WO2006129736A1 - Process for producing cyclic ester - Google Patents

Abstract

It is intended to provide an industrially advantageous process for producing a cyclic ester, an industrially advantageous process for producing a cyclic oxyester which is a raw material of poly(hydroxyalkyloxyacetic acid ester), and an industrially advantageous process for producing a cyclic dimeric ester which is a raw material of poly(α-hydroxycarboxylic acid). The process for producing a cyclic ester of the invention comprises two steps of [a first step] a step of obtaining a polymerization solution by adding an alkylene glycol with a boiling point higher than that of a cyclic ester to be produced to a specific hydroxyalkylcarboxylic acid and/or a condensation product of the hydroxyalkylcarboxylic acid and carrying out a polymerization reaction and [a second step] a step of obtaining a cyclic ester with a purity of 98% or higher by simultaneously carrying out a reaction and distillation by heating the polymerization solution obtained in the first step.

Description

 Specification

 Method for producing cyclic ester

 Technical field

 The present invention relates to a method for producing a hydroxyalkyloxyacetic acid hydroxy cyclic ester

And a method for producing a cyclic ester, such as a method for producing a cyclic dimer ester.

 Background art

 [0002] Poly (hydroxyalkyloxyacetate) is widely used as a biodegradable polymer, and particularly used as a bioabsorbable polymer in the field of medical applications. Oxycyclic esters can be used as starting materials for this poly (hydroxyalkyloxyacetate), and various industrial production methods have been proposed.

[0003] For example, Patent Document 3 discloses a method for producing p-dioxanone, which is an oxycyclic ester, and reacts an ethylene glycol salt with monochloroacetic acid to obtain j8-hydroxyethoxyacetic acid through a purification step. After that, p-dioxanone was obtained by distillation. However, since p-dioxanone obtained by this method has low purity, further purification is required to use it as a raw material for bioabsorbable polymers. Repeated purification operations reduce the yield of p-dioxanone. It is a complicated process.

[0004] Patent Document 5 discloses a method for producing p-dioxanone, and P-dioxanone, which is the target product, is obtained in high yield. However, it has been desired to further improve the operability such that the operability such as taking out is not always sufficient.

[0005] Patent Documents 6 and 7 describe a method for producing a cyclic ester. In this method, a mixture containing an aliphatic polyester and a specific polyalkylene glycol ether having a boiling point of 230 to 450 ° C. and a molecular weight of 150 to 450 is subjected to an oligomer of an aliphatic polyester derived from the aliphatic polyester under normal pressure or reduced pressure. By heating to a temperature at which depolymerization occurs, a cyclic ester is produced, and the produced cyclic ester is distilled off together with a high-boiling polar organic solvent and then taken out from the distillate. In order to obtain a cyclic ester with a high purity, further purification operations must be performed. It is a process.

 [0006] On the other hand, polyhydroxycarboxylic acids are also widely used as biodegradable polymers. In particular, polyglycolic acid is used as a bioabsorbable polymer in the field of medical applications. It is known to use glycolide as a starting material for this polydaricholic acid, and various industrial production methods have been proposed for cyclic dimer esters containing glycolide.

 [0007] For example, in Patent Document 2, glycolide is obtained by polycondensation of glycolic acid, followed by distillation and further purification by dropwise addition to an alcohol solvent. However, in this method, since a colored component of glycolide is mixed during distillation from polycondensation, a purification operation is unavoidable. For this reason, the yield of glycolide is reduced by the purification operation, which is a complicated process.

 [0008] Further, in Patent Document 4, glycolic acid and polyalkylene glycol are polycondensed and then distilled to obtain glycolide. However, in this method, thermal decomposition of polyalkylene glycol occurs during the distillation of glycolide, and thermal decomposition products are mixed in, so a purification operation is unavoidable. Therefore, there is a problem similar to that of Patent Document 1.

 [0009] Patent Documents 6 and 7 describe a method for producing an α-hydroxycarboxylic acid cyclic dimer ester. In this method, a high boiling point polar organic solvent or a mixture of a high boiling point polar organic solvent and a solubilizing agent is added to an α-hydroxycarboxylic acid oligomer, and the oligomer is brought to a temperature at which depolymerization of the oligomer occurs under normal pressure or reduced pressure. (X-hydroxycarboxylic acid cyclic dimer ester is formed by heating, and the produced α-hydroxycarboxylic acid cyclic dimer ester is distilled off together with the high-boiling polar organic solvent, and then removed from the distillate. However, in order to obtain a highly pure α-hydroxycarboxylic acid cyclic dimer ester, further purification operations must be performed, and it is difficult to say that this is an industrially advantageous production method in view of the purification load.

[0010] As a method for producing a cyclic ester, for example, Patent Document 1 discloses a method for producing a macrocyclic ester. Polyester of a dibasic acid and an alkylene glycol is used as a polyoxyester. Ethylene brush rate is obtained by depolymerizing and cyclizing under reduced pressure with additives such as alkylene glycol. However, practical high molecular weight biodegradable polymers On the other hand, cyclic esters used as starting materials for the production of medical materials such as biodegradable packaging materials and bioabsorbable sutures need to be of higher purity and are usually further purified. There was a need to do.

 Patent Document 1: JP-A-55-120581

 Patent Document 2: Japanese Patent Publication No. 51-006673

 Patent Document 3: Japanese Patent Publication No. 60-36785

 Patent Document 4: JP-A 63-152375

 Patent Document 5: JP 2001-288180 A

 Patent Document 6: Japanese Patent Laid-Open No. 9-328481

 Patent Document 7: WO02Z014303

 Disclosure of the invention

 Problems to be solved by the invention

[0011] A first problem to be solved by the present invention is to provide an industrially advantageous production method of a cyclic ester that can be a raw material for a biodegradable polymer.

 [0012] The second problem to be solved by the present invention is an industrially advantageous production in which an oxy cyclic ester which is a raw material of poly (hydroxyalkyloxyacetic acid ester) can be obtained efficiently and in a high yield. It is to provide a method.

[0013] The third problem to be solved by the present invention is an industrially advantageous process for producing a cyclic dimer ester used as a raw material for a biodegradable polymer, particularly glycolide, which is a raw material for polydaricholic acid. Is to provide.

 Means for solving the problem

[0014] As a result of intensive studies to solve the above-mentioned problems, the present inventors have found a production method capable of obtaining a cyclic ester efficiently and in high yield from a specific hydroxycarboxylic acid, etc. It came to complete.

[0015] That is, the present inventor

 Using at least one compound represented by the following formula (1) as a raw material,

[0016] [Chemical 1]

(In the above formula (1), Z represents oxygen or a linear or branched oxyalkyleneoxy group having 2 to 20 carbon atoms, and R ¹ and R ² may be the same or different from each other. It is preferably hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, and p is an integer of 1 to 20000.)

 A method for producing a cyclic ester represented by the following formula (2):

 [0018] [Chemical 2]

 (In the above formula (2), X represents a carbonyl group or a substituted or unsubstituted methylene group,

R ³ and R ⁴ may be the same or different and each represents hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, and n represents an integer of 1 to 4. )

 [First Step] A step of adding an alkylene glycol having a boiling point higher than that of the produced cyclic ester (2) to the compound (1) to carry out a polymerization reaction to obtain a polymerization solution,

 [Second Step] Cyclic ester comprising two steps of heating the polymerization liquid obtained in the first step and simultaneously carrying out the reaction and distillation, a step of obtaining a cyclic ester having a purity of 98% or more from S, etc. A method of manufacturing the same is provided.

 [0020] Further, as a result of diligent studies to solve the above-mentioned problems, the present inventors have found a production method capable of obtaining an oxy cyclic ester from hydroxyalkylacetic acid in an efficient and high yield, and the present invention has been made. It came to be completed.

That is, the present invention uses a hydroxyalkyloxyacetic acid represented by the following formula (3) as a raw material, [0022] [Chemical 3]

(In the above formula (3), R represents a hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms which may be the same or different from each other, and n is 1 Indicates an integer of ~ 4)

 A method for producing an oxycyclic ester represented by the following formula (4):

[0024] [Chemical 4]

 (In the above formula (4), R and each represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, which may be the same or different, and n is 1 Indicates an integer of ~ 4)

 [First Step] To the hydroxyalkyloxyacetic acid (3), an alkylene glycol having a boiling point higher than that of the produced oxycyclic ester (4) is added, and a polymerization reaction is performed to obtain a polymerization solution. Process,

 [Second Step] The step of obtaining the oxy cyclic ester (4) while simultaneously heating and reacting the polymerization solution obtained in the first step!

 A method for producing an oxycyclic ester comprising the following two steps is provided.

[0026] The hydroxyalkyloxyacetic acid (3) is preferably β-hydroxyethoxyacetic acid.

[0027] Further, as a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a cyclic dimer ester is efficiently and highly efficient from ex-hydroxycarboxylic acid and Ζ or α-hydroxycarboxylic acid condensate. Finding a production method that can be obtained with purity, and completing the present invention It was.

 That is, the present invention

 Using α-hydroxycarboxylic acid and カ ル ボ ン or α-hydroxycarboxylic acid condensate represented by the following formula (5) as raw materials,

 [0028] [Chemical 5]

(In the above formula (5), R ¹ and R ² represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, which may be the same or different from each other. M represents an integer from 1 to 20000.)

 A method for producing a cyclic dimer ester represented by the following formula (6):

 [0030] [Chemical 6]

(In the above formula (6), R ¹ and R ² represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, which may be the same or different from each other. M represents an integer from 1 to 20000.)

 [First Step] An alkylene glycol having a boiling point higher than that of the produced cyclic dimer ester (6) is added to the α-hydroxycarboxylic acid and / or the α-hydroxycarboxylic acid condensate (5). A step of performing a polymerization reaction to obtain a polymerization solution,

 [Second Step] The step of obtaining the cyclic dimer ester (6) while simultaneously heating and reacting the polymerization solution obtained in the first step!

A method for producing a cyclic dimer ester comprising the following two steps is provided. As the oc-hydroxycarboxylic acid and Z or (-hydroxycarboxylic acid condensate (5), glycolic acid and z or glycolic acid condensate are preferable.

 [0033] The molecular weight of the alkylene glycol used in the first step when producing the cyclic dimer ester (6) is preferably in the range of 100 to 900.

 The invention's effect

 [0034] The production method of the present invention dramatically reduces the rate of formation of the oxycyclic ester by suppressing the formation of a high-molecular weight hydroxyalkyloxyacetic acid product and maintaining the fluidity of the solution itself. The yield can also be improved. In addition, high-purity oxycyclic ester can be obtained by simultaneously performing depolymerization reaction and distillation purification. That is, the compound can be obtained efficiently and in a high yield.

