Process for preparing 2-arylbenzimidazole-5-sulfonic acids

The invention relates to an improved process for preparing 2-arylbenzimidazole-5-sulfonic acids of the formula I, ##STR1## in which Ar is unsubstituted phenyl or phenyl substituted by one or more C.sub.1 -C.sub.6 alkyl or alkoxy groups and PA1 m is 1, 2 or 3, PA1 wherein o-phenylenediamine is reacted in the presence of sulfuric acid at between room temperature and 250.degree. C. with a benzoic acid derivative of the formula II EQU Ar(--X).sub.m II PA1 in which Ar and m are as above, and X is COO-alkyl, where alkyl is n-alkyl having from 1 to 6 C atoms, COOH, COCl, COBr or CN, and new arylbenzimidazole acids of the formula Ia ##STR2##

This application is a 371 of PCT/EP93/00179 filed Aug. 27, 1993. 
The invention relates to an improved process for preparing 
2-arylbenzimidazole-5-sulfonic acids of the formula I, 
##STR3## 
in which Ar is unsubstituted phenyl or phenyl substituted by one or more 
C.sub.1 -C.sub.6 alkyl or alkoxy groups and 
m is 1, 2 or 3, 
wherein o-phenylenediamine is reacted in the presence of sulfuric acid at 
between room temperature and 250.degree. C. with a benzoic acid derivative 
of the formula II 
EQU Ar(--X).sub.m II 
in which Ar and m are as above, and X is COO-alkyl, where alkyl is n-alkyl 
having from 1 to 6 C atoms, COOH, COCl, COBr or CN. 
2-Phenylbenzimidazole-5-sulfonic acid (Eusolex 232) is an important 
water-soluble UV-B radiation filter with wide application in cosmetics. 
Its use as a UV radiation filter is described, for example, in German 
Reich Patent No. 676 103. 
Its preparation proceeds, according to, for example, V. G. Sayapin et al., 
KhGC [Chemistry of Heterocyclic Compounds] 6, 1970, 630-632, in a 
two-stage reaction in which 2-phenylbenzimidazole is first prepared from 
1,2-phenylenediamine and the bisulfite adduct of benzaldehyde or from 
phenylenediamine and benzoic acid in the presence of polyphosphoric acid, 
and is then reacted with chlorosulfonic acid. A survey of the preparation 
of 2-substituted benzimidazoles can be found, for example, in Chemical 
Reviews Vol. 74, No. 3, 1974 p 279 ff. 
##STR4## 
This process nevertheless has great disadvantages: 
a) It is a two-stage process and therefore more complicated and more 
expensive. 
b) Industrial handling of chlorosulfonic acid causes problems since 
2-phenylbenzimidazole disulfonic acids can be formed which can be 
separated out only with difficulty. 
c) In the first preparation processes for phenylbenzimidazole, sodium 
hydrogen sulfite must be used in large excess, so that large amounts of 
sulfur dioxide are given off during working up; 
1-benzyl-2-phenylbenzimidazole can be formed as a byproduct, which can be 
separated out only with difficulty. In the second process for preparing 
phenylbenzimidazole from benzoic acid phosphoric acid passes into the 
waste water, which is undesirable because Of eutrophication of water 
courses and lakes. 
The disadvantages of the abovementioned process can be conveniently 
circumvented: it has surprisingly been found that in the condensation 
reaction of 1,2-diphenylenediamine with benzoic acid in sulfuric acid at 
high temperatures intermediate products are directly sulfonated, so that 
2-phenylbenzimidazole-5-sulfonic acid is formed directly without isolation 
of an intermediate. 
DE 12 82 855 describes the use of 1,3-bis-(5-sulfobenzimidazol-2-yl)benzene 
as a water-soluble UV-B radiation filter. 
Its preparation proceeds analogously to that of 2-phenylbenzimidazole in a 
two-stage process. 
