[CONTRIBUTION FROM THE DIVISIONOF PHYSIOLOGY, NATIONAL INSTITUTE OF HEALTH]
ATTEMPTS TO FIND NEW ANTIMALARIALS. XIX.’*a AMINO ALCOHOLS OF THE TYPE -CHOHCH2NR2 DERIVED FROM DICHLOROPHENANTHRENES EVERETTE L. MAY AND ERICH MOSETTIG Received July 93,1946
In foregoing communications (1, 2, 3) of this series we have shown that by introducing a chlorine into position 6 of compounds of formula I, and into position 6 or 3 of compounds of formula 11, plasmodicidal activity (E‘. gallinaceurn) is considerably enhanced.
I1 I In this communication we are describing amino alcohols of formula 11,carrying two chlorine atoms in the phenanthrene nucleus, namely, in positions 2,3 and 3,4. By diazotization-ring closure of the cinnamic acid derivative 111,two dichlorophenanthroic acids, IV and V, were obtained in a total yield of approximately 7575, and were separated by fractional crystallization.
IV
I11
v
No efforts were made to prove for either acid the location of the chlorine atoms. The ratio of the acids “A” and “B” was approximately 1:2.5. The less soluble acid “A”, its chloride, the bromomethyl ketone and methyl ketone derived from it, have consistently higher melting points (from 25” to 55”) than the corresponding derivatives of the “B series”. This relationship apparently holds true also ‘The work described in this paper was done under a transfer of funds, recommended by the Committee on Medical Research, from the Office of Scientific Research and Development to the National Institute of Health. ‘Studies in the phenanthrene series XXXV.
631
632
EVERETPE L. MAY A N D ERICH MOSETPIG
for the amino alcohols. These were obtained from the acids “A” and “B”by methods employed previously (3,4) ( 4 O O H 3 4 O C H N 2 -+ -COCH2Br + 4OCH2NR2 -+ CHOHCHaNRa). We prepared of series “A”, the diamylamino alcohol (SN 13664)*and the diheptylamino alcohol (SN 13037), and of series “B”, the dihexylamino alcohol (SN 13036). In respect to toxicity (5) and therapeutic value (6) no significant difference can be observed between the members of the “dichloro series” and the corresponding members of the 3-chloro-10-alkamine series (3). None of the three amino alcohols described in this paper showed any activity against sporozoite-induced gallinaceurn malaria (6). Acbwledgmenk. We wish to thank Mr. Edward A. Garlock, Jr., for carrying out the microanalyses, and Heyden Chemical Corporation for a generous sample of 3,4dichlorobenzyl chloride. EXPERIMENTAL4
J,.4-Dichlorophenylaceticacid. To a steam-heated mixture of 40 g. of sodium cyanide and 40 cc. of water was added. during thirty minutes, a solution of 100 g. of 3,4-dichlorobenzyl chloride in 160 cc. of 95% ethanol. After refluxing the mixture for an additional ninety minutes, it w w cooled, filtered, and the ethanol distilled in uacuo. The residue was refluxed for three t o four hours with a solution of 60 g. of potassium hydroxide and 180 cc. of water. After dilution to about lo00 cc., Norit was added, the mixture heated to boiling, cooled to M)”, filtered, and the filtrate acidified with conc’d HC1 t o yield 95 g. of acid of m.p. 70-77”. Two recrystallizations from ligroin (30-60°)-benzene gave large needles of m.p. 82-82.5”. Anal. Calc’d for Cd3~ClrOe:C, 46.87;H, 2.95. Found: C,46.81; H,3.02. u-(d,4-DichloropLnyl)-o-nitrocinnamicacid. A mixture of 95 g. of the above acid (m.p. 70-77”), 200 cc. of absolute ethanol, and 29.5 g. of potassium hydroxide was heated t o homogeneity, the solution filtered and diluted with 200 cc. of dry ether to yield, after cooling, 70 g. of crystalline potassium 3,4-dichlorophenylacetate. A second fraction of 30 g. was obtained from the filtrate. Ten grams of this salt (dried in a desiccator): 6.5 g. of o-nitrobenzaldehyde, and 50 cc. of acetic anhydride were heated together on the steambath for about sixteen hours. Excess acetic anhydride was decomposed with 100 cc. of water. On cooling, the nitro acid separated and was recrystallized from acetic acid; yield 6.5 g., m.p. 183-185.5”. Another recrystallization gave yellow plates of m.p.
