JPH0959222A - (s)-2-(4-benzyloxybenzoyloxy)-terminated ethoxyalkanone-3 and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new (S)-2-(4-benzyloxybenzoyloxy)-1,1,1-trifluoro-terminated ethoxyalkanone-3 easy in production, also easy in handling, and useful as an intermediate material for antiferrodielectric liquid crystal compounds. SOLUTION: A compound of formula I (m is 3-6). For example, (S)-2-(4- benzyloxybenzoyloxy)-7-ethoxy-1,1,1-trifluoroheptanone-3. The compound of formula I is obtained by reacting a compound of formula II with an alkali metal hydride in an organic solvent such as diethyl ether and subsequently reacting the reaction product with 4-benzyloxybenzoyl chloride in an organic solvent such as diethyl ether.

Description

Detailed Description of the Invention

[0001]

The present invention is, for example, a novel (S) -2- (4-benzyloxybenzoyloxy) which is useful as an intermediate material of an antiferroelectric liquid crystal compound, etc.
-1,1,1-trifluoro-terminated ethoxyalkanone-
The present invention relates to the provision of No. 3 and its manufacturing method.

[0002]

2. Description of the Related Art As a fluorine-containing compound, 2-alkoxy-3,3,3-trifluoroethyl methyl ketone is known. However, since this compound has a low boiling point and high volatility, it is easy to handle and a versatile fluorine-containing carbonyl compound is desired.

[0003]

SUMMARY OF THE INVENTION As a result of intensive studies on novel fluorine-containing carbonyl compounds which are expected to be easy to handle and to be used as intermediate materials for antiferroelectric liquid crystal compounds, etc. The inventors of the present invention have completed the present invention by discovering a method for producing a compound and producing the compound by simple operation, more efficiently and in high yield.

[0004]

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

[0005]

[Chemical formula 3]

(Wherein m represents 3 to 6) (S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-terminated ethoxyalkanone-3 (shown below) , And the compounds of the present invention. The present invention is also directed to a compound of formula (2) in an organic solvent

[0007]

[Chemical formula 4]

[Wherein, m is the same as in formula (1). (S) -1-hydroxy-2,2,2-trifluoroethyl-terminated ethoxyalkyl ketone (hereinafter referred to as a raw material compound) and an alkali metal hydride are reacted with each other, The present invention relates to a process for producing a compound of the present invention by reacting with benzyloxybenzoyl chloride.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION

[Inventive compound: (S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-terminated ethoxyalkanone-3] The inventive compound is as represented by the formula (1), In the formula, m is a methylene group showing 3 to 6, that is, 1,3-trimethylene group, 1,4-tetramethylene group, 1,5-pentamethylene group, 1,6-hexamethylene group and the like. As specific compounds thereof, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, tetrahydrofuran, tetrahydropyran and the like can be mentioned. Preferred specific examples of the compound of the present invention are (S) -2- (4-benzyloxybenzoyloxy) -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
1-trifluorononanone-3 etc. are mentioned.

The compound of the present invention comprises (S) -1-hydroxy-2,2,2-trifluoro-terminated ethoxyalkyl ketone (raw material compound) represented by the formula (2) and an alkali metal hydride in an organic solvent: It is obtained by reacting (first step reaction) and then reacting the reaction product with 4-benzyloxybenzoyl chloride (second step reaction). The raw material compounds are described below.

(Starting Compound) The starting compound is represented by the formula (2)
The (S) -1-hydroxy-2,2,2-trifluoroethyl-terminated ethoxyalkyl ketone represented by is a novel compound. When the above compounds are specifically described,
The methylene group represented by m in the formula corresponds to m in the formula (1), and as a specific example of a preferred compound, (S) -1-hydroxy-2,2,2-trifluoroethyl-3-ethoxy Propyl ketone, (S) -1-hydroxy-2,2,
2-trifluoroethyl-4-ethoxybutyl ketone,
(S) -1-hydroxy-2,2,2-trifluoroethyl-5-ethoxypentyl ketone and (S) -1-
And hydroxy-2,2,2-trifluoroethyl-6-ethoxyhexyl ketone and the like.

