Aliphatically unsaturated hydroxy benzoates and preservative compositions thereof

The hydroxybenzoate compounds of this invention are defined by the formula: ##STR1## wherein Y is hydrogen, hydroxy, halo, a C.sub.1 to C.sub.6 alkyl or a C.sub.2 to C.sub.6 alkyl ether; PA1 R is a C.sub.4 to C.sub.6 mono- or di-olefinically unsaturated hydrocarbon radical, a C.sub.4 to C.sub.7 mono- or di-acetylenically unsaturated hydrocarbon radical or a C.sub.2 to C.sub.3 acetylenically unsaturated hydrocarbon radical when at least one of X and Y is other than hydrogen and PA1 X is hydrogen, hydroxy, halo, a C.sub.1 to C.sub.6 alkyl, a C.sub.2 to C.sub.6 alkyl ether or ##STR2## PA1 in which A is selected from the group of X, PA2 B is selected from the group of Y and PA2 R.sub.1 is hydrogen, hydroxy, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy or --COOR.sub.2 in which R.sub.2 is C.sub.1 to C.sub.6 alkyl, a C.sub.2 to C.sub.6 olefinically unsaturated hydrocarbon radical or a C.sub.2 to C.sub.7 acetylenically unsaturated hydrocarbon radical. The invention also pertains to food, beverage, cosmetic, agrichemical and topically applied pharmaceutical compositions containing an effective preservative amount of the hydroxy aliphatically unsaturated benzoate having the formula: ##STR3## wherein X' is selected from the group of X; Y' is selected from the group of Y and R.sub.4 is a C.sub.2 to C.sub.6 mono- or di-olefinically unsaturated hydrocarbon radical or a C.sub.2 to C.sub.7 mono- or di-acetylenically unsaturated hydrocarbon radical.

BACKGROUND OF THE INVENTION
 Various species of p-hydroxy benzoic acid esters and their salts have found
 use as preservatives for foods and beverages as is disclosed in U.S. Pat.
 Nos. 2,046,324; 2,056,176; 3,767,827; 4,366,171 and 4,568,382. Although
 some of these esters possess preservative properties over a broad spectrum
 of fungicides, they exhibit low solubility in water which limits their
 use. Other hydroxy benzoates are effective only against gram positive
 microorganisms and several of these esters produce residues which are
 harmful to humans or the environment; accordingly their continued use has
 been barred.
 The foregoing drawbacks limit the selection of totally acceptable and
 effective fungicidal agents. Moreover, it has been found that closely
 related compounds exhibit quite different control abilities and
 microorganism selectivity. For example, heptyl p-hydroxybenzoate has been
 used at about 10 ppm as a beer preservative to kill saprogenous
 microorganisms; however it has limited solubility in beer so that the beer
 becomes turbid at about 0.degree. C. Similar drawbacks are noted for the
 treatment of soy and other beverages.
 To be commercially acceptable, the type of hydroxy benzoate must be
 moderately water soluble and leave no toxic residue, they should exhibit
 high activity at low concentrations against a broad spectrum of
 microorganisms and fungi and they must be economical to prepare and apply.
 Accordingly it is an object of this invention to achieve these aims in a
 hydroxy benzoate derivative which is modified so as to balance
 significantly improved water solubility with high anti microorganism and
 fungicidal activity against both gram positive and gram negative species.
 Another object of the invention is to provide non-toxic hydroxy benzoates
 by an economical and commercially feasible process. These and many other
 benefits of the invention will become apparent from the following
 description and disclosure.
