WO2015199202A1 - 4-イソプロピル-3-メチルフェノールの製造方法 - Google Patents
4-イソプロピル-3-メチルフェノールの製造方法 Download PDFInfo
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- WO2015199202A1 WO2015199202A1 PCT/JP2015/068418 JP2015068418W WO2015199202A1 WO 2015199202 A1 WO2015199202 A1 WO 2015199202A1 JP 2015068418 W JP2015068418 W JP 2015068418W WO 2015199202 A1 WO2015199202 A1 WO 2015199202A1
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- methylphenol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
- C07C37/18—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving halogen atoms of halogenated compounds
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
- A01N31/08—Oxygen or sulfur directly attached to an aromatic ring system
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
- C07C39/06—Alkylated phenols
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
Definitions
- the present invention relates to a method for producing 4-isopropyl-3-methylphenol. Specifically, the present invention relates to a production method capable of producing 4-isopropyl-3-methylphenol with high yield. Furthermore, the present invention relates to a production method capable of efficiently producing 4-isopropyl-3-methylphenol with little odor and coloring.
- Isopropylmethylphenol is widely used as an antibacterial agent, bactericidal agent, preservative and the like in pharmaceuticals, quasi drugs, cosmetics and the like.
- Isopropyl methylphenol has isomers, and among them, 4-isopropyl-3-methylphenol (hereinafter sometimes referred to as p-thymol) has a strong antibacterial and bactericidal activity, and has anti-skin properties. It has low irritant and other toxic properties and is colorless and odorless.
- isomers such as 4-isopropyl-3-methylphenol, 6-isopropyl-3-methylphenol (hereinafter sometimes referred to as o-thymol), 5-isopropyl-3-methylphenol (hereinafter, referred to as o-thymol). m-thymol), and 2-isopropyl-3-methylphenol (hereinafter sometimes referred to as vic-thymol).
- 4-isopropyl-3-methylphenol is currently generally reacted with m-cresol and propylene in the presence of a catalyst to obtain a mixture of isomers and then isomerized from these mixtures. It is manufactured through purification operations such as distillation, extraction and crystallization.
- Patent Document 1 a method using calcium oxide as a catalyst
- Patent Document 2 a method using a metal sulfate and ⁇ -alumina as a catalyst
- Patent Document 3 A method using a catalyst solution containing zinc bromide, hydrogen bromide and water (Patent Document 3) is known.
- a method of coexisting phosphoric acid in the reaction of m-cresol and propylene for example, in the production of alkylphenols by reacting phenols such as m-cresol and olefins such as propylene in a liquid phase using activated clay or acidic clay as a catalyst, phosphoric anhydride, condensed phosphoric acid and salts thereof, and A method of coexisting a phosphorus compound selected from the group consisting of phosphoric acid and its salt has been reported (Patent Document 4).
- a phosphoric acid catalyst By using a phosphoric acid catalyst, the reaction is carried out in a liquid phase under heating and under a predetermined propylene pressure, so that the production ratio of o-thymol / p-thymol is 3 mainly composed of p-thymol and o-thymol.
- a method for producing thymol that is 1 or less has also been reported (Patent Document 5).
- 3-methyl-4-isopropylaniline is obtained by isopropylating m-toluidine in the presence of sulfuric acid, and 4-isopropyl-3-methylphenol is produced by diazolysis or hydrolysis under high temperature and high pressure.
- Patent Document 6 A method has also been reported.
- Patent Documents 1 to 3 All of the methods disclosed in Patent Documents 1 to 3 are intended to produce o-thymol, and since the selectivity of the reaction is poor, the isomers o-thymol, p-thymol, m-thymol, Since diisopropylcresol and the like are produced, it is difficult to selectively produce p-thymol. Also, the reactivity itself is insufficient. Although the method disclosed in Patent Document 4 can be expected to improve the reactivity, it does not mention the selectivity of the reaction, and it is still difficult to selectively produce p-thymol.
- Patent Document 5 a product mainly composed of p-thymol and o-thymol can be obtained, and the production of m-thymol can be suppressed.
- it is still inadequate in that only p-thymol is selectively produced, and far from obtaining p-thymol with high selectivity and high yield in the reaction step without depending on purification. .
- p-thymol, o-thymol, and m-thymol have a problem that separation is difficult because of their close boiling points.
- a method for selectively producing only p-thymol has not been found so far, and its appearance has been strongly desired.
- a pressure vessel such as an autoclave is required for the reaction, and there is a problem that the equipment is expensive.
- the conventional method has a problem that odor and coloring remain in the obtained p-thymol. This is considered to be because in the conventional method, there are many substances that can cause odor and coloring such as m-cresol as a raw material and o-thymol, m-thymol, diisopropyl cresol as products. Specifically, it is presumed that this is due to the difficulty in separating the above-mentioned p-thymol, o-thymol, and m-thymol. Attempting to solve this problem places a heavy burden on purification.
- the present invention has been made in view of the above problems, and an object thereof is to provide a production method capable of selectively producing 4-isopropyl-3-methylphenol. Furthermore, an object of the present invention is to provide a production method capable of efficiently producing 4-isopropyl-3-methylphenol which is easily purified and has little odor and color.
- the present invention provides 4-isopropyl-3-methylphenol, which comprises reacting 4-halogenated-3-methylphenol or a phenol derivative thereof with an isopropyl metal compound in the presence of a catalyst and a solvent. Provide a method.
- 4-halogenated-3-methylphenol or a phenol derivative thereof and an isopropyl metal compound are reacted in the presence of a catalyst and a solvent, whereby the isomers of o-thymol and m-thymol are added.
- the raw material can be suppressed and 4-isopropyl-3-methylphenol can be produced with high selectivity and high yield. As a result, 4-isopropyl-3-methylphenol with little odor and coloring can be obtained.
- the 4-halogenated-3-methylphenol is preferably 4-bromo-3-methylphenol. This is because 4-bromo-3-methylphenol is highly reactive and can be obtained at low cost.
- the isopropyl metal compound is preferably isopropyl zinc bromide. This is because isopropyl zinc bromide is highly reactive.
- the catalyst preferably contains one or more selected from palladium, nickel, ruthenium, iron and copper. These transition metal catalysts are applicable to the above reaction.
- the reaction is preferably performed in the presence of a ligand having a biarylphosphine skeleton.
- the above ligand has an appropriate bulkiness, and it is easy to introduce an isopropyl group at the 4-position adjacent to the 3-position methyl group having steric hindrance of 4-halogenated-3-methylphenol. Useful for the above reaction.
- the said ligand is bulky, reaction can be advanced selectively, without protecting a phenolic hydroxyl group, and a manufacturing process can be simplified significantly.
- the ligand has a biaryldialkylphosphine skeleton, and 2-dicyclohexylphosphino-2 ′, 6′-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2 ′, 6 ′. It is more preferably one or a mixture of two or more selected from -dimethoxybiphenyl and 2-dicyclohexylphosphino-2 ', 6'-bis (N, N-dimethylamino) biphenyl. This is because these ligands are suitable in bulk, and thus the selectivity of the reaction is good for the same reason as described above.
- the solvent is preferably a solvent containing an ether capable of dissolving the isopropyl metal compound.
- the catalyst and the ligand are mixed in the solvent, and the 4-halogenated-3-methylphenol and the isopropyl metal compound are added to the mixed solution.
