A radiopaque embolic microsphere and its preparation method

Abstract

The present application relates to the field of materials, and more specifically, to a radiopaque developing embolic microsphere and a preparation method thereof. The radiopaque developing embolic microsphere comprises: a developer containing iodine, polyvinyl alcohol microspheres and polymer microspheres of a water-soluble polymer with a sulfonic acid group coupled by covalent bonds; compared with the common developing embolic microspheres in the prior art, such as developing embolic microspheres obtained by covalently bonding triiodobenzaldehyde as a developer and polyvinyl alcohol microspheres, the radiopaque developing embolic microspheres of the present application have a more stable structure.

Description

Technical Field

[0001] The present application relates to the field of materials, and in particular to a radiopaque developing embolic microsphere and a preparation method thereof. Background Art

[0002] Embolic microspheres are widely used in interventional therapy, usually as an auxiliary treatment for vascular embolism.

[0003] Embolic microspheres are usually used with the help of imaging equipment to determine the location of embolic microspheres and the location of embolism through imaging information of blood flow cutoff.

[0004] At present, the commonly used developing embolic microspheres are obtained by covalently bonding triiodobenzaldehyde as a developer with polyvinyl alcohol microspheres.

[0005] However, since triiodobenzaldehyde increases the hydrophobicity of the developed embolic microspheres and increases the rigidity of the main chain, the drug loading capacity and speed of the microspheres are reduced.

[0006] Patent CN114262279A reported a method for preparing developing embolic microspheres using N-(2,2-diethoxypropyl)-2,3,5-triiodobenzamide. The introduction of amide bonds improved the hydrophilicity of the microspheres. However, since the compound is unstable under high temperature or acidic conditions, it is difficult to prepare developing microspheres with high iodine content. In addition, the degradation products may also be toxic to the body. Summary of the invention

[0007] The purpose of the embodiments of the present application is to provide a radiopaque developing embolic microsphere and a preparation method thereof, which improves the stability of the microsphere and reduces impurities by introducing a side group on the amide group of the developer.

[0008] In a first aspect, the present application provides a radiopaque embolic microsphere, comprising: an iodine-containing developer, polyvinyl alcohol microspheres, and polymer microspheres of a water-soluble polymer with a sulfonic acid group coupled by covalent bonds; and the polymer microspheres comprise the following structure:

[0009]

[0010] Among them, R 1 = Alkyl with 1 to 4 carbon atoms, R 2 = Alkyl group with 1 to 3 carbon atoms.

[0011] Compared with the common developing embolic microspheres in the prior art, the developing embolic microspheres obtained by covalently bonding N-(2,2-diethoxypropyl)-2,3,5-triiodobenzamide as a developer and polyvinyl alcohol microspheres, the radiopaque developing embolic microspheres of the present application have better hydrophilicity, more stable structure and higher iodine content.

[0012] In other embodiments of the present application, the developer preferably comprises at least one of the following structures:

[0013]

[0014] Among them, R 3 It is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group or an ethyl group.

[0015] In other embodiments of the present application, the developer is at least one of the following structures:

[0016]

[0017] In other embodiments of the present application, the iodine content of the above-mentioned radiopaque embolic microspheres is greater than or equal to 140 mg / mL.

[0018] In other embodiments of the present application, the iodine content of the radiopaque embolic microspheres is 143 mg / mL to 185 mg / mL.

[0019] In a second aspect, the present application provides a method for preparing radiopaque embolic microspheres, comprising:

[0020] The iodine-containing developer, polyvinyl alcohol microspheres and a water-soluble polymer with a sulfonic acid group are cross-linked; the iodine-containing developer, polyvinyl alcohol microspheres and a water-soluble polymer with a sulfonic acid group are coupled through covalent bonds to form polymer microspheres, and the polymer microspheres contain the following structure:

[0021]

[0022] Among them, R 1 = Alkyl with 2 to 3 carbon atoms, R 2 = Alkyl group with 1 to 3 carbon atoms.

[0023] In other embodiments of the present application, the method for preparing the developer has the following chemical reaction process:

[0024]

[0025] Among them, R 1 = Alkyl with 2 to 3 carbon atoms, R 2 = Alkyl group with 1 to 3 carbon atoms.

[0026] In other embodiments of the present application, the iodine-containing developer, the polyvinyl alcohol microspheres and the water-soluble polymer with sulfonic acid groups are cross-linked, including:

[0027] The polyvinyl alcohol microspheres are swollen and then reacted with an iodine-containing developer and a water-soluble polymer with a sulfonic acid group.

[0028] In other embodiments of the present application, the polyvinyl alcohol microspheres are swollen, comprising:

[0029] The polyvinyl alcohol microspheres were mixed with a dimethyl sulfoxide solution for swelling.

[0030] In other embodiments of the present application, the water-soluble polymer with a sulfonic acid group is methanesulfonic acid.

[0031] In other embodiments of the present application, the iodine-containing developer, the polyvinyl alcohol microspheres and the water-soluble polymer with sulfonic acid groups are cross-linked, including:

[0032] The reaction is carried out according to the following ratio: iodine-containing developer: polyvinyl alcohol microspheres: water-soluble polymer with sulfonic acid groups is (5-10) g: (2-6) g: (0.5-2) ml.

