2,4-DISUBSTITUTED BENZALDEHYDE THIOSEMICARBAZONES
June, 1951
[CONTRIBUTION
FROM
2801
SCHENLEY LABORATORIES, INC. ]
Antituberculous Compounds 2,4-Disubstituted Benzaldehyde Thiosemicarbazones BY LEONKATZ AND WILLIAM E. HAMLIN~ A series of compounds related to p-aminosalicylic acid and p-acetylaminobenzaldehyde thiosemicarbazone has been prepared for evaluation against Mycobacterium tuberculosis. These compounds were prepared from the corresponding 2-alkoxythiosemicarbazone. 4-nitrotoluenes. The most active compound was 4-acetylamino-2-n-amyloxybenzaldehyde
The efficacy of paminosalicyclic acid (PAS) (I) and 9-acetylaminobenzaldehyde thiosemicarbazone2 (11) in the treatment of tuberculosis has been the subject of considerable research in recent years. These compounds both contain an amino 0 H , X - ~ - C O IIH
I
OH I S
CH~CONH-CH=NISHC~XH,
-
/I
I1
group para to a doubly bound carbon atom. The incorporation of a 2-hydroxyl group in I1 would produce a class of compounds I11 which would be expected to possess antitubercular activity. After the inception of this work, Drain, Goodacre and
terized because of their tendency to oil out or form the polymeric anil. Instead the crude product was acetylated and the acetyl derivative reacted with thiosemicarbazide to give the desired thiosemicarbazones V (Table 111). Attempts to prepare the 2-alkoxy-4-nitrobenzaldehydes by using manganese dioxide and sulfuric acid, selenium dioxide, or chromium trioxide and acetic acid were either unsuccessful or gave very low yields. The reaction using chromyl chloride was satisfactory, and again the substituted benzaldehydes were not isolated but converted directly to the thiosemicarbazones, VI (Table 11). The pharmacology of these compounds will be reported elsewhere. The authors were indebted to Drs. K. Ladenburg and B. Puetzer for their encouragement throughout this project.
Experimental 2-Hydroxy-4-nitrotoluene.-This material was prepared
S
in 90-950/, yield using the method of Ullmann.6 2-Alkoxy-4-nitrotoluene.-Into a 1-1. three-necked flask equipped with a sealed stirrer, reflux condenser and Glascol mantle were charged 102 g. (0.66 mole) of 2-hydroxy-4I OR1 nitrotoluene, 30 g. (0.75 mole) of sodium hydroxide and 400 ml. of water. The mixture was stirred, heated to 100’ 111 and 0.75 mole of the alkyl p-toluenesulfonate added. After Seymour3 published the in d 7 0 pharmacological three t o four hours a t 100’ the reaction mixture was chilled data for 2-hydroxy-4-nitrobenzaldehydethiosemi- to 5 ” , the resultant slurry filtered, and the filter cake washed with water until the drippings ran almost colorless. The carbazone and 2-hydroxy-4-aminobenzaldehyde wet cake was recrystallized by dissolving in 2-2.5 volumes thiosemicarbazone. The latter compound was of hot ethanol. 4-Acetylamino-2-ethoxybenzaldehydeThiosemicarbathirty times as active as 11. At the present time modification of the procedure described by we would like to publish data on a related series of zone.-A Blanksma‘ for the preparation of 4-amino-2-methoxybencompounds which were synthesized as outlined in zaldehyde was used. Into a 1-1. three-necked flask fitted the flow sheet. with a reflux condenser were charged 45.3 g. (0.25 mole) of 2-ethoxy-4-nitrotoluene and 400 ml. of 9570 ethanol. While the mixture -CHO] was heated to reflux a solution of 60.0 E. (0.25 mole) of sodium sulfide nonagydrate and 8.0 g. (0.25 mole) of sulfur IV OR was prepared by heating the two components in a beaker on a hot-plate. 1. NazS S This solution was added to the refluxing 2. AcnO ethanol solution and the mixture refluxed vigorously for five hours. The II reaction mixture was steam distilled to 3. HziYNHCNH2 remove solvent and some 2-ethoxy-pS S toluidine (usually three hours sufficed). I/ /I After chilling the mixture in the flask CH3CONH- ~\- C H = A - N H C N H ~ 0 2 S ~ - C H = N ” C ” 2 overnight the supernatant liquid was decanted and the semi-solid mass transI I ferred to a 250-ml. beaker. Fifty milliV OR \‘I OR liters of acetic anhvdride was added and The 2-alkoxy-4-nitrotoluenes (IV) (Table I) were then 4-5 drops of C.P.sulfuric acid. Acetylation proceeded rapidly and a dark brown solution was obtained which was converted to the corresponding 2-alkoxy-4-amino- added to a boiling solution of 300 ml. of ethanol and 50 ml. of benzaldehydes using the method of B l a n k ~ m a . ~water. The mixture was boiled 10-15 minutes to decomThe substituted benzaldehydes were not charac- pose excess acetic anhydride and 15.0 g. (0.155 mole) of thiosemicarbazide in 100 ml. of boiling water added. A (1) The Upjohn Co., Kalamazoo, Mich. heavy yellow precipitate formed quickly. After heating for (2) Schenley “Tibione” brand of Amithiozone. an additional one-quarter hour, the slurry was chilled for (3) D. 3. Drain, et ai., J . Pharm. Pharmacal., I, 784 (1949) (5) P. Ullmann. Bev 88,3787 11905) (4) J. J. Blanksma, Rcc. Irau. chim.. 29, 408 (1910).
