JP6294063B2 - Process for producing 2- (hydroxyphenyl) benzoxazoles - Google Patents

Description

  The present invention relates to a method for producing 2- (hydroxyphenyl) benzoxazoles. More specifically, the present invention relates to 2- (hydroxyphenyl) benzoxazoles, which are useful as pharmaceuticals, agricultural chemicals, dyes and electronic materials, or intermediates and resin materials thereof, and 1-hydroxy-2-nitro which is easy to handle. The present invention relates to a production method which can be obtained by a method which is industrially easy to implement in high yield by performing a reaction using aromatic hydrocarbon and methylphenol as raw materials.

Conventionally, as a method for producing 2-phenyl-substituted benzoxazoles, a method of obtaining 2,2′-bis (4-fluorophenyl) bisbenzoxazole by reacting 3,3-dihydroxybenzidine and 4-fluorobenzoic acid ( Patent Document 1) is known. However, many benzoic acids as raw materials are expensive, and many benzidine compounds are highly toxic.
Also known is a method (Non-patent Document 1) in which 2-nitrophenol and benzyl alcohol are reacted in the presence of a catalyst to obtain 2-phenylbenzoxazole. Usually, the catalyst used is 1,1- Bis (diphenylphosphino) ferrocene is high molecular weight and expensive, and benzyl alcohol must be theoretically used excessively as a hydrogen source, so benzaldehyde corresponding to half of the added benzyl alcohol is generated as a by-product. It must be removed.
In view of the above situation, a new synthesis method has been demanded, and a method of reacting under conditions with few by-products using a relatively inexpensive and available catalyst is desired.

JP 2007-262204 A

Organic Letters, 14 (11), 2722-2725 (2012)

  This invention makes it a subject to provide the novel manufacturing method which can obtain 2- (hydroxyphenyl) benzoxazole by an industrially easy method.

  As a result of diligent studies for solving the above-mentioned problems, the present inventors have found that 2-nitrophenol having at least one benzene ring in the molecule substituted with a hydroxyl group on one of adjacent carbon atoms and a nitro group on the other. Compounds (hereinafter abbreviated as 2-nitrophenols) and methylphenol compounds (hereinafter abbreviated as methylphenols) having a benzene ring in which both a methyl group and a hydroxyl group are substituted in the molecule. It was found that the target 2- (hydroxyphenyl) benzoxazoles can be obtained by a method industrially easy to carry out by carrying out the reaction using as a starting material.

According to the present invention, there is provided a process for producing 2- (hydroxyphenyl) benzoxazoles, which is a benzene ring substituted with a hydroxyl group on one of adjacent carbon atoms and a nitro group on the other, or a condensed polycycle containing the benzene ring A 2-nitrophenol compound having at least one hydrocarbon ring in the molecule and a methylphenol compound having a benzene ring substituted with a methyl group and a hydroxyl group can be reacted. .

  The method for producing 2- (hydroxyphenyl) benzoxazoles of the present invention does not require the use of expensive benzoic acids and toxic compounds such as benzidines as reaction raw materials, and is easier to handle industrially. In addition, in the reaction, it is not necessary to use methylphenols in excess in theory, and 2-nitrophenols and methylphenols can react in equimolar amounts in the reaction. 2- (hydroxyphenyl) benzoxazoles under the reaction conditions that are industrially easy to implement, such as the use of iron and sulfur, which are relatively inexpensive and available as catalysts, Can be obtained.

Hereinafter, the manufacturing method of 2- (hydroxyphenyl) benzoxazole of this invention is demonstrated in detail.
In the method for producing 2- (hydroxyphenyl) benzoxazoles of the present invention, the target 2- (hydroxyphenyl) benzoxazole is represented, for example, by the following general formula (1).
General formula (1)
(In the formula, A represents a hydrogen atom, a single bond or an n-valent linking group, B represents a monocyclic or polycyclic hydrocarbon group fused to a benzene ring substituted with an oxazoline group, and p represents 0 or 1) When p is 0, A is bonded to a benzene ring substituted with an oxazoline group, and when p is 1, A is a benzene ring substituted with an oxazoline group or a monocyclic or polycyclic carbon formed by B R ₁ and R ₂ each independently represents an alkyl group, an alkoxy group, an aryl group or a halogen atom, a represents an integer of 0 or 1 to 3, and a is 2 or more. In this case, R ₁ may be the same or different, b is 0 or an integer of 1 to 4, and when b is 2 or more, R ₂ may be the same or different, and n is 1 to 6 Indicates an integer.)

n is an integer of 1 to 6, for example, when A is a hydrogen atom, n is 1, and when A is a single bond or a divalent linking group such as a methylene group, n is 2. Preferably n is 1-4, more preferably 1 or 2.
When A is an n-valent linking group, the linking group is a group containing at least one carbon atom, nitrogen atom, oxygen atom, sulfur atom or phosphorus atom, and for example, preferably an ether group (—O— ), A sulfide group (—S—), a sulfonyl group (—SO ₂ —), a carbonyl group (—CO—), or an aliphatic hydrocarbon group or an aromatic hydrocarbon group that may contain a linking group thereof. Can be mentioned.

