JP2000228994A - Production of optically active compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an optical active compound that is useful as a synthetic intermediate for medicines, agrochemicals and the like in high yield by allowing (R, S) sulfur-containing propargyl alcohol to react with an esterifying agent in the presence of a stereospecifically catalyzing lipase. SOLUTION: (R, S) sulfur-containing propargyl alcohol represented by formula I [R1 and R2 are each a (substituted) alkyl, a (substituted) aralkyl, a (substituted) aryl] is reacted with an esterifying agent in an organic solvent in the presence of a lipase that can esterify either the R isomer or the S isomer of the propargyl alcohol to form the ester of one optically active sulfur-containing propargyl alcohol, while the other optically active sulfur-containing propargyl alcohol represented by formula III is allowed to remain. Thus, the objective optically active sulfur-containing propargyl alcohol of high optical purity, useful as a synthetic intermediate for medicines, agrochemicals, physiologically active substances and the like can be inexpensively obtained in high yield.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for obtaining optically active sulfur-containing propargyl alcohol by optically resolving (R, S) sulfur-containing propargyl alcohol in the presence of an enzyme. The obtained optically active substance is an important substance as an intermediate for synthesizing optically active compounds such as pharmaceuticals, agricultural chemicals, and physiologically active substances.

[0002]

2. Description of the Related Art Conventionally, as a method for obtaining an optically active form of sulfur-containing propargyl alcohol, optically active 1-butyne-3 is used.
A method of reacting -ol with a sulfenyl halide (RSX) to introduce an -SR group (R represents an alkyl group, an aryl group or an aralkyl group, and X represents a halogen atom) at the 1-position is known. (JP-A-10-2
No. 51223). In addition, the reaction itself of reacting racemic propargyl alcohol with an esterifying agent in the presence of an enzyme to perform optical resolution is performed by reacting racemic 1-butyn-3-ol with an esterifying agent in the presence of esterase. A method is known (JP-A-9-1079).
No. 89).

[0003]

However, in the method described in JP-A-10-251223, an expensive optically active reducing agent is required for producing an optically active propargyl alcohol as a starting material.
In the method described in Japanese Patent Application Laid-Open Publication No. H11-146, the optical purity and the yield are low, and neither method is practical.

[0004] In view of the above problems, an object of the present invention is to provide a method for synthesizing a sulfur-containing propargyl alcohol having a high yield and a high optical purity by using a relatively simple and relatively inexpensive reagent. .

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, the racemic form of the alcohol was reacted with an esterifying agent in an organic solvent in the presence of lipase to perform stereoselection. The transesterification was performed, and it was found that the racemate could be separated into an optically active sulfur-containing propargyl alcohol ester and the remaining optically active sulfur-containing propargyl alcohol in high yield and high optical purity, The present invention has been completed.

That is, the process for producing an optically active compound according to the present invention is carried out according to the general formula [I]

Embedded image Is reacted with an esterifying agent in an organic solvent in the presence of a lipase capable of stereoselectively esterifying either the R-form or the S-form of the (R, S) -containing propargyl alcohol represented by General formula [II]

Embedded image And the ester of one of the optically active sulfur-containing propargyl alcohols represented by the general formula [III]

Embedded image Characterized in that the other optically active sulfur-containing propargyl alcohol represented by

In the above general formulas [I], [II] and [III], R
¹ , R ² and R ³ may be the same or different,
It means an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent.

The present invention also relates to a method of reacting (R, S) sulfur-containing propargyl alcohol [I] with an esterifying agent in the presence of the above lipase in an organic solvent. I] is divided into an optically active sulfur-containing propargyl alcohol ester [II] and the other optically active sulfur-containing propargyl alcohol [III].

The produced ester [II] of one optically active sulfur-containing propargyl alcohol and the remaining optically active sulfur-containing propargyl alcohol can be separated by an ordinary method.

The method of the present invention is represented by the following reaction formula.

[0011]

Embedded image

The (R, S) sulfur-containing propargyl alcohol [I] used as a starting material in the method of the present invention may be one synthesized by a known method, for example, a reaction between racemic propargyl alcohol and sulfenyl halide. ,
It may be a commercial product as it is or its purified product.

The starting material (R, S) sulfur-containing propargyl alcohol [I] is usually an equimolar mixture of R-form and S-form, that is, a racemic form, but a mixture containing R-form and S-form in an unequal ratio. It may be.

(R, S) sulfur-containing propargyl alcohol
In [I], the optionally substituted alkyl group as R ¹ , R ² and R ³ may be linear or branched, and the alkyl group may be methyl. Group, ethyl group, n-propyl group, isopropyl group, t-butyl group,
It is a lower alkyl group having 1 to 6 carbon atoms such as an n-butyl group, an n-pentyl group and an n-hexyl group. Examples of the substituent include a halogen atom such as a chlorine atom and a bromine atom, an alkoxyl group such as a methoxy group and an ethoxy group, a nitro group, and a cyano group.

