阅读说明：本技术 一种3-吡啶甲脒衍生物及其催化合成方法 (3-pyridine formamidine derivative and catalytic synthesis method thereof ) 是由 杨渭光 赵宇 周子彤 刘绿玲 李立 崔燎 于 2020-12-02 设计创作，主要内容包括：本发明揭示了一种3-吡啶甲脒衍生物及其催化合成方法,所述3-吡啶甲脒衍生物具有如式(I)所示的结构：式(I)中,R~1、R~2、R~4选自其中,*表示与C或N相连,R~3或R~5为H、氰基、硝基、羟基、苯基、亚甲二氧基、C_1-C_6烷基、C_2-C_6烯基、C_1-C_6烷氧基、卤素、卤代C_1-C_6烷基、卤代C_1-C_6烷氧基。本发明提供的一种3-吡啶甲脒衍生物及其催化合成方法,采用“一锅法”合成,产物产率高、纯度高、副产物无害、原子经济性高等诸多优点,具有良好的科研价值和应用前景,为该类化合物的制备提供了一种绿色的合成方法,可在药物中间体、农药中间体等领域中发挥重要作用,降低生产成本,在工业和科研上具有良好的应用价值和潜力。(The invention discloses a 3-pyridine formamidine derivative and a catalytic synthesis method thereof, wherein the 3-pyridine formamidine derivative has a structure shown as a formula (I): in the formula (I), R 1 、R 2 、R 4 Is selected from Wherein, represents a bond to C or N, R 3 Or R 5 Is H, cyano, nitro, hydroxy, phenyl, methylenedioxy, C 1 ‑C 6 Alkyl radical, C 2 ‑C 6 Alkenyl radical, C 1 ‑C 6 Alkoxy, halogen, halogeno C 1 ‑C 6 Alkyl, halo C 1 ‑C 6 An alkoxy group. The invention provides a 3-pyridine formamidine derivative andthe catalytic synthesis method adopts a one-pot synthesis method, has the advantages of high product yield, high purity, harmless byproducts, high atom economy and the like, has good scientific research value and application prospect, provides a green synthesis method for the preparation of the compounds, can play an important role in the fields of drug intermediates, pesticide intermediates and the like, reduces the production cost, and has good application value and potential in industry and scientific research.)

1. A3-pyridinecarboxamidine derivative, wherein the 3-pyridinecarboxamidine derivative has a structure represented by formula (I):

in the formula (I), R¹、R²、R⁴Is selected fromWherein, represents a bond to C or N, R³Or R⁵Is H, cyano, nitro, hydroxy, phenyl, methylenedioxy, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy, halogen, halogeno C₁-C₆Alkyl, halo C₁-C₆An alkoxy group.

2. A catalytic synthesis method of a 3-pyridine formamidine derivative is characterized by comprising the following steps:

taking a copper compound as a catalyst, and carrying out a series of reactions of cycloaddition, ring-opening rearrangement, nucleophilic addition and condensation on an O-acetyl aryl ketoxime derivative in a formula (II), an aryl aldehyde in a formula (III), a sulfonyl azide in a formula (IV), ammonium acetate in a formula (V) and an alpha-carbonyl terminal alkyne in a formula (VI) in an organic solvent to obtain a 3-pyridine formamidine derivative in the formula (I), namely a 2, 4, 6-trisubstituted-N-sulfonyl 3-pyridine formamidine derivative;

3. the process for the catalytic synthesis of 3-pyridinecarboxamidine derivatives according to claim 2,

the method comprises the following steps:

taking a copper compound as a catalyst, and carrying out a series of reactions of cycloaddition, ring-opening rearrangement, nucleophilic addition and condensation on an O-acetyl aryl ketoxime derivative in a formula (II), an aryl aldehyde in a formula (III), a sulfonyl azide in a formula (IV), ammonium acetate in a formula (V) and an alpha-carbonyl terminal alkyne in a formula (VI) in an organic solvent to obtain a 3-pyridine formamidine derivative in the formula (I), namely a 2, 4, 6-trisubstituted-N-sulfonyl 3-pyridine formamidine derivative;

