JPH01163143A - Optically active difluoroalcohol derivative - Google Patents

Abstract

NEW MATERIAL:An optically active difluoroalcohol derivative shown by formula I [R is 1-10C alkyl, 7-10C aralkyl, 6-10C aryl or group shown by formula V (R<1> is H or 1-4C alkyl; R<2> is 1-10C alkyl); X is H, Cl, Br or CnX<1>2n+1 (n is 1-8 integer; X<1> is at least one atom selected from F, Cl and Br)]. EXAMPLE:(S)-(+)-1-Phenyl-2, 2-difluoroethanol. USE:A raw material for esters, ethers and carboxylic acids useful as ferroelectric liquid crystal, preformed chemical mediators, anti-cancers and antienzyme. PREPARATION:A compound shown by formula II is reduced with a reducing agent to give a compound shown by formula III, which is acylated by a conventional method to give a compound (racemic modification) shown by formula IV (COR' is acyl). Then this compound is asymmetrically hydrolyzed with an enzyme to give a compound shown by formula I having high optical purity.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to esters used as ferroelectric liquid crystals, physiologically active substances, anticancer agents, and enzyme inhibitors.

This invention relates to optically active difluoroalcohol derivatives useful as raw materials for ethers and carboxylic acids.

[Prior art and problems to be solved by the invention] Some compounds have been reported as optically active fluorine-containing carbinol applied to liquid crystals, pharmaceuticals, etc. However, there are no fluorine-containing compounds that are satisfactory in terms of optical purity. Optically active carbinol has not yet been reported. Therefore, an object of the present invention is to provide a novel optically active fluorine-containing carbinol with high optical purity.

[Means to solve the problem]

In particular, the present inventors investigated various types of optically active carbinol having a fluoromethyl group at the end, and found that optically active fluorinated carbinol with high optical purity can be obtained by asymmetric hydrolysis using an enzyme. , completed the invention.

The present invention is based on the general formula: [In the formula, R is an alkyl group having 1 to 10 carbon atoms.

An aralkyl group having 7 to 10 carbon atoms, the number of carbon atoms (in the formula, R1 is hydrogen or an alkyl group having 1 to 4 carbon atoms, and R2 is an alkyl group having 1 to 10 carbon atoms), is hydrogen, chlorine, bromine or C7X'! ,,.

+ (n is an integer of 1 to 8, and X' is at least one atom selected from fluorine, chlorine, and bromine)]. .

There are various types of difluoroalcohol derivatives of general formula (1) according to the present invention depending on the types of substituents R and X.
All of them are optically active compounds in which the asymmetric center is the carbon atom bonded to the hydroxyl group (CH). R is an alkyl group having 1 to 10 carbon atoms (e.g., methyl group, ethyl group, propyl group, butyl group, isobutyl group, he=1=syl group, octyl group, nonyl group, etc.), a carbon atom as described above. Number 7 to 10 aralkyl groups (benzyl group, phenethyl group, etc.), carbon atom #! j, 6-10 aryl group (
phenyl group, tolyl group, parachlorophenyl group, metachlorophenyl group, etc.) or the formula -CH-C-
0R"R' 0 (For example, CH, CO□Et, CH2C02C8HI?
.

CH(CH3)Co□Et, etc.). Regarding X, hydrogen, chlorine, bromine or the formula c, x'□1°.

(For example, CF3.CC1FI C2F5.CBrF
z.

CF　z　CF　z　Cl, etc.).

There are various specific examples of such optically active difluoroalcohols of the present invention, and in addition to those described in the Examples below, CHFzCHCH(CH3)COzEt.

H CCI Fz CHCH (CH3) CO□Etsho etc.

By the way, this difluoroalcohol can be produced by various methods, but for boat fishing, it can be produced by the following reaction formula.

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

Next, each manufacturing process will be explained in detail.

First Step ゛-Step 0 D A fluorine-containing carbinol derivative of the general formula (I[[) is produced by reducing the fluorine-containing ketone of the general formula (It) with a reducing agent. The reducing agent that can be used in this step is any reducing agent commonly used to reduce carbonyl groups to hydroxyl groups (eg, sodium borohydride, lithium aluminum hydride.

Examples include palladium-carbon/hydrogen, tin chloride, and the like.

Further, in carrying out the reduction reaction, it is preferable to use an alcohol such as ethanol or isopropanol as a solvent, and the reaction temperature may be set at any temperature from low to high temperature, but it is preferable to carry out the reaction at room temperature.

