Process for the preparation of imidazo-hexaazaheterocycles containing isothiourea fragments

Abstract

The present application relates to the field of organic synthesis, and is a preparation method of imidazo six-membered nitrogen heterocyclic compounds containing isothiourea fragments for medicines and intermediates. The method uses nitrogen atom ortho isocyanomethyl-substituted pyridine, pyrimidine, pyrazine, quinoline and other nitrogen-containing heteroaromatic rings as raw materials, reacts with various disulfides under the action of N-chlorosuccinimide (NCS) and a catalytic amount of TEMPO, and intramolecularly cyclizes to form imidazo six-membered nitrogen heterocyclic compounds containing isothiourea fragments. The method can realize intramolecular ring closure in one step, form imidazo[1,5a] nitrogen-containing heteroaromatic rings containing isothiourea fragments, construct various imidazo[1,5a] nitrogen-containing heteroaromatic rings containing isothiourea fragments, has high yield, low raw material cost, can realize large-scale industrial production, and has market application prospect.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, specifically to the synthesis of pharmaceuticals and intermediates, and more specifically to a method for synthesizing imidazolide hexa-azo compounds containing the isothiourea fragment. Background Technology

[0002] In recent years, imidazolide hexa-nitrogen heterocyclic compounds containing isothiourea fragments have attracted much attention due to their unique biological activities. They often possess a wide range of biological activities, such as anti-inflammatory, antibacterial, anticancer, and analgesic effects. They have inhibitory or promoting effects on many important target enzymes in the human body, such as RORc inhibitors, JAK3 inhibitors, and aldosterone synthase inhibitors. These active compounds containing cyclic isothiourea units can be used to treat metastatic and hyperproliferative diseases.

[0003] For example, compound A of WO2015036411A1 is a RORc inhibitor; compound B of WO2011117160A1 is a JAK3 inhibitor.

[0004] Compound C of WO2009008992A is a TOR (rapamycin target) kinase inhibitor; Compound D of WO2007064993A2 is a protein tyrosine kinase (PTK) inhibitor; Compound E of WO2005042537A1 is a p38 kinase inhibitor; and Compound F of WO2004046145A is an aldosterone synthase inhibitor.

[0005]

[0006] A review of known literature and patents reveals very few studies on the synthesis of isothiourea imidazole [1,5-a]pyridine derivatives. Existing literature, such as Org. Lett. 2022, 24, 3834 and J. Heterocyclic Chem. 1980, 17, 1351, reports on the synthesis of isothiourea imidazole [1,5-a]pyridine derivatives by reacting corresponding amine compounds with isothiocyanate compounds, followed by reaction with halogenated compounds to obtain the target compound. These synthetic methods all involve highly toxic isothiocyanate compounds as raw materials and result in extremely low yields. Therefore, the synthesis of thiourea imidazole [1,5-a]pyridine derivatives, such as cyclic isothiourea fragments of compound A or compound B, is a relatively challenging topic.

[0007] For example, WO2015036411A1 shows that the synthesis of compound A involves a transition metal-catalyzed coupling reaction, resulting in high synthesis costs; WO2011117160A1 shows that the yields of intermediates in each step of the synthesis of compound B are very low; and WO2009008992A2 shows that the raw materials required for compound C are expensive.

[0008] Therefore, it is necessary to develop a general and efficient synthetic method to construct various cyclic isothiourea fragments. The objective of this invention is to develop a synthetic method based on the tandem reaction of molecules containing isocyanates and nitrogen-containing nucleophilic centers with electrophilic sulfur centers (dithioethers) to form intramolecular cyclization compounds containing isothiourea fragments and imidazolide six-membered nitrogen heterocyclic compounds. Summary of the Invention

[0009] The present invention aims to provide a method for preparing imidazolide hexa-nitrogen compounds containing isothiourea fragments.

[0010] The general structural formula of the compound is as follows:

[0011]

[0012] Where X and Y are selected from C or N;

[0013] R1 is H, C1-10 alkyl or substituted alkyl, C3-10 cycloalkyl or substituted cycloalkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, biphenyl or substituted biphenyl, aryl or substituted aryl, or aromatic heterol.

