CN110183378B - Nicotinamide derivative and catalytic synthesis method thereof - Google Patents
Nicotinamide derivative and catalytic synthesis method thereof Download PDFInfo
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- CN110183378B CN110183378B CN201910595185.8A CN201910595185A CN110183378B CN 110183378 B CN110183378 B CN 110183378B CN 201910595185 A CN201910595185 A CN 201910595185A CN 110183378 B CN110183378 B CN 110183378B
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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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Abstract
The invention provides a nicotinamide derivative and a catalytic synthesis method thereof, wherein the derivative is 2-methyl-4, 6-diphenyl-N-p-toluenesulfonyl nicotinamide, and the structure of the derivative is shown in a formula (I); the catalytic synthesis method comprises the following steps: in the presence of a copper catalyst and a ligand, chalcone oxime shown in a formula (II), p-toluenesulfonyl azide shown in a formula (III) and 3-butyn-2 ketone shown in a formula (IV) are stirred to react, so that a compound shown in a formula (I) is obtained.
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a nicotinamide derivative and a catalytic synthesis method thereof.
Background
Nicotinamide derivatives containing pyridine heterocycles are a very important class of organic molecules, which are important structures in coenzymes and drugs. For example, nicotinamide is a component of coenzyme I (nicotinamide adenine dinucleotide), coenzyme II (nicotinamide adenine dinucleotide phosphate), phosphoribosyltransferase, and the like, and plays roles of redox, anti-inflammation, anti-bacterial, anti-aging, and the like in a living body.
The nicotinamide derivative has specificity in antifungal aspect, can specifically inhibit and mediate the activity of 56 th lysine deacetylase on histone H3 to generate antifungal effect, and also has obvious inhibiting effect on pathogenic fungi of skin. In view of the wide and safe pharmacological effects of nicotinamide derivatives, and the existing data, nicotinamide has a relatively single structure and few varieties, and the antifungal efficacy is to be further improved, we expect to develop novel nicotinamide derivatives with higher antifungal efficacy by designing a catalytic synthesis method.
Allais, C.et al ("Metal-free multicomponent syntheses of pyridines", chem.Rev.2014,114,10829-10868.) disclose the synthesis of nicotinamide derivatives by the Hantzsch pyridine synthesis starting from a β -carbonylamide derivative, another carbonyl compound, an aldehyde, and ammonium. The method comprises the steps of synthesizing dihydropyridine under the action of acids such as acetic acid, citric acid, p-toluenesulfonyl acid and the like, adding oxidants such as nitrous acid or potassium ferricyanide and the like for oxidation to obtain a target product, and synthesizing in multiple steps, wherein the operation is complicated.
Khan, m.n. et al ("a simple and effective methods for the surface access of high purity functionalized pyridines and the fluorine properties studios", RSC adv.2012,2,12305-12314.) disclose the synthesis of 3-cyanopyridine starting from malononitrile derivatives, which is further hydrolyzed to give nicotinamide derivatives. The method also needs to be carried out in multiple steps, and has the defects of harsh reaction conditions, poor functional group compatibility, environmental friendliness and the like in the hydrolysis process.
In recent years, the synthesis of polysubstituted pyridines starting from ketoximes or ketoxime esters has been the subject of intense research ("Vessally, E.; Saeidian, H.; Hosseini, A.; Edjlali, L.; Bekhradnia, A.A review on synthetic applications of oxide esters, curr. org. chem.2017,21, 249-" 271 "). The method uses a monovalent copper source reagent for catalysis, introduces oxime with oxidability into the raw material, not only can provide an amine source, but also oxidizes dihydropyridine generated in the reaction, and realizes the synthesis of a one-pot method. However, the diversity of the product is limited due to the low activity of the beta-carbonyl amide derivative in the reaction, low product yield, the complex structure of the beta-carbonyl amide derivative needing to be synthesized in advance and the like. Therefore, it is necessary to develop a one-pot method for synthesizing nicotinamide derivative, which has the advantages of easily available raw materials, simple conditions and high efficiency.
