WO2006129736A1 - Procédé pour produire un ester cyclique - Google Patents

Procédé pour produire un ester cyclique Download PDF

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Publication number
WO2006129736A1
WO2006129736A1 PCT/JP2006/310937 JP2006310937W WO2006129736A1 WO 2006129736 A1 WO2006129736 A1 WO 2006129736A1 JP 2006310937 W JP2006310937 W JP 2006310937W WO 2006129736 A1 WO2006129736 A1 WO 2006129736A1
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Prior art keywords
ester
acid
cyclic
boiling point
cyclic dimer
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PCT/JP2006/310937
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English (en)
Japanese (ja)
Inventor
Masazumi Takaoka
Masanori Iwazumi
Masaru Wada
Ryo Shinagawa
Tadashi Okuma
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Mitsui Chemicals, Inc.
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Priority to JP2007519052A priority Critical patent/JP5132309B2/ja
Publication of WO2006129736A1 publication Critical patent/WO2006129736A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/12—1,4-Dioxanes; Hydrogenated 1,4-dioxanes not condensed with other rings

Definitions

  • the present invention relates to a method for producing a hydroxyalkyloxyacetic acid hydroxy cyclic ester
  • a method for producing a cyclic ester such as a method for producing a cyclic dimer ester.
  • 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.
  • 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.
  • 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.
  • Patent Documents 6 and 7 describe a method for producing a cyclic ester.
  • 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.
  • 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.
  • further purification operations must be performed. It is a process.
  • polyhydroxycarboxylic acids are also widely used as biodegradable polymers.
  • 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.
  • glycolide is obtained by polycondensation of glycolic acid, followed by distillation and further purification by dropwise addition to an alcohol solvent.
  • a purification operation is unavoidable. For this reason, the yield of glycolide is reduced by the purification operation, which is a complicated process.
  • Patent Document 4 glycolic acid and polyalkylene glycol are polycondensed and then distilled to obtain glycolide.
  • 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.
  • Patent Documents 6 and 7 describe a method for producing an ⁇ -hydroxycarboxylic acid cyclic dimer ester.
  • 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 ⁇ -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 ⁇ -hydroxycarboxylic acid cyclic dimer ester is distilled off together with the high-boiling polar organic solvent, and then removed from the distillate.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • Z represents oxygen or a linear or branched oxyalkyleneoxy group having 2 to 20 carbon atoms
  • 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.
  • 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.
  • 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.
  • the present invention uses a hydroxyalkyloxyacetic acid represented by the following formula (3) as a raw material, [0022] [Chemical 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)
  • 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)
  • a method for producing an oxycyclic ester comprising the following two steps is provided.
  • the hydroxyalkyloxyacetic acid (3) is preferably ⁇ -hydroxyethoxyacetic acid.
  • 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.
  • 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 comprising the following two steps is provided.
  • the oc-hydroxycarboxylic acid and Z or (-hydroxycarboxylic acid condensate (5) glycolic acid and z or glycolic acid condensate are preferable.
  • 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 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • the hydroxyalkyloxyacetic acid used as a raw material in the present invention is a compound represented by the following 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.
  • 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.
  • the hydroxyalkyloxyacetic acid used in the present invention is preferably one in which impurities derived from raw materials are excluded as much as possible.
  • the oxycyclic ester obtained by the present invention is a compound represented by the following 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.
  • 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.
  • 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)).
  • oxycyclic ester (4) an oxycyclic ester represented by the above formula (4) obtained by the present invention.
  • an alkylene glycol having a higher boiling point is added to hydroxyalkyloxyacetic acid and a polymerization reaction is performed to obtain a polymerization solution.
  • 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.
  • 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.
  • 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.
  • 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”.
  • 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.
  • the alkylene glycol and the product oxycyclic ester can be easily separated in the second step described later.
  • 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.
  • alkylene glycols may be used alone or in admixture of two or more.
  • 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.
  • 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.
  • 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.
  • polyethylene glycol and polypropylene glycol are preferable from the viewpoint of not producing THF as a decomposition product.
  • the power of availability is more preferable than that of polyethylene glycol.
  • 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 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.
  • the average molecular weight of polyethylene glycol can be determined as follows.
  • 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) ).
  • 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.
  • 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.
