JP3132793B2 - Method for producing polyhydroxycarboxylic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to medical materials and general purpose resins alternative biodegradable polymer - methods for the preparation of a useful poly hydroxy carboxylic acids.

[0002]

2. Description of the Related Art Polyhydroxycarboxylic acid has excellent mechanical properties, physical properties and chemical properties, and is decomposed in a natural environment without harm to others. It has a biodegradable function of becoming carbon dioxide gas, and in recent years has been attracting attention in various fields such as medical materials and alternatives to general-purpose resins from the viewpoint of environmental protection. Expected. Usually, as a production method of polyhydroxycarboxylic acid, in the case of hydroxycarboxylic acid such as lactic acid and glycolic acid, after dehydration dimerization and once obtaining cyclic dimer, ring-opening melting in the presence of various catalysts It is known that a high molecular weight polymer can be obtained by polymerization. This method is not economical because it requires a great deal of labor and cost in the production of lactide or glycolide, which is a cyclic dimer. Some hydroxycarboxylic acids do not form a cyclic dimer, in which case this method cannot be used.

On the other hand, several methods for obtaining polyhydroxycarboxylic acids by direct dehydration from hydroxycarboxylic acids and oligomers thereof have been disclosed (JP-A-59-1984).
096123, JP-A-61-028521). However, the intrinsic viscosity of the polymer obtained by these methods is limited to about 0.3 dl / g, and does not have sufficient mechanical properties, and cannot be used depending on its use or purpose.

[0004]

The direct polycondensation reaction of a hydroxycarboxylic acid such as lactic acid or glycolic acid is a sequential reaction similarly to the esterification reaction between a dibasic acid and a polyhydric alcohol, and the reaction time is short. As the molecular weight increases. In addition, since the water molecules generated at this time have an effect of reducing the molecular weight of the polycondensate by a reverse reaction due to the hydrolysis action, it is necessary to efficiently remove the generated water to the outside of the system by using high molecular weight polylactic acid or polyglycol. It was necessary to obtain luic acid and the like. Examples of this method include a method of increasing the stirring speed during the reaction, a method of increasing the degree of reduced pressure, and a method of introducing an inert gas into the reaction system to volatilize water, but the viscosity of the reaction system increases significantly with an increase in molecular weight. These methods have limitations, and the molecular weights reached are usually 2 with or without a catalyst.
It was less than 000. Therefore, it was impossible to obtain a molded product or a film having sufficient mechanical properties from the polymer produced by these methods.

The present invention provides a method for producing a high molecular weight polyhydroxycarboxylic acid by a direct dehydration condensation reaction of a hydroxycarboxylic acid.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to obtain a high molecular weight polyhydroxycarboxylic acid. As a result, the hydroxycarboxylic acids or their oligomers are heated to reflux in an organic solvent to obtain a hydroxycarboxylic acid. In a method of obtaining polyhydroxycarboxylic acid by removing impurities contained in an acid to the outside of the reaction system and then dehydrating polycondensation, a polymer having a high average molecular weight is obtained in a relatively short time by using a special solvent. It has been found that the present invention has been completed and the present invention has been completed.

That is, the present invention relates to a method for preparing a hydroxycarboxylic acid or an oligomer thereof, which is previously heated to reflux in an organic solvent in the presence of a catalyst to remove water and low-boiling compounds. A method for producing a polyhydroxycarboxylic acid by performing a heat reaction while removing water from a polyhydroxycarboxylic acid, wherein a halogenated hydrocarbon is used as a solvent.

