JP2021017439A - Dimethyl cyclobutanone compound, dimethyl cyclobutane compound, and method of producing these - Google Patents

Abstract

To provide a dimethyl cyclobutane compound useful as an efficient and industrially feasible synthetic intermediate of a sex pheromone compound having a cyclobutane structure, and a method of producing the same.SOLUTION: Provided are compounds of the general formula (1A) and the like represented by the following formula where, in the formula, R1 and R2 are 1-10C univalent hydrocarbon groups, X1 and X2 are HO, an acyloxy group and the like, and X3 is OH, alkoxy and the like.SELECTED DRAWING: None

Description

The present invention relates to dimethylcyclobutanone compounds, dimethylcyclobutane compounds and methods for producing them, which are useful as synthetic intermediates for insect sex pheromones.

Insect sex pheromones are bioactive substances that have the function of attracting male individuals by female individuals, and exhibit high attractive activity even in small amounts. Sex pheromones are widely used as a means of predicting outbreaks and confirming geographical spread (invasion into specific areas), and as a means of pest control. The means of pest control include mass trapping, attracted insecticide (Lure & kill or Actrat & kill), attracted infection (Lure & insect or Acttract & insect), and communication disturbance method (Matting). The control method is widely used in practical use. In order to use sex pheromones, it is necessary to economically produce the required amount of pheromone precursors for basic research and further for application.

The cyclobutane structure is an example of a unique structure among the chemical structures of sex pheromones. For example, the sex pheromone of Planococcus citri (generic name: methylbug), which is widely distributed all over the world and is an economically important pest that harms citrus, is (+)-cis- (3-isopropenyl-2,2). -Dimethylcyclobutyl) Methyl = acetate has been reported by Biel-Leonhard et al. (Non-Patent Document 1). In addition, the sex pheromones of Pseudococcus cryptus (generic name: Citriculus mealybug) and Acutaspis albopicta (generic name: Albopicta scale) are also the sex pheromones of Citrus mealybug (generic name: Albopicta scale), as well as the sex pheromones of Citrus mealybug (generic name: Citrus mearybug) and carboxylic acid. It has a cyclobutyl) methyl ester structure (Non-Patent Documents 2 and 3). In addition, the sex pheromones of Citrus mearybug, such as Maconellicoccus hirsutus (generic name: Pink hibiscus mearybug) and Phenacoccus solenopsis (generic name: Cotton mearybug), are double-bonded to the sex pheromones of Citrus mearybug, which are different from each other. Species that utilize −dimethylcyclobutyl) methyl ester as a sex pheromone are also known (Non-Patent Documents 4 and 5).

As a typical method for producing a sex pheromone having these cyclobutane structures, a method using pinene as a starting material can be mentioned. For example, Passaro et al. Synthesize verbenol or verbenone by oxidizing pinene, further oxidize them to cleave double bonds, and then undergo ketone methyleneation, carboxylic acid reduction, acetylation, etc., and then the sex pheromone of Citrus mailybug. Is synthesized (Non-Patent Document 6). In addition, Zhang et al. Also oxidized velbenone, and then methylated and lactonized ketones, constructed isopropylidene groups by cleaving the lactone ring, and reduced carboxylic acids to obtain the sex pheromones of Pink hibiscus methanol and Cotton methanol. Methanol (3-isopropyridene-2,2-dimethylcyclobutyl) corresponding to the alcohol moiety is synthesized (Non-Patent Document 7). In addition, Matsuo et al. 3-Benzyloxymethyl-2, which has a partial structure common to the sex pheromone of Cyclobutanone by the reaction of ketene-iminium and allyl-benzyl-ether generated from amide and trifluoromethanesulfonic anhydride, 2-Dimethylcyclobutanone is synthesized (Non-Patent Document 8).

Tetrahedron. Lett. 22,389 (1981) J. Chem. Ecole. 29,2213 (2003) J. Econ. Entomol. 105,497 (2012) Proc. Natl. Acad. Sci. 101,9601 (2004) J. Chem. Ecole. 42,1193 (2016) J. Agric. Food Chem. 2004, 52, 2896 (2004) Tetrahedron. Lett. 45,9401 (2004) Tetrahedron. Lett. 53,432 (2012)

However, in the production method described in Non-Patent Document 6, since lead tetraacetate and chromium oxide are used for the oxidation of pinene to verbenol and verbenone, a large amount of harmful and environmentally burdensome heavy metal waste is given. These oxidants are difficult to implement industrially because they can cause explosions. Further, in order to further oxidize verbenol and verbenone, an expensive ruthenium catalyst is used, which is difficult to carry out industrially from the economical point of view. Further, in the production method described in Non-Patent Document 7, pinene is oxidized to verbenone in an oxygen atmosphere, which is industrially difficult to carry out from the viewpoint of safety and requires a reaction time of as long as 7 days. Therefore, it is inefficient and uneconomical. Further, it is uneconomical in that an expensive ruthenium catalyst is used for the oxidation of verbenone as in Non-Patent Document 6. Further, in the method for producing cyclobutanone having a partial structure common to the sex pheromone of Citrus mailybug described in Non-Patent Document 8, it is highly reactive and difficult to handle, and expensive trifluoromethanesulfonic anhydride is used. Therefore, it is difficult to carry out industrially.

A sufficient amount of pheromone progenitor for basic biological and agricultural studies of sex pheromone compounds having a cyclobutane structure represented by sex pheromones of Citrus mearyblog, and for purposes of application and practical use. There is a strong demand for an efficient and industrially feasible manufacturing method capable of supplying

The present invention has been made in view of the above circumstances, and is an efficient and industrially feasible dimethylcyclobutanone compound, a dimethylcyclobutane compound, and a method for producing the same, which is useful as a synthetic intermediate for a sex pheromone compound having a cyclobutane structure. I will provide a.

As a result of diligent studies to solve the above problems, the present inventors have conducted the following general formulas (1A), general formulas (1B), general formulas (2), and general formulas (5) in the present specification. By using the dimethylcyclobutane compound represented by the general formula (6) and the general formula (1), it is efficient without using an oxidation reaction which is difficult to carry out industrially in terms of safety, economy and environmental load. It was found that a sex pheromone compound having a cyclobutane structure, which can be industrially carried out in Japan, can be produced, and the present invention has been made.

According to one aspect of the present invention, the following general formula (2)
(In the formula, X ² is an acyloxy group having 1 to 10 carbon atoms including carbon of a hydroxyl group and a carbonyl group, an alkoxycarbonyloxy group having 2 to 10 carbon atoms including carbon of a carbonyl group, and 1 to 10 carbon atoms. It represents an alkane sulfonyloxy group, an allene sulfonyloxy group having 6 to 20 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, a silyloxy group having 3 to 20 carbon atoms, or a halogen atom. The dimethylcyclobutanone compound represented by and the following general formula (3)
(In the formula, R ¹ and R ² each independently represent a monovalent hydrocarbon group having 1 to 10 carbon atoms.)
By the reaction with the phosphonate ester compound represented by (particularly, the olefination reaction, preferably the Horner-Wadsworth-Emmons reaction), the following general formula (4)
(In the formula, R ¹ and X ² are as defined above.) A step of obtaining an unsaturated ester compound having a dimethylcyclobutane ring, and a step of obtaining an unsaturated ester compound.
By subjecting the unsaturated ester compound (4) having the dimethylcyclobutane ring described above to a reduction reaction, the following general formula (1A)
(Wherein, ^{X 3} represents a hydroxyl group, alkanesulfonyloxy group having 1 to 10 carbon atoms, arenesulfonyl group having 6 to 20 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryloxy group having 6 to 12 carbon atoms , A method for producing a dimethylcyclobutane compound (1A), which comprises at least a step of obtaining a dimethylcyclobutane compound represented by a silyloxy group or a halogen atom having 3 to 20 carbon atoms.

Further, in another aspect of the present invention, each step in the above-mentioned production method of the above-mentioned dimethylcyclobutane compound (1A) and
Hydroxyl dimethyl cyclobutane compound of above (1A), and optionally X ^3, by converting the general formula (1B)
(Wherein, X ⁴ is an acyloxy group having 1 to 10 carbon atoms including carbon atoms of carbonyl groups, alkoxycarbonyloxy groups having 2 to 10 carbon atoms including carbon atoms of carbonyl groups, alkanesulfonyl of 1 to 10 carbon atoms Oxy group, allene sulfonyloxy group with 6 to 20 carbon atoms, alkoxy group with 1 to 12 carbon atoms, aryloxy group with 6 to 12 carbon atoms, silyloxy group with 3 to 20 carbon atoms, trialkyl with 3 to 30 carbon atoms phosphonio group, a triaryl phosphonium niobium group or a halogen atom 12 to 30 carbon atoms, and, X ⁵ represents a hydroxyl group, an acyloxy group having 1 to 10 carbon atoms including carbon atoms of carbonyl groups, the carbon of the carbonyl group Including alkoxycarbonyloxy groups having 2 to 10 carbon atoms, alcansulfonyloxy groups having 1 to 10 carbon atoms, arene sulfonyloxy groups having 6 to 20 carbon atoms, alkoxy groups having 1 to 12 carbon atoms, and 6 to 12 carbon atoms. A step of obtaining a dimethylcyclobutane compound represented by an aryloxy group, a silyloxy group having 3 to 20 carbon atoms or a halogen atom), and
A method for producing a dimethylcyclobutane compound (1B), which comprises at least.

Further, in another aspect of the present invention, the following general formula (1)
(In the formula, X ¹ is an acyloxy group having 1 to 10 carbon atoms including a hydroxyl group and a carbon of a carbonyl group, an alkoxycarbonyloxy group having 2 to 10 carbon atoms including a carbon of a carbonyl group, and 1 to 10 carbon atoms. Alcan sulfonyloxy group, allene sulfonyloxy group with 6 to 20 carbon atoms, alkoxy group with 1 to 12 carbon atoms, aryloxy group with 6 to 12 carbon atoms, silyloxy group with 3 to 20 carbon atoms, 3 to 30 carbon atoms trialkyl phosphonium niobium group, a triaryl phosphonium niobium group or a halogen atom 12 to 30 carbon atoms, X ² is by subjecting to reduction reaction is as defined above.) dimethylcyclobutane compound represented by , The following general formula (5)
(Wherein, X ⁶ represents a hydroxyl group, an acyloxy group having 1 to 10 carbon atoms including carbon atoms of carbonyl groups, alkoxycarbonyloxy groups having 2 to 10 carbon atoms including carbon atoms of carbonyl groups, having 1 to 10 carbon atoms Any of an alkane sulfonyloxy group, an allene sulfonyloxy group having 6 to 20 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, a silyloxy group having 3 to 20 carbon atoms, or a halogen atom. The isopropenyldimethylcyclobutane compound represented by (represented) and / or the following general formula (6)
(Wherein, X ⁶ is as defined above.) Comprising at least the step of obtaining the isopropylidene dimethylcyclobutane compound represented by, isopropenyl dimethyl cyclobutane compound (5) and / or isopropylidene dimethylcyclobutane compound ( The manufacturing method of 6) is provided.

Further, in another aspect of the present invention, the steps in the above-mentioned production method of the above-mentioned isopropenyldimethylcyclobutane compound (5) and / or isopropyridenedimethylcyclobutane compound (6).
The isopropenyl dimethyl cyclobutane compound (5) and / or isopropylidene dimethylcyclobutane compound X ⁶ in (6) is replaced with another group X ⁶ in choice of a particular group X ⁶ as defined above, isopropenyl Preparation of isopropenyldimethylcyclobutane compound (5') and / or isopropyridene dimethylcyclobutane compound (6') comprising at least a step of obtaining a dimethylcyclobutane compound (5') and / or an isopropylidene dimethylcyclobutane compound (6'). A method is provided.

Further, in another aspect of the present invention, the above-mentioned general formula (1)
(In the equation, X ¹ and X ² are as defined above.)
The dimethylcyclobutane compound (1) represented by is provided.
In another aspect of the present invention, in the dimethylcyclobutane compound (1), in particular, X ¹ is a hydroxyl group, and X ² is a hydroxyl group, an alkanesulfonyloxy group having 1 to 10 carbon atoms, and an arene having 6 to 20 carbon atoms. It represents a sulfonyloxy group, an alkoxy group having 1 to 12 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, a silyloxy group having 3 to 20 carbon atoms, or a halogen atom.
In another aspect of the present invention, in particular, in the dimethylcyclobutane compound (1), X ¹ has an acyloxy group having 1 to 10 carbon atoms including a carbon of a carbonyl group and 2 to 10 carbon atoms including a carbon of a carbonyl group. Alkoxycarbonyloxy group, alkanesulfonyloxy group having 1 to 10 carbon atoms, allenesulfonyloxy group having 6 to 20 carbon atoms, alkoxy group having 1 to 12 carbon atoms, aryloxy group having 6 to 12 carbon atoms, 3 carbon atoms It represents a silyloxy group of ~ 20, a trialkylphosphonio group of 3 to 30 carbon atoms, a triarylphosphonio group of 12 to 30 carbon atoms or a halogen atom.

Further, according to another aspect of the present invention, the following general formula (7)
(In the formula, X ⁹ represents a halogen atom.) The acid halide represented by the following general formula (8).
(Wherein, X ¹² is an acyloxy group having 1 to 10 carbon atoms including carbon atoms of carbonyl groups, alkoxycarbonyloxy groups having 2 to 10 carbon atoms including carbon atoms of carbonyl groups, alkanesulfonyl of 1 to 10 carbon atoms Represents an oxy group, an allene sulfonyloxy group having 6 to 20 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, a silyloxy group having 3 to 20 carbon atoms or a halogen atom). Depending on the reaction between the allyl compound and the base, the following general formula (2A)
(Wherein, X ¹² is as defined above.) Is represented by, comprising at least the step of obtaining a dimethyl cyclobutanone compound, method for producing dimethyl cyclobutanone compound (2A) is provided.

Further, in another aspect of the present invention, the following general formula (2B)
(Wherein, X ¹³ is an acyloxy group having 3 to 10 carbon atoms including carbon atoms of carbonyl groups, alkoxycarbonyloxy groups having 2 to 10 carbon atoms including carbon atoms of carbonyl groups, alkanesulfonyl of 1 to 10 carbon atoms It represents an oxy group, an allene sulfonyloxy group having 6 to 20 carbon atoms, an alkoxy group having 2 to 12 carbon atoms excluding the benzyloxy group, an aryloxy group having 6 to 12 carbon atoms, or a silyloxy group having 3 to 20 carbon atoms. )
The dimethylcyclobutanone compound (2B) represented by is provided.

According to the present invention, a sex pheromone compound having a cyclobutane structure can be efficiently and industrially produced without using an oxidation reaction that is difficult to carry out industrially in terms of safety, economy and environmental load. .. The present invention is a sex pheromone of Citrus mearybug, Citriculus mearybug and Albapicta scale (3-isopropenyl-2,2-dimethylcyclobutyl) methyl ester, and Pink hibiscus mearybug and Coton mealybug (3-isopropemone). It can be applied to the production of redene-2,2-dimethylcyclobutyl) methyl ester.

In the chemical formulas of intermediates, reagents and objects in the present specification, isomers having different substitution positions in structure, or stereoisomers such as enantioisomers or diastereoisomers may exist, but in particular. Unless otherwise stated, each chemical formula shall represent all of these isomers. Moreover, these isomers may be alone or a mixture.
[I] Dimethylcyclobutane compound (1)
First, the dimethylcyclobutane compound (1) will be described. The dimethylcyclobutane compound (1) is represented by the following general formula (1).
As X ¹ , an acyloxy group having 1 to 10 carbon atoms including a hydroxyl group and a carbon of a carbonyl group, an alkoxycarbonyloxy group having 2 to 10 carbon atoms including a carbon of a carbonyl group, and an alkanesulfonyloxy having 1 to 10 carbon atoms. Group, allene sulfonyloxy group with 6 to 20 carbon atoms, alkoxy group with 1 to 12 carbon atoms, aryloxy group with 6 to 12 carbon atoms, silyloxy group with 3 to 20 carbon atoms, trialkylphospho with 3 to 30 carbon atoms Examples thereof include a nitro group, a triarylphosphonio group having 12 to 30 carbon atoms, a halogen atom and the like.
Examples of X ² include an acyloxy group having 1 to 10 carbon atoms including a hydroxyl group and a carbon of a carbonyl group, an alkoxycarbonyloxy group having 2 to 10 carbon atoms including a carbon of a carbonyl group, and an alkanesulfonyloxy having 1 to 10 carbon atoms. Examples thereof include an allene sulfonyloxy group having 6 to 20 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, a silyloxy group having 3 to 20 carbon atoms, a halogen atom and the like.
X ¹ and X ² are each independently selected from the groups described above.
Examples of the acyloxy group having 1 to 10 carbon atoms including the carbon of the carbonyl group include a formyloxy group, an acetoxy (AcO) group, a propanoyloxy group, a butanoyloxy group, a pentanoyloxy group, a hexanoyloxy group and a heptanoyl. Linear aliphatic acyloxy groups such as oxy group, octanoyloxy group, nonanoyloxy group, decanoyyloxy group, crotonyloxy group, 2-methylpropanoyloxy group, pivaloyloxy group, 2-methylbutanoyloxy group, Branched aliphatic acyloxy groups such as 3-methyl-2-butenoyloxy group and 3-methyl-3-butenoyloxy group, halogenated acyloxy groups such as trichloroacetoxy group and trifluoroacetoxy group, aromatic acyloxy groups such as benzoyloxy group. Examples thereof include an acyloxy group having an isomer relationship with these.
Further, a part of hydrogen atoms of these acyloxy groups may be substituted with a methyl group, an ethyl group, a halogen atom or the like. Examples of the acyloxy group having 1 to 10 carbon atoms including the carbon of the carbonyl group are formyloxy group, acetoxy group, propanoyloxy group, pivaloyloxy group and 2-methylbutanoyloxy as particularly preferable examples from the viewpoint of easy availability. Groups, benzoyloxy groups and the like can be mentioned.

Examples of the alkoxycarbonyloxy group having 2 to 10 carbon atoms including the carbon of the carbonyl group include methoxycarbonyloxy group, ethoxycarbonyloxy group, n-propoxycarbonyloxy group, n-butoxycarbonyloxy group and n-pentyloxycarbonyloxy. Linear saturated alkoxycarbonyl such as group, n-hexyloxycarbonyloxy group, n-heptyloxycarbonyloxy group, n-octyloxycarbonyloxy group, n-nonyloxycarbonyloxy group, n-decyloxycarbonyloxy group. Linear unsaturated alkoxy such as branched saturated alkoxycarbonyloxy group such as oxy group, isopropoxycarbonyloxy group and t-butoxycarbonyloxy group, 2-propenyloxycarbonyloxy group and 2-propynyloxycarbonyloxy group. Branched unsaturated alkoxycarbonyloxy group such as carbonyloxy group, 2-methyl-2-propenyloxycarbonyloxy group, cyclopropyloxycarbonyloxy group, 2-methylcyclopropyloxycarbonyloxy group, cyclobutyloxycarbonyloxy group , Cyclopentyloxycarbonyloxy group and other cyclic alkoxycarbonyloxy groups, benzyloxycarbonyloxy group, paramethoxybenzyloxycarbonyloxy group and other aromatic ring-containing alkoxycarbonyloxy groups, methoxymethoxycarbonyloxy groups, benzyloxymethoxycarbonyloxy Examples thereof include an oxyalkoxycarbonyloxy group such as a paramethoxybenzyloxymethoxycarbonyloxy group and a halogenated alkoxycarbonyloxy group such as a 2,2,2-trichloroethoxycarbonyloxy group, which are isomers. It may be an alkoxycarbonyloxy group. Further, some of the hydrogen atoms of these alkoxycarbonyloxy groups may be substituted with methyl groups, ethyl groups, halogen atoms and the like. Examples of the alkoxycarbonyloxy group having 2 to 10 carbon atoms including the carbon of the carbonyl group include a methoxycarbonyloxy group, an ethoxycarbonyloxy group, an n-propoxycarbonyloxy group and the like from the viewpoint of easy availability. Can be mentioned.

Examples of the alkanesulfonyloxy group having 1 to 10 carbon atoms include a methanesulfonyloxy (MsO) group, an ethanesulfonyloxy group, a 1-butanesulfonyloxy group, a 1-pentanesulfonyloxy group, a 1-hexanesulfonyloxy group, and a 1-heptane. Sulfonyl oxy group, 1-octane sulfonyl oxy group, 1-nonane sulfonyl oxy group, 1-decane sulfonyl oxy group, allyl sulfonyl oxy group, 10-campa-sulfonyl oxy group, trifluoromethane sulfonyl oxy group, α-benzyl sulfonyl oxy group Etc., and an alkanesulfonyloxy group having an isomer relationship with these may be used.
Further, some of the hydrogen atoms of these alkanesulfonyloxy groups may be substituted with methyl groups, ethyl groups, halogen atoms and the like. Examples of the alkanesulfonyloxy group having 1 to 10 carbon atoms include a methanesulfonyloxy group and an ethanesulfonyloxy group from the viewpoint of easy availability.

Examples of the arene sulfonyloxy group having 6 to 20 carbon atoms include a benzenesulfonyloxy group, a 4-chlorobenzenesulfonyloxy group, a 4-methoxybenzenesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, and a 2,4,6-trimethylbenzenesulfonyloxy group. Examples thereof include a group, a paratoluenesulfonyloxy (TsO) group, a 1-naphthalenesulfonyloxy group, and a 2-naphthalenesulfonyloxy group, and an allenesulfonyloxy group having an isomer relationship with these may be used. Further, some of the hydrogen atoms of these arene sulfonyloxy groups may be substituted with methyl groups, ethyl groups, halogen atoms and the like. Examples of the arene sulfonyl oxy group having 6 to 20 carbon atoms include a benzenesulfonyl oxy group and a paratoluenesulfonyl oxy group from the viewpoint of easy availability.

Examples of the alkoxy group having 1 to 12 carbon atoms include a methoxy (MeO) group, an ethoxy (EtO) group, an n-propoxy (PrO) group, an n-butoxy (BuO) group, an n-pentyloxy (PenO) group, and an n-. Hexyloxy (HexO) group, n-heptyloxy (HepO) group, n-octyloxy (OctO) group, n-nonyloxy (NonO) group, n-decyloxy (DecO) group, n-undecyloxy group, n- Linear saturated alkoxy group such as dodecyloxy group, branched saturated alkoxy group such as isopropoxy group (i-PrO), isobutyloxy group (i-BuO), t-butoxy (t-BuO) group, 2 -Linear unsaturated alkoxy groups such as propenyloxy group and 2-propynyloxy group, branched unsaturated alkoxy groups such as 2-methyl-2-propenyloxy group, cyclopropyloxy group, 2-methylcyclopropyl Cyclic alkoxy group such as oxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy (c-HexO) group, alkoxy group containing aromatic ring such as benzyloxy (BnO) group, paramethoxybenzyloxy group, methoxymethoxy (MOMO) group, 2-methoxyethoxymethoxy group, benzyloxymethoxy group, paramethoxybenzyloxymethoxy group, 1-ethoxyethoxy (EEO) group, 1-allyloxyethoxy group, tetrahydropyran-2-yloxy (THPO) group Oxyalkoxy groups such as, 2,2,2-trichloroethoxy group, halogenated alkoxy groups such as pentafluoroethoxy group and the like, and alkoxy groups having an isomer relationship with these may be used. Further, some of the hydrogen atoms of these alkoxy groups may be substituted with methyl groups, ethyl groups, halogen atoms and the like.

Examples of the alkoxy group having 1 to 12 carbon atoms are particularly preferable from the viewpoint of ease of preparation and the like, as methoxy group, ethoxy group, 2-propenyloxy group, methoxymethoxy group, 1-ethoxyethoxy group and 1-allyloxy. Examples thereof include an ethoxy group and a tetrahydropyran-2-yloxy group.

Examples of the aryloxy group having 6 to 12 carbon atoms include a phenoxy (PhO) group, a 4-chlorophenoxy group, a 4-methoxyphenoxy group, a naphthoxy group, a 4-biphenyloxy group, and the like. It may be an aryloxy group. Further, a part of the hydrogen atoms of these aryloxy groups may be substituted with a methyl group, an ethyl group, a halogen atom or the like. Examples of the aryloxy group having 6 to 12 carbon atoms are particularly preferable from the viewpoint of easy availability, such as a phenoxy group and a naphthoxy group.

Examples of the silyloxy group having 3 to 20 carbon atoms include a trialkylsilyl group such as a trimethylsilyloxy (TMSO) group, a triethylsilyloxy (TESO) group, a triisopropylsilyloxy (TIPSO) group and a t-butyldimethylsilyloxy (TBSO) group. Examples thereof include a monoalkyldiarylsilyloxy group such as an oxy group and a t-butyldiphenylsilyloxy (TBDPSO) group, and a silyloxy group having an isomer relationship with these may be used. Further, a part of hydrogen atoms of these silyloxy groups may be substituted with a methyl group, an ethyl group, a halogen atom or the like. Examples of the silyloxy group having 3 to 20 carbon atoms include a trimethylsilyloxy group, a triethylsilyloxy group, a triisopropylsilyloxy group, a t-butyldimethylsilyloxy group and the like, as particularly preferable examples from the viewpoint of easy availability.

Examples of the trialkylphosphonio group having 3 to 30 carbon atoms include a trimethylphosphonio group, a triethylphosphonio group, a tripropylphosphonio group, a tributylphosphonio group, a tripentylphosphonio group, a trihexylphosphonio group and a triheptylphosphonio. Examples thereof include a group, a trioctylphosphonio group, a trinonylphosphonio group, a tridecylphosphonio group, a tricyclohexylphosphonio group and the like. Examples of the trialkylphosphonio group having 3 to 30 carbon atoms are particularly preferable from the viewpoint of easy availability, such as a tributylphosphonio group, a tricyclohexylphosphonio group, and a trioctylphosphonio group.

Examples of the triarylphosphonio group having 12 to 30 carbon atoms include a triphenylphosphonio group, a tri (2-methylphenyl) phosphonio group, a trifurylphosphonio group, and a tri (1-naphthyl) phosphonio group. Examples of the triarylphosphonio group having 12 to 30 carbon atoms include a triphenylphosphonio group and a tri (2-methylphenyl) phosphonio group as particularly preferable examples from the viewpoint of easy availability.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Chlorine atom and bromine atom are particularly preferable examples from the viewpoint of easy availability.

