CN116751198A - Preparation method of imidazo six-membered aza compound containing isothiourea fragment - Google Patents

Preparation method of imidazo six-membered aza compound containing isothiourea fragment Download PDF

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CN116751198A
CN116751198A CN202310543203.4A CN202310543203A CN116751198A CN 116751198 A CN116751198 A CN 116751198A CN 202310543203 A CN202310543203 A CN 202310543203A CN 116751198 A CN116751198 A CN 116751198A
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substituted
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imidazo
phenyl
isothiourea
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孙智华
杨希辰
郑慧贇
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Shanghai University of Engineering Science
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention relates to the field of organic synthesis, and discloses a preparation method of an isothiourea fragment-containing imidazo six-membered aza compound serving as a medicine and an intermediate. The method takes nitrogen atom ortho-isocyano methyl substituted pyridine, pyrimidine, pyrazine, quinoline and other nitrogen-containing heteroaromatic rings as raw materials, and under the action of N-chlorosuccinimide (NCS) and a catalytic amount of TEMPO, the nitrogen-containing heteroaromatic rings react with various disulfide, and the intramolecular cyclization is carried out to form the isothiourea fragment-containing imidazo six-membered nitrogen heterocyclic compound. The method can realize one-step completion of intramolecular ring closure to form the imidazo [1,5a ] nitrogen-containing heteroaromatic ring containing isothiourea fragments, can construct various imidazo [1,5a ] nitrogen-containing heteroaromatic rings containing isothiourea fragments, has high yield and low raw material cost, can realize large-scale industrial production, and has market application prospect.

Description

Preparation method of imidazo six-membered aza compound containing isothiourea fragment
Technical Field
The invention relates to the field of organic synthesis, and relates to synthesis of medicines and intermediates, in particular to a synthesis method of an isothiourea fragment-containing imidazo six-membered aza compound.
Background
In recent years, the class of imidazohexabasic nitrogen heterocycles containing isothiourea fragments has been attracting attention due to their unique biological activity. They often have rich biological activities such as anti-inflammatory, antibacterial, anticancer, analgesic, etc. They have a deterring or promoting effect on a number of important target enzymes in humans, such as RORc inhibitors, JAK3 inhibitors, aldosterone synthase inhibitors and aldosterone synthase inhibitors. These active compounds containing cyclic isothiourea units are useful in the treatment of tumor metastasis and hyperproliferative diseases.
For example, compound a of WO2015036411A1 is an RORc inhibitor; compound B of WO2011117160A1 is a JAK3 inhibitor;
compound C of WO2009008992a is a TOR (rapamycin target) kinase inhibitor; compound D disclosed in WO2007064993A2 is a Protein Tyrosine Kinase (PTK) inhibitor; compound E disclosed in WO2005042537A1 is a p38 kinase inhibitor; the compound F disclosed in WO2004046145a is an aldosterone synthase inhibitor.
In the recent years, there have been few studies on the synthesis of isothiouronium-containing imidazo [1,5-a ] pyridine derivatives, as reported in org.lett.2022,24,3834 and j. Hepatolic chem.1980,17,1351, by reacting the corresponding amine compounds with isothiocyanate compounds to obtain isothiocyanamide-containing imidazo [1,5-a ] pyridine derivatives, which are then reacted with halogenated compounds to obtain the objective, the above-mentioned synthetic methods involve extremely toxic isothiocyanate compounds as raw materials with extremely low yields. Therefore, the synthesis of sulfur-containing imidazo [1,5-a ] pyridine derivatives such as cyclic isothiourea fragments of compound a or compound B is a relatively challenging problem.
For example, WO2015036411A1 shows that the synthesis of compound a involves a transition metal catalyzed coupling reaction, the synthesis costs are high, WO2011117160A1 shows that the yields of intermediates in each step of the synthesis of compound B are low, and WO2009008992A2 shows that the starting materials required for compound C are expensive.
