[CONTRIBUTION FROM
THE
RESEARCH LABORATORY O F LADYESTHER,LTD.]
ATTEMPTS TO FIND NEW ANTIMALARIALS. XI. DERIVATIVES OF PHENANTHRENE, 111. AMINO ALCOHOLS DERIVED FROM 9-CHLOROPHENANTHRENE J. SCHULTZ', M. A. GOLDBERGe, E . P. ORDAS*, AND G. CARSCH4 Received August lY, 1945
It appeared to be of interest, from a biological point of view to prepare halogenated phenanthryl amino alcohols of the types described by us previously (1, 2), but having a chlorine atom in place of the bromine atom. The following amino alcohols and amino ketones were prepared: side chain
Side chain:
I1 CHOHCHZNRZ I11 COCH(CH3)NRz IV CHOHCH(C&)NRz
V GO CHz CHzNRz
-
Cl
The requisite starting materials, 9-chloro-3-acetyl- and 9-chloro-3-propionylphenanthrene were obtained in satisfactory yields in the Friedel-Crafts reaction on 9-chlorophenanthrene. The structural proof for these two key substances was accomplished in the following manner. The acetyl derivative was oxidized to the known 3-acetyl-9,lO quinone (3). The acetyl- and propionyl-g-chlorophenanthrene were oxidized with sodium hypochlorite t o the same 9-chlorophenanthroic acid. The acetyl-9-chlorophenanthrenewas converted via the oxime to the amino-9-chlorophenanthrene,and the latter by diazotization to the corresponding dichlorophenanthrene which melted at 125-125.5". In this dichlorophenanthrene one chlorine atom occupies position 9, the other one must occupy position 3 or 6. Nyl6n (4) prepared in 1920 by the Pschorr method 3 , l O dichlorophenanthrene which melts at 117-117.5". On this basis Sandquist ( 5 ) could assign t o the dichlorophenanthrene of m.p. 125-125.5", obtained by sulfonation of 9-chlorophenanthrene and the subsequent conversion of the sulfonic group to a chlorine (6), the structure of 3,9-dichlorophenanthrene. Thus, the melting point per se of our dichlorophenanthrene, and the general analogy of substitution in the sulfonation process and the Friedel-Crafts reaction is a very strong indication that this compound is 3,9-dichlorophenanthrene and consequently the acyl compounds are 3-acetyl-9-chlorophenanthreneand 3-propionyl-9-chlorophenanthrene. Moreover, x e have established (1, 2) the constiPresent Present 3 Present Present
address: address: address: address:
,I'ew York Quinine and Chemical Works, Brooklyn, Kew Pork Pepsodent Division, Lever Brothers Co., Chicago 38, Ill. Velsicol Corporation, Chicago 11, 111. 600 S. Michigan Ave., Chicago 5, Ill. 320
ATTEMPTS TO FIND ANTIMALARIALS.
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XI
tution of the 3-acyl-9-bromophenanthrenes by conversion t o the diphenanthroic acid, which mas also obtained from the above 3,9-dichlorophenanthrenevia the corresponding dicyano compound. Since the structural proof of all these acylhalo phenanthrenes hinges on this one melting point and since dimorphism in the phenanthrene series occurs frequently, it appeared advisable to prepare 3,9dicyanophenanthrene by an unambiguous synthesis. Recently May and Mosettig (7) synthesized by the Pschorr method 3-chloro-9-phenanthroyl chloride. We converted this derivative to 3 ,g-dicyanophenanthrene and t o 3,9-dicarboxyphenanthrene dimethyl ester. The last two proved, by melting point and mixed melting point, t o be identical with the dicyanophenanthrene and with the dicarTABLE . 1 ANTIMALARIAL ACTIVITYO F AMINOALCOHOLS SN
C14HS
9x1 3-CHOHCHz-
Q
10228 10229 10163 10123 13454 10230 10225 10124 10227 ciiH8
9-c1 3-CHOHCH (CHI)-
7266
I n the table are listed the compound13which were submitted for biological investigation. I n the first column are given the identification numbers assigned to 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 &. All compoundis listed in the table were administered as hydrochlorides.
