JP2001124752A - Formation method for optically active oxybutynin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially isolate an oxybutynin optical activator with a high purity. SOLUTION: The formation method for oxybutynin is based on liquid chromatography of a pseudo moving bed type (pseudo moving bed method) with the use of a column filled with a filler for optical separation of a polysaccharide derivative. According to the pseudo moving bed method, a plurality of columns are coupled to an endless form, thereby forming a circulation passage. A fluid is forcibly circulated in one direction within the circulation passage. Introduction ports for introducing the fluid to the columns and extraction ports for extracting the fluid from in the columns are alternately arranged in a flow direction of the circulating fluid. The introduction ports and extraction ports are intermittently and simultaneously moved in position in the flow direction of the fluid circulating in the circulation passage, so that a solution including a racemic body of a mevalonoractone-based compound and an eluate are introduced from the separate introduction ports to the circulation passage, and at the same time a highly non-adsorptive solution and a highly adsorptive solution are extracted from separate extraction ports.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing optically active oxybutynin, and more particularly, to an industrial method for producing optically active oxybutynin useful for treating urinary incontinence.

[0002]

2. Description of the Related Art Drugs having an asymmetric center have a biological activity in only one of the optical isomers when they enter a living body, or have a tertiary activity in only one such as thalidomide. It is known that the action differs between optical isomers, for example, due to its properties. However, it is difficult to optically resolve a racemate by conventional techniques such as distillation and crystallization, and many pharmaceuticals having an asymmetric center are commercially available as a racemate.

[0003] Under such circumstances, it is necessary to use only an optically active compound which is one of the racemates as a therapeutic agent from the viewpoint of reducing the dose and reducing the side effects, and from the viewpoint of reducing side effects. It is desired to industrially isolate an intermediate optically active substance with high purity.

[0004] Optically active oxybutynin is very useful for treating urinary incontinence, but there has been no industrial method for obtaining it.

An object of the present invention is to solve the above-mentioned problems. That is, an object of the present invention is to industrially isolate an optically active form of oxybutynin with high purity.

[0006]

The present invention for solving the above problems uses a simulated moving bed method which is a kind of liquid chromatography using a column filled with a packing material for optical resolution.

More specifically, the invention according to claim 1 for solving the above-mentioned problem is characterized in that particles of a polysaccharide ester derivative, particles of a polysaccharide carbamate derivative, and a polysaccharide ester derivative and / or a polysaccharide carbamate derivative are supported on a carrier. A plurality of columns filled with at least one kind of optical splitting filler selected from the group consisting of particles are connected endlessly to form a circulation channel, and the fluid flows in one direction in the circulation channel. Forcibly circulate, the inlet for introducing the fluid into the column along the flow direction of the circulating fluid and the outlet for extracting the fluid from the column are alternately arranged, and circulating in the circulation flow path Intermittently the positions of the inlet and outlet in the flow direction of the fluid
Simultaneously, the solution containing the racemic oxybutynin and the eluent are introduced into the circulation channel from the inlet,
A method for producing an optically active oxybutynin-based compound, wherein a solution rich in a non-adsorbate and a solution rich in an adsorbate are simultaneously withdrawn from an outlet.The invention according to claim 2, wherein the polysaccharide ester derivative and the The polysaccharide carbamate derivative has a part or all of the hydrogen atoms on the hydroxyl group or amino group in the polysaccharide represented by the following formula (1):
The method for producing optically active oxybutynin according to claim 1, wherein the method is substituted with at least one of the atomic groups represented by any of (2), (3) and (4).

[0008]

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[0009]

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[0010]

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[0011]

Embedded image However, in the formula, R is an aromatic hydrocarbon group which may contain a hetero atom, and may be unsubstituted or have 1 to 1 carbon atoms.
12 alkyl groups, an alkoxy group having 1 to 12 carbon atoms, an alkylthio group having 1 to 12 carbon atoms, a cyano group, a halogen atom, an acyl group having 1 to 8 carbon atoms, an acyloxy group having 1 to 8 carbon atoms, a hydroxy group, It may be substituted by at least one group or atom selected from the group consisting of an alkoxycarbonyl group having 1 to 12 carbon atoms, a nitro group, an amino group and an alkylamino group having 1 to 8 carbon atoms.
X is a hydrocarbon group having 1 to 4 carbon atoms, and may include a double bond or a triple bond.

