JPS6265686A - Production of optically active (s)-2-halo-1-phenylethanol - Google Patents

Abstract

PURPOSE:To obtain the titled phenylethanol suitable as a synthetic raw material for pharmaceuticals, agricultural chemicals, animal drugs, perfumes, etc., in high efficiency, by contacting a haloacetophenone with a specific microorganism. CONSTITUTION:The objective phenylethanol of formula II can be produced by contacting (A) an alpha-haloacetophenone of formula I (X is halogen atom) with (B) a microbial strain capable of asymmetrically reducing the compound of formula I to the S-2-halo-1-phenylethanol of formula II having S-configuration and belonging to Nadosonia genus, Aegerita genus, Agrocybe genus, Arachnothica genus, Arxiella genus, Aspergillus genus, Beauveria genus, Botrytis genus, Chloridium genus, Cryptophiale genus, Cylindrocladium genus, Flammulina genus, Fusarium genus, Gibberella genus, etc.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides an α-haloacetophenone represented by the general formula [I] [wherein X represents a halogen atom]
[In the formula, X is the same as [I]] [In the formula, X is the same as [I]] Genus, Arachinotica, Axella, Aspergillus, Beauveria, Botrytes, Chlorizoium, Cryptophiale, Cylindroclavulum, Flamulina, Fusarium, Gibberella, Gliocladium, Gliomastyx , Gymnoascus, Moriteirella, Mucor, Pecilomyces, Penicillium, Scolecobasidium,
Optical activity ( S)-2-halo 1
- This relates to a method for producing phenylethanol.

Optically active (Sl-2-halo 1-phenylethanol has a 2VA functional group and can be easily derived from highly reactive (S)-styrene oxide, so it can be used for pharmaceuticals, agricultural chemicals, etc. that require optical activity. It is an extremely useful substance as a synthetic raw material for animal drugs, fragrances, etc.

[Prior art and problems] Regarding the production method of optically active 2-halo-1-phenylethanol, α-haloacetophenone was extracted from Satucharomyces
Cerviciny [Journal of Chemical Society Chemical Communication (J, Chem
, Soc, Chem, Cor11T+, ).

400 pages, 1975 1 and Cryptococcus macerans [Journal of Organic Chemistry (
J. Org. The three-dimensional configuration is different from that of the body.

[Means for solving problems]

The present inventors prepared α-haloacetophenone by asymmetric reduction (S
As a result of searching for microorganisms that produce )-2-halo-1-phenylethanol, we found that various microorganisms convert it into (S)-2-halo-1-phenylethanol, which has a configuration opposite to the conventional knowledge. Heading, the invention was completed.

Asymmetric reduction L (S
) Microorganisms that convert into -2-halo-1-phenylethanol can be found by the method described below.

For example, Curcose 401. yeast extract 8f,
(NH4)2HPO418f, KH2PO471゜M
gSO4・7H20o, 8f, ZnSO4・7
H2060q.

FeSO44H2090'l, CuSO4H5H205
j%', MnSO4・4H2010q, NaClO
, 1f (per 11) A medium 800g/
Put it in a 21 volume Sakaro flask, sterilize it, plant microorganisms,
Culture with shaking at 0°C for 2 days. Thereafter, the bacterial cells were collected by centrifugation, suspended in 75 g of water containing 0.5% α-chloroacetophenone and 5% sucrose, and shaken at 80°C for 2 to 3 days in a 21-Sakaro flask. Then, an equal amount of ethyl acetate is added and extracted to produce 2-
j + o port = 1-phenylethanol Woka chromatography (column: silicon 0V-17°-0.8 x 20
(11, Column temperature 185°C, N2 gas pressure 1.2&9
/c-4) On the other hand, the optical purity of 2-chloro-1-phenylethanol is determined by distilling and purifying the extracted oil.
High performance liquid chromatography (column: manufactured by JASCO Corporation,
Chiralcel-OC.

Elution solvent hexane-ether (80:1), flow rate 2,2
ml/m, detection 220 nm), the (R) body is 2
9 minutes, (S1 form can be separated with a retention time of 88 minutes and the optical purity can be determined. Also, the microorganism that can convert α-chloroacetophenone to (S)-2-chloro-1-phenylethanol is α - Similarly, bromoacetophenone (
S)-2-bromo-1-phenylethanol.

