CN110183378A - A kind of derivative and its process for catalytic synthesis of niacinamide - Google Patents

Abstract

The present invention provides a derivative of nicotinamide and a catalytic synthesis method thereof. The derivative is 2-methyl-4,6-diphenyl-N-p-toluenesulfonyl nicotinamide, and its structure is as shown in formula (I ); its catalytic synthesis method comprises the following steps: in the presence of a copper catalyst and a ligand, chalcone oxime as shown in formula (II), p-toluenesulfonyl azide as shown in formula (III) and 3-butyne-2 ketone stirring reaction as shown in formula (IV), thereby obtains the compound shown in formula (I), this method reaction condition is simple, through the suitable selection and combination of catalyst and ligand, thereby can high yield The target product can be obtained with high efficiency, which has high theoretical research value and application value.

Description

A derivative of nicotinamide and its catalytic synthesis method

technical field

The invention relates to the field of organic chemical synthesis, in particular to a derivative of nicotinamide and a catalytic synthesis method thereof.

Background technique

Nicotinamide derivatives containing pyridine heterocycles are a very important class of organic molecules, and 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, etc. Inflammation, antibacterial, anti-aging and other effects.

Niacinamide derivatives are specific in antifungal, it can specifically inhibit the activity of mediating 56-position lysine deacetylase on histone H3 to produce antifungal effect, and it also has a significant effect on pathogenic fungi of the skin inhibition. In view of the extensive and safe pharmacological effects of nicotinamide derivatives, and in the existing data, the structure of nicotinamide is relatively single and there are few types, and the antifungal efficacy needs to be further improved. We look forward to the design of catalytic synthesis methods to develop new , a derivative of niacinamide with higher antifungal efficacy.

Allais, C. et al. ("Metal-free multicomponent syntheses of pyridines", Chem. Rev. 2014, 114, 10829-10868.) disclosed that a β-carbonyl amide derivative, another carbonyl compound, an aldehyde, an ammonium Niacinamide derivatives were synthesized from starting materials by Hantzsch pyridine synthesis. The method first synthesizes dihydropyridine under the action of acids such as acetic acid, citric acid, and p-toluenesulfonyl acid, and then adds oxidants such as nitrous acid or potassium ferricyanide to oxidize to obtain the target product. The multi-step synthesis is cumbersome to operate.

Khan, M.N. et al. ("A simple and efficient method for the facile access of highly functionalized pyridines and their fluorescence property studies", RSCAdv.2012, 2, 12305-12314.) disclosed that malononitrile derivatives were used as starting materials Synthesize 3-cyanopyridine, and further hydrolyze the cyano group to obtain nicotinamide derivatives. This method also needs to be carried out in multiple steps, and there are disadvantages such as harsh reaction conditions, poor functional group compatibility, and environmental unfriendliness during the hydrolysis process.

In recent years, the technology of synthesizing polysubstituted pyridines with ketoxime or ketoxime ester as the starting material has been a research hotspot (“Vessally, E.; Saeidian, H.; Hosseinian, A.; Edjlali, L.; Bekhradnia, A.A. review onsynthetic applications of oxime esters.Curr.Org.Chem.2017,21,249-271.). This method is catalyzed by a monovalent copper source reagent, and an oxidative oxime is introduced into the raw material, which not only provides an amine source, but also The dihydropyridine generated by the oxidation in medium realizes the synthesis of one-pot method. However, due to the low activity of β-carbonyl amide derivatives in this reaction, the product yield is low, and its complex structure needs to be synthesized in advance, which limits the product Therefore, it is necessary to develop a one-pot method for synthesizing nicotinamide derivatives with readily available raw materials, simple conditions and high efficiency.

As mentioned above, a variety of synthetic methods of nicotinamide derivatives have been disclosed in the prior art, but these methods have the disadvantages of multi-step synthesis, expensive raw materials and difficult to obtain, and low product yields. Synthetic method still exists and is necessary, and this is just the foundation and power place that the present invention is accomplished.