 [0035] In addition, the production method of the present invention suppresses the formation of a high molecular weight product of a-hydroxycarboxylic acid and keeps the fluidity of the polymerization solution, whereby the production rate of the cyclic dimer ester is increased. As well as the yield. Further, by carrying out the reaction and purification by distillation at the same time, a high-purity cyclic dimer ester can be obtained. That is, the compound can be obtained efficiently and with high purity.

 BEST MODE FOR CARRYING OUT THE INVENTION

[Method for producing cyclic ester]

 The method for producing a cyclic ester in the present invention uses at least one compound represented by the following formula (1) as a raw material,

[0037] [Chemical 7]

(In the above formula (1), Z represents oxygen or a linear or branched oxyalkyleneoxy group having 2 to 20 carbon atoms, and R ¹ and R ² may be the same or different from each other. Or a linear or branched alkyl group having 1 to 4 carbon atoms, p is 1 to 20000 Indicates an integer. )

 A method for producing a cyclic ester represented by the following formula (2):

 [0039] [Chemical 8]

 (In the above formula (2), X represents a carbonyl group or a substituted or unsubstituted methylene group,

R ³ and R ⁴ may be the same or different and each represents hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, and n represents an integer of 1 to 4. )

 [First Step] A step of adding an alkylene glycol having a boiling point higher than that of the produced cyclic ester (2) to the compound (1) to carry out a polymerization reaction to obtain a polymerization solution,

 [Second Step] The second step includes the step of obtaining a cyclic ester having a purity of 98% or more while simultaneously performing the reaction and distillation by heating the polymerization liquid obtained in the first step.

 [0041] Specific examples of the cyclic ester represented by the above formula (2) include an oxy cyclic ester and a cyclic dimer ester. Hereinafter, these production methods will be described more specifically.

 [Method for Producing Oxycyclic Ester]

 Hereafter, the manufacturing method of the oxy cyclic ester by this invention is demonstrated in detail. The hydroxyalkyloxyacetic acid used as a raw material in the present invention is a compound represented by the following formula (3).

 [0043] [Chemical 9]

(In the above formula (3), R and IT represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, which may be the same or different from each other, n is an integer from 1 to 4.)

 As the hydroxyalkyloxyacetic acid represented by the above formula (3) (hereinafter also referred to as hydroxyalkyloxyacetic acid (3)), R and IT are hydrogen, and 13-hydroxyethoxyacetic acid where n = l. Is preferred.

 [0045] Hydroxyalkyloxyacetic acid can be produced by a publicly known method. For example, Tokusho Sho 60

 No. 36785 can be obtained by the examples described in JP-A-2001-288180.

 [0046] The hydroxyalkyloxyacetic acid used in the present invention is preferably one in which impurities derived from raw materials are excluded as much as possible.

 [0047] The oxycyclic ester obtained by the present invention is a compound represented by the following formula (4).

[0048] [Chemical 10]

 [0049] (In the above formula (4), R and IT represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, which may be the same or different from each other, and n Represents an integer from 1 to 4.)

 And, among the hydroxyalkyloxyacetic acids represented by the above formula (3), U, a compound, β-hydroxyethoxy acetic acid, which is a compound, is used as a raw material compound of the present invention. In (4), p dioxanone is obtained in which R and IT are hydrogen and n = l.

 [0050] The method for producing a hydroxyalkyl oxyacetic acid cyclic ester according to the present invention is characterized in that it includes [first step] and [second step] described below. Hereinafter, each process will be described.

[0051] The first step of the method for producing an oxycyclic ester according to the present invention is an oxycyclic ester represented by the above formula (4) obtained by the present invention (hereinafter also referred to as oxycyclic ester (4)). In this step, an alkylene glycol having a higher boiling point is added to hydroxyalkyloxyacetic acid and a polymerization reaction is performed to obtain a polymerization solution.

 [0052] Hereinafter, the first step will be described in detail by the method for producing an oxycyclic ester according to the present invention.

 [0053] This first step is characterized in that an alkylene diol having a boiling point higher than that of the oxy cyclic ester (4) is used.

[0054] By adding such an alkylene glycol in the first step, the hydroxyl group of alkylene dallicol reacts with the carboxyl group at the terminal of hydroxyalkyloxyacetic acid.

 [0055] Therefore, in this first step, a copolymer of the alkylene glycol and hydroxyalkyloxyacetic acid is obtained by using an alkylene glycol having a boiling point higher than that of the epoxy cyclic ester (4). The resulting polymerization solution is uniform until the end of the first step, and tends to maintain high fluidity.

 [0056] On the other hand, if the polymerization is performed without adding the alkylene glycol in the first step, the polymer tends to be a homopolymer and has a high molecular weight, so that the resulting polymerization solution is uniform. In some cases, the fluidity may also decrease.

 [0057] The alkylene glycol used in the first step is usually a liquid having a melting point of 100 ° C or lower, more preferably 70 ° C or lower, and has a boiling point higher than that of the oxycyclic ester (4) obtained by the present invention. If it is alkylene glycol, it is not particularly limited! ,.

 The boiling point 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”.

[0059] The boiling point of alkylene glycol is preferably 30 ° C (converted to normal pressure (76 OmmHg)) or higher than the boiling point of the cyclic ester to be formed, and it is preferably 50 ° C (normal pressure) to the boiling point of the cyclic ester to be formed. (Equivalent to (760mmHg)) Higher than 70 ° C (normal pressure (760mmHg) equivalent) higher than the boiling point of the cyclic ester that is more preferable It is most preferable that it is 100 ° C (normal pressure (760mmHg) conversion) or more higher than the boiling point.

[0060] When the boiling point of the alkylene glycol is in the above range, the alkylene glycol and the product oxycyclic ester can be easily separated in the second step described later. When the resulting oxycyclic ester (4) is p-dioxanone (boiling point: 212 ° C), for example, diethylene glycol (boiling point: 244 ° C), triethylene glycol (boiling point: 287 ° C), tetraethylene glycol (Boiling point: 327 ° C), pentaethylene glycol (boiling point: 430 ° C), hexamethylene glycol (boiling point: 440 ° C), dipropylene glycol (boiling point: 232 ° C), tripropylene glycol, tetrapropylene glycol, Examples thereof include polyethylene glycol and polypropylene glycol.

[0061] These alkylene glycols may be used alone or in admixture of two or more. When the alkylene glycol used in the present invention is a mixture of two or more, the lowest boiling point of the alkylene glycol contained in the mixture is defined as the boiling point of the mixture.

 [0062] Further, when the alkylene glycol used in the present invention is a polyalkylene glycol, the boiling point is lower than that of the cyclic ester to be produced, and the component should substantially contain components. For example, when polyethylene darcol is used in the production of p-dioxanone, it is preferable that low-boiling components such as ethylene glycol and diethylene glycol are not substantially contained in polyethylene glycol. It is most preferable that no low-boiling components such as are included.

[0063] In the present invention, when the above polyalkylene glycol is used as the alkylene glycol, polyethylene glycol and polypropylene glycol are preferable from the viewpoint of not producing THF as a decomposition product. In addition, the power of availability is more preferable than that of polyethylene glycol.

 [0064] The amount of the alkylene glycol used is usually 0.01 to 10 moles, preferably 0.1 to 5 moles, more preferably 0.1 to 1 moles per mole of hydroxyalkyloxyacetic acid. The

[0065] The number of moles is a value obtained by dividing the mass of the alkylene glycol used by the molecular weight of the alkylene glycol. Polymer of alkylene glycol as alkylene glycol When used, the average molecular weight is a value obtained by calculating the hydroxyl value and calculating the hydroxyl value.

 [0066] For example, the average molecular weight of polyethylene glycol can be determined as follows.

 [0067] First, JIS K0070-1992 (Testing method for acid value, saponification value, ester value, iodine value, hydroxyl value and unsaponified product of chemical products) 7.1 (Neutralization titration method) ).

 [0068] By substituting the determined hydroxyl value (B) into the following conversion formula, the average molecular weight (A) is calculated.

[0069] 56106 / B X 2 = A

 (A: average molecular weight, B: hydroxyl value, 56106: conversion factor)

 When the amount of alkylene glycol used is in the above range, it is excellent in terms of the fluidity of the reaction solution, the purification rate of the target product, and the distillation rate.

[0070] In the first step, the polymerization reaction is carried out by heating the alkylene glycol with hydroxyalkyloxyacetic acid (3) and heating. This reaction can be carried out in any temperature range that gives the desired substance. The preferred temperature is 50 to 200 ° C, more preferably 80 to 160 ° C.

 [0071] Further, in the first step, after adding the above-mentioned alkylene glycol to hydroxyalkyloxyacetic acid (3), the reaction is allowed to proceed by distilling off the condensed water produced in the system by heating. By distilling off the condensed water by this heating, the polymerization reaction proceeds and a polymerization solution is obtained.

 [0072] In this first step, hydroxyalkyloxyacetic acid may be added as a solution dissolved in an organic solvent or a solvent such as water, or may itself be added.

 [0073] When hydroxyalkyloxyacetic acid is added as an aqueous solution, at least a part of the water derived from this aqueous solution is distilled off by the above-described operation of distilling condensed water.

 [0074] The reaction conditions for distilling off the condensed water are not particularly limited as long as the condensed water is distilled off. Preferably, the pressure is set in the range of 101.3 kPa to 6.7 kPa, and the temperature is set. Can be set to the boiling point of water contained in the solution in the first step at that pressure.

[0075] Hydroxyalkyloxyacetic acid (3) is, for example, alkylene glycol, monochloro A compound synthesized with an aqueous solution containing an alkali such as chloroacetic acid or sodium hydroxide can also be used as it is.

 [0076] However, since this aqueous solution usually contains a salt, for the purpose of removing the salt contained in this aqueous solution, water in the aqueous solution, for example, 99% or more of water is removed by distillation. Wash with alcohols such as methanol, ethanol, isopropyl alcohol, ketones such as acetone, methyl ethyl ketone, cyclohexanone, amides such as N, N-dimethylacetamide, N, N-dimethylformamide, etc. You can distill further.

 [0077] The conditions for distilling the salt with the alcohols, ketones or amides after washing are preferably set such that the pressure is in the range of 101.3 kPa to 0.1 lkPa, and the temperature is used for washing. The boiling point of the solvent at that pressure can be set.

 [0078] From the viewpoint of promoting distillation for the purpose of further promoting the polymerization, a solvent that azeotropes with water such as toluene and xylene may be added to distill off the above-mentioned condensed water and the like. . When the azeotropic solvent is added and the condensed water is distilled off, the generated water is distilled from the reaction system together with the azeotropic solvent, and the resulting distillate is separated using a separator. The solvent and product water may be separated, and the separated solvent may be polymerized while returning to the reaction system.

 [0079] The amount of water distilled off is 90% or more in terms of theoretical distillation rate, preferably 95% or more in terms of theoretical distillation rate, and more preferably 98% or more in terms of theoretical distillation rate. The polymerization reaction in the process is completed. The solution obtained after distilling off is referred to as a polymerization solution obtained in the first step.

