DERIVATIVES OF SOME AMINOQUINOLINES
Oct., 1944
having @-disubstituted aminoethyl, a-methyl+disubstituted aminoethyl and y-disubstituted
aminopropyl side chains. INDIANAPOLIS, INDIANA
RECEIVED JUNE 14, 1944
-
-.
[CONTRIBUTION FROM THE
1643
LILLYRESEARCH LABURATORIES]
Derivatives of 6-Methoxy-8-aminoquinoline and 2-Methy1-6-1nethoxy-8-arninoquinoline. I1 BY EWALD KOHRMANN A N D H. -1.SHONLE There have been comparatively few substituted 8-aminoquinolines reported containing a free hydroxyl group in the side Magidson and Strukov2 observed that the compound timethoxy - S - (@- hydroxy - y - diethylaminopropylamino)-quinoline was highly active but was somewhat more toxic than the corresponding desoxy compound. The present work was undertaken in order to obtain a better correlation between compounds of the type prepared by Magidson and Strukov? and the corresponding desoxy derivatives. The present paper concerns the preparation of quinoline derivatives of the type
H-
L-dR1 2R'
where K1 and Rz
=
alkyl, cycloalkyl or alkene
carried out by refluxing in ethanol solution at 110-115O for two days. The yield of product varied from 40 to (35%. The reaction products were purified by distillation in vacuo and subsequent conversion to the dihydrochlorides. These compounds have been tested in ducklings infected with Plasmodium loplzurae by hlr. C. L. Rose of these Laboratories. Full details of the activities and toxicities of these compounds will be reported later. The details of the preparation and properties of the secondary amines used in this work will be published a t a later date in THISJOURNAL. We wish to thank Miss Shirley Crandall and the late Mr. J. T. Bryant of these Laboratories for the micro Dumas analyses reported herein. We also wish to thank Mr. R. D. Stayner for his assistance in the preparation of 6-methoxy-Saminoquinoline and 2-methyl-6-methoxy-S-aminoquinoline. Experimental3
6-Methoxy-8-aminoquinoline.-This was prepared by the usual Skraup synthcsis4 from l-aiiiiiio-~-iiitro-~;I I methoxybenzene and the resulting 6-methosy-8-nitroR = --CH2-C-CH2or -CHi--C--CH2quinoline reduced with iron and hydrochloric acid ,s I I The product was purified by distillation in vacuo. OH OH 2-Methyl-6-methoxy-8-aminoquinoline.-This was prepared essentially by the method described by Mathur and and 1t3 = H or CHJ. Kobinson.6 The nitro compound was reduced with iron The dialkylaminohydroxyalkyl chlorides which and hydrochloric acid.6 T h e product was purified by were coupled with 6-niethoxy-S-aminoquinoline distillation in vacuo. Dialkylaminohydroxyalkyl Chlorides.-To a solution of or 2-methyl-G-nietlioxy-h-an1inoquinoline to yield mole of secondary amine dissolved in 25 cc. of ethanol the desired quinoline derivatives were prepared 0.25 and cooled t o 20" was added 0.25 mole of epichlorohydrin by treating epichlorohydrin or B-mcthylepichloro- or ~-methylepiclilorol~ydriii.The iiiis turc may beconir hydrin with the desired secondary amine in :L warm spontaneously ant1 estcriial cooliiig niay be required suitable solvent such as ethanol. In most cases, This was particularly so with thc lower alkyl amines arid with the piperidines. Thc mixture was allowed to stand the reaction proceeds readily a t room tempera- at about 25-30"overnigllt. l h e reaction mixture may br ture. In many cases the dialkylaminohydroxy- used directly in the subsequent condensatioii or in some alkyl chlorides can be purified by distillation, but cases it may be purified by distillation in vacuo. Distillathis is not necessary since the crude reaction mix- tion in vacuo is not advisable if the secoiidary amine is a reactive one, such as diethyl, methyl, n-propyl, ture may be used directly. Certain of the rather pyrrolidine or the pipcridincs. The yields are about 7 0 H*
CHa
dialkylaminohydroxyalkyl chlorides such as the d-hydroxy-y-rliethylamiri(iprop?.l chloride and the $-hydroxy-y-pi€'eridinopru~,\.1 chlorides tend t ( J decompose rather vigorously CXI vacuum distillation and this procedure for these compounds should be avoided. Coupling of the dia1k)-laminohydroxyalkyl chlorides with the desired quinoline nucleus was
(1) British Patent 267,169 (1027); German Patents 480,079. 488,045 (1942). (2) hqapidwti 2nd Striikov, A v r h Phor )#I 871, -vWb f l 9 3 3 )
75?@.
Condensation with 8-Aminoquinolines.- A iiiixturc o f li.1 mole of 6-iucthoxy-8-aminoquinoline or 2-methyl-ti methoxy-8-aniinoquinoline and approximately 0.11 niolt. of the dialkylaminohydroxyalkyl chloride (a considerable excess does not appear to be detrimental to the reaction I was dissolved in 60 cc. of absolute ethanol and the solutioir refluxed on an oil-bath at a temperature of 110-115" for (3) All melting points are uncorrected. (4) Magidson and Strukov,Arch. Pharm., Sll, 359 (1933). ( 5 ) West. J . Chem. S O L . 127, , 494 (1925). ( 6 ) Malhur and Robinson. i h i d . . 1620 (1934).
