Synthesis method of ether or amide substituted aromatic heterocyclic derivative under photoelectric concerted catalysis

Abstract

The invention discloses a method for synthesizing ether or amide substituted aromatic heterocyclic derivatives under photoelectric concerted catalysis, which comprises the following specific synthesis processes: under the protection of inert gas, dissolving nitrogen-containing aromatic heterocyclic compounds and ether and amide substrates in an organic solvent, adding a polypyridine cobalt catalyst, electrolyte and a proton source, and reacting at the temperature of between 20 and 30 DEG C for 2 to 4 hours; reacting under the conditions of visible light irradiation and constant voltage, and performing post-treatment to obtain the ether and amide substituted aromatic heterocyclic derivative. The method can be used for preparing the compound with pharmacological activity or the intermediate thereof, has a certain application prospect in the field of drug synthesis, and has the advantages of cheap and easily available raw materials, high selectivity, mild conditions, wide substrate range, environmental protection, greenness and the like.

Description

Technical Field

[0001] This invention relates to a method for synthesizing ether- or amide-substituted aromatic heterocyclic derivatives under photoelectro-co-catalysis. Background Technology

[0002] Nitrogen-containing aromatic heterocycles, such as isoquinoline, quinoline, phthalazine, and benzothiazole, and their derivatives, constitute an important class of heterocyclic compounds that play a vital role in the pharmaceutical field, exhibiting various biological activities such as antibacterial, antimalarial, antitumor, anti-AIDS, anti-inflammatory, and antidepressant effects. Furthermore, ethers and amides, such as tetrahydrofuran / thiophene, are widely used in medicinal chemistry due to their excellent physicochemical properties and are important functional groups in many active pharmaceutical molecules.

[0003]

[0004] While current cross-dehydrogenation coupling (CDC) strategies can introduce ether or amide structures to achieve the functionalization of nitrogen-containing aromatic heterocycles, they rely on highly active metal catalysts (such as Cu, Ni, and Ag) or stoichiometric oxidants (such as peroxides). Furthermore, efficient conversion requires the use of large excess amounts of ether or amide substrates (typically as solvents, reaching 50-100 equivalents), limiting the technology to reactions with simple aliphatic ethers (such as tetrahydrofuran and 1,4-dioxane) and making it incompatible with pharmaceutical molecular skeletons containing complex functional groups (such as chiral centers and multiple substitution sites). Previously, the MacMillan group designed a photoredox-mediated C–H functionalization pathway, successfully achieving the direct arylation of cyclic and acyclic ethers with heterocyclic aromatic hydrocarbons (Angew. Chem. Int. Ed. 2015, 54, 1565–1569). However, this synthetic method uses expensive iridium catalysts, resulting in high costs. Subsequently, a series of HAT reagents, including BPO, TBHP, selectfluor, and DDQ, have been explored and applied. However, they exhibit weak regioselectivity, and for asymmetric ethers such as 2-methyltetrahydrofuran, they tend to simultaneously generate products substituted at different sites. Previously, the research team had achieved the photocatalytic synthesis of alkylamide-substituted benzo[a]aromatic heterocyclic derivatives using N-methylpyrrolidone as a substrate (Green Chem. 2021, 23, 5753–5758.), but this method is not applicable to ether substrates. Summary of the Invention

[0005] The purpose of this invention is to provide a simple, high-purity, and green method for synthesizing ether- or amide-substituted aromatic heterocyclic derivatives under photoelectric synergistic catalysis. Specifically, it is a green synthesis method that uses a cobalt-polypyridine complex as a photocatalyst to synthesize ether- or amide-substituted aromatic heterocyclic derivatives from nitrogen-containing heterocyclic compounds via CC coupling under the action of a visible light source and a constant voltage power supply.

[0006] The technical solution adopted in this invention is as follows:

[0007] This invention defines a method for synthesizing nitrogen-containing aromatic heterocyclic derivatives substituted with ethers or amides under photoelectro-co-catalysis. The method is characterized by dissolving a nitrogen-containing aromatic heterocyclic compound of Formula I or an ether or amide substrate of Formula II in an organic solvent, adding a cobalt bipyridine catalyst, an electrolyte, and a proton source, mixing to form a reaction solution, inserting a cathode and an anode into the reaction solution and applying an electric current, and carrying out the reaction under visible light irradiation and a constant voltage condition. After the reaction, the reaction solution is post-treated to obtain the ether or amide-substituted nitrogen-containing aromatic heterocyclic derivative of Formula III, the reaction equation of which is as follows:

[0008]

[0009] When X is O, in equation II, the substituent R 1 R 2 Each is independently selected from C1-C5 alkyl or C1-C5 alkyl alcohols;

[0010] When X is N, the substituent R 1 R 2 Cyclic or non-cyclic, substituent R 1 It is a C1-C4 alkyl group, with substituent R. 2 It is a C1-C4 alkyl, carbonyl, ester or amide group, and X also has a third substituent, which is H, C1-C4 alkyl, C1-C4 alkyl alcohol or Boc group.

[0011] Furthermore, the cobalt polypyridine catalyst described in this invention is Co(4,4′-R2bpy)3(PF6). n R is methyl, bromine, tert-butyl, trifluoromethyl, methoxy, or hydrogen, and n = 2 or 3, and its amount is 1 to 10 mol% of substrate I, preferably 4 to 8 mol%.

[0012] Furthermore, the polypyridine cobalt catalyst is preferably at least one of the following compounds:

[0013]

[0014] Furthermore, the polypyridine cobalt catalyst is preferably Co(4,4'-Me2bpy)3(PF6)2, Co(4,4'-Br2bpy)3(PF6)2, Co(4,4'-OMe2bpy)3(PF6)2, or Co(4,4'-tBu2bpy)3(PF6)2.

[0015] Furthermore, the electrolyte described in this invention is lithium perchlorate (LiClO4), tetrabutylammonium perchlorate (n-Bu4NClO4), tetrabutylammonium hexafluorophosphonate (n-Bu4NPF6), or tetrabutylammonium tetrafluoroborate (n-Bu4NBF4), and its amount is 0.5 to 6 equivalents of the molar amount of substrate I, preferably 1 to 3 equivalents of lithium perchlorate.

[0016] Furthermore, the proton source described in this invention is trifluoroacetic acid (TFA), and its amount is 0.5 to 6 equivalents of the molar amount of substrate I, preferably 1 to 3 equivalents.

[0017] Furthermore, the organic solvent described in this invention is selected from one or any combination of the following: acetonitrile, dichloromethane, hexafluoroisopropanol, dichloroethane, acetone, dimethyl sulfoxide or a mixture thereof, preferably acetonitrile, dimethyl sulfoxide or dichloromethane.

[0018] Furthermore, the nitrogen-containing aromatic heterocyclic compound described in this invention is selected from at least one of quinoline, isoquinoline, pyridine, phthalazine, benzothiazole and their derivatives, and preferably from at least one of the following structures:

[0019]

[0020] Furthermore, the ether or amide substrate represented by Formula II is selected from aliphatic alkanes containing nitrogen and / or oxygen atoms, such as tetrahydrofuran, tetrahydropyran, and N-methylpyrrolidone, and preferably at least one of the following structures:

[0021]

[0022] Furthermore, the molar ratio of the nitrogen-containing benzo[a]aromatic heterocyclic compound of Formula I and the ether or amide substrate of Formula II is 1:2 to 1:50, preferably 1:10 to 1:30.

[0023] Furthermore, the visible light source with a wavelength of 390–460 nm described in this invention is preferably a visible light source with a wavelength of 390–430 nm.

[0024] Furthermore, the power supply described in this invention is a constant voltage power supply of 0.5 to 2V, preferably a constant voltage power supply of 1 to 1.5V.

[0025] Furthermore, the anode is a carbon felt and the cathode is a platinum sheet.

[0026] Furthermore, after the reaction described in this invention is completed, the following post-processing steps are also included: quenching the reaction solution in a saturated sodium bicarbonate solution, ultrasonically washing the anode with ethyl acetate, combining the processed solutions and extracting with ethyl acetate, combining the organic phases and drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product, and purifying the crude product on a silica gel column with a volume ratio of n-hexane / ethyl acetate of 20:1 to 1:1 to obtain the target compound.

[0027] By employing the aforementioned specific techniques, the beneficial effects of the present invention compared to the prior art are as follows:

[0028] (1) No additional chemical equivalent of oxidant is required. Electric current is used as the oxidant, which is green and clean and in line with the concept of green chemistry.

[0029] (2) The reaction site is highly selective, generating single-region isomers for asymmetric ether and amide substrates, with precise site selection;

[0030] (3) The present invention has the advantages of simple operation, mild reaction conditions and simple post-processing. Detailed Implementation

[0031] In this embodiment of the invention, all six catalysts are known compounds:

[0032] The CAS number for catalyst PC1 is 79151-82-9;

[0033] The CAS number for catalyst PC2 is 1480716-55-9;

[0034] The CAS number for catalyst PC3 is 1174892-12-6;

[0035] The CAS number for catalyst PC4 is 28392-61-2;

[0036] The CAS number for catalyst PC5 is 79151-77-2;

[0037] The CAS number for catalyst PC6 is 630392-02-8.

