CN117418244A - Preparation method for synthesizing 1, 2, 3 full-substituted indolizine derivative by electrochemical oxidation - Google Patents
Preparation method for synthesizing 1, 2, 3 full-substituted indolizine derivative by electrochemical oxidation Download PDFInfo
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- CN117418244A CN117418244A CN202310126086.1A CN202310126086A CN117418244A CN 117418244 A CN117418244 A CN 117418244A CN 202310126086 A CN202310126086 A CN 202310126086A CN 117418244 A CN117418244 A CN 117418244A
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- 125000003406 indolizinyl group Chemical class C=1(C=CN2C=CC=CC12)* 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 7
- 238000006056 electrooxidation reaction Methods 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 36
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- AVWLPUQJODERGA-UHFFFAOYSA-L cobalt(2+);diiodide Chemical compound [Co+2].[I-].[I-] AVWLPUQJODERGA-UHFFFAOYSA-L 0.000 claims abstract description 14
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims abstract description 13
- 239000012299 nitrogen atmosphere Substances 0.000 claims abstract description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 15
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- 238000003487 electrochemical reaction Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 4
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical group Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 6
- 238000002955 isolation Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 8
- 229910052799 carbon Inorganic materials 0.000 abstract description 8
- 239000002904 solvent Substances 0.000 abstract description 8
- 239000003054 catalyst Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000003792 electrolyte Substances 0.000 abstract 1
- 238000012512 characterization method Methods 0.000 description 21
- 238000001228 spectrum Methods 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 229910001873 dinitrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 238000002390 rotary evaporation Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 238000001308 synthesis method Methods 0.000 description 7
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 6
- 230000009286 beneficial effect Effects 0.000 description 5
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 0.000 description 5
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- PLGPSDNOLCVGSS-UHFFFAOYSA-N Tetraphenylcyclopentadienone Chemical compound O=C1C(C=2C=CC=CC=2)=C(C=2C=CC=CC=2)C(C=2C=CC=CC=2)=C1C1=CC=CC=C1 PLGPSDNOLCVGSS-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YSHMQTRICHYLGF-UHFFFAOYSA-N 4-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=NC=C1 YSHMQTRICHYLGF-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical compound BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 1
- XTUHPOUJWWTMNC-UHFFFAOYSA-N cobalt(2+);dioxido(dioxo)chromium Chemical compound [Co+2].[O-][Cr]([O-])(=O)=O XTUHPOUJWWTMNC-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- CHEPDPSMYKFNAN-UHFFFAOYSA-N methyl 4-(2-bromoacetyl)benzoate Chemical compound COC(=O)C1=CC=C(C(=O)CBr)C=C1 CHEPDPSMYKFNAN-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- SKFLCXNDKRUHTA-UHFFFAOYSA-N phenyl(pyridin-4-yl)methanone Chemical compound C=1C=NC=CC=1C(=O)C1=CC=CC=C1 SKFLCXNDKRUHTA-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/01—Products
- C25B3/07—Oxygen containing compounds
-
- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/01—Products
- C25B3/05—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/01—Products
- C25B3/09—Nitrogen containing compounds
-
- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/20—Processes
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- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Electrochemistry (AREA)
- Materials Engineering (AREA)
- Metallurgy (AREA)
Abstract
The application discloses a preparation method for synthesizing 1, 2 and 3 full-substituted indolizine derivatives by electrochemical oxidation. The compound is obtained by taking N, N-dimethylformamide as a solvent, tetrabutylammonium iodide as an electrolyte and cobalt iodide as a catalyst, adopting a carbon electrode as an electrode, and carrying out reaction under the nitrogen atmosphere at the voltage of 3.5V at the two ends. The reaction raw materials and the solvent involved in the preparation method are all commercial products, and the price is low; the reaction condition is simple and mild, the yield is good, the atom utilization rate is high, the green chemistry characteristic is realized, and the sustainable development concept is met.
