JPH0940663A - Purification of intermolecular cyclic diester of alpha-hydroxy acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a highly purified compound containing slight impurities taken into a crystal by cleaning and purifying a solid diester under a specific condition by using a solvent. SOLUTION: A melted mixture containing an intermolecular cyclic diester of an α-hydroxy acid expressed by the formula (R<1> and R<2> are each H or a 1-5C alkyl) and impurities is gradually cooled (preferably in <=5 deg.C/min) under stirring to deposit crystal granules, then finally crystal aggregates having 20-1,000μm granular diameter are obtained. The resultant aggregates are crushed and/or dispersed in a solvent under stirring and cleaned. As examples of the intermolecular cyclic diester, L-lactide and/or D-lactide or a glycolide, etc., are exemplified.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for purifying cyclic diesters used as a raw material for .alpha.-oxy acid polyesters. The α-oxy acid polyesters represented by polylactic acid and polyglycolic acid have good biodegradability and are used for biodegradable medical materials such as surgical sutures and microcapsules for injection. Further, in recent years, plastic waste has become a problem, and attention has been paid to it as a biodegradable plastic that is expected to be decomposed by enzymes and microorganisms, and research and development is proceeding.

[0002]

2. Description of the Prior Art As a method for obtaining a high molecular weight α-oxy acid polyester, a diester which is an intermolecular cyclic dimer of α-oxy acid represented by the formula (I) is conventionally known in the art. A method of heating and ring-opening polymerization in the presence of a catalyst is known. Such diesters convert the corresponding α-oxy acids and / or their esters into relatively low molecular weight oligomers and their polyol copolymers, which are then heated in the presence of catalysts known in the art. It is produced by depolymerization.

However, the diesters obtained by these methods contain volatile hydroxyl compounds, which are present in small amounts but are volatile, as impurities such as water, α-oxy acids and low molecular weight oligomers thereof. However, it is not preferable because it inhibits ring-opening polymerization. That is, they exert various actions such as an initiator, a chain transfer agent and a catalyst deactivator, and prevent the polyester from reaching the target molecular weight.

Therefore, the diester corresponding to the ring-opening polymerization monomer must be sufficiently purified. In this case, from the viewpoints of the molecular weight control of the obtained polyester, the polymerization rate, and the degree of coloration, it is preferable that the impurities in the diester are as small as possible.For example, the amount of the α-oxy acid or the low molecular weight oligomer thereof is an acid value. Expressed below 10 eq / ton, more preferably 5 eq / to
It is known to be n or less.

As an industrial purification method, a recrystallization method using a dry organic solvent such as toluene, ethyl acetate, isopropanol and t-butyl alcohol is known. However, such a recrystallization operation usually requires several times, which leads to a large decrease in the yield of the diester, and the operation becomes complicated.
The production of oxyacid polyesters is too expensive for applications other than medical materials.

Purification by fractional condensation and distillation lowers the yield because water, α-oxy acid and low molecular weight oligomers thereof contained in the molten mixture cause decomposition and polymerization of the desired diester at the distillation temperature. Invite.
Furthermore, the formation of α-oxy acids and their low molecular weight oligomers over time during the distillation operation often makes it difficult to obtain diesters of the desired purity.

Therefore, since diester is used as a monomer of α-oxy acid polyester, various less expensive purification methods have been studied so far. As an inexpensive purification method instead of recrystallization, for example, a method of washing a diester solid substance containing impurities with an aqueous solvent (Japanese Patent Laid-Open No. 6-22).
No. 8288, JP-A No. 7-165753), a method of washing a diester solid with an ether solvent (JP-A No. 6-172341), and the like have already been disclosed. According to these methods, it is possible to easily obtain a high-purity diester that can be used as a monomer of an α-oxy acid polyester by contact-washing a diester solid containing impurities with a solvent. However, even in these methods, due to the nature of purification by washing,
Mainly, the impurities on the surface of the diester solid are only removed, and the impurities incorporated in the crystal cannot be removed. Therefore, these methods are limited in obtaining a purified diester of higher purity.

In order to eliminate impurities incorporated in the crystal in the above method, some improvement was made by making the diester solid substance into a very fine powder, but as a result of the experiments by the present inventors, It was found that an extension of the operation time is required in the solid-liquid separation and the drying operation after washing, which causes unfavorable effects such as hydrolysis of the diester. Further, even if the diester solid matter was kept in a slurry state for a long time in order to extract impurities in the crystals, a sufficient effect of removing impurities could not be obtained due to low extraction efficiency and hydrolysis of diester.

[0009]

Due to the above reasons, in the method of washing and purifying a diester solid substance by using a solvent, in order to obtain a purified diester of higher purity, the crystalline state of the solid substance to be washed is obtained. Need to control. However, such knowledge has not been obtained so far, and no such method is known at present.

