JP2000186135A - Production of polyhydroxycarboxylic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially and efficiently obtain a polyhydroxycarboxylic acid having high molecular weight useful as a biodegradable polymer for a medical material, etc., by reacting a specific carboxylic acid with a carbonyl halide in the presence of an organic base. SOLUTION: This polyhydroxycarboxylic acid is obtained by reacting (A) a hydroxycarboxylic acid (preferably lactic acid) and/or its oligomer with (C) a carbonyl halide (preferably phosgene) in the presence of (B) an organic base. Preferably, the component C of 90-95 mol.% of total using amount is charged and the remaining substance is charged to one terminal of the component A at 0.1-10 mol.%/h, preferably 0.5-5 mol.%/h in performing the reaction, and e.g. trimethylamine, triethylamine or the like, is used as the component B and the reaction may be performed in a solvent such as ethylene dichloride at a reaction temperature from -20 deg.C to 140 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an improved method for producing a polyhydroxycarboxylic acid useful as a biodegradable polymer as a substitute for a medical material and a general-purpose resin.

[0002]

2. Description of the Related Art Polyhydroxycarboxylic acids have excellent mechanical, physical and chemical properties, and are decomposed in a natural environment without causing any harm. It has a biodegradable function of becoming carbon dioxide gas, and has recently attracted attention in various fields such as medical materials and alternatives to general-purpose resins, and its demand is expected to greatly increase in the future. In particular, when recycling becomes mandatory for existing general-purpose resin products, it is expected that replacement with biodegradable polymers will progress, and beverages,
Demand is expected to increase for uses such as detergents, various containers for cosmetics, storage cases for clothes, miscellaneous goods, etc., food packaging materials, coating films and the like.

[0003] In general, a polyhydroxycarboxylic acid is produced by dehydrating and dimerizing a hydroxycarboxylic acid such as lactic acid or glycolic acid to obtain a cyclic dimer and then opening the ring in the presence of various catalysts. It is known that high molecular weight polymers can be obtained by melt polymerization (U.S. Pat. Nos. 2,703,316 and 2,758,987). These methods are not economical due to the large amount of labor and cost required to produce the cyclic dimer lactide or glycolide, and the final product is expensive. Also, depending on the type of hydroxycarboxylic acid,
Some do not form cyclic dimers, in which case this method cannot be used.

On the other hand, there have been disclosed several methods for obtaining a polyhydroxycarboxylic acid from a hydroxycarboxylic acid and its oligomer by a direct dehydration method (Japanese Patent Application Laid-Open No. 59-1984).
096123, JP-A-61-028521, JP-A-6-65360). In the polymerization method by direct dehydration, it is necessary to quickly remove the water produced during esterification to the outside of the system in order to obtain a high molecular weight polymer,
Therefore, high-pressure reaction conditions of a high degree of reduced pressure and 150 ° C. or higher are required. However, the decomposition reaction is promoted under high temperature conditions, so that a very long processing time is required to obtain a high molecular weight polyhydroxycarboxylic acid,
The problem remains that it is difficult to obtain a practically useful high molecular weight product.

[0005] A method different from the above method is disclosed in
No. 3763, after reacting low molecular weight polylactide, polyglycolide or a copolycondensate thereof with oxalyl chloride, succinyl chloride, dichloride compound such as terephthaloyl dichloride, or acid chloride selected from thionyl chloride, A method for producing polylactide, polyglycolide, or a copolycondensate thereof by performing a melt polycondensation reaction or a polycondensation reaction by adding an amine compound is disclosed. The method of the present invention is to activate the polycondensate terminal carboxyl group by acid chloride by adding an acid chloride to the polycondensate solution to easily carry out the polycondensation reaction. The acid chloride is not quantitatively produced at a low level, the hydroxyl group is chlorinated and the terminal is terminated, and a reaction occurs in which an acid anhydride is formed between the acid chloride and the carboxyl group. There are various problems, such as an inconsistent amount ratio, the obtained polyhydroxycarboxylic acid has a low attainable molecular weight, and the acid chloride is expensive, so that it has not been a satisfactory method in industrial production. As a method of performing polycondensation using a condensing agent, Japanese Patent Application Laid-Open No.
No. 2 discloses a method for producing a polyester by subjecting a hydroxycarboxylic acid or an oligomer thereof to a condensation reaction in the presence of a predetermined binding reagent. According to the production method, a high-molecular-weight polyester is obtained by subjecting a hydroxycarboxylic acid or an oligomer thereof to a condensation reaction in the presence of various binding reagents.Examples include dicyclohexylcarbodiimide, carbonyldiimidazole, and the like as binding reagents. Examples of using bis-trichloromethyl carbonate are described, but all of these have problems such as the use of large amounts of expensive binding reagents and are currently limited to laboratory-based synthesis methods. It is.

