CN111606848A - Preparation method of fluorodiphenyl substituted pyridine compound - Google Patents
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Abstract
The invention discloses a preparation method of a fluorodiphenyl substituted pyridine compound, which comprises the following steps: s1 adding NKC-9 catalyst, 4-hydroxyacetophenone, 2-trifluoromethylbenzaldehyde and appropriate amount of CHCl3 into a round bottom flask, heating and refluxing under the protection of nitrogen, tracking the reaction by TLC, filtering out the catalyst after the reaction is finished, washing the catalyst by using a small amount of chloroform, concentrating the filtrate to obtain a crude product, and recrystallizing by using 95% ethanol to obtain a chalcone precursor compound; adding the product of the last step, malononitrile and ammonium acetate into a round-bottom flask according to a molar ratio of 1:1: 3. The compound of the invention takes substituted acetophenone, substituted benzaldehyde, malononitrile, ethyl cyanoacetate and ammonium acetate as raw materials, a one-pot method is adopted to synthesize the 4, 6-diphenyl-3 cyanopyridine compound, and MTT (methyl thiazolyl tetrazolium) method tests show that the compound has strong inhibition effect on the proliferation of glioma U251 and has good application prospect in screening antitumor drugs.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a preparation method of a fluorodiphenyl substituted pyridine compound.
Background
The organic ligand and metal ion form coordination polymer with novel structure and unique performance through coordination and weak interaction, and the coordination polymer becomes a hot research in the fields of coordination chemistry, supermolecule chemistry, crystal engineering and material chemistry. The design and synthesis of novel coordination polymer materials by utilizing the bonding mode peculiar to coordination chemistry become the direction of the joint development of coordination chemistry and material chemistry.
The compound of the invention takes substituted acetophenone, substituted benzaldehyde, malononitrile, ethyl cyanoacetate and ammonium acetate as raw materials, a one-pot method is adopted to synthesize the 4, 6-diphenyl-3 cyanopyridine compound, and MTT (methyl thiazolyl tetrazolium) method tests show that the compound has strong inhibition effect on the proliferation of glioma U251 and has good application prospect in screening antitumor drugs.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides a preparation method of a fluorodiphenyl substituted pyridine compound.
The invention provides a preparation method of a fluorodiphenyl substituted pyridine compound, which comprises the following steps:
s1 adding NKC-9 catalyst, 4-hydroxyacetophenone, 2-trifluoromethylbenzaldehyde and appropriate amount of CHCl3 into a round bottom flask, heating and refluxing under the protection of nitrogen, tracking the reaction by TLC, filtering out the catalyst after the reaction is finished, washing the catalyst by using a small amount of chloroform, concentrating the filtrate to obtain a crude product, and recrystallizing by using 95% ethanol to obtain a chalcone precursor compound;
adding the product of the last step, malononitrile and ammonium acetate into a round-bottom flask according to a molar ratio of 1:1:3, adding a proper amount of absolute ethanol, heating and refluxing under the protection of nitrogen, tracking the reaction by TLC, concentrating to obtain a post-reaction mixture after the reaction is finished, and adding ethyl acetate: extracting the reacted mixture with 1:1, evaporating ethyl acetate to dryness to obtain a crude product, and recrystallizing the crude product in ethanol to obtain a target product, wherein the name of the target product is 2-amino-6- (4-hydroxyphenyl) -4 (2-trifluoromethylphenyl) -3-cyanopyridine, which is called 1a for short;
s2 adding NKC-9 catalyst, 4-hydroxyacetophenone, 3-trifluoromethylbenzaldehyde into a round-bottom flask, adding a proper amount of CHCl3, heating and refluxing under the protection of nitrogen, tracking the reaction by TLC, filtering out the catalyst after the reaction is finished, washing the catalyst by using a small amount of chloroform, concentrating the filtrate to obtain a crude product, and recrystallizing by using 95% ethanol to obtain a chalcone precursor compound;
