CN111519204B - Method for preparing N- (5-chloro-8-quinolyl) benzamide compound by adopting electrochemical microchannel reaction device - Google Patents
Method for preparing N- (5-chloro-8-quinolyl) benzamide compound by adopting electrochemical microchannel reaction device Download PDFInfo
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Abstract
The invention discloses a method for preparing N- (5-chloro-8-quinolyl) benzamide compounds by adopting an electrochemical microchannel reaction device, which comprises the steps of dissolving 8- (benzoylamino) quinoline compounds in a first organic solvent to prepare a reaction solution A; dissolving dichloromethane and copper acetate in a second organic solvent to prepare a reaction solution B; and respectively pumping the reaction liquid A and the reaction liquid B into a micro mixer of the electrochemical microchannel reaction device at the same time for mixing, and then flowing into a micro reactor for reaction to obtain the catalyst. Compared with the prior art, the invention creatively develops a new method for preparing the chloroquinoline compound by taking methylene dichloride as a chlorination reagent in a micro-flow field electro-catalysis selectivity without the traditional oxidant; meanwhile, the invention utilizes the microchannel reaction device, greatly shortens the reaction time, improves the reaction conversion rate, and obviously improves the yield to 85 percent.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing an N- (5-chloro-8-quinolyl) benzamide compound by adopting an electrochemical microchannel reaction device.
Background
Halogenated aromatic hydrocarbons and heterocyclic compounds are general building blocks for cross-coupling and Grignard reactionsA variety of C-C, C-N, C-O and C-S compounds can be constructed. In addition, aryl halides are often found in drug molecules because the biological properties are often significantly enhanced by the incorporation of halogen atoms. Traditionally, halogenation products are produced by electrophilic substitution of electron-rich aromatic or heterocyclic rings. The electronic nature of the aromatic ring leads to inherent selectivity. Moreover, double halogenated by-products are generally unavoidable. Recently, regioselective halogenation has attracted increasing attention. Also, ortho-metallation-halogen quenching and activation of metallation of the C-metal or C-heteroatom para position are prominent strategies to give overall ortho, meta and para substituted products, respectively. In this case, different halogen sources are used: (1) x2，CuX2，R1R2NX or TBCA; (2) halide (X-) with an exogenous oxidant such as PIDA, O2，O3，NFSI，K2S2O8DDQ; (3) an activated halogenated hydrocarbon, such as DCE. However, X2Is toxic and corrosive. In addition, stoichiometric amounts of oxidizing or halogenating agents, e.g. PIDA, NFSI, K, are used2S2O8，DDQ，CuX 2And N-halosuccinimides, are environmentally unfriendly and produce undesirable waste products to the detriment of atom economy. And, found O2Or O3Is the in situ generation of Cl+An effective and green oxidizing agent. However, the scaling-up effect of the gas-liquid reaction limits its further industrial application. In the last few years, activated halogenated hydrocarbons (such as DCE) have been used as green and economical halogenating agents. However, the use of oxidizing agents limits their intended use. Electrochemistry has become an efficient synthetic method that uses infinite electrons as reagents in the redox process, thereby avoiding the use of hazardous, costly and environmentally unfriendly oxidants and reductants. Therefore, electrosynthesis generally has a high atom economy, avoiding the production of undesirable waste products. In conclusion, the synthesis of the N- (5-chloro-8-quinolyl) benzamide compound by the electrochemical microchannel reaction device has the advantages of high efficiency, environmental friendliness, higher economic benefit and the like. Therefore, the development of an electrochemical microchannel reaction device for preparing N- (5-chloro-8-quinolyl) benzoyl is urgently neededA method for preparing amine compounds.
Disclosure of Invention
The purpose of the invention is as follows: the technical problem to be solved by the invention is to provide a method for preparing N- (5-chloro-8-quinolyl) benzamide compounds by adopting an electrochemical microchannel reaction device, aiming at the defects of the prior art, the method can solve the problems of complicated steps, overlong reaction time and the like in the reaction process, can improve the reaction efficiency, and is suitable for industrial production.
In order to solve the technical problem, the invention discloses a method for preparing an N- (5-chloro-8-quinolyl) benzamide compound by adopting an electrochemical microchannel reaction device, which comprises the steps of dissolving an 8- (benzoylamino) quinoline compound in a first organic solvent to prepare a reaction solution A; dissolving dichloromethane and copper acetate in a second organic solvent to prepare a reaction solution B; and respectively pumping the reaction liquid A and the reaction liquid B into a micro mixer of the electrochemical microchannel reaction device at the same time for mixing, and then flowing into a micro reactor for reaction, thus obtaining the catalyst, wherein the reaction principle is shown in figure 1.
Wherein, the first organic solvent and the second organic solvent are respectively and independently selected from acetonitrile, water or a mixed solvent of acetonitrile and water; preferably, the first organic solvent and the second organic solvent are both mixed solvents of acetonitrile and water; further preferably, the volume ratio of acetonitrile to water is 4: 1.
