JPH03254690A - Production of optically active aromatic cyanohydrin acetate - Google Patents

Abstract

PURPOSE:To easily produce the subject compound useful as an intermediate for pharmaceuticals, etc., in one step and high efficiency at a low cost by simultaneously carrying out the hydroxycyanation and the selective acetylation of an aromatic aldehyde by a specific method using a lipase. CONSTITUTION:The objective compound of formula II is produced by carrying out the above reactions in an organic solvent in the presence of (A) lipase, immobilized lipase, lipase-producing microorganism, immobilized product of said microorganism or treated and immobilized product of said microorganism and (B) an aromatic aldehyde of formula I (R<1> to R<3> are H, halogen, etc.; X is O, S, etc.), a cyano group-donative organic cyanogen compound, an acetyl group-donative acetic acid ester and a catalytic amount of an organic base.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing optically active aromatic cyanohydrin acetate, which is useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, and the like.

[Prior Art] Cyano groups are converted into carboxylic acids, -grade amino groups, and amide groups by conventional chemical methods, such as hydrolysis, oxidation, or reduction reactions, and acetic acid esters are easily converted into hydroxy derivatives by conventional hydrolysis reactions. It can be converted to . Therefore, the aromatic cyanohydrin acetate of the compound of the present invention includes aromatic acetoxyaminoethyl derivatives, aromatic hydroxyaminoethyl derivatives, aromatic acetoxycarbamoylethyl derivatives, aromatic hydroxycarbamoylethyl derivatives, aromatic acetoxyacetic acid derivatives, and aromatic hydroxyl derivatives. It can be easily converted into acetic acid derivatives by conventional chemical methods.

Physiologically active substances of aromatic compounds with 1-hydroxy-2-aminoethyl side chains typically include adrenergic agonists such as epinephrine, norepinephrine, isoproterenol, terbutaline, phenylephrine, epinephrine, and salbutamol. Yes, these drugs are used to treat bronchial asthma, cardiac stimulation, and cardiovascular diseases such as increased blood pressure, as well as adrenergic neuroleptics such as labetalol and sotalol.
These drugs are used to treat hypertension and angina pectoris.

Aromatic compounds with 1-cyano-1-oxycarbonyl side chains are useful as important intermediates for pyrethroid pesticides such as fenvalerate and deltamethrin.

Generally, in the case of pharmaceuticals and agricultural chemicals, one enantiomer of the optical isomer is more biologically active than the other enantiomer. The difference in activity strength can be several hundred times greater. Therefore, efficient production of useful optical isomers is extremely important in developing pharmaceuticals and agricultural chemicals.

Conventionally, aromatic cyanohydrin acetate was synthesized by a chemical method by combining an aromatic aldehyde and acetone cyanohydrin with S)-α-dimethylamino-ε-caprolactam as a catalyst (Inoue et al., Chemistry Letters 1986). Year, 931 pages (S, Ino
ue et, al,, Ches, Lett.

19H, 931)). However, in this method, the optical purity of the target compound is 63% even under the highest conditions, and it is not a practical method for producing pure optical isomers. In a similar reaction, (3S, BS)-3-benzyl-6-<4-imidazolylmethyl)piperazine-2
,5-dione, the optical purity of the target compound was 97% (Inoue et al., Journal of Organic Chemistry, Vol. 55, p. 181, 1990).
Year (J, Org, Ches+, 55181.1990
)reference). However, since this method uses toxic hydrogen cyanide gas, it is not a safe method in actual industrial production because it poses problems in terms of occupational health.

Furthermore, aromatic aldehydes, alkylsilyl cyanides,
and an optically active titanium compound in the presence of an aluminosilicate to obtain an optically active aromatic cyanohydrin acetate with good chemical yield and optical purity (see JP-A-84-90161).

However, this method is not a satisfactory reaction from the viewpoint of industrial production because the reagents used are expensive and need to be used in an equivalent amount relative to the substrate.