As described above, various synthetic methods for nicotinamide derivatives have been disclosed in the prior art, but these methods have disadvantages of multi-step process synthesis, expensive and difficult raw materials, low product yield, etc., and there is still a need for developing new synthetic methods for nicotinamide derivatives, which is the basis and the motivation for the completion of the present invention.
Disclosure of Invention
The invention aims to provide a nicotinamide (nicotinamide) derivative and a catalytic synthesis method thereof, wherein the derivative is a 2-methyl-4, 6-diphenyl-N-p-toluenesulfonyl nicotinamide compound (C)26H22N2O3S), the reaction conditions are simple, and good yield is obtained.
In order to achieve the purpose, the invention is realized by the following technical scheme:
a nicotinamide derivative is 2-methyl-4, 6-diphenyl-N-p-toluenesulfonyl nicotinamide, and the structure of the nicotinamide derivative is shown in a formula (I):
the nicotinamide derivative compound shown in formula (I) in the invention is 2-methyl-4, 6-diphenyl-N-p-toluenesulfonyl nicotinamide compound (C)26H22N2O3S) catalytic synthesis process comprising the steps of: in the presence of a copper catalyst and a ligand, chalcone oxime (a compound of a formula (II)) shown in a formula (II), p-toluenesulfonyl azide (a compound of a formula (III)) shown in a formula (III) and 3-butyn-2 one (a compound of a formula (IV)) shown in a formula (IV) are stirred to react, so that the compound (the compound of the formula (I)) shown in the formula (I) is obtained.
In the catalytic synthesis method of the present invention, the copper catalyst is copper acetate (Cu (OAc)2) Copper chloride (CuCl)2) Copper bromide (CuBr) 2) Copper acetylacetonate (Cu (acac)2) Copper trifluoroacetate (Cu (TFA)2) Any one of cuprous iodide (CuI), cuprous bromide (CuBr), cuprous chloride (CuCl), thiophene-2-carboxylate (CuTc), and cuprous acetate (CuOAc), preferably cuprous iodide (CuI), cuprous chloride (CuCl), or cuprous acetate (CuOAc), and most preferably cuprous acetate (CuOAc).
In the catalytic synthesis method of the present invention, the ligand is acetonitrile (MeCN), N-Dimethylformamide (DMF), triethylamine (Et)3N), N-tributylamine (nBu3N), tri-tert-butylamine (tBu3N), 2-fluoropyridine (2-FPy), 2-chloropyridine (2-ClPy), 2-bromopyridine (2-BrPy), 2-iodopyridine (2-BrPy), tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl]Any one of the amines (TBTA) or without the addition of a ligand, preferably tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl [ ]]Any one of amine (TBTA) and acetonitrile (MeCN) or no ligand is added (acetonitrile is used as a solvent when no ligand is added), and most preferably tri [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl]Amine (TBTA). .
In the catalytic synthesis method of the present invention, the molar ratio of the compound of formula (II) to the catalyst and the ligand is 1:0.05 to 0.4:0.1 to 2, and may be, for example, 1:0.1:0.1, 1:0.2:0.2, 1:0.25:0.5, 1:0.2:1, or the like.
In the catalytic synthesis method of the present invention, the molar ratio of the compound of formula (II), the compound of formula (III) and the compound of formula (IV) is 1:1 to 3, and may be, for example, 1:1:1, 1:1.5:1.5 or 1:3: 3.
In the catalytic synthesis method of the present invention, the organic solvent may be any one of ethanol (EtOH), acetonitrile (MeCN), Tetrahydrofuran (THF), N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), chlorobenzene, benzene, xylene, N-methylpyrrolidone (NMP), and most preferably acetonitrile (MeCN).
Wherein, MeCN can be used as a reaction solvent and a ligand for smoothly carrying out the reaction, so that the method not only can be simply and conveniently operated and is convenient for reaction control, but also can be further and conveniently carried out after treatment, thereby being more convenient for the operation of the whole reaction.