The following are specific examples of the hydroxycarboxylic acid used in the present invention. Glyco-
Luic acid, lactic acid, 2-hydroxybutanoic acid, 2
-Hydroxypentanoic acid, 2-hydroxyhexanoic acid, 2-hydroxyheptanoic acid, 2-hydroxyoctanoic acid,
2-hydroxy-2-methylpropanoic acid,
2-hydroxy-2-methylbutanoic acid, 2
-Hydroxy-2-ethylbutanoic acid, 2-
Hydroxy-2-methylpentanoic acid, 2-
Hydroxy-2-ethylpentanoic acid, 2-
Hydroxy-2-propylpentanoic acid, 2
-Hydroxy-2-butylpentanoic acid, 2
-Hydroxy-2-methylhexanoic acid, 2
-Hydroxy-2-ethylhexanoic acid, 2
-Hydroxy-2-propylhexanoic acid,
2-hydroxy-2-butylhexanoic acid,
2-hydroxy-2-pentylhexanoic acid, 2-hydroxy-2-methylheptanoic acid, 2-hydroxy-2-methylheptanoic acid, 2-hydroxy-2-ethylheptanoic acid, 2-hydroxy-2-pentylhexanoic acid Hydroxy-2- propylheptanoic reed
Head, 2-hydroxy-2-butyl heptanoate dichroic acid, 2-hydroxy-2-pentyl heptanoate dichroic acid, 2-hydroxy-2-hexyl heptanoate dichroic acid, 2-hydroxy-2-methyl-octanoic acid 2-hydroxy-2-ethyloctanoic acid, 2-hydroxy-2-propyloctanoic acid, 2-hydroxy-2-butyloctanoic acid, 2-hydroxy-2-pentyloctanoic acid, 2 -Hydroxy-2-hexyloctanoic acid, 2-hydroxy-2-heptyloctanoic acid, 3-hydroxypropanoic acid, 3-hydroxybutanoic acid, 3-hydroxypentanoic acid, 3-hydroxy Hexanoic acid 3-hydroxyheptanoic acid, 3-hydroxyoctanoic acid, 3-hydroxy-3-methylbutanoic acid, 3-hydroxy-3-methylpentanoic acid, 3-hydroxy-3-ethylpentanoic Acid, 3-hydroxy-3-methylhexanoic acid, 3-hydroxy-3-ethylhexanoic acid, 3-hydroxy-3-propylhexanoic acid, 3-hydroxy-3-methylheptanoic acid, 3-hydroxy-3-ethylheptanoic acid, 3-hydroxy-3-propylheptanoic acid, 3-hydroxy-3-ethylheptanoic acid
Hydroxy-3-butylheptanoic acid, 3-
Hydroxy-3-methyloctanoic acid, 3-
Hydroxy-3-ethyloctanoic acid, 3-
Hydroxy-3-propyloctanoic acid, 3
-Hydroxy-3-butyloctanoic acid, 3
-Hydroxy-3-pentyloctanoic acid,
4-hydroxybutanoic acid, 4-hydroxypentanoic acid, 4-hydroxyhexanoic acid, 4-hydroxyheptanoic acid,
4-hydroxyoctanoic acid, 4-hydroxy-4-methylpentanoic acid, 4-hydroxy-4-methylhexanoic acid, 4-hydroxy-4-ethylhexanoic acid, 4-hydroxy-4- Methylheptanoic acid, 4-hydroxy-4-ethylheptanoic acid, 4-hydroxy-4-propylheptanoic acid, 4-hydroxy-4-methyloctanoic acid, 4-hydroxy-4-ethylocta Neuic acid, 4-hydroxy-4-propyloctanoic acid, 4-hydroxy-4-butyloctanoic acid, 5-hydroxypentanoic acid, 5-hydroxyhexanoic acid, 5-hydroxyheptanoic Acid, 5-hydro Cioctanoic acid, 5-hydroxy-5-methylhexanoic acid, 5-hydroxy-5-methylheptanoic acid, 5-hydroxy-5-ethylheptanoic acid, 5-hydroxy-5-methylocta Neuic acid, 5-hydroxy-5-ethyloctanoic acid, 5-hydroxy-5-propyloctanoic acid, 6-
Hydroxyhexanoic acid, 6-hydroxyheptanoic acid, 6-hydroxyoctanoic acid, 6-hydroxy-6-methylheptanoic acid, 6-hydroxy-6-methyloctanoic acid, 6-hydroxy- 6-ethyloctanoic acid, 7-hydroxyheptanoic acid, 7
Aliphatic hydroxycarboxylic acids such as -hydroxyoctanoic acid, 7-hydroxy-7-methyloctanoic acid, and 8-hydroxyoctanoic acid. These may be used alone or as a mixture of two or more. Particularly preferably used hydroxycarboxylic acids are lactic acid, glycolic acid, 3-hydroxybutyric acid, 4-hydroxybutyric acid,
3-hydroxyvaleric acid, or a mixture thereof.

