CN107556237B - Preparation method of 3- (2-phenethyl) -2-pyridine carboxamide compound - Google Patents
Preparation method of 3- (2-phenethyl) -2-pyridine carboxamide compound Download PDFInfo
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Abstract
The invention discloses a preparation method of a 3- (2-phenethyl) -2-pyridine carboxamide compound (I). The method takes 2-cyano-3-methylpyridine and benzaldehyde compounds as initial raw materials, a 3- (2-styryl) -2-pyridine carboxamide compound is obtained by condensation reaction in a proper solvent under an alkaline condition, and the 3- (2-phenethyl) -2-pyridine carboxamide compound (I) is obtained by catalytic hydrogenation reaction of the intermediate;
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a preparation method of 3- (2-phenethyl) -2-pyridine carboxamide compounds with chemical structures shown as (I),
in the formula: r1And R2Each independently represents H, OH, C1-12Alkyl radical, C1-12Alkoxy radical, CH3OCH2O、F、Cl、Br、CF3、OCF3、CONH2、NH2、N(Me)2、NHCOR5，R5Representation H, C1-12An alkyl group; r1And R2Can be in any possible position of the benzene ring.
Background
3- (2-phenethyl) -2-pyridine carboxamides (I) are synthesized into tricyclic H1An important intermediate of receptor antagonists (Villani F.J. et al.J. Med. Chem., 1972, 15(7), 750-754；Villani F.J. et al.US 4659716), the preparation method of the compounds disclosed in the current literature mainly uses 2-cyano-3-methylpyridine (1) or 3- (2-phenethyl) -2-pyridinecarbonitrile compounds as starting materials, and the specific synthetic method is as follows:
the method comprises the following steps: (Villani F.J. et al. US 4659716）
2-cyano-3-methylpyridine (1) and 3-fluorobenzaldehyde are used as initial raw materials and react for 2 to 3 hours at the temperature of between 20 ℃ below zero and 15 ℃ below zero under the action of anhydrous tetrahydrofuran and potassium tert-butoxide to obtain 3- [2- (3-fluorophenyl) vinyl ] -2-pyridinecarboxamide with the yield of 42.1 percent; the obtained intermediate is subjected to Pd/C catalytic hydrogenation reduction in acetic acid to obtain 3- [2- (3-fluorophenyl) ethyl ] -2-pyridinecarboxamide with the yield of 88.6 percent, and the synthetic route is as follows:
the method needs low temperature and absolute anhydrous reaction conditions; the potassium tert-butoxide is very easy to absorb water and decompose, so that anhydrous conditions are not needed in the weighing, feeding and reaction processes, so that the reaction conditions are harsh, and the operation process is complicated; in addition, the potassium tert-butoxide is expensive and the yield of the method is low.
The second method comprises the following steps: (Walter L.A. 2-Amino-3- (o-chlorophenylethyl) pyridine functional as a diene in a Diels-Alder reaction.Journal of Heterocyclic Chemistry,1969, 6(6), 979-980）
3- [2- (2-chlorphenyl) ethyl ] -2-pyridine carbonitrile is taken as a starting material, and is subjected to reflux reaction for 40 minutes under the conditions of sodium hydroxide, ethanol and water to obtain the corresponding amide compound with the yield of 84%, and the synthetic route is as follows:
the raw materials used in the method are not easy to obtain, so that the preparation cost is high.
In conclusion, the existing method for preparing the 3- (2-phenethyl) -2-pyridine carboxamide compound (I) has the problems of difficult availability of reaction raw materials, harsh reaction conditions, complicated reaction operation and post-treatment process, serious environmental pollution, low yield and the like, so that the mass preparation of the compound is limited. Therefore, there is still a need in the art to develop a novel method for preparing 3- (2-phenylethyl) -2-pyridinecarboxamide compound (I) with cheap and easily available raw materials, mild reaction conditions, simple operation and high yield.
Disclosure of Invention
The invention aims to avoid the defects of the existing method and provide a novel synthesis method which has the advantages of easily obtained reaction raw materials, friendly reaction environment, simple and convenient reaction operation and post-treatment and can be used for preparing 3- (2-phenethyl) -2-pyridine carboxamide compounds (I) in large scale.