The aliphatic hydrocarbon group represented by A may be a saturated aliphatic hydrocarbon group or an unsaturated aliphatic hydrocarbon group, and specifically includes, for example, a linear or branched aliphatic group. Hydrocarbon groups, monocyclic alicyclic hydrocarbon groups, polycyclic alicyclic hydrocarbon groups, bridged cyclic alicyclic hydrocarbon groups or terpene saturated hydrocarbons and aliphatic hydrocarbons containing both these chains and rings And the aliphatic hydrocarbon group includes an aromatic hydrocarbon group, an ether group (—O—), a sulfide group (—S—), a sulfonyl group (—SO ₂ —), and a carbonyl group. Groups such as (—CO—) may be included.

The aromatic hydrocarbon group represented by A may be mononuclear or polynuclear, and may be monocyclic such as a benzene ring or condensed polycyclic such as a naphthalene ring. Moreover, the aromatic hydrocarbon group may have a substituent such as an aliphatic hydrocarbon group or an aromatic hydrocarbon group.
Among these, preferable bonding group A is a hydrogen atom (n = 1), carbon atom-carbon atom single bond (n = 2), and monovalent bonding group (n = 1) is an alkyl group, alkoxy Group, an aryl group, a halogen atom, etc. are mentioned, and specifically, it is the same as R ₁ described later.
Preferred divalent linking groups include, firstly, linear, branched, and cyclic aliphatic hydrocarbon groups, particularly alkylene groups.

Specifically, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,1-decanediyl, 1,1-ethanediyl, 2,2-propanediyl, 2,2-hexafluoropropanediyl, 1 , 1-propanediyl, 2,2-butanediyl, 4-methylpentane-2,2-diyl, 3,3-pentanediyl, 2-methylpropane-1,1-diyl, 2-ethylhexane-1,1-diyl 1,1-cyclohexanediyl, 1,1-cyclopentanediyl, 1-methyl-4-isopropylcyclohexane-1,3-diyl, 3,3,5-trimethylcyclohexane-1,1-diyl, 4-methylcyclohexane -1,1-diyl and the like.
Secondly, preferred divalent linking groups include divalent aromatic groups that may contain an aliphatic group at the center. Specifically, for example, 1,4-phenylene, 1,3-phenylene, 4,4′-biphenylene, 2,2′-biphenylene, 4,4′-isopropylidenediphenylene, 9,9-fluorenediyl, etc. Is mentioned. These aromatic groups may have an alkyl group, an alkoxy group, an aryl group, or a halogen atom substituent.

  Thirdly, preferred divalent linking groups include groups having both a divalent alkylene group and an aromatic hydrocarbon group. Specific examples include phenylmethylmethylene, diphenylmethylene, 1-phenylethane-1,1-diyl and the like. These groups may have an alkyl group, an alkoxy group, an aryl group, or a halogen atom substituent.

Preferred divalent linking groups include those other than those described above, specifically, for example, an ether group (—O—), a sulfur atom (—S—), a sulfonyl group (—SO ₂ —), a carbonyl group (—CO -), 1,3-benzenedicarbonyl, 1,4-benzenedicarbonyl, 4,4'-biphenyldicarbonyl, 3,3'-biphenyldicarbonyl, 1,4-naphthalenedicarbonyl, 2,6-naphthalene Examples include dicarbonyl, 4,4′-diphenylmethane dicarbonyl, 4,4′-diphenyl ether dicarbonyl, 4,4′-benzophenone dicarbonyl, phenylphosphine oxide-P, P-diyl and the like.

Preferred trivalent linking groups include linear, branched, and cyclic alkanetriyl groups. Specific examples of such groups include methanetriyl, 1,1,1-ethanetriyl, 2,2,4-butanetriyl, 1,1,4-cyclohexanetriyl, 1,1,3-cyclohexanetriyl. 1,1,3-cyclopentanetriyl and the like.
Preferred examples of the trivalent linking group include, in addition to the above, for example, a trivalent aromatic group. Specific examples of such a group include 1,3,5-benzenetriyl, Examples thereof include a group having both an alkanetriyl group and an aromatic hydrocarbon group. Specifically as such a group, for example,
(In the formula, * indicates the bonding position)
Etc.

Specific examples of preferable tetravalent linking groups include 1,1,2,2-ethanetetrayl,
(In the formula, * indicates the bonding position)
Etc.

Moreover, as a preferable hexavalent linking group, specifically, for example,
(In the formula, * indicates the bonding position)
Etc.

