CN113603687A - Novel method for synthesizing cyano-substituted imidazo [1,5-a ] pyridine - Google Patents

Novel method for synthesizing cyano-substituted imidazo [1,5-a ] pyridine Download PDF

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CN113603687A
CN113603687A CN202110882291.1A CN202110882291A CN113603687A CN 113603687 A CN113603687 A CN 113603687A CN 202110882291 A CN202110882291 A CN 202110882291A CN 113603687 A CN113603687 A CN 113603687A
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王会巧
徐坤
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Beijing University of Technology
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Abstract

Cyano-substituted imidazole [1,5-a ]]A novel method for synthesizing pyridine, which belongs to the field of chemical synthesis. In a dry reaction tube, NH was added4SCN, pyridine-2-carbaldehyde and amine, and then the reaction solvent was added to the reaction tube. Stirring the reaction system at room temperature for 5min, adding I2O5Then the reaction was further stirred under heating. After completion of the reaction, the reaction mixture was cooled to room temperature and saturated Na was added2S2O3The solution was quenched. The invention is a synthetic method which is simple in operation, low in cost, high in efficiency and green.

Description

Novel method for synthesizing cyano-substituted imidazo [1,5-a ] pyridine
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a novel method for synthesizing cyano-substituted imidazo [1,5-a ] pyridine.
Background
Cyano-substituted imidazo [1,5-a ] pyridines have a number of important biological activities and are commonly used as SSTR4 agonists, FGF inhibitors, and PI 3K-gamma inhibitors (references: US 2014171434A 1; WO 2014184275A 1; US 2008108648A 1). Therefore, the development of a novel method for synthesizing the high-efficiency cyano-substituted imidazo [1,5-a ] pyridine has important research significance and industrial application value. At present, the reported synthetic method needs to prepare cyano-substituted imidazo [1,5-a ] pyridine through multi-step reaction starting from functional imidazo [1,5-a ] pyridine. From the viewpoint of industrial applicability, the multi-step reaction results in a decrease in reaction yield, an increase in reaction cost, and further a decrease in the practicality of the reaction. Therefore, the synthesis of cyano-substituted imidazo [1,5-a ] pyridines via a one-step reaction is the most desirable synthetic strategy starting from readily available starting materials, but such a strategy has not been reported in the literature.
We have recently reported copper salt promoted three-component oxidation of 2-methylquinoline, Trimethylsilylcyanide (TMSCN) and alkylamines for the synthesis of cyano-substituted imidazo [1,5-a ] quinolines (ref: adv. Synth. Catal.2018,360, 4726). Subsequently, the Wanwangxiang Master group developed a similar three-component tandem cyclization reaction under electrochemical conditions (reference: org. Lett.,2019,21,6403) and was used to synthesize cyano-substituted imidazo [1,5-a ] quinolines. Although the above two methods can efficiently synthesize cyano-substituted imidazo [1,5-a ] quinolines, cyano-substituted imidazo [1,5-a ] pyridines cannot be prepared by the above two methods. In addition, the above method uses highly toxic TMSCN as a cyano source during the reaction, and thus strict precautions must be taken during the synthesis. Although the above method does not allow the preparation of cyano-substituted imidazo [1,5-a ] pyridines, the above studies inspire us as follows: through reasonable series reaction design, cyano-substituted imidazo [1,5-a ] pyridine can be synthesized with high efficiency.
The Strecker reaction takes aldehyde or ketone, amine, NaCN or TMSCN as reaction substrates, and is one of the most efficient synthesis methods of alpha-aminonitrile. Since the tandem reaction provides the most direct route to solving the problem of molecular diversity, the tandem reaction by means of the Strecker reaction will facilitate the synthesis of diversity-directed cyanide-functionalized molecules. The reference found that the alpha-aminonitrile obtained via the Strecker cascade further underwent intramolecular nucleophilic addition to form an amino-substituted heterocycle. No examples of the construction of cyano-substituted imidazo [1,5-a ] pyridines by the Strecker cascade reaction have been reported. In view of the high efficiency of the Strecker reaction for introducing cyano functionality, the development of a tandem process via the Strecker reaction and its use in the synthesis of cyano-substituted imidazo [1,5-a ] pyridines is of great research interest and industrial applicability, but this research is still a challenging task.
