JP5126128B2 - Method for producing liquid crystal compound having difluoromethyleneoxy group - Google Patents

Description

  The present invention relates to a simple and efficient method for producing a difluoromethyleneoxy derivative useful as a liquid crystal compound.

  Liquid crystal display elements utilize the optical anisotropy and dielectric anisotropy of liquid crystalline compounds, including watches, calculators, various measuring instruments, automotive panels, word processors, electronic notebooks, printers, personal computers. It is widely used for televisions, mobile phones, etc., and its demand is increasing year by year. The liquid crystal phase is located between the solid phase and the liquid phase, and is roughly classified into a nematic phase, a smectic phase, and a cholesteric phase. Among them, display elements using a nematic phase are currently most widely used. On the other hand, many display systems have been devised so far, including dynamic scattering type (DS type), guest-host type (GH type), twisted nematic type (TN type), super twisted nematic type (STN type), thin film transistor A type (TFT type), a ferroelectric liquid crystal (FLC), and the like are known.

  Recent development trends in these fields have been promoted mainly by miniaturization, low power consumption and high-speed response of liquid crystal display elements, as represented by mobile phones. Liquid crystal compounds and liquid crystal compositions having a low threshold voltage and a low viscosity are required.

The threshold voltage (Vth) is a function of dielectric anisotropy (Δε) as expressed by the following equation (Mol. Cryst. Liq. Cryst., 12, 57 (1970)).
Vth = π (K / ε ₀ Δε) ^1/2
(In the formula, K is an elastic constant, and ε ₀ is a vacuum dielectric constant.)
As can be seen from this equation, in order to reduce the threshold voltage, two methods are conceivable: a method of increasing the dielectric anisotropy or a method of decreasing the elastic constant. However, since it is difficult to control the elastic constant with the existing technology, the requirement for a low threshold voltage is addressed by using a material having a large dielectric anisotropy. For this reason, liquid crystal compounds having a large dielectric anisotropy are being actively developed. Viscosity is a factor governing the response speed of liquid crystal molecules to an electric field. In order to prepare a liquid crystal composition exhibiting high-speed response, it is preferable to use a large amount of a liquid crystal compound having a low viscosity.

  In recent years, liquid crystal display elements have been widely used for applications such as information terminals and portable game machines. Since these display elements are inevitably driven by a battery, they are required to be driven at a low threshold voltage and to have low power consumption so that they can be used for a long time. In particular, in order to reduce the power consumption of the element itself, a reflective display element that does not require a backlight has been developed recently. The liquid crystal composition used in these reflective display elements is required to have low optical anisotropy in addition to low threshold voltage. Therefore, the development of a liquid crystalline compound having a large dielectric anisotropy and a small optical anisotropy as a liquid crystal material constituting the composition is a key in this field. The following compounds 31 and 32 can be shown as typical low-voltage driving liquid crystal materials used in TFT-type liquid crystal display elements (see Patent Document 1).

式中Ｒはアルキル基を表す。

In the formula, R represents an alkyl group.

  Both compounds 31 and 32 have a 3,4,5-trifluorophenyl group at the end of the molecule, and are expected as liquid crystal materials for low voltage driving. However, as the above-described reflective display device application, the compound 31 has a small dielectric anisotropy (Δε = −10), and the compound 32 is satisfactory in the dielectric anisotropy (Δε = ˜12). The anisotropy is as large as about 0.12, and it has been considered difficult to prepare a liquid crystal composition that can sufficiently satisfy the above-described requirements by using these compounds.

  However, while showing the clearing point, optical anisotropy and viscosity equivalent to those of the above-mentioned compound 31, the dielectric anisotropy (Δε) is about 14 and a value much larger than that of the compound 31, and the reflection type described above. In addition to use as a liquid crystal material for display elements, a compound 33 having a difluoromethyleneoxy group as a bonding group, which is expected as a liquid crystal material for low-voltage driving in various TFT systems, is disclosed (see Patent Document 2). ).

式中、Ｒはアルキル基を示す。

In the formula, R represents an alkyl group.

  Three methods for producing a compound having the difluoromethyleneoxy group as a linking group are known. The first method is a method in which a corresponding ester derivative is converted to a thionoester derivative with Lawesson's reagent (Fieser 13, 38), and fluorinated by reacting with hydrogen fluoride-pyridine in the presence of an oxidizing agent (patent) Reference 2 and Patent Reference 3).

In the formula, R ¹ is an alkyl group, ring A ¹ ′, ring A ² ′, ring A ⁴ ′ is a 1,4-cyclohexylene group or 1,4-phenylene group, and Z ¹ ′ is a single bond or -CH ₂ CH ₂ -.

  The second method involves reacting the corresponding carboxylic acid derivative with 1,3-propanedithiol and trifluoromethanesulfonic acid to convert to dithialium triflate, followed by 3,4,5-trifluorophenol, triethylamine, and then fluorinated. In this method, hydrogen-triethylamine and 1,3-dibromo-5,5-dimethylhydantoin are reacted (refer to Patent Document 4).

  The third method is prepared by adding bromine to the corresponding α, α-difluorocyclohexylidene derivative, reacting with 3,4,5-trifluorophenol under basic conditions, and finally hydrogenating the product. (See Patent Document 5).

JP-A-2-233626 Japanese Patent Laid-Open No. 10-204016 JP-A-5-255265 International Publication No. 01/64667 Pamphlet JP 2002-53513 A

  However, the above three methods have problems such as using a reagent having a high corrosiveness or a strong malodor, a high yield and a large amount of by-products, and a difficulty in scaling up. Therefore, development of a simple method for producing a difluoromethyleneoxy derivative that exhibits various physical properties suitable as a liquid crystal compound has been desired. An object of the present invention is to provide a simple and efficient method for producing a difluoromethyleneoxy derivative.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have hydrolyzed and converted to acid chlorides using cyclohexenyl difluoroacetate derivatives, cyclohexylidenepropionate esters, or vinyldifluoroacetate derivatives as starting materials. It was found that the desired difluoromethyleneoxy derivative can be obtained in a high yield by conversion, decarboxylation bromination, Williamson etherification, and hydrogenation.

  It has also been found that difluoromethyleneoxy derivatives can be obtained in high yield by decarboxylation bromination, hydrogenation, and Williamson etherification. Furthermore, hydrogen atoms are added to cyclohexenyl difluoroacetate derivatives, cyclohexylidenepropionate esters, or vinyldifluoroacetate derivatives, followed by hydrolysis, conversion to acid chlorides, decarboxylation bromination, and Williamson etherification to difluoromethylene. The inventors have also found that an oxy derivative can be obtained in a high yield, and have completed the present invention.

In the following description of each production method, N, N′-dicyclohexylcarbodiimide is indicated as “DCC”, N-hydroxypyridinethione is indicated as “omazine”, and N-hydroxypyridinethione sodium salt is indicated as “sodium omadin”. 4-dimethylaminopyridine is shown as “DMAP”.
First, the present invention using the first starting material is a method for producing a difluoromethyleneoxy derivative represented by formula 2 using a cyclohexenyl difluoroacetate ester represented by formula 1 as a starting material.

In the formula, R ¹ and R ² are each independently a hydrogen atom, a halogen atom, a cyano group, or an alkyl group having 1 to 20 carbon atoms, and any —CH ₂ — in the alkyl group is —O—, -S-, -CH = CH-, or -C≡C- may be substituted, but -O- is not continuous, and any hydrogen atom in the alkyl group is replaced by a fluorine atom. R ³ is a monovalent organic group or inorganic group; Ring A ¹ , Ring A ² , Ring A ³ , and Ring A ⁴ are each independently any —CH ₂ — can be —O—. 1,4-cyclohexylene group optionally substituted with -S-, 1,4-phenylene group optionally substituted with ═CH—, or any hydrogen atom on the ring is fluorine Replaced by atoms, cyano groups or alkyl groups of 1 to 10 carbon atoms It is a good 1,4-phenylene ^{group; Z 1, Z 2, Z} 3, and ^{Z 4} are each independently a single bond or an alkylene group having 1 to 4 carbon atoms, any -CH 2 in the alkylene radical ₂ — may be replaced by —O—, —S—, —CH═CH—, or —C≡C—, but —O— is not continuous, and any hydrogen atom in the alkylene group May be replaced by a fluorine atom; Y ¹ , Y ² , Y ³ , and Y ⁴ are each independently a hydrogen atom, a halogen atom, a cyano group, or an alkyl group having 1 to 10 carbon atoms; k , L, m and n are each independently 0 or 1.

That is, the 1st of the manufacturing method which concerns on this invention is a manufacturing method which has five processes of process (1)-(5).
Step (1): Cyclohexenyl difluoroacetic acid ester represented by Formula 1 is hydrolyzed to produce a carboxylic acid represented by Formula 3.
Step (2): The carboxylic acid represented by Formula 3 is reacted with thionyl chloride to produce the acid chloride represented by Formula 4.
Step (3): The acid chloride represented by Formula 4 is reacted with sodium omazine and bromotrichloromethane to produce a bromodifluoromethyl derivative represented by Formula 5.
Step (4): A bromodifluoromethyl derivative of formula 5 is reacted with a phenol compound represented by formula P in the presence of a base to produce a cyclohexenyl difluoromethyleneoxy derivative of formula 6.
Step (5): The cyclohexenyl difluoromethyleneoxy derivative represented by the formula 6 is reduced with hydrogen to produce the difluoromethyleneoxy derivative represented by the formula 2.

In the formula, R ¹ , R ² , R ³ , ring A ¹ , ring A ² , ring A ³ , ring A ⁴ , Z ¹ , Z ² , Z ³ , Z ⁴ , Y ¹ , Y ² , Y ³ , Y ⁴ , k, l, m, and n have the same meanings as in the above formulas 1 and 2, respectively.

A second manufacturing method according to the present invention is the above manufacturing method having the step (2 ′) instead of the steps (2) and (3) in the first manufacturing method, and a total of four steps. .
Step (2 ′): The carboxylic acid represented by Formula 3 is reacted with omadin and bromotrichloromethane in the presence of DCC and a base to produce a bromodifluoromethyl derivative represented by Formula 5.

A third manufacturing method according to the present invention is the above manufacturing method which includes steps (6) and (7) after steps (1) to (3), and has five steps in total.
Step (6): The bromodifluoromethyl derivative represented by Formula 5 is reduced with hydrogen to produce the cyclohexyl bromodifluoromethane derivative represented by Formula 7.
Step (7): In the presence of a base, the cyclohexyl bromodifluoromethane derivative of Formula 7 is reacted with a phenol compound represented by Formula P described in Step (4) to obtain difluoromethyleneoxy represented by Formula 2. A derivative is produced.

In the formula, R ¹ , ring A ¹ , ring A ² , Z ¹ , Z ² , k, and l have the same meanings as in the formulas 1 and 2, respectively.

  A fourth production method according to the present invention includes a step (2 ′) in place of steps (2) and (3) in the third production method, and a difluoromethyleneoxy derivative having four steps in total. It is a manufacturing method.

The fifth manufacturing method according to the present invention is the manufacturing method having the third step (7) of the manufacturing method after the steps (8) to (11), and has five steps in total.
Step (8): Cyclohexenyl difluoroacetic acid ester represented by Formula 1 is reduced with hydrogen to produce a cyclohexyl difluoroacetic acid ester derivative represented by Formula 8.
Step (9): The cyclohexyl difluoroacetic acid ester derivative represented by Formula 8 is hydrolyzed to produce the carboxylic acid derivative represented by Formula 9.
Step (10): The carboxylic acid derivative represented by Formula 9 is reacted with thionyl chloride to produce an acid chloride represented by Formula 10.
Step (11): The acid chloride represented by Formula 10 is reacted with sodium omadin and bromotrichloromethane to produce a cyclohexyl bromodifluoromethane derivative represented by Formula 7.

In the formula, R ¹ , R ³ , ring A ¹ , ring A ² , Z ¹ , Z ² , k, and l have the same meanings as in the above formulas 1 and 2, respectively.

A sixth manufacturing method according to the present invention is the manufacturing method according to the fifth manufacturing method, which includes the step (10 ′) instead of the steps (10) and (11), and has four steps in total. is there.
Step (10 '): The carboxylic acid represented by formula 9 is reacted with omadin and bromotrichloromethane in the presence of DCC and a base to produce a bromodifluoromethyl derivative represented by formula 7.

  Furthermore, in the first of the production methods, the method is a production method of a cyclohexenyl difluoromethyleneoxy derivative having four steps (1) to (4).

  Further, in the second production method, the method is a production method of a cyclohexenyl difluoromethyleneoxy derivative having three steps (1), (2 ′) and (4).

  Further, the present invention using the second starting material is a method for producing a difluoromethyleneoxy derivative represented by the formula 12 using an ethylenedifluoroacetic acid ester derivative represented by the compound 11 as a starting material.

In the formula, R ¹ , R ² , R ³ , ring A ¹ , ring A ² , ring A ³ , ring A ⁴ , Z ¹ , Z ² , Z ³ , Z ⁴ , Y ¹ , Y ² , Y ³ , Y ⁴ , k, l, m, and n are the same as defined in Formulas 1 and 2; ring A ⁵ is independently substituted with any —CH ₂ — by —O— or —S—. 1,4-cyclohexylene group which may be substituted, 1,4-phenylene group where arbitrary ═CH— may be replaced by ═N—, or any hydrogen atom on the ring is a fluorine atom, cyano group or carbon 1,4-phenylene group which may be substituted with an alkyl group of 1 to 10; o is an integer of 0-10.

That is, the seventh of the manufacturing methods according to the present invention is the manufacturing method having the five steps (12) to (16).
Step (12): Ethylene difluoroacetate represented by Formula 11 is hydrolyzed to produce a carboxylic acid represented by Formula 13.
Step (13): The carboxylic acid represented by Formula 13 is reacted with thionyl chloride to produce the acid chloride represented by Formula 14.
Step (14): The acid chloride represented by formula 14 is reacted with sodium omadin and bromotrichloromethane to produce a bromodifluoromethyl derivative represented by formula 15.
Step (15): In the presence of a base, the bromodifluoromethyl derivative represented by the formula 15 is reacted with the phenol compound represented by the formula P described in the step (4) to obtain a cyclohexane represented by the formula 16. A hexenyl difluoromethyleneoxy derivative is produced.
Step (16): The cyclohexenyl difluoromethyleneoxy derivative represented by the formula 16 is reduced with hydrogen to produce the difluoromethyleneoxy derivative represented by the formula 12.

In the formula, R ¹ , R ² , R ³ , ring A ¹ , ring A ² , ring A ³ , ring A ⁴ , ring A ⁵ , Z ¹ , Z ² , Z ³ , Z ⁴ , Y ¹ , Y ² , Y ³ , Y ⁴ , k, l, m, n, and o are the same as defined in Formulas 11 and 12, respectively.

The eighth of the manufacturing methods according to the present invention is the above manufacturing method which has the step (13 ′) instead of the steps (13) and (14) in the seventh manufacturing method and has four steps in total. .
Step (13 ′): The carboxylic acid represented by formula 13 is reacted with omadin and bromotrichloromethane in the presence of DCC and a base to produce a bromodifluoromethyl derivative of formula 15.

The ninth production method according to the present invention comprises steps (17) and (18) after steps (12) to (14), and a method for producing a bromodifluoromethyl derivative having five steps in total. It is.
Step (17): The bromodifluoromethyl derivative represented by Formula 15 is reduced with hydrogen to produce a cyclohexyl bromodifluoromethylalkane derivative represented by Formula 17.
Step (18): In the presence of a base, a cyclohexyl bromodifluoromethylalkane derivative represented by Formula 17 is reacted with a phenol compound represented by Formula P described in Step (4), and represented by Formula 2. A difluoromethyleneoxy derivative is produced.