GB 870,096 discloses a process for obtaining polyesters by reacting a haloformate obtained by reacting a dihydroxy compound with a carbonyl halide with a dicarboxylic acid. However, in this method, a relatively large amount of carbonate is generated by the reaction between the haloformate and the hydroxyl group.
Under the condition that the carboxyl group and the hydroxyl group are equimolar, high molecular weight has not been achieved, and the high molecular weight has been achieved by controlling the hydroxyl group to act twice as much as the carboxyl group. Therefore, it cannot be applied as a method for increasing the molecular weight of a hydroxycarboxylic acid having one carboxyl group and one hydroxyl group in the molecule.

[Problems to be solved by the invention]

According to the present invention, the ring-opening polymerization method using a catalyst requires a complicated operation for removing the catalyst, and the polymerization method using direct dehydration requires a high-temperature and high-pressure reaction to increase the equipment burden. A high-molecular-weight polyhydroxycarboxylic acid cannot be obtained by a polymerization reaction in the presence of a condensing agent or a binding reagent to solve the problems of the prior art such as high cost,
It is an object of the present invention to provide an improved method for industrially efficiently producing a high molecular weight polyhydroxycarboxylic acid.

[0008]

That is, the present invention relates to a method for preparing a hydroxycarboxylic acid and / or an oligomer thereof,
A method for producing a polyhydroxycarboxylic acid, characterized by reacting a carbonyl halide in the presence of an organic base, a method for producing a polyhydroxycarboxylic acid, wherein the hydroxycarboxylic acid is lactic acid. The method for producing a polyhydroxycarboxylic acid according to the above, wherein the carbonyl halide is phosgene, wherein the hydroxycarboxylic acid and / or an oligomer thereof is
In reacting the carbonyl halide in the presence of the organic base, 90 to 95% of the total amount of the carbonyl halide is charged, and the remainder is 0.1 to 10 based on the number of one terminal groups of the hydroxycarboxylic acid and / or its oligomer. Mol% / h
The method for producing a polyhydroxycarboxylic acid according to the above, characterized in that the hydroxycarboxylic acid and / or its oligomer are:
In reacting the carbonyl halide in the presence of the organic base, 90 to 95% of the total amount of the carbonyl halide is charged, and the remainder is 0.5 to 5 parts by weight based on the number of one terminal groups of the hydroxycarboxylic acid and / or its oligomer. The method for producing a polyhydroxycarboxylic acid according to the above, wherein the charging is performed at mol% / h.

According to the present invention, a high molecular weight polyhydroxycarboxylic acid useful as a biodegradable polymer can be efficiently produced.

