CN111825679A

CN111825679A - Novel spiro-pyrrole [2, 1-b ] quinazolinone derivative and preparation method and application thereof

Info

Publication number: CN111825679A
Application number: CN202010640945.5A
Authority: CN
Inventors: 苏桂发; 王望; 庞莉; 谢莹; 潘成学; 莫冬亮
Original assignee: Guangxi Normal University
Current assignee: Guangxi Normal University
Priority date: 2020-07-06
Filing date: 2020-07-06
Publication date: 2020-10-27
Anticipated expiration: 2040-07-06
Also published as: CN111825679B

Abstract

The invention relates to a new spiro pyrrole [2, 1-b ] quinazolinone derivative, a preparation method and application thereof, wherein the new spiro pyrrole [2, 1-b ] quinazolinone derivative is synthesized by a simple method, the yield is high, the production cost is low, the obtained new spiro pyrrole [2, 1-b ] quinazolinone derivative has good anticancer effect on different tumor cells, can be prepared into anticancer drugs of various dosage forms, and has high medical value and wide market prospect.

Description

Novel spiro-pyrrole [2, 1-b ] quinazolinone derivative and preparation method and application thereof

Technical Field

The invention relates to the field of medicinal chemistry, in particular to a novel spiro pyrrole [2, 1-b ] quinazolinone derivative, a preparation method and application thereof.

Background

The tumor is a common disease and frequently encountered disease, wherein malignant tumor has become a main disease threatening human health, and the morbidity and mortality of the malignant tumor are the first of all diseases. In 2 months of 2017, the national cancer center issues the latest Chinese cancer data, and the data shows that about 1 million people in China can diagnose cancer every day, namely about 7 people per minute. Quinazolinone is an important nitrogen-containing heterocyclic compound, is one of the most important structural units in medicinal chemistry, and has wide pharmacological activities such as anti-inflammation, anti-tumor, anti-convulsion, sedation, anti-hypertension, vasodilation, antimicrobial and antibacterial. And thus has been a focus of research by organic synthesis and pharmaceutical chemists. The quinazolone pentacyclic skeleton is one of the more concerned pentacyclic skeletons in the quinazolone compound, and attracts a plurality of synthetic and pharmaceutical chemists to synthesize, modify and study the skeletons and pharmacological activity in recent years.

The novel spiro pyrrole [2, 1-b ] quinazolinone derivatives have various biological activities, have wide application, are easy to cause side reactions in the synthesis process, have low yield and have very limited synthesis method.

Disclosure of Invention

The invention aims to: aiming at the problems, the invention provides a novel spiro pyrrole [2, 1-b ] quinazolinone derivative with high yield and good anti-tumor effect, and a preparation method and application thereof.

The invention is realized by the following technical scheme:

the present invention provides: a new spiro pyrrole [2, 1-b ] quinazolinone derivative has a structural formula shown in formula I,

wherein R is¹Is H, F, Cl, Br, OMe, Me, NO₂Or CF₃；R²H, F, Br, OMe or Me; r³Is H or Me.

Further, the structural formula of the novel spiro pyrrole [2, 1-b ] quinazolinone derivative is shown as follows:

the invention also provides a preparation method of the novel spiro pyrrole [2, 1-b ] quinazolinone derivative, which comprises the following steps:

(1) preparation of compound 3: adding the compound 1, the compound 2 and water into a reaction container in sequence, heating, stirring for reaction, after the reaction is finished, performing suction filtration, taking filter residues, washing and drying to obtain a compound 3;

(2) preparation of compound 4: adding the compound 3, p-toluenesulfonic acid, tetrahydrofuran, anhydrous magnesium sulfate and 3-trimethylsilyl propiolic aldehyde into a reaction vessel in sequence, and reacting at room temperature; adding DDQ in an ice water bath for reaction, removing the solvent after the reaction is finished, and purifying to obtain a compound 4;

(3) preparation of compound 5: adding the compound 4, acetone and silver nitrate aqueous solution into a reaction vessel in sequence, stirring and reacting under the condition of keeping out of the sun, removing the solvent after the reaction is finished, and purifying to obtain a compound 5;

(4) preparing a target product 6: adding the compound 5, palladium acetate, boron trifluoride diethyl etherate solution and trichloromethane into a reaction vessel in sequence, heating, reacting, removing the solvent after the reaction is finished, and purifying to obtain a target product 6;

the structural formula of the compound 1 is as follows:

the structural formula of compound 2 is:

the structural formula of compound 3 is:

the structural formula of compound 4 is:

the structural formula of compound 5 is:

the structural formula of the target product 6 is as follows:

further, in the step (1), the temperature for stirring the reaction is 75-85 ℃.

Further, in the step (1), the stirring reaction time is 8-10 h.

Further, in the step (2), the reaction time at room temperature is 2.5 h-3.5 h.

Further, in the step (2), the DDQ is added in an ice water bath for reaction for 25-35 min.

(2) preparation of compound 4': adding dichloromethane and chlorochromate pyridinium into the reaction vessel in sequence, and reacting at low temperature; after the reaction is finished, a compound 4' containing dichloromethane is obtained;

(3) preparation of compound 5': adding a compound 3, p-toluenesulfonic acid, tetrahydrofuran, anhydrous magnesium sulfate and the compound 4 'containing dichloromethane in the step (2) into a reaction container in sequence, reacting at room temperature, adding DDQ into an ice water bath after the reaction is finished, removing the solvent after the reaction is finished, and purifying to obtain a compound 5';

(4) preparing a target product 6: adding the compound 5', palladium acetate, boron trifluoride ether solution and trichloromethane into a reaction vessel in sequence, heating, stirring for reaction, removing the solvent after the reaction is finished, and purifying to obtain a target product 6;

the structural formula of the compound 1 is as follows:

the structural formula of compound 2 is:

the structural formula of compound 3 is:

the structural formula of compound 4' is:

the structural formula of compound 5' is:

the structural formula of the target product 6 is as follows:

the invention also provides: an application of new spiro pyrrole [2, 1-b ] quinazolinone derivative in preparing antineoplastic medicine is provided.

The invention relates to a preparation route I of a novel spiro pyrrole [2, 1-b ] quinazolinone derivative, which comprises the following steps:

the invention relates to a preparation route II of a novel spiro pyrrole [2, 1-b ] quinazolinone derivative, which comprises the following steps:

the invention synthesizes the new spiro pyrrole [2, 1-b ] quinazolinone derivative by a simple method, has high yield and low production cost, and the obtained new spiro pyrrole [2, 1-b ] quinazolinone derivative has good anticancer effect on different tumor cells, can be prepared into various dosage forms of anticancer drugs, and has high medical value and wide market prospect.

Detailed Description

Any feature disclosed in this specification (including any accompanying claims, abstract) may be replaced by alternative features serving equivalent or similar purposes, unless expressly stated otherwise. That is, unless expressly stated otherwise, each feature is only an example of a generic series of equivalent or similar features.

Example 1: synthesis of Compound 6a

To a 250mL round bottom flask was added isatoic anhydride 2a (5000mg, 30.6mmol), followed by p-anisidine (3774mg, 30.6mmol) and finally water (80mL) with magnetic stirring. The reaction was carried out in an oil bath at 80 ℃ for 9h to precipitate a brown solid. Filtration with suction and drying gave 7405mg (yield 99%) of compound 3a as a brown solid.

To a 150mL round-bottomed flask were added 3a (3000mg, 12.39mmol), p-toluenesulfonic acid (639mg, 3.72mmol), tetrahydrofuran (40.0mL), anhydrous magnesium sulfate (4460mg, 37.17mmol), 3-trimethylsilylpropynaldehyde (1.8mL, 12.39mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours, DDQ (3375mg, 14.87mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10,1:4) to give 3048mg of compound 4a as a pale yellow solid (yield 70%).

To a 100mL round-bottom flask was added sequentially compound 4a (1960mg, 5.6mmol), acetone (25mL) and 1% aqueous silver nitrate (10mL) with magnetic stirring. The reaction was stirred at ambient temperature for 6h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gelPurification by chromatography (eluent: V)_EA:V_PE1:6, 1:4, 1:1) to give compound 5a as a pale yellow solid 1098mg (71%).

To a 10mL round-bottom flask, compound 5a (80mg, 0.29mmol), palladium acetate (6.5mg, 0.029mmol) and finally a 1.0mmol/mL boron trifluoride etherate solution (1.45mL, 1.45mmol) prepared using chloroform as a solvent were added under electromagnetic stirring, and finally chloroform (4mL) was added. Reaction in an oil bath at 60 ℃ for 3h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1) to give compound 6a as a pale yellow solid, 70mg (yield 92%).