4. the method of claim 3, further comprising: after the synthesis reaction is finished, carrying out post-treatment;

and/or, the post-processing comprises: cooling the reaction system to room temperature, adding water and ethyl acetate, extracting for 1-3 times, wherein the volume ratio of water to ethyl acetate is 2-5:1, collecting the upper layer liquid, and extracting with anhydrous Na₂SO₄Drying, evaporating to remove ethyl acetate by using a rotary evaporator after drying, passing the residue through a 200-mesh 300-mesh silica gel column, and taking ethyl acetate/petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:5-15, thereby obtaining the target product, namely the compound shown in the formula (I).

5. The process for the catalytic synthesis of 3-pyridinecarboxamidine derivatives according to claim 2, 3, or 4, characterized in that: the copper compound comprises any one of copper acetate, copper chloride, copper bromide, copper acetylacetonate, copper trifluoroacetate, copper trifluoromethanesulfonate, copper oxide, cuprous iodide, cuprous bromide, cuprous chloride, thiophene-2-copper formate or cuprous acetate.

6. The process for the catalytic synthesis of 3-pyridinecarboxamidine derivatives according to claim 2, 3, or 4, characterized in that: the organic solvent comprises one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, chlorobenzene, benzene, xylene, dimethyl sulfoxide or N-methylpyrrolidone.

7. The process for the catalytic synthesis of 3-pyridinecarboxamidine derivatives according to claim 2, 3, or 4, characterized in that: the molar ratio of the O-acetyl aryl ethyl ketoxime derivative in the formula (II), the aryl aldehyde in the formula (III), the sulfonyl azide in the formula (IV), the ammonium acetate in the formula (V) and the alpha-carbonyl terminal alkyne in the formula (VI) is 1:1-3:1-3: 1-3.

8. The process for the catalytic synthesis of 3-pyridinecarboxamidine derivatives according to claim 2, 3, or 4, characterized in that: the reaction temperature of the series of reactions of cycloaddition, ring-opening rearrangement, nucleophilic addition and condensation is 25-120 ℃, and the reaction time is 1-24 hours.

9. The process for the catalytic synthesis of 3-pyridinecarboxamidine derivatives according to claim 3 or 4, characterized in that: the molar ratio of the O-acetyl aryl ethanone oxime derivative in the formula (II) to the copper compound is 1: 0.05-0.40.

Technical Field

The invention belongs to the technical field of organic chemical synthesis, relates to a 3-pyridine formamidine derivative and a catalytic synthesis method thereof, and particularly relates to a synthesis method of a 2, 4, 6-trisubstituted-N-sulfonyl-3-pyridine formamidine compound.

Background

Amidine compounds are important intermediates of medicines and pesticides, and are common raw materials in organic synthesis. The classical synthesis of amidines is the amide, nitrile aminolysis and orthoformate method. In recent years, great improvements have been made to these synthesis techniques to simplify the synthesis process and improve the yield. The amide acetal method, the ketoxime method and the carboxylic acid method are relatively advanced technologies, so that the range of raw materials for synthesizing amidine is widened, and the method is simple and easy to implement and has a good application prospect. However, the existing synthesis technology has the defects that the synthesis steps are multiple, and harmful SO is generated₂The defects of harsh gas and reaction conditions and the like limit the development of the structural diversity of amidine. Therefore, it is necessary to develop a technology with many advantages such as easily available raw materials, simple conditions, harmless byproducts, high atom economy, and "one-pot" synthesis.

Disclosure of Invention

The invention mainly aims to provide a 3-pyridine formamidine derivative and a catalytic synthesis method thereof, so as to overcome the defects in the prior art.