adding the product of the last step, malononitrile and ammonium acetate into a round-bottom flask according to a molar ratio of 1:1:3, adding a proper amount of absolute ethanol, heating and refluxing under the protection of nitrogen, tracking the reaction by TLC, concentrating to obtain a post-reaction mixture after the reaction is finished, and adding ethyl acetate: extracting the reacted mixture with water at a ratio of 1:1, evaporating ethyl acetate to dryness to obtain a crude product, and recrystallizing the crude product in ethanol to obtain a target product, wherein the name of the target product is 2-amino-6- (4-hydroxyphenyl) -4 (3-trifluoromethylphenyl) -3-cyanopyridine, which is called 2a for short;
s3 adding an NKC-9 catalyst, 2, 4-difluoroacetophenone, 4-hydroxybenzaldehyde and a proper amount of CHCl3 into a round-bottom flask, heating and refluxing under the protection of nitrogen, tracking and reacting by TLC, filtering out the catalyst after the reaction is finished, washing the catalyst by using a small amount of chloroform, concentrating the filtrate to obtain a crude product, and recrystallizing by using 95% ethanol to obtain a chalcone precursor compound;
adding the product of the last step, malononitrile and ammonium acetate into a round-bottom flask according to a molar ratio of 1:1:3, adding a proper amount of absolute ethanol, heating and refluxing under the protection of nitrogen, tracking the reaction by TLC, concentrating to obtain a post-reaction mixture after the reaction is finished, and adding ethyl acetate: extracting the reacted mixture with 1:1, evaporating ethyl acetate to dryness to obtain a crude product, and recrystallizing the crude product in ethanol to obtain a target product, wherein the name of the target product is 2-amino-6- (2, 4-difluorophenyl) -4- (4-hydroxymethylphenyl) -3-cyanopyridine, which is called 3a for short;
s4 adding an NKC-9 catalyst, 2, 4-difluoroacetophenone, 4-hydroxybenzaldehyde and a proper amount of CHCl3 into a round-bottom flask, heating and refluxing under the protection of nitrogen, tracking and reacting by TLC, filtering out the catalyst after the reaction is finished, washing the catalyst by using a small amount of chloroform, concentrating the filtrate to obtain a crude product, and recrystallizing by using 95% ethanol to obtain a chalcone precursor compound; adding the product of the previous step, ethyl cyanoacetate and ammonium acetate into a round-bottom flask according to a molar ratio of 1:1:3, adding a proper amount of absolute ethyl alcohol, heating and refluxing under the protection of nitrogen, tracking the reaction by TLC, concentrating to obtain a post-reaction mixture, and adding ethyl acetate: extracting the reacted mixture with 1:1 of water, evaporating ethyl acetate to dryness to obtain a crude product, and recrystallizing the crude product in ethanol to obtain a target product, wherein the name of the target product is 2-amino-6- (2, 4-difluorophenyl) -4- (4-hydroxymethylphenyl) -2 oxo-1, 2-dihydro-3 cyanopyridine, which is 4a for short.
Preferably, the NKC-9 catalyst is macroporous strong-acid styrene cation exchange resin.
According to the preparation method of the fluorodiphenyl substituted pyridine compound, the compound is prepared from substituted acetophenone, substituted benzaldehyde, malononitrile, ethyl cyanoacetate and ammonium acetate as raw materials by a one-pot method, and the 4, 6-diphenyl-3 cyanopyridine compound is synthesized.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments.
Example one
The synthetic route of 2-amino-6- (4-hydroxyphenyl) -4 (2-trifluoromethylphenyl) -3-cyanopyridine is as follows:
weighing 4-hydroxyacetophenone (408mg, 3mmol), 2-trifluoromethylbenzaldehyde (522mg, 3mmol) and 0.4g of NKC-9 catalyst, adding 5ml of chloroform for dissolving, flushing nitrogen for protection, performing reflux reaction, monitoring the reaction process by TLC, cooling to room temperature after the reaction is completed, filtering out the NKC-9 catalyst, concentrating the filtrate to obtain a crude product of an intermediate, and recrystallizing the crude product of the intermediate with 95% ethanol to obtain a pure product of the intermediate.