[0010]

Therefore, the inventors of the present invention have conducted diligent studies to obtain a purified diester of higher purity in the method of washing and purifying a diester solid substance with a solvent, and as a result, diester and impurities A molten mixture of
Gradually cooling while precipitating crystal particles from the freezing point of the intermolecular cyclic diester containing impurities while stirring, and then finally stirring while stirring to obtain agglomerates of crystals of a specific particle size, which are then stirred in a solvent By pulverizing and / or dispersing below and washing, the content of impurities taken in the crystal is reduced, and it was found that a purified diester of higher purity than that obtained by the conventional methods can be obtained, and finally the present invention is completed. Arrived

That is, in the present invention, a molten mixture containing an intermolecular cyclic diester of an α-oxy acid represented by the following general formula (I) and impurities is crystallized from (1) a freezing point of the intermolecular cyclic diester containing impurities with stirring. Gradually cool while precipitating the particles, and (2) then finally with stirring to 2
A method for purifying an intermolecular cyclic diester of an α-oxy acid, which comprises the step of: (3) pulverizing and / or dispersing this in a solvent with stirring after obtaining a crystal aggregate of 0 to 1000 μm. Is.

[0012]

Embedded image (In the formula, R ¹ and R ² independently represent hydrogen or an alkyl group having 1 to 5 carbon atoms)

The present invention is applicable to the purification of water, hydroxyl impurities that inhibit ring-opening polymerization of α-oxy acids and low molecular weight oligomers thereof, and diesters from the solvent used in the pre-purification step. It is preferably applied to the purification of a mixture of a diester synthesized by depolymerizing a low molecular weight oligomer of an α-oxy acid and / or its ester or a polyol copolymer thereof and an impurity composed of a hydroxyl compound. It is also applied to the purification of a mixture of a diester synthesized by cyclizing an ester obtained from an α-halocarboxylic acid halide and an α-oxy acid and an impurity. Furthermore, it can be applied to purification of a mixture of diester and impurities obtained by a known purification method such as distillation, extraction, washing and recrystallization after synthesis.

In the present invention, as the cyclic diester of α-oxy acid to be purified, glycolide (intermolecular cyclic diester of glycolic acid), lactide (intermolecular cyclic diester of lactic acid), further α-hydroxybutyric acid, α- Hydroxyisobutyric acid, α-hydroxyvaleric acid, α-hydroxyisovaleric acid, α-hydroxy-α-methylbutyric acid, α
-Hydroxycaproic acid, α-hydroxyisocaproic acid, α-hydroxy-β-methylvaleric acid, α-hydroxyheptanoic acid and other intermolecular cyclic diesters can be mentioned.
Further, the compound having an asymmetric carbon may be any of L-form, D-form, racemic form and meso-form, but generally the meso-form is easily hydrolyzed and the yield tends to be extremely lowered.

The preferred diester is glycolide (1,4
-Dioxane-2,5-dione) and lactides, more preferably L-lactide ((3S) -cis-
3,6-dimethyl-1,4-dioxane-2,5-dione), D-lactide ((3R) -cis-3,6-dimethyl-1,4-dioxane-2,5-dione) and DL
-Lactide (a racemic compound of L-lactide and D-lactide). A mixture of these compounds and mesolactide (trans-3,6-dimethyl-1,4-dioxane-2,5-dione) can also be preferably used. Lactides are extremely important compounds as raw materials for lactic acid-based biodegradable plastics, which are currently being widely developed.

Further, the diester may be formed by different α-oxy acid molecules from each other. Specific examples thereof include 3-methyl-1,4-dioxane-2,5-dione, which is a cyclic diester between glycolic acid and lactic acid, and which is known by a common name of monomethyl glycolide.

In the present invention, the diester containing impurities is gradually cooled with stirring while precipitating crystal grains,
The crystal grain size of each of the obtained crystal aggregates is 20 to 10
Purification is carried out by controlling so that it becomes 00μ. If the crystal grain size is less than 20 μm, it is necessary to extend the operation time in the solid-liquid separation operation and the drying operation after washing, which causes hydrolysis of the diester. Further, when the crystal grain size exceeds 1000 microns, the amount of impurities present in the crystal grains is relatively increased by performing the crystallization treatment, and the object of the present invention cannot be achieved.

In the present invention, the stirring strength at the time of crystallization is carefully determined by a person skilled in the art so as to obtain a crystal grain size of 20 to 1000 μ in consideration of the performance and productivity of the machine used. It must be.

In the present invention, when a mixture of these diesters and impurities is melted, exposure to an unnecessarily high temperature for a long time is not preferable because the impurities cause the decomposition of the intended diester. That is, water, α-oxy acid or a low molecular weight oligomer thereof may open the diester to generate a new oxy acid. In the operation of the present invention, the freezing point of the diester containing impurities is usually 15
C., more preferably not higher than 5.degree.