In order to achieve the above object, the technical solution adopted by the embodiment of the present invention includes:

the embodiment of the invention provides a 3-pyridine formamidine derivative, wherein the 3-pyridine formamidine derivative has a structure shown as a formula (I):

in the formula (I), R¹、R²、R⁴Is selected fromWherein, represents a bond to C or N, R³Or R⁵Is H, cyano, nitro, hydroxy, phenyl, methylenedioxy, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₁-C₆Alkoxy, halogen, halogeno C₁-C₆Alkyl, halo C₁-C₆An alkoxy group.

Wherein, C₁-C₆Alkyl means a straight or branched chain alkyl group having 1 to 6 carbon atoms, which includes C₁Alkyl radical, C₂Alkyl radical, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl or C₆Alkyl, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl, and the like.

Wherein, C₁-C₆Alkoxy means C₁-C₆A group in which an alkyl group is bonded to an O atom.

Wherein, the meaning of the halogen refers to halogen elements and can be F, Cl, Br or I.

Wherein is halo C₁-C₆Alkyl means C substituted by halogen₁-C₆Alkyl groups, which may be trifluoromethyl, pentafluoroethyl, difluoromethyl, chloromethyl, and the like.

Wherein is halo C₁-C₆The meaning of alkoxy means C substituted by halogen₁-C₆The alkoxy group may be trifluoromethoxy, pentafluoroethoxy, difluoromethoxy, chloromethoxy, etc.

The embodiment of the invention also provides a catalytic synthesis method of the 3-pyridine formamidine derivative, which comprises the following steps:

taking a copper compound as a catalyst, and carrying out a series of reactions of cycloaddition, ring-opening rearrangement, nucleophilic addition and condensation on an O-acetyl aryl ketoxime derivative in a formula (II), an aryl aldehyde in a formula (III), a sulfonyl azide in a formula (IV), ammonium acetate in a formula (V) and an alpha-carbonyl terminal alkyne in a formula (VI) in an organic solvent to obtain a 3-pyridine formamidine derivative in the formula (I), namely a 2, 4, 6-trisubstituted-N-sulfonyl 3-pyridine formamidine derivative;

further, the catalytic synthesis method of the 3-pyridine formamidine derivative comprises the following steps:

taking a copper compound as a catalyst, and carrying out a series of reactions of cycloaddition, ring-opening rearrangement, nucleophilic addition and condensation on an O-acetyl aryl ketoxime derivative in a formula (II), an aryl aldehyde in a formula (III), a sulfonyl azide in a formula (IV), ammonium acetate in a formula (V) and an alpha-carbonyl terminal alkyne in a formula (VI) in an organic solvent to obtain a 3-pyridine formamidine derivative in the formula (I), namely a 2, 4, 6-trisubstituted-N-sulfonyl 3-pyridine formamidine derivative;

further, the copper compound includes any one of copper acetate, copper chloride, copper bromide, copper acetylacetonate, copper trifluoroacetate, copper trifluoromethanesulfonate, copper oxide, cuprous iodide, cuprous bromide, cuprous chloride, copper thiophene-2-carboxylate, or cuprous acetate, preferably cuprous iodide or cuprous chloride, and most preferably cuprous iodide.

Further, the organic solvent comprises one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, chlorobenzene, benzene, xylene, dimethyl sulfoxide or N-methylpyrrolidone, preferably acetonitrile or dimethyl sulfoxide, and most preferably acetonitrile.

Further, the molar ratio of the O-acetyl aryl ketoxime derivative in the formula (II), the aryl aldehyde in the formula (III), the sulfonyl azide in the formula (IV), the ammonium acetate in the formula (V) and the alpha-carbonyl terminal alkyne in the formula (VI) is 1:1-3:1-3: 1-3.

Further, the reaction temperature of the series of reactions of cycloaddition, ring-opening rearrangement, nucleophilic addition and condensation is 25-120 ℃, and the reaction time is 1-24 hours.

Further, the molar ratio of the O-acetyl arylethanone oxime derivative in the formula (II) to the copper compound is 1: 0.05-0.40.

