CN115710214A - Preparation method for catalytically synthesizing 1, 2-dihydropyridine compound by Al @ SBA-15 (2) - Google Patents
Preparation method for catalytically synthesizing 1, 2-dihydropyridine compound by Al @ SBA-15 (2) Download PDFInfo
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- MMWRGWQTAMNAFC-UHFFFAOYSA-N 1,2-Dihydropyridine Natural products C1NC=CC=C1 MMWRGWQTAMNAFC-UHFFFAOYSA-N 0.000 title claims abstract description 101
- -1 1, 2-dihydropyridine compound Chemical class 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 16
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- 238000000034 method Methods 0.000 claims abstract description 17
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- 238000006243 chemical reaction Methods 0.000 claims description 47
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 18
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- 125000001424 substituent group Chemical group 0.000 claims description 13
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- 238000004440 column chromatography Methods 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 9
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- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000005303 weighing Methods 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 3
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- 125000004799 bromophenyl group Chemical group 0.000 claims description 2
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- 238000001704 evaporation Methods 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 230000003197 catalytic effect Effects 0.000 abstract description 9
- 239000000463 material Substances 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
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- 230000004071 biological effect Effects 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 42
- 239000000047 product Substances 0.000 description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 229910052782 aluminium Inorganic materials 0.000 description 9
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000004949 mass spectrometry Methods 0.000 description 8
- 238000009833 condensation Methods 0.000 description 7
- 230000005494 condensation Effects 0.000 description 7
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- 238000006555 catalytic reaction Methods 0.000 description 6
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- 239000007848 Bronsted acid Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 229930013930 alkaloid Natural products 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 125000003944 tolyl group Chemical group 0.000 description 3
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
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- 238000010438 heat treatment Methods 0.000 description 2
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- 239000002243 precursor Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- BNGXYYYYKUGPPF-UHFFFAOYSA-M (3-methylphenyl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].CC1=CC=CC(C[P+](C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 BNGXYYYYKUGPPF-UHFFFAOYSA-M 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241001202975 Isophanes Species 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000001354 calcination Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 238000006352 cycloaddition reaction Methods 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
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- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000002815 homogeneous catalyst Substances 0.000 description 1
- 238000005470 impregnation Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
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- 238000006722 reduction reaction Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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Abstract
The invention relates to a preparation method for catalytically synthesizing 1, 2-dihydropyridine compounds by using Al @ SBA-15 (2), which takes enamine ketone compounds and alkynol as raw materials and utilizes Al @ SBA-15 (2) materials only containing four-coordination frameworks to catalytically synthesize various 1, 2-dihydropyridine compounds. The key point of the invention is to provide a novel preparation method for preparing the 1, 2-dihydropyridine compound with high yield from the enamine ketone compound and alkynol under Al @ SBA-15 (2) with strong catalytic effect. The 1, 2-dihydropyridine compounds have high molecular value as core structures of a plurality of compounds with biological activity. The invention optimizes the complex synthesis process and reduces the preparation difficulty of the 1, 2-dihydropyridine compound. The catalyst used in the method can be recycled for multiple times, and the catalytic activity can still keep better effect after multiple cycles.
Description
Technical Field
A novel preparation method for synthesizing 1, 2-dihydropyridine compounds under the catalysis of Al @ SBA-15 (2) belongs to the technical field of fine organic synthesis.
Background
1, 2-dihydropyridine is now a precursor for synthesizing alkaloids, dioxane and the like, is an important synthetic intermediate in organic synthesis reaction, can conveniently construct important chiral nitrogen-containing heterocyclic compounds such as piperidine and the like in drug molecules through reduction or cycloaddition reaction, and the position of a double bond in the molecule has certain molecular application value on the pharmacological activity of the compound. However, the existing synthetic routes have some disadvantages which are not overcome. For example, the problems of long synthesis time, adverse effects on the environment and the like caused by the need of glacial acetic acid and concentrated ammonia water as raw materials are not reasonably solved. Therefore, the search for a method for synthesizing the 1, 2-dihydropyridine compound with high synthesis efficiency and green catalysis has remarkable significance. The Al @ SBA-15 (2) mesoporous material catalyst with the Bronsted acid site enables 1, 2-dihydropyridine derivatives to be synthesized in a short time and at a high yield, and meanwhile, the catalyst is convenient to recycle and has a good catalytic effect.
