CN116041258A - Nitrovanillin heterocyclic derivative, preparation method and application thereof - Google Patents
Nitrovanillin heterocyclic derivative, preparation method and application 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
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Abstract
The invention relates to the technical field of vanillin derivative preparation, in particular to a nitrovanillin heterocyclic derivative preparation method and application thereof, which are characterized in that vanillin and concentrated nitric acid are used as raw materials, glacial acetic acid is used as a solvent, and a selective nitration reaction is carried out to obtain a mononitro substituted derivative 5-nitrovanillin; heating and refluxing the mixture with heterocyclic compounds such as 2-chloro-5-chloromethylpyridine and the like and sodium carbonate and the like to generate heterocyclic derivatives such as 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde and the like; and then the mixture is heated and refluxed with aromatic hydrazide or heterocyclic hydrazide compounds such as 4-hydroxybenzohydrazide and the like to generate heterocyclic derivatives such as (4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde) -4-hydroxybenzohydrazide and the like, and active groups such as 5-nitro, aromatic heterocycle, aromatic hydrazide and the like are selectively introduced into vanillin molecules to synthesize a series of nitrovanillin heterocyclic derivatives.
Description
Technical Field
The invention relates to the technical field of preparation of vanillin derivatives, in particular to a nitrovanillin heterocyclic derivative, a preparation method and application thereof.
Background
Vanillin (also known as Vanillin), the scientific name 3-methoxy-4-hydroxybenzaldehyde, is an organic compound extracted from Vanilla sinensis of Rutaceae, is widely used in industries such as cosmetics, tobacco, foods, chemical industry, medicines and the like, can be used as a plant growth promoter, a bactericide, a lubricating oil defoamer and the like, and is also an important intermediate for synthesizing medicines and other spices.
The phenolic hydroxyl and aldehyde groups in the vanillin molecule are both main active sites of vanillin, and when the vanillin molecule is structurally modified, a protection reaction of one of the phenolic hydroxyl or aldehyde groups is usually required. The existing method for introducing nitro and p-phenolic hydroxyl modification on vanillin molecules comprises the following steps: the nitration of vanillin generally uses concentrated nitric acid or concentrated nitric acid/sulfuric acid as nitrating agent, a large amount of concentrated nitric acid is needed, the reaction is severe, the reaction is needed to be carried out at the low temperature of minus 15 ℃, the reaction condition is severe, the product is complex, the excessive nitration is easy to occur, the proportion of byproducts such as 2-nitrovanillin, 2, 6-dinitrovanillin and the like is high, and the separation and purification method is complex.
In view of the above drawbacks, the present inventors have finally achieved the present invention through long-time studies and practices.
Disclosure of Invention
The invention aims to solve the problems that a large amount of concentrated nitric acid is needed in the existing mode of introducing nitro groups and p-phenolic hydroxyl groups on vanillin molecules, the reaction conditions are severe, the products are complex, excessive nitration is easy to occur, the proportion of byproducts such as 2-nitrovanillin, 2, 6-dinitrovanillin and the like is high, and the separation and purification method is complex.
In order to achieve the above purpose, the invention discloses a preparation method of nitrovanillin heterocyclic derivatives, which comprises the following steps:
s1, adding 5-nitrovanillin into ice water, washing, filtering, sequentially adding 2-chloro-5-chloromethylpyridine and sodium carbonate into the obtained solid, and carrying out heating reflux reaction to synthesize a 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde derivative;
s2, carrying out suction filtration on the 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde derivative obtained in the step S1, washing filter residues by adopting ethanol, carrying out rotary evaporation on the obtained filtrate at 40-50 ℃ until solvent liquid is not reduced, adding distilled water into the residual liquid until precipitation is generated, standing for 30min, carrying out suction filtration, adding aromatic hydrazide or heterocyclic hydrazide compound into the obtained solid, and carrying out heating reflux reaction to synthesize the nitrovanillin heterocyclic derivative.
The chemical reaction formula is as follows:
the preparation method of the 5-nitrovanillin in the step S1 comprises the following steps: the 5-nitrovanillin is obtained by using vanillin and concentrated nitric acid as raw materials and glacial acetic acid as a solvent for nitration reaction.
