4414
EDGAR A. STECK, JOHANNES S. BUCKAND LYNNT. FLETCHER
guanazole. The 2-methyl group obliterates not only the effects based upon tautomerism in the 1phenylguanazole but, presumably, also that of some of the ionic contributions. As a consequence, the original pattern is really lost, and a faint memory is apparent only a t the inflection points. The l-aryl-3,5-diimino-l,2,4-triazolidine structure ( k , I) for the 1-arylguanazoles has been preferred by Pelli~zari.’~This diimino formula does not readily explain the loss of only one nitrogen atom when 1-phenylguanazole is treated with causticr5and the behavior on acetylation.’j The formation of monohydrochlorides and picrate^'^,'^ by the 1-arylguanazoles may not necessarily be considered in this matter, for it is well known that the mutual proximity of potentially basic groups may prevent the full showing of the basic properties. As examples of this behavior, one may cite certain polynitrogen heterocycles which form only monosalts. l6--lS Mann and Watson1Y have discussed salt formation in polyamine types, and they comment, inter alia, “it is suggested that the positive pole created by the initial salt formation exerts a strong electronic attraction, and this attraction, relayed by the inductive or mesomeric effect, may virtually immobilize the lone pair of electrons on a neighboring nitrogen atom and so deactivate this atom.” Evidence here presented renders it desirable that the 1-substituted guana(14) G. Pellizzari, GQZZ.chim. hi., 21, 11, 14 (1891); 24, I, 481 (1894). (15) G. Pellizzari and C. Roncagliolo, ibid., 31, I, 477 (1901). (16) C.Stoehr, J . prokl. Chem. [21 61, 466,462 (1895). (17) 0 . Hinsberg, Ann., 237, 335 (1887); 292, 245 (1896). (18) S.Gabriel and J. Colman, Ber., 37, 3651 (1904). (19) F. G. Mann and J. Watson, J . Ovg. Chem.. 13, 502 (1948).
Vol. 79
TABLE I11 SPECTRAL CHARACTERISTICS O F SOME GUAXAZOLE DERIVATIVES -1Slaximaa; A in mv, e X 1030.01 N HCl 0.01 ,V NaOH Guanazole Ethanol A e x c derivatives x e
266 1 0 . 6 (238 4.0) 2-Methyl-1216 30.0 phenyl 245 7.0’ Values for minima giveti point. 1-Phenyl
250 8.4 254 8.9 (237 6 . 6 ) (232 5.1) 220 22.1h 224 1 9 . 7 (218 18.1) 260 6.1b in parentheses. Inflection
zoles should be considered to have the arninoimino structures indicated as I11 or IV rather than as diimino compounds as I. I t does not appear to be possible to exclude the possibility of structure V, use of which has been made in the formulation of the products obtained from 1-phenylguanazole and isothiocyanates.2Q Experimental 1-Arylguanazo1es.--All guanazoles were prepared as described in another publication.2 Absorption Spectra.-The spectrophotometric studies were all carried out xvith a Beckman quartz spectrophotometer, model DU, serial no. D-377. T h e method and solvents used have been described in other Contributions from these laboratories.6,6
Acknowledgments.-To Dr. E. J. Lawson we owe much for his helpful counsel and patience in discussions concerning the potential ionic configurations in 1-arylguanazoles. A considerable portion of the spectrophotometric studies have been due to the efforts of Mrs. M. Becker and Mr. M. Priznar. (20) E. Fromm and R. Kapeller-Adler, Ann., 467, 248, 207 (1928).
REXSSELAER, N. Y.
