JP2008174517A - Method for purifying cyclic ester - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a simple method of purification, obtaining a high purity cyclic ester used as a raw material of a high molecular weight polyester, at a high yield. <P>SOLUTION: This new method for purifying the cyclic ester expressed by formula (1) [wherein, R<SP>1</SP>to R<SP>6</SP>are each the same or different H, or a 1-4C linear or branched alkyl: and (n) is an integer of 1 to 3] is characterized by mixing the cyclic ester expressed by the formula (1) with an isocyanate compound, heating and then distilling. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for purifying cyclic esters. Specifically, the present invention relates to a method for purifying cyclic esters with high purity and high yield.

Polyester is widely used as a biodegradable polymer, and is used as a bioabsorbable polymer particularly in the field of medical applications. Cyclic esters can be used as starting materials for this polyester. In order to use it as a raw material for bioabsorbable polymers, it is necessary to keep the impurities derived from the raw materials and impurities containing hydroxyl groups and carboxyl groups such as acids and water that inhibit the polymerization as low as possible, and various purification methods are provided. Yes.
For example, Patent Document 1 discloses a method for producing p-dioxane as a cyclic ester. After reacting an ethylene glycol salt and monochloroacetic acid to obtain β-hydroxyethoxyacetic acid through a purification step, p-dioxane is obtained by distillation. -Dioxanone is obtained. However, since p-dioxanone obtained by this method has low purity, the desired product is obtained by re-distillation and recrystallization purification for use as a raw material for bioabsorbable polymers. Purification by recrystallization yields high-purity p-dioxanone that can be a raw material for biodegradable polymers, but this is a complicated process and the yield of p-dioxanone is low.

Other methods for purifying cyclic esters include washing with methanol or water in Patent Document 2, distillation using an azeotropic agent in Patent Document 3, use of an adsorbent in Patent Document 4, melting in Patent Document 5 Alternatively, recrystallization using a solvent or sublimation method, Patent Document 6 recrystallizes with an aliphatic ester solvent, Patent Document 7 purifies at the time of hydroxyethoxy acetate, and Patent Document 8 adds an orthoester. There is a method of converting acid and water into alcohol and ester. These purification methods are also complicated processes or low yields.
Japanese Patent Publication No. 60-36785 Japanese Patent Application Laid-Open No. 07-208551 Japanese Patent Laid-Open No. 06-504762 Japanese Patent Laid-Open No. 06-136103 JP 09-157513 A US Pat. No. 5,391,768 JP 2001-288180 A Japanese Patent Laid-Open No. 10-109983

  The problem to be solved by the present invention is to provide a simple purification method for obtaining a high-purity cyclic ester in a high yield.

As a result of intensive studies to solve the above problems, the present inventors have found a purification method capable of obtaining a high-purity cyclic ester by mixing and heating a cyclic ester with an isocyanate compound and then distilling the present invention. It came to be completed.
That is, the present invention
Formula (1)

(In the above formula (1), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ may be the same as or different from each other, hydrogen or a linear chain having 1 to 4 carbon atoms. Or a branched alkyl group is shown, n shows the integer of 1-3.)
A method for purifying a cyclic ester represented by the above formula (1) is provided, wherein the cyclic ester represented by the formula (1) is distilled after mixing and heating with an isocyanate compound.

  A purification method using an isocyanate compound having a boiling point higher than that of the cyclic ester is a preferred embodiment of the present invention.

  The purification method wherein the cyclic ester is p-dioxanone is a preferred embodiment of the present invention.

  The cyclic ester obtained by the purification method according to the present invention has a high yield and high purity, and it is possible to obtain a high molecular weight polyester having no practical problem using the obtained cyclic ester as a raw material.

  The cyclic ester described in the present invention is the following formula (1)

(In the above formula (1), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ may be the same as or different from each other, hydrogen or a linear chain having 1 to 4 carbon atoms. Or a branched alkyl group is shown, n shows the integer of 1-3.)
Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom, more preferably R ¹ , R ² , R ³ , R ⁴ , R ^5. And p 6 -dioxanone in which R ⁶ is a hydrogen atom and n = 1.

