Process for the isomerization of ergovine derivatives

Details Process for the isomerization of ergovine derivatives Process for the isomerization of ergovine derivatives

1982-04-26

1985-05-07

Daus, Donald G.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546 68, 546 69, C07D51902

Patent

active

045159505

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a process for the isomerization of 8.beta. substituted ergolines to produce the corresponding 8.alpha. ergolines.
The 8.alpha. substituted ergolines correspond to an unnatural series of the ergot alkaloids, and may be produced from the natural 8.beta. substituted ergolines derivatives. An important 8.alpha. ergoline is the iso-9,10-dihydrolysergic acid methyl ester. Previously this compound was produced by converting the corresponding 9,10-dihydrolysergic acid methyl ester into the 8,9-ergolene or 7,8-ergolene which was then hydrogenated to give a mixture containing iso-9,10-dihydrolysergic acid methyl ester. This multi-step process proceded in unsatisfactory yields to an often impure compound. It had also been tried to epimerize 9,10-dihydrolysergic acid methyl ester under equilibrium conditions, i.e. in weak basic conditions with sodium methanolate in methanol, whereupon the .beta.-isomer was primarily obtained because the .alpha.-isomer is thermodynamically less stable.
It has now been surprisingly found that protonation effected under kinetic conditions of an anion produced by removal of the proton in the 8.alpha. position from an 8.beta.-substituted ergoline yields mainly the 8.alpha. isomer.
According to the invention 8.alpha.-substituted ergolines are produced by producing in a first step an anion of an ergoline substituted by an electron withdrawing group in the 8.beta. position by removing a proton in the 8.alpha. position and in a second separately effected step protonating the resultant anion and if necessary converting the resultant 8.alpha.-isomer into the desired ergoline.
The ergoline derivatives for use in the isomerisation according to the invention may be ergoline derivatives having an 8.beta.-electron withdrawing group present in nature or also producible by chemical synthesis.
They may bear substituents usual, e.g. in the chemistry of lysergic acid derivatives. Preferably the nitrogen atom in the 1 position is unsubstituted.
As electron withdrawing group in the 8.beta. position there are contemplated all usual radicals which allow the removal of the proton in the 8.beta.-position, e.g. by formation of an enolate, for example the functional radical of an ester, thioester, amide, aldehyde, hydrazide, imine, hydrazone, nitrile or ketone, preferably an ester or amide. The radical may contain aliphatic or aromatic groups.
When the electron withdrawing radical is a functional group of an ester, it corresponds to the formula COOR wherein R is an aliphatic or aromatic hydrocarbyl group, particularly lower alkyl, e.g. methyl. The other above-mentioned functional groups correspond to for example the following groups, alkylthiocarbonyl, arylthiocarbonyl, formyl, cyano, acyl or carbamoyl, hydrazinocarbamoyl, iminomethyl or hydrazinomethyl each of the last four radicals being optionally substituted by alkyl or aryl.
Ergoline derivatives suitable for the isomerisation according to the present invention encompass especially 9,10-dihydrolysergic acid derivatives, e.g. the compounds of formula I, ##STR1## wherein R.sub.1 is an electron withdrawing group,
The conversion of the 8.beta. isomer into the corresponding anion may be effected in known manner under strongly basic conditions e.g. using a non-nucleophilic compound which acts as a strong base under the reaction conditions.
Conveniently a lithium enolate is produced. As base one uses for example lithium dicyclohexylamide, lithium tetramethylpiperide, lithium isopropylcyclohexylamide or preferably lithium diisopropylamide, which may be formed in situ.
Preferably at least one equivalent of base per removable proton is used. Since in the case of an ergoline unsubstituted in the 1 position, the corresponding proton is mainly removed, preferably for production of the dianon at least 2 equivalents of base are used per mole of ergoline. In the case of an ergoline unsubstituted also in the 6 position, 3 equivalents are necessary. Preferably not more than an equivalent excess is used.
The formation of the anion may be effecte

REFERENCES:
patent: 3817988 (1974-06-01), Barton et al.
patent: 4075212 (1978-02-01), Bach et al.
patent: 4417051 (1983-11-01), Sawer et al.
House, Herbert, Modern Synthetic Reactions, Benjamin/Cummings, Menlo Park, Calif., (1979).
(Abst.) Cerny, 2nd European Symposium on Organic Chem. (Preprint), p. 293.
Benes, et al., "Expermization of Esters . . . ", Czech. Chem. Comm. [48](1983), pp. 1333-1340.

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