The molar ratio of the vanillin to the concentrated nitric acid is 1:10-1:18, and the volume of glacial acetic acid added during the nitration reaction is 5-25% of the volume of the concentrated nitric acid.
The temperature of the nitration reaction is 0-15 ℃.
The chemical reaction formula is as follows:
and in the step S1, the heating reflux reaction time is 2-6 hours, and the solvent for the heating reflux reaction is N, N-dimethylformamide.
In the step S2, the heating reflux reaction temperature is 60-80 ℃, and the heating reflux reaction time is 2-6 h.
In the step S2, the reaction mole ratio of 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde and the aromatic hydrazide or heterocyclic hydrazide compound is 1:1-1:5.
In the step S2, 5mL of glacial acetic acid is added as a catalyst in the heating reflux reaction, and the solvent in the heating reflux reaction is absolute ethyl alcohol.
The invention also discloses the nitrovanillin heterocyclic derivative prepared by the preparation method and application of the nitrovanillin heterocyclic derivative in synthesis of novel heterocyclic derivative taking vanillin as a guide and related medicine research.
Compared with the prior art, the invention has the beneficial effects that:
1. compared with the method using concentrated nitric acid or concentrated nitric acid/concentrated sulfuric acid as the nitrifying agent for the nitrifying reaction, the method using concentrated nitric acid/glacial acetic acid as the nitrifying agent for the nitrifying reaction of vanillin has the advantages that glacial acetic acid is used as a solvent and a catalyst, the cost of reagent raw materials is reduced, the environmental pollution is relatively less, the reaction is carried out at the temperature of 0-15 ℃ which is easy to reach, the reaction condition is mild, the selectivity of the nitrifying reaction product is higher, and the post-treatment is simple.
2. The phenolic hydroxyl and aldehyde groups in the vanillin molecule are both main active sites of vanillin, and when the vanillin molecule is structurally modified, a protection reaction of one of the phenolic hydroxyl or aldehyde groups is usually required. The invention respectively modifies aldehyde group and phenolic hydroxyl locus of vanillin molecule, selectively introduces active groups such as 5-nitro, aromatic heterocycle, aromatic hydrazide and the like, evaluates the influence of the active groups on the activity of vanillin derivatives, synthesizes a series of nitrovanillin heterocycle derivatives, enriches the diversity of vanillin compounds and the bioactivity thereof, and further designs and synthesizes novel vanillin high-activity derivatives;
3. the method has the advantages of few steps, mild reaction conditions, less environmental pollution and more than 60 percent of compound yield. The nitro is selectively introduced on the vanillin molecule, the active heterocyclic group is introduced to modify phenolic hydroxyl and aldehyde group, and a series of heterocyclic vanillin derivatives are synthesized, so that the method has important significance for designing, researching and developing new medicines taking vanillin as a matrix.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of 5-nitrovanillin of example 2;
FIG. 2 is an infrared spectrum of 5-nitrovanillin of example 2;
FIG. 3 is a mass spectrum of 5-nitrovanillin of example 2;
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde according to example 5;
FIG. 5 is an infrared spectrum of 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde according to example 5;
FIG. 6 is a mass spectrum of 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde according to example 5;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of (4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde) -4-hydroxybenzohydrazide of example 8;
FIG. 8 is an infrared spectrum of (4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde) -4-hydroxybenzohydrazide of example 8;
FIG. 9 is a mass spectrum of (4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde) -4-hydroxybenzohydrazide of example 8.
Detailed Description
The above and further technical features and advantages of the present invention are described in more detail below with reference to the accompanying drawings.
Example 1
Preparation of 5-nitrovanillin
1.52g (0.01 mol) of vanillin is added into a reaction bottle, 1mL of glacial acetic acid is added, the mixture is stirred uniformly, 7mL (0.11 mol) of concentrated nitric acid is measured and slowly added into the glacial acetic acid solution of vanillin in a dropwise manner, the temperature is maintained at 0-15 ℃, and the reaction progress is monitored by Thin Layer Chromatography (TLC). After the reaction is finished, a large amount of ice water is added into the reaction liquid, the mixture is filtered, washed and dried to obtain a pale yellow solid, and the yield is 62.70%.