Weighing 3mmol of intermediate, malononitrile (198mg, 3mmol) and ammonium acetate (514mg, 9mmol), adding into a round-bottom flask, adding 20ml of anhydrous ethanol, flushing with nitrogen for protection, refluxing for 8h, monitoring the reaction progress by TLC, concentrating to obtain a reaction mixture after reaction, and adding ethyl acetate: and (3) extracting the reacted mixture by 1:1, evaporating ethyl acetate to dryness to obtain a crude product, and recrystallizing the crude product in ethanol to obtain the target product.
The name of the compound is 2-amino-6- (4-hydroxyphenyl) -4 (2-trifluoromethylphenyl) -3-cyanopyridine, which is called 1a for short, and the structural formula is as follows:
product 1a was a light yellow powder solid (43% yield), nuclear magnetic 1HNMR (400MHz, DMSO-d6)9.97(s,1H), 8.13-8.03 (m,0H), 8.00-7.88 (m,2H),7.82(td, J ═ 7.8,1.3Hz,1H), 7.78-7.68 (m,1H), 7.64(s,0H), 7.57-7.49 (m,1H),7.08(s,1H),7.01(s,1H), 6.94-6.82 (m,2H), 13CNMR (101MHz, DMSO-d6)160.17, 158.42,153.36,136.55,133.12,131.36,130.01,129.39,128.64, 128.47,126.72,116.74,115.96,109.12, 87.60.
Example two
2-amino-6- (4-hydroxyphenyl) -4 (3-trifluoromethylphenyl) -3-cyanopyridine
The synthetic route is as follows:
weighing 4-hydroxyacetophenone (408mg, 3mmol), 3-trifluoromethylbenzaldehyde (522mg, 3mmol) and 0.4g of NKC-9 catalyst, adding 5ml of chloroform for dissolving, flushing nitrogen for protection, performing reflux reaction, monitoring the reaction process by TLC, cooling to room temperature after the reaction is completed, filtering out the NKC-9 catalyst, concentrating the filtrate to obtain a crude product of an intermediate, and recrystallizing the crude product of the intermediate with 95% ethanol to obtain a pure product of the intermediate.
Weighing 3mmol of intermediate, malononitrile (198mg, 3mmol) and ammonium acetate (514mg, 9mmol), adding into a round-bottom flask, adding 20ml of anhydrous ethanol, flushing with nitrogen for protection, refluxing for 8h, monitoring the reaction progress by TLC, concentrating to obtain a reaction mixture after reaction, and adding ethyl acetate: and (3) extracting the reacted mixture by 1:1, evaporating ethyl acetate to dryness to obtain a crude product, and recrystallizing the crude product in ethanol to obtain the target product.
The name of the compound is 2-amino-6- (4-hydroxyphenyl) -4 (3-trifluoromethylphenyl) -3-cyanopyridine, which is called 2a for short, and the structural formula is as follows:
product 2a was a light yellow solid (42% yield), nuclear magnetic 1HNMR (400MHz, DMSO-d6)9.97(s,1H), 8.08-7.96 (m,4H), 7.94-7.88 (m,1H),7.80(t, J ═ 7.8Hz,1H),7.27(s,1H),7.01(s,2H), 6.90-6.85 (m,2H).
