Jan., 1950
DERIVATIVES O F 4-AMINO-4’-ETHYLAMINODIPHENYL SULFONE
ture of this compound seems well substantiated, since its preparation has been reported in the literature by three different routes (from x,y,z-tribromoquinoline by nitric acid oxidation,lO from 5-bromoquinolinic acid by decarboxylation,ll and from 5-arninonicotinic a c i d 9 . The yield of 5-bromonicotinic acid was 45%. Anal. Calcd. for C&LBrNO2: C, 35.7; H, 2.00. Found: C, 35.9; H, 2.04. The acid was then converted to the methyl ester by the usual method employing thionyl chloride and methanol. The ester was crystallized from methyol-water and conChromatographsisted of colorless crystals, m. p. 93-95 ing a small sample in benzene over activated alumina raised the m. p. t o 99-100” (lit. 98-99*). A small sample (1 g.) of each of the amines was then oxidized by refluxing in 40 ml. of concentrated nitric acid for twelve hours and the mixture worked up as before. The product in each case was identified as 5-bromonicotinic acid by mixed m. p. of the acid with the authentic sample and mixed m. p. of the methyl ester with the authentic sample. 3-Bromo-6-rnethoxy-8-( 5-isopropylaminopentylamino)quinoline Hydrobromide .-The coupling was accomplished using equimolecular (0.03 mole) quantities of 3-bromo-6methoxy - 8 - aminoquinoline and 5 isopropylamino - 1 bromopentane hydrobromide, and a one-mole excess of sodium acetate. This mixture was heated a t steam-bath temperature for three days. At the end of this time 25 to 50 ml. of a methanol-water mixture was added, and the mixture was refluxed a day longer. When the mixture was removed from the steam-bath, a black oil settled to the bottom of the flask. Without allowing the flask to cool, the supernatant liquid was poured into a beaker. The black oil in the flask was taken up in benzene, decolorized with charcoal and cooled to yield the monohydrobromide
.
-
(10) 0. Srpek, Monotsh., 10,710 (1889). (11) A. Claus and F. Collischon, Bcr., 19, 2763 (1886). (12) R. Graf, J . @ k f . C h e n . , 138, 244 (1933).
[CONTRIBUTION FROM
THE
395
of the drug. As the supernatant liquid cooled, crystals settled out, which generally consisted of a mixture of hydrobromide and the aminoquinoline. If the supernatant liquid was not separated from the black oil, it was not, possible to separate the coupling product from starting amine. The hydrobromide as it was obtained from the first crystallization was quite pure and each crystallization (methanol-benzene solution) decreased the yield immensely. The best yield that could be obtained was 55% based on the amine used in the reaction. Usually, half the quantity of amine used in the reaction is recovered. Anal. Calcd. for ClsHesBrNaO.HBr: N, 9.11; C, 46.8; H,5.86. Found: N.8.62; C, 46.6; H , 5.67. 3 -Bromo - 6 - chloro - 8 - (5 - isopropylamino-1 - pentyl amino)-quinoline Hydrobromide.-This compound was prepared in a similar manner to its 6-methoxy analog. Anal. Calcd. for C11HzaBrClNa.HBr: N, 9.02. Found: N, 8.72.