In the method of the present invention, an oligomer derived from the above-mentioned hydroxycarboxylic acid can be used as a raw material. And they may be used as one kind or a mixture of two or more kinds.

These hydroxycarboxylic acids and their oligomers have an optically active carbon and have D-form and L-form, respectively.
Although it may take the form of a body or a D / L body, the form is not limited in the present invention.

The halogenated hydrocarbon of the solvent which is a feature of the present invention includes aliphatic halogenated hydrocarbons such as trichloromethane, tetrachloromethane, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1 1-trichloroethane, 1,1,2-trichloroethane, 1,
1,1-trichloroethylene, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane,
1-chloropropane, 1-chlorobutane, 1-chloropentane, 1-chlorohexane, 1-chlorooctane, 1
-Chlorodecane, 1-chlorotetradecane, 1,3-dichloropropane, 1,4-dichlorobutane, 1,5-dichloropentane, 1,6-dichlorohexane, 1,8-
Dichlorooctane, 1,10-dichlorodecane, 1,2
-Dibromoethane, 1,1,1-tribromoethane,
1,1,2-tribromoethane, 1,1,1-tribromoethylene, 1,1,1,2-tetrabromoethane,
1,1,2,2-tetrabromoethane, 1-bromopropane, 1-bromobutane, 1-bromopentane, 1-bromohexane, 1-bromooctane, 1-bromodecane, 1,3-dibromopropane, 1,4 -Dibromobutane, 1,5-dibromopentane, 1,6-dibromohexane, 3-bromo-1-propene, 1-bromo-2-chloropropane, 1-bromo-2-chloroethane, 1-bromo-5-chloropentane , Hexachloroethane and the like. Further, as the aromatic halogenated hydrocarbon,
Chlorobenzene, chlorobenzyl, o-chlorotoluene, m-chlorotoluene, p-chlorotoluene, 1-chloroethylbenzene, 2-chloroethylbenzene, o-
Chloroethylbenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, 2,3-dichlorotoluene, 2,4-dichlorotoluene, 2,5-dichlorotoluene, 2,6-dichlorotoluene, 3,4-
Dichlorotoluene, 1,2,3-trichlorobenzene,
1,2,4-trichlorobenzene, 1,3,5-trichlorobenzene, α, α, α-trichlorobenzyl, α,
2,4-trichlorobenzyl, α, 2,6-trichlorobenzyl, α, 3,4-trichlorobenzyl, pentachlorobenzene, hexachlorobenzene, bromobenzene, bromobenzyl, o-bromotoluene, m-bromotoluene, p-bromo Toluene, o-dibromobenzene, m-dibromobenzene, p-dibromobenzene,
2,3-dibromotoluene, 2,4-dibromotoluene, 2,5-dibromotoluene, 2,6-dibromotoluene, 3,4-dibromotoluene, 1-bromoethylbenzene, 2-bromoethylbenzene, o-bromoethylbenzene, 1,2,3-tribromobenzene, 1,2,2
4-tribromobenzene, 1,3,5-tribromobenzene, iodobenzene, iodobenzyl, o-iodotoluene, m-iodotoluene, p-iodotoluene,
-Chloronaphthalene, 2-chloronaphthalene, 1-bromonaphthalene, 2-bromonaphthalene, 1-fluoronaphthalene, 1-iodnaphthalene and the like. These may be used alone or in a mixture of two or more. In particular, aromatic halogenated hydrocarbons are preferred solvents because of their high polymerization rate and higher molecular weight.

