JPS62201926A - Production of polymer or copolymer of hydroxy-polycarboxylic acid - Google Patents

Abstract

PURPOSE:To obtain a polymer or copolymer of a hydroxypolycarboxylic acid by a simple operation, by plycondensing a specified hydroxypolycarboxylic acid or its mixture with its ester by heating in a vacuum. CONSTITUTION:A hydroxypolycarboxylic acid of the formula or its mixture with its ester is polycondensed by heating in a vacuum. In the formula, R is H, methyl, ethyl, phenyl, -COOH or -CH2COOH, X and Y are each H, methyl or ethyl, provided that either of them may be hydroxy and n is 0, 1 or 2, provided that all the carboxyl groups except at least one may be in the form of an ester. The reaction temperature is usually in the range of 50-200 deg.C through it depends on the kind of a starting material, a degree of vacuumness, the desired degree of polymerization, and a polymerization time. The obtained polymer can find utility in absorbable sutures, materials for cementing bones, artificial blood vessels and slow-releasing carriers for fixing medicines, food additives or agricultural chemicals.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a method for producing a polymer or copolymer of anddroxypolycarboxylic acid or its ester.

(Prior art) In recent years, polymers or copolymers of α-oxyacids such as polyglycolic acid, polylactic acid, and polymalic acid have been used as polymer materials for medical and pharmaceutical purposes that are decomposed and metabolized in vivo. These polymers have attracted attention and are utilized as bioabsorbable sutures (U.S. Pat. No. 3,636,956, U.S. Pat.
277.033 details ¥! j:) and other examples in which a composition consisting of this polymer and an agricultural chemical was used as an agricultural chemical for soil treatment and maintained its effect for a long time (Japanese Patent Application Laid-open No. 19963/1996, No. 1)
No. 99604) and the like are known.

Although hydroxymonocarboxylic acids such as glycolic acid and lactic acid can be easily polymerized by mere heating, hydroxypolycarboxylic acid ster such as malic acid is formed, and the desired polycondensate cannot be obtained. Therefore, polycondensates are obtained by the following method.

(1) Penicillium cyclopium
A method for isolating polymalic acid from the culture fluid of Illium cyclopium (Agr, Biol, Oh
em, 33(4) 459 (1969)), (2)
Malic acid monobenzyl (or monomethyl) ester with N,N'-dicyclohexylcarbodiimide (DCC)
directly polymerized with a-polymalic acid-β-benzyl (or methyl) ester and β-° polymalic acid-
Reports of The
Faculty Engj, kneeling.

Tottori University 8 124
(1977)), (3) Ring-opening polymerization of benzyl malolactonate yields β-polymalic acid-α-benzyl ester, and the benzyl ester is further hydrolyzed to give β-
Method for obtaining polymalic acid (U.S. Pat. No. 4.265.24)
7), and (4) Ring-opening polymerization of malide dibenzyl ester to obtain α-polymalic acid-β-benzyl ester, and further hydrolyzing the benzyl ester to obtain α-polymalic acid (Polymer Preprints, J.
apan84(8)744(1985)).

(Problems to be solved by the invention) However, method (1) requires multiple steps for purification;
Method 2) is expensive and requires CC. Also, (3)
The raw materials benzyl malolactonate and malide dibenzyl ester used in the method (4) are both synthesized through a large number of steps, and the yield is very low.

Further, in the method (2) # (3) * (4) above, the polymer synthesis step is long and the yield is low, so it is unsuitable for implementation on an industrial scale.

(Means for Solving the Problems) As mentioned above, it is not possible to obtain a polycondensate by simply heating a hydroxypolycarboxylic acid such as malic acid or its ester, but the present inventors have When an acid, such as malic acid or its monoester, is heated under reduced pressure below its decomposition temperature, intermolecular ester bonds occur preferentially to intramolecular dehydration, resulting in dehydration polycondensation, in the case of malic acid monoester. discovered that both polycondensation reactions through transesterification of ester groups and hydroxyl groups and dehydration polycondensation reactions between carboxyl groups and hydroxyl groups are possible, but the latter occurs preferentially to yield a polymer of malic acid ester. .

The present invention was developed based on these new findings,
Formula % Formula % (wherein R is hydrogen, methyl, ethyl, phenyl or 100OH or -OH, 2COOH group; X and Y are each hydrogen, methyl or ethyl group, even if one of them is a hydroxyl group) of a hydroxypolycarboxylic acid or its ester represented by: n is 0.1 or 2 (provided that the remaining carboxyl groups except at least one in the formula may be esterified) This is a method for producing a polymer or copolymer of hydroxypolycarboxylic acid or its ester, which is characterized by subjecting one type or a mixture of two or more types to polycondensation under reduced pressure.