[0038] Example 1: 1-(tetrahydro-2H-pyran-2-yl)isoquinoline for the preparation of an intermediate for integrin αv receptor antagonists

[0039]

[0040] Isoquinoline (64 mg, 0.5 mmol), tetrahydropyran (1 mL, 10.3 mmol), Co(4,4′-Me2bpy)3(PF6)2 (27 mg, 0.03 mmol), trifluoroacetic acid (TFA, 115 μL, 1.5 mmol), lithium perchlorate (LiClO4, 53 mg, 0.5 mmol), and acetonitrile (5 mL) were added to a pre-dried 10 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). The reaction vessel was sealed with a rubber septum and sealing film, purged with argon for 5 minutes, and irradiated with two 25 W LED lamps (light wavelength 390–400 nm) at room temperature for 30 hours under a constant voltage of 1 V. After the reaction was completed, the reaction solution was quenched in 20 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using a hexane / ethyl acetate solution with a volume ratio of 10:1 to obtain the target product (119 mg, yield 71%).

[0041] The NMR data are as follows:

[0042] 1 H NMR(600MHz,Chloroform-d)δ8.53(d,J=5.6Hz,1H),8.38(d,J=8.5Hz,1H),7.82(d,J=8.3Hz,1H),7.70–7.63(m,1H),7.63–7.54 (m,2H),5.34–5.03(m,1H),4.40–4.13(m,1H),3.91–3.65(m,1H),2.19–2.04(m,2H),2.04–1.97(m,1H),1.94–1.76(m,2H),1.71–

[0043] 1.63 (m, 1H).

[0044] 13 C NMR (151MHz, Chloroform-d) δ159.7,141.7,136.7,129.8,127.4,127.0,126.1,125.3,120.5,79.3,69.4,31.1,25.9,23.9.

[0045] The product of Example 1 can be converted into a carboxylic acid by subsequent oxidation and ring-opening, followed by a series of operations such as condensation reaction to obtain an intermediate of integrin αv receptor antagonist.

[0046]

[0047] Example 2: 1-(1,3-dioxolane-2-yl)isoquinoline was used to prepare a heterocyclic compound intermediate for the treatment of cGAS-related diseases.

[0048]

[0049] Isoquinoline (64 mg, 0.5 mmol), 1,3-dioxapentane (1 mL, 14.3 mmol), Co(4,4′-Me2bpy)3(PF6)2 (27 mg, 0.03 mmol), trifluoroacetic acid (TFA, 115 μL, 1.5 mmol), lithium perchlorate (LiClO4, 53 mg, 0.5 mmol), and dichloromethane (5 mL) were added to a pre-dried 10 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, argon gas was purged for 5 minutes. The reaction system was then irradiated at room temperature with two 25 W LED lamps (light wavelength 390–400 nm) and a constant voltage of 1 V was applied for 30 hours. After the reaction was completed, the reaction solution was quenched in 20 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using n-hexane / ethyl acetate at a volume ratio of 5:1 to obtain the target product (75 mg, yield 75%).

[0050] The NMR data for 1-(1,3-dioxolane-2-yl)isoquinoline are as follows:

[0051] 1 H NMR(400MHz,Chloroform-d)δ8.52(d,J=5.6Hz,1H),8.38(d,J=7.6Hz,1H),7.79(d, J=7.6Hz,1H),7.68–7.53(m,3H),6.45(s,1H),4.34–4.26(m,2H),4.19–4.11(m,2H).

[0052] 13 C NMR (101MHz, Chloroform-d) δ154.6,141.5,136.7,130.1,127.4,127.2,126.3,125.2,122.0,103.5,65.5.

[0053] The product of Example 2 can be converted to isoquinoline-1-carboxaldehyde via a Lewis acid-mediated methoxyl deprotection reaction, a prior art reaction, see Chem. Commun. 2021, 57, 3271–3274. The resulting product reacts with hydroxylamine hydrochloride and potassium acetate to yield an intermediate for preparing heterocyclic compounds used in the treatment of cGAS-related diseases, a prior art reaction, see WO2023081441 A1.

[0054]

[0055] Example 31 - (tetrahydrofuran-2-yl)isoquinoline as an intermediate in the preparation of MALT1 inhibitors

[0056]

[0057] Isoquinoline (65 mg, 0.5 mmol), tetrahydrofuran (1 mL, 12.4 mmol), Co(4,4′-tBu2bpy)3(PF6)2 (34 mg, 0.03 mmol), trifluoroacetic acid (TFA, 115 μL, 1.5 mmol), lithium perchlorate (LiClO4, 53 mg, 1 mmol), and dichloromethane (5 mL) were added to a pre-dried 10 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, argon gas was purged for 5 minutes. The reaction system was then irradiated at room temperature with two 25 W LED lamps (light wavelength 390–400 nm) and a constant voltage of 1 V was applied for 30 hours. After the reaction was completed, the reaction solution was quenched in 20 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using n-hexane / ethyl acetate at a volume ratio of 10:1 to obtain the target product (64 mg, yield 64%).

[0058] The NMR data for 1-(tetrahydrofuran-2-yl)isoquinoline are as follows:

[0059] 1H NMR(600MHz,Chloroform-d)δ8.51(d,J=5.7Hz,1H),8.36(d,J=8.5Hz,1H),7.84(d,J=8.3Hz,1H),7.76–7.65(m,1H),7.65–7.5 6(m,2H),5.74(t,J=7.1Hz,1H),4.27–4.15(m,1H),4.13–3.92(m,1H),2.58–2.49(m,1H),2.48–2.37(m,1H),2.26–2.06(m,2H).

[0060] 13 C NMR (151MHz, Chloroform-d) δ159.6,141.5,136.6,129.9,127.3,127.1,126.6,125.3,120.5,79.1,69.0,30.8,26.2.

[0061] The product of Example 3 can be modified to obtain a MALT1 inhibitor. The modification method is existing technology. See Journal of Organic Chemistry (2024), 89(11), 7455-7471 and US20180170909A1.

[0062]

[0063] Example 4: 4-Bromo-1-(1,4-dioxane-2-yl)isoquinoline as an intermediate in the preparation of MALT1 inhibitors

[0064]

[0065] Add 4-bromoisoquinoline (104 mg, 0.5 mmol), 1,4-dioxane (1 mL, 11.8 mmol), Co(4,4′-OMe2bpy)3(PF6)2 (30 mg, 0.03 mmol), trifluoroacetic acid (TFA, 115 μL, 1.5 mmol), lithium perchlorate (LiClO4, 53 mg, 1 mmol), and acetone (5 mL) to a pre-dried 10 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, purge with argon for 5 minutes. Irradiate the reaction system at room temperature with two 25 W LED lamps (light wavelength 390–400 nm) and apply a constant voltage of 1 V for 30 hours. After the reaction was completed, the reaction solution was quenched in 20 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using a hexane / ethyl acetate solution with a volume ratio of 8:1 to obtain the target product (117 mg, yield 80%).

[0066] The NMR data for 4-bromo-1-(1,4-dioxane-2-yl)isoquinoline are as follows:

[0067] 1 H NMR(600MHz,Chloroform-d)δ8.73(s,1H),8.34(d,J=8.4Hz,1H),8.23(d,J=8.3Hz,1H),7.85–7. 79(m,1H),7.74–7.68(m,1H),5.42(dd,J=9.7,2.8Hz,1H),4.25–4.01(m,4H),3.98–3.63(m,2H).

[0068] 13 C NMR (151MHz, Chloroform-d) δ155.5,143.5,135.1,131.3,128.4,127.8,126.8,125.2,120.1,75.6,70.1,67.6,66.5.

[0069] The product of Example 4 can be modified to obtain a MALT1 inhibitor. The modification method is prior art, see US20180170909A1.

[0070]

[0071] Example 5: 4-Bromo-1-(1-ethoxyethyl)isoquinoline as an intermediate in the preparation of MALT1 inhibitors

[0072]

[0073] Add 4-bromoisoquinoline (104 mg, 0.5 mmol), diethyl ether (1 mL, 9.6 mmol), Co(4,4′-Me2bpy)3(PF6)2 (27 mg, 0.03 mmol), trifluoroacetic acid (TFA, 115 μL, 1.5 mmol), lithium perchlorate (LiClO4, 53 mg, 1 mmol), and dichloromethane (5 mL) to a pre-dried 10 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, purge with argon for 5 minutes. Irradiate the reaction system at room temperature with two 25 W LED lamps (light wavelength 390–400 nm) and apply a constant voltage of 1 V for 30 hours. After the reaction was completed, the reaction solution was quenched in 20 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using n-hexane / ethyl acetate at a volume ratio of 20:1 to obtain the target product (84 mg, yield 60%).

[0074] The NMR data for 4-bromo-1-(1-ethoxyethyl)isoquinoline are as follows:

[0075] 1 H NMR(600MHz,Chloroform-d)δ8.72(d,J=8.5Hz,1H),8.67(s,1H),8.22(d,J=8.5Hz,1H),7.82–7.76(m,1H),7.68–7. 62(m,1H),5.15(q,J=6.7Hz,1H),3.55–3.49(m,1H),3.43–3.37(m,1H),1.70(d,J=6.8Hz,3H),1.20(t,J=7.0Hz,3H).

[0076] 13 C NMR (151MHz, Chloroform-d) δ161.4,143.3,135.3,131.2,127.8,127.4,126.7,125.9,119.3,79.6,64.6,21.6,15.4.

[0077] The product of Example 5 can be modified to obtain a MALT1 inhibitor. The modification method is prior art, see US20180170909A1.

[0078]

[0079] Example 6: 1,3,7-Trimethyl-8-(tetrahydrofuran-2-yl)-3,7-dihydro-1H-purine-2,6-dione for functionalization modification of caffeine.

[0080]

[0081] Caffeine (97 mg, 0.5 mmol), tetrahydrofuran (1 mL, 12.3 mmol), Co(4,4′-Br2bpy)3(PF6)2 (39 mg, 0.03 mmol), trifluoroacetic acid (TFA, 115 μL, 1.5 mmol), lithium perchlorate (LiClO4, 318 mg, 3 mmol), and acetonitrile (5 mL) were added to a pre-dried 10 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). The reaction vessel was sealed with a rubber septum and sealing film, purged with argon for 5 minutes, and irradiated with two 25 W LED lamps (light wavelength 390–400 nm) at room temperature for 30 hours under a constant voltage of 1 V. After the reaction was completed, the reaction solution was quenched in 20 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using a 2:1 (v / v) hexane / ethyl acetate mixture to obtain the target product (79 mg, yield 60%). The NMR data are as follows:

[0082] 1 H NMR(400MHz,Chloroform-d)δ5.09–4.90(m,1H),4.12–3.93(m,3H),3.99–3.85(m,2H),3.62–3.52(m ,3H),3.49–3.30(m,3H),2.73–2.48(m,1H),2.38–2.22(m,1H),2.23–2.11(m,1H),2.12–1.91(m,1H).

[0083] 13 C NMR (101MHz, Chloroform-d) δ155.5,152.4,151.7,147.3,108.4,72.6,68.9,32.2,29.7,29.6,27.9,26.0.

[0084] Example 7: 5-[(1,4-diazacycloheptane-1-yl)sulfonyl]-1-(5-methyltetrahydrofuran-2-yl)isoquinoline for functionalization modification of the drug fasudil.

[0085]

[0086] Add fasudil (164 mg, 0.5 mmol), 2-methyltetrahydrofuran (1 mL, 10 mmol), Co(4,4′-Br2bpy)3(PF6)2 (39 mg, 0.03 mmol), trifluoroacetic acid (TFA, 115 μL, 1.5 mmol), lithium perchlorate (LiClO4, 318 mg, 3 mmol), and acetone (5 mL) to a pre-dried 10 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, purge with argon for 5 minutes. Irradiate the reaction system at room temperature with two 25 W LED lamps (light wavelength 390–400 nm) and apply a constant voltage of 1 V for 30 hours. After the reaction was completed, the reaction solution was quenched in 20 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The treated solutions were combined and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using a hexane / ethyl acetate mixture with a volume ratio of 10:1 to obtain the target product (84 mg, yield 45%, dr = 1.8:1). The NMR data are as follows:

[0087] 1 H NMR (400MHz, Chloroform-d) δ8.73 (dd, J=29.4, 8.6Hz, 1H), 8.64 (d, J=6.1Hz, 1H), 8.39 (t, J=5. 4Hz,1H),8.34(d,J=7.3Hz,1H),7.74–7.60(m,1H),5.86(t,J=7.1Hz,0.36H),5.63(t,J=7.2Hz, 0.64H),4.43–4.25(m,1H),3.55–3.42(m,4H),3.10–2.97(m,4H),2.83–2.64(m,1H),2.50–2.19 (m,2H),2.05–1.98(m,1H),1.95–1.87(m,1H),1.85–1.70(m,1H),1.37(dd,J=11.7,6.1Hz,3H).

[0088] 13 C NMR(151MHz,Chloroform-d)δ160.0,143.5,134.9,132.6,132.6,131.8,131.3,127.8,127.5,125.5,125. 4,117.3,117.1,80.1,78.8,77.1,76.2,50.2,49.9,47.3,47.2,34.0,33.2,31.3,30.4,27.3,21.4,21.2.

[0089] Example 8: 5-(4-bromoisoquinoline-1-yl)pyrrolidone-2-one as an intermediate in the preparation of MALT1 inhibitors

[0090]

[0091] Add 4-bromoisoquinoline (104 mg, 0.5 mmol), pyrrolidone (1 mL, 13.2 mmol), Co(4,4′-Me2bpy)3(PF6)2 (27 mg, 0.03 mmol), trifluoroacetic acid (TFA, 115 μL, 1.5 mmol), lithium perchlorate (LiClO4, 159 mg, 1.5 mmol), and dichloroethane (5 mL) to a pre-dried 10 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, purge with argon for 5 minutes. Irradiate the reaction system at room temperature with two 25 W LED lamps (light wavelength 390–400 nm) and apply a constant voltage of 1 V for 30 hours. After the reaction was completed, the reaction solution was quenched in 20 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using dichloromethane / methanol at a volume ratio of 20:1 to obtain the target product (87 mg, yield 60%).

[0092] The NMR data for 5-(4-bromoisoquinolin-1-yl)pyrrolidine-2-one are as follows:

[0093] 1 H NMR(400MHz, DMSO-d6)δ8.73(s,1H),8.41(d,J=8.9Hz,1H),8.16(d,J=8.9Hz,1H),8.11–7.93(m,2H),7 .89–7.74(m,1H),5.68(dd,J=9.0,4.6Hz,1H),2.72–2.57(m,1H),2.34–2.13(m,2H),2.10–1.89(m,1H).

[0094] 13 C NMR (101MHz, DMSO-d6) δ177.7,161.5,143.4,134.5,132.7,129.4,126.9,126.5,125.7,118.6,54.6,30.0,28.2.

[0095] The product of Example 8 can be modified to obtain a MALT1 inhibitor. The modification method is prior art, see US20180170909A1.

[0096]

[0097] Example 9: N-[(4-bromoisoquinoline-1-yl)methyl]-N-methylacetamide as an intermediate for the preparation of MALT1 inhibitors

[0098]

[0099] Add 4-bromoisoquinoline (104 mg, 0.5 mmol), N,N-dimethylacetamide (1 mL, 10.1 mmol), Co(4,4′-Me2bpy)3(PF6)2 (27 mg, 0.03 mmol), trifluoroacetic acid (TFA, 115 μL, 1.5 mmol), lithium perchlorate (LiClO4, 159 mg, 1.5 mmol), and dimethyl sulfoxide (5 mL) to a pre-dried 10 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, purge with argon for 5 minutes. Irradiate the reaction system at room temperature with two 25 W LED lamps (light wavelength 390–400 nm) and apply a constant voltage of 1 V for 30 hours. After the reaction was completed, the reaction solution was quenched in 20 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using n-hexane / ethyl acetate at a volume ratio of 2:1 to obtain the target product (105 mg, yield 72%).

[0100] The NMR data for N-[(4-bromoisoquinoline-1-yl)methyl]-N-methylacetamide are as follows:

[0101] 1 H NMR(600MHz,Chloroform-d)δ8.65(s,0.15H),8.61(s,0.85H),8.34(d,J=8.4Hz,0.85H),8.20(d,J=8.5Hz,0.15H),8.14(d,J=8.4Hz,0.85H),8.00(d,J =8.4Hz,0.15H),7.82–7.74(m,1H),7.70–7.61(m,1H),5.16(s,1.7H),5.06( s,0.3H),2.99(s,0.45H),2.96(s,2.55H),2.14(s,2.55H),2.10(s,0.45H).

[0102] 13 C NMR(151MHz,Chloroform-d)δ172.0,170.6,156.1,153.9,143.8,143.2,134.9,134.8,131.5,131.4,12 8.6,128.6,127.9,127.2,127.1,126.5,125.8,123.5,119.7,119.3,53.0,50.0,35.6,34.6,21.8,21.5.

[0103] The product of Example 9 can be modified to obtain a MALT1 inhibitor. The modification method is existing technology, see Journal of Organic Chemistry (2017), 82(1), 170-178 and US20180170909A1.

[0104]

[0105] Example 10: N-[(4-bromoisoquinoline-1-yl)methyl]-N-methylformamide as an intermediate for the preparation of MALT1 inhibitors.

[0106]

[0107] Add 4-bromoisoquinoline (104 mg, 0.5 mmol), N,N-dimethylformamide (1 mL, 13.0 mmol), Co(4,4′-Me2bpy)3(PF6)2 (27 mg, 0.03 mmol), trifluoroacetic acid (TFA, 115 μL, 1.5 mmol), lithium perchlorate (LiClO4, 159 mg, 1.5 mmol), and dimethyl sulfoxide (5 mL) to a pre-dried 10 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, purge with argon for 5 minutes. Irradiate the reaction system at room temperature with two 25 W LED lamps (light wavelength 390–400 nm) and apply a constant voltage of 1 V for 30 hours. After the reaction was completed, the reaction solution was quenched in 20 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using a 1:1 volume ratio of n-hexane / ethyl acetate to obtain the target product (83 mg, yield 60%).

[0108] The NMR data for N-[(4-bromoisoquinoline-1-yl)methyl]-N-methylformamide are as follows:

[0109] 1 H NMR(600MHz,Chloroform-d)δ8.69(s,0.25H),8.65(s,0.75H),8.40(s,0.25H),8.34(d,J=8.4Hz,0.75H),8.24(d,J=8.4Hz,0.25H),8.20(d,J=8.4Hz,0 .75H),8.16(s,0.75H),8.06(d,J=8.4Hz,0.25H),7.88–7.79(m,1H),7.74–7 .65(m,1H),5.13(s,1.5H),5.00(s,0.5H),2.91(s,2.25H),2.88(s,0.75H).

[0110] 13 C NMR(151MHz,Chloroform-d)δ163.5,162.4,154.8,153.9,143.7,143.2,135.0,135.0,131.7,131 .6,128.8,128.8,127.8,127.6,127.2,126.7,125.6,123.8,120.0,119.9,52.2,47.5,34.5,30.4.

[0111] The product of Example 10 can be modified to obtain a MALT1 inhibitor.

[0112]

[0113] Example 11: 1-(tert-Butoxycarbonyl)-2-(4-bromoisoquinoline-1-yl)pyrrolidine as an intermediate in the preparation of CXCR4 inhibitors

[0114]

[0115] Add 4-bromoisoquinoline (104 mg, 0.5 mmol), 1-tert-butoxycarbonylpyrrolidine (1 mL, 5.7 mmol), Co(4,4′-Me2bpy)3(PF6)2 (27 mg, 0.03 mmol), trifluoroacetic acid (TFA, 115 μL, 1.5 mmol), lithium perchlorate (LiClO4, 159 mg, 1.5 mmol), and dimethyl sulfoxide (5 mL) to a pre-dried 10 mL three-necked flask (equipped with a magnetic stirrer, carbon felt anode, and platinum cathode). After sealing the reaction vessel with a rubber septum and sealing film, purge with argon for 5 minutes. Irradiate the reaction system at room temperature with two 25 W LED lamps (light wavelength 390–400 nm) and apply a constant voltage of 1 V for 30 hours. After the reaction was completed, the reaction solution was quenched in 20 mL of saturated sodium bicarbonate solution. The carbon felt anode was ultrasonically washed with ethyl acetate for 5 min. The combined solutions were extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column using n-hexane / ethyl acetate at a volume ratio of 8:1 to obtain the target product (137 mg, yield 73%).

[0116] The NMR data for 1-(tert-butoxycarbonyl)-2-(4-bromoisoquinoline-1-yl)pyrrolidine are as follows:

[0117] 1 H NMR(600MHz,Chloroform-d)δ8.63(d,J=15.3Hz,2H),8.26–8.12(m,2H),7.82–7.71(m,1H),7.68–7.59(m,1H),5.82 –5.58(m,1H),3.87–3.77(m,1H),3.73–3.53(m,1H),2.55–2.37(m,1H),2.13–1.86(m,3H),1.44(s,4H),0.96(s,5H).

[0118] 13 C NMR(151MHz,Chloroform-d)δ161.8,160.8,154.6,154.2,143.4,135.0,134.7,131.0,130.9,127.9,12 6.8,124.6,124.4,118.4,118.0,79.3,78.9,59.0,58.4,47.2,47.0,33.8,32.8,28.5,28.0,24.0,23.6.

[0119] The product can be modified to obtain a CXCR4 inhibitor. The modification method is existing technology, see WO2017223243A1.

[0120]

[0121] Example 12 Synthesis of Additional Exemplary Compounds

[0122] Additional exemplary compounds were prepared using methods substantially similar to those described above. Table 1 below provides experimental data parameters for these compounds, with the types of catalysts used indicated by the following formulas: Catalyst List (Catalysts List) and their designations below.

[0123]

[0124] In the reaction conditions of different experiments in Table 1, the molar amount of substrate I, a nitrogen-containing aromatic heterocyclic compound, was kept constant at 0.5 mmol, and the molar amount of ether or amide substrate II was kept constant at 10 mmol.

[0125] Table 1 lists the selections of catalyst, solvent, electrolyte, and proton source for different experiments, with their amounts compared to substrate I. For example, in the first experiment in Table 1, catalyst PC1 (6 mol%) indicates that its amount is 6 mol% of the molar amount of substrate I; LiClO4 (1 equiv.) indicates that its amount is 1 equivalent of the molar amount of substrate I; TFA (3 equiv.) indicates that its amount is 3 equivalents of the molar amount of substrate I; the light source used is two 25W LED lamps with a light wavelength of 390–400 nm to irradiate the reaction system; a constant voltage of 1 V is applied for the reaction; the electrolysis reaction lasts for 30 hours; carbon felt is used as the anode; and platinum sheet is used as the cathode.