In the general formula (1), B represents a monocyclic or polycyclic hydrocarbon group fused to a benzene ring substituted with an oxazoline group, p represents an integer of 0 or 1, and p is preferably 0. It is.
When p is 0, that is, when B is not condensed, the ring substituted by the oxazoline group is a benzene ring, and when p is 1, that is, when B is condensed, benzene substituted by the oxazoline group The ring is a polycyclic compound group containing the benzene ring, and the polycyclic compound group may contain an aliphatic ring or an aromatic ring. Specifically, for example, an indane ring, a tetralin ring, a naphthalene ring, Anthracene ring, fluorene ring, naphthacene ring, pyrene ring, phenanthrene ring and the like can be mentioned. These polycyclic compound groups may be substituted with an alkyl group, an alkoxy group, a halogen, an oxygen atom (cyclic ether group) or the like.

The substituent represented by R ₁ represents an alkyl group, an alkoxy group, an aryl group, or a halogen atom, and a represents an integer of 0 or 1 to 3, preferably 0, 1 or 2. When a is 2 or more, R ₁ may be the same or different.
Preferable alkyl groups include, for example, linear or branched alkyl groups having 1 to 6 carbon atoms, or cyclic alkyl groups having 5 to 6 carbon atoms.
The alkyl group may have a substituent such as a phenyl group, an alkoxy group, a halogen, or an oxygen atom (cyclic ether group) as long as the effects of the present application are not impaired.
Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an isobutyl group, a t-butyl group, a cyclohexyl group, a cyclopentyl group, a cycloheptyl group, and the like. Group and trifluoromethyl group.

Preferable alkoxy groups include, for example, linear or branched alkoxy groups having 1 to 6 carbon atoms or cyclic alkoxy groups having 5 to 6 carbon atoms.
The alkoxy group may have a substituent such as a phenyl group, an alkoxy group, a halogen, or an oxygen atom (cyclic ether group) within a range not impairing the effects of the present application.
Specific examples include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a cyclohexyloxy group, and the like, and a particularly preferred alkoxy group is a methoxy group.

Preferable aryl groups include, for example, aryl groups having 6 to 20 carbon atoms.
Specifically, for example, phenyl group, 2-tolyl group, 3-tolyl group, 4-tolyl group, 2,3-xylyl group, 2,4-xylyl group, 2,5-xylyl group, 2,6-xylyl group Group, 3,4-xylyl group, 3,5-xylyl group, 2,3,4-trimethylphenyl group, 2,3,5-trimethylphenyl group, 2,3,6-trimethylphenyl group, 2,4,4 6-trimethylphenyl group, 3,4,5-trimethylphenyl group, 2,3,4,5-tetramethylphenyl group, 2,3,4,6-tetramethylphenyl group, 2,3,5,6- Tetramethylphenyl group, pentamethylphenyl group, ethylphenyl group, n-propylphenyl group, isopropylphenyl group, n-butylphenyl group, sec-butylphenyl group, tert-butylphenyl group, n-pentylpheny Group, neopentyl phenyl group, n- hexylphenyl group, n- octylphenyl group, n- decyl phenyl group, n- dodecyl phenyl group, n- tetradecyl phenyl group, naphthyl group and anthracenyl group.
Further, the aryl group may have about 1 to 3 alkyl groups, alkoxy groups and / or halogen atoms having 1 to 4 carbon atoms within a range not impairing the effects of the present application.
Specific examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Moreover, the substituent represented by R ₂ is the same as that of R ₁ in the general formula (1). However, R ₂ is preferably an alkyl group or an alkoxy group, particularly preferably a tertiary alkyl group, specifically a t-butyl group. b shows 0 or the integer of 1-4, Preferably it is 0, 1 or 2. When b is 2 or more, R ₂ may be the same or different.
As such 2- (hydroxyphenyl) benzoxazoles represented by the general formula (1), specifically, for example,
2- (4-hydroxyphenyl) benzoxazole,
2- (3-methyl-4-hydroxyphenyl) benzoxazole,
2- (3,5-dimethyl-4-hydroxyphenyl) benzoxazole,
2- (3,5-di-tert-butyl-4-hydroxyphenyl) benzoxazole,
2- (3-t-butyl-4-hydroxyphenyl) benzoxazole,
2- (3,5-dimethoxy-4-hydroxyphenyl) benzoxazole,
2- (3,5-di-tert-butyl-4-hydroxyphenyl) -4-methylbenzoxazole,
2- (3,5-di-tert-butyl-4-hydroxyphenyl) -5-methylbenzoxazole,
2- (3,5-di-tert-butyl-4-hydroxyphenyl) -6-methylbenzoxazole,
2- (3,5-di-tert-butyl-4-hydroxyphenyl) -5-methoxybenzoxazole,
2- (3,5-di-tert-butyl-4-hydroxyphenyl) -5-trifluoromethylbenzoxazole,
2- (3-isopropyl-4-hydroxyphenyl) benzoxazole,
2- (2-methyl-4-hydroxyphenyl) benzoxazole,
2- (3-cyclohexyl-4-hydroxyphenyl) benzoxazole,
2- (3-methoxy-4-hydroxyphenyl) benzoxazole,
2- (3-phenyl-4-hydroxyphenyl) benzoxazole,
2- (3-t-butyl-2-hydroxyphenyl) benzoxazole,
2- (4,6-di-tert-butyl-3-hydroxyphenyl) benzoxazole,
2,2′-bis (3-methoxy-4-hydroxyphenyl) -5,5′-bibenzoxazole,
2,2′-bis (3,5-di-t-butyl-4-hydroxyphenyl) -5,5′-bibenzoxazole,
2,2′-bis (3,5-dimethoxy-4-hydroxyphenyl) -5,5′-bibenzoxazole,
Bis (2- (3,5-dimethoxy-4-hydroxyphenyl) -5-benzoxazolyl) methane,
Bis (2- (3,5-di-tert-butyl-4-hydroxyphenyl) -5-benzoxazolyl) methane,
2,2-bis (2- (3-methoxy-4-hydroxyphenyl) -5-benzoxazolyl) propane,
2,2-bis (2- (3,5-di-t-butyl-4-hydroxyphenyl) -5-benzoxazolyl) propane,
1,1-bis (2- (3-methyl-5-tert-butyl-4-hydroxyphenyl) -5-benzoxazolyl) cyclohexane,
1,1-bis (2- (3,5-di-t-butyl-4-hydroxyphenyl) -5-benzoxazolyl) cyclohexane,
1,1-bis (2- (3-methoxy-4-hydroxyphenyl) -5-benzoxazolyl) -3,3,5-trimethylcyclohexane,
1,1-bis (2- (3,5-di-t-butyl-4-hydroxyphenyl) -5-benzoxazolyl) -3,3,5-trimethylcyclohexane,
1,3,5-tris (bis (2- (3-methoxy-4-hydroxyphenyl) -5-benzoxazolyl) methyl) benzene,
1,3,5-tris (bis (2- (3,5-di-t-butyl-4-hydroxyphenyl) -5-benzoxazolyl) methyl) benzene and the like.

