KR810000932B1 - Process for preparing bis-pyridinium alkane - Google Patents

Abstract

Bis-pyridinium alkanes[I,II; Y = C4-18 alkylene; R = nitro, C6-18 alkyl, C5-7 cyclo alkyl, benzyl, halogen, lower alkyl, lower alkoxy, cyano, substituted phenyl; Q = methyl, Cl; V = 0-4; A = anion; m = 1,3; n = 1,2; X = 1,2,3; (m)2 = (n)(x) , useful as fungicide, were prepd. by reacting 4-(R-amino)pyridine(III) 2 mole with double substituted alkane(IV; Z = chloro, bromo, iodo, methane sulfonyloxy, ethane sulfonyl oxy, p-toluene sulfonyl oxy) 1 mole or α,α'-double substituted xylene(v) 1 mole.

Description

Method for preparing bis-pyridinium alkanes

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'-비스-(4-아미노-1-피리디늄)크실렌류 그리고 이들의 제조방법에 관한 것이다. 상기 화하물은 박테리아, 진균 및 포진바이러스(Herpes Viruses)를 억제하는데 유용하며, 이들 화합물중 몇몇은 치구(齒垢), dental palque)의 형성을 방지하는데 유용하다.The present invention relates to bis- (4-amino-1-pyridinium) alkanes and

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'-Bis- (4-amino-1-pyridinium) xylenes and methods for their preparation. These compounds are useful for inhibiting bacteria, fungi and herpes viruses, and some of these compounds are useful for preventing the formation of dental palques.

A group of bis- (4-amino-1-pyridinium) -alkynes are known as intermediates for preparing the corresponding bis- (4-amino-1-piperidino) alkanes having bacteriostatic and bactericidal effects. .

1, 10-bis- (4-amino-1-pyridinium) decane diiodide and 1,10-bis- (4-acetamino-1-pyridinium) decane diiodide are described by Austin et al. J. Pharm. Pharmacol 11, pp. 80-93 (1959). Several different classes of quaternary ammonium compounds described herein are mentioned to have anti-amoeba, antibacterial, anti-filarial, and saltripnozoma activity, but biological data for these compounds It is not described.

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'-비스-[4-(R-아미노)-1-피리디늄] 크실렌류에 관한 것이다.The present invention relates to bis- [4- (R-amino) -1-pyridinium] -alkanes of the formula (I) and the following formula (II).

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'-Bis- [4- (R-amino) -1-pyridinium] xylenes.

In formula (I) above;

Y is a C ₄ -C ₁₈ alkylene group, which separates two 4- (R-NH) -1-pyridinidinyl groups by C ₄ -C ₁₈ ; R is C ₆ -C ₁₈ alkyl group, C ₅ -C ₇ cycloalkyl group, benzyl or one or two selected from the group consisting of haloken, lower alkyl, lower alkoxy, nitro, cyano and trifluoromethyl Substituents or phenyl substituted by methylene dioxy;

In formula (II) above;

R is hydrogen, a straight or branched chain alkyl group of C ₄ -C ₁₈ or benzyl;

Q is methyl or chlorine;

V is an integer from 0-4;

In the above formulas (I) and (II);

A is an anion; m is 1 or 3; n is 1 or 2;

X is 1, 2 or 3, where (m) (2) = (n) (x).

These compounds are useful as antibacterial and antifungal agents and also have antibias activity against herpes viruses.

Some of the compounds of formula (I)) are also useful as jigsaw protectors. Examples of such compounds are as follows.

1,6-bis- [4- (octylamino) -1-pyridinium] hexane dibromide and the corresponding dichloride,

1,6-bis- [4- (nonylamino) -1-pyridinium] hexane dibromide and the corresponding dichloride,

1,6-bis- [4- (decylamino) -1-pyridinium] hexane dibromide,

1,6-bis- [4- (dodecylamino) -1-pyridinium] hexane dibromide,

1,7-bis- [4- (heptylamino) -1-pyridinium] heptane dibromide,

1,7-bis- [4- (octylamino) -1-pyridinium] heptane dibromide,

1,7-bis- [4- (nonylamino) -1-pyridinium] heptane dibromide,

1,7-bis- [4- (decylamino) -1-pyridinium] heptane dibromide,

1,7-bis- [4- (dodecylamino) -1-pyridinium] heptane dibromide,

1,8-bis- [4- (heptylamino) -1-pyridinium] octane dibromide and the corresponding dichloride,

1,8-bis- [4- (octylamino) -1-pyridinium] octyl dichloride,

1,8-bis- [4- (nonylamino) -1-pyridinium] octane dibromide,

1,8-bis- [4- (decylamino) -1-pyridinium] octane dibromide,

1,8-bis- [4- (dodecylamino) -1-pyridinium] octane dibromide,

1,8-bis- [4- (2-ethylhexylamino) -1-pyridinium] octane dibromide,

1,9-bis- [4- (heptylamino) -1-pyridinium] nonane dibromide,

1,9-bis- [4- (nonylamino) -1-pyridinium] nona dibromide,

1,9-bis- [4- (decylamino) -1-pyridinium] nona dibromide,

1,9-bis- [4- (dodecylamino) -1-pyridinium] nonane dibromide,

1,10-bis- [4- (heptylamino) -1-pyridinium] decane dibromide and the corresponding dichloride,

1,10-bis- [4- (nonylamino) -1-pyridinium] decane dibromide,

1,10-bis- [4- (decylamino) -1-pyridinium] decane dibromide,

1,10-bis- [4- (dodecylamino) -1-pyridinium] decane dibromide,

1,10-bis- [4- (2-ethylhexylamino) -1-pyridinium] decane dichloride,

1,12-bis- [4- (hexylamino) -1-pyridinium] dodecane dibromide and the corresponding dichloride,

1,12-bis- [4- (heptylamino) -1-pyridinium] dodecane dibromide,

1,12-bis- [4- (octylamino) -1-pyridinium] dodecane dibromide

1,12-bis- [4- (nonylamino) -1-pyridinium] dodecane dibromide

1,12-bis- [4- (decylamino) -1-pyridinium] dodecane dibromide

1,12-bis- [4- (dodecylamino) -1-pyridinium] dodecane dibromide

1,12-bis- [4- (2-ethylhexylamino) -1-pyridinium] dodecane dibromide and the corresponding dichloride,

1,14-bis- [4- (heptylamino) -1-pyridinium] tetradecane dibromide and the corresponding dichloride,

1,14-bis- [4- (octylamino) -1-pyridinium] tetradecane dibromide

And as particularly preferred compounds,

1,9-bis- [4- (heptylamino) -1-pyridinium] nonane dibromide,

1,10-bis- [4- (2-ethylhexylamino) -1-pyridinium] decane dibromide,

1,10-bis- [4- (octylamino) -1-pyridinium] decane dichloride and the corresponding dibromide,

1,9-bis- [4- (octylamino) -1-pyridinium] nonane dibromide,

1,12-bis- [4- (heptylamino) -1-pyridinium] dodecane dichloride,

1,8-bis- [4- (octylamino) -1-pyridinium] octane dibromide,

An oral hygiene composition for preventing jigsaw consisting of an effective amount of any one of the compounds and a pharmaceutically acceptable carrier is also within the scope of the present invention.

The present invention also relates to a composition for antimicrobial, antifungal and virucide suitable for topical application consisting of an effective amount of the compound of formula (I) or (II) and a pharmaceutically acceptable carrier.

Skin cleaning compositions comprising an effective amount and a pharmaceutically acceptable surfactant and carrier for the antimicrobial, antifungal and killer virus of the compounds of formula (I) or (II) also belong to the present invention.

The present invention also relates to a composition for antimicrobial, antifungal and virucidal, consisting of a mixture of an effective amount of a compound of formula (I) or (II) with a suitable excipient and suitable for application to inanimate surfaces.

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'-이중 치환된 크실렌과 반응시켜서 제조할 수 있다.Compounds of formulas (I) and (II) may be selected from 4- (R-amino) pyridine of formula (III) or a di-substituted alkane of formula (IV) or a

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It can be prepared by reacting with '-double substituted xylene.

In the above formulas (IV) and (V);

Y is a C ₄ -C ₁₈ alkylene group that separates two Z groups by C ₄ -C ₁₈ ;

Z-chloro, bromo, iodo, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, or P-toluenesulfonyloxy;

Q is methyl or chlorine;

V is an integer from 0-4;

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'-의중 치환된 크실렌(V)과 반응시킬 경우, 구조식(III)의 R은 수조, C1-C₁₈의 직쇄 또는 측홰 알킬기 또는 벤질이다.In this case, when 4- (R-amino) pyridine (III) is reacted with a double substituted alkane (IV), R in structural formula (III) is C ₆ -C ₁₈ alkyl; A cycloalkyl group of C ₅ -C ₇ , benzyl or a phenyl group substituted by methylenedioxy with one or two halogen, lower alkyl, lower alkoxy, nitro, cyano or trifluoromethyl substituents; 4- (R-amino) pyridine (III)

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When reacted with x-substituted xylene (V), R in formula (III) is a water bath, a straight or branched alkyl group of C ₁ -C ₁₈ or benzyl.

In formula (I), alkylene group Y is a divalent saturated aliphatic hydrocarbon group containing straight or branched C ₄ -C ₁₈ , preferably C ₈ -C ₁₂ , two 4- (R-NH)- The 1-pyridinyl group is separated by C ₄ -C ₁₈ , preferably C ₈ -C ₁₂ .

Examples of the alkylene group Y include 1, 4-butylene, 1, 5-pentylene, 1, 6-hexylene, 1, 7-heptylene, 1, 8-octylene, 1, 9-nonylene, 1, 10 -Decylene, 1, 11-undecylene, 1, 12-dodecylene, 1, 13-tridecylene, 1, 14-detradecylene, 1, 15-pentadedecylene, 1, 16-hexadecylene , 1, 17-heptadecylene, 1, 18-octadecylene, 1-methyl-1, 4-butylene, 3-methyl-1,5-pentylene, 2-ethyl-1,4-butylene, 3-methyl-1,6-hexylene, 2,4-dimethyl-1,5-pentylene, 1-methyl-1,7-heptylene, 3-ethyl-1,6-hexylene, 3-propyl- 1,5-pentylene, 4,4-dimethyl-1,7-heptylene, 2,6-dimethyl-1,7-heptylene, 2,4,4-trimethyl-1,6-hexylene, 2, 7-dimethyl-1,8-octylene, 1-methyl-1,10-decylene, 5-ethyl-1,9-nonylene, 3,3,6,6-tetramethyl-1,8-octylene , 3,8-dimethyl-1,10-decylene, 3-methyl-1,11-undecylene, 6-methyl-1,12-dodecylene, 2-methyl-1,13-tridecylene, 4, 9-dimethyl-1,12-dodecylene, 4-methyl-1,14-tetraylene, 2,13-dimethyl-1,14-tetylene, 1,4-dipropyl-1,4-butylene, 3 -(3-pentyl) -1, 5-pentylene, 2- (4,8-dimethylnonyl))-1,4-butylene, 1-heptyl-1,5-pentylene and the like.

When Y contains 4 carbons, the carbon atoms must be linearly arranged as well. Similarly, when Y contains 18 carbon atoms and two 4- (R-NH) -1 pyridinyl groups are separated by C ₁₈ . The carbon atoms should be arranged in a straight chain. In other cases, Y may be linear or branched.

R in formula (I) is a straight or branched chain alkyl group of C ₆ -C ₁₈ , preferably C ₇ -C ₉ , for example n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, 1-methylpentyl, 2,2-dimethyl Butyl, 2-methylhexyl, 1,4-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 2-methylheptyl, 1-ethyllexyl, 2-ethyllexyl, 2-propylpentyl, 2-methyl-3- Ethylpentyl 1,3,5-trimethylhexyl, 1,5-dimethyl-4-ethylhexyl, 2-propylheptyl, 5-methyl-2-butylhexyl, 2-propylnonyl, 2-butyloctyl, 1,1- Dimethyl undecyl, 2-pentylnonyl, 1,2-dimethyltetradecyl, 1,1-dimethylpentadecyl, and the like.

In the formula (I), when R is a C ₅ -C ₇ cycloalkyl group, saclopentyl, cyclohexyl, cycloheptyl and the like are included.

P in the formula (I) when R is phenyl substituted by 1-2 substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro, cyano and trifluoromethyl or by methylenedioxy Chlorophenyl, O-chlorophenyl, m-chlorophenyl, P-bromophenyl, m-fluorophenyl, P-iodophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,5 -Dibromophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3,4-methylenedioxyphenyl, P-enylphenyl, P-methoxyphenyl, m-nitrophenyl, O- Cyanophenyl, m- (trifluoromethyl) phenyl, 2-methoxy-5-methylphenyl and the like.

R in formula (II) is a straight or branched alkyl group of C ₁ -C ₁₃ , preferably C ₆ -C ₁₂ , and in addition to the alkyl groups of C ₆ -C ₁₈ mentioned above, methyl, ethyl, n-propyl, n-butyl , groups such as n-pentyl, isopropyl, 1-methylpropyl, isobutyl, tertiary butyl, isopentyl, neopentyl, 1-methylpentyl and the like.

R in formulas (I) and (II) may also be a benzyl group. If desired, the phenyl moiety of the benzyl group may be substituted with 1-2 substituents such as halogen, hydroxy, lower alkyl, lower alkoxy, nitro, cyano, trifluoromethyl and the like.

R is the same in formulas (I) and (II).

When A is an anion in the above formula, for example bromide, chloride, fluoride, iodide, sulfide, phosphate, nitrate, sulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, P-toluenesulfonate , Naphthalenesulfonate, naphthalenesulfonate, cyclohexylsulfate, acetate, trifluoroacetate, malate, fumarate, succinate, tartrate, oxalate, citrate, lactate, gluconate, ascorbate, lactate Dates, Phthalates, Salicylates, Benzoates, Piclates, Methanephosphates, Algenites, Alzenates, Thiosulfates, Picchlorates, Tatronates, Salcosinates, N-lauroyl salcosinates, Monofluorophosphates Hexafluoroaluminate, hexafluorosiliconite, hexafluorostannate, It includes both anions of organic and inorganic acids such as fluorozirconate, tetrafluoroborate, hexachloroplatinate, tetrachloroaluminate, hexachlorostannate and the like. In this case, bromide and chloride are preferable.