  • hydroxyalkyloxyacetic acid may be added as a solution dissolved in an organic solvent or a solvent such as water, or may itself be added.
  • the reaction conditions for distilling off the condensed water are not particularly limited as long as the condensed water is distilled off.
  • 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.
  • 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.
  • this aqueous solution usually contains a salt
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the hydroxyalkyloxyacetic acid added in the first step is an aqueous solution dissolved in a solvent such as water
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. .
  • 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.
  • the reaction solution is uniform until the end of the reaction in the second step, and the depolymerization is performed.
  • 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.
  • 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.
  • the pressure during depolymerization and distillation in the second step is usually 101.3 kPa to 0.1 lkPa.
  • 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.
  • 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.
  • 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.
  • the ⁇ -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).
  • 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 ⁇ -hydroxycarboxylic acid.
  • 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 ⁇ -hydroxycarboxylic acid and / or ⁇ -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.
  • 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.
  • 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.
  • Examples of the ⁇ -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.
  • 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.
  • glycolic acid glycolic acid condensates, and mixtures thereof are preferred from the viewpoint of easy availability.
  • 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.
  • glycolic acid aqueous solutions examples 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.
  • the glycolic acid 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. ⁇ ⁇ .
  • 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
  • the concentration of glycolic acid is not particularly limited, and can be used in a wide concentration range.
  • 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.
  • glycolic acid 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.
  • impurities those obtained by removing these compounds by adsorption treatment with activated carbon, vacuum distillation or stripping may be used.
  • the raw material a-hydroxycarboxylic acid and Z or ⁇ -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.
  • 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.
  • 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 weight-average molecular weight in terms of ⁇ determined by GPC measurement of ⁇ -hydroxycarboxylic acid and ⁇ or ⁇ -hydroxycarboxylic acid condensate obtained as described above is usually 500 to 300,000. It is 5000-150000.
  • 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.
  • GPC gel permeation chromatograph
  • HFIP hexafluoroisopropyl alcohol
  • 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.
  • 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.
  • 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 ⁇
  • 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.
  • the metal atoms based on the respect ⁇ - 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 ⁇ 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.
  • the cyclic dimer ester obtained by the present invention contains the ⁇ -hydroxycarboxylic acid and
  • 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.
  • 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
  • the branched alkyl group having 1 to 4 carbon atoms is an isopropyl group.
  • Isobutyl group, sec butyl group, and tert butyl group a methyl group and an ethyl group are preferable.
  • 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.
  • 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 ⁇ -hydroxypropionic acid.
  • a cyclic dimer is mentioned.
  • glycolide and ratatide are preferable, and glycolide is more preferable.
  • 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.
  • 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 ⁇ -hydroxycarboxylic acid and ⁇ ⁇ or ⁇ -hydroxycarboxylic acid condensate to obtain a polymerization solution by polymerization reaction.
  • 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.
  • the first step of the production method of the cyclic dimer ester of the present invention will be described in detail.
  • 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.
  • 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”.
  • 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.
  • 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.
  • This first step is characterized in that alkylene glycol having a boiling point higher than that of the cyclic dimer ester (6) is used.
  • the alkylene glycol 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 ⁇ -hydroxycarboxylic acid condensate react.
  • 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.
  • the hydroxyl group of the alkylene dallicol reacts with the terminal carbonyl group of the a-hydroxycarboxylic acid and the Z- or ⁇ -hydroxycarboxylic acid condensate.
  • the alkylene glycol having a boiling point higher than that of the cyclic dimer ester (6) in the first step the alkylene glycol, ⁇ -hydroxycarboxylic acid and ⁇ 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.
  • 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.
  • 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.
  • 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.
  • the above alkylene glycols may be used alone or in admixture 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.
  • alkylene glycol used in the present invention also include polyalkylene glycols such as polyethylene glycol and polypropylene glycol.
  • polyalkylene glycols such as polyethylene glycol and polypropylene glycol.
  • polyethylene Glycol and polypropylene glycol Preferably polyethylene glycol, more preferably polyethylene glycol.
