U.S. Patent 2,438,259; Patented Mar. 23, 1948.

UNITED STATES PATENT OFFICE

2,438,259

d-LYSERGIC ACID DIETHYLAMIDE

Arthur Stoll and Albert Hofmann, Basel, Switzerland,
assignors Sandoz Ltd., Fribourg, Switzerland, a Swiss firm.

No Drawing. Application April 28, 1944, Serial
No. 533,264. In Switzerland April 30, 1943

1 Claim. (CI. 260--236)

	The present invention relates to new d-lysergic acid dialkylamides
which are valuable therapeutic products and to a process for their
preparation.
	It has been found that by condensing azides of d- or d,l-lysergic
acid respectively or of d- or d,l-isolysergic acid respectively or
mixtures of these compounds with diakylamines, d-lysergic acid
dialkylamides are obtained, which products have not yet become known
hitherto. The alkyl groups present in the dialkylamines used according
to the present invention can either be identical or different and may
be of saturated or unsaturated character. Such amines are for instance
dimethylamine, diethylamine, dipropylamine, dibutylamine, diamylamine,
methyl-ethylamine, ethyl-allylamine, butyl-amylamine, etc.
	The new d-lysergic acid amides are distinguished from the known
natural and synthetic ergot alkaloids and from the d-lysergic acid
amides described in our U. S. Patent No. 2,090,430 by their powerful
specific action on the central nervous system.
	The condensation of the d-lysergic acid- or d-isolysergic acid azides
with the dialkylamines is carried out in the presence of an inert
organic solvent and preferably at room temperature. During the
reaction taking place between the azides and the dialkylamine
generally mixtures of different dialkylamides will be obtained. This
can, for instance, be seen in the following illustrative example
showing the reaction of d-lysergic acid azide with diethylamine.
During the interaction of these compounds a mixture will be obtained
consisting of d-lysergic acid diethylamide and of d-isolysergic acid
diethylamide, from which mixture the d-lysergic acid derivative will
be separated. By using as a starting product d-isolysergic acid azide
and diethylamine a mixture of d-lysergic acid diethylamide and of
d-isolysergic acid diethylamide will be obtained, this mixture being
subsequently separated into its constituents. Finally by starting from
racemic lysergic acid azide or racemic isolysergic acid azide,
mixtures consisting of d,l-lysergic acid diethylamide and
d,l-isolysergic acid diethylamide will be obtained, from which the
d-lysergic acid diethyl amide can be separated in a suitable manner,
e.g., in form of its tartaric acid salt.
	The following examples, without being limitative, illustrate the
present invention, the parts being by weight.

Example 1

	3 parts of d-isolysergic acid hydrazide are transformed in the usual
way in a hydrochloric acid solution by a treatment with sodium nitrite
at 0 degrees C. into the azide, and, after neutralization of the acid
solution with sodium bicarbonate, the azide thus formed is shaken out
by means of 300 parts ethyl ether. The ethereal solution is then dried
with freshly calcinated potassium carbonate and treated with 3 parts
of diethylamine. The solution is allowed to stand, preferably in the
dark and at room temperature, for 24 hours with repeated shaking. The
ether is then evaporated in vacuo, the residue triturated with 30
parts of water and filtered by suction. The dark amorphous product
thus obtained possesses a specific rotation of [alpha]20/D=about+100
degrees (in pyridine) and consists essentially of a mixture of nearly
equal parts of d-lysergic acid diethylamide and d-isolysergic acid
diethylamide.
	The separation of both isomers can be carried out for instance by the
so-called chromatographic adsorption method. For this purpose the
mixture is dissolved in chloroform containing about 0.5% of ethanol
and is passed through a column of aluminium oxide of 60 cm. length and
4 cm. radius and the chromatogram developed with the same solvent. The
dark impurities pass rapidly into the filtrate. Then follows a bright
zone, which has a blue appearance in ultra-violet light and which
contains the d-lysergic acid diethylamide. From this fraction 1.0 to
1.3 parts of this product will be obtained.
	A further slowly passing portion of the solution contains the
d-isolysergic acid diethylamide. By evaporating this chloroform
fraction and crystallizing the residue from acetone, 0.8 to 1.2 parts
of a compound crystallizing in beautiful prisms of melting point 182
degrees C. (corr.) under decomposition is obtained, this compound
being the pure d-isolysergic acid diethylamide. Its specific rotation
is [alpha]20/D=+217 degrees (c=0.4 in pyridine). Elementary analysis
has given the following values: C 74.41; H 7.48; N 13.27%. The
calculated values for d-isolysergic acid diethylamide, i.e., C20H25ON3
are C 74.25; H 7.79; N 13.00%.
	The d-isolysergic acid diethylamide can be transformed into
d-lysergic acid diethylamide by using the methods known for the ergot
alkaloids. By allowing the solution of the iso- compound to stand in
dilute alcoholic potassium hydroxide, a mixture of about equal parts
lysergic acid and isolysergic acid compounds will be produced after a
short time. The d-lysergic acid diethylamide can then be separated
from the mixture in the manner described above.
	The amorphous d-lysergic acid diethylamide, which can be separated by
the chromatographic method, crystallizes, by dissolving it in a small
amount of acetone and diluting this solution with ethyl ether, in
bundles of needles. From benzene pointed prisms will be obtained, that
melt under decomposition at 80-85 degrees C. (corr.). The new compound
is difficulty soluble in water, but very soluble in methanol and
ethanol. It possesses the specific rotation of [alpha]20/D=+30 degrees
(c=0.4 in pyridine). Elementary analysis gives the following values: C
73.50; H 7.81; N 12.92%. For d-lysergic acid diethyl amide, C20H25ON3,
the calculated values are C 74.25; H 7.79; N 13.00%.
	By dissolving one equivalent of the base with one equivalent of
d-tartaric acid in a small quantity of methanol the neutral tartrate
of d-lysergic acid diethylamide crystallizes out in form of bundles of
needles. The salt is very easily soluble in water and melts
indistinctly and under decomposition at 200 degrees C. (corr.).