Thus, there is a need to develop a versatile and efficient synthetic method to construct a variety of cyclic isothiourea fragments. The invention aims to develop a synthesis method of an imidazole six-membered nitrogen heterocyclic compound containing isothiourea fragments, which is based on a molecule containing isocyanic and nitrogenous nucleophilic centers and reacts with electrophilic sulfur centers (disulfide) in series, and the intramolecular cyclization is carried out.
Disclosure of Invention
The invention aims at providing a method for preparing an imidazo six-membered aza compound containing isothiourea fragments.
The structural general formula of the compound is as follows:
wherein X, Y is selected from C or N;
R 1 h, C1 is 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 an aryl-heteroaryl group;
alternatively, X and Y and R 1 And the heterocycles in which they are located are combined to form pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, quinolinyl, isoquinolinyl, substituted quinolinyl or substituted isoquinolinyl.
Preferably, X and Y are C, R 1 H, C1 is alkyl or substituted alkyl, C3-10 cycloalkyl or substituted cycloalkyl, phenyl, C1-C4 alkoxyphenyl; or X and Y combine with R1 and the heterocycle in which they are located to form quinolinyl or isoquinolinyl.
R 2 、R 3 Selected from H, C1-10 alkyl or substituted alkyl, C3-10 cycloalkyl or substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, aryl, and aryl heteroaryl.
Preferably, R 2 、R 3 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.
The invention takes nitrogen atom ortho-isocyano methyl substituted pyridine, pyrimidine, pyrazine, quinoline and other nitrogen-containing heteroaromatic rings as raw materials, and reacts with various disulfide compounds under the action of N-chlorosuccinimide (NCS) and a catalytic amount of TEMPO, and the intramolecular cyclization is carried out to form the imidazo six-membered nitrogen heterocyclic compound containing isothiourea fragments.
The preparation method comprises the following steps: compound 2 and disulfide compoundObject R 3 -S-S-R 3 -compound 1 is formed under the action of the oxidizing agent N-chlorosuccinimide (NCS) and the catalyst TEMPO.
The molar ratio of the compound 2 to the disulfide compound, the catalyst and the 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, 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.
The solvent used was Dichloromethane (DCM).
Specifically, disulfide compounds and an oxidant N-chlorosuccinimide are dissolved in a solvent, and a catalyst TEMPO is added for reaction for 1.5-6 hours; then, a solution of compound 2 was added thereto, and the reaction was continued for 1 to 6 hours.
And adding sodium alkoxide after the reaction is finished, continuously stirring and quenching the reaction, and washing, drying and purifying the organic phase. Preferably, the sodium alkoxide is sodium ethoxide or sodium methoxide.
In a preferred mode of the invention, the molar ratio of compound 2 to the disulfide compound, catalyst and oxidant is 1:0.5:0.2:2.
Compound 2 can be purchased commercially or prepared as follows. The synthetic route is as follows:
the preparation method of the compound 2 comprises the steps of starting from nitrogen atom ortho aldehyde substituted pyridine, pyrimidine, pyrazine, quinoline and other nitrogen-containing heteroaromatic rings (compound 7), carrying out dehydration reaction with tert-butylsulfinamide to obtain a compound 6, carrying out nucleophilic addition to obtain a compound 5, carrying out acid hydrolysis to obtain a compound 4, carrying out reaction with ethyl formate to obtain a compound 3, and finally carrying out POCl (physical oxidation reaction) on the compound 3 by using a dehydrating agent 3 Or Burgess reagent to give compound 2.
The method comprises the following specific steps:
(1) The compound 7 and tertiary butyl sulfinamide are dehydrated to generate a compound 6 under the catalysis of titanate; the mol ratio of the compound 2 to the tertiary butyl sulfinamide to the titanate is 1:1-1.6:1-1.6; the titanate is tetraisopropyl titanate;
(2) Compound 6 and Grignard reagent R 2 -MgBr nucleophilic addition reaction to produce compound 5; the molar ratio of compound 6 to grignard reagent is 1:2-3, preferably in a molar ratio of 1:2.5;
(3) Acid hydrolysis of compound 5 to produce compound 4; the acid is hydrochloric acid, and the reaction is carried out in alcohol;
(4) Compound 4 forms compound 3 with formate; preferably, the formate is ethyl formate;
(5) Dehydrating the compound 3 to form a compound 2; preferably, the dehydrating agent used is POCl 3 Or Burgess reagent.