[COSTRIBUTION FROM THE STERLING--WINTHROP
RESEARCH INSTITUTE]
Some 9-Amino-3-nitroacridine Derivatives BY
EDGsR
A. STECK, JOHANNES
s. BUCK^ AND L Y X N T . FLETCHER
RECEIVED MARCH 9, 1957
A series of 9-amino-3-nitroacridine types bearing hydroxylated side-chains was prepared for investigation as potential chemotherapeutic agents. I n most cases, the 6,7-positions of the acridine nucleus were substituted, as b y dimethoxy, also were made. methylenedioxy and ethylenedioxy groups; two derivatives of 9-arnin0-7-butoxy-3-nitroacridine
I t appears that the investigation of 9-amino-3nitroacridine derivatives has been largely neglected because little antimalarial activity has been found in this type2; the most interesting property in the group lies in their activity against microorganisms, which is even exhibited by 9-amino-3-nitroacridine itself. 3-6a 9 - (3 - Diethylamino- 2 - hydroxypropylamino)-G,7-dimethoxy-3-nitroacridine (I),also known (1) Deceased. (2) H.Mauss, Medisin und Chemie, IV, GO (1942). (3) A. Albert, S. D. Rubbo, R. J. Goldacre, M. E. Davey and J. D. Stone, B7if. J. E x p f l . Pafhol., 26, 160 (1945). (4) A. Albert and R. J. Goldacre, J . Chem. Soc., 706 (1956). ( 5 ) J. E. Smadel, J. C. Snyder, E. €3. Jackson, P. J. Fox and H . L. Hamilton, J . Immunol., 67, 155 (1947). (6) (a) M. D. Eaton, A. van Allen and A. Wiener, Proc. Soc Erptl. Diol. M c d . , 66, 141 (1947); (b) M . D. Eaton, F. S. Cheever and C. G. Levenson, J. Immunol., 66, 464 (1951).
as Nitroakridine 3582 (Hoeschst) and 30433B for Entozon (Entozon is a mixture of I with 8,n-dianiino-2-ethoxyacridine,Rivanol, and urea), a n d its salts have been the most carefully studied of the 9-amino-3-nitroacridines.1-6-11 I t has been claimed that this compound, and certain salts and combinations containing it, possess activity against (7)C. S. Miller and C. A. Wagner, J. 0 7 8 . Chem., 13, 891 (1948). (8) British Intelligence Objectives Subcommittee (BIOS),Final Report 766, Items 22 and 24, London, England, 1946. Report by T. Dewing, W. J. C. Dyke, C. C . Green, Hindley, Hohlyn, G. E. H. Skrimshire and Wilkinson, p 11. (9) M. Bockmiihl and A . Fehrle. U. S. Patent 2,040,070;German Patent 608,668. (10) P. E.C. Goissedet and R. L. Depois, E. S. Patent 2,092,114. (11) K. Streitwolf and H. Oesterlin, German Patents, 613,349; 618,507.
Aug. 20, 1957
SOME 9-AACINO-3-NITRO.4CRIDINE
bacteriaJg-l2rickettsia,5.13-15 viruses,6s16-20trichomonadsz1 and b a b e ~ i i d a e . ~While certain antibiotics have ranges of activity which include those mentioned, this investigation was begun before such were well studied and was particularly concerned with those bearing an hydroxylated basic chain attached to position 9 of a 3-nitroacridine nucleus with a t least one alkoxy group in position 6 or 7 or with a methylenedioxy- or ethylenedioxy group bridging positions 6 and 7. HNCHzCH( OH)CHzN( CzH&
4415
DERIVATIVES
H IV
^.
