JPH11196890A - Production of optically active 3-quinuclidinol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as an synthetic intermediate of a physiologically active compound utilized as a medicine or an agrochemical and a liquid crystalline material efficiently by reacting 3-quinuclidinone with a biological catalyst capable of stereoselectively reducing the same. SOLUTION: A method for producing the objective optically active 3- quinuclidinol efficiently by reacting 3-quinuclidinone with a biological catalyst originated from a microorganism belonging to the genus Rhodotorula, Candida, Sporidiobolus, Rhodospridium, Schizosaccharomyces, Cryptococcus or the like capable of stereoselectively reducing 3-quinuclidinone.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to the production of optically active 3-quinuclidinol which is useful as an intermediate for the synthesis of optically active physiologically active compounds and liquid crystal materials used in medicines and agricultural chemicals. More specifically, the present invention relates to the use of a microorganism or an enzyme derived from a microorganism that is a biological catalyst.
The present invention relates to a method for stereoselectively reducing 3-quinuclidinone to produce optically active 3-quinuclidinol, particularly (R)-(-)-3-quinuclidinol.

[0002]

2. Description of the Related Art At present, many biologically active compounds are used as a mixture of their optical isomers. However, the desired activity is often present in only one optical isomer. It is further known that the other optical isomer having no desired activity may be toxic to living organisms. Therefore, in order to provide an effective and safe drug or biologically active compound, there is a strong demand to develop a method for producing an optically active substance having high optical purity used as a raw material or a synthetic intermediate.

[0003] The reduction product of 3-quinuclidinone, 3-
Quinuclidinol is a compound known as a therapeutic agent for arteriosclerosis having a squalene synthase inhibitory action, a bronchodilator having a muscarinic receptor antagonistic action, and a gastrointestinal motility inhibitor such as a synthetic intermediate (Japanese Patent Application Laid-Open No. Hei 8-
No. 134067, EP-404737A2, EP-42
4021A1, WO92 / 04346, and WO93
/ 06098).

[0004] 3-Quinuclidinol having an asymmetric carbon atom has optical isomers. Therefore, it is necessary to separate optically active 3-quinuclidinol useful as a synthetic intermediate, and several attempts have been made to date.

As a method for producing optically active 3-quinuclidinol, for example, 1-benzyl-3-hydroxyquinuclidium chloride has been optically resolved with a D-tartaric acid derivative to give (S)-(+)-3-quinuclidinol. How to Produce (Isr
ael Journal of Chemistry, 9,267-268 (1971)) and a method for synthesizing (S)-(+)-3-quinuclidinol from D-glucose (Tetrahedron Letters, 27, 3057-3058 (198
6)) has been reported.

As a method utilizing microorganisms and enzymes, for example, (R, S) -quinuclidinyl butyrate is reacted with horse serum butylcholinesterase to give optically active (S)-(+)-3-
How to leave quinuclidinyl butyrate (Life Sci
ence, 21, 1293-1302 (1977)) and a method for producing optically active (R)-(-)-3-quinuclidinol with high optical purity by the action of a protease derived from a microorganism belonging to the genus Bacillus (US 5215918A) It has been known.

However, these methods have low optical purity,
In addition, there is a problem that mass production is not easy due to complicated synthesis steps. In each case, the racemic 3-
Since this is a method of obtaining the desired optical isomer by optically resolving quinuclidinol, the other undesired optical isomer remains. Therefore, in these methods, for the undesired optical isomer, a step of inverting the configuration of the asymmetric carbon to convert it to the desired optical isomer, or the undesired optical isomer is racemized, There is a problem that a step of obtaining a desired optical isomer by optical resolution is required, and the production cost is increased.

On the other hand, a method for producing an optically active 3-quinuclidinol by asymmetric hydrogenation of a Lewis acid adduct of 3-quinuclidinone using a rhodium complex compound as a catalyst (Japanese Unexamined Patent Publication No.
194480), but the optical purity is low and it is not an industrial production method.

From such a viewpoint, optically active 3-quinuclidinol, particularly (R)-(-)-3- useful as a synthetic intermediate.
Quinuclidinol with high optical purity and high efficiency
-There is a strong demand for a method of producing directly from quinuclidinone.