In the formula, R ¹ , ring A ¹ , ring A ² , ring A ⁵ , Z ¹ , Z ² , k and l have the same meanings as in the above formulas 11 and 12, respectively.

The tenth manufacturing method according to the present invention includes an eighth step (13 ′) of the manufacturing method instead of the steps (13) and (14) in the ninth manufacturing method, and has four steps in total. It is the said manufacturing method which has.
Step (13 ′): The carboxylic acid of formula 13 is reacted with omadin and bromotrichloromethane in the presence of DCC and a base to produce a bromodifluoromethyl derivative of formula 15.

An eleventh aspect of the manufacturing method according to the present invention is the above manufacturing method including the ninth step (18) of the manufacturing method after the steps (19) to (22) and a total of five steps.
Step (19): Cyclohexenyl difluoroacetate represented by the formula 11 is reduced with hydrogen to produce a cyclohexyl difluoroacetate derivative represented by the formula 18.
Step (20): A cyclohexyldifluoroacetic acid ester derivative represented by the formula 18 is hydrolyzed to produce a carboxylic acid derivative represented by the formula 19.
Step (21): The carboxylic acid derivative represented by Formula 19 is reacted with thionyl chloride to produce an acid chloride represented by Formula 20.
Step (22): The acid chloride represented by formula 20 is reacted with sodium omadin and bromotrichloromethane to produce a cyclohexyl bromodifluoromethane derivative represented by formula 17.

In the formula, R ¹ , R ³ , ring A ¹ , ring A ² , ring A ⁵ , Z ¹ , Z ² , k, l and o have the same meanings as in the above formulas 11 and 12, respectively.

A twelfth manufacturing method according to the present invention is the manufacturing method according to the eleventh manufacturing method, which includes the step (21 ′) instead of the steps (21) and (22), and has four steps in total. .
Step (21 ′): The carboxylic acid represented by Formula 19 is reacted with omadin and bromotrichloromethane in the presence of DCC and a base to produce a bromodifluoromethyl derivative represented by Formula 17.

  Furthermore, in the seventh of the above production methods, the method is a production method of a cyclohexenyl difluoromethyleneoxy derivative having four steps (12) to (15).

  Further, in the eighth of the above production methods, a method for producing a cyclohexenyl difluoromethyleneoxy derivative having three steps (12), (13 ') and (15).

  Furthermore, the present invention using the third starting material is a method for producing a difluoromethyleneoxy derivative represented by the formula 22 using a cyclohexylidene difluoropropionic acid ester represented by the formula 21 as a starting material.

In the formula, R ¹ , R ² , R ³ , ring A ¹ , ring A ² , Z ¹ , Z ² , Y ¹ , Y ² , Y ³ , Y ⁴ , k, l, m, and n are the same as defined above. This is the same as the definitions in equations 11 and 12.

That is, the thirteenth manufacturing method according to the present invention is the manufacturing method having the five steps (23) to (27).
Step (23): The cyclohexenyl difluoroacetate ester represented by the formula 21 is hydrolyzed to produce the carboxylic acid represented by the formula 23.
Step (24): The carboxylic acid represented by Formula 23 is reacted with thionyl chloride to produce the acid chloride represented by Formula 24.
Step (25): The acid chloride represented by formula 24 is reacted with sodium omadin and bromotrichloromethane to produce a bromodifluoromethyl derivative represented by formula 25.
Step (26): In the presence of a base, a bromodifluoromethyl derivative represented by the formula 25 is reacted with a phenol compound represented by the formula P described in the step (4) to obtain a cyclohexane represented by the formula 26. A hexenyl difluoromethyleneoxy derivative is produced.
Step (27): The cyclohexenyl difluoromethyleneoxy derivative represented by the formula 6 is reduced with hydrogen to produce the difluoromethyleneoxy derivative represented by the formula 22.

In the formula, R ¹ , R ² , R ³ , ring A ¹ , ring A ² , ring A ³ , ring A ⁴ , Z ¹ , Z ² , Z ³ , Z ⁴ , Y ¹ , Y ² , Y ³ , Y ⁴ , k, l, m, and n are the same as defined in Formulas 1 and 2, respectively.

A fourteenth manufacturing method according to the present invention is the manufacturing method according to the thirteenth manufacturing method, which includes the step (24 ′) instead of the steps (24) and (25), and has four steps in total. .
Step (24 ′): The carboxylic acid represented by Formula 23 is reacted with omazine and bromotrichloromethane in the presence of DCC and a base to produce a bromodifluoromethyl derivative represented by Formula 25.

The fifteenth manufacturing method according to the present invention is the manufacturing method having the steps (28) and (29) after the steps (23) to (25) and a total of five steps.
Step (28): The bromodifluoromethyl derivative represented by Formula 25 is reduced with hydrogen to produce a cyclohexyl bromodifluoromethane derivative represented by Formula 27.
Step (29): In the presence of a base, a cyclohexyl bromodifluoromethane derivative represented by Formula 27 is reacted with a phenol compound represented by Formula P described in Step (4), and represented by Formula 2. A difluoromethyleneoxy derivative is produced.

In the formula, R ¹ , ring A ¹ , ring A ² , Z ¹ , Z ² , k, and l are the same as defined in the above formulas 1 and 2, respectively.

  The sixteenth manufacturing method according to the present invention has a thirteenth step (24 ′) of the manufacturing method instead of the steps (24) and (25) in the fifteenth manufacturing method, and has four steps in total. It is a manufacturing method of the difluoromethyleneoxy derivative which has.

A seventeenth aspect of the manufacturing method according to the present invention is the manufacturing method according to (29) described in claim 22 after (30) to (33), and further including five steps.
Step (30): Cyclohexenyl difluoroacetate represented by the formula 21 is reduced with hydrogen to produce a cyclohexyl difluoroacetate derivative represented by the formula 28.
Step (31): A cyclohexyldifluoroacetic acid ester derivative represented by the formula 28 is hydrolyzed to produce a carboxylic acid derivative represented by the formula 29.
Step (32): The carboxylic acid derivative represented by Formula 29 is reacted with thionyl chloride to produce an acid chloride represented by Formula 30.
Step (33): The acid chloride represented by Formula 30 is reacted with sodium omadin and bromotrichloromethane to produce a cyclohexyl bromodifluoromethane derivative represented by Formula 27.

In the formula, R ¹ , R ³ , ring A ¹ , ring A ² , Z ¹ , Z ² , k and l are the same as defined in the above formulas 11 and 12, respectively.

The eighteenth aspect of the manufacturing method according to the present invention is the manufacturing method according to the seventeenth aspect of the present invention, which includes the step (32 ′) instead of the steps (32) and (33) and has four steps in total. .
Step (32 ′): The carboxylic acid represented by Formula 29 is reacted with omadin and bromotrichloromethane in the presence of DCC and a base to produce a bromodifluoromethyl derivative represented by Formula 27.

  Furthermore, it is a manufacturing method of the cyclohexenyl difluoromethyleneoxy derivative which has 4 processes of process (23)-(26) as described in 13th of the said manufacturing method.

  Further, it is a method for producing a cyclohexenyl difluoromethyleneoxy derivative having the three steps (23), (24 ') and (26) described in the 14th of the above production method.

Furthermore, the production method of the difluoromethyleneoxy derivative of the present invention can be more suitably carried out in which R ¹ is a linear alkyl group having 2 to 5 carbon atoms; R ² is independently hydrogen. R ³ is a methyl group or an ethyl group; Ring A ¹ is a trans-1,4-cyclohexylene group; k = 1, l = 0; Y ¹ and Y ² are A hydrogen atom; Y ³ and Y ⁴ are each independently a hydrogen atom or a fluorine atom; and m = n = 0.

By using the production method of the present invention, a difluoromethyl ether derivative can be produced easily and safely in a high yield. A method for producing a difluoromethyleneoxy derivative that can be easily scaled up with a high yield and little by-products without using a highly corrosive or bad odor reagent has been developed.
Then, by using this liquid crystalline compound as a component, by appropriately selecting a ring, a substituent, a bonding group and the like constituting the compound, a new liquid crystal composition having optimum physical properties desired by various liquid crystal display elements can be obtained. Can be prepared.

Hereinafter, the production method of the present invention is carried out by using Method A using Compound 1 which is cyclohexenyl difluoroacetic acid ester as a starting material, Method B using vinyldifluoroacetic acid ester 11 as a starting material, and cyclohexylidenepropionic acid ester 21 as a starting material. The method C will be described separately.
The compounds represented by Formulas 1 to 32 may be referred to as “Compound 1” to “Compound 32”.

Method A
In the production method of Compound 2 by Method A, Compound 1 is used as a starting material.

In Formula 1 and Formula 2, R ¹ and R ² are a hydrogen atom, a halogen atom, a cyano group, or any —CH ₂ — in the group is —O—, —S—, —CH═CH—, or — C≡C— may be substituted, but —O— is not continuous, and any hydrogen atom in the group is an alkyl group having 1 to 20 carbon atoms which may be substituted with a fluorine atom.
Examples of R ¹ and R ² include a hydrogen atom, a halogen atom, a cyano group, an alkyl group, an alkoxy group, an alkoxyalkyl group, an alkylthio group, an alkylthioalkyl group, an alkenyl group, an alkenyloxy group, an alkenylthio group, and a fluorine-substituted alkyl group. , A fluorine-substituted alkoxy group, a fluorine-substituted alkoxyalkyl group, a fluorine-substituted alkenyl group, a fluorine-substituted alkenylthio group, and a fluorine-substituted alkenyloxy group are preferred.

  As the halogen atom, fluorine, chlorine and bromine are preferable. As the alkyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group are more preferable. As the alkoxy group, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentoxy group, a heptyloxy group, and an octyloxy group are preferable. As the alkoxyalkyl group, a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, a propoxyethyl group, a methoxypropyl group, an ethoxypropyl group, and a propoxypropyl group are more preferable. As the alkylthio group, a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, a hexylthio group, a heptylthio group, and an octylthio group are preferable. As the alkylthioalkyl group, a methylthiomethyl group, an ethylthiomethyl group, a propylthiomethyl group, a butylthiomethyl group, a methylthioethyl group, an ethylthioethyl group, a propylthioethyl group, a methylthiopropyl group, and a propylthiopropyl group are preferable.

  As the alkenyl group, a vinyl group, 1-propenyl group, 1-butenyl group, 1-pentenyl group, 3-butenyl group and 3-pentenyl group are preferable. As the alkenyloxy group, an allyloxy group is preferable. Examples of the fluorine-substituted alkyl group include trifluoromethyl group, fluoromethyl group, 2-fluoroethyl group, difluoromethyl group, 2,2,2-trifluoroethyl group, 1,1,2,2-tetrafluoroethyl group, A 2-fluoroethyl group, a 3-fluoropropyl group, a 4-fluorobutyl group, and a 5-fluoropentyl group are preferable. Fluorine-substituted alkoxy groups include fluoromethoxy, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoropropoxy, 1,1,2,3 , 3,3-hexafluoropropoxy group is preferred. Examples of the trifluoromethoxymethyl group and fluorine-substituted alkenyl group include 2-fluoroethenyl group, 2,2-difluoroethenyl group, 1,2,2-trifluoroethenyl group, 3-fluoro-1-butenyl group, 4 A -fluoro-1-butenyl group is preferred. As the fluorine-substituted alkenylthio group, a trifluoromethylthio group, a difluoromethylthio group, a 1,1,2,2-tetrafluoroethylthio group, and a 2,2,2-trifluoroethylthio group are preferable.

R ¹ and R ² are most preferably a linear alkyl group having 2 to 5 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, and a pentyl group. .

In Formula 1, R ³ is a monovalent organic group or inorganic group.
Examples of the monovalent organic group include cyano group, alkyl group, alkoxy group, alkoxyalkyl group, alkylthio group, alkylthioalkyl group, alkenyl group, alkenyloxy group, alkenylthio group, halogen alkyl group, halogen-substituted alkoxy group, Examples include a halogen-substituted alkoxyalkyl group, a halogen-substituted alkenyl group, a fluorine-substituted alkenylthio group, and a fluorine-substituted alkenyloxy group.
Examples of the monovalent inorganic group include a halogen atom and a metal atom. As the halogen atom, fluorine, chlorine and bromine are preferable. As a metal atom, sodium, potassium, calcium, and magnesium are preferable.
R ³ is preferably a monovalent organic group, more preferably an alkyl group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group and decyl group. Groups are more preferred, with methyl and ethyl groups being more preferred.

In formula 1 and formula 2, rings A ^{1 to} A ⁴ are each independently a 1,4-cyclohexylene group in which any —CH ₂ — may be replaced by —O— or —S—, ═CH— 1,4-phenylene group which may be replaced by ═N—, or any hydrogen atom in the ring may be replaced by a fluorine atom, a cyano group or an alkyl group having 1 to 10 carbon atoms A phenylene group. Preferred is a 1,4-phenylene group, and more preferred is a trans-1,4-phenylene group.

In Formula 1 and Formula 2, Y ¹ , Y ² , Y ³ , and Y ⁴ are each independently a hydrogen atom, a halogen atom, a cyano group, or an alkyl group having 1 to 10 carbon atoms. Examples of R ¹ and R ² include a hydrogen atom, a halogen atom, a cyano group, an alkyl group, an alkoxy group, an alkoxyalkyl group, an alkylthio group, an alkylthioalkyl group, an alkenyl group, an alkenyloxy group, an alkenylthio group, and a fluorine-substituted alkyl group. , A fluorine-substituted alkoxy group, a fluorine-substituted alkoxyalkyl group, a fluorine-substituted alkenyl group, a fluorine-substituted alkenylthio group, and a fluorine-substituted alkenyloxy group are preferred.

  As the halogen atom, fluorine, chlorine and bromine are more preferable. As the alkyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group are more preferable. As the alkoxy group, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentoxy group, a heptyloxy group, and an octyloxy group are more preferable. As the alkoxyalkyl group, a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, a propoxyethyl group, a methoxypropyl group, an ethoxypropyl group, and a propoxypropyl group are more preferable. As the alkylthio group, a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, a hexylthio group, a heptylthio group, and an octylthio group are more preferable.

As the alkylthioalkyl group, a methylthiomethyl group, an ethylthiomethyl group, a propylthiomethyl group, a butylthiomethyl group, a methylthioethyl group, an ethylthioethyl group, a propylthioethyl group, a methylthiopropyl group, and a propylthiopropyl group are more preferable. As the alkenyl group, a vinyl group, 1-propenyl group, 1-butenyl group, 1-pentenyl group, 3-butenyl group, and 3-pentenyl group are more preferable. As the alkenyloxy group, an allyloxy group is more preferable. Examples of the fluorine-substituted alkyl group include trifluoromethyl group, fluoromethyl group, 2-fluoroethyl group, difluoromethyl group, 2,2,2-trifluoroethyl group, 1,1,2,2-tetrafluoroethyl group, A 2-fluoroethyl group, a 3-fluoropropyl group, a 4-fluorobutyl group, and a 5-fluoropentyl group are more preferable. Fluorine-substituted alkoxy groups include fluoromethoxy, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoropropoxy, 1,1,2,3 , 3,3-hexafluoropropoxy group is more preferred. Examples of the trifluoromethoxymethyl group and fluorine-substituted alkenyl group include 2-fluoroethenyl group, 2,2-difluoroethenyl group, 1,2,2-trifluoroethenyl group, 3-fluoro-1-butenyl group, 4 A -fluoro-1-butenyl group is more preferred. As the fluorine-substituted alkenylthio group, a trifluoromethylthio group, a difluoromethylthio group, a 1,1,2,2-tetrafluoroethylthio group, and a 2,2,2-trifluoroethylthio group are more preferable.
Most preferred Y ¹ , Y ² , Y ³ , and Y ⁴ are a hydrogen atom or a fluorine atom.