Example 2
Preparation of 5-nitrovanillin
1.52g (0.01 mol) of vanillin is added into a reaction bottle, 1mL of glacial acetic acid is added, the mixture is stirred uniformly, 8mL (0.13 mol) of concentrated nitric acid is measured and slowly added into the glacial acetic acid solution of vanillin in a dropwise manner, the temperature is maintained at 0-15 ℃, and the reaction progress is monitored by Thin Layer Chromatography (TLC). After the reaction is finished, a large amount of ice water is added into the reaction liquid, and the pale yellow solid is obtained after suction filtration, washing and drying, and the yield is 69.70%.
As shown in fig. 1, 2 and 3, fig. 1 shows nuclear magnetic resonance hydrogen spectrum (DMSO-d 6), δ/ppm of 5-nitrovanillin of this example: 8.11 (s, 1H, ar-H), 7.63 (s, 1H, ar-H), 3.97 (s, 3H, -OCH) 3 ) 9.88 (s, 3H, -CHO); FIG. 2 is an infrared spectrum (KBr, v/cm) of 5-nitrovanillin of this example -1) ：874(Ar-H)，1470(-OCH 3 )，1230(Ar-OH)，1570(-NO 2 ) 1690 (-c=o); FIG. 3 is a mass spectrum of 5-nitrovanillin of this example: 195.9[ M-H ]] - 。
Example 3
Preparation of 5-nitrovanillin
1.52g (0.01 mol) of vanillin is added into a reaction bottle, 2mL of glacial acetic acid is added, the mixture is stirred uniformly, 8mL (0.13 mol) of concentrated nitric acid is measured and slowly added into the glacial acetic acid solution of vanillin in a dropwise manner, the temperature is maintained at 0-15 ℃, and the reaction progress is monitored by Thin Layer Chromatography (TLC). After the reaction is finished, a large amount of ice water is added into the reaction liquid, and the light yellow solid is obtained after suction filtration, washing and drying, and the yield is 65.32%.
Example 4
Preparation of 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde
0.97g (0.005 mol) of 5-nitrovanillin, 0.82g (0.005 mol) of 2-chloro-5-chloromethylpyridine and 1.59g (0.015 mol) of sodium carbonate are added to a reaction flask, 30mL of DMF is added, stirring is carried out uniformly, the temperature is maintained at 60℃to 80℃and the progress of the reaction is monitored by Thin Layer Chromatography (TLC). After the reaction is finished, filtering the reaction solution, washing filter residues with ethanol, performing rotary evaporation on the obtained filtrate at 40-50 ℃ until no liquid is reduced, adding a certain amount of water into the residual liquid to generate precipitation, standing for 30min, performing suction filtration, and drying to obtain a dark green solid, wherein the yield is 74.32%.
Example 5
Preparation of 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde
0.97g (0.005 mol) of 5-nitrovanillin, 1.64g (0.01 mol) of 2-chloro-5-chloromethylpyridine and 1.59g (0.015 mol) of sodium carbonate are added to a reaction flask, 30mL of DMF is added, stirring is carried out uniformly, the temperature is maintained at 60℃to 80℃and the reaction progress is monitored by Thin Layer Chromatography (TLC). After the reaction is finished, filtering the reaction solution, washing filter residues with ethanol, performing rotary evaporation on the obtained filtrate at 40-50 ℃ until no liquid is reduced, adding a certain amount of water into the residual liquid to generate precipitation, standing for 30min, performing suction filtration, and drying to obtain a dark green solid with the yield of 74.51%.
