JP2017002006A - Method for producing carbonyl compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an efficient method for producing a carbonyl compound useful as a raw material for pharmaceuticals, agricultural chemicals, liquid crystal materials, etc., or an intermediate thereof. A cis-2,5-disubstituted 6-membered heterocyclic compound, or cis-2, of a 2,5-disubstituted 6-membered heterocyclic compound represented by the general formula (i): , 5-disubstituted 6-membered heterocyclic compound and trans-2,5-disubstituted 6-membered heterocyclic compound are reacted with an acid or base to react with the mass of the cis-isomer in the compound or mixture. The value of (mass of trans isomer) / (mass of cis isomer) (the mass of trans isomer) / (mass of cis isomer) before reacting with acid or base, which is the ratio of the mass of the trans isomer “Trans isomers” can be selectively obtained at a high ratio by the production method of larger mixtures. [Selection figure] None

Description

  The present invention relates to the production of a method for producing a carbonyl compound.

  Carbonyl compounds are widely used as medicines / pesticides, electronic materials including liquid crystals, raw materials such as resins, or intermediates thereof. Among them, a carbonyl group is bonded to a ring structure such as a 1,4-phenylene group, a cyclohexane-1,4-diyl group, a tetrahydropyran-2,5-diyl group, or a 1,3-dioxane-2,5-diyl group. A carbonyl compound is frequently used as a compound used in a liquid crystal composition or an intermediate for synthesizing the compound.

  In the case of a disubstituted cyclic compound having a tetrahydropyran-2,5-diyl group, a 1,3-dioxane-2,5-diyl group, etc., the tetrahydropyran-2,5-diyl group in the molecule and 1,3 -There are stereoisomers in which the dioxane-2,5-diyl group and the like are in a "cis form" and a "trans form". For example, when a compound having at least one 1,3-dioxane-2,5-diyl group in the molecule is produced, generally, at least one 1,3-dioxane-2,5-diyl group is a cis-form. And a mixture of all 1,3-dioxane-2,5-diyl groups in a trans form (mixture of isomers). However, when a compound having a cis isomer in the molecule is added to the liquid crystal composition, the liquid crystal properties of the liquid crystal composition are deteriorated. Therefore, the compound used as a component of the liquid crystal composition has a cis isomer ratio of 0% (for example, presently Preferably 0% in the sense that the presence of a compound having a cis isomer in the molecule cannot be substantially detected even using the best analytical means that can be used, and usually a compound having a cis isomer in the molecule The refining is repeated until the content of is about several ppm.

  When the content of the compound having a cis isomer in the molecule is set to about several ppm, the purification operation such as recrystallization is repeatedly performed on the mixture of stereoisomers obtained after the production of the compound, which is not the purpose. Although the removal of the three-dimensional structure compound is performed exclusively, repeated recrystallization has led to a decrease in the yield of the target product and an increase in production cost. Therefore, in order to further improve the yield, selective synthesis of “cis isomer” and “trans isomer” is required.

  Non-Patent Document 1 and Non-Patent Document 2 include boron trifluoride or three compounds for compounds having a dioxane skeleton or a dithian skeleton substituted with various functional groups such as a carboxyl group, a hydroxyl group, a sulfone, and a thiol. Isomerization conditions using a combination of boron fluoride and additives are disclosed. However, although Non-Patent Document 1 and Non-Patent Document 2 disclose the energy difference between “cis isomer” and “trans isomer”, the ratio of cis-trans isomer to “cis isomer” or “trans isomer” It is not something to focus on. Whether to obtain “cis isomer” or “trans isomer” preferentially depends on the substrate, and therefore the selectivity is not sufficiently high.

  Patent Document 1 discloses a method of obtaining a “trans isomer” from a “cis isomer” using a substrate in which an alkyl group and an alkylphenyl group are substituted for dioxane, but the trans isomer is obtained only by an isomerization reaction. The ratio is not sufficiently high, and the yield is only moderate. Therefore, there is a demand for selective isomerization conditions that can obtain a trans isomer at a higher ratio.

J. Org. Chem. 2004, 69, 9063-9072. Tetrahedron Lett. 2002, 43. 9369-9372.

Chinese Patent Application No. 102633768

  The problem to be solved by the present invention is to provide a production method capable of selectively obtaining a “trans isomer” at a high ratio in a carbonyl compound in which a carbonyl group is bonded to a 2,5-disubstituted 6-membered heterocyclic compound. There is.

  As a result of intensive studies to solve the above problems, it has been found that the inclusion of a carbonyl group causes keto-enol tautomerism, which promotes isomerization and provides a trans isomer at a high ratio. The invention has been completed.

  That is, the present invention relates to the general formula (i)

(Wherein R ⁱ¹ represents an alkyl group having 1 to 20 carbon atoms, R ⁱ² represents a hydrogen atom or an alkyl group having 1 to 20 carbon atoms, and one or more of R ⁱ¹ and R ⁱ² —CH ₂ — each independently represents —CH═CH—, —C≡C—, —O—, —S—, —NR ⁱ⁴ —, —N═CH—, —CH═N—, —CH═. N—N═CH—, —CO—, —COO—, —OCO—, —CH ₂ O—, —OCH ₂ —, —CF ₂ O—, —OCF ₂ — or (a) 1,4-cyclohexylene group (this is present in the group one -CH ₂ - or nonadjacent two or more -CH ₂ - is -O -, - S- and ^{-NR i5} - may be substituted in.)
(B) 1,4-phenylene group (one —CH═ present in this group or two or more non-adjacent —CH═ may be substituted with —N═)
(C) Naphthalene-2,6-diyl group, 1,2,3,4-tetrahydronaphthalene-2,6-diyl group or decahydronaphthalene-2,6-diyl group (naphthalene-2,6-diyl group or One —CH═ present in the 1,2,3,4-tetrahydronaphthalene-2,6-diyl group or two or more non-adjacent —CH═ may be substituted with —N═. .)
One or two or more hydrogen atoms in R ⁱ¹ and R ⁱ² may each independently be a cyano group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. May be replaced with
X ⁱ¹ and X ⁱ² each independently represent —O—, —NR ⁱ⁶ —, —S— or —CH ₂ —, wherein at least one of X ⁱ¹ and X ⁱ² represents —O—, —NR ⁱ⁶ —, -S-
R ⁱ⁴ , R ⁱ⁵ and R ⁱ⁶ represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. )
A cis-2,5-disubstituted 6-membered heterocyclic compound, or a cis-2,5-disubstituted 6-membered heterocyclic compound and a trans -By reacting a mixture containing a 2,5-disubstituted 6-membered heterocyclic compound with an acid or base, a cis-2,5-disubstituted 6-membered heterocyclic compound (cis isomer) in the compound or mixture ) Is the ratio of the mass of the trans-2,5-disubstituted six-membered heterocyclic compound (trans isomer) to the mass of (trans isomer) / (cis isomer mass) is an acid or base A method for producing a mixture having a value larger than the value of (mass of trans isomer) / (mass of cis isomer) before reacting with A.