R-CH=NNHCNH,
+
I/
L
~
4
I
LEONKATZAND WILLIAME. HAMLIN
Vol. 73
TABLE I 2-ALKOXY-4-NITRoTOLIJENESo % N - O - c H s
__
1
OR No.
Yield,
1
CHP
2 3
C2HBb n-CaH,
Empirical formula
M.p.,
%
R
OC
Carbon
60 71 CSH803K 52 60-61 CsHiL03S 71 5 48-49 CloHl3OaN 61 53 4 n-C&Ie 70 1 50-52 CilH180aK 63 15 5 n-CaH11 73 4031 c]&1?03x 64 57 a CH,, lit. F. Ullmann and R. Fitzenkanini, Ber., 38,3790 (1905). ibid.,39, 3240 (1906).
Calcd. Hydrogen
Analyses, %
Nitrogen
6 65 7 17 7 63 GHs, lit. L.
___ Found Hydrogen
Carbon
7 18 6.68 6 27 Spiegel,
-
Nitrogen
61 55 6.78 7 09 63.08 7 21 6 73 64 60 7.41 6 44 N. Munblit and H. Kaufmann,
TABLE I1 S
/I
2-ALKOXY-4-NITROBENZALDEHYDETHIOSEMICARBAZONES ozx
OR NO.
Yield,
R
%
Empirical formula
%.P.,
C.
CHI 37 7 39 3 C2H6 3 n-C3H7 38 6 4 n-C,Ho 51.0 Recrystallized from acetic acid.
1 2
250-251" 238 5" 225' 214 2 Recrystallized
CoHioO3S4S CIOH~ZO~X~S CiiH1403X4S CizH1603~4s from methanol.
Nitrogen
Calcd.
-
Analyses, ?&
Sulfur
Found Nitrogen Sulfur
21 89 12 59 20 28 89 11 94 85 19 95 11 3s 10 81 18 83 91 Recrystallized from ethanol.
22 20 10 18
12 85 11 65 11 38 10 83
04
TABLE I11
S 4-ACETAMIN0-2-ALKOXYBENZALDEHYDE
I
THIOSEMICARBAZOZ &.S C H , C O " ~ C __ H;;.K~HcxH~ OR r
NO.
a
R
Yield,
%
Empirical formula
"3:s
1 CHI 28.0 233" 2 CL" 45.0 238,5'l 3 n-C3H? 29.3 229.5'' 4 n-CaH9 42.3 216" 5 n-c6H11 40.4 174. 5b Recrystallized from aqueous isopropyl alcohol.
CiiHiaOzNnS
C12H1602KaS C13H ,so::
*
h-,s
h-itrogen
--__
Calrd
21.05 20.00 IY,0:i
1x. 18 Ci~H2nOyK45 17.38 CisHtzOzNaS Recrystallized froin methanol.
four to five hours. The solid was collected on a Buchner funnel and dried zn vacuo a t 60". The weight of yellow material, m.p. 229-232", was 31.5 g. or&%of theory based on 2-ethoxy-4-nitrotoluene. The other 2-alkoxy-+nitrotoluenes were treated similarly to give the corresponding thiosemicarbazones. 2-Ethoxy-4-nitrobenzaldehyde Thiosemicarbaz0ne.Into a 250-ml. three-necked fldsk equipped with :I sealed stirrer, dropping funnel and ice-water bath u err chdrgetl 9.1 g. (0.05 mole) of 2-ethoxy-4-nitrotolueiie ~ i i 31) d tnl. of chloroforni. Into the dropping funnel n c i b placed J 50111tion of 18.7 g. (0.1 mole) of chromyl chloride u d 3 0 mi. of chloroform. The chroniyl chloride-chloroform 5olution H as added to the stirred reaction mixture a t IO-minute ititervals in the course of two hours so that the temperature did not exceed 35-40'. After stirring an additiorial five hours the reaction mixture was allowed to stand over the weekend. The semi-solid reaction mixture was decomposed by the cautious addition of 100 ml. of water, and then extracted with seven 100-ml. portions of ether. The extracts were dried over magnesium sulfate, treated with 1-2 g. of Darco G-60 and the solvent removed. The residue was taken up in 250 ml. of hot 95% ethanol and 5.0 g. (0.05 mole) of
Analyses, % Sulfur
12.03 1 1 :il 1 I1 .
