CN112851670B - Simple synthesis method of 3-polyfluoroalkyl substituted imidazo [1,2-a ] pyridine - Google Patents

Simple synthesis method of 3-polyfluoroalkyl substituted imidazo [1,2-a ] pyridine Download PDF

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CN112851670B
CN112851670B CN202110078556.2A CN202110078556A CN112851670B CN 112851670 B CN112851670 B CN 112851670B CN 202110078556 A CN202110078556 A CN 202110078556A CN 112851670 B CN112851670 B CN 112851670B
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pyridine
imidazo
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szu
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CN112851670A (en
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朱卫国
黄金波
吴丹丹
白晓康
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Shenzhen University
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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 discloses a simple synthesis method of 3-polyfluoroalkyl substituted imidazo [1,2-a ] pyridine, and relates to the technical field of drug synthesis. The method comprises the following steps of mixing a mixture of a nitrogen gas atmosphere and a nitrogen gas atmosphere in a molar ratio of 1: dissolving 2-2.5 imidazo [1,2-a ] pyridine derivative and polyfluoroalkyl iodide in solvent, adding inducer and additive, and reacting under illumination for 24-96 h. The invention induces the polyfluoroalkyl iodide to generate free radicals by using the initiator under the illumination condition, and then performs polyfluoroalkyl reaction with the imidazo [1,2-a ] pyridine derivative, so that the reaction condition is mild, the yield is high, and the reaction path is environment-friendly and sustainable.

Description

Simple synthesis method of 3-polyfluoroalkyl substituted imidazo [1,2-a ] pyridine
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a simple synthesis method of 3-polyfluoroalkyl substituted imidazo [1,2-a ] pyridine.
Background
The fluorine-containing compound is widely applied to the aspects of materials, medicines and the like, particularly, the fluorine-containing heterocyclic medicine can obviously improve the properties of metabolic pathway, pharmacokinetics, membrane permeability and the like of the medicine, and the development of the fluorine-containing medicine is widely concerned. Furthermore, imidazo [1,2-a ] pyridine structural units are frequently found in various fields such as pharmaceuticals (e.g., antiviral, tubercular, etc. activities) and agriculture, materials, etc. Therefore, the synthesis and functional modification of imidazo [1,2-a ] pyridine derivatives are of great interest to scientists. Statistically, about 20% of the drugs and 30% of the agricultural chemicals on the market contain fluorine atoms. However, no report has been made on a method for substituting 3-position polyfluoroalkyl group of an imidazo [1,2-a ] pyridine derivative. In addition, the photocatalytic reaction has a plurality of outstanding advantages of mild reaction conditions, environmental protection, sustainability and the like, and has important application prospects in the field of pharmacy. Recently, the literature reports that under the condition of illumination, the polyfluoroalkyl iodide derivative can form a donor-acceptor complex (EDA) and then performs a polyfluoroalkyl reaction with beta-keto ester or an aryl compound, and the polyfluoroalkyl iodide derivative has the advantages of mild reaction conditions, high yield and the like.
In view of this, it is intended to develop a sustainable green process for the alkylation of substituted imidazo [1,2-a ] pyridines 3-polyfluoroalkyl via a photocatalytic route.
Disclosure of Invention
The technical problem to be solved by the invention is how to substitute imidazole [1,2-a ] pyridine 3-polyfluoroalkyl by a photocatalysis way.
In order to solve the above problems, the present invention proposes the following technical solutions:
the invention provides a simple synthesis method of 3-polyfluoroalkyl substituted imidazo [1,2-a ] pyridine, which comprises the following steps:
under a nitrogen atmosphere, mixing a mixture of a molar ratio of 1: dissolving 2-2.5 imidazo [1,2-a ] pyridine derivative and polyfluoroalkyl iodide in solvent, adding inducer and additive, and reacting under illumination for 24-96 h.
The further technical scheme is that the illumination condition is an LED lamp or an ultraviolet lamp, and the power is 24-70W.
The further technical proposal is that the reaction temperature is 20-45 ℃.
The further technical scheme is that the solvent is dimethyl sulfoxide (DMSO) or N, N-dimethylformamide, and the dosage of the solvent is 1-3 ml, preferably 2ml, of the solvent for every 0.2mmol of the imidazo [1,2-a ] pyridine derivative.
The technical scheme is that the inducer is at least one of N, N-diisopropylethylamine, N, N, N ', N' -Tetramethylethylenediamine (TMEDA), N, N, N ', N' -Tetraethylethylenediamine (TEDA), triethylenediamine (DABCO) and 1, 8-diazabicycloundecen-7-ene (DBU), and the dosage of the inducer is 1-1.5 molar equivalents (based on the imidazo [1,2-a ] pyridine derivative).
The technical scheme is that the additive is at least one of potassium phosphate, potassium carbonate and cesium carbonate, and the dosage of the additive is 18-25% of molar equivalent (based on the imidazo [1,2-a ] pyridine derivative), preferably 20% of molar equivalent.