Wherein the ratio of the O-acetoacetarylethanone oxime derivative of formula (II) to the solvent in ml is 1:5-15 in mmol, i.e. 5-15 ml of solvent, e.g. 1:5, 1:8, 1:10, 1:12 or 1:15, is used per 1 mmol of the O-acetoacetarylethanone oxime derivative of formula (II).

Further, the method also comprises post-treatment after the synthesis reaction is finished, and specifically comprises the following steps: cooling the reaction system to room temperature, removing the solvent by evaporation with a rotary evaporator, passing the residue through a 200-mesh 300-mesh silica gel column, and taking ethyl acetate/petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:5-15, thereby obtaining the target product, namely the compound shown in the formula (I).

The post-treatment can also be any one or combination of extraction, concentration, crystallization, recrystallization and column chromatography purification.

As another exemplary post-treatment means, for example, there may be mentioned: after the reaction is completed, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline solution in an equal volume ratio, performing oscillation extraction for 2-4 times, collecting an organic layer, drying, performing rotary evaporation and concentration to obtain a crude product, performing 300-400-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:5-10, so as to obtain the target product of the 2, 4, 6-trisubstituted-N-sulfonyl 3-pyridine formamidine in the formula (I).

Preferably, the O-acetyl aryl ethanone oxime derivative of formula (II), the aryl aldehyde of formula (III), the sulfonyl azide of formula (IV), the ammonium acetate of formula (V) and the alpha-carbonyl terminal alkyne of formula (VI) are directly available.

Compared with the prior art, the invention has the following beneficial effects:

the copper compound is used as a catalyst, and the 2, 4, 6-trisubstituted-N-sulfonyl 3-pyridine formamidine compound in the formula (I) can be obtained by reacting the O-acetyl aryl ketoxime derivative in the formula (II), the ammonium acetate in the formula (III), the aryl aldehyde in the formula (IV), the sulfonyl azide in the formula (V) and the alpha-carbonyl terminal alkyne in the formula (VI) in a one-pot method, so that the copper compound has the advantages of high product yield, high purity, harmless byproducts, high atom economy and the like, has good scientific research value and application prospect, provides a brand new route for the preparation of the compound, can play an important role in the fields of drug intermediates, pesticide intermediates and the like, reduces the production cost, and has good application value and potential in industry and scientific research.

Detailed Description

The present inventors have conducted intensive studies in order to find a new synthesis method for synthesizing 3-pyridinecarboxamidine, after having paid extensive creative efforts, and thus completed the present invention. The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. 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.

Example 1

Adding the compounds of the formulas (II), (III), (IV), (V) and (VI) and cuprous iodide (CuI) into acetonitrile, heating to 60 ℃, and stirring at the temperature for sealing reaction for 24 hours; wherein the molar ratio of the compound of the formula (II) to the cuprous iodide (CuI) is 1:0.05, and the molar ratio of the compound of the formula (II) to the compounds of (III), (IV), (V) and (VI) is 1:1:1:1: 1; after the reaction is finished, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline solution in an equal volume ratio, oscillating and extracting for 2-4 times, and collecting an organic layerDrying, rotary evaporation and concentration to obtain a crude product, performing 200-mesh 300-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:5, so as to obtain a target product, namely the compound (C) of the formula (I), which is a white solid₂₆H₂₃N₃O₂S) yield 80.7% and purity 98.4% (HPLC).

Melting point: 230.8-231.4 ℃.

Nuclear magnetic resonance: 1HNMR (400MHz, dimethylsulfoxide DMSO-d6) δ 8.96(s,1H), 8.41(s,1H), 8.17-8.15(m,2H), 7.74(s,1H), 7.56(d, J ═ 7.8Hz,2H), 7.52-7.46(m,5H), 7.44-7.38(m,1H), 7.32-7.28(m,4H), 2.48(s,3H), 2.40(s, 3H).

13CNMR (400MHz, dimethylsulfoxide DMSO-d6) delta 163.7, 155.7, 154.4, 147.7, 142.3, 139.1, 138.0, 137.6, 129.4, 129.2(2C), 128.8(2C), 128.38, 128.36, 128.2(4C), 126.9(2C), 126.2(2C), 118.2, 22.3, 21.0.

