Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1995-04-18
1996-06-04
Prior, Kimberly J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
540 31, 552603, 552611, 552544, 552552, 552555, C07J 100
Patent
active
055234283
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/01606 filed Jun. 22, 1993.
The invention relates to a process for the production of 1-methyl-3-keto-.DELTA..sup.1,4 steroids of general formula I ##STR4## in which
St symbolizes the radical of asteroid molecule, characterized in that a 3-keto-.DELTA..sup.1,4 steroid of general formula II ##STR5## in which
St has the above-mentioned meaning, is reacted in an inert solvent in the presence of a nickel salt soluble herein with an organometallic compound of formula III, IV or V ##STR6## in which
X represents a methyl group, an alkoxy group with at most 6 carbon atoms or a phenoxy radical optionally substituted by halogen atoms, alkoxy groups with at most 6 carbon atoms and/or alkyl groups with at most 6 carbon atoms, and
Y.sub.1, Y.sub.2 and Y.sub.3 as well as Z.sub.1 and Z.sub.2 are the same or different and have the same meaning as X.
The invention preferably relates to a process for the production of 1-methyl-3-keto-.DELTA..sup.1,4 steroids of general formula Ia ##STR7## in which
R.sub.1 and R.sub.2 together represent an oxo group or an alkylenedioxy group with 2 to 6 carbon atoms or in which
R.sub.1 means an acyloxy group with up to 8 carbon atoms or an alkyl radical with at most 10 carbon atoms and
R.sub.2 symbolizes a hydrogen atom under the above-mentioned conditions from 3-keto-.DELTA..sup.1,4 steroids of general formula IIa ##STR8## in which R.sub.1 and R.sub.2 have the above-mentioned meaning.
An alkylenedioxy group R.sub.1 and R.sub.2 preferably is to understood to be, for example, an ethylenedioxy group, a 1,3-propylenedioxy group, a 2,2-dimethylpropylenedioxy group or a 2,3-butylenedioxy group.
An acyloxy group R.sub.1 of the compounds preferably is to be understood to be an alkanoyl group, such as the acetoxy group, the propionyloxy group, the butyryloxy group, the trimethylacetoxy group, etc. or the benzoyloxy group.
An alkyl radical R.sub.1 preferably is to be understood to be one with 8 to 10 carbon atoms, as it is present in the side chains of naturally occurring zoosterols or phytosterols, such as cholesterol, campesterol or .beta.-sitosterol.
It is known that the 1-methyl-androsta-1,4-diene-3,17-dione (=atamestane) is a pharmacologically effective compound, but whose multistage synthesis of androsta-1,4-diene-3,17-dione is quite expensive (DE-A 40 15 247). In contrast, the process according to the invention makes it possible to perform this reaction in one reaction step. That this is possible is surprising to one skilled in the art, since it is known that under comparable conditions, 3-keto-.DELTA..sup.4 steroids are methylated in 5.beta.-position (Aust. J. Chem. 1975, 28, 817ff). Also, the other compounds of general formula Ia can be converted in a simple way to atamestane, by the 17-esters or 17-ketals being saponified and then the 17-hydroxy group being oxidized in a known way (DE-A 33 22 285) or by the side chain of the sterol derivatives of general formula Ia being microbiologically degraded under conditions as they are described in U.S. Pat. No. 4,100,026.
The process according to the invention is performed in an inert solvent. Suitable solvents are aliphatic, cycloaliphatic, or aromatic liquid hydrocarbons, such as hexane, petroleum ether, cyclohexane, benzene, toluene or xylene, ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane, esters, such as ethyl acetate, methyl acetate or mixtures of these solvents.
The reaction is performed in the presence of nickel salts, which are soluble in these solvents or solvent mixtures. Suitable nickel salts are, for example, the nickel(II)-bis-(triphenylphosphine)-chloride, the tetrakis-(triphenylphosphine)nickel(O), the nickel(II)-stearate, the bis-diethyloxalacetatol)-nickel, the pentakis-(ethylacetatolhydroxotrinickel, the bis(1,3-diphenylpropane-1,3-dionatolnickel, the bis(acrolein)-nickel(O) and especially the nickel(II)-acetylacetonate (Aust. J. Chem., 1974, 27, 2569 ff and Aust. J. Chem., 1975, 28, 801 ff). For reaction, preferably 0.01-0.1 mol of nickel salt per mol of steroid to
REFERENCES:
patent: 4022769 (1977-05-01), Grunwell et al.
patent: 4071624 (1978-01-01), Grunwell et al.
patent: 4071625 (1978-01-01), Grunwell et al.
PCT Search Report dated Oct. 25, 1993.
Australian Journal of Chemistry, "Nickel-Catalysed Conjugate Addition of Trimethylaluminum to .alpha.,.beta.-Unsaturated Ketones", vol. 28, Melbourne 1975.
Australian Journal of Chemistry, "Nickel-Catalysed Conjugate Addition of Trimethylaluminum to 3-Oxo-.DELTA..sup.4 -Steroids", vol. 28, Melbourne 1975.
Journal of Organic Chemistry, "Transition Metal Catalyzed Conjugate Methylation of .alpha.,.beta.-Unsaturated Ketones by Trimethylaluminum and Lithium Tetramethylaluminate", vol. 39, No. 22, Nov. 1974.
Nickisch Klaus
Prelle Annette
Westermann Jurgen
Prior Kimberly J.
Schering Aktiengesellschaft
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