The further technical scheme is that the structure of the imidazo [1,2-a ] pyridine derivative conforms to the general formula 1-1:
Figure BDA0002905964370000021
R1、R2wherein n is 1 to 20.
The further technical scheme is that the structure of the polyfluoroalkyl iodide conforms to the following general formula:
CnF2n+1I，ICnF2nCO2Et,ICnF2nCO2me, wherein n is 1-20.
The further technical scheme is that the reaction product is shown as any one of the following structural formulas:
Figure BDA0002905964370000031
the further technical scheme is that the simple synthesis method of the 3-polyfluoroalkyl substituted imidazo [1,2-a ] pyridine further comprises the steps of adding ethyl acetate into a reaction system for extraction after the reaction is finished, washing with saline solution, removing the solvent, and purifying by a silica gel chromatographic column to obtain the final product.
Compared with the prior art, the invention can achieve the following technical effects:
the invention induces the polyfluoroalkyl iodide to generate free radicals by using the initiator under the illumination condition, and then performs polyfluoroalkyl reaction with the imidazo [1,2-a ] pyridine derivative, so that the reaction condition is mild, the yield is high, and the reaction path is environment-friendly and sustainable.
Detailed Description
The technical solutions in the examples will be clearly and completely described below. It is apparent that the embodiments to be described below are only a part of the embodiments of the present invention, and not all of them. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
It will be understood that the terms "comprises" and/or "comprising," when used in this specification and the appended claims, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
It is also to be understood that the terminology used in the description of the embodiments of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the embodiments of the invention. As used in the description of embodiments of the present invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
The invention provides a simple synthesis method of 3-polyfluoroalkyl substituted imidazo [1,2-a ] pyridine, which comprises the following steps:
under nitrogen atmosphere, dissolving imidazole [1,2-a ] pyridine derivative 1-1 and polyfluoroalkyl iodide 1-2 with solvent, adding inducer and additive, and reacting under light irradiation at 20-45 deg.C. Stirring for reaction for 24-96h, adding water into the reaction solution, extracting with ethyl acetate for 2-3 times, washing with saturated saline solution for 2-3 times, removing the solvent by rotary evaporation, and purifying with silica gel chromatographic column to obtain the product.
Specifically, the lighting condition is an LED lamp or an ultraviolet lamp, and the power is 24-70W.
The LED lamp may be a blue fluorescent lamp.
Specifically, the solvent is dimethyl sulfoxide or N, N-dimethylformamide, and the amount of the solvent used is 1 to 3 ml, preferably 2ml, per 0.2mmol equivalent of the imidazo [1,2-a ] pyridine derivative participating in the reaction.
Specifically, the inducer is at least one of N, N-diisopropylethylamine, N, N, N ', N' -tetramethylethylenediamine, N, N, N ', N' -tetraethylethylenediamine, DABCO and DBU, and the use amount of the inducer is 1-1.5 molar equivalents (based on the imidazo [1,2-a ] pyridine derivative).
Specifically, the additive is at least one of potassium phosphate, potassium carbonate and cesium carbonate, and the additive is used in an amount of 18 to 25% equivalent (based on the imidazo [1,2-a ] pyridine derivative), preferably 20% molar equivalent.
In one embodiment, the reaction of the present invention is as follows:
Figure BDA0002905964370000051
R1、R2wherein n is 1 to 20.
Polyfluoroalkyl iodide is RFI, the structure of which corresponds to the following general formula:
CnF2n+1I，ICnF2nCO2Et,ICnF2nCO2me, wherein n is 1-20.
EXAMPLE 1 preparation of Compounds SZU-100
Imidazole [1,2-a ] is put under nitrogen atmosphere]The bipyridine (39mg,0.2mmol) and potassium phosphate (8.5mg,0.04mmol, 20% mmol) were dissolved in anhydrous DMSO (2mL), and n-iodononafluorobutane (34. mu.L, 0.21mmol) and TMEDA (29. mu.L, 0.2mmol) were added. After stirring for 10 minutes, the reaction was stirred under a 24W blue LED lamp for 12 h. N-iodononafluorobutane (34. mu.L, 0.21mmol) and TMEDA (29. mu.L, 0.2mmol) were again added and the reaction was continued for 12 h. After completion of the TLC detection of the reaction of the starting materials, 10mL of water was added to the reaction mixture, extraction was performed with ethyl acetate (25mLX3), the organic phase was washed with saturated brine (25mLX3), the organic layer was dried over anhydrous magnesium sulfate, filtration was performed, and the filtrate was dried by spinner to obtain SZU-10073mg of a white solid with a yield of 89%.1H NMR(600MHz,CDCl3):δ＝8.36(d,J＝8.0Hz,1H),7.87(d,J＝7.8Hz,1H),7.64-7.66(m,2H),7.47-7.49(m,4H),7.06(t,J＝6.2Hz,1H)；13C NMR(125MHz,CDCl3):δ＝149.9,146.3,132.3,129.6,129.1,128.1,128.0,127.9,126.0-126.1(m),118.2-118.3(m),117.9,116.3-116.4(m),114.6-114.7(m),114.5,107.7-107.8(m)；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.2to-106.1(m,2F),-121.7to-121.6(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C17H10F9N2 +[M+1]+413.0695,found 413.0696.