Wherein in the reaction solution A, the 8- (benzoylamino) quinoline compound is N- (quinolin-8-yl) benzamide, 4-methyl-N- (quinolin-8-yl) benzamide, 4-ethyl-N- (quinolin-8-yl) benzoyl, 4-chloro-N- (quinolin-8-yl) benzamide, 4-nitro-N- (quinolin-8-yl) benzamide, 4-phenyl-N- (quinolin-8-yl) benzamide, 2,4, 6-trimethyl- (quinolin-8-yl) benzamide, N- (quinolin-8-yl) -2-naphthamide, Any one of N- (quinolin-8-yl) furan-2-carboxamide and N- (quinolin-8-yl) acetamide.
Wherein, in the reaction liquid A, the concentration of the 8- (benzoylamino) quinoline compound is 0.15-0.45 mol/L, preferably 0.20 mol/L.
Wherein, in the reaction liquid B, the molar ratio of copper acetate is 75-85: 1, and the concentration of copper acetate is 0.01-0.05 mmol/mL; preferably, the molar ratio of copper acetate is 80:1, and the concentration of copper acetate is 0.03 mmol/mL.
Wherein the flow rate of the reaction liquid A pumped into a micro mixer of the electrochemical microchannel reaction device is 0.10-0.55 mL/min, and preferably 0.15 mL/min.
Wherein the flow rate of the reaction liquid B pumped into a micro mixer of the electrochemical microchannel reaction device is 0.05-0.25 mL/min, and preferably 0.10 mL/min.
Wherein the electrochemical microchannel reaction device (figure 2) comprises a first feeding pump, a second feeding pump, a micromixer, a microreactor, a cathode sheet, an anode sheet and a receiver; wherein the first feeding pump and the second feeding pump are connected to the micro mixer in a parallel mode through connecting pipes, and the micro mixer is connected with the micro reactor and the receiver in a series mode through pipelines; wherein, the two sides of the micro-reactor are respectively provided with a cathode sheet and an anode sheet, as shown in fig. 13.
Wherein, the material of the pipeline and other materials in the microchannel reaction device is polytetrafluoroethylene.
Wherein the anode sheet is a graphite carbon electrode or a platinum sheet electrode, and the graphite carbon electrode is preferred; the cathode sheet is a graphite carbon electrode or a platinum sheet electrode, and the platinum sheet electrode is preferred.
Wherein the pump is an HPLC pump or a syringe pump, preferably an HPLC pump.
The type of the micro mixer is T type, Y type or inverted Y type, and the Y type is preferred.
Wherein, the diameter of the connecting pipe is 0.1-5 mm, and the length is 0.5-60 m.
Wherein the diameter of the connecting pipe between the micro mixer and the micro reactor is 0.5-5 mm, preferably 2-5 mm.
Wherein the volume of the microreactor is 0.5-1.5 mL, and 1.25mL is preferred.
Wherein the current of the reaction is 80-120 mA, preferably 100 mA.
Wherein the reaction temperature is 0-50 ℃, and the reaction residence time is 2-15 min; preferably, the temperature of the reaction is 25 ℃ and the reaction residence time is 5 min.
And after the reaction is finished, collecting the effluent of the microreactor, washing with water, drying, filtering, performing column chromatography separation, and distilling under reduced pressure to obtain the N- (5-chloro-8-quinolyl) benzamide compound.
The column chromatography is to obtain a target product by eluting with a mixed solvent (volume ratio of 1: 10-1: 30) of ethyl acetate/petroleum ether as a mobile phase.
Has the advantages that: compared with the prior art, the invention has the following advantages:
(1) the invention creatively develops a new method for preparing the chloroquinoline compound by taking dichloromethane as a chlorination reagent through the electrocatalysis selectivity of the micro-flow field without the traditional oxidant, and simplifies the operation.
(2) The invention utilizes the microchannel reaction device, greatly shortens the reaction time, improves the yield, has high flux, stable product quality, strong continuity, is beneficial to continuous amplification production, has simple operation, high safety and easy separation, can effectively overcome the defects of the traditional synthesis path, and obviously improves the yield to 85 percent.
Drawings
FIG. 1 is a reaction scheme of the preparation method of the present invention.
FIG. 2 is a schematic diagram of a microchannel reaction apparatus and synthesis route according to the present invention; wherein, 1 is a first feeding pump, 2 is a second feeding pump, 3 is a micro mixer, 4 is an electrochemical micro reactor, and 5 is a receiver.
Fig. 3 shows a hydrogen spectrum and a carbon spectrum of 9 a.
Fig. 4 is a hydrogen spectrum and a carbon spectrum of 9 b.
Fig. 5 is a hydrogen spectrum and a carbon spectrum of 9 c.