The starting material of the general formula (II) used in this step is, as shown in the formula below, a fluorine-containing alkyl ester derivative such as a fluorine-containing ethyl ester in an inert solvent such as diethyl ether or tetrahydrofuran. Either react with an organometallic reagent such as a Grignard reagent (RMgX', where X' is a halogen atom) or organolithium (RLi) at 40 to -70°C, or react the fluorine-containing alkyl ester derivative in an inert solvent such as diethyl ether. In the presence of lithium diisopropylamide (hereinafter referred to as LDA), alkyl esters of aliphatic carboxylic acids (R'
CH2C0OR).

Acylation can be carried out in a conventional manner. Examples of the acylating agent include acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride, octyl chloride, and the like.

The compound of general formula (rV) produced in this step is:
It is racemic.

? 1 Sanko'''5'' 7 \-: The compound obtained in the second step is asymmetrically hydrolyzed with an enzyme to obtain a compound of general formula (1) with high optical purity.

As the enzyme, various so-called hydrolytic enzymes can be used, such as 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 selected. For example, when lipase MY is used, if the alcohol derivative produced is dextrorotatory, the acylated product (I a)
When treated with an enzyme such as cellulase or a basic catalyst such as sodium hydroxide, it becomes a levorotatory alcohol. Furthermore, when lipase P is used, an alcohol having 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.

Example IA Synthesis of (S)-(+)-1-phenyl-2,2-difluoroethanol H MacHF2CHPh (a) Synthesis of difluoromethyl phenyl ketone: Is the diethyl ether of phenyl Grignard reagent (44 mmol) harmful? The mixture was slowly added dropwise to a solution of difluoroacetic acid ethyl ester (4.9 g, 40 mmol) in diethyl ether at -70°C. Keep this solution at -70°C for 4
After stirring for an hour, the reaction was terminated with a saturated aqueous ammonium chloride solution. The resulting oil was extracted with diethyl ether, the solvent was evaporated and the product was purified by vacuum distillation.

(b) Reduction step: ○ OH CHF z cph+ NaBH4->CHF z C
HPhEtol (sodium borohydride (0.38 g, 10 mmol)
A solution of difluoromethyl phenyl ketone (5,
A solution of 1 g, 33 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 aqueous ammonium chloride solution. The resulting oil was extracted with diethyl ether, the solvent was evaporated and the product was purified by vacuum distillation.

(c) Acylation step: ■-Phenyl-2,2-difluoroethanol (1,6
g, IQ mmol), acetyl chloride (0.85 g, 12
After stirring a methylene chloride solution (20 mffi) of pyridine (1.20 mmol) and pyridine (1.6 ml, 1.20 mmol) at room temperature for 6 hours, the reaction was terminated with IN hydrochloric acid. The resulting oil was extracted with methylene chloride, the solvent was distilled off, and then purified by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate (5:1).

(Left below) (d) Hydrolysis step: 1-phenyl-2,2-difluoroethyl acetate (
Lipase MY (2.5 g, manufactured by Meito Sangyo Co., Ltd.) was further suspended in a suspension prepared by suspending 1.0 g, 5 mmol) in distilled water (50%). The suspension is kept at 40-41°C and stirred for 2 hours, then ethyl acetate is added, stirred and the suspension is centrifuged. After removing the organic layer, the aqueous layer is extracted again. After distilling off the solvent, the product was purified by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate (5:1) to separate and purify carbinol and acetate.

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

Molecular weight 158 Boiling point 93-94°C/ 10 mmlmm1l
O,44(4:1)19F NMRδ
(ppm) 4 7. O(dd, J(C
HF z) -52, 01lz, J (CHF2CH
)=10.01(z)'HNMRδ(ppm) 2
．． 93 (BS, L H, OH).

δ4.65 (dt, J(CHF2C and)=10.2
Hz, J (C and F2Cdan) = 4.8Hz, L H
, CH).

δ5.66 (dt, J(CHFz)=53.1Hz
.

J (C and F, C and) = 4.8Hz, L H, CHFz
).

δ7.3 (bs, 5H, Ph) IR3400 (OH), 1455 (Ph)
(cm-') Example IB 1-phenyl-2°2-difluoroethyl acetate obtained in Example IA(d) (0.54 g).

In addition, 0.68 g of Cellulase T (manufactured by Amano Pharmaceutical Co., Ltd.) was suspended in a suspension prepared by suspending 2.7 mmol) in distilled water (25d). This suspension was kept at 40-41°C and stirred for 1 hour to react. Thereafter, it was purified and separated in the same manner as in Example IA (d), and (-)-1-phenyl-2,
2-difluoroethanol was obtained. The physical properties of this material are as follows: (dan)-(+)- obtained in Example IA (d)
It was the same as 1-phenyl-2,2-difluoroethanol.

Furthermore, the following compounds could be produced in the same manner as in Example IA.

