JP2016183129A - Method for producing alkene stereoselectively - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing alkene efficiently and stereoselectively, and tetrazole that is a reaction intermediate useful for the production method and represented by formula (2).SOLUTION: The present invention provides a method for producing a compound of formula (3) by use of compounds of formula (1) and formula (2), and a base.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing stereoselective alkenes.

  There are two types of isomers in 1,2-substituted ethylene, but when 1,2-substituted ethylene is produced, it is obtained as a mixture of two types of isomers. The two isomers (E-form and Z-form) of 1,2-substituted ethylene have different physical property values due to the difference in structure. In particular, when 1,2-substituted ethylene is used as a component of the liquid crystal composition, the Z body greatly reduces the liquid crystal properties of the added liquid crystal composition, and therefore, the Z body needs to be removed and used.

  For this reason, when the manufacturing process which contains many Z bodies is employ | adopted, many Z bodies will be discarded in the subsequent refinement | purification process, and it is not efficient.

  For example, an (E) -1,2-bis (cyclohexyl) ethylene derivative is useful for reducing the viscosity of a liquid crystal composition (Non-patent Document 1, Patent Document 1). There are several known manufacturing methods (see Patent Document 1, Patent Document 2, and Non-Patent Document 2). However, these manufacturing methods are not always practical. For example, in Patent Document 1 and Patent Document 2, the Z-form is oxidized with peroxide, then brominated with dibromotriphenylphosphorane, and then reduced with zinc to obtain E-form. Low. In Non-Patent Document 2, 1,2-bis (trans-4-alkylcyclohexyl) ethane-1,2-diketone is converted to dihydrazone and converted to 1,2-bis (trans-4-alkylcyclohexyl) acetylene. Then, E-1,2-bis (cyclohexyl) ethylene derivative was obtained by reducing this, but in addition to using highly toxic hydrazine and hexamethylphosphoric triamide (HMPT), ignitable metallic lithium Is not practical. Moreover, it cannot be said that the selectivity of E body of these manufacturing methods is enough, and the further improvement was calculated | required.

  Moreover, after obtaining a mixture of E-form and Z-form, isomerization with benzenesulfinic acid or the like and purification are also known (Patent Document 3). However, in this method, isomerization is performed. A process is required.

JP-A-6-92924 WO94 / 20443 JP 2003-286279 A

Liquid Crystal Volume 1 Issue 1 (1997) Chemicker-Zeitung, 104, p 269 (1980)

  The problem to be solved by the present invention is to provide an efficient and stereoselective alkene production method and a useful reaction intermediate.

  The inventor of the present application has intensively studied to solve the above problems, and as a result, the present invention has been completed.

  By using a compound represented by one or more general formulas (1), a compound represented by one or two or more general formulas (2), and a base, it is represented by general formula (3). Can be produced stereoselectively with high efficiency. In addition, a compound represented by the general formula (2), which is an important intermediate in the production method, was obtained.

(In the general formula (1), R ¹¹ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, or an alkoxyl group having 2 to 8 carbon atoms. of an alkenyl group or an alkenyloxy Le group having a carbon number of carbon atoms from 2 to 8, -CH 2 in the radical _- or nonadjacent two or more -CH 2 _- are each independently substituted by -O- And one or more hydrogen atoms present in the group may each independently be substituted with halogen,
A ¹¹ is, (a) cyclohexane-1,4-diyl group (this is present in the group one -CH ₂ - or nonadjacent two or more -CH ₂ - is replaced by -O- May be good.)
(B) 1,4-phenylene group (one -CH = present in this group or two or more non-adjacent -CH = may be replaced by -N =).
(C) 1,4-cyclohexenylene group, 1,4-bicyclo (2.2.2) octylene group, piperidine-1,4-diyl group, naphthalene-2,6-diyl group, decahydronaphthalene-2 , 6-diyl group and a group selected from the group consisting of 1,2,3,4-tetrahydronaphthalene-2,6-diyl group, in the above group (a), group (b) or group (c) Each of the hydrogen atoms may be independently substituted with halogen,
Z ¹¹ represents a single bond, —CH ₂ CH ₂ —, — (CH ₂ ) ₄ —, —OCH ₂ —, —CH ₂ O—, —COO—, —OCO—, —OCF ₂ —, —CF ₂ O—. , -CH = CH-, -CF = CF- or -C≡C-
n ¹¹ represents a natural number of 0 to 10, but when n ¹¹ represents 2 to 10, a plurality of A ¹¹ may be the same or different, and when n ¹¹ represents 2 to 10 Z ¹¹ present may be the same or different, and when n ¹¹ represents 0, R ¹¹ does not represent a hydrogen atom,
Sp ¹¹ represents a single bond or an alkylene group of carbon atoms 1 to 20, -CH in group ₂ - or nonadjacent two or more -CH ₂ - may be replaced each independently -O- And one or more hydrogen atoms present in the group may be independently substituted with halogens,
In the general formula (2), R ²¹ represents a hydrogen atom or a substituent represented by the general formula (4), R ²² represents a substituent represented by the general formula (5),