According to a third aspect of the present invention, in the method for producing an optically active oxybutynin according to the first or second aspect, the concentration of the oxybutynin in the solution containing the racemic oxybutynin is 10 mg / ml or more. It is characterized by.

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is a method for producing optically active oxybutynin using a simulated moving bed method.

First, the optical splitting filler used in the simulated moving bed method of the present invention will be described.

As the filler for optical resolution, various fillers can be used without any particular limitation as long as the optically active racemic oxybutynin can be optically resolved. In the present invention, preferred fillers for optical resolution are at least selected from the group consisting of particles of polysaccharide ester derivatives, particles of polysaccharide carbamate derivatives, and particles of polysaccharide ester derivatives and / or polysaccharide carbamate derivatives supported on a carrier. One kind can be mentioned.

The polysaccharide in the polysaccharide ester derivative and the polysaccharide carbamate derivative is not particularly limited as long as it is optically active irrespective of natural polysaccharide, natural product-modified polysaccharide, synthetic polysaccharide, or oligosaccharide.

Specific examples of polysaccharides include α-1,4-glucan (starch (amylose, aminopectin), glycogen), β-1,4-glucan (cellulose), α
-1,6-glucan (dextran), β-1,3-glucan (curdlan, disophyllan, etc.), α-1,3
-Glucan, β-1,2-glucan (Crawn Ga
11 polysaccharide), α-1,6-mannan, β-1,4-mannan, β-1,2-fructan (inulin), β-2,
6-fructan (levan), β-1,4-xylan, β
-1,3-xylan, β-1,4-chitosan, β-1,
4-N-acetylchitosan (chitin), α-1,3-
1,6-glucan (mutan), pullulan, agarose,
Alginic acid and the like can be mentioned.

The upper limit of the number-average degree of polymerization of these polysaccharides (the average number of pyranose or furanose rings contained in one molecule) is 2,000, preferably 500 or less.
It is preferable in terms of ease of handling.

Examples of the oligosaccharide include maltose, maltotetraose, maltopentaose, maltohexaose, maltoheptaose, isomaltose, erose, palatinose, maltitol, maltotriisitol, maltotetriitol, isomaltitol, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin and the like.

As preferred polysaccharide ester derivatives or polysaccharide carbamate derivatives, some or all of the hydrogen atoms on the hydroxyl group or amino group of the polysaccharide are replaced by the following formulas (1), (2), (3) and (4). Compounds obtained by substituting at least one of the atomic groups represented by any of them can be mentioned.

[0021]

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[0022]

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[0023]

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[0024]

Embedded image However, in the formula, R is an aromatic hydrocarbon group which may contain a hetero atom, and may be unsubstituted or have 1 to 1 carbon atoms.
12 alkyl groups, an alkoxy group having 1 to 12 carbon atoms, an alkylthio group having 1 to 12 carbon atoms, a cyano group, a halogen atom, an acyl group having 1 to 8 carbon atoms, an acyloxy group having 1 to 8 carbon atoms, a hydroxy group, It may be substituted by at least one group or atom selected from the group consisting of an alkoxycarbonyl group having 1 to 12 carbon atoms, a nitro group, an amino group and an alkylamino group having 1 to 8 carbon atoms.

The aromatic hydrocarbon group includes a phenyl group, a naphthyl group, a phenanthryl group, an anthracyl group,
Indenyl group, indanyl group, furyl group, thionyl group,
Examples thereof include a pyryl group, a benzofuryl group, a benzthionyl group, an indyl group, a pyridyl group, a pyrimidyl group, a quinolyl group, and an isoquinolyl group. Among them, particularly preferred are a phenyl group, a naphthyl group and a pyridyl group.

X is a hydrocarbon group having 1 to 4 carbon atoms, and may contain a double bond or a triple bond. Examples of X include a methylene group, an ethylene group, an ethylidene group, an ethenylene group, an ethynylene group, a 1,2- or 1,3-propylene group, a 1,1- or 2,2-propylidine group, and the like.

