JP2830891B2 - Optically active alcohol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an optically active alcohol having a pentafluoroethyl or heptafluoropropyl group on an asymmetric carbon and an alkoxy group at a terminal.

[0002]

2. Description of the Related Art Optically active substances have hitherto been used in the fields of pharmaceuticals and agricultural chemicals. In recent years, attention has been paid to functional materials such as ferroelectric liquid crystals and organic nonlinear materials. For example, in the field of organic nonlinear materials, it is desirable that an asymmetric center exists in a molecule in order for the organic material to produce a second-order nonlinear optical effect (for example, Yamaguchi, Nakano,
Fueno, Chemistry, 42 (11), 757 (1987)).

In the field of ferroelectric liquid crystals, it is essential that liquid crystal molecules be optically active in order for the liquid crystal to exhibit ferroelectricity (for example, Jono, Fukuda, Journal of Synthetic Organic Chemistry, 47 (6) ), 568 (1989)). Recently, antiferroelectric liquid crystals have attracted much attention. In such a field, 2-butanol, 2-octanol, 2-
Methyl-1-butanol, amino acid derivatives and the like have been used. However, when these optically active substances are used, the properties of the obtained liquid crystal compound are limited.

Recently, in the field of ferroelectric liquid crystals, CF ₃ C ^* H (O
_{H) CH 2 COOC 2 H 5} , CF 3 C * H (OH) CH 2 CH 2 OC 2 H 5, CF 3 C * H (O
H) CH ₂ CH ₂ CH ₂ OC ₂ H ₅ , CF ₃ C ^* H (OH) CH ₂ CH ₂ CH ₂ CH ₂ OC
^{_{2 H 5, CF 3 C *}} H (OH) C 6 H 13, CF 3 C * H (OH) C 8 H 17, C 2 F 5 C
^* Attempts have been made to synthesize ferroelectric liquid crystals using alcohols such as H (OH) C ₈ H ₁₇ (see, for example,
-3154, JP-A-1-316339, JP-A-1-316367, JP-A-1-316372, JP-A-2-225434, JP-A-2-229128
issue). All of the ferroelectric liquid crystals derived from these alcohols give a large spontaneous polarization and a relatively fast response speed due to the substitution of a highly electronegative fluorine atom on the asymmetric carbon. .

Also, CF ₃ C ^* H (OH) C ₆ H ₁₃ , CF ₃ C ^* H (OH) C ₈ H
₁₇ , a compound derived using C ₂ F ₅ C ^* H (OH) C ₈ H ₁₇ or the like has been recognized as being easy to give a ferroelectric liquid crystal having an antiferroelectric phase, and as a characteristic alcohol, Attracting attention. The use of such an alcohol in which the fluorine is substituted on the asymmetric carbon gives a very useful liquid crystal.

However, CF ₃ C ^* H (OH) C ₆ H ₁₃ , CF ₃ C ^* H (OH) C
₈ antiferroelectric chemistry crystal with _{H 17, C 2 F 5 C} * H (OH) C 8 H 17 and the like are not characteristic sufficiently. Therefore, from this aspect, the appearance of a new optically active alcohol in which fluorine is substituted on an asymmetric carbon which can be used as an optically active source of liquid crystal has been desired. As we new optically active alcohols from such respect, the general formula _{CF 3 C * H (OH)} (CH 2) m OC n H 2n + proposed a new optically active alcohol represented by ₁ (Japanese Patent Application No. 3 -310008).
However, the use of this alcohol has not always yielded satisfactory results, and a new alcohol has been desired. The present invention has been made in view of the above circumstances, and provides a novel alcohol having a pentafluoroethyl and heptafluoropropyl group on an asymmetric carbon and having an alkoxy group at a terminal. .

[0007]

That is, the present invention provides:
It is an optically active alcohol represented by the following formula. ^{_{C p F 2P + 1 C *}} H (OH) (CH 2) m OC n H 2n + 1 (p in the formula 2 or 3, m is 5 to 8, n is an integer of 1 or more.)

