JP2017002005A - Manufacturing method of carbonyl compound using decarboxylation reaction - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an effective manufacturing method of a carbonyl compound useful as a raw material of pharmaceuticals, agrochemicals, liquid crystal material or the like or an intermediate thereof.SOLUTION: There is provided a method of providing a compound having a cis body at high selectivity by manufacturing a carbonyl compound with a decarboxylation reaction shown in the following reaction formula.SELECTED DRAWING: None

Description

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

Carbonyl compounds are widely used as medicines / pesticides, electronic materials including liquid crystals, raw materials such as resins, or intermediates thereof.
An acetoacetate synthesis method and a malonate synthesis method (Non-Patent Document 1) have long been known as methods for producing carbonyl compounds in which a wide variety of functional groups have been modified. When a carbonyl compound is produced by performing a decarboxylation reaction from a compound having a β-oxocarbonyloxy structure such as acetoacetate ester or malonate ester after functional group modification, a two-step process and severe reaction conditions Is often required. That is, a method is generally known in which ester is first hydrolyzed using a strong acid or basicity to obtain a corresponding carboxylic acid and then heated at a high temperature to cause a decarboxylation reaction. However, this method requires a two-step process and further has a problem of low functional group tolerance.
As this improvement method, the decarboxylation reaction reported by Krapcho et al. Is known (Non-patent Document 2). In this reaction, the corresponding decarboxylated product can be obtained in one step by heating the salt while acting on the ester. Since a salt is used instead of a strong acid or strong base, decarboxylation can be achieved under relatively mild reaction conditions close to neutrality.
However, when a skeleton or functional group having a hetero atom such as an oxygen atom, a nitrogen atom, or a sulfur atom is included in a site other than the reaction point of the substrate, the hetero atom coordinates to the salt and the target reaction It can inhibit the progression and consequently reduce the reaction rate.

  In addition, when the reaction is performed for a long time, the action of the salt on the skeleton or functional group having a hetero atom and the heating may cause decomposition of the substrate and the target product, thereby reducing the yield.

  On the other hand, a method of decarboxylation using a copper (I) oxide catalyst or the like for a substrate containing pyran as a skeleton having a hetero atom is known, but this method is limited to a carboxylic acid. Met. (Patent Document 1).

H. O. Hauser, B. E. Hudson Jr., Org. React. 1942, 1, 266. Krapcho, A. P .; Weimaster, J. F .; Eldridge, J. M .; Jahngen, E. G. E .; Lovey, A. J .; Stephens, W. P. J. Org. Chem. 1978, 43, 138.

JP 2011-46703 A

  The problem to be solved by the present invention is to provide a production method capable of producing a carbonyl compound containing a non-hydrocarbon moiety in a higher yield using a decarboxylation reaction.

  As a result of diligent studies to solve the above problems, in the decarboxylation reaction using a compound having a β-oxo-carbonyloxy structure as a substrate, the reaction rate of the decarboxylation reaction is reduced by sterically reducing the ester site. It has been found that it can be increased and that decomposition of the substrate and the target product can be suppressed, and the present invention has been completed.

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

(In the formula, R ⁱ¹ , R ⁱ² and R ⁱ³ each independently represent a hydrogen atom or an alkyl group having 1 to 20 carbon atoms, but R ⁱ¹ and R ⁱ² do not both represent a hydrogen atom, and R ⁱ¹ , R ⁱ² and R ⁱ³ each independently represents one or more —CH ₂ — 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—, -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.)
(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═. .)
The general formula (i) may be substituted by one or more —CH ₂ — in R ⁱ¹ , R ⁱ² and R ⁱ³ , but may be substituted with a group selected from the group consisting of One or two or more —CH ₂ — in R ⁱ¹ and / or R ⁱ² each independently represents —O—, —S—, or two or more β-oxo-carbonyloxy structures. -NR ^i4- ,
One or more hydrogen atoms in R ⁱ¹ , R ⁱ² and R ⁱ³ may be each independently substituted by a cyano group, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and R ⁱ¹ and R ⁱ² May combine to form a ring,
R ⁱ⁴ and R ⁱ⁵ each independently represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. )
By decarboxylation of the compound represented by formula (ii)

(Wherein R ⁱ¹ , R ⁱ² and R ⁱ³ each independently represent the same meaning as R ⁱ¹ , R ⁱ² and R ^{i3 in} general formula (i)).
The manufacturing method of the compound represented by these is provided.