As shown in FIG. 4, FIG. 5 and FIG. 6, FIG. 4 shows the 4- [ (6-chloropyridine) methoxy group of the present example]-nuclear magnetic resonance hydrogen spectrum of 3-methoxy-5-nitrobenzaldehyde (DMSO-d 6), δ/ppm:5.33 (s, 2H, ar-O-CH) 2 -)，3.90(s，3H，-OCH 3 ) 10.0 (s, 1H, -CHO); FIG. 5 shows the 4- [ (6-chloropyridine) methoxy group of this example]Infrared spectrum of-3-methoxy-5-nitrobenzaldehyde (KBr, v/cm) -1) ：839(R 2 C＝CHR)，1590(-C＝N-)，1290(Ar-O-A)，1530(Ar-NO 2 ) 1700 (-c=o); FIG. 6 shows the 4- [ (6-chloropyridine) methoxy group of this example]Mass spectrum of 3-methoxy-5-nitrobenzaldehyde: 322.9[ M+H ]] + 、344.9[M+Na] + 。
Example 6
Preparation of 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde
0.97g (0.005 mol) of 5-nitrovanillin, 1.64g (0.01 mol) of 2-chloro-5-chloromethylpyridine and 3.18g (0.03 mol) of sodium carbonate are added into a reaction flask, 30mL of DMF is added, stirring is uniform, the temperature is maintained at 60-80 ℃, and the reaction progress is monitored by Thin Layer Chromatography (TLC). After the reaction is finished, filtering the reaction solution, washing filter residues with ethanol, performing rotary evaporation on the obtained filtrate at 40-50 ℃ until no liquid is reduced, adding a certain amount of water into the residual liquid to generate precipitation, standing for 30min, performing suction filtration, and drying to obtain a dark green solid with the yield of 73.89%.
Example 7
Preparation of (4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde) -4-hydroxybenzohydrazide
1.625g (0.005 mol) of 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde and 0.76g (0.005 mol) of 4-hydroxybenzoyl hydrazine are added to a reaction flask, 20mL of absolute ethanol and 5mL of glacial acetic acid are added, the mixture is stirred uniformly, the temperature is maintained at 60 ℃ to 80 ℃, and the reaction progress is monitored by Thin Layer Chromatography (TLC). After the reaction, the reaction solution is filtered, filter residues are rinsed by ethanol, and a pale yellow solid is obtained after drying, and the yield is 71.76%.
Example 8
Preparation of (4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde) -4-hydroxybenzohydrazide
1.625g (0.005 mol) of 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde and 1.52g (0.01 mol) of 4-hydroxybenzoyl hydrazine are added to a reaction flask, 20mL of absolute ethanol and 5mL of glacial acetic acid are added, the mixture is stirred uniformly, the temperature is maintained at 60 ℃ to 80 ℃, and the reaction progress is monitored by Thin Layer Chromatography (TLC). After the reaction, the reaction solution is filtered, filter residues are rinsed by ethanol, and a pale yellow solid is obtained after drying, and the yield is 75.21%.
As shown in FIG. 7, FIG. 8 and FIG. 9, FIG. 7 shows the (4- [ (6-chloropyridine) methoxy group of the present embodiment]-nuclear magnetic resonance hydrogen spectrum of 3-methoxy-5-nitrobenzaldehyde) -4-hydroxybenzohydrazide (DMSO-d 6), δ/ppm:11.91 (s, 1H, -NH-), 6.81 (s, 1H, ar-H), 10.22 (s, 1H, -OH), 4.03 (s, 3H, -OCH) 3 )，5.33(s，2H，-O-CH 2 (-) -; FIG. 8 shows the (4- [ (6-chloropyridine) methoxy group of this example]Infrared spectrum (KBr, v/cm) of (E) -3-methoxy-5-nitrobenzaldehyde) -4-hydroxybenzohydrazine -1) ：3310(-NH-)，850(R 2 C=chr), 1180 (Ar-OH), 1610 (-c=n-), 1650 (-c=o); FIG. 9 shows the (4- [ (6-chloropyridine) methoxy group of this example]Mass spectrum of-3-methoxy-5-nitrobenzaldehyde) -4-hydroxybenzohydrazide: 456.9[ M+H ]] + 、478.9[M+Na] + 。
Example 9
Preparation of (4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde) -4-hydroxybenzohydrazide
1.625g (0.005 mol) of 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde and 1.52g (0.01 mol) of 4-hydroxybenzoyl hydrazine are added to a reaction flask, 20mL of absolute ethanol and 10mL of glacial acetic acid are added, the mixture is stirred uniformly, the temperature is maintained at 60 ℃ to 80 ℃, and the reaction progress is monitored by Thin Layer Chromatography (TLC). After the reaction, the reaction solution is filtered, filter residues are rinsed with ethanol, and a pale yellow solid is obtained after drying, and the yield is 74.86%.