(In the general formulas (4) and (5), R ⁴¹ and R ⁵¹ each independently represent the same meaning as R ¹¹ in the general formula (1), and A ⁴¹ and A ⁵¹ each independently represent the general formula The same meaning as A ¹¹ in (1) is represented, Z ⁴¹ and Z ⁵¹ each independently represent the same meaning as Z ¹¹ in General Formula (1), and n ⁴¹ and n ⁵¹ each independently represent a general formula. (It represents the same meaning as n ¹¹ in (1), and Sp ⁴¹ and Sp ⁵¹ each independently represent the same meaning as Sp ¹¹ in general formula (1).)
R ²³ represents an aromatic ring,
In the general formula ^{(3), R 11} has the general formula (1) represent the same substituent as ^{R 11 in, A 11} represents the same substituent as ^{A 11} in the general formula ^{(1), Z 11} is represents a ^{Z 11} and identical substituents in the general formula ^{(1), n 11} represents an integer of same ^{n 11} in the general formula (1), ^{Sp 11} is identical to the ^{Sp 11} in the general formula (1) It represents a natural ^{number, R 21} represents the same substituent as ^{R 21} in the general formula ^{(2), R 22} represents the same substituent as ^{R 22} in the general formula (2). )

  The production method of the present invention enables practical production of E-1,2-substituted ethylene, which has been difficult to produce efficiently. The composition containing the compound produced by the production method of the present invention is a resin, oil, oil filter, oil, fat, ink, pharmaceutical, cosmetics, detergent, liquid crystal material, agricultural chemical, polymer, resin, pigment, dye, adhesive. It is useful for applications such as adhesives, printed materials, foods, optical anisotropic bodies, display elements or electronic devices.

In the general formula (1), R ¹¹ is not particularly limited as long as it provides the target compound in the reaction process, but from the viewpoint of ease of synthesis and from the viewpoint of liquid crystallinity when used in a liquid crystal material, An alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms or an alkenyloxyl group having 2 to 8 carbon atoms is preferable, and is a product of the present invention. From the viewpoint of the stability of the nematic phase of the compound represented by the general formula (3), the number of carbon atoms is preferably 5 or less, and from the viewpoint of the stability of the smectic phase, the number of carbon atoms is 6 or more. Are preferred, and are preferably linear.

A ¹¹ is not particularly limited as long as it provides the target compound in the reaction process, but it is more preferably the following structure:

The following structure is more preferable.

Z ¹¹ is not particularly limited as long as it provides the target compound in the reaction process, but is not limited to a single bond, —CH ₂ CH ₂ —, — (CH ₂ ) ₄ —, —OCH ₂ —, —CH ₂ O—, —OCF ₂ — or —CF ₂ O— is preferred, and when focusing on the yield of the production method of the present invention, a single bond, —CH ₂ CH ₂ —, —OCH ₂ —, —CH ₂ O—, -OCF ₂ - or _-CF 2 O-it is preferred.

n ¹¹ is not particularly limited as long as it gives the target compound in the reaction process, but when the production method of the present invention is carried out in a homogeneous system using a solvent, the compound represented by the general formula (1) 4 or less is preferable and 3 or less is preferable from the relationship of the solubility with respect to a solvent. In order to improve the stereoselectivity of the general formula (3), it is preferably 1 or more. When n ¹¹ represents 2 to 10, at least one of Z ¹¹ is preferably a single bond, and all but one of Z ¹¹ present are preferably single bonds, and all are single bonds. A bond is preferred.

Sp ¹¹ is not particularly limited as long as it provides the desired compound in the reaction process, preferably a single bond and an alkylene group having 1 to 20 carbon atoms, preferably a single bond and an alkylene group having 1 to 8 carbon atoms, A single bond and an alkylene group having 1 to 4 carbon atoms are preferred, and a single bond and an alkylene group having 1 to 2 carbon atoms are preferred.

In the compound represented by the general formula (2), R ²² is a bulky substituent as compared with R ²¹ . Due to the difference in bulkiness between R ²¹ and R ²² , a compound represented by the general formula (3) having a specific three-dimensional structure can be produced.

R ²¹ in the general formula (2) is not particularly limited as long as it gives the target compound in the reaction process, and is preferably a hydrogen atom or a substituent represented by the general formula (4). However, from the viewpoint of ease of synthesis of the compound represented by the general formula (2), from the viewpoint of liquid crystallinity when used for the stereoselectivity of the compound represented by the general formula (3) and a liquid crystal material, More preferably, it is a hydrogen atom.

