a readily available starting material
that has a toxicity and cost profile which is significantly
improved over that possessed by thebaine.
BRIEF SUMMARY OF THE INVENTION
[0026] The present invention provides an improved, high-yield,
method for preparing oxycodone that does not require employment of
a thebaine intermediate in the reaction scheme. The disclosed
method makes use of compound having a morphinan-like ring
structure, such as codeine or morphine, as a starting material for
the synthesis of oxycodone. The method employs the steps of:
converting the starting material to a compound with a morphinone
ring structure, preparing a dienolsilyl ether at the C-ring of the
morphinan-like ring structure by reacting an organosilyl compound
with the starting material, oxidizing the silyl ether, and
hydrogenating the unsaturation in the C-ring. Formation of the
dienolsilyl ether is promoted by efficient dienolization of the
C-ring, which is provided by reacting the
.alpha.,.beta.-unsaturated ketone and organochlorosilane reactants
in the presence of a strong amine base, such as DBU
(1,8-Diazabicyclo[5.4.0.]undec-7-ene) or DBN
(1,5-Diazabicyclo[4.3.0]non-5-ene). Preferably the organosilyl
reactant, for example a triorganosilyl chloride, is stericly
hindered on the silicone atom.
[0027] An aspect of the present invention comprises a method for
producing oxycodone from codeine employing two oxidation steps, one
involved in the oxidation of a hydroxyl group to a ketone, and the
other involving oxidative hydroxylation of a dienolsilyl ether. In
particular, oxycodone free base has been produced in commercially
reasonable yields by forming a dienolsilyl ether derivative of
codienone in the presence of a strong amine base (preferably a
diazabicyclo-base), oxidizing the silyl ether to form
14-hydroxycodeinone, and hydrogenation of the morphinan C-ring
unsaturation to form oxycodone.
[0028] In one embodiment of the present invention, there is
provided an improved method for synthesizing oxycodone from codeine
free base. In this embodiment, codeine free base is converted to
codeinone by oxidation, for example, by using a standard oxidant
such as MnO.sub.2, Na.sub.2WO.sub.4/H.sub.2O.sub.2,
Pd(OAc).sub.2/O.sub.2, and/or a standard oxidation procedure, e.g.,
Swern/Moffat-type oxidation (DMSO-based oxidation), Oppenauer-type
oxidation (employing aluminum alkoxides and cyclohexanone or other
ketones). Preferred oxidants include BaMnO.sub.4 and Oppenauer
oxidation. Codeinone is then reacted with an organosilyl compound
having an effective leaving group, such as a halogen. The resulting
dienolsilyl ether derivative is then oxidized with an oxidizing
agent to afford 14-hydroxycodeinone. It has been found that the
dienolsilyl ether of the morphinone C-ring may efficiently be
converted to 14-hydroxycodeinone using peracetic acid solution.
Hydrogenation of the unsaturation in the C-ring is subsequently
performed and may be accomplished by way of, for example,
pressurized catalytic hydrogenation or catalytic transfer
hydrogenation in acetic acid. Oxycodone produced by such method has
been found to be obtainable in yields approximating 80%.
[0029] One of the novelties of this invention is the discovery that
commercially-practicable yields of therapeutically employed opioid
alkaloids having a morphinan ring structure can be obtained without
recourse to a thebaine intermediate by reacting a compound with a
morphinone ring structure with an organosilyl reactant in the
presence of a strong amine base, preferably a diazabicyclo-base
such as DBU (1,8-Diazabicyclo[ 5.4.0.]undec-7-ene) or DBN
(1,5-Diazabicyclo[4.3.0]non- -5-ene) (to improve enolization and
the promotion of a dienolsilyl ether derivative), followed by
oxidation of the dienolsilyl ether moiety.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
[0030] After considerable experimentation with numerous reaction
schemes designed to form oxycodone from codeine and morphine (two
relatively inexpensive opioid alkaloids), the present inventors
have discovered a unique reaction scheme for manufacturing
oxycodone that provides for industrially-acceptable yields. The
present invention overcomes many of the prior art problems
associated with the production of oxycodone and provides for a
synthetic scheme for oxycodone production which does not employ the
relatively costly, scarce and toxic alkaloid--thebaine.