  According to the production method of the present invention, a carbonyl compound having a carbonyl group bonded to a six-membered heterocyclic structure can be converted from a cis isomer to a trans isomer with high selectivity. Therefore, the target trans compound can be obtained in high yield.

The present invention relates to a cis-2,5-disubstituted 6-membered heterocyclic compound represented by the general formula (i), or a cis-2,5-disubstituted 6-membered heterocyclic compound and trans-2,5- In a mixture containing a disubstituted 6-membered heterocyclic compound, by reacting with an acid or base, the ratio of the mass of the trans isomer to the mass of the cis isomer in the mixture is made larger than the value before the reaction. . Here, when the compound represented by the general formula (i) has a plurality of disubstituted heterocyclic structures, for example, “trans, trans isomer”, “trans, cis isomer”, “cis, trans isomer”, “cis cis” In the present invention, the “cis isomer of general formula (i)” is an isomer in which the ring having X ⁱ¹ and X ⁱ² in general formula (i) represents a cis isomer. The “trans isomer of general formula (i)” refers to an isomer in which the ring having X ⁱ¹ and X ⁱ² in general formula (i) represents a trans isomer.

Since the compound represented by the general formula (i) contains a carbonyl group and the proton at the α-position of the carbonyl group is active, the present invention exhibits keto-enol tautomerism under either acidic or basic conditions. Occurrence promotes isomerization. Any acid and base may be used as long as they allow the reaction to proceed suitably. Specifically, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, carbonate Sodium hydride, sodium methoxide, sodium ethoxide, lithium diisopropylpyramide, sodium hydride, potassium hydride, triethylamine, diisopropylethylamine, pyrrolidine, pyridine, N, N-dimethyl-4-aminopyridine, 1,8- Bases such as diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, p -Toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethane Sulfonic acid, formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, boron trifluoride, aluminum chloride, and acids such as titanium tetrachloride. Under acidic conditions, isomerization is further promoted by the opening and closing of a heterocyclic ring in which both X ⁱ¹ and X ⁱ² in formula (i) are either —O—, —NR ⁱ⁶ — or —S—. Therefore, it is preferable.

  Moreover, in order to obtain a compound of a trans isomer with higher selectivity, among the examples described above, Bronsted acids such as p-toluenesulfonic acid and methanesulfonic acid that do not contain a metal cation, and boron trifluoride, etc. It is preferable to use a Lewis acid, and a Bronsted acid such as p-toluenesulfonic acid and methanesulfonic acid is more preferable. When an isomerization reaction is performed in the presence of a metal cation in the system, as shown in the figure below, the structure in which the metal cation is chelated by the oxygen atom of the carbonyl group and the hetero atom in the heterocyclic ring contributes to stabilization. Since it is presumed that the formation of a cis isomer is advantageous kinetically or thermodynamically, it is preferable that the metal ion does not exist in the reaction system, or even if it exists, the abundance is suppressed.

(In the ^{figure, R i1, R i2, X} i1, X i2 represents in the general formula ^{(i) R i1, R i2} , X i1, X i2, M + is a metal cation.)
The temperature when reacting with the Bronsted acid is preferably 0 ° C to 150 ° C, more preferably 50 ° C to 130 ° C, and the temperature when reacting with the Lewis acid is -78 ° C to The temperature is preferably 100 ° C, more preferably -78 ° C to 25 ° C, and the temperature at the time of reaction with the base is preferably -40 ° C to 150 ° C, preferably 0 ° C to 100 ° C. More preferably, it is temperature.

  The solvent used in the reaction may be any as long as it allows the reaction to proceed suitably, but ether solvents, chlorine solvents, hydrocarbon solvents, aromatic solvents, polar solvents, and the like are preferably used. it can. Examples of ether solvents include 1,4-dioxane, 1,3-dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, and t-butyl methyl ether, and examples of chlorine solvents include dichloromethane, chloroform, 1,2-dichloroethane, and four. Carbon chloride and the like, pentane, hexane, cyclohexane, heptane and octane as hydrocarbon solvents, benzene, toluene, xylene, mesitylene, chlorobenzene and dichlorobenzene as aromatic solvents, N, Preferable examples include N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, methanol and the like.

  When reacting with Bronsted acid, ether solvents such as tetrahydrofuran, diethyl ether and diisopropyl ether and aromatic solvents such as benzene, toluene and xylene are more preferable.

  In the case of reacting with a Lewis acid, ether solvents such as tetrahydrofuran, diethyl ether and diisopropyl ether are more preferable.

  When reacting with a base, among them, ether solvents such as tetrahydrofuran, diethyl ether and diisopropyl ether, aromatic solvents such as benzene, toluene and xylene, chlorine solvents such as dichloromethane, chloroform and carbon tetrachloride, and dimethyl sulfoxide, N A polar solvent such as N-dimethylformamide is more preferable.

  Each of the above solvents may be used alone, or two or more solvents may be mixed and used.

  The isomerization reaction may be performed in the air, or in an inert atmosphere such as a rare gas or nitrogen atmosphere in order to prevent the influence of oxidation by oxygen in the air and the incorporation of moisture into the crystal. You may go. In particular, when an isomerization reaction is performed using a Lewis acid, it is preferable to perform the reaction under an inert atmosphere and in a water-free condition. The present invention relates to a cis-2,5-disubstituted 6-membered heterocyclic compound represented by the general formula (i), or a cis-2,5-bis In a mixture containing a substituted 6-membered heterocyclic compound and a trans-2,5-disubstituted 6-membered heterocyclic compound, trans- with respect to the mass of the cis-2,5-disubstituted 6-membered heterocyclic compound (cis isomer) The value of (mass of trans isomer) / (mass of cis isomer), which is the value of the ratio of the mass of the 2,5-disubstituted 6-membered heterocyclic compound (trans isomer), before reacting with the acid or base It is larger than the value of (mass of trans isomer) / (mass of cis isomer). The value of (mass of trans isomer) / (mass of cis isomer) after reaction with an acid or base is preferably 1/9 or more, preferably 2/8 or more, and preferably 3/7 or more. The above is preferable, 5/5 or more is preferable, 5.5 / 4.5 or more is preferable, 6/4 or more is preferable, 7/3 or more is preferable, 8/2 or more is preferable, and 9/1 or more is preferable. Since the isomerization from the cis form to the trans form is further promoted under acidic conditions, the ratio of the trans form can be increased. (Mass of trans isomer) / (mass of cis isomer) can be measured by gas chromatography, liquid chromatography, or NMR (Nuclear Magnetic Resonance). In the case where no cis-2,5-disubstituted 6-membered heterocyclic compound is detected after the isomerization reaction and the ratio of cis-2,5-disubstituted 6-membered heterocyclic compound is 0, a cis isomer The value of the ratio of the mass of the transformer body to the mass of is the maximum value.