[0014] Alternatively, X and Y combine with R1 and the heterocycle in which it is located to form pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, quinolinyl, isoquinolinyl, substituted quinolinyl, or substituted isoquinolinyl.

[0015] Preferably, X and Y are C, and R1 is H, C1-10 alkyl or substituted alkyl, C3-10 cycloalkyl or substituted cycloalkyl, phenyl, or C1-C4 alkoxyphenyl; or X and Y, together with R1 and the heterocycle therein, form quinolinyl or isoquinolinyl.

[0016] R2 and R3 are selected from H, C1-10 alkyl or substituted alkyl, C3-C10 cycloalkyl or substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, aryl, and aromatic heterol.

[0017] Preferably, R2 and R3 are selected from H, C1-10 alkyl or substituted alkyl, C3-C10 cycloalkyl or substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, quinolinyl, isoquinolinyl, substituted quinolinyl or substituted isoquinolinyl.

[0018] This invention uses nitrogen-containing heterocyclic compounds such as pyridine, pyrimidine, pyrazine, and quinoline with ortho-isocyanomethyl substitution at the nitrogen atom as raw materials. Under the action of N-chlorosuccinimide (NCS) and a catalytic amount of TEMPO, they react with various disulfides to form intramolecular cyclization compounds containing isothiourea fragments and imidazolide six-membered nitrogen heterocyclic compounds.

[0019] The preparation method is as follows: Compound 2 and disulfide compound R3-SS-R3- are reacted with oxidant N-chlorosuccinimide (NCS) and catalyst TEMPO to generate compound 1.

[0020] The molar ratio of compound 2 to the disulfide compound, catalyst, and oxidant is 1:0.45-1:0.15-0.3:1.2-2.5, preferably 1:0.45-0.6:0.2-0.3:1.9-2.1, and more preferably 1:0.5:0.2-0.3:1.9-2.1. In a preferred embodiment of the invention, the ratio is 1:0.5:0.2:2.0.

[0021] The solvent used is dichloromethane (DCM).

[0022] Specifically, the disulfide compound and the oxidant N-chlorosuccinimide are first dissolved in a solvent, and the catalyst TEMPO is added to react for 1.5-6 hours; then the solution of compound 2 is added, and the reaction continues for 1-6 hours.

[0023] After the reaction is complete, sodium alkoxide is added and the reaction is quenched by stirring. The organic phase is then washed, dried, and purified. Preferably, the sodium alkoxide is sodium ethoxide or sodium methoxide.

[0024]

[0025] In a preferred embodiment of the present invention, the molar ratio of compound 2 to the disulfide compound, the catalyst and the oxidant is 1:0.5:0.2:2.

[0026] Compound 2 can be purchased commercially or prepared using the following method. The synthetic route is as follows:

[0027]

[0028] The preparation method of compound 2 can be achieved by starting with nitrogen-containing heteroaromatic rings such as pyridine, pyrimidine, pyrazine, and quinoline (compound 7) with ortho-aldehyde groups substituted at the nitrogen atom, reacting them with tert-butylsulfinamide to give compound 6, then obtaining compound 5 through nucleophilic addition, acid hydrolysis to give compound 4, reacting with ethyl formate to give compound 3, and finally obtaining compound 2 under the action of dehydrating agent POCl3 or Burgess reagent.

[0029] The specific steps are as follows:

[0030] (1) Compound 7 reacts with tert-butyl sulfinamide under the catalysis of titanate to generate compound 6; the molar ratio of compound 2 to tert-butyl sulfinamide and titanate is 1:1-1.6:1-1.6; the titanate is tetraisopropyl titanate.

[0031] (2) Compound 6 undergoes a nucleophilic addition reaction with Grignard reagent R2-MgBr to generate compound 5; the molar ratio of compound 6 to Grignard reagent is 1:2-3, and preferably, the molar ratio is 1:2.5;

[0032] (3) Compound 5 is acidically hydrolyzed to generate compound 4; the acid is hydrochloric acid, and the reaction is carried out in an alcohol.

