JP4993183B2 - Method for producing difluorobenzene derivative and production intermediate - Google Patents

Description

  The present invention relates to a method for producing a difluorobenzene derivative and a production intermediate.

  Liquid crystal display elements are currently widely used because of their excellent features such as low voltage operation and thin display. Conventional liquid crystal display element display methods include TN (twisted nematic), STN (super twisted nematic), or active matrix (TFT: thin film transistor) based on TN, and these have positive dielectric anisotropy values. The liquid crystal composition is used. However, one of the disadvantages of these display methods is a narrow viewing angle, and with the increasing demand for larger liquid crystal panels in recent years, the improvement has become a major issue.

  In recent years, display methods such as vertical alignment and IPS (in-plane switching) have been newly put to practical use as a solution. The vertical alignment method is a method in which the viewing angle is improved by utilizing the vertical alignment of liquid crystal molecules, and a liquid crystal composition having a negative dielectric anisotropy value is used. IPS is a method of improving viewing angle by switching liquid crystal molecules using a horizontal electric field in the horizontal direction with respect to a glass substrate, and a liquid crystal composition having a positive or negative dielectric anisotropy value is used. Is done. As described above, the vertical alignment method and the IPS, which are effective display methods for improving the viewing angle, require a liquid crystal compound and a liquid crystal composition having a negative dielectric anisotropy value. It has become.

  Examples of the liquid crystal compound used in the liquid crystal composition having a negative dielectric anisotropy include 2,3-difluorobenzene derivatives (see Patent Document 1). However, Patent Document 1 discloses only a compound having an alkyl group in the side chain, and does not disclose any compound having an alkenyl group in the side chain, and the production method has not been known. In addition, the development of a method for producing the compound has progressed due to the knowledge that a compound having a cyclohexylmethoxy group at the 1-position and 4-position of the benzene ring is chemically unstable and cannot be used as a liquid crystal material (see Non-Patent Document 1). I did not.

Special Publication No. 2-503568 Numata, “Trends in Liquid Crystal Materials,” Monthly Display, March 1998, Volume 4, Issue 3 (5 pages)

  It is to provide a method for producing a difluorobenzene derivative having an alkenyl group in the side chain. Another object of the present invention is to provide an intermediate compound useful for the production of a difluorobenzene derivative having an alkenyl group in the side chain.

As a result of intensive studies in order to solve the above problems, the present inventors have completed the present invention.
The present invention relates to general formula (1)

（式中、R¹およびR²はそれぞれ独立的にメチル基、エチル基またはプロピル基を表すか、R¹およびR²は-CH₂CH₂-、-CH₂CH₂CH₂-または-CH₂C(CH₃)₂CH₂-を表す。）で表される化合物を酸化して一般式(2)

(Wherein R ¹ and R ² each independently represent a methyl group, an ethyl group or a propyl group, or R ¹ and R ² are —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ — or —CH ₂ C (CH ₃ ) ₂ CH ₂ — represents a compound represented by general formula (2)

（式中、R¹およびR²は一般式(1)と同じ意味を表す。）で表される化合物とした後、一般式(3)

(Wherein R ¹ and R ² represent the same meaning as in general formula (1)), and then the general formula (3)

（式中、X¹は水酸基、塩素、臭素、よう素、ベンゼンスルホニルオキシ基、p-トルエンスルホニルオキシ基、メタンスルホニルオキシ基又はトリフルオロメタンスルホニルオキシ基を表し、R³は炭素原子数1から12のアルキル基、炭素原子数2から12のアルケニル基、炭素原子数1から12のアルコキシ基、炭素原子数3から12のアルケニルオキシ基を表し、nは０又は１を表す。）で表される化合物と反応させてエーテル化することにより一般式(4)

(In the formula, X ¹ represents a hydroxyl group, chlorine, bromine, iodine, benzenesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group or trifluoromethanesulfonyloxy group, and R ³ represents 1 to 12 carbon atoms. And an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, and an alkenyloxy group having 3 to 12 carbon atoms, and n represents 0 or 1. By reacting with a compound and etherifying, the general formula (4)

（式中、R¹およびR²は一般式(1)と同じ意味を表し、R³及びnは一般式(3)と同じ意味を表す。）を表す。）で表される化合物とし、この化合物を脱保護して一般式(5)

(Wherein R ¹ and R ² represent the same meaning as in general formula (1), and R ³ and n represent the same meaning as in general formula (3)). The compound represented by formula (5)

（式中、R³及びnは一般式(3)と同じ意味を表す。）で表される化合物とし、この化合物にアルキルリンイリドを反応させることによる一般式(6)

(Wherein R ³ and n represent the same meaning as in the general formula (3)), and the compound represented by the general formula (6) is obtained by reacting this compound with an alkyl phosphorus ylide.