Example 2: preparation of Compounds SZU-101
With 2- (p-tolyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compound SZU-101 in the same manner as in example 1, giving 68mg of white solid in yield: 80 percent.1H NMR(600MHz,CDCl3):δ＝8.35(d,J＝7.8Hz,1H),7.86(d,J＝7.8Hz,1H),7.54-7.55(m,2H),7.46-7.47(m,1H),7.27-7.29(m,2H),7.03-7.05(m,1H),2.44(s,3H)；13C NMR(125MHz,CDCl3):δ＝150.1,148.3,139.1,129.4,128.8,127.7,127.8,126.0-126.1(m),118.2-118.3(m),117.8,116.3-116.4(m),114.6-114.7(m),114.3,106.6-106.7(m),21.4；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.2to-106.1(m,2F),-121.6to-121.5(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C18H12F9N2 +[M+1]+427.0851,found 427.0853.
Example 3: preparation of Compounds SZU-102
With 2- (p-methoxyphenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-102 in the same manner as in example 1, giving 66mg of a white solid with yield: 75 percent.1H NMR(600MHz,CDCl3):δ＝8.35(d,J＝7.8Hz,1H),7.84(d,J＝8.0Hz,1H),7.54-7.55(m,2H),6.99-7.04(m,3H),3.89(s,3H)；13C NMR(125MHz,CDCl3):δ＝160.4,149.8,146.3,130.9,127.8,126.0-126.1(m),124.6,118.2-118.3(m),117.7,114.5-114.6(m),114.6-114.8(m),113.5,109.6-109.8(m),107.4-107.5(m),55.3；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.2to-106.1(m,2F),-121.7to-121.6(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C18H12F9N2O+[M+1]+443.0800,found 443.0801.
Example 4: preparation of Compounds SZU-103
With 2- (p-fluorophenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-103 by the same method as in example 1, giving 77mg of a white solid in yield: 90 percent.1H NMR(600MHz,CDCl3):δ＝8.34(d,J＝8.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.61-7.64(m,2H),7.45-7.48(m,1H),7.14-7.17(m,2H),7.04(t,J＝6.8Hz,1H)；13C NMR(125MHz,CDCl3):δ＝163.2(d,J＝247.5Hz),149.3,146.5,131.4(d,J＝9.0Hz),128.8,127.8,126.0-126.1(m),118.2-118.3(m),118.0,116.4-116.5(m),115.2,115.0,114.6-114.7(m),114.4,107.8-107.9(m)；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.1to-106.0(m,2F),-112.4(s,1F),-121.8to-121.7(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C17H9F10N2 +[M+1]+431.0601,found 431.0603.
Example 5: preparation of Compounds SZU-104
With 2- (p-chlorophenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-104 in the same manner as in example 1, giving 82mg of a white solid with yield: 92 percent.1H NMR(600MHz,CDCl3):δ＝8.35(d,J＝8.0Hz,1H),7.84(d,J＝6.8Hz,1H),7.59(d,J＝7.2Hz,2H)；7.49-7.50(m,1H),7.29(d,J＝7.2Hz,1H),7.06(t,J＝6.8Hz,1H)；13C NMR(125MHz,CDCl3):δ＝148.8,146.5,135.4,130.9,128.3,128.1,126.0-126.1(m),124.4,123.9,118.2-118.3(m),117.9,116.3-116.4(m),114.6,112.8-112.9(m),108.0-108.1(m)；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.1to-106.0(m,2F),-121.7to-121.6(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C19H9ClF9N2 +[M+1]+447.0305,found 447.0306.
Example 6: preparation of Compounds SZU-105
With 2- (p-bromophenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-105 in the same manner as in example 1, giving 89mg of a white solid in yield: 92 percent.1H NMR(600MHz,CDCl3):δ＝8.36(d,J＝8.0Hz,1H),7.87(d,J＝7.8Hz,1H),7.61-7.62(m,2H)；7.50-7.54(m,3H),7.08(t,J＝6.4Hz,1H)；13C NMR(125MHz,CDCl3):δ＝148.6,148.3,131.3,131.2,128.3,126.1,124.4,123.8,118.2-118.3(m),117.9,116.3-116.4(m),114.7,114.5-114.6(m),112.7-112.8(m),111.1-111.2(m),108.0-108.1(m)；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.2to-106.1(m,2F),-121.7to-121.6(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C17H9BrF9N2 +[M+1]+490.9800,found 490.9800.
