JP6540993B2 - Process for producing stereoselective alkenes - Google Patents

Description

  The present invention relates to a process for the preparation of stereoselective alkenes.

  Although there are two isomers in 1,2-disubstituted ethylene, the production of 1,2-disubstituted ethylene is obtained as a mixture of two isomers. The physical properties of the two isomers (E form, Z form) of 1,2-disubstituted ethylene are different due to the difference in their structures. In particular, when 1,2-disubstituted ethylene is used as a component of the liquid crystal composition, it is necessary to remove and use the Z form in order to greatly reduce the liquid crystallinity of the added liquid crystal composition.

  For this reason, when a manufacturing process that contains many Z-forms is adopted, many Z-forms are discarded in the subsequent purification step, which is not efficient.

  For example, (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). Several methods are known for their production (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 the E form, but the yield is Low. In Non-Patent Document 2, 1,2-bis (trans-4-alkylcyclohexyl) ethane-1,2-diketone is used as dihydrazone, which is converted to 1,2-bis (trans-4-alkylcyclohexyl) acetylene The product is then reduced to give an E-1,2-bis (cyclohexyl) ethylene derivative, but highly toxic hydrazine and hexamethylphosphoric acid triamide (HMPT) are used, as well as pyrophoric metal lithium. Is not practical. Moreover, the selectivity of E form of these production methods is not sufficient, and further improvement has been required.

  In addition, there is also known a method of obtaining E form by isomerizing with a mixture of E form and Z form, then performing isomerization with benzenesulfinic acid or the like and purifying it (Patent Document 3). A process is required.

Japanese Patent Laid-Open No. 6-92924 WO 94/20443 Patent document 1: JP-A 2003-286279

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

  The problem to be solved by the present invention is to provide an efficient and stereoselective process for producing alkenes and to provide useful reaction intermediates.

  The inventors of the present invention made earnest studies to solve the above problems, and as a result, achieved the present invention.

  By using one or more compounds represented by formula (1) and one or more compounds represented by formula (2) and a base, it is represented by 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 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, an alkoxyl group having 1 to 8 carbon atoms, 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 be independently substituted with halogen, respectively.
A ¹¹ is (a) a cyclohexane-1,4-diyl group (one —CH ₂ — present in this group or two or more non-adjacent —CH ₂ — is replaced by —O— Also 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) octyrene group, piperidine-1,4-diyl group, naphthalene-2,6-diyl group, decahydronaphthalene-2 And a group selected from the group consisting of 6, 6-diyl group and 1, 2, 3, 4-tetrahydronaphthalene-2, 6-diyl group, and in the above group (a), group (b) or group (c) Each hydrogen atom may be independently substituted with halogen,
Z ¹¹ is 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. However, when n ¹¹ represents 2 to 10, a plurality of A ¹¹ may be the same or different, and a plurality of 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- Also, one or more hydrogen atoms present in the group may be independently substituted with halogen, respectively.
In the general formula (2), R ²¹ represents a hydrogen atom or a substituent represented by the general formula (4), and 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 as R ¹¹ in the general formula (1), and A ⁴¹ and A ⁵¹ each independently represent the general formula represents the same meaning as ^{a 11} in ^(1), and each of ^{Z 41} and ^{Z 51} independently represent the same meaning as ^{Z 11} in the general formula ^{(1), n 41} and ^{n 51} are each independently the general formula This 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). )

  According to the production method of the present invention, practical production of E-1,2-disubstituted ethylene which has been difficult for efficient production has become possible. Moreover, the composition containing the compound manufactured by the manufacturing method of this invention is resin, oil, oil filter, fats and oils, ink, pharmaceuticals, cosmetics, detergent, liquid crystal material, agrochemical, polymer, resin, pigment, dye, adhesive It is useful for adhesive, printed matter, food, optically anisotropic, display element or electronic device applications.

R ¹¹ in the general formula (1) is not particularly limited as long as it gives a target compound in the reaction process, but from the viewpoint of easiness of synthesis and in the case of liquid crystal material, The alkyl group having 1 to 8 carbon atoms, the alkoxyl group having 1 to 8 carbon atoms, the alkenyl group having 2 to 8 carbon atoms or the alkenyloxyl group having 2 to 8 carbon atoms is preferable, which 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, it is 6 or more carbon atoms Is preferred and linear is preferred.