On the other hand, in addition to the chemical production method of optically active aromatic cyanohydrin acetate, a biochemical production method has been reported. One is a production method using a mixture (racemic form) of optically active aromatic cyanohydrin acetates as a substrate and utilizing a stereospecific enzymatic reaction by microorganisms to obtain one optical isomer using so-called rapid optical resolution. It is (
Ota et al., Agricultural Biological Chemistry, Vol. 53, No. 1, p. 281, 1989 (H, O
ta et al, Agric, Blol, Ches
,.

53, [1), 281.1989)). This method is aqueous, and since the substrate is poorly soluble in water, the substrate concentration cannot be increased, and therefore the reaction time is long, making it inefficient. Furthermore, this method is extremely complicated in post-reaction processing operations, such as the need for a large amount of organic solvent for removing bacterial cells and extracting the target product. The other one is the same as the front wheel.
Mixture of optically active aromatic cyanohydrin acetates (
The difference is that it is a kinetic optical resolution method using a racemic body as a substrate, or that lipase is used instead of a microorganism (see JP-A-62-164857). Since this method is also an aqueous reaction, the problem is that the post-processing after the reaction is complicated, as in the case of the front wheel.

[Problem 8 to be solved by the invention] The present invention solves the problems of the above-mentioned conventional methods. In other words, in the case of the chemical production method of optically active aromatic cyanohydrin acetate, there were problems in the chemical yield of the target product, optical purity, labor hygiene, and the expensive reagents used, but this method overcomes these problems. It is superior in terms of yield, optical purity, occupational hygiene, and inexpensive reagents. Conventionally, it required a lot of labor to extract optically active compounds, and as a result, the price of optically active compounds was expensive, but according to the present invention, optically active compounds can be obtained using simple operations and easy-to-handle reagents. Aromatic cyanohydrin acetate can be obtained at low cost.

In addition, in the biochemical production method of optically active aromatic cyanohydrin acetate, the conventional method selectively hydrolyzes a racemic mixture of aromatic cyanohydrin acetate synthesized in advance in two steps from aromatic aldehyde. In contrast, the present method simultaneously performs hydroxycyanation and selective acetylation from aromatic aldehydes as raw materials to produce the target optically active aromatic cyanohydrin acetate in one step. Furthermore, in the conventional method, the reaction was carried out in an aqueous system, which caused problems in terms of substrate concentration and isolation of the target substance, but according to the present invention, the substrate concentration can be maintained at a high level due to the organic solvent system, making it more efficient. Furthermore, the isolation procedure for the target substance was greatly simplified.

[Means for Solving the Problems] In order to solve the above problems, the present invention provides lipases of microbial origin, aromatic aldehydes, organic cyanide compounds capable of donating cyano groups, and acetyl groups. By coexisting acetic acid esters and a catalytic amount of an organic base in an organic solvent, the production reaction of aromatic cyanohydrins from aromatic aldehydes and stereoselective acetylation are simultaneously performed in one step, resulting in high optical purity. The present invention was completed based on the inventors' knowledge that optically active aromatic cyanohydrin acetates can be obtained.

The biochemical production method of optically active aromatic cyanohydrin acetate of the present invention comprises a group consisting of lipase, an immobilized product of lipase, a microorganism having lipase-producing ability, an immobilized product of the microorganism, and an immobilized product of a processed product of the microorganism. at least one selected from the above, an organic cyanide compound capable of donating a cyano group, such as acetone cyanohydrin and cyanomethyl acetate, and an acetate ester capable of donating an acetyl group, such as isopropenyl acetate and vinyl acetate and a catalytic amount of an organic base such as quinidine, cinchonidine, 2-(
N,~dimethylamino)-ethanol in an organic solvent, thereby achieving the above object.

