JP2015145345A - METHOD FOR PRODUCING CYCLIC DIMERIC ESTER OF α-HYDROXYCARBOXYLIC ACID - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a cyclic dimeric ester economically and efficiently from an α-hydroxycarboxylic acid oligomer.SOLUTION: The method for producing a cyclic dimeric ester of an α-hydroxycarboxylic acid by depolymerizing an α-hydroxycarboxylic acid oligomer comprises: allowing a specific hydroxyl group-containing compound to reside beforehand in a reaction system set at 0.1 kPa to 5 kPa and 160°C to 230°C; continuously supplying an α-hydroxycarboxylic acid oligomer obtained by direct dehydration condensation of an α-hydroxycarboxylic acid or some oligomer into the reaction system; reacting the hydroxyl group-containing compound and the α-hydroxycarboxylic acid oligomer in the reaction system in the presence of a depolymerization catalyst; and continuously distilling off from the reaction system a cyclic α-hydroxycarboxylic acid dimer derived from the α-hydroxycarboxylic acid oligomer, and a cyclic hydroxycarboxylic acid dimer derived from a reaction product of the hydroxyl group-containing compound and the α-hydroxycarboxylic acid oligomer.

Description

  The present invention relates to a method for producing a cyclic α-hydroxycarboxylic acid dimer ester. More specifically, a method for economically and efficiently producing a cyclic α-hydroxycarboxylic acid dimer ester by depolymerizing an α-hydroxycarboxylic acid oligomer and a specific compound while reacting under reduced pressure and heating. About.

In recent years, for the purpose of protecting the global environment, resins that are easily decomposed in a natural environment have attracted attention and have been studied all over the world. Biodegradable polymers represented by aliphatic polyesters such as polylactic acid, polyglycolic acid, poly (3-hydroxybutyrate), and polycaprolactone are known as resins that are easily decomposed in a natural environment.
In particular, polylactic acid and polyglycolic acid are high biosafety and environmentally friendly polymer materials that use lactic acid obtained from plant-derived raw materials or derivatives thereof as raw materials. Therefore, the use as a general-purpose polymer is examined, and the use as a film, a fiber, an injection molded product, etc. is examined.

Poly (α-hydroxycarboxylic acid) typified by polylactic acid and polyglycolic acid is a direct polycondensation method that directly polycondenses lactic acid and glycolic acid, and a cyclic dimer is synthesized from lactic acid and glycolic acid. In view of quality and economy, the latter polymerization method is often employed.
It is widely known that a dimer cyclic ester of α-hydroxycarboxylic acid can be obtained by depolymerizing an oligomer of α-hydroxycarboxylic acid. Here, the α-hydroxycarboxylic acid dimer cyclic ester means a compound having a structure in which a dimer of α-hydroxycarboxylic acid is cyclic esterified, and representative compounds include lactide, glycolide and the like. be able to.

It has been difficult to economically and efficiently mass-produce cyclic α-hydroxycarboxylic acid dimer cyclic esters (see, for example, Patent Documents 1, 2, and 3).
The reason is that a specific method for producing a dimeric cyclic ester by depolymerizing an α-hydroxycarboxylic acid oligomer is to heat a solid α-hydroxycarboxylic acid oligomer to a melt, The dimer cyclic ester, which is a depolymerized product, is volatilized and collected from the surface (hereinafter, the surface of the liquid phase may be simply referred to as “surface”). Because there was a point.

(1) Since the molecular weight of the α-hydroxycarboxylic acid oligomer is high, efficient surface renewal is inhibited, and the generation rate or volatilization rate of the cyclic dimer ester of α-hydroxycarboxylic acid is low.
(2) Since the polycondensation proceeds in the α-hydroxycarboxylic acid oligomer melt phase due to long-time heating and a large amount of heavy products are formed, the yield of cyclic dimer ester of α-hydroxycarboxylic acid is increased. The rate is lowered, and the cleaning of the heavy residue is complicated.
(3) When the cyclic dimer ester of α-hydroxycarboxylic acid is lactide, since the carboxyl terminal of the oligomer is free, racemization proceeds at a high temperature and the purity is lowered.