In the present invention, when the diester containing impurities is gradually cooled from its freezing point while precipitating crystal grains while stirring, the cooling rate is preferably 5 ° C.
/ Min or less is preferable, more preferably 2 ° C / min or less, and most preferably 1 ° C / min or less. By cooling at a cooling rate as low as possible in this way, the diester gradually crystallizes, and the content of impurities incorporated in the formed crystals is lowered, so that a purer diester solid is obtained. If it is higher than 5 ° C./minute, a large amount of impurities are likely to be incorporated into the crystals produced. Even if the resulting solid is washed with a solvent, the object of the present invention cannot be achieved. The intermolecular cyclic diester of α-oxy acid thus purified according to the present invention is as highly polymerized as a diester recrystallized several times from a dry organic solvent such as toluene, ethyl acetate, isopropanol and t-butyl alcohol. It has properties and is suitable as a monomer for producing a high molecular weight α-oxy acid polyester. Therefore, a high molecular weight α-oxy acid polyester can be easily obtained by ring-opening polymerization of the obtained α-oxy acid diester,
It becomes possible to manufacture various biodegradable molded products.

[0021]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto. The characteristic values in the examples were measured by the following methods.

(1) Acid value (AV) 0.8 g of diester was precisely weighed and dissolved in methanol-chloroform (1/1 volume ratio) to give a solution of 0.1N-N.
It was measured by titration with aOCH ₃ methanol solution using phenolphthalein as an indicator, which was used as a measure of impurities contained in the diester.
It was represented by the consumption amount (equivalent number) of NaOCH ₃ per on.

(2) Content of water content 1.0 g of diester was precisely weighed and dissolved in chloroform, and then digital trace water content analyzer AQ- manufactured by Hiranuma Sangyo Co., Ltd.
Measured using 3C and expressed in ppm.

(3) Content of diester and its meso form content 40 mg of diester was precisely weighed, dissolved in acetonitrile, and then quantified by FID-GC (Gas Chromatograph GC-7A manufactured by Shimadzu Corporation) by the internal standard method, and weighed. Expressed in%. OV-225 was used for the column, and nitrogen was used as the carrier gas.

Reference Example 1 From 90% L-lactic acid aqueous solution (98% ee), an L-lactic acid oligomer having glycerin added and the ends blocked was synthesized by dehydration polycondensation using antimony trioxide as a catalyst, and this was synthesized at 200 ° C. AV = by thermally decomposing below 1 mmHg
A light yellow melt mixture of the diester and the impurities was obtained, having a composition of 152 eq / t L-lactide content 89.2%, mesolactide content 5.8%.

Reference Example 2 AV = 166 eq / t, DL-lactide content 55.0 from 90% DL-lactic acid aqueous solution by the same operation as Reference Example 1.
%, A mesolactide content of 33.2%, a pale yellow melt mixture of diester impurities was obtained.

Example 1 40.0 g of a molten mixture of L-lactide and impurities obtained in Reference Example 1 was placed in a separable flask. The melt temperature was kept at 97 ° C. When this was cooled with a commercial three-one motor at a cooling rate of 1 ° C./min under stirring at 50 rpm, minute crystals of L-lactide were observed to grow in the melt at 89 ° C. The temperature rose to 92 ° C due to the heat generated by crystallization. Further, when cooling was performed gradually at a cooling rate of 1 ° C./min, the amount of lactide crystals increased as the temperature decreased, and a slurry was formed. When cooled to 78 ° C., the appearance of the mixture became columnar agglomerates. After cooling this to 35 ° C., 80 g of ion-exchanged water at 24 ° C. was added and stirred, and the obtained slurry was suction filtered. The cake on the filter paper was further washed twice with 40 g of ion-exchanged water and then air-dried in a nitrogen stream for 2 hours. Recovery amount is 33.
It was 0 g. All the lactides obtained were obtained as crystals that passed through a 16-mesh sieve, AV = 2.2e
The content was q / ton, the mesolactide content was 0.7%, and the L-lactide content was 99.2%. The water content is 100
It was below ppm.

