JPH10248593A - Optical resolution of omega-alkoxy-1,1,1-trifluoro-2-alkanol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing an optically active ω-alkoxy-1,1,1-trifluoro-2-alkanol useful as a raw material for liquid crystal materials. SOLUTION: This method for producing an optically active ω-alkoxy-1,1,1- trifluoro-2-alkanol an its ester comprises reacting a compound of the formula [R is a 1-5C alkyl; (n) is an integer of 2-10] with an acylating agent in the presence of lipase to resolve into an optically active alcohol rich in either one of the R-isomer and the S-isomer and the ester of the other.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an optically active ω-alkoxy-1,1,1-trifluoro-2 useful as a starting material or an intermediate of a physiologically active substance or a functional material.
The present invention relates to a method for producing an alkanol and an ester thereof.

[0002]

2. Description of the Related Art Optically active alcohols are used in medicines, pesticides,
It is very useful as a starting material such as a liquid crystal compound or an intermediate. Generally, medicines, pesticides, liquid crystal compounds, etc.
In order to exhibit sufficient activity or characteristics, it is necessary that the optical purity is sufficiently high. Particularly, in the case of a liquid crystal material, both enantiomers are required to meet the required performance.

Heretofore, as a method for obtaining an optically active alcohol, a racemate obtained by a general synthetic chemistry method has been obtained by an optical resolution method, an asymmetric synthesis method, and a stereospecific method from an optically active starting material. There are methods, but all of them have complicated steps and are industrially disadvantageous in most cases. The compound represented by the general formula (1) can be very suitably used as a raw material for a liquid crystal compound. For example, Japanese Unexamined Patent Publication
JP-163208A discloses an optically active liquid crystal compound (a) and a compound (b) as a raw material thereof.

[0004]

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The method for producing the optically active compound (b) corresponding to the general formula (1) is described in the above-mentioned JP-A-5-15-1.
JP-A-63208 and JP-A-6-62872 report the following asymmetric hydrolysis methods.

[0006]

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Japanese Patent Application Laid-Open No. 5-260992 discloses a 4,4,4-trifluoro-3-hydroxybutanoic acid ester obtained by utilizing asymmetric reduction of trifluoroacetoacetic acid ester (5) ( A method combining a stereospecific synthesis technique using 6) as a raw material and asymmetric hydrolysis is disclosed.

[0008]

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The asymmetric hydrolysis reaction using these lipases is usually carried out in an aqueous solution, a phosphate buffer is used to adjust the pH, and the substrate concentration is 0.1-0.5 mol /.
liter is appropriate. However, the use of a phosphate buffer or the like is disadvantageous in an industrial reactor, and a post-treatment step for purification is complicated. In addition, since the optimal conditions for the reaction often exist in a region where the substrate concentration is very low, a large amount of the reaction solution is charged in one reaction, and mass production is difficult. Furthermore, the number of steps is large, which is disadvantageous in terms of manufacturing cost. In addition, lipase cannot be recovered and reused unless it is used after treatment such as immobilization.

In the asymmetric reduction method using baker's yeast, only one enantiomer, R-isomer, can be obtained, and the optical purity is 6%.
It is as low as 0% ee.

[0011]

The present invention makes it possible to carry out the optical resolution of an optically active compound represented by the general formula (1) in an organic solvent, to simplify the post-treatment purification step,
It is another object of the present invention to increase the load of raw materials and to enable mass production.

[0012]

According to the present invention, an acylating agent and a compound represented by the general formula (1):

[0013]

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Wherein R is an alkyl group having 1 to 5 carbon atoms;
n represents an integer of 1 to 10. ) In the presence of a lipase having the ability to act on the compound represented by the formula (1) to preferentially transesterify with either the R-form or the S-form of the compound (R, S) mixture (1) ) Is reacted with the acylating agent to carry out a transesterification reaction to obtain an optically active alcohol (1) rich in either the R-form or the S-form.
4) and one of the other ester compounds (15).
A process for producing trifluoro-2-alkanols and esters thereof.