Examples of the hydroxypolycarboxylic acids used in the present invention include malic acid, α-methylmalic acid, α-oxy-
α'-methysuccinic acid, α-oxy-α'-ethysuccinic acid, α-oxy-α, a'-dimethylmethicic acid, trimethylmalic acid, α-phenylmalic acid, tartronic acid, α-oxygeltaric acid, citric acid Examples include. They may be optically inactive d6 forms or optically active d
or e-form, or a mixture thereof.

The remaining carboxyl groups other than at least one carboxyl group in the hydroxypolycarboxylic acid may be esterified.

The formula for esterified malic acid as an example of hydroxypolycarboxylic acid is as follows.

HO-CH-G! OORHO-CII-C! OOHCH
2-C0OHC1 (2-C00R (In the formula, -G!OOR represents an esterified carboxyl group) In other words, it may be α-monoester (+) or β-monoester (11). R is a saturated or unsaturated aliphatic or aromatic group, examples of which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, tert-butyl, pentyl,
Neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, vinyl, 1-propenyl, allyl, isopropenyl, ethynyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, l
-lyl, xylyl, mesityl, cumenyl, benzyl, phenethyl, styryl, cinnamyl, biphenylyl, naphthyl, anthryl, phenanthryl, hydroxyethyl,
Examples include hydroxypropyl and hydroxyphenyl groups.

The degree of reduced pressure in the present invention depends on the raw material, the type of droxypolycarboxylic acid or its ester, the polymerization time, the degree of polymerization of the desired product, etc., but is usually 20011
It may be less than rlliIp, and particularly preferably less than about 10ffffH,y. A water pump, a vacuum pump, an oil diffusion pump, an ion diffusion pump, etc. can be used to reduce the pressure.

In the present invention, the drugstore temperature refers to the N class of the raw material compound, the degree of vacuum,
It is selected depending on the desired degree of polymerization and polymerization time, but usually 5
A range of 0 to 200°C is used, with 100 to 150°C being most preferred. Although the reaction occurs satisfactorily even at 50 to 100°C, the polymerization time becomes longer and
At temperatures above 0°C, the polymerization reaction speeds up, but decomposition due to intramolecular dehydration tends to occur, which tends to reduce the yield of the desired polymer and, in some cases, causes coloration of the polymer.

As a heating source for maintaining the reaction temperature, in addition to steam, heat medium, electric heat, etc., microwaves can also be used.

The time required for the polymerization reaction depends on the reaction temperature, degree of pressure reduction, etc., but is usually ~50 hours, and preferably 10~30 hours to obtain the desired product with a particularly high degree of polymerization. If the reaction time is too long, decomposition may occur again, resulting in a decrease in the degree of polymerization.

The reaction of the present invention is generally carried out by a bulk polymerization method that does not use a catalyst or solvent, but if desired, the reaction may be carried out by adding a suitable dehydrating agent, transesterification catalyst, or even a solvent that does not hinder the progress of the reaction. . These additives and solvents can be selected and used as long as they do not interfere with the intended use, such as when the desired polymer is used as a medical material, such as having no adverse effect on the human body.

In the present invention, polymers having various structural units can be obtained depending on the Kyoto compound used.

The structural units possessed by the raw materials used next and the polymer synthesized from the raw materials are as follows: (1) When malic acid or its monoester is used as a raw material, as an example, formula (a) is used as a raw material. (Iv
) Polymers having structural units of the above formulas (Ill) (α type) and (IV) (β type) can be obtained.

0)) When malic acid-α-monoester is used as a raw material, a polymer having the structural unit of the above formula (V) is obtained.

(C) Using malic acid-β-monoester as a raw material, a polymer having the preparation unit of the above formula (VI) is obtained.

(d) When a mixture of malic acid and malic acid-α-monoester is used as a raw material: A polymer having three types of preparation units of the formulas (Ill), (IV) and (V) is obtained.

(e) When a mixture of malic acid and malic acid-β-monoester is used as a raw material: A polymer having three types of preparation units of the above formulas (II), (IV) and ('II'') is obtained. It will be done.

(When a mixture of α-monoester and β-monoester of malic acid is used as a raw material: Two types of polymers having the preparation Q1 position of the formulas (V) and (vl) are obtained.

(g) When malic acid, malic acid-α-monoester and malic acid-β-monoester are used as raw materials: Formula (III), (IV), (V) Oyohi (V
[)0)'IEJAME (A polymer having D groove ti units is obtained.

In addition, in formulas (Y) and (■1), -〇〇〇R represents a carboxyl group arranged with an ester in the same manner as in formulas (1) and (II), and in each polymer, even one type of R is Two or more types may be used.

