[CONTRIBUTION FROM THE
DIVISION OF
PHYSIOLOGY,
NATIONAL INSTITUTE
OF HEALTH]
ATTEMPTS TO FIND NEW ANTIMALARIALS. VII.'. AMINO ALCOHOLS OF THE TYFE -CHOHCH(CHs)NR2 DERIVED FROM TETRAHYDROPHENANTHRENE E V E R E T r E L. MAY
AND
ERICH MOSETTIG
Received February 14, 19&
Previous communications of this series dealt with ethanolamines of the type -CHOHCH2NR2 (1, 2) and propanolamines of the type -CHOHCH2CH2NR2 (3), the side chains being attached to position 9 of phenanthrene, tetrahydrophenanthrene, and 3-methoxyphenanthrene (4). In analyzing the structural formula of quinine one notes the presence of a carbinolamine chain (I) containing two asymmetric carbon atoms, similar to that in the ephedrines. With this point in view we undertook the synthesis of compounds represented by formula 11.
I
II
9-Propionyltetrahydrophe1ianthrene,~ the starting material for the synthesis of type I1 was prepared by the Friedel-Crafts reaction. Its structure was proved by converting it to the tetrahydro-9-phenanthroic acid. We obtained the latter by oxidation of 9-acetyltetrahydrophenanthrene with sodium hypochlorite. This ketone WSLSprepared and elucidated in its structure by Bachmann and Struve (6). As a by-product in the preparation of 9-propionyltetrahydrophenanthrene we isolated the 7-propionyltetrahydrophenanthrenein a yield of about 15Oj,, and proved its structure by dehydrogenation to 2-propionylphenanthrene (7). The synthesis of the propanolamines I1 was accomplished by brominating 9propionyltetrahydrophenanthrene, exchanging the bromine with the amino group, and reducing the resulting amino ketones to the amino alcohols, either cat alvtjcally or with aluminum isopropoxide. The tolerated doses (chicks) of the amino alcohols of this series do not show a consistent variation from those of the lower homologs-CHOHCH2NR2 (Dr. 1 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 XXX. 3 The preparation of 9- and 7-propionyltetrahydrophenanthreneand the structural proof of these compounds were accomplished in the time from November 1942 t o February 1943. The publiGation of the data pertriining t o the 9-isomer was anticipated by Bachmann and Cronyn ( 5 ) . 296
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Nathan €3. Eddy) (8). There is an indication that the therapeutic value is decreased by the methyl group on the carbon adjacent to the secondary alcoholic group (Dr. G. Robert Coatney and Dr. W. Clark Cooper) (9). None of these drugs showed any activity towards sporoxoite-induced gallinaceum malaria except the diethylamino derivative (SN 2664),4which does not prevent, but consistentjlydelays infection when given at the tolerated dose (9).