  According to the method for producing 2- (hydroxyphenyl) benzoxazoles of the present invention, a benzene ring substituted with a hydroxyl group on one of adjacent carbon atoms and a nitro group on the other, or a condensed polycyclic hydrocarbon containing the benzene ring Starting materials are 2-nitrophenol compounds (2-nitrophenols) having at least one ring in the molecule and methylphenol compounds (methylphenols) having a benzene ring in which both a methyl group and a hydroxyl group are substituted. By performing the reaction, the desired 2- (hydroxyphenyl) benzoxazoles are obtained.

2-Nitrophenols are compounds having at least one benzene ring substituted with a hydroxyl group on one of adjacent carbon atoms and a nitro group on the other or a condensed polycyclic hydrocarbon ring containing the benzene ring in the molecule. There is no particular limitation as long as it can undergo a condensation reaction with methylphenols. Preferred are 2-nitrophenols represented by the following general formula (2).
General formula (2)
(In the formula, A, B, R ₁ , p, a and n are the same as those in the general formula (1).)

The methylphenol is not particularly limited as long as it is a compound having a benzene ring in which both a methyl group and a hydroxyl group are substituted and can undergo a condensation reaction with the 2-nitrophenol. Preferred are methylphenols represented by the following general formula (3).
General formula (3)
(In the formula, R ₂ and b are the same as those in the general formula (1).)

For example, 2- (3,5-di-t-butyl-4 is obtained by reacting 2-nitrophenol as 2-nitrophenol and 2,6-di-t-butyl-4-methylphenol as methylphenol. The reaction to obtain -hydroxyphenyl) benzoxazole is represented by the following reaction formula (1).
Reaction formula (1)
2-Nitrophenols used as starting materials include at least a benzene ring substituted with a hydroxyl group on one of adjacent carbon atoms and a nitro group on the other or a condensed polycyclic hydrocarbon ring containing the benzene ring in the molecule. Although there is no particular limitation as long as it is a compound having one and can undergo a condensation reaction with methylphenols, 2-nitrophenols represented by the above general formula (2) are preferred.
Such 2-nitrophenols can be obtained by known methods described in, for example, JP-A-63-333353, JP-A-11-106365, WO01 / 81293, and the like. Specifically, for example, it can be obtained by nitration of a phenol derivative containing a 1-hydroxyphenyl skeleton with 50 to 80% nitric acid at a temperature of 5 ° C. or less under the condition that an acid other than nitric acid is not present. The phenol derivative containing a 1-hydroxyphenyl skeleton is preferably represented by the following general formula (4) corresponding to, for example, the bisnitrophenol represented by the general formula (2).
General formula (4)
(In the formula, A, B, R ₁ , p, a and n are the same as those in the general formula (1).)

