JP2509282B2 - Optically active difluoro alcohol derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention provides an optically active material useful as a raw material for a ferroelectric liquid crystal, a physiologically active substance, an anticancer agent and an ester, ether and carboxylic acid used as an enzyme inhibitor. Difluoroalcohol derivative.

[Problems to be Solved by Prior Art and Invention]

As an optically active fluorine-containing alcohol applied to liquid crystals and pharmaceuticals, some compounds have been reported so far, however, a fluorine-containing optically active alcohol which is satisfactory in optical purity has not yet been reported. Therefore, an object of the present invention is to provide a novel optically active fluorine-containing alcohol having high optical purity.

[Means for solving the problem]

The present inventors particularly studied various optically active alcohols having a fluoromethyl group or the like at the terminal, and found that asymmetric hydrolysis using an enzyme yields an optically active fluorine-containing alcohol with high optical purity. Was completed.

The present invention has the general formula: [Wherein R is an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or Wherein R ¹ is hydrogen or an alkyl group having 1 to 4 carbon atoms and R ² is an alkyl group having 1 to 10 carbon atoms, and X is hydrogen, chlorine, bromine or C _n X ¹ _{2n + 1} (n is 1
Is an integer of from 8 to 8 and X ¹ is at least one atom selected from fluorine, chlorine and bromine.]].

The difluoroalcohol derivative of the general formula (I) according to the present invention includes various kinds depending on the kinds of the substituents R and X.
Both are optically active compounds in which the carbon atom bonded to the hydroxyl group (OH) is the asymmetric center. R is an alkyl group having 1 to 10 carbon atoms as described above (eg, methyl group, ethyl group, propyl group, butyl group, isobutyl group,
Hexyl group, octyl group, nonyl group, etc.), aralkyl group having 7 to 10 carbon atoms (benzyl group, phenethyl group, etc.) or formula (For example, CH ₂ CO ₂ Et, CH ₂ CO ₂ C ₈ H ₁₇ ,, CH (CH ₃ ) CO ₂ Et, etc.)
Indicates. As for X, hydrogen, chlorine, bromine or formula C _n X _{¹ 2n +} ¹ _{(e.g., CF 3, CClF 2, C} 2 F 5, CBrF 2, CF 2 CF 2 C
l, etc.).

Specific examples of such an optically active difluoroalcohol of the present invention include various ones, but in addition to those described in Examples below, And so on.

By the way, although this difluoroalcohol can be produced by various methods, it can be generally produced by the following reaction formula.

In the above formula, COR 'represents an acyl group.

 Next, each manufacturing process will be described in detail.

First step (reduction step): The fluorinated ketone of the general formula (II) is reduced with a reducing agent to produce a fluorinated alcohol derivative of the general formula (III).
The reducing agent that can be used in this step may be any reducing agent that is commonly used to reduce a carbonyl group to a hydroxyl group, and may be, for example, sodium borohydride, lithium aluminum hydride, palladium-carbon / hydrogen, or a secondary chloride. Examples include bistin and the like. Further, it is preferable to use an alcohol such as ethanol or isopropanol as a solvent in carrying out the reduction reaction, and the reaction temperature may be set from low temperature to high temperature, but it is preferable to carry out at room temperature.

The starting material of the general formula (II) used in this step is, as shown in the following formula, a fluorine-containing alkyl ester derivative such as a fluorine-containing ethyl ester in an inert solvent such as diethyl ether or tetrahydrofuran. React with a Grignard reagent (RMgX ¹ , X ¹ is a halogen atom) or an organometallic reagent such as organolithium (RLi) at -70 ° C, or use a fluorine-containing alkyl ester derivative in lithium diisopropylamide in an inert solvent such as diethyl ether. (Hereinafter, LD
A) and the alkyl ester (R ¹ CH ₂ COOR) of an aliphatic carboxylic acid such as acetic acid ethyl ester.

Second step (acylation step): Acylation can be carried out by a conventional method. Examples of the acylating agent include acetyl chloride, propionyl chloride,
Butyryl chloride, benzoyl chloride, octyl chloride and the like.

The compound of general formula (IV) produced in this step is
It is a racemate.

Third step (enzymatic hydrolysis): The compound obtained in the second step is subjected to asymmetric hydrolysis with an enzyme to obtain a compound of the general formula (I) having high optical purity.

Various enzymes can be used as long as they are so-called hydrolases, and for example, lipase P, lipase MY, lipase M10, lipase OF, lipase P679, cellulase and the like can be used. In this case, the optical activity varies depending on the enzyme to be selected. For example, when lipase MY is used and the alcohol derivative produced is dextrorotatory, the acylated product (Ia) is treated with an enzyme such as cellulase or sodium hydroxide. When treated with a basic catalyst such as the above, it becomes a levorotatory alcohol. Further, when using Lipase P, an alcohol having an optical rotation opposite to that of Lipase MY may be obtained.

〔Example〕

Next, the present invention will be described in detail based on examples, but the present invention is not limited thereto.