- At least one of the catalyst and the ligand is fixed to a solid support. This is because if the catalyst and the ligand are fixed to the solid support, they can be easily separated after the reaction.
- the present invention also relates to a 4-isopropyl-3-methylphenol composition produced according to the above-described production method, wherein 4-normalpropyl-3-methylphenol is reduced to 0.4-propyl-3-methylphenol.
- Compositions are provided that fall within the range of 1% to 10% by weight.
- the present invention also provides an antibacterial composition or a bactericidal composition comprising 4-isopropyl-3-methylphenol produced according to the production method described above.
- a composition containing 4-isopropyl-3-methylphenol as an antibacterial agent or fungicide can be obtained.
- 4-isopropyl-3-methylphenol can be produced with high selectivity and high yield, and 4-isopropyl-3-methylphenol with less odor and coloring can be obtained. Play.
- 4-isopropyl-3-methylphenol can be produced with high selectivity and high yield without protecting the phenolic hydroxyl group.
- A. Process for Producing 4-Isopropyl-3-methylphenol comprises 4-halogenated 3-methylphenol or a phenol derivative thereof and an isopropyl metal compound, a catalyst and a solvent. It is the method characterized by making it react in presence of.
- the present invention is a method for producing 4-isopropyl-3-methylphenol using a cross-coupling reaction. Specifically, in order to bind an isopropyl group that is a bulky secondary alkyl group to an aromatic ring (aromatic compound), 4-halogenated-3-methylphenol or a phenol derivative thereof and an isopropyl metal compound are combined. In this method, a new carbon-carbon bond is formed by reacting in the presence of a catalyst and a solvent. Therefore, in the present invention, 4-isopropyl-3-methylphenol can be selectively produced.
- o-thymol and m-thymol which are isomers of 4-isopropyl-3-methylphenol
- 4-isopropyl-3-methylphenol can be obtained in a high yield.
- these isomers are difficult to separate because they have a boiling point close to that of 4-isopropyl-3-methylphenol.
- the production of o-thymol and m-thymol is suppressed. Loss can be reduced and the purification process can be simplified.
- m-cresol is not used as a raw material, and generation of o-thymol, m-thymol, etc. is suppressed, so that there are few substances that can cause odor and coloring. Therefore, 4-isopropyl-3-methylphenol with little odor and coloring can be obtained. Since m-cresol was used as a raw material in the conventional method, isopropylation progressed to any of the o-position, m-position and p-position of m-cresol, and among them, the most stable product at the o-position, The target p-position progressed only in a small amount.
- the method of the present invention uses 4-halogenated 3-methylphenol or its phenol derivative in which only the p-position of m-cresol is preliminarily halogenated, generation of o-thymol and m-thymol can be suppressed. .
- propylene gas is not used as a raw material unlike the conventional method, 4-isopropyl-3-methylphenol can be produced without using a pressure vessel such as an autoclave, and the production cost can be reduced. is there.
- 4-halogenated-3-methylphenol used as a raw material in the production method of the present invention includes a derivative of the compound.
- 4-halogenated-3-methylphenol derivatives include compounds in which the hydroxyl group of the compound is protected by a protecting group.
- a compound in which the hydroxyl group of the compound is protected by a protecting group may be referred to as a phenol derivative of the compound.
- a reaction for removing the protecting group may be carried out at any stage until the production of the desired 4-isopropyl-3-methylphenol.
- the deprotection method can be carried out according to a standard method depending on the kind of the protecting group to be used.
- the hydroxyl-protecting group in the phenol derivative is not particularly limited, and may be any hydroxyl-protecting group used in usual organic synthesis. Specific examples include a methyl group, a benzyl group, and p-methoxybenzyl. Ether group with protecting group such as tert-butyl group; acetal group with protecting group such as methoxymethyl group, 2-tetrahydropyranyl group, ethoxyethyl group; protecting group for acetyl group, pivaloyl group, benzoyl group, etc.
- Protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, t-butyldiphenylsilyl and the like, and silyl ether-based protecting groups.
- hydroxyl-protecting group an ether-based protecting group is preferable, and a methyl group is particularly preferable.
- the phenol derivative can be used as a raw material
- the catalyst to be used and the ligand that can be optionally used are appropriately selected as described later.
- the desired 4-isopropyl-3-methylphenol can be obtained without protecting the hydroxyl group. Therefore, from the viewpoint of simplifying the production process, 4-halogenated-3-methylphenol having no protecting group is preferably used as a raw material.
- 4-halogenated-3-methylphenol As 4-halogenated-3-methylphenol, 4-fluoro-3-methylphenol, 4-chloro-3-methylphenol, 4-bromo-3-methylphenol And 4-iodo-3-methylphenol. Of these, 4-chloro-3-methylphenol, 4-bromo-3-methylphenol and 4-iodo-3-methylphenol are preferable from the viewpoint of handleability. Furthermore, 4-bromo-3-methylphenol and 4-iodo-3-methylphenol are preferable because of high reactivity, and 4-bromo-3-methylphenol is particularly preferable from the viewpoint of reactivity and cost. .
- the method for synthesizing 4-halogenated-3-methylphenol is not particularly limited, but is preferably a method for halogenating m-cresol from the viewpoint of cost, yield and quality. Specifically, a method of reacting m-cresol and a metal halide is preferable.
- 4-bromo-3-methylphenol is preferably a brominated form of m-cresol.
- Known methods can be appropriately employed as synthesis conditions, purification methods, and the like. Further, since 4-halogenated-3-methylphenol is commercially available, it can be used by obtaining a commercial product.
- the isopropyl metal compound is used as an organometallic reagent. Any isopropyl metal compound may be used as long as it has a carbon-metal bond, and isopropyl metal halide is particularly preferable.
- Specific examples of the isopropyl metal halide include compounds represented by the following formula (1). (CH 3 ) 2 CH-MX (1) (In the above formula, M represents a metal selected from zinc, magnesium, aluminum, zirconium and lithium, and X represents a halogen atom selected from chlorine, bromine and iodine atoms.)
- isopropyl metal halide zinc or magnesium is preferably selected as the metal M in the above formula (1), and zinc is more preferable.
- the halogen X in the above formula (1) is preferably bromine or iodine, more preferably bromine. That is, isopropyl zinc bromide is particularly preferred.
- the reaction can be carried out satisfactorily under relatively low temperature and normal pressure conditions without using conditions such as high temperature and high pressure.
- examples of the isopropyl metal compound other than the halide include diisopropyl zinc and diisopropyl magnesium.
- the method for preparing isopropyl zinc halide is not particularly limited, but a preparation method by transmetalation of isopropyl magnesium halide and zinc halide can be mentioned.
- the method for producing isopropyl zinc bromide is not particularly limited, and a known method can be adopted, for example, P. Knochel, Comprehensive Org. Syn., Vol. 1, 211, C. F. Malosh et al, J. Am. Chem. Soc., 126, 10240 (2004).
- isopropyl zinc bromide is preferably prepared from isopropyl magnesium bromide and zinc bromide.
- it can also prepare using zinc metal and lithium chloride instead of zinc bromide.
- isopropyl zinc halides such as isopropyl zinc bromide are commercially available, commercially available products can be obtained and used.
- the amount of the isopropyl metal compound used in the reaction is not limited, but is usually in the range of 0.9 to 3 moles, preferably in the range of 1 to 2 moles per mole of 4-halogenated-3-methylphenol. More preferably in the range of 1.0 mol to 1.5 mol, still more preferably in the range of 1.0 mol to 1.3 mol, particularly preferably in the range of 1.0 mol to 1.1 mol. .
