JP2009007312A - Cyclohexyl methyl phosphonate derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for efficiently producing an (E)-1,2-bis(trans-4-alkylcyclohexyl)ethylene derivative and to provide an intermediate useful for the production method. <P>SOLUTION: A cyclohexyl methyl phosphonate derivative represented by general formula (III) is reacted with an aldehyde represented by formula (IV) (wherein R<SP>1</SP>is an alkyl group or the like; A is a phenylene group which may be fluorinated; Y is a fluorine atom or the like; and n, o and p are each an integer) under a strongly basic condition to produce an (E)-1,2-bis(cyclohexyl)ethylene derivative. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a cyclohexylmethylphosphonate derivative useful as an intermediate for producing an electro-optical liquid crystal display material and a method for producing the same.

  Liquid crystal display elements are used in various electric appliances for home use, measuring instruments, automobile panels, electronic notebooks, printers, computers, televisions, etc., including watches and calculators. As a liquid crystal material used for this, a liquid crystal material having positive or negative dielectric anisotropy is indispensable for an electric field response. However, in order to improve the response speed, etc., it works to lower the viscosity of the composition. It is common to use a liquid crystal material (thickening agent) having Although a thinning agent is required to have excellent liquid crystallinity at the same time, (E) -1,2-bis (cyclohexyl) ethylene derivatives are extremely useful for this purpose (see Non-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 the (E) -form. However, the yield is 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. (E) -1,2-bis (trans-4-alkylcyclohexyl) ethylene derivative was obtained by reducing this, but using highly toxic hydrazine and hexamethylphosphoric triamide (HMPT) In addition, ignitable metallic lithium is used and is not practical. On the other hand, as a practical production method, a production method by isomerizing a (Z) -1,2-bis (trans-4-alkylcyclohexyl) ethylene derivative is known, but there is a problem that the number of steps is large. (See Patent Document 3).

JP-A-6-92924 (page 19) Japanese Patent No. 3418398 (5 pages) Japanese Patent Publication No. 2006-89432 Liquid Crystal Volume 1 Issue 1 Page 19 (1997) Chemiker-Zeitung, 104, p. 269 (1980)

  The problem to be solved by the present invention is to provide a production intermediate useful for producing an (E) -1,2-bis (trans-4-alkylcyclohexyl) ethylene derivative, and to efficiently produce the compound. Is to provide a simple manufacturing method.

As a result of intensive studies to solve the above-mentioned problems, a Horner-Wadsworth-Emmons type reaction with a cyclohexylmethylphosphonate derivative and an aldehyde is carried out, and by removing the phosphate diester from the resulting addition product by heating, ( E) -1,2-bis (trans-4-alkylcyclohexyl) ethylene derivative is obtained with high selectivity and can be synthesized in a short process without complicated isomerization, and the present invention is completed. It came to.
The present invention provides the following production methods and production intermediates. That is, the general formula (I)

（式中、Ｒ¹は炭素原子数１〜１０の直鎖状アルキル基を表し、ｎは１又は２を表し、Ｘは塩素、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ロオロメタンスルホニルオキシ基を表す。）で表される化合物に、一般式（II）

(In the formula, R ¹ represents a linear alkyl group having 1 to 10 carbon atoms, n represents 1 or 2, X represents chlorine, bromine, iodine, benzenesulfonyloxy group, p-toluenesulfonyloxy group. Represents a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group), and the compound represented by the general formula (II)

（式中、Ｒ²は炭素原子数１〜１０のアルキル基を表す。）で表される化合物を塩基条件下反応させ、一般式（III）

(In the formula, R ² represents an alkyl group having 1 to 10 carbon atoms.) The compound represented by the general formula (III) is reacted under basic conditions.