  According to the production method of the present invention, the rate of decarboxylation using a compound having a β-oxo-carbonyloxy structure as a substrate can be increased and the decomposition of the substrate and the target product can be suppressed, so that the yield is improved.

  The reaction for obtaining the compound represented by the general formula (ii) by the decarboxylation reaction of the compound represented by the general formula (i) 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 include potassium, tribasic phosphate as the alkali metal phosphate, and sodium carbonate, sodium hydrogen carbonate, cesium carbonate, potassium carbonate, and potassium hydrogen carbonate as the alkali metal 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, and 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. May be. 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 (i), R ⁱ¹ and R ⁱ² do not both represent a hydrogen atom, and at least one or more of —CH ₂ — in R ⁱ¹ and R ⁱ² is —O—, —S— or —NR. Substituted with ^i4- . Therefore, since the compound represented by the general formula (i) has a non-hydrocarbon site other than the decarboxylation reaction point, the decarboxylation reaction rate is lowered. In order to reduce the hydrocarbon group of the ester moiety to a steric small size, the reaction rate is reduced by focusing on the reaction mechanism in which the anion contained in the salt makes a nucleophilic attack on the ester moiety. Can be faster. Moreover, decomposition | disassembly of the compound represented by general formula (i) and general formula (ii) is suppressed by presence of a salt at the time of a decarboxylation reaction, and a heating, and a yield can be improved.

—CH ₂ — in the alkyl group of R ⁱ¹ and R ⁱ² is preferably substituted with —O— or —S—, and more preferably substituted with —O—. Moreover, it is preferable that the carbon atom number of the alkyl group of R ^{< i1>} and R ^<i2> is 1-12, and it is preferable that it is 1-8.

In R ⁱ¹ and R ⁱ² , an alkyl group may be bonded to each other to form a ring, and when forming a ring, the ring may have 5 or 6 carbon atoms. Further, —CH ₂ — in the formed ring may be substituted with —O—, —S—, or —NR ⁱ⁴ —. When R ⁱ¹ and R ⁱ² are bonded to each other to form a ring, for example, as shown in the following general formula (ia), the ends of the respective alkyl groups of R ⁱ¹ and R ⁱ² are bonded to form a ring. However, as represented by the following general formula (ib), a ring may be formed by bonding the alkyl group of R ^{i2 to} —CH ₂ — in the alkyl group of R ⁱ¹ . In addition, in (ia) and (ib), although the formed ring gave the example which is a 6-membered heterocyclic compound, it is not limited to this.

(Wherein R ⁱ³ represents the same meaning as R ⁱ³ in formula (i), and X ^ia1 and X ^ia2 independently represent —O—, —NR ^ia1 —, —S—, or —CH ₂ —. ^And at least one of X ^ia1 and X ^ia2 represents —O—, —NR ^ia1 —, or —S—, and R ^ia1 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.)

(In the formula, R ⁱ³ represents the same meaning as R ⁱ³ in formula (i), and X ^ib1 and X ^ib2 independently represent —O—, —NR ^ib2 —, —S—, or —CH ₂ —. ^And at least one of X ^ib1 and X ^ib2 represents any of —O—, —NR ^ib2 —, and —S—, and R ^ib1 represents an alkyl group having 1 to 17 carbon atoms, One or more of —CH ₂ — is independently —CH═CH—, ^—C≡C— , ^—O— , —S—, —NR ^ib3 —, ^—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 —CH ₂ — not adjacent to each other) ^May be substituted with —O—, —S—, and —NR ^ib4 —.
(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═. .)
^Or one or more hydrogen atoms in R ^ib1 may be independently substituted with a cyano group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Well, R ^ib2 , R ^ib3 and R ^ib4 each independently represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. )
R ⁱ³ is preferably 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 ⁱ³ 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.

