JPH02282340A - Asymmetric synthesis of secondary alcohol - Google Patents

Abstract

PURPOSE:To carry out direct asymmetric synthesis of an optically active secondary alcohol without using troublesome racemic resolution by reducing an aliphatic carboxylic acid ester corresponding to the objective compound with a lipase. CONSTITUTION:An optically active secondary alcohol of formula II, especially a secondary alcohol having halogenated alkyl group and useful as an intermediate for ferroelectric liquid crystal compound is asymmetrically synthesized in high selectivity without using racemic resolution by reducing an aliphatic carboxylic acid ester of formula I (R<1> is 1-4C alkyl or 1-4C halogenated alkyl having one or more halogen atoms substituting the H atoms; R<2> is 4-16C alkyl; R<3> is methyl or ethyl) with preferably 1,000-10,000 unit (preferably 300-5,000 unit) of a lipase based on 1mol of the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field] The present invention relates to a novel asymmetric synthesis method for optically active secondary alcohols.

[Prior art]

Regardless of the production route taken to obtain optically active secondary alcohols, racemic resolution is always required in the end.

The method of directly synthesizing an optically active substance without racemic resolution is generally known as asymmetric synthesis, but the reaction involves the use of optically active α-methylbutyric acid and manganese. Although asymmetric synthesis of zolonitrile is known, the yield is extremely low and it cannot be used industrially.

Regarding the optically active secondary alcohol, which is the target substance of the present invention, only a racemic resolution method is known, and no asymmetric synthesis method has existed.

〔the purpose〕

An object of the present invention is to provide a novel method for asymmetrically synthesizing optically active secondary alcohols from the corresponding esters.

〔composition〕

The present invention is characterized in that an aliphatic carboxylic acid ester represented by the following general formula (I) % formula % is reduced by lipase, and the following general formula (n) (hereinafter referred to as blank space) H R1-C- R''...(II)* (In the formula, R1 and R2 are the same as above) The present invention relates to a method for asymmetrically synthesizing an optically active secondary alcohol.

Lipase is known to be an enzyme that brings 1-liglyceride into contact with a stepwise hydrolysis reaction into glycerin and fatty acids, but it also has the ability to asymmetrically synthesize and select by reducing aliphatic carboxylic acid esters. It is quite surprising that there is a special asymmetric synthesis ability to produce optically active secondary alcohols.

Lipase is 1 mmol of ester represented by general formula (I)
1000-10000 units per unit, preferably 300
It is preferable to use it at a rate of 0 to 5000 units.

The reaction is usually carried out in water or in a mixed system of water and a water-soluble solvent such as alcohol, and methanol or ethanol is preferred as this type of solvent.

The ester is usually present in these solvent systems in an amount of 1-30 wt%, preferably 3-101. This is done by making it exist in a proportion of It%. A low reaction temperature of about 30 to 45°C is sufficient.

Note that R1 is CH3, C2H,, C, R7, C,,
Hg, CH2F, CHF2. CF3. CH,C
F3. CHFCF3. CF, CF3. CH2(I,
CI+CΩ2. C1,,CH2CCf13. CI(
C:12CCQ1. CCQ2CCu,,, CBr3
．． C2Br3. C: [,,C2 King.

etc., but is not limited to this.

The optically active secondary alcohol obtained by the present invention, especially the secondary alcohol containing a halogenated alkyl group, is disclosed in Japanese Patent Application Nos. 63-21159, 63-70212,
Nos. 197957 and 63-229790, and are useful as intermediates for synthesizing ferroelectric liquid crystal compounds.

〔Example〕

Hereinafter, the compounds of the present invention will be explained in more detail with reference to Examples, but the invention is not limited thereto.

<Example 1> (I) Trifluoromethyloctylketone CF, CHC
, H1□ synthetic shaved magnesium 2.92g (0.12mol)
, bromooctane 23.17g (0.12mol)
was dissolved in 120 mQ of ether and added dropwise.
gnard reagent was prepared.

1 to 14.2 g of fluoroethyl ester (0,11
1101) in ether] 40 mQ, and the resulting solution was cooled with water and mixed with previously prepared Grign
The ard reagent was added dropwise and reacted for 6 hours.