Reference Example A Synthesis of ( S )-(+)-1-phenyl-2,2-difluoroethanol (A) Synthesis of difluoromethyl phenyl ketone: A solution of phenyl Grignard reagent (44 mmol) in diethyl ether was slowly added dropwise at -70 ° C into a solution of difluoroacetic acid ethyl ester (4.9 g, 40 mmol) in diethyl ether. The solution was kept at -70 ° C and stirred for 4 hours, and then the reaction was terminated with a saturated aqueous solution of ammonium chloride.
The resulting oil was extracted with diethyl ether, the solvent was evaporated, and the product was purified by vacuum distillation.

(B) Reduction process: A solution of sodium borohydride (0.38 g, 10 mmol) in ethanol (20 ml) was kept at 0 ° C., and a solution of the difluoromethylphenyl ketone (5.1 g, 33 mmol) obtained in (a) in ethanol (20 ml) was added to this solution. Dropped. After stirring at room temperature for 4 hours, the solvent was distilled off and the reaction was terminated with a saturated ammonium chloride aqueous solution. The resulting oil was extracted with diethyl ether, the solvent was evaporated, and the product was purified by vacuum distillation.

(C) Acylation step: 1-phenyl-2,2-difluoroethanol (1.6 g, 10
Methylene chloride solution (20 mmol), acetyl chloride (0.85 ml, 12 mmol) and pyridine (1.6 ml, 20 mmol).
(ml) was stirred at room temperature for 6 hours, and then the reaction was terminated with 1N hydrochloric acid. The resulting oily matter was extracted with methylene chloride, the solvent was distilled off, and then a mixed solvent of hexane and ethyl acetate (5: 1)
Was purified by silica gel column chromatography.

(D) Hydrolysis step: 1-Phenyl-2,2-difluoroethyl acetate (1.0 g, 5 mmol) was suspended in distilled water (50 ml), and lipase MY (2.5 g, manufactured by Meito Sangyo Co., Ltd.) was further added to the suspension. Suspended. The suspension is kept at 40 to 41 ° C. and stirred for 2 hours, ethyl acetate is added, the mixture is stirred, and the suspension is centrifuged. After removing the organic layer, the aqueous layer is extracted again. After the solvent was distilled off, the product was subjected to silica gel column chromatography using a mixed solvent of hexane and ethyl acetate (5: 1) to separate and purify the alcohol form and the acetate form.

The physical properties of the obtained 1-phenyl-2,2-difluoroethanol are shown below.

Molecular weight 158 Boiling point 93-94 ° C / 10mmHg Rf 0.44 (4: 1) ¹⁹ F NMR δ (ppm) 47.0 [dd, J (CHF ₂ ) = 52.0Hz, J (CH F ₂ C H ) = 10.0Hz] ¹ H NMR δ (ppm) 2.93 (bs, 1H, OH), δ4.56 [dt, J (CH F ₂ C H ) = 10.2 Hz, J (C H ₂ C H ) = 4.8 Hz, 1H, CH], δ5 .66 [dt, J (CHF ₂ ) = 53.1Hz, J (C H F ₂ C H ) = 4.8Hz, 1H, CHF ₂ ], δ7.3 (bs, 5H, Ph) IR 3400 (OH), 1455 (Ph) (cm ⁻¹ ) Reference Example 1B Reference Example 1A 1-phenyl-2,2-difluoroethyl acetate obtained in (d) (0.54 g, 2.7 mmol) was suspended in distilled water (25 ml). To the suspension and cellulase T
(Amano Pharmaceutical Co., Ltd.) 0.68 g was suspended. 40 ~ 4 of this suspension
The mixture was kept at 1 ° C and stirred for 1 hour to react. Then, purification and separation were carried out in the same manner as in Reference Example 1A (d) to obtain (-)-1-phenyl-2,2-difluoroethanol. The physical properties of this product were ( S ) -obtained in Example 1A (d).
It was the same as (+)-1-phenyl-2,2-difluoroethanol.

Furthermore, the following compound could be produced in the same manner as in Reference Example 1A.