That is, the present invention relates to a lipase, an immobilized product of lipase, a microorganism capable of producing lipase, an immobilized product of the microorganism, or an immobilized product of the processed product of the microorganism, and the general formula (I): (wherein, R1, R2, and R3 are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, an alkenyl group, an alkoxy group or an aryloxy group, and R1...R2 and R2...R3 form a ring. However, R2 does not form a ring with R1 and R3 at the same time, and when forming a ring, R1, R2
and R3 together have 2 to 5 carbon atoms, of which the carbon atoms may be substituted with an alkyl group and/or an alkoxy group, and the carbon atoms forming the ring may be replaced with oxygen. well, and X is -CH-
C) an aromatic aldehyde represented by l--0--8- or -NH-, an organic cyanide compound capable of donating a cyano group, an acetate ester capable of donating an acetyl group, and a catalyst General formula (II) consisting of coexisting an amount of an organic base in an organic solvent:
The present invention relates to a method for producing an optically active aromatic cyanohydrin acetate represented by the formula (wherein R1, R2, R3 and X are the same as above).

[Example] The present invention produces acetic acid, which can be converted into a cyanohydrin by reacting an aromatic aldehyde with an organic cyanide compound capable of donating a cyano group in the presence of a catalytic amount of an organic base, and at the same time can donate an acetyl group. Only the aromatic cyanohydrin of one of the S or R configuration enantiomers is selectively acetylated by allowing the esters to interact with a biogenic lipase.

The cyanohydrination and acetylation reactions are carried out in organic solvent systems such as diisopropyl ether, diethyl ether, cyclohexane, hexane, and the like. The solvent used is not limited to these, but any organic solvent can be used as long as it dissolves the aromatic aldehydes, organic cyanide compounds, organic bases, and acetic esters serving as substrates and does not lose lipase activity.

The substrate concentration may be within a concentration range that completely dissolves each of the aromatic aldehyde, organic cyanide compound, organic base, and acetate as a substrate, but 1 mmol of aromatic aldehyde to 1 mmol of organic solvent is used for the reaction. It is preferable to use 1011 to 3011, especially 1011 from the viewpoint of reaction control.

The quantitative ratio of substrates is aromatic aldehyde, organic cyanide,
Each of the acetic acid esters is used in the reaction in a quantitative ratio of 1:1:1, but from the viewpoint of reaction yield, preferably 1 to 3 equivalents of the organic cyanide compound and the acetic acid esters are used per equivalent of the aromatic aldehyde. It is particularly preferable to use 1 to 4 equivalents of the organic cyanide compound and 2 equivalents of the acetic acid ester.

The amount of lipase to be mixed depends on the amount of immobilized lipase, the purity of lipase, the activity of lipase, the type of bacterial cells, etc. However, usually 0.5 to 1.0 g of lipase is used per 10 ml of aromatic aldehyde.

The organic base concentration is 1 to 2 in terms of promoting cyanohydrination.
0% mol O1 is preferred, and 5% mol is particularly preferred.

Carriers for the immobilization of lipases and microorganisms include natural products such as alginic acid, carrageenan, collagen, cellulose, acetyl cellulose, agar, cellophane, collodion, diatomaceous earth, polyacrylamide,
These include synthetic polymers such as polystyrene, polyethylene glycol, polyurethane, and polybutadiene.

As the immobilization method, conventional methods can be used, such as carrier binding method, crosslinking method, entrapping method, etc., and preferably immobilization in which the enzyme is physically adsorbed onto a porous inorganic carrier such as diatomaceous earth. law is used.

The amount of lipase and microorganisms immobilized on the carrier depends on the carrier, the type of microbial cells, the purity of the lipase, and the like. However, from the viewpoint of maintaining lipase activity, 1 to 150 g of carrier is usually used per microbial cell ig (wet basis). For lipase, it is appropriate to use 0.1 to 2 g of carrier per 30 enzyme units.