[0031] The present inventors have discovered that enolization of
the C-ring of a morphinone compound having an
.alpha.,.beta.-unsaturated ketone structure, is significantly
enhanced by exposure to a strong amine base, such as DBU or DBN and
similar diazabicyclo-bases. Formation of the dienolsilyl ether (by
reaction with the ketone of such ring with a organosilyl compound
having an effective leaving group) was greatly improved by
effectuating the reaction in the presence of the strong amine base.
The present inventors have further discovered that the dienolsilyl
ether of codeinone (the silyl ether formed at position 6 (chemical
abstract substituent-numbering designation)) may be used to
directly form 14-hydroxycodeinone by oxidation of the silyl ether.
In a preferred embodiment, oxidation is performed at room
temperature for about 3 hours. The dienolsilyl ether of codeinone
may be dissolved in toluene or other similar solvent. Oxidation may
be efficiently performed with relatively high yield using peracetic
acid or other peracids. Hydrogenation of 14-hydroxycodeinone
produces oxycodone. A preferred hydrogenation reaction employs
hydrogen gas or NaH.sub.2PO.sub.2 along with a palladium-carbon
catalyst, with the 14-hydroxycodeinone being dissolved in a weakly
acidic solution such as aqueous acetic acid.
[0032] A codeinone dienol silyl ether, such as the intermediate
compound formed in the conversion of codeine to oxycodone according
to certain embodiments of the present invention, is disclosed in
pending European patent application No. EP 0 889 Q45 A1 to Jen-Sen
Dung. The reference, however, is instructive as to the
unobviousness of the present invention.
[0033] Recognizing the expense and relative scarcity of thebaine,
EP 0 889 045 A1 teaches (as noted above) a process for the
production of thebaine and analogues thereof. While disclosing
codeinone tert-butyldimethylsilyl dienol ether (Example 6), the
patent teaches the production of oxycodone only from thebaine which
is synthesized by the procedures described (See, e.g., Abstract of
the Disclosure, Col. 1, Lines 25-52, Col. 5, Lines 24-29, Col. 9,
Example 8). No recognition is made of the fact that the
tert-butyldimethylsilyl dienol ether could be utilized, without
synthesis of a thebaine intermediate, to produce oxycodone. Further
the reference fails to teach a method for producing organosilyl
dienol ethers of the morphinone ring in commercially practicable
yields. The reference notes that the codeine
tert-butyldimethylsilyl dienol ether produced by the methods
described comprised only 23% of the solid mass recovered (thus
comprising a relatively minor component of the solid mass). EP 0
889 045 A1 does not disclose or imply that yield could be
significantly enhanced by the presence of strong amine base (rather
than tetrahydrofuran as taught by the reference) in the reaction
mix when the ether is being formed.
[0034] The presently disclosed invention provides commercially
practicable yields, yields typically in excess of 50%, and more
typically in excess of 80%, of oxycodone from codeinone (a compound
that is easily obtained from codeine by oxidation). Codienone is
easily synthesized from codeine, an alkaloid that can be obtained
naturally, or semi-synthetically, as from morphine. It has been
discovered that by reacting an organosilyl compound in the presence
of a strong amine base that a high degree of conversion to the
organosilyl dienol ether conjugate of codeinone may be achieved.
The strong amine base is believed to strong favor enolization of
codeinone, a compound having an .alpha.,.beta.-unsaturation in the
"C" ring of the morphinone ring structure, while the organosilyl
moiety captures the enol form. The organosilyl ether form of
codeinone is also promoted by employing an organosilyl compound
having an effective leaving group, such as a halogen, and in
employing a stericly bulky silicone moiety. While the resulting
dienolsilyl ether form of codeinone may be oxidized to
14-hydroxycodeinone using a number of standard oxidizing agents, it
has been found that oxidation with peracetic acid is extremely
efficient, producing about an 80% yield. The 14-hydroxycodeinone is
then hydrogenated, as by catalytic hydrogenation, so as to
hydrogenate the .alpha.,.beta.-unsaturation of the C-ring. A
catalytic transfer hydrogenation method in aqueous acetic acid was
found to produce about the same yield, and similar impurity
patterns, as the method reported by R. Kra.beta.nig, et al.
