ICONTRIBUTION
FROM THE RESEARCH
LABORATORY O F L . \ D Y ESTHER. LTD.1
ATTEMPTS TO FIND NEW ANTIMALARIALS IX DERIVATIVES OF PHENAYTHRENE, I. AMINO ALCOHOLS OF THE TYPE -CHOHCH,NR,, DERIVED FROM 9-BROMOPHESANTHREKE J. SCHULTZl, M. A. GOLDBERGz, E. P. ORDAS3, ASD G. CARSCH4
Received August 17, 19#
The synthesis of this and the following series of phenanthrylamino alcohols was carried out as part of a program outlined at the National Institute of Health, Bethesda, Md. Studies by May and Mosettig (1) have shown that the antimalarial activity of various phenanthrylamino alcohols is enhanced by the introduction of a chlorine atom into the phenanthrene nucleus. 9-Bromo-3- (or 4%)acetylphenanthrene, prepared first by Mosettig and van de Kamp (2), appeared to be a convenient starting material for the synthesis of halogenated amino alcohols different from those to be described by May and Mosettig. In the course of our investigations we succeeded in differentiating between positions 3 and 6 as the locakion of the acetyl group and assign to this compound the structure of 9-bromo-3-acetylphenanthrene (I) on the basis of the reactions indicated in the scheme below:
rBr I,_,, 3(6)-COCH3 I
1
+
9--C' 3(6)-CN V
3(6)-C(NOE[)CH3
I1
2 steps
-+
1
I,,,
+ 3(6)--NHz 111
9-COzCH3 3-COzCHs VI
3 steps
+-
TBr + 3(6)-Br IV
9-41 13-Cl VI1
The amine (111) obtained by Beckmann rearrangement of oxime (11) was diazotized and converted to dibromophenanthrene (IV) and the latter transformed, via the dicyano derivative (V), to the diester (VI). The structure of the latter is established by its formation from 3,9-dichlorophenanthrene. This compound was prepared by reactions completely analogous to those used to prepare the dibromophenanthrene (IV) (3). It corresponded to the 3,9-dichlorophenanthrene prepared by Sandquist (4). Further conclusive proof was later obtained by total synthesis of 3,9-dicyanophenanthrene (3). In this communication we describe the synthesis of a complete series of amino alcohols of type VIII. In the preparation of these amino alcohols we employed essentially the procedures of Mosettig and van de Kamp (5) and the Malaria Research Group at the National Institute of Health. Since elimination of the Present address: New York Quinine and Chemical Works, Brooklyn, New York. Present address: Pepsodent Division, Lever Bros. Co., Chicago 38, Ill. 3 Present address: Velsicol Corporation, Chicago 11, Ill. 4 Present address: 600 S. Michigan Ave., Chicago 5 , 111. 307 1
2
308
SCHULTZ, GOLDBERG, ORD.4S1 AND ClRSCH
nuclear bromine can be expected in the catalytic reduction of the amino ketones to amino alcohols, the aluminum isopropoxide reduction method of MeerweinPonndorf-Verley as modified by Lund (6) was used in this step:
fYH3 a -’
--COCHtBr
-+
-COCHZNRZ
-+
Br
I
VI11 TABLE I6 ANTIMALARIAL AcTiviw
OF
AMINOALCOHOLS
SN
9464 8953 9821 8954 9467 9468 9469 8952 8951 8950
The amino alcohols of this group, when compared with the analogous brominefree derivatives, the phenanthryl-3-amino alcohols (7)) are more toxic (8). In regard to effectiveness against Plasmodium gallinaceum, they are superior t o the bromine-free analogs (9). The corresponding amino ketones6 are devoid of thera5 In Table I are listed the compounds which were submitted for biological investigation. 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 “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 A. All compounds listed in the table were administered as hydrochlorides. 6The Survey Kumbers (SN) of these drugs may be found in Table 11.
