CN108003156B - Synthesis method of imidazopyridyl 1, 2-ethanedione derivative - Google Patents
Synthesis method of imidazopyridyl 1, 2-ethanedione derivative Download PDFInfo
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- 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 aims to solve the problems of complex reaction conditions and complex method existing in the synthesis method of imidazopyridyl 1, 2-ethanedione in the prior art, and provides a synthesis method of imidazopyridyl 1, 2-ethanedione derivatives, in particular to imidazo [1,2-a ]]A method for synthesizing reactants without substituent groups at 2 and 3 positions of pyridine, belonging to the technical field of organic compound synthesis. The process uses R1，R2-substituted imidazo [1,2-a]Pyridine and R3The substituted benzoyl formaldehyde hydrate is taken as raw material, and the bis-carbonylation reaction is carried out for 6 to 10 hours at the temperature of between 60 and 130 ℃ to obtain the product 1- (3-imidazo [1,2-a ]]Pyridyl) -2-aryl-1, 2-ethanedione derivatives. The invention adopts cheap and easily obtained organic acid promoter to directly carry out the double carbonylation reaction, and the system does not need to add ligand, extra additive and the like, and has mild reaction condition and high yield.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a synthesis method of an imidazopyridyl 1, 2-ethanedione derivative.
Background
The nitrogen heterocycles in heterocyclic compounds are widely present in a variety of alkaloids, with imidazole and pyridine being the most typical five-and six-membered heterocycles in nitrogen-containing heterocycles, found in a variety of natural products and exhibiting a wide range of pharmacological activities. The azabicyclic compounds imidazo [1,2-a ] pyridines fused from imidazoles and pyridines are widely used, in addition to their respective properties, in material chemistry (j.s.bae et al, PCT int.appl wo2007011163a1,2007) and medicinal chemistry (g.c.moraski et al, bioorg.med.chem.lett., 2003,13,347), among which the few marketed Drugs, such as the hypnotic Zolpidem (t.s.harrison et al, CNS Drugs,2005,19,65), the vasodilator Olprinone (c.enquehard-guieier et al, Mini-rev.med.chem.2007, 7,888), the anti-ulcer Drugs soraprzan and Zolimidine (a.r. katroky chey, j.68, red, chem.2007, 7,888), the anti-ulcer Drugs soraprazazan and Zolinamide (a.r. katsyzym, J.68, orv. chem., 1990, biochem, bionical.46, and biochem. Therefore, the synthesis and functionalization of imidazo [1,2-a ] pyridine compounds has received a great deal of attention from organic chemists and pharmacologists.
In addition, the 1, 2-dicarbonyl compounds have important applications not only in photosensitizing agents (Matsuschita Electric Industrial Co. ltd. JP Pat. No., 56098203, 1981), corrosion inhibitors (B.I.Ita. et al., Mater. chem. Phys., 2001, 70, 330), and optical stimulators (B.Hus. r et al. J.Phys. chem. B, 2006, 110, 5315), but also in natural products and pharmaceuticals (G.W.Gordonet. et al, J.org.chem., 1992, 57, 3636; W.Yan, PNAS, 111, 38; K.C.Nicolaou. et al., J.chem.chem.Soc., 2004, 126, B.M.Yng.J.18138; K.C.Nicolaou. et al., J.am. chem.SO. J.42, 126, 9, B.M.Yng.J.13, Wolk.Wolk.Wolk.Wolk.Wolk.E.J.Wolk.Wolk.E.E.Wolk.E.7, Wolk.E.Wolk.7, Wolk.7, Wolk.E.7, Wolk.7, Wolk.E.E.7, Wolk.E.E.J.Wolk.7, Wolk.7, Wolk.E.E.E.E.E.Wolk.Wolk.E.J.Wolk.7, Wolk.E.E.E.E.7, Wolk.Wolk.Wolk.Wolk.E., 2010, 12, 5204).
Therefore, the synthesis of imidazopyridinyl 1, 2-ethanedione derivatives is of great importance for the subsequent construction of biologically active and functional compounds.
The prior method for synthesizing the imidazopyridyl 1, 2-ethanedione compound comprises the following steps of firstly, carrying out oxidative dehydrogenation coupling on 2-phenylimidazo [1,2-a ] pyridine and phenylacetaldehyde by adopting copper catalysis to synthesize the imidazopyridyl 1, 2-ethanedione (S.M.A. Shakoor et al, Tetrahedron, 2016, 72 and 645), wherein the reaction equation is as follows:
secondly, methyl ketone is adopted as a carbonylation reagent, and the process I22-Arylimidazo [1,2-a ] promoted with/DMSO/PTSA (p-toluenesulfonic acid)]Direct dicarbonylation of the C-H bond of pyridine to imidazopyridyl 1, 2-ethanedione (M. Chennapuram et al, RSC adv, 2015, 5, 19418) is only applicable to imidazo [1,2-a ]]The substrate having the 2-position of pyridine substituted by phenyl group is shown in the following equation.
Thirdly, copper is adopted to catalyze imidazo [1,2-a ]]The imidazopyridyl-1, 2-ethanedione is synthesized by the double carbonylation of pyridine and methyl ketone, the reaction can be smoothly carried out under the condition that oxygen is taken as an oxidant at 140 ℃ and the reaction is carried out under the airtight condition and the oxygen is generated in imidazo [1,2-a ]]The 3-position of pyridine, the applicability of the substrate is examined and found that when aryl ketone contains sensitive groups such as OH and NH2In this case, the reaction was not smooth (s.lei et al, adv.synth.cat., 2016, 358, 67), and the equation is as follows.
For the synthesis of imidazopyridinyl 1, 2-ethanedione, the synthesis is still limited and there are intractable reagents such as I2The use of the ligand, the addition of the ligand, a closed system, long reaction time and the like. Therefore, it is important to develop a more inexpensive and efficient method for synthesizing imidazopyridinyl 1, 2-ethanedione compounds.
Disclosure of Invention
The invention aims to solve the problems of complex reaction conditions and complex method existing in the synthesis method of imidazopyridyl 1, 2-ethanedione in the prior art, and provides a synthesis method of imidazopyridyl 1, 2-ethanedione derivatives, in particular to imidazo [1,2-a ]]A method for synthesizing a reactant without substituent groups at 2 and 3 positions of pyridine. The method adopts cheap and easily-obtained organic acid promoter, and dicarbonyl reagent is directly reacted with R1，R2-substituted imidazo [1,2-a]Pyridine is subjected to the double carbonylation reaction, a ligand, an additional additive and the like are not required to be added into the system, the reaction condition is mild, and the yield is high.
A method for synthesizing imidazopyridyl 1, 2-ethanedione derivatives comprises the following steps:
a. with R1，R2-substituted imidazo [1,2-a]Pyridine (II) and R3The substituted benzoyl formaldehyde hydrate (III) is taken as a raw material, and the bis-carbonylation reaction is carried out for 6 to 10 hours at the temperature of between 60 and 130 ℃ to obtain the product 1- (3-imidazo [1, 2-a)]Pyridyl) -2-aryl-1, 2-ethanedione (I) derivative reaction liquid; the reaction formula (1) is:
further, an organic acid promoter is added before the double carbonylation reaction;
in the reaction formula, R1Represents any one of hydrogen and alkyl, and R1Single site substitution or multi-site substitution; wherein the alkyl is methyl, ethyl, propyl, isopropyl, etc.;
R2represents any one of a phenyl group and a substituted phenyl group; wherein the phenyl containing the substituent is substituted at the 4-position; further, the phenyl containing the substituent is 4-fluorophenyl, 4-bromophenyl, 4-chlorophenyl or 4-nitrophenyl;
R3represents any one of hydrogen, trifluoromethyl, nitro, ester group, methyl, methoxy, hydroxyl and halogen, and R3Single site substitution or multi-site substitution; wherein, the halogen is any one of fluorine, chlorine, bromine and iodine;
said R1，R2-substituted imidazo [1,2-a]Pyridine and R3-the molar ratio of the charge of the substituted benzaldehyde hydrate is 1: 1.0-1.5;
the organic solvent is toluene or benzene;
the organic solvent and R1，R2-substituted imidazo [1,2-a]The ratio of pyridine is 7-15: 1L/mol;
the promoter and R1，R2-substituted imidazo [1,2-a]The ratio of pyridine is 0.6-4: 1L/mol;
the accelerant is glacial acetic acid;
b. purifying the reaction liquid of the 1- (3-imidazo [1,2-a ] pyridyl) -2-aryl-1, 2-ethanedione derivative to obtain a target product;
wherein, the purification method of the target product comprises the following steps:
1) cooling the reaction liquid to room temperature, adding ethyl acetate and water into the reaction liquid, extracting a water phase by using ethyl acetate, collecting an organic layer, washing the organic layer by using saturated saline solution, drying the organic layer by using anhydrous sodium sulfate, filtering the organic layer, collecting filtrate, adding silica gel, and performing rotary evaporation to obtain a crude product;
2) and separating and purifying the crude product by silica gel column chromatography, wherein the eluent is petroleum ether and ethyl acetate to obtain the target product.
