Antimalarials. 8-Chloro-2-(2'-N,~~--dibu tylaniino- 1'-hpdroxye thyl) benzo[h ] 1,6-11apht h y rid ine"'
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8-Chloro-i-["'-.\.,-~-dib~itylamino-l'-hydrosyethyl )benzo[ h ]- I ,6-naphthyridiiie (17) w:ia >yilthe,.ized f r o m 4-amino-i-chloroquinoline. While a number of electrophiles failed to react with the weakly iiucleophilic 4-amino function of the 4-aminoyuinoline, utilization of diethyl ethosymethylenemalonate, a relatively strong electrophile, provided a route to the tricyclic heteroaroniatic. c o m p a n d . Whereas eight of its intermediate.. lacked antimalarial wtivity, 8-(~hloro-4-(2'-S,S-dibiitylaniiiio-l'-hydro~yeth~l)ben~n[h]-l,6-iiaphthyridiiie wii. active against PIasrriodiuin bcrghei in mice. This coniporind, however, possessed only slight a(-tiviry agai1i.t 1'. gallinactuiii in chicks arid waa ineffective sg.ainst this organism in niosclriitoe-.
Initially, it ma- our de.ire to prepare :!-nieth> 14 - i S , N - dialkylaminomethyl) benzo [ h ] - 1.6-1i:iphthj 1'1(lines The nucleu- and general Yubstitution patterii ot thi. molecule are derived by the "paper cyclization'' ot the chloroquiIie (I) 4de chain (a. indicated hy t h r :crron.), along with xromatization of t8heformed thirci nllg
CH I
I
I1
C ciii,ideratiori of the antimalarial activitj found 111 thci 4-quinolinemethariol serieq a? ne11 :la in that ut thc Iihenttrithrenemethanols? led to the refinement of I cylacing the iornied dialkj laminomethyl group h\ :I 2 '-dialkylainino-l '-hydrox;-eth> 1 species at thc 4 110.it i o i i of the herizo [h]-I,B-naphth~~idine (11). SJ iithesis of tlie candidate nntimalaristl recluiretl thc ~ ~ ~ c v of n ca eusable functional group at the 4-poaitiori o t tlir tricyclic heteroaromatic nucleus. Since '1 benzo[ i , 1-1,(i-rinphtl~j.ridin---ol (9) pos5eYsd :I requiyite fiiiirtion:dit\r, we bought n reaction which n-ould proviclc t h i - t > p e intermediate in high J ielda T h e :tcidC , I t a l ) zed Conrad-Limpach reaction between 4-:iminoc jrurioline arid acetoacetic e-ter h a been reported to 411 e high j ield, of 2-methylbenzo [h]-1.G-iiaphthyridin4-ol -Ippljing this p r o c e d ~ r e ,n~e were uiisble to i-ohte the desired benzo [II ]-1,6-1iaphtliyridiii---olsor t h ~ po,-ible r quinolylcrotonate intermediate- from the i I (a) 'rll~,n-ork described i n this palier u a s uerforined under C o n t r a c t S , , 1).\1~.\1~.6i-C-7060 with the U. S. Army Medical Research a n d De\ + Io) n i r n t C'ommand. This is Contriliution S o . 665 from t h e .\rmy Ke- r u r c h P r o p a i n on malaria. 11,) To n.liom inquiries should be addressed. , ? ) 1:. \-, \Viseloule. Ed. "h Sur\-ey of .\ntimalarial D r u m , 1941-1945,'' I \ V E:d\\ards, .Inn .irlior, >Iich., 1446. ii G. R . C-oatney. "Survey of .intimalarial Agents," I'iil~lic Heal111
l l u n o p r a p h S o . 9, Federal Security Agency, 1952. K. klaririer and G . .\. R ~ ~ n u i .I.d ~Org. , Cheni.. 15, 1224 (14.50)
BENZO [h]-lj6-NAPHTHYR1DINE L4NT131ALSRIALS
RIarch 1970
23 1
TABLE I 8-CHLOROBENZO [ h]-1,6-iXAPHTHYRIDINES
-
Y COzCzHj C02H
R
K O
OH OH OH Br
8 9 10
H H
CN
11 12 1:3
H H H H H
COzH COCl C'OCHK2 COCHLBr 0
14 1.i
Mp,
oc
307-308* d
f 155-1 57 258-259 324b 182-1 87 h 15qb
70 Crystln solvent
Yield
DMF
Analysesn
C, H, C1, S C, H, C1, IS C, H, C1, Iy
93 88e 81' 749
DhIF DAIF-EtOH Petr ether-601-10 EtOAc D1LIF-EtOH
C, H, Br, C1, N C, H, C1, IS C, H, C1, N
789
679 96e
73 e
Cyclohexane
C, H, Br, C1,
K
/\
H 186-188b EtOAc 978 16 CH-CH? 17 C'HOHCHIS(CIH~)Z H 90-91 MeOH-HzO 67' CnHiBClNaO C, H, C1, N a byhere anal>,ey are indicated only by symbols of the elements, analytical results obtained for those elements were within 10.4% of the theoretical value for Organic Synthesis," J o h n \Gley & SJns. Inc., Ken. l-ork. S . 1.. 1967, p 1188. Use of impure SOCI? gives excessive salt formation ivliich interferes with t h e following CHzX? reaction. (19) J . DeRoer a n d H . J. Backer, "Organic Syntheses," Coll. Vol. I\-. Jo!in \\'iley k Sons, Inc.. S e w T o r k , S . T. 1963, p 280. (20) K . Nakanishi, "Infrared .iLsorption Spectroscopy," Holden D a y , San Francisco, Calif., 1962.
