CN110551145B - A class of furocoumarin-Tröger's Base derivatives and their synthetic methods and applications - Google Patents

Abstract

Furocoumarin-

The Base derivative is synthesized by cyclization and coupling reaction of p-bromoaniline, paraformaldehyde, 4-hydroxycoumarin, isonitrile, n-butyl lithium and the like, and has the advantages of mild reaction conditions, short reaction time and high yield required by the synthesis process. The invention relates to a method for producing a coumarin-containing fraction

The Base derivative has excellent luminescence property and high biological activity, wherein some products have anti-tumor activity, show high selective inhibition on human triple negative breast cancer cells (MDA-MB-231), and have research value for further developing anti-tumor drugs; and other products can be applied to synchronous detection of neuroblastoma metabolites homovanillic acid (HVA) and mandelic acid (VMA), and have the potential of being developed into efficient fluorescent probes for early warning and accurate diagnosis of human neuroblastoma.

Description

A class of furocoumarin-Tröger's Base derivatives and their synthetic methods and applications

technical field

Base衍生物及其合成方法与应用。The invention belongs to the field of chemical synthesis, in particular to a class of furanocoumarins

Base derivatives and their synthetic methods and applications.

Background technique

Neuroblastoma (NB) is the most common extracranial solid malignant tumor in children. Nearly half of neuroblastomas occur in infants and young children under 2 years old. The incidence of neuroblastoma in children is second only to leukemia and central nervous system. Nervous system tumors. NB can occur in any part of the sympathetic nervous system and adrenal medulla, and the neck, mediastinum, and abdomen are common sites. The onset of neuroblastoma is relatively insidious, but it develops rapidly. Most of the children have developed distant metastases at the time of consultation, and the clinical manifestations are irregular and varied.

Early detection and diagnosis of neuroblastoma is of great significance to save the lives of more patients. It has been found that homovanillic acid (HVA) and mandelic vanillic acid (VMA) are usually present in the metabolites of patients with this disease. If the presence of HVA and VMA can be detected at the same time, it can indicate the existence of neuroblastoma. At present, most of the methods used to detect neuroblastoma can only detect one of the metabolites, and cannot detect the existence of two metabolites at the same time.

Coumarin is a common natural product that widely exists in orchids, black bean, wild vanilla, fragrant snake chrysanthemum and other plants in nature, exuding the fragrance of coumarin or fresh dried vanilla. Isocoumarin is similar in structure to coumarin, and it is also a natural product commonly found in nature. Some isocoumarin derivatives have pharmacological effects such as laxative, antipyretic, and skin allergy relief.

Coumarin and its derivatives are widely used in the fields of antibacterial, antitumor, anti-HIV, antioxidation, and anticoagulation. In addition, as an excellent fluorophore, coumarin and its derivatives have high fluorescence quantum yield and stable luminescence properties, and are widely used in fluorescent probes, organic dyes, light-emitting devices and other fields.

base(TB)是一种发光性质优异的特殊骨架，独有的V型结构赋予其较好的分子刚性，两个桥头氮原子经常作为氢键配体参与形成金属配合物，TB的桥环骨架和侧翼苯环上有充足的可修饰位点，两个苯环之间形成的空腔有利于电子的空间跃迁，具有优良的光电性质。

base(TB) is a special skeleton with excellent luminescence properties. Its unique V-shaped structure endows it with better molecular rigidity. Two bridgehead nitrogen atoms are often used as hydrogen bonding ligands to form metal complexes. The bridged ring skeleton of TB And there are sufficient modifiable sites on the flanking benzene rings, and the cavity formed between the two benzene rings is conducive to the spatial transition of electrons and has excellent optoelectronic properties.

SUMMARY OF THE INVENTION

Base衍生物。The purpose of the present invention is to connect coumarin fragments into the TB skeleton to obtain a novel coumarin skeleton with excellent luminescence properties, high biological activity and strong molecular recognition ability.

Base derivative.

Base衍生物，其结构式如下式6 或7所示，Specifically, the present invention provides a class of furanocoumarins

Base derivative, its structural formula is shown in the following formula 6 or 7,

Wherein, R ₁ is H, Me or Cl, and R ₂ is cyclohexyl, methylmethoxycarbonyl, benzyl or tert-butyl.

The present invention also provides the synthetic method of the compound shown in above-mentioned formula 6, including:

S1: Preparation of intermediate 1 shown in the following formula,

Mix p-bromoaniline and paraformaldehyde, slowly drop trifluoroacetic acid at low temperature, continue to react at low temperature for a period of time after dropping, then slowly rise to room temperature, TLC tracking reaction ends; pour the reaction mixture into ice water, The pH was adjusted, extracted with dichloromethane, the organic phase was extracted with saturated brine, the organic layers were combined, dried, filtered, the filtrate was distilled under reduced pressure, separated and purified by column chromatography, recrystallized with acetone, and dried to obtain Intermediate 1;

S2: prepare intermediate 2 shown in the following formula,

The intermediate 1 was placed in a container, then dried tetrahydrofuran was added, the system was cooled to -78°C under anhydrous and oxygen-free conditions, n-butyllithium was slowly added dropwise, and then dried N,N-dichloromethane was added dropwise. Methylformamide was added and moved to room temperature to continue the reaction for a period of time. After the reaction, it was quenched with ice water, extracted with dichloromethane, and separated and purified by column chromatography to obtain Intermediate 2;

S3: Dissolve intermediate 2 and coumarin in the dried toluene, add isonitrile dropwise under anhydrous and anaerobic conditions, heat and stir to reflux until the end of the TLC tracking reaction, cool, and spin the excess solvent to obtain a crude The product was separated and purified by column chromatography to obtain the target compound 6;

The structural formula of coumarin is shown in the following formula 4,

R ₁ is H, Me or Cl;

The structural formula of isonitrile is shown in the following formula 5,

Wherein, R ₂ is cyclohexyl, methylmethoxycarbonyl, benzyl or tert-butyl.

Preferably, the bromoaniline and the paraformaldehyde are mixed in a molar ratio of 2:5.

Preferably, the molar ratio of the intermediate 2, the coumarin and the isonitrile is 1:1:1.2.

The present invention also provides the application of the compound represented by the above formula 6 in the detection of homovanillic acid or mandelic vanillic acid.