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309
peutic effect. None of the drugs showed any activity towards sporozoiteinduced gallinaceum malaria (9). EXPE:RIMENTAL7
9-Bromophenanthrene. This was prepared according to the directions of May and Mosettig (IO). I n the recrystallization, isopropanol was employed. The phenanthrene used was purified by partial oxidation with chromic acid followed by vacuum distillation and crystallization from alcohol (11, 12). Material so treated had the melting point 9799". 3-Acety2-9-bromophenanthrene ( 8 ) . T o a mixture of 350 g. of 9-bromophenanthrene and 2620 co. of carbon disulfide cooled to 5" in a 5-liter three-necked flask equipped with a liquidsealed stirrer and vented through a c a l h m chloride tube, was added 128 cc. of acetyl chloride. Five hundred twenty-six grams of anhydrous aluminum chloride was added gradually with stirring and cooling, maintaining the temperature at 5". The temperature was then allowed t o rise slowly to room temperature (never above 30") over a period of 2-3 hours. The reaction mixture, a t fiIst dark green, slowly turned to light brown. Stirring was continued another 2-4 hours (total reaction time about 6 hours) after which the evolution of hydrogen chloride had practically ceased. The precipitate was filtered and washed several times with carbon disulfide. The separated addition product was combined with that from a second preparation (also using 350 g. of 9-bromophenanthrene) The decomposition of the addition product from the acetylation of 700 g. of 9-bromophenanthrene (in two runs) was carried out in a 20-liter Pyrex crock equipped with a stirrer. I n i t was placed 3000 cc. of chloroform, 4610cc. of conc'd hydrochloric acid, and 2000 g. of ice. The addition complex was added in small portions with vigorous stirring, more ice being added as needed to keep the reaction under control. After decomposition was complete, 1 he chloroform layer was syphoned off and the aqueous layer extracted twice with chloroform. The combined chloroformic solutions were washed once with dilute hydrochloric acid and twice with water, clarified by boiling with carbon, filtered, and evaporated to dryness. The residual brownish crystalline mass was crystallized from acetone (1450 cc. for each 100 g. of crude material) using charcoal. I n this way 305 g. of colorless needles, 1n.p. 150151" was obtained. On concentration, the mother liquors yielded 101 g. of less pure material, m.p. 141-149", and a third crop of 90 g . , m.p. 128-148". Recrystallization of the second and third crop material yielded a further 140 g. of pure 3-acetyl-g-bromophenanthrene, m.p. 150-151" [reported (2) m.p. 150-151°]. 3-Acetyl-9-cyanophenanthrene. An intimate mixture of 3 g. of the acetyl compound with 1 g. (1.1 mole) of cuprous cyanide was placed in an oven a t 110". The temperature was allowed to rise to 200-205" over a period of one-half hour with occasional mixing. This temperature was maintained for 1.25 hours and then raised to 250' over a period of one-half hour. .4fter being held a t 250" for 40 minutes, the black mass was cooled, pulverized, and extracted with chloroform. The extract wa3 evaporated to dryness and the residue crystallized twice from acetone. Light yellow, halogen-free crystals were obtained, m.p. 220221': Anal. Calc'd for C I ~ H I ~ N O Tu',: 5.71. Found: N, 5.71. 3-Acetyl-9-bromophenanthrene oxime ( 2 ) . T o a solution of 100 g. of 3-acetyl-9-bromophenanthrene in hot dioxane was added a solution of 55 g. of hydroxylamine hydrochloride in 220 cc. of 10% aqueous sodium hydroxide. Three hundred and seventy-five cubic centimeters of hot 25y0 alcohol was added and the resulting clear solution heated on the steambath for four hours. Hot water was then added to incipient turbidity and the solution
.
7 All analyses except ionizable halogens reported in this paper and in subsequent papers of this series were done by Dr. T. S. Ma.
