Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-22
2001-07-17
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S074000
Reexamination Certificate
active
06262266
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
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.
2. Background of the Related Art
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.
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.
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 usefuil drugs are primarily isolated from the phenanthrene and benzylisoquinoline classes. The principal phenanthrenes are morphine (≈10% of opium), codeine (≈0.5% of opium) and thebaine (≈0.2% of opium). The principal benzylisoquinolines are papaverine (≈1.0% of opium) and noscapine (≈6.0% of opium).
Morphine itself comprises a 5-ring structure, incorporating a partially hydrogenated phenanthrene ring system. Each ring of morphine is designated as set forth below:
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:
The substituent numbering of morphine derivatives follows two common conventions as shown:
Chemical Abstracts
It is the second (Chemical Abstracts) numbering system that shall be made reference to hereinafter.
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.
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).
Among the many morphine structural analogs used in medicine today, widespread use is made of both codeine and oxycodone.
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).
Oxycodone is a white, odorless crystalline powder of semi-synthetic origin with multiple actions qualitatively similar to those of morphine.
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).
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—&Dgr;
6,7
, &Dgr;
8,14
.(i.e., thebaine differs from morphine in that both hydroxyl groups are methylated and the “C” ring has two double bonds—&Dgr;
6,7
, &Dgr;
8,14
).
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)).
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 &Dgr;
6,8
-diene compound among the naturally-ocurring morphine alkaloids (Seiki, 18
Chem. Pharm. Bull
. 671-675, 1970).
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&bgr;nig et al. 329
Arch. Pharm. Pharm. Med. Chem
. 325-326, 1996).
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.
Seki (18 Chem. Pharm. Bull. 671-676, 1970) discloses a method for preparing &Dgr;
6,8
-diene compounds, such as thebaine, from &agr;,&bgr;-unsat
Chiu Fang-Ting
Lo Young S.
Boehringer Ingelheim Chemicals, Inc.
Devlin M-E. M.
Raymond R. P.
Robinson Binta
Rotman Alan L.
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