[CONTRIBUTION FROM THE DIVISION OF
PHYSIOLOGY,
NATIONALINSTITUTE
OF
HEALTH]
ATTEMPTS TO FIND NEW ANTIMALARIALS. 111.'. AMINO ALCOHOLS DERIVED FROM 3-METHOXYPHENANTHRENE EVERETTE L. MAY
AND
ERICH MOSETTIG
Received January 1 , 19&
In the two foregoing communications (1, 2) we have shown that phenanthryl amino alcohols of the types I and I1 exhibit antimalarial activity to a high degree.
I
I1
I11
Since quinine as well as Atabrine and Plasmochin contain a methoxyl group, we thought that the introduction of a methoxyl group into I and I1 might enhance the efficacy of these amino alcohols. Mosettig and Burger (3) found that in the Friedel-Crafts reaction on 3-methoxyphenanthrene the acetyl group enters position 9 readily, the ketone being formed in 75% yield. From this compound we synthesized amino alcohols of type I11 as described in the foregoing papers, via bromo ketone and amino ketone. A great obstacle appeared to be the acquisition of 3-phenanthrol in large amounts. The hitherto most feasible preparation of 3-phenanthrol (sulfonation of phenanthrene and subsequent potassium hydroxide fusion) was developed by Werner and co-workers (4). Fieser ( 5 ) improved the process and was able to obtain this product in an over-all yield of 20-25%. Sandquist ( 6 ) prepared phenanthrene-3-sulfonic acid by sulfonation of 9-bromophenanthrene and subsequent debromination with zinc dust and ammonia. The results of Sandquist, however, could not be duplicated. Under the conditions given by this author, only the 3-sulfonic acid was obtained, but the yields were considerably lower than stated. Eventually we sulfonated 9-bromophenanthrene at steam-bath temperature as recommended by Anschiitz and von Siemienslii (7), and dehalogenated the reaction product catalytically. Phenanthrene-2- and 3-sulfonic acids were formed in over-all yields (from phenanthrene) of 8% to 10% and 40% to 45% respectively. A separation of the isomers waa not necessary for our purpose. The 2-isomer is readily lost on the way to 3-methoxy-9-acetylphenanthrene, 1 The work described in this paper was done in part under a contract, recommended by the Committee on Medical Research, between the Officeof Scientific Research and Development and the National Institute of Health. * Studies in the Phenanthrene Series XXVIII.
15
16
EVERETTE L. MAY AND ERICH MOSETTIG
chiefly in the Friedel-Crafts reaction. The latter compound was obtained pure and in an over-all yield of about 40%, based on phenanthrene. This series, as a whole, appears less effective against Plasmodium gallinaceurn than the two previously described series (Dr. G. Robert Coatney and Dr. W. Clark Cooper) (8). The introduction of a methoxyl group into the 3-position of phenanthrene-9-&amines proved to be therapeutically disadvantageous, while the toxicity (chicks) is not appreciably affected thereby (Dr. Nathan B. Eddy) (9). None of the drugs listed above showed any activity towards sporozoiteinduced galiinnceum malaria (8). ACKNOWLEDGMENTS
We wish to thank Dr. R. C. Elderfield, Columbia University, for the supply of dinonylamine, and Mr. Edward A. Garlock, Jr., for carrying out the microanalyses. TABLE 1 3 ANTIMALARIAL ACTIVITYOF AMINOALCOHOLS SN
-
5985 5993 1780 1781 1782 9470 1784 15046
1783
3-OCHa 9-CHOHCHr
Q
N (CHJ 2 N (CzHs)P N(CaHi)z N(CIHO)P N(CLHII)P N (CeHicJ2 morpholino dl-trans-decahydroquinolino (A) dl-trans-decahydroquinolino (B) EXPERIMENTAL4
9-Bromophenanthrene (10). To an ice-cooled, well-stirred suspension of 200 g. of phenanthrene,6400 cc. of chloroform and 400 cc. of absolute ether was added during fifteen minutes, 180 g. of bromine. The temperature remained at IO" to 15". The mixture was then cooled t o 3" for forty-five to sixty minutes, filtered, and the precipitate washed thoroughly with about 750 cc. of cold dry ether. This dibromo adduct was heated on the steam-bath with hand stirring until a clear melt was obtained (thirty t o forty-five minutes). The yield of 3 I n Table I are listed the compounds which were submitted for biological investigations. I n the first column are given the identification numbers assigned t o the drugs by the Malaria Survey Office of the National Research Council. The third column shows the approximate ' I Quinine equivalents" expressing the effectiveness of the drugs towards Plasmodium gallinaceum, compared with that of quinine. A dash indicates that the equivalent is less than 1/16. The compounds were administered as hydrochlorides. 4 All melting points are uncorrected. 6 A 98% pure Reilly product was used.
