JPH0781000B2 - Process for producing polymer or copolymer of hydroxypolycarboxylic acid ester - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a polymer or copolymer of hydroxypolycarboxylic acid ester.

(Prior Art) In recent years, polymers or copolymers of α-hydroxycarboxylic acids such as polyglycolic acid, polylactic acid, and polymalic acid have been attracting attention as medical and medicinal polymer materials that are decomposed and metabolized in vivo. Has been done. These polymers are used as absorbable sutures in the body (U.S. Pat. Nos. 3,636,956 and 3,297,033), as well as long-term use of a composition comprising the polymer and a pesticide as a pesticide for soil treatment. Example of achieving a lasting effect (Japanese Laid-Open Patent Publication Nos. 59-199603 and -199)
No. 604) is known.

Among these α-hydroxycarboxylic acid polymers, for example, polymalic acid has a carboxyl group on the side chain of the polymer, and a drug or the like can be immobilized on the carboxyl group, so that a so-called sustained-release polymer drug is used. It is considered to be effective as a carrier to be made, and is particularly expected to be used in the fields of medicine and medicine.

However, polymalic acid shows strong acidity in water,
It has been pointed out that the drug carried thereon is decomposed, or the ester bond of the main chain is easily hydrolyzed by the self-catalysis of the carboxyl group of the side chain, and the decomposition rate is a little too fast depending on the purpose.

Further, as a method for obtaining polymalic acid ester, until now, monobenzylmalate or monomethylmalate was directly polycondensed with N, N′-dicyclohexylcarbodiimide (DCC) to obtain α-polymalic acid β-benzyl ester and β-polymaleate. Acid-α-benzyl ester and α
-Polymalic acid β-methyl ester β-Polymalic acid-
Method for obtaining α-methyl ester, (Reports of FaculIty Engineering Tottori Universi
ty 8 124 (1977)) A method of ring-opening polymerization of benzyl malolactonate to obtain β-polymalic acid-α-benzyl ester (US Pat. No. 4,265,247), ring-opening polymerization of malide dibenzyl ester, and α -Method for obtaining polymalic acid-β-benzyl ester (Polyme
r Preprints, Japan 34 (3) 744 (1985)) is known.

(Problems to be Solved by the Invention) However, all of the above-mentioned methods have long synthesis steps and have extremely low yields, and therefore cannot be used for industrial synthesis.

(Solution of Problems) The present inventors have completed the present invention as a result of repeated studies on a method for producing a polymer or copolymer of hydroxypolycarboxylic acid ester easily and at low cost.

The present invention has the formula (In the formula, R ¹ is hydrogen, methyl, ethyl, phenyl or-
COOR ² or —CH ₂ COOR ² group; X and Y are hydrogen, methyl or ethyl group respectively; n is 0, 1 or 2;
The above-mentioned formula and each COOR ² in the parentheses represent the same or different esterified carboxyl group)), and heat polycondensation is performed in the presence of a transesterification catalyst. Is a method for producing a polymer or copolymer of hydroxypolycarboxylic acid ester.

Examples of the hydroxypolycarboxylic acid ester include malic acid, α-methylmalic acid, α-hydroxy-
α'-methylsuccinic acid, -α-hydroxy-α ', α'
-Dimethylsuccinic acid, trimethylmalic acid, α-hydroxyglutaric acid, α-hydroxy-α′-ethylsuccinic acid, tartronic acid, methyltartronic acid, α-phenylmalic acid, esters of hydroxypolycarboxylic acids such as citric acid. To be

In the formula of the esterified carboxyl group (-COOR ² ) in the hydroxypolycarboxylic acid ester, R ² is a saturated or unsaturated aliphatic group or aromatic group, and examples thereof include:
Methyl, ethynyl, propyl, isopropyl, butyl,
Isobutyl, sec-butyl, tert-butyl, pentyl,
Neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, vinyl, 1-propenyl, allyl, isopropenyl, ethynyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl,
Tolyl, xylyl, mesityl, cumenyl, benzyl, phenethyl, styryl, cinnamyl, biphenylyl, naphthyl, anthryl, phenanthryl, hydroxyethyl,
Examples thereof include hydroxypropyl and hydroxyphenyl groups.