  • polyalkylene glycol when used in the present invention, it does not substantially contain a component having a lower boiling point than the cyclic ester to be produced.
  • the polyethylene glycol 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.
  • 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.
  • 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.
  • the molecular weight is the average molecular weight.
  • 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.
  • the average molecular weight of polyethylene glycol is determined, it can be determined as follows.
  • 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.
  • 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.
  • the amount of alkylene glycol to be added is usually from 0.01 to 5 monolayer times the value obtained by converting ⁇ -hydroxycarboxylic acids and Z or ⁇ -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.
  • 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.
  • 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! /.
  • the polymerization reaction may be performed without a catalyst or a catalyst may be used during the polymerization reaction.
  • 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 sulfur
  • the catalyst When using a catalyst, the catalyst, the metal atom based, to ⁇ - hydroxy Shikarubon acid monomers 1 mol, preferably 1 X 10- 5 ⁇ : L0- 2 equivalents, more preferably 3 X 10- 5 to 5 ⁇ 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.
  • 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.
  • the second step will be described in detail.
  • the ⁇ -hydroxycarboxylic acid obtained in the first step and the polymer of ⁇ or ⁇ -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
  • 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.
  • the polymerization solution obtained in the first step contains a copolymer of a high-boiling alkylene glycol, a-hydroxycarboxylic acid, and a Z or ⁇ -hydroxycarboxylic acid condensate.
  • This copolymer has hydroxyl groups at both ends.
  • 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.
  • 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.
  • the reaction solution is uniform until the end of the reaction in the second step.
  • the polymerization solution has good fluidity, and the residual liquid in the distillation still after distillation is also fluid and easy to handle.
  • 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.
  • 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.
  • the depolymerization reaction tends to proceed more efficiently as compared with the case where the polymer is produced without adding alkylene glycol.
  • 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. ⁇ or 100 ⁇ 250 o C, further [this preferably ⁇ or 180 ⁇ 250 o C, especially [this Ru preferably ⁇ or 180 ⁇ 230 o C der.
  • the pressure during the reaction in the second step is preferably 101.3 to 0.1 lkPa, more preferably ⁇ to 10.0 to 0.1 kPa, and further preferably ⁇ to 3.0 to 0. lkPa. is there.
  • 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 ⁇ -hydroxycarboxylic acid and ⁇ or OC-hydroxycarboxylic acid condensate used in the first step. It means what was divided.
  • 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.
  • 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 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.
  • polymerization initiator used examples 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.
  • 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.
  • 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.
  • polyhydroxycarboxylic acid which is a bioabsorbable polymer used for medical materials.
  • 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.
  • 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, ⁇ : 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.
  • the instrument is GC-14A manufactured by Shimadzu Corporation, the detector is a flame ionization detector (FID), and the column is a column (G205, ⁇ : 1.2mm X 40m (film thickness: 2 ⁇ ⁇ ) 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 ⁇ 1 was injected, and a calibration curve was prepared using a standard sample in advance. Each component was analyzed. The results are as follows.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 78.6 g of p-dioxanone having a purity of 99.7% was distilled out by heating for 3 hours.
  • 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.
  • 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 ⁇ m) 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.
  • the distillation rate was calculated by the following formula.
  • the instrument was GC-14A manufactured by Shimadzu Corporation, the detector was a flame ionization detector (FID), and the column was a column (G205, ⁇ : 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 ⁇ 1 was injected and measured, and a calibration curve was prepared using a standard sample. Each component was analyzed using a calibration curve.
  • a 500 ⁇ 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.
  • 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.
  • 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.
  • 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 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 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). .
  • Example 1B 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • the polymer obtained in the first step was uniformly dissolved with PEG # 600 and was not phase-separated.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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 “13 ⁇ 40 # 300”) 42 8 (equivalent to 0.28 mol of alcoholic hydroxyl group) Then, it was heated to 260 ° C.
  • TEGDME tetraethylene glycol dimethyl ether
  • 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.
  • 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.
  • 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.
  • 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 ⁇ 200 after caloring antimony 0. 05g. C, 30. OkPa treatment gave copolymerized prepolymers.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)
  • Example 4B 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.
  • 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.
  • 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.