When R ²¹ is a substituent represented by the general formula (4), n ⁴¹ is preferably 0 to 2, preferably 0 or 1, and preferably 0. Sp ⁴¹ , A ⁴¹ , Z ⁴¹ and R ⁴¹ are preferably the same substituents as A ¹¹ , Z ¹¹ and R ¹¹ in the general formula (1), but R ⁴¹ is more preferably an alkyl group having 1 to 8 carbon atoms. preferable.

In the general formula (2), R ²² is preferably a substituent represented by the general formula (5). However, from the viewpoint of ease of synthesis of the compound represented by the general formula (2), n ⁵¹ in the substituent represented by the general formula (5) is preferably 0 to 2, It is preferable that it is, and it is preferable that it is 0. Sp ⁵¹ , A ⁵¹ , Z ⁵¹ and R ⁵¹ are preferably the same substituents as A ¹¹ , Z ¹¹ and R ¹¹ in formula (1), but R ⁵¹ is more preferably an alkyl group having 1 to 8 carbon atoms. preferable.

R ²³ in the general formula (2) is preferably an aromatic ring, but from the viewpoint of yield, a benzene ring, an alkylbenzene ring, a naphthalene ring, or an anthracene ring is more preferable. Furthermore, R ²³ is more preferably a phenyl group or a 1,4-phenylene group from the viewpoint of ease of synthesis of the compound represented by the general formula (2) and economical efficiency. R ²³ may have a hydrogen atom on the substituent group substituted with halogen or the like, but is preferably unsubstituted from the viewpoint of reactivity.

  In this specification, expressing the same meaning means that both substituents may or may not have the same chemical structure, but are substituents selected from the same option. And “representing the same substituent” means a substituent having the same chemical structure.

  As the base, amine, amide, carbamate, imide, sulfonamide, guanidine, hydrazone, hydrazide, hydrazine, heterocyclic amine, salts thereof, carbonate, metal hydride, metal alkoxide or alkyl metals are preferable. In particular, from the viewpoint of yield, a metal hydride, metal alkoxide, or hydrazide salt that has a basicity of pKa 15.0 or more and a low nucleophilicity is more preferable. Examples include lithium diisopropylamide, sodium hydride, tert-butoxypotassium, potassium hexamethyldisilazide, lithium hexamethyldisilazide, lithium tetramethylpiperidine and the like. Moreover, only one type of base may be used, or two or more types may be used.

  The reaction solvent is not particularly limited as long as it provides the target compound in the reaction process. Specifically, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,2-dichloroethylene, 1,1 , 2,2-tetrachloroethane, trichloroethylene, 1-chlorobutane, carbon disulfide, acetone, acetonitrile, benzonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, diethyl ether, ethylene glycol monoethyl ether , Ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether, ethylene glycol monomethyl ether, diethylene glycol diethyl ether, o-dichlorobenzene, xylene, o-xylene, p-key Len, m-xylene, chlorobenzene, isobutyl acetate, isopropyl acetate, isoamyl acetate, ethyl acetate, butyl acetate, propyl acetate, pentyl acetate, methyl acetate, 2-methoxyethyl acetate, hexamethylphosphate triamide, tris (dimethylamino) phosphine , Cyclohexanone, 1,4-dioxane, styrene, tetrachloroethylene, tetrahydrofuran, pyridine, 1-methyl-2-pyrrolidinone, 1,1,1-trichloroethane, toluene, hexane, pentane, cyclohexane, cyclopentane, heptane, benzene, methyl isobutyl Ketone, tert-butyl methyl ether, methyl ethyl ketone, methyl cyclohexanone, methyl butyl ketone, diethyl ketone, gasoline, coal tar naphtha, petroleum ether, stone Naphtha, petroleum benzine, turpentine oil, and the like. From the viewpoint of yield, those having no active proton are preferred, and examples thereof include hydrocarbons, ethers, formamides, sulfoxides, and nitriles. In particular, from the viewpoint of E / Z, when an additive is used, a nonpolar solvent is desirable, and specific examples include toluene, hexane, pentane, cyclohexane, cyclopentane, heptane, benzene and the like. From the viewpoint of facilitating the production process and the purification process, tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl, or the like may be used.

  As the additive, those having high metal cation scavenging properties, specifically, polyamines, polyetheramines, polyethers, and polyesters are preferable. In particular, polyethers are more preferable from the viewpoints of yield, E / Z, and economy, and specific examples include ethylene glycol dimethyl ether, diethylene glycol dimethyl, triethylene glycol dimethyl ether, and tetraethylene glycol dimethyl.

  The production temperature is preferably −70 ° C. to 0 ° C. The order of addition of the reactants at that time is to activate the compound of the general formula (2) by allowing a base to act, and then react the substrate (1). There are no other restrictions as long as they are in order. However, from the viewpoint of work efficiency and economy, -60 ° C to 0 ° C is preferable, -50 ° C to 0 ° C is preferable, -40 ° C to 0 ° C is preferable, -30 ° C to 0 ° C is preferable, and -20 C. to 0.degree. C. is preferred.

