CN106632301B - Synthesis method of pyridine-bis-thiazole carboxylic acid derivative - Google Patents
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Abstract
The invention discloses a synthesis method of a pyridine-bis-thiazole carboxylic acid derivative. Firstly, pyridine bi-thiazole carboxylic acid is synthesized, then derivatives of the pyridine bi-thiazole carboxylic acid are synthesized by substitution, the pyridine bi-hydrogen thiazole carboxylic acid is generated by the reaction of cyanopyridine and L-cysteine hydrochloride, and the pyridine bi-hydrogen thiazole carboxylic acid is amidated or esterified after forming acyl chloride. The synthetic method disclosed by the invention is simple in operation process, the thiazole can be synthesized without dihydrothiazole, the yield is high, the synthesized pyridine bithiazole amide and pyridine bithiazole ester have good antibacterial activity and anticancer activity, can be well applied to the fields of medicines and agricultural medicines, provides a new thought for creating new pesticides, and has good development prospects.
Description
Technical Field
The invention relates to a synthesis method of a pyridine-bis-thiazole carboxylic acid derivative, belonging to the technical field of chemical synthesis.
Background
The compounds with nitrogen heterocyclic structures play more and more important roles in the current creation and application of medical drugs and agricultural drugs, wherein thiazole and pyridine compounds become important and hot spots for research of new medicines and pesticides due to wide biological activities of the thiazole and pyridine compounds. At present, in the research, development and creation of new medical drugs and agricultural drugs, pyridine and thiazole are more and more widely applied and play more and more important roles in the processes of human health treatment and crop disease prevention and treatment. Pyridine and thiazole compounds are hot spots and important fields of current medicine and pesticide research.
The preparation of pyridine-bis-hydrogen thiazole carboxylic acid is related in the literature, and is prepared by the reaction of 3-cyanopyridine and cysteine hydrochloride in a mixed alkali of sodium bicarbonate and sodium hydroxide and methanol as a solvent at room temperature in the reports of Oleg V.Maltsev et al (Synthesis,2013, 2763-2767); hans Peter Krimmer et al (Chemiker-Zeitung,1987, 111,357-61) reported that 3-cyanopyridine and cysteine hydrochloride were synthesized by reaction with potassium carbonate as a base and methanol water as a solvent. The literature reports that pyridine bithiazole carboxylic acid (WO2012007500) is prepared by reacting thionicotinamide with ethyl 3-bromopyruvate in aqueous sodium hydroxide solution; in patent WO2003027085, thionicotinamide is prepared from 4-methyl-3-cyanopyridine, and then the thionicotinamide reacts with 3-bromopyruvic acid to synthesize pyridinebithiazolecarboxylic acid. Synthesis of pyridine-bithiazole derivatives from pyridine-bithiazole derivatives generally employs manganese dioxide oxidation (MarkC. Bagley, Journal of organic Chemistry,2005,70, 1389-.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a synthesis method of a pyridine-bis thiazole carboxylic acid derivative.
In order to achieve the purpose, the invention is realized by the following technical scheme:
a process for synthesizing the pyridine-bithiazole-type carboxylic acid derivative includes synthesizing pyridine-bithiazole-type carboxylic acid, acid chloridizing, and reacting acyl chloride with amine compound or alcohol.
The synthesis method of the pyridine-bis-thiazole derivative comprises the following steps: putting 3-cyano-R-pyridine, L-cysteine hydrochloride and sodium bicarbonate into a reaction container, adding absolute ethyl alcohol, heating at 90 ℃ for 12 hours until the raw materials react completely, cooling to room temperature, removing the absolute ethyl alcohol by spinning to obtain a milky solid, dissolving with water, slowly adding a hydrochloric acid solution under an ice bath condition until the pH value of the measured solution is 3-4, separating out a white solid, performing suction filtration, washing with ice water for 2-3 times, and drying to obtain the pyridine dihydrothiazolecarboxylic acid.
According to the synthesis method of the pyridine-bis-thiazole derivative, the cyanopyridine compound is 3-cyanopyridine, 4-methyl-3-cyanopyridine or 2-chloro-3-cyanopyridine.