Two or more esterified carboxy groups present in one molecule may be the same or different, and two or more kinds of hydroxypolycarboxylic acid esters may be mixed and copolymerized. When the hydroxypolycarboxylic acid ester has a d-form, a single-form or a racemate of optical isomers, any one or a mixture thereof can be used.

It is difficult to polycondense the hydroxypolycarboxylic acid ester by heating it as it is, but the addition of the transesterification catalyst causes the transesterification reaction to proceed under dealcoholization or dephenolization to give the desired polycondensate. can get.

As the transesterification catalyst, for example, a metal-based catalyst showing activity at about 100 to 200 ° C. is preferable. Examples thereof include tin octylate, monobutylstannyl oxide, tetra-n-butyl titanate, titanium oxysulfate, butyllithium, sodium hydride, sodium methoxide, tert-butoxy potassium, 1,8-diazabicyclo (5 ,
4,0] undec-7-ene and the like.

The amount of the catalyst used is usually in the range of 0.01 to 5% (by weight) with respect to the hydroxypolycarboxylic acid ester, and 0.1 to 1%.
(Weight) is preferred.

The preferred heating temperature is generally 100-200 ° C. As the heat source for heating, for example, steam, heat medium, electric heat, or the like may be used, as well as electromagnetic waves.

Heating is usually performed for 1 to several tens of hours.

In order to remove the alcohol and the like produced by the reaction and accelerate the reaction, it is preferable to heat under reduced pressure. In that case, after heating for 1 to 10 hours at a degree of reduced pressure such that the raw material ester is not distilled off, 1 to 50 hours at 10 mmHg or less, preferably 10 to 30
You may heat for a time.

Although the reaction of the present invention usually proceeds without using a solvent,
A solvent that does not hinder the progress of the reaction, such as toluene, decalin, dimethylformamide, etc., may be used, particularly in the initial stage of polymerization.

The ester bond forming the main chain of the polymer of hydroxycarboxylic acid ester varies depending on the type of hydroxycarboxylic acid. For example, in the case of polymalic acid ester, it is represented by the following general formula.

(In the formula, “COOR ² ” has the same meaning as described above, that is, α-type [I] and β-type [II] exist,
Usually mixed and produced.

Further, in the method of the present invention, the hydroxypolycarboxylic acid ester may be polycondensed with the hydroxymonocarboxylic acid ester to obtain a copolymer.

Examples of the hydroxymonocarboxylic acid ester include α-hydroxymonocarboxylic acid such as glycolic acid, lactic acid, α-hydroxyisobutyric acid, mandelic acid, and phenylglyoxylic acid; β-hydroxybutyric acid, β-hydroxyglutaric acid and the like. -Hydroxymonocarboxylic acid; α, β
And dihydroxyisobutyric acid, esters of dihydroxymonocarboxylic acid of β, β′-dihydroxyisobutyric acid. One or more of these may be copolymerized with the hydroxypolycarboxylic acid ester.

The esterified carboxyl group in the obtained polymer should be modified by reacting with ammonia, primary or secondary amine, thiol, an alcohol different from the alcohol obtained by decomposition of the ester group, or hydrazine. You can

The polymer obtained by the present invention is, for example, a bioabsorbable suture, an osteosynthesis material, an artificial tendon, an artificial blood vessel, a drug,
In addition to use as a sustained-release carrier that can fix food additives or agricultural chemicals, it can be used as a drug or food additive itself. Further, the hydrolysis rate of the ester polymer of the present invention tends to be faster than that of polylactic acid and polyglycolic acid and slower than that of the corresponding hydroxypolycarboxylic acid, but the polymer can be selected by selecting the type of ester group. The hydrophobicity and hydrophilicity of can be adjusted appropriately according to the application.