  Specific examples of 2-nitrophenols include 2-nitrophenol and 2-nitro-3-methylphenol corresponding to 2- (hydroxyphenyl) benzoxazoles represented by the general formula (1). 2-nitro-6-phenylphenol, 2-nitro-6-cyclohexylphenol, 2-nitro-4-methylphenol, 2-nitro-5-methylphenol, 2-nitro-4-methoxyphenol, 2-nitro- 4-trifluoromethylphenol, 1-nitro-2-naphthol, 2-nitro-1-naphthol, 3-nitro-2-naphthol, 2-nitro-3-phenanthrol, 3-nitro-2-phenanthrol, 3 , 3′-dinitro-4,4′-dihydroxybiphenyl, bis (3-nitro-4-hydroxyphenyl) meta 2,2-bis (3-nitro-4-hydroxyphenyl) propane, 1,1-bis (3-nitro-4-hydroxyphenyl) cyclohexane, 1,1-bis (3-nitro-4-hydroxyphenyl) -3,3,5-trimethylcyclohexane, bis (3-nitro-4-hydroxyphenyl) methylphenylmethane, 9,9-bis (3-nitro-4-hydroxyphenyl) fluorene, bis (3-nitro-4- Hydroxyphenyl) diphenylmethane, bis (3-nitro-4-hydroxyphenyl) sulfone, 2,2-bis (3-nitro-4-hydroxyphenyl) hexafluoropropane, 3,3′-dinitro-4,4′-dihydroxy Benzophenone, 1,3-bis (3-nitro-4-hydroxyphenylcarbonyl) benzene, 1,4 Bis (3-nitro-4-hydroxyphenylcarbonyl) benzene, 4,4′-bis (3-nitro-4-hydroxyphenylcarbonyl) biphenyl, 3,3′-bis (3-nitro-4-hydroxyphenylcarbonyl) Biphenyl, 1,4-bis (3-nitro-4-hydroxyphenylcarbonyl) naphthalene, 2,6-bis (3-nitro-4-hydroxyphenylcarbonyl) naphthalene, 4,4′-bis (3-nitro-4) -Hydroxyphenylcarbonyl) diphenylmethane, 4,4'-bis (3-nitro-4-hydroxyphenylcarbonyl) diphenyl ether, 4,4'-bis (3-nitro-4-hydroxyphenylcarbonyl) benzophenone, bis (3-nitro -4-hydroxyphenyl) phenylphosphine oxide, Lis (3-nitro-4-hydroxyphenyl) methane, 1,1,1-tris (3-nitro-4-hydroxyphenyl) ethane, 1,3,5-tris (3-nitro-4-hydroxyphenyl) benzene Etc.

In the method for producing 2- (hydroxyphenyl) benzoxazoles of the present invention, the methylphenol used as a raw material is a compound having a benzene ring in which both a methyl group and a hydroxyl group are substituted, and the 2-nitrophenol There is no particular limitation as long as it can undergo a dehydration condensation reaction with alcohols, but methylphenols represented by the above general formula (3) are preferred.
In the general formula (3), in the formula, the substituent R ₂ is preferably an alkyl group, more preferably a tertiary alkyl group, from the viewpoint of the reactivity of the raw material. Aryl groups and halogen atoms are not preferred in terms of yield. As the substitution position of a hydroxyl group and a substituent R _2, is preferably substituted at the ortho or para position relative to the substituent R ₂ is a hydroxyl group, para or to the hydroxyl groups is a methyl group The ortho position is preferred, and the para position is more preferred.

In the substituent R _2, it is preferable that two ortho positions and one para position with respect to the hydroxyl group are all substituted with a methyl group or the substituent R ₂ . More preferably, the hydroxyl group is in the para position with respect to the methyl group, b = 2, and both of the substituents R ₂ are substituted in the ortho position with respect to the hydroxyl group. It is particularly preferred that the substituent R ₂ is a tertiary alkyl group or an alkoxy group.
Accordingly, specific examples of methylphenols include 2,6-di-tert-butyl-4-methyl corresponding to 2- (hydroxyphenyl) benzoxazoles represented by the general formula (1). Phenol, 2,4-di-tert-butyl-6-methylphenol, 2-tert-butyl-6-methylphenol, 2-tert-butyl-4-methylphenol, 2,4-di-tert-butyl-5 -Methylphenol, 2-methoxy-4-methylphenol, 3-methoxy-5-methylphenol, 2,6-dimethoxy-4-methylphenol, 2-isopropyl-4-methylphenol, 4-isopropyl-3-methylphenol , 2-isopropyl-5-methylphenol, 2-cyclohexyl-4-methylphenol, etc.

In the method for producing 2- (hydroxyphenyl) benzoxazole according to the present invention, in the reaction of 2-nitrophenol with methylphenol, methylphenol is a 2-nitrophenol skeleton contained in 2-nitrophenol. It is 1 mol times or more with respect to 1 mol, Preferably it is the range of 1-10 mol times, More preferably, it is the range of 1.3-5 mol times, Most preferably, it is used in the range of 1.5-4 mol times. However, the present invention is not limited to this.
Moreover, when reacting without using a solvent, it can also be used in excess.
Here, the number of moles of the 2-nitrophenol skeleton is (number of moles of 2-nitrophenol) × (number of 2-nitrophenol skeleton). For example, the 2-nitrophenol is represented by the general formula (2). When expressed, it is the number of moles of 2-nitrophenol × n.