The dimethylcyclobutane compound (1) is a (S, Z) -form dimethylcyclobutane compound represented by the following general formula (1-1), and is represented by the following general formula (1-2) (R, Z). -Form of dimethylcyclobutane compound, represented by the following general formula (1-3) (S, E) -form of dimethylcyclobutane compound, and represented by the following general formula (1-4) (R, E)- Included are dimethylcyclobutane compounds of the form, as well as racemic, diastereomeric and scalemic mixtures thereof.
Examples of the dimethylcyclobutane compound (1) include a dimethylcyclobutane compound having a hydroxyl group and an alkoxy group, a dimethylcyclobutane compound having an acyloxy group and an alkoxy group, a dimethylcyclobutane compound having a halogen atom and an alkoxy group, and a dimethylcyclobutane having a phosphonio group and an alkoxy group. Compound, dimethylcyclobutane compound having two hydroxyl groups, dimethylcyclobutane compound having two acyloxy groups, dimethylcyclobutane compound having two halogen atoms, dimethylcyclobutane compound having phosphonio group and hydroxyl group, dimethylcyclobutane having halogen atom and acyloxy group Examples include compounds.
Examples of the dimethylcyclobutane compound having a hydroxyl group and an alkoxy group include 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol and 2- (3-methoxymethoxymethyl-2,2-dimethyl). 2- (3-alkoxymethyl-) such as cyclobutylidene) propan-1-ol, 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propan-1-ol, etc. Examples thereof include 2,2-dimethylcyclobutylidene) propan-1-ol, 2- [3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutylidene] propan-1-ol compounds (see below). See Examples 11, 12, 13 and 16).
Examples of the dimethylcyclobutane compound having an acyloxy group and an alkoxy group include 2- (3-methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propyl = acetate and 2- [2,2-dimethyl-3- (tetrahydropyran-). 2-Iloxymethyl) cyclobutylidene] 2- (3-alkoxymethyl-2,2-dimethylcyclobutylidene) propyl = acylate compounds such as propyl = acetate can be mentioned (see Examples 20 and 21 below). ).
Examples of the dimethylcyclobutane compound having a halogen atom and an alkoxy group include [3- (2-chloro-1-methylethylidene) -2,2-dimethylcyclobutyl] methoxymethylbenzene and [3- (2-bromo-1-methyl). Ethiliden) -2,2-dimethylcyclobutyl] 1-alkoxymethyl-3- (2-halo2-1methylethylidene) -2,2-dimethylcyclobutane compounds such as methoxymethylbenzene can be mentioned (the following implementation). See Examples 17 and 18).
Examples of the dimethylcyclobutane compound having a phosphonio group and an alkoxy group include 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propyltriphenylphosphonium and the like [2- (3-alkoxymethyl-2,2-). Dimethylcyclobutylidene) propyl] triarylphosphonium compounds and the like (see Example 19 below).
Examples of the dimethylcyclobutane compound having two hydroxyl groups include 2- (3-hydroxyximethyl-2,2-dimethylcyclobutylidene) propane-1-ol (see Examples 14, 15, 22 and 23 below). ).
Examples of the dimethylcyclobutane compound having two acyloxy groups include [3- (2-acetoxy-1-methylethylidene) -2,2-dimethylcyclobutyl] methyl = acetate, (3- [2- (2-methylbutanoyl)). Oxy) -1-methylethylidene] -2,2-dimethylcyclobutyl) Methyl = 2-methylbutanoate and the like [3- (2-acyloxy-1-methylethylidene) -2,2-dimethylcyclobutyl] methyl = Axylate compounds and the like can be mentioned (see Examples 24 and 25 below).
Examples of the dimethylcyclobutane compound having two halogen atoms include 1-halomethyl-3- (2-halo-1) such as 1-chloromethyl-3- (2-chloro-1-methylethylidene) -2,2-dimethylcyclobutane. -Methylethylidene) -2,2-dimethylcyclobutane compounds and the like (see Example 26 below).
Examples of the dimethylcyclobutane compound having a phosphonio group and a hydroxyl group include [2- (3-hydroxymethyl-2,2-) such as triphenyl [2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propyl] phosphonium. Dimethylcyclobutylidene) propyl] triarylphosphonium compounds and the like (see Example 27 below).
Examples of the dimethylcyclobutane compound having a halogen atom and an acyloxy group include [2,2-dimethyl-3- (1-methyl-2-bromoethylidene) cyclobutyl] methyl-acetate and the like [2,2-dimethyl-3- (1). -Methyl-2-haloethylidene) cyclobutyl] methyl = acylate compounds and the like (see Example 28 below).

Examples of the dimethylcyclobutane compound (1) include dimethylcyclobutane compounds represented by the following formulas, in addition to those exemplified above.

[II] Method for Producing Dimethylcyclobutane Compound (1A) Next, a method for producing the dimethylcyclobutane compound (1A) represented by the following two chemical reaction formulas will be described. The production method comprises a reaction between a dimethylcyclobutanone compound represented by the following general formula (2) and a phosphonate ester compound represented by the following general formula (3), particularly an olefination reaction, preferably Horner-Wadsworth Emmons. A step of obtaining an unsaturated ester compound having a dimethylcyclobutanone ring represented by the following general formula (4) by the reaction, and
It includes at least a step of obtaining the dimethylcyclobutane compound (1A) by subjecting the unsaturated ester compound (4) having the dimethylcyclobutane ring described above to a reduction reaction.

First, a step of obtaining the unsaturated ester compound (4) having the above-mentioned dimethylcyclobutane ring from the above-mentioned dimethylcyclobutanone compound (2) will be described.
X ² in the dimethylcyclobutanone compound (2) is as defined above. Dimethyl cyclobutanone compound among the (2), stability and / or after the compounds, certain groups X ² in terms of ease of conversion into another group X ² in defined in selected X ² in the above general The dimethylcyclobutanone compound (2B) represented by the formula (2B) is preferable.
Dimethyl X ¹³ in cyclobutanone compound (2B) is an acyloxy group having 3 to 10 carbon atoms including carbon atoms of carbonyl groups, alkoxycarbonyloxy groups having 2 to 10 carbon atoms including carbon atoms of carbonyl groups, carbon atoms 1 to 10 Alcan sulfonyloxy group, allene sulfonyloxy group having 6 to 20 carbon atoms, alkoxy group having 2 to 12 carbon atoms excluding benzyloxy group, aryloxy group having 6 to 12 carbon atoms, silyloxy group having 3 to 20 carbon atoms. Represent.

Examples of the dimethylcyclobutanone compound (2) include the (S) -form dimethylcyclobutanone compound represented by the following general formula (2-1) and the (R) -form represented by the following general formula (2-2). Included are dimethylcyclobutanone compounds, racemates thereof, and scalemic mixtures.
Specific examples of the dimethylcyclobutanone compound (2) include 3-hydroxymethyl-2,2-dimethylcyclobutanone, (2,2-dimethyl-3-oxocyclobutyl) methyl-acetate, and 3-benzyloxymethyl-2,2. -Dimethylcyclobutanone, 3-methoxymethoxymethyl-2,2-dimethylcyclobutanone, 2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutanone, 3- (1-ethoxyethoxy) methyl-2,2 -Dimethylcyclobutanone, 3- (1-allyloxyethoxy) methyl-2,2-dimethylcyclobutanone, 3-allyloxymethyl-2,2-dimethylcyclobutanone and the like can be mentioned. Stability and / or after the compounds, certain groups X ² in terms of ease of conversion into another group X ² in defined in selected X ² above, dimethyl cyclobutanone compound (2B), 3 −methoxymethoxymethyl-2,2-dimethylcyclobutanone, 2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutanone, 3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutanone, 3 -(1-Allyloxyethoxy) methyl-2,2-dimethylcyclobutanone and 3-allyloxymethyl-2,2-dimethylcyclobutanone are preferred.
As the dimethylcyclobutanone compound (2), one kind or two or more kinds may be used. Further, the dimethylcyclobutanone compound (2) can be produced, for example, as follows. Hereinafter, a hydroxyl group was removed from the definition of X ² in dimethyl cyclobutanone (2), dimethyl cyclobutanone compound (2A), dimethyl cyclobutanone compound (2) X ² is at is hydroxyl 3-hydroxy-2,2-dimethyl-cyclobutanone It will be explained separately.

[III] Dimethylcyclobutane compound (2A)
The dimethylcyclobutane compound (2A) is as described above.

Method for Producing Dimethylcyclobutanone Compound (2A) Next, a method for producing the dimethylcyclobutanone compound (2A) represented by the following chemical reaction formula will be described. The production method is represented by the following general formula (2A) by reacting an acid halide represented by the following general formula (7), an allyl compound represented by the following general formula (8), and a base. , At least includes the step of obtaining a dimethylcyclobutanone compound.
X ⁹ in the acid halide (7) represents a halogen atom. Examples of the halogen atom include a chlorine atom, a bromine atom and an iodine atom.
X ¹² in allyl compounds (8) are as defined above.
Examples of the acyloxy group having 1 to 10 carbon atoms including the carbon of the carbonyl group include a formyloxy group, an acetoxy (AcO) group, a propanoyloxy group, a butanoyloxy group, a pentanoyloxy group, a hexanoyloxy group and a heptanoyl. Linear aliphatic acyloxy groups such as oxy group, octanoyloxy group, nonanoyloxy group, decanoyyloxy group, crotonyloxy group, 2-methylpropanoyloxy group, pivaloyloxy group, 2-methylbutanoyloxy group, Branched aliphatic acyloxy groups such as 3-methyl-2-butenoyloxy group and 3-methyl-3-butenoyloxy group, halogenated acyloxy groups such as trichloroacetoxy group and trifluoroacetoxy group, aromatic acyloxy groups such as benzoyloxy group. Examples thereof include an acyloxy group having an isomer relationship with these.
Further, a part of hydrogen atoms of these acyloxy groups may be substituted with a methyl group, an ethyl group, a halogen atom or the like. Examples of the acyloxy group having 1 to 10 carbon atoms including the carbon of the carbonyl group are formyloxy group, acetoxy group, propanoyloxy group, pivaloyloxy group and 2-methylbutanoyloxy as particularly preferable examples from the viewpoint of easy availability. Groups, benzoyloxy groups and the like can be mentioned.

Examples of the alkoxycarbonyloxy group having 2 to 10 carbon atoms including the carbon of the carbonyl group include methoxycarbonyloxy group, ethoxycarbonyloxy group, n-propoxycarbonyloxy group, n-butoxycarbonyloxy group and n-pentyloxycarbonyloxy. Linear saturated alkoxycarbonyl such as group, n-hexyloxycarbonyloxy group, n-heptyloxycarbonyloxy group, n-octyloxycarbonyloxy group, n-nonyloxycarbonyloxy group, n-decyloxycarbonyloxy group. Linear unsaturated alkoxy such as branched saturated alkoxycarbonyloxy group such as oxy group, isopropoxycarbonyloxy group and t-butoxycarbonyloxy group, 2-propenyloxycarbonyloxy group and 2-propynyloxycarbonyloxy group. Branched unsaturated alkoxycarbonyloxy group such as carbonyloxy group, 2-methyl-2-propenyloxycarbonyloxy group, cyclopropyloxycarbonyloxy group, 2-methylcyclopropyloxycarbonyloxy group, cyclobutyloxycarbonyloxy group , Cyclopentyloxycarbonyloxy group and other cyclic alkoxycarbonyloxy groups, benzyloxycarbonyloxy group, paramethoxybenzyloxycarbonyloxy group and other aromatic ring-containing alkoxycarbonyloxy groups, methoxymethoxycarbonyloxy groups, benzyloxymethoxycarbonyloxy Examples thereof include an oxyalkoxycarbonyloxy group such as a paramethoxybenzyloxymethoxycarbonyloxy group and a halogenated alkoxycarbonyloxy group such as a 2,2,2-trichloroethoxycarbonyloxy group, which are isomers. It may be an alkoxycarbonyloxy group. Further, some of the hydrogen atoms of these alkoxycarbonyloxy groups may be substituted with methyl groups, ethyl groups, halogen atoms and the like. Examples of the alkoxycarbonyloxy group having 2 to 10 carbon atoms including the carbon of the carbonyl group include a methoxycarbonyloxy group, an ethoxycarbonyloxy group, an n-propoxycarbonyloxy group and the like from the viewpoint of easy availability. Can be mentioned.

Examples of the alkanesulfonyloxy group having 1 to 10 carbon atoms include a methanesulfonyloxy (MsO) group, an ethanesulfonyloxy group, a 1-butanesulfonyloxy group, a 1-pentanesulfonyloxy group, a 1-hexanesulfonyloxy group, and a 1-heptane. Sulfonyl oxy group, 1-octane sulfonyl oxy group, 1-nonane sulfonyl oxy group, 1-decane sulfonyl oxy group, allyl sulfonyl oxy group, 10-campa-sulfonyl oxy group, trifluoromethane sulfonyl oxy group, α-benzyl sulfonyl oxy group Etc., and an alkanesulfonyloxy group having an isomer relationship with these may be used.
Further, some of the hydrogen atoms of these alkanesulfonyloxy groups may be substituted with methyl groups, ethyl groups, halogen atoms and the like. Examples of the alkanesulfonyloxy group having 1 to 10 carbon atoms include a methanesulfonyloxy group and an ethanesulfonyloxy group from the viewpoint of easy availability.

Examples of the arene sulfonyloxy group having 6 to 20 carbon atoms include a benzenesulfonyloxy group, a 4-chlorobenzenesulfonyloxy group, a 4-methoxybenzenesulfonyloxy group, a 2-nitrobenzenesulfonyloxy group, and a 2,4,6-trimethylbenzenesulfonyloxy group. Examples thereof include a group, a paratoluenesulfonyloxy (TsO) group, a 1-naphthalenesulfonyloxy group, and a 2-naphthalenesulfonyloxy group, and an allenesulfonyloxy group having an isomer relationship with these may be used. Further, some of the hydrogen atoms of these arene sulfonyloxy groups may be substituted with methyl groups, ethyl groups, halogen atoms and the like. Examples of the arene sulfonyl oxy group having 6 to 20 carbon atoms include a benzenesulfonyl oxy group and a paratoluenesulfonyl oxy group from the viewpoint of easy availability.

Examples of the alkoxy group having 1 to 12 carbon atoms include a methoxy (MeO) group, an ethoxy (EtO) group, an n-propoxy (PrO) group, an n-butoxy (BuO) group, an n-pentyloxy (PenO) group, and n-. Hexyloxy (HexO) group, n-heptyloxy (HepO) group, n-octyloxy (OctO) group, n-nonyloxy (NonO) group, n-decyloxy (DecO) group, n-undecyloxy group, n- Linear saturated alkoxy group such as dodecyloxy group, branched saturated alkoxy group such as isopropoxy group (i-PrO), isobutyloxy group (i-BuO), t-butoxy (t-BuO) group, 2 -Linear unsaturated alkoxy groups such as propenyloxy group and 2-propynyloxy group, branched unsaturated alkoxy groups such as 2-methyl-2-propenyloxy group, cyclopropyloxy group, 2-methylcyclopropyl Cyclic alkoxy group such as oxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy (c-HexO) group, alkoxy group containing aromatic ring such as benzyloxy (BnO) group, paramethoxybenzyloxy group, methoxymethoxy (MOMO) group, 2-methoxyethoxymethoxy group, benzyloxymethoxy group, paramethoxybenzyloxymethoxy group, 1-ethoxyethoxy (EEO) group, 1-allyloxyethoxy group, tetrahydropyran-2-yloxy (THPO) group Oxyalkoxy groups such as, 2,2,2-trichloroethoxy group, halogenated alkoxy groups such as pentafluoroethoxy group, and the like, and alkoxy groups having an isomer relationship with these may be used. Further, some of the hydrogen atoms of these alkoxy groups may be substituted with methyl groups, ethyl groups, halogen atoms and the like.

Examples of the alkoxy group having 1 to 12 carbon atoms are particularly preferable from the viewpoint of ease of preparation and the like, as methoxy group, ethoxy group, 2-propenyloxy group, methoxymethoxy group, 1-ethoxyethoxy group and 1-allyloxy. Examples thereof include an ethoxy group and a tetrahydropyran-2-yloxy group.

Examples of the aryloxy group having 6 to 12 carbon atoms include a phenoxy (PhO) group, a 4-chlorophenoxy group, a 4-methoxyphenoxy group, a naphthoxy group, a 4-biphenyloxy group, and the like. It may be an aryloxy group. Further, a part of the hydrogen atoms of these aryloxy groups may be substituted with a methyl group, an ethyl group, a halogen atom or the like. Examples of the aryloxy group having 6 to 12 carbon atoms are particularly preferable from the viewpoint of easy availability, such as a phenoxy group and a naphthoxy group.

Examples of the silyloxy group having 3 to 20 carbon atoms include a trialkylsilyl group such as a trimethylsilyloxy (TMSO) group, a triethylsilyloxy (TESO) group, a triisopropylsilyloxy (TIPSO) group and a t-butyldimethylsilyloxy (TBSO) group. Examples thereof include a monoalkyldiarylsilyloxy group such as an oxy group and a t-butyldiphenylsilyloxy (TBDPSO) group, and a silyloxy group having an isomer relationship with these may be used. Further, a part of hydrogen atoms of these silyloxy groups may be substituted with a methyl group, an ethyl group, a halogen atom or the like. Examples of the silyloxy group having 3 to 20 carbon atoms include a trimethylsilyloxy group, a triethylsilyloxy group, a triisopropylsilyloxy group, a t-butyldimethylsilyloxy group and the like, as particularly preferable examples from the viewpoint of easy availability.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Chlorine atom and bromine atom are particularly preferable examples from the viewpoint of easy availability.
As the allyl compound (8), one kind or two or more kinds may be used. Further, the allyl compound (8) may be a commercially available compound, or may be an independently synthesized compound.
The amount of the allyl compound (8) used is preferably 0.2 to 100.0 mol, more preferably 0.4 to 50.0 mol, still more preferably 0.6 to 25, based on 1 mol of the acid halide (7). It is 0.0 mol.

Examples of the base used in the above reaction include metal hydrides such as sodium hydride, potassium hydride and calcium hydride, triethylamine, diisopropylethylamine, tributylamine, N, N-dimethylaniline, N, N-diethylaniline and pyridine. , 4-Dimethylaminopyridine, imidazole, quinoline, pyrrolidine, piperidine, colidin, rutidin, morpholin, 1,8-diazabicyclo [5.4.0] -7-undecene and other organic base compounds.
The base may be used alone or in combination of two or more. Further, as the base, a commercially available one can be used.
The amount of the base used is preferably 0.7 to 5.0 mol, more preferably 0.8 to 4.0 mol, and further preferably 0.9 to 3.0 mol with respect to 1 mol of the acid halide (7). is there.
The above reaction can be carried out in the absence of a solvent or in the presence of a solvent.
Examples of the solvent in the above reaction include ethers such as diethyl ether, dibutyl = ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride and chloroform. Chlorine-based solvents such as trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, acetonitrile, propio Examples thereof include nitriles such as nitriles and esters such as ethyl acetate and n-butyl acetate.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 0 to 10,000 g with respect to 1 mol of the acid halide (7).

The reaction temperature in the above reaction is preferably 40 to 200 ° C, more preferably 50 to 190 ° C, and even more preferably 60 to 180 ° C.
The reaction time in the above reaction can be set arbitrarily, but it is desirable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 72 hours.

Further, after obtaining the cyclobutanone compound (2A) by the above reaction, the specific group X ¹² can be converted into another group, a hydroxyl group, and used. For example, when X ¹² is a 1-ethoxyethoxy group, it is possible to convert X ¹² to a hydroxyl group by acid hydrolysis.

R ¹ and R ² in the phosphonic acid ester compound (3) independently represent monovalent hydrocarbon groups having 1 to 10 carbon atoms. The carbon number of R ¹ and R ² is 1 to 10, preferably 1 to 5.
Examples of the monovalent hydrocarbon group include methyl (Me) group, ethyl (Et) group, n-propyl (Pr) group, n-butyl (Bu) group, n-pentyl (Pen) group and n-hexyl (n-hexyl). Linear saturated hydrocarbon groups such as Hex) group, n-heptyl (Hep) group, n-octyl (Oct) group, n-nonyl (Non) group, n-decyl (Dec) group, isopropyl (i-) Branched saturated hydrocarbon groups such as Pr) group, sec-butyl group, isobutyl (i-Bu) group and t-butyl (t-Bu) group, linear chain such as 2-propenyl group and 2-propynyl group. Bifurcated unsaturated hydrocarbon group such as unsaturated hydrocarbon group, 2-methyl-2-propenyl group, cyclopropyl group, 2-methylcyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl (c-Hex) group. Examples thereof include cyclic hydrocarbon groups such as, phenyl (Ph) group, 2-methylphenyl group, 4-methylphenyl group and other aromatic hydrocarbon groups, and hydrocarbon groups having an isomer relationship with these may be used.
Further, a part of hydrogen atoms of these monovalent hydrocarbon groups may be substituted with a methyl group, an ethyl group, a halogen atom or the like. Examples of the halogen atom include a chlorine atom, a bromine atom and an iodine atom.
Considering the availability of the phosphonic acid ester compound (3), particularly preferable examples of R ¹ and R ² are methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and sec-butyl group. , Isobutyl group, t-butyl group and the like, more particularly preferable examples include methyl group, ethyl group, n-propyl group and the like.
Examples of the phosphonate ester compound (3) include triethyl 2-phosphonopropionate and the like.

As the phosphonic acid ester compound (3), one kind or two or more kinds may be used. Further, the phosphonate ester compound (3) may be a commercially available compound, or may be an independently synthesized compound. For example, the phosphonic acid ester compound (3) can be synthesized by an Arbuzov reaction between a phosphite ester and a 2-bromopropionic acid ester.
The amount of the phosphonic acid ester compound (3) used is preferably 0.7 to 5.0 mol, more preferably 0.8 to 4.0 mol, still more preferably 0.9, based on 1 mol of the dimethylcyclobutanone compound (2). It is ~ 3.0 mol.

The bases used in the above reaction include sodium = methoxydo, sodium = ethoxydo, sodium = t-butoxide, sodium = t-amyloxide, lithium = methoxydo, lithium = ethoxydo, lithium = t-butoxide, lithium = t-amyloxide, potassium. = Methylamide, potassium = ethoxydo, potassium = t-butoxide, potassium = t-amyloxide and other alkoxides, methyllithium, ethyllithium, n-butyllithium, methylmagnesium chloride, diisopropylsodium and other organic metal compounds, sodium = amide , Lithium = amide, lithium = diisopropylamide, lithium = hexamethyldisilazide, sodium = hexamethyldisilazide, potassium = hexamethyldisilazide, lithium = dicyclohexylamide and other metal amides, sodium hydride, hydrogenation Metal hydrides such as potassium and calcium hydride, triethylamine, diisopropylethylamine, tributylamine, N, N-dimethylaniline, N, N-diethylaniline, pyridine, 4-dimethylaminopyridine, imidazole, quinoline, pyrrolidine, piperidine, Examples thereof include organic base compounds such as colisine, lutidine, morpholine, and 1,8-diazabicyclo [5.4.0] -7-undecene.
The base may be used alone or in combination of two or more. Further, as the base, a commercially available one can be used.
The amount of the base used is preferably 0.7 to 5.0 mol, more preferably 0.8 to 4.0 mol, still more preferably 0.9 to 3.0 mol, based on 1 mol of the phosphonate ester compound (3). Is.

The above reaction may be carried out in the presence of Lewis acid.
Examples of the Lewis acid include lithium halide such as lithium chloride, lithium bromide and lithium iodide.
The Lewis acid may be used alone or in combination of two or more. Further, as the Lewis acid, a commercially available one can be used.
The amount of the Lewis acid used is preferably 0.7 to 5.0 mol, more preferably 0.8 to 4.0 mol, and even more preferably 0.9 to 3 mol with respect to 1 mol of the phosphonic acid ester compound (3). It is 0 mol.

Examples of the solvent in the above reaction include ethers such as diethyl = ether, dibutyl = ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride and chloroform. Chlorine-based solvents such as trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, acetonitrile, propio Examples thereof include nitriles such as nitriles, esters such as ethyl acetate and n-butyl acetate, alcohols such as methanol, ethanol and t-butyl alcohol, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 10,000 g with respect to 1 mol of the dimethylcyclobutanone compound (2).

The reaction temperature in the above reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the above reaction can be set arbitrarily, but it is desirable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

Examples of the unsaturated ester compound (4) having a dimethylcyclobutane ring include an unsaturated ester compound having a (S, Z) -form dimethylcyclobutane ring represented by the following general formula (4-1) and the following general formula (4). An unsaturated ester compound having a (R, Z) -form dimethylcyclobutane ring represented by -2) and a (S, E) -form dimethylcyclobutane ring represented by the following general formula (4-3). An unsaturated ester compound, an unsaturated ester compound having a (RE) -form dimethylcyclobutane ring represented by the following general formula (4-4), and a racemic mixture, a diastereomeric mixture, and a scalemic mixture thereof Can be mentioned.
Examples of the unsaturated ester compound (4) having a dimethylcyclobutane ring include ethyl = 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propanoate and ethyl = 2- (3-acetoxymethyl-2,). 2-Dimethylcyclobutylidene) propanoate, ethyl = 2- (3-methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propanoate, ethyl = 2- [2,2-dimethyl-3- (tetrahydropyran-2-) Iloxymethyl) cyclobutylidene] compound, ethyl = 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) compound, ethyl = 2- [3- (1-ethoxyethoxy) methyl-2,2 -Dimethylcyclobutylidene] Propanoate and the like.

Next, a step of obtaining the above-mentioned dimethylcyclobutane compound (1A) from the above-mentioned unsaturated ester compound (4) having a dimethylcyclobutane ring will be described.
^{X 3} in dimethylcyclobutane compound (1A) is a hydroxyl group, alkanesulfonyloxy group having 1 to 10 carbon atoms, arenesulfonyl group having 6 to 20 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, 6 to 12 carbon atoms It represents an aryloxy group, a silyloxy group having 3 to 20 carbon atoms, or a halogen atom. As these groups and halogen atoms, the above-mentioned X ¹ and X ² are an alkane sulfonyloxy group having 1 to 10 carbon atoms, an arene sulfonyloxy group having 6 to 20 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, and a carbon number of carbon atoms. Examples thereof include the above-mentioned groups exemplified when it is an aryloxy group of 6 to 12, a silyloxy group having 3 to 20 carbon atoms, and a halogen atom.
In the above reduction reaction, when X ^{2 of the} unsaturated ester compound (4) having a dimethylcyclobutane ring is maintained, X ² and X ³ after the reaction are the same, while X ² is not maintained. X ² and X ³ after the reaction are different.
Examples of the reducing agent used in the reduction reaction include alkylborane compounds such as hydrogen, borane and bis (3-methyl-2-butyl) borane, alkylsilane compounds such as triethylsilane, metal hydrides such as aluminum hydride, and hydrogenation. Alkyl metal hydrides such as diisobutylaluminum, sodium hydride, lithium hydride, potassium hydride, boron hydride, calcium hydride, trimethoxyborone, lithium hydride, lithium aluminum hydride, hydrogenation Complex hydrides such as lithium aluminum, lithium hydride trimethoxyaluminum, lithium hydride diethoxyaluminum lithium, tritert-butoxyaluminum hydride, sodium hydride bis (2-methoxyethoxy) aluminum and their alkoxy or alkyl derivatives And so on.
The reducing agent may be used alone or in combination of two or more. Moreover, as the reducing agent, a commercially available one can be used.
The amount of the reducing agent used is preferably 3.5 to 100.0 mol, more preferably 3.6 to 20.0 mol, in terms of hydride with respect to 1 mol of the unsaturated ester compound (4) having a dimethylcyclobutane ring. More preferably, it is 3.7 to 15.0 mol.

Solvents used in the reduction reaction include ethers such as diethyl = ether, dibutyl = ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride and chloroform. Chlorine-based solvents such as trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, acetonitrile, propio Examples thereof include nitriles such as nitriles, esters such as ethyl acetate and n-butyl acetate, alcohols such as methanol, ethanol and t-butyl alcohol, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 20,000 g with respect to 1 mol of the unsaturated ester compound (4) having a dimethylcyclobutane ring.

The reaction temperature in the reduction reaction is preferably −78 to 180 ° C., more preferably −78 to 160 ° C., and even more preferably −78 to 140 ° C.
The reaction time in the reduction reaction can be set arbitrarily, but it is desirable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and usually 0. It takes about 5 to 24 hours.

Examples of the dimethylcyclobutane compound (1A) include those exemplified in the above-mentioned dimethylcyclobutane compound (1).

[IV] Method for Producing Dimethylcyclobutane Compound (1B) Next, a method for producing the above-mentioned dimethylcyclobutane compound (1B) represented by the following chemical reaction formula will be described. The production method, by converting the hydroxyl group of the dimethyl cyclobutane compound of above (1A), and optionally X ^3, and comprises at least the step of obtaining dimethyl cyclobutane compound (1B).

X ⁴ is carbonyl acyloxy group having 1 to 10 carbon atoms including carbon atoms of the group, alkoxycarbonyloxy group having 2 to 10 carbon atoms including carbon atoms of carbonyl groups, alkanesulfonyloxy group having 1 to 10 carbon atoms, carbon Alane sulfonyloxy group having 6 to 20, an alkoxy group having 1 to 12 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, a silyloxy group having 3 to 20 carbon atoms, a trialkylphosphonio group having 3 to 30 carbon atoms, It represents a triarylphosphonio group or a halogen atom having 12 to 30 carbon atoms. As these groups and halogen atoms, the above-mentioned X ¹ and X ² are acyloxy groups having 1 to 10 carbon atoms including the carbon of the carbonyl group, and alkoxycarbonyloxy groups having 2 to 10 carbon atoms including the carbon of the carbonyl group. , Alcan sulfonyloxy group having 1 to 10 carbon atoms, allene sulfonyloxy group having 6 to 20 carbon atoms, alkoxy group having 1 to 12 carbon atoms, aryloxy group having 6 to 12 carbon atoms, silyloxy group having 3 to 20 carbon atoms. , A trialkylphosphonio group having 3 to 30 carbon atoms, a triarylphosphonio group having 12 to 30 carbon atoms, and the above-mentioned groups exemplified in the case of a halogen atom can be mentioned.
X ⁵ is the same as X ² above.
In the above conversion reaction, when X ³ of the dimethylcyclobutane compound (1A) is maintained, X ³ and X ⁵ after the reaction are the same, while when X ³ is not maintained, X ³ and after the reaction. X ⁵ is different.