In the catalytic synthesis method of the present invention, the ratio of the compound represented by formula (II) in millimoles (mmol) to the solvent in milliliters (mL) is 1:5-15, i.e., 5-15 milliliters (mL) of solvent is used for every 1 millimole (mmol) of the compound represented by formula (II), and the specific ratio can be 1:5, 1:8, 1:10, 1:12 or 1: 15.
In the catalytic synthesis process of the present invention, the reaction temperature is 25 to 80 ℃, and may be, for example, 25 ℃, 40 ℃, 60 ℃ or 80 ℃. The reaction time is 0.5 to 8 hours, and may be, for example, 0.5 hour, 1 hour, 2 hours, 4 hours or 8 hours.
In the method of the present invention, the post-treatment after the completion of the reaction may be any one treatment means or a combination of a plurality of treatment means such as extraction, concentration, crystallization, recrystallization, column chromatography purification, and the like. As an exemplary post-treatment means, for example, there may be mentioned: 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 chromatography on the crude product through 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 1:5-10, thereby obtaining the target product, namely the compound shown in the formula (I).
In the catalytic synthesis method of the present invention, the compounds of formula (III) and the compounds of formula (IV) as starting materials can be purchased directly.
In the catalytic synthesis method of the present invention, the synthesis method of the compound of formula (II) as a starting material is as follows: in an organic solvent, in the presence of alkali, a chalcone compound (a compound of a formula (V)) shown as a formula (V) and a hydroxylamine hydrochloride compound (a compound of a formula (VI)) shown as a formula (VI) are stirred to react, so that a compound of a formula (II) is obtained.
In the synthesis method of the compound of formula (II), the base is any one of pyridine, triethylamine, potassium carbonate, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, etc., preferably pyridine or triethylamine, and most preferably pyridine.
In the method for synthesizing the compound of formula (II), the organic solvent is any one of methanol (MeOH), ethanol (EtOH), acetonitrile (MeCN), N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), chlorobenzene, benzene, xylene, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), preferably methanol (MeOH) or ethanol (EtOH); ethanol (EtOH) is most preferred.
The amount of the organic solvent is not particularly limited, and may be determined and selected by those skilled in the art according to conventional techniques, for example, to facilitate the reaction and control, and to facilitate the post-treatment.
In the synthesis method of the compound of the formula (II), the molar ratio of the compound of the formula (V), the compound of the formula (VI) and the base is 1: 1.5-4: 2-6, for example 1:1.5:2.5, 1:2:3, 1:2.5:4 or 1:3: 6.
In the process for the synthesis of the compounds of formula (II), the reaction temperature is 60-100 ℃ and may be, for example, 60 ℃, 70 ℃, 80 ℃ or 100 ℃. The reaction time is 4 to 12 hours, and may be, for example, 4 hours, 8 hours or 12 hours.
In the synthesis method of the compound of the formula (II), the post-treatment after the reaction is specifically: after the reaction is finished, naturally cooling the reaction system to room temperature, distilling under reduced pressure to remove the solvent to obtain a mixture, pouring the mixture into a reaction kettle with the volume ratio of 1:1, extracting with water and ethyl acetate for 2-4 times, collecting organic phase, washing with 1mol/L dilute hydrochloric acid and saturated brine, and MgSO 4Drying, distilling under reduced pressure and spin-drying to obtain a crude product, and subjecting the crude product to 200-mesh 300-mesh silica gel column chromatography by using 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, namely the compound shown in the formula (II).
As described above, the present invention provides a compound of formula (I), and provides a synthetic method of the compound, wherein the compound of formula (I) can be obtained by selection and synergistic action of a suitable catalyst and a ligand, the reaction conditions are simple, and a good yield is obtained, so that a new synthetic route is provided for preparation of nicotinamide derivatives, and the synthetic method has good application value and potential in industry and scientific research.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
Example 1:
adding chalcone shown in a formula (V), hydroxylamine hydrochloride shown in a formula (VI) and pyridine into a proper amount of EtOH, heating to 60 ℃, and stirring and reacting for 12 hours at the temperature; wherein, the molar ratio of the chalcone shown in the formula (V) to the hydroxylamine hydrochloride shown in the formula (VI) to the pyridine is 1:1.5: 2.5.