The term "halogen" here means blue auro, chlorine, bromine and iodine.

In the term lower aryl and lower alkoxy, “lower” refers to an alkyl moiety of C ₁ -C ₄ , such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl.

The compound of formula (I) or (II) may contain 2 moles of 4- (R-amino) pyridine [formula (III) and 1 mole of moderately double substituted alkane or xylene [formula (IV) or (V)] Reaction in an inert solvent such as, for example, lower alkanol, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetaceur, benzene, toluene, xylene, at a temperature of about 80 ° -150 ° C. for 1-24 hours. It is convenient to make it. In general, the reactants are heated in acetonitrile or N, N-dimethylformamide, a mixed solvent thereof, or lower alkanol at a temperature of 60 ° C.-100 ° C. for 2-20 acids.

The reaction can also be carried out by heating the stoichiometric amount of the reactant to 120-150 ° C. for 2-5 hours without solvent.

Bis- [4- (R-amino) -1-pyridinium] compounds produced as a result of the reaction [Formulas (I) and (II)] are, for example, filtered if the product is insoluble in the reaction medium, or ether, benzene Or the reaction mixture with a nonpolar solvent, such as hexane, is isolated by conventional methods such as dilution to precipitate the product, or by evaporating the reaction medium to leave the product as a residue. The isolated crude product can be purified by crystallization with a suitable solvent, for example in the presence of an adsorbent such as activated carbon or diatomaceous earth.

The bis-4- (R-amino) -1-pyridinium] compound prepared according to the above method is applied to the separated groups [Z in Structural Formulas (IV) and (V)] of a bisubstituted alkane or xylene reactant. It will contain the corresponding anions [A in structural formulas (I) and (II)].

However, the anion moiety of these compounds may be modified according to conventional ion exchange methods, where desired, for example, passing a solution of pyridinium compound in a suitable solvent such as methanol, ethanol or water to a synthetic ion exchange resin containing the desired anion. . The solvent is evaporated and the resulting pyridinium compound containing the desired anion is purified by recrystallization from a suitable solvent.

The pyridinium compound is also reacted with a soluble salt containing the desired anion associated with the corresponding cation which binds with the anion of the pyridinium compound to produce an insoluble precipitate. At this time, separation of the insoluble precipitate leaves a pyridinium compound solution containing the desired anion. For example, a bis- (4- (R-amino) -1-pyridinium] alkane dihalide is reacted with a silver salt of an organic or inorganic acid, which removes the precipitated halides and pyridinium containing the desired organic or inorganic acid anion. The solution of the compound remains.

Such metathesis reactions can also be used to prepare insoluble pyridinium compounds. Soluble bis- (4- (R-amino) -1-pyridinium] compound is reacted with a soluble salt containing the desired anion, which can bind to the pyridinium cation to form an insoluble precipitate, the desired product. Insoluble pyridinium salts are useful for isolation and purification purposes, and when properly combined with emulsions, creams, pastes, lotions, jellies, or powders, they also accumulate to provide a bactericidal pyridinium compound that is slowly and continuously liberated. It can also be used as a preparation for the depot.

Moreover, insoluble salts consisting of certain anions are effective in reducing tooth pigmentation of jigsaws.

As such, the anion moiety of a given compound has properties such as solubility, stability, molecular weight, and in vivo toxicity, depending on the type of compound, and if the form of the compound is inadequate for the desired purpose, the anion moiety is more readily available in another form. You can switch. For application in the skin or other tissues or oral cavity, manufacturing acceptable anions such as fluoro, chlorine, bromine, iodine, methanesulfonate are used.

4- (R-amino) pyridines [formula (III)], which are used as starting materials, are generally known and can be prepared according to the method for preparing known compounds, even if they are particularly novel.

4- (R-amino) pyridines can be prepared by reacting 4-chloro or 4-bromopyridine or N- (4-pyridine) -pyridinium chloride hydrochloride with an appropriately substituted amine. The reaction is generally carried out by heating the reactants at 150-225 ° C. for 1.5-3 hours without solvent. The product is isolated, for example, from an alkaline aqueous medium into an organic solvent such as ether, methylene chloride or chloroform, the organic solvent is evaporated, and the residue is crystallized with a suitable solvent.

In addition, 4- (R-amino) pyridine may be prepared by catalytic reduction of a mixture containing a carbonyl compound and 4-aminopyridine containing a suitable carbon content. The reaction at this time is generally carried out in the presence of a palladium hydrogenation catalyst at a temperature of 50-70 ° C., hydrogen pressure of 20-60 Pa in a suitable solvent such as ethanol. The hydrogenation time is usually 4-10 hours is sufficient. The use of excess carbonyl compound in excess of 200% is advantageous for obtaining a high yield of pure product within 5 hours of reaction time. After the catalyst is removed and the solvent is evaporated to isolate the product, the residue is either distilled off or crystallized with a suitable solvent.

Aldehydes having the appropriate carbon content can be reacted with 4-aminopyridine in the presence of formic acid at high temperature to afford 4 (R-amino) pyridine.

4 (R-amino) pyridine can also be obtained by acylating 4-aminopyridine with an acyl halide having the appropriate carbon content, at which time the resulting amide is reduced. Acylation is carried out according to known methods, for example by reacting 4-aminopyridine with an acyl halide in the presence of an acid acceptor such as triethylamine in an inert solvent such as methylenedichloride or chloroform. The amides thus produced are reduced with a complex metal hydride such as lithium hydride in a suitable solvent such as tetrahydrofuran, ether, or dioxane, and the amine preparation is isolated by known methods.

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'-이중치환 알칸류는 대개 공지의 화합물이며, 특별히 신규한 것이라 할지라도 공지의 화합물을 제조하는 방법으로 제조할 수 있다.Of structural formula (IV) used as starting material

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The '-disubstituted alkanes are usually known compounds, and even if they are particularly novel, they can be produced by a method for producing known compounds.

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'-이중치환 크실렌류도 일반적으로 공지된 화합물이며, 특별히 신규한 것이라 할지라도 공지의 화합물을 제조하는 방법으로 제조할 수 있다.Of structural formula (III) used as starting material

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'-Double substituted xylenes are also generally known compounds, and even though they are particularly novel, they can be prepared by a method for producing known compounds.

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'-디올로 환원된다. 생성된 크실렌-

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'-디올을 예컨대 브롬화수소, 포르포러스 트리브로마이드, 포르포러스 옥시클로라이드 티오닐 클로라이드 또는 요오드화 칼륨 및 오르토 인산과 공지의 방법으로 반응시키면,

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'-디할로크실렌으로 전환된다. 크실렌-

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'-디올을 또한 예컨대 피리딘과 같은 산수용체 존재하에 메탄-, 에탄-, 벤젠-또는 P-톨루엔설폰닐클로라이드와 공지의 방법으로 반응시켜 설포네이트에스테르로 전환시킬 수도 있다.Phthalic acid, isophthalic acid, or terephthalic acid or esters thereof substituted with a suitable chloro or methyl can be reacted with a metal hydride such as lithium aluminum hydride in a suitable solvent such as tetrahydrofuran, ether or dioxane.

,

Reduced to '-diol. Generated Xylene-

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When the '-diol is reacted with a known method with, for example, hydrogen bromide, phosphorus tribromide, phosphorus oxychloride thionyl chloride or potassium iodide and ortho phosphoric acid,

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Converted to dihaloxylene. xylene-

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'-Diol can also be converted to sulfonate esters by reaction with methane-, ethane-, benzene- or P-toluenesulfonylchloride in the presence of an acid acceptor such as pyridine, for example.

As will be described in detail below, the compounds of formulas (I) and (II) exhibit in vitro antimicrobial activity against microorganisms, including their positive and Gram-negative bacteria, some fungi and herpes viruses. Therefore, these compounds can be used as fungicides or preservatives that can be applied locally to sanitize and disinfect human skin or other tissues, and to sanitize and disinfect non-living surfaces. These compounds can be used in topical antiseptic solutions, or surgical hand washes to treat injured people, preoperative skin preparations for patients, antibacterial cleaners such as soaps and shampoos, or household and industrial cleaners and disinfectants, and protective surfaces such as paints, varnishes and waxes. Can be used zero. These compounds are mixed with conventional diluents or carriers, acceptable cationic, anionic or nonionic surfactants, buffers, flavorings, and coloring agents for use in these applications and are used for scrubbing, spraying, and swabing. ) Is applied to the surface to be sterilized by conventional methods such as immersion.

To use as a skin cleanser, bis- [4- (R-amino) -1-pyridinium] compounds can be prepared in the liquid state or, if desired, added to the liquid formulations with a certain additive to thicken it to give a gel or face. It may be made into (paste) or may be in the form of a bar according to a known method. For example, these compounds are pharmaceutically acceptable surfactants, preferably nonionic surfactants such as polyoxeethylene-polyoxypropylene copolymers, known compounds and amine oxides such as stearyl dimethyl amine oxide, or the like. It may be formulated with a mixture. These formulations may also contain pharmaceutically acceptable diluents, such as water, lower alkanols, and the like, and acids, bases, or buffers to maintain the pH at 5.0-7.5, and optionally flavoring and coloring agents. The concentration in the formulation of the bis- [4- (R-amino) -1-pyridinium] compound is generally about 0.5-2.0% by weight, preferably 1.0% by weight.

When making tinctures, bis- [4- (R-amino) -1-pyridinium] compounds can be formulated with 1, lower alkanols such as acetone, and lower altonols such as ethanol. If necessary, the tincture may be colored with a colorant. The concentration of the active ingredient is generally about 0.05-1.0% (w / v), preferably 0.1% (w / v).

These compounds may also be mixed with conventional lotions, ointments or cream bases such as, for example, alkyl polyethers, alcohols, cetyl alcohols, stearyl alcohols, and the like, such as lotions, ointments, or conventional powders such as starch, talc. It can be formulated into suitable pharmaceutical excipients such as incorporation into a gas to make powders or incorporation into conventional jelly bases such as glycerol and tragacand into jelly to be used for the treatment of bacterial, fungal and herpes virus infections. They may also be formulated for use as aerosol sprays or foams.

When used for hypocrisy or disinfection of inanimate surfaces, these compounds can be formulated with known detergents and soap mixtures such as trisodium phosphate, borax and the like. The concentration of bis- [4- (R-amino) -1-pyridinium] compound present in the formulation is up to about 10% by weight.

As will be explained in detail below, any of the compounds of formula (I) is effective for preventing the formation of jig. When used for this purpose, these compounds can be conveniently applied to the teeth in the formulation of mouthwash or dentifrice. These compounds can be mixed with conventional ingredients used in dentifrices or water solubles, such as water, alcons, glycerin, buffers, thickeners, flavoring and coloring agents. These preparations are also known ingredients that are optionally effective for reducing the likelihood of tooth pigmentation, in particular known compounds such as zinc phenolsulfate, 8-hydroxyquinoline, disodium ethane, 1-hydroxy-1,1-diphosphate, and the like. Anti-calculus agents and the like, such as amino carboxylate compounds which are known compounds such as nitrotriacetic acid, 2-hydroxyethylnitrilodiacetic acid or water soluble salts thereof. The concentration of bis- [4- (R-amino) -1-pyridinium] alkanes in such formulations is generally about 0.005-0.05% by weight, preferably about 0.01% by weight.

The excipients, diluents, carriers and additives contained in the above formulations are compatible with the active ingredient, and the antimicrobial, antifungal and viral bactericidal effects of the bis- [4- (R-amino) -1-pyridinium] compound are carriers. Should not be mitigated by the nature of the diluents, excipients or other additives.

The molecular structure of the compound of the present invention was determined by infrared spectra and nuclear magnetic resonance (NMR) spectra, and was confirmed by agreement of theoretical and calculated values by elemental analysis.

The following examples illustrate the invention in detail, but the invention is not limited thereto.

Example 1

A. A mixture containing 130 g (0.67 mole) of 4-bromopyridine hydrochloride and 152 g (1.0 mole) of n-heptylamine hydrochloride was heated in an oil bath. When the temperature of the bath was 180-185 ° C., the reaction mixture began to melt, at which point stirring was started. After melting was complete at 190-195 ° C., the liquid mixture was stirred and heated at 210-220 ° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and the resulting solid was dissolved in water, and made alkaline by adding 35% aqueous sodium hydroxide solution, and the product was extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The resulting viscous oil was diluted with a small amount of n-hexane and cooled to obtain a solid, which was collected by filtration and air dried to give 86.6 g of 4- (heptylamino) pyridine having a melting point of 49-51 ° C.

B. Unlike the above, 4- (heptylamino) pyridine was prepared by the following method. That is, a mixture of 229 g (1.0 mole) of N- (4-pyridyl) pyridinium chloride hydrochloride and 228 g (1.5 mole) of n-heptylamine hydrochloride was burnt while stirring in an oil bath at 215 ° C for 2 hours. The reaction mixture was cooled to 80 ° C. and diluted with ice water, and then made alkaline by adding 35% aqueous sodium hydroxide solution, and extracted successively with ether and chloroform. The organic extracts were combined and evaporated to dryness under reduced pressure. At this time, the remaining viscous oil was dissolved in ether, and the ethereal aqueous solution was washed with water. The aqueous wash was back-exteact with chloroform and the chloroform extract was mixed with ethereal solution. The combined organic solution was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residual oil was cooled to 78 ° C. and partially solidified. The semisolid thus obtained was diluted with a small amount of ether and filtered. The resulting solid was dissolved in a mixture of acetonitrile and chloroform, the solution was treated with activated carbon and filtered, and the filtrate was evaporated to dryness under reduced pressure. The resulting semisolid was diluted with a small amount of ether and cooled. The resulting solid was collected by filtration, washed with a small amount of cold ether and dried to give 84.6 g of 4- (heptylamino) pyridine with a melting point of 50-52 ° C.

C. 4- (heptylamino) pyridine can also be prepared by hydrogenation of a mixture of 4-aminopyridine and heptaaldehyde following the method of Example 10B.

D. A solution of 10.0 g (0.052 mol) of 4- (heptylamino) pyridine dissolved in 40 g of acetonitrile was stirred and warmed, followed by 9.3 g (0.026 mol) of acetonitrile (1,14-dibromotetradecane). 230 ml) was added dropwise. The resulting mixture was heated at reflux for 20 hours. The reaction mixture was cooled to room temperature, and the precipitated product was collected by filtration, washed with cold acetonitrile and dried to give 1,14-bis- [4- (heptylamino) -1-pyridinium] having a melting point of 88-90 占 폚. 13.9 g of tetradecane dibromide was obtained.

