Method for producing aromatic α,α-dihaloalkyl compounds and method for producing cyclopropane derivatives

Abstract

To provide a method for producing aromatic α,α-dihaloalkyl compounds with low environmental load and high yield.SOLUTION: A method for producing aromatic α,α-dihaloalkyl compounds includes a halogenation step in which: in the presence of an aromatic hydrocarbon having an aromatic ring as an organic solvent and at least one fluorine group, an aromatic alkyl compound is reacted with a halogenating agent, to give an aromatic α,α-dihaloalkyl compound.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing an aromatic α,α-dihaloalkyl compound and a method for producing a cyclopropane derivative. [Background technology]

[0002] Aromatic α,α-dihaloalkyl compounds are useful intermediates for pharmaceuticals and industrial materials.

[0003] As a method for producing an aromatic α,α-dihaloalkyl compound, for example, Patent Document 1 describes a method for producing 5,5-dibromo-5-phenyl methyl valerate by reacting 5-phenyl methyl valerate with N-bromosuccinimide using carbon tetrachloride as a solvent.

[0004] Furthermore, as a method for producing an aromatic α-haloalkyl compound, Non-Patent Document 1 describes a method for producing o-bis(bromomethyl)benzene by reacting o-xylene with N-bromosuccinimide using any one of carbon tetrachloride, cyclohexane, benzene, acetic acid, and acetic anhydride as a solvent.

[0005] Furthermore, Patent Document 2 describes a method for producing an aromatic bromomethyl compound by reacting an aromatic methyl compound with N-bromosuccinimide using chlorobenzene as a solvent.

[0006] Furthermore, Patent Document 3 describes a method for producing 1-bromo-1-phenyl-2-butanone by reacting 1-phenyl-2-butanone with bromine using 1,1,1,3,3-pentafluorobutane as a solvent. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2016 / 039262 (Published March 17, 2016) [Patent Document 2] Japanese Patent Application Publication No. 6-234667 (published on August 23, 1994) [Patent Document 3] JP 2011-102280 A (Published May 26, 2011) [Non-patent literature]

[0008] [Non-Patent Document 1] "5th Edition Experimental Chemistry Lectures 13" edited by the Chemical Society of Japan, Maruzen Co., Ltd., February 20, 2004, pp. 375-379 Summary of the Invention [Problem to be solved by the invention]

[0009] The method described in Patent Document 1 has the problem of high environmental impact because it uses carbon tetrachloride as a solvent, the use of which is restricted by the Montreal Protocol. Furthermore, the method described in Non-Patent Document 1 has the problem of low yield when applied to a method for producing aromatic α,α-dihaloalkyl compounds if a solvent other than carbon tetrachloride is used. Furthermore, the methods described in Patent Documents 2 and 3, although not using carbon tetrachloride, have the problem of low yield when applied to a method for producing aromatic α,α-dihaloalkyl compounds.

[0010] One aspect of the present invention has been made in view of the above problems, and an object of the present invention is to provide a method for producing an aromatic α,α-dihaloalkyl compound with a low environmental impact and high yield, and related techniques. [Means for solving the problem]

[0011] In order to solve the above-mentioned problems, one embodiment of the present invention provides a method for producing an aromatic α,α-dihaloalkyl compound, which comprises a halogenation step of reacting an aromatic alkyl compound with a halogenating agent in the presence of an organic solvent to obtain an aromatic α,α-dihaloalkyl compound, wherein the organic solvent comprises an aromatic hydrocarbon having an aromatic ring and at least one fluorine group. [Effects of the Invention]

[0012] According to one aspect of the present invention, it is possible to provide a method for producing an aromatic α,α-dihaloalkyl compound with low environmental impact and high yield. DETAILED DESCRIPTION OF THE INVENTION

[0013] <Terminology> In this specification, the aromatic alkyl compound to be subjected to the production method is a compound having an aromatic ring and a hydrocarbon chain, and the hydrocarbon chain may be either an "alkyl chain (alkyl group)" or an "alkylene chain (alkylene group)." Furthermore, in this specification, unless otherwise specified, the α-carbon of the aromatic alkyl compound means the α-carbon counted from the aromatic ring side of the hydrocarbon chain of the aromatic alkyl compound.

[0014] <Method for producing aromatic α,α-dihaloalkyl compounds> A method for producing an aromatic α,α-dihaloalkyl compound according to one embodiment of the present invention includes a halogenation step of reacting an aromatic alkyl compound with a halogenating agent in the presence of an organic solvent to obtain an aromatic α,α-dihaloalkyl compound, wherein the organic solvent includes an aromatic hydrocarbon having an aromatic ring and at least one fluorine group.

[0015] By using an aromatic hydrocarbon having an aromatic ring and at least one fluorine group as the organic solvent, it is possible to produce an aromatic α,α-dihaloalkyl compound in high yield while reducing the environmental burden caused by the organic solvent during the production.

[0016] [Halogenation step] The halogenation step is a step of reacting an aromatic alkyl compound with a halogenating agent in the presence of an organic solvent to obtain an aromatic α,α-dihaloalkyl compound. The reaction may be a free radical halogenation reaction. The reaction vessel for the reaction may be a light-shielding or non-light-shielding vessel, depending on the types of halogenating agent and radical initiator, whether a radical initiator is used, and whether light irradiation from a light source is performed.