(Production of Starting Compound) The following (S) -N-
To show a method for producing a starting compound from (2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine (hereinafter referred to as a starting material compound) through an original first stage reaction and an original second stage reaction It is as follows. 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 (3)

[0014]

[Chemical formula 5]

[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 (3) is preferably carried out by dropping a solution of the starting material compound in an organic solvent into the 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 (3), 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 (3), -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 the following reaction formula:

[0018]

[Chemical formula 6]

[Wherein, m is the same as the formula (1)], for example, tetrahydrofuran 1 corresponding to m = 4
Add 1 mol of tetrahydropyran corresponding to 1 mol or m = 5, 1.1 mol of ethyl alcohol and 0.05 mol of p-toluenesulfonic acid monohydrate and heat,
After refluxing for 8 hours, add 2 liters of water to the obtained residue, extract with ether, add anhydrous magnesium sulfate to the extract to remove water, and then remove the solvent under reduced pressure. A colorless and clear liquid terminal ethoxy alcohol, 4-ethoxybutyl alcohol, or 5-ethoxypentyl alcohol is obtained in a yield of 90%.

Step 2 The step 2 is expressed by the following equation (5): C ₂ H ₅ O (CH ₂ ) _m OH + P (C ₆ H ₅ ) ₃ + Br ₂ → (terminal ethoxyalkyl 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 ((5) (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 (6) C₂H _FiveO (CH₂)_mBr + 1.1 Mg → C₂H_FiveO (CH₂)_mAs shown by MgBr (6) (terminal ethoxyalkyl bromide) (Grignard reagent), to a nitrogen substituted reactor,
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
4-ethoxybutyl bromide 0.9 mol or 5-eth
0.9 mol of xylbutyl bromide and dry diethyl ether
Put 500 ml of each into the dropping funnel and keep refluxing
To the solution, and after completion of the addition, reflux 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.

(Original Second Stage Reaction) An example of the reaction formula of the original second stage reaction will be described with reference to the case where hydrochloric acid is used as a mineral acid.

[0023]

[Chemical formula 7]

[Wherein, m is the same as in formula (1). The starting compound is formed by hydrolyzing 1 mole of the reaction product obtained in the first step reaction with 3 gram equivalent of mineral acid. Examples of mineral acids include hydrochloric acid, sulfuric acid and nitric acid. The amount of mineral acid used is 3 per mole of starting material compound
-4 gram equivalents are preferred. The concentration of mineral acid is preferably 1 to 5 N. In the reaction of the formula (7), 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 starting compound is a 2,2,2-trifluoroethyl-terminated ethoxyalkyl ketone.

(Method of producing the compound of the present invention) The compound of the present invention is prepared by reacting the starting compound obtained above with an alkali metal hydride in an organic solvent (first step reaction), and then reacting the reaction product with 4-benzyl. It is obtained by reacting with oxybenzoyl chloride (second step reaction). Hereafter, the manufacturing method from a raw material compound is demonstrated in detail.

(First Stage Reaction) The first stage reaction can be expressed by the equation (8).

[0028]

[Image 8]

[Wherein, m is the same as in formula (1), and M is an alkali metal. In the organic solvent, the hydroxyl group in the starting compound reacts with the alkali metal hydride,
A reaction product-1 which is an alkali metal alcoholate is formed. As the organic solvent, diethyl ether, n-hexane, THF, methylene chloride and the like can be mentioned, with particular preference given to diethyl ether. The amount thereof is preferably 1 to 5 L, particularly preferably 2 to 4 L, based on 1 mol of the raw material compound. If it is less than 1 L, the rate of generation of hydrogen may increase due to an increase in heat of reaction, which may be dangerous. If it is more than 5 L, it may not be economical. Examples of the alkali metal hydride include lithium hydride, sodium hydride and potassium hydride, and sodium hydride is particularly preferable from the viewpoint of being economically inexpensive. 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 starting compound.
If it is less than 1.0 mol, the yield of reaction product-1 will be lowered,
If it exceeds 1.2 mol, it can not be said that it is economical.

The mixing method of the starting compound and the alkali metal hydride is carried out in the organic solvent suspension of the alkali metal hydride,
It is preferable to drop the organic solvent solution of the raw material compound. If the solution is dropped in the reverse direction, abnormal generation of hydrogen gas occurs, which may be dangerous and control of reaction heat becomes difficult, resulting in a decrease in yield. The ratio of use of the organic solvent is preferably proportional to the volume ratio of alkali metal hydride / raw material compound = 1/9. The feed rate of the starting compound to the reaction system is preferably such that 1 mol of the starting compound is added dropwise over 30 to 90 minutes. If it is less than 30 minutes, the rate of hydrogen generation may increase, which may be dangerous, and if it exceeds 90 minutes, it may not be economical.
The reaction temperature is preferably -10 to 10 ° C, particularly preferably around 0 ° C. Below -10 ° C, it is not economical.
If it exceeds 10 ° C., the rate of hydrogen generation may be increased, which may be dangerous. After completion of the addition of the starting compound, while stirring,
The temperature is raised to room temperature, and stirring is continued for about 60 minutes to complete the reaction to obtain a reaction product solution-1.