Aqueous ammonium chloride solution was added to the reaction solution to complete the reaction, and IN-hydrochloric acid was added to obtain an oily substance, which was extracted with ether, washed with saturated brine, dehydrated with anhydrous magnesium sulfate, and then distilled off. and distilled and purified (78 mmHg,
85° C.) to obtain 15.4 g of the above compound.

(2) Synthesis of trifluorodecanol○H CF3CHC,H1□ Lithium aluminum hydride 1. ．． 67g (0,04
4 mol) and 50 mQ of ether were placed in a reactor in a water bath, and 15.1 g (0,083 mol.) of 1-lifluoromethyloctylkene obtained in Section 2 (I) was added dropwise. The reaction was allowed to proceed at room temperature for 3.5 hours, and sodium sulfate was added to terminate the reaction. After extraction with ether, the extract was dehydrated with magnesium sulfate and then distilled off to obtain 14.03 g of the above compound.

(3) 1-lifluoromethyloctyl ester C0CR
3 Synthesis of CF5CHCIIH1□ Next, 1-lifluorodecanol obtained in (2) 14.
03 g (0,077 mol) of methylene chloride 65 m
Ω and acetyl chloride 7.15u+Q(0
, 1mol), pyridine 9.65mQ (0.12mol
．． ) was added, and one spatula of dimethylaminopyridine was added, and the mixture was allowed to react at room temperature for 6.5 hours. IN = Hydrochloric acid was added to terminate the reaction, and the resulting product was extracted with ether, washed with distilled water, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dehydrated with anhydrous magnesium sulfate, and then distilled off to purify by distillation ( 78mmt (g, 100-110°C)
12.09g was obtained.

(4) Asymmetric synthesis of trifluorodecanol H CF3CHC, H1□ *Lipase MY (origin Candida cylindra
ceanov, sp, ) (58,900 units/g
2.72 g of polysaccharide industry) was suspended in 1.80 mQ of distilled water, and 12.09 g (0,054 mol) of the trifluoromethyl-octyl ester obtained in (3) above was added to stir the reaction at 40°C. I let it happen. The pH was maintained at 7.0 with a 1N sodium hydroxide solution. After 20 to 24 hours, when the reaction stopped progressing, ether was added and the mixture was filtered under reduced pressure using Celite. The organic layer was extracted and dehydrated by adding anhydrous magnesium sulfate. This was distilled off, and then chromatographed on silica gel (n-hexane:ether=
8: ], ) and further distilled off, the resulting product is distilled and purified (9
0mmHg, 85-95℃) and the above metal compound 1.14
I got g.

The infrared absorption spectrum of the product is shown in FIG. Further, the specific rotation of the product is shown in Table 1.

<Example 2> (I) Synthesis of trifluoromethylundecylketone○ CF, CHC□1H23 0.73 g (0.03 mol
), bromo undecane 7.06 g (0.03 mo
l) dissolved in 120 mΩ of ether was added dropwise to G
Rignard reagent was prepared.

Trifluoroethyl ester 3.55 g (0,02
5 mol) was dissolved in 140 mQ of ether, and the resulting solution was cooled with water and mixed with previously prepared Grigna.
The rd reagent was added dropwise and reacted for 6 hours.

Aqueous ammonium chloride solution was added to the reaction solution to complete the reaction, and 1N hydrochloric acid was added to obtain an oily substance, which was extracted with ether, washed with saturated brine, dehydrated with anhydrous magnesium sulfate, and then distilled off. The product was purified by distillation to obtain 5.4 g of the compound described above.

(2) Synthesis of trifluoroundecanol? H CF3CHC□□H23 Lithium aluminum hydride 0.392 g (0°01
0 mol) and 20 mol of ether were placed in a reactor in a water bath, and 5.4 g (0,021 mol) of the trifluoromethyl undecyl ketone obtained in (I) above was added dropwise. The reaction was allowed to proceed at room temperature for 3.5 hours, and sodium sulfate was added to terminate the reaction.

After extraction with ether, the extract was dehydrated with magnesium sulfate and then distilled off to obtain 5.4 g of the above compound.