Example 2

Adding the compounds of the formulas (II), (III), (IV), (V) and (VI) and cuprous iodide (CuI) into acetonitrile, heating to 80 ℃, and stirring at the temperature for sealing reaction for 12 hours; wherein the molar ratio of the compound of the formula (II) to the cuprous iodide (CuI) is 1:0.2, and the molar ratio of the compound of the formula (II) to the compounds of (III), (IV), (V) and (VI) is 1:2:2:2: 2; after the reaction is completed, naturally cooling the reaction system to room temperature, distilling under reduced pressure to remove the solvent to obtain a crude product, carrying out chromatography on the crude product by a 200-mesh 300-mesh silica gel column, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:8, so as to obtain a target product (C) of the compound (I) which is a white solid₂₇H₂₅N₃O₃S), yield 82.5% and purity 97.2% (HPLC).

Melting point: 227.1-228.3 ℃.

Nuclear magnetic resonance: 1HNMR (400MHz, dimethylsulfoxide DMSO-d6) δ 8.96(s,1H), 8.41(s,1H), 8.13(d, J ═ 6.8Hz,2H), 7.70(s,1H), 7.58(d, J ═ 7.8Hz,2H), 7.51-7.45(m,3), 7.39(d, J ═ 8.4Hz,2H), 7.31(d, J ═ 8.1Hz,2H), 3.79(s,3H), 2.47(s,3H), 2.40(s, 3H).

13CNMR (400MHz, dimethylsulfoxide DMSO-d6) delta 164.1, 160.0, 155.7, 154.5, 147.4, 142.4, 139.1, 138.2, 129.9(2C), 129.6(2C), 129.4, 129.3(2C), 128.8(2C), 128.4, 127.0(2C), 126.4(2C), 118.2, 113.7, 55.2, 22.3, 21.1.

Example 3

Adding the compounds of the formulas (II), (III), (IV), (V) and (VI) and cuprous iodide (CuI) into acetonitrile, heating to 90 ℃, and stirring at the temperature for sealing reaction for 8 hours; wherein the molar ratio of the compound of the formula (II) to the cuprous iodide (CuI) is 1:0.15, and the molar ratio of the compound of the formula (II) to the compounds of (III), (IV), (V) and (VI) is 1:1.5:1.5:1.5: 1.5; after the reaction is completed, naturally cooling the reaction system to room temperature, distilling under reduced pressure to remove the solvent to obtain a crude product, carrying out chromatography on the crude product by a 200-mesh 300-mesh silica gel column, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:6, so as to obtain a target product (C) of the compound (I) which is a white solid₃₀H₂₅N₃O₂S) yield 83.7% and purity 98.6% (HPLC).

Melting point: 215.5-217.4 ℃.

Nuclear magnetic resonance: 1HNMR (400MHz, dimethylsulfoxide DMSO-d6) δ 9.03(s,1H), 8.41(s,1H), 8.17(d, J ═ 6.8Hz,2H), 8.04(s,1H), 7.55(d, J ═ 7.4Hz,2H), 7.86(s,1H), 7.79(d, J ═ 5.7Hz,2H), 7.62-7.55(m,3H), 7.53-7.46(m,3H), 7.43(d, J ═ 8.2Hz,2H), 7.05(d, J ═ 8.0Hz,2H), 2.53(s,3H), 2.30(s, 3H).

13CNMR (400MHz, dimethylsulfoxide DMSO-d6) delta 163.8, 155.8, 154.6, 147.8, 142.2, 138.1, 135.3, 132.7, 132.6, 129.6, 129.1(3C), 128.9(2C), 128.7, 128.3, 127.8, 128.7, 127.6, 127.0, 126.7, 126.6, 126.1(3C), 118.6, 22.4, 21.1.