 [0080] The theoretical distillation rate in the present invention is as follows.

 [0081] The theoretical water distillation rate in the present invention refers to the ratio of the total weight of water distilled out of the reaction system to the total mass of water added to the reaction system.

[0082] When the hydroxyalkyloxyacetic acid added in the first step is an aqueous solution dissolved in a solvent such as water, water contained in the aqueous hydroxyalkyloxyacetic acid solution to be added and polymerization in the first step The combined strength of the resulting condensed water The total weight of the water contained in the raw material of the first step.

[0083] Therefore, the theoretical distillation rate in the case of using the hydroxyalkyloxyacetic acid aqueous solution is that the distillation of water actually starts after the heat treatment in the first step with respect to the total weight of water contained in the raw material. It is the ratio of the total weight of water that has been collected before the end of the force. [0084] In the second step of the method for producing an oxycyclic ester shown in the present invention, the polymerization solution of hydroxyalkyloxyacetic acid and alkylene glycol obtained in the first step is heated under normal pressure or reduced pressure. It is characterized in that the oxy cyclic ester (4) is distilled while simultaneously performing the depolymerization reaction and distillation.

 Hereinafter, the second step of the method for producing an oxycyclic ester according to the present invention will be described in detail.

 [0086] The present invention is characterized in that an alkylene glycol having a boiling point higher than that of the oxy cyclic ester (4) obtained in the second step is used.

 [0087] The polymerization solution obtained in the first step contains a copolymer of a high-boiling alkylene glycol and hydroxyalkyloxyacetic acid. This copolymer has hydroxyl groups at both ends.

 [0088] The presence of hydroxyl groups at both ends of the polymer in the polymerization solution obtained in the first step allows only the depolymerization reaction to proceed efficiently even when heat-treated in the second step, and the resulting oxy The yield of cyclic ester is increased.

 [0089] On the other hand, when alkylene glycol is not added in the first step, the polymerization solution obtained in the first step becomes a homopolymer, and the homopolymer has a hydroxyl group and a carboxyl group at each end. Even if this polymerization solution is heat-treated, only the depolymerization reaction does not occur efficiently, and the polymerization reaction further proceeds. As a result, during the reaction in the second step, the homogeneity of the reaction solution may be impaired and the fluidity may be lowered, and the oxy cyclic ester tends not to be obtained in a high yield.

 [0090] Since the depolymerization reaction of the polymerization solution in the second step needs to be performed at a higher temperature than the polymerization reaction in the first step, if the alkylene glycol contains a low-boiling component, the yield tends to decrease. .

 Accordingly, since the alkylene glycol used has a higher boiling point than the target oxycyclic ester, the low-boiling components derived from the alkylene glycol tend not to be distilled off, and the yield of the target product is high in purity. Become.

[0092] In the second step, even when the oxycyclic ester as the depolymerization product is distilled, the reaction solution is uniform until the end of the reaction in the second step, and the depolymerization is performed. In addition, the fluidity of the reaction solution is good during distillation, and the residual liquid in the still water after distillation is also reduced. It is also fluid and easy to handle.

 [0093] The temperature at the time of depolymerization and distillation in the second step is not particularly limited as long as the polymer obtained in the first step is depolymerized, but preferably 50 to 300 ° C. More preferably, it is 80-200. C.

 [0094] The pressure during depolymerization and distillation in the second step is usually 101.3 kPa to 0.1 lkPa.

 [0095] Addition of stirring is one of the indicators of fluidity.

 [0096] The stirring load in the present invention refers to a measured value of a force (Ncm: -Euton centimeter) applied to the stirring shaft at a rotation speed of 200 rpm using a stirrer with an RZR2101 torque meter manufactured by Heidolph. The stirring load of the residue in the reaction vessel after distillation in the second step is usually 10 Ncm to 90 Ncm, preferably 20 Ncm to 50 Ncm at 80 ° C.

 [0097] The oxy cyclic ester obtained through the first and second steps described above is a practical high molecular weight biodegradable polymer that can be used as a poly (hydroxyalkyl oxyacetate) without any problem. It becomes. In other words, the oxycyclic ester of the present invention can produce a high-purity oxycyclic ester, and thus can obtain a high molecular weight poly (hydroxyalkyloxyacetic acid ester) force S having no practical problem. The obtained poly (hydroxyalkyloxyacetic acid ester) can be suitably used for medical materials such as sutures and medical devices by performing known and public processing.

[Method for producing cyclic dimer ester]

 Hereinafter, the manufacturing method of cyclic dimer ester by this invention is demonstrated in detail. The α-hydroxycarboxylic acid that can be used as one of the raw materials in the present invention is a compound represented by the following formula (5).

[0099] [Chemical 11]

(In the above formula (5), R ¹ and R ² may be the same as or different from each other, and each represents hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms; m = l) The a-hydroxycarboxylic acid condensate that can be used as one of the raw materials in the present invention is a compound represented by the following general formula (7), which is represented by the above formula (5). It is a condensate obtained by polycondensation of α-hydroxycarboxylic acid.

 [0101] [Chemical 12]

[In the above formula (7), R ¹ and R ² represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, which may be the same or different from each other. M represents an integer from 2 to 20000.)

 The α-hydroxycarboxylic acid and / or α-hydroxycarboxylic acid condensate used as a raw material in the present invention refers to the a-hydroxycarboxylic acid represented by the above formula (5) and the a-hydroxycarboxylic acid represented by the above formula (7). Carboxylic acid condensate power One or two or more selected compounds.

[0103] The linear alkyl group having 1 to 4 carbon atoms in R ¹ and R ² of the above formulas (5) and (7) is a methyl group, an ethyl group, an n-propyl group, or an n-butyl group. The branched alkyl group having 1 to 4 carbon atoms is an isopropyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group. Among these groups, a methyl group and an ethyl group are preferable.

[0104] In the compounds represented by formulas (5) and (7), as the combination of R ¹ and R ² , either one is hydrogen and the other is hydrogen or a linear or branched chain having 1 to 4 carbon atoms An alkyl group is preferred, and one of them is hydrogen and the other is more preferably a hydrogen atom or a methyl group or an ethyl group. One of them is hydrogen, the other is more preferably a hydrogen or methyl group, and both are hydrogen. It is particularly preferred.

[0105] Examples of the α-hydroxycarboxylic acid represented by the above formula (5) include glycolic acid, lactic acid, and a-hydroxypropionic acid. Among these compounds, preferably glyco Luric acid and lactic acid are preferred, and glycolic acid is more preferred.

 [0106] Commercially available glycolic acid can be used as the dalicholic acid. Further, recycled polyglycolic acid may be used as a raw material. Commercially available dalicholic acid contains glycolic acid condensates such as glycolyloxyglycolic acid (glycolic acid dimer) and glycolyloxyglycoloxyglycolic acid (glycolic acid trimer) in addition to glycolic acid. May have. These are effective in the production of cyclic dimer esters and can be comprehensively handled as glycolic acid species. The glycolic acid condensate is contained in an industrially available glycolic acid aqueous solution, and it is known that the glycolic acid condensate is produced only by heating and melting high-purity glycolic acid.

 [0107] Among the compounds and mixtures represented by the above formulas (5) and (7), glycolic acid, glycolic acid condensates, and mixtures thereof are preferred from the viewpoint of easy availability.

 [0108] The glycolic acid and its condensate can be obtained in the form of a powdery solid or an aqueous solution, but from the viewpoint of being easily available at a low cost, the aqueous solution is preferred.

 [0109] Examples of available glycolic acid aqueous solutions that can be used in the present invention include industrial 70% glycolic acid and GLYPURE70 manufactured by DuPont, 70% glycolic acid manufactured by Otsuka Chemical, and the like. . The glycolic acid aqueous solution preferably used is GLYPURE70 (registered trademark) manufactured by DuPont.

 [0110] In the production method of the present invention, when glycolic acid and its condensate are used as raw materials, the glycolic acid may be used as a powdered solid as it is, or may be used as the glycolic acid aqueous solution as described above.ヽ ヽ.

[0111] Normally, a commercially available aqueous solution of Daricholic acid is 70% by weight (concentration of total of Daricholic acid and glycolic acid condensate converted to Daricholic acid), but as glycolic acid When a glycolic acid aqueous solution is used, the concentration of glycolic acid is not particularly limited, and can be used in a wide concentration range. However, when considering the efficiency in production, that is, the unit price per reaction batch, that is, increasing the amount charged, shortening the dehydration time, and saving the energy required for dehydration, the glycolic acid concentration is 50 to 90 fold. A range of 60% by weight is more preferred. If it is in the said range, a polymer can be obtained efficiently in the first step.

 [0112] When glycolic acid is used as a raw material of the present invention, the purity of glycolic acid is not particularly limited. However, for example, a commercially available glycolic acid aqueous solution may contain compounds such as formic acid, diglycolic acid, dariosagilic acid, and oxalic acid as trace components. These compounds often inhibit the polymerization reaction, that is, block the growth terminal of the polymerization. Accordingly, the content of these compounds in the aqueous glycolic acid solution is preferably less than 0.5% by weight. When impurities are contained, those obtained by removing these compounds by adsorption treatment with activated carbon, vacuum distillation or stripping may be used.

 [0113] Further, from the viewpoint of obtaining a higher molecular weight poly (a-hydroxycarboxylic acid), the raw material a-hydroxycarboxylic acid and Z or α-hydroxycarboxylic acid condensate can be obtained by a known method, for example, the UK. Patent 550837 can be obtained by dehydration polycondensation by a method such as JP-A-6-65360 or by solid phase polymerization.

 [0114] For example, an ex-hydroxycarboxylic acid aqueous solution and soot or ex-hydroxycarboxylic acid condensate is used, and the pressure is adjusted to 1.0 to: L01. 3 in an inert gas atmosphere, preferably in a soot atmosphere.

 2

 kPa, preferably in the range of 1.0 to 20. OkPa, and the temperature force Sl00 to 250. Heat to C, preferably 140 to 200 ° C, to distill off water and condensed water in the system. The a-hydroxycarboxylic acid and Z or α-hydroxycarboxylic acid condensate obtained at this time are α-hydroxycarboxylic acid condensates having a molecular weight distribution. That is, in the formula (7), m = 2 to 50000, preferably m = 2 to 20000. In formulas (5) and (7), m = l and / or m = 2 to 20000 is the smallest molecular weight and the largest molecular weight measured by gel permeation chromatography. This is the width of the value obtained by dividing the molecular weight by the molecular weight of the α-hydroxycarboxylic acid monomer.

 [0115] The weight-average molecular weight in terms of ΡΜΜΑ determined by GPC measurement of α-hydroxycarboxylic acid and Ζ or α-hydroxycarboxylic acid condensate obtained as described above is usually 500 to 300,000. It is 5000-150000.

