WO2024060825A1

WO2024060825A1 - X-ray developing compound and preparation method therefor, and x-ray developing microsphere and preparation method therefor

Info

Publication number: WO2024060825A1
Application number: PCT/CN2023/109266
Authority: WO
Inventors: 孙宏涛; 李鑫; 孙蓬
Original assignee: 科睿驰（深圳）医疗科技发展有限公司
Priority date: 2022-09-22
Filing date: 2023-07-26
Publication date: 2024-03-28
Also published as: CN115590984A; CN115590984B

Abstract

The present invention relates to an X-ray developing compound and a preparation method therefor, and an X-ray developing microsphere and a preparation method therefor, and belongs to the technical field of embolization visualization under X-rays. The X-ray developing compound has a structural formula shown as follows: (I), wherein n is an integer from 1 to 5. According to the developing compound, an iodo aryl group and an epoxy group are connected by means of an ether bond to form the X-ray developing compound. The epoxy group in the developing compound is easy to subject to a one-step reaction with a hydroxyl group in a polyvinyl alcohol microsphere, such that the polyvinyl alcohol microsphere has a developing function, and the prepared developing microsphere has good hydrophilicity.

Description

X-ray developing compounds and preparation methods thereof, X-ray developing microspheres and preparation methods thereof

Cross-references to related applications

This application requires the priority of the Chinese patent application with application number 202211159438.5 and titled "X-ray developing compounds and preparation methods thereof, X-ray developing microspheres and preparation methods thereof" submitted to the China Patent Office on September 22, 2022. The entire contents of which are incorporated herein by reference.

Technical field

The present application relates to the technical field of embolization visualized under X-rays, and in particular to an X-ray developing compound and its preparation method, X-ray developing microspheres and its preparation method.

Background technique

For more than 40 years since the concept of transcatheter arterial embolization (TAE) was proposed, selecting appropriate embolization materials is a key part of the development of this technology. Due to the strong absorption of X-rays by iodine atoms, iodine-containing compounds, especially iodine-containing organic compounds, can be visualized in the human body under X-ray detection. Therefore, an iodine-containing organic compound can be connected to the embolic material, so that the embolic material has the function of X-ray development.

Patent CN102781974B describes the use of iodobenzyl bromide or benzyl methanesulfonate to modify polyvinyl alcohol (PVA) microspheres under alkaline conditions to obtain a polyvinyl alcohol embolus with an iodobenzyl ether structure. This embolus has X Radiographic development function. However, this method consumes hydroxyl groups while developing and modifying, causing the modified PVA to become less hydrophilic.

Patent 114805644A describes grafting epichlorohydrin onto polyvinyl alcohol under alkaline catalyst conditions, introducing chlorine atoms into the polyvinyl alcohol to obtain activated polyvinyl alcohol; and then combining the activated polyvinyl alcohol with iodine Benzyl alcohol undergoes an etherification reaction to graft the iodobenzyl group onto polyvinyl alcohol, thereby obtaining an iodine-containing polyvinyl alcohol polymer. The polymer is soluble in non-physiological solutions and insoluble under physiological conditions, and can be used as a liquid embolization material in medical treatment with stability and development effects. The chemical structure of the developing base described in this method is -OCH ₂ CH(OH)CH ₂ OR, and R is an iodobenzyl group. This method generates a hydroxyl group while developing and modifying, which can better maintain the hydrophilic properties of PVA. However, developing and modifying requires a two-step reaction and the process is complicated. In addition, active chloride ions are introduced into the process, and the biological safety of chlorinated hydrocarbons needs to be verified. The safety risks of this process are relatively high.

Application content

In view of the shortcomings of the existing technology, the purpose of the embodiments of the present application includes providing an X-ray developing compound and a preparation method thereof, X-ray developing microspheres and a preparation method thereof, based on a new type of developing compound, which can be combined with polyvinyl alcohol microspheres. The ball reacts in one step, the process is safe, and polyvinyl alcohol microspheres with X-ray developing function are obtained, and their hydrophilicity is good.

In the first aspect, embodiments of the present application provide an X-ray developing compound. The structural formula of the X-ray developing compound is as follows:

Here, n is an integer from 1 to 5.

In the above technical solution, an iodoaryl group and an epoxy group are connected through an ether bond to form an Vinyl alcohol microspheres have a developing function, and the prepared developing microspheres are relatively hydrophilic.

In some embodiments of the present application, the structural formula of the X-ray developing compound is:

In a second aspect, this application provides a method for preparing the above-mentioned X-ray developing compound, reaction formula 1:

In the above technical solution, the developing compound can be obtained through a one-step reaction between iodobenzyl alcohol compounds and 3-epoxypropane. The reaction conditions are relatively mild and the preparation is relatively simple.

In a third aspect, this application provides an X-ray developing microsphere. The structural formula of the developing microsphere is as follows:

Among them, n is an integer from 1 to 5. By controlling the cross-linking reaction conditions and time, X-ray developing microspheres with different m values can be obtained, where m is a positive integer greater than 1.

In the above technical solution, the hydrophilicity of the X-ray developing microspheres is relatively good.

In some embodiments of this application, the structural formula of the developing microspheres is as follows:

In a fourth aspect, the present application provides a method for preparing X-ray developing microspheres, including: under the catalytic action of an organic acid or an organic base, the epoxy group of the above-mentioned X-ray developing compound is combined with at least one of the polyvinyl alcohol microspheres. Part of the hydroxyl group reacts to form an ether bond.

In the above technical solution, the preparation of X-ray developing microspheres can be relatively simple, and the polyvinyl alcohol microspheres can be given a developing function through a direct one-step reaction. At the same time, the obtained developing microspheres have good hydrophilicity.