Microorganisms that produce lipase used in the production method of the present invention or used in the production method of the present invention are not particularly limited as long as they have the ability to produce lipase.
For example, Geotrichum s
p, ), Rhizopus (Aspergillus sp.
,), Penicillium (Rh1zopus sp,)
, Mucor sp., javanl
Examples include microorganisms belonging to the genus Shutomonas, and in particular the genus Shutomonas fluorescens from the viewpoint of substrate selectivity.

These, particularly lipase and microorganisms capable of producing lipase, are usually commercially available and easily available.

In the present invention, the treated product of microorganisms refers to a culture obtained by culturing bacterial cells in a liquid medium, bacterial cells isolated from a culture solution, crude lipase, purified lipase, a lipase-containing extract, or a concentrated liquid thereof.

The reaction temperature in the aromatic cyanohydrin acetate synthesis reaction is preferably 20 to 50°C, particularly preferably 2
The temperature is adjusted to 5-40°C. If it is below 20°C, the ester reaction will not proceed sufficiently, and if it is above 50°C, lipase activity will decrease and optical purity will be affected.

The reaction time depends on the substrate used, the type of lipase, the substrate concentration,
Although it varies depending on the activity of lipase, etc., it is appropriate to carry out the treatment for 5 to 250 hours. However, the reaction time can be shortened by increasing the amount of microorganisms or lipase.

Unreacted aromatic cyanohydrin can be easily removed and converted into the raw material aromatic aldehyde by, for example, decomposing it with sodium carbonate and then acting on sodium bisulfite, so it can be used repeatedly.

Examples of the present invention will be shown below and will be described in more detail, but these Examples are not intended to limit the present invention in any way.

Example 1 Production of 1-cyano-1-(3,4-methylenedioxyphenyl)methyl acetate 20if
Pseudomonas ◆fluorescens (Pseudomonas f'1uorescens)
) lipase 40H (lyophilized powder) was dissolved.

Add diatomaceous earth (Hyf'1osuper-eel) to this solution.
) and stirred at 0° C. for 15 minutes. This product was naturally dried on a Petri dish, further dried in a refrigerator for 3 days, then dried under reduced pressure for 1 day in the presence of calcium chloride, and then dried under reduced pressure for 3 days in the presence of phosphorus pentoxide to obtain an immobilized lipase.

1 part piperonal to 100 ml diisopropyl ether
．． 5g (10ml), isopropenyl acetate
) 2.2 ml (20 liters 1O1) and 1.37 ml (15 mmol) of acetone cyanohydrin were added, stirred at room temperature, and to this was added 182 mg (0.5 mmol) of quinidine.
l) and the above immobilized lipase, and stirred at 40°C (
500 rpm) for 98 hours. After the reaction was completed, the reaction solution was filtered under reduced pressure to remove the enzyme, which was then washed successively with sodium carbonate, IN-hydrochloric acid, sodium bisulfite, and saturated saline, dried over anhydrous magnesium sulfate, and distilled off under reduced pressure to obtain a transparent oil. I got it. This product was purified using a silica gel column (developing solvent: n-hexane/ethyl acetate-7/3) to obtain the desired i-cyano-1-(3,4-methylenedioxyphenyl)methyl acetate. I gained 44g (
Yield: 25%).

The optical purity of the target product was analyzed by 50-NMR (200 MHz) using a chiral rearrangement reagent (Europium Tris[3-(heptafluoropropylhydroxymethylene-(+)-camphorate] derivative).

Furthermore, HPLC analysis using an optically active column was also conducted. As a result, 5)-1-cyano-1-(3,4-
The optical purity of methylenedioxyphenyl)methyl acetate was 95% e,e value.

The physicochemical properties of the above target compound are shown below.

Proton nuclear magnetic resonance analysis (in deuterated chloroform solvent, 20
0MHz) δ; 2.15 (3H,S, COCH3), 6.0
3 (2H, s.

