Date: 10-24-96 21:46
Subj: Synthesis of lysergic amides
From: c@in.the.hat (Dr. Moreau)


Patent Number: US4524208
Sauer; Gerhard, et. al.
Date of Patent: Jun. 18, 1985 


ABSTRACT

A process for preparing lysergic acid esters of the formula R'COOR
wherein R is alkyl of up to 3 carbon atoms, comprises reacting
corresponding lysergic acid or isolysergic acid amides with
corresponding alcohols at temperatures of 0 deg. to 65 deg. C. for 2
to 30 hours in the presence of an acid at a pH value of 0-1.
 
SUMMARY OF THE INVENTION

It is an object of the present invention to provide a process that
produces the desired lysergic acid esters in the pure state in a
high yield, e.g., typically at least about 80 molar % of theory. 

It has now been found surprisingly that it is possible to convert
lysergic acid and/or isolysergic acid amides, in the presence of
an inorganic or organic acid, into the natural lysergic acid ester of
8.beta.-configuration, in a smooth reaction, there additionally
occurring in case of the isolysergic acid amide reactant, a surprising
isomerization to the lysergic acid ester. The yields are
practically quantitative.

DETAILED DISCUSSION

In order to conduct the process, a lysergic acid amide or isolysergic
acid amide or a mixture of both is dissolved in the corresponding
alcohol, e.g., methanol, ethanol, n-propanol, or isopropanol.
Generally, amounts of the amide relative to the alcohol are 1-10 parts
by weight, i.e., usually an excess of alcohol is utilized. Suitable
acids include for example sulfuric acid, hydrochloric acid, perchloric
acid, p-toluenesulfonic acid, trifluoroacetic acid,
trifluoromethanesulfonic acid, etc., or an acid in the form of an
acidic ion exchange resin, e.g., sulfonic acids like RSO(3) H, wherein
R is the resin residue. 

The acid is added to the alcohol solution in a quantity so that the pH
value of the reaction solution is about 0-1. The reaction is
carried out at 0 deg. to the boiling temperature of the reaction
mixture, generally up to 65 deg. C.; suitably, the temperature
range is 20 deg. -55 deg. C. The reaction temperature is maintained
for a relatively long period of time. Depending on the acid
concentration and reaction temperature the reaction period is 2 hours,
usually at most 30 hours and, in the normal case, is
completed after about 16 hours. Preferably, the reaction is conducted
under anhydrous conditions. 

Subsequently the reaction mixture is worked up by using known methods,
such as washing, extraction, precipitation, crystallization, etc.
Acid salts of the amides can equivalently be used as starting
materials, e.g., the hydrochloride, tartrate, hydrogen maleate,
methane sulphonate and hydrogen phosphate. 
 
DESCRIPTION
EXAMPLE 1

A suspension is prepared from 5.0 g of isolysergic acid amide in 80 ml
of anhydrous methanol; the mixture is cooled to about -50 deg. C. and,
under agitation, 40 ml of a 13N solution of hydrogen chloride in
anhydrous methanol is added thereto. The clear solution is allowed to
warm up to room temperature and further stirred overnight. The primary
amount of the thus-formed ester hydrochloride is thus crystallized. By
cooling in an ice bath and adding ethyl acetate, the crystallization
is completed, and the precipitate is vacuum-filtered. 

Yield: 5.2 g (84% of theory) of lysergic acid methyl ester,
hydrochloride. 
alpha(D) =+94 deg. (0.5% in methanol).

EXAMPLE 2

Starting with 5.0 g of lysergic acid amide, lysergic acid methyl ester
is obtained as the hydrochloride in an 86% yield according
to Example 1. 
alpha(D) =+94 deg. (0.5% in methanol). 

EXAMPLE 3

A mixture of 2.5 g of lysergic acid amide and 2.5 g of isolysergic
acid amide in 500 ml of methanol is heated with 100 g of
p-toluenesulfonic acid for 4 hours to 50 deg. C. Then half of the
solvent is removed by distillation, the residue is poured into a
mixture of 200 ml of concentrated ammonia and ice, and extracted with
methylene chloride. The organic phase is dried with sodium sulfate and
evaporated, thus obtaining after crystallization from ethanol 4.45 g
(81% by theory) of lysergic acid methyl ester. 
alpha(D) =+68 deg. (0.5% in chloroform). 