- the amount of isopropyl metal compound means a “molar equivalent” in a reaction in which a cross-coupling reaction is performed on 4-halogenated-3-methylphenol.
- the order of addition of each raw material and reaction conditions may be optimized.
- any catalyst that can be applied to the cross-coupling reaction may be used, and examples thereof include transition metal catalysts.
- the transition metal contained in the transition metal catalyst include elements belonging to Group 8 to Group 11 (IUPAC) of the periodic table, and among them, one or two selected from palladium, nickel, ruthenium, iron and copper. It is preferable to be a seed or more. In particular, palladium is preferable because of its excellent catalytic action.
- the transition metal catalyst is an organometallic compound.
- the organometallic compound is not particularly limited as long as a complex in which a ligand is coordinated to a transition metal can be obtained by mixing in a solvent with a ligand described later.
- the anion species that binds to the metal ion is not particularly limited as long as it does not inhibit the coordination of the ligand to the transition metal. There are 20 hydrocarbon groups.
- anion group bonded to the hydrocarbon group examples include a carbanion, a sulfate ion, a cyanate ion, a nitro ion, a halogen (fluorine, chlorine, bromine, iodine) ion, and the like.
- aliphatic carbanions having 1 to 20 carbon atoms are preferable. Specific examples include acetate ion, acetylacetonate, propionate ion, pivalate ion, and the like.
- the valence of the metal varies depending on the type of metal and is not particularly limited.
- the valence of palladium may be zero or bivalent, but is preferably divalent.
- palladium acetate (Pd (OAc) 2 ) is preferably used.
- the catalysts may be used alone or in combination.
- the catalyst may be immobilized on a solid support. This is because if the catalyst is fixed to a solid support, the catalyst can be easily separated and recovered after the reaction and can be reused.
- the production method of the present invention has a very high reaction selectivity and is characterized in that the production of isomers and by-products is suppressed. Therefore, if the catalyst is immobilized, 4-isopropyl-3-methylphenol can be obtained in high yield and high purity by removing the solvent from the solution after the reaction.
- the solid carrier include silica, alumina, synthetic zeolite and the like. As a method of immobilizing the catalyst on the solid support, a known method can be appropriately employed.
- the catalyst may be immobilized by immobilizing only the catalyst, or by forming a complex with a ligand described later, and then immobilizing the complex.
- the amount of the catalyst used is appropriately selected according to the reaction conditions such as the reaction temperature, but is within the range of 0.1 mol% to 2 mol% with respect to 4-halogenated-3-methylphenol. preferable.
- a ligand coexists. That is, 4-halogenated-3-methylphenol and isopropyl metal compound are preferably reacted in the presence of a catalyst, a ligand and a solvent.
- the ligand is not particularly limited as long as it can be coordinated to the transition metal of the transition metal catalyst, but it is preferable to have a bulky structure. This is because reductive elimination can be promoted by selecting a bulky ligand. As a result, the reaction can be performed under mild reaction conditions such as room temperature, and 4-isopropyl-3-methylphenol can be obtained in a high yield. Furthermore, since the ligand is bulky, the reaction can be allowed to proceed selectively without protecting the highly reactive phenolic hydroxyl group. Therefore, protection and deprotection of hydroxyl groups are not necessary, and the process can be greatly simplified.
- a ligand having a biarylphosphine skeleton is preferably used.
- a ligand having a biarylphosphine skeleton forms a complex structure with the above catalyst, it has an appropriate bulkiness and is adjacent to the 3-position methyl group having steric hindrance of 4-halogenated-3-methylphenol. This is because it is easy to introduce an isopropyl group at the 4-position.
- the biaryl structure of the biarylphosphine skeleton is preferably biphenyl.
- the bonding position with the phosphorus atom in the biaryl structure is not particularly limited, but when biphenyl is taken as an example, a position represented by the following formula (2) is preferable. This is because the ligand has an appropriate bulkiness, and thus the selectivity of the reaction is good for the same reason as described above.
- R 1 and R 2 each independently represents an arbitrary hydrocarbon group.
- the aromatic ring having a biaryl structure may have a substituent.
- the substituent preferably has an electron donating property.
- the aromatic ring of the biaryl structure has an electron-donating substituent, the selectivity and reactivity of the reaction according to the present invention are further optimized, and the yield of 4-isopropyl-3-methylphenol obtained is improved. There is a tendency to be able to.
- the electron-donating substituent include an alkyl group, an alkoxy group, and an amino group. Of these, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and an alkylamino group having 1 to 4 carbon atoms are preferable.
- the number of substituents is not particularly limited, but is usually 1 to 4, and preferably 1 to 3.
- the biaryl structure having a substituent is preferably diisopropylpropylbiaryl, dimethoxybiaryl, or bis (dimethylamino) biaryl.
- the hydrocarbon group bonded to the phosphorus atom in the phosphine moiety of the biarylphosphine skeleton is not particularly limited, and is, for example, an aliphatic hydrocarbon group. May be an aromatic hydrocarbon group, but is preferably an aliphatic hydrocarbon group.
- Examples of the aliphatic hydrocarbon group include a chain (linear or branched) alkyl group and a cycloalkyl group, and among them, a branched alkyl group or a cycloalkyl group is preferable.
- R 1, R 2 is a both a cycloalkyl group
- R 1, R 2 is a both a cycloalkyl group
- bulkiness of the ligand is optimal.
- the branched alkyl group is not particularly limited, but is preferably a t-butyl group.
- the cycloalkyl group is not particularly limited, but is preferably a cyclohexyl group.
- hydrogen constituting the ring may be substituted with an alkyl group having 1 to 4 carbon atoms.
- the hydrocarbon group bonded to the phosphorus atom may be one or two cycloalkyl groups, but preferably two. That is, the phosphine moiety is preferably a dicycloalkylphosphino group.
- the ligand preferably has a biaryldialkylphosphine skeleton.
- the ligand having a biaryl dialkyl phosphine skeleton is preferably a biphenyl dialkyl phosphine whose biaryl structure is biphenyl, and is also preferably a biaryl dicycloalkyl phosphine whose dialkyl moiety is cycloalkyl.
- the reaction selectivity may decrease, and the reaction may occur when the raw material 4-halogenated-3-methylphenol is reacted without protecting the hydroxyl group.
- the reactivity may be inferior.
- a ligand having an extremely bulky structure is used, a complex cannot be formed well with the catalyst, or the complex cannot interact with the reaction site and may be inferior in reactivity.
- ligand examples include 2-dicyclohexylphosphino-2 ′, 6′-diisopropoxybiphenyl (hereinafter sometimes referred to as RuPhos), 2-dicyclohexylphosphino-2 ′, 6 ′.
- the ligand may be one kind or a mixture of two or more kinds. Among these, the ligand is preferably one or a mixture of two or more selected from RuPhos, SPhos and CPhos. This is because the reaction rate and selectivity are good.
- the ligand may be immobilized on a solid support. This is because if the ligand is fixed to the solid support, the ligand can be easily separated and recovered after the reaction, and can be reused.
- the solid carrier include silica, alumina, synthetic zeolite and the like.
- the method for immobilizing the ligand on the solid support include a method for immobilizing the ligand on the solid support with a linker and a method for immobilizing the ligand directly on the solid support.
- the amount of ligand used is preferably in the range of 100 mol% to 300 mol%, more preferably 250 mol% or less, based on the catalyst. This is because when the amount of the ligand is small, the reaction rate may be slow, and when the amount of the ligand is large, the cost becomes high.
- Transition metal catalyst and ligand are mixed in a solvent.
- the catalyst and the ligand may be mixed in advance outside the reaction system, or the catalyst and the ligand may be mixed in the reaction system.
- the aprotic polar solvent may be any liquid that is liquid at room temperature.
- ethers such as tetrahydrofuran (THF), tetrahydropyran, dioxane, diethyl ether; dimethyl carbonate (DMC), ethyl methyl carbonate ( EMC), carbonates such as diethyl carbonate (DEC) and propylene carbonate (PC); esters such as ethyl acetate and butyl acetate; aromatic hydrocarbons such as toluene and xylene.
- THF tetrahydrofuran
- DMC dimethyl carbonate
- EMC ethyl methyl carbonate
- PC propylene carbonate
- esters such as ethyl acetate and butyl acetate
- aromatic hydrocarbons such as toluene and xylene.
- the solvent is preferably capable of dissolving the isopropyl metal compound.
- ethers that can dissolve isopropyl metal compounds are preferred.
- Solvents may be used alone or in combination. The usage-amount of a solvent is suitably adjusted according to reaction mode, reaction scale, etc.
- the reaction temperature is not particularly limited, but can be set, for example, within a range of ⁇ 10 ° C. or higher and the boiling point of the solvent or lower.
- the lower limit of the reaction temperature is preferably 0 ° C or higher, more preferably 10 ° C or higher. If the reaction temperature is low, the reaction rate may be slow, or side reactions may easily occur.
- the upper limit of reaction temperature becomes like this. Preferably it is 100 degrees C or less, More preferably, it is 80 degrees C or less, More preferably, it is 60 degrees C or less. This is because, when the reaction temperature is high, side reactions such as the formation of the isomer 4-n-propyl-3-methylphenol tend to occur.
- reaction of 4-halogenated-3-methylphenol with an isopropyl metal compound in the presence of a catalyst and a solvent is an exothermic reaction, if the heat removal is insufficient and the temperature of the reaction system rises, each component It is preferable to suppress the temperature rise by controlling the concentration, the addition rate, the addition timing, etc., or by adding the stirring efficiency of the reactor or adding a cooling device.
- the reaction time depends on the type of 4-halogenated-3-methylphenol and isopropyl metal compound, type of catalyst or ligand, reaction temperature, method of adding each raw material, reaction method (batch method, continuous method), etc. It is selected appropriately.
- the reaction is preferably performed under normal pressure.
- the reaction is preferably performed in an inert gas atmosphere from the viewpoint of reaction inhibition, suppression of side reactions, safety from using a flammable solvent, and the like.
- the inert gas include nitrogen and argon.
- the order of addition of each raw material and the addition timing are not limited, and can be arbitrarily set.
- the reaction proceeds by appropriately mixing 4-halogenated-3-methylphenol, isopropyl metal compound, catalyst and ligand in a solvent, but the catalyst and ligand are mixed in advance in the solvent. It is preferable to keep it.
- an immobilized catalyst is manufactured previously.
- each raw material is described as being dissolved (including suspended) in a solvent, but the target substance may be used as it is without being dissolved in the solvent.
- each of the raw materials may be added all at once, but may be added over time using droplets or the like, or may be added in multiple portions.
- a catalyst and ligand mixture and an isopropyl metal compound solution are added to a solution of 4-halogenated-3-methylphenol.
- the catalyst, ligand and isopropyl metal compound may be added simultaneously or sequentially to the solution.
- the order of addition of the catalyst, the ligand and the isopropyl metal compound in the sequential addition is not particularly limited, but it is preferable to add the isopropyl metal compound sequentially after adding the mixed solution of the catalyst and the ligand. Moreover, you may add what mixed the catalyst, the ligand, and the isopropyl metal compound previously.
- the catalyst, the ligand and 4-halogenated-3-methylphenol may be added simultaneously or sequentially to the solution.
- the order of addition of the catalyst, ligand and 4-halogenated-3-methylphenol during sequential addition is not particularly limited. Further, a catalyst, a ligand, and a 4-halogenated 3-methylphenol previously mixed may be added.
- 4-halogenated-3-methylphenol and isopropyl metal compound may be added simultaneously to the mixed solution. May be.
- the order of addition of 4-halogenated-3-methylphenol and isopropyl metal compound at the time of sequential addition is not particularly limited, but it is preferable to add 4-halogenated-3-methylphenol and isopropyl metal compound sequentially in this order. Further, a premixed mixture of 4-halogenated-3-methylphenol and isopropyl metal compound may be added.
- the reaction may be batch (batch) or continuous.
- the reaction is usually performed using a batch reactor having a stirring blade.
- the reaction may be carried out in a flow-through continuous reactor using the catalyst as a fixed bed. Since the production method of the present invention can produce 4-isopropyl-3-methylphenol at a high conversion rate, if the catalyst is fixed to the reaction apparatus as a fixed bed, the catalyst and coordination can be obtained from the reaction solution. It is possible to simplify the process of separating the child. For this reason, 4-isopropyl-3-methylphenol can be obtained with high productivity and purity.
- the conversion rate of the reaction in the present invention is not limited, but is usually 70 mol% or more, preferably 80 mol% or more, more preferably 90 mol% or more, still more preferably 95 mol% or more, particularly preferably 98 mol% or more, Most preferably, it is 99 mol% or more.
- the conversion rate means a reaction rate at which 4-halogenated 3-methylphenol which is one of raw materials is converted into 4-isopropyl-3-methylphenol. As described later, when 4-normalpropyl-3-methylphenol is produced as a by-product together with 4-isopropyl-3-methylphenol by the production method of the present invention, the total amount of both is treated as the conversion rate. To do.
- 4-Isopropyl-3-methylphenol can be isolated and purified by a general method. Specifically, precipitation by solvent substitution, recrystallization, extraction, and the like can be appropriately combined. Since the production method of the present invention has high reaction selectivity, the resulting 4-isopropyl-3-methylphenol has few impurities, and has little odor and coloration. Therefore, the load on purification is remarkably reduced as compared with the conventional method.
- 4-Isopropyl-3-methylphenol Since the production method of the present invention has high reaction selectivity, by optimizing raw materials, catalysts, production conditions (including purification), etc., high-purity 4-isopropyl- 3-methylphenol can be obtained.
- the purity of 4-isopropyl-3-methylphenol produced by the production method of the present invention is not limited, but is usually 70% by mass or more, preferably 80% by mass or more, more preferably 90% by mass or more, Preferably it is 95 mass% or more, Especially preferably, it is 98 mass% or more, Most preferably, it is 99 mass% or more.
- the purity of 4-isopropyl-3-methylphenol does not include a solvent.
- the content ratio of the isomer contained in 4-isopropyl-3-methylphenol is not limited, but the content ratio of the isomer based on the amount of 4-isopropyl-3-methylphenol is usually 5% by mass.
- it is preferably 3% by mass or less, more preferably 2% by mass or less, still more preferably 1% by mass or less, particularly preferably 0.5% by mass or less, and most preferably below the detection limit.
- the isomer means the total amount of o-thymol, m-thymol and vic-thymol.
- the 4-isopropyl-3-methylphenol produced by the production method of the present invention may contain 4-normalpropyl-3-methylphenol as a by-product.
- the 4-isopropyl-3-methylphenol composition (mixture) containing 4-normalpropyl-3-methylphenol is presumed to be obtained by the production method of the present invention. Can do.
- the content ratio of 4-normalpropyl-3-methylphenol contained in the 4-isopropyl-3-methylphenol composition (mixture) produced by the production method of the present invention is not limited, but 4-isopropyl-
- the content of 4-normalpropyl-3-methylphenol based on the amount of 3-methylphenol is usually 10% by mass or less, preferably 5% by mass or less, more preferably 2% by mass or less, and further preferably 1% by mass. % Or less.
- the lower limit of the content of 4-normalpropyl-3-methylphenol is not limited, but is usually 0.1% by mass or more. Since the production method of the present invention has high reaction selectivity, 4-isopropyl-3-methylphenol containing substantially no isomer or very little can be obtained.
- the production ratio of 4-isopropyl-3-methylphenol and 4-normalpropyl-3-methylphenol can be controlled by the order of addition of each raw material and reaction conditions. Therefore, it is possible to actively increase the content of 4-normalpropyl-3-methylphenol, and the range exceeding the above upper limit, specifically 100% by mass or less, and further 200% by mass or less. In the range described above, 4-normalpropyl-3-methylphenol can also be produced.
- 4-Isopropyl-3-methylphenol produced by the production method of the present invention can be used, for example, as an antibacterial agent, bactericidal agent, preservative and the like.
- the composition containing 4-isopropyl-3-methylphenol produced by the production method of the present invention can be used as, for example, a pharmaceutical product, a quasi-drug, a cosmetic product, and the like.
- Antibacterial composition and bactericidal composition are characterized in that they contain 4-isopropyl-3-methylphenol produced according to the production method described above. 4-Isopropyl-3-methylphenol is contained as an antibacterial agent or bactericidal agent. Antibacterial and bactericidal compositions can contain various components in addition to 4-isopropyl-3-methylphenol. Various components are appropriately selected according to the use of the antibacterial composition and the bactericidal composition. Further, the content ratio of 4-isopropyl-3-methylphenol is also appropriately selected according to the use of the antibacterial composition and the bactericidal composition.
- Liquid materials resin compositions (solid materials) in which 4-isopropyl-3-methylphenol is contained or coated in thermoplastic resins, thermoplastic elastomers, rubbers, thermosetting resins, and the like. Moreover, it may be not only liquid or solid, but may be paste, wax, gel, gum or the like.
- the antibacterial composition and bactericidal composition of the present invention can be used as, for example, pharmaceuticals, quasi-drugs, cosmetics, etc., specifically, detergent compositions, antiperspirant compositions, antifungal compositions. And cosmetic compositions. Furthermore, it can be used for daily necessities with antibacterial properties.
- the present invention is not limited to the above embodiment.
- the above-described embodiment is an exemplification, and the present invention has substantially the same configuration as the technical idea described in the claims of the present invention, and any device that exhibits the same function and effect is the present invention. It is included in the technical scope of the invention.
- Example 1 In a flask, 11.2 mg (0.05 mmol) of palladium acetate (Pd (OAc) 2 ), 41.1 mg (0.1 mmol) of 2-dishexylphosphino-2 ′, 6′-dimethoxybiphenyl (SPhos) and , 4-bromo-3-methylphenol 1870 mg (10 mmol), and the atmosphere was purged with nitrogen. Next, 50 mL of dehydrated and deoxygenated THF was poured into the flask, and the liquid temperature was adjusted to 20 ° C.
- the conversion of 4-bromo-3-methylphenol was 99 mol%.
- the composition of the reaction liquid was almost stable at the above composition after 3 hours after dropping the whole amount of THF solution of isopropyl zinc bromide. .
- Example 2 Instead of 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2', 6'-bis (N, N-dimethylamino) biphenyl (CPhos) is used.
- the reaction was carried out in the same manner as in Example 1 except that.
- the composition of the product was 4-isopropyl-3-methylphenol: 96.6% by mass, 4-normalpropyl-3-methylphenol. : 2.4% by mass, m-cresol: 1.0% by mass, and other impurities were trace amounts.
- the conversion of 4-bromo-3-methylphenol was 99 mol%.
- the composition of the reaction liquid was almost stable at the above composition after 3 hours after dropping the whole amount of THF solution of isopropyl zinc bromide. .
- Example 3 The amount of palladium acetate (Pd (OAc) 2) used was 45.0 mg (0.2 mmol), and instead of 2-dishexylphosphino-2 ′, 6′-dimethoxybiphenyl (SPhos), 2-dicyclohexane The reaction was carried out in the same manner as in Example 1 except that 188.7 mg (0.4 mmol) of xylphosphino-2 ′, 6′-diisopropoxybiphenyl (RuPhos) was used.
- the composition of the product was 4-isopropyl-3-methylphenol: 95.9% by mass, 4-normalpropyl-3-methylphenol. : 4.1% by mass, m-cresol was not detected, and other impurities were also trace amounts.
- the conversion of 4-bromo-3-methylphenol was 95.4 mol%.
- the composition of the reaction liquid was almost stable at the above composition after 3 hours after dropping the whole amount of THF solution of isopropyl zinc bromide. .
- Example 4 A flask was charged with a 0.5 mol / L THF solution of 2826 mg (15 mmol) of isopropyl zinc bromide and purged with nitrogen, and then the temperature of the solution was adjusted to 20 ° C. Next, 11.2 mg (0.05 mmol) of palladium acetate (Pd (OAc) 2), 41.1 mg (0.1 mmol) of 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (SPhos), A solution prepared by previously mixing and dissolving 1870 mg (10 mmol) of 4-bromo-3-methylphenol in 50 mL of dehydrated and deoxygenated THF was added dropwise to the flask while stirring slowly.
- Pd palladium acetate
- SPhos 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl
- Example 5 A fixed carrier (manufactured by Sigma-Aldrich) containing palladium acetate (Pd (OAc) 2 ) and 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (SPhos) in a molar ratio of 1: 2 in a flask.
- Pd (OAc) 2 palladium acetate
- SPhos 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl
- SPhos 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl
- a solution containing an isopropyl metal compound is added to a solution containing 4-halogenated-3-methylphenol, a catalyst, and a ligand.
- B A solution containing 4-halogenated-3-methylphenol, a catalyst, and a ligand is added to a solution containing an isopropyl metal compound.
- BMP, i-PMP and n-PMP represent 4-bromo-3-methylphenol, 4-isopropyl-3-methylphenol and 4-normalpropyl-3-methylphenol, respectively. is there.
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Abstract
Description
特許文献4に開示された方法では、反応性の改良は期待できるものの、反応の選択性については言及されておらず、依然としてp-チモールを選択的に製造することは困難である。
このように従来ではp-チモールのみを選択的に製造する方法は見出されておらず、その出現が強く望まれていた。
また、従来の方法では、原料としてプロピレンガスを使用するため、反応にはオートクレーブ等の圧力容器が必要であり、設備にコストがかかるという問題もあった。
本発明の4-イソプロピル-3-メチルフェノールの製造方法は、4-ハロゲン化-3-メチルフェノール又はそのフェノール誘導体とイソプロピル金属化合物とを、触媒および溶媒の存在下で反応させることを特徴とする方法である。
したがって本発明においては、4-イソプロピル-3-メチルフェノールを選択的に製造することが可能である。これにより、4-イソプロピル-3-メチルフェノールの異性体であるo-チモールやm-チモールの生成を抑制することができ、4-イソプロピル-3-メチルフェノールを高収率で得ることが可能である。
また、これらの異性体は4-イソプロピル-3-メチルフェノールと沸点が近いために分離が困難であるが、本発明においてはo-チモールやm-チモールの生成が抑制されるので、精製でのロスを少なくし、精製工程を簡略化することが可能となる。
また、従来の方法のように原料としてプロピレンガスを使用しないため、オートクレーブ等の圧力容器を用いずに4-イソプロピル-3-メチルフェノールを製造することができ、製造コストを削減することも可能である。
しかしながら、原料として4-ハロゲン化-3-メチルフェノールおよびイソプロピル金属化合物を用い、本発明の目的とする4-イソプロピル-3-メチルフェノールを合成する反応に、この根岸カップリング反応を適応させた例はない。
4-ハロゲン化-3-メチルフェノールとしては、4-フルオロ-3-メチルフェノール、4-クロロ-3-メチルフェノール、4-ブロモ-3-メチルフェノールおよび4-ヨード-3-メチルフェノールを挙げることができる。中でも、取扱い性の観点から、4-クロロ-3-メチルフェノール、4-ブロモ-3-メチルフェノールおよび4-ヨード-3-メチルフェノールが好ましい。さらには、反応性が高いことから、4-ブロモ-3-メチルフェノールおよび4-ヨード-3-メチルフェノールが好ましく、特に、反応性およびコストの観点から、4-ブロモ-3-メチルフェノールが好ましい。
本発明での反応において、イソプロピル金属化合物は有機金属試薬として用いられる。イソプロピル金属化合物としては、炭素-金属結合を有するものであればよいが、中でもイソプロピル金属ハロゲン化物であることが好ましい。イソプロピル金属ハロゲン化物としては、具体的には下記式(1)で表される化合物が挙げられる。
(CH3)2CH-MX (1)
(上記式中、Mは亜鉛、マグネシウム、アルニミウム、ジルコニウムおよびリチウムから選ばれる金属を表し、Xは塩素原子、臭素原子およびヨウ素原子から選ばれるハロゲン原子を表す。)
なお、ハロゲン化物以外のイソプロピル金属化合物としては、例えば、ジイソプロピル亜鉛、ジイソプロピルマグネシウム等が挙げられる。
触媒としては、クロスカップリング反応に適用可能なものであればよく、遷移金属触媒を挙げることができる。遷移金属触媒に含まれる遷移金属としては、周期表の第8族~第11族(IUPAC)に属する元素を挙げることができ、中でも、パラジウム、ニッケル、ルテニウム、鉄および銅から選ばれる一種または二種以上であることが好ましい。特に、触媒作用に優れることから、パラジウムが好ましい。
金属の価数は、金属の種類に応じて異なり、特に限定されない。例えば、パラジウムの価数は0価であっても2価であってもよいが、中でも2価であることが好ましい。特に、酢酸パラジウム(Pd(OAc)2)が好適に用いられる。
触媒は単独で用いてもよく組み合わせて用いてもよい。
固体担体としては、例えばシリカ、アルミナ、合成ゼオライト等が挙げられる。
触媒を固体担体に固定化する方法としては公知の方法を適宜採用することができ、例えば固体担体にリンカーで触媒を固定化する方法が挙げられる。
なお、触媒の固定化は、上記触媒のみを固定化してもよいし、後述する配位子とともに錯体を形成し、当該錯体を固定化してもよい。
本発明での反応においては、配位子を共存させることが好ましい。すなわち、4-ハロゲン化-3-メチルフェノールおよびイソプロピル金属化合物を、触媒、配位子および溶媒の存在下で反応させることが好ましい。
ビアリールホスフィン骨格のビアリール構造としては、ビフェニルであることが好ましい。
ビアリール構造におけるリン原子との結合位置は特に限定されないが、ビフェニルを例にすれば、下記式(2)で表される位置であることが好ましい。この配位子は適度な嵩高さを有するため、上記と同様の理由により反応の選択性が良好だからである。
分岐アルキル基としては特に限定されないが、t-ブチル基であることが好ましい。シクロアルキル基としては特に限定されないが、シクロヘキシル基であることが好ましい。また、シクロアルキル基は、環を構成する水素が炭素数1~4のアルキル基に置換されていてもよい。
リン原子に結合する炭化水素基としてのシクロアルキル基は1つであってもよく2つであってもよいが、2つであることが好ましい。すなわち、ホスフィン部位は、ジシクロアルキルホスフィノ基であることが好ましい。
このように、適度な嵩高さを有する構造の配位子を選択することにより、本発明に係る反応の選択性及び反応性が最適化される傾向がある。一方、嵩高さの小さい配位子を用いた場合は、反応選択性が低下する場合があるとともに、原料である4-ハロゲン化-3-メチルフェノールの水酸基を保護せずに反応させた際の反応性に劣る場合がある。また、極端に嵩高い構造の配位子を用いると、触媒とうまく錯体を形成できない場合や、錯体が反応点と相互作用することができずに反応性に劣る場合がある。
中でも、配位子は、RuPhos、SPhosおよびCPhosから選ばれる一種または二種以上の混合物であることが好ましい。これらは、反応速度や選択率が良好だからである。
配位子を固体担体に固定化する方法としては、例えば固体担体にリンカーで配位子を固定化する方法や、固体担体に配位子を直接固定化する方法が挙げられる。
溶媒としては、反応を阻害しないものであれば特に限定されるものではなく、例えば非プロトン性極性溶媒を挙げることができる。非プロトン性極性溶媒としては、常温で液体のものであればよく、具体的には、テトラヒドロフラン(THF)、テトラヒドロピラン、ジオキサン、ジエチルエーテル等のエーテル類;ジメチルカーボネート(DMC)、エチルメチルカーボネート(EMC)、ジエチルカーボネート(DEC)、プロピレンカーボネート(PC)等のカーボネート類;酢酸エチル、酢酸ブチル等のエステル類;トルエン、キシレン等の芳香族炭化水素が挙げられる。中でも、溶媒はイソプロピル金属化合物を溶解可能であることが好ましい。特に、イソプロピル金属化合物を溶解可能なエーテル類が好ましい。溶媒は単独で用いてもよく混合して用いてもよい。
溶媒の使用量は、反応様式や、反応スケール等に応じて適宜調整される。
本発明において反応温度は特に限定されないが、例えば-10℃以上、溶媒の沸点以下の範囲内で設定することができる。反応温度の下限は、好ましくは0℃以上、より好ましくは10℃以上である。反応温度が低いと反応速度が遅くなる場合や、副反応が起きやすくなる場合がある。また、反応温度の上限は、好ましくは100℃以下、より好ましくは80℃以下、更に好ましくは60℃以下である。反応温度が高いと、異性体である4-n-プロピル-3-メチルフェノールが生成する等の副反応が起こりやすくなるからである。
触媒および溶媒の存在下における4-ハロゲン化-3-メチルフェノールとイソプロピル金属化合物との反応は発熱反応であるので、除熱が不十分で反応系の温度が上昇するような場合は、各成分の濃度や添加速度、添加タイミング等を制御したり、反応器の撹拌効率や冷却装置の付加等を行うことによって温度上昇を抑制することが好ましい。
反応時間は、4-ハロゲン化-3-メチルフェノールおよびイソプロピル金属化合物の種類、触媒や配位子の種類、反応温度、各原料の添加方法、反応方式(バッチ式、連続式)等に応じて適宜選択される。
反応は、常圧下で行うことが好ましい。反応を常圧下で行えば、減圧や加圧のための圧力容器が不要であり、製造コストを削減できるからである。
なお、反応阻害や副反応の抑制、可燃性溶媒を使用することに対する安全上の観点等より、反応は不活性ガス雰囲気で行うことが好ましい。不活性ガスとしては、具体的には、窒素、アルゴン等が挙げられる。
(A)4-ハロゲン化-3-メチルフェノールの溶液に、触媒および配位子の混合液および、イソプロピル金属化合物の溶液を添加する。
(B)イソプロピル金属化合物の溶液に、触媒および配位子の混合液および、4-ハロゲン化-3-メチルフェノールの溶液を添加する。
(C)触媒および配位子の混合液に、4-ハロゲン化-3-メチルフェノールの溶液および、イソプロピル金属化合物の溶液を添加する。
ここで転化率とは、原料の1つである4-ハロゲン化-3-メチルフェノールが4-イソプロピル-3-メチルフェノールへ転化する反応率を意味する。なお、後述する通り、本発明の製造方法によって4-イソプロピル-3-メチルフェノールとともに4-ノルマルプロピル-3-メチルフェノールが副生される場合は、これら双方の合計量を転化率として扱うものとする。
本発明の製造方法は反応選択性が高いため、得られる4-イソプロピル-3-メチルフェノールは不純物が少なく、臭気や着色が少ないものが得られる。従って、従来の方法に較べて精製への負荷が格段に軽減される。
本発明の製造方法は反応選択性が高いため、原料や触媒、製造条件(精製を含む)等を最適化することにより、高純度の4-イソプロピル-3-メチルフェノールを得ることが出来る。本発明の製造方法により製造される4-イソプロピル-3-メチルフェノールの純度は限定されるものではないが、通常70質量%以上、好ましくは80質量%以上、より好ましくは90質量%以上、更に好ましくは95質量%以上、特に好ましくは98質量%以上、最も好ましくは99質量%以上である。なお、ここで4-イソプロピル-3-メチルフェノールの純度には、溶媒は含まれないものとする。
なお、4-イソプロピル-3-メチルフェノールと4-ノルマルプロピル-3-メチルフェノールとの生成比率は、各原料の添加順序や反応条件によって制御することができる。このため、4-ノルマルプロピル-3-メチルフェノールの含有量を積極的に増加させることも可能であり、上記の上限値を超える範囲、具体的には100質量%以下、更には200質量%以下の範囲で4-ノルマルプロピル-3-メチルフェノールを生成することもできる。
本発明の製造方法により製造される4-イソプロピル-3-メチルフェノールは、例えば抗菌剤、殺菌剤、防腐剤等として用いることができる。また、本発明の製造方法により製造される4-イソプロピル-3-メチルフェノールを含む組成物は、例えば医薬品、医薬部外品、化粧品等として利用することができる。
本発明の抗菌性組成物および殺菌性組成物は、上述の製造方法に従って製造された4-イソプロピル-3-メチルフェノールを含むことを特徴とするものである。4-イソプロピル-3-メチルフェノールは、抗菌剤や殺菌剤等として含有される。
抗菌性組成物および殺菌性組成物は、4-イソプロピル-3-メチルフェノールの他に、種々の成分を含有することができる。各種成分は、抗菌性組成物および殺菌性組成物の用途等に応じて適宜選択される。また、4-イソプロピル-3-メチルフェノールの含有割合も、抗菌性組成物および殺菌性組成物の用途等に応じて適宜選択される。
本発明の抗菌性組成物および殺菌性組成物の性状に制限は無く、例えば、水、アルコール、その他の有機溶剤或いはこれらの混合溶液中に4-イソプロピル-3-メチルフェノールが溶解または分散された液状物;熱可塑性樹脂、熱可塑性エラストマー、ゴム、熱硬化性樹脂等に4-イソプロピル-3-メチルフェノールが含有または被覆された樹脂組成物(固形物)等が挙げられる。また、液状や固体状のみならず、ペースト状、ワックス状、ゲル状、ガム状等であってもよい。
本発明の抗菌性組成物および殺菌性組成物は、例えば医薬品、医薬部外品、化粧品等として用いることができ、具体的には洗浄剤組成物、制汗剤組成物、抗真菌剤組成物、化粧料組成物等が挙げられる。更には、抗菌性を付与した日用品等にも用いることができる。
フラスコに、酢酸パラジウム(Pd(OAc)2)11.2mg(0.05mmol)と、2-ジシクヘキシルホスフィノ-2′,6′-ジメトキシビフェニル(SPhos)41.1mg(0.1mmol)と、4-ブロモ-3-メチルフェノール1870mg(10mmol)とを仕込み、窒素置換した。
次いで、上記フラスコに、脱水、脱酸素されたTHF50mLを注入し、液温を20℃とした。次に、上記の混合液に、臭化イソプロピル亜鉛3768mg(20mmol)の0.5mol/L THF溶液を、系内の温度が20℃を維持するようにゆっくり滴下しながら撹拌した。全量を滴下した後、20℃を保持して昼夜撹拌を継続した。
得られた反応液をガスクロマトグラフィー(検出器:FID)で分析した結果、生成物の組成は、4-イソプロピル-3-メチルフェノール:97.7質量%、4-ノルマルプロピル-3-メチルフェノール:1.6質量%、m-クレゾール:0.7質量%、他の不純物は痕跡量であった(溶媒であるTHFを除く。以下同じ。)。また、4-ブロモ-3-メチルフェノールの転化率は99モル%であった。
なお、反応液を経時的に採取してガスクロマトグラフィーで分析した結果、臭化イソプロピル亜鉛のTHF溶液を全量滴下して3時間後には、反応液の組成は上記の組成でほぼ安定していた。
2-ジシクヘキシルホスフィノ-2′,6′-ジメトキシビフェニル(SPhos)の代わりに、2-ジシクロへキシルホスフィノ-2′,6′-ビス(N,N-ジメチルアミノ)ビフェニル(CPhos)を用いたこと以外は、実施例1と同様に反応を行った。
得られた反応液をガスクロマトグラフィー(検出器:FID)で分析した結果、生成物の組成は、4-イソプロピル-3-メチルフェノール:96.6質量%、4-ノルマルプロピル-3-メチルフェノール:2.4質量%、m-クレゾール:1.0質量%、他の不純物は痕跡量であった。また、4-ブロモ-3-メチルフェノールの転化率は99モル%であった。
なお、反応液を経時的に採取してガスクロマトグラフィーで分析した結果、臭化イソプロピル亜鉛のTHF溶液を全量滴下して3時間後には、反応液の組成は上記の組成でほぼ安定していた。
