A method for electrocatalytic synthesis of gamma-deuterated pyridine compounds and deuterated drugs

Abstract

The application provides a method for electrocatalytically synthesizing gamma-deuterated pyridine compounds and deuterated drugs, wherein R 1 , R 2 , R 3 and R 4 are defined in the description. The method is characterized in that pyridine compounds shown in general formula I are mixed with electrolyte, deuterium donor reagent and solvent for reaction under electrocatalysis, and gamma-deuterated pyridine compounds and deuterated drugs shown in general formula II are obtained under suitable electrode, current, temperature and time conditions. The method provided by the application has the advantages of mild conditions, green environmental protection, economy and practicability, high selectivity, high yield and high deuterium substitution rate, and solves the problems of using strong alkali and high temperature, noble metal and its ligand, additional construction of pre-functionalized substrate and low deuterium substitution site selectivity in the prior art.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a method for the electrocatalytic synthesis of γ-deuterated pyridine compounds and deuterated drugs. Background Technology

[0002] Deuterium (D) is a stable, non-radioactive isotope of hydrogen (H) in nature, differing from H by only one neutron. D is slightly less lipophilic than H, Δlog P oct = -0.006, the CD bond is shorter than the CH bond. With higher stability, the C–D bond, as an isosteric group of hydrogen, is widely used in drug design. Deuteration of drugs allows for the study of drug molecule absorption, distribution, metabolism, and excretion without affecting drug efficacy, facilitating the rapid discovery of metabolically active products for mechanistic studies. Furthermore, the C–D bond is more stable than the C–H bond; deuteration of the active site can block metabolic sites, extending drug half-life and reducing dosage and frequency. Deuteration strategies are not only used to improve the pharmacokinetic properties of the parent drug but also to reduce toxic metabolites, decrease isomerization, and design new drugs based on mechanisms of action. The 2017 launch of deuterated bubenazine (trade name: Austedo™) undoubtedly confirmed the success of deuteration drug design strategies.

[0003] Pyridine, as an important reagent and precursor, is one of the most common structural units in natural products and synthetic drugs, and one of the most widely used heterocyclic compounds in drug design. Pyridine is the structural motif for over 7,000 existing drug molecules with significant pharmaceutical value. The U.S. Food and Drug Administration has approved 95 drugs derived from pyridine, such as atazanavir (reyataz) for treating HIV; imatinib mesylate (gleevec) for treating chronic myeloid leukemia; nilvadipine for treating hypertension; and tacrine for treating Alzheimer's disease. Research on the pharmacological activity of pyridine derivatives is constantly evolving, and the synthesis of deuterium-labeled drugs and their derivatives is of great significance for new drug development. Therefore, the preparation of γ-deuterated pyridine compounds is particularly important and has broad development prospects.

[0004] Despite the importance of pyridine, its direct and selective functionalization remains limited due to its electron-depleted nature and nitrogen coordination. In recent years, efforts have been made to develop efficient synthetic methods to construct CD bonds to obtain deuterated pyridine compounds. For example, selective deuteration of pyridine has been achieved through the construction of prefunctionalized substrates: McNally's group (J.Am.Chem.Soc.2018,140(6),1990-1993) reported that pyridine was first converted to the corresponding phosphine salt by the action of triphenylphosphine and trifluoroacetic anhydride, and then deuterated at room temperature using a 9:1 mixture of CD3OD and D2O with potassium carbonate as a nucleophile. Zhang Bing's group (Angew.Chem.,Int.Ed.2020,59(42),18527-18531) reported the electrochemically catalytic dehalogenation of haloaromatics under alkaline conditions using a copper nanowire array as the cathode and D2O as the deuterium source. This deuteration method exhibits excellent chemoselectivity and regioselectivity. However, in most cases, the reaction steps are rather cumbersome, and the prefunctionalization steps may involve substrates that are difficult to obtain.

[0005] Hydrogen-deuterium exchange (HIE) is the most direct synthetic strategy for deuterated drugs, representing the mainstream direction of current deuterated synthesis methods and meeting the needs of deuterated drug development. With the tremendous development of transition metal-catalyzed CH activation, novel HIEs are constantly emerging. Pieters' group (Angew. Chem., Int. Ed. 2020, 59(47), 21114-21120) reported the synthesis of several deuterated drug molecules, including brompheniramine, doxylamine, and bisacodyl, at 55 °C using [Ir(COD)(OMe)]2 as a catalyst, D2 as a deuterium source, and THF as a solvent. These molecules exhibit high functional group tolerance but suffer from deuteration site selectivity. In the same year, Chirik's group (ACS Catal. 2020, 10(15), 8640-8647) and Ruiter's group (J. Am. Chem. Soc. 2020, 142(40), 17131-17139) reported that, under H2 or N2 atmospheres, iron complexes promote the electron-deficient and electron-rich aromatic and heteroaromatic rings with deuterated benzene as the deuterium source, and the C(sp) 2The rapid hydrogen isotope exchange of the γ-H bond is a method whose regioselectivity is regulated by steric hindrance, but lacks selectivity for pyridine molecules. Furthermore, Professor Gao Zhanghua's group (Chem. Commun. 2022, 58(21), 3497-3500) reported the simultaneous deuteration of pyridine at both β and γ positions using DMSO-d6 as a deuterium source under the action of the strong base potassium tert-butoxide. This method can obtain pyridine compounds with high deuteration rates, but the strong base and high temperature reaction conditions result in poor functional group tolerance and inevitably generate benzylic side reaction sites with 93%-97% deuteration rates. In summary, developing a simpler, safer, greener, more economical, and more practical technology to construct diverse γ-deuterated pyridine compounds is of great significance. Summary of the Invention

[0006] To address the shortcomings of existing technologies in the preparation of γ-deuterated pyridine compounds and deuterated drugs, such as the use of strong bases and high temperatures, the construction of noble metals and their ligands, the construction of additional prefunctionalized substrates, and the low selectivity of deuteration sites.