Since our interest in C-N bond formation under oxidative conditions continues, we envisage the synthesis of cyano-substituted imidazoles [1,5-a]and a pyridine. Through experimental exploration, the NH with low price and safety is discovered4SCN is a cyano-group source, 2-aldehyde pyridine and benzylamine are used as initial raw materials, and cyano-substituted imidazole [1,5-a ] can be efficiently synthesized by a one-pot method]And a pyridine. Synthesis of cyano-substituted imidazo [1,5-a ] with the previously reported use of virulent NaCN or TMSCN]Compared with the pyridine method, the method adopts safe and easy-to-operate NH4SCN is used as a cyano reagent, and no special protective measures are needed in the production process. Furthermore, the new synthetic strategy we have developed allows to rapidly obtain, starting from inexpensive and readily available industrial raw materials, a molecular diversity of cyano-substituted imidazo [1,5-a ] with important biological activities]A pyridine compound. Therefore, the new method developed by the people has wide application prospect.
The invention relates to a method for synthesizing cyano-substituted imidazole [1,5-a ] by using Strecker series reaction and starting from cheap and easily-obtained raw materials through a one-pot method]A novel method of pyridine, belonging to the chemical synthesis field. Cyano-substituted imidazoles [1,5-a ]]The bipyridine has many important biological activities, but the reported synthetic method requires multi-step synthetic steps and requires highly toxic sodium cyanide (NaCN) or Trimethylnitrilosilane (TMSCN) as a cyano source. Compared with the above synthetic method, the new method developed by us adopts cheap and safe NH4SCN is used as a cyano source to efficiently synthesize cyano-substituted imidazole [1,5-a ] through one-step reaction]And pyridine, and the strategy is not reported in the literature. Therefore, the new method developed by the people has the remarkable advantages of step economy, low cost and safe operation, accords with the era background of green production, and has stronger industrial application value.
Disclosure of Invention
In view of the important biological activity of cyano-substituted imidazo [1,5-a ] pyridine, the development of a high-efficiency synthetic method thereof has important application value. However, the current synthesis method has the following limitations: 1) a multi-step synthesis is required; 2) highly toxic NaCN or TMSCN needs to be used as a source of cyano groups. In order to solve the problems in the prior art, the invention aims to provide a novel chemical synthesis method which is simple to operate and low in cost, and is used for realizing efficient green synthesis of cyano-substituted imidazo [1,5-a ] pyridine compounds. The reaction route is as follows:
Figure BDA0003192801110000021
the technical route provided by the invention is as follows: in a dry reaction tube, NH was added4SCN, pyridine-2-carbaldehyde and amine, and then the reaction solvent was added to the reaction tube. The reaction system was stirred at room temperature, and I was added2O5Then the reaction is further stirred under heating conditions, e.g. 100 ℃. After completion of the reaction, the reaction mixture was cooled to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate and the organic phase was passed over anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the crude product is purified by column chromatography to give the desired product (formula I).
Figure BDA0003192801110000022
R1represents-H; an alkyl group; halogen; a cyano group; an alkoxy group; a benzene ring structure of a benzene structure is formed with the pyridine ring, such as one or more of quinoline structure and other groups, and the benzene structure can be provided with a substituent; r1Is mono-or polysubstituted.
R2Represents an alkyl group; an alkoxy group; a benzene ring; an alkyl-substituted benzene ring; a cyano-substituted benzene ring; a trifluoromethyl substituted phenyl ring; alkoxy-substituted benzene rings; functional groups such as thiophene ring, furan ring, thiazoie and substituted thiazoie
The number of moles of the amine (III) is 0.8 to 3 times, preferably 2 times the number of moles of the 2-aldehyde pyridine (II).
The solvent is dimethyl sulfoxide (DMSO) or N, N-Dimethylformamide (DMF) or a mixed solvent of DMSO and DMF. The solvent is preferably DMSO. Oxidizing agent I2O5The mole number of the 2-aldehyde pyridine (II) is 0.5 to 2 times of the mole number of the 2-aldehyde pyridine (II), and the mole number of the 2-aldehyde pyridine (II) is preferably 1 time. NH (NH)4Mole number of SCNIs 0.5 to 3 times, preferably 2 times of the mole number of the 2-aldehyde pyridine (II).
The above-mentioned preferred cyanide is NH4SCN。
The reaction temperature is 80-120 ℃. The reaction temperature is preferably 100 ℃.
Compared with the prior art, the method has the following remarkable beneficial effects:
(1) the invention synthesizes the compound shown in the formula I by one step from cheap and easily available raw materials. Whereas the prior art requires 2-4 synthesis steps. Therefore, the method has the remarkable advantages of economical steps and low cost.
