JP2008143881A - Antibacterial agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an antibacterial agent excellent in effectiveness to many kinds of bacteria. <P>SOLUTION: It was found that an α, β-unsaturated ketone compound represented by general formula (1) (wherein R<SP>1</SP>is a 1-12C hydrocarbon group, R<SP>2</SP>is a 1-12C hydrocarbon group having a hydroxy group, R<SP>3</SP>is a hydrogen atom, a 1-6C alkyl group, or a 1-6C alkoxy group, m is an integer of 0-3, n is an integer of 0-3, and m+n satisfies a value of 1-4) has excellent antibacterial and antifungal activity, therefore, this antibacterial agent contains the compound. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an antibacterial agent containing an α, β-unsaturated ketone compound useful in the fields of foods, pharmaceuticals, quasi drugs and the like.

In the fields of food, pharmaceuticals and cosmetics, prevention and treatment of various infectious diseases caused by harmful microorganisms of bacteria and fungi (mold), sterilization of medical equipment, sterilization / place sterilization of food / cosmetic factories Technologies that control the propagation and growth of harmful microorganisms, such as disinfection, product quality degradation, deterioration, and decay, have been rapidly advanced due to the diversification of living environments and changes in living consciousness.
Methods for controlling harmful microorganisms include methods using ultraviolet rays and gamma rays, so-called physical methods using heating and filtration techniques, and chemical methods using various antibacterial / antifungal agents and preservatives. However, it has been performed conventionally. For example, as pharmaceuticals or as preservatives for pharmaceuticals and cosmetics, sorbic acid, dehydroacetic acid and its salts, benzoic acid and its salts, paraoxybenzoic acid ester derivatives (paraben), isopropylmethylphenol, phenoxyethanol, benzalkonium chloride, etc. Quaternary ammoniums, alkylaminoethylglycine hydrochloride, double-sided surfactants such as sodium stearylhydroxyethylbetaine chloride, photosensitizers, iodine and the like.

However, since the preservatives as described above have problems in terms of safety, there are restrictions on the amount of addition and the target product, and it is often impossible to add an amount that actually shows effective antibacterial activity. For example, parabens have been pointed out to have a content of 1.0% for cosmetics and the like due to problems of skin irritation and sensitization, and also show environmental hormone action (for example, Non-Patent Document 1). And 2).
In addition, due to the recent increase in safety orientation, many attempts have been made such as research and development of new anti-bacterial and anti-fungal agents with higher safety, and reduction of usage by increasing the efficacy of anti-bacterial activity. (For example, Patent Documents 1 to 5). However, it is difficult to obtain sufficient antibacterial activity and antiseptic power, and in particular, it is difficult to increase the antiseptic power against fungi.
As an antibacterial agent having potent antifungal activity, capillin extracted from Artemisia capillaris chumb. (For example, Non-Patent Document 3) is a substance having a specific structure, and thus stably at low cost. It is difficult to supply.
In this way, the control of harmful microorganisms by antibacterial and antifungal agents is more effective while being applied and deployed in a wide range of fields from lifestyle-related fields such as clothing, food and housing to industrial-related fields such as plastics products and electronic parts. Development of safe and safe antibacterial and antifungal agents is desired.

  On the other hand, 1-phenyl-4-hydroxy-2-buten-1-one, which is one of α, β-unsaturated ketone compounds, has been reported to be synthesized using a special oxidizing agent (Non-patent Document 4). ). However, there is no known production method using a general-purpose carboxylic acid peroxide from a compound that is easily available. In addition, there has been no report on the use of the compound.

JP-A-6-73372 (Claims) JP-A-11-322591 (Claims) JP 11-310506 A (Claims) JP-A-10-53510 (Claims) JP 2004-352688 A (Claims) Ministry of Health and Welfare, Minutes of “12th Debate on Health Effects of Endocrine Disrupting Substances”, p. 27-28 Oishi, Y., “Effects of Parabens on the Gonadal System of Male Rats”, Abstracts of the 3rd meeting of the Environmental Hormone Society, 2000 279 Satoshi Oshima and three others, “Anti-manicidal action of Artemisia and its application to antibacterial agents for cosmetics”, FRAGRANJO JOURNAL, 2002, p. 67-71 R. Badri, H. Shalbaf, M.A. Heidary, Synthetic Communications, 31 (22), 3473-3479 (2001).

  An object of the present invention is to provide an excellent antibacterial agent effective against various kinds of microorganisms in view of the above situation.

As a result of intensive studies to solve the above problems, the present inventors have found that an α, β-unsaturated ketone compound represented by the following formula (1) has excellent antibacterial and antifungal activities, The present invention has been completed. That is, the present invention
<1> An antibacterial agent characterized by containing an α, β-unsaturated ketone compound represented by the following general formula (1):

In (Equation (1), R ¹ is a hydrocarbon group having 1 to 12 carbon atoms, R ² is a hydrocarbon group having 1 to 12 carbon atoms having a hydroxyl group, R ³ represents a hydrogen atom, a carbon An alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, m is an integer of 0 to 3, n is an integer of 0 to 3, and m + n satisfies a value of 1 to 4. .)

<2> The antibacterial agent according to 1, wherein the general formula (1) is an α, β-unsaturated ketone compound represented by the following formula (2):

(In the formula (2), R ⁴ is a hydrocarbon group having 1 to 12 carbon atoms or a hydrocarbon group having 1 to 12 carbon atoms having a hydroxyl group, and R ³ is a hydrogen atom, having 1 to 6 carbon atoms. It is an alkyl group or an alkoxy group having 1 to 6 carbon atoms.)

<3> The antibacterial agent according to 1, wherein the general formula (1) is an α, β-unsaturated ketone compound represented by the following formula (3):

(In Formula (3), R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and R ⁴ is a hydrocarbon group having 1 to 12 carbon atoms, or a hydrocarbon group having 1 to 12 carbon atoms having a hydroxyl group, R ⁵ is a hydrocarbon group having 1 to 12 carbon atoms having a hydrocarbon group having 1 to 12 carbon atoms or a hydroxyl group.)

<4> The antibacterial agent according to 1 above, wherein the general formula (1) is an α, β-unsaturated ketone compound represented by the following formula (4):

(In Formula (4), R < ⁶ > is a hydrogen atom or a C1-C11 hydrocarbon group, and R < ³ > is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy. And m is an integer of 1 to 3.)

<5> α, represented by the above formula (4), which is produced by epoxidizing a compound represented by the following formula (5) with a carboxylic acid peroxide and then reacting with a basic substance. It is a β-unsaturated ketone compound.

(In the formula (5), R ⁷ is a hydrogen atom or a hydrocarbon group having 1 to 11 carbon atoms, and R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms. And m is an integer of 1 to 3.)

  The α, β-unsaturated ketone compound of the present invention has excellent antibacterial and antifungal activities, including the fields of foods, pharmaceuticals, quasi drugs, plastic products, paper products, fabric products, leather products, etc. It can be applied to related fields.

○ Compound represented by the general formula (1) In the present invention, R ¹ in the formula (1) is a hydrocarbon group having 1 to 12 carbon atoms, and R ² is a carbon atom having 1 to 12 carbon atoms having a hydroxyl group. R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, m is an integer of 0 to 3, and n is an integer of 0 to 3. M + n satisfies the values of 1-4.

In the formula (1), R ¹ is a hydrocarbon group having 1 to 12 carbon chains, and examples of the hydrocarbon group include a linear alkyl group, a branched alkyl group, an aralkyl group (Aralkyl), or an alkyl group. Specifically, a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a 2-ethylhexyl group, a nonyl group, A decyl group, a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 2- (p-tolyl) -ethyl group and the like can be exemplified, and a methyl group, an ethyl group, a propyl group, a butyl group and a phenethyl group are preferable. In the present invention, aryl in the araalkyl group is benzene or naphthalene, and preferably benzene.