For the reasons described above, mass production by scale-up is extremely difficult for the method of heating and depolymerizing the α-hydroxycarboxylic acid oligomer as it is.
In contrast, the α-hydroxycarboxylic acid oligomer is mixed with a high-boiling polar organic solvent and heated to dissolve the oligomer in the solvent to form a solution phase (preferably a substantially homogeneous solution phase). Further, a method for mass-producing the cyclic dimer ester by depolymerizing by heating and distilling the produced dimer cyclic ester together with a solvent has been proposed (see, for example, Patent Document 4).

However, the product in this technique is a mixture of a cyclic dimer ester and a solvent, and furthermore, since the high boiling point solvent is azeotroped, the process temperature is high, and finally the cyclic dimer ester and the solvent It is difficult to say that it is economical.
By the way, there are three types of lactide used for producing polylactic acid: L-lactide, D-lactide, and meso lactide. When producing poly (L-lactic acid), L-lactide (poly ( D-lactic acid) requires D-lactide). Generally, since it causes racemization by processing at a high temperature, it is technically difficult to obtain L-lactide (or D-lactide) with high optical purity.

In order to solve this, a method for producing high-purity lactide directly from a lactic acid ester using a titanium catalyst has been proposed (see, for example, Patent Document 5). However, since the starting material is a lactic acid ester, As lactide is produced, two equivalents of alcohol are generated in the system, so that a process for finally separating lactide and alcohol is necessary as described above, which is not economical.
As described above, the method for producing a cyclic dimer ester of α-hydroxycarboxylic acid by heating and depolymerizing the α-hydroxycarboxylic acid oligomer as it is, is difficult to mass-produce by scale-up.

US Pat. No. 2,668,162 U.S. Pat. No. 4,727,163 US Pat. No. 4,835,293 Japanese Patent No. 4171083 JP 2010-270102 A

  An object of the present invention is to solve the above-mentioned problems of the prior art and to provide a method for producing a cyclic dimer ester economically and efficiently from an α-hydroxycarboxylic acid oligomer.

  As a result of earnest research to overcome the problems of the prior art, the present inventor depolymerized the α-hydroxycarboxylic acid oligomer in a state of being reacted with a specific compound under reduced pressure and high temperature. It has been found that a cyclic dimer ester can be obtained economically and efficiently, and the present invention has been reached through further studies.

That is, the object of the present invention is to
1. In a method for producing a cyclic α-hydroxycarboxylic acid dimer ester by depolymerizing an α-hydroxycarboxylic acid oligomer,
A hydroxyl group-containing compound having the following characteristics (A) to (C) was previously present in the reaction system set to 0.1 kPa to 5 kPa and 160 ° C. to 230 ° C., and α-hydroxycarboxylic acid or The α-hydroxycarboxylic acid oligomer directly dehydrated and condensed from the partial ester is continuously supplied, and the hydroxyl group-containing compound and the α-hydroxycarboxylic acid oligomer are reacted in the presence of the depolymerization catalyst in the reaction system. A cyclic α-hydroxycarboxylic acid dimer derived from a carboxylic acid oligomer and a cyclic hydroxycarboxylic acid dimer derived from a reaction product of a hydroxyl group-containing compound and an α-hydroxycarboxylic acid oligomer are continuously distilled from the reaction system. Which is achieved by a process for producing a cyclic α-hydroxycarboxylic acid dimer ester, Can.
Characteristic (A): It is a liquid under conditions of 5 kPa or less and 160 ° C. to 230 ° C. and does not exhibit volatility.
Characteristic (B): containing at least one hydroxyl group in the compound molecule.
Characteristic (C): React with the carboxyl terminus of α-hydroxylcarboxylic acid.

