JPH104989A - Production of optically active alcohol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply obtain an optically active alcohol of high optical purity, useful in synthesis of liquid crystals and the like in high yield by asymmetric hydrolysis of a specific ester with lipase. SOLUTION: A Grinard reagent derived from a compound of the formula: X(CH2 )m OCn H2n+1 (X is a halogen other than F; m is 3-8; n is 1-6) is allowed to react with a trifluoroacetate salt of the formula: CF3 COOM1 (M1 is Li, Na or K) to give a ketone of the formula: CF3 CO(CH2 )m OCn H2n+1 . Then, the ketone is reduced to prepare a racemic alcohol of the formula: CF3 C*H (OH)-(CH2 )m OCn H2n+1 , then converted to an ester of CF3 C*H (OCOR)-(CH2 )m OCn H2n+1 (COR is a 2-6C alkyloxy). Finally, the ester is asymmetrically hydrolyzed with lipase, the lipase is precipitated with an organic solvent after completion of the hydrolysis and recovered. In the meantime, the objective optically active alcohol of the formula: CF3 C*H(OH)-(CH2 )m OCn H2n+1 and an optically active ester are separated from the filtrate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound of the general formula 1: CF ₃ C * H (OH)
-(CH ₂ ) _m OC _n H _{2n + 1} (wherein, m is an integer of 3 to 8, n is an integer of 1 to 6, and C * means an asymmetric carbon atom) An optically active alcohol having a trifluoromethyl group and an alkoxy group at a carbon chain terminal thereon (hereinafter, simply referred to as "optically active alcohol" as appropriate) with high optical purity,
The present invention relates to a simple and inexpensive manufacturing method. The optically active alcohol of the present invention is attracting attention as a raw material for ferroelectric liquid crystals, antiferroelectric liquid crystals, and the like, and liquid crystals induced using the same exhibit excellent properties such as a low "threshold voltage". Many liquid crystal materials have been synthesized (for example, Japanese Patent Application Laid-Open No. 4-198155).

[0002]

2. Description of the Related Art The present inventors have proposed a method for producing an optically active alcohol represented by the above general formula 1 having a trifluoromethyl group on an asymmetric carbon atom and an alkoxy group at a carbon chain terminal, as 1,1, 1 A method in which ethyl 1-trifluoroacetoacetate is used as a raw material and the synthesis is carried out through 9 steps as the number of reaction stages has been previously proposed (Japanese Patent Laid-Open No. 5-188977: hereinafter, this production method is referred to as "A
Law ").

Further, a method has been proposed in which an alkyl diol represented by the general formula: HO (CH ₂ ) _m OH is used as a starting material (Japanese Patent Laid-Open No. 6-62872: hereinafter, this production method is referred to as "method B"). . The method B has six reaction stages, and does not require expensive raw materials such as ethyl 1,1,1-trifluoroacetoacetate of the method A. Therefore, when compared with the method A, the method B is simple. It is a synthesis method. However, many steps have low reaction yields, and further improvement is required.

[0004]

[Problem to be Solved by the Invention] Method B (JP-A-6-62872)
) Is represented by the following reaction formula in the case of m = 5, n = 2 in the general formula 1. (1) HO (CH ₂ ) ₅ ONa + Br0C ₂ H ₅ → HO (CH ₂ ) ₅ OC ₂ H ₅ (2) HO (CH ₂ ) ₅ OC ₂ H ₅ + PBr ₃ → Br (CH ₂ ) ₅ OC _{2 H 5 (3) Br (} CH 2) 5 OC 2 H 5 + Mg → BrMg (CH 2) 5 OC 2 H 5 BrMg (CH 2) 5 OC 2 H 5 + CF 3 COOH → CF 3 CO (CH 2 ) ₅ OC ₂ H ₅ (4) CF ₃ CO (CH ₂ ) ₅ OC ₂ H ₅ + LiAlH ₄ → CF ₃ CH (OH) (CH ₂ ) ₅ OC ₂ H ₅ (5) CF ₃ CH (OH) ( CH ₂ ) ₅ OC ₂ H ₅ + CH ₃ COCl → CF ₃ CH (OCOCH ₃ ) (CH ₂ ) ₅ OC ₂ H ₅ (6) CF ₃ CH (OCOCH ₃ ) (CH ₂ ) ₅ OC ₂ H ₅ + H ₂ O + (lipase) → (+)-R-CF ₃ C * H (OH) (CH ₂ ) ₅ OC ₂ H ₅ (-)-S-CF ₃ C * H (OCOCH ₃ ) (CH ₂ ) ₅ OC ₂ H ₅

The yield in each reaction stage disclosed in Example 1 of Method B was (1): 50%, (2): 53%, and the overall yield in (3) and (4) was The bromide content is 22%, (5): 88%, (6): 80%, and the yield throughout the entire process is 4%, calculated on the basis of the starting material 1,5-pentanediol. That is, the above-mentioned method B has many steps with a low yield, the yield throughout the entire process is extremely low, and cannot always be said to be an inexpensive production method, and further improvement is required.

In particular, in the step (3), trifluoroacetic acid is used as a substrate to be reacted with 5-ethoxy-1-pentylmagnesium bromide (hereinafter appropriately referred to as "Grignard reagent"). In the example of the method B, 1/3 mole of trifluoroacetic acid is used with respect to the Grignard reagent, and the yield based on trifluoroacetic acid is 66%,
In yields based on Grignard reagents,
It is as low as 22%. However, the present inventors have confirmed that the use of an equimolar amount of trifluoroacetic acid with respect to the Grignard reagent does not improve the yield. That is, the above method B has a problem that the yield based on the Grignard reagent is low and the method is not economical.

The lipase used for the asymmetric hydrolysis in the step (6) is an enzyme derived from a living body, and is a substance which is difficult to obtain at low cost. However, since this lipase is not a reaction substrate, it functions as a catalyst that does not change before and after the reaction. Therefore, if it can be recovered and reused, the cost in the production of optically active alcohol can be significantly reduced.

[0008] However, a method of recovering and reusing lipase has not been studied. Also, JP-A-6-6287
Under the conditions of the example in Unit 2, recovery and reuse were extremely difficult. This is because the aqueous layer from which the product was removed by ether extraction after the completion of the reaction contains, in addition to lipase, phosphate added as a buffer and acetic acid generated by hydrolysis. Recovering only lipase from this aqueous layer
Requires great effort. For these reasons, it has been desired to develop a method that can recover and reuse the lipase used for asymmetric hydrolysis by a simple method.

