CN116947734A - Synthesis method of N-substituted phthalimide compound - Google Patents
Synthesis method of N-substituted phthalimide compound Download PDFInfo
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- -1 N-substituted phthalimide compound Chemical class 0.000 title claims abstract description 62
- 238000001308 synthesis method Methods 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 150000002978 peroxides Chemical class 0.000 claims abstract description 12
- 150000001879 copper Chemical class 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000000654 additive Substances 0.000 claims abstract description 6
- 230000000996 additive effect Effects 0.000 claims abstract description 6
- 238000010189 synthetic method Methods 0.000 claims abstract 3
- XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 21
- 150000001408 amides Chemical class 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 8
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 7
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 150000003022 phthalic acids Chemical class 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- UCFFGYASXIPWPD-UHFFFAOYSA-N methyl hypochlorite Chemical compound COCl UCFFGYASXIPWPD-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000000524 functional group Chemical group 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 125000001424 substituent group Chemical group 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract 1
- 150000003021 phthalic acid derivatives Chemical class 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical class C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 238000012512 characterization method Methods 0.000 description 7
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- JZDSOQSUCWVBMV-UHFFFAOYSA-N 2-ethylisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CC)C(=O)C2=C1 JZDSOQSUCWVBMV-UHFFFAOYSA-N 0.000 description 3
- JBCHWGTZAAZJKG-UHFFFAOYSA-N 2-methyl-5-nitroisoindole-1,3-dione Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(C)C(=O)C2=C1 JBCHWGTZAAZJKG-UHFFFAOYSA-N 0.000 description 3
- DCFSQEWFDPNDPQ-UHFFFAOYSA-N 5-chloro-2-methylisoindole-1,3-dione Chemical compound C1=C(Cl)C=C2C(=O)N(C)C(=O)C2=C1 DCFSQEWFDPNDPQ-UHFFFAOYSA-N 0.000 description 3
- XBMAYZIUFPBRBD-UHFFFAOYSA-N 5-methoxy-2-methylisoindole-1,3-dione Chemical compound COC1=CC=C2C(=O)N(C)C(=O)C2=C1 XBMAYZIUFPBRBD-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- MWFLUYFYHANMCM-UHFFFAOYSA-N 2-(2-hydroxyethyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCO)C(=O)C2=C1 MWFLUYFYHANMCM-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical group [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000005543 phthalimide group Chemical group 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- ZXLYYQUMYFHCLQ-UHFFFAOYSA-N 2-methylisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(C)C(=O)C2=C1 ZXLYYQUMYFHCLQ-UHFFFAOYSA-N 0.000 description 1
- DVIPPHSQIBKWSA-UHFFFAOYSA-N 4-chlorophthalic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1C(O)=O DVIPPHSQIBKWSA-UHFFFAOYSA-N 0.000 description 1
- JKZSIEDAEHZAHQ-UHFFFAOYSA-N 4-methoxyphthalic acid Chemical compound COC1=CC=C(C(O)=O)C(C(O)=O)=C1 JKZSIEDAEHZAHQ-UHFFFAOYSA-N 0.000 description 1
- SLBQXWXKPNIVSQ-UHFFFAOYSA-N 4-nitrophthalic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1C(O)=O SLBQXWXKPNIVSQ-UHFFFAOYSA-N 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- SJDOMIRMMUGQQK-UHFFFAOYSA-N NAN 190 Chemical compound COC1=CC=CC=C1N1CCN(CCCCN2C(C3=CC=CC=C3C2=O)=O)CC1 SJDOMIRMMUGQQK-UHFFFAOYSA-N 0.000 description 1
- 239000004642 Polyimide Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 1
- WOAFDHWYKSOANX-UHFFFAOYSA-N diisopropyl methylphosphonate Chemical compound CC(C)OP(C)(=O)OC(C)C WOAFDHWYKSOANX-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920002382 photo conductive polymer Polymers 0.000 description 1
- 229920001721 polyimide Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000010512 small scale reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- CEIJFEGBUDEYSX-FZDBZEDMSA-N tandospirone Chemical compound O=C([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C1=O)N1CCCCN(CC1)CCN1C1=NC=CC=N1 CEIJFEGBUDEYSX-FZDBZEDMSA-N 0.000 description 1
- 229950000505 tandospirone Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
Abstract
The invention provides a synthesis method of an N-substituted phthalimide compound, and relates to the technical field of organic synthesis. The synthesis method comprises the following steps: in the presence of a solvent or without a solvent, copper salt is used as a catalyst, peroxide is used as an additive, and phthalic acid compounds I and amide compounds II react to synthesize N-substituted phthalimide compounds; the synthetic method has the advantages of cheap and easily obtained reaction raw materials, safety and environmental protection, better tolerance and tolerance to various substituent groups and functional groups, and contribution to large-scale industrial production, and provides a high-efficiency, convenient, green and environmental-friendly synthetic path for the N-substituted phthalimide compounds.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of N-substituted phthalimide compounds.
Background
The N-substituted phthalimide compound is widely applied to medicines, agriculture, fine chemical engineering and functional materials, and the N-substituted phthalimide compound not only is used as a monomer of a polymer, but also is used as a basic structural component in pesticide and potential drug molecules, so that the N-substituted phthalimide compound has great prospect. For example, in vivo anti-inflammatory drug LASBio-468, anti-androgen drug DIMP, antidepressant drug Tandospirone, NAN-190 and other pharmacological action parts contain phthalimide groups, and polyimide obtained by polymerization of phthalimide compounds can improve the transmission characteristics of photoconductive polymers, thereby improving photovoltaic performance and the like.
At present, the synthesis method of the N-substituted phthalimide compound mainly comprises the following steps:
one is to use benzamide as a substrate and use various carbonyl sources to synthesize N-substituted phthalimide compounds, and the following reaction formula is shown in the specification:
however, this method requires the use of noble metal catalysts Pd and Ru, is expensive, and has the disadvantages of high volatility, high toxicity and the like of CO, and is severely limited in terms of storage, transportation, laboratory use, post-treatment and the like, so that the application of the method is limited.
The other is to prepare N-substituted phthalimide compounds by taking phthalimide as a substrate and coupling with a proper alkyl source, wherein the reaction formula is as follows:
however, this method requires pre-functionalization of phthalimide in order to increase the reactivity and yield of the reactants, which is disadvantageous for industrial mass production.
Also disclosed is a process for preparing N-substituted phthalimides from various "N" sources by phthalic acid coupling, which has the following reaction formula:
however, the reaction conditions of this method are severe, high temperature and high pressure are required, the tolerance of the functional group is poor, and the method is difficult to be applicable to some sensitive functional groups.
Therefore, there is a need to provide a synthesis route of phthalimide compounds which is low in cost, economical and practical, and suitable for large-scale industrial production.
Disclosure of Invention
The invention aims to provide a synthesis method of N-substituted phthalimide compounds, which can be used for efficiently synthesizing the phthalimide compounds, has low-cost and easily-obtained reaction raw materials, can effectively reduce the synthesis cost, has good tolerance and tolerance to functional groups, and is beneficial to large-scale industrial production.
The invention provides a synthesis method of an N-substituted phthalimide compound, which comprises the following steps: under the condition of no solvent, copper salt is used as a catalyst, peroxide is used as an additive, and phthalic acid compounds I and amide compounds II react to obtain compounds shown in a formula III;
wherein R is 1 Is hydrogen, methoxy, chlorine or nitro, R 2 Is hydrogen or C 1 -C 2 Alkyl of R 3 Is carboxyl, ester, cyano, formamido, aldehyde or acetyl.
The N-substituted phthalimide compound provided by the invention has the beneficial effects that: the phthalimide compound I and the amide compound II are low in cost and easy to obtain, the synthesis cost can be obviously reduced, meanwhile, the synthesis method has good tolerance to functional groups on aromatic rings of the phthalic acid compound, can also be tolerant to substituents on nitrogen of the amide compound, is green and environment-friendly, and is suitable for large-scale industrial production.
Optionally, the amide compound II is a carboxamide compound. The method has the beneficial effects that the formamide compound is in a liquid state, and can be used as a solvent and a nitrogen alkyl source in a reaction system.
Optionally, the copper salt is CuBr 2 、CuCl 2 And CuBr.
Optionally, the molar ratio of the copper salt to the phthalic acid compound I is 0.3:1.
Optionally, the peroxide is one of tert-butyl hydroperoxide, di-tert-butyl hydroperoxide and hydrogen peroxide.
Alternatively, the molar ratio of the peroxide to the phthalic compound I is 3:1.
Optionally, the duration of the reaction is less than or equal to 20 hours.
Alternatively, the temperature of the reaction is controlled to 158-162 ℃. Furthermore, the reaction temperature can be controlled to 160 ℃, so that better reaction yield and reaction efficiency can be obtained.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. Unless otherwise defined, technical or scientific terms used herein should be given the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.
In all of the following examples, "N-substituted phthalimide compound", "phthalic acid compound" and "formamide" have meanings commonly understood by those skilled in the art:
the N-substituted phthalimide compound is a compound containing the nitrogen of the phthalimide substituted by alkyl or various substituents on the aromatic ring;
the phthalic acid compound is a compound containing an aromatic ring structure directly connected with carboxyl;
the amide compound is a compound in which H on an amide N element is substituted by various alkyl groups.
In the following examples, unless otherwise specified, the synthesis methods used are general methods suitable for synthesizing various N-substituted phthalimides, and the number of substituents and the types of substituents in the phthalic acid compounds and the amide compounds are not particularly limited. The raw materials used are all commercially available conventional products and may be purified if necessary by means well known in the art, and specifically, the raw materials used are available from Shanghai Ala Biotechnology Co., ltd.
The embodiment of the invention provides a synthesis method of an N-substituted phthalimide compound, which comprises the following steps: under the condition of no solvent, copper salt is used as a catalyst, peroxide is used as an additive, and phthalic acid compounds I and amide compounds II react to obtain compounds shown in a formula III;
wherein R is 1 Is hydrogen, methoxy, chlorine or nitro, R 2 Is hydrogen or C 1 -C 2 Alkyl of R 3 Is carboxyl, ester, cyano, formamido, aldehyde or acetyl.
In some embodiments, when the amide compound II is a carboxamide compound, the carboxamide compound is in a liquid state, so that the carboxamide compound can be used as a solvent to dissolve the phthalic acid compound I in the reaction system; when the amide compound II is a non-carboxamide compound, the solvent in the reaction system may be dimethyl sulfoxide. In fact, the synthesis reaction provided by the invention is carried out in a system of a single organic solvent, and the yield and the operation convenience are better.
In some embodiments, since the temperature change during the reaction has a large influence on the reaction yield, the temperature during the reaction can be controlled between 158 and 162 ℃, preferably 160 ℃, and the yield and efficiency achieved by the reaction are superior.
In some embodiments, the specific reaction time can be adaptively adjusted according to the material properties of the specifically selected phthalic acid compound I and the amide compound II, and the reaction time is controlled within 20 hours to achieve a good yield.
In some embodiments, the order of addition of the phthalic acid compound I, the amide compound II, the copper salt and the peroxide may be adjusted according to the actual situation, for example, when small-scale reaction test production is performed in a laboratory, two raw materials, a catalyst and an additive may be added into a reaction vessel in a unified manner, the reaction temperature is controlled at 160 ℃, and after the reaction is completed, the post-treatment and purification may be performed in a conventional manner. In the face of large-scale industrial production, specific reaction parameters thereof can be determined by one skilled in the art through routine experiments.
In some embodiments, the copper salt used in the reaction is specifically CuBr 2 、CuCl 2 And CuBr, and the molar ratio of the copper salt to the phthalic acid compound I is 0.3:1.
In some embodiments, the peroxide used in the reaction is specifically one of t-butyl hydroperoxide, di-t-butyl hydroperoxide and hydrogen peroxide, and the molar ratio of peroxide to phthalic compound I is 3:1. Specifically, the peroxide is mixed in the system in the form of a solution.
In fact, the synthesis method provided by the invention can be represented by the following reaction formula:
the following examples 1-7 provide a method for synthesizing N-substituted phthalimides, and the synthesized N-substituted phthalimides are 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: 1H NMR: CHCl3 was 7.26ppm;13C NMR: CHCl3 was 77.0ppm;1H NMR: DMSO is 2.50ppm;13C NMR: DMSO is 39.53ppm.
Example 1
The synthesis method of the N-substituted phthalimide compound provided in the embodiment 1 specifically comprises the following steps:
33.2mg of phthalic acid and 13.4mg of CuBr 2 mu.L of a 70% strength solution of t-butyl hydroperoxide and 2mLN, N-dimethylformamide were added to a Schlenk tube equipped with a magnetic stirrer;
in the air atmosphere at 160 ℃ for 20 hours, filtering out the reaction liquid, rotary evaporating, concentrating, loading on a column, and sequentially using pure petroleum ether, 5%, 10% and 20% ethyl acetate as mobile phases to prepare 29 mgN-methylphthalimide, wherein the calculated yield is 91%.
The structural characterization data of the obtained N-methylphthalimide are as follows:
1 H NMR(400MHz，CDCl 3 )δ7.84-7.82(m，2H)，7.70-7.68(m，2H)，3.17(s，3H).
13 C NMR(101MHz，CDCl 3 )δ168.4，133.8，132.2，123.1，23.9.
HRMS(Q-TOF)m/z：[M+H] + Clacd for C 9 H 8 O 2 N + 162.0550；Found：162.0548.
example 2
The synthesis method of N-substituted phthalimide compound provided in this example 2, specifically N-methyl-4-methoxyphthalimide, is different from that of example 1 in that 39.2mg of 4-methoxyphthalic acid is used to replace 33.2mg of phthalic acid in example 1, 22.2mg of N-methyl-4-methoxyphthalimide is produced, and the calculated yield is 58%.
The structural characterization data of the obtained N-methyl-4-methoxyphthalimide are as follows:
1 H NMR(400MHz，CDCl 3 )δ7.72(d，J＝8.0Hz，1H)，7.30(s，1H)，7.12(d，J＝8.4Hz，1H)，3.91(s，3H)，3.14(s，3H).
13 C NMR(101MHz，CDCl 3 )δ168.3，168.2，164.5，134.8，124.8，124.1，119.4，108.0，56.0，23.9.
HRMS(Q-TOF)m/z：[M+H] + Clacd for C 10 H 10 O 3 N + 192.0655；Found：192.0654.
example 3
The synthesis method of N-substituted phthalimide compound provided in this example 3, specifically N-methyl-4-chlorophthalimide, was different from example 1 in that 40.0mg of 4-chlorophthalic acid was used in place of 33.2mg of phthalic acid in example 1 to obtain 17.6mg of N-methyl-4-chlorophthalimide, and the calculated yield was 45%.
The structural characterization data of the obtained N-methyl-4-chlorophthalimide are as follows:
1 H NMR(400MHz，CDCl 3 )δ7.76(d，J＝3.6Hz，1H)，7.74(s，1H)，7.64(dd，J＝8.0，1.2Hz，1H)，3.15(s，3H).
13 C NMR(101MHz，CDCl 3 )δ167.4，167.0，140.5，133.9，130.2，124.4，123.60，24.1.
HRMS(Q-TOF)m/z：[M+H] + Clacd for C 9 H 7 O 2 ClN + 196.0160；Found：196.0152.
example 4
The synthesis method of the N-substituted phthalimide compound provided in the embodiment 4 is specifically N-methyl-4-nitrophthalimide, and is different from the embodiment 1 in that 42.2mg of 4-nitrophthalic acid is used to replace 33.2mg of phthalic acid in the embodiment 1, 35.4mg of N-methyl-4-nitrophthalimide is prepared, and the calculated yield is 86%.
The structural characterization data of the obtained N-methyl-4-nitrophthalimide are as follows:
1 H NMR(400MHz，CDCl 3 )δ8.64(d，J＝1.6Hz，1H)，8.59(dd，J＝8.0，2.0Hz，1H)，8.04(d，J＝8.0Hz，1H)，3.23(s，3H).
13 C NMR(101MHz，CDCl 3 )δ166.2，165.9，151.7，136.6，133.6，129.2，124.4，118.6，24.5.
HRMS(Q-TOF)m/z：[M+H] + Clacd for C 9 H 7 O 4 N 2 + 207.0400；Found：207.0399.
example 5
The synthesis method of the N-substituted phthalimide compound provided in the present example 5, specifically phthalimide, is different from example 1 in that 2mL of formamide was used instead of 2mL of LN, N-dimethylformamide in example 1 to prepare 22.3mg of phthalimide, and the calculated yield was 76%.
The structural characterization data of the phthalimide obtained are as follows:
1 H NMR(400MHz，DMSO-d 6 )δ11.32(s，1H)，7.81(s，4H).
13 C NMR(101MHz，DMSO-d 6 )δ169.7，134.7，133.0，123.3.
example 6
The synthesis method of the N-substituted phthalimide compound provided in the present example 6, specifically N-ethylphthalimide, is different from that of example 1 in that 2mLN, N-diethylformamide is used in place of 2mLN, N-dimethylformamide in example 1, 9.8mg of N-ethylphthalimide is obtained, and the calculated yield is 28%.
The structural characterization data of the obtained N-ethylphthalimide are as follows:
1 H NMR(400MHz，CDCl 3 )δ7.83-7.81(m，2H)，7.70-7.68(m，2H)，3.73(q，J＝7.2Hz，2H)，1.26(t，J＝7.6Hz，3H).
13 C NMR(101MHz，CDCl 3 )δ168.2，133.8，132.2，123.1，32.9，13.9.
example 7
The synthesis method of the N-substituted phthalimide compound provided in the present example 7, specifically N-hydroxyethyl phthalimide, is different from that in the example 1 in that 2 LN, N-dimethylformamide in the example 1 is replaced with 2 mLN-formylmorpholine to prepare 24.0 mgN-hydroxyethyl phthalimide, and the calculated yield is 63%.
The structural characterization data of the obtained N-hydroxyethyl phthalimide are as follows:
1 H NMR(400MHz，CDCl 3 )δ7.83-7.81(m，2H)，7.71-7.69(m，2H)，3.89-3.83(m，4H)，2.47(s，1H).
13 C NMR(101MHz，CDCl 3 )δ168.8，134.0，131.9，123.3，60.9，40.8.
HRMS(Q-TOF)m/z：[M+H] + Clacd for C 10 H 10 O 3 N + 192.0655；Found：192.0650.
the structural formulae and yields of the N-substituted phthalimides prepared in examples 1-7 are summarized in Table 1 below.
TABLE 1 starting materials, products and yields for examples 1-7
According to the synthesis method provided by the invention, by adopting the low-cost and easily-obtained phthalic acid compound as a raw material and using CuBr2 as a catalyst and tert-butyl hydroperoxide as an additive and amide as a solvent and an aminoalkyl source, the high-efficiency synthesis of the N-substituted phthalimide compound is realized, functional groups on aromatic rings of the terephthalic acid are better tolerated, and different substituents on amide nitrogen are also tolerated, so that the synthesis method is an environment-friendly and general synthesis method.
While embodiments of the present invention have been described in detail hereinabove, it will be apparent to those skilled in the art that various modifications and variations can be made to these embodiments. It is to be understood that such modifications and variations are within the scope and spirit of the present invention as set forth in the following claims. Moreover, the invention described herein is capable of other embodiments and of being practiced or of being carried out in various ways.
Claims (8)
1. The synthesis method of the N-substituted phthalimide compound is characterized by comprising the following steps of: in the presence of a solvent or without a solvent, copper salt is used as a catalyst, peroxide is used as an additive, and phthalic acid compounds I and amide compounds II react to obtain compounds shown in a formula III;
wherein R is 1 Is hydrogen, methoxy, chlorine or nitro, R 2 Is hydrogen or C 1 -C 2 Alkyl of R 3 Is carboxyl, ester, cyano, formamido, aldehyde or acetyl.
2. The method according to claim 1, wherein the amide compound II is a carboxamide compound.
3. The synthesis according to claim 1, wherein the copper salt is CuBr 2 、CuCl 2 And CuBr.
4. A synthesis according to claim 3, characterized in that the molar ratio of copper salt to phthalic acid compound I is 0.3:1.
5. The method of synthesis according to claim 1, wherein the peroxide is one of t-butyl hydroperoxide, di-t-butyl hydroperoxide and hydrogen peroxide.
6. The method according to claim 5, wherein the molar ratio of the peroxide to the phthalic acid compound I is 3:1.
7. The synthetic method of claim 1 wherein the duration of the reaction is less than or equal to 20 hours.
8. The synthetic method of claim 1 wherein the temperature of the reaction is controlled to be 158-162 ℃.
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