Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
  • A01N33/02—Amines; Quaternary ammonium compounds
  • A01N33/12—Quaternary ammonium compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/41—Amines
  • A61K8/416—Quaternary ammonium compounds

Definitions

• This invention relates to novel germicidal, fungicidal and algicidal quaternary ammonium compounds and to methods for their preparation.
• my invention resides in quaternary ammonium compounds having the structural for- FORMULA I wherein R is alkyl having 1 to 22 carbon atoms, alkenyl having 3 to 22 carbon atoms or phenyl-lower-alkyl; R is lower-alkyl, lower-alkenyl or pheny'l-lower-alkyl; R" is higher-alkyl having 8 to 22 carbon atoms or higheralkenyl having 8 to 22 carbon atoms; An is an anion; v is the valence of An; and n is an integer equal to said valence.
• R is alkyl having 1 to 22 carbon atoms
• R is alkyl having 1 to 22 carbon atoms
• R is alkenyl having 3 to 22 carbon atoms, there are included, for example, allyl, methallyl, hexenyl, nnenyl, dodecenyl, hexadecenyl, nonadecenyl and eicosenyl.
• phenyl-lower-alkyl as used herein means a monovalent hydrocarbon radical consisting of phenyl bonded to one of the valences of a divalent lower-alkylene radical having one to four carbon atoms as exemplified by, but not limited to methylene, l,l-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,4-butylene, and the like.
• examples of phenyl-lower-alkyl are benzyl, 1 phenylethyl, 2-phenylethyl, 3-phenylpropyl, and the like.
• lower-alkyl includes, for example; methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, and n-heptyl; lower-alkenyl includes, for example, allyl, methallyl, 2-butenyl, l-hexenyl, and Z-heptenyl; higher-alkyl includes, for example, octyl, nonyl, tridecyl, hexadecyl, eicosyl, and docosyl; higher-alkenyl includes, for example, l-octenyl, l-hexadecenyl, 9-octadecenyl and l-doco
• anion means the anion of any salt-forming inorganic or organic acid.
• the choice of an anion is not critical to the operation of the processes of my invention. Accordingly, by way of illustration and without limitation thereto, anions that may be employed in the invention are, for example, bromide, chloride, i0- dide, fluoride, nitrate, sulfate, phosphate, acetate, formate, p-toluenesulfonate, phenoxyacetate, and the like.
• the choice of any particular anion will be dependent upon the particular use to be made of the quaternary ammonium salt.
• the anion is chosen from a pharmaceutically-acceptable saltforming inorganic or organic acid.
• a pharmaceutically-acceptable saltforming inorganic or organic acid is one whose anions are non-toxic and innocuous to the animal organism in elfective concentrations of the quaternary ammonium salts so that beneficial properties inherent in the common structural entity are not vitiated by side-effects ascribable to the anion.
• one of the objects of this invention is to provide tasteless quaternary ammonium antiseptics for oral use, I prefer to use salt-forming acids whose anions in combination with the quaternary ammonium compounds of my invention are tasteless. I have found that for this purpose, chloride and sulfate are the preferred anions.
• my invention resides in the process for preparing compounds of Formula I which comprises interacting a compound of the formula FORMULA II wherein R, A and R" have the same meanings indicated hereinabove, with a stoichiometric amount of a salt-forming acid, H An" wherein n and v have the meanings hereinbefore given, and approximately one molecular equivalent of (epoxyethyl)-benzene.
• the reaction is preferably carried out at a temperature between 50 and C. in water or a lower-alkanol having one to three carbon atoms.
• the tertiary amine of Formula II can be employed in the form of a previously isolated addition salt of the strong acid, in a preferred mode I interact the amine and the strong acid in situ in such a way that initially approximately 50 percent of the theoretical quantity of the acid is reacted with the amine. Then approximately half of the total amount of the (epoxyethyl)benzene to be employed is added to the mixture followed by the remainder of the acid and finally by the remainder of the (epoxyethyl)benzene.
• Another method suitable for preparing the new compounds of Formula I comprises alkylating a tertiary amine of Formula II hereinabove with a beta-hydroxyphenethyl halide.