(Second-step reaction) The second-step reaction is represented by the equation (9).

[0032]

Embedded image

[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 and the chlorine of 4-benzyloxybenzoyl chloride react to form the compound of the present invention. As the organic solvent, the same organic solvent as in the first stage reaction can be used. Therefore, in the reaction product-1 solution obtained in the first stage reaction, 4
The reaction can be carried out by direct addition of an organic solvent solution of benzyloxybenzoyl chloride. 4-
The supply ratio of benzyloxybenzoyl chloride to the reaction system is 1.1 to 1.3 based on 1 mol of the raw material compound.
Mol is preferred. If it is less than 1.1 mol, the yield of the compound of the present invention may be lowered. If it is more than 1.3 mol, the purification operation described later becomes complicated and it is not economical.

4-benzyloxybenzoyl chloride is preferably dissolved in an organic solvent and supplied to the reaction system.
The mixing ratio of the organic solvent is preferably 0.5 to 2 L, particularly preferably 0.9 to 1.5 L, per 1 mol of 4-benzyloxybenzoyl chloride. If the amount is less than 0.5 L, control of the reaction temperature becomes difficult, which may cause a decrease in yield, and if it exceeds 2 L, it is not economical. The feed rate of 4-benzyloxybenzoyl chloride to the reaction system is preferably 1 to 3 hours based on 1 mole of the starting compound. If there is a danger of gelation if it is too short, control of the reaction temperature may be difficult, and if the dropping rate is too slow, it is not economical. The reaction temperature is -10 to 10
° C. is preferred, particularly preferably around 0 ° C. -10
Below 10 ° C., the reaction temperature may be difficult to control. 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, use, for example, 1N hydrochloric acid at room temperature to convert excess alkali metal hydride or 4-benzyloxybenzoyl chloride to alkali chloride or 4-benzyloxybenzoate, and then use 5% aqueous sodium carbonate solution. After adjusting the pH to 8 and converting 4-benzyloxybenzoate to a water-soluble soda salt,
After extraction with ether, the extract was washed with water, anhydrous magnesium sulfate was added to remove water, and then the solvent was concentrated under reduced pressure,
The remaining pale yellow syrupy residue is purified by silica gel column chromatography and the like, and then the purified liquid is decolorized with activated carbon and the like, and then concentrated under reduced pressure to obtain a colorless, transparent, liquid target product.

¹ H NMR spectrum of the desired product,
¹⁹ F NMR spectrum, 1R absorption spectrum and MS
As a result of measuring the spectrum, it is confirmed that the target product is 2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-terminated ethoxyalkanone-3. Also, according to the following identification example, the alkali metal hydride is a hydroxyl group bonded to the asymmetric carbon atom at the 1-position of (S) -1-hydroxy-2,2,2-trifluoroethyl terminal ethoxyalkyl ketone which is a raw material compound. React with
Even if it is converted to an alkali metal alcoholate and then reacted with 4-benzyloxybenzoyl chloride to substitute for 4-benzyloxybenzoyloxy group, the asymmetric center at the asymmetric carbon atom at position 1 does not cause optical inversion (S ) The configuration has been confirmed, and the target product is (S) -2- (4)
It can be confirmed that the compound of the present invention is -benzyloxybenzoyloxy) -1,1,1-trifluoro-terminated ethoxyalkanone-3.

The compound of the present invention can be obtained by the following steps: syn- (2S, 3R)-
It is useful as an intermediate for producing terminal ethoxy-3-methoxyalkane derivatives.

[0038]

[Image 10]

The compound represented by the formula (10) has excellent properties [eg, in the formula (10), m = 4, R = n
The compound which is -decyl exhibits a chiral smectic C _A phase having a fast response and a wide viewing angle and having a tristable state] and is an antiferroelectric liquid crystal compound, and can be used as a liquid crystal display element. The preparation examples of the compound represented by the formula (10) and the test examples showing the usefulness as the antiferroelectric liquid crystal compound are shown in the following reference examples.