According to the synthesis method of the pyridine-bithiazole derivative, the molar ratio of the 3-cyano-R-pyridine to the L-cysteine hydrochloride is 1:1.5-1: 2.5.
Taking a compound of pyridine-bis-hydrogen thiazole carboxylic acid in a reaction container, adding dichloromethane as a solvent, slowly dripping thionyl chloride under the ice bath condition, removing the ice bath, reacting at normal temperature for 18 hours, evaporating dichloromethane after complete reaction to obtain an intermediate product A, adding 15mL of dichloromethane to dissolve the intermediate product A, dropwise adding triethylamine into the reaction solution at zero DEG C, then dropwise adding an amine compound, removing the ice bath, and reacting at normal temperature for 16 hours until the raw materials completely disappear; adding saturated NaHCO into the reaction system3Quenching the reaction with aqueous solution, extracting with dichloromethane, washing with saturated NaCl solution, anhydrous Na2SO4Drying, filtering, evaporating dichloromethane, and obtaining the pyridine isothiazole amide by DCM: MeOH: 40: 1-10: 1 or PE: EA: 5: 1-3: 1.
The synthesis method of the pyridine-bis-thiazole derivative comprises the steps of putting a compound pyridine-bis-hydrogen thiazole carboxylic acid into a reaction container, adding an alcohol compound, slowly dripping thionyl chloride under the ice bath condition, removing the ice bath, heating to 80 ℃, refluxing for 4 hours, completely reacting, spin-drying a solvent, adding saturated NaHCO (sodium hydrogen chloride), and performing solid phase reaction3The solution was extracted three times with DCM, washed with saturated NaCl, anhydrous Na2SO4Drying, spin-drying the solvent, and performing column chromatography on PE (ethylene-vinyl acetate copolymer) EA-2: 1 to obtain the pyridine bithiazole ester.
The invention has the beneficial effects that:
the synthetic method disclosed by the invention is simple in operation process, the thiazole can be synthesized without the need of the dihydrothiazole, the yield is high, the synthesized pyridine-bis-hydrogenthiazolecarboxylic acid has good antibacterial activity, and the pyridine-bis-hydrogenthiazolecarboxylic acid can further synthesize pyridine-bis-thiazolylamide and pyridine-bis-thiazolylicester, so that the pyridine-bis-hydrogenthiazolecarboxylic acid can be well applied to the fields of medicines and agricultural medicines, provides a new thought for the creation of new pesticides and medicines, and has a good development prospect.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.
Example 1
The general formula of the synthesis reaction of the pyridine bidihydrothiazole carboxylic acid is as follows:
the structural formula of the pyridine bidihydrothiazole carboxylic acid is as follows:
3-cyanopyridine (10mmol, 1.04g), L-cysteine hydrochloride (15mmol) and sodium bicarbonate (60mmol) are weighed into a 100mL round-bottom flask, 30mL of absolute ethanol is added, the mixture is heated at 90 ℃ for 12 hours until the raw materials are reacted completely, the mixture is cooled to room temperature, and the absolute ethanol is removed in a spinning mode to obtain a milky white solid. Dissolving the raw materials in water, slowly adding a hydrochloric acid solution (the concentration is 2mol/L) under the ice bath condition until the pH of the measured solution is 3-4, precipitating a large amount of white solid in a reaction system, performing suction filtration, washing with ice water for 2-3 times, and drying to obtain a compound pyridine bihydrogen thiazolecarboxylic acid A1, wherein the yield is 87%.
The chemical characteristics are as follows:1H-NMR(300MHz,CDCl3),δ(ppm):8.95(1H,d,J＝1.8Hz),8.75(1H,dd,J＝1.2Hz,J＝4.8Hz),8.17(1H,d,J＝7.8Hz),7.55(1H,dd,J＝1.8Hz,J＝4.8Hz),5.35(1H,t,J＝9.0Hz),3.81～3.64(2H,m).
13C-NMR(75MHz,CDCl3),δ(ppm):171.5,166.2,152.4,148.5,135.6,128.1,124.0,78.2,35.2.
weighing 4-methyl-3-cyanopyridine (10mmol, 1.04g), L-cysteine hydrochloride (20mmol) and sodium bicarbonate (60mmol) into a 100mL round-bottom flask, adding 30mL of absolute ethanol, heating at 90 ℃ for 12 hours until the raw materials are completely reacted, cooling to room temperature, and removing the absolute ethanol by spinning to obtain a milky white solid. Dissolving the raw materials in water, slowly adding a hydrochloric acid solution (the concentration is 2mol/L) under the ice bath condition until the pH of the measured solution is 3-4, precipitating a large amount of white solid in a reaction system, performing suction filtration, washing with ice water for 2-3 times, and drying to obtain a compound pyridine bihydrogen thiazolecarboxylic acid A2, wherein the yield is 91%.
The chemical characteristics are as follows:1H-NMR(300MHz,CDCl3),δ(ppm):8.66(1H,s),8.54(1H,d,J＝4.8Hz),7.40(1H,d,J＝4.8Hz),5.45～5.39(1H,m),3.80～3.65(2H,m),2.51(3H,s).
13C-NMR(75MHz,CDCl3),δ(ppm):171.6,165.8,150.8,149.4,146.2,128.7,126.1,78.8,35.4,19.9
2-chloro-3-cyanopyridine (10mmol, 1.04g), L-cysteine hydrochloride (25mmol) and sodium bicarbonate (60mmol) were weighed into a 100mL round-bottomed flask, 30mL of absolute ethanol was added, and the mixture was heated at 90 ℃ for 12 hours until the starting material was reacted, cooled to room temperature, and the absolute ethanol was removed by rotation to obtain a milky white solid. Dissolving the raw materials in water, slowly adding a hydrochloric acid solution (the concentration is 2mol/L) under the ice bath condition until the pH of the measured solution is 3-4, precipitating a large amount of white solid in a reaction system, performing suction filtration, washing with ice water for 2-3 times, and drying to obtain a compound pyridine bihydrogen thiazole carboxylic acid A3 which is light orange powdery solid with the yield of 88%.
The chemical characteristics are as follows:1H-NMR(300MHz,CDCl3),δ(ppm):8.54(1H,d,J＝2.4Hz),8.11(1H,d,J＝6.9Hz),7.56～7.52(1H,m),5.32(1H,t,J＝9.0Hz),3.82～3.68(2H,m).
13C-NMR(75MHz,CDCl3),δ(ppm):171.3,165.0,151.3,147.4,139.9,128.7,123.3,78.1,36.3.
example 2 synthesis of pyridil isothiazole amides the general formula is:
the structural formula of the pyridine bithiazole carboxamide is as follows:
weighing a compound pyridine bidihydrothiazolecarboxylic acid A (0.2mmol) in a 25mL round-bottom flask, adding dichloromethane (8mL) as a solvent, slowly dropping 0.14mL thionyl chloride under an ice bath condition, removing the ice bath, reacting at normal temperature for 18 hours, evaporating under reduced pressure, adding 15mL dichloromethane for dissolving, dropwise adding triethylamine (2.5eq) into a reaction solution at zero centigrade, then dropwise adding amine (1.1eq) by using a syringe, removing the ice bath, and reacting at normal temperature for 16 hours until the raw materials completely disappear. 20mL of saturated NaHCO was added to the reaction system3The reaction was quenched with aqueous solution, extracted with 3X 15mL of dichloromethane, washed with 25mL of saturated NaCl solution, anhydrous Na2SO4Drying, filtering, evaporating dichloromethane, and obtaining the target product B by using DCM (DCM): MeOH ═ 40: 1-10: 1 or PE ═ EA ═ 5: 1-3: 1.