[0126] Table 1 Experimental data for additional exemplary compounds

[0127]

[0128]

[0129]

[0130]

[0131] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing ether- or amide-substituted aromatic heterocyclic derivatives under photoelectro-co-catalysis, characterized in that... Includes the following steps: Under inert gas protection, nitrogen-containing aromatic heterocyclic compounds of Formula I and ether or amide substrates of Formula II are dissolved in an organic solvent. A cobalt bipyridine catalyst, an electrolyte, and a proton source are added, and the mixture is stirred to form a reaction solution. A cathode and anode are inserted into the reaction solution, and an electric current is applied. The reaction is carried out under visible light irradiation and a constant voltage to obtain ether- or amide-substituted aromatic heterocyclic derivatives of Formula III. The reaction equation is as follows: When X is O, in equation II, the substituent R 1 R 2 Each is independently selected from C1-C5 alkyl or C1-C5 alkyl alcohols; When X is N, the substituent R 1 R 2 Cyclic or non-cyclic, substituent R 1 It is a C1-C4 alkyl group, with substituent R. 2 It is a C1-C4 alkyl, carbonyl, ester or amide group, and X also has a third substituent, which is H, C1-C4 alkyl, C1-C4 alkyl alcohol or Boc group.

2. The method for synthesizing ether- or amide-substituted aromatic heterocyclic derivatives under photoelectro-co-catalysis according to claim 1, characterized in that... The polypyridine cobalt catalyst is Co(4,4′-R2bpy)3(PF6). n R is methyl, bromine, tert-butyl, trifluoromethyl, methoxy, or hydrogen, and n = 2 or 3, the amount of which is 1 to 10 mol% of the molar amount of substrate I, preferably 4 to 8 mol%; the polypyridine cobalt catalyst is preferably at least one of the following compounds:

3. The method for synthesizing ether- or amide-substituted aromatic heterocyclic derivatives under photoelectro-co-catalysis according to claim 1, characterized in that, Its features The electrolyte is lithium perchlorate (LiClO4), tetrabutylammonium perchlorate (n-Bu4NClO4), tetrabutylammonium hexafluorophosphonate (n-Bu4NPF6), or tetrabutylammonium tetrafluoroborate (n-Bu4NBF4), and its amount is 0.5 to 6 equivalents of the molar amount of substrate I, preferably 1 to 3 equivalents of lithium perchlorate.

4. The method for synthesizing ether- or amide-substituted aromatic heterocyclic derivatives under photoelectro-co-catalysis according to claim 1, characterized in that... The proton source is trifluoroacetic acid (TFA), and its amount is 0.5 to 6 equivalents of the molar amount of substrate I, preferably 1 to 3 equivalents.

5. The method for synthesizing ether- or amide-substituted aromatic heterocyclic derivatives under photoelectro-co-catalysis according to claim 1, characterized in that... The organic solvent is acetonitrile, dichloromethane, hexafluoroisopropanol, dichloroethane, acetone, dimethyl sulfoxide, or a mixture thereof, preferably acetonitrile, dimethyl sulfoxide, or dichloromethane.

6. The method for synthesizing ether- or amide-substituted aromatic heterocyclic derivatives under photoelectro-co-catalysis according to claim 1, characterized in that... The nitrogen-containing aromatic heterocyclic compound is selected from at least one of quinoline, isoquinoline, pyridine, phthalazine, benzothiazole and their derivatives, and preferably from at least one of the following structures:

7. The method for synthesizing ether- or amide-substituted aromatic heterocyclic derivatives under photoelectro-co-catalysis according to claim 1, characterized in that... The ether or amide substrates represented by Formula II are selected from aliphatic alkanes containing nitrogen and / or oxygen atoms, preferably at least one of the following structures:

8. The method for synthesizing ether- or amide-substituted aromatic heterocyclic derivatives under photoelectro-co-catalysis according to claim 1, characterized in that... The molar ratio of the nitrogen-containing benzo[a]aromatic heterocyclic compound shown in Formula I to the ether or amide substrate shown in Formula II is 1:2 to 1:50, preferably 1:10 to 1:

30.

9. The method for synthesizing ether- or amide-substituted aromatic heterocyclic derivatives under photoelectro-co-catalysis according to claim 1, characterized in that... The reaction conditions are as follows: the light source is visible light with a wavelength of 390-460nm, and the power supply is a constant voltage power supply of 0.5-2V, preferably a visible light source of 390-430nm and a constant voltage power supply of 1-1.5V; the anode is carbon felt and the cathode is platinum sheet.

10. The method for synthesizing ether- or amide-substituted aromatic heterocyclic derivatives under photoelectro-co-catalysis according to claim 1, characterized in that... After the reaction is complete, the following post-processing steps are also included: the reaction solution is quenched in saturated sodium bicarbonate solution, the anode is ultrasonically washed with ethyl acetate, the combined treatment solutions are extracted with ethyl acetate, the combined organic phases are dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product. The crude product is purified on a silica gel column with a volume ratio of n-hexane / ethyl acetate of 20:1 to 1:1 to obtain the target compound.

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