1) (+)-1,1-difluoro-3-phenyl-2-
Proper tool (in Example IA (a), benzyl Grignard reagent was used instead of phenyl Grignard reagent) (, HFICHC) (ZPh Chang molecular weight 172 Boiling point 100-102 °C / 10 mmHgRf
O, 52 (3:1) 19F NMR δ (ppm) 50.0 (dd,
J (CHF z) = 51.0H2, J (CHF2
CH) = 10.0112) IHNMRδ (ppm)
2.06 (bs, LH, OR).

62, 68 (dd, J (CH-Hb) = 13.
8Hz.

J (CH, HbCH) = 8.111z, 11i.

C and Hb).

δ2.92 (dd, J (CH-Hb) =
13.811z.

J (CH, and C) = 4.2Hz, IH.

CH, and].

63, 80 (dtt, J (CHF2CH)=J
(CHCHHb) = 4.2 Hz.

J (C and C and -Hb) = 8. Itlz.

J (CHFzCH) = 10.0Hz, L H, CH:
l.

δ5.52 (dt, J (CHFz)-55,8
11z.

J (C and F, C and) -4,2Hz, IH.

CHF2).

67, 1-1.4 (m, 5 H, Ph) IR34
00(OH) (am-')2)(+)-1,
1-Difluoro-4-phenyl-2-butanol (in Example IA (a), β-phenethyl Grignard reagent was used instead of phenyl Grignard reagent) CHFzCHCHzCHzph Molecular weight 186 Boiling point 116-118°C/ 11 mmHgRf
O, 25 (5: 1) 19F NMR δ (ppm) 49.7 (dd
, J (CHF 2) ~51,0Hz, J (C
20 on H)~10.0tlz)'HNMRδ(ppm
) 1.6-2.2 (m, 2H.

CHC and 2CH2).

62.05 (BS, IH, OH).

62,5~3.1 (m, 2H,C and 2Ph)
.

63, 3-3.9 (m, LH, C and OH).

65.50 (dt, J(CHFz)~56.7Hz
.

J (CHFzC and) ~ 4.5Hz, L H, CHFz
).

67, 1-7.4 (m, 5 H, Ph) IR34
00(OH) (cm-') In addition, 1,1-difluoro-4-phenyl-2-butyl acetate obtained in this process was hydrolyzed in the same manner as in Example IB to give (-)
-1,1-difluoro-4-phenyl-2-butanol was obtained. The physical properties of this thing are (+)-1゜1
-difluoro-4-phenyl-2-butanol.

3) (and) -(+) -1,1-difluoro-2-octatool (in Example IA (a), n-hexyl Grignard reagent was used instead of phenyl Grignard reagent) CH CHF z CHCb HIj Molecular weight 166 19F NMRδ (ppm) 47.2 (ddd
.

J (CHFsF b) = 264.8 + 1z.

J(C[F　aF　b)　-52,7Hz.

J(CH-Fm, FbCH) ~10.2tlz, CH and Fb).

δ52.8 (dad, J (CHヱ-F b)~2
64.8Hz, J(C and F, F,) = 52.4Hz
, J (CHF-F bC and) ~10.4) 1z, CH
FaFb), 'HNMRδ (ppm) 0.7-1.7 (m,
13H).

δ2.4 (bs, IH, OH).

δ3.3-3.9 (m, LH, CH).

δ5.8 (dt, J (CHF z) = 49.
3Hz.

J (C and F, C and) ~4.0Hz, L H, CHF
z) IR3400 (OH), 2940 (CHz) (cm
-')4)(and)-(+)-1,1-difluoro-2-
Decanol (n-octyl Grignard reagent was used instead of phenyl Grignard reagent in Example IA (a)) CH CHF z CHCs HIt Molecular weight 194 Boiling point 110-112°C/ 16 mmHg19F
NMRδ (ppm) 47.2 (ddd.

J(CHヱ−Fb)=　274.711z.

J (CHF-F b) -54,6Hz.

J (CHF-FbCH) = 11.1llz.

CH-Fm, Fb).

δ52.2 (ddd, J(CHFaFb)=274.
7Hz.

J(CHF-Fb)=54.6Hz.

J(CHF, FbC and) = 11.1 Hz.

CHF, F,)'HNMRδ (ppm) 0.7-1.0 (bt,
J = 7.5 Hz.

3H, CH,).

61.1-1.7 (m, 14H).

62.07 (bs, IH, OH).

δ3.4-3.9 (m, LH, CH).

65.50 (dt, J(CHFz)~56.4Hz
.

J (CHF, CH) ~ 4.5Hz, I H, CHFz:
]IR3375 (OH), 2925 (CHz)
(cm-') Also, 1,1-difluoro-2-decyl acetate obtained in this process was hydrolyzed in the same manner as in Example IB, and (S)-(-)-1,1-difluoro-2
- Decanol was obtained. The physical properties of this substance are as described above (R
)-(+)-1,l-difluoro-2-decanol, and its structural formula was as follows.