Contents of the invention

The object of the present invention is to provide a derivative of nicotinamide (nicotinamide) and its catalytic synthesis method, the derivative is 2-methyl-4,6-diphenyl-N-p-toluenesulfonyl nicotinamide compound (C ₂₆ H ₂₂ N ₂ O ₃ S), the reaction conditions are simple, and a good yield has been obtained.

To achieve the above object, the present invention is achieved through the following technical solutions:

A derivative of nicotinamide, said derivative is 2-methyl-4,6-diphenyl-N-p-toluenesulfonyl nicotinamide, its structure is shown in formula (I):

In the present invention, the nicotinamide derivative compound represented by formula (I), that is, 2-methyl-4,6-diphenyl-N-p-toluenesulfonyl nicotinamide compound (C ₂₆ H ₂₂ N ₂ O ₃ S ) catalytic synthesis method, comprising the following steps: in the presence of a copper catalyst and a ligand, chalcone oxime (compound of formula (II)) as shown in formula (II), p-toluene as shown in formula (III) Sulfonyl azide (formula (Ⅲ) compound) and 3-butyn-2 ketone (formula (Ⅳ) compound) as shown in formula (Ⅳ) stirring reaction, thus obtain the compound (formula (Ⅳ) compound) as shown in formula (I) (I) compound).

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 ), cuprous iodide (CuI), cuprous bromide (CuBr), cuprous chloride (CuCl), copper thiophene-2-carboxylate (CuTc), or Any one of cuprous acetate (CuOAc), preferably cuprous iodide (CuI), cuprous chloride (CuCl) or cuprous acetate (CuOAc), most preferably cuprous acetate (CuOAc).

In the catalytic synthesis method of the present invention, the ligands are acetonitrile (MeCN), N,N-dimethylformamide (DMF), triethylamine (Et ₃ N), n-tributylamine ( ⁿ Bu ₃ N), tri-tert-butylamine (tBu ₃ N), 2-fluoropyridine (2- ^FPy ), 2-chloropyridine (2-ClPy), 2-bromopyridine (2-BrPy), 2-iodopyridine (2-BrPy ), any one of three [(1-benzyl-1H-1,2,3-triazol-4-yl) methyl] amine (TBTA) or no ligand, preferably three [(1- Any one of benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA), acetonitrile (MeCN) or no ligand (when no ligand is added, acetonitrile is used as solvent ), most preferably tris[(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 1:0.05-0.4:0.1-2, such as 1:0.1:0.1, 1:0.2:0.2, 1:0.25:0.5, 1:0.2:1, etc.

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 1:1-3:1-3, for example, it can be 1:1:1 , 1:1.5:1.5 or 1:3:3.

In the catalytic synthesis method of the present invention, the organic solvent can be ethanol (EtOH), acetonitrile (MeCN), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N- Any one of dimethylacetamide (DMA), chlorobenzene, benzene, xylene, and N-methylpyrrolidone (NMP), most preferably acetonitrile (MeCN).

Among them, MeCN can be used not only as a reaction solvent, but also as a ligand for the smooth progress of the reaction, which not only facilitates the operation and control of the reaction, but also facilitates the post-treatment, thus making the operation of the entire reaction more convenient.

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 , that is, the compound of formula (II) per 1 millimole (mmol) uses 5-15 milliliters (mL) of solvent, and the specific ratio can be 1:5, 1:8, 1:10, 1:12 or 1:15 .

In the catalytic synthesis method of the present invention, the reaction temperature is 25-80°C, such as 25°C, 40°C, 60°C or 80°C. The reaction time is 0.5-8 hours, for example, it can be 0.5 hours, 1 hour, 2 hours, 4 hours or 8 hours.

In the method of the present invention, the post-treatment after the reaction can be any one of extraction, concentration, crystallization, recrystallization, column chromatography purification, etc. or a combination of multiple treatment means. As an exemplary post-treatment means, for example, after the reaction is complete, the reaction system is naturally cooled to room temperature, and the solvent is distilled off under reduced pressure to obtain a crude product, and the crude product is subjected to 200-300 mesh silica gel column chromatography, A mixture of ethyl acetate and petroleum ether is used as the eluent, wherein the volume ratio of ethyl acetate to petroleum ether is 1:5-10, so as to obtain the compound of formula (I) as the target product.