3 10
SCHULTZ, GOLDBERG, ORD.4S1 -4XD CARSCH
allowed to cool t o room temperature overnight while the oxime crystallized as colorless needles. The yield was 101 g. (96%), m.p. 212-213.5O.8 Anal. Calc'd for CleHllBrNO: N, 4.46. Found: N, 4.25. 3-Amino-9-bromophenanthrene. 'The procedure of Bachmann and Boatner (13) was followed for the rearrangement of the oxime and subsequent hydrolysis. The hydrochloride of the 3-amino-9-bromophenanthrene was not very soluble in water, however, and the method of isolation was modified accordingly. T o a suspension of 90 g. of 3-acetyl-9-bromophenanthrene oxime in 1450 cc. of dry benzene was added 90 g. of phosphorus pentachloride. The mixture was then refluxed for 20 minutes, after which evolution of hydrogen chloride had ceased and a clear solution remained. The solution was cooled, hydrolyzed by shaking with 1000 cc. of water, and the precipitated product filtered off and washed with water. The benzene layer of the filtrate was washed with water, evaporated to dryness, and the residue added to the precipitate of crude acetylamino-9-bromophenanthrene. The crude acetylamino compound was hydrolyzed by refluxing with 3600 cc. of alcohol and 126 cc. of concentrated hydrochloric acid (mechanical stirring was employed to avoid lumping). After refluxing for 24 hours, the suspension was cooled and the amine hydrochloride filtered off. The filtrate was concentrated and a second crop of amine hydrochloride obtained, which was added to the first. The crude amine hydrochloride was suspended in 1000 cc. of water and lo00 cc. of ether. Sufficient 25% aqueous sodium hydroxide was added to make the aqueous layer alkaline to phenol red, and the suspension shaken mechanically for 30 minutes, addingsodium hydroxide solution as necessary to maintain a slight excess. The remaining insoluble material was filtered off and discarded. The ether layer of the filtrate was separated and the aqueous layer extracted again with ether. The combined ethereal solutions were washed with water, dried over sodium sulfate, and acidified with alcoholic hydrogen chloride. The precipitated amine hydrochloride was filtered, washed with ether, and dried. The 3-amino-9-bromophenanthrene obtained from the hydrochloride was crystallized from benzene-hexane as buff-coloied needles; yield 61.5 g. (71%); m.p. 112.5-113°. Anal. Calc'd for ClaHloBrh': IT,5.15. Found: Pi, 5.37. 3-Acetylamino-9-bromophenanthrene.The 3-amino-9-bromophenanthrene was acetylated with acetyl chloride in benzene in the presence of pyridine. On recrystallization from alcohol, the acetyl derivative was obtained as colorless prisms, m.p. 220.5-221.5'. Anal. Calc'd for CloH12BrKO: Tu', 4.46. Found: ?rT, 4.37. 9,Q-Dibromophenanthrene. The 3-amino-9-bromophenanthrene was diazotized by a modification of the method of Misslin (14) and the diazonium salt converted t o dibromophenanthrene by Schwechten's modification of the Sandmeyer reaction (15). To a solution of 5 g. of 3-amino-9-bromophenanthrene in 50 cc. of concentrated sulfuric acid cooled to 10' was added a solution of 3.5 g. of sodium nitrite in 35 cc. of concentrated sulfuric acid. The temperature was maintained at 8-10' while 250 cc. of glacial acetic acid was added slowly with stirring. The solution was maintained at 10" for one-half hour after all the acetic acid had been added and then diluted to ca. 600 cc. with ice and water, still holding the temperature a t 10". Five grz.ms of urea B-as added and stirring continued for an additional half hour. A solution of 27.5 g. of mercuric bromide and 27.5 g. of potassium bromide in 100 cc. of water was added and stirring continued for another half hour. The suspension was held a t ca. 5" in the refrigerator overnight, the precipitate filtered off, washed with cold water, and dried in a vacuum desiccator.
* Mosettig and van de Kamp (2) report for this oxime m.p. 142.5-143' (uncorr.) n-hile we find the oxime to melt a t 212-213.5'. Dr. Mosettig informs us (private communication) that their oxime was prepared in metlianolic solution. I n repeating this preparation he is able t o obtain either oxime dependinh; on whether methanol or dioxane is used as solvent. He suggests that cis-trans isomerism accounts for this discrepancy. The semicarbazone was prepared and found to have the melting point recorded.
ATTEMPTS TO FIXD ANTIMALARIALS.