The invention thus relates to an improved process for preparing 
2-arylbenzimidazole-5-sulfonic acids of the formula I, 
##STR5## 
in which Ar is unsubstituted phenyl or phenyl substituted by one or more 
C.sub.1 -C.sub.6 alkyl or alkoxy groups and 
m is 1, 2 or 3, 
wherein o-phenylenediamine is reacted in the presence of sulfuric acid at 
between room temperature and 250.degree. C. with a benzoic acid derivative 
of the formula II 
EQU Ar(--X).sub.m II 
in which Ar and m are as above, and X is COO-alkyl, where alkyl is n-alkyl 
having from 1 to 6 C atoms, COOH, COCl, COBr or CN, 
in particular where from 1 to 10 mol, preferably from 3 to 8 mol, 
particularly from 4 to 7 mol of sulfuric acid are used per 1 mol of 
o-phenylenediamine. 
The invention further relates to such a process in which the benzoic acid 
derivative is introduced into the sulfuric acid, o-phenylenediamine of the 
formula II is subsequently added, and the mixture is heated to from 
150.degree. C. to 220.degree. C., or in which o-phenylenediamine and the 
benzoic acid derivative are introduced together into the sulfuric acid. 
A further preferred embodiment is a process in which the sulfuric acid is 
used as solvent, particularly in which 50-100% sulfuric acid is used 
and/or in which the solvent contains from 1 to 50% of water. 
In a particularly preferred embodiment of the process of the invention, the 
mixture of the reactants is stirred for about from 1 to 5 hours at 
temperatures between 80.degree. and 140.degree. C., subsequently heated to 
temperatures between 170.degree. and 250.degree. C. and stirred for 
another 0.5 to 5 hours. 
Carrying out the process of the invention per se is simple. The sulfuric 
acid, preferably in the form of a 50-100% solution, in particular as a 
concentrated about 96% solution, forms the initial charge. In general from 
1 to 10 mol, preferably from 3 to 8 mol, in particular from 4 to 7 mol of 
sulfuric acid are used per 1 mol of phenylenediamine. 
The method of adding the reactants benzoic acid and phenylenediamine is not 
critical. In general one of the two reactants is added at room 
temperature, which generally causes the mixture to warm to temperatures 
between 80.degree. and 140.degree. C. The second reactant is slowly added 
at this temperature, during which the temperature of the reaction mixture 
may rise further. 
The reaction mixture is subsequently heated slowly to temperatures between 
165.degree. and 250.degree. C., preferably between 175.degree. and 
200.degree.C., in particular to the boiling point of the mixture, and 
maintained at this temperature for from 1 to 5 hours, optionally with 
stirring. The reaction mixture is subsequently allowed to cool, preferably 
to temperatures between 100.degree. and 150.degree. C., and water is 
added. 
After stirring for a short time, preferably from 20 minutes to 2 hours, at 
from 50.degree. to 80.degree. C., the solid components are separated off, 
preferably washed with warm water and dried. 
Some of the compounds of the formula I are known and some are new. The 
invention relates also to the new compounds of the formula I, in 
particular the compounds of the formula Ia, in which m is 2 and Ar is a 
group of the formula 
##STR6## 
in which R is C.sub.1-6 -alkyl or alkoxy and n is 0, 1, 2, 3 or 4. 
Surprisingly, it has been found that the compounds of the formula Ia are 
suitable as water-soluble UV-A filters, whereas similar known compounds 
are UV-B filters. 
To purify the dried crude product, the latter is preferably suspended in 
water and neutralized with diluted base. After purification of the 
solution so obtained, preferably with activated carbon, it is preferably 
heated to temperatures between 50.degree. and 100.degree. C. and acidified 
with a mineral acid, preferably concentrated hydrochloric acid. The 
precipitated sulfonic acid is separated off, washed with preferably warm 
water and dried. 