185-186.5”. Anal. Calc’d for Cl&IpClfiO,: C, 53.32;H,2.68. Found: C, 53.23;H, 2.62. a-@,4-Dichloropheny1)-o-aminocinnamicacid ( I I I ) . A hot solution of the above nitro acid (25g.) in 145 cc. of water and 61 cc. of conc’d “,OH was added gradually to a mixture of 163 g. of ferrous sulfate, 410 cc. of water, and 305 cc. of conc’d “,OH (temperature 80-85”). After boiling for 10-15 minutes the mixture was filtered (Filter-Cel) and the filtrate acidified with acetic acid. The yield of amino acid (m.p. 208-209.5’) was 21.0 g. It crystallized from ethanol in oblong plates of m.p. 208-209”. Anal. Calc’d for GlSHIIC12NOa: C, 58.45;H, 3.60. Found: C, 58.68;H, 3.53. sThe Survey Number, designated SN, identifies a drug in the files of the Survey of Antimalarial Drugs. Activities of drugs so listed will be published in a forthcoming monograph. ‘All meiting points given are uncorrected. ‘If the salt is dried a t llOo,the optimal reaction time is 2-2.5 hours, while for air-dried material it is 20-25 hours.
ATTEMPTS TO FIND ANTIMALARIALS.
XIX
633
9,x-Dichloro-10-phenanthrenecarboxylicacid ( A ) and 9,y-dichloro-IO-phenanthrenecarboxylic acid @).e A stirred suspension of 24 g. of I11 in 250 cc. of 15% alcoholic HCl (temperature -5' t o 0") was treated with 35 cc. of isoamyl nitrite during 10-20 minutes. After stirring for two hours at -5" too", the mixturewas poured slowlyinto a stirred mixture of 80 g. of sodium hypophosphite, 3.5 g. of copper-bronze, four drops of conc'd HISO, and 125 cc. of water (temperature not above 45") and the mass stirred for forty-five minutes. The solids were collected, boiled with an excess of dilute sodium hydroxide (Norit), and the whole filtered. Acidification of the filtrate yielded 17 g. of a mixture of phenanthroic acids which was combined with 29 g. from another run and the whole digested with 300 cc. of boiling dioxane. The hot solution was filtered and chilled in the ice-box, giving 15 g. of solid which, on recrystallization from dioxane, yielded 9 g. of acid A, m.p. 297-306". After sublimation in a high vacuum followed by recrystallization i t appeared as long, slender needles of m.p. 307-310". Anal. Calc'd for C1SH&1202: C, 61.90; H, 2.77. Found: C, 62.08; H, 2.95. The first dioxane filtrate above, on concentrating to about 50 cc., diluting with a n equal volume of water and cooling, yielded 18.5 g. of B of m.p. 247-251'. Similarly, the second dioxane filtrate gave 5 g. of B, m.p. 250-256". After sublimation followed by recrystallization from absolute ethanol and acetic acid in succession i t appeared as fine, curved needles of m.p. 253-255". Anal. Calc'd for C1bH8C1202: C, 61.90; H, 2.77. Found: C, 61.76; H, 2.72. S,x-L)ichloro-20-phenanthroylchloride. A mixture of 6.5 g. of A (m.p. 295-305'), 25 cc. of dry benzene, and 25 cc. of thionyl chloride was refluxed for five hours. Solvent and excess reagent were evaporated in vacuo and the resulting solid recrystallized from benzene; yield 5.4 g., m.p. 177-179". After another recrystallization followed by high vacuum sublimation the chloride melted a t 180-181"; large needles. Anal. Calc'd for ClsHrClsO: C, 58.19; H, 2.28. Found: C, 58.55; H, 2.27. 