(Wherein R ¹ represents a linear alkyl group having 1 to 10 carbon atoms, R ² represents an alkyl group having 1 to 10 carbon atoms, and n represents 1 or 2). Provided is a method for producing a compound and the compound, and the compound represented by the general formula (III) is represented by the general formula (IV)

(In the formula, o and p each independently represent 0, 1 or 2, but 1 ≦ o + p ≦ 3, A represents a 1,4-phenylene group optionally substituted by a fluorine atom, Y Is a fluorine atom, trifluoromethoxy group, difluoromethoxy group, trifluoromethyl group, alkyl group having 1 to 10 carbon atoms, alkoxy group having 1 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms, or carbon atom (Representing an alkenyloxy group of formula 3 to 10)) by reacting a compound represented by the formula (V) under strong base conditions

(In the formula, n represents 0, 1 or 2, and o and p each independently represent 0, 1 or 2, but 1 ≦ o + p ≦ 3, and A may be substituted by a fluorine atom. Y represents a fluorine atom, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a carbon atom A alkenyl group having 2 to 10 carbon atoms or an alkenyloxy group having 3 to 10 carbon atoms).

  A cyclohexylmethylphosphonate derivative useful for producing a liquid crystalline compound having an (E) -1,2-bis (trans-4-alkylcyclohexyl) ethylene structure can be efficiently produced by the production method of the present invention. . By using the cyclohexylmethylphosphonate derivative of the present invention, an E-type double bond can be formed with high selectivity, and (E) -1,2-bis (trans A liquid crystalline compound having a -4-alkylcyclohexyl) ethylene structure can be produced simply and efficiently.

The present invention is described in detail below.
In the general formula (I), R ¹ represents a linear alkyl group having 1 to 10 carbon atoms, specifically, —CH ₂ CH ₃ , — (CH ₂ ) ₂ CH ₃ , — (CH ₂ ) ₃ CH _3, - (CH ₂₎ preferably represents a ₄ CH _3. n represents 0, 1 or 2, and X represents chlorine, bromine, iodine, benzenesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group or trifluoromethanesulfonyloxy group, with bromine being preferred.

In the general formula (II), R ² preferably represents an alkyl group having 1 to 10 carbon atoms. Specifically, —CH ₃ , —CH ₂ CH ₃ , — (CH ₂ ) ₂ CH ₃ , —CH ₂ (CH ₃ ) ₂ and — (CH ₂ ) ₃ CH ₃ are preferably represented.

  In the general formula (III), the general formula (I) and the general formula (II) are reacted in the presence of a base, and a metal alkoxide is preferably used as a base. Specifically, sodium methoxide, sodium ethoxide, sodium Tert-butoxide and potassium tert-butoxide are preferred, and sodium tert-butoxide and potassium tert-butoxide are more preferred.

Any solvent may be used as long as it allows the reaction to proceed appropriately. Ether solvents such as tetrahydrofuran (THF), diethyl ether, diisopropyl ether, and methyl t-butyl ether, and N, N-dimethylformamide (DMF) ), N, N-dimethylacetamide (DMA), N-methylpyrrolidone and other amide solvents can be used alone or in combination, but dimethylformamide (DMF) is preferably used.
The reaction temperature can be in the range from the freezing point of the solvent to the reflux temperature, but is preferably from 50 ° C to 70 ° C.

In general formula (IV), o and p each independently represent 0, 1 or 2, but preferably o + p ≦ 3, and A represents a 1,4-phenylene group which may be substituted with a fluorine atom. Is preferred. Y is a fluorine atom, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or carbon. preferably representing the alkenyloxy group having the number of atoms of 3 to 10, specifically _{-F, -OCF 3, -OCF 2 H} , -CF 3, - (CH 2) 2 CH 3, - (CH 2) 3 _{CH 3, - (CH 2)} 4 CH 3, -CH = CH 2, -CH = CHCH 3 (E _{bodies), - OCH 3, -OCH 2} CH 3, -O (CH 2) 2 CH 3, -O It is preferable to represent (CH ₂ ) ₃ CH ₃ , —O (CH ₂ ) ₂ CH═CH ₂ .

  The reaction of general formula (III) and general formula (IV) is carried out under strong base conditions, but it is preferable to use an alkyl metal or metal amide as the base, specifically n-butyllithium, sec-butyllithium. Tert-butyllithium, lithium diisopropylamide (LDA) and the like are preferable, and n-butyllithium and lithium diisopropylamide (LDA) are more preferable.

