CA1059124A - Quaternary compounds and oral compositions containing said compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Novel quaternary ammonium compounds useful as anti-microbial, anti-caries and anti-calculus agents in oral compositions wherein a higher aliphatic or alicyclic group is linked to the quaternary ammonium by a functional group such as ether, thioether, carboxylic ester, carboxamide, keto, carbamate ester, thiocarbamate ester, alcohol or hydrocarbon.

Description

The present invention relates to novel quaternsry ammonium compounds and oral compositLons conta~nLng said quaternary compounds which possess superior anti-microbial, anti-caries and anti-calculus activity.
According to the present invention, there is provided a process of prepsring a quaternary ammonium compound having the structural formula:
[RZ~CH2)nNR2R3F4~ X
wherein R is an alkyl group containing 7-13 carbon atoms or an alicyclic group containing 7-13 carbon atoms and selected from the group consisting of an adamantyl radical, bicyclo [3.3.0~ octane radical and a norbornane radical, R2 and R3 are each methyl or ethyl, R4 is an alkyl chain con-taining 10-18 carbon atoms, Z is selected from the group consisting of CH2J ~ SJ C=OJ COOJ CONH, CHOHJ NHCOOJ and NHCSOJ n is an integer from 1 to 3J and X is selected from the group consisting of chloride, bromide, iodide, sulphate, nitrate and aryl sulphonate anion, which process com-prises reacting a compound containing the RZ radicals with a dialkylamine containing the R2-N-R3 radical to obtain a tertiary amino compound of the formula RZ~CH2)nNR2R3 and subsequently quaternizing with a higher alkyl --halide or ester of sulphuric or arenesulfonic acid of formula R4XJ
provided that when R is an alkyl group containing 7-13 carbons, Z is CONH.
The alicyclic group may be any ring system such as the c adamantyl radical which is derived from tricyclo /3,3,1.13,7 / decane ~ -showing four fused chain cyclohexane rings as follows: ~:

~' '.
"

lOS9lZ4 / C ~ '

2~ /H2 2~ 12 9 CH2 4 /

a bicyclo [3.3.0~ octane showing two joined pentane rings as follows:

CH2 ~ C 2 / ~ CH
\2 ~ CH ~ CH2 CH2 \ CH2 ''' the norbornane radicsl which is represented by the following ring structure: -Cr2 H27 ~ f H2 -:
H2C~ H \ H2 or any other aliphatic ring system containing 7 to 13 carbon atoms.
Typical examples o quaternary ammonium compounds wherein Z
is a carboxamide ~CONH~ radical, in accordance with this invention~
are:

1. 3-Heptaneamidopropyldimethyltetradecyl ammonium chloride, 2. 3-Decaneamîdopropyldimethyltetradecyl ammonium chloride,

3. 3-Octaneamidopropyldimethyldecyl ammonium iodide,

4. ~-Octaneamidopropyldimethyldodecyl ammonium iodide, S. 3-Octaneamidopropyldimethyltetradecyl ammonium chloride, 6. 3-Nonaneamidopropyldimethyltetradecyl ammonium chloride, 7. 3-Dodecaneamidopropyldimethyltetradecyl ammonium chloride, 8. 3-Undecaneamidopropyldimethyltetradecyl ammonium chloride, 9. 3-~ adamantanecarboxamido)propyldimethyldodecyl ammonium bromide, 10. 3-tl'-adamantanecarboxamido)propyldimethyltetradecyl ammonium bromide, 11. 3- ~'-adamantanecarboxamido)propyldimethyltetradecyl ammonium chloride, 12. 2- ~' adamantanecarboxamido)ethyldiethyldecyl ammonium bromide, 13. 2-~1' adamantanecarboxamido) ethyldiethyldodecyl ammonium ~-bromide, 14. 3-~xo,cis-Bicyclooctane-2-carboxamido)propyltetradecyl - -dimethyl ammonium bromide.
15. 3-~exo,cis-Bicyclooctane-2-carboxamido)propyldodecyldimethyl ammonium bromide.
16.~ 3-~2'-norbornanecarboxamido)propyltetradecyldimethyl ammonium bromide.
Typical examples of ~uaternary ammonium compounds wherein -Z is an ether ~0) radical and R is an adamantyl radical in accordance with instant invention include~
17. 2-~1'-adamantyloxy)ethyldimethyldodecyl ammonium bromide, ~
18. 2- ~'-adamantyloxy)ethyldimethyltetradecyl ammonium bromide, ~-19. 2-C1'-adamantyloxy)ethyldimethyldecyl ammonium chloride, 20, 2-~1'-adamantyloxy)ethyldimethylhexadecyl ammonium chloride, 21. 2-~1'-adamantyloxy)ethyldimethyloctadecyl ammonium chloride, 22. 3-~1'-adamantyloxy~propyldimethyldodecyl ammonium bromide.