¹H NMR(400MHz,CDCl₃)8.26(d,J＝7.8Hz,1H),7.84–7.71(m,2H),7.51(t,J＝7.3Hz,1H),6.87(d,J＝5.8Hz,1H),6.66–6.49(m,5H).¹³C NMR(100MHz,CDCl₃)184.0,159.2,156.9,148.9,143.7,141.9,134.8,132.4,129.1,127.7,127.4,126.7,120.9,69.1.

Example 2: synthesis of Compound 6b

To a 250mL round bottom flask, 2b (2500mg, 14.1mmol) was added with magnetic stirring, followed by p-anisidine (1735mg, 14.1mmol) and finally water (80 mL). The reaction was carried out in an oil bath at 80 ℃ for 9h to precipitate a brown solid. Suction filtration and drying gave 3400mg (94% yield) of compound 3b as a brown solid.

Under electromagnetic stirring and cooling in an ice-water bath, 3b (2000mg, 7.8mmol), p-toluenesulfonic acid (402mg, 2.3mmol), tetrahydrofuran (40.0mL), anhydrous magnesium sulfate (2808mg, 23.4mmol), 3-trimethylsilylpropynaldehyde (1.1mL, 7.8mmol) were added in this order to a 150mL round-bottomed flask, the mixture was reacted at room temperature for 3 hours, DDQ (2124mg, 9.4mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was subjected to column chromatographyPurification (eluent: V)_EA:V_PE1.88mg of compound 4b was obtained as a pale yellow solid (yield 67%).

To a 100mL round-bottomed flask, compound 4b (1880mg, 5.2mmol), acetone (25mL) and 1% aqueous silver nitrate (9mL) were added in that order with magnetic stirring. The reaction was stirred at ambient temperature for 6h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:6, 1:4, 1:1) to give 1070mg (yield 71%) of compound 5b as a pale yellow solid.

To a 10mL round bottom flask, compound 5b (150mg, 0.52mmol), palladium acetate (12mg, 0.052mmol) were added under magnetic stirring, followed by 1.0mmol/mL boron trifluoride etherate (2.6mL, 2.6mmol) in chloroform as a solvent, and followed by chloroform (4 mL). Reaction in an oil bath at 60 ℃ for 3h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1) to give compound 6b as a pale yellow solid, 105mg (74% yield).

¹H NMR(400MHz,CDCl₃)7.64–7.54(m,2H),7.24(d,J＝6.8Hz,1H),6.81(d,J＝5.8Hz,1H),6.62–6.53(m,4H),6.51(d,J＝5.8Hz,1H),2.83(s,3H).¹³C NMR(100MHz,CDCl₃)184.0,159.9,156.5,150.7,143.6,142.5,141.7,133.9,132.2,130.2,128.9,126.0,119.3,69.3,23.1.

Example 3: synthesis of Compound 6c

Under the conditions of electromagnetic stirring and ice-water bath cooling, 1c (2000mg, 11.6mmol) and tetrahydrofuran (35mL) are respectively added into a 150mL round-bottom flask, and after the reaction system is cooled, triphosgene is slowly added(1172mg,3.9 mmol). In N₂The reaction was stirred for 6h under protection. After the reaction was completed, the solvent was removed under reduced pressure, and an appropriate amount of petroleum ether was added thereto and subjected to ultrasonic treatment to thereby suspend the precipitated solid in petroleum ether sufficiently, followed by suction filtration and drying to obtain 1790mg (78%) of a white solid of Compound 2 c.

To a 250mL round bottom flask, 2c (1790mg, 9.1mmol) was added with magnetic stirring, followed by p-anisidine (1115mg, 9.1mmol) and finally water (80 mL). The reaction was carried out in an oil bath at 80 ℃ for 6h, and a white solid precipitated. Filtration with suction and drying gave 1020mg (41% yield) of compound 3c as a white solid.

To a 150mL round-bottomed flask were added 3c (1020mg, 3.7mmol), p-toluenesulfonic acid (190mg, 1.1mmol), tetrahydrofuran (40.0mL), anhydrous magnesium sulfate (1328mg, 11.1mmol), 3-trimethylsilylpropyraldehyde (0.55mL, 3.7mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours, DDQ (1005mg, 4.4mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the reaction was terminated, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10,1:4) to yield 600mg of compound 4c as a pale yellow solid (43% yield).

To a 100mL round-bottomed flask, compound 4c (600mg, 1.6mmol), acetone (25mL) and 1% aqueous silver nitrate (3mL) were added in that order with magnetic stirring. The reaction was stirred at room temperature for 4h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:4, 1:1) to give compound 5c as a white solid, 430mg (88% yield).

To a 10mL round-bottom flask, compound 5c (200mg,0.64mmol), palladium acetate (15mg, 0.064mmol) and finally a 1.0mmol/mL boron trifluoride etherate solution (3.3mL, 3.3mmol) prepared using chloroform as a solvent were added under electromagnetic stirring, and finally chloroform (4mL) was added. Reaction in an oil bath at 60 ℃ for 3h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, and the mixture was extracted with dichloromethane (4 × 10mL), and the mixture was combinedThe organic phase is freed of the solvent under reduced pressure and the crude product is purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:4, 1:2, 1:1) to give 103mg (yield 54%) of compound 6c as a pale yellow solid.

¹H NMR(400MHz,CDCl₃)7.65–7.61(m,2H),7.49–7.46(m,1H),6.81(d,J＝5.8Hz,1H),6.61–6.55(m,3H),6.55–6.50(m,2H).¹³C NMR(100MHz,CDCl₃)183.9,157.3,157.3,151.6,144.7,141.6,134.7,134.2,132.6,130.2,128.7,127.1,118.0,69.5.

Example 4: synthesis of Compound 6d

1d (2000mg, 10.15mmol) and tetrahydrofuran (35mL) were added to a 150mL round-bottomed flask under electromagnetic stirring and cooling in an ice-water bath, and after the reaction system had cooled, triphosgene (1021mg, 3.45mmol) was slowly added. In N₂Stirring for reaction for 5h under protection. After the reaction was completed, the solvent was removed under reduced pressure, and an appropriate amount of petroleum ether was added thereto and subjected to ultrasonic treatment to thereby suspend the precipitated solid in petroleum ether sufficiently, followed by suction filtration and drying to obtain 2230mg (yield 99%) of a brown solid of Compound 2 d.

To a 250mL round bottom flask, 2d (2140mg, 10.85mmol) was added with magnetic stirring, followed by p-anisidine (1335mg, 10.85mmol) and finally water (90 mL). The reaction was carried out in an oil bath at 80 ℃ for 7h, a brown solid precipitated. Suction filtration and drying gave 2230mg (70% yield) of Compound 3d as a brown solid.

To a 150mL round bottom flask were added 3d (1500mg, 4.96mmol), p-toluenesulfonic acid (256mg, 1.78mmol), tetrahydrofuran (40.0mL), anhydrous magnesium sulfate (1786mg, 14.88mmol), 3-trimethylsilylpropynaldehyde (0.71mL, 4.96mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3h, DDQ (1351mg, 5.95mmol) was added in an ice-water bath, the reaction was carried out for 30 min, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10) to give 1500mg of compound 4d as a pale yellow solid (yield 74%).

To a 100mL round-bottomed flask, compound 4d (1500mg, 3.67mmol), acetone (20mL) and 1% aqueous silver nitrate solution (6.6mL) were added sequentially with magnetic stirring. The reaction was stirred at room temperature for 4h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:4, 1:1) to give compound 5d as a white solid 450mg (37% yield).

To a 10mL round-bottom flask, compound 5d (50mg,0.15mmol), palladium acetate (3.5mg, 0.015mmol) and finally a 1.0mmol/mL boron trifluoride etherate solution (0.74mL, 0.74mmol) prepared using chloroform as a solvent were added under electromagnetic stirring, and finally chloroform (4mL) was added. Reaction in an oil bath at 60 ℃ for 3h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1) to give 45mg of compound 6d as a pale yellow solid (yield 94%).

¹H NMR(400MHz,CDCl₃)7.58(s,1H),7.14(s,1H),6.82(d,J＝5.8Hz,1H),6.63–6.51(m,5H),4.01(s,3H),3.96(s,3H).¹³C NMR(100MHz,CDCl₃)184.1,158.8,155.8,155.2,149.4,145.1,142.6,142.1,132.3,129.1,114.1,108.1,105.5,69.0,56.4,56.3.

Example 5: synthesis of Compound 6e

To a 250mL round bottom flask, 2e (2000mg, 10.36mmol) was added with magnetic stirring, followed by p-anisidine (1275mg, 10.36mmol) and finally water (80 mL). The reaction was carried out in an oil bath at 80 ℃ for 7h, and a white solid precipitated. Filtration with suction and drying gave 2100mg (75% yield) of compound 3e as a white solid.