Example 2

A chloride (5.0 ml) solution of 5.0 g of 1,14-bis- [4- (heptylamino) -1-pyridinium] tetradecane dibromide was prepared using a chloride-type synthetic anion exchange resin (Amberlite IRA400) The product was added to the upper layer of a 3-inch diameter column containing 500 ml of a product sold by Rohm and Haas, and eluted five times with 125 ml of methanol each. The eluate was collected and dried dry under reduced pressure, the residual oil was redissolved in ethanol, treated with activated charcoal and evaporated to dryness. The remaining solid was triturated with ether containing a few drops of acetonitrile, collected by filtration and dried over phosphorus pentoxide under vacuum to give 1,14-bis- [4- (heptylamino) -1 having a melting point of 113-116 ° C. -Pyridinium] 3.94 g of tetradecane was obtained.

Example 3

11.54 g (0.06 mol) of acetonitrile (75 ml) suspension of 4- (heptylamino) pyridine was stirred and then heated under reflux until a clear homogeneous solution was formed. To this clear solution was then added dropwise a warmed acetodetril (75 ml) solution containing 9.84 g (0.03 mol) of 1,12-dibromododecane. After the addition was heated under reflux for 18 hours. After cooling to room temperature the reaction mixture was evaporated to dryness under reduced pressure. The residual solid was slurried in ether, filtered and collected and dried under vacuum at 60 ° C. for 48 hours to give 1,12-bis- [4- (heptylamino) -1-pyridinium] dodecane di having a melting point of 101-103 ° C. 21.1 g of bromide was obtained.

Example 4

A. A solution of 6.6 g of 1,12-bis- [4- (heptylamino) -1-pyridinium] dodecane dibromide in methanol (25 ml) was prepared using a synthetic anion exchange resin of chloride type in methanol. The product was added to a 3-inch diameter column top layer filled with 1 L), and sold slowly by 100 ml of methanol until 700 ml of eluate was collected. The eluate was collected and dried under reduced pressure at 25 ° C. or lower. The residual rubber is repeatedly softened with a mixture of ether and acetonitrile 6: 1 and dried under vacuum to give 1,12-bis- [4- (heptylamino) -1-pyridinium] dodecane at a melting point of 109-112 ° C. 5.0 g of dichloride were obtained.

B. As another method, a mixture containing 76.8 g (0.4 mol) of 4- (hetylamino) pyridine and 47.8 g (0.2 mol) of 1,12-dichlorododecane was heated at 125-130 ° C. for 4 hours. After cooling slightly, 300 ml of acetonitrile were added and the resulting mixture was heated at steam bath temperature to obtain a complete solution which was stored overnight in the refrigerator. The precipitated product was collected by filtration, washed with cold acetonitrile and etet, and then the hygroscopic product was immediately dried in vacuo to give 1,12-bis- [4- (heptylamino) -1-pyrid at a melting point of 112-115 ° C. Dinium] 112 g of dodecane dichloride was obtained.

Example 5

A. A mixture of 100.0 g (0.51 mol) of 4-bromopyridine hydrochloride and 110 g (0.8 mol) of n-hepsylamine hydrochloride was heated in an oil bath. When the temperature of the bath reached 175-180 ° C. and the reaction mixture began to melt, stirring was started. At this time, the temperature of the bath was 227 ℃, and continued stirring for 3.5 hours. After cooling to room temperature, the reaction mixture was dissolved in hot water, the resulting solution was cooled with ice, diluted with aqueous sodium hydroxide solution, and made alkaline and extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was triturated with ether and then cooled. The resulting solid was collected by filtration and washed with cold ether. The filtrate was evaporated to give a secondary solid product. This was collected, dissolved in chloroform, treated with activated carbon and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with cold ether. The product thus obtained was collected by filtration, washed with cold ether and dried to give 63.6 g of 4- (hexylamino) pyridine with a melting point of 66-68 ° C. The filtrate was evaporated to afford 7.0 g more product having a melting point of 65-67 ° C.

B. As another method, 4- (hexylamino) pyridine was prepared by the following method. That is, a mixture of 229 g (1 mol) of N- (4-pyridyl) pyridinium chloride hydrochloride and 207 g (1.5 mol) of n-hexylamine hydrochloride was stirred and heated at 175-185 ° C. for 1.75 hours. The reaction was cooled and diluted with 750 ml of ice water. The resulting solution was made alkaline by adding 35% aqueous sodium hydroxide solution, and then diluted once more with 1 L of water and extracted with ether and dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The residue was crystallized with ether and redissolved in chloroform, and the resulting solution was treated with activated carbon and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was triturated with a mixture of ether and acetonitrile. The solid thus obtained was reused in chloroform, and the resulting solution was treated with activated carbon and filtered. The filtrate was evaporated to dryness under reduced pressure, and the residue was triturated with cold ether to give 71.0 g of 4- (hexylamino) pyridine with a melting point of 68-70 占 폚.

C. A solution of 10.7 g (0.6 mole) of acetonitrile (50 ml) of 4- (hexylamino) pyridine is warmed and stirred, followed by 10.7 g (0.03 mole) of acetonitrile (1,14-dibromotetradecane). 250 ml) was added dropwise, and the reaction mixture was heated at reflux for 22 hours. The reaction was evaporated to dryness under reduced pressure, the residual solid was dissolved in acetonitrile, and the resulting solution was treated with activated charcoal and filtered. The filtrate was evaporated to dryness under reduced pressure and the resulting oil was crystallized from acetonitrile. The product was collected by filtration and dried for 48 hours at 70 ° C./0.1 mm to give 13.4 g of 1,14-bis- [4- (hexylamino) -1-pyridinium] dedecadecan dibromide having a melting point of 91-93 ° C. Got.

Example 6

The reaction was carried out in a similar manner as in Example 2 except that 5.0 g of 1,14-bis- [4- (hexylamino) -1-pyridinium] tetradecane dibromide was used, and the corresponding melting point was 94-95 ° C. 4.33 g of dichloride were obtained.

Example 7

Melting point 122-124 ° C. by analogous reaction of the method of Example 5C, except that 10.7 g (0.06 mol) of 4- (hexylamino) pyridine and 9.85 g (0.03 mol) of 1,12-dibromododecane were used. 17.6 g of 1,12-bis- [4- (hexylamino) -1-pyridinium] dodecane dibromide was obtained.

Example 8

Reaction was carried out in a similar manner as in Example 2, except that 5.0 g of 1,12-bis- [4- (hexylamino) -1-pyridinium] dodecane dibromide was used, corresponding to a melting point of 86-88 ° C. 3.96 g of dichloride were obtained.

Example 9

A. Mixture of 183.3 g (0.8 mole) of N- (4-pyridyl) pyridinium chloride hydrochloride and 162 g (0.98 mole) of n-octylamine hydrochloride, the bath temperature is 225-230 ° C. (internal temperature 188 ° C.) Heated in an oil bath until the resultant, and the resulting liquid was stirred at that temperature for 2.5 hours. The reaction mixture was cooled to 70 ° C. and diluted with 1 L of ice water, then made alkaline by addition of 35% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate, treated with activated charcoal and then evaporated to dryness in vacuo. The resulting oil was cooled to -78 deg. The semisolid formed was triturated with ether, the resulting solid was collected by filtration, washed with cold ether and dried. 10 g of secondary product was obtained from the filtrate. This was combined, dissolved in chloroform, treated with activated charcoal, filtered (banned 3 times), and the chloroform solution was evaporated to dryness under reduced pressure. The resulting solid was triturated with ether and cooled, then filtered and collected and washed with cold ether-hexane to give 63.3 g of a nearly colorless 4- (octinamino) pyridine with a melting point of 62-63 ° C.

B. As another method, 4- (octylamino) pyridine was prepared by the following method. That is, a mixture of 94 g (1 mol) of 4-aminopyridine, 384 g (3 mol) of octaaldehyde, and 7 g of 10% palladium hydrogenated catalyst on carbon was dissolved in a sufficient amount of anhydrous ethanol to a total capacity of 1.2 L, and the initial hydrogen pressure was 45 psi, 70 Hydrogenation at −90 ° C. for 4.5 hours. After cooling the mixture, the hydrogenation catalyst was removed by filtration and the filtrate was evaporated to dryness under reduced pressure. The residual oil is crystallized under standing, the solid product is triturated with hexane, filtered and collected, washed with fresh nucleic acid and dried at 40 ° C. in vacuo to give 182 g of 4- (octylamino) pyridine with a melting point of 70-73 ° C. Got.

C. Warm and stir 10.0 g (0.049 mol) of acetonitrile (15 ml) solution of 4- (octylamino) pyridine, and add 7.4 g (0.0245 mol) of acetonitrile (50 ml) of 1,10-dibromodecane. ) Was added dropwise and the resulting mixture was heated at reflux for 18 h. After cooling the mixture for 1 hour at room temperature and stirring, the precipitated solids were collected by filtration, washed with acetonitrile and dried at 85 ° C. for 48 hours to give 1,10-bis- [4- at a melting point of 163-164 ° C. (Octylamino) -1-pyridinium] decane dibromide 15.6 g was obtained.

Example 10

A. Reaction was carried out in a similar manner as in Example 2, except that 5.0 g of 1,10-bis- [4- (octylamino) -1-pyridinium] decane dibromide was used, corresponding to a melting point of 213-214 ° C. 4.31 g of dichloride were obtained.

B. As another method, a mixture of 6.8 g of 4- (octylamino) pyridine and 31.5 g of 1,10-dichlorodecane was stirred and heated slowly to 120 ° C. When the heat source was removed, the temperature rose to 180 ° C. due to the exothermic reaction. As soon as the reaction mixture began to crystallize, 250 ml of N, N-dimethylformamide was added rapidly, and the resulting mixture was heated to obtain a clear homogeneous solution and then cooled to 0 ° C. The precipitated product was collected by filtration and washed with ether and then dried in vacuo at 60 ° C. for 24 hours to give 1,10-bis- [4- (octylamino) -1-pyridinium] decan with a melting point of 215-217 ° C. 73 g of dichloride were obtained.

Example 11

The reaction was carried out in a similar manner as in Example 9C, except that 11.1 g (0.054 mol) of 4- (octylamino) pyridine and 7.34 g (0.027 mol) of 1,8-dibromooctane were used. The reflux time was 6 hours to obtain 1.56 g of 1,8-bis- [4- (octylamino) -1-pyridinium] octane dibromide at a melting point of 174-175 ° C.

Example 12

Reaction was carried out in a similar manner as in Example 2 except that 5.0 g of 1,8-bis- [4- (octylamino) -1-pyridinium] octane dibromide was used, and the corresponding di 4.30 g of chloride were obtained.

Example 13

In Example 9C, except that 11.1 g (0.054 mol) of 4- (octylamino) pyridine and 6.6 g (0.027 mol) of 1,6-dibromohexane were used and the reaction mixture was heated at reflux for 9 hours. The reaction was carried out in a similar manner to give 15.1 g of 1,6-bis- [4- (octylamino) -1-pyridinium] hexane dibromide having a melting point of 136-138 ° C.

Example 14

Reaction was carried out in a similar manner as in Example 2, except that 5.0 g of 1,6-bis- [4- (octylamino-1-pyridinium] hexane dibromide was used, and the corresponding dichloride having a melting point of 189-191 ° C. 4.23 was obtained.

Example 15

2.06 g (0.01 mol) of acetonitrile (15 ml) solution of 4- (octylamino) pyridine is warmed and stirred, followed by 1.37 g (0.005 mol) of acetonitrile solution of 1,6-hexanediol dimethanesulfonate. Was added dropwise and the resulting mixture was heated at reflux for 20 h. The reaction mixture was evaporated to dryness under reduced pressure and the residual rubber was triturated with ether to give a colorless hygroscopic solid. This solid was redissolved in a mixture of ethanol, benzene and acetonitrile and the resulting fresh solution was evaporated to dryness under reduced pressure. The residue was triturated with ether, the resulting white solid was collected by filtration, washed quickly with anhydrous ether and dried at 28 ° C./0.1 mm for 72 hours to give a waxy white solid of 1,6-bis- [4- ( Octylamino) -1-pyridinium] 2.65 g of hexane dimethanesulfonate was obtained.

Example 16

The crude product obtained was reacted in a similar manner as in Example 9C, except that 14.24 g (0.08 mol) of 4- (hexylamino) pyridine and 8.64 g (0.04 mol) of 1,4-dibromobutane were used. The mixture was triturated with a mixture of acetonitrile and acetone to obtain 20.45 g of 1,4-bis- [4- (hexylamino) -1-pyridinium] butane dibromide at a melting point of 199-201 占 폚.

Example 17

The crude product was reacted in a similar manner as in Example 9C, except that 10.7 g (0.06 mol) of 4- (hexylamino) pyridine and 7.23 g (0.03 mol) of 1,6-dibromohexane were reacted. The mixture was triturated with a mixture of ether, acetonitrile and acetone to obtain 14.90 g of 1,6-bis- [4- (hexylamino) -1-pyridinium] butane dibromide at a melting point of 178-178 ° C.

Example 18

The crude product obtained was reacted in a similar manner as in Example 9C, except that 10.7 g (0.06 mol) of 4- (hexylamino) pyridine and 7.75 g (0.03 mol) of 1,7-dibromoheptane were used. The mixture was triturated with acetonitrile and acetone to give 16.4 g of 1,7-bis- [4- (hexylamino) -1-pyridinium] butane dibromide at a melting point of 157-158 占 폚.

Example 19

The reaction was carried out in a similar manner as in Example 9C, except that 10.7 g (0.06 mol) of 4- (hexylamino) pyridine and 8.6 g (0.03 mol) of 1,9-dibromonane were used, and the melting point was 114-115 ° C. 17.15 g of 1,9-bis- [4- (hexylamino) -1-pyridinium] nonane dibromide was obtained.

Example 20

Melting point 229-230 ° C by reaction in a similar manner as in Example 9C, except that 15.4 g (0.08 mol) of 4- (heptylamino) pyridine and 8.64 g (0.04 mol) of 1,4-dibromobutane were used. 23.1 g of 1,4-bis- [4- (heptylamino) -1-pyridinium] butane dibromide was obtained.