-OCCO2), 6.31 (IH,s, -〇〇)
, 6.84 (2H, -6sn, -2°H) Mass spectrometry (direct introduction, 20eV) mHz: 219 (M") Example 2 1-cyano-1-(3,4-methylenedi Production of 1-cyano-1-(3,4-methylene dioxyphenyl) methyl acetate was prepared in the same manner as in Example 1, except that Pseudomonas sp. oxyphenyl)methyl acetate was separated.As a result,
Yield: 34%, optical purity: 81% e, e, value of 6)-1
-cyano-1-(3,4-methylenedioxyphenyl)
Changed to methyl acetate.

Example 3 Production of 1-cyano-1-(3,4-methylenedioxyphenyl)methyl acetate As a lipase, Chromobacterium viscosum (C
hromobacterfua+ vlscosua+
), except that the reaction was carried out for 11,818 hours using genus lipase.
l-Cyano-1-(3,4-methylenedioxyphenyl)methyl acetate was separated in the same manner as in Example 1. As a result, yield: 24%, optical purity: 89%e
, e, the value of 6)-1-cyano-1-(3,4-methylenedioxyphenyl)methyl acetate was changed.

Example 4 Production of 1-cyano-1-(3,4-methylenedioxyphenyl)methyl acetate Same as Example 1 except that Pseudoonas sp. lipase was used as the lipase and the reaction was carried out for 11,919 hours. Similarly, 1-cyano-1-<3.4-methylenedioxyphenyl)methyl acetate was separated. As a result, yield: 28%, optical purity = 85% e, e, value of 6) 1
-cyano-1-(3,4-methylenedioxyphenyl)
Changed to methyl acetate.

Example 5 Production of 1-cyano-1-(3,4-methylenedioxyphenyl)methyl acetate As a lipase, Mucor javanicus (Mucor
1-cyano-1-(3,4-methylenedioxyphenyl)methyl
Separation of acetate was carried out. As a result, yield: 22%
, Optical purity: 88%e, e, value of S) ■-Cyano 1-
Changed to (3,4-methylenedioxyphenyl)methyl acetate.

Example 6 1-Cyano-1-phenylmethyl acetate was prepared according to 1. As a result, yield: 35%, optical purity = 79
%e, e, value of 6)-1-cyano-1-phenylmethyl acetate was changed.

The physicochemical properties of the above target compound are shown below.

Proton nuclear magnetic resonance analysis (in deuterated chloroform solvent, 20
0MHz) 7.44-7.60 (5H,s, aromatic ring H) mass spectrometry (
Direct introduction, 20eV) mlz: 175 (M+) Elemental analysis (molecular formula 20089NO2, molecule ffi:
175) Physical value 20% 88.5B, ■% 5.1g,
N%8.00 Actual value = C%6g, 57, H%5.20
, N% 8.14 Example 7 Production of 1-cyano-1-phenylmethyl acetate The reaction was carried out in the same manner as in Example 1, except that benzaldehyde was used as the substrate and reacted for 198 hours. Separation of 1-cyano-l-phenylmethyl acetate Cyano-l-phenylmethyl acetate was separated in the same manner as in Example 2 except for the following changes. the result,
Yield: 26%, optical purity: 54%e, e, value of 6)-1
-cyano-(-phenylmethyl acetate was changed.

Example 8 Production of 1-cyano-1-phenylmethyl acetate l-cyano-1-
Separation of phenylmethyl acetate was carried out. As a result, yield: 32%, optical purity near 8%e, e, value l5
)-1-cyano-l-phenylmethyl acetate was changed.

Example 9 Production of 1-cyano-1-phenylmethyl acetate l-cyano-1-
Separation of phenylmethyl acetate was carried out. As a result, yield: 33%, optical purity = 67%e, e, value of 6)
-1-cyano-1-phenylmethyl acetate was changed.

Example 10 Production of 1-cyano-l-phenylmethyl acetate l-cyano-l-
-Phenylmethyl acetate was separated. As a result, yield: 53%, optical purity = 77%e, e, value of 6
)-1-cyano-1-phenylmethyl acetate was changed.

