A visible light-mediated synthesis method of succinamide compounds
By reacting N-substituted acrylamide compounds with oxalamic acid compounds with catalysts and bases under the action of a catalyst and a base, the complex and costly synthesis of existing succinamide compounds is solved. An efficient and simple synthesis process is achieved.
Patent Information
- Application Number
- CN202310145190.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-02-21
- Publication Date
- 2025-02-07
- Estimated Expiration
- 2043-02-21
AI Technical Summary
The existing synthesis methods of succinamide compounds are complex and costly, requiring multiple reactions and expensive catalysts.
The synthesis process is simplified by reacting N-substituted acrylamide compounds with oxalamic acid compounds under the action of catalysts and bases under blue light irradiation and nitrogen atmosphere.
It has achieved efficient synthesis of succinamide compounds, simple and safe operation, cheap and easy to obtain raw materials, high product yield, good functional group tolerance and substrate application scope.
Smart Images
Figure BDA0004088939450000011 
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of synthesis of succinamide compounds, and particularly relates to a method for synthesizing succinamide compounds mediated by visible light. Background Art
[0002] Succinamide is widely used in drug development as a linking group, for example, it is present in the bivalent protein kinase CK2 inhibitor KN2 (J.Med.Chem.2022,65,1302-1312.). Studies have shown that it can be used as a linking group in the research and development of small molecule PD-1 / PDL1 inhibitors (European Journal of MedicinalChemistry2020,199,112377.). Therefore, the construction of succinamide compounds, especially derivatives with different groups, is of great significance to drug development and organic synthetic chemistry. A common method is to use a single protected succinic acid as a raw material and connect it to the first amine by an amide condensation reaction, and then remove the protecting group and connect it to the second amine by a condensation reaction (J.Med.Chem.2022,65,1302-1312.), which requires a three-step reaction, and the steps are relatively cumbersome, and expensive amide condensation agents such as HATU need to be used. Summary of the invention
[0003] The technical problem solved by the present invention is to provide a method for synthesizing succinamide compounds mediated by visible light with simple process and low cost. The method uses greener and cleaner visible light as energy, the raw materials are simple and easy to obtain, and the product yield is high.
[0004] The present invention adopts the following technical scheme to solve the above technical problems. A visible light-mediated synthesis method of succinamide compounds is characterized in that the specific process is: placing an N-substituted acrylamide compound and an oxalamic acid compound in a solvent, reacting under the action of a catalyst and a base, and simultaneously under the conditions of blue light irradiation and a nitrogen environment, and obtaining the target product succinamide compound by separation after the reaction is completed; the catalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, the base is lithium hydroxide monohydrate, the structure of the N-substituted acrylamide compound is shown in formula A, the structure of the oxalamic acid compound is shown in formula B, and the structure of the succinamide compound is shown in formula C:
[0005]
[0006]
[0007] R in Formula A and Formula C 1 H, Cl, Br, C 1-5 Alkyl or C1-5 Alkoxy, R 1 The substitution on the benzene ring is mono- or di-substituted. R in formula B and formula C 2 C 1-5 Alkyl, adamantyl, phenyl C 1-5 Alkyl or ester-containing alkyl.
[0008] It is further defined that the molar ratio of the N-substituted acrylamide compound, the oxalamide acid compound, the catalyst and the base is 1:1-3:0.01-0.1:1-3.
[0009] It is further defined that the solvent is anhydrous N,N-dimethylacetamide.
[0010] It is further defined that the light source of the blue light is a blue LED lamp with a wavelength of 450-460nm and a power of 5-10W.
[0011] It is further defined that the reaction temperature of the reaction process is 25-40° C., and the reaction time is 6-24 hours.
[0012] It is further specified that after the reaction is completed, a saturated NaCl solution is added to the reaction solution to quench the reaction, and then extracted three times with ethyl acetate. After the organic phases are combined, they are dried over anhydrous sodium sulfate and separated by column chromatography to obtain the target compound, succinamide.
