Method for producing monomer precursor composition

Abstract

The present invention pertains to a method for producing a precursor to be used in a monomer which can be easily prepared, which has high versatility in designing, and which is for use in medical devices having high transparency, especially contact lenses. The present invention provides a method for producing a monomer precursor composition, the method comprising a mixing step for mixing: a compound A having a specific structure (a); an unsaturated carboxylic acid B having a specific structure (b); an unsaturated carboxylic acid metal salt C; and an unsaturated carboxylic acid D having a substituent group selected from the group consisting of halogenated alkyl groups, isocyanate groups, carboxyl groups, epoxy groups, acid anhydride groups, and carboxylic acid halide groups.

Description

Method for producing a monomer precursor composition

[0001] The present invention relates to a method for producing a monomer precursor composition.

[0002] Polymers obtained by polymerizing (meth)acrylic monomers have been known as medical materials, and because of their sufficient transparency and hardness, they are used particularly in ophthalmology and dentistry.

[0003] Known (meth)acrylic monomers include, for example, compounds represented by the following formula (c) or (c') (Patent Document 1). These compounds have two types of polymerizable groups and can therefore be used as crosslinking agents. In particular, when used as crosslinking agents to obtain hydrogel materials, all of these compounds have a hydroxyl group, which means that they are highly compatible with hydrophilic monomers such as hydroxylmethyl methacrylate (HEMA).

[0004]

[0005] On the other hand, it is inevitable that the compound represented by formula (c) or (c') will be contaminated with a compound represented by formula (d) below, which is a by-product produced during the production process. This by-product represented by formula (d) below has three types of polymerizable groups in its molecule and also functions as a cross-linking agent. However, if the amount of this by-product, which is a cross-linking agent with different physical properties, mixed in is not appropriate, it becomes difficult to control the polymerization reaction as originally intended, and quality control of the resulting hydrogel material, etc., becomes extremely unstable.

[0006]

[0007] For example, to reduce by-products, it is possible to purify the cross-linking agent, which is the main component, but this method may reduce the yield of the main component. Also, to increase the amount of by-products mixed in, it is possible to mix separately produced by-products, but this requires a separate process to prepare the by-products.

[0008] As exemplified above, when producing a (meth)acrylic monomer that can be used as a crosslinking agent, it has been required to control the production of by-products as much as possible.

[0009] Patent No. 4617887

[0010] Therefore, an object of the present invention is to provide a method for producing a monomer precursor composition that is capable of controlling the amount of by-products to a desired level by a simple method in the production of a precursor of an acrylic monomer that is suitable as a raw material for medical materials.

[0011] In order to achieve the above object, the present invention provides a method for producing a monomer precursor composition, comprising a mixing step of mixing a compound A represented by the following general formula (a), an unsaturated carboxylic acid B represented by the following general formula (b), an unsaturated carboxylic acid metal salt C, and an unsaturated carboxylic acid D having a substituent selected from the group consisting of a halogenated alkyl group, an isocyanate group, a carboxyl group, an epoxy group, an acid anhydride group, and a carboxylic acid halide group:

[0012]

[0013] [In the general formula (a), L represents a linear or branched alkylene group having 1 to 10 carbon atoms, and R ｅ represents a linear or branched hydrocarbon group containing an unsaturated bond and having 2 to 10 carbon atoms.]

[0014]

[0015] [In general formula (b), R ａ represents hydrogen or a methyl group, X represents a single bond or a linear or branched alkylene group having 1 to 10 carbon atoms, and Z represents a carboxyl group.

[0016] According to the present invention, it is possible to control the amount of by-products produced by a very simple method using only a one-step reaction, and to obtain a monomer precursor composition having a specific structure and containing an appropriate amount of by-products.

[0017] The method for producing a monomer precursor composition of the present invention is required to include a mixing step of mixing a compound A represented by the following general formula (a), an unsaturated carboxylic acid B represented by the following general formula (b), an unsaturated carboxylic acid metal salt C, and an unsaturated carboxylic acid D having a substituent selected from the group consisting of a halogenated alkyl group, an isocyanate group, a carboxyl group, an epoxy group, an acid anhydride group, and a carboxylic acid halide group.

[0018]

[0019] In the general formula (a), L represents a linear or branched alkylene group having 1 to 10 carbon atoms, and R ｅ represents a linear or branched hydrocarbon group having 2 to 10 carbon atoms and containing an unsaturated bond.