[0035] In an aspect of the invention, there is disclosed a method
of producing oxycodone from codeinone which comprises the steps of:
(a) producing a dienol organosilyl ether at position 6 of the
C-ring of codeinone thereby forming a dienol organosilyl ether
congener of codeinone; (b) oxidizing the dienol organosilyl ether
to form 14-hydroxycodeinone; (c) hydrogenating the unsaturation in
the C-ring of 14-hydroxycodeinone to produce oxycodone.
[0036] The dienol organosilyl ether congener of codeinone is
preferably formed by reacting an organosilyl compound with
codeinone, such organosilyl compound having the formula:
R.sub.3.sup.3SiX
[0037] wherein R.sup.3 is alkyl or aryl and the three R.sup.3
groups may be the same or different and X is a leaving group, such
as imidazole, mesylate, tosylate or a halogen. Preferably, the
organosilyl compound is reacted with codeinone in the presence of a
strong amine base, such as diazobicyclo-base, for example, DBU
(1,8-Diazabicyclo[5.4.0.]undec-7-ene) or DBN
(1,5-Diazabicyclo[4.3.0]non-5-ene). Oxidation of the dienol
organosilyl ether may be performed by treating the dienol
organosilyl ether congener of codeinone with peracetic acid,
preferably in the presence of an organic solvent such as
toluene.
[0038] In another aspect of the present invention there is
disclosed a method for oxidizing a dienol silyl ether selected from
the group having the formula: 7
[0039] wherein R.sup.1 is selected from the group of alkyl or acyl
and R.sup.2 is selected from the group of lower alkyl, allyl, or
lower alkyl substituted by cycloalkyl, and R.sup.3 is an alkyl or
aryl group and the three R.sup.3 groups may be the same or
different, which comprises the steps of: (a) reacting the dienol
silyl ether compound with peracetic acid and (b) thereafter a work
up procedure to isolate the product as a free base.
[0040] In yet another aspect of the present invention there is
disclosed a method for forming a dienol silyl ether selected from
the group having the formula: 8
[0041] wherein R.sup.1 is selected from the group of alkyl or acyl
and R.sup.2 is selected from the group of lower alkyl, allyl, or
lower alkyl substituted by cycloalkyl, and R.sup.3 is an alkyl or
aryl group and the three R.sup.3 groups may be the same or
different, which comprises the steps of:
[0042] reacting an morphinan-6-one selected from the group having
the formula: 9
[0043] with an organosilyl compound having the formula
R.sub.3.sup.3SiX
[0044] wherein R.sup.3 is an alkyl or aryl group and the three
R.sup.3 groups may be the same or different group and X is a
leaving group, such as imidazole, mesyate, tosylate or a halogen,
in the presence of a strong amine base. The strong amine base may
be a diazabicyclo-base, and may more specifically be selected from
the group consisting of: DBU (1,8-Diazabicyclo[ 5.4.0.]undec-7-ene)
and DBN (1,5-Diazabicyclo[4.3.0]no- n-5-ene). X is preferably
chloride.
[0045] And yet another aspect of the present invention entails a
method of producing oxycodone from codeine which comprises the
steps of: (a) oxidizing codeine to codeinone; (b) producing a
dienol organosilyl ether at position 6 of the C-ring of codienone
thereby forming a dienol organosilyl ether congener of codeinone;
(c) oxidizing the dienol organosilyl ether to form
14-hydroxycodeinone; (d) hydrogenating the unsaturation in the
C-ring of 14-hydroxycodeinone to produce oxycodone. The dienol
organosilyl ether congener of codeinone of this embodiment may be
formed by reacting an organosilyl halide with codeinone, preferably
an organosilyl halide having the formula: R.sup.3.sub.3SiCl,
wherein R.sup.3 is as defined hereinabove. Preferably the
organosilyl chloride is reacted with codeinone in the presence of a
strong amine base. The strong amine base may be a diazabicyclo-base
and may be selected from the group consisting of: DBU
(1,8-Diazabicyclo[ 5.4.0.]undec-7-ene) or DBN
(1,5-Diazabicyclo[4.3.0]non-5-ene). The oxidation of the dienol
organosilyl ether may be performed by treating the dienol
organosilyl ether congener of codeinone with peracetic acid (which
reaction may be carried out in the presence of an organic solvent
such as toluene).