Example 11 Production of 1-cyano-1-phenylmethyl acetate 1-Cyano-1-acetate was produced in the same manner as in Example 6, except that Pseudomonas sp. Separation of phenylmethyl acetate was carried out. As a result, yield: 41%, optical purity = 52
%e, e, value of 6)-1-cyano-1-phenylmethyl acetate was changed.

Example 12 Production of 1-cyano-1-(4-chlorophenyl)methyl acetate 1-Cyano-1-(4- Separation of chlorophenyl)methyl acetate was carried out. As a result, yield: 45%, optical purity = 81% e, e, value of 6)-1-cyano-1-(4-chlorophenyl)methyl acetate was obtained.

The physicochemical properties of the above target compound are shown below.

Proton nuclear magnetic resonance analysis C in deuterium chloroform solvent, 20
0MHz) 7.40-7.55 (4H, i, aromatic ring H) mass spectrometry (
Direct introduction, 20eV) mlz: 209 (M +) Elemental analysis (molecular formula: CIOH1]ClNO2, molecule Ji: 209) Theoretical value: C% 57.30SHX 3
．． 85, N% 6.88 Actual value 20% 57.4B,
N%3. H, N% 6.87 Example 13 Production of 1-cyano-1-(4-chlorophenyl)methyl acetate Produced in the same manner as in Example 2 except that 4-chlorobenzaldehyde was used as the substrate and the reaction was carried out for 96 hours. -Cyano-1-(4-chlorophenyl)methyl acetate was separated. As a result, yield: 25%, optical purity: 28
3% e, e, value of 6)-1-cyano-1-(4-chlorophenyl)methyl acetate was changed.

Example I4 Production of 1-cyano-1-(4-chlorophenyl)methyl acetate 1-Cyano-1-(4 -chlorophenyl) methyl acetate was separated. As a result, yield: 18%, optical purity = 6
5)-1-Cyano-1-(4-chlorophenyl)methyl acetate with a value of 1% e,e was obtained.

Example 15 Production of 1-cyano-1-(4-chlorophenyl)methyl acetate 1-Cyano-1-(4 -chlorophenyl) methyl acetate was separated. As a result, yield: 28%, optical purity = 7
C3I-1-cyano-1-(4-chlorophenyl)methyl acetate with a value of 9% e,e was changed.

Example 16 Production of 1-cyano-1-(3-phenyloxy)phenylmethyl acetate 1-Cyano-1 -(3-phenyloxy)phenylmethyl acetate was separated.

As a result, yield: 38%, optical purity: 283%, e, value of B)-1-cyano-1-(3-phenyloxy)phenylmethyl acetate was obtained.

The physicochemical properties of the above target compound are shown below.

Proton nuclear magnetic resonance analysis (in deuterated chloroform solvent, 20
0MHz) δ: 2.17 (311,s, C0CHi), 6.
36 (IH, s, -('H), I□ 7°00~7.45 (9H, m, aromatic ring +1) Mass spectrometry (direct introduction, 20 eV) mlz: 267 (M) Elemental analysis (molecular formula: C16813NO3 , molecular weight:
287) Theoretical value = C% 71.90, N% 4.90,
N%5.24 Actual value = C%71.81%H%4.92
, N% 5.48 Example 17 Production of 1-cyano-1-(3-phenyloxy)phenylmethyl acetate The same procedure as Example 2 was carried out except that 3-phenyloxybenzaldehyde was used as the substrate and the reaction was carried out for 119 hours. l-cyano-1-(3-phenyloxy)phenylmethyl acetate was separated. As a result, yield:
27%, optical purity: 85%e, e, value of 61-1-cyano-1-(3-phenyloxy)phenylmethyl acetate was recovered.

Example 18 Production of 1-cyano-1-(3-phenyloxy)phenylmethyl acetate 1-Cyano-1 -(3-phenyloxy)phenylmethyl acetate was separated.