Compared with the earlier synthesis route, the 1, 2-dihydropyridine compound is catalytically synthesized by utilizing a catalytic material Al @ SBA-15 (2), so that the compound can be recycled, the cost is reduced, and a series of adverse effects on the environment can be avoided. Compared with a homogeneous catalyst with Lewis acid, the Al @ SBA-15 (2) mesoporous material with the Bronsted acid site is utilized, so that the method is quicker and more efficient in catalysis, less in by-products and easier for industrial implementation.
Disclosure of Invention
The key point of the invention is to provide a novel preparation method for preparing a series of 1, 2-dihydropyridine compounds with high yield under the action of Al @ SBA-15 (2) material with strong catalytic effect on enamine ketone compounds and alkynol. The 1, 2-dihydropyridine compound is used as an active skeleton of natural active alkaloid and has high molecular value. The invention optimizes the complex synthesis process and reduces the preparation difficulty of the core structure molecules. The catalyst used in the method can be recycled for multiple times, and the catalytic activity can still keep better effect after multiple cycles.
The invention is realized by the following technical scheme:
a novel preparation method for synthesizing 1, 2-dihydropyridine compounds under the catalysis of Al @ SBA-15 (2) is characterized in that the reaction structural formula is as follows:
wherein, the substituent R 1 Respectively is any one of phenyl, chlorphenyl and methoxyphenyl, R 2 Respectively is any one of phenyl, chlorphenyl, methoxybenzene, bromophenyl, tolyl and other substituent groups, R 3 Each is hydrogen or phenyl, and the position, number and conjugation position of the substituent are not fixed.
Synthesizing the novel preparation method, the method comprising the following synthetic route:
process for preparing 1, 2-dihydropyridines
(1) Weighing compound alkynol 2 and enaminone 1, putting the compounds in a round-bottom flask, taking toluene as a reaction solvent, stirring to completely dissolve the compounds, weighing Al @ SBA-15 (2) mesoporous material catalyst, stirring at constant temperature, and condensing and refluxing;
(2) Monitoring the reaction by TCL, cooling to room temperature when the alkynol 2 completely reacts, evaporating the solvent toluene under reduced pressure, and carrying out column chromatography separation on the reaction system by a silica gel column to obtain a target product 1, 2-dihydropyridine 3;
(3) And detecting and analyzing the yield of the target product 1, 2-dihydropyridine 3 by using gas-mass spectrometry (GC-MS) of the reaction system, and processing the target product 1, 2-dihydropyridine 3 by Nuclear Magnetic Resonance (NMR) to confirm the component structure.
The molar ratio of reactants 1 and 2 in the step (1) is as follows: 5:5-6.
The reaction solvent toluene in the step (1) is in an anhydrous state.
The temperature of the reaction system in the step (1) is 70-130 ℃.
The reaction time in the step (1) is 1-4h.
In the step (1), al @ SBA-15 (2) mesoporous material catalyst Si/Al =5-20.
The dosage of the Al @ SBA-15 (2) mesoporous material catalyst in the step (1) is 0.3-4mol%.
And (3) repeatedly utilizing the Al @ SBA-15 (2) mesoporous molecular sieve catalyst in the step (2).
The eluent in the step (2) is V Petroleum ether /V Ethyl acetate ＝40-140:1-4。
The preparation method has the following main advantages:
1. high-efficiency synthesis: the invention provides an Al @ SBA-15 (2) mesoporous material catalyst with a Bronsted acid site, which can efficiently synthesize 1, 2-dihydropyridine compounds. The method has the advantages of simple operation, short reaction time and high yield.
2. Green catalysis: the Al @ SBA-15 (2) catalyst used in the invention can be recycled and reused, and the catalytic effect is still good. The problems of resource waste, environmental pollution and the like are avoided, the green requirement of the reaction process is realized, and the reaction economy is improved.
3. The product has wide application: the present invention prepares a series of 1, 2-dihydropyridines, which are precursors for the synthesis of alkaloids, isophanes, etc., as core structures of many biologically active compounds. Is an important synthetic intermediate in organic synthesis reaction and has wide application value.
Drawings
FIG. 1: of Phenyl (1, 4, 6-tetraphenyl-1, 6-dihydropyridin-3-yl) methanone 3a 1 H NMR chart.