[0116] In the present invention, the weight average molecular weight and molecular weight distribution can be measured by GPC (gel permeation chromatograph) method after dissolving in a predetermined organic solvent. For example, Glico The measurement of phosphoric acid and Z or glycolic acid condensate was performed using HFIP (hexafluoroisopropyl alcohol) in which 0.05% by weight of sodium trifluoroacetate was dissolved in a solvent at 35 ° C, 1 mlZ min. KD—806M + KD—805L + KD—803), molecular weights of known PMMA with molecular weights of 1.6 million, 760,000, 210,000, 550,000, 220,000, 0.7000, and 20,000 A calibration curve obtained from the elution time by RI detection of (polymethylmethacrylate) standard was prepared in advance, the elution time of the measurement sample was obtained, and converted to the weight average molecular weight using the calibration curve.

 [0117] In addition, when ex-hydroxycarboxylic acid and Z or ex-hydroxycarboxylic acid condensate are calo-heated and water in the system is distilled off, it can be carried out without a catalyst. A catalyst may be used. Examples of catalysts used are stannous chloride, stannic chloride, stannous sulfate, stannous oxide, stannic oxide, tetraphenyltin, stannous octoate, stannous acetate, stannous acetate Tin-based catalysts such as ditin, titanium-based catalysts such as titanium tetrachloride, isopropionate titanate, butyl titanate, germanium-based catalysts such as metal germanium, germanium tetrachloride, germanium oxide, zinc oxide, triacid金属 Metallized catalysts such as antimony, lead oxide, acid aluminum, iron oxide, etc., organic sulfonic acid catalysts such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, phosphoric acid And mineral acid catalysts. These catalysts can be used alone or in combination of two or more.

When using the 0118] catalyst, the metal atoms based on the respect α- hydroxy carboxylic acid monomers 1 mol, preferably 1 X 10- ⁵ ~: L0- ² equivalents, more preferably 3 chi It is added at a rate of 10- ⁵ ~5 Χ 10- ² equivalents. The catalyst is added as it is, or dissolved or suspended in a suitable solvent. The accessory can be batched or divided. If the catalyst is substantially until the polycondensation reaction is completed, it can be added to the reaction system at the time of deviation.

[0119] The cyclic dimer ester obtained by the present invention contains the α-hydroxycarboxylic acid and

Amber or oc-hydroxycarboxylic acid condensate power This is a compound represented by the following general formula (6).

[0120] [Chemical 13]

(In the above formula (6), R ¹ and R ² represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, which may be the same or different from each other. )

In the above formula (6), the linear alkyl group having 1 to 4 carbon atoms represents a methyl group, an ethyl group, an n propyl group, and an n butyl group, and the branched alkyl group having 1 to 4 carbon atoms is an isopropyl group. , Isobutyl group, sec butyl group, and tert butyl group. Among these groups, a methyl group and an ethyl group are preferable. In the compound represented by the formula (6), as the combination of R ¹ and R ² , either one is hydrogen and the other is hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, It is particularly preferred that one of them is hydrogen and the other is hydrogen or a methyl group or an ethyl group, and one of them is more preferably hydrogen and the other is hydrogen or a methyl group, and more preferred is both hydrogen.

 [0122] Examples of the cyclic dimer ester represented by the above formula (6) include glycolide, which is a cyclic dimer of glycolic acid, lactide, which is a cyclic dimer of lactic acid, and α-hydroxypropionic acid. A cyclic dimer is mentioned. Among these compounds, glycolide and ratatide are preferable, and glycolide is more preferable.

 [0123] The method for producing a cyclic dimer ester according to the present invention is characterized in that it includes [first step] and [second step] described below. Hereinafter, each step will be described.

[0124] The first step of the production method of the cyclic dimer ester of the present invention is a cyclic dimer ester represented by the above formula (6) obtained by the present invention (hereinafter referred to as cyclic dimer ester (6)). This is a step of adding an alkylene glycol having a higher boiling point to α-hydroxycarboxylic acid and 及 び or α-hydroxycarboxylic acid condensate to obtain a polymerization solution by polymerization reaction. In the method for producing a cyclic dimer ester, the first step refers to the time until the above-described polymerization reaction is performed, the depolymerization in the second step described later occurs, and the cyclic dimer ester starts to distill. [0125] Hereinafter, the first step of the production method of the cyclic dimer ester of the present invention will be described in detail.

[0126] This first step is characterized in that an alkylene glycol having a boiling point higher than that of the cyclic dimer ester (6) is used.

 [0127] The alkylene glycol used in the first step is a liquid having a melting point of 100 ° C or lower, more preferably 70 ° C or lower, and has a higher boiling point than the cyclic dimer (6) obtained by the present invention. If it is alkylene glycol, it will not be restricted in particular!

 The boiling point 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”, and when measured under reduced pressure. Refers to the boiling point converted to normal pressure. The boiling point measured under reduced pressure was converted to the boiling point of atmospheric pressure based on the boiling point conversion chart of “Basic Organic Chemistry Experiment P155, Maruzen (1966); Kazuo Hata”.

 [0129] The boiling point of the alkylene glycol used in the present invention is not less than the boiling point of the cyclic dimer shown in the present invention, preferably not less than 5 ° C from the boiling point of the cyclic dimer and not more than 350 ° C from the boiling point of the cyclic dimer. More preferably, it is in the range of 50 ° C or more from the boiling point of the cyclic dimer and 300 ° C or less from the boiling point of the cyclic dimer, more preferably 100 ° C or more from the boiling point of the cyclic dimer. The range is 250 ° C or less from the boiling point of the polymer.

 [0130] As another preferred embodiment of the present invention, the boiling point of the alkylene glycol is preferably 30 ° C (converted to normal pressure (760mmHg)) or more higher than the boiling point of the cyclic ester to be formed. More preferably, it is higher than the boiling point by 50 ° C (converted to normal pressure (760mmHg)), and more preferably 70 ° C (converted to normal pressure (760mmHg)) or higher than the boiling point of the cyclic ester produced. U, which is more than 100 ° C (converted to normal pressure (760mmHg)) above the boiling point of the cyclic ester to be produced.

 [0131] When the boiling point of the alkylene glycol is in the above range, the alkylene glycol and the product cyclic dimer ester (6) can be easily separated in the second step described later.

 [0132] This first step is characterized in that alkylene glycol having a boiling point higher than that of the cyclic dimer ester (6) is used.

[0133] By adding such an alkylene glycol in the first step, the alkylene glycol The hydroxyl group of-and the terminal carbonyl group of -hydroxycarboxylic acid and Z or α-hydroxycarboxylic acid condensate react.

 Therefore, the first step is characterized in that an alkylene glycol having a boiling point higher than that of the cyclic dimer ester (6) is used.

 [0135] By adding such an alkylene glycol in the first step, the hydroxyl group of the alkylene dallicol reacts with the terminal carbonyl group of the a-hydroxycarboxylic acid and the Z- or α-hydroxycarboxylic acid condensate.

 Therefore, by using an alkylene glycol having a boiling point higher than that of the cyclic dimer ester (6) in the first step, the alkylene glycol, α-hydroxycarboxylic acid and Ζ or a-hydroxy are used. A copolymer with a carboxylic acid condensate is obtained, and the polymerization solution is uniform until the end of the first step, and high fluidity tends to be maintained.

 [0137] On the other hand, if the polymerization is performed without adding alkylene glycol in the first step, the polymer tends to be a homopolymer and has a high molecular weight, so that the resulting polymerization solution is uniform. In some cases, the fluidity may also decrease.

 [0138] The alkylene glycol used in the present invention is an aliphatic compound in which two hydroxyl groups are bonded to two different carbon atoms, and is a cyclic dimer ester obtained in the second step. Higher boiling point than. When the obtained cyclic dimer ester (6) is glycolide (boiling point: 240 ° C), for example, diethylene glycol (boiling point: 244 ° C), triethylene glycol (boiling point: 287 ° C), Examples include tetraethylene glycol (boiling point: 327 ° C), pentaethylene glycol (boiling point: 430 ° C), hexamethylene glycol (boiling point: 440 ° C), tripropylene glycol, and tetrapropylene glycol. Commercially available alkylene glycol can also be used.

 [0139] The above alkylene glycols may be used alone or in admixture of two or more.

 When the alkylene glycol used in the present invention is a mixture of two or more, the boiling point of the alkylene glycol having the lowest boiling point contained in the mixture is defined as the boiling point of the mixture.

[0140] Examples of the alkylene glycol used in the present invention also include polyalkylene glycols such as polyethylene glycol and polypropylene glycol. Preferably polyethylene Glycol and polypropylene glycol, more preferably polyethylene glycol.

 [0141] When polyalkylene glycol is used in the present invention, it does not substantially contain a component having a lower boiling point than the cyclic ester to be produced. For example, when polyethylene glycol is used in the production of glycolide, which is a cyclic dimer ester, the polyethylene glycol is substantially free of low-boiling components such as ethylene glycol. Most preferably, no low-boiling components such as ethylene glycol are contained.

 [0142] In the present invention, when the above polyalkylene glycol is used as the alkylene glycol, polyethylene glycol and polypropylene glycol are preferred from the viewpoint of not producing THF as a decomposition product. Further, polyethylene glycol is more preferable from the viewpoint of availability.

 [0143] The molecular weight of the alkylene glycol used in the present invention is not particularly limited as long as it has a boiling point equal to or higher than that of the cyclic dimer ester, but the molecular weight is preferably 100 or more and less than 900, more preferably 200 to less than 200. 800, more preferably 400 to 600. Moreover, the thing of a liquid at normal temperature is more preferable than an operation surface.

 [0144] When the alkylene glycol used in the present invention is a polymer, the molecular weight is the average molecular weight.

 When an alkylene glycol polymer is used as the alkylene glycol, the average molecular weight is a value obtained by determining its hydroxyl value, and the hydroxyl value power is also determined by a conversion formula.

[0145] For example, when the average molecular weight of polyethylene glycol is determined, it can be determined as follows.

 [0146] First, the hydroxyl value (B) was determined according to JIS K0070-1992 (Test method for acid value, saponification value, ester value, iodine value, hydroxyl value and unsaponified product of chemical products) 7.1 (neutralization titration method). Ask.

 The average molecular weight (A) is calculated by substituting the determined hydroxyl value (B) into the following conversion formula.

[0148] 56106 / B X 2 = A

(A: average molecular weight, B: hydroxyl value, 56106: conversion factor) The average molecular weight is preferably from 100 to less than 900, more preferably from 200 to 800, and even more preferably from 400 to 600. Also, liquids at room temperature are more preferred than the operation surface.

 [0149] The amount of alkylene glycol to be added is usually from 0.01 to 5 monolayer times the value obtained by converting α-hydroxycarboxylic acids and Z or α-hydroxycarboxylic acid condensate into OC-hydroxycarboxylic acid. Preferably, it is 0.01 to 1 monolayer times, more preferably 0.01 to 0.5 monole times.