As a result, (S)-1-cyano-1-(3-phenyloxy)phenylmethyl acetate was obtained with a yield of 27% and an optical purity of 281%.

Example 19 Production of 1-cyano-1-(3-phenyloxy)phenylmethyl acetate 1-Cyano-1 -(3-phenyloxy)phenylmethyl acetate was separated. As a result, yield:
(S)-1-cyano-1-(3-phenyloxy)phenylmethyl acetate with an optical purity of 29%; an e,e value of 55% was obtained.

Example 20 Production of 1-cyano-1-(3-phenyloxy)phenylmethyl acetate 1-Cyano-1 -(3-phenyloxy)phenylmethyl acetate was separated.

As a result, 61-1-cyano-1-(3-phenyloxy)phenylmethyl acetate was obtained with a yield of 32% and an optical purity of 68%.

Example 21 Production of 1-cyano-1-(3-phenyloxy)phenylmethyl acetate 1-Cyano-1 -(3-phenyloxy)phenylmethyl acetate was separated.

As a result, (s)-1-cyano-1-(3-phenyloxy)phenylmethyl acetate was obtained with a yield of 27% and an optical purity of 77%.

Example 22 Production of t->ano-1-(2-naphthyl)methyl acetate Using 2-naphthalenecarbaldehyde as the substrate 240
l-
Separation of cyano-1-(2-naphthyl)methyl acetate was carried out. As a result, yield: 43%, optical purity near 5
%e, e, value of (Sit-cyano-1-(2-naphthyl)methyl acetate changed.

The physicochemical properties of the above target compound are shown below.

Proton nuclear magnetic resonance analysis (in deuterated chloroform solvent, 20
0MHz) δ: 2.19 (3H,s, COC), [i,5
9 (LH, s, -1:H), 7.55-7.70 (3)
1. gourd, aromatic ring 11), 7.85-8.03 (4H,
■, aromatic ring H) Mass spectrometry (direct introduction, 20 eV) mHz: 225 (M) Example 23 Production of 1-cyano-1-(2-naphthyl)methyl acetate Reaction for 77 hours using 2-naphthalenecarbaldehyde as the substrate 1-Cyano-1-(2-naphthyl)methyl acetate was separated in the same manner as in Example 2, except for the following steps. As a result, yield: 33%, optical purity near 8
%e, e, value of (Sml-cyano-1-(2-naphthyl)methyl acetate changed.

Example 24 Production of 1-cyano-1-(l-naphthyl)methyl acetate Using l-naphthalenecarbaldehyde as the substrate 240
1-
Separation of cyano-1-(1-naphthyl)methyl acetate was carried out. As a result, yield: 31%, optical purity 204
%e, e, value of 6i 1-cyano-1-(1-naphthyl)
Changed to methyl acetate.

The physicochemical properties of the above target compound are shown below.

Proton nuclear magnetic resonance analysis (in vertical chloroform solvent, 20
0 MHz) δ: 2.19 (3H,s, C0CHx), 7.2
6 (lLs, -Cll), 7.50-8.15 (7H
, ■, aromatic ring H) Mass spectrometry (direct introduction, 20 eV) mHz: 225 (M) Example 25 Production of 1-cyano-1-(1-naphthyl)methyl acetate Using L-naphthalenecarbaldehyde as the substrate 220
l-
Separation of cyano-1-(1-naphthyl)methyl acetate was carried out. As a result, yield: 21%, optical purity 208
%e, e, value of Bit-cyano-1-(1-naphthyl)
Changed to methyl acetate.

Example 26 ■-Production of cyano-1-(2-furyl)methyl acetate l-Cyano-1-(2-
Separation of (furyl) methyl acetate was carried out. As a result, yield: 45%, optical purity: 47%
-1-cyano-1-(2-furyl)methyl acetate was changed.

The physicochemical properties of the above target compound are shown below.