In the general formula (i), at least one of X ⁱ¹ and X ⁱ² preferably represents —O— or —S—, and more preferably represents —O—. Further, both X ⁱ¹ and X ⁱ² preferably represent —O—, —NR ⁱ⁶ — or —S—, preferably both represent —O— or —S—, and both represent —O—. It is more preferable.

R ⁱ¹ is preferably an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, a chlorine atom, a bromine atom, an iodine atom, a fluorine atom, a cyano group, —CF ₃ or —OCF _3. And particularly preferably an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, a chlorine atom, a bromine atom, an iodine atom or a fluorine atom. Moreover, it is preferable that it is linear. When R ⁱ¹ represents an alkyl group, one or more —CH ₂ — in the alkyl group is each independently —CH═CH—, —C≡C—, —O—, —S—, —NR ^i5. It is preferably substituted with-, -CO-, -COO-, -OCO-, 1,4-cyclohexylene group, 1,4-phenylene group or naphthalene-2,6-diyl group. More preferably, it is substituted with a cyclohexylene group or a 1,4-phenylene group.

R ⁱ² is preferably a hydrogen atom or an alkyl group having 1 to 12 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, and more preferably an alkyl group having 1 to 5 carbon atoms. When R ⁱ² is an alkyl group having 2 to 20 carbon atoms, one or more —CH ₂ — in the alkyl group is independently —CH═CH—, —C≡C—, —O—. , —S—, —NR ⁱ⁴ —, ^—N═CH— , ^—CH═N— , —CO—, ^—COO— , ^—OCO— , preferably substituted with —O—. It is more preferable. Furthermore, it is preferable that R ⁱ² does not become OH. This is because the isomerization reaction of the general formula (i) is performed by the action of an acid or a base, so that a group having high acidity is not present in the molecule of the general formula (i).

  The compound represented by the general formula (i) is preferably a compound represented by the following general formula (i-1).

(Wherein R ⁱ¹ , X ⁱ¹ and X ⁱ² each independently represent the same meaning as R ⁱ¹ , X ⁱ¹ and X ^{i2 in} general formula (i),
R ⁱ¹² represents an alkyl group having 1 to 19 carbon atoms, and one or more of —CH ₂ — in R ⁱ¹² each independently represents ^{—CH═CH—} , ^—C≡C— , —O—. , —S—, —NR ⁱ¹⁴ —, ^—N═CH— , ^—CH═N— , ^{—CH═N—N═CH—} , —CO—, ^—COO— , ^—OCO— , —CH ₂ O—, —OCH ₂ —, —CF ₂ O—, —OCF ₂ — or (a) 1,4-cyclohexylene group (one —CH ₂ — present in this group or two or more non-adjacent — CH ₂ — may be substituted with —O—, —S—, and —NR ⁱ¹⁵ —.
(B) 1,4-phenylene group (one —CH═ present in this group or two or more non-adjacent —CH═ may be substituted with —N═)
(C) Naphthalene-2,6-diyl group, 1,2,3,4-tetrahydronaphthalene-2,6-diyl group or decahydronaphthalene-2,6-diyl group (naphthalene-2,6-diyl group or One —CH═ present in the 1,2,3,4-tetrahydronaphthalene-2,6-diyl group or two or more non-adjacent —CH═ may be substituted with —N═. .)
^And one or more hydrogen atoms in R ⁱ¹² may be independently substituted with a cyano group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Often,
R ⁱ¹⁴ and R ⁱ¹⁵ represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. )
The compound represented by the general formula (i-1) is preferably a compound represented by the following general formula (i-2).

^(Wherein, R ^{i12, X i1} and ^{X i2} are as defined ^{R i12, X i1} and ^{X i2} in the general formula (i1),
R ⁱ²¹ represents a hydrogen atom or an alkyl group having 1 to 15 carbon atoms, and one or two or more —CH ₂ — in R ⁱ²¹ each independently represents ^{—CH═CH—} , ^—C≡C— , —O—, —S—, —NR ⁱ²⁴ —, ^—N═CH— , ^—CH═N— , ^{—CH═N—N═CH—} , —CO—, ^—COO— , ^—OCO— , —CH _2. O—, —OCH ₂ —, —CF ₂ O— or —OCF ₂ — may be substituted, and one or more hydrogen atoms in R ⁱ²¹ are each independently a cyano group, a fluorine atom, a chlorine atom, May be substituted with a bromine atom or an iodine atom,
Z ⁱ²¹ is a single _{bond, -CH 2 CH 2 -, -} (CH 2) 4 -, - OCH 2 -, - CH 2 O -, - OCF 2 -, - CF 2 O -, - N = CH -, - CH = N—, —CH═N—N═CH—, —CH═CH—, —CF═CF—, —C≡C—, —CO—, —COO— or —OCO—,
A ⁱ²¹ represents (a) a 1,4-cyclohexylene group (one —CH ₂ — present in this group or two or more non-adjacent —CH ₂ — represents —O—, —S— and — NR ^i25- may be substituted.)
(B) a 1,4-phenylene group (one —CH═ present in the group or two or more non-adjacent —CH═ may be substituted with —N═, Existing hydrogen atoms may be replaced by fluorine atoms.)
(C) Naphthalene-2,6-diyl group, 1,2,3,4-tetrahydronaphthalene-2,6-diyl group or decahydronaphthalene-2,6-diyl group (naphthalene-2,6-diyl group or One —CH═ present in the 1,2,3,4-tetrahydronaphthalene-2,6-diyl group or two or more non-adjacent —CH═ may be substituted with —N═. , A hydrogen atom present in a naphthalene-2,6-diyl group or a 1,2,3,4-tetrahydronaphthalene-2,6-diyl group may be substituted with a fluorine atom.)
Represents a group selected from the group consisting of
R ⁱ²⁴ and R ⁱ²⁵ represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms,
m ⁱ²¹ represents 0, 1, 2 or 3, but when m ⁱ²¹ is 2 or 3, and a plurality of Z ⁱ²¹ are present, they may be the same or different, and m ⁱ²¹ is 2 or 2 3 and when there are a plurality of A ^{i21 s} , they may be the same or different. )
Z ⁱ²¹ is _{-CH 2 O -, - OCH 2} -, - CF 2 O -, - OCF 2 -, - CF = CF -, - C≡C -, - CH = CH -, - CH 2 CH 2 - or It is preferably a single bond, more preferably —CH ₂ O—, —OCH ₂ —, —CF ₂ O—, —OCF ₂ —, —CH ₂ CH ₂ — or a single bond.