VNR
v VI The synthesis of the 9-chloro-3-nitroacridines required for reaction with the various amines was hydroxyethyl) ethylenediamine (VIII). 9-Chloroaccomplished by the Ullmann reaction22 as modi- 6,7 - dimethoxy - 3 - nitroacridine was caused t o fied by L e S n i a f i ~ k i . ~I~n, ~this ~ procedure, the react with these amines (in the case of VII, comintermediate N-arylanthranilic acids (e.g., IV) pound I being produced) and also N-(2-hydroxyprepared from an aniline (11) and a 2-halobenzoic propyl)-ethylenediamine (IX), N-(2-hydroxy-2acid (e.g., 111) undergo cyclization to the 9-chloro- methylpropyl) -ethylenediamine (X), N- (2-hydroxyacridine (e.g., V) by the action of phosphorus oxy- ethyl)-lI3-propanediamine (XI), N-(Z-hydroxy-2chloride. I n the reactions of 2-chloro-4-nitro- methylpropyl)-1,3-propanediamine (XII) and N(XIII). The benzoic acid with 3,4-dimethoxyaniline, 3,4-methyl- (2-hydroxyethyl)-lJ7-heptanediamine enedioxyaniline and 3,4-ethylenedioxyaniline,meth- compounds produced by use of the amine VI1 anol or ethanol were satisfactory solvents, but were, ordinarily, the most difficult to purify. with 4-butoxyaniline it was necessary to use penta- Since the hydrochlorides of the 9-amino-3-nitrono1 (cf. refs. 25-27). The purified N-arylanthra- acridines (Table I) lost hydrogen chloride readily nilic acids were all cyclized without difficulty by use upon drying a t elevated temperatures, i t was advisable t o dry the products a t room temperature. of phosphorus oxychloride in toluene. The reaction of the 9-chloro-3-nitroacridines(V) Several of the compounds thus obtained were hywith aliphatic amino compounds bearing hydroxyl drated. It was of interest that, while several of the groups, in phenol as a solvent (cf. refs. 27, 28), was intermediates did not give concordant values for exothermic but readily controlled; this produced nitrogen by the Dumas method,29most of the final the type VI of which I is an example. 7-Butoxy- products offered little difficulty. 9-chloro-3-nitroacridine, 9-chloro-6,7-methylenedi- The testing of the compounds herein described oxy-3-nitroacridine and 9-chloro-6,7-ethylenedioxy- will be reported subsequently by other members of 3-nitroacridine were caused to react with 3-di- this Institute. ethylamino-2-hydroxypropylamine(VII) and N-(2Experimenta130 (12) 0. Eisleh. Medizin u. Chemie. 111, 41 (1936). (13) Office of Publication Board (O.P.B.), Dept. of Commerce, Washington, D. C., 1945. (a) V. Conquest, E. C. Kleiderer, J. B. Rice and J. H. Williams, Report 4, p. 15. (b) H. M. Horack, P. J. Leaper, J . E. Smadel, L. M. White and E. H. Volwiler, Report 241, p. 5. (c) E. C. Kleiderer, J. B. Rice, V. Conquest and J . H. Williams, Report 981, p. 19. (14) G. Holler, Med. Klinik, 40, 374 (1944). (15) J. E. Smadel, E . B. Jackson and R . L. Gauld, J . Immunol., 5 7 , 273 (1947). (16) U. Friedemann, Deutsche mcd. Wochenschr., 59, 219 (1933). (17) 0. Muller, Munch. med. Wochenschr , 80, 1844 (1933). (18) R. H. Green, A. F. Rasmussen, Jr., and J. E . Smadel, Public Health Reports, U.S. Public Health Service, 61, 1401 (1946). (19) E. W. Hurst, Brit. J . Pharmacal. Chemother., 3 , 181 (1948). (20) R. Bieling and H. Heinlein, Viruskrankheilen des Menschen (Naturforschung U. Medizin in Deutschland, 1939-1946. Bd. 65), Dieterich'sche Verlagsbuchhandlung. Wiesbaden. 1947, pp. 129, 137. (21) B. B. Morgan, L. Lombard and A. E. Pierce, Proc. SOC. Erptl. B i d . Med., 7 0 , 243 (1946). (22) F. Ullmann, A n n . , 355,312 (1907); F. Ullmann and C. Wagner, ibid., 365, 359 (1907). (23) W. Ldniaxiski, Bull. Inter. Acad. Polon. Sciences, Lelfres, 81 ( A l Q N l ; Chcm. Zenlr., 100, I, 3105 (1929). (24) W. LeSniaxiski and K. Dziewodski, Przemsyl Chem., 13, 401 (1929). (25) F. Mietzsch and H. M a u u , German Patents 553,072, 565,411 (1932); U. S. Patent 2,113,357 (1938). (26) 0. J. Magidson and A. M. Grigorowski, Bey., 66B, 866 (1933). (27) 0. J. Magidson and A. M. Grigorowski, ibid., 69B,396 (1936). (28) H . Jensch and 0 . Eisleb, U. S. Patent 1,962,277.