The novel method for preparing the 3- (2-phenethyl) -2-pyridine carboxamide compound (I) provided by the invention is characterized in that 2-cyano-3-methylpyridine (1) and a benzaldehyde compound (2) are used as initial raw materials, the condensation reaction is carried out in a proper solvent under an alkaline condition to obtain the 3- (2-styryl) -2-pyridine carboxamide compound (3), the obtained intermediate (3) is subjected to a catalytic hydrogenation reaction to obtain the 3- (2-phenethyl) -2-pyridine carboxamide compound (I), and the synthetic route is as follows:
in the formula: r1、R2、R3And R4Each independently represents H, OH, C1-12Alkyl radical, C1-12Alkoxy radical, CH3OCH2O、F、Cl、Br、CF3、OCF3、CONH2、NO2、NH2、N(Me)2、NHCOR5，R5Representation H, C1-12An alkyl group; but R is1And R2Not representing NO2；R1、R2、R3And R4Can be in any possible position of the benzene ring.
For the above synthetic route, the specific steps are:
A) 2-cyano-3-methylpyridine (1) is taken as a starting material and condensed with a benzaldehyde compound (2) under proper solvent and alkaline conditions to obtain a 3- (2-styryl) -2-pyridine carboxamide compound (3);
B) and D) carrying out catalytic hydrogenation reduction on the 3- (2-styryl) -2-pyridine carboxamide compound (3) obtained in the step A) to obtain a 3- (2-phenethyl) -2-pyridine carboxamide compound (I).
The method for synthesizing the 3- (2-phenethyl) -2-pyridine carboxamide compound (I) is specifically described as follows:
step A): condensing 2-cyano-3-methylpyridine (1) with a benzaldehyde compound (2) under proper solvent and alkaline conditions to obtain a 3- (2-styryl) -2-pyridine carboxamide compound (3); wherein, the solvent used in the reactionComprises the following steps: water, C1-6Fatty alcohol, fatty alcohol,N,N-dimethylformamide,N,N-dimethylacetamide,N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, dimethyl sulfoxide, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, acetonitrile, 1, 4-dioxane, C5-10Aliphatic or cycloalkane (e.g., n-hexane, n-heptane, etc.), halogenated hydrocarbon (e.g., dichloromethane, chloroform, 1, 2-dichloroethane, chlorobenzene, o-dichlorobenzene, etc.), benzene, toluene, or xylene, in the above-mentioned single solvent, or in any two of the above-mentioned solvents in a volume ratio of 1: 0.1-10, and the preferable solvent is: tert-butyl alcohol,N,N-dimethylformamide,N,N-dimethylacetamide,N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, ethylene glycol dimethyl ether, tetrahydrofuran, 1, 4-dioxane, chlorobenzene, o-dichlorobenzene, toluene or xylene; the base used in the reaction is: alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal oxides, alkaline earth metal oxides, borax, preferably the bases are: lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, magnesium oxide, calcium oxide, and borax; 2-cyano-3-methylpyridine (1): benzaldehyde compound (2): the molar charge ratio of alkali is 1.0: 1.0-4.0: 0.05-5.0, preferably 1.0: 1.0-2.0: 0.1 to 2.0; the reaction temperature is-5 ℃ to 120 ℃, and preferably 0 ℃ to 80 ℃; the reaction time is 1 to 96 hours, preferably 2 to 48 hours.