In the catalytic synthesis method of the present invention, the compounds of formula (III) and 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 the starting material is as follows: in an organic solvent, in the presence of a base, the chalcone compound (formula (V) compound) and the hydroxylamine hydrochloride compound (formula (VI) compound) shown in formula (VI) are stirred and reacted, thereby obtaining the formula (II) compound.

In the synthesis method of the compound of formula (II), the base is any one of pyridine, triethylamine, potassium carbonate, sodium ethylate, potassium tert-butoxide, sodium hydroxide, etc., preferably pyridine or triethylamine, most preferably Pyridine is preferred.

In the synthesis method of the compound of formula (II), the organic solvent is methanol (MeOH), ethanol (EtOH), acetonitrile (MeCN), N,N-dimethylformamide (DMF), N,N-dimethyl Any one of methyl acetamide (DMA), chlorobenzene, benzene, xylene, dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), preferably methanol (MeOH) or ethanol (EtOH); most Ethanol (EtOH) is preferred.

Wherein, the amount of the organic solvent is not particularly limited, for example, it may be an amount that is convenient for the reaction and control, and for post-treatment, and those skilled in the art can reasonably determine and select according to conventional technical means.

In the synthesis method of the compound of formula (II), the molar ratio of the compound of formula (V), the compound of formula (VI), and the base is 1:1.5-4:2-6, for example, it can be 1:1.5:2.5, 1:2 :3, 1:2.5:4, or 1:3:6.

In the synthesis method of the compound of formula (II), the reaction temperature is 60-100°C, for example, it can be 60°C, 70°C, 80°C or 100°C. The reaction time is 4-12 hours, for example, it can be 4 hours, 8 hours or 12 hours.

In the synthesis method of the compound of formula (II), the post-treatment after the reaction is specifically as follows: after the reaction, the reaction system is naturally cooled to room temperature, and the solvent is removed by distillation under reduced pressure to obtain a mixture, and the mixture is poured into a 1:1 In water and ethyl acetate, extract 2-4 times, collect the organic phase, wash with 1mol/L dilute hydrochloric acid and saturated brine, dry over MgSO ₄ , distill and spin-dry under reduced pressure to obtain the crude product, pass the crude product through 200-300 Silica gel column chromatography, using ethyl acetate and petroleum ether mixture as eluent, wherein the volume ratio of ethyl acetate and petroleum ether is 1:5-10, so as to obtain the target product formula (II) compound.

As mentioned above, the present invention provides a compound of formula (I) and a synthetic method of the compound. The synthetic method can obtain the compound of formula (I) through the selection and synergy of a suitable catalyst and ligand. The reaction conditions The method is simple and achieves good yield at the same time, provides a new synthetic route for the preparation of nicotinamide derivatives, and has good application value and potential in industry and scientific research.

Detailed ways

In order to make the purpose, 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 in conjunction with the embodiments of the present invention. Obviously, the described embodiments are part of the present invention Examples, not all examples. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without creative efforts fall within the protection scope of the present invention.

Example 1:

To an appropriate amount of EtOH, add chalcone shown in formula (V), hydroxylamine hydrochloride and pyridine shown in formula (VI), raise the temperature to 60°C, and stir the reaction at this temperature for 12 hours; wherein, as shown in formula The molar ratio of chalcone shown in (V), hydroxylamine hydrochloride shown in formula (VI), and pyridine is 1:1.5:2.5.

After the reaction, the reaction system was naturally cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a mixture. The mixture was poured into 1:1 water and ethyl acetate, extracted 2-4 times, and the organic phase was collected. Wash with dilute hydrochloric acid and saturated brine, dry over MgSO ₄ , distill under reduced pressure and spin dry to obtain the crude product, the crude product is subjected to 200-300 mesh silica gel column chromatography, with ethyl acetate and petroleum ether mixed solution as eluent, wherein The volume ratio of ethyl acetate to petroleum ether was 1:5 to obtain the compound of formula (II) as a white solid with a melting point of 112.3-114.4° C. and a yield of 82.6%.