FIG. 2 is a schematic diagram: of Phenyl (1, 4, 6-tetraphenyl-1, 6-dihydropyridin-3-yl) methanone 3a 13 C NMR chart.
FIG. 3: preparation of (1- (4-chlorophenylyl) -4, 6-triphenyl-1,6-dihydropyridin-3 yl) (phenyl) methanone 3b 1 H NMR chart.
FIG. 4: preparation of (1- (4-chlorophenylyl) -4, 6-triphenyl-1,6-dihydropyridin-3 yl) (phenyl) methanone 3b 13 C NMR chart.
Detailed Description
The invention will be further described with reference to specific embodiments, but this is not intended to limit the application of the invention:
instruments and reagents:
SHZ-E type circulating water vacuum pump (shanghai rongyan chemical instrumentation plant); model DZE-6120 vacuum drying oven (Shanghai Hengtian scientific instruments manufacturing Co.); WRS-1A digital melting point apparatus (Shanghai cable optical and photoelectric technology Co., ltd.); ZF-I type three-purpose ultraviolet analyzer; EB2005A electronic balance; DE-102J heat collection type constant temperature heating magnetic stirrer (Wanfa chemical instruments factory, hiroshi city); DFX-5L/30 low-temperature constant-temperature reaction bath (Wuchuan instrument factory in Wuxi city); a rotary vane type vacuum oil pump (Daizhiwa instruments, inc., tokyo, inc.) of type 2YZ-4A, 1 h NMR and 13 c NMR was performed using a Varian Mercury 400 model 400MHz NMR spectrometer. Deionized water (AR) petroleum ether (60 ℃ -90 ℃), dichloromethane (AR), ethyl Acetate (AR), toluene (AR), deuterated chloroform (AR), and industrial nitrogen (AR).
Preparation of Al @ SBA-15 (2) catalyst
Al @ SBA-15 (2) catalyst is prepared by adopting an impregnation method. In theoretical ratio of Si/Al =10, with non-hydrated aluminum nitrate (Al (NO) 3 ) 3 ·9H 2 O) as an aluminum source, in water (70 mL) solvent, until the solution is completely clear and the pH is adjusted to 3. Then 1g of spherical SBA-15 was added to the solution containing the aluminum source and stirred continuously for a period of time without precipitation. The mixed solution was transferred to an autoclave lined with polytetrafluoroethylene and crystallization was continued for 24 hours at 140 ℃ under closed conditions. The obtained sample was filtered, washed, dried and calcined at 550 ℃ for 6 hours. Finally, the heat treatment enhances the adhesion of aluminum in the SBA-15 skeleton. Washing with hot ethanol and water for multiple times, and calcining at high temperature to remove crystal phase alumina to obtain the spherical Al @ SBA-15 (2) catalyst material only containing the four-coordination framework aluminum.
Example 1
A preparation method of 1, 2-dihydropyridine and its compound-phenyl (1, 4, 6-tetraphenyl-1, 6-dihydropyridine-3-yl) methanone, the following is a specific embodiment:
the compound enaminone 1a 0.0223g (0.10 mmol) and alkynol 2a 0.0341g (0.12 mmol) (substituent R) were weighed on an analytical balance 1 、R 2 、R 3 Phenyl, phenyl and phenyl respectively) is placed in a round bottom flask, 3mL of anhydrous toluene is weighed and poured into a round bottom flask as a reaction solvent, the alkynol 2a and the enaminone 1a are completely dissolved by stirring, 2mol% of Al @SBA-15 (2) mesoporous material catalyst is weighed and added into a reaction system, the mixture is stirred at a constant temperature of 110 ℃ in an oil bath, and condensation reflux is carried out; TCL monitors the reaction, after 1h, the compound enaminone 1a completely reacts, the system is cooled to room temperature, the solvent toluene is evaporated under reduced pressure, and the reaction system is subjected to column chromatography separation by a silica gel column to obtain a target product 1, 2-dihydropyridine 3a; the reaction system was analyzed by gas-mass spectrometry (GC-MS) detection, and the yield of the target product 1, 2-dihydropyridine 3a was 93%, and the target product 1, 2-dihydropyridine 3a was subjected to Nuclear Magnetic Resonance (NMR) treatment to confirm the structure of the component.
