CN117209505A

CN117209505A - Spiroisoindolinone compound and synthesis method thereof

Info

Publication number: CN117209505A
Application number: CN202311195714.8A
Authority: CN
Inventors: 南江; 郭欣欣; 门欣然; 梁璐
Original assignee: Shaanxi University of Science and Technology
Current assignee: Shaanxi University of Science and Technology
Priority date: 2023-09-15
Filing date: 2023-09-15
Publication date: 2023-12-12

Abstract

The application discloses a spiro isoindolinone compound and a synthesis method thereof, wherein the isoindolinone compound and carbonic acid are added into a solventVinylene ester is reacted with rhodium catalyst and silver additive to produce [3+3]]And (3) cyclizing reaction, separating and purifying to obtain the spiroisoindolinone compound. The method has simple operation, abundant target compound species, and CO as the generated reaction byproduct ₂ And H ₂ In addition, the method has better universality of the substrate, and the target product is easy to separate under the optimized reaction condition, so that the method has potential application value in the fields of materials and medicines.

Description

Spiroisoindolinone compound and synthesis method thereof

Technical Field

The application belongs to the field of organic synthesis, and particularly relates to a spiro isoindolinone compound and a synthesis method thereof.

Background

The spiroindolinone is a heterocyclic alkaloid, widely exists in various natural products, bioactive molecules and pharmacological active molecules, and most indole ring compounds have the effects of resisting tumor, resisting inflammation, reducing blood pressure, relieving fever, easing pain and the like. Because of the unique chemical structure, most indole ring compounds show important biological or chemical properties, can be used for synthesizing dyes, medical intermediates and the like, and are very important heterocyclic fine chemical intermediates. However, the method for synthesizing the spiro isoindolinone compound is not much reported at present, and the cyclization reagent and the generated byproducts used by the existing synthesis method are certain in corrosiveness and toxicity, so that the method has great pollution to the health and environment of human bodies, raw materials are not easy to obtain, and the yield is low. Therefore, the development is convenient, the economy and the pollution-free synthesis method become hot problems in the research of organic synthesis chemistry and pharmaceutical chemistry in recent years.

Disclosure of Invention

Aiming at the problems existing in the prior art, the application aims to provide a spiro isoindolinone compound and a synthesis method thereof, wherein the isoindolinone compound and vinylene carbonate are used as reaction raw materials, and under the combined action of a rhodium catalyst and a silver additive, the reaction is carried out [3+3]]Cyclizing reaction, and separating and purifying to obtain the spiro isoindolinone compound. The synthesis method has the advantages of simple and easily obtained raw materials, simple synthesis route, mild reaction condition, high efficiency and strong selectivity, and the generated byproduct is CO ₂ And H ₂ O effectively solves the problems that byproducts generated in the prior art are toxic, raw materials are difficult to obtain and the yield is low.

The application is realized by the following technical scheme:

a synthesis method of spiro isoindolinone compounds comprises the following steps:

adding isoindolinone compounds, vinylene carbonate, rhodium catalyst and silver additive into an organic solvent, heating and reacting in an air environment, and separating and purifying to obtain the spiroisoindolinone compounds.

Preferably, the spiro isoindolinone compound has the following reaction formula:

wherein R is ¹ Selected from hydrogen, alkyl, methoxy, benzene ring, dibenzothiophene, dibenzofuran, dimethylsilane, fluorine, chlorine, bromine, thiomethyl or heterocycle; r is R ² Is chlormorph, wherein 1 is isoindolinone, 2 is vinylene carbonate and 3 is spiroisoindolinone.

Preferably, the ratio of the amounts of the spiro isoindolinone compound and the vinylene carbonate compound is 1:1-1:5.

Preferably, the concentration of the spiro isoindolinone compound in the solvent is 0.1-1.5 mol/l.

Preferably, the solvent comprises one or more of toluene, tetrahydrofuran and dichloroethane.

Preferably, the rhodium catalyst is Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ Or [ Cp ] IrCl ₂ ] ₂ 。

Preferably, the silver additive is one of silver hexafluoroantimonate, silver acetate and silver tetrafluoroborate.

Preferably, the 3-hydroxy-3- (p-tolyl) isoindolin-1-one, 3-hydroxy-3-phenylisoindolin-1-one, 3-hydroxy-3- (4-methoxyphenyl) isoindolin-1-one, 3-hydroxy-3- (naphthalen-1-yl) isoindolin-1-one, 3- (4-cyclohexylphenyl) -3-hydroxyisoindolin-1-one, 3- (dibenzo [ b, d ] furan-4-yl) -3-hydroxyisoindolin-1-one, 3-hydroxy-3- (4- (trimethylsilyl) phenyl) isoindolin-1-one, 3- (4-fluorophenyl) -3-hydroxyisoindolin-1-one, 3- (4-chlorophenyl) -3-hydroxyisoindolin-1-one, 3- (4-bromophenyl) -3-hydroxyisoindolin-1-one, 3- (dibenzo [ b, d ] thiophen-2-yl) -3-hydroxyisoindolin-1-one, 3- (4-bromophenyl) isoindolin-1-one, 3- (4-chlorophenyl) isoindolin-1-one, 3- (4-bromophenyl) isoindolin-1-one, 3- (3-bromophenyl) isoindolin-1-one, one of 3-hydroxy-3- (2-methoxyphenyl) isoindolin-1-one, 3-hydroxy-3- (m-tolyl) isoindolin-1-one, 3-hydroxy-3- (3-methoxyphenyl) isoindolin-1-one, 3- (3, 5-dimethoxyphenyl) -3-hydroxyisoindolin-1-one, and 3-hydroxy-3- (4- (methylthio) phenyl) isoindolin-1-one.

