JPH10273466A - Method for producing 2-hydroxy-1-indanone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce 2-hydroxy-1-indanone useful as an intermediate for synthesis of pharmaceuticals and the like by an industrial mass production process. SOLUTION: A 2-hydroxy-1-indanone derivative represented by the following general formula (1) is added to a basic compound selected from LiOH, KCN and NaCN, an enzyme selected from lipase, aminoacylase, protease and esterase, or RE. A racemic or optically active 2-hydroxy-1-indanone is produced by reacting a rare earth catalyst represented by (OSO ₂ Rf) ₃ (where RE represents a rare earth metal and Rf represents a perfluoroalkyl group). Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 2-hydroxy-1-indanone, which is useful as a synthetic intermediate for pharmaceuticals and the like.

[0002]

2. Description of the Related Art As a method for producing 2-hydroxy-1-indanone, a method involving hydrolysis or alcoholysis of a corresponding ester or carbonate is preferred in terms of easy industrial production. In general, when producing alcohols by hydrolyzing esters or carbonates, it is known that inorganic bases such as sodium hydroxide can be widely used as a catalyst and can be used well. -1-Indanone derivatives are extremely unstable with respect to bases, and when a base such as sodium hydroxide usually used in hydrolysis is allowed to act, side reactions other than hydrolysis or alcoholysis take precedence. Therefore, the corresponding alcohol, that is, 2-hydroxy-1-indanone, cannot be obtained. In order to prevent decomposition, a method of hydrolyzing 2-acetoxy-1-indanone by the action of potassium carbonate in a hydrogen stream has been known (Ishiwara,
F. , J. et al. Pract. Chem. <2> 108 (19
24) 197), there is a problem in implementing the method using a hydrogen stream on an industrial scale.

[0003] Further, when an alcohol is produced by hydrolyzing an ester or a carbonate, an acid catalyst can be used, but there is a disadvantage that the reaction is generally slow. Means such as heating are used to improve the reaction rate, but when the raw material is an optically active compound, there is a problem that racemization occurs.

As a method for producing optically active 2-hydroxy-1-indanone, a method for asymmetrically oxidizing a silyl enol ether of 1-indanone (JP-A-7-228)
No. 586) is known, but there is a problem in carrying out on an industrial scale such as using an expensive catalyst.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for producing 2-hydroxy-1-indanone which is easy to apply to an industrial mass production process and to produce an optically active substance.

[0006]

Means for Solving the Problems The present invention provides the following general formula (1)

Embedded image (Wherein R represents an acyl group or an alkoxycarbonyl group) when hydrolyzing or alcoholyzing a 2-hydroxy-1-indanone derivative represented by the following formula: a group consisting of lithium hydroxide, potassium cyanide and sodium cyanide. Wherein at least one basic compound selected from the group consisting of

Embedded image Is a method for producing 2-hydroxy-1-indanone.

Further, the present invention provides the following general formula (1 ')

Embedded image (Wherein R is the same as described above), when hydrolyzing or alcoholyzing the (R) -2-hydroxy-1-indanone derivative represented by the formula (I), selected from the group consisting of lipase, aminoacylase, protease and esterase. Wherein at least one enzyme is acted upon,

Embedded image Is a method for producing (R) -2-hydroxy-1-indanone represented by the formula:

Further, the present invention provides a compound represented by the following general formula (1):

Embedded image When a 2-hydroxy-1-indanone derivative represented by the following formula is hydrolyzed or alcoholyzed, a catalyst represented by the following general formula (3) is used.

Embedded image wherein a rare earth catalyst represented by RE (OSO ₂ Rf) ₃ (3) (wherein RE is a rare earth metal element and Rf is a perfluoroalkyl group) is caused to act. 2-hydroxy-1-
This is a method for producing indanone.

Hereinafter, the present invention will be described in detail. 2-hydroxy-1 represented by the general formula (1) used in the present invention
-The indanone derivative can be easily produced by the following method. That is, 1-indanone is reacted with a brominating agent such as bromine, dibromomeldrum acid, and pyridinium bromide perbromide to form 2-bromo 1-indanone, which is then acetate, formate, propionate, and benzoate. Or a method of reacting a carboxylate such as

Embedded image (Wherein R is as defined above) and the following general formula (5)

Embedded image (Wherein, R is the same as described above; X represents a chlorine atom or a bromine atom) via a compound represented by the general formula (1). Is also convenient. At this time, as a method of converting phenylalanine into a compound represented by the general formula (4), a known method can be used. For example, phenylalanine is reacted with nitrite in an acidic solvent to obtain 3 −
Producing phenyl lactic acid (DE 3334739, J.A.
m. Chem. Soc. , 1987, 52, 4978-
4984), and a method in which acyl halides, haloformates, acid anhydrides or carbonates are allowed to act thereon (Tetrahedron Lett., 199).
5, 36, 6449-52). When acetic acid is used as the acidic solvent and sodium nitrite is used as the nitrite, in the 3-phenyllactic acid derivative represented by the general formula (4), a compound in which R is an acetyl group can be directly obtained from phenylalanine ( J. Org.
m. 1987, 52, 4978-4984).