Example 2:

Reaction formula is with embodiment 1, and concrete operation is:

To an appropriate amount of EtOH, add chalcone represented by formula (V), hydroxylamine hydrochloride and pyridine represented by formula (VI), raise the temperature to 70°C, and stir the reaction at this temperature for 8 hours; wherein, wherein, The molar ratio of chalcone represented by formula (V), hydroxylamine hydrochloride represented by formula (VI), and pyridine is 1:2:3.

After the reaction, the reaction system was naturally cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a mixture. The mixture was poured into 1:1 water and ethyl acetate, extracted 2-4 times, and the organic phase was collected. Wash with dilute hydrochloric acid and saturated brine, dry over MgSO ₄ , distill under reduced pressure and spin dry to obtain the crude product, the crude product is subjected to 200-300 mesh silica gel column chromatography, with ethyl acetate and petroleum ether mixed solution as eluent, wherein The volume ratio of ethyl acetate to petroleum ether was 1:8, thereby obtaining the compound of formula (II) as a white solid, the melting point of which was the same as that of Example 1, and the yield was 84.5%.

Example 3:

Reaction formula is with embodiment 1, and concrete operation is:

To an appropriate amount of EtOH, add chalcone shown in formula (V), hydroxylamine hydrochloride and pyridine shown in formula (VI), raise the temperature to 80°C, and stir the reaction at this temperature for 6 hours; wherein, as shown in formula The molar ratio of chalcone shown in (V), hydroxylamine hydrochloride shown in formula (VI), and pyridine is 1:2.5:4.

After the reaction, the reaction system was naturally cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a mixture. The mixture was poured into 1:1 water and ethyl acetate, extracted 2-4 times, and the organic phase was collected. Wash with dilute hydrochloric acid and saturated brine, dry over MgSO ₄ , distill under reduced pressure and spin dry to obtain the crude product, the crude product is subjected to 200-300 mesh silica gel column chromatography, with ethyl acetate and petroleum ether mixed solution as eluent, wherein The volume ratio of ethyl acetate to petroleum ether was 1:7 to obtain the compound of formula (II) as a white solid, the melting point of which was the same as that of Example 1, and the yield was 80.7%.

Example 4:

Reaction formula is with embodiment 1, and concrete operation is:

To an appropriate amount of EtOH, add chalcone shown in formula (V), hydroxylamine hydrochloride and pyridine shown in formula (VI), raise the temperature to 80°C, and stir the reaction at this temperature for 4 hours; wherein, as shown in formula The molar ratio of chalcone shown in (V), hydroxylamine hydrochloride shown in formula (VI), and pyridine is 1:3:6.

After the reaction, the reaction system was naturally cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a mixture. The mixture was poured into 1:1 water and ethyl acetate, extracted 2-4 times, and the organic phase was collected. Wash with dilute hydrochloric acid and saturated brine, dry over MgSO ₄ , distill under reduced pressure and spin dry to obtain the crude product, the crude product is subjected to 200-300 mesh silica gel column chromatography, with ethyl acetate and petroleum ether mixed solution as eluent, wherein The volume ratio of ethyl acetate to petroleum ether was 1:10, thereby obtaining the compound of formula (II) as a white solid, the melting point of which was the same as that of Example 1, and the yield was 83.3%.

Comparative Example 1-24: Investigation of Alkali

Comparative Example 1-4: Except that the base in Example 1-4 was replaced by triethylamine from pyridine, other operations were all unchanged, and Comparative Example 1-4 was implemented.

Comparative Examples 5-8: Except that the bases in Examples 1-4 were replaced by potassium carbonate from pyridine, other operations were all unchanged, and Comparative Examples 5-8 were implemented.

Comparative Examples 9-12: Except that the bases in Examples 1-4 were replaced by sodium ethoxide from pyridine, other operations were all unchanged, and Comparative Examples 9-12 were implemented.

Comparative Examples 13-16: Except that the bases in Examples 1-4 were replaced by potassium tert-butoxide from pyridine, other operations were all unchanged, and Comparative Examples 13-16 were implemented.

Comparative Examples 17-20: Except that the bases in Examples 1-4 were replaced by sodium hydroxide from pyridine, other operations were all unchanged, and Comparative Examples 17-20 were implemented.