Proton nuclear magnetic resonance analysis (in deuterated chloroform solvent, 20
0MHz) δ: 2.17 (3H,S,C0CH5), 6.4
5 (LH, dd, J4'3°-3,4Hz, J4
'5°-1,8Hz, -C4°H), [i,4
8 (LH, dd, J5"4゛-1,8Hz, J5'3'
-0.8Hz.

-C511) Mass spectrometry (direct introduction, 20eV) mHz: 165 (M+) Elemental analysis (molecular formula: Ca) 17 NO3, molecular weight:
11i5) Theory*: CX 58.18.1% 4
．． 27, N% 8.48 Actual value 20% 5B, 45.11
%4.35, N%B, B7 [Effects of the Invention] Since the present invention is configured as described above, it produces the effects described below.

That is, by changing the reaction system from an aqueous system to an organic solvent system, the solubility of the substrate in the solvent is increased, and the substrate concentration can be increased. Therefore, shortening of reaction time and improvement of efficiency can be achieved. Then, the subsequent removal of microbial cells,
The target substance can be easily isolated. Furthermore, by producing optically active aromatic cyanohydrin acetate from aromatic aldehydes in one step, optically active aromatic cyanohydrin acetate, which is a very useful synthetic intermediate, can be produced in a short process and at low cost with simple operations. It will be done.

Ranimy

Claims (1)

[Scope of Claims] 1. Lipase, an immobilized product of lipase, a microorganism capable of producing lipase, an immobilized product of the microorganism, or an immobilized product of the processed product of the microorganism, and general formula (I): ▲Mathematical formula, chemical formula, table, etc. There is a represents R^1...R^2 and R^2...
R^3 may form a ring, but at the same time R^2
^1 and R^3 do not form a ring, and when they do, R^1, R^2 and R^3 together have 2 to 5 carbon atoms, of which carbon atoms may be substituted by an alkyl group and/or an alkoxy group, and the carbon atoms forming the ring may be replaced by oxygen, and X is -CH=CH-, -O-, -S- or An aromatic aldehyde represented by -NH-), an organic cyanide compound capable of donating a cyano group, an acetate ester capable of donating an acetyl group, and a catalytic amount of an organic base are coexisting in an organic solvent. General formula (II) consisting of A method for producing aromatic cyanohydrin acetate. 2 The lipase is derived from Geotrichum, Rhizopus, Aspergillus, Penicillium, Rhodotoral, Clodosporium, Trichoderma, Fusarium, Pseudomonas, Candida, Arachnoid, Mucor, Chromobacterium or 2. The method for producing optically active aromatic cyanohydrin acetate according to claim 1, which is a lipase produced from a microorganism belonging to at least one member of the genus Corejabanicus or an immobilized product thereof. 3 If the microorganism is of the genus Geotrichum, Rhizopus, Aspergillus, Penicillium, Rhodotoral, Clodosporium, Trichoderma, Fusarium, Pseudomonas, Candida, Arachnoid, Mucor, Chromobacterium or 2. The method for producing optically active aromatic cyanohydrin acetate according to claim 1, which is a microorganism belonging to at least one member of the genus Corejabanicus or an immobilized product thereof. 4 The organic base is quinidine, cinchonidine or 2-(
Claim 3: N,N-dimethylamino)-ethanol
The method for producing the optically active aromatic cyanohydrin acetate described above. 5. The method for producing optically active aromatic cyanohydrin acetate according to claim 4, wherein the organic cyanide compound capable of donating a cyano group is acetone cyanohydrin or cyanomethyl acetate. 6. The method for producing optically active aromatic cyanohydrin acetate according to claim 5, wherein the acetate ester capable of donating an acetyl group is isopropenyl acetate or vinyl acetate. 7 Reaction temperature is 20-50°C, preferably 25-40°C
7. The method for producing optically active aromatic cyanohydrin acetate according to claim 6, wherein the temperature is adjusted to .degree.