A method for preparing N-substituted phthalimide compounds

Abstract

The present invention relates to a method for preparing an N-substituted phthalimide compound, the method refers to sequentially adding an N-substituted benzamide compound, a difluorocarbene precursor compound, a catalyst, a ligand, and a base into a container containing a solvent, and sealing and reacting for 5 hours at 90° C. to 120° C. under an argon atmosphere, and obtaining a reaction solution after the reaction is complete; the reaction solution is sequentially subjected to conventional extraction, drying, concentration, and recrystallization to obtain an N-substituted phthalimide compound. The present invention belongs to an atom-economic one-pot reaction, is simple and easy, has low cost, has high reaction selectivity, has few by-products, and is simple to post-process, can realize large-scale production, and has good industrial application prospects in terms of bioactive compounds and drug synthesis containing an N-substituted phthalimide skeleton.

Description

Technical Field

[0001] The invention relates to the field of organic synthetic chemistry, and in particular to a method for preparing an N-substituted phthalimide compound. Background Art

[0002] N-substituted phthalimide is a multifunctional structure that has been widely used in the production of dyes, semiconductors, pesticides, pharmaceuticals and organic synthesis intermediates. It can also be used to synthesize functional organic materials. In addition, it has a variety of biological activities, such as anti-tumor, anti-coagulation, anti-inflammatory, neuroprotective and antibacterial reactivity. Therefore, the development of efficient synthesis methods for N-substituted phthalimide has always attracted the attention of synthetic chemists.

[0003] The currently disclosed synthesis methods of N-substituted phthalimide compounds are as follows: (1) Synthesis involving anhydride, such as: the research group of Shang Zhicai of Zhejiang University used cheap, non-toxic and environmentally friendly polyethylene glycol (PEG) to directly dehydrate and condense amine with phthalic anhydride to obtain the corresponding adduct N-substituted phthalimide under mild reaction conditions. Synthetic Communications . 2009, 39, 16, 2822-2828); Branko's group reported the synthesis of N-substituted phthalimides under microwave conditions. Phthalic anhydride and amine compounds were irradiated with microwaves to generate cyclic imides within a few minutes to a few hours (Tetrahedron Letters. 2010, 51, 2215–2217). (2) CO / CO2 is used as a carbonyl source to synthesize N-substituted phthalimides. For example, the Bhalchandra group used CO as a carbonyl source to synthesize N-substituted phthalimides from 1,2-dihalides and aromatic amines in the presence of a heterogeneous catalyst Pd / C (Adv. Synth. Catal. 2011, 353, 3415-3422). The Tu Tao group used a palladium complex (Pd-NHC 1) to obtain various chiral, drug-like and structurally interesting N-substituted phthalimides by diaminocarbonylation at atmospheric carbon monoxide pressures as low as 0.05 mol% (Org. Chem. Front., 2014, 1, 1261-1265). (3) Generation under aerobic conditions, such as the use of indanone and aromatic amine compounds by Zhang Zehui's research group to generate N-substituted phthalimide by cleaving CC bonds and CO bonds under metal-free and additive-free conditions (ACS Catal. 2022, 12, 21, 13300–13311).

[0004] The presence of N-heterocyclic rings in N-substituted phthalimide compounds makes them widely used in bioactive molecules. Therefore, it is of great significance to continuously research and innovate simple and efficient methods to synthesize N-substituted phthalimides. Sodium difluorochloroacetate, as a cheap difluorocarbene precursor, generates difluorocarbene in situ by breaking C-Cl bonds and CC bonds. It has been widely used in difluoroalkylation or difluoromethylation reactions, and can also be used as a carbonyl source through hydrolysis during the reaction. However, there is no report on the use of sodium difluorochloroacetate as a difluorocarbene precursor, using transition metals to catalyze the activation of CH bonds and NH bonds, and generating CC bonds, CN bonds and C=O bonds in one step to construct a five-membered heterocyclic ring to synthesize N-substituted phthalimide. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing N-substituted phthalimide compounds which is low in cost, simple in operation, highly applicable, efficient and economical.

[0006] In order to solve the above problems, the present invention discloses a method for preparing an N-substituted phthalimide compound, which is characterized in that: the method refers to sequentially adding an N-substituted benzamide compound, a difluorocarbene precursor compound, a catalyst, a ligand, and a base into a container containing a solvent, and reacting the mixture in a sealed container at 90°C to 120°C for 5 hours under an argon atmosphere to obtain a reaction solution after the reaction is complete; the reaction solution is sequentially subjected to conventional extraction, drying, concentration, and recrystallization to obtain an N-substituted phthalimide compound; the molar ratio of the N-substituted benzamide compound to the difluorocarbene precursor compound is 1:1.5 to 1:2.5; the molar ratio of the N-substituted benzamide compound to the catalyst is 20:1 to 10:1; the molar ratio of the N-substituted benzamide compound to the ligand is 5:1 to 2.5:1; and the molar ratio of the N-substituted benzamide compound to the base is 1:2 to 1:2.5.

[0007] The N-substituted benzamide compounds refer to 2-iodo-N-phenylbenzamide, 2-iodo-N-(4-methoxyphenyl)benzamide, 2-bromo-N-(3-methoxyphenyl)benzamide, 2-bromo-N-(3-methylphenyl)benzamide, 2-iodo-N-(3-chlorophenyl)benzamide, 2-iodo-N-(3-nitrophenyl)benzamide, 2-iodo-N-(4-methylphenyl)benzamide, 2-iodo-N-(4-chlorophenyl)benzamide, 2-iodo- N-(4-bromophenyl)benzamide, 2-iodo-N-(4-ethylphenyl)benzamide, 2-iodo-N-(4-ethoxyphenyl)benzamide, 2-iodo-N-(4-trifluoromethylphenyl)benzamide, 2-iodo-N-(4-trifluoromethoxyphenyl)benzamide, 2-iodo-N-(4-fluorophenyl)benzamide, 2-bromo-N-(2-methoxyphenyl)benzamide, 2-iodo-N-(2-methylphenyl)benzamide, 2-iodo-N-(4-nitrophenyl)benzamide benzamide, 2-iodo-N-(2,6-diethylphenyl)benzamide, 2-iodo-N-(2,6-diisopropylphenyl)benzamide, 2-bromo-N-(2,3-dimethylphenyl)benzamide, 2-iodo-N-(2,5-dichlorophenyl)benzamide, 2-iodo-N-(2-methyl-3-chlorophenyl)benzamide, 2-iodo-N-(3,4,5-trimethoxyphenyl)benzamide, 2-iodo-N-(2-methoxy-4-nitrophenyl)benzamide, 2-iodo -N-(4-formylphenyl)benzamide, 2-iodo-N-(4-dimethylaminophenyl)benzamide, 2-iodo-N-(6-methoxypyridine)benzamide, 2-iodo-N-pyridinebenzamide, 2-iodo-N-(1-naphthyl)benzamide, 2-iodo-N-(4-methoxyphenethyl)benzamide, 2-iodo-N-cyclohexylbenzamide, 2-iodo-N-cyclopentylbenzamide, 2-iodo-N-n-butylbenzamide, 2-iodo-N-ethylbenzamide.

[0008] The difluorocarbene precursor compound refers to any one of sodium difluorochloroacetate, potassium difluorobromoacetate, ethyl difluorobromoacetate, and diethyl bromodifluoromethylphosphate.

[0009] The catalyst is any palladium compound selected from the group consisting of palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and palladium diacetylacetonate.

[0010] The ligand is any one of triphenylphosphine, tri(o-methylphenyl)phosphine, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, tricyclohexylphosphine, and bis(diphenylphosphinophenyl)ether.

[0011] The alkali refers to any one of cesium carbonate, potassium carbonate, sodium bicarbonate, sodium carbonate and sodium hydroxide.

[0012] The solvent is any one of N,N-dimethylformamide, dimethyl sulfoxide, toluene and ethylene dichloride.

[0013] Compared with the prior art, the present invention has the following advantages:

[0014] 1. The present invention uses difluorocarbene produced by a difluorocarbene precursor as a carbonyl source, realizes the cleavage of the NH bond under transition metal catalysis, and constructs the CC bond, CN bond and C=O bond in one step. It has good stability, universal substrate compatibility, and is easy to operate, providing a convenient path for the preparation of N-substituted phthalimide compounds.

[0015] 2. The present invention is an atom-economical one-pot reaction, which is simple, easy to operate, low in cost, highly selective, with few by-products and simple post-processing. It can be mass-produced and has good industrial application prospects in the synthesis of bioactive compounds and drugs containing N-substituted phthalimide skeletons. DETAILED DESCRIPTION

[0016] A method for preparing an N-substituted phthalimide compound comprises the steps of sequentially adding an N-substituted benzamide compound, a difluorocarbene precursor compound, a catalyst, a ligand and a base into a container containing a solvent, and reacting the mixture in a sealed container at 90°C to 120°C for 5 hours under an argon atmosphere to obtain a reaction liquid after the reaction is complete; and the reaction liquid is sequentially subjected to conventional extraction, drying, concentration and recrystallization to obtain the N-substituted phthalimide compound.

[0017] Wherein: the molar ratio of the N-substituted benzamide compound to the difluorocarbene precursor compound is 1:1.5~1:2.5; the molar ratio of the N-substituted benzamide compound to the catalyst is 20:1~10:1; the molar ratio of the N-substituted benzamide compound to the ligand is 5:1~2.5:1; the molar ratio of the N-substituted benzamide compound to the base is 1:2~1:2.5.

[0018] The N-substituted benzamide compounds are 2-iodo-N-phenylbenzamide, 2-iodo-N-(4-methoxyphenyl)benzamide, 2-bromo-N-(3-methoxyphenyl)benzamide, 2-bromo-N-(3-methylphenyl)benzamide, 2-iodo-N-(3-chlorophenyl)benzamide, 2-iodo-N-(3-nitrophenyl)benzamide, 2-iodo-N-(4-methylphenyl)benzamide, 2-iodo-N-(4-chlorophenyl)benzamide, 2-iodo-N- (4-bromophenyl)benzamide, 2-iodo-N-(4-ethylphenyl)benzamide, 2-iodo-N-(4-ethoxyphenyl)benzamide, 2-iodo-N-(4-trifluoromethylphenyl)benzamide, 2-iodo-N-(4-trifluoromethoxyphenyl)benzamide, 2-iodo-N-(4-fluorophenyl)benzamide, 2-bromo-N-(2-methoxyphenyl)benzamide, 2-iodo-N-(2-methylphenyl)benzamide, 2-iodo-N-(4-nitrophenyl)benzamide Benzamide, 2-iodo-N-(2,6-diethylphenyl)benzamide, 2-iodo-N-(2,6-diisopropylphenyl)benzamide, 2-bromo-N-(2,3-dimethylphenyl)benzamide, 2-iodo-N-(2,5-dichlorophenyl)benzamide, 2-iodo-N-(2-methyl-3-chlorophenyl)benzamide, 2-iodo-N-(3,4,5-trimethoxyphenyl)benzamide, 2-iodo-N-(2-methoxy-4-nitrophenyl)benzamide, 2-iodo -N-(4-formylphenyl)benzamide, 2-iodo-N-(4-dimethylaminophenyl)benzamide, 2-iodo-N-(6-methoxypyridine)benzamide, 2-iodo-N-pyridinebenzamide, 2-iodo-N-(1-naphthyl)benzamide, 2-iodo-N-(4-methoxyphenethyl)benzamide, 2-iodo-N-cyclohexylbenzamide, 2-iodo-N-cyclopentylbenzamide, 2-iodo-N-n-butylbenzamide, 2-iodo-N-ethylbenzamide.

[0019] The difluorocarbene precursor compound refers to any one of sodium difluorochloroacetate, potassium difluorobromoacetate, ethyl difluorobromoacetate, and diethyl bromodifluoromethylphosphate.

[0020] The catalyst is any palladium compound selected from the group consisting of palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and palladium bisacetylacetonate.

[0021] The ligand is any one of triphenylphosphine, tri(o-methylphenyl)phosphine, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, tricyclohexylphosphine, and bis(diphenylphosphinophenyl)ether.

[0022] The alkali refers to any one of cesium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium carbonate, and sodium hydroxide.

[0023] The solvent is any one of N,N-dimethylformamide, dimethyl sulfoxide, toluene and dichloroethane.

[0024] Example 1 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-phenylbenzamide, sodium difluorochloroacetate, palladium chloride, triphenylphosphine, cesium carbonate and N,N-dimethylformamide, and reacting the mixture at 90° C. for 5 hours in a sealed container.

[0025] Wherein: the molar ratio of 2-iodo-N-phenylbenzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-phenylbenzamide to palladium chloride is 20:1; the molar ratio of 2-iodo-N-phenylbenzamide to triphenylphosphine is 5:1; the molar ratio of 2-iodo-N-phenylbenzamide to cesium carbonate is 1:2.

[0026] The whole reaction process is tracked by thin layer chromatography, that is, sampling is performed every hour, and the reaction solution and the raw material liquid N-benzanilide compound are dropped on the silica gel plate by capillary, and the two spots are in the same straight line, and then the silica gel plate is placed in a display bottle containing a petroleum ether-ethyl acetate mixture with a volume ratio (mL / mL) of 6:1. After the plate is run, the silica gel plate is placed under an ultraviolet lamp or in an iodine bottle for observation. If there is no point in the reaction liquid that is flush with the raw material liquid N-benzanilide compound, it indicates that the reaction is complete, and the reaction liquid is obtained at this time.

[0027] The reaction solution was extracted three times with ethyl acetate in an amount equal to the reaction solvent, and the organic phases were combined to obtain an extract. Anhydrous magnesium sulfate was added to the extract to dry it, and a filtrate was obtained after filtration; then the solvent was evaporated under reduced pressure at 40°C using a RE-52AA rotary evaporator produced by Shanghai Yarong Biochemical Co., Ltd. to obtain a concentrated solution; then, the solution was recrystallized with chloroform and petroleum ether to finally obtain N-substituted phthalimide with a yield of 74%.

[0028] Example 2 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(4-methoxyphenyl)benzamide, sodium difluorochloroacetate, palladium chloride, tri(o-methylphenyl)phosphine, potassium carbonate and dimethyl sulfoxide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0029] Wherein: the molar ratio of 2-iodo-N-(4-methoxyphenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(4-methoxyphenyl)benzamide to palladium chloride is 20:1; the molar ratio of 2-iodo-N-(4-methoxyphenyl)benzamide to tri(o-methylphenyl)phosphine is 5:1, and the molar ratio of 2-iodo-N-(4-methoxyphenyl)benzamide to potassium carbonate is 1:2.

[0030] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated and recrystallized in sequence as described in Example 1 to obtain N-(4-methoxyphenyl)phthalimide with a yield of 83%.

[0031] Example 3 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-bromo-N-(3-methoxyphenyl)benzamide, sodium difluorochloroacetate, tetrakis(triphenylphosphine)palladium, triphenylphosphine, potassium carbonate and toluene, and reacting the mixture at 100° C. for 5 hours in a sealed container.

[0032] The molar ratio of 2-bromo-N-(3-methoxyphenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-bromo-N-(3-methoxyphenyl)benzamide to tetrakis(triphenylphosphine)palladium is 10:1; the molar ratio of 2-bromo-N-(3-methoxyphenyl)benzamide to triphenylphosphine is 5:1, and the molar ratio of 2-bromo-N-(3-methoxyphenyl)benzamide to potassium carbonate is 1:2.

[0033] The entire reaction process was followed by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated and recrystallized in sequence as described in Example 1 to obtain N-(3-methoxyphenyl)phthalimide with a yield of 77%.

[0034] Example 4 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-bromo-N-(3-methylphenyl)benzamide, potassium difluorobromoacetate, bis(triphenylphosphine)palladium dichloride, 1,2-bis(diphenylphosphine)ethane, sodium hydroxide and dichloroethane, and reacting the mixture at 90°C in a sealed container for 5 hours.

[0035] Among them: the molar ratio of 2-bromo-N-(3-methylphenyl)benzamide to potassium difluorobromoacetate is 1:2; the molar ratio of 2-bromo-N-(3-methylphenyl)benzamide to bis(triphenylphosphine)palladium dichloride is 10:1; the molar ratio of 2-bromo-N-(3-methylphenyl)benzamide to 1,2-bis(diphenylphosphine)ethane is 4:1, and the molar ratio of 2-bromo-N-(3-methylphenyl)benzamide to sodium hydroxide is 1:1.5.

[0036] The entire reaction process was followed by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated and recrystallized in sequence as described in Example 1 to obtain N-(3-methylphenyl)phthalimide with a yield of 75%.

[0037] Example 5 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(3-chlorophenyl)benzamide, sodium difluorochloroacetate, diacetylacetonate palladium, tricyclohexylphosphine, cesium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0038] Among them, the molar ratio of 2-iodo-N-(3-chlorophenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(3-chlorophenyl)benzamide to palladium diacetylacetonate is 20:1; the molar ratio of 2-iodo-N-(3-chlorophenyl)benzamide to tricyclohexylphosphine is 4:1, and the molar ratio of 2-iodo-N-(3-chlorophenyl)benzamide to cesium carbonate is 1:2.

[0039] The entire reaction process was followed by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated and recrystallized in sequence as described in Example 1 to obtain N-(3-chlorophenyl)phthalimide with a yield of 54%.

[0040] Example 6 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(3-nitrophenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 120°C in a sealed container for 5 hours.

[0041] The molar ratio of 2-iodo-N-(3-nitrophenyl)benzamide to sodium difluorochloroacetate is 1:2.5; the molar ratio of 2-iodo-N-(3-nitrophenyl)benzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-(3-nitrophenyl)benzamide to bis(diphenylphosphinophenyl)ether is 2.5:1, and the molar ratio of 2-iodo-N-(3-nitrophenyl)benzamide to potassium carbonate is 1:2.5.

[0042] The entire reaction process was tracked by thin layer chromatography according to the method described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated and recrystallized in sequence according to the method described in Example 1 to obtain N-(3-nitrophenyl)phthalimide with a yield of 50%.

[0043] Example 7 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(4-methylphenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0044] The molar ratio of 2-iodo-N-(4-methylphenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(4-methylphenyl)benzamide to palladium acetate is 20:1; the molar ratio of 2-iodo-N-(4-methylphenyl)benzamide to bis(diphenylphosphinophenyl)ether is 5:1, and the molar ratio of 2-iodo-N-(4-methylphenyl)benzamide to potassium carbonate is 1:2.

[0045] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated and recrystallized in sequence as described in Example 1 to obtain N-(4-methylphenyl)phthalimide with a yield of 80%.

[0046] Example 8 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(4-chlorophenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, sodium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0047] The molar ratio of 2-iodo-N-(4-chlorophenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(4-chlorophenyl)benzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-(4-chlorophenyl)benzamide to bis(diphenylphosphinophenyl)ether is 5:1, and the molar ratio of 2-iodo-N-(4-chlorophenyl)benzamide to sodium carbonate is 1:2.

[0048] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(4-chlorophenyl)phthalimide with a yield of 61%.

[0049] Example 9 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(4-bromophenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0050] The molar ratio of 2-iodo-N-(4-bromophenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(4-bromophenyl)benzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-(4-bromophenyl)benzamide to bis(diphenylphosphinophenyl)ether is 4:1, and the molar ratio of 2-iodo-N-(4-bromophenyl)benzamide to potassium carbonate is 1:2.

[0051] The entire reaction process was followed by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized in sequence as described in Example 1 to obtain N-(4-bromophenyl)phthalimide with a yield of 54%.

[0052] Example 10 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(4-ethylphenyl)benzamide, sodium difluorochloroacetate, diacetylacetonate palladium, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0053] The molar ratio of 2-iodo-N-(4-ethylphenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(4-ethylphenyl)benzamide to palladium diacetylacetonate is 10:1; the molar ratio of 2-iodo-N-(4-ethylphenyl)benzamide to bis(diphenylphosphinophenyl) ether is 4:1, and the molar ratio of 2-iodo-N-(4-ethylphenyl)benzamide to potassium carbonate is 1:2.

[0054] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(4-ethylphenyl)phthalimide with a yield of 81%.

[0055] Example 11 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(4-ethoxyphenyl)benzamide, sodium difluorochloroacetate, diacetylacetonate palladium, bis(diphenylphosphinophenyl) ether, sodium bicarbonate and dimethyl sulfoxide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0056] The molar ratio of 2-iodo-N-(4-ethoxyphenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(4-ethoxyphenyl)benzamide to palladium diacetylacetonate is 10:1; the molar ratio of 2-iodo-N-(4-ethoxyphenyl)benzamide to bis(diphenylphosphinophenyl)ether is 4:1, and the molar ratio of 2-iodo-N-(4-ethoxyphenyl)benzamide to sodium bicarbonate is 1:2.

[0057] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(4-ethylphenyl)phthalimide with a yield of 79%.

[0058] Example 12 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(4-trifluoromethylphenyl)benzamide, sodium difluorochloroacetate, diacetylacetonate palladium, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0059] Among them, the molar ratio of 2-iodo-N-(4-trifluoromethylphenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(4-trifluoromethylphenyl)benzamide to palladium diacetylacetonate is 10:1; the molar ratio of 2-iodo-N-(4-trifluoromethylphenyl)benzamide to bis(diphenylphosphinophenyl) ether is 2.5:1, and the molar ratio of 2-iodo-N-(4-trifluoromethylphenyl)benzamide to potassium carbonate is 1:2.

[0060] The entire reaction process was followed by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized in sequence as described in Example 1 to obtain N-(4-trifluoromethylphenyl)phthalimide with a yield of 44%.

[0061] Example 13 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(4-trifluoromethoxyphenyl)benzamide, sodium difluorochloroacetate, diacetylacetonate palladium, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0062] The molar ratio of 2-iodo-N-(4-trifluoromethoxyphenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(4-trifluoromethoxyphenyl)benzamide to palladium diacetylacetonate is 10:1; the molar ratio of 2-iodo-N-(4-trifluoromethoxyphenyl)benzamide to bis(diphenylphosphinophenyl) ether is 4:1, and the molar ratio of 2-iodo-N-(4-trifluoromethoxyphenyl)benzamide to potassium carbonate is 1:2.

[0063] The entire reaction process was followed by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(4-trifluoromethoxyphenyl)phthalimide with a yield of 53%.

[0064] Example 14 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(4-fluorophenyl)benzamide, sodium difluorochloroacetate, diacetylacetonate palladium, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0065] Among them, the molar ratio of 2-iodo-N-(4-fluorophenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(4-fluorophenyl)benzamide to palladium diacetylacetonate is 10:1; the molar ratio of 2-iodo-N-(4-fluorophenyl)benzamide to bis(diphenylphosphinophenyl) ether is 4:1, and the molar ratio of 2-iodo-N-(4-fluorophenyl)benzamide to potassium carbonate is 1:2.

[0066] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(4-fluorophenyl)phthalimide with a yield of 67%.

[0067] Example 15 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-bromo-N-(2-methoxyphenyl)benzamide, sodium difluorochloroacetate, diacetylacetonate palladium, bis-1,3-bis(diphenylphosphine)propane, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0068] Among them: the molar ratio of 2-bromo-N-(2-methoxyphenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-bromo-N-(2-methoxyphenyl)benzamide to palladium diacetylacetonate is 10:1; the molar ratio of 2-bromo-N-(2-methoxyphenyl)benzamide to bis-1,3-bis(diphenylphosphine)propane is 3:1, and the molar ratio of 2-bromo-N-(2-methoxyphenyl)benzamide to potassium carbonate is 1:2.

[0069] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(2-methoxyphenyl)phthalimide with a yield of 72%.

[0070] Example 16 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(2-methylphenyl)benzamide, sodium difluorochloroacetate, diacetylacetonate palladium, bis(diphenylphosphinophenyl) ether, sodium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0071] The molar ratio of 2-iodo-N-(2-methylphenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(2-methylphenyl)benzamide to palladium diacetylacetonate is 10:1; the molar ratio of 2-iodo-N-(2-methylphenyl)benzamide to bis(diphenylphosphinophenyl) ether is 3:1, and the molar ratio of 2-iodo-N-(2-methylphenyl)benzamide to sodium carbonate is 1:2.

[0072] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(2-methylphenyl)phthalimide with a yield of 75%.

[0073] Example 17 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(4-nitrophenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, sodium hydroxide and N,N-dimethylformamide, and reacting the mixture at 120°C in a sealed container for 5 hours.

[0074] The molar ratio of 2-iodo-N-(4-nitrophenyl)benzamide to sodium difluorochloroacetate is 1:2.5; the molar ratio of 2-iodo-N-(4-nitrophenyl)benzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-(4-nitrophenyl)benzamide to bis(diphenylphosphinophenyl)ether is 2.5:1, and the molar ratio of 2-iodo-N-(4-nitrophenyl)benzamide to sodium hydroxide is 1:2.

[0075] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized in sequence as described in Example 1 to obtain N-(4-nitrophenyl)phthalimide with a yield of 45%.

[0076] Example 18 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(2,6-diethylphenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and toluene, and reacting the mixture at 100° C. for 5 hours in a sealed container.

[0077] Among them: the molar ratio of 2-iodo-N-(2,6-diethylphenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(2,6-diethylphenyl)benzamide to palladium acetate is 20:1; the molar ratio of 2-iodo-N-(2,6-diethylphenyl)benzamide to bis(diphenylphosphinophenyl) ether is 5:1, and the molar ratio of 2-iodo-N-(2,6-diethylphenyl)benzamide to potassium carbonate is 1:2.

[0078] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(2,6-diethylphenyl)phthalimide with a yield of 66%.

[0079] Example 19 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(2,6-diisopropylphenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C in a sealed container for 5 hours.

[0080] Among them: the molar ratio of 2-iodo-N-(2,6-diisopropylphenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(2,6-diisopropylphenyl)benzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-(2,6-diisopropylphenyl)benzamide to bis(diphenylphosphinophenyl) ether is 3:1, and the molar ratio of 2-iodo-N-(2,6-diisopropylphenyl)benzamide to potassium carbonate is 1:2.

[0081] The entire reaction process was tracked by thin layer chromatography according to the method described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence according to the method described in Example 1 to obtain N-(2,6-diisopropylphenyl)phthalimide with a yield of 50%.

[0082] Example 20 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-bromo-N-(2,3-dimethylphenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and dichloroethane, and reacting the mixture at 100° C. for 5 hours in a sealed container.

[0083] Among them: the molar ratio of 2-bromo-N-(2,3-dimethylphenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-bromo-N-(2,3-dimethylphenyl)benzamide to palladium acetate is 20:1; the molar ratio of 2-bromo-N-(2,3-dimethylphenyl)benzamide to bis(diphenylphosphinophenyl) ether is 5:1, and the molar ratio of 2-bromo-N-(2,3-dimethylphenyl)benzamide to potassium carbonate is 1:2.

[0084] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(2,3-dimethylphenyl)phthalimide 2 with a yield of 86%.

[0085] Example 21 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(2,5-dichlorophenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0086] Among them: the molar ratio of 2-iodo-N-(2,5-dichlorophenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(2,5-dichlorophenyl)benzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-(2,5-dichlorophenyl)benzamide to bis(diphenylphosphinophenyl) ether is 4:1, and the molar ratio of 2-iodo-N-(2,5-dichlorophenyl)benzamide to potassium carbonate is 1:2.

[0087] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(2,3-dichlorophenyl)phthalimide with a yield of 55%.

[0088] Example 22 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(2-methyl-3-chlorophenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C in a sealed container for 5 hours.

[0089] Wherein: the molar ratio of 2-iodo-N-(2-methyl-3-chlorophenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(2-methyl-3-chlorophenyl)benzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-(2-methyl-3-chlorophenyl)benzamide to bis(diphenylphosphinophenyl)ether is 4:1, and the molar ratio of 2-iodo-N-(2-methyl-3-chlorophenyl)benzamide to potassium carbonate is 1:2.

[0090] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and separated by column chromatography in sequence as described in Example 1 to obtain N-(2-methyl-3-chlorophenyl)phthalimide with a yield of 69%.

[0091] Example 23 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(3,4,5-trimethoxyphenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C in a sealed container for 5 hours.

[0092] Wherein: the molar ratio of 2-iodo-N-(3,4,5-trimethoxyphenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(3,4,5-trimethoxyphenyl)benzamide to palladium acetate is 20:1; the molar ratio of 2-iodo-N-(3,4,5-trimethoxyphenyl)benzamide to bis(diphenylphosphinophenyl) ether is 5:1, and the molar ratio of 2-iodo-N-(3,4,5-trimethoxyphenyl)benzamide to potassium carbonate is 1:2.

[0093] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(3,4,5-trimethoxyphenyl)phthalimide with a yield of 90%.

[0094] Example 24 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(2-methoxy-4-nitrophenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 110°C in a sealed container for 5 hours.

[0095] The molar ratio of 2-iodo-N-(2-methoxy-4-nitrophenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(2-methoxy-4-nitrophenyl)benzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-(2-methoxy-4-nitrophenyl)benzamide to bis(diphenylphosphinophenyl)ether is 4:1, and the molar ratio of 2-iodo-N-(2-methoxy-4-nitrophenyl)benzamide to potassium carbonate is 1:2.

[0096] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(2-methoxy-4-nitrophenyl)phthalimide with a yield of 64%.

[0097] Example 25 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(4-formylphenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C in a sealed container for 5 hours.

[0098] The molar ratio of 2-iodo-N-(4-formylphenyl)benzamide to sodium chlorodifluoroacetate is 1:2; the molar ratio of 2-iodo-N-(4-formylphenyl)benzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-(4-formylphenyl)benzamide to bis(diphenylphosphinophenyl)ether is 4:1, and the molar ratio of 2-iodo-N-(4-formylphenyl)benzamide to potassium carbonate is 1:2.

[0099] The entire reaction process was followed by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(4-formylphenyl)phthalimide with a yield of 57%.

[0100] Example 26 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(4-dimethylaminophenyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C in a sealed container for 5 hours.

[0101] The molar ratio of 2-iodo-N-(4-dimethylaminophenyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(4-dimethylaminophenyl)benzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-(4-dimethylaminophenyl)benzamide to bis(diphenylphosphinophenyl)ether is 4:1, and the molar ratio of 2-iodo-N-(4-dimethylaminophenyl)benzamide to potassium carbonate is 1:2.

[0102] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(4-dimethylaminophenyl)phthalimide with a yield of 80%.

[0103] Example 27 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(6-methoxypyridine)benzamide, sodium difluorochloroacetate, diacetylacetonate palladium, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100°C for 5 hours in a sealed container.

[0104] Among them: the molar ratio of 2-iodo-N-(6-methoxypyridine)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(6-methoxypyridine)benzamide to palladium diacetylacetonate is 10:1; the molar ratio of 2-iodo-N-(6-methoxypyridine)benzamide to bis(diphenylphosphinophenyl) ether is 2.5:1, and the molar ratio of 2-iodo-N-(6-methoxypyridine)benzamide to potassium carbonate is 1:2.

[0105] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-(6-methoxypyridine)phthalimide with a yield of 49%.

[0106] Example 28 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-pyridinebenzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 100° C. for 5 hours in a sealed container.

[0107] The molar ratio of 2-iodo-N-pyridine benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-pyridine benzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-pyridine benzamide to bis(diphenylphosphinophenyl) ether is 2.5:1, and the molar ratio of 2-iodo-N-pyridine benzamide to potassium carbonate is 1:2.

[0108] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-pyridinephthalimide with a yield of 30%.

[0109] Example 29 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(1-naphthyl)benzamide, potassium difluorobromoacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 90°C in a sealed container for 5 hours.

[0110] Among them, the molar ratio of 2-iodo-N-(1-naphthalene)benzamide to potassium difluorobromoacetate is 1:1.5; the molar ratio of 2-iodo-N-(1-naphthalene)benzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-(1-naphthalene)benzamide to bis(diphenylphosphinophenyl) ether is 2.5:1, and the molar ratio of 2-iodo-N-(1-naphthalene)benzamide to potassium carbonate is 1:2.

[0111] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-naphthalenephthalimide with a yield of 72%.

[0112] Example 30 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-(4-methoxyphenethyl)benzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 90°C in a sealed container for 5 hours.

[0113] Wherein: the molar ratio of 2-iodo-N-(4-methoxyphenethyl)benzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-(4-methoxyphenethyl)benzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-(4-methoxyphenethyl)benzamide to bis(diphenylphosphinophenyl) ether is 5:1, and the molar ratio of 2-iodo-N-(4-methoxyphenethyl)benzamide to potassium carbonate is 1:2.

[0114] The entire reaction process was followed by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized in sequence as described in Example 1 to obtain N-(4-methoxyphenethyl)phthalimide with a yield of 68%.

[0115] Example 31 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-cyclohexylbenzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 90°C in a sealed container for 5 hours.

[0116] The molar ratio of 2-iodo-N-cyclohexylbenzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-cyclohexylbenzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-cyclohexylbenzamide to bis(diphenylphosphinophenyl) ether is 5:1, and the molar ratio of 2-iodo-N-cyclohexylbenzamide to potassium carbonate is 1:2.

[0117] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-cyclohexylphthalimide with a yield of 65%.

[0118] Example 32 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-cyclopentylbenzamide, ethyl difluorobromoacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 90°C in a sealed container for 5 hours.

[0119] Among them: the molar ratio of 2-iodo-N-cyclopentylbenzamide to ethyl difluorobromoacetate is 1:2; the molar ratio of 2-iodo-N-cyclopentylbenzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-cyclopentylbenzamide to bis(diphenylphosphinophenyl) ether is 5:1, and the molar ratio of 2-iodo-N-cyclopentylbenzamide to potassium carbonate is 1:2.

[0120] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-cyclopentylphthalimide with a yield of 69%.

[0121] Example 33 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-butylbenzamide, diethyl bromodifluoromethylphosphate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 90°C in a sealed container for 5 hours.

[0122] Among them, the molar ratio of 2-iodo-N-n-butylbenzamide to diethyl bromodifluoromethyl phosphate is 1:2; the molar ratio of 2-iodo-N-n-butylbenzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-n-butylbenzamide to bis(diphenylphosphinophenyl) ether is 5:1, and the molar ratio of 2-iodo-N-n-butylbenzamide to potassium carbonate is 1:2.

[0123] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-n-butylphthalimide with a yield of 75%.

[0124] Example 34 A method for preparing N-substituted phthalimide, the method comprising sequentially mixing 2-iodo-N-ethylbenzamide, sodium difluorochloroacetate, palladium acetate, bis(diphenylphosphinophenyl) ether, potassium carbonate and N,N-dimethylformamide, and reacting the mixture at 90°C for 5 hours in a sealed container.

[0125] The molar ratio of 2-iodo-N-ethylbenzamide to sodium difluorochloroacetate is 1:2; the molar ratio of 2-iodo-N-ethylbenzamide to palladium acetate is 10:1; the molar ratio of 2-iodo-N-ethylbenzamide to bis(diphenylphosphinophenyl) ether is 5:1, and the molar ratio of 2-iodo-N-ethylbenzamide to potassium carbonate is 1:2.

[0126] The entire reaction process was tracked by thin layer chromatography as described in Example 1 to obtain a reaction solution; the reaction solution was extracted, dried, concentrated, and recrystallized and separated in sequence as described in Example 1 to obtain N-ethylphthalimide with a yield of 68%.

Claims

1. A method for preparing an N-substituted phthalimide compound, characterized in that: The method comprises the following steps: sequentially adding an N-substituted benzamide compound, a difluorocarbene precursor compound, a catalyst, a ligand and a base into a container containing a solvent, and reacting the mixture in a sealed state at 90°C to 120°C for 5 hours under an argon atmosphere to obtain a reaction liquid after the reaction is complete; the reaction liquid is sequentially subjected to conventional extraction, drying, concentration and recrystallization to obtain an N-substituted phthalimide compound; the molar ratio of the N-substituted benzamide compound to the difluorocarbene precursor compound is 1:1.5 to 1:2.5; the molar ratio of the N-substituted benzamide compound to the catalyst is 20:1 to 10:1; and the molar ratio of the N-substituted benzamide compound to the ligand is 5:1 to 2.5:

1. ; The molar ratio of the N-substituted benzamide compound to the base is 1:2~1:2.5; the difluorocarbene precursor compound refers to any one of sodium difluorochloroacetate, potassium difluorobromoacetate, ethyl difluorobromoacetate, and diethyl bromodifluoromethyl phosphate; the catalyst refers to any one of palladium compounds selected from palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, and diacetylacetonate; the ligand refers to any one of triphenylphosphine, tri(o-methylphenyl)phosphine, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, tricyclohexylphosphine, and bis(diphenylphosphinophenyl)ether; the base refers to any one of cesium carbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, and sodium hydroxide.

2. The method for preparing an N-substituted phthalimide compound according to claim 1, characterized in that: The N-substituted benzamide compounds refer to 2-iodo-N-phenylbenzamide, 2-iodo-N-(4-methoxyphenyl)benzamide, 2-bromo-N-(3-methoxyphenyl)benzamide, 2-bromo-N-(3-methylphenyl)benzamide, 2-iodo-N-(3-chlorophenyl)benzamide, 2-iodo-N-(3-nitrophenyl)benzamide, 2-iodo-N-(4-methylphenyl)benzamide, 2-iodo-N-(4-chlorophenyl)benzamide, 2-iodo- N-(4-bromophenyl)benzamide, 2-iodo-N-(4-ethylphenyl)benzamide, 2-iodo-N-(4-ethoxyphenyl)benzamide, 2-iodo-N-(4-trifluoromethylphenyl)benzamide, 2-iodo-N-(4-trifluoromethoxyphenyl)benzamide, 2-iodo-N-(4-fluorophenyl)benzamide, 2-bromo-N-(2-methoxyphenyl)benzamide, 2-iodo-N-(2-methylphenyl)benzamide, 2-iodo-N-(4-nitrophenyl)benzamide benzamide, 2-iodo-N-(2,6-diethylphenyl)benzamide, 2-iodo-N-(2,6-diisopropylphenyl)benzamide, 2-bromo-N-(2,3-dimethylphenyl)benzamide, 2-iodo-N-(2,5-dichlorophenyl)benzamide, 2-iodo-N-(2-methyl-3-chlorophenyl)benzamide, 2-iodo-N-(3,4,5-trimethoxyphenyl)benzamide, 2-iodo-N-(2-methoxy-4-nitrophenyl)benzamide, 2-iodo -N-(4-formylphenyl)benzamide, 2-iodo-N-(4-dimethylaminophenyl)benzamide, 2-iodo-N-(6-methoxypyridine)benzamide, 2-iodo-N-pyridinebenzamide, 2-iodo-N-(1-naphthyl)benzamide, 2-iodo-N-(4-methoxyphenethyl)benzamide, 2-iodo-N-cyclohexylbenzamide, 2-iodo-N-cyclopentylbenzamide, 2-iodo-N-n-butylbenzamide, 2-iodo-N-ethylbenzamide.

3. The method for preparing an N-substituted phthalimide compound according to claim 1, characterized in that: The solvent is any one of N,N-dimethylformamide, dimethyl sulfoxide, toluene and ethylene dichloride.