[CONTRIBUTION FROM THE
DANIELS I E F F RESEARCH INSTITUTE]
FURTHER ACYLATION EXPERIMENTS WITH SULFANILAMIDE AND HETEROCYCLIC AMINES FELIX BERGMANN
AND
DAVID SCHAPIRO
Received June $6, 19& PART I1
In a previous communication (1) some rules were suggested for the condensation of aromatic amines with dicarboxylic acid anhydrides. It was found that heterocyclic amines in general behave like their isocyclic analogs, with the exception that maleic anhydride failed to give imide derivatives, which are formed with such extreme ease with succinic or phthalic anhydrides. This exception was especially surprising in the sulfanilamide series, where it was observed that citraconic anhydride yielded as the only reaction product the cyclic imide (2). It seemed worth while to investigate further the peculiar position of maleic anhydride. It was first suspected that the compounds of the series RNHCOCH=CHCOOH derived from maleic anhydride might possess trans structure. It is admitted that cis-trans isomerization has never been observed under the influence of a sulfonamido group. On the other hand, it is known (3) that pyridine is an excellent catalyst for this transformation, so that a similar effect of the tertiary nitrogen in sulfapyridine or 6-methoxy-8-aminoquinoline (1) was not a priom' to be excluded. However, condensation of fumaroyl chloride ethyl ester with sulfanilamide yielded a substance (I) entirely different from the esterification product of maleamidosulfanilamide. Moreover, in the latter reaction a small amount of the imide I1 was formed. Again, the same series of reactions with 6-methoxy-8-aminoquinolinerevealed the essential difference between the cis and trans forms of 111. On the other hand, we now find that citraconic anhydride behaves as predicted, in that the amide acids IV and VI are formed at room temperature and at 50°, and are cyclized to the corresponding imides V and VI1 a t about 100' and 80" respectively. In previous experiments (2) recrystallization from boiling water was sufficient to effect the cyclization of IV.
I/
( p ) NHZSOzCifLNHCOCH CHCOzCzHs
(PI N H 2 s 0 2 c 6 H 4 ~ / c o ~ H
\
CO-CH
*I
I1
NHCOCH=CHCO~H
I11 419
420
F. BERGMLW AND D. SCHAPIRO
( p ) NH2SO2C6H4NHCOCH=&CO2H
CO-CH
L
IVa
NHd302C6HaN
7
Ii
\
CO-CCHa
( p ) NH~S02Ce.H;NHCOC=CHCO~H
I
CH3
V
1%
The different behavior of maleic and citraconic anhydrides probably must be ascribed to the influence of the methyl substituent. It has been found by Ashton (4)that the ratio of the two dissociation constants is, respectively, for 1 1 for 0.01 and for citraconic acid K - X maleic acid K - = K~ 1.3 x 10-4 Kz 6.2 X lo-' molar solutions. It can be concluded that the larger difference in acidity between the two carboxyl groups of maleic acid causes their different ability to condense with amino groups. We feel, however, that this explanation is unsatisfactory, and shall attack the problem by physical methods.