The above conversion reaction can be carried out by a known method.

The dimethylcyclobutane compound having an acyloxy group and an alkoxy group represented by the following general formula (1D) is a dimethyl having a hydroxyl group and an alkoxy group represented by the following general formula (1C) as shown by the following chemical reaction formula. It can be produced by an acylation reaction between a cyclobutane compound and an acylating agent (see Examples 20 and 21 below).
X ⁷ dimethylcyclobutane compound having a hydroxyl group and an alkoxy group (1C) and dimethyl cyclobutane compound having an acyloxy group and an alkoxy group in (1D) represents an alkoxy group having 1 to 12 carbon atoms. Examples of the alkoxy group having 1 to 12 carbon atoms include the above-mentioned groups exemplified when the above-mentioned X ¹ and X ² are alkoxy groups having 1 to 12 carbon atoms.
X ⁸ represents an acyloxy group having 1 to 10 carbon atoms including the carbon of the carbonyl group. As the acyloxy group having 1 to 10 carbon atoms including the carbon of the carbonyl group, the above-mentioned group exemplified when the above-mentioned X ¹ and X ² are the acyl oxy groups having 1 to 10 carbon atoms including the carbon of the carbonyl group is used. Can be mentioned.
Examples of the acylating agent include acid anhydrides such as acetic anhydride, propionic anhydride, butanoic anhydride and 2-methylbutanoic anhydride, and acid anhydrides such as acetyl chloride, propionyl chloride, butanoyl chloride and 2-methylbutanoyl chloride. Can be mentioned.
One kind or two or more kinds of acylating agents may be used. Moreover, as the acylating agent, a commercially available one can be used.
The amount of the acylating agent used is preferably 0.7 to 100 mol, more preferably 0.8 to 50 mol, still more preferably 0, based on 1 mol of the hydroxyl group of the dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group. It is 9 to 20 mol.
The bases used in the acyl reaction include sodium = methoxydo, sodium = ethoxydo, sodium = t-butoxide, sodium = t-amyloxide, lithium = methoxydo, lithium = ethoxydo, lithium = t-butoxide, lithium = t-amyloxide, potassium =. Alkoxides such as methoxydo, potassium = ethoxydo, potassium = t-butoxide, potassium = t-amyloxide, organic metal compounds such as methyllithium, ethyllithium, n-butyllithium, methylmagnesium chloride, and dimethylsodium, sodium = amide, Metal amides such as lithium = amide, lithium = diisopropylamide, lithium = hexamethyldisilazide, sodium = hexamethyldisilazide, potassium = hexamethyldisilazide, lithium = dicyclohexylamide, sodium hydride, potassium hydride , Metals hydrides such as calcium hydride, triethylamine, diisopropylethylamine, tributylamine, N, N-dimethylaniline, N, N-diethylaniline, pyridine, 4-dimethylaminopyridine, imidazole, quinoline, pyrrolidine, piperidine, colisine. , Lucidine, morpholine, organic base compounds such as 1,8-diazabicyclo [5.4.0] -7-undecene and the like.
The base may be used alone or in combination of two or more. Further, as the base, a commercially available one can be used.
The amount of the base used is preferably 0.8 to 110 mol, more preferably 0.9 to 60 mol, and further preferably 1 to 30 mol with respect to 1 mol of the hydroxyl group of the dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group. is there.

Solvents in the acylation reaction include ethers such as diethyl ether, dibutyl ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride and chloroform. Chlorine-based solvents such as trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, acetonitrile, propio Examples thereof include nitriles such as nitrile, esters such as ethyl acetate and n-butyl acetate, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 10,000 g with respect to 1 mol of the dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group.

The reaction temperature in the acylation reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the acylation reaction can be set arbitrarily, but it is preferable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

The dimethylcyclobutane compound having two acyloxy groups represented by the following general formula (1F) is a dimethylcyclobutane compound having two hydroxyl groups represented by the following formula (1E) as shown by the following chemical reaction formula. And can be produced by an acylation reaction with an acylating agent (see Examples 24 and 25 below).
X ⁸ represents an acyloxy group having 1 to 10 carbon atoms including the carbon of the carbonyl group. As the acyloxy group having 1 to 10 carbon atoms including the carbon of the carbonyl group, the above-mentioned group exemplified when the above-mentioned X ¹ and X ² are the acyl oxy groups having 1 to 10 carbon atoms including the carbon of the carbonyl group is used. Can be mentioned.
The acylation reaction can be carried out in the same manner as the above-mentioned step of obtaining a dimethylcyclobutane compound (1D) having an acyloxy group and an alkoxy group.

The dimethylcyclobutane compound having a halogen atom and an alkoxy group represented by the following general formula (1G) is the above-mentioned dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group and a halogen as shown by the following chemical reaction formula. It can be produced by a halogenation reaction between the source and a phosphine compound, or by a halogenation reaction between the above-mentioned dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group and a sulfonyl halide compound (Examples 17 and 18 below). See).
X ⁷ in the dimethylcyclobutane compound (1G) having a halogen atom and an alkoxy group is as defined above.
X ⁹ represents a halogen atom. Examples of the halogen atom include a chlorine atom, a bromine atom and an iodine atom.
First, a halogenation reaction using a halogen source and a phosphine compound will be described (see Example 18 below).
Examples of the halogen source include carbon tetrachloride compounds such as carbon tetrachloride and carbon tetrabromide, and simple halogens such as bromine and iodine.
One kind or two or more kinds of halogen sources may be used. Moreover, as the halogen source, a commercially available one can be used.
The amount of the halogen source used is preferably 0.7 to 1000 mol, more preferably 0.8 to 500 mol, still more preferably 0.9, based on 1 mol of the hydroxyl group of the dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group. ~ 200 mol.
Examples of the phosphine compound include a triarylphosphine compound such as triphenylphosphine and a trialkylphosphine compound such as trioctylphosphine.
The amount of the phosphine compound used is preferably 1.4 to 20.0 mol, more preferably 1.4 to 16 mol, still more preferably 1.5, based on 1 mol of the dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group. ~ 14 mol.
The phosphine compound may be used alone or in combination of two or more. Moreover, as the phosphine compound, a commercially available one can be used.
The above halogenation reaction may be carried out in the presence of a base.
Examples of the base include triethylamine, diisopropylethylamine, tributylamine, N, N-dimethylaniline, N, N-diethylaniline, pyridine, 4-dimethylaminopyridine, imidazole, quinoline, pyrrolidine, piperidine, colidin, lutidine, morpholine, 1 , 8-Diazabicyclo [5.4.0] -7-Undecene and other organic base compounds can be mentioned.
The base may be used alone or in combination of two or more. Further, as the base, a commercially available one can be used.
The amount of the base used is preferably 0 to 1000 mol, more preferably 0 to 500 mol, and further preferably 0 to 200 mol with respect to 1 mol of the hydroxyl group of the dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group.
Examples of the solvent in the above halogenation reaction include ethers such as diethyl = ether, dibutyl = ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, and methylene chloride. Chlorine-based solvents such as chloroform, carbon tetrachloride and trichloroethylene, aprotonic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide and hexamethylphosphoric triamide. Examples include nitriles such as acetonitrile and propionitrile, and esters such as ethyl acetate and n-butyl acetate.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 0 to 20,000 g with respect to 1 mol of the dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group.

The reaction temperature in the halogenation reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the halogenation reaction can be set arbitrarily, but it is preferable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

Next, a halogenation reaction using a sulfonyl halide compound will be described (see Example 17 below).
Examples of the sulfonyl halide compound include an allenesulfonyl = halide compound such as paratoluenesulfonyl chloride and benzenesulfonyl chloride, an alkanesulfonyl = halide compound such as methanesulfonyl chloride, and thionyl chloride.
The sulfonyl halide compound may be used alone or in combination of two or more. Moreover, as the sulfonyl halide compound, a commercially available one can be used.
The amount of the sulfonyl halide compound used is preferably 0.7 to 1000 mol, more preferably 0.8 to 500 mol, still more preferably 0, based on 1 mol of the hydroxyl group of the dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group. It is 9 to 200 mol.
The above halogenation reaction may be carried out in the presence of a base.
Examples of the base include triethylamine, diisopropylethylamine, tributylamine, N, N-dimethylaniline, N, N-diethylaniline, pyridine, 4-dimethylaminopyridine, imidazole, quinoline, pyrrolidine, piperidine, colidin, lutidine, morpholine, 1 , 8-Diazabicyclo [5.4.0] -7-Undecene and other organic base compounds can be mentioned.
The base may be used alone or in combination of two or more. Further, as the base, a commercially available one can be used.
The amount of the base used is preferably 0 to 1000 mol, more preferably 0 to 500 mol, and further preferably 0 to 200 mol with respect to 1 mol of the hydroxyl group of the dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group.

Solvents in the halogenation reaction include ethers such as diethyl = ether, dibutyl = ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride, chloroform, etc. Chlorine-based solvents such as carbon tetrachloride and trichloroethylene, aprotonic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, hexamethylphosphoric = triamide, Examples thereof include nitriles such as acetonitrile and propionitrile, and esters such as ethyl acetate and n-butyl acetate.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 10,000 g with respect to 1 mol of the dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group.

The reaction temperature in the halogenation reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the halogenation reaction can be set arbitrarily, but it is preferable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

The dimethylcyclobutane compound having two halogen atoms represented by the following general formula (1H) is the above-mentioned dimethylcyclobutane compound (1E) having two hydroxyl groups, a halogen source and phosphine as shown by the following chemical reaction formula. It can be produced by a halogenation reaction with a compound (see Example 26 below).
X ⁹ is as defined above.
The halogenation reaction can be carried out in the same manner as the above-mentioned step of obtaining a dimethylcyclobutane compound (1G) having a halogen atom and an alkoxy group.

The dimethylcyclobutane compound having a phosphonio group and a hydroxyl group represented by the following general formula (1I) is the above-mentioned dimethylcyclobutane compound (1E) having two hydroxyl groups and hydrogen phosphine halide as shown by the following chemical reaction formula. It can be produced by a phosphonization reaction with a salt (see Example 27 below).
X ¹⁰ represents a trialkylphosphonio group having 3 to 30 carbon atoms or a triarylphosphonio group having 12 to 30 carbon atoms. Examples of the trialkylphosphonio group having 3 to 30 carbon atoms include the above-mentioned groups exemplified when the above-mentioned X ¹ and X ² are trialkylphosphonio groups having 3 to 30 carbon atoms. Examples of the triarylphosphonio group having 12 to 30 carbon atoms include the above-mentioned groups exemplified when the above-mentioned X ¹ and X ² are triarylphosphonio groups having 12 to 30 carbon atoms. X ¹⁰ is derived from the phosphine hydrohalide used in the phosphonization reaction.
Examples of the phosphine hydrohalide include triphenylphosphine hydrogen chloride salt, triphenylphosphine hydrogen bromide salt, triphenylphosphine hydrogen iodide salt and the like.
The amount of the phosphine hydrohalide used is preferably 0.7 to 10.0 mol, more preferably 0.8 to 8.0 mol, more preferably 0.8 to 8.0 mol, based on 1 mol of the dimethylcyclobutane compound (1E) having two hydroxyl groups. Is 0.9 to 6.0 mol.
The phosphine hydrohalide may be used alone or in combination of two or more. Further, as the phosphine hydrohalide salt, a commercially available one can be used.
Solvents in the phosphonization reaction include ethers such as diethyl = ether, dibutyl = ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride, chloroform, etc. Chlorine-based solvents such as trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, acetonitrile, propio Examples thereof include nitriles such as nitriles, esters such as ethyl acetate and n-butyl acetate, alcohols such as methanol, ethanol and t-butyl alcohol, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 10,000 g with respect to 1 mol of the dimethylcyclobutane compound (1E) having two hydroxyl groups.

The reaction temperature in the phosphonization reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the phosphonization reaction can be set arbitrarily, but it is preferable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

It is also possible to convert the substituents (that is, X ⁴ and X ⁵ ) in the above-mentioned dimethylcyclobutane compound (1B) into other groups in multiple stages.

The dimethylcyclobutane compound having two hydroxyl groups represented by the following general formula (1E) is a desorption of the above-mentioned dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group and an acid as shown by the following chemical reaction formula. It can be produced by a protective reaction (see Example 22 below). Then, the hydroxyl group in the dimethylcyclobutane compound (1E) having two hydroxyl groups can be subjected to a conversion reaction such as acylation, halogenation, and phosphonization.
Acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or salts thereof, formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, and benzene. Organic acids such as sulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid or salts thereof, lithium tetrafluoroborate, boron trifluoride, boron trichloride, boron tribromide, aluminum trichloride, zinc chloride, bromide Luis acids such as zinc, zinc iodide, tin tetrachloride, tin tetrabromide, tin dichloride, titanium tetrachloride, titanium tetrabromide, trimethyliodosilane, oxides such as alumina, silica gel and titania, and minerals such as montmorillonite. And so on.
The acid may be used alone or in combination of two or more. Moreover, as the acid, a commercially available one can be used.
The amount of the acid used is preferably 0.00001 to 10,000 mol, more preferably 0.0001 to 1,000 mol, and even more preferably 0, with respect to 1 mol of the dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group. It is 001 to 100 mol.
Solvents in the deprotection reaction include ethers such as diethyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride, chloroform, etc. Chlorine-based solvents such as trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, acetonitrile, propio Examples thereof include nitriles such as nitrile, esters such as ethyl acetate and n-butyl acetate, alcohols such as methanol, ethanol and t-butyl alcohol, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 10,000 g with respect to 1 mol of the dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group.
The reaction temperature in the deprotection reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the deprotection reaction can be set arbitrarily, but it is desirable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

The dimethylcyclobutane compound having a halogen atom and an acyloxy group represented by the following general formula (1J) is the above-mentioned dimethylcyclobutane compound (1F) having two acyloxy groups and a halogen as shown by the following chemical reaction formula. It can be produced by a halogenation reaction with a hydrogen halide compound (see Example 28 below).
X ⁸ and X ⁹ are as defined above.
Examples of the hydrogen halide compound include hydrogen chloride, hydrogen bromide, hydrogen iodide and the like.
The hydrogen halide compound may be used alone or in combination of two or more. Moreover, as the hydrogen halide compound, a commercially available one can be used.
The amount of the hydrogen halide compound used is preferably 0.7 to 10 mol, more preferably 0.8 to 8 mol, still more preferably 0.9, based on 1 mol of the dimethylcyclobutane compound (1F) having two acyloxy groups. ~ 6 mol.
Solvents in the halogenation reaction include ethers such as diethyl = ether, dibutyl = ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride, chloroform, etc. Chlorine-based solvents such as carbon tetrachloride and trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, Examples thereof include nitriles such as acetonitrile and propionitrile, esters such as ethyl acetate and n-butyl acetate, carboxylic acids such as formic acid, acetic acid and propionic acid, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 10,000 g with respect to 1 mol of the dimethylcyclobutane compound (1F) having two acyloxy groups.

The reaction temperature in the halogenation reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the halogenation reaction can be set arbitrarily, but it is preferable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

The dimethylcyclobutane compound having a phosphonio group and an alkoxy group represented by the following general formula (1K) is the above-mentioned dimethylcyclobutane compound (1G) having a halogen atom and an alkoxy group and phosphine as shown by the following chemical reaction formula. It can be produced by a phosphonization reaction with a compound (see Example 19 below).
X ^{7, X 10} is as defined above.
Examples of the phosphine compound include a triarylphosphine compound such as triphenylphosphine and a trialkylphosphine compound such as trioctylphosphine.
The amount of the phosphine compound used is preferably 0.7 to 10.0 mol, more preferably 0.8 to 8.0 mol, still more preferably 0.8 to 1 mol, based on 1 mol of the dimethylcyclobutane compound (1G) having a halogen atom and an alkoxy group. It is 0.9 to 6.0 mol.
Solvents in the phosphonization reaction include ethers such as diethyl = ether, dibutyl = ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride, chloroform, etc. Chlorine-based solvents such as trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, acetonitrile, propio Examples thereof include nitriles such as nitriles, esters such as ethyl acetate and n-butyl acetate, alcohols such as methanol, ethanol and t-butyl alcohol, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 10,000 g with respect to 1 mol of the dimethylcyclobutane compound (1G) having a halogen atom and an alkoxy group.
The reaction temperature in the phosphonization reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the phosphonization reaction can be set arbitrarily, but it is preferable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

Examples of the dimethylcyclobutane compound (1B) include the compounds exemplified in the above-mentioned dimethylcyclobutane compound (1). However, the case where X ¹ is a hydroxyl group in the dimethylcyclobutane compound (1) is excluded.

When X ¹ is a hydroxyl group and X ² is an acyloxy group or an alkoxycarbonyloxy group in the dimethylcyclobutane compound (1), for example, X ¹ and X ² are an acyloxy group or an alkoxycarbonyloxy group. Examples thereof include a method of converting X ¹ into a hydroxyl group by hydrolysis of the dimethylcyclobutane compound (1).

[V] Method for Producing Isopropenyldimethylcyclobutane Compound (5) and / or Isopropylidenedimethylcyclobutane Compound (6) Next, isopropenyldimethyl represented by the following general formula (5) represented by the following chemical reaction formula. A method for producing a cyclobutane compound and / or an isopropylidenedimethylcyclobutane compound represented by the following general formula (6) will be described. The production method includes at least a step of obtaining an isopropenyldimethylcyclobutane compound (5) and / or an isopropylidenedimethylcyclobutane compound (6) by subjecting the above-mentioned dimethylcyclobutane compound (1) to a reduction reaction (the following steps). See Examples 29-42).
Isopropenyl dimethyl cyclobutane compound (5) and / or carbon X ⁶ in isopropylidene dimethylcyclobutane compound (6), including a hydroxyl group, an acyloxy group having 1 to 10 carbon atoms including carbon atoms of carbonyl groups, the carbon of the carbonyl group Alkoxycarbonyloxy group with 2 to 10 carbon atoms, alkanesulfonyloxy group with 1 to 10 carbon atoms, allene sulfonyloxy group with 6 to 20 carbon atoms, alkoxy group with 1 to 12 carbon atoms, aryloxy group with 6 to 12 carbon atoms Represents a silyloxy group or halogen atom having 3 to 20 carbon atoms. As the above-mentioned respective groups in X ⁶ in isopropenyl dimethyl cyclobutane compound (5) and isopropylidene dimethylcyclobutane compound (6), the above groups X ¹ and X ² described above has exemplified the case where the is the group Can be mentioned.
In the reduction reaction, X ² and X ⁶ after the reaction become identical if the X ² isopropenyl dimethyl cyclobutane compound (5) is maintained, whereas, when X ² is not maintained X ² and the reaction The latter X ⁶ is different.
Examples of the reducing agent include formates such as hydrogen, formate, sodium formate, ammonium formate and triethylammonium formate, alkylborane compounds such as borane and bis (3-methyl-2-butyl) borane, and alkylsilane compounds such as triethylsilane. Metal hydrides such as aluminum hydride, alkyl metal hydrides such as diisobutyl aluminum hydride, sodium boron hydride, lithium boron hydride, potassium hydrogen hydride, calcium boron hydride, sodium trimethoxyborone hydride, hydrogen Triethyl Boranes Borane, Lithium Aluminum Hydride, Lithium Aluminum Hydride, Lithium Aluminum Hydride, Lithium Diethoxy Aluminum Hydride, Tritert-Butoxy Aluminum Hydride, Lithium Bis (2-methoxyethoxy) Aluminum Examples thereof include complex hydrides of the above, alkoxy or alkyl derivatives thereof, and diazenyl agents such as 2-nitrobenzenesulfonohydrazide and N'-isopropyridene-2-nitrobenzenesulfonohydrazide.
The reducing agent may be used alone or in combination of two or more. Moreover, as the reducing agent, a commercially available one can be used.
The amount of the reducing agent used is preferably 0.7 to 100.0 mol, more preferably 0.8 to 80.0 mol, still more preferably 0.9 in terms of hydride with respect to 1 mol of the dimethylcyclobutane compound (1). It is ~ 60.0 mol.

The reduction reaction may be carried out in the presence of a metal catalyst.
Examples of the metal catalyst include palladium catalysts, nickel catalysts, iron catalysts, cobalt catalysts, molybdenum catalysts, tungsten catalysts, rhodium catalysts, iridium catalysts and the like, and from the viewpoint of yield and selectivity, palladium catalysts are preferable.
Examples of the palladium catalyst include zero-valent palladium catalysts such as tetrakis (triphenylphosphine) palladium and bis (dibenzilidenacetone) palladium, palladium acetate, bis (acetato) bis (triphenylphosphine) palladium, trifluoropalladium acetate, and palladium chloride. , Dichlorobis (triphenylphosphine) palladium, allylpalladium = chloride, divalent palladium catalysts such as acetylacetonepalladium and the like.
One type or two or more types of the metal catalyst may be used. Moreover, as the metal catalyst, a commercially available one can be used.
The amount of the metal catalyst used is preferably 0.0001 to 1 mol, more preferably 0.0002 to 0.9 mol, and further preferably 0.0003 to 0.8 mol with respect to 1 mol of the dimethylcyclobutane compound (1). ..

Further, if necessary, a ligand may be used together with the metal catalyst.
Examples of the ligand include phosphite ester compounds such as triethyl phosphine and triphenyl phosphine, tributylphosphine, tricyclohexylphosphine, trioctylphosphine, triphenylphosphine, and 2,2'-bis (diphenylphosphine). Phosphine compounds such as fino) -1,1'-binaphthyl and 2- (di-tert-butylphosphino) biphenyl, acetone derivatives such as acetylacetone and dibenzylideneacetone, nitrile compounds such as acetonitrile and benzonitrile, and dimethylimidazolidinone. , Nitrogen-containing compounds such as ethylenediamine and hexamethylphosphoric triamide, and diene compounds such as 1,5-cyclooctadiene and 2,5-norbornadiene.
One type or two or more types of the ligand may be used. Further, as the ligand, a commercially available one can be used.
The amount of the ligand used is preferably 0.001 to 10,000 mol, more preferably 0.01 to 1,000 mol, and further preferably 0.1 to 100 mol with respect to 1 mol of the metal catalyst.
When a diazenyl agent is used as the reducing agent, the reduction reaction can be carried out through a Mitsunobu reaction with an azodicarboxylate ester compound such as diethyl azodicarboxylate (DEAD) and a phosphine compound such as triphenylphosphine.
The amount of the azodicarboxylic acid ester compound used in the Mitsunobu reaction is preferably 0.7 to 100.0 mol, more preferably 0.8 to 80.0 mol, still more preferably 0., With respect to 1 mol of the dimethylcyclobutane compound (1). It is 9 to 60.0 mol.
The amount of the phosphine compound used in the Mitsunobu reaction is preferably 0.7 to 100.0 mol, more preferably 0.8 to 80.0 mol, still more preferably 0.9 to 60, based on 1 mol of the dimethylcyclobutane compound (1). It is 0.0 mol.

Solvents in the reduction reaction include ethers such as diethyl ether, dibutyl = ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride, chloroform and trichloroethylene. Chlorine-based solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide and other aprotic polar solvents, acetonitrile, propionitrile Examples thereof include nitriles such as ethyl acetate and n-butyl acetate, alcohols such as methanol, ethanol, t-butyl alcohol and trifluoroethanol, ketones such as acetone and 2-butanone, and water. ..
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 150,000 g with respect to 1 mol of the dimethylcyclobutane compound (1).

The reaction temperature in the reduction reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time of the reduction reaction can be set arbitrarily, but it is desirable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and usually 0. It takes about 5 to 30 hours.

The isopropenyl dimethylcyclobutane compound (5) is represented by the following general formula (5-1) (1R, 3R) -3-isopropenyl-2,2-dimethylcyclobutane compound, the following general formula (5-2). (1S, 3S) -3-isopropenyl-2,2-dimethylcyclobutane compound represented by, and (1R, 3S) -3-isopropenyl-2,2- represented by the following general formula (5-3). The dimethylcyclobutane compound and the (1S, 3R) -3-isopropenyl-2,2-dimethylcyclobutane compound represented by the following general formula (5-4), and their racemic, diastereomeric and scalemic mixtures are Can be mentioned.
The isopropenyldimethylcyclobutane compound (5) has an isopropenyldimethylcyclobutane compound having an acyloxymethyl group, an isopropenyldimethylcyclobutane compound having a halomethyl group, an isopropenyldimethylcyclobutane compound having a hydroxymethyl group, and an alkanesulfonyloxymethyl group. Examples thereof include isopropenyldimethylcyclobutane compounds and isopropenyldimethylcyclobutane compounds having an alkoxymethyl group.
Examples of the isopropenyldimethylcyclobutane compound having an acyloxymethyl group include (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = acetate and (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = 2-methyl. Butanoate, (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = 3-methyl-3-butenoate and the like (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = acylate compounds and the like. Be done.
Examples of the isopropenyldimethylcyclobutane compound having a halomethyl group include 1-halomethyl-3-isopropenyl-2,2-dimethylcyclobutane compounds such as 1-chloromethyl-3-isopropenyl-2,2-dimethylcyclobutane.
Examples of the isopropenyldimethylcyclobutane compound having a hydroxymethyl group include (3-isopropenyl-2,2-dimethylcyclobutyl) methanol and the like.
Examples of the isopropenyldimethylcyclobutane compound having an alkanesulfonyloxymethyl group include (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = methanesulfonate and the like (3-isopropenyl-2,2-dimethylcyclobutyl) methyl =. Alkane sulfonate compounds can be mentioned.
Examples of the isopropenyldimethylcyclobutane compound having an alkoxymethyl group include 2-[(3-isopropenyl-2,2-dimethylcyclobutyl) methoxy] tetrahydropyran and (3-isopropenyl-2,2-dimethylcyclobutyl) methoxy. Examples thereof include 1-alkoxymethyl-3-isopropenyl-2,2-dimethylcyclobutane compounds such as methylbenzene.

The isopropyridene dimethylcyclobutane compound (6) is represented by the following general formula (6-1) (1R) -3-isopropylidene-2,2-dimethylcyclobutane compound, and the following general formula (6-2). Examples thereof include (1S) -3-isopropyridene-2,2-dimethylcyclobutane compounds represented by (1S), and racemic and scalemic mixtures thereof.
The isopropyridene dimethylcyclobutane compound (6) has an isopropyridene dimethylcyclobutane compound having an acyloxymethyl group, an isopropyridene dimethylcyclobutane compound having a halomethyl group, an isopropyridene dimethylcyclobutane compound having a hydroxymethyl group, and an alkanesulfonyloxymethyl group. Examples thereof include an isopropyridene dimethylcyclobutane compound and an isopropyridenedimethylcyclobutane compound having an alkoxymethyl group.
Examples of the isopropylidene dimethylcyclobutane compound having an acyloxymethyl group include (3-isopropylidene-2,2-dimethylcyclobutyl) methyl = acetate and (3-isopropylidene-2,2-dimethylcyclobutyl) methyl = 2-methyl. Butanoate, (3-isopropylidene-2,2-dimethylcyclobutyl) methyl = 3-methyl-2-butenoate, (3-isopropylidene-2,2-dimethylcyclobutyl) methyl = 3-methyl-3- Examples thereof include (3-isopropylidene-2,2-dimethylcyclobutyl) methyl = acylate compounds such as butenoate.
Examples of the isopropylidene dimethylcyclobutane compound having a halomethyl group include 1-halomethyl-3-isopropylidene-2,2-dimethylcyclobutane compounds such as 1-chloromethyl-3-isopropylidene-2,2-dimethylcyclobutane. ..
Examples of the isopropyridene dimethylcyclobutane compound having a hydroxymethyl group include (3-isopropyridene-2,2-dimethylcyclobutyl) methanol and the like.
Examples of the isopropylidene dimethylcyclobutane compound having an alkanesulfonyloxymethyl group include (3-isopropylidene-2,2-dimethylcyclobutyl) methyl = methanesulfonate as the isopropenyldimethylcyclobutane compound having an alkanesulfonyloxymethyl group. Examples thereof include 3-isopropylidene-2,2-dimethylcyclobutyl) methyl-alkanesulfonate compounds.
Examples of the isopropyridene dimethylcyclobutane compound having an alkoxymethyl group include 2-[(3-isopropyridene-2,2-dimethylcyclobutyl) methoxy] tetrahydropyran and (3-isopropyriden-2,2-dimethylcyclobutyl) methoxy. Examples thereof include 1-alkoxymethyl-3-isopropylidene-2,2-dimethylcyclobutane compounds such as methylbenzene.