 THE INVENTION
 In accordance with this invention there is provided new and useful hydroxy
 benzoates defined by the formula:
 ##STR4##
 wherein Y is hydrogen, hydroxy, halo, a C.sub.1 to C.sub.6 alkyl or a C2 to
 C.sub.6 alkyl ether;
 R is a C.sub.4 to C.sub.6 mono- or di-olefinically unsaturated hydrocarbon
 radical, a C.sub.4 to C.sub.7 mono- or di-acetylenically unsaturated
 hydrocarbon radical or a C.sub.2 to C.sub.3 acetylenically unsaturated
 hydrocarbon radical when one or both of X and Y is other than hydrogen and
 X is hydrogen, hydroxy, halo, a C.sub.1 to C.sub.6 alkyl, a C.sub.2 to
 C.sub.6 alkyl ether or
 ##STR5##
 in which A is selected from the group of X,
 B is selected from the group of Y and
 R.sub.1 is hydrogen, hydroxy, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6
 alkoxy or --COOR.sub.2 in which R.sub.2 is C.sub.1 to C.sub.6 alkyl, a
 C.sub.2 to C.sub.6 olefinically unsaturated hydrocarbon radical or a
 C.sub.2 to C.sub.7 acetylenically unsaturated hydrocarbon radical.
 Also in accordance with this invention there is provided food, beverage and
 cosmetic compositions containing an effective preservative amount of a
 hydroxy benzoates having the above formula except for substituent R, which
 in the case of the preservative composition for the above substances, can
 be a C.sub.2 to C.sub.6 olefinically unsaturated hydrocarbon radical or a
 C.sub.2 to C.sub.6 acetylenically unsaturated hydrocarbon radical.
 The present hydroxy benzoates exhibit good anti-microbial and fungicidal
 activity for a broad spectrum of gram negative and gram positive
 substances which cause deterioration of beverage, food, drug and cosmetic
 products, including alcoholic and non-alcoholic beverages, such as beer,
 ale, wines, fruit juices, milk, etc., frozen and canned meat, vegetable
 and fruit food products, bread and pastries, shampoo, face and body
 lotions, hair rinses and conditioners, bath oils and the like. The present
 hydroxy benzoate preservative is preferably incorporated with such food,
 beverage, topically applied drug or cosmetic products in a concentration
 of between about 0.1 and about 1.5 wt. %, most preferably between about
 0.2 and about 1 wt. %. In foods and beverages, less that 1 wt. % of the
 hydroxy benzoate is highly effective and can be incorporated as a water or
 aqueous solution.
 The present hydroxy benzoates achieve significantly improved water
 solubility and high anti-microbial and fungicidal activity which is
 achieved by a controlled lipophilic/hydrophilic balance between the
 substituents on the aromatic ring. The activity of the present compounds
 extends over a broad spectrum to include control of both gram negative and
 gram positive microorganisms and fungi including A. niger, B. cepacia, C.
 albicans, E. coli, P. aeruginosa, S. aureus, stephylococcus, salmonella,
 P. eugaris, S corepislac, myxo- and eu-mycotina and other mycota and
 organisms affecting comestable and cosmetic products.
 Particularly preferred among instant hydroxy benzoates are the propargyl
 dihydroxy benzoate, propargyl chloro hydroxy benzoate,
 2,4-hexadienyl-4-hydroxy benzoate, 2,4-hexadienyl-2,4-dihydroxy benzoate,
 1, 3-butadienyl-2,4-dihydroxy benzoate,
 1,3-butadienyl-3-chloro-2,4-dihydroxy benzoate, 3-butynyl-2,4-dihydroxy
 benzoate, and 3-butynyl-4-hydroxy benzoate.
 In each of the above benzoates, the lipophilic R group is selected to
 balance the remaining hydrophilic ring substituents, such as --OH, alkoxy,
 halo etc. It is now discovered that the activity of the preservative
 varies directly with the length of the hydrocarbon chain up to 6 carbon
 atoms in the R of the ester linkage; whereas the water solubility
 decreases and must be modified by selection of the hydrophilic ring
 substituents.