boxyphenanthrene dimethyl ester obtained from our acylated 9-halo-phenanthrenes. The flow sheet depicts the structural proof of the 3-halo-9acylphenanthrenes. The compounds of types I-V were synthesized as described in the two preyious communications (1, 2). Also in this series we did not succeed in preparing the amino alcohol corresponding to V. There is no significant difference either in toxicity or in effectiveness towards Plasmodium gallinaceum between the amino alcohols listed above and their bromo analogs (1, 2) [Dr. Nathan B. Eddy (8); Dr. G. Robert Coatney and Dr. S . Clark Cooper (9)], Sone of the drugs showed any activity towards sporozoite-induced gallinaceum malaria (9).
322
SCHULTZ, GOLDBERG, ORDAS, AND CARSCH
IX-COCHs
'\
: : :1
\
I
(
//
FBr 1
X-COCH2C&
\
Pschorr Synthesis
I
/
I(
/ /
0 CH3
I
i
L ] r i H 2
I
9-c1
lx-Cl
9-CONHz
I
I"'
X-NH2
I ]
9-Br
N :I:]
X-B r
3-CN 3 steps
19-CN
3 steps
EXPERIMENTAL
9-Chlorophenanthrene. In a 5-liter, 3-necked flask fitted with a stirrer was placed 1000 g . of purified phenanthrene (1) and 3000 cc. of carbon disulfide. After cooling the solution to 2-5", a stream of chlorine was introduced while stirring. The chlorine was passed in for five hours a t the rate of 88 g. per hour. A t the end of the reaction, the carbon disulfide was removed by distillation. The residue, mainly phenanthrene dichloride, was then distilled in portions of 200-300 g. After a small amount of solvent and volatile matter was distilled i n oucuo, the bulk of the product passed over a t 360-370" at atmospheric pressure with the liberation of large quantities of hydrogen chloride. Distillation of the dichloride in vacuo was not advantageous. This crude 9-chlorophenanthrene was a light yellow oil which solidified on standing. The combined yield from two runs of 1000 g. of phenanthrene each was 2036 g. (85%), m.p. 43.5-46.5'.
ATTEMPTS TO FIXD ANTIMALARIALS.
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323
The crude material was crystallized from isopropanol to yield 910 g., m.p. 51-51.5" and a second crop of 610 g., m.p. 48.5-50.0". The yield a t this point was 68%. Sandquist and Hagelin reported the melting point 52.5-53" (6). 3-Acetyl-9-chlorophenanthrene. I n a 5-liter, 3-necked flask fitted with a stirrer was placed 400 g. of 9-chlorophenanthrene and 3200 cc. of carbon disulfide. The mixture was cooled to 5" and 140 cc. of acetyl chloride added. Six hundred grams of anhydrous aluminum chloride was then added in small portions over a period of about one hour. When all the aluminum chloride had been added, the mixture was allonred to warm up to room temperature (never above 30") with continued stirring. The reaction mixture, a t first dark green gradually became light brown. After stirring for a total of six hours, evolution of hydrogen chloride had practically ceased and the precipitated addition complex was filtered off and washed several times with carbon disulfide. The combined addition complex from two such runs (total of 800 g. of O-chlorophenanthrene) was decomposed with 1600 cc. of dilute hydrochloric acid, 6000 cc. of chloroform, and about 4000 g. of ice. After washing the chloroformic solution with water, i t was dried over sodium sulfate and evaporated to dryness. The crude residue (955 9 . ) was crystallized from isopropanol (using carbon) to yield 620 g. (65%) of colorless needles, m.p. 154155". Anal. Calc'd for ClsHllClO: C, 75.5; H, 4.69. Found: C, 74.97; H, 4.53. 3-Acetyl-9-chlorophenanthreneoxime. The oxime of 3-acetyl-9-chlorophenanthrenewas prepared from the ketone and hydroxylamine hydrochloride in dioxane-alcohol-water solution in the presence of a n equivalent amount of sodium hydroxide. The oxime, when recrystallized from methanol, was obtained as colorless needles, m.p. 187-188". Anal. Calc'd for CleHzlClNO: K, 5.1!1. Found: N , 5.16. 