In the production method of the present invention, no catalyst may be used in the reaction. However, it is preferable to use it in terms of promoting the reaction and improving the yield. When a catalyst is used, an iron-based catalyst (iron, iron salt), a sulfur-based catalyst (sulfur alone, sulfide), a cobalt-based catalyst (cobalt salt), or the like can be used as the catalyst. Two or more of these catalysts may be used in combination. These may be used in combination with a noble metal such as nickel, palladium, or platinum. However, it is not limited to these.
Specific examples of the iron-based catalyst include iron (iron powder), 1,1-bis (diphenylphosphino) ferrocene (dppf), acetylacetone iron (III), iron acetate (II), iron bromide (II ), Iron (II) chloride, iron (II) iodide, iron (II) fluoride, iron (II) oxalate, iron phthalocyanine (II), iron (II) sulfate, iron (II) sulfide, iron acetate ( III), iron bromide (III), iron chloride (III), iron iodide (III), iron fluoride (III), iron oxalate (III), iron phthalocyanine (III), iron sulfate (III), sulfide Iron (III), iron nitrate (III), etc. are mentioned. Two or more of these may be used in combination, and iron (iron powder) is preferred mainly from the viewpoint of economy.
Specific examples of the sulfur catalyst include sulfur, iron sulfide, sodium sulfide, potassium sulfide, ammonium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide, ammonium hydrogen sulfide, sodium polysulfide, potassium polysulfide, ammonium polysulfide, Examples thereof include tungsten sulfide, copper sulfide, nickel sulfide, molybdenum sulfide, cobalt sulfide, tungsten sulfide / nickel sulfide, molybdenum sulfide / nickel sulfide, molybdenum sulfide / cobalt sulfide, and the like. Two or more of these may be used in combination, and sulfur or sodium sulfide is preferred mainly from the viewpoint of economy. Specific examples of the cobalt-based catalyst include cobalt (II) chloride, cobalt (II) bromide, cobalt (II) iodide, and cobalt (III) chloride. Two or more of these may be used in combination.

The amount of the catalyst used is not particularly limited, and the preferred amount used varies depending on the catalyst and further varies depending on the reaction conditions. With respect to 1 mol of 2-nitrophenol skeleton, the iron-based catalyst is preferably in the range of 0.01 to 5 mol times, more preferably in the range of 0.05 to 3 mol times, particularly preferably 0.05 to 2 mols. Double the range.
In the case of a sulfur catalyst, it is preferably in the range of 0.005 to 10 mol times, more preferably in the range of 0.01 to 5 mol times, and particularly preferably in the range of 0.05 to 3 mol times.
The reaction temperature is preferably 160 to 200 ° C, more preferably 170 to 190 ° C, particularly preferably 175 to 185 ° C.
Under such reaction conditions, the reaction is usually carried out for about 5 to 30 hours while all the raw materials are added to the reaction system and the temperature is raised to a predetermined reaction temperature, while maintaining the reaction temperature.

In the reaction, a reaction solvent may or may not be used. For example, the raw material methylphenols and nitrophenols have a low melting point, and if they are liquid when they are reacted, they become solvents themselves, so that there is no need to use a solvent if there is no problem in reaction operability.
However, it is preferable to use a reaction solvent in the reaction for reasons such as operability during industrial production and improvement in reaction rate.
When a reaction solvent is used, the type of the solvent is not particularly limited as long as it does not distill from the reaction vessel at the reaction temperature and does not adversely affect the reaction, such as being inert to the reaction.
Specific examples of preferable reaction solvents include aromatic hydrocarbons such as biphenyl and terphenyl, halogenated aromatic hydrocarbons such as chlorobenzene and o-dichlorobenzene, and alkylaryl ethers such as phenetole and butylphenyl ether. Aromatic hydrocarbon ethers such as diaryl ethers such as diphenyl ether and di-p-tolyl ether, alkyl-substituted naphthalenes such as diisopropylnaphthalene, aliphatic hydrocarbons such as decalin and kerosene, tetraethylene glycol dimethyl ether, diethylene glycol dibutyl ether, etc. Amide solvents such as polyalkylene glycol ethers and N-methylpyrrolidone. However, it is not limited to these. Two or more of these solvents may be used in combination.

The amount of the solvent used is not particularly limited, and the preferred amount varies depending on the conditions such as the melting point of the raw material and the reaction temperature. The amount is preferably in the range of 1-50 parts by weight, more preferably in the range of 10-40 parts by weight with respect to parts.
In the reaction, the reaction pressure may be normal pressure, increased pressure, or reduced pressure. Although normal pressure is preferred, when the boiling point of the reaction solvent or raw material is lower than the reaction temperature, the reaction pressure may be adjusted to a pressurized condition.
The reaction atmosphere is preferably performed in an inert gas (nitrogen, argon, etc.) atmosphere.
In the reaction, there are no particular limitations on the method for adding the reaction material and the reaction method. For example, the raw material, the catalyst, and, if necessary, the reaction solvent may be charged all at once into the reaction vessel, and then heated to the reaction temperature in an inert gas atmosphere, and the reaction may be performed with stirring. Alternatively, the raw material methylphenols may be sequentially added at a reaction temperature in an inert gas atmosphere to a reaction vessel charged with the raw material 2-nitrophenols, a catalyst and, if necessary, a reaction solvent.
According to a preferred embodiment, for example, a predetermined amount of 2-nitrophenols, methylphenols, a catalyst and a reaction solvent are charged into a reaction vessel, and the temperature is raised to a predetermined reaction temperature while stirring in a nitrogen stream, and the reaction is performed. The reaction is carried out while maintaining the temperature.