The isopropenyldimethylcyclobutane compound having an alkoxymethyl group represented by the following general formula (5A) and the isopropylidenedimethylcyclobutane compound represented by the following general formula (6A) are described above as shown by the following chemical reaction formula. It can be produced by subjecting a dimethylcyclobutane compound (1G) having a halogen atom and an alkoxy group to the reduction reaction (see Example 29 below). The reduction reaction is carried out with a reducing agent, if necessary, in the presence of a metal catalyst and a ligand.
X ⁷ in the isopropenyldimethylcyclobutane compound (5A) and the isopropylidene dimethylcyclobutane compound (6A) having an alkoxymethyl group are as defined above.

The above-mentioned isopropenyldimethylcyclobutane compound (5A) having an alkoxymethyl group and the above-mentioned isopropylidene dimethylcyclobutane compound (6A) are the above-mentioned dimethylcyclobutane compounds having a phosphonio group and an alkoxy group as shown by the following chemical reaction formula. It can be produced by subjecting (1K) to a reduction reaction (see Example 30 below). The reduction reaction is carried out with a reducing agent, if necessary, in the presence of a metal catalyst and a ligand.

The above-mentioned isopropenyl dimethylcyclobutane compound (5A) having an alkoxymethyl group and the isopropylidene dimethylcyclobutane compound (6A) are the above-mentioned dimethylcyclobutane compound (1G) having a halogen atom and an alkoxy group as shown by the following chemical reaction formula. ) Can be produced by subjecting it to a reduction reaction (see Example 31 below). The reduction reaction is carried out with a reducing agent, if necessary, in the presence of a metal catalyst and a ligand.

The isopropenyldimethylcyclobutane compound having a hydroxymethyl group represented by the following formula (5B) and / or the isopropylidenedimethylcyclobutane compound represented by the following formula (6B) are described above as shown by the following chemical reaction formula. It can be produced by subjecting a dimethylcyclobutane compound (1D) having an acyloxy group and an alkoxy group to a reduction reaction (see Examples 32, 41 and 42 below). The reduction reaction is carried out with a reducing agent in the presence of a metal catalyst and optionally a ligand.

The above-mentioned isopropenyldimethylcyclobutane compound (5A) having an alkoxymethyl group and the above-mentioned isopropylidene dimethylcyclobutane compound (6A) are the above-mentioned dimethylcyclobutane compounds having an acyloxy group and an alkoxy group as shown by the following chemical reaction formula. It can be produced by subjecting (1D) to a reduction reaction (see Example 33 below). The reduction reaction is carried out with a reducing agent in the presence of a metal catalyst and optionally a ligand.

The above-mentioned isopropenyl dimethylcyclobutane compound (5A) having an alkoxymethyl group and the isopropylidene dimethylcyclobutane compound (6A) are the above-mentioned dimethylcyclobutane compound (1C) having a hydroxyl group and an alkoxy group as shown by the following chemical reaction formula. Can be produced by subjecting to a reduction reaction (see Example 34 below). The reduction reaction is carried out using, for example, a diazenyl agent as a reducing agent.

The isopropenyldimethylcyclobutane compound having an acyloxymethyl group represented by the following general formula (5C) and the isopropylidenedimethylcyclobutane compound represented by the following general formula (6C) are described above as shown by the following chemical reaction formula. It can be produced by subjecting a dimethylcyclobutane compound (1F) having two acyloxy groups to a reduction reaction (see Examples 35 to 39 below). The reduction reaction is carried out with a reducing agent in the presence of a metal catalyst and optionally a ligand.
X ⁸ is as defined above.

The isopropenyldimethylcyclobutane compound having a halomethyl group represented by the following general formula (5D) and the isopropylidenedimethylcyclobutane compound represented by the following general formula (6D) are described in the above 2 as shown by the following chemical reaction formula. It can be produced by subjecting a dimethylcyclobutane compound (1H) having one halogen atom to a reduction reaction (see Example 40 below). The reduction reaction is carried out with a reducing agent in the presence of a metal catalyst and optionally a ligand.
X ⁹ is as defined above.

The above-mentioned isopropenyl dimethylcyclobutane compound (5B) having a hydroxymethyl group and the isopropylidene dimethylcyclobutane compound (6B) are the above-mentioned dimethylcyclobutane compound (1I) having a phosphonio group and a hydroxyl group as shown by the following chemical reaction formula. Can be produced by subjecting to a reduction reaction (see Example 41 below). The reduction reaction is carried out with a reducing agent, if necessary, in the presence of a metal catalyst and a ligand.

The above-mentioned isopropenyl dimethylcyclobutane compound (5B) having a hydroxymethyl group and the isopropylidene dimethylcyclobutane compound (6B) are the above-mentioned dimethylcyclobutane compound (1J) having a halogen atom and an acyloxy group as shown by the following chemical reaction formula. ) Can be produced by subjecting it to a reduction reaction (see Example 42 below). The reduction reaction is carried out with a reducing agent, if necessary, in the presence of a metal catalyst and a ligand.

Also, if desired, the specific group X ⁶ in the above-mentioned isopropenyldimethylcyclobutane compound (5) and / or the above-mentioned isopropylidene dimethylcyclobutane compound (6) can be added to another of the X ⁶ options defined above. performing functional group transformations by performing the step of converting the group X ^6, isopropenyl dimethyl cyclobutane compound having a substituent of said another (5 ') and / or isopropylidene dimethylcyclobutane compound having a substituent of said another (6') can also be obtained (see Examples 43-52 below).
The conversion of functional groups can be carried out by a known method.

For example, the above-mentioned isopropenyldimethylcyclobutane compound (5C) having an acyloxymethyl group and the above-mentioned isopropylidenedimethylcyclobutane compound (6C) have the above-mentioned isopropenyldimethylcyclobutane having a halomethyl group as shown by the following chemical reaction formula. It can be produced by an acyloxylation reaction between compound (5D) and / or the above-mentioned isopropylidenedimethylcyclobutane compound (6D) and a carboxylate (see Example 46 below).
The chemical reaction formula is to produce a mixture of compounds (5C) and (6C) from a mixture of compounds (5D) and (6D), to produce compound (5C) from compound (5D), and to compound (6D). ) To produce compound (6C).
Examples of the carboxylate include metal carboxylates such as lithium acetate, sodium acetate, potassium acetate, cesium acetate, magnesium acetate and calcium acetate, and ammonium acetate such as ammonium acetate and tetrabutylammonium = acetate.
The carboxylate may be used alone or in combination of two or more. Moreover, as the carboxylate, a commercially available one can be used.
The carboxylic acid salt may be prepared in a reaction system by reacting a carboxylic acid with a base such as sodium hydroxide, potassium carbonate, or tetrabutylammonium hydroxide.
The amount of the carboxylate used is preferably 0.7 to 10 mol, more preferably 0., With respect to a total of 1 mol of the isopropenyldimethylcyclobutane compound (5D) having a halomethyl group and the isopropylidenedimethylcyclobutane compound (6D). It is 8 to 8 mol, more preferably 0.9 to 6 mol.
Further, the acyloxylation reaction may be carried out in the coexistence of a halide.
Examples of the halide include lithium iodide, sodium iodide, potassium iodide, cesium iodide, magnesium iodide, calcium iodide, lithium bromide, sodium bromide, potassium bromide, cesium bromide, and magnesium bromide. Examples thereof include metal halides such as calcium bromide, ammonium iodide, ammonium bromide, tetrabutylammonium = iodide, tetrabutylammonium = bromide, and ammonium = halide compounds such as tetrabutylammonium = chloride.
One type or two or more types of the halide may be used. Moreover, as the halide, a commercially available one can be used.
The amount of the halide used is preferably 0.0001 to 10 mol, more preferably 0.0002, with respect to a total of 1 mol of the isopropenyldimethylcyclobutane compound (5D) having a halomethyl group and the isopropylidenedimethylcyclobutane compound (6D). It is ~ 8 mol, more preferably 0.0003 ~ 6 mol.
Solvents in the acyloxylation reaction include ethers such as diethyl = ether, dibutyl = ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride and chloroform. Chlorine-based solvents such as trichloroethylene, aprotic polarities such as N, N-dimethylacetamide, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide Examples thereof include solvents, nitriles such as acetonitrile and propionitrile, esters such as ethyl acetate and n-butyl acetate, alcohols such as methanol, ethanol and t-butyl alcohol, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 10,000 g with respect to a total of 1 mol of the isopropenyldimethylcyclobutane compound (5D) having a halomethyl group and the isopropylidenedimethylcyclobutane compound (6D).

The reaction temperature in the acyl oxidation reaction is preferably −78 to 200 ° C., more preferably −60 to 180 ° C., and even more preferably −40 to 160 ° C.
The reaction time in the acyloxylation reaction can be set arbitrarily, but it is preferable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

The above-mentioned isopropenyldimethylcyclobutane compound (5C) having an acyloxymethyl group and the above-mentioned isopropylidenedimethylcyclobutane compound (6C) are the above-mentioned isopropenyldimethylcyclobutane compounds having a hydroxymethyl group as shown by the following chemical reaction formula. It can be produced by an acylation reaction between (5B) and / or the above-mentioned isopropylidene dimethylcyclobutane compound (6B) and an acylating agent (see Examples 44, 45 and 50 below).
The chemical reaction formula is to produce a mixture of compounds (5C) and (6C) from a mixture of compounds (5B) and (6B), to produce compound (5C) from compound (5B), and to compound (6B). ) To produce compound (6C).
Examples of the acylating agent include acid anhydrides such as acetic anhydride and acid chlorides such as acetyl chloride.
One kind or two or more kinds of acylating agents may be used. Moreover, as the acylating agent, a commercially available one can be used.
The amount of the acylating agent used is preferably 0.7 to 100 mol, more preferably 0, based on a total of 1 mol of the isopropenyldimethylcyclobutane compound (5B) having a hydroxymethyl group and the isopropylidenedimethylcyclobutane compound (6B). It is .8 to 50 mol, more preferably 0.9 to 20 mol.
The bases used in the acylation reaction include sodium = methoxydo, sodium = ethoxydo, sodium = t-butoxide, sodium = t-amyloxide, lithium = methoxydo, lithium = ethoxydo, lithium = t-butoxide, lithium = t-amyloxide, potassium. = Methylamide, potassium = ethoxydo, potassium = t-butoxide, potassium = t-amyloxide and other alkoxides, methyllithium, ethyllithium, n-butyllithium, methylmagnesium chloride, diisopropylsodium and other organic metal compounds, sodium = amide , Lithium = amide, lithium = diisopropylamide, lithium = hexamethyldisilazide, sodium = hexamethyldisilazide, potassium = hexamethyldisilazide, lithium = dicyclohexylamide and other metal amides, sodium hydride, hydrogenation Metal hydrides such as potassium and calcium hydride, triethylamine, diisopropylethylamine, tributylamine, N, N-dimethylaniline, N, N-diethylaniline, pyridine, 4-dimethylaminopyridine, imidazole, quinoline, pyrrolidine, piperidine, Examples thereof include organic base compounds such as colisine, lutidine, morpholine, and 1,8-diazabicyclo [5.4.0] -7-undecene.
The base may be used alone or in combination of two or more. Further, as the base, a commercially available one can be used.
The amount of the base used is preferably 0.7 to 100 mol, more preferably 0.8, based on a total of 1 mol of the isopropenyldimethylcyclobutane compound (5B) having a hydroxymethyl group and the isopropylidenedimethylcyclobutane compound (6B). It is ~ 50 mol, more preferably 0.9 ~ 20 mol.
Solvents in the acylation reaction include ethers such as diethyl ether, dibutyl ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride and chloroform. Chlorine-based solvents such as trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, acetonitrile, propio Examples thereof include nitriles such as nitrile, esters such as ethyl acetate and n-butyl acetate, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 15,000 g with respect to a total of 1 mol of the isopropenyldimethylcyclobutane compound (5B) having a hydroxymethyl group and the isopropylidenedimethylcyclobutane compound (6B).
The reaction temperature in the acylation reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the acylation reaction can be set arbitrarily, but it is preferable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

The isopropenyldimethylcyclobutane compound having an alkanesulfonyloxymethyl group represented by the following general formula (5G) and the isopropylidenedimethylcyclobutane compound represented by the following general formula (6G) are as shown by the following chemical reaction formula. It can be produced by an alkanesulfonylation reaction between the above-mentioned isopropenyldimethylcyclobutane compound (5B) having a hydroxymethyl group and / or an isopropylidenedimethylcyclobutane compound (6B) and an alkanesulfonylating agent (Example 47 below). See).
The chemical reaction formula is to produce a mixture of compounds (5G) and (6G) from a mixture of compounds (5B) and (6B), to produce compound (5G) from compound (5B), and to compound (6B). ) To produce compound (6G).
X ¹¹ represents an alkanesulfonyloxy group having 1 to 10 carbon atoms. Examples of the alkanesulfonyloxy group having 1 to 10 carbon atoms include the above-mentioned groups exemplified when the above-mentioned X ¹ and X ² are alkane sulfonyloxy groups having 1 to 10 carbon atoms.
Examples of the alkane sulfonyl agent include alkane sulfonic acid anhydrides such as methane sulfonic acid anhydride and alkane sulfonates such as methane sulfonyl chloride.
One kind or two or more kinds of alkane sulfonylating agents may be used. Moreover, as the alkane sulfonylating agent, a commercially available one can be used.
The amount of the alkane sulfonylating agent used is preferably 0.7 to 100 mol, more preferably 0.7 to 100 mol, based on a total of 1 mol of the isopropenyldimethylcyclobutane compound (5B) and the isopropylidenedimethylcyclobutane compound (6B) having a hydroxymethyl group. It is 0.8 to 50 mol, more preferably 0.9 to 20 mol.
The bases used in the alcansulfonylation reaction include sodium = methoxydo, sodium = ethoxydo, sodium = t-butoxide, sodium = t-amyloxide, lithium = methoxydo, lithium = ethoxydo, lithium = t-butoxide, lithium = t-amyloxide, Alkoxides such as potassium = methoxydo, potassium = ethoxydo, potassium = t-butoxide, potassium = t-amyloxide, organic metal compounds such as methyllithium, ethyllithium, n-butyllithium, methylmagnesium chloride, and sodium dimethylamide, sodium = Metal amides such as amide, lithium = amide, lithium = diisopropylamide, lithium = hexamethyldisilazide, sodium = hexamethyldisilazide, potassium = hexamethyldisilazide, lithium = dicyclohexylamide, sodium hydride, hydrogen Metal hydrides such as potassium hydride and calcium hydride, triethylamine, diisopropylethylamine, tributylamine, N, N-dimethylaniline, N, N-diethylaniline, pyridine, 4-dimethylaminopyridine, imidazole, quinoline, pyrrolidine, piperidine , Collidine, lutidine, morpholine, organic base compounds such as 1,8-diazabicyclo [5.4.0] -7-undecene and the like.
The base may be used alone or in combination of two or more. Further, as the base, a commercially available one can be used.
The amount of the base used is preferably 0.7 to 100 mol, more preferably 0.8, based on a total of 1 mol of the isopropenyldimethylcyclobutane compound (5B) having a hydroxymethyl group and the isopropylidenedimethylcyclobutane compound (6B). It is ~ 50 mol, more preferably 0.9 ~ 20 mol.
Solvents in the alkane sulfonylation reaction include ethers such as diethyl ether, dibutyl ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride and chloroform. , Chlorine solvents such as trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, acetonitrile, pro Examples thereof include nitriles such as pionitrile, esters such as ethyl acetate and n-butyl acetate, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 10,000 g with respect to a total of 1 mol of the isopropenyldimethylcyclobutane compound (5B) having a hydroxymethyl group and the isopropylidenedimethylcyclobutane compound (6B).
The reaction temperature in the alkanesulfonylation reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the alcan sulfonylation reaction can be set arbitrarily, but it is preferable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction, and it is usually preferable in terms of yield. It takes about 0.5 to 24 hours.

The above-mentioned isopropenyldimethylcyclobutane compound (5C) having an acyloxymethyl group and the above-mentioned isopropylidenedimethylcyclobutane compound (6C) have the above-mentioned isopropenyldimethyl having an alkanesulfonyloxymethyl group as shown by the following chemical reaction formula. It can be produced by an acyloxylation reaction between a cyclobutane compound (5G) and / or an isopropylidenedimethylcyclobutane compound (6G) and a carboxylate (see Example 48 below).
The chemical reaction formula is to produce a mixture of compounds (5C) and (6C) from a mixture of compounds (5G) and (6G), to produce compound (5C) from compound (5G), and to compound (6G). ) To produce compound (6C).
Examples of the carboxylate include 3-methyl-2-butenoate lithium, 3-methyl-2-butaneate sodium, 3-methyl-2-butenoate potassium, 3-methyl-2-butenoate cesium, and the like. Alkali metal salts of 3-methyl-2-butenoic acid such as alkali metal salts of methyl-2-butenoic acid, magnesium 3-methyl-2-butenoate, calcium 3-methyl-2-butenoate, 3-methyl-2 Examples thereof include ammonium-carboxylate such as ammonium butenoate and tetrabutylammonium = 3-methyl-2-butenoate.
The carboxylate may be used alone or in combination of two or more. Moreover, as the carboxylate, a commercially available one can be used.
The carboxylate may be prepared in the system with a carboxylic acid and a base such as sodium hydroxide, potassium carbonate, tetrabutylammonium hydroxide and the like.
The amount of the carboxylate used is preferably 0.7 to 10 mol, more preferably 0.7 to 10 mol, based on a total of 1 mol of the isopropenyldimethylcyclobutane compound (5G) having an alkanesulfonyloxymethyl group and the isopropylidenedimethylcyclobutane compound (6G). Is 0.8 to 8 mol, more preferably 0.9 to 6 mol.
Further, the acyloxylation reaction may be carried out in the coexistence of a halide.
Examples of the halide include lithium iodide, sodium iodide, potassium iodide, cesium iodide, magnesium iodide, calcium iodide, lithium bromide, sodium bromide, potassium bromide, cesium bromide, and magnesium bromide. Examples thereof include metal halides such as calcium bromide, ammonium iodide, ammonium bromide, tetrabutylammonium = iodide, tetrabutylammonium = bromide, and ammonium = halide compounds such as tetrabutylammonium = chloride.
One type or two or more types of the halide may be used. Moreover, as the halide, a commercially available one can be used.
The amount of the halide used is preferably 0.0001 to 10 mol, more preferably 0.0001 to 10 mol, based on a total of 1 mol of the isopropenyldimethylcyclobutane compound (5G) having an alkanesulfonyloxymethyl group and the isopropylidenedimethylcyclobutane compound (6G). It is 0.0002 to 8 mol, more preferably 0.0003 to 6 mol.
Solvents in the acyloxylation reaction include ethers such as diethyl = ether, dibutyl = ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride and chloroform. Chlorine-based solvents such as trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, acetonitrile, propio Examples thereof include nitriles such as nitriles, esters such as ethyl acetate and n-butyl acetate, alcohols such as methanol, ethanol and t-butyl alcohol, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 10,000 g with respect to 1 mol of the isopropenyldimethylcyclobutane compound (5G) and / or the isopropylidenedimethylcyclobutane compound (6G) having an alkanesulfonyloxymethyl group.
The reaction temperature in the acyl oxidation reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the acyloxylation reaction can be set arbitrarily, but it is preferable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

The above-mentioned isopropenyldimethylcyclobutane compound (5B) having a hydroxymethyl group and the above-mentioned isopropylidene dimethylcyclobutane compound (6B) are the above-mentioned isopropenyldimethylcyclobutane compounds having an alkoxymethyl group as shown by the following chemical reaction formula. It can be produced by a deprotection reaction between (5A) and / or the isopropyridene dimethylcyclobutane compound (6A) and an acid (see Example 43 below).
The chemical reaction formula is to produce a mixture of compounds (5B) and (6B) from a mixture of compounds (5A) and (6A), to produce compound (5B) from compound (5A), and to compound (6A). ) To produce compound (6B).
Acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or salts thereof, formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, and benzene. Organic acids such as sulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid or salts thereof, lithium tetrafluoroborate, boron trifluoride, boron trichloride, boron tribromide, aluminum trichloride, zinc chloride, bromide Luis acids such as zinc, zinc iodide, tin tetrachloride, tin tetrabromide, tin dichloride, titanium tetrachloride, titanium tetrabromide, trimethyliodosilane, oxides such as alumina, silica gel and titania, and minerals such as montmorillonite. And so on.
The acid may be used alone or in combination of two or more. Moreover, as the acid, a commercially available one can be used.
The amount of the acid used is preferably 0.00001 to 10,000 mol, more preferably 0, based on a total of 1 mol of the isopropenyldimethylcyclobutane compound (5A) having an alkoxymethyl group and the isopropylidenedimethylcyclobutane compound (6A). It is .0001 to 1,000 mol, more preferably 0.001 to 100 mol.
Solvents in the deprotection reaction include ethers such as diethyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride, chloroform, etc. Chlorine-based solvents such as trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, acetonitrile, propio Examples thereof include nitriles such as nitrile, esters such as ethyl acetate and n-butyl acetate, alcohols such as methanol, ethanol and t-butyl alcohol, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 10,000 g with respect to a total of 1 mol of the isopropenyldimethylcyclobutane compound (5A) having an alkoxymethyl group and the isopropylidenedimethylcyclobutane compound (6A).
The reaction temperature in the deprotection reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the deprotection reaction can be set arbitrarily, but it is desirable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

The above-mentioned isopropenyldimethylcyclobutane compound (5B) having a hydroxymethyl group and the above-mentioned isopropylidene dimethylcyclobutane compound (6B) are the above-mentioned isopropenyldimethylcyclobutane compounds having an acyloxymethyl group as shown by the following chemical reaction formula. It can be produced by a deprotection reaction between (5C) and / or the isopropyridene dimethylcyclobutane compound (6C) and a base (see Example 49 below).
Bases used in the deprotection reaction include nitrogen compounds such as ammonia and hydrazine, metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and sodium. = Methoxydo, sodium = ethoxide, sodium = t-butoxide, sodium = t-amyloxide, lithium = methoxyd, lithium = ethoxide, lithium = t-butoxide, lithium = t-amyloxide, potassium = methoxyd, potassium = ethoxydo, potassium = t Alkoxides such as -butoxide, potassium = t-amyloxide, triethylamine, diisopropylethylamine, tributylamine, N, N-dimethylaniline, N, N-diethylaniline, pyridine, 4-dimethylaminopyridine, imidazole, quinoline, pyrrolidine, piperidine , Collidine, lutidine, morpholine, organic base compounds such as 1,8-diazabicyclo [5.4.0] -7-undecene and the like.
The base may be used alone or in combination of two or more. Further, as the base, a commercially available one can be used.
The amount of the base used is preferably 0.00001 to 10,000 mol, more preferably 0, based on 1 mol of the total of the isopropenyldimethylcyclobutane compound (5C) and the isopropylidenedimethylcyclobutane compound (6C) having an acyloxymethyl group. It is .0001 to 1,000 mol, more preferably 0.001 to 100 mol.
Solvents in the deprotection reaction include ethers such as diethyl ether, dibutyl ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride and chloroform. Chlorine-based solvents such as trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, acetonitrile, propio Examples thereof include nitriles such as nitrile, alcohols such as methanol, ethanol and t-butyl alcohol, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 10,000 g with respect to a total of 1 mol of the isopropenyldimethylcyclobutane compound (5C) having an acyloxymethyl group and the isopropylidenedimethylcyclobutane compound (6C).
The reaction temperature in the deprotection reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the deprotection reaction can be set arbitrarily, but it is desirable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

Obtained by the above production method (1R, 3R) - (3- isopropenyl-2,2-dimethyl) methyl = acetate (5-1; ^{X 6} is an acetoxy group) sex pheromone composition using It can be prepared and the sex pheromone composition can be used to produce an attractant for Planococcus citri (generic name: Methyl group).

First, the pheromone composition will be described.
The sex pheromone composition comprises at least (1R, 3R)-(3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate, which is the sex pheromone substance of lanococcus citri . It has been reported that the enantiomer (1S, 3S)-(3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate, which is also a cis-form, is not a sex pheromone substance but does not inhibit attraction. (J. Econ. Entomol. 97, 361 (2004)). Therefore, the cis-form may be contained in the sex pheromone composition, and for example, a racemic mixture of cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate and a scalemic mixture are used. be able to.
In addition, the pheromone composition is a trans-form (1S, 3R)-(3-isopropenyl-2,2-dimethylcyclobutyl) methyl = acetate and / or (1R, 3S)-(3-iso. propenyl-2,2-dimethyl) methyl = acetate, it may also contain, optionally further (3-2,2-dimethyl) methyl = acetate (6; ^{X 6} is , Acetoxy group) methyl isomer, (R)-(3-isopropylidene-2,2-dimethylcyclobutyl) methyl = acetate, and / or (S)-(3-isopropylidene-2,2-,2-) Dimethylcyclobutyl) Methyl = acetate may be included.

The content of (1S, 3S)-(3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate in the pheromone composition is (1R, 3R)-(3-isopropenyl-2,2-dimethyl). Cyclobutyl) Methyl = 2 to 100 parts by weight with respect to 100 parts by weight of acetic acid.
The content of (1S, 3R)-(3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate in the pheromone composition is (1R, 3R)-(3-isopropenyl-2,2-dimethyl). Cyclobutyl) Methyl = 4 to 97 parts by weight with respect to 100 parts by weight of acetic acid.
The content of (1R, 3S)-(3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate in the pheromone composition is (1R, 3R)-(3-isopropenyl-2,2-dimethyl). Cyclobutyl) Methyl = 4 to 97 parts by weight with respect to 100 parts by weight of acetic acid.
The content of (R)-(3-isopropylidene-2,2-dimethylcyclobutyl) methyl-acetate in the pheromone composition is (1R, 3R)-(3-isopropenyl-2,2-dimethylcyclobutyl). ) Methyl = 0.1 to 97 parts by weight with respect to 100 parts by weight of acetic acid.
The content of (S)-(3-isopropylidene-2,2-dimethylcyclobutyl) methyl-acetate in the pheromone composition is (1R, 3R)-(3-isopropenyl-2,2-dimethylcyclobutyl). ) Methyl = 0.1 to 97 parts by weight with respect to 100 parts by weight of acetic acid.

Further, the sex pheromone composition includes stabilizers such as 2,6-di-tert-butyl-4-methylphenol (BHT), antioxidants such as butylhydroxytoluene, butylhydroxyanisole, hydroquinone and vitamin E. And / or additives such as UV absorbers such as 2-hydroxy-4-octoxybenzophenone, 2- (2'-hydroxy-3'-tert-butyl-5'-methylphenyl) -5-chlorobenzotriazole, etc. May be added.
The amount of each additive added in the sex pheromone composition is, for example, 100 parts by weight of (1R, 3R)-(3-isopropenyl-2,2-dimethylcyclobutyl) methyl = acetate, and the stabilizer is The amount is preferably 1 to 15 parts by weight, the antioxidant is preferably 1 to 15 parts by weight, and the UV absorber is preferably 1 to 15 parts by weight.

Next, an attractant for Plananococcus citri , which comprises at least a sex pheromone composition and a carrier for supporting the sex pheromone substance in the sex pheromone composition in a releaseable manner , will be described.
The carrier is not particularly limited as long as it can stably hold the sex pheromone composition and at least can release the sex pheromone substance for a certain period of time, and examples thereof include septums, caps, and minerals.

The carrier is not particularly limited as long as it releases a sex pheromone substance or the like at least slowly, but it is preferably made of a polymer.
The polymer is not particularly limited as long as it can allow a sex pheromone substance or the like to permeate and be released to the outside of the polymer film at an appropriate rate. For example, natural rubber, isoprene rubber, for example, cis-polyisoprene, etc. Synthetic rubber exemplified by butadiene rubber, polyolefin exemplified by polyethylene and polypropylene, copolymer containing 80% by weight or more of ethylene exemplified by ethylene-vinyl acetate copolymer and ethylene-acrylic acid ester copolymer, raw. Degradable polyester, vinyl chloride and the like can be mentioned.