Step B): carrying out catalytic hydrogenation reduction on the 3- (2-styryl) -2-pyridine carboxamide compound (3) obtained in the step A) in a proper solvent to obtain a 3- (2-phenethyl) -2-pyridine carboxamide compound (I); wherein, the solvent used in the reaction is: water, C1-6Fatty alcohol, C3-8Aliphatic ketones, C1-6Fatty acid, C1-6Fatty acids with C1-6Esters of aliphatic alcohols, ethers (e.g., diethyl ether, isopropyl ether, methyl t-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, 1, 4-dioxane, etc.), benzene, toluene, xylene, aliphatic hydrocarbons (e.g., hexane, heptane, toluene, etc.),Octane, etc.), preferred solvents are: water, methanol, ethanol, toluene, tetrahydrofuran, acetic acid, or ethyl acetate; the reaction is carried out in the single solvent or any two mixed solvents of the solvents, and the volume ratio of the mixed solvents is 1: 0.1 to 10; the catalysts used for the catalytic hydrogenation were: 1 to 30 weight percent of Pd-C, palladium black, palladium loaded by a polymer carrier (such as D61-Pd, D72-Pd, D153-Pd, D261-Pd, D290-Pd and the like), 1 to 30 weight percent of Pd (OH)2-C, palladium acetate, palladium dichloride, Raney-Ni, Rh-Al2O3、PtO2Preferably, the catalyst is one of Ni-Al or a combination thereof: Raney-Ni, 5% -20% Pd-C, 5% -20% Pd (OH)2-C; the mass ratio of the 3- (2-styryl) -2-pyridine carboxamide compound (3) to the catalyst is 1.0: 0.01 to 1.0; the reaction pressure is normal pressure to 10.0 MPa, preferably normal pressure to 2.0 MPa; the reaction temperature is room temperature-150 ℃, and preferably room temperature-80 ℃; the reaction time is 1 to 48 hours, preferably 1 to 24 hours.
The chemical purity of the 3- (2-phenethyl) -2-pyridine carboxamide compound (I) prepared by the method is more than 98.5 percent. The invention has the advantages that: compared with the prior art, the method has the advantages of cheap and easily obtained raw materials, mild reaction conditions, simple and convenient operation, environmental friendliness, no absolute anhydrous reaction conditions, high yield and suitability for large-scale preparation of the 3- (2-phenethyl) -2-pyridine carboxamide compound (I).
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. All reagents used in this example were commercially available and were not further processed. The term "room temperature" as used in this example means 15 ℃ to 30 ℃.
Comparative example 1
Preparation of 3- [2- (3-fluorophenyl) ethenyl ] -2-pyridinecarboxamide (3-16)
A reaction flask was charged with 1.62 g (14.4 mmol) of potassium tert-butoxide andanhydrous THF (7.5 ml) is placed in a low-temperature bath to be cooled to minus 15 to minus 20 ℃ after being uniformly stirred, then a solution of 1.42 g (12.0 mmol) of 2-cyano-3-methylpyridine and 1.64 g (13.2 mmol) of 3-fluorobenzaldehyde dissolved in the anhydrous THF (7.5 ml) is slowly added dropwise, the dropping speed is controlled, the temperature of the reaction solution is not more than minus 15 ℃ and the dropping is finished for about 20 minutes; then keeping the temperature at minus 15 ℃ to minus 20 ℃, stirring and reacting for 1.0 h, heating to 0-5 ℃, and stirring and reacting for 2.0 h. After completion of the reaction, a saturated aqueous ammonium chloride solution (4.0 ml) and deionized water (2.5 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes to separate an organic layer, the resulting aqueous layer was extracted with dichloromethane (15 ml), the organic layer and dichloromethane layer were combined, washed with a saturated aqueous ammonium chloride solution (4.0 ml), and the organic layer was washed with Na2SO4Drying, filtering, evaporating under reduced pressure to remove the solvent, adding toluene (3.5 ml) into the residue, heating and refluxing, then filtering while the residue is hot, putting the filtrate in a refrigerator for overnight at 0-5 ℃, filtering, and drying to obtain an off-white solid, wherein the yield is 21.6%, and the mp is 153.5-155.0 ℃.
Comparative example 2
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The operation process is the same as that of comparative example 1, except that 3-fluorobenzaldehyde is replaced by 3-chlorobenzaldehyde to obtain a white solid with the yield of 18.5 percent and mp 149.1-151.0 ℃.
