Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1995-11-15
1999-06-01
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
502102, B01J 3114, C07J 100
Patent
active
059089458
DESCRIPTION:
BRIEF SUMMARY
This invention relates to an alkylating agent and a process for 1,4-addition of an alkyl group to an .alpha.,.beta.-unsaturated or an .alpha.,.beta.-double unsaturated ketone or to an .alpha.,.beta.-unsaturated aldehyde.
The 1-methyl introduction to steroids is a first and an important synthesis step in the production of 1-methyl steroids. Examples of this class of substances are atamestane (1) (1-methylandrosta-1,4-diene-3,17-dione), an inhibitor of estrogen biosynthesis (aromatase inhibitor), and mesterolone (2) (1.alpha.-methylandrosta-17.beta.-ol-3-one), a steroid with an androgenic action. ##STR1##
A known method for 1-methyl introduction of, e.g., (3) (androsta-1,4-diene-3,17-dione) to (4) (1.alpha.-methylandrost-4-ene-3,17-dione) is the addition of dimethyl copper lithium, which is produced from methyllithium and copper(I) halides. To this end, molar amounts of the corresponding copper salt are necessary. To achieve complete conversion in the reaction to 4, a considerable excess of reagent Me.sub.2 CuLi is necessary. ##STR2##
This process is the object of German Patents 2,046 640 and 2 253 087. In this case, the copper salts that accumulate in molar amounts and must be worked up constitute a serious problem, but they can be separated by filtration only with extreme difficulty.
The accumulation of sizeable amounts of copper salts can be avoided by copper(I)-catalyzed 1,4-addition with methylmagnesium halides, but in this case an undesirable 1,2-addition occurs as a secondary reaction. Thus, under these conditions, androsta-1,4-diene-3,17-dione (3) cannot be methylated to produce the desired product 1.alpha.-methyl-androst-4-ene-3,17-dione (4). Rather, by attacking at the 3-carbonyl group and after water cleavage, it forms from the intermediately formed carbinol 3-exomethylene-androsta-1,4-dien-17-one (5). ##STR3##
In the literature, there are only a few examples of a 1,4-addition to an .alpha.,.beta.-double unsaturated carbonyl system, as is the case in the example of androsta-1,4-diene-3,17-dione (3). To get directly from 3 to 4, as pointed out above, molar amounts of dimethyl copper lithium are always necessary, which must be produced from molar amounts of methyllithium and copper(I) halides.
As an additional method for introducing a methyl group into a steroid in the 1-position under catalytic conditions, the reaction sequence shown in the diagram below is described by M. Tanabe and D. F. Crowe in Can. J. Chem. 45, 475 (1967) and in German Patent 1 223 837. ##STR4##
To this end, first conversion of 1,4-diene system 6 into a 1,5-diene steroid compound 7 is necessary.
Subsequent addition to deconjugated 1,5-diene system 7 is possible under catalytic conditions, even if in practice the yields in critical addition step 7 to 8 do not exceed 50%. Because of a larger number of stages and the associated reduced total yield, overall there is no advantageous and economical process with the above-described multistage sequence.
To date, there is no usable transition metal-catalytic process, nor suitable methylating agent for the introduction of a methyl group in the 1-position into a 3-keto-1,4-diene steroid (1,4-addition), for example, androsta-1,4-diene-3,17-dione (3).
In non-prepublished German Patent Application P 41 32 755.1 (corresponding to European Patent Application No. 92250276.0, publication number 0 534 582), a new alkylating agent, which contains trimethylaluminum or dimethyl zinc or triethylaluminum as a methyl or ethyl source as well as additional catalytic amounts of one or more copper(I) and/or copper(II) compounds, as well as a new transition metal-catalyzed process for the addition of a methyl or ethyl group to an .alpha.,.beta.-unsaturated ketone or an .alpha.,.beta.-double unsaturated ketone or an .alpha.,.beta.-unsaturated aldehyde, is described using this new alkylating agent.
Preferably, the alkylating agent contains a total of 5-10 mol % of copper (I) and/or copper(II) compound relative to the .alpha.,.beta.-unsaturated keto compound to be alkylated.
As copper(I) and/or copper(II) com
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Nickisch Klaus
Westermann Jurgen
Badio Barbara
Dees Jos,e G.
Schering Aktiengesellschaft
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