[0013] Compared with the prior art, the present invention has the following advantages and beneficial effects: the present invention does not require the use of a transition metal catalyst or an external oxidant, uses a photosensitizer as a catalyst under the mediation of visible light, and reacts at room temperature to synthesize a target product. The method is simple and safe to operate, the reaction conditions are mild, the raw materials are cheap and readily available, and the light source of the method is visible light, which is green and pollution-free, and the catalyst is relatively environmentally friendly. In addition, the yield of the target product synthesized by the present invention is high, and it has good functional group tolerance and a substrate application range. The method can be used for the later modification of drugs and is expected to be used in drug research and development. DETAILED DESCRIPTION
[0014] The above contents of the present invention are further described in detail below through examples, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples, and all technologies implemented based on the above contents of the present invention belong to the scope of the present invention.
[0015] Example 1
[0016] N-phenylacrylamide (0.2mmol), 2-(hexylamino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under the irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. After the organic phases were combined, they were dried with anhydrous sodium sulfate, and the target product was separated by column chromatography. The target product was a white solid, and the yield of the target product was 88% based on the molar amount of N-phenylacrylamide as 100%. The structural formula of the target product is as follows:
[0017]
[0018] The above white solid was subjected to nuclear magnetic spectrum analysis, and the data were as follows: 1 H NMR (400MHz, CDCl3) δ8.90(br,1H),7.53(d,J=8.0Hz,2H),7.29-7.25(m,2H),7.06(t,J=7.2Hz,1H),6.22(br,1H ), 3.22 (dd, J=13.2, 6.8Hz, 2H), 2.76-2.59 (m, 4H), 1.47-1.42 (m, 2H), 1.28-1.24 (m, 6H), 0.85 (t, J=6.4Hz, 3H). 13 C NMR (100MHz, CDCl3) δ172.6, 171.0, 138.4, 128.9, 124.1, 120.1, 39.9, 33.0, 31.8, 31.6, 29.6, 26.7, 22.6, 14.1.
[0019] Example 2
[0020] N-(2-chlorophenyl)acrylamide (0.2mmol), 2-(hexylamino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under the irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. After the organic phase was combined, it was dried with anhydrous sodium sulfate and separated by column chromatography to obtain the target product, which was a white solid. The yield of the target product was 83% based on the molar amount of N-(2-chlorophenyl)acrylamide as 100%. The structural formula of the target product is as follows:
[0021]
[0022] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, CDCl3) δ8.35-8.20(m,2H),7.34(dd,J=7.9,0.8Hz,1H),7.21(t,J=7.5Hz,1H),7.06-6.96(m,1H),6.05(br,1H), 3.24-3.19(m,2H),2.78(t,J=6.0Hz,2H),2.58(t,J=7.0Hz,2H),1.53-1.37(m,2H),1.30-1.16(m,6H),0.84(t,J=6.3Hz,3H). 13 C NMR (100MHz, CDCl3) δ171.8,171.0,134.7,129.2,127.6,124.9,122.3,39.9,33.1,31.6,31.5,29.6,26.7,22.6,14.1. HRMSCalcd for C 16 H 23 ClN2O2[M+Na] + :m / z:333.1341,Found:333.1339.
[0023] Example 3
[0024] N-(3-chlorophenyl)acrylamide (0.2mmol), 2-(hexylamino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. After the organic phases were combined, they were dried with anhydrous sodium sulfate, and the target product was separated by column chromatography. The target product was a white solid, and the yield of the target product was 86% based on the molar amount of N-(3-chlorophenyl)acrylamide as 100%. The structural formula of the target product is as follows:
[0025]
[0026] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, CDCl3) δ9.47(br,1H),7.67(s,1H),7.37(d,J=8.0Hz,1H),7.15(t,J=8.0Hz,1H),7.01(d,J=7.7Hz,1H),6.4 3(br,1H),3.22(dd,J=13.1,6.7Hz,2H),2.85-2.61(m,4H),1.51-1.38(m,2H),1.31-1.16(m,6H),0.84(t,J=6.7Hz,3H). 13 C NMR (100MHz, CDCl3) δ172.6,171.2,139.7,134.5,129.9,124.0,120.1,117.9,40.0,32.9,31.6,31.6,29.6,26.7,22.6,14.1. HRMS Calcd for C 16 H 23 ClN2O2[M+Na] + :m / z:333.1341,Found:333.1343.