As a method for converting a 3-phenyllactic acid derivative represented by the general formula (4) to 2-hydroxy-1-indanone via an acid halide represented by the general formula (5), For the 3-phenyllactic acid derivative represented by the formula (4), thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, oxalyl chloride, carbon tetrachloride-triarylphosphine, After reacting with a halogenating agent selected from carbon bromide-triarylphosphine and cyanuric chloride to derive the acid halide represented by the general formula (5), a Lewis acid such as aluminum chloride or polyisocyanate is used. A method of reacting a protonic acid such as phosphoric acid can be used.

In the above-mentioned method for producing 2-hydroxy-1-indanone through the general formulas (4) and (5) using phenylalanine as a starting material, the optical purity is substantially maintained throughout the entire reaction. That is, if (R) -phenylalanine having an optical purity of 100% is used as a raw material, it is possible to obtain (R) -2-hydroxy-1-indanone having an optical purity of almost 100%. In addition, since the reaction is not affected by the optical purity of the raw materials and the absolute configuration of the optical center, raw materials having any mixing ratio of the (R) -form and the (S) -form can be used. It has optical purity almost equal to the optical purity of the raw material.

In the present invention, R in each formula is an acyl group or an alkoxycarbonyl group. Examples of the acyl group include an acetyl group, a propionyl group and a benzoyl group. An ethoxycarbonyl group is a typical example.

The 2-hydroxy- represented by the general formula (1)
When a basic substance selected from lithium hydroxide, potassium cyanide and sodium cyanide is allowed to act on the 1-indanone derivative to obtain 2-hydroxy-1-indanone, the formula is represented by the general formula (1). 2-hydroxy-
Either the (R) -form or the (S) -form of the 1-indanone derivative may be used, or a mixture thereof may be used. When the above basic substance is allowed to act on a 2-hydroxy-1-indanone derivative, racemization occurs. Therefore, regardless of the absolute configuration and optical purity of the optical center of the raw material, the obtained 2-hydroxy-1-indanone is racemic. Becomes By optically resolving this by a known method, (R) -2-hydroxy-1-indanone and (S) -2-hydroxy-1-indanone can be obtained. As a method of optical resolution, a method of deriving diastereomeric esters by the action of an optically active acid to perform resolution, a method of using an optically active column, or an enzyme having a reaction activity only for one enantiomer is used. And a method in which only one enantiomer is esterified and then split.

In the present invention, when a basic substance is allowed to act on the 2-hydroxy-1-indanone derivative, the amount of the basic substance used is 2-hydroxy-1-
It is usually 0.001 to 10 times, preferably 0.01 to 5 times, the mole of the indanone derivative. When the amount is small, the reaction rate is low, and when the amount is excessive, the decomposition reaction to a target compound other than 2-hydroxy-1-indanone takes precedence, which is not preferable.

In the reaction, water, alcohols such as methanol, ethanol and 2-propanol, or a mixture thereof are usually used as a solvent. In addition to these, ethers such as diethyl ether, tetrahydrofuran and dioxane, dichloromethane, chlorobenzene Halogenated hydrocarbons such as benzene, toluene, xylene, etc .; aliphatic hydrocarbons such as hexane; dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide, 1,3-dimethyl-
So-called polar aprotic solvents such as 2-imidazolidinone, nitrated hydrocarbons such as nitromethane and nitrobenzene, and nitriles such as acetonitrile and benzonitrile may be added to the solvent. The solvent to be added to water or alcohols may be one of the above-mentioned solvents or a mixture of two or more thereof. Water or alcohols such as methanol, ethanol, 2-propanol or a mixture thereof, or ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., dimethylformamide, dimethylacetamide in view of high solubility of raw materials and products Dimethylsulfoxide, hexamethylphosphoramide, 1,3-dimethyl-2-imidazolidinone and the like, so-called polar aprotic solvents, nitrated hydrocarbons such as nitromethane and nitrobenzene, and mixed solvents to which acetonitrile and the like are added.

When other solvents are mixed with water, alcohols or a mixed solvent thereof, water and alcohols are contained in an amount of 5% or more by volume and 10% or more in terms of a high reaction rate. Is preferred.

When the reaction is carried out in the presence of the basic compound, the reaction temperature is usually -100 ° C to 70 ° C, preferably -100 ° C.
The reaction temperature is usually 50 minutes to 40 degrees Celsius, and the reaction time is usually 1 minute to 72 hours, preferably 10 minutes to 24 hours.