(2) The invention adopts safe and cheap NH4SCN as the cyano source. The prior art needs to use highly toxic sodium cyanide (NaCN) and trimethylsilyl cyanide (TMSCN) as the cyanide source, and needs special protection measures. Therefore, the method has the obvious advantages of simple and convenient operation and safety.
Detailed Description
The present invention is further illustrated by, but is not limited to, the following examples.
Example 1: synthesis of 1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3-phenylimidazo [1,5-a ]]Pyridine. Yield: 95 percent.
Figure BDA0003192801110000031
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.35(dt,J＝7.2,1.1Hz,1H),7.78–7.70 (m,3H),7.59–7.50(m,3H),7.18–7.14(m,1H),6.85–6.81(m,1H).13C NMR(100MHz, Chloroform-d)δ140.1,137.7,130.0,129.3,128.5,128.4,124.5,122.9,117.4,115.3,114.8, 103.6.
example 2: synthesis of 1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and benzylamine (0.45mmol), followed by dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3-phenylimidazo [1,5-a ]]Pyridine. Yield: 73 percent.
Figure BDA0003192801110000041
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.35(dt,J＝7.2,1.1Hz,1H),7.78–7.70 (m,3H),7.59–7.50(m,3H),7.18–7.14(m,1H),6.85–6.81(m,1H).13C NMR(100MHz, Chloroform-d)δ140.1,137.7,130.0,129.3,128.5,128.4,124.5,122.9,117.4,115.3,114.8, 103.6.
example 3: synthesis of 1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.45mmol, 35mg), pyridine-2-carbaldehyde (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and further stirred at 100 deg.CThe mixture was stirred for 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3-phenylimidazo [1,5-a ]]Pyridine. Yield: and 69 percent.
Figure BDA0003192801110000042
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.35(dt,J＝7.2,1.1Hz,1H),7.78–7.70 (m,3H),7.59–7.50(m,3H),7.18–7.14(m,1H),6.85–6.81(m,1H).13C NMR(100MHz, Chloroform-d)δ140.1,137.7,130.0,129.3,128.5,128.4,124.5,122.9,117.4,115.3,114.8, 103.6.
example 4: synthesis of 1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.45mmol, 150mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3-phenylimidazo [1,5-a ]]Pyridine. Yield: 82 percent.
Figure BDA0003192801110000043
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.35(dt,J＝7.2,1.1Hz,1H),7.78–7.70 (m,3H),7.59–7.50(m,3H),7.18–7.14(m,1H),6.85–6.81(m,1H).13C NMR(100MHz, Chloroform-d)δ140.1,137.7,130.0,129.3,128.5,128.4,124.5,122.9,117.4,115.3,114.8, 103.6.
example 5: synthesis of 1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (6mmol, 460mg), pyridine-2-carbaldehyde (3mmol) and benzylamine (6mmol) then dimethyl sulfoxide (20mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(3mmol, 1000mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3-phenylimidazo [1,5-a ]]Pyridine. Yield: 90 percent.
Figure BDA0003192801110000051
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.35(dt,J＝7.2,1.1Hz,1H),7.78–7.70 (m,3H),7.59–7.50(m,3H),7.18–7.14(m,1H),6.85–6.81(m,1H).13C NMR(100MHz, Chloroform-d)δ140.1,137.7,130.0,129.3,128.5,128.4,124.5,122.9,117.4,115.3,114.8, 103.6.
example 6: synthesis of 8-fluoro-1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), 3-fluoropyridin-2-al (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. Then using acetic acid BThe reaction mixture was extracted with ester. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 8-fluoro-1-cyano-3-phenylimidazo [1,5-a ]]Pyridine. Yield: 81 percent.
Figure BDA0003192801110000052
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.17(dd,J＝6.6,1.0Hz,1H),7.77– 7.73(m,2H),7.60–7.54(m,3H),6.84–6.77(m,2H).13C NMR(100MHz,Chloroform-d)δ 152.9(1JCF＝256Hz),141.5,130.4,129.4,128.6,128.0,119.4(4JCF＝5Hz),114.7,114.5(3JCF＝ 7Hz),106.8(2JCF＝16Hz).
example 7: synthesis of 6-fluoro-1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), 5-fluoropyridin-2-al (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 6-fluoro-1-cyano-3-phenylimidazo [1,5-a]Pyridine. Yield: 92 percent.