Now, Tetrahedron Letters No. 8, pp 4171-4174, 1977.

"Trimethylaluminum reacts with a secondary amine in a 1:1 ratio at
room temperature in methylene chloride with evolution of methane to
give dimethylaluminum amides. ... Addition of an ester to
dimethylaluminum amide, followed by gentle warming at 25-41 degrees
for 5 to 48 hours produces the carboximide in high yield." 

"In a typical experiment 0.8 ml (2.0 mmol) of a 2.5 M solution of
trimethylaluminum in hexane was slowly added at room temperature to a
solution of 2.0 mmol of amine in 5 ml of dry methylene chloride under
nitrogen. The mixture was stirred at room temperature for 15 min and
2.0 mmol of ester was added. The misture was warmed at 25-41 degrees
under nitrogen until TLC indicated that the reaction had gone to
completion. The reaction was carefully quenched with dilute HCL and
extracted with methylene chloride. The organic extract was dried
(MgSO4) and concentrated to afford the carboxamide which could be
recrystallized, if necessary."

Does the above sound like a feasible synthesis for LSD starting from a
mixture of lysergic/isolysergic amide (from Morning Glories ,HBW or
whathaveyou), conversion of the lysergic amides to the methyl ester
then conversion to the diethylamide by way of trimethylaluminum
diethylamide?


----------------------- 

Another method of reacting lysergic acid methyl ester with amines, 
exemplified for 2-aminobutanol. Should work with diethylamine, too.


Collection Czechoslov. Chem. Commun. Vol. 22 (1957)

Condensation of the d-Lysergic acid-methylester with (+)-2-Aminobutanol-(1)

The mixture of 1.60 g of d-Lysergic acid-methylester with a content of 12%
of crystalbound benzene.[SMP. 168-170 under decomposition, aD(20) +84
(c=0.52, Chloroform) for the crystal solvent-free substance] and 1.33 g
(+)-2-Aminobutanol-(1) was heated in a pipe -which was closed by melting
it- in nitrogen-atmosphere and without direct light for 3 hours in an
oil-bath at 135-140 C.

The viscose dark-green coloured reaction mixture was dissolved in 70 ml of
Chloroform-Ethanol (9:1) and the bases were extracted with 1 % tartaric
acid solution (about 500 ml) from the solution. (until the extract gave no
positive Keller-reaction to ergot-alkaloids) The united aqueous extracts
were filtered after a little amount of Carboraffin was added. The salts
were free-based with 100 ml 1N NaHCO3 and after the addition of 100 mg NaCl
the bases were extracted into ether in 10% ethanol. The united ether
extracts (about 1500 ml) were dried (K2CO3) and freed from the solvent by
vacuum distillation. 

The amorphous hardly coloured sediment weighed 940 mg (55%)

In the semiquantative paper chromatography evaluation of the raw product,
besides a little amount of decomposition products and unused d-lysergic
acid-methylester, the (+)-Butanolamide-(2) of d-and-l-Isolysergic acid (I
and II) and the (+)-Butanolamide-(2) of d- and l-lysergic acid (III and IV)
was found in the proportion of about 35:35:15:15. 

The solution of the mixture (940 mg) in a little amount of chloroform was
added to a column of 25g of Aluminium oxide and the (+)-Butanolamide-(2) of
the isolysergic acids (I and II) were eluted first only with chloroform and
then with chloroform with 0.5% and 1% ethanol. The first extracts were
accumulated at the derivate of the l-Isolysergic acid, the last at the
derivate of the d-iso compound (620 mg).

After the separation of a little extract which included all 4
(+)-Butanolamides (about 10 mg), the elution was continued under the use of
chloroform with 2% and finally with 5% ethanol. This way, a mixture of the
d- and-l-Lysergic acid derivates was received. (190 mg). The first extracts
were accumulated at the d-Lysergic acid-(+)-butanolamide -(2), the last at
the l-lysergic acid derivate.

Yield: roughly 95,000 ug of the d-lysergic acid (+)-butanolamide-(2). The
course of separation was observed with UV-light - in which the Lysergic
acid derivates fluoresced blue - and paper chromatography.


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