1232
BRESLOW,
BLOOM, SHIVERS, ADAMS,WEISS, YOSTAND HAUSER
ether, and the ether was washed with five 100-ml. portions of lOybaqueous sodium hydroxide and with five 100 ml. portions of water, and dried over magnesium sulfate. The ether solution was then filtered and saturated with dry hydrogen chloride gas. The mixture of the hydrochloride of the desired base with the hydrochloride of N-(4-diethylamino-1-methylbutyl) -4-chloro - 8 - quinolinesulfonamide settled as an orange gum. The ether was removed by decanting and the gum was washed with anhydrous ether. It was then dissolved in absolute ethanol, the ethanolic solution was heated with Nuchar C and filtered, and absolute ether was added to the warm ethanolic solution until the first appearance of cloudiness. The ethanolether solution was then maintained a t -5" for two weeks. There resulted from this, 7.3 g. (S70) of light, hygroscopic crystals, m. p. 155-156'. Anal. Calcd. for C~Ht,NbO&3HC1: C1, 17.3; N, 11.35. Found: C1, 17.0; N, 11.59.
summary
1. The repetition of some Russian work on 4-
[CONTRIBUTION FROM
THE
aminoquinolines, SN 3294 and 5063, confirmed their antimalarial activity. 2 . The following modifications of SN 3294 and 7G18 were made: 4-(4-Diethylamino-l-methylbuty1amino)-6-dimethylaminoqqinoline,3-bromo4- (4-diethylamino- 1-methylbutylamino) - quinoline, 7-chloro-4- (3-dih~xylaminopropylamino)quinoline, 7-chloro-4-(3-dioctylaminopropylamino)-quinoline, 6-benzylthio-7-chloro-4-(4diethylamino-1-methylbuty1amino)-quinoline, 4(4-diethylamino- 1-methylbutylamino) -8-quinolinethiol, N - (4-diethylamino- 1-methylbutyl)-4(4-diethylamino-1-methylbutylamino) - S -quinolinesulfonamide. 3. The preparation of some 4-haloquinolines required as intermediates for the above compounds is described. RECEIVED APRIL 5, 194;
EVANSTON, ILLINOIS
DEPARTMENT OF CHEMISTRY OF DUKEUNIVERSITY]
Synthesis of Antimalarials. V. B Y DAVID
Vol. 68
The Synthesis of Certain 4-Aminoquinoline Derivatives?
s. BRESLOW,:' MELVINs. BLOOM, JOSEPH c. SHIVERS, JOE 'r. .'DAMS,4
ARTIN IN J .
WEISS,
ROBERTS . YOSTAND CHARLES R. HAUSER
Certain I-aminoquinolines having appropriate side chains are known to be active antimalarials. These compounds are obtained by coupling a 4-
cfi c1
C1
+
Also, certain di- and triamines have been prepared and coupled with 4,7-dichloroquinoline. The couplings were effected by heating one mole of the 4-chloroquinoline with two moles of the dior triamine; in certain cases, the reaction was effected in the presence of a small amount of phenol. The products were usually converted to H z N E ~ ~ C H ~ J Q ( C+ H,!~ their phosphate salts. The data on the couplings are summarized in Table 11. ? * I T H C H ( C H ~ ) ~ N ( C ~ HVariations ~)~ in the Nucleus.-Compounds I I / . throuch V have been svnthesized and submitted for teiting. Also, nuciei VI and VI1 have been HC1 prepared. The nuclei for compounds I, 11, 111, V and VI,
+
chloroquinoline with a primary amine. This may be illustrated with 4,7-dichloroquinoline and l-diethylamino-4aminopentane, the product of which may be considered the standard in this series. In the present investigation several new 4-chloroquinolines have been synthesized and, in most cases, coupled with 1-diethylamino-4-aminopentanc. ( 1 ) Paper I V of this series,
(1916).
THISJ O U R N A L , 68, 100
(2) T h e work described in rhis paper was done under a contract, recommended by t h e Committee on Medical Research, between the Office of Scientific Research and Development and Duke University. (3) Present address: Hercules Experiment Station, Wilmington. Delaware. (4) Present ;iddress: Carbide and Carbon Chemicals Corp., Chariebton, West Virginia.
