JP2927513B2 - Quaternary pyridinium compounds - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a quaternary pyridinium compound. More specifically, the present invention relates to a quaternary pyridinium compound useful as a physiologically active substance such as an antibacterial agent or an indicator substance relating to the dynamic mechanism of living tissue, and a method for producing the same.

(Prior art and its problems) A reaction for synthesizing pyridine by a gas-phase reaction of titibabin with ammonia has been known for a long time. Pyridine compounds are extremely useful as synthetic raw materials or intermediate compounds for various pharmaceuticals, agricultural chemicals, and the like, and a great deal of attention has been paid to not only their production methods but also their biologically active mechanisms.

The inventor of the present invention has also paid attention to such a pyridine compound from the viewpoint of in vivo reactions, and in particular, that the formation of a quaternary pyridinium compound is deeply involved in the formation of crosslinks in connective tissues of animal organisms. Based on this finding, we have been actively studying the synthesis of various pyridine compounds and quaternary pyridinium compounds using this biological mechanism as a model.

As a result, various types of saturated aldehydes were used as a model of allicin produced by the enzymatic oxidative deamination of lysine residues of cross-linked proteins, and a cross-linked amino acid generation model reaction with primary amine salts containing amino acids at room temperature Thus, quaternary pyridinium compounds branched at 1,3,4,5- and 1,2,3,5-positions could be easily synthesized. In addition to these desmosine and isodesmosine-type pyridinium salts, the formation of many pyridinium salts of unknown structure was also confirmed. From these pyridinium compounds, the corresponding pyridine compounds can be synthesized quantitatively by thermal decomposition.

In protein cross-linking in vivo, allicin, which is a saturated aldehyde, causes aldol condensation at an early stage, and these condensation products, α, β-unsaturated aldehydes, are formed as by-products. It is considered an important intermediate in compound formation.

However, hitherto, the production of pyridinium salts from α, β-unsaturated aldehydes, which are products of an andhdone condensation reaction, has not been studied as a chemical synthesis method.

On the other hand, many quaternary amine salts have an antibacterial action, and many quaternary pyridinium salt antibacterial agents are also known. For example, cetylpyridinium chloride is commercially available under the name of Seprich. From such a viewpoint, there is a high possibility that a novel compound having a strong antibacterial action is found from a combination of an aldehyde and a primary amine.

Therefore, realizing the synthesis of pyridinium compounds and pyridine compounds from α, β-unsaturated aldehydes, which are interesting aldol condensates, is elucidation of the reaction mechanism in vivo and its use, and furthermore, antibacterial agents, etc. It is extremely significant for the search and development of new bioactive substances.

The present invention has been made in view of the above circumstances, and is useful as a physiologically active substance such as an antibacterial agent, or an indicator substance relating to a dynamic mechanism of a living tissue, a quaternary pyridinium compound, and a pyridine compound. And a method for manufacturing the same.

(Means for Solving the Problems) The present invention provides α,
A method for producing a quaternary pyridinium compound, characterized by reacting a β-unsaturated aldehyde with a primary amine compound,
And a method for producing a pyridine compound for thermally decomposing the quaternary pyridinium compound, and a compound obtained by these methods.

In the present invention, there is no particular limitation on the types of α, β-unsaturated aldehyde and primary amine compound. α, β
-Unsaturated aldehydes include aldol condensates formed in the course of the reaction, and primary amine compounds include:
Any compound having a primary amine group, for example, an aliphatic amine, an alicyclic amine, an amino acid, an amino acid ester, or a primary amine compound having any other substituent is used.

The pyridinium compound generated by the reaction can be easily converted to a pyridine compound by being thermally decomposed, that is, decomposed by Hoffman.

The compounds obtained by the method of the present invention are diverse and have a great potential to create many new substance groups. It is expected to be used as an antibacterial agent.

Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1 A reaction between 2-methyl-2-pentenal, which is an aldol condensate from propanal, and n-butylamine was performed.

That is, 15 g (about 0.2 mol) of n-butylamine is dissolved in 100 ml of methanol, and acetic acid 1
3 g (about 0.2 mol) was added to make an acetate, and then stirring was continued while 100 ml (0.8 mol) of 2-methyl-2-pentenal was added dropwise from a separating funnel over 30 minutes. An exotherm occurred immediately, but stirring was continued for another 3 hours after the end of the exotherm. The reaction was then left overnight at room temperature to complete the reaction.

About 3 times the amount of n-hexane was added to the reaction solution, and separated n
The hexane-insoluble portion was separated by a separating funnel, and then the same fraction and the same amount of ethyl ether were added and washed twice to obtain a water-soluble fraction.

The crude fraction was fractionated into each component using ethyl acetate / acetic acid / water (2: 1: 1, V / V) using preparative TLC.

It is known that quaternary amine salts are quantitatively decomposed into tertiary amines by heating (Hoffman decomposition).
The water-soluble reaction products were decomposed in a 190-200 ° C. oil bath under reduced pressure, and the distilling components were collected. Subsequently, excess hydrochloric acid was added to make a hydrochloride, and the aqueous layer obtained by washing with ethyl ether was made alkaline by adding 10% NaOH, and the separated pyridine compound was obtained by ethyl ether extraction.

This Hoffman degradation product was fractionated by preparative normal phase HPLC (n-hexane / ethyl acetate, 80:20, V / V).
A component having a very strong green grass-like odor was distilled out, and the following component was obtained by HPLC.