[0015]

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This reaction is carried out in a substantially water-free state, and does not require a lower alcohol which may be used instead of water in the asymmetric hydrolysis reaction method. Therefore, hydrolysis of the formed ester and generation of an ester other than the target substance can be prevented, and the target substance having high optical purity can be obtained. Furthermore, microbial contamination or the like due to the direct use of bacteria in an organic solvent does not occur, and a special device for microbial contamination and complicated operations such as preservative treatment and sterilization treatment are unnecessary. Since the lipase itself is not deteriorated by the organic solvent, the lipase used in the reaction can be easily separated and recovered by filtration or the like, and can be reused. In addition, the method of the present invention can be carried out at a substrate concentration equal to or higher than the ordinary organic synthesis reaction,
Since the reaction can be carried out even in an open system, the size of the reaction apparatus can be reduced and no pressure-resistant design is required.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (1), n is 2 to
Racemic ω-alkoxy-1,1,1-trifluoro-2-alkanol of 10 is disclosed in JP-A-5-1632.
No. 08, or the following method.

[0018]

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That is, a ketone (22) obtained by reacting an alkoxyalkylmagnesium bromide (21) with a trifluoroacetic acid ester is reduced with a reducing agent such as sodium borohydride or lithium aluminum hydride (23). ) Is obtained. The Grignard reagent (21) alkylates the monobenzyl compound (17) of the alkanediol (16) (18) and deprotects (1).
9), brominated (20), and obtained by reacting magnesium.

In the general formula (1), ω-
Alkoxy-1,1,1-trifluoro-2-alkanol can be suitably produced by the following route. That is, trifluoroacetaldehyde methyl acetal (24)
Is reacted with trimethylsilyl nitrile to give cyanohydrin (25), which is hydrolyzed with sulfuric acid or the like to lead to trifluorolactic acid (26), esterified (27), a protecting group is introduced (28), and the ester moiety is hydrogenated Reduction with a reducing agent such as sodium borohydride or lithium aluminum hydride gives alcohol (29), which is alkylated (30) and then deprotected to give the desired compound (31). Can be

[0021]

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The acylating agent used in the present invention includes carboxylic anhydrides such as benzoic anhydride and 1,2-cyclohexanedicarboxylic anhydride, enol esters such as isopropenyl acetate, triacetin, tripropionin, tributyrin and tristearin. , Trilaurin, trimyristin, triglycerides such as triolein, methyl propionate, ethyl butyrate, ethyl stearate,
Fatty acid esters such as trichloroethyl laurate, butyl laurate, and ethylene glycol diacetate, and vinyl esters such as vinyl acetate, vinyl propionate, vinyl caproate, and vinyl laurate, among which vinyl esters are preferred. It can be used preferably.
In addition, they do not require special treatment for the reaction.

The lipase used in the present invention is
Acts on (R, S) -alcohol to give R-form and S-form
Optically active ω-alkoxy- rich in one of the body
It is a substance having an asymmetric transesterification ability, which converts into an ester of 1,1,1-trifluoro-2-alkanol, and is preferably a substance generally referred to as lipase, lipoprotein lipase or esterase. Specifically, Table 1
Commercially available enzymes such as those shown in (1) can be used.

[0024]

[Table 1]

In addition, cells obtained by culturing a microorganism producing a lipase having the asymmetric transesterification ability are sterilized,
It can be concentrated and dried to use as it is, or it can be purified and used. Examples of microorganisms include Candida, Pseudomonas, Chromobacterium,
Mucor, Rhizopus, Arthrobacter, Achromobacter, Alcaligenes and the like can be mentioned. Further, an extract from an organ of an animal containing the lipase having the above-mentioned asymmetric transesterification ability can also be used.

The reaction is carried out by mixing (R, S) -alcohol and an acylating agent and bringing them into contact with lipase efficiently.
When the alcohol and the acylating agent do not form a uniform mixture and a solid phase exists in the reaction system, it is preferable to use a suitable organic solvent to make the homogeneous phase. Examples of the organic solvent include hexane, heptane, toluene, 1,2-dichloroethane, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like.

The reaction temperature ranges from 20 ° C. to 100 ° C., preferably from 30 ° C. to 45 ° C. The reaction pressure may be atmospheric pressure, but it is also possible to carry out the reaction under increased or reduced pressure. The reaction time is affected by the activity of the lipase, the reaction temperature and the like, and takes several hours to several days. Substrate (R,
The ratio (molar ratio) of S) -alcohol and acylating agent is
1: 0.5 to 1: 2, preferably 1: 1.
Perform in the range of 1 to 1: 1.5.