（式中、R⁵は水素原子または炭素原子数１から５のアルキル基を表し、R³及びnは一般式(3)と同じ意味を表す。）で表される化合物の製造方法を提供する。また、本願発明の製造中間体である一般式(2)、一般式(4)及び一般式(5)で表される化合物もあわせて提供する。

(Wherein R ⁵ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R ³ and n have the same meaning as in general formula (3)). . Also provided are compounds represented by general formula (2), general formula (4) and general formula (5) which are production intermediates of the present invention.

  The production method of the present invention is useful as a production method of a difluorobenzene derivative. In addition, the compound of the present invention is useful as an intermediate for producing a difluorobenzene derivative.

  The oxidation of the compound represented by the general formula (1) can be carried out by deprotonation with an organometallic reagent and then reacting with a trialkyl borate to form a boron compound, followed by the action of an oxidizing agent. Any reaction solvent may be used as long as it allows the reaction to proceed suitably, and examples thereof include ether solvents and hydrocarbon solvents. Examples of ether solvents include 1,4-dioxane, 1,3-dioxane, tetrahydrofuran, diethyl ether, and t-butyl methyl ether. Examples of hydrocarbon solvents include pentane, hexane, cyclohexane, heptane, and octane. Of these, tetrahydrofuran is preferred. Examples of organometallic reagents include n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, lithium diisopropylamide, and lithium 2,2,4,4-tetramerpiperidide. N-Butyllithium, sec-butyllithium and lithium diisopropylamide are preferable from the viewpoint of ease of handling, and sec-butyllithium and lithium diisopropylamide which can be efficiently deprotonated are more preferable. In the deprotonation, a base such as potassium tert-butoxide or tetramethylethylenediamine may be used as an additive together with the organometallic reagent. The reaction temperature at the time of deprotonation is preferably -100 ° C to -20 ° C, more preferably -78 ° C to -40 ° C.

  As the trialkyl borate, trimethyl borate, triethyl borate, tripropyl borate and triisopropyl borate are preferably used, but trimethyl borate and triisopropyl borate are more preferred from the viewpoint of availability and handling. As the combination of trialkyl borate and organometallic reagent, any of the above-mentioned combinations are possible, but the combination of sec-butyl lithium and trimethyl borate, and the combination of lithium diisopropylamide and triisopropyl borate are preferable, and lithium diisopropyl A combination of amide and triisopropyl borate is more preferred. The reaction temperature during boriding is preferably from -100 ° C to -20 ° C, more preferably from -78 ° C to -40 ° C. The obtained boron compound may be isolated once or may be reacted with an oxidizing agent without isolation. Further, the obtained boron compound may be hydrolyzed and converted into a boric acid compound and then reacted with an oxidizing agent.

  As the oxidizing agent, it is preferable to use hydrogen peroxide, peracetic acid or performic acid. The reaction temperature is preferably -78 ° C to 70 ° C, more preferably 0 ° C to 50 ° C. Moreover, water may be contained in the solvent at the time of reaction with an oxidizing agent.

By reacting the compound represented by the general formula (2) with the compound represented by the general formula (3), the compound represented by the general formula (4) is obtained, and the substitution of X ¹ in the general formula (3) is obtained. Several reactions can be used depending on the choice of group.

When a compound in which X ¹ represents chlorine, bromine, iodine, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group, the hydroxyl group of the general formula (2) is replaced with a base. As the phenolate, a method of reacting with the general formula (3) can be used. Examples of the base used in this case include metal hydrides, metal carbonates, metal phosphates, metal hydroxides, metal carboxylates, metal amides and metals, among which alkali metal hydrides and alkali metals. Phosphate, alkali metal phosphate, alkali metal carbonate, alkali metal hydroxide, alkali metal amide and alkali metal are preferred, and alkali metal phosphate, alkali metal hydride and alkali metal carbonate are more preferred. Lithium hydride, sodium hydride and potassium hydride as alkali metal hydrides, tripotassium phosphate as alkali metal phosphates, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate as alkali metal carbonates And potassium hydrogen carbonate can be preferably mentioned.