3-Acetyl-9-chlorophenanthrene semicarba.zone. The semicarbazone was prepared in the usual way. After crystallization from eth,yl alcohol, in which it is very sparingly soluble, it was obtained as light yellow needles, m.p. 251-252'. Anal. Calc'd for C17H&lNO: N, 13.4. Found: N, 13.0. 3-Amino-9-chlorophenanthrene. The procedure was exactly the same as used for the preparation of 3-amino-9-bromophenanthrene (1) nrhich follows, for most part, the method of Bachmann and Boatner (10). The yield from 101 g. of oxime was 66 g. (71%) of buffcolored needles, m.p. 112.5-113'. Anal. Calc'd for C1IHIOClK: N, 5.15. Found: S', 5.37. 3-8cety~amino-9-ch~orophenanthrene.The 3-amino-9-chlorophenanthrene 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'. 3,9-Dichlorophenanthrene. The 3-amino-9-chlorophenanthrenewas diazotized by a modification of the method of Misslin (11) and the diazonium salt converted to dichlorophenanthrene by Schwechten's modification of the Sandmeyer reaction (12). To a solution of 5 g. of 3-amino-9-chlorophenanthrene in 50 cc. of concentrated sulfuric at 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 w7ater,still maintaining the temperature at IO". Five grams of urea was then added and stirring continued for another half hour. A solution of 27.5 g. of mercuric $chlorideand 27.5 g. of potassium chloride in 100 cc. of water was added and gentle stirring continued for a n additional half hour. The suspension was held at ea. 5" in the refrigerator overnight, the precipitate filtered off, washed with cold water, and dried in a vacuum desiccator. The dried double salt was intimately mixed with twice its weight of potassium chloride and decomposed in a beaker heated over a low flame. The residue was extracted with hot water and taken up in warm benzene and the benzene solution filtered. The solvent was
324
SCHULTZ, GOLDBERG, ORDAS, .4ND CARSCH
evaporated and the residue distilled in vacuo, b.p. 220-230" at 6-7 mm. The distillate was crystallized from dioxane-methanol, yielding 1.8 g. (33%) of colorless needles, m.p. 125125.5". 3,9-Dicyanophenanthrene. (A) From diehlorophenanthrene obtained from 3-acetyl-$chlorophenanthrene. An intimate mixture of 1 g. of 3,9-dichlorophenanthrenewith 1 g. of cuprous cyanide was heated for 3 hours at 295-300" in a sealed tube. The reaction product was cooled, pulverized, and shaken with a mixture of ammonium hydroxide solution and chloroform. The chloroform solution was treated with charcoal, filtered, and evaporated t o dryness. The residue was recrystallized three times from toluene to yield 0.5 g. (54%) of colorless needles, m.p. 285-286". The melting point was not depressed by mixture with the dicyanophenanthrene obtained from 3-acetyl-9-bromophenanthrene (1). (B) By total synthesis. 3-Chloro-9-phenanthramide. T o 75 cc. of concentrated ammonium hydroxide was added with vigorous stirring a solution of 3.0 g. of 3-chloro-9phenanthroyl chloride (7) in 35 cc. of dry dioxane. After stirring for an additional 15 minutes, the suspension was diluted to 400 cc. with water and the precipitated amide filtered off, washed, and dried. The crude amide was recrystallized from dioxane-water to yield 2.36 g. (83.5'jZO) of colorless needles, m.p. 253.5-254". Anal. Calc'd for ClsHloClNO: N, 5.52. Found: N , 5.39. 3-Chloro-9-cyanophenanthrene. A mixture of 1.5 g. of 3-chloro-9-phenanthramide,35 cc. of phosphorus oxychloride, and 1.0 g. of phosphorus pentoxide was refluxed for one-half hour, poured on ice, and the product filtered off, washed with water, and dried. The product weighed 1.38 g. (99%) and melted a t 177.9". Recrystallization from alcoholbenzene yielded colorless crystals, m.p. 178.5-179'. Anal. Calc'd for CI~HBCIN: N , 5.87. Found: N, 6.16. 