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

(Wherein R ⁱ¹ and R ⁱ² each independently represent the same meaning as R ⁱ¹ and R ^{i2 in} general formula (i), R ⁱ¹³ represents a hydrogen atom or an alkyl group having 1 to 19 carbon atoms, One or more —CH ₂ — in R ⁱ¹³ 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 — substituted with —O—, —S— and —NR ⁱ¹⁵ —) May be.)
(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═. .)
^May be substituted with a group selected from the group consisting of, but by replacing one or more —CH ₂ — in R ⁱ¹³ , general formula (i-1) may be substituted with two or more β -Represents no oxo-carbonyloxy structure,
One or more hydrogen atoms in R ⁱ¹³ may be each independently substituted by a cyano group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and R ⁱ¹⁴ and R ⁱ¹⁵ are each a hydrogen atom or a carbon atom number of 1 Represents 10 to 10 alkyl groups. )
In general formula (i-1), R ⁱ¹³ is preferably an alkyl group having 1 to 8 carbon atoms or an alkenyl group having 2 to 8 carbon atoms, and an alkyl group having 1 to 5 carbon atoms or the number of carbon atoms. 2-5 alkenyl groups are preferred. Among them, it is more preferable that R ⁱ¹³ represents 1 carbon atom, that is, the general formula (i-1) represents a dimethyl malonate derivative.

Here, general formula (i) represents two or more β-oxo-carbonyloxy structures in the formula by substituting one or more —CH ₂ — in R ⁱ¹ , R ⁱ² and R ^i3. There is no. The general formula (i) has one β-oxo-carbonyloxy structure as an essential component in the formula. For example, one or more —CH ₂ — in R ⁱ¹ , R ⁱ² and R ⁱ³ is —CO In order not to affect the decarboxylation reaction in the present invention by excluding the formation of other β-oxo-carbonyloxy structures by substitution with-, -COO- or -OCO- It is.

  In addition, as what represents two or more (beta) -oxo- carbonyloxy structures, the compound etc. which are represented with the following general formulas are mentioned, for example.

(In the formula, R ⁱ² and R ⁱ³ each independently represent the same meaning as R ⁱ² and R ⁱ³ in the general formula (i), and R represents an alkyl group having 1 to 15 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 ⁱ¹³ represents the same meaning as R ^{i13 in} formula (i-1);
R ⁱ²¹ represents a hydrogen atom or an alkyl group having 1 to 17 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 two or more hydrogen atoms in R ⁱ²¹ each independently represent a cyano group, a fluorine atom, May be substituted with a chlorine atom, a bromine atom or an iodine atom,
X ⁱ²¹ and X ⁱ²² each independently represent —O—, —NR ⁱ²⁵ —, —S— or —CH ₂ —, ^wherein at least one of X ⁱ²¹ and X ⁱ²² represents —O—, —NR ⁱ²⁵ —, -S-
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 ^i26- 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═, The hydrogen atom present may be substituted with a fluorine atom.)
(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═. The hydrogen atom present in the naphthalene-2,6-diyl group or the 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 , R ⁱ²⁵ and R ⁱ²⁶ each independently 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. )
In the general formula (i-2), at least one of X ⁱ²¹ and X ⁱ²² preferably represents —O— or —S—, and more preferably represents —O—. ^Further , both X ⁱ²¹ and X ⁱ²² preferably represent —O—, —NR ⁱ²⁵ — or —S—, preferably both represent —O— or —S—, and both represent —O—. It is more preferable. When at least one of X ⁱ²¹ and X ⁱ²² is substituted with any of —O—, —NR ⁱ²⁵ —, or —S—, when decarboxylation using a salt, general formula (i-2) Since the structure in which the cation component is trapped is stable, the resulting compound is cis-selective.

That is, “MX (wherein M represents a metal cation and X represents a counter anion)” is used as a ^salt, and in general formula (i-2), at least one of X ⁱ²¹ and X ⁱ²² is —O When decarboxylation of a compound substituted with ^either- , -NR ⁱ²⁵ -or -S- is carried out, the hetero atom in X ⁱ²¹ and / or X ⁱ²² and the oxygen atom of carbonyl as shown below It is considered that the reaction proceeds in a cis-selective manner because the structure obtained by chelating the cation component contributes to stabilization.

(In the ^{figure, R i21, R i13, A} i21, Z i21 and ^{m i21} is in the general formula ^{(i-2) R i21,} R i13, A i21, Z as defined represents the ⁱ²¹ and ^{m i21, M +} is Represents a metal cation.)
Examples of M ⁺ in the figure include a lithium cation, a potassium cation, and a sodium cation.

  Therefore, according to the present invention, when the compound represented by the general formula (i-2) is decarboxylated, a cis body can be obtained at a high ratio. Specifically, in a 2,5-disubstituted 6-membered heterocyclic compound obtained by a decarboxylation reaction on the compound represented by the general formula (i-2), a trans-2,5-disubstituted 6-membered heterocyclic compound is obtained. 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 cyclic compound, is 4 or more. It is preferably 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).