[0033] In other embodiments of the present application, the iodine-containing developer, the polyvinyl alcohol microspheres and the water-soluble polymer with sulfonic acid groups are cross-linked, including:

[0034] The iodine-containing developer, polyvinyl alcohol and a water-soluble polymer having a sulfonic acid group are reacted at 50° C.-70° C. for 40 h-60 h. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments.

[0036] Therefore, the following detailed description of the embodiments of the present application is not intended to limit the scope of the present application for protection, but merely represents selected embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present application.

[0037] The inventors have found that the common developing embolic microspheres in the prior art, such as the developing embolic microspheres obtained by covalent bonds between N-(2,2-diethoxypropyl)-2,3,5-triiodobenzamide and polyvinyl alcohol microspheres as the developer, have poor structural stability when there are no side groups in their structures. However, when side groups with more than four carbon atoms are introduced into their structures, the iodine content of the developing embolic microspheres is difficult to reach 100 mg / mL, and the hydrophilicity is poor.

[0038] Based on this, the embodiment of the present application provides a radiopaque developing embolic microsphere, comprising: an iodine-containing developer, polyvinyl alcohol microspheres, and polymer microspheres of a water-soluble polymer with a sulfonic acid group coupled by covalent bonds; and the polymer microspheres comprise the following structure:

[0039]

[0040] Among them, R 1 = alkyl with 1 to 3 carbon atoms, R 2 = Alkyl group with 1 to 3 carbon atoms.

[0041] Compared with the commonly used developing embolic microspheres in the prior art, such as the developing embolic microspheres obtained by covalently bonding triiodobenzaldehyde as a developer and polyvinyl alcohol microspheres, the radiopaque developing embolic microspheres of the present application have a more stable structure, better elasticity, higher iodine content, and better hydrophilicity.

[0042] In other embodiments of the present application, the developer preferably comprises at least one of the following structures:

[0043]

[0044] Among them, R 3 It is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group or an ethyl group.

[0045] In other embodiments of the present application, the method for preparing the developer has the following chemical reaction process:

[0046]

[0047] Among them, R 3 It is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group or an ethyl group.

[0048] Further, in some embodiments of the present application, the above-mentioned iodine-containing developer is at least one of the following structures:

[0049]

[0050] Illustratively, in some embodiments of the present application, the above-mentioned iodine-containing developer is any one of N-(2,2-diethoxypropyl)-2,3,5-triiodobenzamide, N-(2,2-diethoxypropyl)-methyl-2,3,5-triiodobenzamide, and N-(2,2-diethoxybutyl)-2,3,5-triiodobenzamide.

[0051] Illustratively, in some embodiments of the present application, the above-mentioned iodine-containing developer is a mixture of the above two structures.

[0052] Illustratively, in some embodiments of the present application, the above-mentioned iodine-containing developer is a mixture of the above three developers.

[0053] Further, in some embodiments of the present application, in other embodiments of the present application, the iodine content of the above-mentioned radiopaque developing embolic microspheres is greater than or equal to 140 mg / mL.

[0054] Furthermore, in some embodiments of the present application, the iodine content of the radiopaque embolic microspheres is 143 mg / mL to 185 mg / mL.

[0055] Illustratively, the iodine content of the radiopaque embolic microspheres is 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL or 185 mg / mL.

[0056] In some embodiments of the present application, a method for preparing radiopaque embolic microspheres is provided, comprising:

[0057] The iodine-containing developer, polyvinyl alcohol microspheres and a water-soluble polymer with a sulfonic acid group are cross-linked; the iodine-containing developer, polyvinyl alcohol microspheres and a water-soluble polymer with a sulfonic acid group are coupled through covalent bonds to form polymer microspheres, and the polymer microspheres contain the following structure:

[0058]

[0059] Among them, R 1 = Alkyl with 2 to 3 carbon atoms, R 2 =H or an alkyl group of 1 to 3 carbon atoms.

[0060] Further, in some embodiments of the present application, the method for preparing radiopaque embolic microspheres comprises the following steps:

[0061] Step S1, preparing polyvinyl alcohol microspheres.

[0062] Furthermore, in some embodiments of the present application, the steps of preparing polyvinyl alcohol microspheres include:

[0063] Polyvinyl alcohol (PVA) is reacted with N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA) to obtain a macromolecular polyvinyl alcohol monomer, and then the obtained macromolecular polyvinyl alcohol monomer is mixed with acrylamide-2-methylpropanesulfonic acid sodium salt (AMPS sodium) solution to obtain an aqueous phase.

[0064] The oil phase is prepared using butyl acetate and cellulose acetate butyrate.

[0065] The aqueous phase and the oil phase are mixed to prepare polyvinyl alcohol microspheres.

[0066] Further, in some embodiments of the present application, the reaction of polyvinyl alcohol (PVA) with N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA) comprises:

[0067] After PVA is dissolved, N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA) is added, and then concentrated hydrochloric acid is added to react.

