Process for the preparation of a gamma-lactam compound

Abstract

The application relates to a preparation method of a gamma-lactam compound. N The substituted imine compound, a difluorocarbene precursor compound, a catalyst, a ligand, an alkali and an additive are sequentially added into a container containing an excess of solvent, and the reaction is carried out under an air atmosphere at 90 DEG C to 150 DEG C for 6 to 15 hours in a sealed state; after the reaction is completed, a reaction liquid is obtained; the reaction liquid is sequentially subjected to normal extraction, drying, concentration and column chromatography separation, and then a gamma-lactam compound is obtained. N The substituted isoindole ketone structural sequence has good regioselectivity, functional group tolerance and a wide substrate range, and provides a new idea for accurately synthesizing target molecules with potential biological activity of a five-membered heterocyclic structure.

Description

Technical Field

[0001] This invention relates to the field of organic synthetic chemistry, and more particularly to a method for preparing γ-lactam compounds. Background Technology

[0002] γ-lactams, as important nitrogen-containing heterocyclic compounds, are widely found in natural products, bioactive molecules, and multifunctional materials. They are also advanced intermediates in the synthesis of various drug molecules. Due to their unique biological properties, such as anti-anxiety, anti-tumor, anti-leukemia, antifungal, and antihypertensive activities, the efficient construction of γ-lactam compounds is of great significance.

[0003] Currently disclosed synthetic methods for γ-lactam compounds include: In 2015, Kondo's group reported a copper-catalyzed method for synthesizing 2-alkyl- N -Studies on the activation reactions of CH and NH bonds of substituted benzamides, and efficient synthesis of isoindolinones by constructing CN bonds. Org. Lett. (2015, 17, 4479-4481); In 2019, Wu Xiaofeng's research group reported a palladium-catalyzed CH carbonylation reaction, using TFBen as the carbonyl source to achieve the cyclization carbonylation reaction with benzylamine, synthesizing a series of products in moderate to good yields. N -substituted isoindolinones ( J. Org. Chem. 2019, 84, 1421-1429); In 2021, Xiang Jinbao's research group reported an efficient and practical electrochemical method for the selective reduction of cyclic imides. By adjusting the current and reaction time, hydroxylactams and lactam compounds were synthesized controllably. Org. Lett. 2021, 23, 2298-2302); In 2021, Yu Jinquan's research group achieved intramolecular CH amination of aliphatic amides to construct γ-lactam structural sequences through palladium catalysis and the use of 2-pyridone ligands, demonstrating the practicality of the reaction for the efficient synthesis of lenalidomide and brivaceran drug molecules. J. Am. Chem. Soc. 2021, 143, 21657-21666). In 2023, Das's research group achieved the synthesis of γ-lactams through a simple and readily available commercially available cyclization and carbonylation reaction using olefins, amines, and impure carbon dioxide from automobile exhaust using photocatalysis. This synthesis was then applied to the later-stage conversion of existing drugs and natural products into functionalized γ-lactams. Nat. Commun.2023, 14, 7604-7613). Recently, Professor Bingfeng Shi's research group reported a cobalt-catalyzed correspondence-selective carbonylation reaction, using CO as the C1 source to synthesize a series of chiral isoindolinones with good enantioselectivity (99% ee) and excellent yield (up to 92%). The practicality and synthetic potential of this method were demonstrated through the synthesis of the bioactive compounds (S)-PD172938 and (S)-pazinclone. Angew. Chem. Int. Ed. 2024, 63, e202318803).

[0004] Based on the fact that γ-lactams are an important core structure of a series of drug-related natural products and clinical drugs, and the challenges of using difluorocarbene as a carbonyl source in the field of carbonylation reaction research, this study aims to conduct palladium-catalyzed [4+1] cyclization carbonylation reaction to efficiently synthesize γ-lactam compounds. This breakthrough overcomes the limitation that the synthesis of cyclized carbonylation products using difluorocarbene as a carbonyl source requires halogen atom mediation, and achieves palladium-catalyzed, imine-directed C-H bond activation functionalization, providing a new approach for the green, efficient, and precise construction of five-membered ring carbonylation products. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing γ-lactam compounds that is simple to operate, highly applicable, and efficient.

[0006] To address the above problems, the present invention provides a method for preparing γ-lactam compounds, characterized in that: the method refers to sequentially... N A substituted imine compound, a difluorocarbene precursor compound, a catalyst, a ligand, a base, and an additive are sequentially added to a container containing excess solvent. The mixture is then sealed and reacted at 90°C–150°C in air for 6–15 hours. After the reaction is complete, a reaction solution is obtained. This reaction solution is then subjected to conventional extraction, drying, concentration, and column chromatography separation to obtain γ-lactam compounds. N The molar ratio of the substituted imine compound to the difluorocarbene precursor compound is 1:1.2 to 1:3; N The molar ratio of the substituted imine compound to the catalyst is 50:1 to 10:1; N The molar ratio of the substituted imine compound to the ligand is 20:1 to 5:1; N The molar ratio of the substituted imine compound to the base is 1:1 to 1:2.2; N The molar ratio of the substituted imine compound to the additive is 1:1 to 1:1.5.

[0007] The N -Substituted imine compounds refer to N- benzylbenzylamine, N-Benzyl-1-(2-methoxyphenyl)methylimine, N -[(2-methylphenyl)methylene]benzylamine, N -[(2-chlorophenyl)methylene]benzylamine, N- [(3-fluorophenyl)methylene]benzylamine, 3-[[(phenylmethyl)imino]methyl]benzonitrile, N -(4-methoxybenzyl)benzylamine, N -[(4-methylphenyl)methylene]benzylamine, N -(4-Fluorobenzyl)benzylamine, N -(4-chlorobenzyl)benzylamine, N -[(4-bromophenyl)methylene]benzylamine, N -([1,1′-biphenyl]-4-ylmethylene)benzylamine, N -[(4-iodophenyl)methylene]benzylamine, N -[(4-nitrophenyl)methylene]benzylamine, 4-[[(phenylmethyl)imino]methyl]benzonitrile, N -[[4-(dimethylamino)phenyl]methylene]benzylamine, 2-methyl- N -(phenylmethylene)benzylamine, 2-chloro- N -(phenylmethylene)benzylamine, 3-methoxy- N -(phenylmethylene)benzylamine, 3-chloro- N -(phenylmethylene)benzylamine, 3-bromo- N -(phenylmethylene)benzylamine, 4-methoxy- N -(phenylmethylene)benzylamine, 4-fluoro- N -(phenylmethylene)benzylamine, 4-chloro- N -(phenylmethylene)benzylamine, 4-bromo- N -(phenylmethylene)benzylamine, N -(phenylmethylene)-4-(trifluoromethyl)benzylamine, N- (phenylmethylene)-4-(trifluoromethoxy)benzylamine, 4-[[(phenylmethylene)amino]methyl]benzonitrile, N -(phenylmethylene)-1-butylamine, N -(phenylmethylene)cyclopentylamine, N Any one of 3-(phenylmethylene)cyclohexylamine and methyl 3-{4-[(4-methoxybenzylimino)methyl]phenyl}acrylate.

[0008] The difluorocarbene precursor compound refers to any one of potassium 2-bromo-2,2-difluoroacetate, sodium 2-chloro-2,2-difluoroacetate, ethyl difluorobromoacetate, diethyl bromodifluoromethylphosphonate, and (trifluoromethyl)trimethylsilane.

[0009] The catalyst refers to any one of the following palladium compounds: palladium acetate, palladium di(triphenylphosphine) dichloride, palladium tetra(triphenylphosphine) palladium, palladium diacetylacetone, palladium bromide, palladium chloride, and palladium iodide.

[0010] The ligand refers to any one of bis(2-diphenylphosphine) ether, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, triphenylphosphine, tri(o-methylphenyl)phosphine, and 1,3-bis(diphenylphosphine)propane.

[0011] The alkali refers to any one of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium tert-butoxide, and cesium carbonate.

[0012] The additive refers to any one of potassium iodide, sodium iodide, ammonium iodide, potassium fluoride, sodium bromide, and potassium bromide.

[0013] The solvent refers to toluene, benzene, xylene, N,N -Dimethylformamide, N,N - Any one of dimethylacetamide, trifluorotoluene, dimethyl sulfoxide, and chlorobenzene.

[0014] Compared with the prior art, the present invention has the following advantages: 1. This invention realizes the study of transition metal-catalyzed inert CH bond activation and difluorocarbene cyclization carbonylation reaction, avoiding the participation of halogen atoms, and constructing multiple CC bonds, CN bonds and C=O bonds in one step. It has the characteristics of economical reaction steps, simplicity and efficiency, high chemical selectivity, good substrate universality, and has broad application prospects and economic value for the large-scale synthesis of related bioactive compounds.

[0015] 2. This invention uses difluorocarbene as a carbonyl source to participate in cyclization and carbonylation reactions. Unlike traditional strategies, it does not have special requirements for substrates and reaction conditions. It provides a new, efficient, highly selective, and green synthetic route for carbonyl compounds with potential application value that are difficult or hard to synthesize using traditional methods. The reaction conditions are mild and the raw materials are simple and readily available.

[0016] 3. This invention has prepared a variety of pharmacologically active substances with excellent yields. N The -substituted isoindole ketone structural sequence, with its good regioselectivity, functional group tolerance, and broad substrate range, provides a new approach for the precise synthesis of target molecules with potential biological activities and five-membered heterocyclic structures. Detailed Implementation

[0017] A method for preparing a γ-lactam compound, the method comprising sequentially comprising... NA substituted imine compound, a difluorocarbene precursor compound, a catalyst, a ligand, a base, and an additive are sequentially added to a container containing excess solvent. The mixture is then reacted under air at 90°C–150°C for 6–15 hours, preferably at 130°C–140°C for 9–12 hours, and more preferably at 130°C–140°C for 10 hours. After the reaction is complete, a reaction solution is obtained. This reaction solution is then subjected to conventional extraction, drying, concentration, and column chromatography separation to obtain the γ-lactam compound.

[0018] in: N The molar ratio of the substituted imine compound to the difluorocarbene precursor compound is 1:1.2 to 1:3; N The molar ratio of substituted imine compounds to catalysts is 50:1 to 10:1; N The molar ratio of substituted imine compounds to ligands is 20:1 to 5:1; N The molar ratio of substituted imine compounds to bases is 1:1 to 1:2.2; N The molar ratio of substituted imine compounds to additives is 1:1 to 1:1.5.

[0019] N -Substituted imine compounds refer to N- Benzylbenzylamine (CAS: 780-25-6) N -Benzyl-1-(2-methoxyphenyl)methylimine (CAS: 119405-95-7) N -[(2-Methylphenyl)methylene]benzylamine (CAS: 24431-16-1), N -[(2-Chlorophenyl)methylene]benzylamine (CAS: 190067-71-1), N- [(3-Fluorophenyl)methylene]benzylamine (CAS: 1254038-43-1), 3-[[(phenylmethyl)imino]methyl]benzonitrile, N -(4-Methoxybenzyl)benzylamine (CAS: 622-72-0) N -[(4-Methylphenyl)methylene]benzylamine (CAS: 24431-15-0), N -(4-Fluorobenzyme)benzylamine (CAS: 67907-60-2), N -(4-chlorobenzyl)benzylamine (CAS: 13540-93-7), N -[(4-bromophenyl)methylene]benzylamine (CAS: 27046-29-3), N -([1,1′-biphenyl]-4-ylmethylene)benzylamine (CAS: 118578-71-5), N-[(4-iodophenyl)methylene]benzylamine (CAS: 860590-07-4), N -[(4-nitrophenyl)methylene]benzylamine (CAS: 14428-97-8), 4-[[(phenylmethyl)imino]methyl]benzonitrile (CAS: 67907-57-7) N -[[4-(dimethylamino)phenyl]methylene]benzylamine (CAS: 24431-17-2), 2-methyl- N 2-(phenylmethylene)benzylamine (CAS: 872975-16-1), 2-chloro- N -(phenylmethylene)benzylamine (CAS: 1998709-01-5), 3-methoxy- N 3-(phenylmethylene)benzylamine (CAS: 115397-88-1), 3-chloro- N 3-(phenylmethylene)benzylamine (CAS: 67907-54-4), 3-bromo- N -(phenylmethylene)benzylamine (CAS: 67907-53-3), 4-methoxy- N -(phenylmethylene)benzylamine (CAS: 31490-38-7), 4-fluoro- N 4-(phenylmethylene)benzylamine (CAS: 67907-55-5), 4-chloro- N -(phenylmethylene)benzylamine (CAS: 15383-71-8), 4-bromo- N -(phenylmethylene)benzylamine (CAS: 610269-12-0), N -(phenylmethylene)-4-(trifluoromethyl)benzylamine (CAS: 946009-16-1), N- (phenylmethylene)-4-(trifluoromethoxy)benzylamine, 4-[[(phenylmethylene)amino]methyl]benzonitrile (CAS: 67907-52-2) N -(phenylmethylene)-1-butylamine (CAS: 1077-18-5) N -(phenylmethylene)cyclopentanamine (CAS: 27721-47-7), N 3-(phenylmethylene)cyclohexylamine (CAS: 2211-66-7) and methyl 3-{4-[(4-methoxybenzylimino)methyl]phenyl}acrylate.

[0020] 3-[[(phenylmethyl)imino]methyl]benzonitrile was prepared as follows: In a 10 mL dry, pressure-resistant test tube equipped with a magnetic stirrer, 1.2 mmol (1.2 equivalents) of 3-cyanobenzaldehyde (CAS: 24964-64-5), 1.0 mmol (1.0 equivalent), 0.5 g of 3A MS, 0.1 mmol (0.1 equivalent), and 3 mL of dry dichloromethane were added. The mixture was stirred at 70°C for 12 hours. After cooling to room temperature, the solid was filtered off, and the solution was concentrated. The residue was then purified by silica gel chromatography. The obtained 3-[[(phenylmethyl)imino]methyl]benzonitrile was recrystallized from dichloromethane and n-hexane before use. J. Am. Chem. Soc (2014, 136, 1082−1089) N- (Phenylenemethylene)-4-(trifluoromethoxy)benzylamine was prepared as follows: In a 10 mL dry, pressure-resistant test tube equipped with a magnetic stirrer, benzaldehyde (CAS: 100-52-7) (1.2 mmol, 1.2 equivalents), 4-(trifluoromethoxy)benzylamine (CAS: 93919-56-3) (1.0 mmol, 1.0 equivalent), 3A MS (0.5 g), pyrrolidine (0.1 mmol, 0.1 equivalent), and dry dichloromethane (3 mL) were added. The mixture was stirred at 70°C for 12 hours. After cooling to room temperature, the solids were filtered off, and the solution was concentrated. The residue was then purified by silica gel chromatography. The obtained... N- (Phenylenemethylene)-4-(trifluoromethoxy)benzylamine is used after recrystallization from dichloromethane and n-hexane. J. Am. Chem. Soc. 2014, 136, 1082−1089) Methyl 3-{4-[(4-methoxybenzylimino)methyl]phenyl}acrylate was prepared as follows: In a 10 mL dry, pressure-resistant test tube equipped with a magnetic stirrer, methyl p-formylcinnamate (CAS: 7560-50-1) (1.2 mmol, 1.2 equivalents), 4-methoxybenzylamine (CAS: 2393-23-9) (1.0 mmol, 1.0 equivalent), 3A MS (0.5 g), pyrrolidine (0.1 mmol, 0.1 equivalent), and dry dichloromethane (3 mL) were added. The mixture was stirred at 70°C for 12 hours. After cooling to room temperature, the solids were filtered off, and the solution was concentrated. The residue was then purified by silica gel chromatography. The obtained methyl 3-{4-[(4-methoxybenzylimino)methyl]phenyl}acrylate was recrystallized from dichloromethane and n-hexane before use. J. Am. Chem. Soc. 2014,136 , 1082−1089) Difluorocarbene precursor compounds refer to any one of the following: potassium 2-bromo-2,2-difluoroacetate (CAS: 87189-16-0), sodium 2-chloro-2,2-difluoroacetate (CAS: 1895-39-2), ethyl difluorobromoacetate (CAS: 667-27-6), diethyl bromodifluoromethylphosphonate (CAS: 65094-22-6), and (trifluoromethyl)trimethylsilane (CAS: 81290-20-2).

[0021] The catalyst refers to any palladium compound selected from palladium acetate, palladium dichloride (CAS: 13965-03-2), palladium tetra(triphenylphosphine) (CAS: 14221-01-3), palladium diacetylacetonate (CAS: 14024-61-4), palladium bromide, palladium chloride, and palladium iodide.

[0022] The ligand refers to any one of the following: bis(2-diphenylphosphine) ether (CAS: 166330-10-5), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (CAS: 161265-03-8), triphenylphosphine (CAS: 603-35-0), tris(o-methylphenyl)phosphine (CAS: 6163-58-2), and 1,3-bis(diphenylphosphine)propane (CAS: 6737-42-4).

[0023] Alkali refers to any one of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium tert-butoxide, and cesium carbonate.

[0024] Additives refer to any one of potassium iodide, sodium iodide, ammonium iodide, potassium fluoride, sodium bromide, and potassium bromide.

[0025] Solvents refer to toluene, benzene, xylene, N,N -Dimethylformamide, N,N - Any one of dimethylacetamide, trifluorotoluene, dimethyl sulfoxide, and chlorobenzene.

[0026] Example 1: A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N- The benzyltriphenylamine, sodium 2-chloro-2,2-difluoroacetate, palladium dichloride (di(triphenylphosphine) dichloride), bis(2-diphenylphosphine) ether, potassium carbonate, potassium iodide, and excess benzene were mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0027] in: N- The molar ratio of benzylidene amine to sodium 2-chloro-2,2-difluoroacetate is 1:1.7; N- The molar ratio of benzylidene benzylamine to bis(triphenylphosphine)palladium dichloride is 30:1; N-The molar ratio of benzylidene benzylamine to bis(2-diphenylphosphine) ether is 15:1; N- The molar ratio of benzylidene amine to potassium carbonate is 1:1.2; N- The molar ratio of benzylidene amine to potassium iodide is 1:1.2.

[0028] The entire reaction process was monitored using thin-layer chromatography, that is, samples were taken every hour, and the reaction solution and the raw material solution were spotted onto a silica gel plate using a capillary tube. N- Spot the benzyltrimethylamine sample, ensuring the two spots are aligned in a straight line. Then, place the silica gel plate into a developing flask containing a 4:1 petroleum ether-ethyl acetate mixture (volume ratio: mL / mL). After the plate has run, observe the silica gel plate under UV light. If the reaction solution does not contain any substances similar to the starting material solution... N- The point at which benzylidene benzylamine is level with the reaction solution indicates that the reaction is complete.

[0029] The reaction solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined to obtain the extract. Anhydrous magnesium sulfate was added to the extract and dried. After filtration, the filtrate was obtained. Then, the solvent was removed by vacuum evaporation using a RE-52AA rotary evaporator (manufactured by Shanghai Yarong Biochemical Co., Ltd.) at 40℃ to obtain the concentrate. 2-3 times the mass of the concentrate was added to the concentrate for mixing. The mixture was then placed in a chromatography column, and a petroleum ether-ethyl acetate mixture with a volume ratio (mL / mL) of 6:1 was added for elution. The eluent was collected and concentrated in a rotary evaporator at 40℃ to obtain 2-benzylisoindoline-1-one, with a yield of 79%.

[0030] Example 2 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N Benzyl-1-(2-methoxyphenyl)methylimine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, potassium carbonate, potassium iodide, and excess benzene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0031] in: N The molar ratio of benzyl-1-(2-methoxyphenyl)methylimine to sodium 2-chloro-2,2-difluoroacetate is 1:2; N The molar ratio of benzyl-1-(2-methoxyphenyl)methylimine to palladium acetate is 20:1; N The molar ratio of benzyl-1-(2-methoxyphenyl)methylimine to 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene is 10:1; N The molar ratio of benzyl-1-(2-methoxyphenyl)methylimine to potassium carbonate is 1:2.2; NThe molar ratio of benzyl-1-(2-methoxyphenyl)methylimine to potassium iodide is 1:1.

[0032] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-benzyl-4-methoxyisoindoline-1-one was obtained with a yield of 71%.

[0033] Example 3 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N -[(2-methylphenyl)methylene]benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, bis(2-diphenylphosphine) ether, potassium carbonate, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0034] in: N The molar ratio of -[(2-methylphenyl)methylene]benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.6; N The molar ratio of -[(2-methylphenyl)methylene]benzylamine to palladium acetate is 25:1; N The molar ratio of -[(2-methylphenyl)methylene]benzylamine to bis(2-diphenylphosphine) ether is 15:1; N The molar ratio of -[(2-methylphenyl)methylene]benzylamine to potassium carbonate is 1:1.5; N The molar ratio of -[(2-methylphenyl)methylene]benzylamine to potassium iodide is 1:1.

[0035] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After the reaction solution was sequentially extracted, dried, concentrated, and separated by column chromatography according to the method described in Example 1, 2-benzyl-4-methylisoindoline-1-one was obtained with a yield of 76%.

[0036] Example 4: A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N -[(2-chlorophenyl)methylene]benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium diacetylacetone, bis(2-diphenylphosphine) ether, potassium carbonate, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 130°C for 10 hours.

[0037] in: N The molar ratio of -[(2-chlorophenyl)methylene]benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.5; N The molar ratio of -[(2-chlorophenyl)methylene]benzylamine to palladium diacetylacetone is 20:1; NThe molar ratio of -[(2-chlorophenyl)methylene]benzylamine to bis(2-diphenylphosphine) ether is 20:1; N The molar ratio of -[(2-chlorophenyl)methylene]benzylamine to potassium carbonate is 1:2; N The molar ratio of -[(2-chlorophenyl)methylene]benzylamine to potassium iodide is 1:1.5.

[0038] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-benzyl-4-chloroisoindoline-1-one was obtained with a yield of 90%.

[0039] Example 5 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N -[(3-fluorophenyl)methylene]benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, bis(2-diphenylphosphine) ether, cesium carbonate, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 130°C for 12 hours.

[0040] in: N The molar ratio of -[(3-fluorophenyl)methylene]benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.5; N The molar ratio of -[(3-fluorophenyl)methylene]benzylamine to palladium acetate is 10:1; N The molar ratio of -[(3-fluorophenyl)methylene]benzylamine to bis(2-diphenylphosphine) ether is 5:1; N The molar ratio of -[(3-fluorophenyl)methylene]benzylamine to cesium carbonate is 1:2.2; N The molar ratio of -[(3-fluorophenyl)methylene]benzylamine to potassium iodide is 1:1.2.

[0041] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-benzyl-7-fluoroisoindoline-1-one was obtained with a yield of 78%.

[0042] Example 6 A method for preparing a γ-lactam compound, wherein 3-[[(phenylmethyl)imino]methyl]benzonitrile, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, bis(2-diphenylphosphine) ether, potassium carbonate, potassium iodide and excess toluene are mixed uniformly and reacted in a sealed container at 140°C for 11 hours.

[0043] The molar ratio of 3-[[(phenylmethyl)imino]methyl]benzonitrile to sodium 2-chloro-2,2-difluoroacetate is 1:2; the molar ratio of 3-[[(phenylmethyl)imino]methyl]benzonitrile to palladium acetate is 15:1; the molar ratio of 3-[[(phenylmethyl)imino]methyl]benzonitrile to bis(2-diphenylphosphine) ether is 5:1; the molar ratio of 3-[[(phenylmethyl)imino]methyl]benzonitrile to potassium carbonate is 1:1.8; and the molar ratio of 3-[[(phenylmethyl)imino]methyl]benzonitrile to potassium iodide is 1:1.

[0044] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-benzyl-7-cyanoisoindoline-1-one was obtained with a yield of 88%.

[0045] Example 7 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N -(4-methoxybenzyl)benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, bis(2-diphenylphosphine) ether, potassium carbonate, potassium fluoride and excess benzene are mixed evenly and reacted in a sealed container at 130°C for 10 hours.

[0046] in: N The molar ratio of 4-(4-methoxybenzyl)benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:3; N The molar ratio of 4-methoxybenzyl)benzylamine to palladium acetate is 20:1; N The molar ratio of 4-methoxybenzylamine to bis(2-diphenylphosphine) ether is 10:1; N The molar ratio of 4-methoxybenzyl)benzylamine to potassium carbonate is 1:1.5; N The molar ratio of 4-methoxybenzyl)benzylamine to potassium fluoride is 1:1.2.

[0047] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-benzyl-6-methoxyisoindoline-1-one was obtained with a yield of 76%.

[0048] Example 8 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N -[(4-methylphenyl)methylene]benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, triphenylphosphine, potassium carbonate, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 130°C for 12 hours.

[0049] in: NThe molar ratio of -[(4-methylphenyl)methylene]benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.5; N The molar ratio of -[(4-methylphenyl)methylene]benzylamine to palladium acetate is 20:1; N The molar ratio of -[(4-methylphenyl)methylene]benzylamine to triphenylphosphine is 10:1; N The molar ratio of -[(4-methylphenyl)methylene]benzylamine to potassium carbonate is 1:2; N The molar ratio of -[(4-methylphenyl)methylene]benzylamine to potassium iodide is 1:1.2.

[0050] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After the reaction solution was sequentially extracted, dried, concentrated, and separated by column chromatography according to the method described in Example 1, 2-benzyl-6-methylisoindoline-1-one was obtained with a yield of 79%.

[0051] Example 9 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N -(4-fluorobenzyl)benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, bis(2-diphenylphosphine) ether, sodium carbonate, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0052] in: N The molar ratio of 4-fluorobenzyl)benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.8; N The molar ratio of 4-fluorobenzyl)benzylamine to palladium acetate is 40:1; N The molar ratio of 4-fluorobenzyl)benzylamine to bis(2-diphenylphosphine) ether is 20:1; N The molar ratio of 4-fluorobenzyl)benzylamine to sodium carbonate is 1:2.2; N The molar ratio of 4-fluorobenzyl)benzylamine to potassium iodide is 1:1.

[0053] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After the reaction solution was sequentially extracted, dried, concentrated, and separated by column chromatography according to the method described in Example 1, 2-benzyl-6-fluoroisoindoline-1-one was obtained with a yield of 83%.

[0054] Example 10 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N -(4-chlorobenzyl)benzylamine, potassium 2-bromo-2,2-difluoroacetate, palladium dichloride (triphenylphosphine), bis(2-diphenylphosphine) ether, potassium phosphate, potassium iodide, and excess N,N - Dimethylformamide was mixed evenly and then sealed and reacted at 140°C for 10 hours.

[0055] in: N The molar ratio of 4-chlorobenzyl)benzylamine to potassium 2-bromo-2,2-difluoroacetate is 1:1.5; N The molar ratio of 4-chlorobenzyl)benzylamine to bis(triphenylphosphine)palladium dichloride is 20:1; N The molar ratio of 4-chlorobenzyl)benzylamine to bis(2-diphenylphosphine) ether is 10:1; N The molar ratio of 4-chlorobenzyl)benzylamine to potassium phosphate is 1:2; N The molar ratio of -(4-chlorobenzyl)benzylamine to potassium iodide is 1:1.

[0056] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-benzyl-6-chloroisoindoline-1-one was obtained with a yield of 80%.

[0057] Example 11 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N -[(4-bromophenyl)methylene]benzylamine, ethyl difluorobromoacetate, palladium acetate, bis(2-diphenylphosphine) ether, potassium carbonate, sodium iodide, and excess benzene are mixed evenly and reacted in a sealed container at 140°C for 9 hours.

[0058] in: N The molar ratio of -[(4-bromophenyl)methylene]benzylamine to ethyl difluorobromoacetate is 1:1.2; N The molar ratio of -[(4-bromophenyl)methylene]benzylamine to palladium acetate is 50:1; N The molar ratio of -[(4-bromophenyl)methylene]benzylamine to bis(2-diphenylphosphine) ether is 5:1; N The molar ratio of -[(4-bromophenyl)methylene]benzylamine to potassium carbonate is 1:1.5; N The molar ratio of -[(4-bromophenyl)methylene]benzylamine to sodium iodide is 1:1.

[0059] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-benzyl-6-bromoisoindoline-1-one was obtained with a yield of 81%.

[0060] Example 12 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N-([1,1′-biphenyl]-4-ylmethylene)benzylamine, diethyl bromodifluoromethylphosphonate, palladium acetate, bis(2-diphenylphosphine) ether, potassium carbonate, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 130°C for 10 hours.

[0061] in: N The molar ratio of -([1,1′-biphenyl]-4-ylmethylene)benzylamine to diethyl bromodifluoromethylphosphonate is 1:3; N The molar ratio of -([1,1′-biphenyl]-4-ylmethylene)benzylamine to palladium acetate is 10:1; N The molar ratio of -([1,1′-biphenyl]-4-ylmethylene)benzylamine to bis(2-diphenylphosphine) ether is 15:1; N The molar ratio of -([1,1′-biphenyl]-4-ylmethylene)benzylamine to potassium carbonate is 1:2.2; N The molar ratio of -([1,1′-biphenyl]-4-ylmethylene)benzylamine to potassium iodide is 1:1.5.

[0062] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After the reaction solution was sequentially extracted, dried, concentrated, and separated by column chromatography according to the method described in Example 1, 2-benzyl-6-phenylisoindoline-1-one was obtained with a yield of 77%.

[0063] Example 13 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N -[(4-iodophenyl)methylene]benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, triphenylphosphine, potassium carbonate, potassium iodide, and excess toluene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0064] in: N The molar ratio of -[(4-iodophenyl)methylene]benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:2; N The molar ratio of -[(4-iodophenyl)methylene]benzylamine to palladium acetate is 10:1; N The molar ratio of -[(4-iodophenyl)methylene]benzylamine to triphenylphosphine is 5:1; N The molar ratio of -[(4-iodophenyl)methylene]benzylamine to potassium carbonate is 1:1.5; N The molar ratio of -[(4-iodophenyl)methylene]benzylamine to potassium iodide is 1:1.5.

[0065] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After the reaction solution was sequentially extracted, dried, concentrated, and separated by column chromatography according to the method described in Example 1, 2-benzyl-6-iodoisoindoline-1-one was obtained with a yield of 79%.

[0066] Example 14 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N -[(4-nitrophenyl)methylene]benzylamine, (trifluoromethyl)trimethylsilane, palladium acetate, bis(2-diphenylphosphine) ether, potassium carbonate, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 130°C for 10 hours.

[0067] in: N The molar ratio of -[(4-nitrophenyl)methylene]benzylamine to (trifluoromethyl)trimethylsilane is 1:1.5; N The molar ratio of -[(4-nitrophenyl)methylene]benzylamine to palladium acetate is 12:1; N The molar ratio of -[(4-nitrophenyl)methylene]benzylamine to bis(2-diphenylphosphine) ether is 10:1; N The molar ratio of -[(4-nitrophenyl)methylene]benzylamine to potassium carbonate is 1:2; N The molar ratio of -[(4-nitrophenyl)methylene]benzylamine to potassium iodide is 1:1.5.

[0068] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After the reaction solution was sequentially extracted, dried, concentrated, and separated by column chromatography according to the method described in Example 1, 2-benzyl-6-nitroisoindoline-1-one was obtained with a yield of 88%.

[0069] Example 15 A method for preparing a γ-lactam compound, wherein 4-[[(phenylmethyl)imino]methyl]benzonitrile, sodium 2-chloro-2,2-difluoroacetate, palladium dichloride bis(triphenylphosphine)dichloride, bis(2-diphenylphosphine) ether, potassium carbonate, potassium iodide and excess benzene are mixed uniformly and reacted in a sealed container at 140°C for 10 hours.

[0070] The molar ratio of 4-[[(phenylmethyl)imino]methyl]benzonitrile to sodium 2-chloro-2,2-difluoroacetate is 1:2; the molar ratio of 4-[[(phenylmethyl)imino]methyl]benzonitrile to bis(triphenylphosphine)palladium dichloride is 12:1; the molar ratio of 4-[[(phenylmethyl)imino]methyl]benzonitrile to bis(2-diphenylphosphine) ether is 10:1; the molar ratio of 4-[[(phenylmethyl)imino]methyl]benzonitrile to potassium carbonate is 1:2; and the molar ratio of 4-[[(phenylmethyl)imino]methyl]benzonitrile to potassium iodide is 1:1.

[0071] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-benzyl-6-cyanoisoindoline-1-one was obtained with a yield of 80%.

[0072] Example 16 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N -[[4-(dimethylamino)phenyl]methylene]benzylamine, sodium 2-chloro-2,2-difluoroacetate, tetra(triphenylphosphine)palladium, bis(2-diphenylphosphine) ether, potassium carbonate, sodium iodide and excess xylene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0073] in: N The molar ratio of 4-(dimethylamino)phenyl]methylene]benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:2.5; N The molar ratio of -[[4-(dimethylamino)phenyl]methylene]benzylamine to tetra(triphenylphosphine)palladium is 25:1; N The molar ratio of -[[4-(dimethylamino)phenyl]methylene]benzylamine to bis(2-diphenylphosphine) ether is 5:1; N The molar ratio of 4-(dimethylamino)phenyl]methylene]benzylamine to potassium carbonate is 1:2; N The molar ratio of -[[4-(dimethylamino)phenyl]methylene]benzylamine to sodium iodide is 1:1.5.

[0074] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-benzyl-6-dimethylaminoisoindoline-1-one was obtained with a yield of 63%.

[0075] Example 17 A method for preparing a γ-lactam compound, wherein the method refers to sequentially adding 2-methyl- N 1,(phenylmethylene)benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, bis(2-diphenylphosphine) ether, sodium bicarbonate, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0076] Wherein: 2-methyl- N The molar ratio of 2-(phenylmethylene)benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.2; 2-methyl- N The molar ratio of 2-(phenylmethylene)benzylamine to palladium acetate is 30:1; N The molar ratio of 2-(phenylmethylene)benzylamine to bis(2-diphenylphosphine) ether is 10:1; 2-methyl- N The molar ratio of 2-(phenylmethylene)benzylamine to sodium bicarbonate is 1:1.8; N The molar ratio of 1:1 for (phenylmethylene)benzylamine to potassium iodide is 1:1.

[0077] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-(2-methylbenzyl)isoindoline-1-one was obtained with a yield of 87%.

[0078] Example 18 A method for preparing a γ-lactam compound, wherein the method refers to sequentially preparing 2-chloro- N 1,(phenylmethylene)benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium iodide, bis(2-diphenylphosphine) ether, potassium carbonate, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0079] Wherein: 2-chloro- N The molar ratio of 2-(phenylmethylene)benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.5; 2-chloro- N The molar ratio of 2-(phenylmethylene)benzylamine to palladium iodide is 15:1; 2-chloro- N The molar ratio of 1-(phenylmethylene)benzylamine to bis(2-diphenylphosphine) ether is 10:1; 2-chloro- N The molar ratio of 2-(phenylmethylene)benzylamine to potassium carbonate is 1:2; 2-chloro- N The molar ratio of 1-(phenylmethylene)benzylamine to potassium iodide is 1:1.25.

[0080] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After the reaction solution was sequentially extracted, dried, concentrated, and separated by column chromatography according to the method described in Example 1, 2-(2-chlorobenzyl)isoindoline-1-one was obtained with a yield of 69%.

[0081] Example 19 A method for preparing a γ-lactam compound, wherein the method refers to sequentially adding 3-methoxy- N 1,3-(phenylmethylene)benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, 1,3-bis(diphenylphosphine)propane, potassium carbonate, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 130°C for 11 hours.

[0082] Among them: 3-methoxy- N The molar ratio of 3-(phenylmethylene)benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.5; 3-methoxy- N The molar ratio of 3-(phenylmethylene)benzylamine to palladium acetate is 30:1; 3-methoxy- N The molar ratio of 1,3-(phenylmethylene)benzylamine to 1,3-bis(diphenylphosphine)propane is 10:1; 3-methoxy- N The molar ratio of 3-(phenylmethylene)benzylamine to potassium carbonate is 1:2; 3-methoxy-N The molar ratio of 1-(phenylmethylene)benzylamine to potassium iodide is 1:1.5.

[0083] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-(3-methoxybenzyl)isoindoline-1-one was obtained with a yield of 91%.

[0084] Example 20 A method for preparing a γ-lactam compound, wherein the method refers to sequentially preparing 3-chloro -N 1,(phenylmethylene)benzylamine, sodium 2-chloro-2,2-difluoroacetate, tetra(triphenylphosphine)palladium, tri(o-methylphenyl)phosphine, potassium carbonate, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0085] Among them: 3-chloro -N The molar ratio of 3-(phenylmethylene)benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.5; 3-chloro... -N The molar ratio of 3-(phenylmethylene)benzylamine to tetra(triphenylphosphine)palladium is 35:1; 3-chloro -N The molar ratio of 3-(phenylmethylene)benzylamine to tris(o-methylphenyl)phosphine is 20:1; 3-chloro -N The molar ratio of 3-(phenylmethylene)benzylamine to potassium carbonate is 1:1.5; 3-chloro... -N The molar ratio of 1:1 for (phenylmethylene)benzylamine to potassium iodide is 1:1.

[0086] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-(3-chlorobenzyl)isoindoline-1-one was obtained with a yield of 63%.

[0087] Example 21 A method for preparing a γ-lactam compound, wherein the method refers to sequentially preparing 3-bromo- N 1,(phenylmethylene)benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, bis(2-diphenylphosphine) ether, potassium tert-butoxide, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0088] Among them: 3-bromo- N The molar ratio of 3-(phenylmethylene)benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:2; 3-bromo- N The molar ratio of 3-(phenylmethylene)benzylamine to palladium acetate is 30:1; 3-bromo- N The molar ratio of 3-(phenylmethylene)benzylamine to bis(2-diphenylphosphine) ether is 5:1; 3-bromo- NThe molar ratio of 3-(phenylmethylene)benzylamine to potassium tert-butoxide is 1:1.5; 3-bromo- N The molar ratio of 1:1 for (phenylmethylene)benzylamine to potassium iodide is 1:1.

[0089] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-(3-bromobenzyl)isoindoline-1-one was obtained with a yield of 56%.

[0090] Example 22 A method for preparing a γ-lactam compound, wherein the method refers to sequentially adding 4-methoxy- N 1,(phenylmethylene)benzylamine, sodium 2-chloro-2,2-difluoroacetate, bis(triphenylphosphine)palladium dichloride, bis(2-diphenylphosphine) ether, potassium carbonate, ammonium iodide and excess benzene are mixed evenly and reacted in a sealed container at 130°C for 11 hours.

[0091] Among them: 4-methoxy- N The molar ratio of 4-(phenylmethylene)benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:2.5; 4-methoxy- N The molar ratio of 4-(phenylmethylene)benzylamine to bis(triphenylphosphine)palladium dichloride is 20:1; 4-methoxy- N The molar ratio of 4-(phenylmethylene)benzylamine to bis(2-diphenylphosphine) ether is 5:1; 4-methoxy- N The molar ratio of 4-(phenylmethylene)benzylamine to potassium carbonate is 1:2.2; 4-methoxy- N The molar ratio of 1:1 for (phenylmethylene)benzylamine to ammonium iodide is 1:1.

[0092] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-(4-methoxybenzyl)isoindoline-1-one was obtained with a yield of 93%.

[0093] Example 23 A method for preparing a γ-lactam compound, wherein the method refers to sequentially adding 4-fluoro -N 1,(phenylmethylene)benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, bis(2-diphenylphosphine) ether, potassium carbonate, sodium bromide, and excess N,N - Mix dimethylacetamide thoroughly and react in a sealed container at 130°C for 10 hours.

[0094] Of which: 4-fluoro -N The molar ratio of 1-(phenylmethylene)benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:2; 4-fluoro -NThe molar ratio of 4-(phenylmethylene)benzylamine to palladium acetate is 40:1; 4-fluoro -N The molar ratio of 1-(phenylmethylene)benzylamine to bis(2-diphenylphosphine) ether is 10:1; 4-fluoro -N The molar ratio of 4-(phenylmethylene)benzylamine to potassium carbonate is 1:2; 4-fluoro -N The molar ratio of 1:1 for (phenylmethylene)benzylamine and sodium bromide is 1:1.

[0095] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-(4-fluorobenzyl)isoindoline-1-one was obtained with a yield of 68%.

[0096] Example 24 A method for preparing a γ-lactam compound, wherein the method refers to sequentially preparing 4-chloro- N 1,(phenylmethylene)benzylamine, sodium 2-chloro-2,2-difluoroacetate, tetra(triphenylphosphine)palladium, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, potassium phosphate, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0097] Among them: 4-chloro- N The molar ratio of 4-(phenylmethylene)benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.2; N The molar ratio of 4-(phenylmethylene)benzylamine to tetra(triphenylphosphine)palladium is 20:1; 4-chloro- N The molar ratio of 4,5-(phenylmethylene)benzylamine to 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene is 20:1; 4-chloro- N The molar ratio of 4-(phenylmethylene)benzylamine to potassium phosphate is 1:1.8; 4-chloro- N The molar ratio of 1:1 for (phenylmethylene)benzylamine to potassium iodide is 1:1.

[0098] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-(4-chlorobenzyl)isoindoline-1-one was obtained with a yield of 54%.

[0099] Example 25 A method for preparing a γ-lactam compound, wherein the method refers to sequentially preparing 4-bromo- N 1,(phenylmethylene)benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, potassium carbonate, potassium fluoride and excess benzene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0100] Among them: 4-bromo- N The molar ratio of 4-(phenylmethylene)benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.5; 4-bromo- N The molar ratio of 4-(phenylmethylene)benzylamine to palladium acetate is 10:1; 4-bromo- N The molar ratio of 4,5-(phenylmethylene)benzylamine to 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene is 15:1; 4-bromo- N The molar ratio of 4-(phenylmethylene)benzylamine to potassium carbonate is 1:2.2; N The molar ratio of 1-(phenylmethylene)benzylamine to potassium fluoride is 1:1.5.

[0101] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-(4-bromobenzyl)isoindoline-1-one was obtained with a yield of 66%.

[0102] Example 26 A method for preparing a γ-lactam compound, the method comprising sequentially... N -(phenylmethylene)-4-(trifluoromethyl)benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, potassium carbonate, potassium bromide and excess benzene are mixed evenly and reacted in a sealed container at 140°C for 9 hours.

[0103] in: N The molar ratio of 4-(phenylmethylene)-4-(trifluoromethyl)benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.5; N The molar ratio of -(phenylmethylene)-4-(trifluoromethyl)benzylamine to palladium acetate is 25:1; N The molar ratio of -(phenylmethylene)-4-(trifluoromethyl)benzylamine to 4,5-bis(diphenylphosphine)-9,9-dimethyloxane is 10:1; N The molar ratio of 4-(phenylmethylene)-4-(trifluoromethyl)benzylamine to potassium carbonate is 1:1.5; N The molar ratio of -(phenylmethylene)-4-(trifluoromethyl)benzylamine to potassium bromide is 1:1.5.

[0104] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After the reaction solution was sequentially extracted, dried, concentrated, and separated by column chromatography according to the method described in Example 1, 2-(4-trifluoromethylbenzyl)isoindoline-1-one was obtained with a yield of 50%.

[0105] Example 27 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N-(phenylmethylene)-4-(trifluoromethoxy)benzylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, potassium carbonate, potassium iodide and excess chlorobenzene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0106] in: N The molar ratio of 4-(phenylmethylene)-4-(trifluoromethoxy)benzylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.5; N The molar ratio of 4-(phenylmethylene)-4-(trifluoromethoxy)benzylamine to palladium acetate is 20:1; N The molar ratio of -(phenylmethylene)-4-(trifluoromethoxy)benzylamine to 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene is 5:1; N The molar ratio of 4-(phenylmethylene)-4-(trifluoromethoxy)benzylamine to potassium carbonate is 1:2.2; N The molar ratio of -(phenylmethylene)-4-(trifluoromethoxy)benzylamine to potassium iodide is 1:1.25.

[0107] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After the reaction solution was sequentially extracted, dried, concentrated, and separated by column chromatography according to the method described in Example 1, 2-(4-trifluoromethoxybenzyl)isoindoline-1-one was obtained with a yield of 55%.

[0108] Example 28 A method for preparing a γ-lactam compound, wherein 4-[[(phenylmethylene)amino]methyl]benzonitrile, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, bis(2-diphenylphosphine) ether, potassium carbonate, ammonium iodide and excess benzene are mixed uniformly and reacted in a sealed container at 130°C for 11 hours.

[0109] The molar ratios of 4-[[(phenylmethylene)amino]methyl]benzonitrile to sodium 2-chloro-2,2-difluoroacetate are 1:1.5; the molar ratios of 4-[[(phenylmethylene)amino]methyl]benzonitrile to palladium acetate are 30:1; the molar ratios of 4-[[(phenylmethylene)amino]methyl]benzonitrile to bis(2-diphenylphosphine) ether are 15:1; the molar ratios of 4-[[(phenylmethylene)amino]methyl]benzonitrile to potassium carbonate are 1:2.2; and the molar ratios of 4-[[(phenylmethylene)amino]methyl]benzonitrile to ammonium iodide are 1:1.

[0110] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After extraction, drying, concentration, and column chromatography separation according to the method described in Example 1, 2-(4-cyanobenzyl)isoindoline-1-one was obtained with a yield of 43%.

[0111] Example 29 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N 1-(phenylmethylene)-1-butylamine, sodium 2-chloro-2,2-difluoroacetate, palladium acetate, bis(2-diphenylphosphine) ether, potassium carbonate, potassium iodide, and excess dimethyl sulfoxide are mixed thoroughly and reacted in a sealed container at 140°C for 10 hours.

[0112] in: N The molar ratio of 1-(phenylmethylene)-1-butylamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.5; N The molar ratio of 1-(phenylmethylene)-1-butylamine to palladium acetate is 10:1; N The molar ratio of 1-(phenylmethylene)-1-butylamine to bis(2-diphenylphosphine) ether is 5:1; N The molar ratio of 1-(phenylmethylene)-1-butylamine to potassium carbonate is 1:2.2; N The molar ratio of 1-(phenylmethylene)-1-butylamine to potassium iodide is 1:1.25.

[0113] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After the reaction solution was sequentially extracted, dried, concentrated, and separated by column chromatography according to the method described in Example 1, 2-butylisoindoline-1-one was obtained with a yield of 91%.

[0114] Example 30 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N 1,(phenylmethylene)cyclopentanamine, sodium 2-chloro-2,2-difluoroacetate, palladium diacetylacetone, bis(2-diphenylphosphine) ether, potassium carbonate, potassium iodide and excess benzene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0115] in: N The molar ratio of 1-(phenylmethylene)cyclopentanamine to sodium 2-chloro-2,2-difluoroacetate is 1:1.5; N The molar ratio of 2-(phenylmethylene)cyclopentylamine to palladium diacetylacetone is 25:1; N The molar ratio of 1-(phenylmethylene)cyclopentanamine to bis(2-diphenylphosphine) ether is 5:1; N The molar ratio of 1-(phenylmethylene)cyclopentylamine to potassium carbonate is 1:1.5; N The molar ratio of 1:1 between 1-(phenylmethylene)cyclopentylamine and potassium iodide.

[0116] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After the reaction solution was sequentially extracted, dried, concentrated, and separated by column chromatography according to the method described in Example 1, 2-cyclopentylisoindoline-1-one was obtained with a yield of 81%.

[0117] Example 31 A method for preparing a γ-lactam compound, wherein the method refers to sequentially... N 1,(phenylmethylene)cyclohexylamine, sodium 2-chloro-2,2-difluoroacetate, bis(triphenylphosphine)palladium dichloride, bis(2-diphenylphosphine) ether, potassium carbonate, potassium iodide and excess trifluorotoluene are mixed evenly and reacted in a sealed container at 140°C for 10 hours.

[0118] in: N The molar ratio of 1-(phenylmethylene)cyclohexylamine to sodium 2-chloro-2,2-difluoroacetate is 1:2.5; N The molar ratio of 1-(phenylmethylene)cyclohexylamine to bis(triphenylphosphine)palladium dichloride is 10:1; N The molar ratio of 1-(phenylmethylene)cyclohexylamine to bis(2-diphenylphosphine) ether is 15:1; N The molar ratio of 1-(phenylmethylene)cyclohexylamine to potassium carbonate is 1:2; N The molar ratio of 1-(phenylmethylene)cyclohexylamine to potassium iodide is 1:1.5.

[0119] The entire reaction process was tracked using the thin-layer chromatography method described in Example 1 to obtain the reaction solution. After the reaction solution was sequentially extracted, dried, concentrated, and separated by column chromatography according to the method described in Example 1, 2-cyclohexylisoindoline-1-one was obtained with a yield of 76%.

[0120] Example 32 Application of synthesized bioactive compounds with antitumor and anticancer properties A method for preparing a γ-lactam compound, wherein methyl 3-{4-[(4-methoxybenzylimino)methyl]phenyl}acrylate (1), sodium 2-chloro-2,2-difluoroacetate, palladium dichloride bis(triphenylphosphine)chloride, bis(2-diphenylphosphine) ether, potassium carbonate, potassium iodide and excess chlorobenzene are mixed uniformly and reacted in a sealed container at 140°C for 11 hours.

[0121] The molar ratio of methyl 3-{4-[(4-methoxybenzylimino)methyl]phenyl}acrylate (1) to sodium 2-chloro-2,2-difluoroacetate is 1:2.5; the molar ratio of methyl 3-{4-[(4-methoxybenzylimino)methyl]phenyl}acrylate (1) to palladium dichloride (di(triphenylphosphine)dichloride) is 20:1; the molar ratio of methyl 3-{4-[(4-methoxybenzylimino)methyl]phenyl}acrylate (1) to bis(2-diphenylphosphine) ether is 10:1; the molar ratio of methyl 3-{4-[(4-methoxybenzylimino)methyl]phenyl}acrylate (1) to potassium carbonate is 1:2; and the molar ratio of methyl 3-{4-[(4-methoxybenzylimino)methyl]phenyl}acrylate (1) to potassium iodide is 1:1.25.

[0122] The entire reaction process was tracked by the thin-layer chromatography method described in Example 1 to obtain the reaction solution; the reaction solution was then subjected to extraction, drying, concentration and column chromatography separation in sequence as described in Example 1 to obtain methyl(E)-3-(2-(4-methoxybenzyl)-1-oxoisoindoline-5-yl)acrylate (2) with a yield of 40%.

[0123] Compound 2 was reacted with hydroxylamine hydrochloride (NH2OH·HCl) and potassium hydroxide in methanol (3.0 mL) at room temperature for 30 minutes. After the reaction was completed, the mixture was extracted, dried, concentrated, and purified by column chromatography. The target compound 3 (a histone deacetylase (HDAC) inhibitor) was obtained through a two-step tandem reaction with a yield of 35%.

[0124] The reaction formula is as follows:

Claims

1. A method for preparing a γ-lactam compound, characterized in that: This method refers to sequentially... N A substituted imine compound, a difluorocarbene precursor compound, a catalyst, a ligand, a base, and an additive are sequentially added to a container containing excess solvent. The mixture is then sealed and reacted at 90°C–150°C in air for 6–15 hours. After the reaction is complete, a reaction solution is obtained. This reaction solution is then subjected to conventional extraction, drying, concentration, and column chromatography separation to obtain γ-lactam compounds. N The molar ratio of the substituted imine compound to the difluorocarbene precursor compound is 1:1.2 to 1:3; N The molar ratio of the substituted imine compound to the catalyst is 50:1 to 10:1; N The molar ratio of the substituted imine compound to the ligand is 20:1 to 5:1; N The molar ratio of the substituted imine compound to the base is 1:1 to 1:2.2; N The molar ratio of the substituted imine compound to the additive is 1:1 to 1:1.

5.

2. The method for preparing a γ-lactam compound as described in claim 1, characterized in that: The N -Substituted imine compounds refer to N- benzylbenzylamine, N -Benzyl-1-(2-methoxyphenyl)methylimine, N -[(2-methylphenyl)methylene]benzylamine, N -[(2-chlorophenyl)methylene]benzylamine, N- [(3-fluorophenyl)methylene]benzylamine, 3-[[(phenylmethyl)imino]methyl]benzonitrile, N -(4-methoxybenzyl)benzylamine, N -[(4-methylphenyl)methylene]benzylamine, N -(4-Fluorobenzyl)benzylamine, N -(4-chlorobenzyl)benzylamine, N -[(4-bromophenyl)methylene]benzylamine, N -([1,1′-biphenyl]-4-ylmethylene)benzylamine, N -[(4-iodophenyl)methylene]benzylamine, N -[(4-nitrophenyl)methylene]benzylamine, 4-[[(phenylmethyl)imino]methyl]benzonitrile, N -[[4-(dimethylamino)phenyl]methylene]benzylamine, 2-methyl- N -(phenylmethylene)benzylamine, 2-chloro- N -(phenylmethylene)benzylamine, 3-methoxy- N -(phenylmethylene)benzylamine, 3-chloro- N -(phenylmethylene)benzylamine, 3-bromo- N -(phenylmethylene)benzylamine, 4-methoxy- N -(phenylmethylene)benzylamine, 4-fluoro- N -(phenylmethylene)benzylamine, 4-chloro- N -(phenylmethylene)benzylamine, 4-bromo- N -(phenylmethylene)benzylamine, N -(phenylmethylene)-4-(trifluoromethyl)benzylamine, N- (phenylmethylene)-4-(trifluoromethoxy)benzylamine, 4-[[(phenylmethylene)amino]methyl]benzonitrile, N -(phenylmethylene)-1-butylamine, N -(phenylmethylene)cyclopentylamine, N Any one of 3-(phenylmethylene)cyclohexylamine and methyl 3-{4-[(4-methoxybenzylimino)methyl]phenyl}acrylate.

3. The method for preparing a γ-lactam compound as described in claim 1, characterized in that: The difluorocarbene precursor compound refers to any one of potassium 2-bromo-2,2-difluoroacetate, sodium 2-chloro-2,2-difluoroacetate, ethyl difluorobromoacetate, diethyl bromodifluoromethylphosphonate, and (trifluoromethyl)trimethylsilane.

4. The method for preparing a γ-lactam compound as described in claim 1, characterized in that: The catalyst refers to any one of the following palladium compounds: palladium acetate, palladium di(triphenylphosphine) dichloride, palladium tetra(triphenylphosphine) palladium, palladium diacetylacetone, palladium bromide, palladium chloride, and palladium iodide.

5. The method for preparing a γ-lactam compound as described in claim 1, characterized in that: The ligand refers to any one of bis(2-diphenylphosphine) ether, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, triphenylphosphine, tri(o-methylphenyl)phosphine, and 1,3-bis(diphenylphosphine)propane.

6. The method for preparing a γ-lactam compound as described in claim 1, characterized in that: The alkali refers to any one of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, potassium tert-butoxide, and cesium carbonate.

7. The method for preparing a γ-lactam compound as described in claim 1, characterized in that: The additive refers to any one of potassium iodide, sodium iodide, ammonium iodide, potassium fluoride, sodium bromide, and potassium bromide.

8. The method for preparing a γ-lactam compound as described in claim 1, characterized in that: The solvent refers to toluene, benzene, xylene, N,N -Dimethylformamide, N,N - Any one of dimethylacetamide, trifluorotoluene, dimethyl sulfoxide, and chlorobenzene.

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