Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
1996-09-30
2002-04-09
Badio, Barbara P. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C552S636000, C540S002000, C540S106000
Reexamination Certificate
active
06369247
ABSTRACT:
FIELD OF THE INVENTION
The present invention is concerned with a novel process for the catalytic oxidation of compounds containing an allylic group using ruthenium based catalysts. The process is generally useful for the oxidation of compounds containing allylic hydrogens or alcohols, and particularly for &Dgr;-5 steroidal compounds.
BACKGROUND OF THE INVENTION
The principal mediator of androgenic activity in some target organs, e.g. the prostate, is 5&agr;-dihydrotestosterone (“DHT”), formed locally in the target organ by the action of 5&agr;-reductase, which converts testosterone to DHT. Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone (“T”) or similar androgenic hormones in the metabolic system. Inhibitors of 5&agr;-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially U.S. Pat. No. 4,377,584, issued Mar. 22, 1983, and U.S. Pat. No. 4,760,071, issued Jul. 26, 1988, both assigned to Merck & Co., Inc. It is now known that a second 5&agr;-reductase isozyme exists, which interacts with skin tissues, especially in scalp tissues. See, e.g., G. Harris, et al.,
Proc. Natl. Acad. Sci. USA, Vol.
89, pp. 10787-10791 (November 1992). The isozyme that principally interacts in skin tissues is conventionally designated as 5&agr;-reductase 1 (or 5&agr;-reductase type 1), while the isozyme that principally interacts within the prostatic tissues is designated as 5&agr;-reductase 2 (or 5&agr;-reductase type 2).
The oxidation of &Dgr;-5-steroidal alkenes to the corresponding enones is an important step in the synthesis of steroid end-products useful as 5&agr;-reductase inhibitors. Chromium based oxidations have previously been used for the oxidation of allylic groups, but are environmentally unacceptable and require silica gel chromatography. The instant invention provides an improved alternative method for oxidizing &Dgr;-5-steroidal alkenes, which is convenient to run, and is environmentally friendly. Furthermore, the yield and purity of the oxidized intermediate obtained by the instant process meets or exceeds those obtained when other previously known oxidation methods are used.
SUMMARY OF THE INVENTION
The novel process of this invention involves the oxidation of compounds containing an allylic alcohol group or allylic hydrogens to the corresponding enones using a ruthenium based catalyst in the presence of a hydroperoxide. Particularly, this invention involves conversion of &Dgr;-5-steroidal alkenes to &Dgr;-5-7-keto-steroidal alkenes, using a ruthenium based catalyst in the presence of a hydroperoxide. This novel process can be exemplified in the following embodiment:
Compounds of Formula II are useful as intermediates in the preparation of 7&bgr;-substituted 3-keto-4-azasteroid compounds, such as those which are 5&agr;-reductase inhibitors. 5&agr;-Reductase inhibitors are useful in the treatment of hyperandrogenic disorders such as benign prostatic hyperplasia, acne vulgaris, seborrhea, female hirsutism, androgenic alopecia, male pattern baldness, and the prevention and treatment of prostatic carcinoma.
DETAILED DESCRIPTION OF THE INVENTION
The novel process of this invention involves the discovery that steroidal compounds containing a C5-C6 double bond (i.e., &Dgr;-5-steriodal alkenes) can be oxidized to the corresponding 7-keto compounds by treatment with a hydroperoxide in the presence of a ruthenium-based catalyst. Using the same process, compounds containing an allylic alcohol group can likewise be oxidized to their corresponding ketones. For reference, the standard numbering around the unsubstituted core steroid structure and the letter designation of the rings is as follows:
It has surprisingly been discovered that the instant oxidation process will proceed using any catalyst which is ruthenium based. Many ruthenium based catalysts are known in the art, and any such ruthenium based catalyst can be used with the instant process. Examples of ruthenium based catalysts that may be used in this process include but are not limited to the following: RuW
11
O
39
SiNa
5
, RuCl
3
, RuCl
2
(PPh
3
)
3
, Ru(acac)
3
, Ru(dimethylglyoximato)
2
(PPh
3
)
2
, RuO
2
, Ru(TPP)(CO)(THF), Ru(bipy)
2
Cl
2
, Ru(TPP)(CO)(THF), Ru/C and K
5
SiRu(H
2
O)W
11
O
39
. “TPP” is tetraphenylporphine; “acac” is acetylacetonate; “bipy” is bipyridine. Ruthenium based catalysts are described in, e.g., R. Neuman,