1 H NMR(400MHz,CDCl 3 )δ(ppm):7.67(s,1H,Ar-H),7.45(d,J＝7.2Hz,6H,Ar-H),7.28-7.23(m,10H,Ar-H),7.20-7.14(m,5H,Ar-H),7.04(t,J＝8.4Hz,2H,Ar-H),6.98(t,J＝8.4Hz,2H,Ar-H),5.63(s,1H,Ar-H)；.
13 C NMR(101MHz,CDCl 3 )δ(ppm):192.26,146.53,144.19,143.08,140.08,139.52,134.58,130.90,128.91,128.77,128.29,127.91,127.87,127.75,127.56,127.43,126.94,125.68,125.59,124.13,113.95,72.64.
Example 2
A method for preparing 1, 2-dihydropyridine and its compound, 1- (4-chlorophenyl) -4, 6-triphenyl-1, 6-dihydropyridine-3-yl) (phenyl) methanone, the following is a concrete embodiment:
on an analytical balance, 0.0258g (0.10 mmol) of the compound enaminone 1b and 0.0341g (0.12 mmol) of alkynol 2b (substituent R) are weighed 1 、R 2 、R 3 Phenyl, chlorphenyl and phenyl) are placed in a round bottom flask, 3mL of anhydrous toluene is weighed as a reaction solvent and poured into the round bottom flask, the alkynol 2b and the enaminone 1b are completely dissolved by stirring, 2mol percent of Al @SBA-15 (2) mesoporous material catalyst is weighed and added into a reaction system, and the mixture is put into an oil bath kettleStirring at constant temperature of 110 ℃, and condensing and refluxing; TCL monitors the reaction, after 1h, the compound enaminone 1b reacts completely, the system is cooled to room temperature, the solvent toluene is evaporated under reduced pressure, and the reaction system is subjected to column chromatography separation by a silica gel column to obtain a target product 1, 2-dihydropyridine 3b; the yield of the target product 1, 2-dihydropyridine 3b was 91% by gas-mass spectrometry (GC-MS) detection analysis of the reaction system, and the target product 1, 2-dihydropyridine 3b was subjected to Nuclear Magnetic Resonance (NMR) treatment to confirm the structure of the component.
1 H NMR(400MHz,CDCl 3 )δ(ppm):7.59(s,1H,Ar-H),7.42(t,J＝7.2Hz,6H,Ar-H),7.32-7.25(m,8H,Ar-H),7.21-7.14(m,6H,Ar-H),7.01(d,J＝8.4Hz,2H,Ar-H),6.91(d,J＝8.4Hz,2H,Ar-H),5.65(s,1H,Ar-H)；
13 C NMR(101MHz,CDCl 3 )δ(ppm):192.42,145.51,142.78,142.73,139.81,139.24,134.56,131.11,129.35,128.88,128.65,128.39,128.08,127.89,127.82,127.65,127.52,127.06,126.50,124.27,114.65,72.55.
Example 3
A preparation method of 1, 2-dihydropyridine and its compound, (1- (4-bromophenyl) -4, 6-triphenyl-1, 6-dihydropyridine-3-yl) (phenyl) methanone, the following is a specific embodiment:
the compound enaminone 1c 0.0330g (0.10 mmol) and alkynol 2c 0.0341g (0.12 mmol) (substituent R) were weighed on an analytical balance 1 、R 2 、R 3 Phenyl, p-bromophenyl, phenyl) are respectively placed in a round bottom flask, 3mL of anhydrous toluene is weighed and poured as a reaction solvent, stirring is carried out to completely dissolve alkynol 2c and enamine ketone 1c, 2mol% of Al @ SBA-15 (2) mesoporous material catalyst is weighed and added into a reaction system, stirring is carried out at a constant temperature of 110 ℃ in an oil bath, and condensation reflux is carried out; TCL monitors the reaction, after 1h, the compound enaminone 1c completely reacts, the system is cooled to room temperature, the solvent toluene is evaporated under reduced pressure, and the reaction system is subjected to column chromatography separation by a silica gel column to obtain a target product 1, 2-dihydropyridine 3c; the reaction system adopts gas-mass combination (GC-MS) detection analysis shows that the yield of the target product 1, 2-dihydropyridine 3c is 82%, and the Nuclear Magnetic Resonance (NMR) treatment of the target product 1, 2-dihydropyridine 3c confirms the component structure.
