Aug., 1946 [COIITRIBUTION FROM
SYNTHESIS OF SUBSTITUTED AMINOBENZACRIDINES THE
I599
PURDUE RESEARCH FOUNDATION AND THE DEPARTMENT OF CHEMISTRY, PURDUE UNIVERSITY ]
Synthesis of Substituted Aminobenzacridines1B2 BRYANT BACHMAN AND GEORGE M.
B Y G.
PICHA3
Acridine derivatives have long been knoR n to have marked therapeutic effects, and many of those derivatives which have a dialkylaniinoalkylamino group in the 9-position are particularly effective in the treatment of malaria. As very few benzacridine derivatives of this type have been reported in the chemical literature, i t was decided t o prepare a number of dialkylaminoalkylaniinobenzacridines, differing both in the nature of the side-chain and in the nature of the substituents on the nucleus, and to submit these for pharmacological testing. Although one synthesis of a benz [alacridine was carried out, this investig‘1t’ion was largely confined to the preparation of various derivatives of benz [clacridine. I n general, substitutions of a methoxyl group and a chlorine atom on an acridine nucleus are factors which may contribute to increased antimalarial actj vity. The particular derivatives selected for preparation in this work were chosen in such a manner as to determine the influence on antimalarial activity caused by altering the position of the methoxyl group in a benzacridine nucleus. -4 further contribution to this problem has been reported by Bachman and W e t ~ e l . ~ The synthesis of a typical derivative, 7-(3’diethylaminopropylamino)-2-methoxybenz [c]acridine dihydrochloride (111), was carried out in the manner illustrated.
amine gave N- (7’-methoxy- 1’-naphthyl) -anthranilic acid (I), which was converted into 7-chloro2-methoxybenz [clacridine (11) by treatment with phosphorus oxychloride. Condensation of I1 with 3-diethylaminopropylamine in phenol solution gave 111, which was purified and characterized as the dihydrochloride. Other derivatives were prepared by carrying out the initial condensations with other benzoic acid derivatives and naphthylamines, and, in one case, by using 2-hydroxy-3-diethylaminopropylamine in the side-chain condensation. A chlorine atom was introduced into two of the final products by using the potassium salt of 2,4-dichlorobenzoic acid as a starting material. The other benzoic acid derivatives used in this work were 5-methoxyanthranilic acid, 2-chloro-5-methoxybenzoic acid, and 2-bromo-5-methoxybenzoic acid. The synthesis of 5-methoxyanthranilic acid was accomplished by oxidizing 5-methoxyisatin with hydrogen peroxide. The statement of Halberkann5 that 5-methoxyisatin cannot be obtained from 4methoxyisonitrosoacetanilide is incorrect ; this series of reactions was successfully carried out and was found to be a very satisfactory method for obtaining 5-methoxyanthranilic acid. The other benzoic acid derivatives were prepared by familiar reactions. The amines used in this work were l-naphthylamine, 2-naphthylamine] 5-methoxy-1-naphthylOCHi OCHa I I amine, 6-methoxy-1-naphthylamineand 7-niethoxy-1-naphthylamine. The methoxynaphthylamines were all prepared by well-known procedures from the corresponding hydroxynaphthylamines. The experimental data for the N-( 1’-naphthyl)anthranilic acids, 7-chlorobenz [c]acridines, and 7- (3’-diethylaminopropylamino) -benz [clacridines c1 which were prepared are given in Tables I, I1 and I I1 111. Pharmacological Tests.-None of the substituted aminobenzacridines was found to be effective against duck malaria in low or moderate, doses. The details of these tests will be described elsewhere. Acknowledgments.-We wish to express our gratitude for financial support of this investigation by Eli Lilly and Company of Indianapolis I11 and the Purdue Research Foundation, and to Condensation of the potassium salt of o- acknowledge a gift of certain chemicals by the chlorobenzoic acid with 7-methoxy-1-naphthyl- National Aniline Division of the Allied Chemical and Dye Corporation. (1) Read before the Symposium on Antimalarial Agents a t the I
Atlantic City Meeting of the American Chemical Society, April, 1946. (2) From the P h D. thesis of G. M. Picha, Purdue University, February, 1946. (3) Present address: G. D. Searle and Company, Chicago, 11linois. (4) Bachman and Wetzel, J . Org. Chem., in print.
Experimental All melting points and boiling points are corrected. Except where otherwise indicated, the analyses were done by ( 5 ) Halherkann, Ber , 54, 3079-3000 (1921).
G. BRYANT BACHMAN AND GEORGE M. PICHA
1600
Vol. 68
TABLE I 5'
Yield, Derivative
%
M. p., OC.
Formula
Calcd.