summary
1. 2,2,3-Tribromopropanal has been found to react with o-nitro-P-substituted-anilines to produce the 3-bromoquinolines in good yields. Two of these nitroquinolines have been reduced to the amines and coupled with side chains to produce compounds of possible an timalarial activity. 2. o-Nitroaniline itself in this reaction produced little of the expected compound, 3-bromo-8nitroquinoline, and large amounts of 6-bromoand 3,6-dibromo-8-nitroquinolinC. 3. A survey of numerous attempted direct halogenations of 6-methoxy-8-nitroquinoline is presented. EVANSTON, ILLINOIS
RECEIVED SEPTEMBER 30, 1949
EXPERIMENTAL BIOLOGYA N D MEDICINEINSTITUTE,NATIONALINSTITUTES OF HEALTH:
Derivatives of 4-Amino-4 ’-ethylaminodiphenyl Sulfone, 4-Nitro-4’-ethylaminodiphenylSulfone and N’-Ethylsulfanilamide BY ERNEST L. JACKSON*
4-Amino-4’-P-hydroxyethylaminodiphenylsulfone’ (I) possesses interesting pharmacologic and chemotherapeutic properties.2 The first preparations of this compound by the reduction of 4-nitro-4’-P-hydroxyethylaminodiphenylsulfone (11) regularly yielded crystals melting a t 143.5-144.5”, but later a second crystalline form (Table I) melting a t 130.5-131.5’ usually was obtained. The dimorphic forms are distinguishable by the X-ray diffraction patterns (Fig. 1), which also demonstrate their homogeneity. The procedure’ previously employed for the preparation of I1 by hydroxyethylation of 4-amino-4’-nitrodiphenylsulfone has been improved by neutralization of the hydrobromic acid produced in the reaction and other modifications. Since compound I is only slightly soluble in water (74 mg. per 100 cc. of
* Harvard University Ph.D. 1824. (1) Jackson, THISJOURNAL, 70, 680 (1948). (2) Smith, Jackson, Junge and Bhattacharya, A m . Rev. Tubcrc., 68,132(1849).
solution a t 37”), it usually is administered orally in chemotherapeutic experiments. Phosphorylation affords its crystalline phosphoric ester (111), the sodium salt of which is readily soluble in water. This ester is prepared conveniently and in high yield by the reaction of a mixture of orthophosphoric acid and phosphorus pentoxide with I at 100’. It was obtained also by the reduction of compound IV, the phosphoric ester of 11, with ammonium sulfide or ferrous sulfate. The preparation of IV by phosphorylation of I1 with a mixture of orthophosphoric acid and phosphorus pentoxide proved to be a superior method to preparation by way of the reaction of phosphoryl chloride with I1 a t looo,because in the latter reaction a considerable proportion of the material was converted into 4-nitro-4’-P-chloroethylaminodiphenyl sulfone (V). In dry pyridine solution a t room temperature phosphoryl chloride showed no appreciable reaction with 11. The reaction of hot 48y0 hydrobromic acid with I yields crystalline
EFWESTL. JACKSON
396
Vol. 72
TABLE I
I I1
-OH -OH -NHr -OPO(OH)z -N% -OPO(OH)r -NO, -Cl
" I-
-Nor
130.5-131.5
.........
C,JhN*NrolS
............
57.51 5.52 9.68 10.97 57.81 5.31 9.23
... . .. . ..
.. .. ..
..
...
11.02
.. .. ... _ _ . .. 7.16 8.70 ... _ . 6.51 8.11 ...
136-137" C~-IIIN&IPS' 7.53 8.61 189-190 CzrHi.Ns0IPS 6.96 7.97 V 196-197 C~IH,CINIO& 49.34 3.84 8.22 9.41 49.79 3.91 7.99 9.18 VI -NHI -Br 153-154 C,~H,,BrN~O*S 47.33 4.26 7.89 9.02 47.64 4.38 7.80 8.97 VI1 -NO1 -OGH. 149-150 CdiaN*OrS 54.84 5.18 8.00 .. 55.11 5.14 8.18 VI11 -NH* -OW6 125-126 CI.H~SNN~O*S 59.97 6.29 8.75 10.01 60.03 6.34 8.57 9.88 HrO, 8.8; N, 6.88; P, 7.59; 2.45 cc. of 0.1 N d i u m hydroxide solution Dihydrate. Calcd. for C,,H,,N,OaPS.2H,O: per 50 mg. Found: HIO (dried at 100' in wcuo). 9.2; N. 6.84; P. 7.20; 2.47 cc. of 0.1 N sodium hydroxide (phenol phthalein). * P. calcd. 832; found, 7.83 (colorimetric). P. calcd. 7.70; found, 7.65 (colorimetric). Calcd.: 2.40 ec. of 0.1 N sodium hydroxide solution pcr 50 mg. Found: 2.51 cc. (phenolphthalein). U,d c d . 10.41; found, 10.64. ' Br. calcd. 22.50; found, 22.32. 111
IV
.