[0046] A preferred method of the present invention for forming
oxycodone from codeine fundamentally involves four (4) synthetic
steps: (1) oxidation of codeine to codeinone; (2) formation of an
organosilyl ether congener of codeinone; (3) oxidation of the silyl
ether to 14-hydroxycodeinone; and (4) hydrogenation of the
partially unsaturated non-aromatic C-ring to produce oxycodone,
such as described in more detail below and as shown in the
following diagrammatic form: 10
Oxidation of Codeine to Codeinone
[0047] The oxidation of codeine to codeinone may be performed by
numerous methods known to those of ordinary skill in the art
including: CrO.sub.3/TBHP oxidation, dichromate oxidation,
Na.sub.2WO.sub.4/peroxide oxidation, BaFeO.sub.4 oxidation, hydrous
ZrO.sub.2/ketone oxidation, oxidation using CrO.sub.2, Highet
oxidation (Highet et al., 77 J. Am. Chem. Soc. 4399, 1955) using
manganese dioxide, Oppenauer oxidation using aluminum isopropoxide
and cyclohexanone (See, U.S. Pat. No. 2,654,756 to Homeyer et al.),
sodium tungstate activated peroxide oxidation (Sato et al., 119 J.
Am. Chem. Soc. 12386, 1997), Swern/Moffatt type (DMSO-based)
oxidation, palladium acetate catalyzed aerobic oxidation and barium
manganate oxidation (See, Nishimura et al., 39 Tet. Let. 6011).
[0048] As would be understood by one of ordinary skill in the art,
with respect to any oxidation procedure, adjustment of reaction
conditions, such as the concentration of the reactants, the acidity
of the reaction mixture, the presence or absence of solvating
agents, and the like, .may impact upon the yield of oxidized
product. For example, with respect to barium manganate oxidation it
may be preferred to keep the reaction mixture at about 0.degree. C.
and to control the polarity of the solvent to improve yield. With
respect to Oppenauer oxidation, the addition of toluene to the
reaction scheme may improve yield, as well may azeotropic removal
of water from the codeine/toluene solution prior to the addition of
a catalytic amount of aluminum isopropoxide, and the collection of
distillate during and after the addition of the aluminum
isopropoxide. Selection may also be made between numerous potential
reactants such as in Swern/Moffatt type oxidation numerous
activators in DMSO may be employed including: oxalyl chloride,
TsCl, P.sub.2O.sub.5, TFAA, Ac.sub.2O, PySO.sub.3, Ts.sub.2O,
SOCl.sub.2, DCC, DIPC, cyanuric chloride, ClSO.sub.2NCO,
(MeSO.sub.2).sub.2O, Cl.sub.2, hot air, and the like.
Formation of Dienolsilyl Ether of Codeinone
[0049] Codeinone may be modified to form a silyl ether at position
6 (Chemical Abstracts designation) by reaction with an organosilyl
compound R.sub.3.sup.3SiX. Preferred organosilyl compounds were
found to be stericly-hindered at the silicon atom and to have
chlorine as the leaving group. The enolized codeinone was
efficiently trapped with a trialkychlorosilane, such as
tert-butyldimethylchlorosilane or triethylchlorosilane. The
trimethylsilyl ether, however, was found to be rapidly hydrolyzed.
Enolization of codeinone, and the formation of the dienolsilyl
ether, was found to be promoted by the presence of strong amine
base, such as DBU or DBN. Other bases such as LDA, DABCO, DIPEA,
TEA, imidazole, N-methylmorpholine, HMDS-Li salt,
hexamethyldisilazane, and aluminum isopropoxide did not yield a
desirable amount of dienolsilyl ether.
