BIBIUD.~; TliE REACTION 8-AnNOQuriiOLtlmB WITH. NIT~~~OI,4 •' >'•' • or·I,' ",i.
by
Hugh Bu:rknla·p.·,:Ilona.hoe B.s.• ,. Rookhurst College, 194.3 M.A.,, Univ&rESi.ty of ICansas, · 1947 .
Submitted to the Department of ·chemistry and the Faculty. of. the . G:raduate School or the University of Kansas in partial fulfillment ot the ?'equirements for the de• gree of Doctor ot Philosophy.
Advisory Committee ·
May, 19.$0 AOKNOWLEOOMENT
The author wishes to ex.press his thanks and appreciation to Dr. J. H. Burokhalter,, who suggested this problem, and Dr. a. A. Vanderwerf for ·their helpful suggestions and guidance during the course of this work. H.B.D. TABLE OF OONTEN'TS
Chapter Page
I • THE PROBLE?i Olr MALARIA.
A. Introduction • • • • • ...... • • 1 B. The types of malaria. • • • • • • •• 2 O. The biology of malarial infection • • 3 D. The prophylaxis and treatment of malaria: •. ;•' •. • • •. • . ;.. • • : •••• ·• • • ., 6
II. ·Atfl'IMALARIAL ·:DRUGS. :· • · ,, A. Olassific at ion and. screening of antimalarial drugs • • . ,, . .. ' . • • • • 12 B. Historical • • • • • • • • • • • • • 1~ c. Quinine • .. • • • .. • • • • • • • • • 16 D. Synthetic substitutes • • • • • • • • 19 l. Plasmochin • • • • • .. • • • • • 19 2 •. Quinaorine • • • • • .. • • • • • 21 3. Ohloroquine • • • • • • • • • •• 21 q.. Pentaquine •• • • • • • • • • • 23 s. Paludrine • • • • • • • • • • • • 2q. E. Me(lhanism ot action of antimalarial drugs • • • • • • • •• • • • • • • • 2$ 1. The metabolite-antimetaboli te relationship • • • • • • • •• • 2.$ 2. The quinoid•Quinonimine theory • 26 3. Conclusions • • • • • • • • • •• 28 · -Ohapter
III.· THE ANTIMALARIAL PROGRAM 1941-1945
. .A. The overall program • • • • • • • • • 30 .a. :._ Tb(j ·4•aminoquinolinea • • • • • • • • .32 · IV. • DISCUSSION Of THE PROBLEM ) • • • • • .• • • • .38 ·V. · DISCUSSION OF· RESULTS. · - . A.;, Unsymmetrical hybrids related to '. propanediemine * • • • • •. • • • • • 46 B. ··Symmetrical: hybrida related to prc,pan~di8J1iinet ~d methanediamine • • S2 . a. Theoret_~cal oonsidere.tions • • • . • • . 61 VI. EXPERIMENTAL.· Pota·ss!um ·Phthalim1de • • • • • • • • . 69· l-Phthal!mido-2~ .3-epoxypropane · • · • • • · • - 71 · l-Phthalimido-3 .. ohloropropanol-2 · • · • • · • 73 · l~Phthalimido•·J-iodopropanol-2 • · • · • · • · • .15 l-Phthal1mido•3•p-ohloran1lino•· propanQl•2 • • • .. • • • • • • 76 '· • • • • • l•(p•Nitrof;Ulilino)•3-phthalimido- prope.nol•2. · • • ·• · ~ · • • ~ · • : • • • • • • • 80 l•{p•Aoetam1doanil1no)-3-phthal1mido- propanol•2. • • : " .•.• · • · • ·~- • • · • • • ·• • 81 8-(3•Phthal1m1do•2•hydroxypropylamido)- 6-mathoxy-qu.1nol1ne ~- ·• • • · ·• • • · ·• • · • • -- 82 l•Amino-3.·p-chloranilinopropanol-2 • • • Sq. 8~(3-Amino-2-hydroxypropylamino)-6- m,thoxyquinoline • • • • •. ;J •. ~ • •••• 86 7•0hloro-4• ( 3-p-ehl~ranil111-o-2•_. , hydroxyp~opylam1no)•qu1nol1ne. • • • • • • 87 ·7 ~Ohloro-4- (3~ '( 6-methoxy-8..;·qu'inolyl- ·. a:mino}·2~hydroxypropylamino )-qu.inoline • • 89 .: ; .. ~ .. : ' ( - . . . . ' ' . ' ' . ' •' ,, ~ Attempts to react the hydroxyl group of .th~ atroctur.al type. RNHOH20H(OH)O.H2NHR' · with halogenating agents ~- ·• · • ~ · • • • • • 91 2~Ethyl~2-n!tro-l,3'.""propanediol • • • • • 93 2•~ethyl-2~n.1tI'0•l,.3-propaned.iol. • • . • • • 9.5 N,Nt ..-I)1•p•chlorphen:,l•2•ni tro-1, 3~ · . pJ'?plll:lediami11e • • .•. ·• • • : • • , .• • • • • 96 .. .'; .. : ' . ' ' ~ . ' . N,N'-D1•p•chlo:rphenyl~2 .. methyl•2•n1tro- l,3•Propaned1amine •. ·• • , • • • • .• • • • • 98 N•N•-D1·p-ohlo:rphanylmethe.ned1amine • • • 101 · N,N' •Di•P•Ohlorphenyl-2-amino-l, 3• propan.ediamine • • .• ·· • • • • • • • • • • • 102 N,.N• ""'Di-(6-methox.r-8•quinolyl) •2• nitro•l,3•propaned1am1ne (attempted) •••. 103 ••• I ' \ N•N'•Di .. (6-methoxy-8-qu1nolyl)-2-methyl- l,.3•Pt-Opanediamine (attempted) • • •. • • • 10.$ N,.N•-Di-(6-methoxy .. 8-quinolyl)•2-ethyl- l,3•propanediamine. (attempted) . • ••• • • 107 N.N•-D1(6-methoxy-8 .. quinolyl)• methaned1amine • ·• · ·~ • • • • , • • • • • • 108 ·, Di-( a~a.mino-6-methoxy-S.) •Q.uinolyl• methane (pre>bable) • • • • • • · • · • • • • • 109 8•Amino•$•chloro-6~methoxyquinoline. . • • • 110 N,N'-Di-($-chloro-6-methoxy-8.:. q_""°inolyl)•methanediamine • ·• • • .• • • • 112 / . . oh~pter· N• Nt •Di ... '( .S•ehloro ~6-methoxy-.,.8..- .; quinolyl)•2,•me~hyl-2-nltro-:l,.3• . •. • ... : • 113 (attempted) ' ' pl'opa~ed!~irie.- .' ' . . . ' ' ...... : ~ . . ' . ' ' • • ••• OF,FUTU:REWORK- • ' ', : ' . ,. ' - :, .,_, f :· l ' : VII. DISCUSSION• ' ~ : . • • • • • •• • • • • 114 4t • OONOLUSIONS,,. ' - ·'· •., 116 VIII. ; • • . • • .• •. . • • • • • • BIBLIOGRAPHY • • • • ... • • • • • .. . • • • • • • • 119 1. CHAPTER I THE PROBLEM: OF MALARIA' A. INTRODUOTION. Malaria is one of the oldest diseases known to man, and, even today, with the great advances in medical science, it atf'l1ots a large percentage of the human race. It has been estimated (1,.3) that.the disease attacks several hundred million people evet7 year and that it accounts for three million.fatalities in the same period ot time. Approximately twenty•tive per cent ot the hospital admissions among United States tl'Oops stationed at Vera Oroz in the Mexican war was due to malaria and there were · 1,213,685 cases among the white troops on the Union side during the 01 vil War ( 66). The disease prevented action by both Allied and Central Powers in the Near East 1n World War I, and it· has been reported ( 111) that the incidence of malax-ia in the Pacific reached 750 per thousand per annum in the early years ot the Seoond World War. In the United States, which is in a temperate zone, an estimated one million persons are infected and it has been found in every state 1nthe Union. A neve~ ending search for more potent and less toxic antimal~rials has continued and will undoubtedly do so until this scourge is no longer of importance. \ J/ 2. B. THE 'l'Y.PES OF MALARIA. There are tour organisms which cause human · malaria Plasmodium falciparum Plasmodium vive.x Plasmodium malariae Plasmodium ovale but only Pk falcipaxtwn and t£ vivax are of importance, the latter two being rare and mostly of academic interest. ~ talciparum is the causative para.site in malignant tertian malaria. It shows a rise in temperature 'every .36~q.8 hours and frequently causes fatalities unless a . . Sl,litable.drug·is administered promptly attar the initial symptomsof.the disease are ;ioted. Nevertheless, if the attack has been adequately treated, recurrence ot clinical symptoms>are unlikely. It is during the time or initial infectton that the plasmodia .are· most easily destroyed. It 1s prevalent 1n the tropics. 1n the Medita~ranean, and in sub-·tropical American .regions • .L. vivax is the o·iusative agent in ]:>enign ~ertian malaria. This disease is ra~ely ~atal and shows regular 36 hour rises in temperature or an intermittent nature •. In most cases attacks will recu:r periodically even when,: by the use of proper drugs, the clinical symptoms of an acute attack .3. are removed.. This parasite is found all over the world. L.· malariae ca.uses quartan malaria. This disease is not very common. The fever is manifested by a 72 hour period between rigors. J::. ovale causes a mild tertian infection. It recurs every q.8 hou-rs. It is rare and not found in temperate zones. Being a tai:rly mild form,. it yields satisfactorily to prope~ medication. 0. THE BIOLOGY OF MALARIAL.INFECTION. Human malaria is a protozoon disease caused·by four species of plasmodia, which to:rm one ot the families of the suborderhemos;eor1dia. These are sporozoa which possess an asexual cyclical existence in circulating red blood cells ot certain vertebrates and a sexual cycle in the anopheline species of mosquito •.. Laveran discovered the parasite causing malaria in 1880 and eighteen years later Ross showed that the anopheles mosquito ear~ied it from man to man. To understand the disease and what is required with respect to a chemotherapeutic agent, the life cyole and reproduction or the plasmodia m:ust be briefly considered. Man 1s the intermediate host in which the parasite completes its asexual cycle and reproduces by a process or schizogony. The anopheles mosquito is the vector and definitive host in which the sexual oyole is completed and· reproduction is aooomplished by sporogony. lt.- ill.! Oy;ol e !!! !!all• , When an infected mosquito bites a victim, sal1 va containing slender organisms called sporozo!tes are injected into the blood stream. In man the plasmodia live as :-·"'' . parasites in or on the surface of red blood corpuscles which are eventually discharged by the growth and division ot the paras! te. A short time after.the bite of an infected mosquito, the ring·torm-or trophozoite appears and attaches itself to the red blood cell. It grows at the expense of the·cell until it reaches maturity and becomes a schizont, the asexual form of the parasite. The soh1zonte then undergo asexual reproduction (sohizogony) With the formation or a numbett ot merozoi tes. The cell now ruptures and discharges the merozoites into the blood stream! It is this periodic breaki'ng of red cells which causes the typical attacks characteristic or malaria •. ·The·fever -which follows the chill is due to the ' . liberated foreign protein and cell products. In a single ·attack.as many as one-fifth of the circulating red-blood cells n1ay be destroyed. The free-swimming merozoites again attach t~!rti~.tt+ves to blood c-.orpuscles to become t~opo toi tes and to repeat once more the p:rooess ot echizogony. After several of these cycles, and especially when growth conditions are made unfavorable by medication or >· developing immunity, some or the merozoites tail to :follow the asexual pattern of reproduction. They separate into micro (male) and macro (female) gamatooytes~ These· gameto- cytes grow until they .fill and break out ot the blood cells, but they do not divide again in man and cause no symptoms. The gam.etocytes remain free in the blood of human ·"carriers" until they are taken up by a mosquito as it obtains a blood meal·from man. 141.! Q:y:ole; !!!, .!!!!. Mosguitq. A susceptible mosquito b~tes an·ini'ected person and blood containing marozoites and gametocytes enters its stomach. The asexual forms soon die but the sexual forms undergo maturation (ge.metogony) and become micro- and maoro- gemetea. The microgametes throw out flagella which break oft and move about in the body tluids. They ulti~~tely penetrate the'macrogametes and the sexual cycle (sporogony) begins. The result ot the fission is a zygote which elongates and·turns into.a motile o8kinete which penetrates the stomach and encysts on the anterior forming an o6cyst. The organism undergoes growth in the o8cyst, becoming a sporont which then subdivides into sporoblasts ,,hich .cause the cyst to.rupture. Thay escape into the body cavity as sporozoites and are distributed in all the tissues ot the mosquito, but especially in the salivary gland cells and ducts. 6. : When the mosquito bites man, the sporozoi tes in the saliva are liberated into the\victim'a blood stream, invade the red blood cells, and once more become tropho- eo1tes. ·Here. the asexual oycle begins again. Once the foregoing cycles were worked out, the problem seemed complete and to~ appro~imately twenty-five years no more impoi-tant d.iscoveries were made. However, the regula:rly observed late relapses 1n malaria, even after '' thorough treatment and prolonged. absence of paras! tea from the blood, eaused some malaralogists to suspect that. tissue stages might exist. Such stages were found 1n chioken mala~ia by James and ~ate (.$2, .$3) in England.· Similar forms had been noticed.earlier by Raffaele (88) and by Hutt and Bloom (48) 1n the bone marrow of canaries infected w!th!.t,. elongatum, but these worke~s did not seem to appreciate the signiticanoe of thei:r discovery. Sim1.lar stages in other species of. avian malaria were soon recognized and the name 0 exoe.ryth- rocytic torma" wae coined because ot their occurence :outside the· red blood cells. There was still a gap remaining in the. crole ot the b1rd.nta.laria parasite as no one knew where the sporo- zoite went after it was introduced into the body by the mosquito. It 1raa known that the sporozoite did not remain in the blood fott more than one-half hour and that such blood 1. remained ft•ee of malaria parasites for several days. About the time of the war. Kikuth and workers in Germ.any showed some or the early stages ot ls. relictum. '" and E..,. cathemeritum in canaries. Discovery or the complete oyole ot .f.... gallinaceum in chickens by Huff and Coulston (49). soon followed. Such findings intensified the search for corresponding stages in the cycles of human and monkey malarias. In birds• the .favored sites for the development of exoerythrocytio forms are the bone marrow, liver, spleen,· lungs and brain, but study ot these organs in hum~n malaria gave no results. Huff and Coulston (~9) had shown the entry ot:sporozoites into cells of the retiouloendothelian aystem and their later development in this system as .well aa in the spleen, heart; kidne~, and brain. While the work waa done chiefly Y.Iithl.t,. gallinaceum, ther were able to show that ~: the cycltr in la.. cathemer!u.m. infections was very similar. '' Oaretul study or the different species of human malaria showed no convincing evidence of a parallel de-v-elop~ent until~ verr recently whe~, Shortt and Garnham (97, 98)· :t~und t~e missing stages in.. the liver of monkey-a . . ' ' . . infected with .viva.x malai-ia and cynomalgi malaria. While the discovery is too recent to know if knowledge ot these *'hidden forms" will help find better means of treatment, it does make it easier to understand a. why drugs Which affect chiefly the pa~asites in the blood stream act weakly or not at all on the tissue phase. D. THE PROPHYLAXIS AND TREATltlENT OF MALARIA. There are several means by which the prevention -. of malaria can be brought about. The most obvious method is the elimination of the parasite carriers, thus blocking the mosquito halt ot the lite c~cle ot the paras;fte. Although GXpensive, by proper sanitation methods, drainage projects, and syste~atic and repeated sprayings ot swamps, etc., with insecticides and larv1c1des, mosquitoes can be eliminated front a l'&gion. The usa of the cheap and effective insecticide DDT has made thia project much simpler. Since the prevention ot the malax-ia mosquito from bitings. hwnan being would be just as et.feotive as to destroy the mosquito outright, the field. o:r insect repellents 11 an avenue of study in malaria prevention along with inaeotioides. While the foregoing methods or malaria control are of interest, they do not.apply to the problem at hand, the use of chemotherapeutic agents in treating malaria. Hal.aria. control by prophylaxis involves killing the invading spottozoite 8.8 soon as it infects the blood stream. 