Comparative Examples 21-24: Except that the bases in Examples 1-4 were replaced by ammonium acetate from pyridine, other operations were unchanged, and Comparative Examples 21-24 were implemented.

The obtained results are shown in Table 1.

Table 1:

This shows that wherein the type of base has a significant impact on the product yield, and wherein pyridine has the best effect, even if it is triethylamine similar to pyridine, its yield also has a significant reduction.

Comparative Examples 25-32: Investigation of Solvents

Except that the solvent therein is replaced by the following solvent by ethanol, comparative examples 25-32 were implemented respectively in the same manner as in Examples 1-4, and the yields of the solvents used, the corresponding relationship of the examples and the corresponding products are shown in the table 2.

Table 2:

It can be seen that the solvent also has a certain influence on the final result, among which EtOH has the best effect, even if it is very similar to MeOH, its yield is also reduced to a certain extent.

Example 5:

In MeCN, add chalcone oxime shown in formula (II), p-toluenesulfonyl azide shown in formula (III) and 3-butyne-2 ketone shown in formula (IV), acetic acid Cuprous (CuOAc), tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA), then heated to 60 °C, and stirred and sealed at this temperature Reaction for 4 hours; Wherein, formula (II) compound, cuprous acetate (CuOAc), three [(1-benzyl-1H-1,2,3-triazol-4-yl) methyl] amine (TBTA) The molar ratio is 1:0.1:0.1, the molar ratio of the compound of formula (II) to the compound of formula (III) and compound of formula (IV) is 1:1.2:1.2, and the formula (II) in millimoles (mmol) The ratio of compound to MeCN in milliliters (ml) was 1:4.

After the reaction was complete, the reaction system was naturally cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was subjected to 200-300 mesh silica gel column chromatography, using a mixture of ethyl acetate and petroleum ether as an eluent, wherein The volume ratio of ethyl acetate to petroleum ether was 1:5, so that the target compound of formula (I) (C ₂₆ H ₂₂ N ₂ O ₃ S) was obtained as a white solid with a yield of 90.7%.

Melting point: 202.8-204.4°C.

NMR: ¹ HNMR (400MHz, DMSO-d ₆ ) 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).

₍ ^_ 2C), 127.0 (2C), 118.1, 22.3, 21.2.

Embodiment 6:

Reaction formula is with embodiment 5, and concrete operation is:

In MeCN, add chalcone oxime shown in formula (II), p-toluenesulfonyl azide shown in formula (III) and 3-butyne-2 ketone shown in formula (IV), acetic acid Cuprous (CuOAc), tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA), then heated to 80 °C, and stirred and sealed at this temperature Reaction for 8 hours; Wherein, formula (II) compound, cuprous acetate (CuOAc), three [(1-benzyl-1H-1,2,3-triazol-4-yl) methyl] amine (TBTA) The molar ratio is 1:0.2:0.2, the molar ratio of the compound of formula (II) to the compound of formula (III) and the compound of formula (IV) is 1:2:2, and the formula (II) in millimoles (mmol) The ratio of compound to MeCN in milliliters (ml) was 1:8.

After the reaction was complete, the reaction system was naturally cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was subjected to 200-300 mesh silica gel column chromatography, using a mixture of ethyl acetate and petroleum ether as an eluent, wherein The volume ratio of ethyl acetate to petroleum ether was 1:5, so that the target compound of formula (I) (C ₂₆ H ₂₂ N ₂ O ₃ S) was obtained as a white solid with a yield of 87.5%.

Melting point and NMR data are the same as in Example 5.

Embodiment 7:

Reaction formula is with embodiment 5, and concrete operation is:

In MeCN, add chalcone oxime shown in formula (II), p-toluenesulfonyl azide shown in formula (III) and 3-butyne-2 ketone shown in formula (IV), acetic acid Cuprous (CuOAc), tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA), then heated to 90 °C, and stirred and sealed at this temperature Reaction for 2 hours; Wherein, formula (II) compound, cuprous acetate (CuOAc), three [(1-benzyl-1H-1,2,3-triazol-4-yl) methyl] amine (TBTA) The molar ratio 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 formula (II) in millimoles (mmol) The ratio of compound to MeCN in milliliters (ml) was 1:6.