[0040]

EXAMPLES The present invention will be described in more detail based on the following reference examples and examples. Reference Examples 1 to 3 are preparation examples of the compound used as a raw material of the compound of the present invention, Example 1 is a preparation example of the compound of the present invention, and Reference Examples 4 and 5 are the compound of the present invention as a raw material and step by step to final useful compounds. Preparation Examples to 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. FNMR while refluxing
As a result of refluxing for 12 hours while tracking the lactic acid peak in the spectrum, it was confirmed that the lactic acid in the reaction solution had run out, heating to reflux was stopped, and the solution was cooled to room temperature while stirring. Then, the reaction mixture was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate solution.
After adjusting to ~ 9, extract with ether, wash the extract with water, add anhydrous magnesium sulfate to remove water, concentrate the extract under reduced pressure, and distill the remaining syrupy residue under reduced pressure, colorless Clear liquid product [yield 26.9 g
(170 mmol) yield 95%] was obtained.

H NMR spectrum of this product, FNM
R spectrum, 1R absorption spectrum and MS spectrum were measured. Also, this reaction is independent of the configuration of the carbon atom at position 2 of this product, and no optical inversion occurs, so that this product is (S) -2-hydroxy-
It was confirmed to be 3,3,3-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.

H NMR spectrum of this product, FNM
The results of measuring the R spectrum, 1R absorption spectrum, and MS spectrum are as follows, and are independent of the configuration of the asymmetric carbon atom of the product, and no optical inversion takes place: Was confirmed to be the starting material compound (S) -N- (2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine. H NMR spectrum (CDCl) 1.53 to 2.37 ppm (4H, 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. CFCO
OH) −4.2 ppm (d, J = 6.0) 1R absorption spectrum (neat) 1,640 cm (CO), 3,330 cm (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-bottomed 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 In a four-necked round-bottomed flask equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel, 371 ml of the 0.8 mol / l Grignard reagent obtained in Reference Example 2 [4-ethoxybutyl] 60.9 g (297 mmol) of magnesium bromide and the remainder diethyl ether were added, and the mixture 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 that the product is (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 compound (S) -N- (2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine with 4-ethoxybutyl group in a Grignard reagent. can get. 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.

Example 1 [(S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-
Production of 7-Ethoxyheptanone-3] A four-necked round bottom flask equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel was washed with n-hexane, purified, and dried, 2.0 g of dried sodium hydride (83 A millimole of diethyl ether and 23 ml of diethyl ether were introduced, inserted into an ice water bath, and a suspension of 0 ° C. was prepared while stirring. Next, (S) -1-hydroxy- obtained in Reference Example 3 was added to the dropping funnel.
17.1 g (75 mmol) of 2,2,2-trifluoroethyl-4-ethoxybutyl ketone and 202 ml of diethyl ether are added to make a homogeneous solution and 1
It dripped over 7 minutes. After the addition is completed, the ice water bath is removed, and while stirring, the temperature is raised to 25 ° C.
The reaction was completed by stirring for a minute. The above flask was then again inserted into an ice water bath and adjusted to 0.degree. 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 then washed with water, and the extract is washed with water, anhydrous magnesium sulfate is added to remove water, concentrated under reduced pressure and the solvent is distilled off, and the remaining pale yellow syrupy residue is subjected to silica gel column chromatography [ Eluent n-hexane / isopropyl alcohol =
0.52 g of granular activated carbon [the amount of addition of granular activated carbon is (S) -1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone] in a solution purified by 96/4 (volume ratio) 3% by weight based on the charged amount] and stirred for 30 minutes, then the granular activated carbon is removed by filtration, the filtrate is concentrated under reduced pressure, the eluent is distilled off, and the desired product is a colorless, transparent liquid [Yield 26.3 g (60 mmol) yield 80%] was obtained. ¹ HNM of this target product
The results of measurement of the R spectrum, ¹⁹ F NMR spectrum, 1R absorption spectrum and MS spectrum are as follows, and the target product is 2- (4-benzyloxybenzoyloxy) -7-ethoxy-1,1,1-triol It was confirmed to be fluoroheptanone-3.

¹ H NMR spectrum (CDCl ₃ ) 1.07 ppm (3 H), 1.47 to 2.18 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.
27 ppm (5H) (6.75 to 7.00, 7.76 to 7.95) ppm
(4H, A, B 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, the ¹ H NMR spectrum is shown in FIG. This target product is (S) -2- (4-benzyloxybenzoyloxy) -7-ethoxy-1, as described in Identification Example 2 below.
It was confirmed to be 1,1-trifluoroheptanone-3.