  Any reaction solvent may be used as long as it allows the reaction to proceed suitably. Ether solvents, chlorine solvents, hydrocarbon solvents, aromatic solvents, polar solvents, and the like can be preferably used. 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, 1,2-dichloroethane, and carbon tetrachloride. Examples of hydrocarbon solvents include pentane, hexane, cyclohexane, heptane, and octane, aromatic solvents include benzene, toluene, xylene, mesitylene, chlorobenzene, and dichlorobenzene, and polar solvents include N, N-dimethylformamide, Preferable examples include N-methylpyrrolidone, dimethyl sulfoxide, and sulfolane. Among these, ether solvents such as tetrahydrofuran and diethyl ether and polar solvents such as N, N-dimethylformamide are more preferable. Each of the above solvents may be used alone, or two or more solvents may be mixed and used.

  The reaction temperature can be in the range from the freezing point of the solvent to the reflux temperature, but is preferably from 0 ° C to 150 ° C, more preferably from 30 ° C to 120 ° C. The generated phenolate may be isolated once and then reacted with the compound represented by the general formula (3), or may be reacted without isolation, but it is allowed to react without isolation for ease of work. Better.

When a compound in which X ¹ represents a hydroxyl group is used, Mitsunobu reaction can be used. The Mitsunobu reaction is a reaction in which an alcohol and a wide variety of nucleophiles having active protons are dehydrated and used in combination with triphenylphosphine and an azodicarboxylic acid derivative or maleic acid derivative. Specifically, by reacting the compound represented by the general formula (2) and the alcohol derivative represented by the general formula (3) in the presence of a trisubstituted phosphine derivative and an azodicarboxylic acid derivative, The compound represented is obtained.

  Examples of the trisubstituted phosphine derivative include trialkylphosphine and triphenylphosphine, and triphenylphosphine is preferable. Various compounds are used as azodicarboxylic acid derivatives, and it is possible to use maleic acid derivatives instead of azodicarboxylic acid derivatives, but the combination of triphenylphosphine and azodicarboxylic acid derivatives is easier to handle. Is desirable. Examples of azodicarboxylic acid derivatives include diethyl azodicarboxylate, diisopropyl azodicarboxylate, tetramethyl azodicarboxyamide, tetrapropyl azodicarboxyamide, 1,1 '-(azodicarbonyl) dipiperidine. Diethyl azodicarboxylate and diisopropyl azodicarboxylate are preferable from the viewpoint of ease, and diisopropyl azodicarboxylate is more preferable from the viewpoint of ease of handling.

  Any reaction solvent may be used as long as it allows the reaction to proceed suitably, but ether solvents, chlorine solvents, hydrocarbon solvents, aromatic solvents, and the like can be preferably used. 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, 1,2-dichloroethane and carbon tetrachloride. Preferable examples of the hydrocarbon solvent include pentane, hexane, cyclohexane, heptane and octane, and examples of the aromatic solvent include benzene, toluene, xylene, mesitylene, chlorobenzene and dichlorobenzene. Of these, ether solvents such as tetrahydrofuran and aromatic solvents such as toluene are more preferable. Each of the above solvents may be used alone, or two or more solvents may be mixed and used.

  The reaction temperature can be in the range from the freezing point of the solvent to the reflux temperature, but is preferably 0 ° C to 150 ° C, more preferably 0 ° C to 30 ° C.

  The deprotection of the compound represented by the general formula (4) is preferably performed under acidic conditions. Examples of the acid used include protonic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid, and p-toluenesulfonic acid, and Lewis acids such as boron trifluoride. Formic acid is preferably used.

  Any reaction solvent may be used as long as it allows the reaction to proceed suitably, but ether solvents, chlorine solvents, ketone solvents, hydrocarbon solvents, aromatic solvents, polar solvents, and the like are preferably used. And may be reacted without solvent. 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, 1,2-dichloroethane, chloroform, and carbon tetrachloride. Acetone, 2-butanone and the like as ketone solvents, pentane, hexane, cyclohexane, heptane and octane as hydrocarbon solvents, and benzene, toluene, xylene, mesitylene, chlorobenzene and dibenzene as aromatic solvents. Preferable examples include chlorobenzene and acetonitrile, dimethyl sulfoxide and the like as polar solvents. Of these, hydrocarbon solvents such as pentane, hexane, cyclohexane, heptane and octane, and aromatic solvents such as benzene, toluene and xylene are more preferable. Each of the above solvents may be used alone, or two or more solvents may be mixed and used.