After the reaction was complete, the reaction system was naturally cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was subjected to 200-300 mesh silica gel column chromatography, using a mixture of ethyl acetate and petroleum ether as an eluent, wherein The volume ratio of ethyl acetate to petroleum ether was 1:5, so that the target compound of formula (I) (C ₂₆ H ₂₂ N ₂ O ₃ S) was obtained as a white solid with a yield of 88.7%.

Melting point and NMR data are the same as in Example 5.

Embodiment 8:

Reaction formula is with embodiment 5, and concrete operation is:

In MeCN, add chalcone oxime shown in formula (II), p-toluenesulfonyl azide shown in formula (III) and 3-butyne-2 ketone shown in formula (IV), acetic acid Cuprous (CuOAc), tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA), then heated to 70 °C, and stirred and sealed at this temperature Reaction for 12 hours; Wherein, formula (II) compound, cuprous acetate (CuOAc), three [(1-benzyl-1H-1,2,3-triazol-4-yl) methyl] amine (TBTA) The molar ratio 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 formula (II) in millimoles (mmol) The ratio of compound to MeCN in milliliters (ml) was 1:10.

After the reaction was complete, the reaction system was naturally cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was subjected to 200-300 mesh silica gel column chromatography, using a mixture of ethyl acetate and petroleum ether as an eluent, wherein The volume ratio of ethyl acetate to petroleum ether was 1:5, so that the target compound of formula (I) (C ₂₆ H ₂₂ N ₂ O ₃ S) was obtained as a white solid with a yield of 89.6%.

Melting point and NMR data are the same as in Example 5.

Comparative Examples 33-60: Investigation of Catalysts

Comparative Examples 33-36: Except that the catalysts in Examples 5-8 were replaced by cuprous acetate (CuOAc) with cuprous chloride (CuCl), other operations were unchanged, and Comparative Examples 33-36 were implemented.

Comparative Examples 37-40: Except that the catalysts in Examples 5-8 were replaced from cuprous acetate (CuOAc) to copper bromide (CuBr ₂ ), other operations were unchanged, and Comparative Examples 37-40 were implemented.

Comparative Examples 41-44: Except that the catalyst in Examples 5-8 is replaced by copper trifluoromethanesulfonate (Cu(OTf) ₂ ) by cuprous acetate (CuOAc) respectively, other operations are all unchanged, and implemented Comparative Examples 41-44.

Comparative Examples 45-48: Except that the catalyst in Examples 5-8 is replaced by cuprous acetate (CuOAc) by copper acetate (Cu(OAc) ₂ ), other operations are all unchanged, and comparative examples 45- 48.

Comparative example 49-52: except that the catalyst in embodiment 5-8 is replaced by cuprous acetate (CuOAc) by thiophene-2-formic acid copper (CuTc), other operation is all unchanged, and implements comparative example 49- 52.

Comparative Examples 53-56: Except that the catalysts in Examples 5-8 were replaced from cuprous acetate (CuOAc) to copper oxide (CuO), other operations were unchanged, and Comparative Examples 53-56 were implemented.

Comparative Examples 57-60: Except that the catalysts in Examples 5-8 were replaced from cuprous acetate (CuOAc) to cuprous iodide (CuI), other operations were unchanged, and Comparative Examples 57-60 were implemented.

The obtained results are shown in Table 3.

table 3:

It can be seen that the type of catalyst has a significant impact on the product yield, and wherein cuprous acetate (CuOAc) or cuprous iodide (CuI) have a better catalytic effect, while cuprous acetate has the best catalytic performance. The catalytic effect of the valent copper source is generally better than that of the divalent copper source, and the yield of the catalytic reaction of the divalent copper source is reduced to 53.8-56.5%, or even lower, which has lost the value of practical application.

Comparative Examples 61-68: Examination of Ligands

Except that the ligand therein is changed from three [(1-benzyl-1H-1,2,3-triazol-4-yl) methyl]amine (TBTA) to the following ligand, in accordance with Example 5 In the same manner as in -8, comparative examples 61-68 were implemented respectively, and the ligands used, the corresponding relationship of the examples and the yield of the corresponding products are shown in Table 2.