[0020] From the viewpoint of imparting excellent flexibility to the polymer that is the final medical material, L preferably has 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms. ｅ The carbon number is preferably 2 to 8, and more preferably 2 to 4. Here, the term "unsaturated bond" refers to a radically polymerizable carbon-carbon double bond.

[0021] Preferred examples of the compound A represented by general formula (a) in the present invention include aliphatic glycidyl ether monomers, with allyl glycidyl ether being preferred in view of availability.

[0022]

[0023] In general formula (b), R ａ represents hydrogen or a methyl group, X represents a single bond or a linear or branched alkylene group having 1 to 10 carbon atoms, and Z represents a carboxyl group.

[0024] Preferred examples of the unsaturated carboxylic acid B represented by general formula (b) in the present invention include vinyloxyacetic acid, allyloxyacetic acid, (meth)acrylic acid, crotonic acid, 2-(meth)acryloylpropanoic acid, 3-(meth)acryloylbutanoic acid, and 4-vinylbenzoic acid, and (meth)acrylic acid is preferred in view of availability.

[0025] The amount of unsaturated carboxylic acid B in the mixing step of the method for producing a monomer precursor composition of the present invention is preferably 1.0 to 50 equivalents, more preferably 1.5 to 40 equivalents, and even more preferably 2.0 to 30 equivalents, relative to compound A represented by general formula (a) of the present invention, from the viewpoint of increasing the reaction rate of compound A represented by general formula (a) of the present invention.

[0026] Compound A represented by general formula (a) in the present invention is difficult to remove even by various purification methods, and if it remains in the finally obtained polymer, i.e., the medical material, there is a possibility that it may be subsequently eluted, so it is preferable that it is not contained in the monomer precursor composition as much as possible. The content of compound A represented by general formula (a) in the obtained monomer precursor composition is preferably 1500 ppm or less, more preferably 1000 ppm or less for use in medical materials, and even more preferably 500 ppm or less.

[0027] The unsaturated carboxylic acid metal salt C in the present invention refers to a metal salt of an unsaturated carboxylic acid having a carboxyl group. Examples of preferred metal salts include salts of alkali metals such as sodium, potassium, or lithium, or salts of alkaline earth metals such as calcium. From the viewpoint of high reactivity and easy availability, salts of alkali metals, i.e., alkali metal salts, are preferred, and salts of sodium ions or lithium ions are more preferred. Furthermore, from the viewpoint of suppressing the generation of impurities, the unsaturated carboxylic acid metal salt C is preferably a metal salt of an unsaturated carboxylic acid B represented by general formula (b) in the present invention.

[0028] In the mixing step included in the method for producing a monomer precursor composition of the present invention, the unsaturated carboxylic acid metal salt C preferably acts as a catalyst.

[0029] The amount of the unsaturated carboxylic acid metal salt C in the mixing step is preferably 0.001 to 5.000 equivalents, more preferably 0.005 to 3.000 equivalents, and even more preferably 0.010 to 1.000 equivalents, relative to the compound A represented by general formula (a) of the present invention, for the purposes of preventing precipitation while maintaining a favorable reaction rate.

[0030] The unsaturated carboxylic acid D in the present invention has a substituent selected from the group consisting of a halogenated alkyl group, an isocyanate group, a carboxyl group, an epoxy group, an acid anhydride group, and a carboxylic acid halide group.

[0031] As the functional group that the unsaturated carboxylic acid D has, from the viewpoint of reaction convenience, such as suppressing the production of by-products other than the desired by-products, an isocyanate group, an epoxy group, an acid anhydride group, or a carboxylic acid halide group is preferred, an isocyanate group or an acid anhydride group is more preferred, and an acid anhydride group is even more preferred.

[0032] Examples of the unsaturated carboxylic acid D having an isocyanate group include 2-(meth)acryloyloxyethyl isocyanate, 3-methacryloyloxy-n-propyl isocyanate, 2-methacryloyloxyisopropyl isocyanate, 4-methacryloyloxy-n-butyl isocyanate, 2-methacryloyloxy-tert-butyl isocyanate, 2-methacryloyloxybutyl-4-isocyanate, 2-methacryloyloxybutyl-3-isocyanate, 2-methacryloyloxybutyl-2-isocyanate, and 2-methacryloyloxybutyl- Preferred examples include 1-isocyanate, 5-methacryloyloxy-n-pentyl isocyanate, 6-methacryloyloxy-n-hexyl isocyanate, 7-methacryloyloxy-n-heptyl isocyanate, 2-(isocyanatoethyloxy)ethyl methacrylate, 3-methacryloyloxyphenyl isocyanate, 4-methacryloyloxyphenyl isocyanate, and compounds in which the methacryl group in these compounds has been substituted with an acrylic group, with 2-(meth)acryloyloxyethyl isocyanate being preferred from the viewpoint of ease of availability.