In Formula (1), R ² is a hydrocarbon group having 1 to 12 carbon atoms having a hydroxyl group, and the hydrocarbon group is a linear alkyl group having a hydroxyl group, a branched alkyl group having a hydroxyl group, or a hydroxyl group. An aralkyl group, preferably a linear alkyl group having a hydroxyl group at the 1-position or a branched alkyl group having a hydroxyl group at the 1-position, specifically, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group And a hydroxybutyl group, and a hydroxymethyl group is preferred.

In the formula (1), R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and includes a hydrogen atom, a methyl group, an ethyl group, a propyl group, a methoxy group, and ethoxy group. Examples thereof include a hydrogen atom, a methyl group, or a methoxy group, and a hydrogen atom or a methoxy group is more preferable.
In the formula (1), m is an integer of 0 to 3, n is an integer of 0 to 3, and m + n satisfies a value of 1 to 4. Specifically, m = 1 and n = 0, m = 0 and n = 1, m = 2 and n = 0, m = 0 and n = 2, m = 1 and n = 1, m = 2 and n = 1, or m = 1 and n = 2, where m = 1 and n = 0, m = 0 and n = 1, m = 2 and n = 0, m = 0 and n = 2, or Examples where m = 1 and n = 1 are preferable.

O Compound represented by Formula (2) In the present invention, R ^{4 in} Formula (2) is a hydrocarbon group having 1 to 12 carbon atoms or a hydrocarbon group having 1 to 12 carbon atoms having a hydroxyl group. R ^{4 in the} formula (2) is a straight chain alkyl group, a branched alkyl group, an aralkyl group (Aralkyl), or an aralkyl group having an alkyl group, specifically, a methyl group , Ethyl group, propyl group, butyl group, isobutyl group, pentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group, nonyl group, decyl group, benzyl group, phenethyl group, 3-phenylpropyl group , 2- (p-tolyl) -ethyl group and the like, preferably methyl group, ethyl group, propyl group, butyl group, and phenethyl group. The linear alkyl group in which R ^{4 in} formula (2) has a hydroxyl group is a branched alkyl group having a hydroxyl group or an araalkyl group having a hydroxyl group, preferably a linear alkyl group having a hydroxyl group at the 1-position or A branched alkyl group having a hydroxyl group at the 1-position. Specific examples include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, and the like, and a hydroxymethyl group is preferred.

In the present invention, R ³ in the formula (2) is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or An alkoxy group having 1 to 6 carbon atoms such as a hydrogen atom, a methyl group, an ethyl group, a propyl group, a methoxy group, and an ethoxy group, preferably a hydrogen atom, a methyl group, or a methoxy group; Examples of the group are more preferable.
In the present invention, when R ³ in the formula (2) is an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, the bonding position is preferably the 3-position or the 4-position.
In the present invention, R ⁴ in the formula (2) is a hydrocarbon group having 1 to 12 carbon atoms and R ³ is a hydrogen atom.

○ In the compound represented by the present invention by formula (3), R ⁴ of formula (3) is Aaru hydrocarbon group having 1 to 12 carbon atoms having a hydrocarbon group or a hydroxyl group having 1 to 12 carbon atoms. The hydrocarbon group represented by R ^{4 in the} formula (3) is a linear alkyl group, a branched alkyl group, an aralkyl group (Aralkyl), or an araalkyl group having an alkyl group, specifically, a methyl group , Ethyl group, propyl group, butyl group, isobutyl group, pentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group, nonyl group, decyl group, benzyl group, phenethyl group, 3-phenylpropyl group , 2- (p-tolyl) -ethyl group and the like, preferably methyl group, ethyl group, propyl group, butyl group, and phenethyl group. The linear alkyl group in which R ^{4 in} formula (3) has a hydroxyl group is a branched alkyl group having a hydroxyl group or an araalkyl group having a hydroxyl group, preferably a linear alkyl group having a hydroxyl group at the 1-position or A branched alkyl group having a hydroxyl group at the 1-position, specifically, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, etc. are exemplified, and a hydroxymethyl group is preferred.

In the present invention, R ⁵ in the formula (3) is a hydrocarbon group having 1 to 12 carbon atoms or a hydrocarbon group having 1 to 12 carbon atoms having a hydroxyl group. R ^{5 in the} formula (3) is a linear alkyl group, a branched alkyl group, an aralkyl group, or an aralkyl group having an alkyl group, specifically, a methyl group , Ethyl group, propyl group, butyl group, isobutyl group, pentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group, nonyl group, decyl group, benzyl group, phenethyl group, 3-phenylpropyl group , 2- (p-tolyl) -ethyl group and the like, preferably methyl group, ethyl group, propyl group, butyl group, and phenethyl group. The linear alkyl group in which R ^{4 in} formula (3) has a hydroxyl group is a branched alkyl group having a hydroxyl group or an araalkyl group having a hydroxyl group, preferably a linear alkyl group having a hydroxyl group at the 1-position or A branched alkyl group having a hydroxyl group at the 1-position, specifically, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, etc. are exemplified, and a hydroxymethyl group is preferred.

In the present invention, when R ⁵ in the formula (3) is a hydrocarbon group having 1 to 12 carbon atoms or a hydrocarbon group having 1 to 12 carbon atoms having a hydroxyl group, the bonding position of the functional group having R ⁵ is 2 Position, position 3 or position 4, preferably position 3 relative to the functional group having R ⁴ .
In the present invention, R ³ in Formula (3) is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or An alkoxy group having 1 to 6 carbon atoms such as a hydrogen atom, a methyl group, an ethyl group, a propyl group, a methoxy group, and an ethoxy group, preferably a hydrogen atom, a methyl group, or a methoxy group; Examples of the group are more preferable.
In the present invention, when R ³ of formula (3) is an alkyl group or an alkoxy group having 1 to 6 carbon atoms having 1 to 6 carbon atoms, this coupling position, 2-position or towards the functional groups with R ⁴ 4 Is preferred.

In the present invention, R ⁶ in the formula (4) is a hydrocarbon group having 1 to 12 carbon atoms, a linear alkyl group, a branched alkyl group, an araalkyl group. (Aralkyl) or an aralkyl group having an alkyl group, specifically, methyl group, ethyl group, propyl group, butyl group, isobutyl group, pentyl group, hexyl group, heptyl group, octyl group, 2-ethyl Hexyl group, nonyl group, decyl group, benzyl group, phenethyl group, 3-phenylpropyl group, 2- (p-tolyl) -ethyl group and the like can be exemplified, preferably methyl group, ethyl group, propyl group, butyl Group, a phenethyl group.
In the present invention, R ³ in the formula (4) is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or An alkoxy group having 1 to 6 carbon atoms such as a hydrogen atom, a methyl group, an ethyl group, a propyl group, a methoxy group, and an ethoxy group, preferably a hydrogen atom, a methyl group, or a methoxy group; Examples of the group are more preferable.

Compound represented by formula (5) In the present invention, R ^{7 in} formula (5) is a hydrocarbon group having 1 to 12 carbon atoms, and is a linear alkyl group, a branched alkyl group, or an araalkyl group. (Aralkyl) or an aralkyl group having an alkyl group, specifically, methyl group, ethyl group, propyl group, butyl group, isobutyl group, pentyl group, hexyl group, heptyl group, octyl group, 2-ethyl Hexyl group, nonyl group, decyl group, benzyl group, phenethyl group, 3-phenylpropyl group, 2- (p-tolyl) -ethyl group and the like can be exemplified, preferably methyl group, ethyl group, propyl group, butyl Group, a phenethyl group.
In the present invention, R ³ in the formula (5) is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or An alkoxy group having 1 to 6 carbon atoms such as a hydrogen atom, a methyl group, an ethyl group, a propyl group, a methoxy group, and an ethoxy group, preferably a hydrogen atom, a methyl group, or a methoxy group; Examples of the group are more preferable.

