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CN114621236B - Preparation method of quinoline feed additive - Google Patents

Preparation method of quinoline feed additive Download PDF

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CN114621236B
CN114621236B CN202210439743.3A CN202210439743A CN114621236B CN 114621236 B CN114621236 B CN 114621236B CN 202210439743 A CN202210439743 A CN 202210439743A CN 114621236 B CN114621236 B CN 114621236B
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methoxyethoxy
bis
stirring
quinazoline
feed additive
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CN114621236A (en
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侯延生
龚晓庆
孙格
汪贞贞
毛龙飞
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Handan Tongbang Biotechnology Co.,Ltd.
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Henan Wanliu Biotechnology Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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Abstract

The invention discloses a preparation method of a quinoline feed additive, and belongs to the technical field of functional feed additive synthesis. The technical scheme of the invention is as follows: the quinoline feed additive molecule has a structureWherein R is an aromatic ring derivative, and X is a carbon atom or a nitrogen atom. The invention is reformed based on the reported molecular structure of the drug erlotinib on the market, and the triazole or diazole structure is introduced to obtain the compound with novel structure, which can inhibit IDO1 enzyme activity by combining with heme in IDO1 target spot and has a certain inhibition effect on urease, thus being used as a potential feed additive for improving immunity.

Description

Preparation method of quinoline feed additive
Technical Field
The invention belongs to the technical field of synthesis of feed additives, and particularly relates to a preparation method of a quinoline feed additive.
Background
The feed additive is an additive which can make the feed exert the effect better, and can effectively improve the utilization rate of the feed. The feed additive can make up the problem of unbalanced feed nutrition, can effectively improve the quality of livestock and poultry, and has positive significance for the growth of livestock and poultry and the prevention of diseases. The cattle can encounter symptoms of gastroenteritis or endometritis in the feeding process, and the factors for inducing the gastroenteritis of the cattle are various, such as feed deterioration, poor sanitary conditions, germ invasion and the like, which can possibly damage the gastrointestinal mucosa of the cattle, thereby inducing the gastroenteritis; endometritis of cattle is a common reproductive system disease in the production process of cattle raising, and is mainly caused by infection of streptococcus, staphylococcus aureus, corynebacterium suppurative, pathogenic escherichia coli and the like, and the pathogen can invade through a reproductive tract or can be endogenously infected through bacteremia; it was found that bacterial infection is a major factor causing both bovine diseases, and thus the use of antibacterial agents is a major means of preventing and treating both bovine diseases. The research also finds that the urease in the cow stomach hydrolyzes urea to generate ammonia at too high a rate, and cannot be matched with the generation rate of volatile fatty acid, so that ammonia cannot be timely utilized by microorganisms in the rumen to be absorbed into blood, the utilization rate of urea nitrogen by ruminants is reduced, animal ammonia poisoning is caused in severe cases, and the environment is polluted. Ammonia poisoning caused by excessive ammonia in the stomach of the cattle can damage gastric wall cells and further cause the cattle to generate gastroenteritis, and if one drug can inhibit the activity of urease and improve the immunity of the cattle, the drug can kill pathogenic bacteria effectively in time and has great significance for feeding the cattle.
Quinoline compounds are important naphthalene nitrogen-containing heterocyclic compounds, and are widely applied to the research and development of medicines and other active substances because of wide biological activity, and are important skeletons of a plurality of pesticides and medicines, such as antibiotics, antimalarials, bactericides and the like. Because the quinoline ring has strong biological activity, different functional groups can be introduced into the structure to change the activity. In the aspect of pesticides. For example flometoquin is a novel quinoline pesticide which is developed by Ming's drug Co-production and Kagaku Co-production, and the compound has good prevention and control effects on some pests which harm agricultural products such as vegetables, fruit trees, wheat and the like, and also has good prevention and control effects on pests which generate drug resistance to the existing pesticide. Erlotinib and icotinib and gefitinib are classical clinical drugs with quinoline structure in medicine. Also, for example, chloroquinoline, mefloquine, which was originally the only drug of particular utility in the treatment of malaria, was acting primarily in the erythropolis phase and could effectively control malaria attacks by interfering with the replication and transcription of plasmodium schizont DNA, leading to death of the parasite lacking amino acids. The group of people has abundant experience in the molecular development of quinoline active compounds, so that the compounds are expected to be applied to the development of feed additives, and therefore, a compound with a novel structure is designed on the basis of the existing medicines, and the compound is expected to have an inhibitory effect on IDO1 targets and urease.