Example 21

Melting point 142-143 ° C. by reaction in a similar manner as in Example 9C, except that 10.0 g (0.052 mol) of 4- (heptylamino) pyridine and 6.7 g (0.026 mol) of 1,7-dibromobutane were used. 14.05 g of 1,7-bis- [4- (heptylamino) -1-pyridinium] heptane dibromide was obtained.

Example 22

The reaction was carried out in a similar manner as in Example 9C, except that 11.6 g (0.06 mol) of 4- (heptylamino) pyridine and 8.2 g (0.03 mol) of 1,8-dibromooctane were recrystallized from acetonitrile-ether. The mixture was obtained to obtain 18.6 g of 1,8-bis- [4- (heptylamino) -1-pyridinium] octane dibromide at a melting point of 161-162 ° C.

Example 23

Melting point 206-208 ° C by reaction in a similar manner as in Example 2, except that 5.0 g (0.0076 mol) of 1,8-bis- [4- (heptylamino) -1-pyridinium] octane dibromide was used 4.1 g of phosphorous dichloride was obtained.

Example 24

The reaction was carried out in a similar manner as in Example 9C, except that 15.4 g (0.08 mole) of 4- (hepdiamino) pyridine and 11.44 g of 1,9-dibromonan were used, and 1,9 at a melting point of 115-116 ° C. 21.3 g of -bis- [4- (heptylamino) -1-pyridinium] nonane dibromide was obtained.

Example 25

Reaction was carried out in a similar manner as in Example 2, except that 5.0 g (0.0075 mol) of 1,9-bis- [4- (heptylamino) -1-pyridinium] nonane dibromide was used, and the melting point was 154-155 ° C. 4.2 g of phosphorous dichloride was obtained.

Example 26

Melting point 163-165 ° C by reaction in a similar manner as in Example 9C, except that 15.4 g (0.08 mole) of 4- (heptylamino) pyridine and 12.0 g (0.04 mole) of 1,10-dibromodecane were used. 25.7 g of 1,10-bis- [4- (heptylamino) -1-pyridinium] decane dibromide was obtained.

Example 27

Reaction was carried out in a similar manner as in Example 2, except that 5.0 g (0.0073 mol) of 1,10-bis- [4- (heptylamino) -1-pyridinium] decane dibromide was used, and the melting point was 209-210 ° C. 4.35 g of phosphorous dichloride were obtained.

Example 28

Hydrogen fluoride aqueous solution (48%) was added dropwise to 30 ml of a stirred slurry of a hydroxide-type synthetic anion exchange resin (sold under the trade name Amberlite IRA400) in 150 ml of water until the mixture became acidic. . After stirring for an additional 0.5 hours, the slurry was placed in a column. The column was drained and the resin washed with 185 ml of distilled water containing 15 ml of 48% hydrofluoric acid. The resin was then washed with distilled water until the eluate became weakly acidic, followed by 20%, 40% and 50% aqueous methanol, followed by a final wash with anhydrous methanol until the eluent became neutral. 1 ml of a methanol solution containing 0.25 g (0.000365 mol) of 1,10-bis- [4- (heptylamino) -1-pyridinium] decane dibromide was added to the upper layer of the fluoride ion exchange resin column. Five fractions of 15 ml each were collected. The first three fractions were evaporated to dryness under reduced pressure. The oily residue was dissolved in a mixture of toluene and ethanol and the resulting solution was evaporated to dryness under reduced pressure. The residual oil was redissolved in the mixture of benzene and acetone and the solution was concentrated to yield. The separated solids were collected by filtration and dried for 24 hours at 24 ° C./0.1 mm to give 0.11 g of impure 1,10-bis- [4- (heptylamino) -1-pyridinium] decane difluoride having a melting point of 85-90 ° C. Got

Example 29.

A. A solid mixture of 115 g (0.5 mole) of N- (4-pyridyl) pyridinium chloride hydrochloride and 119 g (0.66 mole) of n-nonylamine hydrochloride was prepared at a bath temperature of 220 ° C. (internal temperature 190-194 ° C.). The resulting liquid was heated in an oil bath until the resulting mixture was stirred at this temperature for 2 hours. The reaction mixture was cooled to 80 ° C., diluted with 1.2 liters of ice water, and then made alkaline by adding 35% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate, treated with activated charcoal, filtered and evaporated to dryness under reduced pressure. The remaining viscous oil was cooled to -78 ° C and triturated with ether. The resulting solid was collected by filtration and washed with cold ether. A second solid product was obtained from the filtrate. This was collected, redissolved in chloroform, and the resulting solution was treated with activated carbon and filtered. This was repeated once more and the filtrate was evaporated to dryness under reduced pressure. The remaining semisolid was triturated with ether and cooled to give an almost colorless solid, which was collected by filtration, washed with cold ether and dried. The solid was dissolved in chloroform and the resulting solution was treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The resulting semisolid was cooled and triturated with ether to give a colorless solid, which was collected by filtration, washed with cold ether and dried to give 5- (nonylamino) pyridine 51.7 having a melting point of 59-60 ° C. Further obtained 11.6 g of a secondary product having a melting point of 55-57 ° C. from the filtrate.

B. As another method, 4- (nonylamino) pyridine was prepared as follows. That is, a solution of 4- (aminopyridine 39.5 g (0.42 mole), nonylaldehyde 175 g (1.24 mole) and 5.0 g of 10% carbonaceous palladium hydrogenation catalyst was added with anhydrous ethanol in sufficient amount to warm the solution to a total capacity of 600 ml. The hydrogenation was carried out at 45 psi hydrogen pressure until the end of hydrogen absorption, the reaction mixture was filtered to remove the catalyst, the filtrate was evaporated to dryness under reduced pressure and the residual oil was distilled under vacuum to remove any nonyl alcohol which may have been produced. Fractions of 63-64 ° C./4.5 mm were collected and the residue was triturated with ether and cooled to −78 ° C. Precipitated solids were collected by filtration and washed with cold ether The product was dissolved in chloroform, The resulting solution was treated with activated charcoal, filtered and the filtrate was evaporated to dryness, the mixture was triturated with ether and cooled to -78 ° C. After washing with ether and drying in air, 27.0 g of 4- (nonylamino) pyridine having a melting point of 57-59 占 폚 was obtained.

C. A suspension of 11.0 g (0.05 mol) of acetonitrile (150 ml) of 4- (nonylamino) pyridine was stirred and warmed until a clear and homogeneous solution was obtained. To this clear solution was added 6.9 g (0.025 mol) of acetonitrile (50 ml) of 1,8-dibromooctane solution dropwise, and the resulting mixture was heated under reflux for 19 hours until a solid precipitated from the solution. After cooling, the solid was collected by filtration, and the solution obtained by re-dissolving in ethanol was treated with activated carbon, filtered, and evaporated to dryness under reduced pressure. The residual oil was triturated with ether containing a small amount of acetonitrile to obtain a colorless crystalline solid, which was collected by filtration and dried to dry 1,8-bis- [4- (nonylamino)-with a melting point of 178-179 ° C. 1-pyridinium] octane dibromide 15.5 g was obtained.

Example 30

Melting point 206-207 ° C by reaction in a similar manner as in Example 29C, except that 3.54 g (0.026 mol) of 4- (propylamino) pyridine and 3.90 g (0.013 mol) of 1,10-dibromodecane were used. 5.19 g of phosphorous 1,10-bis- [4- (propylamino) -1-pyridinium] decane dibromide was obtained.

Example 31

The reaction was carried out in a similar manner as in Example 29C, except that 14.24 g (0.08 mol) of 4- (hexylamino) pyridine and 9.20 g (0.04 mol) of 1,5-dibromopentane were recrystallized from acetonitrile-acetone. 12.3 g of 1,5-bis- [4- (hexylamino) -1-pyridinium] pentane dibromide having a melting point of 155-156 占 폚 was obtained.

Example 32

Melting point 180-181 ° C. by reaction in a similar manner as in Example 29C, except that 10.7 g (0.06 mol) of 4- (hexylamino) pyridine and 8.2 g (0.03 mol) of 1,8-dibromooctane were used. 16.3 g of phosphorous 1,8-bis- [4- (hexylamino) -1-pyridinium] octane dibromide was obtained.

Example 33

Melting point 148-149 ° C by reaction in a similar manner as in Example 29C, except that 12.5 g (0.07 mol) of 4- (hexylamino) pyridine and 10.5 g (0.035 mol) of 1,10-dibromodetane were used. 16.0 g of phosphorous 1,10-bis- [4- (hexylamino) -1-pyridinium] decane dibromide was obtained.

Example 34

Melting point 288-290 by reaction in a similar manner as in Example 29C, except that 13.4 g (0.076 mol) of 4- (cyclohexylamino) pyridine and 8.2 g (0.038 mol) of 1,4-dibromobutane were used. 18.2 g of 1,4-bis- [4- (cyclohexylamino) -1-pyridinium] octane dibromide was obtained.

Example 35

Melting point 255-256 by reaction in a similar manner as in Example 29C, except that 13.4 g (0.076 mol) of 4- (cyclohexylamino) pyridine and 8.75 g (0.038 mol) of 1,5-dibromopentane were used. 19.0 g of 1,5-bis- [4- (cyclohexylamino) -1-pyridinium] octane dibromide was obtained.

Example 36

Melting point 307-308 by reaction in a similar manner as in Example 29C, except that 13.4 g (0.076 mol) of 4- (cyclohexylamino) pyridine and 9.3 g (0.038 mol) of 1,6-dibromooctane were used. 19.1 g of 1,6-bis- [4- (cyclohexylamino) -1-pyridinium] hexane dibromide was obtained.

Example 37

Melting point 311-313 by reaction in a similar manner as in Example 29C, except that 13.4 g (0.076 mol) of 4- (cyclohexylamino) pyridine and 9.8 g (0.038 mol) of 1,7-dibromoheptane were used. 2.01 g of 1,7-bis- [4- (cyclohexylamino) -1-pyridinium] heptane dibromide was obtained.

Example 38

Melting point 270-271, by reacting in a similar manner as in Example 29C, except that 13.4 g (0.076 mol) of 4- (cyclohexylamino) pyridine and 10.34 g (0.038 mol) of 1,8-dibromooctane were used. 16.3g of 1,8-bis- [4- (cyclohexylamino) -1-pyridinium] octane dibromide which is ° C was obtained.

Example 39

Melting point 149-151 by reaction in a similar manner as in Example 29C, except that 13.4 g (0.076 mol) of 4- (cyclohexylamino) pyridine and 10.8 g (0.038 mol) of 1,9-dibromonodan were used. 16.3g of 1,9-bis- [4- (cyclohexylamino) -1-pyridinium] nonane dibromide which is ° C was obtained.

Example 40

Melting point 226-227 by reaction in a similar manner as in Example 29C, except that 13.4 g (0.076 mol) of 4- (cyclohexylamino) pyridine and 11.4 g (0.038 mol) of 1,10-dibromooctane were used. 19.0 g of 1,10-bis- [4- (cyclohexylamino) -1-pyridinium] hexane dibromide was obtained.

Example 41

A. A mixture of 198.0 g (1.33 mol) of N- (4-pyridyl) pyridinium chloride hydrochloride and 322 g (2 mol) of 2-ethylhexylamine hydrochloride was heated with stirring in an oil bath at 215 ° C. for 2 hours. The mixture was cooled to 60 ° C., diluted with 500 ml of water, cooled by addition of ice, and made alkaline by adding 35% aqueous sodium hydroxide solution. The alkaline mixture was extracted with ether and the etheric extract was distilled on anhydrous sodium sulfate to give 101.0 g of 4- (2-ethylhexylamino) pyridine having a boiling point of 145-150 ° C./0.9 mm.

B. As another method, 4- (2-ethylhexylamino) pyridine was prepared as follows. That is, a solution of dichloromethane (6.4 L) containing 800 g (8.4 mol) of 4-aminopyridine and 150 ml of triethylamine was stirred, and 1610 g (10.0 mol) of 2-ethylhexanoyl chloride was added thereto (1.6 L). The solution was added over 3 hours. The temperature during the addition was kept at 15 ° C. After the addition was completed, the reaction mixture was warmed in a steam bath for 2 hours. After cooling the reaction mixture, the reaction mixture was washed thoroughly with water and dried over anhydrous sodium sulfate. Then treated with activated carbon and filtered. The filtrate was evaporated to give 1843 g of N- (4-pyridyl) -2-ethylhexaneamide.

570 g (2.62 mol) of N- (4-pyridyl) -2-ethylhexanamide in a 2 liter tetrahydrofuran mixture containing 100 g (2.63 mol) of lithium aluminum hydride at a rate sufficient to maintain moderate reflux Tetrahydrofuran (4 L) solution was added. At the end of the addition (about 3 hours), the reaction mixture was heated under reflux for 7 hours. After cooling, the reaction mixture was treated with 100 ml of water, 100 ml of 15% aqueous sodium hydroxide solution, and 300 ml of water. The solid was removed by filtration, and the solvent was removed from the filtrate under reduced pressure. The residual oil was collected, combined with the product from the repeating process, and vacuum distilled to give 837 g of 4- (2-ethylhexaneamide) pyridine having a boiling point of 135-160 ° C / 0.2 mm.

C. 10.3 g (0.05 mol) of acetonitrile (50 ml) solution of 4- (2-ethylhexylamino) pyridine is warmed and stirred, and then contains 8.2 g (0.025 mol) of 1,12-dibromododecane. One acetonitrile (170 ml) solution was added dropwise. The resulting mixture was heated at reflux for 20 hours, cooled to 0 ° C. to precipitate the primary product which was collected by filtration. The filtrate was evaporated and the residue was triturated with ether to give a secondary product. This was collected, dissolved in methanol, and the resulting solution was treated with activated charcoal, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residual oil is cooled, recrystallized with ether, the product is then softened with ether and acetonitrile and dried under vacuum at 60 ° C. for 72 hours to give a colorless granular 1,12-bis- [4 with melting point of 146-147 ° C. 14.7 g of-(2-ethylhexylamino-1-pyridinium] dodecane dibromide was obtained.