In some embodiments of this application, the catalyst is an organic acid, and the preparation method includes:

Reaction 2:

Under the above conditions, an organic acid is used as a catalyst to react in the next step at a lower temperature to modify the polyvinyl alcohol microspheres to obtain developing microspheres.

In some embodiments of the present application, the mass ratio of the X-ray developing compound to the polyvinyl alcohol microspheres is (1.5-3):1; the mass ratio of the X-ray developing compound to the organic acid is 1:(0.1-2).

In some embodiments of the present application, the organic acid is at least one of methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid; the solvent is dimethyl sulfoxide, N,N-dimethyl At least one of methylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

In some embodiments of the present application, the catalyst is an organic base, and the preparation method includes:

Reaction three:

In some embodiments of the present application, the mass ratio of the X-ray developing compound to the polyvinyl alcohol microspheres is (1.5-3):1; the mass ratio of the X-ray developing compound to the organic base is 1:(0.5-3).

In some embodiments of this application, the organic base is triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diaza At least one of heterobicyclo[2.2.2]octane; the solvent is dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone of at least one.

Description of drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required to be used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present application and therefore do not should be viewed as a limitation of scope.

Figure 1 is an optical picture of the wet bulb of polyvinyl alcohol raw material provided by the implementation team of this application;

Figure 2 is an optical picture of the developed microspheres provided in Example 1;

Figure 3 is an optical picture of the developed microspheres provided in Example 2;

Figure 4 is an optical picture of the developed microspheres provided in Example 3;

Figure 5 is an optical picture of the developed microspheres provided in Example 4;

Figure 6 is an optical picture of the developed microspheres provided in Example 5;

Figure 7 is an optical picture of the developed microspheres provided in Example 6;

Figure 8 is an optical picture of the developed microspheres provided in Example 7;

Figure 9 is an optical picture of the developed microspheres provided in Example 8;

FIG10 is an optical image of the developed microspheres provided in Example 9;

Figure 11 is an optical picture of the developed microspheres provided in Example 10;

Figure 12 is an optical picture of the developed microspheres provided in Example 11;

Figure 13 is an optical picture of the developed microspheres provided in Embodiment 12;

Figure 14 is an optical picture of the developed microspheres provided in Comparative Example 1;

Figure 15 is an optical picture of the developed microspheres provided in Comparative Example 2.

Detailed ways

In order to make the purpose, technical solutions, and advantages of the embodiments of the present application clearer, the technical solutions of the present application are described clearly and completely below.

X-ray developing compounds

In this application, the structural formula of the X-ray developing compound is as follows:

Among them, n is an integer from 1 to 5.

In the above technical solution, the function of I atoms is to develop under X-ray irradiation, and the number of I atoms can be 1, 2, 3, 4 or 5. The number of substitutions of I atoms will not cause differences in the hydrophilicity and suspension properties of the developing microspheres after the developer is combined with the microspheres.

In some embodiments, the structural formula of the X-ray developing compound can be:

In other embodiments, the structural formula of the X-ray imaging compound may also be:

Method for preparing X-ray developing compound

After the structural formula of the X-ray developing compound is introduced above, the preparation method of the X-ray developing compound is introduced in detail below. It is prepared by the method provided by Reaction Formula 1. Reaction Formula 1 is as follows:

Optionally, in an anaerobic environment, compound II, compound III, tetrabutylammonium hydrogen sulfate (2-20 mol%) and tetrahydrofuran (THF) are mixed uniformly to form a solution; 40-60% (w/w) sodium hydroxide or/and potassium hydroxide solution is added at 0-5°C, react for 20-40 minutes, then warm to room temperature and react for 4-24 hours.

For example: under nitrogen protection, add compound II (1.0eq.), compound III (1.1eq.), tetrabutylammonium hydrogen sulfate (2-20mol%) and THF in sequence to a single-mouth reaction bottle, stir and dissolve thoroughly. Add 40-60% (w/w) sodium hydroxide solution at 0-5°C, react for 20-40 minutes, then rise to room temperature and react for 4-24 hours. After TLC monitors the complete reaction of the raw materials, spin THF to dryness under reduced pressure at low temperature, and add anhydrous ether and saturated sodium chloride solution. The liquids were separated, and the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain compound I.

X-ray imaging microspheres

The structural formula of the X-ray developing microsphere is as follows:

Among them, n is an integer from 1 to 5.

In some embodiments, the structural formula of the developing microspheres can be:

In other embodiments, the structural formula of the developing microspheres can also be:

Preparation method of X-ray developing microspheres

In this application, under the catalytic action of an organic acid or an organic base, the epoxy group of the above-mentioned X-ray developing compound is reacted with at least part of the hydroxyl groups on the polyvinyl alcohol microspheres to form an ether bond. The preparation of X-ray developing microspheres can be relatively simple, and the polyvinyl alcohol microspheres can be given a developing function through a direct one-step reaction. At the same time, the obtained developing microspheres have good hydrophilicity.

The preparation method of polyvinyl alcohol microspheres is as follows: polyvinyl alcohol and N-(2,2-dimethoxyethyl)-2-acrylamide are subjected to an acid-catalyzed reaction to obtain a macromolecular polyvinyl alcohol monomer grafted with N-(2,2-dimethoxyethyl)-2-acrylamide; the macromolecular polyvinyl alcohol monomer is prepared with a water-soluble monomer with a sulfonic acid group, an initiator and water to form an aqueous phase, and the aqueous phase is added to the oil phase under mechanical stirring to form an oil-in-water reverse suspension polymerization system; the reverse suspension polymerization system is heated to a reaction temperature, and a catalyst is added to carry out a suspension polymerization reaction; polyvinyl alcohol microspheres are obtained by reaction, and polyvinyl alcohol microsphere dry balls are obtained after purification and drying processes.