105~124 Typical examples of quaternary ammonium compounds ~herein R is an adamantyl group and Z is a keto ~C=0) radical in accordance with th;s invention include:
23. 2-adamantylcarbonylethyldimethyldecyl ammon;um bromide, 24. 3-adamantylcarbonylpropyldimethyltetradecyl ammonium bromide, 25. 2-adamantylcarbonylethyldimethylhexadecyl ammonium bromide, 26. l-adamantylcarbonylethyldimethyloctadecyl ammonium bromide, 27. l-adamantylcarbonylmethyldimethyltetradecyl ammonium bromide, 28. l-adamantylcarbonylmethyldimethyldodecyl ammonium bromide.
Other examples of quaternary ammonium compounds wherein R
is an adamantyl radical and Z is a carboxylic ester ~COO) and thiocarbamate ester ~NHCSO) radical in accordance with the invention include:
29. 2-~1'-adamantanecarbonyloxy)ethyldimethyldecyl ammonium bromide, 30. 2- ~'-adamantanecarbonyloxy)ethyldimethyltetradecyl ammonium bromide, 31. 2- ~'-adamantanecarbonylo,xy)ethyldimethyldodecyl ammonium bromide, 32. 2- ~'-adamantylthiocarbamyloxy)ethyldimethyldodecyl ammonium bromide. ~-Other halides and analogous compounds such as the sulfates, nitrates, aryl sulfonates, etc. may also be employed herein as effective bactericides. -It has been observed that the compounds generally described by the foregoing formula are particularly effective against gram positive organisms such as Staphylococcus aureus; Streptococcus mitis, sanguis and mutans; Bacillus subtilis; Corynbacterium acnes; Actinomycetes naeslundii; and against fungi, such as Candida albicans, Trichophyton mentogrophytes and Aspergillus niger;
and moderately effective against Escherichia coli which is a gram negative bacteria. Compounds wherein R4 is a benzyl radical in lieu of instant higher alk~l radical are devoid o~ antibacterial activity.
The anti-microbial nature of the instant novel compounds was shown by a standard test tube serial dilution test in which an appropriate number of test tubes of broth containing decreasing concentrations of the test agent was innoculated with the test organism. After a suitable period of incubation, the tubes were examined for the presence or absence of growth. The activity of the test agent was the lowest concentration which inhibited the growth of the organism and is expressed as the minimal inhibitory concentration in ppm. As shown in the following table of - ;
antimicrobial data, a definite break occurs between compounds wherein R4 contains 8 carbons and 10 carbons.
TABLE I:
Minimum Inhibitory Concentration ~ppm) C0NHCH2CH2N~c2H5)2R ] Br R4=C4Hg C6H13 C8H17CloH21C12H25 S. aureus 100 100 25 3.12 1.56 ~ B
Str. sanguis 50 50 50 6.25 3.12 Str. mutans 100 100 25 6.25 0.78 A. naeslundii 100 50 12.51.56 0.39 C. albicans 100 100 50 6.25 1.56 T. mentagrophytes 50 50 50 50 3.12 A. niger 100 100 100 50 12.5 These dilution tests evidence the effectiveness of compounds of the in~ention against bacteria and fungi not possessed by amido-quaternary = onium compounds containing 3 lower aliphatic radicals.

', .' ~ ' , , , ," ,, ~OS9124 The superior and unexpected antimicrobial acti~ity exhibited by the novel compounds of instsnt invention i`s clearly shown by the antimiorobîal results in Tables II and III.
TABLE II:
Minimum Inhibitory Concentration ~pm) MicrobeComp.3 Comp.14 Comp.15Comp.16Comp.9 Comp.10 S. aureus 12.5 0.78 1.56 1.56 0.78 0.39 Str. ssnguis 6.25 6.25 3.12 1.56 - -Str. mitis - - - - 0.39 0.39 Str. mutans 0.78 <0.05 0.1 0.1 A. naeslundii 12.5 ~0.05 0.19 0.1 - -E. coli 50. 50 25 50 50.0 25.0 P. aeruginosa 25 50 25 50 C. albicans 6.25 3.12 3.12 3.12 6.25 6.25 T. mentagrophytes 12.5 3.12 6.25 6.25 12.5 25.0 A. niger 25 25 25 25 25.0 50.0 TABLE III:
[RCONHccH2)3 NccH3)2 R ~ X
T. menta~
R R4X S.aureus S.mitis E.coli C.albicans grophytes-1. Cll Cl I 50 50 50 50 50 2~ *c7cbranch) C12 I 1.56 3.12 50 3.12 12.5 * CC4Hg) CC2H5)CH
3~ C8 C12 I 0.78 1.56 12.5 1.56 12.5 4. *C7Cbranch) ~ -C14 Cl ~78 1.56 50 3.12 6.25 -

