[CONTRIBUTION FROM
THE
RESEARCH LABORATORY OF LADYESTHER, LTD.]
ATTEMPTS TO FIND NEW ANTIMALARIALS. X. DERIVATIVES OF -PHENANTHRENE, 11. AMINO ALCOHOLS OF THE TYPE -CHOHCH(CHs)N& AND AMINO KETONES OF THE TYPE COCHzCHzN& DERIVED FROM 9-BROMOPHENANTgRENE J. SCHULTZl, M. A. GOLDBERG*, E. P. ORDASz, AND G. CARSCH4 Received August 17, 1946
In the extension of the series of 9-bromophenanthryl amino alcohols of type I (l),we decided to synthesize the corresponding compounds of type I1 and 111. CH3 I
CHOHCHzNRz
CHOHCHNR2
CHOHCHZ CH?NRZ
/
Br
Br
I
Br I11
I1
The synthesis of the propanolamines of type I1 offered no difEculties and proceeded according t o the scheme: C Hs ArH
+ CH3CH2COC1 --AlC13 -+ C H3
I
ArCOCHNRz
I
ArCOCHBr
ArCOCHzCH3
A1 (C3H7O)s
R?WH+ -
CH3
I
ArCHOHCHNRz
where Ar = 9-bromophenanthryl. As was expected, the exchange of bromine in the a-bromopropionyl-9-bromophenanthrenewith aliphatic amine proved to be considerably more sluggish than in the case of the corresponding a-bromoacetyl compound (1). It was necessary to reflux the reaction mixture with excess amine for some time t o complete the conversion. The removal of the excess aliphatic amine from the amino ketone was effected by fractional precipitation of the hydrochlorides from ether. The structure of the propionyl-9-bromophenanthrenewas proved by oxidation of the propionyl group to yield the same carboxylic acid as 3-acetyl-9-bromophenanthrene, the structural proof of which is reported in other papers of this series Present address: Present address: 8 Present address: 4 Present address: 1 2
New York Quinine and Chemical Works, Brooklyn, New York. Pepsodent Division, Lever Bros. Co., Chicago 38, Ill. 600 S. Michigan Ave., Chicago 5, 111. Velsicol Corporation, Chicago 11, 111.
314
ATTEMPTS TO FIND ANTIMALARIALS.
X
315
(1, 2). Oxidation of the 3-propionyl-9-bromophenanthrenewith sodium hypochlorite was unsuccessful but proceeded with 3-CY-bromopropionyl-9-bromophenanthrene .5 The 9-bromo-3-phenanthroic acid obtained was identified by conversion to the methyl ester, which was shown by direct comparison to be identical with that prepared by Mosettig and van de Kamp (3). As in the foregoing communication, reduction of the amino ketones was effected with aluminum isopropoxide to prevent loss of bromine. In this series, two diastereoisomeric amino alcohols can be expected. We isolated both forms in crystalline of the 3-(2-dimethylamino-l-hydroxypropyl)-9-bromophenanthrene form. However, only one form of the other members of the series was found. T e intended to prepare the amino sllcohols of type I11 by reduction of the corresponding amino ketones. The latter were prepared by the Mannich reaction (4) from 9-bromo-3-acetylphenanthrene (1). Preliminary trials were unsuccessful. Using isoamyl alcohol as solvent, as suggested by van de Kamp and Mosettig ( 5 ) , gave no results. The desired compounds, however, were obtained in satisfactory yields when benzene was employed, according to the modification of Fry (6). Unfortunately, we were not able to find the conditions under which these ketones could be reduced. In hydrogenation, using noble catalysts, the nuclear bromine atom is attacked and the amino group is split off to some extent. This result could not be obviated by reduction in the presence of hydrogen bromide, the addition of which appeared to poison the catalyst. In the aluminum isopropoxide reduction, splitting and other decomposition processes were found to take place, aliphatic amine being removed. The toxicity of the propanolamines is somewhat lower than that of the corresponding ethanolamines (7). Their effectiveness towards Plasmodium gallinaceum, throughout the series [from--X(CzH& to -N(CIoHz1)21, is decidedly loner (8). Only the dibutylamino alcohol (SK10226), the diamylamino alcohol (SS10893), and the dihexylamino alcohol (SN 10892) show weak activity (Qi, $, &). ,111 amino ketones are ther:tpeutically inactive. None of the drugs showed any activity towards sporozoit e-induced gallinaceum malaria (8).6 EXPEIIIMENTAL