A ⁱ²¹ is ^preferably a trans-1,4-cyclohexylene group, an unsubstituted naphthalene-2,6-diyl group, or an unsubstituted 1,4-phenylene group. In addition, as the group in which —CH ₂ —, —CH═, or a hydrogen atom in A ⁱ²¹ is substituted, the following groups are preferable.

R ⁱ²¹ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, a chlorine atom, a bromine atom, an iodine atom, a fluorine atom, a cyano group, —CF ₃ or —OCF ₃ . It is particularly preferably a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, a chlorine atom, a bromine atom, an iodine atom or a fluorine atom. Moreover, it is preferable that it is linear.

  Specific examples of preferred compounds are shown below, but the present invention is not limited thereto.

(In the formula, R ⁱ¹² , X ⁱ¹ , X ⁱ² , Z ⁱ²¹ and A ⁱ²¹ each independently have the same meaning as R ⁱ¹² , X ⁱ¹ , X ⁱ² , Z ⁱ²¹ and A ^{i21 in} general formula (i-2). Y ^i2a1 , Y ^i2a2 , Y ^i2b1 , Y ^i2b2 , Y ^i2c1 , Y ^i2c2 , Y ^i2c3 , Y ^i2d1 , Y ^i2d2 and Y ^i2d3 each independently represents a hydrogen atom or a fluorine atom, R ^i2b , R ^i2b R ^i2c1 and R ^i2d1 are each independently a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, —CF ₃ or -OCF ₃ )
As a compound represented by general formula (i-2a), the following general formula (i-2a-1)-general formula (i-2a-6) are more preferable.

(In the formula, R ⁱ¹² , X ⁱ² and R ^i2a1 each independently represent the same meaning as R ⁱ¹² , X ⁱ² and R ^i2a1 in the general formula (i-2a).)
As a compound represented by general formula (i-2b), the following general formula (i-2b-1)-general formula (i-2b-22) are more preferable.

(In the formula, R ⁱ¹² , X ⁱ² and R ^i2b1 each independently represent the same meaning as R ⁱ¹² , X ⁱ² and R ^{i2b1 in} general formula (i-2b).)
As a compound represented by general formula (i-2c), the following general formula (i-2c-1)-general formula (i-2c-6) are more preferable.

(In the formula, R ⁱ¹² , X ⁱ² and R ^i2c1 each independently represent the same meaning as R ⁱ¹² , X ⁱ² and R ^{i2c1 in} general formula (i-2c).)
As a compound represented by general formula (i-2d), the following general formula (i-2d-1)-general formula (i-2d-10) are more preferable.

(In the formula, R ⁱ¹² , X ⁱ² and R ^i2d1 each independently represent the same meaning as R ⁱ¹² , X ⁱ² and R ^{i2d1 in} general formula (i-2d).)
The compound represented by the general formula (i) can be obtained, for example, by performing a decarboxylation reaction on the compound represented by the general formula (ii).

(Wherein R ⁱ¹ , R ⁱ² , X ⁱ¹ and X ⁱ² each independently represent the same meaning as R ⁱ¹ , R ⁱ² , X ⁱ¹ and X ^{i2 in} general formula (i),
^Rii3 represents an alkyl group having 1 to 4 carbon atoms. )
The reaction for obtaining the compound represented by the general formula (i) by the decarboxylation reaction of the compound represented by the general formula (ii) can be performed by heating with the action of a salt. Any salt may be used as long as it allows the reaction to proceed suitably. Specifically, metal salts such as metal halides, metal cyanides, metal carbonates, metal phosphates, metal carboxylates Among them, alkali metal salts such as alkali metal halides, alkali metal cyanides, alkali metal phosphates, alkali metal carbonates, and alkali metal amides are preferable, alkali metal halides, alkali amides, and the like. Metal cyanides are more preferred. Examples of the alkali metal halide include lithium chloride, lithium bromide, lithium iodide, sodium chloride, sodium bromide, sodium iodide, potassium chloride, potassium bromide, and potassium iodide. Examples of the alkali metal cyanide include sodium cyanide and cyanide. Preferable examples of potassium include tripotassium phosphate as the alkali metal phosphate, and examples of the alkali metal carbonate include sodium carbonate, sodium hydrogen carbonate, cesium carbonate, potassium carbonate, and potassium hydrogen carbonate. Moreover, you may make it react by making a thiol and a base act. Any thiol may be used as long as it allows the reaction to proceed suitably. For example, the thiol described in E. Keinan, D. Eren, J. Org. Chem. 1986, 51, 3165-3169. It is preferable to use thiophenol derivatives. As the base to be used, any base can be used as long as it allows the reaction to proceed suitably, but a metal carbonate is preferable.

  The heating temperature at the time of decarboxylation is preferably 80 ° C. to 180 ° C., preferably 90 ° C. to 150 ° C., and more preferably 100 ° C. to 130 ° C.

  The solvent used in the reaction may be any as long as it allows the reaction to proceed suitably, but ether solvents, chlorine solvents, hydrocarbon solvents, aromatic solvents, polar solvents, and the like are preferably used. it can. Examples of ether solvents include 1,4-dioxane, 1,3-dioxane, tetrahydrofuran, diethyl ether and t-butyl methyl ether. Examples of chlorine solvents include chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride. Pentane, hexane, cyclohexane, heptane, and octane as hydrocarbon solvents, benzene, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, etc. as aromatic solvents, and N, N-dimethyl as polar solvents. Preferred examples include formamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and sulfolane. Of these, ether solvents such as tetrahydrofuran and diethyl ether and polar solvents such as dimethyl sulfoxide, N, N-dimethylformamide, and N, N-dimethylacetamide are more preferable. Each of the above solvents may be used alone, or two or more solvents may be mixed and used.

  The decarboxylation reaction may be performed in the air, or in an inert atmosphere such as a rare gas or nitrogen atmosphere in order to prevent the influence of oxidation by oxygen in the air and the incorporation of moisture into the crystal. You may go. However, since carbon dioxide is generated during the decarboxylation reaction, when the decarboxylation reaction is performed in a closed system, it is preferable to use a closed system that can withstand pressure changes caused by the generated carbon dioxide.