The present invention also provides the preparation method of the compound shown in the above-mentioned formula 7, comprising:

S1: Preparation of intermediate 1 shown in the following formula,

Mix p-bromoaniline and paraformaldehyde, slowly drop trifluoroacetic acid at low temperature, continue to react at low temperature for a period of time after dropping, then slowly rise to room temperature, TLC tracking reaction ends; pour the reaction mixture into ice water, The pH was adjusted, extracted with dichloromethane, the organic phase was extracted with saturated brine, the organic layers were combined, dried, filtered, the filtrate was distilled under reduced pressure, separated and purified by column chromatography, recrystallized with acetone, and dried to obtain Intermediate 1;

S2: prepare intermediate 3 shown in the following formula,

Place the intermediate 1 in a container, add dried tetrahydrofuran, cool the system to -78°C under anhydrous and oxygen-free conditions, slowly add n-butyllithium dropwise, and then dropwise add dried N,N-di Methylformamide was added and moved to room temperature to react for a period of time. After the reaction was completed, it was quenched with ice water, extracted with dichloromethane, and separated and purified by column chromatography to obtain Intermediate 3;

S3: Dissolve intermediate 3 and coumarin in the dried toluene, add isonitrile dropwise under anhydrous and oxygen-free conditions, heat and stir to reflux until the TLC tracking reaction ends, cool, and spin the excess solvent to obtain a crude The product was separated and purified by column chromatography to obtain the target compound 7;

The structural formula of coumarin is shown in the following formula 4,

R ₁ is H, Me or Cl;

The structural formula of isonitrile is shown in the following formula 5,

Wherein, R ₂ is cyclohexyl, methylmethoxycarbonyl, benzyl or tert-butyl.

Preferably, the molar ratio of the intermediate 2, the coumarin and the isonitrile is 1:1:1.2.

The present invention also provides the application of the compound represented by the above formula 7 in the preparation of a drug for inhibiting human triple-negative breast cancer.

Compared with the prior art, the beneficial effects of the present invention:

Base衍生物，合成工艺所需反应条件温和、反应时间短、产率高，具有很好的规模化应用前景；The invention uses p-bromoaniline, paraformaldehyde, 4-hydroxycoumarin, isonitrile, n-butyllithium and the like as raw materials, and synthesizes a class of furanocoumarins through ring formation and coupling reaction

Base derivatives, the synthesis process requires mild reaction conditions, short reaction time and high yield, and has good large-scale application prospects;

Base衍生物，发光性质优良、生物活性高，其中一些产物具有抗肿瘤活性，且对人三阴性乳腺癌细胞(MDA-MB-231)表现出高度选择性抑制，具有进一步开发为抗肿瘤药物的研究价值；另有一些产物可应用于同步检测神经母细胞瘤代谢物高香草酸(HVA)和扁桃香草酸(VMA)，具有开发为人神经母细胞瘤早期预警及确诊高效荧光探针的潜力。Coumarin fragments of the present invention

Base derivatives, with excellent luminescence properties and high biological activity, some of which have anti-tumor activity, and showed highly selective inhibition of human triple-negative breast cancer cells (MDA-MB-231), and have the potential to be further developed as anti-tumor drugs. Research value; some other products can be used for simultaneous detection of neuroblastoma metabolites homovanillic acid (HVA) and mandelic vanillic acid (VMA), which have the potential to be developed as highly efficient fluorescent probes for early warning and diagnosis of human neuroblastoma.

Description of drawings

Fig. 1 is the fluorescence emission spectrum of the effect of 6h with HVA and MVA in the embodiment of the present invention 3;

Fig. 2 is the fluorescence emission spectrum of 6h in the presence of different concentrations of HVA in Example 3 of the present invention;

Figure 3 is the standard curve of compound 6h to HVA in Example 3 of the present invention;

Fig. 4 is the fluorescence emission spectrum of 6h in the presence of different concentrations of VMA in the embodiment of the present invention 3;

Figure 5 is the standard curve of compound 6h in Example 3 of the present invention to VMA.

Detailed ways:

The present invention will be further described below with reference to the accompanying drawings.

Example 1

Base衍生物的合成路线如下：The furocoumarins of the present invention

The synthetic route of Base derivatives is as follows:

Specifically include:

(1) Preparation of Intermediate 1

Add p-bromoaniline (60mmol) and paraformaldehyde (n=3) (150mmol) to a 250mL dry round-bottomed flask, cool to minus 15°C, slowly add 120mL trifluoroacetic acid dropwise through a constant pressure dropping funnel, after the dropping The reaction system was moved to room temperature and reacted for 7 days, quenched with ice water, adjusted to neutral pH with ammonia water, extracted with dichloromethane (50 mL×3), the organic phase was extracted with saturated brine, dried over anhydrous sodium sulfate, column Chromatographic separation and purification (petroleum ether:ethyl acetate=5:1), and finally recrystallization with acetone and drying to obtain Intermediate 1.

(2) Preparation of Intermediate 2

Intermediate 1 (5 mmol) was added to a 100 mL dry round-bottomed flask, then dried tetrahydrofuran (20 mL) was added, the system was cooled to -78°C under anhydrous and oxygen-free conditions, and n-butyllithium (2.5 mL) was slowly added dropwise ), add anhydrous N,N-dimethylformamide (0.6mL), move to room temperature after the addition and continue the reaction for 12h, quench with ice water after the reaction, extract with dichloromethane (50mL×3), the column layer Separation and purification (petroleum ether:ethyl acetate=1:1), intermediate 2 was obtained.

(3) Preparation of Intermediate 3

Intermediate 1 (5 mmol) was added to a 100 mL dry round-bottomed flask, then dried tetrahydrofuran (30 mL) was added, the system was cooled to -78°C under anhydrous and oxygen-free conditions, and n-butyllithium (5 mL) was slowly added dropwise. , add anhydrous N,N-dimethylformamide (1.2mL), move to room temperature to continue the reaction for 12h after the addition, quench with ice water after the reaction, extract with dichloromethane (50mL×3), column chromatography Separation and purification (petroleum ether:ethyl acetate=1:1), intermediate 3 was obtained.