Fig. 6 is a hydrogen spectrum and a carbon spectrum of 9 d.
Fig. 7 is a hydrogen spectrum and a carbon spectrum of 9 e.
Fig. 8 is a hydrogen spectrum and a carbon spectrum of 9 f.
FIG. 9 shows a hydrogen spectrum and a carbon spectrum of 9 g.
FIG. 10 is a hydrogen spectrum and a carbon spectrum of 9 h.
Fig. 11 is a hydrogen spectrum and a carbon spectrum of 9 i.
Fig. 12 is a hydrogen spectrum and a carbon spectrum of 9 j.
FIG. 13 is a schematic diagram of a microreactor in which (i) is a graphite carbon electrode, (ii) is a microreactor channel, and (iii) is a platinum-plate electrode.
Detailed Description
The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the description of the embodiments is only for illustrating the present invention and should not be taken as limiting the invention as detailed in the claims.
The structures, proportions, and dimensions shown in the drawings and described in the specification are for understanding and reading the present disclosure, and are not intended to limit the scope of the present disclosure, which is defined in the claims, and are not essential to the skilled in the art. In addition, the terms "upper", "lower", "front", "rear" and "middle" used in the present specification are for clarity of description, and are not intended to limit the scope of the present invention, and the relative relationship between the terms and the relative positions may be changed or adjusted without substantial technical changes.
The microchannel reaction apparatus described in the following examples, as shown in fig. 2, includes a first feed pump 1 (a tank for a mixed solution of acetonitrile and water to which methylene chloride and copper acetate are connected), a second feed pump 2 (a tank for a mixed solution of acetonitrile and water to which 8- (benzoylamino) quinoline is connected), a micromixer 3, an electrochemical microreactor 4, and a receiver 5.
The first feed pump 1 and the second feed pump 2 are connected in parallel by a connecting pipe and the micromixer 3, the micromixer 3 and the electrochemical microreactor 4 are connected in series by a connecting pipe, and the electrochemical microreactor 4 and the receiving device 5 are connected in series by a connecting pipe. The reaction raw materials enter a mixer through an HPLC pump or an injection pump and then enter a microreactor for reaction.
The model of the micro mixer is Y type. The model of the electrochemical microchannel reactor is an electrochemical micro-reactor.
Example 1:
24mmol (1.99g) of dichloromethane and 0.3mmol (0.06g) of copper acetate are added to a mixed solution of 10mL of acetonitrile and water (acetonitrile: water ═ 4:1, i.e. 8mL of acetonitrile and 2mL of water) to give a homogeneous solution I, which is added to syringe pump 1; 2.0mmol (0.50g) of N- (quinolin-8-yl) benzamide was dissolved in 10mL of a mixed solution of acetonitrile and water (acetonitrile: water: 4:1, i.e., 8mL of acetonitrile and 2mL of water) to obtain a homogeneous solution ii, which was added to syringe pump 2; injecting the solution I and the solution II into a micro mixer 3 by an injection pump 1 and an injection pump 2 at the flow rates of 0.10mL/min and 0.15mL/min respectively, mixing in the micro mixer 3, and then entering an electrochemical micro-channel reactor 4 for reaction; the reaction volume of the first microchannel reactor is 1.25mL, and the reaction retention time is 5.0 min; the temperature of the electrochemical micro-channel reactor is 25 ℃, and the reaction current is 100 mA; after the reaction in the electrochemical microchannel reactor, the reaction liquid was collected, and the product yield was 85% by HPLC. Diluting the reaction liquid by using dichloromethane for five times, washing, drying and filtering the reaction liquid, and leaching and separating the reaction liquid by using a mixed solvent of ethyl acetate/petroleum ether (1: 30) to obtain a product 9 a;1H NMR(400 MHz,CDCl3)δ10.69(s,1H),8.92–8.87(m,2H),8.60(dd,J＝8.5,1.5Hz,1H),8.07(dd,J ＝7.9,1.4Hz,2H),7.66(d,J＝8.4Hz,1H),7.62–7.55(m,4H).13C NMR(101MHz, CDCl3)δ165.58,148.91,139.47,135.04,134.02,133.64,132.15,129.00,127.48,127.43, 126.17,124.64,122.57,116.63.HRMS(ESI)Calcd for C16H12N2OCl[M+H]+:283.0633； found:283.0632.
example 2:
24mmol (1.99g) of dichloromethane and 0.3mmol (0.06g) of copper acetate are added to a mixed solution of 10mL of acetonitrile and water (acetonitrile: water ═ 4:1, i.e. 8mL of acetonitrile and 2mL of water) to give a homogeneous solution I, which is added to syringe pump 1; 2.0mmol (0.50g) of N- (quinolin-8-yl) benzamide was dissolved in 10mL of a mixed solution of acetonitrile and water (acetonitrile: water: 4:1, i.e., 8mL of acetonitrile and 2mL of water) to obtain a homogeneous solution ii, which was added to syringe pump 2; injecting the solution I and the solution II into a micro mixer 3 by an injection pump 1 and an injection pump 2 at the flow rates of 0.10mL/min and 0.15mL/min respectively, mixing in the micro mixer 3, and then entering an electrochemical micro-channel reactor 4 for reaction; the reaction volume of the first microchannel reactor is 1.25mL, and the reaction retention time is 5.0 min; the temperature of the electrochemical micro-channel reactor is 25 ℃, and the reaction current is 80 mA; after the reaction in the electrochemical microchannel reactor, the reaction liquid was collected and the product yield was 65% by HPLC.
