CN117586273A - Benzofuran [2,3-c ] pyrrole-1, 3 (2H) -diketone compound and synthesis method thereof - Google Patents

Benzofuran [2,3-c ] pyrrole-1, 3 (2H) -diketone compound and synthesis method thereof Download PDF

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CN117586273A
CN117586273A CN202311480243.5A CN202311480243A CN117586273A CN 117586273 A CN117586273 A CN 117586273A CN 202311480243 A CN202311480243 A CN 202311480243A CN 117586273 A CN117586273 A CN 117586273A
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pyrrole
benzofuran
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陈万里
余鹏
朱英红
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Zhejiang University of Technology ZJUT
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2

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Abstract

The invention belongs to the technical field of organic synthesis, and in particular relates to a benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compound and a synthesis method thereof. The benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds are prepared by taking the compounds a and b shown in the general formula (1) and the general formula (2) as raw materials and coupling and cyclizing the raw materials. The synthesis method has the excellent characteristics of high reaction efficiency, simple and easy operation, cheap and easily available raw materials and high yield, and has good compatibility for various substituents. The benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compound prepared by the invention has anticancer and antitumor activities, and has wide application prospects in preparation of anticancer drugs.

Description

Benzofuran [2,3-c ] pyrrole-1, 3 (2H) -diketone compound and synthesis method thereof
Technical Field
The invention belongs to the technical field of organic synthesis, and in particular relates to a benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compound and a synthesis method thereof.
Background
The maleimide has good electrophilicity, the unique maleimide skeleton structure is widely applied to natural products and bioactive molecules, and the maleimide has wide application in the fields of medicine and functional material synthesis. Maleimide is a, b-unsaturated imide group, and the imide part brings good thermal stability for the polymer, and can be used as an important skeleton of fluorescent materials. In addition, maleimide compounds also exhibit various biological activities such as antibacterial, antifungal and anticancer activities, etc.
The benzofuran [2,3-c ] pyrrole mother nucleus compound has remarkable effects in the aspects of medicine, agriculture, industry and forestry. 3- (3-oxo-1, 3-dihydro-2H-benzofuran [2,3-c ] pyrrol-2-yl) piperidine-2, 6-dione has been reported to be an effective cerebellar protein (CRBN) ligand, and further to synthesize corresponding PROTACs molecules.
In 2021, international publication No. WO 2021/143816 A1 discloses a method for preparing a benzofuran [2,3-c ] pyrrole mother nucleus compound, which comprises the following steps:
in 2021, min Xiang, chen-Yi Li et al reported that a Michael addition reaction was carried out by imidazole using hydroxy maleimide and benzoquinone as starting materials to produce benzofuro [2,3-c ] pyrroles. The reaction process can be represented by the following reaction formula:
disclosure of Invention
In a first aspect, the present invention is directed to a benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compound.
In a second aspect, the present invention is directed to a method for synthesizing a benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compound.
In order to achieve the aim of the invention, the invention is realized by the following technical scheme:
a benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compound has a structural formula shown in a general formula (4):
wherein R is 1 Is a hydrogen atom, halogen, alkyl or alkoxy; r is R 2 Is a hydrogen atom, a phenyl group, a benzyl group, a phenyl group having a substituent on a benzene ring, or a benzyl group.
Preferably, R 2 The phenyl is phenyl with substituent on benzene ring, and the substituent is any one of methyl, methoxy, halogen and trifluoromethyl.
Preferably, R 2 Phenyl substituted by fluorine or chlorine.
Preferably, R 2 Is para-methyl substituted phenyl.
Preferably, R 1 Is methyl, R 2 Is any one of methoxy substituted phenyl, methyl substituted phenyl and benzyl.
Preferably, R 1 Is methyl, R 2 Is any one of ortho-methyl substituted phenyl and meta-methyl substituted phenyl.
The synthesis method of the benzofuran [2,3-c ] pyrrole-1, 3 (2H) -diketone compound comprises the following steps: (S.1) mixing the compound a and the compound b with alkali, adding dry toluene or dry benzene, heating and stirring, taking a reaction solution after the reaction is finished, and separating and purifying to obtain an intermediate product;
and (S.2) mixing the intermediate product obtained in the step (S.1) with a catalyst and an oxidant, adding anhydrous acetic acid, heating and stirring under the protection of nitrogen, taking a reaction solution after the reaction is finished, and separating and purifying to obtain a product c shown in the general formula (4).
