Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-05-17
2001-02-27
Cook, Rebecca (Department: 1614)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06194565
ABSTRACT:
OBJECTS OF THE INVENTION
It is an object of the invention to provide an improved process for the preparation of 16&agr;-methyl-steroids and novel intermediates produced therein.
THE INVENTION
The novel process of the invention a process for the preparation of a compound of the formula
wherein the A and B rings represent a remainder:
wherein the ketone function in position 3 is optionally protected in the form of a ketal, thioketal, hemithioketal or enol ether, or
wherein R is methyl or —CH
2
—OR′, R′ is hydrogen or ether or ester, R
1
and R
2
form together a second bond, or R
1
and R
2
form together a &bgr;-epoxide, or R
1
is hydrogen, ketone or hydroxy in &agr;- or &bgr;-position, free or protected in the form of an ether or ester and R
2
is hydrogen, or R
1
is hydrogen and R
2
is &agr;-hydroxy, or R
1
is &bgr;-hydroxy, free or protected in the form of an ether or ester and R
2
is &agr;-fluorine or bromine, and R
3
is hydrogen or fluorine or &agr;- or &bgr;-methyl comprises reacting a compound of the formula
wherein A, B, R, R
1
, R
2
and R
3
have the above meaning with a methylation agent in the presence of a copper-based catalyst, then hydrolyzing the methylated intermediate to obtain the corresponding enolate and oxidizing the latter with molecular oxygen in the presence of a reducing and complexing agent of copper to obtain the compound of formula I.
When the 3-ketone function is protected in the form of a ketal, thioketal or hemithioketal, it is preferably a group of the formula:
wherein n is 2 or 3 and particularly an ethylenedioxy or ethylenedithio. When the 3-ketone function is protected in the form of an enol ether, it is preferably an alkoxy or alkoxyalkoxy of 1 to 8 carbons and more particularly methoxy, ethoxy, ethoxyethoxy or 1-ethoxyethoxy, rings A and B in that case comprising a system of &Dgr; 3,5 double bonds.
When R′ is an ether remainder, it can be any remainder known to one skilled in the art and preferably alkyl of 1 to 6 carbon atoms, for example methyl, ethyl or propyl, tetrahydropyranyl, or a remainder of silylated ether, for example trialkylsilyl such as trimethyl- or dimethylterbutylsilyl, triarylsilyl such as triphenylsilyl or diarylalkylsilyl such as diphenylterbutylsilyl.
When R′ is an ester remainder, it can be any remainder known to one skilled in the art and preferably an acyl of 1 to 8 carbon atoms, for example formyl, acetyl, propionyl, butyryl, valeryl or benzoyl. When R
1
is a protected hydroxy function in the form of an ether or ester, it is an ether or ester remainder mentioned above for R′, it being understood that these remainders are not necessarily identical.
In a preferred process of the invention, a compound of formula II is used in which the A and B rings are
in which R
3
is defined as above and the 3-ketone is free. In another embodiment of the invention, a compound of formula II is used in which R
1
and R
2
form a second bond, or R
1
and R
2
form together a &bgr;-epoxide, or R
1
is &bgr;-hydroxy, free or protected in the form of an ether or ester and R
2
is &agr;-fluorine, and R
3
is hydrogen, fluorine or methyl and, preferably, hydrogen.
The methylation agent can be a methylated copper derivative, for example CH
3
Cu, (CH
3
)
2
CuMg, (CH
3
)
2
CuLi or, preferably, methyl-magnesium chloride, bromide or iodide, used in the presence of a copper-based catalyst. The catalyst can be a salt such as cupric acetate, propionate or chloride, cuprous chloride, bromide, iodide or cyanide, or also a complex, for example copper acetylacetonate, cuprous dimethylsulfide bromide or also cuprous tri-nbutylphosphine chloride or any other complex of the same type known to one skilled in the art. Cupric acetate and propionate are particularly preferred.