Preferably, the heating temperature is 60-140 ℃, and the stirring time is 6-24 hours.

The spiro isoindolinone compound is prepared by the synthesis method, and the spiro isoindolinone compound has a structural formula as follows:

wherein R is ¹ Selected from hydrogen, alkyl, methoxy, benzene ring, dibenzothiophene, dibenzofuran, dimethylsilane, fluorine, chlorine, bromine, thiomethyl or heterocycle; r is R ² Is chlorine.

Compared with the prior art, the application has the following beneficial technical effects:

the application provides a spiro isoindolinone compound and a synthesis method thereof, wherein the spiro isoindolinone compound and vinylene carbonate which are easy to obtain are used as reaction raw materials, and the spiro isoindolinone compound is obtained through separation and purification under the combined action of a rhodium catalyst and a silver additive by a [3+3] cyclization reaction. The mechanism is that the silver additive activates rhodium catalyst, rhodium coordinates and activates through C-H bond to form five-membered ring ketimine intermediate, then ethylene carbonate migrates and inserts, then nucleophilic addition reaction occurs, finally the product is obtained through protonation.

Further, compared with the traditional method for synthesizing indole derivatives, the synthesis method has the advantages of simple and easily obtained raw materials, simple synthesis route, mild reaction conditions, high efficiency, strong selectivity, no pollution and targetingThe compound is rich in species, and the by-product is CO ₂ And H ₂ O is in accordance with the concept of green chemistry, and effectively solves the problems that byproducts generated in the prior art are toxic, raw materials are difficult to obtain and the yield is low.

Furthermore, the method has good universality of the substrate, and under the optimized reaction condition, the target product is easy to separate, thereby having potential application value in the fields of materials and medicines.

Drawings

FIG. 1 is a diagram of the product of example 1 ¹ H NMR spectrum;

FIG. 2 is a diagram of the product of example 1 ¹³ C NMR spectrum;

FIG. 3 is a diagram of the product of example 2 ¹ H NMR spectrum;

FIG. 4 is a diagram of the product of example 2 ¹³ C NMR spectrum;

FIG. 5 is a diagram of the product of example 3 ¹ H NMR spectrum;

FIG. 6 is a diagram of the product of example 3 ¹³ C NMR spectrum;

FIG. 7 is a diagram of the product of example 4 ¹ H NMR spectrum;

FIG. 8 is a diagram of the product of example 4 ¹³ C NMR spectrum;

FIG. 9 is a diagram of the product of example 5 ¹ H NMR spectrum;

FIG. 10 is a diagram of the product of example 5 ¹³ C NMR spectrum;

FIG. 11 is a diagram of the product of example 6 ¹ H NMR spectrum;

FIG. 12 is a diagram of the product of example 6 ¹³ C NMR spectrum;

FIG. 13 is a photograph of a product prepared in example 7 ¹ H NMR spectrum;

FIG. 14 is a photograph of a product prepared in example 7 ¹³ C NMR spectrum;

FIG. 15 is a photograph of the product of example 8 ¹ H NMR spectrum;

FIG. 16 is a photograph of the sample prepared in example 8The product is ¹³ C NMR spectrum;

FIG. 17 is a photograph of a product prepared in example 9 ¹ H NMR spectrum;

FIG. 18 is a diagram of the product of example 9 ¹³ C NMR spectrum;

FIG. 19 is a diagram of the product of example 10 ¹ H NMR spectrum;

FIG. 20 is a diagram of the product of example 10 ¹³ C NMR spectrum;

FIG. 21 is a photograph of the product of example 11 ¹ H NMR spectrum;

FIG. 22 is a diagram of the product of example 11 ¹³ C NMR spectrum;

FIG. 23 is a photograph of the product of example 12 ¹ H NMR spectrum;

FIG. 24 is a photograph of a product prepared in example 12 ¹³ C NMR spectrum;

FIG. 25 is a photograph of a product prepared in example 13 ¹ H NMR spectrum;

FIG. 26 is a photograph of a product prepared in example 13 ¹³ C NMR spectrum;

FIG. 27 is a photograph of a product prepared in example 14 ¹ H NMR spectrum;

FIG. 28 is a photograph of a product prepared in example 14 ¹³ C NMR spectrum;

FIG. 29 is a photograph of a product prepared in example 15 ¹ H NMR spectrum;

FIG. 30 is a photograph of a product prepared in example 15 ¹³ C NMR spectrum.

FIG. 31 is a photograph of a product prepared in example 16 ¹ H NMR spectrum;

FIG. 32 is a photograph of a product prepared in example 16 ¹³ C NMR spectrum;

FIG. 33 is a photograph of the product of example 17 ¹ H NMR spectrum;

FIG. 34 is a photograph of the product of example 17 ¹³ C NMR spectrum;

FIG. 35 is a photograph of a product prepared in example 18 ¹ H NMR spectrum;

FIG. 36 is a photograph of a sample of the preparation of example 18The product is ¹³ C NMR spectrum.