[Method for producing cyclic ester]
The cyclic ester shown in the present invention can be obtained by a publicly known method. For example, p-dioxanone in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ in formula (1) are hydrogen and n = 1 is disclosed in Japanese Patent Publication Nos. 60-36785 and 2001-288180. It can be obtained by the method described in Japanese Patent Publication No. WO2006 / 129736.

In the method for producing p-dioxanone described in JP-B-60-36785, an ethylene glycol salt and monochloroacetic acid are reacted to obtain β-hydroxyethoxyacetic acid through a purification step, followed by distillation and recrystallization. Dioxanone has been obtained. In this production method, p-dioxanone obtained after purification contains ethylene glycol used as a raw material as an impurity.
Examples of impurities contained in the cyclic ester represented by the formula (1) include a compound represented by the following formula (2).

(In formula (2), Z represents an alkylene group having 2 to 4 carbon atoms.) Specifically, ethylene glycol, 1,3-propanediol, and 1,4-butanediol. )
In the case of p-dioxanone in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 in} formula (1) are hydrogen and n = 1, in formula (2), Z is a carbon number of 2 Ethylene glycol which is an alkylene group is an impurity derived from the raw material.

Hereinafter, the purification method according to the present invention will be described in detail.
The purification method according to the present invention is characterized in that the cyclic ester is distilled and purified after the isocyanate compound is mixed and heated with the cyclic ester containing impurities.

  By adding the isocyanate compound, the isocyanate group of the isocyanate compound reacts with the hydroxyl group of glycol existing as an impurity to form a urethane compound having a boiling point higher than that of the cyclic ester. Even when the concentration of glycol contained in the cyclic ester is low, the urethanization reaction proceeds rapidly. This urethane compound remains stably as a residue in the distillation pot without the production of glycol by depolymerization.

  On the other hand, when the cyclic ester is distilled without adding an isocyanate compound, the glycol contained in the cyclic ester has a boiling point close to that of the cyclic ester, is difficult to separate by distillation, and the glycol is mixed into the distillate, It is difficult to obtain a high purity cyclic ester. When glycol is present in the cyclic ester, the cyclic ester is cleaved by reaction with the glycol to form an oligomer, leading to a decrease in purity of the cyclic ester, and it is difficult to obtain a high molecular weight polyester.

The isocyanate compound shown in the present invention is an aromatic hydrocarbon, aliphatic hydrocarbon, or alicyclic hydrocarbon compound having at least one isocyanate group. Preferably, it is a compound having an isocyanate group having an isocyanate group of 1 to 4, more preferably 1 to 2. The isocyanate compound has 8 to 15 carbon atoms, more preferably 10 to 15 carbon atoms.
By using an isocyanate compound having a boiling point higher than that of the cyclic ester, it can be easily separated from the isocyanate compound by distillation, and a high-purity cyclic ester can be obtained by one purification, which is preferable.

  The boiling point shown in the present invention is a boiling point measured under normal pressure (760 mmHg) based on JIS K0066-1992 “Method for Distillation Test of Chemical Products”. When measured under reduced pressure, it refers to the boiling point converted to normal pressure. The boiling point measured under reduced pressure was converted to the normal boiling point based on the boiling point conversion chart of "Basic Organic Chemistry Experiment p155, Maruzen (1966); Kazuo Hata".

  The boiling point of the isocyanate compound is preferably 30 ° C. (converted to normal pressure (760 mmHg)) or higher than the boiling point of the cyclic ester to be purified, and is 50 ° C. (converted to normal pressure (760 mmHg)) or higher than the boiling point of the cyclic ester to be purified. Higher is more preferable.

  When the boiling point of the isocyanate compound is in the above range, there is no isocyanate mixing into the cyclic ester obtained by distillation.

  When the cyclic ester to be purified is p-dioxanone (boiling point: 212 ° C.), examples of the isocyanate compound used include naphthalene isocyanate (boiling point: 270 ° C.), tolylene diisocyanate (boiling point: 260 ° C.), and xylylene diene. Isocyanate (boiling point: 310 ° C.), diphenylmethane diisocyanate (boiling point: 310 ° C.), naphthalene diisocyanate (boiling point: 325 ° C.), isophorone diisocyanate (boiling point: 300 ° C.), hexamethylene diisocyanate (boiling point; 265 ° C.) and norbornene diisocyanate (boiling point: 305 ° C.).