In the present invention, an enzyme selected from lipase, aminoacylase, protease and esterase is allowed to act on the (R) -2-hydroxy-1-indanone derivative represented by the general formula (1 ′). so,
In the reaction for obtaining (R) -2-hydroxy-1-indanone, as the enzyme that can be used, the (R) -2-hydroxy-1-indanone derivative represented by (1 ′) is hydrolyzed or alcohololyzed. Lipases, aminoacylases, proteases and esterases having the ability to do so can be used. Specifically, the following enzymes are preferred examples. Achromobacter (Achromo
genus, Alcaligene
nes), Aspergillus (Aspergillus)
s) Genus, Burkholderia
Genus, genus Candida, genus Chromobacterium, genus Humicola, mucor
Genus, Pseudomonas, Rhizomucor, Rhizopus (R)
A microorganism belonging to the genus hizopus, Thermus, or a lipase derived from porcine pancreas, or a microorganism belonging to the genus Aspergillus, or an aminoacylase derived from pig kidney, Aspergillus, Bacillus (Basillus)
genus, or Tritylium (Trit)
protease from a microorganism belonging to the genus irachium) or esterase from pig liver. More specifically, Achromomo sp.
bacter sp. ), Alcaligenes sp., Aspergillus niger, Aspergillus oryzae (Aspergillus o.)
ryzae), Brucorderia SP (Burkh)
olderia sp. ), Candida antarctica, Candida cylindrasse (Candida cyl)
indacea), Candida utilis (C
andida utilis), Chromobacterium
Biscosmum (Chromobacterium vis)
cosum), Humicola Langinosa (Humico)
la langinosa), Mucor Myhai (M
ucor miehei), Pseudomonas cepacia, Pseudomonas ssp.
p. ), Rhizomuco
r Miehei, Rhizops Alitus (Rhizo)
pus arrhizus, Rhizopus sp. (R
hizopus sp. ), Thermus thermophilus, lipase from porcine pancreas, or Aspergillus meleus, aminoacylase from porcine kidney, or Aspergillus melgilus ellaspellus spellus,
ryzae), Aspergillus sp.
gillus sp. ), Bacillus licheniformis,
Tritirachium album
alubum) or an esterase derived from pig liver. The amount of these enzymes to be used is 0.01 to 100% by weight, preferably 0.1 to 50% by weight, based on the (R) -2-hydroxy-1-indanone derivative. When the amount is small, the reaction speed is slow. When the amount is excessive, the reaction result is not significantly improved, and it is not economical.

In the reaction of converting the (R) -2-hydroxy-1-indanone derivative into (R) -2-hydroxy-1-indanone by the action of an enzyme, the starting material (R)
Since 2-hydroxy-1-indanone having an optical purity substantially equal to that of the 2-hydroxy-1-indanone derivative can be obtained, (R) -phenylalanine is converted to (R)-
If a 2-hydroxy-1-indanone derivative is produced and an enzyme is allowed to act on the derivative, it is possible to produce (R) -2-hydroxy-1-indanone without performing an optical resolution operation.

The reaction of the enzyme is usually carried out in a solvent, and water or a buffer can be used as the solvent.
As the buffer, a commonly used buffer of a known inorganic salt such as sodium phosphate or potassium phosphate, or a buffer of an organic acid salt such as sodium acetate, potassium acetate or sodium citrate can be used. PH 5 to 12 for alkali-resistant enzymes, pH 1.5 for acid-resistant enzymes
To 7 are preferred.

During the hydrolysis, in addition to the above-mentioned water or buffer, alcohols such as methanol, ethylene glycol and 2-propanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, and ketones such as acetone and cyclohexanone. , Dichloromethane,
Halogenated hydrocarbons such as chlorobenzene, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide, and 1,3-dimethyl-2 Organic solvents such as so-called polar aprotic solvents such as imidazolidinone, nitrated hydrocarbons such as nitromethane and nitrobenzene, and nitriles such as acetonitrile and benzonitrile may be added. The organic solvent may be used alone or in combination of two or more. Alcohols, ethers, nitriles, halogenated hydrocarbons, and aromatic hydrocarbons are preferred in view of high solubility of raw materials and products. When the above-mentioned organic solvent is mixed and used in addition to water or a buffer, the water or the buffer is used in an amount of 5% or more by volume and the reaction rate is high.
% Is preferable.

The reaction temperature at the time of carrying out the reaction in the presence of this enzyme is usually -20 ° C to 120 ° C, preferably 0 ° C to 90 ° C.
° C, and the reaction time is usually 15 minutes to 40 days, preferably 30 minutes to 20 days.