'l'hia . requ:l res the continued presenoe of a· ~-rug in the blood stream of the exposed person which would immediately kill any spo:rozoites introduced by the mosquito. Proaeptasina (N~•benzy-lsulfanilamide) has shown some prophylactic action (101}, but 1 ts brief period or act1onwh1ah requires frequent doses combined with the inherent toxicity ot the dru.g and other complicating tactoi-s precludes its use.: Paludrine (27),. a derivative of biguanidine, has been.shown to be a complete causal prophylactic of ~.faloiparium, .but only a partial causal prophylactic tor P •. vivax •. Even it the above control measures were suooess- tul, they- wouJ.d be of no help to those. already- infected. The treatment of malaria in man is complicated by ·the tact that ditfe:rent species ot plasmodia do not respond:w!th the same readiness to drug therapy, that gametocytea and. schizonts show different ehemotropisms, that individuals vary in the ~esponses to the drug of ohoioe, and that· the chron1c1ty of ~he infection is en important factor. · · Early infections are, e.s a rule, very easy to cure compared with chronic malaria. "Oure" in this oase usually means the immediate control of symptoms. Relapses can be frequent and difficult to .control, but early and intensive treatment gives the best ohance to obtain a complete.and true cure. inclu~ng prevention of. relapses. In any ,case, the species ot infecting plasmodia must be.known. : The,antimalarial drugs in use at the present time, with the possible. exception of plasmoohin and its chemical' relatives, act merely as suppressive agents tor .lt.. vivax. 10. This means that an individual, exposed to possible malarial infection, can hold such an infection to a subclinical level provided he regularly takes prescribed doses or a "suppress! ve1• drug. In the case of ,!:t. falciparu.m such suppressive therap,- will, in most ca$.es, completely prevent the con- traction of the disease, or cu:re after contraction. However, in the case ot P. vivax, the situation 1s entirely different. A given subjeet may be infected with P. vivax and show no ' . - clinical symptoms as long as he maintains the prescribed dosage ot a suppressive drug. However, if 1ntectedi onoe the suppresaive drug therapt is ended, the person will und&rgo an acute olinioe.l attack of malaria. Also, once an initial clinical attack has been terminated with a suppressive drug. there is no assurance that clinical attacks will not follow indefinitely. ·It is fortunate that vivax malaria rax-ely causes fatalities, but, because or the per;odic !noapaoitation of those infected, it 1s an important problem. At the present time the best hope ror eradicating the disease lies in prompt and effective treatment of 1the initial infection, tor it is at· this time that the plasmodia are most easily destroyed in the body and gametocytas have not yet had an opportunity to develop. It these sexual forms are not allowed to develop the oyole will stop. Oraig ll. and Faust (24) have emphasized this point by saying: "It is undoubtedly true that it eve1.7 ,initial malarial infection were, properly treated, malaria would cease to exist as mosquitoes could not become intected.n 12. CHAPTER II: ANTIMALARIAL DRUGS A. OLASSIFIQATION .um SOREENI~ OF ANTIMALARIAL DRUGS. As it- has been 1nte:rred in the foregoing dis- cussion, antimalarial dru.gs are olaasified on the following b.asis in· so far as thei~ action toward the various human malal'ia ._pa:rasites is concerned: . a. ·~ prophylactic dl'llgs.. These br their ' ' ad.minist~at1on·absolutely prevent:_infection by any; or the recognized .human malarias. To. this time no such ~ 1 s known that is both sufficiently effective and non-toxic to allow generJil· usagtl. · b. :·Suppressive qru.gs. These suppress the symptoms -: of malaria to a auboli·nioal' level aa long as the drugs are administered and will terminate a clinical attaok. In the ease o!' .f£ .talo1parom many in this group will give permanent cures. c. Ou~ative d:rugs. These possess the ability to cure pe?'manently !.t. vivax infections. Since it is obviously impossible to screen:all new dl'llgs against-human malarias, some experimental animal 1s· ne~ded to a.tsar the drugs. Human malaria ! is not trans- m1ssible to any lower animals with the possible exception of the1 monkey, but, sinoe birds are susoeptable to at least fifteen species or malaria, they have been widely used in 13. malaria investigations. tor many years. aanaries were £1.rst used ,s host species_ in. m~le.ria laboratories, but reo~ntlY .. ,duoks, and chickens , have largely taken their place bec~use o:r their larger size, g~eater cheapness, and unive1'1al availability. ·, )Jntil tloggeshall (2_2) discovered .f.t.. lophurae, which w1+l parit.site both chickens and ducks, no.spec!es;of malaria pa?tasi te,;was available in this country which could be used to 1.ntect ~1 ·ot the largei- species ot domestic birds. Brum.pt (1.3), the Fl'ench paraaite>logist, had described. 1!.:,. . ~- galline.c eum from the chickens or Indo.Ohina in l93S. but because or federal regulations governing importation ot pathogenic pa~asites, it did not.become available for . . labore.tory st11dy .1n this country unt11 some .r1ve 1 e·ara later. ' \ Today: new drugs a~e routinely screened against l!.s. lophu:rae 1¥ the duck andY_f: gallinaceum in the chick, Such sc'reening tests )1a~e two main criticisms: a. ~he hosi ts ditterent from the human host in Which thEJ dI'UgS Will eventually be Used; b. The strain of malaria is different 1'~,om that against which the drugs are to be used •. ·Asa result, a high quinine equivalent in avian infections does not mean, of itself. that a oo~respondingly hig~ therapeutic effect will be achieved in man. To date there· baa been no solution ot this problem, but tests against avian m.alattia ·. provide the. only method by. whioh antimalarial activitymay be assayed·wttb.out the use of a verj' large amount ot the. drug end poa.sible harm. to clinical subjects. .. . '• . . ReQent work haa indicated that the asexual .forms (achizonts and merozoites) · and the sexual forms (gametocytes) ot the '"pe.raait& require different drugs tor treatment, and a biological method has been. developed to distinguish between sohizont1cidal · and g~etocidal drugs (9i),; A definite ret·ax-dation o:t the onset of bir-d malaria in canaries 1s used to indioat~ the schizont1ci\1al activity ot a drug, ~hi.le a gametoeidaldrug causes the diaappea.ranoe ot the gametooytea . ' ' ' ' from the peripheral blood stream ot Java sparrows. BIS~ORIOAL. B. .. .. ,1·:·' · Cinchona be.rk was used to relieve chills. and teve:r . ' b;y i1ihe)'.eru.v1an I~dians for many centuritus •. : As early as bark. became known to European· ph,ysioia.ns and was . 1630 . ~he' .. . . ' ,. .< . / ;.. ~.,. used.to .treat.mala:ria either in the,.form of ,powdered bark '. i • or as galenical preparations •. About 1820, .Pelletier and ., . ' .,...... Oaventou:. isolated. tb.e ~ka:~~1·as ·cinchonlne. and· gui~ine and the constitution o.~ lll:e olne~ona ·:~lkalo~ds was established by Rabe (81, 87) ·about 1908. .~he ·atructutte of quinine was established. indirectly 'by meins :Qf its dihydr~ derivative. l Rabe J83) was 'f.ble to report· the total synthesis of d1hydro- quin1ne in: :193,l. fl:nd.. ln l9lt..5 Woodward . arid Doering (.118) reported the total ·synth':?sfs ot quinine,, 1.S. In 1913 Kaufmann (56) published the first work on S1X1thetie _compounds related to quinine, but the first important advances'° in the chemotherapy of malaria were a result of an intensive research program at the.laboratories ot the l·+: G. Farbenindustrie. Basing their work on the demonstration~ by .Ehrlich and Guttman in 1891 that ·met,hylene blue (I) had, a. definite antima.le.rial action, Scb.ulemann, Schonhofer and. ·w1ngler {96) replaced one of the dim~thyl_amino 2 Cl Cl (CHJ Na~X)~(C~l2 (CH3l2No::vN ::2:H2N(C2Hel2 I _I II groups in I by the dialkylaminoalkylam.in~ group .. •N(OH3).•(0H2>2·N(02H$)2 and ·obtained a produat (II) .~_hat had . ' ' enhanced·aot!v.ity. The testing was reported. by Roehl (91). ·The. 'workers nex.t tried the insertion 0£ a similar side chain of the many' compounds.prepared,~ ' nucleus and., 1n the Q.u.inolina~ . the·first to show activity- in canaries .was (III). The moat promising antimalarial of the series (9$) was the substance known as plasmoohin (IV) • : N# NH CH 2CH2 N(C2H5 )2 m #, 16. Since the Germans did not at first reveal the formula ot plasmochin, other European countries redoubled theii- efforts to.learn how to prepare the same drug or to make something better. In France Forneau (38} prepared what was· known as "Forneau 71ou (V), a substance nearly the same as plasmoohin. In the meantime German scientists were actively engaged in t~e search tor something better. .A natural · ucte~sio~ of theii- original t-esearch was to tey similar aubstituente.1n the other heterooyclio ring systems. Their CH3 . I NH-CH2CH2CH2N(C2H5)2 ~ OCH 3 Cl NH _;CH2CH2CH2N(C2H5)2 ,· y ' ' ":ii studies res:u.lted in the discovecy of·quinacrine (atabrine) (VI). Oredit tor the synthesis is given to Mauss and · Mietsch (69, .7l)·while KikUth (S7) f1llst determined its anti- malarial properties by experiments on canaries, Like plaamo~hin it was developed·by I. o. Farbenindustrte. During the war great interest was shown in the J+-am.1noqu1nolines .. This was due in part to favorable reports aa to the antimal.e.rial activity or certain members of the group appearing in the Russian literature and in part to the !'&port that wai-tim& German antimalarial researoh,had .turned to this,series. · ·; ·.;. ··CH 3 CH 3 I I NH-CH-CH2CH2CH2N(C2H5)2 N H-CH-CH2CH2 CH2NCC2fit)2 .~ ~ CH3 Cl Cl JZlJI. TlitL.basio .memb.ers .ot this .groupr.-for example, 4-(4.;.diethy.lamino-l-methylbutyl.~ino) j7•ohloroqu1noline (VII), !lQW kn.own 8.8 :chlOl"O(luine1 and J•meteyl.-q_•(4•d1ethylam1no~l- Dl8thylbuty-la:mino)•7•ChlO~OqUinoline (VIII),. known in Germany- / • • t ' ' • ; • ' ~ ' • • ~ as santo°-hin-~were first desc?,'ibed in the German patent literature (3). The German,phamna,cologists e.~sa-red the value or·· s9:ntoo~in as "supe.rio:r .to quinine and 60 to 100 % ae etteot1ve. ae q~inaorine/1 A. xaeinvestigation under the. ~:traction o.t the Otfioe of Sc>ientifia ReS$arch a.nd Development (OSRD) ot the 4- • ? ·' _' ~ ' '. ' ' • . • : ' ,' , , ;,I ,, : , ' ·, , : , . ' ' ' , ', , ' I , •,'. I , ' ,m1noqui:nolin~s (64-) .showed that cex-tain members. or this class possesse,d marked advant~ges as suppressive drugs over •. , •, , ·, ; ' , , • I • ' th~s~ substances previously used to~ this purpose. For "<' • -,. '. ' • ~ : ' example,.· chloroquine 1s at least fou:r times as effective against avian~malaria as quine.cl'ine and twice as effective against .. human malarias. ·It 1·s ·1nteresting to note· that santochin, the·drug considered by the· Germans as the ·best ot the group;· is o'nly ·about one-third aa etf'eotive against b'cith av1·an an.cf human riialar1as as is chloroquine. This same 18. investigati,on found that a relative of plasmoohin,. 8-(.$-isopropylaminoamylamino)-6-methoxyquinoline, pentaquine, had. the same action, but only,about one-third the toxicity. For the sake of completeness it should be mentioned that palUd'rine (27), whioh,is said to be at least as ei'teotive aa quinacrine, was developed durl.ng the war by the Imperial Chemical Industriies, Ltd.• in Englan4. CJ • QUININE. Quinine is the CH chief alkaloid ot /1~ CH2 CH2 CH-CH=CH2 cinchona, the bark ot I I I CH-OH- CH CH CH the cinchona tree ,. "I/2 2 ~, N which is indigenous to certain regions of IX South America. Cinchona alkaloids are obte.ined,f'rom the bark of the roots, trunk, and branches. More than twenty alkaloids can be obtained, but the most important ot these nre the two pairs or isomers Qu1n1ne-Qu1nid1ne and 01nchonidine-01nohonine. The first member of each pai~ is levoratatory. Quinine is a sch1zonticidal drug and,theretore, 1s fairly ef'f'icient in checking the symptoms ot the disease in man, but it has no effect on the spread ot the disease. During the study ot the relation ot ohem.1oal structure to pharmacological action, the 'following tacts have 19. been determined •. The vinyl group is not·needed tor anti- . ~· . malarial action. . Hydrogenation of the vinyl group to an ethyl group to form hydroquinine will a~tually inorease the·potency·or the drug. On the other hand, the secondary alcobol linkage is necessary tor plasmoo1c1dal power as the reduct1on·,of this group increases toxicity and abolishes ant1p1a.smodial potency. Quinine is used alone as a euppressived:rug ·OX' .in combination with such s1nthetic d?*llg~ asplasmochin or pentaquine. · · Regar-dless or ·the mechanism of action, ·quinine cures .the acute symptoms of, maltu."ia by depressing the multiplioa.tion of plasmodia in the. body end stimulating ao-me of the parasites to Change to the sexual forms (gam.etocy-tesh which cannot ea.use clinical symptoms in man, by ~aking their environment unfavorable. D•.. SYNTHETIC $UBSTITUTES. l. Piasmoahin •. Plasmoohin was ,~ synthesized by N~ Sehulemann, Sohonhofer NH-CH..;. CH2CH2CH2N (C2 H5)2 and Wingler (96) on I . CH3 I2: the basis ot experi- ments with methylene blue. In avian malaria it is approximately- 60 times as effective ·as quinine. It is of particular interest·because 20. of the specific · toxicity-.Jt manifests toward the gameto- cytes otall forms ot pla~odia. While full therapeutio doses ot quinine in man do not oause_ th~ disappearance ot the .sexual: ro·rms even after three weeks, plasmochin effects their elimination· in a few days so that th~ blood ot· . treated patients is no longer .infectious for the :mosquito. Plasmoohin also has some action against the asexual· tormQ or the malarial.ot!tga.nism.~ The margin of safet:r of pla~mochin is narrow. The commonest effect ·of·full doses is oyanosis due to: methemoglobenemia. Feeble patients· and those with heart, kidney or U vex- diseases are .. more . susoeptable to poisoning by the c1rug· and it is oontra•indioated i'n these cases. Full doses are too toxic.to.be given unless the pati~nt.is under close observation• preferably in a hospital. Ple.smoohi.n 1s viewed as an effective addition to :quinine ~ather than a substitute for the latter. It is completely ineffective in the case of malignant tertian malar,ia;:,.but when combined with quinine for the therapy ot ··ac.ute attacks, or when used in alternation with q,uinacrine, plasmochin considettably reduces the relapse rate in oases of benign tertian and quartan malaria end in some cases ot malignant tertian malaria. Pentaquine, an analog ot plasmoohint is letts toxic and ther,efore more useful in combined therapy with quinine. 21. 2. Qu1nacrine (Ats.brine). Quinacrine was introduced into malaria therapy by Sohulem.ann. (95). The drug was synthe- . sized by Mauss and Mietzoh .. {69, · 71),"onthe: basis for" clinical results obtained with .. Piasmochili. In.bird malaria quinacrine is much less etfeotive (l5X) than plasmoohin, but it is also less toxic •. It is, however,· more aeti ve than q:uinine. In contrast to· plasmochin, but Simila~ to. quinine, the drug afteots,mainly the asexual forms. Thus, it is curative·in malaria in the same sense as quinine, but it does not pr-event. the patient•s blood.from remaining infectious for, mosquitoes. The toxicity of quinac:rine being low (211 68), the margin or safety 1s good. ~hile therapeutic doses affect mainly the schizonts, the gametocytes of benign tertian (L. vi vax) and quartan (A:.:. malariae) fo?'llls or th& disease are also inhibited by quinacrine. ). Ohloroguine. · CH 3 I Chloroquine was NH-CH- CH2C H2CH2NCC2Hts)2 first reported in the Ge:t'man patent Cl 22. literature (3). but it and santoehin (.3-methylchloroquine) were not. considered to be better in their action than qu1nacrine. · A reinvest.1gat1on of the OSRD (64) ot the drugs p:roved -.the assay to be faulty and showed chloroquine to ·be t;t,.reetimes as effective as quinacrine against human malaria.a. · The ·drug· was found .to be deposited iri the organa ancl'tissues in quantities proportional .to the dose given. It was concentrated in nucleated cells, especially those ot the livep,·spleen, kidneys, and lungs. These organs contained the highest concent~ation• .. from 200-soox the amount in the plasma. Thie is a general pattern of distri- bution similar to quina~rine, but, because of more rapid absorption end lesser localization, ohlox-oqu1ne is present in substantially higher concentrations on any given dosage schedule~ There is very little difference in toxicity between quinacrine and chloroquine, except that the latte?' does not color the skin. · · Chloroquine 1 s highly e.oti ve against the eeythro- cytio forms of L.