 The hydroxy benzoates of this invention can be prepared by contacting
 reactant the hydroxy benzoic acid
 ##STR6##
 in the presence of an alkali metal hydroxide with a coreactant which is the
 halide of the R group in the above benzoate formula and in the presence of
 a condensing agent, e.g. dicyclohexylcarbamide, in a 1:1-1:1.5 benzoate to
 agent mole ratio. The reaction is carried out in at least 40 wt. %
 solution containing a suitable solvent such as an alcohol, e.g.
 isopropanol, an ether, dioxane, tetrahydrofuran, acetone, methylene
 chloride and the like.
 Alternatively the benzoate can be prepared by reaction of the above hydroxy
 benzoic acid with the aliphatic alcohol coreactant corresponding to the R
 group in the above formula and in the presence of a condensing agent in a
 1:1-1:1.5 benzoate to agent mole ratio. This reaction is also carried out
 in at least a 40 wt. % solution of a suitable solvent of the above group,
 excluding alcohol.
 The mole ratio of reactant to coreactant in the above processes is
 generally between about 1:1 and about 2.5:1, preferably between about 1:1
 and 1.5:1 and the esterification reaction is carried out under constant
 agitation and at reflux temperature, e.g. between about 400 and about
 100.degree. C., preferably between about 500 and about 70.degree. C. over
 a period of from 2 to 24 hours, more often from 4 to 12 hours. The
 resulting solid reaction hydroxy benzoate product is then distilled or
 evaporated to remove solvent, extracted with for example methylene
 chloride followed by water washing and then dried.
 The hydroxybenzoates of this invention exhibit good water solubility and
 preservative properties for foods, beverages, cosmetics, soaps, creams and
 lotions and other formulations, e.g. agrichemical and pharmaceutical
 formulations.
 The hydroxybenzoates having the formula
 ##STR7##
 wherein X' is selected from the group of X; Y' is selected from the group
 of Y and R.sub.4 is a C.sub.2 to C.sub.6 mono- or di-olefinically
 unsaturated hydrocarbon radical or a C.sub.2 to C.sub.7 mono- or
 di-acetylenically unsaturated hydrocarbon radical; exhibit good water
 solubility and preservative properties for foods and beverages, cosmetic
 hair and skin care products such as, soaps, creams and lotions,
 pharmaceutical and agrichemical formulations including pesticides and
 fungicides as well as livestock pesticidal washes or dips.
 When employed as a preservative, effective concentrations of the hydroxy
 benzoates of formula II in the above mixtures can vary from as little as
 about 0.001 up to about 2.0%. The hydroxybenzoates in the above
 concentrations are readily dissolved in liquid foodstuffs, condiments and
 alcoholic or non-alcoholic beverages and can be added in an aqueous
 solution in any stage of a formulation. Formulations of these
 hydroxybenzoates can also be employed with a surfactant, thickener or any
 of the excipients normally included with an active cosmetic component in a
 formulation. Thorough mixing at about room temperature provides a desired
 homogeneous product.

Having generally described the invention, reference is had to the following
 examples which illustrate the preferred embodiments but which are not to
 be construed as limiting to the scope of the invention as set forth in the
 appended claims.
 METHODS FOR PREING THE HYDROXY BENZOATES
 EXAMPLE 1
 Propargylparaben
 p-Hydroxybenzoic acid (0.724 mole) and sodium hydroxide (0.724 mole) were
 dissolved in 50% isopropyl alcohol (400 ml). Propargyl bromide (0.724
 mole) was added and the solution was heated to reflux for 6 hours. The
 solution was then cooled and the isopropyl alcohol was removed under
 vacuum. The residue was taken up in methylene chloride (200 ml), washed
 with water (200 ml), aturated sodium bicarbonate, saline and dried over
 magnesium sulfate. Removal of the solvent yielded crude product, which was
 recrystallized, from CCI.sub.4 to give pure propargylparaben. (62.9%
 yield) m.p. 107-108.degree. C.
