Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-09
2003-01-28
Aulakh, Charanjit S. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S044000, C546S046000
Reexamination Certificate
active
06512117
ABSTRACT:
BACKGROUND OF THE INVENTION
Hydromorphone hydrochloride (sold as Dilaudid, Laudicon, Hydromorphan) is a narcotic analgesic and one of its principle uses is the relief of pain (Physicians Desk Reference, p. 1383; Merck Index, 4700). The precise mechanism of hydromorphone hydrochloride is not known, although it is believed to relate to the existence of opiate receptors in the central nervous system. There is no intrinsic limit to the analgesic effect of hydromorphone hydrochloride; like morphine, adequate doses will relieve even the most severe pain.
Hydromorphone hydrochloride is also a centrally acting narcotic antitussive which acts directly on the cough reflex center. In addition, it produces drowsiness, changes in mood and mental clouding, depresses the respiratory center, stimulates the vomiting center, produces pinpoint constriction of the pupil, enhances parasympathetic activity, elevates cerabrospinal fluid pressure, increases biliary pressure and also produces transient hyperglycemia.
Hydrocodone (dihydrocodeinone, Bekadid, Dicodid) is a semisynthetic narcotic antitussive and analgesic with multiple actions similar to those of codeine. Like hydromorphone and other opiate compounds, the mechanism of action is not known. Hydrocodone can produce meoisis, euphoria, and physical and physiological dependence. In excessive doses, hydrocodone depresses respiration (Physicians Desk Reference, p. 948).
The syntheses of hydromorphine and hydrocodeine are known in the art. For example, the formation of hydromorphine from morphine via room temperature hydrogenation of the double bond with colloidal palladium and hydrogen gas is disclosed in German Patent 260 233. The patent also discloses the formation of hydrocodeine. Yields of the hydrogenated derivatives are not disclosed.
In United Kingdom Patent No. 285,404, the formation of dihydrotheibane (a dimethyl ether derivative of dihydromorphine) at room temperature is disclosed, using platinum oxide as the catalyst. The methyl groups can be removed to yield dihydromorphine. The yield is approximately 55%.
The syntheses of hydrocodone and hydromorphone from codeine and morphine, respectively, are also known in the art.
German Patent 380 919 discloses a method for synthesizing hydromorphone, by treating morphine with a catalytic agent (e.g., platinum or palladium black), hydrochloric acid, and hydrogen gas. The reaction mixture is then heated to 60 to 90° C. under a water pressure of 30 cm. The yield of the ketone is not disclosed.
German Patent 607 931 discloses the synthesis of hydromorphinones. The synthesis involves heating morphine with large amounts of finely divided platinum in dilute acid. The platinum catalyst is saturated with hydrogen gas before the reaction is begun. It was found that additional hydrogen gas was not necessary for the hydrogenation to proceed. Yields from 40% to 85% were reported.
German Patent 617 238, a continuation-in-part of German Patent 607 931, discloses that relatively higher yields of the hydromorphones can be obtained through using smaller amounts of catalyst. The resulting yields ranged from 70% to 95% of the theoretical yield.
U.S. Pat. No. 2,544,291 discloses a process for the preparation of dihydrocodone by treating codeine with supported palladium catalyst in a heated acidic solution. The reaction mixture is purified through treatment with activated alumina. The resulting product was recovered in 66.5% yield and was determined to be “codeine free.”
U.S. Pat. No. 2,628,962 discloses the oxidation of dihydrocodeine to dihydrocodone by the addition of ketones to the reaction mixture in the presence of aluminum alkoxides. The resulting yield was 36.5%.
U.S. Pat. No. 2,654,756, a continuation-in-part of U.S. Patent No. 2,628,962, discloses the use of ketones, such as cyclohexanone and alkoxycyclohexanones, to increase the yield of the narcotic ketones from the corresponding alcohols in the presence of aluminum alkoxides. However, the resulting yields were approximately 40%.