1) (+)-1,1-difluoro-3-phenyl-2-propanol (use benzyl Grignard reagent instead of phenyl Grignard reagent in Reference Example 1A (a)) Molecular weight 172 Boiling point 100 to 102 ° C / 10mmHg Rf 0.52 (3: 1) ¹⁹ F NMR δ (ppm) 50.0 [dd, J (CHF ₂ ) = 51.0Hz, J (CH F ₂ C H ) = 10.0Hz] ¹ H NMR δ (ppm) 2.06 (bs, 1H, OH), δ 2.68 [dd, J (CH _a H _b ) = 13.8 Hz, J (C H _a H _b C H ) = 8.1 Hz, 1 H, C H _a H _b ], δ2.92 [dd, J (CH _a H _b ) = 13.8 Hz, J (CH _a H _b C H ) = 4.2 Hz, 1 H, CH _a H _b ], δ3.80 [dtt, J ( C H F ₂ C H ) = J (C H CH _a H _b ) = 4.2Hz, J (C H C H _a H _b ) = 8.1Hz, J (CH F ₂ C H ) = 10.0Hz, 1H, CH ], Δ5.52 [dt, J (CHF ₂ ) = 55.8Hz, J (C H F ₂ C H ) = 4.2Hz, 1H, CHF ₂ ], δ7.1 to 7.4 (m, 5H, Ph) IR 3400 (OH) (cm ^-1 ) 2) (+)-1,1-difluoro-4-phenyl-2-butanol (Note that β-phenethyl Grignard reagent was used instead of the phenyl Grignard reagent in Reference Example 1A (a). ) Molecular weight 186 Boiling point 116-118 ℃ / 11mmHg Rf 0.25 (5: 1) ¹⁹ F NMR δ (ppm) 49.7 [dd, J (CHF ₂ ) = 51.0Hz, J (CH F ₂ C H ) = 10.0Hz] ¹ H NMR δ (ppm) 1.6 to 2.2 (m, 2H, CHC H ₂ CH ₂ ), δ2.05 (bs, 1H, OH), δ2.5 to 3.1 (m, 2H, C H ₂ Ph), δ3.3 ~ 3.9 (m, 1H, C H OH), δ5.50 [dt, J (CHF ₂ ) = 56.7Hz, J (C H F ₂ C H ) = 4.5Hz, 1H, CHF ₂ ], δ7.1〜 7.4 (m, 5H, Ph) IR 3400 (OH) (cm ^-1 ) Further, the 1,1-difluoro-4-phenyl-2-butylacetate obtained in this process was hydrolyzed in the same manner as in Reference Example 1B. Decomposition gave (-)-1,1-difluoro-4-phenyl-2-butanol. The physical properties of this product were the same as those of (+)-1,1-difluoro-4-phenyl-2-butanol described above.

3) ( R )-(+)-1,1-difluoro-2-octanol (Note that n-hexyl Grignard reagent was used in place of the phenyl Grignard reagent in Reference Example 1A (a)) Molecular weight 166 ¹⁹ F NMR δ (ppm) 47.2 [ddd, J (CH F _a F _b ) = 264.8 Hz, J (CH F _a F _b ) = 52.7 Hz, J (CH F _a F _b C H ) = 10.2 Hz , CH F _a F _b ], δ52.8 [ddd, J (CH F _a F _b ) = 264.8 Hz, J (C H F _a F _b ) = 52.4 Hz, J (CH F _a F _b C H ) = 10.4 Hz, CHF _a F _b ] ¹ H NMR δ (ppm) 0.7 to 1.7 (m, 13H), δ2.4 (bs, 1H, 0H), δ3.3 to 3.9 (m, 1H, CH), δ5.8 [Dt, J (CHF ₂ ) = 49.3Hz, J (C H F ₂ C H ) = 4.0Hz, 1H, CHF ₂ ] IR 3400 (OH), 2940 (CH ₂ ) (cm ^-1 ) 4) ( R )-(+)-1,1-difluoro-2-decanol (Note that n-octyl Grignard reagent is used in place of the phenyl Grignard reagent in Reference Example 1A (a)) Molecular weight 194 Boiling point 110-112 ° C / 16mmHg ¹⁹ F NMR δ (ppm) 47.2 [ddd, J (CH F _a F _b ) = 274.7 Hz, J (C HF _a F _b ) = 54.6 Hz, J (CH F _a F _b C H ) = 11.1 Hz, CH F _a F _b ], δ52.2 [ddd, J (CH F _a F _b ) = 274.7 Hz, J (C H F _a F _b ) = 54.6 Hz, J (CHF _a F _b C H ) = 11.1 Hz, CHF _a F _b ] ¹ H NMR δ (ppm) 0.7 to 1.0 (bt, J = 7.5 Hz, 3H, CH ₃ ), δ1.1 to 1.7 (m, 14H), δ2 .07 (bs, 1H, OH), δ3.4 to 3.9 (m, 1H, CH), δ5.50 [dt, J (CHF ₂ ) = 56.4Hz, J (C H F ₂ C H ) = 4.5Hz , 1H, CHF ₂ ] IR 3375 (OH), 2925 (CH ₂ ) (cm ⁻¹ ) Further, 1,1-difluoro-2-decylacetate obtained in this process was hydrolyzed in the same manner as in Reference Example 1B. ,
( S )-(-)-1,1-difluoro-2-decanol was obtained. The physical properties of this product are ( R )-(+)-1,
It is the same as 1-difluoro-2-decanol, and its structural formula is as follows.

Example 1A ( R )-(+)-4,4-difluoro-3-hydroxybutyric acid ethyl ester A solution of lithium diisopropylamide (200 mmol) in diethyl ether (100 ml) was kept at -70 ° C, and a solution of ethyl acetate (19.5 ml, 200 mmol) in diethyl ether (30 ml) was added dropwise to the solution. This solution was kept at -70 ° C and stirred for 1 hour, and then difluoroacetic acid ethyl ester (12.4 g, 100 mmol) in diethyl ether (40 m
l) was gradually added dropwise. The solution was kept at -70 ° C and stirred for 4 hours, and then the reaction was terminated with a saturated aqueous solution of ammonium chloride. The resulting oil was extracted with diethyl ether,
After distilling off the solvent, the product was purified by vacuum distillation.