· vivax and.).R_. ta.lciparum but it will not \ prevent relapses in. vivax malaria.. even when administered in doses many times .those required to terminate ari acute attack, not' will it prevent the establishment of: a viva.x: infection when administeI'ad as a prophylactic. 1.l!he drug is highl'Y' effective in vivax malaria as a 23. suppressive"agent and in. :the, termination of acute attacks, lengthening the interval between treatment and relapse beyond th.at observed with ,qulnacrine or quinine •.. In falc1parum malaria it will suppres.s an acute attack and will· completely. cure,the infection. 4,. Pentacuine. Part of the c~o research directed N~ by the wartime OSRD NH- CH2CH2 CH 2CH2 CH2 N HCH (CH3 ) 2 (1)4) was the x~ synthesis and testing or many substituted 8-aminoq,uiholihes •. During this flCreening it was· found (6.$) that a·· com.pound prepared by .Drake and coworkers (30) had acute oral toxic! ty ot only one-third that of plasmochin. · '!'his drug (pentaquine) was rapidly absorbed from the intestinal tract and mostly degraded in the body. or importance is the fact that it does not produce the side ;i-eactions that. oharaete~ize intoxication with plasmochin ( anemia,· severe 11 ver injury, etc.).. As with plasmoohin, quinine and pentaquine are synergestic in their joint toxicity (19). While pentaquine is less toxic than plasmoohin, it 1a sutriciently toxic to prevent its use in prophylaxis or in prolonged suppression of ll18.lar1a. However, used in 24. com.b!ned the-rapy with quinine, it is to be. preferred to plasmoohin. $. Paludrine. Cl Paludrine is a 0 NH NH . .... product or the research carried II . 11 . on NH - C- NH - C - N H-:- CH ( C H3) 2 by the Imperial :xr Chemical industries, Ltd.,-"in England (27). The drug was the end product of studies: on certain, del'ivati ves .of p7rimidine, some ot which .had been, to.und. to exhibit oons;derable antimalarial activity. Since the chemical structure differs considerably from the drugs under discussion~ it does not merit muoh more than a ·mention. The drug is said to be .at least as effective as quinacrine, and it has the advantages of not tinting the skin yellow and or being less toxic. Like quinaorine, paludrine will completely prevent or eradicate ~·talciparum and considerably reduce the number of relapses in .t.. vivax. While the drug has been considered a complete causal prophylactic of!... falciparum (i.e., absolute dis- tl'Uction of the blood forms) and a partial causal prophylactic to?t- ~ vivax, the time lag before its action makes the drug undesirable in acute inteotlons. Also. the demonstrated _. acquired resistance to paludrine in P. gallinaaeum (9, 60, 25. 11.3) has raised-doubts as to its effectivenes~ •. E. MECHANISM OF A.OTION' OF ANTIMALARIAL DRUGS. Although the exact.mechanism of,antim~larial drug action ,has not been determined, there have be~n two ...... theories· proposed ,which have shed some light on their possible mode o:r actio_n. These are a metabolite-anti- ·metabolite relationship and the (luinoid•quinonimine theory. ' . l. I!!!. Metabolite-Antimetabolite. Relat1onsh1E• Several authorities ·(75) have indicated that the fact that q.uinacrine. shows a marginal reversal or the metabolic activity of riboflavin when tested onb oasei (99) might be _a clue, to· the. acti~ity or antimalaris.l', drugs. The assumption. is .that the. :utilization of the essential metabolite riboflavin {XII) by;. the malarial pe.raslte _is in some mann&l' inhibited by .the presence or quinacrine (.VI) • CH 3 I CH 2 (CHOH)3 CH 20H NH-.CH- ( CH (~HJ2 ,·. ·. ' . ' . ·,·. J . . 2)/J ~ ~=:oc~_-··· 1___._NX)·_~N- :_-H . . . - N \ - .·. o·. :xm ··.·. This· influence might- be a: competiti.on. between at$btt1ne and riboflavin.according to mass ,action laws of.the same type that is -now established for p-aminobenzoio aoid- sultanilamide (117). 26. On-the basis or this assumption, Mosher (1) and coworkers at- :Pennsylvania. State ·college prepatted basically substituted alloxa.zines whiahmore closely resembled·ribo- flav1n. When; (XIII.) and similar compounds were tasted, they were·.fou.t1d to be completely inactive •. They also· showed no tendency· to reverse the metabolic ef.fects ot riboflavin. · .:xm:.' 2. . ~. gttinoid ..... Quinonimine Theory:~ · It ·haa long been recognized that the amino- quinolines a.re extens'ively degraded in the,body- and it has been suggested that -the achizontac~da~· action or plasmoohin may be due. to. one or more ot its deg~adation products. ' A clue to the ·nature of the produotl formed by . . metabolism. ot: aminoquinolines is found in the observation \ that methemoglob!nemia unitonnly results from their adminis- tration to animals. By analogy with the established behavior of' aniline and othe:r aromatic amines in the body, it may be presumed that, in vivo, derivatives of amino- quinolines are oxidized first t.o hydroxy derivatives and 27. then· to. (luinoniminea.· / ~ NtU{ 0 .i II . 00,, N . tJR The formation ot quinon1m1nes would account for the methemoglob1nem.1a produced. ,Schonhofer (94) has postulated that only·deriva- tives of, 4..... , 6'- 1 and 8-am.inoquinolines: show antimalarial properties because only these derivatives permit a system of qu.inoid linkages between the nitrogen atoms of the quino- ·; line ring and ot the attached side chain. ·· N·R ~~r,a,. coN·f\ . .~· -~-; ln support ot this theory is the findings· that the following compounds, in which the important positions are 28. blocked.,~Sh.ow no schizontooidal activity- in canaries: 8-(4•diethyl~no-l-methJlbutylamino)5,6,7,-trimethoxyquinoline 8•(N-(3-dimethylamino-l-methylpropyl)-acatamido)-6-quinolinol 8..-{4•diethylam.ino-1-meth.ylbutylamino)•5,7•dimethoxyqw.nol1ne 6•(3-dimethylamino-2;2-dimethylpropylamino)-7-methoxyquinoline ', ·P)r."'::,,..., ....-! c.tl o · M .. 3 . tJ~'R Acetylation of the amino group, it should be noted, also cuts out any possibility of quinoid structure.s. 3. Oonelus1·ons. :· Since qu'inine, the 4.. and 8-amino quinolines· and quinacrine all exert e.ntimala.ria.l activity, we must assume that the· intrinsic activity lies in the quinoline nu?leus. ·(we ·Can consider quinaorine to be a quinoline nucleus with a fused benzene ring.) Thus, any changes in potency that result I by modification of the structure of the side chain are determined by the effect· ot these variations on such quantities as·ease of absorption and physiological distri- bution of the drug. The· mol.ecular weight· of the drug· also seems to be an important f'aotor. Slotta and Behnisoh (102) · round that when the:phenolic hydroxyl group of dihydrocupreine is alkylated with dialkylaminoa.lkyl groups of the type used in 29. plasmoohin and quinacrine, antimalarial activity diminishes and ti.nally disappeal"s as the .. weight or . the alkylating group The. authors.. conclude. . ' . that- :a limiting' condition is the inor~ase in molecular weight with. a limiting molecular weight of trom ~ll to 41+0. .30. OHAPTER III THE ANTIMALARIAL PROGRAM 194l•l9q.5 A. THE OVERALL PROGRAM., At the time of Pearl Harbor about 90~ or the sources·ot the·world supply of quinine, up to then the standard antimalarial dl'Ug,, tell into Japanese hands. As a result,· an 1.ntensive. program. to develop alternate and improved antimal&rials peoam.Ef Vital. trnde:r the auspices ot '.the. Office ot So1ent11'1o Research·and Development, &."large scale antimalarial pro- gram wasset up. During the first yea:rprimary emphasis was devoted to an inves'.l;igation of quinacrine- an effective antimalarial already available but little known and used in this. country-._, This wot"k was largely pharmacological and ol1nical., By·the middle or 1943 the emphasis was switched to the aynthe$i s and evaluation ot new drugs. · At the.peak ot activity contracts tor synthesis of new drugs were :l.n fo~ce in 36 institutions, both; academic and industrial, and testing, ,units to carey out screening tests against experimental avian malaria arid to estimate' toxicity were set up .in seven institutions •. , Finally, units tor appraising new drugs on the clinical level were 1n operation in nine centers, including both penitentiaries and hospitals. Jl. >.The objectives.of the antimalarial program for the control or malaria·by 1) ·4-aminoquinollnea 2) 8-aminoqulnolines ,_;J)) · quinolyl-4• ~ ..p1per1dyl methanols 4 ·qu1nolyl~~-diethylam1no methanols S). ,1»4.-napthoquinone der1vat1vea ·Ot these groups. only, the t!rst two are or 1mportanoe in thia work. B. THE 4.:_JU.tlttOQUXMOLlNES. The tint reported compounds in this aeries of antimalarial lnte!'eat weve 6-methoxy-4,-aminoquinolines · pMpare4 (67) and teat$4 4-(alkyl- or-dialkyla.minoalkylamino) quinoline were reported and tested. The structures ot the 7-chloro derivatives tested, except for 2•methyl and 3-methyl derivatives .of chl°-roquine, differed only in variations . ' in side chain· structure •. Only two 6-methoxy derivatives were examined as they showed no improvement over simple 7- chloro compounds. Because of the small number of compounds tested (23 1n .all) it is difficult to draw many conclusions .;as to ih~ re,lation. or toxiofty to ohemioal structure. . ·~ study, however, is able to find· the fol.lowing· facts: · . ·1) Toxicity inore~see with the length of side. ·chain. .. : Side Ohain Toxioit:, (a) Activit:, (b) NH(OH2)3NEt2 o.s 4 30 ~ NHOHMe(OH2)3NEt2· l· Q 1.$-30 ·.; NH(OH2)6NEt2 ·2 Q 10-20 by 2) Toxic-tty- i is redu~·ed. partial '9xidation or the methylene sicie obain separating the_.· two.- n1 trogena. ' ' .. . : ' . . . '. . ;. . ' Side Chain ·~oxici1?y ~~)j Activity (b) NH(OH2)3NEt2 : . o.a Q 15-30 · ' ' ., ' -.:,. ' NHOH20H_(O~,)OH2NEik . o.• S Q 10-30 3) Tox1city-·is geriera~lly increased as .the size ot the substituent in the t'ermirtal nitrogen is increased. (a) Ohloroquine equiv~lents in rats. (b) Quinine eq~iva- lents. Ranges· indicate variation due to different tests. 34.. 'Si'de Ohain Toxicity (a) Activity (b) , ,Nfl(CH2)3NHEt o.s Q 10-20' , NH(OB.2) 3NHBu 1.2 Q 6-,15 q.) The methy-1,groups increase toxicity whan,looated in position., 2, but decre,ase toxicity- in position 3. o. THE 8-AMINOQUINOLINES.'• '\: • r It was not until the mi dd.le ot 1941+ that the 8-am1noq~1nol1nes we?'e given serious consideration. By this time 1t was apparent th~t chloroquine, the most active of the 4-aminoquinolines, would not pi-~vent relapses in individuals infected, 'With; E.~ vivax. Although :plasmoohin was a potent antimalarial, the army (103) no longer advised ita routine use, formalal'1a thel'apy because the margin of safety be~ween_ thel.'apeutic and toxic doses was: too ,~mall. Jn spit~ ,,ot this limitation, plasmochin possessed ,gameto- cidal, actfv,i~Y' int talciparum..(63), reduced the relapse rate in~. vivu: (6.3), and posses~ed causal prophylactic activity- :at tlle toxic dose level (.$1). As a result, an intensive prf:>gram to discover a relatively non-toxic , ' '• curative 8-aminoquinoline was instigated. - During this program ,several hundred 8-emino,- quinoli,ne derivatives were prepared,, including a large (a) Chloroquine equivalents in rats. (b) Quinine equiva- lents. Ranges indicate variation due to different tests., 35. nwnber o_f analogs of ·p1asmochin with_ variations both 1n the,·,side.:chain· (.$',-' 6, 35) .and the aromatic nucleus (18, .62, 73.). as wei'l .as· a cri t!caL study .of th& preparation ot · plasmoch1n. itself (3q_). Over a hundred or these oompounds were ex.a.nli.ned,:_ for. pharmacological ohars.cteristics in at least two species of experimental animals.· Since the avian screening tests seemed to have little. value;Jn predicting the curative properties of drugs in relapsing malaria, the results or the pharme.oologioal studies became or unusual importance and were largely reiponsi ble for guiding both the synthesis of new . derivatives and· the· selection ot compounds tor ollnical trial. The testing program used·as experimental anini~ both the rat and the monkey and in most instances the monke:y seemed,to .. be more sensitive to differences in. to.x1cit1ea ot the 8-aminoquinolines. With the number or <,\ompound~· tested it was possible to draw the following conclus1ona .(ll.$h · · 1). fhe compounds vii th short ohs.ins (2 or 3 carbons) we~e, more toxic than compounds with longer chains (.$,. 9 or 11 carbons)·. · ,Side :.Chain Toxicity (a) NH(OH2))~Et2 .4. ~(OH2)$~t2 l .NH(OH2)11NEt2 o.s (a) Plasmoohin equivalents in the monkey. 36. 2) Branching in,the side chain did not affect toxicity in the. series ,.with terminal :isopropylamino ·or d1ethylamino groups.· 'Branching. appeared to· increase toxicity in the series ·with·teminal prima;-y· 01• 2.;.piperidyl groups. S1de.Oha1n. ·Toxicity (a) NH(OH2)q.NH•iso-Pr ·. ·· o.2S .. NHOH(Me) (OH2).3NH•iso•Pr o•.s · ' NH(OH2)q.NHa 0.2.$ NBOH(Me) (OH2)3NH2 1.0 3) +11:mo,t·oases changing the state or the terminal nitrogen·did not affect toxicity-. In compounds containing three methylene groups in the chain and terminal ethyl groups, changtng the nitrogen from primacy or seoondary to a te~tia'rY amine.markedly increased toxicity. Side· Chain Toxicity (a) NH{OH2)3NHa' 0.12 .NH(OH~)3NHEt NH (OHi) 3N.Bt2 4J Ohallg~s in tenninal alkyl substituents had no great effect.on. toxicity-.' Side Chain Toxicity (a) NH(OH2)3NHEt (i) Plaaniochin equivalents in the monkey. 37. }lii{OH2)3NH.-iso•Pr . o.s NH( OR2 ))NH•is'o-Bu ,l.O $) The 'resulting tox1.c1ty•when any of these drugs were administered with quinine was at least a summation ot the individual toxicities and in some cases,it was greater. 38. O~TER IV DisaussION.OP THE PROBLEM The ··prevention ot relapses in malaria· i~ sti'li ·: ·not a simple· problem despite the development ot new and more. 'potent· a,ntim.alarial ~rugs. Chemotherapeutic. agents in general use against malaria today have a highly seleotive action. Drugs capable ot destroying trophozoites ot the erythrooytio cycle.are incapa:t,le '?~ action on p:re- erythrocytio tor.ms. . Also, drugs. potent against pre-. erythrocyt1c,,foms are largely without effect on eeyth- roo7tic to~a.: . Quinine, quinaorine and chlo?'oquine, as .far as practical benefit .against· asexuai forms is concerned, are aotlve onl7 .on .er:rthroc:,tic foms. Plasmocbin. and pentaquine act exclusively o.n exoe17throcytic format A newer approa~h .(33, 92) calls tot- therapy to be directed ' , ' • .: I toward P.reventlon of th& exoer,-thttocyt!c type ·o~ relapse as •. ' • '1 • ' ~ ' f , ' , • , well asf·toward the eey-thxaooytio type•. Ei~ll,er a s~ngle ' ' . '; .•. . ' ' . . . - drug mu~r be discovered which, has' a twof~ld oapaci~y ot acting again~t the parasites or· both. phas~s.