Cc"""^7%
NHCOCH=CCOzH VIa
I'
/
P f i C H 3
7 {XWCO-CH N
'\/
NHCOC=CHCO,H
I
i
CO--CCHo VI1
CH, VIb
In view of the low toxicity of the sodium salt of N4-sulfanilamidomaleicacid, it was of interest to determine the corresponding figure for the trans isomer. Both derivatives show about the same toxicity in white mice: Lethal dose of the cis form, 4.5 g./kg.; lethal dose of the trans form, 4.0 g./kg. EXPERIMENTAL
Ethyl N4-sulfanilamidomaleate. Condensation between sulfanilamide (17.2 g.) and maleic anhydride (11 9 . ) (5)was easily effected in acetone (150 cc.). The solution turned immediately yellow and became warm. The maleamidosulfanilamide crystallized soon in quantitative yield; m.p. 209-210". Esterification of this compound (13.5 g.) was carried out in boiling absolute ethanol (100 cc.) with 2 cc. of sulfuric acid. I n the course of one hour the amide acid went completely into solution. After twelve hours standing, small amount of white crystals settled down (11). These, when recrystallized from butanol-
ACYLATION OF SULFANILAMIDE
421
pyridine, formed colorless prismatic rods, without a definite melting point. After sintering a t 220"' the substance remained semi-solid to about 285", when i t decomposed. Anal. Calc'd for ClaHsSz04S:C, 47.6; H , 3.2; N , 11.1. Found: C, 47.5; H , 2.8; N , 11.2. The filtrate of I1 was concentrated on a steam-bath and the ester precipitated by addition of water. From butanol, yellowishleaflets, m.p. 204205' (cis form of I). Anal. Calc'd for C1zHlaNzO~S: C, 48.3; H, 4.7; N, 9.4. Found: C, 48.6; H , 4.9; N, 9.5. Condensation of sulfanilamide with maleic anhydride in boiling dioxane or xylene likewise yielded the amide acid of m.p. 209". Melting of the two components at 150-160' gave a yellow powder, which was soluble only in pyridine and could not be recrystallized. Ethyl Nkwlfanilamidofumarate. T o a solution of fumaroyl chloride ethyl ester (4 g.) in acetone (15 cc.) was added dropwise a solution of sulfanilamide (4.5 9.) in acetone (25 cc.) and pyridine (2 cc.). After evaporation of the solvent, the residue crystallized. Recrystallization from ethyl benzoate with a little pyridine yielded the ester (I) as a white, microcrystalline powder, m.p. 219'. Anal. Calc'd for C l Z H l 4 N ~ ON~ ,S9.4; : O C Z H ~15.1. , Found: N, 9.2; O C Z H ~15.1. , The ester was saponified easily with sodium hydroxide a t room temperature, and the trans acid precipitated with hydrochloric acid. It was purified by several reprecipitations, and finally by recrystallization from glacial acetic acid; m.p. 295'. Anal. C a l c ' d f 0 r C ~ ~ I - I ~ ~ NC,44.4;H, ~ 0 ~ S : 3.7;N, 10.4. Found: C , 4 4 . 5 ; H , 3 . 7 ; N , 1 0 . 5 . Condensation of sulfanilamide with citraconic anhydride (ZV and V ). Sulfanilamide (8.6 g.) was dissolved in dioxane (40 cc.) and a solution of citraconic anhydride (5.6 g.) in dioxane (10 cc.) was added dropwise a t $5". The reaction product was filtered off after twelve hours standing. It is easily soluble in cold sodium carbonate solution, and therefore represents the acid (IV a or b) ; yield quantitative. After reprecipitation of the sodium salt of IV with hydrochloric acid, the acid IV shows the m.p. 175". At the melting temperature gas is evolved (water), the product solidifies, and melts again at about 210'. Recrystallization of the acid IV from 50% acetic acid gave only the imide V as fine needles, m.p. 217-218' (2). Anal. of acid (ZV). Calc'd for CllH1~NZO5S: C, 46.5; H, 4.2. Found: C, 46.8; H, 4.4. 