After the reaction is finished, naturally cooling the reaction system to room temperature, distilling under reduced pressure to remove the solvent to obtain a mixture, pouring the mixture into a reaction kettle with the volume ratio of 1:1, extracting with water and ethyl acetate for 2-4 times, collecting organic phase, washing with 1mol/L dilute hydrochloric acid and saturated brine, and MgSO4Drying, distilling under reduced pressure and spin-drying to obtain a crude product, and subjecting the crude product to chromatography on a 200-mesh 300-mesh silica gel column by using 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 the compound of the formula (II) as a white solid, the melting point is 112.3-114.4 ℃, and the yield is 82.6%.
Example 2:
the reaction scheme is the same as that of example 1, and the operation is specifically as follows:
adding chalcone shown in a formula (V), hydroxylamine hydrochloride shown in a formula (VI) and pyridine into a proper amount of EtOH, heating to 70 ℃, and stirring and reacting for 8 hours at the temperature; wherein, the molar ratio of the chalcone shown in the formula (V) to the hydroxylamine hydrochloride shown in the formula (VI) to the pyridine is 1:2: 3.
After the reaction is finished, the reaction system is naturally cooled to room temperature, the solvent is removed through reduced pressure distillation to obtain a mixture, and the mixture is poured into a reaction kettle 1: 1, extracting with water and ethyl acetate for 2-4 times, collecting organic phase, washing with 1mol/L dilute hydrochloric acid and saturated brine, MgSO4Drying, distilling under reduced pressure and spin-drying to obtain a crude product, and subjecting the crude product to 200-mesh 300-mesh silica gel column chromatography with 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 compound of the formula (II) as a white solid, the melting point is the same as that of example 1, and the yield is 84.5%.
Example 3:
the reaction scheme is the same as that of example 1, and the operation is specifically as follows:
adding chalcone shown in a formula (V), hydroxylamine hydrochloride shown in a formula (VI) and pyridine into a proper amount of EtOH, heating to 80 ℃, and stirring and reacting for 6 hours at the temperature; wherein, the molar ratio of the chalcone shown in the formula (V) to the hydroxylamine hydrochloride shown in the formula (VI) to the pyridine is 1:2.5: 4.
After the reaction is finished, naturally cooling the reaction system to room temperature, distilling under reduced pressure to remove the solvent to obtain a mixture, pouring the mixture into a reaction kettle with the volume ratio of 1: 1, extracting with water and ethyl acetate for 2-4 times, collecting organic phase, washing with 1mol/L dilute hydrochloric acid and saturated brine, and MgSO 4Drying, distilling under reduced pressure and spin-drying to obtain a crude product, and subjecting the crude product to chromatography on a 200-mesh 300-mesh silica gel column by using 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 1:7, so as to obtain the compound of the formula (II) as a white solid, the melting point is the same as that of example 1, and the yield is 80.7%.
Example 4:
the reaction scheme is the same as that of example 1, and the operation is specifically as follows:
adding chalcone shown in a formula (V), hydroxylamine hydrochloride shown in a formula (VI) and pyridine into a proper amount of EtOH, heating to 80 ℃, and stirring and reacting for 4 hours at the temperature; wherein, the molar ratio of the chalcone shown in the formula (V) to the hydroxylamine hydrochloride shown in the formula (VI) to the pyridine is 1:3: 6.
After the reaction is finished, naturally cooling the reaction system to room temperature, distilling under reduced pressure to remove the solvent to obtain a mixture, pouring the mixture into a reaction kettle with the volume ratio of 1:1, extracting with water and ethyl acetate for 2-4 times, collecting organic phase, washing with 1mol/L dilute hydrochloric acid and saturated brine, and MgSO4Drying, distilling under reduced pressure and spin-drying to obtain a crude product, and subjecting the crude product to 200-mesh 300-mesh silica gel column chromatography with 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 compound of the formula (II) as a white solid, the melting point is the same as that of example 1, and the yield is 83.3%.