The present invention also includes the following.
2. 2. The production method according to 1 above, wherein the hydroxyl group-containing compound having characteristics (A) to (C) is a kind selected from polyalkylene glycol, polyoxyalkylene monoether, and polyhydric alcohol.
3. 3. The production method according to 1 or 2 above, wherein the α-hydroxylcarboxylic acid oligomer has at least one hydroxyl group and at least one carboxylic acid group in one molecule, and has a molecular weight of 500 to 30,000.
4). 4. The production method according to any one of 1 to 3, wherein the depolymerization catalyst has a metal component, and the metal component is selected from at least one of tin, zirconium, titanium, zinc, aluminum, and magnesium.
5. 5. The production method according to any one of 1 to 4 above, wherein the α-hydroxycarboxylic acid constituting the α-hydroxycarboxylic acid oligomer is any of L-lactic acid, D-lactic acid, racemic lactic acid, and glycolic acid.
6). A cyclic α-hydroxycarboxylic acid dimer ester obtained by the production method according to any one of 1 to 5 above.
7). Use of the cyclic α-hydroxycarboxylic acid dimer ester as described in 6 above as a raw material for polyα-hydroxycarboxylic acid.

According to the production method of the present invention, it is possible to provide a method for producing a cyclic dimer ester economically and efficiently from an α-hydroxycarboxylic acid oligomer.
In addition, this inventor is guessing that it is the following mechanisms that the manufacturing method of this invention has such an effect.

(1) The presence of a specific amount of a specific compound (compound containing at least one hydroxyl group in the molecule) in the reaction system produces a carboxyl-terminal protected α-hydroxycarboxylic acid oligomer, and a polycondensation reaction between the oligomers Is suppressed, and the molecular weight of the carboxyl-terminated α-hydroxycarboxylic acid oligomer is kept low by the presence of the compound containing at least one hydroxyl group in the molecule. The surface renewal is performed remarkably efficiently, and as a result, the production rate of the cyclic dimer ester generated and volatilized is remarkably increased.
(2) When the dimer cyclic ester of α-hydroxycarboxylic acid is lactide, the free carboxyl terminal of the oligomer is blocked, and the viscosity of the oligomer is also lowered, so that the control temperature can be lowered and racemization is achieved. Can be drastically suppressed.

Hereinafter, the present invention will be described in detail.
<Α-hydroxycarboxylic acid>
The production method of the present invention is applied to a production method of a dimer ester of cyclic α-hydroxycarboxylic acid such as glycolic acid, L-lactic acid, D-lactic acid, racemic lactic acid, α-hydroxybutyric acid, α-hydroxyvaleric acid and the like. be able to. By depolymerizing these α-hydroxycarboxylic acid oligomers by the method of the present invention, various cyclic dimer esters such as glycolide and lactide can be produced. The method of the present invention is particularly suitable for the production of high optical purity lactide.

<Hydroxyl group-containing compound>
The hydroxyl group-containing compound used in the production method of the present invention is not particularly limited as long as it has the following characteristics.
Characteristic (A): It is a liquid under conditions of 5 kPa or less and 160 ° C. to 230 ° C. and does not exhibit volatility.
Characteristic (B): containing at least one hydroxyl group in the compound molecule.
Characteristic (C): React with the carboxyl terminus of α-hydroxylcarboxylic acid.
The hydroxyl group of the characteristic (B) is preferably a primary alcohol. Secondary and tertiary alcohols are less likely to react with an α-hydroxylcarboxylic acid oligomer than primary alcohols, and thus racemization tends to proceed.

  Examples of the hydroxyl group-containing compound having characteristics (A) to (C) include polyalkylene glycols having 5 to 10 polyoxyalkylene chains, polyoxyalkylene monoethers, polyoxyalkylene monoesters, and alkyl groups having 20 or more carbon atoms. It can be selected from polyhydric alcohols such as primary alcohol, trimethylolethane, trimethylolpropane, glycerin, monoether of glycerin, monoester derivatives, pentaerythritol, dipentaerythritol, tripentaerythritol, and the like. Particularly preferred from the viewpoints of viscosity and reactivity are polyoxyalkylene aliphatic ethers.

<Method for producing α-hydroxycarboxylic acid oligomer>
The oligomer of α-hydroxycarboxylic acid used as a starting material for the production method of the present invention can be easily synthesized by a known method. That is, α-hydroxycarboxylic acid or an ester partially containing α-hydroxycarboxylic acid is heated at a temperature of 100 to 230 ° C., preferably 120 to 210 ° C. under reduced pressure or normal pressure by autocatalysis, Condensation reaction or transesterification reaction is carried out until low molecular weight substances such as water and alcohol are substantially not distilled off. After completion of the condensation reaction or transesterification reaction, the produced oligomer can be used as it is as a raw material for the production method of the present invention. Further, the obtained oligomer can be taken out of the reaction system and washed with a non-solvent such as benzene or toluene to remove unreacted substances and low-polymerization products before use.