In formulas 1 and 2, rings A ^{1 to} A ⁴ are each independently a 1,4-cyclohexylene group in which any —CH ₂ — may be replaced by —O— or —S—, CH— may be replaced by ═N—, or any hydrogen atom on the ring may be replaced by a fluorine atom, a cyano group or an alkyl group having 1 to 10 carbon atoms, Specific examples thereof include 4-phenylene groups, specifically those having a ring structure represented by (r-1) to (r-21).
A black circle in the ring indicates that the configuration of the six-membered ring is trans.

In Formula 1 and Formula 2, Z ^{1 to} Z ⁴ are each independently a single bond or any —CH ₂ — in the group is —O—, —S—, —CH═CH—, or —C≡C—. It is a C1-C4 alkylene group which may be replaced by. k, l, m, and n are each independently 0 or 1.

Z ^{1 to} Z ⁴ are specifically a single bond, 1,2-ethylene, 1,4-butylene, methyleneoxy, oxymethylene, propyleneoxy, oxypropylene, vinylene, 1 (E) -1,4-butenylene. 2 (Z) -1,4-butenylene, 3 (E) -1,4-butenylene, ethynylene, 1,4-butynylene, 1,1-difluoro-1,2-ethylene, 1,1,2,2 -Tetrafluoro-1,2-ethylene, 1,1-difluoro-1,4-butylene and the like.

Method A of the present invention includes synthetic routes 1-6.
Synthesis route 1 is
Step (1): Compound 1 is produced by hydrolyzing Compound 1.
Step (2): Compound 3 is reacted with thionyl chloride to produce acid chloride 4.
Step (3): Compound 5 is produced by reacting compound 4 with sodium omadin and bromotrichloromethane.
Step (4): Compound 6 is produced by reacting Compound 5 with phenol compound P in the presence of a base.
Step (5): Compound 6 is produced by hydrogen reduction of Compound 6;
It has five steps.

In the synthetic route 2, in the synthetic route 1, instead of the steps (2) and (3),
Step (2 ′): Compound 5 is produced by reacting Compound 3 with omadin and bromotrichloromethane in the presence of DCC and DMAP.
It has 4 processes.

Synthesis route 3 is after steps (1) to (3),
Step (6): Compound 7 is produced by hydrogen reduction of Compound 5;
Step (7): Compound 7 is produced by reacting Compound 7 with phenol compound P in the presence of a base.
It has five steps.

  Synthetic route 4 has step (2 ') in place of steps (2) and (3) in synthetic route 3, and has four steps in total.

Synthesis route 5 is
Step (8): Compound 1 is produced by reducing Compound 1 with hydrogen,
Step (9): Compound 8 is hydrolyzed to produce carboxylic acid 9.
Step (10): Compound 9 is reacted with thionyl chloride to produce acid chloride 10.
Step (11): Compound 10 is produced by reacting compound 10 with sodium omadin and bromotrichloromethane.
Step (7): Compound 7 is produced by reacting Compound 7 with phenol compound P in the presence of a base.
It has five steps.

In synthetic route 5, instead of steps (10) and (11) in synthetic route 5,
Step (10 ′): Compound 7 is produced by reacting Compound 9 with omadin and bromotrichloromethane in the presence of DCC and DMAP.
It has 4 processes.

The synthesis route 1 will be described.
The synthesis route 1 has five steps of steps (1) to (5).
Process (1)
In step (1), compound 1 is hydrolyzed to produce compound 3.

Production Method of Compound 1 Compound 1 is a cyclohexenyl difluoroacetic acid ester derivative.

  The compound 1 that is the starting material of Method A in the method for producing a difluoromethyleneoxy derivative of the present invention can be easily produced by those skilled in the art. For example, according to the method described in CR Hauser and DS Breslow, Org. Syn., Coll. Vol., 3, 408 (1955)., Cyclohexanone derivative 34 and bromodifluoroacetate 35 are reacted in the presence of zinc powder. In this manner, thionyl chloride and pyridine are added to compound 36 according to the method described in WS Allen and S. Bernstein, J. Am. Chem. Soc., 77, 1028 (1955). It can be easily produced by reacting.

In the formula, R ¹ , R ³ , ring A ¹ , ring A ² , Z ¹ , Z ² , k and l represent the same meaning as described above, and preferred examples and specific examples thereof are also the same.
The cyclohexanone derivative 34 can be easily obtained by a method described in an organic synthesis book such as a commercial product or a new experimental chemistry course (published by Maruzen Co., Ltd.).

  As reaction conditions in this case, an acid or base aqueous solution can be used as the hydrolysis reagent. The acid is preferably hydrogen chloride or hydrogen bromide, and the base is preferably lithium hydroxide, sodium hydroxide or potassium hydroxide. The reaction solvent may be water alone or a mixed solvent with an organic solvent that does not react with the acid or base. Organic solvents that can be used as a mixed solvent with water include aromatic compounds, aliphatic hydrocarbons, alicyclic hydrocarbons, aliphatic ether compounds, cyclic ether compounds, protic organic solvents, aprotic polar solvents, halogens It is preferable to use a fluorinated hydrocarbon. As the aromatic compound, benzene, toluene, chlorobenzene, and bromobenzene are preferable. As the aliphatic hydrocarbon, hexane and heptane are preferable. As the alicyclic hydrocarbon, cyclohexane is preferable. As the aliphatic ether compound, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether are preferable. As the cyclic ether compound, tetrahydrofuran (hereinafter referred to as THF) and dioxane are preferable. As the protic organic solvent, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, ethylene glycol, and ethylene glycol monomethyl ether are preferable. As the aprotic polar solvent, N, N-dimethylformamide (hereinafter referred to as DMF), dimethyl sulfoxide (hereinafter referred to as DMSO), and acetonitrile are preferable. As the halogenated hydrocarbon, dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane are preferable. The hydrolysis reaction can also be carried out by mixing the solvent. A more preferable reaction solvent is an aliphatic ether compound, a cyclic ether compound, or a protic organic solvent in which the solubility of the compound 1 is high and is well mixed with water.

About the usage-amount of a solvent, what is necessary is just the quantity which can implement reaction safely and stably. Preferably, it is in the range of 5 to 20 times the weight of Compound 1. The reaction temperature should just be temperature which can stir favorably. Depending on the structure of the compound, a range from -10 ° C to 80 ° C is preferred. More preferably, it is in the range of 0 ° C. to 40 ° C. which can suppress the hydrolysis of —CF ₂ — of compound 1 or product 3 as a raw material and improve the conversion rate. The amount of acid or base used is preferably equivalent to or greater than that of Compound 1. More preferably, it is in the range of 1.5 to 2.0 equivalents relative to Compound 1. If it is this range, the compound 1 which is a raw material can be consumed completely. The reaction time largely depends on the structure of the compound and the reaction temperature, but the reaction time at room temperature is about 30 minutes.

Step (2)
Step (2) is a step for producing acid chloride 4 by reacting compound 3 with thionyl chloride.

  The reaction conditions in step (2) can be carried out by mixing carboxylic acid 3 and thionyl chloride in the absence of a solvent or in a solvent. Any solvent that does not react with any of carboxylic acid, thionyl chloride, and acid chloride can be used. As the reaction solvent, it is preferable to use an aromatic compound, an aliphatic hydrocarbon, an alicyclic hydrocarbon, an aliphatic ether compound, a cyclic ether compound, an aprotic polar solvent, or a halogen atomized hydrocarbon. For example, as the aromatic compound, benzene, toluene, chlorobenzene, and bromobenzene are preferable. As the aliphatic hydrocarbon, hexane and heptane are preferable. As the alicyclic hydrocarbon, cyclohexane is preferable. As the aliphatic ether compound, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether are preferable. As the cyclic ether compound, THF and dioxane are preferable. As the aprotic polar solvent, DMF, DMSO, and acetonitrile are preferable. As the halogen atomized hydrocarbon, dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane are preferable. The reaction can also be carried out by mixing the solvent. More preferred reaction solvents are aromatic compounds, aliphatic hydrocarbons, alicyclic hydrocarbons, aliphatic ethers that can increase the reaction rate, complete the reaction in a short time, and can be easily distilled off by concentration under reduced pressure. Compounds, and cyclic ether compounds.

About the usage-amount of a solvent, what is necessary is just the quantity which can implement reaction safely and stably. Preferably, it is in the range of 5 to 20 times the weight of compound 3. The reaction temperature should just be temperature which can stir favorably. Although depending on the structure of the compound, a range of 20 ° C. to 200 ° C. is preferable. A more preferable reaction temperature is in the range of 40 ° C. to 60 ° C., which can suppress the decomposition of —CF ₂ — of compound 3 as a raw material or compound 4 as a product and improve the conversion rate. The amount of thionyl chloride used is preferably equal to or greater than that of Compound 3. More preferably, it is the range of 1.05-2.0 equivalent with respect to the compound 1. If it is this range, the compound 3 which is a raw material can be consumed almost completely. The reaction time largely depends on the structure of the compound and the reaction temperature, but at room temperature, the reaction is completed in about 3 hours after the start of the reaction.

When no solvent is used, thionyl chloride is used in an excess amount relative to 3, but the amount may be an amount that allows the reaction to be carried out safely and stably. Preferably, it is in the range of 1 equivalent or more and 5 to 20 times the weight of compound 3. The reaction temperature should just be temperature which can stir favorably. Although it depends on the structure of the compound, a range from 20 ° C. to 79 ° C. which is the boiling point of thionyl chloride is preferable. More preferably, it is in the range of 40 ° C. to 60 ° C. which can suppress the decomposition of —CF ₂ — of compound 3 or product 4 as a raw material and can improve the conversion rate.

Process (3)
In step (3), compound 4 is produced by reacting compound 4 with sodium omadin and bromotrichloromethane, followed by decarboxylation bromination.
In the reaction of the step (3), decarboxylation bromination is carried out according to the method of Barton et al. (DHR Barton, B. Lacher, and SZ Zard, Tetrahedron, 43, 4321 (1987)). This can be carried out by reacting chloride 4 with sodium omadin and bromotrichloromethane. Any solvent can be used as long as it does not react with any of acid chloride, sodium omadin, and bromotrichloromethane, and does not react with radicals generated during the reaction. As the reaction solvent, it is preferable to use an aromatic compound or a completely chlorinated hydrocarbon. For example, as the aromatic compound, benzene, toluene, chlorobenzene, o-dichlorobenzene, and bromobenzene are preferable. As the fully chlorinated hydrocarbon, carbon tetrachloride is preferred. The reaction can also be carried out by mixing the solvent. More preferred reaction solvents are benzene, toluene, chlorobenzene, and carbon tetrachloride, which can increase the reaction rate, complete the reaction in a short time, and can be easily distilled off under reduced pressure.

About the usage-amount of a solvent, what is necessary is just the quantity which can implement reaction safely and stably. Preferably, it is in the range of 5 to 20 times the weight of compound 4. The reaction temperature should just be temperature which can stir favorably. Although depending on the structure of the compound, a range of 20 ° C. to 200 ° C. is preferable. More preferably, it is in the range of 70 ° C. to 120 ° C. which can suppress the decomposition of —CF ₂ — of the compound 4 or the product 5 as a raw material and can improve the conversion rate. The amount of sodium omadin used is preferably equal to or greater than that of Compound 4. More preferably, it is in the range of 1.05 to 2.0 equivalents relative to compound 4. If it is this range, the compound 4 which is a raw material can be consumed almost completely. The amount of bromotrichloromethane used is preferably equimolar or more with respect to compound 4. More preferably, it is in the range of 1.05 to 5.0 equivalents relative to compound 4. If it is this range, the compound 4 which is a raw material can be consumed almost completely. The reaction time largely depends on the structure of the compound and the reaction temperature, but at room temperature, the reaction is completed about 30 minutes after the start of the reaction.

  When no solvent is used, bromotrichloromethane is used in an excess amount relative to compound 4, but the amount may be an amount that allows the reaction to be carried out safely and stably. Preferably, it is in the range of 1 equivalent or more and 5 to 20 times the weight of compound 3. The reaction temperature should just be temperature which can stir favorably. Although it depends on the structure of the compound, a range from 70 ° C. to 105 ° C. which is the boiling point of bromotrichloromethane is preferable.

  In the decarboxylation bromination reaction of the step (3), the reaction rate can be improved by adding an azo compound as a radical initiator. Examples of the azo compound include 2,2′-azobisisobutyronitrile (hereinafter referred to as AIBN), 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), and 2,2′-azobis. (2-Methylpropionamidine) dihydrochloride and 4,4′-azobis (4-cyanopentanoic acid) are preferred. The addition amount of the azo compound is preferably 0.03 equivalent or more with respect to the compound 4. More preferably, it is in the range of 0.05 to 0.3 equivalents relative to compound 4.

Process (4)
In step (4), compound 5 is produced by reacting compound 5 with phenol compound P in the presence of a base. That is, it is a step of etherification.

Compound P
The phenol derivative P used in the etherification reaction can be produced according to the method of RL Kidwell et al. (Org. Syn., Coll. Vol., 5, 918 (1973)). First, a Grignard reagent is prepared from the bromobenzene derivative P-1. A boric acid ester derivative is prepared by reacting the Grignard reagent with a trialkyl borate group. The phenol derivative P can be produced by oxidizing this with a peroxide such as hydrogen peroxide atom or peracetic acid.

In the formula, R ² , ring A ³ , ring A ⁴ , Z ³ , Z ⁴ , Y ¹ , Y ² , Y ³ , Y ⁴ , m, and n represent the same meaning as described above, and R ¹⁰ represents an alkyl group. Represents.

  Moreover, it describes in Unexamined-Japanese-Patent No. 62-11716, J. Fluorine Chem., 67, 41 (1994), Unexamined-Japanese-Patent No. 3-246244, Unexamined-Japanese-Patent No. 62-207229, and Unexamined-Japanese-Patent No. 2-334335. The phenol derivative P can also be produced according to this method.

  The etherification reaction in the fourth step can be carried out under the conditions of generally known Williamson reaction. As the base that can be used in the etherification reaction, alkali metal hydroxides, alkali metal carbonates, metal alkoxides, alkali metal hydrides, metal oxides such as silver oxide, and amines are preferable. For example, the alkali metal hydroxide is preferably potassium hydroxide or sodium hydroxide. For example, as the alkali metal carbonate, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, and cesium carbonate are preferable. For example, as the metal alkoxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide are preferable. For example, sodium hydride is preferable as the alkali metal hydride. For example, diethylamine and triethylamine are preferable as the metal oxide. More preferred are alkali metal hydroxides and alkali metal carbonates that are easy to handle.

  In addition, the amount of the base used is preferably equal to or greater than that of Compound 5. More preferably, it is in the range of 2 to 5 equivalents relative to compound 5. If it is this range, the conversion of reaction can be improved. Any reaction solvent can be used as long as it does not react with any of compound 5, base, and phenol compound P. As the reaction solvent, it is preferable to use an aromatic compound, an aliphatic hydrocarbon, an alicyclic hydrocarbon, an aliphatic ether compound, a cyclic ether compound, an aprotic polar solvent, or water. For example, benzene and toluene are preferable as the aromatic compound. As the aliphatic hydrocarbon, hexane and heptane are preferable. As the alicyclic hydrocarbon, cyclohexane is preferable. As the aliphatic ether compound, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether are preferable. As the cyclic ether compound, THF and dioxane are preferable. As the aprotic polar solvent, DMF, DMSO, acetonitrile, and 1-methyl-2-pyrrolidinone (hereinafter referred to as NMP) are preferable. The etherification reaction can also be carried out by mixing the solvent. More preferred reaction solvents are aromatic compounds, cyclic ether compounds, and aprotic polar solvents having a relatively high boiling point that can increase the reaction rate and complete the reaction in a short time.

