CN110724153B - Quinazolinone derivative and application thereof - Google Patents

Quinazolinone derivative and application thereof Download PDF

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CN110724153B
CN110724153B CN201910856134.6A CN201910856134A CN110724153B CN 110724153 B CN110724153 B CN 110724153B CN 201910856134 A CN201910856134 A CN 201910856134A CN 110724153 B CN110724153 B CN 110724153B
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潘成学
孔翔飞
郭秀云
顾子钰
莫冬亮
苏桂发
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract

The quinazolinone derivative is synthesized by a simple method, the yield is high, the production cost is low, when the concentration is 50 mu m and the concentration of LPS is 1 mu g/mL, the NO release inhibition capacity of the compounds 1a, 1i, 1l and 1n is superior to that of indometacin serving as an inflammation medicament, and the NO release inhibition capacity of the compounds 1b, 1e and 1j is equivalent to that of the indometacin; the cytotoxic effect of the compounds 1a, 1i, 1l, 1n, 1b and 1j with stronger NO release inhibition capacity on RAW264.7 cells is lower than that of an anti-inflammatory drug indomethacin; has obvious anti-inflammatory effect and low toxicity, can be prepared into anti-inflammatory medicaments in various dosage forms, and has high medical value and wide market prospect.

Description

Quinazolinone derivative and application thereof
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a quinazolinone derivative and application thereof.
Background
Quinazolinone is an important nitrogen-containing heterocyclic compound, which is abundantly present in various bioactive natural products and drug molecules, and the derivatives thereof show very wide biological activities, such as antitumor, antibacterial, antidiabetic, antiviral, anti-inflammatory and anticonvulsive, and the like. Therefore, the synthesis method and the biological activity research of the quinazolinone derivatives are always the research hotspots of organic synthesis chemistry and pharmaceutical chemistry, and the relevant documents reported every year reach hundreds of thousands.
We have recently synthesized a novel eight-or seven-membered heterocycloquinazolinone derivative, which is not reported in any literature.
Disclosure of Invention
The invention aims to: aiming at the problems, the invention provides a quinazolinone derivative with good anti-inflammatory effect and little toxicity and application thereof.
The invention is realized by the following technical scheme:
the present invention provides: a quinazolinone derivative, the structural formula of which is shown as formula I or formula II or formula III or formula IV,
Figure GDA0003000819780000011
wherein R is1Is H, F, Cl, NO2Or OCH3；R2Is H, Cl or OCH3；R3Is H, CH3Or Ph; r4Is H or Ph; x is O or NCOOC (CH)3)3。
Further, a quinazolinone derivative, the structural formula of which is shown in formula I,
Figure GDA0003000819780000012
wherein R is1Is F or NO2Or OCH3；R2Is H; r3Is H; r4Is H; x is O.
Further, a quinazolinone derivative, the structural formula of which is shown in formula I,
Figure GDA0003000819780000021
wherein R is1Is H; r2Is H; r3Is H or CH3Or Ph; r4Is H or Ph; x is O; when R is4At Ph, R3Is H or Ph; when R is4When is H, R3Is CH3Or Ph.
Further, a quinazolinone derivative, the structural formula of which is shown in formula I,
Figure GDA0003000819780000022
wherein R is1Is H or Cl; r2Is Cl orOCH3；R3Is H; r4Is H; x is O; when R is1When Cl is present, R2Is Cl; when R is1When is H, R2Is Cl or OCH3。
Further, a quinazolinone derivative, the structural formula of which is shown in formula I,
Figure GDA0003000819780000023
wherein R is1Is H or Cl; r2Is H; r3Is H; r4Is H; x is O or NCOOC (CH)3)3(ii) a When R is1When Cl, X is O; when R is1Is H, X is NCOOC (CH)3)3。
The invention also provides: a method for preparing a quinazolinone derivative, comprising the steps of:
(1) preparation of amide 1: 1) fully stirring the compound 1 and the compound 2 for reaction, and purifying by silica gel column chromatography to obtain amide 1;
(2) preparation of compound 3: 1) firstly, carrying out functional group conversion on amide 1; 2) and then the compound is subjected to ring closing and purification with propargyl propionaldehyde derivatives under the acid catalysis condition to obtain a compound 3:
(3) preparing a target product: 1) carrying out cyclization reaction on the compound 3 under the catalysis of silver ions to obtain a target product quinazolinone derivative; the structural formula of the compound 1 is as follows:
Figure GDA0003000819780000031
the structural formula of the compound 2 is as follows:
Figure GDA0003000819780000032
Figure GDA0003000819780000033
the amide 1 has the structural formula:
Figure GDA0003000819780000034
Figure GDA0003000819780000035
Figure GDA0003000819780000036
the structural formula of the compound 3 is:
Figure GDA0003000819780000037
Figure GDA0003000819780000041
the invention also provides application of the quinazolinone derivative in preparation of anti-inflammatory drugs.
The quinazolinone derivative is synthesized by a simple method, the yield is high, the production cost is low, when the concentration is 50mM and the LPS concentration is 1 mu g/mL, the release capacity of the compounds 1a, 1i, 1l and 1n for inhibiting NO is better than that of indometacin serving as an inflammation drug, and the release capacity of the compounds 1b, 1e and 1j is equivalent to that of indometacin: the cytotoxic effect of the compounds 1a, 1i, 1l, 1n, 1b and 1j with stronger capability of inhibiting the release of NO on RAW2647 cells is lower than that of an anti-inflammatory drug indomethacin: has obvious anti-inflammatory effect and low toxicity, can be prepared into anti-inflammatory medicaments in various dosage forms, 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 target product 1a
Figure GDA0003000819780000042
(1) 4-Chloroindigylic anhydride 2a (5mmol, 987mg) and anthranilic acid were stirred magneticallyMethyl ester (25mmol, 3780mg) was added to a 100mL round-bottom flask in sequence, heated under reflux for 12h, and the crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VPetroleum ether1: 1) gave 1124mg of compound 3a as a white solid (74% yield).