Comparative examples 1 to 24: investigation of bases
Comparative examples 1 to 4: comparative examples 1 to 4 were carried out without changing the operation except that the base in examples 1 to 4 was replaced with triethylamine from pyridine, respectively.
Comparative examples 5 to 8: comparative examples 5 to 8 were carried out without changing the operations except that the bases in examples 1 to 4 were respectively replaced with potassium carbonate from pyridine.
Comparative examples 9 to 12: comparative examples 9 to 12 were carried out without changing the operation except that the bases in examples 1 to 4 were respectively replaced with sodium ethoxide from pyridine.
Comparative examples 13 to 16: comparative examples 13 to 16 were carried out without changing the operation except that the bases in examples 1 to 4 were each replaced with potassium tert-butoxide by pyridine.
Comparative examples 17 to 20: comparative examples 17 to 20 were carried out without changing the operation except that the alkali in examples 1 to 4 was replaced with sodium hydroxide from pyridine, respectively.
Comparative examples 21 to 24: comparative examples 21 to 24 were carried out without changing the operation except that the bases in examples 1 to 4 were respectively replaced with ammonium acetate from pyridine.
The results obtained are shown in table 1.
Table 1:
it can be seen that the base species has a significant effect on the product yield, with pyridine having the best effect, and even triethylamine, which is similar to pyridine, has a significant decrease in yield.
Comparative examples 25 to 32: investigation of solvents
Comparative examples 25 to 32 were each conducted in the same manner as in examples 1 to 4 except that the solvent therein was replaced with ethanol in the following manner, and the solvents used, the correspondence with the examples and the yields of the respective products are shown in Table 2.
Table 2:
it follows that the solvent also has some influence on the end result, with EtOH having the best effect, even though MeOH, which is very similar thereto, has a somewhat reduced yield.
Example 5:
adding chalcone oxime shown in a formula (II), p-toluenesulfonyl azide shown in a formula (III), 3-butyn-2 ketone shown in a formula (IV), cuprous acetate (CuOAc) and tri [ (1-benzyl-1H-1, 2, 3-triazole-4-yl) methyl ] amine (TBTA) into MeCN, heating to 60 ℃, and stirring, sealing and reacting for 4 hours at the temperature; wherein the molar ratio of the compound of formula (II), cuprous acetate (CuOAc), tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) is 1:0.1:0.1, the molar ratio of the compound of formula (II) to the compound of formula (III), the molar ratio of the compound of formula (IV) is 1:1.2:1.2, and the ratio of the compound of formula (II) in millimoles (mmol) to MeCN in milliliters (ml) is 1: 4.
Reaction ofAfter 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, performing chromatography on the crude product by using 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 1:5, thereby obtaining a target product, namely the compound (C) of the formula (I), which is a white solid26H22N2O3S), yield 90.7%.
Melting point: 202.8-204.4 ℃.
Nuclear magnetic resonance:1HNMR(400MHz,DMSO-d6)δ12.64(s,1H),8.16(d,J＝6.4Hz,2H),7.78(s,1H),7.71(d,J＝8.2Hz,2H),7.52-7.46(m,3H),7.43-7.39(m,3H),7.37-7.34(m,2H),7.28-7.24(m,2H),2.45(s,3H),2.44(s,3H)。
13CNMR(100MHz,DMSO-d6)δ166.8,156.2,154.1,147.7,144.4,137.8,137.0,135.8,129.6(3C),128.8(2C),128.6,128.5(2C),128.1(3C),127.6(2C),127.0(2C),118.1,22.3,21.2。
example 6:
the reaction scheme is the same as example 5, specifically:
adding chalcone oxime shown in a formula (II), p-toluenesulfonyl azide shown in a formula (III), 3-butyn-2 ketone shown in a formula (IV), cuprous acetate (CuOAc) and tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) into MeCN, heating to 80 ℃, and stirring and sealing at the temperature for reacting for 8 hours; wherein the molar ratio of compound of formula (II), cuprous acetate (CuOAc), tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) is 1:0.2:0.2, the molar ratio of compound of formula (II) to compound of formula (III) and compound of formula (IV) is 1:2:2, and the ratio of compound of formula (II) in millimoles (mmol) to MeCN in milliliters (ml) is 1: 8.
