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DRAKE,ANSPON,DRAPER, HAYWOOD, VAN HOOK,MELAMED, PECK,STERLING Vol. 68
3. The preparation and properties reported 4. The methods used for the preparation of in the literature for 3-chloro-8-aminoquinoline each quinoline nucleus are indicated. are corrected. EVANSTON, ILLINOIS RECEIVED APRIL 15, 1946
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FROhl TFIE LABORATORIES O F T H E
NIVERSITY O F M A R Y L A N D ]
Synthetic Antimalarials. Some Derivatives of 8-Aminoquholine BY rU’A’l3IAN I,. DRAKE,HARRY D. ANSPON,J. DANIELDRAPER,STUART T. HAYWOOD, JOHN VAN HOOK, S I D N E Y I\fELAMED, RICHARD hf. P E C K , JOHN S T E R L I N G , JR., EDWARD WALTON, AND ALFRED
WHITON Plasmochin (pamaquine), 6-(4-diethylamino-lmethylbutylamino)-6-methoxyquinoline, and its derivatives have been the subject of an immense amount of research because of the reported curative action of Plasmochin on vivax malaria2when the drug is administered with quinine a t approximately the maximum tolerated dosage level. The high toxicity of Plasmochin which is reputedly greater for non-Caucasian races, has prompted an intensive search for a better drug which will possess the curative action of plasmochin and be less toxic. The present paper describes the preparation and properties of a number of plasmochin derivatives which were prepared with the above end in view.3 The pharmacology of these drugs will be found elsewhere.2 N-Alkyl derivatives of 8-aminoquinoline are prepared by treating 8-aminoquinoline with a suitable alkylating agent, usually an alkyl halide. The desired compounds have a methoxyl group in the 6-position, and i t has proved impossible in our laboratories and elsewhere4 to use the Bucherer reaction to introduce a desired side chain in place of the hydroxyl group of a 6-methoxy-8-quinolinol, although the reaction is successful when applied to 8-quinolinol. Reductive alkylation has also proved impossible thus far. Alkylation, therefore, remains the only useful method of preparing the desired compounds. I n our work, alkylation was carried out by one of three general procedures as shown in Table I. Method I consisted essentially in heating together two moles of the appropriate 8-aminoquinoline, one mole of the proper 1-halo-x-alkyl (or dialkyl) aminoalkane hydrohalide, and a small amount of water, a t successively higher temperatures until the mixture was eventually heated under reflux for several hours (about 100105’ inside t . ) , The resulting melt was poured (1) This nork was carried out under a contract recommended by the Committee on Medical Research between the Officeof Scientific Research and Development and the University of Maryland. (2) A Survey of Antimalarial Drugs 1941-1945, F. Y. Wiselogle, Editor, Survey Office Monograph, in press. The term curative is used t o desi::nate that the drug prevents the relapses which occur in the absence of au additional infection and which are characteristic of vivax malaria. (3) See also Drake ef ai., THISJOURNAL, 68, 1529 (1946). (4) Dr. R. C. Elderfield, Columbia University, private communication.
w.
into excess hydrochloric acid and the precipitated hydrochloride of the nucleus was removed by filtration and washed with cold water. The resulting filtrate was brought to about pH 5 by the addition of sodium acetate, and extracted with ether to remove the remainder of the nucleus. The extracted solution was made strongly basic by the addition of concentrated sodium hydroxide solution and again extracted with ether. The ether was then removed from the combined extracts by distillation, and the residue was distilled in high vacuum.6 Method I1 was essentially that described by Rohrman and Shonle,6 and method I11 was a variation of this procedure according to which Cellosolve (ethyleneglycol monoethyl ether) and water were used in place of alcohol, and some sodium acetate was added as buffer. By far the majority of the drugs were submitted as salts; in a few cases where crystalline salts could not be obtained the compounds were submitted as a salt in an aqueous-alcoholic solution. Table I lists the compounds prepared with the exception of SN-13,276 and some closely related compound^.^ Those bases for which no carbon and hydrogen analyses are given were analyzed as salts, and the analytical data appear in the experimental part. The free bases are heavy, highboiling oils which are very susceptible to air oxidation and are difficult to keep in a state of analytical purity; for this reason i t was customary to purify salts for analysis. Procedures are given for the preparation of intermediates only when the methods used are new or represent a substantial improvement over methods to be found in the literature. Of these intermediates, only 5,6-dimethoxy-8aminoquinoline deserves special men tion here. This compound was prepared by a four-step process from veratrole. Nitration of veratrole in acetic acid produced 4,5-dinitroveratrole in one step. This substance in methanol was subjected to ammonolysis in a standard hydrogenation bomb. The resulting aminonitroveratrole was obtained from the ammonolysis by crystallization and after drying was used in a Skraup synthesis. The secret of the success of this Skraup reaction is ( 5 ) For an alternate procedure which makes possible a cleaner separation of nucleus see ref. 3. (G) Rohrman and Shonle, THIS JOURNAL, 6 6 , 1640 (1040).