The chemical characterization of the target product pyridine-bithiazole carboxamide B1 is as follows: yellow oily liquid, yield 78%;1H-NMR(300MHz,CDCl3),δ(ppm):9.20(1H,d,J＝2.1Hz),8.72～8.68(2H,m),8.23～8.20(1H,m),8.15(1H,s),7.42(1H,dd,J＝3.4Hz,J＝8.1Hz),3.60(2H,q,J＝6.0Hz),2.63～2.55(6H,m),1.84～1.75(2H,m),1.08(6H,t,J＝7.2Hz).13C-NMR(75MHz,CDCl3),δ(ppm):164.5,160.8,151.9,151.2,147.7,133.7,129.1,123.8,123.3,52.0,47.1,39.5,26.0,11.7.
the chemical characterization of the target product pyridine-bithiazole carboxamide B2 is as follows: orange-red oil-like liquid with a yield of 74%;1H-NMR(300MHz,CDCl3),δ(ppm):8.88(1H,s),8.54(1H,d,J＝2.1Hz),8.44(1H,s),8.23(1H,s),7.71(1H,d,J＝7.8Hz),7.36(1H,d,J＝7.8Hz),7.10～7.26(4H,m),4.65(2H,t,J＝7.2Hz),3.27(2H,t,J＝7.2Hz),2.61(3H,s).
13C-NMR(75MHz,CDCl3),δ(ppm):164.7,161.4,150.4,150.0,148.0,146.2,136.3,128.98.128.3,127.5,126.1,122.4,122.1,119.4,118.8,111.6,111.3,65.7,24.8,20.8.
the chemical characterization of the target product pyridine-bithiazole carboxamide B3 is as follows: yellow oily liquid, yield 73%, melting range: the temperature of 91.5-93.1 ℃,1H-NMR(300MHz,CDCl3),δ(ppm):8.58(1H,dd,J＝1.8Hz,J＝7.8Hz),8.44(1H,dd,J＝1.8Hz,J＝4.5Hz),8.32(1H,s),7.83(1H,s),7.39～7.25(6H,m),4.69(2H,d,J＝6.0Hz).
13C-NMR(75MHz,CDCl3),δ(ppm):161.5,160.8,150.3,149.9,148.3,139.2,138.1,128.8,128.1,127.9,127.6,125.6,122.8,43.4.
example 3 synthesis of pyridine bithiazole esters the general formula is:
the structural formula of the pyridine bithiazole carboxylic ester is as follows:
weighing compound A (0.5mmoL), dissolving in 10eq alcohol in a 25mL round-bottom flask, slowly adding 0.145mL thionyl chloride dropwise at zero centigrade, heating to 80 deg.C, refluxing for 4h, reacting completely, spin-drying the solvent, adding 10mL saturated NaHCO3The solution was extracted three times with 3X 10Ml DCM, washed with 15mL of saturated NaCl, anhydrous Na2SO4Drying, spin-drying the solvent, and performing column chromatography on PE (ethylene-vinyl acetate copolymer) with EA being 2:1 to obtain the target compound C.
The target product C1 was characterized as follows: white solid, yield 75%, melting range: 114.4-115.9 ℃;1H-NMR(300MHz,CDCl3),δ(ppm):9.19(1H,d,J＝1.8Hz),8.70(1H,dd,J＝0.9Hz,J＝4.5Hz),8.35(1H,dd,J＝1.8Hz,J＝8.1Hz),8.21(1H,s),7.44～7.38(3H,m),6.93～6.90(2H,d,J＝8.4Hz),5.37(2H,s),3.82(3H,s).
13C-NMR(75MHz,CDCl3),δ(ppm):165.4,161.1,159.9,151.5,148.3,148.0,134.2,130.51,128.9,127.9,127.7,123.8,114.0,67.1,55.3
the target product C2 was characterized as follows: white powdery solid, yield 70%, melting range: 76.3-76.8 ℃;1H-NMR(300MHz,CDCl3),δ(ppm):8.78(1H,s),8.43(1H,d,J＝4.8Hz),8.21(1H,s),7.15(1H,d,J＝4.5Hz),4.36(2H,q,J＝6.9Hz),2.51(3H,s),1.33(3H,t,J＝7.2Hz).