A ¹¹ is not particularly limited as long as it gives a target compound in the reaction process, but the following structure is more preferable,

The following structure is more preferable.

Although Z ¹¹ is not particularly limited as long as it gives the desired compounds in the reaction process, a single _{bond, -CH 2 CH 2 -, -} (CH 2) 4 -, - OCH 2 -, - CH 2 O-, -OCF ₂ - or _-CF 2 O-are preferred, if the focus on the yield of the manufacturing method of the present invention is 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 a 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) In view of solubility in a solvent, 4 or less is preferable, and 3 or less is preferable. In order to improve the stereoselectivity of the general formula (3), it is preferably at least 1. When n ¹¹ represents 2 to 10, at least one or more of Z ¹¹ is preferably a single bond, and it is preferable that all except one of Z ¹¹ present be a single bond, all Preferably it is a bond.

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

In the compound represented by the general formula (2), R ²² is a bulky substituent compared to R ²¹ . By the difference in bulkiness of R ²¹ and R ²² , a compound represented by General Formula (3) having a specific steric 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 the easiness of synthesis of the compound represented by the general formula (2), the stereoselectivity of the compound represented by the general formula (3), and the liquid crystallinity in the case of use for a liquid crystal material, More preferably, it is a hydrogen atom.

When R ²¹ is a substituent represented by 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 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 General Formula (2), R ²² is preferably a substituent represented by General Formula (5). However, n ⁵¹ in the substituent represented by the general formula (5) is preferably 0 to 2, and preferably 0 or 1, from the viewpoint of the easiness of synthesis of the compound represented by the general formula (2). It is preferable that there be, and it is preferable that it is 0. Sp ⁵¹ , A ⁵¹ , Z ⁵¹ and R ⁵¹ are preferably the same as A ¹¹ , Z ¹¹ and R ¹¹ in the general 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 alkyl benzene ring, a naphthalene ring and an anthracene ring are more preferable. Furthermore, in view of the easiness of synthesis of the compound represented by the general formula (2) and the economy, it is more preferable that R ^{23 be} a phenyl group or a 1,4-phenylene group. Further, R ²³ is a hydrogen atom on a substituent may be substituted with a halogen or the like, it is preferable from the viewpoint of reactivity unsubstituted.

  In the present specification, “representing the same meaning” means that both substituents may or may not have the same chemical structure, but are substituents selected from the same option. The term “same substituent” means that the substituent has the same chemical structure.

  As the base, amines, amides, carbamates, imides, sulfonamides, guanidines, hydrazones, hydrazides, hydrazines, heterocyclic amines, salts thereof, carbonates, metal hydrides, metal alkoxides or alkyl metals are preferable. In particular, from the viewpoint of yield, metal hydrides, metal alkoxides and hydrazide salts, bases having a pKa of 15.0 or more and having a low nucleophilicity are more preferable. For example, lithium diisopropylamide, sodium hydride, potassium tert-butoxide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, lithium tetramethylpiperidine and the like can be mentioned. Also, only one type of base may be used, or two or more types of bases may be used.

  The reaction solvent is not particularly limited as long as it gives the target compound in the reaction process, but specifically, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,2-dichloroethylene, 1,1 2,2,2-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-ki Ren, m-xylene, chlorobenzene, isobutyl acetate, isopropyl acetate, isopropyl acetate, isoamyl acetate, ethyl acetate, butyl acetate, propyl acetate, pentyl acetate, methyl acetate, 2-methoxyethyl acetate, hexamethyl phosphate 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 not having an active proton are preferable, and examples thereof include hydrocarbons, ethers, formamides, sulfoxides and nitriles. In particular, from the viewpoint of E / Z, non-polar solvents are desirable when using additives, and specific examples include toluene, hexane, pentane, cyclohexane, cyclopentane, heptane, benzene and the like. Further, from the viewpoint of facilitation of the production process or 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 a high ability to capture metal cations, specifically, polyamines, polyether amines, polyethers and polyesters are preferable. In particular, polyethers are more preferable from the viewpoint of yield, E / Z and economy, and specific examples thereof include ethylene glycol dimethyl ether, diethylene glycol dimethyl, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl and the like.

  The preparation temperature is preferably -70 ° C. to 0 ° C., and the addition order of the reaction agents in that case is that the compound of the general formula (2) is activated by reacting with a base and then the substrate (1) can be reacted. There is no other limitation if it is an 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, -20 C. to 0.degree. C. is preferred.