Example 3:
24mmol (1.99g) of dichloromethane and 0.3mmol (0.06g) of copper acetate are added to a mixed solution of 10mL of acetonitrile and water (acetonitrile: water ═ 4:1, i.e. 8mL of acetonitrile and 2mL of water) to give a homogeneous solution I, which is added to syringe pump 1; 2.0mmol (0.50g) of N- (quinolin-8-yl) benzamide was dissolved in 10mL of a mixed solution of nitrile and water (acetonitrile: water ═ 4:1, i.e., 8mL of acetonitrile and 2mL of water) to obtain a homogeneous solution ii, which was added to syringe pump 2; injecting the solution I and the solution II into a micro mixer 3 by an injection pump 1 and an injection pump 2 at the flow rates of 0.10mL/min and 0.15mL/min respectively, mixing in the micro mixer 3, and then entering an electrochemical micro-channel reactor 4 for reaction; the reaction volume of the first microchannel reactor is 1.25mL, and the reaction retention time is 5.0 min; the temperature of the electrochemical micro-channel reactor is 25 ℃, and the reaction current is 120 mA; after the reaction in the electrochemical microchannel reactor, the reaction liquid was collected, and the product yield was 70% by HPLC.
Example 4:
24mmol (1.99g) of dichloromethane and 0.3mmol (0.06g) of copper acetate are added to a mixed solution of 10mL of acetonitrile and water (acetonitrile: water ═ 4:1, i.e. 8mL of acetonitrile and 2mL of water) to give a homogeneous solution I, which is added to syringe pump 1; 2.0mmol (0.53g) of 4-methyl-N- (quinolin-8-yl) benzamide was dissolved in 10mL of a mixed solution of nitrile and water (acetonitrile: water ═ 4:1, i.e., 8mL of acetonitrile and 2mL of water) to obtain a homogeneous solution ii, which was added to syringe pump 2; injecting the solutions I and II into a micro mixer 3 at flow rates of 0.10mL/min and 0.15mL/min respectively by using an injection pump 1 and an injection pump 2, mixing in the micro mixer 3, and then feeding into an electric pumpCarrying out reaction in a chemical microchannel reactor 4; the reaction volume of the first microchannel reactor is 1.25mL, and the reaction retention time is 5.0 min; the temperature of the electrochemical micro-channel reactor is 25 ℃, and the reaction current is 100 mA; after the reaction in the electrochemical microchannel reactor, the reaction liquid was collected, and the product yield was 83% by HPLC. Diluting the reaction liquid by using dichloromethane for five times, washing, drying and filtering, and leaching and separating by using a mixed solvent of ethyl acetate/petroleum ether (1: 30) to obtain a product 9 b;1H NMR(400 MHz,CDCl3)δ10.64(s,1H),8.89-8.85(m,2H),8.56(dd,J＝8.5,1.5Hz,1H),7.96(dd,J＝ 7.9,1.4Hz,2H),7.63(d,J＝8.4Hz,1H),7.57(dd,J＝8.5,4.2Hz,1H),7.34(d,J＝8.0Hz, 2H),2.45(s,3H).13C NMR(101MHz,CDCl3)δ165.51,148.81,142.67,139.38,134.07, 133.57,132.15,129.62,127.44,127.41,126.10,124.42,122.48,116.54,21.68.HRMS(ESI) Calcd for C17H14N2OCl[M+H]+:297.0789；found:297.0786.