5. C7 C14 Cl .78 1.56 50 3.12 3.12

6. C8 C14 Cl 1.56 0.78 100 1.56 3.12

7. Cg C14 Cl 3.12 6.25 100 3.12 6.25

8. Cll C14 Cl 6.25 12.5 100 25 25 The above table clearly shows that the novel amidoquaternary ammonium compounds of instant invention which contain two large aliphatic or alicyclic groups possess unexpectedly superior antimicrobial properties not present in prior art quaternary ` ammonium compounds tcompound 1 in Table III, and first 3 compounds in Table I).
TABLE IV:
[adamantyl-OCH2CH2N~CH3)2 R4 ~ Br R =C14H29 12 25 S. aureus 0.78 0.39 Str. mitis 0.39 0.19 C. albicans 1.56 1.56 P. ovale >50 >50 -~
T. mentagrophytes 6.25 3.12 Ps. aeruginosa >25 >25 A. niger 50 50 E. coli 12.5 12.5 These dilution tests evidence the effectiveness o the ~, quaternary ammonium ethers of instant invention against bacteria and fungi.
' ''-lOS91Z4 TABLE V:
[adamantyl Z CH2CH2NCCH3)2 R4~ Br ;~ Z=NHCS0 Z=COO

C12H25R =CloH21C12H25 C14H29 C4H9 S. aureus 1.56 1.56 .02 .78 >100 Str. mitis .78 6.25 .19 .78 >100 B. subtilis .39 1.56 .19 .1 >100 Cornybacterium acne 12.5 1.56 6.25 25 C. albicans 6.25 12.5 .78 6.25 >100 T. mentagrophyte 3.9 7.8 6.25 25 >100 A. niger 62.5 31.2 50 50 >100 E. coIi 25 25 12.5 50 ~100 Pr. aeruginosa - 50 - - >100 The above dilution test results is evidence of the effective-ness of instant compounds, not possessed by quaternary ammonium ~-carboxylate esters wherein the R4 group is a lower aliphatic radical such as butyl. -In general, smaller concentrations of the subject compounds are required to inhibit the growth of the organisms than of , analogous compounds which contain substantially the same number of carbon atoms.
When used against bacteria or fungi, compounds of the instant invention may be applied directly to the surface to be protected or may be dissolved in a pharmaceutical carrier. Typically, an effective amount, e.g., 0.025 to about 10% by weight o the compound, is included in an inert carrier and a dispersing or surface-active agent. Altern,atively, an effective amount, e.g., 0.025 to about 10% by weight may be incorporated into a solid carrier which may be inert, such as talc, clay, diatomaceous earth, flour, etc.

lOS9124 In addition, the quaternary ammonium amides of adamantane-carboxylic acid are particularly effective in inhibiting the de-velopment of dental calculus as shown by the results of tests on littermated albino rats, in groups of 15 males and 15 females who were fed a Z;pkin-McClure calculus producing diet. For six weeks the teeth of each animal were swabbed for thirty seconds each day with a test solution or water for the control group. The animals were then sacrificed, defleshed and scored by Baer's method for calculus. The results were analyzed by Student's "t" test and in the results quoted were 99% significant.

Concentration Calculus Reduction %
Compound Test Solution Males Females .. _ .. _ _ 3-~1'-adamantane- .1% 43.43 6.27`
carboxamido) propyl tetradecyl dimethyl ammonium bromide The results set forth above indicate the significant effectiveness of the quaternary compounds of the invention in inhibiting formation of oral calculus in concentrations as low as 0.1%.
When compounds of the instant invention are intended for use -in compositions which reduce formation of caries and inhibit for-mation of oral calculus, they are typically incorporated in oral ~-preparations in effective amounts up to about 5% by weight, preferably .025-1% and most preferably 0.05-0.5% by weight of the oral preparation. Typically, the oral preparation is a dentifrice, such as dental cream, tablet or powder, containing as a vehicle about 20-95% by weight of a water-insoluble polishing material, preferably including water-insoluble phosphate such as dicalcium phosphate, tricalcium phosphate, trimagnesium phosphate. The dentifrice may also include water; binders such as glycerine, .

lOS9124 sorbitol, propylene glycol and polyethylene glycol 400; detergents;
gelling agents such as Irish moss and sodium carboxy methyl cellulose; additional antibacterial agents; coloring or whitening agents; preservatives; silicones; chlorophyll compounds, addi-tional ammoniated materials; flavoring or sweetening materials;
and compounds which provide fluorine-containing ion such as sodium fluoride, stannous fluoride and sodium monofluorophosphate.
The oral preparstion may also be a liquid such as mouth rinse which typically contains 20-99% by weight of an aqueous lower aliphatic alcohol, preferably having about 1-30% by weight alcohol such as ethanol, n-propyl, or isopropyl alcohol.
Such oral preparations are typically applied by brushing the teeth or rinsing the oral cavity for 30-90 seconds at least once daily. Typical oral preparations of the invention which can be applied in this manner are set forth below.

Dental Cream %

3-Decaneamidopropyldimethyltetradecyl ammonium chloride 0.50 Nonionic detergent~ 1.00 Glycarine 22.00 Sodium pyrophosphate 0.25 Carboxymethyl cellulose 0.85 Sodium saccharin 0.20 Sodium benzoate 0.50 Calcium carbonate (precipitated) 5.00 Dicalcium phosphate dihydrate 46.75 Plavor 0.80 Water 22.15 ~Tween 80 tTrade Mark) - Polyoxyethylene (20 moles ethylene oxide) sorbitan monooleate.

lOS9~24 0.50% of 2(1'-adamantyloxy)ethyldodecyldimethyl ammonium bromide was used in lieu of the amido-quaternary ammonium chlo-ride in Example 1.