The degree of substitution by the above atomic group is at least 30%, preferably at least 50%, more preferably at least 80%.

The above-mentioned polysaccharide derivative which may have a substituent can be produced by a method in which a hydroxyl group or an amino group of a saccharide is reacted with acid chloride or isocyanate.

In the method of the present invention, the particles of the above-mentioned polysaccharide ester derivative and / or polysaccharide carbamate derivative are
It can be used as a filler for optical resolution. In this case, the size of the particles of the polysaccharide ester derivative and the polysaccharide carbamate derivative depends on the size of the column to be used, but is usually 1 μm to 1 mm, preferably 5 μm to 300 μm. The particles of the polysaccharide ester derivative and the polysaccharide carbamate derivative may be non-porous, but are preferably porous. If porous,
The pore size is from 10 to 100 μm, preferably from 10 to 5,000 °.

In the method of the present invention, particles having the above-mentioned polysaccharide ester derivative and / or polysaccharide carbamate derivative supported on a carrier can be used as a filler for optical resolution.

As the carrier, any of an organic carrier and an inorganic carrier may be used as long as the carrier can support the polysaccharide ester derivative or the polysaccharide carbamate derivative. Examples of the organic carrier include polymer substances such as polystyrene, polyacrylamide, and polyacrylate. Examples of the inorganic carrier include silica gel, alumina, magnesia, zirconia, glass, kaolin, titanium oxide, silicate, and diatomaceous earth. These carriers may be subjected to an appropriate treatment for modifying the surface of the carrier itself.

The size of these carriers is usually 1 μm to 1 mm, preferably 5 μm to 300 μm. The carrier may be non-porous, but is preferably porous.
When it is porous, its pore size is 10Å-100 μm
And preferably 100 to 5,000.

The amount of the polysaccharide ester derivative and / or polysaccharide carbamate derivative supported on the carrier is usually 1 to 100% by weight, preferably 5 to 50% by weight, based on the carrier.
% By weight. When the loading amount is less than 1% by weight, optical resolution of oxybutynin may not be effectively performed.
Even if it exceeds 00% by weight, the technical effect commensurate with supporting a large amount may not be exhibited.

In the present invention, the eluent used when adopting the simulated moving bed method includes, for example, alcohols such as methanol, ethanol and isopropanol;
Examples thereof include organic solvents such as hydrocarbons such as hexane, and mixed solvents of hydrocarbons and alcohols. Further, acetonitrile or the like can be used as an eluent depending on the filler used. From these eluents, an eluent is selected such that, in combination with the filler used, the elution time and the degree of separation of oxybutynin to be optically resolved become optimum.

In the simulated moving bed method used in the method of the present invention, a plurality of columns filled with a filler for optical separation are connected endlessly to form a circulation channel, and a fluid is formed in the circulation channel. Are forcedly circulated in one direction, and an inlet for introducing the fluid into the column and an outlet for extracting the fluid from the column are alternately arranged along the flow direction of the circulating fluid, and The positions of the inlet and the outlet are intermittently and simultaneously moved in the direction of flow of the circulating fluid, and the solution containing the racemate to be optically resolved and the eluate are each passed through a separate inlet from the circulation path. And simultaneously withdrawing the non-adsorbate-rich solution and the adsorbate-rich solution from different outlets.

In this simulated moving bed system, for example, as shown in FIG. 1, a liquid passage for circulating a liquid is divided into a plurality of (for example, 12 or 8) unit columns and each unit column is A simulated moving bed arranged in series is used. The liquid circulates in one direction in the liquid passage. Note that the number of unit columns in the simulated moving bed is not limited to the above number, and can be arbitrarily selected from an implementation scale, a reaction engineering viewpoint, and the like.

The simulated moving bed has an eluent inlet, an extract outlet for extracting a liquid containing an optical isomer that can be easily adsorbed to a filler (extract), and a racemic-containing liquid. A liquid inlet and a raffinate outlet for extracting a liquid (raffinate) containing an optical isomer that is difficult to adsorb to the filler are provided in this order, and the positions thereof are intermittently adjusted in the flow direction of the fluid in the packed bed. You can move sequentially.