The enzyme may be used in the form of a powder or solution of the enzyme itself, or may be used after immobilization. Examples of the method of immobilization include an adsorption method, a simple bonding method, a cross-linking method, an inclusive method, and the like. In addition, as a carrier for immobilization at the time of immobilization, inorganic substances such as silica gel, alumina, activated carbon, acid clay, bleached clay, kaolinite, bentonite, hydroxyapatite, calcium phosphate, porous glass, metal oxide, etc. , Polyethylene, polypropylene, polystyrene, acrylic resin, acrylate resin,
Examples include phenol-formalin resin, anion exchange resin, cation exchange resin, starch, and organic polymers such as gluten. Other than these, an immobilized carrier other than those described above may be used as long as the carrier does not inhibit the expression of the active function of the enzyme and is insoluble in the solvent used.

As a method for immobilizing the enzyme on the carrier, a known method conventionally used for supporting an enzyme on a carrier can be used. At this time, the weight of the enzyme to be immobilized is preferably 0.1 to 700 mg of the protein containing 1 to 100% of the enzyme per 1 g of the carrier.

The reaction may be a batch type or a continuous type, but in an industrial scale, it is preferable to carry out the continuous reaction using a bioreactor filled with an immobilized enzyme.

After completion of the reaction, the enzyme can be recovered by filtration or centrifugal precipitation, and the recovered enzyme can be reused. The reaction product and unreacted raw materials can be easily recovered by extracting the reaction mixture or a solution from which the enzyme has been removed from the reaction mixture with an organic solvent and removing the organic solvent.

In the present invention, in a reaction in which a 2-hydroxy-1-indanone derivative represented by the general formula (1) is reacted with a rare earth-based catalyst represented by the general formula RE (OSO ₂ Rf) ₃ as a catalyst. Is the rare earth metal element RE as scandium, yttrium, lanthanum, cerium,
Rare earth elements such as praseodymium, neodymium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, and lutetium can be preferably used. RE may be two or more rare earth elements. Further, as Rf, a perfluoroalkyl group such as a trifluoromethyl group, a pentafluoroethyl group, a nonafluorobutyl group and the like can be shown.

In the present invention, the 2-hydroxy-1-indanone derivative represented by the general formula (1) is reacted with a rare earth catalyst represented by the general formula RE (OSO ₂ Rf) ₃ as a catalyst. , 2-hydroxy-1-indanone is not affected by the optical purity of the raw materials and the absolute configuration of the optical center.
Raw materials of any mixing ratio of the body can be used.
In addition, since racemization does not occur in the reaction process, 2-hydroxy-1-indanone having the absolute configuration of the optical center equal to that of the used raw material and having the optical purity almost equal to that of the raw material can be obtained. That is, if an (R) -2-hydroxy-1-indanone derivative is produced from (R) -phenylalanine and a rare earth catalyst is allowed to act on the derivative, the (R) -2-hydroxy-indanone derivative can be obtained without performing an optical resolution operation.
It is possible to produce 1-indanone, and (S)-
If an (S) -2-hydroxy-1-indanone derivative is produced from phenylalanine and the rare earth catalyst is allowed to act on the derivative, (S) -2-hydroxy-1-indanone can be produced. When a mixture of the (R) form and the (S) form is used as a raw material, the product is a 2-hydroxy-form of a mixture of the (R) form and the (S) form in the same ratio as the raw material.
1-Indanone.

When the rare earth catalyst is allowed to act on the 2-hydroxy-1-indanone derivative, the amount of the rare earth catalyst used is usually 0.001 to 10 times the molar amount of the 2-hydroxy-1-indanone derivative. , Preferably 0.
It is from 1 to 5 times mol. If the amount is small, the reaction speed is slow,
A large excess is not preferred because the decomposition reaction to the desired compound other than 2-hydroxy-1-indanone takes precedence.

The reaction is usually carried out with water or methanol,
Alcohols such as ethanol and 2-propanol, or mixtures thereof are used as solvents. In addition to these, ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as dichloromethane and chlorobenzene, benzene, toluene and xylene Aromatic hydrocarbons such as hexane, aliphatic hydrocarbons such as hexane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide, so-called polar aprotic solvents such as 1,3-dimethyl-2-imidazolidinone, A solvent such as nitrated hydrocarbons such as nitromethane and nitrobenzene, and nitriles such as acetonitrile and benzonitrile may be added. These solvents may be used alone or in combination of two or more. In terms of high solubility of raw materials and products, water, alcohols as described above or a mixed solvent thereof, or diethyl ether, tetrahydrofuran, ethers such as dioxane, dimethylformamide, dimethylacetamide,
Dimethyl sulfoxide, hexamethylphosphoramide,
Preferred are mixed solvents to which so-called polar aprotic solvents such as 1,3-dimethyl-2-imidazolidinone, nitrated hydrocarbons such as nitromethane and nitrobenzene, and acetonitrile are added.