[0007] This invention provides a method for the electrocatalytic synthesis of γ-deuterated pyridine compounds and deuterated drugs. This method is mild, environmentally friendly, economical, practical, highly selective, and yields high deuteration rates. Using this method, γ-deuterated pyridine compounds and deuterated drugs conforming to general formula II were synthesized.

[0008] The method for synthesizing γ-deuterated pyridine compounds and deuterated drugs as shown in general formula II is characterized in that: the pyridine compound shown in general formula I is reacted under electrocatalysis with a mixture of electrolyte, deuterium donor reagent and solvent, and under suitable electrode, current, temperature and time conditions, the γ-deuterated pyridine compound and deuterated drug shown in general formula II are obtained.

[0009]

[0010] in:

[0011] In general formulas I and II, R 1 R 2 R 3 R 4 Selected independently from substituted or unsubstituted C 1-7 Alkyl or alkoxy, substituted or unsubstituted C 3-7 Heterocyclic group, substituted or unsubstituted aryl or heteroaryl group, substituted or unsubstituted acyl group, wherein C 1-7 Alkyl or alkoxy, C 3-7 The heterocyclic, aryl, heteroaryl, and acyl groups may be substituted by 1, 2, or 3 R groups;

[0012] Or R 1 and R2 Connect them together to form ring A;

[0013] Or R 3 and R 4 They are connected together to form ring B;

[0014] Ring A is selected from C 3-7 cycloalkyl and C 3-7 Aryl, the C 3-7 cycloalkyl and C 3-7 The aryl group can be substituted by 1, 2 or 3 R groups;

[0015] Ring B is selected from C 3-7 Aryl, the C 3-7 The aryl group can be substituted by 1, 2 or 3 R groups;

[0016] R is selected from hydrogen, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, benzyloxy, piperidinyl, imidazolyl, benzimidazolyl, dioxopentanolyl, benzothiophene, pyridinyl, oxazolyl, cycloamine, deuterium, carbonyl, acyl, amide, acyloxy, amino, hydroxyl, and halogen.

[0017] The method for synthesizing γ-deuterated pyridine compounds and deuterated drugs as shown in Formula II is characterized by comprising the following steps:

[0018] Step 1: Add a pyridine compound, as shown in general formula I, to the reactor;

[0019] Step 2: Add the electrolyte to the reactor;

[0020] Step 3: Add the deuterium donor reagent to the reactor;

[0021] Step 4: Add the solvent to the reactor;

[0022] Step 5: Insert the electrodes into the reactor;

[0023] Step 6: After electrolyzing the mixed solution at a suitable current and temperature for a certain period of time, the reaction is quenched;

[0024] Step 7: Extract with organic solvent, dry and concentrate the organic phase, and purify to obtain γ-deuterated pyridine compounds and deuterated drugs as shown in general formula II.

[0025] Preferably, in step 1, the reactor is a round-bottom flask;

[0026] Preferably, in step 2, the electrolyte is tetrabutylammonium iodide (Tetrabutylammonium iodide). n- Bu4NI);

[0027] Preferably, in step 3, the deuterium donor reagent is heavy water (D2O);

[0028] Preferably, in step 4, the solvent is N,N-dimethylformamide (DMF);

[0029] Preferably, in step 5, the anode is a graphite rod and the cathode is a zinc rod;

[0030] Preferably, in step 6, the current is 10mA;

[0031] Preferably, in step 7, ethyl acetate is added for extraction, and the organic phase is dried, concentrated, and purified to obtain γ-deuterated pyridine compounds and deuterated drugs as shown in general formula II.

[0032] The beneficial effects of this invention are:

[0033] (1) This invention uses an electrocatalytic method to convert pyridine compounds into γ-deuterated pyridine compounds and deuterated drugs. The operation is simple, green and environmentally friendly, and economical and practical.

[0034] (2) The method of the present invention can synthesize γ-deuterated pyridine compounds and deuterated drugs with high selectivity, high yield of target products and deuteration rate, and wide range of substrates. Detailed Implementation

[0035] The invention will be further illustrated in the following embodiments. These embodiments are for illustrative purposes only and are not intended to limit the invention in any way.

[0036] Example 1

[0037]

[0038] Compound 1a (31 mg, 0.2 mmol), DMF (2.5 mL), and D2O (0.5 mL) were added. n- Bu4NI (111 mg, 0.3 mmol) was added to a 10 mL round-bottom flask equipped with a magnetic stirrer. Then, a fixed graphite rod anode (d = 5 mm) and zinc rod cathode (d = 5 mm) were inserted into the flask. The resulting solution was electrolyzed at room temperature with a constant current of 10 mA (single-output DC power supply: KRP-305DM) for 10.5 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (5 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with saturated brine (3 × 20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The desired product 2a was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1). The yield was 97%, the γ-deuteration rate of pyridine was 95%, and the product was a yellow liquid. 1H NMR (300MHz, CDCl3): δ8.71 (dd, J=4.8, 0.9Hz, 1H), 8.05-7.96 (m, 2H), 7.78-7.71 ( m,1.05H),7.53-7.45(m,2H),7.45-7.38(m,1H),7.25-7.20(dd,J=4.8,0.9Hz,1H).

[0039] Example 2

[0040]

[0041] This embodiment also provides a method for preparing compound 2b, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 10 hours, and the desired product 2b is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1). The yield is 64%, the γ-position deuteration rate of pyridine is 96%, and it is a colorless liquid. 1 HNMR (300MHz, CDCl3): δ8.70(d,J=4.9Hz,1H),7.75(td,J=7.7,1.9Hz,0.04H ),7.43-7.37(m,2H),7.31-7.26(m,3H),7.24(d,J=4.9Hz,1H),2.37(s,3H). 13 C NMR (75MHz, CDCl3): δ160.1, 149.3, 140.5, 135.9 (t, J = 24.4Hz), 135.8, 130.8, 129.7, 128.3, 125.9, 124.1, 121.6, 20.4.