In the method of the present invention, the addition of the polymerization catalyst can be arbitrarily selected depending on the degree of polymerization (intrinsic viscosity and molecular weight) of the target polymer or not.
When a low molecular weight polymer is produced (the weight average molecular weight Mw in terms of polystyrene is less than about 30,000), the desired polymer can be easily obtained with or without the addition of a catalyst. On the other hand, when producing a polymer having a high molecular weight (polystyrene-equivalent weight average molecular weight Mw of 30,000 or more), it is preferable to use a catalyst in view of the reaction time (reaction rate).

Examples of the catalyst used in the present invention include metals belonging to Groups I, II, III, IV and V of the Periodic Table of the Elements, or salts or hydroxides and oxides thereof. For example zinc,
Metals such as tin, aluminum, magnesium, antimony, titanium and zirconium. Tin oxide, antimony oxide,
Metal oxides such as lead oxide, aluminum oxide, magnesium oxide, and titanium oxide. Metal halides such as zinc chloride, stannous chloride, stannic chloride, stannous bromide, stannic bromide, antimony fluoride, zinc chloride, magnesium chloride, and aluminum chloride. Sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, zinc hydroxide, iron hydroxide, cobalt hydroxide, nickel hydroxide, copper hydroxide, cesium hydroxide, strontium hydroxide, hydroxide Metal hydroxides such as barium, lithium hydroxide and zirconium hydroxide. Sulfates such as tin sulfate, zinc sulfate, and aluminum sulfate. Carbonates such as magnesium carbonate, zinc carbonate and calcium carbonate. Organic carboxylate such as tin acetate, tin octoate, tin lactate, zinc acetate, aluminum acetate, iron lactate. Organic sulfonates such as tin trifluoromethanesulfonate and tin p-toluenesulfonate are exemplified.

In addition, an organic metal oxide of the above metal such as dibutyltin oxide or a metal alkoxide of the above metal such as titanium isopropoxide or an alkyl metal of the above metal such as diethyl zinc. And ion exchange resins such as Dowex and Amberlite. The amount of use is 0.0001 to 10% by weight of the above hydroxycarboxylic acid or an oligomer thereof.

Prior to the dehydration polycondensation, hydroxycarboxylic acids are heated and refluxed in an organic solvent in advance. By this operation, impurities derived from the raw materials existing in the reaction system are removed to the outside of the reaction system together with the refluxing solvent. Therefore, the organic solvent containing the refluxing impurities may be once distilled out of the system to remove the impurities and then returned to the reaction system again, or the organic solvent containing the impurities may not be returned to the reaction system. Alternatively, a method in which an organic solvent containing no impurities is newly charged and the organic solvent in the reaction system is replaced may be selected. As a condition for heating and refluxing in an organic solvent, the temperature is 80 to 250.
° C, preferably 110-170 ° C. If the temperature is lower than 80 ° C., the effect of removing impurities is reduced, which is not preferable. Conversely, a temperature exceeding 250 ° C. is not preferable because the hydroxycarboxylic acid is thermally degraded. The pressure may be normal pressure or reduced pressure, and the pressure at which the mixture is refluxed in the above temperature range is appropriately selected depending on the reaction solvent used. The heating and refluxing time varies depending on the temperature conditions, reaction scale and the like, but is preferably 0.5 to 60 hours, preferably 2 to 30 hours. When the time is shorter than 0.5 hour, the effect of removing the impurities described above is not so significant, and even if the time exceeds 60 hours, no further effect of removing impurities can be expected.

The reaction temperature at the time of dehydration polycondensation is set to 50 ° C. under normal pressure, the reflux temperature of the temperature used, or the reduced pressure.
The temperature may be lowered to ２５０250 ° C. More preferably, 1
00-170 ° C is good. If the temperature is lower than 50 ° C., the efficiency of removing water generated by the reaction out of the reaction system by azeotropic distillation with the solvent is deteriorated, so that the reaction rate is significantly reduced. Also 2
If the temperature is higher than 50 ° C., the polymer may be deteriorated or the reaction solution may be colored, thereby deteriorating the quality of the obtained product.