AMINO ALCOHOLS FROM 3-METHOXYPHENANTHRENE
17
9-bromophenanthrene melting a t 57-60" was 225 g. (87%). After one recrystallization from petroleum ether (b.p. 60-71") i t melted at 61.543". Sulfonation of 9-bromophenanthrene. A mixture of 103 g. of 9-bromophenanthrene (m.p. 57-60') and 50 cc. of 96% sulfuric acid was heated in a steam-bath for one hour with frequent shaking. Sixteen cubic centimeters more of sulfuric acid was then added and the heating and shaking continued another hour. Finally, a second 16 cc.-portion of sulfuric acid was addd and the heating and shaking continued forty to sixty minutes until the reaction mixture had set to a grayish semi-solid mass. It was diluted with 1000-1500 cc. of water and made alkaline with 200 g. of potassium hydroxide. After cooling, the precipitated potassium salts of the sulfonation product were collected, washed witha3%potassium chloride solution, and air-dried. This crude product weighed 170 g. Phenanthrene-% and 3-sulfonic acids. Fifty grams of the above crude sulfonation product (dried at 100")and 5 g. of palladium-charcoal catalyst (5% Pd) were suspended in 300 cc. of 95% ethanol, 300 cc. of water, and 5 cc. of concentrated hydrochloric acid. The mixture was shaken under hydrogen a t atmospheric pressure until absorption had ceased (about five hours). It was heated almost to the boiling point, filtered and the clear solution concentrated t o 350400 cc. Upon cooling t o lo", the isomeric potassium phenanthrene sulfonates precipitated and were collected. The yield was 27 g. When this mixture was separated according t o Fieser (5), the 2- and 3-phenanthrene sulfonates were obtained in a ratio of 1 t o 4. A potassium hydroxide fusion of the sulfonate mixture yielded 2- and 3-phenanthrols in a similar ratio. Their separation was effected by sublimation followed by fractional crystallization from a benzene-petroleum ether (30-60") mixture and finally from benzene. 3-Methoxy-9-acetylphenanthrene.The mixture of the isomeric potassium phenanthrene sulfonates was fused as described by Fieser (5) for either of the pure isomers except t h a t milder temperature conditions were used. The nickel crucible containing the potassium hydroxide melt was immersed in a metal-bath maintained at a temperature of 290-295", and the temperature of the melt was 250-260" while adding the sulfonate mixture. During the following five-minute period, the bath temperature was 320-325" and the melt temperature remained a t 280-285". The yield of crude phenanthrol (m.p. 100-104") was quantitative. Fifty grams of this material was dissolved in 125 cc. of 10% sodium hydroxide and the solution mechanically stirred while 25 cc. (35 9.) of dimethyl sulfate was added in twenty minutes without external cooling. After an additional one-half hour of stirring at room temperature, the reaction mixture was cooled to 0" and the methoxyphenanthrene filtered off. The air dried precipitate (46.rj g.) was distilled in a high vacuum t o yield 42 g. of colorless product which solidified almost immediately. From the sodium hydroxide filtrate 5 g. of hydroxyphenanthrene was recovered by acidification with hydrochloric or acetic acids. The 42 g. of distilled product was added in small portions to a stirred mixture of 54 g. of aluminum chloride, 180 cc. of nitrobenzene, and 18 g. of acetyl chloride. The temperature was maintained at -5" t o 0". Stirring was continued a t 0" until the contents of the flask became rather pasty. The reaction product was then allowed t o stand for twenty-four hours at +5". It was decomposed with an ice-hydrochloric acid mixture and the nitrobenzene distilled with steam. The dark residual oil was dried in chloroform over sodium sulfate and distilled under a high vacuum. The distillate (45 g.) was recrystallized from methanol. The yield of 3-methoxy-9-acei ylphenanthrene melting a t 97-98.5" was 38.5 g. (over-all yield from phenanthrene, about 40%). 3-Methozy-9w-bromoacetylphenanthrene (3b). To an ice-cooled, mechanically stirred mixture of 18 g. of 3-methoxy-9-acetylphenanthrene(m.p. 97-98.5"), 100 cc. of dry chloroform, and 100 cc. of dry ether was added 4.0 cc. of bromine during a fifteen-minute period. The reaction mixture was allowed to warm t o room temperature, cooled again in ice and the precipitated bromo ketone collected and washed with cold ether. The yield of product melting a t 116-117" was 15.4 g. By concentration of the mother liquor and dilution with methanol a second fraction of 3.6 g. melting at 114-116° was obtained.