[0017] (aromatic alkyl compounds) The aromatic alkyl compound to be used in the production of the aromatic α,α-dihaloalkyl compound preferably has a structure represented by the following formula (1). Ar-R a ...Equation (1) In formula (1), Ar represents a residue derived from an aromatic ring (also called an aryl group), and R a represents a residue having a hydrocarbon chain. The aromatic ring Ar may be either a monocyclic aromatic ring or a polycyclic aromatic ring, or may be a monocyclic or polycyclic heterocycle (heteroaryl). Examples of monocyclic or polycyclic aromatic rings include carbocycles such as a benzene ring, a naphthalene ring, an anthracene ring, and a phenanthrene ring. Examples of monocyclic or polycyclic heterocycles include heterocycles such as a thiophene ring, a furan ring, a pyrrole ring, and a pyridine ring. Examples of polycyclic heterocycles include a benzothiophene ring, a benzofuran ring, an indole ring, and a quinoline ring.

[0018] The aromatic ring Ar is R a As functional groups other than R, for example, functional groups such as a hydrogen group, a deuterium group, an aryl group, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, an acyloxy group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group having 1 to 8 carbon atoms, an amino group, an acylamino group, an alkylcarbonyl group, an aryloxy group, and a halogen group may be contained. a has a carbon chain that is directly covalently bonded to Ar, and the α-carbon from the Ar side of the carbon chain is bonded to a hydrogen group to form a hydrocarbon group (-CH2-). aIn addition, the aromatic alkyl compound shown in formula (1) has one R in Ar. a It is sufficient if the

[0019] In the above formula (1), R a can be expressed by the following equation (2). -C n H 2n-A -R 1 ...Equation (2) In formula (2), n is an integer of 1 to 8, A is an integer of 0 or 2, and the hydrocarbon chain having n carbon atoms is a linear, branched, or cyclic alkylene group. More specific examples include, but are not limited to, a methylene group, an ethylene group, an n-propylene group, an isopropylene group, an n-butylene group, a tert-butylene group, an isobutylene group, a pentylene group, a hexylene group, a methylenecyclohexylene group, and an octylene group.

[0020] In addition, in formula (2), the functional group R 1 represents a terminal portion of the hydrocarbon chain of the aromatic alkyl compound other than the terminal bonded to Ar, and more specifically may be a functional group selected from a hydroxyl group, an aldehyde group (-(CO)H), an alkylalkoxy group in which hydrogen in a carboxyl group, an amino group, or an amide group is substituted with an alkyl group having 1 to 8 carbon atoms, an alkylcarbonyl group, an alkylcarboxylate group, a monoalkylamino group, a dialkylamino group, a monoalkylamide group, and a dialkylamide group, or may be a hydrogen group, a halogen group, an aldehyde group (-(CO)H), a cyano group, a carbonylcyano group (-(C=O)CN), or an amide group (-(C=O)NH2). 1 may be a functional group that has been protected by acylation (O-acylation or N-acylation) in advance with an acylating agent, such as a hydroxyl group, a carboxyl group, an amino group, or an amide group, which has a substitutable hydrogen atom. 1 is a functional group R 11 i.e., the functional group R 1The alkyl moiety of the above may be a functional group substituted with a perfluoroalkyl group or a polyoxyalkylene group substituted with an alkyl group at the end.

[0021] As shown in the above formulas (1) and (2), the aromatic alkyl compounds to be subjected to the halogenation step contain Ar having various structures and functional groups R having various structures. 1 and functional group R 1 is preferably not an aromatic ring from the viewpoint of successfully introducing a halogen group to the α-carbon.

[0022] (organic solvent) The organic solvent used in the halogenation step is an organic solvent (also referred to as a reaction solvent) that can be used as a dilution solvent for at least the aromatic alkyl compound and the halogenating agent in the halogenation reaction system, and is an aromatic hydrocarbon solvent with a molecular structure having an aromatic ring and at least one fluorine group. The aromatic hydrocarbon solvent is also an aromatic solvent having an aromatic ring and a fluorine group. The aromatic hydrocarbon solvent favorably stabilizes the α-carbon radical of the aromatic alkyl compound, which is the main raw material, thereby enhancing the regioselectivity in the halogenation reaction. Therefore, such an aromatic hydrocarbon is favorably used as an organic solvent for selectively producing an aromatic α,α-dihaloalkyl compound.

[0023] Examples of the aromatic ring that the aromatic hydrocarbon has as part of its molecular structure include a benzene ring and a heterocyclic ring, with a benzene ring being more preferred.

[0024] Furthermore, the aromatic hydrocarbon has at least one fluorine group in its molecular structure. From the viewpoint of increasing the yield of the target product, the number of fluorine groups contained in the aromatic hydrocarbon molecule is one or more, preferably three or more, and more preferably four or more. All or a portion of the fluorine groups may be directly bonded to an aromatic ring contained in the aromatic hydrocarbon. All or a portion of the fluorine groups may be indirectly bonded to the aromatic ring by being bonded to a functional group bonded to the aromatic ring contained in the aromatic hydrocarbon.