When water and alcohols are mixed with another solvent, water, alcohols such as methanol, ethanol, and 2-propanol are at least 5% by volume and at least 10% at the point where the reaction rate is high. It is preferably contained.

The reaction temperature at the time of carrying out the reaction in the presence of a rare earth catalyst is usually -100 ° C to 100 ° C, preferably -5 ° C.
0 ° C to 70 ° C, and the reaction time is usually from 10 minutes to 150 ° C.
Time, preferably 30 minutes to 48 hours.

After completion of the reaction, an organic substance that is immiscible with water is added to the reaction mixture, and an extraction operation is performed with water, whereby the rare-earth catalyst can be extracted into an aqueous phase and separated from the organic substance. The recovered rare earth catalyst can be reused as it is in the form of an extracted aqueous solution or by distilling off water to prepare a powder.

[0034]

BEST MODE FOR CARRYING OUT THE INVENTION

Reference Example Reference Example 1 (±) -2-acetoxy-1-indanone (4.00
g, 20 mmol) was dissolved in methanol (500 ml), potassium carbonate (2.76 g, 20 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Pour the reaction mixture into water,
The mixture was extracted with dichloromethane, the solvent was distilled off with a rotary evaporator, and the residue was analyzed by high performance liquid chromatography (daicel OB column, ethanol:
Hexane = 1: 4, flow rate = 0.5 ml / min, retention time:
2-hydroxy-1-indanone = 11.6 minutes (R form)
And 16.1 minutes (S form), 2-acetoxy-1-indanone = 20.1 minutes (R form) and 22.2 minutes (S form)).
The raw material (±) -2-acetoxy-1-indanone disappeared, but the desired (±) -2-hydroxy-1-indanone was not obtained at all.

Reference Examples 2 to 19 The same reaction as described above was carried out using various bases. HP
The results of LC analysis are shown in Table 1.

[Table 1]

Reference Example 20 (R) -2-acetoxy-1-indanone (500 m
g, 2.63 mmol, ee = 98.3%) in a mixed solvent of methanol (20 mL) and water (5 mL), and concentrated sulfuric acid (129 mg, 1.31 mmol) was added.
Stir at room temperature for 65:30 minutes. The reaction mixture was poured into water, extracted with dichloromethane, and the solvent was distilled off using a rotary evaporator to obtain an oil. The obtained oil was analyzed by high performance liquid chromatography under the same conditions as in Reference Example 1. As a result, ee = 98.4% of (R) -2-hydroxy-1-indanone was 17.7%, and (R)
82.3% of 2-acetoxy-1-indanone (ee
= 98.4%).

Reference Example 21 The same reaction as in Reference Example 20 was carried out, except that the acid was changed from concentrated sulfuric acid to concentrated hydrochloric acid. The analysis result after 65 hours and 30 minutes is ee =
98.1% of (R) -2-hydroxy-1-indanone was produced in a yield of 18.9%, and the raw material (R) -2-acetoxy-1-indanone was 81.1% (ee = 98%). .3
%).

[0038]

【Example】

Example 1 (±) -2-acetoxy-1-indanone (4.00
g, 20 mmol) in methanol (500 ml) and potassium cyanide (1.30 g, 20 mmol).
Was added and stirred at room temperature for 12 hours. The reaction mixture was poured into water, extracted with dichloromethane, and the solvent was distilled off with a rotary evaporator to obtain a pale yellow oil. The oil was analyzed by HPLC under the same conditions as in Reference Example 1, and as a result,
-(R) -hydroxy-1-indanone 41%, 2-
It was found that (S) -hydroxy-1-indanone was produced in a yield of 42%.

Example 2 (±) -2-acetoxy-1-indanone (4.00)
g, 20 mmol) in methanol (500 ml) and sodium cyanide (0.98 g, 20 mmol).
l) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water, extracted with dichloromethane, and the solvent was distilled off with a rotary evaporator to obtain a pale yellow oil. Analysis of the oil by HPLC revealed that 43% of 2- (R) -hydroxy-1-indanone and 43% of 2- (S) -hydroxy-1-indanone were produced. did.

Example 3 (±) -2-acetoxy-1-indanone (4.00
g, 20 mmol) was dissolved in methanol (500 ml), lithium hydroxide (0.84 g, 20 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water, extracted with dichloromethane, and the solvent was distilled off with a rotary evaporator to obtain a pale yellow oil. As a result of analyzing the oil by HPLC, 2- (R) -hydroxy-
48% of 1-indanone, 2- (S) -hydroxy-1
-It was found that indanone was formed in a yield of 47%.