  In addition, when the compound represented by the general formula (i-2) has a plurality of disubstituted cyclic structures, for example, “trans, trans isomer”, “trans, cis isomer”, “cis, trans isomer”, “cis cis” In the present invention, the “cis isomer” is an isomer representing at least one cis isomer in the general formula (i-2), and “trans isomer” Are all isomers in the general formula (i-2) representing trans isomers.

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 ⁱ¹³ , X ⁱ²¹ , X ⁱ²² , Z ⁱ²¹ and A ⁱ²¹ each independently have the same meaning as R ⁱ¹³ , X ⁱ²¹ , X ⁱ²² , 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 ⁱ¹³ , X ⁱ²² and R ^i2a1 each independently represent the same meaning as R ⁱ¹³ , X ⁱ²² and R ^{i2a1 in} 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 ⁱ¹³ , X ⁱ²² and R ^i2b1 each independently represent the same meaning as R ⁱ¹³ , X ⁱ²² 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 ⁱ¹³ , X ⁱ²² and R ^i2c1 each independently represent the same meaning as R ⁱ¹³ , X ⁱ²² 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 ⁱ¹³ , X ⁱ²² and R ^i2d1 each independently represent the same meaning as R ⁱ¹³ , X ⁱ²² and R ^{i2d1 in} general formula (i-2d).)
In general formula (i), the compound represented by the following general formula (i-3) having 1,3-dioxane can be produced, for example, as follows.

  General formula (iii)

^{(Wherein, R i3} has the same meaning as ^{R i3} in the general formula (i).)
And a compound represented by the general formula (iv)

(In the formula, R ⁱ³¹ represents a hydrogen atom or an alkyl group having 1 to 17 carbon atoms, and one or two or more —CH ₂ — in R ⁱ³¹ are each independently —CH═CH—, —C ≡C—, —O—, —S—, —NR ⁱ³⁴ —, ^—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 adjacent to each other) And two or more —CH ₂ — that are not present may be substituted with —O—, —S—, and —NR ⁱ³⁵ —.)
(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═. .)
^Or one or more hydrogen atoms in R ⁱ³¹ may each independently be substituted with a cyano group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Often,
R ⁱ³⁴ and R ⁱ³⁵ represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. )
The compound represented by general formula (i-3) as a compound represented by general formula (i)

^{(Wherein, R i3} has the same meaning as ^{R i3} in the general formula ^{(i), R i 31} represents the same meaning as ^{R i 31} in the general formula (iv).)
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.

  In the present invention, it is preferable to purify the compound represented by the general formula (ii) obtained by the decarboxylation reaction. 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.

  In the present invention, a cis-2,5-disubstituted 6-membered heterocyclic ring of a compound represented by the following general formula (ii-2) obtained by decarboxylation of a compound represented by the general formula (i-2) It is the value of the ratio of the mass of the trans isomer to the mass of the cis isomer in the mixture by reacting an acid or base with a mixture containing the formula compound and the trans-2,5-disubstituted 6-membered heterocyclic compound. The value of (mass of trans isomer) / (mass of cis isomer) may be larger than the value of (mass of trans isomer) / (mass of cis isomer) before reacting with an acid or a base.

^{(Wherein, R i13, R i21, X} i21, X i22, Z i21, A i21 and ^{m i21} is ^R i13 of general formula ^{(i-2), R i21} , X i21, X i22, Z i21, A ^It represents the same meaning as ⁱ²¹ and ^mi21 .)
Since the compound represented by the general formula (ii-2) contains a carbonyl group, and the proton at the α-position of the carbonyl group is active, in the present invention, keto-enol tautomerization is performed under either acidic conditions or basic conditions. Because sexuality occurs, isomerization is promoted. 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 ^achieved by ring-opening-closing of a heterocyclic ring in which both X ⁱ²¹ and X ⁱ²² represent —O—, —NR ⁱ²⁵ — or —S— in general formula (ii-2). This is preferable because it is more promoted.

  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 carried out with a metal cation present in the system, the structure of chelating the metal cation with the oxygen atom of the carbonyl group and the heteroatom in the heterocyclic ring contributes to stabilization, so kinetic or thermodynamic This is because it is presumed that formation of a cis isomer is advantageous.