[0027] Example 4
[0028] N-(3-bromophenyl)acrylamide (0.2mmol), 2-(hexylamino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. After the organic phases were combined, they were dried with anhydrous sodium sulfate, and the target product was separated by column chromatography. The target product was a white solid, and the yield of the target product was 56% based on the molar amount of N-(3-bromophenyl)acrylamide as 100%. The structural formula of the target product is as follows:
[0029]
[0030] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, CDCl3) δ9.38(br,1H),7.81(s,1H),7.43(d,J=8.0Hz,1H),7.18-7.08(m,2H),6.29(br,1H),3. 23 (dd, J=13.1, 6.8Hz, 2H), 2.78-2.61 (m, 4H), 1.48-1.45 (m, 2H), 1.28-1.16 (m, 6H), 0.86 (t, J=6.0Hz, 3H). 13 C NMR (100MHz, CDCl3) δ172.6,171.1,139.9,130.2,127.0,122.9,122.6,118.4,40.1,32.9,31.7,31.6,29.6,26.7,22.7,14.1. HRMS Calcd for C 16 H 23 BrN2O2[M+Na] + :m / z:377.0835Found:377.0816.
[0031] Example 5
[0032] N-(2-bromo-4-methylphenyl)acrylamide (0.2mmol), 2-(hexylamino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the reaction was extracted three times with ethyl acetate. After the organic phase was combined, it was dried with anhydrous sodium sulfate and separated by column chromatography to obtain the target product, which was a white solid. The yield of the target product was 54% based on the molar amount of N-(2-bromo-4-methylphenyl)acrylamide as 100%.
[0033] The structural formula of the target product is as follows:
[0034]
[0035] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, CDCl3) δ8.03(t,J=8.2Hz,2H),7.34(s,1H),7.07(d,J=7.7Hz,1H),5.96(br,1H),3.22(dd,J=12.6,6.7Hz ,2H),2.85-2.68(m,2H),2.63-2.54(m,2H),2.28(s,3H),1.53-1.40(m,2H),1.32-1.16(m,6H),0.85(t,J=6.6Hz,3H). 13 C NMR (100MHz, CDCl3) δ171.8,170.7,135.6,133.2,132.7,128.9,122.6,114.1,39.9,33.1,31.7,31.6,29.7,26.7,22.6,20.6,14.1. HRMS Calcd for C 17 H 25 BrN2O2[M+Na] + :m / z:391.0992Found:391.0976.
[0036] Example 6
[0037] N-(4-ethylphenyl)acrylamide (0.2mmol), 2-(hexylamino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. After the organic phases were combined, they were dried with anhydrous sodium sulfate, and the target product was separated by column chromatography. The target product was a white solid, and the yield of the target product was 76% based on the molar amount of N-(4-ethylphenyl)acrylamide as 100%. The structural formula of the target product is as follows:
[0038]
[0039] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, CDCl3) δ8.79(br,1H),7.42(d,J=8.2Hz,2H),7.09(d,J=8.2Hz,2H),6.29(br,1H),3.21(d d,J=13.0,6.7Hz,2H),2.82-2.51(m,6H),1.52-1.41(m,2H),1.32-1.15(m,9H),0.85(t,J=6.0Hz,3H). 13 C NMR (100MHz, CDCl3) δ172.5,170.8,140.2,136.0,128.3,120.2,39.9,33.0,32.0,31.6,29.6,28.4,26.7,22.6,15.8,14.1. HRMS Calcd for C 18 H 28 N2O2[M+Na] + :m / z:327.2043Found:327.2027.
[0040] Example 7
[0041] N-(3,5-dimethylphenyl)acrylamide (0.2mmol), 2-(hexylamino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10ml reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the reaction was extracted three times with ethyl acetate. After the organic phase was combined, it was dried with anhydrous sodium sulfate and separated by column chromatography to obtain the target product, which was a white solid. The yield of the target product was 83% based on the molar amount of N-(3,5-dimethylphenyl)acrylamide as 100%.