Example 10
Reaction of 5-nitrovanillin with 2-chloro-5-chloromethylpyridine and isoniazid derivatives (Compound E-1): (E) -N' - (4- ((6-chloropyridin-3-yl) methoxy) -3-methoxy-5-nitrobenzoylede) isonicotinohydroide
0.97g (0.005 mol) of 5-nitrovanillin, 0.82g (0.005 mol) of 2-chloro-5-chloromethylpyridine and 1.59g (0.015 mol) of sodium carbonate are added to a reaction flask, 30mL of DMF is added, stirring is carried out uniformly, the temperature is maintained at 60℃to 80℃and the progress of the reaction is monitored by Thin Layer Chromatography (TLC). After the reaction is finished, filtering the reaction solution, washing filter residues with ethanol, performing rotary evaporation on the obtained filtrate at 40-50 ℃ until no liquid is reduced, adding a certain amount of water into the residual liquid to precipitate, standing for 30min, performing suction filtration, weighing 1.625g (0.005 mol) of the obtained solid and 0.686g (0.005 mol) of isoniazid, adding 20mL of absolute ethanol and 5mL of glacial acetic acid into a reaction bottle, stirring uniformly, maintaining the temperature at 60-80 ℃, and monitoring the reaction progress by Thin Layer Chromatography (TLC). After the reaction, the reaction solution was filtered, and the residue was rinsed with ethanol and dried.
Yellow solid, yield 73.89%; 1 HNMR(400MHz,DMSO-d6):δ4.04(s,3H,-OCH 3 ),5.28(s,2H,O-CH 2 -A),12.33(s,H,N-H).IR(v/cm -1 ):1290(Ar-O-A),1170(N-N),1540(Ar-NO 2 ),3440(N-H),1650(C＝O).LC-MS(m/z):[M+H] + for C 20 H 17 ClN 5 O 5 + theoretical value 441.08; test value 441.9.
Example 11
Reaction of 5-nitrovanillin with 2-chloro-5-chloromethylpyridine and benzoyl hydrazine derivatives (Compound E-2): (E) -N' - (4- ((6-chloropyridin-3-yl) methoxy) -3-methoxy-5-nitrobenzoylede) benzodiazide
0.97g (0.005 mol) of 5-nitrovanillin, 0.82g (0.005 mol) of 2-chloro-5-chloromethylpyridine and 1.59g (0.015 mol) of sodium carbonate are added to a reaction flask, 30mL of DMF is added, stirring is carried out uniformly, the temperature is maintained at 60℃to 80℃and the progress of the reaction is monitored by Thin Layer Chromatography (TLC). After the reaction is finished, filtering the reaction solution, washing filter residues with ethanol, performing rotary evaporation on the obtained filtrate at 40-50 ℃ until no liquid is reduced, adding a certain amount of water into the residual liquid to precipitate, standing for 30min, performing suction filtration, weighing 1.625g (0.005 mol) of the obtained solid and 0.681g (0.005 mol) of benzoyl hydrazine, adding 20mL of absolute ethanol and 5mL of glacial acetic acid into the reaction bottle, uniformly stirring, maintaining the temperature at 60-80 ℃, and monitoring the reaction progress by Thin Layer Chromatography (TLC). After the reaction, the reaction solution was filtered, and the residue was rinsed with ethanol and dried.
Yellow solid, 75.34% yield; 1 HNMR(400MHz,DMSO-d6):δ4.02(s,3H,-OCH 3 ),5.25(s,2H,O-CH 2 -A),12.09(s,H,N-H).IR(v/cm -1 ):1310(Ar-O-A),1170(N-N),1530(Ar-NO 2 ),3420(N-H),1660(C＝O).LC-MS(m/z):[M+H] + for C 21 H 18 ClN 4 O 5 + theoretical value 440.09; test value 440.9.