Alternatively, dissolve polyvinyl alcohol in water, then add N-(2,2-dimethoxyethyl)-2-acrylamide, add hydrochloric acid and react at room temperature for 10 hours or more, and then use sodium hydroxide. and, a macromolecular polyvinyl alcohol monomer solution is obtained. Dissolve cellulose acetate butyrate in butyl acetate to form an oil phase; dissolve acrylamide-2-methylpropanesulfonic acid sodium salt in water, add macromolecular polyvinyl alcohol monomer solution and potassium persulfate to form a water phase . Under stirring conditions, add the water phase dropwise to the oil phase. After the addition is completed, raise the temperature to 50-60°C, add tetramethylethylenediamine, and react for 7-9 hours. After a series of purification and drying, dry polyvinyl alcohol microspheres are obtained.

In some embodiments, the catalyst is an organic acid, and the preparation method comprises:

Reaction 2:

Alternatively, dry polyvinyl alcohol microspheres, X-ray developing compound I and solvent are mixed and heated to swell. After swelling, organic acid is added and reacted at 40-90°C for 24-48 hours. After the reaction, clean and remove impurities.

Among them, the mass ratio of the X-ray developing compound and the polyvinyl alcohol microspheres is (1.5-3):1; the mass ratio of the X-ray developing compound and the organic acid is 1:(0.1-2). The organic acid is at least one of methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid; the solvent is dimethyl sulfoxide (DMSO) or N,N-dimethylformamide (DMF). , at least one of N,N-dimethylacetamide and N-methylpyrrolidone (NMP).

Illustratively, the reaction temperature is 40°C, 50°C, 60°C, 70°C, 80°C or 90°C; the reaction time is 24h, 28h, 32h, 36h, 40h, 44h or 48h; the mass ratio of the X-ray developing compound to the polyvinyl alcohol microspheres is 1.5:1, 2:1, 2.5:1 or 3:1; the mass ratio of the X-ray developing compound to the organic acid is 1:0.1, 1:0.5, 1:1, 1:1.5 or 1:2.

For example: Mix dry polyvinyl alcohol microspheres, X-ray developing compound I and DMSO and heat to swell. After swelling, add methanesulfonic acid and react at 40-90°C for 24-48 hours. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and acid.

In other embodiments, the catalyst is an organic base, and the preparation method includes:

Reaction three:

Optionally, polyvinyl alcohol microsphere dry balls, X-ray imaging compound I and solvent are mixed and heated to swell, and then an organic base is added after swelling, and the mixture is reacted at 60-120° C. for 24-48 hours. After the reaction, the mixture is washed and impurities are removed.

Among them, the mass ratio of the X-ray developing compound and the polyvinyl alcohol microspheres is (1.5-3):1; the mass ratio of the X-ray developing compound and the organic base is 1:(0.5-3). The organic bases are triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane At least one of alkane; the solvent is at least one of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

Illustratively, the reaction temperature is 60°C, 70°C, 80°C, 90°C, 100°C, 110°C or 120°C; the reaction time is 24h, 28h, 32h, 36h, 40h, 44h or 48h; the mass ratio of the X-ray developing compound to the polyvinyl alcohol microspheres is 1.5:1, 2:1, 2.5:1 or 3:1; the mass ratio of the X-ray developing compound to the organic base is 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

For example: Mix dry polyvinyl alcohol microspheres, X-ray developing compound I and DMSO and heat to swell. After swelling, add diisopropylethylamine and react at 60-120°C for 24-48 hours. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and alkali.

Based on the above-mentioned X-ray developing compound I, X-ray developing microspheres are prepared through a one-step reaction, and the developing microspheres have good hydrophilicity.

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. If the specific conditions are not specified in the examples, the conditions should be carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not indicated, they are all conventional products that can be purchased commercially.

Example 1: Synthesis of Compound I-1

Under nitrogen protection, compound II-1 (20.6mmol, 10g), compound III (20.6mmol, 1.6mL), tetrabutylammonium hydrogen sulfate (1.0mmol, 339.5mg) and THF (50mL) were added in sequence to the single-mouth reaction bottle. , stir thoroughly to dissolve. Add 5 mL of 50% (w/w) sodium hydroxide solution at 0°C, react for 30 minutes, then rise to room temperature and react for 4-24 hours. After TLC monitors the complete reaction of the raw materials, spin THF to dryness under reduced pressure at low temperature, and add anhydrous ether and saturated sodium chloride solution. The liquids were separated, and the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain the target compound I-1 (9.5 g, 85%), which is a light yellow viscous oily liquid (purity 98%). .

The obtained target product I-1 was characterized by HPLC (high performance liquid chromatography), LCMS (liquid phase mass spectrometry) and ¹ H-NMR (proton nuclear magnetic spectrum). Methods as below:

HPLC: The test instrument is an Agilent 1260 high-performance liquid chromatograph; the chromatographic column is an octadecyl-bonded silica gel column; the mobile phase is 0.1% phosphoric acid aqueous solution and methanol; the detector is a VWD detector; take about 0.1mg of the sample and put it on the sample In the bottle, add DMSO to dissolve and directly inject the sample for testing; determine the product purity based on the integrated area.

LCMS: The test instrument is Agilent 1260-6125 high performance liquid chromatography mass spectrometer; the chromatographic column is an octadecyl bonded silica gel column; the mobile phase is 0.1% formic acid aqueous solution and methanol; the detector is a mass spectrometer detector; take 0.1 Put about mg sample into the sample bottle, add DMSO to dissolve it and directly inject the sample for detection to identify the main ion peaks.