Example 7: preparation of Compounds SZU-106
With 2- (p-trifluoromethylphenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]Preparation of Compounds SZU-106 from bipyridineThe procedure is as in example 1 to give 81mg of a white solid in yield: 84 percent.1H NMR(600MHz,CDCl3):δ＝8.35(d,J＝8.0Hz,1H),7.72-7.80(m,5H),7.47(t,J＝6.4Hz,1H),7.05(t,J＝6.0Hz,1H)；13C NMR(125MHz,CDCl3):δ＝149.1,146.9,136.7,130.6(q,J＝235.4Hz),127.7,126.0-126.1(m),124.8-124.9(m),123.1,120.1,118.4,116.2-116.3(m),114.8-114.9(m),116.3-116.4(m),114.8-114.9(m),114.4,113.0-113.1(m),111.1-111.2(m),108.2-108.3(m)；19F NMR(470MHz,CDCl3):δ＝-62.7(s,3F),-80.9to-80.8(m,3F),-106.1to-106.0(m,2F),-121.8to-121.7(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C18H9F12N2 +[M+1]+481.0569,found 481.0570.
Example 8: preparation of Compounds SZU-107
With 2- (3-methoxyphenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-107 in the same manner as in example 1, giving 79mg of a white solid in yield: 90 percent.1H NMR(600MHz,CDCl3):δ＝8.32-8.34(m,1H),7.86(d,J＝8.1Hz,1H),7.42-7.43(m,1H),7.35-7.37(m,1H),7.23(d,J＝8.2Hz,1H),7.19(s,1H),6.98-7.02(m,2H),3.86(s,3H)；13C NMR(125MHz,CDCl3):δ＝159.1,150.4,146.7,134.3,129.0,127.3,126.0-126.1(m),122.1,118.3-118.4(m),118.1,115.1,114.7-114.8(m),114.6,114.1,113.0-113.1(m),111.3-111.4(m),107.6-107.8(m),55.2；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.1to-106.0(m,2F),-121.7to-121.6(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C18H12F9N2O+[M+1]+443.0800,found 443.0801.
Example 9: preparation of Compounds SZU-108
With 2- (3-chlorophenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-108 by the same method as in example 1, giving 76mg of white solid in yield: 75 percent.1H NMR(600MHz,CDCl3):δ＝8.33-8.35(m,1H),7.79(d,J＝8.0Hz,1H),7.65(s,1H),7.52(d,J＝8.1Hz,1H),7.43-7.47(m,2H),7.38-7.40(m,1H),7.02-7.05(m,1H)；13C NMR(125MHz,CDCl3):δ＝148.9,146.7,134.7,133.9,129.7,129.2,129.1,127.7,127.6,126.0-126.1(m),117.9-118.1(m),116.3,114.7-114.8(m),114.4,112.6-112.8(m),111.3-111.4(m),107.9-108.1(m)；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.1to-106.0(m,2F),-121.7to-121.6(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C17H9ClF9N2 +[M+1]+447.0305,found 447.0307.
Example 10: preparation of Compounds SZU-109
With 2- (3-bromophenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-109 in the same manner as in example 1, giving 78mg of a white solid in yield: 80 percent.1H NMR(600MHz,CDCl3):δ＝8.25(d,J＝7.8Hz,1H),7.71-7.73(m,2H),7.47-7.52(m,2H),7.37-7.40(m,1H),7.23-7.26(m,1H),6.94-6.97(m,1H)；13C NMR(125MHz,CDCl3):δ＝148.7,146.6,134.7,132.6,132.1,129.5,128.2,127.8,126.0-126.1(m),122.0,118.0-118.3(m),118.1,116.2-116.3(m),114.6,113.0-113.1(m),111.2-111.4(m),107.9-108.1(m)；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.1to-106.0(m,2F),-121.7to-121.6(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C17H9BrF9N2 +[M+1]+490.9800,found 490.9802.
Example 11: preparation of Compounds SZU-110
With 2- (3-trifluoromethylphenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-110 by the same method as in example 1, giving 72mg of white solid in yield: 76 percent.1H NMR(600MHz,CDCl3):δ＝8.36(d,J＝7.8Hz,1H),7.93(s,1H),7.80-7.85(m,2H),7.72-7.74(m,1H),7.60(t,J＝6.8Hz,1H),7.46-7.49(m,1H),7.05(t,J＝6.4Hz,1H)；13C NMR(125MHz,CDCl3):δ＝148.8,146.8,133.7,132.8,130.6(q,J＝236.1Hz),128.5,127.8,126.6,126.0-126.1(m),125.6-125.7(m),124.8,123.0,118.2,116.2-116.3(m),114.5,112.7-112.9(m),111.2-111.4(m),108.1-108.3(m)；19F NMR(470MHz,CDCl3):δ＝-62.8(s,3F),-80.9to-80.8(m,3F),-106.2to-106.1(m,2F),-121.7to-121.6(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C18H9F12N2 +[M+1]+481.0569,found 481.0570.