(4) Preparation of compound 6

Intermediate 2 and coumarin were dissolved in the dried toluene, and isonitrile was added dropwise under anhydrous and oxygen-free conditions, heated and stirred to reflux until the end of the TLC tracking reaction, cooled, and the excess solvent was spin-dried to obtain a crude product, Separation and purification by column chromatography (petroleum ether:ethyl acetate=1:3) gave the target compound 6. Wherein, the molar ratio of intermediate 2, coumarin and isonitrile is 1:1:1.2, wherein, R ₁ is selected from one of -H, -Me, -Cl; R ₂ is selected from cyclohexyl, methyl One of methoxycarbonyl, phenyl and tert-butyl.

(5) Preparation of compound 7

Intermediate 3 and coumarin were dissolved in the dried toluene, and isonitrile was added dropwise under anhydrous and oxygen-free conditions, heated and stirred to reflux until the end of the TLC tracking reaction, cooled, and the excess solvent was spin-dried to obtain a crude product, The target compound 7 was isolated and purified by column chromatography. Wherein, the molar ratio of intermediate 3, coumarin and isonitrile is 1:2:2.4. Wherein, R ₁ is selected from one of -H, -Me, and -Cl; R ₂ is selected from one of cyclohexyl, methylmethoxycarbonyl, phenyl, and tert-butyl.

The yield and melting point of each product are shown in Table 1 below

The yield and melting point of the compounds in Table 1

Base衍生物，其合成方法基本相同，下面仅以化合物6a为例详细说明其合成方法：It should be noted that compound 6 (6a-6l) is a class of 2-furocoumarin-8-bromo

Base derivative, its synthetic method is basically the same, the following only takes compound 6a as an example to describe its synthetic method in detail:

Intermediate 2 (0.5 mmol) and 4-hydroxycoumarin (0.5 mmol) were successively added to a 100 mL dry round-bottomed flask, dried toluene (25 mL) was added, and cyclohexyliso was added dropwise under anhydrous and oxygen-free conditions. Nitrile (0.6mmol), heated and stirred under reflux for 28h, after the reaction was completed (TLC tracking), cooled, and the excess solvent was evaporated under reduced pressure, and the crude product was separated and purified by column chromatography (V _{petroleum ether} :V _{ethyl acetate} =1:3) , the compound 6a was obtained with a yield of 82%.

The structural formula of compound 6a is:

The molecular formula is: C ₃₂ H ₂₃ BrN ₃ O ₃

Chinese name is:

3-(8-Bromo-6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaaryloct-2-yl)-2-(cyclohexylamino)- 4H-furo[3,2-c]chromen-4-one

English name is:

3-(8-bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)-2-(cyclohexylamino)-4H-fu ro[3,2-c] chromen-4-one

Appearance: brownish yellow solid

Melting point: 115.3-116.9℃

Hydrogen nuclear magnetic resonance spectrum: ¹ H NMR (400MHz, DMSO) δ7.78 (d, J=6.0Hz, 1H), 7.20 (ddd, J=67.5, 62.8, 33.8Hz, 9H), 6.43 (s, 1H), 4.72-4.57(m, 2H), 4.18(dd, J=39.5, 18.0Hz, 4H), 1.77-1.14(m, 10H).

Carbon NMR spectrum: ¹³ C NMR (101MHz, DMSO) δ 164.25, 134.93, 125.27, 112.46, 97.81, 85.00, 77.36, 73.07, 57.98, 27.45, 17.92.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₃₂ H ₂₃ BrN ₃ O ₃ [M+H] ⁺ : 582.1392; found: 582.1388.

The rest of the product structure characterization:

The structural formula of compound 6b is:

The molecular formula is: C ₂₉ H ₂₂ BrN ₃ O ₅

Chinese name is:

3-(8-Bromo-6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaoct-2-yl)-4-oxo-4H-furan Do[3,2-c]chromen-2-ylglycine methyl ester

English name is:

Methyl(3-(8-bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)-4-oxo-4H-furo[3,2-c]chromen -2-yl)glycinate

Appearance: yellow solid

Melting point: 219.5-221.2℃

Hydrogen nuclear magnetic resonance spectrum: ¹ H NMR (400MHz, DMSO) δ 7.52-7.25 (m, 5H), 7.16-6.94 (m, 5H), 4.69-4.58 (m, 2H), 4.27-4.06 (m, 6H) ,3.91(s,1H),1.35(d,J=84.4Hz,3H).

Carbon NMR spectrum: ¹³ C NMR (101MHz, DMSO) δ171.04, 154.51, 150.00, 129.13, 127.26, 124.62, 119.48, 116.19, 115.12, 112.46, 111.83, 51.98, 44.12, 32.38, 21.4, 13.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₂₉ H ₂₂ BrN ₃ O ₅ [M+H] ⁺ : 572.0821; found: 572.0818.

The structural formula of compound 6c is:

The molecular formula is: C ₃₃ H ₂₄ BrN ₃ O ₃

Chinese name is:

2-Benzylamino-3-(8-bromo-6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaoct-2-yl)-4H- Furo[3,2-c]chromen-4-one

English name is:

2-Benzylamino-3-(8-bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)-4H-furo[3,2-c]chromen-4 -one

Appearance: yellow solid

Melting point: 209.7-211.3℃

^1H NMR (400MHz, DMSO) δ 7.72(s, 1H), 7.57-6.83(m, 14H), 5.32(s, 1H), 4.62(d, J=9.2Hz, 2H), 4.44(s, 2H), 4.19(d, J=34.4Hz, 4H).

Carbon nuclear magnetic resonance spectrum: ¹³ C NMR (101MHz, DMSO) δ129.14, 112.69, 47.46, 26.37, 13.59.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₃₃ H ₂₄ BrN ₃ O ₃ [M+H] ⁺ : 590.1079; found: 590.1076.

The structural formula of compound 6d is:

The molecular formula is: C ₃₀ H ₂₆ BrN ₃ O ₃

Chinese name is:

3-(8-Bromo-6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)-2-(tert-butylamino) -4H-furo[3,2-c]chromen-4-one

English name is:

3-(8-Bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)-2-(tert-butylamino)-4H-furo[ 3,2-c ]chromen-4-one

Appearance: brownish yellow solid

Melting point: 122.2-123.6℃

Hydrogen nuclear magnetic resonance spectrum: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76 (d, J=7.4 Hz, 1H), 7.40 (s, 2H), 7.35-7.28 (m, 2H), 7.18 (d, J= 8.6Hz, 2H), 7.12-6.91(m, 3H), 4.86-4.57(m, 2H), 4.40-4.05(m, 5H), 1.39(s, 9H).