Example 2

	An ethereal solution of d-lysergic acid azide, prepared in the usual
manner from 3 parts of d-lysergic acid hydrazide, is treated with 3
parts of diethylamine and allowed to stand for 24 hours in the dark
and at room temperature with occasional shaking. The isolation of the
compound thus produced is carried out in the manner described in the
Example 1. The first separation by means of the chromatographic
adsorption yields 1.3 to 1.7 parts of d-lysergic acid diethylamide and
about 0.5 to 0.8 part of d-isolysergic acid diethylamide.

Example 3

	3 parts of racemic isolysergic acid hydrazide are transformed in the
usual manner into the respective azide and the formed compound is
precipitated by means of an excess of a sodium bicarbonate solution in
the form of voluminous yellowish flocks, which are separated by
suction and immediately introduced at -5 degrees C. into a solution of
3 parts of diethyl amine in 30 parts of ethanol. The azide readily
dissolves in the solution which becomes brown and is then heated
slowly to 30 degrees C. The solution is maintained at this temperature
for 1 hour, whereupon the solvent is evaporated in vacuo. The sticky
residue is triturated with 30 parts of water and filtered. The raw
condensation product amounting to about 2.8 parts consists of racemic
isolysergic acid diethylamide and of racemic lysergic acid
diethylamide and is separated by the chromatographic method in the
manner described in Example 1. During the chromatographic separation
two zones are obtained which are colored, in ultra-violet light, in
brilliant blue shades. The more rapidly passing zone contains the
racemic lysergic acid diethylamide, whereas the slower passing zone
consists of racemic isolysergic acid diethylamide.
	From the racemic lysergic acid diethylamide the d-lysergic acid
diethylamide can be separated by transforming the same for instance
into its neutral tartaric acid salt. For this purpose 3.2 parts of
racemic lysergic acid diethylamide (1/100 mol.) are dissolved in 6
parts of methanol and added to a solution of 0.75 part of d-tartaric
acid (1/200 mol.) in 2 parts of methanol.
	On inoculation with d-lysergic acid diethylamide tartrate this
compound crystallizes out in nearly colorless bundles of needles.
Yield 1.0 to 1.2 parts. The properties of the compound thus obtained
are identical with those described in Example 1 for the neutral
d-tartaric acid salt of d-lysergic acid diethylamide.
	What we claim is:
	The crystalline d-lysergic acid diethylamide which crystallizes from
benzene in prisms melting with decomposition at 80-85 degrees C.,
which is difficulty soluble in water but easily soluble in methanol
and in ethanol, which possesses the specific rotation [alpha]20/D=+30
degrees (c=0.4 in pyridine) and which corresponds to the formula
C20H25ON3.

ARTHUR STOLL
ALBERT HOFMANN

REFERENCES CITED
The following references are of record in the file of this patent:

UNITED STATES PATENTS
Number............ Name..........................Date
2,090,430....... Stoll et al.............Aug.17, 1937
2,265,207....... Stoll et al.............Dec. 9, 1941
2,265,217....... Stoll et al.............Dec. 9, 1941

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