0.50% of a quaternary ammonium adamantyl ketone was used in lieu of the quaternary ammonium amido compound of Example 1.

0.50% of a quaternary ammonium ester of adamantyl carboxy-lic acid was substituted for the quaternary ammonium amido compound of Example 1.

Mouthwash %
Quaternary ammonium amide of adamantane carboxylic acid 0.025 Nonionic detergent tPluronic F-68)* 1.00 Ethyl alcohol (containing flavor) 15.00 Glycerine 10.00 Saccharin 0.02 Water 73 955 *Trade Mark for a block polymer of 80~ polyoxyethylene and 20% poly- i oxypropylene.

0.05~ of a quaternary ammonium adamantyl-ketone was sub-stituted for the amide of Example 5 and the water content was adjusted accordingly.

lOS9lZ4 0.05% of 2-~l'-adamantyloxy) ethyltetradecyldimethyl ammonium bromide was used in lieu of the amide of Example 5 and the water content was adjusted accordingly.
A preferred ingredient of instant composition is a non-ionic organic surfactant which provides increased prophylactic action, assists in achieving thorough and complete dispersion of instant compositions throughout the oral cavity and renders instant compositions m~ore cosmetically acceptable.
The non-ionic surfactant imparts to the composition, detersive and foaming properties as well as maintains the flavoring materials in solution (i.e., solubilizes flavor oils). In addition, the non-ionics are completely compat-ible with the quaternary ammonium compounds of this invention, thereby pro-viding for a stable, homogeneous composition of enhanced anti-bacterial, anti-caries and anti-calculus activity. The presence of an anionic surfactant would inactivate or negate the beneficial effects of said quaternary com-pounds by coprecipitation and/or interreaction.
The nonionic organic surface active compounds which are contemplat-ed are commercially known and comprise the water-soluble products which are derived from the condensation of an alkylene oxide or equivalent reactant and a reactive-hydrogen hydrophobe. The hydrophobic organic compounds may be aliphatic, aromatic or heterocyclic, although the first two classes are preferred. The preferred types of hydrophobes are higher aliphatic alcohols and alkyl phenols, although others may be used such as carboxylic acids, car-boxamides, mercaptans, sulphonamides, etc. The ethylene oxide condensates with higher-alkyl phenols represent a preferred class of nonionic compounds.
Usually the hydrophobic moiety should contain at least about 6 carbon atoms, and preferably at least about 8 carbon atoms, and may contain as many as about S0 carbon atoms or more. The amount of alkylene oxide will vary considerably depending upon the hydrophobe, but as a general guide and rule, at least about 5 moles of alkylene oxide per mole of hydrophobe should be used. The upper limit of alkylene oxide will vary also, but no particular criticality can be ascribed thereto. As much as 200 or more moles o alkylene oxide lOS91Z4 per mole of hydrophobe may be employed. While ethylene oxide is the pre-ferred and predominating oxyalkylating reagent, other lower alkyle~e oxides such as propylene oxide, butylene oxide, and the like may also be used or substituted in part for the ethylene oxide. Other nonionic co~pounds which are suitable are the polyoxyalkylene esters of the organic acids such as the higher fatty acids, the rosin acids, tall oil acids, acids from petroleum oxidation products, etc. These esters will usually contain from about 10 to about 22 carbon atoms in the acid moiety and from about 12 to about 30 moles of ethylene oxide or its equivalent.
Still other nonionic surfactants are the alkylene oxide condensates with the higher fatty acid amides. The fatty acid group will generally con-tain from about 8 to about 22 carbon atoms and this will be condensed with about 10 to about 50 moles of ethylene oxide as the preferred illustration.
The corresponding carboxamides and sulphonamides may also be used as substan-tial equivalents.
Still another class of nonionic products are the oxyalkylated high-er aliphatic alcohols. The fatty alcohols should contain at least 6 carbon atoms, and preferably at least about 8 carbon atoms. The most preferred alcohols are lauryl, myristyl, cetyl, stearyl and oleyl alcohols and the said alcohols should be condensed with at least about 6 moles of ethylene oxide, and preferably about 10 to 30 moles of ethylene oxide. ,A typical non-ionic product is oleyl alcohol condensed with 15 moles of ethylene oxide. The corresponding alkyl mercaptans when condensed with ethylene oxide are also `
suitable in the compositions of the present invention.
The amount of non-ionic may generally be varied from about 0.2-3.0%
by weight of the total formulation, depending on the speciic nature of the non-ionic utilized as well as on the amounts and nature of the other ingred-ients in the oral formulation.
The method of preparing the quaternary ammonium compounds of inst-ant invention generally comprise the step of reacting a compound containing the RZ radicals with a compound containing the R2R amine radical to obtain a tertiary amine, and subsequently quaternizing with a higher aliphatic .

halide~
The quaternary ammonium amides of instant invention can be prepared by a two-step method of reacting a carboxylic acid, ester or acid chloride with N,N-dialkylethylene diamine or N,N-dialkylpropylene diamine to form a tertiary amino amide and subsequently quaternizing with an alkyl halide or ester of sulfuric or of arenesulfonic acid ~i.e., methyl p-toluenesulfonate) as illustrated by the following equations wherein R, R2, R3, R4 have a afore-defined meanings.