 [0150] The number of moles is a value obtained by dividing the mass of the alkylene glycol used by the molecular weight of the alkylene glycol.

 [0151] When the amount of alkylene glycol used is within the above range, the flowability of the reaction solution, the purification rate of the target product, and the distillation rate are excellent.

 [0152] The addition method of the alkylene glycol may be in any order, either batchwise or divided. The alkylene glycol may be added to the reaction system at any time as long as the polycondensation reaction is substantially completed! /.

[0153] In the first step, the polymerization reaction may be performed without a catalyst or a catalyst may be used during the polymerization reaction. Examples of catalysts used include stannous chloride, stannic chloride, stannous sulfate, stannous oxide, stannic oxide, tetraphenyltin, stannous octoate, stannous acetate, stannic acetate Tin-based catalysts such as tin, titanium-based catalysts such as titanium tetrachloride, isopropionate titanate, butyl titanate, germanium-based catalysts such as germanium metal, germanium tetrachloride, germanium oxide, zinc oxide, antimony trioxide, Metalized catalysts such as lead oxide, aluminum oxide and iron oxide, organic sulfonic acid catalysts such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and toluene sulfonic acid, and mineral acid catalysts such as sulfuric acid and phosphoric acid The These catalysts can be used alone or in combination of two or more. When using a catalyst, the catalyst, the metal atom based, to α- hydroxy Shikarubon acid monomers 1 mol, preferably 1 X 10- ⁵ ~: L0- ² equivalents, more preferably 3 X 10- ^{5 to} 5 Χ 10— Add at a ratio of ² equivalents. The catalyst is added as it is, or dissolved or suspended in a suitable solvent. The accessory can be batched or divided. If the catalyst is substantially until the polycondensation reaction is completed, it may be added to the reaction system at the time of deviation. [0154] In the second step of the production method of the cyclic dimer ester shown in the present invention, the cyclic dimer ester (6) is heated while performing the reaction and distillation by heating the polymerization solution obtained in the first step. It is a process to obtain.

 [0155] Hereinafter, the second step will be described in detail. In this second step, the α-hydroxycarboxylic acid obtained in the first step and the polymer of Ζ or α-hydroxycarboxylic acid condensate and alkylendalicol are heated under normal pressure or reduced pressure to depolymerize. It is characterized by distilling the cyclic dimer ester while carrying out the reaction and distillation including

[0156] Hereinafter, the second step of the method for producing a cyclic dimer ester according to the present invention will be described in detail.

[0157] The present invention is characterized by using an alkylene glycol having a boiling point higher than that of the cyclic dimer ester (6) obtained in the second step.

[0158] The polymerization solution obtained in the first step contains a copolymer of a high-boiling alkylene glycol, a-hydroxycarboxylic acid, and a Z or α-hydroxycarboxylic acid condensate. This copolymer has hydroxyl groups at both ends.

[0159] The presence of hydroxyl groups at both ends of the polymer in the polymerization solution obtained in the first step allows only the depolymerization reaction to proceed efficiently even when heat-treated in the second step, and the resulting cyclic The yield of dimer ester is increased.

 [0160] On the other hand, when alkylene glycol is not added in the first step, the polymerization solution obtained in the first step becomes a homopolymer, and the homopolymer has a hydroxyl group and a carboxyl group at each end. Even if this polymerization solution is heat-treated, only the depolymerization reaction does not occur efficiently, and the polymerization reaction further proceeds. As a result, during the reaction in the second step, the homogeneity of the reaction solution may be impaired and the fluidity may be lowered, and the cyclic dimer ester tends not to be obtained in a high yield.

 [0161] Since the depolymerization reaction of the polymerization solution in the second step needs to be performed at a higher temperature than the polymerization reaction in the first step, the yield tends to decrease when the alkylene glycol contains a low-boiling component. .

[0162] Accordingly, since the alkylene glycol used has a higher boiling point than the cyclic dimer ester of the target product, the low-boiling components derived from the alkylene glycol tend not to distill out, and the purity of the target product yield Becomes higher. [0163] In the second step, even if the cyclic dimer ester as the depolymerization product is distilled, the reaction solution is uniform until the end of the reaction in the second step. When performing depolymerization and distillation, the polymerization solution has good fluidity, and the residual liquid in the distillation still after distillation is also fluid and easy to handle.

 [0164] Therefore, a cyclic dimer ester can be efficiently obtained with a high distillation rate of the cyclic dimer ester. The distillation rate is 0.20 gZmin or more, preferably 0.50 gZmin or more, and more preferably 0.80 gZmin or more. In the present invention, the distillation rate is obtained by dividing the yield of the cyclic dimer ester by the time from the start to the end of the distillation of the cyclic dimer ester.

 Therefore, the depolymerization reaction tends to proceed more efficiently as compared with the case where the polymer is produced without adding alkylene glycol.

[0165] The reaction temperature in the second step is not particularly limited as long as it causes a cyclic ester-forming reaction including depolymerization and can be distilled, but is preferably 50 to 300 ° C. ί or 100~250 ^o C, further [this preferably ί or 180~250 ^o C, especially [this Ru preferably ί or 180~230 ^o C der.

 [0166] The pressure during the reaction in the second step is preferably 101.3 to 0.1 lkPa, more preferably ί to 10.0 to 0.1 kPa, and further preferably ί to 3.0 to 0. lkPa. is there.

 [0167] The method for producing a cyclic dimer ester according to the present invention can provide a cyclic dimer ester in a high yield. The yield is usually 65% or more, preferably 75% or more, and more preferably 85% or more. The yield shown in the present invention is the yield of the cyclic dimer ester obtained in the second step, based on the amount of polycondensate of α-hydroxycarboxylic acid and Ζ or OC-hydroxycarboxylic acid condensate used in the first step. It means what was divided.

 [0168] Furthermore, according to the production method of the present invention, a cyclic dimer ester can be obtained efficiently and with high purity. Its purity is 98% or more, preferably 99% or more. The purity of the cyclic dimer ester shown in the present invention is 7 by gas chromatography using the absolute calibration curve method.

[0169] The cyclic dimer ester (6) obtained in the present invention can be polymerized as it is without re-purification by a conventionally known technique to produce a polyhydroxycarboxylic acid as a high molecular weight product. The That is, the cyclic dimer ester obtained by the production method according to the present invention is polymerized by adding a known and publicly used method, for example, a polymerization initiator and an esterification catalyst, to obtain a high molecular weight polyhydroxycarboxylic acid. Examples of the polymerization initiator used include aliphatic saturated alcohols such as methanol, ethanol monole, propanol, butanol, aminoleanolone, caplinolenoleconole, cyclohexanol, lauryl alcohol, cyclopentanol, Examples include cycloaliphatic alcohols such as cyclohexanol, glycols such as diethylene glycol, and phenols such as lactic acid, aminophenol, and acetophenone. The amount added of the cyclic dimer esters, 0.001 weight _^0/0, preferably from 0.002 to 0.2 wt%. The Ester catalyst used is the conventionally known organic tin series such as stannous dioctanoate and tin triphosphate, organoaluminum series such as trimethylaluminum, triethylaluminum, triisobutylaluminum, etc., jetylzinc, dibutylzinc, etc. These organic dumbbell-based catalysts can be used alone or in combination of two or more. The amount of added force is 0.001 to 1% by weight, preferably 0.002 to 0.5% by weight, based on the cyclic dimer ester. The preferred polymerization temperature is 50 to 300 ° C, more preferably 100 to 250 ° C, further preferably 180 to 250 ° C, and particularly preferably 180 to 230 ° C.

[0170] The cyclic dimer ester obtained through the first step and the second step described above is a purity that can be suitably used as a raw material for producing polyhydroxycarboxylic acid, which is a bioabsorbable polymer used for medical materials. Thus, a high molecular weight polyhydroxycarboxylic acid can be obtained by a known publicly known polymerization method. This polyhydroxycarboxylic acid has high purity and is produced from cyclic esters as raw materials.

In addition to general-purpose uses such as multilayer bottles and films, it can be suitably used for medical materials such as sutures and medical devices.

 Example

 [0171] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

[Production of Oxycyclic Ester]

Hereinafter, the production of the oxy cyclic ester will be described. In the examples of the production of the oxy cyclic ester, all the parts are based on weight. Also stirring load, oxy ring The purity and weight average molecular weight of the ester-like ester were measured by the following methods.

 (1) Stirring load

 Using a stirrer with an RZR2101 torque meter manufactured by Heidolph, the force applied to the stirring shaft (Ncm: -Euton centimeter) at a rotation speed of 200 rpm was measured.

 (2) Purity of oxy cyclic ester

Measured by gas chromatography. The instrument is GC-14A manufactured by Shimadzu Corporation, the detector is a hydrogen flame ionization detector (FID), and the column is a column (G300, φ: 1.2 mm x 40 m, film thickness: 2 m) manufactured by Chemicals Evaluation and Research Institute. It was. 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 lOmlZ. About 50 mg of the sample was dissolved in 10 ml of acetone, and 11 was injected for measurement. A calibration curve was prepared using a standard sample, and the purity of the cyclic ester was analyzed using the calibration curve.

 (3) Weight average molecular weight

Measured by gel permeation chromatography (GPC). The apparatus used was a sysdex em21 manufactured by Shodex. Using HFIP (hexafluoroisopropyl alcohol) in which 0.05% by weight of sodium trifluoroacetate was dissolved as a solvent, a column (SHODEX KD-806M + KD-805L + KD-803) was used at 35 ° C and lmlZ min. Through elution time by RI detection of PMMA (polymethyl methacrylate) standard materials with known molecular weights of 1.6 million, 760,000, 210,000, 550,000, 220,000, 0.7000, and 20,000 A calibration curve obtained from the above was prepared in advance. The elution time of the measurement sample was determined and converted to a PMMA equivalent weight average molecular weight using a calibration curve.

 (4) Measurement of low boiling point components in alkylene glycol

Measured by gas chromatography. The instrument is GC-14A manufactured by Shimadzu Corporation, the detector is a flame ionization detector (FID), and the column is a column (G205, φ: 1.2mm X 40m (film thickness: 2 μ τη) manufactured by Chemical Substance Evaluation Research Organization) The column temperature was held at 80 ° C for 7 minutes, then increased to 2 70 ° C at 10 ° C / min and held for 30 minutes.Indication temperature was 300 ° C, detector temperature was 300 ° C, carrier Nitrogen was used as the gas at a flow rate of 20 ml Z. Approximately lOOmg of the sample was dissolved in 10 ml of acetone, and 1 μ 1 was injected, and a calibration curve was prepared using a standard sample in advance. Each component was analyzed. The results are as follows.