233
of t,he bromomet,hyl ketone was filtered and dissolved in 400 nil of D M F to give a dark brown solution. The crude bromomet,hyl ketone (free base) was precipitated by the addit,ioii of 300 ml of cold HzO to the cooled DRIF solution. The solid was filtered, washed thoroughly with 200 ml of HzO, dried in uucuo over HZSO,, and washed with 60 ml of anhydrous Et20 to yield 3.5 g (61%) of 15, mp 151' dec. The analyt,ical sample (cyclohexane) melted at 154' dec; ir 1692 (C=O); nmr 6 4.60 (s, 2, COCHZBr), 9.48 (d, 1, J = 0.08, aromatic Hz), 7.95 (d, 1, J = 0.08, aromatic Ha), 9.92 (s, 1, aromatic H6), 9.27 (d of d, 1, J = 0.15, 0.01 aromatic Hlo),7.88 (d of d, 1, J = 0.15, 0.04, aromatic H B ) ,8.38 (d, 1, J = 0.04, aromatic H,). 4-(8-Chlorobenzo [ h ]-1,6-naphthyridyl)ethyleneOxide (16).A mixture of 3.3 g (0.01 mol) of 15, 50 ml of anhydrous i-PrOH, and 2.0 g of freshly distilled Al(O-i-Pr)s wa5 heated by an oil bath while effect,ing partial take-off of the distillat,e a t a rate of 20 ml/hr. (The distillate, 43 ml total, was tested with 2,4-DNP t.s. for the presence of Me2C0 which was negative after 2.25 hr.) Anhydroiis i-PrOH was added to t.he react,ioii flask as needed during the distillation. The dark brown react,ioii mixture was concentrated by evaporation with dry -Ut. When the mixture became thick, the flask was immersed in an ice bath and 25 ml of H?O was added. The chunks of solid were broken and stirred into the tan mixture. A cold aqueous solution of 15 g KaOH in 25 ml of H20was added and the mixture was stirred for 20 min with cooling and 10 mi11 at room temperature. The tan solid was collect,ed by filtration, washed thoroughly with 100 ml of H20, filtered, and dried in vacuo (10 Torr) over H?SO, to yield 2.5 g (97%) of the epoxide 16: immediate charring melt at, 194'; ir almost complete loss of 1629 cm-l signal (C=O); nmr 6 4.76 0 / \
(d of d, 1, J = 0.07, 0.04 CH-?Hz), 0 Hh
/ \/
0.04, CH-C),
\
2.92 (d of d, 1, J
3.49 (d of d, 1, J
=
0.1,
0 Hb / \/
=
0.1, 0.07, CH-C
),
\
Ha H a 9.18 (d, 1, J = 0.08, aromatic Hz), 7.58 (d, 1, J = 0.08, aromatic Ha), 9.72 (s, 1, aromatic H5), 9.15 (d of d, 1, J = 0.14, 0.01, aromatic Hlo), 7.72 (d of d, 1, J = 0.14, 0.04, aromatic HB), 8.22 (d, 1, J = 0.04, aromatic H,). 8-Chloro-4-( 2'-N,N-dibutylamino-l '-hydroxyethy1)benzo[ h ] l,6-naphthyridine 117).-A mixture of 2.4 g of crude 16, 7.2 g of dry Bu2SH, and 3 ml of DMF was stirred and heated by a 100125' oil bath for 3 hr. The dark browri solution was diluted with 50 ml of H 2 0and extracted with five 75-ml portions of EtzO. The combined EtzO extract was washed with two 100-ml portions of HzO and dried (X&S04), and the solvent was removed under reduced pressure. The dark brown residue solidified upon standing in vucuo over H2S04(2.6 g) and was recrystallized from MeOHH2O using decolorized charcoal, yielding 1 g of off-white solid, mp 90-91'; ir 3390 (OH), 2940 (CH), 725 em-' [(CHz),]; nmr 6 5.66 (broad, d of d, 1, J = 0.17, 0.07, CHOH), 4.5 (broad, s, OH), 2.67 (NCHQ),1.43 (CCHz), 0.93 (CCH,), 9.31 (d, 1, J 0.08, aromatic H2), 8.07 (d of d, 1, J = 0.08, 0.01, aromatic Hs), 9.74 (s, 1, aromatic HS),9.20 (d of d, 1, J = 0.15, 0.01, aromatic H,O),7.82 (d of d, 1, J = 0.15, 0.04, aromatic H B ) )8.22 (d, 1, J = 0.04, aromatic H,).
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