  These isocyanate compounds may be used alone or in combination of two or more. In addition, when the isocyanate compound used by this invention is a 2 or more types of mixture, let the boiling point of the isocyanate compound with the lowest boiling point contained in the mixture be the boiling point of the mixture. When the isocyanate compound used by this invention is a 2 or more types of mixture, it is preferable that the boiling point of the isocyanate compound with the lowest boiling point contained in the mixture is higher than the boiling point of cyclic ester.

  The amount of the isocyanate compound used is usually 0.5 to 10 moles, preferably 1 to 5 moles, and more preferably 1 to 2 moles per mole of glycol contained.

  In the purification method according to the present invention, it is preferable to carry out distillation after mixing and heating the isocyanate compound to the cyclic ester. Although the temperature heated before distillation is selected suitably, Preferably it is 50-200 degreeC, More preferably, it is 80-150 degreeC. The heating time is 0.1 to 40 hours, preferably 1 to 20 hours.

  Although the temperature in the case of distillation does not have a restriction | limiting in particular, Preferably, it is 50-300 degreeC, More preferably, it is 50-150 degreeC.

The pressure during the distillation is not particularly limited, but is 101.3 kPa to 0.1 kPa, preferably 0.1 to 3 kPa.
The number of distillation stages is not particularly limited, but is 1 to 10 stages, preferably 2 to 5 stages.

  The cyclic ester obtained by the purification method according to the present invention can be converted to polyester by a conventionally known method. That is, polyester is obtained by adding a polymerization initiator and an esterification catalyst and polymerizing. When the cyclic ester is p-dioxanone, the resulting polyester is poly (p-dioxanone). Polymerization initiators used include aliphatic saturated alcohols such as methanol, ethanol, propanol, butanol, amyl alcohol, capryl alcohol, cyclohexanol and lauryl alcohol, alicyclic alcohols such as cyclopentanol and cyclohexanol, and diethylene glycol. Glycols such as lactic acid, aminophenol, and acetophenone. The esterification catalysts used are conventionally known organic tins such as stannous dioctanoate and tin caprylate, organic aluminums such as trimethylaluminum, triethylaluminum and triisobutylaluminum, and organics such as diethylzinc and dibutylzinc. Zinc-based catalysts can be used alone or in combination of two or more. The cyclic ester obtained by this purification method is a practical high molecular weight biodegradable polymer that can be used as a raw material without problems as a polyester. That is, since the cyclic ester obtained by the method of the present invention is a highly pure cyclic ester, a high molecular weight polyester having no practical problem can be obtained. Moreover, the obtained polyester can be used for medical materials such as sutures and medical devices by performing known and public processing.

  Hereinafter, the production of the cyclic ester will be described. In the examples of the production of the cyclic ester, the purity of the cyclic ester, the concentration of ethylene glycol, the concentration of the isocyanate compound, and the weight average molecular weight were measured by the following methods.

(1) Purity of cyclic ester: Measured by gas chromatography. The apparatus was GC-14A manufactured by Shimadzu Corporation, the detector was a hydrogen flame ionization detector (FID), and the column was a column (G300, φ: 1.2 mm × 40 m, film thickness: 2 μm) manufactured by Chemical Substance Evaluation Research Organization. The column temperature was 160 ° C., the injection temperature was 230 ° C., the detector temperature was 230 ° C., and nitrogen was used as the carrier gas at a flow rate of 10 ml / min. About 50 mg of a sample was dissolved in 10 ml of acetone, and 1 μl was injected and measured. A calibration curve was prepared in advance using a standard sample, and the purity of the cyclic ester was analyzed using the calibration curve.

(2) Ethylene glycol concentration Measured by gas chromatography. The apparatus was GC-14A manufactured by Shimadzu Corporation, the detector was a hydrogen flame ionization detector (FID), and the column was a column (G300, φ: 1.2 mm × 40 m, film thickness: 2 μm) manufactured by Chemical Substance Evaluation Research Organization. The column temperature was 160 ° C., the injection temperature was 230 ° C., the detector temperature was 230 ° C., and nitrogen was used as the carrier gas at a flow rate of 10 ml / min. About 500 mg of a sample was dissolved in 10 ml of acetone, and 3 μl was injected and measured. A calibration curve was prepared in advance using a standard sample, and ethylene glycol concentration analysis was performed using the calibration curve.

