JPH0710234B2 - Method for producing lactone - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a lactone by subjecting an esterified product of a hydroxycarboxylic acid to a cyclization reaction.

Many compounds having a lactone structure in the molecule generally exhibit biological activity or have an odor, and are used as medicines, fragrances or raw materials thereof.

[Prior Art] As a method for intramolecularly condensing a hydroxycarboxylic acid to produce a lactone, a polymerization, a depolymerization method and an activation method are widely known.

The former method is a method in which a linear polyester obtained by heat polycondensation of hydroxy fatty acid is depolymerized by using an alkyl metal oxide as a catalyst and the ring is closed (JP-A-50-
69088 or JP-A-55-2640).

On the other hand, in the latter method, the hydroxycarboxylic acid is reacted with a halopyridinium salt or a haloquinolinate conductor,
This is an intramolecular condensation method (JP-A-52-151185, JP-B-61-11231).

[Problems to be Solved by the Invention] In the above-mentioned polymerization and depolymerization methods, the reaction must be carried out under severe conditions such as high temperature and reduced pressure, and the compound is unstable to heat, for example, many side chains and functional groups. It cannot be applied when a material having a group is used as a raw material. Moreover, since it is necessary to control the degree of polymerization, high-purity raw materials must be used,
In addition, since the heat-deteriorated product is mixed in the product, when the final product is a fragrance or the like, there is a problem that the quality thereof is significantly deteriorated.

Further, the activation method is expensive and uses a special reagent, which makes it difficult to obtain or synthesize this reagent, resulting in a significantly high manufacturing cost.

The present invention has solved such problems, and an object of the present invention is to provide a method for producing a lactone under mild conditions and using an inexpensive reagent.

[Means for Solving Problems] The present invention is a method for producing a lactone by subjecting a hydroxycarboxylic acid ester to a cyclization reaction in the presence of lipase, and particularly preferably, a solvent to which lipase is added is used in the cyclization reaction. It is carried out by dropping a solution of hydroxycarboxylic acid ester therein.

Needless to say, the esterification product of the hydroxycarboxylic acid used in the present invention is selected to correspond to the target macrocyclic lactone, but a long-chain ω-hydroxycarboxylic acid having 7 or more carbon atoms or (ω -1)-
Esterified products such as hydroxycarboxylic acid are preferred.
It is preferable to use an esterified product with a lower alcohol such as methyl, ethyl or butyl as the ester because the product after the cyclization reaction can be easily purified.

The lipase is an enzyme that catalyzes the reaction of stepwise hydrolyzing glycerides into glycerin and fatty acids, and lipases derived from any of humans, animals, molds, yeasts, bacteria and the like can be used.

Next, a preferred embodiment of the cyclization reaction will be described.

First, lipase is added to the solvent. The concentration of lipase in this case cannot be unconditionally determined depending on the activity of the enzyme used, but it is usually about 0.01 to 5%.

The liquid in which the lipase is dispersed preferably uses a hydrophobic solvent. Generally, the enzyme catalyzes in the presence of water, but in the reaction of the present invention, the water contained in the lipase itself is sufficient. Therefore, although an organic solvent can be used, among them, a hydrophilic solvent is not preferable because it may have an affinity with water in the lipase and change the three-dimensional structure of the lipase to inactivate it.

When a methyl ester or ethyl ester compound is used as a raw material, hydrophilic methyl alcohol or ethyl alcohol is produced as the reaction progresses, and the catalytic action of lipase is deactivated. On the other hand, it is particularly preferable to use benzene, cyclohexane, toluene, or the like, which has a large dissolving power, because the deactivation is alleviated.

Although water may be used as a solvent, the hydroxycarboxylic acid ester as a raw material is hardly dissolved in water, and thus the reaction takes time, which is not preferable.

As described above, the hydroxycarboxylic acid ester is added dropwise to the lipase-added solvent. It is preferable that the hydroxycarboxylic acid ester is used by dissolving it in a solvent in terms of reaction efficiency. The solvent used in this case is preferably the same as the solvent to which lipase has been added, because it facilitates solvent recovery.

Although the concentration of the hydroxycarboxylic acid ester solution is appropriately determined in relation to the dropping rate, it is usually preferable to set it in the range of 0.01 to 1% by weight. If it is 0.01% by weight or less, the reaction rate becomes extremely slow, which is not preferable. On the other hand, if it is 1% by weight or more, the intermolecular reaction, that is, the polyesterification reaction becomes predominant, and the yield of lactone due to the intramolecular cyclization reaction decreases, which is not preferable. For the same reason, it is preferable to add the ester solution having a concentration within the above range over 5 to 24 hours.

On the other hand, the reaction temperature is not generally determined depending on the type of lipase, but it shows the lactonization activity at the same temperature as the activity of lipase for hydrolyzing glycerides. It is appropriately selected at a temperature of ~ 50 ° C. The reaction time is sufficient if the reaction is continued for 24 hours after the start of dropping.

[Operation] In the present invention, a hydroxycarboxylic acid ester is hydrolyzed by a lipase, and then, although the reaction mechanism thereof has not yet been elucidated, an intramolecular cyclization reaction is caused to generate a lactone.

[Example] 200 ml of dehydrated benzene was placed in the four-necked flask of 1, and a lipase obtained from the bacterium Pseudomonas (Lipase P, manufactured by Nagase Biochemical Co., Ltd.) was placed in the flask.
Add 3 g, keep the temperature at 30 ° C, and stir vigorously with a magnetic stirrer, add dropwise a solution of 60 mg of hydroxycarboxylic acid methyl ester shown in the table in 100 ml of dehydrated benzene, and stir for a certain reaction time. The reaction was continued.

After completion of the reaction, the liquid was subjected to ultrafiltration to remove lipase, separated by a silica gel column, and confirmed to be the product shown in the table by infrared absorption analysis, mass spectrum analysis, and NMR analysis. The yield was measured, and the results are also shown in the table.

EFFECTS OF THE INVENTION Since the present invention lactonizes a hydroxycarboxylic acid ester in the presence of lipase, the reaction can be performed under mild conditions, and thermal deterioration products are not mixed in to obtain a product of excellent quality. You can Further, according to the present invention, since lipase, which is relatively easily available and inexpensive, is used, the production cost can be remarkably reduced. Furthermore, the present invention also has the effect that a lactone having stereospecificity can be produced by using a raw material having an asymmetric carbon because the enzyme action is utilized.

Claims (2)

[Claims] 1. A method for producing a lactone, which comprises subjecting a hydroxycarboxylic acid ester to a cyclization reaction in the presence of a lipase. 2. The method according to claim 1, wherein the cyclization reaction is carried out by dropping a solution of hydroxycarboxylic acid ester into a solvent to which lipase is added.
The method for producing a lactone according to the item.