[0009]

Means for Solving the Problems The present inventors have prepared a simple and inexpensive optically active alcohol represented by the general formula 1: CF ₃ C * H (OH) — (CH ₂ ) _m OC _n H _{2n + 1} Intensive research on various manufacturing methods. As a result, first, general formula 2: X (CH ₂ ) _m O of the present invention
As a substance to be reacted with a Grignard reagent derived from a halogen compound of C _n H _{2n + 1} , the general formula 3: CF ₃ COO of the present invention is used.
M ¹ (M ¹ represents any of Li, Na, and K) or general formula 4: (C
The reaction yield is obtained by using a salt of trifluoroacetic acid represented by F ₃ COO) ₂ M ² (M ² represents either Mg or Ca) (hereinafter, simply referred to as “trifluoroacetic acid salt” as appropriate). Can be greatly improved.

Second, in the asymmetric hydrolysis using lipase, only water is used without using a buffer such as phosphate, and after the reaction is completed, the reaction solution is treated with a specific organic solvent (an organic solvent compatible with water). (Solvent) to precipitate only lipase, collect it by filtration, and develop a method of collecting and reusing lipase that can be reused by drying the collected lipase under reduced pressure.

[0011] In addition to the above-mentioned method, as a method for producing a valogen compound of the general formula 2 of the present invention, a general formula: X (CH ₂ ) _m Y (m
Is the same as in the general formula 1, X and Y each represent a halogen atom other than fluorine, and may be the same), and a general formula: NaOC _n H _{2n + 1} (n is the same as the general formula 1) Can be produced by reacting with a sodium alkoxide represented by

The present inventors have completed a simple, economical and industrially feasible method for producing an optically active alcohol based on a combination of the above-mentioned production methods. That is, the present invention provides a compound represented by the following general formula 1: CF ₃ C * H (OH)-(CH ₂ ) _m OC _n H
_{2n + 1} (wherein, m is an integer of 3 to 8, n is an integer of 1 to 6,
C * means an asymmetric carbon atom), a process for producing an optically active alcohol represented by the following formula: Step (1): General formula 2: X (CH ₂ ) _m OC _n H _{2n + 1} (m and n Is the same as in general formula 1, and X represents a halogen atom other than fluorine. After converting a halogen compound represented by the formula into a Grignard reagent, general formula 3: CF ₃ COOM ¹ (M ¹ is any ^one of Li, Na, and K) shown) or the general formula _{4: (CF 3 COO) 2} M 2 (M 2 is Mg, by reacting with a salt of trifluoroacetic acid represented by indicating one of Ca), the general formula 5: CF ₃ A ketone represented by CO (CH ₂ ) _m OC _n H _{2n + 1} (m and n are the same as in the general formula 1) is produced. Step (2): The ketone of the formula 5 is reduced to give a general formula 6: CF ₃ C * H (O
H)-(CH ₂ ) _m OC _n H _{2n + 1} (wherein m and n are the same as in the general formula 1) to produce a racemic alcohol; Step (3): alcohol of the formula 6 Is esterified with a carboxylic acid halide or a carboxylic anhydride to obtain a compound represented by the general formula 7: CF ₃ C * H (OCOR)-(CH ₂ ) _m OC _n H _{2n + 1} (where COR represents a carbon atom having 2 to 2 carbon atoms). Step 4): carrying out an asymmetric hydrolysis reaction of the ester of the formula 7 with a lipase and bringing the ester into contact with a specific organic solvent after completion of the reaction. This is a method for producing an optically active alcohol, comprising recovering lipase by precipitating and filtering the lipase, and separating the optically active alcohol and the optically active ester from the filtrate from which the lipase has been removed.

First, the production method of the present invention is shown by a reaction formula, and a method for carrying out the present invention in the order of each step will be described. The reaction formula is, for convenience, the optically active alcohol represented by the general formula 1.
m = 5, n = 2, and the case of (CF ₃ COO) ₂ Mg as the trifluoroacetate in the second step was shown. (1) Br (CH ₂ ) ₅ OC ₂ H ₅ + Mg → BrMg (CH ₂ ) ₅ OC ₂ H ₅ BrMg (CH ₂ ) ₅ OC ₂ H ₅ + 1/2 (CF ₃ COO) ₂ Mg → CF ₃ CO (CH ₂ ) ₅ OC ₂ H ₅ (2) CF ₃ CO (CH ₂ ) ₅ OC ₂ H ₅ + NaBH ₄ → CF ₃ CH (OH) (CH ₂ ) ₅ OC ₂ H ₅ (3) CF ₃ CH (OH) (CH ₂ ) ₅ OC ₂ H ₅ + (CH ₃ CO) ₂ O → CF ₃ CH (OCOCH ₃ ) (CH ₂ ) ₅ OC ₂ H ₅ (4) CF ₃ CH (OCOCH ₃ ) (CH ₂ ) ₅ OC ₂ H ₅ + H ₂ O + (lipase) → (+)-R-CF ₃ C * H (OH) (CH ₂ ) ₅ OC ₂ H ₅ (-)-S-CF ₃ C * H ( OCOCH ₃ ) (CH ₂ ) ₅ OC ₂ H ₅

The halogen compound of the general formula 2 of the present invention used in the above (1) includes the above-mentioned general formula: X (CH ₂ ) _m Y
(M is the same as in the general formula 1, X and Y represent halogen atoms other than fluorine, and may be the same), and a general formula: NaOC _n H _{2n + 1} (n is the same as the general formula 1) The same method as described above) is preferably used. This reaction is shown for m = 5, n = 2, X = Br, Y = Br in the same manner as described above. (A) Br (CH ₂ ) ₅ Br + NaOC ₂ H ₅ → Br (CH ₂ ) ₅ OC ₂ the H _5.

This reaction is a method in which one bromine atom of 1,5-dibromopentane (hereinafter referred to as "dibromide") is substituted with an ethoxy group. This can be easily accomplished by the reaction known in Williamson's ether synthesis. Specifically, it is carried out by dropping an ethanol solution of sodium ethoxide into dibromide. If the order of the dropwise addition is reversed, it is not preferable because the amount of 1,5-diethoxypentane (= diether compound) which is a product obtained by ethoxylating both bromine atoms of dibromide increases.

If the reaction temperature is too high, the reaction of dehydrobromide tends to occur.
20 to 50 ° C. is preferred. As the molar amount of sodium ethoxide to dibromide, the theoretical amount is
The ratio is 1: 1. Excessive use of sodium ethoxide is not preferable because the amount of diether compound formed increases and the yield decreases. Conversely, when dibromide is used in excess, the amount of diether compound produced decreases, and the yield of the desired product, 5-ethoxy-1-bromopentane (hereinafter referred to as "monoether compound"), improves. However, it is necessary to collect and reuse a large amount of unreacted dibromide.