About the usage-amount of a solvent, what is necessary is just the quantity which can implement reaction safely and stably. Preferably, it is in the range of 5 to 20 times the weight of compound 5. The reaction temperature is preferably in the range of room temperature to 200 ° C. More preferably, it is in the range of 80 ° C. to 130 ° C. which can suppress the decomposition of the —CF ₂ — group of the compound 5 and the product 6 and can improve the conversion rate. The reaction time largely depends on the type of compound 5 and the reaction temperature, but is preferably 1 to 10 hours when carried out in the range of 80 to 130 ° C. In the etherification reaction in the fourth step, the reaction rate can be improved by adding a halide salt or a quaternary ammonium salt. As the halide salt, potassium bromide and potassium iodide are preferred. As the quaternary ammonium salt, a tetraalkyl group ammonium halide and a tetraalkyl group ammonium tetrafluoroborate are preferable. The amount of the halogenated salt or quaternary ammonium salt used is preferably 0.03 equivalent or more with respect to Compound 5. More preferably, it is in the range of 0.05 to 0.3 equivalents relative to compound 5.

Process (5)
In step (5), compound 6 is produced by reducing compound 6 with hydrogen.
The hydrogen reduction in the fifth step can be carried out using various metal catalysts described in, for example, Shigeo Nishimura, Gen Takamatsu, contact hydrogenation catalyst (published by Tokyo Chemical Co., Ltd.). As a metal catalyst, the metal catalyst which consists of the following metals is preferable. For example, nickel, cobalt, iron, copper, molybdenum, tungsten, ruthenium, rhodium, platinum, palladium, osmium, rhenium, iridium, chrome, titanium, zirconium. More preferred are nickel-based catalysts and palladium-based catalysts. Both are commercially available and easy to obtain, and are easy to handle. Examples of the nickel-based catalyst include a Raleigh nickel-based catalyst, and examples of the palladium-based catalyst include a palladium-carbon catalyst. The amount of the metal catalyst used is preferably in the range of 1 to 30% by weight with respect to compound 6. More preferably, it is in the range of 3 to 10% by weight, which allows the reaction to proceed efficiently and complete the reaction in a short time.

  Any reaction solvent can be used as long as it does not react with compound 6. As the reaction solvent, it is preferable to use aromatic compounds, aliphatic hydrocarbons, alicyclic hydrocarbons, aliphatic ether compounds, cyclic ether compounds, and alcohols. As the aromatic compound, benzene and toluene are preferable. As the aliphatic hydrocarbon, hexane and heptane are preferable. As the alicyclic hydrocarbon, cyclohexane is preferable. As the aliphatic ether compound, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether are preferable. As the cyclic ether compound, THF and dioxane are preferable. As alcohols, ethanol and propanol are preferable. More preferable reaction solvents are aromatic compounds and alcohols in which the compound 6 has high solubility. About the usage-amount of a solvent, what is necessary is just the quantity which can implement reaction safely and stably. Preferably, it is in the range of 5 to 20 times by weight with respect to compound 6.

The reaction temperature is preferably in the range of room temperature to 200 ° C. The reaction temperature is 0 ° C. to room temperature at which a compound in which at least one of Y ¹ , Y ² , Y ³ , and Y ⁴ is a halogen atom in compound 6 can suppress hydrogen reduction of a substituted halogen atom. More preferably, it is the range. Moreover, if it is the range of 0 degreeC-room temperature, the trans selectivity of a cyclohexane ring can also be improved. The hydrogen pressure is preferably in the range of atmospheric pressure to 5 MPa. More preferably, it is in the range of 0.1 to 1 MPa which can improve the trans selectivity of the two cyclohexane rings to be produced and can shorten the reaction time. The reaction time largely depends on the type of compound 6 and the reaction temperature. However, when the reaction is carried out in the range of 0 ° C. to room temperature, 2 to 10 hours are preferable. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 2
Synthesis route 2 has step (2 ′) in place of steps (2) and (3) in synthesis route 1.
Process (1)
The same as described in the step (1).

Process (2 ')
In step (2 ′), compound (5) is produced by reacting carboxylic acid 3 with omazine and bromotrichloromethane in the presence of DCC and a base. That is, it is a step of decarboxylating and brominating carboxylic acid in one step.

  The decarboxylation bromination in the step (2 ') can be carried out by reacting carboxylic acid 3 with omazine and bromotrichloromethane in the presence of DCC and a base without solvent or in a solvent. As the solvent, any solvent can be used as long as it does not react with any of carboxylic acid, omazine, and bromotrichloromethane and does not react with radicals generated during the reaction. As the reaction solvent, an aromatic compound is preferably used. For example, as the aromatic compound, benzene, toluene, chlorobenzene, o-dichlorobenzene, and bromobenzene are preferable. The reaction can also be carried out by mixing the solvent. More preferred reaction solvents are benzene, toluene, and chlorobenzene, which can improve the reaction rate, complete the reaction in a short time, and can be easily distilled off under reduced pressure. Any base that does not react with bromotrichloromethane and does not react with radicals generated during the reaction can be used. Preferably, DMAP, pyridine, 2,6-lutidine, triethylamine, diethylamine, quinoline, aniline, 1,5-diazabicyclo [4.3.0] nonene (hereinafter referred to as DBN), 1,8-diazabicyclo [5.4. 0.0] undecene (hereinafter referred to as DBU) and 1,4-diazabicyclo [2.2.2] octene (hereinafter referred to as DABCO), more preferably DMAP, pyridine and triethylamine.

About the usage-amount of a solvent, what is necessary is just the quantity which can implement reaction safely and stably. Preferably, it is in the range of 5 to 20 times the weight of compound 3. The reaction temperature should just be temperature which can stir favorably. Although it depends on the structure of the compound, a range of -20 ° C to 200 ° C is preferable. More preferably, it is in the range of 0 ° C. to 70 ° C. capable of suppressing decomposition of the —CF ₂ — group of the compound 3 as a raw material or the product 5 as a product and improving the conversion rate. The amount of omadin used is preferably equal to or greater than the amount of compound 3. More preferably, it is the range of 1.05-2.0 equivalent with respect to the compound 3. If it is this range, the compound 3 which is a raw material can be consumed almost completely. The amount of bromotrichloromethane used is preferably equal to or greater than that of Compound 3. More preferably, it is the range of 1.05-5.0 equivalent with respect to the compound 3. If it is this range, the compound 3 which is a raw material can be consumed almost completely. The reaction time largely depends on the structure of the compound and the reaction temperature, but at room temperature, the reaction is completed in about 8 hours after the start of the reaction.

  When no solvent is used, an excessive amount of bromotrichloromethane is used with respect to 3, but the amount may be an amount that allows the reaction to be carried out safely and stably. Preferably, it is in the range of 1 equivalent or more and 5 to 20 times the weight of compound 3. The reaction temperature should just be temperature which can stir favorably. Although it depends on the structure of the compound, a range from 0 ° C. to 70 ° C. which is the boiling point of bromotrichloromethane is preferable.

  In the decarboxylation bromination reaction in the step (2 '), the reaction rate can be improved by adding an azo compound as a radical initiator as in the step (3). Examples of the azo compound include AIBN, 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), 2,2′-azobis (2-methylpropionamidine) dihydrochloride, 4,4′-azobis ( 4-cyano pentanoic acid) is preferred. The amount of the azo compound added is preferably 0.03 equivalent or more with respect to compound 3. More preferably, it is in the range of 0.05 to 0.3 equivalents relative to compound 3.

  The reaction can be promoted by irradiating light instead of or in combination with heating or using a radical initiator. Irradiation light can be ultraviolet or visible light, and its wavelength is preferably in the range of 10 to 700 nm, although it depends on the structure of the compound. As a light source, natural light and electric light as well as a light source for a photochemical reaction device can be used.

  About the usage-amount of a base, 0-10 mol% with respect to the compound 3 is preferable. More preferably, it is in the range of 0.5 to 5 mol% with respect to compound 3.

Process (4)
The same as described in the step (4).

Process (5)
The same as described in the step (5).
The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80% by weight or more as a residue. . A product having a purity of 90% by weight or more can be obtained by subjecting the residue to silica gel column chromatography or distillation. A product having a purity of 95% by weight or more can be obtained by recrystallizing the product having a purity of 90% by weight or more.

Synthesis route 3
Synthetic route 3 is the same as synthetic route 1 until steps (1) to (3) for producing compound 5, step (6) for producing compound 7 by hydrogen reduction of compound 5, and presence of a base in compound 7 It comprises a step (7) of producing compound 2 by reacting with lower phenol compound P.

Process (1)
The same as described in the step (1).

Step (2)
The same as described in the step (2).

Process (3)
The same as described in the step (3).

Step (6)
The hydrogen reduction reaction in the step (6) can be carried out using various metal catalysts described in, for example, Shigeo Nishimura, Gen Takamatsu, catalytic hydrogenation catalyst (published by Tokyo Chemical Co., Ltd.). The conditions for the hydrogen reduction reaction, including the catalyst that can be used for the hydrogen reduction reaction, are the same as those described in Step (5) of Synthesis Route 1.

Step (7)
In step (7), compound 7 is reacted with phenol compound P in the presence of a base to produce compound 2. That is, it is a step of etherification.

Compound P
The phenol derivative P used for the etherification reaction is the same as the phenol derivative P described in the step (4) of the synthesis route 1.

  The etherification reaction in the step (5) can be carried out under generally known Williamson reaction conditions. The conditions for the etherification reaction, including the base that can be used for the etherification reaction, are the same as those described in the fourth step of the synthesis route 1. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 4
The synthetic route 4 has the step (2 ′) in the synthetic route 3 instead of the steps (2) and (3).
Process (1)
The same as described in the step (1).

Process (2 ')
This is the same as described in the step (2 ′).

Step (6)
The same as described in the step (6).

Step (7)
The same as described in the step (7). The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 5
Synthesis route 5 includes a step (8) for producing compound 8 by hydrogen reduction of compound 1, a step (9) for producing carboxylic acid derivative 9 by hydrolyzing compound 8, and a reaction of thionyl chloride with compound 9. A step (10) for producing acid chloride 10, a step (11) for producing compound 7 by reacting compound 10 with sodium omazine and bromotrichloromethane, and compound 7 in the presence of a base with phenol compound P. And a step (7) of producing compound 2 by reaction.

Step (8)
In step (8), compound 1 is produced by reducing compound 1 with hydrogen.

Compound 1 is
It can be produced according to the production method of Compound 1 described in Synthesis Route 1.
The hydrogen reduction reaction in the step (8) can be carried out using various metal catalysts described in, for example, Shigeo Nishimura, Gen Takamatsu, a catalytic hydrogenation catalyst (published by Tokyo Chemical Co., Ltd.). The conditions for the hydrogen reduction reaction, including the catalyst that can be used for the hydrogen reduction reaction, are the same as those described in Step (5) of Synthesis Route 1.

Step (9)
In step (9), compound 8 is hydrolyzed to produce carboxylic acid 9.
The hydrolysis reaction in the step (9) can be carried out under conditions of acid or alkali hydrolysis of generally known esters. The conditions of the hydrolysis reaction including the acid and base that can be used for the hydrolysis reaction are the same as those described in the step (1) of the synthesis route 1.

Step (10)
Step (10) is a step for producing acid chloride 4 by reacting compound 9 with thionyl chloride.
The reaction of step (10) can be carried out by mixing carboxylic acid 9 and thionyl chloride in the absence of solvent or in a solvent. The conditions for the acid chloride synthesis reaction are the same as those described in Step (2) of Synthesis Route 1.

Step (11)
In step (11), compound 10 is produced by reacting compound 10 with sodium omazine and bromotrichloromethane for decarboxylation bromination.
The decarboxylation bromination in step (11) is carried out according to the method of Barton et al. (DHR Barton, B. Lacher, and SZ Zard, Tetrahedron, 43, 4321 (1987).) The reaction can be carried out by reacting sodium omazine with bromotrichloromethane. The conditions for the decarboxylation bromination reaction are the same as those described in the step (3) of the synthesis route 1.

Step (7)
This is the same as described in the step (7) of the synthesis route 3. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 6
The synthetic route 6 has a step (10 ′) instead of the steps (10) and (11) in the synthetic route 5.
Step (8)
The same as described in the step (8).

Step (9)
The same as described in the step (9).

Step (10 ')
In step (10 ′), compound (7) is produced by reacting carboxylic acid 9 with omadin and bromotrichloromethane in the presence of DCC and a base. That is, it is a step of decarboxylating and brominating carboxylic acid in one step. The reaction conditions for decarboxylation bromination are the same as those described in Step (2 ′) of Synthesis Route 2.

Step (7)
This is the same as that described in step (7) of the synthesis route 5. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Method B
The method for producing compound 12 of the present invention is based on compound 11 as a starting material.

The difluoromethyleneoxy derivative that can be produced by Method B of the present invention is represented by Compound 12. In the compound 12, R ¹ , R ² , ring A ¹ to ring A ⁴ , Y ^{1 to} Y ⁴ , Z ^{1 to} Z ⁴ , k, l, m, and n represent the same as in the compound 2. Ring A ⁵ is the same as rings A ^{1 to} A ⁴ , but is independent of ring A ¹ to ring A ⁴ . o represents an integer of 1 to 10.
Method B of the present invention includes synthesis routes 7-12.

Synthesis route 7 is step (12): Compound 11 is hydrolyzed to produce carboxylic acid derivative 13.
Step (13): Compound 13 is reacted with thionyl chloride to produce acid chloride 14.
Step (14): Compound 14 is produced by reacting compound 14 with sodium omadin and bromotrichloromethane to perform decarboxylation bromination.
Step (15): Compound 16 is produced by reacting Compound 15 with phenol compound P in the presence of a base.
Step (16): Compound 16 is produced by hydrogen reduction of Compound 16;
It has five steps.

In the synthetic route 8, instead of the steps (13) and (14) in the synthetic route 7, the step (13 ′): Compound 13 is reacted with omazine and bromotrichloromethane in the presence of DCC and DMAP to produce the compound 15. ,
It has 4 processes.

Synthesis route 9 is after steps (12) to (14),
Step (17): Compound 15 is produced by hydrogen reduction of Compound 15;
Step (18): Compound 12 is produced by reacting Compound 17 with phenol compound P in the presence of a base.
It has five steps.

Synthetic route 10 has step (13 ') instead of steps (13) and (14) in synthetic route 9, and has four steps in total.

Synthesis route 11 is step (19): Compound 11 is produced by hydrogen reduction of Compound 11;
Step (20): Compound 18 is hydrolyzed to produce carboxylic acid derivative 19.
Step (21): Compound 19 is reacted with thionyl chloride to produce acid chloride 20.
Step (22): Compound 20 is produced by reacting compound 20 with sodium omazine and bromotrichloromethane to perform decarboxylation bromination.
Step (18): Compound 12 is produced by reacting Compound 17 with phenol compound P in the presence of a base.
It has five steps.

In the synthetic route 12, instead of steps (21) and (22) in the synthetic route 11, step (21 ′): compound 19 is reacted with omadin and bromotrichloromethane in the presence of DCC and DMAP to produce compound 17. ,
It has 4 processes.

Synthesis route 7
The synthesis route 7 includes five steps (12) to (16).

Step (12)
In the step (12), the compound 11 is hydrolyzed to produce the carboxylic acid derivative 13.

Compound 11
Compound 11 is a vinyl difluoroacetate derivative. The compound 11 that is the starting material of Method B in the method for producing a difluoromethyleneoxy derivative of the present invention can be easily produced by those skilled in the art. For example, in accordance with the method described in CR Hauser and DS Breslow, Org. Syn., Coll. Vol., 3, 408 (1955). Compound 38 is reacted with thionyl chloride and pyridine according to the method described in WS Allen and S. Bernstein, J. Am. Chem. Soc., 77, 1028 (1955). Thus, it can be easily manufactured.