(B) The racemic 4,4-difluoro 4,4-difluoroacetoacetic acid ethyl ester produced in (a) above was reduced with sodium borohydride in ethanol in the same manner as in b) of Reference Example 1A. -3-Hydroxybutyric acid ethyl ester was obtained.

(C) 4,4-difluoro-3-prepared in (b) above
Hydroxybutyric acid ethyl ester was acetylated with acetyl chloride in methylene chloride in the presence of pyridine in the same manner as in (c) of Reference Example 1A to obtain 4,4-difluoro-3-acetoxybutyric acid ethyl ester.

(D) 4,4-difluoro-3-prepared in (c) above
Acetoxybutyric acid ethyl ester was hydrolyzed with lipase MY in the same manner as in (d) of Reference Example 1A to give ( R )-
(+)-4,4-Difluoro-3-hydroxybutyric acid ethyl ester was obtained.

The physical properties of the product obtained were as follows:

Molecular weight 168 Boiling point 115-116 ° C / 71 mmHg ¹⁹ F NMR δ (ppm) 49.0 [ddd, J (CH F _a F _b ) = 266.0 Hz, J (CH F _a F _b ) = 52.3 Hz, J (CH F _a F _b C H ) = 10.8 Hz, CH F _a F _b ], δ50.3 [ddd, J (CH F _a F _b ) = 266.0 Hz, J (C H F _a F _b ) = 52.8 Hz, J (CHF _a F _b C H ) = 12.5 Hz, CHF _a F _b ] ¹ H NMR δ (ppm) 1.34 [t, J = 7.2 Hz, 3H, CH ₃ ], δ2.57 [dd, J (C H _a H _b ). = 17.4Hz, J (C H _a H _b C H ) = 7.2Hz, 1H, C H _a H _b ], δ2.73 [dd, J (C H _a H _b ) = 17.4Hz, J (CH _a H _b C H ) = 15.9Hz, 1H, CH _a H _b ], δ3.74 [bs, 1H, OH], δ4.22 [q, J = 7.2Hz, 2H, CH ₂ ], δ5.73 [dt, _{J (C H F 2) =} 56.3Hz, J (C H F 2 C H) = 3.9Hz, 1H, CHF 2 ] IR 3450 (OH), 3000 ( CH 2), 1725 (C = O) (cm - ¹ ) Table 1 shows the hydrolysis rates in Reference Examples 1A and B and Example 1A, and the optical rotation and optical purity of the obtained products.

In addition, ( S )-(-)-4,4-difluoro- showing the optical rotation opposite to that of ( R )-(+)-4,4-difluoro-3-hydroxybutyric acid ethyl ester obtained in Example 1A. 3-
An example of the production of hydroxybutyric acid ethyl ester is shown in Example 1B.

Example 1B (+)-4,4-difluoro-3-acetoxybutyric acid ethyl ester (1.87 g, 8.9 mmol) obtained in (d) of Example 1A was suspended in distilled water (90 ml). Cellulase T (2.22 g, manufactured by Amano Pharmaceutical Co., Ltd.) was further suspended in the liquid.
The suspension was kept at 40 to 41 ° C. and stirred for 5 hours, ethyl acetate was added, the mixture was stirred, and the suspension was centrifuged. After taking out the organic layer, the aqueous layer was extracted again. After the solvent was distilled off, the product was purified and isolated by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate (5: 1), and ( S )-(-)-4,4-difluoro-3. -Hydroxybutyric acid ethyl ester was obtained. In this reaction, the hydrolysis rate was 100%, and the specific optical rotation [α] _D of the obtained ( S )-(−)-4,4-difluoro-3-hydroxybutyric acid ethyl ester was −11.86 ( The concentration in chloroform was 1.16), and the structural formula was as follows.

Example 1C (1) (−)-1,1-difluoro-3-phenyl-2-
Synthesis of propanol Reference Example 1A except that in Example 1A (a), a benzyl Grignard reagent was used in place of the phenyl Grignard reagent, and Lipase P (manufactured by Amano Pharmaceutical Co.) was used in place of Lipase MY in (d). (A) ~
The same operation as in the step (d) was performed to obtain (-)-1,1-difluoro-3-phenyl-2-propanol. The physical properties of this product are (+)-1,1-difluoro-3-
Same as phenyl-2-propanol.

(2) (-)-1,1-difluoro-4-phenyl-2-
Synthesis of butanol Reference Example 1A (a), except that β-phenethyl Grignard reagent was used instead of the phenyl Grignard reagent, and Lipase P (manufactured by Amano Pharmaceutical Co., Ltd.) was used instead of Lipase MY in (d) Example 1A (a) ~
The same operation as in the step (d) was performed to obtain (-)-1,1-difluoro-4-phenyl-2-butanol. The physical properties of this product were the same as (+)-1,1-difluoro-4-phenyl-2-butanol.