· or a ·combination ot two ·drogs which. give. the s~e final.result must be uaed. ... fo ·date paludr~ne la the only drug having .even a ' . . . partial du~l activity against.both e17throoytio and ·exo- e17throcytic ·torms. Some success has been achieved by a qombination or . plasmoqh_in and. quinine, but, as ·1 t , has alrea ' ' action and s.ttenpt to. incorporate these into one molecule.·, Suoh a process is called nhybridization. 11 The chemical . : . literature 1s filled with such attempts in many fields • . I Several tries have been made· to apply the principle of h7bridiza.t10~·:to. this problem. BUI'Ckhaltel:' and coworkers (J.4.)reoognized that most acr1dine antimalarials display a char-acteristio sohizonticidal action, whereas quinolines usually show greater activit:r against the gametocidal form of the plasmodia, · They therefore . · prepared 2.-methoxy-6- · chloro-9•( r -(6•;•methoxy- 8••quinolylam1no) • · propylamino)-acridine (XIV) and similar der:l.v,atives which aombine the essential structures or atabrine : and.. plasmochin. At approximately the same time, Quin and·Ro~in~on (80). in E;ngland reported the synthesis ot •,' ' the sameieom.p~und•.. (XIV) has been .. shown to be active both in b1:rd1 and .man.• .: ,,Jen~ch (.$4) has repoxrted the synthesis of basic double ethers;of.4 .th~ .Q.uinoline series ot the, type .bis-(2- methyl-4~amino-6-quinolyl)- methylene d1ethe:r (XV), while Sargent .and.Small (93) pre- pared 3•chloro-7-methoxy.;.9. · (8-amino-6-metho.xyqu.inolino)- acridine, (XVI) and ·various tetrahydroquinoline derivatives. ·:tn·~eporting the synthesis ot .camoquin (16) ,.'. / ( Burckhalter and coworkers lµ.. again e.pplie.d: :the.,prinoip,le. of,.p.:rbridization. Noting the fact tha~. am,inoallcy"+ ph~nols possessed ·antimalarial action (l.5) , .., syn~hesis ·.or. -,analogs opntaining .substituted het.ero- cyclio nuclei was.accomplished. Both the .aoridine (XVII) and the 7•ohloroqu1n,oline .(XVIII,.Oamoquin) nuclei were added., .. Olinical activit~r was or the same magnitude as chloroquine (VIII), and atabrine (VI). . ' ' XVI I As ...we have, already seen, the. 8-aminoquinolines have a speci~~c.aetion ont:he ,xoecythi-ocytic forms or malaria,,while the 4-aminoquinolines act as good suppressive agents and ~ttaok, the erythrocytio forms. Applying . the , pt'in~iple ot hybri4ization, it would seem that the synthesis ot, oompo~ds containing both structures would. lead to a drug with biphasic action. W.ith 1ihis in mind, the synthesis of the followi.ng compounds, was attempted. q.2. c~o~.~....t•: ... f.i~cl OC)'' ¥tt~· ~ C~aOQ) .· 1-1t-l-C14z.~~H-CH&~ t-1 tf . NH-CH -~H-CH -Nt4 1 1 otl . HlCM3)2, )()(V B )(X\/IL 13 .:· While a structure such as XXI would. more closely combine the structures of plasmoohin and chloroquine, it was considered that.the probability of greater ease of· preparation of (XIX) and. (XX.) me.de them logioal compounds for introductory research. At the same time, the use ot the· chlorophenyl group in the so-called "open models"·or atabrine (}µ., ~2) and the presence '. ot the p-chloropnenyl group in the drug paludr!ne indicates that compounds (XXII) and (XXIII) might have increased suppressive activity and could also serve as model compounds. -.•H-CI-I -c~ -cH-~ F"'-c.1 N. 2 I. z"=./ ~. ~ .,E~z C.I ~'J.V II A In both eases the_ su~sti tuent on the mid.dle methylene carbon was purposely chosen. The hydroxyl .in the side chain .or the 4•am1noquinol1ne is known to . ' decrease· the toxicity of the molecule. while the diethyl- amino group , should increase . the solubility of the:· 1a.rge molecule.. The proposed method ot synthesis ·1s : shown in Figure 1. In the search for new leads tor antimalarial as well' aa Qther drugs, the study- of bis-propylenadiamines 18 'i' -, a natural consequence of the preparation of the·· unsym.tnetr1- .. ' ;; . .. ; . . .,~ \ ~ \ cal prop11ened1anunes disous·sed above. Ag~in the ·ani1~ee in qt1eation would p•ohlo.ran,111~e· a~d 6-ntethoxy~8-e.mirio·-: ' be ,:•, . . . ,, quinoline. The proposed· ·method of synt~eais tor the~e :· • '' :, '- ,' ·' J,, compounds is. given in Figure 2 •· ·._ -, '. ,,, Figure I. xxv1 A,B Cl :X:XV A,B xx v II A,B (A) . ( 8) Figure 2. 2R'NH 2 + 2 HCHO_+ RCH 2 N02 \_ 1Cot. l Cot. R R I ,H I H / HO-CH ·-C -CH 2 2- OH R-H-CH-2 C-CH-N-2 R I • Cat. . I . N02 N02 R R H I · H I f HCHO , H I H , R-H-CHcC-CHcN-R ...... R-N·-CH - C-CH -N-R HCOOH 2 2 I I N(CH3)2 N H2 . ··) q.6 • . OHAPTEB V ; Dl:SOUSSION ·.OF. RESUL'rS A. UNSY~R,.IOAia HYBRIJ?~-:REL~TED TO PROPANEDIAMINE •. The: known and,.general method for preparat:ton ot - ·,, I • '. ' ' t ' •, :: N'-alkyl substitutedlJ.•aminoquinolines is the condensation ,, . ,- ·: _:. I ,' '. . ,• ' • • • ' ,· _1'1. ' :\ ' ot 4, 7•dichlo~oquin~line with the appropriate primary amine (17, 29, .}8) •. Thus .. the major portion or· this phase or the ~ ' ~ ; ' • • • ' ' ' ' ' : ' ,l • ' w-orlt ·was: th~, synthesis of tbe n~cessary .side chains. ,.. ' ·. ·,· Since. bo:th. :the intermediates and two of the pro- .;. • • " ' •• ' , ' • ';' •• .. J ' ' .t1µ.al a s~condary h,.-droxy:l group . posed products. contained. . . I in the ;side chain, the o:t,vious star~ing matex-ial.was_ l•phthal1m1do-2,3•epoxyprop~ne. This oompc;,und·was chosen because the phthalio acid group could easi~y be rem~ved to ' . ' : .. give - - . ~c-~ ~o- -CH-CH - N"c ..: .. RCH RH + CH2~CH-CH2~t.1, · _ ._ .....__·.····.I ?.~I · , I· - ·; C • z. 2 'c . . . II. . 0 ' •, .. .0 0" ~ . ThEf ep~xid~J· a knowi compound·, had been pr~pared ·· (109.: 110) by. 'the 8.otiori. or. epibromohyd:rin ori potassium : l)hthalimide·: ( 77.) • . This work was· repeated, but, under ' . . . . . ~-· ' anhydrous conditions, 'it·was found ·,.that comparable yields 47. could be obtained.using the less.reactive epichlorohy-drin. ,. ' 'i ' ' 'l'he Usual pl'epal'ative ~thod (31 .. 45, 61) ot N-a.lky1-.8- aminoqyino.lines .1s· the rea:oti6n of one o~ two moles of the quirioli~e;with a.basioallyi~:ubstituted alkyl halide or its < ' ; '. :.:,. • ~ ' ' ' . . . ' : ·' ' •• salt •. .. Bee.a.use of thi~ ,· l•phthaiim1do•2, 3-epoxypropane . . (XX) was treated. iwith both dry: HOl gas and aqueous HOl to give l-phtllaii~:1.aQ.; .. ~hloropl'Opano1'-2 . (~II) ( q.0) •. • This compou·n.d.'.:waS': then 00110.ens~d. w1ti1• P•Ohlo~anilin~ 1n: an,.· attempt to pi-epa.~e 1-phthalimido~J-p•chlorani~U.noprC>pano1-2 (XXI·:.A). Du.riing, the course of >the ·study ·of this ·reaction it w~u,; fourid th~t veey little yield of the; des_l!t'ed produot was ·obtained f'rom. the attempted oo~densation.· \In an: ' ... . ·~ . ' / . . ' ' . . i. ' . i ' ~ttempt' to:· Jnc ree.~e the ·yield, en equi!'.fllen~ amount ' or sodium· 1odid~ .·· w_as· adde~ to the rei'~~ing ~lcohol solution • . .. , ·r '?he- yield was 1noreased to 9 p~~/ ~ent·,. and a significant . r :: ~ ' ' ' ' , . . , . ' amount 'Qt ·l•phthalimido-.3-iodopropano.1•2 was found in· the ~ ', i ; ( •, • ,: • • \ • ; ) ~ • .1 • '•.: • ; < '. •, :.-, ' ,: ' • .··, .; ,' ' • j • • ' • ' : • ; I • / resultant mixtui-e. On thti, basfs ot ·this lead, the 1odo· · < ·t,, '· " compound was pNpa.red rrom·the chloro·compound ·bJ' ret'iuxing .,· . ' ' . ~ ·,' ~ . ' . ' . with ·sodium iodide in dry acetone : solution ( 10). When ·the '1 4a. iodo, compound, was .used in· the condensation in place of the chloro compound; the yield was increased to. 16 per cent. Since the yield.was still poor and sinoe amines are·knownto,react directly with epoxides to give amino alcohols: (19, ,36), the dil'ect .heating or p-chlorani~ine · and l-phthalimido-2,3•epoxypropane (XX) at 1$0° was tried and res_ulted in a. 65 per .cent yield of the desired product. To:test the applicability.of this step, four · aromatic amines were condensed with l-phthal1mido.;.2,3• epoxy-propane (XX).· The ·results ax-e listed in Table l. TABLE I R Yield, o/o M.P., 00 p-oblorphenyl (XX.I A) 6S 178-9 . 6-methoxy-B•quinolyl (XX! B) $6 ~3-4. •. S p•nitrophenyl 58.S 196 •.5-7.S p•acetamidophenyl 53 1a9-90.s_ Both the. p•ahlorphenyl and the 6-methoxy-a~·. quinolylcQmpounds were cleaved with hydrazine hydrate by standard methods (7 ,. ; 50) to the corresponding emino compounds. ·These amino compounds were condensed with 4-,7-dichlQro-quinoline to give 7-chloro-4.-(3-p•chloranilino- 2-hydroxypropylamino)-quinoline (XXV A) and 7-chloro-~(3- (6-1r1etho:x:y•8-quinolylam1no)-2-hydroxypropylamino)-quinoline (XX.V··B) respectively. ·. It should be pointed out that before these studies •' . . ' . were begun_ it was known that both 8-(3•phthal1m1do·2- hydro~ropylamino)•6-m.ethoxyquinoline (XXI B) and 8-{3- am1no•2-h7droxyp:ropylamino)•6-methoxyquinoline (XXIII B) were listed in the "su-rvey. of ~timalarial Drugs" as having been prepared··and tested.·· They- were not reported 1n the literature (23), however, until after the phase ot the.work report1ed here '-W4S Completed. -: It is interesting to note. that a ditt~rent method was usced .. 1n.the preparation. In the· reported work 6•methoxy-8-am1noqu1noline and l•phthal1mido•3•chloro- . . . propanol~2 (XXII) in n•butanol were refluxed 68.houra·to give a 29 per cent. of the. desired product melting at 1'44-.$0 • The procedure listed hare not only doubles the yield·.·(S6%), but also cuts in half the time requi~ed to prepare the compound. Thus, the condensation ot aliphatic or aromatic . amines with l•phthalim.ido-2,3-epoxypropane (XX) followed by so. oleavage '.':fith :hydrazi.ne hydrate appears to be a general method· toi- ··the. ·preparatio:ti ot N-subs;ti tuted-2-hydroxy- propaned.iandnes. These .compo~nds can be condensed with ~:. 7•d.ichloroqu1noline to form possible antimalarial drugs • .< The replacement of the hyd~oxyl gi-oup in the. side ' ,• \ Ohe.inwas,attemptedin several ways. Th!onyl chlorid~ in dry ohlorofo;rm was used in equivalent quantities as·well as in tw~ ·and fo~r fold exce'ss. This reJgent was ·also used in large exoess by using 1t a~ the solvent for the reaction mixture .in. an:attem.pt to inhance.reactivit;r. PhosphorGus o.x:ychlor1de, phospho?'oUs pentac;tilor!de and phosphorous . . . ' tr1bro:mide were also used~/ In every-, instanoe, eithe~·;, starting··nu~.terial or u~ohara~ter1zab,le tars. were obtained. l•:Ph:thal1mido~3-p-ohloran1linopropanoi-2 (XXI A), . . l•amino-3•P•Clll. f\N-CH -CH -CH -NHR . t I 2 ., ) ~f\l- C~z.-C~-/CHf. ' c, 1N, + . CI- H R the tendency for ·;ttearrangement. -Thus, the return ·of the starting;materis.luncha.nged is anindication.·at least, that no reaction had taken place. As a check ot thitl observation, the free base of ·. 7•ohloro•4~ (3-diethyla.m.1no•2-hydroxypropylamino )-quinoline was prepared .fI-om the commercial diphosphate and treated .. with an· exeess ot thionyl chloride.· A b).aokish tar was > ·,$, obtained which could not be cr,yataillzed. There is· at least one other repo~ed instance ot an unreact1ve bydro,cy-l group. In the case of (XXVIII) which closely approaches the atructuJte in question, the hydroxyl group could not be replaced .with ·a; chlorine_ atom _(70). , The only reported. I . , ,. l'e&ction ot that functional group was dehydration. .$2. As, a result .ot. th.e, inability: of chlorinating agents: to :replaoe~:the hydroxyl·group, the. two compounds . (XXVIlc,"Al and, (XXVII a) containing diethylamlno groups in the aide'i<,hain~··could not be s,nthesited. lo' completely· satisfac.toey" e.xplana.tion fol' the u.nreactivity of\ this: secondaq ;hydroxyl is evident. from the data at,p.an.d.: Xt would be.difficult to explain from ster!o effects• · especially ln.· ·the case of l•e.mino•3•p•chloran111n- opropanol-2. A possible explanat1o·n lies in the tact that on:three _a.djacent.cai-bon.atoms there a:re substituted three groups, each ot 'Ahich contains at least one hydrogen .and at ieaat: one 11nsharedpair ot ~leotI'ons. 'rhe possibility of a doubly chelated stru..ctutte which would tie up the aeconda:tiJ". hJdtto:Jtyl c·annot be overlooked, especially when in eveI"1 case there would e:xiat two tive membered,chelate rings~ B. SYMMETRICAL. . ' . m13RI1)S RELATED TO. PROPANEDIAMl:NE' . AND METHANEDIAlfINE • .. .In t.h:e pre.vious. section it was found t;hat. the ' ) ' ' • i ' '· ' ~ • ' ' •• • • • ' replacement the hydroxyl on the middl& ·carbon the '" ' ' or ' or ,. ·~ ' . . . . . propane bridge or unsymmetrical·hyb~ids (XXV A,B) was not posail:>le using the usual methods and reagents. In an attempt to obtain the desiredpx-oducta (XX.VII A,B) oi- oompounds Closely approaching them in structure, it'was considered. best to begin, '1t pOS$ible, with the nitrogen S3. already in ·tne' propei- posi'tion •.;·: As a:. result,. the reaction .with· fol'lllaldehyde' and the: ;nitroparaffins th ot ·amine a,' <, > .'' ._; ,, \.· ' ; I or·• • wl • ' .2•n1tro-l_,3-propa~Eldiols seem.~~ •.to. g~ve _a, possibili t:1; worthy of investigation. P\t.gUr$- ·a· give$ a ·generalized flow sheet iot the proposed/steps in the' syntheais in which 2-nitro•l,3- · , propaned!.'andnes could be, formed~ Hen'~ (q.6,. 47), haa, ~hown that· n:t.trom.ethane ·reacts with N•h.ydroxymethyldimethylamine ' . . . . of;CHzHO~ '+ (c113)~ NC~10H ~'(c~AN-Ctlt-~H-cit1.~rilcH3) 2 N02. _ to: give ;2-n1tro~l',l-bi'sdi1netb.ylaminopropane and' with'\ >.. N•eya.i-Qxyntethyipiper!dine 'to 'give· the· corresponding ,2~nitro- ' ' 1;J•bis~{N•p1peridyl)~p~oparie, ·while',- Duderi, Bock an~ Reid (.32) ·have 'iretja'red ·2•hit·ro·..;.1,3-bisanilinoprop~e'by' the; • .aetlon··o:r··an11ine on the' rea.ction·product of dimethyl.amine, :t'ormaidehyde' and ·nitromethane~ .. (ct1 3) t N-C~1.·f'H~z:-t-1{u13),_2.t/, NH';. cJ> NH~CJli-ftt-CMr.- .a H 4 ~~ N~ Very little work· has, been done on the··:use ot aromatic· ami_ne~' in_ the ·:reaotiori.s shown in Figure 2~ ' Johnson CS~) 'has_' pi-epared a' sel:'i8S ot; aromatic, ni tro~; . -Sq.. antines u.s1ng at sta~ting materials tomaldehyde, 2-ni tro- propane and various amines. or the many ·compounds listed, only N,N! .. cliphenyl--2•nitrQ-2•methyl•l,.3•Propaned1mnine was ot the typ~. that: was of in.teres_t ,in this work. That compound was preparediby the .x-eaction .of. aniline· and 2•nitro-2-math.yl• l.J.. propanediol in the presence .or a stx-ong base. :Also listed as a method ot preparation, . although·:_not :attempted .by Johnson was the direct reaction ot aniline :with .formaldehyde and n1troethane •. . , With. ·tllil backgroundt: 2~methyl•2•nit~-l,.3• propanEtdio~,and,2~~thyl•2•nit~~l,3•propanediol were prepared .by'.the .meth<>d _ot Vanderbilt and Hass (107). With p•chlo:t*aniline as the model compound_. NiN"·di•p-ohlorphenyl- 2•methyl•2•nit:ro•l, .3•propan'ed1amine were ·prepared·. . Because of the. difficulty: in prepa:r-ing., 2•ni tro~i, .3.;p~opaned.iol~ the first·· compound, W'aeL:prepai'ed ··by the, direct .. reaction ot ··: p,-chloranil:lne·, fo~maldebyde and nitrom.ethane, while in the preparation. :o.f ~he second oompound both this. method and the ' " method s·tarting from ,the n1 troaloohol was used·• .· The. s~• reactions when. applied to 1-;utropropana and 2•ethyl•2•n1tr.o-l,3•propanediol gave:a hea:"Y• dark, ' '1 '., v1aoous:o11.wh1ch.could not be crystallized •. These ·reactions ·Were repeated with 6-methox.y~S-am~noquinol:lne \ ' . . \ . '' " ' ·- used in·P,lace·or.p-oh;or-an111ne. When the quinoline was condensed with. formaldehyde and ni trometh.ane in refluxing methanol, a large. amount of amorphous brown solid precipitated slowly as the reaction prog:ressed. A small amount or brownish-yellow crystals (m.p. 212-J.4.0)p~cipitated from the mothe:t- liquors afte~ filtration i'rom·the undissolved ·.S6. solid •. Tht-tunorphous .solid could.not be recrystallized. Ree.ctiono:r 6•metboxy-8-aminoquinoline·w1t1i: 2• :methyl•2•n1tro-11 3-propanediol and 2•ethyl•2-nitro-1,:.3- pflQpanediol in the usual manner· (5$) gave yellow crystals · which proved to ·be identical with each othe~ and with the cryst·a1s dtaminomethylentt com.pound. tt ' When this compound was dis.;. solved in wann hydrochloric acid• a product separated in vermillion crystals melting e.t 2.