In general formula (ii), the alkyl group of R ⁱⁱ³ preferably has a smaller number of carbon atoms, and preferably represents a methyl group. By reducing the ester site containing R ⁱⁱ³ , the decarboxylation reaction rate can be increased. Moreover, it is because the presence and heating of the salt during the decarboxylation reaction may decompose the compound represented by the general formula (ii), but this can be suppressed.

In the general formula (ii), when at least one of X ⁱ¹ and X ⁱ² is substituted with either —O—, —NR ⁱ⁶ —, or —S—, decarboxylation is performed using a salt. At this time, the structure obtained by capturing a cation component such as a lithium cation in the general formula (ii) becomes stable, so that the resulting compound becomes cis-selective.

That is, “MX (wherein M represents a metal cation and X represents a counter anion)” is used as the salt, and in general formula (ii), at least one of X ⁱ¹ and X ⁱ² is —O—, A structure in which a cation component is chelated by a hetero atom in X ⁱ¹ and / or X ⁱ² and an oxygen atom of carbonyl when decarboxylation of a compound substituted with either —NR ⁱ⁶ — or —S— is performed Contributes to stabilization, and thus the reaction is considered to proceed cis-selectively.

  Therefore, when decarboxylation is performed on the general formula (ii), a cis isomer can be obtained at a high ratio. Specifically, in a 2,5-disubstituted 6-membered heterocyclic compound obtained by decarboxylation reaction on the compound represented by the general formula (ii), a trans-2,5-disubstituted 6-membered heterocyclic compound The value of (mass of cis isomer) / (mass of trans isomer), which is the value of the ratio of the mass of the cis-2,5-disubstituted 6-membered heterocyclic compound to the mass of the compound, is 4 or more. Preferably, it is 4.5 or more, more preferably 5 or more. (Mass of cis isomer) / (mass of trans isomer) can be measured by gas chromatography, liquid chromatography, or NMR (Nuclear Magnetic Resonance).

  When the compound represented by the general formula (ii) has a plurality of disubstituted heterocyclic structures, for example, “trans, trans isomer”, “trans, cis isomer”, “cis, trans isomer”, “cis, In the present invention, the “cis isomer” is an isomer representing at least one cis isomer in the general formula (i-2), and the “trans isomer” All of general formula (i-2) are isomers representing a trans isomer.

In general formula (ii), a compound represented by the following general formula (ii-1) in which X ⁱ¹ and X ⁱ² represent oxygen atoms can be produced, for example, as follows.

(In the formula, R ⁱ² and R ⁱⁱ³ each independently represent the same meaning as R ⁱ² and R ^{ii3 in} general formula (ii).)
And a compound represented by the general formula (iv)

^{(Wherein, R i1} represents the same meaning as ^{R i1} in the general formula (ii).)
The compound represented by general formula (ii-1) as a compound represented by general formula (ii) by making it dehydrate-condensate and react.

(In the formula, R ⁱ¹ , R ⁱ² and R ⁱⁱ³ each independently represent the same meaning as R ⁱ¹ , R ⁱ² and R ^{ii3 in} general formula (ii)).
Can be obtained.

  As the solvent to be used, any solvent can be used as long as the reaction proceeds suitably. An aromatic solvent such as toluene, benzene and xylene, an ether solvent such as tetrahydrofuran (THF), diethyl ether and diisopropyl ether, Halogen solvents such as dichloromethane, chloroform and carbon tetrachloride are preferred, and benzene, toluene, diisopropyl ether and dichloromethane are preferred.

  The reaction temperature may be any temperature that allows the reaction to proceed suitably, but is preferably a temperature from room temperature to the reflux of the reaction solvent, and when the solvent used is azeotropic with water. It is particularly preferable to separate and remove water produced by the reaction under reflux using a Dean-Stark apparatus or the like.

  Any acid catalyst may be used as long as it allows the reaction to proceed suitably, but p-toluenesulfonic acid, chlorotrimethylsilane, sulfuric acid and the like are preferable, and p-toluenesulfonic acid or sulfuric acid is more preferable.

Thereafter, the compound represented by the general formula (ii-1) is decarboxylated to obtain a compound in which X ⁱ¹ and X ⁱ² represent an oxygen atom in the general formula (i).

  In the present invention, it is preferable to purify the compound represented by the general formula (i) obtained by the decarboxylation reaction. In the present invention, a cis-2,5-disubstituted 6-membered heterocyclic compound and a trans-2,5-disubstituted 6-membered compound obtained by isomerizing the compound represented by formula (i) It is preferable to purify the mixture containing the heterocyclic compound. The ratio of the trans isomer can be further improved by purification. Examples of the purification method include chromatography, recrystallization, distillation, sublimation, reprecipitation, adsorption, and liquid separation treatment. When using a purification agent, silica gel, alumina, activated carbon, activated clay, celite, zeolite, mesoporous silica, carbon nanotube, carbon nanohorn, Bincho charcoal, charcoal, graphene, ion exchange resin, acid clay, silicon dioxide, diatomaceous earth, Examples include perlite, cellulose, organic polymer, and porous gel.

The compound represented by the general formula (i), the compound represented by the general formula (i-1), the compound represented by the general formula (i-2), and the compound represented by the general formula (ii) And in the compound represented by the general formula (ii-1):
Two or more —CH ₂ — in R ⁱ¹ , R ⁱ² , R ⁱ³ , R ⁱ¹² , R ⁱ²¹ and R ⁱⁱ³ are each independently —CH═CH—, ^—C≡C— , ^—O— , —S. —, —NR ⁱ⁴ —, —N═CH—, —CH═N—, —CH═N—N═CH—, —CO—, —COO—, —OCO—, —CH ₂ O—, —OCH _2. -, -CF ₂ O- or -OCF _2-, when two or more adjacent -CH ₂ -are substituted with the above -CH = CH-, -C≡C-, -O-, -S-, —NR ⁱ⁴ —, —N═CH—, —CH═N—, —CH═N—N═CH—, —CO—, —COO—, —OCO—, —CH ₂ O—, —OCH ₂ —, There is no substitution with —CF ₂ O— or —OCF ₂ —.