Therefore, the amount ratio of sodium ethoxide to dibromide is preferably from 1: 1 to 1: 5, and more preferably from 1: 1 to 1: 3 in consideration of the operation of recovering and recycling dibromide. .
As a solvent, sodium ethoxide is not particularly necessary since it is used as an ethanol solution, but a solvent which does not react with sodium ethoxide may be added. In the present invention, besides the above-mentioned production method, those produced from the diol described in the explanation of the production method of the above-mentioned method B as a raw material, and others can be used.

The reaction (1) is a step of preparing 5-ethoxy-1-pentylmagnesium bromide (= Grignard reagent) from a monoether compound and magnesium and reacting it with a trifluoroacetate. Preparation of Grignard reagent
It can be carried out by a general method in which a solution of a monoether compound such as tetrahydrofuran is dropped on magnesium. The solvent to be used is not particularly limited as long as the Grignard reagent can be prepared, and ether solvents such as diethyl ether and tetrahydrofuran are suitable.

The general formula 3: CF ₃ COOM ¹ (M ¹ represents any of Li, Na and K) or the general formula 4: (CF ₃ COO) ₂ M ² (M ² is Indicates either Mg or Ca)
The trifluoroacetate represented by can be easily synthesized from the corresponding metal simple substance or metal hydride and trifluoroacetic acid. Specifically, bis (trifluoroacetic acid) magnesium is used as an example. It is prepared by adding magnesium to tetrahydrofuran, dropping a theoretical amount of trifluoroacetic acid, and reacting until magnesium disappears. The trifluoroacetate prepared here is obtained as a tetrahydrofuran solution, which can be used as it is.
Alternatively, tetrahydrofuran may be distilled off and isolated, and then dissolved in another solvent before use.

Next, the above-mentioned method of reacting a Grignard reagent with a trifluoroacetate can be easily carried out by dropping a solution of a trifluoroacetate into the Grignard reagent. Conversely, the Grignard reagent may be dropped into the trifluoroacetate solution. The reaction temperature is not particularly limited as long as it is equal to or lower than the boiling point of the solution.
~ 70 ° C is suitable, 20 ~ 50 ° C is preferred.

The amount of the trifluoroacetate relative to the Grignard reagent is preferably used in a theoretical amount. If the amount is small, the yield based on the Grignard reagent is undesirably reduced. On the contrary, it is meaningless because the yield does not change even if a large amount is used. Here, the stoichiometric amount means that the Grignard reagent and the trifluoroacetyl group are equimolar. Specifically, in the case of the general formula 3, the molar amount is 1-fold the molar amount of the Grignard reagent, and in the case of the general formula 4, the molar amount is 1 / 2-fold.

The reaction (2) is a reduction of 7-ethoxy-1,1,1-trifluoro-2-heptanone (hereinafter referred to as "ketone body"), and can be easily carried out by a general reduction method of ketone. Can be implemented. As the reducing agent, lithium aluminum hydride or sodium borohydride can be used, and sodium borohydride (= NaBH ₄ ) which is easy to handle is preferable.
Further, when the tetrahydrofuran solution of the ketone body obtained in the above reaction (1) is directly reduced, an acid component such as trifluoroacetic acid is mixed, and a reducing agent is used for neutralizing the acid component, and the ketone is reduced. A large amount of reducing agent is required compared to the theoretical amount of body reduction. Therefore, it is desirable to add the reducing agent after performing the neutralization treatment in advance. Further, an aqueous NaBH ₄ solution (NaBH ₄ ; 12) capable of simultaneously performing the neutralization treatment and the reduction reaction
%, NaOH; commercially available as a 40% solution), the reduction reaction can be carried out more easily.

The reaction of (3) is carried out by reacting 7-ethoxy-1,1,1-trifluoro-2-heptanol (hereinafter referred to as "alcohol"
The enantiomer is an esterification reaction of R form and S form respectively), and can be easily carried out by a general esterification method. Specifically, it is achieved by reacting a carboxylic acid anhydride or a carboxylic acid halide in the presence of a tertiary amine. In addition, the kind of the carboxylic acid is the final target compound of the general formula 1 so that the alcohol and the ester, which are the products after the asymmetric hydrolysis as the last reaction, are separated by distillation so that the distillation separation property becomes good. Is appropriately selected depending on the type of the optically active alcohol represented by

In the reaction of (4), 2-acetoxy-7-ethoxy-1,1,1-trifluoroheptane (hereinafter referred to as "acetate", and the enantiomers are denoted by R-form and S-form, respectively) ) Is asymmetrically hydrolyzed. The reaction is carried out by adding water to the lipase to sufficiently swell, then adding racemic acetate and stirring. By this reaction, a reaction liquid is obtained in which one of the enantiomers R-acetate is hydrolyzed to an R-form alcohol, and the other enantiomer S-acetate remains an ester.

The higher the reaction temperature, the higher the reaction rate. However, if the reaction temperature is higher than 60.degree. C., it is not preferable because the lipase is gradually deactivated. Then, a sufficient reaction rate is obtained, and the lipase is not inactivated.
40 ° C. is preferred. The amount of water to be used is not less than the stoichiometry required for asymmetric hydrolysis, and an amount sufficient to bring the lipase into a swollen and suspended state is required. The amount required to bring the lipase into the suspension swelling state is at least 3 times the weight of the lipase. If too much water is used, a large amount of a solvent (eg, acetone) is used to recover lipase after the reaction, which is not economical. Therefore, it is preferable to use 10 to 100 times by mole, preferably 20 to 50 times by mole, relative to the racemic acetate.

Since the amount of lipase is directly proportional to the reaction rate, it is appropriately selected according to a desired reaction completion time.
As a guideline for completing the reaction in 24 hours when the reaction is carried out at around room temperature (25 ° C.), reaction conditions using 100 g / mol of lipase MY with respect to 1 mol of racemic acetate can be mentioned. When the reaction completion time is 48 hours, the necessary amount of lipase is 50 times less than 50 g / mol, and when it is desired to complete the reaction in 12 hours, double the amount of 200 g / mol. Can be achieved. In addition, the reaction completion mentioned here means
This is the point at which almost all of the R-acetate has been hydrolyzed, and the hydrolysis rate is about 50% based on racemic acetate.