The present inventors have disclosed in Japanese Patent Application No. 4-216163 a simple production of an optically active alcohol represented by the general formula CF ₃ C * H (OH) (CH ₂ ) _m OC _n H _{2n + 1.} Proposed the law. The method is as described below, and the present invention can be implemented in a similar manner. _{(1) HO (CH 2)} m OH + Na + C n H 2n + 1 Br; HO (CH 2)
_m OC _n H _{2n + 1} (2) HO (CH ₂ ) _m OC _n H _{2n + 1} + PBr ₃ ; Br (CH ₂ )
_m OC _n H _{2n + 1} (3) Br (CH ₂ ) _m OC _n H _{2n + 1} + Mg; MgBr (CH
₂ ) _m OC _n H _{2n + 1} (4) MgBr (CH ₂ ) _m OC _n H _{2n + 1} + CF ₃ COOH; CF ₃ CO
(CH ₂ ) _m OC _n H _{2n + 1} (5) CF ₃ CO (CH ₂ ) _m OC _n H _{2n + 1} + (LiAlH ₄ ); CF ₃ CH (O
H) (CH ₂ ) _m OC _n H _{2n + 1} (6) CF ₃ CH (OH) (CH ₂ ) _m OC _n H _{2n + 1} + CH ₃ COCl; CF ₃ CH
(OCOCH ₃ ) (CH ₂ ) _m OC _n H _{2n + 1} (7) CF ₃ CH (OCOCH ₃ ) (CH ₂ ) _m OC _n H _{2n + 1} + (reverse); CF ₃ C ^* H (OH) ( CH ₂ ) _m OC _n H _{2n + 1} ; CF ₃ C ^* H (OCOCH ₃ ) (CH ₂ ) _m OC _n H _{2n + 1}

The above reaction formula (1) is an alkylation of an aliphatic diol with an alkyl bromide, which is easily achieved by a known method (for example, Lee Irvin et al., JACS., 65, 1276 (1943)). You. The amount of sodium metal and alkyl bromide used in this reaction is suitably 1/2 to 1/3 mol based on the diol. When these amounts are more than 1/2 mole with respect to the diol, the amount of diether compound formed increases. Suitable solvents are aromatic hydrocarbons having a relatively high boiling point, such as benzene, toluene, and xylene, and the reaction is carried out at the boiling point of these solvents.

The above reaction formula (2) is for the bromination of the alcohol obtained in (1), and this can also be easily achieved by a known method using phosphorus tribromide (the above-mentioned literature). Phosphorus tribromide is used in an amount of 1/2 to 1/3 mol with respect to the alcohol, and preferably reacts at around room temperature. The above reaction formula (3) is for preparing a Grignard reagent, but can be carried out without any problem by a usual method. The above reaction formula (4) is a reaction between the Grignard reagent prepared in (3) and trifluoroacetic acid, and is performed by a known method (for example, KN Campbell et al., JACS., 72, 4380 (1950), KT
Dishart et al., JACS., 78, 2268 (1956), CA, 77, 10986.
It can be easily implemented by referring to j).

In the present invention, the objective can be achieved by using pentafluoropropionic acid and heptafluorobutyric acid instead of trifluoroacetic acid in the above reaction formula (4). The above reaction formula (5) can be easily carried out by applying a general reduction method of ketone. The above reaction formula (6) is an acetylation of a hydroxyl group with acetyl chloride using pyridine as a catalyst and can be easily achieved by a known method.

Reaction formula (7) is an asymmetric hydrolysis of acetate with a lipase. Asymmetric hydrolysis of acetate by lipase has been proposed by Kitazume et al.
(T. Kitazume et al., J. Org. 52, 3211 (1987),
-282340). According to this, by using lipase MY, acetate represented by CF ₃ CH (OCOCH ₃ ) C _n H _{2n + 1} is asymmetrically hydrolyzed in a phosphate buffer. However, the asymmetric recognition ability of lipase MY greatly depends on the chemical structure of the compound to be hydrolyzed, and is described by Kitazume et al.
As shown in Table 1 of et al., J. Org. 52, 3211 (1987), the optical purity of the hydrolyzate obtained by the chemical structure is significantly different from 55 to 98 ee%. This means
It is difficult to predict whether asymmetric hydrolysis of a target compound will be successful, and it will be necessary to carry out the reaction to determine whether the target alcohol can be obtained with high optical purity. Is shown.