EWALD RO"N
AND
~ - M E T H O X @-HYDROXYY-~~
5 6
i
8 9 10 11
12
13 14 I3 ili
17 18 19
20
TABLE I ? R A1 p ,
Kl
K1
Methyl n-Propyl Ethyl Isopropyl n-Propyl a-Propyl Isopropyl Isobutyl Isopropyl n-Butyl n-Butyl $-Butyl n-Butyl n-Butyl n-Butyl Isobutyl Isobutyl Isobutyl Isobutyl $-Butyl Isobutyl 1-Methyl-butyl Isobutyl Cyclopentyl n-Amyl n-Amyl Isoamyl Isoamyl Allyl Allyi 2-Methylpiperidino 3-Me thylpiperidino 2,LDimethylpiperidino 2,3-Dimethylpiperidino ",ti-Dimethylpiperidino
1 2 3 4
H.A. SHONLE
oc.
183-185 2 17-21 9 209-2 11 183-186 173-1 76 190-192 155-1 57 180-182 197-199 185-187 190-192 181-184 134-136 135-138 I is-177
162-163 208-21 1 163-166 171-174 212-315
I
R
z
Vol. 66
-
Formula
~
~
~
~
~
~
~
N analyses, % ' Calcd. Found
CirHzsNaOt.ZHC1 11.17 Ci8HzrN30z.2HCl 10.77 C~gHz9N30z2HC1 10.40 C2&3iN@ '2HC1 10.03 CzaHsiNaOz.ZHC1 10.03 CziHsaN30z.2HC1 9.73 CziHa3IL'a02,2HCl 9.73 C2iH33NaOz.2HCl 9.73 9.73 CziH3aNsOz.2HCl CziH33NaOz 2HC1 9.73 C2zHarNaOz.2HCl 9.42 CaHaN102.2HCI 9.45 C~sHirNaOz.2HCl 9.13 C Z ~ H ~ ? P ' ; ~ O ~ ~ ~ I ~ 9C. 1I 3 C1gH26N302 2HCl 10.50 10,44 C igH2,i\i302.2HCl 10.44 CisIIz:S30~~2HCl 10.1 C?nHz9N302 2HC1 C?OHZON~OZ.~HC~ 10.1 CzoHz~N~Oz~2HCl 10.1
10.7 10.78 10.25 9.85 9.90 9.89 9.75 9.60 9.60 9.82 9.48
9.56 9.09 9.27 10.32 10.48 10.49 9.5 9.84 9.9
TABLE I1 G-METHOXY-8-( ~ - H Y D R 0 X Y - ~ - M E T € I Y L - ~ - R i R z - A M I ~ 0 P R ~ P Y L A M I N O ) - Q U I ~ 0 L I ~ E S K?
AI. p., " C .
Ra
Methyl %-Propyl Ethyl Ethyl Ethyl Isopropyl n-Propyl n-Propyl iillyl Allyl Isobutyl Isopropyl n-Butyl n-Butyl ?t-Butyl Isobutyl Isobutyl Isobutyl Isobutyl s-Butyl n-Amyl n-Amyl Isoamyl Isoamyl Piperidino 2-Methylpiperidino 3-Methylpiperidino 2,4-Dimethylpiperidino 2,3-Dimethylpiperidino l'yrrolidino
1 2 3 4 5 G 7 8 0 10
11 12 13 14 15 16 17 18
236-230 230-233 231-233 228-230 165-168 211-213 185-187 151-154 135 192-195 172-174 210-213 247-250 232-235 214-216 232-235 239-241 365-258
Formula
N analyses, % Calcd. Found
CisHz7N302.2HCl 10.76 CisII2,I\;30z~2HCl 10.76 CigHzoS30z.2HCl 10.39 C ~ O I - I ~ ~ N ~ O Z . Z H C ~10 02 9.86 CzoHziNaOz.2HCI C ? I H ~ ~ N ~ O ~ . ~ H C I 9.73 9.42 CzzH3sN30z.2HCl CzH3~N30z.2HCl 9.42 C22IIasNaOz.2HCl 9.42 9.13 CzzH36r\j302.2Hc1 8.86 CzrH3sX30z.2WCl 8.86 CztH3pSs0z.2HCl CigHzTSJOz.2HCl 10.43 C z n H z ~ S ~ 0 ~ ~ 2 H C l 10.1 C2oHzsN30z.2HCl 10.1 CziH3iN302.2HCI 9.77 C ~ ~ H ~ I N ~ O Z . ~ H C9.77 ~ CiaHzsX30z.2HCl 10.82
10.6 10.66 10.33 9.91 10.0 9.74 9.50 9.31 9.37 9.29 9.1 8.68 10.63 10.23 9.91 9.89 9.6 10.75
TADLE 111
~ - ~ ~ ~ ~ t I ~ , i , - ~ ( ~ (- ~ ~ ~l ~ I ~ 1l U l D o R ~ ~ ~ ~- ~ Y - ~ - ~ ~ - y - ~ ~ ~ ~ ~ - A M l N ~ ~ R ~ ~ Y I ~ A M ~ ~ ~ ) - Q U I N O IC I
II
)
If
I>opr(qiyI I / - I311 t yl
>
IT IT CII, CH,
Isobutyl Isobutyl Isobutyl
% >
6
I