In the formula I Ar is unsubstituted phenyl or phenyl substituted by one or 
more C.sub.1 -C .sub.6 alkyl or alkoxy groups, preferably unsubstituted 
phenyl or phenyl substituted, particularly in the 4-, 3-, 3,4- or 
3,5-position, by 1 or 2 C.sub.1 -C .sub.3 alkyl or alkoxy groups, in 
particular unsubstituted phenyl. In the case where m=2 Ar is preferably 
1-, 3- or 1,4-phenylene, in particular 1,4-phenylene. In the case where 
m=3 Ar is preferably benzene-1,3,5-triyl. In the formula II X is 
COO-alkyl, in which alkyl is n-alkyl having from 1 to 6 C atoms, 
preferably 1 or 2 C atoms, COOH, COCl or CN, preferably COOH, COOCH.sub.3, 
COCl or CN, in particular COOH or CN. 
The advantages of the process over the previously mentioned processes are: 
a) Simple single-stage process, no difficulties with pH control. 
b) The product is not contaminated by 
1-benzyl-2-phenylbenzimidazole-6-sulfonic acid and 
2-phenylbenzimidazoledisulfonic acids. 
c) No elemental sulfur is formed, so that the waste water has a 
substantially lower chemical oxygen demand. 
d) The intermediate products can be very simply and quickly centrifuged off 
and washed. 
e) The yield is comparable to or greater than that in the processes known 
from the prior art. 
f) Addition of sodium hydrogen sulfite is not needed, so that handling of 
sulfur dioxide is no longer necessary either. 
The invention further relates to cosmetic preparations which contain an 
effective amount of at least one compound of the formula Ia in a carrier 
suitable for cosmetics. 
Preference is given to such cosmetic preparations which contain from 0.1 to 
10% by weight, preferably from 0.4 to 1.0% by weight, in particular about 
0.5% by weight, of at least one compound of the formula Ia, in particular 
preparations which additionally contain a UV-B filter. 
The invention further relates to the use of the compounds of the formula Ia 
as a cosmetic product or as a medicament. 
The invention furthermore relates to the compound of the formula Ia for use 
in the preventive treatment of inflammations and allergies of the skin, 
and for use in the prevention of certain types of cancer. 
The invention likewise relates to pharmaceutical preparations which contain 
an effective amount of at least one compound of the formula Ia in a 
physiologically tolerated carrier or excipient, in particular for topical 
application. 
The invention furthermore relates to the use of the compounds of the 
formula Ia as medicaments. 
Even without further explanations it is assumed that a person skilled in 
the art can use the above description in the widest scope. The preferred 
embodiments are hence to be taken as only descriptive, not as an in any 
way limiting disclosure. 
The complete disclosure of all applications, patents and publications cited 
above or below, and the corresponding application P 42 03 072, filed on 
04.02.92, granted on 03.07.92 as German Patent DE-42 03 072 C, is 
incorporated into this application by reference.

The examples below are intended to illustrate the invention. 
Example 1 
A 1 1 three-necked flask is initially charged with 275 g (2.70 mol) of 96% 
sulfuric acid and subsequently 54.1 g (0.50 mol) of 1,2-phenylenediamine 
are carefully introduced. 85.5 g (0.70 mol) of benzoic acid are added to 
the suspension, which at this point has a temperature of about 120.degree. 
C., and the mixture is heated while stirring (clear solution from about 
130.degree. C.) to about 200.degree. C. for 5 hours, during which a small 
proportion of the benzoic acid sublimes. The mixture is then allowed to 
cool to about 150.degree. C. and is stirred into 1 l of cold water, which 
warms to about 65.degree. C. The mixture is stirred for a further hour at 
65.degree. C. and the precipitate is then filtered off with suction and 
washed with water at a temperature of 80.degree. C. until free of sulfate. 