[0010]

DISCLOSURE OF THE INVENTION The present invention has been made to solve the above-mentioned problems, and an object of the present invention is to use a biological catalyst having a high stereoselectivity and an optical activity 3 having a high optical purity. -To provide a method for efficiently producing quinuclidinol.

[0011]

SUMMARY OF THE INVENTION The present invention relates to an optically active 3-
A process for producing quinuclidinol, comprising the following formula:

[0012]

Embedded image

Reacting 3-quinuclidinone represented by the formula with a biological catalyst capable of stereoselectively reducing 3-quinuclidinone.

In a preferred embodiment, the method further comprises a step of separating the produced optically active 3-quinuclidinol from 3-quinuclidinone.

[0015] In a preferred embodiment, the biological catalyst is Rhodotorula, Candida, Sporidiobolu.
s), Rhodosporidium, Schizosaccharomyces, Cryptococcus, Trichosporon (Tr)
ichosporon), Gordona and Pichia
hia) and a microorganism selected from the group consisting of microorganisms belonging to the genus Nocardia.

In a preferred embodiment, the optically active 3-quinuclidinol is (R)-(-)-3-quinuclidinol.

In a preferred embodiment, the biological catalyst is selected from the group consisting of microbial cells, microbial cultures, processed products of microbial cells, and purified enzymes. In a more preferred embodiment, the biological catalyst is an acetone-treated microbial cell.

In a preferred embodiment, the microorganism is Rhodotorula rubra, Rhodotorulaglutinis, Rhodotula
orula graminis, Rhodotorula minuta, Candida albica
ns, Candida parapsilosis, Candida intermedia, Cand
ida antarctica, Sporidiobolus salmonicolor, Rhodos
poridium toruloides, Schizosaccharomyces octosporu
s, Cryptococcus laurentii, Cryptococcus terreus, T
richosporon cutaneum, Gordona terrae, Pichia anoma
la, and a microorganism selected from the group consisting of Nocardia asteroides. In a more preferred embodiment, the microorganism is Rhodotorula rubra JCM3782, Rhodotorula
rubra JCM3785, Rhodotorula rubra JCM8113, Rhodoto
rula rubra JCM8117, Rhodotorula glutinis IFO389, R
hodotorula graminis IFO0190, Rhodotorula minuta IF
O0879, Candida albicans JCM1542, Candida albicans
JCM2909, Candida parapsilosis JCM1618, Candida par
apsilosis JCM1785, Candida intermedia IFO0761, Can
dida antarctica JCM3941, Sporidiobolus salmonicolo
r IFO1035, Sporidiobolus salmonicolor IFO1845, Spo
ridiobolus salmonicolor AKU4429, Rhodosporidium to
ruloides IFO8766, Cryptococcus laurentii IFO0609,
Cryptococcus terreus IFO0727, Trichosporon cutaneu
m IFO1198, Gordona terrae JCM3206, Pichia anomala
A microorganism selected from the group consisting of IFO10213 and Nocardia asteroides IFO3384.

[0019]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.

The method of the present invention converts 3-quinuclidinone into optically active 3-quinuclidinol by reacting 3-quinuclidinone with a biological catalyst to stereoselectively reduce 3-quinuclidinone.

The biological catalyst substrate used in the method of the present invention has the formula:

[0022]

Embedded image

Is 3-quinuclidinone. Substrates used in the method of the present invention include inorganic acid salts such as hydrochloride salts and organic acid salts such as acetate salts.

The biological catalyst which can be used in the present invention is 3
-Can stereoselectively reduce the carbonyl group of quinuclidinone. In particular, biological catalysts that can be used in the present invention include any that contain (produce) a carbonyl reductase that stereoselectively reduces the carbonyl group of 3-quinuclidinone to convert it to optically active 3-quinuclidinol. Derived from microorganisms such as yeasts, molds and bacteria. Microorganisms containing (producing) such an enzyme are described, for example, in Example 1.
Screening by analyzing for (R)-(-)-3-quinuclidinol produced from 3-quinuclidinone or its optical isomer (S)-(+)-3-quinuclidinol using the method described in 1. Can be done.