Figure BDA0003192801110000061
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.28(dd,J＝4.5,1.9Hz,1H),7.75– 7.71(m,3H),7.60–7.53(m,3H),7.13–7.08(m,1H).13C NMR(100MHz,Chloroform-d)δ 154.6(1JCF＝244Hz),140.9,135.3,130.3,129.4,128.2,128.0,118.5(3JCF＝9Hz),117.8,117.5, 114.8,109.7,109.2,104.9.
example 8: synthesis of 5-fluoro-1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), 6-fluoropyridin-2-al (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 5-fluoro-1-cyano-3-phenylimidazo [1,5-a]Pyridine. Yield: 62 percent.
Figure BDA0003192801110000062
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ7.64(ddd,J＝7.9,3.8,2.0Hz,2H),7.57 –7.46(m,4H),7.19–7.14(m,1H),6.47(td,J＝7.0,0.9Hz,1H).13C NMR(100MHz, Chloroform-d)δ149.3(1JCF＝272Hz),140.0(JCF＝2Hz),138.7(JCF＝3Hz),129.89,129.87, 129.84,129.78,129.75,128.1,125.7(JCF＝5Hz),114.8,113.1(JCF＝6Hz),104.7,95.2,95.0.
example 9: synthesis of 6-chloro-1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), 5-chloropyridine-2-aldehyde (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. Reaction (TLC)) After completion, the reaction mixture was allowed to cool to room temperature and saturated Na was used2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 6-chloro-1-cyano-3-phenylimidazo [1,5-a]Pyridine. Yield: 98 percent.
Figure BDA0003192801110000071
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.36(t,J＝1.3Hz,1H),7.74–7.71(m, 2H),7.68(dd,J＝9.5,1.0Hz,1H),7.60–7.54(m,3H),7.11(dd,J＝9.6,1.6Hz,1H).13C NMR (100MHz,Chloroform-d)δ140.2,135.7,130.4,129.5,128.4,127.8,126.1,123.7,120.6,117.9, 114.7,104.8.
example 10: synthesis of 5-chloro-8-fluoro-1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), 3-fluoro-6-chloropyridine-2-aldehyde (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 5-chloro-8-fluoro-1-cyano-3-phenylimidazo [1,5-a ]]Pyridine. Yield: 87 percent.
Figure BDA0003192801110000072
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ7.53–7.43(m,5H),6.78(d,J＝6.5Hz, 2H).13C NMR(100MHz,Chloroform-d)δ151.6(J＝256Hz),142.7,131.4,131.1,130.2,129.9, 127.6,122.5(J＝5Hz),115.4(J＝7Hz),114.0,107.2(J＝18Hz),103.3(J＝4Hz).
example 11: synthesis of 6-bromo-1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), 5-bromopyridine-2-aldehyde (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 6-bromo-1-cyano-3-phenylimidazo [1,5-a ]]Pyridine. Yield: 85 percent.
Figure BDA0003192801110000073
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ7.53–7.43(m,5H),6.78(d,J＝6.5Hz, 2H).13C NMR(100MHz,Chloroform-d)δ151.6(J＝256Hz),142.7,131.4,131.1,130.2,129.9, 127.6,122.5(J＝5Hz),115.4(J＝7Hz),114.0,107.2(J＝18Hz),103.3(J＝4Hz).
example 12: synthesis of 5-bromo-1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), 6-bromopyridine-2-aldehyde (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. Then using BThe reaction mixture was extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 5-bromo-1-cyano-3-phenylimidazo [1,5-a ]]Pyridine. Yield: 78 percent.
Figure BDA0003192801110000081
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ7.76(dd,J＝8.9,1.2Hz,1H),7.53– 7.43(m,5H),7.08–6.98(m,2H).13C NMR(100MHz,Chloroform-d)δ141.9,139.7,131.5, 130.6,130.0,127.5,124.6,121.2,116.5,114.7,113.9,104.1.
example 13: synthesis of 6-methyl-1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), 5-methylpyridine-2-carboxaldehyde (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 6-methyl-1-cyano-3-phenylimidazo [1,5-a]Pyridine. Yield: 83 percent.
Figure BDA0003192801110000082
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.11(q,J＝1.3Hz,1H),7.74–7.71(m, 2H),7.62–7.50(m,4H),7.01(dd,J＝9.3,1.3Hz,1H),2.31(d,J＝1.2Hz,3H).13C NMR(100 MHz,Chloroform-d)δ139.5,136.8,129.9,129.2,128.6,128.5,128.1,124.9,120.1,116.6,115.6, 103.2,18.5.
example 14: synthesis of 5-methyl-1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), 6-methylpyridine-2-carboxaldehyde (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 5-methyl-1-cyano-3-phenylimidazo [1,5-a]Pyridine. Yield: 56 percent.