[0033] (4) Compound 4 reacts with formate to form compound 3; preferably, the formate is ethyl formate;

[0034] (5) Compound 3 is dehydrated to generate compound 2; preferably, the dehydrating agent used is POCl3 or Burgess reagent.

[0035] We utilize the reaction of an isocyanate group and a nucleophilic nitrogen group simultaneously contained in a molecule with an in-situ activated disulfide to achieve intramolecular ring closure in one step to form an imidazo[1,5a] nitrogen-containing heteroaromatic ring containing an isothiourea fragment, with yields ranging from 76% to 89%.

[0036] This method is a general synthetic approach that can construct various imidazo[1,5a] nitrogen-containing heteroaromatic rings containing isothiourea fragments with high yield and low raw material cost. It can be used for large-scale industrial production and has promising market application prospects. Detailed Implementation

[0037] Example 1: 1-Phenylacetyl-3-phenylthio-imidazo[1,5-a]pyridine (1a)

[0038] Step 1: Pyridine-2-methyleneamino-N-tert-butylsulfinamide (6a)

[0039]

[0040] In a 250 mL reaction flask, 120 mL of tetrahydrofuran was added, followed by 8.75 g (81.7 mmol) of 2-aldehyde pyridine, 14.9 g (123 mmol) of tert-butylsulfinamide, and 34.8 g (122 mmol) of tetraisopropyl titanate. The reaction was carried out overnight at 70 °C. The reaction was then terminated. 50 mL of water and 50 mL of ethyl acetate were added to the reaction mixture, and the organic phase was separated, dried over anhydrous Na₂SO₄, and the solvent was recovered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 13.9 g of a colorless oil, 6a, in 81% yield. 1H NMR (400MHz, CDCl3) δ8.72(d,J=4.5Hz,1H),8.67(s,1H),8.00(d,J=7.9Hz,1H),7.80(td,J=7.7,1.5Hz,1H),7.44–7.35(m,1H),1.26(s,10H).

[0041] Step 2: α-Phenylidene-2-methyleneamino-N-tert-butylsulfinamide (5a)

[0042]

[0043] Under nitrogen protection, 10 mL of anhydrous tetrahydrofuran was added to a 50 mL reaction flask, followed by 2 g (9.6 mmol) of compound 6a. The mixture was cooled to -70 °C, and 0.06 mL (24 mmol) of bromobenzene Grignard reagent was added dropwise. The reaction was allowed to proceed for 1 hour. 20 mL of saturated ammonium chloride solution was added to the reaction mixture, and stirring was continued for 20 minutes. 50 mL of water and 50 mL of ethyl acetate were added to the reaction mixture, and the organic phase was separated, dried over anhydrous Na₂SO₄, and the solvent was recovered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 2.08 g of a pale yellow oil, 5a, in 76% yield. 1 H NMR (400MHz, CDCl3) δ8.58–8.55(m,1H),7.59–7.55(m,1H),7.39–7.27(m,6H),7.16(dd,J=7.2 ,5.1Hz,1H),7.06(d,J=7.9Hz,1H),5.80(d,J=2.5Hz,1H),5.65(d,J=3.0Hz,1H),1.27(s,9H).

[0044] Step 3: α-Phenylacetylmethylamine (4a)

[0045]

[0046] In a 25 mL reaction flask, 9 mL of anhydrous methanol containing 20 mmol of hydrogen chloride was added, followed by 1 g (3.4 mmol) of compound 5a. The reaction was allowed to proceed for 3 hours at room temperature. The reaction mixture was quenched with saturated sodium carbonate, extracted with 20 mL of ethyl acetate, and the organic phase was separated, washed with saturated sodium carbonate, dried over anhydrous Na₂SO₄, and the solvent was recovered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 0.6 g of a yellow oil 4a, in 94% yield.

[0047] Step 4: N-(α-phenyl-2-pyridinemethyl)formamide (3a)

[0048]

[0049] In a 50 mL reaction flask, 1.84 g (10 mmol) of compound 4a was added to 10 mL (123.7 mmol) of ethyl formate. The reaction was refluxed overnight to terminate the reaction. Extraction was performed with ethyl acetate, and the organic phase was dried over anhydrous Na₂SO₄. The solvent was recovered, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 1.72 g of a colorless oil 3a, in 81% yield.