13CNMR(101MHz,DMSO-d6)161.20,160.15,159.38, 138.60,133.04,130.32,129.56,128.87,128.67,126.57(d,J ＝3.9Hz),125.53(d,J＝4.0Hz),117.54,115.86,108.74,85.62。
Example three
2-amino-6- (2, 4-difluorophenyl) -4- (4-hydroxymethylphenyl) -3-cyanopyridine;
the synthetic route is as follows:
weighing 2, 4-difluoroacetophenone (408mg, 3mmol), 4-hydroxybenzaldehyde (522mg, 3mmol) and 0.4g of NKC-9 catalyst, adding 5ml of chloroform for dissolving, charging nitrogen for protection, carrying out reflux reaction, monitoring the reaction process by TLC, cooling to room temperature after the reaction is completed, filtering out the NKC-9 catalyst, concentrating the filtrate to obtain a crude product of an intermediate, and recrystallizing the crude product of the intermediate with 95% ethanol to obtain a pure product of the intermediate.
Weighing 3mmol of intermediate, malononitrile (198mg, 3mmol) and ammonium acetate (514mg, 9mmol), adding into a round-bottom flask, adding 20ml of anhydrous ethanol, flushing with nitrogen for protection, refluxing for 8h, monitoring the reaction progress by TLC, concentrating to obtain a reaction mixture after reaction, and adding ethyl acetate: and (3) extracting the reacted mixture by 1:1, evaporating ethyl acetate to dryness to obtain a crude product, and recrystallizing the crude product in ethanol to obtain the target product.
The name of the compound is 2-amino-6- (2, 4-difluorophenyl) -4- (4-hydroxymethyl phenyl) -3-cyanopyridine, which is called 3a for short, and the structural formula is as follows:
product 3a was a white solid (40% yield), nuclear magnetic 1HNMR (400MHz, DMSO-d6) 10.00(d, J ═ 1.3Hz,1H), 8.06-7.80 (m,1H),7.51(dd, J ═ 8.4,1.6Hz,2H),7.39(ddd, J ═ 11.7,9.2,2.4Hz,1H), 7.26(td, J ═ 8.5,2.3Hz,1H), 7.10-6.98 (m,3H), 6.99-6.87 (m,2H), 13CNMR (101MHz, DMSO-d6)161.38,159.52, 155.10,154.50,133.52-131.96 (m),130.24,127.60,124.05-122.29 (m),117.58,116.08,113.30-112.19 (m),105.22(t, J ═ 26.8Hz), 87.21.
Example four
2-amino-6- (2, 4-difluorophenyl) -4- (4-hydroxymethylphenyl) -2 oxo-1, 2-dihydro-3 cyanopyridine
The de-synthesis route is as follows:
weighing 2, 4-difluoroacetophenone (408mg, 3mmol), 4-hydroxybenzaldehyde (522mg, 3mmol) and 0.4g of NKC-9 catalyst, adding 5ml of chloroform for dissolving, charging nitrogen for protection, carrying out reflux reaction, monitoring the reaction process by TLC (thin layer chromatography), cooling to room temperature after the reaction is completed, filtering out the NKC-9 catalyst, concentrating the filtrate to obtain a crude product of an intermediate, recrystallizing the crude product of the intermediate with 95% ethanol to obtain a pure product of the intermediate
Weighing 3mmol of intermediate, ethyl cyanoacetate (340mg, 3mmol) and ammonium acetate (514mg, 9mmol), adding into a round-bottom flask, adding 20ml of anhydrous ethanol, flushing with nitrogen for protection, refluxing for 8h, monitoring the reaction progress by TLC, concentrating to obtain a reaction mixture after the reaction is completed, and adding ethyl acetate: and (3) extracting the reacted mixture by 1:1, evaporating ethyl acetate to dryness to obtain a crude product, and recrystallizing the crude product in ethanol to obtain the target product.