As the microorganism that can be used in the present invention, any microorganism can be used as long as it has the ability to reduce α-haloacetophenone and convert it into 5)-2-halo-1-phenylethanol. For example, Nadsonia elongata (N
adsonia elongata) IFO0665
, Aegerita candida (Aegerita ca.
ndida) IFO6988, Agrocybe・
Agrocybecylyndrac
ea) I F 0 80299, Arakinoteika °
Arachnotica glomer
ata) IFo 9689, Arxella terrestris I
FO80208, Aspergillus niger (Aspe
rgillus niger) IFO4280, Beauveria bassiana (Beauveria bassi)
ana) I F O8554, Botryt(s fabae) I F 0
5895, Chloribrum chlamydospolis (Chlo
ridium chlamydosporis ) l
F 07070, Cryptophiale guadalcan
alense ) IFO80029, Cyllndrocladium camelliae
camelliae) I F 08979,Flatnmulina v
eltipes) I F 0 8829, Fusarium culmorum
) IFO6902, Gibberella fujikuroi (Gibb
erella fujikuroi) I F 0
6604, Gliocladium precuescens (
Gliocadium deliquescens
) I F 0 6617, Gliomastix murorum I
F O8269, Gymnoascas Rezii (Gym
noascus reessii) I F 076
89. Mortiere lamanniana (Mortiere)
lla ramanniana) I FO7825
, Mucor Abunda
ns ) IFO9B9B, Paecilomyces elegans I
F 0 7060, Penicillium restrictum (
Penicillium restrictum) I
F 0 7922, Scolecobasideim Telerum (
Scolecobasidium terreum) IF
O8854, Septoria tritici (5eptor
ia tritici) I F 07847, Stachybotrys chartarum (5tachybotrys)
chartarum) I F 0 5869, etc.

For culturing these microorganisms, any nutrient source that can be assimilated by these microorganisms can be used. For example, carbohydrates such as glucose and sucrose; alcohols such as ethanol and glycerol; hydrocarbons such as paraffin; organic acids such as monoacetic acid and propionic acid; carbon sources such as soybean oil or mixtures thereof; yeast extract, peptone, meat extract,
A normal medium containing nitrogen-containing inorganic organic nutrients such as corn staple liquor, ammonium sulfate, and ammonia; inorganic nutrients such as phosphate, magnesium, iron, manganese, and potassium; used. As a culture method, the culture is carried out aerobically at a pH of 4.0 to 9.5 in a nutrient medium at a temperature of 20 to 40°C for 1 to 5 days.

Reduction methods include using the culture solution as it is, separating the bacterial cells by centrifugation, etc.
There is a method of adding α-haloacetophenone to a resuspended solution in J solution or water, etc., and causing a reaction. In this reaction, a carbon source such as glucose, sucrose, etc. may be added as an energy source. Furthermore, the bacterial cells may be kept as viable cells, or may be treated with acetone, freeze-drying, or the like. Furthermore, these bacterial cells can also be used by immobilizing them on a carrier.

The α-haloacetophenone may be added all at once or in portions from the beginning of the reaction by dissolving it in an organic solvent that does not affect the crystal tt or reaction time. The reaction was carried out at a temperature of 10 to 60 °C at a pH of 5 to 9.
Carry out under stirring for 0 hours.

The (S)-2-halo-1-phenylethanol produced by the reaction can be collected directly from the reaction solution, or after bacterial cell isolation, extraction with a solvent such as ethyl acetate or dichloromethane.
After dehydration, distillation produces highly pure (S)-2-halo 1-
Phenylethanol is easily obtained.

〔Example〕

EXAMPLES The present invention will be specifically described below with reference to Examples, but the present invention is not limited to these Examples.