[0025] The aromatic hydrocarbon may have a functional group other than an aromatic ring. Examples of functional groups that the aromatic hydrocarbon may have in its molecule include a hydrogen atom, a halogen atom other than a fluorine atom, an alkoxy group having 1 to 4 carbon atoms, an alkoxycarbonyl group, a cyano group, a trihalomethyl group, and an α,α-dihaloalkyl group having 2 to 4 carbon atoms. Examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a tert-butoxy group, and an isobutoxy group. Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, a tert-butoxycarbonyl group, and an isobutoxycarbonyl group.

[0026] When the aromatic hydrocarbon has a halogen atom other than a fluorine group as a halogen group, the yield of the target product, an aromatic α,α-dihaloalkyl compound, can be further increased by using such an aromatic hydrocarbon as an organic solvent. The number of halogen atoms other than fluorine contained in the aromatic hydrocarbon molecule can be preferably one or more, more preferably two or more.

[0027] Furthermore, in the method for producing an aromatic α,α-dihaloalkyl compound according to one embodiment, the aromatic hydrocarbon preferably has a fluorine group and a halogen group other than a fluorine group, and the halogen atom of the halogen group other than a fluorine group is the same as the halogen atom of the halogen group contained in the halogenating agent described below. This can suppress the production of aromatic α-monohaloalkyl compounds as by-products, thereby increasing the yield of the aromatic α,α-dihaloalkyl compound. When the halogen atom contained in the aromatic hydrocarbon molecule and the halogen atom contained in the halogenating agent are the same type of element, the number of halogen atoms contained in the aromatic hydrocarbon molecule can be preferably one or more, more preferably two or more.

[0028] Examples of aromatic hydrocarbons include hexafluorobenzene, chloropentafluorobenzene, bromopentafluorobenzene, dichlorotetrafluorobenzene, dibromotetrafluorobenzene, methyl pentafluorobenzoate, pentafluorobenzene, tetrafluorobenzene, (trifluoromethyl)benzene, tribromotrifluorobenzene, pentafluorobenzonitrile, and pentafluoroanisole, but are not limited to these aromatic hydrocarbons.

[0029] In the halogenation step, the amount of organic solvent used is preferably 2 L or more, more preferably 4 L or more, per mole of aromatic alkyl compound. Using an organic solvent in this range can increase the yield of the target product, the aromatic α,α-dihaloalkyl compound. Furthermore, the amount of organic solvent used is preferably 20 L or less, more preferably 15 L or less, per mole of aromatic alkyl compound. Using an organic solvent in this range can reduce the amount of organic solvent removed during purification of the target product.

[0030] (Halogenating agent) In the halogenation step, a halogenating agent is used as a halogen source for the desired product, an aromatic α,α-dihaloalkyl compound. From the viewpoint of regioselectivity of the reaction, a halogenating agent that undergoes a free radical halogenation reaction is preferred. Examples of halogenating agents include halogen molecules, halosuccinimides, halohydantoins, and haloisocyanuric acids. Examples of halogen molecules include fluorine, chlorine, bromine, and iodine. Examples of halosuccinimides include N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, and N-fluorosuccinimide. Halohydantoins include 1-chlorohydantoin, 1-bromohydantoin, 1-iodohydantoin, 3-chlorohydantoin, 3-bromohydantoin, 3-iodohydantoin, 1,3-dichlorohydantoin, 1,3-dibromohydantoin, 1,3-diiodohydantoin, 1-chloro-5-methylhydantoin, 1-bromo-5-methylhydantoin, 1-iodo-5-methylhydantoin, 3-chloro-5-methylhydantoin, 3-bromo-5-methylhydantoin, 3-iodo-5-methylhydantoin, 1,3-dichloro-5-methylhydantoin, 1,3-dibromo ... Examples of haloisocyanuric acids include trifluoroisocyanuric acid, trichloroisocyanuric acid, tribromoisocyanuric acid, and triiodoisocyanuric acid. In the halogenation step, the type of halogenating agent used may be one type or two or more types. When two or more types of halogenating agents are used, the halogen atoms contained in the halogenating agents used may be one type or two or more types.

[0031] From the viewpoint of obtaining the target product, an aromatic α,α-dihaloalkyl compound, in the halogenation step, the molar equivalent of the halogen group possessed by the halogenating agent relative to 1 mole of the aromatic alkyl compound is preferably 1.9 molar equivalents or more, more preferably 2.0 molar equivalents or more. Furthermore, from the viewpoint of obtaining the target product in high yield by suppressing the formation of by-products, the amount of the halogenating agent relative to 1 mole of the aromatic alkyl compound is preferably 2.5 molar equivalents or less, more preferably 2.3 molar equivalents or less.

[0032] (radical initiator) In the halogenation step, a radical initiator may be used to increase the rate of the free radical halogenation reaction.

