Direct carbon isotope labeling method of alpha-keto acid compound
Direct carbon isotope labeling of α-ketoacid compounds by photocatalytic methods solves the problems of expensive raw materials and cumbersome processes in the prior art, and achieves efficient and low-cost labeling effects, and meets the requirements of green chemistry.
Patent Information
- Application Number
- CN202411940055.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-26
- Publication Date
- 2025-04-29
AI Technical Summary
The prior art has problems in the expensive raw materials, cumbersome processes and unfriendly environment when carbon isotope labeling α-ketoacid compounds, and requires substrate activation and multi-step reaction.
Using a photocatalytic method that does not require substrate activation, the carbon isotope labeling of the α-ketoic acid compound, base and organic solvent were added to the reaction flask, and the [13C]CO2 gas was directly realized by irradiating it with LED blue light for 5 minutes to 48 hours.
Direct carbon isotope labeling with high product yield and high isotope labeling rate is achieved, and the separation process is simple and meets the requirements of green chemistry.
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Abstract
Description
Technical Field
[0001] The invention belongs to the field of organic synthesis and relates to a direct carbon isotope labeling method for alpha-keto acid compounds. Background Art
[0002] α-keto acids are a class of organic carboxylic acid compounds containing an α-carbonyl group. These compounds play an important role in organisms. Take pyruvate as an example. It is one of the simplest α-keto acids and plays a central role in amino acid metabolism and maintaining redox states. α-keto acids are widely used in medicine, food, cosmetics and industry.
[0003] Carbon isotope labeling technology plays an important role in biology and medicine. It helps to understand the dynamic behavior of drugs in the body. For example, ADME studies the absorption, distribution, metabolism and excretion of drugs in the body. These four processes together determine the bioavailability, duration of action and required dosage of drugs in the body, thereby optimizing drug dosage regimens and predicting drug interactions. In addition, toxicity is often considered in conjunction with ADME to form ADME / T to comprehensively evaluate the safety and efficacy of drugs. Since the traditional synthesis routes of carbon isotope labeled products generally have the disadvantages of expensive raw materials, cumbersome processes and unfriendly environment, it is necessary to explore a simple and low-cost synthesis route. At present, there is only one case of benzoyl sp 2 There are reports on photocatalytic carbon isotope exchange reactions on hybrid carbon, but this requires a multi-step reaction of polarity reversal of carbonyl protection and deprotection. However, the present invention provides a direct carbon isotope labeling method for α-keto acid compounds that does not require substrate activation and is photocatalytic. Summary of the invention
[0004] The present invention aims to provide a method for direct carbon isotope labeling of α-keto acid compounds, which has the characteristics of high product yield, high isotope labeling rate, and simple separation process. The method comprises the following steps:
[0005] In a reaction flask, add α-keto acid compound, base and organic solvent, add or not add photosensitizer, and then pass [ 13 C]CO2 gas, irradiated with LED blue light for 5 minutes to 48 hours, can obtain carbon isotope labeled α-keto acid compounds. The copper metal catalytic system consists of copper salt and ligand. The labeling method and ligand structure are as follows:
[0006]
[0007] Ligands
[0008]
[0009] In substrate 1, Ar is phenyl, biphenyl, tolanyl, halogenated phenyl, C1-C8 alkyl-substituted phenyl, C1-C8 alkoxy-substituted phenyl, C1-C8 alkylthio-substituted phenyl, C1-C8 alkylnitro-substituted phenyl, borate-substituted phenyl, halogenated biphenyl, halogenated tolanyl, C1-C8 alkyl-substituted biphenyl, C1-C8 alkoxy-substituted biphenyl, C1-C8 alkyl-substituted tolanyl, C1-C8 alkoxy-substituted tolanyl, cyano-substituted phenyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 2-thienyl, 2-pyrazinyl, C1-C8 alkyl, 9-anthryl, etc. The substitution position of the group can be selected individually or multiple times; the groups substituted at multiple positions can be the same or different. *C is a carbon isotope, including 11 C. 13 C. 14 C.
[0010] According to the preferred embodiment of the present invention, the solvent is one or more of acetonitrile, tetrahydrofuran, dioxane, ether, dichloromethane, ethyl acetate, toluene, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide or ethylene glycol dimethyl ether; the ratio of the volume of the solvent to the molar number of the carboxylic acid ester compound I is 1 mL: 0.1 mmol. The solvent is anhydrous.