After completion of the reaction, the production method of the present invention is appropriately used from the resulting reaction mixture by appropriately using known methods such as catalyst separation, distillative separation of low boiling point components, concentration, and crystallization filtration according to conventional methods. A crude product of 2- (hydroxyphenyl) benzoxazole, which is a product, can be obtained, and if this is further purified again by a method such as crystallization filtration or column separation, it is a high-purity product. Can be obtained.
For example, when the crystal is precipitated by cooling the reaction solution as it is or by adding a poor solvent and cooling, the crystal can be filtered to obtain a crude or high-purity target product. Alternatively, after completion of the reaction, the reaction solvent and the like are concentrated under reduced pressure, and the residue can be purified by column chromatography or the like to obtain a high-purity product.

EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not restrict | limited only to a following example.
Example 1
Preparation of 2- (3,5-di-t-butyl-4-hydroxyphenyl) benzoxazole In a 100 ml test tube equipped with a reflux condenser, 417.4 mg (3.00 mmol) 2-nitrophenol, 2,6- Di-tert-butyl-p-cresol 1321.1 mg (6.00 mmol), sulfur powder 96.1 mg (3.00 mmol), iron powder 16.8 mg (0.30 mmol) and o-dichlorobenzene 8 ml were charged at room temperature. The reaction vessel was purged with argon.
Thereafter, the temperature was raised to 180 ° C., and the reaction was carried out for 24 hours with stirring while refluxing at the temperature. The reaction yield by liquid chromatography was 76%.
After completion of the reaction, low-boiling substances were distilled off under reduced pressure, and the concentrated residue was purified by silica gel column chromatography to obtain a crude product. Further, the crude product was purified by reverse phase column chromatography to obtain 559.5 mg of 2- (3,5-di-tert-butyl-4-hydroxyphenyl) benzoxazole. The yield based on 2-nitrophenol was 58%.
¹ H NMR identification results (300 MHz, solvent: CDCl 3, internal standard: tetramethylsilane)

Examples 2-12
Production of 2- (3,5-di-tert-butyl-4-hydroxyphenyl) benzoxazole The reaction was carried out in the same manner as in Example 1 except that the catalyst and solvent described in Table 2 were used. The reaction yield is shown in Table 2.
dppf: 1,1-bis (diphenylphosphino) ferrocene
Fe (acac) ₃ : Acetylacetone iron (III)

Example 13
Synthesis of 1,1-bis [2- (3,5-di-t-butyl-4-hydroxyphenyl) -5-benzoxazolyl] -3,3,5-trimethylcyclohexane In a test tube, 1,1-bis (3-nitro-4-hydroxyphenyl) -3,3,5-trimethylcyclohexane 600.5 mg (1.50 mmol) and 2,6-di-tert-butyl-p-cresol 1322 .3 mg (6.00 mmol), 96.2 mg (3.00 mmol) of sulfur powder, 16.8 mg (0.30 mmol) of iron powder, 8 ml of o-dichlorobenzene, and a magnet for stirring were added to the test tube at room temperature. Replaced.
Thereafter, the temperature was raised to 180 ° C. with stirring, and the reaction was carried out for 48 hours while refluxing at the temperature. After completion of the reaction, low-boiling substances were distilled off under reduced pressure, and the concentrated residue was purified by silica gel column chromatography to obtain 1,1-bis [2- (3,5-di-tert-butyl-4-hydroxy). Phenyl) -5-benzoxazolyl] -3,3,5-trimethylcyclohexane 571.5 mg was obtained. The yield based on 1,1-bis (3-nitro-4-hydroxyphenyl) -3,3,5-trimethylcyclohexane was 50%.
Molecular weight (M + H) ⁺ 769.4964 (HRMS / MALDI-TOF)
¹ H NMR measurement (300 MHz, solvent: CDCl ₃ ): see Table 3
¹ H NMR identification result (300 MHz, solvent: CDCl ₃ , internal standard: tetramethylsilane)