¹ H-NMR: The test instrument is a Bruker 400M nuclear magnetic tester; the probe used is a normal temperature hydrogen spectrometer probe; add 20-30mg of the sample into the nuclear magnetic tube, add 0.3-0.5mL of deuterated chloroform to dissolve and test. The hydrogen nuclear magnetic spectrum of the obtained target product I-1 is: ¹ H NMR (400MHz, CDCl ₃ ) δ8.07 (d, J = 2.1 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 4.65- 4.56(m,2H),3.82(dd,J＝11.4,3.0Hz,1H),3.46(dd,J＝11.4,5.9Hz,1H),3.21-3.17(m,1H),2.82(t,J＝ 4.7Hz, 1H), 2.65-2.63 (m, 1H); MS (ESI): m/z 543 (M+H ⁺ ).

Example 2: Synthesis of Compound I-2

Under nitrogen protection, compound II-2 (20.6mmol, 4.8g), compound III (20.6mmol, 1.6mL), tetrabutylammonium hydrogen sulfate (1.0mmol, 339.5mg) and THF (50mL) were added in sequence to the single-neck reaction flask. ), stir thoroughly to dissolve. Add 5 mL of 50% (w/w) sodium hydroxide solution at 0°C, react for 30 minutes, then rise to room temperature and react for 4-24 hours. After TLC monitors the complete reaction of the raw materials, spin THF to dryness under reduced pressure at low temperature, and add anhydrous ether and saturated sodium chloride solution. The liquids were separated, and the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain the target compound I-2 (5.38 g, 90%) as a light yellow oily liquid (purity 98%). The detection method is the same as in Example 1, and the results obtained are: ¹ H NMR (400MHz, CDCl ₃ ) δ7.39-7.26 (m, 4H), 4.65-4.60 (m, 2H), 3.82 (dd, J = 11.4, 3.0Hz ,1H),3.46(dd,J＝11.4,5.9Hz,1H),3.21-3.17(m,1H),2.82(t,J＝4.7Hz,1H),2.66-2.64(m,1H);MS( ESI): m/z 291(M+H ⁺ ).

Example 3: Synthesis of Compound I-3

Under nitrogen protection, compound II-3 (20.6mmol, 4.8g), compound III (20.6mmol, 1.6mL), tetrabutylammonium hydrogen sulfate (1.0mmol, 339.5mg) and THF (50mL) were added in sequence to the single-neck reaction flask. ), stir thoroughly to dissolve. Add 5 mL of 50% (w/w) sodium hydroxide solution at 0°C, react for 30 minutes, then rise to room temperature and react for 4-24 hours. After TLC monitors the complete reaction of the raw materials, spin THF to dryness under reduced pressure at low temperature, and add anhydrous ether and saturated sodium chloride solution. The liquids were separated, and the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain target compound I-3 (5.44 g, 91%) as a light yellow oily liquid (purity 98%). The detection method is the same as in Example 1, and the results obtained are: ¹ H NMR (400MHz, CDCl ₃ ) δ7.41-7.25 (m, 4H), 4.64-4.53 (m, 2H), 3.82 (dd, J = 11.4, 3.0Hz ,1H),3.46(dd,J＝11.4,5.9Hz,1H),3.21-3.17(m,1H),2.82(t,J＝4.7Hz,1H),2.66-2.63(m,1H);MS( ESI): m/z 291(M+H ⁺ ).

Example 4: Synthesis of Compound I-4

Under nitrogen protection, compound II-4 (20.6mmol, 4.8g), compound III (20.6mmol, 1.6mL), tetrabutylammonium hydrogen sulfate (1.0mmol, 339.5mg) and THF (50mL) were added in sequence to the single-neck reaction flask. ), stir thoroughly to dissolve. Add 5 mL of 50% (w/w) sodium hydroxide solution at 0°C, react for 30 minutes, then rise to room temperature and react for 4-24 hours. After TLC monitors the complete reaction of the raw materials, spin THF to dryness under reduced pressure at low temperature, and add anhydrous ether and saturated sodium chloride solution. The liquids were separated, and the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain the target compound I-4 (5.68 g, 95%) as a light yellow oily liquid (purity 98%). The detection method is the same as in Example 1, and the results obtained are: ¹ H NMR (400MHz, CDCl ₃ ) δ7.45 (d, J = 13.2 Hz, 2H), 7.05 (d, J = 13.2 Hz, 2H), 4.68 (s, 2H),3.82(dd,J＝11.4,3.0Hz,1H),3.46(dd,J＝11.4,5.9Hz,1H),3.21-3.17(m,1H),2.82(t,J＝4.7Hz,1H ), 2.66-2.63(m,1H); MS(ESI): m/z 291(M+H ⁺ ).

Example 5: Synthesis of Compound I-5

Under nitrogen protection, compound II-5 (20.6mmol, 7.4g), compound III (20.6mmol, 1.6mL), tetrabutylammonium hydrogen sulfate (1.0mmol, 339.5mg) and THF (50mL) were added in sequence to a single-mouth reaction flask. ), stir thoroughly to dissolve. Add 5 mL of 50% (w/w) sodium hydroxide solution at 0°C, react for 30 minutes, then rise to room temperature and react for 4-24 hours. After TLC monitors the complete reaction of the raw materials, spin THF to dryness under reduced pressure at low temperature, and add anhydrous ether and saturated sodium chloride solution. The liquids were separated, and the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain the target compound I-5 (5.44 g, 91%) as a light yellow oily liquid (purity 98%). The detection method is the same as Example 1, and the results obtained are: ¹ H NMR (400MHz, CDCl ₃ ) δ7.63 (dd, J = 11.2, 3.2 Hz, 1H), 7.45 (dd, J = 11.2, 5.4 Hz, 1H), 7.18(dd,J＝5.4,3.2Hz,1H),4.64-7.55(m,2H),3.82(dd,J＝11.4,3.0Hz,1H),3.46(dd,J＝11.4,5.9Hz,1H) ,3.21-3.18(m,1H),2.82(t,J=4.7Hz,1H),2.65-2.63(m,1H); MS(ESI):m/z 417(M+H ⁺ ).