CH MacHF z CHHCIIH17 Example 2A (and)-(+)-4,4-difluoro-3-hydroxyacetic acid ethyl ester ♀H0 II II CHFzCOEt+ CH:+COEt Lithium diisopropylamide (200 mmol) in diethyl ether solution (100d) was maintained at -70°C and ethyl acetate (19.5d.

200 mmol) in diethyl ether (30d) was added dropwise. The solution was kept at -70°C and stirred for 1 hour, then difluoroacetic acid ethyl ester (12.4 g, 1
00 mmol) in diethyl ether 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 ammonium chloride solution. The resulting oil was dissolved in diethyl ether. After extraction and evaporation of the solvent, the product was purified by vacuum distillation.

(b) 4,4-difluoroacetoacetic acid ethyl ester prepared in (a) above in ethanol b of Example IA.
), racemic 4,4-difluoro-3-hydroxybutyric acid ethyl ester was obtained by reduction with sulfur borohydride.

(C) 4,4-difluoro-3 produced in (b) above
-Hydroxybutyric acid ethyl ester of Example IA (C
) to give 4,4-difluoro-3- by acetylation with acetyl chloride in the presence of pyridine in methylene chloride.
Acetoxyacetic acid ethyl ester was obtained.

(d) 4,4-difluoro-3 produced in (C) above
- acetoxybutyric acid ethyl ester as in Example IA (d)
Hydrolyzed using lipase MY in the same manner as (R)
-(+)-4,4-difluoro-3-hydroxybutyric acid ethyl ester was obtained.

The physical properties of the obtained product were as follows.

Molecular weight 168 Boiling point 115-116°C/71 mmHg19F
NMRδ (ppm) 49. O(ddd.

J (CHF, Fb) = 266.0IIz.

J(CHF, Fb) = 52.3Hz.

J(CI(ヱ-,F,Cand)=10.8)1z
.

CHfjFbL 650, 3 (ddd, J (CHF, Fb) = 26
6.0Hz, J (C and F, Fb) = 52.8Hz
, J(CHF-FbCH)=12.5 Hz, CHF
*F b )'HNMRδ (ppm) 1.34
(t, J=7.2Hz.

3) f, CH3].

δ2.57 (dd, J (CH-Hb) = 17.4
Hz.

J(CH, HbC and) = 7.2Hz.

I H, CH, Hb).

62, 73 (dd, J (C and b) = 17
．． 4 Hz.

J(CH, and C) = 15.9Hz, LH.

CH, and].

δ3.74 (bs, LH, OH).

64.22 (q, J=7.2Hz, 2H, CHz)
.

δ5.73 (dt, J (C and Fz) = 56.3
Hz.

J (C and F2CH) = 3.9H2, I H, CHF2)
IR3450 (OH), 3000 (CH2).

1725 (C=O) (cm-') Example IA,
Table 1 shows the hydrolysis rates in B and Example 2, as well as the optical rotation and optical purity of the obtained products.

Note that (R)-(+)-4,4- obtained in Example 2A
(S)-(-)-4,4-difluoro- exhibiting an optical rotation opposite to difluoro-3-hydroxy acetic acid ethyl ester
Example 2 shows an example of the production of 3-hydroxybutyric acid ethyl ester.
Shown in B.

Example 2B (+)-4,4-difluoro-3-acetoxybutyric acid ethyl ester (1,87
g, 8.9 mmol) was suspended in distilled water (90 d).
Tenshu Pharmaceutical Co., Ltd.) was suspended. This suspension was heated at 40-41°
After stirring for 5 hours while maintaining the temperature at C.C., ethyl acetate was added and stirred, and the suspension was centrifuged. After removing the aqueous layer, the aqueous layer was extracted again. After distilling off the solvent, the product was purified and isolated by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate (5:1) to obtain (dan)-(-)-4,4-difluoro-3. -Hydroxybutyric acid ethyl ester was obtained. In this reaction, the hydrolysis rate was 100%, and the obtained (S)-(-)-
Specific rotation [α] of 4,4-difluoro-3-hydroxybutyric acid ethyl ester.

was -11,86 (concentration in chloroform: 1.16), and the structural formula was as follows.

OH○ Ma 1I CHFzCHCHzCOEt (Left below) Table 1 *1 General formula of alcohol derivatives: CHF, CH
R*2 Example IAO is also OOH *3 Example IB Example 2C (1)(-)-1,1-difluoro-3-phenyl-2
- Synthesis of propatool In Example IA(a), a benzyl Grignard reagent is used instead of a phenyl Grignard reagent, and (d
Example IA (a) to (d) except that Lipase P (manufactured by Amano Pharmaceutical) was used instead of Lipase MY in Example IA.
The same operation as in step ) was performed to obtain (-)-1,1-difluoro-3-phenyl-2-propatol. The physical properties of this substance are (+)-1,1-difluoro-3-
It was the same as phenyl-2-propatol.