To a 150mL round bottom flask with an electromagnetic stirring barTo this mixture were added 3e (2100mg, 5.50mmol), p-toluenesulfonic acid (284mg, 1.65mmol), tetrahydrofuran (40.0mL), anhydrous magnesium sulfate (1980mg, 16.50mmol), 3-trimethylsilylpropynaldehyde (0.81mL, 5.50mmol) in this order, the mixture was reacted at room temperature for 3 hours, DDQ (1498mg, 6.60mmol) was added under an ice-water bath, the reaction was terminated, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10,1:6) to yield 975mg of compound 4e as a pale yellow solid (47% yield).

To a 100mL round-bottomed flask, compound 4e (970mg, 2.56mmol), acetone (20mL) and 1% aqueous silver nitrate (4.6mL) were added sequentially with magnetic stirring. The reaction was stirred at room temperature for 5h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:4, 1:1) to give compound 5e as a white solid 700mg (89% yield).

To a 10mL round-bottom flask, compound 5e (200mg,0.65mmol), palladium acetate (14.6mg, 0.065mmol) and finally a 1.0mmol/mL boron trifluoride etherate solution (3.25mL, 3.25mmol) prepared using chloroform as a solvent were added under electromagnetic stirring, and finally chloroform (3mL) was added. Reaction in an oil bath at 60 ℃ for 2h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give compound 6e as a pale yellow solid, 152mg (yield 80%).

¹H NMR(400MHz,CDCl₃)7.65(d,J＝8.9Hz,1H),7.60(d,J＝2.9Hz,1H),7.35(dd,J＝8.9,3.0Hz,1H),6.83(d,J＝5.8Hz,1H),6.61–6.49(m,5H),3.87(s,3H).¹³C NMR(100MHz,CDCl₃)184.0,159.1,158.8,154.9,143.3,142.3,142.0,132.3,129.2,129.1,124.7,121.7,106.3,68.9,55.8.

Example 6: synthesis of Compound 6f

1f (2000mg, 13.23mmol) and tetrahydrofuran (35mL) were added to a 150mL round-bottomed flask under magnetic stirring and cooling in an ice-water bath, and after the reaction system had cooled, triphosgene (1335mg, 4.49mmol) was slowly added. In N₂Stirring for reaction for 5h under protection. After the reaction, the solvent was removed under reduced pressure, and a suitable amount of petroleum ether was added thereto and subjected to ultrasonic treatment to thereby suspend the precipitated solid in petroleum ether sufficiently, followed by suction filtration and drying to obtain 2320mg (yield 99%) of a white solid of Compound 2 f.

To a 250mL round bottom flask, 2f (2300mg, 13.00mmol) was added with magnetic stirring, followed by p-anisidine (1599mg, 13.00mmol) and finally water (100 mL). The reaction was carried out in an oil bath at 80 ℃ for 8h to precipitate a pale yellow solid. Suction filtration and drying gave 2750mg (83% yield) of compound 3f as a pale yellow solid.

To a 150mL round-bottomed flask were added 3f (2700mg, 10.50mmol), p-toluenesulfonic acid (541mg, 3.15mmol), tetrahydrofuran (40.0mL), anhydrous magnesium sulfate (3780mg, 31.5mmol), 3-trimethylsilylpropynaldehyde (1.6mL, 10.50mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours, DDQ (2860mg, 12.60mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10) to give 3000mg of compound 4f as a pale yellow solid (yield 79%).

To a 100mL round-bottomed flask, compound 4f (760mg, 2.10mmol), acetone (15mL) and 1% aqueous silver nitrate solution (3.7mL) were added sequentially with magnetic stirring. The reaction was stirred at room temperature for 4h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:4, 1:1) to give compound 5f as a white solid 510mg (95% yield).

To a 10mL round bottom flask, add the compound with magnetic stirring5f (100mg,0.34mmol), palladium acetate (7.6mg, 0.034mmol), and finally, 1.0mmol/mL of boron trifluoride etherate (1.70mL, 1.70mmol) prepared using chloroform as a solvent, and finally, chloroform (4mL) were added. Reaction in an oil bath at 60 ℃ for 2h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1) to give compound 6f as a pale yellow solid 76mg (yield 80%).

¹H NMR(400MHz,CDCl₃)8.01(s,1H),7.63–7.60(m,2H),6.83(d,J＝5.8Hz,1H),6.61–6.49(m,5H),2.47(s,3H).¹³C NMR(100MHz,CDCl₃)184.1,159.2,156.1,146.9,143.1,142.1,137.8,136.2,132.3,129.2,127.4,126.1,120.6,69.0,21.4.

Example 7: synthesis of Compound 6g

To a 150mL round bottom flask, 2g (2000mg, 11.00mmol) was added with magnetic stirring, followed by p-anisidine (1353mg, 11.00mmol) and finally water (60 mL). The reaction was carried out in an oil bath at 80 ℃ for 6h, and a white solid precipitated. Suction filtration and drying gave compound 3g of 2400mg (84% yield) as a white solid.

To a 150mL round-bottomed flask were added 3g (2400mg, 9.23mmol), p-toluenesulfonic acid (476mg, 2.77mol), tetrahydrofuran (50.0mL), anhydrous magnesium sulfate (3322mg, 27.69mmol), 3-trimethylsilylpropynaldehyde (1.36mL, 9.23mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours, DDQ (2514mg, 11.08mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10,1:4) to give 1290mg of compound 4g as a pale yellow solid (38% yield).

To a 100mL round bottom flask was added sequentially 4g of compound (1290mg, 3.52 mm) with magnetic stirringol), acetone (20mL) and 1% aqueous silver nitrate solution (6.3 mL). The reaction was stirred at room temperature for 5h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:4, 1:1) to give compound 5g as a white solid 820mg (yield 79%).

To a 10mL round-bottom flask, 5g (200mg,0.68mmol) of the compound, palladium acetate (15.3mg, 0.068mmol) and finally a 1.0mmol/mL boron trifluoride ether solution (3.40mL, 3.40mmol) prepared using chloroform as a solvent were added under electromagnetic stirring, and finally chloroform (3mL) was added. Reaction in an oil bath at 60 ℃ for 2h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give compound 6g as a pale yellow solid 140mg (yield 74%).

¹H NMR(400MHz,CDCl₃)8.27–8.23(m,1H),7.38(dd,J＝9.6,2.4Hz,1H),7.23–7.18(m,1H),6.85(d,J＝5.8Hz,1H),6.65–6.56(m,3H),6.56–6.49(m,2H).¹³C NMR(100MHz,CDCl₃)183.8,166.7(J＝253.6Hz),158.4,158.0,151.3(J＝13.0Hz),144.5,141.5,132.5,129.3(J＝10.7Hz),129.0,117.6(J＝2.1Hz),116.0(J＝23.4Hz),113.2(J＝22.0Hz),69.1.

Example 8: synthesis of Compound 6h

To a 150mL round bottom flask was added 2h (2000mg, 10.10mmol) with magnetic stirring, followed by p-anisidine (1245mg, 10.10mmol) and finally water (60 mL). The reaction was carried out in an oil bath at 80 ℃ for 6h, a brown solid precipitated. Filtration with suction and drying gave compound (3 h) as a brown solid (2420 mg, 87% yield).

Under an electromagnetic stirring bar, the mixture is sintered to a round bottom of 150mL3h (2400mg, 8.69mmol), p-toluenesulfonic acid (448mg, 2.61mol), tetrahydrofuran (50.0mL), anhydrous magnesium sulfate (3128mg, 26.07mmol), 3-trimethylsilylpropynaldehyde (1.28mL, 8.69mmol) were added to the flask in this order, the mixture was reacted at room temperature for 3h, DDQ (2367mg, 10.07mmol) was added to the mixture in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10,1:6) to give 1500mg of compound 4h as a pale yellow solid (44% yield).

To a 100mL round bottom flask was added compound 4h (1500mg, 3.92mmol), acetone (20mL) and 1% aqueous silver nitrate (7.0mL) in that order with magnetic stirring. The reaction was stirred at room temperature for 5h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:4, 1:1) to give compound 5h as 825mg (68% yield) as a pale yellow solid.

To a 10mL round bottom flask, compound 5h (150mg,0.48mmol), palladium acetate (11mg, 0.048mmol) and finally a 1.0mmol/mL boron trifluoride etherate solution (2.40mL, 2.40mmol) in chloroform as solvent were added with magnetic stirring and finally chloroform (4 mL). Reaction in an oil bath at 60 ℃ for 2h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give 127mg of compound 6h as a pale yellow solid (yield 89%).

¹H NMR(400MHz,CDCl₃)8.19(d,J＝2.3Hz,1H),7.74–7.67(m,2H),6.86(d,J＝5.8Hz,1H),6.64–6.58(m,3H),6.55–6.50(m,2H).¹³C NMR(100MHz,CDCl₃)183.8,158.0,157.0,147.5,144.0,141.4,135.2,133.2,132.6,129.2,129.0,126.1,122.0,69.2.

Example 9: synthesis of Compound 6i

To a 150mL round bottom flask, 2i (1170mg, 4.87mmol) was added, followed by p-anisidine (600mg, 4.87mmol) and finally water (40mL) with magnetic stirring. The reaction was carried out in an oil bath at 80 ℃ for 6h, a brown solid precipitated. Suction filtration and drying gave 1170mg (75% yield) of Compound 3i as a brown solid.

To a 150mL round-bottomed flask were added 3i (1170mg, 3.65mmol), p-toluenesulfonic acid (188mg, 1.05mol), tetrahydrofuran (20.0mL), anhydrous magnesium sulfate (1314mg, 10.95mmol), 3-trimethylsilylpropenal (0.53mL, 3.65mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours, DDQ (994mg, 4.38mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the reaction was terminated, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10) to give 1010mg of compound 4i as a pale yellow solid (yield 65%).

To a 100mL round-bottomed flask, compound 4i (1000mg, 2.34mmol), acetone (20mL) and 1% aqueous silver nitrate solution (7.0mL) were added sequentially with magnetic stirring. The reaction was stirred at ambient temperature for 6h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:4, 1:1) to give compound 5i as a pale yellow solid, 800mg (97% yield).

To a 10mL round-bottom flask, compound 5i (100mg,0.28mmol), palladium acetate (6mg, 0.028mmol) and finally a 1.0mmol/mL boron trifluoride etherate solution (1.40mL, 1.40mmol) prepared using chloroform as a solvent were added under electromagnetic stirring, and finally chloroform (5mL) was added. Reaction in an oil bath at 60 ℃ for 2h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE＝1:4，1:2，1:1, 2:1) to give 77mg (yield 80%) of compound 6i as a pale yellow solid.

¹H NMR(400MHz,CDCl₃)8.34(d,J＝2.3Hz,1H),7.86–7.84(m,1H),7.61–7.59(m,1H),6.84(d,J＝5.8Hz,1H),6.63–6.57(m,3H),6.54–6.49(m,2H).¹³C NMR(100MHz,CDCl₃)183.8,157.9,157.2,147.8,144.1,141.4,137.9,132.6,129.4,129.3,129.0,122.3,120.9,69.2.

Example 10: synthesis of Compound 6j

1j (2000mg, 11.96mmol) and tetrahydrofuran (35mL) were added to a 150mL round-bottomed flask under electromagnetic stirring and cooling in an ice-water bath, and after the reaction system had cooled, triphosgene (1204mg, 4.07mmol) was slowly added. In N₂Stirring for reaction for 6h under protection. After the reaction, the solvent was removed under reduced pressure, and a suitable amount of petroleum ether was added thereto and subjected to ultrasonic treatment to sufficiently suspend the precipitated solid in petroleum ether, followed by suction filtration and drying to obtain 2250mg (yield: 97%) of a brown solid of compound 2 j.

To a 250mL round bottom flask, 2j (2250mg, 11.65mmol), additional p-anisidine (1550mg, 11.65mmol), and finally water (80mL) were added with magnetic stirring. The reaction was carried out in an oil bath at 80 ℃ for 8h, a brown solid precipitated. Suction filtration and drying gave 2470mg (78% yield) of compound 3j as a brown solid.

To a 150mL round-bottomed flask were added 3j (1500mg, 5.50mmol), p-toluenesulfonic acid (283mg, 1.65mmol), tetrahydrofuran (40.0mL), anhydrous magnesium sulfate (1980mg, 16.50mmol), 3-trimethylsilylpropynaldehyde (0.81mL, 5.50mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours, DDQ (1498mg, 6.60mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10) to yield 1930mg of compound 4j as a pale yellow solid (93% yield).

To a 50mL round bottom flask was added compound 4j (650mg,1.72mmol), acetone (15mL) and 1% aqueous silver nitrate (3 mL). The reaction was stirred at room temperature for 4h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:4, 1:1) to give 400mg of compound 5j as a white solid (yield 76%).

To a 10mL round-bottom flask, compound 5j (150mg,0.49mmol), palladium acetate (11mg, 0.049mmol) and finally a 1.0mmol/mL boron trifluoride etherate solution (2.45mL, 2.45mmol) prepared using chloroform as a solvent were added under electromagnetic stirring, and finally chloroform (4mL) was added. Reaction in an oil bath at 60 ℃ for 2h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1) to give 102mg (yield 72%) of compound 6j as a pale yellow solid.

¹H NMR(400MHz,CDCl₃)8.13(d,J＝8.8Hz,1H),7.12–7.11(m,1H),7.05(dd,J＝8.8,2.4Hz,1H),6.82(d,J＝5.8Hz,1H),6.63–6.46(m,5H),3.92(s,3H).¹³C NMR(100MHz,CDCl₃)184.0,164.9,158.8,157.5,151.3,143.9,142.1,132.3,129.1,128.1,117.0,114.3,108.8,69.0,55.8.

Example 11: synthesis of Compound 6k

1j (2000mg, 13.23mmol) and tetrahydrofuran (45mL) were added to a 150mL round-bottomed flask under electromagnetic stirring and cooling in an ice-water bath, and after the reaction system had cooled, triphosgene (1335mg, 4.49mmol) was slowly added. In N₂Stirring for reaction for 5h under protection. After the reaction, the solvent was removed under reduced pressure, and a suitable amount of petroleum ether was added thereto and subjected to ultrasonic treatment to thereby suspend the precipitated solid in petroleum ether sufficiently, followed by suction filtration and drying to obtain 2170mg (yield) of a gray solid of Compound 2k93％)。

To a 250mL round bottom flask, 2k (2170mg, 12.25mmol) was added with magnetic stirring, followed by p-anisidine (1507mg, 12.25mmol) and finally water (80 mL). The reaction was carried out in an oil bath at 80 ℃ for 8h, a grey solid precipitated. Filtration with suction and drying gave 2350mg (75% yield) of compound 3k as a grey solid.

To a 150mL round bottom flask were added 3k (2350mg, 9.18mmol), p-toluenesulfonic acid (473mg, 2.75mmol), tetrahydrofuran (40.0mL), anhydrous magnesium sulfate (3304mg, 27.54mmol), 3-trimethylsilylpropynaldehyde (1.30mL, 9.18mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3h, DDQ (2500mg, 11.02mol) was added in an ice-water bath, the reaction was carried out for 30 min, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10) to give 3000mg of compound 4k as a pale yellow solid (yield 90%).

To a 50mL round bottom flask was added sequentially compound 4k (960mg, 2.65mmol), acetone (15mL) and 1% aqueous silver nitrate (5mL) with magnetic stirring. The reaction was stirred at room temperature for 4h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:4, 1:1) to give 526mg of compound 5k as a white solid (yield 68%).

To a 10mL round bottom flask, compound 5k (150mg,0.51mmol), palladium acetate (11.5mg, 0.051mmol) was added under magnetic stirring, and finally, a 1.0mmol/mL boron trifluoride etherate solution (2.60mL, 2.60mmol) prepared using chloroform as a solvent was added, and finally, chloroform (4mL) was added. Reaction in an oil bath at 60 ℃ for 2h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give 122mg (yield 86%) of compound 6k as a pale yellow solid.

¹H NMR(400MHz,CDCl₃)8.11(d,J＝8.1Hz,1H),7.51(s,1H),7.30(dd,J＝8.1,1.0Hz,1H),6.83(d,J＝5.8Hz,1H),6.60–6.50(m,5H),2.51(s,3H).¹³C NMR(100MHz,CDCl₃)184.0,159.1,156.9,149.1,145.9,143.5,142.1,132.3,129.2,128.9,127.5,126.4,118.4,69.0,22.0.

Example 12: synthesis of Compound 6l

1l (2000mg, 12.89mmol) of tetrahydrofuran (45mL) was added to a 150mL round-bottomed flask under magnetic stirring and cooling in an ice-water bath, and after the reaction system had cooled, triphosgene (1300mg, 4.38mmol) was slowly added. In N₂Stirring for reaction for 5h under protection. After the reaction, the solvent was removed under reduced pressure, and a suitable amount of petroleum ether was added thereto and subjected to ultrasonic treatment to thereby suspend the precipitated solid in petroleum ether sufficiently, followed by suction filtration and drying to obtain 2260mg (yield 97%) of 2l of a white solid as a compound.

To a 250mL round bottom flask, 2l (2260mg, 12.48mmol) was added with magnetic stirring, followed by p-anisidine (1536mg, 12.48mmol) and finally water (80 mL). The reaction was carried out in an oil bath at 80 ℃ for 7h, a brown solid precipitated. Suction filtration and drying gave 2560mg (yield 79%) of compound 3l as a brown solid.

To a 150mL round bottom flask were added 3l (1500mg, 5.76mmol), p-toluenesulfonic acid (297mg, 1.73mmol), tetrahydrofuran (30.0mL), anhydrous magnesium sulfate (2070mg, 17.28mmol), 3-trimethylsilylpropynaldehyde (0.85mL, 5.76mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours, DDQ (1569mg, 6.91mol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the reaction was terminated, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:10,1:6) to give 2040mg of compound 4l as a pale yellow solid (yield 97%).

To a 100mL round-bottomed flask, 4l of compound (2000mg, 5.46mmol), acetone (30mL) and 1% aqueous silver nitrate solution (9.8mL) were added sequentially with magnetic stirring. Stirring and reacting for 6h at normal temperature under the condition of keeping out of The Light (TLC)Monitoring the reaction V_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:6, 1:4, 1:2) to give 560mg of compound 5l as a white solid (yield 35%).

To a 10mL round-bottomed flask, 5l of the compound (80mg,0.27mmol), palladium acetate (6.1mg, 0.027mmol) and finally a boron trifluoride ether solution (1.36mL, 1.36mmol) formulated in chloroform as a solvent were added, and finally chloroform (5mL) was added, with electromagnetic stirring. Reaction in an oil bath at 60 ℃ for 3h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give 65mg (yield 87%) of compound 6l as a pale yellow solid.

¹H NMR(400MHz,CDCl₃)7.86(dd,J＝8.3,2.9Hz,1H),7.75–7.72(m,1H),7.53–7.46(m,1H),6.84(d,J＝5.8Hz,1H),6.62–6.55(m,3H),6.54–6.51(m,2H).¹³C NMR(100MHz,CDCl₃)183.8,161.2(J＝248.3Hz),158.4(J＝3.4Hz),156.3(J＝2.2Hz),145.6(J＝2.1Hz),143.5,141.6,132.5,130.1(J＝8.1Hz),129.0,123.2(J＝23.9Hz),122.2(J＝8.6Hz),111.8(J＝23.8Hz),69.0.

Example 13: synthesis of Compound 6m

To a 250mL round bottom flask, 2m (2000mg, 8.30mmol) was added with magnetic stirring, followed by p-anisidine (1021mg, 8.30mmol), and finally water (80 mL). The reaction was carried out in an oil bath at 80 ℃ for 6h, and a white solid precipitated. Suction filtration and drying were carried out to obtain 1270mg (48% yield) of compound 3m as a white solid.

To a 150mL round-bottomed flask were added 3m (1270mg, 3.96mmol), p-toluenesulfonic acid (204mg, 1.19mol) in this order with electromagnetic stirring,tetrahydrofuran (30.0mL), anhydrous magnesium sulfate (1425mg, 11.88mmol), 3-trimethylsilylpropylaldehyde (0.57mL, 3.96mmol), the mixture was reacted at room temperature for 3h, DDQ (1078mg, 4.75mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10,1:4) to yield 851mg of compound 4m as a pale yellow solid (51% yield).

To a 100mL round-bottomed flask, compound 4m (850mg, 1.99mmol), acetone (15mL) and 1% aqueous silver nitrate solution (4mL) were added in that order with magnetic stirring. The reaction was stirred at room temperature for 5h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:4, 1:2) to give 435mg of compound 5m as a white solid (yield 62%).

To a 10mL round bottom flask, compound 5m (100mg,0.28mmol), palladium acetate (6.3mg, 0.028mmol) and finally boron trifluoride etherate (1.40mL, 1.40mmol) in 1.0mmol/mL prepared using chloroform as a solvent were added under electromagnetic stirring, and finally chloroform (5mL) was added. Reaction in an oil bath at 60 ℃ for 2h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give 79mg (yield 82%) of compound 6m as a pale yellow solid.

¹H NMR(400MHz,CDCl₃)8.09(d,J＝8.5Hz,1H),7.91(d,J＝1.8Hz,1H),7.61(dd,J＝8.5,1.9Hz,1H),6.86(d,J＝5.8Hz,1H),6.65–6.58(m,3H),6.55–6.50(m,2H).¹³C NMR(100MHz,CDCl₃)183.8,158.6,157.9,150.0,144.4,141.4,132.6,130.7,130.4,129.5,129.0,128.0,119.7,69.2.

Example 14: synthesis of Compound 6n

1n (2000mg, 9.70mmol) and tetrahydrofuran (45mL) were added to a 150mL round-bottomed flask under magnetic stirring and cooling in an ice-water bath, and after the reaction system had cooled, triphosgene (984mg, 3.32mmol) was slowly added. In N₂Stirring for reaction for 5h under protection. After the reaction was completed, the solvent was removed under reduced pressure, and an appropriate amount of petroleum ether was added thereto and subjected to ultrasonic treatment to thereby suspend the precipitated solid in petroleum ether sufficiently, followed by suction filtration and drying to obtain 2200mg (yield 98%) of a white solid of Compound 2 n.

To a 250mL round bottom flask, 2n (2200mg, 9.52mmol) was added with magnetic stirring, followed by p-anisidine (1171mg, 9.52mol) and finally water (80 mL). The reaction was carried out in an oil bath at 80 ℃ for 8h, a brown solid precipitated. Suction filtration and drying gave 2530mg (86% yield) of compound 3n as a brown solid.

To a 150mL round-bottomed flask were added 3n (1500mg, 4.80mmol), p-toluenesulfonic acid (247mg, 1.44mmol), tetrahydrofuran (30.0mL), anhydrous magnesium sulfate (1728mg, 14.4mmol), 3-trimethylsilylpropynaldehyde (0.71mL, 4.80mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours, DDQ (1307mg, 5.76mol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:10,1:4) to give 1714mg of compound 4n as a pale yellow solid (86% yield).

To a 100mL round-bottomed flask, compound 4n (1714mg, 4.12mmol), acetone (30mL) and 1% aqueous silver nitrate (7.4mL) were added sequentially with magnetic stirring. The reaction was stirred at ambient temperature for 6h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:6, 1:4, 1:1) to give 1130mg of compound 5n as a white solid (yield 80%).

To a 10mL round bottom flask, compound 5n (150mg,0.44mmol), palladium acetate (9.8mg, 0.044mmol) were added under magnetic stirring, and finally chloroform was added as a solvent1.0mmol/mL boron trifluoride in diethyl ether (2.18mL, 2.18mmol) was prepared and chloroform (5mL) was added last. Reaction in an oil bath at 60 ℃ for 2h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give 125mg (yield 87%) of compound 6n as a pale yellow solid.

¹H NMR(400MHz,CDCl₃)8.37(d,J＝8.3Hz,1H),8.02(s,1H),7.71(d,J＝8.2Hz,1H),6.89(d,J＝5.8Hz,1H),6.68(d,J＝5.8Hz,1H),6.64–6.61(m,2H),6.55–6.52(m,2H).¹³C NMR(100MHz,CDCl₃)183.7,158.2,158.0,149.1,144.7,141.1,136.3(J＝65.6Hz),132.7,128.9,127.8,125.2(J＝8.0Hz),123.4(J＝6.9Hz),123.3(J＝271.4Hz),123.2,69.2.

Example 15: synthesis of Compound 6o

Under the conditions of electromagnetic stirring and cooling in an ice-water bath, 1o (2000mg, 10.98mmol) and tetrahydrofuran (45mL) were added to a 150mL round-bottomed flask, and after the reaction system had cooled, triphosgene (1104mg, 3.73mmol) was slowly added. In N₂Stirring for reaction for 5h under protection. After the reaction, the solvent was removed under reduced pressure, and a suitable amount of petroleum ether was added thereto and subjected to ultrasonic treatment to thereby suspend the precipitated solid in petroleum ether sufficiently, followed by suction filtration and drying to obtain 2000mg (yield: 88%) of compound 2o as a yellow solid.

To a 250mL round bottom flask, 2o (2000mg, 9.60mmol) was added with magnetic stirring, followed by p-anisidine (1180mg, 9.60mol) and finally water (80 mL). The reaction was carried out in an oil bath at 80 ℃ for 8h, and a yellow solid precipitated. Suction filtration and drying gave 2200mg (80% yield) of compound 3o as a yellow solid.

To a 150mL round bottom flask were added 3o (2200mg, 7.66mmol), p-toluenesulfonic acid (395mg, 1.40mmol), tetrahydrofuran (30.0mL) sequentially with electromagnetic stirring,anhydrous magnesium sulfate (2758mg, 22.98mmol), 3-trimethylsilylpropenal (1.13mL, 7.66mmol), the mixture was reacted at room temperature for 3 hours, DDQ (2086mg, 9.19mol) was added under an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:10,1:6) to yield 1650mg of compound 4o as a yellow solid (56% yield).

To a 100mL round bottom flask was added sequentially compound 4o (1650mg, 4.20mmol), acetone (30mL) and 1% aqueous silver nitrate (7.5mL) with magnetic stirring. The reaction was stirred at ambient temperature for 6h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:6, 1:4, 1:2) to give 1300mg (96% yield) of compound 5o as a yellow solid.

To a 10mL round bottom flask, compound 5o (150mg,0.47mmol), palladium acetate (10.6mg, 0.047mmol) and finally a 1.0mmol/mL boron trifluoride etherate solution (2.35mL, 2.35mmol) prepared using chloroform as a solvent were added under magnetic stirring, and finally chloroform (4mL) was added. Reaction in an oil bath at 60 ℃ for 3h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give compound 6o as a brown solid 105mg (73% yield).

¹H NMR(400MHz,CDCl₃)8.55(d,J＝2.1Hz,1H),8.41(d,J＝8.7Hz,1H),8.25(dd,J＝8.7,2.2Hz,1H),6.91(d,J＝5.8Hz,1H),6.73(d,J＝5.8Hz,1H),6.65–6.62(m,2H),6.55–6.52(m,2H).¹³C NMR(100MHz,CDCl₃)183.6,158.8,157.8,151.8,149.7,145.3,140.6,132.9,128.8,128.5,125.0,123.2,121.0,69.4.

Example 16: synthesis of Compound 6p

To a 250mL round bottom flask, 2p (2500mg, 14.10mmol) was added with magnetic stirring, followed by p-anisidine (1735mg, 14.10mmol) and finally water (80 mL). The reaction was carried out in an oil bath at 80 ℃ for 6h, a grey solid precipitated. Filtration with suction and drying gave 2870mg (80% yield) of compound 3p as a gray solid.

To a 150mL round-bottomed flask were added 3p (2500mg, 9.70mmol), p-toluenesulfonic acid (500mg, 2.91mol), tetrahydrofuran (30.0mL), anhydrous magnesium sulfate (3492mg, 29.10mmol), 3-trimethylsilylpropynaldehyde (1.4mL, 9.70mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours, DDQ (2642mg, 11.64mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10,1:4) to give 2580mg of compound 4p as a pale yellow solid (73% yield).

To a 100mL round-bottomed flask, compound 4p (2580mg, 7.12mmol), acetone (25mL) and 1% aqueous silver nitrate solution (12.7mL) were added sequentially with magnetic stirring. The reaction was stirred at room temperature for 8h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:4, 1:2) to give compound 5p as a white solid 870mg (42% yield).

To a 10mL round-bottom flask, compound 5p (150mg,0.51mmol), palladium acetate (11.5mg, 0.051mmol) were added under magnetic stirring, and finally, a 1.0mmol/mL boron trifluoride etherate solution (2.60mL, 2.60mmol) prepared using chloroform as a solvent was added, and finally, chloroform (4mL) was added. Reaction in an oil bath at 60 ℃ for 4h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give 111mg of compound 6p as a pale yellow solid (yield)78％)。

¹H NMR(400MHz,CDCl₃)8.10(dd,J＝7.9,0.9Hz,1H),7.64–7.62(m,1H),7.38(t,J＝7.6Hz,1H),6.90(d,J＝5.8Hz,1H),6.61–6.49(m,5H).¹³C NMR(100MHz,CDCl₃)184.0,159.6,155.7,147.6,143.1,142.2,136.3,135.5,132.3,129.5,126.9,124.3,120.8,68.9,17.7.

Example 17: synthesis of Compound 6q

1q (2000mg, 11.65mmol) of tetrahydrofuran (45mL) was added to a 150mL round-bottomed flask under electromagnetic stirring and cooling in an ice-water bath, and after the reaction system had cooled, triphosgene (1172mg, 3.96mmol) was slowly added. In N₂Stirring for reaction for 5h under protection. After the reaction, the solvent was removed under reduced pressure, and a suitable amount of petroleum ether was added thereto and subjected to ultrasonic treatment to sufficiently suspend the precipitated solid in petroleum ether, followed by suction filtration and drying to obtain 1570mg (yield 68%) of a yellow solid of compound 2 q.

To a 250mL round bottom flask, 2q (1570mg, 7.94mmol) was added with magnetic stirring, followed by p-anisidine (977mg, 7.94mol) and finally water (60 mL). The reaction was carried out in an oil bath at 80 ℃ for 6h, a brown solid precipitated. Filtration with suction and drying gave 1780mg (81% yield) of compound 3q as a brown solid.

To a 150mL round-bottomed flask were added 3q (1780mg, 6.47mmol), p-toluenesulfonic acid (330mg, 1.94mmol), tetrahydrofuran (30.0mL), anhydrous magnesium sulfate (2300mg, 19.41mmol), 3-trimethylsilylpropynaldehyde (0.96mL, 6.47mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours, DDQ (1760mg, 7.76mol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:10,1:4) to give 1500mg of compound 4q as a yellow solid (61% yield).

To a 100mL round-bottomed flask was added sequentially compound 4q (1500mg, 3.90mmol), acetone (30mL) and 1% aqueous silver nitrate solution (7mL) with magnetic stirring. In the process of avoidingThe reaction was stirred at ambient temperature for 6h under light conditions (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:6, 1:4, 1:2) to give compound 5q as a white solid 1200mg (99% yield).

To a 10mL round-bottomed flask, compound 5q (100mg,0.32mmol), palladium acetate (7.2mg, 0.032mmol) and finally a boron trifluoride ether solution (1.60mL, 1.60mmol) prepared in chloroform as a solvent were added under electromagnetic stirring, and finally chloroform (5mL) was added. Reaction in an oil bath at 60 ℃ for 5h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give 83mg (yield 87%) of compound 6q as a white solid.

¹H NMR(400MHz,CDCl₃)8.16(dd,J＝8.0,1.4Hz,1H),7.86(dd,J＝7.8,1.4Hz,1H),7.41(t,J＝7.9Hz,1H),6.98(d,J＝5.8Hz,1H),6.65–6.58(m,3H),6.53–6.50(m,2H).¹³C NMR(100MHz,CDCl₃)183.8,158.5,157.5,145.7,144.4,141.3,135.2,132.6,132.1,129.32,127.4,125.5,122.5,69.2.

Example 18: synthesis of Compound 6r

To a 250mL round bottom flask, 2r (1500mg, 9.19mmol) was added under magnetic stirring, followed by 3, 4-dimethoxyaniline (1407mg, 9.19mmol) and finally water (60 mL). The reaction was carried out in an oil bath at 80 ℃ for 5h, a brown solid precipitated. Suction filtration and drying gave 2000mg (yield 80%) of compound 3r as a brown solid.

To a 150mL round-bottomed flask were added 3r (1500mg, 5.50mmol), p-toluenesulfonic acid (284mg, 1.65mol), tetrahydrofuran (30.0mL), anhydrous sulfuric acid in that order with electromagnetic stirringMagnesium (1980mg, 16.50mmol), 3-trimethylsilylpropenal (0.80mL, 5.50mmol), the mixture was reacted at room temperature for 3h, DDQ (1498mg, 6.60mmol) was added under ice-water bath, the reaction was terminated for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10,1:4) to give 910mg of compound 4r as a pale yellow solid (yield 44%).

To a 100mL round-bottomed flask, compound 4r (910mg, 2.40mmol), acetone (20mL) and 1% aqueous silver nitrate solution (4.3mL) were added sequentially with magnetic stirring. The reaction was stirred at room temperature for 5h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:6, 1:2) to give compound 5r as a white solid, 500mg (yield 68%).

To a 10mL round bottom flask, compound 5r (150mg,0.49mmol), palladium acetate (11.0mg, 0.049mmol) and finally a 1.0mmol/mL boron trifluoride etherate solution (2.45mL, 2.45mmol) prepared using chloroform as a solvent were added under electromagnetic stirring, and finally chloroform (4mL) was added. Reaction in an oil bath at 30 ℃ for 12h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give compound 6r as a white solid (99 mg, yield 70%).

¹H NMR(400MHz,CDCl₃)8.24(dd,J＝8.0,1.1Hz,1H),7.81–7.73(m,2H),7.55–7.45(m,1H),6.82–6.81(m,1H),6.64–6.55(m,3H),5.40(d,J＝2.6Hz,1H),3.70(s,3H).¹³CNMR(100MHz,CDCl₃)179.5,159.0,156.8,153.6,148.9,145.1,142.2,134.7,131.8,128.0,127.6,127.3,126.6,121.1,108.4,70.4,55.4.

Example 19: synthesis of Compound 6s

To a 250mL round bottom flask, 2s (1500mg, 9.19mmol) was added with magnetic stirring, followed by 3-methyl-4-methoxyaniline (1260mg, 9.19mmol) and finally water (60 mL). The reaction was carried out in an oil bath at 80 ℃ for 9h to precipitate a brown solid. Suction filtration and drying gave 2000mg (85% yield) of compound 3s as a brown solid.