Identification Example 2 [The target product obtained in Example 1 is (S) -2- (4-benzyloxybenzoyloxy) -7-ethoxy-1,1,1-trifluoroheptanone- Identification of being 3] The desired product 2.19 obtained above in a four-neck round bottom flask equipped with a thermometer, a stirrer, a reflux condenser, and a dropping funnel.
g (5 mmol), 25 ml of 3N hydrochloric acid and 100 ml of methanol were added, and immersed in a warm water bath at a temperature of 80 ° C. . 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.

The various spectral analysis of this product was in accordance with Reference Example 3, and it was confirmed that the product was 1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone. In addition, the above product was identified as Reference Example 3 in Identification Example 1.
As a result of applying optically active gas chromatography under the same conditions as in (1), one optically active peak was obtained, and its retention time was 34.67 minutes, which was consistent with FIG. 3 of Reference Example 3 (S) The configuration was confirmed and the product was confirmed to be (S) -1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone. Therefore, (S) -1-hydroxy-2,2,2
A hydroxyl group bonded to the asymmetric carbon atom at the 1-position of the starting compound which is trifluoroethyl-4-ethoxybutyl ketone is reacted with an alkali metal hydride to change to an alkali metal alcoholate, and then 4-benzyloxybenzoyl The target product obtained by reacting the chloride is hydrolyzed with a mineral acid to obtain a product consistent with the starting compound, whereby the target product obtained by reacting the starting compound with the above-mentioned compound The product is found to be in the (S) configuration and the target product is (S) -2- (4-benzyloxybenzoyloxy) -7-ethoxy-1,
It was confirmed to be 1,1-trifluoroheptanone-3.

Reference Example 4 [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,
Production of 1,1-trifluoroheptane, provided that a stable aqueous solution of sodium borohydride is used as a metal hydride] (First-step reaction) [syn isomer (2S, 3R) type / anti
Preparation of a reaction product which is a diastereomeric mixture consisting of body (2S, 3S) form = 70/30 (area ratio): Reduction of the compound of Example 1 to -CO- to -CH (OH)-] Temperature (S) -2 obtained in Example 1 in a four-neck round bottom flask equipped with a scale, stirrer, reflux condenser and dropping funnel.
-(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 sodium borohydride aqueous solution containing 0.27 g (7 mmol) of sodium borohydride, 28 g of a 5% aqueous sodium hydroxide solution (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 the mixture is cooled to room temperature while stirring, and then extracted with ether, and the extract is 40% of a 20% aqueous solution of sodium hydrogen carbonate
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.

[0067]

[Table 1]

[0068] Further, ¹ HNMR spectrum methyl group of the product -2 (1.75ppm, 1.82ppm) an area ratio of 70% of trans-isomer 1,3-dioxolane derivative of the ¹⁹ FNMR 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 above first step reaction 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.

Therefore, the first peak (-0.48) of the ¹⁹ F NMR spectrum of the product-1 in which the area ratio is in agreement with the trans 1,3-dioxolane derivative of the 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, 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 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-step reaction) (Removal of benzyl group by H ₂ , Pd / C) Sealed 4-neck round bottom equipped with a thermometer, stirrer, dropping funnel, hydrogen gas charge tube and polyethylene resin balloon In a flask, 3.86 g (8.5 mmol) of the O-methylated derivative obtained in the second step reaction described above and 58 m of methanol
The mixture was stirred at room temperature, and 0.08 g of 10% palladium / carbon catalyst was charged into a dropping funnel and slowly dropped to prepare a uniformly dispersed suspension. Next, while stirring at room temperature, the reaction system was sealed with hydrogen gas at a pressure of about 1.1 kg / cm ² to carry out a reduction reaction. 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.

[0075]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 identified by the following identification example 2, 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 (2S, 3R) / anti (2S, 3S) = 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 Then, 1.82 g (4 mmol) of the O-methylated derivative obtained in the second step reaction of Reference Example 4, 20 ml of 3 N hydrochloric acid and 80 ml of methanol were added, and the temperature was raised to 80.degree. 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 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

FIG. 9 is a chart of optically active gas chromatography. 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)

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, each 2-position and 3 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).

Next, 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.