  The reaction temperature can be in the range from the freezing point of the solvent to the reflux temperature, but is preferably 0 ° C to 100 ° C, more preferably 30 ° C to 60 ° C.

  The compound represented by the formula (5) thus obtained may be obtained as a mixture of a cis isomer and a trans isomer relating to a cyclohexane ring, but is preferably a trans isomer for use as an intermediate of a liquid crystal compound. . Regarding the cyclohexane ring of the compound represented by the formula (5), cis-trans isomerization can be carried out by allowing a base to act as necessary, and an excess of the trans isomer can be obtained. The base used at this time is preferably sodium hydroxide, potassium hydroxide or the like, the reaction solvent is preferably methanol, ethanol or tetrahydrofuran, the reaction temperature is preferably -40 ° C to 20 ° C, more preferably -20 ° C to 10 ° C. preferable.

  The compound represented by the general formula (6) can be obtained by reacting the compound represented by the formula (5) with an alkyl phosphorus ylide. The phosphorus ylide can be adjusted from a phosphonium salt, a phosphonic acid ester or the like, but is preferably adjusted from an alkyltriphenylphosphonium salt.

  When adjusting an ylide using an alkyltriphenylphosphonium salt, a base is allowed to act. As the base to be used, potassium-t-butoxide, n-butyllithium, phenyllithium, sodium hydride and the like are preferable, and potassium-t -Butoxide is more preferred. As the reaction solvent, ether solvents, aromatic solvents, polar solvents and the like can be preferably used. Examples of ether solvents include 1,4-dioxane, 1,3-dioxane, tetrahydrofuran, diethyl ether, and t-butyl methyl ether. Examples of aromatic solvents include benzene, toluene, xylene, mesitylene, and the like as polar solvents. A good example is N, N-dimethylformamide. Tetrahydrofuran and toluene are more preferred. Each of the above solvents may be used alone, or two or more solvents may be mixed and used. The reaction temperature can be in the range from the freezing point of the solvent to the reflux temperature, but is preferably -40 ° C to 30 ° C, more preferably -20 ° C to 20 ° C. The obtained ylide is preferably reacted with the compound represented by the formula (5) without isolation. Further, a base may be added to the mixture of the alkyltriphenylphosphonium salt and the compound represented by the formula (5). As the alkyltriphenylphosphonium salt, methyltriphenylphosphonium salt is preferable.

  The present invention uses the compound represented by the general formula (1) as a starting material, the general formula (6) via the compound represented by the general formula (2), the general formula (4) and the general formula (5). A compound represented by general formula (2) is used as a starting material, and a compound represented by general formula (4) and general formula (5) is passed through the compound represented by general formula (4). It is also preferable to produce the compound represented by (6), using the compound represented by the general formula (4) as a starting material and the compound represented by the general formula (5) via the compound represented by the general formula (5). It is also preferable to produce the compound represented by the formula (6), and it is also preferred to produce the compound represented by the formula (6) using the compound represented by the formula (5) as a starting material.

  In addition, as a method for producing the compound represented by the general formula (2), which is an intermediate product of the present invention, the compound represented by the general formula (2) obtained by oxidizing the compound represented by the general formula (1) It is also preferable as a manufacturing method.

In the general formula (1) and the general formula (2), R ¹ and R ² each independently represent a methyl group, an ethyl group, or a propyl group, or R ¹ and R ² are —CH ₂ CH ₂ —, — CH ₂ CH ₂ CH ₂ — or —CH ₂ C (CH ₃ ) ₂ CH ₂ —, wherein R ¹ and R ² are both methyl groups, or R ¹ and R ² are —CH ₂ CH ₂ — or -CH ₂ CH ₂ CH _2- is preferred. Specifically, the general formula (1) is preferably a compound represented by the following general formula (1-1) to general formula (1-3).

Specifically, the general formula (2) is preferably a compound represented by the following general formula (2-1) to general formula (2-6).

In the general formula (3), X ¹ represents a hydroxyl group, chlorine, bromine, iodine, benzenesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group or trifluoromethanesulfonyloxy group. In the case of reaction with phenolate, it is preferable to represent bromine or methanesulfonyloxy group, and in the case of reaction with general formula (2) using Mitsunobu reaction, X ¹ preferably represents a hydroxyl group.