[0011] According to the preferred embodiment of the present invention, the copper metal catalyst is cuprous cyanide, cuprous iodide, cuprous bromide, cuprous thiocyanate, cuprous diphenyl phosphate, cuprous trifluoromethanesulfonate, cuprous acetate, tetra(acetonitrile)copper tetrafluoroborate, copper iodide, copper bromide, copper trifluoromethanesulfonate; the molar ratio of the copper metal catalyst to the α-ketoacid compound is 0.02:0.1. The molar ratio of copper to ligand in the copper catalyst is 1:1. The copper metal catalyst system is prepared according to the following method: under nitrogen protection, copper salt and ligand are added to the solvent, stirred at room temperature for 30 minutes, and the resulting solution is a copper catalyst system.
[0012] According to the preferred embodiment of the present invention, the reaction conditions are visible blue light irradiation (wavelength range is 440-450 nanometers), and the reaction can be carried out at room temperature. According to the decarboxylation speed of the raw materials in the reaction, the reaction time is 5 minutes to 48 hours. The base used is potassium phosphate, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, zinc cyanide, zinc acetate, zinc carbonate, sodium methoxide, potassium ethoxide, potassium tert-butoxide, 1,8-diazabicyclo [5.4.0] undec-7-ene, triethylamine or one or more. Under the condition of not containing a copper metal catalyst system, the raw material structure can also react. The reaction can also proceed by adding a photosensitizer such as 4CzIPN, 4ClCzIPN, 4MeOCzIPN, 4CzBnBN, 4CzTPN, 4CzPN, 5CzBN, 3Cz1ClIPN, 3Cz2FBN, 4DPAIPN, 3DPA2FBN, TBADT, [Ir(dtbbpy)(ppy)2][PF6], [Ir[dF(CF3)ppy]2(dtbbpy)][PF6], [Ir(dF(Me)ppy)]2(dtbbpy)][PF6], etc. The change of gas atmosphere, the addition of materials to the reaction bottle and the preparation of the copper metal catalyst system need to be carried out in a nitrogen atmosphere at the beginning. After that, the gas in the bottle needs to be evacuated to a vacuum, and then [ 13 C] CO2 gas, the gas pressure is 0.1-10atm. The photosensitizer is as follows:
[0013]
[0014]
[0015] According to the present invention, after the reaction of direct labeling of α-keto acid compounds by carbon isotope exchange is completed, the corresponding labeled products can be separated and characterized by conventional separation and purification methods. The specific post-reaction treatment steps are as follows: the labeled product is obtained by extraction with deionized water and ethyl acetate; or after esterification with methyl iodide, a crude product is obtained by extraction with deionized water and ethyl acetate, and the crude product is separated by silica gel column chromatography to obtain the labeled α-keto acid compounds, and the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the mixed solvent of petroleum ether and ethyl acetate in the mixed solvent is 50 to 20:1.
[0016] Compared with the prior art, the present invention has the advantages of high reaction efficiency, convenient operation, wide application range of substrates, cheap and easy to obtain reaction raw materials, low purification difficulty, etc., and meets the requirements of green chemistry. DETAILED DESCRIPTION
[0017] The present invention is further described below in conjunction with specific embodiments, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following embodiments. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.
[0018] Meanwhile, the experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents, materials and equipment described are all commercially available unless otherwise specified.
[0019] Example 1
[0020]
[0021] In a N2 atmosphere, 0.1 mmol of substrate 1, 0.1 mmol of K3PO4, and 1 mL of DMSO were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump and then filled with 4 psi [ 13 C]CO2, the reaction bottle was placed under a blue LED lamp, the lamp distance was 5 cm, stirred at room temperature for 24 hours, and the illumination was stopped. Iodomethane was added for esterification for 30 minutes, and the crude product was extracted with deionized water and ethyl acetate. The crude product was then separated by silica gel column chromatography to obtain the target product 1-[ 13 C], the yield was 82%, and the isotope labeling rate of the product was 56% calculated by mass spectrometry.
[0022] 1 HNMR (400MHz, CDCl3) δ8.02(d,J=7.2Hz,2H),7.69–7.64(m,1H),7.52(t,J=8.0Hz,2H),3.99(t,J=1.6Hz,3H);
[0023] 13 C NMR (101MHz, CDCl3) δ186.2,164.2,135.1,132.6,130.2,129.1,52.9;
[0024] HRMS(ESI):calcd.forC8[ 13 C]H8O3[M+Na] + :188.0399.Found:188.0397.
[0025] Example 2
[0026]
[0027] In a N2 atmosphere, 0.1 mmol of substrate 2, 0.1 mmol of K3PO4, and 1 mL of DMSO were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump and then filled with 4 psi [ 13C]CO2, place the reaction bottle under the irradiation of blue LED light, the lamp distance is 5cm, stir at room temperature for 12h, and stop irradiation. Add iodomethane for esterification for 30min, extract with deionized water and ethyl acetate to obtain a crude product, and then separate the crude product by silica gel column chromatography to obtain the target product 2-[ 13 C], the yield was 56%, and the isotope labeling rate of the product was 33% calculated by mass spectrometry.
[0028] 1 HNMR (400MHz, CDCl3) δ7.91 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 3.97 (t, J = 2.0 Hz, 3H), 2.44 (s, 3H); 13 C NMR (101MHz, CDCl3) δ185.9,164.4,146.5,130.4,130.2,129.8,52.9,22.1;
[0029] HRMS(ESI):calcd.forC9[ 13 C]H 10 O3[M+Na] + :202.0556.Found:202.0557.
[0030] Example 3
[0031]
[0032] In a N2 atmosphere, 0.1 mmol of substrate 3, 0.1 mmol of K3PO4, and 1 mL of DMSO were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump and then filled with 4 psi [ 13 C]CO2, place the reaction bottle under the irradiation of blue LED light, the lamp distance is 5cm, stir at room temperature for 24h, and stop irradiation. Add iodomethane for esterification for 30min, extract with deionized water and ethyl acetate to obtain a crude product, and then separate the crude product by silica gel column chromatography to obtain the target product 3-[ 13 C], the yield was 47%, and the isotope labeling rate of the product was 54% calculated by mass spectrometry.
[0033] 1 H NMR (400MHz, CDCl3) δ7.95 (d, J = 8.8Hz, 2H), 7.53 (d, J = 8.8Hz, 2H), 3.97 (t, J = 2.0Hz, 3H), 1.35 (s, 9H);
[0034] 13C NMR (101MHz, CDCl3) δ185.9,164.4,159.4,130.3,126.1,52.9,35.6,31.2;
[0035] HRMS(ESI):calcd.forC 12 [ 13 C]H 16 O3[M+Na] + :244.1025.Found:244.1024.
[0036] Example 4
[0037]
[0038] In a N2 atmosphere, 0.1 mmol of substrate 4, 0.1 mmol of K3PO4, and 1 mL of DMSO were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump and then filled with 4 psi [ 13 C]CO2, place the reaction bottle under the irradiation of blue LED light, the lamp distance is 5cm, stir at room temperature for 12h, and stop irradiation. Add iodomethane for esterification for 30min, extract with deionized water and ethyl acetate to obtain a crude product, and then separate the crude product by silica gel column chromatography to obtain the target product 4-[ 13 C], the yield was 75%, and the isotope labeling rate of the product was 28% calculated by mass spectrometry.
[0039] 1 HNMR(400MHz, CDCl3) δ8.01(d,J=8.8Hz,2H),6.97(d,J=8.8Hz,2H),3.96(s,3H),3.89(s,3H);
[0040] 13 C NMR (101MHz, CDCl3) δ184.6,165.3,164.5132.8,125.7,114.4,55.8,52.8;
[0041] HRMS(ESI):calcd.forC9[ 13 C]H 10 O4[M+Na] + :218.0505.Found:218.0514.
[0042] Example 5
[0043]
[0044] In a N2 atmosphere, 0.1 mmol of substrate 5, 0.1 mmol of K3PO4, and 1 mL of DMSO were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump and then filled with 4 psi [ 13 C]CO2, the reaction bottle was placed under a blue LED lamp, the lamp distance was 5 cm, stirred at room temperature for 11 hours, and the illumination was stopped. Iodomethane was added for esterification for 30 minutes, and the crude product was extracted with deionized water and ethyl acetate. The crude product was then separated by silica gel column chromatography to obtain the target product 5-[ 13 C], the yield was 34%, and the isotope labeling rate of the product was 26% calculated by mass spectrometry.