[0068] Further optionally, after dissolving PVA, N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA) is added, and then concentrated hydrochloric acid is added to react, comprising:

[0069] 15 g of PVA was heated to 95°C to dissolve, and then cooled to room temperature; 0.7654 g of N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA) was added, followed by 10 mL of concentrated hydrochloric acid, and the reaction was carried out at room temperature for 14 hours.

[0070] Further optionally, after the polyvinyl alcohol (PVA) and N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA) are reacted, a sodium hydroxide solution is added to the system for neutralization.

[0071] Further optionally, a 2.5 M sodium hydroxide solution is used to neutralize the system to pH=7.

[0072] For example, in some specific embodiments, 100 mL of purified water is added to a 250 ml three-necked flask equipped with an overhead mechanical stirrer, about 15 g of PVA (model 1888) is added, the temperature is raised to 95° C. to dissolve, and then cooled to room temperature; 0.7654 g of N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA) is added, followed by 10 mL of concentrated hydrochloric acid, the reaction is carried out at room temperature for 14 hours, and then neutralized with 2.5 M sodium hydroxide solution to pH = 7 to obtain a macromolecular polyvinyl alcohol monomer solution.

[0073] Further, in some embodiments of the present application, the prepared macromolecular polyvinyl alcohol monomer is mixed with acrylamide-2-methylpropanesulfonic acid sodium salt (AMPS sodium) solution, comprising:

[0074] The prepared macromolecular polyvinyl alcohol monomer is mixed with acrylamide-2-methylpropanesulfonic acid sodium salt (AMPS sodium) solution, and potassium persulfate is added to obtain an aqueous phase.

[0075] For example, in some specific embodiments, 8.61 g of acrylamido-2-methylpropanesulfonic acid sodium salt (AMPS sodium) is dissolved in 60 ml of water, 160 g of a macromolecular polyvinyl alcohol monomer solution is added, and 1.5 g of potassium persulfate is added to obtain an aqueous phase.

[0076] Further, in some embodiments of the present application, butyl acetate and cellulose acetate butyrate are used, including:

[0077] An oil phase was prepared by mixing 600 mL of butyl acetate with 18 g of cellulose acetate butyrate.

[0078] For example, 600 mL of butyl acetate was added to a 1 L three-necked flask equipped with an overhead mechanical stirrer, and 18 g of cellulose acetate butyrate was added and dissolved to obtain an oil phase.

[0079] Further, in some embodiments of the present application, the aqueous phase and the oil phase are mixed to prepare polyvinyl alcohol microspheres, comprising:

[0080] Under rotating stirring, the aqueous phase was added dropwise to the oil phase. After the addition was complete, the temperature was raised to 55°C, 2.2 ml of tetramethylethylenediamine was added, and the reaction was carried out for 8 hours.

[0081] Further optionally, the rotation speed during rotational stirring is set to 400 rpm.

[0082] Furthermore, the polyvinyl alcohol microspheres prepared above are purified and dried.

[0083] The above purification and drying can be carried out by conventional purification and drying methods in the art.

[0084] Step S2, cross-linking the iodine-containing developer, the polyvinyl alcohol microspheres and the water-soluble polymer with sulfonic acid groups.

[0085] The iodine-containing developer, polyvinyl alcohol microspheres and a water-soluble polymer with a sulfonic acid group are cross-linked; the iodine-containing developer, polyvinyl alcohol microspheres and a water-soluble polymer with a sulfonic acid group are coupled through covalent bonds to form polymer microspheres, and the polymer microspheres contain the following structure:

[0086]

[0087] Among them, R 1 = Alkyl with 2 to 3 carbon atoms, R 2 =H or an alkyl group of 1 to 3 carbon atoms.

[0088] Furthermore, in some embodiments of the present application, the iodine-containing developer, the polyvinyl alcohol microspheres and the water-soluble polymer with sulfonic acid groups are cross-linked, including:

[0089] The polyvinyl alcohol microspheres are swollen and then reacted with an iodine-containing developer and a water-soluble polymer with a sulfonic acid group.

[0090] Further, in some embodiments of the present application, the polyvinyl alcohol microsphere dry ball is swollen, comprising:

[0091] The polyvinyl alcohol microspheres were mixed with dimethyl sulfoxide solution (DMSO) for swelling.

[0092] Further, in some embodiments of the present application, the polyvinyl alcohol microsphere dry ball is swollen, comprising:

[0093] The swelling is carried out according to (2-5) g of polyvinyl alcohol microsphere dry ball: (100-150) ml of dimethyl sulfoxide solution.

[0094] For example, 4.0 g of the dry polyvinyl alcohol microspheres prepared in the above step S1 are swollen with 120 ml of DMSO.

[0095] Furthermore, in some embodiments of the present application, when the iodine-containing developer, polyvinyl alcohol microspheres and the water-soluble polymer with sulfonic acid groups undergo a cross-linking reaction, the water-soluble polymer with sulfonic acid groups is selected to be methanesulfonic acid.

