Preparation method of macromolecular heterocyclic compound

Abstract

The invention discloses a preparation method of a macromolecular heterocyclic compound, and relates to the technical field of chemical synthesis. The macromolecular heterocyclic compound is bis 2-[3-(2 ', 6'-dichloro) phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester, and the preparation method comprises the following steps: weighing protoporphyrin dimethyl ester and 2, 6-dichlorobenzene cyanogen oxide, adding dichloromethane under the protection of nitrogen, carrying out heating reflux reaction, and after the reaction is finished, naturally cooling to obtain the macromolecular heterocyclic compound. The invention discloses a preparation method of bis (2-[3-(2 ', 6'-dichloro) phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.The preparation method has the advantages that the bis (2-[3-(2 ', 6'-dichloro) phenyl-4-dihydro-5-hydroisoxazolyl)-protoporphyrin dimethyl ester.The preparation method is high in yield and purity, and the obtained product is high in molar extinction coefficient.

Description

Technical Field

[0001] The present application relates to the field of chemical synthesis technology, and in particular to a method for preparing a macromolecular heterocyclic compound. Background Art

[0002] Heme is an iron-containing porphyrin compound. As a component of hemoglobin, it plays an important physiological role in transporting oxygen in the body. Protoporphyrin dimethyl ester is an intermediate extract when extracting heme. It has a high molar extinction coefficient and absorbs in the ultraviolet-visible light region and the near-infrared region. Based on these advantages, protoporphyrin dimethyl ester is often used as a second-generation photosensitizer in photodynamic therapy (PDT) in the medical field.

[0003] Although protoporphyrin dimethyl ester has many advantages, it still has some defects in practical applications. First, the photophysical and chemical properties of protoporphyrin dimethyl ester are not ideal and it is sensitive to light and air, which limits its application under certain specific conditions. There are multiple functional modification sites in the structure of protoporphyrin dimethyl ester, so the water solubility, optical imaging or fluorescence switching properties of protoporphyrin dimethyl ester can be adjusted by modifying the structure of these sites. Summary of the invention

[0004] In order to provide a protoporphyrin dimethyl ester derivative and to improve the molar extinction coefficient of protoporphyrin dimethyl ester, the present application provides a method for preparing a macromolecular heterocyclic compound.

[0005] The present application provides a method for preparing a macromolecular heterocyclic compound, which adopts the following technical scheme: A method for preparing a macromolecular heterocyclic compound, wherein the macromolecular heterocyclic compound is bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester, and the preparation method comprises the following steps: Weigh protoporphyrin dimethyl ester and 2,6-dichlorobenzocyanide, add dichloromethane under nitrogen protection, heat and reflux to react, and after the reaction is completed, cool naturally, spin dry, and separate and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0006] By adopting the above technical scheme, the present application adopts 2,6-dichlorobenzocyanate to carry out 1,3-dipolar cycloaddition reaction and coupling reaction on protoporphyrin dimethyl ester to obtain a protoporphyrin dimethyl ester derivative bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester; 2,6-dichlorobenzocyanate has high reactivity; after protoporphyrin dimethyl ester undergoes cycloaddition of the vinyl ring outside the β-ring, the degree of conjugation between the original double bond and the porphyrin ring is reduced, resulting in a blue shift in the absorption spectrum and a corresponding blue shift in the fluorescence emission spectrum; the porphyrin ring is no longer conjugated with the outer double bond, so that its planarity is further optimized, which promotes it to have a higher molar extinction coefficient and improves the absorption of visible light.

[0007] Preferably, the molar ratio of the protoporphyrin dimethyl ester to 2,6-dichlorobenzocyanate is 1:2-3.

[0008] Preferably, the solid-liquid ratio of the protoporphyrin dimethyl ester to dichloromethane is 1:500-600 g / mL.

[0009] Preferably, the temperature of the heating reflux reaction is 40-60° C., and the reaction time is 6-8 h.