[0042] Example 3

[0043]

[0044] This embodiment also provides a method for preparing compound 2c, which is basically the same as the method for preparing compound 2a provided in Example 1. The main difference is that the reaction time is 10 hours, and the desired product 2c is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 1). The yield is 89%, the γ-position deuteration rate of pyridine is 96%, and the product is a yellow liquid. 1HNMR (300MHz, CDCl3): δ8.70(d,J=4.8Hz,1H),7.81(s,1H),7.76(dd,J=7.6,1.8Hz,1H),7.70(td,J=7.6,1.8Hz,0.04H), 7.38(ddd,J=8.4,7.5,1.8Hz,1H),7.20(d,J=4.6Hz,1H),7.08(td,J=7.5,1.0Hz,1H),7.00(d,J=8.4Hz,1H),3.85(s,3H). 13 C NMR (75MHz, CDCl3): δ157.0, 156.2, 149.5, 135.4 (t, J = 24.0Hz), 131.2, 130.0, 129.2, 125.1, 121.7, 121.1, 111.5, 55.7.

[0045] Example 4

[0046]

[0047] This embodiment also provides a method for preparing compound 2d, which is basically the same as the method for preparing compound 2a provided in Example 1. The desired product 2d is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1). The yield is 63%, the γ-position deuteration rate of pyridine is 97%, and it is a colorless liquid. 1 H NMR (300MHz, CDCl3): δ8.73(dd,J=4.8,0.6Hz,1H),7.97(td,J=7.8,1.9Hz,1H),7.78(s,1H),7.73(ddd ,J=8.3,1.4,0.6Hz,0.03H),7.42-7.32(m,1H),7.30-7.23(m,2H),7.16(ddd,J=11.3,8.2,1.2Hz,1H). 13 C NMR (75MHz, CDCl3): δ160.6 (d, J = 249.6Hz), 153.5, 149.8, 136.1 (t, J = 24.3Hz), 131.1 (d, J = 2.8Hz) ,130.5(d,J=8.5Hz),127.6(d,J=11.7Hz),124.6(d,J=3.7Hz),124.5,122.4,116.3(d,J=23.1Hz).

[0048] Example 5

[0049]

[0050] This embodiment also provides a method for preparing compound 2e, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 10 hours, and the desired product 2e is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1). The yield is 92%, the γ-position deuteration rate of pyridine is 96%, and it is a colorless liquid. 1 HNMR (300MHz, CDCl3): δ8.68 (dd, J=4.8, 0.9Hz, 1H), 7.90 (d, J=8.0Hz, 2H), 7.73-7.68 ( m,1.04H),7.29(dt,J=8.0,0.7Hz,2H),7.23-7.16(dd,J=4.8,0.9Hz,1H),2.41(s,3H). 13 CNMR (75MHz, CDCl3): δ157.6, 149.7, 139.0, 136.7, 136.4 (t, J = 2.0Hz), 129.6, 126.9, 121.8, 120.3, 21.4.

[0051] Example 6

[0052]

[0053] This embodiment also provides a method for preparing compound 2f, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 10 hours, and the desired product 2f is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 1). The yield is 91%, the γ-position deuteration rate of pyridine is 100%, and the product is a yellow liquid. 1 HNMR (300MHz, CDCl3): δ8.68(d,J=4.4Hz,1H),7.93(d,J=8.4Hz,2H),7.72(s,1H),7.51(d,J=8.4Hz,2H),7.20(d,J=4.4Hz,1H),1.37(s,9H). 13 C NMR (75MHz, CDCl3): δ157.5, 152.2, 149.7, 136.8, 136.4 (t, J = 24.4Hz), 126.7, 125.8, 121.8, 120.3, 34.8, 31.4.

[0054] Example 7

[0055]

[0056] This embodiment also provides a method for preparing compound 2g, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 10 hours and the reaction time is 3 hours. The desired product 2g is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1). The yield is 77%, the γ-position deuteration rate of pyridine is 95%, and it is a white solid with a mp value of 84.3-85.6℃. 1 H NMR (300MHz, CDCl3): δ8.66(dd,J=4.8,0.9Hz,1H),7.96(d,J=8.9Hz,2H),7.67(m,1.05H),7.46(m,2 H),7.43-7.37(m,2H),7.37-7.30(m,1H),7.17(d,J=4.6Hz,1H),7.08(d,J=8.9Hz,2H),5.13(s,2H).

[0057] 13 C NMR (75MHz, CDCl3): δ159.7, 157.1, 149.6, 136.9, 136.4 (t, J = 23.3Hz) 132.4, 128.7, 128.3, 128.1, 127.6, 121.4, 119.8, 115.1, 70.1.

[0058] Example 8

[0059]

[0060] This embodiment also provides a method for preparing compound 2h, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 10 hours, and the desired product 2h is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1). The yield is 80%, the γ-position deuteration rate of pyridine is 93%, and the product is a yellow liquid. 1 HNMR (300MHz, CDCl3): δ8.67 (dd, J=4.8, 0.8Hz, 1H), 7.73 (td, J=7.5, 7.1, 1.8Hz, 0 .07H),7.68(s,1H),7.24(s,2H),7.21(d,J=4.8Hz,1H),3.96(s,6H),3.90(s,3H). 13 C NMR (75MHz, CDCl3): δ157.1, 153.6, 149.6, 139.1, 136.5 (t, J = 24.0H), 135.1, 122.0, 120.3, 104.2, 61.01, 56.31.

[0061] Example 9

[0062]

[0063] This embodiment also provides a method for preparing compound 2i, which is basically the same as the method for preparing compound 2a provided in Example 1. The main difference is that the reaction time is 10 hours, and the desired product 2i is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1). The yield is 96%, the γ-position deuteration rate of pyridine is 95%, and the product is a yellow liquid. 1 HNMR (300MHz, CDCl3): δ8.63 (dd, J=4.8, 0.8Hz, 1H), 7.70 (td, J=7.7, 1.8Hz, 0.05H), 7. 62(s,1H),7.56-7.45(m,2H),7.17(d,J=4.6Hz,1H),6.90(d,J=8.1Hz,1H),6.01(s,2H). 13 CNMR(75MHz, CDCl3)δ157.0,149.6,148.5,148.4,136.5(t,J=24.8H),134.0,121.7,121.0,120.0,108.5,107.5,101.4.

[0064] Example 10

[0065]

[0066] This embodiment also provides a method for preparing compound 2j, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 10 hours, and the desired product 2j is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 1). The yield is 73%, the γ-position deuteration rate of pyridine is 95%, and it is a white solid with a mp value of 92.9-94.0℃. 1 H NMR (300MHz, CDCl3): δ8.82(d,J=1.8Hz,1H),8.76(dd,J=4.8,1.0Hz,1H),8.32-8.24(m,1H),8.07(dd,J =8.4,1.8Hz,1H),7.93(d,J=8.4Hz,1H),7.89–7.73(m,2.05H),7.53-7.40(m,2H),7.25(d,J=5.5Hz,1H). 13C NMR (75MHz, CDCl3): δ157.2, 149.7, 140.2, 139.8, 136.5 (t, J = 24.0Hz), 136.1, 1 35.9,135.6,126.9,125.4,124.5,122.9,122.8,121.96,121.89,120.4,120.0.

[0067] Example 11

[0068]

[0069] This embodiment also provides a method for preparing compound 2k, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 16 hours, and the desired product 2k is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1). The yield is 86%, the γ-position deuteration rate of pyridine is 94%, and it is a white solid with a mp value of 101.0-101.6℃. 1 H NMR (300MHz, CDCl3): δ8.10-8.00(m,2H),7.65-7.57(m,1.06H),7.53-7.34(m,8H),2.61(s,3H). 13 C NMR (75MHz, CDCl3): δ155.8, 155.8, 140.1, 139.6, 137.7 (t, J = 24.0Hz), 135.4, 129.2, 128.8, 128.5, 127.5, 127.1, 117.8, 23.8.

[0070] Example 12

[0071]

[0072] This embodiment also provides a method for preparing compound 2l, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 10 hours, and the desired product 2l is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1). The yield is 92%, the γ-position deuteration rate of pyridine is 95%, and it is a pale yellow solid with a mp value of 49.5-50.2℃. 1 H NMR (300MHz, CDCl3): δ8.53(s,1H),8.05-7.92(m,2H),7.63(s,1H),7.55(ddd, J=8.0,2.3,0.6Hz,0.05H),7.53-7.43(m,2H),7.43-7.35(m,1H),2.37(s,3H). 13C NMR (75MHz, CDCl3): δ154.9, 150.2, 139.5, 137.1 (t, J = 24.0Hz), 131.6, 128.8, 128.7, 126.8, 120.0, 18.2.

[0073] Example 13

[0074]

[0075] This embodiment also provides a method for preparing compound 2m, which is basically the same as the method for preparing compound 2a provided in Example 1. The main difference is that the reaction time is 8 hours, and the desired product 2m is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 1). The yield is 95%, the deuteration rate at the γ-position of pyridine is 96%, the deuteration rate at the 6-position is 42%, and it is a white solid with a mp value of 52.1-52.9℃. 1 H NMR (300MHz, CDCl3): δ8.40(d,J=3.2Hz,0.58H),7.93(d,J=7.0Hz,2H),7.66(s,1H),7.50- 7.41(m,2H),7.41-7.33(m,1H),7.28-7.27(m,0.02H),7.25-7.24(m,0.02H),3.89(s,3H). 13 C NMR (75MHz, CDCl3): δ154.8, 150.0, 139.1, 137.2, 128.7, 128.2, 126.4, 120.9 (t, J = 24.0Hz), 120.7, 55.7.

[0076] Example 14

[0077]

[0078] This embodiment also provides a method for preparing compound 2n, which is basically the same as the method for preparing compound 2a provided in Example 1. The desired product 2n is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1). The yield is 76%, the γ-position deuteration rate of pyridine is 95%, and it is a colorless liquid. 1 H NMR (300MHz, CDCl3): δ8.02-7.93(m,2H),7.64(t,J=7.9Hz,0.05H),7.52(s,1H),7.50-7.43(m,2H),7.43-7.35(m,1H),7.10(s,1H),2.63(s,3H). 13C NMR (75MHz, CDCl3): 158.5, 157.1, 139.9, 136.7 (t, J = 24.0Hz), 128.8, 127.1, 121.6, 117.6, 24.9.

[0079] Example 15

[0080]

[0081] This embodiment also provides a method for preparing compound 2o, which is basically the same as the method for preparing compound 2a provided in Example 1. The desired product 2o is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1). The yield is 92%, the γ-position deuteration rate of pyridine is 95%, and it is a colorless liquid. 1 H NMR (300MHz, CDCl3): δ8.12-8.02(m,2H),7.75(t,J=76.5Hz,0.05H),7.67(s,1H),7.5 3-7.43(m,3H),7.43-7.34(m,1H),4.19-4.07(m,2H),4.04-3.92(m,2H),1.85(s,3H). 13 C NMR (75MHz, CDCl3): δ160.7, 156.9, 139.3, 137.0 (t, J = 24.0Hz), 129.0, 128.7, 127.1, 119.5, 117.6, 109.0, 65.2, 25.1.

[0082] Example 16

[0083]

[0084] This embodiment also provides a method for preparing compound 2p, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 13 hours, and the desired product 2p is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1). The yield is 89%, the γ-position deuteration rate of pyridine is 94%, the benzylic deuteration rate is 10%, and it is a white solid with a mp value of 38.0-39.0℃. 1 H NMR (300MHz, CDCl3): δ8.05-7.97(m,2H),7.74(t,J=7.7Hz,0.06H),7.64(s,1H),7.53-7.39(m,3H),7.16(s,1H),4.82(s,1.81H). 13C NMR (75MHz, CDCl3): δ158.7, 156.2, 138.9, 137.3 (t, J = 24.0Hz), 129.3, 128.8, 127.0, 119.0, 118.8, 64.0.