...
monohydrdoride of di-&aminoethylphosphoric acid (IX), m. p. 250°, resulted from the reaction, under specified conditions, of phosphoryl chloride with 2-aminoethanol in carbon tetrachloride medium. Outhouse6employed the same reactants in aqueous solution for the preparation of monoaminoethylphosphoric acid, which has been isolated from tumors3 and also from the intestines of pigs and rabbitsn In accordance with formula IX,nitrogen analyses of di-b-aminoethylphosphoricacid by the Kjeldahl method and the Van Slyke nitrous acid procedure for the determination of primary amino groups yielded concordant results. Compound IX reacts readily with N-acetylsulfanilyl Fig. 1.-X-Ray diffraction patterns of the dimorphic chloride in aqueous acetonesolution to yield di-8forms (upper, m a . 130.5-131.5'; lower. m.p. 143.5144.5") ~ ~ ~ a c e ~ y ~ s u l f a n ~ ? y l ~ ~ n o e ~ y ~ acid, p~osp~o~c of 4-amino-4'-~-hydraxyethylaminwliphenylsulfone. which was isolated as the crystalline trihydrate of its sodium salt (X).Deacetylation of X by reacN-pSulfanilylphenylglycine' has been isolatedl tion 6 t h 19% hy&whloric acid at l o o ~during from the urine of a cat receiving I. This oxidation one hour produced crystalline in high yield, tests On the chemothera~uticac- This result demonstrates the resistance of the of I tivity and stability in vivo of the ethoxy derivative phosphoric ester linkage to acid hydrolysis, The (VIII). Compound VI11 Was Prepxed by the re- ester (X)was not hydrolyzed during two hours a t duction Of the corresponding nitro 37.5" and PH 5.0 by human prostatic phosphatase (VII). which resulted from the reaction of 1on =aum&glycerophosphate, 4500 bromo-2-ethoxyethane with 4-amino-4'-nitrodi- ,,its, per milk phosphatase g,), nor by cowts phenyl sulfone. The ethoxy derivative (VIII)is (activity on sodium p-glycerophosphate, 150 units Of mstauine hu- per 100 cc.) a t p H 9.0 in the presence of 0.1 molar more in aqueous man serum albumina than in water. The solubih- magnesium chloride, as indicated by the negative 10 mg. in wa- FiskeSubbaRow test for phosphate ion. Failure ties' Per 100cc. of solution a t 37" ter and 17.5 mg. in 3% albumin solution, the pH to hydrolyze the ester may be due to the speciof the latter solution being 5.1. ficitysof action of these enzymes for monoesters. The sulfanilamide derivatives, sodium di-8-N'HCI.H&THCH*O acetylsulfanilylaminoethylphosphate (X)and di>(OH) 8-sulfanilylaminoethylphosphoric acid dihydroHINCHICH~O chloride (XI), are related to the diaminodipheuyl IX sulfone derivatives with respect to the type of substituent in the amido group. The crystalline Sulfanilylamino-@-bromoethane(XIII)in pure
4-amino-4'-~-bromoethylaminodiphenyl sulfone
(VI).
(3) The albumin developed, from blood collected b s the American Red Crma. by the Depnltment of Physical Chemistry, Hnrvnrd Medical khool, Boston. Man?i.. under I contract recornmended by the Committee on Mcdird Research, between the Omcc OF %entifie R n e l r c h nod Development and Harvard Univerrifs. (4) Cf.Mlditcin. I.Phornarol. E s g . Theng., (11) 95, I02 11849); Heymann and Fieser. ibid.. 94, 102 (1948); Davis. J . Clin. I n m l . , 11,753 (1943).
151 Outhouse. Bierhem. 3.. 110, 197 (1936); 11, I460 (1937); Plimmer and Burch. ibid., SI, 398 (1937): Christensen. 3. Bioi. Chrm.. 185.399 (1940). ( 6 ) Coloniek and Cori. Pior. So