[0096] Furthermore, in some embodiments of the present application, the iodine-containing developer, the polyvinyl alcohol microspheres and the water-soluble polymer with sulfonic acid groups are cross-linked, including:

[0097] The reaction is carried out according to the following ratio: iodine-containing developer: polyvinyl alcohol microspheres: water-soluble polymer with sulfonic acid groups is (5-10) g: (2-6) g: (0.5-2) ml.

[0098] Further optionally, the iodine-containing developer, the polyvinyl alcohol microspheres and the water-soluble polymer with sulfonic acid groups are cross-linked, comprising:

[0099] The reaction is carried out according to the following ratio: iodine-containing developer: polyvinyl alcohol microspheres: water-soluble polymer with sulfonic acid groups is (6-9) g: (2-5) g: (0.6-1.9) ml.

[0100] Exemplarily, the reaction is carried out according to the following ratio: iodine-containing developer: polyvinyl alcohol microspheres: water-soluble polymer with sulfonic acid groups is (6g, 7g, 8g or 9g): (2g, 3g, 4g or 5g): (0.6ml, 0.8ml, 1ml, 1.2ml, 1.5ml or 1.8ml).

[0101] Furthermore, in some embodiments of the present application, the iodine-containing developer, the polyvinyl alcohol microspheres and the water-soluble polymer with sulfonic acid groups are cross-linked, including:

[0102] The iodine-containing developer, polyvinyl alcohol and a water-soluble polymer having a sulfonic acid group are reacted at 50° C.-70° C. for 40 h-60 h.

[0103] Further optionally, in some embodiments of the present application, the iodine-containing developer, the polyvinyl alcohol microspheres and the water-soluble polymer with sulfonic acid groups are cross-linked, comprising:

[0104] The iodine-containing developer, polyvinyl alcohol and a water-soluble polymer having a sulfonic acid group are reacted at 51° C.-69° C. for 41 h-59 h.

[0105] Further optionally, in some embodiments of the present application, the iodine-containing developer, the polyvinyl alcohol microspheres and the water-soluble polymer with sulfonic acid groups are cross-linked, comprising:

[0106] The iodine-containing developer, polyvinyl alcohol and a water-soluble polymer having a sulfonic acid group are reacted at 52° C.-68° C. for 42 h-58 h.

[0107] Illustratively, an iodine-containing developer, polyvinyl alcohol and a water-soluble polymer having a sulfonic acid group are reacted at 54° C., 55° C., 58° C., 60° C., 62° C., 65° C. or 67° C. for 45 h, 48 h, 50 h, 52 h, 55 h or 57 h.

[0108] The radiopaque developing embolic microspheres prepared by the method of the present application have a more stable structure, better elasticity, higher iodine content, and better hydrophilicity.

[0109] The features and performance of the present application are further described in detail below in conjunction with the embodiments:

[0110] Example 1

[0111] Provided is a radiopaque embolic microsphere, prepared according to the following steps:

[0112] (1) Add 100 mL of purified water to a 250 mL three-necked flask equipped with an overhead mechanical stirrer, add about 15 g of PVA (model 1888), heat to 95° C. to dissolve, and cool to room temperature; add 0.7654 g of N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA), then add 10 mL of concentrated hydrochloric acid, react at room temperature for 14 hours, and then use 2.5 M sodium hydroxide solution to neutralize to pH = 7 to obtain a macromolecular polyvinyl alcohol monomer solution; 8.61 g of acrylamido-2-methylpropanesulfonic acid sodium salt (AMPS sodium) is dissolved in 60 mL of water, 160 g of the macromolecular polyvinyl alcohol monomer solution is added, and 1.5 g of potassium persulfate is added to obtain an aqueous phase;

[0113] In a 1L three-necked flask equipped with an overhead mechanical stirrer, add 600mL of butyl acetate and 18g of cellulose acetate butyrate to dissolve to obtain an oil phase;

[0114] The speed was set to 400 rpm, and the aqueous phase was added dropwise to the aqueous phase; after the addition was completed, the temperature was raised to 55°C, 2.2 ml of tetramethylethylenediamine was added, and the reaction was continued for 8 hours. After a series of purification and drying, the raw material dry ball was obtained.

[0115] (2) Synthesis of molecule 1:

[0116]

[0117] Under nitrogen protection, add 2,3,5-triiodobenzoic acid (10g, 20.01mmol, 1.0eq), anhydrous DMF (32mL), and anhydrous DCM (23mL) to a 250mL single-mouth reaction bottle (the mass ratio of anhydrous DMF to anhydrous DCM is 1:1). After stirring and dissolving, add HATU (9.13g, 24.01mmol, 1.2eq) at 5°C. After addition, continue stirring for 10-20min, then add methylaminoacetaldehyde dimethyl acetal (2.86g, 24.01mmol, 1.2eq), and then slowly add triethylamine (6.07g, 60.02mmol, 3.0eq) dropwise. After addition, continue to control the temperature at 5°C and react for 1h. TLC monitoring shows that the reaction is complete and post-treatment is carried out. Add 60mL of water to the 250mL single-mouth bottle and stir for 30min. Stop stirring, extract twice with EA, wash the organic phase with brine twice, dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase, purify by column, collect the target product, and concentrate to obtain 12 g of the product (yield: 90.7%), a light yellow oil (purity 98.98%). Characterize by LCMS, HPLC and HNMR.