Carbon nuclear magnetic resonance spectrum: ¹³ C NMR (101MHz, DMSO) δ157.01, 150.00, 129.13, 126.89, 124.19, 112.66, 84.15, 52.83, 30.08, 17.93.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₃₀ H ₂₆ BrN ₃ O ₃ [M+H] ⁺ : 556.1236; found: 556.1230.

The structural formula of compound 6e is:

The molecular formula is: C ₃₃ H ₃₀ BrN ₃ O ₃

Chinese name is:

3-(8-Bromo-6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaaryloct-2-yl)-2-(cyclohexylamino)- 8-Methyl-4H-furo[3,2-c]chromen-4-one

English name is:

3-(8-Bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)-2-(cyclohexylamino)-8-methanoi-4H-furo[3, 2-c]chromen-4-one

Appearance: yellow green solid

Melting point: 114.7-116.5℃

^1H NMR (400MHz, DMSO) δ 7.92(s, 1H), 7.70(d, J=13.6, 7.7Hz, 1H), 7.62-7.54(m, 1H), 7.44(m, J ＝19.4,8.5Hz,1H),7.34(d,J＝8.3,4.5Hz,1H),7.26(d,J＝11.1,6.5 Hz,2H),7.20-7.03(m,2H),6.36(m, J＝8.1Hz, 1H), 4.71(m, J＝17.0Hz, 2H), 4.28(m, J＝28.1, 15.8 Hz, 4H), 2.45-2.30(m, 4H), 1.94-1.43(m, 10H) ).

Carbon nuclear magnetic resonance spectrum: ¹³ C NMR (101MHz, DMSO) δ208.60, 203.77, 196.79, 191.62, 189.42, 160.37, 155.47, 155.21, 149.06, 116.73, 112.32, 25.60, 24.78, 20.91.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₃₃ H ₃₀ BrN ₃ O ₃ [M+H] ⁺ : 596.1549; found: 596.1545.

The structural formula of compound 6f is:

The molecular formula is: C ₃₀ H ₂₄ BrN ₃ O ₅

Chinese name is:

3-(8-Bromo-6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)-8-methyl-4-oxo Substituted-4H-furo[3,2-c]chromen-2-ylglycine methyl ester

English name is:

Methyl(3-(8-bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)-8-methyl-4-oxo-4H-furo[3,2 -c]chromen-2-yl)glycinate

Appearance: yellow solid

Melting point: 109.4-111.2℃

H NMR spectrum: ¹ H NMR (400MHz, DMSO) δ7.73(d, J=15.0Hz, 2H), 7.38(s, 1H), 7.30-7.07(m, 4H), 6.95(s, 1H), 6.65(s, 1H), 5.95(s, 1H), 5.09(s, 1H), 5.05(s, 1H), 4.61(s, 4H), 4.31(d, J＝13.7Hz, 2H), 3.66(s ,3H),2.50(s,3H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ171.45,154.08,152.58,150.10,146.62,145.95,142.37,135.27,134.76,133.61,132.97,132.43,131.10,130.57,127.56,125.12,124.71, 118.65,117.05 ,115.64,112.95,106.29,99.80,67.99,57.66,51.87,46.23,21.23.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₃₀ H ₂₄ BrN ₃ O ₅ [M+H] ⁺ : 586.0977; found: 586.0980.

The structural formula of compound 6g is:

The molecular formula is: C ₃₄ H ₂₆ BrN ₃ O ₃

Chinese name is:

2-(benzylamino)-3-(8-bromo-6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaoct-2-yl)- 8-Methyl-4H-furo[3,2-c]chromen-4-one

English name is:

2-(Benzylamino)-3-(8-bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)-8-methyl- 4H-furo[3,2 -c]chromen-4-one

Appearance: yellow solid

Melting point: 108.5-110.2℃

^1H NMR (400MHz, DMSO) δ9.68(s, 1H), 7.73(d, J=15.0Hz, 2H), 7.38(s, 1H), 7.33-7.05(m, 9H), 6.95(s, 1H), 6.65(s, 1H), 5.00(d, J=2.3Hz, 2H), 4.61(s, 6H), 2.50(s, 3H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ154.98,152.58,150.10,146.62,145.95,142.37,139.91,135.27,134.76,133.61,132.97,132.43,131.10,130.57,128.34,127.83,127.56, 127.35,125.12 ,124.71,118.65,117.05,115.64,112.95,106.29,100.54,67.99,57.66,47.16,21.23.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₃₄ H ₂₆ BrN ₃ O ₃ [M+H] ⁺ : 604.1236; found: 604.1236.

The structural formula of compound 6h is:

The molecular formula is: C ₃₂ H ₂₈ BrN ₃ O ₃

Chinese name is:

3-(8-Bromo-6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)-2-(tert-butylamino) -8-Methyl-4H-furo[3,2-c]chromen-4-one

English name is:

3-(8-Bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)-2-(tert-butylamino)-8-methyl-4H-furo[ 3,2-c]chromen-4-one

Appearance: yellow solid

Melting point: 119.9-122.1℃

^1H NMR (400MHz, DMSO) δ9.94(s, 1H), 7.73(d, J=15.0Hz, 2H), 7.38(s, 1H), 7.30-7.07(m, 4H), 6.95(s, 1H), 6.65(s, 1H), 5.05(d, J=19.0Hz, 2H), 4.61(s, 4H), 2.50(s, 3H), 1.36(s, 9H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ164.67,152.58,150.10,146.62,145.95,142.37,135.27,134.76,133.61,132.97,132.43,131.10,130.57,127.56,125.12,124.71,118.65, 117.05,115.64 ,112.95,107.10,106.29,67.99,57.66,53.59,29.59,21.23.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₃₂ H ₂₈ BrN ₃ O ₃ [M+H] ⁺ : 570.1392; found: 570.1393.

The structural formula of compound 6h is:

The molecular formula is: C ₃₂ H ₂₇ BrClN ₃ O ₃

Chinese name is:

3-(8-Bromo-6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)-8-chloro-2-(cyclo Hexylamino)-4H-furo[3,2-c]chromen-4-one

English name is:

3-(8-Bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)-8-chloro-2-(cyclohexylami no)-4H-furo[3, 2-c]chromen-4-one

Appearance: brownish yellow solid

Melting point: 117.3-119.1℃

Hydrogen nuclear magnetic resonance spectrum: ¹ H NMR (400MHz, DMSO) δ 7.81-7.66 (m, 2H), 7.54 (m, J=11.5, 9.2, 2.7 Hz, 2H), 7.32-7.25 (m, 2H), 7.19 -6.92(m,3H),6.72(d,J＝10.4Hz,1H),4.66(dd,J＝28.5,11.6Hz,2H),4.20(m,J＝29.2,10.8Hz,4H),2.53- 2.49(m,1H),1.79-1.58(m,4H),1.25-1.18(m,6H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ152.58,150.33,149.75,146.62,145.95,142.37,135.27,133.61,132.36,131.98,131.10,130.57,127.56,125.12,122.38,120.83,117.05, 115.64,112.92 ,111.12,106.29,102.06,67.99,57.66,50.35,33.63,25.92,24.73.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₃₂ H ₂₇ BrClN ₃ O ₃ [M+H] ⁺ : 616.1002; found: 616.1003.

The structural formula of compound 6j is:

The molecular formula is: C ₂₉ H ₂₁ BrClN ₃ O ₅

Chinese name is:

3-(8-Bromo-6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaaryloct-2-yl)-8-chloro-4-oxo -4H-furo[3,2-c]chromen-2-yl)glycine methyl ester

English name is:

Methyl(3-(8-bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)-8-chloro-4-oxo-4H-furo[3,2 -c]chromen-2-yl)glycinate

Appearance: brownish yellow solid

Melting point: 102.2-103.6℃

^1H NMR (400MHz, DMSO) δ 7.94(s, 1H), 7.72(s, 1H), 7.46(s, 1H), 7.53-7.12(m, 5H), 6.95(s, 1H) ), 6.65(s, 1H), 5.07(d, J=18.2Hz, 2H), 4.61(s, 4H), 4.42(s, 1H), 4.28(s, 1H), 3.66(s, 3H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ171.45,154.08,152.58,149.75,146.62,145.95,142.37,135.27,133.61,132.36,131.98,131.10,130.57,127.56,125.12,122.38,120.83, 117.05,115.64 ,112.92,111.12,106.29,99.80,67.99,57.66,51.87,46.23.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₂₉ H ₂₁ BrClN ₃ O ₅ [M+H] ⁺ : 606.0431; found: 606.0432.

The structural formula of compound 6k is:

The molecular formula is: C ₃₃ H ₂₃ BrClN ₃ O ₃

Chinese name is:

2-(benzylamino)-3-(8-bromo-6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaoct-2-yl)- 8-Chloro-4H-furo[3,2-c]chromen-4-one

English name is:

2-(Benzylamino)-3-(8-bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)-8-chloro-4 H-furo[3, 2-c]chromen-4-one

Appearance: green solid

Melting point: 117.5-119.1℃

Hydrogen nuclear magnetic resonance spectrum: ¹ H NMR (400MHz, DMSO) δ 7.95-7.88 (m, 1H), 7.79-7.50 (m, 5H), 7.47-7.16 (m, 7H), 7.13-7.07 (m, 1H) ,7.01(m,J＝14.0,11.2,5.3Hz,1H),4.72-4.59(m,2H),4.41(d,J＝6.3Hz,2H),4.29-4.01(m,4H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ154.73,147.30,141.40,138.94,135.08,130.48,129.95,129.89,129.63,129.28,129.15,129.03,128.88,127.82,127.55,127.39,124.97, 123.41,121.29 , 115.79, 67.99, 57.66, 47.16.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₃₃ H ₂₃ BrClN ₃ O ₃ [M+H] ⁺ : 624.0689; found: 624.0690.

The structural formula of compound 6l is:

The molecular formula is: C ₃₀ H ₂₅ BrClN ₃ O ₃

Chinese name is:

3-(8-Bromo-6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)-2-(tert-butylamino) -8-Chloro-4H-furo[3,2-c]chromen-4-one

English name is:

3-(8-Bromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocin-2-yl)-2-(tert-butylamino)-8-chlor o-4H-furo[ 3,2-c]chromen-4-one

Appearance: brownish yellow solid

Melting point: 101.7-103.1℃

^1H NMR (400MHz, DMSO) δ 7.74-7.50(m, 3H), 7.35-6.90(m, 6H), 6.75(s, 1H), 4.70-4.60(m, 2H), 4.18 (m,J＝25.4,18.4,10.6Hz,4H),2.54-2.39(m,3H),1.34(d,J＝1.5Hz,3H),1.27-1.22(m,3H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ164.67,152.58,149.75,146.62,145.95,142.37,135.27,133.61,132.36,131.98,131.10,130.57,127.56,125.12,122.38,120.83,117.05, 115.64,112.92 ,111.12,107.10,106.29,67.99,57.66,53.59,29.59.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₃₀ H ₂₅ BrClN ₃ O ₃ [M+H] ⁺ : 590.0846; found: 590.0850.

Base衍生物，其合成方法基本相同，下面仅以化合物7a为例详细说明其合成方法：Compounds 7 (7a-7l) are a class of 2,8-bis(furocoumarins)-

Base derivative, its synthetic method is basically the same, the following only takes compound 7a as an example to describe its synthetic method in detail:

A 100 mL dry round-bottomed flask was sequentially added intermediate 3 (0.5 mmol) and 4-hydroxycoumarin (1 mmol), dried toluene (25 mL) was added, and cyclohexyl isocyanide was added dropwise under anhydrous and oxygen-free conditions. (1.2mmol), heated and stirred under reflux for 28h, after the reaction was completed (TLC tracking), cooled, and the excess solvent was evaporated under reduced pressure, and the crude product was separated and purified by column chromatography (V _{petroleum ether} :V _{ethyl acetate} =1:3), Compound 7a was obtained in 67% yield.

The structural formula of compound 7a is:

The molecular formula is: C ₄₉ H ₄₄ N ₄ O ₆

Chinese name is:

3,3'-(6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaaryloct-2-yl)bis(2-(cyclohexylamino)- 4H-furo[3,2-c]chromen-4-one

English name is:

3,3'-(6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diyl)bis(2-(cyclohexylamino)-4H-fu ro[3,2- c]chromen-4-one

Appearance: brown solid

Melting point: 115.4–166.3℃

Hydrogen nuclear magnetic resonance spectrum: ¹ H NMR (400MHz, DMSO) δ 7.81-6.90 (m, 14H), 6.41 (d, J=7.9Hz, 2H), 4.69 (d, J=16.3Hz, 2H), 4.26 ( dd,J＝27.3,16.2Hz,4H),2.04(d,J＝40.2Hz,2H),1.79-1.06(m, 20H).