Disclosure of Invention
The invention relates to a preparation method of a quinoline feed additive, which is characterized in that the molecular structure of the feed additive is as follows: wherein R is an aromatic ring derivative, and X is a carbon atom or a nitrogen atom.
The preparation method of the quinoline feed additive with the function of improving immunity is characterized by comprising the following steps of:
(1) Adding a certain amount of 6, 7-dimethoxyethoxyquinazolin-4-one and phosphorus oxychloride into N, N-dimethylformamide, uniformly stirring, slowly heating to 110 ℃, adding saturated sodium bicarbonate solution at 0-10 ℃ after the reaction is finished, extracting for a plurality of times by using methylene dichloride after stirring, merging organic phases, washing once by using saturated saline water, washing for a plurality of times by using water, drying by using anhydrous sodium sulfate, and concentrating to obtain 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline; the mass ratio of the 6, 7-dimethoxyethoxyquinazolin-4-one to the phosphorus oxychloride is 1:3 to 3.5.
(2) Adding a certain amount of 3, 4-bis (2-methoxyethoxy) aniline into dichloroethane, adding N-chlorosuccinimide, heating to reflux for reacting for a period of time, concentrating the reaction solution, adding the reaction solution into N, N-dimethylformamide, adding a certain amount of formamide, barium hydroxide and potassium dihydrogen phosphate, stirring, adding bis (triphenylphosphine) palladium dichloride and additional tetrahydrofuran, slowly heating to a certain temperature in a nitrogen atmosphere, reacting for a period of time, vacuum evaporating tetrahydrofuran, pouring the rest reaction system into water, stirring, filtering, adding ethyl acetate into the reaction solution, stirring, separating out an organic phase, washing the organic phase twice with saturated sodium chloride solution, drying with anhydrous magnesium sulfate, concentrating under a vacuum condition, and obtaining 4-amino-6, 7-bis (2-methoxyethoxy) quinazoline; the feeding amount molar ratio of the 3, 4-bis (2-methoxyethoxy) aniline to the N-chlorosuccinimide is 1:1.1 to 1.5; the molar ratio of the 3, 4-di (2-methoxyethoxy) aniline to the formamide to the barium hydroxide to the potassium dihydrogen phosphate is 1:2:1 to 1.1:1 to 1.1; the mass ratio of the 3, 4-bis (2-methoxyethoxy) aniline to the bis (triphenylphosphine) palladium dichloride is 10:1 to 1.1; the reaction temperature is 80-100 ℃.
(3) Adding a certain amount of 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline or 4-amino-6, 7-bis (2-methoxyethoxy) quinazoline into N, N-dimethylformamide, adding an iodobenzene compound, heating to a certain temperature, reacting for a period of time, adding palladium acetate, triphenylphosphine and triethylamine, slowly dropwise adding a dimethyl sulfoxide solution dissolved with an ethylene compound under the protection of nitrogen at room temperature, keeping the room temperature, slowly dropwise adding the solution, heating to 120 ℃ under the protection of nitrogen, reacting for a period of time, cooling to room temperature again, filtering the reaction solution, adding water into the filtrate for washing for a plurality of times, extracting the filtrate with dichloromethane for a plurality of times, merging organic phases, vacuum concentrating, evaporating the organic solvent, and separating by silica gel column chromatography to obtain N- (4-ketophenyl) -6, 7-bis (2-methoxyethoxy) -4-quinolinamine; the reaction temperature is 60-100 ℃; the iodobenzene compound is 4-iodoaniline or 1, 4-diiodobenzene; the feeding amount molar ratio of the 4-chloro-6, 7-di (2-methoxyethoxy) quinazoline or the 4-amino-6, 7-di (2-methoxyethoxy) quinazoline to the iodobenzene compound is 1:1 to 1.2; the feeding amount molar ratio of the 4-chloro-6, 7-di (2-methoxyethoxy) quinazoline or 4-amino-6, 7-di (2-methoxyethoxy) quinazoline to palladium acetate to triphenylphosphine is 1:0.15:0.5; the vinyl compound is vinyl butyl ether or vinyloxy trimethylsilane; the feeding amount molar ratio of the 4-chloro-6, 7-di (2-methoxyethoxy) quinazoline or the 4-amino-6, 7-di (2-methoxyethoxy) quinazoline to the vinyl compound is 1:1 to 1.2.