[0050] Step 5: α-Phenylacetyl-2-(isocyanomethyl)pyridine (2a)

[0051]

[0052] In a 50 mL reaction flask, 20 mL of dichloromethane was added, followed by 2.12 g (10 mmol) of compound 3a. The mixture was cooled to -5 °C, and 2.38 g of Burgess reagent was dissolved in 5 mL of dichloromethane and added dropwise to the reaction solution. The reaction was allowed to proceed for 30 minutes. 20 mL of dichloromethane was then added to the reaction solution, and the organic phase was separated, dried over anhydrous Na₂SO₄, and the solvent was recovered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give 1.72 g of a yellow oily substance 2a, in 88% yield. 1 H NMR (400MHz, CDCl3) δ8.17(s,1H),8.00–7.88(m,3H),7.82(d,J=9.3Hz,1H),7.49(dd,J=1 0.7, 4.9Hz, 2H), 7.35–7.26 (m, 1H), 6.78 (ddd, J=9.3, 6.4, 0.8Hz, 1H), 6.61–6.55 (m, 1H).

[0053] Step 6: 1-Phenylacetyl-imidazo[1,5-a]pyridine (1a)

[0054]

[0055] Under nitrogen protection, in a 25 mL reaction flask, 218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5 mL of dichloromethane. Then, 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution. The mixture was stirred at room temperature for 2 hours, and the reaction solution turned red. Subsequently, 390 mg (2 mmol) of compound 2a was dissolved in 2 mL of dichloromethane to form a solution, which was added to the above reaction solution. The mixture was stirred for 1 hour, and the reaction was completed. 1 mmol of sodium ethoxide was added, and the reaction was quenched by stirring for another 2 hours, and the solution turned yellow. Water was added, and the organic phase was separated. The organic phase was washed twice with saturated brine, dried over anhydrous Na2SO4, and the solvent was recovered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 0.53 g of yellow oily substance 1a, with a yield of 88%. 1 H NMR (400MHz, CDCl3) δ8.18(d,J=7.1Hz,1H),7.99(d,J=7.3Hz,2H),7.91(d,J=9.2Hz,1H),7.51(t,J=7.7Hz,2H),7.35 (t,J=7.4Hz,1H),7.27–7.21(m,2H),7.17(dd,J=9.1,7.7Hz,3H),6.94(dd,J=9.1,6.5Hz,1H),6.70(t,J=6.8Hz,1H); 13 C NMR (100MHz, CDCl3) δ136.64,134.55,134.23,133.46,129.70,129.31,128.78,127.53,126.89,126.76,126.57,122.76,121.30,118.76,113.73.

[0056] The preparation methods of intermediates 2b-2h in Examples 2-8 below are the same as those of the intermediates in Example 1.

[0057] Example 2 1-(4-methoxyphenyl)-3-phenylthio-imidazo[1,5-a]pyridine (1b)

[0058]

[0059] Under nitrogen protection, in a 25 mL reaction flask, 218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5 mL of dichloromethane. Then, 32 mg (0.2 mmol) of TEMPO was added to the reaction solution. The mixture was stirred at room temperature for 2 hours, and the reaction solution turned red. Subsequently, 450 mg (2 mmol) of compound 2b was dissolved in 2 mL of dichloromethane to form a solution, which was added to the above reaction solution. The mixture was stirred for 1 hour, and the reaction was completed. 1 mmol of sodium ethoxide was added, and the reaction was quenched by stirring for another 2 hours, and the solution turned yellow. Water was added, and the organic phase was separated. The organic phase was washed twice with saturated brine, dried over anhydrous Na2SO4, and the solvent was recovered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 0.55 g of a pale yellow oily substance 1b, with a yield of 83%. 1 H NMR (400MHz, CDCl3) δ8.15(d,J=7.2Hz,1H),7.90(d,J=8.4Hz,2H),7.91(d,J=8.0Hz,1H),7.51(t,J=6.8Hz,2 H),7.18–7.133(m,3H),7.05(d,J=8.8Hz,2H),6.90(dd,J=9.2,Hz,1H),6.74(t,J=6.8Hz,1H),3.89(s,1H).; 13 C NMR (100MHz, CDCl3) δ158.86,134.54,133.68,129.29,129.06,128.00,127. 45,127.27,126.52,126.04,122.69,120.68,118.85,114.27,113.70,55.37.

