Antimalarials. 8-Chloro-2-(2'-N,~~--dibu tylaniino- 1'-hpdroxye thyl) benzo[ h ] - 1,6-11 aph thy rid ine"'

8-Chloro-i-["'-.\.,-~-dib~itylamino-l '-hydrosyethyl )benzo [ h ] - I ,6-naphthyridiiie (17) w:ia >yilt he,.ized f rom 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. compand . Whereas eight of its intermediate.. lacked anti- malarial 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> 1- 4 - 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 thr :crron.), along with xromatization of t8he formed 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.i-

t i o i i of the herizo [h]-I ,B-naphth~~idine (11). SJ iithesis of tlie candidate nntimalaristl recluiretl thc

~ ~ ~ c v n c e of a usable functional group at the 4-poaitiori ot 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 th i - t>pe intermediate in high J ielda The :tcid- C , I t a l ) zed Conrad-Limpach reaction between 4-:imino- c jrurioline arid acetoacetic e-ter h a been reported to 411 e high j ield, of 2-methylbenzo [h]-1 .G-iiaphthyridin- 4-ol -Ippljing this p r o c e d ~ r e , ~ n e were uiisble to i-ohte the desired benzo [ I I ]-1,6-1iaphtliyridiii---ols or t h ~ r po,-ible quinolylcrotonate intermediate- from the

i I (a) 'rll~, n-ork described in this palier uas uerforined under Contract S , , 1).\1~.\1~.6i-C-7060 with the U. S. Army Medical Research and De- \ + Io) nirnt C'ommand. This is Contriliution S o . 665 from the .\rmy Ke- -rurch P r o p a i n on malaria.

, ? ) 1:. \-, \Viseloule. Ed. "h Sur\-ey of .\ntimalarial Drum, 1941-1945,'' I \V E:d\\ards, .Inn .irlior, >Iich., 1446.

ii G. R. C-oatney. "Survey of .intimalarial Agents," I'iil~lic Heal111

11,) To n.liom inquiries should be addressed.

l lunopraph S o . 9, Federal Security Agency, 1952. K. klaririer and G. .\. R ~ ~ n u i d ~ , .I. Org . Cheni.. 15, 1224 (14.50)

RIarch 1970 BENZO [h]-lj6-NAPHTHYR1DINE L4NT131ALSRIALS 23 1

TABLE I 8-CHLOROBENZO [ h]-1,6-iXAPHTHYRIDINES

K O - 8 9

10 11 12 1 :3 14 1 .i

R OH OH OH Br C N COzH COCl C'OCHK2 COCHLBr

0

Y COzCzHj C02H H H H H H H H

Mp, oc 307-308*

d f

155-1 57 258-259 324b 182-1 87

h 15qb

70

DMF 9 3 DhIF 8 8 e DAIF-EtOH 81' Petr ether-601-10 749 EtOAc 789 D1LIF-EtOH 679

96e

Crystln solvent Yield

Cyclohexane 73 e

Analysesn

C, H, C1, S C, H, C1, IS C, H, C1, Iy C, H, Br, C1, N C, H, C1, IS C, H, C1, N

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% c Yield of washed product based upon the amouilt of 4-amino-7-chloroquinoline.

9 Yield of recrystallized of the theoretical value<.

pr(diti.t

b Melt with decomposition. +ample charted at 310", no melt below 360". e Yield of washed product. f Charred at 360", no melt. - E u p h v e decomposition above 187'. * Yield of crude product based on the amount of biomomethyl ketone (15).

SCHEME I yH'

5 EMME H I

6

7

8 9

In contraat to the reduction of some quinolyl bromo- methyl ketones in which SaBH4 or Al(O-i-Pr)311 can be u-ed to reduce t3he ketone function, only lil(O-i-Pr)3 u a? of value mice SaBH4 gave concurrent partial reduction of the tricyclic, heteroaromatic ring system when used in an equimolar concentration at 5'. The crude bromohydrin product of the Meerwein-l'onn- dorf-Verleg reduction was treated with base to yield the oxirane (16) as given in Scheme 111. This in turn wab treated with ri-Bu,SH to prepare 17, the final product. It ha. been shown that this type of oxide is equivalent to the bromohydrin in the subsequent re- action with

(11) R. C. Elderfield. A I Israel, J H. Ross, and J. A . Waters, J. Ore.

(12) S TLinstein et al J . Amer . Chem. SOC., 68, 1831 (1946). Chem., 26, 2827 (1961).

SCHEME I1

10

&CN hydro1 ysls cl&C02H

00 00 c1

11 12

dCHLML 111

SOC12 CH?1Z'? HHr B-COzH -+ B-COCl-+ B-COCHN? +

12 13 14 0

1 .41(O-t-Prls / \ H N B U + B-CH-CHz -+ B-COCHzBr ___- 15 2. S a O H 16

B-CHOHCH~SBII~ 17

I3 = 4-(&chloiobeiizo [h]-1,6-1iaphthyridyl)