(Step 4) [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-
Preparation of 1,1,1-trifluoroheptane: Separation of diastereomers by silica gel chromatography] 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- (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, the second fraction being anti- (2S, 3S)-
It could be confirmed that this was 2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.

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

Reference Example 5 [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-
Each production of 1,1,1-trifluoroheptane, but
When hydrogenated diisobutylaluminum is used as the metal hydride]

(First-step reaction) [syn form (2S, 3R)
Preparation of a reaction product which is a mixture of diastereomers consisting of type / anti form (2S, 3S) type = 40/60 (area ratio): -CO- of -CH- (OH) of compound of Example 1
Reduction to-A four-necked round-bottomed flask equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel, obtained in Example 1 (S) -2
-(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 obtained as described above (starting compound) in a three-necked 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 the identification example 1 of the reference example 4, 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 the reference example 4, as a result of measuring a ¹⁹ F NMR spectrum, 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) (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 80% obtained in the first stage reaction Add the reaction product solution [(S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-7-ethoxyheptanone-a solution containing 20 mmol of 3 equivalent] in an ice water bath And adjusted to 0.degree. C. with 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, 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 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-step reaction) (Removal of benzyl group by H ₂ , Pd / C) Sealed 4-neck round bottom equipped with a thermometer, stirrer, dropping funnel, hydrogen gas charge tube and polyethylene resin balloon In a flask, 4.99 g (11 mmol) of the O-methylated derivative obtained in the second step reaction described above and 75 ml of methanol
Add 0.10 g of 10% palladium / carbon catalyst to the dropping funnel while stirring at room temperature, and slowly add
A uniformly dispersed suspension was prepared. Next, while stirring at room temperature, the reaction system was sealed with hydrogen gas at a pressure of about 1.1 kg / cm ² to carry out a reduction reaction. While the reduction reaction is stirring the suspension, until the absorption of hydrogen gas is lost,
The reaction was completed by feeding for 4-5 hours. 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 is purified by silica gel column chromatography [eluent n-hexane / isopropyl alcohol = 96/4 (volume ratio)], the eluent is distilled off under reduced pressure, and a diastereomer mixture which is a colorless and transparent liquid product -2 [yield 3.92 g (10.78
Millimoles) yield 98%].

¹ H NMR spectrum of this product, 1 R
The results of measuring the absorption spectrum and MS spectrum are the same as in the third step reaction of Reference Example 4, and the product is 2-
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 according to 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 Reference Example 5
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)

Further, the above-mentioned product was subjected to optically active gas chromatography under the same conditions as in Identification Example 2 of Reference Example 4. 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 Reference Example 4, 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 Reference Example 4. 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.

(Step 4) [syn- (2S, 3R)
-2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane and anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy Preparation of -3-methoxy-1,1,1-trifluoroheptane: Separation of diastereomers by silica gel chromatography] Diastereomer 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 Reference Example 4, 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
-Trifluoroheptane, the second fraction is a
nti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,
It could be confirmed that this was 1-trifluoroheptane.

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

[0114]Reference Example 6[Syn- (2S, 3R) -2-
{4- [4- (4 -N-decylphenyl) benzoyl io
Xy] benzoyloxy} -7-ethoxy-3-methoxy
Production of chi-1,1,1-trifluoroheptane] Equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel
In a 4-neck round bottom flask, the syn- obtained in Reference Example 5
(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%].

Of this target product¹H 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 ¹ H NMR spectrum is shown in FIG.

Identification Example 4 [Compound Obtained in Reference Example 6]
Is syn- (2S, 3R) -2- {4- [4- (4) -N
-Decylphenyl) benzoyloxy] benzoyloxy
7-Ethoxy-3-methoxy-1,1,1-tri
Identification of being a fluoroheptane] A thermometer, a stirrer, a reflux condenser, a quartet 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.

In addition, the same conditions as above for the above-mentioned 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 7 (Characteristics of final useful compound of Reference Example 6) (Measurement of phase transition temperature of compound of Reference Example 6) The compound of Reference Example 6 was subjected to DSC, and the electric field response of the liquid crystal display element described later was polarized microscope The results obtained by measuring the phase transition temperature by observing with are as follows. However, cry: crystal phase, S
_CA ☆: antiferroelectric liquid crystal phase, SA: smectic A phase and ISO: isotropic liquid phase. The upper value is 4 ° C
When the temperature is raised at / min, the lower value represents the phase transition temperature when the temperature is lowered at 4 ° C./min. Phase transition temperature:

[0124]

[Image 11]

Thus, the compound of Reference Example 6 was an antiferroelectric liquid crystal compound including near room temperature. (Preparation of Liquid Crystal Display Element) An alignment film spin-coated with polyimide is rubbed on two glass substrates with transparent electrodes, and the gap distance is 1.7 um so that the rubbing directions are parallel to each other. The cells were assembled by bonding. The compound obtained in Reference Example 6 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 transmitted light amount was 100% when the transmission axis of the analyzer was rotated to coincide with the transmission axis of the polarizer.