The molecular weight of the oligomer of α-hydroxycarboxylic acid used is estimated from the value calculated from the neutralization titration of the carboxyl group, and the molecular weight is preferably from 500 to 30,000, particularly preferably from 700 to 10,000.
When the molecular weight is 500 or less, low molecular weight oligomers are entrained and the purity of the distilled dimer ester decreases.

  On the other hand, when the molecular weight is 30000 or more, the melt viscosity of the oligomer in the reaction system becomes high, so the surface renewal efficiency is remarkably lowered, the production rate of the cyclic dimer ester is greatly reduced, and the surface renewal efficiency is further reduced. In order to improve the temperature, the temperature will be increased, but with this, further high molecular weight progresses, not only remarkably decreases the surface renewal, but also racemization progresses. Harder to get.

  In the case of producing an oligomer using L-lactic acid or D-lactic acid, from the viewpoint of racemization, a polycondensation catalyst or a transesterification catalyst is not used. Is preferred. If it is a racemic α-hydroxycarboxylic acid, a transesterification catalyst may be used at this point, but the above molecular weight range is preferable from the viewpoint of the production rate of cyclic dimer at the time of depolymerization.

<Method for producing cyclic dimer ester>
The production method of the present invention is carried out by the following process.
In the reaction system, α-hydroxycarboxylic acid oligomer is continuously supplied in the presence of a compound containing at least one hydroxyl group in the molecule and a depolymerization catalyst in the range of 5 kPa or less and 160 ° C to 230 ° C. The cyclic dimer ester of α-hydroxycarboxylic acid is produced while reacting, and then continuously distilled and recovered.

The relative weight ratio between the α-hydroxycarboxylic acid oligomer in the reaction system and the compound containing at least one hydroxyl group in the molecule is not particularly limited, but the carboxyl group of the α-hydroxycarboxylic acid oligomer is blocked. It is preferable to adjust the amount so as to be an appropriate melt viscosity, and it is preferably 1 to 50% by weight, preferably 3 to 40% by weight, more preferably 5 to 25% by weight based on the total weight of the reactants in the reaction system. It may be added only at the initial stage in a proportion by weight.
The molecular weight of the α-hydroxycarboxylic acid oligomer in the reaction system can be controlled by the amount of the compound containing at least one hydroxyl group in the molecule, and the addition amount is adjusted so as to obtain an optimum melt viscosity. It is preferable to perform the update without hindering the update.

In the production method of the present invention, heavy substances derived from oligomers are hardly generated at the time of heating, so that it is possible to save the labor of cleaning in the reaction system.
Moreover, when recovering the cyclic dimer ester of α-hydroxycarboxylic acid, a low molecular weight oligomer (for example, lactic acid or lactoyl lactic acid) is azeotroped. In this case, it can be separated by putting a packing in the distillation line and increasing the number of theoretical plates, or by adding distillation or a rectifying column. Alternatively, the purity can be further increased by performing distillation, rectification or melt crystallization in the next step.
In the production method of the present invention, since the solvent is not distilled together with the cyclic dimer ester of α-hydroxycarboxylic acid, it can be easily carried out even when the purification treatment in the next step is performed.

<Depolymerization catalyst>
The depolymerization catalyst used in the production method of the present invention is a metal catalyst selected from at least one of tin, zirconium, titanium, zinc, aluminum and magnesium, and is not particularly limited, but particularly preferably, tin octylate, dibutyltin oxide, Examples include dioctyltin oxide, tetrabutyl titanate, phenylbutyl titanate, tetraphenyl titanate, zirconium acetyl acetate, zirconium octylate, zinc acetyl acetate, zinc stearate, and aluminum acetyl acetate. Particularly preferred is tin octylate.