[0060] The preparation method of 2b is similar to that of Example 1, except that 4-methoxyphenyl magnesium bromide is used as a Grignard reagent in the second step.

[0061] Example 3 1-(3-pyridyl)-3-phenylthio-imidazo[1,5-a]pyridine (1c)

[0062]

[0063] Under nitrogen protection, in a 25 mL reaction flask, 218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5 mL of dichloromethane. Then, 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution. The mixture was stirred at room temperature for 2 hours, and the reaction solution turned red. Subsequently, 392 mg (2 mmol) of compound 2c was dissolved in 2 mL of dichloromethane to form a solution, which was added to the above reaction solution. The mixture was stirred for 1 hour, and the reaction was completed. 1 mmol of sodium ethoxide was added, and the reaction was quenched by stirring for another 2 hours, and the solution turned yellow. Water was added, and the organic phase was separated. The organic phase was washed twice with saturated brine, dried over anhydrous Na2SO4, and the solvent was recovered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 0.46 g of brown oily substance 1c, with a yield of 76%. 1 H NMR (400MHz, CDCl3) δ9.04(s,1H),8.76(d,J=5.1Hz,2H),8.21(d,J=6.9Hz,1H),8.14(d,J=8.0Hz,1H),7.96(d,J=7.0Hz, 1H),7.78(d,J=9.4Hz,1H),7.55(d,J=5.1Hz,2H),7.30–7.21(m,2H),6.84(dd,J=9.1,6.5Hz,1H),6.63(t,J=6.7Hz,1H); 13 CNMR (100MHz, CDCl3) δ140.88,139.42,133.24,130.55,128.80,127.77,127. 45,127.45,127.24,126.95,126.68,121.92,121.03,119.92,118.88,113.67.

[0064] The preparation method of 2c is similar to that of Example 1, except that 3-pyridyl magnesium bromide is used as a Grignard reagent in the second step.

[0065] Example 4 1-(4-[1,1'-biphenyl])-3-phenylthio-imidazo[1,5-a]pyridine (1d)

[0066]

[0067] Under nitrogen protection, in a 25 mL reaction flask, 218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5 mL of dichloromethane. Then, 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution. The mixture was stirred at room temperature for 2 hours, and the reaction solution turned red. Subsequently, 542 mg (2 mmol) of compound 2d was dissolved in 2 mL of dichloromethane to form a solution, which was added to the above reaction solution. The mixture was stirred for 1 hour, and the reaction was completed. 1 mmol of sodium methoxide was added, and the reaction was quenched by stirring for another 2 hours, and the solution turned yellow. Water was added, and the organic phase was separated. The organic phase was washed twice with saturated brine, dried over anhydrous Na2SO4, and the solvent was recovered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 0.65 g of a yellow oily substance 1d, with a yield of 86%. 1 H NMR(400MHz, CDCl3)δ7.96(d,J=8.3Hz,1H),7.88(dd,J=15.3,8.3Hz,1H),7.75–7.66(m,2H),7 .49(t,J=7.6Hz,1H),7.38(t,J=7.4Hz,1H),6.87(dd,J=9.2,6.4Hz,1H),6.74(t,J=6.8Hz,1H); 13 C NMR (100MHz, CDCl3) δ140.77,139.42,133.24,130.51,128.80,127.77,127.45,1 27.24,126.95,126.68,121.95,126.68,121.95,121.03,119.92,118.88,113.67.

[0068] The preparation method of 2d is similar to that of Example 1, except that 4-[1,1'-biphenyl]magnesium bromide is used as a Grignard reagent in the second step.

[0069] Example 5 1-Cyclopropyl-3-phenylthio-imidazo[1,5-a]pyridine (1e)

[0070]

[0071] Under nitrogen protection, in a 25 mL reaction flask, 218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5 mL of dichloromethane. Then, 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution. The mixture was stirred at room temperature for 2 hours, and the reaction solution turned red. Subsequently, 318 mg (2 mmol) of compound 2e was dissolved in 2 mL of dichloromethane to form a solution, which was added to the above reaction solution. The mixture was stirred for 1 hour, and the reaction was completed. 1 mmol of sodium ethoxide was added, and the reaction was quenched by stirring for another 2 hours, and the solution turned yellow. Water was added, and the organic phase was separated. The organic phase was washed twice with saturated brine, dried over anhydrous Na2SO4, and the solvent was recovered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 0.43 g of yellow oily substance 1e, with a yield of 82%. 1 H NMR (400MHz, CDCl3) δ8.05(d,J=8.0Hz,1H),7.58(d,J=8.1Hz,1H),7.21(t,J=6.7Hz,2H),7.15(d,J=8.1Hz,1H),7.04(t,J =6.7Hz,2H),7.76(dd,J=16.1,7.5Hz,1H),6.59(t,J=6.7Hz,1H),2.19-2.15(m,1H),1.12-1.09(m,2H),1.04-1.01(m,2H), 13 C NMR (100MHz, CDCl3) δ136.08,134.95,130.15,129.26,127.00,126.38,123.91,122.26,118.57,117.82,113.46,8.21,7.38.

[0072] The preparation method of 2e is similar to that of Example 1, except that cyclopropylmagnesium bromide is used as a Grignard reagent in the second step.

[0073] Example 6 1-Phenylacetyl-3-ethylthio-imidazo[1,5-a]pyridine (1f)

[0074]

[0075] Under nitrogen protection, in a 25 mL reaction flask, 122 mg (1 mmol) of diethyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5 mL of dichloromethane. Then, 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution. The mixture was stirred at room temperature for 2 hours, and the reaction solution turned red. Subsequently, 390 mg (2 mmol) of compound 2a was dissolved in 2 mL of dichloromethane to form a solution, which was added to the above reaction solution. The mixture was stirred for 1 hour, and the reaction was completed. 1 mmol of sodium ethoxide was added, and the reaction was quenched by stirring for another 2 hours, and the solution turned yellow. Water was added, and the organic phase was separated. The organic phase was washed twice with saturated brine, dried over anhydrous Na2SO4, and the solvent was recovered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 0.45 g of a pale yellow oil 1a, with a yield of 89%. 1 H NMR (400MHz, CDCl3) δ8.26(d,J=8.0Hz,1H),7.93(d,J=8.1Hz,2H),7.84(d,J=8.1Hz,1H), 7.48(t,J=6.7Hz,2H),7.33(d,J=8.0Hz,1H),6.88(t,J=6.7Hz,1H),6.15(t,J=6.5Hz,1H); 13 C NMR (100MHz, CDCl3) δ146.09,138.34,132.96,132.58,129.75,129.54,129.06,128.55,128.37,127.36,127.29,29.66,29.58.

[0076] Example 7: 1-Phenylacetyl-imidazo[1,5-a]quinoline (1g)

[0077]

[0078] Under nitrogen protection, in a 25 mL reaction flask, 218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5 mL of dichloromethane. Then, 32 mg (0.2 mmol) of TEMPO was added to the reaction solution. The mixture was stirred at room temperature for 2 hours, and the reaction solution turned red. Subsequently, 2 g of 490 mg (2 mmol) of the compound was dissolved in 2 mL of dichloromethane to form a solution, which was then added to the reaction solution. The mixture was stirred for 1 hour, and the reaction was complete. 1 mmol of sodium ethoxide was added, and the reaction was quenched by stirring for another 2 hours, turning the solution yellow. Water was added, and the organic phase was separated. The organic phase was washed twice with saturated brine, dried over anhydrous Na2SO4, and the solvent was recovered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 1 g of 0.59 g of yellow oil, with a yield of 85%.1 H NMR (400MHz, CDCl3) δ9.10(d,J=8.5Hz,1H),8.41–8.11(m,2H),7.96–7.79(m,3H),7.71–7.47(m,8H),7.37(t,J=7.3Hz,1H),7.10(d,J=9.6Hz,1H); 13 C NMR (100MHz, CDCl3) δ133.61,133.00,132.36,131.45,130.58,130.06,128.76,128.54,1 28.40,128.13,128.10,127.36,127.28,125.93,125.73,122.52,120.83,116.93,116.50

[0079] The preparation method of 2g is similar to that of Example 1, except that 2-aldehyde quinoline is used instead of 2-aldehyde pyridine in the first step.