The microorganism containing (or producing) the enzyme having the above-mentioned enzyme activity is preferably a genus Rhodotorula, a genus Candida, a genus Sporidiobolus, or a rhodosporidium ( Rhodosporidium, Schizosaccharomyces (Sc
hizosaccharomyces, Cryptococcus (Cryptococ)
cus), Trichosporon, Gordona, Pichia, and Nocardia. More preferably, Rhodotorula rubra JCM3782, Rhodotoru
la rubra JCM3785, Rhodotorula rubra JCM8113, Rhodo
torula rubra JCM8117, Rhodotorula glutinis IFO38
9, Rhodotorula graminis IFO0190, Rhodotorula minut
a IFO0879, Candida albicans JCM1542, Candida albic
ans JCM2909, Candida parapsilosis JCM1618, Candida
parapsilosis JCM1785, Candida intermedia IFO076
1, Candidaintermedia AKU4429, Candida antarctica J
CM3941, Sporidiobolus salmonicolor IFO1035, Sporid
iobolus salmonicolor IFO1845, Sporidiobolus salmon
icolor AKU4429, Rhodosporidium toruloides IFO876
6, Cryptococcus laurentii IFO0609, Cryptococcus te
rreus IFO0727, Trichosporon cutaneum IFO1198, Gord
ona terrae JCM3206, Pichia anomala IFO10213, and Nocardia asteroides IFO3384. These microbial strains are available from RIKEN Microorganism Strain Preservation Facility (JC
M), Fermentation Research Institute (IFO), or a microorganism preservation institution such as Kyoto University Faculty of Agriculture (AKU).

In the method of the present invention, the microorganism used as a biological catalyst may be a wild-type strain, a mutant strain (for example, induced by irradiation with ultraviolet light), or a genetic engineering technique such as a cell fusion or genetic recombination method. Any strain such as a recombinant derived by the above method may be used. Engineered microorganisms such as recombinants are, for example, MolecularClo
ning A Laboratory Manual 2nd edition (edited by Sambrook, J. et al.,
Cold Spring Harborlaboratory Press, 1989), and can be readily prepared using techniques known to those skilled in the art.

For cultivation of the above microorganism, either a solid medium or a liquid medium which is commonly used and well known to those skilled in the art may be used. Preferably, the microorganism is cultured using a liquid medium. As a component of the medium used for culturing the microorganism, any carbon source and nitrogen source that can be used by the microorganism to be cultured can be used as the carbon source and the nitrogen source. Such carbon sources are preferably sugars such as starch, sucrose or glucose, alcohols such as glycerol, and organic acids (eg acetic acid and citric acid) or salts thereof (eg sodium salts)
It is. As the nitrogen source, preferably, natural nitrogen sources such as yeast extract, casein, corn steep liquor, peptone, meat extract and the like and inorganic nitrogen compounds such as ammonium sulfate, ammonium salt, urea and the like can be used. The concentration of the carbon source is 1-20%,
Preferably it is in the range of 1 to 5%. The concentration of nitrogen source is 1 ~
It is in the range of 20%, preferably 1-5%. The culture temperature can be any temperature as long as the above enzyme is stable and the microorganism to be cultured can grow sufficiently.
Preferably it is 20-30 degreeC. The culturing time is arbitrary as long as the above-mentioned enzyme is sufficiently produced, but is preferably about 16 to 48 hours. The cultivation can preferably be performed under aerobic conditions, for example, using aeration stirring or shaking.

[0028] The biological catalyst used in the method of the present invention may include any preparation obtained from the microbial culture described above. Such preparations include, for example, microbial cells obtained from the above-described microbial culture, microbial culture solutions, processed products of the microbial cells, and enzymes purified to various degrees. The microorganism culture solution refers to both a culture solution containing microbial cells and a culture solution from which microbial cells have been removed by centrifugation or the like. Examples of the processed microbial cells include acetone-treated products, cell crushed products obtained by ultrasonic treatment, and immobilized microbial cells. These can be prepared according to methods known to those skilled in the art. For example, the acetone-treated product retains the above-mentioned enzyme activity, which is obtained by stirring microbial cells obtained by culturing or a suspension thereof in cooled (eg, −20 ° C.) acetone and then obtaining, for example, by filtration. It is a powdery processed bacterial body. The immobilization of the microbial cells is performed, for example, by gelling a gelling agent such as carrageenan or acrylamide in the presence of the microbial cells. The enzyme is purified using, for example, acetone-treated products and cell lysates, using methods well known to those skilled in the art, such as ammonium sulfate precipitation, ion exchange chromatography, and hydrophobic interaction chromatography. (Including enzymes purified to near homogeneity) can be obtained.