In the formula, R ¹ , R ³ , ring A ¹ , ring A ² , ring A ⁵ , Z ¹ , Z ² , k and l represent the same meaning as described above, and preferable examples, specific examples and the like are the same as above is there.
The cyclohexanone derivative 34 can be easily obtained by a method described in an organic synthesis book such as a commercial product or a new experimental chemistry course (published by Maruzen Co., Ltd.).

  An acid or base aqueous solution can be used as the hydrolysis reagent. The acid is preferably hydrogen chloride or hydrogen bromide, and the base is preferably lithium hydroxide, sodium hydroxide or potassium hydroxide. The reaction solvent is the same as that described as the reaction solvent preferably used in the first step of the synthesis route 1 of the method A. The same applies to the amount of solvent used, the reaction temperature, the amount of acid or alkali used, and the reaction time.

Step (13)
In step (13), acid chloride 14 is produced by reacting compound 13 with thionyl chloride.
The reaction conditions in the step (13) are the same as those described in the step (2) of the synthesis route 1 of the method A.

Step (14)
In Step (14), Compound 14 is produced by reacting Compound 14 with sodium omadin and bromotrichloromethane for decarboxylation bromination.
The reaction conditions for the decarboxylation bromination reaction in the step (14) are the same as those described in the step (3) of the synthesis route 1 of the method A.

Step (15)
In step (15), compound 15 is produced by reacting compound 15 with phenol compound P in the presence of a base. That is, it is a step of etherification.

Compound P
The phenol derivative P used in the etherification reaction is the same as the phenol derivative P described in the step (4) of the synthesis route 1 of the method A.
The etherification reaction in the step (15) can be carried out under generally known Williamson reaction conditions. The conditions for the etherification reaction, including the base that can be used for the etherification reaction, are the same as those described in step (4) of synthesis route 1 of Method A.

Process (16)
In step (16), compound 12 is produced by reducing compound 16 with hydrogen.
The catalyst and its use amount and the reaction solvent and its use amount in the hydrogen reduction in the step (16) are the same as the conditions described in the step (5) of the synthesis route 1 of the method A. The reaction temperature can suppress hydrogen reduction of the substituted halogen atom in the compound 16 in which any one or more of Y ¹ , Y ² , Y ³ , and Y ⁴ is substituted with a halogen atom. A range of 0 ° C. to room temperature is more preferable. The reaction time largely depends on the type of compound 16 and the reaction temperature, but 2 to 10 hours are preferable when the reaction is carried out in the range of 0 ° C. to room temperature. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 8
The synthetic route 8 has the step (13 ′) in the synthetic route 7 instead of the steps (13) and (14).
Step (12)
This is the same as step (12) of the synthesis route 7.

Step (13 ')
In step (13 ′), carboxylic acid 13 is reacted with omadin and bromotrichloromethane in the presence of DCC and a base to produce compound (15). That is, it is a step of decarboxylating and brominating carboxylic acid in one step. The reaction conditions for decarboxylation bromination are the same as those described in Step (2 ′) of Synthesis Route 2.

Step (15)
Step (15) is the same as Step (15) described in Synthesis Route 7.

Process (16)
Step (16) is the same as that described in Step (16) of Synthesis Route 7. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 9
The synthetic route 9 is the same as the synthetic route 7 from (12) to (14). The compound 15 is produced, the compound 15 is hydrogen-reduced to produce the compound 17 (17), and the compound 17 is converted into a base. (18) which reacts with the phenolic compound P in the presence of

Step (12)
This is the same as step (12) of the synthesis route 7.

Step (13)
This is the same as step (13) of the synthesis route 7.

Step (14)
This is the same as the step (14) of the synthesis route 7.

Step (17)
In step (17), compound 18 is produced by reducing compound 15 with hydrogen.
The hydrogen reduction reaction in the step (17) can be carried out using various metal catalysts described in a book such as Shigeo Nishimura, Gen Takamatsu, and a catalytic hydrogenation catalyst (published by Tokyo Chemical Co., Ltd.). The conditions of the hydrogen reduction reaction including the catalyst that can be used for the hydrogen reduction reaction are the same as those described in the step (16) of the synthesis route 7.

Step (18)
In step (18), compound 12 is produced by reacting compound 17 with phenol compound P in the presence of a base. That is, it is a step of etherification.

Compound P
The phenol derivative P used for the etherification reaction is the same as the phenol derivative P described in the step (15) of the synthesis route 7.
The etherification reaction in step (18) can be carried out under the conditions of generally known Williamson reaction. The conditions for the etherification reaction, including the base that can be used for the etherification reaction, are the same as those described in Step (15) of Synthesis Route 7. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 10
The synthetic route 10 has (13 ′) instead of (13) and (14) in the synthetic route 9, and has four steps in total.

Step (12)
Step (12) is the same as step (12) of the synthesis route 7.

Step (13 ')
In step (13 ′), compound 15 is produced by reacting carboxylic acid 13 with omazine and bromotrichloromethane in the presence of DCC and a base. That is, it is a step of decarboxylating and brominating carboxylic acid in one step. The reaction conditions for decarboxylation bromination are the same as those described in Step (2 ′) of Synthesis Route 2.

Step (17)
Step 17 is the same as step (17) of the synthetic route 9.

Step (18)
Step 18 is the same as step (18) of the synthetic route 9. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 11
The synthesis route 11 has the step (18) after the steps (19) to (22), and has five steps in total.

Process (19)
In step (19), compound 11 is produced by reducing compound 11 with hydrogen.

Compound 11
The same as described in the synthesis route 7.
The hydrogen reduction reaction in the step (19) can be carried out using various metal catalysts described in a book such as Shigeo Nishimura, Gen Takamatsu, and a catalytic hydrogenation catalyst (published by Tokyo Chemical Co., Ltd.). The conditions of the hydrogen reduction reaction including the catalyst that can be used for the hydrogen reduction reaction are the same as those described in the step (16) of the synthesis route 7.

Step (20)
In step (20), compound 18 is hydrolyzed to produce carboxylic acid 19.
The hydrolysis reaction in the step (20) can be carried out under generally known conditions of ester acid or alkali hydrolysis. The conditions for the hydrolysis reaction including the acid and base that can be used for the hydrolysis reaction are the same as those described in the step (12) of the synthetic pathway 7.

Step (21)
Step (21) is a step for producing acid chloride 20 by reacting compound 19 with thionyl chloride.
The reaction of step (21) can be carried out by mixing carboxylic acid 19 and thionyl chloride in the absence of solvent or in a solvent. The conditions for the acid chloride synthesis reaction are the same as those described in step (13) of the synthesis route 7.

Step (22)
In step (22), compound 20 is produced by reacting compound 20 with sodium omadin and bromotrichloromethane for decarboxylation bromination.
The decarboxylation bromination in the step (22) is carried out according to the method of Barton et al. (DHR Barton, B. Lacher, and SZ Zard, Tetrahedron, 43, 4321 (1987)). The reaction can be carried out by reacting sodium omazine with bromotrichloromethane. The conditions for the decarboxylation bromination reaction are the same as those described in the step (14) of the synthesis route 7.

Step (18)
This is the same as described in the synthetic route 9 step (18). The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 12
The synthesis route 12 has the step (21 ′) instead of the steps (21) and (22) in the synthesis route 11, and has four steps in total.

Process (19)
The step (19) is the same as the step (19) of the synthesis route 11.

Step 20
The step (20) is the same as the step (20) of the synthesis route 11.

Step 21 '
In the step (21 ′), Compound 17 is produced by reacting carboxylic acid 19 with omazine and bromotrichloromethane in the presence of DCC and a base. That is, it is a step of decarboxylating and brominating carboxylic acid in one step. The reaction conditions for decarboxylation bromination are the same as those described in Step (2 ′) of Synthesis Route 2.

Step 18
The step (18) is the same as the step (18) of the synthesis route 11. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Method C
The method for producing compound 22 of the present invention is based on compound 21 as a starting material.

The difluoromethyleneoxy derivative that can be produced by Method C of the present invention is represented by Compound 22. In the compound 22, R ¹ , R ² , ring A ¹ to ring A ⁴ , Y ^{1 to} Y ⁴ , Z ^{1 to} Z ⁴ , k, l, m, and n represent the same as in the compound 2. o represents an integer of 1 to 10. Method C of the present invention includes synthesis routes 13-18.

The synthesis route 13 is
Step (23): Compound 21 is hydrolyzed to produce carboxylic acid derivative 23.
Step (24): Compound 23 is reacted with thionyl chloride to produce acid chloride 24.
Step (25): Compound 24 is produced by reacting compound 24 with sodium omadin and bromotrichloromethane to perform decarboxylation bromination.
Step (26): Compound 25 is produced by reacting compound 25 with phenol compound P in the presence of a base.
Step (27): There are five steps of producing compound 22 by reducing compound 26 with hydrogen.

Synthetic pathway 14 replaces steps (24) and (25) in synthetic pathway 13
Step (24 ′): Compound 23 is reacted with omazine and bromotrichloromethane in the presence of DCC and DMAP to produce Compound 25.
There are four steps in total.

The synthesis route 15 is after steps (23) to (25),
Step (26): Compound 25 is produced by reducing Compound 25 with hydrogen.
Step (27): Compound 22 is produced by reacting compound 27 with phenol compound P in the presence of a base.
There are five steps.

  The synthetic route 16 has the step (24 ') in place of the steps (24) and (25) in the synthetic route 15, and has four steps in total.

Synthesis route 17 is
Step (29): Compound 21 is reduced with hydrogen to produce Compound 28.
Step (30): Compound 28 is hydrolyzed to produce carboxylic acid derivative 29.
Step (31): Compound 29 is reacted with thionyl chloride to produce acid chloride 30.
Step (32): Compound 27 is produced by reacting compound 30 with sodium omazine and bromotrichloromethane to perform decarboxylation bromination.
Step (28): Compound 22 is produced by reacting Compound 27 with phenol compound P in the presence of a base.
There are five steps.

Synthetic pathway 18 is the same as synthetic pathway 17 in place of steps (31) and (32).
Step (32 ′): Compound 29 is reacted with omazine and bromotrichloromethane in the presence of DCC and DMAP to produce Compound 27.
It has 4 processes.

Synthesis route 13
The synthesis route 13 has five steps of steps (23) to (27).

Step (23)
In the step (23), the compound 21 is hydrolyzed to produce the carboxylic acid derivative 23.

Compound 21
Compound 21 is a cyclohexylidene difluoropropionic acid ester derivative. The compound 21 that is the starting material of Method C in the method for producing a difluoromethyleneoxy derivative of the present invention can be easily produced by those skilled in the art. For example, according to the method described in CR Hauser and DS Breslow, Org. Syn., Coll. Vol., 3, 408 (1955)., Cyclohexanecarboacetaldehyde derivative 39 and bromodifluoroacetic acid ester 35 are added in the presence of zinc powder. After reacting to compound 40, for example, thionyl chloride and pyridine are added to compound 40 according to the method described in WS Allen and S. Bernstein, J. Am. Chem. Soc., 77, 1028 (1955). Compound 21 can be easily produced by reacting.

In the formula, R ¹ , R ³ , R ³ , ring A ¹ , ring A ² , Z ¹ , Z ² , k and l represent the same meaning as described above, and preferred examples and specific examples are also the same.
The cyclohexane carbaldehyde derivative 39 can be easily obtained by a method described in an organic synthesis book such as a commercial product or a new experimental chemical course (published by Maruzen Co., Ltd.).

  An acid or base aqueous solution can be used as the hydrolysis reagent. The acid is preferably hydrogen chloride or hydrogen bromide, and the base is preferably lithium hydroxide, sodium hydroxide or potassium hydroxide. The reaction solvent is the same as that described as the reaction solvent preferably used in the first step of the synthesis route 1 of the method A. The same applies to the amount of solvent used, the reaction temperature, the amount of acid or alkali used, and the reaction time.

Process (24)
In step (24), compound 23 is reacted with thionyl chloride to produce acid chloride 24.
The reaction conditions in the step (24) are the same as those described in the second step of the synthesis route 1 of the method A.

Step (25)
In the step (25), compound 24 is produced by reacting compound 24 with sodium omazine and bromotrichloromethane for decarboxylation bromination.
The reaction conditions for the decarboxylation bromination reaction in the step (25) are the same as those described in the step (3) of the synthesis route 1 of the method A.

Step (26)
In step (26), compound 25 is produced by reacting compound 25 with phenol compound P in the presence of a base. That is, it is a step of etherification.

Compound P
The phenol derivative P used in the etherification reaction is the same as the phenol derivative P described in the step (4) of the synthesis route 1 of the method A.
The etherification reaction in step (26) can be carried out under the conditions of generally known Williamson reaction. The conditions for the etherification reaction, including the base that can be used for the etherification reaction, are the same as those described in step (4) of synthesis route 1 of Method A.

Step (27)
In step (27), compound 26 is reduced by hydrogen to produce compound 22.
The catalyst and its use amount and the reaction solvent and its use amount in the hydrogen reduction in the step (27) are the same as the conditions described in the step (5) of the synthesis route 1 of the method A. The reaction temperature can suppress hydrogen reduction of the substituted halogen atom in the compound 26 in which one or more of Y ¹ , Y ² , Y ³ , and Y ⁴ is substituted with a halogen atom. A range of 0 ° C. to room temperature is more preferable. The reaction time largely depends on the type of compound 26 and the reaction temperature, but 2 to 10 hours are preferable when carried out in the range of 0 ° C. to room temperature. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 14
The synthetic route 14 has a step (24 ′) instead of the steps (24) and (25) in the synthetic route 13, and has four steps in total.

Step (23)
Step (23) is the same as step (23) of the synthesis route 13.

Step 24 '
In step (24 ′), compound 25 is produced by reacting carboxylic acid 23 with omazine and bromotrichloromethane in the presence of DCC and a base. That is, it is a step of decarboxylating and brominating carboxylic acid in one step. The reaction conditions for decarboxylation bromination are the same as those described in Step (2 ′) of Synthesis Route 2.

Step (26)
This is the same as the step (26) of the synthesis route 13.

Step (27)
This is the same as the step (27) of the synthesis route 13. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 15
The synthesis route 15 has steps (28) and (29) after steps (23) to (25), and has five steps in total.

Step (23)
This is the same as step (23) of the synthesis route 13.

Process (24)
This is the same as the step (24) of the synthesis route 13.

Step (25)
This is the same as step (25) of the synthesis route 13.

Step (28)
In step (28), compound 25 is produced by reducing compound 25 with hydrogen.
The hydrogen reduction reaction in the step (28) can be carried out using various metal catalysts described in, for example, Shigeo Nishimura, Gen Gen Takamatsu, a catalytic hydrogenation catalyst (published by Tokyo Chemical Co., Ltd.). The conditions for the hydrogen reduction reaction including the catalyst that can be used for the hydrogen reduction reaction are the same as those described in the step (27) of the synthesis route 13.

Step (29)
In step (29), compound 27 is reacted with phenol compound P in the presence of a base to produce compound 22. That is, it is a step of etherification.

Compound P
The phenol derivative P used for the etherification reaction is the same as the phenol derivative P described in the fourth step of the synthetic route 13.
The etherification reaction in the step (29) can be carried out under generally known Williamson reaction conditions. The conditions for the etherification reaction including the base that can be used for the etherification reaction are the same as those described in the step (26) of the synthesis route 13. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 16
The synthetic route 16 has the step (24 ′) instead of the steps (24) and (25) in the synthetic route 15, and has four steps in total.