The α, β-unsaturated ketone compound represented by the formula (1) of the present invention is exemplified below.
In the formula (2), R ³ is a hydrogen atom and R ⁴ has 1 to 12 carbon atoms, such as 1-phenyl-2-buten-1-one, 1-phenyl-2-penten-1-one, -Phenyl-2-hexen-1-one, 1-phenyl-2-hepten-1-one, 1-phenyl-2-octen-1-one, 1-phenyl-2-nonen-1-one, 1-phenyl Examples include 2-decen-1-one.

In the formula (2), R ³ is a hydrogen atom, and R ⁴ is a hydroxyl group having 1 to 12 carbon atoms, such as 1-phenyl-4-hydroxy-2-penten-1-one, 1-phenyl-4- Hydroxy-2-hexen-1-one, 1-phenyl-4-hydroxy-2-hepten-1-one, 1-phenyl-4-hydroxy-2-octen-1-one, 1-phenyl-4-hydroxy- Examples include 2-nonen-1-one and 1-phenyl-4-hydroxy-2-decen-1-one.

In the formula (2), R ³ is a methoxy group, and R 4 is a group having 1 to 12 carbon atoms: 1- (3′methoxy-) phenyl-2-penten-1-one, 1- (4′methoxy-) Examples thereof include phenyl-2-penten-1-one, 1- (3′methoxy-) phenyl-2-hexen-1-one, and 1- (4′methoxy-) phenyl-2-hexen-1-one.

In the formula (2), R ³ is a methoxy group, and R 4 is a hydroxyl group having 1 to 12 carbon atoms, such as 1- (3′methoxy-) phenyl-4-hydroxy-2-penten-1-one, -(4'methoxy-) phenyl-4-hydroxy-2-penten-1-one, 1- (3'methoxy-) phenyl-4-hydroxy-2-hexen-1-one, 1- (4'methoxy- ) Phenyl-4-hydroxy-2-hexen-1-one and the like.

In the formula (3), R ³ is a hydrogen atom, R ⁴ has 1 to 12 carbon atoms, R ⁵ has 1 to 12 carbon atoms, and the m-position or p-position is R ⁴ and Examples where R ⁵ is the same and different are exemplified. Examples of the same R ⁴ and R ⁵ include those in which R ⁴ and R ⁵ are at the p-position, such as an ethyl group, a propyl group, a butyl group, or a phenethyl group. , A propyl group, a butyl group, or a phenethyl group.
R ⁴ and R ⁵ are different from each other in that R ⁴ and R ⁵ are p-position, such as ethyl group and propyl group, propyl group and butyl group, ethyl group and butyl group, ethyl group and phenethyl group, etc. In the m-position, ethyl group and propyl group, propyl group and butyl group, ethyl group and butyl group, ethyl group and phenethyl group and the like can be exemplified.

Examples are those in which R ^{3 in} formula (3) is a hydrogen atom, R ⁴ is one having 1 to 12 carbon atoms, R ⁵ is one having 1 to 12 carbon atoms having a hydroxyl group, and is in the m-position or p-position. . Examples of R ⁴ and R ⁵ are p-position, ethyl group and hydroxymethyl group, propyl group and hydroxymethyl group, butyl group and hydroxymethyl group, or phenethyl group and hydroxymethyl group. Examples include an ethyl group and a hydroxymethyl group, a propyl group and a hydroxymethyl group, a butyl group and a hydroxymethyl group, or a phenethyl group and a hydroxymethyl group.

In formula (3), R ³ is a hydrogen atom, R ⁴ is a group having 1 to 12 carbon atoms having a hydroxyl group, R ⁵ is a group having 1 to 12 carbon atoms having a hydroxyl group, and is in the m-position or p-position Can be illustrated. Examples where R ⁴ and R ⁵ are at the p-position, such as hydroxymethyl group and hydroxymethyl group, hydroxyethyl group and hydroxymethyl group, hydroxypropyl group and hydroxymethyl group, or hydroxybutyl group and hydroxymethyl group, can be exemplified. And m-position, such as hydroxymethyl group and hydroxymethyl group, hydroxyethyl group and hydroxymethyl group, hydroxypropyl group and hydroxymethyl group, or hydroxybutyl group and hydroxymethyl group.

Examples include those in which R ^{3 in} formula (3) is a methoxy group, R ⁴ has 1 to 12 carbon atoms, and R ⁵ has 1 to 12 carbon atoms having a hydroxyl group.
Examples thereof include those in which R ^{3 in} formula (3) is a methoxy group, R ⁴ has 1 to 12 carbon atoms having a hydroxyl group, and R ⁵ has 1 to 12 carbon atoms having a hydroxyl group.

The synthesis of the α, β-unsaturated ketone compound represented by the formula (1) may differ depending on the types of R ¹ and R ² and the integers represented by m and n. For example, when R ¹ in the formula (1) is a hydrocarbon group, m = 1, n = 0, it is easy to obtain a β-hydroxyketone compound by an aldol reaction between acetophenone and an aldehyde compound and then perform a dehydration reaction. Can be prepared.
For example, when R ¹ and R ² are different hydrocarbon groups, m = 1, n = 1, an aldol reaction between ^one acetyl group of diacetylbenzene and R ¹ CHO is performed, and then obtained. It can be easily prepared by performing an aldol reaction again between the other acetyl group of the aldol product and R ² CHO, followed by a dehydration reaction.
When R ¹ and R ² are a hydrocarbon group having a hydroxyl group, the protective group is introduced into the hydroxyl group by a conventional method in organic synthetic chemistry, and a desired reaction is performed. The compound represented by 1) can also be synthesized.

In the present invention, the aldol reaction can be carried out in the presence of a base catalyst. Examples of the base catalyst include sodium carbonate, potassium carbonate, metallic lithium, metallic sodium, metallic potassium, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, Potassium t-butoxide, 1,8-diazabicyclo [5,4,0] -7-undecene (DBU), lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), n-butyllithium, s- Examples include butyllithium, t-butyllithium, n-butylmagnesium chloride, s-butylmagnesium chloride, t-butylmagnesium chloride, n-butylmagnesium bromide, s-butylmagnesium bromide, t-butylmagnesium bromide, etc. be able to. Among these, sodium hydroxide, potassium hydroxide, potassium t-butoxide, lithium diisopropylamide, or lithium hexamethyldisilazide is preferable in the present invention.
These base catalysts are used in an amount of 0.1 to 10 equivalents, preferably 0.5 to 3 equivalents, relative to the raw material aldehyde compound, and if necessary, an additive that promotes the reaction is added to the reaction system. May be added. The acetophenone and the aldehyde compound are stoichiometrically equimolarly reacted, but it is desirable in the present invention to use a small excess of which one is readily available in order to reliably complete the reaction.

In the present invention, the solvent used for the aldol reaction includes alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; halogen solvents such as methylene chloride and chloroform; hexane and toluene. Hydrocarbon solvents such as, etc .; water-soluble solvents such as dimethylformamide and dimethyl sulfoxide; water; or a mixed solvent thereof can be preferably used.
The reaction temperature of the aldol can be selected from the range of -100 ° C to 150 ° C, preferably -80 ° C to 100 ° C.

  After completion of the aldol reaction, the β-hydroxyketone compound can be obtained by separation and purification by a conventionally known method such as solvent extraction, column chromatography, or crystallization method.

  The target compound of the present invention can be obtained by further dehydrating the β-hydroxyketone compound obtained above. The dehydration reaction of this β-hydroxyketone compound is carried out by using an acid such as hydrochloric acid, sulfuric acid, potassium hydrogen sulfate, oxalic acid, p-toluenesulfonic acid, iodine, anhydrous copper sulfate and the like; a halogenating agent such as thionyl chloride and phosphoric acid chloride; It can be suitably performed by using a sulfonating agent such as methanesulfonyl chloride as a dehydrating agent.

  After completion of the dehydration reaction, the α, β-unsaturated ketone compound of the present invention can be easily obtained by separation and purification by a conventionally known method such as solvent extraction, column chromatography, or crystallization method.

In the present invention, the compound represented by the formula (5) can be synthesized by epoxidizing the compound represented by the formula (5) with a carboxylic acid peroxide and then reacting with a basic substance. .
In this reaction, the first epoxidation reaction and the subsequent reaction may be carried out continuously, or once the epoxy compound is purified by a conventional method such as solvent extraction or silica gel column chromatography, The reaction can also be carried out.

In the present invention, the carboxylic acid peroxide is not particularly limited, and examples thereof include peracetic acid, perbenzoic acid, 3-chloroperbenzoic acid, and the like, and perbenzoic acid or 3-chloroperbenzoic acid. Can be preferably used.
In the production method of the present invention, the amount of peroxide of carboxylic acid is basically a stoichiometric amount with respect to the double bond in the compound represented by the formula (5), taking into account the reactivity and the like. Thus, it is preferable to use 0.5 to 2.0 times, preferably 0.8 to 1.2 times the stoichiometric amount. If the amount of the carboxylic acid peroxide used is too small, the progress of the reaction is insufficient, and if the amount used is too large, the cost increases and the side reaction tends to proceed, which is not preferable.

In the present invention, this reaction is preferably carried out in a solvent. Halogen solvents such as dichloromethane and carbon tetrachloride, aromatic solvents such as toluene and xylene, ethyl acetate, acetone, water, and mixtures thereof A solvent can be used.
In the present invention, the temperature for reacting with the peroxide of carboxylic acid varies depending on the peroxide used and the amount used, but can be -20 ° C to 90 ° C, preferably 0 ° C to 60 ° C. When the reaction temperature is too low, the progress of the reaction is slow, and when it is too high, the side reaction tends to proceed, which is not preferable.
In the present invention, the reaction time of the carboxylic acid with the peroxide varies depending on the conditions, but is usually from several hours to several tens of hours.

In this invention, after epoxidizing the double bond in the compound represented by Formula (5), it is converted into an epoxy compound by acting a basic substance. Examples of the basic substance include sodium carbonate and potassium carbonate. Examples include inorganic basic substances such as sodium hydroxide, organic amines such as triethylamine and diisopropylethylamine, and metal alkoxides such as sodium methoxide and potassium t-butoxide. Organic amines such as triethylamine and diisopropylethylamine are preferably used. can do.
In this invention, the quantity of the said basic substance is 0.1-3 equivalent with respect to the peroxide of carboxylic acid, Preferably it is 0.3-1.2 equivalent. If the amount of the basic substance is too small, the progress of the reaction becomes insufficient, and if the amount used is too large, the cost increases, which is not preferable.

  In the present invention, the reaction temperature with the basic substance is −20 ° C. to 90 ° C., preferably 10 ° C. to 60 ° C., although it varies depending on the product used and the amount used. If the reaction temperature is too low, the progress of the reaction is slow, and if it is too high, the side reaction tends to proceed, which is not preferable. The reaction time varies depending on conditions, but is usually from several hours to several tens of hours.

  In this invention, after completion | finish of reaction, the compound represented by General formula (4) can be isolate | separated and refine | purified by conventionally well-known methods, such as solvent extraction, column chromatography, and the crystallization method.

  In the present invention, the effective content and use amount of the compound represented by the formula (1) depends on conditions such as the use form, the use form, the type of microorganisms to be used, the expected generation time and period thereof, and the like. Depending on the situation, it can be varied widely.

In the present invention, the compound represented by the formula (1) alone exhibits excellent antibacterial and antifungal activities. Usually, when the compound represented by the formula (1) of the present invention is used as an antibacterial agent, when used alone or in combination with other antibacterial agents, the concentration is the total amount of the antibacterial agent. The content is preferably 0.001 to 10% by weight, more preferably 0.01 to 5% by weight. If the concentration is less than 0.001% by weight, the effect of the present invention cannot be sufficiently obtained, and if it exceeds 10% by weight, it is not preferable because it is disadvantageous in terms of preparation or cost.
However, in special cases, it is possible to exceed or fall below these ranges. For example, when a synergistic effect or an additive effect is observed when used in combination with other antibacterial agents or antifungal agents, it can be used at a lower dose.

In the present invention, the form as an antibacterial agent or preservative is not particularly limited, and can be used in any form such as powder, granule, tablet, solution, emulsion, and suspension. For example, the compound represented by the formula (1) of the present invention can be used by appropriately supporting it on a solid or liquid, and if necessary, other components such as a surfactant can be blended into an emulsion, hydration It can also be used as an agent, a granular material, a powder, a spray, an aerosol agent and the like. Furthermore, a normal effective base may be used according to the form of the antibacterial agent, for example, drugs such as tranexamic acid, dipotassium glycyrrhizinate, vitamin E, azulene, other surfactants, solvents, pH adjusters, preservatives, A sweetening agent, a fragrance | flavor, a binder, an abrasive | polishing agent, etc. can also be mix | blended.
For example, when using as a one-part preparation in liquid form, there is no particular limitation on the method of making a one-part preparation, it can be dissolved in a solvent to make a one-part preparation, suspended in water to make a one-part preparation You can also

  In the present invention, the compound represented by the formula (1) can be dissolved in a solvent to form a one-part preparation. In this case, when the object to be sterilized or preserved is aqueous, it is preferable to use water or a hydrophilic organic solvent in consideration of the solubility and dispersibility of the active ingredient. Examples of the hydrophilic organic solvent include amides such as dimethylformamide, glycols such as ethylene glycol, propylene glycol, diethylene glycol, and dipropylene glycol, methyl cellosolve, phenyl cellosolve, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and dipropylene. Examples include glycol ethers such as glycol monomethyl ether, esters such as methyl acetate, ethyl acetate, 3-methoxybutyl acetate, 2-methoxyethyl acetate, 2-ethoxyethyl acetate and propylene carbonate, alcohols having 8 or less carbon atoms, and the like. be able to.

  In the present invention, when the compound represented by the formula (1) is suspended in water to form a one-pack preparation, xanthan gum, lambzan gum, guar gum and the like are used as a thickener, and a nonionic surfactant, an anionic surfactant, Cationic surfactants, amphoteric surfactants and the like can be used. Further, in order to obtain a water suspension, wet pulverization can be performed using a ball mill, an attritor or the like.

  When the object to be sterilized or preserved is an oil system such as heavy oil sludge, cutting oil, oil paint, etc., it can be made into a one-part preparation using a hydrocarbon solvent such as heavy oil, kerosene, spindle oil or the like. When preparing a one-component preparation using a hydrocarbon solvent, nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, and the like can also be used.

  As described above, the compound represented by the formula (1) of the present invention has a broad antibacterial spectrum against various bacteria and fungi, as shown in the examples below, for example, eye drops, Pharmaceuticals such as disinfectants, detergents, quasi-drugs such as antibacterial and deodorant processed fiber products, as well as a wide range of fields such as leather products, building materials, wood, adhesives, plastics, films, paper, pulp, and metalworking oils Useful.

<Example>
EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these Examples. % Is% by weight.

<Synthesis Example 1>
Synthesis of 1-phenyl-2-penten-1-one To a solution of acetophenone (1.2 g, 10.0 mmol) in tetrahydrofuran (20 mL), 2.0 M lithium diisopropyl at −78 ° C. in a nitrogen atmosphere. Amide (6 mL) was added dropwise. After stirring at the same temperature for 1 hour, a solution of propionaldehyde (0.80 mL, 11 mmol) dissolved in tetrahydrofuran (5 mL) was added dropwise. After stirring at the same temperature for 1 hour, 1N aqueous hydrochloric acid was added dropwise to stop the reaction. The separated organic phase was washed twice with a saturated aqueous sodium chloride solution (10 mL), and then the combined aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phase was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 1.5 g (yield 84%) of 3-hydroxy-1-phenylpentan-1-one as a pale yellow medium-viscosity liquid compound. It was.

Physicochemical properties of 3-hydroxy-1-phenylpentan-1-one
¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 1.02 (3H, t, J = 7.6 Hz), 1.57-1.65 (2H, m), 3.04 (1 H, dd, J = 8.8, 17.6 Hz), 3.18 ( 1H, dd, J = 2.8, 17.6Hz), 3.27 (1H, d, J = 2.8Hz), 4.09-4.18 (1H, m), 7.45-7.49 (2H, m), 7.56-7.60 (1H, m) , 7.95-7.97 (2H, m).
IR νmax (KBr): 3400, 2830, 1710 (cm ^-1 )

  To a solution of the above 3-hydroxy-1-phenylpentan-1-one (0.71 g, 4.00 mmol) in methylene chloride (20 mL), triethylamine (1.2 mL, 8.8 mmol) at 0 ° C., And methanesulfonyl chloride (0.34 mL, 4.4 mmol) were added dropwise. The mixture was stirred for 1 hour with heating under reflux. The resulting reaction mixture was washed twice with a saturated aqueous sodium bicarbonate solution (10 mL) and then the combined aqueous phases were extracted with chloroform (20 mL). The combined organic phase was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 0.51 g (yield 75%) of 1-phenyl-2-penten-1-one as a pale yellow medium viscosity liquid compound. (Hereinafter referred to as Compound 1).

-Physicochemical properties of Compound 1
¹ H-NMR (CDCl ₃ , 400MHz) δppm: 1.15 (3H, t, J = 7.6Hz), 2.32-2.37 (2H, m), 6.88 (1H, d, J = 15.2Hz), 7.12 (1H, dt , J = 6.4, 15.6Hz), 7.45-7.49 (2H, m), 7.53-7.57 (1H, m), 7.92-7.94 (2H, m)
IR νmax (KBr): 2830, 1710, 1640, 1600 (cm ^-1 )

<Synthesis Example 2>
○ Synthesis of 1-phenyl-2-hexen-1-one In the same manner as in Synthesis Example 1, light yellow medium viscosity liquid was obtained from acetophenone (1.2 g, 10.0 mmol) and n-butyraldehyde (1.00 mL, 11 mmol). As a compound, 1.2 g (yield 61%) of 3-hydroxy-1-phenylhexane-1-one was obtained.

Physicochemical properties of 3-hydroxy-1-phenylhexane-1-one
¹ H-NMR (CDCl ₃ , 400MHz) δppm: 0.95 (3H, t, J = 7.6Hz), 1.45-1.63 (4H, m), 3.07 (1H, dd, J = 9.2, 17.6Hz), 3.18 (1H , dd, J = 2.8, 17.6Hz), 3.22 (1H, d, J = 2.8Hz), 4.22-4.26 (1H, m), 7.46-7.49 (2H, m), 7.56-7.61 (1H, m), 7.95-7.97 (2H, m)
IR νmax (KBr): 3400, 2830, 1710 (cm ^-1 )

  Next, from the above 3-hydroxy-1-phenylhexane-1-one (0.96 g, 5.00 mmol), 0.66 g (yield of 1-phenyl-2-hexen-1-one as a pale yellow medium viscosity liquid compound) was obtained. (76%) was obtained (hereinafter referred to as Compound 2).

-Physicochemical properties of Compound 2
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 1.00 (3H, t, J = 7.6 Hz), 1.54-1.61 (2H, m), 2.27-2.33 (2H, m), 6.88 (1H, d, J = 15.6Hz), 7.12 (1H, dt, J = 6.8, 15.6Hz), 7.45-7.57 (3H, m), 7.92-7.94 (2H, m)
IR νmax (KBr): 2830, 1710, 1640, 1600 (cm ^-1 )

<Synthesis Example 3>
○ Synthesis of 1-phenyl-2-heptan-1-one In the same manner as in Synthesis Example 1, acetophenone (1.2 g, 10.0 mmol) and n-pentanal (1.16 mL, 11 mmol) As a compound, 1.2 g (yield 58%) of 3-hydroxy-1-phenylheptan-1-one was obtained.

Physicochemical properties of 3-hydroxy-1-phenylheptan-1-one
¹ H-NMR (CDCl ₃ , 400MHz) δppm: 0.93 (3H, t, J = 7.6Hz), 1.36-1.62 (6H, m), 3.04 (1H, dd, J = 9.2, 17.6Hz), 3.16-3.23 (2H, m), 4.22-4.26 (1H, m), 7.46-7.50 (2H, m), 7.57-7.61 (1H, m), 7.95-7.97 (2H, m)
IR νmax (KBr): 3400, 2830, 1710 (cm ^-1 )

  Next, from the above 3-hydroxy-1-phenylheptan-1-one (0.83 g, 4.00 mmol), 0.64 g (yield of 1-phenyl-2-hepten-1-one as a pale yellow medium viscosity liquid compound) was obtained. 85%) was obtained (hereinafter referred to as Compound 3).

-Physicochemical properties of Compound 3
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 0.94 (3H, t, J = 7.6 Hz), 1.38-1.57 (4H, m), 2.30-2.36 (2H, m), 6.88 (1H, d, J = 15.6Hz), 7.06 (1H, dt, J = 6.8, 15.6Hz), 7.45-7.56 (3H, m), 7.91-7.94 (2H, m)
IR νmax (KBr): 2830, 1710, 1640, 1600 (cm ^-1 )

<Synthesis Example 4>
Synthesis of 1-phenyl-2-octen-1-one In the same manner as in Synthesis Example 1, from acetophenone (1.2 g, 10.0 mmol) and n-hexanal (1.34 mL, 11 mmol) as a colorless crystalline compound 1.59 g (yield 72%) of 3-hydroxy-1-phenyloctane-1-one was obtained.

・ Physicochemical properties of 3-hydroxy-1-phenyloctane-1-one
¹ H-NMR (CDCl ₃ , 400MHz) δppm: 0.92 (3H, t, J = 7.6Hz), 1.24-1.64 (8H, m), 3.04 (1H, dd, J = 8.8, 17.6Hz), 3.15-3.24 (2H, m), 4.22-4.26 (1H, m), 7.46-7.50 (2H, m), 7.57-7.61 (1H, m), 7.95-7.97 (2H, m)
IR νmax (KBr): 3400, 2830, 1710 (cm ^-1 )

  Next, 1.09 g of 1-phenyl-2-octen-1-one (yield) was obtained from the above 3-hydroxy-1-phenyloctane-1-one (1.46 g, 6.60 mmol) as a pale yellow medium viscosity liquid compound. 81%) was obtained (hereinafter referred to as Compound 4).