Carbon nuclear magnetic resonance spectrum: ¹³ C NMR (101MHz, DMSO) δ154.95, 150.01, 128.35, 127.72, 116.40, 112.03, 52.83, 48.90, 33.24, 32.81, 32.16, 30.31, 24.74, 24.30, 23.31.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₄₉ H ₄₄ N ₄ O ₆ [M+H] ⁺ : 785.3339; found: 785.3332.

The rest of the product structure characterization:

The structural formula of compound 7b is:

The molecular formula is: C ₄₃ H ₃₂ N ₄ O ₁₀

Chinese name is:

2,2'-(((6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)bis(4-oxo-4H -furan)[3,2-c]chromene-3,2-diyl))bis(azanediyl))diacetate methyl ester

English name is:

Dimethyl-2,2'-((((6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diyl)bis(4-oxo-4H-furo[ 3,2 -c]chromene-3,2-diyl))bis(azanediyl))diacetate

Appearance: brown solid

Melting point: 113.3-114.6℃

Hydrogen nuclear magnetic resonance spectrum: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.75 (dt, J=3.9, 3.3 Hz, 2H), 7.70 (dd, J=6.4, 5.1 Hz, 4H), 7.61 (d, J= 3.2Hz, 1H), 7.58(d, J＝3.0Hz, 1H), 7.39-7.24(m, 4H), 6.96-6.90(m, 2H), 5.16-5.10(m, 2H), 4.61-4.58(m ,4H),4.36-4.32(m,2H),4.28-4.25(m,2H),3.67-3.63(m,6H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ171.45,154.08,152.58,151.86,145.35,142.37,135.27,134.22,132.43,131.10,127.56,124.59,123.38,118.47,112.98,110.92,106.29, 99.80,67.99 ,57.66,51.87,46.23.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₄₃ H ₃₂ N ₄ O ₁₀ [M+H] ⁺ : 765.2196; found: 765.2195.

The structural formula of compound 7c is:

The molecular formula is: C ₅₁ H ₃₆ N ₄ O ₆

Chinese name is:

3,3'-(6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)bis(2-(benzylamino)- 4H-furo[3,2-c]chromen-4-one)

English name is:

3,3'-(6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diyl)bis(2-(benzylamino)-4-H-furo[3 ,2 -c]chromen-4-one)

Appearance: brown solid

Melting point: 158.7-160.3℃

Hydrogen nuclear magnetic resonance spectrum: ¹ H NMR (400MHz, DMSO) δ8.37-7.02 (m, 24H), 7.00-6.09 (m, 2H), 4.91-3.94 (m, 10H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ154.98,152.58,151.86,145.35,142.37,139.91,135.27,134.22,132.43,131.10,128.34,127.83,127.56,127.35,124.59,123.38,118.47, 112.98,110.92 ,106.29,100.54,67.99,57.66,47.16.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₅₁ H ₃₆ N ₄ O ₆ [M+H] ⁺ : 801.2713; found: 801.2711.

The structural formula of compound 7d is:

The molecular formula is: C ₄₅ H ₄₀ N ₄ O ₆

Chinese name is:

3,3'-(6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)bis(2-(tert-butylamino) -4H-furo[3,2-c]chromen-4-one

English name is:

3,3'-(6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diyl)bis(2-(tert-butylamin)-4H-furo[ 3,2 -c]chromen-4-one

Appearance: Brown green solid

Melting point: 287.3-288.1℃

Hydrogen nuclear magnetic resonance spectrum: ¹ H NMR (400MHz, DMSO) δ 7.82-7.12 (m, 14H), 5.71 (d, J=18.1Hz, 2H), 4.71 (d, J=16.5Hz, 2H), 4.26 ( dd,J=26.3,16.3Hz,4H),1.36-1.22(m,18H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ156.72,154.76,150.82,149.79,146.80,129.33,128.29,127.77,127.42,125.45,124.67,124.28,119.68,116.51,112.04,109.49,102.07, 57.95,52.86 ,51.02,30.09,28.26,27.07.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₄₅ H ₄₀ N ₄ O ₆ [M+H] ⁺ : 733.3026; found: 733.3028.

The structural formula of compound 7e is:

The molecular formula is: C ₅₁ H ₄₈ N ₄ O ₆

Chinese name is:

3,3'-(6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaaryloct-2-yl)bis(2-(cyclohexylamino)- 8-Methyl-4H-furo[3,2-c]chromen-4-one

English name is:

3,3'-(6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diyl)bis(2-(cyclohexylamino)-8-methanoi-4H-furo[ 3,2-c]chromen-4-one

Appearance: yellow green solid

Melting point: 147.3-149.1℃

^1H NMR (400MHz, DMSO) δ9.84(s, 5H), 7.73(d, J=15.0Hz, 10H), 7.38(s, 5H), 7.25(d, J=10.0Hz, 11H), 6.95(s, 5H), 5.13(d, J=9.0Hz, 5H), 4.61(s, 10H), 3.73(s, 2H), 2.50(s, 15H), 1.87(s, 6H), 1.60(s, 13H), 1.24(s, 13H), 1.12(s, 9H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ152.58,150.33,150.10,145.95,142.37,135.27,134.76,132.97,132.43,131.10,127.56,124.71,118.65,112.95,106.29,102.06,67.99, 57.66,50.35 ,33.63,25.92,24.73,21.23.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₅₁ H ₄₈ N ₄ O ₆ [M+H] ⁺ : 813.3652; found: 813.3659.

The structural formula of compound 7f is:

The molecular formula is: C ₄₅ H ₃₆ N ₄ O ₁₀

Chinese name is:

2,2'-(((6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)bis(8-methyl-4 -Oxo-4H-furo[3,2-c]chromene-3,2-diyl))bis(azanediyl))diacetate methyl ester

English name is:

Dimethyl-2,2'-((((6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diyl)bis(8-methyl-4-oxo-4H-furo [3,2-c]chromene-3,2-diyl))bis(azanediyl))diacetate

Appearance: brownish yellow solid

Melting point: 164.2-165.8℃

Hydrogen nuclear magnetic resonance spectrum: ¹ H NMR (400MHz, DMSO) δ 7.73(d, J=15.0Hz, 2H), 7.38(s, 1H), 7.25(d, J=10.0Hz, 2H), 6.95(s, 1H), 5.14(d, J=4.8Hz, 1H), 4.61(s, 2H), 4.38(s, 1H), 4.33(s, 1H), 3.66(s, 3H), 2.50(s, 3H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ171.45,154.08,152.58,150.10,145.95,142.37,135.27,134.76,132.97,132.43,131.10,127.56,124.71,118.65,112.95,106.29,99.80, 67.99,57.66 ,51.87,46.23,21.23.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₄₅ H ₃₆ N ₄ O ₁₀ [M+H] ⁺ : 793.2509; found: 793.2506.

