CN112409248B - 3-pyridine formamidine derivative and catalytic synthesis method thereof - Google Patents
3-pyridine formamidine derivative and catalytic synthesis method thereof Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
The utility model 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), R1、R2、R4Is selected from
Wherein, 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. The 3-pyridine formamidine derivative and the catalytic synthesis method thereof provided by the utility model are synthesized by a one-pot method, have the advantages of high product yield, high purity, harmless byproducts, high atom economy and the like, have good scientific research value and application prospect, provide a green synthesis method for the preparation of the compound, can play an important role in the fields of drug intermediates, pesticide intermediates and the like, reduce the production cost, and have good application value and potential in industry and scientific research.
Description
Technical Field
The utility model 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, these synthesis techniques have been usedGreat improvement has been made 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 utility model 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 utility model 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 from
Wherein, 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 utility model 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 utility model 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 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 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 above formulae (II), (III), (IV), (V) and (VI) to acetonitrile, iodinatingCuprous (CuI), then 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, and performing 200-mesh-300-mesh silica gel column chromatography on the crude product to obtain a productUsing a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of ethyl acetate to petroleum ether is 1:10, thereby obtaining a target product, namely a compound (C) of the formula (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
Adding the compounds of the above 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 6 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 1:3:3:3: 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 utility model, 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 (invention) is not meant to limit the disclosure; each section may apply to any aspect, embodiment, or feature of the disclosure.
Throughout this specification, 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 utility model 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 utility model 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 utility model. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the utility model without departing from its scope. Therefore, it is intended that the utility model not be limited to the particular embodiment disclosed for carrying out this invention, but that the utility model 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.
Claims (6)
1. A catalytic synthesis method of 3-pyridine formamidine derivatives is characterized in that,
adding the compounds of the formulas (II), (III), (IV), (V) and (VI) and cuprous iodide 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 cuprous iodide 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, performing oscillation extraction for 2-4 times, collecting an organic layer, drying, performing rotary evaporation and concentration to obtain a crude product, performing 200-mesh and 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 formula (I) which is a white solid; the yield was 80.7% and the HPLC purity was 98.4%.
2. A catalytic synthesis method of 3-pyridine formamidine derivatives is characterized in that,
adding the compounds of the formulas (II), (III), (IV), (V) and (VI) and cuprous iodide into acetonitrile, heating to 80 ℃, and stirring and sealing at the temperature for reaction for 12 hours; wherein the molar ratio of the compound of the formula (II) to cuprous iodide 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, carrying out reduced pressure distillation to remove the solvent to obtain a crude product, carrying out 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 1:8, so as to obtain the target product formula (I) which is a white solid, wherein the yield is 82.5%, and the purity of HPLC is 97.2%.
3. A catalytic synthesis method of 3-pyridine formamidine derivatives is characterized in that,
adding the compounds of the formulas (II), (III), (IV), (V) and (VI) and cuprous iodide into acetonitrile, heating to 90 ℃, and stirring and sealing at the temperature for reaction for 8 hours; wherein the molar ratio of the compound of the formula (II) to cuprous iodide 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, carrying out reduced pressure distillation to remove the solvent to obtain a crude product, carrying out 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 1:6, so as to obtain the target product formula (I) which is a white solid, wherein the yield is 83.7%, and the purity of HPLC is 98.6%.
4. A catalytic synthesis method of 3-pyridine formamidine derivatives is characterized in that,
adding the compounds of the formulas (II), (III), (IV), (V) and (VI) and cuprous iodide into acetonitrile, 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 cuprous iodide 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, carrying out reduced pressure distillation to remove the solvent to obtain a crude product, carrying out 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 1:10, so as to obtain the target product formula (I) which is a white solid, wherein the yield is 80.7%, and the purity of HPLC is 98.7%.
5. A catalytic synthesis method of 3-pyridine formamidine derivatives is characterized in that,
adding the compounds of the formulas (II), (III), (IV), (V) and (VI) and cuprous iodide into acetonitrile, heating to 90 ℃, and stirring and sealing at the temperature for reaction for 6 hours; wherein the molar ratio of the compound of the formula (II) to cuprous iodide 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, carrying out reduced pressure distillation to remove the solvent to obtain a crude product, carrying out 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 1:12, so as to obtain the target product formula (I) which is a white solid, wherein the yield is 85.6%, and the purity of HPLC is 98.8%.
6. A catalytic synthesis method of 3-pyridine formamidine derivatives is characterized in that,
adding the compounds of the formulas (II), (III), (IV), (V) and (VI) and cuprous iodide 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 cuprous iodide 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, naturally cooling the reaction system to room temperature, carrying out reduced pressure distillation to remove the solvent to obtain a crude product, carrying out 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 1:15, so as to obtain the target product formula (I) which is a white solid, wherein the yield is 83.6%, and the purity of HPLC is 97.2%.
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| CN110483391A (en) * | 2019-09-17 | 2019-11-22 | 广东医科大学 | A kind of five component synthetic methods of nicotimine amide derivatives |
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| CN110483391A (en) * | 2019-09-17 | 2019-11-22 | 广东医科大学 | A kind of five component synthetic methods of nicotimine amide derivatives |
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| Highly Efficient One-Pot Synthesis of N-Sulfonylamidines by Cu-Catalyzed Three-Component Coupling of Sulfonyl Azide, Alkyne, and Amine;Imhyuck Bae et al.,c;《J. AM. CHEM. SOC.》;20051231;第127卷(第7期);第2038-2039页 * |
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