Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-09-15
2003-04-29
Barts, Samuel (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S018100, C536S018500, C536S119000
Reexamination Certificate
active
06555665
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to glycosidation of 4,5-Epoxymorphinan-6-ols using Thioglycosides as glycoside donors. This approach is particularly useful for preparation of protected 4,5-Epoxymorphinan-6-&bgr;-D-glucuronides of formula [1]
wherein:
position 7 and 8 can be olefin as shown or dihydro adduct;
R is acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl;
R
1
is alkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl;
R
2
is alkyl, haloalkyl, aralkyl;
R
3
is alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl;
R
4
is alkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl.
Since it was established that Morphine-6-&bgr;-D-glucuronide (M6G) [1a] is not only a metabolite of Morphine [5] but also has greater analgesic activity
1
, substantial amounts have been required for clinical trials and evaluation. According to recent publications the morphine metabolite M6G is a more effective and longer lasting analgesic drug than Morphine itself and has fewer side effects.
2
Unfortunately, morphine is also metabolized to Morphine-3-glucuronide (M3G) [6], a compound which antagonizes the analgesic effect of Morphine. Since M3G is formed in greater abundance than M6G, there is much interest in using the latter, rather than Morphine, as a pain killing drug.
3
The traditional approach to glycosidation of 4,5-Epoxymorphinan-6-ols explores haloglycosides as glycoside donors and the Koenings-Knorr procedure for the activation of haloglycosides (Berrang, B. et al., Synthesis, 1997, 1165 and references cited therein). The main drawbacks of this approach are: low stability of haloglycosides, heterogenic reaction media that make industrial scale-up very tedious, with low and unstable yields, use of heavy metals. Another more recent approach, described by F. Sheinmann et al. (U.S. Pat. No. 5,621,087), describes use of trichloroacetimidates as glycoside donors. The main disadvantages of this approach are: the tedious methods for preparation of the starting trichloroacetimidates; relatively low yields in the glycosidation reaction; difficult purification of the desired product from the reaction mixture.
These methods have, therefore, serious drawbacks for producing bulk material to be used as a pharmaceutical drug. A desirable goal, met by the present invention, has been to devise synthetic methods which avoid toxic and/or expensive reagents, and which cleanly produce the desired products, avoiding tedious and expensive purification steps.
SUMMARY OF THE INVENTION
Glycosidation of 4,5-Epoxymorphinan-6-ols with Thioglycosides as a glycoside donors is disclosed. The process comprises reacting 4,5-Epoxymorphinan-6-ols and Thioglycosides in the presence of thiophilic promoters under conditions capable of forming 4,5-Epoxymorphinan-6-glycosides. This novel approach was used for preparation of protected 4,5-Epoxymorphinan-6-&bgr;-D-glucuronides. The process provides both high stereo-selectivity and high yields.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the use of Thioglycosides as glycoside donors for glycosidation of 4,5-Epoxymorphinan-6-ols.
This novel approach has several advantages:
Thioglycosides can be prepared according to known methods starting from inexpensive and commercially available raw materials.
Thioglycosides have high thermal and chemical stability.
Reagents used for the Thioglycoside activation are not toxic and not expensive.
Although any 4,5-Epoxymorphinan-6-ols, suitable for this glycosylation, can be used, preferably compounds of formula [3] are used.
wherein:
position 7 and 8 can be olefin as shown or dihydro adduct;
R
3
and R
4
are as previously defined
More preferably, said 4,5-Epoxymorphinanes are selected from 3-O-Acylmorphine, 3-O-Acylnormorphine, 3-O-Acylnalbuphine, 3-O-Acylnalorphine, 3-O-Acyldihydromorphine, 3-O-Benzylmorphine, 3-O-Benzyldihydromorphine, N,O
3
-Dibenzylnormorphine, Codeine, Ethylmorphine, Dihydrocodeine, Pholcodine, 3-O-Alkoxycarbonylmorphine, 3-O-Benzyloxycarbonylmorphine, N,O
3
-Bis(benzyloxycarbonyl)normorphine.
Although any Thioglyoside may be used, it is preferred that Thioglycosides of formula [2] are used.
wherein
R, R
1
and R
2
are as previously defined
R
5
is alkyl or aryl.
More preferably the Thioglycosides of the present invention are selected from the compounds of formula [12].
wherein
R, R
2
and R
5
are as previously defined;
Most preferably Thioglycosides of formula [11] are used.
wherein
R and R
5
are as previously defined.
Thiophilic promoters used in said glycosidation could be selected from halonium ion source, Dimethyl(methylthio)sulfonium triflate or tetrafluoroborate, Methyl triflate or fluorosulfonate.
The Halonium ion source used in the present invention is a mixture of N-Halosuccinimide and acid, or lodonium dicollidine perchlorate (IDCP). The said N-Halosuccinimide is preferably selected from N-Iodosuccinimide (NIS) or N-Bromosuccinimide (NBS).
The said acids may be selected from triflic acid, trimethylsilyl triflate, silver triflate or tetrafluoroborate or trifluoromethanesulfonic acid.
Most preferably the said thiophilic promoters are a mixture of NIS and triflic acid, or Dimethyl(methylthio)sulfonium triflate.
Preferably the said reaction occurs in the presence of reaction-inert solvents.
Any reaction-inert solvent may be used. As used above and elsewhere herein, the expression “reaction-inert solvent” refers to a solvent which does not react or decompose with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product. In general, the solvent can comprise a single entity, or contain multiple components.
Preferably the said reaction-inert solvents are non-protic and are selected from Dichloromethane, Chloroform, 1,2-Dichloroethane, Ether, Acetonitrile, or mixture thereof. Diethyl ether or ethyl acetate may alternatively or additionally be used as a non-protic reaction-inert solvent. Dichloromethane is an especially preferred solvent.
It may be also preferred to conduct the said coupling reaction in the presence of additives to buffer or to activate the thiophilic promoter. The above additives may be selected from molecular sieves, tertiary amines, tetraalkylureas, organic and inorganic acids and salts.
Preferably about 1 equivalent to about 2 equivalents of the Thioglycoside is used. It is specially preferred that about 1 equivalent to about 1.5 equivalents of Thioglycoside is used. The said 4,5-Epoxymorphinanes may be used as an individual compounds or alternatively as corresponding salts thereof or complexes.
Any environment or conditions (e.g. temperature, time, solvent) suitable for the glycosidation reaction may be used. However, it is preferred that the reaction occurs at a temperature of about −50° C. to about 100° C. and preferably from about −20° C. to 20° C. This reaction is conveniently carried out at about 0.5 to about 3 atmospheres.
This invention makes a significant advance in the chemistry of 4,5-Epoxymorphinan-6-ols by providing an efficient method for preparation of a large number of known and new 4,5-Epoxymorphinan-6-glycosides.
Particularly, protected 4,5-Epoxymorphinan-6-&bgr;-D-glucuronides [1] could be obtained by glycosidation of 4,5-Epoxymorphinan-6-ols of formula [3] or salts thereof or complexes containing thereof
wherein:
position 7 and 8 can be olefin as shown or dihydro adduct;
R
3
and R
4
are as previously defined.
with thioglycoside of the formula [2]
wherein
R, R
1
, R
2
and R
5
are as previously defined.
under conditions capable of forming said protected 4,5-Epoxymorphinan-6-&bgr;-D-glucuronides [1] or salts thereof or complexes
Gutman Arie
Nisnevitch Genadi
Rochman Igor
Yudovitch Lev
Barts Samuel
Cenes Limited
Henry Michael C.
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