The pmr spectra for intermediates 6, 10, 11, 14, 15. and 16 were consistent with the assigned structures and with the expected changes within the series of spectra which includes the starting material and final product. Compounds 7, 8, 9, 12. arid 13 were not sufficiently soluble in pmr solvents to permit recording of their spectra. Thus, the pmr qpectrum of the ring closure product of the acrylate, 6, bhowed the loss of the 3- quinoline proton with concurrent collapse of the number 2 proton doublet to a singlet. Analysis of the pmr spectra not only allowed for assignment of all signals in the pmr spectra but also yielded the coupling con- stants. The doublet of the aromatic number 3 proton of the oxirane, 16, showed an additional splitting of 0 . i Hz which is attributed to long-range coupling with the ethylene oxide methine proton. The methine signals were broad but the corresponding 0.7-H~ splitting could

-\larch 1970 BENZO [h ] -1 ,6-S .~PHl~HYri IUISE ~ N T I l I I L A R I A L Y 233

solid which gradually diminished upon continued reflux. The cooled, oraiige, semisolid reactmion mixture was stirred vigorously while adding 600 ml of 10% aqueous NaCX. After an additional 200 ml of H20 was added, the mixture was stirred vigorously until creamy white. The white solid was filtered, washed thoroughly with 500 ml of HZO, and dried in uucuo (10 Torr) over H?SO,. One recrystallization of the product from EtOAc provided 10 g of cream colored crystalline solid, mp 255-258.,5'. Concentration of the recrystallization filtrate yielded an addi- tional 1.4 g of solid, mp 242-252' (78% t,ot,al yield). The white, fluffy crystals of the analytical sample melted a t 258-2.59'; ir and nmr as expected.

8-Chlorobenzo [h] -1,6-naphthyridine-4-carboxylic Acid ( 12).- Sitrile 11 (11.4 g) was hydrolyzed by a solut,ion containing 5.7 g of YaOH and 1.5 ml of DJISO in 100 ml of HzO. DRISO was reqiiired since the intermediate was not wetted by aqueous KaOH. Aft,er heat,iiig a t reflux for 4.5 hr (odor of NH3 no longer present), the cooled yellow soliit,ion was filtered through a medium porosity sintered fiinnel and dilut,ed wit,h 900 ml of H20. Acidification of the soliition with concentrated HCl (ca. 13 ml) t o pH 2 (pIIydrion paper) followed by filtration and drying of the precipitate yielded the criide acid which after re- crystallization from EtOH-IIMF (4: 1.25) afforded 8.3 g of solid, mp 317-;320" der. The analytical sample melted at 324" dec; ir as expect,ed.

8-Chlorobenzo [ h ] -1,6-naphthyridine-4-carboxoyl Chloride ( 13). --i mixtiire of 43 nil of freshly distilled SOC1218 and 43 g of the acid 12 war heated at refliix for 6 hr. Excess SOClz was removed by dist,illat,ion at rednced pressure and the residue was refluxed nit,h 50 ml of Skellysolve B. The acid chloride (13) was filtered under dry N? and dried over (10 Torr) to yield 4.5 g (96%) of yellow solid; mp 1%-188'; ir as expected.

4-( 8-Chlorobenzo [h] -1,6-naphthyridyl) Diazomethyl Ketone (14).-The washed acid chloride 13 (4.5 g, 0.017 mol) was slowly added to a cold (0 t,o loo), well-stirred, solution of CH2N2 in Et2019 containing 0.07 mol of CHzN2. The reaction mixture was protected from light since the diazomethyl ket,one was light sensitive. The mixture was stirred for 1 hr a t ice bath tempera- ture and then for 15 min at room temperature. The solid was collected by filtration and pressed dry. Insertion of a sample of this material into the melting point apparatus a t tempera- ture. above 187" produced an immediate explosive decomposi- tion: ir as expected (only a very weak signal was observed at 1739, indicative of a small amount of acid chloride20 contamination in the sample), nmr as expected.

4 4 8-Chlorobenzo [h] -1,6-naphthyridyl) Bromomethyl Ketone (15).--A solution contaiiiing 5.7 g of 487, HBr (0.035 mol) in 4 ml of ailhydrous Et.?O was added t,o a mixture of the crude 14 and 35 nil of CH2C1, over a 5-min period with stirring and then heated with a 70" water bath, refluxing for 1 hr. The HBr salt

(18) L. F. and .\I. Fieser. "Reagent> for Organic Synthesis," John \Gley & SJns. Inc. , Ken. l -ork. S. 1.. 1967, p 1188. Use of impure SOCI? gives excessive salt formation ivliich interferes with the following CHzX? reaction.

(19) J . DeRoer and 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 Day, San Francisco, Calif., 1962.

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 HB) , 8.38 (d, 1, J = 0.04, aromatic H,).

4-(8-Chlorobenzo [h] -1,6-naphthyridyl)ethylene Oxide (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 H20 was 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), 3.49 (d of d, 1, J = 0.1, 0 Hh 0 Hb / \/ / \/

0.04, CH-C), 2.92 (d of d, 1, J = 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 100- 125' oil bath for 3 hr. The dark browri solution was diluted with 50 ml of H 2 0 and 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 re- duced pressure. The dark brown residue solidified upon standing in vucuo over H2S04 (2.6 g) and was recrystallized from MeOH- H2O 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,

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 HB) ) 8.22 (d, 1, J = 0.04, aromatic H,).

OH), 2.67 (NCHQ), 1.43 (CCHz), 0.93 (CCH,), 9.31 (d, 1, J