O R2 0 R2 ;
Il , 11 l .
1. RCOH ~ NH2~CH2)3 N ~ R-c-NH~cH2)3 N ~ H20 2. RCNH~CH2)3 N + R4X > RCNH~CH2)3 -N-R4 X

The quaternary ammonium esters of adamantane carboxylic acid can also be prepared by a two-step process of reacting adamantane-carboxylic acid chloride with a dimethylaminoethanol to form the carboxylate, followed by quaternizing with an alkyl halide as illustrated by the following equations:

1. COCl C

¦ CH12 ~ ~ HOCH2CH2 N ~ 3 ?

~ 2 CH2 -` 1059124 ,COOCH2CH2NCCH3)2 2C ~ ¦ \ CH2 CH12 ¦ +HCl ~ H ~ C ~

HC \ / CH
~H2 CoocH2cH2NccH3)2 COOCH2CH2N~CH3)2cl2c25 +

~CIzH25~r > ~ ~ ~r-The quaternary ammonium ethers of instant invention can also be prepared by a two-step method of reacting a l-haloadamentane with a dimethyl aminoethanol to form a tertiary amino ether and subsequently quaternizing with an alkyl halide or ester of sulfuric or of arenesulfonic acid ~i.e., methyl toluene sulfonate) as illustrated by the ollowing equations wherein ~ -R and R4 have the aforedefined meanings:

C,H3 C, 3 .
1. RBr + HOCH2-CH2-N > R-o-ccH2)2 N + H Br ,:
CH3 3 - -:

2. ROCCH2~2N + R4X , iRCCH2)2-N -R ~ X

Similarly, the quaternary ammonium compounds of this invention : :
represented by the following formulae:
[RCoccH2)nN~cH3)2R4~ X~
[RNHcSOccH2~nNccH3)2R ] X
[Rs~cH2)nNccH3)2R ] X ,, [RNHCOOccH2)nNccH3)2R J X

HOHccH2)nNccH3)2R ] X
[RCH2 CCH2) nN CcH3) 2R ,~ X
wherein R, R4, n and X have the same designations as in the general formula, can also be prepared by a similar two-step method of reacting a compound containing the adamantane or other R radical with a compound containing the dimethyl amine radical and then quaternizing with a higher aliphatic halide.
Another method of preparing the adamantyl ketones comprises reacting adaman-tylhalo-lower alkyl ketone with dimethyl hàgher alkyl amine.
The following examples illustrate the manner in which compounds of this invention are prepared.

Preparation of 2-Cl'-adamantanecarbonyloxy)-ethyldimethyl-dodecyl ammonium bromide:
A solution of 21.7 g CO.ll mole) l-adamantanecarboxylic acid chloride in 100 ml. ether was added to a solution of 19.4g ~0.22 mole) 2-dimethylaminoethanol in 200 ml. ether. The reaction mixture was stirred overnight at room temperature. Since unreacted acid chloride could still be detected by infrared spectrum, additional 15g Co.17 mole) 2-dimethylaminoeth-anol was added and the reaction mixture again stirred overnight. The react-ion mixture was poured into 300 ml. water and treated with 20 ml. of 10%
NaOH solution. From the ether layer was recovered 23g of oil with an infrared spectrum compatible with the proposed structure of 2-Dimethylaminoethyl l-adamantanecarboxylate.
Analysis: Calculated for C15H25NO2: C, 71-67; H~ 10.
Found: C, 71.26, H, 9.94.
Ten grams C0.04 mole) of the product of step 1 was mixed with 10g C0.04 mole) l-bromododecane and allowed to stand for six weeks. The result-ant crystalline mass was washed with ether and dried to 17.5g white crystals C88% of theory). Two recrystallizations from ethyl acetate gave 15.6 g white crystals having a melting point of 176-178C.