When considering the asymmetric hydrolysis of a racemate, the maximum achievable hydrolysis rate is 50%. In this regard, in order to obtain one enantiomer with high optical purity, Kitazume et al. State that the hydrolysis rate must be kept at 45% or less. Therefore, it is necessary to set conditions so that a high optical purity can be achieved with a hydrolysis rate as high as possible. The asymmetric hydrolysis in the present invention is performed in a phosphate buffer (pH = 7.3) and the substrate concentration is 0.1 to
The appropriate range is 0.5 mol / l (liter), the lipase concentration is 2 to 10%, and the reaction temperature is 20 to 50 ° C.

Under such conditions, when the hydrolysis rate is set to be close to 50%, the optical purity of CF ₃ C ^* H (OH) (CH ₂ ) _m OC _n H _{2n + 1} is almost 100%. Yes, very favorable results were obtained. In the present invention, asymmetric hydrolysis was similarly performed, and the target optically active alcohol was obtained with very high optical purity.

[0015]

EXAMPLES The present invention will be described in more detail by way of examples, but the present invention is not limited thereto. Example 1 8-ethoxy-1,1,1,2,2 preparation of pentafluoro-3-octanol (formula ^{_{C p F 2P + 1 C *}} H (OH) (CH 2) m OC n H 2n + 1 At p
= 2, m = 5, n = 2)

(1) Synthesis of 5-ethoxypentanol 156 g (1.5 mol) of 1,5-pentanediol and xylene 50
11.5 g (0.5 mol) of metallic sodium was added little by little while stirring the ml (milliliter) mixture at 120 ° C. After the sodium had completely reacted, 54.5 g (0.5 mol) of ethyl bromide was added dropwise. After completion of the dropwise addition, the mixture was further stirred at 120 ° C for 1 hour. After allowing the reaction mixture to cool, poured into 500 ml of water, extracted with ether,
Dry over anhydrous sodium sulfate. Thereafter, the solvent is distilled off, and the boiling point is 95 ° C (22 Torr) to 100 ° C by vacuum distillation.
(12 Torr) fraction of 39.4 g was obtained. Its purity as 5-ethoxypentanol was 83% (according to gas chromatography analysis).

(2) Preparation of 5-ethoxy-1-bromopentane To 39.4 g (0.3 mol) of 5-ethoxypentanol, 32.2 g (0.12 mol) of phosphorus tribromide was added dropwise at room temperature. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulfate. The residue was distilled under reduced pressure except for the desiccant and the solvent to obtain 36.5 g of a fraction having a boiling point of 71.5 to 77 ° C. (9 Torr). This was analyzed by gas chromatography to find that
The purity as ethoxy-1-bromopentane was 85%.

(3) Production of 8-ethoxy-1,1,1,2,2-pentafluoro-3-octanol (racemate) Tetrahydrofuran was added to 3.5 g (0.145 mol) of metallic magnesium.
Add 16 ml, and add 25.6 g of 5-ethoxy-1-bromopentane
(0.13 mol) of a tetrahydrofuran solution (35 ml) was added dropwise to prepare a Grignard reagent. 13 ml of a tetrahydrofuran solution of 10.3 g (0.063 mol) of pentafluoropropionic acid was added dropwise, and the mixture was refluxed for 2 hours.

The reaction mixture was poured into 300 ml of 1N hydrochloric acid and extracted with ether. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. An ether solution of the crude product obtained by removing the drying agent and the solvent was added dropwise at room temperature to an ether solution of 2.5 g of lithium aluminum hydride. Water / tetrahydrofuran = 1 with excess lithium aluminum hydride
/ L solution, and the precipitate was filtered by suction, and the resulting solution was washed with saturated saline and dried over anhydrous sodium sulfate. Purified by vacuum distillation except for the desiccant and solvent (boiling point 88-
90 ° C / 4 Torr). Purity by gas chromatography is 91
%Met.