Detailed Description

The application will now be described in further detail with reference to specific examples, which are intended to illustrate, but not to limit, the application.

A synthesis method of a spiro-isoindolinone compound comprises the steps of adding the isoindolinone compound shown in a formula 1, vinylene carbonate shown in a formula 2, a catalyst and an additive into a solvent, wherein the mass ratio of the isoindolinone compound to the vinylene carbonate is 1:1-1:5, adding the isoindolinone compound, the vinylene carbonate, the catalyst and the additive into the solvent, heating and stirring at 60-140 ℃ for 6-24 hours, and separating and purifying to obtain the spiro-isoindolinone compound shown in a formula 3.

The solvent is one or more of toluene, tetrahydrofuran and dichloroethane.

The following detailed description is of embodiments, and is intended to provide further details of the application. Unless defined otherwise, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the application.

Example 1

Preparation of 5-methylppiro [ isochromene-1,1 '-isoinolin ] -3' -one

First, 0.2mmol of 3-hydroxy-3- (p-tolyl) isoindolin-1-one, 0.6mmol of vinylene carbonate and a catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver hexafluoroantimonate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction is completed, the reactant is cooled to room temperature, concentrated by a decompression rotary evaporator, then the crude product is separated and purified by column chromatography, eluent containing the target product is collected for evaporation concentration, and then the obtained product is pumped by a vacuum oil pump to obtain 37.88mg of white solid compound, wherein the yield is 72%.

The structural formula of the obtained product is as follows: ,

as shown in fig. 1 and 2, the product nuclear magnetism is characterized: ¹ H NMR(400MHz,CDCl ₃ )δ7.85(d,J＝7.2Hz,1H),7.66–7.49(m,3H),7.18(s,1H),6.97(s,1H),6.92(d,J＝8.0Hz,1H),6.71(d,J＝5.7Hz,1H),6.65(d,J＝7.9Hz,1H),6.00(d,J＝5.7Hz,1H),2.32(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ168.5,147.1,143.8,139.5,133.1,130.6,130.2,129.6,128.3,125.2,124.7,124.3,123.7,123.7,104.8,90.1,21.

example 2

Preparation of spiro [ isochromene-1,1 '-isoinolin ] -3' -one

First, 0.2mmol of 3-hydroxy-3-phenylisoindolin-1-one, 0.6mmol of vinylene carbonate and the catalyst Cp [ Rh (CH) were introduced into a 25ml pressure-resistant tube equipped with stirring magnet ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver hexafluoroantimonate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction is completed, the reactant is cooled to room temperature, concentrated by a decompression rotary evaporator, then the crude product is separated and purified by column chromatography, eluent containing the target product is collected for evaporation concentration, and then the obtained product is pumped by a vacuum oil pump to obtain 33.87mg of white solid compound, wherein the yield is 68%.

The structural formula of the obtained product is as follows:

as shown in fig. 3 and 4, the product nuclear magnetism is characterized: ¹ H NMR(400MHz,DMSO)δ9.91(s,1H),7.77–7.69(m,1H),7.67–7.58(m,2H),7.50(d,J＝6.9Hz,1H),7.33(t,J＝7.5Hz,1H),7.23(d,J＝7.6Hz,1H),7.13(t,J＝7.6Hz,1H),6.86(d,J＝5.7Hz,1H),6.70(d,J＝7.7Hz,1H),6.13(d,J＝5.7Hz,1H). ¹³ C NMR(101MHz,DMSO)δ168.0,147.3,144.0,133.2,130.5,130.3,129.8,129.3,128.1,127.4,124.1,124.0,123.4,123.0,104.4,90.0.

example 3

Preparation of 6-methoxospiro [ isochromene-1,1 '-isoinolin ] -3' -one

First, 0.2mmol of 3-hydroxy-3- (4-methoxyphenyl) isoindolin-1-one, 0.6mmol of vinylene carbonate and a catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver acetate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction is completed, the reactant is cooled to room temperature, concentrated by a decompression rotary evaporator, then the crude product is separated and purified by column chromatography, eluent containing the target product is collected for evaporation concentration, and then the obtained product is pumped by a vacuum oil pump to obtain 37.95mg of white solid compound, the yield is 65%, and the obtained product has the following structural formula:

as shown in fig. 5 and 6, the product nuclear magnetism was characterized: ¹ H NMR(400MHz,DMSO)δ9.79(s,1H),7.73(d,J＝5.9Hz,1H),7.68–7.55(m,2H),7.48(d,J＝7.8Hz,1H),6.85(d,J＝5.8Hz,1H),6.82(d,J＝2.6Hz,1H),6.71(d,J＝8.6Hz,1H),6.64(d,J＝8.6Hz,1H),6.09(d,J＝5.8Hz,1H),3.75(s,3H). ¹³ C NMR(101MHz,DMSO)δ167.9,159.8,147.6,144.3,132.9,131.2,130.1,125.4,123.1,122.8,120.3,113.0,108.7,104.1,90.1,55.1.

example 4

Preparation of spiro [ benzo [ h ] isochromene-1,1 '-isoinolin ] -3' -one

First, 0.2mmol of 3-hydroxy-3- (naphthalen-1-yl) isoindolin-1-one, 0.6mmol of vinylene carbonate and a catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver hexafluoroantimonate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction is completed, the reactant is cooled to room temperature, concentrated by a decompression rotary evaporator, then the crude product is separated and purified by column chromatography, eluent containing the target product is collected for evaporation concentration, and then the obtained product is pumped by a vacuum oil pump to obtain 44.86mg of white solid compound, the yield is 75%, and the obtained product has the following structural formula:

as shown in fig. 7 and 8, the product nuclear magnetism was characterized: ¹ H NMR(400MHz,DMSO)δ10.16(s,1H),8.00–7.80(m,3H),7.73–7.57(m,2H),7.49–7.34(m,2H),7.29(t,J＝7.5Hz,1H),7.10(t,J＝7.9Hz,1H),6.98(d,J＝5.5Hz,1H),6.87(d,J＝8.8Hz,1H),6.22(d,J＝5.5Hz,1H). ¹³ C NMR(101MHz,DMSO)δ168.2,149.4,144.0,133.5,133.3,130.5,130.5,130.2,130.1,129.3,128.6,126.6,124.7,124.0,123.6,123.5,122.9,119.4,104.2,90.3.

example 5

Preparation of 6-cyclopyxylspiro (isochrome-1, 1 '-isoinolin-3' -one)

First, 0.2mmol of 3- (4-cyclohexylphenyl) -3-hydroxyisoindolin-1-one, 0.6mmol of vinylene carbonate and the catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver hexafluoroantimonate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. Cooling the reactant to room temperature after the reaction is completed, concentrating by a decompression rotary evaporator, separating and purifying the crude product by column chromatography, collecting eluent containing the target product, evaporating and concentrating, and pumping by a vacuum oil pump to obtain 51.66mg whiteThe solid compound was produced in 78% yield, and the resulting product had the following structural formula:

as shown in fig. 9 and 10, the product nuclear magnetism was characterized: ¹ H NMR(400MHz,DMSO)δ9.92(s,1H),7.79(d,J＝6.9Hz,1H),7.72–7.59(m,2H),7.53(d,J＝6.5Hz,1H),7.13(s,1H),7.02(d,J＝8.0Hz,1H),6.88(d,J＝5.7Hz,1H),6.66(d,J＝7.9Hz,1H),6.15(d,J＝5.7Hz,1H),2.61–2.38(m,1H),1.89–1.65(m,5H),1.50–1.18(m,5H). ¹³ C NMR(101MHz,DMSO)δ167.9,148.7,147.4,143.8,133.0,130.4,130.3,129.7,125.8,125.7,124.0,123.4,122.9,122.2,104.5,90.0,43.6,33.8,33.8,26.3,25.5.

example 6

Preparation of spiro [ benzofuro [3,2-h ] isochromene-1,1 '-isoinolin ] -3' -one

First, 0.2mmol of 3- (dibenzo [ b, d) was introduced into 25ml of a pressure-resistant tube equipped with stirring magnet]Furan-4-yl) -3-hydroxyisoindolin-1-one, 0.6mmol vinylene carbonate and catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver acetate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction is completed, the reactant is cooled to room temperature, concentrated by a decompression rotary evaporator, then the crude product is separated and purified by column chromatography, eluent containing the target product is collected for evaporation concentration, and then the white solid compound with the yield of 66% is obtained after the eluent is pumped by a vacuum oil pump, wherein the structural formula of the obtained product is as follows:

as shown in fig. 11 and 12, the product nuclear magnetism was characterized: ¹ H NMR(400MHz,DMSO)δ10.04(s,1H),8.11(d,J＝7.9Hz,1H),8.02(d,J＝6.6Hz,1H),7.84(d,J＝7.3Hz,1H),7.68–7.55(m,2H),7.48(d,J＝7.4Hz,1H),7.40–7.25(m,3H),7.20–7.13(m,1H),6.99(d,J＝5.7Hz,1H),6.27(d,J＝5.8Hz,1H). ¹³ C NMR(101MHz,DMSO)δ168.2,155.1,150.6,147.9,144.1,132.9,130.4,130.3,129.9,127.4,123.4,123.4,123.2,123.1,122.9,122.1,120.7,119.9,111.3,111.3,103.5,87.6.

example 7

Preparation of 6- (trimethyllyl) spiro (isochromene-1, 1 '-isoinolin-3' -one)

First, 0.2mmol of 3-hydroxy-3- (4- (trimethylsilyl) phenyl) isoindolin-1-one, 0.8mmol of vinylene carbonate and catalyst [ Cp ] IrCl were introduced into a 25ml pressure-resistant tube equipped with stirring magnet ₂ ] ₂ The additive is silver hexafluoroantimonate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction is completed, the reactant is cooled to room temperature, concentrated by a decompression rotary evaporator, then the crude product is separated and purified by column chromatography, eluent containing the target product is collected for evaporation concentration, and then the obtained product is pumped by a vacuum oil pump to be dried, thus 46.88mg of white solid compound can be obtained, the yield is 73%, and the obtained product has the following structural formula:

as shown in fig. 13 and 14, the product nuclear magnetism was characterized: ¹ H NMR(400MHz,CDCl ₃ )δ7.90(d,J＝6.3Hz,1H),7.64(t,J＝8.4Hz,1H),7.58(d,J＝8.1Hz,1H),7.37–7.30(m,2H),7.22(s,1H),6.83–6.75(m,2H),6.12(d,J＝5.7Hz,1H),0.30(s,9H). ¹³ CNMR(101MHz,CDCl ₃ )δ168.6,146.7,143.8,142.4,133.1,132.5,130.5,130.3,129.1,128.7,128.2,123.8,123.7,123.4,105.0,89.9.

example 8

Preparation of 6-fluoropiporo [ isochromene-1,1 '-isoinolin ] -3' -one

First, 0.2mmol of 3- (4-fluorophenyl) -3-hydroxyisoindolin-1-one, 0.6mmol of vinylene carbonate and a catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver hexafluoroantimonate, which is dissolved in toluene, and is oil at 70deg.C after sealing the pressure-resistant tubeStirring in a bath for 12h. After the reaction is completed, cooling the reactant to room temperature, concentrating by using a decompression rotary evaporator, separating and purifying a crude product by using column chromatography, collecting eluent containing a target product, evaporating and concentrating, and pumping by using a vacuum oil pump to obtain 34.72mg of white solid compound, wherein the yield is 65%, and the obtained product has the following structural formula:

as shown in fig. 15 and 16, the product nuclear magnetism was characterized: ¹ H NMR(400MHz,DMSO)δ9.95(s,1H),7.74(d,J＝6.4Hz,1H),7.69–7.58(m,2H),7.50(d,J＝8.0Hz,1H),7.13(d,J＝9.6Hz,1H),7.00–6.89(m,2H),6.79–6.70(m,1H),6.15(d,J＝5.8Hz,1H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ167.9,162.5(d,J＝244.6Hz),147.1,145.3,133.3,132.4(d,J＝9.5Hz),130.6,130.3,126.6(d,J＝9.1Hz),124.1(d,J＝2.9Hz),123.4,123.1,114.0(d,J＝22.4Hz),110.4(d,J＝22.7Hz),103.7,89.9. ¹⁹ FNMR(376MHz,DMSO)δ-112.8.

example 9

Preparation of 6-chlorospiro [ isochromene-1,1 '-isoinolin ] -3' -one

First, 0.2mmol of 3- (4-chlorophenyl) -3-hydroxyisoindolin-1-one, 0.6mmol of vinylene carbonate and the catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver acetate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction is completed, the reactant is cooled to room temperature, concentrated by a decompression rotary evaporator, then the crude product is separated and purified by column chromatography, eluent containing the target product is collected for evaporation concentration, and then the obtained product is pumped by a vacuum oil pump to be dried, thus 38.49mg of white solid compound with the yield of 68% is obtained, and the obtained product has the following structural formula:

as shown in fig. 17 and 18, the product nuclear magnetism was characterized: ¹ H NMR(400MHz,DMSO)δ9.97(s,1H),7.79–7.72(m,1H),7.70–7.60(m,2H),7.51(d,J＝6.9Hz,1H),7.37(d,J＝2.2Hz,1H),7.18(d,J＝8.3Hz,1H),6.94(d,J＝5.7Hz,1H),6.70(d,J＝8.3Hz,1H),6.15(d,J＝5.7Hz,1H). ¹³ C NMR(101MHz,DMSO)δ167.9,147.0,145.4,133.9,133.3,132.0,130.7,130.3,127.0,126.7,126.2,123.5,123.4,123.1,103.4,89.7.

example 10

Preparation of 6-bromosporiro [ isochromene-1,1 '-isoinolin ] -3' -one

First, 0.2mmol of 3- (4-bromophenyl) -3-hydroxyisoindolin-1-one, 0.6mmol of vinylene carbonate and a catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver hexafluoroantimonate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction is completed, cooling the reactant to room temperature, concentrating by using a decompression rotary evaporator, separating and purifying a crude product by using column chromatography, collecting eluent containing a target product, evaporating and concentrating, and pumping by using a vacuum oil pump to obtain 45.77mg of white solid compound, wherein the yield is 70%, and the obtained product has the following structural formula:

as shown in fig. 19 and 20, the product nuclear magnetic characterization: ¹ H NMR(400MHz,DMSO)δ9.97(d,J＝2.9Hz,1H),7.74(d,J＝7.6Hz,1H),7.68–7.58(m,2H),7.55–7.46(m,2H),7.31(d,J＝8.3Hz,1H),6.93(d,J＝5.7Hz,1H),6.65(d,J＝8.3Hz,1H),6.15(d,J＝5.8Hz,1H). ¹³ C NMR(101MHz,DMSO)δ167.9,146.9,145.4,133.3,132.3,130.6,130.3,129.9,127.1,126.4,126.3,123.4,123.1,122.5,103.3,89.8.

example 11

Preparation of spiro [ benzo [4,5] thiano [2,3-g ] isochromene-1,1 '-isohendolin ] -3' -one

First, 0.2mmol of 3-D-C was introduced into 25ml of a pressure-resistant tube equipped with a stirring magnet(dibenzo [ b, d)]Thiophene-2-yl) -3-hydroxy isoindolin-1-one, 0.6mmol vinylene carbonate and catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver hexafluoroantimonate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction is completed, the reactant is cooled to room temperature, concentrated by a decompression rotary evaporator, then the crude product is separated and purified by column chromatography, eluent containing the target product is collected for evaporation concentration, and then the eluent is pumped by a vacuum oil pump to be dried, thus 51.84mg of white solid compound can be obtained, the yield is 73%, and the obtained product has the following structural formula:

as shown in fig. 21 and 22, the product nuclear magnetism was characterized: ¹ H NMR(400MHz,DMSO)δ9.98(s,1H),8.14(d,J＝7.8Hz,1H),7.96(t,J＝6.6Hz,1H),7.90(d,J＝4.6Hz,1H),7.78(d,J＝5.2Hz,2H),7.67–7.58(m,2H),7.58–7.51(m,1H),7.47–7.39(m,1H),7.39–7.31(m,1H),6.94(t,J＝5.7Hz,1H),6.26(t,J＝5.6Hz,1H). ¹³ C NMR(101MHz,DMSO)δ168.4,147.6,144.7,139.7,138.4,134.7,134.0,133.2,130.5,129.9,129.2,127.0,125.9,124.8,123.2,123.1,123.0,122.0,118.0,117.6,104.5,90.7.

example 12

Preparation of 5' -bromosporiro [ isochromene-1,1' -isoinolin ] -3' -one

First, 0.2mmol of 6-bromo-3-hydroxy-3-phenylisoindolin-1-one, 0.6mmol of vinylene carbonate and catalyst [ Cp ] IrCl were introduced into 25ml of pressure-resistant tube equipped with stirring magnet ₂ ] ₂ The additive is silver hexafluoroantimonate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction is completed, the reactant is cooled to room temperature, concentrated by a decompression rotary evaporator, then the crude product is separated and purified by column chromatography, eluent containing the target product is collected for evaporation concentration, and then the eluent is pumped by a vacuum oil pump to be dried, thus obtaining 50.35mg of white solid compound with the yield of 77%, and the obtained product has the following structural formula:

as shown in fig. 23 and 24, the product nuclear magnetism was characterized: ¹ H NMR(400MHz,DMSO)δ10.09(s,1H),7.88(d,J＝1.9Hz,1H),7.82(d,J＝8.0Hz,1H),7.46(d,J＝8.1Hz,1H),7.34(t,J＝7.5Hz,1H),7.24(d,J＝7.6Hz,1H),7.14(t,J＝7.6Hz,1H),6.86(d,J＝5.7Hz,1H),6.74(d,J＝7.8Hz,1H),6.15(d,J＝5.7Hz,1H). ¹³ C NMR(101MHz,DMSO)δ166.4,146.2,143.9,135.9,132.7,129.7,129.5,127.5,127.4,125.9,125.6,124.2,124.1,123.7,104.5,89.8.

example 13

Preparation of 8-methylppiro [ isochromene-1,1 '-isoinolin ] -3' -one

First, 0.2mmol of 3-hydroxy-3- (o-tolyl) isoindolin-1-one, 0.6mmol of vinylene carbonate and a catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver hexafluoroantimonate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction is completed, the reactant is cooled to room temperature, concentrated by a decompression rotary evaporator, then the crude product is separated and purified by column chromatography, eluent containing the target product is collected for evaporation concentration, and then the eluent is pumped by a vacuum oil pump to be dried, thus 39.98mg of white solid compound can be obtained, the yield is 76%, and the obtained product has the following structural formula:

as shown in fig. 25 and 26, the product nuclear magnetism was characterized: ¹ H NMR(400MHz,DMSO)δ9.90(s,1H),7.76(d,J＝5.1Hz,1H),7.66–7.54(m,2H),7.39(d,J＝7.8Hz,1H),7.23(t,J＝7.6Hz,1H),7.09(d,J＝7.5Hz,1H),6.95(d,J＝7.5Hz,1H),6.80(d,J＝5.6Hz,1H),6.03(d,J＝5.6Hz,1H),1.55(s,3H). ¹³ C NMR(101MHz,DMSO)δ168.4,148.3,143.0,134.4,133.1,131.1,130.9,130.4,130.3,129.1,125.1,123.2,123.2,123.1,103.9,89.9,20.3.

example 14

Preparation of 8-methoxospiro [ isochromene-1,1 '-isoinolin ] -3' -one

First, 0.2mmol of 3-hydroxy-3- (2-methoxyphenyl) isoindolin-1-one, 0.4mmol of vinylene carbonate and a catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver tetrafluoroborate, all of which is dissolved in toluene, and the mixture is stirred for 12 hours in an oil bath at 70 ℃ after a pressure-resistant pipe is closed. After the reaction is completed, the reactant is cooled to room temperature, concentrated by a decompression rotary evaporator, then the crude product is separated and purified by column chromatography, eluent containing the target product is collected for evaporation concentration, and then the obtained product is pumped by a vacuum oil pump to be dried, thus 38.51mg of white solid compound is obtained, the yield is 69%, and the obtained product has the following structural formula:

as shown in fig. 27 and 28, the product nuclear magnetic characterization: ¹ H NMR(400MHz,DMSO)δ9.59(s,1H),7.67(d,J＝7.1Hz,1H),7.53(t,J＝9.5Hz,2H),7.38–7.25(m,2H),6.87–6.74(m,3H),5.99(d,J＝2.9Hz,1H),3.20(d,J＝3.0Hz,3H). ¹³ C NMR(101MHz,DMSO)δ168.3,155.4,149.9,143.5,132.1,131.4,130.6,130.0,128.9,122.2,122.0,116.9,115.0,111.1,102.7,87.9,55.5.

example 15

Preparation of 7-methylppiro [ isochromene-1,1 '-isoinolin ] -3' -one

First, 0.2mmol of 3-hydroxy-3- (m-tolyl) isoindolin-1-one, 0.6mmol of vinylene carbonate and a catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver tetrafluoroborate, all of which is dissolved in toluene, and the mixture is stirred for 12 hours in an oil bath at 70 ℃ after a pressure-resistant pipe is closed. Cooling the reaction product to room temperature after the reaction is completed, concentrating the reaction product by a reduced pressure rotary evaporator, separating and purifying the crude product by column chromatography, collecting eluent containing the target product, and feedingEvaporating and concentrating, and pumping by a vacuum oil pump to obtain 42.09mg of white solid compound with the yield of 80%, wherein the structural formula of the obtained product is as follows:

as shown in fig. 29 and 30, the product nuclear magnetic characterization: ¹ H NMR(400MHz,DMSO)δ9.78(s,1H),7.72(d,J＝6.0Hz,1H),7.66–7.57(m,2H),7.48(d,J＝6.6Hz,1H),7.13(d,J＝2.6Hz,2H),6.79(d,J＝5.7Hz,1H),6.54(s,1H),6.08(d,J＝5.7Hz,1H),2.15(s,3H). ¹³ C NMR(101MHz,DMSO)δ167.9,147.4,143.0,136.6,133.0,130.2,130.1,129.8,128.0,127.1,124.1,124.0,123.2,122.9,104.1,90.0,20.7.

example 16

Preparation of 7-methoxospiro [ isochromene-1,1 '-isoinolin ] -3' -one

First, 0.2mmol of 3-hydroxy-3- (3-methoxyphenyl) isoindolin-1-one, 0.6mmol of vinylene carbonate and a catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver hexafluoroantimonate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction is completed, the reactant is cooled to room temperature, concentrated by a decompression rotary evaporator, then the crude product is separated and purified by column chromatography, eluent containing the target product is collected for evaporation concentration, and then the obtained product is pumped by a vacuum oil pump to be dried, thus 37.39mg of white solid compound is obtained, the yield is 67%, and the obtained product has the following structural formula:

as shown in fig. 31 and 32, the product nuclear magnetism was characterized: ¹ H NMR(400MHz,DMSO)δ9.89(s,1H),7.73(d,J＝6.1Hz,1H),7.69–7.58(m,2H),7.49(d,J＝6.4Hz,1H),7.10(t,J＝8.0Hz,1H),6.99(d,J＝8.2Hz,1H),6.85(d,J＝5.8Hz,1H),6.31–6.22(m,2H),3.84(s,3H). ¹³ C NMR(101MHz,DMSO)δ167.9,152.6,147.2,143.4,133.1,130.4,128.8,128.1,123.5,123.0,118.8,116.0,111.1,98.7,89.7,55.7.

example 17

Preparation of 5, 7-Dimethoxospiro (isochrome-1, 1 '-isoinolin-3' -one)

First, 0.2mmol of 3- (3, 5-dimethoxyphenyl) -3-hydroxyisoindolin-1-one, 0.6mmol of vinylene carbonate and catalyst [ Cp ] IrCl are introduced into a 25ml pressure-resistant tube equipped with stirring magnet ₂ ] ₂ The additive is silver hexafluoroantimonate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction is completed, cooling the reactant to room temperature, concentrating by using a decompression rotary evaporator, separating and purifying a crude product by using column chromatography, collecting eluent containing a target product, evaporating and concentrating, and pumping by using a vacuum oil pump to obtain 40.18mg of white solid compound, wherein the yield is 65%, and the obtained product has the following structural formula:

as shown in fig. 33 and 34, the product nuclear magnetism was characterized: ¹ H NMR(400MHz,DMSO)δ9.84(d,J＝6.3Hz,1H),7.73(d,J＝6.0Hz,1H),7.67–7.56(m,2H),7.50(d,J＝5.7Hz,1H),6.72(d,J＝5.8Hz,1H),6.60(s,1H),6.20(d,J＝5.5Hz,1H),5.86(d,J＝2.5Hz,1H),3.84(s,3H),3.60(s,3H). ¹³ C NMR(101MHz,DMSO)δ168.2,159.6,154.3,147.1,141.2,133.1,130.4,130.3,129.9,123.3,123.0,112.1,100.6,99.0,98.6,89.9,55.8,55.3.

example 18

Preparation of 6' -bromosporiro [ isochromene-1,1' -isoinolin ] -3' -one

First, 0.2mmol of 5-bromo-3-hydroxy-3-phenylisoindolin-1-one, 0.6mmol of vinylene carbonate and a catalyst Cp [ Rh (CH) ₃ CN) ₃ ][SbF ₆ ] ₂ The additive is silver hexafluoroantimonate, all of which is dissolved in toluene, and the mixture is stirred in an oil bath at 70 ℃ for 12 hours after the pressure-resistant pipe is closed. After the reaction was completed, the reaction was cooled to room temperature, usingConcentrating by a reduced pressure rotary evaporator, separating and purifying the crude product by column chromatography, collecting eluent containing the target product, evaporating and concentrating, and pumping by a vacuum oil pump to obtain 51.01mg of white solid compound, wherein the yield is 78%, and the obtained product has the following structural formula:

as shown in fig. 35 and 36, the product nuclear magnetism was characterized: ¹ H NMR(400MHz,DMSO)δ10.04(s,1H),7.82(d,J＝8.0Hz,1H),7.68(d,J＝4.8Hz,2H),7.35(t,J＝7.5Hz,1H),7.25(d,J＝7.6Hz,1H),7.16(t,J＝7.6Hz,1H),6.87(d,J＝5.7Hz,1H),6.76(d,J＝7.7Hz,1H),6.15(d,J＝5.7Hz,1H). ¹³ C NMR(101MHz,DMSO)δ167.0,149.2,143.9,133.8,129.7,129.6,129.5,127.6,127.4,126.6,126.3,125.2,124.3,124.1,104.5,89.6。

the above description is only of the preferred embodiments of the present application, and is not intended to limit the present application in any way; those skilled in the art will readily appreciate that the present application may be implemented as shown in the drawings and described above; however, those skilled in the art will appreciate that many modifications, adaptations, and variations of the present application are possible in light of the above teachings without departing from the scope of the application; meanwhile, any equivalent changes, modifications and evolution of the above embodiments according to the essential technology of the present application still fall within the scope of the present application.

Claims

1. The synthesis method of the spiro isoindolinone compound is characterized by comprising the following steps of:

adding isoindolinone compound, vinylene carbonate, rhodium catalyst and silver additive into organic solvent, heating and stirring under air condition, separating and purifying to obtain the final product.

2. The method for synthesizing the spiroisoindolinone compound according to claim 1, wherein the spiroisoindolinone compound has a reaction formula:

wherein R is ¹ Selected from hydrogen, alkyl, methoxy, benzene ring, cyclohexane, dibenzothiophene, dibenzofuran, dimethylsilane, fluorine, chlorine, bromine, thiomethyl or heterocycle; r is R ² Is chlorine.

3. The method for synthesizing the spiro isoindolinone compound according to claim 1, wherein the specific separation and purification process is as follows: and cooling the reacted reactant to room temperature, concentrating under reduced pressure, performing chromatographic separation and purification, collecting eluent containing a target product, and performing evaporation concentration to obtain the spiroisoindolinone compound.

4. The method for synthesizing the spiro isoindolinone according to claim 1, wherein the ratio of the amounts of the isoindolinone and the vinylene carbonate is 1:1-1:5; the concentration of the isoindolinone compound in the organic solvent is 0.1-1.5 mol/L.

5. The method for synthesizing a spiro isoindolinone according to claim 1, wherein the organic solvent comprises one or more of toluene, tetrahydrofuran and dichloroethane.

6. The method for synthesizing a spiro isoindolinone according to claim 1, wherein the rhodium catalyst is Cp [ Rh (CH ₃ CN) ₃ ][SbF ₆ ] ₂ Or [ Cp ] IrCl ₂ ] ₂ 。

7. The method for synthesizing a spiro isoindolinone according to claim 1, wherein the silver additive is one of silver hexafluoroantimonate, silver acetate and silver tetrafluoroborate.

8. The method for synthesizing spiroisoindolinone according to claim 1, wherein the isoindolinone comprises 3-hydroxy-3- (p-tolyl) isoindoline-1-one, 3-hydroxy-3-phenylisoindoline-1-one, 3-hydroxy-3- (4-methoxyphenyl) isoindoline-1-one, 3-hydroxy-3- (naphthalen-1-yl) isoindoline-1-one, 3- (4-cyclohexylphenyl) -3-hydroxyisoindoline-1-one, 3- (dibenzo [ b, d ] furan-4-yl) -3-hydroxyisoindoline-1-one, 3-hydroxy-3- (4- (trimethylsilyl) phenyl) isoindoline-1-one, 3- (4-fluorophenyl) -3-hydroxyisoindoline-1-one, 3- (4-chlorophenyl) -3-hydroxyisoindoline-1-one, 3- (4-bromophenyl) -3-hydroxyisoindoline-1-one, 3- (4-chlorophenyl) -3-hydroxyisoindoline-1-one, 3- (3-hydroxy-4-phenylo-4-yl) isoindoline-1-one, 3- (3-hydroxy-4-phenylo-4-phenyl) -3-hydroxyisoindoline-1-one, 3-hydroxy-2-phenylo-3-hydroxy isoindoline-1-one One of 3-hydroxy-3- (o-tolyl) isoindolin-1-one, 3-hydroxy-3- (2-methoxyphenyl) isoindolin-1-one, 3-hydroxy-3- (m-tolyl) isoindolin-1-one, 3-hydroxy-3- (3-methoxyphenyl) isoindolin-1-one, 3- (3, 5-dimethoxyphenyl) -3-hydroxyisoindolin-1-one, and 3-hydroxy-3- (4- (methylthio) phenyl) isoindolin-1-one.

9. The method for synthesizing the spiro isoindolinone compound according to claim 1, wherein the heating temperature is 60-140 ℃ and the stirring time is 6-24 h.

10. A spiroisoindolinone compound, characterized in that it is prepared based on the synthesis method of any one of claims 1-9, and has the structural formula:

wherein R is ¹ Selected from hydrogen, alkylMethoxy, benzene ring, dibenzothiophene, dibenzofuran, dimethylsilane, fluorine, chlorine, bromine, thiomethyl or heterocycle; r is R ² Is chlorine.