The optionally substituted aralkyl group as R ¹ , R ² and R ³ may be an unsubstituted or substituted benzyl group, an unsubstituted or substituted phenethyl group, an unsubstituted or substituted trityl group, And unsubstituted or substituted heterocyclic (pyridyl, thienyl, imidazoyl, etc.) alkyl groups. This substituent may be present on an aromatic ring or an aliphatic group, and may be present on a chlorine atom, a halogen atom such as a bromine atom, a methoxy group, an alkoxyl group such as an ethoxy group, a nitro group, a cyano group, or the like. , Methyl, ethyl, propyl, butyl, pentyl and the like.

The optionally substituted aryl group as R ¹ , R ² and R ³ is, for example, an unsubstituted or substituted phenyl group, an unsubstituted or substituted naphthyl group, an unsubstituted or substituted heterocyclic group. (Pyridyl, thienyl, imidazoyl, etc.). Examples of the substituent include an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl and pentyl; a halogen atom such as a chlorine atom and a bromine atom; an alkoxyl group such as a methoxy group and an ethoxy group; a nitro group and a cyano group. Is mentioned.

The esterifying agent used in the method of the present invention comprises:
Esters or anhydrides of carboxylic acids having an alkyl group, an aralkyl group or an aryl group R ³ as defined above; methyl acetate, ethyl acetate, 2,2,2-trifluoroethyl acetate, 2,2,2-trichloroacetic acid; Alkyl esters of aliphatic carboxylic acids such as ethyl; vinyl esters of carboxylic acids such as vinyl acetate, isopropenyl acetate, vinyl pivalate, vinyl benzoate, and isopropenyl benzoate; aliphatic acid anhydrides such as acetic anhydride and butyric anhydride; And aliphatic cyclic acid anhydrides such as succinic acid and glutaric anhydride. Among them, vinyl carboxylate such as vinyl acetate, isopropenyl acetate, vinyl pivalate, vinyl benzoate, and isopropenyl benzoate are particularly preferable.

The lipase used in the method of the present invention comprises:
(R, S) It exerts a catalytic effect in a reaction for stereoselectively esterifying one of the R-form and the S-form of sulfur-containing propargyl alcohol. As lipase,
Enzymes derived from microorganisms belonging to the genus Pseudomonas or Candida are preferred. The lipase used may be a crude product or a purified product thereof. The form may be in the form of a powder as it is, or may be supported on a suitable carrier and used as immobilized lipase.

As carriers for immobilizing lipase, high molecular organic materials such as polystyrene, polypropylene, starch, gluten, activated carbon, porous glass, celite, zeolite, kaolinite, bentonite, alumina, silica gel, hydroxyapatite, calcium phosphate, An inorganic material such as a metal oxide is exemplified, and the lipase is supported and immobilized by, for example, a physical adsorption method. The immobilized lipase retains sufficient activity and stereoselectivity of the reaction even after being recovered from the reaction solution by a usual filtration operation or the like after completion of the reaction, and thus can be reused repeatedly.

Commercially available lipases include lipase AK and lipase P derived from Pseudomonas fluorescens.
, Lipase CES, lipase PS derived from Pseudomonas cepacia, lipase AH (all of which are from Amano Pharmaceutical Co., Ltd.),
An example is lipase MY (manufactured by Meito Sangyo Co., Ltd.) derived from Candida syrup.

The organic solvent used in the method of the present invention includes diethyl ether, diisopropyl ether,
ethers such as t-butyl methyl ether; aliphatic hydrocarbons such as pentane, hexane and heptane; alicyclic compounds such as cyclohexane; aromatic compounds such as benzene, toluene and xylene; Halogenated hydrocarbons are exemplified. Preferably, ethers, aliphatic hydrocarbons, aromatic compounds and the like, particularly preferably diisopropyl ether, t-butyl methyl ether, benzene, toluene, cyclohexane and the like are used alone or in combination. Further, the esterifying agent itself as a reactant can be used as the solvent.

In the method of the present invention, the concentration of the substrate (R, S) sulfur-containing propargyl alcohol [I] in the reaction solution is 0.1 to 30% by weight, preferably 0.1 to 20% by weight. The concentration of the enzyme lipase is 0.1 to 3 in the reaction solution.
0% by weight, preferably 0.1 to 20% by weight. The amount of the enzyme to be used is preferably 0.05 to 50 times (weight ratio) with respect to the substrate in view of the reaction rate and the stirring efficiency, and the amount is preferably 0.1 to 50 times.
The amount is more preferably 5 to 30 times. The amount of the esterifying agent to be used is preferably 0.5 to 20 times (weight ratio) to the substrate, more preferably 1 to 8 times.