Example 12: preparation of Compounds SZU-111
With 2- (2-methoxyphenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compound SZU-111 in the same manner as in example 1, giving 65mg of a white solid in yield: 74 percent.1H NMR(600MHz,CDCl3):δ＝8.32-8.35(m,1H),7.85(d,J＝8.0Hz,1H),7.41-7.43(m,1H),7.35-7.37(m,1H),7.19-7.23(m,1H),7.98-7.02(m,2H),3.86(s,3H)；13C NMR(125MHz,CDCl3):δ＝159.2,150.5,146.7,134.5,129.3,127.6,122.4,118.3-118.5(m),118.2,116.0,114.7-114.9(m),114.6,114.3,113.0-113.2(m),111.4-111.5(m),107.8-107.9(m),55.3；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-107.9to-107.8(m,2F),-122.3to-122.2(m,2F),-126.1to-126.0(m,2F)；HRMS(ESI):Exact mass calcd for C18H12F9N2O+[M+1]+443.0800,found443.0802.
Example 13: preparation of Compounds SZU-112
With 2- (2-fluorophenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-112 in the same manner as in example 1, giving 65mg of a white solid in yield: 76 percent.1H NMR(600MHz,CDCl3):δ＝8.42-8.45(m,1H),8.09-8.22(m,1H),7.76-7.84(m,1H),7.29-7.46(m,4H),6.90-7.20(m,1H)；13C NMR(125MHz,CDCl3):δ＝163.6(d,J＝246.8Hz),149.5,146.8,131.5(d,J＝10.2Hz),128.9,127.9,126.3-126.4(m),118.3-118.4(m),118.3,116.4-116.5(m),115.4,114.9,113.8-113.9(m),113.8,113.7,111.4-111.7(m),107.8-107.9(m)；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.1to-106.0(m,2F),-112.4(s,1F),-121.8to-121.7(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C17H9F10N2 +[M+1]+431.0601,found 431.0601.
Example 14: preparation of Compounds SZU-113
With 2- (2-fluorophenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-113 by the same method as in example 1, giving 67mg of white solid in yield: 75 percent.1H NMR(600MHz,CDCl3):δ＝8.35(d,J＝8.0Hz,1H),7.82(d,J＝8.0Hz,1H),7.46-7.52(m,2H),7.40-7.42(m,2H),7.33-7.36(m,1H),7.06(t,J＝6.4Hz,1H)；13C NMR(125MHz,CDCl3):δ＝147.2,146.5,134.3,131.9,131.6,130.4,129.4,127.6,126.0,125.8-125.9(m),118.3,116.3-116.4(m),114.5,112.4-112.6(m),112.5-112.6(m),111.0-111.2(m),111.3-111.4(m),109.3-109.5(m)；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-105.9to-105.8(m,2F),-121.6to-121.5(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C17H9ClF9N2 +[M+1]+447.0305,found 447.0306.
Example 15: preparation of Compounds SZU-114
With 6-methyl- (2-phenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-114 in the same manner as in example 1, giving 69mg of a white solid in yield: 81 percent.1H NMR(600MHz,CDCl3):δ＝8.19(s,1H),7.70(d,J＝7.9Hz,1H),7.61-7.63(m,2H),7.44-7.46(m,3H),7.29(s,1H),2.43(s,3H)；13C NMR(125MHz,CDCl3):δ＝150.1,145.6,133.1,130.6,129.5,128.8,127.9,127.6,124.1,123.5-123.6(m),118.3-118.4(m),117.2,116.0-116.1(m),114.5-114.7(m),111.2-111.4(m),107.4-107.6(m),18.5；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-105.9to-105.8(m,2F),-121.6to-121.5(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C18H12F9N2 +[M+1]+427.0851,found 427.0852.
Example 16: preparation of Compounds SZU-115
With 6-fluoro- (2-phenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-115 by the same method as in example 1, giving 65mg of white solid in yield: 76 percent.1H NMR(600MHz,CDCl3):δ＝8.28-8.29(m,1H),7.74-7.76(m,1H),7.61-7.63(m,2H),7.45-7.47(m,3H),7.28-7.37(m,1H)；13C NMR(125MHz,CDCl3):δ＝153.7(d,J＝237.1Hz),151.6,144.5,132.8,129.4,129.0,128.0,119.6,119.4,118.7,116.3-116.4(m),114.4-114.6(m),113.2-113.3(m),111.0-111.2(m),109.2-109.3(m),18.5；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.7to-106.6(m,2F),-121.8to-121.7(m,2F),-126.0to-125.9(m,2F),-136.9to-136.8(s,1F)；HRMS(ESI):Exact mass calcd for C17H9F10N2 +[M+1]+431.0601,found 431.0603.