Example 42

A. The mixture of 4- (2- (ethylhexylamino pyridine 353.5 g (1.72 mol) and 205 g (0.86 mol) 1,12-dichlorododecane was heated to 120 ° C. and the heat source was removed. Rose to 180-190 ° C. When the temperature reached 135 ° C. 1 L of acetonitrile was carefully added and the mixture was heated under reflux to obtain a clear solution A hot acetonitrile solution from two different streams. Combined with a similar solution, treated with activated charcoal and filtered, the filtrate was cooled and the precipitated product was collected by filtration, washed with cold acetonitrile, recrystallized twice with acetonitrile, 1,12 with melting point 168-171 ° C. -Bis- [4- (2-ethylhexylamino) -1-pyridinium] also obtained 970 g of decane dichloride

B. Similar to Example 2, except that 3.0 g (0.00405 moles) of 1,12-bis- [4- (2-ethylhexylamino) -1-pyridinium] dodecane dibromide was used as another method. The reaction was carried out to give 2.0 g of the corresponding dichloride having a melting point of 172-173 ° C.

Example 45

Melting point 129-131 ° C by reaction in a similar manner as in Example 41C, except that 10.3 g (0.05 mol) of 4- (octylamino) pyridine and 6.45 g (0.025 mol) of 1,7-dibromoheptane were used. 14.85 g of phosphorous 1,7-bis- [4- (octylamino) -1-pyridinium] heptane dibromide was obtained.

Example 44

A. Melting point 117- by reacting in a similar manner as in Example 41C, except that 11.1 g (0.054 mol) of 4- (octylamino) pyridine and 7.72 g (0.027 mol) of 1,9-dibromononane were used. 17.0 g of 1,9-bis- [4- (octylamino) -1-pyridinium] nonane dibromide at 119 ° C was obtained.

B. By the method of Example 2, the corresponding dichloride was prepared having a melting point of 161-162 ° C.

Example 45

Melting point 119-120 ° C by reaction in the same manner as in Example 41C, except that 10.3 g (0.05 mol) of 4- (octylamino) pyridine and 8.2 g (0.025 mol) of 1,12-dibromodecane were used. 15.2 g of phosphorus 1,12-bis- [4- (octylamino) -1-pyridinium] dodecane dibromide was obtained.

Example 46

Melting point 113-115 by reaction in a similar manner as in Example 41C, except that 5.8 g (0.028 mol) of 4- (octylamino) pyridine and 5.0 g (0.014 mol) of 1,14-dibromotetradecane were used. 9.3g of 1,14-bis- [4- (octylamino) -1-pyridinium] tetradecane dibromide which is ° C was obtained.

Example 47

Melting point 152-154 ° C by reaction in a similar manner as in Example 41C, except that 11.0 g (0.05 mol) of 4- (nonylamino) pyridine and 6.1 g (0.025 mol) of 1,6-dibromohexane were used. 15.2 g of phosphorous 1,6-bis- [4- (nonylamino) -1-pyridinium] hexane dibromide was obtained.

Example 48

1,6-bis- [4- (nonylamino) -1-pyridinium] Hexane dibromide was reacted in a similar manner as in Example 4 except that 6.5 g (0.0095 mol) was used, and the melting point was 194-195 ° C. 4.95 g of phosphorous dichloride was obtained.

Example 49

Melting point 132-134 ° C by reaction in a similar manner as in Example 41C, except that 8.8 g (0.4 mol) of 4- (nonylamino) pyridine and 5.2 g (0.02 mol) of 1,7-dibromoheptane were used. 12.2 g of phosphorous 1,7-bis- [4- (nonylamino) -1-pyridinium] heptane dibromide was obtained.

Example 50

Melting point 121-122 ° C by reaction in a similar manner as in Example 41C, except that 11.0 g (0.05 mol) of 4- (nonylamino) pyridine and 7.15 g (0.025 mol) of 1,9-dibromononane were used. 15.7 g of phosphorous 1,9-bis- [4- (nonylamino) -1-pyridinium] nonane dibromide was obtained.

Example 51

Melting point 172-173 ° C by reaction in a similar manner as in Example 41C, except that 11.0 g (0.05 mol) of 4- (nonylamino) pyridine and 7.5 g (0.025 mol) of 1,10-dibromomecan were used. 15.63 g of phosphorous 1,10-bis- [4- (nonylamino) -1-pyridinium] decane dibromide was obtained.

Example 52

Melting point 105-106 ° C by reaction in a similar manner as in Example 41C, except that 10.12 g (0.046 mol) of 4- (nonylamino) pyridine and 7.54 g (0.023 mol) of 1,12-dibromododecane were used 16.4 g of phosphorous 1,12-bis- [4- (nonylamino) -1-pyridinium] dodecane dibromide was obtained.

Example 53

After stirring and warming the acetonitrile (100 ml) solution containing 12.4 g (0.06 mol) of 4- (2-ethylhexylamino) pyridine, 6.9 g (0.03 mol) of aceto of 1,5-dibromopentane was added thereto. Nitrile (25 ml) solution was added dropwise and the resulting solution was heated at reflux for 20 h. The reaction mixture was cooled and diluted with ether until slightly cloudy. It was cooled again and stirred to give a solid precipitate, which was collected by filtration and washed with a cold mixture of acetonitrile and ether. The solid thus obtained was dissolved in ethanol and the resulting solution was treated with activated carbon and filtered. The filtrate was evaporated to give a viscous pale yellow oil which was crystallized from acetonitrile-ether. The resulting Gote was collected by filtration, washed with cold acetonitrile-ether, and dried under vacuum at 90 ° C. for 24 hours to give 1,5-bis- [4- (2-ethylhexylamino)-with a melting point of 150-151 ° C. 13.6 g of 1-pyridinium] pentane dibromide was obtained.

Example 54

Melting point 208 was carried out in the same manner as in Example 53, except that 12.4 g (0.06 mol) of 4- (2-ethylhexylamino) pyridine and 7.32 g (0.03 mol) of 1,6-dibromohexane were used. 16.1 g of 1,6-bis- [4- (2-ethylhexylamino) -1-pyridinium] hexane dibromide at -209 ° C was obtained.

Example 55

Melting point 219 by reaction in a similar manner as in Example 53, except that 12.4 g (0.06 mol) of 4- (2-ethylhexylamino) pyridine and 7.75 g (0.03 mol) of 1,7-dibromoheptane were used. 17.9 g of 1,7-bis- [4- (2-ethylhexylamino) -1-pyridinium] heptane dibromide at -220 ° C was obtained.

Example 56

Melting point 160 by reaction in a similar manner as in Example 53, except that 12.4 g (0.06 mol) of 4- (2-ethylhexylamino) pyridine and 8.2 g (0.03 mol) of 1,8-dibromooctane were used. 15.2g of 1,8-bis- [4- (2-ethylhexylamino) -1-pyridinium] octane dibromide which is -161 degreeC was obtained.

Example 57

Melting point 158 by reaction in a similar manner as in Example 53, except that 12.4 g (0.06 mol) of 4- (2-ethylhexylamino) pyridine and 8.6 g (0.03 mol) of 1,9-dibromononane were used. 15.2 g of 1,9-bis- [4- (2-ethylhexylamino) -1-pyridinium] nonane dibromide at -159 ° C was obtained.

Example 58

Melting point 162 was carried out in a similar manner as in Example 53, except that 12.4 g (0.06 mol) of 4- (2-ethylhexylamino) pyridine and 9.0 g (0.03 mol) of 1,10-dibromodecane were used. 17.4 g of 1,10-bis- [4- (2-ethylhexylamino) -1-pyridinium] decane dibromide at -163 ° C was obtained.

Example 59

The reaction was carried out in the same manner as in Example 2 except that 5.0 g of 1-10-bis- [4- (2-ethylhexylamino) -1-pyridinium] decane dibromide was used, and the melting point was 191-192 ° C. 4.11 g of the corresponding dichloride was obtained.

Example 60

After stirring and warming 12.0 g (0.063 mol) of acetonitrile (100 ml solution of 4- (heptylamino) pyridine (100 ml solution), 7.1 g (0.032 mol) of acetonitrile (25 ml) solution of 1,5-dibromopentane was added thereto. The reaction mixture was heated to reflux for 19 hours under reflux, and the reaction mixture was cooled on ice and ether slowly added until a colorless solid precipitated out, the solids were collected by filtration and recrystallized from acetonitrile-ether. It dried for 48 hours at 90 degreeC / 1mm, and obtained 15.9g of 1.5-bis- [4- (heptylamino) -1-pyridinium] pentane dibromide which has a melting point of 153-154 degreeC.

Example 61

27.5 g of crude product was reacted in a similar manner as in Example 60 except that 12.2 g (0.05 mole) of 1,6-dibromohexane of 19.2 g (0.1 mole) of 4- (heptylamino) pyridine was used. Got it. 15 g of the sample was recrystallized from acetonitrile-ether to obtain 11.45 g of 1,6-bis- [4- (heptylamino) -1-pyridinium] hexane beadamide having a melting point of 149-150 ° C.

Example 62

A suspension obtained by adding 24.0 g of crude 1,6-bis- [4- (heptylamino) -1-pyridinium] hexane dibromide to 500 ml of water was alkalized with an aqueous 3N barium hydroxide solution, and then extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The solution obtained by dissolving the residual oil in methanol was acidified with methane-sulfonic acid and then evaporated to dryness under reduced pressure. The residue was redissolved in methanol, treated with activated charcoal, filtered and evaporated to dryness under reduced pressure to give an oily residue which was triturated with ether and acetonitrile to give 18.2 g of a gummy solid. The crude replacement obtained was dissolved in water and the solution obtained was made alkaline with 35% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. The resulting solid was triturated with ether and acetonitrile, collected by filtration and dried to give 16.3 g of a tan solid with a melting point of 105-108 ° C. The solution obtained was dissolved in 100 ml of methanol and the resulting solution was acidified with methanesulfonic acid. Evaporated to dryness under reduced pressure to give a viscous oil, which was dissolved in 20 ml of methanol and treated with 150 ml of water little by little. The resulting suspension was cooled on ice and the suspended solids were collected by filtration and washed with cold water. The solid was slurried in hot acetone, cooled, collected by filtration, washed with cold acetone, and dried for 48 hours at 95 ° C./1 mm to give 10.8 g of a tan solid having a melting point of 163-165 ° C. This product was positive in the chlorine ion test by silver nitrate, and no methanesulfonate group appeared in the hex resonance spectrum.

B. 1,6-bis- [4- (heptylamino) -1-pyridinium] 14.0 g of hexanes dibromide was added to 500 ml of water, and the suspension was made alkaline with 35% aqueous sodium hydroxide solution and then extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The solution obtained by dissolving the partially solid residue in 1 L of acetonitrile-benzene was evaporated to dryness in vacuo. This process was repeated three times. The final residue was dissolved in 50 ml of acetonitrile and the resulting solution was diluted with 50 ml of benzene, cooled on ice, filtered and dried to give 5.3 g of a tan solid. From the filtrate, 4.8 g of secondary product was obtained. This was combined and dissolved in 50 ml of acetonitrile. The precipitated solid was diluted with ether, collected by filtration and dried for 48 hours at 95 ° C / 1 mm to obtain 8.85 g of a tan solid having a melting point of 174-176 ° C. This product was also positive in the chlorine ion test by nitric acid temperature.

C. The products of A and B were combined and mixed with 300 ml of water and heated until a homogeneous solution. The solution was filtered and the filtrate was treated with 50 ml of 12N hydrochloric acid. The resulting suspension was concentrated under reduced pressure and the residue was treated with ice. The solid thus obtained was collected by filtration, washed with cold water and dried. This product was dissolved in acetone and the resulting solution was diluted with a mixture of benzene and ethanol and then all evaporated to dryness in vacuo. The solid residue was slurried in 100 ml of acetone, the slurry was diluted with ether, filtered and dried for 48 hours at 105 ° C./1 mm and 72 hours at 115 ° C./1 mm to give a coarse white solid at a melting point of 176-178 ° C. 16.3 g of 1,6-bis- [4- (heptylamino) -1-pyridinium] hexane dichloride was obtained.

Example 63

Melting point 245 was carried out in the same manner as in Example 60, except that 10.30 g (0.050 mol) of 4- (2-ethylhexylamino) pyridine and 5.4 g (0.025 mol) of 1,4-dibromobutane were used. 14.0 g of 1,4-bis- [4- (2-ethylhexylamino) -1-pyridinium] hexane dibromide at -246 ° C was obtained.

Example 64

A. A mixture of 229 g (1.0 mole) of N- (4-pyridine) pyridinium chloride hydrochloride and 244 g (1.26 mole) of n-decylamine hydrochloride was stirred and then heated at 190-195 ° C. for about 2.5 hours. The reaction mixture was slowly cooled to 40 ° C. and diluted with 2 liters of water. Ice was added to the resultant solution, followed by cooling, and made alkaline with 200 ml of 35% aqueous sodium hydroxide solution. The separated blackish solid was collected by filtration and washed with cold water. After dissolving this material in 1 l of chloroform, the resulting solution was washed with activated charcoal and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with 150 ml of ether. The solution obtained by dissolving the solid thus obtained in chloroform was treated with activated carbon and filtered. The filtrate was again treated with activated charcoal and filtered. The filtrate was evaporated to dryness under reduced pressure and the residual solid was triturated with ether. Recrystallized from acetonitrile and dried in vacuo to give 96.1 g of 4- (decylamino) pyridine having a melting point of 71-73 占 폚.

B. 12.2 g (0.052 mol) of a 4- (decylamino) pyridine-acetonitrile (150-170 ml) solution was stirred and warmed, followed by aceto containing 6.35 (0.026 mol) of 1,6-dibromohexane. Nitrile (60 ml) solution was added dropwise. The resulting mixture was heated at reflux for about 20 hours. The reaction mixture was cooled with ice and the precipitated solid was collected by filtration and washed with cold acetonitrile. The product thus obtained was dissolved in methanol and the resulting solution was treated with activated charcoal and filtered. The filtrate was evaporated to dryness under reduced pressure, the yarn was triturated with 50 ml of cold ether, collected by filtration, and dried over 70 days at 70 ° C./0.1 mm phosphorus pentoxide to give 1,6-bis- [4- ( Decylamino) -1-pyridinium] hexane dibromide 14.6 g was obtained.

Example 65

Melting point 145-147 ° C by reaction in a similar manner as in Example 64B, except that 12.2 g (0.052 mol) of 4- (decylamino) pyridine and 6.7 g (0.026 mol) of 1,7-dibromoheptane were used. 16.0 g of phosphorous 1,8-bis- [4- (decylamino) -1-pyridinium] heptane dibromide was obtained.