(2) Compound 3a (5mmol, 1520mg), tetrahydrofuran (30mL), and lithium aluminum hydride (10mmol, 380mg) were sequentially added to a 1000mL round-bottomed flask with magnetic stirring, the mixture was reacted at 0 ℃ for 4 hours, after completion of the reaction, the reaction solution was made alkaline with a 10% NaOH solution until a white precipitate was formed, suction filtration was performed, the cake was washed three times with dichloromethane, the filtrate was collected, and the solvent was removed under reduced pressure to obtain 840mg of compound 4a as a white solid (yield 61%).
(3) Compound 4a (253mmol, 700mg), anhydrous sodium sulfate (1400mg), tetrahydrofuran (20mL), 3-trimethylsilylpropynaldehyde (354mmol, 446mg), and p-toluenesulfonic acid (0.76mmol, 130mg) were sequentially added to a 250mL round-bottom flask with electromagnetic stirring, the mixture was reacted at room temperature for 3h, then DDQ (2.78mmol, 632mg) was added under an ice-water bath, reacted for 20min, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 410mg of compound 5a as a white solid (yield 73%).
(4) Compound 5a (1.57mmol, 600mg), methanol (10mL) and 1% silver nitrate aqueous solution (0.16mmol, 2.67g) were added sequentially to a 100mL round-bottomed flask under electromagnetic stirring, the mixture was reacted at room temperature for 2.5 hours, after completion of the reaction, sodium chloride (1g) was added, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VEthyl acetate40: 1) gave 467mg of compound 6a as a white solid (96% yield).
(5) Compound 6a (0.32mmol, 100mg), silver trifluoromethanesulfonate (0.016mmol, 4.14mg) and tetrahydrofuran (10mL) were successively added to a 100mL round-bottom flask with electromagnetic stirring, the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 94.3mg of compound 1a as a white solid (yield 94%). ).1H NMR(400MHz，CDCl3)δ8.22-8.15(m，1H)，7.88-7.82(m，1H)，7.59-7.53(m，3H)，7.41-7.35(m，2H)，6.16(d，J＝9.0Hz，1H)，5.48(d，J＝9.0Hz，1H)，5.10(d，J＝12.2Hz，1H)，4.94(d，J＝12.2Hz，1H)。
Example 2
Synthesis of target product 1b
Figure GDA0003000819780000051
(1) Under electromagnetic stirring, 5-fluoroisatoic anhydride 2b (5mmol, 905mg) and methyl anthranilate (25mmol, 3780mg) were sequentially added to a 100mL round-bottomed flask, heated under reflux for 12 hours, and the crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VPetroleum ether1: 1) gave 1036mg of compound 3b as a white solid (72% yield).
(2) Compound 3b (5mmol, 1440mg), tetrahydrofuran (30mL), and lithium aluminum hydride (10mmol, 380mg) were added in this order to a 100mL round-bottomed flask with magnetic stirring, the mixture was reacted at 0 ℃ for 4 hours, after completion of the reaction, the reaction solution was made alkaline with a 10% NaOH solution until a white precipitate was formed, suction filtration was performed, the cake was washed three times with dichloromethane, the filtrate was collected, and the solvent was removed under reduced pressure to obtain 1112mg of compound 4b as a white solid (yield 86%).
(3) Compound 4b (0.72mmol, 190mg), anhydrous calcium chloride (400mg), tetrahydrofuran (10mL), 3-trimethylsilylpropyraldehyde (1.08mmol, 140mg), and p-toluenesulfonic acid (0.22mmol, 37mg) were added in this order to a 50mL round-bottomed flask, the mixture was reacted at room temperature for 3h until completion (the reaction was monitored by TLC, developing solvent: DCM), then DDQ (0.79mmol, 180mg) was added under ice-water bath, reacted for 20min, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 170mg of compound 5b as a white solid (yield 64%).
(4) Compound 5b (1.6mmol, 590mg), tetrahydrofuran (10mL) and 1% silver nitrate aqueous solution (0.16mmol, 0.94g) were added in this order to a 100mL round-bottomed flask, and the mixture was reacted at room temperature for 2.5 hours with exclusion of light, and the reaction was completed,sodium chloride (1g) was added thereto, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VEthyl acetate40: 1) gave 364mg of compound 6b as a white solid (77% yield).
(5) Compound 6b (0.34mmol, 100mg), silver triflate (0.014mmol, 4.37mg) and tetrahydrofuran (10mL) were added successively to a 100mL round-bottom flask with magnetic stirring, the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 95.3mg of compound 1b as a white solid (yield 95%). ).1H NMR(400MHz，CDCl3)δ7.94-7.86(m，1H)，7.73-7.68(m，1H)，7.59-7.54(m，3H)，7.53-7.46(m，IH)，7.44-7.38(m，1H)，6.14(d，J＝9.0Hz，1H)，5.36(d，J＝9.0Hz，1H)，5.08(d，J＝12.2Hz，1H)，4.94(d，J＝12.2Hz，1H)。
Example 3
Synthesis of target product 1c
Figure GDA0003000819780000061
(1) Under electromagnetic stirring, 5-nitroisatoic anhydride (5mmol, 1040mg) and methyl anthranilate (25mmol, 3780mg) were sequentially added to a 100mL round-bottomed flask, heated under reflux for 12h, and the crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VPetroleum ether1: 1) to give 2100mg of compound 3c as a white solid (67% yield).
(2) Compound 3c (3.2mmol, 1000mg), tetrahydrofuran (30mL), and lithium aluminum hydride (6.4mmol, 243mg) were added sequentially to a 250mL round-bottomed flask with magnetic stirring, the mixture was reacted at 0 ℃ for 4 hours, after completion of the reaction, the reaction solution was made alkaline with a 10% NaOH solution until a white precipitate was formed, suction filtration was performed, the cake was washed three times with dichloromethane, the filtrate was collected, and the solvent was removed under reduced pressure to obtain 470mg of compound 4c as a white solid (yield 51%).
(3) Compound 4c (1.22mmol, 350mg), anhydrous magnesium sulfate (700mg), tetrahydrofuran (30mL), 3-trimethylsilylpropynaldehyde (1.83mmol, 230mg), and concentrated sulfuric acid (0.37mmol, 36mg) were added sequentially to a 100mL round-bottomed flask, the mixture was reacted at room temperature for 3h to completion, then DDQ (1.34mmol, 304.63mg) was added under ice-water bath, reacted for 20min, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 259mg of compound 5c as a white solid (yield 54%).
(4) Compound 5c (0.62mmol, 243mg), acetonitrile (10mL) and 1% aqueous silver nitrate solution (0.062mmol, 1.05g) were added in this order to a 100mL round-bottomed flask, the mixture was reacted at room temperature for 2.5 hours, the reaction was completed, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VEthyl acetate40: 1) gave 156mg of compound 6c as a white solid (78% yield).
(5) Compound 6c (0.31mmol, 100mg), silver triflate (0.015mmol, 4.00mg) and tetrahydrofuran (10mL) were added successively to a 100mL round-bottom flask with magnetic stirring, the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give compound 1c as a white solid (76.6 mg, yield 77%). ).1H NMR(400MHz，CDCl3)δ9.10(d，J＝2.6Hz，1H)，8.55(dd，J＝9.0，2.6Hz，1H)，7.79(d，J＝9.0Hz，1H)，7.62-7.56(m，3H)，7.42-7.37(m，1H)，6.23(d，J＝9.0Hz，1H)，5.40(d，J＝9.0Hz，1H)，5.12(d，J＝12.2Hz，1H)，4.99(d，J＝12.2Hz，1H)。
Example 4
Synthesis of target product 1d
Figure GDA0003000819780000071
(1) Under electromagnetic stirring, 5-methoxyisatoic anhydride (5mmol, 965mg) and methyl anthranilate (25mmol, 3780mg) were added in sequence to a round-bottomed flask, heated under reflux for 12h, and the crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VPetroleum ether1: 1) to yield 400mg ofCompound 3d as a white solid (27% yield).
(2) Compound 3d (3mmol, 910mg), tetrahydrofuran (30mL), and lithium aluminum hydride (6mmol, 228mg) were added in this order to a 100mL round-bottomed flask with magnetic stirring, the mixture was reacted at 0 ℃ for 4 hours, after completion of the reaction, the reaction solution was made alkaline with a 10% NaOH solution until a white precipitate was formed, suction filtration was performed, the cake was washed three times with dichloromethane, the filtrate was collected, and the solvent was removed under reduced pressure to obtain 751mg of compound 4d as a white solid (yield 92%).
(3) Compound 4d (1.84mmol, 500mg), anhydrous sodium sulfate (1000mg), tetrahydrofuran (30mL), 3-trimethylsilylpropyraldehyde (2.76mmol, 347mg), and p-toluenesulfonic acid (0.55mmol, 95mg) were sequentially added to a 100mL round-bottomed flask, the mixture was reacted at room temperature for 3h to completion, then DDQ (2.02mmol, 460mg) was added under an ice-water bath, reacted for 20min, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 348mg of compound 5d as a white solid (yield 65%).
(4) Compound 5d (1.14mmol, 330mg), ethanol (10mL) and 1% silver nitrate aqueous solution (0.11mmol, 1.94g) were sequentially added to a 100mL round-bottomed flask, the mixture was reacted for 2.5 hours at room temperature in the absence of light, sodium chloride (1g) was added, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VEthyl acetate40: 1) to yield 150.5mg of compound 6d as a white solid (43% yield).
(5) Compound 6d (0.24mmol, 73.5mg), silver triflate (0.012mmol, 3.08mg), and tetrahydrofuran (10mL) were successively added to a 100mL round-bottom flask with electromagnetic stirring, the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give compound 1d as a white solid (68 mg, yield 93%). ).1H NMR(500MHz，CDCl3)δ7.67-7.61(m，2H)，7.57-7.53(m，3H)，7.43-7.36(m，2H)，6.11(d，J＝8.9Hz，1H)，5.36(d，J＝8.9Hz，1H)，5.08(d，J＝12.1Hz，1H)，4.92(d，J＝12.1Hz，1H)，3.91(s，3H)。
Example 5
Synthesis of Compound 1e
Figure GDA0003000819780000081
(1) Adding 5-chloroisatoic anhydride (8.74mmol, 1730mg) and methyl 5-chloroanthranilate into round-bottomed flask under electromagnetic stirring, heating under reflux for 12 hr, and purifying the crude product by silica gel column chromatography (eluent: V)Methylene dichloride：VPetroleum ether1: 1) to give compound 3e as a white solid (52% yield).
(2) Compound 3e (2.95mmol, 1000mg), tetrahydrofuran (20mL), and lithium aluminum hydride (7.37mmol, 280mg) were added sequentially to a 250mL round-bottomed flask with magnetic stirring, the mixture was reacted at 0 ℃ for 4 hours, after completion of the reaction, the reaction solution was made alkaline with a 10% NaOH solution until a white precipitate was formed, suction filtration was performed, the cake was washed three times with dichloromethane, the filtrate was collected, and the solvent was removed under reduced pressure to obtain 320mg of compound 4e as a white solid (yield 35%).
(3) Compound 4e (1.04mmol, 323.5mg), anhydrous copper sulfate (647mg), tetrahydrofuran (30mL), 3-trimethylsilylpropyraldehyde (1.46mmol, 184mg), p-toluenesulfonic acid (0.31mmol, 54mg) were added in this order to a 100mL round-bottom flask, the mixture was reacted at room temperature for 3h, then DDQ (1.14mmol, 260mg) was added under ice-water bath, reacted for 20min, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 173mg of compound 5e as a white solid (40% yield).
(4) Compound 5e (0.35mmol, 144mg), butanone ketone (10mL) and 1% aqueous silver nitrate solution (0.035mmol, 0.58g) were added in this order to a 100mL round-bottomed flask, the mixture was reacted at room temperature for 2.5 hours, sodium chloride (1g) was added, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VEthyl acetate40: 1) gave 118.3mg of compound 6e as a white solid (99% yield).
(5) Under electromagnetic stirring, Compound 6e (0.26mmol, 90mg), silver triflate(0.013mmol, 3.36mg) and tetrahydrofuran (10mL) were sequentially added to a 100mL round-bottom flask, the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 67.8mg of Compound 1e as a white solid (yield 75%). ).1H NMR(400MHz，CDCl3)δ8.19(d，J＝2.4Hz，1H)，7.70(dd，J＝8.7，2.4Hz，1H)，7.63(d，J＝8.7Hz，1H)，7.56-7.48(m，2H)，7.35(d，J＝8.7Hz，1H)，6.16(d，J＝9.0Hz，1H)，5.36(d，J＝9.0Hz，1H)，5.02(d，J＝12.3Hz，1H)，4.88(d，J＝12.3Hz，1H)。
EXAMPLE 6
Synthesis of Compound 1f
Figure GDA0003000819780000091
(1) Under electromagnetic stirring, compound 2f (11.05mmol, 2050mg), THF (65mL), triethylamine (33.15mmol, 4.62mL) and o-nitrobenzoyl chloride (22.10mmol, 1.40mL) were added sequentially to a 100mL round-bottomed flask, the mixture was reacted at 0 ℃ for 3h, the reaction was complete, suction filtered, washed three times with DCM, the filtrate was collected, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VPetroleum ether2: 3) to give 3659mg of compound 3f as a white solid (yield 99%).
(2) Compound 3f (6mmol, 2000mg), methanol (35mL), nickel nitrate (6mmol, 1426mg) and sodium borohydride (60mmol, 2269mg) were added sequentially to a 250mL round-bottom flask with magnetic stirring, the mixture was reacted for 2h in an ice-water bath to completion, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 1040mg of compound 4f as a white solid (yield 77%).
(3) Compound 4f (3.06mmol, 930mg), THF (30mL), lithium aluminum hydride (6.12mmol, 232mg) were added sequentially to a 250mL round bottom flask, the mixture was reacted at 0 ℃ for 4h, the reaction was completed, the reaction solution was made basic with 10% NaOH solution until white precipitate appeared, suction filtration was performed, THF was washed three times, the filtrate was collected, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: DCM) to give 725.5mg of compound 5f as a white solid (yield 86%).
(4) Compound 5f (2.53mmol, 700mg), anhydrous magnesium sulfate (1400mg), THF (30mL), 3-trimethylsilylpropynaldehyde (3.79mmol, 479mg), and concentrated sulfuric acid (0.76mmol, 74mg) were added in this order to a 100mL round-bottomed flask, the mixture was reacted at room temperature for 3h to completion, DDQ (2.78mmol, 632mg) was added under an ice-water bath, the reaction was carried out for 20min, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 411.5mg of compound 6f as a white solid (yield 43%).
(5) Compound 6f (0.99mmol, 380mg), dichloromethane (10mL) and 1% aqueous silver nitrate solution (0.09mmol, 1.68g) were added in this order to a 100mL round-bottomed flask, the mixture was reacted at room temperature for 2.5h, the reaction was completed, sodium chloride (1g) was added, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VEthyl acetate40: 1) gave 243.5mg of compound 7f as a white solid (79% yield).
(6) Compound 7f (0.19mmol, 59mg), silver triflate (0.009mmol, 2.45mg), THF (10mL) were added successively to a 100mL round-bottom flask, and the mixture was heated to reflux for 11h (TLC monitor reaction, developing reagent: DCM). ). The solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 40.3mg of compound 1f as a white solid (yield 68%). ).1H NMR(500MHz，CDCl3)δ8.25(dd，J＝7.9，0.9Hz，1H)，7.81-7.75(m，1H)，7.69(d，J＝8.1Hz，1H)，7.57-7.43(m，3H)，7.37(d，J＝8.4Hz，1H)，6.15(d，J＝9.0Hz，1H)，5.39(d，J＝9.0Hz，1H)，5.04(d，J＝12.3Hz，1H)，4.88(d，J＝12.3Hz，1H)。
EXAMPLES example 7
Synthesis of 1g of the target product
Figure GDA0003000819780000101
(1) Under electromagnetic stirring, 2g (1.1 m) of the compound was addedmol, 200mg), THF (10mL), triethylamine (3.3mmol, 0.5mL) and o-nitrobenzoyl chloride (1.1mmol, 0.15mL) were added sequentially to a 50mL round bottom flask, the mixture was reacted at 0 ℃ for 3h, the reaction was completed, suction filtered, DCM washed three times, the filtrate was collected, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: vMethylene dichloride：VPetroleum ether2: 3) to yield 275.5mg of compound 3g as a white solid (76% yield).
(2) To a 250mL round-bottom flask were added successively 3g (6.06mmol, 2000mg) of the compound, methanol (35mL), nickel nitrate (6.06mmol, 1760mg) and sodium borohydride (60.6mmol, 2300mg) under electromagnetic stirring, the mixture was reacted in an ice-water bath for 2h to completion, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 1696mg of the compound as a white solid, 4g (yield 89%).
(3) The compound (4 g, 3.75mmol, 1180mg), THF (30mL), lithium aluminum hydride (7.40mmol, 285mg) were added in this order to a 250mL round-bottom flask, the mixture was reacted at 0 ℃ for 4 hours, (TLC monitoring reaction, developing reagent: DCM), reaction was completed, the reaction solution was made basic with 10% NaOH solution until white precipitate appeared, suction filtration was carried out, THF was washed three times, the filtrate was collected, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: DCM) to obtain 1000mg of the compound (5 g, yield 98%) as a white solid.