The addition amount is not particularly limited as long as the reaction system is not particularly inhibited, but is 0.01 to 10 parts by weight, preferably 0.05 to 5 parts by weight with respect to the oligomer in consideration of productivity.
If the amount is 0.01 parts by weight or less, a part of the catalyst is deactivated by the moisture generated in the reaction system, so that the catalytic activity is lowered and the cyclic dimer ester can be efficiently produced efficiently. difficult. If it is 10 parts by weight or more, it is not preferable because of cost, and depending on the temperature, racemization is promoted or extreme thickening is caused, which is not preferable in terms of productivity and quality. The addition method may be either the case where the oligomer is added continuously with respect to the flow rate of the oligomer or the case where addition is performed in a batch in the reaction system and the effect is lowered.
According to the present invention, the obtained cyclic dimer ester of α-hydroxycarboxylic acid can be used as a high purity monomer for poly α-hydroxycarboxylic acid.

Hereinafter, the present invention will be further described by examples. Each physical property was measured by the following methods.
(1) Molecular weight:
The molecular weight of the oligomer used was estimated from the carboxyl end amount calculated from neutralization titration.
For the oligomer, the sample was dissolved in methanol / chloroform (v / v = 1/1), dissolved in a nitrogen stream, 0.1 w / v% bromthymol blue (BTB) ethanol (50) solution as an indicator, 0.05 Titrated with ethanol solution of normal potassium hydroxide.
Molecular weight = sample amount / (0.05 × factor × (titration amount−blank))

(2) Optical purity The optical purity of the obtained cyclic dimer ester was hydrolyzed and measured by chiral HPLC.
The cyclic dimer ester was hydrolyzed with a mixed solution of 5N aqueous sodium hydroxide / methanol, diluted to a predetermined amount, and then diluted with 1 mM aqueous copper sulfate.
This solution was measured by chiral HPLC.
Apparatus: Shimadzu Corporation HPLC
Column: Sumika Chemical Analysis Co., Ltd. “Sumichiral (registered trademark)” OA-5000
Column temperature: 40 ° C
Eluent: 1 mM copper sulfate aqueous solution

(3) Confirmation of hydroxyl group-containing compound in cyclic dimer ester The presence or absence of a hydroxyl group-containing compound was confirmed by ¹ H-NMR.

[Production Example 1] Oligo L-lactic acid:
A 500 mL flask was charged with 350 g of L-lactic acid (Tokyo Chemical Industry Co., Ltd.), stirred at normal pressure (0.1 MPa), gradually heated to 120 ° C., and subjected to a condensation reaction while distilling water. . Further, the temperature was gradually raised to 170 ° C. under 4 kPa, and a condensation reaction was further performed. The molecular weight of the obtained oligomer was 1500.

[Production Example 2] Oligo L-lactic acid:
A 500 mL flask was charged with 350 g of L-lactic acid (Tokyo Chemical Industry Co., Ltd.), stirred at normal pressure (0.1 MPa), gradually heated to 120 ° C., and subjected to a condensation reaction while distilling water. . Further, the temperature was gradually raised to 200 ° C. under 4 kPa, and a condensation reaction was further performed. The molecular weight of the obtained oligomer was 5000.

[Production Example 3] Oligo L-lactic acid:
A 500 mL flask was charged with 350 g of L-lactic acid (Tokyo Chemical Industry Co., Ltd.), stirred at normal pressure (0.1 MPa), gradually heated to 120 ° C., and subjected to a condensation reaction while distilling water. . Furthermore, 0.03 part of tin octylate was added to the amount of lactic acid charged, and then the temperature was raised stepwise to 170 ° C. under 4 kPa, and a condensation reaction was further performed. The molecular weight of the obtained oligomer was 12000.

[Production Example 4] Oligo D-lactic acid:
While charging 350 g of D-lactic acid (Pureac Japan Co., Ltd.) into a 500 mL flask and stirring at normal pressure (0.1 MPa), the temperature was raised stepwise to 120 ° C. while distilling water. A condensation reaction was performed. Further, the temperature was gradually raised to 170 ° C. under 4 kPa, and a condensation reaction was further performed. The molecular weight of the obtained oligomer was 1560.

[Production Example 5] Oligoglycolic acid:
A 500 mL flask was charged with 350 g of glycolic acid (Tokyo Kasei Co., Ltd.), stirred at normal pressure (0.1 MPa), gradually heated to 200 ° C., and subjected to a condensation reaction while distilling water. . Further, the condensation reaction was further carried out at 200 ° C. under 4 kPa. The molecular weight of the obtained oligomer was 3000.