3-Propionyl-9-bromophenanthrene.To a mixture of 450 g. of 9-bromophenanthrene and 3800 cc. of carbon disulfide cooled to 5" in a 5-liter three-necked flask equipped with a liquid-
sealed stirrer and vented through a calcium chloride tube, was added 208 cc. of propionyl chloride. Six hundred seventy-five grams of anhydrous aluminum chloride was then added slowly with stirring and cooling, maintaining the temperature at 5'. ilfter all the aluminum chloride had been added, the temperature was allowed to rise slowly to room temperature (never above 30") over a period of 2-3 hours. The reaction mixture, at first dark green, slowly turned light brown. Stirring was continued another 3 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 decomposition of the addition product from the propionylation of 900 g. of 9-bromo5 Subsequently it was found that the hypochlorite oxidation of acylphenanthrenes prosceeds smoothly in the presence of pyridine 112). 8 The Survey Xumbers (SN) of all the drugs which have been submitted to biological tests are given in the Experimental Part (Tables I, 11, and 111).
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SCHULTZ, GOLDBERG, ORDAS, AND CARSCH
phenanthrene (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, 150 cc. 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 t o keep the reaction under control. After decomposition was complete, the chloroform layer was removed 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 twice from acetone to yield 550 g. (50%) of colorless needles, m.p. 116-117'. Anal. Calc'd for ClrH1*BrO: C, 65.15;H, 4.15. Found: C, 65.58;H, 4.54. Oxime of 3-propionyl-9-bromophenanthrene. The oxime was prepared by reaction with hydroxylamine hydrochloride in dilute alcohol in the presence of sodium acetate. Colorless needles were obtained by recrystallization from alcohol, m.p. 166.5167". TABLE I ~ - ( ~ - ~ I A L K Y L A M I ~ O - ~ - O X O P R O P Y L ) - ~ - B R O M O P H E N A N HYDROCHLORIDES" THRENE
ALKYL GROUP
SN
1044!
10441
1044:
SOLVENT
M.P.,
"C.
Methanol-dioxane- 227-227.5 ether Methanol-acetone- 209-210.5 ether Methanol-acetone- 209-212 ether Methanol-acetone- 214.5-216.E ether Acetone 155-156 Methanol-acetone- 164-165.5 ether Acetone 149.5-151.E Acetone 134.0-137.C Acetone 125 .O-126.C Acetone 116-118.5
FORMULA
--'-IT 94 9.049.163.563.47 67 8.448.423.333.15
67 7.937.993.122.96
I 68 7.407.502.942.78 59 7.057.1412.782.92 53 6.656.7112.632.64 30 6.306.33(2.502.67 82 6.03 5.882.37,2.38 61 5.755.832.272.46
All compounds colorless needles.
Anal. Calc'd for C17H1aBrNO: N, 4.27. Found: Tu', 4.09. 8-a-Bromopropionyl-9-bromophenanthrene. To a well-stirred suspension of 40 g. of 3-propionyl-9-bromophenanthrene in 600 cc. of absolute ether a t 30" was added a few drops of a solution of bromine in chloroform. When decolorization had taken place, the mixture was cooled t o 12' and 20.4 g. of bromine dissolved in 60 cc. of chloroform added as rapidly as it was taken up. Stirring was continued for 15 minutes after all the bromine had been added. The mixture was chilled to 0" for one hour and the precipitated bromo ketone filtered and washed with cold ether. The crude 3-a-bromopropionyl-9bromophenanthrene was obtained as pale pink needles; yield 45 g. (goyo),m.p. 16G-168°. Anal. Calc'd for C17H12Br20: Br, 40.8. Found: Br, 40.54. J-(Z-DiaEkylamino-l -oxopropy1)-9-bromophenanthrenehydrochlorides. A mixture of 20 g
ATTEMPTS TO FIND ANTIMALARIALS.