(3) Concentration of isocyanate compound Measured by gas chromatography. The apparatus was GC-14A manufactured by Shimadzu Corporation, the detector was a hydrogen flame ionization detector (FID), and the column was a column made by Chemical Substance Evaluation Research Organization (G250, φ: 1.2 mm × 40 m, film thickness: 2 μm). The column temperature was 250 ° C., the injection temperature was 290 ° C., the detector temperature was 300 ° C., and nitrogen was used as a carrier gas at a flow rate of 15 ml / min. About 500 mg of a sample was dissolved in 10 ml of acetone, and 3 μl was injected and measured. A calibration curve was prepared in advance using a standard sample, and the concentration analysis of the isocyanate compound was performed using the calibration curve.

(4) Weight average molecular weight It measured by the gel permeation chromatograph method (GPC). As the apparatus, a system 21 manufactured by Shodex was used. HFIP (hexafluoroisopropyl alcohol) in which 0.05% by weight of sodium trifluoroacetate was dissolved was used as a solvent and passed through a column (KD-806M + KD-805L + KD-803 manufactured by SHODEX) at 35 ° C. and 1 ml / min. The calibration curve obtained from the elution time by RI detection of PMMA (polymethylmethacrylate) standard substances with known molecular weights of 760,000, 210,000, 55,000, 22,000, 7,000, and 20,000 in advance Created. The elution time of the measurement sample was obtained and converted to a weight average molecular weight in terms of PMMA using a calibration curve.

[Synthesis Example 1]
A reaction vessel was charged with 170 g (4.08 mol) of 96 wt% sodium hydroxide and 1241.4 g (20.0 mol) of ethylene glycol, and heated to 130 ° C. Thereafter, 40 g of toluene was added, and 97.6 g of water was distilled out of the system while performing azeotropic dehydration. Thereafter, the temperature was lowered to 100 ° C., 189 g (2.0 mol) of monochloroacetic acid was charged over 1 hour, and the mixture was further stirred for 1.5 hours. Next, the pressure in the reaction vessel was 3.3 kPa, the temperature was 95 ° C., 40 g of toluene and 724.6 g of ethylene glycol were distilled out of the system, and the reaction solution was concentrated. Thereafter, 920 g of acetone was added dropwise over 1.5 hours, followed by crystallization and filtration. The filter cake was washed with 232.8 g of acetone and dried to obtain 371.2 g of sodium β-hydroxyethoxyacetate. The yield of sodium β-hydroxyethoxyacetate at this time was 88.1% with respect to the monochloroacetic acid charged. Subsequently, 670 g of 60% methanol water was added to 371.2 g of sodium β-hydroxyethoxyacetate, which was heated to 70 ° C., and then 1170 g of acetone was added dropwise over 2 hours. After cooling to room temperature and filtering, the filter cake was washed with 490 g of acetone and dried to obtain 335.6 g of sodium β-hydroxyethoxyacetate. The purification yield of sodium β-hydroxyethoxyacetate at this time was 82.3% with respect to the monochloroacetic acid charged. Subsequently, 367 g of water was added to 335.6 g of the obtained β-hydroxyethoxyacetate sodium and neutralized with 38.9% by weight of 168.9 g (1.65 mol) of aqueous hydrochloric acid to obtain 871.5 g of hydroxyethoxyacetic acid aqueous solution. Obtained.

  Subsequently, 64 g (0.32 mol) of tetraethylene glycol (boiling point: 314 ° C.) was added to 871.5 g of the obtained hydroxyethoxy acetic acid aqueous solution (2.0 mol of hydroxyethoxy acetic acid), and the pressure was 8.7 kPa and the temperature was 65 ° C. After distilling off water under the above conditions (dehydration rate: 99%), 376 g of acetone was added to crystallize and filter, and the filter cake was washed with 290 g of acetone. Furthermore, acetone in the filtrate was distilled off under conditions of a pressure of 101.3 MPa and a temperature of 65 ° C. to 120 ° C., then 20 g of toluene was added, and azeotropic dehydration was performed under the conditions of a pressure of 101.3 MPa and a temperature of 110 ° C. to 150 ° C. The polymerization reaction occurred. Since the theoretical distillation rate reached 99%, the polymerization reaction was terminated.