9,9-Dicyanophenanthrene. An intimate mixture of 0.18 g. of 3-chloro-9-cyanophenanthrene with 0.075 g. (10% excess) of cuprous cyanide was heated at 270-285" for 3 hours. The fused mass was sublimed at 1.5 mm. pressure and the sublimate crystallized from toluene. The dicyanophenanthrene separated as fine needles and the yield was 0.065 g. (38%), m.p. 284-285". The melting point was not depressed by admixture of the dicyanophenanthrene obtained from 3-acetyl-9-chlorophenanthrene, nor by that obtained from 3-acetyl-9bromophenanthrene(1). Phenanthrene-3,9-dicarboxylic acid dimethyl ester. (A) From 3-acetyl-9-chlorophenanthrene. Phenanthrene-3,9-dicarboxylic acid. A suspension of 0.2 g. of 3 ,g-dicyanophenanthrene (derived from 3-acetyl-9-chlorophenanthrene)in 20 cc. of a 25% potassium hydroxide solution in methanol was refluxed for 10 hours during which ammonia was evolved and a clear solution was obtained. The solution was then 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 to the free acid by precipitation from methanolic solution by dilute hydrochloric acid. After drying in a vacuum desiccator, the purified acid remained as R light yellow poRrder, m.p. above 330". Phenanthrene-d,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 eight hours during which a clear solution was obtained. On cooling, the ester separated in the form of colorless needles. Two recrystallizations from methanol yielded 0.05 g. of colorless needles, m.p. 126.5-127.5'. The melting point was not depressed by admixture of the diester'obtained from 3-acetyl-9-bromophenanthrene (1). (B) By total synthesis. A sample of 3,9-dicyanophenanthrene prepared by total synthesis was hydrolyzed to the dicarboxylic acid and then esterified to the dimethyl ester by the procedure indicated above. The dimethyl ester had the melting point 126.5-127.5" which was not depressed by admixture of the diester obtained from the 3-acetyl-9-chlorophenanthrene (u.s.) nor by that obtained from 3-acetyl-9-bromophenanthrene (1). 3-or-Bromoacetyl-9-chlorophenanthrene. A suspension of 60 g . of acetyl-9-chlorophenan-
A'IY"EMPTS TO FIND ANTIMALARIALS.
325
XI
threne in 600 cc. of absolute ether was brominated with 39 g. of bromine in 150 cc. of chloroform. The reaction was similar to the bromination of acetyl-9-bromophenanthrene (1) but was carried out at 3" after initiating the reaction a t 33". Recrystallization of the product from two runs (120 g. of starting material) from benzene-hexane gave 105 g. (67%) of greenish yellow needles, m.p. 135-135.5'. A second crop of less pure material (m.p. 128.5-130') amounted to 28.3 g. Including the second crop material, the total yield was 84 5%). i l n a l . Calc'd for ClsHloBrC10: Br, CX, 34.6. Found: Br, C1, 34.6. $-(8'-Dialkylamino-l -oxoethyl)-9-chlorophenanthrenehydrochloride. The procedure here was essentially the same as that used for Ihe corresponding 9-bromophenanthrene(l) series. A mixture of 15.7 g . (0.047 mole) of 3-bromoacetyl-9-chlorophenanthrene and 0.094 mole of dialkylamine in 50 cc. of benzene was shaken for 20 minutes. During this time the reaction mixture became quite warm and rather thick. An additional 25 cc. of benzene was added and the shaking continued for a total of 50 minutes. One hundred cubic centimeters of absolute ether was then added and the mixture was chilled to 0' for one hour. Filtration TABLE I1 3-(2-DIALKYLAMINO-1-OXO-ETHYL)-~~-CHLOROPHENINTHRENE HYDROCRLORIDES~
-
c., % ALKYL
GROUP
SOLVENT
Met hanol-isopropanol Ethanol -acetone Methanol -acetone Methanol -acetone ether Met hanol-acetoneether Acetone Acetone Acetone Acet one-ether Acetone
M.P.