[0080] Example 8: 1-Phenylacetyl-imidazo[1,5-a]isoquinoline (1h)

[0081]

[0082] Under nitrogen protection, in a 25 mL reaction flask, 218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5 mL of dichloromethane. Then, 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution. The mixture was stirred at room temperature for 2 hours, and the reaction solution turned red. Subsequently, 490 mg (2 mmol) of compound 2h (X = R1 = ) was dissolved in 2 mL of dichloromethane to form a solution, which was added to the above reaction solution. The mixture was stirred for 1 hour, and the reaction was completed. 1 mmol of sodium ethoxide was added, and the reaction was quenched by stirring for another 2 hours, and the solution turned yellow. Water was added, and the organic phase was separated. The organic phase was washed twice with saturated brine, dried over anhydrous Na2SO4, and the solvent was recovered. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 0.51 g of a yellow oily substance, with a yield of 72%. 1 H NMR (400MHz, CDCl3) δ8.17(d,J=8.1Hz,1H),8.07(d,J=7.4Hz,1H),7.82(d,J=7.1Hz,2H),7.62(d,J=7.8Hz,1H),7. 54(t,J=7.4Hz,2H),7.46(dd,J=16.1,7.5Hz,2H),7.38(d,J=7.1Hz,1H),7.27–7.18(m,5H),6.91(d,J=7.4Hz,1H). 3C NMR (100MHz, CDCl3) δ137.05,136.59,135.84,134.50,129.76,129.32,128.78,128.57,1 28.04,128.01,127.96,127.79,127.47,127.31,126.67,125.20,122.77,120.91,114.77.

[0083] The preparation method for 2h is similar to that in Example 1, except that 2-aldehyde isoquinoline is used instead of 2-aldehyde pyridine in the first step.

[0084] Comparison Example

[0085] The model reaction of NCS-activated diphenyl disulfide with α-phenyl-2-(isocyanomethyl)pyridine was explored using the conditions shown in Table 1, with different catalyst, oxidant ratio, and solvent. The results are shown in Table 1, and condition 3 was found to be optimal (Example 1), i.e., 1 mole of compound 2a, 0.2 moles of TEMPO, 2 moles of NCS, and 0.5 moles of disulfide, reacted at room temperature for 1 hour in dichloromethane as solvent, yielding the target product in 88% yield.

[0086]

[0087]

Claims

1. A method for preparing imidazohexa-azo compounds containing isothiourea fragments, characterized in that, The isothiourea fragment-containing imidazolide hexa-azo compound is shown in Formula 1; The steps include: compound 2 reacts with disulfide compound R3-SS-R3 in the presence of oxidant N-chlorosuccinimide and catalyst TEMPO to generate compound 1; the solvent used in the reaction is dichloromethane; Where X and Y are selected from C; R1 is H or a phenyl group; Alternatively, X and Y combine with R1 and the heterocycle in which it is located to form pyridyl, quinolinyl, or isoquinolinyl; R2 is selected from phenyl, pyridyl, 4-methoxy-phenyl, and 4-phenyl-phenyl; R3 is selected from phenyl or ethyl.

2. The preparation method according to claim 1, characterized in that, The molar ratio of compound 2 to disulfide compounds, catalysts and oxidants is 1:0.45-1:0.15-0.3:1.2-2.

5.

3. The preparation method according to claim 1, characterized in that, The preparation method of compound 2 is as follows: (1) Compound 7 reacts with tert-butylsulfinamide to form compound 6 through dehydration; (2) Compound 6 undergoes a nucleophilic addition reaction with Grignard reagent R2-MgBr to generate compound 5; (3) Compound 5 is hydrolyzed by acid to form compound 4; (4) Compound 4 reacts with formate to form compound 3; (5) Compound 3 is dehydrated to form compound 2; the dehydrating agent used is POCl3 or Burgess reagent.

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