Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2003-02-25
2004-06-22
Shippen, Michael L. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
Reexamination Certificate
active
06753451
ABSTRACT:
The present invention relates to a process for the preparation of phenylphenol compounds and to the use of the latter as antibacterial active substances.
The present process for the preparation of phenylphenol compounds of formula
is carried out in accordance with the invention by reaction of a keto compound of formula
with dioxolane of formula
and with an ammonium compound of formula
to form a &bgr;-aminoketone compound of formula
(reaction step (I)), reaction of the compound of formula (6) with a compound of formula
to form a compound of formula
(reaction step (II)), and subsequent alkylation to form a compound of formula (1) (reaction step (III)) in accordance with the following scheme:
In the above,
R
1
, R
2
, R
3
, R
6
and R
7
are each independently of the others hydrogen or C
1
-C
8
alkyl;
R
4
, R
5
and R
8
are each independently of the others hydrogen or C
1
-C
5
alkyl; and
Hal is a halogen atom.
C
1
-C
5
Akyl and C
1
-C
8
alkyl are straight-chain or branched alkyl radicals, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, octyl or isooctyl. Some or all of the alkyl radicals may be substituted by C
3
-C
6
cycloalkyl, for example cyclopropyl or cyclohexyl, or by C
1
-C
7
side-chain alkyls. Examples of side-chain alkyl radicals include dimethylpropyl, 1,1-dimethyloctyl and tert-butyl-hexyl.
Halogen is fluorine, bromine, iodine or, preferably, chlorine.
The 1,3-dioxolane of formula (4) used as reactant in reaction step (I) can simultaneously also be used as solvent, the amounts used being from 1 to 6 mol, especially from 1 to 5 mol, based on the keto compound of formula (3).
Reaction step (I) is preferably carried out at a temperature of from 60 to 95° C., preferably from 80 to 90° C.
Reaction step (II) is preferably carried out at a temperature of from 60 to 85° C., preferably from 70 to 85° C.
The reaction is preferably carried out in a mixture of ethanol and triethylamine or other suit-able solvents or solvent mixtures.
In formula (2), R
1
, R
2
and R
3
are preferably hydrogen.
R
4
and R
5
are preferably methyl or ethyl.
The compound of formula (7) is obtained by the reaction of chloroacetone and pyridine or substituted pyridine:
The reaction is preferably carried out in ethanol or other suitable solvents.
For the introduction of C
1
-C
8
alkyl radicals R
1
, R
2
, R
3
, R
6
and R
7
, reaction step (III) is preferably a Friedel-Crafts alkylation. The reaction is carried out in the presence of a Lewis acid, e.g. an aluminum halide, especially aluminum chloride, and where appropriate in the presence of a suitable solvent, for example methylene chloride, ethylene chloride, chloroform, CS
2
or nitrobenzene. The Lewis acid is used in an amount of from 1 to 3 mol, preferably from 1.25 to 2 mol, based on the compound of formula (2). There comes into consideration as the alkylation reagent for that reaction the corresponding alkyl halide R
1
-X, R
2
-X, R
3
-X, R
6
-X or R
7
-X, respectively, X preferably being chlorine. The reaction of the phenol compound of formula (2) with one equivalent of the alkyl halide yields compounds alkyl-substituted (R
7
) preferentially in the ortho position to the hydroxy group of the compound of formula (1). The reaction of the phenol compound of formula (2) with two or more equivalents of the alkyl halide yields di- or poly-alkylated compounds. Polyalkylation can also be carried out stepwise.
When R
1
, R
2
and R
3
in formula (2) are hydrogen, C
1
-C
8
alkyl radicals R
1
, R
2
and R
3
can preferably be introduced by Friedel-Crafts alkylation.