EXAMPLES Hereinafter, although an Example is given and this invention is further explained in full detail, this invention is not limited to these Examples. The ratio of trans / cis in the obtained cis isomer and the mixture of trans isomers, and the yield were determined by gas chromatography (hereinafter GC) (column: DB-17ms 30 m, film thickness 0.25 μm, inner diameter 0.25 mm, detector. : FID) or NMR. The following non-patent documents were referred to for NMR analysis and determination of cis and trans.
E. Juaristi, F. Diaz, G. Cuellar, HA Jimenez-Vazquez, J. Org. Chem. 1997, 62, 4029-4035.
When GC was used, the peak area ratio of each component such as cis isomer and trans isomer was calculated as the proportion of each component. In addition, when using the said column in this invention, the peak area ratio of each component which analyzed has substantially corresponded to the mass% of each component. This is because there is almost no difference in the correction coefficients of the compounds of the respective components.

“%” In the compositions of the following Examples and Comparative Examples means “% by mass” unless otherwise specified.
The following abbreviations are used below.
Me: methyl group Et: ethyl group DMSO: dimethyl sulfoxide DMF: N, N-dimethylformamide THF: tetrahydrofuran PTSA · H ₂ O: p-toluenesulfonic acid monohydrate CSA: 10-camphorsulfonic acid (Example 1)

(1-1) Triethylamine (4.6 g) was added dropwise to a THF (2 L) solution of dimethyl malonate (320.3 g) and a formaldehyde solution (36% aqueous solution, 435.4 g) under ice cooling in a nitrogen atmosphere. The reaction solution was stirred at room temperature for 1 day, and the solvent was evaporated under reduced pressure. Sodium chloride (150 g), water (400 mL) and ethyl acetate (500 mL) are added and separated, and the aqueous layer is extracted three times with ethyl acetate (400 mL, 300 mL, 200 mL), and the combined organic layer is added to saturated brine. Washed with anhydrous sodium sulfate and dried. The solvent was distilled off under reduced pressure to obtain a colorless oily substance (436.3 g). Recrystallization from a mixed solvent of dichloromethane (350 mL) and hexane (220 mL) gave dimethyl bis (hydroxymethyl) malonate (218.7 g, yield 47%) as a white solid.

(1-2) Under a nitrogen atmosphere, p-bromobenzaldehyde (44.3 g), bis (hydroxymethyl) malonate dimethyl (72.0 g), p-toluenesulfonic acid monohydrate (2.3 g), cyclohexane ( 220 mL) and diisopropyl ether (45 mL) were heated to reflux for 3 hours and dehydrated using a Dean-Stark apparatus. After allowing to cool, a saturated aqueous sodium hydrogen carbonate solution (200 mL) was added to separate the solution, the aqueous layer was extracted three times with ethyl acetate (200 mL), and the combined organic layer was washed with saturated brine, and anhydrous sodium sulfate was added. In addition, it was dried. The solvent was distilled off under reduced pressure to obtain a colorless oily substance (83.2 g). Recrystallization from a mixed solvent of ethanol (250 mL) and hexane (80 mL) gave 2- (4-bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (71.1 g, yield 83). %) As a white solid.

(1-3) Under a nitrogen atmosphere, 2- (4-bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (10.0 g), lithium chloride (2.3 g), water (0 0.5 g) and dimethyl sulfoxide (20 mL) were heated and stirred at 120 ° C. for 6 hours. After allowing to cool, water (50 mL) was added and ice-cooled, and the white precipitate obtained by filtration was washed with water and dried under reduced pressure. 2- (4-Bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was purified by silica gel column chromatography (silica gel 10 g, mobile phase: ethyl acetate / toluene = 1/1 → 1/3). (8.3 g, 99% yield, trans / cis = 9/91) was obtained as a white solid. This was recrystallized from an acetone / methanol mixed solvent (once) to give cis-2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane (6.0 g, yield 71%). , No trans isomer detected by NMR) was obtained as a white solid.
Cis-2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane
¹ H NMR: (CDCl ₃ , TMS internal standard) δ (ppm) = 2.44 (s, 1H), 3.81 (s, 3H), 4.10 (axial, m, 2H), 4.72 ( Equatorial, d, 2H, J = 10.8 Hz), 5.47 (s, 1H), 7.32 (dd, 2H, J = 6.4 Hz, 2.0 Hz), 7.47 (dd, 2H, J = 6.4Hz, 2.0Hz)
[M]: 300

(1-4) 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane (51.4 g, cis / trans = 89/11), p-toluenesulfonic acid monoester under nitrogen atmosphere A mixture of hydrate (1.6 g), cyclohexane (150 mL) and diisopropyl ether (50 mL) was heated to reflux for 2 hours. After allowing to cool, toluene (200 mL), THF (100 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and water (200 mL) were added to separate the solution, and the aqueous layer was twice with a mixed solvent of toluene / THF = 1/2. (300 mL, 150 mL) extracted, the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (silica gel 50 g, mobile phase: toluene), followed by recrystallization from an acetone / ethanol mixed solvent to obtain trans-2- (4-bromophenyl) -5. -(Methoxycarbonyl) -1,3-dioxane (44.0 g, yield 86%, cis isomer not detected by NMR) was obtained as a white solid.
Trans-2- (4-Bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane
¹ H NMR: (CDCl ₃ , TMS internal standard) δ (ppm) = 3.14 (m, 1H), 3.71 (s, 3H), 3.98 (axial, t, 2H, J = 12.0 Hz) ), 4.46 (equatorial, dd, 2H, J = 12.0 Hz, 4.8 Hz), 5.39 (s, 1H), 7.35 (d, 2H, J = 8.0 Hz), 7.50 (D, 2H, J = 8.0Hz)
[M]: 300
(Example 2)

(2-1) Under a nitrogen atmosphere, 4-chloro-3-fluorobenzaldehyde (27.6 g), dimethyl bis (hydroxymethyl) malonate (50.0 g), p-toluenesulfonic acid monohydrate (1.7 g) ), Cyclohexane (135 mL) and diisopropyl ether (30 mL) were heated to reflux for 2 hours and dehydrated using a Dean-Stark apparatus. After allowing to cool, a saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (100 mL) were added, and the mixture was ice-cooled. The white precipitate obtained by filtration was washed with water and dried under reduced pressure. By reprecipitation from silica gel column chromatography (silica gel 60 g, mobile phase: hexane / toluene = 1/2 mixed solvent), followed by a mixed solvent of ethanol / hexane = 3/1, 2- (4-chloro-3- Fluorophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (49.7 g, 86% yield) was obtained as a white solid.