In the simulated moving bed shown in FIG. 1, an eluent inlet, an extract outlet, a racemic-containing liquid inlet, and a raffinate outlet are provided for each of the three unit columns. In order to intermittently move these inlets and outlets sequentially, for example, a rotary valve, a solenoid valve, an air-operated valve or the like is used.

The adsorptive separation of racemic oxybutynin by the simulated moving bed method is realized by performing the following basic steps by continuously circulating the following adsorption step, concentration step, desorption step and eluate recovery step. You.

(1) Adsorption step In this step, the racemic oxybutynin comes into contact with the filler for optical resolution, and the optically active substance (adsorbate) which is easily adsorbed is adsorbed on the filler for optical resolution, and the adsorption is difficult. Is recovered as a raffinate component together with the eluent. This adsorption step is substantially performed in a simulated moving bed from injection of an eluent to extraction of a raffinate component, and the simulated moving bed in which the adsorption step is performed forms an adsorption zone (zone I).

(2) Concentration Step In this step, the filler for optical resolution adsorbing the adsorbate comes into contact with a part of the extract described later, and the non-adsorbate remaining on the filler for optical resolution is expelled. And the adsorbate is concentrated. This concentration step is performed substantially in a simulated moving bed from the time when the raffinate component is extracted to the time when the racemate-containing liquid is injected, and the simulated moving bed in which the concentration step is performed forms a purification zone (Zone II). .

(3) Desorption step In this step, the packing material for optical resolution containing the concentrated adsorbate is brought into contact with the eluent, the adsorbate is expelled from the packing material for optical resolution, and the extra It is discharged from the simulated fluidized bed as a component. This desorption step is substantially performed in a simulated moving bed from the injection of the racemic solution-containing liquid to the extraction of the extract, and the simulated moving bed performing the desorption step forms a concentration zone (Zone III). I do.

(4) Eluent Recovering Step In this step, the filler for optical resolution, which has substantially adsorbed only the eluent, comes into contact with a part of the raffinate, and the eluent contained in the filler for optical resolution is removed. A part is collected as the eluate liquid. The eluent recovery step is substantially performed in a simulated moving bed from extracting the extract to injecting the eluent, and the simulated moving bed performing the eluent step forms a desorption zone (zone IV). .

The following is a more detailed description with reference to the drawings.

In FIG. 1, reference numerals 1 to 12 denote unit columns containing a filler for optical division, which are connected to each other by a liquid passage. Reference numeral 13 denotes an eluent supply line, reference numeral 14 denotes an extract extraction line, reference numeral 15 denotes a racemic-containing liquid supply line containing a racemic oxybutynin, and reference numeral 16 denotes a raffinate extraction line. The line, designated by 17, is a recycle line, and designated by 18 is a circulation pump.

In the arrangement state of the unit columns 1 to 12 and the lines 13 to 16 shown in FIG. 1, the desorption step is performed by the unit columns 1 to 3, the concentration step is performed by the unit columns 4 to 6, and the adsorption step is performed by the unit columns 7 to 9. The eluent recovery step is performed by the unit columns 10 to 12, respectively.

In such a simulated moving bed, the eluent supply line, the racemic-containing liquid supply line and each extraction line are moved by one unit column in the solvent flow direction at regular time intervals, for example, by operating a valve.

Therefore, in the second stage, the unit column 2
To 4, desorption step, unit columns 5 to 7, concentration step, unit columns 8 to 10, adsorption step, unit column 1
1 to 1, the eluate recovery step is performed respectively. By sequentially performing such operations, each process is shifted by one unit column, and the separation of racemic oxybutynin is continuously and efficiently achieved.

The size of the column used in the simulated moving bed method of the present invention can be appropriately set according to the amount of the sample to be processed. The ratio between the inner diameter and the length of the column is 1: 5 to 2
When the ratio is 0: 1, the pressure loss during the operation is suppressed, so that the operation can be performed under a condition where the flow velocity is high, which is preferable in that high productivity can be obtained.

The feed rate of the sample was 10 times the flow rate in zone II.
% Or less is preferable in that stable operation conditions can be set without disturbing the sample concentration distribution in the system.
The racemic concentration of oxybutynin in the sample is 10%.
When the concentration is not less than mg / ml, particularly 10 to 150 mg / ml, the sample supply rate can be kept low. Therefore, stable operation without disturbing the sample concentration distribution in the system becomes possible, and high productivity is achieved. It is preferable in that it can be obtained.