Comparative example 3
Preparation of 3- [2- (3-fluorophenyl) ethenyl ] -2-pyridinecarboxamide (3-16)
Adding 1.42 g (12.0 mmol) of 2-cyano-3-methylpyridine, 1.64 g (13.2 mmol) of 3-fluorobenzaldehyde and 15 ml of anhydrous THF (tetrahydrofuran), stirring uniformly, placing in a low-temperature bath, cooling to-15 to-20 ℃, adding 1.62 g (14.4 mmol) of potassium tert-butoxide, keeping the temperature at-15 to-20 ℃, stirring for reaction for 1.0 h, heating to 0 to 5 ℃, and stirring for reaction for 2.0 h. After completion of the reaction, a saturated aqueous ammonium chloride solution (4.0 ml) and deionized water (2.5 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes to separate an organic layer, and the resulting aqueous layer was extracted with dichloromethane (15 ml), and the organic layer and dichloromethane layer were combined, washed with a saturated aqueous ammonium chloride solution (4.0 ml) to remove impuritiesMachine layer warp Na2SO4Drying, filtering, evaporating under reduced pressure to remove the solvent, adding toluene (3.5 ml) into the residue, heating and refluxing, then filtering while the residue is hot, putting the filtrate in a refrigerator for overnight at 0-5 ℃, filtering, and drying to obtain an off-white solid, wherein the yield is 20.3%, and mp is 152.0-154.0 ℃.
Comparative example 4
Preparation of 3- [2- (3-fluorophenyl) ethenyl ] -2-pyridinecarboxamide (3-16)
1.42 g (12.0 mmol) of 2-cyano-3-methylpyridine, 1.64 g (13.2 mmol) of 3-fluorobenzaldehyde and 15 ml of anhydrous THF were charged into a reaction flask, and after stirring the mixture uniformly, 1.62 g (14.4 mmol) of potassium tert-butoxide was added thereto at room temperature, and the reaction was further stirred at room temperature (progress of the reaction was monitored by TLC). After completion of the reaction, a saturated aqueous ammonium chloride solution (4.0 ml) and deionized water (2.5 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes to separate an organic layer, the resulting aqueous layer was extracted with dichloromethane (15 ml), the organic layer and dichloromethane layer were combined, washed with a saturated aqueous ammonium chloride solution (4.0 ml), and the organic layer was washed with Na2SO4Drying, filtering, evaporating under reduced pressure to remove the solvent, adding toluene (3.5 ml) into the residue, heating and refluxing, then filtering while the residue is hot, putting the filtrate in a refrigerator for overnight at 0-5 ℃, filtering, and drying to obtain an off-white solid, wherein the yield is 12.7%, and mp is 152.0-154.0 ℃.
Example 1
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
2-cyano-3-methylpyridine (10.0 mmol), 3-chlorobenzaldehyde (12.0 mmol) andN, Ndimethylformamide (25 ml), after stirring well, lithium hydroxide (3.0 mmol) was added and the reaction stirred at room temperature (progress of reaction was monitored by TLC) for about 24 h to completion. After the reaction, deionized water (50.0 ml) was added and extracted with ethyl acetate several times; combining the organic layers, and sequentially washing with deionized water and a saturated NaCl aqueous solution; the organic layer was passed over anhydrous Na2SO4Drying, filtering, evaporating under reduced pressure to remove solvent, and recrystallizing the residue to obtain white solid with yield of 48.0%; mp 149-150 ℃;1H NMR(CDCl3) d: 8.48(d, J=4.4 Hz, 1H), 8.43(d, J=16.4 Hz, 1H), 8.04(d, J=8.0 Hz, 1H), 7.97(brs, 1H), 7.55(s, 1H), 7.46(dd, J=4.4 Hz, 8.0 Hz, 1H), 7.45(d, J=8.0 Hz, 1H), 7.29(t, J=8.0 Hz, 1H), 7.24(d, J=8.0 Hz, 1H), 6.91(d, J=16.4 Hz, 1H), 5.75(brs, 1H); 13C NMR(DMSO-d 6 ) d: 168.18, 146.95, 145.44, 138.94, 135.64, 134.61, 134.51, 130.95, 129.84, 128.00, 127.30, 126.95, 126.30, 125.15; ESI-MS (m/z, +Q): 259.1 [M+H]+。
example 2
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The operation process is the same as that of example 1, except that the lithium hydroxide is replaced by sodium hydroxide to obtain a white-like solid with a yield of 46.5 percent; the chemical structure was confirmed by NMR.