Description
Technical Field
The invention belongs to the field of organic synthetic chemistry, and in particular relates to a preparation method for synthesizing 1, 2, 3 full-substituted indolizine derivatives by electrochemical oxidation
Background
1. The 2, 3 full-substituted indolizine derivatives are compounds with excellent biological activity and have wide application in the field of biological medicine. The existing methods for fully substituted indolizine derivatives 1, 2 and 3 mainly comprise the following three methods:
the method I adopts cyclization reaction of three bromoketone molecules and pyridine molecules under the action of an oxidant TPCD (tetrapyridyl cobalt chromate), and the chemical reaction formula of the method is shown as formula (1).
The disadvantage of this process is that the reaction yields are low, and the oxidant TPCD in the reaction is expensive and the economic return is not high.
In the second method, pyridine and aromatic methyl ketone react under the action of iodine and DMSO (dimethyl sulfoxide), and the chemical reaction formula of the method is shown as formula (2).
The disadvantage of this process is that an excess of elemental iodine (3 equiv) is used in the reaction, as well as a relatively high reaction temperature (100 ℃), which affects the synthetic value of the reaction.
And thirdly, carrying out reaction by adopting aromatic methyl ketone and pyridine molecules under the promotion of copper bromide, wherein the chemical reaction formula of the method is shown as a formula (3).
The disadvantages of this method are the high copper bromide usage (0.5 equiv), the long reaction time (12 h), the high reaction temperature (90 ℃) and the need for an oxygen atmosphere.
Disclosure of Invention
The invention aims to: the invention aims to provide a simple and convenient 1, 2 and 3 full-substituted indolizine derivative with easily available raw materials and a preparation method thereof, wherein the preparation method can greatly improve the atom economy and the step economy of the reaction, is beneficial to researching the pharmacological activity of the compound and is beneficial to environmental protection.
The technical scheme is as follows: in one aspect, the invention provides a preparation method of 1, 2 and 3 full-substituted indolizine derivatives, which is characterized by referring to formula 1:
adding a pyridine structure shown as a formula (1), a bromide structure shown as a formula (2), sodium carbonate, tetrabutylammonium iodide, cobalt iodide and a reaction solvent into a reaction device;
adding N, N-dimethylformamide into the mixture, sealing the pipe for reaction in a nitrogen atmosphere, and synthesizing the mixture in one step to obtain a product mixture;
extracting and filtering the product mixture obtained in the step (2) after the reaction in the step (3) is finished, and concentrating and separating the obtained filtrate to obtain the 1, 2 and 3 full-substituted indolizine derivative structural formula (3); wherein R is 1 、R 2 Each independently selected from H, C1-C12 alkyl, C1-C20 substituted or unsubstituted aryl.
The beneficial effects are that:
compared with the prior art, the invention has the following beneficial effects:
1. the reaction conditions are milder: in the prior art, high temperature (more than 90 ℃) is needed, the reaction can be smoothly carried out at normal temperature, the heating consumption in the experiment is reduced, and the economy of the experiment is greatly improved.
2. The dosage and the reaction time of the metal catalyst are reduced: in the prior art, the method either uses an excessive oxidant or uses a larger amount of metal compound (0.5 equiv), the cobalt iodide only needs to be used (0.1 equiv), and meanwhile, the reaction time in the prior art is 12-24 hours, and the method only needs 4 hours, so that the atomic economy and the step economy of the reaction are greatly improved, and the method is beneficial to environmental protection.
3. The 1, 2, 3 full-substituted indolizine derivative prepared by the invention has excellent biological activity and can be used for treating inflammation, cardiovascular diseases and HIV infection.
Drawings
FIG. 1 shows the results of the hydrogen spectrum characterization of the compound prepared in example 1 of the present application;
FIG. 2 is a graph showing the results of carbon spectrum characterization of the compound prepared in example 1 of the present application;
FIG. 3 shows the results of the hydrogen spectrum characterization of the compound prepared in example 2 of the present application;
FIG. 4 is a graph showing the results of carbon spectrum characterization of the compound prepared in example 2 of the present application;
FIG. 5 shows the results of the hydrogen spectrum characterization of the compound prepared in example 3 of the present application;
FIG. 6 is a graph showing the results of carbon spectrum characterization of the compound prepared in example 3 of the present application;
FIG. 7 shows the results of the hydrogen spectrum characterization of the compound prepared in example 4 of the present application;
FIG. 8 is a graph showing the results of carbon spectrum characterization of the compound prepared in example 4 of the present application;
FIG. 9 shows the results of the hydrogen spectrum characterization of the compound prepared in example 5 of the present application;
FIG. 10 is a graph showing the results of carbon spectrum characterization of the compound prepared in example 5 of the present application;
FIG. 11 shows the results of the hydrogen spectrum characterization of the compound prepared in example 6 of the present application;
FIG. 12 is a graph showing the results of carbon spectrum characterization of the compound prepared in example 6 of the present application;
FIG. 13 is a graph showing the results of hydrogen spectrum characterization of the compound prepared in example 7 of the present application;
FIG. 14 is a graph showing the results of carbon spectrum characterization of the compound prepared in example 7 of the present application;
Detailed Description
The following further illustrates the preparation of the fully substituted indolizine derivatives of the invention, 1, 2, 3, by means of specific examples, without restricting the scope of the invention.