Analyses, % ' Carbon Hydrogen Found Calcd. Found
Unsulistituted" 25 207-208 CI7H130ZN 29 236-237.5 CnHizOzNCl 68.57 68.50 68.64 4.06 4.10 4.15 4-Cliloro 73.64 73.57 5.16 5.20 5.26 5-Methosy C'1&1603N 73.70 24' 1&4-185.5 73.66 73.61 5.16 5.01 4.97 Ci~Hi503N 73.70 A '-Met hoxy 38 203-205 l-Chloro-5'-nirthoxy 65.99 66.06 4.31 4.22 4.30 C&,,O3NC1 65.96 18 242-243 73.67 73.55 5.16 5 . 2 6 5.21 ClalbOaN 73.70 (i '-hlethoxj 15 209-210 73.57 73.63 5.16 5.20 5.26 7'-hlcthoxy CiaHid&N 73.70 28 234-236 Reported by Ullmann, Aniz., 355,347-352 (1907), in.p. 208'. The yield is that obtained from 2-bromo-5-methoxybenzoic acid. h yield of only 12y0 was obtained froin the corresponding chloro acid. 0
TABLE I1 2
C1 7
Derivative
Yield,
%
M. p., OC.
Uiisubstitui ed 87 144-145 94 152-153 2-Methoxy 91 171-172 3-Slcthoxy 4-Mcthoxy 53 196-197 50 236 5 2 3 7 4-Methoxy-IO-chloro 9-Methoxy 69 200-201 10-Chloro 79 201-202 a\iialytical i:imple lost; no more available.
Formula
CirH~oNCl Cl~H1201\;Cl C,sH,ZONCl CisH1zONCl CisHI1ONC12 Cl~HlzONC1 CiHsNClz
Calcd.
77 73 73 73 65 73 68
Analyses, % Carbon Hydrogen Found Calcd. Found
42 59 59 59 87 50 48
76 73 '73 73 65
90 64 59 65 86
76 73 73 73 65
94 53 51 53 92
a
68 63 68 52
3 82 4 14 4 14 4 14 3 38 4 14 3 04
3 4 4 4 3
89 16 OB I9 46
3 85 4 11 3 99 4 09 3 50
3 01 3 Ofi
TABLE I11
DERIVATIVES OF 7- (3'-DIETHYLAMINOPROPYLAMINO)-BENZ~C]ACRIDINElo&x\fi DIHYDROCHLORIDE
7
Derivative
Yield,
%
hld p.,"
C.
Formula
Calcd.
-2HC1
Analyses, %--Carbon Hydrogen Found Calcd. Found
-
6.79 6.92 F6.75 66.87 6.79 Unsubstitutedh C2&"sNaClz 66 97 56 228-230 6.79 6.82 6.93 Cz~H310~aC12 65 21 2-Methoxycvf 65.00 65.20 48 190-192 6.89 6.92 CzsHnOX3Clz 65.21 65.06 65.15 6.79 3-Methoxyd 55 242-244 6.78 6.86 4-Methoxydg' CzsH3iONaClz 65.21 65.03 65.30 6.79 64 260-262 6.62 6.64 62.84 62.92 6.56 CZ~HBIOZN&!IZ 63.02 4-Methoxy-2'-hydroxy6 48 224-226 6.20 6.19 60.67 60.86 60.73 6.11 C25HsoONsC13 4-Methoxy-10-chlorob*.d'f 53 224-226 6.35 6.25 6.45 10 - Chloro".I 69 253-255 G~H~28NsC4.1.5H~0 58.60 58.47 58.49 Recrystallized from ethanol. 0 Recrystallized from methanola ,411 rnrltirig points are those of anhydrous samples. Recrystallized from ethanol-isopropyl ether. ' The free bise is only moderately soluble in ether isopropyl ether. Analysis by P. I). Somers, Purdue University.
Aug., 1946 the Huffman Colorado.