J. Am. Chem. Soc., Vol.
112, 6025 (1990); S-I. Murahashi,
Tetrahedron Letters, Vol.
34, 1299 (1993).
Particularly, a ruthenium sodium tungstate-based catalyst is used, and more particularly RuW
11
O
39
SiNa
5
. A catalytic amount of the ruthenium compound is used in this reaction. Those skilled in the art are familiar with the use of catalytic amounts of reaction catalysts, and will appreciate that the amount of catalyst that can be used may vary with the scale of the reaction and the particular ruthenium based catalyst employed. An exemplary amount of the ruthenium based catalyst ranges from about 0.05 to 5 mol %, and particularly about 0.5 mol % of catalyst per mole % of starting material, but variations beyond this range would be acceptable as well.
The alkene starting material is treated with a hydroperoxide in the presence of the ruthenium-based catalyst for conversion to the corresponding enone. Many hydroperoxides are known in the art, and any such hydroperoxide can be used with the instant process. Examples of hydroperoxides that may be used in this process include but are not limited to t-butyl hydrogen peroxide (t-BuOOH), cumene hydroperoxide, hydrogen peroxide, and benzoyl peroxide, with t-BuOOH being preferred. An amount of hydroperoxide sufficient to complete the oxidation should be used, for example at least about 2 moles, and preferably about 8 to 10 moles per mole of starting material.
Any commercially available solvent or combinations thereof may be employed in the instant process step, such as alkanes, ethers, alcohols, halogenated solvents, water, etc. Examples of the variety of solvents that may be used include but are not limited to toluene, ethyl acetate, hexane, chlorobenzene, heptane, t-butyl methyl ether (MTBE), benzene, acetonitrile, cyclohexane, methylene chloride, 1,2-dichloroethane and t-butyl alcohol (t-BuOH), or a combination thereof. When using RuW
11
O
39
SiNa
5
as the catalyst, heptane is the preferred solvent. With RuCl
2
(PPh
3
)
3
, chlorobenzene or benzene are preferred solvents.
This oxidation process may be run at a temperature between about −20° C. and up to the reflux temperature of the solvent used, for example about 100° C., and particularly between about 5° C. and 50° C., and more particularly at about 15° C. The reaction may be run at any pH, and particularly at an acidic pH, and more particularly at a pH of about 1. The pH of the reaction mixture may be adjusted prior to addition of t-BuOOH by addition of an aqueous acid such as sulfuric acid. Although not required, the reaction is preferably run under an inert atmosphere, such as nitrogen or argon.
&Dgr;-5-Steroidal alkenes that can be used in this process are known in the art. For example, see those listed and available through the Sigma Chemical Co.
One embodiment of the present invention comprises the step of treating a compound of Formula I
with a hydroperoxide in the presence of a ruthenium based catalyst in a solvent to form a compound of Formula II
wherein Y is hydroxy, an esterified hydroxy group, keto or ethylene ketal, X is —CH
2
—, —NH—, or —N(CH
3
)— or —N-2,4-dimethoxybenzyl, and Z is
The oxidation reaction is not affected by the substituent at the 16- or 17-position of the steroid, and thus “A” can be any synthetically feasible substituent. The flexibility and broad applicability of the instant process is demonstrated by the fact that it is not limited by the choice of s
Bakshi Raman K.
Corley Edward G.
Miller Ross A.
Thompson Andrew S.
Badio Barbara P.
Fitch Catherine D.
Merck & Co. , Inc.
Winokur Melvin
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