The dried crude product (83 g) is suspended in 830 ml of water and the pH 
is adjusted to 8 with 32% sodium hydroxide solution. After addition of 6.5 
g of activated carbon the mixture is stirred for a further 30 minutes at 
room temperature and subsequently clarified by filtration. The filtrate is 
heated to 80.degree. C. and the pH is adjusted to 3 with concentrated 
hydrochloric acid. The precipitated Eusolex 232 is filtered off with 
suction while warm, washed with 2 l of water at a temperature of 
90.degree. C. and dried to constant weight in a vacuum drying cabinet at 
75.degree. C. and 20 mbar. 67.0 g (245 mmol, 49% of theory) of 
2-phenylbenzimidazole-5-sulfonic acid are obtained, 410.degree. C. 
(decomposition). 
The compounds below are prepared analogously: 
2-(4'-methoxyphenyl)benzimidazole-5-sulfonic acid 
2-(3'-methoxyphenyl)benzimidazole-5-sulfonic acid 
2-(4'-ethoxyphenyl)benzimidazole-5-sulfonic acid 
2-(3'-ethoxyphenyl)benzimidazole-5-sulfonic acid 
2-(3',5'-dimethoxyphenyl)benzimidazole-5-sulfonic acid 
2-(3',4'-dimethoxyphenyl)benzimidazole-5-sulfonic acid 
2-(3',5'-diethoxyphenyl)benzimidazole-5-sulfonic acid 
2-(3',4'-diethoxyphenyl)benzimidazole-5-sulfonic acid. 
Example 2 
The procedure is as in Example 1 but using 72.2 g (0.70 mol) of 
benzonitrile instead of benzoic acid. 72.0 g (263 mmol, 53% of theory) of 
2-phenylbenzimidazole-5-sulfonic acid are obtained. 
Example 3 
The procedure is as in Example 1 but using 95.3 g (0.70 mol) of methyl 
benzoate instead of benzoic acid. 64.0 g (233 mmol, 47% of theory) of 
2-phenylbenzimidazole-5-sulfonic acid are obtained. 
Example 4 
A 1 l three-necked flask is initially charged with 275 g (2.70 mol) of 96% 
sulfuric acid and subsequently 85.5 g (0.70 mol) of benzoic acid are 
introduced. 54.1 g (0.50 mol) of 1,2-phenyleneamine [sic] are carefully 
added, during which the mixture warms to about 100.degree. C.; the mixture 
is then heated while stirring (clear solution from about 130.degree. C.) 
to about 180.degree. C. for 2 hours, during which a small proportion of 
the benzoic acid sublimes. The mixture is then stirred into 1 l of cold 
water, which warms to about 65.degree. C. The mixture is stirred for a 
further hour at 65.degree. C. and the precipitate is then filtered off 
with suction and washed with water at a temperature of 80.degree. C. until 
free of sulfate. The dried crude product (83 g) is suspended in 830 ml of 
water and the pH is adjusted to 8 with 32 % sodium hydroxide solution. 
After addition of 6.5 g of activated carbon the mixture is stirred for a 
further 30 minutes at room temperature and subsequently clarified by 
filtration. The filtrate is heated to 80.degree. C. and the pH is adjusted 
to 3 with concentrated hydrochloric acid. The precipitated Eusolex 232 is 
filtered off with suction while warm, washed with 2 l of water at a 
temperature of 90.degree. C. and dried to constant weight in a vacuum 
drying cabinet at 75.degree. C. and 20 mbar. 67.0 g (245 mmol, 49% of 
theory) of 2-phenylbenzimidazole-5-sulfonic acid are thus obtained. 