The amount carried on the carrier varies depending on the application method and application rate, but is preferably 10 μg to 1000 mg, and more preferably 10 μg to 100 mg per preparation.
The attractant including at least the carrier can be produced by a well-known technique such as kneading or impregnation into the carrier.

Next, a method for attracting Planococcus citri , which includes at least a step of installing an attractant in a field and releasing the sex pheromone active substance in the attractant, will be described.
The installation of the attractant in the field is not particularly limited, but for example, the installation density of the attractant is uniformly preferably 0.1 to 100 places / ha, more preferably 1 to 50 places / in the field to be attracted. ha.
The period of release of the sex pheromone substance of the sex pheromone composition of Planococcus citri into the field is not particularly limited as long as the pest can be attracted.
The amount released from one release location cannot be unequivocally determined depending on the field environment, weather conditions, etc., but is preferably 0.01 to 100 μg / day / ha.

Examples of the control method using the attraction of Planococcus citri include mass trapping, attracting insecticidal method (Lure & kill or Attract & kill), and attracting infection method (Lure & infect or Attract).

[Example]
Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.
Samples for spectral measurement of compounds are optionally obtained by purifying the crude product.
The crude yield means a yield calculated without purification.

Example 1
Production of 3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutanone

Under a nitrogen atmosphere, 3- (1-ethoxyethoxy) -1-propene (1761 g, 13.53 mol) and triethylamine (301.3 g, 2.978 mol) were added to the reactor, and the mixture was stirred at 100 ° C. Isobutyryl-chloride (288.4 g, 2.707 mol) was added dropwise to the solution at intervals of 48.07 g every 6 hours so that the temperature inside the reactor did not exceed 110 ° C. After completion of the dropping, the solution was stirred at 100 ° C. for 10 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrated solution was distilled under reduced pressure to obtain the desired 3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutanone (280.8 g, 1.402 mol) in a yield of 52%.

The spectral data of 3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutanone (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): ν = 2973,2932,2871,1779,1463,1446,1380,1341,1268,1133,1087,1062,986,946,869 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.11 (1.5H, s), 1.12 (1.5H, s), 1.19 (3H, t, J = 7.1 Hz), 1.210 (1.5H, s), 1.211 (1.5H, s), 1.29 (3H, d, J = 5.4Hz), 2.27-2.34 (1H, m), 2.74 (0.5H, dd, J = 1.4, 17.6Hz), 2.75 (0.5H, dd, J = 1.3, 17.6Hz), 3.10 (0.5H, 0.5H, dd, J = 2.9, 17.6Hz), 3.12 (0.5H, dd, J = 3.0, 17.6Hz), 3.42-3.76 (4H, m), 4.66 -4.70 (1H, m) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 15.23, 15.25, 16.69, 16.72, 19.64, 19.70, 23.99, 24.03, 35.62, 35 .65, 45.77, 60.67, 60.74, 60.93, 65.08, 65.55, 99.58, 99.75, 214.27, 214.29 ppm.

Example 2
Production of 3- (1-allyloxyethoxy) methyl-2,2-dimethylcyclobutanone

Under a nitrogen atmosphere, 3- (1-allyloxyethoxy) -1-propene (757.8 g, 5.329 mol) and triethylamine (255.8 g, 2.528 mol) were added to the reactor, and the mixture was stirred at 100 ° C. Isobutyryl-chloride (224.4 g, 2.106 mol) was added dropwise to the solution at intervals of 74.80 g every 10 hours so that the temperature inside the reactor did not exceed 110 ° C. After completion of the dropping, the solution was stirred at 100 ° C. for 12 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrated solution was distilled under reduced pressure to obtain the desired 3- (1-allyloxyethoxy) methyl-2,2-dimethylcyclobutanone (228.0 g, 1.074 mol) in a yield of 51%. ..

The spectral data of 3- (1-allyloxyethoxy) methyl-2,2-dimethylcyclobutanone (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): ν = 3081,263,2930, 2869, 1779, 1647, 1464, 1383, 1344, 1267, 1132, 1098, 106, 1040, 993,923 cm ^-1 .
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 1.11 (1.5H, s), 1.12 (1.5H, s), 1.212 (1.5H, s), 1.214 ( 1.5H, s), 1.31 (3H, d, J = 5.4Hz), 2.28-2.34 (1H, m), 2.75 (0.5H, dd, J = 1.5) , 17.6Hz), 2.76 (0.5H, dd, J = 1.5, 17.6Hz), 3.10 (0.5H, dd, J = 3.0, 17.6Hz), 3. 12 (0.5H, dd, J = 3.3, 17.6Hz), 3.51 (0.5H, dd, J = 6.7, 9.8Hz), 3.56 (0.5H, dd, J = 7.5, 9.8Hz), 3.69 (0.5H, dd, J = 6.8, 9.8Hz), 3.74 (0.5H, dd, J = 7.6, 9. 8Hz), 3.96-4.00 (1H, m), 4.06-4.11 (1H, m), 4.72-4.76 (1H, m), 5.13-5.17 (1H, m) 1H, m), 5.24-5.29 (1H, m), 5.85-5.93 (1H, m) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 16.72, 16.74, 19.53, 19.60, 23.98, 24.01, 35.60, 35.62, 45.76, 60 .68, 65.04, 65.49, 66.09, 66.26, 99.21, 99.40, 116.65, 134.53, 134.55, 214.20, 214.22 ppm.

Example 3
Production of 2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutanone

Under a nitrogen atmosphere, 3- (tetrahydropyran-2-yloxy) -1-propene (644.4 g, 4.486 mol) and triethylamine (215.3 g, 2.128 mol) were added to the reactor, and the mixture was stirred at 100 ° C. Isobutyryl-chloride (188.9 g, 1.773 mol) was added dropwise to the solution at intervals of 62.97 g every 8 hours so that the temperature inside the reactor did not exceed 110 ° C. After completion of the dropping, the solution was stirred at 100 ° C. for 10 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrated solution was distilled under reduced pressure to obtain the desired 2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutanone (138.8 g, 0.6539 mol) in a yield of 37%. Obtained.

The spectral data of 2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutanone (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.12 (1.5H, s), 1.14 (1.5H, s), 1.212 (1.5H, s), 1.214 ( 1.5H, s), 1.46-1.64 (4H, m), 1.65-1.72 (1H, m), 1.72-1.84 (1H, m), 2.30- 2.38 (1H, m), 2.77 (0.5H, dd, J = 6.9, 17.6Hz), 2.80 (0.5H, dd, J = 6.9, 17.6Hz) , 3.10 (0.5H, dd, J = 1.6, 17.6Hz), 3.12 (0.5H, dd, J = 1.6, 17.6Hz), 3.44-3.54 (2H, m), 3.79-3.85 (1H, m), 3.87 (0.5H, dd, J = 6.7, 10.3Hz), 3.93 (0.5H, dd, J = 7.2, 10.3 Hz), 4.57-4.62 (1 H, m) ppm.

Example 4
Production of 3-allyloxymethyl-2,2-dimethylcyclobutanone

Under a nitrogen atmosphere, diallyl-ether (405.9 g, 4.136 mol) and triethylamine (90.72 g, 0.8966 mol) were added to the reactor, and the mixture was stirred at 95 ° C. Isobutyryl-chloride (86.85 g, 0.8151 mol) was added dropwise to the solution at intervals of 28.95 g every 6 hours so that the temperature inside the reactor did not exceed 100 ° C. After completion of the dropping, the solution was stirred at 95 ° C. for 10 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrated solution was distilled under reduced pressure to obtain the desired 3-allyloxymethyl-2,2-dimethylcyclobutanone (53.55 g, 0.3183 mol) in a yield of 39%.

The spectral data of 3-allyloxymethyl-2,2-dimethylcyclobutanone (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): ν = 3534,3081,296,2929,2866,1779,1647,1463,1400,1381,1363,1328,1264,1090,1066,994,926,561 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.12 (3H, s), 1.21 (3H, s), 2.30-2.37 (1H, m), 2.75 (1H, 1H, dd, J = 6.8, 17.6Hz), 3.10 (1H, dd, J = 9.2, 17.6Hz), 3.52 (1H, dd, J = 6.5, 9.6Hz) , 3.58 (1H, dd, J = 7.6, 9.6Hz), 3.93-4.01 (2H, m), 5.15-5.19 (1H, m), 5.23- 5.28 (1H, m), 5.84-5.93 (1H, m) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): 16.65, 23.99, 35.60, 45.60, 60.78, 70.43, 72.01, 116.98, 134.56, 214.27 ppm ..

Example 5
Production of ethyl = 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propanoate

A suspension was prepared by adding sodium hydride (1.38 g, 57.4 mmol) and tetrahydrofuran (THF) (140 g) to the reactor under a nitrogen atmosphere and stirring at 25 ° C. A solution of triethyl 2-phosphonopropionate (13.7 g, 57.4 mmol) in THF (10 g) was added dropwise to the suspension so that the temperature inside the reactor did not exceed 35 ° C. After completion of the dropwise addition, the solution is stirred at 55 ° C. for 1 hour, and then a solution of 3-benzyloxymethyl-2,2-dimethylcyclobutanone (10.9 g, 49.9 mmol) in THF (30 g) is added to the temperature inside the reactor. Was added dropwise so that the temperature did not exceed 60 ° C., and the mixture was stirred under reflux for 10 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 40: 1), and the desired ethyl = 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propanoate ( 12.2 g, 40.4 mmol) was obtained as a geometric isomer mixture of E: Z = 30: 70 in a yield of 81%.

The spectral data of ethyl = 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propanoate (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.22-1.35 (9H, m), 1.67-1.69, 1.77-1.80 (3H, m), 2.27 -3.16 (3H, m), 3.45-3.50 (1H, m), 3.57-3.65 (1H, m), 4.10-4.25 (2H, m), 4 .47-4.44 (2H, m), 7.26-7.38 (5H, m) ppm.

Example 6
Production of Ethyl = 2- (3-Methoxymethoxymethyl-2,2-Dimethylcyclobutylidene) propanoate

A suspension was prepared by adding sodium hydride (386 mg, 16.1 mmol) and tetrahydrofuran (THF) (70 g) to the reactor under a nitrogen atmosphere and stirring at 25 ° C. A solution of triethyl 2-phosphonopropionate (3.84 g, 16.1 mmol) in THF (9 g) was added dropwise to the suspension so that the temperature inside the reactor did not exceed 30 ° C. After completion of the dropwise addition, the solution is stirred at 55 ° C. for 1 hour, and then a solution of 3-methoxymethoxymethyl-2,2-dimethylcyclobutanone (2.63 g, 15.3 mmol) in THF (30 g) is added to the temperature inside the reactor. Was dropped so that the temperature did not exceed 60 ° C. After completion of the dropping, the solution was stirred under heating under reflux for 7 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1), and the desired ethyl = 2- (3-methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propanoate ( 2.55 g, 9.95 mmol) was obtained as a geometric isomer mixture of E: Z = 30: 70 in a yield of 65%.

The spectral data of ethyl = 2- (3-methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propanoate (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.20-1.33 (9H, m), 1.67, 1.78 (3H, t, J = 1.1 Hz, t, J = 2. 1Hz), 2.21-2.38 (2H, m), 2.58-2.65, 2.73-2.80 (1H, m), 3.36 (3H, s), 3.47- 3.58 (1H, m), 3.63-3.76 (1H, m), 4.11-4.23 (2H, m), 4.60, 4.68 (2H, m) ppm.

Example 7
Production of Ethyl = 2- [2,2-Dimethyl-3- (Tetrahydropyran-2-yloxymethyl) Cyclobutylidene] Propanoate

A suspension was prepared by adding sodium hydride (10.7 g, 449 mmol) and tetrahydrofuran (THF) (1500 g) to the reactor under a nitrogen atmosphere and stirring at 25 ° C. Triethyl 2-phosphonopropionate (107 g, 449 mmol) was added dropwise to the suspension so that the temperature inside the reactor did not exceed 30 ° C. After completion of the dropwise addition, the solution is stirred at 55 ° C. for 1 hour, and then 2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutanone (90.9 g, 428 mmol) is added to the reactor at a temperature of 428 mmol. The mixture was added dropwise so as not to exceed 60 ° C. After completion of the dropping, the solution was stirred under heating under reflux for 9 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was distilled under reduced pressure to obtain the desired ethyl = 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propanoate (80.0 g, 270 mmol). ) Was obtained as a diastereomeric mixture in a yield of 63%.

The spectral data of ethyl = 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propanoate (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.20-1.35 (9H, m), 1.45-1.92 (9H, m), 2.22-2.38, 2.59 -2.66, 2.72-2.80, 3.06-3.14, 3.34-3.40, 3.44-3.54, 3.74-3.80, 3.82-3 .91, 4.10-4.20, 4.55-4.59, 4.93-4.96 (10H, m) ppm.

Example 8
Production of ethyl = 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propanoate

A suspension was prepared by adding sodium hydride (996 mg, 41.5 mmol) and tetrahydrofuran (THF) (50 g) to the reactor under a nitrogen atmosphere and stirring at 10 ° C. A solution of triethyl 2-phosphonopropionate (9.89 g, 41.5 mmol) in THF (10 g) was added dropwise to the suspension so that the temperature inside the reactor did not exceed 20 ° C. After completion of the dropping, the solution was stirred at 55 ° C. for 1 hour, and a solution of 3-hydroxymethyl-2,2-dimethylcyclobutanone (2.47 g, 19.3 mmol) in THF (10 g) was added to the reactor at a temperature of 60. The mixture was added dropwise so as not to exceed ° C. After completion of the dropping, the solution was stirred under heating under reflux for 9 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired ethyl = 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propanoate (2). (0.05 g, 9.65 mmol) was obtained as a 50:50 geometric isomer mixture in a yield of 50%.

The spectral data of ethyl = 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propanoate (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): νmax = 3433, 2985, 2928, 2869, 1702, 1448, 1417, 1366, 1304, 1281, 1254, 1148, 1096, 1065, 1039, 905, 864, 772 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.23-1.31 (9H, m), 1.32 (3H, s), 1.33 (3H, s), 1.67, 1. 77 (3H, t, J = 1.5Hz, t, J = 2.1Hz), 1.72 (1H, brs), 2.13-2.22 (1H, m), 2.28-2.34 , 2.56-2.63 (1H, m), 2.71-2.78, 3.04-3.12 (1H, m), 3.61-3.68 (1H, m), 3. 75-3.82 (1H, m), 4.07-4.21 (2H, m) ppm.

Example 9
Production of Ethyl = 2- (3-acetoxymethyl-2,2-dimethylcyclobutylidene) propanoate

A suspension was prepared by adding sodium hydride (224 mg, 9.33 mmol) and tetrahydrofuran (THF) (30 g) to the reactor under a nitrogen atmosphere and stirring at 20 ° C. A solution of triethyl 2-phosphonopropionate (2.22 g, 9.33 mmol) in THF (6 g) was added dropwise to the suspension so that the temperature inside the reactor did not exceed 30 ° C. After completion of the dropwise addition, the solution is stirred at 55 ° C. for 1 hour, and then a solution of (2,2-dimethyl-3-oxocyclobutyl) methyl-acetate (1.38 g, 8.11 mmol) in THF (8 g) is added. The mixture was added dropwise so that the temperature inside the reactor did not exceed 60 ° C. After completion of the dropping, the solution was stirred under heating under reflux for 7 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1), and the desired ethyl = 2- (3-acetoxymethyl-2,2-dimethylcyclobutylidene) propanoate (654 mg) was purified. , 2.57 mmol) as a mixture of 50:50 geometric isomers in 32% yield.

The spectral data of ethyl = 2- (3-acetoxymethyl-2,2-dimethylcyclobutylidene) propanoate (one geometric isomer) (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.10 (3H, s), 1.25 (3H, s), 1.28 (3H, t, J = 7.1 Hz), 1.84- 1.86 (3H, m), 1.92-1.94 (3H, m), 2.19-2.23 (2H, m), 2.32-2.40 (1H, m), 3. 86 (1H, t, J = 9.4Hz), 4.17 (2H, q, J = 7.1Hz), 4.26 (1H, dd, J = 7.3, 9.2)
Hz) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 14.17, 15.62, 18.22, 20.91.233.31, 32.72, 41.46, 44.52, 60.29, 69 .28, 125.29, 140.83, 169.34, 181.76 ppm.

The spectral data of ethyl = 2- (3-acetoxymethyl-2,2-dimethylcyclobutylidene) propanoate (the other geometric isomer) (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.07 (3H, s), 1.23 (3H, s), 1.27 (3H, t, J = 7.1 Hz), 1.76- 1.78 (3H, m), 1.84 (3H, brs), 2.27-2.31 (1H, m), 2.33-2.40 (1H, m), 2.69 (1H, 1H, m) dd, J = 10.9, 12.8 Hz), 4.03 (1 H, t, J = 9.8 Hz), 4.13-4.19 (3 H, m) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 14.23, 15.97, 18.11,20.18, 23.20, 32.65, 41.44, 44.81, 60.29, 69 .43, 125.54, 141.95, 168.99, 182.26 ppm.

Example 10
Production of Ethyl = 2- [3- (1-ethoxyethoxy) Methyl-2,2-Dimethylcyclobutylidene] Propanoate

Under a nitrogen atmosphere, potassium = t-butoxide (120 g, 1.07 mol), toluene (1420 g) and N, N-dimethylacetamide (DMAC, 710 g) were added to the reactor, and the mixture was stirred at 20 ° C. Triethyl 2-phosphonopropionate (255 g, 1.07 mol) was added dropwise to the solution so that the temperature inside the reactor did not exceed 30 ° C. After completion of the dropwise addition, the solution is stirred at 75 ° C. for 1 hour, and then 3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutanone (164 g, 819 mmol) is added, and the temperature inside the reactor does not exceed 80 ° C. It was dropped in this way. After completion of the dropping, the solution was stirred at 75 ° C. for 18 hours. Subsequently, a saline solution was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was distilled under reduced pressure to obtain the desired ethyl = 2- [3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutylidene] propanoate (182 g, 639 mmol) in E: Z. A mixture of geometric isomers at 70:30 was obtained in a yield of 78%.

The spectral data of ethyl = 2- [3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutylidene] propanoate (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): νmax = 2977, 2930, 2870, 1780, 1704, 1669, 1460, 1381, 1366, 1304, 1281, 1254, 1137, 1097, 1059, 1043, 982, 947, 930, 874,766 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.17-1.34 (15H, m), 1.67 (0.9H, t, J = 1.5Hz), 1.77 (2.1H) , T, J = 1.9Hz), 2.11-2.34 (1.3H, m), 2.54-2.70 (0.7H, m), 2.72-2.79 (0.72-2.79). 3H, m), 3.00-3.13 (0.7H, m), 3.37-3.70 (4H, m), 4.00-4.22 (2H, m), 4.63- 4.69 (1H, m) ppm.

Example 11
Production of 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propanol-1-ol

Under a nitrogen atmosphere, a 1.00 M toluene solution of diisobutylaluminum hydride (DIBAL) (120 ml, 120 mmol) and tetrahydrofuran (THF) (322 g) were added to the reactor, and the mixture was stirred at −60 ° C. In the solution, E: Z = 30: 70 of ethyl = 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propanoate (12.2 g, 40.2 mmol) obtained in Example 5 The geometric isomer mixture was added dropwise so that the temperature inside the reactor did not exceed −50 ° C. After completion of the dropping, the mixture was stirred for 3 hours while gradually raising the temperature to 10 ° C. Subsequently, a saturated aqueous solution of Rochelle salt was added to the mixture, and the separated organic layer was subjected to post-treatment by ordinary washing, drying and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propane-1-. All (9.30 g, 35.7 mmol) was obtained as a geometric isomer mixture of E: Z = 30: 70 in 89% yield.

The spectral data of 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.17 (3H, s), 1.29, 1.30 (3H, s), 1.48 (1H, brs), 1.56-1. 58, 1.67-1.69 (3H, m), 2.15-2.38 (2H, m), 2.60-2.75 (1H, m), 3.40-3.50 (1H) , M), 3.58 (1H, dd, J = 8.0, 9.6Hz), 3.90, 4.01 (1H, d, J = 11.4Hz, d, J = 11.5Hz), 3.92, 4.05 (1H, d, J = 11.4Hz, d, J = 11.5Hz), 4.43-4.53 (2H, m), 7.26-7.38 (5H, 5H, m) ppm.

Example 12
Production of 2- (3-Methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol

Under a nitrogen atmosphere, a 1.00 M toluene solution of diisobutylaluminum hydride (DIBAL) (40.0 ml, 40.0 mmol) and tetrahydrofuran (THF) (150 g) were added to the reactor, and the mixture was stirred at -60 ° C. In the solution, E: Z = 30: 70 of ethyl = 2- (3-methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propanoate (2.52 g, 9.82 mmol) obtained in Example 6 The geometric isomer mixture was added dropwise so that the temperature inside the reactor did not exceed −50 ° C. After completion of the dropping, the mixture was stirred for 3 hours while gradually raising the temperature to 10 ° C. Subsequently, a saturated aqueous Rochelle salt solution was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired 2- (3-methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propane-1-. Oar (2.02 g, 9.43 mmol) was obtained as a geometric isomer mixture of E: Z = 30: 70 in a yield of 96%.

The spectral data of 2- (3-methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propane-1-ol (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.16 (3H, s), 1.27 (3H, s), 1.51 (1H, brs), 1.55-1.56, 1. 65-1.67 (3H, m), 2.14-2.25 (2H, m), 2.59-2.72 (1H, m), 3.35 (3H, s), 3.45- 3.57 (1H, m), 3.61-3.68 (1H, m), 3.90, 4.00 (1H, d, J = 3.8Hz, d, J = 8.0Hz), 4 .59, 4.67 (2H, s) ppm.

Example 13
Production of 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propane-1-ol

Under a nitrogen atmosphere, a 3.60 M toluene solution of bis (2-methoxyethoxy) aluminum sodium hydride (120 ml, 432 mmol) and toluene (122 g) were added to the reactor, and the mixture was stirred at 0 ° C. Diastereomers of ethyl = 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propanoate (71.4 g, 241 mmol) obtained according to Example 6 in the solution. The mixture was added dropwise so that the temperature inside the reactor did not exceed 10 ° C. After completion of the dropping, the mixture was stirred for 9 hours while gradually raising the temperature to 26 ° C. Subsequently, an aqueous solution of caustic soda is added to the reaction mixture, and the separated organic layer is subjected to post-treatment by ordinary washing, drying and concentration to obtain the desired 2- [2,2-dimethyl-3- (tetrahydropyran-2-yl)). A crude product of oxymethyl) cyclobutylidene] propan-1-ol (50.4 g, 198 mmol) was obtained as a diastereomeric mixture in a crude yield of 82%.

The spectral data of 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propane-1-ol (colorless to pale yellow oily liquid) obtained above are shown below. Shown.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.15, 1.18, 1.19 (3H, s, s, s), 1.27 (3H, s), 1.40-1.85 (10H, m), 2.09-2.28 (2H, m), 2.58-2.73 (1H, m), 3.32-3.37 (2H, m), 3.71-3 .78, 3.82-3.93, 3.98-4.60 (4H, m), 4.53-4.59 (4H, m) ppm.

Example 14
Production of 2- (3-Hydroxymethyl-2,2-Dimethylcyclobutylidene) Propane-1-ol

Under a nitrogen atmosphere, a 1.01 M toluene solution of diisobutylaluminum hydride (DIBAL) (100 ml, 101 mmol) and tetrahydrofuran (THF, 300 g) were added to the reactor, and the mixture was stirred at −60 ° C. A mixture of E: Z = 50: 50 geometric isomers of ethyl = 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propanoate obtained according to Example 8 in the solution (5.36 g, 25). .3 mmol) was added dropwise so that the temperature inside the reactor did not exceed −50 ° C. After completion of the dropping, the mixture was stirred for 8 hours while gradually raising the temperature to 10 ° C. Subsequently, a saturated aqueous solution of Rochelle salt is added to the reaction mixture, and the separated organic layer is subjected to post-treatment by ordinary washing, drying and concentration to obtain the desired 2- (3-hydroxymethyl-2,2-dimethylcyclo). A crude product of (butylidene) propane-1-ol (4.31 g, 25.3 mmol) was obtained as a geometric isomer mixture of E: Z = 50: 50 in a crude yield of 100%.

The spectral data of (E) -2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propane-1-ol (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): νmax = 3322, 2955, 2922, 2864, 1703, 1459, 1382, 1361, 1311, 1276, 1224, 1167, 1101, 1053, 1031, 1005, 942,886 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.18 (3H, s), 1.28 (3H, s), 1.66 (3H, t, J = 1.9 Hz), 1.76 ( 2H, brs), 2.06-2.13 (1H, m), 2.19-2.26 (1H, m), 2.66-2.72 (1H, m), 3.61 (1H, 1H, m) dd, J = 7.2, 10.7 Hz), 3.75 (1H, dd, J = 7.6, 10.7 Hz), 3.89 (2H, brs) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 14.19, 20.51.275.54, 28.24, 42.71, 44.40, 63.78, 63.88, 125.64, 142 .47 ppm.

The spectral data of (Z) -2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propane-1-ol (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): νmax = 3329, 2954, 2925, 2865, 1702, 1445, 1374, 1362, 1312, 1272, 1249, 1166, 1121, 1066, 1026, 1003, 888 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.18 (3H, s), 1.28 (3H, s), 1.56 (3H, t, J = 1.3 Hz), 1.57 ( 2H, brs), 2.07-2.23 (2H, m), 2.59-2.65 (1H, m), 3.62 (1H, dd, J = 6.8, 10.7Hz), 3.76 (1H, dd, J = 7.6, 10.7Hz), 3.98-4.05 (2H, m) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 15.07, 21.90, 27.63, 29.56, 42.49, 44.58, 62.51, 63.97, 126.32, 143 .79 ppm.

Example 15
Production of 2- (3-Hydroxymethyl-2,2-Dimethylcyclobutylidene) Propane-1-ol

Under a nitrogen atmosphere, a 1.01 M toluene solution of diisobutylaluminum hydride (DIBAL) (100 ml, 101 mmol) and tetrahydrofuran (THF, 200 g) were added to the reactor, and the mixture was stirred at −60 ° C. A mixture of E: Z = 50: 50 geometric isomers of ethyl = 2- (3-acetoxymethyl-2,2-dimethylcyclobutylidene) propanoate obtained according to Example 9 in the solution (4.28 g, 16). .8 mmol) was added dropwise so that the temperature inside the reactor did not exceed −50 ° C. After completion of the dropping, the mixture was stirred for 8 hours while gradually raising the temperature to 10 ° C. Subsequently, a saturated aqueous solution of Rochelle salt is added to the reaction mixture, and the separated organic layer is subjected to post-treatment by ordinary washing, drying and concentration to obtain the desired 2- (3-hydroxymethyl-2,2-dimethylcyclo). A crude product of (butylidene) propane-1-ol (2.86 g, 16.8 mmol) was obtained as a geometric isomer mixture of E: Z = 50: 50 in a crude yield of 100%. The obtained spectral data of 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol (colorless to pale yellow oily liquid) is the same as the spectral data obtained in Example 14. It was the same.

Example 16
Production of 2- [3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutylidene] propane-1-ol

Under a nitrogen atmosphere, a 3.60 M toluene solution of bis (2-methoxyethoxy) aluminum sodium hydride (258 ml, 928 mmol) and toluene (534 g) were added to the reactor, and the mixture was stirred at 20 ° C. The solution is reacted with a mixture of ethyl = 2- [3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutylidene] propanoate (175 g, 615 mmol) in E: Z = 70: 30. The mixture was dropped so that the temperature inside the vessel did not exceed 30 ° C. After completion of the dropping, the mixture was stirred for 4 hours while gradually raising the temperature to 65 ° C. Subsequently, an aqueous solution of caustic soda is added to the reaction mixture, and the separated organic layer is subjected to post-treatment by ordinary washing, drying and concentration to obtain the desired 2- [3- (1-ethoxyethoxy) methyl-2,2-dimethyl. A crude product of [cyclobutylidene] propane-1-ol (149 g, 615 mmol) was obtained as a geometric isomer mixture of E: Z = 70: 30 in a crude yield of 100%.