(4) Adding a certain amount of N- (4-ketophenyl) -6, 7-bis (2-methoxyethoxy) -4-quinolinamine into a reaction solvent, stirring, adding iodobenzene diacetate and copper triflate, heating to 80 ℃, filtering the reaction solution after a period of reaction, concentrating the filtrate in vacuum by an oil pump to remove most of the solvent, then pouring into dichloromethane, regulating the pH of the system to be neutral by using a saturated solution of sodium carbonate in a stirring state, separating an organic phase, washing the organic phase with water for a plurality of times, concentrating, adding into dimethyl sulfoxide, adding a certain amount of p-toluenesulfonyl hydrazine, 1-aminopyridine iodine and iodine, heating to 100 ℃, stirring for a period of reaction, pouring the reaction solution into water, extracting for a plurality of times by using dichloromethane, merging the organic phases, and separating and purifying by silica gel column chromatography to obtain a target compound; the molar ratio of the N- (4-ketophenyl) -6, 7-bis (2-methoxyethoxy) -4-quinolinamine to iodobenzene diacetate to copper triflate is 1:1 to 1.1:0.5; the volume ratio of glacial acetic acid to acetic anhydride serving as a reaction solvent is 1:1, a step of; the molar ratio of the N- (4-ethyl ketophenyl) -6, 7-bis (2-methoxyethoxy) -4-quinolinamine to the p-toluenesulfonyl hydrazine to the 1-aminopyridine iodine to the iodine is 1:1 to 1.1:0.5 to 0.7; or adding a certain amount of N- (4-ethyl ketophenyl) -6, 7-bis (2-methoxyethoxy) -4-quinolinamine and potassium iodide into benzene, stirring, adding 18g of copper triflate, stirring, slowly dripping benzene solution dissolved with phosphorus oxychloride, heating to reflux, removing water in a reaction system through a water separator, filtering the reaction solution after reacting for a period of time, vacuum concentrating to remove most of solvent, pouring into dichloromethane, regulating the pH value of the system to be neutral by using a sodium carbonate saturated solution in a stirring state, separating an organic phase, washing the organic phase for a plurality of times by using water, concentrating, adding into dimethyl sulfoxide, adding p-toluenesulfonyl hydrazine, 1-aminopyridine iodine and iodine, heating to 100 ℃ for stirring, pouring the reaction solution into water for a plurality of times, extracting by using dichloromethane, merging organic phases, concentrating, and separating and purifying by using a silica gel column chromatography to obtain a target compound; the molar ratio of the N- (4-ethyl ketophenyl) -6, 7-bis (2-methoxyethoxy) -4-quinolinamine to potassium iodide to copper triflate to phosphorus oxychloride is 1:1:0.5:1 to 1.2.