1 H NMR(400MHz,CDCl 3 )δ(ppm):7.59(s,1H,Ar-H),7.42(t,J＝7.2Hz,5H,Ar-H),7.32-7.25(m,8H,Ar-H),7.21-7.14(m,9H,Ar-H),6.85(d,J＝8.4Hz,2H,Ar-H)5.65(s,1H,Ar-H)；
13 C NMR(101MHz,CDCl 3 )δ(ppm):192.44,145.36,143.28,142.69,139.78,139.20,134.55,131.34,131.12,128.87,128.64,128.09,127.90,127.82,127.66,127.51,127.08,126.75,124.37,118.94,114.82,72.49.
Example 4
A method for preparing 1, 2-dihydropyridine and its compound, 1- (4-methoxyphenyl) -4, 6-triphenyl-1,6-dihydro pyridine-3-yl) (phenyl) methanone, the following is a specific embodiment:
on an analytical balance, the compound enaminone 1d 0.0253g (0.10 mmol) and alkynol 2d0.0341 g (0.12 mmol) (substituent R) are weighed 1 、R 2 、R 3 Phenyl, methoxyphenyl and phenyl respectively) is placed in a round bottom flask, 3mL of anhydrous toluene is weighed and poured as a reaction solvent, stirring is carried out to completely dissolve alkynol 2d and enaminone 1d, 2mol percent of Al @ SBA-15 (2) mesoporous material catalyst is weighed and added into a reaction system, stirring is carried out at constant temperature of 110 ℃ in an oil bath, and condensation reflux is carried out; TCL monitors the reaction, after 1h, the compound enaminone 1d reacts completely, the system is cooled to room temperature, the solvent toluene is evaporated under reduced pressure, and the reaction system is subjected to column chromatography separation by a silica gel column to obtain a target product 1, 2-dihydropyridine 3d; the yield of the target product 1, 2-dihydropyridine 3d is 87% by detecting and analyzing the reaction system by gas-mass spectrometry (GC-MS), and the component structure of the target product 1, 2-dihydropyridine 3d is confirmed by Nuclear Magnetic Resonance (NMR) treatment.
1 H NMR(400MHz,CDCl 3 )δ(ppm):7.61(s,1H,Ar-H),7.47-7.42(m,6H,Ar-H),7.30-7.15(m,14H,Ar-H),6.89(d,J＝8.8Hz,2H,Ar-H),6.55(d,J＝8.8Hz,2H,Ar-H),5.58(s,1H,Ar-H),3.66(s,3H,OCH 3 )；
13 C NMR(101MHz,CDCl 3 )δ(ppm):192.04,157.49,147.38,143.20,140.22,139.72,137.46,134.53,130.79,128.95,128.80,127.92,127.86,127.72,127.58,127.42,127.28,126.86,123.56,113.43,112.70,72.88,55.33.
Example 5
A preparation method of 1, 2-dihydropyridine and its compound-phenyl (4, 6-triphenyl-1- (p-tolyl) -1, 6-dihydropyridine-3-yl) methanone, the following is a specific implementation mode:
the compounds enaminone 1e 0.0237g (0.10 mmol) and alkynol 2e 0.0341g (0.12 mmol) (substituent R) were weighed on an analytical balance 1 、R 2 、R 3 Phenyl, methylphenyl and phenyl respectively) are placed in a round bottom flask, 3mL of anhydrous toluene is weighed and poured as a reaction solvent, stirring is carried out to completely dissolve alkynol 2e and enamine ketone 1e, 2mol percent of Al @ SBA-15 (2) mesoporous material catalyst is weighed and added into a reaction system, stirring is carried out at a constant temperature of 110 ℃ in an oil bath, and condensation reflux is carried out; TCL monitors the reaction, after 1h, the compound enaminone 1e is reacted completely, the system is cooled to room temperature, the solvent toluene is evaporated under reduced pressure, and the reaction system is subjected to column chromatography separation by a silica gel column to obtain a target product 1, 2-dihydropyridine 3e; the yield of the target product 1, 2-dihydropyridine 3e is 86% by detecting and analyzing the reaction system by gas-mass spectrometry (GC-MS), and the Nuclear Magnetic Resonance (NMR) treatment is carried out on the target product 1, 2-dihydropyridine 3e to confirm the component structure.