The spectral data of (E) -2- [3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutylidene] propane-1-ol (colorless to pale yellow oily liquid) obtained above are shown below. Shown in.
IR (D-ATR): νmax = 3404, 2965, 2923, 2866, 1459, 1445, 1380, 1361, 1342, 1275, 1223, 1133, 1087, 1058, 1001, 945, 930, 875 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.14-1.24 (6H, m), 1.24-1.35 (6H, m), 1.60 (1H, s), 1. 62-1.67 (3H, m), 2.07-2.26 (2H, m), 2.66-2.71 (1H, m), 3.34-3.92 (6H, m), 4.61-4.69 (1H, m) ppm.

The spectral data of (Z) -2- [3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutylidene] propan-1-ol (colorless to pale yellow oily liquid) obtained above are shown below. Shown in.
IR (D-ATR): νmax = 3416,2957,2926,2866,1458,1445,1379,1362,1342,1223,113,1087,1058,1038,1002,930,875cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.14-1.24 (6H, m), 1.24-1.34 (6H, m), 1.50 (1H, s), 1. 52-1.56 (3H, m), 2.07-2.28 (2H, m), 2.59-2.67 (1H, m), 3.35-4.05 (6H, m), 4.60-4.78 (1H, m) ppm.

Example 17
[3- (2-Chloro-1-methylethylidene) -2,2-dimethylcyclobutyl] Production of methoxymethylbenzene

In a nitrogen atmosphere, the E: 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol (1.35 g, 5.17 mmol) obtained in Example 11 was placed in the reactor. A mixture of geometric isomers at Z = 30: 70, methylene chloride (50 g) and triethylamine (1.57 g, 15.5 mmol) were added, and the mixture was stirred at 0 ° C. Paratoluenesulfonyl chloride (1.18 g, 6.20 mmol) was added to the solution, and the mixture was stirred for 24 hours while gradually raising the temperature to 25 ° C. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to obtain the desired [3- (2-chloro-1-methylethylidene) -2,2-dimethylcyclobutyl]. Methoxymethylbenzene (586 mg, 2.10 mmol) was obtained as a geometric isomer mixture of E: Z = 30: 70 in a yield of 41%.

The spectral data of [3- (2-chloro-1-methylethylidene) -2,2-dimethylcyclobutyl] methoxymethylbenzene (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.21 (3H, s), 1.33 (3H, s), 1.59-1.61 (3H, m), 2.17-2. 33 (2H, m), 2.63-2.69 (1H, m), 3.47 (1H, dd, J = 6.5,9.5Hz), 3.58 (1H, dd, J = 8) 0.0, 9.5 Hz), 4.00-4.08 (2H, m), 4.51 (2H, s), 7.26-7.38 (5H, m) ppm.

Example 18
[3- (2-Bromo-1-methylethylidene) -2,2-dimethylcyclobutyl] Production of methoxymethylbenzene

E: Z = of 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol (469 mg, 1.80 mmol) obtained in Example 11 was placed in the reactor under a nitrogen atmosphere. A 25:75 geometric isomer mixture, methylene chloride (30 g) and triphenylphosphine (734 mg, 2.80 mmol) were added and stirred at 0 ° C. Then, carbon tetrabromide (929 mg, 2.80 mmol) was added, and the mixture was stirred for 15 hours while gradually raising the temperature to 25 ° C. Subsequently, 3 ml of ethanol was added to the reaction mixture, which was then concentrated and the precipitated triphenylphosphine-oxide was removed by filtration through hexane. The obtained filtrate was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to obtain the desired [3- (2-bromo-1-methylethylidene) -2,2-dimethylcyclobutyl]. Methoxymethylbenzene (454 mg, 1.40 mmol) was obtained as a geometric isomer mixture of E: Z = 25: 75 in a yield of 78%.

The spectral data of [3- (2-bromo-1-methylethylidene) -2,2-dimethylcyclobutyl] methoxymethylbenzene (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.17, 1.22 (3H, s, s), 1.28, 1.34 (3H, s, s), 1.61, 1.72 (3H, t, J = 1.5Hz, t, J = 1.9Hz), 2.16-2.33 (2H, m), 2.64, 2.67-2.73 (1H, dd, J) = 8.8, 16.0Hz, m), 3.47 (1H, dd, J = 6.9, 9.6Hz), 3.59 (1H, dd, J = 8.2, 9.4Hz), 3.86, 3.99 (2H, s, s), 4.51 (2H, s) ppm.

Example 19
2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propyl (triphenyl) phosphonium = bromide

In a nitrogen atmosphere, the E: of [3- (2-bromo-1-methylethylidene) -2,2-dimethylcyclobutyl] methoxymethylbenzene (220 mg, 0.680 mmol) obtained in Example 18 was added to the reactor. A mixture of geometric isomers at Z = 25: 75, acetonitrile (8 g) and triphenylphosphine (232 mg, 0.884 mmol) were added, and the mixture was stirred under heating under reflux for 13 hours. The reaction mixture was concentrated under reduced pressure. Next, toluene (18 g) was added to the concentrate, and the operation of concentration under reduced pressure was performed twice to obtain the desired 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propyl (triphenyl) phosphonium =. A crude product of bromide (500 mg) was obtained as a mixture of geometric isomers with E: Z = 25: 75.

The spectral data of 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propyl (triphenyl) phosphonium = bromide (colorless solid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CD ₃ CN): δ = 0.69, 1.06 (3H, s, s), 0.86, 1.17 (3H, s, s), 1.28-1. 31, 1.43-1.46 (3H, m), 2.00-2.25 (2H, m), 2.58-2.67 (1H, m), 3.16, 3.30 (1H) , Dd, J = 6.5,9.6Hz, dd, J = 6.5,9.5Hz), 3.34, 3.38 (1H, dd, J = 7.6,9.6Hz, dd, J = 8.0, 9.6 Hz), 4.36, 4.39 (2H, s, s), 7.20-7.80 (20H, m) ppm.

Example 20
Production of 2- (3-methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propyl acetate

E: Z = of 2- (3-methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol (812 mg, 3.79 mmol) obtained in Example 12 was placed in the reactor under a nitrogen atmosphere. A mixture of geometric isomers at 30:70, pyridine (3.0 g, 38 mmol) was added and stirred at 25 ° C. Then, acetic anhydride (2.00 g, 19.6 mmol) was added dropwise so that the temperature inside the reactor did not exceed 30 ° C. After completion of the dropping, the mixture was stirred at 25 ° C. for 24 hours. Subsequently, water was added to the mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1), and the desired 2- (3-methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propyl acetate ( 952 mg (3.71 mmol) was obtained as a geometric isomer mixture of E: Z = 30: 70 in a yield of 98%.

The spectral data of 2- (3-methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propyl acetate (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.16 (3H, s), 1.27 (3H, s), 1.52, 1.60-1.62 (3H, brs, m), 2.04, 2.05 (3H, s, s), 2.16-2.25 (2H, m), 2.62-2.73 (1H, m), 3.35 (3H, s), 3.46-3.59 (1H, m), 3.61-3.68 (1H, m), 4.35, 4.48 (2H, brs, brs), 4.59, 4.67 (2H) , S, s) ppm.

Example 21
Production of 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propyl acetate

In a nitrogen atmosphere, the reactor was charged with 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propane-1-ol (50.1 g,) obtained in Example 13. A 197 mmol) diastereomer mixture, pyridine (81 g, 1.0 mol) and toluene (311 g) were added and stirred at 25 ° C. Then, acetic anhydride (41.6 g, 408 mmol) was added dropwise so that the temperature inside the reactor did not exceed 30 ° C. After completion of the dropping, the mixture was stirred at 25 ° C. for 24 hours. Subsequently, water was added to the mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was distilled under reduced pressure to obtain the desired 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propyl acetate (54.5 g, 184 mmol). ) Was obtained as a diastereomeric mixture in a yield of 94%.

The spectral data of 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propyl acetate (colorless to pale yellow oily liquid) obtained above is shown below.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 1.14-1.19 (3H, m), 1.24-1.29 (3H, m), 1.44-1.59 (6H, m) ), 1.60-1.62 (1H, m), 1.63-1.71 (1H, m), 1.74-1.83 (1H, m), 2.00-2.06 (3H) , M), 2.15-2.29 (2H, m), 2.60-2.73 (1H, m), 3.31-3.37, 3.42-3.51 (2H, m) , 3.71-3.77, 3.81-3.87 (2H, m), 4.32-4.38, 4.47-4.48 (2H, m), 4.52-4.58 (1H, m), ppm.

Example 22
Production of 2- (3-Hydroxymethyl-2,2-Dimethylcyclobutylidene) Propane-1-ol

An isomer mixture of 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propane-1-ol obtained in Example 13 was placed in the reactor under a nitrogen atmosphere. 45.0 g, 177 mmol), p-toluenesulfonic acid (189 mg, 0.0011 mmol) and methanol (1100 g) were added, and the mixture was stirred at 20 ° C. for 24 hours. Subsequently, baking soda (200 mg) was added to the reaction mixture, and the mixture was concentrated to crudely produce the desired 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol (30.1 g, 177 mmol). The product was obtained as a mixture of geometric isomers with E: Z = 50: 50 in a crude yield of 100%. The obtained spectral data of 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol (colorless to pale yellow oily liquid) is the same as the spectral data obtained in Example 14. It was the same.

Example 23
Production of 2- (3-Hydroxymethyl-2,2-Dimethylcyclobutylidene) Propane-1-ol

E: Z = 70: 30 of 2- [3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutylidene] propan-1-ol obtained in Example 16 in a reactor under a nitrogen atmosphere. The crude product of the geometric isomer mixture (149 g, 615 mmol), tetrahydrofuran (THF) (306 g), acetic acid (34 g) and water (102 g) were added, and the mixture was stirred at 20 ° C. Subsequently, the mixture was gradually heated to 75 ° C. while reducing the pressure so that gentle reflux continued, and low boiling point components were distilled off. After completion of distillation, saline is added to the reaction mixture, and the separated organic layer is subjected to post-treatment by ordinary washing, drying and concentration to obtain the desired 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene). A crude product of propane-1-ol (105 g, 615 mmol) was obtained as a geometric isomer mixture of E: Z = 70: 30 in a crude yield of 100%. The obtained spectral data of 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol (colorless to pale yellow oily liquid) is the same as the spectral data obtained in Example 14. It was the same.

Example 24
[3- (2-acetoxy-1-methylethylidene) -2,2-dimethylcyclobutyl] Production of methyl-acetate

A geometric isomer mixture of 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol obtained in Example 14 at E: Z = 57: 43 was placed in the reactor under a nitrogen atmosphere. (24.5 g, 0.144 mol), toluene (202 g) and pyridine (114 g, 1.44 mol) were added, and the mixture was stirred at 10 ° C. Acetic anhydride (73.6 g, 0.721 mol) was added dropwise to the solution so that the temperature inside the reactor did not exceed 20 ° C. After completion of the dropping, the mixture was stirred at 15 ° C. for 6 hours. Subsequently, water was added to the mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was distilled under reduced pressure to obtain the desired [3- (2-acetoxy-1-methylethylidene) -2,2-dimethylcyclobutyl] methyl-acetate at E: Z = 57: 43. It was obtained as a geometric isomer mixture (30.0 g, 0.118 mol) in a yield of 82%.

The spectral data of [(E) -3- (2-acetoxy-1-methylethylidene) -2,2-dimethylcyclobutyl] methyl-acetate (colorless to pale yellow oily liquid) obtained above is shown below. ..
IR (D-ATR): νmax = 2985, 1740, 1459, 1380, 1365, 1235, 1171, 1023, 974, 893, 830, 605 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.16 (3H, s), 1.27 (3H, s), 1.61 (3H, t, J = 1.9 Hz), 2.02 ( 3H, s), 2.04 (3H, s), 2.20-2.29 (2H, m), 2.68-2.75 (1H, m), 4.06-4.14 (2H, m) m), 4.32 (1H, d, J = 11.8Hz), 4.35 (1H, d, J = 11.8Hz) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 14.51,250,20.92, 20.95,27.72,27.85,39.05,44.62,65.25,65 .31, 121.57, 144.58, 171.06, 171.11 ppm.

The spectral data of [(Z) -3- (2-acetoxy-1-methylethylidene) -2,2-dimethylcyclobutyl] methyl-acetate (colorless to pale yellow oily liquid) obtained above is shown below. ..
IR (D-ATR): νmax = 2957,1741,1462,1366,1236,1024,975,891,631,606 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.15 (3H, s), 1.26 (3H, s), 1.51-1.52 (3H, m), 2.02 (3H, s), 2.04 (3H, s), 2.17-2.27 (2H, m), 2.61-2.69 (1H, m), 4.09 (1H, d, J = 5. 4Hz), 4.12 (1H, d, J = 5.4Hz), 4.47 (2H, brs) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 15.46, 20.91.209, 21.65, 27.80, 28.82, 38.88, 44.79, 64.06, 65 .23, 121.91, 145.70, 171.05, 171.14 ppm.

Example 25
(3- [2- (2-Methylbutanoyloxy) -1-methylethylidene] -2,2-dimethylcyclobutyl) Methyl = 2-Methylbutanoate

A mixture of E: Z = 50: 50 geometric isomers of 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol obtained in Example 14 in a nitrogen atmosphere in a reactor. (1.72 g, 10.1 mmol), tetrahydrofuran (THF) (36 g) and pyridine (16 g, 200 mmol) were added, and the mixture was stirred at 0 ° C. 2-Methylbutanoyl chloride (4.85 g, 40.2 mmol) was added dropwise to the solution so that the temperature inside the reactor did not exceed 20 ° C. After completion of the dropping, the mixture was stirred at 20 ° C. for 3 hours. Subsequently, water was added to the mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to obtain the desired (3- [2- (2-methylbutanoyloxy) -1-methylethylidene] -2. , 2-Dimethylcyclobutyl) methyl = 2-methylbutanoate was obtained as a mixture of geometric isomers of E: Z = 50: 50 (1.88 g, 5.56 mmol) in 55% yield.

(3- [2- (2-Methylbutanoyloxy) -1-methylethylidene] -2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate (colorless to pale yellow oily liquid) obtained above ) Spectral data is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 0.87-0.91 (6H, m), 1.12 (3H, d, J = 4.2 Hz), 1.13 (3H, d, J) = 4.6Hz), 1.14, 1.16 (3H, s, s), 1.26, 1.27 (3H, s, s), 1.40-1.52, 1.61-1. 72 (7H, m), 2.19-2.41 (4H, m), 2.62-2.76 (1H, m), 4.08-4.27 (2H, m), 4.32- 4.40, 4.44-4.50 (2H, m) ppm.

Example 26
Production of 1-chloromethyl-3- (2-chloro-1-methylethylidene) -2,2-dimethylcyclobutane

In a nitrogen atmosphere, a mixture of 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol obtained in Example 14 with E: Z = 50: 50 was placed in the reactor. (1.64 g, 9.61 mmol) and carbon tetrachloride (48 g, 0.31 mol) were added, and the mixture was stirred at 0 ° C. Subsequently, triphenylphosphine (7.56 g, 28.8 mmol) was added, and the mixture was stirred for 24 hours while gradually raising the temperature to 20 ° C. Subsequently, at ambient temperature, methanol (5 g) was added to the reaction mixture and the mixture was stirred for 1 hour. The reaction mixture was concentrated, then hexane was added and the precipitate was removed by filtration. The filtrate is concentrated, and the concentrate is purified by silica gel column chromatography (hexane) to obtain the desired 1- (2-chloro-1-methylethylidene) -3-chloromethyl-2,2-dimethylcyclobutane E: Z. The mixture was obtained as a 50:50 geometric isomer mixture (1.06 g, 5.13 mmol) in a yield of 53%.

The spectral data of 1-chloromethyl-3- (2-chloro-1-methylethylidene) -2,2-dimethylcyclobutane (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.20, 1.23 (3H, s), 1.31,1.35 (3H, s), 1.59, 1.71 (3H, m) ), 2.21-2.37 (2H, m), 2.70-2.85 (1H, m), 3.50-3.54 (1H, m), 3.61-3.66 (1H) , M), 3.89, 4.02 (2H, m) ppm.

Example 27
Production of 2- (3-Hydroxymethyl-2,2-dimethylcyclobutylidene) propyl (triphenyl) phosphonium = bromide

In a nitrogen atmosphere, the reactor was charged with 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol (300 mg, 1.76 mmol), acetonitrile (12 g), obtained in Example 14. Triphenylphosphine hydrobromide (670 mg, 1.95 mmol) was added, and the mixture was stirred under heating under reflux for 5 hours. Pyridine (1.0 g, 13 mmol) was added to the obtained [2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propyl] triphenylphosphonium = bromide solution, and the mixture was concentrated under reduced pressure and further concentrated. Toluene (12 g) was added to the mixture, and the mixture was concentrated under reduced pressure twice to produce a crude product of triphenyl [2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propyl] phosphonium = bromide (872 mg, 1). .76 mmol) was obtained in a crude yield of 100%.

The spectral data of 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propyl (triphenyl) phosphonium = bromide (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CD ₃ CN): δ = 0.72, 1.06 (3H, s), 0.85, 1.17 (3H, s), 1.28-1.32, 1. 43-1.47 (3H, m), 1.47-2.70 (3H, m), 3.18-3.22, 3.32-3.46 (2H, m), 3.83, 3 .91 (2H, d, J = 14.6Hz, d, J = 14.6Hz), 7.26-7.92 (15H, m) ppm.

Example 28
[2,2-Dimethyl-3- (1-methyl-2-bromoethylidene) cyclobutyl] Production of methyl-acetate

The E: Z = 50: 50 geometry of [3- (2-acetoxy-1-methylethylidene) -2,2-dimethylcyclobutyl] methyl-acetate obtained in Example 24 was placed in the reactor under a nitrogen atmosphere. An isomer mixture (1.78 g, 6.99 mmol), methylene chloride (30 g) and a 30% hydrogen bromide acetic acid solution (2.83 g, 10.5 mmol) were added, and the mixture was stirred at 20 ° C. for 6 hours. Subsequently, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to obtain the desired [2,2-dimethyl-3- (1-methyl-2-bromoethylidene) cyclobutyl] methyl. = Acetic acid was obtained as a mixture of geometric isomers of E: Z = 50: 50 (1.70 g, 6.18 mmol) in a yield of 88%.

The spectral data of [2,2-dimethyl-3- (1-methyl-2-bromoethylidene) cyclobutyl] methyl-acetate (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.15, 1.20 (3H, s, s), 1.26, 1.31 (3H, s, s), 1.59-1.60 , 1.70-171 (3H, m), 2.03 (3H, s), 2.15-2.29 (2H, m), 2.60-2.75 (1H, m), 3.82 , 3.94, 3.97 (2H, s, d, J = 9.6Hz, d, J = 9.6Hz), 4.08-4.15 (2H, m) ppm.

Example 29
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methoxymethylbenzene and (3-isopropylidene-2,2-dimethylcyclobutyl) methoxymethylbenzene

In a nitrogen atmosphere, the E: of [3- (2-chloro-1-methylethylidene) -2,2-dimethylcyclobutyl] methoxymethylbenzene (502 mg, 1.80 mmol) obtained in Example 17 was added to the reactor. A mixture of geometric isomers of Z = 12: 88, acetonitrile (24 g), triphenylphosphine (200 mg, 0.763 mmol) and bis (dibenzylideneacetone) palladium (200 mg, 0.348 mmol) were added and stirred at 20 ° C. Then, ammonium formate (400 mg, 6.34 mmol) was added, and the mixture was stirred at 60 ° C. for 6 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 40: 1) to obtain the desired (3-isopropenyl-2,2-dimethylcyclobutyl) methoxymethylbenzene (415 mg, 1. 70 mmol) as a 68:30: 2 isomer mixture of cis-form, trans-form and double bond positional isomer (3-isopropylidene-2,2-dimethylcyclobutyl) methoxymethylbenzene, yield 94 Obtained in%.

The spectral data of cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methoxymethylbenzene (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 0.81 (3H, s), 1.24 (3H, s), 1.55-1.64 (1H, m), 1.65-1. 69 (3H, m), 1.91 (1H, dt, J = 7.6, 10.7Hz), 2.18-2.28 (1H, m), 2.40 (1H, dd, J = 7) .6, 10.7Hz), 3.37 (1H, dd, J = 6.5, 9.6Hz), 3.44 (1H, dd, J = 8.4, 9.6Hz), 4.47 ( 1H, d, J = 11.9Hz), 4.51 (1H, d, J = 11.9Hz), 4.57 (1H, brs), 4.79-4.82 (1H, m), 7. 26-7.37 (5H, m) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 15.68, 21.69, 28.41, 29.06, 40.17, 45.04, 45.78, 71.59, 73.22, 123 .32, 127.65, 127.72, 128.47, 138.67, 147.37 ppm.

Example 30
(3-Isopropenyl-2,2-dimethylcyclobutyl) Production of methoxymethylbenzene

Lithium aluminum hydride (650 mg, 17.1 mmol) and tetrahydrofuran (THF) (24 g) were added to the reactor under a nitrogen atmosphere, and the mixture was stirred at 0 ° C. A solution of 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propyl (triphenyl) phosphonium = bromide crude product (500 mg) in THF (32 g) obtained in Example 19 was added to the solution. Was added dropwise so that the temperature inside the reactor did not exceed 10 ° C. After completion of the dropping, the mixture was stirred for 1.5 hours while gradually raising the temperature to 30 ° C. Subsequently, water (650 mg), a 15 wt% aqueous sodium hydroxide solution (650 mg), and then water (1.95 g) were further added, and filtration was performed. The obtained filtrate was concentrated under reduced pressure, and silica gel column chromatography (silica gel column chromatography) was performed. Purify with hexane: ethyl acetate = 50: 1) and add the desired (3-isopropenyl-2,2-dimethylcyclobutyl) methoxymethylbenzene (143 mg, 0.585 mmol) to the diastereo of cis: trans = 74: 26. Obtained as a mer mixture. The yield was 86% in two steps from [3- (2-bromo-1-methylethylidene) -2,2-dimethylcyclobutyl] methoxymethylbenzene.
The double bond position isomer (3-isopriden-2,2-dimethylcyclobutyl) methoxymethylbenzene was not detected on GC.

The spectral data of cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methoxymethylbenzene (colorless to pale yellow oily liquid) obtained above is shown below.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 0.81 (3H, s), 1.24 (3H, s), 1.56 (1H, d, J = 10.7 Hz), 1.60 ( 1H, d, J = 10.7Hz), 1.65-1.69 (3H, m), 1.91 (1H, dt, J = 7.6, 10.7Hz), 2.18-2.28 (1H, m), 2.40 (1H, dd, J = 7.6, 10.7Hz), 3.37 (1H, dd, J = 6.5, 9.6Hz), 3.44 (1H, 1H, m) dd, J = 8.4,9.6Hz), 4.47 (1H, d, J = 11.9Hz), 4.51 (1H, d, J = 11.9Hz), 4.57 (1H, brs) ), 4.79-4.82 (1H, m), 7.26-7.37 (5H, m) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 15.68, 21.69, 28.41, 29.06, 40.17, 45.04, 45.78, 71.59, 73.22, 123 .32, 127.65, 127.72, 128.47, 138.67, 147.37 ppm.

Example 31
(3-Isopropylidene-2,2-dimethylcyclobutyl) Production of methoxymethylbenzene

Lithium aluminum hydride (630 mg, 16.6 mmol) and tetrahydrofuran (THF) (120 g) were added to the reactor under a nitrogen atmosphere, and the mixture was stirred at 0 ° C. To the solution was a solution of [3- (2-bromo-1-methylethylidene) -2,2-dimethylcyclobutyl] methoxymethylbenzene (440 mg, 1.36 mmol) obtained in Example 18 in THF (20 g). The solution was added dropwise so that the temperature inside the reactor did not exceed 10 ° C. After completion of the dropping, the mixture was stirred for 4 hours while raising the temperature to 30 ° C. Subsequently, water (630 mg), a 15 wt% sodium hydroxide aqueous solution (630 mg), and then water (1.89 g) were further added. Then, filtration is performed, the obtained filtrate is concentrated under reduced pressure, purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1), and the desired (3-isopropyridene-2,2-dimethylcyclobutyl) methoxy is used. Methylbenzene (269 mg, 1.10 mmol) was obtained in a yield of 81%.
The double bond position isomer (3-isopropenyl-2,2-dimethylcyclobutyl) methoxymethylbenzene was not detected on GC.

The spectral data of methoxymethylbenzene (colorless to pale yellow oily liquid) obtained above (3-isopropyridene-2,2-dimethylcyclobutyl) is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.16 (3H, s), 1.29 (3H, s), 1.46-1.49, 1.59-1.61 (6H, m) ), 2.10-2.17, 2.21-2.28, 2.58-2.65 (3H, m), 3.47 (1H, dd, J = 6.8, 9.6Hz), 3.60 (1H, dd, J = 8.2,9.3Hz), 4.52 (2H, s), 7.26-7.40 (5H, m) ppm.

Example 32
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methanol and (3-isopropenylden-2,2-dimethylcyclobutyl) methanol

E: Z = 30: of 2- (3-methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propyl = acetate (902 mg, 3.52 mmol) obtained in Example 20 in a reactor under a nitrogen atmosphere. A mixture of 70 geometric isomers, acetonitrile (24 g), triphenylphosphine (200 mg, 0.763 mmol) and bis (dibenzylideneacetone) palladium (200 mg, 0.348 mmol) were added, and the mixture was stirred at 20 ° C. Then, ammonium formate (670 mg, 10.6 mmol) was added, and the mixture was subsequently stirred under heating under reflux for 12 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired (3-isopropenyl-2,2-dimethylcyclobutyl) methanol (152 mg, 0.986 mmol). Was obtained as a 68:30: 2 isomer mixture of cis-form, trans-form and double bond positional isomer (3-isopropylidene-2,2-dimethylcyclobutyl) methanol in a yield of 28%. ..

The spectral data of cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methanol (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 0.82 (3H, s), 1.22 (3H, s), 1.55 (1H, q, J = 10.7 Hz), 1.65 ( 3H, s), 1.85-1.91 (1H, m), 2.03-2.10 (1H, m), 2.34-2.39 (1H, m), 3.52 (1H, m) dd, J = 6.5,10.7Hz), 3.59 (1H, dd, J = 8.3,10.7Hz), 4.55 (1H, brs), 4.78-4.81 (1H) , M) ppm.

The spectral data of trans- (3-isopropenyl-2,2-dimethylcyclobutyl) methanol (colorless to pale yellow oily liquid) obtained above are shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 0.95 (3H, s), 1.12 (3H, s), 1.51 (1H, brs), 1.58-1.63 (1H, m), 1.65 (3H, s), 1.76-1.90 (1H, m), 2.03-2.14 (1H, m), 2.53-2.59 (1H, m) , 3.69 (1H, dd, J = 7.6, 10.7Hz), 3.85 (1H, dd, J = 7.3, 10.7Hz), 4.62 (1H, brs), 4. 81-4.84 (1H, m) ppm.

Example 33
Production of 2-[(3-isopropenyl-2,2-dimethylcyclobutyl) methoxy] tetrahydropyran and 2-[(3-isopropylidene-2,2-dimethylcyclobutyl) methoxy] tetrahydropyran

In a nitrogen atmosphere, the reactor was charged with 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propyl acetate (46.2 g, 156 mmol) obtained in Example 21. The diastereomeric mixture, tetrahydrofuran (THF) (440 g), trioctylphosphine (2.31 g, 6.24 mmol) and palladium acetate (350 mg, 1.56 mmol) were added and stirred at 20 ° C. Then, in order to prepare triethylammonium formate in the reaction system, triethylamine (63.1 g, 623 mmol) and formic acid (21.5 g, 467 mmol) were added, and the mixture was subsequently stirred at 35 ° C. for 15 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, by distilling the obtained concentrate under reduced pressure, the desired 2-[(3-isopropenyl-2,2-dimethylcyclobutyl) methoxy] tetrahydropyran (35.3 g, 148 mmol) was added to the cis-form and trans. -Position of double bond with isomer Obtained in 95% yield as a 64: 35: 1 isomer mixture with isomer 2-[(3-isopropylidene-2,2-dimethylcyclobutyl) methoxy] tetrahydropyran. ..

The spectral data of 2-[(3-isopropenyl-2,2-dimethylcyclobutyl) methoxy] tetrahydropyran (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 0.78-1.25 (6H, m), 1.40-1.75 (10H, m), 1.76-2.62 (3H, m) ), 3.24-3.97 (4H, m), 4.50-4.65 (2H, m), 4.77-4.83 (1H, m) ppm.

Example 34
Production of 2-[(3-isopropenyl-2,2-dimethylcyclobutyl) methoxy] tetrahydropyran

A diastereomeric mixture of 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propane-1-ol obtained in Example 13 in a nitrogen atmosphere. (560 mg, 2.20 mmol), tetrahydrofuran (THF) (24 g), triphenylphosphine (761 mg, 2.90 mmol), N'-isopropylidene-2-nitrobenzenesulfonohydrazide (IPNBSH, 746 mg, 2.90 mmol) were added. , Stirred at 0 ° C. Then, a 40% toluene solution (1.22 g, 2.80 mmol) of diethyl azodicarboxylate (DEAD) was added, and the mixture was stirred for 2 hours while gradually raising the temperature to 30 ° C. Subsequently, a mixed solution of trifluoroethanol (14 g) and water (14 g) was added to the reaction mixture, and the mixture was stirred at 30 ° C. for 6 hours. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ether, and the separated organic layer was post-treated by conventional washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 40: 1) to obtain the desired 2-[(3-isopropenyl-2,2-dimethylcyclobutyl) methoxy] tetrahydropyran ( 202 mg, 0.846 mmol) was obtained as a 51:49 isomer mixture of cis-form and trans-form in a yield of 38%.
The double bond positional isomer 2-[(3-isopropylidene-2,2-dimethylcyclobutyl) methoxy] tetrahydropyran was not detected on GC.

Example 35
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate and (3-isopropylidene-2,2-dimethylcyclobutyl) methyl-acetate

The E: Z = 57: 43 geometry of [3- (2-acetoxy-1-methylethylidene) -2,2-dimethylcyclobutyl] methyl-acetate obtained in Example 24 was placed in the reactor under a nitrogen atmosphere. Add isomer mixture (483 mg, 1.90 mmol), acetonitrile (12 g), 2- (di-tert-butylphosphino) biphenyl (230 mg, 0.771 mmol), palladium acetate (40 mg, 0.18 mmol) and add at 20 ° C. Was stirred with. Then, in order to prepare triethylammonium formate in the reaction system, triethylamine (770 mg, 7.61 mmol) and formic acid (260 mg, 5.65 mmol) were added, and the mixture was subsequently stirred at 30 ° C. for 19 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to obtain the desired (3-isopropenyl-2,2-dimethylcyclobutyl) methyl acetate as a cis-form. Yield 88 as a 78:18: 4 isomer mixture (328 mg, 1.67 mmol) of trans-form and double-bonded position isomer (3-isopropyridene-2,2-dimethylcyclobutyl) methyl acetate. Obtained in%.

The spectral data of cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): νmax = 3080, 2957, 2870, 1743, 1647, 1460, 1385, 1368, 1240, 1162, 1031, 972, 886, 641, 607, 556 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 0.81 (3H, s), 1.19 (3H, s), 1.59 (1H, q, J = 10.7 Hz) 1.64 (3H) , T, J = 0.8Hz), 1.89 (1H, dt, J = 7.6, 10.7Hz), 2.02 (3H, s), 2.13-2.22 (1H, m) , 2.37-2.41 (1H, m), 3.94 (1H, dd, J = 8.6, 11.3Hz), 4.04 (1H, dd, J = 6.3, 11.3Hz) ), 4.56 (1H, brs), 4.79-4.82 (1H, m) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 16.07, 21.02, 22.92, 22.96, 30.92, 39.74, 41.05, 48.83, 64.95, 109 .42, 144.93, 171.05 ppm.

Example 36
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate and (3-isopropylidene-2,2-dimethylcyclobutyl) methyl-acetate

The E: Z = 57: 43 geometry of [3- (2-acetoxy-1-methylethylidene) -2,2-dimethylcyclobutyl] methyl-acetate obtained in Example 24 was placed in the reactor under a nitrogen atmosphere. The isomer mixture (483 mg, 1.90 mmol), acetonitrile (12 g), triphenylphosphine (200 mg, 0.763 mmol) and palladium acetate (40 mg, 0.18 mmol) were added, and the mixture was stirred at 20 ° C. Then, in order to prepare triethylammonium formate in the reaction system, triethylamine (770 mg, 7.61 mmol) and formic acid (260 mg, 5.65 mmol) were added, and the mixture was subsequently stirred under heating under reflux for 24 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to obtain the desired (3-isopropenyl-2,2-dimethylcyclobutyl) methyl acetate as a cis-form. Yield 86 as a 68:30: 2 isomer mixture (321 mg, 1.63 mmol) of trans-form and double-bonded position isomer (3-isopropylidene-2,2-dimethylcyclobutyl) methyl acetate. Obtained in%. The spectral data of the obtained cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate (colorless to pale yellow oily liquid) is the same as the spectral data obtained in Example 35. It was.

Example 37
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate and (3-isopropylidene-2,2-dimethylcyclobutyl) methyl-acetate

The E: Z = 57: 43 geometry of [3- (2-acetoxy-1-methylethylidene) -2,2-dimethylcyclobutyl] methyl-acetate obtained in Example 24 was placed in the reactor under a nitrogen atmosphere. The isomer mixture (1.86 g, 7.33 mmol), tetrahydrofuran (THF) (19 g), trioctylphosphine (220 mg, 0.594 mmol) and palladium acetate (33 mg, 0.15 mmol) were added and stirred at 20 ° C. Then, in order to prepare triethylammonium formate in the reaction system, triethylamine (2.97 g, 29.3 mmol) and formic acid (1.01 g, 22.0 mmol) were added, and the mixture was subsequently stirred at 35 ° C. for 5 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to obtain the desired (3-isopropenyl-2,2-dimethylcyclobutyl) methyl acetate as a cis-form. Collected as a 65:34: 1 isomer mixture (1.27 g, 6.45 mmol) of trans-form and double bond positional isomer (3-isopropylidene-2,2-dimethylcyclobutyl) methyl acetate. Obtained at a rate of 88%. The spectral data of the obtained cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate (colorless to pale yellow oily liquid) is the same as the spectral data obtained in Example 35. It was.

Example 38
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate and (3-isopropylidene-2,2-dimethylcyclobutyl) methyl-acetate

Palladium acetate (1.86 g, 8.27 mmol), tetrahydrofuran (THF) (1602 g), trioctylphosphine (12.3 g, 33.1 mmol), [3- (2-acetoxy-1), in a nitrogen atmosphere. -Methylethylidene) -2,2-dimethylcyclobutyl] A mixture of methyl-acetate E: Z = 70: 30 geometric isomers (420 g, 1.65 mol) was added and stirred at 45 ° C. Subsequently, a solution of triethylamine (335 g, 3.31 mol) and formic acid (114 g, 2.48 mol) in acetonitrile (MeCN) (335 g) was added dropwise so that the temperature inside the reactor did not exceed 50 ° C. After completion of the dropping, the mixture was stirred at 45 ° C. for 4 hours. Subsequently, acetic acid and a saline solution were added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate is distilled under reduced pressure to obtain the desired (3-isopropenyl-2,2-dimethylcyclobutyl) methyl acetate as a double bond positional isomer with the cis-form and the trans-form. A 68:31: 1 isomer mixture (310 g, 1.58 mmol) with 3-isopropylidene-2,2-dimethylcyclobutyl) methyl acetate was obtained in 96% yield. The spectral data of the obtained cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate (colorless to pale yellow oily liquid) is the same as the spectral data obtained in Example 35. It was.

Example 39
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate and (3-isopropylidene-2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate

In a nitrogen atmosphere, the reactor was charged with (3- [2- (2-methylbutanoyloxy) -1-methylethylidene] -2,2-dimethylcyclobutyl) methyl = 2-methylbuta obtained in Example 25. Noate (1.84 g, 5.43 mmol) E: Z = 50:50 isomer mixture, tetrahydrofuran (THF) (40 g), trioctylphosphine (160 mg, 0.436 mmol), palladium acetate (24 mg, 0. 11 mmol) was added, and the mixture was stirred at 20 ° C. for 1 hour. Then, in order to prepare triethylammonium formate in the reaction system, triethylamine (2.19 g, 21.7 mmol) and formic acid (750 mg, 16.3 mmol) were added, and the mixture was subsequently stirred at 35 ° C. for 24 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 1) to obtain the desired (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate. 64 of (1.15 g, 4.84 mmol) with cis-form and trans-form and double bond positional isomer (3-isopropylidene-2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate It was obtained as a mixture of 32: 4 isomers in a yield of 89%.

The spectral data of cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate (colorless to pale yellow oily liquid) obtained above is shown below.
¹ H-NMR (500MHz, CDCl ₃ ): δ = 0.81 (3H, s), 0.89 (3H, t, J = 7.5Hz), 1.11 (3H, q, J = 7.0Hz) ), 1.20 (3H, s), 1.40-1.51 (1H, m), 1.56-1.72 (5H, m), 1.87 (1H, dt, J = 7.6) , 10.7Hz), 2.13-2.22 (1H, m), 2.29-2.41 (2H, m), 3.92, 3.94 (1H, dd, J = 6.11) 11.1Hz, dd, J = 6.1, 11.1Hz), 4.04, 4.05 (1H, dd, J = 6.1, 11.1Hz, dd, J = 6.1, 11.1Hz ), 4.55 (1H, brs), 4.78-4.81 (1H, m) ppm.

Example 40
Production of 1-Chloromethyl-3-isopropenyl-2,2-dimethylcyclobutane and 1-chloromethyl-3-isopropylidene-2,2-dimethylcyclobutane

Geometric isomerism of E: Z = 50: 50 of 1-chloromethyl-3- (2-chloro-1-methylethylidene) -2,2-dimethylcyclobutane obtained in Example 26 in a reactor under a nitrogen atmosphere. The body mixture (988 mg, 4.77 mmol), tetrahydrofuran (THF) (20 g), trioctylphosphine (280 mg, 0.763 mmol) and palladium acetate (40 mg, 0.18 mmol) were added, and the mixture was stirred at 20 ° C. for 1 hour. Then, in order to prepare triethylammonium formate in the reaction system, triethylamine (1.93 g, 19.1 mmol) and formic acid (660 mg, 14.3 mmol) were added, and the mixture was subsequently stirred at 55 ° C. for 24 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane), and the target 1-chloromethyl-3-isopropenyl-2,2-dimethylcyclobutane was double-bonded to the cis-form and the trans-form. It was obtained as a 53: 46: 1 isomer mixture (553 mg, 3.20 mmol) with the positional isomer 1-chloromethyl-3-isopropyridene-2,2-dimethylcyclobutane in a yield of 67%.

The spectral data of 1-chloromethyl-3-isopropenyl-2,2-dimethylcyclobutane (colorless to pale yellow oily liquid) obtained above is shown below.
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 0.85,0.98 (3H, s), 1.14, 1.26 (3H, s), 1.57, 1.72 (1H, q) , J = 10.7Hz, m), 1.66-1.67 (3H, m), 1.98, 2.04-2.10 (1H, dt, J = 7.7, 10.7Hz, m) ), 2.15-2.30 (1H, m), 2.35-2.39, 2.52-2.57 (1H, m), 3.40-3.49, 3.60, 3. 72 (2H, m, dd, J = 8.8, 10.7Hz, dd, J = 6.8, 10.7Hz), 4.56, 4.66 (1H, brs, brs), 4.80- 4.83, 4.85-4.87 (1H, m) ppm.

Example 41
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methanol

A crude product (872 mg, 1.76 mmol) of triphenyl [2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propyl] phosphonium = bromide obtained in Example 27 was placed in the reactor under a nitrogen atmosphere. ), tetrahydrofuran (THF) (70 g) was added, and the mixture was stirred at 0 ° C. Subsequently, a 3.60 M toluene solution (2.00 ml, 7.20 mmol) of sodium bis (2-methoxyethoxy) aluminum hydrogen was added dropwise so that the temperature inside the reactor did not exceed 10 ° C. After completion of the dropping, the mixture was stirred for 1 hour while gradually raising the temperature to 20 ° C. Subsequently, a 10 wt% sodium hydroxide aqueous solution was added to the reaction mixture, and the separated organic layer was subjected to post-treatment by ordinary washing, drying and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), and the desired (3-isopropenyl-2,2-dimethylcyclobutyl) methanol was added to the cis-form and trans-. It was obtained as a 77:23 geometric isomer mixture (195 mg, 1.27 mmol) with the body in a yield of 72%. The obtained cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methanol (colorless to pale yellow oily liquid) and spectrum- (3-isopropenyl-2,2-dimethylcyclobutyl) methanol (colorless) The spectral data of (to pale yellow oily liquid) was the same as the spectral data obtained in Example 32, respectively.
The double bond positional isomer (3-isopropylidene-2,2-dimethylcyclobutyl) methanol was not detected on GC.

Example 42
(3-Isopropylidene-2,2-dimethylcyclobutyl) Methanol production

Lithium aluminum hydride (570 mg, 15.0 mmol) and tetrahydrofuran (THF) (60 g) were added to the reactor under a nitrogen atmosphere, and the mixture was stirred at 0 ° C. for 1 hour. In the solution is a mixture of [2,2-dimethyl-3- (1-methyl-2-bromoethylidene) cyclobutyl] methyl-acetate E: Z = 50: 50 geometric isomers obtained in Example 28 (1). .62 g, 5.89 mmol) was added dropwise so that the temperature inside the reactor did not exceed 5 ° C. After completion of the dropping, the mixture was stirred for 6 hours while gradually raising the temperature to 20 ° C. Subsequently, water (570 mg), a 15 wt% sodium hydroxide aqueous solution (570 mg), and then water (1.71 g) were further added to the reaction mixture. Then, the reaction mixture is filtered, the obtained filtrate is concentrated under reduced pressure, purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), and the desired (3-isopropyridene-2,2-dimethylcyclo) is purified. Butyl) methanol (909 mg, 5.89 mmol) was obtained in 100% yield.
The double bond positional isomer (3-isopropenyl-2,2-dimethylcyclobutyl) methanol was not detected on GC.

The spectral data of the (3-isopropyridene-2,2-dimethylcyclobutyl) methanol (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.15 (3H, s), 1.26 (3H, s), 1.45 (3H, s), 1.56-1.58 (3H,) m), 1.63 (1H, brs), 2.03-2.14 (2H, m), 2.54-2.62 (1H, m), 3.61 (1H, dd, J = 6. 9,10.7Hz), 3.76 (1H, dd, J = 7.7, 10.7Hz) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 18.48, 19.53, 20.90, 27.70, 28.67, 42.65, 44.05, 64.30, 122.42, 137. .39 ppm.

Example 43
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methanol and (3-isopropenylden-2,2-dimethylcyclobutyl) methanol

An isomer mixture of 2-[(3-isopropenyl-2,2-dimethylcyclobutyl) methoxy] tetrahydropyran obtained in Example 34 (32.7 g, 137 mmol), p-, was placed in the reactor under a nitrogen atmosphere. Toluenesulfonic acid (320 mg, 0.0019 mmol) and methanol (436 g) were added, and the mixture was stirred at 20 ° C. for 24 hours. Subsequently, baking soda (210 mg) was added to the reaction mixture, concentrated, and the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired (3-isopropenyl-2, A mixture of 2-dimethylcyclobutyl) methanol with cis-form and trans-form and double-bonded positional isomers (3-isopropylidene-2,2-dimethylcyclobutyl) methanol with a 64: 35: 1 isomer ( 21.1 g, 137 mmol) was obtained in a yield of 100%. The obtained cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methanol (colorless to pale yellow oily liquid) and spectrum- (3-isopropenyl-2,2-dimethylcyclobutyl) methanol (colorless) The spectral data of (to pale yellow oily liquid) was the same as the spectral data obtained in Example 32, respectively.

Example 44
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate

In a nitrogen atmosphere, the reactor was charged with an isomer mixture (154 mg, 1.00 mmol) of methanol (3-isopropenyl-2,2-dimethylcyclobutyl) obtained in Example 41 with cis: toluene = 77: 23. Pyridine (316 mg, 4.00 mmol) and toluene (10 g) were added, and the mixture was stirred at 0 ° C. Subsequently, acetic anhydride (204 mg, 2.00 mmol) was added dropwise so that the temperature inside the reactor did not exceed 10 ° C. After completion of the dropping, the mixture was stirred for 6 hours while gradually raising the temperature to 20 ° C. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to obtain the desired (3-isopropenyl-2,2-dimethylcyclobutyl) methyl acetate as a cis-form. A 77:23 isomer mixture (183 mg, 0.930 mmol) with the trans-form was obtained in a yield of 93%. The spectral data of the obtained cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate (colorless to pale yellow oily liquid) is the same as the spectral data obtained in Example 35. It was.

Example 45
Production of (3-isopropylidene-2,2-dimethylcyclobutyl) methyl-acetate

Under a nitrogen atmosphere, the reactor was charged with (3-isopropylidene-2,2-dimethylcyclobutyl) methanol (818 mg, 5.30 mmol), toluene (10 g), pyridine (1.68 g, 21) obtained in Example 42. .2 mmol) and acetic anhydride (1.09 g, 10.7 mmol) were added, and the mixture was stirred at 20 ° C. for 24 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to obtain the desired (3-isopropyridene-2,2-dimethylcyclobutyl) methyl acetate (911 mg, 4. 64 mmol) was obtained in a yield of 88%.

The spectral data of the (3-isopropyridene-2,2-dimethylcyclobutyl) methyl-acetate (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.13 (3H, s), 1.24 (3H, s), 1.45 (3H, s), 1.57 (3H, t, J = 1.9Hz), 2.03 (3H, s), 2.10-2.22 (2H, m), 2.56-2.63 (1H, m), 4.07-4.15 (2H, 2H,) m) ppm.

Example 46
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate and (3-isopropylidene-2,2-dimethylcyclobutyl) methyl-acetate

A mixture of 1-chloromethyl-3-isopropenyl-2,2-dimethylcyclobutane and 1-chloromethyl-3-isopropylidene-2,2-dimethylcyclobutane obtained in Example 40 was placed in a reactor under a nitrogen atmosphere. (535 mg, 3.10 mmol), sodium acetate (580 mg, 7.07 mmol), sodium iodide (100 mg, 0.667 mmol) and dimethylacetamide (DMAC, 20 g) were added, and the mixture was stirred at 150 ° C. for 24 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to obtain the desired (3-isopropenyl-2,2-dimethylcyclobutyl) methyl acetate as a cis-form. Yield 42 as a 57:42: 1 isomer mixture (255 mg, 1.30 mmol) of trans-form and double-bonded positional isomer (3-isopropyridene-2,2-dimethylcyclobutyl) methyl-acetate. Obtained in%. The spectral data of the obtained cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate (colorless to pale yellow oily liquid) is the same as the spectral data obtained in Example 35. It was.

Example 47
Production of (3-isopropylidene-2,2-dimethylcyclobutyl) methyl-methanesulfonate

Under a nitrogen atmosphere, the reactor was charged with the (3-isopropyridene-2,2-dimethylcyclobutyl) methanol (858 mg, 5.56 mmol) obtained in Example 42, tetrahydrofuran (THF) (20 g), triethylamine (1. 71 g, 16.9 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. Methanesulfonyl chloride (MsCl) (1.09 g, 10.7 mmol) was added dropwise to the solution so that the temperature inside the reactor did not exceed 10 ° C. After completion of the dropping, the mixture was stirred at 20 ° C. for 1 hour. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), and the desired (3-isopropyridene-2,2-dimethylcyclobutyl) methyl = methanesulfonate (1.29 g) was purified. , 5.56 mmol) was obtained in 100% yield.

The spectral data of the (3-isopropyridene-2,2-dimethylcyclobutyl) methyl-methanesulfonate (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.17 (3H, s), 1.27 (3H, s), 1.45 (3H, brs), 1.58 (3H, t, J = 1.9Hz), 2.15-2.22 (1H, m), 2.25-2.33 (1H, m), 2.61-2.67 (1H, m), 3.00 (3H, 3H,) s), 4.23 (1H, dd, J = 7.3, 9.9 Hz), 4.31 (1H, dd, J = 8.0, 10.0 Hz) ppm.

Example 48
Production of (3-isopropylidene-2,2-dimethylcyclobutyl) methyl = 3-methyl-2-butenoate

In a nitrogen atmosphere, the reactor was charged with the (3-isopropyridene-2,2-dimethylcyclobutyl) methyl-methanesulfonate (1.29 g, 5.56 mmol) obtained in Example 47, toluene (40 g), water ( 430 mg), senesioic acid (3-methyl-2-butenoic acid) (690 mg, 6.92 mmol), potassium carbonate (610 mg, 4.39 mmol), tetrabutylammonium-chloride (60 mg, 0.23 mmol), and 100 ° C. Was stirred for 24 hours. Subsequently, water was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to obtain the desired (3-isopropyridene-2,2-dimethylcyclobutyl) methyl = 3-methyl-2-. Butenoate (1.20 g, 5.06 mmol) was obtained in a yield of 91%.

The spectral data of (3-isopropyridene-2,2-dimethylcyclobutyl) methyl = 3-methyl-2-butenoate (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): νmax = 2965, 2917, 2864, 1719, 1659, 1449, 1376, 1361, 1349, 1272, 1227, 1146, 1076, 993,851 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.14 (3H, s), 1.25 (3H, s), 1.45 (3H, brs), 1.56-1.58 (3H,) m), 1.88 (3H, d, J = 1.5Hz), 2.12-2.30 (5H, m), 2.56-2.64 (1H, m), 4.11 (1H, 1H, dd, J = 6.8, 11.4 Hz), 4.15 (1H, dd, J = 8.0, 11.5 Hz), 5.64-5.66 (1 H, m) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 18.50, 19.54, 20.15, 20.99, 27.34, 27.78, 28.39, 39.14, 44.21, 64 .75, 116.15, 122.53, 137.18, 156.25, 166.82 ppm.

Example 49
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methanol and (3-isopropenylden-2,2-dimethylcyclobutyl) methanol

Under a nitrogen atmosphere, the reactor was charged with an isomer mixture of (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate obtained in Example 38 (60.3 g, 307 mmol), methanol (94 g), 25. A% aqueous sodium hydroxide solution (94 g) was added, and the mixture was stirred at 20 ° C. for 12 hours. Subsequently, a saline solution was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate is distilled under reduced pressure to obtain the desired (3-isopropenyl-2,2-dimethylcyclobutyl) methanol as a double bond positional isomer (3-isopropenyl-2,2-dimethylcyclobutyl) with a cis-form and a trans-form. It was obtained as a 67:32: 1 isomer mixture (46.0 g, 298 mmol) with isopropylidene-2,2-dimethylcyclobutyl) methanol in a yield of 97%. The obtained cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methanol (colorless to pale yellow oily liquid) and spectrum- (3-isopropenyl-2,2-dimethylcyclobutyl) methanol (colorless) The spectral data of (to pale yellow oily liquid) was the same as the spectral data obtained in Example 32, respectively.

Example 50
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate and (3-isopropylidene-2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate

An isomer mixture of methanol (3-isopropenyl-2,2-dimethylcyclobutyl) obtained in Example 49 (12.6 g, 82.0 mmol), tetrahydrofuran (THF) (100 g) was placed in the reactor under a nitrogen atmosphere. ) And pyridine (16.9 g, 213 mmol) were added, and the mixture was stirred at 0 ° C. 2-Methylbutanoyl chloride (12.9 g, 107 mmol) was added dropwise to the solution so that the temperature inside the reactor did not exceed 15 ° C. After completion of the dropping, the mixture was stirred for 6 hours while gradually raising the temperature to 20 ° C. Subsequently, a saline solution was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, by distilling the obtained concentrate under reduced pressure, the target (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate is double-bonded to the cis-form and the trans-form. Positional isomer (3-isopropylidene-2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate as a 68:31: 1 isomer mixture (19.5 g, 81.6 mmol) with a yield of 100 Obtained in%. The spectral data of the obtained cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate was the same as the spectral data obtained in Example 39.

Example 51
Production of (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = 3-methyl-3-butenoate and (3-isopropylidene-2,2-dimethylcyclobutyl) methyl = 3-methyl-3-butenoate

In a nitrogen atmosphere, the isomer mixture of methanol (3-isopropenyl-2,2-dimethylcyclobutyl) obtained in Example 49 (13.4 g, 86.6 mmol), dichloromethane (665 g), 3 -Methyl-3-butenoic acid (12.5 g, 125 mmol) and 4-dimethylaminopyridine (DMAP, 1.06 g, 8.66 mmol) were added, and the mixture was stirred at 0 ° C. N, N'-dicyclohexylcarbodiimide (DCC, 24.8 g, 120 mmol) was added to the solution. Then, the mixture was stirred for 2 hours while gradually raising the temperature to 20 ° C. Subsequently, ether and saline solution were added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 40: 1), and the target (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = 3-methyl-3-3. Butenoate is a 67: 32: 1 isomer of cis-form, trans-form and double bond position isomer (3-isopropyridene-2,2-dimethylcyclobutyl) methyl = 3-methyl-3-butenoate. It was obtained as a mixture (20.2 g, 85.6 mmol) in a yield of 99%.

The spectral data of cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = 3-methyl-3-butenoate (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): νmax = 3080, 2965, 2870, 1738, 1648, 1454, 1385, 1370, 1337, 1284, 1241, 1153, 1075, 1030, 994, 889 cm ^-1 .
¹ H-NMR (500MHz, CDCl ₃ ): δ = 0.80 (3H, s), 1.19 (3H, s), 1.61 (1H, q, J = 10.7Hz), 1.64- 1.65 (3H, m), 1.79-1.81 (3H, m), 1.88 (1H, dt, J = 10.7, 7.5Hz), 2.15-2.22 (1H) , M), 2.39 (1H, dd, J = 10.7, 7.5Hz), 3.00-3.01 (2H, m), 3.96 (1H, dd, J = 8.8, 11.1Hz), 4.07 (1H, dd,
J = 6.5, 11.1Hz), 4.56 (1H, s), 4.79-4.81 (1H, m), 4.83-4.84 (1H, m), 4.89- 4.91 (1H, m) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 16.09, 22.46, 22.86, 22.94, 30.91, 39.78, 41.07, 43.57, 48.81, 65 .12, 109.44, 114.61, 138.52, 144.94, 171.32 ppm.

Example 52
Production of (3-isopropylidene-2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate

Under a nitrogen atmosphere, the reactor was charged with (3-isopropylidene-2,2-dimethylcyclobutyl) methanol (9.16 g, 59.4 mmol), tetrahydrofuran (THF) (100 g), pyridine (3-isopropyridene-2,2-dimethylcyclobutyl). 14.1 g, 178 mmol) was added, and the mixture was stirred at 0 ° C. 2-Methylbutanoyl chloride (10.8 g, 89.2 mmol) was added dropwise to the solution so that the temperature inside the reactor did not exceed 15 ° C. After completion of the dropping, the mixture was stirred for 3 hours while gradually raising the temperature to 20 ° C. Subsequently, a saline solution was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrated solution is distilled under reduced pressure to obtain the desired (3-isopropyridene-2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate (14.2 g, 59.4 mmol) in yield. Obtained at 100%.

The spectral data of (3-isopropyridene-2,2-dimethylcyclobutyl) methyl = 2-methylbutanoate (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): νmax = 2964, 2935, 2878, 1735, 1461, 1383, 1361, 1264, 1240, 1186, 1152, 1081, 1013, 973, 889, 755 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 0.89 (3H, t, J = 7.5 Hz), 1.13 (3H, d, J = 8.0 Hz), 1.13 (3H, s) ), 1.24 (3H, s), 1.42-1.50 (4H, m), 1.57 (3H, t, J = 1.7Hz), 1.60-1.77 (1H, m) ), 2.09-2.23 (2H, m), 2.30-2.39 (1H, m), 2.55-2.61 (1H, m), 4.08-4.15 (2H) , M) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 11.64, 16.58, 16.63, 18.50, 19.54, 21.02, 21.04, 26.72, 26.75, 27 .50, 27.52, 28.40, 39.12, 39.15, 41.17, 44.20, 65.33, 122.60, 136.99, 176.73 ppm.

