An isoindolinone compound, a preparation method and application thereof

Abstract

The application discloses an isoindolinone compound and a preparation method and application thereof, and the isoindolinone compound has a structure shown in formula (IV); wherein, n is greater than or equal to 1; R 1 and R 3 are independently selected from H, C 1～10 alkyl, C 1～10 alkoxy, halogen, ester, substituted or unsubstituted phenyl; or R 1 and R 3 are cycled through a C 2～15 alkyl chain; R 2 is connected to the A ring through a single bond, R 2 is selected from H, C 1～10 alkyl, C 1～10 alkoxy, halogen, ester, substituted or unsubstituted phenyl, alkenyl, cyano; or R 2 forms a fused ring with the A ring; and R 2 includes phenyl or dioxolane. The isoindolinone compound shown in the application has high anti-inflammatory effect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to an isoindolinone compound and a preparation method and application thereof. BACKGROUND

[0002] The isoindolinone compound is a special nitrogen-containing benzoheterocyclic compound, is an important skeleton of natural products, has numerous physiological activities, such as anti-hyperlipidemia, antibacterial, antimicrobial, anti-inflammatory and anticancer, and the like; in particular, in recent years. The anti-inflammatory effect of the isoindolinone compound in the prior art is poor.

[0003] In summary, it is necessary to provide a new isoindolinone compound which has high anti-inflammatory effect. SUMMARY

[0004] The present application aims at at least solving one of the problems in the prior art. To this end, the present application provides, in a first aspect, an isoindolinone compound which has high anti-inflammatory effect.

[0005] The present application provides, in a second aspect, a preparation method of the isoindolinone compound.

[0006] The present application provides, in a third aspect, an application of the isoindolinone compound.

[0007] According to the first aspect of the present application, the isoindolinone compound has the structure shown in formula (IV).

[0008]

[0009] wherein n is greater than or equal to 1; R 1 and R 3 are independently selected from H, C 1～10 alkyl, C 1～10 alkoxy, halogen, ester group, substituted or unsubstituted phenyl; or R 1 and R 3 are cyclized through a C 2～15 alkyl chain.

[0010] R 2 is connected to the A ring through a single bond, R 2 is selected from H, C 1～10 alkyl, C 1～10 alkoxy, halogen, ester group, substituted or unsubstituted phenyl, alkenyl, cyano;

[0011] or R 2 forms a fused ring with the A ring; R 2 includes phenyl or dioxolane group.

[0012] The isoindolinone compound according to the embodiments of the present application has at least the following beneficial effects:

[0013] The present application develops a series of isoindolinone compounds shown in formula (IV), which has high anti-inflammatory effect.

[0014] According to some embodiments of the present application, R 1 and R 3 are independently selected from H, C 1～6 alkyl, C 1～6 alkoxy, halogen, C1-C5 ester group, substituted or unsubstituted phenyl; or R 1 and R 3 are cycled through C 2～10 alkyl chain;

[0015] According to some embodiments of the present application, R 2 is connected to the A ring through a single bond, R 2 is selected from H, C 1～10 alkyl, C 1～10 alkoxy, halogen, C1-C5 ester group, substituted or unsubstituted phenyl, C1-C5 alkenyl, cyano;

[0016] or R 2 forms a fused ring with the A ring; R 2 includes phenyl or dioxolane group.

[0017] According to some embodiments of the application, the isoindolinone compound is selected from the group consisting of 2-benzoyl-3-hydroxy-3-phenylisoindolin-1-one, 2-(3-chlorobenzoyl)-3-(3-chlorophenyl)-3-hydroxyisoindolin-1-one, 2-(4-bromobenzoyl)-3-(4-bromophenyl)-3-hydroxyisoindolin-1-one, ethyl 4-(2-(4-(ethoxycarbonyl)benzoyl)-1-hydroxy-3-isoindolin-1-yl)benzoate, 3-hydroxy-2-(4-methylbenzoyl)-3-(p-tolyl)isoindolin-1-one, 2-benzoyl-3-hydroxy-6-methyl-3-phenylisoindolin-1-one, 2-benzoyl-3-hydroxy-3-phenyl-5-vinylisoindolin-1-one, 2-benzoyl-3-hydroxy-1-oxo-3-phenylisoindoline-5-carbonitrile, 2-benzoyl-3-hydroxy-7-methyl-3-phenylisoindolin-1-one, 2-benzoyl-3-hydroxy-1-oxo-3-phenylisoindoline-5-carboxylate, 6-benzoyl-7-hydroxy-7-phenyl-6,7-dihydro-5H-[1,3]dioxepino[4,5-f]isoindol-5-one, 2-benzoyl-3-hydroxy-5,6-dimethoxy-3-phenylisoindolin-1-one, 2-benzoyl-3-hydroxy-5-iodo-3-phenylisoindolin-1-one, 2-benzoyl-5-(tert-butyl)-3-hydroxy-3-phenylisoindolin-1-one, 2-benzoyl-5-chloro-3-hydroxy-3-phenylisoindolin-1-one, 2-benzoyl-3-hydroxy-3,6-diphenylisoindolin-1-one, 2-benzoyl-4,6-dimethyl-3-phenylisoindolin-1-one, 2-butyryl-3-hydroxy-3-propylisoindolin-1-one, 2-benzoyl-3-hydroxy-3-methylisoindolin-1-one, 2-benzoyl-3-hydroxy-3-phenyl-2,3-dihydro-1H-benzoisoindol-1-one, 2-(2-fluorobenzoyl)-3-(2-fluorophenyl)-3-hydroxyisoindolin-1-one, 2-(4-chlorobenzoyl)-3-(4-chlorophenyl)-3-hydroxy-5,7-dimethylisoindolin-1-one, 2-acetyl-1-hydroxy-3-isoindolin-1-carboxylic acid ethyl ester, 2-acetyl-1-hydroxy-3-isoindolin-1-carboxylic acid tert-butyl ester, 2-butyryl-1-hydroxy-3-isoindolin-1-carboxylic acid methyl ester, 10b-hydroxy-1,2,3,10b-tetrahydropyrano[2,1-a]isoindole-4,6-dione, 11a-hydroxy-9,10,11,11a-tetrahydro-5H-azapyrano[2,1-a]isoindole-5,7(8H)-dione, 9b-hydroxy-1,9b-dihydro-3H-pyrrolo[2,1-a]isoindole-3,5(2H)-dione, 13a-hydroxy-9,10,11,12,13,13a-hexahydro-5H-azapyrano[2,1-a]isoindole-5,7(8H)-dione, 12a-hydroxy-8,9,10,11,12,12a-hexahydroazapyrano[2,1-a]isoindole-5,7-dione, 17a-hydroxy-9,10,11,12,13,14,15,16,17,17a-decahydro-5H-[1]azacyclotrideceno[2,1-a]isoindole-5,7(8H)-dione, 2-benzoyl-3-hydroxy-3-(p-tolyl)isoindolin-1-one, 3-hydroxy-3-phenyl-2-(4-(trifluoromethyl)benzoyl)isoindolin-1-one.

[0018] According to the second aspect of the present application, a preparation method of an isoindolinone compound is provided, comprising the following steps:

[0019] The compound shown in formula (IV) is obtained by mixing and reacting the compound shown in formula (I), the compound shown in formula (II) and a solvent.

[0020] The structural formula of the compound shown in formula (I) and the compound shown in formula (II) is as follows:

[0021]

[0022] According to the preparation method of the present application, at least the following beneficial effects are achieved:

[0023] The isoindolinone compound is directly constructed in one step under the action of the m-chloroperoxybenzoic acid in the preparation raw material of the present application. The preparation raw material of the present application is simple, environment-friendly and low in price; the reaction condition is mild, the operation is simple and the yield is high; the reaction can be carried out without adding a transition metal catalyst; the post-treatment of the reaction is simple and suitable for industrial production.

[0024] According to some embodiments of the present application, the molar ratio of the compound shown in formula (I) and the compound shown in formula (II) is 1:(1-3).

[0025] According to some embodiments of the present application, the solvent is selected from at least one of dichloroethane, trifluoroethanol, tetrahydrofuran or acetonitrile.

[0026] According to some embodiments of the present application, the volume molar ratio of the solvent to the compound of formula (I) is (10-30) mL / mmol.

[0027] According to some embodiments of the present application, the temperature of the reaction is 30-100℃. For example, the temperature of the specific reaction in the examples can be about 40℃.

[0028] According to some embodiments of the present application, the time of the reaction is 12-24h.

[0029] According to some embodiments of the present application, after the reaction is completed, quenching, extraction, washing, concentration and column chromatography are further included.

[0030] According to some embodiments of the present application, after the reaction is completed, pure water is added to quench the reaction, ethyl acetate is added for washing, the organic phase is obtained by separation of layers, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, dried, and the solvent is removed by distillation under reduced pressure, and then column chromatography is performed.

[0031] The third aspect of the present application provides the use of the above-mentioned isoindolinone compound in the preparation of anti-inflammatory drugs, antibacterial drugs and anticancer drugs.

[0032] Definitions and general terms

[0033] As used herein, "substituted or unsubstituted" means that a group can or can not be further substituted with one or more groups selected from C 1～10 alkyl, C 1～10 alkoxy, nitro, halogen, hydroxyl, cyano, carboxyl, C 2～5 ester, C 1～10 haloalkyl.

[0034] "C 1～10 alkyl" means an alkyl group having a total number of carbon atoms of 1-10, including C 1～10 linear alkyl, C 1～10 branched alkyl and C 3～10 cycloalkyl, for example, can be a linear alkyl group having a total number of carbon atoms of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, a branched alkyl group having a total number of carbon atoms of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or a cycloalkyl group having a total number of carbon atoms of 3, 4, 5, 6, 7, 8, 9 or 10, for example, can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, etc. "C 1～6"alkyl" has a similar interpretation, except that the number of carbon atoms is different.

[0035] “C 1～10 "Alkoxy" refers to alkoxy groups with a total number of carbon atoms of 1-10, including C1-10 straight-chain alkoxy groups, C1-10 branched-chain alkoxy groups, and C2-10 cycloalkoxy groups. For example, it can be a straight-chain alkoxy group with a total number of carbon atoms of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; a branched-chain alkoxy group with a total number of carbon atoms of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or a cycloalkoxy group with a total number of carbon atoms of 2, 3, 4, 5, 6, 7, 8, 9, or 10, such as methoxy, ethoxy, n-propoxy, isopropoxy, etc. "C 1～6 The "alkoxy group" has a similar explanation, except that the number of carbon atoms is different.

[0036] “C 1～10 "halogenated alkyl" and "C" 1～10 The definition of "alkyl" is similar, except that the optional H atom in the alkyl group is replaced by a halogen.

[0037] "Substituted or unsubstituted phenyl" means that at least one H in the phenyl group is optionally substituted by the corresponding group defined herein.

[0038] "Ester group" indicates the structural formula is The ester group, wherein C 2～5 The ester group is represented by an ester group with a total number of carbon atoms of 2 to 5. Representative examples include methyl formate, ethyl formate, ethyl acetate, methyl acetate, etc.

[0039] “C 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having one or more double bonds, and the total number of carbon atoms in the alkenyl group is 2-6, and the double bonds in the group can be in any position.

[0040] "Halogen" includes any one or more of fluorine, chlorine, bromine, and iodine.

[0041] Unless otherwise specified, the term "about" in this invention actually means that the error is allowed to be within ±2%, for example, about 100 is actually 100 ± 2% × 100.

[0042] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. Attached Figure Description

[0043] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0044] Figure 1 is a graph of anti-inflammatory activity of the compounds prepared in Examples 1-4, Example 6, Example 12, Example 15, and Example 19 of the present application. DETAILED DESCRIPTION

[0045] The following are specific examples of the present application, and the technical solutions of the present application are further described in combination with the examples, but the present application is not limited to these examples.

[0046] The reagents, methods and equipment used in the present application are all conventional reagents, methods and equipment in the technical field unless otherwise specified.

[0047] The yield calculation method of the present application embodiment is: yield = product mass / (molecular weight * amount of material fed).

[0048] Example 1

[0049] Example 1 provides an isoindolinone compound, the chemical name of which is 2-benzoyl-3-hydroxy-3-phenylisoindolin-1-one, the structural formula and preparation method of which are as follows:

[0050]

[0051] Take 15 mL pressure-resistant tube, add meta-chloro peroxybenzoic acid (CAS number: 937-14-4) 86.2 mg (0.50 mmol), 3,4-diphenylisoquinoline-1 (2H)-ketone (CAS number: 93119-96-1) 60.0 mg (0.20 mmol) and dichloroethane (CAS number: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is completed, add sodium bicarbonate (CAS number: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL water to quench the reaction, then add 10 mL ethyl acetate (CAS number: 141-78-6) and 5 mL saturated brine to wash, collect the organic phase after separation, extract the aqueal phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify the product by column chromatography, the eluent being a mixture of petroleum ether and ethyl acetate (PE / EA = 4 / 1, Rf = 0.39), the product after purification is 60.5 mg of white powder, with a yield of 92%.

[0052] The characterization data of the product are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.90 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.7 Hz, 2H), 7.65 - 7.61 (m, 3H), 7.58 (m, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.41 - 7.36 (m, 3H), 7.33 (d, J = 7.6 Hz, 1H), 5.86 (s, 1H). 13 C NMR (126 MHz, Chloroform-d) δ 172.1, 166.2, 148.0, 140.6, 135.2, 134.2, 132.6, 130.2, 129.1, 129.0, 128.8, 128.3, 128.030, 125.2, 124.8, 123.4, 93.2. ESI-MS: calculated for C 21 H 15 NO3[M+Na] + : 352.0944, found: 352.0952.

[0053] Example 2

[0054] Example 2 provides an isoindolinone compound, chemical name 2-(3-chlorobenzoyl)-3-(3- chlorophenyl)-3-hydroxyisoindolin-l-one, structural formula and preparation method as follows:

[0055]

[0056] Take 15 mL pressure tube, add meta-chloro peroxibenzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 3,4-bis(3-chlorophenyl)isoquinoline-l(2H)-one (CAS No: 2608586-53-2) 73.2 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05M), temperature 40°C, reaction for 24h, after the reaction is completed, add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL water to quench the reaction, then add 10 mL ethyl acetate (CAS No: 141-78-6) and 5 mL saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, the eluent is a mixture of petroleum ether and ethyl acetate (PE / EA = 4 / 1, Rf = 0.34), the product after purification is 58.9 mg of white powder, with a yield of 74%. The characterization data of the product are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 7.6 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.64 (d, J = 7.7 Hz, 2H), 7.59 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 7.7 Hz, 2H), 5.73 (s, 1H). 13 C NMR (126 MHz, CDC13) δ 170.5, 165.8, 147.4, 142.6, 135.7, 135.6, 135.2, 134.2, 132.6, 130.6, 130.4, 129.3, 129.1, 129.0, 127.9, 127.0, 125.5, 125.3, 123.4, 122.9, 92.4. ESI-MS: calculated for C 21 H 13 Cl2NO3[M+Na] + : 420.0164, found: 420.0166.

[0057] Example 3

[0058] Example 3 provides an isoindolinone compound, 2-(4-bromobenzoyl)-3-(4- bromophenyl)-3-hydroxyisoindolin-l-one, with chemical name, structural formula and preparation method as follows:

[0059]

[0060] Take 15 mL pressure tube, add meta-chloro peroxy benzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 3,4-bis(4-bromophenyl)isoquinolin-1(2H)-one (CAS No: 2328084-68-8) 91.0 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05 M), temperature 40 °C, reaction 24 h, after the reaction is complete, add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3 h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, the eluent is a mixture of petroleum ether and ethyl acetate (PE / EA = 4 / 1, Rf = 0.33), the product after purification is 81.8 mg of white powder, the yield is 84%. The characterization data of the product are:

[0061] 1 H NMR (500 MHz, Chloroform-d) δ 7.90 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.60 (d, J = 7.7 Hz, 2H), 7.55 (t, J = 7.7 Hz, 3H), 7.51 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 7.7 Hz, 1H), 5.84 (s, 1H). 13 C NMR (126 MHz, CDCl3) δ 171.1, 166.0, 147.5, 139.6, 135.5, 132.7, 132.2, 131.4, 130.7, 130.5, 128.0, 127.8, 126.6, 125.4, 123.3, 123.1, 92.7. ESI-MS: calculated for C 21 H 13 Br2NO3[M+Na] + : 507.9154, found: 507.9148.

[0062] Example 4

[0063] Example 4 provides an isoindolinone compound, the chemical name of which is ethyl 4-(2-(4-(ethoxycarbonyl)benzoyl)-1-hydroxy-3-isoindolin-1-yl)benzoate, the structural formula and preparation method of which are as follows:

[0064]

[0065] Take 15 mL pressure tube, add m-chloroperbenzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 4,4'-(1-oxo-1,2-dihydroisoquinoline-3,4-diyl)dibenzoate diethyl ester (CAS No: 2323112-66-7) 88.2 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05 M), temperature 40 °C, reaction for 24 h, after the reaction is complete, add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3 h. After the reaction is complete, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time using 5 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, using a mixture of petroleum ether and ethyl acetate (PE / EA = 4 / 1, Rf = 0.3) as the eluent, the product is white powder after purification, with a yield of 83.3 mg, 88%. The characterization data of the product are as follows:

[0066] 1 H NMR (500 MHz, Chloroform-d) δ 8.14 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.70 - 7.64 (m, 3H), 7.58 (t, J = 7.2 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 5.70 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 171.0, 165.9, 165.9, 165.7, 147.3, 145.2, 137.8, 135.6, 133.7, 131.0, 130.6, 130.4, 129.2, 128.6, 127.9, 125.5, 124.8, 123.4, 92.6, 61.4, 61.2, 14.3. ESI-MS: calculated for C 27 H 23 NO7[M+Na] + :496.1366, found:496.1370.

[0067] Example 5

[0068] Example 5 provides an isoindolinone compound, chemical name 3-hydroxy-2-(4- methylbenzoyl)-3-(p-tolyl)isoindolin-1-one, structural formula and preparation method as follows:

[0069]

[0070] Take 15 mL pressure tube, add m-chloroperbenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 3,4-di-p-tolylisoquinolin-1(2H)-one (CAS No.: 1360651-42-8) 65.0 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No.: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, and extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and then purify by column chromatography to obtain the product, with a mixture of petroleum ether and ethyl acetate (PE / EA=4 / 1, Rf=0.34) as the eluent. The product is white powder with a yield of 62.9 mg after purification, which is 88%. The characterization data of the product are as follows:

[0071] 1 H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 7.6 Hz, 1H), 7.68 - 7.63 (m, 3H), 7.56 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 5.94 (s, 1H), 2.45 (s, 3H), 2.34 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 172.2, 166.3, 148.2, 143.6, 138.6, 137.7, 135.1, 131.4, 130.1, 129.6, 129.4, 128.7, 128.4, 125.1, 124.8, 123.3, 93.3, 21.8, 21.1. ESI-MS: calculated for C 23 H 19 NO3[M+Na]+ :380.1257, found:380.1249.

[0072] Example 6

[0073] Example 6 provides an isoindolinone compound, chemical name 2-benzoyl-3-hydroxy-6-methyl-3-phenylisoindolin-1-one, structural formula and preparation method as follows:

[0074]

[0075] Take 15 mL pressure tube, add meta-chloro peroxy benzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 7-methyl-3,4-diphenylisoquinoline-1(2H)-one (CAS No.: 1293990-77-8) 62.2 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No.: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, add anhydrous sodium sulfate to dry, remove the solvent under reduced pressure, then column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=4 / 1, Rf=0.32), the product after purification is 61.8 mg of white powder, the yield is 90%.

[0076] The product characterization data are: 1 H NMR (500 MHz, Chloroform-d) δ 7.72-7.68 (m, 3H), 7.60 (d, J = 7.3 Hz, 2H), 7.57 (d, J = 7.5 Hz, 1H), 7.48-7.44 (m, 3H), 7.38 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 7.26-7.22 (d, J = 7.3 Hz, 1H), 5.83 (s, 1H), 2.44 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 172.1, 166.4, 145.6, 140.8, 140.7, 136.3, 134.3, 132.6, 130.3, 129.1, 128.9, 128.7, 128.0, 125.2, 124.8, 123.1, 93.0, 21.4. ESI-MS: calculated for C22 H 17 NO3[M+Na] + :366.1100, found:366.1103.

[0077] Example 7

[0078] Example 7 provides an isoindolinone compound, chemical name 2-benzoyl-3-hydroxy-3-phenyl-5-vinylisoindolin-1-one, structural formula and preparation method as follows:

[0079]

[0080] Take 15 mL pressure tube, add m-chloroperoxybenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 3,4-diphenyl-6-vinylisoquinoline-1 (2H)-ketone 64.9 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No.: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, add anhydrous sodium sulfate to dry, remove the solvent under reduced pressure, then column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=4 / 1, Rf=0.46), the product after purification is 23.4 mg of white powder, the yield is 33%.

[0081] The product characterization data are: 1 H NMR (500 MHz, Chloroform-d) δ 7.84 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.63 (d, J = 7.7 Hz, 2H), 7.57 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.35 - 7.31 (m, 2H), 6.72 (dd, J = 17.6, 10.9 Hz, 1H), 5.88 (s, 1H), 5.85 (d, J = 17.6 Hz, 1H), 5.42 (d, J = 10.9 Hz, 1H). 13C NMR (126 MHz, CDC13) δ 172.1, 165.8, 148.6, 144.7, 140.5, 135.7, 134.2, 132.6, 129.1, 129.0, 128.8, 128.3, 128.0, 127.4, 125.5, 124.9, 120.8, 118.1, 93.0. ESI-MS: calculated for C 23 H 17 NO3[M+Na] + :378.1100, found:378.1101.

[0082] Example 8

[0083] Example 8 provides an isoindolinone compound, chemical name 2-benzoyl-3-hydroxy-1-oxo-3-phenylisoindoline-5-carbonitrile, structural formula and preparation method as follows:

[0084]

[0085] Take 15 mL pressure tube, add meta-chloroperbenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 1-oxo-3,4-diphenyl-1,2-dihydroisoquinoline-6-carbonitrile (CAS No.: 180959-89-2) 64.5 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is completed, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir for 3h at room temperature. After the reaction is completed, add 5 mL water to quench the reaction, then add 10 mL ethyl acetate (CAS No.: 141-78-6) and 5 mL saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=2 / 1, Rf=0.44), the product after purification is 51.7 mg of white powder, the yield is 73%.

[0086] The characterization data of the product are as follows: 1H NMR (500 MHz, Chloroform-d) δ 8.00 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.65 (s, 1H), 7.60 (d, J = 8.0 Hz, 3H), 7.49 (t, J = 7.8 Hz, 2H), 7.43 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 5.87 (s, 1H). 13 C NMR (126 MHz, CDC13) δ 171.9, 164.5, 148.3, 139.2, 133.8, 133.6, 133.2, 131.9, 129.4, 129.4, 129.2, 128.2, 127.7, 126.1, 124.7, 118.4, 117.3, 93.0. ESI-MS: calculated for C 22 H 14 N2O3[M+Na] + : 377.0896, found: 377.0890.

[0087] Example 9

[0088] Example 9 provides an isoindolinone compound, chemical name: 2-benzoyl-3-hydroxy-7-methyl-3-phenylisoindolin-1-one, structural formula and preparation method as follows:

[0089]

[0090] Take 15 mL pressure tube, add meta-chloro peroxy benzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 8-methyl-3,4-diphenyl isoquinoline-1 (2H)-ketone (CAS No: 1360651-33-7) 62.3 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is completed, add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir for 3h at room temperature. After the reaction is completed, add 5 mL water to quench the reaction, then add 10 mL ethyl acetate (CAS No: 141-78-6) and 5 mL saturated brine to wash, collect the organic phase after separation, extract the water phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, the eluent is a mixture of petroleum ether and ethyl acetate (PE / EA = 4 / 1, Rf = 0.44), the product after purification is 63.1 mg of white powder, with a yield of 92%.

[0091] The product was characterized by the following data: 1 H NMR (500 MHz, Chloroform-d) δ 7.70 (d, J = 7.6 Hz, 2H), 7.63 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.6 Hz, 3H), 7.38 (t, J = 7.5 Hz, 2H), 7.32 (d, J = 7.3 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 5.84 (s, 1H), 2.68 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 172.3, 166.8, 148.7, 140.9, 139.90, 134.7, 134.6, 132.5, 132.1, 128.9, 128.9, 128.6, 128.0, 125.2 124.9, 120.9, 92.1, 18.0. ESI-MS: calculated for C 22 H 17 NO3[M+Na] + : 366.1100, found: 366.1109.

[0092] Example 10

[0093] Example 10 provides an isoindolinone compound, chemical name: 2-benzoyl-3-hydroxy-1-oxo-3-phenylisoindoline-5-carboxylate, structural formula and preparation method as follows:

[0094]

[0095] Take 15 mL pressure tube, add meta-chloroperoxybenzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 1-oxo-3,4-diphenyl-1,2-dihydroisoquinoline-6-carboxylic acid methyl ester (CAS No: 1360651-32-6) 71.0 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05 M), temperature 40 °C, reaction 24 h, after the reaction is complete, add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3 h. After the reaction is complete, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No: 141-78-6) and 5 mL of saturated brine to wash, separate the organic phase, and extract the aqueous phase with ethyl acetate twice, each time using 5 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA = 2 / 1, Rf = 0.44), after purification, the product is 57.3 mg of white powder, the yield is 74%.

[0096] The characterization data of the product are: 1 H NMR (500 MHz, Chloroform-d) δ 8.22 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.63 (d, J = 7.4 Hz, 2H), 7.58 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.2 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 5.86 (s, 1H), 3.91 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 172.0, 165.5, 165.3, 148.0, 139.9, 136.3, 133.9, 132.9, 132.0, 131.5, 129.1, 129.0, 128.1, 125.3, 124.8, 124.8, 93.2, 52.7. ESI-MS: calculated for C 23 H 17 NO5[M+Na] + : 410.0998, found: 410.0997.

[0097] Example 11

[0098] Example 11 provides an isoindolinone compound, the chemical name of which is: 6-benzoyl-7-hydroxy-7-phenyl-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindol-5-one, the structural formula and the preparation method of which are as follows:

[0099]

[0100] Take 15 mL pressure-resistant tube, add m-chloroperbenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 7,8-diphenyl-[1,3]dioxolo[4,5-g]isoquinoline-5(6H)-one 68.2 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05 M), temperature 40℃, reaction for 24 h, after the reaction is completed, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3 h. After the reaction is completed, add 5 mL water to quench the reaction, then add 10 mL ethyl acetate (CAS No.: 141-78-6) and 5 mL saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, the eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=4 / 1, Rf=0.28), the product after purification is 32.8 mg of white powder, the yield is 44%. The characterization data of the product are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.68 (d, J = 7.3 Hz, 4H), 7.57 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.46 (t, J = 7.3 Hz, 2H), 7.40 (t, J = 7.3 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.12 (s, 1H), 6.00 (s, 1H), 5.89 (s, 1H).13C NMR (126 MHz, CDCl3) δ 172.1, 165.1, 154.2, 141.7, 139.5, 134.3, 132.5, 129.0, 128.8, 128.8, 127.9, 127.4, 125.1, 122.6, 120.7, 110.7, 103.2, 91.5. ESI-MS: calculated for C 22 H 15 NO5[M+Na] + :396.0842, found:396.0836.

[0101] Example 12

[0102] Example 12 provides an isoindolinone compound, chemical name: 2-benzoyl-3-hydroxy-5,6-dimethoxy-3-phenylisoindolin-1-one, structural formula and preparation method as follows:

[0103]

[0104] Take 15 mL pressure tube, add meta-chloro peroxy benzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 6,7-dimethoxy-3,4-diphenylisoquinolin-1(2H)-one (CAS No: 1404499-96-2) 71.4 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05 M), temperature 40℃, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, the eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=2 / 1, Rf=0.34), the product after purification is 37.3 mg of white powder, the yield is 48%.

[0105] The product characterization data are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.71-7.66 (m, 2H), 7.60 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.7 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.31 (d, J = 7.7 Hz, 1H), 7.28 (s, 1H), 6.74 (s, 1H), 5.92 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 171.7, 166.1, 155.6, 151.3, 142.8, 140.7, 134.3, 132.5, 129.1, 129.0, 128.7, 127.9, 124.8, 120.3, 105.6, 104.4, 92.6, 56.5, 56.4. ESI-MS: calculated for C 23 H 19 NO5[M+Na]+ :412.1155found:412.1153.

[0106] Example 13

[0107] Example 13 provides an isoindolinone compound, chemical name: 2-benzoyl-3-hydroxy-5-iodo-3-phenylisoindolin-1-one, structural formula and preparation method as follows:

[0108]

[0109] Take 15 mL pressure tube, add meta-chloro peroxybenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 6-iodo-3,4-diphenylisoquinolin-1(2H)-one (CAS No.: 1360651-29-1) 84.6 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No.: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, the eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=4 / 1, Rf=0.38), the product after purification is 18.2 mg of white powder, with a yield of 20%.

[0110] The product characterization data are: 1 H NMR (500 MHz, Chloroform-d) δ 7.90 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.4 Hz, 3H), 7.59 (d, J = 8.0 Hz, 4H), 7.47 (t, J = 7.4 Hz, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 5.84 (s, 1H). 13 C NMR (126 MHz, CDCl3) δ 172.0, 165.6, 149.1, 139.84, 139.7, 134.0, 132.8, 132.7, 129.2, 129.1, 129.1, 128.0, 127.7, 126.4, 124.8, 102.8, 92.6. ESI-MS: calculated for C 21 H 14 INO3[M+Na]+ : 477.9910, found: 477.9905.

[0111] Example 14

[0112] Example 14 provides an isoindolinone compound, chemical name 2-benzoyl-5-(tert-butyl)-3-hydroxy-3-phenylisoindolin-1-one, structural formula and preparation method as follows:

[0113]

[0114] Take 15 mL pressure tube, add meta-chloro peroxybenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 6-(tert-butyl)-3,4-diphenylisoquinoline-1(2H)-one (CAS No.: 1346684-66-9) 70.7 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No.: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=4 / 1, Rf=0.42), the product after purification is 44.7 mg of white powder, the yield is 58%.

[0115] The product characterization data are: 1 H NMR (500 MHz, Chloroform-d) δ 7.82 (d, J = 7.3 Hz, 1H), 7.69 (d, J = 7.7 Hz, 2H), 7.62 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 6.3 Hz, 1H), 7.54 (d, J = 6.3 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.33 (s, 1H), 7.31 (t, J = 7.3 Hz, 1H), 5.91 (s, 1H), 1.28 (s, 9H). 13C NMR (126 MHz, CDC13) δ 172.1, 166.2, 159.9, 148.3, 140.8, 134.4, 132.5, 129.1, 128.9, 128.7, 128.1, 128.0, 125.7, 124.9, 124.9, 119.7, 93.2, 35.8, 31.1. ESI-MS: calculated for C 25 H 23 NO3[M+Na] + : 408.1570, found: 408.1562.

[0116] Example 15

[0117] Example 15 provides an isoindolinone compound, chemical name 2-benzoyl-5-chloro-3- hydroxy-3-phenylisoindolin-l-one, structural formula and preparation method as follows:

[0118]

[0119] Take 15 mL pressure tube, add meta-chloro peroxybenzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 6-chloro-3,4-diphenylisoquinoline-l(2H)-one (CAS No: 1346684-68-1) 66.4 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05M), temperature 40°C, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL water to quench the reaction, then add 10 mL ethyl acetate (CAS No: 141-78-6) and 5 mL saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, add anhydrous sodium sulfate to dry, remove the solvent under reduced pressure, then column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=4 / 1, Rf=0.38), the product after purification is 37.1 mg of white powder, the yield is 51%.

[0120] The characterization data of the product are: 1H NMR (500 MHz, Chloroform-d) δ 7.83 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 7.3 Hz, 2H), 7.58 (d, J = 7.5 Hz, 1H), 7.51 (dd, J = 8.1, 1.6 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.41 (t, J = 7.3 Hz, 2H), 7.36 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 5.86 (s, 1H). 13 C NMR (126 MHz, CDC13) δ 172.0, 165.2, 149.4, 141.7, 139.9, 134.0, 132.8, 131.0, 129.2, 129.1, 129.1, 128.0, 126.6, 126.5, 124.8, 123.9, 92.7. ESI-MS: calculated for C 21 H 14 ClNO3[M+Na] + : 386.0554, found: 386.0550.

[0121] Example 16

[0122] Example 16 provides an isoindolinone compound, 2-benzoyl-3-hydroxy-3,6-diphenylisoindolin-l-one, with chemical name, structural formula and preparation method as follows:

[0123]

[0124] Take 15 mL pressure tube, add meta-chloroperbenzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 3,4,7-triphenylisoquinolin-1 (2H)-one (CAS No: 2328084-61-1) 74.7 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05 M), temperature 40℃, reaction 24h, after the reaction is complete, add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No: 141-78-6) and 5 mL of saturated brine to wash, separate the organic phase, the aqueous phase is extracted with ethyl acetate twice, each time the amount of ethyl acetate is 5 mL, combine the organic phase, add anhydrous sodium sulfate to dry, remove the solvent under reduced pressure, then column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA = 4 / 1, Rf = 0.37), the product after purification is 58.3 mg of white powder, the yield is 72%.

[0125] The characterization data of the product are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 7.2 Hz, 3H), 7.53 - 7.49 (m, 4H), 7.47 (d, J = 5.2 Hz, 1H), 7.44 (dd, J = 7.3, 4.7 Hz, 3H), 7.37 (d, J = 7.3 Hz, 1H), 5.91 (s, 1H). 13 CNMR (126 MHz, CDC13) δ 172.1, 166.2, 146.8, 143.8, 140.5, 139.4, 134.3, 132.7, 129.2, 129.1, 129.0, 128.8, 128.3, 128.0, 127.3, 124.9, 123.7, 123.5, 93.1. ESI-MS: calculated for C 27 H 19 NO3[M+Na] + : 428.1257, found: 428.1251.

[0126] Example 17

[0127] Example 17 provides an isoindolinone compound, the chemical name of which is: 2-benzoyl-4,6-dimethyl-3-phenylisoindolin-1-one, the structural formula and preparation method of which are as follows:

[0128]

[0129] Into a 15 mL pressure tube, add meta-chloroperoxybenzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 5,7-dimethyl-3,4-diphenylisoquinolin-1 (2H)-one (CAS No: 2323112-65-6) 65.1 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05 M), temperature 40 °C, reaction for 24 h, after completion of reaction add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir for 3 h at room temperature. After completion of reaction, add 5 mL of water to quench the reaction, further add 10 mL of ethyl acetate (CAS No: 141-78-6) and 5 mL of saturated brine solution to wash, collect the organic layer, the aqueous layer is again extracted with ethyl acetate for 2 times, each time ethyl acetate used is 5 mL, combine the organic layer, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, further purify the product by column chromatography using mixture of petroleum ether and ethyl acetate (PE / EA = 4 / 1, Rf = 0.5) as eluent, the product obtained after purification is 54.3 mg as white powder, yield is 76%.

[0130] The product characterization data are:

[0131] 1 H NMR (500 MHz, Chloroform-d) d 7.63 (d, J = 7.0 Hz, 2H), 7.58 (d, J = 7.3 Hz, 2H, s, 1H), 7.44 (t, J = 7.3 Hz, 2H), 7.38 (t, J = 7.0 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.24 (s, 1H), 6.07 (s, 1H), 2.44 (s, 3H), 2.09 (s, 3H).13C NMR (126 MHz, CDCl3) d 172.2, 166.5, 143.1, 140.8, 139.7, 138.3, 134.4, 134.4, 132.5, 129.1, 129.0, 128.4, 128.4, 127.9, 125.9, 122.6, 93.4, 21.3, 17.4. ESI-MS: calculated for C 23 H 19 NO3[M+Na] + : 380.1257, found: 380.1253.

[0132] Example 18

[0133] Example 18 provides an isoindolinone compound, the chemical name of which is 2-butyryl-3-hydroxy-3-propylisoindolin-l-one, the structural formula and the preparation method of which are as follows:

[0134]

[0135] Take 15 mL pressure-resistant tube, add meta-chloro peroxy benzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 3,4-dipropylisoquinoline-l(2H)-one (CAS No.: 1253388-77-0) 45.8 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is completed, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir for 3h at room temperature. After the reaction is completed, add 5 mL water to quench the reaction, then add 10 mL ethyl acetate (CAS No.: 141-78-6) and 5 mL saturated brine to wash, collect the organic phase after separation, extract the water phase with ethyl acetate twice, each time with 5 mL ethyl acetate, combine the organic phase, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, the eluent is a mixture of petroleum ether and ethyl acetate (PE / EA = 2 / 1, Rf = 0.29), the product after purification is 49.6 mg of white powder, with a yield of 95%.

[0136] The characterization data of the product are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.86 (d, J = 7.6 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 4.93 (s, 1H), 3.11 - 2.99 (m, 2H), 2.60 (ddd, J = 13.5, 11.8, 5.0 Hz, 1H), 2.18 (ddd, J = 13.5, 11.8, 5.0 Hz, 1H), 1.79 - 1.71 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.98 (d, J = 7.3 Hz, 1H), 0.79 - 0.74 (m, 3H), 0.74 - 0.67 (m, 1H). 13 CNMR (126 MHz, Chloroform-d) δ 176.4, 166.7, 146.3, 134.8, 130.2, 129.6, 124.7, 122.4, 93.2, 41.3, 39.6, 17.8, 17.7, 13.8, 13.7. ESI-MS: calculated for C 15 H 19NO3[M+Na] + : 284.1257 found: 284.1265.

[0137] Example 19

[0138] Example 19 provides an isoindolinone compound, chemical name: 2-benzoyl-3- hydroxy-3-methylisoindolin-1-one, structural formula and preparation method as follows:

[0139]

[0140] Take 15 mL pressure tube, add meta-chloro peroxybenzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 4-methyl-3-phenylisoquinoline-1 (2H)-one (CAS No: 423176-02-7) 47.1 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, add anhydrous sodium sulfate to dry, remove the solvent under reduced pressure, then column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=2 / 1, Rf=0.65), the product after purification is 40.0 mg of white powder, the yield is 75%.

[0141] The product characterization data are: 1 H NMR (500 MHz, Chloroform-d) δ 7.85 (d, J = 7.6 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.61 - 7.56 (m, 2H), 7.47 (t, J = 8.0 Hz, 2H), 5.27 (s, 1H), 2.12 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 172.6, 165.6, 147.7, 135.0, 134.9, 132.3, 130.3, 128.8, 128.7, 128.0, 125.2, 122.3, 91.2, 26.5. ESI-MS: calculated for C 16 H 13 NO3[M+Na] +: 290.0787, found: 290.0779.

[0142] Example 20

[0143] Example 20 provides an isoindolinone compound, chemical name: 2-benzoyl-3-hydroxy-3-phenyl-2,3-dihydro-1H- benzoisoindol-1-one, structural formula and preparation method as follows:

[0144]

[0145] Take 15 mL pressure tube, add meta-chloro peroxybenzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 3,4-diphenylbenzo[h]isoquinolin-1(2H)-one (CAS No: 2608586-42-9) 75.0 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, add anhydrous sodium sulfate to dry, remove the solvent under reduced pressure, then column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=4 / 1, Rf=0.45), the product after purification is 47.0 mg of white powder, the yield is 62%.

[0146] The product characterization data are: 1 H NMR (500 MHz, Chloroform-d) δ 9.09 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 7.0 Hz, 2H), 7.70 (t, J = 8.1 Hz, 1H, d, J = 7.7 Hz, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.43 - 7.38 (m, 3H), 7.33 (t, J = 7.4 Hz, 1H), 5.96 (s, 1H). 13C NMR (126 MHz, CDC13) δ 171.8, 166.9, 149.2, 140.2, 136.6, 134.5, 134.0, 132.5, 129.3, 129.2, 129.0, 129.0, 128.8, 128.7, 128.0, 127.7, 125.0, 124.3, 121.9, 119.5, 92.2. ESI-MS: calculated for C 25 H 17 NO3[M+Na] + :402.1100, found:402.1108.

[0147] Example 21

[0148] Example 21 provides an isoindolinone compound, chemical name: 2-(2- fluorobenzoyl)-3-(2-fluorophenyl)-3-hydroxyisoindolin-1-one, structural formula and preparation method as follows:

[0149]

[0150] Take 15 mL pressure tube, add meta-chloroperoxybenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 3,4-bis(4-fluorophenyl)isoquinoline-1(2H)-one (CAS No.: 1346684-69-2) 66.6 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is completed, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir for 3h at room temperature. After the reaction is completed, add 5 mL water to quench the reaction, then add 10 mL ethyl acetate (CAS No.: 141-78-6) and 5 mL saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=4 / 1, Rf=0.30), the product after purification is 51.1 mg of white powder, with a yield of 70%.

[0151] The characterization data of the product are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.91 (d, J = 7.6 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.68 - 7.65 (m, 1H), 7.59 - 7.55 (m, 3H), 7.34 (d, J = 7.7 Hz, 1H), 7.14 (t, J = 8.6 Hz, 2H), 7.07 (t, J = 8.6 Hz, 2H), 5.89 (s, 1H). 13 C NMR (126 MHz, Chloroform-d) δ 171.0, 166.5, 166.1, 164.5, 163.9, 161.9, 147.9, 136.3 (d, J = 3.0 Hz), 135.4, 132.0 (d, J = 9.3 Hz), 130.1, 130.1, 128.0, 126.8 (d, J = 8.4 Hz), 125.3, 123.3, 116.0 (d, J = 21.9 Hz), 115.3 (d, J = 22.2 Hz), 92.9. 19 F NMR (471 MHz, Chloroform-d) δ -104.9, -113.0. ESI-MS: calculated for C 21 H 13 F2NO3[M+Na] + : 388.0755, found: 388.0749.

[0152] Example 22

[0153] Example 22 provides an isoindolinone compound, chemical name: 2-(4-chlorobenzoyl)-3-(4-chlorophenyl)-3-hydroxy-5,7-dimethylisoindolin-1-one, structural formula and preparation method as follows:

[0154]

[0155] Take 15 mL pressure tube, add meta-chloroperbenzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 3,4-bis(3-chlorophenyl)-5,7-dimethylisoquinolin-1(2H)-one 78.9 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05 M), temperature 40 °C, reaction 24 h, after the reaction is complete, add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3 h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, add anhydrous sodium sulfate to dry, remove the solvent under reduced pressure, then column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA = 4 / 1, Rf = 0.58), the product after purification is 64.7 mg of white powder, the yield is 76%.

[0156] The characterization data of the product are: 1 H MR (500 MHz, Chloroform-d) δ 7.55 (d, J = 9.5 Hz, 2H), 7.50 (d, J = 9.5 Hz, 2H), 7.45 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.29 (d, J = 5.6 Hz, 2H), 7.25 - 7.23 (m, 1H), 5.91 (s, 1H), 2.41 (s, 3H), 2.09 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 170.5, 166.1, 142.4, 141.9, 141.2, 138.7, 135.8, 134.6, 134.6, 134.5, 134.1, 132.4, 129.8, 129.3, 128.9, 128.8, 128.7, 126.9, 126.2, 124.0, 122.9, 92.8, 21.3, 17.5. ESI-MS: calculated for C 23 H 17 Cl2NO3[M+Na] + : 448.0477, found: 448.0484.

[0157] Example 23

[0158] Example 23 provides an isoindolinone compound, the chemical name of which is: 2-acetyl-1-hydroxy-3-isoindolin-1-carboxylic acid ethyl ester, the structural formula and preparation method are as follows:

[0159]

[0160] Into a 15 mL pressure tube, add meta-chloroperoxybenzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 3-methyl-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid ethyl ester (CAS No: 76746-91-3) 46.0 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05 M), temperature 40 °C, reaction for 24 h, after completion of reaction add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir for 3 h at room temperature. After completion of reaction, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No: 141-78-6) and 5 mL of saturated brine solution, separate the organic layer, the aqueous layer is extracted with ethyl acetate twice, each time 5 mL of ethyl acetate is used, combine the organic layers, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify the product by column chromatography using a mixture of petroleum ether and ethyl acetate (PE / EA = 2 / 1, Rf = 0.23) as the eluent. The product is obtained as a white powder after purification, 36.8 mg in yield, 70%.

[0161] The product characterization data are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.3 Hz, 1H), 7.59 (d, J = 7.3 Hz, 1H), 5.08 (s, 1H), 4.25 (dd, J = 10.7, 7.1 Hz, 1H), 4.11 (dd, J = 10.7, 7.1 Hz, 1H), 2.66 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). 13 CNMR (126 MHz, Chloroform-d) δ 171.8, 168.7, 166.1, 142.1, 135.1, 131.3, 129.8, 125.3, 122.7, 87.6, 63.3, 24.8, 13.9. ESI-MS: calculated for C 13 H 13 NO5[M+Na] + : 286.0685, found: 286.0692.

[0162] Example 24

[0163] Example 24 provides an isoindolinone compound, the chemical name of which is: 2-acetyl-l-hydroxy-3-isoindolin-l-carboxylic acid tert-butyl ester, the structural formula and preparation method of which are as follows:

[0164]

[0165] Take 15 mL pressure-resistant tube, add meta-chloro peroxybenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 3-methyl-l-oxo-l,2-dihydroisoquinoline-4-carboxylic acid tert-butyl ester (CAS No.: 1159410-93-1) 51.0 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05 M), temperature 40℃, reaction for 24 h, after the reaction is completed, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3 h. After the reaction is completed, add 5 mL water to quench the reaction, then add 10 mL ethyl acetate (CAS No.: 141-78-6) and 5 mL saturated brine to wash, collect the organic phase after separation, extract the water phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, add anhydrous sodium sulfate to dry, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, the eluent is a mixture of petroleum ether and ethyl acetate (PE / EA = 4 / 1, Rf = 0.46), the product after purification is 18.1 mg of white powder, with a yield of 31%.

[0166] The characterization data of the product are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 5.01 (s, 1H), 2.66 (s, 3H), 1.36 (s, 9H). 13 C NMR (126 MHz, Chloroform-d) δ 171.5, 167.5, 166.4, 142.6, 135.0, 131.1, 129.8, 125.2, 122.3, 87.8, 84.4, 27.5, 24.9. ESI-MS: calculated for C 15 H 17 NO5[M+Na] + : 314.0998, found: 314.0998.

[0167] Example 25

[0168] Example 25 provides an isoindolinone compound, the chemical name of which is: 2-butyryl-1-hydroxy-3-isoindolin-1-carboxylic acid methyl ester, the structural formula and preparation method of which are as follows:

[0169]

[0170] Take 15 mL pressure-resistant tube, add meta-chloro peroxybenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 1-oxo-3-propyl-1,2-dihydroisoquinoline-4-carboxylic acid ethyl ester (CAS No.: 1159410-97-5) 51.8 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is completed, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir for 3h at room temperature. After the reaction is completed, add 5 mL water to quench the reaction, then add 10 mL ethyl acetate (CAS No.: 141-78-6) and 5 mL saturated brine to wash, collect the organic phase after separation, extract the water phase with ethyl acetate twice, each time with 5 mL ethyl acetate, combine the organic phase, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, the eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=4 / 1, Rf=0.15), the product after purification is 53.5 mg of white powder, with a yield of 92%.

[0171] The characterization data of the product are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 5.05 (s, 1H), 4.30-4.23 (m, 1H), 4.16-4.09 (m, 1H), 3.11 (d, J = 7.1 Hz, 2H), 1.75 (d, J = 7.4 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 174.9, 168.8, 166.0, 142.0, 135.0, 131.2, 130.0, 125.3, 122.7, 87.7, 63.3, 38.6, 17.6, 13.9, 13.7. ESI-MS: calculated for C 15 H 17 NO5[M+Na] + :314.0998, found:314.0998.

[0172] Example 26

[0173] Example 26 provides an isoindolinone compound, chemical name: 10b-hydroxy-1,2,3,10b-tetrahydropyrido[2,1-a]isoindole-4,6-dione, structural formula and preparation method as follows:

[0174]

[0175] Take 15 mL pressure tube, add m-chloroperbenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 1,2,3,4-tetrahydro-5H-cyclopenta[c]isoquinolin-5-one (CAS No.: 120637-35-6) 37.0 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is completed, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL water to quench the reaction, then add 10 mL ethyl acetate (CAS No.: 141-78-6) and 5 mL saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, add anhydrous sodium sulfate to dry, remove the solvent under reduced pressure, then column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=1 / 1, Rf=0.25), the product after purification is 36.9 mg of white powder, the yield is 85%.

[0176] The characterization data of the product are as follows: 1 H NMR (500 MHz, DMSO-d6) δ 7.81-7.74 (m, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 6.96 (s, 1H), 2.64 (m, 1H), 2.47 (m, 1H), 2.22 (m, 1H), 1.90-1.83 (m, 1H), 1.81-1.74 (m, 1H). 13 C NMR (126 MHz, DMSO) δ 170.5, 164.8, 147.9, 135.0, 130.5, 129.2, 124.4, 123.1, 88.8, 32.8, 31.9, 16.6. ESI-MS: calculated for C 12 H 11 NO3[M+Na] + : 240.0631, found: 240.0637.

[0177] Example 27

[0178] Example 27 provides an isoindolinone compound, chemical name: 11a-hydroxy-9,10,11,11a-tetrahydro-5H-azepino[2,1-a]isoindole-5,7(8H)-dione, structural formula and preparation method as follows:

[0179]

[0180] Take 15 mL pressure tube, add meta-chloroperoxybenzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 1,3,4,5-tetrahydrophenanthridin-6(2H)-one (CAS No: 80031-06-7) 40.0 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No: 141-78-6) and 5 mL of saturated brine to wash, separate the organic phase, the aqueous phase is extracted with ethyl acetate twice, each time the amount of ethyl acetate is 5 mL, combine the organic phase, add anhydrous sodium sulfate to dry, remove the solvent under reduced pressure, then column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=1 / 1, Rf=0.23), the product after purification is 40.7 mg of white powder, the yield is 88%.

[0181] The product characterization data are: 1 H NMR (500 MHz, Chloroform-d) δ 7.70 (t, J = 7.5 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 4.33 (s, 1H), 3.15 (t, J = 13.8 Hz, 1H), 2.59 (d, J = 13.8 Hz, 1H), 2.48 (dd, J = 13.5, 7.2 Hz, 1H), 2.24 (q, J = 13.5 Hz, 1H), 1.93 (d, J = 7.2 Hz, 1H), 1.85 (m, 1H), 1.65 - 1.59 (t, J = 13.1 Hz, 1H), 1.54 (d, J = 13.1 Hz, 1H). 13C NMR (126 MHz, CDC13) δ 175.2, 166.9, 148.4, 134.8, 130.2, 128.6, 124.6, 122.3, 90.3, 39.5, 39.2, 23.8, 22.9. ESI-MS: calculated for C 13 H 13 NO3[M+Na] + : 254.0787, found: 254.0780.

[0182] Example 28

[0183] Example 28 provides an isoindolinone compound, chemical name: 9b-hydroxy-1,9b-dihydro-3H-pyrrolo[2,1-a]isoindole-3,5(2H)-dione, structural formula and preparation method as follows:

[0184]

[0185] Take 15 mL pressure tube, add meta-chloroperbenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 1,3-dihydrocyclo-ta[c]isoquinoline-4(2H)-one 34.0 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40°C, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No.: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA = 1 / 1, Rf = 0.40), the product after purification is 12.2 mg of white powder, with a yield of 30%.

[0186] The product characterization data are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.84 (d, J = 7.5 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 3.60 (s, 1H), 3.33 - 3.26 (m, 1H), 2.78 - 2.67 (m, 2H), 2.27 - 2.20 (m, 1H) ESI-MS: calculated for C 11H9NO3[M+H] + : 204.0655, found: 204.0654.

[0187] Example 29

[0188] Example 29 provides an isoindolinone compound, chemical name: 13a-hydroxy-9,10,11,12,13,13a-hexahydro-5H-azepino[2,1-a]isoindol-5,7(8H)-dione, structural formula and preparation method as follows:

[0189]

[0190] Take 15 mL pressure tube, add meta-chloroperoxybenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 7,8,9,10,11,12-hexahydrocycloocta[c]isoquinolin-5(6H)-one 45.4 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No.: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phases, add anhydrous sodium sulfate to dry, remove the solvent under reduced pressure, then column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=4 / 1, Rf=0.30), the product after purification is 40.4 mg of white powder, the yield is 78%.

[0191] The product characterization data are: 1 H NMR (500 MHz, Chloroform-d) δ 7.89 (d, J = 7.3 Hz, 1H), 7.71 (t, J = 7.1 Hz, 1H), 7.57 (t, J = 7.1 Hz, d, J = 7.3 Hz, 1H), 4.86 (s, 1H), 3.90-3.85 (m, 1H), 2.42-2.34 (m, 3H), 1.87-1.19 (m, 1H), 1.67-1.64 (m, 1H), 1.59-1.54 (m, 1H), 1.49-1.41 (m, 2H), 1.36-1.27 (m, 2H), 0.49-0.42 (m, 1H). 13C NMR (126 MHz, CDC13) δ 181.1, 166.4, 145.8, 134.8, 130.2, 130.1, 124.7, 122.3, 93.6, 38.4, 35.2, 27.2, 22.3, 21.8, 19.7. ESI-MS: calculated for C 15 H 17 NO3[M+Na] + : 282.1100, found: 282.1094.

[0192] Example 30

[0193] Example 30 provides an isoindolinone compound, chemical name: 12a-hydroxy-8,9,10,11,12,12a-hexahydroazepino[2,1-a]isoindol-5,7-dione, structural formula and preparation method as follows:

[0194]

[0195] Take 15 mL pressure tube, add meta-chloroperbenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 6,7,8,9,10,11-hexahydro-5H-cyclohepta[c]isoquinolin-5-one (CAS No.: 1135377-32-0) 43.0 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40°C, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No.: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, then purify by column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA = 1 / 1, Rf = 0.46), the product after purification is 25.9 mg of white powder, the yield is 53%.

[0196] The product characterization data are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.85 (d, J = 7.2 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H, t, 7.2 Hz, 1H), 4.25 (s, 1H), 3.42 - 3.36 (m, 1H), 2.64 (td, J = 12.7, 12.0, 6.2 Hz, 1H), 2.44 (dd, J = 15.0, 8.3 Hz, 1H), 2.35 (dd, J = 15.0, 8.0 Hz, 1H), 1.95 - 1.90 (m, 1H), 1.63 - 1.76 (m, 3H), 1.35 (dd, J = 15.0, 8.0 Hz, 1H), 0.74 - 0.66 (m, 1H). 13 C NMR (126 MHz, CDC13) δ 181.3, 166.5, 146.5, 134.6, 130.2, 129.7, 124.6, 122.4, 92.3, 40.6, 37.4, 28.0, 26.3, 24.3. ESI-MS: calculated for C 14 H 15 NO3[M+Na] + : 268.0944, found: 268.0937.

[0197] Example 31

[0198] Example 31 provides an isoindolinone compound, chemical name: 17a-hydroxy-9,10,11,12,13,14,15,16,17,17a-decahydro-5H-[l]azacyclotridecana[2,l-a]isoindole-5,7(8H)-dione, structural formula and preparation method as follows:

[0199]

[0200] Take a 15 mL pressure-resistant tube and add 86.2 mg (0.50 mmol) of m-chloroperoxybenzoic acid (CAS No.: 937-14-4), 56.6 mg (0.20 mmol) of 6a, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 16a-dodecylcyclododecane[c]isoquinoline-5(6H)-one, and 4 mL (0.05 M) of dichloroethane (CAS No.: 107-06-2). The reaction is carried out at 40 °C for 24 h. After the reaction is complete, add 52 mg (0.6 mmol) of sodium bicarbonate (CAS No.: 144-55-8) and stir at room temperature for 3 h. After the reaction was completed, 5 mL of water was added to quench the reaction, followed by washing with 10 mL of ethyl acetate (CAS No.: 141-78-6) and 5 mL of saturated brine. The organic phase was collected in layers, and the aqueous phase was extracted twice with ethyl acetate, 5 mL each time. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The product was then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 4 / 1, Rf = 0.57). The purified product weighed 40.3 mg and was a white powder with a yield of 64%.

[0201] The product's characterization data are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.88(d,J=7.6Hz,1H),7.73(t,J=7.5Hz,1H),7.58(t,J=7.6Hz ,1H,1H),7.56(d,J=7.5Hz,1H),5.16(s,1H),3.88–3.81(m,1H),2.78–2.72(m,1H),2.49–2.4 3(m,1H),2.18–2.12(m,1H),1.92–1.85(m,1H),1.79(dd,J=14.2,6.2Hz,1H),1.52(dd,J=14 .2,6.2Hz,1H),1.37(m,2H),1.32–1.20(m,7H),1.18–1.12(m,2H),0.76(m,1H),0.68(m,1H). 13 C NMR (126MHz, CDCl3) δ177.9,166.79,146.1,135.0,130.2,129.6,124.9,122.2,94 .0,37.6,37.2,27.0,26.9,26.5,26.1,26.0,24.8,24.5,22.2.ESI-MS:calculated for C 19 H 25 NO3[M+Na] + :338.1726,found:338.1718.

[0202] Example 32

[0203] Example 32 provides an isoindolinone compound, chemical name: 2-benzoyl-3-hydroxy-3-(p-tolyl)isoindolin-1-one, structural formula and preparation method as follows:

[0204]

[0205] Take 15 mL pressure tube, add m-chloroperbenzoic acid (CAS No.: 937-14-4) 86.2 mg (0.50 mmol), 3-phenyl-4-(p-tolyl)isoquinoline-1(2H)-one 62.2 mg (0.20 mmol) and dichloroethane (CAS No.: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No.: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No.: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, and extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and then purify by column chromatography to obtain the product, with a mixture of petroleum ether and ethyl acetate (PE / EA=4 / 1, Rf=0.35) as the eluent. The product after purification is 57.6 mg of white powder, with a yield of 84%.

[0206] The characterization data of the product are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.89 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 7.1 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.45 (t, J = 7.1 Hz, 2H), 7.37 (d, J = 7.5 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 5.81 (s, 1H), 2.32 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 172.1, 166.2, 148.2, 138.7, 137.6, 135.2, 134.3, 132.6, 130.1, 129.7, 129.1, 128.2, 128.0, 125.2, 124.7, 123.3, 93.2, 21.1. ESI-MS: calculated for C 22 H 17NO3[M+Na] + Found: 366.1096.

[0207] Example 33

[0208] Example 33 provides an isoindolinone compound, chemical name: 3-hydroxy-3-phenyl-2-(4- (trifluoromethyl)benzoyl)isoindolin-1-one, structural formula and preparation method as follows:

[0209]

[0210] Take 15 mL pressure tube, add meta-chloro peroxybenzoic acid (CAS No: 937-14-4) 86.2 mg (0.50 mmol), 4-phenyl-3-(4-(trifluoromethyl)phenyl)isoquinoline-1(2H)-one 73.1 mg (0.20 mmol) and dichloroethane (CAS No: 107-06-2) 4 mL (0.05M), temperature 40℃, reaction for 24h, after the reaction is complete, add sodium bicarbonate (CAS No: 144-55-8) 52 mg (0.6 mmol) and stir at room temperature for 3h. After the reaction is completed, add 5 mL of water to quench the reaction, then add 10 mL of ethyl acetate (CAS No: 141-78-6) and 5 mL of saturated brine to wash, collect the organic phase after separation, extract the aqueous phase with ethyl acetate twice, each time with 5 mL of ethyl acetate, combine the organic phase, add anhydrous sodium sulfate to dry, remove the solvent under reduced pressure, then column chromatography to obtain the product, eluent is a mixture of petroleum ether and ethyl acetate (PE / EA=4 / 1, Rf=0.38), the product after purification is 69.9 mg of white powder, the yield is 88%.

[0211] The characterization data of the product are: 1 H NMR (500 MHz, Chloroform-d) δ 7.90 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.43 - 7.38 (m, 3H), 7.35 (d, J = 7.3 Hz, 1H), 5.66 (s, 1H). 13C NMR (126 MHz, CDC13) δ 170.5, 166.2, 148.0, 140.3, 137.6, 135.6, 133.8, 133.6, 130.4, 129.1, 129.1, 128.9, 128.5, 128.4, 127.8, 125.3, 125.1, 125.1, 125.1, 125.0, 124.6, 123.5, 93.1. ESI-MS: calculated for C 22 H 17 NO3[M+Na] + : 420.0817, found: 420.0821.

[0212] Anti-inflammatory activity assay

[0213] Anti-inflammatory activity assay

[0214] 1. Cells were seeded at 2*10 5 cells / well in 24-well plates (volume 100 μL) and incubated at 37 °C in a 5% CO2atmosphere until 80% confluence, ready for use.

[0215] 2. The medium was carefully removed and fresh complete medium containing the indicated concentration of compounds was added. Groups were set up: blank (-LPS), stimulated (+LPS) (1 μg / mL LPS), dosed (10 μM compound + 1 μg / mL LPS). Dexamethasone (DEX, 1 μM) was set up as a control in the dosed group. LPS (1 μg / mL) was added to induce for 4 hours.

[0216] 3. After the treatment time, the plates were removed and the change in the expression level of inflammatory cytokines was determined by qPCR. The results were analyzed using the 2 -ΔΔCt method and are shown in Table 1 and Figure 1 .

[0217] Table 1 2 -ΔΔCt method analysis of experimental results

[0218] Sample Relative expression level of IL-6 - 1 Example 3 Q-780 244.60 Example 1 Q-758 257.43 Example 2 Q-779 279.14 Example 6 Q-790 289.51 Example 4 Q-782 311.62 Example 15 Q-823 343.97 Example 12 Q-815 346.24 Example 19 Q-835 389.14 Example 17 Q-829 410.76 DEX (1 μΜ) 544.27 + 1283.49

[0219] Anti-inflammatory activity data are shown in Figure 1 and Table 1. The isoindolinone compounds of the present application have anti-inflammatory activity. The compounds tested were dosed at 10 μM, the positive control was dexamethasone (DEX) at a dose of 1 μM and Vehicle was the inflammatory mouse model, from Figure 1See, all the measured compounds have anti-inflammatory activity, can reduce the content of IL-6, wherein the anti-inflammatory effect of examples 1 and 3 is relatively good.

[0220] The above is described in detail in combination with the embodiments of the present application, but the present application is not limited to the above-described embodiments, and various changes can be made within the knowledge range possessed by those skilled in the art without departing from the purpose of the present application.

Claims

1. An isoindolinone compound, characterized by, The isoindolinone compound has a structure shown in formula (IV); ； wherein n is 1 or 2; R 1 selected from phenyl, halo-substituted phenyl, C 2~5 substituted phenyl; R 3 selected from phenyl, halo-substituted phenyl, C 2~5 substituted phenyl; R 2 with the A ring being attached by a single bond, R 2 is selected from H, C 1~10 1-4 alkyl, C 1~10 1-4 alkoxy, halogen.

2. An isoindolineone compound, characterized in that, The isoindolinone compound is selected from 2-benzoyl-3-hydroxy-3-phenylisoindolin-1-one, 2-(3-chlorobenzoyl)-3-(3-chlorophenyl)-3-hydroxyisoindolin-1-one, 2-(4-bromobenzoyl)-3-(4-bromophenyl)-3-hydroxyisoindolin-1-one, 4-(2-(4-(ethoxycarbonyl)benzoyl)-1-hydroxy-3-isoindolin-1-yl)benzoic acid ethyl ester, 2-benzoyl-3-hydroxy-6-methyl-3-phenylisoindolin-1-one, 2-benzoyl-3-hydroxy-5,6-dimethoxy-3-phenylisoindolin-1-one, 2-benzoyl-3-hydroxy-5-iodo-3-phenylisoindolin-1-one, 2-benzoyl-5-(tert-butyl)-3-hydroxy-3-phenylisoindolin-1-one, 2-benzoyl-5-chloro-3-hydroxy-3-phenylisoindolin-1-one, 2-benzoyl-4,6-dimethyl-3-phenylisoindolin-1-one, 2-benzoyl-3-hydroxy-3-methylisoindolin-1-one, 2-(2-fluorobenzoyl)-3-(2-fluorophenyl)-3-hydroxyisoindolin-1-one, 2-(4-chlorobenzoyl)-3-(4-chlorophenyl)-3-hydroxy-5,7-dimethylisoindolin-1-one.

3. The process for the preparation of isoindolinone compounds according to claim 1 or 2, characterized in that, The method comprises the following steps: The compound shown in formula (IV) is obtained by mixing and reacting the compound shown in formula (I), the compound shown in formula (II) and a solvent; The compound shown in formula (I) and the compound shown in formula (II) have the following structural formulae: 。 4. The production method according to claim 3, characterized by, The molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1: (1-3).

5. The preparation method according to claim 3, characterized in that, The solvent is at least one selected from dichloroethane, trifluoroethanol, tetrahydrofuran and acetonitrile.

6. The preparation method according to claim 3, characterized in that, The volume-molar ratio of the solvent to the compound shown in formula (I) is (10-30) mL / mmol.

7. The preparation method according to claim 3, characterized in that, The reaction temperature is 30-100 DEG C.

8. The preparation method according to claim 3, characterized in that, The reaction time is 12-24 h.

9. The isoindolinone compound according to claim 1 or 2 is used for preparing an anti-inflammatory drug.

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