(A) 4-ethyl-3.5 dimethylpyridine UV (MeOH) λ _max (nm): 264, IR (neat) ν _max (cm ^-1 ): 1638,1595 ¹ H-NMR δ _ppm (CDCl ₃ ): 8.01 ( 2H, s) 1.97 (6H, s) MS (m / z): 135 (M ⁺ ), 120,107 (A) A-picrate mp. 155-156 ° C ¹ H-NMR δ _ppm (CDCl ₃ ): 8.48 (2H , s) 2.92 (2H, m) 2.54 (6H, s) 1.24 (3H, t) Elemental analysis (calculated) C ₁₅ H ₁₅ N ₄ O ₇ C 49.59, H 4.16, N 15.42 (actual) C 49.50, H 4.42, N 15.51 (c) 2-ethyl-3,5-dimethylpyridine UV (MeOH) λ _max (nm): 271 IR (neat) ν _max (cm ^-1 ): 1635,1595 ¹ H-NMR δ _ppm ( _{CDCl 3): 8.04 (1H,} s) 7.011 (1H, s) 2.00 (6H, s) MS (m / z): 135 (M +), 134,107 ( d) B- picrate mp.157-158 ℃ ¹ H -NMR δ _ppm (CDCl ₃ ): 8.44 (1H, s) 7.98 (1H, s) 3.18 (2H, m) 2.53 (6H, sd) 1.34 (3H, t) Elemental analysis value (calculated) C ₁₅ H ₁₅ N _{4 O 7 C 49.59, H 4.16} , N 15.42 ( Found) C 49.03, H 4.27, N 15.55 ( e) - propyl-3,5-dimethylpyridine _{UV (MeOH) λ max (nm} ): 271 MS (m / z): 149 (M +), was obtained as 148,134,121 (mosquito) C- picrate crystals.

_{^{1 H-NMR δ ppm (CDCl}} 3): 8.43 (1H, s) 7.97 (1H, s) 3.15 (2H, t) 2.56 (6H, s) 1.74 (2H, t) 1.01 (3H, t) ( g) 2- (1-methyl-1-butenyl) -3.5-dimethylpyridine UV (MeOH) λ _max (nm): 273,279 (HCl) IR (neat) ν _max (cm ⁻¹ ): 1655,1640 1470,1210 970 MS (Shown in FIG. 1) (h) D-picrate mp. 101-102 ° C. ¹ H-NMR (shown in FIG. 2) Elemental analysis value (calculated value) C ₁₈ H ₁₉ N ₄ O ₇ C 53.59, H 4.75, N 13.89 (actual value) C 53.43, H 4.79, N 13.91 (q) Undetermined substance UV (MeOH) λ _max (nm): 272 MS (m / z): 177 (M ⁺ ), 160,145,135 Among these compounds, compound (A) is 1-butyl-
4-ethyl-3.5-dimethylpyridinium salt was used as a precursor, and compound (C) was 1-butyl-2-ethyl-3.
5-dimethylpyridinium salt was used as a precursor quaternary pyridium salt.

The compound (E) is a dimer of unsaturated aldehyde and n
It is considered to be a pyridine compound synthesized by intramolecular condensation of a Schiff base of -butylamine.

Compound (G) is a novel pyridine compound, and is considered to be formed by condensing and cyclizing two molecules of aldol dimer with a primary amine.

Example 2 2-Methyl-2-pentenal and the following formula Was reacted in the same manner as in Example 1.

Since this lysine is insoluble in methanol, a small amount of water is added to lysine hydrochloride, and about 4 parts of 2-methyl-2-pentenal is added to lysine with vigorous stirring under conditions of suspension in water. In addition, it was reacted. The reaction was terminated by stirring overnight. As a quaternary pyridinium salt, the reaction was terminated by stirring according to the following formula (A).

As a quaternary pyridinium salt, the following formula (A) Was obtained.

UV (MeOH) λ _max (nm): 279 IR (neat) ν _max (cm ⁻¹ ): 1655,1644 1470,1440 1370,1220 1010 ¹ H-NMR δ _ppm (CDCl ₃ ): 9.06 (1H, s) 7.98 (1H, s) 5.69 (1H, m) 2.50 (3H, s) 2.30 (3H, s) 2.23 (2H, m) 1.99 (3H, d) 1.17 (3H, t) MS (m / z): 306 (M: FAB) The compound (A) was subjected to Hoffman degradation to give Example 1.
Was obtained, that is, 2- (1-methyl-1-butenyl) -3.5-dimethylpyridine.

Example 3 The compound (A) obtained in Example 2 was evaluated for its antibacterial activity.

The evaluation was performed by impregnating a sample with a phosphate buffer (0.01 M, pH 7.0) solution in a paper disk having a diameter of 8 mm and using a paper disk method using a tryptosome bouillon agar medium. The test bacteria used was E. coli.

Compound (A) 100 μg / ml solution with an inhibition circle of 14 mm and 50 μg
In the / ml solution, 11 mg was observed.

It was foreseen that pyridinium compounds having strong antibacterial activity were found depending on the carbon number of the aldehyde.

[Brief description of the drawings]

FIG. 1 shows 2- (1) obtained in the embodiment of the present invention.
-Methyl-1-butenyl) -3.5-dimethylpyridine M
It is an S chart figure. FIG. 2 is also a diagram showing a ¹ H-NMR chart and structural parts of D-picrate.

Claims (5)

(57) [Claims] 1. A method for producing a quaternary pyridinium compound, comprising reacting an α, β-unsaturated aldehyde with a primary amine compound. 2. The method for producing a quaternary pyridinium compound according to claim 1, wherein the α, β-unsaturated aldehyde is an aldol condensation product. 3. The method for producing a quaternary pyridinium compound according to claim 1, wherein the primary amine is an amino acid. 4. A method for producing a pyridine compound, comprising thermally decomposing the quaternary pyridinium compound obtained by the method according to claim 1, 2 or 3. 5. A quaternary pyridinium compound represented by the following formula: