JPH0959221A - Syn(2s,3r)type and anti(2s,3s)type 3-methoxyalkane derivatives and production thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compounds each exhibiting an antiferrodielectric liquid crystal phase at room temperature, easy in a switching operation at room temperature, and useful as a precursor for antiferrodielectric liquid crystal compounds used as raw materials for large face plate liquid crystal displays. SOLUTION: A compound of formula I (m is 3-6), or a compound of formula II. For example, syn-(2S,3R)-2-(4-hydroxybenzoyloxy)-7-ethoxy-3-methoxy-1,1,1- trifluoroheptane, and anti-(2S,3S)-2-(4hydroxybenzoyloxy)-7-ethoxy-3-methoxy-1,1,1- trifluoroheptane. The compounds of formulas I and II are obtained by reducing a compound of formula III with a metal hydride in an organic solvent, reacting the reaction product with methyl iodide, reducing the obtained O-methylated derivative with hydrogen in the presence of palladium-carbon catalyst in a solvent, and subsequently separating the obtained diastereomers from each other by means of silica gel chromatography.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel syn compound (2S, 3R) useful as a precursor of an antiferroelectric liquid crystal compound which is a material of, for example, a large screen liquid crystal display.
The present invention relates to the provision of a type and anti body (2S, 3S) type 3-methoxyalkane derivative and a method for producing the same.

[0002]

2. Description of the Related Art (R) -2- (4) as a precursor of an antiferroelectric liquid crystal compound which is a material of a large screen liquid crystal display etc.
-Hydroxybenzoyloxy) -1,1,1-trifluoroalkanes are known. However, since the antiferroelectric liquid crystal compound derived from this compound has an antiferroelectric liquid crystal phase existing at a temperature higher than normal temperature, it is inferior in room temperature workability and has not been put to practical use as a large screen liquid crystal display material. There is a demand for the appearance of antiferroelectric liquid crystal compounds which can be easily switched at room temperature.

[0003]

Therefore, as a result of intensive studies on novel optically active compounds which are useful as precursors of antiferroelectric liquid crystal compounds which can be easily switched at room temperature, the present inventors have found that The inventors of the present invention have invented a compound of the present invention and also found a method for efficiently producing the compound and completed the present invention.

[0004]

SUMMARY OF THE INVENTION The present invention is a novel compound represented by the formula (1)

[0005]

[Chemical formula 4]

(Wherein m represents an integer of 3 to 6) syn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoro Terminal ethoxyalkane [syn form (2
It is also referred to as S, 3R) type 3-methoxyalkane derivative or as the compound of the present invention. ], And Formula (2)

[0007]

[Chemical formula 5]

[Wherein, m is the same as the formula (1)] anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoro terminal Ethoxyalkane [hereinafter referred to as anti form (2S,
3S) -type 3-methoxyalkane derivatives, also referred to as compounds of the present invention. ].

Further, according to the present invention, there is provided a method of efficiently producing the above-mentioned compound, ie, in an organic solvent, a compound of the formula (3)

[0010]

[Chemical formula 6]

[Wherein, m is the same as the above] (S)
-2- (4-benzyloxybenzoyloxy) -1,
1,1-trifluoro-terminated ethoxyalkane [hereinafter referred to as a starting compound. Is reduced using a metal hydride, and then the reaction product is reacted with methyl iodide to obtain an O-methylated derivative, which is then reacted with a palladium / carbon catalyst in a solvent. Method for producing the compound of the present invention represented by the formula (1) and / or the formula (2) by reducing the mixture with hydrogen in the presence and separating the obtained diastereomer mixture by silica gel column chromatography It is about

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION

[Inventive compounds: syn isomer (2S, 3R) type 3-methoxyalkane derivative and anti isomer (2S, 3S) type 3
-Methoxyalkane Derivative] The compound of the present invention is as shown by the formula (1) and the formula (2), wherein m is 3 to 6
It is. For methylene groups where m is less than 3, the compounds at the starting point have low boiling points and are difficult to handle, and those in which m exceeds 6 are difficult to form. Preferred methylene groups are 1,
3-trimethylene group, 1,4-tetramethylene group, 1,
Examples thereof include 5-pentamethylene and 1,6-hexamethylene groups. A preferred specific example of the syn-form (2S, 3R) type 3-methoxyalkane derivative represented by the formula (1) as a compound of the present invention is disclosed as syn- (2S, 3)
R) -2- (4-hydroxybenzoyloxy) -6-
Ethoxy-3-methoxy-1,1,1-trifluorohexane, syn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-
1,1,1-trifluoroheptane, syn- (2S,
3R) -2- (4-hydroxybenzoyloxy) -8
-Ethoxy-3-methoxy-1,1,1-trifluorooctanone and syn- (2S, 3R) -2- (4-)
And hydroxybenzoyloxy) -9-ethoxy-3-methoxy-1,1,1-trifluorononane and the like.

Compounds of the present invention represented by formula (2) a
The preferred specific examples of nti body (2S, 3S) type 3-methoxyalkane derivatives are disclosed in anti- (2S, 3).
S) -2- (4-hydroxybenzoyloxy) -6-
Ethoxy-3-methoxy-1,1,1-trifluorohexane, anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoro Heptane, anti-(2
S, 3S) -2- (4-hydroxybenzoyloxy)
-8-Ethoxy-3-methoxy-1,1,1-trifluorooctane and anti- (2S, 3S) -2-
(4-hydroxybenzoyloxy) -9-ethoxy-
3-methoxy-1,1,1-trifluorononane etc. are mentioned.

[Raw material compound: (S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-terminated ethoxyalkanone-3] The raw material compound is represented by the above-mentioned formula (3). The (S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-terminated ethoxyalkanone-3 which is a new compound. When the above compounds are described concretely, in the formula, the methylene group represented by m corresponds to m of the formula (1), and as a specific example of a suitable compound, (S) -2- (4-benzyloxybenzoyl) Oxy) -6-ethoxy-1,1,1-trifluorohexanone-3, (S) -2- (4-benzyloxybenzoyloxy) -7-ethoxy-1,1,1-trifluoroheptanone-3 , (S) -2- (4-benzyloxybenzoyloxy) -8-ethoxy-1,1,1-
Trifluorooctanone-3 and (S) -2- (4-)
Benzyloxybenzoyloxy) -9-ethoxy-
1,1,1-trifluorononanone-3 etc. is mentioned.

(Method of producing the starting compound) The following (S)-
A method of producing a starting compound from N- (2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine (hereinafter referred to as a starting material compound) through an original first stage reaction to an original fourth stage reaction Show. Although the starting material compounds are not novel compounds, they have to be produced because they are not commercially available. The following Reference Example 1 shows a preparation example of the starting material compound.

(First Stage First Reaction) The reaction formula of the first stage first reaction is represented by the formula (4)

[0017]

[Chemical formula 7]

[Wherein, m is the same as in formula (1). 1 mole of the terminal ethoxyalkylmagnesium bromide is added to the carbonyl group in the starting material compound, and the hydroxyl group of the starting material compound is reacted with 1 mole of the Grignard reagent to react with the reaction product. Terminal ethoxy alkanes are formed. The reaction in the formula (4) is preferably carried out by dropping a solution of a starting material compound in an organic solvent to a Grignard reagent. Examples of the organic solvent include ether solvents such as diethyl ether, THF, diglyme and the like. The amount of the organic solvent used to dissolve the starting material compound is 0.5 to 2 with respect to 1 mol of the starting material compound
A liter is preferred. In the reaction of the formula (4), the feed ratio of the starting material compound to the Grignard reagent is preferably 2 to 3 moles of the Grignard reagent per 1 mole of the starting material compound. The feed rate of the starting material compound to the reaction system is preferably such that 1 mole of the starting material compound is added dropwise over 100 to 250 minutes. As for the reaction temperature of Formula (4), -10-10 degreeC is preferable. After completion of the addition of the starting material compound solution, stirring is continued for 2 hours to complete the reaction and produce a reaction product.

The above Grignard reagent is not commercially available, and can be produced in the following three steps. The outline of the method for producing a Grignard reagent having m = 4 and 5 will be described below as an example.

First step The first step is represented by a reaction formula:

[0021]

[Image 8]

[Wherein, m is the same as the formula (1)], for example, tetrahydrofuran 1 corresponding to m = 4
Mix 1 mole of tetrahydropyran corresponding to 1 mole or m = 5, 1.1 mole of ethyl alcohol and 0.05 mole of p-toluenesulfonic acid monohydrate and heat to 80 ° C.
After refluxing for 8 hours, the solution is concentrated under reduced pressure, and the resulting residue is added to water 2
After adding 1 liter, extract with ether, add anhydrous magnesium sulfate to the extract to remove water, remove the solvent under reduced pressure, and remove 4-ethoxybutyl alcohol which is a colorless and transparent liquid terminal ethoxy alcohol, or 5 Obtain ethoxypentyl alcohol in 90% yield.

Step 2 The step 2 is expressed by the following equation (6) C ₂ H ₅ O (CH ₂ ) _m OH + P (C ₆ H ₅ ) ₃ + Br ₂ → (terminal ethoxy alkyl alcohol) C ₂ H _The terminal ethoxy alcohol 4-ethoxybutyl alcohol obtained in the first step, as shown by ₅ O (CH ₂ ) _m Br + HBr + P (C ₆ H ₅ ) ₃ O ((6) (terminal ethoxyalkyl bromide) Alternatively, a solution of 1 mole each of 5-ethoxypentyl alcohol dissolved in 3 liters of methylene chloride is adjusted to 0 ° C. Then 1 mole of triphenylphosphine and 1,00 methylene chloride
1 mol of bromine and 50 methylene chloride in a solution to which 0 ml was added
Add a solution containing 0 ml, and stir at 10 ° C.
The reaction solution is added dropwise over 0 minutes, and after completion of the dropwise addition, stirring is continued for 1 hour to complete the reaction. Then raise the temperature to room temperature,
Stirring is continued for one hour to form triphenylphosphine oxide microcrystals. It is then concentrated to distill off methylene chloride and small bromide, and the resulting sludge is
Add 8 L of hexane, dissolve, cool and crystallize, remove most triphenylphosphine oxide which is white needle crystals by filtration, concentrate the filtrate and obtain syrupy residue. The residue is then purified by silica gel column chromatography to give 4-ethoxybutyl bromide or 5 which is a colorless and transparent liquid terminal ethoxyalkyl bromide.
The ethoxypentyl bromide is obtained in a yield of 80%.

Step 3 The step 3 is expressed by the following equation (7) C₂H _FiveO (CH₂)_mBr + 1.1 Mg → C₂H_FiveO (CH₂)_mAs shown by MgBr (terminal ethoxyalkyl bromide) (Grignard reagent) (7), a nitrogen-substituted reactor was used to
1.1 mol of sodium and 200 ml of dry diethyl ether
Then add 1 millimole of iodine and a reddish brown solution
Stir until colorless. Then the end obtained in the second step
End ethoxyalkyl bromide 4-ethoxybutyl
Each of bromide or 5-ethoxypentyl bromide was added at 0.
Add 1 mole and stir until reflux occurs. Then the rest
0.9 mol of 4-ethoxybutyl bromide, or 5-
0.9 mol of toxyl bromide and dry diethyl ether
500ml each into the dropping funnel and reflux will continue
The solution was added dropwise, and after completion of the addition, it was refluxed for 1 hour to complete the reaction.
Ru. Then withdraw the reaction solution with a syringe and at the bottom of the reaction vessel
Diethyl dry lumps of unreacted metallurgical magnesium
Wash with 300 ml of ether, 0.8 mol / liter
4-ethoxybutyl magnesium bromide or 5-
Ether solution of methoxypentyl magnesium bromide
The Grignard reagent which is (yield 80%) is obtained.

(Early Second Stage Reaction) An example of the reaction formula of the original second stage reaction is shown by the equation (8) when hydrochloric acid is used as a mineral acid.

[0026]

Embedded image

[Wherein, m is the same as in formula (1). The (S) hydroxyketone is formed by hydrolyzing 1 mole of the reaction product obtained in the first step reaction with 3 gram equivalent of mineral acid. As mineral acids, hydrochloric acid, sulfuric acid,
Nitric acid etc. are mentioned. The amount of mineral acid used is starting material compound 1
3 to 4 gram equivalents to mole are preferred. The concentration of mineral acid is preferably 1 to 5 N. In the reaction of the formula (8), it is preferable to add an aqueous solution of mineral acid dropwise to the reaction product solution obtained in the original first stage reaction. The dropping time of the aqueous mineral acid solution to the reaction system is preferably 30 to 60 minutes per mole of the starting material compound. The hydrolysis reaction is preferably at normal temperature. After the addition of the mineral acid is completed, the hydrolysis reaction is completed by maintaining the stirring for 20 minutes.

After completion of the hydrolysis reaction, the solution is adjusted to pH 8 with 20% aqueous sodium hydrogen carbonate solution, and then extracted with ether,
The extract is washed with water, anhydrous magnesium sulfate is added to remove water, and the solvent is evaporated under reduced pressure to obtain a syrupy residue. The residue is purified by silica gel column chromatography to obtain a colorless and transparent liquid product. ¹ H NMR spectrum, ¹⁹ F NMR spectrum of this product,
As a result of measuring 1 R absorption spectrum and MS spectrum, it is confirmed that the product is 1-hydroxy-2,2,2-trifluoroethyl terminal ethoxyalkyl ketone. Further, when the above-mentioned product is subjected to optically active gas chromatography, only one optically active peak is obtained, so that the configuration of the asymmetric carbon atom at the 2-position of the starting material compound does not change before and after the reaction. As optical inversion does not occur, the product is (S) -1-hydroxy-
It is confirmed that the 2,2,2-trifluoroethyl-terminated ethoxyalkyl ketone [(S) -hydroxyketone] is used.

The original third stage reaction can be expressed by the following equation (9)

[0030]

[Image 10]

[Wherein, m is the same as in formula (1), and M is an alkali metal. In organic solvents,
The hydroxyl group in the (S) -form hydroxyketone reacts with an alkali metal hydride to form a reaction product 1 which is an alkali metal alcoholate. Examples of the organic solvent include diethyl ether, n-hexane, THF and methylene chloride. The amount used is (S) hydroxyketone 1
1 to 5 L is preferred, based on moles. Examples of the alkali metal hydride include lithium hydride, sodium hydride and potassium hydride. Since commercially available alkali metal hydrides are usually oily, they are preferably washed with n-hexane or the like, purified, dried and then suspended in an organic solvent. The alkali metal hydride is preferably 1.0 to 1.2 mol based on 1 mol of the (S) hydroxyketone.

In the method of mixing the (S) hydroxyketone and the alkali metal hydride, it is preferable to add an organic solvent solution of the starting compound dropwise to the organic solvent suspension of the alkali metal hydride. The use ratio of the organic solvent is preferably proportional to the volume ratio of alkali metal hydride / (S) hydroxyketone = 1/9. The feed rate of the (S) -form hydroxyketone to the reaction system is preferably such that 1 mol of the starting compound is dropped over a period of 30 to 90 minutes. Reaction temperature is -10 to 1
0 ° C. is preferred. (S) After completion of dropwise addition of the hydroxyketone, the temperature is raised to room temperature while stirring, and the stirring is continued for about 60 minutes to complete the reaction, and the reaction product solution-
Get one.

(Fourth Stage Reaction) The original fourth stage reaction can be expressed by the following equation (10)

[0034]

[Image 11]

[Wherein, m is the same as in formula (1), and M is an alkali metal. In the organic solvent, the alkali metal of reaction product-1 is reacted with the chlorine of 4-benzyloxy benzoyl chloride to form a starting compound.
As the organic solvent, the same organic solvent as used in the original third step reaction can be used.
Therefore, in the reaction product-1 solution obtained in the original third step reaction, 4
The reaction can be carried out by direct addition of an organic solvent solution of benzyloxybenzoyl chloride. The feed ratio of 4-benzyloxybenzoyl chloride to the reaction system is, based on 1 mole of (S) -form hydroxyketone,
1.1 to 1.3 mol is preferable. 4-benzyloxy benzoyl chloride is preferably dissolved in an organic solvent and supplied to the reaction system. The preferred mixing ratio of the organic solvent is 0.5 per mole of 4-benzyloxybenzoyl chloride
-2 L is preferable. The feed rate of 4-benzyloxybenzoyl chloride to the reaction system is preferably 1 to 3 hours based on 1 mole of (S) hydroxyketone. The reaction temperature is preferably -10 to 10 ° C, particularly preferably around 0 ° C. After the addition of the 4-benzyloxybenzoyl chloride solution is completed, the temperature is raised to room temperature and then the stirring is continued for 150 minutes to complete the reaction.

After completion of the reaction, excess alkali metal hydride or 4-benzyloxybenzoyl chloride is converted to alkali chloride or 4-benzyloxybenzoate using, for example, 1N hydrochloric acid at room temperature, and then 5% sodium carbonate The pH is adjusted to 8 with an aqueous solution, 4-benzyloxy benzoate is made soluble in water, then it is extracted with ether, and the extract is washed with water, anhydrous magnesium sulfate is added to remove water, and the solvent is removed. The solution is concentrated under reduced pressure, and the remaining pale yellow syrupy residue is purified by silica gel column chromatography or the like, and the purified solution is decolorized with activated carbon or the like, and then concentrated under reduced pressure to obtain a colorless and transparent liquid starting material compound.

The spectrum analysis of the starting compound was conducted, and it was confirmed that the starting compound was 2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-terminated ethoxyalkanone-3. Ru. The hydroxyl group bonded to the asymmetric carbon atom at position 1 of the (S) -1-hydroxy-2,2,2-trifluoroethyl-terminated ethoxyalkyl ketone is reacted with an alkali metal hydride,
Even if it is converted to an alkali metal alcoholate and then reacted with 4-benzyloxy benzoyl chloride and substituted to a 4-benzyloxy benzoyloxy group, the asymmetric center at the asymmetric carbon atom at position 1 does not cause optical inversion (S ) It is confirmed that it is the arrangement, and the starting compound is (S) -2- (4)
It can be confirmed that it is -benzyloxybenzoyloxy) -1,1,1-trifluoro-terminated ethoxyalkanone-3.

[Inventive compound: syn- (2S, 3R)
-2- (4-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoro-terminated ethoxyalkane and the compound of the present invention: anti- (2S, 3S) -2-
(4-hydroxybenzoyloxy) -3-methoxy-
Process for producing 1,1,1-trifluoro-terminated ethoxyalkanes. The compound of the present invention is as described above. First, the starting compound represented by the formula (3) is reduced with a metal hydride in an organic solvent (first stage reaction), and then the reaction product and methyl iodide are The reaction is carried out to obtain an O-methylated derivative (second step reaction). The O-methyl derivative is then reduced with hydrogen in the presence of a palladium / carbon catalyst (third stage reaction),
The compound of the present invention can be produced by fractionating the obtained diastereomeric mixture by silica gel column chromatography (fourth step). Hereinafter, the method for producing the compound of the present invention will be described in more detail.

(First Step Process) The reaction formula for the case where the first-step reaction is carried out, for example, using a stabilized sodium borohydride aqueous solution stabilized as a metal hydride is shown by the formula (1
1)

[0040]

[Chemical formula 12]

[Wherein, m is the same as the formula (1)], which is obtained by the original fourth step reaction in an organic solvent (S) -2-
(4-benzyloxybenzoyloxy) -1,1,1
-A reaction product is produced via a diastereoscopic attack of the hydride on the carbonyl carbon of the starting compound by reducing the starting compound which is trifluoro-terminated ethoxyalkanone-3 using a metal hydride. I can do it. Suitable metal hydrides include sodium borohydride and diisobutylaluminum hydride and the like. In the case of sodium borohydride, methanol (the amount of methanol used is sodium borohydride) in a 5% aqueous solution of sodium hydride (the amount of sodium hydroxide used is 5 times the molar amount with respect to 1 mol of sodium borohydride) Stabilized sodium borohydride aqueous solution is used which is prepared by adding 1 liter per mole) and then adding 1 mole of sodium borohydride. In aqueous sodium hydroxide solution, sodium borohydride becomes stable and withstands long-term storage. Furthermore, methanol dissolves sodium borohydride.

The feed ratio of the starting compound to the metal hydride is preferably 1.0 to 1.2 gram equivalent (based on hydrogen atom, hereinafter the same) with respect to 1 mole of the starting compound. If it is less than 1.0 gram equivalent, the yield of the reaction product may be reduced,
It is not economical if it exceeds 1.2 gram equivalent. Examples of the organic solvent include diethyl ether, THF, n-hexane, toluene and methanol. The amount used is 1.0 to 2.5 L based on 1 mol of the starting compound
Is preferred. If it is less than 1.0 L, the ester moiety may be cleaved to lower the yield of the reaction product, and if it exceeds 2.5 L, it is not economical. In the method of mixing the starting compound and the metal hydride, it is preferable to add an organic solvent solution of the metal hydride dropwise to the organic solvent solution of the starting compound. If the reverse feeding method is carried out, the ester part of the raw material compound may be cleaved, leading to a decrease in the yield of the reaction product.

For example, when a stabilized aqueous solution of sodium borohydride is used as the metal hydride, about 1.6 L of an organic solvent is used with respect to 1 mol of the starting compound.
The remaining organic solvent is preferably methanol in stabilized aqueous sodium borohydride solution. Also,
When diisobutylaluminum hydride is used as the metal hydride, isobutylaluminum hydride 1.0 is added to a solution in which 1 mol of the raw material compound and 0.9 L of the organic solvent are mixed.
It is preferable to add a solution of 1.2 g equivalent and 0.9 L of the organic solvent dropwise. The feed time of the metal hydride solution into the starting compound solution was 3 per 1 mol of the starting compound.
0 to 90 minutes are preferred. If it is less than 30 minutes, removal of the heat of reaction becomes difficult, the ester part of the raw material compound is cleaved, and the yield of the reaction product may be reduced. If it exceeds 90 minutes, it is not economical. The reaction temperature of the raw material compound and the metal hydride is preferably -10 to 10 ° C. If the temperature is lower than -10 ° C, it is not economical. If the temperature exceeds 10 ° C, the control of the reaction temperature becomes difficult, and the yield of the reaction product may be reduced. After the addition of the metal hydride solution is completed, the temperature is raised to room temperature,
Subsequently, stirring is maintained for about 90 minutes to complete the reaction,
The reaction product is obtained.

[Confirmation that the reaction product is a mixture of diastereomers consisting of syn (2S, 3R) and anti (2S, 3S) forms] As is apparent from the later-identified Identification Examples 1 and 3. Then, 1 part of the reaction product obtained in the above-mentioned Identification Examples 1 and 3 was taken, and 3 N hydrochloric acid and methanol were added to a concentrated reaction product solution obtained by evaporating most of the ether under reduced pressure, Then, it was refluxed for 6 hours to carry out a hydrolysis reaction. After completion of the reaction, the reaction solution is cooled to room temperature and then extracted with ether, and the extract is washed with a 20% aqueous sodium hydrogen carbonate solution and then with water, then anhydrous magnesium sulfate is added to remove water, and the solvent is removed by concentration under reduced pressure. Evaporate to obtain a syrupy residue. The residue is purified by silica gel column chromatography to obtain a colorless and transparent liquid product. As a result of measuring various spectra of this product, it is confirmed that the product is 1,1,1-trifluoro-terminated ethoxyalkane-2,3-diol. In addition, since the ¹⁹ F NMR spectrum has two peaks and the first peak / second peak have a predetermined ratio,
The product is identified to be a diastereomeric mixture of 1,1,1-trifluoroterminated ethoxyalkane-2,3-diols.

Then, 2,2-dimethoxypropane and paratoluenesulfonic acid monohydrate are added to the product obtained above, and the mixture is refluxed at 95 ° C. for 5 hours to carry out an acetal exchange reaction for purification and clear and colorless. A liquid compound is obtained. The result of measuring various spectra of this compound is a diastereomer consisting of 2,2-dimethyl-4- (terminal ethoxyalkyl) -5-trifluoromethyl-1,3-dioxolane (hereinafter referred to as 1,3-dioxolane derivative) It is confirmed that it is a mixture. Also, according to the position and area ratio of methyl groups in the ¹ H NMR spectrum, the compound is trans-
2,2-dimethyl-4- (terminal ethoxyalkyl) -5
Trifluoromethyl-1,3-dioxolane (hereinafter referred to as
tran form 1,3-dioxolane derivative) and cis-2,2-dimethyl-4- (terminal ethoxyalkyl) -5-trifluoromethyl-1,3-dioxolane (hereinafter referred to as cis form 1,3-dioxolane derivative) )
It turns out that it is a mixture of diastereomers consisting of

Thus, the ¹⁹ F NMR of the compound corresponding to the area ratio of the trans 1,3-dioxolane derivative
The first peak of the spectrum is the tran 1,3-dioxolane derivative, and the second peak of the ¹⁹ F NMR spectrum of the compound corresponding to the area ratio of the cis 1,3-dioxolane derivative is the cis 1,3-dioxolane derivative It is confirmed that there is. Furthermore, ¹⁹ FNM of the product is consistent with the area ratio of the trans 1,3-dioxolane derivative
The first peak of the R spectrum is the syn-1,1,1-trifluoro-terminated ethoxyalkane 2,3-diol, which is the ¹⁹ F NMR spectrum of the product consistent with the area ratio of the cis 1,3-dioxolane derivative 2 peaks are a
It is confirmed that it is nti-1,1,1-trifluoro-terminated ethoxyalkane 2,3-diol.

Also, since the starting compound (S) -terminal ethoxyalkanone-3 is obtained by reduction with a metal hydride and this is hydrolyzed, the asymmetric center of the asymmetric carbon atom at position 2 is obtained. The products are syn- (2S, 3R) -1,1,1-trifluoroterminated ethoxyalkane-2,3-diol and anti- (2S, 3S) -1 because the (2S) configuration is unchanged. It is confirmed that the mixture is a mixture of diastereomers consisting of 1,1,1-trifluoro-terminated ethoxyalkane-2,3-diol. Therefore, since the absolute configuration of the asymmetric carbon atom at the 2nd and 3rd positions is not changed before and after the hydrolysis reaction, the reaction product is a dia consisting of syn (2S, 3R) type and anti (2S, 3S) type It is confirmed to be a stereomer mixture. The reaction product may be syn (2S, 3R) / anti (2S, 3S) = 70 depending on the type of metal hydride.
A mixture of diastereomers of -40 / 30-60 (area ratio) is obtained.

(Second-step reaction) The second-step reaction is represented by the equation (12).

[0049]

Embedded image

[Wherein, m is the same as the formula (1)], and sodium boron in the reaction product obtained in the first step reaction reacts with iodine in methyl iodide to give O
-Produce a methylated derivative. As for methyl iodide, 1.0-1.1 mol is preferable with respect to 1 mol of raw material compounds. 1.
If it is less than 0 mol, the yield of the O-methylated derivative is lowered,
It is not economical if it exceeds 1.1 mol. In the reaction, it is preferable to add a solution of methyl iodide in an organic solvent dropwise to the reaction product solution. When the reverse dropping is performed, the heat of reaction is increased, and the yield of the O-methylated derivative may be decreased.

The organic solvent is not particularly restricted but includes, for example, diethyl ether, n-hexane, toluene and THF, with diethyl ether being particularly preferred. The mixing ratio of the organic solvent is preferably 0.5 to 2 L per 1 mol of methyl iodide, and particularly preferably 1
It is ~ 1.5L. If the amount is less than 0.5 L, removal of the heat of reaction becomes difficult, the ester portion may be cleaved, and the yield of the O-methylated derivative may be decreased. If it exceeds 2 L, it is not economical. The feed rate of methyl iodide to the reaction system is preferably 1 to 2 hours based on 1 mole of the starting compound. If it is less than 1 hour, control of reaction temperature will become difficult, an ester part may also be cut | disconnected, the yield fall of O-methylated derivative may be caused, and it can not be said that it is not economical if it exceeds 2 hours.

The reaction temperature is preferably -10 to 10 ° C, particularly preferably around 0 ° C. If it is less than -10 ° C, it is not economical, but if it exceeds 10 ° C, control of the reaction temperature becomes difficult, and the ester part may be cleaved, which may lead to a decrease in the yield of the O-methylated derivative. After the dropwise addition of the organic solvent solution of methyl iodide is completed, the temperature is raised to room temperature while stirring, and then the reaction is completed by keeping stirring for about 2 hours at room temperature. After completion of the reaction, a 5% aqueous sodium hydrogen carbonate solution is added for neutralization, followed by concentration, and after distilling off the solvent, a saturated aqueous sodium thiosulfate solution is added, and then extraction with ether is carried out.
Anhydrous magnesium sulfate is added to the extract to remove water, and then concentrated to obtain a syrupy residue. The residue is purified by silica gel column chromatography to obtain a colorless and transparent liquid O-methylated derivative.

(Third Stage Reaction) The third stage reaction is represented by the following equation (13)

[0054]

[Image 14]

[Wherein, m is the same as the formula (1)], and in a solvent, the O-methylated derivative obtained in the second step is reacted with hydrogen in the presence of a palladium / carbon catalyst Toluene is removed by reduction to give syn compound (2S, 3R)
Type 3-methoxyalkane derivatives and anti (2
A diastereomeric mixture of S, 3S) -type 3-methoxyalkane derivatives (hereinafter referred to as a diastereomeric mixture-
1) can be manufactured.

In the formula (13), m corresponds to the formula (1) and the formula (2), and a preferred specific example of the diastereomer mixture-1 is disclosed as syn- (2S, 3R) -2 -
(4-hydroxybenzoyloxy) -6-ethoxy-
3-methoxy-1,1,1-trifluorohexane and anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -6-ethoxy-3-methoxy-1,
It consists of 1, 1-trifluoro hexane, and its formation ratio syn body (2S, 3R) type / anti body (2S, 3S)
A mixture of diastereomers of known type, syn- (2
S, 3R) -2- (4-hydroxybenzoyloxy)
-7-Ethoxy-3-methoxy-1,1,1-trifluoroheptane and anti- (2S, 3S) -2-
(4-hydroxybenzoyloxy) -7-ethoxy-
It consists of 3-methoxy-1,1,1-trifluoroheptane, and its formation ratio syn isomer (2S, 3R) type / ant
A mixture of diastereomers of which the i-form (2S, 3S) is known, syn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -8-ethoxy-3-methoxy-
1,1,1-trifluorooctane and anti-
(2S, 3S) -2- (4-hydroxybenzoyloxy) -8-ethoxy-3-methoxy-1,1,1-trifluorooctane, having a formation ratio syn isomer (2
Mixtures of diastereomers of known type S, 3R) / anti form (2S, 3S), and syn- (2S, 3)
R) -2- (4-hydroxybenzoyloxy) -9-
Ethoxy-3-methoxy-1,1,1-trifluorononane and anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -9-ethoxy-3-methoxy-1,1,1-trifluoro It consists of nonane, and its formation ratio syn body (2S, 3R) type / anti body (2S,
Diastereomeric mixtures of which type 3S) is known, and the like.

Hereinafter, the method for producing diastereomer mixture-1 will be described in detail. Examples of the solvent include methanol, ethanol, water, diethyl ether, n-hexane and THF. Among them, particularly preferable is methanol. The amount used is preferably 4 to 26 ml, particularly preferably 13 to 17 ml, based on 1 gram of O-methylated derivative. If the amount is less than 4 ml, the viscosity of the reaction system increases, the palladium / carbon catalyst may not be uniformly dispersed, and the yield of diastereomeric mixture-1 may be decreased. It can not be said. The palladium / carbon catalyst includes, for example, palladium content, 1, 3, 5, 10% of each palladium / carbon catalyst, and among them,
A 10% palladium / carbon catalyst is preferred because it is inexpensive in terms of palladium atom. The feed ratio of palladium / carbon catalyst to the reaction system is 5 to 35 milligrams based on 10 g of O-methylated derivative (palladium purity conversion,
Hereinafter the same), preferably 10 to 30 milligrams are particularly preferred. If it is less than 5 milligrams, the reducing ability may be insufficient, and the yield of diastereomeric mixture-1 may be decreased.
If it exceeds 35 mg, it is not economical.

The reaction method is, for example, in a closed reaction vessel
The O-methylated derivative and the solvent are added and a homogeneous solution is prepared, and then, with stirring, the palladium / carbon catalyst is introduced to prepare a suspension as uniformly dispersed as possible. Next, the reaction system is sealed with hydrogen gas at about 1.05 to 1.15 atm. The reduction time is supplied until the absorption of hydrogen gas is lost. For example, it is preferable to supply hydrogen gas for about 5 to 7 hours based on 10 g of the O-methylated derivative. If it is less than 5 hours, the reduction is insufficient, leading to a decrease in the yield of diastereomer mixture 1, and if it is more than 7 hours, it is not economical. The reduction temperature is preferably 15 to 30 ° C. 15 ° C
If it is less than 30, the reduction rate is slow and not economical. If it exceeds 30 ° C., the amount of hydrogen gas used increases, which may lead to a decrease in the yield of diastereomer mixture-1.

After completion of the reaction, the palladium / carbon catalyst is removed, for example by filtration, the filtrate is concentrated under reduced pressure and then
The solvent generated is removed by a vacuum pump or the like to obtain a syrupy residue. The residue is purified by silica gel column chromatography or the like to obtain a colorless and transparent liquid product, diastereomer mixture-1. ¹ H NMR of this product
As a result of measuring the spectrum, ¹⁹ F NMR spectrum, 1R absorption spectrum and MS spectrum, the product is
(4-hydroxybenzoyloxy) -3-methoxy-
It is confirmed that it is 1,1,1-trifluoro-terminated ethoxyalkane. Also, when the product is subjected to optically active liquid chromatography, two optically active peaks are observed. Further, according to Identification Example 2 and Identification Example 4 described later, diastereomer mixture-1 is syn- (2S, 3R) -2-.
(4-hydroxybenzoyloxy) -3-methoxy-
Composed of 1,1,1-trifluoro-terminated ethoxyalkane and anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoro-terminated ethoxyalkane, its formation Ratio sy
n-body (2S, 3R) type / anti body (2S, 3S) type =
It is confirmed by the following that it is a diastereomer mixture which is 70-40 / 30-60 (area ratio).

[Diastereomeric mixture-1 is syn-
2- (4-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoro-terminated ethoxyalkane and anti-2- (4-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoro It is confirmed that the mixture is a mixture of diastereomers consisting of terminal ethoxyalkanes] The reaction product of the first step reaction is identified in Example 1 described later.
As is clear from and and Identification Example 3, the syn form (2S,
3R) type / anti body (2S, 3S) type = 70 to 40 /
It has already been confirmed that it is a mixture of diastereomers consisting of 30 to 60 (area ratio).

In the second step reaction, when the ¹⁹ F NMR spectrum of the O-methylated derivative obtained by reacting the above reaction product with methyl iodide is measured, two peaks are obtained, the first peak thereof Hydrolyzes the reaction product of the first stage reaction, and the first peak of the ¹⁹ F NMR spectrum of product 1 obtained is syn- (2S, 3R)-
1,1,1-trifluoro-terminated ethoxyalkane-2,
By agreement with the area ratio of 3-diol, the first peak of the ¹⁹ F NMR spectrum of the O-methylated derivative is sy
n bodies (2S, 3R) a type, ¹⁹ of the other second peak with the product of ^O-19 FNMR spectra of methylated derivatives -1
Anti- (2) which is the second peak of F NMR spectrum
By agreement with the area ratio of S, 3S) -1,1,1-trifluoro-terminated ethoxyalkane-2,3-diol, the second of ¹⁹ F NMR spectra of O-methylated derivatives
The peak is found to be anti (2S, 3S).

Further, in the third step reaction, the diastereomeric mixture 1 in which the O-methylated derivative is detolueneed with hydrogen gas in the presence of a palladium / carbon catalyst is at the 2-position and 3
Position 2 and 3 because they are not related to the asymmetric carbon atom
As the asymmetry center of position does not change, syn form (2S,
It is predicted to be a mixture of diastereomers consisting of 3R) / anti form (2S, 3S).

When the diastereomer mixture-1 obtained in the third step reaction is subjected to optically active liquid chromatography, two optically active peaks are obtained, the first peak of which is ^{19 of the} O-methylated derivative. The first of F NMR spectrum
As the area ratio agrees with the syn form (2S, 3R) which is the peak, the first peak of optically active liquid chromatography of diastereomer mixture 1 is syn form (2
The area ratio of the second peak of optically active liquid chromatography is the same as that of the anti form (2S, 3S) which is the second peak of the ¹⁹ F NMR spectrum of the O-methylated derivative. Diastereomeric mixture-
The second peak of the optically active liquid chromatography of 1 is a
It is confirmed that it is nti body (2S, 3S) type. Furthermore, in the ¹⁹ F NMR spectrum of diastereomer mixture 1, two peaks are observed, and the first peak is a syn isomer (2S, 3R) which is the first peak of optically active liquid chromatography of diastereomer mixture 1. ¹⁹ FNM of diastereomeric mixture 1 by matching the form
The first peak of R spectrum is Syn form (2S, 3R) type while the second peak is anti form by matching with anti form (2S, 3S) type which is the second peak of optically active liquid chromatography. It is confirmed that it is of the (2S, 3S) type.

From the above results, diastereomer mixture-1 is obtained by the syn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoro-terminated ethoxyalkane and anti -(2
S, 3S) -2- (4'-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoro-terminated ethoxy alkane, its formation ratio syn form (2
S, 3R) type / anti body (2S, 3S) type = 70 to 4
It is confirmed that it is a diastereomer mixture which is 0/30-60 (area ratio).

(Step 4) If the step 4 step is shown by a step formula, the formula (14)

[0066]

[Image 15]

[Wherein, m is the same as the formula (1)], and the diastereomer mixture-1 obtained in the third step reaction is separated by preparative silica gel column chromatography Syn-type (2S, 3R) type 3-
Compounds of the present invention which are methoxyalkane derivatives and an
It is possible to obtain the compound of the present invention which is a ti-body (2S, 3S) type 3-methoxyalkane derivative. That is, by applying diastereomer mixture-1 obtained in the third step reaction to preparative silica gel column chromatography, two peaks are confirmed, and the first peak and the second peak
By separating the peaks and distilling off the solvent, it is possible to obtain the first fraction and the second fraction, which are colorless and transparent liquid target products.

From the respective target products, the first fraction is syn- (2S, 3R) -2 by making the acquisition ratio of the first fraction the area ratio of the first peak of the ¹⁹ F NMR spectrum of the third step reaction. It is confirmed to be-(4-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoro-terminated ethoxyalkane. In addition, when optically active liquid chromatography analysis is performed, one optically active peak is obtained.
It can be confirmed that the compound is an S, 3R) type compound of the present invention.

Also, by making the acquisition ratio of the second fraction identical to the area ratio of the second peak of the ¹⁹ F NMR spectrum of the third step reaction, the second flanking is anti
It is confirmed to be (2S, 3S) -2- (4-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoro-terminated ethoxyalkane. In addition, when optically active liquid chromatography analysis is performed, one optically active peak is obtained, and from the retention time, the anti form (2S, 3
It can be confirmed that the S) type of the compound of the present invention.

The compounds of the present invention can be produced, for example, by
5)

[0071]

Embedded image

(Wherein, R represents a linear C 6 to C 14 al
Represents a kill group, and m is the same as in formula (1). Indicated by)
Syn- (2S, 3R) -2- {4- [4- (4) -
Alkylphenyl) benzoyloxy] benzoyloxy
} -Terminal ethoxy-3-methoxy-1,1,1-tri
Fluoroalkane, or the following formula (16)

[0073]

[Image 17]

(Wherein, R represents a linear C 6-14 alkyl)
Represents a kill group, and m is the same as in formula (1). Indicated by)
Anti- (2S, 3S) -2- {4- [4- (4)
-Alkylphenyl) benzoyloxy] benzoyl io
Xy] -terminal ethoxy-3-methoxy-1,1,1-t
It is useful as a production intermediate of trifluoroalkane. Below
Below, taking the compound of the formula (15) as an example, the final useful compound
Although the preparation method is described, the compound of the formula (16) is also a compound of the present invention
Similarly prepared from the anti- (2S, 3S) body of
I can do it. The compound of the formula (15) has the following reaction formula (1
It can be obtained by 7).

[0075]

[Image 18]

That is, syn represented by equation (15)
-(2S, 3R) -2- {4- [4- (4) -Alkyl group
Phenyl) benzoyloxy] benzoyloxy} -end
Ethoxy-3-methoxy-1,1,1-trifluoro
Lucan is a compound of the present invention syn- (2) in an organic solvent.
S, 3R) -2- (4-hydroxybenzoyloxy)
-Terminal ethoxy-3-methoxy-1,1,1-triful
Oroalkane and 4- (4-n-alkylphenyl) ester
As a dehydrating condensing agent, dicyclohexylcarbophilic acid
N, N-dimethyl-4- as a catalyst using a diimide etc.
Reacting with an organic base such as aminopyridine
Can be easily manufactured. Organic solvent is chlorinated
Chlorinated solvents such as methylene or chloroform are preferred.
The amount of organic solvent used is based on 1 mol of the starting compound of the present invention.
Preferably 20 to 40 liters. Less than 20 liters
In the case of 4- (4-n-alkylphenyl) benzoic acid
It may be difficult to dissolve, which may lead to a decrease in yield,
It is not economical if it exceeds 40 liters. Departure book
Bright compounds and 4- (4-n-alkylphenyl) benzoic acid
The feed ratio with is based on 1 mol of the starting compound of the present invention
1.1 to 1.3 mol is preferable. Less than 1.1 moles
May cause a decrease in yield, and if it exceeds 1.3 mol
It is not economic.

The mixing ratio of the starting compound of the present invention to N, N-dimethylaminopyridine is preferably 0.4 to 0.8 mol based on 1 mol of the starting compound of the present invention. If it is less than 0.4 mol, dehydration time will be long, which may lead to a decrease in yield, and if it exceeds 0.8 mol, it is not economical. Methylene chloride is added to the starting compound of the present invention, 4- (4-n-alkylphenyl) benzoic acid and N, N-dimethylaminopyridine to prepare a homogeneous solution while stirring at room temperature. Dicyclohexyl carbodiimide is then added to the above solution to make a homogeneous solution with stirring. The feed amount of dicyclohexylcarbodiimide to the above solution is 1.3 to 1.7, based on 1 mol of the starting compound of the present invention.
Mol is preferred. If it is less than 1.3 mol, the dehydration condensation reaction may be insufficient, which may lead to a decrease in yield, and if it exceeds 1.7 mol, it is not economical. After the dicyclohexyl carbodiimide is completely fed, the reaction is carried out at room temperature with stirring.
The reaction time is 25 per mol of the starting compound of the present invention.
-35 hours are preferable. If it is less than 25 hours, the yield may be lowered. If it is more than 35 hours, it is not economical. The reaction temperature is preferably room temperature.

After completion of the reaction, precipitated dicyclohexyl urine
The white crystals of the pigment are removed by filtration, and the filtrate is washed with 1 N hydrochloric acid.
After cleaning, 10 Washed with aqueous sodium bicarbonate solution
Then, wash with water and add anhydrous magnesium sulfate to remove water
After removal of the solvent under reduced pressure, the syrupy residue is removed.
Get After dissolving the obtained residue with hot n-hexane,
Cooling crystallization gives white crude crystals. Then the crude obtained
The crystals are purified by liquid chromatography to give a colorless clear liquid
-(2S, 3R)-as a final useful compound
2- {4- [4- (4) -Alkylphenyl) benzoyl
Oxy] benzoyloxy} -terminal ethoxy-3-meth
The xy-1,1,1-trifluoroalkane is obtained.

Also, since this reaction is independent of the configuration of the two asymmetric carbon atoms of the starting compound of the present invention,
The optically active asymmetric center does not change, but the syn form (2S, 3
R) type. Furthermore, in the identification example of Reference Example 5 described later,
It has been confirmed that the final useful compound is in syn form (2S, 3R).

Formula (15) or Formula (1) obtained above
The final useful compound represented by 6) has excellent properties [for example, in the formula (15), a compound in which m = 4, R = n-decyl has fast response and a wide viewing angle and is stable in three) (Showing chiral smectic C _A phase having a state) antiferroelectric liquid crystal compound, which can be used as a liquid crystal display element. The preparation examples of the final useful compounds and the test examples showing the usefulness as the antiferroelectric liquid crystal compound are shown in the following reference examples.

[0081]

EXAMPLES The present invention will be described in more detail based on the following reference examples and examples. Reference Examples 1 to 4 are Production Examples of Compounds Used as Raw Materials of the Present Invention Compounds, Examples 1 and 2 are Production Examples of Present Compounds of the Present Invention, Reference Example 5 Production Examples of Final Useful Compounds Starting from the Compounds of the Present Invention, Reference Example 6 is a test example showing the usefulness of the final useful compound.

Reference Example 1 [Starting Material Compound: (S) -N-
(Preparation of 2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine In a three-necked round bottom flask equipped with a thermometer, a stirrer and a reflux condenser, 25.8 g (179 mmol) of (S) -trifluorolactic acid , 520 ml of methanol and 270 ml of concentrated sulfuric acid
The mixture was heated to reflux with stirring. During reflux, ¹⁹ FNM
As a result of refluxing for 12 hours while tracking a lactic acid peak in R spectrum, it was confirmed that the lactic acid in the reaction solution was gone.
Then, the reaction solution is adjusted to pH with a saturated aqueous solution of sodium hydrogen carbonate
The extract is extracted with ether and the extract is washed with water, anhydrous magnesium sulfate is added to remove water, the extract is concentrated under reduced pressure, and the remaining syrupy residue is distilled under reduced pressure, Colorless and transparent liquid product [yield 26.9 g
(170 mmol) yield 95%] was obtained.

¹ H NMR spectrum of this product, ¹⁹ F
NMR spectrum, 1R absorption spectrum and MS spectrum were measured. Also, the product is (S) -2-hydroxy-3, which is independent of the configuration of the carbon atom at position 2 of this product and optical inversion does not occur.
It was confirmed to be 3,3-trifluoropropionic acid methyl ester.

Next, attach a Liebig condenser to a branch of a Claisen flask with a thermometer, a stirrer, and a dropping funnel, attach a methyl alcohol recovery bottle at the outlet, and connect the outlet to the aspirator. Obtained by (S) -2-hydroxy-
26.1 g (165 mmol) of 3,3,3-trifluoropropionic acid methyl ester and 12.8 g of pyrrolidine
(180 mmol) and 0.7 mmol of concentrated sulfuric acid were introduced and reacted at 200 mmHg.times.60.degree. C. The methyl alcohol vapor generated was continuously sent to a Liebig condenser to recover methyl alcohol. Confirm that generation of methyl alcohol vapor has disappeared, and stop heating,
After cooling to room temperature, the pressure was returned to normal pressure to complete the reaction.
Next, the light brown solid formed is taken out, washed with water, dissolved by adding hot n-hexane, and then crystallized by cooling to give a white needle-like crystalline product [yield 27.6 g (14
0 mmol) yield 85%] was obtained.

¹ H NMR spectrum of this product, ¹⁹ F
The results of measurement of NMR spectrum, 1R absorption spectrum, and MS spectrum are as follows, and are independent of the configuration of the asymmetric carbon atom of this product, and optical inversion does not occur. Was confirmed to be the starting compound (S) -N- (2-hydroxy-3,3,3-triculopropionyl) pyrrolidine. ¹ H NMR spectrum (CDCl ₂ ) 1.53 to 2.37 ppm (4 H, m), 3.21 to
3.88 ppm (4H, m), 4.14 ppm (1 H,
br), 4.58 (1 H, q) ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) −4.2 ppm (d, J = 6.0) 1R absorption spectrum (neat) 1,640 cm ⁻¹ (CO), 3,330 cm ⁻¹ (OH) MS spectrum m / z 197 (M ⁺ )

Reference Example 2 ( Preparation of Grignard reagent: 4-ethoxybutyl magnesium bromide) 40.0 g of tetrahydrofuran (55 g) in a four-necked round bottom flask equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel.
6 mmol), 28.2 g (612 mmol) of ethyl alcohol and 5.2 g of para-toluenesulfonic acid monohydrate
(29 mmol) was added and immersed in a hot water bath. Then, after refluxing at 80 ° C. for 6 hours, concentration was performed under reduced pressure to obtain a syrupy residue. To this residue is added 620 ml of water, followed by extraction with ether, extraction and addition of anhydrous magnesium sulfate to remove water, and then the solvent is distilled off under reduced pressure to give colorless clear liquid 4-ethoxybutanol [yield 59.0 g ( 500 mmol) yield 90%] was obtained.

Next, 57.2 g (485 mmol) of 4-ethoxybutanol obtained above and methylene chloride 1, 4 were obtained in a three-necked flask equipped with a thermometer, a stirrer and a dropping funnel.
50 L was added and immersed in an ice water bath and adjusted to 0 ° C. Then add triphenylphosphine 126.6 to the dropping funnel.
Put g (485 millimoles) and 485 liters of methylene chloride,
A completely homogeneous solution was prepared. Then 77.6 g of bromine
A solution of (485 mmol) mixed with 240 ml of methylene chloride was added to the dropping funnel. The mixture was added dropwise over 68 minutes while stirring the mixture from the dropping funnel, and after completion of the addition, the mixture was further stirred for 1 hour to complete the reaction. Then, the ice water bath was removed, the temperature was raised to room temperature with stirring, and then the stirring was maintained for 1 hour to form triphenylphosphine oxide microcrystals. Then concentrate under reduced pressure,
Methylene chloride and hydrogen bromide were removed to obtain a sludge. Next, after 3,850 ml of hot n-hexane is added and dissolved, cooling crystallization is carried out, most of triphenylphosphine oxide which is white needle crystals is removed by filtration, and the filtrate is concentrated to obtain a syrupy residue. The The residue was purified by silica gel column chromatography (eluent n-hexane) to obtain colorless, clear liquid 4-ethoxybutyl bromide [yield 70.2 g (388 mmol) yield 80%].

Next, 10.9 g (456 mmol) of metallic magnesium and 76 ml of dry diethyl ether are placed in a nitrogen-substituted flask equipped with a thermometer, stirrer, reflux condenser, dropping funnel and nitrogen insertion cock, and then iodine 0 is added. Add 1 g (0.38 mmol). The mixture was stirred until the reddish brown color disappeared. Then 6.9 g (38 mmol) of 4-ethoxybutyl bromide obtained above
Was added and stirred to reflux. If reflux occurs, 4-
61.9 g (342 mmol) of ethoxybutyl bromide
And 190 ml of dry diethyl ether were added to the dropping funnel and added dropwise to maintain reflux, and after completion of the addition, the mixture was refluxed for 1 hour to complete the reaction. Then, the reaction solution is taken out from the flask with a syringe, and the remaining unreacted metal magnesium solid is washed with 114 ml of dry ether, and the washing solution is returned to the reaction solution, and diethyl ether of 4-ethoxybutylmagnesium bromide at a concentration of 0.8 mol / liter. Solution 3
A Grignard reagent was obtained which was 80 ml [4-ethoxybutylmagnesium bromide [yield 62.3 g (304 mmol) yield 80%].

Reference Example 3 [(S) -1-hydroxy-2,
Production of 2,2-Trifluoroethyl-4-Ethoxybutyl Ketone] A four-neck round bottom flask equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel was subjected to 0.8 mol / 371 ml of a Grignard reagent of 1 [60.9 g (297 mmol) of 4-ethoxybutyl magnesium bromide, remaining diethyl ether] was added, and it was immersed in an ice water bath and adjusted to 0 ° C. A solution obtained by adding 200 ml of diethyl ether to 26.6 g (135 mmol) of (S) -N- (2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine obtained in Reference Example 1 was added to a dropping funnel and dissolved. The reaction solution was added dropwise with stirring over 60 minutes, and after completion of the dropwise addition, the reaction was continuously completed by continuing stirring for 2 hours to obtain a reaction product solution. The ice water bath was then removed and allowed to warm to room temperature while stirring. Next, 160 ml of 3 N hydrochloric acid was put into the dropping funnel and 2
It dripped over 3 minutes. After completion of the dropwise addition of 3 N hydrochloric acid, the hydrolysis reaction was completed by maintaining the stirring for 20 minutes.

After completion of the hydrolysis reaction, 20 % Sodium bicarbonate
After adjusting to pH 8 with aqueous lithium solution, extract with ether,
The extract is washed with water and then anhydrous magnesium sulfate is added
After removing the water, the solvent was removed by
Obtained a residue. The residue is subjected to silica gel column chromatography
[Eluent n-hexane / isopropyl alcohol
= 9/1 (volume ratio)] to form a colorless and transparent liquid
Product [yield 18.5 g (81 mmol) yield 60%] is obtained
The Of this product¹H NMR spectrum,¹⁹F NMR
Spectrum, 1R absorption spectrum and MS spectrum
The measured results are as follows, 1-hydroxy-2,
2,2-Trifluoroethyl-4-ethoxybutyl keto
Was confirmed. Note that from the identification example 1 described later
The product is (S) -1-hydroxy-2,2,2-trif
Be a fluoroethyl-4-ethoxybutyl ketone
confirmed.

¹ H NMR spectrum (CDCl ₃ ) 0.94 to 1.08 ppm (3 H), 1.18 to 1.4
8 ppm (6 H), 2.61 to 2.80 ppm (2
H), 3.20 to 3.35 ppm (2H), 3.46 to
3.78 ppm (1 H), 4.21 to 4.31 ppm
(1H) ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH)-4.66 ppm 1R absorption spectrum 1,120 cm ^-1 (COC), 1,670 cm ^-1 (C
O), 3,280 cm ^-1 (OH) MS spectrum m / z 228 (M ⁺ ) Also, the ¹ H NMR spectrum is shown in FIG.

Identification Example 1 Identification of the Product as (S) -1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone (S) -N- (2-) In place of hydroxy-3,3,3-trifluoropropionyl) pyrrolidine, N- (2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine is used, and it is the above 1/10 scale of the above-mentioned experiment. In the same manner as above, and the colorless and transparent liquid product-1 [yield 1.85 g (8.1 mmol) yield 60%]
I got The results of measuring various spectra of this product-1 were the same as above, and were 1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone.

This product 1 was subjected to gas chromatography (hereinafter referred to as
It is called optically active gas chromatography. ). Column: trade name CHIRALDEX, B-TA (ASTEC) inner diameter 0.25 mm, length 10 m, silica capillary column Column temperature: 100 ° C. for 10 minutes, then rise to 200 ° C. at a heating rate of 4 ° C./min. Temperature Carrier gas: Helium, gas flow rate 70 Nl / min, split ratio 100/1 Detection: FID The chart of optically active gas chromatography is as shown in Fig. 2. From the analysis results of Fig. 2, two optically active peaks are obtained. The peak retention time and area ratio of the peaks are determined as follows: First peak: retention time 34.67 minutes, area ratio 1 (S) body ☆ 1 second peak: retention time 37.67 minutes, area ratio 1 (R) body ☆ 1 (* 1 confirmed in this identification example) Therefore, the product-1 is 1-hydroxy-2,2,2
Enantiomeric mixture of trifluoroethyl-4-ethoxybutyl ketone.

Next, the product obtained above was subjected to optically active gas chromatography under the same conditions as above. The chart of optically active gas chromatography is as shown in FIG. 3. From FIG. 3, one optically active peak was obtained, and its retention time was 34.67 minutes. The product is obtained by replacing the N-pyrrolidinyl group of the starting material compound (S) -N- (2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine with 4-ethoxybutyl group in a Grignard reagent. Is obtained. Therefore, it was confirmed that it is (S) configuration because it is irrelevant to the configuration of the asymmetric carbon atom at the 2 position and optical inversion does not occur before and after the reaction. Therefore, the retention time of 34.67 minutes of optically active gas chromatography of the product was found to be (S) isomer, and the product was (S) -1-hydroxy-2,
It was confirmed to be 2,2-trifluoroethyl-4-ethoxybutyl ketone. The retention time of the second peak of optically active gas chromatography of product-1 37.
It turned out that 67 minutes were (R) form.

Reference Example 4 [Material Compound: (S) -2- (4)
-Benzyloxybenzoyloxy) -7-ethoxy-
Production of 1,1,1-Trifluoroheptanone-3] A four-necked round bottom flask equipped with a thermometer, a stirrer, a reflux condenser, and a dropping funnel, washed with n-hexane, purified, and dried sodium hydride Add 1.99 g (83 mmol) and 23 ml of diethyl ether, insert into an ice water bath, and prepare a 0 ° C. suspension while stirring. Next, (S) -1-hydroxy- obtained in Reference Example 3 was added to the dropping funnel.
Add 17.0 g (75 mmol) of 2,2,2-trifluoroethyl-4-ethoxybutyl ketone and 202 ml of diethyl ether to make a homogeneous solution and stir 1
It dripped over 7 minutes. After the addition was completed, the ice water bath was removed, and while stirring, the temperature was raised to 25 ° C., and the stirring was continued for 60 minutes to complete the reaction. Then, the above-mentioned flask was again inserted into an ice water bath and adjusted to 0 ° C. Separately into the dropping funnel, 22.2 g (90 mmol) of 4-benzyloxybenzoyl chloride and diethyl ether 108
The ml was charged and added dropwise over 33 minutes while stirring.
After the addition is complete, remove the ice water bath and while stirring, 25
The reaction was completed by raising the temperature to ° C. and then maintaining the stirring for 150 minutes.

After completion of the reaction, add 75 ml of 1 N hydrochloric acid,
After stirring for 60 minutes, the pH was adjusted to 8 with 5% aqueous sodium hydrogen carbonate solution. The extract is washed with water, and anhydrous magnesium sulfate is added to remove water, concentrated under reduced pressure, the solvent is distilled off, and the remaining pale yellow syrupy residue is subjected to silica gel column chromatography. 0.52 g of granular activated carbon in the solution purified by chromatography [eluent n-hexane / isopropyl alcohol = 96/4 (volume ratio)] [addition amount of granular activated carbon is (S) -1-hydroxy-2,2,2,2 3% by weight relative to the charge of trifluoroethyl-4-ethoxybutyl ketone. After stirring for 30 minutes, the granular activated carbon is removed by filtration, the filtrate is concentrated under reduced pressure, the eluent is distilled off, and a colorless transparent liquid product [yield 26.3 g (60 mmol) is obtained. 80%]. ¹ H NMR of this product
The results of measurement of the spectrum, ¹⁹ F NMR spectrum, 1R absorption spectrum and MS spectrum are as follows, and the product is 2- (4-benzyloxybenzoyloxy) -7-ethoxy-1,1,1-trifluorohepta It was confirmed to be non-3.

¹ H NMR spectrum (CDCl ₃ ) 1.07 ppm (3 H), 1.18 to 1.48 ppm
(6H), 2.92 to 3.04 ppm (2H), 3.2
4 to 3.35 ppm (2H), 4.17 to 4.27 pp
m (1 H), 4.49-4.67 ppm (2 H), 7.
25 ppm (2H), (6.75 to 7.00, 7.76
-7.95 ppm (4H, AB pattern) ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) -5.5 ppm 1R absorption spectrum (neat) 1,110 cm ^-1 (COC), 1,660 cm ^-1 (C
O), 1,740 cm ^-1 (COO) MS spectrum m / z. 438 (M ⁺ ) Also, ¹ H NMR spectrum is shown in FIG.

Identification Example [The product obtained in Reference Example 4 is (S) -2- (4-benzyloxybenzoyloxy)
Identification as being -7-ethoxy-1,1,1-trifluoroheptanone-3] A four-necked round bottom flask equipped with a thermometer, a stirrer, a reflux condenser, and a dropping funnel, obtained as described above 2.19 g of product
(5 mmol), 25 ml of 3N hydrochloric acid and methanol 1
The reaction solution was immersed in a hot water bath at a temperature of 80 ° C., heated to a boiling temperature while stirring, and then refluxed for 6 hours to carry out a hydrolysis reaction. Then, after cooling to room temperature, extraction with ether is carried out, and the extract is washed with 20 ml of 20% aqueous sodium hydrogen carbonate solution and then with 200 ml of water, then anhydrous magnesium sulfate is added to remove water, and the solvent is distilled under reduced pressure. Removed to give a syrupy residue. The residue was subjected to silica gel column chromatography [eluent n
-Hydrogen / isopropyl alcohol = 90/10 (volume ratio)], colorless and transparent liquid product [yield 0.
91 g (4 mmol) yield 80%] was obtained.

When various spectra of the obtained product are measured, various spectral analysis of (S) -1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone which is a starting compound of Reference Example 4 And when applied to optically active gas chromatography, the retention time is 3
4.67 minutes were confirmed to be in the (S) configuration, and the product was the same as the starting compound (S) -1-hydroxy-2,
It was found to be 2,2-trifluoroethyl-4-ethoxybutyl ketone. Therefore, an alkali metal hydride is reacted with a hydroxyl group bonded to the asymmetric carbon atom at position 1 of (S) -1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone to give an alkali metal alcoholate. And then reacting with 4-benzyloxybenzoyl chloride does not change the absolute configuration,
It is confirmed that (S) configuration is obtained, and the product is (S) -2
It was confirmed to be-(4-benzyloxybenzoyloxy) -7-ethoxy-1,1,1-trifluoroheptanone-3.

Example 1 [Compound of the Invention: syn- (2
S, 3R) -2- (4-hydroxybenzoyloxy)
-7-Ethoxy-3-methoxy-1,1,1-trifluoroheptane, and the compound of the present invention: anti- (2
S, 3S) -2- (4-hydroxybenzoyloxy)
Preparation of -7-Ethoxy-3-methoxy-1,1,1-trifluoroheptane, provided that a stable aqueous solution of sodium borohydride was used as a metal hydride] (First-step reaction) [syn isomer (2S , 3R) type / anti
Production of a reaction product which is a diastereomeric mixture consisting of body (2S, 3S) type = 70/30 (area ratio)] Four-necked round-bottomed flask equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel (S) -2 obtained in Reference Example 4
-(4-benzyloxybenzoyloxy) -7-ethoxy-1,1,1-trifluoroheptanone-3, 1
0.95 g (25 mmol) and 40 m of diethyl ether
The solution was poured into a homogeneous solution while stirring, inserted into an ice water bath, and adjusted to 0.degree.

Next, a stabilized aqueous solution of sodium borohydride containing 0.27 g (7 mmol) of sodium borohydride, 28 g of a 5% aqueous solution of sodium hydroxide (1.4 g (35 mmol) of NaOH) and 7 ml of methanol in the dropping funnel Was added dropwise over 10 minutes while stirring. After the addition is complete, remove the ice water bath and while stirring,
The temperature was raised to room temperature, and then stirring was continued for 90 minutes to complete the reaction and obtain a reaction product. The resulting reaction product solution was obtained from the identification example 1 described below: syn form (2S, 3R) type / anti form (2S, 3S) type = 70/30 (area ratio)
It was confirmed that the mixture was a mixture of diastereomers.

Identification Example 1: The reaction product is a syn compound (2
S, 3R) / anti body (2S, 3S) = 70/3
Identification of being a diastereomeric mixture consisting of 0 (area ratio)] In a three-necked round bottom flask equipped with a thermometer, a stirrer and a reflux condenser, the above-obtained 40% by weight reaction product solution [raw material Compound conversion 10 mmol containing reaction product solution], 50 ml of 3 N hydrochloric acid and methanol 20
0 ml was introduced, inserted into a hot water bath at a temperature of 80%, and while stirring, the temperature was raised to a boiling point, and then the mixture was heated to reflux for 7 hours to carry out a hydrolysis reaction.

After completion of the hydrolysis reaction, the hot water bath is removed, and after cooling to room temperature while stirring, extraction with ether is carried out, and the extract is extracted with 40% aqueous 20% sodium hydrogen carbonate solution.
After washing with 300 ml of water, anhydrous magnesium sulfate was added to remove water, and then the solvent was evaporated under reduced pressure to obtain a syrupy residue. The residue was purified by silica gel column chromatography [eluent n-hexane / isopropyl alcohol = 95/5 (volume ratio)] to give colorless transparent liquid product-1 [yield 1.84 g (8
ppm) yield 80%]. ¹ HN of this product- ¹
As a result of measuring an MR spectrum, ¹⁹ F NMR spectrum, 1R absorption spectrum and MS spectrum, the product
1 was found to be 7-ethoxy-1,1,1-trifluoroheptane-2,3-diol.

¹ H NMR spectrum (CDCl ₃ ) 0.86 to 1.00 ppm (3 H), 1.06 to 1.2
4 ppm (6 H), 2.69 to 2.80 ppm (2
H), 2.95 to 3.16 ppm (1 H), 3.20 to
3.35 ppm (2H), 3.52 to 3.66 ppm
(2H), 4.08 to 4.16 ppm (1H) ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) 1st peak: -0.48 ppm, area ratio 70% [Syn
Body (2S, 3R) type ☆ 1] Second peak: -2.21 ppm, area ratio 30% [ant
i form (2S, 3S) type] 1] (☆ 1 confirmed in this identification example) 1R absorption spectrum (neat) 1,150 cm ^-1 (COC), 3,270 cm ^-1 (O
H), MS spectrum m / z. 230 (M ⁺ ) Also, the ¹ H NMR spectrum is shown in FIG.

Then, the product obtained above in a three-necked round bottom flask equipped with a thermometer, a stirrer and a reflux condenser,
Add 1.15 g (5 mmol), 5 ml of 2.2-dimethoxypropane and 0.1 mg of p-toluenesulfonic acid monohydrate, and insert in a hot water bath at a temperature of 90 ° C., while stirring,
The temperature is raised to boiling and reflux is continued for 5 hours to carry out acetal exchange reaction. After completion of the reaction, the reaction product is distilled at 82 ° C., and the fraction is concentrated to give a colorless and transparent liquid product-1.
I got ¹ H NMR spectrum of this product-2, ¹⁹ F
The results of measurement of NMR spectrum, 1R absorption spectrum and MS spectrum are as follows, and product-2 is 2,2-dimethyl-4- (4-ethoxybutyl) -5-
Trifluoromethyl-1,3-dioxolane (hereinafter referred to as
It is called a 1,3-dioxolane derivative. ) Was confirmed.

¹ H NMR spectrum (CDCl ₃ ) 1.00 to 1.05 ppm (3 H), 1.36 to 2.0
7 ppm (6 H), 1.58 ppm (CH ₃ ), 1.7
_{5ppm (CH 3), 1.82ppm (} CH 3), 1.9
0 ppm (CH ₃ ), 2.73 to 2.84 ppm (2
H), 2.95 to 3.04 ppm (2H), 3.55 to 5
3.80 ppm (2H) ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) 1st peak: -0.46 ppm, area ratio 70% [tra
ns form 1,3-dioxolane derivative ☆ 2] Second peak: -3.66 ppm, area ratio 30% [cis
Body 1,3-Dioxolane Derivative ☆ 2] (Confirmed by ☆ 2 Identification Example) 1 R Absorption Spectrum (neat) 1,140 cm ⁻¹ (OH), MS Spectrum m / z. 270 (M ⁺ ) Also, the ¹ H NMR spectrum is shown in FIG.

Also, the product-2 obtained above is 1, 3
The position and area ratio of the methyl group in the ¹ H NMR spectrum of the dioxolane derivative are as shown in Table 1. Table 1
Therefore, the position of the methyl group which is 70% of area ratio
-2, 2-Dimethyl-4- (4-ethoxybutyl) -5
Trifluoromethyl-1,3-dioxolane (hereinafter referred to as
It is called a trans 1,3-dioxolane derivative. The position of the methyl group which is 30% in area ratio is
2,2-Dimethyl-4- (4-ethoxybutyl) -5-
Trifluoromethyl-1,3-dioxolane (hereinafter referred to as c)
The compound is referred to as a 1,3-dioxolane derivative. It turned out to be). Thus, product-2 is trans-
2,2-Dimethyl-4- (4-ethoxybutyl) -5-
Trifluoromethyl-1,3-dioxolane and ci
It consists of s-2,2-2 dimethyl 4- (4-ethoxy butyl) -5- trifluoromethyl 1- 3-dioxolane, and the formation ratio trans body / cis body = 70
It was confirmed that the mixture was a / 30 (area ratio) diastereomer mixture.

[0108]

[Table 1]

Also, in the ¹⁹ F NMR spectrum of the trans 1,3-dioxolane derivative and the product 2 having an area ratio of 70% of methyl groups (1.75 ppm, 1.82 ppm) in the ¹ H NMR spectrum of the product 2 By matching the area ratio of the first peak (-0.46 ppm),
The first peak is a trans 1,3-dioxolane derivative, which is a methyl group (1.58p) in the ¹ H NMR spectrum.
¹⁹ F NMR of cis 1,3-dioxolane derivative and product-2 having an area ratio of 30% of pm, 1.90 ppm)
As the area ratio of the second peak (-3.66 ppm) of the spectrum is matched, the second peak is a cis 1,3-form.
It was confirmed to be a dioxolane derivative.

Also, the reaction product obtained in the first step reaction described above is (S) -2- (4-benzyloxybenzoyloxy) -7-ethoxy-1,1,1-trifluoroheptanone-3. The asymmetric carbon atom at position 2 is not related to the reduction reaction and was confirmed to be of the (2S) configuration, since it is obtained by reducing the carbonyl carbon of the compound with a metal hydride. Also, 7-ethoxy-1,1,1-trifluoroheptane-2,3-hydrolyzed of the obtained reaction product
The asymmetric carbon atom at position 2 of the diol was confirmed to be the (2S) configuration by the fact that the absolute configuration does not change upon hydrolysis.

Accordingly, the first peak (-0.48) of the ¹⁹ F NMR spectrum of product 1 whose area ratio is identical to that of the trans 1,3-dioxolane derivative of product 2
ppm) is syn- (2S, 3R) -7-ethoxy-
¹⁹ F NMR of product 1, which is 1,1,1-trifluoroheptane-2,3-diol, while the area ratio matches the cis 1,3-dioxolane derivative of product-2
The second peak of the spectrum (-2.21 ppm) is ant
i- (2S, 3S) -7-Ethoxy-1,1,1-trifluoroheptane-2,3-diol is found and the product-1 is syn- (2S, 3R) -7-ethoxy -1,1,1-trifluoroheptane-2,3-diol and anti- (2S, 3S) -7-ethoxy-
It consists of 1,1,1-trifluoroheptane-2,3-diol, and its formation ratio syn form (2S, 3R) type / a
It was confirmed that the nti isomer (2S, 3S) form = 70/30 (area ratio) was a diastereomer mixture. Therefore, the reaction product obtained in the first step reaction is a syn compound (2
S, 3R) / anti body (2S, 3S) = 70/3
It could be confirmed that this was a mixture of diastereomers consisting of 0 (area ratio).

(Second Stage Reaction) (Production of O-Methylated Derivative) In a round bottom flask equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel, the remaining 60% obtained in the first stage reaction Add the reaction product solution [(S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-7-ethoxyheptanone-a solution containing 15 millimoles converted] in an ice water bath And adjusted to 0.degree. C. with stirring. Then add methyl iodide 2.27g to the dropping funnel
Put (16 mmol) and 20 ml of diethyl ether,
It was added dropwise over 11 minutes while stirring. After completion of dripping
Remove the ice water bath and warm up to room temperature while stirring,
Subsequently, stirring was maintained at room temperature for 2 hours to complete the reaction.

After completion of the reaction, a 5% aqueous sodium hydrogen carbonate solution is added for neutralization, and the solvent is distilled off under reduced pressure. A saturated aqueous sodium thiosulfate solution is then added, followed by ether extraction and extraction with anhydrous magnesium sulfate. The reaction mixture was concentrated to dryness under reduced pressure to give a syrupy residue. The residue is subjected to silica gel column chromatography [eluent n-hexane / isopropyl alcohol = 95/5 (volume ratio)]
To give a colorless, clear liquid O-methylated derivative [yield 5.79 g (12.75 mmol) yield 85%]. As a result of measuring the ¹⁹ F NMR spectrum of the obtained O-methylated derivative, two peaks are recognized, and the position and area ratio of each peak are shown as follows: ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) 1st peak: -2.20 ppm, area ratio 70%, [Sy
n-form (2S, 3R) type ☆ 3] Second peak: −3.90 ppm, area ratio 30%, [an
ti form (2S, 3S) type 3 3] (☆ 3, confirmed in identification example 2 described later) Therefore, according to the result of ¹⁹ F NMR spectrum and identification example 2 described later, the O-methylated derivative is a syn isomer (2S,
3R) type / anti body (2S, 3S) type = 70/30
It was confirmed to be a mixture of diastereomers consisting of (area ratio).

(Third Stage Reaction) A sealed 4-neck round bottom flask equipped with a thermometer, a stirrer, a dropping funnel, a hydrogen gas charge pipe and a polyethylene resin balloon was obtained by the above-mentioned second stage reaction. 3.86 g (8.5 mmol) of O-methylated derivative and 58 ml of methanol are charged, and 10% palladium / carbon catalyst 0.0 is added to the dropping funnel while stirring at room temperature.
8 g was added and slowly dropped to prepare a uniformly dispersed suspension. Then pressure 1.1 with stirring at room temperature
The reaction system was sealed with hydrogen gas of about kg / cm ² and reduction reaction was performed. In the reduction reaction, the suspension was stirred, and supplied for 4 hours until absorption of hydrogen gas ceased to complete the reaction.

After completion of the reduction reaction, the resulting reaction suspension is filtered to remove the palladium / carbon catalyst, and the filtrate is concentrated under reduced pressure to distill off methanol, and then by-product toluene is vacuum-pumped. Removal gave a syrupy residue. The residue was subjected to silica gel column chromatography [eluent n-hexane / isopropyl alcohol = 96
/ 4 (volume ratio)], the eluent was distilled off under reduced pressure, and diastereomer mixture-1 as a colorless and transparent liquid product
[A yield of 3.03 g (8.33 mmol) of 98% yield] was obtained. ¹ H NMR spectrum of this product, ¹⁹ F NMR
The results of measuring the spectrum, 1R absorption spectrum, and MS spectrum are as follows, and the product is 2- (4)
-Hydroxybenzoyloxy) -7-ethoxy-3-
It was confirmed to be methoxy-1,1,1-trifluoroheptane.

[0116]¹H NMR spectrum (CDCl₃) 0.87 to 0.96 ppm (3H), 1.09 to 1.5
3 ppm (6 H), 2.60 to 2.72 ppm (2
H ), 2.75 ppm (3H), 2.87 to 3.00 p
pm (1 H), 3.27 to 3.42 ppm (2 H),
4.18 to 4.35 ppm (1H), 5.41 ppm
(1H), 6.69 to 7.98 ppm (4H, AB puta
ー)¹⁹ F NMR spectrum (from ext. CF₃C
OOH) 1st peak: -1.86 ppm, area ratio 70% [Syn
Body (2S, 3R) type ☆ 4] Second peak: -2.33 ppm, area ratio 30% [ant
i-form (2S, 3S) type ☆ 4] (☆ 4, confirmed in Identification Example 2 described later) 1R absorption spectrum 1,110 cm^-1(COC), 1,740 cm^-1(CO
O), 3,300 cm^-1(OH), MS spectrum m / z. 364 (M⁺) Also,¹The HNMR spectrum is shown in FIG.

The product obtained is, according to the identification example 2 described later, s
yn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1
A diastereomeric mixture consisting of trifluoroheptane and anti-2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane, and the formation ratio syn isomer (2
S, 3R) / anti body (2S, 3S) = 70/3
It was confirmed that it is diastereomer mixture-1 which is 0 (area ratio).

Identification Example 2: The O-methylated derivative obtained in the second step reaction is a dia consisting of syn form (2S, 3R) type / anti form (2S, 3S) type = 70/30 (area ratio) It is a stereomeric mixture, and the diastereomeric mixture-1 obtained in the third step reaction is syn- (2S, 3)
R) -2- (4-hydroxybenzoyloxy) -7-
It is composed of ethoxy-3-methoxy-1,1,1-trifluoroheptane and anti- (2S, 3S) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane, and the formation ratio syn isomer ( 2S, 3R) type / an
Identification of the diastereomer mixture-1 of ti form (2S, 3S) = 70/30 (area ratio)] In a four-neck round bottom flask equipped with a thermometer, a stirrer, a reflux condenser, and a funnel First, 1.82 g (4 mmol) of the O-methylated derivative obtained in the second step reaction of Example 1, 20 ml of 3N hydrochloric acid and 80 ml of methanol were added, and the temperature was raised to 80 ° C. with stirring for 6 hours. Reflux to obtain a hydrolysis reaction. Then
After cooling to room temperature, extract with ether and extract 20%
After washing with an aqueous solution of sodium hydrogen carbonate and then with water, anhydrous magnesium sulfate is added to remove water, and then the solvent is distilled off under reduced pressure to obtain a colorless and transparent liquid product [yield 0.78 g (3. 2 mmol) yield 80%] was obtained.

Of this product¹H NMR spectrum,¹⁹F
NMR spectrum, 1R absorption spectrum, and MS spectrum
The results of measuring the spectra are as follows, and the product is 2
-Hydroxy-7-ethoxy-3-methoxy-1,1,
It was 1-trifluoroheptane.¹ H NMR spectrum (CDCl₃) 0.81 to 1.00 ppm (3H), 1.04 to 1.3
0 ppm (6 H), 2.48 to 2.64 ppm (3
H ), 2.69 ppm (3H), 2.84 to 3.00 p
pm (1 H), 3.12 to 3.26 ppm (2 H),
3.77 to 3.90 ppm (1 H), 4.02 to 4.1
4 ppm (1 H)¹⁹ F NMR spectrum (from ext. CF₃C
OOH) 1st peak: -2.12 ppm, area ratio 70% [Syn
Body (2S, 3R) type ☆ 5] Second peak: -4.14 ppm, area ratio 30% [ant
i form (2S, 3S) type ☆ 5] (☆ 5, confirmed by this identification example) 1R absorption spectrum (neat) 1,120 cm^-1(COC), 1,670 cm^-1(O
H), MS spectrum m / z 244 (M⁺) Also,¹The HNMR spectrum is shown in FIG.

Then, the above-mentioned product was subjected to gas chromatography (hereinafter referred to as optically active gas chromatography) having a column for separating optical isomers under the following conditions. Column: trade name Cyclodex β 236 M (made by Chrompack): size: inner diameter 0.25 mm, length 25 m: silica capillary column column temperature: 100 ° C. for 10 minutes and then raised to 200 ° C. at a heating rate of 4 ° C./min. Temperature Carrier gas: Helium, gas flow rate 60 NL / min, split ratio 100/1 Detection: FID

The chart of optically active gas chromatography is shown in FIG. From the analysis results of the chart in FIG. 9, two optically active peaks are observed, and the retention time and the area ratio of each peak are as follows. First peak: retention time 14.55 minutes, area ratio 70%,
[Syn form (2S, 3R) type ☆ 6] Second peak: retention time 15.27 minutes, area ratio 30%,
[Anti body (2S, 3S) type ☆ 6] (confirmed with this example ☆ 6 identification)

The syn form (2S, 3) obtained in the first step reaction
Alcoholates and methyl iodides of metal compounds bound to the asymmetric carbon atom at position 3 of the reaction product which is a diastereomeric mixture consisting of R) type / anti form (2S, 3S) type = 70/30 (area ratio) The product obtained by acid hydrolysis of the O-methylated derivative obtained by reacting with a compound gives two optically active peaks, and the first peak / second peak = 70/30 (area That the absolute configuration of the asymmetric carbon atom at the 2-position and the 3-position does not change between the reaction product and the product because the ratio (A) corresponds to the area ratio of the reaction product obtained in the first step reaction Was confirmed.

Therefore, the first peak (retention time 1) which is 70% of the area ratio of product optically active gas chromatography
4.55 minutes) is syn- (2S, 3R) -2-hydroxy-7-ethoxy-3-methoxy-1,1,1-trifluoroheptane, while the area ratio of optically active gas chromatography is 30% Second peak (retention time 1
5.27 min) was found to be anti- (2S, 3S) -2-hydroxy-7-ethoxy-3-methoxyheptane, syn- (2S, 3R) -2-hydroxy-
First peak of the ¹⁹ F NMR spectrum of the product having the same area ratio as 7-ethoxy-3-methoxyheptane (-2.
12 ppm) is syn- (2S, 3R) -2-hydroxy-7-ethoxy-3-methoxy-1,1,1-trifluoroheptane, while anti- (2S, 3
S) -2-hydroxy-7-ethoxy-3-methoxy-
The second peak (-4.1) of the ¹⁹ F NMR spectrum of the product having the same area ratio as 1,1,1-trifluoroheptane
4 ppm) was confirmed to be anti- (2S, 3S) -2-hydroxy-7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.

Therefore, the 2-position and 3 each of the product obtained by hydrolyzing the O-methyl derivative and the O-methylated derivative
As the absolute configuration of the asymmetric carbon atom at the position does not change,
70% of area ratio of ¹⁹ F NMR spectrum of methylated derivative
Is the first peak (-2.20 ppm) is syn compound (2
S, 3R) type, with an area ratio 3 of ¹⁹ F NMR spectrum
The second peak (-3.90 ppm) at 0% is anti
Body (2S, 3S) type was found, and the O-methylated derivative was syn (2S, 3R) type / anti (2
It was confirmed that the mixture was a mixture of diastereomers consisting of S, 3S) type = 70/30 (area ratio).

Then, the diastereomer mixture-1 obtained in the third step reaction was subjected to optically active liquid chromatography under the following conditions. Optical isomer separation column: [trade name: HPLC for separating amylose optical isomers Column: manufactured by Daicel Chemical Industries, Ltd.] Separation agent: amylose tris [(S) -1-phenylethyl carbamate] is coated with silica gel What (Great CHIRALPAKAS) Size: 4.6 mmφ × 250 mm H Eluent: n-hexane / isopropyl alcohol = 96/4 (volume ratio) Flow rate: 0.5 ml / min. Detection: UV absorption at a wavelength of 254 mm was used as a UV detector. Sample: 0.1 mg

The chart of the above-mentioned optically active liquid chromatography is as shown in FIG. 10, and from the analysis result of FIG.
Two optically active peaks were obtained, and their retention time and area ratio were as follows. First peak [syn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane ☆ 7] retention time 10.11 minutes area ratio 70% second peak [anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane ☆ 7] retention time 11.46 minutes Area ratio 30% (Checked from this example of ☆ 7 identification)

Incidentally, according to the above-mentioned identification example 2, syn body (2
S, 3R) / anti body (2S, 3S) = 70/3
O which is a mixture of diastereomers consisting of 0 (area ratio)
Diastereomeric mixtures by reducing methylated derivatives with hydrogen gas in the presence of a palladium / carbon catalyst
In the reaction from which 1 is obtained, it is irrelevant to the configuration of the asymmetric carbon atom at the 2- and 3-positions. Therefore, the first peak (retention time: 10.11 minutes) of optically active liquid chromatography of diastereomeric mixture-1 corresponding to the area ratio of the syn isomer (2S, 3R) of the O-methylated derivative is syn
-(2S, 3R) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane, while the anti form of O-methylated derivative (2S, 3S The second peak (retention time 11.46 minutes) of optically active liquid chromatography of diastereomer mixture 1 in agreement with the area ratio of type) is the anti-
It was found to be (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.

Thus, ^{19 of} diastereomer mixture-1
The first peak (-1.86 ppm), which has an area ratio of 70% in the FNMR spectrum, is syn- (2S, 3R) -2-
(4-hydroxybenzoyloxy) -7-ethoxy-
The second peak (−2.33 p) which is 3-methoxy-1,1,1-trifluoroheptane and has an area ratio of 30%
pm) was confirmed to be anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane; 1 is syn- (2S,
3R) -2- (4-hydroxybenzoyloxy) -7
-Ethoxy-3-methoxy-1,1,1-trifluoroheptane and anti-2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,-
It consists of 1-trifluoroheptane, and its production ratio sy
n-body (2S, 3R) type / anti body (2S, 3S) type =
It could be confirmed that the mixture was a 70/30 (area ratio) diastereomer mixture.

[Four-step reaction] [compound of the present invention: syn-
(2S, 3R) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane and the compound of the present invention: anti- (2
S, 3S) -2- (4-hydroxybenzoyloxy)
Preparation of 7-ethoxy-3-methoxy-1,1,1-trifluoroheptane] Diastereomer mixture obtained in the third step reaction-1, 2
The first peak and the second peak are separated respectively using 00 g (5.5 mmol) of silica gel column chromatography under the following conditions, the eluent is distilled off under reduced pressure, and both are colorless and transparent liquid Of each target product of the first fraction [acquisition amount 1.26 g (3.47 mmol) acquisition rate 63%] and the second fraction [acquisition amount 0.54 g
(1.48 mmol) yield 27%] were obtained respectively.

The ¹ H NMR spectrum, 1 R absorption spectrum and MS spectrum of these desired products are in agreement with diastereomer mixture 1, and each desired product is 2- (4-)
Hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.
The ¹⁹ F NMR spectra are as follows, each one
A book peak was observed. Furthermore, identification example 2 of the third step reaction
Under the same conditions as in the above. The chart of the optically active liquid chromatography is as shown in FIG. 11 and FIG. 12, respectively.
From the analysis results of 2, one optically active peak is obtained, and when the retention time is indicated, it is as follows, and the first fraction as the target product is syn- (2S, 3R) -2
-(4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane is a compound of the present invention, and the second fraction is an anti-
It could be confirmed that the compound was (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane of the present invention.

Preparative silica gel column chromatography [trade name: Inert Siel PREP-ODS fraction, guard column 2-point set No. 5020-35112, GL Science Co., Ltd.] Filler: one having an octadecyl group chemically bonded to 10 μ silica gel having a purity of 99.9% Size: 10 mmφ × 250 mm H Eluent: n-hexane / isopropyl alcohol = 96
/ 4 (volume ratio) Flow rate: 2 ml / min Detection: UV detector, wavelength 254 nm Sample supply amount: 1 g

The first fraction [syn- (2S, 3)
R) -2- (4-hydroxybenzoyloxy) -7-
Ethoxy-3-methoxy-1,1,1-trifluoroheptane] Retention time 10.11 minutes Yield 1.95 g (5.36 mmol) yield 63% ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) -1.86 ppm Optically active liquid chromatography: retention time 10.11
Minute second flankion [anti-(2S, 3S) -2-
(4'-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane] retention time 11.46 minutes yield 0.83 g (2.30 mmol) yield 27% ¹⁹ F NMR Spectrum (from ext. CF ₃ C
OOH) -2.33 ppm Optically active liquid chromatography: retention time 11.46
Minutes

Example 2 [Compound of the Invention: syn- (2
S, 3R) -2- (4-hydroxybenzoyloxy)
-7-Ethoxy-3-methoxy-1,1,1-trifluoroheptane, and the compound of the present invention: anti- (2
S, 3S) -2- (4-hydroxybenzoyloxy)
Preparation of -7-Ethoxy-3-methoxy-1,1,1-trifluoroheptane, Wherein Diisobutylaluminum hydride is used as metal hydride]

(First-step reaction) [syn isomer (2S, 3R)
Production of a reaction product which is a mixture of diastereomers consisting of type / anti form (2S, 3S) type = 40/60 (area ratio)] Four-neck, equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel (S) -2 obtained in Reference Example 4 in a round bottom flask
-(4-benzyloxybenzoyloxy) -7-ethoxy-1,1,1-trifluoroheptanone-3, 1
23 ml was added to 0.95 g (25 mmol), made into a homogeneous solution with stirring, inserted into an ice water bath, and adjusted to 0 ° C. Then, 3.91 g (27.5 mmol) of diisobutylaluminum hydride and 23 ml of diethyl ether were charged into the dropping funnel and added dropwise over 10 minutes while stirring. After the addition is completed, the ice water bath is removed, and while stirring, the temperature is raised to room temperature, and the stirring is continued for 90 minutes.
The reaction was completed to obtain a reaction product solution. The obtained reaction product is syn form (2S, 3R) according to the identification example 3 described later.
It was confirmed that the mixture was a mixture of diastereomers consisting of type / anti form (2S, 3S) type = 40/60 (area ratio).

Identification Example 3: The reaction product is a syn isomer (2
S, 3R) / anti body (2S, 3S) = 40/6
Identification of being a diastereomeric mixture consisting of 0 (area ratio)] 20% by weight reaction product solution (raw material compound obtained above in a three-neck round bottom flask equipped with a thermometer, a stirrer and a reflux condenser Reaction product solution containing 5 mmol), 25 ml of 3N hydrochloric acid and 100 m of methanol
The reaction mixture was introduced into a warm water bath at a temperature of 80.degree. C., and while stirring, the temperature was raised to a boil, followed by heating to reflux for 7 hours to carry out a hydrolysis reaction. After the hydrolysis reaction is completed, the hot water bath is removed, and after cooling to room temperature while stirring,
After extraction with ether, the extract was washed with 20 ml of 20% aqueous sodium hydrogen carbonate solution and then with 200 ml of water, anhydrous magnesium sulfate was added to remove water, and then the solvent was distilled off under reduced pressure to give a syrupy residue. I got The residue was subjected to silica gel column chromatography [eluent n
Purification with -hexane / isopropyl alcohol = 95/5 (volume ratio) to obtain a colorless and transparent liquid product-3 [yield 0.9 g (3.92 ppm) 78.4%].

¹ H NMR spectrum of this product-3,
^The results of measurement of ¹⁹ F NMR spectrum and 1 R absorption spectrum are in agreement with those of Identification Example 1 of Example 1, and 7-ethoxy-
It was confirmed to be 1,1,1-trifluoroheptane-2,3-diol. Moreover, based on the result of the identification example 1 of Example 1, the result of measuring ¹⁹ F NMR spectrum is 2
From the position and area ratio of each peak, the product-3 is syn- (2S, 3R) -7-ethoxy-1,1,1-trifluoroheptane-2,3-diol and anti -(2S, 3S) -7-ethoxy-
It consists of 1,1,1-trifluoroheptane-2,3-diol, and its formation ratio syn form (2S, 3R) type / a
It turned out that it is a diastereomer mixture which consists of nti body (2S, 3S) type = 40/60 (area ratio). ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) First peak: -0.48 ppm, area ratio 40 syn body (2S, 3R) type Second peak: -2.21 ppm, area ratio 60 anti
Body (2S, 3S) type Therefore, the reaction product syn body (2S, 3R) type / anti body (2S, 3S) type = 40 obtained in the first step reaction
It could be confirmed that this was a mixture of diastereomers consisting of / 60 (area ratio).

(Second Stage Reaction) (O-Methylated Derivative) The remaining 80% of the reaction product obtained in the first stage reaction was produced in a round bottom flask equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel. Solution [(S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-7-ethoxyheptanone-a solution containing 20 millimoles of 3-equivalent] is added and inserted into an ice water bath The mixture was adjusted to 0.degree. C. while stirring. Then add methyl iodide 3.12g to the dropping funnel
Put (22 mmol) and 28 ml of diethyl ether,
It was added dropwise over 13 minutes while stirring. After completion of dripping
The ice water bath was removed, the temperature was raised to room temperature, and stirring was continued at room temperature for 2 hours to complete the reaction.

After completion of the reaction, the reaction solution is neutralized by the addition of a 5% aqueous solution of sodium hydrogen carbonate, and the solvent is distilled off under reduced pressure. A saturated aqueous solution of sodium thiosulfate solution is then added, followed by extraction with ether. The reaction mixture was concentrated to dryness under reduced pressure to give a syrupy residue. The residue is subjected to silica gel column chromatography [eluent n-hexane / isopropyl alcohol = 95/5 (volume ratio)]
To give a colorless, clear liquid O-methylated derivative [yield 7.54 g (16.6 mmol) 83%].
As a result of measuring a ¹⁹ F NMR spectrum of the obtained O-methylated derivative, two peaks are recognized, and the position and area ratio of each peak are shown as follows. ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) 1st peak: -2.20 ppm, area ratio 40% [syn
Body (2S, 3R) type ☆ 7] Second peak:-3.90 ppm, area ratio 60% [ant
i form (2S, 3S) type ☆ 7] (☆ 7, confirmed in the identification example 4 described later)

(Third Stage Reaction) A closed four-neck round bottom flask equipped with a thermometer, a stirrer, a dropping funnel, a hydrogen gas charge pipe and a polyethylene resin balloon was obtained by the above-mentioned second stage reaction. Add 4.99 g (11 mmol) of O-methylated derivative and 75 ml of methanol, and while stirring at room temperature, add 10% palladium / carbon catalyst to the dropping funnel.
g was added and slowly dropped to prepare a uniformly dispersed suspension. Then, while stirring at room temperature, the pressure 1.1 k
The reaction system was sealed with hydrogen gas of about g / cm ² and reduction reaction was performed. In the reduction reaction, the suspension was stirred, and supplied for 4 to 5 hours until absorption of hydrogen gas ceased to complete the reaction. After completion of the reduction reaction, the resulting reaction suspension is filtered to remove the palladium / carbon catalyst, and the filtrate is concentrated under reduced pressure to distill off methanol, and then by-product toluene is removed by a vacuum pump. A syrupy residue was obtained.
The residue was subjected to silica gel column chromatography [eluent n-hexane / isopropyl alcohol = 96/4
(Volume ratio)], and the eluent was distilled off under reduced pressure to obtain a colorless and transparent liquid product diastereomer mixture-2 [yield 3.92 g (10.78 mmol) yield 98%] The

¹ H NMR spectrum of this product, 1 R
The absorption spectrum and the result of measuring the MS spectrum are the same as the third step reaction of Example 1, and the product is
It was confirmed to be (4'-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane. As a result of measuring the ¹⁹ F NMR spectrum of the obtained product, two peaks are observed, and the position and area ratio of each peak are shown as follows. ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) 1st peak: -1.86 ppm, area ratio 40% [Syn
Body (2S, 3R) type ☆ 8] Second peak: -2.33 ppm, area ratio 60% [ant
i body (2S, 3S) type ☆ 8] (☆ 8, confirmed in the identification example 4 described later)

The product obtained is identified by the identification example 4 described later.
yn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1
-Trifluoroheptane and anti-(2S, 3
S) -2- (4-hydroxybenzoyloxy) -7-
It is a mixture of diastereomers consisting of ethoxy-3-methoxy-1,1,1-trifluoroheptane, and its formation ratio syn form (2S, 3R) type / anti form (2S,
It was confirmed that it is diastereomer mixture 2 which is 3S) type = 40/60 (area ratio).

Identification Example 4: The O-methylated derivative obtained in the second step reaction is a dia consisting of syn (2S, 3R) / anti (2S, 3S) = 40/60 (area ratio) It is a stereomer mixture, and diastereomer mixture-2 obtained in the third step reaction is syn- (2S, 3R)
-2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane and anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy -3-Methoxy-1,1,1-trifluoroheptane, and its formation ratio syn isomer (2S, 3R) type / anti isomer (2S,
Identification of being a mixture of diastereomers of 3S) type = 40/60 (area ratio)]

In a four-necked round-bottomed flask equipped with a thermometer, a stirrer, a reflux condenser, and a funnel, 2.27 g (5 mmol) of the O-methylated derivative obtained in the second step reaction of Example 2
Then, 25 ml of 3 N hydrochloric acid and 100 ml of methanol were added, and while stirring, the temperature was raised to 80 ° C., and the mixture was refluxed for 6 hours,
The hydrolysis reaction was carried out. Then, after cooling to room temperature,
The mixture is extracted with ether, and the extract is washed with a 20% aqueous solution of sodium carbonate and then with water, and then anhydrous magnesium sulfate is added to remove water, and then the solvent is distilled off under reduced pressure to give a colorless and transparent liquid product [Yield 0.98 g (4 mmol)
The yield is 80%].

Of this product¹H NMR spectrum, 1R
Measurement results of absorption spectrum and MS spectrum are identified
Consistent with Example 2, the product is 2-hydroxy-7-ethoxy
-3-Methoxy-1,1,1-trifluoroheptane
there were. Of the obtained product¹⁹Measure FNMR spectrum
As a result, two peaks are observed, and the position of each peak and
The area ratio is as follows.¹⁹ F NMR spectrum (from ext. CF₃C
OOH) 1st peak: -2.12 ppm, area ratio 40% [syn
Body (2S, 3R) type ☆ 9] Second peak: -4.14 ppm, area ratio 60% [ant
i body (2S, 3S) type ☆ 9] (☆ 9, confirmed by this identification example)

The above-mentioned product was also subjected to optically active gas chromatography under the same conditions as in Identification Example 2 of Example 1. Fig. 13 is a chart of optically active gas chromatography. From the analysis results of the chart in FIG. 13, two optically active peaks are observed, and the retention time and the area ratio of each peak are as follows. 1st peak: retention time 14.55 minutes, area ratio 40% [s
yn body (2S, 3R) type ☆ 10] Second peak: retention time 15.27 minutes, area ratio 60% [a
nti body (2S, 3S) type ☆ 10]

Based on the results of Identification Example 2 of Example 1, the first
The peak (retention time 14.55 min) is syn- (2S, 3
R) -2-hydroxy-7-ethoxy-3-methoxy-
1,1,1-trifluoroheptane, second peak (retention time 15.27 min) is anti- (2S, 3S)
-2-hydroxy-7-ethoxy-3-methoxy-1,
It is confirmed to be 1,1-trifluoroheptane,
The product is syn- (2S, 3R) -2-hydroxy-7
Consisting of -ethoxy-3-methoxy-1,1,1-trifluoroheptane and anti- (2S, 3S) -2-hydroxy-7-ethoxy-3-methoxy-1,1,1-trifluoroheptane, Generation ratio syn body (2
S, 3R) / anti body (2S, 3S) = 40/6
It could be confirmed that this was a mixture of diastereomers consisting of 0 (area ratio).

Syn- (2S, 3R) -2-hydroxy-7-ethoxy-3-methoxy-1,1,1-trifluoroheptane: The first peak of the ¹⁹ F NMR spectrum of the product having the same area ratio (- 2.12 ppm) is syn-
(2S, 3R) -2-hydroxy-7-ethoxy-3-
It was confirmed that it may be methoxy-1,1,1-trifluoroheptane. anti-(2S, 3S)
-2-hydroxy-7-ethoxy-3-methoxy-1,
The second peak (-4.14p) of the ¹⁹ F NMR spectrum of the product having the same area ratio as that of 1,1-trifluoroheptane
pm) is anti- (2S, 3S) -2-hydroxy-
It was confirmed to be 7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.

Accordingly, the absolute configuration of the asymmetric carbon atoms at positions 2 and 3 of the product obtained by hydrolyzing the O-methylated derivative and the O-methylated derivative is not changed.
-Area ratio 40 of ¹⁹ F NMR spectrum of methylated derivative
% Peak (-2.20 ppm) is a syn isomer (2S, 3 R) type, and the second peak (−3.90 ppm) in the ¹⁹ F NMR spectrum has an area ratio of 60% is an
It turned out that it is ti body (2S, 3S) type, and the O-methylated derivative is a diastereomer consisting of syn body (2S, 3R) type / anti body (2S, 3S) type = 40/60 (area ratio) It could be confirmed that it was a mer mixture.

Then, the diastereomer mixture-2 obtained in the third step reaction was subjected to optically active liquid chromatography under the same conditions as in Identification Example 2 of Example 1. The chart of the optically active liquid chromatography is as shown in FIG. 14. From the analysis result of FIG. 14, two optically active peaks were obtained, and the retention time and the area ratio were as follows. First peak: [syn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane ☆ 11] retention time: 10.11 minutes Area ratio 40% Second peak: [anti- (2S, 3S) -2- (4-)
Hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane * 11] Retention time: 11.46 minutes, area ratio 60% (* 11 confirmed from this identification example)

Incidentally, syn body (2S, 3R) type / ant
Diastereomeric mixture by reducing O-methylated derivative which is a diastereomeric mixture consisting of Form i (2S, 3S) = 40/60 (area ratio) with hydrogen gas in the presence of a palladium / carbon catalyst- In the reaction from which 2 is obtained, the configuration of the asymmetric carbon atom at the 2 and 3 positions is irrelevant. Therefore, the syn-isomer of O-methylated derivative (2
The first peak (retention time: 10.11 minutes) of optically active liquid chromatography of diastereomeric mixture-2 corresponding to the area ratio of S, 3R) type is syn- (2S, 3R)-
2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane, while the anti form of O-methylated derivative (2S,
Diastereomeric mixture consistent with area ratio of 3S) type
The second peak of the optically active liquid chromatography of No. 2 (retention time 11.46 minutes) is anti- (2S, 3S) -2
It was found to be-(4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.