Example 6: Synthesis of Compound I-6

Under nitrogen protection, compound II-6 (20.6mmol, 10g), compound III (20.6mmol, 1.6mL), tetrabutylammonium hydrogen sulfate (1.0mmol, 339.5mg) and THF (50mL) were added in sequence to a single-mouth reaction bottle. , stir thoroughly to dissolve. Add 5 mL of 50% (w/w) sodium hydroxide solution at 0°C, react for 30 minutes, then rise to room temperature and react for 4-24 hours. After TLC monitors the complete reaction of the raw materials, spin THF to dryness under reduced pressure at low temperature, and add anhydrous ether and saturated sodium chloride solution. The liquids were separated, and the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain the target compound I-6 (9.7g, 87%), which was a light yellow viscous oily liquid (purity 98%). . The detection method is the same as in Example 1, and the results obtained are: ¹ H NMR (400MHz, CDCl ₃ ) δ8.03 (s, 2H), 4.68 (s, 2H), 3.82 (dd, J = 11.4, 3.0Hz, 1H), 3.46(dd,J＝11.4,5.9Hz,1H),3.21-3.18(m,1H),2.82(t,J＝4.7Hz,1H),2.63-2.60(m,1H); MS(ESI):m /z 543(M+H ⁺ ).

Implementation group: Preparation of PVA dry balls:

Add 100 mL of purified water to a 250 mL three-necked flask equipped with overhead mechanical stirring, add about 15 g of PVA (model 1888), heat to 95°C to dissolve, and lower to room temperature; add 0.7654 g of N-(2,2-dimethoxy ethyl)-2-acrylamide (NAAADA), then 10 mL of concentrated hydrochloric acid was added, the reaction was carried out at room temperature for 14 hours, and then neutralized to pH=7 with 2.5 M sodium hydroxide solution to obtain macromolecular polyvinyl alcohol monomer solution.

Add 600 mL of butyl acetate to a 1L three-necked bottle equipped with overhead mechanical stirring, add 18g of cellulose acetate butyrate to dissolve, and obtain an oil phase; 8.61g of acrylamide-2-methylpropanesulfonate sodium salt (AMPS sodium) Dissolve in 60 mL of water, add 160 g of macromolecular polyvinyl alcohol monomer solution, and add 1.5 g of potassium persulfate to obtain a water phase.

The speed was set to 400 rpm, and the aqueous phase was added dropwise to the oil 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 purifications and drying, the raw material dry ball was obtained.

Example 1: Preparation of developing microspheres catalyzed by compound I-1 organic acid

Add 5g dry polyvinyl alcohol microspheres, 10g compound I-1 and 125mL DMSO (dimethyl sulfoxide) into a three-necked flask equipped with a mechanical stirring paddle at the top, adjust the stirring speed to 100rpm/min, and heat and swell at 60°C . After swelling, add 5 mL methanesulfonic acid and keep the reaction at 60°C for 24 hours. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and acid to obtain developed microspheres. Take a 2.0 mL wet bulb, dry it with acetone, dry it at 105°C for 5 hours to a constant weight and then weigh it to be 632 mg. Take some dry balls and measure the iodine content of the dry balls to be 40.1%. The calculated wet bulb iodine content is 127 mg/mL.

Example 2: Preparation of developing microspheres catalyzed by compound I-1 organic base

Add 5g dry polyvinyl alcohol microspheres, 10g compound I-1 and 125mL DMSO (dimethyl sulfoxide) into a three-necked flask equipped with a mechanical stirring paddle at the top, adjust the stirring speed to 100rpm/min, and heat and swell at 60°C . After swelling, add 5 mL of diisopropylethylamine, raise the temperature to 80°C, and react for 48 hours. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and alkali to obtain developed microspheres. Take a 2.0 mL wet bulb, dry it with acetone, dry it at 105°C for 5 hours to constant weight, and weigh it to 567 mg. Take some dry balls and measure the iodine content of the dry balls to be 30.1%. The calculated wet bulb iodine content is 85.3 mg/mL.

Example 3: Preparation of developing microspheres by organic acid catalysis of compound I-2

Add 5g dry polyvinyl alcohol microspheres, 10g compound I-2 and 125mL DMSO (dimethyl sulfoxide) into a three-necked flask equipped with a mechanical stirring paddle at the top, adjust the stirring speed to 100rpm/min, and heat and swell at 60°C . After swelling, add 5 mL methanesulfonic acid and keep the reaction at 60°C for 24 hours. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and acid to obtain developed microspheres. Take a 2.0 mL wet bulb, dry it with acetone, dry it at 105°C for 5 hours to a constant weight and then weigh it to be 551 mg. Take some dry balls and measure the iodine content of the dry balls to be 15.1%. The calculated wet bulb iodine content is 41.6 mg/mL.