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 1:5, so as to obtain a target product (C) of the compound (I) which is a white solid 26H22N2O3S)，The yield was 87.5%.
Melting point and NMR data were the same as in example 5.
Example 7:
the reaction scheme is the same as example 5, specifically:
adding chalcone oxime shown in a formula (II), p-toluenesulfonyl azide shown in a formula (III), 3-butyn-2 ketone shown in a formula (IV), cuprous acetate (CuOAc) and tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) into MeCN, heating to 90 ℃, and stirring and sealing at the temperature for reaction for 2 hours; wherein the molar ratio of the compound of formula (II), cuprous acetate (CuOAc), tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) is 1:0.15:0.3, the molar ratio of the compound of formula (II) to the compound of formula (III) and the compound of formula (IV) is 1:1.5:1.5, and the ratio of the compound of formula (II) in millimoles (mmol) to MeCN in milliliters (ml) is 1: 6.
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 1:5, so as to obtain a target product (C) of the compound (I) which is a white solid26H22N2O3S), yield 88.7%.
Melting point and NMR data were as in example 5.
Example 8:
the reaction scheme is the same as example 5, specifically:
adding chalcone oxime shown in a formula (II), p-toluenesulfonyl azide shown in a formula (III), 3-butyn-2 ketone shown in a formula (IV), cuprous acetate (CuOAc) and tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) into MeCN, heating to 70 ℃, and stirring and sealing at the temperature for reaction for 12 hours; wherein the molar ratio of the compound of formula (II), cuprous acetate (CuOAc), tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) is 1:0.25:0.5, the molar ratio of the compound of formula (II) to the compound of formula (III) and the compound of formula (IV) is 1:2.5:2.5, and the ratio of the compound of formula (II) in millimoles (mmol) to MeCN in milliliters (ml) is 1: 10.
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 1:5, so as to obtain a target product (C) of the compound (I) which is a white solid26H22N2O3S), the yield was 89.6%.
Melting point and NMR data were the same as in example 5.
Comparative examples 33 to 60: examination of catalyst
Comparative examples 33 to 36: comparative examples 33-36 were performed without changing the operation of the catalysts of examples 5-8 from cuprous acetate (CuOAc) to cuprous chloride (CuCl), respectively.
Comparative examples 37 to 40: except that the catalysts in examples 5-8 were replaced with copper (CuOAc) acetate instead of copper (CuBr) bromide (CuOAc), respectively2) In addition, comparative examples 37 to 40 were carried out without changing the other operations.
Comparative examples 41 to 44: except that the catalysts in examples 5-8 were replaced with copper (Cu) (OTf) trifluoromethanesulfonate instead of copper (CuOAc) acetate2) In addition, comparative examples 41 to 44 were carried out without changing the other operations.
Comparative examples 45 to 48: except that the catalysts in examples 5-8 were replaced with copper acetate (CuOAc) for copper acetate (Cu (OAc)2) In addition, comparative examples 45 to 48 were carried out without changing the other operations.
Comparative examples 49 to 52: comparative examples 49-52 were conducted without changing the operation of the catalysts of examples 5-8 from copper acetate (CuOAc) to copper thiophene-2-carboxylate (CuTc), respectively.
Comparative examples 53 to 56: comparative examples 53 to 56 were carried out without changing the operation of the catalysts of examples 5 to 8 from cuprous acetate (CuOAc) to copper oxide (CuO), respectively.
Comparative examples 57 to 60: comparative examples 57-60 were conducted without changing the operation of the catalysts of examples 5-8 from copper acetate (CuOAc) to copper iodide (CuI), respectively.
The results obtained are shown in Table 3.