After the asymmetric transesterification in this manner, the lipase can be removed by a usual filtration operation. This can be reused. The filtrate from which lipase has been removed is subjected to distillation under reduced pressure, chromatography or the like to separate the remaining alcohol from the target ester produced. The optically active alcohol enantiomer of the remaining alcohol is obtained by a usual treatment method such as alkali hydrolysis or acid hydrolysis of the produced target ester. If the conversion is insufficient and the optical purity of the obtained optically active alcohol is low, the optical purity can be increased by performing the transesterification again.

[0029]

The production method of the present invention will be described in more detail with reference to the following examples. Example 1 (+)-7-ethoxy-1,1,1-trifluoro-2
-Preparation of heptanol Stage 1 194 g of pentanediol monobenzyl ether (1 m
ol) of tetrahydrofuran (hereinafter abbreviated as THF) 1L
While cooling the solution in an ice bath, 48 g (2 mol) of sodium hydride was added, and the mixture was heated under reflux for 2 hours. The reaction solution was allowed to cool to room temperature and 140 g of ethyl bromide
After a solution of (1.3 mol) in 300 ml of THF was added dropwise, the mixture was further heated under reflux for 6 hours. 500 ml of water was added to terminate the reaction, and the product was extracted with 500 ml of ether. After drying the ether layer with anhydrous magnesium sulfate,
The ether was distilled off and the remaining oil was purified by distillation under reduced pressure to give pentanediol benzyl ethyl ether 19
2 g were obtained. Its boiling point is 110-117 ° C (1 m
mHg).

Second stage In 500 ml of ethanol, 90 g (0.4 mol) of pentanediol benzyl ethyl ether and 5.7 g of palladium hydroxide carbon were added and stirred at room temperature until about 9 L of hydrogen was absorbed. After filtering the reaction solution to remove palladium hydroxide carbon, the solvent was distilled off, and the remaining oil was purified by distillation under reduced pressure to obtain pentanediol monoethyl ether. Its boiling point is 55-58 ° C
(0.3 mmHg).

Third stage 78 g (0.29 mol) of phosphorus tribromide was added to dry benzene 5
After dissolving in 0 ml, 10 g of pyridine was added dropwise. 10
After stirring for 5 minutes, the mixture was cooled to −5 ° C., and a mixture of 102 g (0.77 mol) of pentanediol monoethyl ether and 5 g of pyridine was added dropwise. After stirring for 2 hours while maintaining the liquid temperature at 0 ° C., the mixture was stirred at room temperature for 8 hours. Water 100
The reaction was terminated by adding ml, and the product was extracted with ether. The ether layer was washed sequentially with 6N aqueous hydrochloric acid and aqueous sodium hydrogen carbonate, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the ether was distilled under reduced pressure to obtain 103 g of (5-bromopentyl) ethyl ether. Its boiling point was 47 to 48 ° C (1 mmHg).

Fourth Step (5-Bromopentyl) was dissolved in 6.4 g (0.27 mol) of metallic magnesium in 150 ml of dry ether.
48.7 g (0.25 mol) of ethyl ether was added dropwise to prepare a Grignard reagent. 35.5 g (0.25 mol) of ethyl trifluoroacetate in 300 m of ether
After cooling the solution dissolved in l to −60 ° C., the Grignard reagent prepared above was added dropwise over 45 minutes.
While stirring for 2 hours. After raising the liquid temperature to −20 ° C., aqueous ammonium chloride was added to terminate the reaction. The ether layer was separated, washed with water, and dried over anhydrous magnesium sulfate. Ether was distilled off, and the residue was purified by distillation under reduced pressure to obtain 31 g of 7-ethoxy-1,1,1-trifluoro-2-heptanone. Its boiling point is 9
0 to 92 ° C (47 mmHg).

Fifth stage 30 g (0.14 mol) of 7-ethoxy-1,1,1-trifluoro-2-heptanone was added to 200 ml of ethanol.
Was cooled to 0 ° C., and then 2.6 g (0.07 mol) of sodium borohydride was gradually added.
After stirring at room temperature for 24 hours, 200 ml of water was added to terminate the reaction. The product was extracted with ether. After washing the ether layer with a small amount of water, it was dried over anhydrous magnesium sulfate. Ether was distilled off, and the residue was purified by distillation under reduced pressure to obtain 28 g of racemic 7-ethoxy-1,1,1-trifluoro-2-heptanol. Its boiling point is 1
33 to 137 ° C (50 mmHg).