(Function) Although the hydroxypolycarboxylic acid ester does not undergo polycondensation even if it is heated as it is, in the present invention, when the hydroxypolycarboxylic acid ester is heated under the dealcohol (or phenol) by using the transesterification catalyst. The polycondensation reaction proceeds.

(Example) Hereinafter, the present invention will be further described in the form of an example.

Example 1 A glass test tube with a branch is provided with d, l-malic acid dimethyl ester.
5.0 g and tin octylate 25 mg were added and heated to 160 ° C.
After that, the pressure was gradually reduced with a vacuum pump, and while maintaining the system internal pressure at 50 mmHg, heating was continued for 4.0 hours and then at 1.0 mmHg for 10 hours. As a result, 2.8 g of a candy-like polymer was obtained.

The infrared absorption spectrum of this polymer is 1100 cm.
The absorption of ^-1 (OH) was smaller than that of d, l-malic acid dimethyl ester, confirming the progress of the condensation reaction. In addition, the proton nuclear magnetic resonance spectrum shows 3.0 ppm (CH ₂ ), 3.7 p
pm (α-CH ₃ ), 3.8ppm (β-CH ₃ ), 5.6ppm (CH), 6.9pp
A signal was obtained in m (OH), and the intensity ratio between 5.6 ppm and 6.9 ppm was 12: 1, confirming that this polymer was polymalic acid methyl ester.

Example-2 The same operation as in Example-1 was carried out under the conditions of a polymerization temperature of 170 ° C and 180 ° C.

Example-3 Using monobutylstannyl oxide as a catalyst, the same operation as in Example-1 was carried out at polymerization temperatures of 160 ° C, 170 ° C and 180 ° C to obtain a polymer.

Example-4 Using tetra-n-butyl titanate as a catalyst, the same operation as in Example-1 was carried out at polymerization temperatures of 150 ° C, 160 ° C, 170 ° C and 180 ° C to obtain a polymer.

Example-5 Titanium oxysulfate was used as a catalyst, and the polymerization temperature was 150.
The same operation as in Example-1 was carried out at each temperature of ℃, 160 ℃, 170 ℃, 180 ℃ to obtain a polymer.

The following table shows the yields of the polymers obtained in Examples-1 to 5 and the weight average molecular weight (converted to polystyrene) by gel permeation chromatography.

Example-6 In a branched test tube, 5.0 g of d, l-malic acid diethyl ester was added.
And 25 mg of octyl tin were added and heated to 150 ° C. After that, the pressure was gradually reduced with a vacuum pump, and heating was continued for 6.0 hours while maintaining the system internal pressure at 50 mmHg, and then for 15.0 hours at 1.0 mmHg. As a result, 2.7 g of a malic acid ethyl ester polymer was obtained, and the weight average molecular weight thereof by GPC was 3,800.

Example-7 To 2.5 g of d, l-malic acid diethyl ester and 2.5 g of d, l-malic acid dibenzyl ester, 25 mg of monobutylstannyl oxide was added and the same operation as in Example-6 was performed. As a result, 3.0 g of product was obtained, which product had IR and ¹ H.
-As a result of NMR measurement, it was confirmed to be a malic acid ethyl ester-malic acid benzyl ester copolymer. Also,
The weight average molecular weight of the polymer by GPC was 3,500.

Example-8 5.0 g of 1-malic acid dimethyl ester and 25 parts of tin octylate
mg was added and the same operation as in Example-6 was performed. As a result, 3.2 g of malic acid methyl ester polymer was obtained.
The weight average molecular weight of the product was 2,800.