Example 3
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The operation process is the same as that of example 1, except that the lithium hydroxide is replaced by potassium hydroxide to obtain a white-like solid with a yield of 54.0 percent; the chemical structure was confirmed by NMR.
Example 4
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The operation process is the same as that of example 1, except that the lithium hydroxide is replaced by cesium hydroxide to obtain a white-like solid with a yield of 60.2%; the chemical structure was confirmed by NMR.
Example 5
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The operation process is the same as that of example 1, except that the lithium hydroxide is replaced by magnesium hydroxide to obtain a white-like solid with the yield of 56.3 percent; the chemical structure was confirmed by NMR.
Example 6
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The operation process is the same as that of example 1, except that the lithium hydroxide is replaced by calcium hydroxide to obtain a white-like solid with a yield of 63.6 percent; the chemical structure was confirmed by NMR.
Example 7
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The operation process is the same as that of the example 1, except that the lithium hydroxide is replaced by calcium oxide, the reaction temperature is adjusted to 60-70 ℃ from room temperature to obtain a white-like solid, and the yield is 60.7%; the chemical structure was confirmed by NMR.
Example 8
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The operation process is the same as that of the example 1, except that the lithium hydroxide is replaced by the magnesium oxide, the reaction temperature is adjusted to 60-70 ℃ from the room temperature, and the white-like solid is obtained, wherein the yield is 66.3%; the chemical structure was confirmed by NMR.
Example 9
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The operation process is the same as that of example 1, except that the lithium hydroxide is replaced by borax to obtain a white-like solid with a yield of 45.0 percent; the chemical structure was confirmed by NMR.
Example 10
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The procedure is as in example 1, except that the lithium hydroxide is replaced by calcium hydroxide,N,N-dimethyl formamide is replaced by tert-butanol to obtain a white solid with a yield of 43.2%; the chemical structure was confirmed by NMR.
Example 11
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The procedure is as in example 1, except that the lithium hydroxide is replaced by calcium hydroxide,N,Nfor dimethyl formamideN,N-dimethylacetamide to obtain a white solid with a yield of 63.2%; the chemical structure was confirmed by NMR.
Example 12
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The procedure is as in example 1, except that the lithium hydroxide is replaced by calcium hydroxide,N,Nfor dimethyl formamideN-methyl pyrrolidone to obtain a white solid with a yield of 67.5%; the chemical structure was confirmed by NMR.
Example 13
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The procedure is as in example 1, except that the lithium hydroxide is replaced by calcium hydroxide,N,Nthe-dimethylformamide is replaced by 1, 3-dimethyl-2-imidazolidinone to obtain a white solid with the yield of 67.0 percent; the chemical structure was confirmed by NMR.
Example 14
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The procedure is as in example 1, except that the lithium hydroxide is replaced by calcium hydroxide,N,Ndimethyl formamide is replaced by dimethyl sulfoxide to obtain a white solid with the yield of 59.0 percent; the chemical structure was confirmed by NMR.
Example 15
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The procedure is as in example 1, except that the lithium hydroxide is replaced by calcium hydroxide,N,Nthe-dimethylformamide is replaced by 1, 4-dioxane to obtain a white solid with the yield of 53.3 percent; the chemical structure was confirmed by NMR.
Example 16
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The procedure is as in example 1, except that the lithium hydroxide is replaced by calcium hydroxide,N,Ntetrahydrofuran is used for replacing dimethylformamide to obtain a white solid with the yield of 49.7 percent; the chemical structure was confirmed by NMR.
Example 17
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The procedure is as in example 1, except that the lithium hydroxide is replaced by calcium hydroxide,N,N-dimethyl formamide is replaced by toluene to obtain similar whiteA colored solid, yield 45.0%; the chemical structure was confirmed by NMR.
Example 18
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The procedure is as in example 1, except that the lithium hydroxide is replaced by calcium hydroxide,N,N-dimethyl formamide is replaced by chlorobenzene to obtain a white solid with the yield of 44.0 percent; the chemical structure was confirmed by NMR.