Thus, ^{19 of} diastereomer mixture-2
The first peak (-1.86 ppm), which has an area ratio of 40% in the FNMR spectrum, is syn- (2S, 3R) -2-
(4-hydroxybenzoyloxy) -7-ethoxy-
The second peak (−2.33 p) which is 3-methoxy-1,1,1-trifluoroheptane and has an area ratio of 60%
pm) was confirmed to be anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane; 2 is syn- (2S,
3R) -2- (4-hydroxybenzoyloxy) -7
-Ethoxy-3-methoxy-1,1,1-trifluoroheptane and anti-2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,-
It consists of 1-trifluoroheptane, and its production ratio sy
n-body (2S, 3R) type / anti body (2S, 3S) type =
It could be confirmed that the mixture was a 40/60 (area ratio) diastereomer mixture.

[Four-step reaction] [compound of the present invention: syn-
(2S, 3R) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane, and a compound of the present invention: anti-
Preparation of (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane] Diastereomeric mixture 2 obtained in the third step reaction ,
Under the same conditions as in the fourth step reaction of Example 1, 2.91 g (8 mmol) of the first peak and the second peak were fractionated respectively using silica gel column chromatography, and the eluent was distilled off under reduced pressure. The first fraction [a yield of 1.05 g (2.
A millimole yield of 36%] and a second fraction [yield 1.57 g (4.32 millimoles) 54%] were obtained respectively.

The ¹ H NMR spectrum, 1 R absorption spectrum and MS spectrum of these target products are in agreement with diastereomer mixture 2, and each target product is 2- (4- (4-)
Hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.
The ¹⁹ F NMR spectrum is as follows, and one peak was observed for each. Furthermore, when optically active liquid chromatography was applied under the same conditions as in the fourth step reaction of Example 1, charts similar to FIGS. 11 and 12 were obtained. From the above results, the first fraction, which is the target product, is s
yn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1
-A compound according to the invention of trifluoroheptane, the second fraction being anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane It was confirmed that the compound of the present invention was

First fraction [syn- (2S, 3
R) -2- (4-hydroxybenzoyloxy) -7-
Ethoxy-3-methoxy-1,1,1-trifluoroheptane] Retention time 25.30 to 32.30 minutes Yield 1.05 g (2.88 mmol), yield 36
% ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) -1.86 ppm Optically active liquid chromatography Retention time 10.11 minutes Second fraction [anti- (2S, 3S) -2-
(4-hydroxybenzoyloxy) -7-ethoxy-
3-methoxy-1,1,1-trifluoroheptane] retention time 34.25 to 44.25 minutes yield 1.57 g (4.32 mmol) yield 54
% ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) -2.33 ppm Optically active liquid chromatography Retention time 11.46 minutes

[0155]Reference Example 5[Syn- (2S, 3R) -2-
{4- [4- (4 -N-decylphenyl) benzoyl io
Xy] benzoyloxy} -7-ethoxy-3-methoxy
Cis-1,1,1-trifluoroheptane (final useful compound
Production of the product] equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel
In a 4-neck round bottom flask, the syn- obtained in Example 1
(2S, 3R) -2- (4-hydroxy benzoyl ester
C) -7-Ethoxy-3-methoxy-1,1,1-tri
1.46 g (4 mmol) of fluoroheptane, 4-
1.62 g of (4-n-decylphenyl) benzoic acid (4.
8 mmol), N, N-dimethylaminopyridine 0.
29 g (2.4 mmol) and methylene chloride 120 m
The solution was stirred at room temperature to prepare a homogeneous solution. Next
Dicyclohexyl carbodiimide in a dropping funnel 1.
Add 22 g (6 mmol), add dropwise with stirring,
Next, keep stirring at room temperature for 5 hours to complete the reaction.
The

After completion of the reaction, precipitated white crystals of dicyclohexylurea are removed by filtration, and the filtrate is diluted with 1N hydrochloric acid, 1
After washing with 0% aqueous sodium hydrogen carbonate solution and then with water,
Anhydrous magnesium sulfate was added to remove water, and then the solvent was evaporated under reduced pressure to remove methylene chloride to obtain a syrupy residue. The residue was dissolved in hot n-hexane and then crystallized by cooling to obtain white crude crystals. The resulting crude crystals are purified by liquid chromatography [eluent n-hexane / isopropyl alcohol = 93/7 (volume ratio)] to give a colorless, transparent, liquid target product [yield: 2.33 g (3.4 mmol) The yield is 85%].

The objective product is¹H NMR spectrum,
¹⁹F NMR spectrum, 1R absorption spectrum and MS
The results of measuring the spectrum are as follows.
The object is 2- {4- [4- (4) -N-decylphenyl) ben
Zoyloxy] benzoyloxy} -7-ethoxy-3
-Methoxy-1,1,1-trifluoroheptane
The Also, the target product is the two asymmetric carbons of the starting compound.
It is unrelated to the configuration of the element atom, and is optically active
Since the heart does not change, syn-(2S, 3R)-2
-{4- [4- (4) -N-decylphenyl) benzoyl
Oxy] benzoyloxy} -7-ethoxy-3-meth
Be xy-1,1,1-trifumeoroheptane
confirmed. Furthermore, according to the identification example described later, the syn form (2
It confirmed that it was S, 3R type.

¹ H NMR spectrum (CDCl ₃ ) 0.8 to 1.04 ppm (6 H), 1.09 to 1.62
ppm (24H), 2.07 to 2.20 ppm (2
H), 2.60 ppm (3 H), 3.07 to 3.20 p
pm (2H), 4.15 to 4.20 ppm (1H),
4.52 to 4.56 ppm (1H), 6.58 to 8.0
4 ppm (12 H) ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH)-4.95 ppm 1R absorption spectrum (neat) 1,120 cm ^-1 (COC), 1,730 cm ^-1 (CO
O) MS spectrum m / z 684 (M ⁺ ) Also, a ¹⁹ F NMR spectrum is shown in FIG.

Identification Example [The target product is syn- (2
S, 3R) -2- {4- [4- (4) -N-decyl pheny
Le) Benzoyloxy] Benzoyloxy} -7-Eto
Xy-3-methoxy-1,1,1-trifluorohepta
Identification of being a water heater] A thermometer, a stirrer, a reflux condenser, a four-piece equipped with a dropping funnel
Raw material compound 0.36 g (1 millimole) in a round bottom flask
And 5 mmol of 3 N hydrochloric acid and 20 ml of methanol.
Heat to 80 ° C and reflux for 6 hours to carry out hydrolysis reaction
The Then, after cooling to room temperature, ether extraction and extraction
The effluent is washed with 20% aqueous sodium carbonate solution and then with water
After washing with water, add anhydrous magnesium sulfate to
After removal, the solvent is distilled off under reduced pressure to produce a colorless and transparent liquid.
1 [yield 0.2 g (0.8 mmol) yield 80%]
I got

¹ H NMR spectrum of this product-1,
¹⁹ F NMR spectrum, 1R absorption spectrum and MS
The results of measuring the spectrum are as follows.
1 is 2-hydroxy-7-ethoxy-3-methoxy-
It was 1,1,1-trifluoroheptane. ¹ H NMR spectrum (CDCl ₃ ) 0.80 to 1.00 ppm (3 H), 1.04 to 1.3
0 ppm (6 H), 2.48 to 2.64 ppm (3
H), 2.69 ppm (3H), 2.84 to 3.00 p
pm (1 H), 3.12 to 3.26 ppm (2 H),
3.77 to 3.90 ppm (1 H), 4.02 to 4.1
4 ppm (1 H) ¹⁹ F NMR spectrum-2.12 ppm 1 R absorption spectrum (neat) 1,120 cm ^-1 (COC), 1,670 cm ^-1 (O
H) MS spectrum m / z 244 (M ⁺ ) Also, a ¹ H NMR spectrum is shown in FIG.

Then, under the following conditions, the above-mentioned product-1:
It was applied to gas chromatography (hereinafter referred to as optically active gas chromatography) having an optical isomer separation column. Column: trade name Cyclodex β 236 M (manufactured by Chrompack): size ID 0.25 mm, length 25 m: silica capillary column Column temperature: 100 ° C. × 10 minutes and then raised to 200 ° C. at a heating rate of 4 ° C./min Warm carrier gas: Helium, gas flow rate 60 Nl / min, split ratio 10 0/1 Detection: FID

A chart of optically active gas chromatography is shown in FIG. From the analysis result of FIG. 15, one optically active peak was observed, and the retention time was 14.55 minutes. The product-1 obtained by hydrolyzing the starting compound has only one optical activity, and the product is sy.
n- (2S, 3R) -2-hydroxy-7-ethoxy-
It was found to be 3-methoxy-1,1,1-trifluoroheptane. Then 0.36 g of the starting compound (1
0.68 g (1 ppm) of the desired product instead of ppm)
The hydrolysis reaction is carried out in the same manner as described above except that a colorless and transparent liquid product-2 [yield 0.2 g (0.
8 mmol) yield 80%] was obtained. As a result of measuring various spectra of this product-2, it is the same as the product-1, and 2-hydroxy-7-ethoxy-3-methoxy-
It was 1,1,1-trifluoroheptane.

Further, the same conditions as above for the above product-2
And one with optical activity gas chromatography
The optically active peak of is obtained with a retention time of 14.55.
Product-2 is similar to product-1 and syn-
(2S, 3R) -2-hydroxy-7-ethoxy-3-
It is methoxy-1,1,1-trifluoroheptane
The Therefore, even if the target product is hydrolyzed,
From the fact that the absolute configuration of the asymmetric carbon atom at position 3 does not change,
It is determined that the target product is syn (2S, 3R) type
Light, syn- (2S, 3R) -2- {4- [4- (4)
-N-decylphenyl) benzoyloxy] benzoyl
Oxy} -7-ethoxy-3-methoxy-1,1,1-
It could be confirmed that it was trifluoroheptane.

Reference Example 6 (Characteristics of Compound of Reference Example 5) (Measurement of Phase Transition Temperature of Compound of Reference Example 5) With respect to the compound of Reference Example 5, DSC and the electric field response of the liquid crystal display element described later by polarized light microscope The results of measuring the phase transition temperature by observation are as follows. However, cry represents a crystal phase, _SCA ☆: an antiferroelectric liquid crystal phase, SA: a smectic A phase, and ISO: an isotropic liquid phase. Also, when the temperature in the upper row is raised at 4 ° C / min, the value in the lower row is 4 ° C / m
It shows the phase transition temperature when the temperature is lowered by in. Phase transition temperature:

[0165]

[Image 17]

Thus, the compound of Reference Example 5 was an antiferroelectric liquid crystal compound including near room temperature.

(Production of Liquid Crystal Display Element) 2 with Transparent Electrode
An alignment film spin-coated with polyimide was rubbed on a sheet of glass substrates, and the cells were assembled at a gap interval of 1.7 μm so that the rubbing directions were parallel to each other. The compound obtained in Reference Example 5 was injected into the cell obtained above as an isotropic liquid phase. Then, it was gradually cooled to a liquid crystal state. This liquid crystal cell is placed between a polarizer and an analyzer whose transmission axes are orthogonal, and placed so that the normal direction of the molecular layer in the chiral smectic C phase coincides with the direction of the polarizer or analyzer, and no electric field is applied. At the time (0 V), the third stable state is made into a dark state, and by applying an electric field, it is changed to a chiral smectic C phase, and by using that state as a bright state, liquid crystal display capable of displaying dark and light The device was made. That is, when the applied voltage was 0 V, the angle of the cell to the polarizer was adjusted so as to minimize the amount of transmitted light. The amount of transmitted light is 1 when the transmission axis of the analyzer is rotated to coincide with the transmission axis of the polarizer.
It is 00%.

(Evaluation of Liquid Crystal Display Element) Using the liquid crystal display element prepared above, an applied voltage of ± 8.7 at 25 ° C.
FIG. 15 shows a diagram in which the change in the amount of transmitted light with respect to V is measured.
It became. From the figure, a double hysteresis curve was obtained showing one dark state and two bright states. Moreover, the result of having evaluated the performance of the liquid crystal display element by the transmitted light amount change with respect to the applied voltage change in 25 degreeC was as follows. Response time: 28.2us (time to change from bright state to dark state at 25 ° C) Threshold voltage: 5.12 V / um (voltage to be fully bright state at 25 ° C) Tilt angle: 30.20 (The angle at which the optical axis at the threshold voltage is a polarizer at 25 ° C.) As a result, the compound of Reference Example 5 has an antiferroelectric liquid crystal phase near room temperature, and a liquid crystal display using it The element is at 25 ° C,
A double hysteresis curve with three stable states is shown, response time is short, threshold voltage is low, tilt angle is large, and it has been confirmed that it is an antiferroelectric liquid crystal compound excellent as a large screen display material etc. .

[0169]

The present invention is a novel syn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -3 which is useful as a precursor of an antiferroelectric liquid crystal compound which can be easily switched at room temperature. -Methoxy-1,1,1-trifluoro-terminated ethoxyalkane and anti- (2S, 3
S) -2- (4-hydroxybenzoyloxy) -3-
It is a provision of methoxy-1,1,1-trifluoro-terminated ethoxyalkane, (S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-terminated ethoxyheptanone-3 metal hydrogen The compound can be efficiently produced by reduction with a halide, methoxylation of the formed hydroxy group, and detolueneing.

Brief Description of the Drawings

1 is 1-hydroxy-2,2,2 obtained in Reference Example 3. FIG.
2-trifluoroethyl-4-ethoxybutyl ketone
^{It is a 1} H NMR spectrum figure.

FIG. 2 is a chart of optically active gas chromatography of an enantiomeric mixture of 1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone obtained in Identification Example 1 in Reference Example 3; .

[FIG. 3] (S) -1-obtained in Identification Example 1 in Reference Example 3
1 is a chart of optically active gas chromatography of hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone.

FIG. 4 is a ¹ H NMR spectral diagram of 2- (4-benzyloxybenzoyloxy) -7-ethoxy-1,1,1-trifluoroheptanone-3 obtained in Reference Example 4;

FIG. 5 shows the identification 7 of the first-step reaction of Example 1.
-Ethoxy-1,1,1-trifluoroheptane-2,
It is a < ¹ > H NMR spectrum figure of 3-diol.

FIG. 6 is an identification example 1 of the first step reaction of Example 1
2,2-Dimethyl-4- (4-ethoxybutyl) -5-
Trifluoromethyl-1,3-dioxolane  ¹HN
It is a MR spectrum figure.

FIG. 7 is a graph showing the results of 2-step reaction obtained in the third step reaction of Example 1;
Droxybenzoyloxy) -7-ethoxy-3-meth
Of xyl-1,1,1-trifluoroheptane  ¹HNM
It is R spectrum figure.

FIG. 8 shows the identification 2 of the third step reaction of Example 1.
-Hydroxy-7-ethoxy-3-methoxy-1,1,
It is a ¹ H NMR spectrum figure of 1-trifluoro heptane.

[FIG. 9] Identification Example 3 of the third step reaction of Example 1
yn- (2S, 3R) -2-hydroxy-7-ethoxy-3-methoxy-1,1,1-trifluoroheptane and anti- (2S, 3S) -2-hydroxy-7-
It consists of ethoxy-3-methoxy-1,1,1-trifluoroheptane, and its formation ratio syn form (2S, 3R)
It is a chart of the optically active gas chromatography of the diastereomer mixture of type / anti body (2S, 3S) type = 70/30 (area ratio).

10 is a mixture of diastereomers-1 obtained in the third step reaction of Example 1: syn- (2S, 3R) -2- (4).
-Hydroxybenzoyloxy) -7-ethoxy-3-
Methoxy-1,1,1-trifluoroheptane / ant
i- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-
It is a chart of the optically active liquid chromatography of the diastereomer mixture which consists of trifluoro heptane = 70/30 (area ratio).

11 is a compound of the present invention obtained by the fourth step reaction of Example 1: syn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,
It is a chart of an optically active liquid chromatography of 1, 1-trifluoro heptane.

12 is a compound of the present invention obtained by the fourth step reaction of Example 1: anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-
1 is a chart of optically active liquid chromatography of 1,1,1-trifluoroheptane.