Step 6 Racemic 7-ethoxy-1,1,1-trifluoro-
21.4 g (0.1 mol) of 2-heptanol was dissolved in 30 ml of heptane, and 5.17 g (0.06 g) of vinyl acetate was dissolved.
0 mol) and 3.0 g of lipase (Novozyme 435, manufactured by Novo Nordisk) were sequentially added, followed by stirring at 35 ° C. for 4 days. The reaction mixture was filtered and the lipase was filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: heptane / ethyl acetate = 10/1 (v /
v)) and purified using (+)-7-ethoxy-1,
8.17 g of 1,1-trifluoro-2-heptanol
And 10.57 g of (-)-acetic acid 2- (7-ethoxy-1,1,1-trifluoroheptyl) were obtained. (+)-
The specific rotation of 7-ethoxy-1,1,1-trifluoro-2-heptanol is [α] ₂₆ ^D +14.93 (c
1.147, CHCl ₃ )].

Seventh step (+)-7-ethoxy-1,1, obtained in the sixth step
10.81 g of 1-trifluoro-2-heptanol was dissolved in 30 ml of heptane, and 2.58 g of vinyl acetate was added thereto.
(0.030 mol) and 3.0 g of the lipase used in the sixth step were sequentially added, followed by stirring at 35 ° C. for 6 days. The lipase was removed from the reaction mixture by filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: heptane / ethyl acetate = 10/1 (v / v)).
And purified using (+)-7-ethoxy-1,1,1-
7.31 g of trifluoro-2-heptanol were obtained. This was esterified with (R)-(-)-α-methoxy-α-trifluorophenylmethylacetic acid chloride (hereinafter abbreviated as MTPA chloride) in the presence of pyridine, and analyzed by capillary column gas chromatography. The optical purity was 95.2% ee.

Example 2 (-)-7-ethoxy-1,1,1-trifluoro-2
Preparation of heptanol Obtained in the sixth step of Example 1
(-)-Acetic acid 2- (7-ethoxy-1,1,1-trifluoroheptyl) 10.57 g (0.0412mo)
l) was dissolved in methanol and sodium hydroxide 2.08
g (0.0495 mol) dissolved in 50 ml of water was added, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, extraction was performed with 100 ml of chloroform in total, and this was dried over magnesium sulfate. After magnesium sulfate was filtered off, the solution was concentrated under reduced pressure, and 8.47 g (0.0395 mol) of (-)-7-ethoxy-1,1,1-trifluoro-2-heptanol was added.
l) obtained. Its specific rotation is [α] ₂₆ ^D -19.
45 (c 1.052, CHCl ₃ ).

This was esterified with MTPA chloride and analyzed by capillary column gas chromatography to find that the optical purity was 93.7% ee.

[0038]

Industrial Applicability According to the present invention, an optically active ω-alkoxy-1,1,1-trifluoro-2-alkanol and an ester thereof can be efficiently and efficiently (90% ee or more).
It can be manufactured with optical purity. As compared with the hydrolysis method, the number of steps for producing a racemic ester can be reduced. The substrate concentration in the reaction solution can be increased.
The lipase can be easily recovered and reused.

The optically active ω-alkoxy-1,1,1-trifluoro-2-alkanol and its ester obtained by the production method of the present invention are disclosed in JP-A-64-31.
54, JP-A-5-163208, JP-A-5-18
It can be used as a raw material for liquid crystal materials described in JP-A-6402 and JP-A-8-157423.

Claims (5)

[Claims] 1. An acylating agent and a compound represented by the general formula (1): (Wherein, R represents an alkyl group having 1 to 5 carbon atoms, and n represents 1
And an integer of 10 to 10. ) In the presence of a lipase having the ability to act on the compound represented by formula (1) to preferentially transesterify either the R-form or the S-form with the (R, S) mixture of the compound and the acyl. A transesterification reaction by reacting with an agent and an optically active alcohol enriched in one of the R-form and the S-form and the other ester form to form an ω-alkoxy-
An optical resolution method for 1,1,1-trifluoro-2-alkanol. 2. The optical resolution method according to claim 1, wherein in the general formula (1), R is a methyl group or an ethyl group, and n is an integer of 4 to 7. 3. The optical resolution method according to claim 1, wherein the lipase is derived from Candida. 4. The optical resolution method according to claim 1, wherein the acylating agent is a vinyl ester. 5. The optical resolution method according to claim 1, wherein the lipase is derived from Candida and the acylating agent is a vinyl ester.