Example 5 
A 2 l four-necked flask is initially charged with 182 ml of distilled 
water, and 1533 g (15 mol) of 96% sulfuric acid are carefully added. 367 g 
(3.0 mol) of benzoic acid are introduced into the sulfuric acid, which at 
this point has a temperature of about 100.degree. C., over a period of 
about 10 minutes while stirring vigorously (during this the temperature 
drops to about 80.degree. C.). The mixture is subsequently heated to an 
internal temperature of 100.degree. C., the benzoic acid dissolving almost 
completely. 325 g (3.0 mol) of 1,2-phenylenediamine are subsequently 
metered in at such a rate that the temperature of the mixture does not 
rise above 125.degree. C. After completion of the addition the mixture is 
heated to reflux temperature (about 178.degree. C.) and stirred for a 
further 6 hours at this temperature, during which a small proportion of 
the benzoic acid sublimes. The mixture is then stirred into 6 l of water 
at a temperature of 100.degree. C. and then stirred for a further 30 
minutes at 100.degree. C. and the precipitate is then filtered off with 
suction and washed with 2 l of water at a temperature of 80.degree. C. 
until free of sulfate. The dried crude product (580 g, 70% of theory) is 
suspended in 2.5 l of water and the pH is adjusted to 8 with 32% sodium 
hydroxide solution. After addition of 20 g of activated carbon the mixture 
is stirred for a further 60 minutes at room temperature and subsequently 
clarified by filtration. The filtrate is heated to 80.degree. C. and the 
pH is adjusted to 3 with concentrated sulfuric acid. The precipitated 
product is filtered off with suction while hot, washed with 4 l of water 
at a temperature of 90.degree. C. and dried to constant weight in a vacuum 
drying cabinet at 75.degree. C. and 20 mbar. 493 g (1.8 mol, 60% of 
theory) of 2-phenylbenzimidazole-5-sulfonic acid are thus obtained. 
Example 6 
A 2 l four-necked flask was initially charged with 1022 g (10 mol) of 96% 
sulfuric acid. 166.1 g (1 mol) of terephthalic acid are introduced into 
this over a period of about 10 minutes while stirring vigorously. A 
solution at a temperature of 80.degree. C. and containing 216.6 g (2.0 
mol) of 1,2-phenylenediamine in 140 ml of fully deionized water is metered 
into the sulfuric acid at such a rate that the temperature of the mixture 
does not rise above 130.degree. C. After completion of the addition the 
mixture is heated to from 175.degree. to 180.degree. C. and stirred for 
about 4 hours at this temperature. During this time water is distilled off 
under reduced pressure. At the end of the reaction time the hot mixture is 
stirred into 4 l of water at a temperature of 80.degree. C. The mixture is 
again allowed to cool to 80.degree. C., the precipitate is filtered off 
with suction and washed with 2 l of water at a temperature of 80.degree. 
C. The crude product is suspended in 2.5 1 of water and the pH is adjusted 
to 8 with 32% sodium hydroxide solution. After addition of 20 g of 
activated carbon the mixture is stirred for a further 60 minutes at room 
temperature and subsequently clarified by filtration. The filtrate is 
first adjusted to a pH of 6.0 with concentrated sulfuric acid and then 
heated to 80.degree. C. The pH is subsequently adjusted to 2.0 with 
concentrated sulfuric acid (temperature rise to about 100.degree. C.). The 
mixture is again allowed to cool to 80.degree. C., the precipitate is 
filtered off with suction and washed with 1 l of water at a temperature of 
80.degree. C. (Test for freedom from sulfate). The final product is dried 
to constant weight in a vacuum drying cabinet at 75.degree. C. and about 
20 mbar. 306 g (65%) of 1,4-bis-(B-sulfobenzimidazol-2'-yl)benzene are 
thus obtained. The spectra of the new compounds are as expected 
(.lambda..sub.max =349 nm). 
The compounds below are prepared analogously: 
From isophthalic acid: 
1,3-bis-1(5-sulfobenzimidazol-2'-yl)benzene [sic] (.lambda..sub.max =307 
nm). 
From 1,3,5-benzenetricarboxylic acid: 
1,3,5-tris(5-sulfobenzimidazol-2'-yl)benzene.