317
X
(0.051 mole) of 3-~~-bromopropionyl-9-bromophenanthrene, 0.153mole of dialkylamine, and 120 cc. of benzene was refluxed for 3.5 hours. After cooling t o room temperature, the reaction mixture was filtered to remove precipitated dialkylammonium bromide. The filtrate was washed with dilute sodium carbonate solution, then with water. The benzene was removed by steam distillation i n vacuo, the temperature being held below 45”. The residue was taken up in ether, and the ethereal solution dried over sodium sulfate and filtered. The solution a t this point had a volume of about 500 cc. Alcoholic hydrogen chloride (10 N ) was added slowly from a burette until the ,oH, indicated by a drop of solution on “Hydrion A” test paper, changed from about 9 to abciut 6. This change is quite sharp and appears to correspond to neutralization of the dialkplamine. The mixture was allowed to stand a t room temperature for one-half hour with frequent shaking, then chilled for three hours. The precipitated dialkyalmine hydrochloride was filtered off, leaving fairly pure amino ketone in solution. TABLE I1 ~ - ( ~ - ~ I A L K Y L A M I N O - ~ - H Y D R O X Y P R O P Y L ~ ~ - ~ - B R O M O P H E N ~ N T HYDROCHLORIDES“ HRENE
ss
SOLVENT
M.P.,
--
___
Methanol
10438 10439 10226 10893 10832 10894 10440 10441 10442
“c.
261-262.5 249-250 Methanol acetone- 204-205.5 ether Methanol acetone- 228-229 ether Methanol acetone- 186.5-188.( ether Methanol acetone- 189-190. ether Acetone 136.5-137.! 147.0-148.( Acetone Acetone-ether 143.5-144.( Acetone 144 .0-145. ( Acetone 1136.0-136.1
FORMULA
----3.5 8.998.973.553.74 3.58.998.943.553.46 69 8.408.213.323.63 71 7.927.883.11 2.74 65 7.437.592.932.70 83 7.007.032.762.66 74 71 77 72 76
6.646.642.622.63 6.306.332.492.55 6.016.022.372.39 5.745.792.272.35 5.495.W/2.11i2.16
All compounds colorless needles. The solution was acified strongly (Hydrion test paper showed pH about 1) and the amino ketone hydrochloride allowed to separate a t room temperature for about two hours, then chilled overnight. The crude product was filtered off and purified by crystallization from the appropriate solvent (see Table I). 3-(2-Dialkylamino-1-hydroxypropyl)-9-bromophenanthrene hydrochlorides. The 3-(2-dialkylamino-I-oxopropyl) -9-bromophenanthrene hydrochloride was reduced with aluminum isopropoxide using the technique described for 3-(2-dialkylamino-l-hydroxyethyl)-9-bromophenani hrene (1). The yield of crude carbinol was almost quantitative. Purification was readily effected by recrystallization from the appropriate solvent (see Table 11). $-($-Dialkylamino-l-oxopropyl)-9-bromophenanthrene hydrochloride. I n a 2-necked, 300-cc. flask fitted with a stirrer and reflux condenser were placed 29.7 g. (0.1mole) of 3acetyl-9-bromophenanthrene,0.122 mole of dialkylamine hydrochloride, 3.28 g. of paraformaldehyde, 0.17 cc. of concentrated hydrochloric acid, and 120 cc. of benzene. The mixture was brought t o boiling in 15 minutes with vigorous stirring. After refluxing for
318
SCHLTTZ, GOLDBERG, ORDAS, AND CARSCH