  The order of adding the reactants is to add the compound represented by the general formula (1) and the general formula (2) to the base, or add the base to the compound represented by the general formula (1) and the general formula (2). The order of addition is more preferred. In this case, it is preferable to use them together with a solvent.

  Furthermore, when the production is performed at a relatively high temperature such as −20 ° C. to 0 ° C., the compound represented by the general formula (1) is an aldehyde having a hydrogen atom that can be deprotonated at the α-position. From the viewpoint of yield, the order of addition in which a base is added to the compounds represented by formulas (1) and (2) is more preferred.

  EXAMPLES Hereinafter, although an Example is given and this invention is further described, this invention is not limited to these Examples. “%” In the compositions of the following examples and comparative examples means “% by mass”. The hydrogen pressure means a pressure when the atmospheric pressure is 0 MPa. Although the compound manufactured by the manufacturing method of this invention and the manufacturing method of a comparative example is described below, in order to make it easy to understand, the compound manufactured by the manufacturing method of this invention adds only a number to the end like (3-1). The compound produced by the production method of the comparative example is suffixed with an alphabet as in (3-1a).

The purity of the compound was analyzed by GC or UPLC. The analysis conditions are as follows.
(GC analysis conditions)
Column: Agilent Technologies, J & W Column DB-1HT, 15 m × 0.25 mm × 0.10 μm
Temperature program: 100 ° C (1 minute)-(20 ° C / minute)-250 ° C-(10 ° C / minute)-380 ° C-(7 ° C / minute)-400 ° C (2.64 minutes)
Inlet temperature: 350 ° C
Detector temperature: 400 ° C
(UPLC analysis conditions)
Column: Waters ACQUITY UPLC BEH C ₁₈ , 2.1 × 100 mm, 1.7 μm
Elution solvent: acetonitrile / water (90:10)
Flow rate: 0.5 mL / min
Detector: UV, 210nm
Column oven: 40 ° C
Example 1 Production of Compound Represented by Formula (3-1) Production of TDA-1

In a reaction vessel equipped with a stirrer and a thermometer, 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) (65.5 mg, 0.275 mmol) and tris (2- ( 2-Methoxyethoxy) ethyl) amine (TDA-1) (55.0 μL, 0.172 mmol) was dissolved in toluene (140 μL) and cooled to −70 ° C. with stirring. Subsequently, potassium hexamethyldisilazide (11% toluene solution, about 0.5 mol / L) (600 μL, 0.300 mmol) was added and stirred for 5 minutes, and then dissolved in toluene (135 μL), 4-((4 -Ethoxy-2,3-difluorophenoxy) methyl) cyclohexane-1-carbaldehyde (1-1) (74.6 mg, 0.250 mmol) was added, and the mixture was further stirred for 30 minutes. After warming to room temperature and further stirring for 2 hours, the reaction was stopped by adding an excess amount of saturated aqueous ammonium chloride and analyzed by gas chromatography. 1-Ethoxy-2,3-difluoro-4- ( Formation of (4- (propen-1-yl) cyclohexyl) methoxy) benzene (3-1) (conversion 87%, E / Z = 97: 3) was confirmed.
(Example 2) Production of a compound represented by the formula (3-1), in which the dropping order and the reaction temperature were changed.

In a reaction vessel equipped with a stirrer and a thermometer, 4-((4-ethoxy-2,3-difluorophenoxy) methyl) cyclohexane-1-carbaldehyde (1-1) (500 mg, 1.68 mmol) under an argon atmosphere. ), 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) (438 mg, 1.84 mmol) and tris (2- (2-methoxyethoxy) ethyl) amine (TDA-1) (370 μL, 1.16 mmol) was dissolved in toluene (1.8 mL) and cooled to −20 ° C. with stirring. Subsequently, potassium hexamethyldisilazide (11% toluene solution, about 0.5 mol / L) (4.00 mL, 2.01 mmol) was added dropwise at the same reaction temperature, and the mixture was further stirred for 1 hour. After warming to room temperature, the reaction was stopped by adding an excess amount of saturated aqueous ammonium chloride and analyzed by gas chromatography. As a result, 1-ethoxy-2,3-difluoro-4-((4- (propene- Formation of 1-yl) cyclohexyl) methoxy) benzene (3-1) (91% conversion, E / Z = 98: 2) was confirmed.
(Example 3) Production of a compound represented by the formula (3-1) by changing the additive