 EXAMPLE 2
 Propargyl 3,4-Dihydroxybenzoate
 Using the above procedure, 3,4-dihydroxybenzoic acid (0.0649 mole) and
 sodium hydroxide (0.0649 mole) were dissolved in 50% isopropyl alcohol
 (200 ml). Propargyl bromide (0.0649 mole) was added and the solution was
 heated to reflux for 6 hours. The solution was then cooled and the
 isopropyl alcohol was removed under vacuum. The residue was taken up in
 methylene chloride (200 ml), washed with water (200 ml), saturated sodium
 bicarbonate, saline and dried over magnesium sulfate. Removal of the
 solvent yielded crude product, which was recrystallized, from CCI.sub.4 to
 give the pure product. (68.0% yield) m.p. 127-129.degree. C.
 EXAMPLE 3
 Propargyl 2,4-Dihydroxybenzoate
 Using the above procedure, 2-4-dihydroxybenzoic acid (0.01 mole) and sodium
 hydroxide (0.01 mole) were dissolved in 50% isopropyl alcohol (200 ml).
 Propargyl bromide (0.01 mole) was added and the solution was heated to
 reflux for 6 hours. The solution was then cooled and the isopropyl alcohol
 was removed under vacuum. The residue was taken up in methylene chloride
 (200 ml), washed with water (200 ml), saturated sodium bicarbonate, saline
 and dried over magnesium sulfate. Removal of the solvent yielded crude
 product, which was recrystallized, from CCI.sub.4 to give the pure
 product. (26.6% yield) m.p. 104-106.degree. C.
 EXAMPLE 4
 Propargyl 3-Chloro-4-Hydroxybenzoate
 Using the above procedure, 3-chloro-4-hydroxybenzoic acid (0.0826 mole) and
 sodium hydroxide (0.0826 mole) were dissolved in 50% isopropyl alcohol
 (200 ml). Propargyl bromide (0.0826 mole) was added and the solution was
 heated to reflux for 6 hours. The solution was then cooled and the
 isopropyl alcohol was removed under vacuum. The residue was taken up in
 methylene chloride (200 ml), washed with water (200 ml), saturated sodium
 bicarbonate, saline and dried over magnesium sulfate. Removal of the
 solvent yielded crude product, which was recrystallized, from CCI.sub.4 to
 give the pure product. (64.3% yield) m.p. 144-145.degree. C.
 EXAMPLE 5
 2,4-Hexadienyl-4-Hydroxybenzoate
 p-Hydroxybenzoic acid (0.0724 mole) and 2,4-hexadienyl alcohol (0.0796
 mole) were dissolved in diethyl ether (100 ml). Dicyclohexylcarbamide
 (0.0796 mole) in diethyl ether (50 ml) was added and the solution was
 stirred for 6 hours. The solution was filtered and the diethyl ether was
 removed under vacuum. The residue was taken up in methylene chloride (200
 ml), washed with water (200 ml), saturated sodium bicarbonate, saline and
 dried over magnesium sulfate. Removal of the solvent yielded crude
 product, which was recrystallized, from CCI.sub.4 to give the pure
 propargylparaben. (55.3% yield) m.p. 65-67.degree. C.
 EXAMPLE 6
 2,4-Hexadienyl-2,4-Dihydroxybenzoate
 2,4-Dihydroxybenzoic acid (0.0649 mole) and 2,4-hexadienyl alcohol (0.0714
 mole) were dissolved in diethyl ether (100 ml). Dicyclohexylcarbamide
 (0.0714 mole) in diethyl ether (50 ml) was added and the solution was
 stirred for 6 hours. The solution was filtered and the diethyl ether was
 removed under vacuum. The residue was taken up in methylene chloride (200
 ml), washed with water (200 ml), saturated sodium bicarbonate, saline and
 dried over magnesium sulfate. Removal of the solvent yielded crude
 product, which was recrystallized, from CCI.sub.4 to give the pure
 propargylparaben. (41.5% yield) m.p. 82-84.degree. C.
 TEST METHODS
 Activity Test
 The present hydroxy benzoates were prepared in an emulsion of the
 composition: