Method for synthesizing isoindolinone compound through palladium catalysis

Abstract

The invention relates to the fields of medicine, organic chemical industry and fine chemical industry, and particularly discloses a method for synthesizing an isoindolinone compound through palladium catalysis. According to the method, oxamide-protected benzylamine and ethyl glyoxylate are taken as raw materials, and the isoindolinone compound is synthesized in the presence of a palladium catalyst, an oxidizing agent and an additive. The reaction conditions are as follows: the reaction lasts for 24-36 hours under the heating condition of 100-120 DEG C; trifluorotoluene, toluene, chlorobenzene and acetonitrile are used as reaction solvents; di-tert-butyl peroxide, cumyl hydroperoxide, tert-butyl hydroperoxide and tert-butyl peroxybenzoate are used as oxidizing agents; and sodium persulfate and potassium persulfate are used as additives. And a series of substituted isoindolinone compounds can be obtained at high yield after simple post-treatment in the reaction.

Description

Technical Field

[0001] The invention relates to the fields of medicine, organic chemical industry and fine chemical industry, and specifically discloses a method for synthesizing isoindolinone compounds catalyzed by palladium. Background Art

[0002] Isoindolinone derivatives are widely present in natural products and drug molecules, have good physiological activity and broad medicinal value, and play a key role in anti-virus, anti-cardiovascular disease, anti-tumor, anti-bacterial and anti-inflammatory fields. There is no doubt that further modification of the isoindolinone skeleton structure will obtain a series of prodrug molecule libraries with biological activity and potential drug activity. [EC Lawson, DK Luci, S. Ghosh, WA Kinney, CH Reynolds, J. Qi, CE Smith, Y. Wang, LK Minor, BJ Haertlein, TJ Parry, B P Damiano, BE Maryanoff, J. Med. Chem. 2009, 52, 7432; F. Fleming, Nat. Prod.Rep.1999,16,597.;FFLeming,L.Yao,PCRavikumar,L.Funk,BCShook,J.Med.Chem.2010,53,7902.;E.Li,L.Jiang,L.Guo,H.Zhang,Y.Che,Bioorg.Med.Chem.2008,16,7894.].

[0003] Isoindolone is an important class of nitrogen-containing heterocyclic skeletons. The study of the synthesis method of isoindolinone has important application value and has always been a research hotspot. The currently developed methods for synthesizing isoindolinones mainly include Heck cyclization (Grigg, R.; Dorrity, MJR; Malone, JF; Mongkolaus Savaratana, T.; Norbert, WDJA; Sridharan, V. Tetrahedron Lett. 1990, 31, 3075.), hydrazone ring closure (Adachi, S.; Onozuka, M.; Yoshida, Y.; Ide, M.; Saikawa, Y.; Nakata, M. Org. Lett. 2014, 16, 358.), Diels-Alder cycloaddition (McAlonan, H.; Murphy, JP; Nieuwenhuyzen, M.; Reynolds, K.; Sarma, PKS; Stevenson, PJ; Thompson, NJ Chem. Soc., Perkin Trans. 1 2002, 33, 69.), etc. These methods generally require complex substrate preparation processes, and the substrate range is limited, the universality is poor, and the reaction conditions are harsh. In recent years, transition metal-catalyzed hydrocarbon carbonylation has developed into an efficient method for synthesizing isoindolinone derivatives (Wang, C.; Zhang, L.; Chen, C.; Han, J.; Yao, Y.; Zhao, Y. Chem. Sci. 2015, 6, 4610.; Han, J.; Wang, N.; Huang, Z.-B.; Zhao, Y.; Shi, D.-QJ Org. Chem. 2017, 82, 6831). However, these methods use highly toxic carbon monoxide or isocyanate as the carbonyl source, which does not conform to the concept of green synthetic chemistry. Summary of the invention

[0004] The purpose of the present invention is to provide a simple method of using ethyl glyoxylate as a carbonylation reagent to react with oxamide-protected benzylamine, undergo carbonylation and intramolecular cyclization to obtain a series of differently substituted isoindolinone compounds. The method is simple to operate and has mild reaction conditions, and is an efficient and convenient method for synthesizing isoindolinone compounds.

[0005] The synthesis method of the isoindolinone compound of the present invention is carried out according to the following steps: in a solvent, oxalamide-protected benzylamine and ethyl glyoxylate are used as raw materials, and the isoindolinone compound is synthesized by heating in the presence of a palladium catalyst, an oxidant and an additive.

[0006] The specific process of the reaction is as follows:

[0007]

[0008] The specific reaction conditions of the present invention are: heating at 100-120° C. for 24-36 hours to complete the reaction;

[0009] The solvents used in the reaction are trifluorotoluene, toluene, chlorobenzene, and acetonitrile;

[0010] The molar ratio of the oxalamide-protected benzylamine compound to the ethyl glyoxylate compound used is 1:2.

[0011] The structural formula of the reaction raw material oxalamide protected benzylamine compound is: The substituents on the benzene ring are: fluorine, chlorine, bromine, methyl, methoxy, and trifluoromethyl.

[0012] The catalysts used are palladium acetate, palladium chloride and palladium trifluoroacetate; the amount of the palladium catalyst used is 0.1 times the molar number of the oxalamide-protected benzylamine compound.

[0013] The oxidants used are di-tert-butyl peroxide, isopropylbenzene hydroperoxide, tert-butyl peroxide, and tert-butyl perbenzoate; the amount of the oxidant used is 4 times the molar number of the oxalamide-protected benzylamine compound.

[0014] The additives used are potassium persulfate and sodium persulfate; the amount of the additives used is twice the molar number of the oxalamide-protected benzylamine compound.

[0015] The post-reaction treatment of the present invention is simple, and pure various substituted isoindolinone compounds can be obtained by using a column chromatography separation method with a mixed solvent of petroleum ether and ethyl acetate as an eluent.

[0016] Beneficial effects:

[0017] The invention uses benzylamine with a wide range of sources as a starting material, introduces an oxalamide protecting group, uses ethyl glyoxylate as a carbonylation reagent, and undergoes carbonylation and intramolecular cyclization through carbon-hydrogen bond activation in the presence of a palladium catalyst, an oxidant and an additive, thereby obtaining a series of isoindolinone compounds with different substitutions in one pot.

[0018] The advantages of the method of the present invention are that ethyl glyoxylate is abundant in source and low in toxicity, thus avoiding the use of highly toxic gas carbon monoxide; the reaction conditions are mild, thus enabling efficient synthesis of various substituted isoindolinone compounds; the carbonylation reagent is simple and readily available; the reaction conditions are mild, and the reaction can occur at 100-120°C; the post-treatment is simple, and a pure target product can be obtained through simple column chromatography separation; the reaction efficiency is high, and the yield can reach 89%; the reaction has excellent universality and functional group tolerance, and can synthesize various substituted isoindolinone compounds. DETAILED DESCRIPTION

[0019] The present invention is described in detail below in conjunction with embodiments, and each embodiment of the present invention is as follows:

[0020]

[0021] Example 1

[0022] Synthesis of benzylamines substituted with different substituents protected by oxalamide: At a reaction temperature of 0°C, a dichloromethane solution (50 mL) of diisopropylamine (20 mmol) was slowly added dropwise to a 500 mL reaction bottle containing a dichloromethane solution (50 mL) of oxalyl chloride (30 mmol). After stirring for 10 minutes, triethylamine (22 mmol) was slowly added dropwise to the 500 mL reaction bottle and stirred to return to room temperature. After 6 hours, the excess oxalyl chloride and solvent were removed under reduced pressure to obtain a light yellow solid. The obtained light yellow solid was redissolved in a dichloromethane solution, and a dichloromethane solution (50 mL) of benzylamine (20 mmol) and triethylamine (22 mmol) was slowly added dropwise at a reaction temperature of 0°C, and stirred to return to room temperature. After 6 hours, water was added to quench, extracted, dried, and purified by column chromatography to obtain the corresponding oxalamide-protected benzylamine raw materials (1a-1l).

[0023]

[0024] Example 2

[0025] Add oxalamide protected 2-fluorobenzylamine 1a (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100°C and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3a with a yield of 75%. 1 H NMR (400 MHz, CDCl 3 )δ7.74(d,J=7.6Hz,1H),7.57-7.50(m,1H),7.39(t,J=8.4Hz,1H),4.90(s,2H), 3.71-3.64(m,1H),3.62-3.55(m,1H),1.64-1.50(m,6H),1.26(d,J=6.6Hz,6H).

[0026] Example 3

[0027] Add oxalamide protected 2-fluorobenzylamine 1a (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), and toluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100°C and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3a with a yield of 22%.

[0028] Example 4

[0029] Add oxalamide protected 2-fluorobenzylamine 1a (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), and chlorobenzene (1mL) into a Schlenk reaction tube and seal it. Heat to 100°C and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3a with a yield of 10%.

[0030] Example 5

[0031] Add oxalamide protected 2-fluorobenzylamine 1a (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), acetonitrile (1mL) into a Schlenk reaction tube and seal it. Heat to 100°C and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3a with a yield of 27%.

[0032] Example 6

[0033] Add oxalamide protected 2-fluorobenzylamine 1a (0.2mmol), ethyl glyoxylate (0.4mmol), palladium trifluoroacetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100°C and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3a with a yield of 50%.

[0034] Example 7

[0035] Add oxalamide protected 2-fluorobenzylamine 1a (0.2mmol), ethyl glyoxylate (0.4mmol), palladium chloride (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100°C and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3a with a yield of 36%.

[0036] Example 8

[0037] Add oxalamide protected 2-fluorobenzylamine 1a (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), cumene hydroperoxide (CHP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100℃ and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3a with a yield of 8%.

[0038] Example 9

[0039] Add oxalamide protected 2-fluorobenzylamine 1a (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), tert-butyl peroxide (TBHP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100°C and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3a with a yield of 11%.

[0040] Example 10

[0041] Add oxalamide protected 2-fluorobenzylamine 1a (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), tert-butyl peroxybenzoate (TBPB, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100°C and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3a with a yield of 30%.

[0042] Embodiment 11

[0043] Add oxalamide protected 2-fluorobenzylamine 1a (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), sodium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100°C and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3a with a yield of 66%.

[0044] Example 12

[0045] Add oxalamide protected 2-chlorobenzylamine 1b (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100℃ and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3b with a yield of 68%. 1 H NMR (400 MHz, CDCl 3 )δ7.84(d,J=7.6Hz,1H),7.67(d,J=7.9Hz,1H),7.51(t,J=7.7Hz,1H),4.85(s,2H ),3.71-3.63(m,1H),3.61-3.54(m,1H),1.60-1.52(m,6H),1.26(d,J=6.6Hz,6H).

[0046] Embodiment 13

[0047] Add oxalamide protected 2-bromobenzylamine 1c (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100℃ and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3c with a yield of 68%. 1 H NMR (400 MHz, CDCl 3 )δ7.89(d,J=7.6Hz,1H),7.83(d,J=7.8Hz,1H),7.44(t,J=7.8Hz,1H),4.79(s,2H ),3.71-3.63(m,1H),3.61-3.54(m,1H),1.61-1.53(m,6H),1.25(d,J=6.6Hz,6H).

[0048] Embodiment 14

[0049] Add oxalamide protected 2-methylbenzylamine 1d (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100℃ and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3d with a yield of 87%. 1 H NMR (400 MHz, CDCl 3 )δ7.76(d,J=7.4Hz,1H),7.52-7.40(m,2H),4.77(s,2H),3.72-3.64(m, 1H), 3.61-3.53 (m, 1H), 2.39 (s, 3H), 1.58 (s, 6H), 1.25 (d, J = 6.6Hz, 6H).

[0050] Embodiment 15

[0051] Add oxalamide protected 2-methoxybenzylamine 1e (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100℃ and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3e with a yield of 76%. 1 H NMR (400 MHz, CDCl 3 )δ7.51-7.45(m,2H),7.13(dd,J=6.4,2.5Hz,1H),4.77(s,2H),3.93(s,3H) ,3.71-3.63(m,1H),3.60-3.53(m,1H),1.58(s,6H),1.25(d,J=6.6Hz,6H).

[0052] Example 16

[0053] Add oxalamide protected 2-trifluoromethylbenzylamine 1f (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100℃ and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3f with a yield of 69%. 1 H NMR (400 MHz, CDCl 3 )δ8.13(d,J=7.7Hz,1H),7.96(d,J=7.7Hz,1H),7.76-7.66(m,1H),5.04(s,2 H), 3.73-3.65 (m, 1H), 3.63-3.54 (m, 1H), 1.58 (s, 6H), 1.26 (d, J = 6.6Hz, 6H).

[0054] Embodiment 17

[0055] Add 1g (0.2mmol) of oxalamide-protected 2,4-dimethoxybenzylamine, ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100°C and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain 3g of the target product with a yield of 75%. 1 H NMR (400 MHz, CDCl 3 )δ6.93(s,1H),6.70(d,J=1.9Hz,1H),4.84-4.57(m,2H),3.88(s,3H),3.84(s, 3H), 3.71-3.63 (m, 1H), 3.61-3.52 (m, 1H), 1.57 (s, 6H), 1.25 (d, J = 6.6Hz, 6H).

[0056] Embodiment 18

[0057] Add oxalamide protected 2,3-dimethylbenzylamine 1h (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 120℃, and the reaction time is 36h. After the reaction is completed, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3h with a yield of 65%.1 H NMR (400 MHz, CDCl 3 )δ7.66(d,J=7.8Hz,1H),7.32(d,J=7.8Hz,1H),4.77(s,2H),3.71-3.63(m,1H), 3.61-3.52(m,1H),2.41(s,3H),2.27(s,3H),1.58(s,6H),1.25(d,J=6.6Hz,6H).

[0058] Embodiment 19

[0059] Add oxalamide protected 2,5-dimethylbenzylamine 1i (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100℃ and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3i with a yield of 86%. 1 H NMR (400 MHz, CDCl 3 )δ7.32(d,J=7.6Hz,1H),7.16(d,J=7.6Hz,1H),4.70(s,2H),3.70-3.62(p,J=6.6Hz, 1H), 3.61-3.53 (m, 1H), 2.64 (s, 3H), 2.32 (s, 3H), 1.58 (s, 6H), 1.25 (d, J = 6.6Hz, 6H).

[0060] Embodiment 20

[0061] Add oxalamide protected 2,4-difluorobenzylamine 1j (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 120℃, and the reaction time is 36h. After the reaction is completed, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3j with a yield of 68%. 1 H NMR (400 MHz, CDCl 3 )δ7.44(d,J=6.6Hz,1H),7.22-7.11(m,1H),4.87(s,2H),3.69-3.62(m,1H),3.61-3.51(m,1H),1.56(d,J=5.9Hz,6H),1.26(d,J=6.6Hz,6H).

[0062] Embodiment 21

[0063] Add oxalamide protected α-methylbenzylamine 1k (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100℃ and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3k with a yield of 89%. 1 H NMR (400 MHz, CDCl 3 )δ7.91(d,J=7.7Hz,1H),7.75-7.67(m,1H),7.55-7.47(m,2H),5.23(q,J=6.0Hz,1H),3.7 2-3.63(m,1H),3.61-3.52(m,1H),1.68(s,3H),1.65-1.50(m,6H),1.26(d,J=6.6Hz,6H).

[0064] Embodiment 22

[0065] Add oxalamide protected 4-bromobenzylamine 1l (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), potassium persulfate (0.4mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100°C and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3l with a yield of 53%. 1 H NMR (400 MHz, CDCl 3 )δ7.93(d,J=7.7Hz,1H),7.73-7.66(m,1H),7.58-7.49(m,2H),4.86(s,2H) ,3.72-3.64(m,1H),3.62-3.54(m,1H),1.58(s,6H),1.26(d,J=6.6Hz,6H).

[0066] Embodiment 23

[0067] The product 3e (0.2 mmol) was dissolved in a mixed solvent of 3 mL methanol and 1 mL water, and a strong base sodium hydroxide (0.6 mmol) was added, and the mixture was stirred at a reaction temperature of 60°C for 2 h. After the reaction was completed, dilute hydrochloric acid (1 N) was added for neutralization, and the mixture was extracted with ethyl acetate and separated by column chromatography to obtain the target product 4-methoxyisoindolinone 4 with a yield of 90%. 1 H NMR (400 MHz, CDCl 3 )δ7.55(s,1H),7.49-7.42(m,2H),7.03(dd,J=7.3,1.4Hz,1H),4.40(s,2H),3.92(s,3H).

[0068]

[0069] Comparative Example 1

[0070] Add oxalamide protected 2-fluorobenzylamine 1a (0.2mmol), ethyl glyoxylate (0.4mmol), palladium acetate (0.02mmol), di-tert-butyl peroxide (DTBP, 0.8mmol), trifluorotoluene (1mL) into a Schlenk reaction tube and seal it. Heat to 100°C and react for 24h. After the reaction, add ethyl acetate, filter, remove the solvent under reduced pressure, and separate by column chromatography to obtain the target product 3a with a yield of 38%.

Claims

1. A method for synthesizing isoindolinone compounds using palladium catalysis, characterized in that: The method comprises the following steps: in a reaction solvent, using oxalamide-protected benzylamine and ethyl glyoxylate as raw materials, in the presence of a palladium catalyst, an oxidant and an additive, and under heating conditions, synthesizing an isoindolinone compound.

2. The method for synthesizing isoindolinone compounds by palladium catalysis according to claim 1, characterized in that: The reaction solvent is trifluorotoluene, toluene, chlorobenzene and acetonitrile.

3. The method for synthesizing isoindolinone compounds by palladium catalysis according to claim 1, characterized in that: The oxalamide-protected benzylamine compound is an aromatic methylamine compound having a methyl group, a methoxy group, a fluorine group, a chlorine group, a bromine group or a trifluoromethyl group on the benzene ring.

4. The method for synthesizing isoindolinone compounds by palladium catalysis according to claim 1, characterized in that: The molar ratio of the oxamide-protected benzylamine to ethyl glyoxylate is 1:

2.

5. The method for synthesizing isoindolinone compounds by palladium catalysis according to claim 1, characterized in that: The palladium catalyst is: palladium acetate, palladium chloride, palladium trifluoroacetate, and the amount of the palladium catalyst is 0.1 times the molar number of the oxalamide-protected benzylamine compound.

6. The method for synthesizing isoindolinone compounds by palladium catalysis according to claim 1, characterized in that: The oxidant is: di-tert-butyl peroxide, cumene hydroperoxide, tert-butyl peroxide, tert-butyl peroxide benzoate, and the amount of the oxidant is 4 times the molar number of the oxalamide-protected benzylamine compound.

7. The method for synthesizing isoindolinone compounds by palladium catalysis according to claim 1, characterized in that: The additive is sodium persulfate or potassium persulfate, and the amount of the additive is twice the molar number of the oxalamide-protected benzylamine compound.

8. The method for synthesizing isoindolinone compounds by palladium catalysis according to claim 1, characterized in that: The heating synthesis conditions are: reacting at 100-120° C. for 24-36 hours.

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