Example 2 40.0 g of a molten mixture of DL-lactide and impurities obtained in Reference Example 2 was placed in a separable flask. The melt temperature was kept at 102 ° C. When this is cooled at a cooling rate of 1 ° C./min with a commercial three-one motor under stirring at 50 rpm, minute crystals of DL-lactide start to grow in the melt at 95 ° C. Observed, the temperature rose to 96 ° C. due to the exotherm of crystallization. Further cooling rate 1 ℃
When the cooling was gradually performed at a speed of 1 / min, the lactide crystal amount increased as the temperature decreased, and a slurry was formed. The appearance of the produced solid is a plate-like crystal, and D is almost 100%.
It had an L-lactide content. After cooling to 45 ° C. and further cooling at a cooling rate of 0.2 ° C./minute, the eutectic of mesolactide and DL-lactide began to solidify at 39 ° C., and the temperature was kept constant for 1 hour. The slurry turned creamy. The temperature drops further and this
After the temperature was maintained at 0 ° C., 80 g of ion exchanged water at 24 ° C. was added and stirred, and the obtained slurry was suction filtered. The cake on the filter paper was further washed twice with 120 g of ion-exchanged water and then air-dried in a nitrogen stream for 2 hours. Recovery amount is 28.0g
Met. All of the obtained lactides passed through a 16-mesh sieve, AV = 2.2 eq / ton, mesolactide content 23.0%, and L-lactide content 76.0%. The water content was 120 ppm.

Comparative Example 1 40.0 g of a molten mixture of L-lactide and impurities obtained in Reference Example 1 was put into a separable flask. The melt temperature was kept at 97 ° C. When this was cooled at a cooling rate of 10 ° C./min using a commercially available three-one motor under stirring at 50 rpm, minute crystals were suddenly generated in the melt at 60 ° C. It changed to, and it became impossible to stir because it completely solidified. After cooling this to 35 ° C., 80 g of ion-exchanged water at 24 ° C. was added and stirred, but it was impossible to disperse the crystal lumps and obtain crystal particles, so the powder was crushed again using a mixer. The resulting slurry was suction filtered. The cake on the filter paper was further washed twice with 40 g of ion-exchanged water and then air-dried in a nitrogen stream for 2 hours. The recovered amount was 32.5 g. In the obtained lactide, it was observed that many large lumps were scattered and did not pass through a 16-mesh sieve. This lactide
AV = 32.2 eq / ton, mesolactide content 3.
The content was 1% and the L-lactide content was 94.2%. The water content was 350 ppm.

Comparative Example 2 40.0 g of a molten mixture of DL-lactide and impurities obtained in Reference Example 2 was charged in a separable flask. The melt temperature was kept at 102 ° C. When this was cooled with a commercial three-one motor at a cooling rate of 10 ° C./min under stirring at 50 rpm, minute crystals were suddenly generated in the melt at 52 ° C. It changed to, and it became impossible to stir because it completely solidified. After cooling this to 35 ° C., 80 g of ion-exchanged water at 24 ° C. was added and stirred, but it was impossible to disperse the completely solidified wax-like crystal lumps, so it was crushed again using a mixer. did. The resulting slurry was suction filtered. After further washing the cake on the filter paper twice with 40 g of ion-exchanged water,
It was air dried for 2 hours in a nitrogen stream. The recovered amount was 26.7 g. In the obtained lactide, it was observed that many large lumps were scattered and did not pass through a 16-mesh sieve. This lactide had an AV of 35.5 eq / ton, a mesolactide content of 22.1%, and a DL-lactide content of 73.3%. The water content was 450 ppm.

[0031]

As is apparent from the above examples, the intermolecular cyclic diester of α-oxy acid purified in the present invention has a higher purity than the conventional methods. By ring-opening polymerization of this diester, a high molecular weight α-oxy acid polyester can be easily obtained, various biodegradable molded products can be produced, and a wide range of applications can be expected. It greatly contributes to the solution.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Minako Arichi, 1-1 1-1 Katata, Otsu City, Shiga Prefecture Toyobo Co., Ltd. (72) Inventor Keiichi Uno 2-1-1 Katata, Otsu City, Shiga Prefecture Toyobo Co., Ltd. head office

Claims (5)

[Claims] 1. Crystal particles are prepared by stirring a molten mixture containing an intermolecular cyclic diester of an α-oxy acid represented by the following general formula (I) and impurities (1) from the freezing point of the intermolecular cyclic diester containing impurities with stirring. Gradually cool while precipitating, (2) then 20-1000 finally with stirring
Purification of intermolecular cyclic diester of α-oxy acid, which comprises a step of (3) pulverizing and / or dispersing this in a solvent with stirring after obtaining a crystal aggregate having a particle size of μ. Method. Embedded image (In the formula, R ¹ and R ² independently represent hydrogen or an alkyl group having 1 to 5 carbon atoms) 2. The cooling rate in step (1) is 5 ° C. /
The purification method according to claim 1, which is less than or equal to minutes. 3. The purification method according to claim 1 or 2, wherein the intermolecular cyclic diester is L-lactide and / or D-lactide. 4. The purification method according to claim 1 or 2, wherein the intermolecular cyclic diester is glycolide. 5. The case where mesolactide is further contained as the intermolecular cyclic diester, and the eutectic with mesolactide is also recovered by keeping the temperature at a constant temperature at the eutectic point with mesolactide. Purification method.