Neron
(Hive Bee)
04-18-02 01:03
No 298569
      Paspalic acid isomerization to Lysergic acid
(Rated as: excellent)
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Process of preparing lysergic acid
United States Patent 6,242,603

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-(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 35C, 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(C.sub.1 -C.sub.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.degree. 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.degree. 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.degree. C. and allowed to react at this temperature for 20 hours. The reaction medium is cooled to about 20.degree. 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.degree. C. The reaction mixture is then cooled to 10.+-.2.degree. 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.degree. 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.degree. C. and allowed to react at this temperature for 20 hours. The reaction medium is cooled to about 20.degree. 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.degree. C. The reaction mixture is then cooled to 10.+-.2.degree. 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.degree. 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.degree. 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.degree. C. This gives 2.86 g of lysergic acid comprising 1% of isolysergic acid and the RRi is 49.8%.




Beagle
Member
posted 03-03-99 12:36 PM

Best info I've seen on isolation/purification of ergot alkaloids is found in 1900-1940's US Pharmacopoea. I'd be interested in any info on alkaloid content or ability to establish pure cultures that you might obtain. American Type Culture collection maintains pure cultures of ergots etc, that might be a better source than JLF. Also C. paspali etc. may be a better choice for alkaloid production by submerged culture.





Cherrie Baby(Member)
03-31-00 18:57
No 108018
Re: Successful Crude Ergot Alkaloid Recovery

Claviceps paspali is much easier to grow than C purpurea. C purpurea will not produce much LSAs when grown in liquid culture in the lab but C. paspali grows more quickly and produces large amounts of paspalic acid when grown in liquid culture. The paspalic acid is easy to convert to lysergic acid under basic catalysis - like safrole to isosafrole - it just involves the migration of a double bond see Helv. Chim. Acta. 1964, vol 47, 1052; also Helv. Chim. Acta. 1968, vol 51, 1372.





alice_d25
(Hive Bee)
06-13-00 19:58
No 17162
Ergot  

Does anyone have any details on where to find Claviceps Paspali?Does it grow in commercial cultivars (Wheat/oats/rye/etc), and is it present in the soil etc.  Has anyone found this in OZ, and if so, in which areas?I have some idea of what it looks like, now I have to find it!!Does it grow in the grain after harvest, (ie in the silos?) or is it only while the plant is growing?  Once I have a culture can I grow it in a Lab environment, and if so, what would be the best culture medium?Is it true that it grows on the surface of mashed weetbix when they are made up & left in cool place for X weeks?





In the thread ergot and agar, starting with Post 209459 (formula54: "ergot and agar", Tryptamine Chemistry):


bottleneck
(Stranger)
09-04-01 09:59
No 210036
Re: ergot and agar

The species used mostly used for production of lysergic acid amide seems to be Claviceps paspali, whereas Claviceps purpurea is used for production of ergotamine.

I read an article on selection of strains for high alkaloid production in submerged culture. I think they succeeded in finding high-yielding strains (3 grams per liter), but these reverted to lower-yielding strains after a few "generations" or something like that.





Later on in the thread bujinkan started posting some refs, Post 246864 (bujinkan: "Re: ergot and agar", Tryptamine Chemistry), Post 246869 (bujinkan: "Re: ergot and agar", Tryptamine Chemistry), and Post 246873 (bujinkan: "Re: ergot and agar", Tryptamine Chemistry).  More information on these might be useful.

And those numbers seem SO tempting... 107.8 grams of lysergic acid...  I think this could use some more discussion...

I have yet to be able to find out anything whatsoever about Paspalic acid.  TFSE, Chemfinder, google, etc... nothing.

What the hell is it?

 
 
 
 
    Sunlight
(Pioneer Researcher)
04-18-02 05:18
No 298630
      Very interesting but ...  Bookmark   

What is paspalic acid and where could we found it ?
Its not in Merck Index, and not in sigmaldrich...
 
 
 
 
    UKBEE
(Hive Bee)
04-18-02 05:20
No 298632
      Claviceps paspali  Bookmark   

Check out

http://lamar.colostate.edu/~sasapp/metamol-lsd.html

looks like Paspalic acid  can be brewed up from  Claviceps paspali.


:-)

I love the smell of Ketone in the morning.
 
 
 
 
    lugh
(Moderator)
04-18-02 08:14
No 298685
      Isomer  Bookmark   

Paspalic acid is an isomer of lysergic acid, Claviceps paspali is native to Portugal smile
 
 
 
 
    bujinkan
(Hive Addict)
04-18-02 18:15
No 298889
      thanks  Bookmark   

great post. ill see what else i can find.

please insert coin
 
 
 
 
    obia
(Stranger)
04-20-02 16:28
No 299619
      when i looked into this a few years ago it was ...  Bookmark   

when i looked into this a few years ago it was obvious that papsalic acid even though it is not controlled or listed explicitly is a sensitive compound to aquire.
it seemed from those i talked to  that industry is interested in paspalic acid over say lysergic acid because it can be used to make dihydrolysergic acid derivatives such as the the ergoloid mesylates, but paspalic acid doesn't require the same amount of paperwork as lysergic acid.
as far as yields from submerged cultures of C. papsali go there is little or no difference between the industrial paspalic acid producing stains and the lysergic acid amide producers (chiefly ergonovine producers)
papsalic could offer some interesting avenues, it could be used to synthesise the legal LAD (ethlad prolad al lad see tihkal )series of compound without have to work with illegal lysergic acid or illegal lysergide (LSD)