A. 9-Chloro-3-nitroacridines. I. 7-Butoxy-9-chloro-3nitroacridine . 4 B u t o x y n i t r o b e n z e n e was obtained in 68.5y0 yield by the action of butyl bromide upon potassium 4nitrophenolate in butanol.31 Use of butyl iodide gave yields of 54-5870.a2 The reduction of the nitro compound to 4-butoxyaniline in methanol with Raney nickel catalyst (25', 80 atm.) gave a conversion of 92.570; b.p. 95-98' (1 mm.), Thirty-three grams (0.2 mole) of 4-butoxyaniline, 35.3 g. (0.26 mole) of powdered, anhydrous potassium carbonate, 36.3 g. (0.18 mole) of 2-chloro-4-nitrobenzoic acids3and 0 . 5 g. of copper powder in 150 cc. of pentanol were stirred and refluxed for 5 hr. The excess amine and solvent were steam distilled, the residues diluted to 500 cc. with water, boiled with Darco G-60 and filtered. Acidification of the cooled filtrates gave 86.0 g. (85% yield) of crude greenish product, m.p. 170-174". T o obtain pure N-(4'-butoxyphenyl)-4nitroanthranilic acid from the crude, it was necessary to crystallize from 85% ethanol, dissolve the greenish solid in (29) Satisfactory nitro nitrogen values were obtained in such cases by use of the method described by S. Siggia, "Quantitative Organic Analysis via Functional Groups," John Wiley and Sons, Inc., New York 16, N. Y., 1949, p. 82. (30) All melting points recorded were corrected, whereas boiling points were not. (31) J G. McNally and J. B. Dickey, British Patent 585,940. 44, 1742 (32) G. 0. Gutekunst and H. LeB. Gray, TAISJOURNAL, (1922). (33) All of this acid was crystallized from water (charcoal) before use and melted no lower than 137-138' (E. Wenis and T. S. Gardner, J. A m . Pharm Assn., Sci. E d . , 38, 9 (1949) reported m.p. 139-140O).
4416
EDGAR -1. STECK, JOHANNES
S.BUCKAND LYNNT. FLETCHER
Vol. '79
caustic and re-precipitate after treatment with Darco. crude N-(3,4-methylenedioxyphenyl)-4-nitroanthranilicacid The product crystallized from 80% ethanol as orange blades, (m.p. ca. 210') was collected; two crystallizations from 60% m.p. 197.3-197.8", yield 64.5%. methanol (charcoal) gave a 60% yield of pure compound. Anal. Calcd. for C17H18N20j: C, 61.81; H, 5.49; N, T h e beautiful garnet plates melted a t 246-247'. 8.48. Found: C, 61.81; H , 5.60; X,8.27. Anal. Calcd. for C14HloN,O8: C, 55.63; H , 3.34; S , Cyclization of N-(4'-butoxyphenyl)-4-nitroanthranilicacid 9.27. Found: C,55.52; H , 3 . 3 6 ; IY,9.40. to 7-butoxy-9-chloro-3-nitroacridinewas accomplished by Conversion of the above acid t o 9-chloro-6,7-methyleneuse of phosphorus oxychloride in toluene as described below dioxy-3-nitroacridine followed the same pattern as the related for the 6,7-dimethoxy type. The pure compound was ob- types. T h e crude material was crystallized from chlorotained in 69% yield after three crystallizations from heptane; benzene t o give the desired compound as fluffy yellon long, golden-brown needles, m.p. 159-160". needles, m.p. >300°, in a purified yield of 63YG. Anal. Calcd. for C17HIjC1S2O3: C, 61.73; H, 4.51; C1, Anal. Calcd. for Cl4H7C1X204: C, 55.55; H , 2.33; Cl, 10.72; S , 8.47. Found: C, 61.60; H, 4.51; C1, 10.79; 11.71; N,29 4.63. Found: C, 55.51; H, 2.33; C1, 11.82: S , 8.52. N,294.57. 11. 9-Chlor0-6,7-dimethoxy-3-nitroacridine.~~-4-KitroIV. 9-Chloro-6,7-ethylenedioxy-3-nitroacridine.-l,4veratrole was prepared in 75% pure yield from v e r a t r ~ l e . ~Benzodioxane ~ (1,2-ethylenedioxybenzene) was made by the -1suspension of 450 g. (2.46 mole) of 4-nitroveratrole in 1.4 method of G h o ~ h . The ~ ~ nitration according to the direc1. of ethanol was reduced a t 25" and 50 a t m . with 10% pal- tions of V ~ r I a n d e rmas ~ ~ not particularly satisfactory, but ladium-charcoal catalyst. The reduction mixture contain- the modification of Heertjes, et U Z . , ~ readily ~ gave 80% ing 4-aminoveratrole was filtered and kept under nitrogen. yields of pure 4-nitro-1,2-ethylenedioxybenzeneeven with -1mixture of 337 g. (2.44 moles) of anhydrous potassium large batches. carbonate, 492 g. (2.66 moles) of 2-chloro-4-nitrobenzoic The reduction of pure 4-nitro-1,2-ethylenedioxybenzene acid and 0.5 1. of water a t 60" was prepared, then the solu- with A d a m catalyst at 40' and 3 atrn. was run in methanol. tion of 4-aminoveratrole, 25 g. of copper povider and 25 g. T h e filtered reduction liquors were employed in the same of Filter-cel were added. The mixture was stirred vigor- manner as described above for t h e 3,4-dimethoxyaniline; ously and the alcohol removed until the still temperature hT-(3,4-ethylenedioxypheny1)-4-nitroanthranilicacid was reached 92", then refluxed for 5 hr. The solids which were isolated in 69% yield (after one crystallization from dilute collected were extracted with 2 1. of boiling water after mix- ethanol with use of Darco G-60; m.p. ca. 235'). Further ing with 25 g. of Darco G-60 and 50 g. of Filter-cel; t h e crystallization gave the pure compound in the form of golden filter-cake was re-extracted with the boiling liquors, then needles, m.p. 249-250.5'. chilled. T h e potassium salt of S-(3,4-dirnethoxyphenyl)-4Anal. Calcd. for ClaHlzN206: C, 56.96; H, 3.83; S,29 nitroanthranilic acid was collected from the extracts (357 g.) 4.43. Found: G 5 7 . 2 3 ; H , 3 . 5 3 ; N,294.32. and the liquors concentrated. A total yield of 392 g. (4570) Interaction of the anthranilic acid type with phosphorus of the salt was obtained; acid isolated from the salt melted oxychloride in toluene was accomplished in the usual mana t 221-223.5'. ner. T h e 9-chloro-6,7-ethylenedioxy-3-nitroacridine iso.I mixture of 356.3 g. (1.0 mole) of potassium IY-(3,4- lated after one crystallization from xylene melted ca. 285" dimethovyphenyl)-4-nitroanthranilateand 3.5 1. of toluene yield). Further crystallization from chlorobenzene was stirred while ca. 0.5 1. of distillate was collected t o en- (86.5y0 (followed by extraction with boiling ether t o remove the adsure anhydrous conditions before the addition of 220 cc; hering solvent) produced the pure compound; orange micro(368 g., 2.4 moles) of phosphorus oxychloride during l o crystals, m.p. 298.7-299.5' (76% yield from the acid). minutes. The well-stirred mixture was refluxed for 3 hr. Anal. Calcd. for ClsHsC1Nn04: C, 56.88; H , 2.87; C1, and then 0.5 1. of distillate removed z n uacuo. Cooling of 11.19; 4.43. Found: C, 56.96; H, 2.92; Cl, 11.23; the residue gave the phosphorus salt of 9-chloro-6,7-dimethX,z94.23. oxy-3-nitroacridine, which was collected, then washed with B. Side-Chains. 3-Diethylamino-2-hydroxypropylamine toluene and ether, The complex was decomposed b y (VI!) and N-(2-hydroxyethyl)-ethylenediamine (VIII) were gradually adding it to a well-stirred mixture of 310 cc. of 367@sodium hydroxide solution, 1300 cc. of water a n d 1300 redistilled commercial products. g. of ice and stirring for 2 or 3 hr. d t 0 " . rl brownish prodN-(2-Hydroxypropy1)-ethylenediamine(IX), b.p. 88-91 O uct resulted; this was washed free of alkali, air-dried and (3 mm.), nZsD 1.4744, was obtained in 48y0 yield from ethylenediamine and propylene oxide.48 T h e by-product, K,K'washed with benzene. T h e 9-chloro-6,7-dimethoxy-3-nitroacridine was boiled with 4 1. of ethylene dichloride for 2 hr., bis-(2-hydroxypropyl)-ethylenediamine, was isolated in cooled and the light yellow product dried. A1yield of 230 21.57& yield; shimmering white platelets from ethanol, m.p. 147-147.5'. g. ('i2yO) resulted, m.p. 246-248" dec. 111. 9-Chloro-6,7-methylenedioxy-3-nitroacridine.-A Anal. Calcd. for C8H&202: C, 54.51; H , 11.44; N, portion of the required 3,4-methylenedioxyaniline was oh- 15.90. Found: C,54.80; H, 11.41; N, 15.88. tained in 88% yield, h.p. 85-86' ( 1 mm.) (m.p. 44.5-45.5'), N-(2-Hydroxy-Z-methylpropyl)-ethylenediamine ( X ) , from the reduction of 3,4-methylenediouynitrobenzenein b.p. 84-93' (2 mm.), n Z 51.4670, ~ was prepared (58.5% methanol with Adams catalyst a t 3 a t m . hydrogen pressure. yield) from ethylenediamine and isobutylene oxide.43 N,S'The nitro compound was a by-product from the preparation Bis-(2-hydroxy-2-methylpropyl)-ethyIenediaminewas also of 6-nitropiperonals or made from 1,2-methylenedioxyben(22.5y0 yield); it crystallized from hexane as white zene37 b y nitration.38 Some had been prepared earlier by formed blades, m.p. 69.5-70". a Hofmann degradation of p i p e r ~ n y l a m i d e . ~ ~ Anal. Calcd. for CloH24N2O2: C , 58.79; H , 11.84; S, T h e reaction of 3,4-methylenedioxyaniline,2-chloro-413.72. Found: C, 58.74; H, 11.12; S , 13.60. nitrobenzoic acid and potassium carbonate in the presence of copper powder and Filter-cel was carried out after the N-(Z-Hydroxyethyl)-l,1-propanediamine(XI) resulted method described for 4-aminoveratrole. A 91% yield of when 2-(2-hydroxyethyl)-propionitrilewas catalytically reduced in ammoniacal e t h a n ~ l ~ ~ b.p. ~ * s ;70:-107° (1 mni.), n 2 5 1.4837. ~ (34) This procedure was devised by Dr. B. F. Tullar of the DevelopN-(2-Hydroxy-2-methylpropyl)-1,3-propanediamine (XII) ment Laboratories of this Institute during 1945. It was partly based upon experiments of Drs. C. E. Kwartler, W, Boehme and E. 4. was obtained by catalytic reduction of the related propionitrile in ammoniacal ethanol4fi; h.p. 102-106° (4 tnm.), nZ6n Steck. T h e over-all yield obtained from veratrole and 2-chloro1.4672. 4-nitrobenzoic acid was uniformly about 24%, while the procedure of Miller and Wagner' would produce 9-chloro-6,7-dimethoxy-3-nitro(40) B. N. Ghosh, ihid., 10'7 1588 (1915). acridine in ca. 13% yield. (41) D. Vorlander, A n n . , 280, 206 (1894). (3.5) E. P. Clark, THISJ O U R N A L , 53, 3434 (1931). (36) J , B. Ekeley and XI. S. Klemme, THISJ O U R N A L , 50, 2713 (42) P. M . Heertjes, E. A. M. F. Dahmen and T. G. Wierda, Rec. (1928). fvarr. chirn., 60, 569 (1941). (37) P. P. Shorygin, A. A. Simanovskaya and A . V. Rogdanova, (43) L. J. Kitchen and C. B. Pollard, J . Or#. Chem., 8, 342 (1943). J . Gen. Chenz. ( U S S R ) , 8 , 978 (1938). (44) Wingfoot Corp., British Patent 571,017. (38) W . H. Perkin, J r . , R . Robinson and F. Thomas, J . Chew. Soc., (45) A. R. Surrey, U. S. Patent 2,531,013. 96, 1979 (1909). (46) E. A. Steck, L. L. Hallock and C. >I Suter, . THISJ O U R N A L . (39) G R. Clemo and I. Weiss, i b i d . , 704 (1945). 70. 4063 (1948).
=lug. 20, 1957
SOME
4417
9-AMINO-3-NITROACRIDINE DERIVATIVES
TABLE I 9-AMINO-3-NITROACRIDINE HYDROCHLORIDES Calcd.