In a reaction vessel equipped with a stirrer and a thermometer, 4-((4-ethoxy-2,3-difluorophenoxy) methyl) cyclohexane-1-carbaldehyde (1-1) (500 mg, 1. 68 mmol), 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) (522 mg, 2.18 mmol) and triethylene glycol dimethyl ether (605 μL, 2.32 mmol) in toluene (1.8 mL). Dissolved and cooled to −20 ° C. with stirring. Subsequently, potassium hexamethyldisilazide (11% toluene solution, about 0.5 mol / L) (4.40 mL, 2.18 mmol) was added dropwise at the same reaction temperature, and the mixture was further stirred for 1 hour. After warming to room temperature, the reaction was stopped by adding an excess amount of saturated aqueous ammonium chloride and analyzed by gas chromatography. As a result, 1-ethoxy-2,3-difluoro-4-((4- (propene- Formation of 1-yl) cyclohexyl) methoxy) benzene (3-1) (94% conversion, E / Z = 98: 2) was confirmed. The organic layer was separated, washed with water (10 mL) and then with saturated brine (10 mL), and then dried using sodium sulfate. The dried mixture was concentrated under reduced pressure, purified by column chromatography (silica gel 1 g, hexane 10 mL solution, hexane 30 mL expelled), concentrated and recrystallized twice to obtain the desired product (427 mg, E / E Z = 100: 0, recovery rate 82%).
(Example 4) No additive used, production of compound represented by formula (3-1)

To a reaction vessel equipped with a stirrer and a thermometer, toluene (140 μL) was added 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) (65.5 mg, 0.275 mmol) under an argon atmosphere. And cooled to −70 ° C. with stirring. Subsequently, potassium hexamethyldisilazide (11% toluene solution, about 0.5 mol / L) (600 μL, 0.300 mmol) was added and stirred for 5 minutes, and then dissolved in toluene (135 μL), 4-((4 -Ethoxy-2,3-difluorophenoxy) methyl) cyclohexane-1-carbaldehyde (1-1) (74.6 mg, 0.250 mmol) was added, and the mixture was further stirred for 30 minutes. After warming to room temperature and further stirring for 2 hours, the reaction was stopped by adding an excess amount of saturated aqueous ammonium chloride and analyzed by gas chromatography. 1-Ethoxy-2,3-difluoro-4- ( Formation of (4- (propen-1-yl) cyclohexyl) methoxy) benzene (3-1) (conversion 55%, E / Z = 56: 44) was confirmed.
Example 5 Production of Compound Represented by Formula (3-2)

In a reaction vessel equipped with a stirrer and a thermometer, compound (1-2) (100 mg, 0.285 mmol), 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) under an argon atmosphere. ) (74.8 mg, 0.314 mmol) and tris (2- (2-methoxyethoxy) ethyl) amine (TDA-1) (63.0 μL, 0.197 mmol) were dissolved in toluene (320 μL). The mixture was cooled to −40 ° C. with stirring. Subsequently, potassium hexamethyldisilazide (11% toluene solution, about 0.5 mol / L) (628 μL, 0.314 mmol) was added dropwise at the same reaction temperature, and the mixture was further stirred for 1 hour. After warming to room temperature, the reaction was stopped by adding an excess amount of saturated aqueous ammonium chloride and analyzed by gas chromatography to find the desired product (3-2) (conversion 90%, E / Z = 92: The generation of 8) was confirmed.
Example 6 Production of Compound Represented by Formula (3-3)

In a reaction vessel equipped with a stirrer and a thermometer, compound (1-3) (100 mg, 0.476 mmol), 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) under an argon atmosphere. ) (125 mg, 0.524 mmol) and tetraethylene glycol dimethyl ether (115 μL, 0.524 mmol) were dissolved in toluene (530 μL) and cooled to −40 ° C. with stirring. Subsequently, potassium hexamethyldisilazide (11% toluene solution, about 0.5 mol / L) (1.05 mL, 0.524 mmol) was added dropwise at the same reaction temperature, and the mixture was further stirred for 1 hour. After warming to room temperature, the reaction was stopped by adding an excess amount of a saturated aqueous ammonium chloride solution and analyzed by gas chromatography. As a result, the desired product (3-3) (conversion rate: 93%, E / Z = 96: The generation of 4) was confirmed.
(Example 7) Production of compound represented by formula (2-1)