[0085] Example 17

[0086]

[0087] This embodiment also provides a method for preparing compound 2q, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 12 hours, and the desired product 2q is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1). The yield is 75%, the γ-position deuteration rate of pyridine is 100%, and it is a colorless liquid. 1 H NMR (300MHz, CDCl3): δ8.04-7.95(m,2H),7.62(s,1H),7.50-7.37(m,4H),4.68(s,2H),3.52(s,3H). 13 C NMR (75MHz, CDCl3): δ158.6, 156.9, 139.5, 137.1 (t, J = 23.3Hz), 129.0, 128.8, 127.1, 119.4, 119.1, 75.9, 58.9.

[0088] Example 18

[0089]

[0090] This embodiment also provides a method for preparing compound 2r, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 11 hours, and the desired product 2r is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1). The yield is 81%, the γ-position deuteration rate of pyridine is 95%, the benzylic deuteration rate is 11%, and the product is a pale yellow liquid. 1 H NMR (300MHz, CDCl3): δ8.59(s,1H),8.00-7.89(m,2H),7.75(dd,J=8.1,2.2Hz,0.05H),7.68(s,1H),7.50-7.36(m,3H),4.71(s,1.79H),2.47(s,1H). 13 C NMR (75MHz, CDCl3): δ156.6, 148.2, 139.0, 135.7 (t, J = 24.0Hz), 135.1, 129.1, 128.8, 127.0, 120.6, 62.0.

[0091] Example 19

[0092]

[0093] This embodiment also provides a method for preparing compound 2s, which is basically the same as the method for preparing compound 2r provided in Example 1. The desired product 2s is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1). The yield is 73%, the γ-position deuteration rate of pyridine is 94%, and it is a colorless liquid. 1 H NMR (300MHz, CDCl3): δ8.03-7.97(m,2H),7.71(t,J=7.7Hz,0.06H),7.57(s,1H),7.51-7 .42(m,3H),7.42-7.36(m,1H),3.84(s,2H),2.64(q,J=7.1Hz,4H),1.10(t,J=7.1Hz,6H). 13 C NMR (75MHz, CDCl3): δ160.1, 156.6, 139.7, 136.8 (t, J = 22.9Hz), 128.8, 128.7, 127.0, 121.3, 118.5, 59.3, 47.7, 12.0.

[0094] Example 20

[0095]

[0096] This embodiment also provides a method for preparing compound 2t, which is basically the same as the method for preparing compound 2a provided in Example 1. The desired product 2t is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1). The yield is 80%, the γ-position deuteration rate of pyridine is 95%, and the product is a yellow liquid. 1 H NMR (300MHz, CDCl3): δ7.99 (ddd, J=8.1, 4.2, 1.5Hz, 2H), 7.77-7.65 (m, 0.05H) ,7.65(s,0.47H),7.59(s,0.51H),7.51-7.36(m,3H),7.21(s,0.50H),7.10(s, 0.45H),4.75(s,1.03H),4.66(s,0.91H),3.49(dq,J=11.7,7.1Hz,2H),2.19(s ,1.54H),2.16(s,1.36H),1.20(t,J=7.2Hz,1.57H),1.14(t,J=7.1Hz,1.37H). 13C NMR (75MHz, CDCl3): δ171.1,170.5,157.9,157.4,157.1,156.7,139.4,138.9,137.5(t,J=24.0Hz),137.2(t,J=24.0 Hz),129.3,129.0,128.9,128.7,126.9,120.4,119.0,118.8,118.6,53.8,50.5,43.7,41.4,22.0,21.3,13.9,12.9.

[0097] Example 21

[0098]

[0099] This embodiment also provides a method for preparing compound 2u, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 10 hours, and the desired product 2u is obtained by purification by silica gel column chromatography (dichloromethane / ethyl acetate = 5 / 1). The yield is 65%, the γ-position deuteration rate of pyridine is 94%, and the product is a yellow liquid. 1 HNMR (300MHz, CDCl3): δ8.02-7.95 (m, 2H), 7.72 (t, J = 7.7Hz, 0.06H), 7.58 (s ,1H),7.50-7.35(m,4H),4.14(q,J=7.1Hz,2H),3.75(s,2H),2.96(dt,J=11. 8,3.4Hz,2H),2.31(tt,J=11.2,4.4Hz,1H),2.20(td,J=11.5,3.0Hz,2H),1. 96-1.86(m,2H),1.80(ddd,J=13.2,11.2,3.6Hz,2H),1.25(t,J=7.1Hz,3H). 13 C NMR (75MHz, CDCl3): δ175.3, 159.0, 156.8, 139.7, 136.9 (t, J = 24.0H), 128.8, 128.7, 127.1, 121.1, 118.7, 64.9, 60.4, 53.2, 41.2, 28.5, 14.3.

[0100] Example 22

[0101]

[0102] This embodiment also provides a method for preparing compound 2v, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 10 hours, and the desired product 2v is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1). The yield is 35%, the γ-position deuteration rate of pyridine is 95%, and it is a colorless liquid. 1 HNMR (300MHz, CDCl3): δ8.59(d,J=4.9Hz,1H),8.03(dd,J=1.6,0.9Hz,1H),7.68(td,J=7.8,1.9H z,0.05H),7.50(t,J=1.7Hz,1H),7.46(s,1H),7.15(d,J=4.8Hz,1H),6.90(dd,J=1.9,0.9Hz,1H). 13 C NMR (75MHz, CDCl3): δ151.9, 149.8, 144.0, 141.3, 136.4 (t, J = 24.0Hz), 127.2, 121.7, 120.1, 108.7.

[0103] Example 23

[0104]

[0105] This embodiment also provides a method for preparing compound 2w, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 12 hours, and the desired product 2w is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1). The yield is 43%, the γ-position deuteration rate of pyridine is 94%, the α-position deuteration rate is 11%, and the product is a yellow liquid. 1 H NMR (300MHz, CDCl3): δ8.93(d,J=4.2Hz,0.89H), δ8.19-8.14(m,0.05H),8.12(d,J=8.5Hz ,1H),7.87-7.79(m,1H),7.77-7.68(m,1H),7.55(t,J=8.1Hz,1H),7.40(d,J=4.1Hz,1H).

[0106] Example 24

[0107]

[0108] This embodiment also provides a method for preparing compound 2x, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 10 hours, and the desired product 2x is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1). The yield is 55%, the γ-position deuteration rate of pyridine is 91%, and it is a yellow solid with a mp of 38.4-39.4℃. 1 H NMR (300MHz, CDCl3): δ8.23(dd,J=8.5,4.5Hz,0.09H),8.10(ddd,J=8.5,1.2,0.7Hz,1H),7.84(ddd,J=8.1,1.5,0.7Hz,1H),7.74(ddd,J=8.5,6.9,1.5Hz ,1H),7.67(d,J=4.4Hz,1H),7.58(ddd,J=8.1,6.9,1.2Hz,1H),3.62(q,J=7. 1Hz, 2H), 3.45 (q, J = 7.1Hz, 2H), 1.32 (t, J = 7.1Hz, 3H), 1.23 (t, J = 7.1Hz, 3H). 13 C NMR (75MHz, CDCl3): δ168.8, 154.8, 146.7, 136.7 (t, J = 24.4Hz), 130.0, 129.8, 127.9, 127.6, 127.4, 120.3, 43.6, 40.4, 14.5, 13.0.

[0109] Example 25

[0110]

[0111] This embodiment also provides a method for preparing compound 2y, which is basically the same as the method for preparing compound 2a provided in Example 1. The desired product 2y is obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 25 / 1). The yield is 48%, the γ-position deuteration rate of pyridine is 91%, and it is a pale yellow solid; mp: 124.4-125.0℃. 1 H NMR (300MHz, CDCl3): δ8.54(d,J=3.7Hz,1H),8.28(d,J=9.0Hz,0.09H),8.16(d,J=8.5Hz,1H),7.92-7.83(m,2H),7.7 5(ddd,J=8.4,6.9,1.5Hz,1H),7.58(ddd,J=8.1,6.9,1.2Hz,1H),7.50-7.44(m,1H),7.41-7.30(m,2H),4.46(s,3H). 13C NMR(75MHz, CDCl3)δ150.5,150.0,147.2,142.6,137.5,136.5(t,J=24.0Hz), 136.2,129.8,129.6,127.7,127.2,123.7,122.7,121.7,120.2,110.0,33.1.

[0112] Example 26

[0113]

[0114] This embodiment also provides a method for preparing compound 2z, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 12 hours, and the desired product 2z is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 1). The yield is 73%, the γ-position deuteration rate of pyridine is 96%, and it is a pale yellow solid with a mp value of 98.0-99.0℃. 1 H NMR (300MHz, CDCl3): δ8.78 (s, 0.04H), 8.25 (dt, J=8.8, 1.0Hz, 2H), 8.01 (ddd, J=8.4, 1.5, 0.7Hz, 2H), 7.79 (ddd, J=8.9, 6.6, 1.5Hz, 2H), 7.54 (ddd, J=8.5, 6.6, 1.1Hz, 2H). 13 C NMR (75MHz, CDCl3): δ149.1, 135.8 (t, J = 24.7H), 130.4, 129.5, 128.2, 126.6, 125.8.

[0115] Applications of electrocatalytic synthesis of γ-deuterated pyridine compounds

[0116] Deuteration of natural products or known active molecules can not only improve their pharmacokinetic properties, but also reduce toxic metabolites, decrease isomer conversion, and enable the design of new drugs based on their mechanisms of action. To illustrate the practicality of the electrocatalytic synthesis of pyridine compounds involved in claim 1, we have achieved the synthesis of the following deuterated drugs or deuterated active molecules.

[0117] Application Example 1

[0118]

[0119] This embodiment also provides a method for preparing deuterated quinaldinic acid 2aa, which is basically the same as the method for preparing compound 2a provided in Example 1, except that the reaction time is 10 hours, and the desired product 2aa is obtained by purification by silica gel column chromatography (dichloromethane / methanol = 100 / 1). The yield is 52%, the deuteration rate at the γ-position of pyridine is 95%, and the product is a pale yellow solid with a mp value of 98.2-99.3℃. 1 H NMR(300MHz,DMSO-d6)δ8.55(d,J=7.7Hz,0.05H),8.16(d,J=8.0Hz,1H),8.11 (s,1H),8.08(d,J=8.2Hz,1H),7.87(d,J=14.1Hz,1H),7.73(t,J=7.5Hz,1H). 13 C NMR (75MHz, DMSO-d6) δ166.4, 148.6, 146.7, 137.4 (t, J = 24.0Hz), 130.5, 129.6, 128.7, 128.5, 127.9, 120.6.

[0120] Application Example 2

[0121]

[0122] This embodiment also provides a method for preparing the deuterated product of CYP1A2 inhibitor 1ab, a natural component from the root of *Peucedantupraeruptorum*. The preparation method is basically the same as that for compound 2a provided in Example 1, except that the reaction time is 14 hours, and the desired product 2ab is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1). The yield is 71%, the deuteration rate at the γ-position of pyridine is 99%, and it is a white solid with a mp of 41.4-42.3 °C. 1 H NMR (300MHz, CDCl3): δ7.96 (s, 0.01H), 7.91 (d, J = 8.7Hz, 1H), 7.56-7.45 (m, 2H), 7.23 (s, 1H), 2.72 (s, 3H), 2.51 (d, J = 0.9Hz, 3H). 13 C NMR (75MHz, CDCl3): δ158.1, 146.5, 135.5 (t, J = 24.0Hz), 131.8, 128.4, 126.5, 126.5, 122.0, 25.3, 21.6.