Analyses,
Yo
Found
Re" Yield, yo Appearanceb M.P., O C C N c1 N c1 13.30" VI1 58.5 Smrlet microcrystals 182- 1Md 10.72 13.57 10.58" VI11 76 11.89 15.04 11.86f 15.OOf 290-292 Orange platelets 240-243 VI11 71 Scarlet needles 11.96 15.14 11.74vJ 1 5 .220rh 14.80 78.5 Orange microcrystals 250-251 IX 11.84 14.68 11.99 14.39; X 70 253-257 11.29 14.29 11.19; Orange needlets 13.88' XI 68 11.oo 13.82 11.oo' 228-228.5 Brick red microcrystals 14.19 XI1 11.17 14.14 11.01 235-235.5 Brick red needlets 73 XI11 6 5 . 5 Scarlet microcrystals 10.58 13.39 10.48 13.46 238-239 VI1 11.54 1 4 . 6 1 11.32k1L 1 4 .62k 62 -0CH20251-251.5 Bright orange prisms VI11 7 2 . 5 Orange microcrystals 15.38" >300" 12.38 15.67 12.42" VI11 50 12.25 15.51 12.24 15.45 -0CHzCH20236-238 Garnet needlets VI1 13.87' 74 198-199 10.83 13.70 10.68" Russet microcrystals 0 Code a s given in text. Method of purification as detailed for compound I except in cases of those bearing side-chain Melting with decomposition unless otherwise stated. I t was ad(VII), which have been noted in the Experimental. visable t o immerse the sample in bath a t a temperature ca. 20' below the m.p. and heat rapidly t o obtain reproducible values. d No decomposition. This compound was investigated as a trypanocide by R. Schnitzer and W. Silberstein [ Z . Hyg. Infektionskrankh., 109, 519 (1929)], but no constants were given. n Hemihydrate. Anal. Calcd. for C~rHazS404.2HC1.0.5 Hemihydrate. Anal. Calcd. for HzO: H 2 0 , 1.72. Found: H20, 1.57. f Dry basis; sample contained 0.61% water. C19H22N406.2HC1.0.5H~O: HzO, 1.92. Found: H20, 2.04. Anhydrous material was obtained by prolonged drying a t 100' (0.5 mm.) and replacing lost HC1 by action of an absolute ether solution of hydrogen chloride. The product was washed with 5: 1 ether-ethanol and dried; scarlet microcrystals resulted, m.p. 260-263". Anal. Calcd. for Cl0H22N4Os.2 HCl: N, 12.20; C1 15.44. Found: N, 12.43; C1, 15.42. ' Hemihydrate. Anal. Calcd. for C Z I H ~ ~ ~ \ T ~ O ~ . ~ H C ~ . O . ~ H ~ &0, 1.81. Found: HzO, 1.82. 1 Dihydrate. Anal. Calcd. for C ~ O H Z ~ N ~ O ~ . ~ HHzO, C~.~ 7.07. H ~ OFound: : HZC, Dumas determination made with use of copper(I1) acetate after 6.90. k Dry basis; sample contained 1.23% water. Chars at ca. 250". Hemihydrate. method of D. F. Hayman and S. Adler, Ind. Eng. Chem., A n d . Ed., 9 , 197 (1937). Anal. Calcd for C I ~ H I ~ N ~ O E , . ~ H C H2O. ~ . O1.99. . ~ HFound: Z O : H10, 1.89. a Monohydrate. Anal. Calcd. for Cz2H28N406.2HC1.Hz0: HzO, 3.48. Found: H20, 3.15.