[0033] Preferred examples of the unsaturated carboxylic acid D having an acid anhydride group, that is, the unsaturated carboxylic acid D which is an acid anhydride, include acetic anhydride, (meth)acrylic anhydride, succinic anhydride, phthalic anhydride, maleic anhydride, benzoic anhydride, itaconic anhydride, n-decylsuccinic anhydride, n-dodecylsuccinic anhydride, n-tetradecylsuccinic anhydride, and n-hexadecylsuccinic anhydride, with (meth)acrylic anhydride being preferred in terms of ease of availability.

[0034] The amount of unsaturated carboxylic acid D in the mixing step of the method for producing a monomer precursor composition of the present invention is preferably 0.001 to 30% by mass, more preferably 0.005 to 25% by mass, and even more preferably 0.010 to 20% by mass, relative to compound A represented by general formula (a) in the present invention, in order to ensure an appropriate reaction rate and reactivity in the mixing step.

[0035] The monomer precursor composition in the present invention refers to a composition that contains a monomer precursor represented by the following general formula (e) as a main component, which is synthesized by the production method of the present invention, and contains a compound represented by the following general formula (e') as a by-product.

[0036]

[0037]

[0038] In the general formulas (e) and (e′), R ａ represents hydrogen or a methyl group, and L represents a linear or branched alkylene group having 1 to 10 carbon atoms. From the viewpoint of imparting excellent flexibility to the final polymer, the number of carbon atoms in L is preferably 1 to 8, and more preferably 1 to 4.

[0039] R ｃ represents hydrogen or a linear or branched hydrocarbon group having 1 to 10 carbon atoms, but from the viewpoint of avoiding steric hindrance, R ｃ is preferably hydrogen or a hydrocarbon group having 2 to 4 carbon atoms.

[0040] R ｄ represents a linear or branched hydrocarbon group having an unsaturated bond and having 1 to 10 carbon atoms. From the viewpoint of avoiding steric hindrance, R ｄ is preferably a hydrocarbon group having 1 to 10 carbon atoms, more preferably a hydrocarbon group having 2 to 8 carbon atoms, and even more preferably a hydrocarbon group having 2 to 4 carbon atoms.

[0041] The amount of the compound represented by the general formula (e') in the monomer precursor composition may be adjusted as appropriate depending on the required properties of the polymer to be finally obtained. From the viewpoint of ensuring ease of molding, the amount of the compound represented by the general formula (e) is preferably 0.001 to 40 mol %, more preferably 0.5 to 30 mol %, and even more preferably 2.0 to 20 mol %, relative to the monomer precursor represented by the general formula (e).

[0042] The compound represented by the above general formula (e) or (e') has a structure that is generated by adding the unsaturated carboxylic acid B represented by the general formula (b) of the present invention to the compound A represented by the general formula (a) of the present invention, and then reacting mainly with the functional group possessed by the unsaturated carboxylic acid D of the present invention.

[0043] Y is preferably a structure represented by any one of the following structural formulas (f).

[0044]

[0045] In structural formula (f), * represents R ｃ or R ｄ Represents a covalent bond with

[0046] In view of the reactivity with the functional group of the unsaturated carboxylic acid D, Y is more preferably a structure represented by any one of the following formulas (f2):

[0047]

[0048] In structural formula (f2), * represents R ｃ or R ｄ Represents a covalent bond with

[0049] In the mixing step of the method for producing a monomer precursor composition of the present invention, a polymerization inhibitor may be added to prevent polymerization of the resulting monomer precursor, etc. Preferred examples of the polymerization inhibitor include hydroquinones such as hydroquinone, methylhydroquinone, t-butylhydroquinone, 2,6-di-t-butyl-4-methylphenol, and hydroquinone monomethyl ether; nitroso compounds such as p-nitrosophenol, nitrosobenzene, N-nitrosodiphenylamine, isononyl nitrite, N-nitrosocyclohexylhydroxylamine, N-nitrosophenylhydroxylamine, and N,N'-dinitrosophenylenediamine, and salts thereof; nitrone compounds such as α-phenyl-N-t-butylnitrone and α-naphthyl-N-t-butylnitrone; and nitroxide compounds such as 2,2,6,6-tetramethyl-1-piperidinoxide (TEMPO) and 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinoxide.