 [0173] [Table 1]

 [Synthesis Example 1]

96 weight _^0/0 Mizusani匕sodium 170 g (4. 08 Monore) and ethylene glycol Honoré 1241. 4g was heated to (20.0 mol) and the reaction vessel to feed 130 ° C. Thereafter, 97.6 g of water was distilled off from the system while azeotropically dehydrating 40 g of toluene. Thereafter, the temperature was lowered to 100 ° C., and 189 g (2.0 mol) of monochloroacetic acid was charged over 1 hour, followed by further stirring for 1.5 hours. Subsequently, 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 monohydroxyethoxyacetate. The extraction yield of sodium hydroxyethoxyacetate at this time was 88.1% with respect to the monochloroacetic acid charged. Subsequently, after adding 670 g of 60% aqueous methanol to 371.2 g of sodium j8-hydroxyethoxyacetate obtained and heating to 70 ° C., 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 give 335.6 g of sodium 3-hydroxyethoxyacetate. The purification yield of sodium hydroxyethoxyacetate at this time was 82.3% with respect to the monochloroacetic acid charged. Subsequently, the resulting j8- hydroxyethoxy acetate Na Bok potassium 335. 6 g of water 367g was added to, hydroxyethoxy acetic acid was neutralized with 35.7 weight _^0/0 hydrochloric acid aqueous 168. 9g (l. 65 molar) 871.5 g of aqueous solution was obtained.

 (Example 1A)

[First step] Tetraethylenedaricol (boiling point: 314 ° C) 32g (0.16mol) was added to the hydroxyethoxyacetic acid aqueous solution 435.8g (hydroxyethoxyacetic acid 1.0mol) obtained in Synthesis Example 1. In addition, water was distilled off under conditions of a pressure of 8.7 kPa and a temperature of 65 ° C. (dehydration rate: 99%), 188 g of acetone was added for crystallization and filtration, and the filter cake was washed with 145 g of acetone. Further, the 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 removed, and the pressure was 101.3 MPa and the temperature was 110 ° C to 150 ° C. The polymerization reaction was carried out with azeotropic dehydration. Since the theoretical distillation rate reached 99%, the polymerization reaction was terminated. The stirring load of this polymerization solution was 40 Ncm at 30 ° C and 30 Ncm at 80 ° C, and the weight average molecular weight of the polymer in the polymerization solution was 6800.

 [Second step] Subsequently, the polymerization solution obtained in the first step itself was heated in a reaction vessel at a pressure of 1.3 kPa at 150 ° C for 3 hours while simultaneously performing depolymerization and distillation. 75.6 g of distillate was obtained. The purity of P-dioxanone in the distillate was 99.8% by weight, and the removal yield of P-dioxanone (boiling point: 212 ° C) was 73.9% in terms of monochloroacetic acid. The stirring load of the residue after distillation was 40 Ncm at 30 ° C, 30 Ncm at 80 ° C, and the weight average molecular weight of the residue was 5000.

(Comparative Example 1A)

 [First Step] The first step was carried out in the same manner as in Example 1 except that tetraethylene glycol was not added to 435.8 g of the hydroxyethoxyacetic acid aqueous solution obtained in Synthesis Example 1. At the end of the first step, the stirring load of the polymerization solution was 40 Ncm at 30 ° C, 30 Ncm at 80 ° C, and the weight average molecular weight of the polymer was 15000.

 [Second step] Subsequently, the polymerization solution obtained in the first step itself was heated in a reaction vessel at a pressure of 1.3 kPa at 150 ° C for 12 hours while simultaneously performing depolymerization and distillation. And 65.5 g of distillate was obtained. The purity of P-dioxanone in the distillate was 99.7% by weight, and the yield of P-dioxanone was 63.9% in terms of monochloroacetic acid. The residue in the kettle immediately after distillation was a viscous liquid that solidified when cooled to room temperature and left to stand. The stirring load of the residue after distillation was 110 Ncm at 30 ° C, 100 Ncm at 80 ° C, and the weight average molecular weight of the residue was 19000.

(Example 3A)

Example 1 Tetraethylene glycol of 1A and polyethylene glycol having an average molecular weight of 400 (boiling point: 314 ° C: ethylene glycol, diethylene glycol and triethylene glycol) P-dioxanone was obtained in the same manner as in Example 1, except that the change was changed to “not detected”. The stirring load of the polymerization solution obtained in the first step was 40 Ncm at 30 ° C and 30 Ncm at 80 ° C, and the weight average molecular weight of the polymer in the polymerization solution was 8000. In the second step, 78.6 g of p-dioxanone having a purity of 99.7% was distilled out by heating for 3 hours. The yield of p-dioxanone was 76.7% in terms of monochloroacetic acid. The stirring load of the residue after distillation was 40 Ncm at 30 ° C and 30 Ncm at 80 ° C, and the weight average molecular weight of the residue was 7000. (Reference Example 1A)

 70 g (0.69 mol) of P-dioxanone obtained in Example 1, 60 mg of lauryl alcohol and 70 mg of stannous octoate were added and reacted at 90 ° C. for 10 hours. The resulting poly (p-dioxanone) had a weight average molecular weight of 300,000.

[Production of cyclic dimer ester]

 Hereinafter, production of the cyclic dimer ester will be described.

[0176] The main physical properties in the production of the cyclic dimer ester according to the present invention were measured by the following methods.

 [0177] (1) Weight average molecular weight (polymer obtained in the first step)

 It was measured by gel permeation chromatography (GPC). The apparatus used was sy stem21 manufactured by Shodex. Column with HFIP (hexafluoroisopropyl alcohol) dissolved in 0.05% by weight of sodium trifluoroacetate at 35 ° C and lmlZ min. (SHODE X KD—806M + KD—805L + KD—803) Elution of PMMA (polymethyl methacrylate) standard substances with molecular weights of 1.6 million, 760,000, 210,000, 550,000, 220,000, 70,000, and 20,000 by RI detection A calibration curve obtained from the time was prepared in advance. The dissolution time of the measurement sample was determined, and converted to PMMA equivalent weight average molecular weight using a calibration curve.

 [0178] (2) Melting point (Tm)

 Using a DSC-60 series differential thermal analyzer manufactured by Shimadzu Corporation, the measurement was performed under the following conditions.

 [0179] In the case of a-hydroxycarboxylic acid polycondensate, about 10 mg of sample is packed in an aluminum pan, heated from room temperature to 280 ° C at a rate of 10 ° CZ under a nitrogen stream of 50 mlZ, and endothermic. The peak temperature was taken as the melting point.

[0180] In the case of cyclic dimer ester, about 10 mg of sample is packed in an aluminum pan, Under a nitrogen stream, the temperature was raised from room temperature to 150 ° C at a rate of 5 ° CZ, and the endothermic peak temperature was taken as the melting point.

 (3) Analysis of glycolic acid (high performance liquid chromatographic method)

Sho (16 column 1 ^ ₁ ^ 1 ^ «-811) was connected to a high-performance liquid chromatograph (PU-1580, UV-970, CO-965) manufactured by Enomoto Spectroscopy, and 0.05% phosphoric acid aqueous solution was eluted. The sample was analyzed by an internal standard method at a column temperature of 35 ° C, an eluent flow rate of 0.8 mlZ, and a wavelength of 210 nm.

 (4) Moisture analysis in glycolic acid (force Fischer method)

In the Karl Fischer moisture meter MCK-510N manufactured by Kyoto Electronics Co., Ltd., analysis was performed using Riedel De Haan Hydranal Claw Mat A as the generation solution and Riedel De Haan Hydranal Chromat CG-K as the counter electrode solution.

 (5) Purity of glycolide (gas chromatographic method)

Measured by gas chromatography. The instrument is GC-14A manufactured by Shimadzu Corporation, the detector is a hydrogen flame ionization detector (FID), and the column is a column (G250, 1.2 mm X 40 m, film thickness: 2 μm) manufactured by the Chemical Substance Evaluation Research Organization. It was. The column temperature was 150 ° C, the injection temperature was 290 ° C, the detector temperature was 290 ° C, and nitrogen was used as the carrier gas at a flow rate of lOmlZ. About 50 mg of the sample was dissolved in 10 ml of acetone, and 31 was injected for measurement. First, a calibration curve was prepared using a standard sample, and the purity of glycolide was analyzed using the calibration curve.

 (6) Yield

The yield was calculated by the following formula.

Yield (%) = (aZb) X 100

a: Yield of cyclic dimer ester (g)

b: Weight polycondensate amount of α-hydroxycarboxylic acid and / or a-hydroxycarboxylic acid condensate used in the first step (g)

 (7) Distillation speed

 The distillation rate was calculated by the following formula.

Distillation rate (gZmin) = aZt a: Yield of cyclic dimer ester (g)

 t: Time from the start to the end of distillation of the cyclic dimer ester (min)

 (8) Measurement of low boiling point components contained in alkylene glycol

 Measured by gas chromatography. The instrument was GC-14A manufactured by Shimadzu Corporation, the detector was a flame ionization detector (FID), and the column was a column (G205, φ: 1.2 mm x 40 m (film thickness: 2 m), manufactured by Chemicals Evaluation and Research Institute. The column temperature was held at 80 ° C for 7 minutes, then heated to 270 ° C at 10 ° C / min and held for 30 minutes.Injection temperature was 300 ° C, detector temperature was 300 ° C, carrier gas Nitrogen was used at a flow rate of 20 ml Z. Approximately lOO mg of sample was dissolved in 1 O ml of acetone, and 1 μ1 was injected and measured, and a calibration curve was prepared using a standard sample. Each component was analyzed using a calibration curve.

 The results are as follows.

[0181] [Table 2]

 [0182] The present invention will be specifically described below with reference to experimental apparatuses, synthesis examples, examples, and comparative examples.

 (Experimental device)

 A 500π four-necked flask was connected with a stirring blade, thermometer, and distillation line, and a vacuum line and a receiver were attached to the outlet of the distillation line. A mantle heater is used to heat the flask, and the distillate line is kept at 90 ° C using a ribbon heater to prevent solidification of the cyclic dimer ester, and the receiver is kept at 90 ° C using an oil bath. We used what we did.

 (Synthesis Example 1B)

A 500 ml flask was charged with 500 g of an aqueous glycolic acid solution. Under atmospheric pressure, with stirring, the temperature was raised to 140 ° C over 2 hours, and the produced water was distilled off. Glico used here The composition of the aqueous oxalic acid solution is as follows. Analysis was performed by high performance liquid chromatography and Karl Fischer methods.

 Glycolic acid 58.4 wt%

 Glycolic acid dimer 9.9 wt%

 Oxalic acid 0.01% by weight

 Water 29.8% by weight

Next, the internal pressure was reduced to 6. OkPa, the temperature was raised to 200 ° C., and the produced water was further distilled to obtain a glycolic acid condensate (1). The resulting condensate had a weight average molecular weight of 8000 (m = 1 to 902) and a melting point (Tm) of 215 ° C.