[0033] Examples of the radical initiator include azo compounds and organic peroxides such as dialkyl peroxides and diacyl peroxides. Examples of the azo compounds include 2,2'-azobisisobutyronitrile, 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobis(2-methylbutyronitrile), 1,1'-azobis(cyclohexane-1-carbonitrile), 2-phenylazo-4-methoxy-2,4-dimethylvaleronitrile, 2,2'-azobis(2-methylpropane), and dimethyl-2,2'-azobis(2-methylpropionate). Examples of dialkyl peroxides include dimethyl-2,5-di(t-butylperoxy)hexane, 2,5-dimethyl-2,5-di(t-butylperoxy)hexyne-3, 1,3-bis(t-butylperoxy-i-propyl)benzene, t-butylcumyl peroxide, tris-(t-butylperoxy)triazine, 1,1-di-t-butylperoxy-3,3,5-trimethylcyclohexane, 1,1-di-t-butylperoxycyclohexane, 2,2-di(t-butylperoxy)butane, 4,4-di-t-butylperoxy butyl valerate, and 2,2-bis(4,4-di-t-butylperoxycyclohexyl)propane. Examples of diacyl peroxides include benzoyl peroxide, 2,4-dichlorobenzoyl peroxide, o-chlorobenzoyl peroxide, lauroyl peroxide, acetyl peroxide, isobutyryl peroxide, bis-3,5,5-trimethylhexanoyl peroxide, etc. In addition, known photoradical initiators such as α-hydroxyketone-based photoradical initiators may be used as the radical initiator.

[0034] Among these radical initiators, the radical initiator is more preferably an azo compound from the viewpoint of ease of controlling the reaction rate.

[0035] The radical initiator may be manufactured or commercially available. Examples of commercially available radical initiators that can be used include V-70 (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and AIBN (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.).

[0036] In the halogenation step, the amount of radical initiator used is preferably 0.01 moles or more, more preferably 0.03 moles or more, per mole of aromatic alkyl compound. Using the radical initiator in this range can increase the reaction rate. Furthermore, the amount of radical initiator used is preferably 0.15 moles or less, more preferably 0.10 moles or less, per mole of aromatic alkyl compound. Using the radical initiator in this range can reduce the heat of reaction and make it easier to control the reaction temperature.

[0037] In addition, in the method for producing an aromatic α,α-dihaloalkyl compound according to one embodiment, a reaction inhibitor such as hydroquinone or 4-tert-butylcatechol may be added to the organic solvent in order to adjust the reaction rate within a range that does not impair the effects of the present invention.

[0038] (Reaction conditions) In the halogenation step, the reaction is preferably carried out in an inert gas atmosphere such as nitrogen gas or argon gas, in order to prevent inhibition of the radical reaction by oxygen.

[0039] In the halogenation step, the reaction may be carried out under light irradiation. By carrying out the halogenation step under light irradiation, the generation of radical species in the reaction solution can be promoted, thereby increasing the rate of the free radical halogenation reaction. Known light sources such as high-pressure mercury lamps, low-pressure mercury lamps, LED lamps, halogen lamps, and metal halide lamps can be used as the light source for light irradiation. The output of the irradiated light is preferably 40 W or more and 200 W or less. The illuminance of the light irradiated by the light source is preferably adjusted appropriately within a range that increases the reaction rate and prevents the generation of by-products. In the halogenation step, the reaction solution in a light-shielded reaction vessel (a photoreaction flask) may be irradiated with light, or the reaction solution in a non-light-shielded reaction vessel may be irradiated with light. However, it is more preferable to irradiate the reaction solution in a light-shielded reaction vessel with light. Furthermore, the reaction solution containing a halogenating agent may be irradiated with light.

[0040] In the halogenation step, the procedure for adding the reaction substances to the organic solvent (sometimes referred to as the "feeding method") can be changed as appropriate. The reaction substances may be added all at once to the organic solvent before, during, or after adjusting the organic solvent to the reaction temperature. Alternatively, the reaction substances may be added to the organic solvent in multiple batches. Preferably, the reaction substances are added all at once to the organic solvent.

[0041] In the halogenation step, the reaction temperature is preferably 10° C. or higher, more preferably 20° C. or higher, from the viewpoint of increasing the reaction rate. In addition, the reaction temperature is preferably 100° C. or lower, more preferably 80° C. or lower, from the viewpoint of preventing the production of by-products.

[0042] In the halogenation step, the reaction time is preferably 0.25 hours or more, more preferably 0.5 hours or more, from the viewpoint of sufficiently proceeding the reaction and increasing the yield.

[0043] (aromatic α,α-dihaloalkyl compounds) The aromatic α,α-dihaloalkyl compound obtained as the target product can be represented by the following formula (3): Ar-CX2C m H 2m-A -R 1 ...Equation (3) In formula (3), X represents a halogen group, m represents n-1, that is, an integer of 0 to 7, and A represents an integer of 0 or 2. 1 is Ar and R shown in the above formula (2). 1 Since this is the same as the formula (1), a description thereof will be omitted. Furthermore, each X is independently selected from chlorine, bromine, iodine, and fluorine, and is preferably chlorine, bromine, or iodine. That is, the aromatic α,α-dihaloalkyl compound represented by formula (3) can be obtained by reacting the aromatic alkyl compound represented by formula (1) or formula (2) with a halogen. The aromatic α,α-dihaloalkyl compound represented by formula (3) is preferably used to introduce a structure derived from the aromatic alkyl compound to an unsaturated carbon in the aromatic alkyl group introduction step described below.