BEST MODE FOR CARRYING OUT THE INVENTION

The hydroxycarboxylic acid used in the present invention is not particularly limited as long as it has a hydroxyl group and a carboxyl group in the same molecule, and specific examples thereof include the following. Glycolic 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-butylhexanoic acid, 2-hydroxy-
2-pentylhexanoic acid, 2-hydroxy-2-methylheptanoic acid, 2-hydroxy-2-ethylheptanoic acid, 2-hydroxy-2-propylheptanoic acid, 2-hydroxy-2- Pentylheptanoic acid, 2-hydroxy-2-hexylheptanoic acid, 2-hydroxy-2-methyloctanoic acid, 2-hydroxy-2-ethyloctanoic acid, 2-hydroxy-2-propylocta Neuic acid, 2-hydroxy-2-butyloctanoic acid, 2-hydroxy-2-pentyloctanoic acid, 2-
Hydroxy-2-hexyloctanoic acid, 3
-Hydroxypropanoic acid, 3-hydroxybutanoic acid, 3-hydroxypentanoic acid, 3-hydroxyhexanoic 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-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-hydroxypentane Neuc 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-ethyloctanoic acid, 4-hydroxy-4-propyloctanoic acid, 4-hydroxy-4-butyloctanoic acid, 5-hydroxypentanoic Ic acid, 5-hydroxyhexanoic acid, 5
-Hydroxyheptanoic acid, 5-hydroxyoctanoic acid, 5-hydroxy-5-methylhexanoic acid, 5-hydroxy-5-methylheptanoic acid, 5-hydroxy-5-ethylheptanoic acid , 5-hydroxy-5-methyloctanoic acid, 5-hydroxy-5-ethyloctanoic acid, 5-hydroxy-5-propyloctanoic acid, 6-hydroxyhexanoic acid, 6-hydroxyheptano Ic acid, 6-hydroxyoctanoic acid, 6-hydroxy-6-methylheptanoic acid, 6-hydroxy-6-methyloctanoic acid, 6-hydroxy-6-ethyloctanoic acid, 7-hydroxy Heptanoi Acid, 7-hydroxy-octanoic acid, 7-hydroxy-7-methyl-octanoic acid include aliphatic hydroxycarboxylic acids, such as 8-hydroxy-octanoic acid. These may be used alone or as a mixture of two or more. Particularly preferred hydroxycarboxylic acids are lactic acid,
Glycolic acid, 3-hydroxybutanoic acid,
4-hydroxybutanoic acid, 3-hydroxypentanoic acid, and mixtures thereof.

In the method of the present invention, an oligomer derived from the above-mentioned hydroxycarboxylic acid can be used as a raw material. The method for producing the oligomer may be a method in which the hydroxycarboxylic acid is simply heated and dehydrated in the presence or absence of a catalyst under a nitrogen atmosphere, and the conditions of the production method are particularly limited as long as the condensed water is removed out of the system. There is no. The average degree of polymerization of the oligomer may be any, but preferably n is 5 to 100, more preferably 10 to 80, and is appropriately selected in consideration of the reaction time, the volumetric efficiency of the reactor, and the like. Can be.

In the present invention, the reaction can be carried out using a solvent. As specific examples of the solvent, ethylene dichloride, dichloromethane, aliphatic halogenated hydrocarbons such as chloroform, benzene, toluene, xylene, aromatic hydrocarbons such as mesitylene, chlorobenzene, o-dichlorobenzene, p-dichlorobenzene, Examples thereof include, but are not limited to, aromatic halogenated hydrocarbons such as fluorobenzene, and ethers such as tetrahydrofuran.

Specific examples of the organic base used in the present invention include trimethylamine, triethylamine, tri-n
-Propylamine, diethyl-n-propylamine, tri-n-butylamine, triethylenediamine, N, N
Alkyl having 1 to 8 carbon atoms such as -dimethylcyclohexylamine, N, N-diethylcyclohexylamine, N, N-dimethylbenzylamine, N, N, N ', N'-tetramethyl-1,3-propanediamine Trialkylamines having a group, aromatic nitrogen compounds such as N, N-dimethylaniline, N, N-diethylaniline, pyridine, α-picoline, β-picoline, γ-picoline, 2-ethylpyridine, -Ethylpyridine, 3,
5-lutidine, 2,6-lutidine, pyrazine, pyrimidine, pyridazine, 2-dimethylaminopyridine, quinoline, quinoxaline, quinazoline, triazine, tetrazine, pentazine, 4-methylmorpholine, 4-ethylmorpholine, 4- [2- ( [Dimethylamino) ethyl] morpholine, 2,4,6-collidine, N-ethylpiperidine, N, N'-dimethylpiperazine, N, N-diethylpiperazine, acridine, pteridine and other heterocyclic aromatic compounds. These can also be used in combination.

