Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-25
2003-07-15
Padmanabhan, Sreeni (Department: 1617)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S304400, C548S305400
Reexamination Certificate
active
06593476
ABSTRACT:
The present invention relates to a preparation process for 2-arylbenzimidazolesulfonic acids, to the use thereof as UV filters, and to cosmetic preparations which comprise compounds prepared according to the process of the invention.
A suntan of the skin to whatever degree is regarded in today's society as attractive and as an expression of vigor and health. As well as this desired effect of the sun on the skin, however, a number of undesired secondary effects arise, such as sunburn or premature skin aging and the development of wrinkles. A number of performance UV filters have been developed which, when applied to the skin in the form of creams, lotions or gels, can effectively delay the development of sunburn even when the incidence of solar rays is relatively high.
The UV filter present in the pharmaceutical or cosmetic preparation forms a film or a layer on the surface of the skin and does not penetrate into deeper skin layers with other care substances present in the preparation. Known UV filters or sun protection agents thus act only by absorbing certain regions of sunlight, meaning that this radiation cannot penetrate into deeper layers of the skin.
As is known, the most hazardous part of solar radiation is formed by the ultraviolet (UV) rays having a wavelength of less than 400 nm. The lower limit of the ultraviolet rays which reach the surface of the earth is limited by the absorption in the ozone layer of UV rays up to about 280 nm. The sun protection filters which are currently customary in cosmetics absorb in a wavelength range from 280 to 400 nm. This range includes UV-B rays having a wavelength between 280 and 320 nm, which play a decisive role in the formation of a solar erythema. This range includes also UV-A rays having a wavelength between 320 and 400 nm, which tan the skin but also age it, favors the triggering of an erythematous reaction or can exacerbate this reaction in certain people, or can even trigger phototoxic or photoallergic and irritative reactions.
The object of skin care cosmetics is to obtain the impression of a youthful skin. In principle, there are various ways of achieving this object. For example, existing skin damage, such as irregular pigmentation or the development of wrinkles, can be smoothed out by covering powders or creams. Another approach is to protect the skin against environmental influences which lead to permanent damage and thus aging of the skin. The idea is therefore to intervene in a preventative manner and thus to delay the aging process. One example of this approach is the UV filters already mentioned which, as a result of absorption of certain wavelength regions, prevent or at least reduce skin damage. Depending on the position of their absorption maxima, UV absorbers for cosmetic and dermatological preparations are divided into UV-A and UV-B absorbers, UV-A absorbers usually also absorb in the UV-B region and are thus alternatively referred to as broad-band absorbers or broad-band filters.
Of decisive importance for the formulation is the solubility of the filter substances in both the oil and water phases since it is necessary, particularly for establishing a high protection factor, to incorporate filters into all phases of a formulation. The oil-soluble UV-B filters include isooctyl methoxycinnamate, isoamyl methoxycinnamate and methylbenzylidenecamphor. Examples of water-soluble UV filters are, in particular, the salts of 2-phenylbenzimidazole-5-sulfonic acid, the use of which as an UV ray filter has already been described in German Reichspatent No. 676 103.
Various processes are known for the preparation of arylbenzimidazolesulfonic acids. An overview of the preparation of 2-substituted benzimidazoles is given, for example, in Chemical Reviews Vol. 74, No. 3, 1974 p. 279 et seq., e.g., the preparation according to V. G. Sayapin et al., KhGC [Chemistry of Heterocyclic Compounds] 6, 1970 630-632. The method therein takes place in a two-stage reaction in which 2-phenylbenzimidazole is prepared by either reaction 1,2-phenylenediamine and the bisulfite adduct of benzaldehyde, or by reacting phenylenediamine and benzoic acid in the presence of polyphosphoric acid. The 2-phenylbenzimidazole is then reacted with chlorosulfonic acid.
However, this process has big disadvantages:
It is a two-stage process and is thus complex and expensive.
In the first preparation process of phenylbenzimidazole
sodium hydrogensulfite must be used in large excess so that large amounts of sulfur dioxide are freed in the course of the work-up,
1-benzyl-2-phenylbenzimidazole may form as by-product, which can only be separated off with difficulty,
elemental sulfur is produced as by-product in colloidal, finely divided form which may pass into the end product.
In the second process of the preparation of phenylbenzimidazole from benzoic acid, phosphoric acid passes into the waste water, which is undesired because of eutrophication in lakes and rivers.
International application WO 93/15061 describes a process in which monosulfonated products are obtained directly in a single-stage process by the reaction of o-phenylenediamine with arylcarboxylic acids in 96% sulfuric acid as solvent.
The use of chlorosulfonic acid for the preparation of bisbenzimidazoloylsulfonic acids in a single-stage process is described in European patent application EP-A-669 323. Here, double sulfonation of the benzimidazole units is achieved by the chlorosulfonic acid. However, various problems are associated with the use of chlorosulfonic acid:
gas (HCl) is evolved during the reaction, making pressure regulation necessary,
collection and disposal of the aggressive and toxic gas (HCl) is required,
extremely corrosion-resistant apparatuses are required for the chloride-containing sulfuric acid which is formed,
recycling of the chloride-containing sulfuric acid resulting from the use of chlorosulfonic acid is only possible with difficulty.
There is therefore a need for an alternative process for the preparation of arylbenzimidazolesulfonic acids, in particular of at least disulfonated arylbenzimidazolesulfonic acids in which the problems discussed above do not arise.
It has now surprisingly been found that the preparation of said arylbenzimidazolesulfonic acid is possible using oleum instead of chlorosulfonic acid, avoiding the abovementioned problems.
The present invention provides a process for the preparation of 2-arylbenzimidazolesulfonic acids of the formula I
in which Ar is a substituted or unsubstituted phenyl or naphthyl radical and R is a C
1-8
-alkyl or C
1-8
-alkoxy radical, n is 1, 2, 3 or 4, m is 1, 2 or 3 and o is 0, 1 or 2. In this process, a o-phenylenediamine according to formula II
is reacted in the presence of sulphuric acid activated by oleum (activated sulfuric acid) with a compound according to formula III
where R1, R2, R3, R4 and R5, in each case independently of one another, are a radical such as an H, C
1-8
-alkyl, C
1-8
-alkoxy, hydroxyl, nitro, F, Cl, Br, I, COOH, COOR′, COCl, COBr or CN radical, X is a radical such as a —COOH, —COOR′, —COCl, —COBr, or —CN radical. R1 and R2 together, or R2 and R3 together, may also be a fused-on, optionally substituted phenylene unit, and R′ is a C
1-20
-alkyl radical. Examples of substituents of the phenylene unit are the same which define the radicals for R1, R2, R3, R4 and R5.
The use of oleum (sulfur trioxide) for the activation of the sulfuric acid has various advantages compared with the use of chlorosulfonic acid:
gas (HCl) is not evolved during the reaction, meaning that pressure regulation is not necessary,
accordingly, the collection and disposal of the aggressive gas (HCl) is not required,
while extremely corrosion-resistant apparatuses is required to handle the chloride-containing sulfuric acid which is formed when chlorosulfonic acid is used, the process with oleum can be carried out with less complex equipment,
after hydrolysis of the oleum, sulfuric acid is present which can be recycled with relative case, while the recycling of the chloride-containing sulfuric acid r
Heywang Ulrich
Pflücker Frank
Schwarz Michael
Merck Patent Gesellschaft mit Beschränkter Haftung
Millen White Zelano & Branigan P.C.
Padmanabhan Sreeni
Willis Michael A.
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