Oxidation of Dienolsilyl Ether of Codeinone to
14-Hydroxycodeinone
[0050] Oxidation of the dienolsilyl ether of codeinone to
14-hydroxycodeinone may be performed using the many oxidizing
agents and methods known in the art. For example, the dienolsilyl
ether may be oxidized in a hydrogen peroxide-free performic acid
mixture according to the method published by Swern (D. Swern,
Organic Reactions VII, 378, 1953), by way of MnO.sub.2 or performic
acid. A preferred oxidation procedure, however, was found to employ
peracetic acid prepared from acetic anhydride, hydrogen peroxide
and a catalytic amount of sulfuric acid. Aging of the peracetic
acid solution and treatment with acetic anhydride was found to
improve optimum oxidation hydroxylation) presumably by removal of
any free hydrogen peroxide. Anhydrous peracetic acid up to 25 days
old was found to be most effective. The yield of
14-hydroxycodeinone was found to be also effected by the molar
ratio and percentage of oxidant in the mixture. Optimal oxidation
conditions may vary with different organosilyl ethers. For example,
the presence of trifluoroacetic acid (TFA) was found to improve the
oxidation of the triethylsilyldienolate of codeinone. The isolation
of 14-hydroxycodeinone may entail de-activation of the spent
peracetic acid by treating with either sodium hydrogen sulfite or
sodium thiosulfate aqueous solution, and removal of acetic acid
solvent (in vacuo), and organic neutral by-products like disiloxane
or silanol and N-oxide, by acid/base work up procedures. Oxidation
of either t-butyldimethylsilyldienolate or triethylsilyldienolate
of codeinone may afford a similar yield of 14-hydroxycodeinone (or
its acid salt). Oxidation of the triethylsilyl dienol ether and
t-butyldimethylsilyl ether of codeine with peracetic acid was found
to produce yields of 14-hydroxycodeinone in excess of about
80%.
Hydrogenation of 14-Hydroxycodeinone to Oxycodone
[0051] 14-Hydroxycodeinone was converted to oxycodone by
hydrogenation of the .alpha.,.beta.-unsaturation in the C-ring.
Hydrogenation may be performed by using any of the methods known
for hydrogenation of 14-hydroxycodeinone to oxycodone. For example,
diphenylsilane and Pd(Ph.sub.3P)/ZnCl.sub.2 may be used to reduce
14-hydroxycodeinone, as may sodium hypophosphite in conjunction
with a Pd/C catalyst in aqueous acetic acid, and Pd/C catalytic
transfer hydrogenation.
[0052] The following examples illustrate various aspects of the
present invention. They are not, however, to be construed as
limiting the claims in any manner whatsoever.
EXAMPLE 1
Formation of Codeinone from Codeine
[0053] Codeinone was prepared by oxidation of codeine sulfate
trihydrate. A reaction mixture was prepared containing codeine
sulfate trihydrate (10.4 g), de-ionized water (20 g) and isopropyl
acetate (87.2 g) at ambient temperature. The reaction mixture was
agitated and the resultant mixture cooled to about 20.+-.5.degree.
C. Concentrated ammonium hydroxide (18.0 g) was added in several
portions and the mixture was maintained at a temperature of about
20.+-.5.degree. C. with stirring. Stirring was continued for about
15 minutes, and then a small portion of the aqueous layer was
withdrawn to check for pH value, which was to be advantageously
maintained between 11.0 and 12.0. The aqueous layer was then
separated and re-extracted with isopropyl acetate (35 g). The
combined organic layers (isopropyl acetate) were concentrated in
vacuo to near dryness at temperature NMT 45.degree. C. The residual
isopropyl acetate solvent was chased by adding 18 g of toluene. The
concentration process was then repeated in vacuo. Codeine free base
dissolved in a mixture of toluene (177 g) and cyclohexanone (47.4
g) at temperature NMT 45.degree. C. was then transferred to the
reaction flask which was equipped with magnetic stirrer,
thermocouple, Dean-Stark trap with condenser attached, addition
funnel with an extender (about 4 inches height), and a
nitrogen-inlet adapter. The mixture was heated to boiling
temperature (about 116-118.degree. C.) under a nitrogen atmosphere
and 26 g (30 ml) of distillate were collected in the Dean-Stark
trap. A solution of aluminum isopropoxide (3.5 g) in 35.5 g (41 ml)
of toluene was then added to the addition funnel. The heating rate
was adjusted and the aluminum isopropoxide/toluene solution was
added into the reaction mixture at such a rate that the total
volume was added over a 10-20 minute period (approximately the same
volume (41 ml) of distillate was collected in the Dean-Stark trap).
After completion of the addition, collection of the distillate was
continued such that 57 g (66 ml) of distillate was collected in the
Dean-Stark trap at a similar distillation rate. The heat source was
removed and the mixture allowed to cool down to ambient temperature
(under nitrogen atmosphere) over a period of about 30 minutes.
Reaction completeness was determined by withdrawing a small sample
from the batch, extracting it with a saturated sodium bicarbonate
solution and ethyl acetate, concentrating the organic layer,
re-dissolving it with the HPLC mobile phase, and analyzing the
sample on HPLC. The reaction was considered complete if the area %
of codeine was less than 3.5A %.