[0050] The amount of the polymerization inhibitor to be added is preferably 0.0005 to 5 equivalents, more preferably 0.0010 to 3 equivalents, and even more preferably 0.0050 to 1 equivalent, relative to the compound A represented by general formula (a) in the present invention, from the viewpoint of obtaining a sufficient polymerization inhibitory effect while not inhibiting the polymerization of the polymer to be finally obtained.

[0051] The temperature in the mixing step in the method for producing a monomer precursor composition of the present invention is preferably 50 to 180°C, more preferably 60 to 170°C, and even more preferably 70 to 160°C, from the viewpoint of ensuring an appropriate reaction time and reactivity.

[0052] The method for producing a monomer precursor composition of the present invention may further include a washing step in which the monomer precursor composition obtained in the mixing step is washed. This washing step allows for the removal of unreacted raw materials and generated impurities. Examples of the operation in the washing step include adding an organic solvent to the obtained monomer precursor composition, and then adding an aqueous alkali or electrolyte solution or pure water, and mixing and shaking the mixture, followed by allowing the mixture to stand and separate. Preferred examples of the organic solvent used include aromatic organic solvents such as benzene, toluene, and xylene; halogenated organic solvents such as dichloromethane, chloroform, and dichloroethane; ketone organic solvents such as methyl isobutyl ketone, diethyl ketone, and cyclohexanone; and ester solvents such as n-butyl acetate and isobutyl acetate.

[0053] The monomer precursor composition obtained by the production method of the present invention may be used as it is, or may be used after adding a compound having an alkyl group or an aryl group having a siloxanyl group, a hydroxyl group, a carboxyl group, an amino group, or the like to an active terminal group of the monomer precursor.

[0054] The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these examples.

[0055] <Measurement method> Gas chromatograph (GC) measurements were performed using a Shimadzu GC-2014 (FID detector) main unit and a J&W ULTRA-2 (0.32 mm x 30 m x 0.52 μm) capillary column. The carrier gas was a mixture of helium and nitrogen (110 kPa), the inlet temperature was 300°C, the detector temperature was 320°C, and the heating program was 50°C (1 minute) → 10°C / min → 300°C (14 minutes). The sample was prepared by dissolving 100 μL of the measurement sample in 1 mL of acetonitrile, and 1 μL was injected.

[0056] <Reaction rate> Measured using a gas chromatograph (GC), the reaction rate was calculated from the peak area ratio of allyl glycidyl ether in each reaction solution at the initial stage of the reaction and after 6 hours of stirring.

[0057] <GC Purity, (e') / (e)> Measurement was performed using a gas chromatograph (GC). The GC purity of the final reaction solution was calculated by the area percentage method, based on the peak proportion of the main component, the monomer precursor represented by general formula (e). The amount of by-products was also calculated by the area percentage method, based on the ratio of the peak proportions of general formulas (e) and (e'), as (e') / (e).

[0058] <Yield> The yield was calculated by dividing the molar mass of the finally obtained monomer precursor composition by the molar mass of the raw material allyl glycidyl ether.

[0059] Example 1: 5 g (43.8 mmol) of allyl glycidyl ether, 8.0 g (92.9 mmol) of methacrylic acid, 0.80 g (7.4 mmol) of sodium methacrylate, 0.09 g (0.6 mmol) of methacrylic anhydride, and 0.07 g (0.6 mmol) of 4-methoxyphenol were added to a 100 mL recovery flask and stirred at 85°C in a water bath for 6 hours. After the mixture was cooled to room temperature, 14.8 g (160.6 mmol) of toluene was added. The mixture was washed four times with 25 g of a 2% by weight aqueous sodium hydroxide solution and twice with 25 g of a 15% by weight saline solution. A polymerization inhibitor was added, and the solvent was distilled off using an evaporator. The purity of the resulting liquid was measured by GC, and the results shown in Table 1 were obtained.