(3) Synthesis of ( S )-(-)-1,1-difluoro-2-octanol In Reference Example 1A (a), n-hexyl Grignard reagent was used instead of phenyl Grignard reagent, and lipase was used in (d). (A) of Reference Example 1A except that Lipase P (manufactured by Amano Pharmaceutical Co., Ltd.) was used instead of MY.
By performing the same operation as in the step (d), ( S )-(-)-
1,1-difluoro-2-octanol was obtained. The physical properties of this product are ( R )-(+)-1,1-difluoro-2
-Same as octanol.

(4) Synthesis of ( S )-(-)-1,1-difluoro-2-decanol In Reference Example 1A (a), n-octyl Grignard reagent was used instead of phenyl Grignard reagent, and lipase was used in (d). (A) of Reference Example 1A except that Lipase P (manufactured by Amano Pharmaceutical Co., Ltd.) was used instead of MY.
By performing the same operation as in the step (d), ( S )-(-)-
1,1-difluoro-2-decanol was obtained. The physical properties of this product are ( R )-(+)-1,1-difluoro-2-
It was the same as decanol.

(5) Synthesis of ( S )-(-)-4,4-difluoro-3-hydroxybutyric acid ethyl ester Except that Lipase P (manufactured by Amano Pharmaceutical Co., Ltd.) was used in place of Lipase MY in Example 1A (d). Then, the same operation as in the steps (a) to (d) of Example 1A was carried out to obtain ( S )-
(-)-4,4-Difluoro-3-hydroxybutyric acid ethyl ester was obtained. The physical properties of this product are ( R )-
The same as (+)-4,4-difluoro-3-hydroxybutyric acid ethyl ester.

The results of these Examples 2C (1) to (5) are shown in Table 1A.

Reference Example 2 Synthesis of ( R )-(-)-1-phenyl-2-chloro-2,2-difluoroethanol (A) Synthesis of chlorodifluoromethylphenylketone A solution of phenyl Grignard reagent (44 mmol) in diethyl ether was slowly added dropwise to a solution of chlorodifluoroacetic acid methyl ester (5.8 g, 40 mmol) in diethyl ether at -70 ° C. The solution was kept at -70 ° C and stirred for 4 hours, and then the reaction was terminated with a saturated aqueous solution of ammonium chloride. The resulting oil was extracted with diethyl ether,
The solvent was distilled off and the product was purified by vacuum distillation.

(B) Reduction step A solution of sodium borohydride (0.38 g, 10 mmol) in ethanol (20 ml) was kept at 0 ° C., and this solution was mixed with chlorodifluoromethylphenylketone (3.8
g, 20 mmol) in ethanol (20 ml) was added dropwise.
After stirring at room temperature for 4 hours, the solvent was distilled off and the reaction was terminated with a saturated ammonium chloride aqueous solution. The resulting oil was extracted with diethyl ether, the solvent was distilled off, and the product was purified by distillation under reduced pressure.

(C) Acylation (acetylation) step 1-phenyl-2-chloro-2,2- produced in (b)
Difluoroethanol (1.1 g, 6 mmol), pyridine (1.0 ml, 12 mmol) and acetyl chloride (0.5 ml, 12 mmol) in methylene chloride (20 ml) were stirred at room temperature for 6 hours and then the reaction was terminated with 1N hydrochloric acid. Let The resulting oily matter was extracted with methylene chloride, the solvent was evaporated, and the residue was purified by silica gel chromatography using a mixed solvent of hexane and ethyl acetate (5: 1).

(D) Asymmetric hydrolysis 1-Phenyl-2-chloro-2,2-difluoroethyl acetate (0.9 g, 4 mmol) was suspended in distilled water (40 ml), and further lipase MY (2.0 g, name sugar). (Manufactured by Sangyo) was suspended. After keeping this suspension at 40-41 ° C and stirring for 2 hours,
Ethyl acetate was added, stirred and the suspension was centrifuged. After removing the organic layer, the aqueous layer is extracted again. After the solvent was distilled off, the product was separated and produced into an alcohol form and an acetate form by silica gel chromatography using a mixed solvent of hexane and ethyl acetate (5: 1).

The physical properties of the obtained ( R )-(-)-1-phenyl-2-chloro-2,2-difluoroethanol were as follows.

Molecular weight 192.5 boiling ^{99~100 ℃ / 11mmHg 19 F NMR δ} (ppm) -12.7 _{[dd, J (C F a F} b C1) = 170Hz, J (C F a F b C1C H) = 8Hz ], [delta]-15.9 [Dd, J (C F _a F _b C1) = 170 Hz, J (CF _a F _b C1 C H ) = 8 Hz] ¹ H NMR δ (ppm) 3.0 (bs, 1H, OH), δ4.9 [bt, J _{(C F a F b C1C H} ) = 7.8Hz, 1H, CF 2 C1C H ], δ7.2~7.5 (m, 5H, Ph ) IR 3430 (OH) (cm -1) same manner as in reference example 2 It was possible to produce the following compound.