U.S. Pat. No. 2,649,454 discloses a method of producing ketone derivatives of opiates by heating the alcohols in the presence of potassium t-butoxide. The yields of the reaction ranged from 71-83%.
Most recently, it was reported that it was possible to form dihydroketones from narcotic alkaloids with colloidal platinum or palladium as the catalyst. It was noted that if hydrogen was not introduced, the reaction could be carried out in the presence of a larger amount of finely divided platinum. However, it was reported that the purest products or the most easily purified products were obtained when the reaction was performed in a stream of hydrogen, rather than in the absence of hydrogen (Gaal, C.
M.T.A. Kemai Oszt. Kozl.
24:307-313 (1965)).
SUMMARY OF THE INVENTION
In one aspect, the invention features a method of preparing a ketone from a narcotic alkaloid having an allyl alcohol moiety. The method comprises mixing the narcotic alkaloid with an acid in the presence of a catalyst in the substantial absence of hydrogen gas. Advantageously, the narcotic alkaloid is morphine, codeine or salts thereof.
Preferably, the narcotic alkaloid is of formula (I):
wherein R is hydrogen or, an alcohol protecting moiety. In an advantageous embodiment, R is hydrogen or methyl.
The invention also pertains to a hydromorphone composition that is substantially free of impurities. In an advantageous embodiment, the composition comprises hydromorphone and from about 0.05% up to about 1.0% dihydromorphine; up to about 0.1% morphine; up to about 0.8% 8-hydroxy hydromorphone; up to about 0.5% bis-hydromorphone; and up to about 0.2% other impurities.
In another aspect, the invention is directed to a method of forming a pharmaceutical composition comprising a hydromorphone salt, 8-hydroxy hydromorphone and dihydromorphone. The method comprises heating an aqueous mixture of the salt, 8-hydroxy hydromorphone and dihydromorphone for a time sufficient to reduce the concentration of 8-hydroxy hydromorphone to less than 1.0%. In yet another aspect, the invention is directed to a hydromorphone composition which is prepared by a process, which includes mixing morphine with an acid in the presence of a catalyst wherein said process is carried out in the substantial absence of hydrogen gas.
DETAILED DESCRIPTION OF THE INVENTION
The invention pertains to a method of synthesizing ketone derivatives of narcotic alkaloids by mixing the narcotic alkaloid with an acid in the presence of a catalyst in the substantial absence of hydrogen gas. The product obtained from the methods of the invention has a novel composition profile, discussed in detail below.
1. Definitions
Before further description of the invention, certain terms employed in the specification, examples and appended claims are, for convenience, collected here.
The term “alcohol protecting moiety” includes moieties which can be removed and/or derivatized after the formation of the ketone in accordance with the methods of the invention to yield the free alcohol. Advantageously, the alcohol protecting moiety is inert to the conditions used to generate the ketone. Alcohol protecting moieties include, but are not limited to, hydroxyl protecting groups known in the art (see, for example, Greene, T. W.
Protective Groups in Organic Synthesis
(Wiley:New York, 1981)). Examples include methoxymethyl ethers (MOM), &bgr;-methoxyethoxymethyl ethers (MEM), tetrahydropyranyl ethers (THP), methylthiomethyl ethers (MTM), benzyl groups, and silyl ethers (e.g., trimethyl silyl ethers (TMS), t-butyldimethyl silyl ethers(TBDMS)). Furthermore, the term “alcohol protecting moiety” includes alkyl, alkenyl, alkynyl, aralkyl, aryl, and heteroaryl moieties.
The term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described below, but that contain at least one double bond. Unless the number of carbons is otherwise specified, “lower alkenyl” refers to an alkenyl group, as defined above, but having from two to four carbon atoms in its backbone structure.
The term “alkyl” inclu
Gault Robert
Harclerode William H.
Sandison Mark D.
Abbott Laboratories
Aulakh Charanjit S.
DeConti, Jr. Giulio A.
Lahive & Cockfield LLP
Lauro Peter C.
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