IX
311
The dried double salt was intimately mixed with twice its weight of potassium bromide and decomposed in a beaker heated over a low flame. The residue was extracted with hot water and taken up in warm benzene and the benzene solution filtered. The solvent was evaporated and the residue distilled in vc~cuo,b.p. 220-230" a t 6-7 mm. The distillate was crystallized from benzene-alcohol, yielding 3.5 g. (57%) of colorless needles, m.p. 144-145". Sandyuist reported 143-143.5" (4). 3,9-Dzcyanophenanthrene. An intimate mixture of 1 g. of 3,Q-dibromophenanthrenewith 1 g of cuprous cyanide was heated for 3 hours a t 295-300" in a sealed tube. The reaction product was cooled, pulverized, and shaken with a mixture of ammonium hydroxide and chloroform. The chloroformic solution was treated with charcoal, filtered, and evaporated t o dryness. The residue was recrystallized three times from toluene to yield 0.54 g. (79%) of colorless needles, m.p. 285-286". Anal. Calc'd for CleH8N2: C, 84.3; W, 3.51; N, 12.2. Found: C, 84.35; H, 3.21; N, 12.39. Phenanthrene-$,9-dicarboxylic aczd. A suspension of 0.2 g. of 3,9-dicyanophenanthrene in 20 cc. of a 25% methanolic potassium hydroxide solution was refluxed for 10 hours, during which ammonia was evolved and a clear solution was obtained. The solution was diluted with water, acidified, and the precipitate filtered off and washed with water. The crude 3,9-dicarboxylic acid was converted to the dipotassium salt which was crystallized from methanol-acetone, then reconverted t o the free acid. After drying in a vacuum desiccator, the purified acid remained as a light yellow powder, m.p. above 330". Ancl. Calc'd for CI6Hl0O4:Beut. Equiv., 133. Found: Neut. Equiv., 136.7. Phenanthrene-3,9-dicarboxylicacid dimethyl ester. A suspension of 0.1 g. of the dicarboxylic acid in 10 cc. of methanol containing 0.18 g. of concentrated sulfuric acid was refluxed for 8 hours, when a clear solution was obtained. On cooling, the ester separated in the form of colorless needles. Two rimystallizations from methanol yielded 0.05 g. of colorless needles, m.p. 126.6-127.5'. Anal. Calc'd for ClsHlaO4: C, 73.5; H 4.76. Found: C, 73.47; H, 4.56. 3-Bromoacetyl-9-bromophenanthrene.To a well-stirred suspension of 60 g. of 3-acetyl-9bromophenanthrene in 225 cc. of anhydrous ether at 30" was added a few drops of bromine in chloroform. After the bromine was consumed, the temperature was gradually lowered t o 12" while adding bromine in chloroform. The bromination was completed a t 12", a total of 33 g. of bromine in 150 cc. of chloroform being added. The stirring was continued for 15 minutes after all the bromine had been added, and the reaction mixture was chilled for one hour. The sludge was filtered off, rind washed with cold ether. The mother liquor and washings were combined, washed with water to remove hydrogen bromide, dried over sodium sulfate, and concentrated to about 75 cc. An equal volume of petroleum ether (35-60") was added, the mixture chilled, and a second crop of crude product obtained. This was combined with the original precipitate and the whole recrystallized from dioxanemethanol. The crystals obtained melted at 131-133'. Further crystallization yielded colorless needles, m.p. 133-134". The total yield from the bromination of 276 g. of 3-acetyl9-bromophenanthrene was 282 g. (80.8%). Anal. Calc'd for ClaHloBrO: Br, 42.29. Found: Br, 42.29. 3-(??-Dialkylamino-l -oxoethyl)-9-bromophc!nanthrene hydrochlorides. A mixture of 53 g. (0.14 mole) of 3-~-bromoacetyl-9-bromophenanthrene,0.28 mole of dialkylamine,g and 150 cc. of benzene was shaken for 30 minutes, 200 cc. of dry ether was added, the mixture shaken again for 10 minutes, and chilled for two hours. Filtration yielded about 0.135 mole of dialkylammonium bromide (96%). The filtrate was acidified with alcoholic hydrogen chloride and chilled, whereby the crude amino ketone hydrochloride precipitated. Recrystallization from the appropriate solvent (see Table 11) yielded the pure compound in the form of colorless needles. 9 We are indebted to Dr. R. C. Elderfield., Columbia University, for the amines used in the work reported here, and in the subsequent papers of this series.
312
SCHULTZ, GOLDBERG, ORDAS, AND CARSCH
9-(l-Dialliylamino-l-hydrozyethyl)-g-bromophenanthrene hydrochloride. -4 mixture of 0.0366mole of 3-(2-dialkylamino-l~~oxoethyl)-9-bromophenanthrene hydrochloride, 22.5 g. TABLE I1 ~-(~-~IALKYLAMINO-~-OXO-E'I'HYL)-~-BROMOPHENANTHRENE HYDROCHLORIDES"
SN
FORMULA
-
____
13307 CH1 9061 CzHs 10403 C3H7 9471 C4H9 10125 C5Hll 14448
C&3 C 7H15
9060 C8H17 9477 CeH1e 9476 CioHzi
-
Methanol-dioxane ether Methanol-dioxane ether Methanol-ether Methanol-acetone ether Isopropanol Isopropanol Acetone-methanol ether Acetone Acetone Acetone
226-229
C18H17BrClN0
220-221
CzoHz1BrClNO
223-225 195-198
CzzH2sBrClN0 CzaHzeBrCl SO
185-187 153-157 142-144
CzsHIaBrCIXO CZ8H37BrClS0 CaoHalBrClNO
70 8.728.7513.4613.42
I
63 7.247.2712.853.01 45 6.856.93'2.692.57 35 6.496.5512.j6'2.76
C32HlbBrC1N0 65 6.216.312.452.46 Cs4Ha~BrC1N0 60 5.896.tK12.32~2.29 C3eHs3BrC1N0 65 15.635.582.222.25
All compounds colorless needles.
a
TABLE I11 3-(2-DIALKYLAMINO-1-HYDROXI.-ETHYL)-g-BROYOPHENAPI'THRENE HYDROCHLORIDES~
ALKYL GROUP
SOLVENT
M.P.,
"C.