9,x-Dichloro-10-o-bromoacetylphenanthrene. To a stirred mixture of 175 cc. of a n ether solution of diazomethane (from 18 g. of nitrosomethylurea) and 120 cc. of dry benzene was added at 0" to 5", 7.7 g. of the foregoing acid chloride during forty-five minutes. The mixture was stirred for five hours at room temperature, allowed t o stand overnight and cooled in ice; yield of diazo ketone 6.4 g., m.p. 154-155' with gas evolution. It was stirred in suspension with 200 cc. of dioxane, and a mixture of 6.5 cc. of 40% HBr and 6.5 cc. of dioxane was added during ten minutes. After ten more minutes, 6.5 g. of sodium carbonate and 200 cc. of water were added, the precipitate was collected, and washed with 95% ethanol. It crystallized from benzene in a yield of 6.7 g., m.p. 184-185'; fine needles. Anal. Calc'd for Ct&oBrClpO: C, 52.22; H, 2.46. Found: C, 52.64; H, 2.52. ~,x-Dichloro-iO-acetylphenanthrene.A mixture of 0.5 g. of the above bromo ketone, 0.2 g. of palladium-charcoal (5% Pd), and 25 cc. of absolute ethanol absorbed 0.9 mole of hydrogen in one hour. After warming, removal of catalyst, and concentration of the filtrate to about 20 cc., 0.2 g. of ketone, m.p. 173-175") separated. It crystallized from absolute ethanol in silky needles of m.p. 174.5-178.5'. Anal. Calc'd for CldHl&llO: C, 66.46; H, 3.49. Found: C, 66.65; H, 3.58. 9,y-nichloro-lO-phenunthroylchloride. A mixture of 11.7 g. of B (m.p. 248-253')) 25 CC. of benzene, and 25 cc. of thionyl chloride was refluxed for two hours. Solvent and excess reagent were removed in vacuo,the crystalline residue dissolved in 50 cc. of boiling benzene and the solution left a t room temperature for 1.5 hours. The acid chloride (10.2 9.) was OThe Pschorr synthesis was modified as suggested by Ruggli and Staub (7). Lewis and Elderfield (8) and ref. 9 .
See also
634
EVERE'XTE L. MAY AND ERICH MOSETTIG
again recrystallized; yield 7.4 g., m.p. 146-151". Another recrystallization followed by a high vacuum sublimation gave the constant m.p. 155.5-157"; needles. Anal. Calc'd for ClrH,ClaO: C, 58.19; H, 2.28. Found: C, 58.00; H, 2.10. 3, y-Dichloro-low-bromoaeetylphenanthrene.The preceding acid chloride (7.4 g., m.p. 146-151") was converted to the diazo ketone (3.7 g., after cooling in ice-salt) essentially as described above, with 150 cc. of an ether solution of diazomethane (from 15 g. of nitrosomethylurea) and 75 cc. of dry benzene. The 3.7 g. of diazo ketone and 40 cc. of dioxane were stirred together, and a solution of 3 cc. of 40% HBr and 3 cc. of dioxane was added during fifteen minutes (20-25'). Potassium carbonate (3.5 g.) in 10 cc. of water was added t o the solution and the dioxane evaporated in vacuo. The residue was partitioned between benzene and water, the benzene layer dried (NazSO,), concentrated t o 10-15 cc. and diluted t o a faint turbidity with ligroin (3040'). The yield of bromo ketone of m.p. 133-137", was 3.4 g. It crystallized from ethyl acetate (Norit) in long needles or prisms, m.p. 132.5133". The melt solidified and remelted at 137-138'. If the temperature rise was slow only the higher m.p. was observed. Anal. Calc'd for CldXoBrC1~O:C, 52.22; H, 2.46. Found: C, 52.97; H, 2.41. 