In the method of the present invention, for example, 3-quinuclidinone is stereoselectively reduced in a suitable reaction solution containing the above-mentioned biological catalyst, and as a product, optically active 3-quinuclidinol, particularly (R) This gives-(-)-3-quinuclidinol.

In one embodiment of the method of the present invention,
Optically active 3-quinuclidinol, such as (R)-(-)-3-quinuclidinol, can be obtained by culturing the microorganism in the presence of 3-quinuclidinone. The amount of 3-quinuclidinone added to the culture solution is 0.1 to 10 wt.
/ vol%, preferably 0.1 to 5 wt / vol%. The added 3-quinuclidinone does not have to be completely dissolved. When the added 3-quinuclidinone does not completely dissolve, for example, the solubility may be improved as a salt (eg, hydrochloride) or an organic solvent such as ethanol may be added to such an extent that the reduction reaction is not substantially inhibited. (For example,
5%).

In another embodiment of the method of the present invention, an optically active 3-quinuclidinol, such as (R)-(-)-3-quinuclidinol, is added in a suitable reaction solution (water or buffer).
It can be obtained by contacting 3-quinuclidinone with a cell of a cultured microorganism or a treated product thereof (for example, an acetone-treated product) and reacting with 3-quinuclidinone. 3 to be added to the reaction solution
The amount of quinuclidinone is from 0.1 to 20 wt / vol%, preferably from 0.1 to 10 wt / vol%; The added 3-quinuclidinone does not have to be completely dissolved. If the added 3-quinuclidinone does not completely dissolve, for example, the solubility may be improved as a salt (eg, hydrochloride) or a solvent such as ethanol may be used to substantially reduce the reduction reaction with a biological catalyst. Concentration that does not inhibit
(Up to 5%). In particular, when a treated bacterial cell is used, NADP of the coenzyme of the above carbonyl reductase is used.
It is preferable to add H. The addition amount is 2 to 40
0 g / l, more preferably 2 to 200 g / l.

In yet another embodiment of the method of the present invention, by appropriately selecting the biological catalyst used for the reaction, under the same reaction conditions as described above, the configuration of the optically active 3- (S) configuration is (S). Quinuclidinol can be obtained.

The reaction can be carried out under a controlled pH. A buffer such as a phosphate buffer is used to maintain an optimal pH for the reaction. PH of reaction solution
Is 5 to 9, preferably 6 to 8. Alternatively, the pH of the reaction solution is maintained and adjusted to an optimum pH by adding an acid (for example, sulfuric acid) and an alkali (for example, sodium hydroxide) while monitoring the pH that changes as the reaction proceeds. obtain.

The amount of the biological catalyst used in the method of the present invention is not particularly limited, but is about 0.1 to 10 g / mol substrate, preferably about 1 to 5 g / mol of 3-quinuclidinone. Substrate mol.

The reaction temperature is 10 ° C. to 50 ° C., preferably 2 ° C.
5 ° C to 35 ° C. The reaction time varies depending on the amount of the biological catalyst used, the reaction temperature, the reaction pH, etc.,
Usually, it is about 1 to 72 hours.

In the method of the present invention, the optically active 3-
Quinuclidinol can be separated, if necessary, by utilizing the difference in the chemical or physical properties of the substrate 3-quinuclidinone and the generated optically active 3-quinuclidinol. In the method of the present invention, as shown in Table 1, by selecting an appropriate biological catalyst, an optical purity of 10
0% of optically active 3-quinuclidinol, ie (R)-(-)
Since -3-quinuclidinol or (S)-(+)-3-quinuclidinol is produced, only one optical isomer of optically active 3-quinuclidinol can be obtained.