$0° (dee.) which was ''probably· the d1-(8-am1no•6-methoxy•5)-quinolylm.ethane- hydrochloride.f' • freatment of the hydl'ochloride with alkali gave an orange solid melting above 2.$0° which they state also could not b& ·recrystallized. $7. + HCHO N~ .-.--CHz Nl-4-z. :. 1\Jtli_ . 2. tfC,\ •2. \-lz-0 ,{ 1t1. p. ::. >250 ° (~. p. = 2.50 ° decotft .) , Iri light ot this .work,. the hydrochloride or the · compound obt~in~d: by the ·three different reactions was· pre.pared (~.p~··21.t-J-4°) and then treated with alkali~ The original compoundwas·obte.ine~ ·1n ' ' shown by diazot1zation.1n acetic acid solution. This compound was c.onsidered. to have the probable structu?'e·or di-(8•amino•6-~ethoxy-5)-quinolylmethane XXIX. This compound ... could .only be formed from the ni trodiola if' tree formaldehyde were present in the reaction mi~ture. sa .. This \VOUld indiijate that the nitrodiol must ·b:reak,down.into to:rma.lde- 'hyde·an.d.'tbe nitroalkane xx1x, and the tpresence of the etrong bas& acts. as a eata1yst_, indicating that the reaction is reversible. (( l .. HO-CH2-~-cr11-0l-l N01.. · A more careful study ot this reaction led to the isolation ot a low melting (130°) white.solid having the same moleoular formula (021H20N4-02) as the yell'ow compound already obtained trom the reaction mixture. This low melting compound, on treatment with HOl, precipitated a red hyd~ochloride identical with that ot· the yellow compound and treatment or the salt with alkali gave rise to the same yellow compound that was first obtained. Thus, irithis case, there was a rearrangement. Identities were again shown by mixed melt1ng·points. The low melting.white solid was oonsidered \\JH-- to have the sti'uctu:re or N,N'-d1-(6-methox.y-8-quinolyl)-methaned1amine (XXX). The identity ot (XXX) was definitely proved to be the methane- diamine structure by independent synthesfs ·or the compound t:rom.6-methoxy•B•sminoquinoline and formalin solution. The two were allowed to ,re·act: at'::~oom temperature tor on& week and the low.melti:ng compound obtained in this manner was identical with. that ·obtai~ed. in the· reaction ot 6-tnethoxy- a~~tnoquinoline ;e.n.d the· n1 trod.iols '• N\1----- CHz..--N\-1 xx¥~ To check as to whether the reaction was general in nature,.· the $'-chloro de~ivative of 6-metho.xy-8-am.ino- qulnoline was prepared according to the method ot ])rake (31) and tx-eated ~1th formaldehyde and with 2-meth11•2-n1t.ro-1,3- propanediol. In both c·ases the same compound was isolated which was· ~ons!dered to be N,N'-di-(.$-ohloro-6-methoxy-8- q,uinolyl)-metht.Uiediamine (XXXI) C( + HC.KO ,N~l Wtt Ctlz.-.. - NH )(XXC Treatment ot this compound·.with HOl did not result in a rearrangement as before, but isolated from the reaction 60. was 5•Chloro-6-metho~:-8-am1noquinol!ne, ~esulting from the toss of.'fo~aidehyde. This .~s .in keeping with the· reported )•' / • a (8)• ,,- results.' . ; with,, the'.' s1m1lar·p-..chloraniline: , . •- .I ; .. ':· ' compound. . ' . ' Bi s:ohof,'t . and Rein~e:L ' I • ' die.mine w1 th H.Ol . to obtain elimination of f'ormaldehyd_e. A restudy or the reaction o~ p-~~loran1line, fc,rmal~ehyde and ni tromethane_ led to th~ isolation of \,.is- p-chlorphenylm~~ha.nediamine. The struct~re was proved by independent synthesis (8) and.mixed melting point. While the yields were· lo~ Ut-5~) for the reaction ot p•chloran111ne and 2-methyl-2-nitro-1,3-propaned.iol, and a large _amount or light colored oil was obtained, it was not possible to isolate the methanediamine. This result is not c~nclusive because-or the low melting point ot·the compound and the fac"t that·· all the compounds in the reaction mixture had · approximat,iy,the-same ~olubility. relationships •. :Using the high' pressure, low temperature me;thod of Johnson (5$), it.was possible to reduce the aliphatic- . . ni tro·. group of N, N' •di•p-chlorphenyl-2•n1t ro-l t 3-propane- diant1ne to give the tr1am1ne, N,N'·d1·p-ohlorphenyl-2• amino•l,J~propanediam!ne.... The ni tro compound was reduced at 1000 :, pounds pressure.· at room te·mperature tor four hours and then at S5~ for two. addi tione.l hours. An attempt to methylate the f.ree . amino group with tormaldehyde•formic . '· acid was unsuccessful, This.was not une.x.peoted as such 61. methyl.:ation· has -bee·n f9und ·to', be uaetuJ. only tor low molecular weight alip_hati(t compounds~ C, .. THEQRET.IOAL QO~~l;1:l1RRA~I0MS. Th~. f1miitlgs, \he 'pre~ious section are in keeping ' • ', ' , ' ,' ' .. • . • ~ ' '1 . Jr ·; ' \ '. ' , ' I ; f I ! • I w1 th 1 what. is known. about· the ·consideration of formaldehyde ~ '.' ; • .'' • • •• ' ' I • , ~ i '.. ; ' \ :. • ,J • : :- ' ' • :' , ; • '. , i '\ '. w;t:i,. aromatic.am1nes. It .has 1:>een shown (71+) that in the pttesenoe ot dilute al~s.11, aniline and formaldehyde react to form N,N'•diphenylme~hanedia.m.ine. . . . This 11 a general reaction Which.haa·been shown to hold tor ', - . •, (\ • ' > • '• • I ' such compounds as methyl aniline ( 39), ethyl aniline ( 39), o-toluidine (ll) and p-toluidine (106). ,· ..i In. tl;le...Presence ot ~o.ida 1t. is possible to isolate , ·,,·' ' ' ' . ·' . ' " ', ,;, . directly de:rivati ves of diphecylm.etbane. The hyd~ohloxalde : . . ' ' ' '· ' . . -~ . . . ' ' ; . . : ' . ' '' ' . ' ' ,, ,,. ' . ' ot a.n~llne1 ·when ~l'tU.tted.with formaldehyde at 60-900 will form 4,4"·d1e.m.1~odiphenylme~hane in 60.:.7,0 per ·cent yield (89). , . ' ' ·~ i' With cydro.ablor1c .acid, methyl .aniline and formaldehy'de give 4,Q.•-dlni.ethylaminodipheilylmethane. together with complex amorphous, condensation products (13). 62. Wht3n .N, li'-dip~enylmeth~ned1anune . is heated with an chemical• .. ' 1rreverse.ble'. ' hyd~chloride, : ' ,. aniline . . t : ,. / .' ' •. anilinE(.and .• ' '. ' ·,· . . . ohange,:taktHk:place.,in whi9h: tf).e ;m,thyle11.e group s~ins's into the aron.t,tio< n~olE>us .givi~ ri.~e maip.ly_ ( 90%) .to 4,4~ ... diaminodiphenyl111ot~ane (74) 1 although King (58) has s~own that .. about·:10\pe~ oent of .the ·tru4e produce consists of the . . . 2,4•aompoundt · ::. The. work of \V e.gnel' ( 72: 1 108) and Simons ·. ( 10.0) has e • •, '''amines with, ,, tormalde-• • ',; of. aromaticl interaotlon.,'•,' shown - that•, the''' '; hyde in'..s.cl~.,media •. can. be· a•sumed ,to pr_oceed ,with prima'ey . tormati·~n. :ot. diaeylaminomethanedi~mine (ArNH)20H2 ·.or .. a Schiff... base. :~~N==<.Hi2. The· end: pr9duct. of the condensation, howevex>,: app.ear.s. t<>. be the resu):t of further reactions · in~uoed py.'. :the inatab.ility.. in.. acid. media. 9t the g~C>~J>.in~ N•0~2~Nf · Among ,tlie se.oond.arr reactions .is the is.omerization ot the ~ethane: :<.iiami11:e (or Scbitt b~se) to the amino~ beneylani.l~n$ . o~ ·41phen1lmethane ·..base:s •. .. 'Tii~ aminobenzy1an.111ne base ma.y be obtained ·as a major p~duct tr~m 'a. 'mixture of. the' methanediamine . (or' Schiff base).with th~ corre$ponding amine and_amine salt under mild conditions and in the absence of water. At ~igher 6.3. temperatures, essentially ·th~ same. reaction yields the. d.iphen,lmethane basa,:and, as this~$ formed also.it the ·aminobenzylaniline base ls used., 1t· is obvious and I : generally accJpted ,· that the entire ti'ansformat1on involves the two well•detined steps shown above. ·. Thi'a behavior appear.a to be general tor primary- 0 mnines.. and tn!H~onda:ey amines or the t.ype ArN.HR. Substi• tution or:the para hydi--ogen reduces the possib111ty·or this x-earrangement. As already indicated, treatment·ot bis•p•chlorphenylmethan~di~ne with HOl. causes the mole- o.ule to be ,broken up into its components. (8) ~ The :P~.· toluidine·-rormaldehyde addition product whioh can be formed ve1!'1 ~eadily ·can be forced· into'. a re~rrang~ment. · Tollens {196,), report~ that,~ the oompo·and will :x-eluctantly pas~int~_2,2•-d1sm1no---S,.S•-dimethy1<11phet17lmeth(lne ! ~ . ·. in V81!Y ..small. 71.lds •. In~ .the c·ase N,Ji 1 •d1•(~.:.aliioro-6- ,-. . .ot meth6xy-8-quinoljl)-methaned1amin:~ (XlCX!). the_ reaoti·o_n ia similait ~o ,the _p ... chlorphenyldiamine in tha~/the only . oom- ., pound isolated from the· t~e.atm'.ent .with HOl was the original 5-chloro~6~methox,.-s-·aminoquinofine·. '!'he reaction or 6-:methoxy-8,....am1noqttinol1ne .with . ; . ·-;:.-... : .·' the 2•al.kyl~2-nitro•l, 3~propaned~ols is important, ·8.S ~hese reactions' give.the :first chemical evidence .ror establisb.ing ~' ; - ' : ' ; .· . ' ," . : ' . \ ' . . ' . . ' the meohanism ot theit- reaction with amines. · The work of John~on (SS} .did not. give ·suti'icient ' . . evidElnoe tor establishing the mechanism of the reaction. He., postulated howevett that;: since his Method A (the reaction of the tmd.~e, formaldehyde and the n!tropax-affin) is more rapid than the Method B (the reaction or the amine with ·the. nitro alcohol), the following mechanism was probable: .MerHoo R: RNH~ + HC.HO ---=, RNHCH 2 ot-r r . When n!tl'o alcohols a.re used (Method Bl. the .first step was postulated as: ow--'.., followed by·the reaction o:r the amine with formaldehyde as in Method A. The .f'o:Mnation ot the nitro alcohols is thus conside!'ed. to be a reversible reaction, and the tu.notion of calcium' hydroxide, v1hich is usually employed_ in the reaction, is to prevent the reverse reaction from taking place. The isolation of N,N'-di-(6-methoxy-8-quinolyl)· methanediamine (XXX) and N;N•-di-(5•ohloro-6-metho.xy-8- qu1nolyl)•methanediamine (XX.XI) from the reaction mixture starting with the nitroaloohol and a strong base is definite proof that in the presence of that base the nit:rodiol liberates formaldehyde. / 6$. , ,· R , . . t-10-c.wr?-cJ1 2oH , N02. : The second step of the reaction. is the inter- action ot·the amine·present with ·the formaldehyde to form theN..-hyd.roxymeth7l derivative ot the amine. ·This compound ·would easily· lose a mole of water to form. the anhydroformaldehyde . o:r methylene anil.1ne type , ( 8) • The ·possibility:of two final px-oduots results from the o.~mp~titive reaction between··the :unreacted amine present in the solution and the anion of the nitroparaf1'1n (formed in the presence ot the strong base) for the 1n:~thyle~e' aniline compound •. NW2 . .. t ,. . The secon9- reaction could be completed by a rearrangement add1 ·or· r the··, 1nterm.ediate, ' . • ' .' ·1on f , and•• • tion' ' of another molecule 66. · M1i_J-.. - 4 R_.·· c \-12. .[~·-r~ .. '-~.·-~1-\ ' t . \ · ·: !NI~,, \ l ~tfR It is important tc:>.note that ·1n the case or 6- methoxy-8•am1noquinoli:t1e · and tonna.ldehyde ,: '.Whan the .. temperatur,e ls, ele_vated, nucle_ar alkylation tsltes place Etveri. in basic solution. The s,lkylated,quinoline (XXIX) was i~ole.ted:lrom the ..reaction of 6411methoxy-8-amino- quiho11ne,' formaldehyde and ni tl*Ometba.ne even .though the reaction :m1xtu.fe wa.s never acidic .. · Even the reaction of formaldehyde · and the q,u.inoline. at room. temperature seemed to give some. of the .. alkylated. com.pound, ._but results· , ' were ' . : . ~ ' . . .. ' not oonciiisfve as the solve~t had to be heated ·during the . workup of the reaction mixture. · ··Thes·e r·esults are not unfeasable in view or what 1s known about compounds containing two electron donor groups meta to each other. It is a. known fact (74) that when. fot'maldehyde con.dens~s. with metad18lllines, the . formaldehyde passes direotly,_inte> the, ring~ 67. Price· and coworkeJ;'S ( 79) during a study of the cycl1zation of ,8-m-chloranilinoacrylates, obta:tne4. not only the expected.·7•chloro-4-hydrofy-, and 5-ohloro-J+- hydroxyqui:nQlines, .but l,l._-bi$.,:l7-ohlo:ro•4•hydroxy•.3· qu.inolyl)-,ethane ~ . ~c-oR aH 0 . rotfOr::O)Otl-.:: ' \ + . .. ~ N,. Cl ·._·.':_.a.'.·· ~ .... ,CH~H 2so; 00·~ ··I ~_,,. C.I . :· WK C. I M +oot. " l O oJ., The biqu1noline at~uatu:re was established. by isolation. ot the_:identical 'material by_ treatment or' 7-chloro-4-hydroxy- quinoline with acetaldehyde undei- the conditions ot the e.x:periment. - Cl j An interesting, it somewhat anwnolous, result is the tact that while traces of both predicted products were found in the p-ohloraniline runs, there was no evidences of the 1,3-diami'no-2-nitro compound in those experiments in which 6-methoxy-8-am!noquinoline was used. This is or even more puzzling nature when e. stud1 of relative acid and basic 68. strengths ot, the compounds : i,n question indicate that they are very close. . Albert and Goldaok ( 2) in comparing _the diss6ciation constants of seven isomeric aminoquinolines found th~t- 8-aminoquinoline had a pKa value 0£ .3.93 whioh was approximately one lowe:r than the value for quinolin·e This decrease'in basic s::trength, was said to be due to "ortho" ,. effects, but. it was not indicated as to whether it was due to H•bonding or steric hindrance to approach or the hydronium 1on. Several, values f·or the Kb of p-chloraniline are listed 1n· the>Jiterature. Myrbllok<: (76) J..ists 0 Kb : J;.9 x 10-ll,. ''armer (37) lists 14.9· x io"".'l1,· and Willie.ms (112) gives 8.45 x 10-ll. Conversion of these values to the pK 11 values for comparison gives 3.77, 4-.17 and 3.93 respectively. Mo values were given for 6-methoxy- see v1hy the 8-aminoquinoline, but it is difficult to . .•6- substituted compound should differ much from the parent. However, the difference in reactivity could be due to either a sterio effect or to a difference in basic strength due to the presence of the methoxy group in position six. :• 69. OHAPTER.'.VI EXPERIMENTAL· POTASSIUM-~HTHALIMIDE ?. ... C, . +. l(OH C .,M".'9M ----. ·o· + tfOH II !:w-~ O. .·': 0 . :. 0II . . .' , . ' . ·, ' . . ]47•. 13. ,, . .$6.10 ... 18$.,22 18.02 160g. (l.08M) ,6lg. (l.08M) . l.$2g.(0.82M'.) YIELD=~ 2 x 100 l52(?2, ::75.3~ . . . In.a three litett flask· was place~ a mixture of . 80 grams(. co·.s4M> of phthalim!de and 2000 ml. 'or absolute alcohol (77). The. mixture . was heated under reflux until all the solid··>had dissolved. The hot solution was then ·.·de ' 'I ' ' . product filtered by suction •.. To the mothex- liqu6:r$ were added an additional 80 ·gr~s. of phthalimide and the procedure was repeated. The Con1bined.produets from the two 'preoipitationawere washed with acetone to remove, any unreacted starting .. material, ; · 10. filtered and <.i:ried. :. Obtained· was ·i,2 gr~s (0.82M) ot potassium. phthalimide. The:.Y.ield was 75.3 per cont._ l•Pm'J:iALil~ID0-2, )~EPOXYPROPANE 0 ~.n~ N-1( + O''' '' : :oJI / , 18.$.22 . 137.0·0 203.20· SO :,;.{0.27M) ... 99-· g. (0.6$M)· 39 g.(0.19M) ·.. YIELD' :: X 100 = 721, .· ,, . *·.. ', ' ' .. , A' nd.xtur~. ot $0 grams '(o.27Mj ot potass~l).ln phthai1mfde ~d-90 grams (0.6$M) ot _epib?'~mohYdri.~ w~re . heated at: 140.. 500. 1~- an ·011. bath :fo?l four· h~.1:1-r.~·~ 'T~e-'. flask ,; ; . and contents Vfe.re··oooled " ' • i . ' and·_the• • ' , • voiatile:material. ' "' • • • , , ' ~ . ~as ,, I • removed 'at 'reduced pressure.' The < i , I ' resfdual l - • oil I • was i • ' ', ' poured ~ ' into 3oo·m1. of_iee watar and.stirred until it solidified. The ws.te~wasdecanted and the.resi~ue receystallized from jo() mi.' oj9j~ ~~~hol.. · Obtained were .39 grams of 8. white iiolid melting at ' The ! 92-3°. reported ' ,- ' • melting I point '' • , 'or • ' l•phthalimido-2,3-epoxypropane ' 93.. . " . . . ' . ' .was' . 