F. F. BLICKEAND A. P.CENTOLELLA
2924
Vol. 60
In a manner similar to that described above, allyl-@Cartland in The Upjohn Company Laboratophenylethylmalonic ester was prepared from sodium ethylr i e ~ . It ~ was quite surprising to find that none of ate, obtained from 300 cc. of alcohol and 13.8 g. of sodium, these ureas were effective to any great degree 159 g. of 8-phenylethylmalonic ester and 73.2 g. of allyl when injected intraperitoneally into white rats bromide; yield 159 g. or 88% of the calcd. amount. A mixture of 80 g. of potassium hydroxide, 260 cc. of although, in a second paper, it will be shown that some of the corresponding acetamides are 70% alcohol and 101 g. of the disubstituted r n a b i c ester was refluxed for twenty-four hours, most of the alcohol restrong hypnotics. moved, 250 cc. of water added and then about 140 cc. of The ureas were obtained by the following gen- hydrochloric acid added to the cold mixture. The crude eral method: conversion of malonic ester into acid separated from the acidic mixture as an oil but soon the required disubstituted derivative, R$C(CO- solidified; yield 78 g. or 94% of the calcd. amount. Fifteen grams of the allyl-P-phenylethylmalonic acid OGHJ2, hydrolysis of the ester, elimination of was heated in an oil-bath a t 180" until most of the carbon carbon dioxide with the formation of a disubdioxide had been evolved and then heated at 160-160° for stituted acetic acid, RGH-COOH, prepara- six hours; yield 10.7 g. or 86% of the calcd. amount. tion of the corresponding acetyl chloride and -4mixtuie of 28 g. of the acetic acid and 45 g. of cointreatment of the latter with urea or m e t h y l ~ r e a . ~niercial thionyl chloride was heated for two hours on a The new intermediates are described in Table I. steam-bath after the initial vigorous reaction had sub-
Experimental Part The procedures are illustrated in the case of allyl-@phenylethylacetylurea. To sodium ethylate, prepared from 1000 cc. of absolute alcohol and 46 g. of sodium, there was added, slowly, 320 g. of malonic ester. After one hour the mixture was stirred and refluxed and 370 g. of 8-phenylethyl b r m i d e added during the course of two hours. The mixture was stirred and refluxed for two hours longer, most of the alcohol removed by distillation and 500 cc of water added to the cold residue The ester layer was separated and the aqueous layer extracted six times with 75-cc. portions of ether; yieid of 8-phcnylethylmalonic ester 424 g. or 8070 of the calcd. amount: h p lX2-18370 (12 mm.) ( 3 ) Their results will be published h> them i n detail in another journal (4) DaLiis and Blanchard, ' 1 ~ 1 5JOURNAL, 61, 1797 (1920) ( 5 ) Dolique [ A m ?hzm I101 16, 447 (193131 reported 184-185' a1 1.5 inm
cided and the excess thionyl chloride then removed; the yield of acid chloride was 21 g. or 70% of the calcd. amount. Nine grams of allyl-6-phenylethylacetyl chloride and 9 8 g. of dry urea were heated in an oil-bath a t 125'. As soon as the material had melted the temperature was dropped to 110-115'. After six hours the product was cooled and rubbed in a mortar with enough loyosodium carbonate solution to keep the mixture alkaline. The solid material was filtered, washed with water and recryystalli7cd; yield % 9 g. or 9070 of the calcd. amount
Summaky A number of new disubstituted malonic esters, malonic acids, acetic acids, acetyl chlorides and acetylureas have been described. No strong hypnotics were found among the disubstituted acetylureas, R&H-CO--NH-CO"2, studied. ANIS ARBOR, hfICIiIGAT\'
RECEIVED OCTOBER 10, 1938
[CONlRIBUTION FROM THE COLLEGE O F PHARMACY, UNIVERSITY OF MICHIGAN]
Acid Amides as Hypnotics. 11. Acetamides' BY F. F. BLICKEAND A. P. CENTOLELLA~ It has been known for a long time that certain representatives of three types of acid amidessubstituted acetamides, acylureas and cyclic amides such as substituted barbituric acids and hydantoins-exhibit stroQg hypnotic activity. late y to the popularity af b wid a, the study of the acetamide type has been neglected except for Horace H. Raekh (2) The ITpjohn Cornpan:- Fe!!ow
tion submitted to the e s by A. P. CmatQleHa
the publications of Volwiler and Taberna and of Junkmann. Most of the acetamides, described hitherto as compounds which possess hypnotic action, are trisubstituted derivatives such as die general, trisubstit amides @re ~ Q d%bdt W to obtain than the disubstituted compounds we have prepared a considmble n& of the latter in order to determine their activity as hypnotics. ( 3 ) Volwiler and Tabern, THIS JOURNAL, 68, 1353 (1936). (4) Tunkmann A i c h e x p t l . Path Phornakol.. 186, 552 (1937)
ACETAWTDVS AS HYPNOTICS
Dec., 1938
2Q25
T4BW 5 6VEISTiTUTBD A ~ T A M I D E S
The amides were recrystallized in the following manner: compound 4was recrystallized from water; compounds 2,5, 9,10,14,16,17,18,21 and 25 from petroleum ether (90-100"); compounds 6,11, 12 and 20 from dilute alcohol; compounds 13, 15 and 22 from 50% acetone and compound 19 from acetone. Acetamide