Example 66

Melting point 180-182 ° C by reaction in a similar manner as in Example 64B, except that 11.7 g (0.050 mole) of 4- (decylamino) pyridine and 6.8 g (0.025 mole) of 1,8-dibromooctane were used. 16.9 g of phosphorous 1,8-bis- [4- (decylamino) -1-pyridinium] octane dibromide was obtained.

Example 67

Melting point 124-126 ° C by reaction in a similar manner as in Example 64B, except that 11.7 g (0.050 mole) of 4- (decylamino) pyridine and 7.15 g (0.025 mole) of 1,9-dibromononane were used. 15.1 g of phosphorous 1,9-bis- [4- (decylamino) -1-pyridinium] nonane dibromide was obtained.

Example 68

Melting point 173-174 ° C. by reaction in a similar manner as in Example 64B, except that 11.2 g (0.048 mole) of 4- (decylamino) pyridine and 7.2 g (0.024 mole) of 1,10-dibromooctane were used. 14.6 g of phosphorous 1,10-bis- [4- (decylamino) -1-pyridinium] octane dibromide was obtained.

Example 69

Melting point 102-106 ° C by reaction in a similar manner as in Example 64B, except that 11.2 g (0.050 mole) of 4- (decylamino) pyridine and 7.9 g (0.024 mole) of 1,12-dibromododecane were used. 16.5 g of phosphorus 1,12-bis- [4- (decylamino) -1-pyridinium] dodecane dibromide was obtained.

Example 70

Acetonitrile (140 ml) solution containing 13.6 g (0.052 mol) of 4- (dodecylamino) pyridine was stirred and warmed, followed by 6.34 g (0.026 mol) of acetonitrile (50 ml) of 1,6-dibromohexane. The solution was added dropwise and the resulting mixture was heated at reflux overnight. The reaction mixture was cooled down and the precipitated solid was collected by filtration. This solid was dissolved in anhydrous ethanol, and the resulting solution was treated with activated carbon and filtered. The filtrate was evaporated to dryness under reduced pressure to give a white residual solid which was slurried with ether, filtered and collected and dried at 60 ° C./0.1 mm to give 1,6-bis- [4- (dodecyl having a melting point of 164-165 ° C. Amino) -1-pyridinium] hexane dibromide 17.63 g was obtained.

Example 71

Melting point 148-150 by reaction in the same manner as in Example 70 except that 13.6 g (0.052 mol) of 4- (dodecylamino) pyridine and 6.71 g (0.026 mol) of 1,7-dibromoheptane were used. 18.03 g of 1,7-bis- [4- (dodecylamino) -1-pyridinium] heptane dibromide was obtained.

Example 72

Melting point 148-185 by reaction in a similar manner as in Example 70, except that 12.59 g (0.048 mol) of 4- (dodecylamino) pyridine and 6.53 g (0.024 mol) of 1,8-dibromooctane were used. 16.18 g of 1,8-bis- [4- (dodecylamino) -1-pyridinium] octane dibromide was obtained.

Example 73

Melting point 134-135 by reaction in a similar manner as in Example 70, except that 12.59 g (0.048 mol) of 4- (dodecylamino) pyridine and 6.86 g (0.024 mol) of 1,9-dibromononane were used. 19.35 g of 1,9-bis- [4- (dodecylamino) -1-pyridinium] nonane dibromide was obtained.

Example 74

Melting point 178-180 by reaction in a similar manner as in Example 70, except that 12.59 g (0.048 mol) of 4- (dodecylamino) pyridine and 7.2 g (0.024 mol) of 1,10-dibromodecane were used. 18.08 g of 1,10-bis- [4- (dodecylamino) -1-pyridinium] decane dibromide which is ° C was obtained.

Example 75

Melting point 75-77 by reacting in a similar manner as in Example 70, except that 11.54 g (0.044 mol) of 4- (dodecylamino) pyridine and 7.22 g (0.022 mol) of 1,12-dibromodecane were used. 17.68 g of 1,12-bis- [4- (dodecylamino) -1-pyridinium] dodecane dibromide was obtained.

Example 76

A. A solution of N, N-dimethylformamide (150 ml) containing 21.0 g (0.102 mol) of 4- (P-chlorophenylamino) pyridine was stirred and warmed, followed by 11.02 g of 1,4-dibromobutane. Acetonitrile (50 ml) solution containing 0.051 mol) was added dropwise. The resulting mixture was heated in a steam bath for 2.5 hours. The reaction mixture was cooled at room temperature, bevoled with ether and the product crystallized. The precipitated solids were collected by filtration, washed with a mixture of acetonitrile and ether, and then dried in air to produce 1,4-bis- [4- (P-chlorophenylamino) -1-pyridium with a melting point of 182-189 ° C. 27.4 g of butane dibromide were obtained.

B. The product was treated with ice and 2N aqueous sodium hydroxide solution in suspension suspended in 500 ml of water. The resulting mixture was extracted completely with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 21.0 g of a compatible anhydrous base in an oily state which solidified upon standing.

C. 250 ml of the methanol solution containing the anhydrous base was acidified with a metal of methane-sulfonic acid. Evaporation to dryness under reduced pressure afforded an oil which was crystallized from methanol-ether. The solid thus obtained was recrystallized from methanol-ether and dried at 92 ° C./0.1 mm for 48 hours to give 1,4-bis [4- (P-chloro phenylamino (-1-pyridinium] butane having a melting point of 245-247 ° C. Dimethylsulfonate 18.95 was obtained

Example 77

A. N, N-dimethylformamide solution (200 ml) containing 21.0 g (0.102 mol) of 4- (P-chlorophenylamino) pyridine was stirred and warmed, followed by 12.45 g of 1,6-dibromohexane. 0.051 mole) of acetonitrile (50 ml) was added dropwise. The resulting mixture was heated in a steam bath for 4 hours. After cooling to room temperature solids began to precipitate. The reaction mixture was diluted with 150 ml of acetonitrile and cooled once more on ice. The precipitated solid was collected by filtration and, upon air drying, 27.2 g of 1,6-bis- [4- (P-chlorophenylamino) -1-pyridinium] hexane dibromide was obtained at a 148-150 ° C. point.

B. The methanol solution of the corresponding anhydrous base prepared from the dibromide according to the method of Example 76B was acidified with methanesulfonic acid and then evaporated to dryness under reduced pressure. The residual oil was crystallized with acetone-methanol and dried at 75 ° C./0.1 mm for 48 hours to give 1,6-bis- [4- (P-chlorophenylamino-1-pyridinium] hexane dimethane having a melting point of 108-110 ° C. 25.2 g of sulfonate were obtained.

Example 78

A. N, N-dimethylformamide solution (200 ml) containing 21.0 g (0.102 mol) of 4- (P-chlorophenylamino) pyridine was stirred and warmed, followed by 13.9 g of 1,8-dibromooctane. Acetonitrile (50 ml) solution containing 0.051 mol) was added dropwise. The resulting mixture was heated in a steam bath for 1.5 hours. The reaction mixture was diluted with 100 ml of acetonitrile and further heated for 2.5 hours before further 100 ml of acetonitrile. After further heating for 2 hours, the reaction mixture was cooled, the precipitated solid was collected by filtration, washed with a mixture of acetonitrile and ether, and then dried to obtain 1,8-bis- [4- (P-) having a melting point of 245-247 ° C. 30.1 g of chloro phenylamino) -1-pyrididium] octane dibromide were obtained.

B. The methanol solution of the corresponding inorganic base prepared from the dibromide according to the method of Example 76B was acidified with methanesulfonic acid and then evaporated to dryness under reduced pressure. The residual oil was dissolved in acetonitrile and the resulting solution was treated with acetone until cloudy and cleared with a small amount of methanol and then cooled. The precipitated crude solid was collected, recrystallized from acetonitrile-acetone and dried for 36 hours at 80 ° C./0.1 mm to give 1,8-bis- [4- (P-chlorophenylamino-1- at 164-165 ° C. 25.2 g of pyridinium] octane dimethanesulfonate was obtained.

Example 79

A. N, N-dimethylformamide solution (200 ml) containing 21.0 g (0.102 mol) of 4- (P-chlorophenylamino) pyridine was stirred and warmed, followed by 15.3 g of 1,10-dibromodecane ( 0.0051 mole) of acetonitrile (50 ml) was added dropwise. The resulting mixture was heated in a steam bath for 3.5 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residual oil was crystallized from methanol-acetonitrile. The resulting solids were collected by filtration and washed with a cold mixture of acetonitrile and ether to give 1,10-bis- [4- (P-chloro phenylamino) -1-pyridinium] decane dibromide 28.0 having a melting point of 225-230 ° C. g was obtained.

B. The methanol solution of the corresponding anhydrous base prepared from the dibromide according to the method of Example 76B was acidified with methanesulfonic acid and then evaporated to dryness under reduced pressure. The residual oil was crystallized with acetonitrile-ether and the resulting crude solid was dissolved in methanol. This solution was treated with activated charcoal and filtered. The filtrate was evaporated to give an oil which was suspended in the mixture with acetonitrile and acetone to give a crude solid. Recrystallized from methanol-ether and dried for 48 hours at 95 ° C./0.1 mm to obtain 18.4 g of 1,10-bis- [4- (P-chlorophenylamino-1-pyridinium] decane sulfonate at a melting point of 202-204 ° C. Got it.

Example 80

A mixture solution of 275 ml of acetonitrile containing 10.0 g (0.04 mol) of 4- (P-chloro phenylamino) pyridine and 100 ml of N, N-dimethylformamide was stirred and warmed, and then 1,5-dibromopentane 5.75 g (0.025 mol) of acetonitrile (25 ml) solution was added dropwise. This mixture was heated at reflux for 24 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residue was triturated with ether and acetonitrile. The resulting pale yellow solid was redissolved in ethanol, and the resulting solution was treated with split coal and filtered. The filtrate was evaporated to dryness under reduced pressure and the residual oil was crystallized from ether-acetonitrile. The colorless solid was recrystallized from methanol-acetonitrile and dried for 48 hours at 115 ° C./0.1 mm to give 1,5-bis- [4- (P-chloro phenylamino) -1-pyridinium] having a melting point of 166-168 ° C. 8.1 g of pentane dibromide was obtained.

Example 81

In a mixture of 125 ml of N, N-dimethylformamide and 50 ml of acetonitrile, a solution containing 10.0 g (0.049 mol) of 4- (P-chlorophenylamino) pyridine was stirred and warmed, followed by 1,7-dibro 6.45 g of acetonitrile (25 ml) solution of moheptane was added dropwise, and the mixture was heated at reflux for 19 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residual oil was crystallized from ethanol-acetonitrile. The solid thus produced was dissolved in methanol, and the resulting solution was treated with activated carbon and filtered. The filtrate was evaporated to dryness in vacuo and the residual oil was crystallized again with ethanol-acetonitrile. The collected product was dried for 36 hours at 105 ° C./0.1 mm to obtain 10.4 g of 1,7-bis- [4- (P-chlorophenylamino) -1-pyridinium] heptane dibromide having a melting point of 202-204 ° C. Got it.

Example 82

Melting point 178 by reaction in a similar manner as in Example 81, except that 10.0 g (0.049 mol) of 4- (P-chlorophenylamino) pyridine and 7.15 g (0.025 mol) of 1,9-dibromononane were used. 11.2 g of 1,9-bis- [4- (P-chlorophenylamino) -1-pinidinium] nonane dibromide at -179 ° C was obtained, and the following bis- [4- ( R-amino) -1-pyridinium] alkane was obtained. In other words,

N- (4-pyridyl) -pyridinium chloride hydrochloride was reacted with tetradecylamine hydrochloride to give 4- (tetradecylamino) pyridine, followed by 1,6-dibromo-3-ethylhexane The reaction was carried out to obtain 3-ethyl-1,6-bis- [4- (tetradecylamino) -1-pyridinium] hexane dibroide.

N- (4-pyridyl) -pyridinium chloride hydrochloride was reacted with octadecylamine hydrochloride to obtain 4- (octadecylamino) pyridine, which was then reacted with 1,5-dibromopentane to give 1, 5-bis- [4- (octadecylamino) -1-pyridinium] hexanes dibromide was obtained.

N- (4-pyridyl) -pyridinium chloride hydrochloride is reacted with 2,2-dimethylbutylamine hydrochloride to give 4- (2,2-dimethylbutylamino) pyridine, followed by 1,11-di Bromo-3-methyl undecane was reacted to obtain 1,11-bis- [4- (2,2-dimethylbutylamino) -1-pyridinium] -3-methyl undecane dibromide.

N- (4-pyridyl) -pyridinium chloride hydrochloride is reacted with 1,4-dimethylpentylamine hydrochloride to give 4- (1,4-dimethylpentylamino) pyridine, followed by 1,18-di Bromoocta tadecane was reacted to obtain 1,18-bis- [4- (1,4-dimethylpentylamino) -1-pyridinium] octadecane dibromide.

N- (4-pyridyl) -pyridinium chloride hydrochloride is reacted with 1,5-dimethyl-4-ethylhexylmin hydrochloride to give 4- (1,5-dimethyl-4-ethylhexylamino) pyridine, This was then reacted with 1,12-dibromo-4,9-dimethyldodecane to give 4,9-dimethyl-1,12-bis- [4- (1,5-dimethyl-4-ethylhexylamino)- 1-pyridinium] dodecane dibromide was obtained.

N- (4-pyridyl) -pyridinium chloride hydrochloride was obtained with 1,4- (cyclopentylamino) pyridine, and then reacted with 1,10-dichlorodecane to give 1,10-bis- [4- ( Cyclopentylamino) -1-pyridinium] decane dichloride was obtained.

N- (4-pyridyl) -pyridinium chloride hydrochloride is reacted with cycloheptylamine hydrochloride to give 4- (cycloheptylamino) pyridine, followed by reaction with 1,12-dibromo octadecane 1 , 12-bis- [4- (cycloheptylamino) -1-pyridinium] dodecane dichloride was obtained.

N- (4-pyridyl) -pyridinium chloride hydrochloride is reacted with P-bromoaniline hydrochloride to give 4- (P-bromophenylamino) pyridine, followed by 1,6-dibromo- 3-methylhexane was reacted to obtain 1,6-bis- [4- (P-bromophenylamino) -1-pyridinium] -3-methylhexane dibromide.