(2-2) 2- (4-chloro-3-fluorophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (48.0 g), lithium chloride (12.0 g) under nitrogen atmosphere , Water (13.0 g) and dimethyl sulfoxide (100 mL) were stirred with heating at 130 ° C. for 5 hours and a half. After allowing to cool, water (200 mL) was added and ice-cooled, and the white precipitate obtained by filtration was washed with water and dried under reduced pressure. 2- (4-Chloro-3-fluorophenyl) -5- (methoxycarbonyl) -1,3-dioxane (36.3 g, yield) was purified by silica gel column chromatography (silica gel 40 g, mobile phase: ethyl acetate). 92%, trans / cis = 9/91) was obtained as a white solid.
Cis-2- (4-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -1,3-dioxane
¹ H NMR: (CDCl ₃ , TMS internal standard) δ (ppm) = 2.46 (s, 1H), 3.82 (s, 3H), 4.12 (axial, m, 2H), 4.74 ( Equatorial, d, 2H, J = 11.8 Hz), 5.48 (s, 1H), 7.18 (d, 1H, J = 8.0 Hz), 7.27 (dd, 1H, J = 9.8 Hz) , 1.8 Hz), 7.37 (t, 1 H, J = 8.0 Hz)
[M]: 274

(2-3) 2- (4-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -1,3-dioxane (32.1 g, trans / cis = 9/91), p- under nitrogen atmosphere A mixture of toluenesulfonic acid monohydrate (1.1 g), cyclohexane (90 mL) and diisopropyl ether (30 mL) was heated to reflux for 2.5 hours. After standing to cool, toluene (100 mL), THF (200 mL), saturated aqueous sodium hydrogen carbonate solution (30 mL) and water (100 mL) were added and separated, and the aqueous layer was a mixed solvent of toluene / THF = 1/2 (150 mL). And the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (silica gel 30 g, mobile phase: toluene), followed by recrystallization from an acetone / ethanol mixed solvent to obtain trans-2- (4-chloro-3-fluoro Phenyl) -5- (methoxycarbonyl) -1,3-dioxane (28.2 g, yield 88%, cis not detected by NMR) was obtained as a white solid.
Trans-2- (4-Chloro-3-fluorophenyl) -5- (methoxycarbonyl) -1,3-dioxane
¹ H NMR: (CDCl ₃ , TMS internal standard) δ (ppm) = 3.14 (m, 1H), 3.72 (s, 3H), 3.98 (axial, t, 2H, J = 11.6 Hz) ), 4.47 (equatorial, dd, 2H, J = 11.6 Hz, 4.8 Hz), 5.39 (s, 1H), 7.20 (dd, 1H, J = 8.0 Hz, 1.8 Hz) 7.30 (dd, 1H, J = 9.8 Hz, 1.8 Hz), 7.40 (t, 1H, J = 8.0 Hz)
[M]: 274
(Example 3)
(3-1), (3-2) and (3-3)
In the same manner as in (1-1), (1-2) and (1-3) of Example 1, cis-2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was obtained. Got.

(3-4) Under a nitrogen atmosphere, cis-2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane (100 mg), potassium tert-butoxide (3.7 mg) and DMF (0 0.5 mL) was stirred for 4 hours under ice cooling. The organic layer diluted with toluene and washed with water and saturated brine was evaporated under reduced pressure. The sample was analyzed by NMR. From the peak area ratio, the trans / cis ratio of 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was 23/77.
Example 4
(4-1), (4-2) and (4-3)
In the same manner as in (1-1), (1-2) and (1-3) of Example 1, cis-2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was obtained. Got.

(4-4) Under a nitrogen atmosphere, cis-2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane (100 mg), potassium tert-butoxide (3.7 mg) and dichloromethane (0 0.5 mL) was stirred for 3 hours under ice cooling. The organic layer diluted with toluene and washed with water and saturated brine was evaporated under reduced pressure. The sample was analyzed by NMR. From the peak area ratio, the trans / cis ratio of 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was 40/60.
(Example 5)
(5-1), (5-2) and (5-3)
In the same manner as in (1-1), (1-2) and (1-3) of Example 1, cis-2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was obtained. Got.

(5-4) Under a nitrogen atmosphere, cis-2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane (100 mg), boron trifluoride (10.9 mg) and THF (1 .5 mL) was stirred at room temperature for 5 hours. The organic layer diluted with toluene and washed with water and saturated brine was evaporated under reduced pressure. The sample was analyzed by NMR. From the peak area ratio, the trans / cis ratio of 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was 72/28.
(Example 6)
(6-1), (6-2) and (6-3)
In the same manner as in (1-1), (1-2) and (1-3) of Example 1, cis-2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was obtained. Got.

(6-4) Under a nitrogen atmosphere, cis-2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane (100 mg), 10-camphorsulfonic acid (3.8 mg), cyclohexane (0 .4 mL) and diisopropyl ether (0.1 mL) were heated to reflux for 6 hours. The organic layer diluted with toluene and washed with water and saturated brine was evaporated under reduced pressure. The sample was analyzed by NMR. From the peak area ratio, the trans / cis ratio of 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was 80/20.
(Comparative Example 1)

Under nitrogen atmosphere, 2- (4-bromophenyl) -5-((2,6-difluoro-4-propylphenoxy) methyl) -1,3-dioxane (20.5 g, trans / cis = 27/73), A mixture of p-toluenesulfonic acid monohydrate (0.5 g), cyclohexane (100 mL) and diisopropyl ether (35 mL) was heated to reflux for 1 hour. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. From the peak area ratio, the trans / cis ratio of 2- (4-bromophenyl) -5-((2,6-difluoro-4-propylphenoxy) methyl) -1,3-dioxane was 52/48.
(Comparative Example 2)

Under a nitrogen atmosphere, 5-((4-butyl-2,6-difluorophenoxy) methyl) -2- (3 ′, 4 ′, 5′-trifluoro- [1,1′-biphenyl] -4-yl) A mixture of -1,3-dioxane (514.8 g, trans / cis = 35/65), p-toluenesulfonic acid monohydrate (9.9 g), cyclohexane (1350 mL) and diisopropyl ether (450 mL) was added for 1 hour. Heated to reflux. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution (400 mL) and water (600 mL) were added and the phases were separated, the aqueous layer was extracted with toluene (500 mL), and the combined organic layer was washed with saturated brine, and anhydrous sulfuric acid Sodium was added and dried. After the solvent was distilled off under reduced pressure, analysis was performed by GC. From the peak area ratio, 5-((4-butyl-2,6-difluorophenoxy) methyl) -2- (3 ′, 4 ′, 5′-trifluoro- [1,1′-biphenyl] -4-yl ) -1,3-Dioxane had a trans / cis ratio of 47/53.
(Comparative Example 3)

  2- (4-Chloro-3-fluorophenyl) -5-((2,6-difluoro-4-pentylphenoxy) methyl) -1,3-dioxane (168.3 g, trans / cis = 40 under nitrogen atmosphere / 60), p-toluenesulfonic acid monohydrate (3.7 g), cyclohexane (330 mL) and diisopropyl ether (110 mL) were heated to reflux for 1 hour. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. From the peak area ratio, the trans / cis ratio of 2- (4-chloro-3-fluorophenyl) -5-((2,6-difluoro-4-pentylphenoxy) methyl) -1,3-dioxane was 52/48. Met.