(Evaluation of Liquid Crystal Display Element) Using the liquid crystal display element prepared above, an applied voltage of ± 8.7 at 25 ° C.
FIG. 18 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 6 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. .

[0127]

The present invention is a novel (S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-terminated ethoxyal useful as an intermediate material of an antiferroelectric liquid crystal compound, etc. The present invention provides a method for producing the above compound by simple operation, more effectively and in high yield.

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
Hydroxy-2,2,2-trifluoroethyl-4-
It is a chart of optically active gas chromatography of ethoxy butyl ketone.

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

[FIG. 5] 7 obtained in Identification Example 1 of the first step reaction of Reference Example 4
-Ethoxy-1,1,1-trifluoroheptane-2,
It is a < ¹ > H NMR spectrum figure of 3-diol.

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

[Fig. 7] 2- (4-hydride) obtained in the third step reaction of Reference Example 4
Droxybenzoyloxy) -7-ethoxy-3-meth
Of xyl-1,1,1-trifluoroheptane  ¹HNM
It is R spectrum figure.

[FIG. 8] Identification 2 of the third step reaction of Reference Example 4
-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 Reference Example 4
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).

FIG. 10 is a mixture of diastereomers-1 obtained in the third step reaction of Reference Example 4: 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).

[Fig. 11] syn- obtained from the fourth step reaction of Reference Example 4
It is a chart of an optically active liquid chromatography of (2S, 3R) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.

[FIG. 12] anti- obtained in the fourth step reaction of Reference Example 4
It is a chart of an optically active liquid chromatography of (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.

13 is identification of the third step reaction of Reference Example 5 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 the diastereomeric mixture 2 obtained in Example 4 of the third step reaction of Reference Example 5: 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 6
-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 6: 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 6.

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] 0038

【Correction method】 Change

[Content of correction]

[0038]

[Image 10]

[Procedure amendment 2]

[Name of document to be corrected] statement

[Item name to be corrected] 0044

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[Content of correction]

H NMR spectrum of this product, FNM
The results of measuring the R spectrum, 1R absorption spectrum, and MS spectrum are as follows, and are independent of the configuration of the asymmetric carbon atom of the product, and no optical inversion takes place: Was confirmed to be the starting material compound (S) -N- (2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine. H NMR spectrum ( CDCl ₃ ) 1.53 to 2.37 ppm (4H, 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
COOH ) -4.2 ppm (d, J = 6.0) 1 R absorption spectrum (neat) 1,640 cm (CO), 3,330 cm (OH) MS spectrum m / z 197 (M ⁺ )

[Procedure amendment 3]

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【Name of item to be corrected】 0059

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[Content of correction]

Reference Example 4 [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,
Production of 1,1-trifluoroheptane, provided that a stable aqueous solution of sodium borohydride is used as a metal hydride] (First-step reaction) [syn isomer (2S, 3R) type / anti
Preparation of a reaction product which is a mixture of diastereomers consisting of body (2S, 3S) form = 70/30 (area ratio): Diastereoface group of hydride to -CO- of the compound of Example 1
Another reaction ] (S) -2 obtained in Example 1 in a four-neck round bottom flask equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel.
-(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 with stirring, inserted into an ice water bath, and adjusted to 0.degree.

[Procedure amendment 4]

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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 316 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 5]

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[Content of correction]

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
s- 2,2 -dimethyl-4- (4-ethoxybutyl)-
It consists of 5-trifluoromethyl- 1, 3- dioxolane, The production ratio trans body / cis body = 70/30
It was confirmed to be a mixture of diastereomers (area ratio).