(3) Trifluoromethylundecyl ester○C0C
Synthesis of R3 CF5CHC1□H23 Next, trifluoroundecanol obtained in (2) 5.
4 g (0,021 mol) of methylene chloride 20II
Acetyl chloride 2.0+++Q in a water bath by adding IQ,
2.8 mQ of pyridine was added, and 11 spatulas of dimethylaminopyridine were added, followed by reaction at room temperature for 6.5 hours. IN = Add hydrochloric acid to terminate the reaction, extract with ether, wash with distilled water, saturated aqueous sodium bicarbonate solution, and saturated saline, dehydrate with anhydrous magnesium sulfate, and then evaporate. 5.2g was obtained.

(4) Asymmetric synthesis of trifluoroundecanol H CF3CHC1□H23 *Lipase OF (origin Candida Cyco1ndra
cea) (360,0OOunit/g: winter clothing industry)
4.9 g of trifluoromethylundecyl ester obtained in (3) above by suspending 0.2 g in 60 mQ of distilled water (
0,019 mol) and stirred and reacted at 40°C.

The pH was maintained at 7.0 with 1N sodium hydroxide solution.

After 120 to 124 hours, when the reaction stopped progressing, ether was added and the mixture was filtered under reduced pressure using Celite. The organic layer was extracted and dehydrated by adding anhydrous magnesium sulfate.

This was distilled off, and then silica gel chroma 1-(
n-hexane:ether=8:1), and the distilled product was purified by distillation to obtain 1.00 g of the above compound.

The infrared absorption spectrum of the product is shown in FIG. Further, the specific rotation of the product is shown in Table 1.

<Example 3> (I) Pentafluoroethyl octyl ketone C2F
5CHC [lH□7 synthetic shaved magnesila is 1.46 g (0.06 m
ol), bromooctane 1 ], , 6 g (0
, 06 mol) dissolved in 70 mQ of ether was added dropwise to prepare Grignard reagent.

Pentafluoroethyl ester 9.61 g (0°0
5 mol) was dissolved in 50 mQ of ether, and the resulting solution was cooled with water and mixed with previously prepared Grignard.
The reagent was added dropwise and reacted for 5 hours.

An aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, and IN-hydrochloric acid was added to obtain an oily substance, which was extracted with ether, washed with saturated brine, dehydrated with anhydrous magnesila sulfate 11, and then distilled. Compound 7.
3g was obtained.

(2) Synthesis of pentafluorodecanol H C2F, CHCl1H□7 So-1-lium borohydride 4゜21 g (0,],,
11.2 ml) and 10 mQ of ethanol were placed in a reactor in a water bath, and 7.3 g (0,028 mol.) of pentafluoroethyl octyl ketone obtained in (I) above was added dropwise. The reaction was carried out at room temperature for 12 hours and simple distillation was performed to remove ethanol. An aqueous ammonium chloride solution and IN-hydrochloric acid were added to the reaction mixture, extracted with ether, dehydrated with magnesium sulfate, and then distilled off to obtain 2.6 g of the compound described above.

(3) Pentafluoroethyl octyl ester ○C
Synthesis of OCH3 C2F, CHC,, H□7 Next, pentafluorodecanol obtained in (2) 2.6
g (0.01 mol) was added with 10 mu of methylene chloride, and 1.26 mfl of n-butyryl chloride (0.01 mol) was added in a water bath.
012 mol) and pyridine 1,62- were added thereto, and one spatula of dimethylaminopyridine was added, followed by reaction at room temperature for 18 hours. IN-Hydrochloric acid was added to terminate the reaction, and the resulting mixture was extracted with ether, methylene chloride, distilled water,
Wash with saturated sodium bicarbonate aqueous solution and saturated saline,
After dehydration with anhydrous magnesium sulfate, the residue was distilled off to obtain 1.72 g.