(4) The compound (5 g, 2.83mmol, 770mg), anhydrous sodium sulfate (1600mg), THF (30mL), 3-trimethylsilylpropynaldehyde (4.12mmol, 518.6mg), p-toluenesulfonic acid (0.88mmol, 151.7mg) were sequentially added to a 100mL round-bottom flask, the mixture was reacted at room temperature for 3h to completion, DDQ (3.23mmol, 734mg) was added under ice-water bath, the solvent was removed under reduced pressure for 20min, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to obtain 394mg of the compound as a white solid (6 g, 48% yield).
(5) Adding compound 6g (1.20mmol, 350mg), acetone (10mL) and 1% silver nitrate aqueous solution (0.12mmol, 2.05g) in sequence into a 100mL round-bottom flask, reacting the mixture at room temperature for 2.5h, adding sodium chloride (1g), removing solvent under reduced pressure, and extracting the crude product by silica gel column chromatographyPure (eluent: V)Methylene dichloride：VEthyl acetate40: 1) to yield 244.5mg of compound 7g as a white solid (93% yield).
(6) The compound (7 g, 0.46mmol, 100mg), silver trifluoromethanesulfonate (0.023mmol, 5.89mg) and THF (10mL) were successively added to a 100mL round-bottom flask, and the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to obtain 61.4mg of the compound (1g, yield 61%) as a white solid. ).1H NMR(400MHz，CDCl3)δ8.26(dd，J＝8.0，1.0Hz，1H)，7.81-7.73(m，1H)，7.69(d，J＝8.0Hz，1H)，7.51-7.41(m，1H)，7.33(d，J＝8.8Hz，1H)，7.08(dd，J＝8.8，2.8Hz，1H)，7.01(d，J＝2.8Hz，1H)，6.15(d，J＝9.0Hz，1H)，5.39(d，J＝9.0Hz，1H)，5.04(d，J＝12.1Hz，1H)，4.86(d，J＝12.1Hz，1H)，3.88(s，3H)。
EXAMPLES example 8
Synthesis of target product for 1h
Figure GDA0003000819780000111
(1) Under electromagnetic stirring, compound 2h (9mmol, 1220mg), THF (25mL), triethylamine (27mmol, 3.69mL) and o-nitrobenzoyl chloride (9mmol, 1.19mL) were added sequentially to a 100mL round-bottomed flask, the mixture was reacted at 0 ℃ for 3h, the reaction was completed, suction filtration and DCM washing were carried out three times, the filtrate was collected, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VPetroleum ether2: 3) to yield 2220mg of compound as a white solid 3h (87% yield).
(2) Compound 3h (5.28mmol, 1500mg), methanol (35mL), nickel nitrate (5.28mmol, 1260mg) and sodium borohydride (15.85mmol, 600mg) were added sequentially to a 100mL round-bottom flask with magnetic stirring, the mixture was reacted for 2h in an ice-water bath (TLC monitoring reaction, developing agent: DCM), the reaction was complete, the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (eluent: DCM) to give 800mg of compound as a white solid for 4h (yield 59%).
(3) Compound 4h (2.79mmol, 714.5mg), anhydrous magnesium sulfate (1500mg), THF (30mL), 3-trimethylsilylpropynaldehyde (3.906mmol, 492.16mg), p-toluenesulfonic acid (0.84mmol, 143.96mg) were sequentially added to a 20mL round-bottomed flask with electromagnetic stirring, the mixture was reacted at room temperature for 3h to completion, DDQ (3.07mmol, 697mg) was added under ice-water bath, reacted for 20min, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 271.6mg of compound as a white solid for 5h (yield 27%).
(4) Under electromagnetic stirring, compound 5h (0.33mmol, 120mg), acetone (10mL) and 1% silver nitrate aqueous solution (0.033mmol, 0.5g) were added sequentially to a 100mL round-bottom flask, the mixture was reacted at room temperature in the dark for 2.5h, sodium chloride (1g) was added, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VEthyl acetate40: 1) to yield 77mg of compound 6h as a white solid (81% yield).
(5) Compound 6h (0.23mmol, 67.3mg), silver triflate (0.023mmol, 2.98mg), THF (10mL) were added successively to a 100mL round-bottom flask with electromagnetic stirring, the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 37.8mg of compound as a white solid for 1h (yield 56%).1H NMR(400MHz，CDCl3)δ8.28(dd，J＝8.0，1.2Hz，1H)，7.81-7.74(m，1H)，7.70(d，J＝7.6Hz，1H)，7.64-7.60(m，1H)，7.59-7.44(m，3H)，7.359-7.34(m，1H)，6.12(d，J＝9.0Hz，1H)，5.45(q，J＝6.5Hz，1H)，5.33(d，J＝9.0Hz，1H)，1.71(d，J＝6.5Hz，3H)。
EXAMPLES example 9
Synthesis of target product 1i
Figure GDA0003000819780000131
(1) Under electromagnetic stirring, Compound 2i (9mmol, 1770mg), THF (25mL), triethylamine (27mmol, 1.2mL) and o-nitrobenzoyl were addedAdding chlorine (9mmol, 1.19mL) into 100mL round-bottom flask, reacting at 0 deg.C for 3 hr, filtering, washing with DCM for three times, collecting filtrate, removing solvent under reduced pressure, and purifying the obtained crude product by silica gel column chromatography (eluent: V)Methylene dichloride：VPetroleum ether2: 3) to yield 2700mg of compound 3i as a white solid (yield 87%).
(2) Compound 3i (2.13mmol, 738mg), methanol (35mL), nickel nitrate (2.13mmol, 506mg) and sodium borohydride (21.3mmol, 809mg) were added successively to a 100mL round-bottomed flask with electromagnetic stirring, the mixture was reacted in an ice-water bath for 2h, the reaction was completed, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 650mg of compound 4i as a white solid (yield 67%).
(3) Compound 4i (2.16mmol, 688mg), anhydrous sodium sulfate (1400mg), THF (30mL), 3-trimethylsilylpropynaldehyde (3.02mmol, 381.48mg), and concentrated hydrochloric acid (0.648mmol, 64) were added successively to a 250mL round-bottomed flask with electromagnetic stirring, the mixture was reacted at room temperature for 3h to completion, DDQ (2.38mmol, 540.10mg) was added under ice-water bath, the solvent was removed under reduced pressure for 20min, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 319.8mg of compound 5i as a white solid (yield 35%).
(4) Under electromagnetic stirring, compound 5i (0.61mmol, 260mg), N-dimethylformamide (15mL) and 1% aqueous silver nitrate solution (0.061mmol, 1.04g) were added in this order to a 100mL round-bottomed flask, the mixture was reacted at room temperature for 2.5 hours in the dark to complete the reaction, sodium chloride (1g) was added, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VEthyl acetateYield 170mg of compound 6i as a white solid (79% yield).
(5) Compound 6i (0.28mmol, 100mg), silver trifluoromethanesulfonate (0.014mmol, 3.60mg), and THF (10mL) were successively added to a 100mL round-bottom flask with electromagnetic stirring, and the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM), yielding 73.9mg of compound 1i as a white solid (yield 74%).1H NMR(400MHz，CDCl3)δ7.90(dd，J＝8.0，1.4Hz，1H)，7.68-7.55(m，4H)，7.44(d，J＝8.0Hz，1H)，7.34-7.25(m，2H)，7.15(d，J＝8.3Hz，2H)，6.90(t，J＝7.8Hz，2H)，6.64-6.58(m，1H)，6.52(s，1H)，6.33(d，J＝8.9Hz，1H)，5.49(d，J＝8.9Hz，1H)。
EXAMPLES 10
Synthesis of target product 1j
Figure GDA0003000819780000141
(1) Under electromagnetic stirring, compound 2j (1.32mmol, 200mg), THF (10mL), triethylamine (3.96mmol, 0.55mL) and o-nitrobenzoyl chloride (2.65mmol, 0.35mL) were added sequentially to a 50mL round-bottomed flask, the mixture was reacted at 0 ℃ for 3h, the reaction was complete, suction filtered, washed with DCM three times, the filtrate was collected, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VPetroleum ether2: 3) to give 289mg of compound 3j as a white solid (73% yield).
(2) Compound 3j (4.93mmol, 1480mg), methanol (35mL), nickel nitrate (4.93mmol, 1400mg) and sodium borohydride (49.3mmol, 1860mg) were added sequentially to a 250mL round bottom flask with magnetic stirring, the mixture was reacted for 2h in an ice-water bath to completion, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 880mg of compound 4.j (yield 66%) as a white solid.
(3) Compound 4j (2.22mmol, 600mg), anhydrous chloride (1200mg), THF (30mL), 3-trimethylsilylpropynaldehyde (3.1mmol, 391mg), p-toluenesulfonic acid (0.66mmol, 115mg) were added successively to a 100mL round-bottom flask with magnetic stirring, the mixture was reacted at room temperature for 3h to completion, DDQ (2.44mmol, 554mg) was added under an ice-water bath, the solvent was removed under reduced pressure for 20min, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 363mg of compound 5j as a white solid (yield 40%).
(4) Under electromagnetic stirring, compound 5j (0.93mmol, 350mg), methanone (15)mL) and 1% silver nitrate aqueous solution (0.093mmol, 1.6g) were sequentially added to a 100mL round-bottomed flask, the mixture was reacted for 2.5 hours at room temperature in the dark, sodium chloride (1g) was added, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: vMethylene dichloride：VEthyl acetate40: 1) to yield 246mg of compound 6j as a white solid (87% yield).
(5) Compound 6j (0.33mmol, 100mg), silver trifluoromethanesulfonate (0.016mmol, 4mg) and THF (10mL) were successively added to a 100mL round-bottom flask with electromagnetic stirring, the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 47.5mg of compound 1j as a white solid (yield 48%).1H NMR(500MHz，CDCl3)δ8.35-8.29(m，1H)，7.82-7.72(m，2H)，7.53-7.42(m，2H)，7.41-7.33(m，2H)，7.02(d，J＝7.2Hz，1H)，6.42(d，J＝5.0Hz，1H)，6.14(d，J＝5.0Hz，1H)，1.84(s，3H)，1.61(s，3H)。
EXAMPLES example 11
Synthesis of target product 1k
Figure GDA0003000819780000151
(1) 4-Chloroindigylic anhydride 2a (5mmol, 987mg) and methyl anthranilate (25mmol, 3780mg) were added in sequence to a 100mL round-bottomed flask with electromagnetic stirring, heated under reflux for 12h, and the crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VPetroleum ether1: 1) gave 1124mg of compound 3a as a white solid (74% yield).
(2) Adding isatoic anhydride (15.3mmol, 2500mg) and methyl anthranilate (60mmol) into round-bottomed flask in sequence under electromagnetic stirring, heating and refluxing for 15h, and purifying the crude product by silica gel column chromatography (eluent: V)Methylene dichloride：VPetroleum ether1: 1) to yield compound 3k as a white solid (72% yield).
(3) Compound 3k (8.5mmol, 2300mg), tetrahydrofuran (40mL), and lithium aluminum hydride (17mmol, 810mg) were added sequentially to a 250mL round-bottomed flask with magnetic stirring, the mixture was reacted at 0 ℃ for 4 hours, after completion of the reaction, the reaction solution was made alkaline with a 10% NaOH solution until a white precipitate was formed, suction filtration was performed, the cake was washed three times with dichloromethane, the filtrate was collected, and the solvent was removed under reduced pressure to obtain 1700mg of compound 4k as a white solid (yield 83%).
(4) Compound 4k (2.07mmol, 500mg), anhydrous calcium chloride (1000mg), THF (30mL), 3-trimethylsilylpropynaldehyde (3.1mmol, 403mg), and p-toluenesulfonic acid (0.62mmol, 107mg) were added in this order to a 100mL round-bottom flask with magnetic stirring, the mixture was reacted at room temperature for 3h to completion, DDQ (2.28mmol, 517mg) was added under ice-water bath, the solvent was removed under reduced pressure for 20min, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 229mg of compound 5k as a white solid (yield 31%).
(5) Compound 5k (0.28mmol, 100mg), silver trifluoromethanesulfonate (0.014mmol, 3.65mg), and THF (10mL) were successively added to a 100mL round-bottom flask with electromagnetic stirring, and the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM), giving 54.5mg of compound 1k as a white solid (yield 55%).1H NMR(400MHz，CDCl3)δ8.31(dd，J＝8.0，0.9Hz，1H)，7.83-7.72(m，2H)，7.64-7.59(m，1H)，7.57-7.44(m6H)，7.37-7.26(m，3H)，6.04(s，1H)，5.26(d，J＝12.3Hz，1H)，5.14(d，J＝12.3Hz，1H)。
EXAMPLE 12
Synthesis of target product 11
Figure GDA0003000819780000161
(1) Under electromagnetic stirring, compound 2l (9mmol, 1770mg), THF (25mL), triethylamine (27mmol, 1.2mL) and o-nitrobenzoyl chloride (9mmol, 1.19mL) were added sequentially to a 250mL round-bottom flask, the mixture was reacted at 0 ℃ for 3h, the reaction was complete, suction filtered, washed three times with DCM, the filtrate was collected, the solvent was removed under reduced pressure, and the crude product was chromatographed on silica gel columnPurification (eluent: V)Methylene dichloride：VPetroleum ether2: 3) to yield 2700mg of compound 3l as a white solid (yield 87%).
(2) To a 250mL round-bottom flask were added successively 3l (2.13mmol, 738mg), methanol (35mL), nickel nitrate (2.13mmol, 506mg) and sodium borohydride (21.3mmol, 809mg) of compound, under electromagnetic stirring, the mixture was reacted in an ice-water bath for 2h, the reaction was completed, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 650mg of compound 4l as a white solid (yield 67%).
(3) To a 100mL round-bottomed flask were added the compound 4l (1.51mmol, 480mg), magnesium sulfate (1000mg), THF (30mL), 3-trimethylsilylpropyraldehyde (2.13mmol, 300mg), and concentrated sulfuric acid (0.45mmol, 44mg) in this order under electromagnetic stirring, the mixture was reacted at room temperature for 3h to completion, DDQ (1.66mmol, 390mg) was added under ice-water bath, the solvent was removed under reduced pressure for 20min, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to obtain 71mg of the compound 5l as a white solid (yield 11%).
(4) To a 100mL round-bottomed flask were added compound 5l (0.21mmol, 90mg), silver trifluoromethanesulfonate (0.011mmol, 2.70mg) and THF (10mL) in this order under electromagnetic stirring, the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give compound 1l (yield 93%) as a white solid 84 mg.1H NMR(400MHz，CDCl3)δ8.37(dd，J＝8.1，1.1Hz，1H)，7.85-7.74(m，2H)，7.70-7.63(m，2H)，7.55-7.44(m，5H)，7.43-7.31(m，7H)，7.19(d，J＝7.5Hz，1H)，6.66(s，1H)，6.11(s，1H)。
EXAMPLES example 13
Synthesis of target product 1m
Figure GDA0003000819780000171
(1) Isatoic anhydride (3.01mmol, 500mg), tetrachlorofuran (60mL) and propanolamine (3.37 mmol, 0.25mL) were added successively to a 250mL round-bottomed flask with electromagnetic stirring, the mixture was reacted at room temperature for 12 hours, the reaction was completed, extracted with EA (3 × 25mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 415mg of a white solid compound (3m, yield 70%).
(2) Compound 3m (5.15mmol, 1000mg), calcium sulfate anhydrous (2000mg), THF (40mL), 3-trimethylsilylpropynaldehyde (7.21mmol, 908mg), and p-toluenesulfonic acid (1.5mmol, 274mg) were sequentially added to a 250mL round-bottom flask with electromagnetic stirring, the mixture was reacted at room temperature for 3h to completion, DDQ (5.71mmol, 1296mg) was added under an ice-water bath, the solvent was removed under reduced pressure for 20min, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 778.2mg of compound 4m as a white solid (50% yield).
(3) Under electromagnetic stirring, compound 4m (0.73mmol, 220mg), acetone (10mL) and 1% silver nitrate aqueous solution (0.083mmol, 1.4g) were added in this order to a 100mL round-bottomed flask, the mixture was reacted at room temperature in the dark for 2.5 hours until completion, sodium chloride (1g) was added, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VEthyl acetate40: 1) to yield 133.6mg of compound 5m as a white solid (yield 80%).
(4) Compound 5m (035mmol, 100mg), silver trifluoromethanesulfonate (0.017mmol, 4.5mg), and THF (10mL) were successively added to a 100mL round-bottom flask with electromagnetic stirring, the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM), giving 39.7mg of compound 1m as a white solid (yield 40%).1H NMR(400MHz，CDCl3)δ8.24(dd，J＝8.0，1.2Hz，1H)，7.75-7.68(m，1H)，7.62(d，J＝8.0Hz，1H)，7.45-7.38(m，1H)，6.69(d，J＝8.6Hz，1H)，5.34(d，J＝8.6Hz，1H)，4.44(s，2H)，4.17-4.05(m，2H)，2.18-2.05(m，2H)。
EXAMPLES example 14
Synthesis of target product 1n
Figure GDA0003000819780000181
(1) Compound 2N (25mmol, 3000mg), N-diisopropylethylamine (26mmol, 13mL), THF (50mL) and Boc anhydride (26mmol, 5000mg) were sequentially added to a 100mL round-bottomed flask under electromagnetic stirring, the mixture was reacted at room temperature for 2 hours to complete the reaction, 10% citric acid (25mL) was added to the reaction solution, extracted with EA (3 × 25mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 4760mg of compound 3N as a white solid (yield 86%).
(2) Compound 3n (4.5mmol, 1000mg) and isatoic anhydride (4.5mmol, 733mg) were added successively to a 50mL round-bottomed flask with electromagnetic stirring, the mixture was heated under reflux for 12 hours to complete the reaction, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 755mg of compound 4n as a white solid (yield 50%).
(3) Compound 4n (1.90mmol, 647mg), anhydrous copper sulfate (1300mg), THF (30mL), 3-trimethylsilylpropynaldehyde (2.65mmol, 334mg), and concentrated hydrochloric acid (0.57mmol, 56mg) were successively added to a 250mL round-bottom flask under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours to completion, DDQ (2.09mmol, 473mg) was added under an ice-water bath, the solvent was removed under reduced pressure for 20min, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to obtain 364mg of compound 5n as a white solid (yield 43%).
(4) Under electromagnetic stirring, compound 5n (0.56mmol, 250mg), methanol (10mL) and 1% silver nitrate aqueous solution (0.056mmol, 0.9g) were sequentially added to a 100mL round-bottomed flask, the mixture was reacted at room temperature for 2.5 hours in the dark, sodium chloride (1g) was added, stirring was carried out for 1min, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VEthyl acetate40: 1) to yield 21g.3mg of compound 6n as a white solid (yield 99%).
(5) Compound 6n (0.27mmol, 100mg), silver trifluoromethanesulfonate (0.013mmol, 3.4mg) and THF (10mL) were successively added to a 100mL round-bottom flask with electromagnetic stirring, the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was extracted by silica gel column chromatographyPure (eluent: DCM) gave 27mg of compound 1n as a white solid (yield 27%).1H NMR(400MHz，CDCl3)δg.27(d，J＝7.2Hz，1H)，7.81-7.73(m，1H)，7.70(d，J＝8.1Hz，1H)，7.53-7.45(m，4H)，7.41-7.34(m，1H)，6.g1(s，1H)，5.44(d，J＝9.5Hz，2H)，4.18(s，1H)，1.52(s，9H)。
EXAMPLE 15
Synthesis of the target product 1o
Figure GDA0003000819780000191
(1) Compound 2o (13.7mmol, 1500mg), isatoic anhydride (13.7mmol, 2200mg) and water (50mL) were added successively to a 100mL round-bottomed flask with magnetic stirring, the mixture was heated under reflux for 12h to complete the reaction, extracted with EA (3X 25mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to give 2530mg of compound 3o as a white solid (yield 81%).
(2) Compound 3o (2.19mmol, 500mg), magnesium sulfate (1000mg), THF (30mL), 3-trimethylsilylpropynaldehyde (3.07mmol, 387mg), and p-toluenesulfonic acid (0.66mmol, 113mg) were sequentially added to a 100mL round-bottomed flask under electromagnetic stirring, the mixture was reacted at room temperature for 3 hours to completion, DDQ (2.41mmol, 547mg) was added under ice-water bath, reacted for 20min, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM) to give 709.8mg of compound 4o as a white solid (yield 97%).
(3) Under electromagnetic stirring, compound 4o (1.05mmol, 350mg), methanol (10mL) and 1% silver nitrate aqueous solution (0.11mmol, 1.78g) were added sequentially to a 100mL round-bottomed flask, the mixture was reacted at room temperature in the dark for 2.5h, the reaction was completed, sodium chloride (1g) was added, stirring was carried out for 1min, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: V)Methylene dichloride：VEthyl acetate40: 1) to yield 189.2mg of compound 5o as a white solid (69% yield).
(4) Under electromagnetic stirring, compound 5o (0.38mmol, 100mg), trifluoroSilver methanesulfonate (0.02mmol, 4.9mg) and THF (10mL) were added successively to a 100mL round-bottom flask, and the mixture was heated under reflux for 11h, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM), giving 29mg of compound 1o as a white solid (yield 29%).1H NMR(500MHz，CDCl3)δ8.25(d，J＝7.7Hz，1H)，7.80-7.74(m，2H)，7.50-7.44(m，1H)，7.30-7.26(m，1H)，6.84(d，J＝5.8Hz，1H)，6.67(d，J＝5.8Hz，1H)，6.62-5.57(m，1H)，6.45(d，J＝10.0Hz，1H)，6.07(d，J＝8.7Hz，1H)。
And (4) carrying out primary screening on the anti-inflammatory activity of the target product. The method for evaluating the anti-inflammatory activity is determined by measuring the inhibition of the release of mouse macrophage RAW264.7NO induced by Lipopolysaccharide (LPS) by the compound according to the Griess method. The results of experiments on inhibition of LPS (lipopolysaccharide) induced NO release from mouse macrophage RAW264.7 by part of the target compounds are shown in Table 1.
TABLE 1
Figure GDA0003000819780000192
Figure GDA0003000819780000201
The results of experiments representing that compound 1a inhibits the release of NO from mouse macrophage RAW264.7 induced by Lipopolysaccharide (LPS) at different concentrations are shown in Table 2.
TABLE 2
Figure GDA0003000819780000202
The effect of the target compound on RAW264.7 cell viability at a concentration of 100 μ M is shown in table 3.
TABLE 3
Figure GDA0003000819780000203
From the test results, when the concentration is 50mM and the concentration of LPS is 1 mug/mL, the release capacity of the compounds 1a, 1i, 1l and 1n for inhibiting NO is better than that of indometacin serving as an inflammation drug, and the release capacity of the compounds 1b, 1e and 1j is equivalent to that of indometacin; the cytotoxic effect of the compounds 1a, 1i, 1l, 1n, 1b and 1j with stronger NO release inhibition capacity on RAW264.7 cells is lower than that of an anti-inflammatory drug indomethacin; has obvious anti-inflammatory effect and low toxicity.
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 (2)

1. A quinazolinone derivative is characterized in that the structural formula of the derivative is shown as a formula IV,
Figure DEST_PATH_IMAGE002
。
2. use of a quinazolinone derivative according to claim 1 for the preparation of an anti-inflammatory agent.
CN201910856134.6A 2019-09-11 2019-09-11 Quinazolinone derivative and application thereof Active CN110724153B (en)

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