  The order of adding each reactant 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. At this time, it is preferable to use them together with a solvent.

  Furthermore, when the preparation is carried out at a relatively high temperature such as -20 ° C to 0 ° C and the compound represented by the general formula (1) is an aldehyde having a deprotonatable hydrogen atom at the α position The order of addition of adding a base to the compounds represented by the general formula (1) and the general formula (2) is more preferable from the viewpoint of yield.

  Hereinafter, the present invention will be further described by way of examples, but the present invention is not limited to these examples. “%” In the compositions of the following examples and comparative examples means “mass%”. The hydrogen pressure means the pressure when the atmospheric pressure is 0 MPa. The compounds produced by the production method of the present invention and the production methods of the comparative examples are described below, but for the sake of clarity, the compounds produced by the production method of the present invention are appended with only numerals at the end like (3-1). The compounds prepared according to the process of Comparative Example are appended with an alphabet at the end like (3-1a).

The purity of the compounds was analyzed by GC or UPLC. The analysis conditions are as follows.
(GC analysis conditions)
Column: Agilent Technologies, J & W Column DB-1HT, 15m × 0.25mm × 0.10μm
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: 0.5mL / min
Detector: UV, 210 nm
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, under an argon atmosphere, 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) (65.5 mg, 0.275 mmol) and tris (2- (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. Then, after adding potassium hexamethyl disilazide (11% toluene solution, about 0.5 mol / L) (600 μL, 0.300 mmol) and stirring for 5 minutes, it was 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. The reaction mixture was warmed to room temperature and stirred for a further 2 hours, after which the reaction was stopped by adding an excess amount of saturated aqueous ammonium chloride solution and analyzed by gas chromatography, 1-ethoxy-2,3-difluoro-4- ( The formation of (4- (propen-1-yl) cyclohexyl) methoxy) benzene (3-1) (conversion rate 87%, E / Z = 97: 3) was confirmed.
Example 2 Production of a Compound Represented by Formula (3-1) in Which the Order of Addition 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) in 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 up to room temperature, the reaction was quenched by the addition of an excess amount of saturated aqueous ammonium chloride solution and analyzed by gas chromatography, 1-ethoxy-2,3-difluoro-4-((4- (propene-) The formation of 1-yl) cyclohexyl) methoxy) benzene (3-1) (conversion rate 91%, E / Z = 98: 2) was confirmed.
Example 3 Production of a Compound Represented by Formula (3-1) in which Additives are Modified

In a reaction vessel equipped with a stirrer and a thermometer and under an argon atmosphere, 4-((4-ethoxy-2,3-difluorophenoxy) methyl) cyclohexane-1-carbaldehyde (1-1) (500 mg, 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) Dissolve and cool to -20 ° C while stirring. Subsequently, potassium hexamethyldisilazide (11% solution in toluene, 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 up to room temperature, the reaction was quenched by the addition of an excess amount of saturated aqueous ammonium chloride solution and analyzed by gas chromatography, 1-ethoxy-2,3-difluoro-4-((4- (propene-) The formation of 1-yl) cyclohexyl) methoxy) benzene (3-1) (conversion rate 94%, E / Z = 98: 2) was confirmed. The organic layer was separated, washed with water (10 mL) and then with saturated brine (10 mL), and dried over sodium sulfate. The dried mixture is 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 /) Z = 100: 0, 82% recovery rate was obtained.
Example 4 Additive-Free, Production of Compound Represented by Formula (3-1)

In a reaction vessel equipped with a stirrer and a thermometer, toluene (140 μL) of 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) (65.5 mg, 0.275 mmol) in an argon atmosphere And cooled to -70 ° C while stirring. Then, after adding potassium hexamethyl disilazide (11% toluene solution, about 0.5 mol / L) (600 μL, 0.300 mmol) and stirring for 5 minutes, it was 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. The reaction mixture was warmed to room temperature and stirred for a further 2 hours, after which the reaction was stopped by adding an excess amount of saturated aqueous ammonium chloride solution and analyzed by gas chromatography, 1-ethoxy-2,3-difluoro-4- ( The formation of (4- (propen-1-yl) cyclohexyl) methoxy) benzene (3-1) (conversion rate 55%, E / Z = 56: 44) was confirmed.
Example 5 Production of Compound Represented by Formula (3-2)