"C
FORMULA
YIELD
%
____232-233 CisH17Clzr\'O
89
0.61 10.724.193.82
212-213.5 C2oHzIClzNO 236-238 CzzHziClzNO 192-193.5 CzcHpsClzNO
85 80 65
9.79 9.83 3.87 3.76 9.09 9.103.593.52 8.48 8.653.35 3.22
176.5-178
C2aHaiClzNO
49
7.94 7.99 3.14 3.02
147-148 153.5-154.5 122-123 108-111 106-108
CzsHa7ClzNO CaoH4iClzNO CszHasClaNO CscH,,ClzPU'O CssHsaClziYO
56 42 76 45 64
7.48 7.05 6.68 6.35 6.04
7.692.962.89 6.862.792.44 6.70 2.64 2.72 6.452.51 2.46 6.31 2.39 2.30
_ .
a
All compounds colorless needles.
yielded 0.045-0.047 mole of dialkylamine hydrobromide. The filtrate was acidified with alcoholic hydrogen chloride and chilled. Light yellow to colorless needles of the dialkyl amino ketone hydrochloride were obtained and washed with dry ether. Crystallization from the appropriate solvent (see Table 11) gave practically colorless needles. S-(%Dialkylamino-l -hydroxyethy1)-9-~hlorophenanthrenehydrochloride. A mixture of -9-chlorophenanthrene hydrochloride, 0.028 mole of purified 3-(2-dialkylamino-l-oxoethyl) 17.4 g. (0.085 mole) of aluminum isopropoxide, and 300 cc. of isopropanol was distilled through a Snyder column by the same method used for the analogous compounds in the 9bromophenanthrene series (1). The remaining isopropanol was removed by distillation under diminished pressure and the residual complex decomposed with citric acid, sodium hydroxide, and water. The amino alcohol was extracted with ether. After drying the ethereal solution with anhydrous sodium sulfate, the amino alcohol hydrochloride was precipitated by alcoholic hydrogen chloride and purified by recrystallization (Table 111). 3-Propionyl-9-chlorophenanthrene. To a well-stirred suspension of 170 g. of 9-chloro-
326
SCHULTZ, GOLDBERG, ORDAS, AND CARYCH
phenanthrene in 1600 cc. of carbon disulfide cooled to 5", was added 67 g. of propionyl chloride and then 255 g. of anhydrous aluminum chloride in small portions over a period of one hour. The mixture was allowed t o warm up to room temperature and stirring was continued until the evolution of hydrogen chloride was practically at an end. The precipitate was filtered off, washed with carbon disulfide and decomposed with 100 cc. of conc'd hydrochloric acid, 300 cc. of chloroform, and about 250 g. of ice. The chloroformic solution was washed with water, dried over sodium sulfate, and evaporated to dryness. The residue was dissolved in about 1700 cc. of isopropanol, treated with carbon, filtered with the aid of a few grams of Filter-eel, and allowed to crystallize. Recrystallization from isopropanol yielded 88 g. (41%) of yellow crystals, m.p. 111.5-112.5°. Anal. Calc'd for C17Hl;rClO:C, 76.0; H, 4.88. Found: C, 76.47;H, 4.90. 3-Propionyl-9-chlorophenanthrene oxime. 3-Propionyl-9-chlorophenanthrene was treated with hydroxylamine hydrochloride in the usual manner. The product P;hen recrystallized from methanol yielded colorless needles, m.p. 160.5-161.5'. TABLE I11 3-(2-DIALKYLAMINO-l-HYDROXYETHYL)-9-CHLOROPEENANTHRENEHYDROCHLORIDESO SOLVENT
Methanol-acetone Methanol-acetoneether Isopropanol Methanol -acetoneether Methanol-acetoneether Isopropanol Acetone Isopropanol Acetone ~1
Y.P.
