JPH0959203A - (s)-1-hydroxy-2,2,2-trifluoroethyl-terminated ethoxyalkyl ketone and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as an intermediate for antiferroelectric liquid crystal compounds, or as a building blocking agent capable of introducing various functional groups into compounds to be used as medicines or agrochemicals. SOLUTION: This new compound is expressed by the formula (m is 3-6), e.g. (S)-1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone. The compound of the formula is obtained by reaction between (S)-N-(2-hydroxy-3,3,3- trifluoropropionyl)pyrrolidine and a compound of the formula C2 H5 O(CH2 )m MgBr in an organic solvent such as diethyl ether, tetrahydrofuran or diglyme followed by the hydrolysis of the reaction product with a mineral, acid such as hydrochloric acid, sulfuric acid or nitric acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention is useful as, for example, an intermediate raw material of an antiferroelectric liquid crystal compound, or a novel building block agent capable of introducing various functional groups into compounds used for pharmaceuticals, agricultural chemicals and the like. (S) -1-
TECHNICAL FIELD The present invention relates to a hydroxy-2,2,2-trifluoroethyl-terminated ethoxyalkyl ketone and a method for producing the same.

[0002]

2. Description of the Related Art Terminal intermediate ethoxyalkyl ketones such as 1-trifluoromethyl-5-ethoxypentyl ketone are known as intermediate raw materials for antiferroelectric liquid crystal compounds.
However, since these compounds do not have a hydroxyl group, they cannot be used as a building block agent for medicines or agricultural chemicals.

[0003]

Therefore, the inventors of the present invention have conducted diligent research on the (S) -form hydroxy-terminated alkyl ketone in search of a compound applicable to the above-mentioned uses, and as a result, The present invention has been completed by finding a method for efficiently producing a high yield.

[0004]

The present invention relates to a novel compound represented by the formula (1):

[0005]

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(In the formula, m represents an integer of 3 to 6) (S) -1-hydroxy-2,2,2-trifluoroethyl-terminated ethoxyalkyl ketone (hereinafter referred to as the compound of the present invention). ) Is related to. In addition, the compound of the present invention is (S) -N- (2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine and the compound of the formula (2) C ₂ H ₅ O (CH ₂ ) _{m in} an organic solvent. It can be produced by reacting with a terminal ethoxyalkyl magnesium bromide represented by MgBr (2) (in the formula, m is the same as above), and then hydrolyzing the reaction product with a mineral acid.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION

(Compound of the present invention) The compound of the present invention is as represented by formula (1), wherein m represents a methylene group showing an integer of 3 to 6, and a compound having m less than 3 has a low boiling point and is difficult to handle. , M is more than 6, it is difficult to manufacture. Specifically disclosed methylene groups are 1,3-trimethylene groups, 1,4
-Tetramethylene group, 1,5-pentamethylene group and 1,6-hexamethylene group. When the compound of the present invention is specifically disclosed, (S) -1-hydroxy-2,
2,2-trifluoroethyl-3-ethoxypropyl ketone, (S) -1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone, (S) -1-
Hydroxy-2,2,2-trifluoroethyl-5-ethoxypentyl ketone and (S) -1-hydroxy-
2,2,2-trifluoroethylhexyl ketone may be mentioned.

Further, the compound of the present invention is
(S) -N- (2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine (hereinafter referred to as a raw material compound) and a terminal ethoxyalkyl magnesium bromide represented by the formula (2) (hereinafter referred to as Grignard reagent). )
It can be produced by reacting with and then hydrolyzing the reaction product with a mineral acid.

[Raw Material Compound: (S) -N- (2-Hydroxy-3,3,3-trifluoropropionyl) pyrrolidine Production Method] The raw material compound is not a novel compound but is not commercially available. I have to. The reaction method for producing the raw material compound is represented by the formula (3)

[0010]

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As shown in (1), 1 mol of (S) -2-hydroxy-3,3,3-trifluoropropionic acid methyl ester, 1.07 mol of pyrrolidine and 3 m of concentrated sulfuric acid.
1 is mixed and reacted at 200 mmHg × 60 ° C., the generated methanol vapor is continuously removed, the reaction is continued until the vapor generation is stopped, and the reaction is completed. The light brown solid formed is taken out, washed with water and then recrystallized with hot n-hexane to give the product as white needle crystals. ¹ H NMR spectrum, ¹⁹ F NMR spectrum,
The product was (S) -N- (2- It is confirmed to be hydroxy-3,3,3-trifluoropropionyl) pyrrolidine.

(Grignard Reagent: Production of Terminal Ethoxyalkyl Magnesium Bromide) The Grignard reagent is as shown by the formula (2), and in the formula, m is the same as the formula (1). , 3-ethoxypropyl magnesium bromide, 4-ethoxybutyl magnesium bromide, 5-ethoxypentyl magnesium bromide and 6-ethoxyhexyl magnesium bromide. These Grignard reagents are not commercially available and can be produced by the following three steps. Hereinafter, as an example, an outline of a method for producing a Grignard reagent with m = 4 and 5 is as follows.

The first step The reaction of the first step is represented by the formula (4)

[0014]

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As shown in [in the formula, m is the same as the formula (1)], for example, tetrahydrofuran 1 corresponding to m = 4
Mol, or 1 mol of tetrahydropyran corresponding to m = 5, 1.1 mol of ethyl alcohol and 0.05 mol of paratoluenesulfonic acid monohydrate are mixed and heated to 80
After refluxing for 8 hours at ℃, concentrated under reduced pressure, 2 liters of water was added to the obtained residue, followed by ether extraction, anhydrous magnesium sulfate was added to the extract to remove water, and then the solvent was distilled off under reduced pressure. A colorless and transparent liquid terminal ethoxy alcohol, 4-ethoxybutyl alcohol or 5-ethoxypentyl alcohol, is obtained with a yield of 90%.

Second Step The reaction of the second step is represented by the formula (5) C ₂ H ₅ O (CH ₂ ) _m OH + P (C ₆ H ₅ ) ₃ + Br ₂ → (terminal ethoxyalkyl alcohol) C ₂ H ₅ O (CH ₂ ) _m Br + HBr + P (C ₆ H ₅ ) ₃ O ↓ (5) (Terminal ethoxyalkyl bromide), 4-ethoxybutyl alcohol, which is the terminal ethoxy alcohol obtained in the first step, or 5
A solution of 1 mol each of ethoxypentyl alcohol dissolved in 3 liters of methylene chloride is adjusted to 0 ° C. Then 1 mol of triphenylphosphine and 1,000 methylene chloride
To a solution added with ml, 1 mol of bromine and 500 methylene chloride.
Add the solution containing ml and stir it at 0 ° C for 100
The reaction mixture is added dropwise over a period of 1 minute, and after completion of the addition, the reaction is completed by keeping the mixture for 1 hour with stirring. Then, the temperature is raised to room temperature, followed by stirring and holding for 1 hour to generate fine crystals of triphenylphosphine oxide. Then, the mixture was concentrated, the methylene chloride and hydrogen bromide were distilled off, and 8 L of hot n-hexane was added to the generated sludge to dissolve it, followed by cooling and crystallization to remove most of the triphenylphosphine oxide as white needle crystals. Remove by filtration and concentrate the filtrate to give a syrupy residue. Then, the residue was purified by silica gel column chromatography to obtain 4-ethoxybutyl bromide or 5-ethoxybutyl bromide which is a colorless and transparent liquid terminal ethoxyalkyl bromide.
Ethoxypentyl bromide is obtained with a yield of 80%.

Third Step The reaction of the third step is represented by the formula (6) C₂H _FiveO (CH₂)_mBr + 1.1Mg → C₂H_FiveO (CH₂)_mMgBr (6) (Terminal ethoxyalkyl bromide) (Grignard reagent)
1.1 mol of sium and 200 ml of dry diethyl ether
And then 1 millimole of iodine to give a reddish brown solution
Stir until colorless. Then the powder obtained in the second step
4-Ethoxybutyl which is a terminal ethoxyalkyl bromide
Bromide or 5-ethoxypentyl bromide was added to each.
Add 1 mol and stir until reflux occurs. Then the rest
4-Ethoxybutyl bromide 0.9 mol, or 5-E
Toxibutyl bromide 0.9 mol and dry diethyl ether
Put 500 ml of each into the dropping funnel and the reflux will continue.
And then reflux for 1 hour to complete the reaction.
You. Then withdraw the reaction liquid with a syringe and put it on the bottom of the reaction container.
Dried diethyl lumps of unreacted metallic magnesium
Washed with 300 ml of ether, 0.8 mol / l
4-ethoxybutyl magnesium bromide or 5-d
Toxypentyl magnesium bromide in ether
A Grignard reagent with a yield of 80% is obtained.

[Compound of the present invention: Production of (S) -1-hydroxy-2,2,2-trifluoroethyl-terminated ethoxyalkyl ketone] The compound of the present invention is represented by the raw material compound and the formula (2) in an organic solvent. It can be produced by reacting with a Grignard reagent (first step reaction), and then hydrolyzing the reaction product with a mineral acid (second step reaction). Hereinafter, (S) -N- (2-hydroxy-3,3,3
The production method from the starting compound which is -trifluoropropionyl) pyrrolidine will be described in detail. (First Step Reaction) The first step reaction is represented by the reaction formula (7).

[0019]

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[Wherein m is the same as in formula (1)], 1 mol of the Grignard reagent is added to the carbonyl group in the starting compound, and the hydroxyl group of the starting compound reacts with 1 mol of the Grignard reagent, The reaction in the formula (7) in which the reaction product and the terminal ethoxyalkane are formed is preferably carried out by dropping the organic solvent solution of the raw material compound into the Grignard reagent from the viewpoint of obtaining a high yield. Examples of the organic solvent include ether solvents such as diethyl ether, THF and diglyme, and among them, diethyl ether is particularly preferable. The amount of the organic solvent used to dissolve the raw material compound is 0.5 to 1 mol of the raw material compound.
2 liters is preferred. If it is less than 0.5 liters, the raw material compound may not be sufficiently dissolved, and if it exceeds 2 liters, it cannot be said to be economical.

