*!Lug., 1940
~-~~ETHYL-(i-METHOXY-~-(~'-DIETHYLAMINOETHYLAMINO)-QUINOLINE1551
ated, reduced to the amine, acetylated and nitrated. The nitroacetylamino compound was submitted to the Skraup reaction and the product was hydrogenated and alkylated with 3-diethylaminopropyl chloride. The intermediate nitration product was shown
to have the nitro group in a position ortho to the acetylamino group by hydrolysis to the free amine, reduction to the diamine and condensation with phenanthraquinone to form a phenazine derivative. URBASA,
ILLINOIS
.CONTRIBUTION FROM THE DEPARTMENT O F CHEMIS7 RY AND CHEMICAL SYLVANIA ]
RECEIVED APRIL 5, 1946
ENGIKEERING O F THE
cNIVERSITP OF P E S N -
5-M ethyl-6-me thoxy-8- (2 '-diet hylamino ethylamino)-quinoline BY
hfARVIN
CARMACK, L .
w.
The synthesis of the potential antimalarial drug, 3 - methyl - G - methoxy - S - (2' - diethylaminoethylamino) - quinoline (I),4was accomplished in a nine-step procedure starting with o-cresol. The drug and its parent base, 5-methyl-6-methosy-8-aminoquinoline, have not been previously described, although most of the intermediates are known.
who prepared the compounds by a different method. The melting points were in disagreement with those ascribed by Robinson? to these compounds. Since Robinson gave few data on the sources of her starting materials, we believe that the agreement between our data and those of the well documented experiments of Heidelberger and Jacobs affords a confirmation of the correctness of the structures assigned to our c11 products. Nitration of the 3-methyl-4-methoxyacetanilide by the procedure of Arnold and McCOOlg gave 94-97% of 2-nitro-4-methoxy-5-methylacetanilide. The anilide was converted in 57% yield h F l I< ~ ~ to 5-methyl-6-methoxy-8-nitroquinoline by a speo-Cresol waz, nitrosated and the nitroso deriva- cial modification of the Skraup synthesis devised by Elderfield and co-workersIOfor their preparative oxidized to 2-methyl-4-nitrophenol in i 5 % yield by the prxedure of Clemmence and R a i ~ i s s . ~tion of 5,6-dimethoxy-8-nitroquinoline.The hyThe phenol was methylated with methyl sulfate drogenation of the nitroquinoline took place according to Gibson6; high yields (85-00%) were smoothly over Raney nickel, giving 5-methyl-Cobtained in runs of a few grams, but the methyla- tnethoxy-8-aminoquinoline in 81% yield. When the conventional procedure using a tion was usua1l.y less complete in larger scale runs. In spite of the limitation on the scdc of the buffered solution in aqueous alcohol for the atmethylation step, however, the iiiethod of C31'bso11 tachment of side chains was applied to the reacand was preferablc to thc procedure of I b b i ~ i s o n , ~tion of 5-methyl-6-methoxy-8-aminoquinoline since the latter gave a product which behaved iii diethylaminoethyl chloride hydrochloride, only a an anomalous manner in subsequent steps, indi- small yield of drug was isolated and most of the cating that i t was contaminated with by-products starting amine was recovered. A modified procedure involving the addition of dioxane and of unknown structure. %Met hyl-4-mitroanisole was hydrogenated over diethylene glycol to the aqueous alcoholic soluKaney nickel a t 130 atmospheres tn give 3- tion greatly increased the yield of drug, probably methyl-4-methoxyaniline. The iiieltirig points by increasing the solubility of the reactants in the (of the amine ax1 its acetyl derivative agrced with reaction mixture. Even the modified procedure failed, however, the values reported by Heidelberger and Jacobs,# to give the compound I1 from diethylaminu1) T h e work described in this paper was carried (rut under a cont r a c t , r r c ~ , r r i ~ n e ~ i d1,y r t ! t h e i'oniniittee on hlci11c:li I < i ~ ~ t ~ , ~ rI)?rli, hexyl chloricte aiid 5-metliyl-(j-iiietho~v-~-ai~iinoIUt1rii ilir I J r i i v r ~ r ~ i royf 1 ' ~ 1 1 1 1 ~ y I v ; ;inil iiii~~ Otliw Sririilifir c l u i t i o l i r i t . . Ap~iareritlythis linlide was ~ i o tsuflitar,irch axid 1)rirlopmriit ficirritly ri~aetivr,since t h r starting rnii terial was ( 2 ) P r e s e n t dLidrtss I 13rdudicr l . ~ t m r ~ t o r\i-ashirl,,t~~ ,. largely recovered even after a long period of u . L. (3) Present address: Calco Chemical Division, American Cyanaheating. (
tilt.
c ~ f
r\
mide Company, Bound Brook, New Jersey. (4) T h i s compound was submitted f o r tests of i t s antimalarial activity under t h e Survey N u m b e r 14,008. Results of t h e tests will be reprinted in a forthcoming publication entitled Antimalarial Drugs 1941-45 ( 6 ) Clemmenrr nr.d Kaiziss, J . .lm.Phurm, A s i o c . , 23, 536 (1934). ( G ) Gibson, J . Chrm. S o c . , 137, 42 (1923). (7) 0 hI. Robinson, J . Chem. SOL..109, 1078 (1816). ( 8 ) 1IcidrIlicr;;cr m d [acobs, THISJ o u ~ x a r . ,41, 1433 (1919).
Experimental 3-M ethyl-4-methoxyaniline.-2-Methyl-4-nitroanisole (m. p. 64-65') was hydrogenated in absolute alcohol over Raney nickel a t 95-100" and an initial pressure of approximately 2000 lb. per sq. in. The crude amine (yield,81571 ( 0 ) Arnold and M c C o o l , ' h i s J O U R N A L , 64, 1317 (1942). ( I O ) I