FORMULA
-/-I-+-!-
Absolute alcohol 227-230 Methanol-dioxane195-195.5 ether 21c-211 Met hanol-acet one ether Alcohol-ether 198-198.5 Isopropanol 198-199 156-157.5 Isopropanol 131.5-133 Acetone Acetone 131-132.5 127.5-128.5 Acetone Ethyl - acetate or 126.5-128 isopropanol-ether 0
C18Hl~BrClS0 C20H23BrClN0 CzzHz7BrClN0 Cz4H31BrC1S0 CzsHssBrClSO C28H89BrClS0 C3oH43BrClNO C3~H47BrClN0 C3rH61BrC1S0 C16HssBrClN0
.Oh
7.7017.59i3 .87 68 7.217.1612.8412.83 84 6.816.842.6912.93 80 6.476.452.55'2.60 85 6.216.132.4512.56 86 5.875.902.31,2.29 2.27 65 5.625.5212.21
85
I t1
All compounds colorless needles.
(0.11 mole) of aluminum isopropoxide, and 450 cc. of isopropanol was distilled slowly through a 10-ballSnyder column. Acetone was detected in the distillate only for the first
ATTEMPTS TO FIND ANTIMALARIALS.
IX
3 13
2 hours, but the distillation of the isopropmol was continued for 3.25 hours. The remaining isopropanol was then removed by distillrttion i n vacuo from a water-bath at 50-55”. The residue was diluted with ether, a solution of 45 g. of citric acid in about 100 cc. of water was added, and the solution made alkaline to phenol red with 25% sodium hydroxide solution. The ether was separated, the aqueous portion extracted with ether and discarded. The combined ether extracts were washed with water, dried over sodium sulfate, acidified with alcoholic hydrogen chloride, and chilled t o complete precipitation. The yield of crude carbinol was almost quantitative. Purification was effected by crystallization from the appropriate solvent (see Table 111). ACKNOWLEDGMENTS
The authors of this paper and the following papers comprising this research project are deeply grateful to ILliss Syma Busiel and Mr. Alfred Busiel for having made this work possible. The authors wish to express their gratitude to Dr. L. F. Small, Dr. Erich Mosettig, Dr. E. M. Fry, and Dr. E:. L. May, all of the National Institute of Health, for helpful suggestions throughout the course of the work reported here and in the subsequent papers of this rieries. SIJMMARY
1. A homologous series of 3-(2-dialkylamino-l-oxoethyl)-9-bromophenanthrenes has been synthesized. 2. Each of these amino ketones has been reduced to the corresponding amino carbinol. 3. The evaluation as antimalarials of the amino alcohols and amino ketones described herein is discussed. CHIP.4G0, I L L .
REFERENCES (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15)
h I 4 AND ~ MOSETTIG, J.Org. Chem., in press. ~IOSETT AND I GVAN DE KAMP, J.A m . Chem. Soc., 64,3328 (1932). SCHULTZ, GOLDBERO, ORDAS,AND CAI~SCH, J . Org. Chem., in press. SANDQUIST, Ber., 63, 168 (1920). MOSETTIG AND VAN DE KAMP, J. A m . Chem. Soc., 66, 3448 (1933). “Organic Reactions,’’ 11, 178, John Wiley and Sons, Inc. (1944). GARLOCK, MOSETTIG, AND SHAVER, Unpublished work. K. B. EDDY,Unpublished results. G. R. COATNEY AND W. C. COOPER,Unpublished results. MAYAND MOSETTIG, J . Org. Chem., 11, 15 (1946). BACHMANN, J . A m . Chem. SOC.,67,555 (1935). D ~ R L A AND N D ADKIXS,J. A m . Chem. Soc., 69, 135 (1937). B - ~ C H M A N NAND BOATNER, J. Am. Chem. soc., 68,2097 (1936). MISSLIN,Helv. Chim. Acta., 3, 626 (1920). SCHWECHTEN, Be?-., 66, 1605 (1932).