. . . . . .

lOS9lZ4 Analysis: Found Calculated Carbon 64.95 64.78 Hydrogen 10.15 10.07 The decyl homolog of the above carboxylate, i.e., where R4 is CloH21, was prepared similarly to Example 8. The recovered crystals had a t melting point of 183-184.5C and the following analysis:
Found Calculated Carbon 63.00 63.54 10Hydrogen 9.90 9.81 The tetradecyl homolog was prepared in accordance with the process defined in Example-8, yielding cryst~ls having a melting point of 176-178C
with the following analysis:
Found Calculated Carbon 65.33 65.89 Hydrogen 10.18 10.30 I~

Preparation of 3- ~'-adamantanecarboxamido)propyldodecyl-dimethyl ammonium bromide: 2.5 grams of N,N-dimethyl-l, 3-propane diamine was added to a cold solution of 5 grams l-adamantane carboxylic acid chloride in 15cc benzene. An immediate precipitate formed~ The mixture was stirred and permitted to sit for thirty minute5. The precipitate was washed with benzene several times, centrifuged, and dried in vacuum, yielding 5 grams of N-~3- ~
dimethylaminopropyl) adamantane l-carboxamide hydrochloride having a melting `
point of 154-157C. This product was dissolved in 150cc acetone, placed in -~
a refrigerator for crystal growth and 4.8 gms of the product was recovered.
This hydrochloride was dissolved in 100cc water and 25cc of lN NaOH
was added. A white precipitate formed which was extracted with ether, dried by flash evaporation and 3.2 grams o the free base having a melting point of 78-80C was recovered. The infrared spectrum confirmed the structure of this product.

'' ' : ..................... ', , ': :
.

lOS91Z4 ~ he aforedefined reaction product was quaternized by reacting 1.6 grams ~.06 mole) of N-¢3-dimqthylaminopropyl)-1-adamantane-carboxamide with 1.5 grams ~.Q6 mole) of l-bromododecane dissolved in 4 cc acetone. -After standing for two weeks the reaction mixture was chilled with dry ice. The resultant crystalline mass was washed with ether, dried in vacuum and recrystallized from ethyl acetate, giving a crys~alline product having a melting point of 122-124C and the following analysis:
Found Calculated Carbon 64.81 65.47 10~ydrogen 10.84 10.40 Molecular weight: 513.66.

The tetradecyl homolog of the above carboxyamide was prepared in accordance with the process of Example 11. The recovered crystals had a melting point of 120-122C and the following analysis:
Found Calculated Carbon 65.80 66.52 Hydrogen 10.54 10.61 Molecular weight: 541.7I.

Preparation of 2~1'-adamantyloxy)ethyldimethyltetradecyl ammonium bromide: A mixture of 3.6g ~0.015 mole) 1-~2'-dimethylaminoethoxy)adamantane [prepared by the method o Charkrabarti, Faulis and Szinai, Tetrahedron Letters, No. 60, 6249 ~1968)~ and 4.3g ~0.05 mole) l-bromotetradecane was prepared and allowed to stand at room temperature for six`days. The resultant solid was recrystallized from 30cc ethyl acetate to 4.75g white crystals.
After recrystallization it melted at 132-135.
Found Calculated Carbon ~7.32 67.17 Hydrogen 10.96 10.87 Bromine 15.92 15.96 lOS91Z4 The dodecyl homolog was prepared by the procedure of Example 13, yielding hygroscopic crystals having a melting point when dry of 128-130 and the following analysis:
Found Calculated Bromine 16.91 16.91 EXAMPLE lS
Preparstion of l-adamantylcarbonylmethyldimethyltetradecyl ammonium bromite.
A mixture o 1.3g ~0~005 mole) l-adamantyl bromomethyl ketone and ~;
1.23g ~0.005 mole) dimethyltetradecylamine was solubilized by the addition of 30cc acetone. The next day the solidified mixture was washed with ether and recrystallized from ethyl acetate to yield 2.1g white crystals, m.p.
134-135.5.
Found Calculated Carbon 67.72 67.45 Hydrogen 10.65 10.51 The dodecyl homolog was prepared by the procedure of Example 15 yielding white crystals of melting point 140-141.5 and with the following analysis:
Found Calculated Carbon 66.55 66.36 Hydrogen 9.87 10.28 2- ~ '-adamantylthiocarbamyloxylethyldimethyldodecyl ammonium bro-mide was prepared by a two-step process. First, l-adamantyl isothiocyanate was reacted with the sodium derivative of 2-dimethylaminoethanol. The product after recrystallization from ethylacetate and from hexane had a melting point of 86-88.5 and an analysis of Found Calculated Carbon 64.02 63.19 . .
' ' ' , ,', ,' ' ' ~ ;