N- (4-pyridyl) -pyridinium chloride hydrochloride is reacted with m-fluoro aniline hydrochloride to give 4- (m-fluorophenylamino) pyridine, followed by 1,10-dibromodecane The reaction was carried out to obtain 1,10-bis- [4- (m-fluorophenylamino) -1-pyridinium] decane dibromide.

N- (4-pyridyl) -pyridinium chloride hydrochloride is reacted with 3-chloro-4-fluoroaniline hydrochloride to give 4- (3-chloro-4-fluoro phenylamino) pyridine, followed by 1,4-dibromo-2-ethylbutane was reacted to obtain 1,4-bis- [4- (3-chloro-4-fluorophenylamino) -1-pyridinium-2-ethylbutane dibromide . 1,10-dichlorodecane was reacted with 4- (benzylamino) pyridine to give 1,10-bis- [4- (benzylamino) -1-pyridinium] decane dichlororod.

N- (4-pyridyl) -pyridinium chloride hydrochloride was reacted with 3,4-methylenedioxyaniline hydrochloride to obtain 4- (3,4-methylenedioxyphenylamino) pyridine, followed by 1, 8-dibromooctane was reacted to obtain 1,8-bis- [4- (3,4-methylenedioxyphenylamino-1-pyridinium] octane dibromide.

N- (4-pyridyl) pyridinium chloride hydrochloride is reacted with P-ethylaniline hydrochloride to obtain 4- (P-enylphenylamino) pyridine, which is then reacted with 1,9-dibromononane 1,9-bis- [4- (P-ethylphenylamino) -1-pyridiniumnonane dibromide was obtained.

N- (4-pyridyl) pyridinium chloride hydrochloride is reacted with P-anisidine hydrochloride to give 4- (P-methoxyphenylamino) pyridine, which is then reacted with 1,10-dichlorodecane to give 1 , 10-bis- [4- (P-methoxyphenylamino) -1-pyridinium] decane dichloride was obtained.

N- (4-pyridyl) pyridinium chlorolide hydrochloride is reacted with m-fluoro aniline hydrochloride to give 4- (m-nitrophenylamino) pyridine, followed by 1,11-dibromodecane The reaction was carried out to obtain 1,11-bis- [4- (m-nitrophenylamino) -1-pyridinium] undecane dibromide.

N- (4-pyridyl) pyridinium chlorolide hydrochloride is reacted with 0-cyano aniline hydrochloride to give 4- (0-cyanophenylamino) pyridine, followed by 1,12-dibromododecane Was reacted to obtain 1,12-bis- [4- (0-cyanophenylamino) -1-pyridinium] dodecane dibromide.

N- (4-pyridyl) pyridinium chlorolide hydrochloride was reacted with m- (trifluoromethyl) aniline hydrochloride to give 4- [m- (trifluoromethyl) phenylamino) pyridine, 1,16-dibromo hexadecane was reacted to obtain 1,16-bis- [4- [m- (trifluoromethyl) phenylamino) -1-pyridinium] hexadecane dibromide.

N- (4-pyridyl) pyridinium chlorolide hydrochloride is reacted with 2-methoxy-5-methylaniline hydrochloride to give 4- (2-methoxy-5-methylphenylamino) pyridine, followed by 1 , 7-dibromoheptane was reacted to obtain 1,7-bis- [4- (2-methoxy-5-methylphenylamino) -1-pyridinium] heptane dibromide.

Specific examples of bis- [4- (R-amino-1-pyridinium] alkanes of the formula (I) prepared according to the above-described method are shown below.

3-methyl-1,5-bis [4-undecylamino) -1-pyridinium] pentane dibromide, 3-methyl-1,5-bis [4-tridecylamino) -1-pyridinium] pentane di Chloride, 4,4-dimethyl-1,7-bis- [4- (pentadecylamino) -1-pyridinium] hentane sulfate, 2,6-dimethyl-1,7-bis- [4- (hexadecylamino ) -1-pyridinium) heptane disulfamate, 1-methyl-1,4-bis- [4-heptadecylamino) -1-pyridinium] butane dibenzenesulfonate, 2,4,4-trimethyl-1 , 6-bis- [4- (2-methylhexylamino) -1-pyridinium] hexane bis-cyclohexylsulfamate, 1,17-bis- [4- (3-ethylpentylamino) -1-pyridinium ] Heptadecane dibromide, 1,16-bis- [4- (1- (ethylhexylamino) -1-pyridinium] hexadecane dinitrate, 1,15-bis- [4- (heptylamino) -1 -Pyridinium] pentadecane dibromide, 1,13-bis- [4- (octylamino) -1-pyridinium] tridecane di-2-naphthalenesulfonate, -1,11-bis- [4- (3 Ethylheptylamino) -1-pyridinium) undecane 2,6- Naphthalenesulfonate, 4-methyl-1,14-bis- [4- (2-propylpentylamino) -1-pyridinium) tetradecane dichloride, 5-ethyl-1,9-bis- [4 (1, 3,5-trimethylhexylamino) -1-pyridinium] nonane dibromide, 3,3,6,6-tetramethyl-1,8-bis- [4- (heptylamino (-1-pyridinium] octane di Bromide, 2,13-dimethyl-1,14-bis [4- (1,2-dimethyltetradecylamino) -1-pyridinium] tetradecyldibromide, 1,6-bis- [4- (1-methyl Pentylamino) -1-pyridinium] hexanedi-P-toluenesulfonate, 1,8-bis- [4- (2-methylheptylamino) -1-pyridinium] octane diiodide, 1,8-bis -[4- (2-methyl-3-ethylpentylamino) -1-pyridinium] octanediethanesulfonate, 1,9-bis- [4- (0-chlorophenylamino) -1-pyridinium] no Nadibromide, 1,8-bis- [4- (P-iodophenylamino) -1-pyridinium] octane diioide, 1,12-bis- [4- (2,4-difluorophenylamino ) -1-pyridinium] dodecanedibromide, 1,11- S- [4- (2,5-dibromophenylamino) -1-pyridinium] undecandibromide, 1,10-bis- [4- (3,5-dichlorophenylamino) -1-pyridinium] Decandichloride, 1,8-bis- [4- (2-fluorobenzylamino) -1-pyridinium] octanedichloride, 1,18-bis- [4- (3,4-dichlorobenzylamino)- 1-pyridinium] octadecanedibromide, 1,4-bis- [4- (4-hydroxy-3-methoxybenzylamino) -1-pyridinium] butanedibromide and 1,12-bis [4- (4-methylbenzylamino) -1-pyridinium] dodecanedibromide.

Example 83

,

'-디브로모-P-크실렌 7.92g(0.03몰)의 아세토니트릴(150ml)용액을 소량씩 적가했다. 첨가가 끝난후 다량의 무색 결정을 용액으로 부터 분리시켰다. 반응혼합물을 환루하에서 6시간 가열했다. 실온으로 냉각한 후 고체 생성물을 여과하여 모으고, 아세토니트릴-에테르로 새척한 후, 앞서 얻어진 생성물 3.1g과 함해서 100℃/0.1mm에서 28시간 건조시켜, 융점 297-298℃인

,

'-비스-[4-(헵틸아미노)-피리디늄]-P-크실렌디브로마이드 22.0g을 얻었다.After acetonitrile (100 ml) solution containing 11.52 g (0.06 mol) of 4- (heptylamino) pyridine is warmed and stirred,

,

7.92 g (0.03 mol) of acetonitrile (150 ml) of '-dibromo-P-xylene was added dropwise in small portions. After the addition was completed, a large amount of colorless crystals were separated from the solution. The reaction mixture was heated under reflux for 6 hours. After cooling to room temperature, the solid product was collected by filtration, carburized with acetonitrile-ether, and then dried at 100 ° C./0.1 mm with 3.1 g of the previously obtained product for 28 hours to obtain a melting point of 297-298 ° C.

,

22.0 g of '-bis- [4- (heptylamino) -pyridinium] -P-xylenedibromide was obtained.

Example 81

,

'-디브로모-P-크실렌 8.7g(0.033)몰을 사용하고 반응 혼합물을 20시간동안 환류시킨 것을 제외하고는 실시예 83에서와 유사하게 반응시켜, 융점 313-315℃인

,

'-비스-[4-(헥실아미노)피리디늄]-P-크실렌디 브로마이드 19.3g을 얻었다.11.6 g (0.065 mol) of 4- (hexylamino) pyridine

,

The reaction was conducted in a similar manner as in Example 83 except that 8.7 g (0.033) mole of '-dibromo-P-xylene was used and the reaction mixture was refluxed for 20 hours, and the melting point was 313-315 ° C.

,

19.3 g of '-bis- [4- (hexylamino) pyridinium] -P-xylenedi bromide was obtained.

Example 85

,

'-디클로로-2,3,5,6-테트라메틸-P-크실렌 23g을 메탄올 600ml에 현탁시키고, 이 현탁액을 완전 용액의 되도록 증기욕상에서 가열했다. 소량의 불용성 물질을 여과한 후 맑은 용액을 증기욕에서 2시간 가온하였을 때 흰색고체가 분리되기 시작했다. 반응혼합ㅁ루을 실온까지 냉각하고, 고형 생성물을 여과하여 모은후 메탄올 및 에테르로 세척하고 100℃ 진공하에서 24시간 건조시켜, 융점이 340℃ 이상인

,

'-비스-(4-아미노-1-피리디늄)-2,3,5,6-테트라메틸-P-크실렌디클로라이드 29g을 얻었다.19 g of 4-aminopyridine and

,

23 g of '-dichloro-2,3,5,6-tetramethyl-P-xylene were suspended in 600 ml of methanol, and the suspension was heated in a steam bath so as to be a complete solution. After filtering a small amount of insoluble material, the white solid began to separate when the clear solution was warmed in a steam bath for 2 hours. The reaction mixture was cooled to room temperature, the solid product was collected by filtration, washed with methanol and ether, dried under vacuum at 100 ° C. for 24 hours, and the melting point was 340 ° C. or higher.

,

29 g of '-bis- (4-amino-1-pyridinium) -2,3,5,6-tetramethyl-P-xylenedichloride was obtained.

Example 86

,

'-디클로로--P-크실렌 11.6g(0.066몰)을 가하고, 이어 메탄올 400ml를 가했다. 혼합물을 완전 용액이 될때까지 가열했다. 불용성 물질소량을 여과한 후, 맑은 용액을 에틸아세테이느 500ml로 희석하여 실온으로 냉각했다. 고형 생성물을 여과하여 모으고 에틸아세테이트로 세척한 후, 건조시켜, 융점 332-335℃인

,

'-비스-(4-아미노-1-피리디늄)-P-크실렌디클로라이드 16g을 얻었다.In 100 ml of hot 2-propanol solution containing 12.5 g (0.132 mol) of 4-aminopyridine

,

11.6 g (0.066 mol) of '-dichloro-P-xylene was added followed by 400 ml of methanol. The mixture was heated until complete solution. After filtering a small amount of insoluble matter, the clear solution was diluted with 500 ml of ethyl acetate and cooled to room temperature. The solid product was collected by filtration, washed with ethyl acetate and dried to give a melting point of 332-335 ° C.

,

16 g of '-bis- (4-amino-1-pyridinium) -P-xylenedichloride was obtained.

,

'-비스-[4-(R-아미노)-1-피리디늄]크실렌의 구체적인 예를 다음에 표시했다.

,

'-디브로모-P-크실렌을 4-(에틸아미노) 피리딘과 반응시켜

,

'-비스-[4-(에틸아미노)-1-피리디늄]-P-크실렌디브로마이드를 얻었다.Of structural formula (II) prepared according to the above method

,

Specific examples of '-bis- [4- (R-amino) -1-pyridinium] xylene are shown next.

,

'-Dibromo-P-xylene is reacted with 4- (ethylamino) pyridine

,

'-Bis- [4- (ethylamino) -1-pyridinium] -P-xylenedibromide was obtained.

,

'-디클로로-P-크실렌을 반응시켜

,

'-비스-[4-(2-에틸헥실아미노)-1-피리디늄]-P-크실렌디클로라이드를 얻었다.N- (4-pyridyl) pyridinium chloride hydrochloride was reacted with 2-ethylhexylamine hydrochloride to give 4- (2-ethylhexylamino) pyridine (boiling point: 145-150 ° C./0.9 mm). and

,

By reacting '-dichloro-P-xylene

,

'-Bis- [4- (2-ethylhexylamino) -1-pyridinium] -P-xylenedichloride was obtained.

,

'-디클로로-P-크실렌을 반응시켜

,

'-비스-[4-(데실아미노)-1-피리디늄]-P-크실렌디브로마이드를 얻었다.N- (4-pyridyl) pyridinium chloride hydrochloride was reacted with n-decylamine hydrochloride to obtain 4- (decylamino) pyridine (melting point: 71-73 ° C.), followed by

,

By reacting '-dichloro-P-xylene

,

'-Bis- [4- (decylamino) -1-pyridinium] -P-xylenedibromide was obtained.

,

'-디클로로-P-크실렌을 4-(도데실아미노)피리딘과 반응시켜

,

'-비스-[4-(도데실아미노)-1-피리디늄]-P-크실렌디클로라이드를 얻었다.

,

'-Dichloro-P-xylene is reacted with 4- (dodecylamino) pyridine

,

'-Bis- [4- (dodecylamino) -1-pyridinium] -P-xylenedichloride was obtained.

,

'-디브로모-P-크실렌을 반응시켜

,

'-비스-[4-(옥타데실아미노)-1-피리디늄]-P-크실렌디브로마이드를 얻었다.N- (4-pyridyl) pyridinium chloride hydrochloride is reacted with octadecylamine hydrochloride to obtain 4- (octadecylamino) pyridine, which is followed by

,

'-Dibromo-P-xylene reacted

,

'-Bis- [4- (octadecylamino) -1-pyridinium] -P-xylenedibromide was obtained.

,

'-디브로모-m-크실렌을 반응시켜

,

'-비스-[4-(데트라데실아미노)-1-피리디늄]-m-크실렌디브로마이드를 얻었다.N- (4-pyridyl) pyridinium chloride hydrochloride was reacted with detradecylamine hydrochloride to obtain 4- (detradecylamino) pyridine (melting point: 91-93 ° C.), followed by

,

'-Dibromo-m-xylene reacted

,

'-Bis- [4- (detradecylamino) -1-pyridinium] -m-xylenedibromide was obtained.

,

'-디브로모-0-크실렌을 4-(부틸아미노) 피리딘과 반응시켜

,

'-비스-[4-(부틸아미노)-1-피리디늄]-0-크실렌디브로마이드를 얻었다.