Claims (9)

Formula (i)

(Wherein R ⁱ¹ represents an alkyl group having 1 to 20 carbon atoms, R ⁱ² represents a hydrogen atom or an alkyl group having 1 to 20 carbon atoms, and one or more of R ⁱ¹ and R ⁱ² —CH ₂ — each independently represents —CH═CH—, —C≡C—, —O—, —S—, —NR ⁱ⁴ —, —N═CH—, —CH═N—, —CH═. N—N═CH—, —CO—, —COO—, —OCO—, —CH ₂ O—, —OCH ₂ —, —CF ₂ O—, —OCF ₂ — or (a) 1,4-cyclohexylene group (this is present in the group one -CH ₂ - or nonadjacent two or more -CH ₂ - is -O -, - S- and ^{-NR i5} - may be substituted in.)
(B) 1,4-phenylene group (one —CH═ present in this group or two or more non-adjacent —CH═ may be substituted with —N═)
(C) Naphthalene-2,6-diyl group, 1,2,3,4-tetrahydronaphthalene-2,6-diyl group or decahydronaphthalene-2,6-diyl group (naphthalene-2,6-diyl group or One —CH═ present in the 1,2,3,4-tetrahydronaphthalene-2,6-diyl group or two or more non-adjacent —CH═ may be substituted with —N═. .)
One or two or more hydrogen atoms in R ⁱ¹ and R ⁱ² may each independently be a cyano group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. May be replaced with
X ⁱ¹ and X ⁱ² each independently represent —O—, —NR ⁱ⁶ —, —S— or —CH ₂ —, wherein at least one of X ⁱ¹ and X ⁱ² represents —O—, —NR ⁱ⁶ —, -S-
R ⁱ⁴ , R ⁱ⁵ and R ⁱ⁶ represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. )
A cis-2,5-disubstituted 6-membered heterocyclic compound, or a cis-2,5-disubstituted 6-membered heterocyclic compound and a trans -By reacting a mixture containing a 2,5-disubstituted 6-membered heterocyclic compound with an acid or base, a cis-2,5-disubstituted 6-membered heterocyclic compound (cis isomer) in the compound or mixture ) Is the ratio of the mass of the trans-2,5-disubstituted six-membered heterocyclic compound (trans isomer) to the mass of (trans isomer) / (cis isomer mass) is an acid or base Of a mixture having a value larger than the value of (mass of trans isomer) / (mass of cis isomer) before reacting with. The manufacturing method of Claim 1 using general formula (i) in which R ⁱ² is not OH. The production method according to claim 1, wherein R ⁱ¹ in the general formula (i) is a group having a 1,4-cyclohexylene group or a 1,4-phenylene group. The compound represented by the general formula (i) is represented by the general formula (i-1).

(Wherein R ⁱ¹ , X ⁱ¹ and X ⁱ² each independently represent the same meaning as R ⁱ¹ , X ⁱ¹ and X ^{i2 in} general formula (i),
R ⁱ¹² represents an alkyl group having 1 to 19 carbon atoms, and one or more of —CH ₂ — in R ⁱ¹² each independently represents ^{—CH═CH—} , ^—C≡C— , —O—. , —S—, —NR ⁱ¹⁴ —, ^—N═CH— , ^—CH═N— , ^{—CH═N—N═CH—} , —CO—, ^—COO— , ^—OCO— , —CH ₂ O—, —OCH ₂ —, —CF ₂ O—, —OCF ₂ — or (a) 1,4-cyclohexylene group (one —CH ₂ — present in this group or two or more non-adjacent — CH ₂ — may be substituted with —O—, —S—, and —NR ⁱ¹⁵ —.
(B) 1,4-phenylene group (one —CH═ present in this group or two or more non-adjacent —CH═ may be substituted with —N═)
(C) Naphthalene-2,6-diyl group, 1,2,3,4-tetrahydronaphthalene-2,6-diyl group or decahydronaphthalene-2,6-diyl group (naphthalene-2,6-diyl group or One —CH═ present in the 1,2,3,4-tetrahydronaphthalene-2,6-diyl group or two or more non-adjacent —CH═ may be substituted with —N═. .)
^And one or more hydrogen atoms in R ⁱ¹² may be independently substituted with a cyano group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Often,
R ⁱ¹⁴ and R ⁱ¹⁵ represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. )
The manufacturing method as described in any one of Claims 1-3 which is a compound represented by these. Formula (ii)

(Wherein R ⁱ¹ , R ⁱ² , X ⁱ¹ and X ⁱ² each independently represent the same meaning as R ⁱ¹ , R ⁱ² , X ⁱ¹ and X ^{i2 in} general formula (i),
^Rii3 represents an alkyl group having 1 to 4 carbon atoms. )
The compound represented by general formula (i) is subjected to a decarboxylation reaction to obtain a six-membered heterocyclic compound, and then the compound represented by general formula (i) is acid or The manufacturing method as described in any one of Claims 1-4 with which a base is made to react. General formula (iii)

(In the formula, R ⁱ² and R ⁱⁱ³ each independently represent the same meaning as R ⁱ² and R ^{ii3 in} general formula (ii).)
And a compound represented by the general formula (iv)

^{(Wherein, R i1} represents the same meaning as ^{R i1} in the general formula (ii).)
Is reacted with a compound represented by the general formula (ii-1) as a compound represented by the general formula (ii)

(In the formula, R ⁱ¹ , R ⁱ² and R ⁱⁱ³ each independently represent the same meaning as R ⁱ¹ , R ⁱ² and R ^{ii3 in} general formula (ii)).
After obtaining the compound represented by general formula (ii-1), the compound represented by general formula (ii-1) is decarboxylated to obtain the six-membered heterocyclic compound represented by general formula (i). The method for producing a compound according to claim 5, wherein the compound represented by the general formula (i) is reacted with an acid or a base. The manufacturing method as described in any one of Claims 1-6 whose acid to be used is a Bronsted acid. The production method according to claim 1, wherein a value of (mass of trans isomer) / (mass of cis isomer) after reaction with an acid is 7/3 or more. The manufacturing method of the compound as described in any one of Claims 1-8 which refine | purifies the obtained mixture.