To complete the reaction, a part of the reaction solution is taken and subjected to gas chromatography (CP Cyclodex β 2
It can be easily discriminated by analyzing with 36M). Further, the reaction completion time can be predicted in advance from the reaction rate constant obtained from the amount of lipase used and the reaction temperature.

Next, a method of recovering and reusing lipase from the asymmetric hydrolysis reaction solution obtained by the above method will be described. The reaction solution after the reaction is in an emulsified state,
Although it is difficult to separate lipase by filtration as it is, an organic solvent compatible with water (hereinafter referred to as "compatible solvent")
By contacting the lipase, lipase can be aggregated and powdered. This powdered lipase can be easily filtered and recovered by a usual filtration operation.

Examples of the compatible solvent include organic solvents such as acetone, methanol, ethanol, and tetrahydrofuran, which are miscible with water at an arbitrary ratio. Acetone having a high lipase recovery rate is preferred. In addition, if the amount of the compatible solvent used is small, the recovery of lipase is low, and if it is used too much, the recovery of lipase hardly changes, and the amount of solvent that must be removed in subsequent operations becomes large. Not economic. Usually, the amount of water used for the asymmetric hydrolysis
20 times the volume is suitable.

The method of contacting the compatible solvent with the reaction solution can be carried out by either the method of dropping the compatible solvent into the reaction solution or the method of dropping the reaction solution into the compatible solvent. The latter method having a large particle size and good filterability is suitable. The lipase recovered by the above operation can be reused by vacuum drying at 50 ° C. or lower without deterioration in hydrolysis activity and enantioselectivity.

Next, a method for isolating R-form alcohol and S-form acetate from the reaction solution from which the lipase has been removed by the above operation will be described. In the following description, a case where acetone is used as a compatible solvent will be described as an example. The reaction solution from which the lipase has been filtered off is separated into two layers by distilling off acetone. After the aqueous layer is neutralized, the liquid is separated and the organic layer is washed with water and distilled under reduced pressure to obtain the desired R-form optically active alcohol and S-form acetate. Instead of distillation, R-alcohol and S-
Body acetate can also be isolated. The S-acetate is reacted with an aqueous solution of sodium hydroxide to react with an alkali.
By saponifying, an S-form optically active alcohol can also be obtained.

[0032]

According to the present invention, there is provided a method for producing an optically active alcohol having a trifluoromethyl group on an asymmetric carbon atom and an alkoxy group at a carbon terminal with high optical purity, easily and economically. This optically active alcohol
It is useful as a synthetic intermediate for functional materials such as pharmaceuticals, agricultural chemicals, and liquid crystals.

[0033]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Example 1 Production of (+)-R-7-ethoxy-1,1,1-trifluoro-2-heptanol (general formula 1: when m = 5, n = 2) (1) 5-ethoxy-1 Preparation of 1-bromopentane 1.13 kg (44 mol) of 1,5-dibromopentane and 15 kg (44 mol) of a 20% ethanol solution of sodium ethoxide at a reaction temperature
The solution was added dropwise at 40 ° C or lower. After stirring was continued for 1 hour after the completion of the dropwise addition, ethanol was distilled off at 80 ° C. under reduced pressure.

The obtained residue was washed by adding 6.2 kg of 1% hydrochloric acid to remove sodium bromide as a by-product salt.
The organic layer was washed with 2 kg. The washed organic layer was distilled at 7 mmHg using a rectification column to obtain 4.99 kg of a fraction having a boiling point of 68 to 74 ° C. The product is 4.92 kg (content = 86%) of the desired product, 5-ethoxy-1-bromopentane, and 1,5-
The mixture was 1.41 kg of diethoxypentane (content = 14%). By distilling the previous distillation residue, 1,5-
2.40 kg of dibromopentane was recovered. Therefore, the actually consumed 1,5-dibromopentane is 7.71 kg (33.6 mol)
Based on this, the yield of 5-ethoxy-1-bromopentane was 66%, and the yield of 1,5-diethoxypentane was 13%.
Met.

(2) 7-ethoxy-1,1,1-trifluoro-2-
Production of heptanone (a) Preparation of Grignard reagent 2.27 kg of a solution containing 10 mol of 5-ethoxy-1-bromopentane obtained in the above (1) was dissolved in 3 L (liter) of tetrahydrofuran. This solution was added dropwise to 252 g (10.5 mol) of magnesium under nitrogen so that the reaction temperature became 50 ° C. or lower, to prepare a Grignard reagent (hereinafter referred to as “solution a”).

(B) Preparation of magnesium bis (trifluoroacetate) To 122 g (5 mol) of magnesium was added 1 L of tetrahydrofuran, and 1,140 (10 mol) of trifluoroacetic acid was added dropwise. The reaction temperature at this time was adjusted so as not to exceed 100 ° C. while maintaining a temperature at which the reaction solution was slowly refluxed. After dropping,
When heat generation disappeared, 1 L of tetrahydrofuran was added, and the reaction was carried out at 90 ° C. until magnesium disappeared. After the completion of the reaction, the mixture was cooled to room temperature, and tetrahydrofuran was further added to prepare a solution having a bis (trifluoroacetic acid) magnesium content of 35 wt% (hereinafter referred to as “solution b”).

(C) Reaction between Solution a and Solution b The condensation reaction was carried out by dropping Solution b onto Solution a so that the reaction temperature was 50 ° C. or lower. After completion of the reaction, an aging reaction was performed at 40 ° C. for 1 hour, and after cooling to room temperature, 6 kg of 15% hydrochloric acid was added dropwise to carry out hydrolysis. Next, the organic layer was washed with 3 kg of water to obtain a target product of 7-ethoxy-1,1,1-trifluoro-2-heptanone in tetrahydrofuran. As a result of analyzing this solution by gas chromatography, 7-ethoxy-1,1,1
The content of 1-trifluoro-2-heptanone was 1.38 kg, and the yield was 65%.

(3) Production of racemic 7-ethoxy-1,1,1-trifluoro-2-heptanol (reduction of ketone). 7-ethoxy-1,1,1-trifluoro-2-heptanone (content = 1.38 kg (6.5 mol) in a tetrahydrofuran solution obtained in the above (2) was added to a sodium borohydride aqueous solution (NaBH ₄ = 12 wt%,
788 g (2.5 mol) of NaOH = 40 wt% was added dropwise so that the reaction temperature became 40 ° C. or lower. After completion of the dropwise addition, an aging reaction was performed for 1 hour, the aqueous layer was separated and removed, and the organic layer was washed with 1 L of water. Tetrahydrofuran was distilled off from the washed organic layer under reduced pressure to obtain 1.99 kg of a solution containing 7-ethoxy-1,1,1-trifluoro-2-heptanol. This solution contains 7-ethoxy-1,
It contained 1.39 kg (71%) of 1,1-trifluoro-2-heptanol and the yield was 100%.