Example 12
Reaction of 5-nitrovanillin with 2-chloro-5-chloromethylthiazole and 4-hydroxybenzohydrazide derivative (Compound F-1) (E) -N' - (4- ((2-chlorothiazol-5-yl) methoxy) -3-methoxy-5-nitrobenzofuranzlide) -4-hydroxybenzenehydrazde
0.97g (0.005 mol) of 5-nitrovanillin, 0.840g (0.005 mol) of 2-chloro-5-chloromethylthiazole and 1.59g (0.015 mol) of sodium carbonate are added to a reaction flask, 30mL of DMF is added, stirring is carried out uniformly, the temperature is maintained at 60℃to 80℃and the progress of the reaction is monitored by Thin Layer Chromatography (TLC). After the reaction is finished, filtering the reaction solution, washing filter residues with ethanol, performing rotary evaporation on the obtained filtrate at 40-50 ℃ until no liquid is reduced, adding a certain amount of water into the residual liquid to precipitate, standing for 30min, performing suction filtration, weighing 1.641g (0.005 mol) of the obtained solid and 0.761g (0.005 mol) of 4-hydroxybenzoyl hydrazine, adding 20mL of absolute ethanol and 5mL of glacial acetic acid, stirring uniformly, maintaining the temperature at 60-80 ℃, and monitoring the reaction progress by Thin Layer Chromatography (TLC). After the reaction, the reaction solution was filtered, and the residue was rinsed with ethanol and dried.
Yellow solid, yield 71.54%; 1 HNMR(400MHz,DMSO-d6):δ4.03(s,3H,-OCH 3 ),10.17(s,H,Ar-OH),5.39(s,2H,O-CH 2 -A),11.87(s,H,N-H),8.43(s,H,N＝CH-Ar).IR(v/cm -1 ):1270(Ar-OH)，1530(Ar-NO 2 )，1310(Ar-O-A)，3320(N-H)，1650(C＝O).LC-MS(m/z):[M+H] + for C 19 H 16 ClN 4 O 6 S + theoretical value 462.04; test value 463.0.
Example 13
Reaction of 5-nitrovanillin with 2-chloro-5-chloromethylthiazole and benzoyl hydrazine derivatives (Compound F-2) (E) -N' - (4- ((2-chlorothiazol-5-yl) methoxy) -3-methoxy-5-nitrobenzofuranzlide) benzohydrazide
0.97g (0.005 mol) of 5-nitrovanillin, 0.840g (0.005 mol) of 2-chloro-5-chloromethylthiazole and 1.59g (0.015 mol) of sodium carbonate are added to a reaction flask, 30mL of DMF is added, stirring is carried out uniformly, the temperature is maintained at 60℃to 80℃and the progress of the reaction is monitored by Thin Layer Chromatography (TLC). After the reaction is finished, filtering the reaction solution, washing filter residues with ethanol, performing rotary evaporation on the obtained filtrate at 40-50 ℃ until no liquid is reduced, adding a certain amount of water into the residual liquid to precipitate, standing for 30min, performing suction filtration, weighing 1.641g (0.005 mol) of the obtained solid and 0.681g (0.005 mol) of benzoyl hydrazine, adding 20mL of absolute ethanol and 5mL of glacial acetic acid, stirring uniformly, maintaining the temperature at 60-80 ℃, and monitoring the reaction progress by Thin Layer Chromatography (TLC). After the reaction, the reaction solution was filtered, and the residue was rinsed with ethanol and dried.
Yellow solid, yield 76.21%; 1 HNMR(400MHz,DMSO-d6):δ4.04(s,3H,-OCH 3 ),5.39(s,2H,O-CH 2 -A),12.09(s,H,N-H),8.47(s,H,N＝CH-Ar).IR(v/cm -1 ):1270(Ar-OH),1530(Ar-NO 2 ),1310(Ar-O-A),3320(N-H),1650(C＝O).LC-MS(m/z):[M+H] + for C 19 H 16 ClN 4 O 5 S + theoretical value 446.05; test value 446.9.
Example 14
Reaction of 5-nitrovanillin with 2-chloro-5-chloromethylthiazole and isoniazid derivatives (Compound F-3): (E) -N' - (4- ((2-chlorothiazol-5-yl) methoxy) -3-methoxy-5-nitrobenzolide) isonicotinohydroxide
0.97g (0.005 mol) of 5-nitrovanillin, 0.840g (0.005 mol) of 2-chloro-5-chloromethylthiazole and 1.59g (0.015 mol) of sodium carbonate are added to a reaction flask, 30mL of DMF is added, stirring is carried out uniformly, the temperature is maintained at 60℃to 80℃and the progress of the reaction is monitored by Thin Layer Chromatography (TLC). After the reaction is finished, filtering the reaction solution, washing filter residues with ethanol, performing rotary evaporation on the obtained filtrate at 40-50 ℃ until no liquid is reduced, adding a certain amount of water into the residual liquid to precipitate, standing for 30min, performing suction filtration, weighing 1.641g (0.005 mol) of the obtained solid and 0.686g (0.005 mol) of isoniazid, adding 20mL of absolute ethanol and 5mL of glacial acetic acid into a reaction bottle, stirring uniformly, maintaining the temperature at 60-80 ℃, and monitoring the reaction progress by Thin Layer Chromatography (TLC). After the reaction, the reaction solution was filtered, and the residue was rinsed with ethanol and dried.