[0010] Preferably, the preparation method of 2,6-dichlorobenzocyanate comprises the following steps: S1. Dissolve hydroxylamine hydrochloride and sodium acetate in water to obtain a mixed solution; add ethanol to 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. Add N-bromosuccinimide to intermediate A, mix and stir evenly, then add a mixed solvent, heat the reaction at 30-50°C for 2-4 hours, add triethylamine dropwise, cool naturally to room temperature, wash, dry, spin dry, and purify by column chromatography to obtain 2,6-dichlorobenzocyanide.

[0011] Preferably, the mass ratio of hydroxylamine hydrochloride, sodium acetate, 2,6-dichlorobenzaldehyde and ethanol is 0.8-0.9:1.8-2.2:1:30-40.

[0012] Preferably, the mass ratio of N-bromosuccinimide to 2,6-dichlorobenzaldehyde is 1.1-1.3:1.

[0013] Preferably, the solid-to-liquid ratio of the N-bromosuccinimide to the mixed solvent is 1:170-190 g / mL.

[0014] Preferably, the mixed solvent includes N,N-dimethylformamide and dichloromethane, and the volume ratio of the two is 1:16-18.

[0015] Preferably, the mass ratio of triethylamine to 2,6-dichlorobenzaldehyde is 1-1.2:1.

[0016] In summary, the present application includes at least one of the following beneficial technical effects: 1. By adopting the above technical scheme, the present application adopts 2,6-dichlorobenzocyanate to carry out 1,3-dipolar cycloaddition reaction and coupling reaction on protoporphyrin dimethyl ester to obtain a protoporphyrin dimethyl ester derivative bis 2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester; 2,6-dichlorobenzocyanate has high reactivity; after protoporphyrin dimethyl ester undergoes cycloaddition of the vinyl ring outside the β-ring, the degree of conjugation between the original double bond and the porphyrin ring is reduced, resulting in a blue shift in the absorption spectrum and a corresponding blue shift in the fluorescence emission spectrum; the porphyrin ring is no longer conjugated with the outer double bond, which makes its planarity more optimized, prompting it to have a higher molar extinction coefficient and improve the absorption of visible light. DETAILED DESCRIPTION

[0017] The present application is further described in detail below with reference to the embodiments. Example

[0018] Example 1 S1. Dissolve 0.8 g of hydroxylamine hydrochloride and 1.8 g of sodium acetate in 30 g of water to obtain a mixed solution; add 30 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.1 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 160 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.1 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 32.8 mg of 2,6-dichlorobenzocyanate obtained in S2, add 25 mL of dichloromethane under nitrogen protection, heat and reflux at 40°C for 8 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0019] Example 2 S1. Dissolve 0.85 g of hydroxylamine hydrochloride and 2.0 g of sodium acetate in 35 g of water to obtain a mixed solution; add 35 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.1 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 160 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.1 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 32.8 mg of 2,6-dichlorobenzocyanate obtained in S2, add 25 mL of dichloromethane under nitrogen protection, heat and reflux at 40°C for 8 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0020] Example 3 S1. Dissolve 0.9 g of hydroxylamine hydrochloride and 2.2 g of sodium acetate in 40 g of water to obtain a mixed solution; add 40 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.1 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 160 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.1 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 32.8 mg of 2,6-dichlorobenzocyanate obtained in S2, add 25 mL of dichloromethane under nitrogen protection, heat and reflux at 40°C for 8 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0021] Example 4 S1. Dissolve 0.8 g of hydroxylamine hydrochloride and 1.8 g of sodium acetate in 30 g of water to obtain a mixed solution; add 30 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.2 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 170 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.32 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 32.8 mg of 2,6-dichlorobenzocyanate obtained in S2, add 25 mL of dichloromethane under nitrogen protection, heat and reflux at 40°C for 8 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0022] Example 5 S1. Dissolve 0.8 g of hydroxylamine hydrochloride and 1.8 g of sodium acetate in 30 g of water to obtain a mixed solution; add 30 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.3 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 180 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.56 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 32.8 mg of 2,6-dichlorobenzocyanate obtained in S2, add 25 mL of dichloromethane under nitrogen protection, heat and reflux at 40°C for 8 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0023] Example 6 S1. Dissolve 0.8 g of hydroxylamine hydrochloride and 1.8 g of sodium acetate in 30 g of water to obtain a mixed solution; add 30 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.1 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 160 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.1 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 39.8 mg of 2,6-dichlorobenzocyanate obtained in S2, add 25 mL of dichloromethane under nitrogen protection, heat and reflux at 40°C for 8 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0024] Example 7 S1. Dissolve 0.8 g of hydroxylamine hydrochloride and 1.8 g of sodium acetate in 30 g of water to obtain a mixed solution; add 30 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.1 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 160 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.1 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 47.7 mg of 2,6-dichlorobenzocyanate obtained in S2, add 25 mL of dichloromethane under nitrogen protection, heat and reflux at 40°C for 8 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0025] Example 8 S1. Dissolve 0.8 g of hydroxylamine hydrochloride and 1.8 g of sodium acetate in 30 g of water to obtain a mixed solution; add 30 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.1 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 160 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.1 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 23.9 mg of 2,6-dichlorobenzocyanate obtained in S2, add 25 mL of dichloromethane under nitrogen protection, heat and reflux at 40°C for 8 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0026] Example 9 S1. Dissolve 0.8 g of hydroxylamine hydrochloride and 1.8 g of sodium acetate in 30 g of water to obtain a mixed solution; add 30 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.1 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 160 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.1 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 55.7 mg of 2,6-dichlorobenzocyanide obtained in S2, add 25 mL of dichloromethane under nitrogen protection, heat and reflux at 40°C for 8 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0027] Example 10 S1. Dissolve 0.8 g of hydroxylamine hydrochloride and 1.8 g of sodium acetate in 30 g of water to obtain a mixed solution; add 30 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.1 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 160 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.1 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 32.8 mg of 2,6-dichlorobenzocyanate obtained in S2, add 25 mL of dichloromethane under nitrogen protection, heat and reflux at 50°C for 7 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0028] Embodiment 11 S1. Dissolve 0.8 g of hydroxylamine hydrochloride and 1.8 g of sodium acetate in 30 g of water to obtain a mixed solution; add 30 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.1 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 160 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.1 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 32.8 mg of 2,6-dichlorobenzocyanate obtained in S2, add 25 mL of dichloromethane under nitrogen protection, heat and reflux at 60°C for 6 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0029] Example 12 S1. Dissolve 0.8 g of hydroxylamine hydrochloride and 1.8 g of sodium acetate in 30 g of water to obtain a mixed solution; add 30 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.1 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 160 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.1 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 32.8 mg of 2,6-dichlorobenzocyanate obtained in S2, add 25 mL of dichloromethane under nitrogen protection, heat and reflux at 30°C for 9 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0030] Embodiment 13 S1. Dissolve 0.8 g of hydroxylamine hydrochloride and 1.8 g of sodium acetate in 30 g of water to obtain a mixed solution; add 30 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.1 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 160 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.1 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 32.8 mg of 2,6-dichlorobenzocyanate obtained in S2, add 25 mL of dichloromethane under nitrogen protection, heat and reflux at 70°C for 5 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0031] Embodiment 14 S1. Dissolve 0.8 g of hydroxylamine hydrochloride and 1.8 g of sodium acetate in 30 g of water to obtain a mixed solution; add 30 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.1 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 160 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.1 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 32.8 mg of 2,6-dichlorobenzocyanate obtained in S2, add 27.5 mL of dichloromethane under nitrogen protection, heat and reflux at 40°C for 8 hours. After the reaction is completed, cool naturally, spin dry, separate and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0032] Embodiment 15 S1. Dissolve 0.8 g of hydroxylamine hydrochloride and 1.8 g of sodium acetate in 30 g of water to obtain a mixed solution; add 30 g of ethanol to 1.0 g of 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux at 75°C for 2 h; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. 1.1 g of N-bromosuccinimide was added to the intermediate A, mixed and stirred evenly, and then a mixed solvent consisting of 10 mL of N, N-dimethylformamide and 160 mL of dichloromethane was added, and the mixture was heated at 30 ° C for 2 h, and then 1.1 g of triethylamine was added dropwise, and the mixture was naturally cooled to room temperature, and 2,6-dichlorobenzocyanide was obtained after washing, drying, spin drying, and purification by column chromatography; S3. Weigh 50 mg of protoporphyrin dimethyl ester and 32.8 mg of 2,6-dichlorobenzocyanate obtained in S2, add 30 mL of dichloromethane under nitrogen protection, heat and reflux at 40°C for 8 hours. After the reaction is completed, cool naturally, spin dry, and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

[0033] Performance testing 1. The product obtained in Example 1-15, bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester, was sampled and subjected to liquid phase analysis to obtain the purity and yield of the product. The results are shown in Table 1.

[0034] 2. The molar extinction coefficient of the product obtained in Example 1-15, bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester, was detected by spectrophotometry. The results are shown in Table 1.

[0035] The specific test results are as follows: Table 1 Performance test results It can be seen from the test results in Table 1 that the method for preparing a macromolecular heterocyclic compound bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester provided in the present application has a high yield and purity of the obtained product; from the comparison of the molar extinction coefficient of the products of Examples 1-15 with the molar extinction coefficient of protoporphyrin dimethyl ester, it can be seen that the method for preparing 2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester provided in the present application has a significantly increased molar extinction coefficient of the obtained product, which can effectively improve the absorption of visible light.

[0036] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A method for preparing a macromolecular heterocyclic compound, characterized in that: The macromolecular heterocyclic compound is bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester, and the preparation method comprises the following steps: Weigh protoporphyrin dimethyl ester and 2,6-dichlorobenzocyanide, add dichloromethane under nitrogen protection, heat and reflux to react, and after the reaction is completed, cool naturally, spin dry, and separate and purify by column chromatography to obtain the product bis-2-[3-(2',6'-dichloro)phenyl-4-dihydro-5-hydroisoxazolyl]-protoporphyrin dimethyl ester.

2. The method for preparing a macromolecular heterocyclic compound according to claim 1, characterized in that: The molar ratio of the protoporphyrin dimethyl ester to 2,6-dichlorobenzocyanate is 1:2-3.

3. The method for preparing a macromolecular heterocyclic compound according to claim 1, characterized in that: The solid-liquid ratio of the protoporphyrin dimethyl ester to dichloromethane is 1:500-600 g / mL.

4. The method for preparing a macromolecular heterocyclic compound according to claim 1, characterized in that: The temperature of the heating reflux reaction is 40-60° C., and the reaction time is 6-8 hours.

5. The method for preparing a macromolecular heterocyclic compound according to claim 1, characterized in that: The preparation method of 2,6-dichlorobenzocyanate comprises the following steps: S1. Dissolve hydroxylamine hydrochloride and sodium acetate in water to obtain a mixed solution; add ethanol to 2,6-dichlorobenzaldehyde, stir evenly, then add the mixed solution, heat and reflux; after the reaction is completed, naturally cool to room temperature; add water to the product, stir, filter, and vacuum dry to obtain intermediate A; S2. Add N-bromosuccinimide to intermediate A, mix and stir evenly, then add a mixed solvent, heat the reaction at 30-50°C for 2-4 hours, add triethylamine dropwise, cool naturally to room temperature, wash, dry, spin dry, and purify by column chromatography to obtain 2,6-dichlorobenzocyanide.

6. The method for preparing a macromolecular heterocyclic compound according to claim 5, characterized in that: The mass ratio of hydroxylamine hydrochloride, sodium acetate, 2,6-dichlorobenzaldehyde and ethanol is 0.8-0.9:1.8-2.2:1:30-40.

7. The method for preparing a macromolecular heterocyclic compound according to claim 5, characterized in that: The mass ratio of the N-bromosuccinimide to 2,6-dichlorobenzaldehyde is 1.1-1.3:

1.

8. The method for preparing a macromolecular heterocyclic compound according to claim 5, characterized in that: The solid-to-liquid ratio of the N-bromosuccinimide to the mixed solvent is 1:170-190 g / mL.

9. The method for preparing a macromolecular heterocyclic compound according to claim 8, characterized in that: The mixed solvent includes N,N-dimethylformamide and dichloromethane, and the volume ratio of the two is 1:16-18.

10. The method for preparing a macromolecular heterocyclic compound according to claim 5, characterized in that: The mass ratio of the triethylamine to 2,6-dichlorobenzaldehyde is 1-1.2:1.

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