1A) (+)-1-chloro-1,1-difluoro-3-phenyl-2-propanol (the benzyl Grignard reagent is used in place of the phenyl Grignard reagent in Example 3 (a)) Molecular weight 206.5 Boiling point 106 ° C. ^{/ 9mmHg 19 F NMR δ (ppm} ) -12.1 _{[dd, J (C F a F} b C1) = 170Hz, J (C F a F b C1C H) = 8Hz ], [delta]-15.3 [dd, J (C F _a F _b C1) = 170 Hz, J (CF _a F _b C1 C H ) = 8 Hz] ¹ H NMR δ (ppm) 2.69 [dd, J (C H _a H _b ) = 15.0 Hz, J (C H C H _a H _b ) = 9.8 Hz, 1H, C H _a H _b ], δ2.80 [bs, 1H, OH], δ3.00 [dd, J (C H _a H _b ) = 15.0 Hz, J (C H CH _a H _b ) = 3.0Hz, 1H, CH _a H _b ], δ3.7 to 4.1 (m, 1H, CH), δ7.0 to 7.3 (m, 5H, Ph) IR 3440 (OH) (cm ^-1 1B) 1-chloro-1, obtained in the enzymatic hydrolysis step of 1A) above,
1-Difluoro-3-phenyl-2-propyl acetate was added to acetone (3 ml), 2N aqueous sodium hydroxide solution (3 m
l) was added dropwise to the mixed solvent, the solution was stirred at room temperature for 12 hours, and then the solution was neutralized with 1N hydrochloric acid to terminate the reaction. The obtained oily matter was extracted with methylene chloride, the solvent was distilled off, and the residue was purified by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate (5: 1).

2) (+)-1-chloro-1,1-difluoro-4-phenyl-2-butanol (Note that β-phenethyl Grignard reagent is used in place of the phenyl Grignard reagent in Reference Example 2 (a)) Molecular weight 220.5 Boiling point 106 ° C / 9 mmHg ¹⁹ F NMR δ (ppm) -12. 1 [dd, J (C F _a F _b C 1) = 171 Hz, J (C F _a F _b C 1 C H ) = 8 Hz], δ-15.2 [dd, J ( C F _a F _b C 1) = 171 Hz, J (CF _a F _b C ¹ C H ) = 8 Hz] ¹ H NMR δ (ppm) 1.5 to 2.2 (m, 2H, C H ₂ CH ₂ Ph), δ 2.2 to 2.5 (bd, 1H, OH), δ2.5 to 3.1 (m, 2H, CH ₂ C H ₂ Ph), δ3.6 to 4.0 (m, 1H, CH), δ7.0 to 7.3 (m, 5H, Ph) IR 3250 (OH) (cm ^-1 ) 3) ( R )-(+)-1-chloro-1,1-difluoro-
2-Octanol (Note that n-hexyl Grignard reagent is used in place of the phenyl Grignard reagent in Reference Example 2 (a)) Molecular weight 200.5 Boiling point 99 ° C./30 mmHg ¹⁹ F NMR δ (ppm) -11.9 [dd, J (CC1 F _a F _b ) = 169 Hz, J (CC1 F _a F _b C H ) = 8 Hz], δ-15.1 [dd, J (CC1 F _a F _b ) = 169 Hz, J (CC1 F _a F _b C H ) = 8 Hz] ¹ H NMR δ (ppm) 0.8. To 2.0 (m, 13H), δ 2.2 to 2.4 (bd, 1H, OH), δ 3.6 to 4.1 (m, 1H, CC1F ₂ C H ) IR 3400 (OH) (Cm ⁻¹ ) 4) ( R )-(+)-1-chloro-1,1-difluoro-
2- decanol (Note, reference example using n- octyl Grignard reagent in place of the phenyl Grignard reagent in 2 (a)) molecular weight ^{228.5 19 F NMR δ (ppm)} -11.7 _{[dd, J (C F a F} b C1) = 170Hz, J (C F _a F _b C1C H ) = 8Hz], δ-15.3 [dd, J (C F _a F _b C1) = 170 Hz, J (CF _a F _b C1C H ) = 8Hz] ¹ H NMR δ (ppm) 0.8 to 2.1 (m, 17H), δ 2.1 (bs, 1H, OH), δ 3.7 to 4.1 (m, 1H, CH) IR 3350 (OH) (cm ^-1 ) 5) ( R )-(+)-4-chloro-4,4-difluoro-
3-Hydroxybutyric acid ethyl ester The same operation as in Example 2A was performed except that chlorodifluoroacetic acid methyl ester was used in place of difluoroacetic acid ethyl ester in Example 1A. However, hydrolysis was performed for 40 minutes using lipase MY. as a result,
( R )-(+)-4-chloro-4,4-difluoro-3-
Hydroxybutyric acid ethyl ester was obtained with a hydrolysis rate of 24%.