1 Diethylthio 2 N-Methyldiethyl 3 N-Butyldiethyl
4 Ethylbutyl
Nitrogen, % Calcd. Found
M. p., ' C .
(24.45
80-81 79-80 34-35 106-107" 69-70 58-59 47-496
10.84
8.15
..
24.50 S) 10.76 8.00
..
9.07 8.93 7.94 8.18 7.48 7.25 6.77 7.03 OilC 8.99 8.91 102-103d 8.06 8.18 106-107 7.10 7.09 134-135 6.63 6.65 111-112 6.21 13 N-Ethylethyl-8-cyclohexylethyl 96-97 6.07 5.82 14 N-P-Hydroxyethylethyl-j3'-cyclohexylethyl 5.80 90-91 61-62 15 N-Butylethyl-@-cyclohexylethyl 5.39 5.53 173-174 5.07 5.01 16 Di-8-cyclohexylethyl 4.78 4.80 164-165 17 N-Methyldi- 8-cyclohaxylethyl 4.56 4.78 137-138 18 N-Ethyldi-0-cyclohexylethyl 140-141 6.ai 6.26 19 Butyl-8-cyclohexylethyl 5.85 5.55 110-111 20 N-Methylbutyl-@-cyclobexylethyl 5.53 5.64 21 N-Ethylbutyl-0-cyclohexylethyl 94-95 5.20 5.13 22 N-0-Hydroxyethylbutyl-0'-cydohexylethyl 92-93 7.21 7.56 23 N-(Diethylacetyl)-morpholine Oile 6.57 6.32 24 N- (Ethylbutylacetyl) -morphoIiie 011 25 N,N'-bis-(Diethylacetyl)-ethylenediamine 230-231 10.95 10.70 Raper [J.Chem. SOC., 91, 1837 (1901)l reported 101-102°. B. p. 199-200' a t 15 mm. ' B. p. 177-178" a t 5 mm. VolGer and Tabern [THISJOURNAL, 58, 1353 (1936)] found 96". B. p. 159-160"a t 9 mm. B. p. 185-186" a t 9 mm. 5 N-Methylethylbutyl 6 N-Ethyle t hylbutyl 7 N-P-Hydroxyethylethylbutyl 8 N-Butylethylbutyl 9 Ethylamyl 10 Ethylhexyl 11 Ethyl-8-cyclohexylethyl 12 NZMethylethyl-8-cyclohexylethyl
f
'
In Table I of this paper there have been described di-n-alkyl- and n-al kyl-~-cyclohexylethy1acetamides and, in some instances, corresponding N-alkyl and N-hydroxyalkyl derivatives. The evaluation of all of our compounds, from the pharmacological standpoint, has been carried out by Mr. J. W. Nelson and Dr. G, F. Cartland in The Upjohn Company Laboratories and the data obtained will be published by them in another journal. However, it may be stated that the following amides in Table I have been shown to be very effective hypnotics when injected intraperitoneally into white rats : diethylthio-, ethylbutyl-, N-methylethylbutyl-, ethylamyl-, ethylhexyl- and N-j3-hy&rxyethylethyl-/3'-cyclohexylethylaeetamide. Eqpecidy interesting is the relatively high activity of diethylthioacetamide; in fact, it is the strongest hypnotic in the group (Table 1) and is approximately five times as potent as diethylacetamide. However, the therapeutic index (minimum lethal dose/minimum hypnotic dose)
of both diethylthioacetamide and diethylacetamide is low, 1.2 in each instance. The disubstituted acetamides, described in Table 11, are of three types. In type I, one substituent is represented by the P-phenylethyl CeHsCHz-CHz
)CH-CO-NH$
R I CeHs-CH2-CH
>CH-CO-NH(R/) R
I1 C6Hs--(CHz), CHs-CHp
)CH-CO-NH~ I11
group, the other, R, by ethyl, propyl, isopropyl, allyl, butyl, isobutyl, p-eydohexyiethyl br @phenylethyl. In this group the ethyl, propyl, isopropyl, allyl and isobutyl compounds are strang hypnotics. A second type, 11, represents compounds of type I in which a substituent, R', has been in-
F. F. BLICKEAND A. P. CENTOLELL.~
2926
TABLE 11 SUBSTITUTED ACETAMIDES Thc amides were recrystaiiized in the following manner: compound 2 from water; compounds 8, 9, 10, 11, 12, 15, 16, 20, 22, 24, 25, 26 and 27 from petroleum ether (90-1CN)"); compounds 18, 19 and 2 1 from dilute alcohol; compound I i from acetone; compound 13 from 50% a c e t o y ; compounds 5 and 23 from a mixture of one part acetone and two parts petroleum ether (90-lnOo), compounds 1 , 4, ti, I , 10 and 1 1 from a miytnre of one part acetone and nine parts petroleuni ether. i\eetamitlr