(2)(-)-1,1-difluoro-4-phenyl-2
- Synthesis of Butanol Example IA In (a), using β-phenethyl Grignard reagent instead of phenyl Grignard reagent,
Also, in (d), lipase P instead of lipase MY
(a) of Example IA except that (manufactured by Amano Pharmaceutical)
) to (d) to obtain (-)-1,
1-difluoro-4-phenyl-2-butanol was obtained. The physical properties of this were the same as (+)-1,1-difluoro-4-phenyl-2-butanol.

(3) Synthesis of (S) -(-)-1,1-difluoro-2-octatool In Example 1A (a), n-hexyl Grignard reagent was used instead of phenyl Grignard reagent, and (d) (a) to Example IA except that Lipase P (manufactured by Amano Pharmaceutical) was used instead of Lipase MY in
Perform the same operation as in step (d) to obtain (S)-(-)-
1,1-difluoro-2-octatool was obtained. The physical properties of this were the same as (R)-(+)-1,1-difluoro-2-octatool.

(4) Synthesis of (dan)-(-)-1,1-difluoro-2-decanol In Example IA (a), n-octyl Grignard reagent was used instead of phenyl Grignard reagent, and in (d), lipase (a) to Example IA except that Lipase P (manufactured by Amano Pharmaceutical) was used instead of MYO.
Perform the same operation as in step (d), (dan)-(-)-
1,1-difluoro-2-decanol was obtained. The physical properties of this substance are (and)-(+)-1,1-difluoro-
It was the same as 2-decanol.

(5) Synthesis of (dan)-(-)-4,4-difluoro-3-hydroxybutyric acid ethyl ester Example 2A Except for using Lipase P (manufactured by Tenshu Pharmaceutical Co., Ltd.) in place of Lipase MY in (d). , by performing the same operations as steps (a) to (d) of Example 2A, (S)-(-)-4,4-
Difluoro-3-hydroxybutyric acid ethyl ester was obtained.

The physical properties of this thing are (and) −(+) −4,4−
It was the same as difluoro-3-hydroxybutyric acid ethyl ester.

The results of Examples IC (1) to (5) are shown in Table 1 A.

Table 1 A (blank below) Example 3 (R)-(-)-1-phenyl-2-chloro-2゜2-
Synthesis of difluoroethanol H CCj2FzCHPh (a) Synthesis of chlorodifluoromethyl phenyl ketone Add a solution of phenyl Grignard reagent (44 mmol) in diethyl ether to a solution of chlorodifluoroacetic acid methyl ester (5.8 g, 40 mmol) in diethyl ether at 70°C. It slowly dripped inside.

The solution was kept at -70°C and stirred for 4 hours, and then the reaction was terminated with a saturated aqueous ammonium chloride solution.

The resulting oil was extracted with diethyl ether, the solvent was evaporated and the product was purified by vacuum distillation.

(b) Reduction step Sodium borohydride (0.38 g, 10 mmol)
of ethanol (20 mj) The solution was kept at O''C, and chlorodifluoromethylphenyl ketone (3.8 g, 20 mmol) prepared in (a) was added to this solution in ethanol (20 mj).
mj2) The solution was added dropwise. After stirring at room temperature for 4 hours, the solvent was distilled off, and the reaction was terminated with a saturated aqueous ammonium chloride solution. The resulting oil was extracted with diethyl ether, the solvent was distilled off and the product was purified by vacuum distillation.

(C) 1-phenyl-2-chloro-2,2- produced in acylation (acetylation) step (b)
Difluoroethanol (1,1 g, 6 mmol), pyridine (1,0 d, 12 mmol) and acetyl chloride (0
, 5 mN, 12 mmol) in methylene chloride solution (20 d
) was stirred at room temperature for 6 hours, and then the reaction was terminated with IN hydrochloric acid. The resulting oil was extracted with methylene chloride, the solvent was distilled off, and then a mixed solvent of hexane and ethyl acetate (5:1
) and purified by silica gel chromatography.

(d) Asymmetric hydrolysis 1-phenyl-2-chloro-2,2-difluoroethyl aceter) (0.9 g, 4 mmol) was dissolved in dilute distilled water (40 m
ffi) and further suspended in Lipase MY (2.0 g, manufactured by Awa-Nori Sangyo). This suspension was heated to 40-41°C.
After stirring for 2 hours, ethyl acetate was added, stirred, and the suspension was centrifuged. After removing the organic layer,
Extract the aqueous layer again. After distilling off the solvent, the product was subjected to silica gel chromatography using a mixed solvent of hexane and ethyl acetate (5:1) to separate carbinol and acetate.