• Quaternary ammonium salts heretofore used as germicidal and fungicidal agents have suffered from inherent drawbacks.
• One of these drawbacks is that such compounds are usually waxy solids or viscous liquids which tend to readily absorb moisture from the atmosphere. This renders the compounds difiicult to handle and makes it virtually impossible to supply the consumer with a form of the compound that can conveniently be dispensed in measured quantity.
• a preferred group of my biocidal N-fl-hydroxyphenethyl quaternary ammonium compounds are represented by the formula FORMULA III wherein R", An, n, and v have the meanings given hereinbefore.
• R an, n, and v have the meanings given hereinbefore.
• These compounds of Formula III are devoid of 3 the above-mentioned drawbacks.
• N,N- dimethyl N fi hydroxyphenethyl N myristylammonium chloride is incorporated in biocidally effective amount in a composition for oral hygiene, the composition is devoid of unpleasant taste, tingling sensation, and after-taste.
• N,N-dimethyl-N-fi-hydroxyphenethyl-N-myristylammonium chloride is a free-flowing, white powder which does not tend to absorb moisture from the air.
• organic tertiary amines used as starting materials for the preparation of the compounds of the present invention are either generally known in the art or are prepared by conventional alkylation processes, for example, the alkylation of the appropriate primary or secondary amine.
• the tertiary amine reactant is a mixture represented by the formula N,N-di (lower alkyl -N- [CH (CH Y] Formula IV wherein Y has the same significance indicated above.
• N,N-di lower alkyl -N- [CH (CH Y] Formula IV wherein Y has the same significance indicated above.
• a mixture consisting of alpha-olefins having from 8 to 20 carbon atoms is catalytically hydrochlorinated by adding hydrogen chloride to the double bond in the absence of actinic light or peroxides.
• the resulting 2-chloroalkane is caused to interact with a di-(lower-alkyl)amine to give Z-[di-(lower-alkyl)amino]alkane, which, when caused to interact with (epoxyethyl)benzene gives corresponding mixtures of the desired quaternary ammonium compounds.
• the hydrochlorination step has been found to proceed readily at reduced temperatures (040 C.) in the presence of a Lewis acid.
• the preferred Lewis acid is stannic chloride, but other Lewis acids, for example, aluminum chloride, ferric chloride, zinc chloride and the like are satisfactory.
• reaction of the mixed 2-chloroalkanes with a di (1ower-alkyl)amine is conveniently carried out in aqueous 4 solution, at a pressure of 5 00-1000 pounds per square inch and a temperature of about ZOO-250 C.
• the use of an excess of the amine reduces the formation of unwanted quaternaries at this stage of the process.
• the structure of the compounds of the invention is established by the mode of synthesis, by chemical analysis and by appropriate spectral properties.
• EXAMPLE 1 A stirred solution of 192 g. (0.795 mole) of freshlydistilled N,N-dimethylmyristylamine in 40 g. of anhydrous isopropyl alcohol was cooled to 20 C. During a period of thirty minutes at a temperature between 20 and 25 C., there was added dropwise 39.2 g. (0.397 mole) of 37% aqueous hydrochloric acid solution. The mixture was then heated to C. during a period of thirty minutes. At a temperature between 80 and C. there was added over a 1.5 hour period 49.6 g. (0.415 mole) of (epoxyethyl) benzene. The temperature of the mixture was maintained at 80-85" C.
• Phenol coefficients obtained for this product by standard biological testing procedure are- Organism: Phenol coefficient at 20 C. Staph. aureus 637 Sal. typhosa 667 Association of Official Agricultural Chemists, tenth edition, pages 87-439, Association of Oflicial Agricultural Chemists, Washington, DC, 1965. For example, a solution of 200 parts per million of N,N-dimethyl-N-B-hydroxyphenethyl- N-myristylammoniumchloride in water containing 600 parts per million of dissolved calcium and magnesium salts at 25 C., was found to kill in thirty seconds 99.999 percent or more of the viable cells of Escherichia coli at a concentration of 1X10 cells per milliliter.
• N,N-dimethyl-N-fl-hydroxyphenethyl-N myristylammonium chloride was substantially tasteless and when incorporated into a mouthwash composed of a 112000 aqueous solution, the resulting product had neither the bitter taste nor the metallic aftertaste usually found in such germicidal mouthwashes containing quaternary ammoniurn compounds.