SYNTHESIS OF SUBSTITUTED AMINOBBNZACRlbINES
Microanalytical
Laboratories,
Denver,
1601
sium salt of o-chlorobenzoic acid, 20 g. of potassium car-
bonate, 120 cc. of amyl alcohol and 1 g. of copper powder was heated at 125' for eight hours. The reaction mixture 1-naphthylamines8 were prepared by the method of Lockett was poured into potassium hydroxide solution, and the and Short from the corresponding hydroxy-l-naphthyl- amyl alcohol was removed by distillation with steam. The amines. They were purified readily by vacuum distilla- residual solution was filtered, and the filtrate was added tion: 5-methoxy-l-naphthylarnine, b. p. 143-145' (5 slowly to dilute hydrochloric acid t o precipitate the prodmm.) ; 6-methoxy-1-naphthylamine,b. p. 178-180° (6 uct. After one or more reprecipitations from basic solumm.) ; 7-methoxy-l-naphthylamine,b. p. 151-153 '' (5 tion, the product was recrystallized from ethanol, acetone mxn.). The last compound was carefully pyified for or a mixture of these solvents. analysis. It formed white crystals, m. p. 75-77 . Using 6-methoxy-1-naphthylamineand the potassium Ana1.Q Calcd. for CllHllON: C, 76.27; H , 6.40. salt of o-chlorobenzoic acid, it was necessary t o run the condensation for twelve hours a t 130' in order to obtain a Found: C, 76.5, 76.3; H, 6.8, 6.6. 5-Methoxyanthranilic Acid.-The procedure given in satisfactory yield. The condensation between 1-naphthylamine and 2"Organic for the preparation of isonitrosoacetanilide was employed for the preparation of its 4- chloro-5-methoxybenzoic acid (or the corresponding bromo inethoxy derivative, with the substitution of an equivalent acid) was carried out by heating a solution of the free acid amount of p-anisidirie for the aniline. The yields from a in 4-5 parts by weight of 1-naphthylamine, along with large number of runs averaged 85y0 of a tan, crystalline potassium carbonate and copper powder. This condensaproduct. Four recrystallizations from ethanol-water gave tion was run for two hours a t 180-185". N-(2'-Naphthyl) -anthranilic Acid.-This compound was Although reference large white plates, m. p. 181-182'. t o this compound has been made in the literature: no prepared in a nianner analogous t o the proccdure for the corresponding derivatives of 1-naphthylamine. The yield physical constant:; or analytical data are reported. 41%, m. p. 210-211"; reported by Ullmann,l4 m. p. Anal. Calcd. for CQH~OOZNZ: C, 55.66; H, 5.20. was 212". Found: C , 55.74, 55.83; H, 5.36, 5.48. 7-Chlorobenz[c]acridines(see Table 11) .-The prepara5-Methoxyisatin was prepared from 4-methoxyiso- tion of 7-chloro-2-methoxybenz[c]acridine is typical for nitrosoacetanilide by a procedure analogous to that given in all members of this series, with the exceptions noted below "Organic Syntheses"'O for the preparation of isatin. 'The and in Table 11. Eighteen grams of N-(7'-methoxy-l'average yield of 5-methoxyisatin (m. p. 185-190') was naphthyl)-anthranilic acid was suspended in 135 g. of re46%. A recryststllized sample (glacial acetic acid) was distilled phosphorus oxychloride, and the mixture was reobtained as lustrous, almost black needles, m. p. 200-201 '; fluxed for two hours, giving a dark, viscous solution. Most reported by Halberkann: who prepared it from 5-meth- of the excess phosphorus oxychloride was removed by disoxydioxindole, in. p. 201-202'. The identity of this com- tillation, and the residual solution was poured into a mixpound was confirmed by preparation of two of the deriva- ture of ammonia, ice, and sufficient chloroform (800 cc.) t o tives described by Halberkann, N-acetyl-5-methoxyisatin, dissolve the product after one hour of continual stirring. In. p. 143" (reported, m. p. 144-145"), and 9-methoxyindoThe chloroform solution was dried, filtered, and allowed t o phenazine, m. p. 231 (reported m. p. 247 "). evaporate; it deposited a yellow, crystalline product. One hundred grams of crude 5-methoxyisatin was dis- With some derivatives the product thus obtained was solved in one liter of 5% sodium hydroxide solution and satisfactory for use without purification. Samples of all oxidized by the dr'opwise addition of 150 cc. of 30% hydro- members of this series were recrystallized from dry bengen peroxide. The solution was made distinctly acidic zene, dry heptane, or a mixture of these solvents. with hydrochloric acid and filtered from an insoluble resiThose derivatives which had a methoxyl group in the 4due. The filtrate was evaporated t o dryness on a steam- position (to a limited extent in the %position also) were bath, and the dry residue was extracted with 600 cc. of hot always contaminated with darkly colored by-products, ethanol in three portions. When the extracts were cooled whose removal necessitated additional recrystallizationi. and diluted with ether, 56 g. (49%) of the hydrochloride Those derivatives which had a chlorine atom in the 10precipitated. I t mas converted to the free base (9495, m. position were relatively insoluble in chloroform, and it was p. 148-150") by treating it with the equivalent amount of necessary to remove part of the product by filtration. sodium hydroxide. Sublimation (15 mm.) gave long, IZ-Chlorobenz[a ]acridine.