lOS9lZ4 Found Calculated Hydrogen 9.41 9.28 A solution of 4.5g of the above prepared 0-~2-dimethylaminoethyl)l-adamantylthiocarbamate and 4.0g l-bromododecane in 15cc acetone was allowed to stand for four days. The product was recrystallized from ethylacetate and from acetone in white crystals, m.p. 143-143.5 and had the following analysis:
Found Calculated Carbon 61.04 60.99 Hydrogen 9.65 9.67 Preparation of 3-Decaneamidopropyldimethyltetradecyl ammonium chloride: A solution of 102g ~1 mole) N,N-dimethylpropylenediamine in 400 mole benzene was stirred during the addition of 95.3g ~0.5 mole) decanoyl chloride and kept below 50C with an ice bath. After standing overnight at room temperature, the reaction mixture was poured into 1 liter of 2% sodium -hydroxide solution. The benzene layer was separated and combined with four subsequent 100 ml ether extracts of the aqueous layer. The organic solution was washed with water and dried over sodium sulfate. Vacuum evaporation left 116.5g oil ~91% yield). Infrared and nmr spectra showed the product to be N-~3-dimethylaminopropyl)decamide.
26g ~0.1 mole) of the above amino amide was mixed with 23g ~0.1 mole) l-chlorotetradecane and maintained in a~ oven at 100C for 70 hours.
The reaction mixture was cooled to room temperature, washed with ether and recrystallized successively from acetone and ethyl acetate, givine a crystall-ine monohydrate product having a melting point of 55-57CIto liquid crystal, ;-and 173C to liquid. Upon drying said monohydrate at 75C, a hygroscopic anhydrous form is obtained. This product, calculated for C29H61ClN20.H20 has the following analysis:
Found Calculated Carbon 69.09 68.66 Hydrogen 12.66 12.52 Found Calculated Nitrogen 5.59 5.52 Chlorine 6.98 6.99 3-~exo,cis-Bicyclo[3.3.0~octane-2-carboxamido) propyltetradecyldimethylammonium bromide .
To a solution of 23g exo,cis-bicyclo~3.3.0~octane-2-carboxylic acid ~Drganic Syntheses 47 10) in 100 ml benzene was added 12 ml thionyl chloride and 1 ml dimethyl formamide. The reaction mixture was stirred 15 minutes at room temperature and then dry nitrogen gas was bubbled through the solution for 30 minutes to remoYe HCl. The solution of acid chloride was transferred to a dropping unnel and slowly added to a stirred solution of 34g N,N-dimethylpropylene-diamine in 100 ml benzene at 20-25C. :
After 30 minutes, the reaction was worked up by pouring into sodium hydroxide solution and extracting the product with ether. Hydrochloric acid solution was added for neutralization and again extracted with ether. ^Evaporation of the ether left 31g of a crystalline solid ~86% of theory).
Recrystallized from hexane, it melted at 60-63C.
Analysis: Neutral equivalent: Calcd, 238.4. Found, 241.3.
A mixture of 12g of the above compound and 14g l-bromotetradecane in 100 ml acetone was refluxed for 24 hours. On chilling, 20.4g ~78% o theory) cryst-als separated. After crystallizing from acetone, the compound melted at t,;~-, 119-122C .
Analysis: Based on C28H55BrN2O:
Calculated Pound Carbon 65.21 65.05 Hydrogen 10.75 10.81 Bromine 15.50 15.26 ,~
Nitrogen 5.43 5.21 3-~exo,cis-Bicyclo~3.3.0~octane-2-carboxamido) propyldodecyldimethylammonium bromide Prepared by the same procedure as in Example 19J this compound ... . ..

lOS91Z4 melted at 119-120.5C. -Analysis: Based on C26H51BrN20:
CalcuIated Found Carbon 64.04 64.01 ~ydrogen 10.54 10.64 Bromine 16.39 16.21 Nitrogen S.75 5,57 3-~2'-Norbornanecarboxamido)propyltetradecyl-dimethylammoniùm bromide Prepared by a similar procedure as in Example 19, starting with 2-norbornanecarbo~ylic acid chloride. Recrystallized from ethyl acetate, the compound melted at 129-1~1C.
Analysis: Bromîde: Calc. 15.93%.~ Found. 15.61%.
Although this invention has been described with reference to specif-ic examples, it will be apparent to one skilled in the art that various modifications may be made thereto which fall wlthin its scope.

,~ .
'

Claims (26)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process of preparing a quaternary ammonium compound having the structural formula:
[RZ(CH2)nNR2R3R4]+X-wherein R is an alkyl group containing 7-13 carbon atoms or an alicyclic group containing 7-13 carbon atoms and selected from the group consisting of an adamantyl radical, bicyclo [3.3.0] octane radical and a norborane radical, R2 and R3 are each methyl or ethyl, R4 is an alkyl chain containing 10-18 carbon atoms, Z is selected from the group consisting of CH2, O, S, C=O, COO, CONH, CHOH, NHCOO, and NHCSO, n is an integer from 1 to 3, and X is selected from the group consisting of chloride, bromide, iodide, sulphate, nitrate and aryl sulphonate anion, which process comprises reacting a compound containing the RZ radicals with a dialkylamine containing the R2-N-R3 radical to obtain a tertiary amino compound of the formula RZ(CH2)nNR2R3 and subsequently quaternizing with a higher alkyl halide or ester of sulphuric or arenesulfonic acid of formula R4X, provided that when R is an alkyl group containing 7-13 carbons, Z is CONH.

2. A process in accordance with claim 1, wherein the quaternary ammonium compound is a quaternary ammonium amide, prepared by reacting an alkyl or ali-phatic ring carboxylic acid containing 7-13 carbon atoms with N,N-dialkylalky-lene diamine to form a tertiary amino amide, and subsequently quaternizing with a higher alkyl halide.