  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, and t-butyl methyl ether. Examples of chlorine solvents include dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride. Pentane, hexane, cyclohexane, heptane and octane as hydrocarbon solvents, benzene, toluene, xylene, mesitylene, chlorobenzene and dichlorobenzene as aromatic solvents, and N, N-dimethyl as polar solvents. Preferred examples include formamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and 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 preferred.
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 preferably performed under an active atmosphere and under water-free conditions. The present invention relates to a 2,5-disubstituted 6-membered heterocyclic compound represented by the general formula (ii-2), a cis-2,5-disubstituted 6-membered heterocyclic compound and trans-2,5- In a mixture containing a disubstituted 6-membered heterocyclic compound, a trans-2,5-disubstituted 6-membered heterocyclic compound (trans) relative 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 mass ratio of (body), is (mass of trans isomer) / (mass of cis isomer) before reacting with an acid or base. Is greater than the value. 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, 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 cis isomer) / (mass of trans isomer) can be measured by gas chromatography, liquid chromatography, or NMR (Nuclear Magnetic Resonance).

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 general formula (i-3). A compound represented by general formula (ii) and a compound represented by general formula (ii-2),
Two or more —CH ₂ — in R ⁱ¹ , R ⁱ² , R ⁱ³ , R ⁱ¹³ , R ⁱ²¹ and R ⁱ³¹ 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 cis / trans ratio of the obtained compound was determined by 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.
Yield is the peak of each component to be measured by isolation or using gas chromatography (hereinafter GC) (column: DB-17ms 30 m, film thickness 0.25 μm, inner diameter 0.25 mm, detector: FID). The area ratio was calculated as the ratio 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 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: dimethylformamide PTSA · H ₂ O: p-toluenesulfonic acid monohydrate THF: tetrahydrofuran aq. : Aqueous solution (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, cis / trans = 91/9) was obtained as a white solid. This was recrystallized from an acetone / methanol mixed solvent to obtain cis-2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane (6.0 g, yield 71%, NMR). Trans not detected) 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 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%, cis / trans = 91/9) 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) In a nitrogen atmosphere, 2- (4-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -1,3-dioxane (32.1 g, cis / trans = 91/9), p- 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) and (3-2)
2- (4-Bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane was obtained in the same manner as in (1-1) and (1-2) of Example 1.

(3-3) Under a nitrogen atmosphere, 2- (4-bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (100.0 mg), lithium chloride (23.4 mg), water (5 0.0 mg) and dimethyl sulfoxide (0.2 mL) were heated and stirred at 130 ° C. for 1 hour. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. In the GC area ratio, the yield of 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was 89%, and the yield of p-bromobenzaldehyde was 8%.
Example 4
(4-1) and (4-2)
2- (4-Bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane was obtained in the same manner as in (1-1) and (1-2) of Example 1.

(4-3) 2- (4-bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (100.0 mg), lithium bromide (48.7 mg), water (under nitrogen atmosphere) 5.0 mg) and dimethyl sulfoxide (0.2 mL) were heated and stirred at 130 ° C. for 1 hour. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. In the GC area ratio, the yield of 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was 86%, and the yield of p-bromobenzaldehyde was 10%.
(Example 5)
(5-1) and (5-2)
2- (4-Bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane was obtained in the same manner as in (1-1) and (1-2) of Example 1.

(5-3) Under a nitrogen atmosphere, 2- (4-bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (100.0 mg), lithium iodide (75.0 mg), water ( 5.0 mg) and dimethyl sulfoxide (0.2 mL) were heated and stirred at 130 ° C. for 1 hour. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. In the GC area ratio, the yield of 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was 90%, and the yield of p-bromobenzaldehyde was 6%.
(Example 6)
(6-1) and (6-2)
2- (4-Bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane was obtained in the same manner as in (1-1) and (1-2) of Example 1.

(6-3) 2- (4-Bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (100.0 mg), tetramethylammonium chloride (61.6 mg), water under nitrogen atmosphere (5.0 mg) and a mixture of dimethyl sulfoxide (0.2 mL) were heated and stirred at 130 ° C. for 1 hour. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. In the GC area ratio, the yield of 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was 20%, and the yield of p-bromobenzaldehyde was 60%.
(Example 7)
(7-1) and (7-2)
2- (4-Bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane was obtained in the same manner as in (1-1) and (1-2) of Example 1.

(7-3) Under a nitrogen atmosphere, 2- (4-bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (100.0 mg), lithium chloride (23.4 mg), water (5 0.0 mg) and dimethyl sulfoxide (0.2 mL) were heated and stirred at 115 ° C. for 9 hours. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. In the GC area ratio, the yield of 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was 98%, and the yield of p-bromobenzaldehyde was 2%.
(Example 8)
(8-1) and (8-2)
2- (4-Bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane was obtained in the same manner as in (1-1) and (1-2) of Example 1.

