SYNTHESIS OF ANALOGS OF LYSERGIC

ACID DIETHYLAMIDE

I. L. Kotlyarevskii and L. A. Mal'kova UDC 542.91:547.752

In a s e a r c h for new m e d i c i n a l s , and also in o r d e r to a s c e r t a i n the relation between the s t r u c t u r e of

LSD-25 ( l y s e r g i c acid diethylamide, I) and the physiological activity, we synthesized s o m e analogs of (I)
[compounds (III)-(VIII)], which differed f r o m (I) by the a b s e n c e of two rings, the distance between the
a m i d e and amino g r o u p s , and the r a d i c a l s attached to the nitrogen a t o m of the a m i d e group

~
CONEt2
--'CHa

~'%/\N/ O)
H
In o r d e r to a c c o m p l i s h t h e s e s y n t h e s e s we s e l e c t e d the following scheme:

\c
c l +BrC
,CONR+'+
(II) %,~ (Ill)-(vnl)

NR2'= bIMe2(III); NEt~2(IV); NBu2 (V); NPh2 (u

N ~ > (vn): ~/--\o,,
,, (wn)
The b r o m o a c e t i c a m i d e s w e r e synthesized by the condensation of b r o m o a c e t y l chloride with s e c o n d a r y
amines
IBrCH~COC1+ HNR2' --~ BrCH~CONR~'
NR2' = NMe2 (IX); NEts(X); NBu2 (XI); NPh2 (XII);
N(--), (XIII); N/-\^X_/O (XIV)

The s t r u c t u r e of a m i d e s (IX)-(XIV) was c o n f i r m e d by the IR and NMR s p e c t r a , in which a r e p r e s e n t

all of the bands that c h a r a c t e r i z e the s t r u c t u r e of t h e s e compounds, and also by t h e i r purity, as indicated
by the p r e s e n c e of one spot during TLC in various s y s t e m s of eluants.
The condensation of (II) with a m i d e s (IX)-(XIV) p r o c e e d s easily when e q u i m o l a r amounts of the r e -
actants a r e heated for 40-120 min at 110-120~ B e s i d e s (III)-(VIII), which during TLC give spots with a
high Rf value, the condensation products always contain a n o t h e r s e r i e s of compounds, which r e m a i n at the
s t a r t during TLC.
The question of the s t r u c t u r e of (III)-(VIII) was solved by analyzing the NMR s p e c t r a . In the NMR
s p e c t r a of N - m e t h y l t r y p t a m i n e (II) a r e p r e s e n t two singlets in a 1 : 1 ratio. The singlet at 5 11.38 p p m (in
D - p y r i d i n e , r e l a t i v e to HMDS) c o r r e s p o n d s to the hydrogen attached to the nitrogen in the indole ring, while

Institute of Chemical Kinetics and Combustion, Siberian Branch of the A c a d e m y of Sciences of the
USSR. T r a n s l a t e d f r o m I z v e s t i y a Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, pp. 2613-2614,
N o v e m b e r , 1972. Original a r t i c l e submitted J a n u a r y 7, 1972.

9 1973 Consultants Bureau, a division of Plenum Publishing Corporation, 227 West 17th Street, New York,
N. Y. 10011. All rights reserved. This article cannot be reproduced for any purpose whatsoever without
permission of the publisher. A copy of this article is available from the publisher for $15.00.

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 TABLE 1
% . N, % Rf
Amide Time, Yield, Empirical formula
No. found calc. acetone ether
I
III 1~5 20 ClsHmON3 t6,2t / t5,88 0,65 0,09
IV 35,4 CzTH~ONs t4,62 I t4,80 0,86 0,t0
V 2~5 2i ,6 C2zHs3ON3 t2,32 t2,23 0,90 0,08
VI * 40,0 CesH280N3Br 9,05 8,96 0,92 0,05
VII 0,5 29,2 CzsH~5ON3 t4,03 13,76 0,89 0,06
* Hydrobromide of (Vl), mp 232 - 233 ~

the singlet at 6 5.81 ppm c o r r e s p o n d s to the hydrogen on the nitrogen in the side chain. This a s s i g n m e n t
was confirmed by the r e s p e c t i v e p r e s e n c e of singlets at 5 11.44 and 11.56 ppm in the s p e c t r a of fi-.(3-in-
dolyl)ethanol and fi-(3-indolylSethyl b r o m i d e (in D-pyridine). The position of the singlets depends on the
solvent: in CC14 they a r e shifted upfield, while in D - p y r i d i n e and D - a c e t o n e , due to the f o r m a t i o n of a
hydrogen bond and the deshielding that is a s s o c i a t e d with this, they a r e shifted downfield. A singlet also
a p p e a r s downfield in the s p e c t r a of the condensation p r o d u c t s , while the singtet, c o r r e s p o n d i n g to the
N - H of the side chain, is absent. This p r o v e s that the nitrogen in the side chain of N - m e t h y l t r y p t a m i n e
takes p a r t in the reaction with the b r o m o a c e t i c acid a m i d e s .
Methods for the synthesis of the o t h e r models, analogous to (III)-(VIII), but with a variation in the
distance between the amino and a m i d e groupings in the side chain, a r e being developed at the p~:esent time.

EXPERIMENTAL METHOD
Synthesis of Monobromoaoetie Acid Morpholide (XVl). A solution of 15.7 g of monobromoacetyl
chloride in 50 ml of dichloroethane was added at <-20 o to 17.4 g of morpholine in i00 ml of dichloroethane.
The mixture was stirred at -20 ~ for 30 min, the morpholine hydrochloride was filtered rapidly, ~.nd the
precipitate was washed with chilled dichloroethane, evaporated, and fractionally distilled in vacue. The
yield of amide (XIV) was 40%, bp 108 o (0.5 mm), n}~ 1.5342. On Al203 (If activity), Rf = 0.84 in ether,
0.26 in benzene, and 0.97 in acetone.

In a similar manner, from 7.8 g of the acid chloride and 16.9 g of diphenylamine was obtained amide
(XII) in 65% yield, mp I15-I16 ~ Rf = 0.78 in ether, 0.93 in acetone, and 0.20 in benzene.
The constants of amides (IX)-(XI) and (XIII) coincide with those of the compounds described in [1, 2].
Synthesis of N-methyl-N[fi-(fl-indolyl)ethyl]glycine Morpholide (VIII). A mixture of 2 g of N-methyl-
tryptamine (If) and 2.39 g of amide (XIV5 was heated at 110-120 ~ for 2 h, and the product was dissolved in
i0 ml of hot water, made weakly acid with HCI, washed with ether, the aqueous layer was made alkaline,
and the product was extracted with ether. The extract after drying over K2CO 3 was chromatographed on an
AI203 column. Acetone was used to elute the reaction product (VIIIS, which was obtained as a glassy sub-
stance in 52~c yield. Found: N 13.79%. CI?H3302N 3. Calculated: N 13.91%. Rf = 0.84 in acetone, and
0.04 in ether.

Compounds (III)-(VII) were obtained in a similar manner. The data are given in Table I.

CONCLUSIONS
A n u m b e r of N-methyl-N[p-(B-indolyl)ethyl]glyeine a m i d e s , r e p r e s e n t i n g analogs of l y s e r g i c acid
diethylamide, w e r e obtained.

LITERATURE CITED
1. E. W. W e a v e r and W. H. Whaley, J. Am. Chem. See., 69, 515 (19475.
2. I. P a r r o t , I. Hervieu, Y. U r s y , and M. Paty, Bull. Soc'~-Chim. F r a n c e , 1063 (19645.

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