The name is 2-amino-6- (2, 4-difluorophenyl) -4- (4-hydroxymethyl phenyl) -2 oxo-1, 2-dihydro-3 cyanopyridine, 4a for short, and the structural formula is as follows:
product 4a was a white solid (yield 45%), nuclear magnetic 1HNMR (400MHz, DMSO-d6) 12.77(s,1H),10.18(s,1H),7.81(td, J ═ 8.6,6.4Hz,1H), 7.71-7.58 (m,2H),7.49(ddd, J ═ 11.4,9.3,2.5Hz,1H), 7.28(td, J ═ 8.5,2.6Hz,1H), 7.05-6.89 (m,2H),6.63(s, 1H), 13CNMR (101MHz, DMSO-d6)165.38(d, J ═ 12.7Hz), 162.89(d, J ═ 12.4Hz),162.19,161.36(d, J ═ 12.9Hz),160.40, 158.84(d, J ═ 0, 13.7 Hz), 3.7 (ddd, J ═ 12.4Hz), 3.26 (ddd, 3, 3.7 Hz), 3.7 (ddd, 3Hz, 3H).
The anti-tumor effect of the bisphenyl pyridine compounds 1-4;
u251 is selected as target cell, 10-hydroxycamptothecin is used as positive drug, and MTT colorimetric method is used to determine cell antiproliferative effect. U251 cells in monolayer culture were digested with 0.25% trypsin, adjusted to 1 × 105 single cell suspension per ml using DEME medium containing 10% fetal bovine serum, and seeded into 96-well plates at 100ul per well.
Placing the culture plate into a carbon dioxide CO2 incubator, culturing for 24h under the condition of 37 ℃ and 5% CO2 saturated humidity, sucking out old culture medium after cells adhere to the wall, respectively adding culture medium () containing 40uM, 20uM, 10uM, 5uM, 2.5uM to-be-detected drugs and 5% fetal calf serum, setting 5 multiple holes for each concentration, setting blank groups for experiments, continuously placing the culture plate into a CO2 incubator, and culturing for 48h under the condition of 37 ℃ and 5% CO2 saturated humidity; then sucking out the culture medium, adding 20ul of MTT (5mg/L) into each hole, continuously putting into a CO2 incubator, and culturing for 1h at 37 ℃ under the condition of 5% CO2 saturated humidity; DMSO100ul was added, formazan precipitate was resolved with shaking, and absorbance (A) was measured at 490nm for each well on an ELISA detector according to the formula: the inhibition rate was 100% (average a value of negative control group-average a value of administration group)/(average a value of control group-average a value of blank control group).
Calculating the inhibition rate of the compound on cells
Shown in the table are the antitumor proliferation activities of 4, 6-diphenyl-3 cyanopyridine compounds
| Compound (I) | u251IC50(umol/l) |
| 10-hydroxycamptothecin | 55.35 |
| 1a | 23.05 |
| 2a | 17.64 |
| 3a | 6.03 |
| 4a | 12.01 |
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (2)
1. A preparation method of a fluorodiphenyl substituted pyridine compound is characterized by comprising the following steps:
s1 adding NKC-9 catalyst, 4-hydroxyacetophenone, 2-trifluoromethylbenzaldehyde and appropriate amount of CHCl3 into a round bottom flask, heating and refluxing under the protection of nitrogen, tracking the reaction by TLC, filtering out the catalyst after the reaction is finished, washing the catalyst by using a small amount of chloroform, concentrating the filtrate to obtain a crude product, and recrystallizing by using 95% ethanol to obtain a chalcone precursor compound;
adding the product of the last step, malononitrile and ammonium acetate into a round-bottom flask according to a molar ratio of 1:1:3, adding a proper amount of absolute ethanol, heating and refluxing under the protection of nitrogen, tracking the reaction by TLC, concentrating to obtain a post-reaction mixture after the reaction is finished, and adding ethyl acetate: extracting the reacted mixture with 1:1, evaporating ethyl acetate to dryness to obtain a crude product, and recrystallizing the crude product in ethanol to obtain a target product, wherein the name of the target product is 2-amino-6- (4-hydroxyphenyl) -4 (2-trifluoromethylphenyl) -3-cyanopyridine, which is called 1a for short;