(8-3) Under a nitrogen atmosphere, 2- (4-bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (100.0 mg), lithium chloride (23.4 mg), water (5 0.0 mg) and dimethyl sulfoxide (0.2 mL) were heated and stirred at 100 ° C. for 15 hours. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. In the GC area ratio, the yield of 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was 98%, and the yield of p-bromobenzaldehyde was less than 1%.
Example 9
(9-1) and (9-2)
2- (4-Bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane was obtained in the same manner as in (1-1) and (1-2) of Example 1.

(9-3) Under a nitrogen atmosphere, 2- (4-bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (100.0 mg), lithium chloride (23.4 mg), water (5 0.0 mg) and dimethyl sulfoxide (0.2 mL) were heated and stirred at 80 ° C. for 4 hours. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. In the GC area ratio, the yield of 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was 10%, and the yield of p-bromobenzaldehyde was less than 1%.
(Example 10)
(10-1) and (10-2)
2- (4-Bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane was obtained in the same manner as in (1-1) and (1-2) of Example 1.

(10-3) 2- (4-bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (93 mg), p-aminothiophenol (48 mg), cesium carbonate (25 mg) under an argon atmosphere ) And N, N-dimethylformamide (0.5 mL) were heated and stirred at 85 ° C. for 1 hour. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. In GC area ratio, 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was quantitatively obtained.
(Example 11)
(11-1) and (11-2)
2- (4-Bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane was obtained in the same manner as in (1-1) and (1-2) of Example 1.

(11-3) Under an argon atmosphere, 2- (4-bromophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (93 mg), p-aminothiophenol (48 mg), potassium carbonate (10 mg) ) And N, N-dimethylformamide (0.5 mL) were heated and stirred at 85 ° C. for 1 hour. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. In GC area ratio, 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was quantitatively obtained.
(Comparative Example 1)

(1-1) Under a nitrogen atmosphere, 2- (4-bromophenyl) -5,5-bis (ethoxycarbonyl) -1,3-dioxane (1.0 g), lithium chloride (220 mg), water (50 mg) and A mixture of dimethyl sulfoxide (2.0 mL) was reacted at 130 ° C. for 11 hours. As a result of GC analysis, the reaction was not completed. Subsequently, the mixture was stirred with heating at 140 ° C. for 6 hours. After dilution with toluene and washing with saturated saline, a sample purified by alumina column chromatography was analyzed by GC. In the GC area ratio, the yield of 2- (4-bromophenyl) -5- (ethoxycarbonyl) -1,3-dioxane was 73%, and the yield of p-bromobenzaldehyde was 21%.

From Example 1 and Comparative Example 1, compared with Comparative Example 1, in Example 1, the target reaction proceeded more smoothly and the yield was improved. In Comparative Example 1, decomposition of 2- (4-bromophenyl) -5- (ethoxycarbonyl) -1,3-dioxane occurred to produce p-bromobenzaldehyde, and the yield was 73%. In contrast, in Example 1, 2- (4-bromophenyl) -5- (methoxycarbonyl) -1,3-dioxane was obtained in a high yield of 99%.
(Comparative Example 2)

(2-1) 2- (4-Bromophenyl) -5,5-bis (ethoxycarbonyl) -1,3-dioxane (100 mg), tetramethylammonium acetate (127 mg) and dimethyl sulfoxide (2. (0 mL) was stirred at 85 ° C. for 5 hours. An organic layer diluted with ethyl acetate and washed with water was used as a sample and analyzed by GC. In the GC area ratio, the yield of 2- (4-bromophenyl) -5- (ethoxycarbonyl) -1,3-dioxane was 4%, and the yield of p-bromobenzaldehyde was 26%.

From Example 6 and Comparative Example 2, compared to Comparative Example 2, the target reaction proceeded more smoothly in Example 6 and the yield was improved. Further, in view of the ratio between the yield of 2- (4-bromophenyl) -5- (alkoxycarbonyl) -1,3-dioxane and the yield of p-bromobenzaldehyde, Example 6 is more preferable than Comparative Example 2. The decarboxylation reaction proceeded more selectively than the decomposition reaction.
(Comparative Example 3)

(3-1) Under an argon atmosphere, 2- (4-bromophenyl) -5,5-bis (ethoxycarbonyl) -1,3-dioxane (100 mg), p-aminothiophenol (48 mg), cesium carbonate (25 mg) ) And N, N-dimethylformamide (0.5 mL) were heated and stirred at 85 ° C. for 1 hour. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. In GC area ratio, the yield of 2- (4-bromophenyl) -5- (ethoxycarbonyl) -1,3-dioxane was 42%.