example 5:
24mmol (1.99g) of dichloromethane and 0.3mmol (0.06g) of copper acetate are added to a mixed solution of 10mL of acetonitrile and water (acetonitrile: water ═ 4:1, i.e. 8mL of acetonitrile and 2mL of water) to give a homogeneous solution I, which is added to syringe pump 1; 2.0mmol (0.55g) of 4-ethyl-N- (quinolin-8-yl) benzamide was dissolved in 10mL of a mixed solution of nitrile and water (acetonitrile: water ═ 4:1, i.e., 8mL of acetonitrile and 2mL of water) to obtain a homogeneous solution ii, which was added to syringe pump 2; injecting the solution I and the solution II into a micro mixer 3 by an injection pump 1 and an injection pump 2 at the flow rates of 0.10mL/min and 0.15mL/min respectively, mixing in the micro mixer 3, and then entering an electrochemical micro-channel reactor 4 for reaction; the reaction volume of the first microchannel reactor is 1.25mL, and the reaction retention time is 5.0 min; the temperature of the electrochemical micro-channel reactor is 25 ℃, and the reaction current is 100 mA; after the reaction in the electrochemical microchannel reactor, the reaction liquid was collected, and the product yield was 80% by HPLC. Diluting the reaction liquid by using dichloromethane for five times, washing, drying and filtering, and leaching and separating by using a mixed solvent of ethyl acetate/petroleum ether (1: 30) to obtain a product 9 c;1H NMR(400 MHz,CDCl3)δ10.66(s,1H),8.89–8.86(m,2H),8.58(dd,J＝8.5,1.6Hz,1H),7.99(d,J ＝8.2Hz,2H),7.64(d,J＝8.4Hz,1H),7.58(dd,J＝8.5,4.2Hz,1H),7.37(d,J＝8.2Hz, 2H),2.75(q,J＝7.6Hz,2H),1.30(t,J＝7.6Hz,3H).13C NMR(101MHz,CDCl3)δ 165.58,148.89,148.84,139.43,134.12,133.56,132.43,128.47,127.52,127.46,126.12, 124.42,122.50,116.50,29.00,15.46.HRMS(ESI)Calcd for C18H16N2OCl[M+H]+: 311.0946；found:311.0934.
example 6:
24mmol (1.99g) of dichloromethane and 0.3mmol (0.06g) of copper acetate are added to a mixed solution of 10mL of acetonitrile and water (acetonitrile: water ═ 4:1, i.e. 8mL of acetonitrile and 2mL of water) to give a homogeneous solution I, which is added to syringe pump 1; 2.0mmol (0.56g) of 4-chloro-N- (quinolin-8-yl) benzamide was dissolved in 10mL of a mixed solution of nitrile and water (acetonitrile: water ═ 4:1, i.e., 8mL of acetonitrile and 2mL of water) to obtain a homogeneous solution ii, which was added to syringe pump 2; injecting the solution I and the solution II into a micro mixer 3 by an injection pump 1 and an injection pump 2 at the flow rates of 0.10mL/min and 0.15mL/min respectively, mixing in the micro mixer 3, and then entering an electrochemical micro-channel reactor 4 for reaction; the reaction volume of the first microchannel reactor is 1.25mL, and the reaction retention time is 5.0 min; the temperature of the electrochemical micro-channel reactor is 25 ℃, and the reaction current is 100 mA; after the reaction in the electrochemical microchannel reactor, the reaction liquid was collected, and the product yield was 78% by HPLC. Diluting the reaction liquid by using dichloromethane for five times, washing, drying and filtering, and leaching and separating by using a mixed solvent of ethyl acetate/petroleum ether (1: 30) to obtain a product 9 d;1H NMR(400MHz, CDCl3)δ10.65(s,1H),8.90(dd,J＝4.2,1.5Hz,1H),8.85(d,J＝8.4Hz,1H),8.61(dd,J＝ 8.5,1.5Hz,1H),8.01(dt,J＝8.6,1.6Hz,2H),7.66(d,J＝8.4Hz,1H),7.61(dd,J＝8.5,4.2 Hz,1H),7.53(dt,J＝8.5,1.6Hz,2H).13C NMR(101MHz,CDCl3)δ164.32,148.84, 139.27,138.35,133.62,133.60,133.27,129.14,128.73,127.33,126.06,124.78,122.50,
116.61.HRMS(ESI)Calcd for C16H11N2OCl2[M+H]+:317.0243；found:317.0287.
example 7:
24mmol (1.99g) of dichloromethane and 0.3mmol (0.06g) of copper acetate are added to a mixed solution of 10mL of acetonitrile and water (acetonitrile: water ═ 4:1, i.e. 8mL of acetonitrile and 2mL of water) to give a homogeneous solution I, which is added to syringe pump 1; 2.0mmol (0.59g) of 4-nitro-N- (quinolin-8-yl) benzamide was dissolved in 10mL of a mixed solution of nitrile and water (acetonitrile: water ═ 4:1, i.e., 8mL of acetonitrile and 2mL of water) to obtain a homogeneous solution ii, which was added to syringe pump 2; injecting the solution I and the solution II into a micro mixer 3 by an injection pump 1 and an injection pump 2 at the flow rates of 0.10mL/min and 0.15mL/min respectively, mixing in the micro mixer 3, and then entering an electrochemical micro-channel reactor 4 for reaction; the reaction volume of the first microchannel reactor is 1.25mL, and the reaction retention time is 5.0 min; the temperature of the electrochemical micro-channel reactor is 25 ℃, and the reaction current is 100 mA; after the reaction in the electrochemical microchannel reactor, the reaction liquid was collected, and the product yield was 50% by HPLC. Diluting the reaction liquid by using dichloromethane for five times, washing, drying and filtering, and leaching and separating by using a mixed solvent of ethyl acetate/petroleum ether (1: 10) to obtain a product 9 e;1H NMR(400 MHz,CDCl3)δ10.79(s,1H),8.93(dd,J＝4.3,1.6Hz,1H),8.87(d,J＝8.4Hz,1H),8.66 (dd,J＝8.5,1.6Hz,1H),8.44–8.39(m,2H),8.26–8.21(m,2H),7.70(d,J＝8.4Hz,1H), 7.66(dd,J＝8.5,4.3Hz,1H).13C NMR(101MHz,CDCl3)δ163.27,149.92,148.88, 140.29,139.00,134.02,133.08,128.54,127.39,126.17,125.54,124.11,122.65,117.21. HRMS(ESI)Calcd for C16H11N3O3Cl[M+H]+:328.0483；found:328.0492.