[0045] 1 HNMR (400MHz, CDCl3) δ7.69(s,2H),3.97(s,3H),3.78(s,3H),2.33(s,6H);
[0046] 13 C NMR (101MHz, CDCl3) δ185.6,164.6,163.2,132.1,131.4,128.1,59.9,52.9,16.4;
[0047] HRMS(ESI):calcd.forC 11 [ 13 C]H 14 O4[M+Na] + :246.0818.Found:246.0827.
[0048] Example 6
[0049]
[0050] In a N2 atmosphere, 0.1 mmol of substrate 6, 0.1 mmol of K3PO4, and 1 mL of DMSO were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump and then filled with 4 psi [ 13 C]CO2, the reaction bottle was placed under a blue LED lamp, the lamp distance was 5 cm, stirred at room temperature for 4 hours, and the illumination was stopped. Iodomethane was added for esterification for 30 minutes, and the crude product was extracted with deionized water and ethyl acetate. The crude product was then separated by silica gel column chromatography to obtain the target product 6-[ 13 C], the yield was 35%, and the isotope labeling rate of the product was 27% calculated by mass spectrometry.
[0051] 1H NMR (400MHz, CDCl3) δ8.16(d,J=3.6Hz,1H),7.83(d,J=4.4Hz,1H),7.22–7.18(t,J=4.8Hz,1H),3.97(s,3H);
[0052] 13 C NMR (101MHz, CDCl3) δ176.1,162.2,139.1,137.8,137.6,128.9,53.4;
[0053] HRMS(ESI):calcd.forC6[ 13 C]H6O3S[M+Na] + :193.9963.Found:193.9958.
[0054] Example 7
[0055]
[0056] Under nitrogen atmosphere, the DMSO solution of cuprous cyanide CuCN and BINAP ligand was stirred at room temperature for thirty minutes, then 0.1mmol of substrate 7 and 0.1mmol of K3PO4 were added, and the N2 in the reaction bottle was evacuated by a vacuum pump and filled with 4psi[ 13 C]CO2, place the reaction bottle under the irradiation of blue LED light, the lamp distance is 5cm, stir at room temperature for 0.5h, and stop irradiation. Add iodomethane for esterification for 30min, extract with deionized water and ethyl acetate to obtain a crude product, and then separate the crude product by silica gel column chromatography to obtain the target product 7-[ 13 C], the yield was 50%, and the isotope labeling rate of the product was 40% calculated by mass spectrometry.
[0057] 1 HNMR (400MHz, CDCl3) δ8.10(d,J=8.4Hz,2H),7.68(d,J=8.4Hz,2H),7.63–7.57(m,2H),7.17(t,J=8.4Hz,2H),4.00(s,3H);
[0058] 13 C NMR (101MHz, CDCl3) δ 185.6, 164.1, 163.4 (d, J = 249.5Hz), 146.8, 135.7, 131.4, 131.0, 129.3 (d, J = 8.3Hz), 127.5, 116.3 (d, J = 21.7Hz), 53.0;
[0059] HRMS(ESI):calcd.forC 14[ 13 C]H 11 FO3[M+Na] + :282.0618.Found:282.0620.
[0060] Example 8
[0061]
[0062] Under nitrogen atmosphere, the DMSO solution of cuprous cyanide CuCN and BINAP ligand was stirred at room temperature for thirty minutes, then 0.1 mmol of substrate 8 and 0.1 mmol of K3PO4 were added, and the N2 in the reaction bottle was evacuated by a vacuum pump and filled with 4 psi [ 13 C]CO2, place the reaction bottle under the irradiation of blue LED light, the lamp distance is 5cm, stir at room temperature for 0.5h, and stop irradiation. Add iodomethane for esterification for 30min, extract with deionized water and ethyl acetate to obtain a crude product, and then separate the crude product by silica gel column chromatography to obtain the target product 8-[ 13 C], the yield was 71%, and the isotope labeling rate of the product was 58% calculated by mass spectrometry.
[0063] 1 H NMR (400MHz, CDCl3) δ8.10(d,J=8.4Hz,2H),7.74(d,J=8.4Hz,2H),7.62(d,J=8.0Hz,2H),7.52(d,J=8. 0Hz, 2H), 6.77 (dd, J = 17.6Hz, 10.8Hz, 1H), 5.83 (d, J = 17.6Hz, 1H), 5.33 (d, J = 11.2Hz, 1H), 4.00 (s, 3H); 13 C NMR (101MHz, CDCl3) δ185.6,164.2,147.3,138.8,138.2,136.3,131.3,130.9,127.7,127.4,127.1,115.1,53.0;
[0064] HRMS(ESI):calcd.forC 16 [ 13 C]H 14 O3[M+Na] + :290.0869.Found:290.0866.
[0065] Example 9
[0066]
[0067] Under nitrogen atmosphere, the DMSO solution of cuprous cyanide CuCN and BINAP ligand was stirred at room temperature for thirty minutes, then 0.1mmol of substrate 9 and 0.1mmol of K3PO4 were added, and the N2 in the reaction bottle was evacuated by a vacuum pump and filled with 4psi[ 13 C]CO2, place the reaction bottle under the irradiation of blue LED light, the lamp distance is 5cm, stir at room temperature for 0.5h, and stop irradiation. Add iodomethane for esterification for 30min, extract with deionized water and ethyl acetate to obtain a crude product, and then separate the crude product by silica gel column chromatography to obtain the target product 9-[ 13 C], the yield was 61%, and the isotope labeling rate of the product was 49% calculated by mass spectrometry.
[0068] 1 H NMR (400MHz, CDCl3) δ8.01(d,J=8.4Hz,2H),7.63(d,J=8.4Hz,2H),7.45(d,J=8.0Hz,2H),7.19(d,J=7.6Hz,2H),3.99(s,3H),2.39(s,3H);
[0069] 13 C NMR (101MHz, CDCl3) δ185.2,163.9,139.6,132.0,131.9,131.5,130.7,130.2,129.4,119.5,94.8,88.1,53.0,21.8;
[0070] HRMS(ESI):calcd.forC 20 [ 13 C]H 20 O3[M+Na] + :302.0869.Found:302.0872.
[0071] Example 10
[0072]
[0073] Under nitrogen atmosphere, the DMSO solution of cuprous cyanide CuCN and BINAP ligand was stirred at room temperature for thirty minutes, then 0.1 mmol of substrate 10 and 0.1 mmol of K3PO4 were added, and the N2 in the reaction bottle was evacuated by a vacuum pump and filled with 4 psi [ 13 C]CO2, the reaction bottle was placed under a blue LED lamp, the lamp distance was 5 cm, stirred at room temperature for 0.5 h, and the illumination was stopped. Iodomethane was added for esterification for 30 min, and the crude product was extracted with deionized water and ethyl acetate. The crude product was then separated by silica gel column chromatography to obtain the target product 10-[ 13C], the yield was 61%, and the isotope labeling rate of the product was 72% calculated by mass spectrometry.
[0074] 1 H NMR (400MHz, CDCl3) δ8.01(d,J=8.4Hz,2H),7.61(d,J=8.8Hz,2H),7.50(d,J=8.8Hz,2H),6.90(d,J=8.8Hz,2H),3.99(s,3H),3.84(s,3H);
[0075] 13 C NMR(101MHz, CDCl3)δ184.8,164.0,160.5,133.6,131.9,130.9,130.2,114.6,114.4,94.8,87.7,55.5,53.0; HRMS(ESI):calcd.forC 17 [ 13 C]H 14 O4[M+Na] + :318.0818.Found:318.0818.
[0076] The above are only some embodiments of the present invention, and do not limit the present invention in any form. Any simple modification, equivalent changes and modifications made to the above embodiments based on the technical essence of the invention are within the scope of the technical solution of the present invention.
Claims
1. A method for direct carbon isotope labeling of an α-keto acid compound, comprising the following steps: In a reaction flask, add α-keto acid compound, base and organic solvent, add or not add photosensitizer, and then pass [ 13 C]CO2 gas, irradiated with LED blue light for 5 minutes to 48 hours, can obtain carbon isotope labeled α-keto acid compounds. The copper metal catalytic system consists of copper salt and ligand, and the labeling method and ligand structure are as follows: In substrate 1, Ar is phenyl, biphenyl, tolanyl, halogenated phenyl, C1-C8 alkyl-substituted phenyl, C1-C8 alkoxy-substituted phenyl, C1-C8 alkylthio-substituted phenyl, C1-C8 alkylnitro-substituted phenyl, borate-substituted phenyl, halogenated biphenyl, halogenated tolanyl, C1-C8 alkyl-substituted biphenyl, C1-C8 alkoxy-substituted biphenyl, C1-C8 alkyl-substituted tolanyl, C1-C8 alkoxy-substituted tolanyl, cyano-substituted phenyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 2-thienyl, 2-pyrazinyl, C1-C8 alkyl, 9-anthryl, etc. The substitution position of the group can be selected singly or multiple times; the groups substituted at multiple positions can be the same or different. *C is a carbon isotope, including 11 C. 13 C. 14 C.
2. The method for direct carbon isotope labeling of α-keto acid compounds according to claim 1, characterized in that: The solvent is one or more of acetonitrile, tetrahydrofuran, dioxane, ether, dichloromethane, ethyl acetate, toluene, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide or ethylene glycol dimethyl ether. The ratio of the volume of the solvent to the molar number of the carboxylic acid ester compound I is 1 mL: 0.1 mmol. The solvent is anhydrous.
3. The method for direct carbon isotope labeling of α-keto acid compounds according to claim 1, characterized in that: The copper metal catalyst is cuprous cyanide, cuprous iodide, cuprous bromide, cuprous thiocyanate, cuprous diphenyl phosphate, cuprous trifluoromethanesulfonate, cuprous acetate, tetra(acetonitrile)copper tetrafluoroborate, cupric iodide, cupric bromide, and cupric trifluoromethanesulfonate. The molar ratio of the copper metal catalyst to the α-keto acid compound is 0.02:0.
1. The molar ratio of copper to the ligand in the copper catalyst is 1:
1.
4. The method for direct carbon isotope labeling of α-keto acid compounds according to claim 1, characterized in that: The copper metal catalyst system is prepared according to the following method: under nitrogen protection, copper salt and ligand are added to a solvent, and stirred at room temperature for 30 minutes, and the obtained solution is a copper catalyst system.
5. The method for direct carbon isotope labeling of α-keto acid compounds according to claim 1, characterized in that Change of gas atmosphere: Initially, adding materials to the reaction bottle and preparing the copper metal catalyst system need to be carried out in a nitrogen atmosphere. Then, the gas in the bottle needs to be evacuated to a vacuum and then introduced into the [ 13 C]CO2 gas, gas pressure is 0.1~10atm.
6. The method for direct carbon isotope labeling of α-keto acid compounds according to claim 1, characterized in that: The reaction conditions are visible blue light irradiation (wavelength range is 440-450 nanometers) and room temperature reaction. According to the decarboxylation speed of the raw materials in the reaction, the reaction time is 0.5-24 hours.
7. The method for direct carbon isotope labeling of α-keto acid compounds according to claim 1, characterized in that: The raw material structure can also react in the absence of a copper metal catalyst system. join in The reaction can also proceed using a photosensitizer such as 4CzIPN, 4ClCzIPN, 4MeOCzIPN, 4CzBnBN, 4CzTPN, 4CzPN, 5CzBN, 3Cz1ClIPN, 3Cz2FBN, 4DPAIPN, 3DPA2FBN, TBADT, [Ir(dtbbpy)(ppy)2][PF6], [Ir[dF(CF3)ppy]2(dtbbpy)][PF6], [Ir(dF(Me)ppy)]2(dtbbpy)][PF6], etc.
8. The method for direct carbon isotope labeling of α-keto acid compounds according to claim 1, characterized in that: The base used is one or more of potassium phosphate, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, zinc cyanide, zinc acetate, zinc carbonate, sodium methoxide, potassium ethoxide, potassium tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, and triethylamine.
9. The method for direct carbon isotope labeling of α-keto acid compounds according to claim 1, characterized in that: After the reaction is completed, the labeled α-keto acid compounds can be separated and characterized by conventional separation and purification methods. The specific post-reaction treatment steps are as follows: the labeled product is obtained by extraction with deionized water and ethyl acetate; or after esterification with methyl iodide, the crude product is extracted with deionized water and ethyl acetate, and the crude product is separated by silica gel column chromatography to obtain the labeled α-keto acid compounds, and the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the mixed solvent of petroleum ether and ethyl acetate in the mixed solvent is 50 to 20:1.