In a reaction vessel equipped with a stirrer and a thermometer, compound (2-1a) (14.9 g, 83.3 mmol) and potassium carbonate (17.3 g, 125 mmol) were dissolved in acetone (60 mL) under an argon atmosphere. The mixture was stirred at 25 ° C. The reaction vessel was immersed in an ice bath, ethyl iodide (15.6 g, 100 mmol) was added dropwise, and the mixture was further stirred at 25 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, toluene (200 mL) and water (200 mL) were added, and the mixture was separated into an organic layer and an aqueous layer. The organic layer was washed with saturated brine (200 mL) and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure to obtain an oily colorless residue (2-1b) (14.4 g, purity 99.8%).
In a reaction vessel equipped with a stirrer and a thermometer, compound (2-1b) (16.3 g, 79.2 mmol) was dissolved in ethanol (160 mL) under an argon atmosphere and stirred at room temperature. A solution prepared by dissolving hexammonium hexamolybdate tetrahydrate (9.78 g, 7.92 mmol) in 35% aqueous hydrogen peroxide (78.4 g) in advance was added dropwise to the reaction vessel. . Immediately after the start of dropping, heat was generated, and the mixture was stirred for 2 hours while being cooled to about 25 ° C in an ice bath. A 10% aqueous sodium sulfite solution (200 mL) was added slowly, and the mixture was stirred for 20 minutes at room temperature. The layers were separated, extracted from the aqueous layer with ethyl acetate (200 mL), the organic layers were combined, and washed with saturated brine (200 mL). And dried over sodium sulfate. The obtained solution was passed through a column packed with silica gel (16 g), further expelled with ethyl acetate (500 mL), and the solution was concentrated under reduced pressure to obtain a crude product (24.0 g). Recrystallization from hexane and ethyl acetate gave the target compound (2-1) (17.9 g, purity 99.9%).
Example 8 Production of Compound Represented by Formula (2-2)

Synthesis of (Compound 2-2d) Compound (2-2c) (30.0 g, 99.9 mmol) and pyridine (9.90 mL, 120 mmol) were added to toluene in a reaction vessel equipped with a stirrer and a thermometer in an argon atmosphere. (120 mL) and stirred with ice cooling. Methanesulfonyl chloride (9.32 mL, 120 mmol) was added dropwise thereto, the temperature was raised to room temperature, and the mixture was stirred for 3 hours. Thereafter, the mixture was ice-cooled again, saturated sodium hydrogen carbonate (240 mL) was added, and the mixture was further stirred for 30 minutes. The mixture was warmed to room temperature and extracted from the separated aqueous layer with toluene (240 mL). The organic layers were combined, washed with saturated brine (240 mL), and dried over sodium sulfate. When this was concentrated under reduced pressure, the target product (2-2d) (34.8 g, 92.0 mmol) was obtained.
Synthesis of (Compound 2-2) In a reaction vessel equipped with a stirrer and a thermometer, compound (2-2a) (14.9 g, 83.3 mmol) and potassium carbonate (17.3 g, 125 mmol) were added in an argon atmosphere. It was dissolved in acetone (60 mL) and stirred at 25 ° C. The reaction vessel was immersed in an ice bath, and compound (2-2d) (34.8 g, 92.0 mmol) dissolved in acetone (100 mL) was added dropwise, and the mixture was further stirred at 25 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, toluene (200 mL) and water (200 mL) were added, and the mixture was separated into an organic layer and an aqueous layer. The organic layer was washed with saturated brine (200 mL) and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure to obtain a colorless crystalline residue (2-2b) (37.3 g, purity 99.8%).
In a reaction vessel equipped with a stirrer and a thermometer, compound (2-2b) (37.3 g, 81.0 mmol) was dissolved in ethanol (400 mL) under an argon atmosphere and stirred at room temperature. A solution prepared by dissolving hexammonium hexamolybdate tetrahydrate (10.0 g, 8.10 mmol) in 35% hydrogen peroxide (80.1 g) in advance was added dropwise to the reaction vessel. . Immediately after the start of dropping, heat was generated, and the mixture was stirred for 2 hours while being cooled to about 25 ° C in an ice bath. A 10% aqueous sodium sulfite solution (200 mL) was added slowly, and the mixture was stirred for 20 minutes at room temperature. The layers were separated, and the aqueous layer was extracted with ethyl acetate (200 mL). And dried over sodium sulfate. The obtained solution was passed through a column packed with silica gel (40 g), further expelled with ethyl acetate (800 mL), and the solution was concentrated under reduced pressure to obtain a crude product (33.0 g). Recrystallization from hexane and ethyl acetate gave the target compound (2-2) (28.2 g, purity 99.2%).
Example 9 Production of Compound Represented by Formula (3-1)

In a reaction vessel equipped with a stirrer and a thermometer, acetaldehyde (21.0 mg, 0.476 mmol), compound (2-2) (125 mg, 0.524 mmol) and tetraethylene glycol dimethyl ether (115) were added under an argon atmosphere. μL, 0.524 mmol) was dissolved in toluene (530 μL) and cooled to −40 ° C. with stirring. Subsequently, potassium hexamethyldisilazide (11% toluene solution, about 0.5 mol / L) (1.05 mL, 0.524 mmol) was added dropwise at the same reaction temperature, and the mixture was further stirred for 1 hour. After warming to room temperature, the reaction was stopped by adding an excess amount of a saturated aqueous ammonium chloride solution and analyzed by gas chromatography. The target product (3-1) (conversion rate 89%, E / Z = 97: The generation of 3) was confirmed.
(Example 10) Production of a compound represented by the formula (3-4)