then stirred for a n hour or two. A brick-red hydrochloride N-(2-Hydroxyethyl)-1,7-heptanediamine (XIII).-Pimelonitrile47 was reduced in 10% ammoniacal ethanol with Raney resulted and was leached well with acetone t o remove phenol. nickel catalyst a t 60 atm. and 90". An 8870 yield of 1,7- The crude product was dissolved in 1 1. of water a t 70-75" heptanediamine was collected a t 52-54' (1 mm.); this com- and charcoaled. The filtrates were a t 40-45" when 350 cc. of concd. hydrochloric acid was added and thereafter cooled pound was prepared48earlier by sodium-ethanol reduction of very slowly, then collected, slurried the product with acepimelonitrile. A solution of 33.3 g. (0.26 mole) of 1,7-heptanediamine in tone, washed with acetone and ether. This scarlet dihydro100 cc. 90% methanol was stirred a t 0' in a flask equipped chloride was dried in TJUCUO below 50' to avoid loss of HCl; m.p. 223-225' dec. The product weighed up t o 250 g. and with condenser through which brine was circulated a t -10'. T o this there was added 12 cc. (10.6 g., 0.24 mole) of lique- contained some 5-9.5y0 moisture; the yield, on the dry fied ethylene oxide contained in a jacketed dropping funnel basis, was 56-65%. Miller and Wagner7 have reported a having brine circulated through the jacket. When addition product containihg 6.870 water; HurstIgemployed a sample had been completed (ca. 0.5 hour), the reaction mixture was containing ca. 8y0 moisture.49 In the case of most compounds listed in Table I , the allowed t o warm t o room temperature, and reaction caused t h e temperature t o rise t o 40". The mixture was stirred for method detailed for the preparation and purification of 93 hr., then refluxed for 1 hr. before fractionation. A yield of (3-diethylamino-2-hydroxypropylam~no)-6,7-dimethoxy-320.9 g. (47%) of N-(2-hydroxyethyl)-1,7-heptanediamine nitroacridine dihydrochloride was t h a t followed. However, in the case of the types bearing the 3-diethylamino-2-hy( X I I I ) wascollected a t 164-168' ( 1 mm.), n2% 1.4751. Anal. Calcd. for CQHZ?&'ZO: li, 16.08. Found: Ii, droxypropylamine chain ( V I I ) , variations were desirable. In most cases the phenol melt was quenched in acetone-40%> 16.10. ethanolic hydrogen chloride mixture, and the crude products C. 9-Amino-j-nitroacridines.-The 9-amino-3-nitroacri- crystallized from ethanol-ether. A pure sample of 9-(3dine derivatives which were prepared by the reaction of the diethylamino-2-hydroxypropylamino) - 6,7 -methylenedioxyappropriate 9-chloro-3-nitroacridine and amine in phenol 3-nitroacridine dihydrochloride was most readily obtained melt have been presented with pertinent data in Table I. by merely extracting the crude with boiling e t h a o l and dryIndication of the procedure employed is given in the prepara- ing the residue. Tkie products were, ordinarily, dried in tion of 9-(3-diethylamino-2-hydroxypropylamino)-6,7-di- vacuo over phosphoric anhydride, sodium hydroxide pellets methoxy-3-nitroacridine, for this is somewhat different in and wax. Use of high temperatures for drying led t o concertain respects from those p ~ b l i s h e d . ~ ~ ~ siderable loss of hydrogen chloride, which was sometimes I. 9-(3-Diethylamino-2-hydroxypropylamino)-6,7-di- difficult t o replace. All determinations of water content methoxy-3-nitroacridine Dihydroch1oride.--A melt com- were done by the Karl Fischer method. prised of 440 g . of phenol and 220 g. (0.69 mole) of 8-chloro6,7-dimethoxy-3-nitroacridinewas stirred under reflux a t Acknowledgment.-The authors wish to express 70'. The heat was removed and 123 g. (0.84 mole) of 3- their appreciation to Mr. M. E. Auerbach and diethylamino-2-hydroxypropylamine was added a t such a rate that the temperature did not exceed 95'. At the end Mr. K. D. Fleischer and their groups in the Anof the addition, heating was resumed for 1 hr.; the mixture alytical Laboratories for the analyses. was cooled t o 40" and poured into a well-stirred solution of (49) The authors wish to express their appreciation to Dr. P. 120 cc. of concd. hydrochloric acid in 4 1. of acetone a t 20°, (47) J. Cason, L. Wallcave and C. N. Whiteside, J. Org. Chem., 14, 37 (1949). (48) J. YOU Braun and C. Mdller, R e ? , 5 8 , 2206 (1908).
Gauhert and Dr. E. W. Hurst of Imperial Chemical Industries, Ltd., for their friendly communications concerning these and related matters.
RENSSELAER, N. Y.