Yellow solid, 75.25% yield; 1 HNMR(400MHz,DMSO-d6):δ4.05(s,3H,-OCH 3 ),5.41(s,2H,O-CH 2 -A),12.35(s,H,N-H),8.48(s,H,N＝CH-Ar).IR(v/cm -1 ):1610(C＝N),1540(Ar-NO 2 ),1290(Ar-O-A),3430(N-H),1690(C＝O).LC-MS(m/z):[M+H] + for C 18 H 15 ClN 5 O 5 S + theoretical value 447.04; test value 448.0.
The foregoing description of the preferred embodiment of the invention is merely illustrative of the invention and is not intended to be limiting. It will be appreciated by persons skilled in the art that many variations, modifications, and even equivalents may be made thereto without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. A method for preparing a nitrovanillin heterocyclic derivative, which is characterized by comprising the following steps:
s1, adding 5-nitrovanillin into ice water, washing, filtering, sequentially adding 2-chloro-5-chloromethylpyridine and sodium carbonate into the obtained solid, and carrying out heating reflux reaction to synthesize a 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde derivative;
s2, carrying out suction filtration on the 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde derivative obtained in the step S1, washing filter residues by adopting ethanol, carrying out rotary evaporation on the obtained filtrate at 40-50 ℃ until solvent liquid is not reduced, adding distilled water into the residual liquid until precipitation is generated, standing for 30min, carrying out suction filtration, adding aromatic hydrazide or heterocyclic hydrazide compound into the obtained solid, and carrying out heating reflux reaction to synthesize the nitrovanillin heterocyclic derivative.
2. The method for preparing a nitrovanillin heterocyclic derivative according to claim 1, wherein the method for preparing 5-nitrovanillin in the step S1 is as follows: the 5-nitrovanillin is obtained by using vanillin and concentrated nitric acid as raw materials and glacial acetic acid as a solvent for nitration reaction.
3. The method for preparing a nitrovanillin heterocyclic derivative as described in claim 2, wherein the molar ratio of vanillin to concentrated nitric acid is 1:10-1:18, and the volume of glacial acetic acid added during the nitration reaction is 5% -25% of the volume of the concentrated nitric acid.
4. The process for producing a nitrovanillin heterocyclic derivative according to claim 2, characterized in that the temperature of the nitration reaction is 0 ℃ to 15 ℃.
5. The method for preparing nitrovanillin heterocyclic derivatives according to claim 1, characterized in that the heating reflux reaction time in the step S1 is 2-6 h, and the solvent of the heating reflux reaction is N, N-dimethylformamide.
6. The process for preparing nitrovanillin heterocyclic derivatives as described in claim 1, characterized in that the heating reflux reaction temperature in the step S2 is 60-80 ℃ and the heating reflux reaction time is 2-6 h.
7. The method for preparing nitrovanillin heterocyclic derivatives according to claim 1, characterized in that the molar ratio of 4- [ (6-chloropyridine) methoxy ] -3-methoxy-5-nitrobenzaldehyde to aromatic hydrazide or heterocyclic hydrazide compound in the step S2 is 1:1-1:5.
8. The method for preparing nitrovanillin heterocyclic derivatives according to claim 1, wherein 5mL of glacial acetic acid is added as a catalyst in the heating reflux reaction in the step S2, and the solvent of the heating reflux reaction is absolute ethanol.
9. A nitrovanillin heterocyclic derivative produced by the production method of any one of claims 1 to 8.
10. Use of a nitrovanillin heterocycle derivative as claimed in claim 9 in the synthesis of novel vanillin-led heterocycle derivatives and related pharmaceutical research.
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