Example 4 2- (R) -acetoxy-1-indanone (4.00
g, 20 mmol) in methanol (500 ml) and potassium cyanide (1.30 g, 20 mmol).
Was added and stirred at room temperature for 12 hours. The reaction mixture was poured into water, extracted with dichloromethane, and the solvent was distilled off with a rotary evaporator to obtain a pale yellow oil. As a result of analyzing the oil by HPLC, 2- (R) -hydroxy-
38% of 1-indanone, 2- (S) -hydroxy-1
-It was found that indanone was formed in a yield of 40%.

Example 5 2- (R) -acetoxy-1-indanone (4.00
g, 20 mmol) in methanol (500 ml) and sodium cyanide (0.98 g, 20 mmol).
l) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water, extracted with dichloromethane, and the solvent was distilled off with a rotary evaporator to obtain a pale yellow oil. The oil was analyzed by HPLC, and it was found that 43% of 2- (R) -hydroxy-1-indanone and 42% of 2- (S) -hydroxy-1-indanone were produced. did.

Example 6 2- (R) -acetoxy-1-indanone (4.00
g, 20 mmol) was dissolved in methanol (500 ml), lithium hydroxide (0.84 g, 20 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water, extracted with dichloromethane, and the solvent was distilled off with a rotary evaporator to obtain a pale yellow oil. As a result of analyzing the oil by HPLC, 2- (R) -hydroxy-
47% of 1-indanone, 2- (S) -hydroxy-1
-It was found that indanone was formed in a yield of 45%.

Example 7 (±) -Phenylalanine (50 g, 302 mmol)
Was dissolved in 4N sulfuric acid (250 ml), and an aqueous solution of sodium nitrite (62.5 g, 906 mmol, 150 ml) was dissolved.
Was added dropwise at 0 ° C. over 1 hour. After stirring at 0 ° C. for 5 hours and at room temperature for 12 hours, the mixture was extracted with ethyl acetate (170 ml × 3), and the collected organic layers were washed with water (100 ml) and saturated saline (300 ml), and the solvent was removed with a rotary evaporator. Removal gave a white solid. This is dichloromethane-
The crystals were recrystallized from a mixed solvent of hexane to give white crystals of (±) -3-phenyllactic acid (26.7 g, 160 mmol, yield 5).
3%). The total amount of the obtained (±) -3-phenyllactic acid was dissolved in pyridine (270 ml), and acetic anhydride (18.
1 ml, 192 mmol) and stirred at room temperature for 12 hours. The pyridine was distilled off under reduced pressure to give a pale yellow oil (±)
-2-acetoxy-3-phenylpropionic acid (33.
3 g, 160 mmol). The obtained (±) -2-
The whole amount of acetoxy-3-phenylpropionic acid was dissolved in diethyl ether (700 ml), and phosphorus pentachloride (36.6 g, 176 mmol, 1.1 equivalent) was added at 0 ° C under nitrogen. After stirring at 0 ° C. for 30 minutes, the solvent was distilled off using a rotary evaporator, and the pressure was further reduced using a pump for 30 minutes. The total amount of the obtained oily substance was changed to dichloromethane (1400
ml), and aluminum chloride (44.8 g, 33
6 mmol, 2.1 equivalents) and stirred at room temperature for 1 hour. While cooling with ice, water (1000 ml) was added, and the mixture was extracted with dichloromethane (300 ml × 3). The collected organic layer was washed with water (600 ml) and saturated saline (1400 ml), dried over sodium sulfate, and rotary evaporated. The solvent was removed with, and a pale yellow liquid (±) -2-acetoxy-1-indanone (29.5 g, 97% in two steps)
I got The obtained (±) -2-acetoxy-1-indanone (29.0 g, 152 mmol) was dissolved in methanol (900 ml), and potassium cyanide (9.88) was dissolved.
g, 152 mmol) and stirred at room temperature for 12 hours. The reaction mixture is poured into water, extracted with dichloromethane,
The solvent was distilled off using a rotary evaporator to obtain a pale yellow oil. The oil was purified under the same conditions as in Reference Example 1 by HP
As a result of analysis by LC, (±) -2-hydroxy-1-
It was found that indanone was produced in a yield of 88%.

Example 8 (R) -phenylalanine (50 g, 302 mmol,
The same reaction as in Example 7 was carried out using the optical purity [ee] = 99%) as a raw material to obtain (R) -2-acetoxy-1-indanone (27.7 g, optical purity [ee] = 99%). Was.
A reaction similar to that of Example 2 was carried out using the entire amount of the compound, and yellow oily (±) -2-hydroxy-1-indanone (1
9.6 g, yield 91%, optical purity [ee] = 0%) were obtained.

Example 9 (S) -phenylalanine (50 g, 302 mmol,
The same reaction as in Example 7 was carried out using the optical purity [ee] = 99%) as a raw material to obtain (S) -2-acetoxy-1-indanone (27.1 g, optical purity [ee] = 99%). Was.
A reaction similar to that of Example 3 was carried out using the entire amount thereof, and yellow oily (±) -2-hydroxy-1-indanone (1
9.6 g, yield 93%, optical purity [ee] = 0%) were obtained.