An embodiment of the present application provides a preparation method of a 1, 2, 3 full substituted indolizine derivative, which is characterized in that the preparation method is as follows in formula 1:
adding a pyridine structure shown as a formula (1), a bromide structure shown as a formula (2), sodium carbonate, tetrabutylammonium iodide, cobalt iodide and a reaction solvent into a reaction device;
adding N, N-dimethylformamide into the mixture, sealing the pipe for reaction in a nitrogen atmosphere, and synthesizing the mixture in one step to obtain a product mixture;
extracting and filtering the product mixture obtained in the step (2) after the reaction in the step (3) is finished, and concentrating and separating the obtained filtrate to obtain the 1, 2 and 3 full-substituted indolizine derivative structural formula (3); wherein R is 1 、R 2 Each independently selected from H, C1-C12 alkyl, C1-C20 substituted or unsubstituted aryl.
In one embodiment, the pyridine has a chemical structure of any one of the following formulas:
the chemical structure of the bromide is any one of the following structural formulas:
the structural formula of the 1, 2 and 3 full-substituted indolizine derivatives is as follows:
in one embodiment, the reaction condition shown in the formula 1 is that the reaction is carried out for 2 to 6 hours at normal temperature, and the reaction solvent is N, N-dimethylformamide; the molar ratio of the compound (1) to the compound (2) added in the reaction represented by the formula 1 is 2:1.
In one embodiment, the molar ratio of the compound (2) to the sodium carbonate added in the reaction of formula 1 is 1:2.
In one embodiment, the molar ratio of the compound (2) to the tetrabutylammonium iodide added in the reaction of formula 1 is 1:0.5.
In one embodiment, the molar ratio of the compound (2) to the cobalt iodide added in the reaction of formula 1 is 1:0.1.
In one embodiment, the preparation process is carried out under a nitrogen atmosphere.
In one embodiment, the method uses a reaction device that is an electrochemical reaction tube.
In one embodiment, the method further comprises the step of isolating and purifying the product after the reaction is completed.
In one embodiment, in step (3), the crude product obtained is separated by column chromatography to obtain 1, 2, 3 fully substituted indolizine derivatives as yellow solids; the yield of the 1, 2 and 3 full-substituted indolizine derivative products is 58-82%.
Example 1
3a synthesis method: methyl isonicotinate (1.2 mmol) and bromoacetophenone (0.6 mmol) were added to the electrochemical reaction tube, 4mL of N, N-dimethylformamide solvent was added, then 1.2mmol of sodium carbonate and 0.3mmol of tetrabutylammonium iodide, and 0.06mmol of cobalt iodide were added respectively, after sufficiently mixing, the reaction apparatus was assembled (the reaction tube was filled with nitrogen gas, air was purged), and the voltage was set to 3.5V, and the reaction was carried out for 4 hours. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 79.9mg, yield: 82%. Mp:171-173 ℃ its characterization is shown in figures 1 and 2. 1 H NMR(400MHz,CDCl 3 )δ：3.98(s,3H),7.07(t，J＝7.6Hz,2H)，7.14-7.18(m,4H)，7.26-7.40(m,7H)，7.46(d,J＝7.6Hz，2H),7.65(d,J＝7.2Hz,1H),8.74(s,1H),9.51(d,J＝7.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ：191.5,191.4,188.0,165.2,139.8,139.7,138.6,136.9,136.6,133.2,132.7,132.6,129.2,129.1,129.0,128.4,128.3,127.6,123.6,122.6,118.1,115.2,53.1.
Example 2
3b synthesis method: 4-benzoylpyridine (1.2 mmol) and bromoacetophenone (0.6 mmol) were added to the electrochemical reaction tube, 4mL of N, N-dimethylformamide solvent was added, then 1.2mmol of sodium carbonate and 0.3mmol of tetrabutylammonium iodide, and 0.06mmol of cobalt iodide were added, respectively, after sufficiently mixing, the reaction apparatus was assembled (the reaction tube was filled with nitrogen gas, air was purged), and the voltage was set to 3.5V, and the reaction was carried out for 4 hours. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 74.4mg, yield: 70%, mp:209-211 ℃ and the characterization spectrograms are shown in fig. 3 and 4. 1 H NMR(400MHz，CDCl 3 )δ：7.11(t，J＝7.6Hz，2H)，7.15–7.20(m，4H)，7.29–7.47(m，9H)，7.55(d，J＝7.6Hz，2H)，7.65(d，J＝7.2Hz，2H)，7.86(d，J＝7.6Hz，2H)，8.43(s，1H)，9.58(d，J＝7.6Hz，1H). 13 C NMR(100MHz，CDCl 3 )δ：193.4，191.0，190.9，187.5，139.2，139.1，138.0，136.5，136.1，135.8，134.5，132.9，132.7，132.2，132.1，129.9，129.6，128.6，128.5，127.9，127.8，127.4，123.2，122.8，117.8，115.1.
Example 3
3c synthesis method: 4-tert-butylpyridine (1.2 mmol) and bromoacetophenone (0.6 mmol) were added to an electrochemical reaction tube, followed by 4mL of N, N-di-After 1.2mmol of sodium carbonate and 0.3mmol of tetrabutylammonium iodide, and 0.06mmol of cobalt iodide were added, respectively, and after thoroughly mixing, a reaction apparatus was assembled (the reaction tube was filled with nitrogen gas and air was purged), and the voltage was set at 3.5V to react for 4 hours. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 72.6mg, yield: 75%, mp 213-214 ℃ and the characterization spectrogram is shown in fig. 5 and 6. 1 H NMR(400MHz，CDCl 3 )δ：1.37(s，9H)，7.03(t，J＝7.6Hz，2H)，7.14(t，J＝7.2Hz,4H)，7.21–7.29(m，4H)，7.32–7.33(m，4H)，7.43(d，J＝7.2Hz，2H)，8.00(s，1H)，9.58(d，J＝7.2Hz，1H). 13 C NMR(100MHz，CDCl 3 )δ：191.8，191.4，187.3，152.2，140.0，139.9，138.6，138.3，137.1，132.5，131.7，131.5，128.6，128.5，127.9，127.8，127.7，127.5，121.6，115.4，114.5，114.3，35.1，30.1.
Example 4
3e, the synthesis method comprises the following steps: methyl isonicotinate (1.2 mmol) and 2-bromo-1- (4-methyl) acetophenone (0.6 mmol) were added to the electrochemical reaction tube, 4mL of N, N-dimethylformamide solvent was added, then 1.2mmol of sodium carbonate and 0.3mmol of tetrabutylammonium iodide, and 0.06mmol of cobalt iodide were added, respectively, after thoroughly mixing, the reaction instrument was assembled (the reaction tube was filled with nitrogen gas, and air was purged), and the voltage was set to 3.5V for 4 hours of reaction. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 82.5mg, yield: 78%, mp:209-211 ℃ and the characterization spectrograms are shown in fig. 7 and 10. 1 H NMR(400MHz，CDCl 3 )δ：2.23(s，3H)，2.27(s，3H)，2.31(s，3H)，3.94(s，3H)，6.85(d，J＝8.0Hz，2H)，6.92–6.96(m，4H)，7.15(d，J＝8.0Hz，2H)，7.28(d，J＝8.0Hz，2H)，7.36(d，J＝8.0Hz，2H)，7.57(d，J＝7.2Hz，1H)，8.67(s，1H)，9.38(d，J＝7.2Hz，1H). 13 C NMR(100MHz，CDCl 3 )δ：191.3，191.2，187.8，165.3，144.0，143.5，137.2，137.0，136.6，136.5，136.2，129.4，129.3，129.2，129.1，129.0，128.9，128.8，127.7，127.4，123.8，122.6，118.3，114.8，53.0，22.0，21.9，21.8.
Example 5
3f synthesis method: methyl isonicotinate (1.2 mmol) and methyl 4- (2-bromoacetyl) -benzoate (0.6 mmol) were added to an electrochemical reaction tube, 4mL of N, N-dimethylformamide solvent was added, 1.2mmol of sodium carbonate and 0.3mmol of tetrabutylammonium iodide, and 0.06mmol of cobalt iodide were then added, respectively, after thoroughly mixing, the reaction instrument was assembled (the reaction tube was filled with nitrogen gas, and air was purged), and the voltage was set to 3.5V for 4 hours. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 78.8mg, yield: 60%, mp:170-172 deg.C, see FIG. 11 and FIG. 12 for their characterization spectra. 1 H NMR(400MHz，CDCl 3 )δ：3.98(s.9H)，4.04(s，3H)，7.57(s，1H)，7.80(dd，J＝7.2，1.6Hz，1H)，7.85(dd，J＝8.0，1.2Hz，4H)，8.14–8.20(m，7H)，9.32(s，1H)，10.03(d，J＝7.6Hz，1H). 13 C NMR(100MHz，CDCl 3 )δ：189.2，184.8，166.1，166.0，164.7，142.8，142.6，139.4，134.2，132.9，132.8，130.2，129.9，129.8，129.6，129.4，128.6，128.5，128.4，123.1，122.3，115.7，52.7，52.3，52.2.
Example 6
3g of synthesis method: methyl isonicotinate (1.2 mmol) and 2-bromo-1- (4-methoxy) acetophenone (0.6 mmol) were added to an electrochemical reaction tube, 4mL of N, N-dimethylformamide solvent was added, followed by separation1.2mmol of sodium carbonate and 0.3mmol of tetrabutylammonium iodide and 0.06mmol of cobalt iodide were added respectively, and after sufficiently mixing, a reaction apparatus was assembled (the reaction tube was filled with nitrogen gas and air was purged), and the voltage was set to 3.5V to react for 4 hours. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 83.6mg, yield: 72%, mp:158-160 c, see fig. 13 and 14 for their characterization spectra. 1 H NMR(400MHz，CDCl 3 )δ：3.75(s，3H)，3.78(s，3H)，3.83(s，3H)，3.97(s，3H)，6.60(d，J＝8.8Hz，2H)，6.66–6.69(m，4H)，7.39(d，J＝8.8Hz，2H)，7.44(d，J＝8.4Hz，2H)，7.51(d，J＝8.8Hz，2H)，7.57(dd，J＝7.2，1.6Hz，1H)，8.69(s，1H)，9.33(d，J＝7.6Hz，1H). 13 C NMR(100MHz，CDCl 3 )δ：189.8，189.6，186.2，184.9，163.1，163.0，162.9，135.5，135.4，132.1，132.0，131.8，131.1，131.0，130.8，126.8，126.7，123.2，122.1，117.7，114.1，113.2，113.1，112.7，55.3，55.2，55.1.
Example 7
The synthesis method for 3h comprises the following steps: methyl isonicotinate (1.2 mmol) and 2-bromo-1- (3-methoxy) acetophenone (0.6 mmol) were added to the electrochemical reaction tube, 4mL of N, N-dimethylformamide solvent was added, then 1.2mmol of sodium carbonate and 0.3mmol of tetrabutylammonium iodide, and 0.06mmol of cobalt iodide were added, respectively, after thoroughly mixing, the reaction instrument was assembled (the reaction tube was filled with nitrogen gas, and air was purged), and the voltage was set to 3.5V for 4 hours of reaction. After the reaction is completed, the mixture is extracted and filtered, the filtrate is concentrated by rotary evaporation and then separated by silica gel column chromatography to obtain yellow solid, and the yield is: 75.8mg, yield: 65%, mp:138-140 ℃ its characterization is shown in fig. 13 and 14.1H NMR (400 MHz, CDCl 3) delta: 3.60 (s, 3H), 3.65 (s, 6H), 3.97 (s, 3H), 6.62 (s, 1H), 6.85-7.03 (m, 10H), 7.12 (t, j=8.0 hz, 1H), 7.64 (dd, j=7.6, 1.6hz, 1H), 8.79 (s, 1H), 9.48 (d, j=7.6 hz, 1H). 13C NMR (100 mhz, cdcl 3) δ:191.0, 190.9, 187.5, 164.9, 159.4, 159.3, 140.9, 140.8, 139.9, 136.5, 136.4, 129.2, 129.1, 129.0, 128.0, 127.2, 123.4, 122.5, 122.4, 121.9, 121.8, 120.1, 119.6, 119.5, 117.8, 115.0, 112.4, 112.3, 111.5, 55.3, 55.2, 52.8.
The above is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiment, and all technical solutions belonging to the concept of the present invention belong to the protection scope of the present invention. It should be noted that modifications and adaptations to the invention without departing from the principles thereof are intended to be within the scope of the invention as set forth in the following claims.
Claims (10)
1. A process for the preparation of a 1, 2, 3 fully substituted indolizine derivative, characterized in that said process is described by formula 1:
adding a pyridine structure shown as a formula (1), a bromide structure shown as a formula (2), sodium carbonate, tetrabutylammonium iodide, cobalt iodide and a reaction solvent into a reaction device;
adding N, N-dimethylformamide into the mixture, sealing the pipe for reaction in a nitrogen atmosphere, and synthesizing the mixture in one step to obtain a product mixture;
extracting and filtering the product mixture obtained in the step (2) after the reaction in the step (3) is finished, and concentrating and separating the obtained filtrate to obtain the 1, 2 and 3 full-substituted indolizine derivative structural formula (3); wherein R is 1 、R 2 Each independently selected from H, C1-C12 alkyl, C1-C20 substituted or unsubstituted aryl.
2. A process for preparing 1, 2, 3-fully substituted indolizine derivatives according to claim 1,
the pyridine is characterized in that the chemical structure of the pyridine is any one of the following structural formulas:
the chemical structure of the bromide is any one of the following structural formulas:
the structural formula of the 1, 2 and 3 full-substituted indolizine derivatives is as follows:
3. the method for preparing 1, 2, 3 full substituted indolizine derivatives according to claim 1, wherein the reaction condition shown in formula 1 is 2-6 hours of reaction at normal temperature, and the reaction solvent is N, N-dimethylformamide; the molar ratio of the compound (1) to the compound (2) added in the reaction represented by the formula 1 is 2:1.
4. A process for preparing a 2, 3-fully substituted indolizine derivative according to claim 1 or 3, characterized in that the molar ratio of the compound (2) to the sodium carbonate added in the reaction represented by formula 1 is 1:2.
5. A process for preparing a 1, 2, 3-fully substituted indolizine derivative according to claim 1 or 3, characterized in that the molar ratio of the compound (2) to the tetrabutylammonium iodide added in the reaction represented by formula 1 is 1:0.5.
6. A process for preparing a 1, 2, 3-fully substituted indolizine derivative according to claim 1 or 3, characterized in that the molar ratio of the compound (2) to the cobalt iodide added in the reaction represented by formula 1 is 1:0.1.
7. A process for the preparation of 1, 2, 3 fully substituted indolizine derivatives according to claim 1 or 3, characterized in that it is carried out under nitrogen atmosphere.
8. A process for preparing 1, 2, 3-fully substituted indolizine derivatives according to claim 1 or 3, characterized in that the reaction apparatus used in the process is an electrochemical reaction tube.
9. A process for the preparation of 1, 2, 3-fully substituted indolizine derivatives according to claim 1 or 3, characterized in that it further comprises a step of isolation and purification of the product after the end of the reaction.
10. The process for preparing a 1, 2, 3 full substituted indolizine derivative according to claim 1, characterized in that: in the step (3), the obtained crude product is separated by column chromatography to obtain yellow solid 1, 2 and 3 full-substituted indolizine derivatives; the yield of the 1, 2 and 3 full-substituted indolizine derivative products is 58-82%.
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