In a reaction vessel equipped with a stirrer and a thermometer, in an argon atmosphere, compound (1-4) (386 mg, 1.68 mmol), 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) (522 mg, 2.18 mmol) and triethylene glycol dimethyl ether (605 μL, 2.32 mmol) were dissolved in toluene (1.8 mL) and cooled to −20 ° C. with stirring. Subsequently, potassium hexamethyldisilazide (11% toluene solution, about 0.5 mol / L) (4.40 mL, 2.18 mmol) was added dropwise at the same reaction temperature, and the mixture was further stirred for 1 hour. After warming to room temperature, the reaction was stopped by adding an excess amount of saturated aqueous ammonium chloride and analyzed by gas chromatography. Compound (3-4) (conversion rate 96%, E / Z = 98: 2 ) Was confirmed.
(Comparative Example 1) Production of a compound represented by the formula (3-1) by the production method described in Patent Document 3.

Ethyltriphenylphosphonium bromide (277 g, 746 mmol) was dissolved in THF (700 mL) and stirred at −10 ° C. under a nitrogen atmosphere in a reaction vessel equipped with a stirrer and a thermometer. Subsequently, tert-butoxy potassium (80.3 g, 715 mmol) was added followed by 4-((4-ethoxy-2,3-difluorophenoxy) methyl) cyclohexane-1-carbaldehyde dissolved in THF (700 mL). (1-1) (186 g, 622 mmol) was added dropwise. After the addition, the mixture was warmed to room temperature and stirred for 2 hours, and then a small amount of water was added to confirm that the color of the reaction solution was decolorized. The obtained mixture was concentrated under reduced pressure, extracted with hexane / toluene / sodium hypochlorite / water / methanol (350 mL / 80 mL / 45 mL / 250 mL / 520 mL), and washed with water / methanol (200 mL / 400 mL). Then, it was washed with water (400 mL) and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel 180 g, hexane / toluene (4/1)), and the obtained solution was concentrated under reduced pressure to give 1-ethoxy-2,3-difluoro-4- ( (4- (propen-1-yl) cyclohexyl) methoxy) benzene (3-1a) (174 g, 89% yield, E / Z = 9: 91) was obtained.
In a reaction vessel equipped with a stirrer and a thermometer, the obtained compound (3-1a) (174 g, 559 mmol), sodium benzenesulfinate (4.60 g, 28.0 mmol) and 10% hydrochloric acid (in a nitrogen atmosphere) 21.1 g, 55.9 mmol) was dissolved in toluene (680 mL) and stirred at 85 ° C. for 2 hours. When the reaction solution was analyzed by gas chromatography, it was confirmed that the compound (3-1) (E / Z = 82: 18) was produced. A saturated aqueous sodium hydrogen carbonate solution (500 mL) was added thereto, and the mixture was further stirred for 1 hour, and then the organic layer was separated and washed with water (500 mL). The resulting mixture was concentrated under reduced pressure, purified by column chromatography (silica gel 200 g, hexane 600 mL solution, hexane 1500 mL expelled), concentrated and recrystallized 12 times to obtain compound (3-1). (68.3 g, E / Z = 99.85: 0.15, recovery rate 42%) was obtained.
In this production method, the stereoselectivity after completion of the reaction is low, so that the recrystallization must be repeated in order to increase the purity of the E form, and the recovery rate was greatly reduced.

Claims (9)

Compound represented by general formula (3) using one or more compounds represented by general formula (1), one or more compounds represented by general formula (2) and a base Manufacturing method.

(In the general formula (1), R ¹¹ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, or an alkoxyl group having 2 to 8 carbon atoms. of an alkenyl group or an alkenyloxy Le group having a carbon number of carbon atoms from 2 to 8, -CH 2 in the radical _- or nonadjacent two or more -CH 2 _- are each independently substituted by -O- And one or more hydrogen atoms present in the group may each independently be substituted with halogen,
A ¹¹ is, (a) cyclohexane-1,4-diyl group (this is present in the group one -CH ₂ - or nonadjacent two or more -CH ₂ - is replaced by -O- May be good.)
(B) 1,4-phenylene group (one -CH = present in this group or two or more non-adjacent -CH = may be replaced by -N =).
(C) 1,4-cyclohexenylene group, 1,4-bicyclo (2.2.2) octylene group, piperidine-1,4-diyl group, naphthalene-2,6-diyl group, decahydronaphthalene-2 , 6-diyl group and a group selected from the group consisting of 1,2,3,4-tetrahydronaphthalene-2,6-diyl group, in the above group (a), group (b) or group (c) Each of the hydrogen atoms may be independently substituted with halogen,
Z ¹¹ represents a single bond, —CH ₂ CH ₂ —, — (CH ₂ ) ₄ —, —OCH ₂ —, —CH ₂ O—, —COO—, —OCO—, —OCF ₂ —, —CF ₂ O—. , -CH = CH-, -CF = CF- or -C≡C-
n ¹¹ represents a natural number of 0 to 10, but when n ¹¹ represents 2 to 10, a plurality of A ¹¹ may be the same or different, and when n ¹¹ represents 2 to 10 Z ¹¹ present may be the same or different, and when n ¹¹ represents 0, R ¹¹ does not represent a hydrogen atom,
Sp ¹¹ represents a single bond or an alkylene group of carbon atoms 1 to 20, -CH in group ₂ - or nonadjacent two or more -CH ₂ - may be replaced each independently -O- And one or more hydrogen atoms present in the group may be independently substituted with halogens,
In the general formula (2), R ²¹ represents a hydrogen atom or a substituent represented by the general formula (4), R ²² represents a substituent represented by the general formula (5),