18
EVERETTE L. MAY AND ERICH MOSE'ITIO
3-Methoxy-9-(8-dipropylamino-1 -hydroxyethyl)phenanthrenehydrochloride. Ten grams of 3-methoxy-9-~-bromoacetyl phenanthrene, 6 g. of dipropylamine, and 60 CC. of dry ether were shaken together for about fifteen hours. After cooling in the ice-box, dipropylamine hydrobromide (5.5g.) was filtered off. The filtrate was slowly acidified with 11 cc. of 12% alcoholic hydrogen chloride. The amino ketone hydrochloride separated as an oil which slowly crystallized. It was collected (8.6g.) and recrystallized from an absolute ethanolether mixture. The use of Norit was necessary to ensure success of the subsequent reduction. The yield of recrystallized product (fine needles) was 7.5 g. It absorbed 85% of one molecular equivalent of hydrogen in 48 hours when shaken under hydrogen with 0.3 g. of platinum oxide catalyst in 100 cc. of 80% aqueous methanol. The catalyst was removed, the solvent evaporated in vacuo, and the syrupy residue dissolved in the minimal amount of warm acetone. On standing for some time, the amino alcohol hydrochloride crystallized. After cooling in ice a yield of 4.5 g., m.p. 200-202", was obtained. By dilution of the filtrate with ether a second fraction of 0.8 g., melting a t 125-135'was obtained. It ww found to be a mixture of amino ketone and amino alcohol hydrochlorides and when subjected to reduction as described above yielded 0.5 g. more of amino alcohol salt. The latter fraction was combined with the 4.5 g. and the whole recrystallized from absolute ethanol-ether. Yield 4.1 g., m.p. 202.5-203'; clusters of large needles. Anal. Calc'd for CtsH&lNO9: C, 71.19;H, 7.79. Found: C, 70.91;H, 8.15. S-Methoxy-9-(8-dibutylamino-l-hydroxyethyl)phenanthrene hydrochloride. This compound was prepared essentially as described for the dipropyl homolog. Nine grams of bromo ketone yielded 7.7g. of purified amino ketone h3drochloride. It absorbed 1.2 molecular equivalents of hydrogen in twenty-two hours when shaken with 0.4 g. of platinum oxide catalyst in 100 cc. of 80% aqueous methanol. From acetone-ether 4.6 g. of amino alcohol hydrochloride separated. It melted a t 174.5-176'. From the mother liquor a 1.1 g. mixture of amino ketone hydrochloride and amino alcohol hydrochloride was obtained. Recrystallization of the 4.6 g. from acetone-methanol-ether gave 3.9 g. of clusters of large white needles melting a t 176-177". Anal. Calc'd for C2sH&1N02: C, 72.18;H, 8.24. Found: C, 71.90;H, 8.54. 3-Methoxy-3-(2-morpholino-1 -hydroxyethyl)phenanthrenehydrochloride. This amino alcohol was prepared similarly to the two foregoing ones. The over-all yield from bromo ketone was about 60%. From methanol-ether the product crystallized in white hexagonal plates melting a t 211-212' (decomp.). Anal. Calc'd for C21H2aClNOS: C, 67.45;H, 6.47. Found: C, 67.45;H, 6.85. It was not attempted to prepare the foregoing amino alcohols by the aluminum isopropoxide procedure described subsequently. 