[0118] (3) Select molecule 1 as the developer: add 4.0 g of dry polyvinyl alcohol microspheres to a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, and swell with 120 ml of DMSO; add 8 g of N-(2,2-diethoxypropyl)-2,3,5-triiodobenzamide, add 1 ml of methanesulfonic acid and react at 60 °C for 48 h to obtain microspheres.

[0119] Example 2

[0120] Provided is a radiopaque embolic microsphere, prepared according to the following steps:

[0121] The method is the same as step (1) of Example 1, except for steps (2) and (3). Specifically, step (2) is as follows:

[0122] The synthesis method of molecule 2:

[0123] (2) Synthesis of Molecule 2

[0124]

[0125] Under nitrogen protection, add 1,3,5-triiodobenzoic acid (10g, 20.01mmol, 1.0eq), anhydrous DMF (32mL), and anhydrous DCM (23mL) to a 250mL single-mouth reaction bottle (the mass ratio of anhydrous DMF to anhydrous DCM is 1:1). After stirring and dissolving, add HATU (9.13g, 24.01mmol, 1.2eq) at 5°C. After addition, continue stirring for 10-20min, then add methylaminoacetaldehyde dimethyl acetal (2.86g, 24.01mmol, 1.2eq), and then slowly add triethylamine (6.07g, 60.02mmol, 3.0eq) dropwise. After addition, continue to control the temperature at 5°C and react for 1h. TLC monitoring shows that the reaction is complete and post-treatment is carried out. Add 60mL of water to the 250mL single-mouth bottle and stir for 30min. Stop stirring, extract twice with EA, wash the organic phase with brine twice, dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase, purify by column, collect the target product, and concentrate to obtain 12 g of the product (yield: 90.7%), a light yellow oil (purity 98.98%). Characterize by LCMS, HPLC and HNMR.

[0126] Molecule 3 was selected as the developer: 4.0 g of dry polyvinyl alcohol microspheres were added to a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, and swollen with 120 ml of DMSO; 8 g of molecule 2 was added, and 1 ml of methanesulfonic acid was added to react at 60°C for 48 h to obtain microspheres.

[0127] Example 3

[0128] The method is the same as step (1) of Example 1, except for steps (2) and (3). Specifically, step (2) is as follows:

[0129] The synthesis method of molecule 3:

[0130] (2) Synthesis of Molecule 3

[0131]

[0132] Under nitrogen protection, add 1,3,5-triiodobenzoic acid (10g, 20.01mmol, 1.0eq), anhydrous DMF (32mL), and anhydrous DCM (23mL) to a 250mL single-mouth reaction bottle (the mass ratio of anhydrous DMF to anhydrous DCM is 1:1). After stirring and dissolving, add HATU (9.13g, 24.01mmol, 1.2eq) at 5°C. After addition, continue stirring for 10-20min, then add propylaminoacetaldehyde dimethyl acetal (3.53g, 24.01mmol, 1.2eq), and then slowly add triethylamine (6.07g, 60.02mmol, 3.0eq) dropwise. After addition, continue to control the temperature at 5°C and react for 1h. TLC monitoring shows that the reaction is complete and post-treatment is carried out. Add 60mL of water to a 250mL single-mouth bottle and stir for 30min. Stop stirring, extract twice with EA, wash the organic phase with brine twice, dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase, purify by column, collect the target product, and concentrate to obtain 12 g of the product (yield: 90.7%), a light yellow oil (purity 98.98%). Characterize by LCMS, HPLC and HNMR.

[0133] Molecule 3 was selected as the developer: 4.0 g of dry polyvinyl alcohol microspheres were added to a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, and swollen with 120 ml of DMSO; 8 g of molecule 2 was added, and 1 ml of methanesulfonic acid was added to react at 60°C for 48 h to obtain microspheres.

[0134] Example 4

[0135] The method is the same as step (1) of Example 1, except for steps (2) and (3). Specifically, step (2) is as follows:

[0136] The synthesis method of molecule 4:

[0137] (2) Synthesis of molecule 4

[0138]

[0139] Under nitrogen protection, add 1,3,5-triiodobenzoic acid (10g, 20.01mmol, 1.0eq), anhydrous DMF (32mL), and anhydrous DCM (23mL) to a 250mL single-mouth reaction bottle (the mass ratio of anhydrous DMF to anhydrous DCM is 1:1). After stirring and dissolving, add HATU (9.13g, 24.01mmol, 1.2eq) at 5°C. After addition, continue stirring for 10-20min, then add methylaminopropionaldehyde diethyl acetal (3.87g, 24.01mmol, 1.2eq), and then slowly add triethylamine (6.07g, 60.02mmol, 3.0eq) dropwise. After addition, continue to control the temperature at 5°C and react for 1h. TLC monitoring shows that the reaction is complete and post-treatment is carried out. Add 60mL of water to the 250mL single-mouth bottle and stir for 30min. Stop stirring, extract twice with EA, wash the organic phase with brine twice, dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase, purify by column, collect the target product, and concentrate to obtain 12 g of the product (yield: 90.7%), a light yellow oil (purity 98.98%). Characterize by LCMS, HPLC and HNMR.