[0123] Application Example 3

[0124]

[0125] This embodiment also provides a method for preparing the deuterated product of 1ac, a natural component from Galipea longiflora Krause (Rutaceae) with anti-leishmaniasis activity. The preparation method is essentially the same as that for compound 2a provided in Example 1. The desired product 2ac was obtained by purification using silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 1). The yield was 82%, the deuteration rate at the γ-position of pyridine was 97%, and it was a white solid with a mp value of 77.0-78.1℃. 1 H NMR (300MHz, CDCl3): 8.25-8.14(m,3.03H),7.89(s,1H),7.87-7.79(m,1H),7.78-7.69(m,1H),7.59-7.50(m,3H),7.50-7.43(m,1H). 13 C NMR (75MHz, CDCl3): δ157.5, 148.4, 139.8, 136.5 (t, J = 24.4Hz), 129.8, 129.8, 129.4, 128.9, 127.7, 127.5, 127.2, 126.4, 119.0.

[0126] Application Example 4

[0127]

[0128] This embodiment also provides a method for preparing the deuterated product of Staphylococcus aureus NorA inhibitor 1ad. The preparation method is basically the same as that for compound 2a provided in Example 1, except that the reaction time is 10 hours, and the desired product 2ad is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1). The yield is 85%, the deuteration rate at the γ-position of pyridine is 97%, and it is a white solid with a mp value of 116.8-118.0℃. 1 H NMR (300MHz, CDCl3): δ8.19(s,0.03H),8.16(d,J=8.3Hz,1H),7.89(d,J=2.1Hz,1H),7.85(s,1H),7.83-7.79(m,1H),7.76-7 .69(m,1H),7.67(dd,J=8.4,2.1Hz,1H),7.50(ddd,J=8.1,6.9,1.2Hz,1H),7.00(d,J=8.4Hz,1H),4.05(s,3H),3.96(s,3H). 13C NMR (75MHz, CDCl3): δ156.9, 150.5, 149.5, 148.3, 136.3 (t, J = 24.0Hz), 13 2.6,129.7,129.6,127.5,127.0,126.0,120.3,118.5,111.1,110.5,56.1.

[0129] Application Example 5

[0130]

[0131] This embodiment also provides a method for preparing the deuterated product of the natural product H. dubium alkaloid 1ae. The preparation method is basically the same as that for compound 2a provided in Example 1, except that the reaction time is 10 hours, and the desired product 2ae is obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1). The yield is 86%, the deuteration rate at the γ-position of pyridine is 98%, and it is a white solid with a mp of 88.9-90.2℃. 1 H NMR (300MHz, CDCl3): δ8.18(s,0.02H),8.14(ddd,J=8.5,1.2,0.6Hz,1H),7.80(d,J=8.5Hz,2H),7.76(d,J=1.8Hz,1H),7.72(d dd,J=8.4,6.9,1.5Hz,1H),7.66(dd,J=8.1,1.8Hz,1H),7.50(ddd,J=8.1,6.9,1.2Hz,1H),6.95(d,J=8.1Hz,1H),6.04(s,2H). 13 C NMR (75MHz, CDCl3): δ156.7, 148.9, 148.5, 148.3, 136.8 (t, J = 22.9Hz), 134 .2,129.7,129.6,127.5,127.0,126.1,121.8,118.6,108.6,108.0,101.5.

[0132] Application Example 6

[0133]

[0134] This embodiment also provides a method for preparing the deuterated product of 1af, a natural component extracted and isolated from Crocus sativus, which has micro-promoting nerve growth factor activity. The preparation method is basically the same as that for compound 2a provided in Example 1. The desired product 2af was obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 1). The yield was 87%, the deuteration rate at the γ-position of pyridine was 95%, and it was a white solid with a mp value of 72.0-73.0℃. 1 H NMR (300MHz, CDCl3): δ8.19-8.13(m,4H),7.83(dd,J=8.8,7.0Hz,0.05H),7.70(s,2H),7.54-7.47(m,4H),7.47-7.39(m,2H). 13 C NMR (75MHz, CDCl3): δ156.9, 139.6, 137.3 (t, J = 23.6Hz), 129.1, 128.8, 127.1, 118.6.

[0135] Application Example 7

[0136]

[0137] This embodiment also provides a method for preparing the deuterated product of CYP11B1 inhibitor 1ag, which is basically the same as the method for preparing compound 2a provided in Example 1. The desired product 2ag is obtained by purification by silica gel column chromatography (dichloromethane / ethyl acetate = 3 / 1). The yield is 97%, the deuteration rate at the γ-position of pyridine is 95%, and it is a pale yellow solid with a mp of 74.9-76.1℃. 1 H NMR (300MHz, CDCl3): δ8.59-8.54(m,1H),8.37-8.30(m,2H),8.00-7.93(m,2H),7.66(s,1H ), δ7.56-7.41(m,2.03H),7.43-7.35(m,1H),7.31-7.27(m,1H),3.97(s,2H),2.29(s,3H). 13 C NMR (75MHz, CDCl3) δ155.8,149.88,149.85,148.59,148.55,147.18,147.15,139.0,136.9 ,136.8(t,J=24.4Hz),134.9,133.8,133.2,128.9,128.8,126.8,120.3,35.7,18.4,18.3.

[0138] Application Example 8

[0139]

[0140] This embodiment also provides a method for preparing the deuterated product of the CYP11B1 inhibitor 1ah, which is basically the same as the preparation method of compound 2a provided in Example 1, except that the reaction time is 12 hours, and the desired product 2ah is obtained by silica gel column chromatography (ethyl acetate / triethylamine = 100 / 1). The yield is 85%, the deuteration rate at the γ-position of pyridine is 97%, the deuteration rate at the β-position is 15%, and it is a white solid with a mp value of 112.0-113.2℃. 1 H NMR (300MHz, CDCl3): δ8.59 (s, 1H), 7.98 (dd, J = 8.2, 1.5Hz, 2H), 7.72 (s, 1H), 7.63(s,0.85H),7.51-7.40(m,3.03H),7.13(s,1H),6.94(s,1H),5.19(s,2H). 13 C NMR (75MHz, CDCl3): δ157.6, 148.6, 138.6, 137.4, 135.5 (t, J = 24.0), 130.1, 130.0, 129.4, 128.9, 126.9, 120.5, 119.1, 48.1.