R ³ represents an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an alkenyloxy group having 3 to 12 carbon atoms, An alkyl group having 1 to 12 or an alkenyl group having 2 to 12 carbon atoms is preferred, and production of a compound representing an alkyl group having 1 to 7 carbon atoms is particularly preferred.

In the general formula (4), R ¹ and R ² each independently represent a methyl group, an ethyl group, or a propyl group, or R ¹ and R ² are —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ -Or -CH ₂ C (CH ₃ ) ₂ CH _2- , wherein R ¹ and R ² are both methyl groups, or R ¹ and R ² are -CH ₂ CH ₂ -or -CH ₂ CH ₂ CH _2- is preferred.

R ³ represents an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an alkenyloxy group having 3 to 12 carbon atoms, A 1 to 12 alkyl group or an alkenyl group having 2 to 12 carbon atoms is preferred, and a compound representing an alkyl group having 1 to 7 carbon atoms is particularly preferred.

  Specifically, the general formula (4) is preferably a compound represented by the following general formula (4-1) to general formula (4-6).

(Wherein R ³ represents an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, or an alkenyloxy group having 3 to 12 carbon atoms. )
In the general formula (4), R ³ represents an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, or an alkenyloxy group having 2 to 12 carbon atoms. More preferably, n represents 1, or R ³ represents an alkenyl group having 2 to 12 carbon atoms or an alkenyloxy group having 2 to 12 carbon atoms, and n represents 0.

In the general formula (5), R ³ is an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, or an alkenyloxy group having 3 to 12 carbon atoms. However, an alkyl group having 1 to 12 carbon atoms or an alkenyl group having 2 to 12 carbon atoms is preferable, and a compound representing an alkyl group having 1 to 7 carbon atoms is particularly preferable.

  Specifically, the general formula (5) is preferably a compound represented by the following general formula (5-1) to general formula (5-2).

(Wherein R ³ represents an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, or an alkenyloxy group having 3 to 12 carbon atoms. )
In the general formula (6), R ³ is an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, and an alkenyloxy group having 3 to 12 carbon atoms. However, an alkyl group having 1 to 12 carbon atoms or an alkenyl group having 2 to 12 carbon atoms is preferable, and a compound representing an alkyl group having 1 to 7 carbon atoms is particularly preferable. R ⁴ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom.

  Specifically, the general formula (5) is preferably a compound represented by the following general formula (6-1) to general formula (6-4).

(In the formula, R ⁴ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.)
In the compounds represented by the general formulas (6-1) to (6-12), R ³ is preferably an alkyl group having 1 to 12 carbon atoms or an alkenyl group having 2 to 12 carbon atoms, A compound representing an alkyl group of 1 to 7 is particularly preferred, and R ⁴ is preferably a hydrogen atom or a methyl group, more preferably a hydrogen atom.

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 structure of the compound was confirmed by nuclear magnetic resonance spectrum (NMR), mass spectrum (MS) and the like.
The following abbreviations are used in compound descriptions.
THF: tetrahydrofuran
LDA: Lithium diisopropylamide
i-Pr: Isopropyl
DIAD: Diisopropyl azodicarboxylate
Ph: Phenyl (Example 1) Synthesis of 4- (trans, trans-4 '-(1,3-dioxolan-2-yl) bicyclohexyl-4-ylmethoxy) -2,3-difluorophenol (Ib)

LDA (0.37 M, 135 mL, THF: hexane = 75: 25) was prepared and 1- (trans, trans-4 ′-(1,3-dioxolan-2-yl) bicyclohexyl-4-ylmethoxy) -2 , 3-Difluorobenzene (Ia, 14.0 g) in THF (42 mL) was added dropwise at an internal temperature of −40 to −55 ° C., and the mixture was stirred for 2 hours while maintaining the internal temperature. Triisopropyl borate (10.5 g) was added dropwise at an internal temperature of −50 to −55 ° C., and the temperature was raised to 0 ° C. The reaction was stopped by adding an aqueous ammonium chloride solution, the organic layer was separated, and the aqueous layer was extracted with toluene. To the combined organic layers, 15% hydrogen peroxide (12.7 g) was slowly added and stirred at 40 ° C. for 2 hours. Water was added, stirred for a while, and extracted with toluene. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 4- (trans, trans-4 '-(1,3-dioxolan-2-yl) bicyclohexyl. 4-ylmethoxy) -2,3-difluorophenol (Ib, 13.1 g) was obtained. Compound (Ib) is useful as an intermediate for producing a liquid crystal compound.
MS m / z: 397 (M ⁺ +1)
¹ H-NMR (60 MHz, CDCl ₃ )
δ: 0.90 1.15 (m, 10 H), 1.44 1.54 (m, 1 H), 1.65 1.96 (m, 9 H), 3.75 (d, J = 6.4 Hz, 2 H), 3.83 3.89 (m, 2 H) , 3.90 3.96 (m, 2 H), 4.60 (d, J = 4.8 Hz, 1 H), 6.59 6.68 (m, 2 H).
Example 2 6- (3-Butenyloxy) -3- (trans, trans-4 ′-(1,3-dioxolan-2-yl) bicyclohexyl-4-ylmethoxy) -1,2-difluorobenzene (Ic )