"c.
FORMULA
1%
'IELD
Zalc'd
Found lalc'd Found ---
194.5-196 198.5-199
9.75 9.74 3.84 3.91 9.05 9.13 3.57 3.31
198-199 197-198
8.45 8.50 3.33 3.20 7.91 7.92 3.12 2.89 I
131-131 .l 132-133 132.5-134 126.5-128 121-122
7.45 7.47 7.03 6.66 6.33 6.03
7.14 6.71 6.39 6.17
2.78 2.63 2.50 2.38
2.93 2.40 2.51 2.39
I
All compounds colorless needles.
Anal. Calc'd for C1,H1&lNO: N , 4.93. Found: N, 4.84. 3-a-Bromopropionyl-9-chlorophenanthrene.A suspension of io g. of 3-propionyl-9chlorophenanthrene in 500 cc. of absolute ether was brominated with 35.7 g. of bromine in 150 cc. of chloroform. The procedure was exactly the same as for the bromination of 3-acetyl-9-chlorophenanthrene.The yield of a-bromo ketone (not quite pure) after crystallization from dioxane-petroleum ether (35-60') was 35 g. (45%), m.p. 163.5-164". Anal. Calc'd for C17H12BrC10: C, 55.6;H, 3.71. Found: C, 57.4; H, 3.60. 3-(8-Diamylamino-l-ozopropyl)-9-chlorophenanthrene hydrochloride. This substance was prepared by the same method used for the preparation of 3-(2-dialkylamino-l-oxopropyl)-9-bromophenanthrene hydrochlorides (2). A solution of 18.9 g. of 3-or-bromopropionyl-9-chlorophenanthrene and 25.6 g. of diamylamine in 125 cc. of benzene was refluxed for six hours. The diamylamine hydrobromide which was formed was filtered off and after neutralization with alcoholic hydrogen chloride the remaining secondary amine was separated as hydrochloride. The filtrate was acidified with alcoholic hydrogen chloride and the solution cooled until precipitation was complete. The product, amounting to
ATTEMPTS TO FIND AhTIMALARIALS.
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327
18.5 g., was filtered off, washed with ether, and dried, m.p. 157-160". After recrystallization from methanol-acetone-ether, colorless needles were obtained, m.p. 160-161". Anal. Calc'd for C2,HasC12NO: N, 3.14. Found: N, 2.84. 8-(B-Diamylamino-l-hydroxypropyl)-9-chlorophenanthrene hydrochloride. This substance was prepared from the ketone by reduction with aluminum isopropoxide in isopropanol. From 9 g. of 3-(2-diamylamino-E.-oxopropyl)-9-chlorophenanthrene hydrochloride and 12 g. of aluminum isopropoxide, 8 g. of the carbinol was obtained, m.p. 186-188". Recrystallized from methanol-acetone-ether, m.p. 184-185". Anal. Calc'd for C27H37CI2NO:C1, 7.71; N, 3.13. Found: C1, 7.72; N, 2.88. S-(8-Dihexylamino-l-oxopropyl)-9-chlorophenanthrenehydrochloride. This ketone was prepared by the same method as that used for the analogous bromo derivatives (2). From 5.6 g. of starting material, 6.6 g. (66%) of the amino ketone hydrochloride was obtained, m.p. 123.5-126" with decomposition. Anal. Calc'd for C28H3&1&0: C1, 7.69. Found: C1, 7.72. Conversion of 9-chlorophenanthrene to O-cyanophenanthrene. This reaction was effected using essentially the procedure described by Mosettig andvan de Kamp (13). A mixture of 4.25 g. of 9-chlorophenanthrene and 1.96 g. of cuprous cyanide was heated at 275-285 for three hours. The cooled black mass &-as pulverized, extracted with chloroform, and after evaporation of the solvent the residue was recrystallized three times from ethyl ~ 1 ~ 0 hol. The cyanophenanthrene showed no depression in melting point when mixed with material prepared from 9-bromophenanthrene. Oxidation