[0060] Example 2: 5 g (43.8 mmol) of allyl glycidyl ether, 8.0 g (92.9 mmol) of methacrylic acid, 0.80 g (7.4 mmol) of sodium methacrylate, 0.26 g (1.6 mmol) of methacrylic anhydride, and 0.07 g (0.6 mmol) of 4-methoxyphenol were added to a 100 mL recovery flask and stirred at 85°C in a water bath for 6 hours. After the mixture was cooled to room temperature, 14.8 g (160.6 mmol) of toluene was added. The mixture was washed four times with 25 g of a 2% by weight aqueous sodium hydroxide solution and twice with 25 g of a 15% by weight saline solution. A polymerization inhibitor was added, and the solvent was distilled off using an evaporator. The purity of the resulting liquid was measured by GC, and the results shown in Table 1 were obtained.

[0061] Example 3: 5 g (43.8 mmol) of allyl glycidyl ether, 8.0 g (92.9 mmol) of methacrylic acid, 0.80 g (7.4 mmol) of sodium methacrylate, 0.40 g (2.6 mmol) of methacrylic anhydride, and 0.07 g (0.6 mmol) of 4-methoxyphenol were added to a 100 mL recovery flask and stirred at 85°C in a water bath for 6 hours. After the mixture was cooled to room temperature, 14.8 g (160.6 mmol) of toluene was added. The mixture was washed four times with 25 g of a 2% by weight aqueous sodium hydroxide solution and twice with 25 g of a 15% by weight saline solution. A polymerization inhibitor was added, and the solvent was distilled off using an evaporator. The purity of the resulting liquid was measured by GC, and the results shown in Table 1 were obtained.

[0062] Example 4 An experiment was carried out in the same manner as in Example 1, except that methacrylic anhydride was replaced with 2-isocyanatoethyl acrylate. The purity of the obtained liquid was measured by GC, and the results shown in Table 1 were obtained.

[0063] Example 5 An experiment was carried out in the same manner as in Example 1, except that methacrylic anhydride was replaced with methacryloyl chloride. The purity of the obtained liquid was measured by GC, and the results shown in Table 1 were obtained.

[0064] Comparative Example 1: 5 g (43.8 mmol) of allyl glycidyl ether, 15.0 g (174.2 mmol) of methacrylic acid, 1.42 g (13.2 mmol) of sodium methacrylate, and 0.07 g (0.6 mmol) of 4-methoxyphenol were added to a 100 mL recovery flask and stirred at 85°C in a water bath for 6 hours. The mixture was then cooled to room temperature and 18.6 g (201.8 mmol) of toluene was added. The mixture was washed with 42.8 g of a 2% by weight aqueous sodium hydroxide solution and 42.8 g of a 15% by weight saline solution, a polymerization inhibitor was added, and the solvent was distilled off using an evaporator. The purity of the resulting liquid was measured by GC, and the results shown in Table 1 were obtained.

[0065] Comparative Example 2 An experiment was carried out in the same manner as in Example 1, except that the amounts of raw materials charged were changed to 6.8 g (79.0 mmol) of methacrylic acid and 0.45 g (4.2 mmol) of sodium methacrylate, and no methacrylic anhydride was added.

[0066]

Claims

1. A method for producing a monomer precursor composition, comprising a mixing step of mixing a compound A represented by the following general formula (a), an unsaturated carboxylic acid B represented by the following general formula (b), an unsaturated carboxylic acid metal salt C, and an unsaturated carboxylic acid D having a substituent selected from the group consisting of a halogenated alkyl group, an isocyanate group, a carboxyl group, an epoxy group, an acid anhydride group, and a carboxylic acid halide group. [In formula (a), L represents a linear or branched alkylene group having 1 to 10 carbon atoms, R ｅ represents a linear or branched hydrocarbon group containing an unsaturated bond and having 2 to 10 carbon atoms. [In formula (b), R ａ represents hydrogen or a methyl group, X represents a single bond or a linear or branched alkylene group having 1 to 10 carbon atoms, and Z represents a carboxyl group.

2. The method for producing a monomer precursor composition according to claim 1, wherein the unsaturated carboxylic acid metal salt C is a metal salt of the unsaturated carboxylic acid B.

3. The method for producing a monomer precursor composition according to claim 1 or 2, wherein the unsaturated carboxylic acid metal salt C is an alkali metal salt.

4. The method for producing a monomer precursor composition according to claim 1 or 2, wherein the unsaturated carboxylic acid D is an acid anhydride.

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