In the method of the present invention, the reaction temperature is usually 0.
0 ° C. to the boiling point of the solvent used, preferably 0 ° C. to 50 ° C., particularly preferably around room temperature, for example 10 to 10 ° C.
30 ° C.

In the method of the present invention, the reaction time can generally be adjusted as appropriate by increasing the reaction temperature, increasing the substrate concentration, or increasing the amount of the enzyme.

When the stereoselectivity of the enzyme is low, and when a high alcohol is to be obtained as the remaining alcohol, the reaction rate is increased to 50% or more, and the alcohol is obtained in a yield of 50% or less. In this case, the yield of the produced ester is as high as 50% or more, but the optical purity is low. In order to obtain high optical purity of the produced ester, the reaction rate is set at 50%.
% To obtain the ester in a yield of 50% or less. In this case, the yield of the remaining alcohol is as high as 50% or more, but the optical purity is low. In the method of the present invention,
(R, S) A lipase that catalyzes the esterification of either the R-form or the S-form of sulfur-containing propargyl alcohol with high stereoselectivity is used, and a compound containing sulfur is used as a substrate. Almost 50%
And both are obtained with high optical purity.

The one optically active sulfur-containing propargyl alcohol ester [II] obtained by the method of the present invention and the remaining other optically active sulfur-containing propargyl alcohol are:
Separation can be carried out by a common separation method, for example, a common method such as distillation, extraction, column chromatography or a combination thereof. The ester [II] of sulfur-containing propargyl alcohol can be converted to an alcohol by, for example, alkali hydrolysis. Thus, R-form sulfur-containing propargyl alcohol and S-form sulfur-containing propargyl alcohol having high optical purity can be obtained.

[0027]

According to the method of the present invention, a sulfur-containing propargyl alcohol having a high yield and a high optical purity can be synthesized in a simple step using a relatively inexpensive reagent.

[0028]

Now, the present invention will be described in further detail with reference to Examples. However, it should be understood that the scope of the present invention is by no means restricted thereby.

In the following Examples and Comparative Examples, (R,
S) A sulfur-containing propargyl alcohol [I] is dissolved in an organic solvent,
The mixture was reacted with the esterifying agent while stirring in the presence of lipase. The lipase was removed by filtration at an appropriate reaction rate (the ratio of the starting alcohol to the ester), and the reaction was stopped. Next, one optically active sulfur-containing propargyl alcohol ester [II] and the other optically active sulfur-containing propargyl alcohol [III] were separated from the reaction product by column chromatography. Analysis of optical purity is performed by CHIR
High performance liquid chromatography using ALCEL OD (manufactured by Daicel) and gas chromatography using CHIRALDEX G-TA (manufactured by ASTEC) were performed. The progress of the reaction was tracked by the above-described high performance liquid chromatography or gas chromatography, and the reaction rate was determined from the area of the alcohol compound and the ester compound.

Example 1 Racemic 4-phenylthio-3-butyn-2-ol 1
0 mg (56 mmol) and vinyl acetate 39 mg (450
mmol), lipase (“Lipase AK” manufactured by Amano Pharmaceutical Co., Ltd.)
10 mg was put in 2 ml of hexane, 50 mg of molecular sieve 4A was added, and the mixture was stirred at 30 ° C. for 3 hours. It was confirmed that the reaction rate had reached 47.9%.
At this time, the S-form of 4-phenylthio-3- was contained in the reaction solution.
Butyn-2-ol remains, and its optical purity is 9
1.2% ee. In addition, R-form 4-
An ester of phenylthio-3-butyn-2-ol was produced, and its optical purity was 99.1% ee.

Example 2 The same operation as in Example 1 was performed, except that the same amount of diisopropyl ether was used instead of hexane as a solvent.

It was confirmed that the reaction rate reached 49.5% in 9 hours. At this time, the reaction solution contains 4 S-forms.
-Phenylthio-3-butyn-2-ol remained, and its optical purity was 96.9% ee. In addition, R-form 4-phenylthio-3-butyn-2-
All esters are formed and their optical purity is 9
It was 8.8% ee.

Example 3 The procedure of Example 1 was repeated except that 6.5 mg (56 mmol) of racemic 4-methylthio-3-butyn-2-ol was used as the starting material (R, S) sulfur-containing propargyl alcohol. The same operation was performed.