(4) 8-ethoxy-3-acetoxy-1,1,1,2,
Preparation of 2-pentafluoro-3-octane To a solution of 3.2 g (0.041 mol) of acetyl chloride in toluene was added 8-ethoxy-1,1,1,2,2-pentafluoro-3-octanol 7.0
4 g (0.0266 mol) and 5 ml of pyridine were added and stirred at room temperature overnight. The reaction mixture was poured into a saturated saline solution, extracted with ether, and washed with hydrochloric acid, an aqueous sodium hydroxide solution, and a saturated saline solution. After drying over anhydrous sodium sulfate, the desiccant and solvent are removed, and the residue is distilled under reduced pressure to obtain a fraction having a boiling point of 78 to 79 ° C (4 Torr).
5.66 g was obtained. As a result of gas chromatography analysis, the product was 99% in purity.

(5) Production of (+)-8-ethoxy-1,1,1,2,2-pentafluoro-3-octanol Lipase MY (manufactured by Akashi Sangyo) 5.65 g was added to a phosphate buffer
75ml (pH 7.3, 1 / 15MKH ₂ PO ₄ 14ml and 1 / 15M NaPO ₄ 46m
l was mixed) and stirred at 40-41 ° C for 15 minutes. To this was added 5.66 g (0.0185 mol) of 8-ethoxy-3-acetoxy-1,1,1,1,2,2-pentafluoro-3-octane, and the reaction was followed by gas chromatography. %
The reaction was stopped at.

100 ml of 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ether. After the ether layer was dried over anhydrous sodium sulfate, the ether was distilled off to obtain a crude product. Purification by column chromatography packed with silica gel using hexane / ethyl acetate as a developing solvent gave 1.02 g of the desired product. FIG. 1 shows the NMR spectrum of this product. The assignment of each proton corresponds to the sign of the equation shown in FIG. Analysis by gas chromatography revealed that the chemical purity was 98.7%. Also, [α] ²⁸
_D = + 18.7 °.

(6) Determination of the optical purity of (+)-8-ethoxy-1,1,1,2,2-pentafluoro-3-octanol R-(+)-α-methoxy-α- (trifluoro Methyl) phenylacetic acid (R-MTPA) 1 g (0.004 mol), thionyl chloride 2 ml, salt
20 mg were refluxed for about 30 hours. Excess thionyl chloride was removed to obtain an acid chloride of MTPA. (+)-8-ethoxy-1,1,1,2,
26.8 mg (0.101 mmol) of 2-pentafluoro-3-octanol
To a pyridine solution (1.5 ml) of 4-dimethylaminopyridine
98 mg (0.0008 mol) and 1.5 ml of dichloromethane were added. To this was added 39.5 mg (0.156 mmol) of the MTPA acid chloride obtained above, and the mixture was stirred at room temperature for 24 hours.

After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and the solvent was removed under reduced pressure to obtain an MTPA ester. The dichloromethane solution of this was converted to a capillary column with OV-1 as the liquid phase (0.25 mm ×
25m), a chromatogram as shown in FIG. 3 was obtained. The symbols (R)-(R) in FIG. 3 are (R) -MTPA and (R)-
Represents an ester with 8-ethoxy-1,1,1,2,2-pentafluoro-3-octanol, where (R)-(S) is (R) -MTPA and (S) -8-
Shows esters with ethoxy-1,1,1,2,2-pentafluoro-3-octanol. From this, (+)-8-ethoxy-1,1,1,
The optical purity of 1,2,2-pentafluoro-3-octanol is
It was estimated to be 97% ee.

[0025] EXAMPLE 2 9-ethoxy -1,1,1,2,2,3,3- preparation of heptafluoro-4- nonanol (formula ^{_{C p F 2P + 1 C *}} H (OH) (CH 2) _m OC _n H _{2n + 1} p
= 3, m = 5, n = 2) (1) Synthesis of 5-ethoxypentanol The target product was obtained in exactly the same manner as (1) in Example 1. (2) Production of 5-ethoxy-1-bromopentane The target compound was obtained in exactly the same manner as in (2) of Example 1.