[0044] [Refining process] The method for producing an aromatic α,α-dihaloalkyl compound according to one embodiment of the present invention may include a purification step of purifying the aromatic α,α-dihaloalkyl compound obtained in the halogenation step.

[0045] In the purification step, the aromatic α,α-dihaloalkyl compound can be purified by any purification method known in the art. For example, after cooling a solution containing the aromatic α,α-dihaloalkyl compound, insoluble matter is filtered off, the organic solvent is removed from the filtrate by distillation under reduced pressure, the resulting concentrate is recrystallized using a recrystallization solvent, the precipitated crystals are collected by filtration, and the resulting crystals are dried to isolate and purify the compound. The recrystallization solvent may be the same type of organic solvent as used in the halogenation step, or a different type of organic solvent may be used. When a different type of organic solvent is used, it is preferable to use a mixed solvent of ethyl acetate and hexane as the recrystallization solvent.

[0046] <Method of producing cyclopropane derivatives> A method for producing a cyclopropane derivative according to one embodiment of the present invention includes a production step of carrying out the method for producing an aromatic α,α-dihaloalkyl compound according to one embodiment of the present invention, and an aromatic alkyl group introduction step, after the production step, of reacting the aromatic α,α-dihaloalkyl compound with a compound containing an unsaturated carbon to obtain a cyclopropane derivative.

[0047] [Aromatic alkyl group introduction step] The aromatic alkyl group introduction step is a step of using an aromatic α,α-dihaloalkyl compound produced by the method for producing an aromatic α,α-dihaloalkyl compound according to one embodiment of the present invention to introduce a molecular structure derived from the aromatic α,α-dihaloalkyl compound into a compound having an unsaturated carbon-carbon double bond. The aromatic α,α-dihaloalkyl compound derivatization reaction can be a cycloaddition reaction between the α-carbon of an alkylene halide and an unsaturated carbon. The molecular structure of a cyclopropane derivative obtained by the derivatization reaction with the aromatic α,α-dihaloalkyl compound of formula (3) above can be represented by formula (4) below.

[0048] [ka]

[0049] In formula (4), R 1 is R in the above formula (2) and formula (3). 1 is the same as the functional group R 11 where m represents an integer of 0 to 7, and A represents an integer of 0 or 2. In formula (4), the carbon marked with "*" is a carbon that constitutes the unsaturated carbon in the compound subjected to the derivatization reaction, and constitutes part of the three-membered ring in the cyclopropane derivative together with the α-carbon of the aromatic alkyl compound.

[0050] The compound having an unsaturated carbon used in the derivatization reaction is not limited as long as it has a carbon-carbon conjugated bond, and examples thereof include olefins such as alkenes, and carbon materials such as fullerenes, graphene, and carbon nanotubes.

[0051] The reaction of an aromatic α,α-dihaloalkyl compound with a compound having a carbon-carbon conjugated bond, such as an alkene, can be carried out by methods known in the art. A typical example of the derivatization reaction is the Simmons-Smith reaction.

[0052] <Other processes> A method for producing an aromatic α,α-dihaloalkyl compound according to one embodiment of the present invention includes further reacting an aromatic α,α-dihaloalkyl compound or an aromatic alkyl compound to produce R 1 A part of the functional group R may be substituted with a substituent. 1 The aromatic α,α-dihaloalkyl compound partially substituted with a substituent and the aromatic α,α-dihaloalkyl compound may be a compound represented by the following formula (2′) or formula (3′). Ar-C n H 2n-A -R 11 ...Equation (2') Ar-CX2C m H 2m-A -R 11 ...Equation (3') In formula (2') and formula (3'), R 11 Except for this, the formulas are the same as those in (2) and (3) above, and R 11 is the functional group R shown in formula (2) 1 It can be obtained by substituting the hydrogen of R 11 is the functional group R 1 The alkyl moiety of the alkylalkoxy group or alkylcarboxylate group selected from the above may be a functional group substituted with a perfluoroalkyl group or fluoroalkyl group having 1 to 10 carbon atoms, or a polyoxyalkylene group terminally substituted with an alkyl group. Here, the polyoxyalkylene group terminally substituted with an alkyl group is represented by the following formula (5). -(C p H 2p O) q -R 2 ...Equation (5) In formula (5), p is an integer of 2 to 4, q is an integer of 1 to 75, and R 2 can be an alkyl group having 1 to 4 carbon atoms. Methods known in the art can be used depending on the aromatic α,α-dihaloalkyl compound and the desired aromatic α,α-dihaloalkyl compound derivative. 1The substitution reaction may be carried out on an aromatic alkyl compound before the halogenation step, or on an aromatic α,α-dihaloalkyl compound after the halogenation step and before the aromatic alkyl group introduction step.