Examples 10 to 44 (R) -2-acetoxy-1-indanone (4.00)
g, 20 mmol, ee = 99%) in a mixed solvent of phosphate buffer (400 ml) and methanol (150 ml) at pH 7, and various enzymes (1 g) were added.
Stir for 6 hours. 80 g of ammonium sulfate in the reaction mixture
Was added, and the mixture was extracted with dichloromethane, and the solvent was distilled off using a rotary evaporator to obtain a pale yellow oil.
Tables 2 and 3 show the results (HPLC yield and optical purity [(R) -2-hydroxy-1-indanone) of (R) -2-hydroxy-1-indanone) obtained by analyzing the type of enzyme and the oily substance by HPLC.

[0048]

[Table 2]

[0049]

[Table 3]

Example 45 (R) -phenylalanine (50 g, 302 mmol,
The same reaction as in Example 7 was performed using the optical purity [ee] = 99%) as a raw material to obtain (R) -2-acetoxy-1-indanone (26.1 g, optical purity [ee] = 99%). Was.
Dissolve the whole amount in methanol (900ml) and adjust pH
7 (2400 ml) and an enzyme (Lipase PS (Lipase derived from Pseudomonas sp., 10.0 g) manufactured by Amano Pharmaceutical Co., Ltd., 10.0 g), and the mixture is appropriately saturated with carbonic acid so that the pH falls within the range of 6 to 7. The mixture was stirred at 40 ° C. for 2 hours while a sodium aqueous solution was added dropwise. Ammonium sulfate (150 g) was added and dichloromethane (600 g) was added.
ml), and the collected organic layer was washed with water (700 ml x 7).
2), washed with saturated saline (1000 ml × 2), and the solvent was removed with a rotary evaporator to obtain a pale yellow solid. This was recrystallized from a mixed solvent of dichloromethane-hexane to give white crystals of (R) -2-hydroxy-1-indanone (14.4 g, yield 71%, optical purity [ee] = 9).
9%).

Example 46 (R) -2-acetoxy-1-indanone (500 m
g, 2.63 mmol, ee = 98.3%) was dissolved in a mixed solvent of methanol (20 mL) and water (5 mL), and scandium trifluoromethanesulfonate (2
59 mg, 0.526 mmol) and stirred at room temperature for 10 hours. The reaction mixture was poured into water, extracted with dichloromethane, and the solvent was distilled off with a rotary evaporator.
A pale yellow oil was obtained. The oil was analyzed by HPLC, and it was found that (ee) = 98.0% of (R) -2-hydroxy-1-indanone was produced in a yield of 91%.

Example 47 (R) -phenylalanine (50 g, 302 mmol,
ee = 99%) in 4N sulfuric acid (250 ml)
Aqueous solution of sodium nitrite (62.5g, 906mmo
1, 150 ml) was added dropwise at 0 ° C. over 1 hour. 0 ° C
After stirring at room temperature for 5 hours and at room temperature for 12 hours, ethyl acetate (1
70 ml × 3) and the collected organic layer was washed with water (100 m
l) and washed with saturated saline (300 ml), and the solvent was removed with a rotary evaporator to obtain a white solid. This was recrystallized from a mixed solvent of dichloromethane-hexane to give white crystals of (R) -3-phenyllactic acid (26.7 g, 1
(60 mmol, ee = 100%, yield 53%).
The total amount of the obtained (R) -3-phenyllactic acid was converted to pyridine (2
Acetic anhydride (18.1 ml, 192 ml).
(mmol, ee = 100%) and stirred at room temperature for 12 hours. Pyridine was distilled off under reduced pressure to obtain (R) -2-acetoxy-3-phenylpropionic acid (33.3 g, 160 mmol) as pale yellow oil. The total amount of the obtained (R) -2-acetoxy-3-phenylpropionic acid was dissolved in diethyl ether (700 ml), and phosphorus pentachloride (36.6 g, 176 mmol,
1.1 equivalents). After stirring at 0 ° C. for 30 minutes, the solvent was distilled off using a rotary evaporator, and the pressure was further reduced using a pump for 30 minutes. The whole amount of the obtained oil was dissolved in dichloromethane (1400 ml), and aluminum chloride (4
(4.8 g, 336 mmol, 2.1 equivalents) and stirred at room temperature for 1 hour. While cooling on ice, water (1000 ml)
And extracted with dichloromethane (300 ml × 3),
The collected organic layer was washed with water (600 ml) and saturated saline (140 ml).
0 ml), dried over sodium sulfate, and the solvent was removed with a rotary evaporator. The light yellow liquid (R)-
2-acetoxy-1-indanone (29.5 g, ee =
98.3%, 97% yield in two steps). The obtained (±) -2-acetoxy-1-indanone (500 m
g, 152 mmol, ee = 98.3%) in a mixed solvent of methanol (20 mL) and water (5 mL),
Scandium trifluoromethanesulfonate (259
mg, 0.526 mmol) and stirred at room temperature for 10 hours. The reaction mixture was poured into water, extracted with dichloromethane, and the solvent was distilled off with a rotary evaporator to obtain a pale yellow oil. The oil was analyzed by HPLC to find that ee = 98.2% of (R) -2-hydroxy-1-
It was found that indanone was formed in a yield of 92%.