1 Ethylbenzyi 2 Ethyl-8-phenylethyl > N-Methylethyl-B-phenylethyl 1 N-Ethylethyl-8-phenylethyl 7 D i- 8-phenyleth yl ti N-Methyldi-8-phenylethyl -I N-Butyldi-8-phenylethyl 8 p-Cyclohexylethyl- @'-phenylethyl 9 Propyl-8-phenylet hyl 10 N-Methylpropyl-/3-pheiiylethyl 11 N-E thylpropyl-p-phenylethyl 12 N-a-H ydroxyethylprop yl-@'-phenylethyl 13 N-Butylpropyl-i3-phenylelhyl 14 Isopropyl- P-phenylethyl 13 N- p-Hydrosyethylisoprop yl-lY-phenylethyl 1t i Allyl-8-phenylet hyl 17 Butyl-8-phenylethyl 18 N-Methylbutyl-P-phenylethyl 19 N-Ethylbutyl-6-phenylethyl 20 N-P-Hydroxyethylbutyl-p'-phenylethyl 21 N-Bu tylbutyl-8-phenylethyl 22 Isobutyl-8-phenylethyl 2 3 Ethyl-7-phenylpropyl 24 Ethyl-&phenylbutyl 25 Ethyl-c-phenylamyl 26 Ethyl-f-phenylhexyl 27 E thylcinnamyl c)
Nitrogen, % Calcd. Found
A I . p . , 'C.
117-118
105-106" 98-99 72-73 162-1 6:l 124-123 86-87 170-1i1
109-1 10 93-94
x4-85 7-4-75
7.90 7.32 6.83 6.39 5 , 53 5.24
8.00 i,30
4,43 5 14 6.81 f i . 39 6.00 5.63
4.29 5.41
5.36 6.81 5 . ti3
(i9-70 121-122
$3-84 YO-91
6.89 6.40 6.00 5.67 5.36 5.28 6.40 6.81 f i .40 6.01
124-125 108-1119 71-72
A6-67 39-60
89-9(l 118-119 107-1 08 98-99 113-114 94- Sfi
e. 93 t i , 5fi
.5, 42 5.15
6,i8 6.33 0.08 5.70 5 , 2:1 tj .85
- ->:I --
a
7.1:; 6,66
5,75 585
5.67
5.25 5.01 &til ii 82 .:1 4: 6.12 5.75
t i . 89
6.72
' Levy [Contp!. r e i d , 194, 175 (1Y32)] found 104" but did not record an analysis
troduced into the amide group; R' = methyl, ethyl, butyl or 8-hydroxyethyl. Three compounds in this series proved to be strong hypnotics : N-ethylethyl-8-phenylethylacetamide,N ethylpropyl-P-phenylethylacetamideand N-(3-hydroxyethylpropyl-@'-phenylethylacetamide. Six compounds of the general formula I11 were prepared in which .L' = I , 2 , 3,4, 3 and 6. Two of these compounds are strong hypnotics, namely, ethyl-/3-phenylethylacetamide and ethyl-e-phenylamylacr t amide.
Experimental Part The amides were obtained by interaction of the disubstituted acetyl chloride with ammonia or the required amine. The new acid chlorides and their general method of preparation were described previously.6 Allyl-@-phenylethylac yield when 4.5 g. of was added slowly, with nionia water which was cooled with ice. To prepare N,N'-bis-(diethylacetyl)-ethylenedianlme
20 cc. of a 66% aqueous solution of ethylenediamine was stirred, cooled and 2.6 g. of diethylacetyl chloride added dropwise. The precipitate was filtered, washed with water, dried and recrystallized four titlles from petroleum ether; yield 2.4 g. or 95% of the calcd. amount. N o attempt was made to discover a satisfactory procedure for the preparation of diethylthioacetamide. However, sufficient material for our purpose was obtained when 32 g. of p h q h o r u s pentadfide and 23 g. of diethylacetamide were mixed intimately, 175 cc. of benzene added and the mixture refluxed for five minutes. The wariii benzene was decanted from the pasty residue and the latter extracted with three 25-cc. portions of hot benzene The solvent was removed from the combined benzene solutions and the gummy, yellow residue recrystallized froin petroleum ether (90-100").
Summ$rV
A number of new dialkyl-, alkyl-8-cyclohexylethyl- and alkyl-8-phenykthylacetamides have been described. In some instances N-alkyl derivatives were prepared. Some of the amides have beeii found to b v strong hypnotics. A V Y .IRFIOR, M I C I I ~ G A V KECFIYFDOCTOBER10, 1Y:W
