May l9tiS
x,x
No.
1 2 3 4 5 6
H, H, H, H, H, H.
ti3 1
KOTEH
Ihlp,
oc
121-124 106-109 222-226 dec 244-246 208-210 110-112dec
C1 C1 C1 C1 C1 C1
Yield p urified,
70 65 48 53 88 19
%
Purifcn solvent
Formula
EtOH-HZO EtOH-H,O i-PrOH NeOH AIeOH-Et20 i-PrOH-EtzO
Ci3HaClXsO C13H7C12S3 Ci,H?oCINj.2HC1 CigHzoClN,. 2HC1 CiQH22ClN5.2HCl C2uH&1K,~2HC1
InalysesQ
H, 9; Ca C, H, S C, H, r\' C, H, X C, H, K C, H, S
C,lHz4C1NL.2HC1~0. 9H.0 C, H, S , C1, HZO Ci3H7C1PK3Ob c, €1, h' 8 Cl, C1 OH 2 17-219 .io MeOH CigHziC12N5.HCI C, H, K NH(CH,),N(C,€I,)z 258-2,59 dec 84 MeOH 9 C1, C1 KH(CHz)aN(CHz)4 233-235 dec 91 NeOH-Et,O 10 C1, C1 CaoHiiClzNa.2HC1 c, H, N Ci5Hi3S30 H, S ; CC 11 CHa, CH, OH 219-222 35 MeOH CI~HI~CIN, C, H, K 12 CH3, CH, C1 135-137 5.5 EtOH-H,O CzOH2bNb.2HC1.1 6THzO C, H, Tu', H,O 248-250 64 EtOH 13 CH3, CH3 NH(CHz)aS(CH3), CZ1H27Ke.ZHCl.O 33HgO C, H, N,HzO 236-238 63 i-PrOH 14 CH3. CH3 KH(CHz)zN(CzHS), a C: calcd, 60.5i; found, 59.72. The chloro compound from 8 was not obtained analytically pure. The crude material, mp 120130", wab used directly for the nest step. c C: calcd, 71.69; found, 71.19.
7 H,C1
151-153
27
0.1 mole of a substituted o-phenylenediamine in 350 ml of 35% H2SOh was stirred at 7,5' for 18 hr. The solid which formed on heating was removed by filtration and dissolved in H20. The solution was adjusted t'o pH 8 with NH40H and the solid which formed was removed by filtration, washed thoroughly wit,h H20, and recrystallized to yield the product. 6,743ubstituted 2-Chloro-3-(2-pyridyl)quinoxalines (IV) (Table I).-A slurry of 0.4 mole of a 6,7-subst'ituted 3-(2-pyridyl)2-quinoxalinol in 200 ml of PoC13 was heated under reflux for 7 hr. The resulting solution was cooled, poured slowly into 4 1. of iced HzO, and made basic with ",OH. The product was removed by filtration and recrystallized. 2-1 [(Dialkylamino)alkyI]amino 1-342-pyridyl)quinoxalines ( V ) (Table I).-A solution of 0.01 mole of a 6,7-substituted 2chloro-3-( 2-pyridy1)quinoxaline and 0.02 mole of diamine in 50 nil of Et20 and 15 ml of C,H, was held at' 5' for 24-48 hr. The solid amine hydrochloride which formed was removed by filtration. The ether solution was washed successively with HZO, dilute NaOH, and HzO, and then dried over NazS04. To this solution was added i-PrOH saturated with gaseous HCl to give the hydrochloride salt of t'he product which was removed by filt,ration and recrystallized.
Acknowledgments.-The authors are indebted to Dr. Leo IZane of t'he University of Niami and to Dr. Paul E. Thompson and Dr. AI. W. Fisher of Parke, Davis and Company for the biological testing. We also wish t'o thank A h . C. E. Childs and associates for the microanalyses and Dr. J. 31. Vandenbelt and coworkers for deterniinatiori of the spectral data reported herein. Antimalarial Agents.
I.
Reduction of Sydnone Derivatives IYINC. POPOFF AKD GOPAL H. SIXGHAL Pennsalt Chemicals Corporation, Kzng of Prussaa, Penns?/lvanza 19406 Rrwii
rjrl
Octolw 19, 196'7
3-1 p - [(4-Aminophenyl)sulfonyl]phenyl} sydnone (la) and other amino-substituted sydnories related to the
i-PrOW-Et,O
antimalarial drug bis(p-aminophenyl) sulfone (DDS) are of interest to us in our program on antimalarial agents because of their structural relationship to DDS and 3-piperonylsydnone. The latter compound was active against Plasmodium beryhei in the m0use.l The logical way to prepare I a seemed to be the reduction of 3- { p - [ (4-nitrophenyl)sulfonyl]phenyl]sydnone (Ib),
la, IZ = NHZ
b, R = SO2 C, R = Ac?rTH d, R = C1
Ha, It b. R
= =
NOZ; It1 = H SHo: R' = H
e, R = K' = H f. R = HOKH' I?' = H
which we had synthesized in an eight-step reaction sequence. Another approach would be the hydrolysis of 3-( p - [(4-acetamidophenyl)sulfonyl]phenyl}sydnone (IC)or the replacement of C1 with NH, in 3-{p-[(4chlorophenyl)sulfonyl]phenyl ] sydnone (Id). However the sydnone ring of ICand I d should be opened under the hydrolytic conditions or the amination reaction conditions. Thus the reduction of the nitrosydnone I b was chosen for the preparation of the aminosydnone Ia. The more readily available 3-(p-nitropheny1)sydnone (IIa) appeared to be a good model for this reduction study before we initiated any work with the nitro compound Ib. A search of the literature revealed that although 3-(pnitropheny1)sydnone (IIa) is known, 3-(p-aminopheny1)sydnorie (IIb) has not been described. Similarly, 3-(p-nitrophenyl)-l-methylsydnone (IIc) is known, but 3-(p-aminophenyl)-4-methylsydnone(IId) is unknown. (1) \II