(3) Production of 9-ethoxy-1,1,1,2,2,3,3-heptafluoro-4-nonanol (racemic) 6.3 g (0.257 mol) of magnesium metal, 5-ethoxy-1 Using exactly 45.6 g (0.234 mol) of -bromopentane and 24.01 g (0.112 mol) of heptafluorobutyric acid instead of pentafluoropropionic acid, the operation was carried out in exactly the same manner as (3) of Example 1. After reduction of lithium aluminum hydride, 9-ethoxy-1,1,1,2,2,3,3-
Heptafluoro-4-nonanol (racemic) and 6-ethoxy-1-, a structure in which a heptafluoropropyl group is eliminated
An almost 1/1 mixture of hexanol was obtained. Since it was difficult to separate each from this mixture, the mixture was used for the next reaction as it was.

(4) 9-ethoxy-4-acetoxy-1,1,1,2,
Production of 2,3,3-heptafluorononane 4.5 g (0.057 mol) of acetyl chloride, 11.9 g of the mixture obtained in (3)
And the operation was carried out in exactly the same manner as in Example 1, (4).

(5) Preparation of (+)-9-ethoxy-1,1,1,2,2,3,3-heptafluoro-4-nonanol Lipase MY (manufactured by Akashi Sangyo) 14.34 g, (4) Using exactly 13.9 g of the crude product obtained in the above, the operation was carried out exactly as in (5) of Example 1.
As a result, 3.74 g of a reaction product was obtained, which was purified in the same manner as in Example 1 to obtain 1.58 g of (+)-9-ethoxy-1,
1,1,2,2,3,3-heptafluoro-4-nonanol was obtained. Its NMR spectrum is shown in FIG. The assignment of each proton corresponds to the sign of the equation shown in FIG. The specific rotation was [α] ²⁸ _D = + 14.9 °.

(6) Determination of the optical purity of (+)-9-ethoxy-1,1,1,2,2,3,3-heptafluoro-4-nonanol In exactly the same manner as in (6) of Example 1, I asked. The gas chromatograph of the R-MTPA ester is shown in FIG. The symbols (R)-(R) in FIG. 4 are (R) -MTPA and (R) -9-ethoxy-1,1,1,2,
Represents an ester with 2,3,3-heptafluoro-4-nonanol, where (R)-(S) is (R) -MTPA and (S) -9-ethoxy-1,1,1,2,
2 shows an ester with 2,3,3-heptafluoro-4-nonanol. From this, the optical purity was estimated to be 99% ee.

[0030]

According to the present invention, an optically active alcohol having a pentafluoro group or a heptafluoro group on an asymmetric carbon and an alkoxy group at a terminal of a carbon chain is obtained with extremely high optical purity.
It is related to a simple and inexpensive manufacturing method,
This is expected to be useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, functional materials, especially liquid crystals.

[0031]

[Brief description of the drawings]

1 shows the NMR spectrum of (+)-8-ethoxy-1,1,1,2,2-pentafluoro-3-octanol obtained in Example 1. FIG.

FIG. 2 shows an NMR spectrum of (+)-9-ethoxy-1,1,1,2,2,3,3-heptafluoro-4-nonanol obtained in Example 1.

FIG. 3 shows a gas chromatogram of (+)-8-ethoxy-1,1,1,2,2-pentafluoro-3-octanol obtained in Example 1.

FIG. 4 shows a gas chromatogram of (+)-9-ethoxy-1,1,1,2,2,3,3-heptafluoro-4-nonanol obtained in Example 1.

Claims (3)

(57) [Claims] 1. A optically active alcohol represented by the following formula ^{_{C p F 2P + 1 C *}} H (OH) (CH 2) m OC n H 2n + 1 (p in the formula 2 or 3, m is 5 To 8, n represents an integer of 1 or more.) 2. The optically active alcohol according to claim 1, which is (+)-8-ethoxy-1,1,1,2,2-pentafluoro-3-octanol. 3. The optically active alcohol according to claim 1, which is (+)-9-ethoxy-1,1,1,2,2,3,3-heptafluoro-4-nonanol.