example 8:
24mmol (1.99g) of dichloromethane and 0.3mmol (0.06g) of copper acetate are added to a mixed solution of 10mL of acetonitrile and water (acetonitrile: water ═ 4:1, i.e. 8mL of acetonitrile and 2mL of water) to give a homogeneous solution I, which is added to syringe pump 1; 2.0mmol (0.65g) of 4-phenyl-N- (quinolin-8-yl) benzamide was dissolved in 10mL of a mixed solution of nitrile and water (acetonitrile: water 4:1, i.e., 8mL of acetonitrile and 2mL of water) to obtain a solutionAdding the homogeneous phase solution II into the injection pump 2; injecting the solution I and the solution II into a micro mixer 3 by an injection pump 1 and an injection pump 2 at the flow rates of 0.10mL/min and 0.15mL/min respectively, mixing in the micro mixer 3, and then entering an electrochemical micro-channel reactor 4 for reaction; the reaction volume of the first microchannel reactor is 1.25mL, and the reaction retention time is 5.0 min; the temperature of the electrochemical micro-channel reactor is 25 ℃, and the reaction current is 100 mA; after the reaction in the electrochemical microchannel reactor, the reaction liquid was collected, and the product yield was 72% by HPLC. Diluting the reaction liquid by using dichloromethane for five times, washing, drying and filtering the reaction liquid, and leaching and separating the reaction liquid by using a mixed solvent of ethyl acetate/petroleum ether (1: 30) to obtain a product 9 f;1H NMR(400 MHz,CDCl3)δ10.75(s,1H),8.93–8.90(m,2H),8.61(dd,J＝8.5,1.6Hz,1H),8.15(dt,J ＝8.4,1.6Hz,2H),7.78(dt,J＝8.4,1.6Hz,2H),7.69-7.65(m,3H),7.61(dd,J＝8.5,4.2Hz, 1H),7.50(tt,J＝7.4,1.6Hz,2H),7.42(tt,J＝7.3,1.2Hz,1H).13C NMR(101MHz,CDCl3) δ165.29,148.93,144.95,140.11,139.48,134.04,133.66,129.13,128.26,127.98,127.65, 127.50,127.40,126.19,124.64,122.59,116.65.HRMS(ESI)Calcd for C22H16N2OCl [M+H]+:359.0946；found:359.0950.
example 9:
24mmol (1.99g) of dichloromethane and 0.3mmol (0.06g) of copper acetate are added to a mixed solution of 10mL of acetonitrile and water (acetonitrile: water ═ 4:1, i.e. 8mL of acetonitrile and 2mL of water) to give a homogeneous solution I, which is added to syringe pump 1; 2.0mmol (0.58g) of 2,4, 6-trimethyl- (quinolin-8-yl) benzamide was dissolved in 10mL of a mixed solution of nitrile and water (acetonitrile: water ═ 4:1, i.e., 8mL of acetonitrile and 2mL of water) to obtain a homogeneous solution II, which was added to syringe pump 2; injecting the solution I and the solution II into a micro mixer 3 by an injection pump 1 and an injection pump 2 at the flow rates of 0.10mL/min and 0.15mL/min respectively, mixing in the micro mixer 3, and then entering an electrochemical micro-channel reactor 4 for reaction; the reaction volume of the first microchannel reactor is 1.25mL, and the reaction retention time is 5.0 min; the temperature of the electrochemical micro-channel reactor is 25 ℃, and the reaction current is 100 mA; after reaction in the electrochemical microchannel reactor,the reaction liquid was collected and the product yield was 75% by HPLC. Diluting the reaction liquid by using dichloromethane for five times, washing, drying and filtering, and leaching and separating by using a mixed solvent of ethyl acetate/petroleum ether (1: 30) to obtain 9g of a product;1H NMR (400MHz,CDCl3)δ9.87(s,1H),8.93(d,J＝8.4Hz,1H),8.77(dd,J＝4.2,1.6Hz,1H), 8.58(dd,J＝8.5,1.6Hz,1H),7.66(d,J＝8.4Hz,1H),7.56(dd,J＝8.5,4.2Hz,1H),6.93(s, 2H),2.39(s,6H),2.34(s,3H).13C NMR(101MHz,CDCl3)δ169.27,148.86,139.25, 139.07,135.27,134.68,133.89,133.54,128.61,127.39,126.15,124.78,122.50,116.76, 21.30,19.55.HRMS(ESI)Calcd for C19H18N2OCl[M+H]+:325.1102；found:325.1107.
example 10:
24mmol (1.99g) of dichloromethane and 0.3mmol (0.06g) of copper acetate are added to a mixed solution of 10mL of acetonitrile and water (acetonitrile: water ═ 4:1, i.e. 8mL of acetonitrile and 2mL of water) to give a homogeneous solution I, which is added to syringe pump 1; 2.0mmol (0.60g) of N- (quinolin-8-yl) -2-naphthamide was dissolved in 10mL of a mixed solution of nitrile and water (acetonitrile: water: 4:1, i.e., 8mL of acetonitrile and 2mL of water) to obtain a homogeneous solution II, which was added to syringe pump 2; injecting the solution I and the solution II into a micro mixer 3 by an injection pump 1 and an injection pump 2 at the flow rates of 0.10mL/min and 0.15mL/min respectively, mixing in the micro mixer 3, and then entering an electrochemical micro-channel reactor 4 for reaction; the reaction volume of the first microchannel reactor is 1.25mL, and the reaction retention time is 5.0 min; the temperature of the electrochemical micro-channel reactor is 25 ℃, and the reaction current is 100 mA; after the reaction in the electrochemical microchannel reactor, the reaction liquid was collected, and the product yield was 75% by HPLC. Diluting the reaction liquid by using dichloromethane for five times, washing, drying and filtering, and leaching and separating by using a mixed solvent of ethyl acetate/petroleum ether (1: 30) to obtain a product for 9 hours;1H NMR(400MHz, CDCl3)δ10.83(s,1H),8.96–8.92(m,2H),8.61(dd,J＝8.5,1.4Hz,1H),8.59(s,1H), 8.12(dd,J＝8.6,1.6Hz,1H),8.06–8.03(m,1H),8.00(d,J＝8.6Hz,1H),7.94–7.91(m, 1H),7.68(d,J＝8.4Hz,1H),7.64–7.57(m,3H).13C NMR(101MHz,CDCl3)δ165.63, 148.92,139.43,135.14,134.04,133.73,132.87,132.20,129.37,128.90,128.18,128.11, 127.95,127.53,127.02,126.19,124.70,123.78,122.57,116.81.HR-MS(ESI)Calcd for C20H14N2OCl[M+H]+:333.0789；found:333.0789.
example 11:
24mmol (1.99g) of dichloromethane and 0.3mmol (0.06g) of copper acetate are added to a mixed solution of 10mL of acetonitrile and water (acetonitrile: water ═ 4:1, i.e. 8mL of acetonitrile and 2mL of water) to give a homogeneous solution I, which is added to syringe pump 1; 2.0mmol (0.48g) of N- (quinolin-8-yl) furan-2-carboxamide was dissolved in 10mL of a mixed nitrile and water solution (acetonitrile: water ═ 4:1, i.e., 8mL of acetonitrile and 2mL of water) to obtain a homogeneous solution II, which was added to syringe pump 2; injecting the solution I and the solution II into a micro mixer 3 by an injection pump 1 and an injection pump 2 at the flow rates of 0.10mL/min and 0.15mL/min respectively, mixing in the micro mixer 3, and then entering an electrochemical micro-channel reactor 4 for reaction; the reaction volume of the first microchannel reactor is 1.25mL, and the reaction retention time is 5.0 min; the temperature of the electrochemical micro-channel reactor is 25 ℃, and the reaction current is 100 mA; after the reaction in the electrochemical microchannel reactor, the reaction liquid was collected, and the product yield was 60% by HPLC. Diluting the reaction liquid by using dichloromethane for five times, washing, drying and filtering, and leaching and separating by using a mixed solvent of ethyl acetate/petroleum ether (1: 30) to obtain a product 9 i;1H NMR(400MHz, CDCl3)δ10.72(s,1H),8.93(dd,J＝4.2,1.6Hz,1H),8.82(d,J＝8.4Hz,1H),8.59(dd,J＝ 8.5,1.6Hz,1H),7.65–7.58(m,3H),7.31(d,J＝3.6,0.8Hz,1H),6.60(dd,J＝3.5,1.7Hz, 1H).13C NMR(101MHz,CDCl3)δ156.49,149.03 148.29,144.79,139.34,133.62,133.56, 127.40,126.18,124.79,122.59,116.71115.53,112.68.HRMS(ESI)Calcd for C14H10N2O2Cl[M+H]+:273.0425；found:273.0406.