To a 150mL round-bottomed flask were added 3s (1100mg, 4.30mmol), p-toluenesulfonic acid (221mg, 1.29mol), tetrahydrofuran (20.0mL), anhydrous magnesium sulfate (1548mg, 12.90mmol), 3-trimethylsilylpropynaldehyde (0.64mL, 4.30mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours, DDQ (1171mg, 5.16mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10,1:4) to give 985mg of compound 4s as a pale yellow solid (63% yield).

To a 100mL round-bottomed flask, compound 4s (985mg, 2.70mmol), acetone (15mL) and 1% aqueous silver nitrate (4.8mL) were added sequentially with magnetic stirring. The reaction was stirred at room temperature for 5h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:6, 1:2) to give 767mg of compound 5s as a white solid (yield 99%).

To a 10mL round bottom flask, compound 5s (100mg,0.35mmol), palladium acetate (7.80mg, 0.035mmol) and finally boron trifluoride etherate (1.70mL, 1.70mmol) in 1.0mmol/mL prepared using chloroform as a solvent were added under electromagnetic stirring, and finally chloroform (5mL) was added. Reaction in an oil bath at 60 ℃ for 3h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give compound 6s as a white solid 84mg (yield)88％)。

¹H NMR(400MHz,CDCl₃)8.24(dd,J＝8.0,1.0Hz,1H),7.79–7.71(m,2H),7.52–7.45(m,1H),6.81(d,J＝5.8Hz,1H),6.61–6.48(m,3H),6.29–6.28(m,1H),2.00(d,J＝1.4Hz,3H).¹³C NMR(100MHz,CDCl₃)184.8,159.2,157.0,149.0,144.5,141.5,139.6,136.6,134.7,132.1,128.6,127.6,127.3,126.6,121.0,69.6,16.2.

Example 20: synthesis of Compound 6t

To a 250mL round bottom flask, 2t (1500mg, 9.19mmol) was added with magnetic stirring, followed by 3-fluoro-4-methoxyaniline (1297mg, 9.19mmol) and finally water (60 mL). The reaction was carried out in an oil bath at 80 ℃ for 6h, a brown solid precipitated. Suction filtration and drying gave 1450mg (61% yield) of compound 3t as a brown solid.

To a 150mL round bottom flask were added 3t (1450mg, 5.57mmol), p-toluenesulfonic acid (287mg, 1.67mmol), tetrahydrofuran (20.0mL), anhydrous magnesium sulfate (2005mg, 16.71mmol), 3-trimethylsilylpropynaldehyde (0.82mL, 5.57mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3h, DDQ (1517mg, 6.68mmol) was added under ice-water bath, the reaction was carried out for 30 min, the reaction was terminated, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10,1:4) to give 1780mg of compound 4t as a pale yellow solid (87% yield).

To a 100mL round-bottomed flask, compound 4t (1780mg, 4.86mmol), acetone (25mL) and 1% aqueous silver nitrate (8.7mL) were added sequentially with magnetic stirring. The reaction was stirred at room temperature for 5h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:6, 1:2) to give compound 5t as a white solid 620mg (43% yield).

To a 10mL round bottom flask, add under electromagnetic stirringCompound 5s (100mg,0.34mmol), palladium acetate (7.60mg, 0.034mmol), and finally, boron trifluoride etherate (1.70mL, 1.70mmol) prepared in 1.0mmol/mL using chloroform as a solvent, and finally, chloroform (5mL) were added. Reaction in an oil bath at 60 ℃ for 3h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give 39mg (yield 41%) of compound 6t as a pale yellow solid.

¹H NMR(400MHz,CDCl₃)8.27(dd,J＝7.9,1.2Hz,1H),7.81(ddd,J＝20.2,13.5,4.4Hz,2H),7.57–7.51(m,1H),6.91(d,J＝5.8Hz,1H),6.69–6.60(m,2H),6.57(dd,J＝9.9,2.7Hz,1H),6.16(dd,J＝10.8,2.7Hz,1H).¹³C NMR(100MHz,CDCl₃)177.1(J＝22.0Hz),159.1,156.3,155.6(J＝270.0Hz),148.8,142.9(J＝2.5Hz),142.6(J＝2.4Hz),134.9,131.8(J＝4.5Hz),129.4,127.8,127.6,126.7,120.9,118.5(J＝16.8Hz),69.9(J＝8.7Hz).

Example 21: synthesis of Compound 6u

To a 250mL round bottom flask, 2u (1500mg, 9.19mmol) was added under magnetic stirring, followed by 2-methyl-4-methoxyaniline (1260mg, 9.19mmol) and finally water (60 mL). The reaction was carried out in an oil bath at 80 ℃ for 6h, a brown solid precipitated. Suction filtration and drying gave compound 3u as a brown solid 1610mg (yield 68%).

To a 150mL round-bottomed flask were added 3u (1000mg, 3.90mmol), p-toluenesulfonic acid (201mg, 1.17mmol), tetrahydrofuran (20.0mL), anhydrous magnesium sulfate (1404mg, 11.70mmol), 3-trimethylsilylpropynaldehyde (0.58mL, 3.90mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3h, DDQ (1062mg, 4.68mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the reaction was terminated, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10) to give 847mg of compound 4u as a pale yellow solid (yield 60%).

To a 100mL round-bottomed flask, compound 4u (847mg, 2.33mmol), acetone (15mL) and 1% aqueous silver nitrate solution (4.2mL) were added in that order with magnetic stirring. The reaction was stirred at room temperature for 5h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:6, 1:2) to give 450mg of compound 5u as a yellow solid (yield 67%).

To a 10mL round-bottomed flask, compound 5u (80mg,0.27mmol), palladium acetate (6.1mg, 0.027mmol) were added under electromagnetic stirring, and finally, a 1.0mmol/mL boron trifluoride etherate solution (1.35mL, 1.35mmol) formulated with chloroform as a solvent, and finally, chloroform (5mL) were added. Reaction in an oil bath at 60 ℃ for 4h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give 68mg (yield 89%) of compound 6u as a pale yellow solid.

¹H NMR(400MHz,CDCl₃)8.26(dd,J＝7.9,1.0Hz,1H),7.86–7.72(m,2H),7.56–7.47(m,1H),6.91(d,J＝5.8Hz,1H),6.58–6.44(m,4H),1.68(d,J＝1.2Hz,3H).¹³C NMR(100MHz,CDCl₃)183.7,157.8,156.3,150.2,148.1,143.9,140.8,133.9,131.1,129.4,128.4,126.7,126.4,125.7,119.6,70.7,16.4.

Example 22: synthesis of Compound 6v

To a 250mL round bottom flask, 2v (2000mg, 12.26mmol) was added with magnetic stirring, followed by 2-bromo-4-methoxyaniline (2477mg, 12.26mmol) and finally water (60 mL). The reaction was carried out in an oil bath at 80 ℃ for 6h, a grey solid precipitated. Filtration with suction and drying gave compound 3v as a gray solid, 3500mg (89% yield).

To a 150mL round-bottom flask were added 3V (3500mg, 10.93mmol), p-toluenesulfonic acid (564mg, 3.28mmol), tetrahydrofuran (40.0mL), anhydrous magnesium sulfate (3935mg, 32.79mmol), 3-trimethylsilylpropynaldehyde (1.60mL, 10.93mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 4h, DDQ (2977mg, 13.12mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10,1:6) to yield 690mg of compound 4v as a pale yellow solid (15% yield).

To a 100mL round bottom flask was added sequentially compound 4v (690mg, 1.6mmol), acetone (10mL) and 1% aqueous silver nitrate (2.8mL) with magnetic stirring. The reaction was stirred at room temperature for 4h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:6, 1:2) to give compound 5v as a white solid 450mg (yield 80%).

To a 10mL round bottom flask, compound 5v (60mg,0.17mmol), palladium acetate (3.8mg, 0.017mmol) and finally boron trifluoride etherate (0.95mL, 0.95mmol) prepared in 1.0mmol/mL using chloroform as a solvent were added under electromagnetic stirring, and finally chloroform (6mL) was added. Reaction in an oil bath at 30 ℃ for 15h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give compound 6v as a pale yellow solid 35mg (yield 61%).

¹H NMR(400MHz,CDCl₃+MeOH)8.24–8.22(m,1H),7.80–7.76(m,1H),7.74–7.72(m,1H),7.53–7.48(m,1H),7.02(d,J＝1.2Hz,1H),6.96(d,J＝5.8Hz,1H),6.66–6.57(m,2H),6.54(d,J＝5.8Hz,1H).¹³C NMR(100MHz,CDCl₃+MeOH)182.5,158.7,156.8,148.7,143.1,141.3,140.9,135.9,135.1,131.5,130.6,127.7,127.7,126.8,120.6,72.0.

Example 23: synthesis of Compound 6w

Under electromagnetic stirring and ice-water bath conditions, 1w (700mg, 10.00mmol) was added to a 150mL round bottom flask, followed by dichloromethane (30M) and finally chlorochromate pyridinium salt (PCC) (3888mg, 18.00mmol) and stirring at 0 ℃ for 2 h. After the reaction was completed, a large amount of the solvent was removed under reduced pressure at a low temperature to obtain a mixture containing a small amount of the solvent and the compound 4 w.