Acknowledgment. We are indebted to Mr. Edward A. Garlock, Jr. for carrying out the microanalyses. EXPERI~NTAL~
Propionylation of 1,8,3,4-tetrahydrophenanthrene. T o a well-stirred mixture of 93 g. of aluminum chloride, 300 cc. of nitrobenzene, and 35.5 g. of propionyl chloride was added slowly at -5" t o 0", 68 g. of 1,2,3,4-tetrahydrophenanthrene. The reaction mixture was allowed t o stand for twenty-four hours at 6", and poured into an ice-hydrochloric acid mixture. After distilling the nitrobenzene with steam, the dark oil remaining was shaken into ether, the ether solution dried, and solvent evaporated. The residue, on distillation, yielded 68 g. of straw-colored liquid boiling at 212-217" (5 mm.). From this distillate a few crystals separated after standing for several days. T o further the separation 325 cc. of ligroin was added, the solution was cooled slowly, and finally allowetl to stand in the ice-box for twenty-four hours. The crystallirie material, consisting of the pure 7-isomer, weighed 6.3 g. and melted at 95-96". 7-Propiimyl-l,d,J,4-tetrahydrophenanthrene crystallized from 9570 ethanol as hexagonal plates melting a t 96-96.5". Anal. Calc'd for C17H160: C, 85.69; H, 7.61; M.W., 238. Found: C, 85.69; H, 7.80; M.W., 238. The sem,icarbazone, prepared in alcohol, crystallized from dioxane in well-formed prisms and melted a t 222.5-223.5'. Anal. Calc'd for ClsHttNaO: N, 14.22. Found: N, 13.98. The picrate crystallized from 70% ethanol in rectangular plates of m.p. 121.5-122.5'. Dehydrogenation (6). A mixture of 0.5 g. of the material of m.p. 96-96.5' and 0.17 g. of sulfur was heated a t 210-220' for three hours. A small amount of copper-bronze was added and heating continued for ten minutes. The mixture was extracted with benzene and the residue from this extract evaporatively distilled at 160-175" (0.5 mm.). The yield of solid melting ai; 98-103" was 0.4 g. After a recrystallization from ethanol-acetone the m.p. was 103-104' alone or when mixed with an authentic sample of 2-propionylphenanthrene. Further, the picrate melted at 105-106.5" and gave no depression in a mixture m.p. with authentic 2-propionylphenanthrene picrate. g-PropionyE-l,,$,3,4-tetrahydrophenanthrene(5). The ligroin filtrate of the 7-isomer (see above) was evaporated to dryness leaving an oil consisting mainly of 9-propionyl1,2,3,4-tel;rahydrophenanthrenebut still containing about 6% of the '?-isomer. (This estimate n-as based on a separation of the semicarbazones.) This oily ketone was, however, sufficiently pure for the subsequent reactions. For complete separation from the 7-isomer i t was purified through the picrate which Crystallized from 95% ethanol in yellow needles of m.p. 127.5-128'. Anal. Calc'd for C & & Z I N ~ O C,~ 59.10; : H, 4.53. Found: C, 58.90; H, 4.63. 4 SN signifies the identification numbers assigned t o the drugs by the Malaria Survey Office of the National Research Council. The SN for the drugs which have been submitted t o testing, are given in the Experimental. 6 All melting points are uncorrected.
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EVERXTTE L. MAY AND ERICH MOSETTIG
The semicarbazone, prepared from ketone which had been purified through the picrate, crystallized from 70% ethanol as white prisms of m.p. 161-163'. It was a great deal more soluble than that of the 7-isomer. Anal. Calc'd for C18H2JJ30e?HIO: C, 71.03; H, 7.29. Found: C, 71.44; I€, 7.38. The sample was dried at 97' for five hours in vacuo,m.p. 165-168". Anal. Calc'd for ClsH211\T80:C, 73.19; H, 7.17. Found: C, 73.06; B, 7.30. Ozidation. 9-Propiony1-lJ2,3,4-tetrahydrophenanthrene was oxidized t o the acid (5) by refluxing i t for 1.5 hours with 3% potassium hypochlorite solution. It crystallized from 80% ethanol or glacial acetic acid in white blades of m.p. 213-215". 