-Physicochemical properties of compound 4
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 0.90 (3H, t, J = 7.6 Hz), 1.32-1.57 (6H, m), 2.29-2.35 (2H, m), 6.88 (1H, d, J = 15.6Hz), 7.06 (1H, dt, J = 6.8, 15.6Hz), 7.45-7.56 (3H, m), 7.91-7.94 (2H, m)
IR νmax (KBr): 2830, 1710, 1640, 1600 (cm ^-1 )

<Synthesis Example 5>
○ Synthesis of 1-phenyl-2-nonen-1-one In the same manner as in Synthesis Example 1, from acetophenone (1.2 g, 10.0 mmol) and n-heptanal (1.54 mL, 11 mmol) as a colorless crystalline compound 1.46 g (62% yield) of 3-hydroxy-1-phenylnonan-1-one was obtained.

Physicochemical properties of 3-hydroxy-1-phenylnonan-1-one
¹ H-NMR (CDCl ₃ , 400MHz) δppm: 0.89 (3H, t, J = 7.6Hz), 1.23-1.66 (10H, m), 3.04 (1H, dd, J = 9.2, 17.6Hz), 3.16-3.24 (2H, m), 4.22-4.26 (1H, m), 7.46-7.50 (2H, m), 7.57-7.61 (1H, m), 7.95-7.97 (2H, m)
IR νmax (KBr): 3400, 2830, 1710 (cm ^-1 )

  Next, 0.73-g of 1-phenyl-2-nonen-1-one (yield) was obtained from the above 3-hydroxy-1-phenylnonan-1-one (0.94 g, 4.00 mmol) as a pale yellow medium viscosity liquid compound. 84%) was obtained (hereinafter referred to as Compound 5).

-Physicochemical properties of compound 5
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 0.90 (3H, t, J = 7.6 Hz), 1.28-1.60 (8H, m), 2.29-2.35 (2H, m), 6.88 (1H, d, J = 15.6Hz), 7.06 (1H, dt, J = 6.8, 15.6Hz), 7.45-7.58 (3H, m), 7.91-7.94 (2H, m)
IR νmax (KBr): 2830, 1710, 1640, 1600 (cm ^-1 )

<Synthesis Example 6>
○ Synthesis of 1-phenyl-2-decen-1-one In the same manner as in Synthesis Example 1, from acetophenone (1.2 g, 10.0 mmol) and n-octanal (1.73 mL, 11 mmol) as a colorless crystalline compound 1.55 g (63% yield) of 3-hydroxy-1-phenyldecan-1-one was obtained.

Physicochemical properties of 3-hydroxy-1-phenyldecan-1-one
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.89 (3H, t, J = 7.6 Hz), 1.28-1.64 (12H, m), 3.04 (1H, dd, J = 9.2, 18.0 Hz), 3.16-3.23 (2H, m), 4.21-4.22 (1H, m), 7.46-7.50 (2H, m), 7.57-7.61 (1H, m), 7.95-7.97 (2H, m) ppm
IR νmax (KBr): 3400, 2830, 1710 (cm ^-1 )

  Next, 1.19 g of 1-phenyl-2-decen-1-one (yield 86) was obtained from 3-hydroxy-1-phenyldecan-1-one (1.49 g, 6.00 mmol) as a pale yellow medium viscosity liquid compound. %) (Hereinafter referred to as Compound 6).

-Physicochemical properties of compound 6
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 0.89 (3H, t, J = 7.6 Hz), 1.26-1.56 (10H, m), 2.29-2.34 (2H, m), 6.87 (1H, d, J = 15.6Hz), 7.06 (1H, dt, J = 6.8, 15.6Hz), 7.45-7.58 (3H, m), 7.91-7.94 (2H, m)
IR νmax (KBr): 2830, 1710, 1640, 1600 (cm ^-1 )

<Synthesis Example 7>
-Synthesis of compound 8
A 2.0 M lithium diisopropylamide / tetrahydrofuran-heptane-ethylbenzene solution (10.0 ml) diluted with tetrahydrofuran (10 ml) was cooled to −15 ° C. To this solution was added dropwise a solution of 1,4-diacetylbenzene (1.63 g, 10.0 mmol) in tetrahydrofuran (30 ml). After stirring for 30 minutes, propionaldehyde (2.20 ml, 30.5 mmol) was added. After stirring at the same temperature for 15 minutes, saturated brine (20 ml) was added and partitioned. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain a light yellow liquid compound 7 represented by the following formula (7) (1.19 g, yield 43%).

・ Physicochemical properties of Compound 7
¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm: 1.04 (6H, t, J = 6.8 Hz), 1.56-1.70 (4H, m),
3.06-3.22 (6H, m), 4.12-4.20 (2H, m), 8.05 (4H, s)

  Compound 8 represented by the following formula (8) was synthesized by reacting the compound 7 with 2 equivalents of methanesulfonyl chloride in the same manner as in <Synthesis Example 1>.

-Physicochemical properties of compound 8
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 1.16 (6H, t, J = 7.2 Hz), 2.36 (4H, dq, J = 6.0 and 7.2 Hz),
6.86 (2H, d, J = 16.4Hz), 7.10-7.18 (2H, m), 7.99 (4H, s).

<Synthesis Example 8>
Synthesis of Compound 10 Compound 9 represented by the following formula (9) is prepared by reacting 1,4-diacetylbenzene and 3-phenylpropionaldehyde in the same manner as in Synthesis Example 7, and further, Compound 9 Was subjected to a dehydration reaction to synthesize Compound 10 represented by the following formula (10).

-Physicochemical properties of compound 9
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 1.82-1.87 (2H, m), 1.91-2.04 (2H, m), 2.72-2.80 (2H,
m), 2.86-2.93 (2H, m), 3.12-3.18 (6H, m), 4.23-4.28 (2H, m), 7.18-7.31 (10H, m), 8.00 (4H, s).

-Physicochemical properties of compound 10
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 2.64-2.69 (4H, m), 2.86 (4H, t, J = 7.6 Hz), 6.83 (2H, d,
J = 15.2Hz), 7.09 (2H, dt, J = 7.2 and 15.2Hz), 7.20-7.26 (10H, m), 7.91 (4H, s).

<Synthesis Example 9>
-Synthesis of compound 13
A solution prepared by diluting a 2.0 M lithium diisopropylamide / tetrahydrofuran-heptane-ethylbenzene solution (10.0 ml) with tetrahydrofuran (10 ml) was cooled in an ice-salt bath. To this solution, a solution of 1,4-diacetylbenzene (3.25 g, 20.0 mmol) in tetrahydrofuran (60 ml) was added dropwise. After stirring for 20 minutes, 3-phenylpropionaldehyde (3.00 ml, 22.8 mmol) was added. After stirring at the same temperature for 15 minutes, 2 N hydrochloric acid (10 ml) was added to neutralize. Saturated brine (30 ml) was added and partitioned. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a pale yellow liquid compound 11 (2.28 g, yield 38%) represented by the following formula (11).

-Physicochemical properties of compound 11
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 1.77-1.87 (1H, m), 1.92-2.03 (1H, m), 2.59 (1H, d,
J = 7.2Hz), 2.65 (3H, s), 2.72-1.82 (1H, m), 2.87-2.92 (1H, m), 3.13-3.18 (2H, m), 4.21-4.31 (1H, m), 7.15 -7.36 (5H, m), 7.97-8.08 (4H, m).

  To a solution of compound 11 (1.20 g, 4.05 mmol) in tetrahydrofuran (12.0 ml) was added dropwise 2.0 M lithium diisopropylamide / tetrahydrofuran-heptane-ethylbenzene solution (4.10 ml) at -78 ° C. After stirring for 60 minutes, propionaldehyde (0.45 ml, 6.24 mmol) was added. After stirring at the same temperature for 15 minutes, 2 N hydrochloric acid (4 ml) was added to neutralize. Saturated brine (20 ml) was added and partitioned. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a pale yellow liquid compound 12 (252 mg, 18% yield) represented by the following formula (12).