[0140] Molecule 4 was selected as the developer: 4.0 g of dry polyvinyl alcohol microspheres were added to a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, and swollen with 120 ml of DMSO; 8 g of molecule 2 was added, and 1 ml of methanesulfonic acid was added to react at 60°C for 48 h to obtain microspheres.

[0141] Example 5

[0142] The method is the same as step (1) of Example 1, except for steps (2) and (3). Specifically, step (2) is as follows:

[0143] The synthesis method of molecule 5:

[0144] (2) Synthesis of Molecule 5

[0145]

[0146] Under nitrogen protection, add 1,3,5-triiodobenzoic acid (10g, 20.01mmol, 1.0eq), anhydrous DMF (32mL), and anhydrous DCM (23mL) to a 250mL single-mouth reaction bottle (the mass ratio of anhydrous DMF to anhydrous DCM is 1:1). After stirring and dissolving, add HATU (9.13g, 24.01mmol, 1.2eq) at 5°C. After addition, continue stirring for 10-20min, then add methylaminobutyraldehyde dimethyl acetal (3.53g, 24.01mmol, 1.2eq), and then slowly add triethylamine (6.07g, 60.02mmol, 3.0eq) dropwise. After addition, continue to control the temperature at 5°C and react for 1h. TLC monitoring shows that the reaction is complete and post-treatment is carried out. Add 60mL of water to the 250mL single-mouth bottle and stir for 30min. Stop stirring, extract twice with EA, wash the organic phase with brine twice, dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase, purify by column, collect the target product, and concentrate to obtain 12 g of the product (yield: 90.7%), a light yellow oil (purity 98.98%). Characterize by LCMS, HPLC and HNMR.

[0147] Molecule 5 was selected as the developer: 4.0 g of dry polyvinyl alcohol microspheres were added to a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, and swollen with 120 ml of DMSO; 8 g of molecule 2 was added, and 1 ml of methanesulfonic acid was added to react at 60°C for 48 h to obtain microspheres.

[0148] Comparative Example 1

[0149] Provided is a radiopaque embolic microsphere, prepared according to the following steps:

[0150] The method is the same as step (1) of Example 1, except for steps (2) and (3). Specifically, step (2) is as follows:

[0151] Under nitrogen protection, 2,3,5-triiodobenzoic acid (50 g, 100.04 mmol, 1.0 eq) and anhydrous THF (200 mL) were added to a 500 mL single-necked reaction bottle in sequence, stirred and dissolved, and then thionyl chloride (71.41 g, 600.23 mmol, 6.0 eq) was slowly added. The temperature was raised to 70°C and refluxed for 3 hours. After TLC monitoring (a small amount of the reaction solution was quenched with methanol), the reaction solution was directly concentrated to dryness to obtain an off-white acyl chloride solid. At the same time, in another 500 mL three-necked flask, amino was added in sequence under nitrogen protection. Acetaldehyde dimethyl acetal (12.62g, 120.05mmol, 1.2eq), anhydrous DCM (200mL), triethylamine (50.61g, 500.19mmol, 5.0eq), then cooled to -5~0℃, slowly added the prepared acyl chloride solution (dissolve the prepared acyl chloride solid in 150mL of anhydrous DCM), after adding, moved to room temperature and allowed to react for 1.5hr, after TLC monitoring the reaction of the raw materials, added 200mL of water to the reaction solution to quench the reaction, then extracted and layered, leaving the organic phase, concentrated the organic phase to dryness, and then added 600mL After EA was dissolved, it was washed three times with water (200 mL × 3), and the organic phase was retained. After drying with anhydrous sodium sulfate, the organic phase was concentrated. After concentrating to a certain extent (150 mL of EA was retained), a large amount of solid was precipitated. The temperature was lowered to -5 to 0 ° C, and the solid was precipitated by stirring. Then, it was filtered by suction, and the filter cake was rinsed with a small amount of cold EA. After the filter cake was vacuum dried at 45 ° C for 2 hours, 35 g of the target product was obtained as a white solid (purity 98%). It was characterized by LCMS, HPLC and HNMR.

[0152] Step (3)

[0153] N-(2,2-dimethoxyethyl)-2,3,5-triiodobenzamide was selected as the developer: 4.0 g of dry polyvinyl alcohol microspheres were added to a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, and swollen with 120 ml of DMSO; 8 g of N-(2,2-dimethoxyethyl)-2,3,5-triiodobenzamide was added, and 1 ml of methanesulfonic acid was added to react at 60 °C for 48 h to obtain microspheres.