The shorter the column switching time is, the better the productivity is. The shorter the column switching time is, the better. The column switching time should be 3 minutes or less, preferably 1 minute or less.

A column temperature of 10 to 50 ° C. is preferable in that the operation is easily controlled and the performance of the separation column is the best.

The extract extracted by the simulated moving bed method described above contains 90% or more, specifically, for example, 9%.
An optically active substance is contained in a solvent with an optical purity as high as 5% or more, or 98% or more, and other optically active substances are also contained in a solvent with the same high optical purity as the raffinate.

The simulated moving bed used in the method of the present invention is not limited to the one shown in FIG. 1, but a simulated moving bed shown in FIG. 2 can be used.

In the arrangement state of the unit columns 1 to 8 and the lines 13 to 16 shown in FIG. 2, the eluent recovery step is performed in the unit column 1, the adsorption step is performed in the unit columns 2 to 5, the unit column 6 is used.
7, the concentration step is performed, and the unit column 8 performs the desorption step.

In such a simulated moving bed, each supply liquid and withdrawal line are moved by one unit column in the liquid flow direction by operating a valve at regular time intervals. Therefore, in the next arrangement state of the unit columns, the eluent recovery step in the unit column 2 and the unit columns 3 to 6
To perform the adsorption step, the unit columns 7 and 8 to perform the concentration step, and the unit column 1 to perform the desorption step. By sequentially performing such steps, a separation treatment of a mixture of optical isomers is continuously and efficiently achieved.

In FIG. 1, reference numeral 19 denotes a first falling thin film evaporator 19 for concentrating the extract, and reference numeral 20 denotes a second falling thin film evaporator for further concentrating the concentrate. A forced thin film evaporator 21 for further concentrating the concentrate; a collection tank 22 for temporarily storing the recovered solvent;
Is a storage tank for storing a concentrated solution containing the optical isomer concentrated by the evaporator, 24 is a racemization tank for racemizing raffinate, and 25 is a recovery tank. This is a distillation apparatus for increasing the solvent stored in 22 to a required purity.

On the other hand, the raffinate contains a solvent and another optically active substance which is an enantiomer of the optically active substance contained in the extract. The solvent can be recovered from the raffinate in the same manner as the solvent is recovered from the extract. However, in any case, the means for concentrating the separated optically active substance and the process for recovering the used solvent are not limited to the means and processes described herein, and may achieve the object of the present invention. If possible, any means and process can be used.

[0059]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Embodiments of the present invention will be described below, but the present invention is not limited to these embodiments, and can be modified as appropriate within the scope of the present invention. Example 1 Amylose Tris (3,5-dimethylphenylcarbamate) was filled with silica gel as a carrier, and was filled with a filler for optical resolution (CHIRALPAK ^? AD, manufactured by Daicel Chemical Industries, Ltd., particle diameter: 20 μm). In a simulated moving bed apparatus in which eight columns each having an inner diameter of 1.0 cm and a length of 10 cm are connected, racemic oxybutynin is added in an amount of 0.33 ml / min (racemate concentration of 130 mg / m2).
1). The simulated moving bed apparatus was operated under the following conditions.

Eluent; mixture of n-hexane and 2-propanol n-hexane / 2-propanol volume ratio = 9/1 Eluent supply rate: 8.0 ml / min Adsorbate-rich fluid outlet Flow rate: 5.0 ml / min. Flow rate at the outlet of the fluid rich in non-adsorbate: 3.3 ml / min.
Min Column switching time; 1.0 min Temperature; 40 ° C. As a result, the adsorbate-rich fluid is discharged from the outlet of the adsorbate-rich fluid at an adsorbate concentration of 4370 ppm and an optical purity of 9
6.2% ee. Was obtained. From the outlet of the fluid rich in non-adsorbate, a fluid rich in non-adsorbate has a non-adsorbate concentration of 6450 ppm and an optical purity of 100% ee. Could be obtained. (Example 2) An amylose tris (3,5-dimethylphenylcarbamate) was filled with a filler for optical resolution (CHIRALPAK ^? AD, manufactured by Daicel Chemical Industries, Ltd., particle diameter: 20 µm) supported on silica gel as a carrier. In a simulated moving bed apparatus in which eight columns each having an inner diameter of 1.0 cm and a length of 10 cm are connected, a racemic form of oxybutynin is added at 7.30 ml / min (racemate concentration of 10 mg / m2).
1). The simulated moving bed apparatus was operated under the following conditions.