Example 9 5.0 g of diethyl tartronic acid was added to 25 g of tin octylate.
mg was added and it heated at 150 degreeC. After that, gradually reduce the pressure with a vacuum pump and continue for 5.0 hours while maintaining the system pressure at 50 mmHg.
As a result of continuing heating at 1.0 mmHg for 5 hours, 2.7 g of a product was obtained, and its IR spectrum and 1 H-NMR spectrum confirmed that it was a tartronic acid ethyl ester polymer.
Further, the molecular weight in terms of NPC measured by GPC was 3,000.

Example-10 To 5.0 g of α-hydroxyglutarate diethyl ester, 25 mg of monobutylstannyl oxide was added and polymerized in the same manner as in Example-9. As a result, 2.9 g of α-hydroxyglutarate polymer was obtained.

The styrene-converted molecular weight was 3,500.

Example-11 25 g of tin octylate was added to 2.5 g of d, l-malic acid diethyl ester and 2.5 g of glycolic acid ethyl ester at 150 ° C.
Heated for 2.0 hours, then gradually reduce the pressure with a vacuum pump,
5.0 hours while maintaining the system pressure at 50 mmHg, then 1.0 mm
As a result of continued heating at Hg for 5.0 hours, 2.7 g of malic acid ethyl ester-glycolic acid copolymer was obtained. The polystyrene-reduced molecular weight of the polymer by GPC was 5,000.

Example-12 2.5 g of d, l-malic acid diethyl ester and 2.5 g of d, l-lactic acid ethyl ester were added with 25 mg of monobutylstannyl oxide and polymerized in the same manner as in Example-11, resulting in malic acid ethyl ester- 2.8 g of lactic acid copolymer was obtained.
The molecular weight measured by GPC was 5,500.

Example-13 To 5.0 g of diethyl d, l-malic acid was added 25 mg of butyllithium, and the mixture was heated to 150 ° C. After that, gradually reduce the pressure with a vacuum pump to 4.0 while keeping the system pressure at 50 mmHg.
The heating was continued for 8 hours at 1.0 mmHg. As a result, 3.0 g of a polymer was obtained, which was confirmed to be polymalic acid ethyl ester by IR, ¹ H-NMR, and the molecular weight by GPC was 4000.

(Effects of the Invention) According to the present invention, a polymer or copolymer of hydroxypolycarboxylic acid ester can be easily produced at low cost and in high yield.

Claims (5)

[Claims] 1. A formula (In the formula, R ¹ is hydrogen, methyl, ethyl, phenyl or −
COOR ² or —CH ₂ COOR ² group; X and Y are hydrogen, methyl or ethyl group respectively; n is 0, 1 or 2;
The above-mentioned formula and each COOR ² in the parentheses represent the same or different esterified carboxyl group)), and heat polycondensation is performed in the presence of a transesterification catalyst. A method for producing a polymer or copolymer of hydroxypolycarboxylic acid ester. 2. The process according to claim 1, wherein the transesterification catalyst is a metal-based catalyst which exhibits activity at about 100 to 200 ° C. 3. A transesterification catalyst comprising tin octylate, monobutylstannyl oxide, tetra-n-butyl titanate, titanium oxysulfate, butyl lithium, sodium hydride, sodium methoxide, tert-butoxy potassium, 1,8-dia. Zabicyclo [5,4,0] Undec-7-
The manufacturing method according to claim 1 or 2, which is EN. 4. The method according to claim 1, wherein the hydroxypolycarboxylic acid ester is a malic acid ester. 5. A formula (In the formula, R ¹ is hydrogen, methyl, ethyl, phenyl or −
COOR ² or —CH ₂ COOR ² group; X and Y are hydrogen, methyl or ethyl group respectively; n is 0, 1 or 2;
A hydroxypolycarboxylic acid ester represented by the above formula and each COOR ² in the parentheses represents the same or different esterified carboxyl group) together with hydroxymonocarboxylic acid ester in the presence of a transesterification catalyst. A method for producing a copolymer, which comprises condensing.