Compared with the prior art of the same type, the invention has the following remarkable beneficial effects:
the synthesis method of the imidazopyridyl 1, 2-ethanedione derivative provided by the invention is a new synthesis method, and adopts cheap and easily-obtained organic acid promoter R2-substituted benzoyl formaldehyde hydrate as dicarbonylating agent directly with R1，R2-substituted imidazo [1,2-a]Pyridine is subjected to double carbonylation reaction, and a system does not need to add a ligand, an additional additive and the likeThe reaction condition is mild, the yield is high, and a new method guide is provided for the synthesis of the compounds.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to be limiting in any way.
Examples 1 to 23: synthesis of imidazopyridinyl 1, 2-ethanedione
Adding 0.5mmol of imidazo [1,2-a ] pyridine, 0.5mmol of 59.1mg of 4-bromobenzoyl formaldehyde hydrate, 115.5mg of the imidazole and an accelerator into a 25mL two-necked bottle provided with a magnetic stirrer, heating to a target temperature for reaction for 6-10 h, tracking the reaction through thin-layer chromatography, cooling the reaction liquid to room temperature after the raw materials are completely consumed, adding ethyl acetate and water into the reaction liquid, and extracting the water phase with ethyl acetate. Collecting organic layer, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, collecting filtrate, adding silica gel, rotary evaporating, separating and purifying the crude product by silica gel column chromatography, eluting with petroleum ether and ethyl acetate to obtain target product, vacuum drying, weighing, and calculating separation yield as shown in table 1 below:
TABLE 1 results of Synthesis of imidazopyridinyl 1, 2-ethanedione under different conditions
Note: PdCl in the tables2、Pd(OAc)2、Cu(OAc)2·H2The Chinese names of O, CuBr and CuI are respectively palladium chloride, palladium acetate, copper acetate monohydrate, cuprous bromide and cuprous iodide; toluene, Benzene, Dioxane, HOAc, MeCN, DMSO, EtOH, TFA, HCOOH, CH3CH2The Chinese names of COOH are toluene, benzene, dioxane, glacial acetic acid, acetonitrile, dimethyl sulfoxide, ethanol, trifluoroacetic acid, formic acid and propionic acid respectively.
Examples 24 to 44:
r is to be1，R2-substituted imidazo [1,2-a]Pyridine 0.5mmol, R20.5mmol of-substituted benzoyl formaldehyde hydrate,Glacial acetic acid 0.5mL and toluene 4mL are added into a 25mL two-mouth bottle with a magnetic stirrer, the reaction temperature is 100 ℃, and the double carbonylation reaction is carried out for 6-12 hours. Other operation methods and steps are the same as those of examples 1 to 23, and the specific contents are shown in Table 2:
TABLE 2 Structure and yield of different products
The structural characterization data for the product obtained in example 1 are:
Yellow solid,m.p.:215.8-217.2℃.1H NMR(500MHz,DMSO-d6):δ9.62(d, J＝6.5Hz,1H),8.48(d,J＝1.5Hz,1H),7.99(dd,J＝9.0,2.0Hz,3H),7.85-7.83(m,3H), 7.48(dd,J＝7.0,6.5Hz,1H)；13C NMR(125MHz,DMSO-d6)δ190.58,180.12, 149.33,147.33,132.05,131.86,131.57,131.50,129.18,128.85,120.86,117.55,116.62. HRMS(ESI)for C15H9N2O2NaBr([M+Na]+):calcd 350.9745,352.9725,found 350.9738,352.9710.