Compound (1-2) (100 mg, 0.285 mmol) 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) in an argon atmosphere in a reaction vessel equipped with a stirrer and a thermometer ) (74.8 mg, 0.314 mmol) and tris (2- (2-methoxyethoxy) ethyl) amine (TDA-1) (63.0 μL, 0.197 mmol) in toluene (320 μL) It cooled to -40 degreeC, 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 quenched by the addition of an excess of saturated aqueous ammonium chloride solution and analyzed by gas chromatography to find that the desired product (3-2) (conversion rate 90%, E / Z = 92: The generation of 8) was confirmed.
Example 6 Production of Compound Represented by Formula (3-3)

Compound (1-3) (100 mg, 0.476 mmol) 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) in an argon atmosphere in a reaction vessel equipped with a stirrer and a thermometer (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 quenched by the addition of an excess of saturated aqueous ammonium chloride solution and analyzed by gas chromatography to find 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, under argon atmosphere, the compound (2-1a) (14.9 g, 83.3 mmol) and potassium carbonate (17.3 g, 125 mmol) are dissolved in acetone (60 mL), It stirred under 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 give 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 heptamolybdate hexaammonium tetrahydrate (9.78 g, 7.92 mmol) in 35% aqueous hydrogen peroxide (78.4 g) was prepared in advance, and this was dropped into the reaction vessel . Immediately after the start of the addition, the mixture was stirred for 2 hours while being cooled to about 25 ° C with an ice bath because of heat generation. Slowly add 10% aqueous sodium sulfite solution (200 mL), stir at room temperature for 20 minutes, separate layers, extract the aqueous layer with ethyl acetate (200 mL), combine the organic layers, and wash with saturated brine (200 mL) , Dried over sodium sulfate. The resulting solution was passed through a column packed with silica gel (16 g), and further chased with ethyl acetate (500 mL), and the solution was concentrated under reduced pressure to give a crude purified 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) in toluene in a reaction vessel equipped with a stirrer and a thermometer under an argon atmosphere The mixture was dissolved in (120 mL) and stirred with ice cooling. The methanesulfonyl chloride (9.32 mL, 120 mmol) was dripped at this, and it heated up to normal temperature, and 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 temperature was raised to room temperature, and the separated aqueous layer was extracted with toluene (240 mL), then the organic layers were combined, washed with saturated brine (240 mL) and dried over sodium sulfate. The mixture was concentrated under reduced pressure to obtain the desired product (2-2d) (34.8 g, 92.0 mmol).
Synthesis of (Compound 2-2) Compound (2-2a) (14.9 g, 83.3 mmol) and potassium carbonate (17.3 g, 125 mmol) were added to a reaction vessel equipped with a stirrer and a thermometer under 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 the 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 give 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 heptamolybdate hexaammonium tetrahydrate (10.0 g, 8.10 mmol) in 35% aqueous hydrogen peroxide (80.1 g) was prepared beforehand, and this was dropped into the reaction vessel . Immediately after the start of the addition, the mixture was stirred for 2 hours while being cooled to about 25 ° C with an ice bath because of heat generation. Slowly add 10% aqueous sodium sulfite solution (200 mL), stir at room temperature for 20 minutes, separate layers, extract the aqueous layer with ethyl acetate (200 mL), combine the organic layers, and wash with saturated brine (200 mL) , Dried over sodium sulfate. The obtained solution was passed through a column packed with silica gel (40 g), and further chased with ethyl acetate (800 mL), and the solution was concentrated under reduced pressure to give a crudely purified 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, under argon atmosphere, acetaldehyde (21.0 mg, 0.476 mmol), compound (2-2) (125 mg, 0.524 mmol) and tetraethylene glycol dimethyl ether (115) Dissolve .mu.L, 0.524 mmol) in toluene (530 .mu.L) and cool to -40.degree. 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 quenched by the addition of an excess of saturated aqueous ammonium chloride solution and analyzed by gas chromatography to find the desired product (3-1) (conversion rate 89%, E / Z = 97: The generation of 3) was confirmed.
Example 10 Production of Compound Represented by Formula (3-4)

Compound (1-4) (386 mg, 1.68 mmol) 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) in an argon atmosphere in a reaction vessel equipped with a stirrer and a thermometer (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% solution in toluene, 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 up to room temperature, the reaction was quenched by the addition of an excess of saturated aqueous ammonium chloride solution and analyzed by gas chromatography to find that compound (3-4) (conversion rate 96%, E / Z = 98: 2 The generation of) was confirmed.
Comparative Example 1 Production of a Compound Represented by Formula (3-1) According to the Production Method Described in Patent Document 3