-Physicochemical properties of compound 12
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 1.03 (3H, t, J = 7.6 Hz), 1.46-1.72 (2H, m), 1.77-1.87
(1H, m), 1.92-2.00 (1H, m), 2.72-2.82 (1H, m), 2.85-2.97 (1H, m), 3.13-3.23 (4H, m), 4.10-4.30 (2H, m) , 7.15-7.36 (5H, m), 7.97-8.07 (4H, m).

  Compound 13 represented by the following formula (13) was synthesized by reacting the above compound 12 with 2 equivalents of methanesulfonyl chloride in the same manner as in <Synthesis Example 1>.

-Physicochemical properties of compound 13
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 1.16 (3H, t, J = 7.2 Hz), 2.34-2.39 (2H, m), 2.64-2.69
(2H, m), 2.86 (2H, t, J = 7.6Hz), 6.82-6.88 (2H, m), 7.06-7.33 (7H, m), 7.91-7.98 (4H, m).

<Example 1>
○ Synthesis of 1-phenyl-4-hydroxy-2-buten-1-one (compound 14) (Part 1)
To a solution of 1-phenyl-3-buten-1-one (317 mmol) in dichloromethane (1000 ml) was added 65% 3-chloroperbenzoic acid (100 g, 377 mmol). After heating under reflux for 18 hours, the mixture was allowed to cool, and 10% aqueous sodium thiosulfate solution (500 ml) was added to stop the reaction. The organic layer was separated, and the aqueous layer was extracted twice with chloroform (200 ml). The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
Next, the obtained residue was dissolved in acetone (600 ml), triethylamine (26.0 ml, 187 mmol) was added, and the mixture was heated to reflux. After 3 hours, the mixture was allowed to cool and the solvent was distilled off under reduced pressure. The residue was partitioned by adding ethyl acetate (500 ml) and 20% aqueous sodium carbonate (400 ml). The organic layer was collected and washed with saturated brine (200 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain pale yellow crystalline compound 14 represented by the following formula (14) (24.2 g, yield 47%).

-Physicochemical properties of compound 14
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 2.59 (1H, br), 4.73 (2H, s), 7.11-7.17 (1H, m), 7.21-
7.28 (1H, m), 7.44-7.49 (2H, m), 7.55-7.96 (1H, m), 7.97 (2H, d, J = 7.6Hz).

<Example 2>
-Synthesis of Compound 14 (Part 2)
65% 3-chloroperbenzoic acid (70.0 g, 264 mmol) was added to a solution of 1-phenyl-3-buten-1-one (260 mmol) in dichloromethane (1300 ml). After stirring at room temperature for 20 hours, 10% aqueous sodium thiosulfate solution (300 ml) was added and stirred for 15 minutes. Next, triethylamine (38.0 ml, 273 mmol) was added and stirred. After 5 hours, the organic layer was separated, and the aqueous layer was extracted twice with chloroform (150 ml). The combined organic layers were concentrated under reduced pressure. Next, the concentrated residue was dissolved in ethyl acetate (300 ml) and washed successively with a 10% aqueous sodium carbonate solution (100 ml × 2) and saturated brine (100 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain pale yellow crystalline compound 14 (8.00 g, yield 19%).

<Example 3>
-Synthesis of compound 16
A tetrahydrofuran solution (450 ml) of isophthalaldehyde (51.0 g, 380 mmol) was added dropwise to a 2.0 M allylmagnesium chloride / tetrahydrofuran solution (400 ml) under ice-cooling. After stirring at the same temperature for 15 minutes, 3 N hydrochloric acid (300 ml) was added to stop the reaction. Ethyl acetate (300 ml) was added and partitioned, and the organic layer was collected. The organic layer was washed with saturated brine (300 ml), and the solvent was evaporated under reduced pressure.
The resulting residue was then dissolved in acetone (1500 ml) and cooled. Jones reagent (a solution in which 75.0 g of chromic anhydride was dissolved in 225 ml of 47% sulfuric acid and distilled water was added to make a total volume of 300 ml) was adjusted so that the temperature of the reaction solution was in the range of -5 to 20 ° C. Added in minutes. After stirring for 10 minutes, isopropyl alcohol (50 ml) was added. After stirring for 10 minutes, the insoluble material was filtered off, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate (400 ml) and washed successively with distilled water (300 ml) and saturated brine (150 ml × 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography to obtain a light yellow liquid compound 15 represented by the following formula (15) (yield 30.1). g).

-Physicochemical properties of compound 15
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 3.81 (4H, d, J = 6.8 Hz), 5.22-5.28 (4H, m), 6.04-6.14
(2H, m), 7.57-7.62 (1H, m), 8.15-8.18 (2H, m), 8.54 (1H, s).

To a solution of compound 15 (61.6 mmol) in dichloromethane (500 ml) was added 65% 3-chloroperbenzoic acid (33.0 g, 124 mmol). After stirring at room temperature for 20 hours, 10% aqueous sodium thiosulfate solution (200 ml) was added and stirred for 15 minutes. The organic layer was separated, and the aqueous layer was extracted twice with chloroform (150 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
Next, the concentrated residue was dissolved in acetone (150 ml), triethylamine (5.20 ml, 37.3 mmol) was added, and the mixture was heated to reflux. After 3 hours, the mixture was allowed to cool and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain a light yellow liquid compound 16 represented by the following formula (16) (1.80 g, yield 12%).

-Physicochemical properties of compound 16
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 3.00-3.41 (2H, br), 4.48 (4H, q, J = 4.0 Hz), 7.13-7.28
(4H, m), 7.53 (1H, t, J = 7.6Hz), 8.10 (2H, dd, J = 4.0 and 7.6Hz), 8.44 (1H, s).

<Example 4>
-Synthesis of 1- (4-methylphenyl) -4-hydroxy-2-buten-1-one (compound 17)
To a solution of 1- (4-methylphenyl) -3-buten-1-one (173 mmol) in dichloromethane (600 ml) was added 3-chloroperbenzoic acid (222 mmol). After heating at reflux for 3 hours, the mixture was allowed to cool. The organic layer was washed sequentially with a 10% aqueous sodium thiosulfate solution (200 ml) and a 10% aqueous sodium carbonate solution (300 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
Next, the obtained residue was dissolved in acetone (200 ml), a solution prepared by previously dissolving triethylamine (87.6 mmol) and acetic acid (175 mmol) in acetone (200 ml) was added, and the mixture was stirred at 50 ° C. After 1 hour, the mixture was allowed to cool and the solvent was distilled off under reduced pressure. The residue was partitioned by adding chloroform (200 ml) and 10% aqueous sodium carbonate (150 ml). The organic layer was collected and the aqueous layer was extracted 3 times with chloroform (50 ml). The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and then recrystallized from toluene to obtain colorless plate crystal compound 17 (the following formula (17)) (12.7 g, yield 42%).

○ Physicochemical properties of compound 17 Melting point 61.7-62.6 ℃
¹ H-NMR (CDCl ₃ , 400 MHz) δppm: 1.90 (1H, t, J = 6.0 Hz), 2.42 (3H, s), 4.74 (2H, m), 7.12 (1H, dt, J = 3.6 and 15.6 Hz ), 7.22 (1H, d, J = 15.6 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.89 (2H, d, J = 8.0 Hz).

<Example 5>
Evaluation of antimicrobial activity Compounds 1 to 6 prepared in Synthesis Examples 1 to 6 above, and methyl p-hydroxybenzoate (methylparaben, manufactured by Wako Pure Chemical Industries, Ltd.), p-hydroxybenzoyl butyl (Comparative Examples) For butylparaben (manufactured by Wako Pure Chemical Industries, Ltd.), the minimum concentration (MIC) for inhibiting the growth of the test bacteria was measured.