• EXAMPLE 2 Using rapid stirring, 120.7 g. (0.5 mole) of freshlydistilled N,N-dimethylmyristylamine was treated at an initial temperature of 25 C. with 95.4 g. (0.25 mole) of 25.69% aqueous solution of sulfuric acid. The mixture became nearly solid and the temperature rose to about 40 C. Fifty ml. of distilled water was added and the mixture was heated to 70 C. To the mixture there was then added during a thirty minute period 62.0 g. (0.515 mole) of (epoxyethyl)benzene. During a period of ten minutes the mixture was heated to 100 C. and heating at 100 to 101 C. was continued for a total of three hours.
• the pH at he end of the heating period was between 7.0 and 7.1.
• the mixture was cooled to a temperature between 55 and 60 C. and 136 g. of acetone was added.
• the resultant solution was then cooled to C., and 408 g. of acetone was added.
• N,N-dimethyl-N-B-hydroxyphenethyl-N-myristylammonium sulfate separated, from solution. This solid was collected, washed with fresh acetone at 0 to C. and recrystallized from boiling acetone with the aid of decolorizing charcoal.
• the product was obtained as a colorless free-flowing solid, melting at 73.5 to 177 C.
• Phenol coefficients obtained for this product by standard biological testing procedure are- Organism: Phenol coefficient at 20 C. Staph. aureus 687 Sal. typhosa 667 This product was effective as a germicidal agent in hard water as determined by the Chambers test method (100. cit.). For example, a solution of 200 parts per million of N,N-dimethyl-N-fi-hydroxyphenethyl N myristylammonium sulfate in water containing 400 parts per million of I dissolved calcium and magnesium salts at 25 C., was found to kill in thirty seconds 99.999 percent or more of the viable cells of Escherichia coli at a concentration of 1X cells per milliliter.
• EMMPLE 9 EXAMPLE 11 Following the procedure given in Example 80, a mixture of N,N-dimethyl-2-hydroxy-2-(4-bromophenyl)ethyl- N-l-methylalkylammonium chlorides having an alkyl chain length of C -C is prepared from 1-(epoxyethyl)- 4abromobenzene and the mixture of the 2-dimethylamino alkanes described in Example 8B.
• compositions can also be prepared from the mixture of Z-dimethylaminoalkanes and the indicated (epoxyethyDbenzene according to the procedure given in Example 80:
• EXAMPLE 12 A 1:2000 solution of N,N-dimethyl-N18-hydroxyphenethyl-N-myristylammonium chloride in water was prepared. Then a 35.0 ml. portion of the solution was held in the mouth for one minute and then spat out. The solution had a flat taste with no bitterness. The mouth was then rinsed with one 35.0 ml. portion of water. No metallic after-taste or tingling sensation was detected.
• R OH 11 A compound of the formula R OH 11 wherein R is alkyl having 1 to 22 carbon atoms, alkenyl having 3 to 22 carbon atoms, or phenyl lower-alkyl;
• R is lower-alkyl, lower-alkenyl or phenyl lower-alkyl
• R is higher-alkyl having 8 to 22 carbon atoms or higheralkenyl having 8 to 22 carbon atoms;
• An is a pharmaceutically-acceptable anion, v is the valence of An; and n is an integer equal to said valence.
• R is alkyl having 1 to 22 carbon atoms
• R is lower-alkyl
• R" is higher-alkyl having 8 to 22 carbon atoms.
• a compound according to claim 4 which is N,N- dimethyl-N-fl-hydroxyphenethyl N myristylammonium chloride or sulfate.
• An aqueous biocidal composition which contains as an essential biocidal ingredient N,N-dimethyl-N-fi-h droxyphenethyl-N-myristylammonium chloride or sulfate according to claim 5.

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• Life Sciences & Earth Sciences (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Epidemiology (AREA)
• Birds (AREA)
• Agronomy & Crop Science (AREA)
• Pest Control & Pesticides (AREA)
• Plant Pathology (AREA)
• Engineering & Computer Science (AREA)
• Dentistry (AREA)
• Wood Science & Technology (AREA)
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• Environmental Sciences (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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Cited By (4)

• 1967
  • 1967-07-05 US US651134A patent/US3576873A/en not_active Expired - Lifetime
• 1968
  • 1968-06-26 GB GB30599/68A patent/GB1214734A/en not_active Expired
  • 1968-07-03 FR FR157727A patent/FR8078M/fr not_active Expired
  • 1968-07-05 CH CH1009068A patent/CH485657A/fr not_active IP Right Cessation
  • 1968-07-05 DE DE1768846A patent/DE1768846C3/de not_active Expired

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