(4) Racemic 2-acetoxy-7-ethoxy-
Production of 1,1,1-trifluoroheptane (acetylation reaction)
. To a solution of 7-ethoxy-1,1,1-trifluoro-2-heptanol obtained in (3) above, 791 g (10 mol) of pyridine and 1,020 g (10 mol) of acetic anhydride were added, and the mixture was reacted at 80 ° C. for 3 hours. Was.
After completion of the reaction, 2 L of water was added, and the mixture was stirred for 1 hour to decompose unreacted acetic anhydride. Then, liquid separation was performed to remove an aqueous layer. The obtained organic layer was washed with 1% hydrochloric acid (1 L), saturated aqueous sodium hydrogen carbonate solution (1 L) and water (1 L) in that order, and crude product containing 2-acetoxy-7-ethoxy-1,1,1-trifluoroheptane 1.88 kg
I got 2-acetoxy-7-ethoxy-1,
1.51 kg (6.2 mol; 84%) of 1,1-trifluoroheptane was contained, and the yield was 95%.

(5) Production of (+)-R-7-ethoxy-1,1,1-trifluoro-2-heptanol (R-form alcohol) (asymmetric hydrolysis of acetate). (a) Asymmetric hydrolysis reaction Lipase MY (Meito Sangyo) 620 g and ion exchange water 2.4 kg
Was added and stirred at room temperature for 30 minutes to obtain a swollen and suspended state.
The 2-acetoxy-7-ethoxy- obtained in (4) above was added to this solution.
The reaction was performed by adding a crude product of 1,1,1-trifluoroheptane and stirring for 24 hours.

(B) Measurement of the change over time in the reaction The reaction solution was analyzed at predetermined intervals by gas chromatography and the change over time was measured. As a result, the reaction solution at the time of the reaction for 24 hours was found to have a hydrolysis rate of 50.7% and alcohol The optical purity of the isomer (R form) was 96% ee, and the optical purity of the acetate form (S form) was 99% ee. Also, as a result of the measurement of the change over time,
The reaction proceeds to first order at each enantiomeric concentration,
It was found that the reaction rate constant of the R-form was 0.21 (1 / hr) and the reaction rate constant of the S-form was 0.008 (1 / hr), and the enantioselectivity represented by the reaction rate ratio between the R-form and the S-form ( E value) was E = 250.

FIG. 1 shows the composition change for each reaction time. First-order reaction rate formula: ln (C / C ₀ ) =-Kt (C: concentration at time t, C ₀ : initial concentration, k: reaction The results plotted according to the rate constant, t: reaction time) are shown in FIG.
For analysis of the reaction solution, 0.5 g of the reaction solution was sampled, 10 ml (milliliter) of acetone was added, lipase was filtered off, acetone was distilled off from the filtrate, and 1 ml of pyridine and 1 ml of propionic anhydride were added to the organic layer. The solution in which the alcohol form was converted to propionate was analyzed and determined by gas chromatography for optically active substance analysis.

(C) Recovery of lipase The solution obtained by reacting in the above (a) for 24 hours is treated with acetone 20
When the mixture was poured into L and stirred slowly, the lipase aggregated and turned into powder. The lipase was filtered off and washed with 2 L of acetone. The obtained lipase is dried in a vacuum dryer at 50 ℃, 1mmHg
578 g (recovery rate = 93%) of the recovered lipase was obtained.

(D) Separation of Optically Active Alcohol The filtrate and washings from which lipase was filtered off in (c) above were combined, and acetone was distilled off under reduced pressure. The residue was separated into two layers. Sodium carbonate was added to the residue to neutralize the aqueous layer, and the layers were separated to remove the aqueous layer. Next, the organic layer was washed twice with 1 L of a saturated aqueous solution of sodium chloride. The obtained organic layer was distilled at 7 mmHg using a rectification column, and the boiling point was 96 ° C.
723 g of (-)-S-2-acetoxy-7-ethoxy-1,1,1-trifluoroheptane (S-form acetate) (yield = 91%, chemical purity = 99%, optical purity = 99% ee ), 524 g of (+)-R-7-ethoxy-1,1,1-trifluoro-2-heptanol (R-alcohol) at a boiling point of 104 ° C. (yield = 79%, chemical purity = 99%, optical purity) = 96% ee, optical rotation [α] ²⁹ _D = 26.8 (nea
t)).

The yield of the obtained R-form alcohol was 32% when calculated based on the starting material 1,5-dibromopentane used in the above (1). Further, the obtained compound was identified by structural analysis of NMR spectrum and measurement of optical rotation. Optical purity is measured by gas chromatograph for analysis of optically active substance in the case of S-acetate.
It was calculated from the peak area ratio in the analysis of (CP Cyclodex β236M). On the other hand, in the case of the R-form alcohol, it was converted into a propionate using pyridine and propionic anhydride, and then calculated from the peak area ratio in the analysis of the gas chromatograph for optically active substance analysis.

Example 2 Production of (+)-R-7-ethoxy-1,1,1-trifluoro-2-heptanol (general formula 1: when m = 5, n = 2) (1) 5- Production of ethoxy-1-bromopentane In Example 1, 10.13 kg of 1,5-dibromopentane (44
mol) was reacted in the same manner except that 5 kg (14.7 mol) of a 20% ethanol solution of sodium ethoxide was used, and post-treatment was performed.

The obtained organic layer was similarly distilled at 7 mmHg using a rectification column to give 5-ethoxy-1-bromopentane 2.4.
2.58 kg of a mixture of 5 kg (content = 95%) and 0.08 kg (content = 3%) of by-product 1,5-diethoxypentane was obtained. 6.34 kg of 1,5-dibromopentane was recovered from the distillation residue. Therefore, the amount of 1,5-dibromopentane actually consumed is 3.77 kg (16.4 mol), and the yield based on this is 76% of 5-ethoxy-1-bromopentane and 1,5-diethoxy. Pentane was 3%.

(2) 7-ethoxy-1,1,1-trifluoro-2-
Production of heptanone (a) Preparation of Grignard reagent 227 g of a liquid containing 1 mol of 5-ethoxy-1-bromopentane obtained in the above (1) was dissolved in 300 ml of tetrahydrofuran.
This solution was added dropwise to 25.2 g (1.05 mol) of magnesium under nitrogen at a reaction temperature of 50 ° C. or lower to prepare a Grignard reagent (hereinafter referred to as “solution a”).

(B) Preparation of sodium trifluoroacetate 23 g (1 mol) of sodium was placed in 300 ml of tetrahydrofuran, and 114 g (1 mol) of trifluoroacetic acid was added dropwise. The reaction is
The operation was performed at 60 ° C. until sodium disappeared to obtain a solution of sodium trifluoroacetate in tetrahydrofuran (hereinafter referred to as “solution b”).

(C) Reaction between Solution a and Solution b The solution b is kept at 50 ° C. to form a solution, and while the reaction temperature is adjusted so as not to exceed 60 ° C., the above solution a is added dropwise to carry out the condensation reaction. went. After completion of the reaction, an aging reaction was carried out at 40 ° C. for 1 hour, and after cooling to room temperature, 600 g of 15% hydrochloric acid was added dropwise to carry out hydrolysis. Next, the organic layer was washed with 300 g of water to obtain a target product, a 7-ethoxy-1,1,1-trifluoro-2-heptanone solution in tetrahydrofuran. As a result of analyzing the solution by gas chromatography, the content of 7-ethoxy-1,1,1-trifluoro-2-heptanone was 144 g, and the yield =
68%.

(3) Production of racemic 7-ethoxy-1,1,1-trifluoro-2-heptanol (reduction of ketone). The same operation as in Example 1- (3) was performed using the 7-ethoxy-1,1,1-trifluoro-2-heptanone solution obtained in the above (2). The resulting solution contained 142 g (yield = 98%) of 7-ethoxy-1,1,1-trifluoro-2-heptanol.

(4) Production of 2-acetoxy-7-ethoxy-1,1,1-trifluoroheptane (acetylation reaction). Using a solution of the racemic 7-ethoxy-1,1,1-trifluoro-2-heptanol obtained in the above (3), the operation was carried out in the same manner as in Example 1- (4). The resulting solution contained 163 g of racemic 2-acetoxy-7-ethoxy-1,1,1-trifluoroheptane (yield = 96%).

(5) Production of (+)-R-7-ethoxy-1,1,1-trifluoro-2-heptanol (R-form alcohol) (asymmetric hydrolysis of acetate). The same operation as in Example 1- (5) was carried out using 52 g (0.2 mol) of the racemic 2-acetoxy-7-ethoxy-1,1,1-trifluoroheptane obtained in the above (4). The separation of the R-form alcohol and the S-form acetate was carried out not by distillation but by column chromatography using silica gel using hexane / ethyl acetate as a developing solvent. as a result,
(-)-S-2-acetoxy-7-ethoxy-1,1,1-trifluoroheptane (S-acetate) 24 g (yield = 92%, chemical purity = 98%, optical purity = 98% ee) and 19 g of (+)-R-7-ethoxy-1,1,1-trifluoro-2-heptanol (R-form alcohol) (yield = 87%, chemical purity = 98%, optical purity = 9
8% ee).

Example 3 (Reuse of recovered lipase) 10 g of lipase MY recovered in Example 1 and ion-exchanged water 3
Using 9 g and 25.6 g (0.1 mol) of 2-acetoxy-7-ethoxy-1,1,1-trifluoroheptane according to Example 1- (5), an asymmetric hydrolysis reaction was performed, and the change over time was measured. Measurements were taken to determine the reaction rate constant and enantioselectivity. After the completion of the reaction, the lipase was similarly recovered, and the asymmetric hydrolysis reaction was similarly repeated on a scale corresponding to the amount of the recovered lipase, and the reaction rate constant and enantioselectivity were measured. Table 1 shows the measurement results of the reaction rate and enantioselectivity for each use of the lipase. Reaction rates and enantioselectivities were recyclable without deactivation.

[0055]

[Table 1] Reaction rate and number of enantioselective lipases used according to the number of times of use of recovered lipase 1 2 3 4 5 5 5 5 5 5 5 5 5 R 1 R 2 reaction rate constant (hr ^-1 ) 0.21 0.19 0.23 0.20 0.20 Enantioselectivity 250 295 208 270 290 290 Lipase recovery ( %) 93 85 90 89 91 Remarks Example 1 Example 3 Same as left Same as left Same as left

Example 4 (Effect of Drop Order on Filterability of Lipase) In the same manner as in Example 1, an asymmetric hydrolysis reaction solution (lipase amount = 5 g, water amount = 20 g) was prepared. This hydrolysis reaction solution was dropped into 500 ml of acetone to precipitate lipase,
The lipase was recovered by filtration through o.5A filter paper. At this time, the filtrate was transparent, and the recovered amount of lipase was 4.75 g (recovery rate = 95%). On the other hand, 500 ml of acetone was added dropwise to the asymmetric hydrolysis reaction solution (lipase amount = 5 g, water usage = 20 g) prepared in the same manner to precipitate lipase, and the lipase was recovered by filtration through No. 5A filter paper. The filtrate at this time was cloudy, and the amount of lipase recovered was 4.15 g (recovery rate = 83%). Further, 0.2 g of lipase was recovered by filtering the filtrate with a membrane filter having a pore size of 1 μm.
As described above, it is possible to recover lipase by either operation.However, the method in which the asymmetric hydrolysis reaction solution is dropped into acetone has a large particle size of the precipitated lipase and has good filterability. there were.

Example 5 (Effect of Amount of Lipase Recovered by Use of Acetone) An asymmetric hydrolysis reaction solution (lipase amount = 5 g, water amount = 20 g) prepared in the same manner as in Example 1 was used in an amount shown in Table 2. The lipase was precipitated by dropping into acetone, and filtered through No. 5A filter paper to recover the lipase. The results are shown in Table 2.

[0058]

[Table 2] Lipase recovery test according to the amount of acetone used No. 1 2 3 4 5 6 Amount of acetone (ml) 100 140 200 300 400 1,000 Amount of water used (g) 20 20 20 20 20 20 Acetone / water (ml / g) 5 7 10 15 20 50 Lipase recovery (g) 3.81 4.35 4.65 4.80 4.75 4.76 Lipase recovery (%) 76 87 93 96 95 95

Example 6 (Effect of Amount of Lipase Recovered by Compatible Solvent) Asymmetric hydrolysis reaction solution (lipase amount = 5 g, water amount = 20 g) prepared in the same manner as in Example 1 was used instead of acetone in Table 3 The lipase was precipitated by dropping into 300 ml of the compatible medium shown in (1) and filtered through No. 5A filter paper to recover the lipase.
The results are shown in Table 3.

[0060]

Table 3 Amount of lipase recovered due to difference in compatible solvent Type of compatible solvent Amount of lipase recovered Amount of lipase Remark Acetone 4.80 g 96% Example 5 Methanol 4.61 g 92% Example 6 Ethanol 4.23 g 85% Same as above Tetrahydrofuran 3.86 g 77% Same as above

Example 7 (Effect of reaction rate depending on reaction temperature) 53 g of ion-exchanged water was added to 5 g of lipase MY, and the mixture was stirred for 30 minutes to form a swelling suspension, and 2-acetoxy-7-ethoxy-1,
1,1-trifluoroheptane (racemic acetate) 10g
(0.02 mol), and the reaction temperature was changed to carry out an asymmetric hydrolysis reaction. The change over time was measured in the same manner as in Example 1- (5), and the reaction rate constant (k) was calculated. Table 4 shows the obtained reaction rate constants. When the results were plotted by the Arrhenius equation, the results showed a linear relationship up to 55 ° C., and it was possible to estimate the reaction rate constant at an arbitrary temperature.

[0062]

[Table 4] Effect of reaction rate on reaction temperature Reaction temperature (° C) 5 15 25 35 45 55 60 Reaction rate constant (k) (hr ^-1 ) 0.08 0.15 0.31 0.46 0.88 1.01 0.55

Example 8 (Effect of reaction rate by amount of lipase) 53 g of ion-exchanged water was added to the amount of lipase MY shown in Table 5, and the mixture was stirred for 30 minutes to form a swelling suspension, and 2-acetoxy-7-
10 g (0.02 mol) of ethoxy-1,1,1-trifluoroheptane (racemic acetate) was added to carry out an asymmetric hydrolysis reaction at 25 ° C. The change with time was measured in the same manner as in Example 1- (5), and the reaction rate constant was calculated. The obtained reaction rate constant was directly proportional to the amount of lipase as shown in Table 5.

[0064]

[Table 5] Test for the effect of the amount of lipase on the reaction rate No. 123 Amount of lipase (g) 7.80 3.90 1.95 Ratio to acetate (g / mol) 200 100 50 Reaction rate constant (hr ^-1 ) 0.44 0.21 0.10

Examples 9 to 14 (Preparation of Various Optically Active Alcohols) Instead of 1,5-dibromopentane (m = 5) and sodium ethoxide (n = 2) used in Example 1, each methylene chain has Using the compounds m and n in Table 6, the corresponding optically active alcohols were produced in the same manner as in Example 1. The reaction scale was set to 1/20 of that in Example 1,
Separation of R-form alcohol / S-form acetate was performed by column chromatography in the same manner as in Example 2. Table 6 shows the yield in each reaction. Further, the obtained optically active alcohol was converted into propionate in the same manner as in Example 1, and then a gas chromatograph for optical activity analysis (CP Cyclodex)
β236M), and the results are shown in Table 7. The product was identified by structural analysis of the NMR spectrum, which is shown in Table 7 below.

[0066]

Table 6: Production of various optically active alcohols Yield in each reaction of alkylene chain carbon number ^{* 1} (%) mn (1) (2) (3) (4) (5) Example 9 7 2 72 62 98 96 83 Example 10 5 3 70 66 95 95 88 Example 11 4 1 78 69 99 96 81 Example 12 4 2 75 67 96 96 82 Example 13 4 4 66 61 96 93 83 Example 14 3 2 32 42 91 90 80 Note) * 1 Reaction (1): Production yield of Br (CH ₂ ) _m OC _n H _{2n + 1} {monoether form} Reaction (2): CF ₃ C (O) (CH ₂ ) _m OC _n H Production yield of _{2n + 1} << ketone body >> Reaction (3): CF ₃ CH (OH) (CH ₂ ) _m OC _n H _{2n + 1} << Production yield of racemic alcohol body >> Reaction (4): CF ₃ CH (OAc) (CH ₂ ) _m OC _n H _{2n + 1}製造 Production yield of racemic acetate form Reaction (5): CF ₃ C * H (OH) (CH ₂ ) _m OC _n H _{2n + 1} ｛ Production yield of R-alcohol｝

[0067]

[Table 7] Physical property values of various optically active alcohols Example No. 9 10 11 12 13 14 Alkylene chain m 7 444 3 4 carbon number n 2 3 1 2 4 2 Purity (%) 99 98 98 98 98 97 Optical purity (% ee) 98 97 98 97 97 99 Example 1: (+)-R-7-ethoxy-1,1,1-trifluoro-2-heptanol CF ₃ C * H (OH) (CH ₂ ) ₄ CH ₂ 0CH ₂ CH ₃ (General formula 1: m = 5, n = 2) abcdef δ = 1.23H, t (corresponding H: f) 1.3 to 1.88H, m (corresponding H: c) 2.71H, d (corresponding H: b) 3.4 to 3.64H, m (corresponding H: d, e) 3.8 to 4.0 1H, m (corresponding H: a) Example 9: (+)-R-9-ethoxy-1,1,1-trifluoro-2-nonanol CF ₃ C * H (OH) (CH ₂ ) ₆ CH ₂ 0CH ₂ CH ₃ (General formula 1: m = 7, n = 2) abcdef δ = 1.23H, t (corresponding H: f) 1.3 to 1.812H, m (corresponding H: c) 2.4 1H, d (corresponding H: b) 3.4 to 3.64H, m (corresponding H: d, e) 3.8 to 4.0 1H, m (corresponding H: a) Example 10: (+)-R-6-propoxy-1,1,1-trifluoro-2-heptanol CF ₃ C * H (OH) (CH ₂ ) ₄ CH ₂ 0CH ₂ CH ₂ CH ₃ (General formula 1: m = 5, n = 3) abcdefg δ = 0.93H, t (corresponding H: g) 1.3 to 1.810H, m (corresponding H: c, f) 2.4 1H, d (corresponding H: b) 3.3 to 3.54H, m (corresponding H: d, e) 3.8 to 4.0 1H, m (corresponding H: a) Example 11: (+)-R-6-methoxy-1,1,1-trifluoro-2-hexanol CF ₃ C * H (OH) (CH ₂ ) ₃ CH ₂ 0CH ₃ (General formula 1: m = 4, n = 1) abcde δ = 1.4 to 1.86H, m (corresponding H: c) 2.71H, d (corresponding H: b) 3.3 to 3.55H, m (corresponding H: d, e) 3.8 to 4.0 1H, m (corresponding H: a) Example 12: (+)-R-6-ethoxy-1,1,1-trifluoro-2-hexanol CF ₃ C * H (OH) (CH ₂ ) ₃ CH ₂ 0CH ₂ CH ₃ (general formula 1: m = 4, n = 2) abcdef δ = 1.23H, t (corresponding H: f) 1.5 to 1.86H, m (corresponding H: c) 3.1 1H, d (corresponding H: b) 3.4 to 3.64H, m (corresponding H: d, e) 3.8 to 4.0 1H, m (corresponding H: a) Example 13: (+)-R-6-butoxy-1,1,1-trifluoro-2-hexanol CF ₃ C * H (OH) (CH ₂ ) ₃ CH ₂₀ CH ₂ (CH ₂ ) ₂ CH ₃ (General formula 1: m = 4, n = 4) abcdefg δ = 0.93H, t (corresponding H: g) 1.2 to 1.810H, m (corresponding H: c, f) 2.71H, d (corresponding H: b) 3.4 to 3.54H, m (corresponding H: d, e) 3.8 to 4.0 1H, m (corresponding H: a) Example 14: (+)-R-5-ethoxy-1,1,1-trifluoro-2-pentanol CF ₃ C * H (OH) (CH ₂ ) ₂ CH ₂ 0CH ₂ CH ₃ (General formula 1: m = 3, n = 2) abcdef δ = 1.23H, t (corresponding H: f) 1.6 to 2.04H, m (corresponding H: c) 3.4 to 3.64H, m (corresponding H: d, e) 3.8 to 4.0 1H, m (corresponding H: a) 4.5 1H, d (corresponding H: b)

[Brief description of the drawings]

FIG. 1 is a graph showing the change over time showing the composition ratio of each component at each reaction time in the asymmetric hydrolysis reaction of Example 1- (5).

FIG. 2 is a graph in which a change in composition in an asymmetric hydrolysis reaction of Example 1- (5) is plotted according to a primary reaction formula.
The linear relationship indicates a primary reaction.

FIG. 3 shows a gas chromatograph (CP Cyclod) for analyzing an optically active substance, using 2-acetoxy-7-ethoxy-1,1,1-trifluoroheptane (racemic acetate) obtained in Example 1- (4).
exβ236M). FIG. It is a racemate and shows that the peak ratio of the R-form and the S-form is 1: 1.

FIG. 4 An aliquot of the reaction solution obtained in Example 1- (5) is taken, R-alcohol produced is converted to propionate with pyridine / propionic anhydride, and then a gas chromatograph for optically active substance analysis (CP FIG. 3 is a gas chromatographic diagram analyzed by Cyclodex β236M). As can be seen from the figure, the unreacted acetate contained only a trace amount of the R-form, whereas the hydrolyzed alcohol (analyzed as propionate) was mostly the R-form and the content of the S-form was very small. Therefore, the lipase almost completely recognized the optically active substance and reacted, which was a favorable result.

Claims (10)

[Claims] [Claim 1] General formula 1: CF ₃ C * H (OH)-(CH ₂ ) _m OC _n H _{2n + 1}
(Wherein m is an integer of 3 to 8, n is an integer of 1 to 6, and C * means an asymmetric carbon atom). After converting a halogen compound represented by the general formula 2: X (CH ₂ ) _m OC _n H _{2n + 1} (m and n are the same as in the general formula 1, X represents a halogen atom other than fluorine) into a Grignard reagent, Formula 3: CF ₃ COOM ¹ (M ¹ represents Li, Na, K) or Formula 4: (CF ₃ COO) ₂ M ² (M ² represents either Mg, Ca) By reacting with a salt of trifluoroacetic acid represented by the formula, a ketone represented by the general formula 5: CF ₃ CO (CH ₂ ) _m OC _n H _{2n + 1} (m and n are the same as in the general formula 1) is produced. Step (2): reducing the ketone of the formula 5, the general formula 6: CF ₃ C * H (O
H)-(CH ₂ ) _m OC _n H _{2n + 1} (wherein m and n are the same as in the general formula 1) to produce a racemic alcohol; Step (3): alcohol of the formula 6 Is esterified with a carboxylic acid halide or a carboxylic anhydride to obtain a compound represented by the general formula 7: CF ₃ C * H (OCOR)-(CH ₂ ) _m OC _n H _{2n + 1} (where COR represents a carbon atom having 2 to 2 carbon atoms). Step 4): carrying out an asymmetric hydrolysis reaction of the ester of the formula 7 with a lipase and bringing the ester into contact with a specific organic solvent after completion of the reaction. And recovering the lipase by filtration, and separating the optically active alcohol and the optically active ester from the filtrate from which the lipase has been removed. 2. The general formula 2: X (CH ₂ ) _m OC _n H of the step (1)
_{The 2n + 1} barogen compound is an alkyl represented by the general formula: X (CH ₂ ) _m Y (m is the same as general formula (1), X and Y each represent a halogen atom other than fluorine, and may be the same) The method for producing an optically active alcohol according to claim 1, wherein the method is produced by reacting a dihalide with a sodium alkoxide represented by the general formula: NaOC _n H _{2n + 1} (n is the same as in the general formula 1). . 3. The process for producing an optically active alcohol according to claim 1, wherein in the step (1), a salt of trifluoroacetic acid reacted with a Grignard reagent is used as a tetrahydrofuran solution. 4. The process for producing an optically active alcohol according to claim 3, wherein in the step (1), the salt of trifluoroacetic acid reacted with the Grignard reagent is bis (trifluoroacetic acid) magnesium. 5. The process for producing an optically active alcohol according to claim 1, wherein in the step (2), an aqueous NaBH ₄ solution containing sodium hydroxide is used as a ketone reducing agent. 6. The process for producing an optically active alcohol according to claim 1, wherein in the step (4), the asymmetric hydrolysis reaction with lipase is carried out at 20 to 40 ° C. 7. In the step (4), the amount of water used in the asymmetric hydrolysis reaction with lipase is 20
The method for producing an optically active alcohol according to claim 1, wherein the molar amount is from 50 to 50 times. 8. In the step (4), lipase is precipitated by contacting the asymmetric hydrolysis reaction solution with lipase with an organic solvent in an amount of 5 to 20 times the amount of water used for the asymmetric hydrolysis, The method for producing an optically active alcohol according to claim 1, wherein the precipitated lipase is collected by filtration, dried under reduced pressure, and reused. 9. The method for producing an optically active alcohol according to claim 8, wherein the organic solvent is acetone, methanol, ethanol or tetrahydrofuran which is compatible with water. 10. The optical activity according to claim 8, wherein in the step (4), the contact between the asymmetric hydrolysis reaction solution and the organic solvent is carried out by dropping the asymmetric hydrolysis reaction solution into the organic solvent. A method for producing alcohol.