As solvents, use ether solvents such as tetrahydrofuran (THF), diethyl ether, diisopropyl ether, methyl t-butyl ether, and aromatic solvents such as benzene, toluene, xylene, mesitylene, chlorobenzene, etc., alone or in combination. However, it is preferable to use toluene.
The reaction temperature can be in the range from the freezing point of the solvent to the reflux temperature, but is preferably -70 ° C to -40 ° C.

  Although this invention can manufacture efficiently the compound represented by general formula (V), manufacture of the compound shown next is more suitable.

(In the formula, R represents a linear alkyl group having 1 to 10 carbon atoms.) Particularly preferred compounds include the following compounds.

（式中Ｒは炭素原子数１〜１０の直鎖状アルキル基を表す。）

(In the formula, R represents a linear alkyl group having 1 to 10 carbon atoms.)

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).
The following abbreviations are used in compound descriptions.

DMF: Dimethylformamide
Pr: Propyl group
Bu: butyl group (Example 1) Synthesis of dimethyl (trans-4-propylcyclohexylmethyl) phosphonate

To a DMF solution (500 mL) of 71 g (0.632 mol) of t-BuOK, 73 g (0.663 mol) of dimethyl phosphite is added dropwise (about 20 minutes) at such a rate that the temperature is maintained at 10 ° C. or lower. Subsequently, 100 g (0.456 mol) of trans-4-propylcyclohexylmethyl bromide was added dropwise (approximately 20 minutes) at such a rate that the temperature was maintained at 10 ° C. or lower. Allow to cool. Add 500 mL of water and 500 mL of toluene to separate the organic layer. Extract the water layer twice with 300 mL of toluene. All the organic layers are combined, washed 3 times with 250 mL of water and evaporated. About 110 g of the obtained crude product is distilled to obtain 92.5 g (147-152 ^° C., 7 mmHg) of dimethyl (trans-4-propylcyclohexylmethyl) phosphonate as a colorless transparent liquid.
¹ H-NMR (400 MHz, CDCl ₃ ): 0.851.30 (m, 11H), 1.501.91 (m, 8H), 3.74 (s, 3H), 3.74 (s, 3H).
Example 2 Synthesis of (E) -trans-4- [2- (trans-4-propylcyclohexyl) ethenyl] -trans-4 ′-(3,4-difluorophenyl) bicyclohexane

A toluene solution (65 mL) of 10.6 g (42.69 mmol) of dimethyl (trans-4-propylcyclohexylmethyl) phosphonate is cooled to −55 ° C., and 26.5 mL of a 1.60 M BuLi hexane solution at a rate that maintains -50 ° C. or lower ( 42.40 mmol) is added dropwise (about 15 minutes) and stirred at -55 ° C for 1 hour. Subsequently, a toluene solution (65 mL) of cyclohexanecarbaldehyde derivative (10 g, 32.63 mmol) is added dropwise (about 30 minutes) at such a rate that the temperature is maintained at −50 ° C. or lower, and the mixture is stirred at −55 ° C. for 1 hour. Add 30 mL of acetic acid at once, stop cooling, and gradually raise the reaction temperature to room temperature. Here, after partially removing the reaction solution as a TLC sample, heating is started and the temperature is raised to the reflux temperature. After 3 hours, TLC measurement (hexane / ethyl acetate = 1/1) is performed, and if the phosphonate adduct remains, heating under reflux is continued. After confirming the completion of the reaction, it is allowed to cool to room temperature. Add 100 mL of 1% hydrochloric acid and separate the organic layer. The obtained organic layer is washed twice with 100 mL of 1% hydrochloric acid, 100 mL of saturated aqueous sodium carbonate solution and 3 times with 50 mL of saturated brine, and dried over sodium sulfate. The solvent was distilled off, and about 16.57 g of the obtained crude product was purified by silica gel column chromatography to obtain 10.51 g (E / Z = 92/8) of white crystals (yield 75%). Further, recrystallization (MEK 40 mL) is performed to obtain 9.74 g of white crystals (E / Z = 99.7 / 0.3) (yield 70%).
¹ H-NMR (400 MHz, CDCl ₃ ): 0.851.37 (m, 28H), 1.681.90 (m, 12H), 2.362.44 (m, 1H), 5.30 (d, J = 4.8Hz, 2H) , 7.056.89 (m, 3H).
Example 3 Synthesis of (E) -1,2-bis (trans-4-propylcyclohexyl) ethylene