9-Acetyl-1,2,3,4tetrahydrophenanthrene (6) was also oxidized t o the acid with hypochlorite. It likewise melted at 213-215"; mixed m.p. 213-215'. Bachmann and Cronyn (5) reported 215-216'. The methyl ester, prepared by boiling the acid with methanolic hydrogen chloride crystallized from 80% methan.01 in white prisms of m.p. 71.5-72'. Bachmann and Cronyn (5) reported 70.5-71'. Amino kelones and amino alcohols. T o a stirred solution of 20 g. of the oily 9-propionyltetrahydrophenanthrene in 100 cc. of dry ether (cooled in ice-water) was added during forty-minute period, 4.5 cc. of bromine. After stirring a n additional thirty-five minutes without external cooling, the clear solution was shaken successively with water, 2% sodium carbonate solution, and water, dried over sodium sulfate, concentrated t o 75 cc., and stored in the cold-room. This bromo ketone could not be obtained crystalline even when crystal(m.p. 43-45') (5) waa used i n the brominaline 9-propionyl-lJ2,3,4-tetrakiydrophenanthrene tion. 9-(R-Dimethylamino-l-hydrot.ypropyl)-l ,b,S,&tetrahydrqphenanthrene hydrochloride (SN 6814). A 38-cc. portion of the ether solution of the bromo ketone equivalent t o 11.4 g. of the latter was treated with 5.6 g. (3.5 moles) of dry gaseous dimethylamine during a tenminute period (ice cooling). 'The reaction mixture was allowed t o stand in ice-water for one-half hour, at room temperature for five hours, and finally i n the ice-box for five hours. The dimethylamine hydrobromide (4.4 g.) was collected, and the filtrate extracted twice with dilute hydrochloric acid. The acid extracts were combined, made ammoniacal, and the liberated base was shaken into ether. The ether solution, after drying and evaporation, yielded 10.5 g. of oily amino ketone. This, in 50 cc. of absolute ethanol, absorbed 0.9 mole of hydrogen in 25 to 35 hours (platinum oxide, 0.3 g,), The clear solution was filtered from catalyst and concentrated until the amino alcohol base began to separate. After cooling in ice, 5.2 g. (m.p. 158.5-159.5') was collected. On evaporating the filtrate t o dryness, dissolving the residue in acetone and adding 3.5 cc. of 20% alcoholic hydrogen chloride, an additional 0.7 g. of amino alcohol (as hydrochloride) was obtained. The base crystallized from absolute ethanol in white prismatic rods of m.p. 159.5-160'. AnaE. Calc'd for ClsH2sNO: C, 80.52; H, 8.89. Found: C, 80.21; H, 9.28. The hydrochloride crystallized from absolute ethanol-ether a~ clusters of white plates of m.p. 221-222". Anal. Calc'd for C19HzsC1NO:C, 71.33; H, 8.19. Found: C, 71.45; H , 8.24. There was no indication of the presence of a diastereoisomer. 9-(8-Diethylamino-l -oxopropgl)-1,R,3,4-tetrahydrophenanthrenepicrate. A portion of the ether solution of bromo ketone equivalent t o 9 g. of the latter waa concentrated t o 15 CC. and 8 cc. of diethylamine was added. After allowing this mixture t o stand for twenty-four hours at room temperature and for fifteen hours in the ice-box, 3.4 g. of diethylamine hydrobromide was collected. The filtrate was shaken with three portion8 of dilute hydrochloric acid. The combined acid extrai:ts were then made alkaline, the liberated base was shaken into ether, and the ether washed four times with water. After drying the ether over sodium sulfate, 100 cc. of warm 7% alcoholic picric acid solution was added. After two hours at
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room temperature 7.2 g. (47%) of pure amino ketone picrate of m.p. 163-164" was obtained. A recrystallization from 95% ethanol did not change the melting point; yellow plates. Anal. Calc'd for C1,H30N408: C, 60.22;H, 5.62. Found: C, 60.14;H, 6.02. The hydrochloride could not be obtained crystalline. Attempts to improve the yield by varying conditions, such as elevating the temperature, and using different solvents, were without success. 