Step (23)
Step (23) is the same as step (23) of the synthesis route 13.

Step (24 ')
The step (24 ′) is the same as the step (24 ′) of the synthesis route 13.

Step (28)
The step (28) is the same as the step (28) of the synthesis route 15.

Step (29)
The step (29) is the same as the step (29) of the synthesis route 15. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 17
The synthesis route 17 has the step (28) after the steps (29) to (32), and has five steps in total.

Step (29)
In step (29), compound 21 is produced by reducing compound 21 with hydrogen.

Compound 21
This is the same as described in the synthesis route 13.
The hydrogen reduction reaction in the step (29) can be carried out using various metal catalysts described in a book such as Shigeo Nishimura, Gen Takamatsu, and a catalytic hydrogenation catalyst (published by Tokyo Chemical Co., Ltd.). The conditions for the hydrogen reduction reaction including the catalyst that can be used for the hydrogen reduction reaction are the same as those described in the step (27) of the synthesis route 13.

Step (30)
In step (30), compound 28 is hydrolyzed to produce carboxylic acid 29.
The hydrolysis reaction in the step (30) can be carried out under conditions of acid or alkali hydrolysis of generally known esters. The conditions for the hydrolysis reaction including the acid and base that can be used for the hydrolysis reaction are the same as those described in the step (23) of the synthesis route 13.

Step (31)
Step (31) is a step for producing acid chloride 30 by reacting compound 29 with thionyl chloride.
The reaction of step (31) can be carried out by mixing carboxylic acid 29 and thionyl chloride in the absence of solvent or in a solvent. The conditions for the acid chloride synthesis reaction are the same as those described in the step (24) of the synthesis route 13.

Process (32)
In step (32), compound 30 is produced by reacting compound 30 with sodium omadin and bromotrichloromethane for decarboxylation bromination.
The decarboxylation bromination in the step (32) is carried out according to the method of Barton et al. (DHR Barton, B. Lacher, and SZ Zard, Tetrahedron, 43, 4321 (1987)). The reaction can be carried out by reacting sodium omazine with bromotrichloromethane. The conditions for the decarboxylation bromination reaction are the same as those described in the step (25) of the synthesis route 13.

Step (28)
This is the same as described in the step (28) of the synthetic route 15. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Synthesis route 18
The synthetic route 18 has the step (32 ′) instead of the steps (32) and (33) in the synthetic route 17, and has four steps in total.

Step (30)
Step (30) is the same as step (30) of the synthesis route 17.

Step (31)
The step (31) is the same as the step (31) of the synthesis route 17.

Step (32 ')
In step (32 ′), compound 27 is produced by reacting carboxylic acid 29 with omadin and bromotrichloromethane in the presence of DCC and a base. That is, it is a step of decarboxylating and brominating carboxylic acid in one step. The reaction conditions for decarboxylation bromination are the same as those described in Step (2 ′) of Synthesis Route 2.

Step (29)
Step (29) is the same as step (29) of the synthesis route 17. The product in each production process of the difluoromethyleneoxy derivative of the present invention can be separated by a method usually used in organic synthesis. For example, water and an organic solvent for extraction are added to the reaction and stirred. The organic layer is separated, washed with water, dried with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and then the organic solvent is distilled off under reduced pressure to obtain a product having a purity of 80 to 100% by weight as a residue. it can. A product having a purity of 90 to 100% by weight can be obtained by subjecting the residue to silica gel column chromatography or distillation. By recrystallizing the product, a product having a purity of 95 to 100% by weight can be obtained.

Hereinafter, the present invention will be described in more detail with reference to examples.
In the following examples, Cr represents a crystal, Sm represents a smectic phase, N represents a nematic phase, and Iso represents an isotropic liquid. The notation “Cr 43.5 N 103.0 Iso” indicates that the transition point between Cr and N is 43.5 ° C., and the transition point between N and Iso is 103.0 ° C. In the ¹ H-NMR data display, s represents a single line, d represents a double line, t represents a triple line, and in GC-MS, M ⁺ represents a molecular ion peak. Indicates the strength.

Example 1
Example of production method of liquid crystal compound 2 1- (trans-4- (trans-4-propylcyclohexyl) cyclohexyldifluoromethoxy) -3,4,5-trifluorobenzene (k = 1 in compound 2) according to synthesis route 1 l = m = n = 0, R ¹ is an n-propyl group, ring A ¹ is a trans-1,4-cyclohexylene group, Z ¹ is a single bond, Y ¹ and Y ² are both hydrogen atoms, Y ³ and Y ⁴ And R ² is a fluorine compound (Compound No. 57)).

Production process of starting compound 1 In a nitrogen atmosphere, 13.8 g (217 mmol) of zinc powder and 37.1 g (167 mmol) of 4- (trans-4-propylcyclohexyl) cyclohexanone were suspended in 83 ml of THF, and ethyl bromodifluoroacetate at room temperature. A solution of 40.9 g (202 mmol) in THF (84 ml) was added dropwise over 30 minutes. The mixture was heated to maintain the temperature at 50 ° C. and stirred for 5 hours, and then ice-cooled and 73 ml of 3M hydrochloric acid was added to stop the reaction. After separation, ordinary post-treatment operations were performed, and the extract was concentrated under reduced pressure to obtain 59.9 g of 1-ethoxycarbonyldifluoromethyl-4- (trans-4-propylcyclohexyl) cyclohexanol in a crude state. Crude yield 103%.
This was dissolved in 344 ml of toluene, 66.0 g (835 mmol) of pyridine and then 39.7 g (334 mmol) of thionyl chloride were added and stirred at 80 ° C. for 2.5 hours. After cooling in an ice bath, 334 ml of 3M hydrochloric acid was added to carry out ordinary workup, the extract was concentrated under reduced pressure, and the residue was distilled under reduced pressure to give 48.8 g of 4- (trans-4-propylcyclohexyl) -1-cyclohexenyldifluoro. Ethyl acetate was obtained. Two-stage yield 89%.

Process (1)
To a solution of 82.8 g (252 mmol) of ethyl 4- (trans-4-propylcyclohexyl) -1-cyclohexenyldifluoroacetate in ethanol (504 ml) was added dropwise 504 ml of 1M aqueous sodium hydroxide over 7 minutes while cooling with ice. After stirring for 30 minutes, 252 ml of 3M hydrochloric acid was added for normal post-treatment, and the extract was concentrated under reduced pressure to obtain 76.5 g of a crude product. This was recrystallized from 750 ml of heptane to give 70.8 g of 4- (trans-4-propylcyclohexyl) -1-cyclohexenyl difluoroacetic acid. Yield 94%.

Step (2)
To 24.0 g (80 mmol) of 4- (trans-4-propylcyclohexyl) -1-cyclohexenyl difluoroacetic acid, 160 ml of thionyl chloride was added and refluxed for 5 hours. The reaction solution was concentrated under reduced pressure to remove excess thionyl chloride, and the residue was distilled under reduced pressure to obtain 24.3 g of 4- (trans-4-propylcyclohexyl) -1-cyclohexenyl difluoroacetyl chloride. Yield 95%.

Process (3)
A suspension of 13.4 g (90 mmol) of sodium omadin in bromotrichloromethane (90 ml) was refluxed, and 19.1 g (60 mmol) of 4- (trans-4-propylcyclohexyl) -1-cyclohexenyldifluoroacetyl chloride was added to bromotrichloro. A methane (90 ml) solution was added dropwise over 20 minutes. After further refluxing for 10 minutes, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; heptane) to obtain 17.1 g of 4- (trans-4-propylcyclohexyl) -1-bromodifluoromethylcyclohexene. Obtained. Yield 85%.

Process (4)
3,4,5-trifluorophenol 8.15 g (55 mmol), potassium carbonate 7.60 g (55 mmol), tetrabutylammonium bromide 0.806 g (2.5 mmol), and 4- (trans-4-propylcyclohexyl) -1-bromo A suspension of 16.8 g (50 mmol) of difluoromethylcyclohexene in DMF (100 ml) was stirred at 115 ° C. for 30 minutes, then cooled, water and toluene were added for normal post-treatment, and the extract was concentrated under reduced pressure to give a residue. Was purified by silica gel column chromatography (developing solvent; heptane) to give 19.1-g of 1- (4- (trans-4-propylcyclohexyl) cyclohexen-1-yl-difluoromethoxy) -3,4,5-trifluorobenzene. Was obtained as colorless crystals. Yield 95%.

Process (5)
1- (4- (trans-4-propylcyclohexyl) cyclohexen-1-yl-difluoromethoxy) -3,4,5-trifluorobenzene 6.84 g (17 mmol) in toluene (17 ml) -ethanol (17 ml) in 5 0.684 g of% palladium on carbon was added, and the mixture was stirred at room temperature and a hydrogen atomic pressure of 0.5 MPa for 10 hours. After the catalyst was filtered off from the reaction solution and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; heptane), and further recrystallized from an equivalent mixture of heptane-ethanol to give colorless crystals 1 -Trans-4- (trans-4-propylcyclohexyl) cyclohexyl-difluoromethoxy) -3,4,5-trifluorobenzene (4.81 g) was obtained. The yield was 70%.
The compound showed a liquid crystal phase and showed the transition point described below.
Cr 43.5 N 103.0 Iso
The measurement results of various spectral data strongly supported the structure of the compound.
¹ H-NMR (δ ppm, CDCl ₃ ): 0.87-1.34 (m, 20H), 1.57-2.02 (m, 7H), 6.82-6.85 (m, 2H)
¹⁹ F-NMR (δ ppm, CDCl ₃ ): -79.33 (d, 2F, -CF ₂ O-), -133.76-133.83 (m, 2F), -165.21-165.31 (m, 1F)

Example 2
1- (trans-4- (trans-4-propylcyclohexyl) cyclohexyldifluoromethoxy) -3,4,5-trifluorobenzene (in compound 2, k = 1, l = m = n = 0, R according to synthesis route 2 ¹ is an n-propyl group, ring A ¹ is a trans-1,4-cyclohexylene group, Z ¹ is a single bond, Y ¹ and Y ² are both hydrogen atoms, Y ³ , Y ⁴ and R ² are both fluorine atoms This is the production of a compound (Compound No. 57).

Process (1)
4- (trans-4-propylcyclohexyl) -1-cyclohexenyl difluoroacetic acid was produced according to the step (1) of Example 1.

Process (2 ')
A solution of 24.0 g (80 mmol) of 4- (trans-4-propylcyclohexyl) -1-cyclohexenyl difluoroacetic acid, 12.2 g (96 mmol) of omadin and 0.49 g (4 mmol) of DMAP in bromotrichloromethane (160 ml) was ice-cooled. A solution of DCC 19.8 g (96 mmol) in bromotrichloromethane (20 ml) was added dropwise over 10 minutes. The mixture was further reacted for 24 hours at the same temperature, and then stirred at 70 ° C. for 30 minutes. After cooling the reaction solution to room temperature, insoluble matters were filtered off, the filtrate was concentrated under reduced pressure, and the residue was distilled under reduced pressure to obtain 17.1 g of 4- (trans-4-propylcyclohexyl) -1-bromodifluoromethylcyclohexene. . Yield 85%.

Process (4)
According to the step (4) of Example 1, 1- (4- (trans-4-propylcyclohexyl) cyclohexen-1-yl-difluoromethoxy) -3,4,5-trifluorobenzene was obtained as colorless crystals. . The yield was 95%.

Process (5)
According to the step (5) of Example 1, 1-trans-4- (trans-4-propylcyclohexyl) cyclohexyl-difluoromethoxy) -3,4,5-trifluorobenzene (4.81 g) was obtained. The yield was 70%.

Example 3
1- (trans-4- (trans-4-pentylcyclohexyl) cyclohexyldifluoromethoxy) -4-trifluoromethoxybenzene (in compound 2, k = 1, l = m = n = 0, R ¹ is n A compound in which the pentyl group, ring A ¹ is a trans 1,4-cyclohexylene group, Z ¹ is a single bond, Y ¹ , Y ² , Y ³ and Y ⁴ are all hydrogen atoms, and R ² is a trifluoromethoxy group ( Compound No. 58).

Production process of starting compound 1 In a nitrogen atmosphere, 13.8 g (217 mmol) of zinc powder and 41.8 g (167 mmol) of 4- (trans-4-pentylcyclohexyl) cyclohexanone were suspended in 83 ml of THF and bromodifluoro at room temperature. A solution of 40.9 g (202 mmol) of ethyl acetate in THF (84 ml) was added dropwise over 30 minutes. The mixture was heated to maintain the temperature at 50 ° C. and stirred for 5 hours, and then ice-cooled and 73 ml of 3M hydrochloric acid was added to stop the reaction. After separation, ordinary post-treatment operations were performed, and the extract was concentrated under reduced pressure to obtain 67.5 g of 1-ethoxycarbonyldifluoromethyl-4- (trans-4-pentylcyclohexyl) cyclohexanol in a crude state. The crude yield was 103%.
This was dissolved in 344 ml of toluene, 66.0 g (835 mmol) of pyridine and then 39.7 g (334 mmol) of thionyl chloride were added and stirred at 80 ° C. for 2.5 hours. After cooling in an ice bath, 334 ml of 3M hydrochloric acid was added to carry out ordinary workup, and the extract was concentrated under reduced pressure. The residue was distilled under reduced pressure, and ethyl 4- (trans-4-pentylcyclohexyl) -1-cyclohexenyl difluoroacetate 55.1 g was obtained. Two-stage yield 89%.

Process (1)
To a solution of 83.6 g (252 mmol) of ethyl 4- (trans-4-pentylcyclohexyl) -1-cyclohexenyldifluoroacetate in ethanol (504 ml) was added dropwise 504 ml of 1M aqueous sodium hydroxide over 7 minutes while cooling with ice. After stirring for 30 minutes, 252 ml of 3M hydrochloric acid was added for normal post-treatment, and the extract was concentrated under reduced pressure to obtain 86.4 g of a crude product. This was recrystallized from 750 ml of heptane to obtain 80.0 g of 4- (trans-4-pentylcyclohexyl) -1-cyclohexenyl difluoroacetic acid. Yield 94%.

Step (2)
To 27.1 g (80 mmol) of 4- (trans-4-pentylcyclohexyl) -1-cyclohexenyl difluoroacetic acid, 160 ml of thionyl chloride was added and refluxed for 5 hours. The reaction solution was concentrated under reduced pressure to remove excess thionyl chloride, and the residue was distilled under reduced pressure to obtain 27.5 g of 4- (trans-4-pentylcyclohexyl) -1-cyclohexenyl difluoroacetyl chloride. Yield 95%.

Process (3)
A suspension of 13.4 g (90 mmol) of sodium omadin in bromotrichloromethane (90 ml) was refluxed, and 21.2 g (60 mmol) of 4- (trans-4-pentylcyclohexyl) -1-cyclohexenyl difluoroacetyl chloride in bromotrichloro was refluxed. A methane (90 ml) solution was added dropwise over 20 minutes. After further refluxing for 10 minutes, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane) to obtain 19.3 g of 4- (trans-4-pentylcyclohexyl) -1-bromodifluoromethylcyclohexene. Yield 85%.

Process (4)
4-trifluoromethoxyphenol 9.80 g (55 mmol), potassium carbonate 7.60 g (55 mmol), tetrabutylammonium bromide 0.806 g (2.5 mmol), and 4- (trans-4-pentylcyclohexyl) -1-bromodifluoromethylcyclohexene A suspension of 19.0 g (50 mmol) of DMF (100 ml) was stirred at 115 ° C. for 30 minutes, then cooled and added with water and toluene for normal post-treatment, the extract was concentrated under reduced pressure, and the residue was concentrated on a silica gel column. Purification by chromatography (developing solvent; heptane) yielded 21.9 g of 1- (trans-4- (trans-4-pentylcyclohexyl) cyclohexen-1-yldifluoromethoxy) -4-trifluoromethoxybenzene as colorless crystals. It was. Yield 95%.