Example 17: preparation of Compounds SZU-116
With 6-chloro- (2-phenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-116 in the same manner as in example 1, giving 81mg of a white solid with yield: 91 percent.1H NMR(600MHz,CDCl3):δ＝8.37(s,1H),7.78-7.80(m,1H),7.62-7.63(m,2H),7.44-7.49(m,4H)；13C NMR(125MHz,CDCl3):δ＝150.7,144.7,131.9,129.5,129.3,129.2,128.1,123.6-123.8(m),122.9,120.7-120.8(m),118.3,115.9-116.0(m),114.0-114.2(m),111.2-111.3(m),108.4-108.6(m)；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.3to-106.2(m,2F),-121.8to-121.7(m,2F),-126.0to-125.9(m,2F)；HRMS(ESI):Exact mass calcd for C17H9ClF9N2 +[M+1]+447.0305,found447.0306.
Example 18: preparation of Compounds SZU-117
With 6-bromo- (2-phenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]Preparation of Compounds SZU-117 from bipyridine1, yield 90mg of white solid: 92 percent.1H NMR(600MHz,CDCl3):δ＝8.45(s,1H),7.68(d,J＝8.0Hz,1H),7.61-7.63(m,2H),7.50-7.51(m,1H),7.45-7.48(m,3H)；13C NMR(125MHz,CDCl3):δ＝151.1,145.1,132.5,131.0,129.5,129.1,128.0,125.7-125.9(m),118.7,118.3-118.4(m),116.2-116.3(m),114.4-114.5(m),111.2-111.4(m),109.0,108.2-108.6(m)；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.2to-106.1(m,2F),-121.6to-121.5(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C17H9BrF9N2 +[M+1]+490.9800,found 490.9802.
Example 19: preparation of Compounds SZU-118
With 7-chloro- (2-phenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-118 by the same method as example 1, giving 71mg of white solid in yield: 80 percent.1H NMR(600MHz,CDCl3):δ＝8.24(d,J＝8.0Hz,1H),7.77(s,1H),7.61-7.63(m,2H),7.45-7.48(m,3H),6.98-7.00(m,1H)；13C NMR(125MHz,CDCl3):δ＝151.5,146.7,134.1,132.6,129.5,129.1,128.0,126.1-126.3(m),118.3-118.4(m),116.9,116.2-116.4(m),115.7,114.4-114.6(m),111.2-111.4(m),108.2-108.6(m)；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.1to-106.0(m,2F),-121.7to-121.6(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C17H9ClF9N2 +[M+1]+447.0305,found 447.0306.
Example 20: preparation of Compounds SZU-119
With 7-bromo- (2-phenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compound SZU-119 by the same method as example 1, giving 74mg of white solid in yield: 75 percent.1H NMR(600MHz,CDCl3):δ＝8.17(d,J＝7.6Hz,1H),7.95(s,1H),7.61-7.63(m,2H),7.45-7.47(m,3H),7.09-7.10(m,1H)；13C NMR(125MHz,CDCl3):δ＝151.4,146.9,132.6,129.5,129.1,128.0,126.1-126.2(m),121.5,120.4,118.3-118.5(m),118.0,116.3-116.5(m),114.4-114.6(m),111.2-111.3(m),108.2-108.4(m)；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.1to-106.0(m,2F),-121.7to-121.6(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C17H9BrF9N2 +[M+1]+490.9800,found 490.9802.
Example 21: preparation of Compounds SZU-120
With 8-methyl- (2-phenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-120 by the same method as in example 1, giving 64mg of white solid, yield: 75 percent.1H NMR(600MHz,CDCl3):δ＝8.20(d,J＝7.8Hz,1H),7.62-7.64(m,2H),7.44-7.46(m,3H),7.21-7.22(m,1H),6.89-6.92(m,1H),2.71(s,3H)；13C NMR(125MHz,CDCl3):δ＝150.1,147.2,133.4,129.7,128.7,128.3,127.9,126.1,123.6-123.8(m),118.1-118.3(m),116.3-116.5(m),114.7-114.8(m),113.9,113.6,111.2-111.3(m),17.2；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.1to-106.0(m,2F),-121.7to-121.6(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C18H12F9N2 +[M+1]+427.0851,found 427.0852.
Example 22: preparation of Compounds SZU-121
With 8-bromo- (2-phenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-121 in the same manner as in example 1, giving 64mg of a white solid in yield: 66 percent.1H NMR(600MHz,CDCl3):δ＝8.32(d,J＝7.8Hz,1H),7.68-7.70(m,1H),7.62-7.64(m,2H),7.44-7.46(m,3H),6.87-6.89(m,1H)；13C NMR(125MHz,CDCl3):δ＝151.3,144.8,132.8,129.8,129.6,129.0,127.9,125.2-125.3(m),118.1-118.3(m),116.2-116.4(m),114.4-114.6(m),114.0,112.7-112.8(m),112.3,109.6-109.7(m)；19F NMR(470MHz,CDCl3):δ＝-80.9to-80.8(m,3F),-106.3to-106.2(m,2F),-121.7to-121.6(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C17H9BrF9N2 +[M+1]+490.9800,found 490.9802.