the structural characterization data for the product obtained in example 24 are:
Yellow solid,m.p.:182.8-183.6℃.1H NMR(500MHz,DMSO-d6):δ9.62(dd, J＝5.5,1.0Hz,1H),8.48(d,J＝2.0Hz,1H),8.09-8.07(m,2H),7.99(d,J＝8.5Hz,1H), 7.84(dd,J＝8.5,7.0Hz,1H),7.71-7.69(m,2H),7.49-7.47(m,1H)；13C NMR(125 MHz,DMSO-d6)δ190.36,180.15,149.33,147.32,139.82,131.85,131.56,131.18, 129.09,128.85,120.86,117.55,116.61.HRMS(ESI)for C15H9N2O2NaCl([M+Na]+): calcd 307.0250,309.0221,found 307.0241,309.0214.
the structural characterization data for the product obtained in example 25 are:
Yellow solid,m.p.:167.3-167.6℃.1H NMR(500MHz,DMSO-d6):δ9.62(d, J＝6.5Hz,1H),8.46(s,1H),8.17-8.14(m,2H),7.97(d,J＝9.0Hz,1H),7.85-7.82(m, 1H),7.49-7.44(m,3H)；13C NMR(125MHz,DMSO-d6)δ190.06,180.49,165.83(d, J＝252.5Hz),149.30,147.21,133.22(d,J＝8.75Hz),131.51,129.22(d,J＝2.5Hz), 128.84,120.89,117.54,116.57,116.17(d,J＝22.5Hz).HRMS(ESI)for C15H9N2O2NaF ([M+Na]+):calcd 291.0546,found 291.0523.
the structural characterization data for the product obtained in example 26 are:
Yellow solid,m.p.:138.4-138.8℃.1H NMR(500MHz,DMSO-d6):δ9.61(d, J＝7.0Hz,1H),8.46(s,1H),8.02(d,J＝8.0Hz,3H),7.80(d,J＝7.5Hz,2H),7.70(d, J＝8.0Hz,1H),7.47(d,J＝7.0,7.0Hz,1H)；13C NMR(125MHz,DMSO-d6)δ191.00, 180.23,149.31,147.28,131.74,131.56,131.41,130.73,128.84,120.85,117.55,116.62, 104.22.HRMS(ESI)for C15H9N2O2NaI([M+Na]+):calcd 398.9606,found 398.9615.
the structural characterization data for the product obtained in example 27 are:
Yellow solid,m.p.:142.7-144.1℃.1H NMR(500MHz,DMSO-d6):δ9.63(d, J＝6.5Hz,1H),8.55(s,1H),8.26(d,J＝7.5Hz,2H),8.01-7.98(m,3H),7.85(d,J＝8.5, 8.0Hz,1H),7.49(d,J＝7.0,6.5Hz,1H)；13C NMR(125MHz,DMSO-d6)δ190.36, 179.40,149.38,147.58,135.80,133.58(d,J＝3.25Hz),131.67,130.84,130.00,129.92, 128.89,125.77(q,J＝3.75Hz),120.84,117.34(d,J＝111.25Hz).HRMS(ESI)for C16H9N2O2NaF3([M+Na]+):calcd 341.0514,found 341.0528.
the structural characterization data for the product obtained in example 28 are:
Yellow solid,m.p.:219.4-212.0℃.1H NMR(500MHz,DMSO-d6):δ9.62(d, J＝7.0Hz,1H),8.48(d,J＝2.5Hz,1H),7.99(dd,J＝8.0,2.5Hz,3H),7.86-7.82(m,3H), 7.48(d,J＝7.0,6.5Hz,1H)；13C NMR(125MHz,DMSO-d6)δ190.58,180.11,149.33, 147.33,132.05,131.86,131.57,131.50,129.18,128.85,120.85,117.55,116.62.HRMS (ESI)for C15H9N3O4Na([M+Na]+):calcd 318.0491,found 318.0498.
the structural characterization data for the product obtained in example 29 are:
Yellow solid,m.p.:168.8-167.9℃.1H NMR(500MHz,DMSO-d6):δ9.63(dd, J＝7.0,1.5Hz,1H),8.52(d,J＝1.5Hz,1H),8.18(d,J＝7.5Hz,2H),8.15(d,J＝8.5Hz, 2H),7.80(d,J＝8.5Hz,1H),7.85(dd,J＝8.5,7.0Hz,1H),7.48(dd,J＝7.0,6.5Hz,1H), 3.89(s,3H)；13C NMR(125MHz,DMSO-d6)δ190.83,179.84,165.44,149.38,147.48, 135.89,132.98,130.29,129.40,129.15,128.87,120.83,117.58,116.68,52.27.HRMS (ESI)for C17H12N2O4Na([M+Na]+):calcd 331.0695,found 331.0687.
the structural characterization data for the product obtained in example 30 are:
Yellow solid,m.p.:154.9-156.7℃.1H NMR(500MHz,DMSO-d6):δ9.63(d, J＝7.0Hz,1H),8.44(s,1H),8.05(d,J＝7.0Hz,2H),7.98(d,J＝9.0Hz,1H),7.85-7.82 (m,1H),7.78(dd,J＝7.5,7.0Hz,1H),7.62(dd,J＝7.5,7.5Hz,2H),7.47(dd,J＝6.5,6.5 Hz,1H)；13C NMR(125MHz,DMSO-d6)δ191.65,181.00,149.28,147.10,134.85, 132.42,131.46,129.96,128.93,128.81,120.89,117.54,116.57.HRMS(ESI)for C15H10N2O2Na([M+Na]+):calcd 273.0640,found 273.0658.
the structural characterization data for the product obtained in example 31 are:
Yellow solid,m.p.:110.5-112.3℃.1H NMR(500MHz,DMSO-d6):δ9.59(d, J＝6.5Hz,1H),8.41(s,1H),7.97(d,J＝9.0Hz,1H),7.81(dd,J＝7.5,7.5Hz,1H),7.68 (d,J＝7.5Hz,1H),7.44(dd,J＝7.0,6.0Hz,1H),7.27(s,1H),7.16(d,J＝8.0Hz,1H), 2.59(s,3H),2.36(s,3H)；13C NMR(125MHz,DMSO-d6)δ193.60,182.03,149.11, 146.79,144.31,140.45,132.79,131.25,128.67,126.50,120.89,117.51,116.48,20.99. HRMS(ESI)for C17H14N2O2Na([M+Na]+):calcd 301.0953,found 301.0967.
the structural characterization data for the product obtained in example 32 are:
Yellow solid,m.p.:110.6-111.9℃.1H NMR(500MHz,DMSO-d6):δ9.62(d, J＝7.0Hz,1H),8.37(s,1H),8.02(dd,J＝9.0,2.0Hz,2H),7.97(d,J＝8.5Hz,1H), 7.83-7.80(m,1H),7.47-7.44(m,1H),7.13(dd,J＝9.0,2.0Hz,2H),3.89(s,3H)；13C NMR(125MHz,DMSO-d6)δ190.22,181.68,164.48,146.80,132.49,131.28,128.74, 125.20,120.97,117.51,116.48,114.37,55.66.HRMS(ESI)for C16H12N2O3Na ([M+Na]+):calcd 303.0746,found 303.0758.
the structural characterization data for the product obtained in example 34 are:
Yellow solid,m.p.:139.4-140.7℃.1H NMR(500MHz,DMSO-d6):δ9.72(d, J＝7.0Hz,1H),7.98(d,J＝9.0Hz,1H),7.87(dd,J＝8.0,8.0Hz,1H),7.70(d,J＝8.0Hz, 2H),7.66(d,J＝8.0Hz,2H),7.47(dd,J＝7.0,7.0Hz,1H),7.33-7.29(m,3H),7.14(dd, J＝7.5,7.5Hz,2H)；13C NMR(125MHz,DMSO-d6)δ190.07,183.04,157.76,147.80, 132.74,131.87,131.84,131.68,131.03,129.74,129.26,128.82,128.70,127.57,118.08, 117.23,116.50.HRMS(ESI)for C21H13N2O2NaBr([M+Na]+):calcd 427.0058, 429.0038,found 427.0036,429.0023.
the structural characterization data for the product obtained in example 35 are:
Yellow solid,m.p.:134.2-135.4℃.1H NMR(500MHz,DMSO-d6):δ9.72(d, J＝7.0Hz,1H),8.00(d,J＝9.0Hz,1H),7.89(dd,J＝8.5,8.0Hz,1H),7.73(d,J＝8.5Hz, 2H),7.68(d,J＝8.0Hz,2H),7.50(dd,J＝7.5,7.0Hz,1H),7.36(d,J＝8.0Hz,2H),7.24 (d,J＝8.0Hz,2H)；13C NMR(125MHz,DMSO-d6)δ190.30,182.80,156.37,147.79, 132.03,131.99,131.90,131.69,131.53,131.06,130.58,128.97,128.89,123.01,118.15, 117.30,116.69.HRMS(ESI)for C21H12N2O2NaBr2([M+Na]+):calcd 504.9163, 506.9143,508.9122,found 504.9147,506.9134,508.9113.
the structural characterization data for the product obtained in example 36 are:
Yellow solid,m.p.:148.2-149.5℃.1H NMR(500MHz,DMSO-d6):δ9.72(d, J＝7.0Hz,1H),7.98(d,J＝9.0Hz,1H),7.88(dd,J＝8.5,8.0Hz,1H),7.72(d,J＝8.0Hz, 2H),7.67(d,J＝8.5Hz,2H),7.49(dd,J＝7.0,7.0Hz,1H),7.33(dd,J＝7.0,6.0Hz,2H), 7.00(dd,J＝8.5,8.5Hz,2H)；13C NMR(125MHz,DMSO-d6)δ190.30,182.90,162.57 (d,J＝246.25Hz),156.68,147.75,132.01,131.95(d,J＝2.5Hz),131.90,131.53,131.00, 129.21(d,J＝2.5Hz),128.91,128.85,118.24,117.23,116.59,114.61(d,J＝22.5Hz). HRMS(ESI)for C21H12N2O2NaBrF([M+Na]+):calcd 444.9964,446.9943,found 444.9946,446.9935.
the structural characterization data for the product obtained in example 37 are:
Yellow solid,m.p.:136.7-138.4℃.1H NMR(500MHz,DMSO-d6):δ9.72(d, J＝7.0Hz,1H),8.00(d,J＝9.5Hz,1H),7.89(dd,J＝8.0,8.0Hz,1H),7.73(d,J＝7.5Hz, 2H),7.68(d,J＝7.5Hz,2H),7.50(dd,J＝7.0,7.0Hz,1H),7.31(d,J＝7.5Hz,2H),7.22 (d,J＝7.5Hz,2H)；13C NMR(125MHz,DMSO-d6)δ190.29,182.80,156.33,147.77, 134.27,132.03,131.91,131.64,131.52,131.46,131.07,128.98,128.88,127.66,118.19, 117.29,116.69.HRMS(ESI)for C21H12N2O2NaBrCl([M+Na]+):calcd 460.9668, 462.9648,found 460.9643,462.9632.
the structural characterization data for the product obtained in example 38 are:
Yellow solid,m.p.:154.4-155.8℃.1H NMR(500MHz,DMSO-d6):δ9.56(s,1H), 7.91(d,J＝9.0Hz,1H),7.76(d,J＝9.5Hz,1H),7.72(d,J＝8.0Hz,2H),7.66(d,J＝8.5 Hz,2H),7.34(d,J＝8.0Hz,2H),7.21(d,J＝7.5Hz,2H),2.50(s,3H)；13C NMR(125 MHz,DMSO-d6)δ190.33,182.64,156.19,146.73,134.54,132.07,131.89,131.67, 131.57,131.01,130.54,128.92,126.59,126.46,122.91,117.92,116.61,17.75.HRMS (ESI)for C22H14N2O2NaBr2([M+Na]+):calcd 518.9320,520.9299,522.9279,found 518.9309,520.9276,522.9263.
the structural characterization data for the product obtained in example 39 are:
Yellow solid,m.p.:173.8-175.4℃.1H NMR(500MHz,DMSO-d6):δ9.56(s,1H), 7.91(d,J＝9.0Hz,1H),7.76(d,J＝9.0Hz,1H),7.72(d,J＝8.5Hz,2H),7.65(d,J＝8.5 Hz,2H),7.31(dd,J＝5.5,3.0Hz,2H),7.00(dd,J＝8.5,8.5Hz,2H),2.50(s,3H)；13C NMR(125MHz,DMSO-d6)δ190.35,182.75,162.52(d,J＝246.25Hz),156.51,146.70, 134.50,131.98,131.91,131.57,130.95,129.29(d,J＝2.5Hz),128.87,126.58,126.37, 118.03,116.57,114.57(d,J＝22.5Hz),17.75.HRMS(ESI)for C22H14N2O2NaBrF ([M+Na]+):calcd 459.0120,461.0100,found 459.0134,461.0109.
the structural characterization data for the product obtained in example 40 are:
Yellow solid,m.p.:157.2-159.8℃.1H NMR(500MHz,DMSO-d6):δ9.56(s,1H), 7.91(d,J＝9.0Hz,1H),7.76(d,J＝9.0Hz,1H),7.73(d,J＝8.5Hz,2H),7.67(d,J＝8.5 Hz,2H),7.29(d,J＝8.0Hz,2H),7.21(d,J＝8.0Hz,2H),2.50(s,3H)；13C NMR(125 MHz,DMSO-d6)δ190.31,182.64,156.16,146.72,134.53,134.18,131.91,131.73, 131.56,131.44,131.02,128.93,127.62,126.58,126.46,117.96,116.61,17.75.HRMS (ESI)for C22H14N2O2NaBrCl([M+Na]+):calcd 474.9825,476.9804,found 474.9847, 476.9835.
the structural characterization data for the product obtained in example 41 are:
Brown solid,m.p.:134.4-135.7℃.1H NMR(500MHz,DMSO-d6):δ9.55(s,1H), 7.91(d,J＝9.0Hz,1H),7.76(d,J＝8.5Hz,1H),7.73(d,J＝8.5Hz,2H),7.66(d,J＝8.0 Hz,2H),7.34(d,J＝8.0Hz,2H),7.21(d,J＝8.0Hz,2H),2.49(s,3H)；13C NMR(125 MHz,DMSO-d6)δ190.33,182.64,156.19,146.73,134.53,132.07,131.89,131.67, 131.57,131.01,130.54,128.92,126.59,126.45,122.91,117.92,116.61,17.75.HRMS (ESI)for C22H14N3O4NaBr([M+Na]+):calcd 486.0065,488.0045,found 486.0072, 488.0055.
the structural characterization data for the product obtained in example 42 are:
Yellow solid,m.p.:152.2-152.9℃.1H NMR(500MHz,DMSO-d6):δ9.59(d, J＝7.0Hz,1H),7.80(s,1H),7.71(dd,J＝8.5,2.0Hz,2H),7.64(dd,J＝8.5,2.0Hz,2H), 7.35-7.30(m,2H),7.28(d,J＝7.5Hz,2H),2.54(s,3H)；13C NMR(125MHz,DMSO-d6) δ190.20,182.57,158.07,148.22,143.40,132.81,131.83,131.76,131.00,129.69, 129.22,128.63,127.99,127.55,118.64,117.83,115.93,20.93.HRMS(ESI)for C22H15N2O2NaBr([M+Na]+):calcd 441.0215,443.0194,found 441.0236,443.0185.
the structural characterization data for the product obtained in example 43 are:
Yellow solid,m.p.:144.4-145.2℃.1H NMR(500MHz,DMSO-d6):δ9.58(dd, J＝7.0,2.5Hz,1H),7.81(s,1H),7.73(dd,J＝8.5,2.0Hz,2H),7.67(dd,J＝8.5,2.0Hz, 2H),7.35(dd,J＝8.0,2.5Hz,3H),7.22(dd,J＝8.0,2.5Hz,2H),2.54(s,3H)；13C NMR (125MHz,DMSO-d6)δ190.41,182.33,156.66,148.20,143.56,132.06,131.89, 131.64,131.03,130.55,128.90,128.03,127.15,122.95,118.80,117.89,115.97,20.93. HRMS(ESI)for C22H14N2O2NaBr2([M+Na]+):calcd 518.9320,520.9299,522.9279, found 518.9309,520.9276,522.9263.
the structural characterization data for the product obtained in example 44 are:
Yellow solid,m.p.:120.1-120.9℃.1H NMR(500MHz,DMSO-d6):δ9.59(d, J＝7.0Hz,1H),7.80(s,1H),7.72(d,J＝8.0Hz,2H),7.66(d,J＝8.0Hz,2H),7.35(d, J＝7.0Hz,1H),7.31(dd,J＝7.0,6.5Hz,2H),6.99(d,J＝9.0,8.5Hz,2H),2.54(s,3H)；13C NMR(125MHz,DMSO-d6)δ190.43,182.44,156.99,148.17,143.52,131.96, 131.90,131.53,131.11,130.97,128.84,128.48,128.01,118.72,115.93,114.67,114.50, 20.93.HRMS(ESI)for C22H14N3O4NaBr([M+Na]+):calcd 486.0065,488.0045,found 486.0072,488.0055.
Claims (5)
1. a method for synthesizing an imidazopyridyl 1, 2-ethanedione derivative, comprising the steps of:
a. with R1，R2-substituted imidazo [1,2-a]Pyridine and R3The substituted benzoyl formaldehyde hydrate is taken as a raw material, and the bis-carbonylation reaction is carried out for 6 to 10 hours at the temperature of 100 ℃ to obtain the product 1- (3-imidazo [1,2-a ]]Pyridyl) -2-aryl-1, 2-ethanedione derivative reaction liquid; the reaction formula is as follows:
b. purifying the reaction liquid of the 1- (3-imidazo [1,2-a ] pyridyl) -2-aryl-1, 2-ethanedione derivative to obtain a target product;
in the reaction formula, R1Represents any one of hydrogen and methyl, and R1Is a single site substitution;
R2represents 4-fluorophenyl, 4-bromophenyl, 4-chlorophenyl;
R3represents bromine, and R3Is a single site substitution;
in the step a, glacial acetic acid is added as an organic acid promoter before the bis-carbonylation reaction, and toluene is added as an organic solvent.
2. The method for synthesizing imidazopyridinyl 1, 2-ethanedione derivative as claimed in claim 1, wherein R is1，R2-substituted imidazo [1,2-a]Pyridine and R3-the molar ratio of the charged substituted benzoyl formaldehyde hydrate is 1: 1.0-1.5.
3. The method of claim 1, wherein said toluene and R are used in the synthesis of imidazopyridinyl 1, 2-ethanedione derivatives1，R2-substituted imidazo [1,2-a]The ratio of pyridine is 7-15: 1L/mol.
4. The method of claim 1, wherein glacial acetic acid and R are used in the synthesis of imidazopyridyl 1, 2-ethanedione derivatives1，R2-substituted imidazo [1,2-a]The ratio of pyridine is 0.6-4: 1L/mol.
5. The method for synthesizing imidazopyridinyl 1, 2-ethanedione derivatives as claimed in any one of claims 1 to 4, wherein the purification method of the target product in step b comprises the steps of:
1) cooling the reaction liquid to room temperature, adding ethyl acetate and water into the reaction liquid, extracting a water phase by using ethyl acetate, collecting an organic layer, washing the organic layer by using saturated saline solution, drying the organic layer by using anhydrous sodium sulfate, filtering the organic layer, collecting filtrate, adding silica gel, and performing rotary evaporation to obtain a crude product;
2) and separating and purifying the crude product by silica gel column chromatography, wherein the eluent is petroleum ether and ethyl acetate to obtain the target product.
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| FeCl3‑Catalyzed Cross-Dehydrogenative Coupling between Imidazoheterocycles and Oxoaldehydes;Sadhanendu Samanta et al.;《The Journal of Organic Chemistry》;20161004;第81卷;10088-10093 * |
| Synthesis of Pyrido-Fused Imidazo[4,5-c]quinolines by I2-DMSO Promoted Oxidative Cross Coupling and Intramolecular Cyclization;Ashok Kale et al.;《Synthesis》;20161207;第49卷;1603-1612 * |
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