[0053] In addition, in a method for producing a cyclopropane derivative according to one embodiment of the present invention, a structure derived from an aromatic α,α-dihaloalkyl compound is introduced into a compound having an unsaturated carbon, and then a functional group R 1 By substituting the functional group R 12 may be formed.

[0054] [ka]

[0055] In formula (6), R 12 is the functional group R 1 The hydroxyl group, carboxylic acid group, amino group, or amide group may be obtained by hydrolyzing an alkylalkoxy group or alkylcarboxylate group obtained by substituting hydrogen atoms of the hydroxyl group, aldehyde group (-(CO)H), carboxyl group, amino group, or amide group in the above formula with an alkyl group having 1 to 8 carbon atoms, or by eliminating or dissociating the acylating agent from the acylated hydroxyl group, carboxyl group, amino group, or amide group. Such a step of hydrolysis, elimination, or dissociation is referred to as an elimination step, and the elimination step is preferably carried out after the aromatic alkyl group introduction step.

[0056] The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention. [Example]

[0057] Using the production methods described in Examples 1 to 21, Comparative Examples 1 to 10, and Reference Example 1, methyl 5-phenylvalerate (PVM) was used as the main raw material to carry out the reaction, and the proportions of the main raw material (PVM), monobromo compound (methyl 5-bromo-5-phenylvalerate), and dibromo compound (methyl 5,5-dibromo-5-phenylvalerate, BPVM) contained in the product were measured by gas chromatography (GC) analysis.

[0058] <Measurement method> The proportions of the main raw material, monobromo compounds, and dibromo compounds contained in the product were measured by GC analysis under the following conditions: Column: TC-1, 30 m x 0.25 mm, 0.25 μm (GL Sciences Inc.) Carrier gas: He Total flow rate: 67.4mL / min. Split ratio: 50 Detector: Flame ionization detector (FID) Oven temperature: 50°C → 10°C / min. → 150°C → 15°C / min. → 280°C (hold for 11.33 min) Injection temperature: 250℃ Detector temperature: 310℃ Injection volume: 0.1 μL After subtracting the solvent peak from the peak of each component measured by GC analysis, the proportions of the main raw material, monobromo compounds, and dibromo compounds contained in the product were calculated by the area percentage method. Specifically, the "GC ratio" was defined as follows as an indicator of the proportion of each component contained in the product. Note that, since by-products such as methyl 2-bromo-5-phenylvalerate and methyl 2,5,5-tribromo-5-phenylvalerate were also produced in this reaction, the sum of the GC ratios of the main raw material, monobromo compounds, and dibromo compounds does not equal 100%. GC ratio (%) = (peak area of each component) / (peak area of all components - peak area of solvent) × 100

[0059] <Consideration of organic solvents and radical initiators> In Examples 1 to 13, Comparative Examples 1 to 10, and Reference Example 1, halogenation of the α-position of an aromatic alkyl compound was carried out by changing the organic solvent used in the reaction.

[0060] Example 1 Under a nitrogen atmosphere, 3.86 g (20.08 mmol) of 5-phenylmethyl valerate (PVM), 180 mL of hexafluorobenzene, 7.83 g (43.99 mmol) of N-bromosuccinimide (NBS), and 164 mg (0.999 mmol) of 2,2'-azobis(isobutyronitrile) (AIBN) were added to a 200 mL flask to form a reaction solution. The reaction solution was heated to 70°C and reacted for 1 hour to obtain a product.

[0061] Example 2 A product was obtained in the same manner as in Example 1, except that the same amount of chloropentafluorobenzene was used instead of hexafluorobenzene as the organic solvent.

[0062] Example 3 A product was obtained in the same manner as in Example 1, except that the same amount of bromopentafluorobenzene was used instead of hexafluorobenzene as the organic solvent.

[0063] Example 4 Under a nitrogen atmosphere, 3.86 g (20.08 mmol) of methyl 5-phenylvalerate (PVM), 180 mL of hexafluorobenzene, 7.83 g (43.99 mmol) of N-bromosuccinimide (NBS), and 312 mg (1.011 mmol) of 2,2'-azobis(4-methoxy-2,4'-dimethylvaleronitrile) (V-70, Fujifilm Wako Pure Chemical Industries, Ltd.) were added to a 200 mL flask. The reaction solution was heated to 50°C and reacted for 1 hour to obtain the product.

[0064] Example 5 A product was obtained in the same manner as in Example 4, except that the same amount of chloropentafluorobenzene was used instead of hexafluorobenzene as the organic solvent.

[0065] Example 6 A product was obtained in the same manner as in Example 4, except that the same amount of bromopentafluorobenzene was used instead of hexafluorobenzene as the organic solvent.

[0066] Example 7 A product was obtained in the same manner as in Example 4, except that the same amount of methyl pentafluorobenzoate was used instead of hexafluorobenzene as the organic solvent.

[0067] Example 8 A product was obtained in the same manner as in Example 4, except that the same amount of pentafluorobenzene was used instead of hexafluorobenzene as the organic solvent.

[0068] Example 9 A product was obtained in the same manner as in Example 4, except that the same amount of tetrafluorobenzene was used instead of hexafluorobenzene as the organic solvent.