Although malic acid and its ester have been explained above as an example, preparation units of polymers obtained using other hydroxypolycarboxylic acids and their esters as raw materials can also be inferred from this example.

Furthermore, in the method of the present invention, a copolymer can also be obtained by polycondensing a hydroxypolycarboxylic acid or an ester thereof with a hydroxymonocarboxylic acid.

As the hydroxymonocarboxylic acid, j is
α-hydroxymonocarboxylic acids such as glycolic acid, lactic acid, a-hydroxyisobutyric acid, mandelic acid, and phenylglyoxylic acid; β-hydroxymonocarboxylic acids such as β-hydroxybutyric acid and β-hydroxyglutaric acid; α, β-dihydroxy Examples include dihydroxymonocarboxylic acids such as isobutyric acid and β,β'-dihydroxyisobutyric acid. One or more of these may be copolymerized with a hydroxypolycarboxylic acid or an ester thereof.

The carboxyl group in the obtained polymer can be modified by reacting with an epoxy compound, an isocyanate compound, or an ester, if desired, and the ester group can be modified with ammonia, a primary or secondary amine, or a thiol. can be modified by reacting with an alcohol different from the alcohol obtained by decomposing its ester group, or with hydrazine or the like.

The polymer obtained by the present invention can be used as, for example, bioabsorbable fibers, materials for bone attachment, artificial blood vessels, medicines, sustained-release carriers capable of fixing food additives, agricultural chemicals, etc. In addition, it can also be used as a medicine or food additive. Furthermore, polymers having carboxyl groups can also be used as curing agents for epoxy resins, urethane resins, unsaturated polyester resins, and the like.

(Function) In the present invention, since hydroxypolycarboxylic acid or its ester is heated under reduced pressure, dehydration polycondensation that produces intermolecular ester bonds occurs more favorably than the decomposition reaction due to intramolecular dehydration, resulting in polymerization. Something comes into being.

The present invention will be explained in more detail below in the form of examples.

Example 1 A glass test tube made of branch wood, d, 71! -malic acid5. OL
After adding i and heating at 140°C to normal pressure F to melt malic acid, the pressure was gradually reduced using a vacuum pump. Heating was continued at 140°C for 10 hours from the time the pressure in the system reached 1.011 FIIH. The system gradually becomes viscous and finally resinous polymalic acid yields i4.3y (yield 10
0%). The melting point of this polymer is 60°C, and the relative viscosity is 0.05 (30±0.1''C in 0.5I ldl T FIF), as measured by gel permeation chromatography (a p c ). The weight average molecular weight in terms of boris dylene was 3500.
The infrared absorption spectrum of this polymer shows that the ester bond is 1740 (Jn=, 1180CIn-', 105
0C thin' (J) absorption was confirmed, and the 'H-NMR spectrum of the polymer obtained by methyl esterifying the carboxylic acid on the polymer side was 2.9 ppm (CH2), 3.7.3.
8ppm (CI-Is) + 4.5ppm (CJ:I)
, 5.6 ppm (O)I, C00H) CD peak was obtained, confirming that it was a conopolymer polymalic acid. Furthermore, from the peak intensity of the 'H-NM 几spectrum, the ratio of the α-type grooved unit to the β-type structural unit was 1:1.

Example 2 In the operation of Example 1, after heating and melting at 140°C, the temperature was adjusted to 130°C, and the pressure was 0ptxl-1y.
As a result of the 25 hour market, a malic acid polymer was obtained with a yield of 96%, and the weight average molecular weight of the polymer was determined by gel permeation chromatography (GPC).
Polystyrene equivalent) was 2100.

Example 3 After putting 5.0 l of d,l-malic acid into a glass test tube with a branch and heating and melting it at 140°C, the temperature was lowered and when the internal temperature of the system reached 120°C, it was heated with a vacuum pump. The pressure was gradually reduced. After the system pressure reached 1.0 mmH, it was heated at 120°C for 2 hours, and then the system pressure was increased to 1.0 × I Q -3rlHy using an oil diffusion pump.
Heating was continued at 120°C for 15 hours. As a result, the heavy average molecule fl1000(GI)C was obtained with a yield of 98%.
A malic acid polymer (measured) was obtained.

Example 4 In the operation of Example 3, e-malic acid was used and the polymerization was carried out at a polymerization temperature of 100°C for 20 hours. As a result, a malic acid polymer with a yield of 100% and a weight average molecular weight of 2100 was obtained. was gotten.

Example 5 5.0y of d,ff-malic acid-〇-monoethyl ester was placed in a test tube with branches, heated to 120°0 in an oil bath, and then gradually depressurized with a vacuum pump until the system pressure was 1. .0
Heating was continued at 120°C for 20 hours after reaching rlHy. As a result, product 4.317 was obtained, and the product was confirmed to be β-polymalic acid-α-ethyl ester by NMR measurement.The molecular weight by GPC was It was 2600.

