January 1968
KOTES
different alkylamino side chains to the same ring systems may not be practical. Proper modification of the ring iiucleus, on the other hand, might provide valuable antimalarial agents with less probability of cross resistance. The cinnoline analogs of chloroquine3 and quinine4 xvere studied in 1946. Alagidson,b Endicott,6 Price,7 and Curdq8and their eo-workers have synthesized a number of 4-dialkylaminoalkylamino derivatives in the quinazoline series. The corresponding phthalazine analog of chloroquine was prepared by Drake and P e c k g Certain 1,5- and 1,S-naphthyridine derivatives with a 4-diethylamino-1-methylbutylamino moiety n ere reported by hdams, et al.,1° and by Goldberg, et al." 2-Butoxy-8-(4- diethylamino -l-methylbutylamino)-l15naphthyridine was found to be more active than quinacrine against Plasiriodiuiii gallinaceuiii in chicks, and equiactive against Plasmodium berghei in mice." In the quinacrine series, the isoalloxazine12 and the phenazine13 analogs have been synthesized. Many of these analogs have shovn antimalarial activity.14 I n particular, 2-methoxy-G-chloro-9-(4diet hylitmino -1-methylbutylamino) -1,lO- diazaant h r acene (Azacrin) is highly active against P . gallinaceuiii in chicks, P . berghei in mice, and Plasmodium vivax and Plasniodiuni f a k i p a r u m in man.15 Since a chlorine atom attached to a phenyl ring is known for its electron-withdrawing effect, introduction of a nitrogen in the ring in place of the C-C1 linkage in the chloroquine and quinacrine structure would also be expected t o produce systems having a similar inductive effect. The same type of activity would probably be retained in these aza analogs. The synthesis of some 4-(substituted amino)-l,7-naphthyridines(Ia-c) and lo-(substitut ed amino) -2,9-diazaanthracenes (IIa, b) has therefore been studied in our laboratory.
4-Chloro-l17-naphthyridine(Ie) , the key intermediate for the synthesis of Ia-c, was prepared via I d according to the method of Murray and Hauser16 and others,l7,18T\ ith the exception that the starting material, 3-aminopyridine 1-oxide, was obtained by a different method. I n the present work, the peracetic acid oxidation of 3-acetamidopyridine followed by hydroly ~ i s ' g -was ~ ~ found to be more efficient than the method involving the hydrogen peroxide oxidation and amination of 3-bromopyridine. For the preparation of the chloroquine analog Ia, 1-diethylamino-4-aminopentanewas condensed with Ie at elevated temperature. The solid product was obtained by distillation of the crude syrupy residue through a short-path column under reduced pressure followed by induced crystallization. X related compound, 4-(3-diethylaminopropylamino)-l,T-naphthyridine(Ib) , was prepared in a similar fashion. Although this compound was smoothly distilled and correctly analyzed, it remained as a viscous oil even after long standing and many crystallization efforts. On the other hand, the corresponding amodiaquine analog ICwas readily obtained as a crystalline product by the treatment of compound Ie it h 3- (diethylaminomet hyl) -4-hydroxyaniline. Bachman and Barkerzz reported failure in preparing G-methoxy-lO-chloro-2,9-diazaanthracene (IId) by the attempted chlorination-cyclization reaction of 3-(panisidino) isonicotinic acid with phosphorus oxychloride. When 3-(p-anisidino)isonicotinic acid was heated in polyphosphoric acid in the presence of a small amount of phosphorus oxychloride, according to the reaction conditions for the synthesis of a similar compound,zJ cyclization was readily achieved to yield G-methoxy-10hydroxy-2,9-diazaarithracene (IIc or 6-methoxypyrido[3,4-b]quinolin-5(1OH)-one). Chlorination of IIc with phosphorus oxychloride gave compound IId in good yield. Heating a mixture of 3-diethylaminomethyl-4-hydroxyaniline and I I d readily yielded 6-methoxy-10(3-diethylaminomethyl-4-hydroxyanilino) - 2,g-diazaanthracene (IIb) as an orange-red crystalline compound. An analogous preparation of the corresponding quinacrine analog I I a failed to yield x solid derivative. Attempted distillation of the crude reaction product, as for the purification of Ia, gave a ;\.ellow solid. Elemental analysis and nmr study revealed that the compound was G-methoxy-2,9-diazaanthracene (IIe). The same product mas obtained when the crude reaction product was first heated at a relativelj high temperature in vacuo (for the removal of solvent) nnd purified by silica gel chromatography. Albert?4reported that acridine could readily be obtained from 9-chloroacridine through treatment of the latter with a substituted sulfonylh;\.drazide or h;\.drazine. Studies of the mechanism of this reaction and its possible relatioiiship to that of Albert's vi11 be conducted in the future.
d, It e, R
= =
OH C1
d, R = C1 e , R = H
(8) (a) N. J. Leonard and S. N. Doyd, Jr., J . Ory. Chem., 11, 419 (1946); (h) J. R. lieneford and J. C. E. Simpson, J . Chem. Soc., 917 (1947). (4) T. L. Jacobs, S. W k s t e i n , R. D. Henderson, and E. C . Spaeth, J. A m . Chem. SOC..68, 1810 (1946). ( 5 ) 0. Y. hlagidson a n d E. S. Golovchinskaya, J . Gen. Chem. U S S R , 8, 1797 (1938). (6) (a) 11. !VI. Endicott, E. Wick, hI. L. Lfercury, a n d M. L. Sherrill, J . Am. Chem. Sac., 68, 1299 (1946); (b) AI. E. Smith, E. Elisberg, and hl. L. Sillerrill, ibid., 68, 1301 (1946); (c! AI. 31. Endicott, U . \IAlden, -. and 11. L. Slierrill, tbid., 68, 1303 (1946). ( i )C . C. Price, N. J. Leonard, and L). T. Curtin, ibid., 68, 1305 (1946). (81 F. H. S. Curd, J. Ii. Landquist, and F. L. Rose, J . Chem. S O C . ,l i 5 9 (1948). (9) N. L. Drake and R. hl. Peck, J . Am. Chem. Soc., 68, 1313 (1946). (10) J. T. Adams, C . Pi. Bradsiier, D. S. Rresloa, R. T. Amore, and C. R. Hauser, ibid., 68, 1317 (1946). (11) A . A . Goldberg, R. 9. Theobald, and K . Williamson, J . Chem. Soc., 2387 (1954). (12) h l . hf. Neeman. ;Lid.,811 (lY46). (13) K . G. Jones and H. A. Siionle. J. Am. Chem. Soc., 68, 22-16 (1946). (14) F. T.Wiselogle, "A Survey of Antimalarial Drugs 1941-1945, ' J . W. Edwards. .inn Arbor, Mioh,, 1946. (1.5) D. h l . Desly a n d A . A . Goldberg, J . Cirem. Soc.. 2448 (1954).
1GZ
(16) J. G. 3Iurray and C. R. Hauser, J . 01.8.Chem.. 19, 2008 (1954). ( 1 2 0. Sds and K. hloller, A n n . , 599, 233 (1956). (1s) A. .4lbert, J . Chem. Soc., 1790 (1960). (19) H . H. Jaffe and G. 0. Doak, J . A m . Chem. Soc., 1 7 , 4-1-11 (1955). (20) F. Leonard and A. Wajngurt, J. Org. Chem., 21, 1077 (1956). (21) IY. Hera and D. R.I