Preferably, in the step (s.1), the structural formulas of the compound a, the compound b and the intermediate product are sequentially shown as a general formula (1), a general formula (2) and a general formula (3):
preferably, the base in the step (s.1) is any one of cesium carbonate, potassium tert-butoxide, and sodium tert-butoxide.
Preferably, the catalyst in the step (s.2) is any one of palladium acetate, palladium chloride and palladium nitrate.
Preferably, the oxidizing agent in the step (s.2) is any one of potassium persulfate, copper acetate, and silver nitrate.
Preferably, the reaction temperature in the step (S.1) is 45 to 60 ℃ and the reaction time is 1 to 6 hours.
Preferably, the reaction temperature in the step (S.2) is 90 to 110℃and the reaction time is 10 to 18 hours.
Preferably, the molar ratio of the compound a, the compound b and the base added in the step (S.1) is 1.05 to 1.2:1 (1.05 to 1.2).
Preferably, the molar ratio of the intermediate product, the catalyst and the oxidizing agent added in the step (S.2) is 1 (0.05-0.2) to 3-5.
Preferably, the benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds are synthesized as follows:
preferably, the reaction progress in the step (S.1) is monitored by TLC, and when the reaction of the compound b represented by the general formula (2) is complete, TLC monitors the completion of the reaction.
Preferably, the reaction progress in the step (S.2) is monitored by TLC, and when the intermediate product represented by the general formula (3) is reacted completely, TLC monitors the completion of the reaction.
Preferably, the reaction liquid separation and purification process in the step (s.1) includes the steps of:
and (3) spin-drying toluene or benzene in the reaction liquid by using a spin-steaming instrument, adding water into the reaction liquid, extracting for 2-3 times by using dichloromethane, combining organic phases, drying by using anhydrous magnesium sulfate, filtering, and spin-drying filtrate to obtain a crude product. The crude product was then recrystallized (EA: PE) and purified to give the intermediate product.
Preferably, the reaction liquid separation and purification process in the step (s.2) includes the steps of:
water was added to the reaction solution, extraction was performed 2 to 3 times with ethyl acetate, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluent containing the product c is collected, and the solvent is distilled off to obtain benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds (namely the product c shown in the general formula (4)). The eluent for silica gel column chromatography purification adopts petroleum ether and ethyl acetate mixed solvent with the volume ratio of 10:1.
Therefore, the invention has the following beneficial effects:
(1) The benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds are prepared by taking the compounds a and b shown in the general formula (1) and the general formula (2) as raw materials and coupling and cyclizing the raw materials with high efficiency;
(2) The synthesis method has the excellent characteristics of high reaction efficiency, simple and easy operation, cheap and easily available raw materials and high yield, and has good compatibility for various substituents;
(3) The benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compound prepared by the invention has anticancer and antitumor activities, and has wide application prospects in preparation of anticancer drugs.
Drawings
FIG. 1 shows the product c of example 1 1 H spectrum.
FIG. 2 shows the product c of example 1 13 C spectrogram.
FIG. 3 shows the product c of example 6 1 H spectrum.
FIG. 4 is a diagram of product c in example 6 13 C spectrogram.
FIG. 5 is a diagram of product c in example 9 1 H spectrum.
FIG. 6 is a diagram of product c in example 9 13 C spectrogram.
FIG. 7 is a diagram of product c in example 10 1 H spectrum.
FIG. 8 is a diagram of product c in example 10 13 C spectrogram.
Detailed Description
The invention is further described below with reference to the drawings and specific examples. Those of ordinary skill in the art will be able to implement the invention based on these descriptions. In addition, the embodiments of the present invention referred to in the following description are typically only some, but not all, embodiments of the present invention. Therefore, all other embodiments, which can be made by one of ordinary skill in the art without undue burden, are intended to be within the scope of the present invention, based on the embodiments of the present invention.
Example 1
A synthesis method of benzofuran [2,3-c ] pyrrole-1, 3 (2H) -diketone compound comprises the following steps:
(S.1) in a 25mL single-neck dry flask, 0.5mmol of Compound a, 0.55mmol of Compound b, 0.55mmol of cesium carbonate, 8mL of dry toluene (i.e., anhydrous toluene) were added, and the reaction was stirred at 60℃with an oil bath, and TLC monitored for progress of the reaction. After the reaction, toluene in the reaction liquid is dried by spin-drying by a spin-steaming instrument, water is added into the reaction liquid, and the reaction liquid is extracted for 2 to 3 times by dichloromethane, and is washed by saturated saline water. The organic phases were combined and dried over anhydrous magnesium sulfate, filtered, and the filtrate was dried by spinning to give the crude product. Recrystallizing the crude product (EA: PE) and purifying to obtain an intermediate product;
(S.2) 0.3mmol of the intermediate obtained in step (S.1), 3eq of potassium persulfate, 10% of palladium acetate, 5mL of dry acetic acid (i.e. anhydrous acetic acid) were placed in a 25mL two-necked round bottom dry flask, N 2 The reaction was stirred at 100deg.C in an oil bath and monitored by TLC. After the reaction, water was added to the reaction mixture, followed by extraction with ethyl acetate 2 to 3 times. The organic phases were combined and dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, collecting eluent containing product c, and evaporating solvent to obtain cyan solid, namely product c (namely benzofuran [2,3-c]Pyrrole-1, 3 (2H) -diones. The eluent for silica gel column chromatography purification adopts petroleum ether and ethyl acetate mixed solvent with the volume ratio of 10:1. The yield was 90%. FIG. 1 shows the product c of this example 1 H spectrogram; FIG. 2 shows the product c of this example 13 C spectrogram. In addition, in this example, the structural formula of compound a as substrate 1, compound b as substrate 2, and product c as the final productShown in table 1 below.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.59(d，J＝9.25Hz，1H)，7.50(t，J＝7.58Hz，2H)，7.39-7.42(m，3H)，7.28(d，J＝2.49Hz，1H)，7.14(dd，J 1 ＝9.23Hz，J 2 ＝2.57Hz，1H)，3.89(s，3H)。
13 C NMR(125MHz，CDCl 3 )δ161.8，158.23，158.21，158.1，156.5，131.5，129.1，128.1，126.9，123.6，121.1，118.4，114.3，103.0，56.0。
example 2
This embodiment differs from embodiment 1 in that:
in this example, a method for synthesizing benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds is provided, wherein the structural formulae of compound a as substrate 1 and product c as final product are different. The other components are the same as those in example 1. The structural formulae of the compound a as the substrate 1, the compound b as the substrate 2 and the product c as the final product in this example are shown in Table 1 below. The yield was 77%.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.59(d，J＝9.27Hz，1H)，7.35-7.39(m，2H)，7.27(d，J＝2.56Hz，1H)，7.13-7.20(m，3H)，3.90(s，3H)。
13 C NMR(125MHz，CDCl 3 )δ161.9(d，J＝248.3Hz)，161.7，158.3，158.1，157.9，156.5，128.75(d，J＝8.36Hz)，127.39(d，J＝3.27Hz)，123.6，121.0，118.5，116.1(d，J＝22.84Hz)，114.4，103.0，56.0。
example 3
This embodiment differs from embodiment 1 in that:
in this example, a method for synthesizing benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds is provided, wherein the structural formulae of compound a as substrate 1 and product c as final product are different. The other components are the same as those in example 1. The structural formulae of the compound a as the substrate 1, the compound b as the substrate 2 and the product c as the final product in this example are shown in Table 1 below. The yield was 85%.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.59(d，J＝9.22Hz，1H)，7.43-7.48(m，1H)，7.27(d，J＝2.52Hz，1H)，7.22-7.23(m，1H)，7.08-7.19(m，3H)，3.89(s，3H)。