1 H NMR(400MHz,CDCl 3 )δ(ppm):7.65(s,1H,Ar-H),7.45(t,J＝6.8Hz,6H,Ar-H),7.30-7.21(m,10H,Ar-H),7.19-7.11(m,4H,Ar-H),6.87-6.82(m,4H,Ar-H),5.61(s,1H,Ar-H),2.16(s,3H,CH 3 )；
13 C NMR(101MHz,CDCl 3 )δ(ppm):192.15,147.09,143.16,141.78,140.15,139.61,135.57,134.54,130.82,128.92,128.89,128.78,127.89,127.87,127.74,127.57,127.39,126.90,125.44,124.03,113.40,72.62,20.81.
Example 6
A method for preparing 1, 2-dihydropyridine and its compound- (4-methoxyphenyl) (1, 4, 6-tetraphenyl-1, 6-dihydropyridine-3-yl) methanone, which comprises the following steps:
the compounds enaminone 1f 0.0253g (0.10 mmol) and alkynol 2f 0.0341g (0.12 mmol) (substituent R) were weighed on an analytical balance 1 、R 2 、R 3 Methoxyphenyl, phenyl and phenyl respectively) is placed in a round bottom flask, 3mL of anhydrous toluene is weighed and taken as a reaction solvent to be poured into the round bottom flask, stirring is carried out to completely dissolve alkynol 2f and enaminone 1f, 2mol percent of Al @ SBA-15 (2) mesoporous material catalyst is weighed and added into a reaction system, stirring is carried out at a constant temperature of 110 ℃ in an oil bath, and condensation reflux is carried out; TCL monitors the reaction, after 1h, the compound enaminone 1f completely reacts, the system is cooled to room temperature, the solvent toluene is evaporated under reduced pressure, and the reaction system is subjected to column chromatography separation by a silica gel column to obtain a target product 1, 2-dihydropyridine 3f; the yield of the target product 1, 2-dihydropyridine 3f is 91% by detecting and analyzing the reaction system by gas-mass spectrometry (GC-MS), and the target product 1, 2-dihydropyridine 3f is processed by Nuclear Magnetic Resonance (NMR) to confirm the component structure.
1 H NMR(400MHz,CDCl3)δ(ppm):7.63(s,1H,Ar-H),7.47-7.10(m,6H,Ar-H),7.30-7.21(m,6H,Ar-H),7.17-7.09(m,5H,Ar-H),6.99-6.95(m,5H,Ar-H),6.97(d,J＝8.4Hz,2H,Ar-H),5.63(s,1H,Ar-H),3.74(s,3H,OCH 3 )；
13 C NMR(101MHz,CDCl 3 )δ(ppm): 13 C NMR(101MHz,CDCl 3 )δ191.47,161.94,145.21,144.28,143.22,139.49,134.81,132.63,131.05,128.79,128.25,127.87,127.78,127.51,127.38,126.96,125.53,125.47,123.72,114.21,113.06,72.51,55.30.
Example 7
A method for preparing 1, 2-dihydropyridine and its compound- (4-methoxyphenyl) (4, 6-triphenyl-1- (p-tolyl) -1, 6-dihydropyridin-3-yl) methanone, which comprises the following steps:
on an analytical balance, 1g of the compound enaminone 0.0267g (0.10 mmol) and 2g of alkynol 0.0341g (0.12 mmol) (substituent R) 1 、R 2 、R 3 Methoxyphenyl, phenyl and methylphenyl respectively) is placed in a round bottom flask, 3mL of anhydrous toluene is weighed and taken as a reaction solvent and poured into the round bottom flask, stirring is carried out to completely dissolve 2g of alkynol and 1g of enaminone, 2mol percent of Al @ SBA-15 (2) mesoporous material catalyst is weighed and added into a reaction system, stirring is carried out at a constant temperature of 110 ℃ in an oil bath, and condensation reflux is carried out; TCL monitors the reaction, 1g of enaminone after 1 hour completely reacts, the system is cooled to room temperature, the solvent toluene is evaporated under reduced pressure, and the reaction system is separated by column chromatography through a silica gel column to obtain 3g of target product 1, 2-dihydropyridine; the yield of 3g of the target product 1, 2-dihydropyridine is 88% by detecting and analyzing the reaction system by gas-mass spectrometry (GC-MS), and the component structure of 3g of the target product 1, 2-dihydropyridine is confirmed by Nuclear Magnetic Resonance (NMR) treatment.