4- (trans, trans-4 ′-(1,3-dioxolan-2-yl) bicyclohexyl-4-ylmethoxy) -2,3-difluorophenol (Ib, 12.9 g), 3-butenol (2.81 g), Triphenylphosphine (10.6 g) and THF (58 mL) were mixed, and diisopropyl azodicarboxylate (7.88 g) was added dropwise at 5 ° C. After stirring at room temperature for 1 hour, it was concentrated to remove THF. Add a 67% aqueous methanol solution to disperse the solid, filter the crystals, and dry, 6- (3-butenyloxy) -3- (trans, trans-4 '-(1,3-dioxolan-2-yl) Bicyclohexyl-4-ylmethoxy) -1,2-difluorobenzene (Ic, 14.3 g) was obtained. Compound (Ic) is useful as an intermediate for producing a liquid crystal compound.
MS m / z: 450 (M ⁺ )
¹ H-NMR (60 MHz, CDCl ₃ )
δ: 0.94 1.16 (m, 10 H), 1.43 1.53 (m, 1H), 1.70 1.95 (m, 9 H), 2.54 (dt, J = 1.2 Hz, 6.8 Hz, 1 H), 3.75 (d, J = 6.4Hz, 2 H), 3.82 3.88 (m, 1 H), 3.89 3.95 (m, 1 H), 4.02 (t, J = 6.8 Hz, 2 H), 4.59 (d, J = 5.2 Hz, 1 H) , 5.11 (dd, J = 3.0 Hz, 10.0 Hz, 1 H), 5.17 (dd, J = 2.4 Hz, 17.2 Hz, 1 H), 5.89 (ddd, J = 6.4 Hz, 10.8 Hz, 16.8 Hz, 1 H ), 6.57 6.65 (m, 2 H).
Example 3 Synthesis of 6- (3-butenyloxy) -3- (trans, trans-4′-formylbicyclohexyl-4-ylmethoxy) -1,2-difluorobenzene (Id)

6- (3-Butenyloxy) -3- (trans, trans-4 '-(1,3-dioxolan-2-yl) bicyclohexyl-4-ylmethoxy) -1,2-difluorobenzene (Ic, 14.3 g) It melt | dissolved in toluene (70 mL), formic acid (28 mL) was added, and it stirred at 50 degreeC for 5 hours. After cooling to room temperature, water and saturated brine were added, and the organic layer was separated, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the solvent was evaporated under reduced pressure to give 6- (3-butenyloxy) -3- (trans, trans-4′-formylbicyclohexyl-4-ylmethoxy) -1,2-difluorobenzene (Id, 12.8 g) was obtained. The compound (Id) is useful as an intermediate for producing a liquid crystal compound.
MS m / z: 406 (M ⁺ )
δ: 0.95 1.16 (m, 8 H), 1.25 (q, J = 12.4Hz, 2 H), 1.70 2.05 (m, 9 H), 2.10 2.20 (m, 1H), 2.54 (tq, J = 1.4 Hz, 6.8 Hz, 2 H), 3.76 (d, J = 6.4 Hz, 2 H), 4.03 (t, J = 6.8 Hz, 2 H), 5.11 (dd, J = 1.6 Hz, 10.4 Hz, 1 H), 5.18 (dd, J = 1.6 Hz, 18.8 Hz, 1 H), 5.89 (ddd, J = 6.8 Hz, 10.0 Hz, 20.0 Hz, 1 H), 6.57 6.65 (m, 2 H).
Example 4 Synthesis of 6- (3-butenyloxy) -3- (trans, trans-4′-vinylbicyclohexyl-4-yl) methoxy-1,2-difluorobenzene (Ie)