The structural formula of compound 7g is:

The molecular formula is: C ₃₄ H ₂₆ BrN ₃ O ₃

Chinese name is:

3,3'-(6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)bis(2-(benzylamino)- 8-Methyl-4H-furo[3,2-c]chromen-4-one

English name is:

3,3'-(6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diyl)bis(2-(benzylamino)-8-methyl- 4H-furo[3 ,2-c]chromen-4-one

Appearance: yellow solid

Melting point: 173.8-175.4℃

^1H NMR (400MHz, DMSO) δ7.73(d, J=15.0Hz, 2H), 7.38(s, 1H), 7.33-7.22(m, 7H), 6.95(s, 1H), 4.99(d, J=2.4Hz, 1H), 4.61(s, 4H), 2.50(s, 3H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ154.98,152.58,150.10,145.95,142.37,139.91,135.27,134.76,132.97,132.43,131.10,128.34,127.83,127.56,127.35,124.71,118.65, 112.95,106.29 (s), 100.54, 67.99 (s), 57.66, 47.16, 21.23.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₅₃ H ₄₀ N ₄ O ₆ [M+H] ⁺ : 829.3026; found: 829.3033.

The structural formula of compound 7h is:

The molecular formula is: C ₄₇ H ₄₄ N ₄ O ₆

Chinese name is:

3,3'-(6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)bis(2-(tert-butylamino) -8-Methyl-4H-furo[3,2-c]chromen-4-one

English name is:

3,3'-(6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diyl)bis(2-(tert-butylamino)-8-methyl-4H- furo[3,2-c]chromen-4-one

Appearance: green solid

Melting point: 275.3-276.5℃

^1H NMR (400MHz, DMSO) δ 9.97(s, 1H), 7.73(d, J=15.0Hz, 2H), 7.38(s, 1H), 7.25(d, J=10.0Hz, 2H), 6.95(s, 1H), 5.14(d, J=8.5Hz, 1H), 4.61(s, 2H), 2.50(s, 3H), 1.36(s, 9H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ164.67,152.58,150.10,145.95,142.37,135.27,134.76,132.97,132.43,131.10,127.56,124.71,118.65,112.95,107.10,106.29,67.99, 57.66,53.59 ,29.59,21.23.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₄₇ H ₄₄ N ₄ O ₆ [M+H] ⁺ : 761.3339; found: 761.3334.

The structural formula of compound 7i is:

The molecular formula is: C ₄₉ H ₄₂ Cl ₂ N ₄ O ₆

Chinese name is:

3,3'-(6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)bis(8-chloro-2-(cyclo) Hexylamino)-4H-furo[3,2-c]chromen-4-one

English name is:

3,3'-(6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diyl)bis(8-chloro-2-(cyclohexylami no)-4H-furo[ 3,2-c]chromen-4-one

Appearance: green solid

Melting point: 176.5-177.8℃

^1H NMR (400MHz, DMSO) δ9.89(s, 11H), 7.94(s, 11H), 7.72(s, 11H), 7.46(s, 9H), 7.42(d, J=21.4 Hz, 3H), 7.31(d, J＝65.0Hz, 25H), 6.95(s, 11H), 5.14(d, J＝7.7Hz, 11H), 4.61(s, 22H), 3.74(s, 4H), 1.87(s, 13H), 1.60(s, 29H), 1.24(s, 28H), 1.12(s, 24H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ152.58,150.33,149.75,145.95,142.37,135.27,132.36,131.98,131.10,127.56,122.38,120.83,112.92,111.12,106.29,102.06,67.99, 57.66,50.35 ,33.63,25.92,24.73.

Mass spectrum: HRMS (ESI) m/z: _calcd for _{C49H42Cl2N4O6 [} M ₊ H] ⁺ : _853.2559 ; found: 853.2555.

The structural formula of compound 7j is:

The molecular formula is: C ₄₃ H ₃₀ Cl ₂ N ₄ O ₁₀

Chinese name is:

2,2'-(((6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)bis(8-chloro-4- Methyl oxo-4H-furo[3,2-c]chromene-3,2-diyl))bis(azanediyl))diacetate

English name is:

Dimethyl-2,2'-((((6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diyl)bis(8-chloro-4-oxo-4H-furo [3,2-c]chromene-3,2-diyl))bis(azanediyl))diacetate

Appearance: yellow solid

Melting point: 128.3-130.1℃

^1H NMR (400MHz, DMSO) δ 7.94(s, 2H), 7.72(s, 2H), 7.46(s, 1H), 7.38(s, 3H), 7.25(s, 2H), 6.95(s, 2H), 5.13(d, J=7.5Hz, 2H), 4.61(s, 4H), 4.40(s, 2H), 4.31(s, 2H), 3.66 (s, 6H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ171.45,154.08,152.58,149.75,145.95,142.37,135.27,132.36,131.98,131.10,127.56,122.38,120.83,112.92,111.12,106.29,99.80, 67.99,57.66 ,51.87,46.23.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₄₃ H ₃₀ Cl ₂ N ₄ O ₁₀ [M+H] ⁺ : 833.1417; found: 833.1418.

The structural formula of compound 7k is:

The molecular formula is: C ₅₁ H ₃₄ Cl ₂ N ₄ O ₆

Chinese name is:

3,3'-(6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)bis(2-(benzylamino)- 8-Chloro-4H-furo[3,2-c]chromen-4-one

English name is:

3,3'-(6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diyl)bis(2-(benzylamino)-8-chloro- 4H-furo[3 ,2-c]chromen-4-one

Appearance: yellow solid

Melting point: 158.8-160.2℃

^1H NMR (400MHz, DMSO) δ7.94(s, 1H), 7.72(s, 1H), 7.46(s, 1H), 7.38(s, 1H), 7.33-7.13(m, 6H) ), 6.95(s, 1H), 5.01(d, J=4.2Hz, 1H), 4.61(s, 4H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ154.98,152.58,149.75,145.95,142.37,139.91,135.27,132.36,131.98,131.10,128.34,127.83,127.56,127.35,122.38,120.83,112.92, 111.12,106.29 ,100.54,67.99,57.66,47.16.