A toluene solution (130 mL) of dimethyl (trans-4-propylcyclohexylmethyl) phosphonate (21 g, 84.58 mmol) was cooled to -60 ° C, and 53 mL of a 1.59 M BuLi hexane solution was added at such a rate that the temperature was kept below -60 ° C. 84.27 mmol) is added dropwise (about 15 minutes) and stirred at -60 ° C for 1.5 hours. Subsequently, a toluene solution (30 mL) of trans-4-propylcyclohexanecarbaldehyde derivative (10 g, 64.83 mmol) was added dropwise (about 30 minutes) at a rate at which −55 ° C. or lower was maintained, and then at −55 ° C. for 1 hour. Stir. Add 30 mL of acetic acid at once, stop cooling, and raise the reaction temperature to room temperature. Here, after partially removing the reaction solution as a TLC sample, heating is started and the temperature is raised to the reflux temperature. After 3 hours, TLC measurement (hexane / ethyl acetate = 1/1) is performed, and if the phosphonate adduct remains, heating under reflux is continued. Add toluene and acetic acid as necessary. Allow to cool to room temperature after 8 hours. Add 100 mL of 1% hydrochloric acid and separate the organic layer. The obtained organic layer is washed with 100 mL of 1% hydrochloric acid, 100 mL of water, 100 mL of saturated aqueous sodium hydrogen carbonate solution and 100 mL of 10% brine, and dried over sodium sulfate. The solvent is distilled off, and about 28.51 g of the resulting crude product is purified by silica gel column chromatography to obtain 13.29 g (E / Z = 93/7) of white crystals. Recrystallize (Acetone 26 mL) to obtain white crystals 10.12 g (E / Z = 99.5 / 0.5), further recrystallize (Acetone 40 mL), white crystals 9.75 g (E / Z = 100/0) (Yield 54%).
Comparative Example 1 Synthesis of (E) -1,2-bis (trans-4-propylcyclohexyl) ethylene

1,2-bis (trans-4-propylcyclohexyl) ethylene (313.4 g) was obtained from trans-4-propylcyclohexanecarbaldehyde (196.2 g) and trans-4-propylcyclohexylmethyltriphenylphosphonium bromide (673.7 g). It was. (E) -1,2-bis (trans-4-propylcyclohexyl) ethylene (hereinafter referred to as (E) -isomer) and (Z) -1,2-bis (trans-4-propylcyclohexyl) ethylene in this product (Hereinafter referred to as (Z) -body) was 5:95. Hereinafter, this product was treated as (Z) -body.

  Add 186.5 g of 30% hydrogen peroxide solution to 2000 mL of formic acid and warm to 38 ° C. Add 303.4 g of (Z) -form dropwise so that the system is kept at 50 ° C or less, and further at 45-50 ° C for 9 hours Stir. After cooling to room temperature, 500 mL of water was added and stirred for a while, followed by extraction with toluene. The separated organic layer was washed with water, saturated aqueous sodium hydrogensulfite solution, water, saturated aqueous sodium bicarbonate, and saturated brine in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 423.32 g of a solid reaction mixture. It was. The total amount of the obtained reaction mixture was dispersed in 500 mL of ethanol while stirring vigorously at room temperature, and 600 g of a 30% aqueous sodium hydroxide solution was added thereto, followed by vigorous stirring for 2 hours. Next, 400 mL of concentrated hydrochloric acid was added on an ice bath so that the reaction solution kept at 40 ° C. or lower, and the system was acidified. The white precipitate was filtered off and dissolved in a mixed solvent of tetrahydrofuran (THF) 1500 mL and toluene 100 mL. The aqueous layer was separated, and the organic layer was washed with saturated brine until neutral, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 337.6 g of 1,2-bis (trans-4-propylcyclohexyl) -1,2-ethanediol was obtained.