[0054] An aqueous solution of 13 wt. % Rochelle salt was then
prepared by dissolving 19.5 g of potassium sodium tartrate
tetrahydrate in 130.5 g of de-ionized water at 20.+-.5.degree. C.
The aqueous Rochelle salt solution (90 ml) was added into the
reaction mixture in one portion at ambient temperature, the batch
stirred for about 10 minutes, and filtered. Both layers were saved.
The organic layer was washed with 60 ml of aqueous Rochelle salt
solution (both layers were saved). The organic layer was washed
with a mixture of 30 ml brine solution and 30 ml 5% sodium
bicarbonate solution (both layers were saved). All aqueous layers
were then combined and extracted with 43 g (50 ml) of toluene. The
aqueous layer was discarded. The organic layers were then combined
and concentrated in vacuo at temperature NMT 55.degree. C. to near
dryness. Twenty-two grams (25 ml) of toluene was added and the
resultant organic layer concentrated in vacuo twice more to remove
residual cyclohexanone. Subsequently, 11.8 g (15 ml) of 2-propanol
was added and the mix slurried at 0-5.degree. C. for at least eight
hours under a nitrogen atmosphere. Solids were then filtered and
the flask/wet cake rinsed with the chilled (about 5.degree. C.)
recycled filtrate. The latter operation was repeated until no
solids were left in the flask. The chilled wet cake was then rinsed
with chilled (5-10.degree. C.) 2-propanol (12 g, 15 ml), and filter
dried. The wet cake was then rinsed with heptane (6.8 g, 10 ml) and
filter-dried. The resulting solids were vacuum dried at temperature
NMT 50.degree. C. to a constant weight. A yield of 5.2 to 6.45 g
(65.4 to 81.2%) of off-white solids, with HPLC purity of about 96A
%-99.3A % was obtained. The compound was stored in a dark and cool
place.
EXAMPLE 2
Preparation of Dienolsilyl Ether of Codeinone
[0055] Codeinone (6.0 g) with toluene (104 g) was added to a
reaction flask equipped with a mechanical stirrer, thermocouple,
Dean-Stark trap with condenser attached, and a nitrogen-inlet
adapter. The batch was heated to reflux and about 27.7 g (32 ml) of
distillate was collected in the Dean-Stark trap. The contents were
then cooled to 20.+-.5.degree. C. under a nitrogen atmosphere. A
solution of DBU (4.22 g) in toluene (3 g) was added in one portion.
Subsequently, a solution of t-BDMSiCl (4.22 g) in toluene (5 g) was
likewise added in one portion. The batch was slowly warmed to
58.+-.3.degree. C. and stirred at this temperature for about 2
hours. Completion of the reaction was adjudged by withdrawing a
small sample from the batch, extracting it with a mixture of ethyl
acetate and saturated sodium bicarbonate solution, spotting the
organic layer on a TLC plate, and then eluting it with a mobile
phase of 9:1 mixture of dichloromethane and methanol plus 3-4 drops
of concentrated ammonium hydroxide. If the reaction was determined
to be incomplete, stirring was continued at 58.+-.3.degree. C. for
an additional 2 hours and a TLC check performed once more.
Alternatively reaction completion was accomplished by adding about
5-10% more of both DBU and tBDMSiCl to the reaction mixture at the
same temperature. The contents were then cooled to 20.+-.5.degree.
C., and a mixture of 5% sodium bicarbonate solution (80 ml) and 60
ml of water was added in one portion. Stirring continued for about
10 minutes. The aqueous layer was then separated and discarded. The
organic layer was washed with a mixture of 50 ml brine and 50 ml
saturated ammonium chloride solution (the aqueous layers were
discarded). The organic layer was concentrated to near dryness in
vacuo at temperature NMT 50.degree. C., and the residue diluted
with 33.2 g of toluene to make up a 20 wt. % stock solution. Yield
was approximately quantitative. The stock solution was found to be
stable at ambient temperature under nitrogen atmosphere for at
least 6 months.