The present process is concerned more especially with the preparation of compounds of formula (1) wherein
R
1
, R
3
and R
6
are hydrogen and
R
2
and R
7
are C
1
-C
8
alkyl,
especially the preparation of the compound of formula
By way of example, further compounds that can be prepared in accordance with the process of the invention are as follows:
2-tert-butyl-5-phenylphenol
2,4-di-tert-butyl-5-phenylphenol
2-tert-butyl-4-(1,1-dimethylpropyl)-5-phenylphenol
2-tert-butyl-5-(4′-tert-butylphenyl)phenol
2-methyl-5-(4′-cyclopropylphenyl)phenol
2-octyl-5-(4′-cydohexyiphenyl)phenol
2-cyclohexyl-5-(4′-isopropylphenyl)phenol
2,4-diisopropyl-5-phenylphenol
2,4-dicyclopropyl-5-phenylphenol
2,4-dimethyl-5-phenylphenol
2-tert-butyl-5-(4′-isopropylphenyl)phenol
2-tert-butyl-5-(4′-cyclohexylphenyl)phenol
2-tert-butyl-4-(1,1-dimethyloctyl)-5-phenylphenol
2-(1-cyclopropylbutyl)-4-tert-butyl-5-phenylphenol
2-isooctyl-5-phenylphenol
2-cyclopropyl-5-phenylphenol
2-methyl-5-phenylphenol
2-(1-tert-butylhexyl)-5-phenylphenol.
The phenylphenol compounds prepared in accordance with the invention exhibit pronounced antimicrobial action, especially against pathogenic gram-positive and gram-negative bacteria and against bacteria of the skin flora, and also against yeasts and moulds. They are accordingly suitable especially for disinfection, deodorisation, and for general and antimicrobial treatment of the skin and mucosa and of integumentary appendages (hair), more especially for the disinfection of hands and wounds.
They are accordingly suitable as antimicrobial active ingredients and preservatives in personal care preparations, such as shampoos, bath additives, haircare preparations, liquid and solid soaps (based on synthetic surfactants and salts of saturated and/or unsaturated fatty acids), lotions and creams, deodorants, other aqueous or alcoholic solutions, e.g. cleansing solutions for the skin, moist cleansing cloths, oils or powders.
The invention accordingly relates also to a personal care preparation comprising at least one compound of formula (1) and cosmetically acceptable carriers or adjuvants.
The personal care preparation according to the invention contains from 0.01 to 15% by weight, preferably from 0.1 to 10% by weight, based on the total weight of the composition, of a compound of formula (1), and cosmetically tolerable adjuvants.
Depending upon the form of the personal care preparation, it comprises, in addition to the phenylphenol compound of formula (
1
), further constituents, such as sequestering agents, colourings, perfume oils, thickening or solidifying agents (consistency regulators), emollients, UV-absorbers, skin protective agents, antioxidants, additives that improve the mechanical properties, such as dicarboxylic acids and/or aluminium, zinc, calcium or magnesium salts of C
14
-C
22
fatty acids, and, optionally, preservatives.
The personal care preparation according to the invention may be in the form of a water-in-oil or oil-in-water emulsion, an alcoholic or alcohol-containing formulation, a vesicular dispersion of an ionic or non-ionic amphiphilic lipid, a gel, a solid stick or an aerosol formulation.
As a water-in-oil or oil-in-water emulsion the cosmetically tolerable adjuvant contains preferably from 5 to 50% of an oil phase, from 5 to 20% of an emulsifier and from 30 to 90% water. The oil phase may comprise any oil suitable for cosmetic formulations, for example one or more hydrocarbon oils, a wax, a natural oil, a silicone oil, a fatty acid ester or a fatty alcohol. Preferred mono- or poly-ols are ethanol, isopropanol, propylene glycol, hexylene glycol, glycerol and sorbitol.
Cosmetic formulations according to the invention are used in various fields. There come into consideration, for example, especially the following preparations:
skin-care preparations, e.g. skin-washing and cleansing preparations in the form of tab let-form or liquid soaps, soapless detergents or washing pastes,
bath preparations, e.g. liquid (foam baths, milks, shower preparations) or solid bath preparations, e.g. bath cubes and bath salts;
skin-care preparations, e.g. skin emulsions, multi-emulsions or skin oils;
cosmetic personal care preparations, e.g. facial make-up in the form of day creams or powder creams, face powder (loose or pressed), rouge or cream make-up, eye-care preparations, e.g. eyeshadow preparations, mascara, eyeliner, eye creams or eye-fix creams; lip-care preparations, e.g. lipsticks, lip gloss, lip contour pe
Hoffmann Martina
Nussbaum Klaus
Ciba Specialty Chemicals Corporation
Mansfield Kevin T.
Shippen Michael L.
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