To a 250mL round bottom flask, 2w (3000mg, 18.4mmol) was added with magnetic stirring, followed by 4-methoxyaniline (2266mg, 18.4mmol) and finally water (80 mL). The reaction was carried out in an oil bath at 80 ℃ for 6h, a brown solid precipitated. Filtration with suction and drying gave compound 3w as a brown solid 3960mg (89% yield).

To a 150mL round-bottomed flask were added 3w (730mg, 3.00mmol), p-toluenesulfonic acid (155mg, 0.9mmol), tetrahydrofuran (10.0mL), anhydrous magnesium sulfate (1080mg, 9.0mmol), and the above-obtained crude product 4w in this order under electromagnetic stirring, the mixture was reacted at room temperature for 4h, DDQ (817mg, 3.60mmol) was added in an ice-water bath, the reaction was terminated, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10,1:6) to yield 570mg of compound 5w as a pale yellow solid (66% yield).

To a 10mL round bottom flask, compound 5w (70mg,0.24mmol), palladium acetate (5.4mg, 0.024mmol) was added under magnetic stirring, and finally a 1.0mmol/mL solution of boron trifluoride in ethyl ether (1.20mL, 1.20mmol) in chloroform as solvent was added, and finally chloroform (5mL) was added. Reaction in an oil bath at 60 ℃ for 6h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1) to give compound 6w as a pale yellow solid, 30mg (yield 45%).

¹H NMR(400MHz,CDCl₃)8.25(dd,J＝7.9,1.1Hz,1H),7.81–7.76(m,1H),7.73–7.71(m,1H),7.51–7.45(m,1H),6.67–6.61(m,3H),6.49–6.47(m,2H),1.95(d,J＝1.3Hz,3H).¹³C NMR(125MHz,CDCl₃)184.2,159.1,156.9,154.4,148.9,142.8,134.7,132.9,127.4,126.9,126.6,125.0,120.5,71.0,12.2.

Example 24: synthesis of Compound 6x

To a 250mL round bottom flask, 2X (1500mg, 9.19mmol) was added with magnetic stirring, followed by 2, 4-dimethoxyaniline (1407mg, 9.19mmol) and finally water (60 mL). The reaction was carried out in an oil bath at 80 ℃ for 5h to precipitate a purple solid. Filtration with suction and drying afforded 2100mg (84% yield) of compound 3x as a purple solid.

To a 150mL round-bottomed flask were added 3X (1500mg, 5.50mmol), p-toluenesulfonic acid (284mg, 1.65mol), tetrahydrofuran (30.0mL), anhydrous magnesium sulfate (1980mg, 16.50mmol), 3-trimethylsilylpropynaldehyde (0.85mL, 5.50mmol) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours, DDQ (1498mg, 6.60mmol) was added in an ice-water bath, the reaction was carried out for 30 minutes, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (eluent: V)_EA:V_PE1:20, 1:10,1:4) to yield 1000mg of compound 4x as a pale yellow solid (48% yield).

To a 100mL round bottom flask was added sequentially compound 4X (1000mg, 2.64mmol), acetone (20mL) and 1% aqueous silver nitrate (4.7mL) with magnetic stirring. The reaction was stirred at room temperature for 5h in the absence of light (reaction monitored by TLC: V)_EA:V_PE1: 2); after the reaction was complete, extraction was carried out with ethyl acetate (4X 20mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel (eluent: V)_EA:V_PE1:6, 1:2) to give compound 5x as a white solid 700mg (87% yield).

To a 10mL round bottom flask, compound 5X (100mg,0.33mmol), palladium acetate (7.30mg, 0.033mmol) were added under magnetic stirring, and finally, a 1.0mmol/mL boron trifluoride etherate solution (1.63mL, 1.63mmol) prepared using chloroform as a solvent was added, and finally, chloroform (5mL) was added. Reaction in an oil bath at 60 ℃ for 1h (reaction monitored by TLC: V)_EA:V_PE1:1), after the reaction was completed, saturated sodium bicarbonate solution was added to quench, extraction was performed with dichloromethane (4 × 10mL), the organic phases were combined, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)_EA:V_PE1:4, 1:2, 1:1, 2:1) to give compound 6x as a white solid 85mg (89% yield).

¹H NMR(400MHz,CDCl₃)8.25(d,J＝7.6Hz,1H),7.82–7.75(m,2H),7.55–7.47(m,1H),6.86(d,J＝5.8Hz,1H),6.62(d,J＝5.8Hz,1H),6.53–6.50(m,1H),6.29(d,J＝9.8Hz,1H),5.88(s,1H),3.68(s,3H).¹³C NMR(100MHz,CDCl₃)186.1,167.2,158.8,157.5,149.1,143.9,137.5,134.7,131.8,129.5,127.7,127.3,126.7,120.8,104.6,70.0,56.5.

The antitumor activity of the compound prepared in the above example was preliminarily screened, and the cytotoxicity of some compounds against different tumor cells was determined by the MTT method as the antitumor activity evaluation method.

The test tests 13 compounds for their inhibitory effect on cells and the test results are shown in table 1.

The test procedure was as follows:

1) cell culture, in which LO2, NCI-H460, HepG-2, MCF-7, MCG-803 and T24 cells are revived by DMEM medium and put in CO₂Culturing in an incubator, and changing the culture solution every other day. Cells in logarithmic growth phase were taken for experiments.

2) Starting from CO₂Taking out cells from the incubator, removing the old culture medium, washing twice with PBS, digesting with trypsin, quickly adding a new culture medium when the cells are slightly rounded to stop cell digestion and lightly blowing and beating the suspended cells, taking a proper amount of cell culture solution, adding a certain amount of culture medium for dilution, inoculating the diluted solution into a 96-well plate, wherein each well is 180 mu L, and 200 mu L of PBS is added into each well around the 96-well plate.

3) And (3) adding medicine, namely adding samples to be detected when the cells in the 96-well plate grow to 70-80%, wherein the concentration of each sample is set to be 200 mu M/mL, and 5 auxiliary holes are set, and the concentration of each hole is 20 mu L, so that the final concentration of the sample is 20 mu M/mL. Adding compound, and adding CO₂Culturing in incubator for 48 hr, adding 10 μ L of prepared MTT solution into each well, and discharging CO₂And continuously culturing for 4-6 h in the incubator.

4) In the test, the culture medium in a 96-well plate is removed, 100. mu.L of DMSO is added, and the mixture is shaken on a shaking table for 8min to completely dissolve the crystallized formazan. The absorbance (OD) was measured at an absorption wavelength of 570nm and a reference wavelength of 630nm using a microplate reader, and the inhibition ratio was calculated. The inhibition rate was (1-sample group OD value/blank group OD value) × 100%, all experiments were repeated 3 times, and the average value was taken, and the relative error was calculated.

TABLE 1

As can be seen from the cytotoxicity test results of the compounds in the table 1, the novel spiro [2, 1-b ] quinazolinone derivative prepared by the invention has good anticancer effects on different tumor cells, can be prepared into anticancer drugs in various dosage forms, and has high medical value and wide market prospect.

Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims

1. A new spiro pyrrole [2, 1-b ] quinazolinone derivative is characterized in that the structural formula of the derivative is shown as a formula I,

2. The novel spiro [2, 1-b ] quinazolinone derivatives according to claim 1, characterized in that said derivatives have the following structural formula:

3. a process for the preparation of a novel spiro pyrrolo [2, 1-b ] quinazolinone derivative according to claim 1, comprising the steps of:

the structural formula of the compound 1 is as follows:

the structural formula of compound 2 is:

the structural formula of compound 3 is:

the structural formula of compound 4 is:

the structural formula of compound 5 is:

the structural formula of the target product 6 is as follows:

4. the method according to claim 3, wherein the temperature of the stirring reaction in the step (1) is 75 ℃ to 85 ℃.

5. The method according to claim 3, wherein the stirring reaction time in step (1) is 8 to 10 hours.

6. The method according to claim 3, wherein the reaction time at room temperature in the step (2) is 2.5 to 3.5 hours.

7. The preparation method according to claim 3, wherein in the step (2), the DDQ is added under the ice-water bath for 25-35 min.

8. A process for the preparation of a novel spiro pyrrolo [2, 1-b ] quinazolinone derivative according to claim 1, comprising the steps of:

the structural formula of the compound 1 is as follows:

the structural formula of compound 2 is:

the structural formula of compound 3 is:

the structural formula of compound 4' is:

the structural formula of compound 5' is:

the structural formula of the target product 6 is as follows:

9. the use of a novel spiro pyrrolo [2, 1-b ] quinazolinone derivative according to claim 1 for the preparation of an anti-tumor medicament.