(Synthesis Example 2B)

 A 500 ml flask was charged with 500 g of the aqueous glycolic acid solution used in Synthesis Example 1B. The temperature was raised to 140 ° C over 2 hours with stirring under atmospheric pressure to distill the product water. Next, the internal pressure was reduced to 6. OkPa and maintained at 140 ° C., and the produced water was further distilled to obtain a glycolic acid condensate (2). The resulting condensate had a weight average molecular weight of 6000 (m = 1 to 777) and T m of 172 ° C.

(Synthesis Example 3B)

The glycolic acid condensate (1) obtained in Synthesis Example 2B was pulverized, and the obtained pulverized product was sieved to fractionate a pulverized product having a diameter of 1.0 to 2.8 mm. The separated pulverized product was filled in a SUS column tube and heated at 200 ° C. for 20 hours under a nitrogen stream. After completion of the heating, the mixture was cooled to room temperature to obtain a glycolic acid condensate (3). The resulting condensate had a weight average molecular weight of 410,000 (m = 1-3123) and Tm of 228 ° C.

(Synthesis Example 4B)

The glycolic acid condensate (3) obtained in Synthesis Example 3B was filled again into a SUS column tube and further subjected to solid phase polymerization under a nitrogen stream at 220 ° C. for 20 hours to obtain a glycolic acid condensate (4). . The resulting condensate has a weight average molecular weight of 72,000 (m = 1 to 4949) and a Tm of 232 ° C.

 (Synthesis Example 5B)

In Synthesis Example 4B, the glycolic acid condensate (4) obtained above is packed again into a SUS column tube. Further, solid state polymerization was performed under a nitrogen stream at 220 ° C. for 20 hours to obtain a glycolic acid condensate (5). The obtained condensate had a molecular weight of 10,000,000 (m = l to 7995) and Tm of 236 ° C. (Example IB)

As a first step, 270 g of the glycolic acid condensate (1) obtained in Synthesis Example 1B was charged into a 500 ml flask, and polyethylene glycol 400 [PEG # 400 (liquid), Wako Pure Chemical Industries, Ltd., boiling point 314 ° C: Ethylene glycol, diethylene glycol and triethylene glycol are not detected (catalog value: boiling point 450 ° C or higher), freezing point 4-8 ° C, weight average molecular weight about 400 (hereinafter referred to as PEG # 400)] It was. Under a nitrogen atmosphere: 1. A mixture of glycolic acid condensate and PEG # 400 was heated to 230 ° C under reduced pressure of OkPa. The polymerization reaction proceeds by this heating. It was confirmed by visual observation that the obtained polymer was uniformly dissolved in polyethylene glycol 400, fluidity was ensured, and no phase separation was observed. By continuing the heating, the depolymerization reaction was started, and the cyclic dimer ester glycolide (GLD) was distilled out and accumulated in the receiver, and the second step was started. The glycolide was collected by heating at the above temperature until the distillation of glycolide substantially stopped. Distillation time was 270 minutes. When the inside of the flask was observed after completion of the distillation, a residue was present. In both the first step and the second step, the flowability of the polymer could be operated without any particular problems. Distillate was found adhering to the distilling line between the flask and the receiver, but the accumulated amount was very small. It was glycolide (melting point: 92-93 ° C, boiling point: 240 ° C) collected in the receiver, and the yield was 88% and the purity was 99.86%. The distillation rate was 0.87 gZmin.

(Example 2B)

The same operation as in Example 1B was performed except that the addition amount of PEG # 400 was changed to 53.3 g. It was visually confirmed that the polymer obtained in the first step was uniformly dissolved with PEG # 400, fluidity was ensured, and no phase separation was observed. By further heating, the depolymerization reaction started, and the generated cyclic dimer ester, glycolide (GLD), distilled out and accumulated in the receiver, and the second step was started. The distillate was collected by heating in the above temperature range (230 ° C.) until the distillation of the cyclic dimer ester (glycolide) substantially stopped. After completion of the distillation, the inside of the flask was observed, and polycondensate and PEG # 400 were observed as residues. Distillate was found adhering to the distilling line between the flask and the receiver, but the accumulated amount was small. It was small. The cyclic dimer ester collected in the receiver was glycolide, and the yield was 88.1% and the purity was 99.83%. The distillation rate was 0.54 gZmin.

(Example 3B)

As a first step, 206.2 g of the glycolic acid condensate (4) prepared in Synthesis Example 4B was charged into a 500 ml flask, and 82.6 g of PEG # 400 was added. Under a nitrogen gas atmosphere: 1. A mixture of glycolic acid condensate and PEG # 400 was heated to 230 ° C under reduced pressure of OkPa. This heating causes the polymerization reaction to proceed. It was confirmed by visual observation that the obtained polymer was uniformly dissolved with PEG # 400, fluidity was ensured, and no phase separation was observed. By further heating, the depolymerization reaction started, and the produced cyclic dimer ester (glycolide) was distilled out and accumulated in the receiver, and the second step was started. The distillate was collected by heating in the above temperature range until the distillation of the cyclic dimer ester (dalicolide) substantially stopped. After completion of the distillation, the inside of the flask was observed, and polycondensate and PEG # 400 were seen as residues. The distillate line between the flask and the receiver was found to have a cyclic dimer ester, but the accumulated amount was very small. The cyclic dimer ester collected in the receiver was glycolide, and the yield was 89.3% and the purity was 99.85%. Distillation rate is 2. 05gZmin and 7 at a time.

(Example 4B)

As a first step, 20.5 g of the glycolic acid condensate (3) prepared in Synthesis Example 3B was charged to a 500 ml flask, and PEG # 400 84.9 g was released. Under a honey-gas atmosphere, vigorously: 1. A mixture of glycolic acid condensate and PEG # 400 was heated to 230 ° C under reduced pressure of OkPa. By this heating, the polymerization reaction proceeds. The obtained polymer was uniformly dissolved with PEG # 400, and it was visually confirmed that no phase separation occurred. By further heating, the depolymerization reaction was started, and the produced cyclic dimer ester (glycolide) was distilled out and accumulated in the receiver, and the second step was started. The distillate was collected by heating in the above temperature range until the distillation of the cyclic dimer ester (glycolide) substantially stopped. After completion of the distillation, the inside of the flask was observed, and polycondensate and PEG # 400 were found as residues. The distillate line between the flask and the receiver was found to have a cyclic dimer ester, but the amount accumulated was small. The cyclic dimer ester collected in the receiver is glycolide, and the yield is 86.3. The purity was 99.80%. The distillation rate was 0.87 gZmin.

(Example 5B)

As the first step, 189.4 g of the glycolic acid condensate (5) prepared in Synthesis Example 5B was charged into a 500 ml flask, and 80.2 g of PEG # 400 was added. Under a nitrogen gas atmosphere: 1. A mixture of glycolic acid condensate and PEG # 400 was heated to 230 ° C under reduced pressure of OkPa. This heating causes the polymerization reaction to proceed. It was confirmed by visual observation that the obtained polymer was uniformly dissolved with PEG # 400, fluidity was ensured, and no phase separation was observed. By further heating, the depolymerization reaction was started, and the produced cyclic dimer ester was distilled out and accumulated in the receiver, and the second step was started. Heat at a temperature of 230 ° C until the distillate of the cyclic dimer substantially stops, then heat at a temperature of 250 ° C until the distillate of the cyclic dimer stops practically. Was collected. After completion of distillation, the inside of the flask was observed, and polycondensate and PEG # 400 were found as residues. In the distilling line between the flask and the receiver, the force in which the cyclic dimer ester was found to adhere was very small. The cyclic dimer ester collected in the receiver was glycolide, and the yield was 95.9% and the purity was 99.83%. The distillation rate was 0.76 gZmin.

(Example 6B)

In the first step, polyethylene glycol with a depolymerization temperature of 230 ° C and PEG # 400 molecular weight of about 600 [PEG # 600 (liquid) manufactured by Wako Pure Chemical Industries, Ltd., boiling point 314 ° C: ethylene glycol, diethylene glycol and triethylene glycol Except that ethylene glycol was not detected (catalog value: boiling point 450 ° C or higher), freezing point 15 to 25 ° C, molecular weight about 600 (hereinafter referred to as PEG # 600)], the same as in Example 1B Glycolic acid condensate strength also produced a cyclic dimer ester (dalicolide). It was visually confirmed that the polymer obtained in the first step was uniformly dissolved with PEG # 600 and was not phase-separated. By further heating, the depolymerization reaction was started, and the produced cyclic dimer ester was distilled off and accumulated in the receiver, and the second step was started. The distillate was collected by heating in the above temperature range until the distillation of the cyclic dimer ester (glycolide) substantially stopped. After completion of the distillation, the inside of the flask was observed, and polycondensate and polyethylene glycol 600 were observed as residues. The distillate line between the flask and the receiver showed cyclic dimer ester adhesion, but the accumulation amount was very small. there were. The cyclic dimer ester collected in the receiver was glycolide, the yield was 85.2%, and the purity was 99.86%. The distillation rate was 0.57 gZmin.

(Example 7B)

 Polyethylene glycol with a depolymerization temperature of 230 ° C and PEG # 400 of about 1000 molecular weight [PEG # 1000 (bulk) made by Wako Pure Chemical Industries, Ltd., boiling point 430 ° C: ethylene glycol, diethylene glycol, triethylene glycol and tetraethylene Glycol was not detected (catalog value: boiling point 450 ° C or higher), freezing point 30 to 40 ° C, molecular weight about 1000 (hereinafter referred to as “PEG # 1000”;))] Thus, a cyclic dimer ester (glycolide) was also produced with the glycolic acid condensate power. The polymer obtained in the first step was uniformly dissolved with PEG # 1000, and it was confirmed by visual observation that it was not phase-separated, but the fluidity was bad. By further heating, the depolymerization reaction was started, and the produced cyclic dimer ester (glycolide) was distilled out and accumulated in the receiver, and the second step was started. However, the polymer in the flask was so viscous that it was difficult to stir and foaming was intense. The distillate was collected by heating in the above temperature range (230 ° C.) until the distillation of the cyclic dimer ester (glycolide) substantially stopped. After completion of the distillation, the inside of the flask was observed, and polycondensate and PEG # 1000 were found as residues. The distillate line between the flask and the receiver was found to have attached cyclic dimer ester, but the accumulated amount was very small. The cyclic dimer ester collected in the receiver was glycolide and had a purity of 99.82%, a yield of 76.0%, and a distillation rate of 0.23 gZ min.