X
cQ-cH3 I
X
CH30-
=
-NHCHCH2CH?CH?f\;(C?H,),
I
X
CH, X
I
CH3 X
IV c1
SYNTHESIS OF (ZERTAIN 4AMINOQUINOLINES
July, 1946
1233
TABLE I CYCLIZATIONS O F ANILINES IVITH ETHYL a-ETHOXALYLPROPfONATE c
Yield, Substituent
7-Meth0xy'~ G-Methyl-7-chloro' 5-Methyl-8-chloro" 6-Chloro"" 8-Ch l ~ r o ' ~ ~
XI. p . ,
7 -
Calcd.-
-.
Analyses, 7c -------Found-C
7% "C. Formula C H N Substituted Ethyl 3-Methyl-4-hydroxyquinoline-2-carboxylates
24"* 60' 62 73 68
189-191"
CirHijOsN
120-12 1 242-243' 146'
Ci,HlaOjNCI C1aH1?0sNCl
-H
5.36 60.1 58.8
5.04 4.55
5.01 5.27
N
5.38 60.8 59.5
5.01 4.87
4.95 5.02
Substituted 3-Methyl-4-hydroxyquino1ine-2-carboxylic Acids 7-Methoxy 6-Methyl-7-chloro' 5-Methyl-8-chloro 6-Chlorov 8-Chlorou
98
250-251"
Ci2HiiO~X
61.8
4.76
(3.01
61.6
4.86
6.02
72a 66
239-240' 258'
57.3
4.01
3.86
BOP
55.6
3.39
5.57 5.89 5.89
57.2
70'
Ci2H1o03NCI CiiHs03NC1 CiiHs03NC1
55.9
3.77
5.53 5.48 5.68
Substituted 3-M~:thyl-4-hydroxyquinolines 7-Methoxy 6-Methyl-7-chloro" 5-Methyl-8-chloro 5-Methyl' 6-Chloro" 8-Chlorog
60 84h 99 75"
275-276'
C,l"1OLN
69.8
5.86
7.40
70.3
5.82
7.69
268-270P 26O-2(ilp 325-327"" 219"
CuHiiON CIO&ONC~' Cio&ONCI'
76.3 62.0 62.0
6.40 4.16 4.16
8.09 7.23 7.23
76.0 62.0 62.3
6.50 4.40 4.21
8.39 7.00 7.24
Substituted 3-Methyl-4-chloroquinolines
78' 6.75 63.2 77- 78" CIIHI,,ONCI 63.0 4.85 4.85 7-Methoxy 6.83 6.22 19', 129-130' CI113IQNCI* 58.7 4.03 58.4 0-Methyl-7-cliloro 4.08 11.31 67' 7.31 59- GO. gk'" CiillioNCl 5-Met liyl (i .97 63' 118-119" CioH7NCI2 56.6 3.33 6.61 G-Chloro" 57.0 3.31 0.31 91' 98 CioH?NCIz 5G.6 3.33 6.61 8-Chloro" 56.9 3.67 8.34 From 3-methoxyaniiine. b From .7-chloro-l-niethylaniline. From 2-chloro-5-methylaniline. From 4-chloroaniline. e From 2-chloroaniline. Mixed with the 5-chloro-6-methyl isomer. Obtained by the dechlorination of 5methyl-8-chloro compound. Yield on catalytic dechlorination. A n a l . Calcd. for CI: 18.3. Found: 18.6. j Anfll. Calcd. for CI: 18.3. Found: 18.3. B. p., 115-152", 5 mm. Yield after six recrystallizations from acetone. m The mixture of the 7- and the 5-methoxy isomers was obtained in 6 2 5 yield. '' Sample recrystallized from acetone. 0 Saniple recrystallized from glacial acetic acid. P Sample recrystallized from ethanol. Sample recrystallized from methanol. Hydrolyzed by refluxing twelve hours with 2570 sulfuric acid. Yield of recrystallized product. 1 Yield of pure compound. u Yield for hydrolysis of the ester, decarboxylation of the acid and formation of the chloro compound. The chloro compound was recrystallized four times from methanol to remove the 5-chloro-6-methyl isomer. u Sample reSample recrystallized from methanol-water. = Sample recrystallized from ethcrystallized from 750/, acetic acid. anol-water. Y Reported recently by Steck, et ~ 1 . ~ 1'
0
'
7
which are substituted 3-methylquinolines, were prepared from appropriately substituted anilines and ethyl cu-ethoxnlylpropionate.6 The m i l , prepttred from the amine and the a-keto ester, was cyclized in hot mineral oil to a quinoline ester which was hydrolyzed and decarboxylated. The resulting 4hydroxyquinoline was converted to the corresponding 4-chloro derivative by means of phosphorus oxychloride. The results with substituted anilines are summarized in Table 1. The method may be illustrated with aniline itself, thus (5) After the present work was completed, Steck, Hallock and Holland, THISJOURNAL, 68, 129,132 (1946),published results on t h e use of ethyl a-ethoxalylpropionate for the preparation of certain 3methylqulnolines having substituents in the 6- or 8-positions. However, only two of our nuclei, those obtaineu from 0- and p-chloroaniline, were drsxibed by these workers and our data diRer in certain respect, from their-s; moreover. we have aitached the niicleus froin p-chloroaiiiliiie t o ii dilierent side chain.