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

Molecular weight 192.5 Boiling point 99-100°C/ 11 mm 11 g”F
NMRδ (ppm) -12,7 (dd.

J (C, LLFJLcI) = 17011z.

J (CF-F bclc H)"" 8 Hz).

δ−15,9(dd, J (Cヱ−FbCl)=1
70Hz.

J (CF, F, CtC and) = 8Hz) 'HNMRδ (ppm) 3.0 (bs, L H,
OH).

δ4.9 [:bt, J (Cヱ□bc+c且)=
7.8Hz, I H, CFzC]C[].

67, 2-7.5 (m, 5 H, Ph) IR34
30(OH) (cm-') The following compound could be produced in the same manner as in Example 3.

LA)(+)-1-chloro-1,1-difluoro-3-
Phenyl-2-propatur (in Example 3(a), benzyl Grignard reagent was used instead of phenyl Grignard reagent) Molecular weight 206.5 Boiling point 106°C/9 mm 11 g 9FN
MRδ (pI) zn) −12,1(dd.

J(Cヱ□F, C1) = 170 Hz.

J(CF, FbCIC and)=811z:l.

δ−15,3(dd, J (CueyuF CI) =
1701 (z.

J (CF, F, CiC and) = 8 Hz) 'HNMRδ (ppm) 2.69 (dd, J (
C and JL Th )~15.0Hz, J(CHCH,H
-) = 9.811z, L H, C and -t'tb).

δ2.80 (bs, IH, OH).

δ3. OO(dd, J (C-danyu LIL) =
15.0Hz.

J (C and CHa Hb) = 3.0 Hz + I H
+CH, and].

63, 7-4.1 (m, LH, CH).

δ7. O~7.3 (m, 5H, Ph)IR3
440 (OH) (cm-') 1B) The 1-chloro-1,1-difluoro-3-phenyl-2-propylacetate obtained in the enzymatic hydrolysis step of LA) above was mixed with acetone (3d) and 2N water. It was added dropwise to a mixed solvent of sodium oxide aqueous solution (3d), and the solution was stirred at room temperature for 12 hours.
The reaction was terminated by making the solution neutral with N hydrochloric acid. The obtained oil was extracted with methylene chloride, the solvent was distilled off, and then 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 (in Example 3(a), β-phenethyl Grignard reagent was used instead of phenyl Grignard reagent) Molecular weight 220. 5 Boiling point 106°C/9mm11g+9F NM
Rδ(ppm) −12,1(dd.

J(Cヱ-FbCl)=171Hz.

J(Cヱ-m　bCIC〔)～81(z:l.

δ−15,2(dd, J(CueyuFbCi)=1
71Hz, J (CF, FbCtC and) = 811z) IH
NMRδ (ppm) 1.5-2.2 (m, 2
H.

CH2CH2Ph).

62.2-2.5 (bd, LH, OH).

62, 5-3.1 (m, 2 H, CHzCIIz
Ph).

δ3.6-4.0 (m, LH, CH).

δ7. O ~ 7.3 (m, 5) (, Ph)IR
3250(OH) (cm-')3)(and)-(+)
-1-chloro-1,1-difluoro-2-octatool (in Example 3(a), n-hexyl Grignard reagent was used instead of phenyl Grignard reagent) Molecular weight 200.5 Boiling point 99°C/30 mm11g19F NM
Rδ(ppm) −11,9(dd.

J (CCILILF,) = 169Hz.

J (CCIF, F, C and) = 81fz).

δ-15,1(dd, J (CClueyuFJL)~1
69Hz, J(CCIF-FbCH)-8Hz)'HNMRδ(ppm) 0.8-2.0 (m,
13H).

62.2-2.4 (bd, IH, OH).

δ3.6~4.1 (m, LH, CCIF
z CH)IR3400(OH) (cm-')4)
(R)-(+)-1-chloro-1,1-difluoro-2
-decanol (in Example 3(a), n-octyl Grignard reagent was used instead of phenyl Grignard reagent) Molecular weight 228.5 19F NMR δ (ppm) -11,7 (dd.

J (CFJhCl) = 170Hz.

J(CF, F, CIC and)=8t(z).

δ−15,3(dd, J (CFIFJLCl) =
170Hz, J (CF, ebctc) = 8H
z) IHNMRδ (ppm) 0.8-2.1 (m,
17H).

62, 1 (bs, IH, OH).

δ3.7~4.1 (m, I H, CH) IR33
50 (OH) (cm) 5) (shaku) - (+) -4
-Chloro-4,4-difluoro-3-hydroxybutyric acid ethyl ester In Example 2A, the same operation as Example 2A was performed except that chlorodifluoroacetic acid methyl ester was used instead of difluoroacetic acid ethyl ester. . However, hydrolysis was performed using lipase MY for 40 minutes. As a result, (R)-(+)-4-chloro-4,4
-Difluoro-3-hydroxybutyric acid ethyl ester was obtained with a hydrolysis rate of 24%.