Mass spectrum: HRMS (ESI) m/z: _calcd for _{C51H34Cl2N4O6 [} M ₊ H] ⁺ : _869.1933 ; found: 869.1894.

The structural formula of compound 71 is:

The molecular formula is: C ₄₅ H ₃₈ Cl ₂ N ₄ O ₆

Chinese name is:

3,3'-(6H,12H-5,11-methylenedibenzo[b,f][1,5]diazaphan-2-yl)bis(2-(tert-butylamino) -8-Chloro-4H-furo[3,2-c]chromen-4-one

English name is:

3,3'-(6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diyl)bis(2-(tert-butylamino)-8-chlor o-4H- furo[3,2-c]chromen-4-one

Appearance: green solid

Melting point: 191.4-192.6℃

^1H NMR (400MHz, DMSO) δ9.96(s, 1H), 7.93(s, 1H), 7.71(s, 1H), 7.45(s, 1H), 7.31(d, J=64.9 Hz, 2H), 6.94(s, 1H), 5.14(d, J=8.5Hz, 1H), 4.61(s, 2H), 1.36(s, 9H).

核磁共振碳谱： ¹³ C NMR(101MHz,DMSO)δ164.67,152.58,149.75,145.95,142.37,135.27,132.36,131.98,131.10,127.56,122.38,120.83,112.92,111.12,107.10,106.29,67.99, 57.66,53.59 ,29.59.

Mass spectrum: HRMS (ESI) m/z: calcd for C ₄₅ H ₃₈ Cl ₂ N ₄ O ₆ [M+H] ⁺ : 801.2246; found: 801.2248.

Example 2 Antitumor activity:

Compounds 6 and 7 were preliminarily tested against human triple-negative breast cancer cells (MDA-MB-231), human hepatoma cells (HepG-2), human lung cancer cells (A549) and human liver immortalized cells (THLE) by MTT assay. , Cytotoxicity of human bronchial epithelial cells (HBE). The results are shown in Table 2, there are three compounds (7h, 7i, 7l), at different concentrations (μg/mL), showing different degrees of inhibition rate and no inhibition on human bronchial epithelial cells (HBE).

Table 2. Inhibitory ^ratea of compound 7 on cancer cells and normal cells (IC ₅₀ , μg/mL)

^a IC ₅₀ values above 50 are marked as "-"

Example 3 Recognition of neuroblastoma markers homovanillic acid (HVA) and mandelic vanillic acid (VMA) by compounds

This example is to test the fluorescence properties of compounds 6 and 7 to detect their recognition of neuroblastoma markers homovanillic acid (HVA) and mandelic vanillic acid (VMA). The test results are shown in Figures 1-5 and the following table 3 shown. Among them, Table 3 shows the fluorescence properties of compound 6h on HVA and VMA, Figure 1 shows the fluorescence emission spectrum of 6h with HVA and MVA, Figure 2 shows the fluorescence emission spectrum of 6h in the presence of different concentrations of HVA, and Figure 3 shows the effect of compound 6h on HVA The standard curve of , Figure 4 is the fluorescence emission spectrum of 6h in the presence of different concentrations of VMA, Figure 5 is the standard curve of compound 6h to VMA. After testing, it was found that 6h has a fluorescent recognition effect on both HVA and VMA, and can be used for simultaneous qualitative and quantitative detection of HVA and VMA. Further detailed research will hopefully develop it into a new type of detection reagent for efficient early warning and diagnosis of NB.

Table 3 shows the fluorescence properties of compound 6h on HVA and VMA

^a Maximum fluorescence emission wavelength; ^b Relative fluorescence intensity decrease; ^c Detection limit 10 ^-5 mol·L ^-1 .

Claims (4)

1. A class of furanocoumarins-

The synthetic method of Base derivative is characterized in that, its structural formula is shown in the following formula 6,

R ₁ is Cl; R ₂ is cyclohexyl; include: S1: Preparation of intermediate 1 shown in the following formula,

Mix p-bromoaniline and paraformaldehyde, slowly add trifluoroacetic acid dropwise at minus 15°C, move the reaction system to room temperature for 7 days after dropping, TLC tracking reaction ends; pour the reaction mixture into ice water, adjust pH, Extract with dichloromethane, extract the organic phase with saturated brine, combine the organic layers, dry, filter, distill the filtrate under reduced pressure, separate and purify by column chromatography, recrystallize with acetone, and dry to obtain Intermediate 1; S2: prepare intermediate 2 shown in the following formula,

The intermediate 1 was placed in a container, then dried tetrahydrofuran was added, the system was cooled to -78°C under anhydrous and oxygen-free conditions, n-butyllithium was slowly added dropwise, and then dried N,N-dichloromethane was added dropwise. Methylformamide was added and moved to room temperature to continue the reaction for a period of time. After the reaction, it was quenched with ice water, extracted with dichloromethane, and separated and purified by column chromatography to obtain Intermediate 2; S3: Dissolve intermediate 2 and coumarin compounds in the dried toluene, add isonitrile dropwise under anhydrous and oxygen-free conditions, heat and stir to reflux until the end of the TLC tracking reaction, cool, and spin dry the excess solvent The crude product was obtained, which was separated and purified by column chromatography to obtain the target compound 6; The structural formula of the coumarin compound is shown in the following formula 4,

R ₁ is Cl; The structural formula of isonitrile is shown in the following formula 5,

wherein, R ₂ is cyclohexyl. 2. synthetic method according to claim 1 is characterized in that, described p-bromoaniline and described paraformaldehyde are mixed in molar ratio of 2:5. 3. The synthetic method according to claim 2, wherein the molar ratio of the intermediate 2, the coumarin compound, and the isonitrile is 1:1:1.2. 4. A class of furanocoumarins-

The application of Base derivative in the preparation of detection reagent for detecting homovanillic acid or mandelic vanillic acid, characterized in that its structural formula is shown in the following formula 6

R ₁ is Cl; R ₂ is cyclohexyl.

Images