[0042] The structural formula of the target product is as follows:
[0043]
[0044] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, CDCl3) δ8.69(br,1H),7.16(s,2H),6.71(s,1H),6.21(br,1H),3.22(dd,J=13.0,6.9H z,2H),2.75-2.55(m,4H),2.24(s,6H),1.50-1.41(m,2H),1.29-1.19(m,6H),0.85(t,J=6.5Hz,3H). 13 CNMR (100MHz, CDCl3) δ172.6,170.9,138.5,138.2,125.8,117.8,39.9,33.1,31.9,31.6,29.6,26.7,22.6,21.4,14.1. HRMS Calcd for C 18 H 28 N2O2[M+Na] + :m / z:327.2043Found:327.2026.
[0045] Example 8
[0046] N-(o-tolyl) acrylamide (0.2mmol), 2-(hexylamino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under the irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. After the organic phase was combined, it was dried with anhydrous sodium sulfate and separated by column chromatography to obtain the target product, which was a white solid. The yield of the target product was 60% based on the molar amount of N-(o-tolyl) acrylamide as 100%. The structural formula of the target product is as follows:
[0047]
[0048] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR(400MHz, CDCl3)δ8.22(br,1H),7.70(d,J=8.0Hz,1H),7.18-7.10(m,2H),7.08-7.01(m,1H),6.16(br,1H), 3.21-3.16(m,2H),2.75-5.58(m,4H),2.23(s,3H),1.49-1.39(m,2H),1.32-1.20(m,6H),0.86(t,J=6.0Hz,3H). 13 C NMR (100MHz, CDCl3) δ172.3,171.1,136.0,130.6,129.9,126.6,125.2,123.4,39.9,32.9,32.1,31.6,29.6,26.7,22.6,18.0,14.1. HRMS Calcd forC 17 H 26 N2O2[M+Na] + :m / z:313.1886Found:313.1881.
[0049] Example 9
[0050] N-(3,5-dimethoxyphenyl)acrylamide (0.2mmol), 2-(hexylamino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the reaction was extracted three times with ethyl acetate. After the organic phase was combined, it was dried with anhydrous sodium sulfate and separated by column chromatography to obtain the target product, which was a white solid. The yield of the target product was 71% based on the molar amount of N-(3,5-dimethoxyphenyl)acrylamide as 100%.
[0051] The structural formula of the target product is as follows:
[0052]
[0053] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, CDCl3) δ9.05(br,1H),6.79(d,J=4.0Hz,2H),6.34(br,1H),6.17(t,J=4.0Hz,1H),3.71(s,6H),3.20(dd, J=13.2,7.2Hz,2H),2.76-2.70(m,2H),2.63-2.57(m,2H),1.50-1.34(m,2H),1.30-1.14(m,6H),0.83(t,J=6.6Hz,3H). 13 C NMR (100MHz, CDCl3) δ172.5,171.1,161.0,140.2,98.2,96.5,55.4,40.0,33.1,31.7,31.6,29.6,26.7,22.6,14.1. HRMS Calcd forC 18 H 28 N2O4[M+Na] + :m / z:359.1941Found:359.1926.
[0054] Example 10
[0055] N-phenylacrylamide (0.2mmol), 2-(butylamino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under the irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. After the organic phase was combined, it was dried with anhydrous sodium sulfate and separated by column chromatography to obtain the target product, which was a white solid. The yield of the target product was 58% based on the molar amount of N-phenylacrylamide as 100%. The structural formula of the target product is as follows:
[0056]
[0057] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, CDCl3) δ9.02(br,1H),7.53(d,J=7.9Hz,2H),7.26(t,J=7.2Hz,2H),7.06(t,J=7.4Hz,1H),6.36(br ,1H),3.22(dd,J=13.1,6.8Hz,2H),2.8-2.6(m,4H),1.49-1.39(m,2H),1.32-1.26(m,2H),0.86(t,J=7.3Hz,3H). 13 C NMR (100MHz, CDCl3) δ172.6,171.0,138.4,128.9,124.1,120.1,39.6,33.0,31.8,31.7,20.1,13.8. HRMS Calcd for C 14 H 20 N2O2[M+Na] + :m / z:271.1417Found:271.1420.
[0058] Embodiment 11
[0059] N-phenylacrylamide (0.2mmol), 2-(tert-butylamino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. After the organic phases were combined, they were dried with anhydrous sodium sulfate, and the target product was separated by column chromatography. The target product was a white solid, and the yield of the target product was 83% based on the molar amount of N-phenylacrylamide as 100%. The structural formula of the target product is as follows:
[0060]
[0061] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR(400MHz, CDCl3)δ8.97(br,1H),7.53-7.51(d,J=7.9Hz,2H),7.26(t,J=8.1Hz,2H),7.0 5(t,J=7.3Hz,1H),5.92(br,1H),2.68(t,J=5.9Hz,2H),2.52(t,J=7.1Hz,2H),1.31(s,9H). 13 C NMR (100MHz, CDCl3) δ171.9,171.1,138.4,128.9,124.0,120.0,51.5,33.2,32.9,28.8. HRMS Calcd forC 14 H 20 N2O2[M+Na] + :m / z:271.1417Found:271.1425.
[0062] Example 12
[0063] N-phenylacrylamide (0.2mmol), 2-((6-methoxy-6-oxohexyl)amino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. After the organic phases were combined, they were dried with anhydrous sodium sulfate, and the target product was separated by column chromatography. The target product was a white solid, and the yield of the target product was 62% based on the molar amount of N-phenylacrylamide as 100%. The structural formula of the target product is as follows:
[0064]
[0065] The white solid was subjected to NMR and mass spectrometry analysis, and the data were as follows: 1 H NMR (400MHz, CDCl3) δ8.84(br,1H),7.51(d,J=7.9Hz,2H),7.31-7.22(m,2H),7.06(t,J=7.3Hz,1H),6.30(br,1H),3.6 4(s,3H),3.22(dd,J=13.0,6.6Hz,2H),2.77-2.54(m,4H),2.25(t,J=7.4Hz,2H),1.62-1.43(m,4H),1.31-1.27(m,2H). 13 C NMR (100MHz, CDCl3) δ174.2,172.6,170.9,138.4,129.0,124.2,120.0,51.6,39.6,33.9,33.1,31.9,29.2,26.4,24.5. HRMS Calcd forC 17 H 24 N2O4[M+Na] + :m / z:343.1628Found:343.1620.
[0066] Example 13
[0067] N-phenylacrylamide (0.2mmol), 2-((8-methoxy-8-oxooctyl)amino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. After the organic phases were combined, they were dried with anhydrous sodium sulfate, and the target product was separated by column chromatography. The target product was a white solid, and the yield of the target product was 59% based on the molar amount of N-phenylacrylamide as 100%. The structural formula of the target product is as follows:
[0068]
[0069] Embodiment 14
[0070] N-phenylacrylamide (0.2mmol), 2-(benzylamino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis (9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under the irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. After the organic phase was combined, it was dried with anhydrous sodium sulfate and separated by column chromatography to obtain the target product, which was a white solid. The yield of the target product was 77% based on the molar amount of N-phenylacrylamide as 100%. The structural formula of the target product is as follows:
[0071]
[0072] Embodiment 15
[0073] N-phenylacrylamide (0.2mmol), 2-oxo-2-((2-phenylpropan-2-yl)amino)acetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the reaction was extracted three times with ethyl acetate. After the organic phase was combined, it was dried with anhydrous sodium sulfate and separated by column chromatography to obtain the target product, which was a white solid. The yield of the target product was 86% based on the molar amount of N-phenylacrylamide as 100%. The structural formula of the target product is as follows:
[0074]
[0075] Example 16
[0076] N-phenylacrylamide (0.2mmol), 2-((1-(benzyloxy)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the reaction was extracted three times with ethyl acetate. After the organic phase was combined, it was dried with anhydrous sodium sulfate and separated by column chromatography to obtain the target product, which was a white solid. The yield of the target product was 67% based on the molar amount of N-phenylacrylamide as 100%.
[0077] The structural formula of the target product is as follows:
[0078]
[0079] Embodiment 17
[0080] N-phenylacrylamide (0.2mmol), 2-(((3s,5s,7s)-adamantan-1-yl)amino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under the irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the reaction was extracted three times with ethyl acetate. After the organic phase was combined, it was dried with anhydrous sodium sulfate and separated by column chromatography to obtain the target product, which was a white solid. The yield of the target product was 65% based on the molar amount of N-phenylacrylamide as 100%. This embodiment is a late modification of the antiviral drug adamantane. The structural formula of the target product is as follows:
[0081]
[0082] Embodiment 18
[0083] N-phenylacrylamide (0.2mmol), 2-((3-methoxy-3-oxopropyl)amino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. After the organic phases were combined, they were dried with anhydrous sodium sulfate, and the target product was separated by column chromatography. The target product was a white solid, and the yield of the target product was 72% based on the molar amount of N-phenylacrylamide as 100%. The structural formula of the target product is as follows:
[0084]
[0085] Embodiment 19
[0086] N-(o-tolyl) acrylamide (0.2mmol), 2-((3-methoxy-3-oxopropyl)amino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the reaction was extracted three times with ethyl acetate. After the organic phase was combined, it was dried with anhydrous sodium sulfate and separated by column chromatography to obtain the target product, which was a white solid. The yield of the target product was 51% based on the molar amount of N-(o-tolyl) acrylamide as 100%. The structural formula of the target product is as follows:
[0087]
[0088] Embodiment 20
[0089] N-(3,5-dimethylphenyl)acrylamide (0.2mmol), 2-((3-methoxy-3-oxopropyl)amino)-2-oxoacetic acid (0.4mmol), lithium hydroxide monohydrate (0.4mmol) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (0.01mmol) were added to a 10mL reaction tube equipped with a magnetic electron; the reaction tube was evacuated and replaced with nitrogen three times, and then anhydrous N,N-dimethylacetamide (2mL) was added as a solvent, and the reaction tube was stirred for 12h under irradiation of a blue light LED lamp with a wavelength of 455nm and a reaction temperature of 35°C. After the reaction was completed, a saturated NaCl solution was added to quench the reaction, and the reaction was extracted three times with ethyl acetate. After the organic phase was combined, it was dried with anhydrous sodium sulfate and separated by column chromatography to obtain the target product, which was a white solid. The yield of the target product was 54% based on the molar amount of N-(3,5-dimethylphenyl)acrylamide as 100%. The structural formula of the target product is as follows:
[0090]
[0091] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for illustrating the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.
Claims
1. A visible light-mediated synthesis method of succinamide compounds, characterized in that The specific process is: placing N-substituted acrylamide compounds and oxalamide compounds in a solvent, reacting under the action of a catalyst and a base, and under the conditions of blue light irradiation and a nitrogen environment, and separating to obtain the target product succinamide compounds after the reaction is completed; the catalyst is 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile, the base is lithium hydroxide monohydrate, the structure of the N-substituted acrylamide compounds is shown in formula A, the structure of the oxalamide acid compounds is shown in formula B, and the structure of the succinamide compounds is shown in formula C: R in Formula A and Formula C 1 H, Cl, Br, C 1-5 Alkyl or C 1-5 Alkoxy, R 1 The substitution on the benzene ring is mono- or di-substituted. R in formula B and formula C 2 C 1-5 Alkyl, adamantyl, phenyl C 1-5 Alkyl or ester-containing alkyl.
2. The method for synthesizing succinamide compounds mediated by visible light according to claim 1, characterized in that: The molar ratio of the N-substituted acrylamide compound, the oxalamide acid compound, the catalyst and the base is 1:1-3:0.01-0.1:1-3.
3. The method for synthesizing succinamide compounds mediated by visible light according to claim 1, characterized in that: The solvent is anhydrous N,N-dimethylacetamide.
4. The method for synthesizing succinamide compounds mediated by visible light according to claim 1, characterized in that: The blue light source is a blue LED lamp with a wavelength of 450-460nm and a power of 5-10W.
5. The method for synthesizing succinamide compounds mediated by visible light according to claim 1, characterized in that: The reaction temperature of the reaction process is 25-40°C, and the reaction time is 6-24h.
6. The method for synthesizing succinamide compounds mediated by visible light according to claim 1, characterized in that After the reaction was completed, saturated NaCl solution was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, and separated by column chromatography to obtain the target compound, succinamide.