When a desiccant is used, for example, metal sieves such as molecular sieves (3A, 4A, 5A etc.), diphosphorus pentoxide, calcium hydride, sodium hydride, lithium aluminum hydride, sodium hydride, etc. And alkali metals such as lithium.

The reaction apparatus may be such that the distilled solvent passes through a column filled with a desiccant and returns to the reactor. For those that cannot be packed in a column, the solvent should be distilled off in a separate reactor in the presence of a drying agent by reflux dehydration to partially distill the solvent and return it to the reactor where the condensation reaction is being performed. Can be. Alternatively, a method may be adopted in which a reaction is carried out in a reactor equipped with a device having distillation separation ability, a mixture of a refluxing solvent and water is separated by distillation as it is to remove water, and only the dehydrated solvent is returned to the system. Further, the solvent containing the distilled water may be removed as it is, and the solvent may be newly added to the reaction system.

In the method of the present invention, a polycondensation may be carried out by adding a coloring inhibitor in order to suppress coloring due to thermal deterioration during the polycondensation. As the coloring inhibitor to be used, phosphorus compounds such as phosphoric acid, triphenyl phosphate, pyrophosphoric acid, phosphorous acid and triphenyl phosphite are preferred. The amount added
It is 0.01 to 5% by weight, more preferably 0.5 to 2% by weight, based on the polymer. If it is less than 0.01% by weight, the effect of preventing coloration is small, and if it is 5% by weight or more, the effect of further preventing coloration is weak and the degree of polymerization may not be increased.

[0020]

EXAMPLES Examples of the present invention will be described below, but the present invention is not limited to the methods and apparatuses described below. The molecular weight of the polymer described in this specification can be determined by gel permeation chromatography (column temperature 2).
3 ° C.) in comparison with a polystyrene standard sample.

Example 1 75 g of 90% L-lactic acid was charged into a 500 ml four-necked flask equipped with a thermometer, a stirring blade, and a distilling tube.
The mixture was heated and stirred at 50 mmHg for 3 hours while removing water outside the system. Next, the distilling tube was removed, a Dean stack was attached instead, and 325 g of 1,2,4-trichlorobenzene and 0.4 g of tin powder were added.
The mixture was heated and refluxed at 0 mmHg for 5 hours. At this time, a mixture of refluxing 1,2,4-trichlorobenzene and generated water was separated in Dean stack, and an aqueous layer was sequentially extracted. Next, Dean-Stack was removed, a tube filled with 50 g of Molecular Sieve 3A was attached instead, and the solvent distilled off by reflux was returned to the system through the Molecular Sieve, and the reaction conditions were set to 130. ℃ / 5
The reaction was set at 0 to 60 mmHg and reacted for 20 hours. After the reaction was completed, 400 ml of chloroform was added to the reaction mass, and after dissolving, the mixture was suction-filtered to remove tin powder. 1400 ml of methanol was added to the obtained chloroform solution, and the precipitated white solid polylactic acid was separated by filtration and dried. Yield 52.4
g, yield 96.9%, weight average molecular weight 210,000
(In terms of polystyrene; the same applies hereinafter).

Example 2 A white solid polylactic acid was obtained as a result of performing the same method as in Example 1 except that o-dibromobenzene was used instead of 1,2,4-trichlorobenzene as the polymerization solvent. Was.
Yield 52.0 g, yield 96.2%, weight average molecular weight 20
It was 0000.