Process (5)
5% palladium in a solution of 7.82 g (17 mmol) of 1- (trans-4- (trans-4-pentylcyclohexyl) cyclohexen-1-yldifluoromethoxy) -4-trifluoromethoxybenzene in toluene (17 ml) -ethanol (17 ml) 0.684 g of carbon was added, and the mixture was stirred at room temperature and a hydrogen atomic pressure of 0.5 MPa for 10 hours. The catalyst was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane), and recrystallized from an equal volume of heptane-ethanol to give 1- (trans 4.50 g of -4- (trans-4-pentylcyclohexyl) cyclohexyldifluoromethoxy) -4-trifluoromethoxybenzene was obtained. Yield 70%. The compound showed a liquid crystal phase and showed the transition point described below.
Cr 35.1 Sm 116.7 N 156.9 Iso
The measurement results of various spectral data strongly supported the structure of the compound.
¹ H-NMR (δ ppm, CDCl3): 0.6-2.2 (m, 31H), 7.19 (bs, 4H)
¹⁹ F-NMR (δ ppm, CDCl3): -51.68 (s, 3F, -OCF ₃ ), -78.77 (s, 2F, -CF ₂ O-)

Example 4
1- (trans-4- (trans-4-pentylcyclohexyl) cyclohexyldifluoromethoxy) -4-trifluoromethoxybenzene (in compound 2, k = 1, l = m = n = 0, R ¹ is n A pentyl group, ring A ¹ is a trans-1,4-cyclohexylene group, Z ¹ is a single bond, Y ¹ , Y ² , Y ³ , and Y ⁴ are all hydrogen atoms, and R ² is a trifluoromethoxy group This is the production of the compound (Compound No. 58).

Process (1)
4- (trans-4-pentylcyclohexyl) -1-cyclohexenyl difluoroacetic acid was prepared by the step (1) of Example 1.

Process (2 ')
A solution of 24.0 g (80 mmol) of 4- (trans-4-propylcyclohexyl) -1-cyclohexenyl difluoroacetic acid, 12.2 g (96 mmol) of omadin and 0.49 g (4 mmol) of DMAP in bromotrichloromethane (160 ml) was ice-cooled. A solution of DCC 19.8 g (96 mmol) in bromotrichloromethane (20 ml) was added dropwise over 10 minutes. The mixture was further reacted for 24 hours at the same temperature, and then stirred at 70 ° C. for 30 minutes. After cooling the reaction solution to room temperature, insoluble matters were filtered off, the filtrate was concentrated under reduced pressure, and the residue was distilled under reduced pressure to obtain 17.1 g of 4- (trans-4-propylcyclohexyl) -1-bromodifluoromethylcyclohexene. . Yield 85%.

Process (4)
In the same manner as in Step (4) of Example 3, 21.9 g of 1- (trans-4- (trans-4-pentylcyclohexyl) cyclohexen-1-yldifluoromethoxy) -4-trifluoromethoxybenzene was obtained as colorless crystals. Got as. Yield 95%.

Process (5)
By the method according to the step (5) of Example 3, 1.50 g of 1- (trans-4- (trans-4-pentylcyclohexyl) cyclohexyldifluoromethoxy) -4-trifluoromethoxybenzene was obtained. Yield 70%.

Example 5
1- (3- (trans-4- (trans-4-pentylcyclohexyl) -1,1-difluoro-2-propenyloxy) -3,4,5-trifluorobenzene (k = 1 in compound 16) according to synthetic route 7 , L = m = n = o = 0, R ¹ is an n-pentyl group, ring A ¹ and ring A ⁵ are both trans-1,4-cyclohexylene groups, Z ¹ is a single bond, Y ¹ and Y ² are This is the production of a compound (compound number 145) in which both hydrogen atom, Y ³ , Y ⁴ and R ² are both fluorine atoms.

Production Process of Compound 11 as Starting Material In a nitrogen atmosphere, 13.8 g (217 mmol) of zinc powder and 46.5 g (167 mmol) of 4- (tran-4-pentylcyclohexyl) cyclohexylacetaldehyde were suspended in 83 ml of THF, and bromo at room temperature. A solution of 40.9 g (202 mmol) of ethyl difluoroacetate in THF (84 ml) was added dropwise over 30 minutes. The mixture was heated to maintain the temperature at 50 ° C. and stirred for 5 hours, and then ice-cooled and 73 ml of 3M hydrochloric acid was added to stop the reaction. After separation, the usual post-treatment operation was performed, and the extract was concentrated under reduced pressure to obtain 69.3 g of 1-ethoxycarbonyldifluoromethyl-2- (trans-4- (trans-4-pentylcyclohexyl) cyclohexyl) ethanol in a crude state. It was. Crude yield 103%. This was dissolved in 344 ml of toluene, 66.0 g (835 mmol) of pyridine and then 39.7 g (334 mmol) of thionyl chloride were added and stirred at 80 ° C. for 2.5 hours. After cooling in an ice bath, 334 ml of 3M hydrochloric acid was added to carry out ordinary workup, and the extract was concentrated under reduced pressure. The residue was distilled under reduced pressure to give E-1-ethoxycarbonyldifluoromethyl-2- (trans-4- (trans-4- (trans There was obtained 59.5 g of -4-pentylcyclohexyl) cyclohexyl) ethylene. Two-stage yield 89%.

Step (12)
E-1-Ethoxycarbonyldifluoromethyl-2- (trans-4- (trans-4-pentylcyclohexyl) cyclohexyl) ethylene In 101.0 g (252 mmol) of ethanol (504 ml) was added to a solution of 504 ml of 1M aqueous sodium hydroxide solution in ice. The solution was added dropwise over 7 minutes. After stirring for 30 minutes, 252 ml of 3M hydrochloric acid was added to carry out ordinary workup, and the extract was concentrated under reduced pressure to obtain 86.4 g of a crude product. This was recrystallized from 750 ml of heptane to obtain 88.2 g of E-2- (trans-4- (trans-4-pentylcyclohexyl) cyclohexyl) ethenyl difluoroacetic acid. Yield 94%.

Step (13)
160 ml of thionyl chloride was added to 29.8 g (80 mmol) of E-2- (trans-4- (trans-4-pentylcyclohexyl) cyclohexyl) ethenyl difluoroacetic acid and refluxed for 5 hours. The reaction solution was concentrated under reduced pressure to remove excess thionyl chloride, and the residue was distilled under reduced pressure to obtain 29.7 g of E-2- (trans-4- (trans-4-pentylcyclohexyl) cyclohexyl) ethenyl difluoroacetyl chloride. It was. Yield 95%.

Step (14)
A suspension of 13.4 g (90 mmol) of sodium omadin in bromotrichloromethane (90 ml) was refluxed, and 23.5 g of E-2- (trans-4- (trans-4-pentylcyclohexyl) cyclohexyl) ethenyl difluoroacetyl chloride was added thereto. A solution of (60 mmol) in bromotrichloromethane (90 ml) was added dropwise over 20 minutes. After further refluxing for 10 minutes, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; heptane) to give E-1-bromodifluoromethyl-2- (trans-4- (trans-4). -20.8 g of pentylcyclohexyl) cyclohexyl) ethylene was obtained. Yield 85%.

Step (15)
3,4,5-trifluorophenol 8.15 g (55 mmol), potassium carbonate 7.60 g (55 mmol), tetrabutylammonium bromide 0.806 g (2.5 mmol), and E-1-bromodifluoromethyl-2- (trans-4) -(Trans-4-pentylcyclohexyl) cyclohexyl) A suspension of 20.4 g (50 mmol) of ethylene in DMH (100 ml) was stirred at 115 ° C. for 30 minutes, then cooled and added with water and toluene for normal post-treatment. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; heptane) to give 1- (3- (trans-4- (trans-4-pentylcyclohexyl) -1,1-difluoro-2. -Propenyloxy) -3,4,5-trifluorobenzene (Compound No. 145) 22.5 g was obtained as colorless crystals, yield 95%.

Example 6
1- (3- (trans-4- (trans-4-pentylcyclohexyl) -1,1-difluoro-2-propenyloxy) -3,4,5-trifluorobenzene (k = 1 in compound 16) according to synthetic route 8 , L = m = n = o = 0, R ¹ is an n-pentyl group, ring A ¹ and ring A ⁵ are both trans-1,4-cyclohexylene groups, z ¹ is a single bond, Y ¹ and Y ² are This is the production of a compound (compound number 145) in which both hydrogen atom, Y ³ , Y ⁴ and R ² are both fluorine atoms.

Step (12)
E-2- (trans-4- (trans-4-pentylcyclohexyl) cyclohexyl) ethenyl difluoroacetic acid was prepared by the step (12) of Example 5.

Step (13 ')
A solution of E-2- (trans-4- (trans-4-pentylcyclohexyl) cyclohexyl) ethenyldifluoroacetic acid 29.8 g (80 mmol), omadin 12.2 g (96 mmol) and DMAP 0.49 g (4 mmol) in bromotrichloromethane (160 ml) Was cooled with ice, and a solution of 19.8 g (96 mmol) of DCC in bromotrichloromethane (20 ml) was added dropwise over 10 minutes. The mixture was further reacted for 24 hours at the same temperature, and then stirred at 70 ° C. for 30 minutes. After cooling the reaction solution to room temperature, insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the residue was distilled under reduced pressure to give E-1-bromodifluoromethyl-2- (trans-4- (trans-4-pentylcyclohexyl). ) 20.8 g of cyclohexyl) ethylene was obtained. Yield 85%.

Step (15)
1- (3- (trans-4- (trans-4-pentylcyclohexyl) -1,1-difluoro-2-propenyloxy) -3,4,5 is prepared by a method according to the step (4) of Example 5. -22.5 g of trifluorobenzene (Compound No. 145) was obtained as colorless crystals, yield 95%.

Example 7
1- (3- (trans-4- (trans-4-pentylcyclohexyl) cyclohexyl-1,1-difluoropropoxy) -3,4,5-trifluorobenzene (in compound 12, k = 1, l = m = n = o = 0, R ¹ is an n-pentyl group, ring A ¹ and ring A ⁵ are both trans-1,4-cyclohexylene groups, Z ¹ is a single bond, Y ¹ and Y ² are both hydrogen atoms, Y ³ , This is the production of a compound (Compound No. 106) in which Y ⁴ and R ² are both fluorine atoms.

Process (16)
1- (3- (trans-4- (trans-4-pentylcyclohexyl) -1,1-difluoro-2-propenyloxy) -3,4,5-trifluorobenzene 8.07 g obtained in Example 5 above ( 17 mmol) in toluene (17 ml) -ethanol (17 ml) was added with 0.684 g of 5% palladium on carbon, and the mixture was stirred for 10 hours at room temperature and at a hydrogen atomic pressure of 0.5 MPa, the catalyst was filtered off from the reaction solution, and the filtrate was concentrated under reduced pressure. Thereafter, the residue was purified by silica gel column chromatography (developing solvent; heptane), and recrystallized from an equal volume mixture of heptane-ethanol to give colorless crystals of 1- (3- (trans-4- (trans-4-pentyl). Cyclohexyl) cyclohexyl-1,1-difluoropropoxy) -3,4,5-trifluorobenzene 5.67 g was obtained, yield 70%.
The compound showed a liquid crystal phase and showed the transition point described below.
Cr 65.5 (SA 50.76) N 116.9 Iso
The measurement results of various spectral data strongly supported the structure of the compound.
¹ H-NMR (δ ppm, CDCl ₃ ): 2.2 (m, 35H), 6.88 (m, 2H)
¹⁹ F-NMR (δ ppm, CDCl ₃ ): -79.26 (t, 2F, -CF ₂ O-), -133.53 to -133.65 (m, 2F), -165.00 to -165.06 (m, 1F)
GC-MS (EI): 460 (M ⁺ , 12.5%), 148 (92.4), 97 (93.6), 83 (100), 81 (55), 69 (54.9), 55 (76.4), 41 (30.7)

Example 8
1- (3-4′-propyl-3,5-difluorobiphenyl-4-yl) -1,1-difluoropropenyloxy) -3,4,5-trifluorobenzene (in formula 16, k = 1, l = m = n = o = 0, R ¹ is an n-propyl group, ring A ¹ is a 1,4-phenylene group, ring A ⁵ is a 3,5-difluoro-1,4-phenylene group, Z ¹ Is a single bond, Y ¹ and Y ² are both hydrogen atoms, and Y ³ , Y ⁴ , and R ² are both fluorine atoms (Compound No. 148).

First step of production process of compound 11 as starting material In a nitrogen atmosphere, n-butyllithium (1.6%) was added to a solution of 23.2 g (100 mmol) of 3,5-difluoro-4′-propylbiphenyl in THF (300 ml) at −70 ° C. M hexane solution) 69 ml (110 mmol) was added dropwise. After stirring at -70 ° C. for 1 hour, a THF solution (100 ml) of DMF 9.3 ml (120 mmol) was added dropwise and further stirred for 1 hour. 200 ml of 1N hydrochloric acid was poured into the reaction mixture and the mixture was extracted with heptane. The organic layer was washed successively with 200 ml of water, 200 ml of a saturated aqueous sodium hydrogen carbonate solution and 200 ml of water, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; heptane: toluene = 4: 6), and 3,5-difluoro-4-formyl-4′-propylbiphenyl (colorless oil) 26.0 g was obtained. Yield 100%.

Second step of the production process of compound 11 as a starting material In a nitrogen atmosphere, 14.6 g (130 mmol) of potassium tert-butoxide was added little by little to a THF solution (250 ml) of 42.2 g (130 mmol) of methoxymethyltriphenylphosphonium chloride at 0 ° C. Added and stirred for 1 hour at room temperature. After cooling again to 0 ° C., a solution of 3,6.0-difluoro-4-formyl-4′-propylbiphenyl 26.0 g (100 mmol) obtained above in THF (150 ml) was added dropwise and stirred at room temperature for 2 hours. The reaction mixture was poured into 200 ml of water and extracted with toluene, and the organic layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; heptane: toluene = 1: 10) to obtain 28.8 g of a reaction product (colorless oil). This was dissolved in a total amount of 200 ml of toluene, and 70 ml of formic acid was added and refluxed for 6 hours. After cooling, the reaction solution was poured into 200 ml of water and extracted with 100 ml of toluene, and the organic layer was washed successively with water (100 ml × 3), saturated aqueous sodium hydrogen carbonate solution (100 ml × 2), water (200 ml × 1), and dried over anhydrous magnesium sulfate. . After the solvent was distilled off, the residue was purified by silica gel column chromatography (developing solvent; heptane: toluene = 1: 1) to give 2- (3,5-difluoro-4′-propylbiphenyl-4-yl) acetaldehyde ( 26.2 g of colorless oil) was obtained. Yield 96%.

Third step of production process of compound 11 as starting material In a nitrogen atmosphere, 45.8 g (167 mmol) of 2- (3,5-difluoro-4′-propylbiphenyl-4-yl) acetaldehyde obtained above was suspended in 83 ml of THF. Then, a solution of 40.9 g (202 mmol) of ethyl bromodifluoroacetate in THF (84 ml) was added dropwise at room temperature over 30 minutes. The mixture was heated to maintain the temperature at 50 ° C. and stirred for 5 hours, and then ice-cooled and 73 ml of 3M hydrochloric acid was added to stop the reaction. After separation, normal post-treatment is performed, and the extract is concentrated under reduced pressure to give crude 4- (3,5-difluoro-4′-propylbiphenyl-4-yl) -3-hydroxy-2,2-difluoro. 68.5 g of ethyl butanoate was obtained. Crude yield 103%. This was dissolved in 344 ml of toluene, 66.0 g (835 mmol) of pyridine and then 39.7 g (334 mmol) of thionyl chloride were added and stirred at 80 ° C. for 2.5 hours. After cooling in an ice bath, 334 ml of 3M hydrochloric acid was added to carry out ordinary post-treatment, the extract was concentrated under reduced pressure, the residue was distilled under reduced pressure, and E-4- (3,5-difluoro-4′-propylbiphenyl- 56.7 g of ethyl 4-yl) -2,2-difluoro-3-butenoate was obtained. Two-stage yield 89%.