Example 6 d,e-malic acid-β-monomethyl ester as raw material 5.
As a result of carrying out the same operation as in Example 5 using 0y, 4.4 g of product was obtained, and the product was IR and 'H-N
As a result of MR measurement, it was confirmed that it was α-polymalic acid-β-methyl ester, and G1. ) The molecular weight according to C was 2500.

Example 7 Raw material R: d*l! 'J nchoic acid 5.09 (
! : d*e') As a result of carrying out the same operation as in Example 5 using UIJ of 5.0y of the e-α-monobenzyl ester, the product 8.7d was obtained, and the IR and 'f■- As a result of NM measurement, it was determined that the copolymer had a ratio of about 3:2 between the malic acid FrIt structural unit and the malic acid-α-benzyl ester groove GIi position, and the molecular weight by GPC was 4000. Ta.

Example 8 Raw materials include 5.0 da of d,e-malic acid and 5.0 da of d,e-malic acid.
β-monoethyl ester5. As a result of preparing the U compound of oy and performing the same operation as in Example 5, the product 8.3
y was obtained. As a result of IR and 'H-NMR measurements of the product, it was confirmed that it was a malic acid-malic acid-β-ethyl ester copolymer, and the molecular weight by GPC was 3000.
Met.

Example 9 d,e-linchoic acid-α-benzyl ester 5,O as a raw material
f and d, 6-malic acid-β-ethyl ester5. The same operation as in Example 5 was carried out using a mixture of Oy. As a result, an 8.7y malic acid-72-benzyl ester-malic acid-β-ethyl ester copolymer was obtained.

Example 10 Raw materials d, e-') Malic acid 5.0 y, a, (!-'
J Nchoic acid-α-ethyl ester 5.0y, d, ff-
Malic acid-β-(2-hydroxyethyl) ester5.
As a result of performing the same operation as in Example 5 using 0zo,
The product ta,oy was obtained. The product was a malic acid-malic acid-a-methyl ester-malic acid-β-(2-hydroxyethyl) ester copolymer.

Example 11 5.0 g of d, e-malic acid and 5.0 g of d, e-mandelic acid were placed in a glass test tube with branches at 140°C under normal pressure.
After heating and melting, the pressure was gradually reduced using a vacuum pump.

Heating was continued at 130°C for 6 hours from the time the pressure within the system reached 1.0 MmHg. As a result, 8.9 g of a colorless and transparent fat-like product was obtained. The product's I-
N MR spectrum and IR spectrum (from
It was confirmed that it is a malic acid-mandelic acid copolymer,
The polystyrene equivalent molecular weight determined by GPC measurement was 2,000.

Example 12 Using 2.5 y of e-malic acid and 2.5 d of e-lactic acid, 4.1 g of a colorless and transparent capsicum-like product was obtained by the same operation as in Example 11. It was confirmed to be a malic acid-lactic acid copolymer by NMR and IIt, and the molecular weight was 2500 by GPC measurement.

Example ■3 Citric acid in a glass test tube with branches], 0. After heating and melting at 160'C under normal pressure, the pressure was gradually reduced with a vacuum pump, and from the point when it reached 1.0 MLHg,
．． As a result of continued heating at 160°C for 0 hours, a crumbled polymer 468y was obtained. I R,'II-N of the polymer
It was confirmed by the MR spectrum that it was a citric acid polymer, and the molecular weight by GPC was 3000.

Example 14 Using tartronic acid I O,01, the same operation as in Example 13 was performed to obtain a product 5.5y, and the product was found to be tartronic acid according to its H-NMR spectrum. It was confirmed that it was a polymer, and the molecular weight by GPC was 2.
It was 000.

(Effects of the Invention) According to the present invention, a polymer or copolymer thereof can be obtained using hydroxypolycarboxylic acid or its ester as a raw material by a simple operation of heating under reduced pressure.

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is hydrogen, methyl, ethyl, phenyl or -
COOH or -CH_2COOH group; X and Y are each hydrogen, methyl or ethyl group, one of which may be a hydroxyl group; n represents 0, 1 or 2; (However, the remaining carboxyl groups except for at least one in the formula may be esterified.) One or a mixture of two or more of the hydroxypolycarboxylic acid or its ester is heated under reduced pressure. A method for producing a polymer or copolymer of hydroxypolycarboxylic acid or its ester, which comprises polycondensation. 2. The production method according to claim 1, wherein the ester of hydroxypolycarboxylic acid is a lower alkyl or benzyl ester. 3. The manufacturing method according to claim 1, wherein the hydroxypolycarboxylic acid is malic acid.