6-~Methoxyquinoline-8(N-maleamido acid) ethyl ester (ZZZ,--COOCzHs in place of-COOH). Condensation is best accomplished by dissolving 6-methoxy-8-aminoquinoline and maleic anhydride in acetone and boiling for two minutes. The mixture solidifies immediately, and the acid I11 (cis form) is obtained in quantitative yield; m.p. 225". Four grams of this amide acid in ethanol (35 cc.) was boiled with 2 cc. of concentrated hydrochloric acid for six hours. The reaction product crystallized slowly; from butanol, long yellow rods, m.p. 212" (with decomp.). This hydrochloride of the ester of I11 retains half a molecule of water, which cannot be removed by drying without loss of hydrogen chloride. For analysis, the substance was dried a t 56". Anal. Calc'd for C l ~ H l s N z 0 4 ~ H C0.5 l HzO; C, 55.7; H , 5.2; N, 8.1. Found: C, 55.8, 55.9; H , 5.5, 5.4; N , 8.4. The free ester-base was obtained by trituration of the above product with cold ammonia. Recrystallization was extremely difficult and could be effected only by short boiling with nitrobenzene, prolonged boiling causing decomposition; long fine needles of m.p. 177'. Anal. Calc'd for CI6H16N204:C, 64.0 H , 5.3; N , 9.3. Found: C, 63.85; H, 5.0; N , 9.1. 6-Methoxyquinoline-8(N-furnaramido acid) ethyl ester (transform of ZZZ,--COOCZH~ i n place of --COOH). Fumaroyl chloride ethyl ester (4 g.) was dissolved in acetone (20 cc.) and added dropwise to a solution of 6-methoxy-8-aminoquinoline (4g.) in acetone (15 cc.). Every drop produced a yellow precipitate of the hydrochloride. The product was filtered
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422
F. BERGMANN AND D. SCHAPIRO
off and recrystallized from butanol; sharp rods, m.p. 195" (decomp.), yield quantitative. During recrystallization, partial hydrolysis of the hydrochloride occurred; therefore i t was necessary to add a few drops of hydrochloric acid to the recrystallization mixture. Anal. Calc'd for ClsHleNz04.HC1:N , 8.3; OCH3 OCPHS,22.3. Found: N , 8.4; OCHI OCZH~, 21.6. The free ester-base was obtained by treating the above hydrochloride with ice-cold ammonia and was recrystallized from isopropanol; rods, m.p. 105". Anal. Calc'd for CleHlsN~O4:C, 64.0; H , 5.3; N , 9.3; OCH3 OCZH,25.3. Found: C, 64.3; H , 5.7; N , 9.4; OCH3 OCzH5,25.6. The ester-base was not saponified by sodium hydroxide at room temperature. At 100" only the free aminoquinoline was obtained. 6-Methoxyquinoline-8-citraconimide(VZZ) . The quinoline base (1.7 g.) and citraconic anhydride (1.2 g.) were dissolved in acetone (15 cc.). A red color appeared immediately, and the mixture solidified after two minutes. After washing with ethanol, the crystals showed the m.p. 131"; yield 90%. No method other than reprecipitation was found to purify the acid VI. Even from methyl ethyl ketone, the imide VI1 was obtained in beautiful prisms, m.p. 179". From 30y0 ethanol, there was first precipitated a mixture of VI and VII, which was converted completely into VI1 by longer boiling. Anal. of VZZ. Calc'd for C16HlzN203:C, 67.2; H , 4.5; N , 10.4. Found: C, 67.1; H, 4.3; N , 9.9.
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PART I11
In the search for derivatives of 6-rnethoxy-8-aminoquinolinewith antimalarial activity, it was soon found (6) that the aliphatic chain introduced into the amino group must possess a strong basic center, in order to give the substance sufficient solubility in the body fluids, and in this way plasmoquine (VIII) and its homologs were developed (7). The question arises, how far the specific structure of the side chain in (VIII) is necessary for the desired chemotherapeutic effect. We therefore attempted to replace the -NHCHz-group by the -NHCO-grouping. Condensation of 6-methoxy-8-aminoquinoline with P-chloropropionyl chloride yielded the acyl amide of IX, but our attempts to exchange the &chlorine with diethylamine invariably led to the acroyl derivative X by splitting off hydrogen chloride. When the derivative IX was heated alone in ethanol for 10 hours, it was recovered unchanged. Therefore, it is concluded that the elimination of hydrogen chloride is due to the action of diethylamine and not to the influence of the tertiary quinoline nitrogen.