[0069] Example 10 A product was obtained in the same manner as in Example 4, except that the same amount of (trifluoromethyl)benzene was used instead of hexafluorobenzene as the organic solvent.

[0070] Example 11 Under a nitrogen atmosphere, 1.92 g (10.0 mmol) of methyl 5-phenylvalerate (PVM), 90 mL of hexafluorobenzene, and 3.91 g (22.0 mmol) of N-bromosuccinimide (NBS) were added to a 100 mL photoreaction flask. The mixture was irradiated with a low-pressure mercury lamp (100 W) at room temperature for 1 hour to obtain the product.

[0071] Example 12 A product was obtained in the same manner as in Example 11, except that the same amount of chloropentafluorobenzene was used instead of hexafluorobenzene as the organic solvent.

[0072] Example 13 A product was obtained in the same manner as in Example 11, except that the same amount of bromopentafluorobenzene was used instead of hexafluorobenzene as the organic solvent.

[0073] Comparative Example 1 A product was obtained in the same manner as in Example 1, except that the same amount of acetic acid was used instead of hexafluorobenzene as the organic solvent.

[0074] Comparative Example 2 A product was obtained in the same manner as in Example 1, except that the same amount of N,N-dimethylformamide (DMF) was used instead of hexafluorobenzene as the organic solvent.

[0075] Comparative Example 3 A product was obtained in the same manner as in Example 1, except that the same amount of acetonitrile was used instead of hexafluorobenzene as the organic solvent.

[0076] Comparative Example 4 A product was obtained in the same manner as in Example 1, except that the same amount of methylcyclohexane was used instead of hexafluorobenzene as the organic solvent.

[0077] Comparative Example 5 A product was obtained in the same manner as in Example 1, except that the same amount of chlorobenzene was used instead of hexafluorobenzene as the organic solvent.

[0078] Comparative Example 6 A product was obtained in the same manner as in Example 1, except that the same amount of hexane was used instead of hexafluorobenzene as the organic solvent.

[0079] Comparative Example 7 A product was obtained in the same manner as in Example 1, except that the same amount of 1,2-dichloroethane was used instead of hexafluorobenzene as the organic solvent.

[0080] Comparative Example 8 A product was obtained in the same manner as in Example 1, except that the same amount of tetrahydrofuran (THF) was used instead of hexafluorobenzene as the organic solvent.

[0081] Comparative Example 9 A product was obtained in the same manner as in Example 1, except that the same amount of chloroform was used instead of hexafluorobenzene as the organic solvent.

[0082] Comparative Example 10 A product was obtained in the same manner as in Example 1, except that the same amount of tetradecafluorohexane was used instead of hexafluorobenzene as the organic solvent.

[0083] [Reference example 1] A product was obtained in the same manner as in Example 1, except that the same amount of carbon tetrachloride was used instead of hexafluorobenzene as the organic solvent.

[0084] Table 1 shows the results of measuring the proportions of the main raw material, monobromo compounds, and dibromo compounds contained in the crude products obtained by the production methods of Examples 1 to 13, Comparative Examples 1 to 10, and Reference Example 1.

[0085] [Table 1]

[0086] The production method according to one embodiment of the present invention enabled the production of a dibromo compound of PVM in good yield.

[0087] <Consideration of halogenating agents> In Examples 14 to 17, halogenation of the α-position of an aromatic alkyl compound was carried out by changing the type of halogenating agent used in the reaction and the ratio of the amount of halogenating agent used to the main raw material PVM.

[0088] Example 14 Under a nitrogen atmosphere, 3.86 g (20.08 mmol) of methyl 5-phenylvalerate (PVM), 180 mL of hexafluorobenzene, 6.29 g (22.00 mmol) of 1,3-dibromo-5,5-dimethylhydantoin (DBH), and 164 mg (0.999 mmol) of 2,2'-azobis(isobutyronitrile) (AIBN) were added to a 200 mL flask. The reaction solution was heated to 70°C and reacted for 1 hour to obtain the product.

[0089] Example 15 Under a nitrogen atmosphere, 3.86 g (20.08 mmol) of methyl 5-phenylvalerate (PVM), 180 mL of bromopentafluorobenzene, 6.29 g (22.00 mmol) of 1,3-dibromo-5,5-dimethylhydantoin (DBH), and 164 mg (0.999 mmol) of 2,2'-azobis(isobutyronitrile) (AIBN) were added to a 200 mL flask. The reaction solution was heated to 70°C and reacted for 1 hour to obtain the product.

[0090] Example 16 A product was obtained in the same manner as in Example 14, except that 7.19 g (40.40 mmol) of N-bromosuccinimide (NBS) was used instead of 6.29 g (22.00 mmol) of 1,3-dibromo-5,5-dimethylhydantoin (DBH) as the halogenating agent.

[0091] Example 17 A product was obtained in the same manner as in Example 15, except that 7.19 g (40.40 mmol) of N-bromosuccinimide (NBS) was used instead of 6.29 g (22.00 mmol) of 1,3-dibromo-5,5-dimethylhydantoin (DBH) as the halogenating agent.

