Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-21
2001-06-05
Aulakh, Charanjit S. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S062000, C546S067000
Reexamination Certificate
active
06242603
ABSTRACT:
The present invention relates to a novel process for preparing lysergic acid by isomerizing paspalic acid.
Lysergic acid is an intermediate in the synthesis of nicergoline, marketed for ameliorating symptoms of failing mental health in the elderly, in retinal problems of vascular origin and in the treatment of acute cerebrovascular accidents.
The synthesis of nicergoline requires the use of a pure lysergic acid, i.e. one which comprises only a small percentage of isolysergic acid.
It is known that lysergic acid can be prepared by isomerizing paspalic acid, using potassium hydroxide (Helvetica Chimica Acta, 64, 47, 478 (1981)) or sodium hydroxide (Helvetica Chimica Acta, 47, 115, 1052 (1964) and JP70013302), but these processes do not allow either good yields or a product comprising small quantities of isolysergic acid to be obtained industrially.
A process has now been found, which is the subject of the present application, allowing lysergic acid of sufficient purity to be obtained in very good yields by isomerizing paspalic acid.
This isomerization is brought about using a tetra(C
1
-C
6
)alkylammonium hydroxide. It is also possible to use the tetra(C
1
-C
6
)alkylammonium hydroxide in a mixture with a small quantity of an alkali metal hydroxide.
Tetra(C
1
-C
6
)alkylammonium hydroxides which may be used are in particular tetramethylammonium hydroxide, tetraethylammonium hydroxide and tetrabutylammonium hydroxide.
Use is preferably made of tetrabutylammonium hydroxide.
The alkali metal hydroxide used may be in particular sodium hydroxide or potassium hydroxide.
Preference is given to the use of sodium hydroxide.
The process is generally carried out in an inert solvent, such as water or an aliphatic (C
1
-C
4
) alcohol (methanol or ethanol, for example), or in a mixture of these solvents, at a temperature between 20° C. and 60° C. and preferably between 25 and 35° C. It is advantageous to leave the reaction medium at this temperature for from 20 to 30 hours and in particular for 24 hours.
The quantity of tetra(C
1
-C
6
)alkylammonium hydroxide is generally from 1.5 to 10 mol and preferably 2.5 mol per mole of paspalic acid.
When use is made of a mixture of tetra (C
1
-C
6
)alkylammonium hydroxide and alkali metal hydroxide, the quantity of tetra(C
1
-C
6
)alkylammonium hydroxide is generally from 0.5 to 2 mol, preferably 1.5 mol, and the quantity of alkali metal hydroxide is generally from 4.5 to 0.5 mol, preferably 1 mol, per mole of paspalic acid.
Still more preferably, the process is carried out in an aqueous medium at a temperature of from 28 to 32° C., either in the presence of 2.5 mol of tetrabutylammonium hydroxide for one mole of paspalic acid or in the presence of 1.5 mol of tetrabutylammonium hydroxide and of 1 mol of sodium hydroxide for one mole of paspalic acid.
The lysergic acid is then precipitated by acidifying the reaction medium, using a mineral acid, preferably using sulphuric acid, and is filtered. It is advantageous to acidify to a pH of about 3-4, in particular to 3.5, while not exceeding 30° C.
REFERENCES:
Kobel, H. et al. : 6-Methyl-8-ergolene-8-carboxylic acid, prepared by saprophytic cultivation of appropriate ergot strains in fermenters. Helvetica Chim. Acta, vol. 47, pp. 1052-1064, 1964.*
Oppolzer, W. et al. : Total synthesis of lysergic acid by an intramolecular imino-diels-alder reaction. Helvetica Chim Acta, vol. 64, pp. 478-481, 1981.
Aulakh Charanjit S.
Aventis Pharma S.A.
Irving Newman
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