(4) Asymmetric synthesis of pentafluorodecanol ○H C2F,, CHC8H1□ * Obtained in the above (3) by suspending 0.038 g of lipase OF (360.0 OOunit/g: Fuyugi Sangyo) in 50 mQ of distilled water. Added 1.53 g (0,005 mol) of pentafluoroethyl-octyl ester and heated at 40°.
The reaction was stirred at C. IN-p with sodium hydroxide solution
Maintained at H7.0. After 72 hours, when the reaction stopped progressing, ether was added and the mixture was filtered under reduced pressure using Celite. The organic layer was extracted and dehydrated by adding anhydrous magnesium sulfate. This product was distilled off, then treated with silica gel chroma I (n-hexane:ether = 8:1), and the distilled product was again treated with silica gel chromatography (n-hexane:ether = 8:1). 0.34 g of the above compound was obtained.

The infrared absorption spectrum of the product is shown in FIG. Further, the specific rotation of the product is shown in Table 1.

<Example 4> (I) Synthesis of Tric[Rodecanol H CCQ3CHC8H□7 2.92 g of magnesium in the form of shavings (0.12 mo)
, bromooctane 23.17g (0,'12mol
) dissolved in 120 mQ of ether was added dropwise to make Gr.
The ignarcl reagent was prepared.

14.7 g (0.1 mol) of chloral in ether 8
The Grj gnard reagent prepared in advance was added dropwise to the resulting solution under water cooling and allowed to react for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture to terminate the reaction, further IN-hydrochloric acid was added, and the mixture was extracted with ether. The residue was washed with saturated brine, dehydrated and dried over anhydrous magnesium sulfate, and then distilled off to obtain 17.63 g of the above compound.

(2) Synthesis of trichloromethyloctyl ester C0CH5 CCQ3CHC8H, □ Next, trichlorodecanol obtained in (I) 17.63
g (0,069 mol) to methylene chloride 70 mfl
and 6.34 mQ of acetyl chloride (0°0
89 mo1), pyridine 8.64 m12 (0,108 m
ol) was added thereto, and one spatula of dimethylaminopyridine was further added, and the mixture was allowed to react at room temperature for 21 hours.

After extraction with ether, the extract was washed with distilled water, saturated aqueous sodium bicarbonate solution, and saturated brine, dehydrated with anhydrous magnesium sulfate, and then distilled off to obtain 15.96 g.

(3) Asymmetric synthesis of l-lichlorodecanol H CC flood, CHC, H, □ * Lipase PL (origin Alcalj, genes sp,
) (I00,000unit/g: Uzume Sangyo) 2.0
1.4.04 g of trichloromethyloctyl ester obtained in (2) above by suspending g in distilled water]-00mQ
(0,046 mo], ) was added and stirred at 40°C to react. The pH was maintained at 9.0 with 1N sodium hydroxide solution. After 120 hours, when the reaction stopped progressing, ether was added and the mixture was filtered under reduced pressure using Celite. The organic layer was extracted and dehydrated by adding anhydrous magnesium sulfate. This product was distilled off, then subjected to silica gel chromatography (n hexane:ether = 871 L), and the distilled product was further distilled to obtain 2.18 g of the above compound.

The infrared absorption spectrum of the product is shown in FIG.

*) <Specific rotation measurement method> A sample was accurately weighed into a 5 mQ weighing flask, and methanol was poured up to the marked line. The concentration of the sample in 100 mQ of methanol was calculated by multiplying by 20. A DIP-140 type polarimeter (manufactured by JASCO Corporation) was used for the measurement. First, methanol alone was placed in a cell (cell length 50 nanometers) for zero adjustment, and then the above sample was placed in the same cell and measured.

Measurements were performed several times to confirm reproducibility.

A sodium lamp (589 nm) was used as a light source.

〔effect〕

The present invention has developed a new asymmetric synthesis method using lipase, which eliminates the need for troublesome racemic resolution.

[Brief explanation of drawings]

1 to 4 are infrared absorption spectra of the products of Examples 1 to 4 of the present invention.

Claims (1)

[Claims] 1. The following general formula (I) ▲There are numerical formulas, chemical formulas, tables, etc.▼... (I) In the formula, (R^1 is an alkyl group having 1 to 4 carbon atoms or a hydrogen atom is substituted with one or more halogens and has 1 to 4 carbon atoms
(R^2 is an alkyl group having 4 to 16 carbon atoms, R^3 is a methyl group or an ethyl group) is reduced by lipase. The following general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(II) (In the formula, R^1 and R^2 are the same as above) Asymmetric synthesis method for secondary alcohols.