3-Methoxy-3-(S-dimethylamino-l -hydroxyethyl)phenanthrenehydrochloride. To 2.8 g. of a dry ethereal solution containing 3 g. of dimethylamine was added 5 g. of 3-methoxy-94bromoacetylphenanthrene. The mixture was alternately shaken and cooled in ice-water for a period of fifteen minutes, then allowed to stand a t room temperature for two hours. After thorough cooling in the ice-box, dimethylamine hydrobromide (1.8 g.) was filtered off and washed with dry ether. The ether was evaporated (the last few cc. in vacuo) and the oily amino ketone remaining reduced with 25 cc. of 3 N aluminum isopropoxide as described previously (2). The time required for the reduction was 2.5 hours. After evaporating the isopropanol under a vacuum, the residue was partitioned between an excess of 10% sodium hydroxide and ether. The ether layer was washed twice with water, dried over sodium sulfate and acidified with 3 cc. of 20% alcoholic hydrogen chloride. The amino alcohol salt precipitated as a brown solid in a yield of 3.9 g. After one recrystallization from ethanol-ethyl acetate (Norit) 2.8 g. of product melting a t 206-207' was obtained. Burger and Mosettig (ab) report 207-208". 9-Methoxy-3-(8-diethylamino-l-hydroxyethyE)phenanthrenehydrochloride. A mixture of
AMINO ALCOHOLS FROM 3-METHOXYPHENANTHRENE
19
5.6 g. of 3-methoxy-9w-bromoacetylphenanthrene, 2.9 g. of diethylamine and 40 cc. of dry ether was shaken for fifteen hours and cooled in the ice-box for one hour. Diethylamine hydrobromide (2.3 g) was filtered off and the ether filtrate washed twice with water, dried over sodium sulfate, and the solvent evaporated. The amino ketone residue was reduced as above with 25 cc. of 3 N aluminum isopropoxide solution. Reduction time was 1.5hours and the yield of crude hydrochloride (m.p. 180-185') was 3.7 g. Upon recrystallization from absolute ethanol (Norit) 2.6 g. of product melting at 189-191" was obtained. For analysie a small sample was recrystallized t o the constant melting point 191-192' and dried at 110' for one hour. Anal. Calc'd for C~IHZ&INOY~HZO: C, 68.37;H, 7.36;H20,2.4. Found: C, 68.70;H, 7.19;H20,2.5. J-Methoxy-9-(d-diamylamino-f-hydroxyethyl)phenanthrenehydrochloride. This compound was prepared essentially as described for the dimethyl and diethylamino homologs. The amino alcohol base was evaporatively distilled at 0.01mm. pressure and at an air-bath temperature of 200-205". The distillate was dissolved in ether and made slightly acidic with alcoholic hydrogen chloride. The over-all yield of hydrochloride from bromo ketone was about 40%. It crystallized from acetone-ether as white shining plates and melted at 124-125.5'. Anal. Calc'd for C2,H&IN02: C, 73.03;H , 8.62. Found: C, 73.01;H, 8.89. S-Methoxy-9-(d-dinonyEamino-l-hydroxyethyl)phenanthrene hydrochloride. This compound was prepared like the foregoing dimethyl, diethyl, and diamyl derivatives. Here, however, the reduction product was not distilled. On acidifiation of the dried ether solution of the crude base, 4.8 g. of hydrochloride (from 5 g. of bromo ketone) melting at 123-127" was obtained. One recrystallization from an acetone-ether mixture yielded 4.1 g. of needles which melted at 91-95'. Another recrystallization from acetone gave 3.0 g. of plates melting a t 130-133". Finally for analysis a small sample was recrystallized again from acetone. The melting point was 131-134". The modification melting at 91-95' was not encountered after the recrystallization from acetone-ether. Anal. Calc'd for CasHs4C1NO2:C, 75.56; H, 9.78. Found: C,75.56;H, 9.77. S-Methoxy-9-(d-dl-trans-decahydroquinolino-l-hydroxyethyl)phenanthrene hydrochloride. A mixture of 3.8 g. of 3-methoxy-9w-bromoacetylphenanthrene, 3.4 g. of dl-trans-decahydroquinoline (II), and 