Eluent; mixed solution of n-hexane and 2-propanol n-hexane / 2-propanol volume ratio = 9/1 Eluent supply rate; 56.0 ml / min Adsorbate-rich fluid outlet Flow rate; 33.3 ml /
Min Flow rate at the outlet of the fluid rich in non-adsorbate; 30.0 ml
/ Min Column switching time; 0.59 min Temperature; 40 ° C. As a result, from the outlet of the fluid rich in adsorbate, the fluid rich in adsorbate is adsorbed at a concentration of 1100 ppm and an optical purity of 9
7.3% ee. Was obtained. From the outlet of the fluid rich in non-adsorbate, a fluid rich in non-adsorbate has a non-adsorbate concentration of 1230 ppm and an optical purity of 96.3% ee. Could be obtained.

[0062]

According to the present invention, a racemic oxybutynin can be efficiently and efficiently separated, and an optically active oxybutynin having a high optical purity can be produced.

[Brief description of the drawings]

FIG. 1 is an explanatory view showing an example of an apparatus for implementing the method of the present invention.

FIG. 2 is an explanatory view showing another apparatus for performing the method of the present invention.

[Explanation of symbols]

 1-12 Unit packed bed 13 Desorption liquid supply line 14 Extract extraction line 15 Optical isomer mixture containing liquid supply line 16 Raffinate extraction line 17 Recycle line 18 Circulation pump 19 First falling film evaporator 20 Second falling film Evaporator 21 Forced thin film evaporator 22 Recovery tank 23 Storage tank 24 Racemization tank 25 Distillation apparatus

Claims (3)

[Claims] 1. A filler for optical resolution which is at least one selected from the group consisting of particles of a polysaccharide ester derivative, particles of a polysaccharide carbamate derivative, and particles having a polysaccharide ester derivative and / or a polysaccharide carbamate derivative supported on a carrier. Is connected endlessly to form a circulation flow path, forcibly circulate the fluid in one direction in the circulation flow path, and into the column along the flow direction of the circulating fluid. The inlet for introducing the fluid and the outlet for extracting the fluid from inside the column are alternately arranged, and the positions of the inlet and the outlet are intermittent in the flow direction of the fluid circulating in the circulation channel, and , Move at the same time,
A solution containing a racemic form of oxybutynin and an eluent are introduced into the circulation channel from separate inlets, and simultaneously, a non-adsorbate-rich solution and an adsorbate-rich solution are withdrawn from separate outlets. A method for producing an optically active oxybutynin-based compound. 2. The polysaccharide ester derivative and the polysaccharide carbamate derivative have a part or all of a hydrogen atom on a hydroxyl group or an amino group in the polysaccharide represented by the following formula (1):
The method for producing an optically active oxybutynin according to claim 1, wherein the method is substituted with at least one of the atomic groups represented by any one of (2), (3) and (4). Embedded image Embedded image Embedded image Embedded image (Wherein, R is an aromatic hydrocarbon group which may contain a hetero atom, and may be unsubstituted or have 1 carbon atom
Alkyl group of 12 to 12, alkoxy group having 1 to 12 carbon atoms,
C1-C12 alkylthio group, cyano group, halogen atom, C1-C8 acyl group, C1-C8 acyloxy group, hydroxy group, C1-C12 alkoxycarbonyl group, nitro group, amino Group and carbon number 1-8
May be substituted with at least one group or atom selected from the group consisting of alkylamino groups. X is a hydrocarbon group having 1 to 4 carbon atoms, and may include a double bond or a triple bond. ) 3. The method for producing optically active oxybutynin according to claim 1, wherein the concentration of oxybutynin in the solution containing the racemic oxybutynin is 10 mg / ml or more.