[0154] Comparative Example 2

[0155] Provided is a radiopaque embolic microsphere, prepared according to the following steps:

[0156] The method is the same as step (1) of Example 1, except for step (2). Specifically, step (2) is as follows:

[0157] Under nitrogen protection, 2,3,5-triiodobenzoic acid (50 g, 100.04 mmol, 1.0 eq) and anhydrous THF (200 mL) were added to a 500 mL single-necked reaction bottle in sequence, stirred and dissolved, and then thionyl chloride (71.41 g, 600.23 mmol, 6.0 eq) was slowly added. The temperature was raised to 70°C and refluxed for 3 hours. After TLC monitoring (a small amount of the reaction solution was quenched with methanol), the reaction solution was directly concentrated to dryness to obtain an off-white acyl chloride solid. At the same time, in another 500 mL three-necked flask, amino was added in sequence under nitrogen protection. Acetaldehyde dimethyl acetal (12.62g, 120.05mmol, 1.2eq), anhydrous DCM (200mL), triethylamine (50.61g, 500.19mmol, 5.0eq), then cooled to -5~0℃, slowly added the prepared acyl chloride solution (dissolve the prepared acyl chloride solid in 150mL of anhydrous DCM), after adding, moved to room temperature and allowed to react for 1.5hr, after TLC monitoring the reaction of the raw materials, added 200mL of water to the reaction solution to quench the reaction, then extracted and layered, leaving the organic phase, concentrated the organic phase to dryness, and then added 600mL After EA was dissolved, it was washed three times with water (200 mL × 3), and the organic phase was retained. After drying with anhydrous sodium sulfate, the organic phase was concentrated. After concentrating to a certain extent (150 mL of EA was retained), a large amount of solid was precipitated. The temperature was lowered to -5 to 0 ° C, and the solid was precipitated by stirring. Then, it was filtered by suction, and the filter cake was rinsed with a small amount of cold EA. After the filter cake was vacuum dried at 45 ° C for 2 hours, 35 g of the target product was obtained as a white solid (purity 98%). It was characterized by LCMS, HPLC and HNMR.

[0158] Step 3 is as follows:

[0159] N-(2,2-dimethoxyethyl)-1,3,5-triiodobenzamide was selected as the developer: 4.0 g of dry polyvinyl alcohol microspheres were added to a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, and swollen with 120 ml of DMSO; 8 g of N-(2,2-dimethoxyhexyl)-2,3,5-triiodobenzamide was added, and 1 ml of methanesulfonic acid was added to react at 60 °C for 48 h to obtain microspheres.

[0160] Comparative Example 3

[0161] Provided is a radiopaque embolic microsphere, prepared according to the following steps:

[0162] The method is the same as step (1) of Example 1, except for steps (2) and (3). Specifically, step (2) is as follows:

[0163] Under nitrogen protection, 2,3,5-triiodobenzoic acid (50 g, 100.04 mmol, 1.0 eq) and anhydrous THF (200 mL) were added to a 500 mL single-necked reaction bottle in sequence, stirred and dissolved, and then thionyl chloride (71.41 g, 600.23 mmol, 6.0 eq) was slowly added. The temperature was raised to 70°C and refluxed for 3 hours. After TLC monitoring (a small amount of the reaction solution was quenched with methanol), the reaction solution was directly concentrated to dryness to obtain an off-white acyl chloride solid. At the same time, in another 500 mL three-necked flask, amino was added in sequence under nitrogen protection. Propionaldehyde diethyl acetal (17.67g, 120.05mmol, 1.2eq), anhydrous DCM (200mL), triethylamine (50.61g, 500.19mmol, 5.0eq), then cool to -5~0℃, slowly add the prepared acyl chloride solution (dissolve the prepared acyl chloride solid in 150mL of anhydrous DCM), after adding, move to room temperature and let it react for 1.5hr, after TLC monitoring the reaction of the raw materials, add 200mL of water to the reaction solution to quench the reaction, then extract and layer, keep the organic phase, concentrate the organic phase to dryness, and then add 600mL After EA was dissolved, it was washed three times with water (200 mL × 3), and the organic phase was retained. After drying with anhydrous sodium sulfate, the organic phase was concentrated. After concentrating to a certain extent (150 mL of EA was retained), a large amount of solid was precipitated. The temperature was lowered to -5 to 0 ° C, and the solid was precipitated by stirring. Then, it was filtered by suction, and the filter cake was rinsed with a small amount of cold EA. After the filter cake was vacuum dried at 45 ° C for 2 hours, 35 g of the target product was obtained as a white solid (purity 98%). It was characterized by LCMS, HPLC and HNMR.

[0164] Step 3 is as follows

[0165] N-(2,2-diethoxypropyl)-2,3,5-triiodobenzamide was selected as the developer: 4.0 g of dry polyvinyl alcohol microspheres were added to a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, and swollen with 120 ml of DMSO; 8 g of N-(2,2-diethoxypropyl)-1,3,5-triiodobenzamide was added, and 1 ml of methanesulfonic acid was added to react at 60 °C for 48 h to obtain microspheres.

