Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-05-18
2004-05-18
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S017400, C536S018100, C514S025000
Reexamination Certificate
active
06737518
ABSTRACT:
BACKGROUND OF THE INVENTION
According to recent publications the morphine metabolite Morphine-6-&bgr;-D-glucuronide (M6G) [6] is a more effective and longer lasting analgesic drug than Morphine [5] with fewer side effects
1
and, therefore, there is much interest in using M6G, rather than Morphine, as a pain killing drug.
2
The traditional approach to glycosylation of 4,5-Epoxymorphinan-6-ols explores Bromoglucuronides as glycoside donor and the Koenings-Knorr procedure for the activation of Bromoglucuronides (Berrang, B., et al., Synthesis, 1997, p. 1165 and references cited therein).
Another approach (Scheinmann, F. et. al., U.S. Pat. No. 5,621,087, see claim 1, 2, 5 and 6, abstract, examples, column 4, line 25-line 45) explores the use of Lewis acids (of the type BF
3
and TMSOTf) rather than heavy metals based Lewis acids (March, J., “Advanced Organic Chemistry”, 4-th edition, A Whiley-Interscience publicaiton, pp. 260-3) for the activation of Bromoglucuronides.
Unfortunately, we did not succeed to obtain 4,5-Epoxymorphinan-6-oxyglucuronide from Bromoglucuronides using activators proposed in U.S. Pat. No. 5,621,087 and did not find such examples in the literature.
Unexpectedly we found that the O-glycosylation of 4,5-Epoxymorphinan-6-ols with Bromoglucuronides was accelerated by Zinc containing compounds to give 4,5-Epoxymorphinan-6-oxyglucuronides of formula [1] with high yield.
wherein:
position 7 and 8 can be olefin as shown or dihydro adduct;
R
1
are alkyl, haloalkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl,
R
2
is alkyl, haloalkyl or aralkyl;
R
3
is alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl or hydrogen;
R
4
is alkyl, haloalkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl.
We also found that the &agr; and &bgr; anomeric selectivity of the conjugation product can be controlled by using different O-protecting groups in aglycon and in Bromoglucuronide as well as by varying the ratio between 4,5-Epoxymorphinan-6-ols and Zinc containing compounds.
It is important to note that only the &bgr;-anomer of 4,5-Epoxymorphinan-6-oxyglucuronides was obtained according to Koenings-Knorr procedure and U.S. Pat. No. 5,621,087 procedure (but with other than a Bromoglucuronide glycoside donor).
All of the previously disclosed methods have serious drawbacks for producing material to be used as a pharmaceutical drug. A desirable goal, met by the present invention, has been to devise a synthetic procedure without using commercially inaccessible and expensive reagents, and which cleanly produces the desired 4,5-Epoxymorphinan-6-oxyglucuronides, avoiding tedious and expensive purification steps.
SUMMARY OF THE INVENTION
The present invention provides a commercially acceptable process for conjugation of 4,5-Epoxymorphinan-6-ols of formula [3] with Bromoglucuronides of formula [2] in the presence of Zinc containing compounds under conditions capable of forming 4,5-Epoxymorphinan-6-oxyglucuronides [1].
wherein
position 7 and 8 can be olefin as shown or dihydro adduct;
R
1
, R
2
, R
3
, and R
4
, are as defined above.
This novel approach was used for the preparation of the known analgesic agent Morphine-6-&bgr;-glucuronide [4] and of its &agr;-anomer.
Other features and advantages will be apparent from the specification and claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is related to a novel process for conjugation of 4,5-Epoxymorphinan-6-ols with Bromoglucuronides.
Particularly, the present invention relates to the use of Zinc containing compounds for the activation of Bromoglucuronides in the O-glycosylation reaction of 4,5-Epoxymorphinan-6-ols.
This novel approach has the following advantages:
Zinc containing compounds as activating reagents of Bromoglucuronides are inexpensive and commercially available.
Use of different O-protecting, groups in the aglycon and in the Bromoglucuronide as well as different ratio of 4,5-Epoxymorphinan-6-ols and Zinc containing compounds enable to obtain high anomeric selectivity and produce at will with a high degree of preference either the &agr; or the &bgr; anomer.
Although any 4,5-Epoxymorphinan-6-ols are suitable for this O-glycosylation, 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-Epoxymorphinan-6-ols 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 Bromoglucuronide may be used, it is preferred that compounds of formula [2] are used.
wherein
R
1
and R
2
are as previously defined.
More preferably the Bromoglucuronides of the present invention are selected from the compounds of formula [2a].
wherein
R are acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl;
R
2
is as previously defined.
Most preferably Bromoglucuronides of formula [2b] are used.
wherein
R are as previously defined.
Although any Zinc containing compound suitable as activating reagents for this O-glycosylation can be used, preferably, Zinc Bromide is used.
It is preferred that about 0.01 equivalents to about 4 equivalents and especially preferred that about 0.5 equivalents to about 2 equivalents of Zinc containing compound is used.
Preferably about 1 equivalent to about 2 equivalents of the Bromoglucuronide [2] is used. It is specially preferred that about 1 equivalent to about 1.5 equivalents of Bromoglucuronide [2] is used. The said 4,5-Epoxymorphinan-6-ol [3] may be used as an individual compound or alternatively as corresponding salts thereof or complexes. Especially preferred is the use of said Zinc containing salt or complexes of [3] without using additional Zinc containing compounds as promoter for said coupling. It is preferred that the said complexes may be prepared in situ.
It may be also preferred to conduct the said Zinc activated O-glycosylation in the presence of additives to buffer or to promote the said Zinc containing compounds. The above additives may be selected from molecular sieves, tertiary amines, tetraalkylureas, organic and inorganic acids and salts.
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 sovent is a non-protic reaction inert solvent and it is especially preferred that the solvent is Dichloromethane because of the exellent stereoselectivity it provides. Another solvent may be Chloroform or Dichloroethane.
Any environment or conditions (e.g. temperature, time, solvent) suitable for (i.e., capable of) forming the desired 4,5-Epoxymorphinane-6-oxyglucuronides may be used. However, it is preferred that the reaction occurs at a temperature of about −20° C. to about 100° C. and preferably from about 40° C. to 65° C. Below about −20° C. the reaction can be slow and above about 100° C. undesired side reactions (e.g. anomerisation) can occur. This reaction is conveniently carried out at about 0.5 to about 3 atmospheres, however, the high pressures are espesially preferred for the said coupling.
The present invention could be used as a general method to produce a large number
Gutman Arie L.
Nisnevitch Genadi
Rokhman Igor
Yudovitch Lev
CeNeS Limited
Finnegan Henderson Farabow Garrett & Dunner LLP
Owens, Jr. Howard V.
Wilson James O.
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