10 minutes considerable foaming occurred. After 30 minutes the foam disappeared and a clear yellow solution was formed. After boiling for a n additional 45 minutes the reaction mixture was chilled for one hour and some dialkylamine hydrochloride filtered off. Dry J to the filtrate to a volume of about 550 cc. and the mixture chilled overether W ~ E added night. The crude amino ketone hydrochloride was filtered off, washed with ether, and crystallized from the appropriate solvent (see Table 111). 9-Bromophenanthrene-3-carboqjlicacid. A mixture of 0.5 g. of 3-a-bromopropionyl-9. bromophenanthrene, 10 cc. of 5.5 N sodium hypochlorite, and 2 cc. of chloroform was refluxed gently for three and one-half hours. About 10 cc. of chloroform was then added, and the mixture extracted several times with water. The aqueous solution was filtered hot (the sodium salt tends t o crystallize on cooling), acidified, and extracted with ether. On evaporation of the ether extract, a residue of 70 mg. remained. Crystallization from glacial acetic acid gave 50 mg. of the carboxylic acid as colorless needles, m.p. 279-280'. The melting point was not depressed by admixture of a sample of the acid described by Mosettig and van de Kamp (3).7 TABLE 111 3-(3-DIALKYLAMINO-1-OXOPROPYL~-9-BROMOPHENANTHRENE HYDROCHLORIDES~
ALKYL GROUP
SN
947: 947:
9471 947! a
b
SOLVENT
Ethanol Ethanol Methanol-ether Methanol-ether Methanol-ether Ethanol-ether Methanol-acetoneether Benzene-hexane Benzene-hexane Benzene-ether
Y.P..
"C.
FORMULA
197-199 158.5-159.5 172-175 dec. 156-158 148-150 112-115 101-101.5
_-__-ClpHloBrCINO 72 9.048.883.563.42b Cz1Hz3BrClN0 62 8.448.353.332.83 C23H27BrC1N0 56 7.937.923.122.67 CzsH31BrC1N0 51 7.407.622.942.80 CZ7HasBrC1NO 45 7.05 7.042.782.75 CzoHaoBrCINO 54 6.796.722.63 2.64 CaiHiaBrClNO 47 6.306.632.49 2.28
111.5-113.5 110-111.5 110-112.5
C33H47BrC1N0 45 6.036.282.382.17 C36H61BrC1N0 34 5.755.902.272.46 Ca7Hs6BrClN0 35 5.505.652.172.14
All compounds colorless needles. See ref. (6).
9-Bromophenanthrene-3-carboxylicacid methyl ester. The carboxylic acid obtained was esterified with methanol. The methyl ester had the melting point 154-155.5' and the melting point was not depressed by admixture of a sample of the ester prepared by Mosettig and van de Kamp SUMiK4RY
A homologous series of 3-(2-dialkylamino-l-oxopropyl)-9-bromophenant~enes has been prepared. Each of these amino ketones has been reduced to the corresponding amino carbinol. A homologous series of 3-(3-dialkylamino-l-oxopropyl) -9-bromophenanthrenes has been synthesized. 7
Sample furnished by Dr. Mosettig.
ATTEMPTS TO FIND ANTIMALA4RIALS. X
319
The evaluation as antimalarials of the amino alcohols and amino ketones described herein is discussed. CHICAGO,ILL. (1) SCHULTZ, GOLDBERG, ORDAS,AND CARSCH,J . Org. Chem., 11, 307 (1946). GOLDBERG, ORDAS,AND CAIXSCH, J . Org. Chem., 11, 320 (1946). (2) SCHULTZ, (3) MOSETTIG AND VAN DE KAMP,J . Am. (‘hem. SOC., 154,3328 (1932). (4) ‘(Organic Reactions,” I, 303, John Wiley and Sons, Inc., (1942). (5) VAN DE KAMPAND MOSETTIG, J.Am. C‘hem. Soc., 68,1568 (1936). (6) FRY,J. Org. Chem., 10, 259 (1945). (7) N. B. EDDY,Unpublished results. (8) G. R. COATNEYAND W. C . COOPER,Cnpublished results.