-This compound was prewhite needles, rn. p. 151". Reported by Pschorr,ll m . p. pared in a manner analogous t o the procedure for deriva150°, by Friedlaender,I2 m. p. 179-180". tives of benz[c]acridine. The yield was 87%, m. p. 1562-Chloro- and 2-Bromo-5-methoxybenzoic Acids.158". Recrystallization (benzene-heptane) to constant These acids were both prepared in about 80% yields by the melting point gave large, yellow crystals, m. p. 158". Sandmeyer reaction from 5-methoxyanthranilic acid. Anal. Calcd. for C17HloNCl: C, 77.42; I$, 3.82. The chloro acid was recrystallized from ethanol-water and then sublimoed. I t formed pale yellow needles, m. p. Found: C. 77.43. 77.43; H. 3.87.3.85. Derivatives of 7-(3'-Diethylaminopropy1amino)-benz[c1172.5-173.0 . Reported by Mazzara,13 who prepared it acridine Dihydrochloride (see Table 111) .-The preparaotherwise, m. p. 170-171 '. of 7-(3'-diethylaminopropylamino)-2-methoxyThe bromo acid was also prepared in 8270 yield by tion brominating rn-methoxybenzoic acid in hot water with the benz[c]acridiiie dihydrochloride is typical for ail members calculated amount of bromine introduced slowly below 1he of this series. A mixture of 10.6 g. of 7-chloro:2-methoxysurface of the liquid. Both methods gave whiteo crystals, benz[c]acridine, 5.17 g. (a 10% excess) of 3-diethylaminopropylamine, and 32 g. of anhydrous, redistilled phenol m. p. 160"; reported by Pschorr,I1 m. p. 161-162 . was heated at.110" for two and one-half hours, giving a N-(I '-Naphthyl)-anthranilic Acids (see Table I) -The preparation of X-(7'-methoxy-1'-naphthyl)-anthranilic dark red, very viscous solution. Precautions were taken acid is typical for all members of this series. A mixture to ensure that all reactants and the reaction vessel were of 40 g. of 7-methoxy-1-naphthylamine, 43 g. of the potas- free from traces of moisture. The reaction mixture was poured into a solution of 70 g. of potassium hydroxide in (6) Lockett and Short, J . Chem. Soc.. 788 (1939). 500 cc. of water, and the free base which separated was (7) Butenandt and Schramm, Ber., 68,2087 (1935). extracted with ether. The ether solution of the free base (8) Davis, Chem. F e w s , 74, 302 (1896). No physical constants was dried and filtered, and the filtrate was treated with nor analytical data are given. dry hydrogen chloride until precipitation of the gummy (9) Analysis by P. :D.Somers, Purdue University. (occasionally solid) dihydrochloride was complete. This (10) "Organic Syntheses," 6, 71-74 (1925). product was recrystallized two or more times from a suit(11) Pschorr, A n n . , 391, 23-29 (1912). able solvent (cf. Table 111) containing enough hydrogen
Methoxy-I-naphthylamines.-The 5-,6-7 and 7-methoxy-
(12) Friedlaender, i?er., 49, 963-964 (1916). (13) Mazzara, Gozz chim. dd.,29, I, 378-379 (1899).
(14) Ullmann. Ann., 356, 347-352 (1907)
1602
DRAKE,EAKER,GARMAN, HAMLIN, HAYES,HAYWOOD, PECK,PRESTON, STERLING vo1. 68
chloride to make the solution acidic to congo red paper. The yields were determined largely by the recovery which each recrystallization solvent permitted, as the condensation reaction itself was almost quantitative. One derivative was prepared by using 2-hydroxy-3diethylaminopropylamine as the side-chain. Whenever the dihydrochloride was obtained as a hydrate, a sample of the anhydrous form (very hygroscopic) was prepared for characterization by heating the hydrate a t 140°, or by recrystallizing it from an inert solvent containing thionyl chloride. 12-( 3 ’-Diethylaminopropylamino) -benz[alacridin e Dihydrochloride.-This compound was prepared in a manner analogous to the procedure used for the corresponding benz-
[CONTRIBUTION FROM
THE
[clacridine derivatives. The yield after two recrystallizations from propanol-dibutyl ether was 31y0 of very small, yellow needles, m. p. 250-252’ by the instantaneous method. Anal. Calcd. for C2dH29N3C12: C, 66.9i; H, 6.79. Found: C, 67.06, 67.15; H, 6.75, 6.82.