4° (109, 110). The '. ' : ' ', ~ ' yield waa 72 pe~ ~en~. 72. 0 C... - ' w- c11,-c H-cw,. +l(CI C., ' / II 0 0 ' 0 . 1ss.a2 - . 92.S3 . 203.20 6$. g. ( O.3$?/i) · - 600 g.(b.5M). 56 g. (0.275M) YIELD :_---~- x 100' :: 78.Si& ' ' 'll."; ', ' ·Exactly 6$ ,_grams (0.3SM) ot potassium phthalimide waa heated:unde:r .reflux with a large excess of epiohloro- . '' hyd:rin (600 g.;, h.~M) tor 16 hours •. The solution was cooled to -room ,temperature and filtered by suction from the preo1p1 tated potassium chloride. The __ excess epiohloro- hydrin ·w-s removed by distillation at reduced pressure. The solid ~emain1ng after removal of the solvent ~as re- ceystallized trom high boiling skelly. ·obtained were S6 gr~s of l-phthalimido-2,J-epoxypropane melting at 93-4°. (,' . ' . · -The yield wi.s 78.$ per cent. - 73 • .,'.l•.PH'l.'HALIMID0•.3•0HLORO:PROPANOL•2 ,'•: ,·- ' .. ·• ·,•: •• ·1 •• ' ' ·.,' • • A. Fl'Otn 'Gaseous HOl •...... ···:------ HCI . 203.20: 239.66 10 g.(0.049M) 10 g.(o.• 042M) "~actly 10 'grams (O.oq.9M) otl-phthalimido-2,3- epoxyprc,pa.ne were dissolved in $0 ml. of chloroform. This ' • ' I • ' mixture' was 'oool~d.'in an ice bath and saturated. with dry l!Ol gas. ·'rhe solution w·as then washed first with .water, then with 10·,t s~d.ium carbonate,· and finally with water > • • ... ti.gain, dl'ied, ·and the solvent removed. Obtaine.d were 11 . . ' . grams of.white l-phthalimido•3-chloropropanol-2 melting at ' . ,; . ' ,(... . 90-2°. ·Recrystallization from high boiling skelly gave 0 Whit~·crystals melting at 9~•S • A mixed melting point with the· starting material was depressed to 76-80°. The reported melting point (38, 110) was 96°. The purified · yield was 10 grams. This was 8.$ per cent or theoretical. '' 0 c M H -;.( z + MCI M.�'.�..·.,.' · ''._ 0 ,, f..--.·.'.,, _:_· ·'.. O. 0 ... ' ' · · · 239.66 . · 203.20 '. · 20 g.(O.lOM) 17 g. (0.071M) ..J:1.. YIELD: 23.b x 100: 72% , To .$0 grams· of a 2.$% aqueous solution ot HOl was added.· 20 grams :(0 • .lOlvI) of l•phthalimido�2, 3-�poxypropane. Th6 mixture waifJi.eated. two hour's·. on a steam bath and then poured l-l?HTI!ALIMID0-3•I0DOPROPANOL•2 0 H· . c, ' c' _.N-CHz.-~11-... CHzCI n OH O.· . 0 ··. ' ' ' 239.66 · ,: 331.12 9.6 g.(o.04M) 9.3 g.(0.028:M) YIELD: .-2..J x 100: -70 .. $;>& . 13.2 · In a 250 ml. round bottom flask 9.6 grams (0 •. 04,M) ot l~phthe.l1mido•3•chloropropanol•2 end 12 ·grams (.0 .08M) of sodium iodide,were dissolved in 12.$ ml. or dry acetone. !ehe solution·was heated thirty hours .at reflux temperatu:re. On cooling the,preoip1tated. sodiumohloride waa filtered and the solution poured into a large excess or water· to· g! ve a white solid.. One crystallization from iaopropanol gave 9.3 gl'ami of ·white crystals of l•phthalim1do-3•iodopropanol-2 having the repo?'ted (q.O., 110) melting point or 124°. Th:is·. waa a yield of 10.s per cent. : 16. , .·•l..,:PHTHALIMIDO~)•p-OHLORANILINOPROPANOL-2 A. f£2.!!.··. l•Phthalimi.do•3•chloropropanol-2. + : ' '.' ' ' . 239.66 127.$7 .330.77 :,~;g.(.0.0)3M), .$ g.(0.039M) l g. (0.003M) Exactly 8 grams (0.033M) ot l•phthalimido-3• chloroprop.e.nol•2, $ grams ( 0. 039M) or p•chlo;aniline ;and 4.2$ g~ams (0.027M) of sodium iodide were dissolved in SO ml. of alcohol.· ·The,mixture was refluxed twenty-two.hours,· then cooled and carefully diluted with water. A yellow oil separated. which . solidified when cooled fol' several hours to give 10 g:rams of yellow solid. Recrystallization from isopropylaloohol deposited one gram of yellow needles melting at 176-8°. Reductio.n ot the volume of the solvent to approximately one•he.lf and cooling preolpitated 4.$ grams . . . . ot white·solid melting at 118-20°. Recrystallization from high.boiling skelly raised the melting point to 124°. A . . . mixed.melting point with l•phthalimido-.3-iodopropanol-2 gave no depreasion. 77. I 1, '• '.l'wo·recr,stallization~ from isopropyl al~ohol ·' .. _,:,; ·.... ·.... , .' ... ', ':.'' ··.,' '• ,· : '... : .· . : . ' 0 P~ised, the melt~ng ·point .or the .r1~st. traction to 177-8 • r ' • •' ' '• ,'. ' • ',., ' • the 7ield ot l•phthalimido•3•p-chlot'an1.linopropa.nol-~ was : • ,' ' .1 .. /> '. . ' '" ' 9.l.Pf.tr cent.· 78. B. x !£2!!:l•Phthalimido•;)-Iodopropanol-2 · Cl , · + 0 .· ~ 127.57"", 330.77. 2.$ g.(C>.Ol9M) o.8 g.(o.oo~) YIELD : ~. x 100 : 16% .· 'Exae)tly 5 grams (O.Ol.$M) of l•phthalimido-3.;. iodoprop_anol•·2 and 2.5. grams (0.019M). ot p-chloraniline ' ' were .d1s$olved. ill ·4-0 ml. ot. absolute alcohol·. The mixture was. retlUXect for· .twenty-tour hours, then cooled and oare- tully. diluted with water. The solution was ntade definitely acidic by the addition·ot aqueous HOl to extract the amino compounds. Filtration from undissolved s~lid (4 grams melting at 118-20°) gave a clear solution, which, when made basio with '' ' sodium carbonate precipitated o.8' grams of yellowish solid melting at 177.79°. !he yield of l•phtha~imido-3-p- . chloranilinop:ropanol-2 was . 16 per oent •. 79. 0 • ~.·l--Phthalimido-2 1 3-?Eoxy;eropane •. 0 ~' N•Ctfi-,.C ..-C.iz. + C'" ' ''o. o~ Cr 0 ' t4Hz. - 203.20 . 127.57 19.2 I• (0\•15M) . ;1.s g. (.o.l.$5:M) Y!ELD: ~:$ x. 100: 65% To 19.i grams (O.lSM) ot molten p-chloran111ne 31.5. grams {0.15SM) ot l•phthalimido-2,3-epoxypropane was added over a period,ot i,hour. The temperature ot the reaotion-mixtu~e was. kept. at_ 1S0-6o.0 • · and the _solution •as ·_const_atltlt sti~red •. ·· _When addition was complete, hee.t_ing .an~ stirring was continued for. forty-ti ve minutes at whie.ll. ": time th.e reaction mixture had. turned to a yellow solid., - .'ReC%'ystall1Za_tion trom absolute a.lc_ohol _gave 32 - grams ot ·wh~te_ c:eystal.s melting ~t l 78•9o... The. yield ot l-phthalim1d<;,··.3~p•chloran111nopropanol-2. was 65. per oent. Anal. Oalcd.; for_ c17H1503N20l_: :01, -10. 72; N, 8.47. Found: a1._10.98, 10.80; N, _8.52, 8.42. l• ( p-.NIT-ROANILIIiQ) .. 3• PifrHALIMIDOPROP ANOL•2 0 ..·.. . -o~_,,h_·_.. __ ·t.,w-c.1-1_2-t~·fHz + . .. . II . . 0 . 0 . 3q.l.33 10 g.·(0.029'11) YIELD: _l2._ x 100: $8.S~ . 11.1 I To 6.9 grams (0~05M) of molten p-nitroaniline were ·added over a period ot 1/2 h~ur 10.2 grams.(o.~S3M) ' of l•phthalimido-2,3-epoxypropane. The temperature was mainta1ned at .. 160° .e.~d the .x-eaotion mixture stirred constantly. ·4fter. the add1t1onwae complete, heating and stirring was continued fo~ an additional ·l/2 ._hour.· Upon coolingr . . the.: malt.·· ... , .,,set. , to' an, amber. ·. , ,,·mass. which, • was. triturated. ; wi~h 350·Jnlt .. ot al)so~ute alcohol. Ob~ained were· 1$ grams cru.de;7ellow.oompound·me:l.ting_at 183-.$0 • Beorystall1- or . ) . ' ' zat1on from absolute al~ohol gave 10 grams of l•(p- . . . ' . 0 nitroan111no)-3-phthal1midopropanol-2 melting at 196~5-97.$ • Thia was a 58..$_pet- ~e?,t yield. Anal. Oalod,. t~r· 017H150.5N3i O, 59._82; H, ~.43; N, -12.33. Founds a, 60.08; H, q..71; N. 12.22. 81 . . l• {p_•AOETAMIDOAMIL~NO) ~3-PHTHALIMI:DOPRO.PANOL-2. · : ·, .. 20:.3. 20 , . .. . ., ', ' ·.· 150.:18 . . .. 353.38 10 •. 2 .. g. (C> •. 0$3M) 7~$ g.(O.O!,M) 9.3. g.·( 0.026M) YiELD : x 100 = 1f:~ 53%, To·, ·1 .5 grams (0.'05MLot molten ·p-·~cetam1doan1line was added. ov~:r ~ perio·d ot ·i;2 hou·r 10·.2 '~ra~~ ·fo •. 05.3Ml. ' . ·or 1~·phtha.limfdo~2, 3·.:·epoxypropane·. 'The tempera.tu~e was. kept 1 ' tit 160-65° •. ~d 'the reaction .rni~ture stix-red ~·o~st~tly. A:fte?J,the addition ·was oompiete, heating and stir:r:-1,ng· was; Oc;nt!ilued to~ in additional: i/2 ·hour. On cooling >the m1.xt11re .ae·t to a. reddish black: s·olid. , Ocystall1zat1~n from 600 m.l. ot alcohol gave a orude yield or 12 grams of a . yellow s:ol1~r.melt1ng at 178.-82°. Recr,-stalliza~fon irom ab.solute ·alcohol gave 9.·j grams· o~ 1-(p-aoet~do.ani11no)- 3-phthalimidopropa~ol•2 melting at 189.90 • .$0 • This was a S3 pe·~ cent ,-1~1t1. Anal, · Oaiod·~. -ror. 019H1904N3; : _O, '64 •.$3;. H, ·5.42; N, _11.99. Found:.: 0, -64" •.34-J' :H,· -.$.52;, N, 12.l.4. 82. . l7h..20 . . 20).20 ,, 377.40 11 •4. g •. (o.•:lM). 21; g. (Q.lOqlt) •.21; .S• (0·•.0.$6M) ' ..~ YIELD.:: ~: x 3 7 100: 56% To :.17.4- srams. (O.lM) or 6•methoxy-8-aminoquinol1ne ·was e.d.de ' ' ' . of .'l•ph'thalimido•2,)•'epox:ypropan$. The reaction temperature ' , ' ••• ' •• ~·.::.. .', .1, • '' one ·hour<' after· addition was ,complete •.. ··. The dark red liquid was; poured. into:·112.$ ml. : of' .. alcohol, and .heated until all had ·. '' gone· lnto. solution,. ·On standing a small .amount of brown tar preo,ipitated trom·_the solution •. This was. removed. and :the remain1ng;iq~id.wa.s,reheated wit~deoolorizing. oharooal, · filtered,·. 27,. cl'Ude '. _material - ··, and , cooled.·' , ,. .. On standing . . . , , grams. . of. . . . . ' melting at_l36~8°.were deposited. Recrystallization from ab$olutealoc,hol gave;a sample of· :B•(3.-phthal!mido-2- 0 hydroxypropylamino)-6•m.ethoxyqu1noli~e ~elti_ng at J.4.3-44 •.$ • The l'eported melting point. (23) waa -1~• .,o. The purified yield waa .21 grams,. This -was, S6 per cent or theoretical. 83. : . '.,; Anal •.. Oalc~. ·tol' (l2fBi904N3s O,. 66.82J H, 5.01; N, 11.1~. Found: ,a, .66.7.9; H, 5.30; N, 10.98. l-Abt_IN0•.3•p~OHI,ORANILINOPROPANOL-2 . ,- 0 '.· '. '. . . .o·."..~.'_. N_,_,__ H_-i:M-Cl4~:--ff\\.c1 + N~M..·M.O - ~ c.~ _ . 2 , - a . ~ • "T • u' . ' Otf . 0 ' 6MM -c~,.-c.t4-c.; ~z." "4 z. OH' 330.77 .· . . ., so.04.. 200.sa 22 g.(o.o67MJ -.-- 3 .4- g. (0. 06810 12 g.(o.o6M) · YIELD,·=· 12 . ·lt 100 ·~ 90% ' . .. 13.£i. . · A· mixture of 22 grams·. (0.067M) ·or l;..p~thalimido-3- p•chl.oi-ari.1:tinopropanol~2, 3.q. grams· ~ ; '. {0.068M): : ;· /, hjd~azine . . ,· ' of ' 1 ' ' hydrate' and ·20_0 mi., 9t absolute_ 'al~ohoi' was .. refltixeJ' ,'tlµ'~e- hours. 'l'he .solvent .was .remoyed ·on a ste·mn _bath ·and the.' dey .residue was heated fol' one and one-halt hours .with: an e.xcesf)· ·of ,.dilute- Ii0l •. (:Prepared. by mixing SO ml.· _Of' 12M ltOl and l.,SO ·:nu... of watex,. ) · The precipi tate.d. pht'halhyd:razide was i-emo'ted br tiltrat1o_n and the solution m~de basi~ with ~ co~e~t'.r~ted solµtion ~t ~5 grams of NaOH in. ~he presence of a chlorQtorm. layer t'o remo1'e -th$ free base as formed.· The aqueous layer was .extracted with ohlorof'oi-m tour times and dried-over .~drous sodium s·ulfate.. The solvent·'was redua~d to~ 150 ml. volume on :a·steam bath and the.rest stI'ipped .oft at reduced pres.sure •. Obtained were 12, grams ' , ' , •. . of 1-amino.. 3-p~chloranilinop:ropanol-2 melting at 94-5.0. . ' The yield was 90 pe:r cent. 8.$. An; ·analftios.l ·· sample was prepal'ed by passing dey Hat into a chlorotorm solution of the compound. and. re- ti • ' k ceystalliz.in.g trom absolute alcohol to give a white solid melting at.218 •.$•200. .$ • Anal. ··Oalod. tor o9H13N2ool •2HOl; · 0; 29 .Sll .H, .$J; N1 10.~; 01, 38.89" -Found:. .Q, 29 • .$1; .. H, $.q.O; N, 10.26;_ 01, 38. 78, 86. . .., 3'77~q:o · .. . · ; . . so.04. · 11.9 g.(0.029M) 2.'l ...· g •. (P.Oq.2M) ~ x 100 nm:.n.= 7 2 ~·84%· , A so.lution ot 11 grams. (o.o'29M) ot 8-(3- ·. : · · phth~l1;1d6~2~hydrox~propyla.rnino,>-6-methoxyquinoline. and ~.1 •s~!ilnll (0.o4.2M) )11.' hyc11'azine h,-ai-ate in 110 mi. of ... abso~utt: alcoh~l was heated: under r•tiux tor two hours •.. fhe· ~loohol -.~s r$moved. under reduoed pressure'·and the . residue refiu:ted tor .fifteen minutes .with ·· 10$. ml•. ot ·water ; containixig. o;o.75M ·ot: HOl •. .Ute~ cooling and separatioxf ·ot the phth;lfu-dzt$J§ide: by filtration, 100 ml~ of a_: 1.0:<-ii . 1 ~ol11tion ~f .iQof! was e,dded~ .· After cooling, the ol'Ystii.l.line 1 . Pl'od~ot se~a;~t'e~·. ·.. The y:l~ia was 6. gPams of light yellow 8-(.3•amino•2-hydr~.xyp1'0pylamin0) .:.6-m&thoxyquino lin~ \,.el ting at .157-•8.5~ •..The repo:ttted melting point ·(2.3) was 1>7-8°. The yield was 8~ per cent. Anal. Oalod. tor o13H1702N3t Jl, 6:,.14; ,H, 6.93; N, 16.99~ Found: 0, .63.2$; H,. 6.80; N, 16.88. 7~OHLOR0~4- (.3~p-Oi:lLORANILIN0•2_:HYDROXYPROPYLAMINO) •QUINOLINE ~ l~CI y ~ IJ "-Cll,·~14-Clli t-1 t4 01'1 200.68 362.26 9 g.(o.01t.SM)_· · 10 g.(0.028M) YIELD : :x: 100: 1t,~2 6~.5% Exactly 9.9 g?'runs (O.O.$M) or 4,7-d!chloroquinoline an~ 9 grams (Cf.04-$M). ot ·1~anu.no-.)-p•chlora~il1nopropanol-2 were··heated' with stirring ~n an oil bath·. , The tempe~at~re ot the'-bath and :~he' reaction· mixture were observed closely until. an: exothermic ~eaction occurred around l.30~. The·· reaotion,.mixture \Vas cooled slightly and held at a -t~mperature slightl:r ·below .l_,·oo ~ The reaction mixture became very viscous ,s.n.d finally, so11ditied into a tan solid •. ·After cooling the ·solid was pulve,rized ·and extracted in a Soxb.let apparatus overnight with ether to remove any un- reacted quinoline. ·The· yellow solid that remained·was dissolved 1n hot alcohol and 'poured into a ·large excess otwate:r,oontaining enough NaOH to make ·the .final 'solution basic. The white solid that separated was purified: by 88. recry~t·allizat1:ot'l·•, ' ' • ' , • • ' ' ., ' • ; ' alcohol. from,isopropyl~ , • • · purified The • ' s' I 71eld.,of 1.-chlox-o-4.;.(3•:p•ohle>ran~lino•2•hydroxypropylamino)- qu1noline wa's .. 10 grams .Qf white crystals melting at 221-2° • .The .field was. 61. ·$ pe~ cep.t. I. :·.I; 89. 7•0HLO'.f{0•4•(.3•(6-METHOX;l~8~QU:J:NOLYLAMIN0)-2-HYDROXY-· i>ROJ?YLA1t1INO,) •QVINOLINE , 2lt-7~29 ·. ~08.88 6.S g.(o.026M) .$ g.(0.012M) YIELD: l0~6 x lOQ: 47.3% A mixture 0£ 6.5 grams (0.026M) or 8-(3-amino-2- hydro.xy-propylamino)-6-methoxyquinoline and 5.S grama (0.027M) of ~,7-dichloroquinoline was heated with stirring. The ~emperature was ~ai,sed, slowly to 130~5° and held there tor l/2 hour. Wb.e temperatur.e was then ve'!!Y slowly raise.d to. ]40-$0 and held the~e until the ~eaetion was complete. (At no time. was t.he temperature allowed to get above J.4..5°.) At this temper~tlll'e the reaction mixture slowly became j ,· ~ more viscous until it was almost solid. The bath temperature · was held around 140° tor one hou~.and. then allowed to ~ool to room temperatu:re to obtain a.reddish.mass.which was pulverized into a yellow solid. To remove excess ~,7-d1chloroquinoline the powder was extracted with ether in a Soxhlet.overnight. The resulting powder was dissolved in alcohol and poured into a 90. lax,ge .. quantity: of wate~ o()nt~ining enough 'NaOH to. make the &ntire,,mixtu.:re ·basio.. The :yellow solid. that, .,. precipit~ted ~as tilter~.dr ,d.ttied and rec·;t'Ystalliz ed ~rom ' ' ' benzene., O.~tained. . ', .were. - ' ~- gl'ams.. f, or yellow cry-stals, of : 5 < 7•chlo.r<>•4(-'•.(6-methoxy~8-qu1noly~am1no) .. 2-hydroxypr<,py-lam1no)- . ' ; quinoli~e,.melting at ,190-1°. The·.1teld was 47.3 per oent. Ana,l. Oalod •. fo~ ·022H2102NJ+Ol1 · O, 64.:.;62; H. 5.18·; N;: 13. 71. 'Found: . a. 64 •. 73; a,. 4..94; N., 13.66~ 91. ATTEMPT.S TO REAO'l\.THE, HYDROXYL .GROUP .OF THE STRUCTURAL ... fYPE. RNBCH20H(OHjOH2N.HRt WITH HALOGENATING AGENTS . A. l-Phthalimido-~~p-ohl~re.nilinop~ops.nol-2. This :compound wa- dissolved· in dry- chloroform and converted to the b7droohloride with dry HOl. To the solution: was added approximately tour•i'old excess of thio~y~ .c~oride. Reflwd.ng the solution ror two hours and.then working.up gave unreacted.starting material • . This was proved by mixed melt~ng points •... Also tried was the. same reaction aa above without the addition of· the HOl.: .i Addition ot pyridine to the reaot1pn mixture .and use .of t~_op.yl chloride as a solvent did not change the results. Phospho.rous oxychloride, ,., phosphorous·pentaohloride and phosphorous tribromide were also used. Iri no· case wa2' 1t possible to isolate a compound in which. the 'h1droxyl was replaced with a halogen. In those ' . , : runs wb.ere ,too vigorous conditions were used unoharacter- izable tars were obtained, but in all other oases the starting material was returned unchanged. B. l•Amino-J-p-chloranilinopropanol-2. ExactlJ~ .L, gram~ ;.. o't this coq)ound were dissolved ml. , cl:J.lo~form. and treated drop- in $0 ot d!!Y., a].00,bol-tree ' . , ,, .