Step (12)
E-4- (3,5-difluoro-4′-propylbiphenyl-4-yl) -2,2-difluoro-3-butenoate ethyl 95.9 g (252 mmol) in ethanol (504 ml) in solution with 1M sodium hydroxide 504 ml of the aqueous solution was added dropwise over 7 minutes while cooling with ice. After stirring for 30 minutes, 252 ml of 3M hydrochloric acid was added for normal post-treatment, and the extract was concentrated under reduced pressure to obtain 86.4 g of a crude product. This was recrystallized from 750 ml of heptane to obtain 83.5 g of E-4- (3,5-difluoro-4′-propylbiphenyl-4-yl) -2,2-difluoro-3-butenoic acid. Yield 94%.

Step (13)
160 ml of thionyl chloride was added to 28.2 g (80 mmol) of E-4- (3,5-difluoro-4′-propylbiphenyl-4-yl) -2,2-difluoro-3-butenoic acid and refluxed for 5 hours. The reaction solution was concentrated under reduced pressure to remove excess thionyl chloride, and the residue was distilled under reduced pressure to obtain E-4- (3,5-difluoro-4′-propylbiphenyl-4-yl) -2,2-difluoro- 30.6 g of 3-butenoic acid chloride was obtained. Yield 95%.

Step (14)
A suspension of 13.4 g (90 mmol) of sodium omadin in bromotrichloromethane (90 ml) was refluxed, and E-4- (3,5-difluoro-4′-propylbiphenyl-4-yl) -2,2- A solution of 24.2 g (60 mmol) of difluoro-3-butenoic acid chloride in bromotrichloromethane (90 ml) was added dropwise over 20 minutes. After further refluxing for 10 minutes, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane) to give E-2- (3,5-difluoro-4′-propylbiphenyl-4-yl)- 20.7 g of 1-bromodifluoromethylethylene was obtained. Yield 85%.

Step (15)
3,4,5-trifluorophenol 8.15 g (55 mmol), potassium carbonate 7.60 g (55 mmol), tetrabutylammonium bromide 0.806 g (2.5 mmol), and E-2- (3,5-difluoro-4′- Propylbiphenyl-4-yl) -1-bromodifluoromethylethylene (21.6 g, 50 mmol) in DMF (100 ml) suspension was stirred at 115 ° C. for 30 minutes, then cooled and added with water and toluene for normal workup. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; heptane) to give 1- (3-4′-propyl-3,5-difluorobiphenyl-4-yl) -1 , 1-Difluoropropenyloxy) -3,4,5-trifluorobenzene (Compound No. 148) was obtained as colorless crystals. Yield 95%.
This compound exhibits a liquid crystal phase, and its transition point is described below.
Cr 47.4 N 51.5 Iso

The measurement data of various spectra strongly supported the structure.
¹ H-NMR (δ ppm CDCl ₃ ): 0.97 (t, J = 7.3 Hz, 3H), 1.67 (m, 2H), 6.65 (dt, J = 6.8, 16.5 Hz, 1H), 6.94 (dd, J = 6.1, 7.7 Hz, 2H), 7.18 (d, 10.1 Hz, 2H), 7.26 (d, 16.5 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H )
¹³ C-NMR (δ ppm CDCl ₃ ): 14.2, 24.8, 38.1, 107.5 (d, J = 5.7 Hz), 107.7 (d, J = 5.7 Hz), 121.7 (t, J = 261.5 Hz), 123.9 (t , J = 7.5 Hz), 124.2 (tt, J = 8.7, 32.2 Hz), 126.8, 129.8, 135.7, 137.6 (t, J = 15.9 Hz), 139.5 (t, J = 15.0 Hz), 143.3, 144.8 (dd , J = 5.8, 10.8 Hz), 152.4 (dd, J = 5.5, 10.6 Hz), 161.0 (d, J = 7.9 Hz), 163.0 (d, J = 8.1 Hz)
¹⁹ F-NMR (δ ppm CDCl ₃ ): -68.1 (d, J = 6.2 Hz), -111.9 (d, J = 10.4 Hz), -133.2 (m), -164.3 (m)
GC-MS (EI), m / z (%): 454 (M ⁺ , 1), 309 (2), 308 (21), 307 (100), 279 (3), 278 (13), 277 (2 ), 259 (3)

Example 9
1- (3-4′-propyl-3,5-difluorobiphenyl-4-yl) -1,1-difluoropropenyloxy) -3,4,5-trifluorobenzene (in formula 16, k = 1, l = m = n = o = 0, R ¹ is an n-propyl group, ring A ¹ is a 1,4-phenylene group, ring A ⁵ is a 3,5-difluoro-1,4-phenylene group, Z ¹ Is a single bond, Y ¹ and Y ² are both hydrogen atoms, and Y ³ , Y ⁴ and R ² are both fluorine atoms (Compound No. 148).

Step (12)
E-4- (3,5-difluoro-4′-propylbiphenyl-4-yl) -2,2-difluoro-3-butenoic acid was produced by a method according to Example 8 step (12).

Step (13 ')
E-4- (3,5-Difluoro-4′-propylbiphenyl-4-yl) -2,2-difluoro-3-butenoic acid 28.2 g (80 mmol), 12.2 g (96 mmol) omadin and 0.49 g (4 mmol) DMAP ) In bromotrichloromethane (160 ml) was ice-cooled, and a solution of DCC 19.8 g (96 mmol) in bromotrichloromethane (20 ml) was added dropwise over 10 minutes. The mixture was further reacted for 24 hours at the same temperature, and then stirred at 70 ° C. for 30 minutes. After cooling the reaction solution to room temperature, insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the residue was distilled under reduced pressure to obtain E-2- (3,5-difluoro-4′-propylbiphenyl-4-yl)- 20.7 g of 1-bromodifluoromethylethylene was obtained. Yield 85%.

Step (15)
1- (3-4′-propyl-3,5-difluorobiphenyl-4-yl) -1,1-difluoropropenyloxy) -3,4, in a manner similar to Example 8 step (15). 23.7 g of 5-trifluorobenzene (Compound No. 148) was obtained as colorless crystals. Yield 95%.

  In accordance with the methods shown in Examples 1 to 4 and 7, for example, the following difluoromethyl ether derivatives (Compound Nos. 41 to 131) can be preferably produced. The compounds of Examples 1 to 4 and 7 are also shown.

  According to the methods shown in Examples 5 and 6 and Example 8 above, for example, the following compounds (compound numbers 132 to 182) having the following 1,1-difluoro-2-propenyloxy group as a linking group can be preferably produced. . The compounds of Examples 5, 6, and 8 are also shown.

Claims (9)

A process for producing a difluoromethyleneoxy derivative represented by formula 12, wherein an ethylenedifluoroacetate derivative represented by formula 11 having five steps of steps (12) to (16) is used as a starting material.
Step (12): Ethylene difluoroacetate represented by Formula 11 is hydrolyzed to produce a carboxylic acid represented by Formula 13.
Step (13): The carboxylic acid represented by Formula 13 is reacted with thionyl chloride to produce the acid chloride represented by Formula 14.
Step (14): The acid chloride represented by formula 14 is reacted with N-hydroxypyridinethione sodium salt and bromotrichloromethane to produce a bromodifluoromethyl derivative represented by formula 15.
Step (15): the presence of a base, bromo difluoromethyl derivative of formula 15, is reacted with a phenol compound represented by the formula P, and produce ethylene difluoromethyleneoxy derivative of formula 16.
Step (16): The ethylenedifluoromethyleneoxy derivative represented by Formula 16 is reduced with hydrogen to produce the difluoromethyleneoxy derivative represented by Formula 12.

In the formula, R ¹ and R ² are each independently a hydrogen atom, a halogen atom, a cyano group, or an alkyl group having 1 to 20 carbon atoms, and at least one —CH ₂ — in the alkyl group is —O—. , -S-, -CH = CH-, or -C≡C-, but -O- is not consecutive, and at least one hydrogen atom in the alkyl group is replaced by a fluorine atom. R ³ is a monovalent organic group or inorganic group; Ring A ¹ , Ring A ² , Ring A ³ , A ⁴ and Ring A ⁵ are each independently at least one —CH ₂ —. , -O-, -S-, a 1,4-cyclohexylene group optionally substituted with at least one ═CH- with ═N—, or at least on the ring One hydrogen atom is a fluorine atom, cyano Or an alkyl replaced by or 1,4-phenylene group with a group having 1 to 10 carbon ^{atoms; Z 1, Z 2, Z} 3, and ^{Z 4} are each independently a single bond or a 1 to 4 carbon atoms Wherein at least one —CH ₂ — in the alkylene group may be replaced by —O—, —S—, —CH═CH—, or —C≡C—, And at least one hydrogen atom in the alkylene group may be replaced with a fluorine atom; Y ¹ , Y ² , Y ³ , and Y ⁴ are each independently a hydrogen atom, a halogen atom, cyano Or an alkyl group having 1 to 10 carbon atoms; k, l, m, and n are each independently 0 or 1, and o is an integer of 0 to 10. In the series of steps (12) to (16) according to claim 1, the step (13 ′) is provided instead of the steps (13) and (14), and four steps are combined, that is, (12) (13 ′). (15) A process for producing a difluoromethyleneoxy derivative represented by the formula 12 according to claim 1, which comprises (16).
Step (13 ′): The carboxylic acid represented by Formula 13 is reacted with N-hydroxypyridinethione and bromotrichloromethane in the presence of N, N′-dicyclohexylcarbodiimide and 4-dimethylaminopyridine to obtain Formula 15 The represented bromodifluoromethyl derivative is prepared.

After the steps described (12) to (14) in claim 1, step (17) and (18) have, together with five of the method for manufacturing difluoromethyleneoxy derivative according to claim 1 having a step.
Step (17): The bromodifluoromethyl derivative represented by Formula 15 is reduced with hydrogen to produce a cyclohexyl bromodifluoromethylalkane derivative represented by Formula 17.
Step (18): In the presence of a base, the cyclohexyl bromodifluoromethylalkane derivative represented by the formula 17 is reacted with the phenol compound represented by the formula P according to the step ( 15 ) of claim 1 to obtain The difluoromethyleneoxy derivative is produced.

In the formula, R ¹ is a hydrogen atom, a halogen atom, a cyano group, or an alkyl group having 1 to 20 carbon atoms, and at least one —CH ₂ — in the alkyl group is —O—, —S—, —CH. ═CH— or —C≡C— may be substituted, but —O— is not consecutive, and at least one hydrogen atom in the alkyl group may be substituted with a fluorine atom ; ring A ¹ , Ring A ² and ring A ⁵ are each independently a 1,4-cyclohexylene group in which at least one —CH ₂ — may be replaced by —O— or —S—, and at least one ═CH— 1,4-phenylene group which may be replaced by ═N—, or 1,4-phenylene group in which at least one hydrogen atom on the ring may be replaced by a fluorine atom, a cyano group or an alkyl group having 1 to 10 carbon atoms A phenylene group; ¹ and ^{Z 2} are each independently a single bond or an alkylene group having 1 to 4 carbon atoms, at least one -CH ₂ in the alkylene group - is -O -, - S -, - CH = CH-, Alternatively, -C≡C- may be substituted, but -O- is not continuous, and at least one hydrogen atom in the alkylene group may be replaced by a fluorine atom; k and l are each independently And 0 is an integer of 0-10. In the series of steps (12) to (14) (17) (18) according to claim 3, the step (13 ′) according to claim 2 is provided instead of steps (13) and (14), The method for producing a difluoromethyleneoxy derivative represented by the formula 12 according to claim 1, comprising four steps, that is, (12) (13 ') (17) (18). After the steps (19) to (22), the difluoromethyleneoxy derivative represented by the formula 12 described in claim 1 has the step (18) according to claim 3 and has five steps in total. Production method.
Step (19): Ethylene difluoroacetate represented by Formula 11 is reduced with hydrogen to produce an ethyl difluoroacetate derivative represented by Formula 18.
Step (20): The ethyldifluoroacetic acid ester derivative represented by Formula 18 is hydrolyzed to produce a carboxylic acid derivative represented by Formula 19.
Step (21): The carboxylic acid derivative represented by Formula 19 is reacted with thionyl chloride to produce an acid chloride represented by Formula 20.
Step (22): The acid chloride represented by formula 20 is reacted with N-hydroxypyridinethione sodium salt and bromotrichloromethane to produce a cyclohexyl bromodifluoromethane derivative represented by formula 17.

In the formula, R ¹ is a hydrogen atom, a halogen atom, a cyano group, or an alkyl group having 1 to 20 carbon atoms, and at least one —CH ₂ — in the alkyl group is —O—, —S—, —CH. = CH-, or it may be replaced by -C≡C-, but never -O- is continuous, at least one hydrogen atom may be replaced by fluorine atom in the alkyl group; R ³ is A monovalent organic group or an inorganic group; ring A ¹ , ring A ^2, and ring A ⁵ may each independently have at least one —CH ₂ — replaced by —O— or —S—. 1,4-cyclohexylene group, 1,4-phenylene group in which at least one ═CH— may be replaced by ═N—, or at least one hydrogen atom on the ring is a fluorine atom, cyano group or carbon number 1 Replaced with -10 alkyl groups Each of Z ¹ and Z ² independently represents a single bond or an alkylene group having 1 to 4 carbon atoms, and at least one —CH ₂ — in the alkylene group. May be replaced by —O—, —S—, —CH═CH—, or —C≡C—, but —O— is not continuous, and at least one hydrogen atom in the alkylene group is fluorine. May be replaced by an atom; k and l are each independently 0 or 1, and o is an integer from 0 to 10; In the series of steps (19) to (22) (18) according to claim 5, the step (21 ′) is provided instead of the steps (21) and (22), and a total of four steps, that is, (19) (20) The method for producing a difluoromethyleneoxy derivative represented by the formula 12 according to claim 1, which has (21 ′) (18).
Step (21 ′): The carboxylic acid derivative represented by the formula 19 is reacted with N-hydroxypyridinethione and bromotrichloromethane in the presence of N, N′-dicyclohexylcarbodiimide and 4-dimethylaminopyridine to obtain the formula 17 A bromodifluoromethyl derivative represented by the formula:

A process for producing an ethylenedifluoromethyleneoxy derivative represented by the formula 16 according to claim 1, comprising four steps (12) to (15) according to claim 1. In the series of steps (12) to (15) according to claim 7, the step (13 ′) according to claim 2 is provided instead of the steps (13) and (14), and three steps, namely ( 12) A process for producing an ethylenedifluoromethyleneoxy derivative represented by the formula 16 according to claim 1, which has (13 ′) (15). In formulas 11 to 20 according to claims 1 to 6, R ¹ is a linear alkyl group having 2 to 5 carbon atoms; R ² is a hydrogen atom or a fluorine atom; R ³ is methyl or ethyl. Yes; ring A ¹ is a trans-1,4-cyclohexylene group; k = 1, l = 0; Y ¹ and Y ² are hydrogen atoms; Y ³ and Y ⁴ are each independently hydrogen The method for producing a difluoromethyleneoxy derivative according to any one of claims 1 to 6, which is an atom or a fluorine atom; and m = n = 0.