In the reaction of the formula (7), the feed ratio of the raw material compound and the Grignard reagent is preferably 2 to 3 moles per 1 mole of the raw material compound. If it is less than 2 mol, the yield of the reaction product is lowered, and if it exceeds 3 mol, it is not economically advantageous. The feed rate of the raw material compound to the reaction system is preferably such that 1 mol of the raw material compound is added dropwise over 100 to 250 minutes. If it is less than 100 minutes, it becomes difficult to control the heat of reaction, which may lead to bumping of ether and a decrease in yield of the reaction product. If it exceeds 250 minutes, it is not economical. The reaction temperature of the formula (7) is -10 to
10 ° C. is preferred. Particularly, 0 ° C. is preferable. If it is less than -10 ° C, it is not economical, and if it exceeds 10 ° C, the yield of the reaction product is lowered. After completion of dropping the raw material compound solution, the mixture is continuously stirred and held for 2 hours to complete the reaction and produce a reaction product.

(Second Stage Reaction) An example of the reaction formula of the second stage reaction is shown in the case where hydrochloric acid is used as the mineral acid.

[0023]

[Chemical 6]

[Wherein m is the same as in formula (1)], and 1 mol of the reaction product obtained in the first stage reaction is hydrolyzed with 3 g equivalent of a mineral acid to give the present invention. A compound is produced. Examples of the mineral acid include hydrochloric acid, sulfuric acid, and nitric acid, and among them, hydrochloric acid is particularly preferable. The amount of the mineral acid used is preferably 3 to 4 gram equivalents relative to 1 mol of the raw material compound. If it is less than 3 gram equivalents, hydrolysis of the reaction product tends to be incomplete, and if it exceeds 4 gram equivalents, it is not economical. The concentration of the mineral acid is preferably 1 to 5 N. If it is less than 1 N, the amount of the water layer is too large, and the target product is also dissolved in the water layer,
The extraction operation of the target product is complicated and not economical. When it exceeds 5 N, the heat of reaction makes temperature control difficult, which may lead to a decrease in the yield of the target product.

In the reaction of the formula (8), it is preferable to add an aqueous solution of a mineral acid dropwise to the reaction product solution obtained in the first stage reaction in order to obtain the desired product in high yield. When the opposite dropping is performed, it becomes difficult to control the heat of reaction and the yield of the target product decreases. The dropping time of the aqueous mineral acid solution to the reaction system is preferably 30 to 60 minutes with respect to 1 mol of the raw material compound. If it is too fast, it will be difficult to control the heat of reaction, and the yield of the target product will be reduced. If it is too long, it will not be economical. The hydrolysis reaction of the formula (8) is preferably carried out at a temperature as mild as possible, and room temperature is particularly suitable. If the temperature is too high, there is a danger that the solvent, ether, will ignite, and the yield of the desired product will decrease. Too low temperatures are not economical. After the completion of the addition of the mineral acid, the hydrolysis reaction is completed by continuously maintaining the stirring for 20 minutes.

After completion of the hydrolysis reaction, the pH was adjusted to 8 with a 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 distilled off under reduced pressure to obtain a syrupy residue. The residue is purified by silica gel column chromatography to obtain a colorless transparent liquid target product.

Each of the desired products was analyzed by spectral analysis.
It is confirmed to be 1-hydroxy-2,2,2-trifluoroethyl terminated ethoxyalkyl ketone. In addition, according to the optically active gas chromatography analysis, a single optically active peak was obtained in the target product, so that racemization did not occur and the stereochemistry of the asymmetric carbon atom at the 2-position of the starting compound was obtained. The arrangement is unrelated before and after the reaction,
Optical inversion does not occur. From the above results, it can be confirmed that the target product is the compound of the present invention which is (S) -1-hydroxy-2,2,2-trifluoroethyl-terminated ethoxyalkyl ketone.

The compound of the present invention is useful as an intermediate for producing a syn- (2S, 3R) -terminal ethoxy-3-methoxyalkane derivative represented by the following formula (9) obtained by the following steps.

[0029]

[Chemical 7]

The compound represented by the formula (9) has excellent properties [for example, in the formula (9), the compound in which m = 4 and R = n-decyl has a fast response and a wide viewing angle]. ,
An antiferroelectric liquid crystal compound having a chiral smectic (indicating an A phase) having three stable states, and can be used as a liquid crystal display device. Production examples of the compound represented by the formula (9) and test examples showing its usefulness as an antiferroelectric liquid crystal compound are shown in Reference Examples below. In addition, as described above, the compound of the present invention is also useful as a building block agent capable of introducing various functional groups into compounds used for medicines and agricultural chemicals.

[0031]

EXAMPLES The present invention will be specifically described below based on Reference Examples and Examples. Reference Examples 1 and 2 are production examples of compounds used as starting materials for the compounds of the present invention, Example 1 is production examples of compounds of the present invention, and Reference Examples 3 to 6 are starting compounds of the present invention, and finally used as final useful compounds. Manufacturing example, reference example 7
Is a test example showing the usefulness of the final useful compound.

Reference Example 1 [Raw material compound: (S) -N- (2
Production of -Hydroxy-3,3,3-trifluoropropionyl) pyrrolidine] In a three-necked round bottom flask equipped with a thermometer, a stirrer, and a reflux condenser, (S) -trifluorolactic acid 25.8 g (179 mmol), methanol 520 ml and concentrated sulfuric acid 270 ml
Was charged and heated to reflux with stirring. During reflux, ¹⁹ FNM
As a result of refluxing for 12 hours while tracing the lactic acid peak with the R spectrum, it was confirmed that lactic acid in the reaction solution was exhausted, heating reflux was stopped, and the mixture was cooled to room temperature with stirring.
Then, the reaction solution was adjusted to pH with saturated aqueous sodium hydrogen carbonate solution.
After adjusting to 8-9, it was extracted with ether, the extract was washed with water, water was removed by adding anhydrous magnesium sulfate, the extract was concentrated under reduced pressure, and the remaining syrupy residue was distilled under reduced pressure. Colorless clear liquid product [yield 26.9 g
(170 mmol) yield 95%] was obtained.

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

Then, a Liebig condenser was attached to a branch pipe of a Claisen flask equipped with a thermometer, a stirrer, and a dropping funnel, a methyl alcohol recovery bottle was attached to its outlet, and the outlet was connected to an aspirator. (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 added and reacted at 200 mmHg × 60 ° C., and the generated methyl alcohol vapor was continuously sent to a Liebig condenser to collect methyl alcohol. Confirm that the generation of methyl alcohol vapor has stopped, stop heating,
After allowing to cool to room temperature, the pressure was returned to normal pressure to complete the reaction.
Then, the produced light brown solid was taken out and washed with water, and then hot n-hexane was added to dissolve it, followed by cooling and crystallization to give a product as a white needle crystal [yield 27.6 g (14
0 mmol) yield 85%] was obtained.

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

Reference Example 2 (Production of Grignard reagent: 4-ethoxybutylmagnesium bromide) Tetrahydrofuran 40.0 g (55) in a four-necked round bottom flask equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel.
6 mmol), 28.2 g (612 mmol) of ethyl alcohol and 5.2 g of paratoluenesulfonic acid monohydrate.
(29 mmol) was added and immersed in a warm water bath. Then, the mixture was refluxed at 80 ° C. for 6 hours and then concentrated under reduced pressure to obtain a syrupy residue. After adding 620 ml of water to this residue, extraction with ether was performed, anhydrous magnesium sulfate was added after the extraction to remove water, and the solvent was distilled off under reduced pressure to give 4-ethoxybutanol as a colorless transparent liquid [yield 59.0 g ( 500 mmol) yield 90%] was obtained.

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

Next, 10.9 g (456 mmol) of magnesium metal and 76 ml of dry diethyl ether were placed in a nitrogen-replaced flask equipped with a thermometer, a stirrer, a reflux condenser, a dropping funnel and a nitrogen insertion cock, and then iodine 0 was added. 0.1 g (0.38 mmol) was added. 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 until reflux. When reflux occurs, 4-
61.9 g (342 mmol) ethoxybutyl bromide
Then, 190 ml of dry diethyl ether was placed in a dropping funnel and added dropwise so that the reflux was maintained. After completion of the dropping, the mixture was refluxed for 1 hour to complete the reaction. Then, the reaction solution was taken out from the flask with a syringe, the remaining unreacted solid of magnesium metal was washed with 114 ml of dry ether, and the washing solution was returned to the reaction solution. Solution 3
80 ml [4-ethoxybutylmagnesium bromide [yield 62.3 g (304 mmol) yield 80%]] of Grignard reagent was obtained.

Example 1 [Production of the compound of the present invention: (S) -1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutylketone] A thermometer, a stirrer, a reflux condenser and a dropping funnel were used. In a four-necked round bottom flask provided, 371 ml of 0.8 mol / l Grignard reagent obtained in Reference Example 2 [60.9 g (297 mmol) of 4-ethoxybutylmagnesium bromide, the remaining diethyl ether] was put, and an ice water bath was added. And was adjusted to 0 ° C. A solution prepared 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 placed in the dropping funnel. Then, the mixture was added dropwise with stirring over 60 minutes, and after completion of the dropwise addition, the reaction was completed by maintaining the mixture for 2 hours with stirring to obtain a reaction product solution. Next, the ice water bath was removed, and the temperature was raised to room temperature while stirring. Next, add 3N hydrochloric acid (160 ml) to the dropping funnel, and while stirring,
It was dripped over a period of minutes. After completion of dropping hydrochloric acid, continue to 20
The hydrolysis reaction was completed by stirring and holding for a minute.

After completion of the hydrolysis reaction, the pH was adjusted to 8 with a 20% aqueous sodium hydrogen carbonate solution, and then extracted with ether,
The extract was washed with water, anhydrous magnesium sulfate was added to remove water, and the solvent was evaporated under reduced pressure to give a syrupy residue. The residue was purified by silica gel column chromatography [eluent n-hexane / isopropyl alcohol = 9/1 (volume ratio)] to give the desired product as a colorless transparent liquid [yield 18.5 g (81 mmol), yield 60%]. ]
I got ¹ H NMR spectrum of this desired product, ¹⁹ F
The results of measuring the NMR spectrum, 1R absorption spectrum and MS spectrum are as follows and were confirmed to be 1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone. In addition, ¹ HNMR
The spectrum diagram is shown in FIG. ¹ H NMR spectrum (CDCl ₂ ) 0.94 to 1.08 ppm (3H), 1.18 to 1.4
8ppm (6H), 2.61-2.80ppm (2
H), 3.21 to 3.35 ppm (2H), 3.46.
~ 3.78 ppm (1H), 4.21 to 4.34 ppm
(1H) ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) −4.66 ppm 1R absorption spectrum (neat) 1,120 cm ⁻¹ (COC), 1,670 cm ⁻¹ (C
O), 3,280 cm ⁻¹ (OH) MS spectrum 228 (M ⁺ ).

Further, (S) -N- (2-hydroxy-
N- (2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine was used in place of 3,3,3-trifluoropropionyl) pyrrolidine, and the amount was 1/10 each.
The product of a colorless transparent liquid [yield 1.85 g (8.1 mmol) Yield 6
0%]. The results of measuring various spectra of this product are the same as above, and 1-hydroxy-2,2,2-
It was trifluoroethyl-4-ethoxybutyl ketone.

This product was subjected to gas chromatography having a column for separating optical isomers (hereinafter referred to as optically active gas chromatography) under the following conditions. Column: Product name CHIRALDX, BT
A (manufactured by ASTEC) Inner diameter 0.25 mm, length 10 m, silica capillary column Column temperature: 100 ° C. × 10 minutes, and then heated to 200 ° C. at a heating rate of 4 ° C./min Carrier gas: Helium, flow rate gas flow rate 70 Nml /
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 were obtained, and their retention time and area ratio were No. 1 peak: retention time 34.67 minutes, area ratio 1 (S)
Body ☆ 1st peak: retention time 37.67 minutes, area ratio 1 (R)
Body * 1 (* 1: confirmed later) Therefore, the product was a mixture of enantiomers of 1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone.

Then, the desired product was treated under the same conditions as above.
Subjected to optically active gas chromatography. The chart of optically active gas chromatography is as shown in FIG.
From FIG. 3, one optically active peak was obtained, and the retention time was 34.67 minutes. The target product uses the S form as a starting material, and each synthetic reaction is irrelevant to the configuration of the asymmetric carbon atom at the 2-position of the starting material, and optical inversion does not occur before and after the reaction. From this, it was confirmed that the configuration was the (S) configuration, and it was revealed that the retention time of 34.67 minutes was the (S) configuration. Therefore, it was confirmed that the target product was (S) -1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutyl ketone. Also, the second peak retention time of the product is 37.67.
Minutes were found to be the (R) form.

Reference Example 3 [(S) -2- (4-benzyloxybenzoyloxy) -7-ethoxy-1,1,1-
Production of Trifluoroheptanone-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 to give 1.99 g (83 mmol) of sodium hydride. ) And 23 ml of diethyl ether were put into an ice water bath, and a suspension at 0 ° C. was prepared while stirring. Then, the compound of the present invention (S) -obtained in Example 1 was added to the dropping funnel.
1-hydroxy-2,2,2-trifluoroethyl-4
-Add 17.0 g (75 mmol) of ethoxybutyl ketone and 202 ml of diethyl ether to make a uniform solution,
With stirring, the mixture was added dropwise over 17 minutes. After completion of dropping
The ice-water bath was removed, the temperature was raised to 25 ° C. with stirring, and the mixture was continuously stirred for 60 minutes to complete the reaction. Then, the above-mentioned flask was again inserted into the ice water bath and adjusted to 0 ° C. Separately, 22.2 g (90 mmol) of 4-benzyloxybenzoyl chloride and 108 ml of diethyl ether were placed in a dropping funnel and stirred while stirring to 3
It dripped over 3 minutes. After the completion of dropping, remove the ice water bath, raise the temperature to 25 ° C with stirring, and continue to 150
The reaction was completed by stirring and holding for a minute.

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

¹ H NMR spectrum (CDCl ₃ ) 1.07 ppm (3 H), 1.18 to 1.48 ppm
(6H), 2.92 to 3.04 ppm (2H), 3.2
4 to 3.35 ppm (2H), 4.17 to 4.27 pp
m (1H), 4.49-4.67 ppm (2H), 7.
25 ppm (2H), (6.75 to 7.00, 7.76)
.About.7.95) ppm (4H, AB pattern) ¹⁹ F NMR spectrum (from ext. CF ₃ C)
OOH) −5.50 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 ⁺ ). Further, the ¹ HNMR spectrum diagram is shown in FIG.

(Identification Example) [The product obtained in Reference Example 3 was (S) -2- (4-benzyloxybenzoyloxy)]
Identification of -7-Ethoxy-1,1,1-trifluoroheptanone-3] A four-necked round bottom flask equipped with a thermometer, a stirrer, a reflux condenser, and a dropping funnel was obtained as described above. 2.19 g of product
(5 mmol), 3N hydrochloric acid (25 ml) and methanol (1)
Then, 00 ml was added, the sample was immersed in a warm water bath at a temperature of 80 ° C., the temperature was raised to boiling with stirring, and the mixture was refluxed for 6 hours to carry out a hydrolysis reaction. Then, after cooling to room temperature, extraction with ether was performed, and the extract was washed with 20 ml of a 20% aqueous sodium hydrogen carbonate solution and then with 200 ml of water, and anhydrous magnesium sulfate was added to remove water, and the solvent was distilled off under reduced pressure. Then, a syrupy residue was obtained. This residue was subjected to silica gel column chromatography [eluent n
-Hexane / isopropyl alcohol = 90/10 (volume ratio)], and a colorless transparent liquid product [yield 0.
91 g (4 mmol) yield 80%] was obtained.

Various spectra of the obtained product were measured, and various spectral analyzes of (S) -1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutylketone as the starting compound of Reference Example 3 were carried out. And the retention time was 3 when subjected to optically active gas chromatography.
It was confirmed to have (S) configuration at 4.67 minutes, and the product was the same as the starting compound (S) -1-hydroxy-2,
It was found to be 2,2-trifluoroethyl-4-ethoxybutyl ketone. Therefore, the hydroxyl group bonded to the 1-position asymmetric carbon atom of (S) -1-hydroxy-2,2,2-trifluoroethyl-4-ethoxybutylketone is reacted with an alkali metal hydride to form an alkali metal alcoholate. However, the absolute configuration does not change even if the 4-benzyloxybenzoyl chloride is reacted next,
The product was confirmed to be in the (S) configuration, and the product was (S) -2.
It was confirmed to be-(4-benzyloxybenzoyloxy) -7-ethoxy-1,1,1-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,
Each production of 1,1-trifluoroheptane, but when using a stable sodium borohydride aqueous solution as a metal hydride] (First-step reaction) [syn body (2S, 3R) type / anti]
Production of Reaction Product as Diastereomer Mixture of Body (2S, 3S) Type = 70/30 (Area Ratio)] Four-necked round bottom flask equipped with thermometer, stirrer, reflux condenser and dropping funnel And (S) -2 obtained in Reference Example 3
-(4-Benzyloxybenzoyloxy) -7-ethoxy-1,1,1-trifluoroheptanone-3,1
0.95 g (25 mmol) and diethyl ether 40 m
1 was added to the solution, and the solution was stirred to form a uniform solution.

Then, in a dropping funnel, 0.27 g (7 mmol) of sodium borohydride, 28 g of 5% sodium hydroxide aqueous solution [1.4 g (35 mmol) of NaOH [NaOH], and 7 ml of methanol were added to the stabilized sodium borohydride aqueous solution. Was added dropwise with stirring over 10 minutes. After completing the dropping, remove the ice water bath and, while stirring,
The temperature was raised to room temperature, followed by stirring and holding for 90 minutes to complete the reaction and obtain a reaction product. The obtained reaction product solution is syn-body (2S, 3R) type / anti-body (2S, 3S) type = 70/30 (area ratio) according to Identification Example 1 described later.
It was confirmed that the mixture was a diastereomer mixture consisting of

[Identification Example 1: Reaction product is syn-form (2
S, 3R) type / anti body (2S, 3S) type = 70/3
Identification of Diastereomer Mixture Consisting of 0 (Area Ratio)] In a three-necked round bottom flask equipped with a thermometer, a stirrer and a reflux condenser, the 40 wt% reaction product solution obtained above [starting Reaction product solution containing 10 mmol of compound, 50 ml of 3N hydrochloric acid and 20 ml of methanol
0 ml was added, the mixture was inserted into a hot water bath having a temperature of 80%, the temperature was raised to boiling with stirring, and the mixture was heated under reflux for 7 hours to carry out the hydrolysis reaction.

After completion of the hydrolysis reaction, the warm water bath was removed, the mixture was cooled to room temperature while stirring, and extracted with ether, and the extract was extracted with 40 ml of 20% aqueous sodium hydrogen carbonate solution.
After washing with water and then with 300 ml of water, anhydrous magnesium sulfate was added to remove water, and then the solvent was distilled off 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 a colorless transparent liquid product-1 [yield 1.84 g (8
(ppm) yield 80%] was obtained. ¹ HN of this product- ¹
As a result of measuring the MR spectrum, ¹⁹ FNMR 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 (3H), 1.06 to 1.2
4 ppm (6H), 2.69 to 2.80 ppm (2
H), 2.95-3.16 ppm (1H), 3.20-
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) First peak: -0.48 ppm, area ratio 70% [Syn
Body (2S, 3R) type ☆ 1] Second peak: -2.21 ppm, area ratio 30% [ant
i-body (2S, 3S) type ☆ 1] (☆ 1 confirmed by this identification example) 1R absorption spectrum (neat) 1,150 cm ^-1 (COC), 3,270 cm ^-1 (O
H), MS spectrum m / z. 230 (M ⁺ ) Further, the ¹ HNMR spectrum diagram is shown in FIG.

Then, the product-1 obtained above was placed in a three-necked round bottom flask equipped with a thermometer, a stirrer, and a reflux condenser.
1.15 g (5 mmol), 2.2 ml of 2-dimethoxypropane and 0.1 mg of paratoluene sulfonic acid monohydrate were put into a warm water bath at a temperature of 90 ° C., and stirred.
The temperature is raised to boiling and then refluxed for 5 hours to carry out an 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 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 the product-2 is 2,2-dimethyl-4- (4-ethoxybutyl) -5-
Trifluoromethyl-1,3-dioxolane (hereinafter,
It is called a 1,3-dioxolane derivative. ) Was confirmed.

¹ H NMR spectrum (CDCl ₃ ) 1.00 to 1.05 ppm (3H), 1.36 to 2.0
7ppm (6H), 1.58ppm (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
3.80 ppm (2H) ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) First peak: -0.46 ppm, area ratio 70% [tra
ns form 1,3-dioxolane derivative ☆ 2] Second peak: -3.66 ppm, area ratio 30% [cis
1,3-dioxolane derivative ☆ 2] (☆ 2 confirmed in this identification example) 1R absorption spectrum (neat) 1,140 cm ⁻¹ (OH), MS spectrum m / z. 270 (M ⁺ ) Further, the ¹ HNMR spectrum diagram is shown in FIG. 6.

Further, the product-2 obtained above is 1,3
The position and area ratio of the methyl group in the ¹ HNMR spectrum of the -dioxolane derivative are shown in Table 1. Table 1
Therefore, the position of the methyl group whose area ratio is 70% is trans
-2,2-Dimethyl-4- (4-ethoxybutyl) -5
-Trifluoromethyl-1,3-dioxolane (hereinafter,
It is called a trans isomer 1,3-dioxolane derivative. ), And the position of the methyl group having an area ratio of 30% is cis-
2,2-Dimethyl-4- (4-ethoxybutyl) -5-
Trifluoromethyl-1,3-dioxolane (hereinafter, c
It is called an is-form 1,3-dioxolane derivative. ). Therefore, product-2 is trans-
2,2-Dimethyl-4- (4-ethoxybutyl) -5-
Trifluoromethyl-1,3-dioxolane and ci
It is composed of s-2,2-2-dimethyl-4- (4-ethoxybutyl) -5-trifluoromethyl-1,3-dioxolane, and its production ratio is trans body / cis body = 70.
It was confirmed to be a diastereomer mixture of / 30 (area ratio).

[0057]

[Table 1]

In addition, the ¹ F NMR spectrum of the product-2, the ¹⁹ F NMR spectrum of the trans-2,3-dioxolane derivative having an area ratio of 70% of the methyl groups (1.75 ppm, 1.82 ppm) of the product-2 and the product-2 Since the area ratio of the first peak (-0.46 ppm) was the same,
The first peak is a trans-form 1,3-dioxolane derivative, ¹ HNMR spectrum methyl group (1.58P
¹⁹ F NMR of the cis isomer 1,3-dioxolane derivative having an area ratio of 30% (pm, 1.90 ppm) and the product-2
Since the area ratios of the second peaks (-3.66 ppm) of the spectra were the same, the second peaks were cis-form 1,3-
It was confirmed to be a dioxolane derivative.

The reaction product obtained in the above-mentioned first step reaction is (S) -2- (4-benzyloxybenzoyloxy) -7-ethoxy-1,1,1-trifluoroheptanone-3. It was confirmed that the asymmetric carbon atom at the 2-position was irrelevant to the reduction reaction and was in the (2S) configuration, since it was obtained by reducing the carbonyl carbon of the above with a metal hydride. Further, the obtained reaction product is hydrolyzed 7-ethoxy-1,1,1-trifluoroheptane-2,3-
It was confirmed that the asymmetric carbon atom at the 2-position of the diol had the (2S) configuration because the absolute configuration did not change even when hydrolyzed.

Therefore, the first peak (−0.48) of the ¹⁹ FNMR spectrum of product-1 having the same area ratio as the trans 1,3-dioxolane derivative of product-2 was obtained.
ppm) is syn- (2S, 3R) -7-ethoxy-
¹⁹ F NMR of product-1, which is 1,1,1-trifluoroheptane-2,3-diol, and whose area ratio matches the cis-form 1,3-dioxolane derivative of product-2
The second peak (-2.21 ppm) of the spectrum is ant
It was found to be i- (2S, 3S) -7-ethoxy-1,1,1-trifluoroheptane-2,3-diol and product-1 was syn- (2S, 3R) -7-ethoxy. -1,1,1-trifluoroheptane-2,3-diol and anti- (2S, 3S) -7-ethoxy-
It is composed of 1,1,1-trifluoroheptane-2,3-diol, and its production ratio is syn-form (2S, 3R) type / a.
It was confirmed to be a diastereomer mixture of the nti form (2S, 3S) type = 70/30 (area ratio). Therefore, the reaction product obtained in the first step reaction is a syn form (2
S, 3R) type / anti body (2S, 3S) type = 70/3
It was confirmed that the mixture was a diastereomer mixture 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 was charged. A reaction product solution [(S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-7-ethoxyheptanone-3 solution containing 15 mmol] was added, and the mixture was placed in an ice water bath. It was inserted into the flask and adjusted to 0 ° C. with stirring. Then, 2.27 g of methyl iodide was added to the dropping funnel.
(16 mmol) and 20 ml of diethyl ether were added,
With stirring, the solution was added dropwise over 11 minutes. After completion of dropping
Remove the ice water bath, warm to room temperature with stirring,
Then, the reaction was completed by keeping the mixture at room temperature for 2 hours with stirring.

After completion of the reaction, 5% aqueous sodium hydrogen carbonate solution was added for neutralization, the solvent was distilled off under reduced pressure, saturated aqueous sodium thiosulfate solution was added, and the mixture was extracted with ether. Was added to remove water and then concentrated under reduced pressure to obtain a syrupy residue. This residue was subjected to silica gel column chromatography [eluent n-hexane / isopropyl alcohol = 95/5 (volume ratio)].
To obtain a colorless and transparent liquid O-methylated derivative [yield 5.79 g (12.75 mmol) yield 85%]. As a result of measuring the ¹⁹ FNMR spectrum of the obtained O-methylated derivative, two peaks were observed, and the position and the area ratio of each peak are shown as follows: ¹⁹ FNMR spectrum (from ext. CF ₃ C
OOH) First peak: -2.20 ppm, area ratio 70%, [Sy
n-type (2S, 3R) type ☆ 3] Second peak: -3.90 ppm, area ratio 30%, [an
ti form (2S, 3S) type ☆ 3] (☆ 3, confirmed in Identification Example 2 described below) Therefore, from the results of ¹⁹ FNMR spectrum and Identification Example 2 described below, the O-methylated derivative is a Syn form (2S,
3R) type / anti body (2S, 3S) type = 70/30
It was confirmed to be a mixture of diastereomers consisting of (area ratio).

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

After completion of the reduction reaction, the resulting reaction suspension was filtered to remove the palladium / carbon catalyst, and the filtrate was concentrated under reduced pressure to distill off methanol, and then the by-produced toluene was vacuum pumped. Removal gave a syrupy residue. This 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 a colorless and transparent liquid product, diastereomer mixture-1 was obtained.
[Yield 3.03 g (8.33 mmol) yield 98%] was obtained. ¹ H NMR spectrum, ¹⁹ F NMR of this product
The results of measurement of spectrum, 1R absorption spectrum and MS spectrum are as follows, and the product was 2- (4
-Hydroxybenzoyloxy) -7-ethoxy-3-
It was confirmed to be methoxy-1,1,1-trifluoroheptane.

[0065]¹HNMR spectrum (CDCl_Three) 0.87-0.96 ppm (3H), 1.09-1.5
3 ppm (6H), 2.60 to 2.72 ppm (2
H ), 2.75 ppm (3H), 2.87 to 3.00 p
pm (1H), 3.27 to 3.42 ppm (2H),
4.18-4.35ppm (1H), 5.41ppm
(1H), 6.69 to 7.98 ppm (4H, AB pattern
)¹⁹ FNMR spectrum (from ext. CF_ThreeC
OOH) First peak: -1.86 ppm, area ratio 70% [Syn
Body (2S, 3R) type ☆ 4] Second peak: -2.33 ppm, area ratio 30% [ant
i-body (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 1 HNMR spectrum diagram is shown in FIG. 7.

The obtained product was s according to Identification Example 2 described later.
yn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1
-Trifluoroheptane and anti-2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane, which is a diastereomeric mixture having a production ratio syn-form (2
S, 3R) type / anti body (2S, 3S) type = 70/3
It was confirmed to be 0 (area ratio) of the diastereomeric mixture-1.

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

Of this product¹HNMR spectrum,¹⁹F
NMR spectrum, 1R absorption spectrum, and MS spectrum
The results of measuring the vector are as follows, and the product is 2
-Hydroxy-7-ethoxy-3-methoxy-1,1,
It was 1-trifluoroheptane.¹ HNMR spectrum (CDCl_Three) 0.81 to 1.00 ppm (3H), 1.04 to 1.3
0 ppm (6H), 2.48 to 2.64 ppm (3
H ) 2.69 ppm (3H), 2.84 to 3.00 p
pm (1H), 3.12 to 3.26 ppm (2H),
3.77 to 3.90 ppm (1H), 4.02 to 4.1
4ppm (1H)¹⁹ FNMR spectrum (from ext. CF_ThreeC
OOH) First peak: -2.12 ppm, area ratio 70% [Syn
Body (2S, 3R) type ☆ 5] Second peak: -4.14 ppm, area ratio 30% [ant
i-body (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 1 HNMR spectrum diagram is shown in FIG.

Next, the above-mentioned product was subjected to gas chromatography having a column for separating optical isomers (hereinafter referred to as optically active gas chromatography) under the following conditions. Column: Trade name Cyclodex β236M (manufactured by Chrompack): Size Inner diameter 0.25 mm, length 25 m: Silica capillary column Column temperature: Hold at 100 ° C for 10 minutes, then increase to 200 ° C at a heating rate of 4 ° C / min Temperature Carrier gas: Helium, Gas flow rate 60 NL / min, Split ratio 100/1 Detection: FID

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

The syn form (2S, 3 obtained in the first step reaction)
R) type / anti body (2S, 3S) type = 70/30 (area ratio), which is a diastereomer mixture, and the alcoholate of the metal compound bonded to the asymmetric carbon atom at the 3-position of the reaction product and methyl iodide. The product obtained by hydrolyzing the O-methylated derivative obtained by reacting with the compound with an acid has two optically active peaks, and the first peak / second peak = 70/30 (area (Ratio) is in agreement with the area ratio of the reaction product obtained in the first-step reaction, so that the absolute configuration of the asymmetric carbon atoms at the 2-position and 3-position does not change between the reaction products. Was confirmed.

Therefore, the first peak (retention time 1
4.55 min) 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%. 2nd peak (holding time 1
5.27 min) was found to be anti- (2S, 3S) -2-hydroxy-7-ethoxy-3-methoxyheptane, syn- (2S, 3R) -2-hydroxy-
The first peak of the ¹⁹ F NMR spectrum of the product having the same area ratio as that of 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 of the ¹⁹ F NMR spectrum (-4.1) of the product having the same area ratio as 1,1,1-trifluoroheptane
4 ppm) was confirmed to be anti- (2S, 3S) -2-hydroxy-7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.

Therefore, the product obtained by hydrolyzing the O-methyl derivative and the 2- and 3-positions of the O-methylated derivative, respectively.
Since the absolute configuration of the asymmetric carbon atom at
Area ratio of ¹⁹ F NMR spectrum of methylated derivative 70%
The first peak (-2.20 ppm) is a syn-body (2
S, 3R) type, and the area ratio of ¹⁹ F NMR spectrum is 3
The second peak (-3.90 ppm), which is 0%, is anti
(2S, 3S) type, and the O-methylated derivative is a syn (2S, 3R) type / anti type (2
It was confirmed that the mixture was a diastereomer mixture consisting of (S, 3S) type = 70/30 (area ratio).

Then, the diastereomer mixture-1 obtained in the third reaction was subjected to optically active liquid chromatography under the following conditions. Optical isomer separation column: [Brand name: amylose-based HPLC column for optical isomer separation: Daicel Chemical Industries, Ltd.]
Separation agent: Amylose tris [(S) -1-phenylethylcarbamate] coated with silica gel (Great CHIRALPAKAS) Size: 4.6 mmφ × 250 mmH Eluent: n-hexane / isopropyl alcohol = 96/4 ( Volume ratio) Flow rate: 0.5 ml / min. Detection: Ultraviolet absorption with a wavelength of 254 mm was used with an ultraviolet detector. Sample: 0.1 mg

The chart of the above-mentioned optically active liquid chromatography is as shown in FIG. 10. From the analysis result of FIG.
Two optically active peaks were obtained, and their retention time and area ratio were as follows. 1st 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% (* 7 Confirmed from this identification example)

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

Thus, the diastereomer mixture-1 of ¹⁹
The first peak (-1.86 ppm) having 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, and the diastereomer mixture- 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 is composed of 1-trifluoroheptane, and its production ratio sy
n-body (2S, 3R) type / anti-body (2S, 3S) type =
It was confirmed that the mixture was a 70/30 (area ratio) diastereomer mixture.

(Fourth stage reaction) [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-
Production of 1,1,1-trifluoroheptane] Diastereomeric mixture-1,2 obtained in the third step reaction
The first peak and the second peak were separately separated from each other using 00 g (5.5 mmol) under the following conditions using preparative silica gel column chromatography, and the eluent was distilled off under reduced pressure. The first fraction [acquired amount 1.26 g (3.47 mmol) acquisition rate 63%] and the second fraction [acquired amount 0.54 g] which are the target products of
(1.48 mmol) acquisition rate 27%] was obtained.

¹ H NMR spectra of these products,
The 1R absorption spectrum and the MS spectrum are in agreement with the diastereomer mixture-1, and each product is 2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-
1,1,1-trifluoroheptane. Also, ¹⁹
The FNMR spectrum is as follows, and one peak was observed for each. Furthermore, optically active liquid chromatography was performed under the same conditions as in Identification Example 2 of the third step reaction. The chart of the above-mentioned optically active liquid chromatography is shown in FIG.
1 and FIG. 12, one optical activity peak each was obtained from the analysis results of FIG. 11 and FIG. 12, and the retention time was as follows, and the 1st fraction of the desired product was syn- (2S, 3R) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane, the second
The fraction is anti- (2S, 3S) -2- (4-
It was confirmed to be hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.

Preparative silica gel column chromatography [Product name: Inert Shell PREP-ODS preparative, guard column two-piece set No. 5020-35112, manufactured by GL Sciences Inc.] Filler: 10 μ silica gel having a purity of 99.9% chemically bound with an octadecyl group Size: 10 mmφ × 250 mmH 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 min Yield 1.95 g (5.36 mmol) Yield 63% ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) -1.86 ppm Optical active liquid chromatography: retention time 10.11
Min 2nd flank [anti- (2S, 3S) -2-
(4'-Hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane] Retention time 11.46 min Yield 0.83 g (2.30 mmol) Yield 27% ¹⁹ FNMR Spectrum (from ext. CF ₃ C
OOH) -2.33 ppm Optical active liquid chromatography: retention time 11.46
Minute

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,
When using diisobutylaluminum hydride as the metal hydride]

(First-step reaction) [syn form (2S, 3R)]
Type / anti body (2S, 3S) type = production of reaction product which is a diastereomer mixture consisting of 40/60 (area ratio)] Four-neck equipped with thermometer, stirrer, reflux condenser and dropping funnel (S) -2 obtained in Reference Example 3 in a round bottom flask.
-(4-Benzyloxybenzoyloxy) -7-ethoxy-1,1,1-trifluoroheptanone-3,1
23 ml was added to 0.95 g (25 mmol), and a uniform solution was prepared with stirring, and the solution was 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 placed in the dropping funnel and added dropwise over 10 minutes while stirring. After completion of dropping, remove the ice water bath, raise the temperature to room temperature with stirring, and continue stirring and holding for 90 minutes,
The reaction was completed and a reaction product solution was obtained. The obtained reaction product is a syn form (2S, 3R) according to Identification Example 3 described later.
It was confirmed that the mixture was a diastereomer mixture consisting of type / anti body (2S, 3S) type = 40/60 (area ratio).

[Identification Example 3: The reaction product was syn (2
S, 3R) type / anti body (2S, 3S) type = 40/6
Identification of Diastereomer Mixture Consisting of 0 (Area Ratio)] In a three-necked round bottom flask equipped with a thermometer, a stirrer, and a reflux condenser, the 20 wt% reaction product solution obtained above (starting compound 5 mmol conversion reaction product solution), 3N hydrochloric acid 25 ml and methanol 100 m
1 was put into a hot water bath at a temperature of 80 ° C., the temperature was raised to boiling with stirring, and the mixture was heated under reflux for 7 hours to carry out a hydrolysis reaction. After completion of the hydrolysis reaction, remove the warm water bath, cool to room temperature with stirring,
After extraction with ether, the extract was washed with 20 ml of a 20% aqueous sodium hydrogen carbonate solution and then with 200 ml of water, and anhydrous magnesium sulfate was added to remove water, and then the solvent was distilled off under reduced pressure to give a syrupy residue. Got This residue was subjected to silica gel column chromatography [eluent n
-Hexane / isopropyl alcohol = 95/5 (volume ratio)] to obtain a colorless and transparent liquid product-3 [yield 0.9 g (3.92 ppm) yield 78.4%].

¹ H NMR spectrum of this product-3,
^The results of measurement of ¹⁹ FNMR spectrum and 1R absorption spectrum are in agreement with those of Identification Example 1 of Reference Example 4, and 7-ethoxy-
It was confirmed to be 1,1,1-trifluoroheptane-2,3-diol. In addition, as a result of measuring ¹⁹ FNMR spectrum based on the result of Identification Example 1 of Reference Example 4, 2
From this peak, the product-3 was identified as syn- (2S, 3R) -7-ethoxy-1,1,1-trifluoroheptane-2,3-diol and anti. -(2S, 3S) -7-Ethoxy-
It is composed of 1,1,1-trifluoroheptane-2,3-diol, and its production ratio is syn-form (2S, 3R) type / a.
It was found to be a diastereomeric mixture consisting of the nti form (2S, 3S) type = 40/60 (area ratio). ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) 1st peak: -0.48ppm, area ratio 40 syn body (2S, 3R) type 2nd peak: -2.21ppm, area ratio 60anti
Body (2S, 3S) type Therefore, the reaction product obtained in the first step reaction: syn body (2S, 3R) type / anti body (2S, 3S) type = 40
It was confirmed that the mixture was a diastereomer mixture consisting of / 60 (area ratio).

(Second-stage reaction) (O-methylated derivative) In a round-bottomed flask equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel, the reaction product of the remaining 80% obtained in the first-stage reaction was obtained. Solution ([S) -2- (4-benzyloxybenzoyloxy) -1,1,1-trifluoro-7-ethoxyheptanone-3 solution containing 20 mmol] was added, and the solution was inserted into an ice water bath. Then, the temperature was adjusted to 0 ° C. with stirring. Then, 3.12 g of methyl iodide was added to the dropping funnel.
(22 mmol) and 28 ml of diethyl ether were added,
While stirring, the solution was added dropwise over 13 minutes. After completion of dropping
The ice water bath was removed, the temperature was raised to room temperature, and then the mixture was stirred and held at room temperature for 2 hours to complete the reaction.

After completion of the reaction, 5% aqueous sodium hydrogencarbonate solution was added for neutralization, the solvent was distilled off under reduced pressure, saturated aqueous sodium thiosulfate solution was added, followed by ether extraction, and the extracted solution was dried over anhydrous magnesium sulfate. Was added to remove water and then concentrated under reduced pressure to obtain a syrupy residue. This residue was subjected to silica gel column chromatography [eluent n-hexane / isopropyl alcohol = 95/5 (volume ratio)].
To obtain a colorless transparent liquid O-methylated derivative [yield 7.54 g (16.6 mmol) yield 83%].
As a result of measuring the ¹⁹ FNMR spectrum of the obtained O-methylated derivative, two peaks were recognized, and the position and area ratio of each peak are as follows. ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) First peak: -2.20 ppm, area ratio 40% [syn
Body (2S, 3R) type ☆ 7] Second peak: -3.90 ppm, area ratio 60% [ant
i-body (2S, 3S) type ☆ 7] (☆ 7, confirmed in Identification Example 4 below)

(Third stage reaction) The above-mentioned second stage reaction was carried out in a closed four-neck round bottom flask equipped with a thermometer, a stirrer, a dropping funnel, a hydrogen gas charge tube and a polyethylene resin balloon. 4.99 g (11 mmol) of O-methylated derivative and 75 ml of methanol were added, and 10% palladium / carbon catalyst 0.10 was added to the dropping funnel while stirring at room temperature.
g was added and slowly added dropwise to prepare a uniformly dispersed suspension. Then, while stirring at room temperature, pressure 1.1k
The reaction system was sealed with hydrogen gas of about g / cm ² to carry out a reduction reaction. In the reduction reaction, the suspension was stirred and hydrogen gas was supplied for 4 or 5 hours until the absorption of hydrogen gas ceased to complete the reaction. After completion of the reduction reaction, the obtained reaction suspension was filtered, the palladium / carbon catalyst was removed, and the filtrate was concentrated under reduced pressure to distill off methanol, and then the by-produced toluene was removed by a vacuum pump, A syrupy residue was obtained.
This residue was subjected to silica gel column chromatography [eluent: n-hexane / isopropyl alcohol = 96/4].
(Volume ratio)], and the eluent was distilled off under reduced pressure to obtain a diastereomer mixture-2 [amount 3.92 g (10.78 mmol) yield 98%] as a colorless transparent liquid product. It was

¹ H NMR spectrum of this product, 1R
The results of measurement of absorption spectrum and MS spectrum are the same as in the third step reaction of Example 1, 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 ¹⁹ FNMR spectrum of the obtained product, two peaks were recognized, and the position and area ratio of each peak are as follows. ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) First 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 Identification Example 4 below)

The obtained product was s according to 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 diastereomer mixture consisting of ethoxy-3-methoxy-1,1,1-trifluoroheptane, and the production ratio thereof is syn-form (2S, 3R) type / anti-form (2S,
It was confirmed to be a diastereomer mixture-2 in which 3S) type = 40/60 (area ratio).

[Identification Example 4] The O-methylated derivative obtained in the second reaction was a di-form consisting of syn-form (2S, 3R) type / anti-form (2S, 3S) type = 40/60 (area ratio). It is a stereomeric mixture, and the 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 It is composed of -3-methoxy-1,1,1-trifluoroheptane, and its production ratio is a syn body (2S, 3R) type / anti body (2S,
Identification of a diastereomer mixture of 3S) type = 40/60 (area ratio)]

In a four-necked round bottom 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 reaction of Example 2 was introduced.
Then, add 25 ml of 3N hydrochloric acid and 100 ml of methanol, raise the temperature to 80 ° C. with stirring, and reflux for 6 hours.
A hydrolysis reaction was performed. Then, after cooling to room temperature,
The product was extracted with ether and the extract was washed with 20% aqueous sodium carbonate solution and then with water, and anhydrous magnesium sulfate was added to remove water, and then the solvent was distilled off under reduced pressure to obtain a colorless transparent liquid product. [Yield 0.98 g (4 mmol)
Yield 80%] was obtained.

Of this product¹HNMR spectrum, 1R
The results of measuring absorption spectrum and MS spectrum are identified
Consistent with Example 2, the product is 2-hydroxy-7-ethoxy
With 3-methoxy-1,1,1-trifluoroheptane
there were. Of the obtained product¹⁹Measure FNMR spectrum
As a result, two peaks were recognized, and the position of each peak was
The area ratio is as follows.¹⁹ FNMR spectrum (from ext. CF_ThreeC
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 in this identification example)

Further, the above product was subjected to optically active gas chromatography under the same conditions as in Identification Example 2 of Reference Example 4. The chart of the optically active gas chromatography is shown in FIG. From the analysis result of the chart of FIG. 13, two optically active peaks were recognized, and the retention time and area ratio of each peak are as follows. First 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 result of Identification Example 2 of Reference Example 4, the first
The peak (holding time 14.55 minutes) is syn- (2S, 3
R) -2-Hydroxy-7-ethoxy-3-methoxy-
It is 1,1,1-trifluoroheptane, and the second peak (retention time 15.27 minutes) is anti- (2S, 3S).
-2-hydroxy-7-ethoxy-3-methoxy-1,
Confirmed to be 1,1-trifluoroheptane,
The product is syn- (2S, 3R) -2-hydroxy-7.
-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) type / anti body (2S, 3S) type = 40/6
It was confirmed that the mixture was a diastereomer mixture consisting of 0 (area ratio).

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

Therefore, since the absolute configuration of the asymmetric carbon atoms at the 2-position and 3-position of the product obtained by hydrolyzing the O-methylated derivative and the O-methylated derivative does not change,
-Area ratio 40 in ¹⁹ F NMR spectrum of methylated derivative
% Of the first peak (−2.20 ppm) is a syn-type (2S, 3R) type, and the second peak (−3.90 ppm) of which the area ratio of ¹⁹ FNMR spectrum is 60% is an
It was found to be a ti body (2S, 3S) type, and the O-methylated derivative is a diastereomer consisting of a syn body (2S, 3R) type / anti body (2S, 3S) type = 40/60 (area ratio). It was confirmed to be a mixture of mer.

Then, the diastereomer mixture-2 obtained in the third 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 above-mentioned 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, the syn body (2S, 3R) type / ant
O-methylated derivative, which is a diastereomer mixture consisting of i-form (2S, 3S) type = 40/60 (area ratio), is reduced with hydrogen gas in the presence of a palladium / carbon catalyst to form a diastereomer mixture- In the reaction from which 2 is obtained, it is irrelevant to the configuration of the asymmetric carbon atoms at the 2- and 3-positions. Therefore, the syn form of the O-methylated derivative (2
The first peak (retention time: 10.11 min) of the diastereomer mixture-2 which matches the area ratio of the (S, 3R) type is syn- (2S, 3R)-.
2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane, while the anti-form (2S, of O-methylated derivative)
Diastereomeric mixture matching the area ratio of 3S)-
The second peak (retention time 11.46 minutes) of the optically active liquid chromatography of 2 was anti- (2S, 3S) -2.
It was found to be-(4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.

Thus, the diastereomer mixture-2 of ¹⁹
The first peak (-1.86 ppm) having 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, while the area ratio is 60%)
pm) was confirmed to be anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane, and the diastereomer mixture- 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 is composed of 1-trifluoroheptane, and its production ratio sy
n-body (2S, 3R) type / anti-body (2S, 3S) type =
It was confirmed to be a 40/60 (area ratio) diastereomer mixture.

(Fourth stage reaction) [syn- (2S, 3R)
-2- (4-Hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane and anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy Production of 3-methoxy-1,1,1-trifluoroheptane] Diastereomeric mixture-2 obtained in the third step reaction,
2.91 g (8 mmol) of the first and second peaks were separately collected using preparative silica gel chromatography under the same conditions as in the fourth step reaction of Reference Example 4, and the eluent was distilled off under reduced pressure. However, the first fraction, which is each objective product in the form of a colorless transparent liquid, [collection amount 1.05 g (2.88
And a second fraction [amount of 1.57 g (4.32 mmol) of 54%] was obtained.

The ¹ H NMR spectrum, 1R absorption spectrum and MS spectrum of these desired products were in agreement with the diastereomer mixture-2, and each desired product was 2- (4-
It was hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.
The ¹⁹ F NMR spectrum is as follows, and one peak was recognized for each. Furthermore, when optically active liquid chromatography was applied under the same conditions as in the fourth step reaction of Reference Example 4, the same charts as in 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 was confirmed to be 1-trifluoroheptane.

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 Acquisition amount 1.05 g (2.88 mmol), acquisition rate 36
% ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) -1.86 ppm Optical active liquid chromatography Retention time 10.11 min Second fraction [anti- (2S, 3S) -2-
(4-Hydroxybenzoyloxy) -7-ethoxy-
3-Methoxy-1,1,1-trifluoroheptane] Retention time 34.25 to 44.25 minutes Retrieval amount 1.57 g (4.32 mmol) Retrieval rate 54
% ¹⁹ F NMR spectrum (from ext. CF ₃ C
OOH) -2.33 ppm Optical active liquid chromatography Retention time 11.46 minutes

[0104]Reference example 6[Syn- (2S, 3R) -2-
{4- [4- (4 -N-decylphenyl) benzoyl
[Xy] benzoyloxy} -7-ethoxy-3-methoxy
Production of Ci-1,1,1-trifluoroheptane] A thermometer, a stirrer, a reflux condenser and a dropping funnel were provided.
The syn-obtained in Reference Example 4 was added to a 4-neck round bottom flask.
(2S, 3R) -2- (4-hydroxybenzoyloxy)
Ci) -7-Ethoxy-3-methoxy-1,1,1-tri
1.46 g (4 mmol) of fluoroheptane and 4-
1.62 g of (4-n-decylphenyl) benzoic acid (4.
8 mmol) and N, N-dimethylaminopyridine 0.
29 g (2.4 mmol) and methylene chloride 120 m
1 was added and stirred at room temperature to prepare a uniform solution. Next
Then add dicyclohexylcarbodiimide to the dropping funnel.
Add 22 g (6 mmol) and add dropwise with stirring.
Continue to stir for 5 hours at room temperature to complete the reaction.
Was.

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

Of this desired product¹HNMR spectrum,
¹⁹FNMR spectrum, 1R absorption spectrum and MS
The result of spectrum measurement is as follows.
The thing is 2- {4- [4- (4 -N-decylphenyl) ben
Zoyloxy] benzoyloxy} -7-ethoxy-3
-Methoxy-1,1,1-trifluoroheptane
Was. In addition, the target product is two asymmetric carbons as raw material compounds.
It is irrelevant to the configuration of elementary atoms,
Since the mind does not change, syn- (2S, 3R) -2
-{4- [4- (4 -N-decylphenyl) benzoyl
Oxy] benzoyloxy} -7-ethoxy-3-meth
Be xyl-1,1,1-trifumeoroheptane
confirmed. Furthermore, from the identification example described below, the syn-body (2
S, 3R) type was confirmed.

¹ H NMR spectrum (CDCl ₃ ) 0.8 to 1.04 ppm (6H), 1.09 to 1.62
ppm (24H), 2.07 to 2.20 ppm (2
H), 2.60 ppm (3H), 3.07 to 3.20p
pm (2H), 4.15 to 4.20 ppm (1H),
4.52-4.56 ppm (1H), 6.58-8.0
4 ppm (12H) 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 ⁺ ) Further, the ¹ HNMR spectrum diagram is shown in FIG. 15.

(Identification Example) [The above target compound is syn-
(2S, 3R) -2- {4- [4- (4 -N-decylph
Benzoyloxy] benzoyloxy} -7-
Ethoxy-3-methoxy-1,1,1-trifluoro
Identification of Putane] Four tools equipped with a thermometer, stirrer, reflux condenser, and dropping funnel
0.36 g of the compound obtained in Reference Example 4 in a round bottom flask.
(1 mmol), 3N hydrochloric acid 5 mmol, and methanol 2
Add 0 ml, raise the temperature to 80 ° C, reflux for 6 hours, and add water.
A decomposition reaction was performed. Then, after cooling to room temperature,
Tell extraction and wash the extract with 20% aqueous sodium carbonate.
After cleaning and then washing with water, dry magnesium sulfate
In addition, after removing water, the solvent was distilled off under reduced pressure, and
Clear liquid product-1 [yield 0.2 g (0.8 millimolar
(Yield 80%).

¹ H NMR spectrum of this product-1
¹⁹ FNMR spectrum, 1R absorption spectrum and MS
The results of measuring the spectrum are as follows, and the product-
1 is 2-hydroxy-7-ethoxy-3-methoxy-
1,1,1-trifluoroheptane. ¹ H NMR spectrum (CDCl ₃ ) 0.80 to 1.00 ppm (3H), 1.04 to 1.3
0 ppm (6H), 2.48 to 2.64 ppm (3
H), 2.69 ppm (3H), 2.84-3.00p
pm (1H), 3.12 to 3.26 ppm (2H),
3.77 to 3.90 ppm (1H), 4.02 to 4.1
4 ppm (1H) ¹⁹ F NMR spectrum-2.12 ppm 1R absorption spectrum (neat) 1,120 cm ^-1 (COC), 1,670 cm ^-1 (O
H) MS spectrum m / z 244 (M ⁺ ) Further, the ¹ HNMR spectrum diagram is shown in FIG. 16.

Then, the above-mentioned product-1 was prepared under the following conditions:
It was subjected to gas chromatography having an optical isomer separation column (hereinafter referred to as optically active gas chromatography). Column: Trade name Cyclodex β236M (made by Chrompack): Size inner diameter 0.25 mm, length 25 m: Silica capillary column Column temperature: After holding at 100 ° C for 10 minutes, increase to 200 ° C at a heating rate of 4 ° C / min. Temperature Carrier gas: Helium, Gas flow rate 60Nl / min, Split ratio 100/1 Detection: FID

A chart of optically active gas chromatography is shown in FIG. From the analysis result of FIG. 17, one optically active peak was recognized, and its retention time was 14.55 minutes. The product-1 obtained by hydrolyzing the compound obtained in Reference Example 4 has only one optically active substance. Therefore, the product is syn- (2S, 3R) -2-hydroxy-.
It was found to be 7-ethoxy-3-methoxy-1,1,1-trifluoroheptane. Then, a hydrolysis reaction was carried out in the same manner as described above except that 0.68 g (1 ppm) of the target product was used in place of 0.36 g (1 ppm) of the compound obtained in Reference Example 4 to produce a colorless transparent liquid. Product-2 [yield 0.2 g (0.8 mmol) yield 80%]
I got As a result of measuring various spectra of this product-2, it was the same as that of the product-1 and was 2-hydroxy-7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.

The above product-2 was treated under the same conditions as above.
Then, using optically active gas chromatography,
Is obtained and the retention time is 14.55.
And the product-2 is syn-like as the product-1.
(2S, 3R) -2-Hydroxy-7-ethoxy-3-
Methoxy-1,1,1-trifluoroheptane
Was. Therefore, even if the desired product is hydrolyzed, it is converted to the 2-position.
Since the absolute configuration of the asymmetric carbon atom at the 3-position does not change,
The target product was found to be of the syn form (2S, 3R) type.
Remarks, syn- (2S, 3R) -2- {4- [4- (4
-N-decylphenyl) benzoyloxy] benzoyl
Oxy} -7-ethoxy-3-methoxy-1,1,1-
It was confirmed to be trifluoroheptane.

Reference Example 7 (Characteristics of the compound of Reference Example 6) (Measurement of the phase transition temperature of the compound of Reference Example 6) The compound of Reference Example 6 was observed by DSC and the electric field response of the liquid crystal display device described later with a polarizing microscope. By doing so, the results of measuring the phase transition temperature are as follows. However, cry: crystalline phase, S
_CA *: Antiferroelectric liquid crystal phase, SA: smectic A phase and ISO: isotropic liquid phase. The upper value is 4 ℃
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:

[0114]

Embedded image

Therefore, the compound of Reference Example 6 was an antiferroelectric liquid crystal compound containing a substance around room temperature. (Preparation of liquid crystal display element) Two glass substrates with transparent electrodes were rubbed with alignment films spin-coated with polyimide, with a gap interval of 1.7 um so that the rubbing directions were parallel to each other. The cells were assembled by laminating. The compound obtained in Reference Example 6 was injected into the cell obtained above in an isotropic liquid phase. Next, it was gradually cooled to a liquid crystal state. This liquid crystal cell is sandwiched between a polarizer and an analyzer whose transmission axes are orthogonal to each other, and the cell is installed so that the normal direction of the molecular layer in the chiral smectic C phase and the direction of the polarizer or the analyzer are the same, and no electric field is applied. At the time (0 V), the third stable state is set to a dark state, a chiral smectic C phase is changed by application of an electric field, and the state is used as a bright state, whereby a liquid crystal display capable of displaying dark and bright A device was created. That is, the angle of the cell with respect to the polarizer was adjusted so that the amount of transmitted light was minimized when the applied voltage was 0V. The amount of transmitted light was 100% when the transmission axis of the analyzer was rotated to match the transmission axis of the polarizer.

(Evaluation of Liquid Crystal Display Element) Using the liquid crystal display element prepared above, the applied voltage ± 8.7 at 25 ° C.
FIG. 18 shows a diagram in which a change in transmitted light amount with respect to V is measured.
It became. From the figure, a double hysteresis curve showing one dark state and two bright states was obtained. Further, the results of performance evaluation of the liquid crystal display element by the change of the transmitted light amount with respect to the change of the applied voltage at 25 ° C. are as follows. Response time: 28.2us (time to change from a bright state to a dark state at 25 ° C) Threshold voltage: 5.12V / um (voltage at which a completely bright state is obtained at 25 ° C) Tilt angle: 30.20 (Angle where Optical Axis Becomes Polarizer at Threshold Voltage at 25 ° C.) As a result, the compound of Reference Example 6 has an antiferroelectric liquid crystal phase at around room temperature, and a liquid crystal display using it. The element is 25 ℃,
A double hysteresis curve having three stable states was shown, and it was confirmed that it was an antiferroelectric liquid crystal compound excellent in a large response time, a low threshold voltage, a large tilt angle and a large screen display material. .

[0117]

INDUSTRIAL APPLICABILITY The present invention is useful as an intermediate raw material for an antiferroelectric liquid crystal compound or as a building block agent capable of introducing various functional groups into a compound used for pharmaceuticals or agricultural chemicals (S) -1. -Hydroxy-2,
2,2-trifluoroethyl-terminated ethoxyalkyl ketone, which also comprises (S) -N- (2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine and terminal ethoxyalkylmagnesium bromide. By reacting and then hydrolyzing the reaction product with a mineral acid, it can be efficiently produced in a high yield.

[Brief description of drawings]

1-hydroxy-2,2 obtained in Example 1 FIG.
Of 2-trifluoroethyl-4-ethoxybutyl ketone
It is a < ¹ > H NMR spectrum figure.

FIG. 2 1-hydroxy-2,2 obtained in Example 1
1 is a chart of optically active gas chromatography of a mixture of enantiomers of 2-trifluoroethyl-4-ethoxybutyl ketone.

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

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

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 was obtained in Identification Example 1 of the first step reaction of Reference Example 4.
2,2-Dimethyl-4- (4-ethoxybutyl) -5-
Of trifluoromethyl-1,3-dioxolane  ¹HN
It is an MR spectrum figure.

FIG. 7 is a graph showing 2- (4-hi) obtained in the third step reaction of Reference Example 4.
Droxybenzoyloxy) -7-ethoxy-3-meth
Of xy-1,1,1-trifluoroheptane  ¹HNM
It is an R spectrum figure.

FIG. 8: 2 obtained in Identification Example 2 of 3rd stage reaction of Reference Example 4
-Hydroxy-7-ethoxy-3-methoxy-1,1,
FIG. 3 is a ¹ HNMR spectrum diagram of 1-trifluoroheptane.

FIG. 9: s obtained in identification example 2 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 production ratio is syn (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: Diastereomeric mixture-1 obtained in the third-step reaction of Reference Example 1: syn- (2S, 3R) -2- (4
-Hydroxybenzoyloxy) -7-ethoxy-3-
Methoxy-1,1,1-trifluoroheptane / ant
i- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-
1 is a chart of optically active liquid chromatography of a diastereomeric mixture consisting of trifluoroheptane = 70/30 (area ratio).

FIG. 11: syn- obtained in the fourth step reaction of Reference Example 4
It is a chart of 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 optically active liquid chromatography of (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane.

FIG. 13 is a syn- (2S, 3R) -2-hydroxy-7-ethoxy-3-methoxy-1,1,1-trifluoroheptane obtained in Identification Example 4 of the third step reaction of Reference Example 5 and anti- (2S, 3S) -7-ethoxy-3-
It is composed of methoxy-1,1,1-trifluoroheptane, and its production ratio is a syn body (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 third step reaction of Reference Example 5 Diastereomeric mixture-2: syn- (2S, 3R) obtained in Example 4.
-2- (4-hydroxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane / anti- (2S, 3S) -2- (4-hydroxybenzoyloxy) -7-ethoxy -3-Methoxy-
1 is a chart of optically active liquid chromatography of a diastereomeric mixture consisting of 1,1,1-trifluoroheptane = 40/60 (area ratio).

FIG. 15: syn- (2S, 3R) obtained in Reference Example 6
-2- {4- [4- (4 -N-decylphenyl) benzo
Iloxy] benzoyloxy} -7-ethoxy-3-
Of methoxy-1,1,1-trifluoroheptane¹HN
It is an MR spectrum figure.

FIG. 16: Product-1: s obtained in the identification example of Reference Example 6
of 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 the optically active gas chromatography of the product-1 obtained in the identification example of Reference Example 6.

FIG. 18: syn- (2S, 3R) -2- {4- [4-
(4 -N-decylphenyl) benzoyloxy] benzo
Iloxy} -7-ethoxy-3-methoxy-1,1,
Double hiss of 1-trifluoroheptane liquid crystal display device
It is a therisis curve.

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[Procedure amendment]

[Submission date] January 8, 1996

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0018

[Correction method] Change

[Correction contents]

[Compound of the present invention: Production of (S) -1-hydroxy-2,2,2- trifluoroethyl -terminated ethoxyalkyl ketone] The compound of the present invention is prepared by reacting the starting compound with the compound of the formula (2) in an organic solvent. It can be produced by reacting with the indicated Grignard reagent (first step reaction), and then hydrolyzing the reaction product with a mineral acid (second step reaction). Hereinafter, (S) -N- (2-hydroxy-3,3,3
The production method from a starting compound which is 3-trifluoropropionyl) pyrrolidine will be described in detail. (First Step Reaction) The first step reaction is represented by the reaction formula (7).

[Procedure amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0029

[Correction method] Change

[Correction contents]

[0029]

[Chemical 7]

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0062

[Correction method] Change

[Correction contents]

After completion of the reaction, 5% aqueous sodium hydrogen carbonate solution was added for neutralization, the solvent was distilled off under reduced pressure, saturated aqueous sodium thiosulfate solution was added, and the mixture was extracted with ether. Was added to remove water and then concentrated under reduced pressure to obtain a syrupy residue. This residue was subjected to silica gel column chromatography [eluent n-hexane / isopropyl alcohol = 95/5 (volume ratio)].
To obtain a colorless and transparent liquid O-methylated derivative [yield 5.79 g (12.75 mmol) yield 85%]. As a result of measuring the ¹⁹ FNMR spectrum of the obtained O-methylated derivative, two peaks were observed, and the position and area ratio of each peak are shown as follows. ¹⁹ FNMR spectrum (from ext. CF ₃
COOH) ^Thus, from 19 FNMR the regular 2 Results and below the spectrum, O- methylated derivatives s yn body (2
S, 3R) type / anti body (2S, 3S) type = 70/3
It was confirmed to be a diastereomer mixture consisting of 0 (area ratio).

[Procedure amendment 4]

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[Correction method] Change

[Correction contents]

¹ H NMR spectrum (CDCl ₃ ) 0.87 to 0.96 ppm (3H), 1.09 to 1.5
3 ppm (6H), 2.60 to 2.72 ppm (2
H), 2.75 ppm (3H), 2.87-3.00p
pm (1H), 3.27 to 3.42 ppm (2H),
4.18-4.35ppm (1H), 5.41ppm
(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 ⁺ ) Further, the ¹ HNMR spectrum diagram is shown in FIG. 7.

[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0067

[Correction method] Change

[Correction contents]

[Identification Example 2] The O-methylated derivative obtained in the second reaction was a di-form consisting of syn-form (2S, 3R) type / anti-form (2S, 3S) type = 70/30 (area ratio). It is a stereomeric mixture, and the diastereomer 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-hi )
Droxybenzoyloxy) -7-ethoxy-3-methoxy-1,1,1-trifluoroheptane, and the production ratio thereof is a syn body (2S, 3R) type / anti body (2
S, 3S) type = identification of 70/30 (area ratio) diastereomer mixture-1] In a four-necked round bottom flask equipped with a thermometer, a stirrer, a reflux condenser, and a funnel, Reference Example 4 O-methylated derivative 1.82 obtained in the second reaction of
g (4 mmol), 3N hydrochloric acid (20 ml) and methanol (80 ml) were added, the temperature was raised to 80 ° C. with stirring, and 6
Reflux for an hour to obtain a hydrolysis reaction. Then, after cooling to room temperature, extraction with ether was performed, the extract was washed with a 20% aqueous sodium hydrogen carbonate solution, and then with water, and anhydrous magnesium sulfate was added to remove water, and then the solvent was distilled off under reduced pressure. And a colorless transparent liquid product [yield 0.78 g
(3.2 mmol) yield 80%] was obtained.

[Procedure correction 6]

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[Correction contents]

¹ H NMR spectrum of this product, ¹⁹
FNMR spectrum, 1R absorption spectrum, and MS
The results of the spectrum measurement are as follows, and the product is 2-hydroxy-7-ethoxy-3-methoxy-1,
It was 1,1-trifluoroheptane. ¹ H NMR spectrum (CDCl ₃ ) 0.81 to 1.00 ppm (3 H), 1.04 to 1.3
0 ppm (6H), 2.48 to 2.64 ppm (3
H), 2.69 ppm (3H), 2.84-3.00p
pm (1H), 3.12 to 3.26 ppm (2H),
3.77 to 3.90 ppm (1H), 4.02 to 4.1
4 ppm (1H) 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 ⁺ ) Further, the ¹ HNMR spectrum diagram is shown in FIG. 8.

[Procedure amendment 7]

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[Name of item to be corrected] 0070

[Correction method] Change

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

[Procedure amendment 8]

[Document name to be amended] Statement

[Correction target item name] 0081

[Correction method] Change

[Correction contents]

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 min Yield 1.95 g (5.36 mmol) Yield 63% ¹⁹ F NMR spectrum (from ext. CF ₃
COOH) -1.86 ppm Optical active liquid chromatography: retention time 10.11
Min 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 0.83 g (2.30 mmol) Yield 27% ¹⁹ F NMR spectrum (from ext. CF ₃
COOH) -2.33 ppm Optical active liquid chromatography: retention time 11.46.
Minute

[Procedure amendment 9]

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Therefore, the compound of Reference Example 6 was an antiferroelectric liquid crystal compound containing a substance around room temperature. The two glass substrates with liquid crystal display (creation of device) transparent electrode, an alignment film of polyimide was spin coated rubbed, so that the respective rubbing directions are mutually parallel, 1.7 [mu] m gap interval The cells were assembled by bonding with. The compound obtained in Reference Example 6 was injected into the cell obtained above in an isotropic liquid phase. Next, it was gradually cooled to a liquid crystal state. This liquid crystal cell is sandwiched between a polarizer and an analyzer whose transmission axes are orthogonal to each other, and the cell is installed so that the normal direction of the molecular layer in the chiral smectic C phase and the direction of the polarizer or the analyzer are the same, and no electric field is applied. At the time of (OV), the third stable state is set to the dark state, a chiral smectic C phase is changed by applying an electric field, and the state is used as the bright state, whereby a liquid crystal display capable of displaying dark and bright A device was created. That is, the angle of the cell with respect to the polarizer was adjusted so that the amount of transmitted light was minimized when the applied voltage was OV. The amount of transmitted light was 100% when the transmission axis of the analyzer was rotated to match the transmission axis of the polarizer.

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(Evaluation of Liquid Crystal Display Element) Using the liquid crystal display element prepared above, the applied voltage ± 8.7 at 25 ° C.
FIG. 18 shows a diagram in which a change in transmitted light amount with respect to V is measured.
It became. From the figure, a double hysteresis curve showing one dark state and two bright states was obtained. Further, the results of performance evaluation of the liquid crystal display element by the change of the transmitted light amount with respect to the change of the applied voltage at 25 ° C. are as follows. Response time: 28.2 μs (time changed from bright state to dark state at 25 ° C.) Threshold voltage: 5.12 V / μm (voltage at which a completely bright state is obtained at 25 ° C.) Tilt angle: 30. 20 ° (angle at which the optical axis at 25 ° C. becomes the polarizer at the threshold voltage) As a result, the compound of Reference Example 6 had an antiferroelectric liquid crystal phase near room temperature, The liquid crystal display device is 25 ℃,
A double hysteresis curve having three stable states was shown, and it was confirmed that it was an antiferroelectric liquid crystal compound excellent in a large response time, a low threshold voltage, a large tilt angle and a large screen display material. .

[Procedure amendment 11]

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FIG. 11

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FIG.

[Procedure amendment 13]

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[Procedure Amendment 14]

[Document name to be amended] Drawing

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FIG.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical indication C07M 7:00

Claims (2)

[Claims] 1. Formula (1): (In the formula, m represents an integer of 3 to 6.) (S) -1-hydroxy-2,2,2-trifluoroethyl-terminated ethoxyalkyl ketone. 2. In an organic solvent, (S) -N- (2-hydroxy-3,3,3-trifluoropropionyl) pyrrolidine and a compound of the formula (2) C ₂ H ₅ O (CH ₂ ) _m MgBr ( 2) reacting with a terminal ethoxyalkyl magnesium bromide represented by the formula (where m is the same as above), and then hydrolyzing the reaction product with a mineral acid.
A process for producing the described (S) -1-hydroxy-2,2,2-trifluoroethyl-terminated ethoxyalkyl ketone.