(In the general formulas (4) and (5), R ⁴¹ and R ⁵¹ each independently represent the same meaning as R ¹¹ in the general formula (1), and A ⁴¹ and A ⁵¹ each independently represent the general formula The same meaning as A ¹¹ in (1) is represented, Z ⁴¹ and Z ⁵¹ each independently represent the same meaning as Z ¹¹ in General Formula (1), and n ⁴¹ and n ⁵¹ each independently represent a general formula. (It represents the same meaning as n ¹¹ in (1), and Sp ⁴¹ and Sp ⁵¹ each independently represent the same meaning as Sp ¹¹ in general formula (1).)
R ²³ represents an aromatic ring,
In the general formula ^{(3), R 11} has the general formula (1) represent the same substituent as ^{R 11 in, A 11} represents the same substituent as ^{A 11} in the general formula ^{(1), Z 11} is represents a ^{Z 11} and identical substituents in the general formula ^{(1), n 11} represents an integer of same ^{n 11} in the general formula (1), ^{Sp 11} is identical to the ^{Sp 11} in the general formula (1) It represents a natural ^{number, R 21} represents the same substituent as ^{R 21} in the general formula ^{(2), R 22} represents the same substituent as ^{R 22} in the general formula (2). )   2. The base according to claim 1, wherein an amine, amide, carbamate, imide, sulfonamide, guanidine, hydrazone, hydrazide, hydrazine, heterocyclic amine, a salt thereof, a carbonate, a metal hydride, a metal alkoxide or an alkyl metal is used as the base. Manufacturing method.   As a solvent, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,2-dichloroethylene, 1,1,2,2-tetrachloroethane, trichloroethylene, 1-chlorobutane, carbon disulfide, acetone, acetonitrile, benzonitrile N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, diethyl ether, ethylene glycol monoethyl ether, ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether, ethylene glycol monomethyl ether, diethylene glycol diethyl ether, o- Dichlorobenzene, xylene, o-xylene, p-xylene, m-xylene, chlorobenzene, isobutyl acetate, isopropyl acetate, isoacetate , Ethyl acetate, butyl acetate, propyl acetate, pentyl acetate, methyl acetate, 2-methoxyethyl acetate, hexamethylphosphate triamide, tris (dimethylamino) phosphine, cyclohexanone, 1,4-dioxane, styrene, tetrachloroethylene, tetrahydrofuran, Pyridine, 1-methyl-2-pyrrolidinone, 1,1,1-trichloroethane, toluene, hexane, pentane, cyclohexane, cyclopentane, heptane, benzene, methyl isobutyl ketone, tert-butyl methyl ether, methyl ethyl ketone, methyl cyclohexanone, methyl butyl The ketone, diethyl ketone, gasoline, coal tar naphtha, petroleum ether, petroleum naphtha, petroleum benzine and turpentine oil are used alone or in combination. Manufacturing method.   The production method according to any one of claims 1 to 3, wherein a base is added in the presence of the compound represented by the general formula (1) and the compound represented by the general formula (2).   The production method according to any one of claims 1 to 4, wherein polyamines, polyetheramines, polyethers, and polyesters are further added as additives.   The manufacturing method according to any one of claims 1 to 5, wherein the manufacturing temperature is -70 ° C to 0 ° C. R < ²¹ > in General formula (2) is a hydrogen atom, The manufacturing method of any one of Claims 1-6. The manufacturing method according to claim 1, wherein the number of carbon atoms of the substituent represented by the general formula (1-1) in the general formula (1) is 3 or more.

^{(R 11, A 11, Z 11} , n 11 and ^{Sp 11} are as defined ^{R 11, A 11, Z 11} , n 11 and ^{Sp 11} in the general formula (1).)   The compound represented by General formula (2) of Claim 1.