酢酸パラジウム(Pd(OAc)2)の使用量を45.0mg(0.2mmol)とし、2-ジシクヘキシルホスフィノ-2′,6′-ジメトキシビフェニル(SPhos)の代わりに、2-ジシクロへキシルホスフィノ-2′,6′-ジイソプロポキシビフェニル(RuPhos)を188.7mg(0.4mmol)用いたこと以外は、実施例1と同様に反応を行った。
得られた反応液をガスクロマトグラフィー(検出器:FID)で分析した結果、生成物の組成は、4-イソプロピル-3-メチルフェノール:95.9質量%、4-ノルマルプロピル-3-メチルフェノール:4.1質量%、m-クレゾールは検出されず、他の不純物も痕跡量であった。また、4-ブロモ-3-メチルフェノールの転化率は95.4モル%であった。
なお、反応液を経時的に採取してガスクロマトグラフィーで分析した結果、臭化イソプロピル亜鉛のTHF溶液を全量滴下して3時間後には、反応液の組成は上記の組成でほぼ安定していた。
フラスコに、臭化イソプロピル亜鉛2826mg(15mmol)の0.5mol/L THF溶液を仕込み、窒素置換した後、液温を20℃とした。
次いで、酢酸パラジウム(Pd(OAc)2)11.2mg(0.05mmol)と、2-ジシクヘキシルホスフィノ-2′,6′-ジメトキシビフェニル(SPhos)41.1mg(0.1mmol)と、4-ブロモ-3-メチルフェノール1870mg(10mmol)を脱水、脱酸素されたTHF50mLで予め混合溶解した溶液を上記フラスコに、ゆっくり滴下しながら撹拌した。系内の温度を20℃に維持しながら全量を滴下し、20℃を保持して昼夜撹拌を継続した。
得られた反応液をガスクロマトグラフィー(検出器:FID)で分析した結果、生成物の組成は、4-イソプロピル-3-メチルフェノール:98.0質量%、4-ノルマルプロピル-3-メチルフェノール:2.0質量%、m-クレゾールは検出されず、他の不純物も痕跡量であった。また、4-ブロモ-3-メチルフェノール転化率は93モル%であった。
なお、反応液を経時的に採取してガスクロマトグラフィーで分析した結果、臭化イソプロピル亜鉛のTHF溶液を全量滴下して3時間後には、反応液の組成は上記の組成でほぼ安定していた。
フラスコに、酢酸パラジウム(Pd(OAc)2)と2-ジシクヘキシルホスフィノ-2′,6′-ジメトキシビフェニル(SPhos)とをモル比1:2で含有する固定担体(シグマ・アルドリッチ社製、商品名:酢酸パラジウム ChemDose tablet)472.2mg(10錠、SPhosとして10mmol)と、4-ブロモ-3-メチルフェノール93.6mg(5mmol)とを仕込み、窒素置換した。
次いで、上記フラスコに、脱水、脱酸素されたTHF16mLを加え、液温を40℃とした。次に、上記の混合液に、臭化イソプロピル亜鉛のTHF溶液2.5mL(臭化イソプロピル亜鉛として12.5mmol)を1時間かけて滴下しながら撹拌した。全量を滴下した後、40℃を保持して1時間撹拌を継続した。得られた反応液からは、濾過によって固定担体を容易に除去することができた。
得られた反応液をガスクロマトグラフィー(検出器:FID)で分析した結果、生成物の組成は、4-イソプロピル-3-メチルフェノール:59.4質量%、4-ノルマルプロピル-3-メチルフェノール:6.3質量%、m-クレゾール:4.6質量%、原料の4-ブロモ-3-メチルフェノール:29.7質量%であった。また、4-ブロモ-3-メチルフェノールの転化率は75モル%であった。
実施例1~5の結果を表1に示す。溶媒に溶解した触媒を用いて製造を行った実施例1~4では、何れにおいても極めて高い転化率(反応選択性)で4-イソプロピル-3-メチルフェノールを生成することが確認された。
また、触媒を固定化して固定床反応装置とした実施例5においても、目的とする4-イソプロピル-3-メチルフェノールを高い転化率で生成することが可能であることが確認された。更に上記装置を流通式連続反応器とし、原料を連続的に供給するとともに、得られる4-イソプロピル-3-メチルフェノールを回収する方式とすることにより、高純度の4-イソプロピル-3-メチルフェノールを効率良く製造することができる。
なお、表1中の添加順序(A)および(B)は、以下の順序を示すものである。
(A)4-ハロゲン化-3-メチルフェノール、触媒、配位子を含む溶液に、イソプロピル金属化合物を含む溶液を添加。
(B)イソプロピル金属化合物を含む溶液に、4-ハロゲン化-3-メチルフェノール、触媒、配位子を含む溶液を添加。
また、表1中のBMP、i-PMPおよびn-PMPは、それぞれ、4-ブロモ-3-メチルフェノール、4-イソプロピル-3-メチルフェノールおよび4-ノルマルプロピル-3-メチルフェノールを示すものである。
Claims (12)
- 4-ハロゲン化-3-メチルフェノール又はそのフェノール誘導体とイソプロピル金属化合物とを、触媒および溶媒の存在下で反応させることを特徴とする4-イソプロピル-3-メチルフェノールの製造方法。
- 前記4-ハロゲン化-3-メチルフェノールが4-ブロモ-3-メチルフェノールである、請求項1に記載の4-イソプロピル-3-メチルフェノールの製造方法。
- 前記イソプロピル金属化合物が臭化イソプロピル亜鉛である、請求項1または請求項2に記載の4-イソプロピル-3-メチルフェノールの製造方法。
- 前記触媒がパラジウム、ニッケル、ルテニウム、鉄および銅から選ばれる一種又は二種以上を含む、請求項1から請求項3までのいずれかに記載の4-イソプロピル-3-メチルフェノールの製造方法。
- ビアリールホスフィン骨格を有する配位子の存在下で反応を行うことを特徴とする請求項1から請求項4までのいずれかに記載の4-イソプロピル-3-メチルフェノールの製造方法。
- 前記配位子が、ビアリールジアルキルホスフィン骨格を有する、請求項5に記載の4-イソプロピル-3-メチルフェノールの製造方法。
- 前記配位子が、2-ジシクロへキシルホスフィノ-2′,6′-ジイソプロポキシビフェニル、2-ジシクロヘキシルホスフィノ-2′,6′-ジメトキシビフェニル、および2-ジシクロへキシルホスフィノ-2′,6′-ビス(N,N-ジメチルアミノ)ビフェニルから選ばれる一種又は二種以上の混合物である、請求項5または請求項6に記載の4-イソプロピル-3-メチルフェノールの製造方法。
- 前記溶媒が、前記イソプロピル金属化合物を溶解可能なエーテル類を含む溶媒である、請求項1から請求項7までのいずれかに記載の4-イソプロピル-3-メチルフェノールの製造方法。
- 前記触媒および前記配位子を前記溶媒に混合し、当該混合液に前記4-ハロゲン化-3-メチルフェノールおよび前記イソプロピル金属化合物を添加することを特徴とする請求項5から請求項8までのいずれかに記載の4-イソプロピル-3-メチルフェノールの製造方法。
- 前記触媒および前記配位子の少なくともいずれかが固体担体に固定されていることを特徴とする請求項5から請求項9までのいずれかに記載の4-イソプロピル-3-メチルフェノールの製造方法。
- 請求項1から請求項10までのいずれかに記載の製造方法に従って製造された4-イソプロピル-3-メチルフェノール組成物であって、4-ノルマルプロピル-3-メチルフェノールを4-イソプロピル-3-メチルフェノールに対して0.1質量%~10質量%の範囲内で含有する、4-イソプロピル-3-メチルフェノール組成物。
- 請求項1から請求項10までのいずれかに記載の製造方法に従って製造された4-イソプロピル-3-メチルフェノールを含む、抗菌性組成物または殺菌性組成物。
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