3. A process in accordance with claim 1, wherein the quaternary ammonium compound is quaternary ammonium ester of adamantane carboxylic acid, prepared by reacting adamantanecarboxylic acid chloride with lower dialkylaminoalkanol to form the carboxylate, and then quaternizing with a higher alkyl halide.

4. A process in accordance with claim 1, wherein the quaternary ammonium compound is a quaternary ammonium ether, prepared by reacting a 1-haloadaman-tane with lower dialkylaminoalkanol to form a tertiary amino-ether and subse-quently quaternizing with a higher alkyl halide.

5. A quaternary ammonium compound having the structural formula:

[RZ(CH2)nNR2R3R4]+X-wherein R is an alkyl group containing 7-13 carbon atoms or an alicyclic group containing 7-13 carbon atoms and selected from the group consisting of an adamantyl radical, bicyclo [3.3.0] octane radical and a norbornane radical, R2 and R3 are each methyl or ethyl, R4 is an alkyl chain containing 10-18 carbon atoms, Z is selected from the group consisting of ca2, O, S, C=O, COO, CONH, CHOH, NHCOO and NHCSO, n is an integer from 1 to 3, and X is selected from the group consisting of chloride, bromide, iodide, sulphate, nitrate and aryl sulphonate anion provided that when R is an alkyl group containing 7-13 carbons, Z is CONH whenever prepared by the process according to claim 1.

6. A process according to claim 3 wherein adamantane carboxylic acid chloride is reacted with a dialkylaminoalkanol, and the dialkylaminoalkyl adamantane carboxylate thus formed being subsequently quaternized with an alkyl halide.

7. A quaternary ammonium ester according to claim 5 wherein R is adaman-tyl, Z is COO, whenever prepared by the process according to claim 6.

8. A process according to claim 3 wherein 1-adamantane carboxylic acid chloride is reacted with 2-dimethylaminoethanol to give 2-dimethylaminoethyl 1-adamantane carboxylate which is then reacted with 1-bromo dodecane to give 2-(1'-adamantanecarbonyloxy) ethyldimethyldodecylammonium bromide.

9. 2-(1'-adamantanecarbonyloxy)ethyldimethyldodecylammonium bromide, whenever prepared by the process according to claim 8.

10. A process according to claim 2 wherein adamantane carboxylic acid chloride is reacted with a dialkylalkylene diamine, and the dialkylamino alkyl adamantane carboxamide thus formed being subsequently quaternized with an alkyl halide.

11. A quaternary ammonium amide according to claim 5, wherein R is an adamantyl group and Z is CONH, whenever prepared by the process according to claim 10.

12. A process according to claim 2 wherein N,N-dimethyl-1,3-propane diamine is reacted with 1-adamantane carboxylic acid chloride to give N-(3-dimethylamino-propyl)-1-adamantane-carboxamide which is then reacted with 1-bromotetradecane to give 3-(1'-adamantanecarboxamido)propyltetradecyldimethyl ammonium bromide.

13. 3-(1'adamantanecarboxamido)propyltetradecyldimethyl ammonium bromide, whenever prepared by the process according to claim 12.

14. A process according to claim 2 wherein a bicyclooctane carboxylic acid chloride is reacted with a dialkylaminoalkanol, the reaction product thus formed being quaternized with an alkyl halide.

15. A quaternary ammonium amide according to claim 5, wherein R is a bicyclooctane group and Z is CONN, whenever prepared by the process according to claim 14.

16. A process according to claim 2 wherein a norbornane carboxylic acid chloride is reacted with a dialkylamino alkanol, the reaction product thus formed being quaternized with an alkyl halide.

17. A quaternary ammonium amide according to claim 5, wherein R is a norbornane radical and Z is CONH, whenever prepared by the process according to claim 16.

18. A process according to claim 2, wherein decyl carboxylic acid chloride is reacted with a N,N-dialkylalkylene diamine, the reaction product thus formed being quaternized with an alkyl halide.

19. A quaternary ammonium amide according to claim 5, wherein R is a decane radical and Z is CONH, whenever prepared by the process according to claim 18.

20. A quaternary ammonium ether according to claim 5, wherein R is 1-adamantyl, and Z is -O-, whenever prepared by the process according to claim 4.

21. A process according to claim 4 wherein a 1-haloadamantane is reacted with dimethylaminomethanol, the reaction product thus formed being quaternized with dodecyl bromide.

22. 2-(1'adamantyloxy)ethyl-dimethyldodecylammonium bromide, whenever prepared by the process according to claim 21.

23. A process according to claim 4 wherein a 1-haloadamantane is reacted with a dialkyl aminoalkanol, the reaction product thus formed being quaternized with an alkyl halide.

24. A quaternary ammonium ether according to claim 5, wherein R is 1-adamantyl, and Z is 0, whenever prepared by the process according to claim 23.

25. A process according to claim 4 wherein 1-bromoadamantane is reacted with dimethylaminomethanol, the reaction product thus formed being quaternized with 1-bromotetradecane.

26. 2-(1-adamantyloxy)ethyldimethyltetradecylammonium bromide, whenever prepared by the process according to claim 25.