Example 3 75 g of 90% L-lactic acid was charged into a 500 ml four-necked flask equipped with a thermometer, a stirring blade, and a distilling tube.
The mixture was heated and stirred at 50 mmHg for 3 hours while removing water outside the system. Next, the distilling tube was removed, a Dean stack was attached instead, and o-dichlorobenzene 325 was added.
g and tin powder 0.4 g were added, and the mixture was heated and refluxed at 140 ° C. under a slight reduced pressure for 5 hours. At this time, a mixture of refluxing o-dichlorobenzene and generated water was separated in Dean stack, and an aqueous layer was sequentially extracted. Next, Dean-Stack was removed, a tube filled with 50 g of Molecular Sieve 3A was attached instead, and the solvent distilled off by reflux was returned to the system through the Molecular Sieve, and the reaction conditions were set to 130. The reaction was carried out at a temperature of 200 ° C./300 to 300 mmHg for 25 hours. After completion of the reaction, chloroform 4 was added to the reaction mass.
After adding and dissolving 00 ml, the mixture was suction-filtered to remove tin powder. 1400 m of methanol was added to the obtained chloroform solution.
was added, and the precipitated white solid polylactic acid was filtered off and dried. The yield was 51.7 g, the yield was 95.6%, and the weight average molecular weight was 170,000.

Example 4 A white solid polylactic acid was obtained in the same manner as in Example 1 except that dichloropentane was used instead of o-dichlorobenzene as the polymerization solvent. Yield 51.0
g, the yield was 94.3%, and the weight average molecular weight was 150,000.

Example 5 75 g of 90% L-lactic acid was charged into a 500 ml four-necked flask equipped with a thermometer, a stirring blade, and a distilling tube.
The mixture was heated and stirred at 50 mmHg for 3 hours while removing water outside the system. Next, the distilling tube was removed, a Dean stack was attached instead, 325 g of chlorobenzene and 0.4 g of tin powder were further added, and the mixture was heated to reflux at 132 ° C. for 5 hours. At this time, the mixture of refluxing chlorobenzene and generated water is
The mixture was separated in Dean Stack and the aqueous layer was sequentially extracted. Next, Dean-Stack was removed, a tube filled with 50 g of Molecular Sieve 3A was attached instead, and the solvent distilled off by reflux was returned to the system through the Molecular Sieve, and the reaction conditions were changed to 132. C., and reacted for 30 hours. After the reaction was completed, 400 ml of chloroform was added to the reaction mass, and after dissolving, the mixture was suction-filtered to remove tin powder. 1400 ml of methanol was added to the obtained chloroform solution, and the precipitated white solid polylactic acid was separated by filtration and dried. The yield was 50.3 g, the yield was 93.1%,
The weight average molecular weight was 130,000 (in terms of polystyrene; the same applies hereinafter).

Comparative Example 1 The procedure of Example 1 was repeated, except that dibenzyl ether was used instead of 1,2,4-trichlorobenzene as the polymerization solvent, but the molecular weight hardly increased.

[0027]

The process of the present invention is a process which makes it possible to obtain a polymer having a high molecular weight from hydroxycarboxylic acid or an oligomer thereof directly by dehydration polycondensation industrially, in a short time and at low cost. is there.

Continuation of front page (58) Field surveyed (Int.Cl. ⁷ , DB name) C08G 63/00-63/91

Claims (5)

(57) [Claims] 1. A method in which a hydroxycarboxylic acid or an oligomer thereof is heated and refluxed in an organic solvent in advance in the presence of a catalyst to remove water and low-boiling compounds. A method for producing a polyhydroxycarboxylic acid by dehydration polycondensation while removing a solvent, wherein a halogenated hydrocarbon is used as a solvent. 2. The method for producing a polyhydroxycarboxylic acid according to claim 1, wherein the halogenated hydrocarbon used as the solvent is an aromatic halogenated hydrocarbon. 3. The method according to claim 1, wherein the solvent distilled under reflux of the solvent is treated with a desiccant or dehydrated by distillation and then returned to the reaction system.
A method for producing the polyhydroxycarboxylic acid according to the above. 4. The desiccant used is a molecular sieve.
The method according to claim 3 , wherein the metal is hydrogen chloride, diphosphorus pentoxide, a metal hydride, or an alkali metal. 5. The method according to claim 1, wherein the hydroxycarboxylic acid is lactic acid, glycolic acid, 3-hydroxybutyric acid, 4-hydroxybutyric acid, 3-hydroxyvaleric acid, or a mixture thereof. Item 5. The method according to any one of Items 1 to 4.