13 C NMR(125MHz，CDCl 3 )δ162.6(d，J＝247.16Hz)，161.3，158.3，157.8，157.7，156.5，132.9(d，J＝l0.02Hz)，130.2(d，J＝8.98Hz)，123.6，122.23(d，J＝3.31Hz)，120.9，118.7，115.0，114.9(d，J＝20.91Hz)，114.4，114.1(d，J＝24.37Hz)，56.0。
example 4
This embodiment differs from embodiment 1 in that:
in this example, a method for synthesizing benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds is provided, wherein the structural formulae of compound a as substrate 1 and product c as final product are different. The other components are the same as those in example 1. The structural formulae of the compound a as the substrate 1, the compound b as the substrate 2 and the product c as the final product in this example are shown in Table 1 below. The yield was 95%.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.60(d，J＝9.18Hz，1H)，7.50(dd，J 1 ＝6.41Hz，J 2 ＝2.34Hz，1H)，7.25-7.33(m，3H)，7.15(dd，J 1 ＝9.26Hz，J 2 ＝2.58Hz，1H)，3.90(s，3H)。
13 C NMR(125MHz，CDCl 3 )δ161.3，158.35，157.67(d，J＝2.14Hz)，157.4(d，J＝250.6Hz)，156.6，129.1，127.96(d，J＝3.46Hz)，126.68(d，J＝7.93Hz)，123.7，121.6(d，J＝18.73Hz)，120.9，118.8，117.0，116.8，114.4，103.0，56.1。
example 5
This embodiment differs from embodiment 1 in that:
in this example, a method for synthesizing benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds is provided, wherein the structural formulae of compound a as substrate 1 and product c as final product are different. The other components are the same as those in example 1. The structural formulae of the compound a as the substrate 1, the compound b as the substrate 2 and the product c as the final product in this example are shown in Table 1 below. The yield was 92%.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.59(d，J＝9.22Hz，1H)，7.44(t，J＝1.90Hz，1H)7.42(d，J＝7.92Hz，1H)，7.36-7.38(m，1H)，7.30-7.33(m，1H)，7.28(d，J＝2.53Hz，1H)，7.15(dd，J 1 ＝9.26Hz，J 2 ＝2.72Hz，1H)，3.90(s，3H)。
13 C NMR(125MHz，CDCl 3 )δ161.3，158.3，157.8，157.7，156.6，134.6，132.6，130.0，128.1，126.9，124.8，123.7，121.0，118.7，114.4，103.0，56.1。
example 6
This embodiment differs from embodiment 1 in that:
in this example a benzofuran [2,3-c ] is provided]A method for synthesizing pyrrole-1, 3 (2H) -diketone compounds, wherein the structural formulas of a compound a serving as a substrate 1 and a product c serving as an end product are different. The other components are the same as those in example 1. The structural formulae of the compound a as the substrate 1, the compound b as the substrate 2 and the product c as the final product in this example are shown in Table 1 below. The yield was 70%. FIG. 3 shows the product c of this example 1 H spectrogram; FIG. 4 shows the product c of this example 13 C spectrogram.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.52(d，J＝9.28Hz，1H)，7.41(d，J＝7.24Hz，2H)，7.26-7.34(m，3H)，7.20(d，J＝2.55Hz，1H)，7.07(dd，J 1 ＝9.25Hz，J 2 ＝2.67Hz，1H)，4.78(s，2H)，3.86(s，3H)。
13 C NMR(125MHz，CDCl 3 )δ162.6，159.0，158.4，158.1，156.3，136.5，128.7，128.5，127.8，123.7，121.1，118.0，114.2，102.8，56.0，41.7。
example 7
This embodiment differs from embodiment 1 in that:
in this example, a method for synthesizing benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds is provided, wherein the structural formulae of compound a as substrate 1 and product c as final product are different. The other components are the same as those in example 1. The structural formulae of the compound a as the substrate 1, the compound b as the substrate 2 and the product c as the final product in this example are shown in Table 1 below. The yield was 87%.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.60(d，J＝9.37Hz，2H)，7.51-7.54(m，1H)，7.37(d，J＝5.10Hz，2H)，7.28(d，J＝2.59Hz，1H)，7.15(dd，J 1 ＝9.34Hz，J 2 ＝2.65Hz，1H)，3.90(s，3H)。
13 C NMR(125MHz，CDCl 3 )δ161.3，158.3，157.7，156.6，132.7，131.0，130.3，129.8，125.3，123.7，122.4，121.0，118.7，114.4，103.0，56.1。
example 8
This embodiment differs from embodiment 1 in that:
in this example, a method for synthesizing benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds is provided, wherein the structural formulae of compound a as substrate 1 and product c as final product are different. The other components are the same as those in example 1. The structural formulae of the compound a as the substrate 1, the compound b as the substrate 2 and the product c as the final product in this example are shown in Table 1 below. The yield was 96%.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.58-7.62(m，3H)，7.26-7.30(m，3H)，7.14(dd，J 1 ＝9.19Hz，J 2 ＝2.61Hz，1H)，3.89(s，3H)。
13 C NMR(125MHz，CDCl 3 )δ161.4，158.3，157.9，157.8，156.5，132.3，130.6，128.2，123.6，121.7，120.9，118.6，114.4，103.0，56.0。
example 9
This embodiment differs from embodiment 1 in that:
in this example a benzofuran [2,3-c ] is provided]A method for synthesizing pyrrole-1, 3 (2H) -diketone compounds, wherein the structural formulas of a compound b serving as a substrate 2 and a product c serving as an end product are different. The other components are the same as those in example 1. The structural formulae of the compound a as the substrate 1, the compound b as the substrate 2 and the product c as the final product in this example are shown in Table 1 below. The yield was 88%. FIG. 5 shows the product c of this example 1 H spectrogram; FIG. 6 shows the product c of this example 13 C spectrogram.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.93(d，J＝7.70Hz，1H)，7.73(d，J＝8.42Hz，1H)，7.55-7.59(m，1H)，7.50(t，J＝7.74Hz，3H)，7.39-7.42(m，3H)。
13 C NMR(125MHz，CDCl 3 )δ161.6，161.5，158.3，157.9，131.5，129.2，128.6，128.1，126.9，126.1，123.8，122.1，120.5，113.7。
example 10
This embodiment differs from embodiment 1 in that:
in this example a benzofuran [2,3-c ] is provided]A method for synthesizing pyrrole-1, 3 (2H) -diketone compounds, wherein the structural formulas of a compound b serving as a substrate 2 and a product c serving as an end product are different. The other components are the same as those in example 1. In this example, the structural formula of compound a as substrate 1, compound b as substrate 2 and product c as final product are shownShown in table 1 below. The yield was 86%. FIG. 7 shows the product c of this example 1 H spectrogram; FIG. 8 shows the product c of this example 13 C spectrogram.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.92(d，J＝1.23Hz，1H)，7.67(d，J＝9.01Hz，1H)，7.49-7.54(m，3H)，7.38-7.43(m，3H)。
13 C NMR(125MHz，CDCl 3 )δ161.0，159.7，159.0，157.9，132.1，131.3，129.2，128.9，128.2，126.9，123.0，121.7，121.6，114.7。
example 11
This embodiment differs from embodiment 1 in that:
in this example, a method for synthesizing benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds is provided, wherein the structural formulae of compound b as substrate 2 and product c as final product are different. The other components are the same as those in example 1. The structural formulae of the compound a as the substrate 1, the compound b as the substrate 2 and the product c as the final product in this example are shown in Table 1 below. The yield was 88%.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.85(d，J＝8.37Hz，1H)，7.76(d，J＝1.59Hz，1H)，7.49-7.52(m，3H)，7.38-7.43(m，3H)。
13 CNMR(125MHz，CDCl 3 )δ161.3，161.1，158.3，157.9，134.7，131.3，129.2，128.2，127.1，126.9，123.6，122.5，119.1，114.3。
example 12
This embodiment differs from embodiment 1 in that:
in this example, a method for synthesizing benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds is provided, wherein the structural formulae of compound b as substrate 2 and product c as final product are different. The other components are the same as those in example 1. The structural formulae of the compound a as the substrate 1, the compound b as the substrate 2 and the product c as the final product in this example are shown in Table 1 below. The yield thereof was found to be 63%.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.71(s，1H)，7.59(d，J＝8.68Hz，1H)，7.49(t，J＝7.81Hz，2H)，7.38(m，4H)，2.52(s，3H)。
13 C NMR(125MHz，CDCl 3 )δ161.8，160.1，158.4，157.8，136.2，131.5，129.9，129.1，128.0，126.9，123.4，121.7，120.5，113.1，21.4。
example 13
This embodiment differs from embodiment 1 in that:
in this example, a method for synthesizing benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds is provided, wherein the structural formulae of compound b as substrate 2 and product c as final product are different. The other components are the same as those in example 1. The structural formulae of the compound a as the substrate 1, the compound b as the substrate 2 and the product c as the final product in this example are shown in Table 1 below. The yield was 96%.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.78(d，J＝7.71Hz，1H)，7.48-7.52(m，3H)，7.31-7.40(m，4H)，2.55(s，3H)。
13 C NMR(125MHz，CDCl 3 )δ162.0，161.8，158.4，157.1，139.7，131.6，129.1，128.0，127.6，126.9，123.9，121.4，118.0，113.7，22.0。
example 14
This embodiment differs from embodiment 1 in that:
in this example, a method for synthesizing benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds is provided, wherein the structural formulae of compound b as substrate 2 and product c as final product are different. The other components are the same as those in example 1. The structural formulae of the compound a as the substrate 1, the compound b as the substrate 2 and the product c as the final product in this example are shown in Table 1 below. The yield thereof was found to be 83%.
Product c 1 H spectrum, 13 The C-spectrum data are as follows:
1 H NMR(500MHz，CDCl 3 )δ7.73-7.74(m，1H)，7.49-7.52(m，2H)，7.35-7.42(m，5H)，2.62(s，3H)。
13 C NMR(125MHz，CDCl 3 )δ161.8，160.8，158.5，157.4，131.5，129.5，129.1，128.0，126.9，126.1，124.3，124.0，120.0，119.4，15.0。
the structural formulae of the compound a as the reaction substrate 1, the compound b as the reaction substrate 2 and the product c as the final product in examples 1 to 14 and the yields of the product c are shown in table 1 below.
TABLE 1
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Example 15
The benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds prepared by the synthesis procedure in example 6 can be further used to synthesize 3- (hydroxymethyl) -5-methoxy-N-phenylbenzofuran-2-carboxamide compounds which are novel cannabinoid receptor modulators. The synthetic reaction route of the 3- (hydroxymethyl) -5-methoxy-N-phenylbenzofuran-2-carboxamide compound provided in the example is as follows:
the reaction conditions in the above synthetic reaction scheme are as follows:
N 2 adding 7-methoxy-2-phenyl-1H-benzofuro [2,3-c ] under atmosphere]Pyrrole-1, 3 (2H) -dione (0.088 g,0.3 mmol) was placed in a 25mL two-neck dry flask. Adding dry tetrahydrofuran in ice bath, stirring until the temperature in the bottle is reduced to 0 ℃, and adding NaBH 4 (0.025 mg,0.6 mmol). The reaction was carried out for about 5-6 hours, and TLC monitored the progress of the reaction. After the reaction was completed, THF was removed by rotary evaporation, quenched with ice water, extracted with 10mL of dichloromethane, washed with 80mL of water, washed with 30mL of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and column chromatography to give an intermediate product. The intermediate was added to a 25mL two-port dry flask, and 10mL of quinoline, potassium persulfate (0.08 g,0.3 mmol) was added thereto and stirred at 100℃for 2 hours. Copper powder (0.02 g,0.33 mmol) was then added thereto, and the reaction mixture was heated to 230℃and reacted for 5 to 6 hours. After the TLC monitoring reaction is finished, cooling the reaction liquid to 100 ℃, pouring the reaction liquid into ice water, extracting the reaction liquid with diethyl ether for 2 to 3 times, washing the reaction liquid with brine for 2 to 3 times, merging organic phases, drying the organic phases by anhydrous magnesium sulfate, concentrating the organic phases under reduced pressure, and finally obtaining the novel N-benzyl benzofuran-2-carboxamide cannabinoid receptor modulator through column chromatography.
Example 16
The benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds prepared by the synthesis procedure described in example 9 can be further used to synthesize a cerebellar protein E3 ubiquitin ligase protein binding ligand compound. The synthetic reaction route of the cerebellar protein E3 ubiquitin ligase protein binding ligand compound provided in the embodiment is as follows:
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the reaction conditions in the above synthetic reaction scheme are as follows:
antimony pentafluoride (0.5 g,2.3 mmol) was added to 2-phenyl-1H-benzofuro [2,3-c ] at room temperature]CF of pyrrole-1, 3 (2H) -dione (0.05 g,0.2 mmol) 3 SO 3 H (1 g,6.7 mmol). After stirring for 3min, 0.3mL cyclohexane was added and the reaction mixture was stirred for 1h at 25 ℃. After the reaction, the reaction solution was poured into ice water, and thenNeutralizing sodium bicarbonate, extracting with chloroform for 2-3 times, mixing organic phases, drying, concentrating under reduced pressure, and performing column chromatography to obtain 2-phenyl-2, 3-dihydro-1H-benzofuro [2,3-c ]]Pyrrol-1-one.
The foregoing is only illustrative of the preferred embodiments and principles of the present invention, and changes in specific embodiments will occur to those skilled in the art upon consideration of the teachings provided herein, and such changes are intended to be included within the scope of the invention as defined by the claims.

Claims (10)

1. The benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compound is characterized by having a structural formula shown in a general formula (4):
wherein R is 1 Is a hydrogen atom, halogen, alkyl or alkoxy; r is R 2 Is a hydrogen atom, a phenyl group, a benzyl group, a phenyl group having a substituent on a benzene ring, or a benzyl group.
2. A benzofuran [2,3-c ] according to claim 1]Pyrrole-1, 3 (2H) -dione compounds, characterized in that R 2 The phenyl is phenyl with substituent on benzene ring, and the substituent is any one of methyl, methoxy, halogen and trifluoromethyl.
3. A benzofuran [2,3-c ] according to claim 1 or 2]Pyrrole-1, 3 (2H) -dione compounds, characterized in that R 2 Phenyl substituted by fluorine or chlorine.
4. A benzofuran [2,3-c ] according to claim 1 or 2]Pyrrole-1, 3 (2H) -dione compounds, characterized in that R 2 Is para-methyl substituted phenyl.
5. A benzofuran [2,3-c ] according to claim 1]Pyrrole-1, 3 (2H) -diketonesAn object, characterized in that R 1 Is methyl, R 2 Is any one of methoxy substituted phenyl, methyl substituted phenyl and benzyl.
6. A benzofuran [2,3-c ] according to claim 5]Pyrrole-1, 3 (2H) -dione compounds, characterized in that R 1 Is methyl, R 2 Is any one of ortho-methyl substituted phenyl and meta-methyl substituted phenyl.
7. A method for synthesizing benzofuran [2,3-c ] pyrrole-1, 3 (2H) -dione compounds according to any one of claims 1 to 6, comprising the following steps:
(S.1) mixing the compound a and the compound b with alkali, adding dry toluene or dry benzene, heating and stirring, taking a reaction solution after the reaction is finished, and separating and purifying to obtain an intermediate product;
and (S.2) mixing the intermediate product obtained in the step (S.1) with a catalyst and an oxidant, adding anhydrous acetic acid, heating and stirring under the protection of nitrogen, taking a reaction solution after the reaction is finished, and separating and purifying to obtain a product c shown in the general formula (4).
8. The synthesis method according to claim 7, wherein the structural formulae of the compound a, the compound b and the intermediate in the step (s.1) are shown in general formula (1), general formula (2) and general formula (3) in sequence:
9. the synthesis method according to claim 7, wherein the molar ratio of the compound a, the compound b and the base added in the step (S.1) is 1.05 to 1.2:1 (1.05 to 1.2).
10. The synthesis process according to claim 7, wherein the molar ratio of the intermediate product, the catalyst and the oxidizing agent added in the step (S.2) is 1 (0.05 to 0.2): 3 to 5.
CN202311480243.5A 2023-11-08 2023-11-08 Benzofuran [2,3-c ] pyrrole-1, 3 (2H) -diketone compound and synthesis method thereof Pending CN117586273A (en)

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