example 12:
a mixed solution of 24mmol (1.99g) of methylene chloride and 0.3mmol (0.06g) of copper acetate in 10mL of acetonitrile and water (acetonitrile: water: 4:1, i.e., 8mL of acetonitrile and 2mL of acetonitrile)Water) to obtain a homogeneous phase solution I, and adding the homogeneous phase solution I into the injection pump 1; 2.0mmol (0.37g) of N- (quinolin-8-yl) acetamide was dissolved in 10mL of a mixed solution of nitrile and water (acetonitrile: water ═ 4:1, i.e., 8mL of acetonitrile and 2mL of water) to obtain a homogeneous solution ii, which was added to syringe pump 2; injecting the solution I and the solution II into a micro mixer 3 by an injection pump 1 and an injection pump 2 at the flow rates of 0.10mL/min and 0.15mL/min respectively, mixing in the micro mixer 3, and then entering an electrochemical micro-channel reactor 4 for reaction; the reaction volume of the first microchannel reactor is 1.25mL, and the reaction retention time is 5.0 min; the temperature of the electrochemical micro-channel reactor is 25 ℃, and the reaction current is 100 mA; after the reaction in the electrochemical microchannel reactor, the reaction liquid was collected, and the product yield was 75% by HPLC. Diluting the reaction liquid by using dichloromethane for five times, washing, drying and filtering the reaction liquid, and leaching and separating the reaction liquid by using a mixed solvent of ethyl acetate/petroleum ether (1: 30) to obtain a product 9 j;1H NMR(400MHz, CDCl3)δ9.74(s,1H),8.84(dd,J＝4.2,1.6Hz,1H),8.70(d,J＝8.4Hz,1H),8.56(dd,J＝ 8.5,1.6Hz,1H),7.60–7.55(m,2H),2.35(s,3H).13CNMR(101MHz,CDCl3)δ168.90, 148.79,138.89,133.91,133.59,127.39,126.03,124.34,122.45,116.48,25.26.HRMS(ESI) Calcd for C11H10N2OCl[M+H]+:221.0476；found:221.0478.
table 1 shows the structural formula of the N- (5-chloro-8-quinolyl) benzamide compound products prepared in examples 1-12, which is determined by nuclear magnetic characterization, and nuclear magnetic maps of the products are shown in FIGS. 3-12.
The present invention provides a method and a method for preparing N- (5-chloro-8-quinolyl) benzamide compound by using an electrochemical microchannel reaction device, and a method and a way for implementing the technical scheme are many, and the above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention. All the components not specified in the present embodiment can be realized by the prior art.
Claims (5)
1. Preparation by adopting electrochemical microchannel reaction deviceNA method of a- (5-chloro-8-quinolyl) benzamide compound, characterized by dissolving a 8- (benzoylamino) quinoline compound in a first organic solvent to prepare a reaction solution a; dissolving dichloromethane and copper acetate in a second organic solvent to prepare a reaction solution B; respectively and simultaneously pumping the reaction liquid A and the reaction liquid B into a micro mixer of an electrochemical microchannel reaction device for mixing, and then flowing into a micro reactor for reaction to obtain the catalyst;
wherein the concentration of the 8- (benzoylamino) quinoline compound in the reaction liquid A is 0.15-0.45 mol/L;
wherein the molar ratio of dichloromethane to copper acetate in the reaction liquid B is 75-85: 1, and the concentration of copper acetate is 0.01-0.05 mmol/mL;
wherein the flow rate of the reaction liquid A pumped into a micro mixer of the electrochemical microchannel reaction device is 0.10-0.55 mL/min;
wherein the flow rate of the reaction liquid B pumped into a micro mixer of the electrochemical microchannel reaction device is 0.05-0.25 mL/min;
wherein the reaction temperature is 0-50 ℃;
wherein the current of the reaction is 80-120 mA.
2. The method according to claim 1, wherein the first organic solvent and the second organic solvent are each independently selected from acetonitrile, water, or a mixed solvent of acetonitrile and water.
3. The method of claim 1, wherein the electrochemical microchannel reactor device comprises a first feed pump, a second feed pump, a micromixer, a microreactor, a cathode sheet, an anode sheet, and a receiver; wherein the first feeding pump and the second feeding pump are connected to the micro mixer in a parallel mode through connecting pipes, and the micro mixer is connected with the micro reactor and the receiver in a series mode through pipelines; wherein, the two sides of the micro-reactor are respectively provided with a cathode sheet and an anode sheet.
4. The method of claim 1, wherein the microreactor has a volume of 0.5 to 1.5 mL.
5. The method of claim 1, wherein the residence time of the reaction is 2 to 15 min.
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