Structural formula The physical properties of the product obtained were as follows:

Molecular weight 202.5 Boiling point 109 ° C / 65mmHg ¹ H NMR δ (ppm) 1.28 [t, J = 7.2Hz, 3H, OCH ₂ C H ₃ ], δ2.52 [dd, J = 7.8Hz, J = 16.8Hz, 1H, COHC H _a H _b CO], δ 2.75 [dd, J = 4.8 Hz, J = 16.8 Hz, 1H, COHCH _a H _b CO], δ 3.5 to 4.0 [m, 1 H, OH], δ 4.13 [ q, J = 7.2Hz, 2H, OC H 2 CH 3 ], Deruta4.45 [dq, J = 4.8Hz, J = 7,8Hz, 1H, C H OH ] ^{IR 3450 (OH) (cm -1} ) reference The hydrolysis rate and optical rotation and optical purity of the product in Example 2 are shown in Table 2 below.

Reference Example 2A (1) ( S )-(+)-1-phenyl-2-chloro-2,
Synthesis of 2-difluoroethanol 1-phenyl-obtained in the hydrolysis step (d) of Reference Example 2
2-Chloro-2,2-difluoroethyl acetate was treated in the same manner as in 1B) of Reference Example 2 to give ( S )-(+)-1.
-Phenyl-2-chloro-2,2-difluoroethanol was obtained. The physical properties of this product are ( R )-(-)-1
Same as -phenyl-2-chloro-2,2-difluoroethanol.

(2) Synthesis of (−)-1-chloro-1,1-difluoro-4-phenyl-2-butanol 1-chloro-1,1-difluoro-4-phenyl-2 obtained in 2) of Reference Example 2 -Butyl acetate is used in Reference Example 2-1.
Perform the same operation as in (B), and then (-)-1-chloro-1,1-
Difluoro-4-phenyl-2-butanol was obtained. The physical properties of this were the same as (+)-1-chloro-1,1-difluoro-4-phenyl-2-butanol.

(3) Synthesis of ( S )-(-)-1-chloro-1,1-difluoro-2-octanol The 1-chloro-1,1-difluoro-2-octylacetate obtained in 3) of Reference Example 2 was subjected to the same operation as in 1B) of Reference Example 2 to give ( S )-(-)-1-chloro. -1,1-Difluoro-2-octanol was obtained. The physical properties of this product were the same as those of ( R )-(+)-1-chloro-1,1-difluoro-2-octanol.

(4) Synthesis of ( S )-(-)-1-chloro-1,1-difluoro-2-decanol 1-Chloro-1,1-difluoro-2-decylacetate obtained in 4) of Reference Example 2 was subjected to the same operation as in 1B) of Reference Example 2 to give ( S )-(-)-1-chloro-1. There was obtained 1,1-difluoro-2-decanol. The physical properties of this product are ( R )-(+)-1-chloro-1,1-difluoro-
It was the same as 2-decanol.

 The results are shown in Table 2A.

Example 2 (-)-1,1,1,2,2-pentafluoro-5-phenyl-
Synthesis of 3-pentanol (a) Pentafluoropropionic acid ethyl ester (5.
8 g, 30 mmol) in tetrahydrofuran (30 ml)
, Β-phenethylmagnesium bromide (β
A solution of (phenethyl Grignard reagent) (33 mmol) in tetrahydrofuran was slowly added dropwise. This solution was kept at -70 ° C and stirred for 3 hours, and then the reaction was terminated with a saturated aqueous solution of ammonium chloride. The resulting oily substance was extracted with diethyl ether, the solvent was distilled off, and the product was purified by distillation under reduced pressure.

(B) Sodium borohydride (0.44 g, 11.6 mmol)
The ethanol solution (35 ml) of the above was kept at 0 ° C., and the solution of pentafluoroethyl β-phenethyl ketone (2.2 g, 9.3 mmol) prepared in (a) was added to this solution (10 ml).
Was dripped. After stirring at room temperature for 24 hours, the solvent was distilled off,
The reaction was terminated with a saturated aqueous solution of ammonium chloride. The resulting oily substance was extracted with diethyl ether, the solvent was evaporated, and the product was purified by silica gel chromatography using a mixed solvent of hexane and ethyl acetate (3: 1).

(C) To a solution of 1,1,1,2,2-pentafluoro-5-phenyl-3-pentanol (2.2 g, 9 mmol) and pyridine (1.48 ml, 18.3 mmol) in methylene chloride (10 ml). Acetyl chloride (0.78 ml, 11 mmol) was added dropwise, the mixture was stirred at room temperature for 3 hours, and then the reaction was terminated with 1N hydrochloric acid. The resulting oily matter was extracted with methylene chloride, the solvent was distilled off, and the product was purified by silica gel chromatography using a mixed solvent of hexane and ethyl acetate (5: 1).