Structural formula: 9H0 cciFz6HCHzCOCzHs The physical properties of the obtained product were as follows.

Molecular weight 202.5 Boiling point 109°C/ 65 mm1I'HNMRδ
(ppm) 1.28 (t, J = 7.211z
.

3H,0CH2CH3).

δ2.52 (dd, J = 7.8Hz, J =
16.8Hz.

IH, C0HCH Yu Hbco].

δ2.75 [dd, J ~4.8) 1z, J
= 16.811z.

IH, COHCH, lC○].

63.5-4.0 (m, IH, OH).

δ4.13 (q, J ~ 1.2Hz, 21(.

OCHzCH3).

δ4.45 (dq, J ~4.8Hz, J =
7.8Hz.

LH,Cdan0H) IR3450(CH) (cm-') The hydrolysis rate and the optical rotation and optical purity of the product in Example 3 are shown in Table 2 below.

(Left below) Table 2 OH ■ *1 =General formula of alcohol derivative: C(/!F2
(+)-1-chloro-1,1- obtained in CHR* *2 1A)
(-)-1-chloro-1,1~ obtained with difluoro-3-phenyl-2-propatol*3 1B)
Difluoro-3-phenyl-2-propanol Example 3A (1) (dan)-(+)-1-phenyl-2-chloro-2
, 2-difluoroethanol synthesis H MacCfFzCHPh 1-phenyl-2 obtained in the (d) hydrolysis step of Example 3
-Chloro-2,2-difluoroethyl acetate was treated in the same manner as in Example 3 IB) to obtain (S)-(+)-
1-phenyl-2-chloro-2,2-difluoroethanol was obtained. The physical properties of this are (R)-(-)
It was the same as -1-phenyl-2-chloro-2,2-difluoroethanol.

(2)(-)-1-chloro-1,1-difluoro-4-
Synthesis of phenyl-2-butanol 1-chloro-1,1-difluoro-4-phenyl-2- obtained in Example 3-2)
Butyl acetate was treated in the same manner as in Example 3 IB) to obtain (-)-1-chloro-1,1-difluoro-4-
Phenyl-2-butanol was obtained. The physical properties of this substance are (+)-1-chloro-1,1-difluoro-4-
It was the same as phenyl-2-butanol.

(3) Synthesis of (S)-(-)-1-chloro-1,1-difluoro-2-octatool ○H MacCI F z CHCb Ht 3 1-chloro-1 obtained in Example 3-3) , 1-difluoro-2-octyl acetate was treated in the same manner as in Example 3 IB) to obtain (Σ) -(-) -1-chloro-1,
1-difluoro-2-octatool was obtained. The physical properties of this substance are (and)-(+)-1-chloro-1,1-
It was the same as difluoro-2-octatool.

(4) Synthesis of (S)-(-)-1-chloro-1,1-difluoro-2-decanol H MaCCj! FzCHCsH+ was treated with 1-chloro-1,1-difluoro-2-decyl acetate obtained in 4) of Example 3 in the same manner as in IB) of Example 3 to obtain (d) -(-) -1-chloro. -1,1
-difluoro-2-decanol was obtained. The physical properties of this were the same as (and)-(+)-1-chloro-1,1-difluoro-2-decanol.

These results are shown in Table 2A.

(Left below) Table 2 A H *1 General formula of alcohol derivative: CCIFtCH
R* (blank below) Example 4 Synthesis of (-)-1,1,1,2,2-pentafluoro-5-phenyl-3-pentanol (a) Pentafluoropropionic acid ethyl ester (5.8 g, 30 mmol) in tetrahydrofuran solution (30d) at -70°C.
A solution of β-phenethylmagnesium bromide (β-phenethyl Grignard reagent) (33 mmol) in tetrahydrofuran was slowly added dropwise. Add this solution to -70°
After stirring for 3 hours while maintaining the temperature at C, the reaction was terminated with a saturated aqueous ammonium chloride solution. The resulting oil was extracted with diethyl ether, the solvent was distilled off, and the product was purified by vacuum distillation.

(b) Sodium borohydride (0.44 g, 11.6
An ethanol solution (35d) of 1 mmol) was kept at 0 °C, and pentafluoroethyl β prepared in (a) was added to this solution.
- A solution of phenethyl ketone (2.2 g, 9.3 mmol) in ethanol (10 d) was added dropwise.

After stirring at room temperature for 24 hours, the solvent was distilled off, and the reaction was terminated with a saturated aqueous ammonium chloride solution. The resulting oil was extracted with diethyl ether, the solvent was distilled off, and the product was purified by silica gel chromatography using a mixed solvent of hexane and ethyl acetate (3:1).

(c) 1.1,1°2.2 in methylene chloride (10 relatives)
-pentafluoro-5-phenyl-3-pentanol (
2,2 g, 9 mmol) and pyridine (1,48++4
! , 18.3 mmol) of acetyl chloride (0,7
After stirring at room temperature for 3 hours, the reaction was terminated with IN hydrochloric acid. The resulting oil 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-pentylacetate (2,2 g.

Lipase P (3.8 g, manufactured by Tenshu Pharmaceutical Co., Ltd.) was suspended in a suspension prepared by suspending 7.6 mmol) in distilled water (80+1). The suspension was kept at 40-41°C and stirred for 43 hours, then ethyl acetate (80d) was added and stirred, and the solution was filtered through a bed of Celite. After separating the batter layer, the aqueous layer was extracted again with ethyl acetate. After distilling off the solvent, the product was dissolved in a mixed solvent of hexane and ethyl acetate (10
:1), the target product and acetate were separated and purified by silica gel chromatography. The hydrolysis rate in this example was 61%. The physical properties of this product were as follows.

Molecular weight 242 Rf O, 64 (3: 1) 19F NMR δ (pl) m) 2.8 (s, 3 F
, CF3CFz).

δ43.3 (dd, J(Cヱ-Fb)=266Hz
.

J (CF, F, C and) = 7.5 Hz, IF.

CF, Cdan-Fb).

δ50.8 (dd, J(CF, Fb)-266)1z
.

J (CF-FbCH)-13,2Hz, IF.

CFsCF-Fb) 'HNMRδ (ppm) 2.0 (m, 3H,C
HzPh.

OH).

δ2.8 (m, 2H, C[zcHzPh).

δ 3.9 (m+IH, CH(OH)).

δ 7.0-7.4 (m, 5 H, Ph) I R3
400(OH) (cm-') in a similar manner (but using n-hexyl Grignard reagent instead of β-phenethyl Grignard reagent in (a) above), (+)-
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 mm11g”F N
MRδ (ppm) 4.0 (s, 3F, CF
3).

δ44.0 (dd, J(CF-Fb)~269.5
tlz.

J (CF, F, C and) = 7.5Hz, IF.

CF3CF-Fb).

δ52.3 (dd, J (CF-Fb) = 269
, 5Hz.

J(CF, FbC and) = 16.0Hz, IF.

CF3CF-Fb)'HNMRδ(ppm)1.0 (brt, 3H,
CH3).

61, 2-2.2 (m, 10 H, (CHz)s)
.

63.2 (d, J (OHCH) = 8.4Hz, OH
).

64.17 (m, I H, CI-I (OH)) I
R3400(OH) (cm-') can also be used in the same manner (but using n-octyl Grignard reagent instead of β-phenethyl Grignard reagent in (a) above, and using chloride instead of acetyl chloride in (C)). using isobutyryl and lipase M instead of lipase P in (d).
(+)-1,1,1,2°2-pentafluoro-3-undecanol was obtained with a hydrolysis rate of 60% in 186 hours. The physical properties of this product were as follows.

Molecular weight 262 Boiling point 110-112/60mmHgI9F NM
Rδ (ppm) 4.0 (s, 3F, CF
3).

δ43.6 [dd, J (CF-Fb) = 268
Hz.

J (CF-FbCH) = 7.5Hz, IF.

CFICF, Fb).

652.0 (dd, J (CF-Fb) = 268Hz.

J(CF-FbCH)=16.0HzlIF.

CF z CF -F b )'HNMRδ (ppm) 0.9 (m, 3 H, CH
3).

61.33 (m, 14 Hl (CHz),).

δ3.6 (t, J(C and CH2) = 6.OIl
z.

CH(OH)).

δ 4°O (bs, L H, OH) IR3400 (OH) (cm-') The optical rotation and optical purity of the obtained compound are shown in Table 3.

Table 3? 1 *General formula of alcohol derivative: C, F, CHR* Example 5 The same procedure as in Example 1 was carried out, and the type and enzyme of the acylating agent (acyl group is represented by R' Co) used in step (C) were determined. 1-phenyl-2゜2-difluoroethanol was produced by varying the type of
Shown in the table.

(Hereinafter in the margin) Table 4 (Hereinafter in the margin) [Effects of the invention] As mentioned above, the optically active difluoroalcohol derivative according to the present invention has extremely poor optical purity, and can be used in various pharmaceutical products such as liquid crystals, etc. It is expected to be widely and effectively used as an intermediate.

Claims (1)

[Claims] (1) General formula: ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R is an alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms. There are groups or ▲mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, 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_2_n_+_1 (n is an integer from 1 to 8,
^1 is at least one type of atom selected from fluorine, chlorine and bromine).