Synthesis of Lysergic Acid from Paspalic Acid
It is known that lysergic acid can be prepared by isomerizing paspalic acid, using potassium hydroxide [2] or sodium hydroxide [3], 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-(C1-C6)-alkylammonium hydroxide. It is also possible to use the tetra-(C1-C6)-alkylammonium hydroxide in a mixture with a small quantity of an alkali metal hydroxide. Tetra-(C1-C6)-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 (C1-C4) alcohol (methanol or ethanol, for example), or in a mixture of these solvents, at a temperature preferably between 25 and 35°C, and then letting the reaction progress for 24 hours. The quantity of tetra-(C1-C6)-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.sub.1 -C.sub.6)alkylammonium hydroxide and alkali metal hydroxide, the quantity of tetra(C1-C6)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.
EXAMPLE 1
130 g of paspalic acid are added rapidly to 780.1 g of a 40% strength solution of tetrabutylammonium hydroxide in water, with stirring and under a stream of nitrogen. The mixture is brought to 30.+-.2°C. and allowed to react at this temperature for 20 hours. The reaction medium is cooled to about 20°C. and held at this temperature for 3 h 30 min. 918 g of water are added, followed by acidification using 95% strength sulphuric acid until the pH is 3.5, while maintaining the temperature at about 30°C. The reaction mixture is then cooled to 10.+-.2°C. and held at this temperature for 30 minutes. The mixture is filtered through a sinter funnel under a vacuum of 0.4 bar, washed 3 times with 300 ml of water and then dried for 14 hours at 75.+- .2°C. and 20 mbar. This gives 107 g of lysergic acid comprising less than 3% of isolysergic acid and the RRi is 80% (RRi=weight of 100% lysergic acid isolated/weight of 100% paspalic employed).
EXAMPLE 2
130 g of paspalic acid are added rapidly to 472.3 g of a 40% strength solution of tetrabutylammonium hydroxide in water, with stirring and under a stream of nitrogen, followed by 316 g of a 1.5N aqueous solution of sodium hydroxide. The mixture is brought to 30.+-.2°C. and allowed to react at this temperature for 20 hours. The reaction medium is cooled to about 20°C. and held at this temperature for 3 h 30 min. 918 g of water are added, followed by acidification using 95% strength sulphuric acid until the pH is 3.5, while maintaining the temperature at about 30°C. The reaction mixture is then cooled to 10.+-.2°C. and held at this temperature for 30 minutes. The mixture is filtered through a sinter funnel under a vacuum of 0.4 bar, washed 3 times with 300 ml of water and then dried for 14 hours at 75.+-.2°C. and 20 mbar. This gives 107.8 g of lysergic acid comprising only 2.8% of isolysergic acid and the RRi is 81.6%.
Preparation of Lysergic Acid with Sodium Hydroxide Alone
5 g of paspalic acid in 100 ml of a 2N aqueous solution of sodium hydroxide are heated at reflux for 2 hours. After cooling, the pH of the reaction medium is brought to 5.5 by adding an aqueous solution of hydrochloric acid and glacial acetic acid (20 ml of water, 10 ml of hydrochloric acid and 10 ml of acetic acid). The precipitate is filtered, washed with 3 times 20 ml of a water/methanol (50:50) mixture, then dried in vacuo at 75°C. This gives 3.15 g of lysergic acid comprising 6.8% of isolysergic acid and the RRi is 59.3%.
Preparation of Lysergic Acid with Potassium Hydroxide Alone
5 g of paspalic acid in 360 g of a 0.5N solution of potassium hydroxide in a water/ethanol (50:50) mixture are heated at reflux for 1 hour. After cooling, the pH of the reaction medium is brought to 5.5 by adding 1N hydrochloric acid. The precipitate is filtered, washed with 3 times 20 ml of a water/methanol (50:50) mixture, then dried in vacuo at 75°C. This gives 2.86 g of lysergic acid comprising 1% of isolysergic acid and the RRi is 49.8%.
References
[1] United States Patent 6,242,603
[2] Helvetica Chimica Acta, 64, 47, 478 (1981)
[3] Helvetica Chimica Acta, 47, 115, 1052 (1964)