Summary A series of dialkylaminoalkylaniinobenzacridines has been prepared for testing as antimalarials. LAFAYETTE, INDIANA
RECEIVED h I A R C H 30, 1946
LABORATORIES OF THE UNIVERSITY OF MARYLAND]
Synthetic Antimalarials. The Preparation of Certain Derivatives of Sulfanilamide B Y NATHAN L. DR;\KE,CHARLES bf. EAKEII, JOHN A. GARMAN, KENNETH E. HAMLIN, JR., ROBERT A. HAYES,STUART T . HAYWOOD, RICHARD M. PECK, ROBERT K. PRESTON, JOHN STERLING, JR., JOHN 0 . VANHOOKAND EDWARD WALTON
Conflicting reports on the value of sulfanilamide in the treatment of malaria are to be found in the earlier literature; a review of some of these papers has been made by SintonJ2whose work indicated that sulfanilamide itself was of no value in human malaria, of little or no value in avian malaria, but did, however, have a definite effect upon P. KnowZesi in monkeys. Walker and Van Dyke3 have shown that sulfathiazole, sulfadiazine and sulfanilamide, in this order, are effective against P. bophurae in ducklings. Coggeshal14 and co-work.ers, employing sulfadiazine, showed it to be effective against all forms of human m:daria. When i t thus became apparent that the sulfa drugs were effective against malaria, and when it appeared6 that sulfadiazine was a causal prophylactic in avian malaria, investigations were undertaken with t:he object of finding a more active drug which might act as a causal prophylactic in. man. The present paper describes the preparation of twenty-two drugs which were synthesized for this purpose. Data concerning the activity of the compounds will be found elsewhere.‘j The sulfanilamide derivatives were prepared by coupling N-acetylsulfanilyl chloride with the appropriate .amine or amine salt, followed by hydrolysis, in some cases with acid and in others with base, t o remove the acetyl group. The amines in some instances are known compounds, and were (1) This work was carriqd nut under a contract recommended by the Committee o n Medical Research between t h e Office of Scientific Research and Development a n d the University of Maryland. ( 2 ) Sinton. Hiitton and Shute, A n x . Tvop. .\fed., 3 3 , 37-44 (1939). (3) Walker and Van Dyke. I’YOC. SOC.Ezptl. B i d . .\fed., 48, 368 (1941); C.A , , 36, ,367 (1942). (4) Coggeshall. ?*Iaier and Best, J . A m . .!fed. d s s o c . , 117, 1077 (1941). (5) “Antirnalarial Drugs, 1941-1945,” F. Y . Wiselogle, editor, Chapter V . in press. (6) “ kntirnalarial Drugs, 1941-1945,” published by the Survey of Antimalarial Drugs, in press. Drugs described herein are identified by the S N number used in this monograph.
prepared by methods reported in the literature or were obtained from stock. I n many instances the precursor of the desired amine was prepared by a known series of reactions, and this compound was converted to the desired amine by an appropriate method. I n a few cases neither the amine nor any of its immediate precursors are reported in the literature, and methods of synthesis were devised for these compounds. The coupling was carried out in pyridine solution a t temperatures varying from 60 to looo, and for times ranging from one to four hours in all cases except that of 3-chloro-4-dimethylaminosulfanilanilide (SN-5069). I n this instance 2-chloroT\J1,N1-dirnethyl-$-phenylenediaminein ether solution was stirred and refluxed with N-acetylsulfanilyl chloride in the presence of anhydrous sodium carbonate for one and one-half hours. Coupling in pyridine was not used in this case because all attempts to isolate the free amine resulted in extensive decomposition ; the reduction mixture from 2-chloro-4-nitro-N,N-dimethylaniline, therefore, was coupled directly with Nacetylsulfanilyl chloride as described above without isolating the 2-chloro-N1,N‘-dimethyl-$-phenylenediamine. X1- (2 - Hydroxy - 3 - camphanyl) - sulfanilamide was prepared by a Meerwein-Ponndorf reduction of a- (N-acetylsulfani1amido)-camphor,followed by acid hydrolysis. The a-(N-acetylsulfanilamido) -camphor was prepared in the usual manner by coupling a-aminocamphor with X-acetylsulfanilyl chloride in pyridine. p-,4minobenzenesulfinic acid was prepared by the standard method7i8 starting with N-acetylsulf anilyl chloride. ( 7 ) Smiles and Bere. “Organic Syntheses,” Coll. Vol. I , 2nd ed., John Wiley and Sons, Inc., New York, X. Y.,p. 7 . (8) Tensen a n d Linquist, Dansk. T i d s . Farm.. 14, 120 (1940): C. A , , 35, 3087 (1941).