From Example 10 and Comparative Example 3, compared to Comparative Example 3, the target reaction proceeded more smoothly in Example 10 and the yield was improved.
(Comparative Example 4)

(4-1) Under an argon atmosphere, 2- (4-bromophenyl) -5,5-bis (ethoxycarbonyl) -1,3-dioxane (200 mg), p-aminothiophenol (90 mg), potassium carbonate (20 mg) ) And N, N-dimethylformamide (1.0 mL) were heated and stirred at 85 ° C. for 1 hour. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. In the GC area ratio, the yield of 2- (4-bromophenyl) -5- (ethoxycarbonyl) -1,3-dioxane was 14%.

From Example 11 and Comparative Example 4, compared to Comparative Example 4, the target reaction proceeded more smoothly in Example 11 and the yield was improved.
(Comparative Example 5)

(5-1) Under a nitrogen atmosphere, 2- (4-bromophenyl) -5,5-bis (ethoxycarbonyl) -1,3-dioxane (100.0 mg), lithium chloride (23.4 mg), water (5 0.0 mg) and dimethyl sulfoxide (0.2 mL) were heated and stirred at 60 ° C. for 4 hours. An organic layer diluted with toluene and washed with water was used as a sample and analyzed by GC. By GC, 2- (4-bromophenyl) -5- (ethoxycarbonyl) -1,3-dioxane was not detected.

From Example 9 and Comparative Example 5, the reaction of Comparative Example 5 did not proceed, but the reaction of Example 9 proceeded.
(Comparative Example 6)

(6-1) To a mixture of potassium hydroxide (60 g) and 95% ethanol (500 mL) was added 2-phenyl-5,5-bis (ethoxycarbonyl) -1,3-dioxane (77.0 g). Heated for hours. Ethanol was distilled off under reduced pressure, and the resulting solid was dissolved in dichloromethane (400 mL). The solution was acidified with 10% hydrochloric acid under ice cooling. This organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2-phenyl-5,5-dicarboxy-1,3-dioxane (24.1 g, yield 40%) as a white solid. Obtained.
(6-2) Subsequently, a mixture of 2-phenyl-5,5-dicarboxy-1,3-dioxane (10.0 g) and triethylamine (15 mL) was heated to reflux for 40 minutes. Triethylamine was distilled off, and the resulting solid was dissolved in dichloromethane (100 mL). Under ice cooling, the solution was acidified (pH 2) using 10% hydrochloric acid. This mixture was extracted twice with diethyl ether (100 mL), the combined organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to remove 2-phenyl-5-carboxy-1,3-dioxane (7 Yield of 35%, trans / cis = 60/40 in two stages through 3 g, (6-1) and (6-2). The cis-trans mixture was separated by flash column chromatography to obtain cis-2-phenyl-5-carboxy-1,3-dioxane (14% yield over 2 steps) and trans-2-phenyl-5- Carboxy-1,3-dioxane (21% yield over 2 steps) was obtained as a white solid, respectively.

  From Example 1 and Comparative Example 6, Comparative Example 6 used harsh conditions of strong acid and strong base, and further two steps were required, but Example 1 was mild neutral conditions and only one step. Using this process, it was found that the reaction proceeds with a high yield.

Claims (8)

Formula (i)

(In the formula, R ⁱ¹ , R ⁱ² and R ⁱ³ each independently represent a hydrogen atom or an alkyl group having 1 to 20 carbon atoms, but R ⁱ¹ and R ⁱ² do not both represent a hydrogen atom, and R ⁱ¹ , R ⁱ² and R ⁱ³ each independently represents one or more —CH ₂ — 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—, -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.)
(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═. .)
The general formula (i) may be substituted by one or more —CH ₂ — in R ⁱ¹ , R ⁱ² and R ⁱ³ , but may be substituted with a group selected from the group consisting of One or two or more —CH ₂ — in R ⁱ¹ and / or R ⁱ² each independently represents —O—, —S—, or two or more β-oxo-carbonyloxy structures. Substituted with -NR ⁱ⁴ ,
One or more hydrogen atoms in R ⁱ¹ , R ⁱ² and R ⁱ³ may be each independently substituted by a cyano group, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and R ⁱ¹ and R ⁱ² May combine to form a ring,
R ⁱ⁴ and R ⁱ⁵ each independently represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. )
By decarboxylation of the compound represented by formula (ii)

(Wherein R ⁱ¹ , R ⁱ² and R ⁱ³ each independently represent the same meaning as R ⁱ¹ , R ⁱ² and R ^{i3 in} general formula (i)).
The manufacturing method of the compound represented by these. The compound represented by the general formula (i) is represented by the general formula (i-1).