Example 23: preparation of Compounds SZU-122
With 5-methyl- (2-phenyl) imidazole [1,2-a ]]And pyridine was substituted for imidazo [1,2-a ] in example 1]And pyridine was used to prepare compounds SZU-122 by the same method as in example 1, giving 38mg of white solid in yield: 45 percent.1H NMR(600MHz,CDCl3):δ＝8.24(d,J＝7.8Hz,1H),7.60-7.62(m,2H),7.42-7.44(m,3H),7.20-7.21(m,1H),6.85-6.90(m,1H),2.72(s,3H)；13C NMR(125MHz,CDCl3):δ＝150.2,146.9,133.6,129.6,128.4,128.2,128.0,126.0,123.5-123.7(m),118.0-118.2(m),116.2-116.4(m),114.6-114.8(m),114.0,113.4,111.2-111.4(m),17.4；19F NMR(470MHz,CDCl3):δ＝-80.8to-80.7(m,3F),-106.2to-106.1(m,2F),-121.8to-121.7(m,2F),-125.9to-125.8(m,2F)；HRMS(ESI):Exact mass calcd for C18H12F9N2 +[M+1]+427.0851,found 427.0852.
Example 24: preparation of Compounds SZU-123
Compounds SZU-123 were prepared using iodoperfluoroethane instead of iodoperfluoron-butane in example 1, using the same procedure as in example 1, to give 51mg of a white solid in yield: 83 percent.1H NMR(600MHz,CDCl3):δ＝8.23(d,J＝7.4Hz,1H),7.67-7.69(m,1H),7.54-7.56(m,2H),7.31-7.38(m,4H),6.89-6.92(m,1H)；13C NMR(125MHz,CDCl3):δ＝150.2,146.7,133.1,129.5,128.8,128.0,127.1,125.9-126.0(m),127.6-127.8(m),118.1,114.0,111.7-111.9(m),107.4-107.6(m)；19F NMR(470MHz,CDCl3):δ＝-83.8to-83.7(m,3F),-110.5to-110.4(m,2F)；HRMS(ESI):Exact mass calcd for C15H10F5N2 +[M+1]+313.0759,found 313.0760.
Example 25: preparation of Compounds SZU-124
Preparation of Compounds SZU-124 using iodoperfluoropentane instead of iodoperfluoron-butane in example 1 the procedure was as in example 1 to give 73mg of a white solidThe yield is as follows: 80 percent.1H NMR(600MHz,CDCl3):δ＝8.33(d,J＝7.9Hz,1H),7.77-7.79(m,1H),7.61-7.63(m,2H),7.41-7.45(m,4H),6.98-7.01(m,1H)；13C NMR(125MHz,CDCl3):δ＝150.6,146.7,132.9,129.6,128.9,128.0,127.5,125.9-126.0(m),118.1,116.2-116.3(m),114.9-115.0(m),114.1,113.0-113.1(m),111.9-112.0(m),110.4-110.5(m),107.7-108.0(m)；19F NMR(470MHz,CDCl3):δ＝-62.7(s,3F),-80.8to-80.9(m,2F),-106.1to-106.2(m,2F),-121.6to-121.7(m,2F),-125.8to-125.9(m,2F)；HRMS(ESI):Exact mass calcd for C18H10F7N2 +[M+1]+463.0663,found 463.0665.
Example 26: preparation of Compounds SZU-125
Compounds SZU-125 were prepared using iodoperfluorohexane instead of iodoperfluoron-butane in example 1, using the same procedure as in example 1, to give 74mg of a white solid in yield: 73 percent.1H NMR(600MHz,CDCl3):δ＝8.23(d,J＝7.9Hz,1H),7.66-7.68(m,1H),7.53-7.54(m,2H),7.18-7.36(m,4H),6.87-6.90(m,1H)；13C NMR(125MHz,CDCl3):δ＝150.7,146.8,133.1,129.5,128.8,127.9,127.3,125.9-126.0(m),118.1,116.1-116.2(m),114.9-115.0(m),114.0-114.1(m),113.1-113.2(m),111.9-112.0(m),111.0-111.1(m),110.1-110.2(m),107.8-108.0(m)；19F NMR(470MHz,CDCl3):δ＝-80.8to-80.7(t,J＝14.1Hz,3F),-105.9to-105.8(m,2F),-120.8to-120.7(m,2F),-121.8to-121.7(m,2F),-122.7to-122.6(m,2F),-126.1to-126.0(m,2F)；HRMS(ESI):Exact mass calcd for C19H10F13N2 +[M+1]+513.0631,found 513.0633.