(D) 1,1,1,2,2-pentafluoro-5-phenyl-3
-Lipase P (3.8 g, manufactured by Amano Pharmaceutical Co., Ltd.) was suspended in a suspension of pentyl acetate (2.2 g, 7.6 mm) in distilled water (80 ml). Keep this suspension at 40-41 ° C,
After stirring for 43 hours, ethyl acetate (80 ml) was added and stirred, and this solution was passed through a Celite layer. After separating the organic layer, the aqueous layer was extracted again with ethyl acetate. After the solvent was distilled off, the product was separated and purified by silica gel chromatography using a mixed solvent of hexane and ethyl acetate (10: 1). The hydrolysis rate in this example was 61%. The physical properties of this product were as follows.

Molecular weight 242 Rf 0.64 (3: 1) ¹⁹ F NMR δ (ppm) 2.8 (s, 3F, C F ₃ CF ₂ ), δ43.3 [dd, J (C F _a F _b ) = 266Hz, J (C F _a F _b C H ) = 7.5Hz, 1F, CF ₃ C F _a F _b ], δ50.8 [dd, J (C F _a F _b ) = 266Hz, J (C F _a F _b C H ) = 13.2 _{Hz, 1F, CF 3 CF a} F b ] ^{1 H NMR δ (ppm) 2.0} (m, 3H, C H 2 Ph, OH), δ2.8 (m, 2H, C H 2 CH 2 Ph), δ3. 9 (m, 1H, C H (OH)), δ7.0 to 7.4 (m, 5H, Ph) IR 3400 (OH) (cm ^-1 ) In a similar manner (however, in (a) above, β-phenethyl) N-hexyl Grignard reagent is used instead of Grignard reagent), (+)-1,1,1,2,2-pentafluoro-
3-Nonanol was obtained with a hydrolysis rate of 24% in 5 hours. The physical properties of this product were as follows.

Molecular weight 234 Boiling point 73-74 / 50 mmHg ¹⁹ F NMR δ (ppm) 4.0 (s, 3F, CF ₃ ), δ44.0 [dd, J (C F _a F _b ) = 269.5 Hz, J (C F _a F _b C H ) = 7.5Hz, 1F, CF ₃ C F _a F _b ], δ52.3 [dd, J (C F _a F _b ) = 269.5Hz, J (CF _a F _b C H ) = 16.0Hz, 1F , CF ₃ CF _a F _b ] ¹ H NMR δ (ppm) 1.0 (brt, 3H, CH ₃ ), δ1.2 to 2.2 (m, 10H, (CH ₂ ) ₅ ), δ3.2 [d, J ( OHCH) = 8.4Hz, 0H], δ4.17 (m, 1H, C H (OH)) IR 3400 (OH) (cm ^-1 ) In the same manner (however, in (a) above, β-phenethyl) N-octyl Grignard reagent is used in place of Grignard reagent, isobutyryl chloride is used in place of acetyl chloride in (c), and lipase MY (manufactured by Meito Sangyo) is used in place of lipase P in (d)) , (+)-
1,1,1,2,2-pentafluoro-3-undecanol is 1
It was obtained with a hydrolysis rate of 60% in 86 hours. The physical properties of this product were as follows.

Molecular weight 262 Boiling point 110-112 / 60 mmHg ¹⁹ F NMR δ (ppm) 4.0 (s, 3F, CF ₃ ), δ43.6 [dd, J (C F _a F _b ) = 268 Hz, J (C F _a F _b C H ) = 7.5Hz, 1F, CF ₃ C F _a F _b ], δ52.0 [dd, J (C F _a F _b ) = 268 Hz, J (CF _a F _b C H ) = 16.0 Hz, 1F, CF ₃ CF _a F _b ] ¹ H NMR δ (ppm) 0.9 (m, 3H, CH ₃ ), δ1.33 (m, 14H, (CH ₂ ) ₇ ), δ3.6 [t, J (C H C H ₂ ) = 6.0 Hz, CH (OH)], δ4.0 (bs, 1H, OH) IR 3400 (OH) (cm ⁻¹ ) Table 3 shows the optical rotation and optical purity of the obtained compound.

Reference Example 3 1-Phenyl-2,2- was operated in the same manner as in Reference Example 1 except that the type of acylating agent (acyl group represented by R'CO) and the type of enzyme used in the step (c) were varied. Difluoroethanol was produced, the optical purity was measured, and the results are shown in Table 4 below.

[Effects of the Invention] As described above, the optically active difluoroalcohol derivative according to the present invention has a remarkably high optical purity and is expected to be widely and effectively used as various pharmaceuticals including liquid crystal, or an intermediate thereof. To be done.

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Claims (1)

(57) [Claims] 1. A general formula [Wherein R is an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or (R ¹ is hydrogen or an alkyl group having 1 to 4 carbon atoms, R ² is an alkyl group having 1 to 10 carbon atoms), and X is hydrogen, chlorine, bromine or C _n X ¹ _{2n + 1} (n is 1 to
Is an integer of 8 and X ¹ is at least one atom selected from fluorine, chlorine, and bromine.]].