(Wherein R ⁱ¹ and R ⁱ² each independently represent the same meaning as R ⁱ¹ and R ^{i2 in} general formula (i), R ⁱ¹³ represents a hydrogen atom or an alkyl group having 1 to 19 carbon atoms, One or two or more of —CH ₂ — in R ⁱ¹³ are each independently —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 (this is present in the group one -CH ₂ - or nonadjacent two or more -CH ₂ - is -O -, - S- and ^{-NR i15} It may be substituted with-.)
(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═. .)
^May be substituted with a group selected from the group consisting of, but by replacing one or more —CH ₂ — in R ⁱ¹³ , general formula (i-1) may be substituted with two or more β -Represents no oxo-carbonyloxy structure,
One or more hydrogen atoms in R ⁱ¹³ may be each independently substituted by a cyano group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and R ⁱ¹⁴ and R ⁱ¹⁵ are each a hydrogen atom or a carbon atom number of 1 Represents 10 to 10 alkyl groups. )
The method for producing a compound according to claim 1, wherein the compound is represented by the formula: The compound represented by the general formula (i-1) is represented by the general formula (i-2).

( ^Wherein R ⁱ¹³ represents the same meaning as R ^{i13 in} formula (i-1);
R ⁱ²¹ represents a hydrogen atom or an alkyl group having 1 to 17 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 two or more hydrogen atoms in R ⁱ²¹ each independently represent a cyano group, a fluorine atom, May be substituted with a chlorine atom, a bromine atom or an iodine atom,
X ⁱ²¹ and X ⁱ²² each independently represent —O—, —NR ⁱ²⁵ —, —S— or —CH ₂ —, ^wherein at least one of X ⁱ²¹ and X ⁱ²² represents —O—, —NR ⁱ²⁵ —, -S-
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 ^i26- 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═, The hydrogen atom present may be substituted with a fluorine atom.)
(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═. The hydrogen atom present in the naphthalene-2,6-diyl group or the 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 , R ⁱ²⁵ and R ⁱ²⁶ each independently 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. )
The manufacturing method of the compound of Claim 2 which is a compound represented by these. In the 2,5-disubstituted 6-membered heterocyclic compound obtained by decarboxylation to the compound represented by the general formula (i-2), the mass of the 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, is 4 or more. A method for producing the described compound. General formula (iii)

^{(Wherein, R i3} has the same meaning as ^{R i3} in the general formula (i).)
And a compound represented by the general formula (iv)

(In the formula, R ⁱ³¹ represents a hydrogen atom or an alkyl group having 1 to 17 carbon atoms, and one or two or more —CH ₂ — in R ⁱ³¹ are each independently —CH═CH—, —C ≡C—, —O—, —S—, —NR ⁱ³⁴ —, ^—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 adjacent to each other) And two or more —CH ₂ — that are not present may be substituted with —O—, —S—, and —NR ⁱ³⁵ —.)
(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═. .)
^Or one or more hydrogen atoms in R ⁱ³¹ may be independently substituted with a cyano group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Often,
R ⁱ³⁴ and R ⁱ³⁵ represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. )
Is reacted with a compound represented by the general formula (i-3) as a compound represented by the general formula (i).

^{(Wherein, R i3} has the same meaning as ^{R i3} in the general formula ^{(i), R i 31} represents the same meaning as ^{R i 31} in the general formula (iv).)
The manufacturing method of the compound of Claim 1 which performs a decarboxylation reaction using the compound represented by these. The manufacturing method of the compound as described in any one of Claims 1-5 which makes a salt act and decarboxylates. The manufacturing method of the compound as described in any one of Claims 1-6 which decarboxylates at the temperature of 80 to 180 degreeC. The manufacturing method of the compound of Claims 1-7 which refine | purifies the compound represented by the obtained general formula (ii).