The operation takes place in a solvent which is preferably an ether such as tetrahydrofuran, dioxane, terbutylmethylether or dimethoxyethane and tetrahydrofuran is particularly preferred. The operation advantageously takes place at temperature of 0 to −30° C. and, preferably at −20° C.
The hydrolysis of the methylated intermediate is preferably carried out by pouring the reaction solution into an aqueous solution of monoalkali metal phosphate, for example sodium or potassium, or in a buffer of weakly acidic pH, notably phosphate buffer in an aqueous solution of ammonium chloride or, more generally, in weak acidic agent such as acetic acid, propionic acid or butyric acid.
The oxidation of the enol is carried out by bubbling oxygen through or, preferably, by bubbling air through the hydrolysis medium and the reaction takes place in the presence of a reducing and complexing agent of copper and compatible with the oxidizing agent, which is preferably dialkylsulfide, tetrahydrothiophene, trialkyl or triphenylphosphite or triphenylphosphine. Dimethyl sulfide and tetrahydrothiophene are particularly preferred and the reaction preferably takes place at ambient temperature.
The preparation of the compounds of formula I has already been described, for example in Application WO 87/07612. The process of the invention consists of methylating an unsaturated 16 derivative with a methylation agent in the presence of a copper-based catalyst and a silylation agent with the purpose of intermediately isolating a derivative of the type:
which is then treated with peracid to form the 17&agr;-20 epoxide which is finally hydrolyzed with an acid or base.
The process of the invention does not require the isolation of any intermediate, the product resulting from the methylation reaction being directly hydrolyzed, then oxidized under conditions which have never been envisaged to date and is particularly useful from an industrial point of view. Its implementation is far more straightforward than that of known processes and particularly than that of the above Application.
British Patent No. 2,001,990 also describes a process for the preparation of compounds of formula I which consists of methylating an unsaturated 16 derivative, then preparing and isolating the hydroperoxide of the formula:
which is then reduced with zinc in acetic acid or with an alkali metal iodide in an aliphatic ketone. It should be noted 1) that such process which first isolates a hydroperoxide and then treats it with a reducing agent is not industrially viable due to the dangers inherent in these operations; and 2) that contrary to the process of the invention which permits the oxidation and the reduction to take place in a single stage by using a compatible reducing agent, the above process does not allow this due to incompatibility between the reagents used. In others words, the principle on which the process of the invention is based is different and this essentially relates to the reducing (or oxidizable) ligand that it uses and whose presence is indispensable.
The novel intermediates of the invention are compounds of the formula
in which A, B, R, R
1
, R
2
and R
3
have the above meanings and especially the compounds of formula III as defined above wherein the A and B rings are
in which R
3
is defined as above and the 3-ketone is free and those wherein R
1
and R
2
form together a second bond, or R
1
and R
2
form together a &bgr;-epoxide or R
1
is &bgr;-hydroxyl free or protected as an ether form and R
2
is &agr;-fluorine and R
3
is hydrogen, fluorine or methyl.
The compounds of formula II are known and described, for example, in U.S. Pat. Nos. 2,345,711, No. 2,883,400, No. 2,963,496, No. 2,966,504, No. 2,975,197, No. 3,029,233, No. 3,210,341, No. 3,377,343, No. 3,839,369, No. 3,976,638, No. 4,031,080, No. 4,277,409, No. 4,929,395, German Patent No. 2,207,420, Dutch Patent No. 69 02 507 or Belgian Patents No. 539,498, No. 540,478, No. 711,016, or can be easily prepared starting from compounds described in these Patents by processes known to one skilled in the art.
The 16&agr;-methyl compounds of formula I are known to possess an anti-inflammatory activity and includes dexamethasone, its derivatives (6&agr;-fluoro)-flumethasone, (6&agr;-fluoro 9H)-paramethasone and possi
Buendia Jean
Roussel Patrick
Vivat Michel
Bierman, Muserlian and Lucas
Cook Rebecca
Hoechst Marion Roussel
LandOfFree
Process for preparing 16 &agr;-methyl-steroids does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for preparing 16 &agr;-methyl-steroids, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing 16 &agr;-methyl-steroids will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2576274