13C-NMR(75MHz,CDCl3),δ(ppm):164.6,161.2,150.4,145.0,1478.0,145.9,128.8,128.1,125.9,61.5,20.6,14.3.
the target product C3 was characterized as follows: white powdery solid, yield 82%, melting range: the temperature of the mixture is 98.8-99.5 ℃,1H-NMR(300MHz,CDCl3),δ(ppm):8.76(1H,dd,J＝1.8Hz,J＝7.8Hz),8.47(1H,dd,J＝1.8Hz,J＝4.5Hz),8.34(1H,s),7.46(1H,t,J＝1.8Hz),7.41(1H,dd,J＝4.8Hz,J＝8.1Hz),6.54(1H,d,J＝3.3Hz),6.40(1H,t,J＝1.8Hz),5.38(2H,s).
13C-NMR(75MHz,CDCl3),δ(ppm):162.2,160.8,150.4,149.1,148.2,146.6,143.5,139.9,129.7,128.2,122.9,111.4,110.7,58.9.
bacteriostatic activity determination experiment
(1) Preparation of the culture Medium
5g of sodium chloride, 10 g of peptone and 5g of yeast extract were weighed, respectively dissolved in hot water, heated and boiled (LB solid medium to boil agar) to a constant volume of 1L. And (3) subpackaging the prepared culture medium into triangular flasks or test tubes, and placing in a sterilization pot for high-temperature sterilization for 20 minutes.
(2) Solvent selection
Selecting acetone: a mixed solution of water and 10:1(V/V) is used as a solvent of the pyridine dihydrothiazolecarboxylic acid to prepare a compound solution A with 500 ppm;
preparing 500ppm streptomycin sulfate solution B by using distilled water; using acetone: a mixed solution of 10:1(V/V) water was used as solvent control C.
(3) Experimental procedure
Dissolving a certain amount of new compound with a solvent to prepare a solution of 500ppm for later use, inoculating pseudomonas syringae in an LB liquid culture medium, and culturing in an incubator at 25 ℃ for 24 hours. Taking about 0.3ml of bacterial liquid to evenly coat the bacterial liquid on an LB plate, airing, adsorbing a solvent, a streptomycin sulfate solution and a new compound solution by using filter paper sheets, respectively placing the filter paper sheets on three points of the plate, placing the plate in an incubator at 25 ℃ for culturing for 24-36 hours, observing the size of a sterile loop around the filter paper sheets, and paralleling for three times.
The results of the experiment are shown in the following table:
therefore, the pyridine bithiazole carboxylic acid amide and the pyridine bithiazole carboxylic ester have obvious inhibition effect on the growth of pseudomonas syringae.
Anticancer activity test of pyridine-bithiazole compounds
(1) Preparation of a buffer solution: buffer solution a 50mM Tris and 18mM NaCl were adjusted with hydrochloric acid solution to pH 7.20. The buffer solution b was 5 Xthe reaction-terminated solution, 0.25% bromophenol blue, 4.5% SDS and 45% glycerol. TBE electrophoresis buffer 4.5g EDTA, 27.5g H3BO3 and 54g Tris were dissolved in 1000mL redistilled water to obtain a boric acid system solution of SXTBE, which was diluted 5 times when used to obtain 89mM H3BO3 solution, 89mM Tris and 2mM EDTA (pH 8.3).
(2) Agarose gel electrophoresis experiment
Adding complex solutions with different volumes into solutions containing the same amount of DNA respectively, mixing uniformly, transferring 20uL of reaction final solution, irradiating for a certain time under a 365nm long light source, and adding a bromophenol blue solution to terminate the reaction. Load to 0.8% agarose gel plate well and electrophore in TBE at 95V for 1.2 h. And finally, recording and analyzing the electrophoresis picture under a chemical fluorescence imaging analysis system.
(3) Topo II inhibition assay
Topo II was purchased from GE and used as received. The reaction mixture (20uL) contained 10mM Tris-HCl (pH 7.9), 5.0mM MgC12, 50mM KCI, 50mM NaCI, 15ug/mL BSA, 1.0mM ATP, 0.1mM EDTA, 2UnitTopo II, 0.1ug pBR322DNA and a range of different concentrations of Ru (II) complex. After incubating the reaction mixture at 30 ℃ for 15min, 4 uL.times.5 of a reaction stop solution was added to terminate the reaction. The electrophoresis method and the analysis mode are the same as above. The concentration of the novel compound that inhibits 50% of Topo II activity is defined as IC 50.