(1) Preparation of test sample A test sample was accurately weighed and dissolved in dimethylsulfoxide (DMSO) to a concentration of 25.6 mg / ml. A 2-fold dilution series was prepared using DMSO sequentially as the first drug dilution series at 25.6 mg / ml.

(2) Test strains Various fungi used in the test Trichophyton mentagrophytes IFO (NBRC) 6124, Trichophyton rubrum IFO (NBRC) 5467, Aspergillus niger NBRC6341, Aspergillus terreus NBRC6346, Aureobasidium pullulans NBRC6353, Eurotium tonophilum NBRC We used stocks that were sold by PMDA.
After subculture, the cells were cultured in Potato Dextrose Agar (Difco) slant for 10 days at 27 ° C. After culturing, the slant surface was washed with 0.1% Tween 80-added physiological saline to prepare a conidia suspension. The prepared suspension was filtered with a Cell strainer (40 μm, FALCON), adjusted to 10 ⁵ cells / ml with physiological saline, and used as an inoculum.
As the bacteria, Staphylococcus aureus 209P, Bacillus subutillis ATCC 6633, and Escherichia coli NIH JC-2 were used. After subculture, the culture solution cultured at 37 ° C. for 24 hours with Mueller Hinton broth (Difco) was adjusted to 10 ⁴ cells / ml with the same medium to prepare an inoculum solution.

(3) Culture
After injecting 2 μl of each 2-fold diluted test sample prepared in DMSO prepared in (1) above into each well of a 96-well microplate, the fungus is Potato Dextrose Agar, the bacteria is Mueller Hinton agar (Difco) 198 μl Injected. After the injected agar solidified, 10 ⁵ cell / ml of fungus and 10 ⁴ cell / ml of bacteria were inoculated on the surface of 2 μl medium. As a growth control, a drug-free well was provided.
Fungi were cultured at 30 ° C. for 3-5 days, and bacteria were cultured at 37 ° C. for 24 hours. In the determination of MIC, the lowest concentration among wells in which growth was not visually confirmed was defined as MIC.
Table 1 shows the MIC (μg / ml) of each compound test sample for each test bacterium.

<Example 6>
Evaluation of antimicrobial activity With respect to Compound 8, Compound 10, Compound 13, Compound 14, and Compound 16 synthesized in Synthesis Example 7 to Synthesis Example 11, the minimum concentration (MIC) for inhibiting the growth of test bacteria was measured. .
Table 2 shows the MIC (μg / ml) of each compound test sample for each test bacterium.

  Compound 1-6, Compound 8, Compound 10, Compound 13, Compound 14, and Compound 16 had good antibacterial and antifungal activities against all test bacteria. In particular, it showed a strong effect on fungi.

<Example 7>
○ Preservation efficacy test (1) Test strain
S. aureus NBRC 13276, E.coli NBRC 3972, P. aeruginosa NBRC 13275 bacteria, A. niger NBRC 9455, C. albicans NBRC 1594 fungi received the product evaluation from the National Institute of Technology and Evaluation It was.
After two subcultures, A.niger NBRC 9455 was planted in Potato dextrose agar (Difco) slant at 25 ° C for 1 week, and C. albicans NBRC 1594 was Sabouraud agar (Nissui). At 25 ° C. for 48 hours, the three bacteria were cultured at 37 ° C. for 24 hours in Tryptosoya (Soybean / Casein Digest) agar medium (Nissui).
The cultured bacteria were washed with 0.1% Tween 80-added physiological saline to prepare a bacterial suspension. The bacterial solution prepared Cell strainer (40μm, FALCON) to measure the turbidity in the filtration after OD600, the calculated the amount of bacteria from OD600 and viable cell count of a calibration curve was examined beforehand, the bacteria of about 10 ⁸ CFU / ml The fungus was adjusted to about 10 ⁶ CFU / ml and used as an inoculum.
(2) Preservation Solution Formulation Table 3 shows the formulation (preservation formulation) used in the storage efficacy test. A test lotion was used for the purpose of knowing the storage stability when used in lotions.

(3) S. aureus NBRC 13276, E. coli NBRC 3972, P. aeruginosa NBRC 13275, A. niger NBRC 9455 prepared in 1 by adding 0.025 to 0.2% of compound 14 to the liquid prescribed in Test Method 2. C. albicans NBRC 1594 was added so that the final bacterial amount was about 10 ⁶ CFU / ml for bacteria and about 10 ⁴ CFU / ml for fungi, and stored at 25 ° C. The number of viable bacteria was measured on 1, 3, 7, 14, 21, and 28 days after storage.

(4) Test results Tables 4 to 7 show the results of preservative efficacy tests for the formulations using Compound 14 in terms of indices (unit: log CFU / ml, ND: not detected). Compound 14 is highly resistant to bacteria such as S. aureus and E. coli and fungi A. niger and C. albicans at a total concentration of 0.025 to 0.2% and in any of the formulas 1 to 4. Showed the effect. That is, in many of the tested bacteria and formulations, the bacteria were below the detection limit (ND: <10 CFU / ml) one day after the bacterial inoculation, and the effect was maintained until the end of the 28-day observation. Even in cases where it took 3 days or 1 week until the bacteria disappeared, the effect continued until the end of the observation period.

  The α, β-unsaturated ketone compound of the present invention has an excellent antibacterial and antifungal activity, and as an antibacterial agent or preservative in the fields of foods, pharmaceuticals, and quasi drugs, plastic products, paper products, It can be applied to related fields such as fabric products and leather products.

Claims (5)

An antibacterial agent comprising an α, β-unsaturated ketone compound represented by the following general formula (1).

In (Equation (1), R ¹ is a hydrocarbon group having 1 to 12 carbon atoms, R ² is a hydrocarbon group having 1 to 12 carbon atoms having a hydroxyl group, R ³ represents a hydrogen atom, a carbon An alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, m is an integer of 0 to 3, n is an integer of 0 to 3, and m + n satisfies a value of 1 to 4. .) The antibacterial agent according to claim 1, wherein the general formula (1) is an α, β-unsaturated ketone compound represented by the following formula (2).

(In the formula (2), R ⁴ is a hydrocarbon group having 1 to 12 carbon atoms or a hydrocarbon group having 1 to 12 carbon atoms having a hydroxyl group, and R ³ is a hydrogen atom, having 1 to 6 carbon atoms. It is an alkyl group or an alkoxy group having 1 to 6 carbon atoms.) The antibacterial agent according to claim 1, wherein the general formula (1) is an α, β-unsaturated ketone compound represented by the following formula (3).

(In Formula (3), R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms, and R ⁴ is a hydrocarbon group having 1 to 12 carbon atoms, or a hydrocarbon group having 1 to 12 carbon atoms having a hydroxyl group, R ⁵ is a hydrocarbon group having 1 to 12 carbon atoms having a hydrocarbon group having 1 to 12 carbon atoms or a hydroxyl group.) The antibacterial agent according to claim 1, wherein the general formula (1) is an α, β-unsaturated ketone compound represented by the following formula (4).

(In Formula (4), R < ⁶ > is a hydrogen atom or a C1-C11 hydrocarbon group, and R < ³ > is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy. And m is an integer of 1 to 3.) Α, β- represented by the formula (4) of claim 4 produced by epoxidizing a compound represented by the following formula (5) with a carboxylic acid peroxide and then reacting with a basic substance. Unsaturated ketone compounds.

(In the formula (5), R ⁷ is a hydrogen atom or a hydrocarbon group having 1 to 11 carbon atoms, and R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms. And m is an integer of 1 to 3.)