Example 48 (S) -2-acetoxy-1-indanone (50
(0 mg, 2.63 mmol, ee = 98.7%), and the same reaction as in Example 46 was carried out to obtain a pale yellow oil. The oil was analyzed by HPLC.
It was found that 8.3% of (S) -2-hydroxy-1-indanone was formed in a yield of 93%.

Example 49 (S) -Phenylalanine (50 g, 302 mm
ol, ee = 99%), and the same reaction as in Example 47 was carried out to obtain a pale yellow oil. The oil was analyzed by HPLC, and it was found that (S) -2-hydroxy-1-indanone with ee = 98.6% was produced in a yield of 91%.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Tanijiro Hiyama 4-29-3-101 Kamizuruma, Sagamihara City, Kanagawa Prefecture

Claims (5)

[Claims] [Claim 1] The following general formula (1) (Wherein, R represents an acyl group or an alkoxycarbonyl group) when hydrolyzing or alcoholyzing a 2-hydroxy-1-indanone derivative represented by the following formulas: lithium hydroxide, potassium cyanide and sodium cyanide. The following formula (2) characterized by allowing a selected basic substance to act: A method for producing 2-hydroxy-1-indanone represented by the formula: 2. The following general formula (1 ′): (Wherein, R represents an acyl group or an alkoxycarbonyl group) when hydrolyzing or alcoholyzing a (R) -2-hydroxy-1-indanone derivative represented by the following formula: lipase, aminoacylase, protease and esterase Wherein an enzyme selected from the following is acted on: A method for producing (R) -2-hydroxy-1-indanone represented by the formula: 3. The method according to claim 1, wherein the enzyme is Achromobacter.
genus, Alcalig
enes), Aspergillus (Aspergillus)
s) Genus, Burkholderia
Genus, genus Candida, genus Chromobacterium, genus Humicola, mucor
Genus, Pseudomonas, Rhizomucor, Rhizopus (R)
A microorganism belonging to the genus hizopus, Thermus, or a lipase derived from porcine pancreas, or a microorganism belonging to the genus Aspergillus, or an aminoacylase derived from pig kidney, Aspergillus, Bacillus (Basillus)
genus, or Tritylium (Trit)
The protease according to claim 2, which is a protease derived from a microorganism belonging to the genus irachium or an esterase derived from pig liver, and has an ability to hydrolyze a 2-hydroxy-1-indanone derivative represented by the general formula (1). Production method. 4. The method according to claim 1, wherein the enzyme is Achromobacter sp.
chromobacter sp. ), Alcaligenes sp., Aspergillus niger
er), Aspergillus oryzae (Aspergil)
lux oryzae), Burkholderia sp., Candida antarctica (Candida antarctica)
ica), Candida Sylindrasse (Candi)
da cylindracea, Candida utilis, Chromobacterium biscosum (Chromobacterium)
um viscosum), Humicola Langinosa, Mucor
Mycorm (Mucormiehei), Pseudomonas cepacia (Pseudomonas cepaci)
a), Pseudomon sp.
as sp. ), Rhizomucor My High (Rhizo)
mucor miehei), Rhizopus alitus (R
hizopus arrhizu, Rhizopus sp., Thermus thermophilu (Thermus thermophilu)
s) or lipase derived from pig pancreas, Aspergillus
Meleus (Aspergillus melleu)
s), aminoacylase from pig kidney, or Aspergillus meleus
eus), Aspergillus oryzae (Aspergi)
lplus oryzae), Aspergillus sp., Bacillus lichenifofo
rmis) or Tritylakium album (Tri)
The production method according to claim 2, wherein the production method is a protease derived from T. lactis (Tirachium album) or an esterase derived from pig liver. 5. The following general formula (1): (Wherein R represents an acyl group or an alkoxycarbonyl group) when hydrolyzing or alcoholyzing a 2-hydroxy-1-indanone derivative represented by the following general formula (3): RE (OSO ₂ Rf) ₃ (3) (wherein, RE is a rare earth metal element, and Rf represents a perfluoroalkyl group). 2) A method for producing 2-hydroxy-1-indanone represented by the formula: