CN120058717B

CN120058717B - 12-chlorobenzo[f]benzofurano[3,2-c]isoquinoline and its preparation method and application

Info

Publication number: CN120058717B
Application number: CN202510526181.XA
Authority: CN
Inventors: 房成龙
Original assignee: Shanghai Longsheng Chemical Co ltd
Current assignee: Shanghai Longsheng Chemical Co ltd
Priority date: 2025-04-25
Filing date: 2025-04-25
Publication date: 2025-08-26
Anticipated expiration: 2045-04-25
Also published as: CN120058717A

Abstract

The present invention relates to the field of organic synthesis technology, and in particular to a kind of 12-chlorobenzo [f] benzofuran [3,2-c] isoquinoline and its preparation method and application. The present invention synthesizes a kind of organic compound 12-chlorobenzo [f] benzofuran [3,2-c] isoquinoline, is very promising organic intermediate, material intermediate, fills the gap of prior art, has broad application prospect. The compound has fluorescent properties, and contains multiple active sites in the compound, and these active sites can react quickly with pollutants in the environment. Therefore, 12-chlorobenzo [f] benzofuran [3,2-c] isoquinoline compound can be used as a highly sensitive, highly selective fluorescent probe to detect antibiotics in the environment.

Description

12-Chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline and preparation method and application thereof

Technical Field

The invention relates to the technical field of organic synthesis, in particular to 12-chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline, and a preparation method and application thereof.

Background

Antibiotic contamination has become an important environmental problem in the world today. Because the antibiotic wastewater has the characteristics of high biological toxicity, containing antibacterial substances and the like, the traditional physical adsorption method and biological treatment method have poor effect when treating the degradation-resistant toxic organic wastewater, especially the wastewater containing residual trace antibiotics. Norfloxacin (Norfloxacin, NOR) belongs to the class of fluoroquinolones and is commonly used for the prevention and treatment of inflammation, such as respiratory tract and skin infections, in animals. However, due to the excessive use of NOR, the NOR content in the environment is far beyond the standard, and norfloxacin undergoes a series of migration and conversion processes including adsorption, degradation, photolysis, hydrolysis and the like after entering the environment. Because of its stable structure, norfloxacin is difficult to degrade completely in the environment, is easily accumulated in soil and sediment, and is enriched by the food chain, and may ultimately pose a potential threat to human health and ecosystem.

In order to evaluate the environmental risk of norfloxacin, an effective pollution control strategy is formulated, and it is important to establish a sensitive, accurate and rapid detection method of norfloxacin in environmental samples. The environment sample matrix is complex, and the norfloxacin content is usually low, so that a proper sample pretreatment method and an analysis detection technology are required to be selected, so that the detection sensitivity and accuracy are improved, and the matrix interference is reduced. The method for detecting norfloxacin in the environment in the prior art mainly comprises the following steps:

(1) HPLC is the most widely used norfloxacin detection method at present, and has the advantages of high separation efficiency, good sensitivity, good selectivity and the like. Commonly used detectors are ultraviolet detectors, fluorescence detectors, and mass spectrometric detectors.

(2) LC-MS combines high separation capacity of liquid chromatography with high sensitivity and high selectivity of mass spectrum, is one of the most sensitive and accurate methods for detecting norfloxacin at present, and is suitable for detecting trace norfloxacin in complex matrixes.

(3) The immunoassay method is based on antigen-antibody specific reaction, has the advantages of simple and rapid operation, low cost and the like, and is suitable for on-site rapid screening. Common immunoassay methods include enzyme-linked immunosorbent assay and fluorescent immunoassay.

(4) The electrochemical analysis method utilizes the oxidation-reduction reaction of norfloxacin on the surface of the electrode to detect, and has the advantages of high sensitivity, good selectivity, simple operation and the like. Common electrochemical analysis methods include cyclic voltammetry, differential pulse voltammetry, and square wave voltammetry.

The fluorescence analysis method has great potential in the field of antibiotic detection due to the advantages of high sensitivity, simple and convenient operation, high response speed and the like. The technology realizes qualitative or quantitative analysis through the change of fluorescent signals based on the fluorescent characteristics (such as excitation/emission wavelength, fluorescent lifetime and the like) of target molecules or derivatives thereof. Some antibiotics (e.g., tetracyclines, quinolones) have fluorescent properties per se and can be detected directly, while others (e.g., β -lactams, aminoglycosides) can be detected indirectly by fluorescent labeling, nanomaterial enhancement, or molecular imprinting techniques. In recent years, the introduction of novel fluorescent probes (such as carbon quantum dots and metal organic framework materials) and signal amplification strategies (such as fluorescence resonance energy transfer and ratiometric fluorescence) further improves the specificity and the anti-interference capability of the method.

However, in practical application, the content of residual antibiotics in the practical sample is often small, coexisting materials are complex, and the pretreatment of the sample by the method is complex, especially depends on expensive experimental instruments, and has high requirements on detection conditions, so that the establishment of a rapid, high-sensitivity and high-selectivity antibiotic detection method has important practical significance.

Disclosure of Invention

In a first aspect, the invention provides a process for the preparation of 12-chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline comprising the steps of:

s1, synthesizing 2-chloro-3-fluoro-4-iodo-5-methylpyridine by using 2-chloro-3-fluoro-5-methylpyridine and iodine simple substance;

S2.2-chloro-3-fluoro-4-iodo-5-methylpyridine and (2-formylphenyl) boronic acid to 2- (2-chloro-3-fluoro-5-methylpyridin-4-yl) benzaldehyde;

S3.2- (2-chloro-3-fluoro-5-methylpyridin-4-yl) benzaldehyde and (3-chloro-2-methoxyphenyl) boric acid are synthesized into 2- (2- (3-chloro-2-methoxyphenyl) -3-fluoro-5-methylpyridin-4-yl) benzaldehyde;

s4.2- (2- (3-chloro-2-methoxyphenyl) -3-fluoro-5-methylpyridin-4-yl) benzaldehyde and boron tribromide are synthesized into 2- (2- (3-chloro-2-hydroxyphenyl) -3-fluoro-5-methylpyridin-4-yl) benzaldehyde;

S5.2- (2- (3-chloro-2-hydroxyphenyl) -3-fluoro-5-methylpyridin-4-yl) benzaldehyde and potassium carbonate are synthesized into 2- (6-chloro-3-methylbenzofuran [3,2-b ] pyridin-4-yl) benzaldehyde;

S6.2- (6-chloro-3-methylbenzofuran [3,2-b ] pyridin-4-yl) benzaldehyde and sodium tert-butoxide 12-chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline.

In some embodiments, the ratio of 2-chloro-3-fluoro-5-methylpyridine to elemental iodine is 400g (3.0-3.1) mol.

In some embodiments, the molar ratio of 2-chloro-3-fluoro-4-iodo-5-methylpyridine to (2-formylphenyl) boronic acid is (3.0-3.5): 3.5-4.0.

In some embodiments, the molar ratio of 2- (2-chloro-3-fluoro-5-methylpyridin-4-yl) benzaldehyde to (3-chloro-2-methoxyphenyl) boronic acid is (7.5-8.0): 8.0-8.5.

In some embodiments, the molar ratio of 2- (2- (3-chloro-2-methoxyphenyl) -3-fluoro-5-methylpyridin-4-yl) benzaldehyde to boron tribromide is from (6.0 to 6.5): from (12.5 to 13.0).

In some embodiments, the molar ratio of 2- (2- (3-chloro-2-hydroxyphenyl) -3-fluoro-5-methylpyridin-4-yl) benzaldehyde to potassium carbonate is from (5.0 to 5.5): from (26 to 30).

In some embodiments, the molar ratio of 2- (6-chloro-3-methylbenzofuran [3,2-b ] pyridin-4-yl) benzaldehyde to sodium tert-butoxide is (5.0-5.5): 13-15.

In a second aspect the invention provides a 12-chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline obtainable by a process as hereinbefore described.

In a third aspect, the invention provides the use of 12-chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline for the fluorescence detection of the antibiotic norfloxacin.

In some embodiments, the method of fluorescence detection comprises blending 12-chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline with norfloxacin and determining the fluorescence intensity of the mixture.

The synthetic route of the invention is as follows:

compared with the prior art, the invention has the following beneficial effects:

1. The invention synthesizes the organic compound 12-chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline, is an organic intermediate and a material intermediate with very good application prospect, fills the blank of the prior art and has wide application prospect.

2. The 12-chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline compound synthesized by the invention has fluorescent property, and the compound contains a plurality of active sites which can rapidly react with pollutants in the environment. Therefore, the 12-chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline compound can be used as a fluorescent probe with high sensitivity and high selectivity for detecting antibiotics in the environment.

3. The invention also provides a detection method of norfloxacin in the environment, which can realize detection without expensive experimental instruments and operation steps, and is convenient and rapid.

Drawings

FIG. 1 is a graph showing the results of fluorescence sensing of Compound 1 against various antibiotics.

FIG. 2 is a graph of the results of a fine titration of the antibiotic NOR.

Fig. 3 is a graph of the linear relationship exhibited by NOR over the range of 60 ppm.

FIG. 4 is a graph showing the effect of detection of NOR on Compound 1 in the presence of coexisting ions.

Detailed Description

The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Example 1

The embodiment provides a 12-chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline, which comprises the following steps:

Diisopropylamine (392 g,3.87 mol) and 4L tetrahydrofuran were added in this order to a 5L reactor, the temperature was lowered to-78 ℃, n-butyllithium (1.4L, 3.5 mol) was added dropwise, and the reaction was continued at-78 ℃ for 1 hour after the completion of the dropwise addition. 2-chloro-3-fluoro-5-methylpyridine (400 g) was added and the reaction was carried out at-78℃for 1 hour. Elemental iodine (765 g,3.01 mol) was added and the reaction was continued at room temperature for 16 hours. The saturated ammonium chloride is added for quenching reaction, then ethyl acetate is used for extraction, the organic phase is dried, and the light yellow target product of 600 g of 2-chloro-3-fluoro-4-iodo-5-methylpyridine is obtained through column chromatography, and the yield is 80.4%.

2-chloro-3-fluoro-4-iodo-5-methylpyridine (858 g, 3.16 mol), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (115 g,157.5 mmol), tripotassium phosphate (1341 g, 6.32 mol), (2-formylphenyl) boric acid (569 g, 3.78 mol), 5.2L1,4-dioxane and 1.3L water were added to a 10L reaction vessel, nitrogen was substituted 3 times, and the system was reacted overnight at an L temperature of 80℃under nitrogen protection. Cooling to room temperature, diluting with water, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, and subjecting to PE/EA=10/1-8/1 silica gel column chromatography to obtain 476 g of yellow solid target product 2- (2-chloro-3-fluoro-5-methylpyridin-4-yl) benzaldehyde with a yield of 60.3%.

¹H NMR (400 MHz, CDCl₃) δ 9.38 (d, J = 8.7 Hz, 1H), 8.29 (t, J = 7.0 Hz, 2H), 7.75 (d, J = 9.0 Hz, 1H), 7.68 (td, J = 8.2, 6.4 Hz, 1H), 7.46 – 7.32 (m, 2H), 4.32 (s, 3H).

To a 2L reactor was added 2- (2-chloro-3-fluoro-5-methylpyridin-4-yl) benzaldehyde (190 g,761 mmol), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (27 g,36.9 mmol), sodium carbonate (161 g,1.52 mol), (3-chloro-2-methoxyphenyl) boric acid (156 g,837 mmol), 1.5L 1, 4-dioxane and 0.4L water, nitrogen substitution 3 times, L temperature to 80℃and reaction overnight. Cooled to room temperature, then water was added, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, and purified by PE/ea=20/1-5/1 silica gel column chromatography to give the desired product 2- (2- (3-chloro-2-methoxyphenyl) -3-fluoro-5-methylpyridin-4-yl) benzaldehyde as a yellow oil in 225 g in 83.1% yield.

2- (2- (3-chloro-2-methoxyphenyl) -3-fluoro-5-methylpyridin-4-yl) benzaldehyde (225 g,634.4 mmol) and 1125mL of dichloromethane are added into a 3L reaction bottle, the internal temperature is controlled to be-5-0 ℃, then a dichloromethane solution 1125-mL of boron tribromide (317 g,1264.8 mmol) is dropwise added, the internal temperature is not more than 0 ℃ and the reaction is carried out for 2 hours at 0 ℃, after the reaction is finished, water is added at 0 ℃ for 1L quenching reaction, the aqueous phase is extracted by 1L of dichloromethane, the organic phases are combined, and the organic phases are dried by anhydrous sodium sulfate and concentrated to obtain 180 g of the target product yellow 2- (2- (3-chloro-2-hydroxyphenyl) -3-fluoro-5-methylpyridin-4-yl) benzaldehyde, and the yield is 83.3%.

2- (2- (3-chloro-2-hydroxyphenyl) -3-fluoro-5-methylpyridin-4-yl) benzaldehyde (180 g,527.8 mmol), 1.8 LN, N-dimethylformamide and potassium carbonate (136.7 g,2639 mmol) were successively added to a 3L reaction flask, and the reaction system was stirred at 55℃for 20 hours. After the reaction is finished, the reaction solution containing the target product 2- (6-chloro-3-methylbenzofuran [3,2-b ] pyridine-4-yl) benzaldehyde can be directly used for the next reaction without other operations.

S6.2- (6-chloro-3-methylbenzofuran [3,2-b ] pyridin-4-yl) benzaldehyde and sodium tert-butoxide to synthesize 12-chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline;

sodium tert-butoxide (126.7 g,1319.6 mmol) was added in portions to the reaction solution of the previous step containing 2- (6-chloro-3-methylbenzofuran [3,2-b ] pyridin-4-yl) benzaldehyde (169.7g,527.8 mmol) at an internal temperature of 55℃and the internal temperature was maintained at 55℃for 20 hours. After the reaction, 3.6L of water is added to quench the reaction, the mixture is stirred for 2 hours, filtered, the filter cake is rinsed with 1L of water, the filter cake is stirred for half an hour with 0.9L acetonitrile, the mixture is filtered, and the filter cake is dried to obtain 85 g of crude product. The crude product is added into 0.85L of N, N-dimethylformamide, stirred for half an hour, filtered, and the filter cake is leached by 100 mL ethanol, and 57 g of target product of off-white solid 12-chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline is obtained after drying, the yield is 35.6%, and the content is 98.5%.

¹H NMR (400 MHz, DMSO) δ 9.43 (d, J = 8.3 Hz, 1H), 9.41 (s, 1H), 8.22 (dd, J = 15.7, 6.9 Hz, 3H), 8.14 (d, J = 8.8 Hz, 1H), 7.98 (t, J = 7.0 Hz, 1H), 7.91 (t, J = 7.0 Hz, 1H), 7.82 (d, J = 7.1 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H).

Example 2

This example provides the use of 12-chlorobenzo [ f ] benzofuro [3,2-c ] isoquinoline (hereinafter compound 1) for the fluorescence detection of the antibiotic norfloxacin.

Compound 1 was ground and dispersed in 3.5 mL of 0.1mol/L of chloramphenicol metronidazole (CAP), penicillin G sodium (PCL), sulfadiazine (SDZ), sulfadimidine (SMZ), ornidazole (ODZ), luo Xiao (RDZ), nitrofural (NZF), nitrofurantoin (NFT), norfloxacin (NOR), respectively, and the fluorescence intensities of the various antibiotics containing Compound 1 were measured by a fluorescence spectrometer (RF-5301 PC) for experiments.

As shown in figure 1, the compound 1 has good fluorescence quenching effect on Norfloxacin (NOR), and the compound 1 is proved to be capable of fluorescence sensing antibiotics norfloxacin with high selectivity and high sensitivity.

In order to further refine the fluorescence process of the compound 1 on the antibiotic norfloxacin, the invention develops a refinement titration experiment, namely, dripping NOR solutions with different contents into an aqueous solution containing the compound 1, and measuring the fluorescence intensity of the Norfloxacin (NOR) solutions with different contents by using a fluorescence spectrometer (RF-5301 PC).

The results are shown in FIG. 2, when the fluorescence intensity is quenched by 50%, the NOR at this time is 30 ppm. Compound 1 exhibited a very good linear relationship for NOR concentration over the concentration range of 60 ppm (R ² =0.98, fig. 3).

Furthermore, the present invention continues to explore the effect of compound 1 on NOR detection in the presence of coexisting antibiotics. The fluorescence intensities of the various coexisting antibiotics containing Compound 1 were measured by a fluorescence spectrometer (RF-5301 PC) for [NOR(1.75mL 0.1 mol/L)+CAP(1.75mL 0.1 mol/L),NOR(1.75mL 0.1 mol/L)+PCL(1.75mL 0.1 mol/L),NOR(1.75mL 0.1 mol/L)+SDZ(1.75mL 0.1 mol/L),NOR(1.75mL 0.1 mol/L)+SMZ(1.75mL 0.1 mol/L),NOR(1.75mL 0.1 mol/L)+ODZ(1.75mL 0.1 mol/L),NOR(1.75mL 0.1 mol/L)+RDZ(1.75mL 0.1 mol/L),NOR(1.75mL 0.1 mol/L)+NZF(1.75mL 0.1 mol/L),NOR(1.75mL 0.1 mol/L)+NFT(1.75mL 0.1 mol/L)], experiments in which Compound 1 was dispersed in the respective coexisting antibiotics, respectively, 4 mg. As shown in fig. 4, compound 1 had little effect on NOR detection before and after addition of the interferent. Therefore, the compound 1 has high selectivity, good anti-interference performance and high sensitivity for NOR detection.

While the foregoing is directed to the preferred embodiments of the present invention, it will be appreciated by those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the present invention.

Claims

1. A method for preparing 12-chlorobenzo[f]benzofuro[3,2-c]isoquinoline, comprising the steps of:

S1. Synthesis of 2-chloro-3-fluoro-4-iodo-5-methylpyridine from 2-chloro-3-fluoro-5-methylpyridine and iodine;

S2. Synthesis of 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde from 2-chloro-3-fluoro-4-iodo-5-methylpyridine and (2-formylphenyl)boronic acid;

S3. Synthesis of 2-(2-(3-chloro-2-methoxyphenyl)-3-fluoro-5-methylpyridin-4-yl)benzaldehyde from 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde and (3-chloro-2-methoxyphenyl)boric acid;

S4. Synthesis of 2-(2-(3-chloro-2-hydroxyphenyl)-3-fluoro-5-methylpyridin-4-yl)benzaldehyde from 2-(2-(3-chloro-2-methoxyphenyl)-3-fluoro-5-methylpyridin-4-yl)benzaldehyde and boron tribromide;

S5. Synthesis of 2-(6-chloro-3-methylbenzofuro[3,2-b]pyridin-4-yl)benzaldehyde from 2-(2-(3-chloro-2-hydroxyphenyl)-3-fluoro-5-methylpyridin-4-yl)benzaldehyde and potassium carbonate;

S6. Synthesis of 12-chlorobenzo[f]benzofuro[3,2-c]isoquinoline from 2-(6-chloro-3-methylbenzofuro[3,2-b]pyridin-4-yl)benzaldehyde and sodium tert-butoxide;

The 12-chlorobenzo[f]benzofurano[3,2-c]isoquinoline has the following structural formula:

.

2. The preparation method according to claim 1, characterized in that the ratio of 2-chloro-3-fluoro-5-methylpyridine to elemental iodine is 400g:(3.0-3.1)mol.

3. The preparation method according to claim 1, characterized in that the molar ratio of 2-chloro-3-fluoro-4-iodo-5-methylpyridine to (2-formylphenyl)boric acid is (3.0-3.5): (3.5-4.0).

4. The preparation method according to claim 1, characterized in that the molar ratio of 2-(2-chloro-3-fluoro-5-methylpyridin-4-yl)benzaldehyde to (3-chloro-2-methoxyphenyl)boric acid is (7.5-8.0):(8.0-8.5).

The preparation method according to claim 1 , wherein the molar ratio of 2-(2-(3-chloro-2-methoxyphenyl)-3-fluoro-5-methylpyridin-4-yl)benzaldehyde to boron tribromide is (6.0-6.5):(12.5-13.0).

6. The preparation method according to claim 1, characterized in that the molar ratio of 2-(2-(3-chloro-2-hydroxyphenyl)-3-fluoro-5-methylpyridin-4-yl)benzaldehyde to potassium carbonate is (5.0-5.5):(26-30).

7. The preparation method according to claim 1, characterized in that the molar ratio of 2-(6-chloro-3-methylbenzofuro[3,2-b]pyridin-4-yl)benzaldehyde to sodium tert-butoxide is (5.0-5.5):(13-15).

8. A 12-chlorobenzo[f]benzofuro[3,2-c]isoquinoline, characterized in that the 12-chlorobenzo[f]benzofuro[3,2-c]isoquinoline has the following structural formula:

.

9. An application of 12-chlorobenzo[f]benzofuro[3,2-c]isoquinoline, characterized in that it is used in the fluorescence detection of the antibiotic norfloxacin;

.

10. The use according to claim 9, characterized in that the fluorescence detection method comprises: mixing 12-chlorobenzo[f]benzofurano[3,2-c]isoquinoline with norfloxacin in the environment, and measuring the fluorescence intensity of the mixed solution.