Example 19
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The operation process is the same as that of example 1, except that the lithium hydroxide is replaced by calcium hydroxide, the dosage of the calcium hydroxide is 10.0 mmol,N,Nthe-dimethylformamide is replaced by 1, 3-dimethyl-2-imidazolidinone to obtain a white solid with the yield of 65.0 percent; the chemical structure was confirmed by NMR.
Example 20
Preparation of 3- [2- (3-chlorophenyl) ethenyl ] -2-pyridinecarboxamide (3-17)
The operation process is the same as example 1, except that the lithium hydroxide is replaced by calcium hydroxide, the dosage of the calcium hydroxide is 1.0 mmol,N,Nthe-dimethylformamide is replaced by 1, 3-dimethyl-2-imidazolidinone to obtain a white solid with the yield of 58.2 percent; the chemical structure was confirmed by NMR.
Example 21
Preparation of 3- [2- (3-fluorophenyl) ethenyl ] -2-pyridinecarboxamide (3-16)
The operation process is the same as that of example 1, except that 3-chlorobenzaldehyde is replaced by 3-fluorobenzaldehyde, lithium hydroxide is replaced by calcium hydroxide,N,Nthe-dimethylformamide is replaced by 1, 3-dimethyl-2-imidazolidinone to obtain a white solid with the yield of 63.0 percent; the chemical structure was confirmed by NMR.
Example 22
General method for preparing 3- (2-styryl) -2-pyridine carboxamide compound (3)
2-cyano-3-methylpyridine (10.0 mmol), benzaldehyde compound (2) (12.0 mmol) and 1, 3-dimethyl-2-imidazolidinone (15 ml) were put in a reaction flask and stirredAfter homogenization, calcium hydroxide (3.0 mmol) was added and the reaction stirred at room temperature (progress of the reaction was monitored by TLC) taking about 12-48 h to complete. After the reaction, deionized water (50.0 ml) was added and extracted with ethyl acetate several times; combining the organic layers, and sequentially washing with deionized water and a saturated NaCl aqueous solution; the organic layer was passed over anhydrous Na2SO4Drying, filtering, distilling under reduced pressure to remove solvent, and purifying the residue by conventional recrystallization operation or silica gel column chromatography to obtain corresponding 3- (2-styryl) -2-pyridine carboxamide compounds with yield of 48.5% -76.0%, and chemical structures thereof1H-NMR、13C-NMR and ESI-MS confirmation; the target prepared by the method has the following structure:
example 23
Preparation of 3- [2- (3-chlorophenyl) ethyl ] -2-pyridinecarboxamide (I-17)
3- [2- (3-chlorophenyl) ethenyl]-2-pyridinecarboxamide (3-17) (10.0 mmol), methanol (25 ml) and tetrahydrofuran (15 ml), stirring uniformly at room temperature, adding 10% Pd-C catalyst 0.3 g, replacing reaction flask with hydrogen for three times, stirring and reacting at normal temperature and normal pressure for 24 hours; after the reaction is finished, filtering, washing a filter cake by a small amount of hot methanol, combining the filtrate and the washing liquid, and evaporating the solvent under reduced pressure to obtain the 3- [2- (3-chlorphenyl) ethyl]-2-pyridinecarboxamide (I-17), mp: 119-120 ℃, yield 96.0%;1H NMR(CDCl3) d: 8.44(dd, J=1.2 Hz, 4.4 Hz, 1H), 7.96(brs, 1H), 7.48(d, J=8.0 Hz, 1H), 7.33(dd, J=4.4 Hz, 8.0 Hz, 1H), 7.23(s, 1H), 7.20(t, J=7.6 Hz, 1H), 7.17(d, J=7.6 Hz, 1H), 7.12(d, J=7.6 Hz, 1H), 5.57(brs, 1H), 3.44(t, J=8.0 Hz, 1H), 2.95(t, J=8.0 Hz, 1H)。
example 24
Preparation of 3- [2- (3-fluorophenyl) ethyl ] -2-pyridinecarboxamide (I-16)
3- [2- (3-fluorophenyl) vinyl group is added into a reaction bottle]-2-pyridinecarboxamide (3-16) (10.0 mmol), ethanol (50 ml), stirring well, adding 10% Pd (OH)20.5 g of-C catalyst, replacing the reaction bottle with hydrogen for three times, and stirring and reacting for 24 hours at normal temperature and normal pressure; after the reaction is finished, filtering, washing a filter cake by a small amount of hot ethanol, merging filtrate and washing liquor, and evaporating the solvent under reduced pressure to obtain the 3- [2- (3-fluorophenyl) ethyl]-2-pyridinecarboxamide (3-16), mp: 101.5-103.0 ℃, yield 94.8%.