After the completion of the reaction, the produced optically active 3-quinuclidinol has properties (eg, solubility, hydrophobicity).
Depending on the method, the unreacted 3-quinuclidinone is separated using a separation operation commonly used in the art, such as a solvent extraction method, a crystal precipitation method, and a column chromatography method. For example, in the solvent extraction method, after extracting unreacted 3-quinuclidinone from the reaction solution with toluene under basic conditions, the generated optically active 3-quinuclidinol can be recovered using a solvent such as chloroform or dichloromethane. .

The product obtained can be further purified, if necessary, using the means described above. In this case, the second means is preferably different from the first means (for example, when solvent extraction is used as the first means, for example, column chromatography is given as the second means).

[0039]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

The quantification of the produced 3-quinuclidinone and the measurement of the optical purity were carried out by gas chromatography under the following analysis conditions.

(Gas Chromatography Analysis Conditions) Column: alpa-DEX120 (length: 30 m, inner diameter: 0.25 mmI)
D; manufactured by Spelco) Column initial temperature: 140 ° C (10 minutes) Injector temperature: 220 ° C Detector temperature: 220 ° C Carrier gas: helium (200 kPa) Detector: FID <Example 1> 100 ml in a 500 ml Erlenmeyer flask Of Y
M medium (polypeptone (Nippon Pharmaceutical) 5 g / l, yeast extract (Nippon Pharmaceutical) 3 g / l, malt extract (Difco) 3 g / l, glucose 10 g / l, pH 5.5)
After autoclaving at 121 ° C for 15 minutes, Rhodotorula rubra (Rh.
odotorula rubra) Inoculate the culture solution of JCM3782, and rotate culture on a rotary shaker at 25 ° C for 2 days (160 rp).
m).

To this culture solution, 808 mg (50 mM) of 3-quinuclidinone hydrochloride was added, and the rotation culture was further continued for 5 days. After completion of the culture, 100 g of potassium carbonate was added to the culture solution to make it basic, and unreacted 3-quinuclidinone was extracted and removed twice with 50 ml of toluene. afterwards,
The product was extracted twice from the reaction solution with 50 ml of chloroform.

As a result of analyzing the extract by gas chromatography, 210 mg (yield 33%) of (R)-(-)-3-quinuclidinol was obtained with an optical purity of 100% ee (enantiomeric excess).

Example 2 Using various microorganisms, the reaction was carried out as described in Example 1, and the product was extracted. Table 1 shows the analysis results of the extract.

[0045]

[Table 1]

Table 1 shows that many microorganisms have an optical purity of 10
Optically active 3-quinuclidinol at 0% ee (ie,
Only one optical isomer) was obtained.

Example 3 2 L of the YM medium described in Example 1 was placed in a 3 L jar fermenter at 121 ° C.
After autoclaving for 15 minutes, Rhodotorula pre-cultured in the same medium
rubra) A culture solution of JCM3782 was inoculated, and aeration and agitation culture (aeration amount: 1 vvm, agitation speed: 500 rpm) was performed at 25 ° C for 2 days. The resulting culture was centrifuged (18000 rpm,
20 minutes) and 61 g of Rhodotorul
a rubra) Wet cells of JCM3782 were obtained.

400 ml of a 0.1 M phosphate buffer (pH 7.
In 0), 61 g of the obtained cells were suspended, and then 12.9 g (200 mM) of 3-quinuclidinone hydrochloride and sucrose 4 were added.
0 g was added and the mixture was stirred at 25 ° C. for 4 days. After completion of the reaction, 400 g of potassium carbonate was added to the mixture under basic conditions, and unreacted 3-quinuclidinone was extracted and removed twice with 200 ml of toluene. Thereafter, the product was extracted twice with 200 ml of chloroform.

As a result of analyzing the extract by gas chromatography, (R)-(-)-3-quinuclidinol was obtained in an amount of 6.6 g (yield: 65%), and the optical purity was 100% ee (enantiomeric excess). )Met.

Example 4 After suspending 61 g of cells obtained by culturing as described in Example 3 in 400 ml of 0.1 M phosphate buffer (pH 7.0), -6.5 g (100 mM) of quinuclidinone hydrochloride and sucrose 4
0 g was added and the mixture was stirred at 25 ° C. for 4 days. After completion of the reaction, 400 g of potassium carbonate was added and the mixture was made to a basic condition, and the product was extracted twice with 200 ml of chloroform.