3, y-Dichloro-10-acetylphenanthrene. The preceding bromo ketone (0.5 g.) was debrominated as described above for the 3,x-isomer. The yield of ketone (m.p. 147-150') was 0.2 g. After a sublimation in high vacuum followed by recrystallization from absolute ethanol, the m.p. was 150-151". The solidified melt remelted a t 117-117.5'. This form was converted by recrystallization t o the one melting a t 1W151". Anal. Calc'd for CJ3loCl~O:C, 66.46; H, 3.49. Found: C, 66.15; H, 3.47. 3,z-Dichloro-lO-(d-diamylamino-l -hydrozyethyl)phenanthrene hydrochloride (SN 13,664). 3,x-Dichloro-low-bromoacetylphenanthrene (3.6 g.), 3.1 g. of diamylamine, 15 CC. of dry cooled and ether, and 3 cc. of acetone were shaken together for five hours, the mixture w a ~ filtered. The a t r a t e was evaporated to dryness in vacuo and the residue reduced with 20 cc. of 3 N aluminum isopropoxide (75-90 minutes) (10). After evaporation of the isopropanol in vacuo,the residue was partitioned between ether and an excess of 10% sodium hydroxide. The ether layer was washed twice with water, dried, and acidified t o Congo Red with dry gaseous HCl; yield of amino alcohol hydrochloride 2.7 g., m.p. 224-226'. It crystallized from absolute ethanol-acetone in slender needles of m.p. 225-227'. Anal. Calc'd for Cd€&lrNO: C, 64.67; H, 7.10. Found: C, 64.53; H, 7.13. 3,x-Dichloro-lO-(ldiheptylamino-l -hydrozyethyl)phenanthrene hydrochloride (SN 15,037). This compound was prepared like the foregoing one. The yield from 5 g. of bromo ketone was 4.5 g., m.p. 200-208". Two recrystallizations from absolute ethanol-acetone gave the constant m.p. 208-209.5"; felted needles. Anal. Calc'd for CsDHlpClsNO: C, 66.85; H, 7.86. Found: C, 66.62; H, 7.63. 3,y-Dichloro-lO-(d-dihezylamino-l -hydrozyethyl)phenanthrenehydrochloride (SN 13,036). From 5 g. of 3, y-dichloro-l0w-bromoacetylphenanthrene,2.5 g. of this hydrochloride, m.p. 179-182" was obtained, using the same procedure as in the two preceding cases; large prisms from absolute ethanol-acetone, m.p. 180-182". Anal. Calc'd for C&tsClaNO: C, 65.81; H, 7.50. Found: C, 65.44; H, 7.15. SUMMARY
Three amino alcohols of the type --CHOHCH2N&, and derived from dichlorophenanthrenes have been prepared. The evaluation of these compounds as antimalarials is discussed. BETEE~DA 14, MD.
ATTEMPTS TO FIND ANTIMALARIALS. XIX
REFERENCES
(1) MAYAND MOSETTIQ, J . Org. Chem., 11,429 (1946). J . Org.Chem., 11,435 (1946). (2) MAYAND MOSETTIQ, (3) MAYAND MOSETTIQ, J . Org. Chem., 11, 441 (1946). J. Org.Chem., paper XVIII of this series. (4) MAYAND MOSETTIQ, (5) EDDY,Unpublished results. (6) COATNEY AND COOPER, Unpublished results. (7) RIJQQLI AND STAUB,Helv. Chim. Acta, 20, 37 (1937). (8) LEWISAND ELDERFIELD, J . Org.Chem., 6,290 (1940). (9) “Organic Reactions”, 11, (John Wiley and Sons, Inc.) p. 277 (1944). (10) MAYAND MOSETTIQ, J . erg. Chem., 11, 1 (1946).
635