,

'-Dibromo-0-xylene is reacted with 4- (butylamino) pyridine

,

'-Bis- [4- (butylamino) -1-pyridinium] -0-xylenedibromide was obtained.

,

'-디브로모-5-메틸-m-크실렌을 반응시켜

,

'-비스-4-(3-에틸헵틸아미노)-1-피리디늄]--5-메틸-m-크실렌디브로마이드를 얻었다.N- (4-pyridyl) pyridinium chloride hydrochloride was reacted with 3-ethylheptylamine hydrochloride to obtain 4- (3-ethylheptylaminopyridine.

,

'-Dibromo-5-methyl-m-xylene is reacted

,

'-Bis-4- (3-ethylheptylamino) -1-pyridinium]-5-methyl-m-xylenedibromide was obtained.

,

'-디브로모-2,5-디메틸-P-크실렌을 반응시켜

,

'-비스-[4-(2-메틸헵틸아미노)-1-피리디늄]-2,5-디메틸-P-크실렌디브로마이드를 얻었다.N- (4-pyridyl) pyridinium chloride hydrochloride is reacted with 2-methylheptylamine hydrochloride to obtain 4- (2-methylheptylamino) pyridine, which is followed by

,

'-Dibromo-2,5-dimethyl-P-xylene is reacted

,

'-Bis- [4- (2-methylheptylamino) -1-pyridinium] -2,5-dimethyl-P-xylenedibromide was obtained.

,

'-디클로로-2,4,6-트리메틸-m-크실렌을 반응시켜

,

'-비스-[4-(옥틸아미노)-1-피리디늄]-2,4,6-트리메틸-m-크실렌디클로라이드를 얻었다.N- (4-pyridyl) pyridinium chloride hydrochloride was reacted with n-octylamine hydrochloride to obtain 4- (octylamino) pyridine (melting point; 62-63 ° C.), followed by

,

'-Dichloro-2,4,6-trimethyl-m-xylene is reacted

,

'-Bis- [4- (octylamino) -1-pyridinium] -2,4,6-trimethyl-m-xylenedichloride was obtained.

,

',2-트리클로로-P-크실렌을 반응시켜

,

'-비스-[4-(2,2-디메틸부틸아미노)-1-피리디늄]-2-클로로-P-크실렌디클로마이드를 얻었다.N- (4-pyridyl) pyridinium chloride hydrochloride is reacted with 2,2-dimethylamine hydrochloride to give 4- (2,2-dimethylbutylamino) pyridine, which is followed by

,

', 2-trichloro-P-xylene is reacted

,

'-Bis- [4- (2,2-dimethylbutylamino) -1-pyridinium] -2-chloro-P-xylenedichloromide was obtained.

,

'-디브로모-4-클로로-0-크실렌올 4-(메틸아미노) 피리딘과 반응시켜

,

'-비스-[4-(메틸아미노)-1-피리디늄]-4-클로로-0-크실렌디브로마이드를 얻었다.

,

React with '-dibromo-4-chloro-0-xyleneol 4- (methylamino) pyridine

,

'-Bis- [4- (methylamino) -1-pyridinium] -4-chloro-0-xylenedibromide was obtained.

,

', 2,5-테트라클로로-P-크실렌을 반응시켜

,

'-비스-[4-(2-프로필펜틸아미노)-1-피리디늄]-2,5-디클로로-P-크실렌디클로라이드를 얻었다.N- (4-pyridyl) pyridinium chloride hydrochloride is reacted with 2-propylpentylamine hydrochloride to give 4- (2-propylpentylamino) pyridine, which is followed by

,

', By reacting 2,5-tetrachloro-P-xylene

,

'-Bis- [4- (2-propylpentylamino) -1-pyridinium] -2,5-dichloro-P-xylenedichloride was obtained.

,

', 2,3,5-펜타클로로-P-크실렌을 반응시켜

,

'-비스-[4-(1,1-디메틸운데실아미노)-1-피리디늄]-2,3,5-트리클로로-P-크실렌디클로라이드를 얻었다.N- (4-pyridyl) pyridinium chloride hydrochloride is reacted with 1,1-dimethylundecylamine hydrochloride to obtain 4- (1,1-dimethylundecylamino) pyridine, which is followed by

,

', 2,3,5-pentachloro-P-xylene is reacted

,

'-Bis- [4- (1,1-dimethylundecylamino) -1-pyridinium] -2,3,5-trichloro-P-xylenedichloride was obtained.

,

', 2,3,5,6-헥사클로로-P-크실렌을 반응시켜

,

'-비스-[4-(노닐아미노)-1-피리디늄]-2,3,5,6-테트라클로로-P-크실렌디클로라이드를 얻었다.N- (4-pyridyl) pyridinium chloride hydrochloride was reacted with n-nonylamine hydrochloride to obtain 4- (nonylamino) pyridine (melting point; 59-60 ° C.), followed by

,

', 2,3,5,6-hexachloro-P-xylene is reacted

,

'-Bis- [4- (nonylamino) -1-pyridinium] -2,3,5,6-tetrachloro-P-xylenedichloride was obtained.

,

'-디브로모-P-크실렌을 반응시켜

,

'-비스-[4-(벤질아미노)-1-피리디늄]-P-크실렌디브로마이드를 얻었다.N- (4-pyridyl) pyridinium chloride hydrochloride is reacted with benzylamine to obtain 4- (benzylamino) pyridine,

,

'-Dibromo-P-xylene reacted

,

'-Bis- [4- (benzylamino) -1-pyridinium] -P-xylenedibromide was obtained.

,

',2-트리클로로-P-크실렌을 반응시켜

,

'-비스-[4-(벤질아미노)-1-피리디늄]-2-클로로-P-크실렌디클로라이드를 얻었다.N- (4-pyridyl) pyridinium chloride hydrochloride is reacted with benzylamine to obtain 4- (benzylamino) pyridine,

,

', 2-trichloro-P-xylene is reacted

,

'-Bis- [4- (benzylamino) -1-pyridinium] -2-chloro-P-xylenedichloride was obtained.

The antimicrobial and antifungal activity of the representative compounds of the formula (I) were determined by the modification of the autotiter assay described by Goss et al. (Microbiology, 16 (9), 1414-1416 (1968)). Here, 1000 mcg / ml solution of the test compound was prepared. 0.1 ml of the test solution is added to the first cup of the autotray. The activity of the autotiter assay device is initiated by the operation of diluting 0.05 ml of the test compound solution with a microtiter transfer loop and then diluting with 0.05 ml of sterile water. Following this operation, 0.05 ml of inoculated double titer semisynthetic bash (glucose) is automatically added to each cup. As a result of this manipulation, the concentration of the final drug is ½ reduced to 500-0.06 mcg / ml. After incubating the auto tray for 18-20 hours at 37 ° C., growth by turbidity was visually observed. The final sample concentration of the series that showed no growth (ie, zero turbidity) is taken as the minimum growth inhibition concentration (mcg / ml). The compounds are in solution, Staphylococcus aureus, Proteus mirabilis, Escheria coli, Klebseilla pneuminiae, Pseudomonas Against a variety of Gram-positive and negative bacteria, including Pseudomonas aeruginosa, Streptococcus pyogense, and Aspergillus niger, Candida albicans and Fungi, such as Trichophyton mentagrophytes, were tested.

Many compounds of formula (I) also exhibited antimicrobial effects against Streptococcus mutan and Actinomyes A-viscosis.

The bactericidal virus effect on the herpes simplex type 2 virus of representative compounds is described by EC Herman [Jr. Proc. Soc. Exp. Biol. Med. 107, 142 (1961)] as published by the method similar to the detection of specific inhibitors of the DNA- containing viruses, place the test compound 2mg to the culture medium surface was examined in vitro. As a result, Examples 3,5C, 7,9C, 10,11,13,17,18,21,22,24,31,33,35,36,37,53,54,55,56,57,58, It was found that the compounds of 60, 61, 63, 81, 82, 83 and 84 are active and the compounds of Examples 16, 34, 39, 40 and 79B are inactive.

The jigogenesis inhibitory effect of several compounds of the present invention was determined according to the following method for measuring the ability of the compound to inhibit jigogenesis by Streptococcus mutans OMZ 61.

BBL beef extract containing jig-forming streptococcus mutan OMZ-61, 1.5 g of sodium chloride, 5 g of dehydrated trypti case, 5 g of sugar and distilled water were added, and the culture medium with a total volume of 1000 ml was adjusted to pH 7.0. (membrane filtration) to sterilize. The medium is sterilized in 10 x 150 x 16 mm test tubes and stored at refrigerated temperature until use.

To 1 ml of distilled water, 0.1 N of martium hydroxide, 10% dimethyl sulfoxide, or 10% N, N-dimethylformamide was added to dissolve 100 mg of the test compound, and the resulting solution was diluted to 10 ml with distilled water. Prepare the test compound. This 1.0% solution and 1:10 diluent (0.1%) in distilled water are sterilized by membrane filtration before use.

Sterilized pieces of toothbrush-free all tooth enamel or synthetic hydroxyl apatite are suspended in compounds of each concentration twice for 1 minute and air-dried for 1 minute between them. Each piece is suspended in each test tube containing sterile distilled water (cleaning solution) and shaken for 5 minutes. They are then suspended in liquid beef extraction medium (10 ml), and then 0.3 ml of a 24-hour anaerobic culture of Streptococcus mutan is added thereto. Subsequently, test tubes containing the “treated” hydroxyl apatite and Streptococcus mutan were incubated anaerobicly at 37 ° C. for 24 hours. In the same way, the solution was immersed twice in the compound solution twice for 1 minute, air-dried for 1 minute between them, and the washing was repeated for the last 5 minutes, and then again in a new test tube containing 10 ml of 10% beef extract medium and 0.3 ml of inoculum. Suspend hydroxyl apatite. After incubation for another 24 hours, the hydroxyl apatite is rinsed with each piece for 1 minute in three consecutive test tubes containing distilled water. This is then suspended in F, D, C red No. 3 dye solution for 1 minute. The purpose of this staining process is to more easily distinguish the development of jig after 48 hours of exposure to jig forming microorganisms. Rinse for 10 seconds to remove excess dye. If a jig is formed, it is colored bright pink. Indicate the test results as whether the fixture is inhibited (active) or not (inactive) at the percentage of concentration used. The test is conducted continuously at low concentrations to determine the minimum effective concentration of the active compound. In some cases, the formation of the jig interferes with the release of the compound from the hydroxyl apatite, creating an antimicrobial level in the medium, which in turn inhibits the growth of microorganisms in the culture medium. In this case, the compound is tested at low concentrations such that the growth of microorganisms in the surrounding medium is the same as in the non-drug control medium.

At such low concentrations, a jig may or may not be formed.

If a new test compound is added to the tooth surface to prevent jig formation, there is a possibility that colorants, such as coffee, tobacco and colored food, may accumulate on the tooth surface. Therefore, the method is also used as a method of measuring the coloring potential, that is, the extent to which the adhesion of the coloring agent to the tooth surface by the test compound is promoted. That is, the uniform pale pink color remaining on the surface of the test article after the final cleaning is expressed as the coloring density as indicating the coloring possibility at the test concentration percentage. The uniform pale pink due to the test compound is easily distinguished from the bright pink due to jig formation. In general, the staining concentration of the compound is advantageous because it is significantly higher than the minimum effective concentration for jig inhibition.

Numerical data of antimicrobial, antifungal, and jig inhibition tests of these compounds are shown in Table A below. Two known compounds, namely 1,8-bis- (4-amino-1-pyridinium) octanedibromide (reference compound I) and 1,10-bis- (4 amino-1-pyridinium) tecandibromide ( Corresponding data of Reference Compound II) are also included in Table A for comparison purposes. Coloring concentrations of representative compounds are shown in Table C below.

The antimicrobial effect of serum in the presence of representative compounds was measured by standard dilution series method, in which serum (40%) of horses inactivated by heating (30 minutes, 56 ° C) was present or not present in the test medium. The minimum Jersey concentration (MIC) of the cases was compared and measured. The results of this measurement indicate that the minimum stop concentration (mcg / ml) of Staphylococcus aureus and Escherichia coli increased by the presence of serum, which is shown in Table B below.

The antipruritic effect of a representative compound in the presence of saliva (50%) in sterile humans was measured and the results were expressed as minimum effective concentrations, which are shown in Table C below.

Acute oral toxicity (ALD ₅₀ ) of several representative compounds was determined as follows. That is, a group of three grown male Swiss-Webster strain amino mice were starved for about 4 hours before the drug tour and administered orally once through the gastrointestinal tract. All mice were observed for 7 days after dosing. As a result of dissecting all the mice, no gross tissue change was found except that 2 out of 3 rats of 1000 mg / kg of the compound of Example 25 showed congestion in the gastric gland. . The results are shown in Table D below.

TABLE A

TABLE B

TABLE C

※ There was no bacterial growth at this concentration, and jig was formed at 0.005%.

TABLE D

* G.T. Trigacanth rubber

Claims (1)

2 moles of 4- (R-amino) pyridine of formula (III) are substituted with 1 mole of double-substituted alkane of formula (IV) or

,

A process for preparing bis-pyridinium alkanes of formula (I) or (II), characterized in that it reacts with 1 mol of '-disubstituted xylene.

In the above formula Y is a C ₄ -C ₁₈ alkylene group that separates two 4- (R-NH) -1-pyridinyl groups by C ₄ -C ₁₈ ; R is a C ₆ -C ₁₈ alkyl group, a C ₅ -C ₇ cycloalkyl group, benzyl, or halogen, lower alkyl, lower alcohol, 1-2 nitro, cyano or trifluoromethyl substituents or methylene dioxy Phenyl substituted by

Wherein R is hydrogen, C ₁ ~ C ₁₈ linear or branched alkyl group A is an anion; Or benzyl; m is 1 or 3; Q is methyl or chlorine; n is 1 or 2; V is an integer from 0-4; x is 1,2 or 3; In the above formulas (I) and (II)); (M) 2 = (n) (x) at this time.

In the above formula R corresponds to R in formula (I) when preparing a compound of formula (I), and R in formula (II) when preparing a compound of formula (II).

In the above formula Z is chloro, bromo, iodo, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, or P-toluenesulfonyl oxy; In the compounds of formulas (I) and (II) A corresponds to Z; Y, Q and V are as described above.