25 cc. of dry ether was shaken for eighteen hours. After cooling in ice, 2.7 g. of trans-decahydroquinoline hydrobromide was filtered off, the filtrate was evaporated to dryness, and the residue reduced with 20 cc. of 3 N aluminum isopropoxide. The dried ether solution of the amino alcohol was evaporated t o dryness and the residual oil triturated with a 2:1 ether-petroleum ether (30-60")mixture, whereupon prisms separated. After cooling they were collected. The yield of base (Isomer A) melting a t 148-154' was 1.3 g. It was suspended in acetone and neutralized with 15% alcoholic hydrogen chloride. The resulting hydrochloride weighed 1.3 g. and melted a t 247-248" (decomp.). On recrystallization from 95% ethanol-ether i t appeared as rectangular plates of m.p. 247-248" (decomp.)! Anal. Calc'd for C2aH&lN02: C, 73.29;H, 7.58. Found: C, 72.79;H, 7.37. The base was prepared by adding aqueous ammonia t o the hydrochloride followed by extraction with ether. It crystallized from absolute ethanol as prisms of m.p. 154-155'. 6 In a previous experiment the isomer A was isolated first as the hydrochloride and appeared as small prisms of m.p. 228.5-230" (decomp.). Anal. Found: C, 68.17;H, 7.25. I t was dried for four hours at 130". Anal. Found: C, 68.28;H, 7.28. The base, liberated from this salt melted at 154-155" and gave no depression in a mixture m.p. with that prepared from the hydrochloride of m.p. 247-248'. After about two years, the hydrochloride of m.p. 228.5-230"had changed to the one melting at 247-248".
20
EVERETTE L. MAY AND ERICH MOSETTIG
Anal. Calc'd for CmHalN02: C, 80.16; H, 8.02. Found: C, 79.68; H, 8.02. Another recrystallization from absolute ethanol did not change the melting point. The resulting sample gave C, 79.68; H, 8.17. The ether-petroluem ether filtrate from base A was acidified with 3 cc. of 15% alcoholic hydrogen chloride, and the precipitated oil was just dissolved by addition of acetone. Overnight in the ice-box 2.0 g. of a crystalline hydrochloride melting at 229-233" (decornp.) separated. After two recrystallizations from 95% ethanol-ether the melting point was constant a t 240-241' (decornp.). This is Isomer B . It was in the form of large needles. Anal. Calc'd for CwH&lNOz: C, 73.29; H, 7.58. Found: C, 73.09; H, 7.58. The base could not be induced t o crystallize. SUMMARY
A series of amino alcohols carrying the side chain-CHOHCHtNR8 in position 9 and a methoxy group in position 3 of phenanthrene, has been prepared. The evaluation of these compounds m antimalarials is discussed. BETHESDA 14, MD.
REFERENCES (1) MAYAND MOSETTIO, J . Org. Chem., 11, 1 (1946). (2) MAYAND MOSETTIG, J . Org. Chem., 11, 10 (1946). (3) (a) MOSETTIGAND BURGER,J . A m . Chem. SOC.,66, 2981 (1933); (b) BUEOERAND MOSETTIG, J . A m . Chem. Soc., 66, 1745 (1934). (4) WERNER,Ann., 321, 248 (1902). (5) FIESER,J . A m . Chem. SOC.,61,2460 (1929). (6) (a) SANDQUIST, Ann., 398, 125 (1913); (b) SANDQUIST, Ber., 63, 168 (1920). (7) ANSCRUTZ AND VON SIEMIENSKI, Ber., 13,1179 (1880). (8) COATNEY AND COOPER, Unpublished results. (9) EDDY,Unpublished results. (10) (a) FITTIGAND OSTERMAYER, Ann., 166,363 (1873); (b) ANSCHBTZ, BW.,11,1217 (1878); (c) HAYDUCK, Ann., 167, 180 (1873); (d) AUSTIN,J. Chem. Soc., 95, 1763 (1908); (e) SANDQUIST, Ber., 48, 1146 (1915). (11) ADKINSAND CRAMER, J . Am. Chem. SOC., 62,4349 (1930).