(Comparative Example 1B)

According to WO2002Z083661 Publication Example (Example 1), glyceric acid condensate (1) 100 g obtained in Synthesis Example 1B, tetraethylene glycol dimethyl ether (hereinafter “TEGDME” t) ) 200g, and polyethylene glycol # 300 [(PEG # 300 (liquid) manufactured by Wako Pure Chemical Industries, Ltd.), boiling point 287 ° C: ethylene glycol and diethylene glycol are not detected, triethylene glycol (boiling point 287 ° C) is 2 1% detection (catalog value: boiling point 400 ° C or higher), molecular weight of about 300, (hereinafter referred to as “1¾0 # 300”) 42 ₈ (equivalent to 0.28 mol of alcoholic hydroxyl group) Then, it was heated to 260 ° C. At this time, the oligomer obtained from the glycolic acid condensate (1) was uniformly dissolved with TEGDME and PEG # 300, and the phase fraction was It was confirmed visually that they were not separated. When the depolymerization reaction was carried out under reduced pressure, the distillate collected from the vicinity of 25. OkPa in the vacuum, and it was difficult to perform stable operation due to bumping of the contents of the flask. After the distillation was completed, the distillate in the receiver was prayed by GC and found to be TEGDME containing 3% of the cyclic dimer ester of the amount of the condensate charged. After the TEGDME distillation, the pressure was further reduced to 3. OkPa and the operation was continued. As a result, cyclic dimer ester accumulated in the distillation receiver. Distillate was collected by heating in the above temperature range until distillation of the cyclic dimer ester substantially stopped. After completion of the distillation, the inside of the flask was observed, and polycondensate and PEG # 300 were observed as residues. In the distillation line between the flask and the receiver, the force in which the cyclic dimer ester was found to adhere was very small. The distillate collected in the receiver was the low-boiling fraction contained in glycolide and PEG # 300, with a purity of 85.68%, yield of 58%, and a distillation rate of 0.53 gZmin. there were. (Comparative Example 2B)

According to Example (Example 1) of JP-A-63-152375, 200 g of glycolic acid recrystallized from Dupont Dali Pure 99 using an aqueous medium, 400 g of DuPont Teracol-1000 (molecular weight 1000), and triacid匕 200 after caloring antimony 0. 05g. C, 30. OkPa treatment gave copolymerized prepolymers. At this time, 31.5 g of distillate was collected in the receiver, and the distillate in the receiver was analyzed by GC. As a result, it was 20% THF and 80% water. Furthermore, although the heating was continued, THF was contained in the cyclic dimer ester that was distilled off, so the reaction was stopped.

(Comparative Example 3B)

In Example 1B, the depolymerization temperature was changed to two steps of 230 ° C and 250 ° C, and PEG # 400 was not added, and the cyclic dimer ester was converted from the glycolic acid condensate in the same manner as in Example 1B. Manufactured. By further heating the polymer obtained in the step corresponding to the first step of the present invention, the depolymerization reaction is started, and the produced cyclic dimer ester is distilled out and collected in a receiver. A process corresponding to the second process of the invention has started. The mixture was heated at 230 ° C until the distillation of the cyclic dimer ester substantially stopped and collected in a receiver. The purity of the distillate was 99.68%, the yield was 32.7%, and the distillation rate was 0.45 gZmin. Then, at 250 ° C, heat until the distillation of the cyclic dimer ester stopped practically. I collected things. After completion of the distillation, the inside of the flask was observed, and a polycondensate was seen as a residue. The distillate line between the flask and the receiver was found to have a cyclic dimer ester, but the accumulated amount was very small. The cyclic dimer ester collected in the receiver was glycolide with a purity of 99.68%, a yield of 4.5%, and a distillation rate of 0.19 gZmin (Comparative Example 4B).

In Example 1B, the temperature is 230 ° C, PEG # 400 is polyethylene glycol having a molecular weight of about 200 (PEG # 200 (liquid) manufactured by Wako Pure Chemical Industries, Ltd., boiling point 244 ° C: ethylene glycol not detected, diethylene glycol ( (Boiling point 244 ° C) is 3.2% detected, triethylene glycol (boiling point 287 ° C) is 21.8% detected (catalog value: boiling point 400 ° C or higher), molecular weight about 200, (hereinafter referred to as “PEG # 200 ")] except that the change was made to Example 1B. It was visually confirmed that the polymer obtained in the first step was uniformly dissolved with PEG # 200, fluidity was ensured, and no phase separation was observed.

 By further heating, the depolymerization reaction started, the distillate accumulated in the receiver, and the second step started. Distillate was collected by heating in the above temperature range until distillation stopped substantially. After completion of distillation, the inside of the flask was observed, and polycondensate and PEG # 200 were found as residues. In the distilling line between the flask and the receiver, the amount of force and deposits observed was small. The distillate collected in the receiver was the low-boiling fraction contained in glycolide and PEG # 200, purity 71.4%, yield 77.9%, and distillation rate was 0.80g. / te in mill.

(Comparative Example 5B)

A cyclic dimer ester was produced from a glycolic acid condensate in the same manner as in Example 3B except that PEG # 400 was changed to PEG # 200. It was visually confirmed that the polymer obtained in the first step was uniformly dissolved with PEG # 200 and was not phase-separated. By continuing the heating, the depolymerization reaction was started, the produced cyclic dimer ester was distilled off, accumulated in the receiver, and the second step was started. The distillate was collected by heating in the above temperature range (230 ° C.) until the distillation of the cyclic dimer ester substantially stopped. After completion of the distillation, the inside of the flask was observed, and polycondensate and PEG # 200 were seen as residues. Between flask and receiver The distillate line had a cyclic dimer ester attached, but the accumulated amount was very small. The distillate collected in the receiver was the low-boiling fraction contained in glycolide and PEG # 200, with a purity of 72.8%, a yield of 79.3%, and a distillation rate of 0.81 gZmin. Met. The results are summarized in Table 3.

[Table 3]

 GA condensate: glycolic acid and glycolic acid condensate, GLD: glycolide, PEG # 400: Polyethylene glycol (PEG # 400, manufactured by Wako Junna Co., Ltd., molecular weight about 400) GA condensate molecular weight: glycolic acid and glycolic acid Weight average molecular weight of condensate, PEG # 2∞: Polyethylene glycol (PEG # 200, molecular weight of about 200, manufactured by Wako Junna Co., Ltd.) PEG / GA ratio: alkylene glycol / (glycolic acid and glycolic acid condensation) Product), PEG «00: Polyethylene glycol (PEG # 300, W about Sako 300, Wako Pure Chemical Industries, Ltd.)

PEG # 1000: Polyethylene glycol (PEG # 1000, molecular S approx. 1000, manufactured by Wako Junna)

To 250 g of glycolide obtained in the same manner as in Example 4B, 300 Oppm of lauryl alcohol and 30 ppm of tin octoate were charged, and after nitrogen substitution, the temperature was raised from room temperature to 210 ° C over 2 hours. After holding at C for 30 minutes, the temperature was raised to 230 ° C and held for 1 hour. Thereafter, it was cooled and the polymerized product was taken out. The obtained polydaricholic acid had a weight average molecular weight of 210,000 and a melting point of 221 ° C.

 Industrial applicability

[0188] According to the method for producing a cyclic ester of the present invention, an oxy cyclic ester such as p-dioxane can be efficiently obtained. Furthermore, according to the method for producing a cyclic ester of the present invention, a cyclic dimer ester such as dalicolide can be obtained with high purity and efficiency.

[0189] The P-dioxanone, glycolide, and the like obtained by the present invention can be used without any problem in the bioabsorbable suture field that is currently in practical use in the medical field.

Claims

[Claim 1] Using at least one compound represented by the following formula (1) as a raw material,

[In the above formula (1), Z represents oxygen or a linear or branched oxyalkyleneoxy group having 2 to 20 carbon atoms, and R ¹ and R ² may be the same or different from each other, Represents a linear or branched alkyl group having 1 to 4 carbon atoms, and p represents an integer of 1 to 20000. ]

 A method for producing a cyclic ester represented by the following formula (2):

[In the above formula (2), X represents a carbonyl group, or a substituted or unsubstituted methylene group, and R ³ and R ⁴ may be the same or different from each other, hydrogen or C 1-4 A linear or branched alkyl group is shown, and n is an integer of 1 to 4. [First Step] A step of adding an alkylene glycol having a boiling point higher than that of the produced cyclic ester (2) to the compound (1) to carry out a polymerization reaction to obtain a polymerization solution,

[Second Step] The step of heating the polymerization liquid obtained in the first step to simultaneously carry out the reaction and distillation while obtaining a cyclic ester having a purity of 98% or more,

A method for producing a cyclic ester comprising the two steps.

 Using hydroxyalkyloxyacetic acid represented by the following formula (3) as a raw material,

[Chemical 3]

 [In the above formula (3), R and R are the same or different and each represents hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, and n is 1 to 4 Indicates an integer

. ]

 A method for producing an oxycyclic ester represented by the following formula (4):

 [Chemical 4]

 [In the above formula (4), R and each independently represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, and n represents 1 to 4 O to indicate an integer

 [First Step] To the hydroxyalkyloxyacetic acid (3), an alkylene glycol having a boiling point higher than that of the produced oxycyclic ester (4) is added, and a polymerization reaction is performed to obtain a polymerization solution. Process,

 [Second Step] While the polymerization liquid obtained in the first step is heated to carry out the reaction and distillation at the same time, the oxy cyclic ester comprising the two steps of obtaining the oxy cyclic ester (4) is obtained. How to manufacture.

 [3] The method for producing an oxycyclic ester according to [2], wherein the hydroxyalkyloxyacetic acid (3) is β-hydroxyethoxyacetic acid.

 [4] The raw material is ex hydroxycarboxylic acid and お よ び or ex hydroxycarboxylic acid condensate represented by the following formula (5):

[Chemical 5]

[In the above formula (5), R ¹ and R ² represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms, which may be the same or different, and m is Indicates an integer from 1 to 20000. ]

 A method for producing a cyclic dimer ester represented by the following formula (6):

 [Chemical 6]

[In the above formula (6), R ¹ and R ² represent hydrogen or a linear or branched alkyl group having 1 to 4 carbon atoms which may be the same or different, and m is Indicates an integer from 1 to 20000. ]

 [First Step] An alkylene glycol having a boiling point higher than that of the produced cyclic dimer ester (6) is added to the α-hydroxycarboxylic acid and / or the α-hydroxycarboxylic acid condensate (5). A step of performing a polymerization reaction to obtain a polymerization solution,

 [Second Step] The step of obtaining the cyclic dimer ester (6) while simultaneously heating and reacting the polymerization solution obtained in the first step!

 A process for producing a cyclic dimer ester comprising the two steps.

[5] The cyclic dimer ester according to claim 4, wherein the ex hydroxycarboxylic acid and Ζ or (X hydroxycarboxylic acid condensate (5) are glycolic acid and Ζ or glycolic acid condensate. How to manufacture.

6. The method for producing a cyclic ester according to claim 4 or 5, wherein the molecular weight of the alkylene glycol used in the first step is in the range of 100 to 900.