メチルトリフェニルホスホニウムブロミド（14.4 g）をTHF（43 mL）に分散し、5℃でカリウム-t-ブトキシド（4.50 g ）を加え、30分攪拌した。その後、6-(3-ブテニルオキシ)-3-(トランス,トランス-4’-ホルミルビシクロヘキシル-4-イルメトキシ)-1,2-ジフルオロベンゼン (Id、12.6 g)のTHF（25 mL）溶液を滴下し、30分攪拌した。水10 mLを加えた後溶媒を減圧留去し、残渣に50%メタノール水溶液およびヘキサンを加えて有機層を分取した。有機層を50%メタノール水溶液および飽和食塩水で洗浄し、溶媒を減圧留去した。残渣を再結晶およびカラムクロマトグラフィーにより精製し、無色結晶として2,3-ジフルオロ-1-(3-ブテニルオキシ)-4-(トランス，トランス-4’-ビニルビシクロヘキシル‐4‐イル)メトキシベンゼン（Ie、10.5 g）を得た。

Methyltriphenylphosphonium bromide (14.4 g) was dispersed in THF (43 mL), potassium-t-butoxide (4.50 g) was added at 5 ° C., and the mixture was stirred for 30 minutes. Then, a solution of 6- (3-butenyloxy) -3- (trans, trans-4′-formylbicyclohexyl-4-ylmethoxy) -1,2-difluorobenzene (Id, 12.6 g) in THF (25 mL) was added dropwise. And stirred for 30 minutes. After adding 10 mL of water, the solvent was distilled off under reduced pressure, 50% aqueous methanol and hexane were added to the residue, and the organic layer was separated. The organic layer was washed with 50% aqueous methanol solution and saturated brine, and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization and column chromatography, and 2,3-difluoro-1- (3-butenyloxy) -4- (trans, trans-4'-vinylbicyclohexyl-4-yl) methoxybenzene ( Ie, 10.5 g) was obtained.

Phase transition temperature C 64.5 N 119.5 I
MS m / z: 404 (M ⁺ ), 55 (100)
¹ H-NMR (400 MHz, CDCl ₃ )
δ: 0.95-1.15 (m, 10H), 1.65-2.00 (m, 10H), 2.50 2.60 (m, 2H), 3.76 (d, J = 6.4 Hz, 2 H), 4.03 (t, J = 6.8 Hz, 2 H), 4.80 5.30 (m, 4 H), 5.79 (ddd, J = 6.4 Hz, 10.4 Hz, 17.2 Hz, 1 H), 5.83 5.95 (m, 1 H), 6.55 6.70 (m, 2 H).

  The production method of the present invention is useful as a production method of a liquid crystal compound. Moreover, the compound of this invention is useful as a manufacturing intermediate of a liquid crystal compound.

Claims (18)

General formula (1)

(In the formula, R ¹ and R ² each independently represent a methyl group, an ethyl group, or a propyl group, or R ¹ and R ² are connected to each other to form —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH _2- or -CH ₂ C (CH ₃ ) ₂ CH _2- represents a compound represented by general formula (2)

(Wherein R ¹ and R ² represent the same meaning as in general formula (1)), and then the general formula (3)

(In the formula, X ¹ represents a hydroxyl group, chlorine, bromine, iodine, benzenesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group or trifluoromethanesulfonyloxy group, and R ³ has 1 to 12 carbon atoms. And an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, or an alkenyloxy group having 3 to 12 carbon atoms, and n represents 0 or 1. By reacting with a compound and etherifying, the general formula (4)

(Wherein R ¹ and R ² represent the same meaning as in general formula (1), and R ³ and n represent the same meaning as in general formula (3)). The compound represented by formula (5)

(Wherein R ³ and n represent the same meaning as in the general formula (3))

( Wherein R ⁴ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R ³ and n have the same meaning as in formula (3)). General formula (2)

(In the formula, R ¹ and R ² each independently represent a methyl group, an ethyl group, or a propyl group, or R ¹ and R ² are connected to each other to form —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH _2- or -CH ₂ C (CH ₃ ) ₂ CH _2- represents a compound represented by the general formula (3)

(In the formula, X ¹ represents a hydroxyl group, chlorine, bromine, iodine, benzenesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group or trifluoromethanesulfonyloxy group, and R ³ represents 1 to 12 carbon atoms. And an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, or an alkenyloxy group having 3 to 12 carbon atoms, and n represents 0 or 1. By reacting with a compound and etherifying, the general formula (4)

(Wherein R ¹ and R ² represent the same meaning as in general formula (2), and R ³ and n represent the same meaning as in general formula (3)). The compound represented by formula (5)

(Wherein R ³ and n represent the same meaning as in the general formula (3)), and the compound represented by the general formula (6) is obtained by reacting this compound with an alkyl phosphorus ylide.