0
OH
OH
OH
CI
The corresponding reactions with 0- and 1chloroanilines were effected without difficulty to
BRESLOW, BLOOM, SHIVERS,
1234
ADAMS, W E I S S , YOST AND HAUSER
form 3-methy1-4,8-dichloroquirloline (VI) and 3methyl-4,6-dichloroquinoline(nucleus of V), respectively ; the latter nucleus was attached to ydiethylaminopropylamine instead of the standard 1-diethylamino-4-aminopentane. However, cyclization of the anil from m-anisidine, used in the preparation of compound I, produced a mixture of isomeric quinoline esters the separation o f which was tedious. After six recrystallizations from ace-tone, the desired 7-methoxy isomer was isolated in fair yield. It was converted without difficulty to the corresponding 4-chloroquinoline. The structure of the nucleus was proved by oxidationgof the 4-quinolinol and hydrolysis of the resulting amide to 4-methoxyanthranilic acid, which mehed a t 165-166* in agreement with the literature.' The isomeric 6-methoxyanthranilic acid melts a t XT,' .8 Cyclization of the anil from 2-chloro-4-aminotoluene, used in the preparation of compound I I , likewise produced a mixture of isomeric quinoline esters. These were separated on a small scale and the desired G-rnethyl-7-chloro isomer converted to the corresponding 4-quinolinol, which was used in the proof of structure of the nucleus. However, for the prepnration of the drug it was found mtire convenient to convert the mixture of quinoline esters to a mixture of the corresponding 3chloroquinolixies from which the desired 6methyl-7-chloro isomer was isolated in fair yield by four recrystallizations from methanol. The structure of the nucleus was established by oxidizing the 4-quinolinol, hydrolyzing the amide and deaminating the resulting anthranilic acid. 'The product was 3-methy1-4-chlorobenzoic acid which was identical with a synthetic sample prepared by oxidizing 4-c.hloro-m-xylene.9 T o avoid the formation of isomers, the nucleus for cclmpoutid I I I was prepared from X-amino-9chlorotoluene'O instead of from .'l-aminotoluene, and the chlorine was subsequently removed catalytically from the quinolinol using palladium charcoal.11 Since one position ortho to the ailiiiio group is blocked, cyclization can take place in cme direction only and this leads to the formation of the desired 5-methyl derivative. s\, final proof, the 4-chloroquinolixie was dechlorirlatcd to the known 3,5-dirnethylquinoline." These reactioiis may be indicated, thus cIrIOH
CH3
4 -39 3 Steps
,
I
NHI
c1 -
1
CHa
[HI
x-z
c1
(6) The procedure used wa5 that of Kretchy ( M o n n t s h . , 4, 156 (1883)) a s modified by Drs. K . C. Elderfield and J . B. Wright of Columbia [Jniversity (private communicntion). ( 7 ) Ullinan and Dootsou, Bo'., 61, 20 (1918). ( 8 1 Liuehler, Ueebel and Evans, J. Or#. C h e m . , 6, !?I(; i l l 1 I I I (10 \'ollrath. Ann., 144, 266 (1867); bee alsu M a ~ l l t r H u h ) I N c h i m . . (41 19, 290 (1821). (10) Ullman and Gluck, Bcr.. 49, 2494 (1010). (11) Ainley and King, Proc. Roy. Soc. (London). l!26B, XI il'l381 (12) Manskc, C o i i n d i u n J. K c s . , ?OB,133 (i!j42).