13 is identification of the third step reaction of Example 2. syn- (2S, 3R) -2-hydroxy-7-ethoxy-3-methoxy-1,1,1-trifluoroheptane obtained in Example 4 and anti- (2S, 3S) -7-ethoxy-3-
It consists of methoxy-1,1,1-trifluoroheptane, and its formation ratio syn form (2S, 3R) type / anti
It is a chart of the optically active gas chromatography of the diastereomer mixture of body (2S, 3S) type = 40/60 (area ratio).

FIG. 14 Identification of third step reaction of Example 2 Diastereomer mixture obtained in Example 4-2: syn- (2S, 3R)
-2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane / anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy -3-Methoxy-
It is a chart of the optically active liquid chromatography of the diastereomer mixture which consists of 1, 1, 1- trifluoro heptane = 40/60 (area ratio).

[FIG. 15] syn- (2S, 3R) obtained in Reference Example 5
-2- {4- [4- (4) -N-decylphenyl) benzo
Yloxy] benzoyloxy} -7-ethoxy-3-
Of methoxy-1,1,1-trifluoroheptane¹HN
It is a MR spectrum figure.

[Fig. 16] Product-1 obtained in the identification example of Reference Example 5: s
yn- (2S, 3R) -2-hydroxy-7-ethoxy-3-methoxy-1,1,1-trifluoroheptane
^{It is a 1} H NMR spectrum figure.

FIG. 17 is a chart of optically active gas chromatography of product-1 obtained in the identification example of Reference Example 5;

FIG. 18: syn- (2S, 3R) -2- {4- [4-]
(4 -N-decylphenyl) benzoyloxy] benzo
Iroxy} -7-ethoxy-3-methoxy-1,1,
Double Hiss of 1-Trifluoroheptane Liquid Crystal Display Device
It is a terrisis curve.

── ── ── ── ── ──

【Procedure Amendment】

[Submission Date] January 8, 1996

[Procedure amendment 1]

[Name of document to be corrected] statement

[Item name to be corrected]

【Correction method】 Change

[Content of correction]

[0066]

[Image 15]

[Procedure amendment 2]

[Name of document to be corrected] statement

[Item name to be corrected] 0068

【Correction method】 Change

[Content of correction]

From the respective target products, the first fraction is syn- (2S, 3R) -2 by making the acquisition ratio of the first fraction the area ratio of the first peak of the ¹⁹ F NMR spectrum of the third step reaction. It is confirmed to be-(4-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoro-terminated ethoxyalkane. Further, when optically active liquid chromatography analysis is performed, one optical activity peak is obtained, and it can be confirmed from the retention time that the compound is a syn isomer (2S, 3R) of the present invention compound.

[Procedure amendment 3]

[Name of document to be corrected] statement

[Item name to be corrected] 0075

【Correction method】 Change

[Content of correction]

[0075]

[Image 18]

[Procedure amendment 4]

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【Correction method】 Change

[Content of correction]

¹ H NMR spectrum of this product, ¹⁹
F NMR spectrum, 1R absorption spectrum, and MS
The results of measuring the spectrum are as follows, and are independent of the configuration of the asymmetric carbon atom of this product, and the product is the starting compound (S) -N- because optical inversion does not occur. It was confirmed that it is (2-hydroxy-3,3,3-triculopropionyl) pyrrolidine. ¹ H NMR spectrum ( CDCl ₃ ) 1.53 to 2.37 ppm (4H, m), 321 to
3.88 ppm (4H, m), 4.14 ppm (1 H,
br), 4.58 (1 H, q) ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) −4.2 ppm (d, J = 6.0) 1 R absorption spectrum (neat) 1,640 cm ⁻¹ (CO), 3,330 cm ⁻¹ (O
H) MS spectrum m / z 197 (M ⁺ )

[Procedure amendment 5]

[Name of document to be corrected] statement

[Item name to be corrected] 0104

【Correction method】 Change

[Content of correction]

¹ H NMR spectrum (CDCl ₃ ) 0.86 to 1.00 ppm (3 H), 1.06 to 1.2
4 ppm (6 H), 2.69 to 2.80 ppm (2
H), 2.95 to 3.16 ppm (1 H), 3.20 to
3.35 ppm (2H), 3.52 to 3.66 ppm
(2H), 4.08 to 4.16 ppm (1H) ¹⁹ F NMR spectrum (from ext. CF ₃
COOH) 1R absorption spectrum (neat) 1,150 cm ⁻¹ (COC), 3,270 cm
⁻¹ (OH), MS spectrum m / z. 230 (M ⁺ ) Also, the ¹ H NMR spectrum is shown in FIG.

[Procedure amendment 6]

[Name of document to be corrected] statement

[Item name to be corrected] 0113

【Correction method】 Change

[Content of correction]

After completion of the reaction, a 5% aqueous sodium hydrogen carbonate solution is added for neutralization, and the solvent is distilled off under reduced pressure. A saturated aqueous sodium thiosulfate solution is then added, followed by ether extraction and extraction with anhydrous magnesium sulfate. The reaction mixture was concentrated to dryness under reduced pressure to give a syrupy residue. The residue is subjected to silica gel column chromatography [eluent n-hexane / isopropyl alcohol = 95/5 (volume ratio)]
To give a colorless, clear liquid O-methylated derivative [yield 5.79 g (12.75 mmol) yield 85%]. As a result of measuring the ¹⁹ F NMR spectrum of the obtained O-methylated derivative, two peaks are recognized, and the position and area ratio of each peak are shown as follows: ¹⁹ F NMR spectrum (from ext. CF ₃
COOH) ^Thus, from 19 FNMR the regular 2 Results and below the spectrum, O- methylated derivatives s yn body (2
S, 3R) / anti body (2S, 3S) = 70/3
It was confirmed that the mixture was a mixture of diastereomers consisting of 0 (area ratio).

[Procedure amendment 7]

[Name of document to be corrected] statement

[Item name to be corrected] 0116

【Correction method】 Change

[Content of correction]

¹ H NMR spectrum (CDCl ₃ ) 0.87 to 0.96 ppm (3 H), 1.09 to 1.5
3 ppm (6 H), 2.60 to 2.72 ppm (2
H), 2.75 ppm (3H), 2.87 to 3.00 p
pm (1 H), 3.27 to 3.42 ppm (2 H),
4.18 to 4.35 ppm (1H), 5.41 ppm
(1H), 6.69 to 7.98 ppm (4H, AB pattern) ¹⁹ F NMR spectrum (from ext. CF ₃
COOH) 1R absorption spectrum (neat) 1,110 cm ⁻¹ (COC), 1,740 cm
⁻¹ (COO), 3,300 cm ⁻¹ (OH), MS spectrum m / z. 364 (M ⁺ ) Also, the ¹ H NMR spectrum is shown in FIG.

[Procedure amendment 8]

[Name of document to be corrected] statement

[Item name to be corrected] 0118

【Correction method】 Change

[Content of correction]

Identification Example 2: The O-methylated derivative obtained in the second step reaction is a dia consisting of syn form (2S, 3R) type / anti form (2S, 3S) type = 70/30 (area ratio) It is a stereomeric mixture, and the diastereomeric mixture-1 obtained in the third step reaction is syn- (2S, 3)
R) -2- (4-hydroxybenzoyloxy) -7-
Ethoxy-3-methoxy-1,1,1-trifluoroheptane and anti- (2S, 3S) -2- (4- hydrine)
It is composed of droxybenzoyloxy ) -7-ethoxy-3-methoxy-1,1,1-trifluorohepron and the formation ratio syn form (2S, 3R) type / anti form (2
Identification of the S, 3S) type = 70/30 (area ratio) of diastereomer mixture-1] Example 4 in a four-necked round bottom flask equipped with a thermometer, a stirrer, a reflux condenser, and a funnel. O-methylated derivative 1.82 obtained by the second step reaction of
g (4 mmol), 20 ml of 3N hydrochloric acid and 80 ml of methanol were added, and the temperature was raised to 80 ° C. while stirring,
Reflux for an hour to obtain a hydrolysis reaction. Then, after cooling to room temperature, extract with ether, wash the extract with 20% aqueous sodium hydrogen carbonate solution and then with water, add anhydrous magnesium sulfate to remove water, and then remove the solvent under reduced pressure Colorless, clear liquid product [yield 0.78g
(3.2 mmol) yield 80%] was obtained.

[Procedure amendment 9]

[Name of document to be corrected] statement

[Item name to be corrected] 0119

【Correction method】 Change

[Content of correction]

¹ H NMR spectrum of this product, ¹⁹
F NMR spectrum, 1R absorption spectrum, and MS
The results of measuring the spectrum are as follows, and the product is 2-hydroxy-7-ethoxy-3-methoxy-1,
1,1-trifluoroheptane. ¹ H NMR spectrum (CDCl ₃ ) 0.81 to 1.00 ppm (3 H), 1.04 to 1.3
0 ppm (6 H), 2.48 to 2.64 ppm (3
H), 2.69 ppm (3H), 2.84 to 3.00 p
pm (1 H), 3.12 to 3.26 ppm (2 H),
3.77 to 3.90 ppm (1 H), 4.02 to 4.1
4 ppm (1 H) ¹⁹ F NMR spectrum (from ext. CF ₃
COOH) 1R absorption spectrum (neat) 1,120 cm ^-1 (COC), 1,670 cm
^-1 (OH), MS spectrum m / z 244 (M ⁺ ) Also, ¹ H NMR spectrum is shown in FIG.

[Procedure amendment 10]

[Name of document to be corrected] statement

[Item name to be corrected] 0121

【Correction method】 Change

[Content of correction]

The chart of optically active gas chromatography is shown in FIG. From the analysis results of the chart in FIG. 9, two optically active peaks are observed, and the retention time and the area ratio of each peak are as follows.

[Procedure amendment 11]

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[Item name to be corrected] 0132

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[Content of correction]

The first fraction [syn- (2S, 3)
R) -2- (4-hydroxybenzoyloxy) -7-
Ethoxy-3-methoxy-1,1,1-trifluoroheptane] retention time 25.30 to 32.30 minutes yield 1.95 g (5.36 mmol) yield 63% ¹⁹ F NMR spectrum (from ext. CF ₃
COOH) -1.86 ppm Optically active liquid chromatography: retention time 10.11
Minute second flankion [anti-(2S, 3S) -2-
(4'-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane] retention time 34.25 to 44.25 minutes yield 0.83 g (2.30 mmol) yield 27% ¹⁹ F NMR spectrum (from ext. CF ₃
COOH) -2.33 ppm Optically active liquid chromatography: retention time 11.46
Minutes

[Procedure amendment 12]

[Name of document to be corrected] statement

[Item name to be corrected] 0140

【Correction method】 Change

[Content of correction]

¹ H NMR spectrum of this product, 1 R
The absorption spectrum and the result of measuring the MS spectrum are the same as the third step reaction of Example 1, and the product is
It was confirmed to be (4'-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane. ¹⁹ F NMR of the obtained product
As a result of measuring the spectrum, two peaks are observed,
The position and area ratio of each peak are as follows. ¹⁹ F NMR spectrum (from ext. CF ₃
COOH)

[Procedure amendment 13]

[Name of document to be corrected] statement

[Name of item to be corrected] 0160

【Correction method】 Change

[Content of correction]

¹ H NMR spectrum of this product-1,
¹⁹ F NMR spectrum, 1R absorption spectrum and M
The results of measurement of the S spectrum are as follows, and the product-1 is 2-hydroxy-7-ethoxy-3-methoxy-
It was 1,1,1-trifluoroheptane. ¹ H NMR spectrum (CDCl ₃ ) 0.80 to 1.00 ppm (3 H), 1.04 to 1.3
0 ppm (6 H), 2.48 to 2.64 ppm (3
H), 2.69 ppm (3H), 2.84 to 3.00 p
pm (1 H), 3.12 to 3.26 ppm (2 H),
3.77 to 3.90 ppm (1 H), 4.02 to 4.1
4 ppm (1 H) ¹⁹ F NMR spectrum (from ext. CF ₃
COOH) -2.12 ppm 1R absorption spectrum (neat) 1,120 cm ^-1 (COC), 1,670 cm
^-1 (OH) MS spectrum m / z 244 (M ⁺ ) Also, a ¹ H NMR spectrum is shown in FIG.

[Procedure amendment 14]

[Name of document to be corrected] statement

[Name of item to be corrected] 0167

【Correction method】 Change

[Content of correction]

(Production of Liquid Crystal Display Element) 2 with Transparent Electrode
An alignment film spin-coated with polyimide was rubbed on a sheet of glass substrate, and the cells were assembled at a gap interval of 1.7 μm so that the rubbing directions were parallel to each other. The compound obtained in Reference Example 5 was injected into the cell obtained above as an isotropic liquid phase. Then, it was gradually cooled to a liquid crystal state. This liquid crystal cell is placed between a polarizer and an analyzer whose transmission axes are orthogonal, and placed so that the normal direction of the molecular layer in the chiral smectic C phase coincides with the direction of the polarizer or analyzer, and no electric field is applied. At the time (0 V), the third stable state is made into a dark state, and by applying an electric field, it is changed to a chiral smectic C phase, and by using that state as a bright state, liquid crystal display capable of displaying dark and light The device was made. That is, when the applied voltage was 0 V, the angle of the cell to the polarizer was adjusted so as to minimize the amount of transmitted light. The amount of transmitted light is 1 when the transmission axis of the analyzer is rotated to coincide with the transmission axis of the polarizer.
It is 00%.

[Procedure amendment 15]

[Name of document to be corrected] statement

[Item name to be corrected] 0168

【Correction method】 Change

[Content of correction]

(Evaluation of Liquid Crystal Display Element) Using the liquid crystal display element prepared above, an applied voltage of ± 8.7 at 25 ° C.
FIG. 15 shows a diagram in which the change in the amount of transmitted light with respect to V is measured.
It became. From the figure, a double hysteresis curve was obtained showing one dark state and two bright states. Moreover, the result of having evaluated the performance of the liquid crystal display element by the transmitted light amount change with respect to the applied voltage change in 25 degreeC was as follows. Response time: 28. 2 μs (time to change from bright state to dark state at 25 ° C) Threshold voltage: 5.12 V / μm (voltage at which completely bright state at 25 ° C) Tilt angle: 30.20 ° (The angle at which the optical axis at the threshold voltage becomes a polarizer at 25 ° C) As a result, the compound of Reference Example 5 has an antiferroelectric liquid crystal phase near room temperature, and a liquid crystal using it The display is at 25 ° C,
A double hysteresis curve with three stable states is shown, response time is short, threshold voltage is low, tilt angle is large, and it has been confirmed that it is an antiferroelectric liquid crystal compound excellent as a large screen display material etc. .

[Procedure amendment 16]

[Name of document to be corrected] statement

[Item name to be corrected] 0169

【Correction method】 Change

[Content of correction]

[0169]

The present invention is a novel syn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -3 which is useful as a precursor of an antiferroelectric liquid crystal compound which can be easily switched at room temperature. -Methoxy-1,1,1-trifluoro-terminated ethoxyalkane and anti- (2S, 3
S) -2- (4-hydroxybenzoyloxy) -3-
It is a provision of methoxy-1,1,1-trifluoro-terminated ethoxyalkane, (S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-terminated ethoxyheptanone-3 metal hydrogen The reaction product can be efficiently produced by reducing with azide and methoxylating the formed reaction product, followed by detolueneing.

[Procedure amendment 17]

[Document name to be corrected] Drawing

[Item to be corrected] Figure 12

【Correction method】 Change

[Content of correction]

[Fig. 12]

[Procedure amendment 18]

[Document name to be corrected] Drawing

【Items to be corrected】 Fig. 14

【Correction method】 Change

[Content of correction]

[Fig. 14]

[Procedure amendment 19]

[Document name to be corrected] Drawing

[Item to be corrected] Fig. 15

【Correction method】 Change

[Content of correction]

[Fig. 15]

Claims (3)

[Claim of claim] 1. Formula (1) embedded image (Wherein, m represents an integer of 3 to 6)
-(2S, 3R) -2- (4-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoroterminated ethoxyalkane. (2) Formula (2) [Wherein, m is the same as the formula (1)]
(2S, 3S) -2- (4-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoroterminated ethoxyalkane. 3. An organic solvent according to the formula (3) [Wherein, m is the same as the above] (S) -2- (4-
Reduction of benzyloxybenzoyloxy) -1,1,1-trifluoro-terminated ethoxyalkanone-3 with metal hydride, then reaction of the reaction product with methyl iodide to give an O-methylated derivative, then In a solvent, the O-
The syn- (2S) according to claim 1, characterized in that the methylated derivative is reduced with hydrogen in the presence of a palladium / carbon catalyst, and the resulting diastereomeric mixture is fractionated by silica gel column chromatography. , 3R) -2
-(4-hydroxybenzoyloxy) -3-methoxy-1,1,1-trifluoro-terminated ethoxyalkane and / or anti- (2S, 3) according to claim 2
S) -2- (4-hydroxybenzoyloxy) -3-
Process for the preparation of methoxy-1,1,1-trifluoroterminated ethoxyalkanes.