[Procedure amendment 6]

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[Content of correction]

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 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) Therefore, according to the result of the ¹⁹ F NMR spectrum and the identification example 2 described later, the O-methylated derivative is a syn isomer (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]

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[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]

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Identification Example 2: The O-methylated derivative obtained in the second step reaction is a dia consisting of syn (2S, 3R) / anti (2S, 3S) = 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)
Droxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane composed of syn form (2S, 3R) form / anti form (2)
Identification of the S, 3S) type = 70/30 (area ratio) of diastereomer mixture-1] In a four-neck round bottom flask equipped with a thermometer, a stirrer, a reflux condenser, and a funnel, Reference Example 4 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]

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[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]

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[Content of correction]

FIG. 9 is a chart of optically active gas chromatography. 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] 0090

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[Content of correction]

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 μm silica gel having a purity of 99.9% Size: 10 mm φ × 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

[Procedure amendment 12]

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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 13]

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[Content of correction]

(First-step reaction) [syn form (2S, 3R)
Preparation of a reaction product which is a mixture of diastereomers consisting of type / anti form (2S, 3S) type = 40/60 (area ratio): di-hydride of the compound of Example 1 to -CO-
Astereo-Surface Distinguishing Reaction ] (S) -2 obtained in Example 1 in a four-necked round-bottom flask equipped with a thermometer, a stirrer, a reflux condenser, and a dropping funnel
-(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. Next, 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, the temperature is raised to room temperature while stirring, 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).

[Procedure amendment 14]

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【Correction method】 Change

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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 the identification example 1 of the reference example 4, and 7-ethoxy-
It was confirmed to be 1,1,1-trifluoroheptane-2,3-diol. Moreover, as a result of measuring a ¹⁹ F NMR spectrum based on the result of the identification example 1 of the reference example 4,
From the position and area ratio of each peak, product-3 is syn- (2S, 3R) -7-ethoxy-1,1,1-trifluoroheptane-2,3-diol and two peaks are observed. anti- (2S, 3S) -7-ethoxy-1,1,1-trifluoroheptane-2,3-diol, and its formation ratio syn form (2S, 3R) type /
It turned out that it is a diastereomer mixture which consists of anti-form (2S, 3S) type = 40/60 (area ratio). ¹⁹ F NMR spectrum (from ext. CF ₃
COOH) First peak: -0.48 ppm, area ratio 40 syn isomer (2S, 3 R) type Second peak: -2.21 ppm, area ratio 60 anti
(2S, 3S type Therefore, the reaction product obtained in the first step reaction is syn
Body (2S, 3R) type / anti body (2S, 3S) type = 4
It could be confirmed that this was a mixture of diastereomers consisting of 0/60 (area ratio).

[Procedure amendment 15]

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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 (6H, 2.48 to 2.64 ppm (3H),
2.69 ppm (3H), 2.84 to 3.00 ppm
(1H), 3.12 to 3.26 ppm (2H), 3.7
7 to 3.90 ppm (1 H), 4.02 to 4.14 pp
m (1H) 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 16]

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[Content of correction]

Thus, the compound of Reference Example 6 was an antiferroelectric liquid crystal compound including near room temperature. (Preparation of Liquid Crystal Display Element) An alignment film spin-coated with polyimide was rubbed on two glass substrates with transparent electrodes, and the gap distance of 1.7 μm was set so that the rubbing directions would be parallel to each other. The cells were assembled by pasting together. The compound obtained in Reference Example 6 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 transmitted light amount was 100% when the transmission axis of the analyzer was rotated to coincide with the transmission axis of the polarizer.

[Procedure amendment 17]

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[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. 18 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 which becomes completely bright state at 25 ° C.) Tilt angle: 30. (at 25 ° C., the optical axis angle becomes a polarizer when the threshold voltage) 20 ° above results, the compound of reference example 6 has an antiferroelectric liquid crystal phase at around room temperature, using the same The liquid crystal 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 18]

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[Item to be corrected] Figure 12

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[Fig. 12]

[Procedure amendment 19]

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[Fig. 14]

[Procedure amendment 20]

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[Fig. 15]

Claims (2)

[Claim of claim] 1. Formula (1) embedded image (Wherein, m represents 3 to 6) (S) -2
-(4-benzyloxybenzoyloxy) -1,1,
1-Trifluoro-terminated ethoxyalkanone-3. 2. An organic solvent according to the formula (2) [Wherein, m is the same as in formula (1). ] (S) -1 shown by
-A method comprising reacting a -hydroxy-2,2,2-trifluoroethyl-terminated ethoxyalkyl ketone with an alkali metal hydride, and then reacting the reaction product with 4-benzyloxybenzoyl chloride. 1) A method for producing (S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-terminated ethoxyalkanone-3 as described in 1).