Figure BDA0003192801110000091
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ7.62(d,J＝9.0Hz,1H),7.52–7.45(m, 5H),7.07(dd,J＝9.1,6.6Hz,1H),6.54(d,J＝6.7Hz,1H),2.16(s,3H).13C NMR(100MHz, Chloroform-d)δ140.7,139.0,135.3,132.0,131.0,129.9,127.8,124.9,115.7,115.5,115.2,102.7, 21.7.
example 15: synthesis of 5-methoxy-1-cyano-3-phenylimidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), 6-methoxypyridine-2-aldehyde (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying, concentrating under reduced pressure to obtain crude residueAnd (5) slag. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 5-methoxy-1-cyano-3-phenylimidazo [1,5-a]Pyridine. Yield: 60 percent.
Figure BDA0003192801110000092
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ7.56–7.53(m,2H),7.44–7.32(m,4H), 7.14(dd,J＝8.9,7.3Hz,1H),6.01(dd,J＝7.3,0.8Hz,1H),3.84(s,3H).13C NMR(100MHz, Chloroform-d)δ150.4,139.9,139.7,131.9,130.4,128.9,127.2,126.5,115.6,108.9,103.0,89.9, 56.3.
example 16: synthesis of 3-cyano-1-phenylimidazo [1,5-a ] quinoline
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), quinoline-2-carbaldehyde (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 3-cyano-1-phenylimidazole [1,5-a ]]Quinoline. Yield: 98 percent.
Figure BDA0003192801110000101
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ7.76(dd,J＝7.9,1.5Hz,1H),7.64–7.52 (m,7H),7.47–7.42(m,2H),7.33–7.28(m,1H).13C NMR(100MHz,Chloroform-d)δ143.6, 137.1,132.1,132.0,130.4,129.7,129.4,129.2,129.0,127.0,126.5,125.2,117.5,115.0,114.8, 105.8.
example 17: synthesis of 1-cyano-3- (4-fluorophenyl) imidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and p-fluorobenzylamine (0.6mmol), followed by addition of dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3- (4-fluorophenyl) imidazo [1,5-a]Pyridine. Yield: 96 percent.
Figure BDA0003192801110000102
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.28(dt,J＝7.2,1.1Hz,1H),7.77– 7.72(m,3H),7.29–7.26(m,2H),7.19–7.15(m,1H),6.87–6.83(m,1H).13C NMR(100 MHz,Chloroform-d)δ163.5(1JCF＝253Hz),139.1,137.7,130.6(3JCF＝8Hz),124.7,124.5 (4JCF＝3Hz),122.7,117.5,116.6(2JCF＝22Hz),115.3,115.1,103.5.
example 18: synthesis of 1-cyano-3- (4-chlorophenyl) imidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and p-chlorobenzylamine (0.6mmol), followed by dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3- (4-chlorphenyl) imidazo [1,5-a]Pyridine. Yield: 98 percent.
Figure BDA0003192801110000111
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.31(dt,J＝7.2,1.1Hz,1H),7.77– 7.71(m,3H),7.57–7.53(m,2H),7.20–7.16(m,1H),6.88–6.85(m,1H).13C NMR(100MHz, Chloroform-d)δ138.9,137.8,136.2,129.7,129.6,126.8,124.7,122.7,117.6,115.2,115.2,103.8.
example 19: synthesis of 1-cyano-3- (2-bromophenyl) imidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and o-bromobenzylamine (0.6mmol), followed by addition of dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3- (2-bromophenyl) imidazo [1,5-a]Pyridine. Yield: 90 percent.
Figure BDA0003192801110000112
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ7.78–7.72(m,3H),7.57–7.45(m, 3H),7.23–7.19(m,1H),6.85(td,J＝6.9,1.2Hz,1H).13C NMR(100MHz,Chloroform-d)δ 138.7,137.1,133.5,133.4,132.1,129.6,128.1,124.9,124.0,123.7,117.1,115.3,114.5,103.0.
example 20: synthesis of 1-cyano-3- (3-bromophenyl) imidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and m-bromobenzylamine (0.6mmol), followed by addition of dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3- (3-bromophenyl) imidazo [1,5-a]Pyridine. Yield: 97 percent.
Figure BDA0003192801110000113
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.34(dt,J＝7.2,1.1Hz,1H),7.94(t,J ＝1.8Hz,1H),7.77–7.65(m,3H),7.44(t,J＝7.9Hz,1H),7.22–7.18(m,1H),6.91–6.87(m, 1H).13C NMR(100MHz,Chloroform-d)δ138.4,137.8,133.1,131.4,130.8,130.3,126.9,124.8, 123.4,122.8,117.6,115.3,115.1,103.90.
example 21: synthesis of 1-cyano-3- (4-bromophenyl) imidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and p-bromobenzylamine (0.6mmol), followed by addition of dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is rotatingConcentrate on evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3- (4-bromophenyl) imidazo [1,5-a]Pyridine. Yield: 97 percent.
Figure BDA0003192801110000121
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.31(dd,J＝7.2,1.1Hz,1H),7.75– 7.63(m,5H),7.20–7.16(m,1H),6.87(td,J＝6.9,1.2Hz,1H).13C NMR(100MHz, Chloroform-d)δ138.9,137.8,132.6,129.9,127.3,124.7,124.4,122.7,117.6,115.2,115.1,103.0.
example 22: synthesis of 1-cyano-3- (4-trifluoromethyl) imidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and 4-trifluoromethylbenzylamine (0.6mmol), followed by dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3- (4-trifluoromethyl) imidazo [1,5-a]Pyridine. Yield: 89 percent.
Figure BDA0003192801110000122
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.37(dt,J＝7.2,1.1Hz,1H),7.94– 7.92(m,2H),7.84–7.77(m,3H),7.24–7.20(m,1H),6.93–6.89(m,1H).13C NMR(100MHz, Chloroform-d)δ138.4,137.9,131.9,131.88,131.6,128.7,126.3(q,JCF3＝4Hz),125.0(d,J＝3.0 Hz),122.7,122.3,117.7,115.5(d,J＝3.0Hz),115.0(d,J＝4.0Hz).
example 23: synthesis of 1-cyano-3- (4-cyano) imidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and 4-cyanobenzylamine (0.6mmol), followed by addition of dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3- (4-cyano) imidazo [1,5-a]Pyridine. Yield: 89 percent.
Figure BDA0003192801110000131
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.38(dt,J＝7.2,1.1Hz,1H),7.96– 7.94(m,2H),7.87–7.85(m,2H),7.81–7.78(m,1H),7.27–7.23(m,1H),6.94(td,J＝6.9,1.2 Hz,1H).13C NMR(100MHz,DMSO-d6)δ138.5,138.4,133.5,132.9,129.5,127.2,125.0,118.9, 117.0,116.4,115.9,112.3,102.7.
example 24: synthesis of 1-cyano-3- (4-methoxy) imidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and 4-methoxybenzylamine (0.6mmol), followed by addition of dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, theThe organic phase was concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3- (4-methoxy) imidazo [1,5-a]Pyridine. Yield: 92 percent.
Figure BDA0003192801110000132
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.29(dt,J＝7.2,1.1Hz,1H),7.72– 7.66(m,3H),7.15–7.05(m,3H),6.82–6.79(m,1H),3.89(s,3H).13C NMR(100MHz, Chloroform-d)δ160.9,140.1,137.5,123.0,124.4,123.0,120.6,117.4,115.6,114.8,114.7,103.1, 55.5.
example 25: synthesis of 1-cyano-3- (4-methyl) imidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and 4-methylbenzylamine (0.6mmol), followed by addition of dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3- (4-methyl) imidazo [1,5-a]Pyridine. Yield: 68 percent.
Figure BDA0003192801110000141
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.33(dd,J＝7.3,1.1Hz,1H),7.73– 7.63(m,3H),7.36(d,J＝7.9Hz,2H),7.14(dd,J＝9.1,6.5Hz,1H),6.83–6.79(m,1H),2.45(s, 3H).13C NMR(100MHz,Chloroform-d)δ140.3,140.3,137.6,130.0,128.3,125.4,124.4,123.0, 117.4,115.5,114.7,103.3,21.5.
example 26: synthesis of 1-cyano-3- (benzo [ d ] [1,3] dioxan-5-yl) imidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and 3, 4-methylenedioxybenzylamine (0.6mmol), followed by dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3- (benzo [ d ]][1,3]Dioxa-5-yl) imidazo [1,5-a]Pyridine. Yield: 40 percent.
Figure BDA0003192801110000142
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.30(dt,J＝7.2,1.1Hz,1H),7.69(dt, J＝9.1,1.2Hz,1H),7.23–7.11(m,3H),6.96(d,J＝8.0Hz,1H),6.82(td,J＝7.0,1.2Hz,1H), 6.07(s,2H).13C NMR(100MHz,Chloroform-d)δ149.1,148.5,139.8,137.6,124.5,123.0, 122.6,121.9,117.4,115.5,114.8,109.0,108.9,103.1,101.8.
example 27: synthesis of 1-cyano-3- (thiophene-2-thio) imidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and 2-thiophenemethylamine (0.6mmol), followed by addition of dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying, concentrating under reduced pressure to obtainAnd (5) coarse residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3- ((thiophene-2-sulfur)) imidazo [1, 5-a)]Pyridine. Yield: and 55 percent.
Figure BDA0003192801110000151
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.46(dt,J＝7.2,1.1Hz,1H),7.72(dt,J ＝9.2,1.3Hz,1H),7.59(dd,J＝3.7,1.1Hz,1H),7.53(dd,J＝5.1,1.1Hz,1H),7.23–7.16(m,2H), 6.92(td,J＝6.9,1.2Hz,1H).13C NMR(100MHz,Chloroform-d)δ137.7,134.7,129.9,127.9, 127.9,126.94,124.6,123.2,117.4,115.4,115.1,103.7.
example 28: synthesis of 1-cyano-3- (furan-2-oxy) imidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and 2-furanmethanamine (0.6mmol), followed by addition of dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 1-cyano-3- (furan-2-oxygen) imidazo [1,5-a]Pyridine. Yield: 92 percent.
Figure BDA0003192801110000152
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.82(dt,J＝7.2,1.1Hz,1H),7.69(dt, J＝9.1,1.2Hz,1H),7.61(d,J＝1.7Hz,1H),7.19–7.15(m,1H),7.11(d,J＝3.5Hz,1H),6.91 (td,J＝7.0,1.2Hz,1H),6.62(dd,J＝3.5,1.8Hz,1H).13C NMR(100MHz,Chloroform-d)δ 144.6,143.1,137.2,131,9,124.8,124.6,117.1,115.3,115.1,112.1,110.8,103.7.
example 29: synthesis of 1-cyano-3- (2-chlorothiazol-5-yl) imidazo [1,5-a ] pyridine
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), pyridine-2-carbaldehyde (0.3mmol) and (2-methylthiazol-5-yl) methylamine (0.6mmol), followed by addition of dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator.
The crude product is purified by column chromatography to obtain 1-cyano-3- (2-chlorothiazole-5-yl) imidazo [1,5-a ] pyridine. Yield: 98 percent.
Figure BDA0003192801110000161
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ8.34(dt,J＝7.2,1.1Hz,1H),7.99(s, 1H),7.80(dt,J＝9.2,1.2Hz,1H),7.28(dd,J＝2.5,0.9Hz,1H),7.04(td,J＝6.9,1.2Hz,1H). 13C NMR(100MHz,DMSO-d6)δ151.9,139.99,138.3,131.2,129.3,127.3,125.6,117.0,116.8, 115.4,102.7.
example 30: synthesis of 3-cyano-1- (4- (trifluoromethyl) phenyl) imidazo [1,5-a ] quinoline
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), quinoline-2-carbaldehyde (0.3mmol) and 4-trifluoromethylbenzylamine (0.6mmol), followed by addition of dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 3-cyano-1- (4- (trifluoromethyl) phenyl) imidazo [1,5-a]Quinoline. Yield: 83 percent.
Figure BDA0003192801110000162
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ7.85–7.79(m,5H),7.60(d,J＝9.3 Hz,1H),7.53–7.48(m,3H),7.38(td,J＝7.8,1.6Hz,1H).13C NMR(100MHz,Chloroform-d) δ141.9,137.4,135.6,132.4,132.1,131.7,130.2,129.7,129.2,127.4,126.8,126.1(q,JCF3＝4 Hz),125.3,125.1,122.4,117.3,114.74,114.72,106.4.
example 31: synthesis of 3-cyano-1- (4- (methoxy) phenyl) imidazo [1,5-a ] quinoline
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), quinoline-2-carbaldehyde (0.3mmol) and 4-methoxybenzylamine (0.6mmol), followed by addition of dimethyl sulfoxide (2 mL). After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 3-cyano-1- (4- (methoxy) phenyl) imidazo [1,5-a]Quinoline. Yield: 90 percent.
Figure BDA0003192801110000171
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ7.75(dd,J＝7.8,1.6Hz,1H),7.62– 7.53(m,4H),7.47–7.40(m,2H),7.35–7.30(m,1H),7.09–7.06(m,2H),3.93(s,3H).13C NMR(100MHz,Chloroform-d)δ161.1,143.7,137.1,132.2,131.1,129.3,128.9,126.8,126.4, 125.2,124.1,117.4,115.2,114.8,114.5,105.6,55.5.HRMS(ESI):calcd for C19H14N3O[M+H]+ 300.1131,found 300.1129.
example 32: synthesis of 3-cyano-8-chloro-1-phenylimidazo [1,5-a ] quinoline
In a dry reactor, NH is added4SCN (0.6mmol, 46mg), 7-chloroquinoline-2-carbaldehyde (0.3mmol) and benzylamine (0.6mmol) then dimethyl sulfoxide (2mL) was added. After stirring the mixture at room temperature for 5min, I was added2O5(0.3mmol, 100mg) and the mixture was stirred at 100 ℃ for a further 5 h. After completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature and saturated Na was added2S2O3The solution was quenched. The reaction mixture was then extracted with ethyl acetate. The organic phase is passed through anhydrous Na2SO4Drying and concentrating under reduced pressure to obtain a crude residue. Finally, the organic phase is concentrated on a rotary evaporator. Purifying the crude product by column chromatography to obtain 3-cyano-8-chloro-1-phenylimidazo [1,5-a]Quinoline. Yield: and 55 percent.
Figure BDA0003192801110000172
Structural characterization data:1H NMR(400MHz,Chloroform-d)δ7.70–7.57(m,7H),7.48(d,J＝1.9 Hz,1H),7.43–7.38(m,2H).13C NMR(100MHz,DMSO-d6)δ143.9,137.2,133.5,132.5, 131.8,131.6,131.2,130.2,129.7,127.4,127.1,124.1,117.1,115.6,115.2,104.5。

Claims (6)

1. cyano-substituted imidazole [1,5-a ]]The new method for synthesizing the pyridine is characterized in that: pyridine-2-formaldehyde (II), amine (III) and NH are respectively added into a reaction tube4SCN (IV), then adding a reaction solvent into the reaction tube, stirring the mixture evenly at room temperature, and adding I2O5Then further stirring and reacting under the heating condition until the reaction is finishedAfter completion, the reaction mixture was cooled to room temperature and saturated Na was added2S2O3Quenching the solution to obtain cyano-substituted imidazole [1,5-a ]]And pyridine (I);
Figure FDA0003192801100000011
R1represents-H; an alkyl group; halogen; a cyano group; an alkoxy group; a benzene ring structure of a benzene structure is formed with the pyridine ring, such as one or more of quinoline structure and other groups, and the benzene structure can be provided with a substituent; r1Is mono-or poly-substituted;
R2represents an alkyl group; an alkoxy group; a benzene ring; an alkyl-substituted benzene ring; a cyano-substituted benzene ring; a trifluoromethyl substituted phenyl ring; alkoxy-substituted benzene rings; functional groups such as thiophene ring, furan ring, thiazoie and substituted thiazoie
2. The process according to claim 1, wherein the number of moles of amine (III) is 0.8 to 3 times, preferably 2 times the number of moles of 2-aldehyde pyridine (II).
3. The method according to claim 1, wherein the solvent is dimethyl sulfoxide (DMSO) or N, N-Dimethylformamide (DMF) or a mixed solvent of DMSO and DMF, and the solvent is preferably DMSO.
4. The method of claim 1 wherein said oxidizing agent is I2O5(ii) a The mole number of the oxidant is 0.5-2 times, preferably 1 time of that of the 2-aldehyde pyridine (II).
5. The method of claim 1, wherein NH4The number of moles of SCN is 0.5 to 3 times, preferably 2 times that of the 2-aldehyde pyridine (II).
6. The process according to claim 1, wherein the reaction temperature is 80 to 120 ℃, preferably 100 ℃.
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CN101160309A (en) * 2005-03-16 2008-04-09 赛诺菲-安万特 Novel imidazo [1, 5-a] pyridine derivatives, method for preparing same and pharmaceutical compositions containing same
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CN101160309A (en) * 2005-03-16 2008-04-09 赛诺菲-安万特 Novel imidazo [1, 5-a] pyridine derivatives, method for preparing same and pharmaceutical compositions containing same
CN103649093A (en) * 2011-05-06 2014-03-19 拜耳知识产权有限责任公司 Substituted imidazopyridines and imidazopyridazines and the use thereof

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