CH3 OH
CHa C1
VOl. 68 CII3
Nucleus for I11
The nucleus for compound I V was prepared by the cyclization of 2-chloro-3-aminotoluene with ethoxymethylenemalonic ester, l 3 followed by hydrolysis, decarboxylation and catalytic removal of the chlorine. The resulting quinolinol was converted t o the desired 4-chloroquinoline in the usual manner. The presence of chlorine ortho to the amino group insured that the cyclization proceeded in the desired direction. As final proof of the structure, a sample of the 4-chloro-7-methylquinoline was dechlorinated to the known 7 methylquinoline. l 2 3-Methoxy-4,7-dichloroquinolineVI1 has been obtained by the cyclization of m-chloroaniline with ethyl methoxyethoxalylacetate, followed by hydrolysis, decarboxylation and treatment with phosphorus oxychloride. The reactions are analogous to those represented above with ethyl CYethoxalylpropionate. However, in contrast to the latter reagent, ethyl methoxyethoxalylacetate has produced only a low yield of the quinoline ester, although the yields are good for the remainder of the steps. Moreover, even the low yield on cyclization could be duplicated only on small scale runs. Compound VI1 has also been prepared by iodinating methyl 4-hydroxy-7chloroquinoline-2-carboxylate, replacing the iodine by methoxy, and hydrolyzing, decarboxylating arid replacing the 4-hydroxy groups by chlorine in the usual manner. The yields appear to be good but thus far these reactions have beeu carried out only on a small scale. Although the meltirig point of the product obtained by this method has been slightly lower than that obtained by the cyclization method, there is little doubt that the products are identical, since the mixed melting point is in between. This is considered to establish the structure of the cyclization product a s the desired 3-methoxy-7-chlor0, rather than the 3-mcthoxy-5-chloro, isomer. The synthesis of compound VI1 was also attempted in other ways. Since it has been reportedI4that 3-nitro-4hydroxyquinoline may be obtained from anthranilic acid and methazonic acid, it appeared possible that the reaction might be effected with 4-chloroanthranilic acid to form a product which might be reduced t o the amino derivative and the amino replaced by methoxy. However, a preliminary experiment with anthranilic acid itself gave only a low yield. Nitration of 4-hydroxy-7clilorc~quinc~liiie in refluxing acetic acid, followed f)y retli~tioii,gave an amine (assumed to be the ( 1 3 1 'l'iic methud of cyclization of this ester with aniline derivat i v e s . 6r;tdrscribrd by Jacobs and Gould [ T H I S J O U R N A L , 61, 2800 (19;lU)], has been greatly extended by Price and co-workers; see
Price and Roberts, i b : f . , 68, in press (1946). , I A) Musajo aud Chiancone, Gum. chirn. ;tal., 67, 218 (1037).
July, 1946
SYNTHESIS OF
e ERTAIN 4-AMINOQUINOLINES
,3-amino derivative) but, on diazotization followed by treatment with methanol, the amino group was replaced by hydrogen rather than by methoxy even when the diazonium fluoborate salt was Although the Pfitzinger reaction with isatin anti ethoxyacetone has been reportedle we were unable to effect the corresponding reaction with isatin and methoxyacetaldoxime. Variations in the Side Chain.--Compounds \'I11 and IX were prepared and submitted for tcstirig. Compound x was presumably obt:iiried, but it could riot be isolated in the pure coiidition. Y
The diamine for compound VIII, 4-diethylamino-1-aminopentane, was prepared by the method of Kharasch and Fuchs.'' The method produces this diamine contaminated with 10% of the isomeric 1-diethylamino-4-aminopentane, the separation of which is troublesome. The mixture of isomers arises because the cyclic quaternary ammonium chloride, which reacts with potassium phthalimide, may cleave i n two ways.
+ CICHzCHzN(CzH6)z +
CHz=CHCHZMgCl
H CI CH,=CH (CH?i;