of 3-acetyl-9-chlorophenanthrsnewith chromic acid. One gram of 3-acetyl-gchlorophenanthrene was oxidized with chromic acid by the method of Mosettig and van de Kamp (3). The product, 3-acetylphenant hrene-g,lo-quinone was shown by mixed melting point to be identical with the quinone n;.ade by oxidizing 3-acetyl-9-bromophenanthrene (13). Oxidation of 3-acetyl-9-chlorophenanthrene with sodium hypochlorite. One and one-half grams of the ketone was dissolved in 15 cc. of pyridine. T o this was added 5.0 C C . of 5.5 N sodium hypochlorite and 3.0 cc. of water. The mixture which separated into layers was refluxed for 30 minutes, then poured into 150 cc. of 5% hydrochloric acid. The solid which separated was filtered off, washed with a little dilute hydrochloric acid and water, and heated to boiling with 300 cc. of 2% sodium hydroxide solution. The alkaline mixture was treated with carbon, and the filtrate after acidification with 6 N hydrochloric acid gave a white gelatinous precipitate. The dried 9-chlorophenanthrene-3-carboxylicacid on recrystallization from glacial acetic acid yielded colorless needles which melted a t 276.5277.5". Anal. Calc'd for C15H&lO2: Xeut. equiv., 256.5. Found: 249. Oxidation of 3-propionyl-9-chlorophenanthrene with sodium hypochlorite. This oxidation was done in the same manner as that described above for the acetyl derivative. The 9chlorophenanthrene-3-carboxylicacid melted at 277-277.5'. A mixed melting point, with the acid obtained from 3-acetyl-9-chlorophenanthreneshowed no depression. 9-Chlorophenanthrene-8-carboxylicacid methyl ester. The 9-chlorophenanthrene-3carboxylic acid was esterified with methanol in the presence of sulfuric acid. The ester was recrystallized from methanol, yielding colorless needles which melted a t 165.5-156". A mixture of the esters derived from 3-acetyl-9-chlorophenanthrene and from 3-propionyl9-chlorophenanthrene also melted a t 155.5-156'. Anal. Calc'd for ClGHllClO2: C, il.0; H, 4.07. Found: C, 71.18; H, 3.94. SUMMARY
1. A. homologous series of threnes has been synthesized.
3-(2..dialkylamino-l-oxoethyl)-9-chlorophenan-
328
SCHULTZ, GOLDBERG, ORDAS, AND CARSCH
2. 3-(2-Diamylamino-l-oxopropyl)-9-chlorophenanthrene has been synthesized. 3. Each of the above amino ketones has been reduced to the corresponding amino carbinol. 4. 3-(3-Dihexylamino-l-oxopropyl)-9-chlorophenanthrenehas been synthesized. 5. The structure of the compounds described in this paper has been elucidated. 6. The evaluation of the amino alcohols described herein as antimalarials is discussed. CHICAGO, ILL. REFERENCES SCHULTZ, GOLDBERG, ORDAS,AND CARSCH,J. Org. Chem., 11, 307 (1946); SCHULTZ, GOLDBERG, ORDAS,AND CARSCH, J. Org. Chem., 11, 314 (1946): MOSETTIGAND VAN DE KAMP,J . Am. Chem. Soc., 62,3704 (1930). N Y L ~ ~Ber, N , 63, 158 (1920). SANDQUIST, Ber., 63, 168 (1920). SANDQUISTAND HAGELIN,Ber., 61, 1515 (1918). MAYAND MOSETTIG,J. Org. Chem., in press. EDDY,Unpublished results. COATNEY AND COOPER,Unpublished results. (IO) BACHMANN AND BOATNER, J. A m . Chem. SOC.,68, 2097 (1936). (11) MISSLIN,Helu. chim. Acta, 3, 626 (1920). (12) SCHWECHTEN, Ber., 66, 1605 (1932). AND VAN DE KAMP,J. A m . Chem. SOC., 64, 3328 (1930). (13) MOSETTIG (1) (2) (3) (4) (5) (6) (7) (8) (9)