By utilizing the reaction of isocyano and nucleophilic nitrogen in one molecule and in-situ activated disulfide, the intramolecular ring closure is completed to form imidazo [1,5a ] nitrogen-containing heteroaromatic ring containing isothiourea segment in one step, and the yield is 76-89%.
The method is a general synthesis method, can construct various imidazo [1,5a ] nitrogen-containing heteroaromatic rings containing isothiourea fragments, has high yield and low raw material cost, can realize large-scale industrial production, and has market application prospect.
Detailed Description
Example 1 1-phenyl-3-phenylsulfanyl-imidazo [1,5-a ] pyridine (1 a)
The first step: pyridine-2-methylamino-N-tert-butylsulfinamide (6 a)
In a 250mL reaction flask, 120mL of tetrahydrofuran was added, followed by 8.75 g (81.7 mmol) of 2-aldehyde pyridine, 14.9 g (123 mmol) of t-butylsulfinamide and 34.8 g (122 mmol) of tetraisopropyl titanate, and the reaction was terminated at 70℃overnight. 50mL of water and 50mL of acetic acidEthyl ester is added into the reaction liquid, and the organic phase and anhydrous Na are separated 2 SO 4 The solvent was dried and recovered, and 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 a yield of 81%. 1 H NMR(400MHz,CDCl 3 )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).
And a second step of: alpha-phenyl-pyridine-2-methyleneamino-N-t-butylsulfinamide (5 a)
Under the protection of nitrogen, 10mL of anhydrous tetrahydrofuran is added into a 50mL reaction bottle, then 2g (9.6 mmol) of compound 6a is added, the temperature is reduced to-70 ℃, 0.06mL (24 mmol) of bromobenzene format reagent is added dropwise, and the reaction is finished for 1 hour. 20mL of saturated ammonium chloride solution was added to the reaction solution, and stirring was continued for 20 minutes. 50mL of water and 50mL of ethyl acetate were added to the reaction solution, and the organic phase, anhydrous Na, was separated 2 SO 4 The solvent was dried and recovered, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=4/1) to give 2.08 g of a pale yellow oil 5a in 76% yield. 1 H NMR(400MHz,CDCl 3 )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).
And a third step of: alpha-phenyl-2-pyridinemethylamine (4 a)
In a 25mL reaction flask, 9mL of anhydrous methanol containing 20mmol of hydrogen chloride was added, followed by 1g (3.4 mmol) of compound 5a, and the reaction was completed at room temperature for 3 hours. Quenched with saturated sodium carbonate, extracted with 20mL of ethyl acetate, the organic phase separated, washed with saturated sodium carbonate, and dried over anhydrous Na 2 SO 4 Drying, recovering solvent, and collecting residueThe residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=3/1) to give 0.6 g of 4a as a yellow oil in 94% yield.
Fourth step: n- (alpha-phenyl-2-picolyl) carboxamide (3 a)
In a 50mL reaction flask, 1.84 g (10 mmol) of compound 4a was added to 10mL (123.7 mmol) of ethyl formate, and the reaction was refluxed overnight to terminate the reaction. Extracting with ethyl acetate, and collecting organic phase anhydrous Na 2 SO 4 The solvent was dried and 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 a yield of 81%.
Fifth step: alpha-phenyl-2- (isocyanomethyl) pyridine (2 a)
In a 50mL reaction flask, 20mL of methylene chloride was added, then 2.12 g (10 mmol) of Compound 3a was added, the temperature was lowered to-5℃and 2.38 g of Burgess reagent was dissolved in 5mL of methylene chloride, and the mixture was added dropwise to the reaction mixture to complete the reaction for 30 minutes. 20mL of methylene chloride was added to the reaction mixture to separate an organic phase and anhydrous Na 2 SO 4 The solvent was dried and recovered, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=8/1) to give 1.72 g of a yellow oil 2a in 88% yield. 1 H NMR(400MHz,CDCl 3 )δ8.17(s,1H),8.00–7.88(m,3H),7.82(d,J＝9.3Hz,1H),7.49(dd,J＝10.7,4.9Hz,2H),7.35–7.26(m,1H),6.78(ddd,J＝9.3,6.4,0.8Hz,1H),6.61–6.55(m,1H).
Sixth step: 1-phenyl-3-phenylsulfanyl-imidazo [1,5-a ] pyridine (1 a)
Under the protection of nitrogenIn a 25mL reaction flask, 218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5mL of methylene chloride, then 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution, and the reaction solution was stirred at room temperature for 2 hours, and then 390 mg (2 mmol) of compound 2a was dissolved in 2mL of methylene chloride to form a solution, which was added to the above reaction solution, and stirred for 1 hour, and the reaction was completed. 1mmol of sodium ethoxide was added and stirring was continued for 2 hours, the reaction was quenched and the solution turned yellow. Adding water, separating out organic phase, washing the organic phase with saturated saline solution for 2 times, anhydrous Na 2 SO 4 The solvent was dried and recovered, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/1) to give 0.53 g of yellow oil 1a in 88% yield. 1 H NMR(400MHz,CDCl 3 )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.
The following preparation methods for intermediates 2b-2h in examples 2-8 were prepared with reference to the methods for the relevant intermediates in example 1.
Example 2 1- (4-methoxyphenyl) -3-phenylsulfanyl-imidazo [1,5-a ] pyridine (1 b)
218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5mL of methylene chloride in a 25mL reaction flask under the protection of nitrogen, then 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution, the reaction solution was stirred at room temperature for 2 hours, and then 450 mg (2 mmol) of compound 2b was dissolved in 2mL of methylene chloride to form a solution, which was added to the above reaction solution, and stirred for 1 hour, and the reaction was completed. 1mmol of sodium ethoxide was added and stirring was continued for 2 hours, the reaction was quenched and the solution turned yellow. Adding water to separate out organic phase, and making organic phaseThe phases were washed with saturated brine for 2 times, anhydrous Na 2 SO 4 The solvent was dried and recovered, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/1) to give 0.55 g of pale yellow oily substance 1b in 83% yield. 1 H NMR(400MHz,CDCl 3 )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,2H),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,CDCl 3 )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.
2b was prepared in a similar manner to example 1, using 4-methoxyphenylmagnesium bromide as grignard reagent in the second step.
Example 3 1- (3-pyridinyl) -3-phenylthio-imidazo [1,5-a ] pyridine (1 c)
218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5mL of methylene chloride in a 25mL reaction flask under the protection of nitrogen, then 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution, the reaction solution was stirred at room temperature for 2 hours, and then 392 mg (2 mmol) of compound 2c was dissolved in 2mL of methylene chloride to form a solution, which was added to the above reaction solution, and stirred for 1 hour, and the reaction was completed. 1mmol of sodium ethoxide was added and stirring was continued for 2 hours, the reaction was quenched and the solution turned yellow. Adding water, separating out organic phase, washing the organic phase with saturated saline solution for 2 times, anhydrous Na 2 SO 4 The solvent was dried and recovered, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=30/1) to give 0.46 g of brown oil 1c in 76% yield. 1 H NMR(400MHz,CDCl 3 )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.
2c was prepared in a similar manner to example 1, the second step using 3-pyridylmagnesium bromide as grignard reagent.
Example 4 1- (4- [1,1' -Biphenyl ]) -3-phenylsulfanyl-imidazo [1,5-a ] pyridine (1 d)
218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5mL of methylene chloride in a 25mL reaction flask under the protection of nitrogen, then 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution, the reaction solution was stirred at room temperature for 2 hours, and then 542 mg (2 mmol) of compound 2d was dissolved in 2mL of methylene chloride to form a solution, which was added to the above reaction solution, and stirred for 1 hour, and the reaction was completed. 1mmol of sodium methoxide was added and stirring was continued for 2 hours, the reaction was quenched and the solution turned yellow. Adding water, separating out organic phase, washing the organic phase with saturated saline solution for 2 times, anhydrous Na 2 SO 4 The solvent was dried and recovered, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=30/1) to give 0.65 g of a yellow oil 1d in 86% yield. 1 H NMR(400MHz,CDCl 3 )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)δ140.77,139.42,133.24,130.51,128.80,127.77,127.45,127.24,126.95,126.68,121.95,126.68,121.95,121.03,119.92,118.88,113.67.
The preparation of 2d was similar to that of example 1, the second step using 4- [1,1' -biphenyl ] magnesium bromide as grignard reagent.
Example 5 1-cyclopropyl-3-thiophenyl-imidazo [1,5-a ] pyridine (1 e)
218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5mL of methylene chloride in a 25mL reaction flask under the protection of nitrogen, then 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution, the reaction solution was stirred at room temperature for 2 hours, and then 318 mg (2 mmol) of compound 2e was dissolved in 2mL of methylene chloride to form a solution, which was added to the above reaction solution, and stirred for 1 hour, and the reaction was completed. 1mmol of sodium ethoxide was added and stirring was continued for 2 hours, the reaction was quenched and the solution turned yellow. Adding water, separating out organic phase, washing the organic phase with saturated saline solution for 2 times, anhydrous Na 2 SO 4 The solvent was dried and recovered, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/1) to give 0.43 g of yellow oil 1e in 82% yield. 1 H NMR(400MHz,CDCl 3 )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.
2e was prepared in a similar manner to example 1, the second step using cyclopropyl magnesium bromide as grignard reagent.
Example 6 1-phenyl-3-ethylsulfanyl-imidazo [1,5-a ] pyridine (1 f)
122 mg (1 mmol) of diethyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5mL of methylene chloride in a 25mL reaction flask under the protection of nitrogen, then 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution, the reaction solution was stirred at room temperature for 2 hours, and then 390 mg (2 mmol) of compound 2a was dissolved in 2mL of methylene chloride to form a solution, which was added to the above reaction solution, and stirred for 1 hour, and the reaction was completed. 1mmol of sodium ethoxide was added and stirring was continued for 2 hours, the reaction was quenched and the solution turned yellow. Adding water, separatingThe organic phase was washed with saturated brine 2 times, and anhydrous Na 2 SO 4 The solvent was dried and recovered, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/1) to give 0.45 g of pale yellow oily substance 1a in 89% yield. 1 H NMR(400MHz,CDCl 3 )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,CDCl 3 )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.
Example 7 1-phenyl-3-phenylsulfanyl-imidazo [1,5-a ] quinoline (1 g)
218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5mL of methylene chloride in a 25mL reaction flask under the protection of nitrogen, then 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution, the reaction solution was stirred at room temperature for 2 hours, the reaction solution was turned red, and then 490 mg (2 mmol) of compound 2g was dissolved in 2mL of methylene chloride to form a solution, which was added to the above reaction solution, and the reaction was completed after stirring for 1 hour. 1mmol of sodium ethoxide was added and stirring was continued for 2 hours, the reaction was quenched and the solution turned yellow. Adding water, separating out organic phase, washing the organic phase with saturated saline solution for 2 times, anhydrous Na 2 SO 4 The solvent was dried and recovered, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/1) to give 0.59 g of a yellow oil 1g in 85% yield. 1 H NMR(400MHz,CDCl 3 )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)δ133.61,133.00,132.36,131.45,130.58,130.06,128.76,128.54,128.40,128.13,128.10,127.36,127.28,125.93,125.73,122.52,120.83,116.93,116.50
2g of the compound were prepared in a similar manner to example 1, using 2-aldehyde quinoline instead of 2-aldehyde pyridine in the first step.
Example 8 1-phenyl-3-phenylsulfanyl-imidazo [1,5-a ] isoquinoline (1 h)
In a 25mL reaction flask under nitrogen protection, 218 mg (1 mmol) of diphenyl disulfide and 266 mg (2 mmol) of NCS were dissolved in 5mL of methylene chloride, then 32 mg (0.2 mmol) of TEMPO was added to the above reaction solution, stirred at room temperature for 2 hours, the reaction solution was turned red, then 490 mg (2 mmol) of compound was 2h (X=R1=dissolved in 2mL of methylene chloride to form a solution, it was added to the above reaction solution, stirred for 1 hour, the reaction was ended, 1mmol of sodium ethoxide was added, stirring was continued for 2 hours, the reaction was quenched, the solution was turned yellow, water was added, an organic phase was separated, and the organic phase was washed with saturated brine for 2 times, anhydrous Na 2 SO 4 The solvent was dried and recovered, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/1) to give 0.51 g of a yellow oil for 1h in 72% yield. 1 H NMR(400MHz,CDCl 3 )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). 3 C NMR(100MHz,CDCl3)δ137.05,136.59,135.84,134.50,129.76,129.32,128.78,128.57,128.04,128.01,127.96,127.79,127.47,127.31,126.67,125.20,122.77,120.91,114.77.
The preparation for 2h is similar to example 1, the first step being to use 2-aldehydoisoquinoline instead of 2-aldehydylpyridine.
Comparative example
The conditions shown in table 1 were used to explore the model reaction of NCS-activated diphenyl disulfide with α -phenyl-2- (isocyanatomethyl) pyridine, with different catalysts, oxidant dosing ratios, and solvents. As a result, as shown in Table 1, it was found that condition 3 was optimal (example 1), namely, 1 molar amount of compound 2a, 0.2 molar amount of TEMPO, 2 molar amount of NCS, 0.5 molar amount of disulfide, and methylene chloride as a solvent were reacted at room temperature for 1 hour to obtain the objective product in 88% yield.

Claims (6)

1. The preparation method of the imidazo six-membered aza compound containing the isothiourea fragment is characterized in that the imidazo six-membered aza compound containing the isothiourea fragment is shown as a formula 1;
the method comprises the following steps: compound 2 and disulfide compound R 3 -S-S-R 3 Under the action of an oxidant N-chlorosuccinimide and a catalyst TEMPO, a compound shown in a formula 1 is generated;
wherein X, Y is selected from C or N;
R 1 h, C1 is 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 an aryl-heteroaryl group;
alternatively, X and Y and R 1 And the heterocycles in which they are located are combined to form pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, quinolinyl, isoquinolinyl, substituted quinolinyl, or substituted isoquinolinyl;
R 2 、R 3 selected from H, C1-10 alkyl or substituted alkyl, C3-10 cycloalkyl or substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, aryl, and aryl heteroaryl.
2. The preparation method according to claim 1, wherein the molar ratio of the compound 2 to the disulfide compound, the catalyst and the oxidant is 1:0.45-1:0.15-0.3:1.2-2.5.
3. The process of claim 1, wherein the solvent used in the reaction is methylene chloride.
4. The process of claim 1 wherein X and Y are C and R 1 H, C1 is alkyl or substituted alkyl, C3-10 cycloalkyl or substituted cycloalkyl, phenyl, C1-C4 alkoxyphenyl; or X and Y combine with R1 and the heterocycle in which they are located to form quinolinyl or isoquinolinyl.
5. The process of claim 1, wherein R is 2 、R 3 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.
6. The preparation method according to claim 1, wherein the preparation method of the compound 2 is as follows:
(1) The compound 7 is dehydrated with tertiary butyl sulfinamide to generate a compound 6;
(2) Compound 6 and Grignard reagent R 2 -MgBr nucleophilic addition reaction to produce compound 5;
(3) Acid hydrolysis of compound 5 to produce compound 4;
(4) Compound 4 forms compound 3 with formate;
(5) Dehydrating the compound 3 to form a compound 2; the dehydrating agent is POCl 3 Or Burgess reagent.
CN202310543203.4A 2023-05-15 2023-05-15 Preparation method of imidazo six-membered aza compound containing isothiourea fragment Pending CN116751198A (en)

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