[0092] Table 2 shows the results of measuring the proportions of the main raw material, monobromo compounds, and dibromo compounds contained in the crude products obtained by the production methods of Examples 14 to 17.

[0093] [Table 2]

[0094] By using the production method according to the present invention, when a halogenating agent was added in an amount of 2 or more equivalents relative to PVM, a dibromo compound of PVM could be obtained in high yield.

[0095] <Consideration of solvent amount> In Examples 18 to 21, the amount of organic solvent was investigated.

[0096] Example 18 Under a nitrogen atmosphere, 3.86 g (20.08 mmol) of methyl 5-phenylvalerate (PVM), 80 mL of hexafluorobenzene, 7.19 g (40.40 mmol) of N-bromosuccinimide (NBS), and 164 mg (0.999 mmol) of 2,2'-azobis(isobutyronitrile) (AIBN) were added to a flask. The reaction solution was heated to 70°C and reacted for 1 hour to obtain the product.

[0097] Example 19 A product was obtained in the same manner as in Example 18, except that 250 mL of hexafluorobenzene was used instead of 80 mL of hexafluorobenzene as the organic solvent.

[0098] Example 20 A product was obtained in the same manner as in Example 18, except that 80 mL of bromopentafluorobenzene was used instead of 80 mL of hexafluorobenzene as the organic solvent.

[0099] Example 21 A product was obtained in the same manner as in Example 18, except that 250 mL of bromopentafluorobenzene was used instead of 80 mL of hexafluorobenzene as the organic solvent.

[0100] Table 3 shows the results of measuring the proportions of the main raw material, monobromo compounds, and dibromo compounds contained in the crude products obtained by the production methods of Examples 18 to 21.

[0101] [Table 3]

[0102] By using the production method according to the present invention, when the concentration of the main raw material PVM was set in the range of 0.08M to 0.25M, a dibromo compound of PVM could be obtained in high yield. [Industrial Applicability]

[0103] INDUSTRIAL APPLICABILITY The present invention can be suitably used for producing aromatic α,α-dihaloalkyl compounds and cyclopropane derivatives.

Claims

1. a halogenation step of reacting an aromatic alkyl compound with a halogenating agent in the presence of an organic solvent to obtain an aromatic α,α-dihaloalkyl compound; The halogenation step is carried out in the presence of a radical initiator or under light irradiation, The organic solvent includes an aromatic hydrocarbon having an aromatic ring and at least one fluorine group, The aromatic alkyl compound has a structure represented by the following formula (1): Ar-R a Formula (1) In the above formula (1), Ar is selected from monocyclic aromatic rings and polycyclic aromatic rings; R a is represented by the following formula (2): -C n H 2n-A -R 1 ...Formula (2) In the above formula (2), n is an integer from 1 to 8, A is an integer of 0 or 2, R 1 is selected from alkyl carboxylic acid ester groups in which a carboxylic acid is substituted with an alkyl group having 1 to 8 carbon atoms; The halogenating agent is selected from the group consisting of halosuccinimides and halohydantoins.

2. 2. The method for producing an aromatic α,α-dihaloalkyl compound according to claim 1, wherein the aromatic hydrocarbon has three or more fluorine groups.

3. 3. The method for producing an aromatic α,α-dihaloalkyl compound according to claim 1 or 2, wherein the aromatic ring of the aromatic hydrocarbon has a functional group selected from the group consisting of a hydrogen group, a halogen group other than a fluorine group, an alkoxy group, an alkoxycarbonyl group, a cyano group, a trihalomethyl group, and an α,α-dihaloalkyl group.

4. The method for producing an aromatic α,α-dihaloalkyl compound according to claim 3, wherein the aromatic hydrocarbon has at least one halogen group other than the fluorine group on at least one of the aromatic ring and the functional group.

5. The method for producing an aromatic α,α-dihaloalkyl compound according to any one of claims 1 to 4, wherein the aromatic hydrocarbon is at least one organic solvent selected from the group consisting of hexafluorobenzene, chloropentafluorobenzene, bromopentafluorobenzene, dichlorotetrafluorobenzene, dibromotetrafluorobenzene, methyl pentafluorobenzoate, pentafluorobenzene, tetrafluorobenzene, (trifluoromethyl)benzene, tribromotrifluorobenzene, pentafluorobenzonitrile, and pentafluoroanisole.

6. The method for producing an aromatic α,α-dihaloalkyl compound according to claim 4 or 5, wherein the element of the halogen group other than the fluorine group contained in the aromatic hydrocarbon is the same element as the element of the halogen group contained in the halogenating agent.

7. The method for producing an aromatic α,α-dihaloalkyl compound according to any one of claims 1 to 6, wherein the reaction temperature in the halogenation step is adjusted to within a range of 10°C to 100°C.

8. A method for producing a cyclopropane derivative, comprising: a production step of carrying out the method for producing an aromatic α,α-dihaloalkyl compound according to any one of claims 1 to 7; and, after the production step, a step of introducing an aromatic alkyl group, in which the aromatic α,α-dihaloalkyl compound is reacted with a compound having an unsaturated carbon to obtain a cyclopropane derivative.

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