COOCH3 LOCH3
C O O NHCOCH=CHz C H 3
NHCH(CHJ iN"CzHd2
I
NHCOCHiCHiCl
CHs
VI11
Ix
X
The behavior of the @-chloropropionylcompound IX is surprising, in view of the fact that ethyl 8-chloropropionate easily exchanges its halogen with dialkylamines (8), and that even ethyl acrylate is transformed a t 100' into ethyl b-diethylaminopropionate (9).
ACYLATION OF SULFANILAMIDE
423
EXPERIMENTAL
6'-Methoxy-8(~-chloropropionylamido)quinoline(ZX), To a solution of 6-methoxy-8aminoquinoline (4.4 9.) in benzene (25 cc.) was added dropwise P-chloropropionoyl chloride (3.5 g.) in benzene (10 cc.) a t 0". After twelve hours, the crystals (6.5 g.) were removed by filtration. The crude hydrochloride of IX melted a t 185-190" and was converted into the free base by trituration with sodium carbonate; from 90% ethanol, needles m.p. 104". .4nal. Calc'd for CI3Hl3C1N202:N , 10.6. Found: N, 10.8. 6-Methoxy-8-acroylaminoquinoline( X ) . Five grams of IX in methanol (20 cc.) and diethylamine (4 cc.) was boiled for 3 hours. After evaporation of the solvent, the residue was shaken with ether and soda solution, and the ethereal layer dried over sodium carbonate. The base X was purified by distillation, b.p. 210' (0.4 mm.). The yellow oil was triturated with methanol and recrystallized with ethanol; prismatic rods, m.p. 119-120". .4nal. Calc'd for Cl3HI2N2O2: N, 12.3; OCH3, 13.6. Found: N , 12.5; OCH3, 13.3. The hydrochloride of X was precipitated from ethanol solution by addition of ethanolic hydrogen chloride. Recrystallization from ethanol gave prismatic plates, m.p. 208'. When the acroyl derivative X was dissolved in chloroform and bromine added, a vigorous reaction occurred. The residue which was left after evaporation of the solvent was triturated with cold sodium hydroxide and recrystallized from butyl acetate; long, yellowish needles, m.p. 171-172". .4naZ. Calc'd for C13H12Br2N202:C, 40.2; H, 3.1. Found: C, 40.7; H, 2.9. SUMMARY
I. Condensation of sulfanilamide and 6-methoxy-8-aminoquinoline with maleic or fumaric acids, respectively, gives different reaction products. The geometrical structure of the unsaturated acid remains, therefore, unaffected. 2. Citraconic anhydride, in contrast to maleic anhydride, shows a very pronounced inclination to form cyclic imides. The theoretical basis for the different behavior of the two unsaturated homologs is discussed. 3. Attempts to introduce the side chain -COCH2CHzN(C2H& into the amino group of 6-methoxy-8-aminoqu$oline failed. REHOVOTH, PALESTINE REFERENCES (1) SCHAPIRO AND F. BERGMANN, J. Org. Chem., 6, 774 (1941). (2) F. BERGMANN AND HASKELBERG, J. Am. Chem. SOC.,63, 2243 (1941). (3) PFEIFFER, Ber., 47, 1592 (1914). (4) ASHTONAND PARTINGTON, Trans. Faraday SOC.,30, 598 (1934). AND MOORE,J. Am. Chem. Soc., 61, 1198 (1939). (5) MILLER,ROCK, (6) BALDWIN, J. Chem. SOC.,1929, 2959. (7) HORLEIN, Naturwissenschaften, XIV, 1154 (1926). (8) WILLST~TTER, Ber., 36, 584 (1902); FUSON, J. Am. Chem. SOC.,60,1444 (1928). (9) FL~RSCHEIM, J. prakt. Chem., (2), 68,347 (1903);MORSCH, Monatsh, 63,220 (1933).