Example 1 The above A medium Boost was placed in a 21-volume sloped flask, and after sterilization, the microorganisms shown in Table 1 were inoculated. and 8
The culture was carried out aerobically for 2 days at 0°C with shaking. Bacterial cells were collected from this culture solution by centrifugation, suspended in 75 g of 0.1 M phosphoric acid solution (pH 7,0) containing 0.5% α-chloroacetophenone and 5% sucrose, and placed in a 21-saka flask. The mixture was shaken at 30°C for 120 hours. After the reaction, extract an equal amount of ethyl acetate from the reaction solution (twice)
(Sl-2-chloro-1-phenylethanol was extracted, and the ethyl acetate layer was analyzed by gas chromatography.
The reaction rate was investigated. Next, after dehydrating ethyl acetate with anhydrous sodium sulfate,
The solvent was removed to obtain an oily substance. This was purified by mini-distillation to obtain (S)-2-chloro-1-phenylethanol. This was dissolved in methanol and the optical purity was measured using high performance liquid chromatography. The results are shown in Table 1.

Table 1 □ Table 1 continued Example 2 The microorganisms shown in Table 2 were cultured in the same manner as in Example 1, and α-bromoacetophenone was used instead of α-chloroacetophenone, and the reaction and analysis were carried out in the same manner. The results are shown in Table 2.

Table 2 Example 8 51 Volume Mini Jar Ferment p-+r Containing A Medium 81
-y Inoculated with Supergillus nikah IFo 4280, 30°C1 aeration 1 v vm % bQ stirring 500
The cells were cultured for 24 hours at rpm. After completion of the culture, the bacterial cells were collected by centrifugation, suspended in 750 g of water, added with 7.5 f of α-chloroacetophenone and 889 g of sucrose, and stirred while keeping the pH at 7.0 with NaOH.

The reaction was stirred at 150 rpm for 72 hours. After the reaction was completed, the mixture was extracted twice with 750 g of ethyl acetate. After dehydrating the ethyl acetate layer with anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain oily substance 2.1f. Distill this (75-76°C/2
nHf)L, colorless oil (S)-2-chloro-1
- 6.8f of phenylethanol was obtained.

Sonospecific optical rotation K Ha[α] ”o' + 4'!, 2°
(c=2, cyclohexane), and according to high performance liquid chromatography analysis, the optical purity was 90% e, e,
Met.

Example 4 Aspergillus niger IFO as in Example 8
4280 was cultured and reacted with α-bromoacetophenone as a substrate to obtain 1.5f of (S)-2-bromo-1-phenylethanol (boiling point 85°C, 70.5flH1. The specific optical rotation was [α] The compound exhibited a molecular weight of +481 ((==l, chloroform), and the optical purity as determined by high-performance liquid chromatography analysis was 90% e, e,.

〔Effect of the invention〕

According to the present invention, as shown in Examples, optically active (S)-
2-Hero-1-phenylethanol can be produced efficiently.

Claims (3)

[Claims] (1) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, X represents a halogen atom] Formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] [In the formula, X is the same as [I]] Nadsonia, Aegerita, Agrocybe, Arachinoteica, Axella, Aspergillus, Beauveria, Botrytes, Chlorideum, Cryptophiale, Cylindrocladeum, Flamyulina, Fusarium, Gibberella with the ability to reduce Genus, Gliocladium, Gliomasthecus, Gymnoascus, Moriteirella, Mucor, Pecilomyces, Penicillium, Scholecobasidium,
An optical system characterized in that the (S)-2-halo-1-phenylethanol produced by the general formula [II] is collected by contacting a microorganism selected from a group of microorganisms belonging to the genus Septoria and Scytabotrys. Active (S)-2-halo-
Method for producing 1-phenylethanol. (2) The production method according to claim 1, wherein in the general formulas [I] and [II], the halogen atom is Cl or Br. (3) The microorganisms are Nadsonia elongata, Aegerita kyandida, Agrocybe cylindracae, Arachinoteca glomerata, Axella tersteris, Aspergillus niger, Beauveria bassiana, Botulytes huavee, Chlorideum chlamydospolis, Cryptophiale guadar Canarense, Cylindrocladium camelliae, Flamyulina verteipes, Fusarium curmorum, Gibberella fujikuroi, Gliocladium delicituescens, Glioasteix murorum, Gymnoascus reziii, Moriteirella ramanniana, Mucor avantans, 3. The production method according to claim 1 or 2, which is Pecilomyces elegans, Penicillium restrictum, Scholecobasidium terreum, Septoria triticii, Stachybotrys chiaritarum.