Example 14
Preparation of 2- (3,5-di-t-butyl-4-hydroxyphenyl) -4-methylbenzoxazole Example 1 except that 2-nitro-3-methylphenol was used instead of 2-nitrophenol The same reaction and isolation were performed. The yield was 84%.
¹ H NMR measurement (300 MHz, solvent: CDCl ₃ , internal standard: tetramethylsilane): δ 8.09 (s, 2H), 7.37 (br d, J = 7.9 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 7.10 (br d, J = 7.3 Hz, 1H), 5.60 (s, 1H), 2.67 (s, 3H), 1.53 (s, 18H)
¹³ C NMR measurement (75 MHz, solvent: CDCl ₃ , internal standard: CDCl ₃ ): δ 163.4, 156.9, 150.4, 141.7, 136.4, 130.0, 125.0, 124.8, 123.9, 118.7, 107.6, 34.5, 30.2, 16.6
Molecular weight (M) ⁺ 337.2017 (HRMS / EI)

Example 15
Preparation of 2- (3,5-di-t-butyl-4-hydroxyphenyl) -5-methoxybenzoxazole Example 1 except that 2-nitro-4-methoxyphenol was used instead of 2-nitrophenol The same reaction and isolation were performed. The yield was 76%.
¹ H NMR measurement (300 MHz, solvent: CDCl ₃ , internal standard: tetramethylsilane): δ 8.07 (s, 2H), 7.43 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 2.6 Hz, 1H ), 6.90 (dd, J = 8.8, 2.5 Hz, 1H), 5.64 (s, 1H), 3.86 (s, 3H), 1.52 (s, 18H)
¹³ C NMR measurement (75 MHz, solvent: CDCl ₃ , internal standard: CDCl ₃ ): δ 164.9, 157.2, 157.0, 145.3, 143.2, 136.5, 124.9, 118.5, 112.7, 110.4, 102.7, 55.9, 34.5, 30.2
Molecular weight (M) ⁺ 353.1984 (HRMS / EI)

Example 16
Preparation of 2- (3,5-di-t-butyl-4-hydroxyphenyl) -5-trifluoromethylbenzoxazole Except that 2-nitro-4-trifluoromethylphenol was used instead of 2-nitrophenol Reaction and isolation were carried out in the same manner as in Example 1. The yield was 43%.
¹ H NMR measurement (300 MHz, solvent: CDCl ₃ , internal standard: tetramethylsilane): δ 8.10 (s, 2H), 8.01 (br s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.57 ( dd, J = 8.7, 1.4 Hz, 1H), 5.72 (s, 1H), 1.53 (s, 18H)
¹³ C NMR measurement (75 MHz, solvent: CDCl ₃ , internal standard: CDCl ₃ ): δ 165.8, 157.7, 152.4, 142.6, 136.7, 127.1 (q, J = 32.4 Hz), 125.3, 124.3 (q, J = 272.2 Hz), 121.5 (q, J = 3.4 Hz), 117.7, 117.1 (q, J = 3.7 Hz), 110.6, 34.5, 30.2
¹⁹ F NMR measurement (280 MHz, solvent: CDCl ₃ , external standard: CF ₃ COOH): δ -60.0
Molecular weight (M) ⁺ 391.1735 (HRMS / EI)

Example 17
Preparation of 2- (3,5-dimethoxy-4-hydroxyphenyl) benzoxazole Examples except that 2,6-dimethoxy-p-cresol was used instead of 2,6-di-t-butyl-p-cresol The reaction was carried out in the same manner as in 1 and isolated. The yield was 21%.
¹ H NMR measurement (300 MHz, solvent: CDCl ₃ , internal standard: tetramethylsilane): δ 7.76-7.73 (m, 1H), 7.58-7.55 (m, 1H), 7.52 (s, 2H), 7.37-7.30 ( m, 2H), 6.00 (s, 1H), 4.02 (s, 6H)
¹³ C NMR measurement (75 MHz, solvent: CDCl ₃ , internal standard: CDCl ₃ ): δ 163.2, 150.7, 147.3, 142.1, 138.1, 124.7, 124.5, 119.6, 118.2, 110.3, 104.6, 56.5
Molecular weight (M) ⁺ 271.0854 (HRMS / EI)

As described above, according to the method of the present invention, it is not necessary to use expensive benzoic acids or toxic compounds such as benzidine as a reaction raw material, and it is easier to handle industrially and is easily available. Raw materials can be used.
Even when a catalyst is used, the reaction can be promoted by using iron and sulfur, which are relatively inexpensive and available, under the reaction conditions that are industrially easy to implement. The effect of obtaining phenyl) benzoxazoles could be exhibited.
The 2- (hydroxyphenyl) benzoxazoles thus obtained can be used as, for example, resins such as epoxy resins and polybenzoxazole resins, raw materials for pharmaceuticals, agricultural chemicals, paints and electronic materials, or intermediates thereof. it can.

Claims (1)

  A method for producing 2- (hydroxyphenyl) benzoxazoles, comprising a benzene ring substituted with a hydroxyl group on one of adjacent carbon atoms and a nitro group on the other, or a condensed polycyclic hydrocarbon ring containing the benzene ring A production method comprising reacting at least one 2-nitrophenol compound in a molecule with a methylphenol compound having a benzene ring substituted with a methyl group and a hydroxyl group.