( Wherein R ⁴ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R ³ and n have the same meaning as in formula (3)). General formula (4)

(In the formula, R ¹ and R ² each independently represent a methyl group, an ethyl group, or a propyl group, or R ¹ and R ² are connected to each other to form —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ -or -CH ₂ C (CH ₃ ) ₂ CH _2- , and R ³ and n represent the same meaning as in the general formula (3). ) To remove the compound represented by the general formula (5)

(Wherein R ³ and n represent the same meaning as in the general formula (3)), and the compound represented by the general formula (6) is obtained by reacting this compound with an alkyl phosphorus ylide.

( Wherein R ⁴ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, R ³ represents an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, or 1 to carbon atoms) 12 represents an alkoxy group or an alkenyloxy group having 3 to 12 carbon atoms, and n represents 0 or 1.) 4. The process according to claim 1, 2, or 3, wherein the alkyl phosphorus ylide is an ylide prepared from an alkyl triphenylphosphonium salt. General formula (1)

(In the formula, R ¹ and R ² each independently represent a methyl group, an ethyl group, or a propyl group, or R ¹ and R ² are connected to each other to form —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH _2- or -CH ₂ C (CH ₃ ) ₂ CH _2- represents a compound represented by the general formula (2)

(Wherein R ¹ and R ² represent the same meaning as in general formula (1)). In the method of oxidizing the compound represented by the general formula (1), the 4-position of the compound represented by the general formula (1) is deprotonated with an organometallic reagent and reacted with a trialkyl borate. The manufacturing method of Claim 1 or 5 by making it react. The process according to claim 6, wherein n-butyllithium, sec-butyllithium, lithium diisopropylamide and lithium 2,2,4,4-tetramerpiperidide are used as the organometallic reagent. The production method according to claim 6, wherein hydrogen peroxide, performic acid or peracetic acid is used as the oxidizing agent. The production method according to claim 1 or 2, wherein X ¹ represents a hydroxyl group, bromine or methanesulfonyloxy group. The etherification of the compounds represented by the general formula (2) and the general formula (3) is a method of reacting in the presence of a base or a method of reacting in the presence of a trisubstituted phosphine derivative and an azodicarboxylic acid derivative. The manufacturing method as described. R ¹ and R ² both represent a methyl group, or R ¹ and R ² are linked to each other to represent -CH ₂ CH ₂ -or -CH ₂ CH ₂ CH _2- 5. The production method according to 5. General formula (2)

(In the formula, R ¹ and R ² each independently represent a methyl group, an ethyl group, or a propyl group, or R ¹ and R ² are connected to each other to form —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH _2- or -CH ₂ C (CH ₃ ) ₂ CH _2- . General formula (4)

(In the formula, R ¹ and R ² each independently represent a methyl group, an ethyl group, or a propyl group, or R ¹ and R ² are connected to each other to form —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH _{2 represents} -or -CH ₂ C (CH ₃ ) ₂ CH _2- , and R ³ represents an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, or an alkoxy group having 1 to 12 carbon atoms Represents an alkenyloxy group having 2 to 12 carbon atoms, and n represents 0 or 1.). In the general formula (4), R ³ represents an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, or an alkenyloxy group having 2 to 12 carbon atoms. 14. A compound according to claim 13, wherein n represents 1. The compound according to claim 13, wherein R ³ in the general formula (4) represents an alkenyl group having 2 to 12 carbon atoms or an alkenyloxy group having 2 to 12 carbon atoms, and n represents 0. General formula (5)

(Wherein R ³ represents an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an alkenyloxy group having 2 to 12 carbon atoms, n represents 0 or 1.). In general formula (5), R ³ represents an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, or an alkenyloxy group having 2 to 12 carbon atoms. 17. A compound according to claim 16, wherein n represents 1. The compound according to claim 16, wherein R ³ in formula (5) represents an alkenyl group having 2 to 12 carbon atoms or an alkenyloxy group having 2 to 12 carbon atoms, and n represents 0.