1 H NMR(400MHz,CDCl 3 )δ(ppm):7.61(s,1H,Ar-H),7.44-7.15(m,17H,Ar-H),6.85-6.67(m,6H,Ar-H),5.59(s,1H,Ar-H),3.74(s,3H,OCH 3 ),2.16(s,3H,CH 3 )
13 C NMR(101MHz,CDCl 3 )δ(ppm):191.37,161.86,145.71,143.33,141.88,139.59,137.39,135.32,134.81,132.73,131.03,128.81,127.83,127.75,127.52,127.32,126.90,125.41,123.55,113.67,113.03,72.51,55.29,20.78.
Example 8
A method for preparing 1, 2-dihydropyridine and its compound- (6-methyl-1, 4,6-triphenyl-1, 6-dihydro-3-yl) (phenyl) methanone, the following is a specific embodiment:
on an analytical balance, compound enaminone 1h 0.0223g (0.10 mmol), alkynol 2h 0.0341g (0.12 mmol) (substituent R) was weighed 1 、R 2 、R 3 Phenyl, phenyl and methyl respectively) are placed in a round bottom flask, 3mL of anhydrous toluene is weighed and poured as a reaction solvent, stirring is carried out to completely dissolve alkynol for 2h and enaminone for 1h, 2mol% of Al @ SBA-15 (2) mesoporous material catalyst is weighed and added into a reaction system, stirring is carried out at a constant temperature of 110 ℃ in an oil bath kettle, and condensation reflux is carried out; TCL monitors the reaction, after 1h, the enamine ketone compound reacts completely for 1h, the system is cooled to room temperature, the solvent toluene is evaporated under reduced pressure, and the reaction system is subjected to column chromatography separation by a silica gel column to obtain a target product 1, 2-dihydropyridine for 3h; the reaction system is detected and analyzed by gas-mass spectrometry (GC-MS), the yield of the target product 1, 2-dihydropyridine is 88% in 3h, and the Nuclear Magnetic Resonance (NMR) treatment is carried out on the target product 1, 2-dihydropyridine in 3h to confirm the component structure.
1 H NMR(400MHz,CDCl 3 )δ(ppm):7.69(d,J＝6.8Hz,2H,Ar-H),7.55(d,J＝7.6Hz,2H,Ar-H),7.40-7.32(m,6H,Ar-H),7.25-7.17(m,9H,Ar-H),6.87(d,J＝3.0Hz,2H,Ar-H),5.19(s,1H,Ar-H),1.82(s,3H,CH 3 )；
13 C NMR(101MHz,CDCl 3 )δ(ppm):191.46,149.92,146.12,143.44,140.10,133.66,131.85,130.83,129.13,128.91,128.66,128.05,127.83,127.74,127.21,127.06,126.76,126.45,124.57,124.11,110.56,64.63,26.83.
Experiment on recycling of Al @ SBA-15 (2) catalyst
Under the reaction conditions of the embodiment 1, the recovered catalyst can still maintain larger catalytic activity after 5 times of repeated catalysis, and the Al @ SBA-15 (2) catalyst catalyzes the reaction, so that the yield can still reach 88%.
The key point of the invention is to provide a novel preparation method for preparing a series of 1, 2-dihydropyridine compounds with synthesis limitation in high yield under the action of Al @ SBA-15 (2) material with strong catalytic effect. The 1, 2-dihydropyridine compounds have high molecular value as core structures of a plurality of compounds with biological activity. The invention optimizes the complex synthesis process and reduces the preparation difficulty of the core structure molecules.
The above description is only a preferred embodiment of the present invention, but not intended to limit the application of the present invention, and the raw material ratio and equivalent alternatives can be changed without departing from the scope of the concept of the present invention, and such changes should be covered by the protection scope of the present invention.
Claims (8)
1. A preparation method for catalytically synthesizing 1, 2-dihydropyridine compounds by using Al @ SBA-15 (2) is characterized in that the reaction structural formula is as follows:
wherein the substituents R 1 Is any one of phenyl, chlorphenyl and methoxyphenyl; r is 2 Is any one of phenyl, chlorphenyl, methoxybenzene, bromophenyl and tolyl substituents; r is 3 Is hydrogen or phenyl; the substituent position, number and conjugate position are not fixed.