[0141] Application Example 9

[0142]

[0143] This invention also provides a method for preparing deuterated AWQ051, which is basically the same as the method for preparing compound 2a provided in Example 1. The desired product, deuterated AWQ051, was obtained by purification using silica gel column chromatography (ethyl acetate / triethylamine = 100 / 1). The yield was 85%, the γ-position deuteration rate of pyridine was 95%, and the α-position deuteration rate was 57%. It was a white solid, mp: 108.1-109.3℃. 1 HNMR (300MHz, CDCl3): δ8.32 (d, J=0.5Hz, 0.43H), 7.85-7.78 (m, 2H), 7.61 (s, 1H), 7.29-7.21(m,2H),7.19(dd,J=8.8,2.2Hz,0.05H),4.41(dt,J=8.0,3.8Hz,1H),3. 30(ddd,J=14.3,8.1,2.2Hz,1H),3.05-2.71(m,5H),2.38(s,3H),2.17(h,J=3.1Hz ,1H),2.05-1.92(m,1H),1.82-1.69(m,1H),1.63-1.48(m,1H),1.46-1.33(m,1H). 13C NMR (75MHz, CDCl3): δ152.6, 150.1, 138.2, 138.0, 136.3, 129.4, 126.2, 122.7 (t, J = 24.0Hz), 120.4, 74.2, 55.6, 47.3, 46.6, 25.0, 24.4, 21.2, 19.1.

[0144] Application Example 10

[0145]

[0146] This invention also provides a method for preparing a deuterated estradiol derivative, which is basically the same as the method for preparing compound 2a provided in Example 1. The desired deuterated product 1aj was obtained by purification by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1). The yield was 50%, the deuteration rate at the γ-position of pyridine was 95%, and it was a white solid, mp: 146.1-147.5℃. 1 H NMR (300MHz, CDCl3): δ8.67 (dd, J=4.8, 0.8Hz, 1H), 7.77-7.68 (m, 3.05H), 7.39 (d, J=7.8 Hz,1H),7.23-7.15(m,1H),3.73(t,J=8.4Hz,1H),2.96(dd,J=8.3,3.8Hz,2H),2.39(dq, J=12.9,4.0Hz,1H),2.28(td,J=10.9,4.3Hz,1H),2.19-2.04(m,1H),1.95(ddt,J=16.1, 11.2,4.0Hz,2H),1.77-1.62(m,1H),1.60-1.43(m,3H),1.41-1.15(m,4H),0.80(s,3H). 13 CNMR (75MHz, CDCl3): δ157.6, 149.6, 141.6, 137.3, 136.7, 136.5 (t, J = 24.0Hz), 127.5, 125.9 ,124.2,121.8,120.4,81.9,50.3,44.6,43.3,38.7,36.9,30.7,29.8,27.3,26.2,23.3,11.2.

[0147] The above description is only used to illustrate the technical solution and features of the present invention, but the scope of protection of the present invention is not limited thereto. Any person skilled in the art can easily conceive of various equivalent modifications or substitutions within the technical scope disclosed in the present invention, and these modifications or substitutions should all be covered within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for electrocatalytic synthesis of γ-deuterated pyridine compounds and deuterated drugs, characterized in that, The following steps are used to achieve the following: The pyridine compound represented by general formula I undergoes an electrocatalytic reaction with an electrolyte, a deuterium donor reagent, and a solvent, under suitable electrode, current, temperature, and time conditions, to obtain the γ-deuterated pyridine compound and deuterated drug represented by general formula II: General Formula I General Formula II in: In general formulas I and II, R 1 R 2 R 3 R 4 Selected independently from substituted or unsubstituted C 1-7 Alkyl or alkoxy, substituted or unsubstituted C 3-7 Heterocyclic group, substituted or unsubstituted aryl or heteroaryl group, substituted or unsubstituted acyl group, wherein C 1-7 Alkyl or alkoxy, C 3-7 The heterocyclic, aryl, heteroaryl, and acyl groups may be substituted by 1, 2, or 3 R groups; Or R 1 and R 2 Connect them together to form ring A; Or R 3 and R 4 They are connected together to form ring B; Ring A is selected from C 3-7 cycloalkyl and C 3-7 Aryl, the C 3-7 cycloalkyl and C 3-7 The aryl group can be substituted by 1, 2 or 3 R groups; Ring B is selected from C 3-7 Aryl, the C 3-7 The aryl group can be substituted by 1, 2 or 3 R groups; R is selected from hydrogen, alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, benzyloxy, dioxopentyl, deuterium, acyl, amide, acyloxy, amino, hydroxyl, and halogen; The electrode material is a combination of two of the following: carbon, stainless steel, zinc, platinum, and nickel. The electrolyte is a tetraalkyl quaternary ammonium salt; The deuterium donor reagent is one of heavy water, deuterated methanol, and deuterated dimethyl sulfoxide; The solvent is one or a combination of two or more of N,N-dimethylformamide, N,N-dimethylacetamide, and ether solvents.

2. The method for electrocatalytic synthesis of γ-deuterated pyridine compounds and deuterated drugs according to claim 1, characterized in that, Includes the following steps: Step 1: Add a pyridine compound, as shown in general formula I, to the reactor; Step 2: Add the electrolyte to the reactor; Step 3: Add the deuterium donor reagent to the reactor; Step 4: Add the solvent to the reactor; Step 5: Insert the electrodes into the reactor; Step 6: After electrolyzing the mixed solution at a suitable current and temperature for a certain period of time, the reaction is quenched; Step 7: Extract with organic solvent, dry and concentrate the organic phase, and purify to obtain γ-deuterated pyridine compounds and deuterated drugs as shown in general formula II.

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