[Example 1]
Polyethylene glycol 33 g and oligomer 165 g prepared in Production Example 1 were mixed at 200 ° C. under 1 kPa at 300 ° C. in a 300 mL flask provided with an oligomer charging line and a distillation line, and then 1 g of tin octylate was added. The depolymerization reaction was carried out together with the reaction with polyethylene glycol as the hydroxy group-containing compound.
After the cyclic dimer ester began to distill off, the liquid level in the reaction system was kept constant, and the oligomer prepared in Production Example 1 was continuously supplied, and this reaction was carried out for 8 hours.
The optical purity of the obtained L-lactide was 99%, and the average distillation rate, which is an index of productivity, was 80 g / hr. The viscosity of the contents in the reaction system was not increased and could be continued. Further, no hydroxy group-containing compound was detected in the obtained L-lactide.

[Examples 2 to 17]
The same operation as in Example 1 was carried out except that the reactant (hydroxy group-containing compound) and the addition amount thereof, the raw material oligomer type to be used, the reaction temperature, the depolymerization catalyst, and the depolymerization catalyst addition amount were changed as shown in Table 1. went. The results are shown in Table 1.

[Comparative Examples 1 and 2]
The same operation as in Example 1 was carried out except that the reactant (hydroxy group-containing compound) was not used. The results are shown in Table 1. Not only is the optical purity of the obtained lactide low, but the distillation rate is also greatly reduced. Furthermore, in the late stage of depolymerization, an increase in viscosity was observed, making it difficult to continue.

  The dimer cyclic ester obtained by the production method of the present invention can be used as a starting material (monomer) of poly (α-hydroxycarboxylic acid) useful as a biodegradable polymer or a medical polymer, and the like. Industrial significance is great.

Claims (7)

In a method for producing a cyclic α-hydroxycarboxylic acid dimer ester by depolymerizing an α-hydroxycarboxylic acid oligomer,
A hydroxyl group-containing compound having the following characteristics (A) to (C) was previously present in the reaction system set to 0.1 kPa to 5 kPa and 160 ° C. to 230 ° C., and α-hydroxycarboxylic acid or The α-hydroxycarboxylic acid oligomer directly dehydrated and condensed from the partial ester is continuously supplied, and the hydroxyl group-containing compound and the α-hydroxycarboxylic acid oligomer are reacted in the presence of the depolymerization catalyst in the reaction system. A cyclic α-hydroxycarboxylic acid dimer derived from a carboxylic acid oligomer and a cyclic hydroxycarboxylic acid dimer derived from a reaction product of a hydroxyl group-containing compound and an α-hydroxycarboxylic acid oligomer are continuously distilled from the reaction system. A process for producing a cyclic α-hydroxycarboxylic acid dimer ester, characterized by comprising leaving.
Characteristic (A): It is a liquid under conditions of 5 kPa or less and 160 ° C. to 230 ° C. and does not exhibit volatility.
Characteristic (B): containing at least one hydroxyl group in the compound molecule.
Characteristic (C): React with the carboxyl terminus of α-hydroxylcarboxylic acid.   The manufacturing method of Claim 1 whose hydroxyl group containing compound which has characteristics (A)-(C) is 1 type chosen from polyalkylene glycol, polyoxyalkylene monoether, and a polyhydric alcohol.   The production method according to claim 1 or 2, wherein the α-hydroxylcarboxylic acid oligomer has at least one hydroxyl group and at least one carboxylic acid group in one molecule, and has a molecular weight of 500 to 30,000.   The production method according to claim 1, wherein the depolymerization catalyst has a metal component, and the metal component is selected from at least one of tin, zirconium, titanium, zinc, aluminum, and magnesium.   The production method according to claim 1, wherein the α-hydroxycarboxylic acid constituting the α-hydroxycarboxylic acid oligomer is any of L-lactic acid, D-lactic acid, racemic lactic acid, and glycolic acid.   A cyclic α-hydroxycarboxylic acid dimer ester obtained by the production method according to claim 1.   Use of the cyclic α-hydroxycarboxylic acid dimer ester according to claim 6 as a raw material for polyα-hydroxycarboxylic acid.