The reaction rate was 51.4% in a reaction time of 2.5 hours.
It was confirmed that was reached. At this time, S-form sulfur-containing propargyl alcohol remained in the reaction solution, and its optical purity was 97.2% ee. An R-form ester of sulfur-containing propargyl alcohol was formed in the reaction solution, and its optical purity was 91.9% ee.

Example 4 Except for using 12.5 mg (56 mmol) of racemic 4- (4-nitrophenylthio) -3-butyn-2-ol as a starting material (R, S) sulfur-containing propargyl alcohol Then, the same operation as in Example 1 was performed.

It was confirmed that the reaction rate reached 50.3% in 3 hours. At this time, S-form sulfur-containing propargyl alcohol remained in the reaction solution, and its optical purity was 98.8% ee. An R-form ester of sulfur-containing propargyl alcohol was formed in the reaction solution, and its optical purity was 97.5% ee.

Example 5 Example 1 was repeated except that 10.8 mg (56 mmol) of racemic 5-phenylthio-4-pentyn-3-ol was used as the starting material (R, S) sulfur-containing propargyl alcohol. The same operation as described above was performed.

The reaction rate is 50.7% in a reaction time of 2.5 hours.
It was confirmed that was reached. At this time, S-form sulfur-containing propargyl alcohol remained in the reaction solution, and its optical purity was 98.1% ee. In addition, an R-form ester of sulfur-containing propargyl alcohol was formed in the reaction solution, and its optical purity was 95.6% ee.

Example 6 As a starting material (R, S) sulfur-containing propargyl alcohol, racemic 4- (benzylthio) -3-butyne-2-
The same operation as in Example 1 was performed, except that 10.8 mg (56 mmol) of oar was used.

It was confirmed that the reaction rate reached 50.1% in 3 hours. At this time, S-form sulfur-containing propargyl alcohol remained in the reaction solution, and its optical purity was 98.1% ee. Further, an ester of sulfur-containing propargyl alcohol of R-form was formed in the reaction solution, and its optical purity was 97.8% ee.

Example 7 Except that 13.5 mg (56 mmol) of racemic 3-phenylthio-1-phenyl-2-propyn-1-ol was used as the starting material (R, S) sulfur-containing propargyl alcohol, The same operation as in Example 1 was performed.

It was confirmed that the reaction rate reached 51.3% in 4 hours. At this time, S-form sulfur-containing propargyl alcohol remained in the reaction solution, and its optical purity was 95.6% ee. An R-form ester of sulfur-containing propargyl alcohol was produced in the reaction solution, and its optical purity was 90.9% ee.

Comparative Example 1 Racemic 3-butyn-2-ol 10 mg (143 mm
ol), 98 mg (1140 mmol) of vinyl acetate, and 10 mg of lipase (“Lipase AK” manufactured by Amano Pharmaceutical Co., Ltd.) in 2 ml of hexane, and 50 mol of molecular sieve 4A was added.
mg was added and the mixture was stirred at 30 ° C. for 13 hours. It was confirmed that the reaction rate reached 54.7%. At this time, S-form 3-butyn-2-ol remained in the reaction solution, and its optical purity was 75.6% ee. An R-form 3-butyn-2-ol ester was formed in the reaction solution, and its optical purity was 62.6% ee.

Continuing on the front page (72) Inventor Yoshiro Furukawa 9 Daitakasu-cho, Amagasaki-shi, Hyogo Daiso Corporation F-term (reference) 4B064 AC09 AC17 CA02 CA06 CA21 CB26 CC03 CD05 CD11 CD27 DA01 DA11 DA16 4H006 AA02

Claims (5)

[Claims] 1. A compound of the general formula [I] The (R, S) sulfur-containing propargyl alcohol represented by
In an organic solvent, in the presence of a lipase capable of stereoselectively esterifying either the R-form or the S-form of the alcohol, the alcohol is reacted with an esterifying agent to give a compound of the general formula [II] To form an ester of one of the optically active sulfur-containing propargyl alcohols represented by the general formula [III] A method for producing an optically active compound, characterized in that the other optically active sulfur-containing propargyl alcohol represented by (In the above general formulas [I], [II] and [III], R ¹ , R
² and R ³ may be the same or different, and may have an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent. Respectively. ) 2. The process according to claim 1, wherein the one produced optically active sulfur-containing propargyl alcohol [II] is separated from the remaining optically active sulfur-containing propargyl alcohol. 3. The method according to claim 1, wherein the esterifying agent is a vinyl carboxylate compound. 4. The lipase is an enzyme derived from a microorganism belonging to the genus Pseudomonas or Candida.
4. The method according to any one of items 1 to 3. 5. The organic solvent is diisopropyl ether, t
The method according to any one of claims 1 to 4, wherein the method is at least one selected from the group consisting of -butyl methyl ether, benzene, toluene, and cyclohexane.