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  • Organic Chemistry (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Polyesters Or Polycarbonates (AREA)

Abstract

L'invention a pour objet un procédé industriellement avantageux pour produire un ester cyclique, un procédé industriellement avantageux pour produire un oxyester cyclique qui est une matière première de poly(ester d'acide hydroxyalkyloxyacétique) et un procédé industriellement avantageux pour produire un ester dimérique cyclique qui est une matière première de poly(acide α-hydroxycarboxylique). Le procédé pour produire un ester cyclique selon l'invention comprend deux étapes : une première étape consistant à obtenir une solution de polymérisation en ajoutant un alkylèneglycol ayant un point d'ébullition supérieur à celui d'un ester cyclique qu'on doit produire à un acide hydroxyalkylcarboxylique spécifique et/ou à un produit de condensation de l'acide hydroxyalkylcarboxylique et en effectuant une réaction de polymérisation et une seconde étape consistant à obtenir un ester cyclique ayant une pureté supérieure ou égale à 98 % en effectuant simultanément une réaction et une distillation en chauffant la solution de polymérisation obtenue dans la première étape.
PCT/JP2006/310937 2005-06-01 2006-05-31 Procédé pour produire un ester cyclique WO2006129736A1 (fr)

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JP2013535433A (ja) * 2010-07-14 2013-09-12 ソルヴェイ（ソシエテ アノニム） アルファ−ヒドロキシ酸の環状ジエステルの製造方法
WO2014080876A1 (fr) 2012-11-22 2014-05-30 株式会社クレハ Procédé de production de glycolide, doté d'une étape de rectification au moyen d'un contact gaz-liquide à contre-courant et procédé de purification de glycolide brut
CN115073415A (zh) * 2022-05-31 2022-09-20 江苏景宏新材料科技有限公司 一种制备高纯度乙交酯的方法

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JPH05287056A (ja) * 1992-04-07 1993-11-02 Toyobo Co Ltd 脂肪族ポリエステルの製造方法
JPH06287278A (ja) * 1993-04-07 1994-10-11 Toyobo Co Ltd 脂肪族ポリエステルの製造方法
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JPH1045744A (ja) * 1996-08-08 1998-02-17 Tokuyama Corp ２−ｐ−ジオキサノンの製造方法
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013535433A (ja) * 2010-07-14 2013-09-12 ソルヴェイ（ソシエテ アノニム） アルファ−ヒドロキシ酸の環状ジエステルの製造方法
WO2014080876A1 (fr) 2012-11-22 2014-05-30 株式会社クレハ Procédé de production de glycolide, doté d'une étape de rectification au moyen d'un contact gaz-liquide à contre-courant et procédé de purification de glycolide brut
US9365536B2 (en) 2012-11-22 2016-06-14 Kureha Corporation Method for producing glycolide, which is provided with rectification step by means of gas-liquid countercurrent contact, and method for purifying crude glycolide
CN115073415A (zh) * 2022-05-31 2022-09-20 江苏景宏新材料科技有限公司 一种制备高纯度乙交酯的方法

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