[0166] Comparative Example 4

[0167] The method is the same as step (1) of Example 1, except for steps (2) and (3). Specifically, step (2) is as follows:

[0168] Under nitrogen protection, 2,3,5-triiodobenzoic acid (50 g, 100.04 mmol, 1.0 eq) and anhydrous THF (200 mL) were added to a 500 mL single-necked reaction bottle in sequence, stirred and dissolved, and then thionyl chloride (71.41 g, 600.23 mmol, 6.0 eq) was slowly added. The temperature was raised to 70°C and refluxed for 3 hours. After TLC monitoring (a small amount of the reaction solution was quenched with methanol), the reaction solution was directly concentrated to dryness to obtain an off-white acyl chloride solid. At the same time, in another 500 mL three-necked flask, amino was added in sequence under nitrogen protection. Butyraldehyde dimethyl acetal (17.67g, 120.05mmol, 1.2eq), anhydrous DCM (200mL), triethylamine (50.61g, 500.19mmol, 5.0eq), then cool to -5~0℃, slowly add the prepared acyl chloride solution (dissolve the prepared acyl chloride solid in 150mL of anhydrous DCM), after adding, move to room temperature and let it react for 1.5hr, after TLC monitoring the reaction of the raw materials, add 200mL of water to the reaction solution to quench the reaction, then extract and layer, keep the organic phase, concentrate the organic phase to dryness, and then add 600mL After EA was dissolved, it was washed three times with water (200 mL × 3), and the organic phase was retained. After drying with anhydrous sodium sulfate, the organic phase was concentrated. After concentrating to a certain extent (150 mL of EA was retained), a large amount of solid was precipitated. The temperature was lowered to -5 to 0 ° C, and the solid was precipitated by stirring. Then, it was filtered by suction, and the filter cake was rinsed with a small amount of cold EA. After the filter cake was vacuum dried at 45 ° C for 2 hours, 35 g of the target product was obtained as a white solid (purity 98%). It was characterized by LCMS, HPLC and HNMR.

[0169] Step (3)

[0170] N-(2,2-dimethoxybutyl)-2,3,5-triiodobenzamide was selected as the developer: 4.0 g of dry polyvinyl alcohol microspheres were added to a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, and swollen with 120 ml of DMSO; 8 g of N-(2,2-diethoxypropyl)-1,3,5-triiodobenzamide was added, and 1 ml of methanesulfonic acid was added to react at 60 °C for 48 h to obtain microspheres.

[0171] Experimental Example 1

[0172] The performance of the radiopaque embolic microspheres provided in Examples 1-2 and Comparative Examples 1-4 was tested, and the test results are shown in Table 1.

[0173] Iodine content testing steps:

[0174] The content of triiodobenzamide before sterilization and triiodobenzamide after sterilization was determined by high performance liquid chromatography.

[0175] Table 1

[0176]

[0177] From the results in Table 1 above, it can be seen that the reaction efficiency of the microspheres is significantly improved and the iodine content is significantly increased by introducing the side groups. In addition, the introduction of the side groups also improves the stability of the microspheres under sterilization conditions, and the impurities generated after sterilization are significantly reduced.

[0178] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A radiopaque embolic microsphere, characterized in that: include: The iodine-containing developer, polyvinyl alcohol microspheres and methanesulfonic acid are reacted at 50° C. to 70° C. for 40 h to 60 h to obtain polymer microspheres; the ratio of the iodine-containing developer: the polyvinyl alcohol microspheres: the methanesulfonic acid is (5-10) g: (2-6) g: (0.5-2) ml; The preparation steps of the polyvinyl alcohol microspheres include: reacting polyvinyl alcohol with N-(2,2-dimethoxyethyl)-2-acrylamide to obtain a macromolecular polyvinyl alcohol monomer; then mixing the macromolecular polyvinyl alcohol monomer with acrylamide-2-methylpropanesulfonic acid sodium salt solution to obtain an aqueous phase; The oil phase is prepared by using butyl acetate and cellulose acetate butyrate; Mixing the water phase and the oil phase to obtain the polyvinyl alcohol microspheres; The iodine-containing developer comprises at least one of the following structures: Wherein, R3 is an alkyl group of 1 to 4 carbons; And the polymer microspheres include at least one of the following structures: Wherein, R1=alkyl group with 1 to 4 carbon atoms, R2=alkyl group with 1 to 3 carbon atoms; R1 and R2 are not alkyl groups with 1 carbon atoms at the same time; and the iodine content of the radiopaque embolic microspheres is greater than 140 mg / mL.

2. The radiopaque embolic microspheres according to claim 1, characterized in that: R3 is methyl or ethyl.

3. The radiopaque embolic microspheres according to claim 1, characterized in that: The iodine-containing developer is at least one of the following structures: 。 4. The method for preparing the radiopaque embolic microspheres according to any one of claims 1 to 3, characterized in that: include: The iodine-containing developer, polyvinyl alcohol microspheres and methanesulfonic acid are reacted at 50° C.-70° C. for 40 h-60 h to obtain polymer microspheres; the ratio of the iodine-containing developer: the polyvinyl alcohol microspheres: the methanesulfonic acid is (5-10) g: (2-6) g: (0.5-2) ml.

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