The total amount of 1,2-bis (trans-4-propylcyclohexyl) -1,2-ethanediol obtained, 1000 mL of trimethyl orthoformate and 2 mL of concentrated hydrochloric acid were mixed and refluxed for 2 hours. After cooling, excess trimethyl orthoformate was distilled off under reduced pressure to obtain 400.4 g of a crude oily 2-methoxy-4,5-di (trans-4-propylcyclohexyl) -1,3-dioxane as a yellow oil. .
The obtained crude product and 1200 mL of acetic anhydride were mixed and refluxed for 5 hours. The mixture was cooled to room temperature and extracted with hexane. The separated organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, dried over anhydrous sodium sulfate, and concentrated to obtain 301.4 g of a reaction mixture. The ratio of (E) -form to (Z) -form in this reaction mixture was 95: 5.

Subsequently, after silica gel column chromatography (solvent: hexane), recrystallization from acetone gave 243.1 g of (E) -1,2-bis (trans-4-propylcyclohexyl) ethylene. (Yield 69%)
Whereas the synthetic route of the present invention is one step from trans-4-propylcyclohexanecarbaldehyde, the method of the comparative example has four steps and is inferior to the method of the present invention in terms of the number of steps.

Claims (7)

Formula (III)

(Wherein R ¹ represents a linear alkyl group having 1 to 10 carbon atoms, R ² represents an alkyl group having 1 to 10 carbon atoms, and n represents 1 or 2). Cyclohexylmethylphosphonate derivative. Formula (I)

(In the formula, R ¹ represents a linear alkyl group having 1 to 10 carbon atoms, n represents 1 or 2, X represents chlorine, bromine, iodine, benzenesulfonyloxy group, p-toluenesulfonyloxy group. Represents a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group), and the compound represented by the general formula (II)

(In the formula, R ² represents an alkyl group having 1 to 10 carbon atoms.) By reacting the compound represented by the basic conditions,

(Wherein R ¹ represents a linear alkyl group having 1 to 10 carbon atoms, R ² represents an alkyl group having 1 to 10 carbon atoms, and n represents 1 or 2). A method for producing a cyclohexylmethylphosphonate derivative. General formula (III)

(Wherein R ¹ represents a linear alkyl group having 1 to 10 carbon atoms, R ² represents an alkyl group having 1 to 10 carbon atoms, and n represents 0, 1 or 2). After obtaining the cyclohexylmethylphosphonate derivative, the compound represented by the general formula (III) is converted into the general formula (IV)

(In the formula, o and p each independently represent 0, 1 or 2, but 1 ≦ o + p ≦ 3, A represents a 1,4-phenylene group optionally substituted by a fluorine atom, Y Is a fluorine atom, trifluoromethoxy group, difluoromethoxy group, trifluoromethyl group, alkyl group having 1 to 10 carbon atoms, alkoxy group having 1 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms, or carbon atom (Representing an alkenyloxy group of formula 3 to 10)) by reacting a compound represented by the formula (V) under strong base conditions

(In the formula, n represents 0, 1 or 2, and o and p each independently represent 0, 1 or 2, but 1 ≦ o + p ≦ 3, and A may be substituted by a fluorine atom. Y represents a fluorine atom, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a carbon atom Represents an alkenyl group having 2 to 10 carbon atoms or an alkenyloxy group having 3 to 10 carbon atoms). The production method according to claim 2, wherein a metal alkoxide is used as a base during the reaction of the compound represented by the general formula (II). The production method according to claim 3, wherein an alkyl metal is used as a base during the reaction of the compound represented by formula (III). 6. The production method according to claim 5, wherein lithium amide is used as the base. A represents a 1,4-phenylene group, a 3-fluoro-1,4-phenylene group, a 3,5-difluoro-1,4-phenylene group, or a 2,3-difluoro-1,4-phenylene group. The manufacturing method as described.