Results of the inhibitory Effect of the novel Compounds on TopoII
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (2)
1. A method for synthesizing pyridine-bithiazole carboxylic acid derivatives comprises the steps of firstly synthesizing pyridine-bithiazole carboxylic acid, and then synthesizing the pyridine-bithiazole carboxylic acid derivatives by substitution, wherein the pyridine-bithiazole carboxylic acid is generated by the reaction of cyanopyridine compounds and L-cysteine hydrochloride;
pyridine-bithiazole carboxylic acid is used as a raw material to react with thionyl chloride in an oxygen environment, and amine compounds or alcohol compounds are dropwise added to obtain pyridine-bithiazole amide or pyridine-bithiazole ester;
the synthetic route of the synthetic method of the pyridine-bis-thiazole carboxylic acid derivative is as follows:
taking cyanopyridine compounds, L-cysteine hydrochloride and sodium bicarbonate as raw materials, taking absolute ethyl alcohol as a solvent, carrying out reflux reaction for 12 hours, removing the absolute ethyl alcohol to obtain a milky white solid, dissolving the milky white solid with water, acidifying the milky white solid to a pH value of 3-4 under the ice bath condition, carrying out suction filtration, washing and drying to obtain pyridine bihydrogen thiazole carboxylic acid; the cyanopyridine compounds are 3-cyanopyridine, 4-methyl-3-cyanopyridine and 2-chloro-3-cyanopyridine; the mol ratio of the cyanopyridine compound to the L-cysteine hydrochloride is 1:1.5-1: 2.5;
the method comprises the following specific steps: putting a compound pyridine bihydrogen thiazole carboxylic acid into a reaction container, adding dichloromethane as a solvent, slowly dripping thionyl chloride under the ice bath condition, removing the ice bath, reacting for 18 hours at normal temperature, evaporating dichloromethane after complete reaction to obtain an intermediate product, adding 15mL of dichloromethane to dissolve the intermediate product, dropwise adding triethylamine into the reaction solution at zero DEG C, then dropwise adding an amine compound, removing the ice bath, and reacting for 16 hours at normal temperature until the raw materials completely disappear; adding saturated NaHCO into the reaction system3Quenching the reaction with aqueous solution, extracting with dichloromethane, washing with saturated NaCl solution, anhydrous Na2SO4Drying, filtering, evaporating dichloromethane, and obtaining pyridine isothiazole amide by using DCM (DCM) with MeOH being 40: 1-10: 1 or PE with EA being 5: 1-3: 1;
the structural formula of the pyridine bithiazole carboxamide is as follows:
pyridine bithiothiazole carboxylic acid is taken as a raw material to react with thionyl chloride in an oxygen environment, and an alcohol compound is dropwise added to obtain pyridine bithiothiazole ester;
the structural formula of the pyridine bithiazole ester is as follows:
2. the method for synthesizing a pyridinebithiazole carboxylic acid derivative according to claim 1, characterized in that the compound pyridinebithiazole is takenAdding hydrogen thiazole carboxylic acid into a reaction container, adding dichloromethane as a solvent, slowly dripping thionyl chloride under the ice bath condition, removing the ice bath, reacting for 18 hours at normal temperature, evaporating dichloromethane after complete reaction to obtain an intermediate product, taking the intermediate product into the reaction container, adding an alcohol compound, slowly dripping thionyl chloride at zero centigrade degree, heating to 80 ℃, refluxing for 4 hours, completely reacting, spin-drying the solvent, adding saturated NaHCO3The solution was extracted three times with DCM, washed with saturated NaCl, anhydrous Na2SO4Drying, spin-drying the solvent, and performing column chromatography on PE (ethylene-vinyl acetate copolymer) EA-2: 1 to obtain the pyridine bithiazole ester.
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| 2-(3-Pyridyl)thiazolidine-4-carboxamide derivatives. II. Structure-activity relationship and active configuration of 2-(3-Pyridyl)thiazolidine-4-carboxamide as platelet-activating factor receptor antagonists;Takeshi Suzuki, et al.;《Chem. Pharm. Bull.》;19980915;第46卷;第1472页 * |
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