Example 53
Cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate and trans- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate obtained by the method of Example 35 and ( After separating the mixture of 3-isopropyridene-2,2-dimethylcyclobutyl) methyl = acetate by 10% silver nitrate silica gel column chromatography (hexane: ethyl acetate = 100: 1), 100: 43: 4, 100: 5 Mix to a weight ratio of 1, 100: 96: 96, and each consist of isoprene so that the amount of cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl = acetate carried is 200 μg. Luars A, B and C shown in Table 1 below were prepared by supporting them on a rubber cap.

Navel orange field in Port Elizabeth, South Africa Installed in. Then, the number of adult male worms of Planococcus citri (generic name: Citrus mearybug) killed in each trap was measured every other week. Each lure was replaced every month. Table 2 below shows the total number of adult males killed from late September to early February.

Lure B with low content of trans- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate and (3-isopropylidene-2,2-dimethylcyclobutyl) methyl-acetate is equivalent to commercial lures. While they showed attractive activity, lures A and C with high content did not show attractive activity. Therefore, it is considered that trans- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate and (3-isopropylidene-2,2-dimethylcyclobutyl) methyl-acetate have an attraction inhibitory activity.

The dimethylcyclobutane compound (1) is a (S, Z) -form dimethylcyclobutane compound represented by the following general formula (1-1), and is represented by the following general formula (1-2) (R, Z). -Form of dimethylcyclobutane compound, represented by the following general formula (1-3) (S, E) -form of dimethylcyclobutane compound, and represented by the following general formula (1-4) (R, E)- Included are dimethylcyclobutane compounds of the form, as well as racemic, diastereomeric and scalemic mixtures thereof.
Examples of the dimethylcyclobutane compound (1) include a dimethylcyclobutane compound having a hydroxyl group and an alkoxy group, a dimethylcyclobutane compound having an acyloxy group and an alkoxy group, a dimethylcyclobutane compound having a halogen atom and an alkoxy group, and a dimethylcyclobutane having a phosphonio group and an alkoxy group. Compound, dimethylcyclobutane compound having two hydroxyl groups, dimethylcyclobutane compound having two acyloxy groups, dimethylcyclobutane compound having two halogen atoms, dimethylcyclobutane compound having phosphonio group and hydroxyl group, dimethylcyclobutane having halogen atom and acyloxy group Examples include compounds.
Examples of the dimethylcyclobutane compound having a hydroxyl group and an alkoxy group include 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol and 2- (3-methoxymethoxymethyl-2,2-dimethyl). 2- (3-alkoxymethyl-) such as cyclobutylidene) propan-1-ol, 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propan-1-ol, etc. Examples thereof include 2,2-dimethylcyclobutylidene) propan-1-ol compound , 2- [3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutylidene] propan-1-ol compound (below). 11), 12, 13 and 16).
Examples of the dimethylcyclobutane compound having an acyloxy group and an alkoxy group include 2- (3-methoxymethoxymethyl-2,2-dimethylcyclobutylidene) propyl = acetate and 2- [2,2-dimethyl-3- (tetrahydropyran-). 2-Iloxymethyl) cyclobutylidene] 2- (3-alkoxymethyl-2,2-dimethylcyclobutylidene) propyl = acylate compounds such as propyl = acetate can be mentioned (see Examples 20 and 21 below). ).
Examples of the dimethylcyclobutane compound having a halogen atom and an alkoxy group include [3- (2-chloro-1-methylethylidene) -2,2-dimethylcyclobutyl] methoxymethylbenzene and [3- (2-bromo-1-methyl). ethylidene) -2,2-dimethyl-cyclobutyl] and methoxymethyl benzene 1-alkoxymethyl-3- (2-ha b - 1-methyl-ethylidene) -2,2-dimethyl-cyclobutane compounds and the like (the implementation of the following See Examples 17 and 18).
Examples of the dimethylcyclobutane compound having a phosphonio group and an alkoxy group include 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propyltriphenylphosphonium and the like [2- (3-alkoxymethyl-2,2-). Dimethylcyclobutylidene) propyl] triarylphosphonium compounds and the like (see Example 19 below).
Examples of the dimethylcyclobutane compound having two hydroxyl groups include 2- (3-hydroxyximethyl-2,2-dimethylcyclobutylidene) propane-1-ol (see Examples 14, 15, 22 and 23 below). ).
Examples of the dimethylcyclobutane compound having two acyloxy groups include [3- (2-acetoxy-1-methylethylidene) -2,2-dimethylcyclobutyl] methyl = acetate, (3- [2- (2-methylbutanoyl)). Oxy) -1-methylethylidene] -2,2-dimethylcyclobutyl) Methyl = 2-methylbutanoate and the like [3- (2-acyloxy-1-methylethylidene) -2,2-dimethylcyclobutyl] methyl = Axylate compounds and the like can be mentioned (see Examples 24 and 25 below).
Examples of the dimethylcyclobutane compound having two halogen atoms include 1-halomethyl-3- (2-halo-1) such as 1-chloromethyl-3- (2-chloro-1-methylethylidene) -2,2-dimethylcyclobutane. -Methylethylidene) -2,2-dimethylcyclobutane compounds and the like (see Example 26 below).
Examples of the dimethylcyclobutane compound having a phosphonio group and a hydroxyl group include [2- (3-hydroxymethyl-2,2-) such as triphenyl [2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propyl] phosphonium. Dimethylcyclobutylidene) propyl] triarylphosphonium compounds and the like (see Example 27 below).
Examples of the dimethylcyclobutane compound having a halogen atom and an acyloxy group include [2,2-dimethyl-3- ( 2-bromo-1-methylethylidene ) cyclobutyl] methyl-acetate and the like [2,2-dimethyl-3- ( 2). −Halo-1-methylethylidene ) cyclobutyl] methyl = acylate compounds and the like (see Example 28 below).

The isopropenyldimethylcyclobutane compound having a hydroxymethyl group represented by the following formula (5B) and / or the isopropylidenedimethylcyclobutane compound represented by the following formula (6B) are described above as shown by the following chemical reaction formula. can be produced by subjecting dimethyl cyclobutane compound having an acyloxy group and an alkoxy group with (1D) to a reduction reaction (see example 32 below). The reduction reaction is carried out with a reducing agent in the presence of a metal catalyst and optionally a ligand.

The above-mentioned isopropenyldimethylcyclobutane compound (5B) having a hydroxymethyl group and the above-mentioned isopropylidene dimethylcyclobutane compound (6B) are the above-mentioned isopropenyldimethylcyclobutane compounds having an acyloxymethyl group as shown by the following chemical reaction formula. It can be produced by a deprotection reaction between (5C) and / or the isopropyridene dimethylcyclobutane compound (6C) and a base (see Example 49 below).
The chemical reaction formula is to produce a mixture of compounds (5B) and (6B) from a mixture of compounds (5C) and (6C), to produce compound (5B) from compound (5C), and to compound (6C). ) To produce compound (6B).
Bases used in the deprotection reaction include nitrogen compounds such as ammonia and hydrazine, metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and sodium. = Methoxydo, sodium = ethoxide, sodium = t-butoxide, sodium = t-amyloxide, lithium = methoxyd, lithium = ethoxide, lithium = t-butoxide, lithium = t-amyloxide, potassium = methoxyd, potassium = ethoxydo, potassium = t Alkoxides such as -butoxide, potassium = t-amyloxide, triethylamine, diisopropylethylamine, tributylamine, N, N-dimethylaniline, N, N-diethylaniline, pyridine, 4-dimethylaminopyridine, imidazole, quinoline, pyrrolidine, piperidine , Collidine, lutidine, morpholine, organic base compounds such as 1,8-diazabicyclo [5.4.0] -7-undecene and the like.
The base may be used alone or in combination of two or more. Further, as the base, a commercially available one can be used.
The amount of the base used is preferably 0.00001 to 10,000 mol, more preferably 0, based on 1 mol of the total of the isopropenyldimethylcyclobutane compound (5C) and the isopropylidenedimethylcyclobutane compound (6C) having an acyloxymethyl group. It is .0001 to 1,000 mol, more preferably 0.001 to 100 mol.
Solvents in the deprotection reaction include ethers such as diethyl ether, dibutyl ether, tetrahydrofuran and 1,4-dioxane, hydrocarbons such as hexane, heptane, benzene, toluene, xylene and cumene, methylene chloride and chloroform. Chlorine-based solvents such as trichloroethylene, aprotic polar solvents such as N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethyl = sulfoxide, hexamethylphosphoric = triamide, acetonitrile, propio Examples thereof include nitriles such as nitrile, alcohols such as methanol, ethanol and t-butyl alcohol, and water.
The solvent may be used alone or in combination of two or more. Further, as the solvent, a commercially available solvent can be used.
The amount of the solvent used is preferably 10 to 10,000 g with respect to a total of 1 mol of the isopropenyldimethylcyclobutane compound (5C) having an acyloxymethyl group and the isopropylidenedimethylcyclobutane compound (6C).
The reaction temperature in the deprotection reaction is preferably −78 to 180 ° C., more preferably −60 to 160 ° C., and even more preferably −40 to 140 ° C.
The reaction time in the deprotection reaction can be set arbitrarily, but it is desirable to follow the reaction by gas chromatography (GC) or silica gel thin layer chromatography (TLC) to complete the reaction in terms of yield, and it is usually 0. It takes about 5 to 24 hours.

First, the pheromone composition will be described.
The sex pheromone composition comprises at least the (1R, 3R)-(3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate, which is the sex pheromone material of the Planococcus citri . It has been reported that the enantiomer (1S, 3S)-(3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate, which is also a cis-form, is not a sex pheromone substance but does not inhibit attraction. (J. Econ. Entomol. 97, 361 (2004)). Therefore, the cis-form may be contained in the sex pheromone composition, and for example, a racemic mixture of cis- (3-isopropenyl-2,2-dimethylcyclobutyl) methyl-acetate and a scalemic mixture are used. be able to.
In addition, the pheromone composition is a trans-form (1S, 3R)-(3-isopropenyl-2,2-dimethylcyclobutyl) methyl = acetate and / or (1R, 3S)-(3-iso. propenyl-2,2-dimethyl) methyl = acetate, it may also contain, optionally further (3-2,2-dimethyl) methyl = acetate (6; ^{X 6} is , Acetoxy group) methyl isomer, (R)-(3-isopropylidene-2,2-dimethylcyclobutyl) methyl = acetate, and / or (S)-(3-isopropylidene-2,2-,2-) Dimethylcyclobutyl) Methyl = acetate may be included.

The spectral data of 3- (1-ethoxyethoxy) methyl-2,2-dimethylcyclobutanone (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): ν max = 2973,2932,2871,1779,1463,1446,1380,1341,1268,1133,1087,1062,986,946,869 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.11 (1.5H, s), 1.12 (1.5H, s), 1.19 (3H, t, J = 7.1 Hz), 1.210 (1.5H, s), 1.211 (1.5H, s), 1.29 (3H, d, J = 5.4Hz), 2.27-2.34 (1H, m), 2.74 (0.5H, dd, J = 1.4, 17.6Hz), 2.75 (0.5H, dd, J = 1.3, 17.6Hz), 3.10 (0.5H, 0.5H, dd, J = 2.9, 17.6Hz), 3.12 (0.5H, dd, J = 3.0, 17.6Hz), 3.42-3.76 (4H, m), 4.66 -4.70 (1H, m) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 15.23, 15.25, 16.69, 16.72, 19.64, 19.70, 23.99, 24.03, 35.62, 35 .65, 45.77, 60.67, 60.74, 60.93, 65.08, 65.55, 99.58, 99.75, 214.27, 214.29 ppm.

The spectral data of 3- (1-allyloxyethoxy) methyl-2,2-dimethylcyclobutanone (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): ν max = 3081,263,2930, 2869, 1779, 1647, 1463, 1383, 1344, 1267, 1132, 1098, 1066, 1040, 993,923 cm ^-1 .
¹ H-NMR (500 MHz, CDCl ₃ ): δ = 1.11 (1.5H, s), 1.12 (1.5H, s), 1.212 (1.5H, s), 1.214 ( 1.5H, s), 1.31 (3H, d, J = 5.4Hz), 2.28-2.34 (1H, m), 2.75 (0.5H, dd, J = 1.5) , 17.6Hz), 2.76 (0.5H, dd, J = 1.5, 17.6Hz), 3.10 (0.5H, dd, J = 3.0, 17.6Hz), 3. 12 (0.5H, dd, J = 3.3, 17.6Hz), 3.51 (0.5H, dd, J = 6.7, 9.8Hz), 3.56 (0.5H, dd, J = 7.5, 9.8Hz), 3.69 (0.5H, dd, J = 6.8, 9.8Hz), 3.74 (0.5H, dd, J = 7.6, 9. 8Hz), 3.96-4.00 (1H, m), 4.06-4.11 (1H, m), 4.72-4.76 (1H, m), 5.13-5.17 (1H, m) 1H, m), 5.24-5.29 (1H, m), 5.85-5.93 (1H, m) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): δ = 16.72, 16.74, 19.53, 19.60, 23.98, 24.01, 35.60, 35.62, 45.76, 60 .68, 65.04, 65.49, 66.09, 66.26, 99.21, 99.40, 116.65, 134.53, 134.55, 214.20, 214.22 ppm.

The spectral data of 3-allyloxymethyl-2,2-dimethylcyclobutanone (colorless to pale yellow oily liquid) obtained above is shown below.
IR (D-ATR): ν max = 3534,3081,296,2929,2866, 1779, 1647, 1464, 1400, 1381, 1363, 1328, 1264, 1090, 1066, 994, 926,561 cm ^-1 .
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.12 (3H, s), 1.21 (3H, s), 2.30-2.37 (1H, m), 2.75 (1H, 1H, dd, J = 6.8, 17.6Hz), 3.10 (1H, dd, J = 9.2, 17.6Hz), 3.52 (1H, dd, J = 6.5, 9.6Hz) , 3.58 (1H, dd, J = 7.6, 9.6Hz), 3.93-4.01 (2H, m), 5.15-5.19 (1H, m), 5.23- 5.28 (1H, m), 5.84-5.93 (1H, m) ppm.
¹³ C-NMR (150 MHz, CDCl ₃ ): 16.65, 23.99, 35.60, 45.60, 60.78, 70.43, 72.01, 116.98, 134.56, 214.27 ppm ..

Under a nitrogen atmosphere, a 3.60 M toluene solution of bis (2-methoxyethoxy) aluminum sodium hydride (120 ml, 432 mmol) and toluene (122 g) were added to the reactor, and the mixture was stirred at 0 ° C. Diastereomers of ethyl = 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propanoate (71.4 g, 241 mmol) obtained according to Example 7 in the solution. The mixture was added dropwise so that the temperature inside the reactor did not exceed 10 ° C. After completion of the dropping, the mixture was stirred for 9 hours while gradually raising the temperature to 26 ° C. Subsequently, an aqueous solution of caustic soda is added to the reaction mixture, and the separated organic layer is subjected to post-treatment by ordinary washing, drying and concentration to obtain the desired 2- [2,2-dimethyl-3- (tetrahydropyran-2-yl)). A crude product of oxymethyl) cyclobutylidene] propan-1-ol (50.4 g, 198 mmol) was obtained as a diastereomeric mixture in a crude yield of 82%.

E: Z = of 2- (3-benzyloxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol (469 mg, 1.80 mmol) obtained in Example 11 was placed in the reactor under a nitrogen atmosphere. 30 : A mixture of 70 geometric isomers, methylene chloride (30 g) and triphenylphosphine (734 mg, 2.80 mmol) were added and stirred at 0 ° C. Then, carbon tetrabromide (929 mg, 2.80 mmol) was added, and the mixture was stirred for 15 hours while gradually raising the temperature to 25 ° C. Subsequently, 3 ml of ethanol was added to the reaction mixture, which was then concentrated and the precipitated triphenylphosphine-oxide was removed by filtration through hexane. The obtained filtrate was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to obtain the desired [3- (2-bromo-1-methylethylidene) -2,2-dimethylcyclobutyl]. Methoxymethylbenzene (454 mg, 1.40 mmol) was obtained as a geometric isomer mixture of E: Z = 30 : 70 in a yield of 78%.

A diastereomeric mixture of 2- [2,2-dimethyl-3- (tetrahydropyran-2-yloxymethyl) cyclobutylidene] propan-1-ol obtained in Example 13 in a reactor under a nitrogen atmosphere. (45.0 g, 177 mmol), p-toluenesulfonic acid (189 mg, 0.0011 mmol) and methanol (1100 g) were added, and the mixture was stirred at 20 ° C. for 24 hours. Subsequently, baking soda (200 mg) was added to the reaction mixture, and the mixture was concentrated to crudely produce the desired 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol (30.1 g, 177 mmol). The product was obtained as a mixture of geometric isomers with E: Z = 50: 50 in a crude yield of 100%. The obtained spectral data of 2- (3-hydroxymethyl-2,2-dimethylcyclobutylidene) propan-1-ol (colorless to pale yellow oily liquid) is the same as the spectral data obtained in Example 14. It was the same.

Example 28
[2,2-Dimethyl-3- ( 2-bromo-1-methylethylidene ) cyclobutyl] Production of methyl-acetate

The E: Z = 50: 50 geometry of [3- (2-acetoxy-1-methylethylidene) -2,2-dimethylcyclobutyl] methyl-acetate obtained in Example 24 was placed in the reactor under a nitrogen atmosphere. An isomer mixture (1.78 g, 6.99 mmol), methylene chloride (30 g) and a 30% hydrogen bromide acetic acid solution (2.83 g, 10.5 mmol) were added, and the mixture was stirred at 20 ° C. for 6 hours. Subsequently, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the separated organic layer was post-treated by ordinary washing, drying, and concentration. Then, the obtained concentrate was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to obtain the desired [2,2-dimethyl-3- ( 2-bromo-1-methylethylidene ) cyclobutyl] methyl. = Acetic acid was obtained as a mixture of geometric isomers of E: Z = 50: 50 (1.70 g, 6.18 mmol) in a yield of 88%.

The spectral data of [2,2-dimethyl-3- ( 2-bromo-1-methylethylidene ) cyclobutyl] methyl-acetate (colorless to pale yellow oily liquid) obtained above is shown below.
^{1 1} H-NMR (500 MHz, CDCl ₃ ): δ = 1.15, 1.20 (3H, s, s), 1.26, 1.31 (3H, s, s), 1.59-1.60 , 1.70-171 (3H, m), 2.03 (3H, s), 2.15-2.29 (2H, m), 2.60-2.75 (1H, m), 3.82 , 3.94, 3.97 (2H, s, d, J = 9.6Hz, d, J = 9.6Hz), 4.08-4.15 (2H, m) ppm.

Lithium aluminum hydride (570 mg, 15.0 mmol) and tetrahydrofuran (THF) (60 g) were added to the reactor under a nitrogen atmosphere, and the mixture was stirred at 0 ° C. for 1 hour. A mixture of E: Z = 50: 50 geometric isomers of [2,2-dimethyl-3- ( 2-bromo-1-methylethylidene ) cyclobutyl] methyl acetate obtained in Example 28 in the solution (1). .62 g, 5.89 mmol) was added dropwise so that the temperature inside the reactor did not exceed 5 ° C. After completion of the dropping, the mixture was stirred for 6 hours while gradually raising the temperature to 20 ° C. Subsequently, water (570 mg), a 15 wt% sodium hydroxide aqueous solution (570 mg), and then water (1.71 g) were further added to the reaction mixture. Then, the reaction mixture is filtered, the obtained filtrate is concentrated under reduced pressure, purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), and the desired (3-isopropyridene-2,2-dimethylcyclo) is purified. Butyl) methanol (909 mg, 5.89 mmol) was obtained in 100% yield.
The double bond positional isomer (3-isopropenyl-2,2-dimethylcyclobutyl) methanol was not detected on GC.

Claims (7)

The following general formula (2)
(In the formula, X ² is an acyloxy group having 1 to 10 carbon atoms including carbon of a hydroxyl group and a carbonyl group, an alkoxycarbonyloxy group having 2 to 10 carbon atoms including carbon of a carbonyl group, and 1 to 10 carbon atoms. It represents an alkane sulfonyloxy group, an allene sulfonyloxy group having 6 to 20 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, a silyloxy group having 3 to 20 carbon atoms, or a halogen atom. The dimethylcyclobutanone compound represented by and the following general formula (3)
(In the formula, R ¹ and R ² each independently represent a monovalent hydrocarbon group having 1 to 10 carbon atoms.)
Depending on the reaction with the phosphonic acid ester compound represented by, the following general formula (4)
(Wherein, R ^1, X ² is the is as defined in.) And is expressed by, give the unsaturated ester compounds with dimethyl cyclobutane ring step,
By subjecting the unsaturated ester compound (4) having a dimethylcyclobutane ring to a reduction reaction, the following general formula (1A)
(Wherein, ^{X 3} represents a hydroxyl group, alkanesulfonyloxy group having 1 to 10 carbon atoms, arenesulfonyl group having 6 to 20 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryloxy group having 6 to 12 carbon atoms A method for producing a dimethylcyclobutane compound (1A), which comprises at least a step of obtaining a dimethylcyclobutane compound represented by (representing a silyloxy group or a halogen atom having 3 to 20 carbon atoms). Each step in the production method according to claim 1 of the dimethylcyclobutane compound (1A), and
The dimethylcyclobutane compound hydroxyl group of (1A), and optionally X ^3, by converting the general formula (1B)
(Wherein, X ⁴ is an acyloxy group having 1 to 10 carbon atoms including carbon atoms of carbonyl groups, alkoxycarbonyloxy groups having 2 to 10 carbon atoms including carbon atoms of carbonyl groups, alkanesulfonyl of 1 to 10 carbon atoms Oxy group, allene sulfonyloxy group with 6 to 20 carbon atoms, alkoxy group with 1 to 12 carbon atoms, aryloxy group with 6 to 12 carbon atoms, silyloxy group with 3 to 20 carbon atoms, trialkyl with 3 to 30 carbon atoms phosphonio group, a triaryl phosphonium niobium group or a halogen atom 12 to 30 carbon atoms, and, X ⁵ represents a hydroxyl group, an acyloxy group having 1 to 10 carbon atoms including carbon atoms of carbonyl groups, the carbon of the carbonyl group Including alkoxycarbonyloxy groups having 2 to 10 carbon atoms, alcansulfonyloxy groups having 1 to 10 carbon atoms, arene sulfonyloxy groups having 6 to 20 carbon atoms, alkoxy groups having 1 to 12 carbon atoms, and 6 to 12 carbon atoms. A step of obtaining a dimethylcyclobutane compound represented by an aryloxy group, a silyloxy group having 3 to 20 carbon atoms or a halogen atom), and
A method for producing a dimethylcyclobutane compound (1B), which comprises at least. The following general formula (1)
(In the formula, X ¹ is an acyloxy group having 1 to 10 carbon atoms including a hydroxyl group and a carbon of a carbonyl group, an alkoxycarbonyloxy group having 2 to 10 carbon atoms including a carbon of a carbonyl group, and 1 to 10 carbon atoms. Alcan sulfonyloxy group, allene sulfonyloxy group having 6 to 20 carbon atoms, alkoxy group having 1 to 12 carbon atoms, aryloxy group having 6 to 12 carbon atoms, silyloxy group having 3 to 20 carbon atoms, carbonyl group 3 to 30 trialkyl phosphonium niobium group, a triaryl phosphonium niobium group or a halogen atom 12 to 30 carbon atoms, and, X ² represents a hydroxyl group, an acyloxy group having 1 to 10 carbon atoms including carbon atoms of carbonyl groups, carbonyl groups Alkoxycarbonyloxy groups with 2 to 10 carbon atoms including carbon, alcansulfonyloxy groups with 1 to 10 carbon atoms, arene sulfonyloxy groups with 6 to 20 carbon atoms, alkoxy groups with 1 to 12 carbon atoms, 6 to 12 carbon atoms By subjecting the dimethylcyclobutane compound represented by 12 aryloxy groups, silyloxy groups having 3 to 20 carbon atoms or halogen atoms) to the reduction reaction, the following general formula (5)
(Wherein, X ⁶ represents a hydroxyl group, an acyloxy group having 1 to 10 carbon atoms including carbon atoms of carbonyl groups, alkoxycarbonyloxy groups having 2 to 10 carbon atoms including carbon atoms of carbonyl groups, having 1 to 10 carbon atoms It represents an alkane sulfonyloxy group, an allene sulfonyloxy group having 6 to 20 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, a silyloxy group having 3 to 20 carbon atoms, or a halogen atom. Isopropenyldimethylcyclobutane compound represented by and / or the following general formula (6)
(Wherein, X ⁶ is as defined above.) Comprising at least the step of obtaining the isopropylidene dimethylcyclobutane compound represented by, isopropenyl dimethyl cyclobutane compound (5) and / or isopropylidene dimethylcyclobutane compound ( 6) Manufacturing method. The step in the production method according to claim 3 for the isopropenyldimethylcyclobutane compound (5) and / or the isopropylidenedimethylcyclobutane compound (6).
Isopropenyl by converting the specific group X ⁶ in the isopropenyl dimethylcyclobutane compound (5) and / or the isopropylidene dimethylcyclobutane compound (6) into another group X ⁶ in the choice of X ⁶ defined above. Preparation of isopropenyldimethylcyclobutane compound (5') and / or isopropyridene dimethylcyclobutane compound (6') comprising at least a step of obtaining a dimethylcyclobutane compound (5') and / or an isopropylidene dimethylcyclobutane compound (6'). Method. The following general formula (1)
(In the formula, X ¹ is an acyloxy group having 1 to 10 carbon atoms including a hydroxyl group and a carbon of a carbonyl group, an alkoxycarbonyloxy group having 2 to 10 carbon atoms including a carbon of a carbonyl group, and 1 to 10 carbon atoms. Alcan sulfonyloxy group, allene sulfonyloxy group having 6 to 20 carbon atoms, alkoxy group having 1 to 12 carbon atoms, aryloxy group having 6 to 12 carbon atoms, silyloxy group having 3 to 20 carbon atoms, carbonyl group 3 to 30 trialkyl phosphonium niobium group, a triaryl phosphonium niobium group or a halogen atom 12 to 30 carbon atoms, and, X ² represents a hydroxyl group, an acyloxy group having 1 to 10 carbon atoms including carbon atoms of carbonyl groups, carbonyl groups Alkoxycarbonyloxy groups with 2 to 10 carbon atoms including carbon, alcansulfonyloxy groups with 1 to 10 carbon atoms, arene sulfonyloxy groups with 6 to 20 carbon atoms, alkoxy groups with 1 to 12 carbon atoms, 6 to 12 carbon atoms A dimethylcyclobutane compound represented by 12 aryloxy groups, a silyloxy group having 3 to 20 carbon atoms, or a halogen atom). The following general formula (7)
(In the formula, X ⁹ represents a halogen atom.) The acid halide represented by the following general formula (8).
(Wherein, X ¹² is an acyloxy group having 1 to 10 carbon atoms including carbon atoms of carbonyl groups, alkoxycarbonyloxy groups having 2 to 10 carbon atoms including carbon atoms of carbonyl groups, alkanesulfonyl of 1 to 10 carbon atoms Represents an oxy group, an allene sulfonyloxy group having 6 to 20 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, a silyloxy group having 3 to 20 carbon atoms or a halogen atom). Depending on the reaction between the allyl compound and the base, the following general formula (2A)
(Wherein, X ¹² is as defined above.) Represented by, comprising at least the step of obtaining a dimethyl cyclobutanone compound, method for producing dimethyl cyclobutanone compound (2A). The following general formula (2B)
(Wherein, X ¹³ is an acyloxy group having 3 to 10 carbon atoms including carbon atoms of carbonyl groups, alkoxycarbonyloxy groups having 2 to 10 carbon atoms including carbon atoms of carbonyl groups, alkanesulfonyl of 1 to 10 carbon atoms It represents an oxy group, an allene sulfonyloxy group having 6 to 20 carbon atoms, an alkoxy group having 2 to 12 carbon atoms excluding the benzyloxy group, an aryloxy group having 6 to 12 carbon atoms, or a silyloxy group having 3 to 20 carbon atoms. )
A dimethylcyclobutanone compound represented by.