In an embodiment of the present invention, for example, hydroxycarboxylic acid and / or an oligomer thereof is mixed with an organic base, and the reaction is carried out while charging carbonyl halide. The amount of the organic base used is not problematic as long as it is not less than the stoichiometric amount with respect to halogen hydrogen that can be generated by the reaction,
Although an organic base may be used as a reaction solvent, it is usually used in an amount of 1 to 3 times the stoichiometric amount, preferably 1 to 1.5 times.
Double the amount. Examples of the carbonyl halide include phosgene, bromophosgene and the like, and phosgene is particularly preferred from the economical viewpoint. The amount of the carbonyl halide to be used is selected in a range of preferably 0.9 to 1.2 mol times based on one terminal group of the hydroxycarboxylic acid and / or oligomer thereof used in the reaction, and particularly preferably 1.0 to 1.2 times. The range is 1.1 mole times. The reaction can be sufficiently carried out at a temperature in the range of -20 ° C to 140 ° C. Although it can be carried out at -20 ° C or lower or 140 ° C or higher, depending on the type of raw material hydroxycarboxylic acid to be used, the polycondensation reaction rate becomes extremely low at low temperatures or causes side reactions such as decomposition at high temperatures. There are cases. Further, excessive cooling or heating is not economical and undesirable from an industrial point of view. In the method of the present invention, a high molecular weight polyhydroxycarboxylic acid can be efficiently produced, preferably by continuously or stepwise decreasing the charging rate of carbonyl halide in accordance with an increase in molecular weight, that is, a decrease in terminal group concentration. . The carbonyl halide charging rate is adjusted, for example, by charging 90 to 95% of the amount of carbonyl halide used and the remaining 5 to 10%.
%, The so-called charging rate in the latter half of the reaction is preferably 0.1 to 10 mol% based on one terminal group of the hydroxycarboxylic acid and / or its oligomer used in the reaction.
/ H, particularly preferably 0.5 to 5 mol% / h.

The reaction solution after the synthesis of the polyhydroxycarboxylic acid is a mixture of the polyhydroxycarboxylic acid and a hydrogen halide of an organic base. The hydrogen halide of the organic base is filtered by a known method such as filtration and extraction. It can be easily separated from polyhydroxycarboxylic acid. Further, by evaporating the solvent from the reaction solution after separation of the hydrogen halide salt of the organic base or by pouring the solvent into a suitable precipitant, a high-molecular-weight polyhydroxycarboxylic acid [weight average molecular weight (Mw) of about 50,000] can be easily obtained. ~ 200,000] can be isolated.

[0016]

The present invention is not limited to the following examples. The weight average molecular weight of the polymer (M
w) is Shodex GPC system-11
(Manufactured by Showa Denko KK), chloroform solvent, 40
Measured in ° C. The Mw value is a value in terms of polystyrene. The carboxyl group content of the oligomer was determined by dissolving a sample (W; g) in dichloromethane / methanol = 7/3 (volume ratio) and titrating with a methanol solution of sodium methylate.

Carboxyl group content: a (mol / g) = E
X10-3xc / WE: titration (ml) c: specified concentration of titrant (mol / l)

Synthesis Example 1 (Synthesis of lactic acid oligomer) 1200 g of 90% L-lactic acid (manufactured by ADM) (12.00)
mol) and 60 g of benzene were placed in a 1500 ml flask and dehydrated at 160 ° C. for 16 hours under a nitrogen atmosphere. The obtained oligomer had a yield of 953.7 g and a carboxyl group content of 5.69 × 10 ⁻⁴ mol / g.

Synthesis Example 2 (Synthesis of lactic acid oligomer) 2000 g (20.00%) of 90% L-lactic acid (manufactured by ADM)
mol) was charged into a 3000 ml flask and dehydrated at 160 ° C. for 12 hours while blowing nitrogen into the liquid. The obtained oligomer had a weight average molecular weight of 1,000 and a carboxyl group content of 1.03 × 10 −3 mol / g.

Example 1 The lactic acid oligomer 13 obtained in Synthesis Example 1 was placed in a 500 ml four-necked flask equipped with a stirring blade, a gas injection tube, and a reflux tube.
1.7 g (0.075 mol of carboxyl groups) were charged together with 420 g of dichloromethane, dissolved uniformly, cooled to 0 ° C., and 8.1 g of phosgene (0.082 m 2).
ol). Next, 13.5 g of pyridine (0.
17 mol) was added dropwise over 3 hours and 30 minutes while maintaining the temperature at 0 ° C., and the mixture was reacted at 0 ° C. for 2 hours and 30 minutes. Mw of the obtained polylactic acid was 26,000.

Example 2 1000 ml equipped with a stirring blade, a gas blowing tube and a reflux tube
Lactate oligomer 9 obtained in Synthesis Example 2 in a four-necked flask
After 7.1 g (0.1 mol of carboxyl group) and 551.9 g of chlorobenzene were charged and uniformly dissolved, 19.78 g (0.25 mol) of pyridine was charged. The temperature was then raised to 100 ° C. and 9.89 g of phosgene
(0.10 mol) at a rate of 25 mol% / h over 4 hours. Thereafter, 0.99 g of phosgene (0.01
mol) was charged over 4 hours at a rate of 2.5 mol% / h and aged at the same temperature for 4 hours. The reaction solution was discharged into 500 g of isopropyl alcohol, and the precipitated polymer was isolated. Mw of the obtained polylactic acid was 170,000.