Example 4: Preparation of developing microspheres catalyzed by compound I-2 organic base

Add 5g dry polyvinyl alcohol microspheres, 10g compound I-2 and 125mL DMSO (dimethyl sulfoxide) into a three-necked flask equipped with a mechanical stirring paddle at the top, adjust the stirring speed to 100rpm/min, and heat and swell at 60°C . After swelling, add 5 mL of diisopropylethylamine, raise the temperature to 80°C, and react for 48 hours. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and alkali to obtain developed microspheres. Take a 2.0 mL wet bulb, dry it with acetone, dry it at 105°C for 5 hours to a constant weight and then weigh it to be 502 mg. Take some dry balls and measure the iodine content of the dry balls to be 13.3%. The calculated wet bulb iodine content is 33.4 mg/mL.

Example 5: Preparation of developing microspheres catalyzed by compound I-3 under organic acid

Add 5g dry polyvinyl alcohol microspheres, 10g compound I-3 and 125mL DMSO (dimethyl sulfoxide) into a three-necked flask equipped with a mechanical stirring paddle at the top, adjust the stirring speed to 100rpm/min, and heat and swell at 60°C . After swelling, add 5 mL methanesulfonic acid and keep the reaction at 60°C for 24 hours. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and acid to obtain developed microspheres. Take a 2.0 mL wet bulb, dry it with acetone, dry it at 105°C for 5 hours to a constant weight and then weigh it to be 535 mg. Take some dry balls and measure the iodine content of the dry balls to be 15.0%. The calculated wet bulb iodine content is 40.1 mg/mL.

Example 6: Preparation of developing microspheres catalyzed by compound I-3 organic base

Add 5g dry polyvinyl alcohol microspheres, 10g compound I-3 and 125mL DMSO (dimethyl sulfoxide) into a three-necked flask equipped with a mechanical stirring paddle at the top, adjust the stirring speed to 100rpm/min, and heat and swell at 60°C. . After swelling, add 5 mL of diisopropylethylamine, raise the temperature to 80°C, and react for 48 hours. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and alkali to obtain developed microspheres. Take a 2.0 mL wet bulb, dry it with acetone, dry it at 105°C for 5 hours to a constant weight and then weigh it to be 515 mg. Take some dry balls and measure the iodine content of the dry balls to be 14.1%. The calculated wet bulb iodine content is 36.3 mg/mL.

Example 7: Preparation of developing microspheres catalyzed by compound I-4 organic acid

Add 5g dry polyvinyl alcohol microspheres, 10g compound I-4 and 125mL DMSO (dimethyl sulfoxide) into a three-necked flask equipped with a mechanical stirring paddle at the top, adjust the stirring speed to 100rpm/min, and heat and swell at 60°C . After swelling, add 5 mL methanesulfonic acid and keep the reaction at 60°C for 24 hours. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and acid to obtain developed microspheres. Take a 2.0 mL wet bulb, dry it with acetone, dry it at 105°C for 5 hours to constant weight, and then weigh it to be 530 mg. Take some dry balls and measure the iodine content of the dry balls to be 16.7%. The calculated wet bulb iodine content is 44.3 mg/mL.

Example 8: Preparation of developing microspheres catalyzed by compound I-4 organic base

Add 5g polyvinyl alcohol microsphere dry ball, 10g compound I-4 and 125mL DMSO (dimethyl sulfoxide) to a three-necked flask with a mechanical stirring paddle at the top, adjust the stirring speed to 100rpm/min, and heat at 60℃ to swell. After swelling, add 5mL diisopropylethylamine and heat to 80℃ for 48h. After the reaction, wash the microspheres with DMSO, 10% sodium bicarbonate and water in turn to remove residual impurities and alkali to obtain developing microspheres. Take 2.0mL of wet bulbs, dry them with acetone, dry them at 105℃ for 5h to constant weight, and weigh them to be 533mg. Take part of the dry bulbs to measure the dry bulb iodine content, which is 13.7%. The wet bulb iodine content is calculated to be 36.5mg/mL.

Example 9: Preparation of developing microspheres catalyzed by compound I-5 organic acid

Add 5g dry polyvinyl alcohol microspheres, 10g compound I-5 and 125mL DMSO (dimethyl sulfoxide) into a three-necked flask equipped with a mechanical stirring paddle at the top, adjust the stirring speed to 100rpm/min, and heat and swell at 60°C . After swelling, add 5 mL methanesulfonic acid and keep the reaction at 60°C for 24 hours. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and acid to obtain developed microspheres. Take a 2.0 mL wet bulb, dry it with acetone, dry it at 105°C for 5 hours to a constant weight, and weigh it to 618 mg. Take some dry bulbs and measure the iodine content of the dry bulbs, which is 32.7%. The calculated wet bulb iodine content is 101mg/mL.

Example 10: Preparation of developing microspheres catalyzed by compound I-5 under organic base

Add 5g dry polyvinyl alcohol microspheres, 10g compound I-5 and 125mL DMSO (dimethyl sulfoxide) into a three-necked flask equipped with a mechanical stirring paddle at the top, adjust the stirring speed to 100rpm/min, and heat and swell at 60°C. . After swelling Add 5 mL of diisopropylethylamine, raise the temperature to 80°C and react for 48 hours. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and alkali to obtain developed microspheres. Take a 2.0 mL wet bulb, dry it with acetone, dry it at 105°C for 5 hours to a constant weight and then weigh it to be 603 mg. Take some dry balls and measure the iodine content of the dry balls to be 30.2%. The calculated wet bulb iodine content is 91.1mg/mL.

Example 11: Preparation of developing microspheres catalyzed by compound I-6 organic acid

Add 5g dry polyvinyl alcohol microspheres, 10g compound I-6 and 125mL DMSO (dimethyl sulfoxide) into a three-necked flask equipped with a mechanical stirring paddle at the top, adjust the stirring speed to 100rpm/min, and heat and swell at 60°C . After swelling, add 5 mL methanesulfonic acid and keep the reaction at 60°C for 24 hours. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and acid to obtain developed microspheres. Take a 2.0 mL wet bulb, dry it with acetone, dry it at 105°C for 5 hours to a constant weight and then weigh it to be 698 mg. Take some dry balls and measure the iodine content of the dry balls to be 42.3%. The calculated wet bulb iodine content is 147.6 mg/mL.

Example 12: Preparation of developing microspheres catalyzed by compound I-6 organic base

Add 5g dry polyvinyl alcohol microspheres, 10g compound I-6 and 125mL DMSO (dimethyl sulfoxide) into a three-necked flask equipped with a mechanical stirring paddle at the top, adjust the stirring speed to 100rpm/min, and heat and swell at 60°C . After swelling, add 5 mL of diisopropylethylamine, raise the temperature to 80°C, and react for 48 hours. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and alkali to obtain developed microspheres. Take a 2.0 mL wet bulb, dry it with acetone, and then dry it at 105°C for 5 hours to a constant weight and then weigh it to be 652 mg. Take some dry balls and measure the iodine content of the dry balls to be 40.7%. The calculated wet bulb iodine content is 132.7mg/mL.

Comparative Example 1: Preparation of developing microspheres

Under nitrogen protection, add 5g dry polyvinyl alcohol microspheres and 300mL NMP (N-methylpyrrolidone) into a three-necked flask with a mechanical stirring paddle on the top, adjust the stirring speed to 100rpm/min, and heat and swell at 60°C. After swelling, add 10g of ground NaOH and mix for 10 minutes. Add 100g of 2,3,5-triiodobenzyl bromide and react for 48 hours before cooling to room temperature. After the reaction, the microspheres were washed with NMP, DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and alkali to obtain developed microspheres. Take a 2.0 mL wet bulb, dry it with acetone, dry it at 105°C for 5 hours to a constant weight, and weigh it to 425 mg. Take some dry balls and measure the iodine content of the dry balls to be 10.7%. The calculated wet bulb iodine content is 22.7 mg/mL. Experiments show that using the process described in patent CN102781974B, the developed microspheres obtained have low iodine content, the volume of the microspheres expands, and the microsphere structure is partially destroyed during the reaction process. Since 2,3,5-triiodobenzyl bromide preferentially reacts on the surface of microspheres, The reaction will make the surface hydrophilicity worse, it will be difficult for the reaction reagent to reach the inside of the microsphere, and the iodine content of the dry sphere will be low. Due to the partial destruction of the microsphere structure, the volume of the microspheres expands, and the dry weight of the microspheres of a certain volume decreases, resulting in a low wet bulb iodine content.

Comparative Example 2: Preparation of developing microspheres

Add 5g dry polyvinyl alcohol microspheres and 50mL purified water to a three-necked bottle equipped with a mechanical stirring paddle at the top, adjust the stirring speed to 100rpm/min, and heat and swell at 90°C. After swelling, add 11g propylene oxide and 0.25g NaOH catalyst and react at 70°C. Slowly add the reaction solution dropwise into the beaker containing methanol precipitant. Stir with a glass rod while adding dropwise. PVA microspheres are then repeatedly filled with methanol. Filter and wash with suction three times and then dry at 50-60°C until constant weight to obtain activated polyvinyl alcohol microspheres.

Under nitrogen flow, the obtained activated polyvinyl alcohol was dissolved in 50 ml of anhydrous NMP. The reaction mixture was stirred at 130°C for 5 minutes; then the temperature was allowed to drop to 50°C. 55 g of 2,3,5-triiodobenzyl alcohol (0.113 mol) were added and the reaction mixture was stirred for 10 minutes. Then, 0.05 g of ground and dried NaOH was added over 10 minutes. After 4 hours, cool to room temperature. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and water in sequence to remove residual impurities and alkali to obtain developed microspheres. Experiments found that the surface morphology of the prepared microspheres was poor, and a large number of microspheres were stuck together and could not be separated. Take a 2.0 mL wet bulb, dry it with acetone, dry it at 105°C for 5 hours to a constant weight and then weigh it to be 512 mg. Take some dry balls and measure the iodine content of the dry balls to be 17.3%. The calculated wet bulb iodine content is 44.3 mg/mL. Due to the surface deterioration and adhesion of the microspheres, it is difficult for 2,3,5-triiodobenzyl alcohol to reach the interior of the microspheres, and the iodine content is low.

Figure 1 is an optical picture of the polyvinyl alcohol wet ball provided by the implementation group of this application; Figure 2 is an optical picture of the developed microsphere provided in Example 1; Figure 3 is an optical picture of the developed microsphere provided in Example 2; Figure 4 Figure 5 is an optical picture of the developed microspheres provided in Example 3; Figure 5 is an optical picture of the developed microspheres provided in Embodiment 4; Figure 6 is an optical picture of the developed microspheres provided in Embodiment 5; Figure 7 is provided in Embodiment 6 Optical pictures of the developed microspheres; Figure 8 is an optical picture of the developed microspheres provided in Embodiment 7; Figure 9 is an optical picture of the developed microspheres provided in Embodiment 8; Figure 10 is an optical picture of the developed microspheres provided in Embodiment 9 Optical pictures; Figure 11 is an optical picture of the developed microspheres provided in Embodiment 10; Figure 12 is an optical picture of the developed microspheres provided in Embodiment 11; Figure 13 is an optical picture of the developed microspheres provided in Embodiment 12. It can be seen from Figure 1 and Figure 2 to Figure 13 that the morphology of the polyvinyl alcohol microsphere wet sphere is good. After development and modification, the obtained product is a spherical shape with good morphology and good hydrophilicity.

Figure 14 is an optical picture of the developed microspheres provided in Comparative Example 1. It can be seen from Figure 14 that the microspheres provided in Comparative Example 1 expanded in volume and were destroyed. Figure 15 is an optical picture of the developed microspheres provided in Comparative Example 2. As can be seen from Figure 15, the microspheres provided in Comparative Example 2 have poor morphology and a large number of adhesions.

Test the performance of the developing microspheres provided in Examples 1 to 12 and Comparative Examples 1 and 2. The test results are as shown in Table 1, and the test method is as follows:

Take a 2.0 mL wet bulb, dry it with acetone, dry it at 105°C for 5 hours to constant weight and weigh it. Take some dry bulbs and measure the iodine content of the dry bulbs.

Weigh about 5 mg of the sample on dust-free paper, and operate according to the second part of the "Chinese Pharmacopoeia". The absorption solution is: 10 mL 5 g/L sodium hydroxide and 10 mL 1% vitamin C. Rapidly oxygenate for 1 minute, and cover the bottle with a watch glass. mouth, let it stand for 10 minutes, ignite the tail of the filter paper wrapped with the sample, quickly insert the stopper into the combustion bottle, press the stopper tightly, and seal the bottle mouth with a small amount of water. After burning (there should be no gray or black fragments or particles, if after burning There should be no gray or black fragments or particles left, which means the test sample is not completely burned. In this case, resample and burn). Shake immediately and fully to make the generated smoke completely inhaled into the absorbing liquid. Leave it for 15 minutes and open the cork. Rinse the bottle stopper and platinum wire with a small amount of water, combine the washing liquid and absorb liquid, and at the same time do a blank experiment in the same way. Add 3 drops of signature red indicator, titrate with 0.01mol/L silver nitrate standard titrant, record the consumed volume, and operate twice in parallel.

calculate:
X = (C × V × 127 × M _{wet bulb} ) / (M × V _{wet bulb} ) × 100%

X: iodine content in the sample;

C: is the concentration of silver nitrate, mol/L;

V: is the consumption volume of silver nitrate, mL;

M: is the sample mass, mg;

M (wet bulb): is the wet bulb mass, mg;

V (wet bulb): is the wet bulb volume, mL;

127: is the relative molecular mass of iodine.

The formula for calculating wet bulb iodine content is as follows:
Wet bulb iodine content = (microsphere dry weight × dry bulb iodine content)/wet bulb volume

HU value test method: The developing microspheres of each example were subjected to Micro CT testing, and the radiopacity of the developing microsphere samples prepared according to the above method was evaluated. Beads were suspended in 0.5% agarose gel in Nunc cryovial vials, and the micro-CT imaging system scanner equipped with a tungsten anode was used to develop micro-computed tomography (micro-CT imaging system). Radiopacity was tested. The images were then segmented to separate the polymer from the pore structure in order to report the polymer radiation density. The radiation density in HU was then calculated using water standards obtained on the same day.

Table 1 Properties of the developed microspheres

As can be seen from Table 1, under the catalytic action of organic acids or organic bases, the X-ray developing compounds provided in this application can all make polyvinyl alcohol microspheres have a developing function through a one-step reaction. And by using organic acids as catalysts, the developed microspheres obtained have higher iodine content, higher HU value, and stronger developing ability.

The above-described embodiments are part of the embodiments of the present application, but not all of the embodiments. The detailed description of the embodiments of the application is not intended to limit the scope of the application as claimed, but rather to represent selected embodiments of the application. Based on the embodiments in this application, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of this application.

Claims

An X-ray developing compound, characterized in that the structural formula of the X-ray developing compound is as follows:

Among them, n is an integer from 1 to 5.
The X-ray developing compound according to claim 1, wherein the structural formula of the X-ray developing compound is:
A method for preparing an X-ray developing compound according to claim 1 or 2, characterized in that it includes:

Reaction 1:
An X-ray developing microsphere, characterized in that the structural formula of the developing microsphere is as follows:

Among them, n is an integer from 1 to 5.
The X-ray developing microsphere according to claim 4, characterized in that the structural formula of the developing microsphere is as follows:
A method for preparing X-ray developing microspheres, characterized in that it comprises: reacting the epoxy group of the X-ray developing compound according to claim 1 or 2 with at least part of the hydroxyl groups on the polyvinyl alcohol microspheres under the catalytic action of an organic acid or an organic base to form an ether bond.
The preparation method according to claim 6, characterized in that the catalyst is an organic acid, and the preparation method includes:

Reaction 2:
The preparation method according to claim 7, characterized in that the mass ratio of the X-ray developing compound and the polyvinyl alcohol microsphere is (1.5-3):1; the mass ratio of the X-ray developing compound and the organic The mass ratio of acids is 1:(0.1-2);

Or/and, the organic acid is at least one of methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid; the solvent is dimethyl sulfoxide, N,N-dimethyl At least one of formamide, N,N-dimethylacetamide, and N-methylpyrrolidone.
The preparation method according to claim 6, characterized in that the catalyst is an organic base, and the preparation method includes:

Reaction three:
The preparation method according to claim 9, characterized in that the mass ratio of the X-ray developing compound to the polyvinyl alcohol microspheres is (1.5-3):1; the mass ratio of the X-ray developing compound to the organic base is 1:(0.5-3);

Or/and, the organic base is triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo [2.2.2] At least one of octane; the solvent is dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone. At least one.