Example 4

Adding the compounds of the above formulas (II), (III), (IV), (V) and (VI) and copper iodide (CuI) into acetonitrile, then heating to 70 ℃, and stirring and sealing at the temperature for reaction for 12 hours; wherein the molar ratio of the compound of the formula (II) to the cuprous iodide (CuI) is 1:0.4, and the molar ratio of the compound of the formula (II) to the compounds of (III), (IV), (V) and (VI) is 1:2.5:2.5:2.5: 2.5; after the reaction is completed, naturally cooling the reaction system to room temperature, distilling under reduced pressure to remove the solvent to obtain a crude product, carrying out chromatography on the crude product by a 200-mesh 300-mesh silica gel column, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:10, so as to obtain a target product (C) of the compound (I) which is a white solid₂₄H₂₁N₃O₃S) yield 80.7% and purity 98.7% (HPLC).

Melting point: 135.4-136.6 ℃.

Nuclear magnetic resonance: 1HNMR (400MHz, dimethylsulfoxide DMSO-d6) δ 8.99(s,1H), 8.62(s,1H), 8.14(d, J ═ 7.2Hz,2H), 8.04(s,1H), 7.71-7.64(m,3H), 7.54-7.46(m,3H), 7.32(d, J ═ 7.0Hz,2H), 7.03(s,1H), 6.59-6.58(m,1H), 2.40(s,3H), 2.38(s, 3H).

13CNMR (400MHz, dimethyl sulfoxide DMSO-d6) delta 155.9, 155.1, 148.9, 144.8, 142.4, 138.0, 135.2, 129.5, 129.3(2C), 128.9(3C), 126.8(3C), 126.5(2C), 112.8, 112.5, 112.0, 22.2, 21.1.

Example 5

To acetonitrile, the compounds of the above formulae (II), (III), (IV), (V) and (VI), copper iodide (CuI) were added, followed by heating to 90 ℃ and stirring at that temperature to seal the reaction 6Hours; wherein the molar ratio of the compound of the formula (II) to the cuprous iodide (CuI) is 1:0.2, and the molar ratio of the compound of the formula (II) to the compounds of (III), (IV), (V) and (VI) is 1:3:3:3: 3; after the reaction is completed, naturally cooling the reaction system to room temperature, distilling under reduced pressure to remove the solvent to obtain a crude product, carrying out chromatography on the crude product by a 200-mesh 300-mesh silica gel column, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:12, so as to obtain a target product (C) of the compound (I) which is a white solid₂₆H₂₃N₃O₂S) yield 85.6% and purity 98.8% (HPLC).

Melting point: 148.2-150.3 ℃.

Nuclear magnetic resonance: 1HNMR (400MHz, dimethylsulfoxide DMSO-d6) δ 8.83(s,1H), 8.27(s,1H), 8.16, (d, J ═ 7.0Hz,2H), 7.77(s,1H), 7.58(d, J ═ 4.0Hz,2H), 7.52-7.44, (m,6H), 7.33-7.31(m,5H), 4.36(s,2H), 2.51(s, 3H).

13CNMR (400MHz, dimethylsulfoxide DMSO-d6) delta 164.2, 155.7, 154.6, 147.9, 138.1, 138.0, 131.1(2C), 130.2, 129.5, 128.9(2C), 128.6(3C), 128.5(3C), 128.1(2C), 127.9, 127.0(2C), 118.2, 58.6, 22.5.

Example 6

Adding the compounds of the formulas (II), (III), (IV), (V) and (VI) and cuprous iodide (CuI) into acetonitrile, heating to 100 ℃, and stirring and sealing at the temperature for reaction for 4 hours; wherein the molar ratio of the compound of the formula (II) to the cuprous iodide (CuI) is 1:0.2, and the molar ratio of the compound of the formula (II) to the compounds of (III), (IV), (V) and (VI) is 1:1.5:1.5:1.5: 1.5; after the reaction is completed, the reaction system is naturally cooled to room temperature, the solvent is removed by distillation under reduced pressure to obtain a crude product, the crude product is subjected to 200-mesh 300-mesh silica gel column chromatography, a mixed solution of ethyl acetate and petroleum ether is used as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:15, and thus the target product compound (I) (C26H22ClN3O2S) which is a white solid is obtained, the yield is 83.6%, and the purity is 97.2% (HPLC).