  Subsequently, depolymerization and distillation were simultaneously performed for 3 hours while heating the obtained polymerization solution itself in a reaction vessel under a pressure of 1.3 kPa at 150 ° C. to obtain 151.2 g of a distillate. . The purity of p-dioxanone in the distillate was 99.8% by weight, the ethylene glycol contained was 1200 ppm, and the extraction yield of p-dioxanone (boiling point: 212 ° C.) was 73.9% in terms of monochloroacetic acid. .

[Example 1]
To 40 g (0.392 mol) of p-dioxanone obtained in Synthesis Example 1, 0.23 g (0.0009 mol) of 4,4′-diisocyanatophenylmethane was added and heated at 130 ° C. for 10 hours. The ethylene glycol concentration in the reaction system was 5 ppm. Subsequently, distillation was carried out using a distillation column packed with 5 stages of McMahon packing material to obtain 38 g of p-dioxanone. Ethylene glycol in p-dioxanone was not detected (detection limit 5 ppm or less), and 4,4′-diisocyanatophenylmethane was also not detected (detection limit 5 ppm or less). The purification yield was 95% based on the charged p-dioxanone.

[Comparative Example 1]
40 g (0.392 mol) of p-dioxanone obtained in Synthesis Example 1 was distilled using a distillation column packed with 5-stage equivalent McMahon filler to obtain 38 g of p-dioxanone. Ethylene glycol in p-dioxanone was 1100 ppm. The purification yield was 95% based on the charged p-dioxanone.

[Comparative Example 2]
40 g (0.392 mol) of p-dioxanone obtained in Synthesis Example 1 was heated and stirred at 130 ° C. for 40 hours. The ethylene glycol concentration in the system was 5 ppm. Subsequently, distillation was carried out using a distillation column packed with 5 stages of McMahon packing material to obtain 34.8 g of p-dioxanone. Ethylene glycol in p-dioxanone was 25 ppm. The purification yield was 87% based on the charged p-dioxanone.

[Example 2]
To 40 g (0.392 mol) of p-dioxanone obtained in Synthesis Example 1, 0.19 g (0.0009 mol) of norbornene diisocyanate was added and heated at 130 ° C. for 15 hours. The ethylene glycol concentration in the reaction system was 7 ppm. Subsequently, distillation was carried out using a distillation column packed with 5 stages of McMahon packing material to obtain 38 g of p-dioxanone. Ethylene glycol in p-dioxanone was not detected (detection limit 5 ppm or less), and norbornene diisocyanate was not detected (detection limit 5 ppm or less). The purification yield was 95% based on the charged p-dioxanone.

[Reference example]
38 g (0.37 mol) of p-dioxanone obtained in Example 1, 32 mg of lauryl alcohol and 38 mg of tin octoate were charged and reacted at 90 ° C. for 10 hours. The obtained poly (p-dioxanone) had a weight average molecular weight of 300,000.

According to the method for purifying a cyclic ester of the present invention, highly pure p-dioxane which can be a raw material for a biodegradable polymer can be obtained efficiently.
The p-dioxanone obtained by the present invention can be used without any problem in the bioabsorbable suture field currently in practical use in the medical field.

Claims (3)

Formula (1)

(In the above formula (1), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ may be the same as or different from each other, hydrogen or a linear chain having 1 to 4 carbon atoms. Or a branched alkyl group is shown, n shows the integer of 1-3.)
A method for purifying a cyclic ester represented by the above formula (1), wherein the cyclic ester represented by the formula (1) is distilled after mixing and heating with an isocyanate compound.   2. The purification method according to claim 1, wherein an isocyanate compound having a boiling point higher than that of the cyclic ester is used.   The purification method according to claim 1 or 2, wherein the cyclic ester is p-dioxanone.