Methylation or ethylation agent and process for 1,4-addition of

Details Methylation or ethylation agent and process for 1,4-addition of Methylation or ethylation agent and process for 1,4-addition of

1994-09-30

1999-06-01

Dees, Jose G.

Organic compounds -- part of the class 532-570 series

Organic compounds

Cyclopentanohydrophenanthrene ring system containing

552604, 552641, 552643, 549336, 25218313, 568329, 568330, 568376, C07J 100, C07J 700, C09K 300, C07D31772

Patent

active

059089440

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a methylation or ethylation agent and a process for the 1,4-addition of a methyl or ethyl group to an .alpha.,.beta.-unsaturated or an .alpha.,.beta.-double unsaturated ketone or an .alpha.,.beta.-unsaturated aldehyde.
The 1-methyl introduction in steroids is a first and an important synthesis step in the production of 1-methyl steroids. Examples of this class of substances are atamestan (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 androgenic effect. ##STR1##
A known method for the introduction of 1-methyl in, e.g., (3) (androsta-1,4-diene-3,17-dione) to (4) (1-methylandrost-4-ene-3,17-dione) is the addition of dimethyl copper-lithium which is produced from methyl lithium and copper(I)-halides. Molar amounts of the corresponding copper salt are necessary for this purpose. A marked excess of reagent Me.sub.2 CuLi is necessary to achieve a complete conversion in the reaction to 4. ##STR2##
This process is an object of German patents 204 66 40 and 225 30 87. The copper salts thus accumulating in molar amount, that have to be worked up, represent a great problem, however they are extremely difficult to separate by filtration.
The accumulation of sizable amounts of copper salts can be avoided by copper(I)-catalyzed 1,4-addition with methyl magnesium halides, but an undesirable 1,2-addition as secondary reaction occurs in this way. Thus, under these conditions, androsta-1,4-diene-3,17-dione (3) cannot be methylated to the desired product 1.alpha.-methyl-androst-4-ene-3,17-dione (4). Rather 3-exomethyleneandrosta-1,4-dien-17-one (5) is formed here by attack on the 3-carbonyl group and after elimination of water from the intermediarly formed carbinol. ##STR3##
There are only few examples in the literature 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 go directly from 3 to 4, as explained above, molar amounts of dimethyl copper lithium are always necessary, that must be produced from molar amounts of methyl lithium and copper(I) halides.
The reaction sequence of M. Tanabe and D. F. Crowe in Can. J. Chem. 45, 475 (1967) shown in the following diagram and in German patent 1 223 837 is described as another method for the introduction of a methyl group in a steroid in 1-position under catalytic conditions. ##STR4##
For this purpose a conversion of the 1,4-diene system 6 into a 1,5-diene steroid compound 7 is first necessary.
The subsequent addition to the deconjugated 1,5-diene system 7 is possible under catalytic conditions, although in practice the yields in the decisive addition step 7 to 8 do not exceed 50%. Because of the additional number of stages and, connected therewith, reduced total yield, all things considered no advantageous and economical process is available with the above-described multistage sequence.
Thus so far neither a usable transition-metal catalytic process nor a suitable methylation agent is available for the introduction of a methyl group in 1-position in a 3-keto-1,4-diene steroid (1,4-addition), for example, androsta-1,4-diene,3,17-dione (3).
The object of this invention is to make available a new methylation or ethylation agent as well as to indicate a new transition-metal catalytic process for the 1,4-addition of a methyl or ethyl group to an .alpha.,.beta.-unsaturated or an .alpha.,.beta.-double unsaturated ketone or an .alpha.,.beta.-unsaturated aldehyde using this new alkylation agent indicated. The process to be developed is to be suitable especially for the 1-methylation of 3-keto-1,4-diene steroids.
This object is achieved by the alkylation agent according to the invention, which contains trimethyl aluminum or dimethyl zinc or triethyl aluminum as methyl or ethyl source as well as in addition catalytic amounts of one or more copper(I) and/or copper(II) compounds.
Preferably the alkylation agent altogether contains 5-10 mol

REFERENCES:
patent: 4404344 (1983-09-01), Sinn et al.
patent: 5043515 (1991-08-01), Slaugh et al.
Kuchin et al., Highly Selective Carboalumination of monosubstituted acetylenes by alumino cuprate reagents, Izv. Akad. Nauk SSSR, Ser. Khim, 1987, 2, 397-403, 1987.
Bagnell et al., "Nickel Catalysed Conjugate Addition of Trimethylaluminium to alpha, beta-Unsaturated Ketones", Australian Journal of Chemistry, vol. 28 (1975), pp. 801-815.
Bagnell et al., "Nickel Catalyzed Conjugate Addition of Trymethylaluminium to 3-oxo-delta4-steroids", Australian Journal of Chemistry, vol. 28 (1975), pp. 817-820.
Merck Index, Ninth Edition, (1976) pp. 769, 5762.
Ashby, et al. J. of Org. Chem., 39, pp. 3297-3299, 1974.

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