EXAMPLE 3
Preparation of Peracetic Acid Solution
[0056] 14-Hydroxycodeinone was synthesized from the dienolsilyl
ether of codeinone by oxidative hydroxylation using a peracetic
acid solution preparation. The peracetic acid solution was prepared
as follows: 11
[0057] Acetic anhydride (80.0 g) and concentrated sulfuric acid
(0.15 g, or about 6 drops) at ambient temperature were added to a
clean and dried round bottom flask (3-neck, 250 ml) equipped with
mechanical stirrer, thermocouple, nitrogen-inlet adapter and
addition funnel. The mixture was cooled to about 10.+-.3.degree. C.
under a nitrogen atmosphere. A 14.0 g of 30% aqeous hydrogen
peroxide solution was slowly added through the addition funnel. The
addition of hydrogen peroxide was performed drop by drop
maintaining content temperature at NMT 27.degree. C. (formation of
peracetic acid and the hydrolysis of acetic anhydride are strongly
exothermic, cooling is absolutely essential, but over-chilling the
batch is not recommended). After complete addition, the batch was
stirred for about 30 minutes in a 10.+-.3.degree. C. bath. Acetic
acid (10.0 g) was then added through the addition funnel, and the
batch slowly warmed to 25.+-.5.degree. C. The batch was then
stirred for an additional hour (the batch should be kept in water
bath all the time in order to avoid any unexpected exotherm).
EXAMPLE 4
Preparation of 14-Hydroxycodeinone from Dienolsilyl Ether of
Codeinone
[0058] Peracetic acid solution (107.7 g of 9.0 wt. % peracetic
acid) at ambient temperature (22.+-.5.degree. C.) was added to a
reaction flask (3-neck, 500 ml) equipped with mechanical stirrer
and thermocouple, nitrogen-inlet adapter and addition funnel. A 20
wt. % stock solution of the dienolsilyl ether of codeinone (41.7 g)
was added through the addition funnel over a period of about 5
minutes and the temperature of the contents maintained at NMT
28.degree. C. The batch was stirred at 22.+-.5.degree. C. for at
least 3 hours. In order to test reaction completeness, a small
sample was withdrawn from the batch and quenched with saturated
sodium bicarbonate solution, and extracted with ethyl acetate. The
EtOAc layer was spotted onto a TLC plate and subsequently checked
for the disappearance of starting dienolsilyl ether of codeinone.
The TLC mobile phase was a mixture of 95:5 of dichloromethane and
methanol plus 3-5 drops of concentrated ammonium hydroxide. If the
reaction was adjudged incomplete, the mixture was stirred at the
same temperature for an additional 2 hours then analyzed by TLC
again. Alternatively completion of the reaction was pushed by the
addition of 10 g of peracetic acid (9.0 wt. %) and stirring for an
additional 1 h (analysis was then once more preformed using
TLC).
[0059] Upon determination of the completion of the reaction 20.0 g
of 10 wt. % of aqueous sodium hydrogen sulfite solution was added
in one portion, and the resultant admixture stirred for 10 minutes
at ambient temperature. The batch was then concentrated in vacuo at
temperature NMT 45.degree. C. to dryness. Subsequently water (180
g), toluene (69 g), ethyl acetate (36 g) were added and vigorous
stirring for about 10 minutes undertaken. The resulting layers were
separated and the aqueous layer saved in a flask. The organic layer
was washed thrice with a solution of 26 ml of 2.5% HCl. The
combined aqueous layers were then filtered through a pad of wet
(with water) hyflo-supercel filter aid. Subsequently, EtOAc (85 g)
was added to the filtrate and concentrated ammonium hydroxide added
in a quantity to adjust the pH of the aqueous layer to about 11.
The mixture was stirred for 10 minutes at about 60.degree. C. and
the layers were separated and saved. The aqueous layer was washed
with EtOAc (50 g) and then discarded. The combined organic layers
were concentrated in vacuo to dryness at temperature NMT 50.degree.
C. To the residue was added 2-propanol (13 g), and the resultant
mixture stirred at 5-10.degree. C. for at least 5 hours. The solids
were filtered, the flask and solids rinsed with the chilled
(5.degree. C.) filtrate followed by chilled (5-10.degree. C.)
2-propanol (10 g) and heptane (8 g). The solid was then vacuum
dried at temperature NMT 50.degree. C. to a constant weight. A
yield of between 3.50-4.96 g (55%-78%) of 14-hydroxycodeinone free
base with a purity of over 96A % was obtained.