Table 3:
therefore, the kind of catalyst has a significant influence on the product yield, wherein cuprous acetate (CuOAc) or cuprous iodide (CuI) has a better catalytic effect, cuprous acetate has the best catalytic performance, the catalytic effect of the monovalent copper source is generally better than that of the divalent copper source, the yield of the catalytic reaction of the divalent copper source is reduced to 53.8-56.5% or even lower, and the value of the practical application is lost.
Comparative examples 61 to 68: investigation of ligands
Comparative examples 61 to 68 were each carried out in the same manner as in examples 5 to 8 except that the ligand was changed from tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) to the following ligand, and the ligand used, the correspondence relationship of examples and the yield of the corresponding product were as shown in Table 2.
Table 4:
it can be seen that, of all the ligands, tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl]Amine (TBTA) or solvent acetonitrile (which is also a ligand when no ligand is added) has proper coordination, and other ligands have obviously reduced yield, even the product cannot be obtained. Furthermore, it can be seen that even with tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl group ]Triethylamine (Et) with very similar amine (TBTA)3N) and the like, the coordination effect is also greatly reduced to 28.4 percent, and other 1, 10-phenanthroline (Phen) and the like with strong coordination have more remarkable reduction or even no reaction.
Comparative examples 69 to 76: investigation of solvents
Comparative examples 69 to 76 were each carried out in the same manner as in examples 5 to 8 except that the solvent was replaced with acetonitrile, and the solvents used, the correspondence among examples, and the yields of the respective products were as shown in Table 5.
Table 5:
it follows that the solvent also has some influence on the end result, with acetonitrile having the best effect and a considerable reduction in yield even if the complexation is DMF which is very similar to it.
From the above, it is clear from all the examples that when the method of the present invention is adopted, the compound of formula (II), the compound of formula (III) and the compound of formula (IV) can be smoothly reacted to obtain the desired 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 when any one of the factors is changed, the yield is significantly reduced.
It will be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should also be understood that various alterations, modifications and/or variations can be made to the present invention by those skilled in the art after reading the technical content of the present invention, and all such equivalents fall within the protective scope defined by the claims of the present application.
Claims (4)
1. A catalytic synthesis method of nicotinamide derivatives is characterized in that the nicotinamide derivatives are 2-methyl-4, 6-diphenyl-N-p-toluenesulfonyl nicotinamide, and the structure of the nicotinamide derivatives is shown in a formula (I):
the catalytic synthesis method of the nicotinamide derivative comprises the following steps: in the presence of a copper catalyst and a ligand, chalcone oxime shown in a formula (II), p-toluenesulfonyl azide shown in a formula (III) and 3-butyn-2 ketone shown in a formula (IV) are stirred to react to obtain a compound shown in a formula (I),
the copper catalyst is any one of cuprous iodide, cuprous chloride and cuprous acetate;
the ligand is acetonitrile or tri [ (1-benzyl-1H-1, 2, 3-triazole-4-yl) methyl ] amine;
the synthesis method of the compound shown as the formula (II) is as follows: in an organic solvent, in the presence of alkali, stirring and reacting a compound shown as a formula (V) and a compound shown as a formula (VI) to obtain a compound shown as a formula (II);
The organic solvent is acetonitrile, methanol or ethanol; the alkali is pyridine or triethylamine.
2. The catalytic synthesis method of nicotinamide derivatives of claim 1, characterized in that the molar ratio of chalcone oxime represented by formula (II), copper catalyst and ligand is 1:0.05-0.4: 0.1-2; the molar ratio of chalcone oxime shown in a formula (II), p-toluenesulfonyl azide shown in a formula (III) and 3-butyn-2 one shown in a formula (IV) is 1:1-3: 1-3.
3. The process for the catalytic synthesis of derivatives of nicotinamide according to claim 1, characterized in that, in the step of preparing formula (I), the reaction temperature is 25-80 ℃ and the reaction time is 0.5-8 hours.
4. The catalytic synthesis method of nicotinamide derivative according to claim 1, characterized in that, when the compound shown as formula (II) is synthesized, the reaction temperature is 60-100 ℃, and the reaction time is 4-12 hours.
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