Table 4:

It can be seen that among all the ligands, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) or the solvent acetonitrile (when no ligand was added , solvent acetonitrile is also a kind of ligand) has suitable coordination property, and other ligands then productive rate all has remarkably reduced, even can't obtain product. Furthermore, it can also be seen that even triethylamine (Et ₃ N ) and other tertiary amines, the coordination effect is also greatly reduced to 28.4%, while other strong coordination 1,10-phenanthroline (Phen), etc., have a more significant reduction, or even no reaction.

Comparative Examples 69-76: Investigation of Solvents

Except that the solvent therein is replaced by the following solvent by acetonitrile, Comparative Examples 69-76 were respectively implemented in the same manner as in Examples 5-8, and the solvents used, the corresponding relationship of the examples and the yield of the corresponding products are shown in the table 5.

table 5:

It can be seen that the solvent also has a certain influence on the final result, and acetonitrile has the best effect, even if the coordination property is very similar to DMF, its yield is also greatly reduced.

In summary, it can be clearly seen from all the above 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 reacted smoothly, thereby obtaining the target product , and the yield is good, and the post-treatment is simple. The achievement of these effects depends on the comprehensive synergy of multiple factors such as catalysts, ligands, and solvents. When any one of these factors is changed, the yield will be significantly reduced.

It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the protection scope of the present invention. In addition, it should also be understood that after reading the technical content of the present invention, those skilled in the art can make various changes, modifications and/or variations to the present invention, and all these equivalent forms also fall within the appended claims of the present application. within the defined scope of protection.

Claims (10)

1. a kind of derivative of niacinamide, which is characterized in that the derivative is 2- methyl -4,6- diphenyl-N- to toluene sulphur Acyl group niacinamide, shown in structure such as formula (I):

2. the process for catalytic synthesis of the derivative of niacinamide according to claim 1, which is characterized in that the method includes Following steps: in the presence of copper catalyst and ligand, the chalcone oxime as shown in formula (II), as shown in formula (III) to toluene Sulfonyl nitrine is stirred to react with the 3- crotonylene ketone as shown in formula (IV), thus obtain such as formula (I) compound represented,

3. the process for catalytic synthesis of the derivative of niacinamide according to claim 2, which is characterized in that the copper catalyst For any one in cuprous iodide, stannous chloride, cuprous acetate.

4. the process for catalytic synthesis of the derivative of niacinamide according to claim 2, which is characterized in that the ligand is second Nitrile or three [(1- benzyl -1H-1,2,3- triazole-4-yl) methyl] amine.

5. the process for catalytic synthesis of the derivative of niacinamide according to claim 2, which is characterized in that as shown in formula (II) Chalcone oxime, catalyst, ligand molar ratio be 1:0.05-0.4:0.1-2；The chalcone oxime as shown in formula (II), such as formula (III) molar ratio of p-toluenesulfonyl nitrine shown in and the 3- crotonylene ketone as shown in formula (IV) is 1:1-3:1-3.

6. the process for catalytic synthesis of the derivative of niacinamide according to claim 2, which is characterized in that described is organic molten Agent is acetonitrile.

7. the process for catalytic synthesis of the derivative of niacinamide according to claim 2, which is characterized in that process for catalytic synthesis In, reaction temperature is 25-80 DEG C, and the reaction time is 0.5-8 hours.

8. the process for catalytic synthesis of the derivative of the niacinamide according to any one of claim 2-7, which is characterized in that such as The synthetic method of compound shown in formula (II) is as follows: in organic solvent, in the presence of alkali, such as formula (V) compound represented and If formula (VI) compound represented is stirred to react, to obtain the compound as shown in formula (II)；

9. the process for catalytic synthesis of the derivative of niacinamide according to claim 8, which is characterized in that the alkali is pyridine Or triethylamine；The organic solvent is methanol or ethyl alcohol.

10. the process for catalytic synthesis of the derivative of niacinamide according to claim 8, which is characterized in that synthesis is such as formula (II) shown in when compound, reaction temperature is 60-100 DEG C, and the reaction time is 4-12 hours.