9-(I-Diethylamino-i -hydroxypropyl)-1,a, 3,4-tetrahydrophenanthrene hydrochloride (SN 2664). A mixture of 3.8 g. of the amino ketone obtained from the picrate above, 0.35 g. of platinum oxide, and 60 cc. of methanol absorbed 0.9 mole of hydrogen in forty hours. After filtration of catalyst and evaporation of solvent in vacuo,the amino alcohol base was dissolved in acetone and acidified with dry gaseous hydrogen chloride. The hydrochloride separated in a yield of 2.9 g., map. 218-219". From absolute ethanol-acetone-ether i t crystallized as white blades of m.p. 219-220O (decomp.). Anal. Calc'd for C21H3OClNO: C, 72.49;€I, 8.69. Found: C, 72.30;H, 8.95. There was no indication of the presence of a second isomer. 9-(I-Dipropylamino-i-hydroxypropyZ)-i ,I,8,4-tetrahydrophenanthrenehydrochloride (SN 6820). A mixture of 25 cc. of an ether solution of bromo ketone equivalent t o 12.5 g. of the latter and 10 g. of dipropylamine was kept at room temperature for 48 hours and in the icebox for 24 hours. Dipropylamine hydrobromide was collected (4.9g.) and the filtrate freed of excess dipropylamine by partial neutralization with 20% alcoholic hydrogen chloride and filtration of the resulting dipropylamine hydrochloride. The filtrate was then made slightly acidic with dry gaseous hydrogen chloride, whereupon 8.6 g. of the dipropylamino ketone salt crystallized out. This was reduced with 50 cc. of 3 A' aluminum isopropoxide solution as described previously (1). The time required was 2.5 hours. After distillation (invacuo)of most of the isopropanol, the residue was partitioned between an excess of 10% sodium hydroxide solution and ether. The ether layer was washed twice with water, dried, and treated with a slight excess of 20y0 alcoholic hydrogen chloride. The hydrochloride of the amino alcohol crystallized in a yield of 3.0 g., m.p. 190-193". A second fraction of less pure material weighed 1.6 g. and melted a t 160-180". Two recrystallizations from absolute ethanol-ether gave the constant melting point 195.5-197'; white oblong plates. Anal. Calc'd for C2rHdXNO: C, 73.46;IT, 9.12. Found: C, 73.17;H, 9.19. The filtrate contained a large amount of oily hydrochloride which may be the diastereoisomeric form of the above compound. It could not be crystallized. When the amino ketone base was used in i,his reduction the yields were somewhat lower and the material was more difficult to purify. 9-(I-hl'orphoZino-i-hydroxypropyl)-i,I,8,4.tetrahydrophenan~hrenehydrochloride ( S N 6904)! 9-(cr-Bromopropionyl)-l,2,3,4-tetrahydrophenanthrenewas condensed with morpholine by the same procedure as that described for the condensation with 1,2,3,4-tetrahydroisoquinoline by Wright and Elderfield (10). After separation of the crude amino ketone hydrochloride and reduction of the aniino ketone hydrochloride a 35y0 yield of amino alcohol liydrochloride was obtained. The product separated from methanol-ether as clusters of colorless needles which melted at 234-235" dec. (corr.) Anal. Calc'd for C21H2sClN02: C, 69.7;H, 7.8. Found: C, 69.2; H, 8.0. SUMMARY
A series of amino alcohols derived from tetrahydrophenanthrene, and carrying the side chain -CHOHCH(CH3)NR2in position 9 has been prepared. The evaluation of these compounds aa antimalarials is discussed. BETHESDA 14,MD. 6 This compound was prepared by Dr. S. Morris Kupchan, Columbia University.
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EVERETTE L. MAY AND ERICH MOSETTIG
REFERENCES MAYAND MOSETTIG, J . Org. Chem., 11, 1 (1946). MAYAND MOSETTIG, J . Org. Chem., 11, 10 (1946). MAYAND MOSETTIG, J. O r g . Chem., 11, 105 (1946). MAYAND MOSETTIG, J. O r g . Chem., 11, 15 (1946). BACHMAWN AND CRONYN, J . Org. Chem., 8, 457 (1943). BACHMAPI’W AND STRUVE, .I. Org. Chem., 4, 472 (1939). (a) BACHMANN AND STRUYE, J. Am. Chem. Soc., 58, 1659 (1936). (b) YANGAND HSIEH,J . Chinese Chem. Soc., 5,35 (1937); Chem. Abstr., 31,4448 (1937). (8) EDDY, unpublished result$. (9) COATKEY AND COOPER, unpublished results. (10) WRIGHTAND ELDERFIELD, J . Org. Chem., 11, 111 (1946). (1) (2) (3) (4) (5) (6) (7)
