A method for synthesizing an N-substituted phthalimide compound

Abstract

The application provides a synthesis method of N-substituted phthalimide compounds and relates to the technical field of organic synthesis. The synthesis method comprises the following steps: under the condition of having or not having a solvent, using a copper salt as a catalyst and a peroxide as an additive, synthesizing N-substituted phthalimide compounds by reacting phthalic acid compounds I with amide compounds II; the reaction raw materials of the synthesis method are cheap and easy to obtain, are safe and environmentally friendly, have good tolerance and resistance to various substituents and functional groups, are beneficial to large-scale industrial production, and provide an efficient, convenient, green, environmentally-friendly and low-cost synthesis path for N-substituted phthalimide compounds.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a synthesis method of N-substituted phthalimide compounds. BACKGROUND

[0002] N-substituted phthalimide compounds are widely used in medicine, agriculture, fine chemicals and functional materials, and the N-substituted phthalimide compounds are not only used as monomers of polymers, but also used as basic structural components in pesticides and potential drug molecules, which have great prospects. For example, the anti-inflammatory drug LASSBio-468, the anti-androgen drug DIMP, the antidepressant drug Tandospirone, the NAN-190 and the like all contain phthalimide groups, and the polyimides obtained by polymerization of the phthalimide compounds can improve the transmission characteristics of the photorefractive polymers, thereby improving the photovoltaic performance and the like.

[0003] At present, the synthesis methods of the N-substituted phthalimide compounds mainly include the following methods:

[0004] One method is to use benzamide as a substrate and use various “carbonyl” sources to synthesize N-substituted phthalimide compounds, as shown in the following reaction formula:

[0005]

[0006] However, this method needs to use noble metal catalysts Pd and Ru, which are expensive, and CO has the disadvantages of high volatility and high toxicity, and is strictly limited in storage, transportation, laboratory use and post-processing, so that the application of the method is limited.

[0007] Another method is to use phthalimide as a substrate and couple with a suitable “alkyl” source to prepare N-substituted phthalimide compounds, as shown in the following reaction formula:

[0008]

[0009] However, in order to improve the activity of the reactants and the yield, the phthalimide needs to be pre-functionalized, which is not conducive to large-scale industrial production.

[0010] Another method is to couple various “N” sources with phthalic acid to prepare N-substituted phthalimide compounds, as shown in the following reaction formula:

[0011]

[0012] However, the reaction conditions of this method are relatively harsh, and need to be carried out at high temperature and high pressure, and the functional groups have poor tolerance, and are difficult to be applied to some sensitive functional groups.

[0013] Therefore, it is urgent to provide a synthesis method of phthalimide compounds, which is low in cost, economic and practical, and suitable for large-scale industrial production. SUMMARY

[0014] The present application aims to provide a synthesis method of N-substituted phthalimide compounds, which can efficiently synthesize phthalimide compounds, and the raw materials are cheap and easy to obtain, thereby effectively reducing the synthesis cost, and the method has good tolerance and resistance to functional groups, and is beneficial to large-scale industrial production.

[0015] The synthesis method of the N-substituted phthalimide compound provided by the present application comprises the following steps: under the condition of no solvent, using a copper salt as a catalyst and a peroxide as an additive, reacting a phthalic acid compound I with an amide compound II to obtain a compound as shown in formula III.

[0016]

[0017] wherein R1 is hydrogen, methoxy, chlorine or nitro, R2 is hydrogen or C1-C2 alkyl, and R3 is carboxyl, ester, cyano, formamide, aldehyde or acetyl.

[0018] The N-substituted phthalimide compound provided by the present application has the following beneficial effects: the phthalimide compound I and the amide compound II are cheap and easy to obtain, which can significantly reduce the synthesis cost, and the synthesis method has good tolerance to the functional groups on the aromatic ring of the phthalic acid compound, and can also tolerate the substituents on the nitrogen of the amide compound, is relatively green and environmentally friendly, and is suitable for large-scale industrial production.

[0019] Optionally, the amide compound II is a formamide compound. The formamide compound is in liquid state, and can act as a solvent and a nitrogen alkyl source in the reaction system.

[0020] Optionally, the copper salt is one of CuBr2, CuCl2 and CuBr.

[0021] Optionally, the molar ratio of the copper salt to the phthalic acid compound I is 0.3:1.

[0022] Optionally, the peroxide is one of tert-butyl hydroperoxide, di-tert-butyl hydroperoxide and hydrogen peroxide.

[0023] Optionally, the molar ratio of the peroxide to the phthalic acid compound I is 3:1.

[0024] Optionally, the reaction time is less than or equal to 20 hours.

[0025] Optionally, the reaction temperature is controlled at 158-162℃. Further, the reaction temperature can be controlled at 160℃, which can obtain better reaction yield and reaction efficiency. DETAILED DESCRIPTION

[0026] In order to make the objectives, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present application. Unless otherwise defined, the technical terms or scientific terms used herein should have the meanings commonly understood by those skilled in the art.

[0027] It should be noted that in all the following embodiments, the "N-substituted phthalimide compound", "phthalic acid compound" and "formamide" all have the meanings commonly understood by those skilled in the art:

[0028] The N-substituted phthalimide compound is a compound containing an alkyl group substituted on the phthalimide nitrogen or an aromatic ring with various substituents;

[0029] The phthalic acid compound is a compound containing an aromatic ring structure directly connected to a carboxyl group;

[0030] The amide compound is a compound in which the H on the amide N element is substituted by various alkyl groups.

[0031] In the following embodiments, the synthesis method used without special instructions is a general method, which is applicable to the synthesis of various N-substituted phthalimide compounds. Meanwhile, the number and type of substituents in the phthalic acid compound and the amide compound are not particularly limited. The raw materials used are commercially available conventional products, and if necessary, they can be purified by means known in the art before use. Specifically, the raw materials used can be purchased from Shanghai Aldrin Biochemical Technology Co., Ltd.

[0032] The embodiment of the present application provides a synthesis method of an N-substituted phthalimide compound, which comprises the following steps: under the condition of no solvent, using a copper salt as a catalyst and a peroxide as an additive, performing the following reaction of a phthalic acid compound I and an amide compound II to obtain a compound as shown in formula III;

[0033]

[0034] R1 is hydrogen, methoxy, chlorine or nitro, R2 is hydrogen or C1-C2 alkyl, and R3 is carboxyl, ester, cyano, carboxamide, aldehyde or acetyl.

[0035] In some embodiments, when the amide compound II is a carboxamide compound, the carboxamide compound is in liquid state, and thus can dissolve the phthalic compound I as a solvent in the reaction system; when the amide compound II is a non-carboxamide compound, the solvent in the reaction system can be dimethyl sulfoxide. In fact, the synthesis reaction provided by the present application is carried out in a single organic solvent system, and the yield and operation convenience are better.

[0036] In some embodiments, the temperature during the reaction has a great influence on the yield of the reaction, and thus the temperature during the reaction can be controlled at 158-162°C, preferably at 160°C, and the yield and efficiency of the reaction are better.

[0037] In some embodiments, the specific time of the reaction can be adjusted according to the material properties of the phthalic compound I and the amide compound II, and the reaction time is usually controlled within 20 hours to achieve a good yield.

[0038] In some embodiments, the adding order of the phthalic compound I, the amide compound II, the copper salt and the peroxide can be adjusted according to the actual situation. For example, in a small-scale reaction test production in the laboratory, the two raw materials, one catalyst and one additive can be added into the reaction container, the reaction temperature is controlled at 160°C, and after the reaction is completed, the post-treatment and purification can be carried out by the conventional method. In the case of large-scale industrial production, the specific reaction parameters can be determined by the person skilled in the art through conventional tests.

[0039] In some embodiments, the copper salt used in the reaction is one of CuBr2, CuCl2 and CuBr, and the molar ratio of the copper salt to the phthalic compound I is 0.3:1.

[0040] In some embodiments, the peroxide used in the reaction is one of tert-butyl hydroperoxide, di-tert-butyl hydroperoxide and hydrogen peroxide, and the molar ratio of the peroxide to the phthalic compound I is 3:1. Specifically, the peroxide is mixed in the system in the form of a solution.

[0041] In fact, the synthesis method provided by the present application can be represented by the following reaction formula:

[0042]

[0043] The following examples 1-7 respectively provide a method for synthesizing an N-substituted phthalimide compound, and the synthesized N-substituted phthalimide compound is measured by Agilent-400MR DD2 instrument for 1H NMR and 13C NMR, the test temperature is room temperature, the solvent is deuterated chloroform or deuterated dimethyl sulfoxide, and the reference is selected as follows: 1H NMR: CHCl3 is 7.26 ppm; 13C NMR: CHCl3 is 77.0 ppm; 1H NMR: DMSO is 2.50 ppm; 13C NMR: DMSO is 39.53 ppm.

[0044] Example 1

[0045] The method for synthesizing an N-substituted phthalimide compound provided in this example 1 is specifically N-methyl phthalimide, which comprises the following steps:

[0046] 33.2 mg of phthalic acid, 13.4 mg of CuBr2, 83 μL of t-butyl hydroperoxide solution with a concentration of 70%, and 2 mL of N,N-dimethylformamide were added to a Schlenk tube equipped with a magnetic stirrer;

[0047] After reacting at 160°C for 20 h in an air atmosphere, filtration was performed, and the filtered reaction solution was subjected to rotary evaporation and concentration for column chromatography. Pure petroleum ether, 5%, 10%, and 20% ethyl acetate were used as mobile phases in sequence to obtain 29 mg of N-methyl phthalimide, and the calculated yield was 91%.

[0048] The structural characterization data of the obtained N-methyl phthalimide are as follows:

[0049] 1 H NMR (400 MHz, CDCl3) δ 7.84-7.82 (m, 2H), 7.70-7.68 (m, 2H), 3.17 (s, 3H).

[0050] 13 C NMR (101 MHz, CDCl3) δ 168.4, 133.8, 132.2, 123.1, 23.9.

[0051] HRMS (Q-TOF) m / z: [M+H] + Clacd for C9H8O2N + 162.0550; Found: 162.0548.

[0052] Example 2

[0053] The synthesis method of the N-substituted phthalimide compound provided in this embodiment 2 is specifically N-methyl-4-methoxy phthalimide, which is different from embodiment 1 in that 39.2 mg of 4-methoxy phthalic acid is used to replace 33.2 mg of phthalic acid in embodiment 1, and 22.2 mg of N-methyl-4-methoxy phthalimide is prepared, and the calculated yield is 58%.

[0054] The structural characterization data of the obtained N-methyl-4-methoxy phthalimide are as follows:

[0055] 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H), 3.14 (s, 3H).

[0056] 13 C NMR (101 MHz, CDCl3) δ 168.3, 168.2, 164.5, 134.8, 124.8, 124.1, 119.4, 108.0, 56.0, 23.9.

[0057] HRMS (Q-TOF) m / z: [M+H] + Calcd for C 10 H 10 O3N + 192.0655; Found: 192.0654.

[0058] Embodiment 3

[0059] The synthesis method of the N-substituted phthalimide compound provided in this embodiment 3 is specifically N-methyl-4-chlorophthalimide, which is different from embodiment 1 in that 40.0 mg of 4-chlorophthalic acid is used to replace 33.2 mg of phthalic acid in embodiment 1, and 17.6 mg of N-methyl-4-chlorophthalimide is prepared, and the calculated yield is 45%.

[0060] The structural characterization data of the obtained N-methyl-4-chlorophthalimide are as follows:

[0061] 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 3.6 Hz, 1H), 7.74 (s, 1H), 7.64 (dd, J = 8.0, 1.2 Hz, 1H), 3.15 (s, 3H).

[0062] 13C NMR (101 MHz, CDC13) δ 167.4, 167.0, 140.5, 133.9, 130.2, 124.4, 123.60, 24.1.

[0063] HRMS (Q-TOF) m / z: [M+H] + Claccd for C9H7O2ClN + 196.0160; Found: 196.0152.

[0064] Example 4

[0065] This Example 4 provides a method for synthesizing an N-substituted phthalimide compound, specifically N-methyl-4-nitrophthalimide. The difference between this Example 4 and Example 1 is that 42.2 mg of 4-nitrophthalic acid is used instead of 33.2 mg of phthalic acid in Example 1, and 35.4 mg of N-methyl-4-nitrophthalimide is produced with a calculated yield of 86%.

[0066] The structural characterization data of the obtained N-methyl-4-nitrophthalimide are as follows:

[0067] 1 H NMR (400 MHz, CDC13) δ 8.64 (d, J = 1.6 Hz, 1H), 8.59 (dd, J = 8.0, 2.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 3.23 (s, 3H).

[0068] 13 C NMR (101 MHz, CDC13) δ 166.2, 165.9, 151.7, 136.6, 133.6, 129.2, 124.4, 118.6, 24.5.

[0069] HRMS (Q-TOF) m / z: [M+H] + Claccd for C9H7O4N2 + 207.0400; Found: 207.0399.

[0070] Example 5

[0071] This Example 5 provides a method for synthesizing an N-substituted phthalimide compound, specifically phthalimide. The difference between this Example 5 and Example 1 is that 2 mL of formamide is used instead of 2 mL of N,N-dimethylformamide in Example 1, and 22.3 mg of phthalimide is produced with a calculated yield of 76%.

[0072] The structural characterization data of the obtained phthalimide are as follows:

[0073] 1 H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.81 (s, 4H).

[0074] 13 C NMR (101 MHz, DMSO-d6) δ 169.7, 134.7, 133.0, 123.3.

[0075] Example 6

[0076] This example 6 provides a method for synthesizing N-substituted phthalimide compounds, specifically N-ethyl phthalimide. The difference between this example and example 1 is that 2 mL of N, N-dimethylformamide in example 1 is replaced by 2 mL of N, N-diethylformamide, and 9.8 mg of N-ethyl phthalimide is prepared, with a calculated yield of 28%.

[0077] The structural characterization data of the obtained N-ethyl phthalimide is as follows:

[0078] 1 H NMR (400 MHz, CDCl3) δ 7.83-7.81 (m, 2H), 7.70-7.68 (m, 2H), 3.73 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H).

[0079] 13 C NMR (101 MHz, CDCl3) δ 168.2, 133.8, 132.2, 123.1, 32.9, 13.9.

[0080] Example 7

[0081] This example 7 provides a method for synthesizing N-substituted phthalimide compounds, specifically N-hydroxyethyl phthalimide. The difference between this example and example 1 is that 2 mL of N, N-dimethylformamide in example 1 is replaced by 2 mL of N-formylmorpholine, and 24.0 mg of N-hydroxyethyl phthalimide is prepared, with a calculated yield of 63%.

[0082] The structural characterization data of the obtained N-hydroxyethyl phthalimide is as follows:

[0083] 1 H NMR (400 MHz, CDCl3) δ 7.83-7.81 (m, 2H), 7.70-7.68 (m, 2H), 3.73 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H).

[0084] 13 C NMR (101 MHz, CDC13) δ 168.8, 134.0, 131.9, 123.3, 60.9, 40.8.

[0085] HRMS (Q-TOF) m / z: [M+H] + Cl acd for C 10 H 10 O3N + 192.0655; Found: 192.0650.

[0086] The N-substituted phthalimide compounds prepared in Examples 1-7 above, the structures of each raw material, product and yield are summarized in Table 1 below.

[0087] Table 1 Each raw material, product and yield in Examples 1-7

[0088]

[0089]

[0090] As can be seen from Examples 1-7, the synthesis method provided by the present application realizes efficient synthesis of N-substituted phthalimide compounds by using cheap and readily available phthalic acid compounds as raw materials, CuBr2 as catalyst, t-butyl hydroperoxide as additive, amide as solvent and nitrogen alkyl source. The synthesis method has good tolerance to functional groups on the aromatic ring of phthalic acid, and different substituents on the amide nitrogen can also be tolerated. It is an environmentally friendly general synthesis method.

[0091] Although the embodiments of the present application have been described in detail above, it is obvious to those skilled in the art that various modifications and changes can be made to the embodiments. However, it should be understood that such modifications and changes all fall within the scope and spirit of the present application as described in the claims. Moreover, the present application described herein can have other embodiments and can be implemented or realized in various ways.

Claims

1. A method for synthesizing an N-substituted phthalimide compound, characterized by, The method comprises the following steps: The following reaction is carried out between phthalic acid compound I and amide compound II under the catalysis of copper salt and the addition of peroxide to obtain a compound shown in formula III; ； R1 is hydrogen, methoxy, chlorine or nitro, R2 is hydrogen or C1-C2 alkyl, and R3 is carboxyl, ester, cyano, formamide, aldehyde or acetyl; the molar ratio of the copper salt to the phthalic acid compound I is 0.3:1, the molar ratio of the peroxide to the phthalic acid compound I is 3:1, the copper salt is one of CuBr2, CuCl2 and CuBr, and the peroxide is one of t-butyl hydroperoxide, di-t-butyl hydroperoxide and hydrogen peroxide.

2. The method of synthesis of claim 1, wherein, The amide compound II is a formamide compound.

3. The method of synthesis of claim 1, wherein, The reaction time is less than or equal to 20 hours.

4. The method of synthesis of claim 1, wherein, The reaction temperature is controlled at 158-162 DEG C.

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