Ethyl triphenylphosphonium 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 thermometer. Then 4-((4-ethoxy-2,3-difluorophenoxy) methyl) cyclohexane-1-carbaldehyde in the presence of potassium tert-butoxide (80.3 g, 715 mmol) and then dissolved in THF (700 mL) (1-1) (186 g, 622 mmol) was dropped. After dropping, the mixture was warmed to room temperature and stirred for 2 hours, then a small amount of water was added, and it was confirmed that the color of the reaction solution was decolorized. The resulting 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). (4- (propen-1-yl) cyclohexyl) methoxy) benzene (3-1a) (174 g, yield 89%, E / Z = 9: 91) was obtained.
The resulting compound (3-1a) (174 g, 559 mmol), sodium benzenesulfinate (4.60 g, 28.0 mmol) and 10% hydrochloric acid (in a reaction vessel equipped with a stirrer and a thermometer and under a nitrogen atmosphere) 21.1 g (55.9 mmol) was dissolved in toluene (680 mL) and stirred at 85 ° C. for 2 hours. The reaction solution was analyzed by gas chromatography to confirm that compound (3-1) (E / Z = 82: 18) was formed. Saturated sodium hydrogencarbonate aqueous solution (500 mL) was added to this, and after stirring for further 1 hour, the organic layer was separated, and this was washed with water (500 mL). The resulting mixture is 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, compound (3-1) (68.3 g, E / Z = 99.85: 0.15, recovery rate 42%) was obtained.
In this production method, since the stereoselectivity after completion of the reaction is low, it is necessary to repeat recrystallization to increase the purity of the E form, and the recovery rate is greatly reduced.

Claims (7)

Polyamines, as an additive , using one or more compounds represented by general formula (1), one or more compounds represented by general formula (2), a base and an additive , and The manufacturing method of the compound represented by General formula (3) which uses polyetheramines, polyethers, or polyesters .

(In 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, an alkoxyl group having 1 to 8 carbon atoms, 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 be independently substituted with halogen, respectively.
A ¹¹ is (a) a cyclohexane-1,4-diyl group (one —CH ₂ — present in this group or two or more non-adjacent —CH ₂ — is replaced by —O— Also 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) octyrene group, piperidine-1,4-diyl group, naphthalene-2,6-diyl group, decahydronaphthalene-2 And a group selected from the group consisting of 6, 6-diyl group and 1, 2, 3, 4-tetrahydronaphthalene-2, 6-diyl group, and in the above group (a), group (b) or group (c) Each hydrogen atom may be independently substituted with halogen,
Z ¹¹ is 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. However, when n ¹¹ represents 2 to 10, a plurality of A ¹¹ may be the same or different, and a plurality of 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- Also, one or more hydrogen atoms present in the group may be independently substituted with halogen, respectively.
In the general formula (2), R ²¹ represents a hydrogen atom or a substituent represented by the general formula (4), and 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 as R ¹¹ in the general formula (1), and A ⁴¹ and A ⁵¹ each independently represent the general formula represents the same meaning as ^{a 11} in ^(1), and each of ^{Z 41} and ^{Z 51} independently represent the same meaning as ^{Z 11} in the general formula ^{(1), n 41} and ^{n 51} are each independently the general formula This 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). )   Amines, amides, carbamates, imides, sulfonamides, guanidines, hydrazones, hydrazides, hydrazines, heterocyclic amines, their salts, carbonates, metal hydrides, metal alkoxides or alkyl metals are used as bases. 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, iso acetate Ethyl acetate, butyl acetate, propyl acetate, pentyl acetate, methyl acetate, 2-methoxyethyl acetate, hexamethylphosphoric acid 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 method according to any one of claims 1 to 3, wherein a base is added in the coexistence of the compound represented by the general formula (1) and the compound represented by the general formula (2). The method according to any one of claims 1 to 4 , wherein the production temperature is -70 ° C to 0 ° C. The method according to any one of claims. 1 to 5 R ²¹ is a hydrogen atom in the general formula (2). The method according to any one of claims 1 to 6 , wherein the carbon atom number of the substituent represented by General Formula (1-1) in 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).)