Melting point: 160.7-162.6 ℃.

Nuclear magnetic resonance: 1HNMR (400MHz, dimethylsulfoxide DMSO-d6) δ 8.93(s,1H), 8.40(s,1H), 8.20(d, J ═ 8.4Hz,2H), 7.78(s,1H), 7.56-7.54(m,4H), 7.47(d, J ═ 7.4Hz,2H), 7.40-7.34(m,1H), 7.31-7.26(m,4H), 2.47(s,3H), 2.40(s, 3H).

13CNMR (400MHz, dimethylsulfoxide DMSO-d6) delta 163.6, 154.6, 154.2, 147.9, 142.3, 137.6, 136.8, 134.3, 129.4, 129.3(2C), 128.9(2C), 128.7(3C), 128.5, 128.3(3C), 126.2(2C), 125.7, 118.4, 22.3, 21.1.

Comparative examples 7 to 14: investigation of the catalyst

Examples 7 to 14 were each carried out in the same manner as in examples 1 to 4 except that the CuI therein was replaced with the following copper compound, and the copper compounds used, the correspondence relationships between examples and the yields of the respective products are shown in the following tables.

The results obtained are shown in the following table.

It can be seen that when other copper compounds are used, the corresponding products are obtained, and the reaction of the monovalent copper compounds is generally more effective than that of the divalent, which demonstrates that the monovalent copper compound catalyst of the process of the present invention has good catalytic properties for the substrate, with CuI being the most effective catalyst for the reaction.

Comparative examples 15 to 22: investigation of solvents

Examples 15 to 22 were each carried out in the same manner as in examples 1 to 4 except that the solvent was replaced with acetonitrile as follows, and the solvents used, the correspondence among examples, and the yields of the respective products were as shown in the following tables.

It can be seen that the solvent also has some influence on the final result, with acetonitrile having the best effect, dimethylsulfoxide DMSO being inferior, and the yield of other solvents being greatly reduced.

From the above, it is clear from all the above examples that when the method of the present invention is used, the compounds of formulae (II), (III), (IV), (V) and (VI) can be smoothly reacted to obtain the target product, and the yield is good, the post-treatment is simple, and the effects are obtained depending on the combined synergistic effect of a plurality of factors such as the catalyst, the ligand and the solvent, and the yield is significantly reduced when any one of the factors is changed.

The aspects, embodiments, features and examples of the present invention should be considered as illustrative in all respects and not intended to be limiting of the invention, the scope of which is defined only by the claims. Other embodiments, modifications, and uses will be apparent to those skilled in the art without departing from the spirit and scope of the claimed invention.

The use of headings and chapters in this disclosure is not meant to limit the disclosure; each section may apply to any aspect, embodiment, or feature of the disclosure.

Throughout this disclosure (the present invention), where a composition is described as having, containing, or comprising specific components or where a process is described as having, containing, or comprising specific process steps, it is contemplated that the composition taught by the present invention also consists essentially of, or consists of, the recited components, and the process taught by the present invention also consists essentially of, or consists of, the recited process steps.

Unless specifically stated otherwise, use of the terms "comprising", "including", "having" or "having" is generally to be understood as open-ended and not limiting.

It should be understood that the order of steps or the order in which particular actions are performed is not critical, so long as the teachings of the invention remain operable. Further, two or more steps or actions may be performed simultaneously.

In addition, the inventors of the present invention have also made experiments with other materials, process operations, and process conditions described in the present specification with reference to the above examples, and have obtained preferable results.

While the invention has been described with reference to illustrative embodiments, it will be understood by those skilled in the art that various other changes, omissions and/or additions may be made and substantial equivalents may be substituted for elements thereof without departing from the spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from its scope. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Moreover, unless specifically stated any use of the terms first, second, etc. do not denote any order or importance, but rather the terms first, second, etc. are used to distinguish one element from another.