2. The preparation method for catalytically synthesizing 1, 2-dihydropyridines according to claim 1 by using Al @ SBA-15 (2), characterized in that the method comprises the following synthetic route:
the method comprises the following steps:
(1) Weighing compound enamine ketone 1 and alkynol 2 in a container, taking toluene as a reaction solvent, stirring to completely dissolve the enamine ketone and the alkynol, weighing catalyst Al @ SBA-15 (2) mesoporous material, adding the catalyst Al @ SBA-15 (2) mesoporous material, stirring at constant temperature, and condensing and refluxing;
(2) And (3) monitoring the reaction by TCL, cooling to room temperature and evaporating the solvent toluene under reduced pressure when the alkynol 2 compound completely reacts, and carrying out column chromatography separation on the reaction system to obtain the target product 1, 2-dihydropyridine 3.
3. The preparation method for catalytically synthesizing the 1, 2-dihydropyridines by using the Al @ SBA-15 (2) as claimed in claim 2, is characterized in that: in the step (1), the mol ratio of the compound enaminone 1 to the alkynol 2 is 1:1-2.
4. The preparation method for catalytically synthesizing the 1, 2-dihydropyridines by using the Al @ SBA-15 (2) as claimed in claim 2, is characterized in that: in the step (1), the reaction solvent toluene is dry toluene.
5. The preparation method for catalytically synthesizing the 1, 2-dihydropyridine compound by using Al @ SBA-15 (2) as claimed in claim 2, which is characterized by comprising the following steps: the reaction temperature in the step (1) is 70-130 ℃.
6. The preparation method for catalytically synthesizing the 1, 2-dihydropyridine compound by using Al @ SBA-15 (2) as claimed in claim 2, which is characterized by comprising the following steps: the reaction in the step (1) is completed for 1-4h.
7. The preparation method for catalytically synthesizing the 1, 2-dihydropyridines by using the Al @ SBA-15 (2) as claimed in claim 2, is characterized in that: in the step (1), the dosage of the catalyst Al @ SBA-15 (2) mesoporous material is 0.3-4mol%.
8. The preparation method for catalytically synthesizing the 1, 2-dihydropyridine compound by using Al @ SBA-15 (2) as claimed in claim 2, which is characterized by comprising the following steps: eluent for column chromatography in step (2) is V Petroleum ether /V Ethyl acetate ＝40-140：1-4。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4780538A (en) * | 1986-02-12 | 1988-10-25 | Merck & Co., Inc. | Process for 1,4-dihydropyridine compounds using a titanamine catalyst |
| KR20170070912A (en) * | 2015-12-14 | 2017-06-23 | 영남대학교 산학협력단 | Synthesis method of pyridine derivative through N-annulation reaction |
| CN112939004A (en) * | 2021-03-15 | 2021-06-11 | 三峡大学 | Preparation method of Al modified SBA-15 and application of Al modified SBA-15 in catalyzing alkynol dehydration reaction |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4780538A (en) * | 1986-02-12 | 1988-10-25 | Merck & Co., Inc. | Process for 1,4-dihydropyridine compounds using a titanamine catalyst |
| KR20170070912A (en) * | 2015-12-14 | 2017-06-23 | 영남대학교 산학협력단 | Synthesis method of pyridine derivative through N-annulation reaction |
| CN112939004A (en) * | 2021-03-15 | 2021-06-11 | 三峡大学 | Preparation method of Al modified SBA-15 and application of Al modified SBA-15 in catalyzing alkynol dehydration reaction |
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| Title |
|---|
| YI-WEN LIU等: "Efficient Iron-Catalyzed Synthesis of Polysubstituted 1, 2-Dihydropyridine Derivatives", RUSSIAN JOURNAL OF GENERAL CHEMISTRY, vol. 85, no. 9, 31 December 2015 (2015-12-31), pages 2163 - 2166, XP035574605, DOI: 10.1134/S1070363215090212 * |
| 罗享豪: "新型负载型介孔分子筛SBA-15的设计制备及其催化有机合成反应的研究", 万方学位论文, 31 October 2022 (2022-10-31), pages 15 - 19 * |
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