Example 27: preparation of Compounds SZU-126
Compound SZU-126 was prepared by using iodoperfluorooctane instead of iodoperfluoron-butane in example 1 in the same manner as in example 1 to give a white solid 86mg, yield: 71 percent.1H NMR(600MHz,CDCl3):δ＝8.37(d,J＝7.6Hz,1H),7.90-7.92(m,1H),7.64-7.68(m,2H),7.47-7.52(m,4H),7.08(t,J＝5.0Hz,1H)；13C NMR(125MHz,CDCl3):δ＝150.7,146.6,133.1,129.4,128.8,127.9,127.5,125.9-126.1(m),118.3,116.1-116.3(m),114.9-115.1(m),114.0-114.1(m),113.0-113.2(m),111.9-112.1(m),111.0-111.2(m),110.1-110.2(m),107.8-108.2(m)；19F NMR(470MHz,CDCl3):δ＝-80.7to-80.5(t,J＝14.9Hz,3F),-106.0to-106.9(m,2F),-120.6to-120.5(m,2F),-121.8to-121.4(m,2F),-122.6to-122.5(m,2F),-126.1to-126.0(m,2F)；HRMS(ESI):Exact mass calcd for C21H10F17N2 +[M+1]+613.0567,found 613.0568.
Example 28: preparation of Compounds SZU-127
Compound SZU-127 was prepared by substituting ethyl iododifluoroacetate for iodoperfluoron-butane in example 1, using the same procedure as in example 1, to give 38mg of a white solid in yield: 61 percent.1H NMR(600MHz,CDCl3):δ＝8.56(d,J＝7.4Hz,1H),7.77-7.79(m,1H),7.66-7.68(m,2H),7.40-7.49(m,4H),6.99-7.02(m,1H),4.00(t,J＝4.0Hz,2H),1.17(t,J 4.0Hz,3H)；13C NMR(125MHz,CDCl3):δ＝162.3(t,JF-C＝126.9Hz),145.9,132.9,129.6,128.9,128.1,127.0,126.6(t,JF-C＝23.5Hz),117.7,113.6,111.3,109.4,99.9,63.7,13.6；19F NMR(470MHz,CDCl3):δ＝-98.6(s,2F)；HRMS(ESI):Exact mass calcd for C21H10F17N2 +[M+1]+613.0567,found 613.0568.
In the above embodiments, the descriptions of the respective embodiments have respective emphasis, and for parts that are not described in detail in a certain embodiment, reference may be made to related descriptions of other embodiments.
While the invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (6)

1. A synthetic method of 3-polyfluoroalkyl substituted imidazo [1,2-a ] pyridine is characterized by comprising the following steps:
under a nitrogen atmosphere, mixing a mixture of a molar ratio of 1: dissolving 2-2.5 imidazo [1,2-a ] pyridine derivatives and polyfluoroalkyl iodide in a solvent, adding an inducer and an additive, and reacting under illumination for 24-96 hours;
the solvent is dimethyl sulfoxide or N, N-dimethylformamide, and the dosage of the solvent is 1-3 ml for every 0.2mmol of imidazo [1,2-a ] pyridine derivative;
the inducer is at least one of N, N-diisopropylethylamine, N, N, N ', N' -tetramethylethylenediamine, N, N, N ', N' -tetraethylethylenediamine, DABCO and DBU, and the use amount of the inducer is 1-1.5 molar equivalents based on the imidazo [1,2-a ] pyridine derivative;
the additive is at least one of potassium phosphate, potassium carbonate and cesium carbonate, and the dosage of the additive is 18-25% of molar equivalent based on the imidazo [1,2-a ] pyridine derivative;
the structure of the imidazo [1,2-a ] pyridine derivative conforms to the general formula 1-1:
Figure FDA0003323170730000011
R1＝CnH2n+1，X(F，Cl，Br，I)，CF3，NO2，CO2Et，CH3O，NHEt，COPh
Figure FDA0003323170730000012
R2＝CnH2n+1，X(F，Cl，Br，I)，CH2OPh，NO2，CO2Et，CH3O，NHEt，COPh
Figure FDA0003323170730000013
R1、R2wherein n is 1 to 20.
2. The method of synthesizing a 3-polyfluoroalkylated substituted imidazo [1,2-a ] pyridine as claimed in claim 1, where the illumination is an LED lamp or an ultraviolet lamp and the power is 24-70W.
3. The process for the synthesis of 3-polyfluoroalkylated substituted imidazo [1,2-a ] pyridines according to claim 1, characterized by the fact that the reaction temperature is from 20 to 45 ℃.
4. 3-polyfluoroalkylated substituted imidazoles [1,2-a ] as claimed in claim 1]The synthesis method of the pyridine is characterized in that the structure of the polyfluoroalkyl iodide conforms to the following general formula: cnF2n+1I，ICnF2nCO2Et，ICnF2nCO2Me, wherein n is 1-20.
5. The method of synthesizing a 3-polyfluoroalkylated substituted imidazo [1,2-a ] pyridine of claim 4, wherein the reaction product is represented by any of the following structural formulae:
Figure FDA0003323170730000021
Figure FDA0003323170730000031
6. the process for synthesizing 3-polyfluoroalkylated substituted imidazo [1,2-a ] pyridine as claimed in claim 5, which further comprises adding water to the reaction system after the completion of the reaction, extracting with ethyl acetate, washing with brine, removing the solvent, and purifying with a silica gel column chromatography to obtain the final product.
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