s2 adding NKC-9 catalyst, 4-hydroxyacetophenone, 3-trifluoromethylbenzaldehyde into a round-bottom flask, adding a proper amount of CHCl3, heating and refluxing under the protection of nitrogen, tracking the reaction by TLC, filtering out the catalyst after the reaction is finished, washing the catalyst by using a small amount of chloroform, concentrating the filtrate to obtain a crude product, and recrystallizing by using 95% ethanol to obtain a chalcone precursor compound;
adding the product of the last step, malononitrile and ammonium acetate into a round-bottom flask according to a molar ratio of 1:1:3, adding a proper amount of absolute ethanol, heating and refluxing under the protection of nitrogen, tracking the reaction by TLC, concentrating to obtain a post-reaction mixture after the reaction is finished, and adding ethyl acetate: extracting the reacted mixture with water at a ratio of 1:1, evaporating ethyl acetate to dryness to obtain a crude product, and recrystallizing the crude product in ethanol to obtain a target product, wherein the name of the target product is 2-amino-6- (4-hydroxyphenyl) -4 (3-trifluoromethylphenyl) -3-cyanopyridine, which is called 2a for short;
s3 adding an NKC-9 catalyst, 2, 4-difluoroacetophenone, 4-hydroxybenzaldehyde and a proper amount of CHCl3 into a round-bottom flask, heating and refluxing under the protection of nitrogen, tracking and reacting by TLC, filtering out the catalyst after the reaction is finished, washing the catalyst by using a small amount of chloroform, concentrating the filtrate to obtain a crude product, and recrystallizing by using 95% ethanol to obtain a chalcone precursor compound;
adding the product of the last step, malononitrile and ammonium acetate into a round-bottom flask according to a molar ratio of 1:1:3, adding a proper amount of absolute ethanol, heating and refluxing under the protection of nitrogen, tracking the reaction by TLC, concentrating to obtain a post-reaction mixture after the reaction is finished, and adding ethyl acetate: extracting the reacted mixture with 1:1, evaporating ethyl acetate to dryness to obtain a crude product, and recrystallizing the crude product in ethanol to obtain a target product, wherein the name of the target product is 2-amino-6- (2, 4-difluorophenyl) -4- (4-hydroxymethylphenyl) -3-cyanopyridine, which is called 3a for short;
s4 adding an NKC-9 catalyst, 2, 4-difluoroacetophenone, 4-hydroxybenzaldehyde and a proper amount of CHCl3 into a round-bottom flask, heating and refluxing under the protection of nitrogen, tracking and reacting by TLC, filtering out the catalyst after the reaction is finished, washing the catalyst by using a small amount of chloroform, concentrating the filtrate to obtain a crude product, and recrystallizing by using 95% ethanol to obtain a chalcone precursor compound; adding the product of the previous step, ethyl cyanoacetate and ammonium acetate into a round-bottom flask according to a molar ratio of 1:1:3, adding a proper amount of absolute ethyl alcohol, heating and refluxing under the protection of nitrogen, tracking the reaction by TLC, concentrating to obtain a post-reaction mixture, and adding ethyl acetate: extracting the reacted mixture with 1:1 of water, evaporating ethyl acetate to dryness to obtain a crude product, and recrystallizing the crude product in ethanol to obtain a target product, wherein the name of the target product is 2-amino-6- (2, 4-difluorophenyl) -4- (4-hydroxymethylphenyl) -2 oxo-1, 2-dihydro-3 cyanopyridine, which is 4a for short.
2. The method for preparing a fluorodiphenyl-substituted pyridine compound according to claim 1, wherein said NKC-9 catalyst is a macroporous strongly acidic styrene cation exchange resin.
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| AYA M. SERRY 等: ""One-Pot Synthesis of 4,6-Diaryl-2-oxo(imino)-1,2-dihydropyridine-3-carbonitrile; a New Scaffold for p38αMAP Kinase Inhibition"", 《J. COMB. CHEM.》 * |
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