The extract was analyzed by gas chromatography. As a result, 5.0 g (yield: 99%) of (R)-(-)-3-quinuclidinol was obtained, and its optical purity was 100% ee (enantiomeric excess). )Met.

Example 5 12 g of cells of Rhodotorula rubra JCM3782 obtained in the same manner as in Example 3 were dispersed in 200 ml of cold acetone (−20 ° C.) and stirred for about 5 minutes. The cells were collected by filtration. After the same treatment was performed three more times, acetone was removed by vacuum drying to obtain 2.4 g of powdery acetone-treated cells.

20 ml of a 0.1 M phosphate buffer (pH 7.
In 0), 2.4 g of the obtained acetone-treated cells were dispersed, 648 mg (200 mM) of 3-quinuclidinone hydrochloride and 1.8 g of NADPH were added, and the mixture was stirred at 25 ° C. for 48 hours. After completion of the reaction, 20 g of potassium carbonate was added to the mixture under basic conditions.
It was extracted and removed twice with l of toluene. The product is then
Extracted twice with 0 ml of chloroform.

The extract was analyzed by gas chromatography. As a result, 364 mg (yield: 71%) of (R)-(-)-3-quinuclidinol was obtained with an optical purity of 100% ee (enantiomeric excess).

<Example 6> As described in Example 5, the cultured cells were treated with acetone using various microorganisms, the reaction was performed, and the product was extracted. Table 2 shows the analysis results of the extract.

[0056]

[Table 2]

Table 2 shows that the product can be obtained with high optical purity even using the acetone-treated cells. Furthermore, it is shown that the yield is increased by treating the cultured cells with acetone.

[0058]

According to the present invention, optically active 3-quinuclidinol, particularly (R)-(-)-3-quinuclidinol, can be efficiently produced with high optical purity. Acetone-treated microbial cells have higher yields than cultured cells with (R)-(-)-
3-Quinuclidinol can be produced. The obtained optically active 3-quinuclidinol is useful as a synthetic intermediate for producing a therapeutic agent for arteriosclerosis, bronchial asthma, or gastrointestinal motility suppression.

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Claims (7)

[Claims] 1. A method for producing optically active 3-quinuclidinol, comprising the following formula: Reacting 3-quinuclidinone represented by the formula with a biological catalyst capable of stereoselectively reducing 3-quinuclidinone. 2. The method according to claim 1, further comprising a step of separating the produced optically active 3-quinuclidinol from 3-quinuclidinone. 3. The method of claim 1, wherein the biological catalyst is Rhodtorla.
otorula), Candida, Sporidiobolus, Rhodosporidium (R
hodosporidium), Schizosac
charomyces), Cryptococcus
Genus, Trichosporon, Gordona
The method according to claim 1 or 2, wherein the method is derived from a microorganism selected from the group consisting of microorganisms belonging to the genus rdona), the genus Pichia, and the genus Nocardia. 4. The optically active 3-quinuclidinol comprises (R)
The method according to any one of claims 1 to 3, wherein the method is-(-)-3-quinuclidinol. 5. The method according to claim 1, wherein the biological catalyst is selected from the group consisting of a microbial cell, a microbial culture solution, a processed product of a microbial cell, and a purified enzyme. . 6. The method according to claim 1, wherein the biological catalyst is an acetone-treated microbial cell. 7. The microorganism according to claim 7, wherein the microorganism is Rhodotorula rubra, Rho
dotorula glutinis, Rhodotorula graminis, Rhodotoru
la minuta, Candida albicans, Candida parapsilosi
s, Candida intermedia, Candida antarctica, Sporidi
obolus salmonicolor, Rhodosporidium toruloides, Sc
hizosaccharomyces octosporus, Cryptococcus laurent
ii, Cryptococcus terreus, Trichosporon cutaneum, G
ordonaterrae, Pichia anomala, and Nocardia aster
The method according to any one of claims 1 to 6, which is a microorganism selected from the group consisting of oides.