Aug., 1946
SOME bERIVATIVES OF
8-AMINOQUINOLINE
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a very short reaction time' (less than four minutes). method TI (nuc1eus:phthalimide = 2: 1). Unreacted nucleus was removed by distalation in vacuum, and the Our early experiments with this Skraup reaction residue was subjected to hydrolysis in a large excess of boilby all of the known modifications were uniformly ing concentrated hydrochloric acid overnight. The soluunsuccessful u.ntil a very short reaction time was tion was concentrated in vacuum and made strongly alkaline with concentrated sodium hydroxide. A dark brown employed. separated and was separated from the aqueous layer. The resulting 5,6-dimethoxy-8-nitroquinoline oil The oil was dissolved in methanol and a small amount of was reduced by means of stannous chloride, and gummy product was removed by filtration. The filtrate the aminoquinoline was isolated by filtration from was brought to an apparent pH of 4.1 by means of 85% the reduction mixture after the latter had been phosphoric acid whereupon the salt separated as a yellowbrown precipitate. The phosphate was recrystallized from made strongly alkaline to dissolve tin salts. One an ethanol-water solution (2.5: 1) with use of decolorizing crystallization from alcohol sufficed to yield a carbon. The diphosphate, which melted a t 207-209 ",was product which. was satisfactory for use in alkyla- obtained in 22oJ, over-all yield (based on one-half the tion processes. The over-all yield from 4,5- amount of nucleus used). The estimated inhomogeneity9 %'as 16 * 5%. Anal. Calcd. for C ~ & I N ~ O . ~ H ~ P O ~ : dinitroveratrole was 16-19%. C, 39.56; H , 5.98. Found: C, 39.64,39.50; H, 5.91,5.92. It should be emphasized that the ease of puri8-Amino-5-chloro-6-rnethoxyq~0~~ne.~~-One hundred fication of 8-aminoquinoline drugs is influenced in and thirteen grams of acetic anhydride was added to 174 large measure by the purity of the starting ma- g. of 8-amino-6-methoxyquinoline in 260 nil. of acetic acid and the resulting solution was heated to boiling under reterials. The 6-methoxy-8-aminoquinoline8used flux for ten minutes. One ml. of water was added, and the in our work was purified by distillation under mixture was cooled and transferred to an 8-liter battery jar, nitrogen a t about 50 microns pressure followed by whereupon an ice-cold solution of 71 g. of chlorine in 1.75 crystallization from methanol (0.4 ml. methanol/g. liter of acetic acid was added over a period of ten seconds to the vigorously stirred solution. 8-Acetamino-5-chlorobase). 6-Methoxy-8-aminoquinoline purified by 6-methoxyquinoline hydrochloride separated rapidly and distillation only contains some very easily oxi- the mixture became semi-solid. Water (4.35 liter) and dizable substance which is the cause of the rapid concentrated ammonium hydroxide (170 ml.) mere added discoloration of the product when exposed to air. and the slurry was stirred for a few minutes and filtered and sucked as dry as possible. The product was suspended A distilled product, recrystallized from methanol in 870 ml. of hot water in an apparatus provided with a several times, will remain colorless even in the open stirrer and a reflux condenser; the mixture was stirred and air for a relatively long period of time. One crys- heated while 870 ml. of 1:1 hydrochloric acid was added tallization after distillation removes the bulk of the through the condenser. Boiling and stirring were continfor fifty minutes, whereupon heating was discontinued unknown contaminant and yields a product which ued and an ice-bath was placed about the flask while 520 ml. of is quite satisfactory. The homogeneity of B-amino- ammonium hydroxide was added. The pr;duct was removed by filtration; it melted a t 150-152 . The crude 6-methoxyquinoline so purified is about 98%.!' It will be noted that the yields given in Table I product was dissolved in about 4 liters of hot methanol, treated with decolorizing carbon, and allowed to crystalare rather low. These figures should not be con- lize. The yield was 125-135 g. (60-650j0); m. p. 153-154'. sidered to represent the optimum yields obtain1-Bromo-6-methoxyhexane. 14,15-A solution of 230 g. able in any case; it should be remembered that of sodium in 4.5 1. of anhydrous methanol was added over the object of our work was to prepare for screen- a five-hour period to a stirred refluxing solution of 2440 g. of hexamethylene bromide in 2.6 1. of anhydrous ether. ing a large number of pure drugs in the shortest The mixture was boiled under reflux for an additional three possible time. It seems likely in the light of our hours whereupon the condenser was adjusted for downaccumulated experience that the majority if not ward distillation and 4 liters of distillate was removed. all of these yields could be raised to 50-70% by The precipitated sodium bromide wa s removed by filtration and washed with 2 liters of dry ether. After the comproper attention to detail. bined filtrate and washings had been washed with three 1.5-liter portions of water, the organic layer was dried and Experimental lo 845-Aminoamglamino) -6-methoxyquinoline Diphosphate (SN-3851-.5).11-6-Methoxy-8-( 5-phthalimidoamylamino) -quinoline was prepared from 8-amino-6-methoxyquinoline and N-(5-bromoamyl)-phthalimide11a~12 by (7) This important fact which makes the difference between success and failure was discovered in the laboratories of Columbia UniJOIJRNAL, 68, 1584 (1'346). versity. See R . C. Elderfield, et a l . , THIS Elderfield used 4-acetamino-5-nitroveratrole obtained by nitrating 4-acetaminoveratroli:. The reaction works equally well with 4amino-5-nitroveratrole. (8) Purchased From the Winthrop Chemical Company. (9) Determined by the counter-current extraction process. See Craig, J. Biol. CIiem., 155, 519 (1944); Craig, el a!., i b i d . , 161, 321 (1945). We should 'like to express our thanks to Dr. R. C . Elderfield for his kindness in he.ving this determination carried out for us. (10) Microanalyses by Miss Eleanor Werble of this Laboratory. (11) (a) Baldwin, J. Chem. Soc., 2959 (1929): (b) Beer, J. Gen. Chem. (U. S. S. I