Example 25
General preparation method of 3- (2-phenethyl) -2-pyridine carboxamide compound (I)
Adding 3- (2-styryl) -2-pyridine carboxamide compound (3) (10.0 mmol) and ethanol (50 ml) into a reaction bottle, uniformly stirring, adding 0.5 g of 5% Pd-C catalyst, replacing the reaction bottle with hydrogen for three times, and stirring and reacting at normal temperature and normal pressure for 12-36 hours; after the reaction is finished, filtering, washing a filter cake by a small amount of hot ethanol, combining the filtrate and the washing liquid, decompressing and steaming to remove the solvent, and purifying the residue by conventional recrystallization operation or silica gel column chromatography to obtain the corresponding 3- (2-phenethyl) -2-pyridine carboxamide compound with the yield of 88.0-99.0 percent and the chemical structures of the compounds are all purified by1H-NMR、13C-NMR and ESI-MS confirmation; the target prepared by the method has the following structure:
Claims (3)
1. a preparation method of 3- (2-styryl) -2-pyridine carboxamide compound (3) is characterized in that 2-cyano-3-methylpyridine (1) is used as a starting material and condensed with benzaldehyde compound (2) under proper solvent and alkaline conditions to obtain the 3- (2-styryl) -2-pyridine carboxamide compound (3); the base used in the reaction is: potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide; the reaction formula is as follows:
in the formula: r3And R4Each independently representing H, C1-12Alkyl radical, C1-12Alkoxy radical, CH3OCH2O、F、Cl、Br、CF3、OCF3、CONH2、NO2、NH2、N(Me)2、NHCOR5，R5Is represented by C1-12An alkyl group; r3And R4At any possible position of the phenyl ring.
2. The process for producing 3- (2-styryl) -2-pyridinecarboxamide compound (3) according to claim 1, characterized in that the solvent used for the reaction is: tert-butyl alcohol,N,N-dimethylformamide,N,N-dimethylacetamide,N-methylpyrrolidone, 1, 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, 1, 4-dioxane, toluene or chlorobenzene.
3. A process for the preparation of 3- (2-styryl) -2-pyridinecarboxamide compound (3) according to claim 1, characterized in that 2-cyano-3-methylpyridine (1): benzaldehyde compound (2): the molar charge ratio of alkali is 1.0: 1.0-4.0: 0.05 to 5.0; the reaction temperature is-5 ℃ to 120 ℃; the reaction time is 1-96 hours.
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| US4659716A (en) * | 1984-02-15 | 1987-04-21 | Schering Corporation | Antihistaminic 8-(halo)-substituted 6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines |
| CN107400083A (en) * | 2017-08-28 | 2017-11-28 | 四川大学 | A kind of preparation method of 3 [2 (3 chlorphenyl) ethyl] 2 pyridine carbonitriles |
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| US4659716A (en) * | 1984-02-15 | 1987-04-21 | Schering Corporation | Antihistaminic 8-(halo)-substituted 6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines |
| CN107400083A (en) * | 2017-08-28 | 2017-11-28 | 四川大学 | A kind of preparation method of 3 [2 (3 chlorphenyl) ethyl] 2 pyridine carbonitriles |
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| Aza-analogue dibenzepinone scaffolds as p38 mitogen-activated protein kinase inhibitors: design, synthesis, and biological data of inhibitors with improved physicochemical properties;Karcher S C et al.;《J. Med. Chem.》;20090302;第52卷(第6期);第1778-1782页 * |
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