Example 3 1000 ml equipped with a stirring blade, a gas blowing tube and a reflux tube
Lactate oligomer 9 obtained in Synthesis Example 2 in a four-necked flask
7.1 g (0.1 mol of carboxyl group) was added to 1,2-
After charging with 551.9 g of dichloroethane and uniformly dissolving, 23.28 g of β-picoline (0.25 mol
l) was charged. Then, the temperature was set to 50 ° C., and 10.05 g (0.102 mol) of phosgene was charged at a rate of 50 mol% / h for 1 hour, 25 mol% / h for 1 hour, 14 mol%.
/ H for 2 hours, for a total of 4 hours. Thereafter, 0.31 g (0.003 mol) of phosgene was charged at a charging rate of 0.1 g.
Charged at 4 mol% / h over 8 hours, and aged at the same temperature for 6 hours. 200 g of 20% hydrochloric acid was added to the reaction solution, mixed well, allowed to stand, and the separated aqueous layer was discarded. 200 g of 5% hydrochloric acid was again added to the organic layer, mixed well, allowed to stand, and the separated aqueous layer was discarded. Finally, the organic layer was washed with 200 g of pure water. Mw of polylactic acid obtained by concentrating the organic layer is 1
It was 50,000.

Example 4 1000 ml equipped with a stirring blade, a gas blowing tube and a reflux tube
Lactate oligomer 9 obtained in Synthesis Example 2 in a four-necked flask
After 7.1 g (0.1 mol of carboxyl group) and 551.9 g of dichloromethane were charged and uniformly dissolved, 25.30 g (0.25 mol) of triethylamine was added.
Was charged. Then, the temperature was raised to 25 ° C. and phosgene 1
Loading rate of 0.05 g (0.102 mol) 26 mol%
/ H over 4 hours. Then phosgene 0.8
0 g (0.008 mol) at a charging rate of 1 mol% / h
It was charged over time and aged at the same temperature for 24 hours. After adding 300 g of water and 100 g of xylene to the reaction solution, dichloromethane and xylene were distilled off under reduced pressure to obtain an aqueous slurry of polylactic acid. M of polylactic acid obtained by isolating this
w was 124,000.

[0024]

According to the present invention, it is possible to efficiently produce a high molecular weight polyhydroxycarboxylic acid and contribute to providing an inexpensive product.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Masaru Wada, Inventor F-term (reference) 4F029 AA08 AB04 AC01 AC02 AD01 AD10 AE01 AE06 EA02 EA03 EA05 HA01 HB01 HC01 JC021 JC031 JC041 JC051 JC231 JC261 JC281 JC291 KB03 KB11 KB12 KB23 KC01 KC05 KD01 KD09 KE09 KE15 KH04

Claims (5)

[Claims] 1. A method for producing a polyhydroxycarboxylic acid, comprising reacting a hydroxycarboxylic acid and / or an oligomer thereof with a carbonyl halide in the presence of an organic base. 2. The method for producing polyhydroxycarboxylic acid according to claim 1, wherein the hydroxycarboxylic acid is lactic acid. 3. The method for producing a polyhydroxycarboxylic acid according to claim 1, wherein the carbonyl halide is phosgene. 4. The reaction of a hydroxycarboxylic acid and / or an oligomer thereof with a carbonyl halide in the presence of an organic base, wherein the carbonyl halide is used in an amount of 9%.
2. The polyhydroxycarboxylic acid according to claim 1, wherein after charging 0 to 95%, the remainder is charged at 0.1 to 10 mol% / h with respect to one end of the hydroxycarboxylic acid and / or its oligomer. Method for producing acid. 5. The reaction of hydroxycarboxylic acid and / or its oligomer with carbonyl halide in the presence of an organic base, the carbonyl halide being used in an amount of 9
2. The polyhydroxycarboxylic acid according to claim 1, wherein after charging 0 to 95%, the remainder is charged at 0.5 to 5 mol% / h to one end of the hydroxycarboxylic acid and / or its oligomer. Method for producing acid.