-·.. .. wise w1th·l5 grams of thionyl chloride (a five-told excess). The solution was allowed to stand at room 92. tempe?*ature for ·.foux-.houl*ll aµ.d then heated at reflux for two hours. ·wor,k-up of the i-eaotion mixture resulted in the isolation ot a near,ly .q.uantitative yield of the hydro• chlor1de'ot. th.estart1Q.g material. The identity was proved by m1.xed.melt~ngpo1nta-w1th' a known sample. 0. T-Ohloro•ls.• (3-~-.chloranil1no-2•h:ydroxypropy:lamino )- 9,uinoline ~.·: .The above compound was .·trea~ed as before with th1on,-l ohloridf) ~n dry chlo:rotorm. solution. After . . . . • ·o, ' isolation or· the :product, ·1t wa~: tound, that' the · compound did not depr~ss the melting point or the hydrochloride ot the stal'*t1ng·mate:r1al, indicating that no reaction had taken place~·- D. 7-.0hl~ro-~-.< 3•dieth:y:lam.ino-2-hydroxyprop:ylamin? )- quin?l!ne <_ , The ·commercial salt (as diphosphate)(lOq.). was dissolved ,in a minimum of water and made basic with ~odium hydroxide. The· isolated. ,tree base was treated with thionyl ~ . ' ' . ' . ' . . ' . chloride. as· bef'ore.. During the r~tluxing of the mixture the change color of ti;e solution to black indic,ated a • ' ••• ••• J.in ' • • • " - .. large. amount o.t ·deoomposl~ion. Renioval of solvent and . voiatile ma_terial at. re~~o·e~ pressure left a tarry: mass whreh could not be. characterized. ' . 93 .. 2•ETHYL-2•NITRO•l,3-PROPANEDIOL . Czl-lS" I >· HO-CH -C-Ci-1 -OH Z I 1. "IOz ·. :. 89~09 .30.03 159.15 . 71.2 g.(P4'8M) 48 g.(l.6M). 88 g.(0 • .$6M) YIELD= .Jill. x 100 = 69~5~ 127 J'(JliowJ.ng the p;ocedure of.Vanderbilt and.Hass , ' . . . . : . . (107)• in a one liter flask were plac.ed 71~2 grams (0.8M) of i•nitropropane and.0.2 gram ·of hydrated lime. To the.well- atirred mixture. was .. added siowly 128 grams or to~alin solution (equivalent to q.8 g;ams (1.~M) of tormaldehyde). During th'e addition the temperature .was kept at 300 by l running tap water. Upon the addition ot approximately 1/2 ot the formalin solution, the contents ot the flask b~oame one pha.ae. After the addition was. complete and the exothermic reaction ~ad subsided, the solutio~ was allowed to stand at room, tempex-ature for forty-,three hours and then made slightly acid~e by bubl:>ling in 002 in veey slight exoess. The p:re~ipitated Oa00.3 was removed by filtration and the tolid washed with 5 ml. of wate:r. The combined filtrate and washings were evaporated on a steam bath at 35 mm. pressure. The molten product which remain~,~. solld11'ied -0.~ ·oopling. Obtained were ·88 grams ·or 2-ethyl•2..,n1t~ ' ' 1s.a1' 30.03 13$.12 120 g.(l.6M) 96. g.J).2M) . 16$ g.(l.22M) . Y,IELD :: _m x 100 : 76.5% ,, ' As outlined by Vanderbilt. :and Hass (107), 12? grams (1.6M) ot ·n:ttx-oethane and 0.4 °gram <>f' hyd:rated lime were plaoed;in a one, u ter flask. ' To this Well sti,rred mixture . ' was:added.slo':'lY: 2$6.grams or ra~aiin.s~lution (equivalent t~ 96 gram~ (J.2M) of lormaidehyde). During the addition the temper'atu:re 'Was kept at 30° by ·running tap wate:r~ . Up.on the addi~iQn ot appJ19x!mately l/2 of the· ; . . : . ~ '. ' . ' . ' - : '. . . formalin. solution. ~he.· contents of. the tlask became. orie phase. ' ' 1. : ' : l . ·, • ~ .. , • • : ' • • ·' • • ' •• . • • •• • • reaction' , I ' f the exothermic . , , • complete.end , was When.the, addition 1 had ~ubs1ded, .the. sollltion was allowed to·· stand at room . temper~tu:re· ·t'or:'rorty~three ·hours· and then made. slightly acidic ·bY': bubb~ing in .002 in ·veJ!Y slight excess. Th~ Oa003 WQS femoved: by filtt'ation and, Upon remO'f8.l Of water and . . . unre.acted starting materials,. 16.$ grams (l.2211!). ot white c%'y'sta.ls,or 2--methyl-2•nitro-l,.3•propan$d1ol were. obtained wliich ~elted at 14a.500. The reported melting point .(107) · was 1~9-soo. This was 76.S per cent of the theoretical. .N,N'•DI•p•Om.ORPHENYL~2•NITRO-l,3-PROPANEDIAMINE.·'' ·.. . ,,·, •.,,· ·. ·, . 2Cf\O 127.$7 ··... . 30.0.3 61.o~ 127.6g~(lM) .30 g.(lM) .30 • .$ g.(O • .$M) YIELD, : l ~~ x 100 :: lj.8 ~ 6% A.mixture consisting ot 127.6,grams (lM) or p- chlo·ran!line, 30.s1 grams (o •..s:rrn of, nitro methane. and 10 ml. ·ot· a 40:: pei- cent solution of tetraethanolammonium hydroxide was dissolved in 2.$0 ml. ot methanol and placed in a one-liter th1:>ee necked flask equipped with mechanical · • , ., > " stirrer, oondensett and.dropping funnel .according to the procedure ot Johnson, ($.$) • The solution w~s heated to gentle retlux. To the solution heated,, mixture was addeci grams formalin ,', ' 83.J+' ... ' . :,· . . ot .(equival.ent )o ~o.S grams (O.$.M) of formaldehyde on a dey basis). · *?he .:addition was carried out over a six hour period. ' • ' • ' , I ' - ' ' ' • ,I ' .. At the end; ot .this period the solution was cooled and~ filteped tro~the precip~ated.solid. Washing with absolute alcohol gave 7.1+ gra~s ot yellow solid melting a.t l 76-8°. An add~tional 18 grams wer~ obtained f'rom the mother liquors.. . Recrystall1zati,on trom alcohol gav& 8.$ grants ot 97. 1•~low crystals _r;,f N,.N 1•di•p•9hlorphenyl-2•n1tro-l,3· prop~n$d1e.mine ,melting ,at .186-70.. '?his waa 48.6 per cent ··-,1e1d. Anal,,., Oalod. H, 12.).$. for01s~15~302Ql2: : o, 52;.95;, 4.44; ~' Found:-, .0. ; 52.801 R, 4".29; N, 12.5.3. 98 • .. N, ~! ~DI-p•OHLORPHENYL-2•METHYL•2-NITRO-l, 3-PROPANEDIAMINE . ' ' '· A. From· 2-Meth?:l~2-n1tro-l1}~propaned1ol. Cl Cll3 • + HO-C~ -c-ci, -OJ-I .2CJ ... 'l. ' i. llllz.' NOz.. 135.12' . 354..23 17 .g. (0.12,SM) . 18.6 g.(0.05.5M) YIELD: 18.6 x 100 • ~2.3% ,,,,~.· ,•, A fuixture of 17 grams (0.125M) ot 2-methyl-2~n1tro- i,·3-~r,opaned1ol, 31.9 .grams (0.2.$M) ot p•ch1oran111ne and '' ' . 2 ml •. of tetraethanolammonium hydroxi.de was placed in a. 2.$0 ·ml/ flask~ · Th.& flask was kept at So0 for two days. At the end:of this period a _two phase ;liquid system had separated. ~his mixture· was extracted with approximately 3$0 ml.·ot benzene and.the a.q,ueous layer removed. The ' ' benzene: was treated twice with decolorizing charcoal. . . Evaporation ·or··the solvent gave .32 grams ot a dark 011. Tr:lturation with alcohol and subsequent recrystallization trom -the same solvent resulted in the isolation of 18.6 , , grams of N,N•-d1-p-chlorphen71.:.2-methyl•2.;.nitro-l,.3-. propanediamine meiting at 141-2° •. This was a q.2.3 per oen~. yield. 99. ' . B. FX*om.Nitroetha~e and.Forma.ldeh;tde. 127-.57 • .· · 30.03 1,.01 . · q.2 • .$ .• g. (0.331d) ... 10 g. (0.33~ ~ 12 • .$ g. ( O.l66M) YIELD :: .~.· x ~09 = 1,.2.5% : ; ~ ·A. miJtture._qt ;q.2.5. srmri~ (9._),JM). or p•ohloranil_ine, ~. -, 12 • .$ gi-e.ms, .(0~16614)..-.or: nitroet~~e .' and 2 ml. of tetra- ··· . ·- - .. ·. . , ' ethanol~nion1Uin hyµro.,cide; ~as) d.1,isolved _in 100 ml. ot .' ·.-·' .• " .''.. '. . ' 'methyl a.lcoho'J..• . The .. ~O~UtiOll>.Wfll place~·.in a one 11 tei- _·- :, • stirrer,• ,. ; ••:.: mechanical,• ·, a > .' .....with ·three/necked ·flask ·,· ••• ·.,,.; • • ·, •• • : '';' • < fitted, condenser and_d.~pping tu.npel. e.11~ heated to.reflux. temper- atu1:9e on,:a ste~ be.~h •. T~ '.l;he con~ents _w~p~ added 27.6 . grams ~t·tor.ma.iin .~<>llltipn .. (equiv_al~nt. to 10 grams; (o:.166M) ot form.1.(l.d~b.y 1 we11e :pretiipitated,. • 'Rec17stall~zation 'trom alcohol ·ga,ve '/,. • ? •• 2.$ .r granuf ~t··y~liow.017stals melting. at J.41-2°. Thie was ~2.$_pe~ cent yield. 100. An.al •. o·e.1cd .• for ·016H17N3029l21 ·a,; Sq..25J H; 4..a4-; N, 11.86. · Found.: , :o, 54~42; H, 4-.68; N,' 11.81 • . Evapoxaltion· ·or the.,solven~: gai.re. approximately : ' . . ·:' ... ,,. 1·· " .. ; ,' .30 gx-am, ot .a dai:-~ oil •. Thia .residue was .washed several times with hot ..wat&t' and then heated .with petroleum ether. ,'' ; ; • < I(, ' •!· ;\"' ' • ' j ' ' '• ' Alth?ugh the ·.mS:terial ,oiled. out. ~everal times. 1t· wa1i ' ' l ' . _· ' j ' : . . . • ' : ,/ ' ~ ·• ' < ' ' / • ' • \ • possible to.isolate on cooling .a Vihite solid melting at .$80. '•·. This ~ompound wae shown. to.be N;N'-di-p-chlorphecylm.etha.ne- , .. ··• ;· ;· i ,, •. ' . . ' . ' ' .•·• : ' . d1amin~ b:,· means ot a m1xecf !ll8lt.1ng point with a known .' - '1 ·,' ,>. sample.. There was no depre.ssion in. the melting point·. 101. N,JT•-DI-p-OHLORPHENYLMETHANEDIMUNE c Cl H CHO 0 6N 1-1 - C 111. - N M 127.57 .30.03 . . 268.16 12.2$ g,;(0.096M) l.!57 .. g •. (O.O$q.M) 8.2 g.(O. M) YIELD= 8.~ x 100 • 64~ ... 12. . A mixture of 12.~5 .grams (0.096M) of p•ohlor- aniline, 2 g~ams ~£ K.OH, 4.2.$ oc. (O.O$q.M) of formalin and ' 10 ml.- of alcohol was .refluxed for one· hour. The contents or· the: r~~otion' tiask were :deoanted' into 400 m1.· or water. The oily fayer. the.t. separated· was w,ished with hot water aeverai· times and then ·cooled. The 011 so11d1r1ed qu1ok11 . ' and was recrystallized from petroleum.ether. Obtained were 8.2 grams of:N,N'.;.di-p-ohlorphenylmethanediamine melting at 60°. The reported melting point (8) was 60°. This was a 64 per cent yield. 102. 6 ~.u~-c~ ~ 1-fH -Cllz."6 H"1. 310.22 , · 19 g.(O.OolM) YIELD~.·~ x 100 : 83~5,' ' . ~ ' ' lb:act,ly .'2.$ grams (0~074,M) ot N,N'-di-p-ohlor-· phenyl-2.-lli.tro•l, 3-propanedi.runine ~ and. one gram . .. ' ' ' of Rane1 . : . ' ( ' nicke~: ·were J.>laced in an Am.erioan, Instrument Company high pressure h7drogenator with :too ml. of methyl alcohol. The mixture was hydrogenated at 1000 lbs. pressu.re and room temperature toi- tou:r houtts.and~hen the "t;emperature was. ' . ' . . raieed toss<> fol' two hOU?"~. ,Vpon cooling, the solution we.a :riltered and 200 ml •. of benzene.added. Heating t~ reflux, the water and alcohol were: removed and the resulting benzene.solution was concentrated at ?'educed pressure. Removal·o£ the solvent .left, 22 grams ot crude white solid melting at 98-100°. :RecrJs°j;allization from. a. .$0 per ·;cent w·ate·r-alcoht)i mixture. ga~e 19 grams o:t N,N'•d1•p•chlorphenyl- 2•8lflino-1,3-propanediam1n_e melting at 103-4.5°. This. was an 83.~ pe~ eent 7ield. Anal. Calod, to'r* 01,SH17'.N30l2: 0, $8.07; H, .$.53; N, 1.) • .$4,. Foundt a, .$8.32; H, .$~66; N. 13.$$. 103. N• N'_' ..-DI-(6-.METHOXY-.8.-QUINOLYLl•2•NITRO-l, )•PROPA.NE• DIAMINE (ATTEMPTED)· ,, ' A. mixtu~ of 87 .l grams (0.5M) ·of 6-m~thoxy-8- aminoquin:oline .. ' 15 g:ram~l ( 0. 2.$:M) of ,nitromethane and' 2 •.5 ml. . ' . . ·, . :, . ' of tetraethanolammC>ni~.h,-droxide ,wa.s_,diss~l,red ::in 200 'ml.;, ot methanol and placed in a one litel!' three 'necked ,,flask ' .. .·· ...' ,. . . ,· ·.. \. . ,. . equipped with.a 1J1eclianioal 'stirrer., condenser and dropping tunnel .. , The reaction mixture was heated under gentle ·. ' '1' ' x-etlux as 41~7 grams ot formalin solution (equivalent to, ' ) '; . ' \ . ' ' ,. 1$ gram.a .(O.$M) .of formaldehyde on dry basis) was ·added -, ; , ·. , ' . .'. I , •• "\ period. The peating-was then continue~ . over a '.'$1:xhour. . . ' ' . . i one extra hour. 'i At, the end ot the re_a~t!on period a large s.mou~t 1 of brown ~orphous solid 'had precipitated f;rom the,_~0l~t-ion. .. ' ~ The mixture was tilte:t'ed hot to give ··79 grams ·ot a brown solid Which could not be rec17stallized. ' ,, ~he mother liquol"S on. standing overnight.deposited S ·grams of ,a oeystalline,b~ownish-7ellow solid melting around aooo~ Recl"y'stallizat1on trom a~solute alco~o~ gave : 104. a y&+low. solid melting at. 212-11+0 • · This :·compound showed no depi-~asion in.melting point, when mixed with th~ c6mpound having .the .probable structure ot di•(6-amino-6-methoxy-S)- qui.nolylmet.hane •. X~,,tf .second run U~ing .the same. quantities df materisis.'.'the.f'ormaldehydJ .a ':N, N' •DI•(6-METHOXY-8-QUINOLYL )-2-METHYL•2•NITRO- l, )•PROPANED:tAIYlINE (ATTEMPTED) 135.12 17 g. (O.l2$M) A,mixture of 17 g~ams (O.l2$M) or 2-methyl•2- nitro-l,l•prop~ed1~1, 43.6 gr~s (0.2$U) ot 6-methoxy'.""6 ... ' ·-. ,' . ' aminoquinc;,;1ne'. and 2 ml. of tetraethanolammon1um hydroxide ' .' . . ·.·\. ; ' ' . . _: . . \ ' ' ' . : . " \ 1 1 •as placed; in a 2.$0 ml. ErlenmeY:e~ and the ,.flask· put in · a constant tempe:?tatu:r~· oven_ .at $0°. After heating, sixty- - • • ; ~ • • • ' •• ) - < ' ' - , • ' . • • : ·~ : . ' . - ' ' six hours· reac~i<;>n mixture h~d ' sol.14.it'ied ,, I ,•, • ' with a layer ~he < ' • ,''! I I ,, ' of water on top-. , The .solid was tri turated with approxi- matel1200 ~£.alcohol to,giv& 38 gI'amS ot brpWn solid. '..·ml. ' . . .,, ' ' ' . ' . . . . ' ' Thie reaid:ue was recrystallized from absolut~ alc,ohol ' ' to ' . . ' . ' ·-., ' .. give 21 grams ot. yellow solid melting at 2!4-1.5°;~ . Mixed melting_point determination showed this compou!id b·e ' to ' l ; ' identical with a compound having the probable ·structure ,.- , . ' ' ' . ;. .. ' . . . . ' ,' ot di-(8-e.mino•6-methoxy•.$)-quinolylmethane. · In·a second run using the same quantities ;ot materials, the reaction flask was kept\ at room temperature , . ' . , . .· . . . ·'- : r .'..'\. ' tor eight days. At the end of .that time the cont·e~ts of ' , the flask had solidified as before. T~ituration with absolute alcohol gave 10 grems of whiti~h solid melting at 106. 1a6.9° •. :. Mixed melt1~ p:oint determinations showed this compoµnd tQ. l).e identical<,. with a; ~ompoµnd having t.he pl'Obabl~ structure N, ', N• -di-( , ' 6-metho.Jty-8-quinolyl .. ot. , ' , . . . . ' )- methaned1amine. Heating of this residue with absolute alcohol . N , '151t•D I~ 6 - ( b ~THOXY ; . . . 8 ~QU INOLYL } - 2 -ETHYL - 2 - ?UTRO - . l _ . 3 - PRO PANED(ATTEM IMUNE J >TED . ) . ·. i74 .20. l .$9. . l) 461 .$2 4).. .6g. (0 .2 .$M ) 20g. (0 .12 ; ,M ) A · , t r lx20g tu l 'am~ r(0 , .125M .o t.or ·2 ) -e tey l - .2 -n1 t ro - 1 , .3 •p? 'opaned...g . .3.g ,6 ram fo(0 si .25M ., .of )6~me : tho x y -8· . ;~ ino~ ,.' ' '", .. ,.• '' '. '·... · '_-! .- . ' ' . . ' ' '' ' . ' qu inoand l i..~ r ml ie •. of t e tx - e . e th s .~ohyd l rox ammon1umwas ide . p lac~~ina .2SO ml. 'E~ .~ enm,and eythe ef r lask s~!n t a . ,: Cons ttem~~~a .an t · :tu :.. ,ov~n :at' t$0? te Af . . terhea t sev~n ing . ty~ twohou . the rsreac .m t ion ix tu·had reso . l id iThe f ied·s ,o . l , id ' ·, '·,. ~ ' . ' . . . ''. ' .' '. . ' ' . . . wa .~ : . t r1witb t iu~00 ra~~ ted ora lcoho · tog l ive . app r< ?x im a t e ly 40g ram ot. sb rown so l : idTh . .res is iduewasrec . ry s ta l l ized :·:,·, ·.. ,,. ' ' . ,, ·-· •, .. · f romabao , lua lo9ho t ,to· g l ive . 20 g ram .ot sy :e lso11 low . , ·d ' . ,, ..' ·,... •i'· ' ' ....·- '•• ' . . . me l t...,at ing 213 .5°M : i~ec .me l l tpo ing in~.de te rm ina: t ion s ,,'...-. ' ..; ..·' .:...... :. . , . . . ·.· ·. lho1; red th ,Con is ipo to ib" lndiden tW i~a i tha oomp~uh l f :h av ing thep .rob~b s t le rue or tud i~re (8 . - am i ,no . .. :6 -m e~hoxy - -S ) - qu ino ly lme thane . Ina seco : .nd run .uthe s ing.as , .mequan . t io:r t. ies , ma te~·the ia ree ls .o .f t i~n laskwas a . l ' lowed tos tand :atroom , tempe ra..tor i ;ue igh re days t Id . ,ep ..resu t ica were . l l ts ob ta ined aawhen 2 -me thy l -2 -n i t rowas •used l ,3 -p . ropaned io l 108 . +.HCHO l7q .· .20 . 30 .03 360 .39 228• .(0 .126M.2 ) .0S• (0 .06610 9S•(0 .02 ! ,M ) .·.Y IEL .· : :O22 -2 ·~x .__100 , ' 39 :•.$ ; :& Xn:a' 12S , :ff ·.. ts l1 .- r . l"~e f lask :were ,e:m r ixed 22g ram s (O . i26Mo t :6~m ) e thoxy -8with • am~.l inoqu1no gre .m so t l : l .n e ...... ; ' .· .·...... ·... . · .. '. . . . \ 31 .Spe1 cen t to t rm .n11nao : lu (equ t ion : t .vat~2 . .0 len g ra t ins. • •. <.- .'...l . • I fo .0661{ondey bas ) is}~ ~ .m . ix tuwas rea : l lowed · 'tos tana : ,'' . ' ~ atro .~tempe taf tn 'or· i roux re .days . -du , r ingwh ich t iu1e : the· con tenso ts l id i· . · t, : ied f i -1 .with : tu 100 ra mi. t1on of. 'a lcoho l . . gave10 g rams or awh iso te lme id l ta~ ing126 -8°•. '.Be- \ cu ,11 ta lf l rom izape t t ro ioe leum r ther i gave ·9 g ram ot s·. N,N '-d 6 -mi-( e tbox1 -8) -qu1no -m e th an ly edme l i l a t :mat ing in e 129 .30°.Tllia •as . a 39 ,5 per cen y t ie ld . AnaOa l . lcd to• .0 2 1H a ow 4O, 0 ,69 a s .98 R,S ; .S9 N, ;lS .S5 FoundC, :70 .21H,5 ; .71 N,lS ; .$6 . .109. 360.39. . 4.2 g. (0.01214). YIELD = h,,52 x 100 : 8.3:'. · Sxactl7 S gr:una (0.014?4) ·ot H,N~·di-(6-methoxy-8- 4utnolyl.)•methanediatttine weN d.1ssoived in So ml. ·or absolute.alcohol and one ml. ot concentrated HOl was added• .A red hydro~lortd~· immodiattly separated. The solution . was heated to boiling and then allowed to oool . to 'room .temperatu.tte. · Dilute so~wn hydroxide solution was added tlowly until the mixture was baslo ta litmus. On eomp~ete . . . neutl'alieation S grams of rellow solid melting at 210-13° · were obtained. Be. Anal. Calcd. tor 021H20N4021 o, 69.98; H, ,s.s9. Found; a, 69.90, 69,70; H, $.$$, S.7S llO. '8-,Ai\l!Ill0.-.5-0HLORO-~~ME~HOXYQ.UiliOLINE C"3o(f;J + HCI NHi . 174..20 . 208.66 75 'g. ( 0 .q.)M) 5S g.·(0.26M) l'IELD.:~.x .100 = 61.5% :According,to the method.of Drake and coworkers ·('31), 49 grams .. of a~etio anhydride was· add~d t~ 7S grams ' . ' ' . . ' . , (0.4.3M) ·ot 8..;..arnino-6-methoxyquinoiine in lli ml. or glacial · ace.tic. acid and the ttesulting solution was heated to ·boiling and kept' under 'reflux fo:tt ten minutes. One-halt milliliter . cf water was added and' .the mixtur~ cooled and transf'erred . . to a four llte:rbeaker. To this an iae-oold solution of ,;o.5 grMts (0.4.3M) o·f chlorine in 750 mi. of acetic ~cid . . was added over a period of ten_ seconds with vigorous · stirring. 8-Acetamido-5-chloro-6-methoxyquinoline hydro- '. chloride separated rapidly s.nd the mixture became semisolid. Water (l.87 lit'er) and concentrated ammonium hydroxide . :( 7lt. ml.)· were added and the slurry was stirred for a few minutes, filtered and sucked as dry as possible. The product was suspended in 375 ml. of hot water in an : lll.·. apparatus. equipped wit!?, ~ .stirre;r and a reflux condenser. The mixture ws.11 st1l'red and heated .. while 37$ ml •.or l:l HOl -~~: added through.the condenser. ·, Bo~linga~d stirring was continued for ~!tty minutes• then. heating was discontinued and an ice bath waa placed e.bout the flask while 225 ml, of ammonium. hyd.:ro:Jd.de was added. The 8•amino~5•chloro-6-methoxy-, quinollne was. removed by tiltration. Th& crude prod4ct . . ' ' .... ' flas decolol'ized.and.reor,.stallized from.absolute alcohol . ' . ' to .sive SS grams o:f yellow crystals ..melting at 153•4,0 • The r1.tported ()1) melting point was l~.3•4-°.• · ·This. ,ias a ~l • .$ per .cent; 7ield. 112. N,N'~DI-($-OHLOR0~6-METHOXY-8-QUINOLYL)-METHANEDIAMINE 208.,66, 30,03 1$ g.(o.072M) ... 1.• 1. g.{0.037M) · A mixture ot l.$ grams (0.072M). of 5..;.ohloro-6- tnethoX,-.. 8-aminoquinoline, ·3 ml. of 37,$ ·per· cent. formalin (equivalent .to 1.1 grams of tofflaldehy.de on a ·dey basis). and 25·ml •. of·absolute alcohol were allowed to' stand at room temperatu~~ for seven. da:rs~: At~ the end of that· period the yellow solid obtained: was f1ltere'd and recrystallize~ tram. acetone. Obtained were; 9.7 grams of .N,N'-di-(5-chloro- . 6-metho:q-8-quinQlyl)-methane.~famine melting ~t 179 ... aoo. This was a 64 per cent yield ... Anal. Oalad. tor 021H18N4020lz: Oi ..$8.7S; H, q..2l.J.; N, 13.0.S. Pound: 0, 58.8$; H, 3.98; N, 12.9~. . 113 • . N, N• ~l?l•( 5-<;JHLOR0~6-1Uin'HOXY..,:8.QUINOLYL) •2•METHYL• · 2•NIT1'0.-l.,.3•PR0l'ANEDIAMINE (ATTEMPTED) CJl5 • + f,fO-C"z-~ - C"i,-Oll NOz. 208.66 . . . . .19 g. (0.093M) ''~ J " .A mixtu~e · of· 19.~ gre.ms. ( o.·093M) of .$-ohloro-6- . . methoxy•8•aminoqu1noline, ·. 6. 2 grams ( O. 04-6M) of 2-methyl- 2-nftro... ;i,3..:p:ropan~diol. and 2 ml. ot .tetraethanolammonium . ' •. ' . ·: ': J ·• . . ' : . '. ' ' ' hydroxide ·were placed in a 12·, ml. Erlenmeye:r ~lask_ With so ml. of absolute alcohol. and kept at so0 for' five .·d~ys. At -the end ot that period· the dark solid that formed was. . . filtered from the blaok solution, washed three times with e.bsolut~ alcohol ·and recrystallized from .acetone. Obtained was a solid melting at 174..5°. A mixed melt.ing point with the ·compound p;repared br the interaction or S-chloro-6- . methoxy-8-amirtoquinoline and formaldehyde gave no ,depression. llq. • . OHAPIJ:IER ,.VII. DIS There e.reprob~bly three main lin~s of. attack that could be followed as a :result of this work. · H:rbrid antlmalarials •· ·. . ·, ~ . , , .-, ·· · The .seneral method; .for .the preparation ot .N-s~b- . . - ( ' ' . . ' stit~ted~2-hydl'o_xy-propanediamines ..could be used .to ~urther stud1 :the .J+-aminoquitioli~e. sar}es in search. ot new .'anti- malarit~Js. .In vei~ another. EJy"nthesis,. which ~s : this I ~ •, •.-~ • • • ' • \ ' , actually a mixture. ot thoset ttsed .1n .this work, suggests i ts~li'. ,!.The reac ti()n of 6~~thoxy-8-filllinoquinoli~e \,1i;h ·1-n.1~~0.-2;.propane :follo~ed.b:, reaction.of the ·addition. prod'tl.Ot"with .formaldehyde and .an .amine:.:W~Uld· give a 2-nitro•l,3•pttopantt dis.mine whi~h_ o·ou1d .be reduced and . ' coupled with 7-dich.lor~qu:tnoli~e .to give a hybrid., ~ • ,. • 4•' > ' 115,. B. The·unreactive hyd~~&l. compounds •. The resistance"ot:the secondary hydroxyl to ' ' ?eplaoement when in the structure RNHOH2CH(OH)OU2N,HR' 1s· ce~t-e!nl:y wo:rthy of furt"?er study .to _de~erm_i~e · ju~t what 1 structures make '-replacen,.~nt-.!mpossible. 'Studies. thls ' .. ' '/'···1, ,, ;. : of trpe .could thr,ow light. on the ··aot~a;L meol,lanism or hydroxyl ' • ' • '• ' I repiace;ment, when that': is nea:r other reaot1 ve, gro'\1ps ~ ' g~oup' ' . . . . . ; . . suoh as NHR, ·NR , OR, etc. · tess complex but rele.te.d . . . . 2 ' .. ', ' .··' ' ... '. ,·. ' . : ' ; . ;' ' ,· '· • , ·, ,l struotux-es should upon treatment with chlorinating agents give replacement;~·· Building up to. the stru·oture in'question '11houia·:~ndioa§e··1r there. were, any' "limiting"' .structure. beyon~whi'ch ,there, wou:14 be no re~ction. o:. · !h! reactfon.,.2£.;gufnolines ~ nitrodiols. . 1 ' Bi :.Qh~ce the· least, b·asio of. all the amino- q~inolines was us~d fn this work •. · The use of the more basic. ·aminoquinolines (lt.•aminoquinoline is ·3000x s:tronger ' ··, • . I ,,, .'·. . ' ' t1:tan: quin~l,i~e) might· change.· the· course 0,f the reaction. Use. of tht(.stro~er. amines migh.t result in tp.f:l isolation the 2•rtitro-l.,3-propanediamines .rather :than the methane '.of . ! • ' \ ; ' : : . • ·_ • ' • . ' ' ' ' • • • ' .. )• • ~ diamines as fouQ..d £or the 8-aminoquin_~linee. "' . ' •, '' ( ., 116. q~APTER VIII OONOLUSIONS 1. The condensation ot aliphatic or aromatic amines .with l•phthalimido•2,3~epoxypropane followed by- the removal·.ot the phthalio acid res.idue was shown to be a general method for.the p:reparation of N-substituted-2~ hydroxypropanediamines •. ·:.·'·2. These diamines, when condensed with 4,7-di• ehloroquinoline and. simi_la:r compounds, rorm possible ·new. . . . antimalarials in which the side chain is partially oxidized. )~ Us~ng the ~et~od described in (2), · two :·new hybi'id oompou~ds. of possible antims.lar1a:i activityiand six int&rinediates.·were prepared in better yields than.expected from othe~· methods •. ·4·~ .~ii~. seco~dilry hydrox7l group in the ,type;, ' I • \ • structure .. RliH9H2qM{OH)9H2ijHR.'/··~~~-·fo~d .. to be .unreactive to· I ' • • ' ' ' • : ' ; ,': ', • • -~ ''. ; • ' ;_ •! • • • • ', ' ' • • •' ! ' : ! .; • .; th~ llsu.al .. chlor~p.a.tlng agents,. : No .. s·atisfactory explanation ,' ·· •. :· :.. ','; .. ·• ·,· . ····'.;.·.... '· ,'.. ,. ·.·. .. " . ·' '. . : ' ,- ··..' for· thi~ ,~~llavior· has: ·been ·round. However, the possi~.i+ity 0~ a doU:l:>ly chelated. st~cture :is . s,ugge~ted: :&ft'· an·' ·•:' explanation for ,the ti.nrea~tiv1ty ot the .structural type. , , , S~ · The reaction of ~-metho~-8-ami~oquin6.~ine with. 2~alkyl~2-nitro•l,)-p:ropa~ed.1ol~ was.· found. to. 's1 ve rise to compounds containing a methylene bridge instead of the expected derivative of the nitrodialcohol •. 117. 6. Under the influence of strong bases the 2- alkyl•2•nitro-l,3-prbpanediois were found to exist ·1n equilibrium with formaldehyde and the nitro paraffin. The 1'ormal~ehyde thus formed reacted with both 6-methoxy-8- aminoquinoline and 5-chlo~o-6-methoxy-8-aminoquinoline to give methylene b~idge structures instead of. the expec·ted derivative of: the .. nitrodialcohol. \ ··· 7. The ,r~act1on of fo~.aldehyde and of 2-·a1,ky'~-2- ,.,. ', . ' ) ni t~o;J., 3-p~panediols With 6-metho.xy-8-aminoquinoli.D:ea under basic conditions give. d~pending ,tin the reaotion temper11tur~.·-· either:li,N•-di-{6-methoxy-8-quinolyl)- alkylated ·whiQh methe.nedie.m.ine or a nucleal biquinoline' has ' . ', \ been a$s1gne~ the probable structure of di ... (8-amino-6-methoxy-- .$l•ctuinolylmethane. ... 8~· The reaction_ or., formaldehyde and or·2-alkyl- . 2•n1tro-l,3•propanediols with S-chlox-o~6-methoxy-8-amino- qu1noline under basic conditions gave in eaoh case N,N'-(5- chloro.-6-methoxy--8-quinolyl)-meth~nediamine. This compound could. n~t be. rearra~ed to .the nuclear compound containing the methylene bridge. " ' 9. The formation ot the methylene ty-pe compounds from the nitroaloohols gives the first chemical proof oi' the mechanism of the :reacti?n of the diols.with .amines. 118. I A ' · 10. • '.' n,'.e~smin•,· '' acoord .facts • '. with.the known 1s postulated for the .zteaetioti''o"i·· 2-a~ky1_~2-.nitro-l,3• propanediols .. and like \,()mPotfnas ·w!th amines. .119. BIBLIOGRAP.rlY. l. Adams, _·Weisel and Mosher, J. Am •.. Chem. Soc., .§!!, 883 · (1946). 2. Albert and Golde.ck, Nature, fil, 467 (1944). · ). Anderaag, Bre1tner and Jung, Gez-man PQtent 683,691; · 0 .A~, J.2, 4973 (1942) • It• Andersag, Bre1tnel' and .Tung, u.s. Patent 2,233,970; .': 0 •'A•, .J.2, 3771 ( 19111) • $. . Bachman and Szmant·,· J. Am. Chem. Soc., -2!!, 31 (1946.). 6. Baker ~t. al., J. Am, ~hem·. Soc.,. J&, 1$32 (1946) •· 7. Bald.win; J._Ohem. Soo~, ~. 2959. 8. Bis~h,ott and Reinfeld, Ber., J.2, 41 (1903)i Bishop and Birkett,. Natu:re, l.23.,. 885 (1947) •. · 9. • ~· l • • 10. Bl1cke and.B~rckhalter •. J:-, Am. Ohem. 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O~~i.g ~d Faust, f'Olinical Par~si tology, ri Lea and ·: Febiger. ·Philadelphia,· 1937 • 2$ •. ,, Oromwe·.11 1_' ·.· B~bso11 and.·· Harris, J. Am. dhem. Soo., .22, 312 , ,, ( 1~43) • i • , • , , • ' , • I , , • "i ', J ~ ', ; ; ' . 26. Cromwell and Hoeksema, .J. Am~ Chem. Soc., fil., 124 (194.S). 27. Ou.rd, Davey ancl Rose, Ann •. Trop. Med., J.2,, 139, 1.$7 > ; " ' ( l.94..$ ) • ' " :• C ' ' : ' ' < • • • ' ' 28., Drake e.t.al. ,' J. Am. Ohem. Soo., \M., .14 (1946).· Drake, et~al., Am.. .:so~ .. 68,:-1208 (1946). 29. J. Oh~m. ·,. ~ .•.. ,t.' .)O. Drlll.keiet.al., J. Am •. Ohe:m. Soc., ·6a, 1.529 -":(,1946). 31. D1'$.ka e.t.~al., J;, .Am. Ohem. S~c,, .;, i$.36 (1946)·. > 32. Du~en, B~()k and Reid, .Ber. t ii; :20.36' (i905) ~ '.' : 3.3.« Edito-rial,: J. b. Me·d. Ass~., 1Jh:, 1176 (1.946). , .34. Eld~rfi;ld et.al., J. Am. Chem. Soc~. M, 1516 (194-6). 35.. Eldertield et.al., J. Am. Oham. Soc., .2§., 1524 {1946). ' ' ' ' • ' .;· • < 36. Emel'son/ J. Am.· Chem. 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Soc. t .1926,· 2346 • . .$1 •. :James,; :N1cof:and. Shulei ,Lanoet, (2), 341 (1931) • . .$2 •. James :_a,nd .. T~te,, Natul'e, .l.l2., .. Sq.$. (1937) • . %3. James end·~ate.s Pa~asit •.. , ..lQ.,. :128 ,(1938). , S!J. •.. JefiS~h,.:.U.S~ :.Patent 2,22.8,166; O.A., J2; 3990 (l9q_l). :S$. Joht1;son;·... J. Am.~,Oheµi~ SooO •• ~', l!t. (194.6): $6. Kaufmann;, j3er'••. !!&., _ia23 (1913h, $7. ·Kikuth and. Mudi--ow, .Zent_ralbl •. .f'. · Bakt. ,. !!Jg,: 1938., $8. King~ J •· Cham·. s.oc., 1920, 988. . . S9. · King. and,· B~er, CJ. Ob.em.· Soe. ~ · ~' 791 • . ·60. · Koppers. ·Natu·re, 160,. ,608 (l9q.7) ~· Jt J J. Am. Ohem. Soc. • M, 61. : Lauer· .. • ·• ; ' . • ·:~al. 1. ' • 1546 ( 1946). 62~ Lauer, Amold and Buckles, J. Am; Ohem. Soc.,' .2§., lS.$2 ' :. (1946).' ~ '. . .·. . . 6.3. L~~gue or. Nat10l;l8, .q.th General Repol't .. o~ Malaria . Oom..111ission, Geneva,.:·1937, P• 120. . 6q.. Loeb ·et. e.l·., J~ Am. Med .... Assoc., 130, 1069 (19q.6) •. 65. Loeb,·J. 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(191,.6)-. . ., , . · . · ...... - . :· • ," e'• P;l.o·e,, Leonard:~nd Reiteeme.,·~J •. Am. Ohem. Soo,, 68, · 12$0 (194.6) • · . · · ·. · . . · · 80~ Q.uin '&ll4 Robinson, ·J. •ahem. ·So~. , . 00, 555. ·· ·. . . :. , .. 81. Rabe, .Ber., .k!., 62 (1908) •.. .82. Ra~e, A~., /!a~. 2.42 (1932) • . Rabe· et;·.ai.-,· .§!J:; 24~7 (19.31). 83.\ :·Be~., ~ _. . ~ .., li.66 (1918) ~ · , •: e.n{Jtindler, • '. •j' • • ·• • '• • I ' • Ber., ~ • • 84. Ra;e· .z!, • R6.be and .Kindle?',· ,.Ber.·, >1842 .(1919). as. ' ': £, : -, 86.· Rabe, .P.aate·r~ack a~d Kindler; Ber:., 29.~· 144, (19i7). 87. Rabe and· Sohtlltze·~ 'Ber.~· ~~ · 120 ;(19j3). ·. · · ' ,._ · 88. Rafi'aele , ·Ri;. di Mala;i.01. , .ll. 332 (193lj.} • 123. 89. Revier and Fraine,· Helv. Chim. Aota·. ,· 12·, 86S (1929). ' . '," ,· . '. ·- ' '. ' Riegel et J .• Am,f Ohem. Soc., : 68, ,· 1229 ( 194.6) • .al.; 1 90. .__ . ; . ' ' ' ,. ,. ' •· ' Boehl, Aroh. Sohiffs. u .. Tropen-Hyg., lQ., 11 (1926). 91. ) ' ~ \ . , . . . . ' . . . '' , ' ) -, I ; ' ' , 92.. $apero., :Am. •. :r. Trop,. Med., gz, .271. (1947). 93. Sargent:<,antf Small, J. Org. Ohem., ll, 175 (l9q.9) •.. 94.·. Sch8Ilh.8fer,· ·z. ·pllysiol~ chem., fil, l (1942) •.. ,-.r, I• ' l'j;,.J 9$.· · Sohulemann and Mermni, Arch. Schi:rfs u •. Tropen-Hyg., · . ..ll., :. $9 ( 19,27 J• · ·96~..· Scb.ulemann, Schonb.oter and Wingler, Proo. Roy. Soc. Med~, · -~., 32 (1932).. . · · ·. . : · . . 97. ·. Shortt et• al., Brit" Med. J. , March 20, l 948. 98. ·. Shortt a'.nd Garnham, Nature, 161, 126 (1948). , ,·,'f 99,.· Silvennan and Evan~, J. Biol. Oham., 150, 265 (194-5) • .. loo. Simona, J. Am. ·Chem. Soe. ,. 22., 518 (19.3T). 101. · Sinton, Hutton and Shute, Ann •. Trop. Med., :U., 31 . · · (l939 )-. ' · · · 102. Slot ta ~d Behmi.sch, Ber., £!!, 7!,)i. (193.5), 103. Surgeon:General.•s Office, Circular Letter No. i.5); .· J. Aln •.. Med •.Assoe", _12j, 205 (194)). 104. Su~ttey and Hammer, J. Am. Ohem. Soo., ~,. 4.3 (1946). . ' . . 10$. Tarbell et.al., J. Am. Ohem. Soc., .22,, 1217 (1946). 106. Tollentt~ Ber., 1&, .3302 (1895). · 107. Vanderbilt -and)iass, Ind. Eng. Ohem., Jg, )48 (1940). 108. Wagner,. J.Am. Chem. S~c·., ~, ·660, 724 ·(1933) •. 109. We~~e.nn -and Malkawa., Bull •. soo. ohim., !(l, 356 ·(1930). . . . 110. Weizmann and .Mall!awa, Oompt._ :rend., 190~ 495 (1930)~ 111 •.. Wenyon, Trans. Roy. Soe. Trop. Med. and Hyg., J,2., 177 ' (194$).. '.. . ,, ·.· . '' . 112. :Williams and Soper, . J. ,,O~~m •. Soc.; ~, 2469. 11.3. W111iamson, lfature,; la; ·886 (1947). 114,. Wi~eM~{e,. ,surv,1 .or Antima1a1:'1ai Dl'U.gs,n Edwards, · . ' ..An~. A~b~:r, .1946, P• ~9 •. '.·. ' . . . . . , '' 11.$ • Ib1 d •, .J>. ~17 ft. 116. -.Ibi