Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-29
2002-05-28
Aulakh, Charanjit S. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S039000, C546S035000, C546S015000
Reexamination Certificate
active
06395900
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a method for the N-deprotection of an opioid compound, a method for the N-deprotection and O-demethylation of an opioid compound, a method for the aromatic O-demethylation of an opioid compound, and a method for the selective O-demethylation of a nonpeptidic delta agonist compound or an opioid compound having a hindered amide.
BACKGROUND OF THE INVENTION
An increasing demand for medicinal opiates, coupled with a finite supply of raw materials from opium, has created a need for simple high yielding procedures for opiate transformations.
A 3-phenolic group is essential for the important pharmacological profile of the opium alkaloids and their derivatives (opioid compounds). 3-methyl ethers, such as codeine and thebaine, are the most widely used starting materials for opioid synthesis. Aromatic O-demethylation is a key step in the synthesis of virtually all opioid medical narcotics-and their antagonists. Current procedures involve the use of toxic and carcinogenic reagents, such as boron tribromide, propane thiolate, and potassium hydroxide. These reagents have a limited range of applicability and non-toxic alternatives are highly desirable.
Known methods of converting codeine to morphine are not entirely satisfactory. Exposure of codeine or morphine to strong acid or alkaline conditions at higher temperatures has been found to promote substantial decomposition of these opiates. Previously, codeine has been converted to morphine by treatment with acids, such as pyridine hydrochloride, for a brief period at 220° C. or with the toxic boron tribromide.
Journal Med. Chem
., 20:164-65 (1977). Also, demethylation of a compound similar to codeine has been achieved by use of the diphenyl phosphide ion. The O-demethylation of codeine has also been achieved by treatment with sodium propylmercaptide in dimethylformamide at 125° C. However, none of these previously known methods are desirable due to the need for toxic agents and/or the resulting substantial decomposition of the opiates.
Thebaine has no medicinal use in and of itself, but is a relatively abundant widely used raw material derived from opium. Thebaine is the key intermediate in the synthesis of many opiate derivatives. This is the case for the oripavine derivatives initiated from the Diels-Alder adducts of thebaine. Oripavine is naturally occurring only in extremely minor amounts, but is of interest since it may obviate the final and difficult 3-O-methyl-ether cleavage in the synthesis of Diels-Alder derived narcotics.
Journal of Med. Chem
., 20:1074-77 (1975). No method for the direct transformation of thebaine to oripavine has been discovered, despite many attempts made over the course of seventy years. Even methods which are undesirable for other opioid conversions due to toxicity or decomposition of the opioid compounds do not work at all for the conversion of thebaine to oripavine. For example, as mentioned above, the O-demethylation of codeine has been achieved by treatment of sodium propylmercaptide in dimethylformamide at 125° C. However, this same procedure applied to thebaine did not yield oripavine.
Journal Med. Chem
., 20:165-66 (1977).
N-alkylation is also a key step in the synthesis of opioid compounds. Previously known methods that have been developed for N-alkylation have resulted in low yields or were subject to hazards associated with the procedures. For example, in the codeine to norcodeine conversion, N-deprotection of an intermediate carbamate has been accomplished using hydrazine. However, this procedure is less than ideal due to the potential presence of air-sensitive anhydrous hydrazine which is explosive.
J. Org. Chem
., 40:1850-51 (1975).
O-demethylation and N-deprotection may occur simultaneously or one after the other under the proper conditions. Currently, O-demethylation and N-deprotection may occur simultaneously by subjecting the compound to alkaline conditions by heating with potassium hydroxide under vigorous conditions.
J. Amer. Chem. Soc
., 89:13 (1967). This reaction has been found to be unreliable at times and some compounds are not stable under the vigorous conditions.
L-Selectride®, having the chemical name lithium tri-sec-butylborohydride, has recently been reported as an efficient O-demethylating reagent for simple systems and stable compounds not normally prone to rearrangements or decomposition when subjected to strong acids or bases or hydride reagents.
Tetrahedron Letters
, 35:8727-30 (1994). In contrast, opioid compounds can be very susceptible to rearrangement and decomposition in the presence of strong acids and bases. For example, thebaine is known to be very sensitive to hydride reagents, the epoxide bridge being readily cleaved by hydride reagents. Thus, heretofore, hydride reagents, such as L-Selectride®, have not been used as O-demethylating agents in opioid synthesis.
Never before has it been shown that trialkylborohydride reagents are capable of N-deprotecting an N-protected opioid intermediate or that these hydride reagents can both N-deprotect and C-demethylate such compounds.
Accordingly, it is a principle object of the present invention to provide a method for the N-deprotection of an N-protected opioid intermediate. It is another object of the invention to provide a method for both the N-deprotection and aromatic O-demethylation of the N-protected opioid intermediate without the use of toxic or carcinogenic reagents.
It is also a principal object of the present invention to provide a method for the aromatic O-demethylation of opioids that can be carried out without the use of toxic or carcinogenic reagents. It is a further object of the invention to provide a method for the aromatic O-demethylation of opioids with a hydride reagent. It is yet another object of the invention to provide a method for the aromatic O-demethylation of opioids in which the hydride reagent is a lithium trialkylborohydride.
It is a still further object of the present invention to provide a method for the aromatic O-demethylation of codeine by treatment with L-Selectride® to obtain morphine.
It is another object of the present invention to directly convert thebaine to oripavine by treatment with L-Selectride®.
It is a further object of the present invention to provide a method for the aromatic O-demethylation of a nonpeptidic delta agonist compound or an opioid compound having a tertiary amide group or other amide group resistant to reaction with L-Selectride®.
These and other objects and advantages of the present invention, as well as other inventive features, will be apparent from the description of the invention provided herein.
SUMMARY OF THE INVENTION
The present invention provides a method for the N-deprotection of an opioid compound with a hydride reagent. N-deprotection can be accomplished by admixing an N-protected opioid intermediate of an opioid compound with the hydride reagent and allowing the reagent to react. The present invention further provides a method for the N-deprotection and O-demethylation of an opioid compound which includes admixing an N-protected opioid intermediate of an opioid compound with the hydride reagent.
The present invention further provides a method for the aromatic O-demethylation of opioid compounds with a hydride reagent. Aromatic O-demethylation may be accomplished by admixing an opioid compound with the hydride reagent and allowing the reagent to react, without the use of toxic or carcinogenic agents.
In each of these methods, the hydride reagent is a lithium trialkylborohydride, including lithium tri-sec-butylborohydride (L-Selectride®), lithium trisiamylborohydride (LS-Selectride®), and lithium triethylborohydride (SuperHydride®).
The present invention also provides a direct method for the conversion of thebaine to oripavine by contacting thebaine with lithium tri-sec-butylborohydride (L-Selectride®).
The present invention still further provides a method for the aromatic demethylation of a nonpeptidic delta agonist compound or an opioid compound having a tertiary amide group with mini
Coop Andrew
Rice Kenner C.
Aulakh Charanjit S.
Leydig , Voit & Mayer, Ltd.
The United States of America as represented by the Department of
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