EXAMPLE 5
Preparation of Oxycodone from 14-Hydroxycodeinone by Catalytic
Hydrogenation
[0060] 14-Hydroxycodeinone (4.98 g) and acetic acid (155 g) were
added to a Parr shaker equipped with hydrogen inlet and outlet
connectors. The mixture was shaken for about 5 minutes to
completely dissolve the 14-hydroxycodeinone at ambient temperature.
The system was then evacuated and the Parr shaker was filled with
nitrogen. In one portion, under the nitrogen atmosphere, 10% Pd/C
(50% water wet, 4.0 g) was added. The system was then evacuated,
and was filled with hydrogen gas to a pressure of about 38 psi. The
hydrogen inlet from the supply tank was then closed and the mixture
was shaken at an initial pressure of 38 psi for about 3 hours (at
ambient temperature). After 3 hours of shaking, the system was
evacuated and filled with nitrogen. The contents were filtered over
a hyflo-supercel filtering pad (3 g, wetted with water). The Parr
bottle and wet cake were then rinsed with acetic acid (2.times.21
g). The filtrate was concentrated in vacuo to dryness at
temperature NMT 50.degree. C. The residue was then dissolved with
de-ionized water (50 g), and the pH adjusted to about 11.0 to 12.0
using 20% aqueous KOH solution and concentrated ammonium hydroxide
(4 g). The mixture was then extracted with ethyl acetate
(4.times.135 g), and the combined organic layers concentrated in
vacuo to dryness. A yield of 3.51 to 4.26 g of crude oxycodone with
HPLC purity of over 85A % (70.0 to 85.0% yield) was obtained.
EXAMPLE 6
Preparation of Oxycodone from 14-Hydroxycodeinone by Catalytic
Transfer Hydrogenation Method
[0061] 14-Hydroxycodeinone (4.98 g) and acetic acid (137 g) were
added to a reaction flask (3-neck, 250 ml) equipped with mechanical
stirrer, addition funnel, thermocouple and nitrogen-inlet adapter.
The system was evacuated and the flask filled with nitrogen.
Subsequently, 5% Pd/C (50% water wet, 3.0 g) in one portion was
added under the nitrogen atmosphere. While the mixture was stirred
for about 5 minutes at ambient temperature (22.+-.50.degree. C.), a
solution of sodium hypophosphite (6.0 g) in de-ionized water (25 g)
was prepared. The aqueous sodium hypophosphite solution was
transferred into the addition funnel, and added to the reaction
mixture over a period of about 30 minutes with maintenance of
content temperature at about 22.+-.5.degree. C. The mixture was
then warmed to about 45.degree. C. and stirred for about 1
hour.
[0062] To determine the completeness of the reaction, a small
sample was withdrawn from the batch and the sample was filtered by
means of a syringe filter into a mixture of ethyl acetate and
saturated sodium bicarbonate solution. After extraction, the
organic layer was concentrated to dryness and the residue dissolved
with HPLC mobile phase. The disappearance of 14-hydroxycodeinone
was determined. If the reaction was discerned to be incomplete, the
batch was stirred for an additional 2 h period at 45.degree. C.,
and the HPLC check performed once more.
[0063] Upon determination that the reaction was complete, the batch
was cooled to ambient temperature (22.+-.5.degree. C.) under the
nitrogen atmosphere, and the contents filtered over a
hyflo-supercel filtering pad (3.0 g, wetted with water). The flask
and wet cake were rinsed with acetic acid (20 g). The filtrate was
concentrated in vacuo to near dryness at temperature NMT 50.degree.
C. The residue was dissolved with de-ionized water (50 g) and the
pH adjusted to 11.0 to 12.0 with 20% aqueous KOH solution and
concentrated ammonium hydroxide (about 4 g). The mixture was then
extracted with ethyl acetate (4.times.135 g) and the combined
organic layers concentrated to dryness in vacuo. Crude oxycodone
with an HPLC purity of over 85A % was obtained in a yield of 70.0
to 85.0% (3.51 to 4.26 g).
[0064] While the invention has been described with respect to
preferred embodiments, those skilled in the art will readily
appreciate that various changes and/or modifications can be made to
the invention without departing from the spirit or scope of the
invention as defined by the appended claims.
* * * * *