(5) Adding a certain amount of 4-amino-6, 7-bis (2-methoxyethoxy) quinazoline and potassium carbonate into benzene, adding a certain amount of phenylacetaldehyde compound, heating to 100 ℃, adding potassium iodide and copper triflate after reacting for a period of time, slowly dropwise adding a benzene solution dissolved with phosphorus oxychloride under the protection of nitrogen, heating to reflux under the protection of nitrogen, removing water in a reaction system through a water separator, cooling to room temperature for a period of time, filtering a reaction solution, adding water into filtrate, extracting for a plurality of times by using dichloromethane, merging organic phases, concentrating in vacuum, evaporating an organic solvent, and separating by silica gel column chromatography to obtain a target compound; the feeding amount molar ratio of the 4-amino-6, 7-di (2-methoxyethoxy) quinazoline to the phenylacetaldehyde compound is 1:1 to 1.1; the feeding amount molar ratio of the 4-amino-6, 7-bis (2-methoxyethoxy) quinazoline to the potassium iodide to the copper triflate is 1:0.2:0.5; the feeding amount molar ratio of the 4-amino-6, 7-di (2-methoxyethoxy) quinazoline to the phosphorus oxychloride is 1:1 to 1.2; or adding a certain amount of 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline into ethanol, slowly dripping a certain amount of hydrazine hydrate at the temperature of 0 ℃, keeping the temperature at not more than 10 ℃ after dripping, reacting for a period of time, adding triethylamine and benzaldehyde compounds, heating to reflux under the protection of nitrogen, vacuum concentrating after the reaction is finished, adding benzene, adding potassium iodide and copper triflate, slowly dripping a benzene solution dissolved with phosphorus oxychloride at the room temperature under the protection of nitrogen, heating to reflux under the protection of nitrogen, removing water in a reaction system by a water separator, reacting for a period of time, cooling to the room temperature, filtering the reaction solution, adding water into filtrate, extracting for a plurality of times by using dichloromethane, merging organic phases, vacuum concentrating to remove an organic solvent, and separating by silica gel column chromatography to obtain a target compound; the feeding amount molar ratio of the 4-chloro-6, 7-di (2-methoxyethoxy) quinazoline to the hydrazine hydrate is 1: 8-10; the feeding amount molar ratio of the 4-chloro-6, 7-di (2-methoxyethoxy) quinazoline to the triethylamine to the benzaldehyde compound is 1:1:1, a step of; the feeding amount molar ratio of the 4-chloro-6, 7-di (2-methoxyethoxy) quinazoline to the potassium iodide to the copper triflate is 1:0.2:0.5; the feeding amount molar ratio of the 4-amino-6, 7-di (2-methoxyethoxy) quinazoline to the phosphorus oxychloride is 1:1 to 1.2.
The preparation method of the quinoline feed additive has the following technical advantages: (1) The invention is modified on the basis of reported molecular structure of the drug erlotinib on the market to obtain a compound with novel structure; (2) The triazole or diazole structure of the compound can be combined with heme in an IDO1 target point, so that the activity of the compound is inhibited; (3) The compound also has a certain inhibition effect on urease, can inhibit nitrogen source loss, can be used for veterinary drugs according to frequent human administration, and has the characteristic of low toxicity of human administration, so that the compound can be used as a potential feed additive with good activity.
Drawings
FIG. 1 is a hydrogen spectrum of the compound obtained in example 3.
FIG. 2 is a mass spectrum of the compound obtained in example 10.
Detailed Description
The above-described matters of the present invention will be described in further detail by way of examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and all techniques realized based on the above-described matters of the present invention are within the scope of the present invention.
Example 1
Adding 23g of N-Boc-3, 4-dihydroxyaniline and 14g of potassium carbonate into 400mL of N, N-dimethylformamide in a reaction bottle, heating to 90 ℃ under the protection of nitrogen, stirring for 30min, then slowly adding 200mL of N, N-dimethylformamide solution dissolved with 25g of 2-chloroethyl methyl ether, continuing to react for 14h at 90 ℃, monitoring the complete reaction of the N-Boc-3, 4-dihydroxyaniline by TLC, evaporating about 500mL of N, N-dimethylformamide by using an oil pump in vacuum, adding the concentrate into 500mL of dichloromethane, stirring uniformly, adding 500mL of 2N hydrochloric acid at 0-10 ℃, stirring for reacting for 5h, separating out an organic phase, extracting the reaction liquid by using 150mL of dichloromethane for 4 times, merging the organic phase, regulating the pH of the organic phase to 8 by using a saturated solution, separating out the organic phase, drying and concentrating to obtain 20.72g of 3, 4-bis (2-methoxyethoxy) aniline; LC-MS (ESI) m/z 242[ M+H ] +.
Example 2
Adding 24g of 3, 4-bis (2-methoxyethoxy) aniline into 400mL of formamide in a reaction bottle, adding 20g of ammonium formate, slowly heating to 140 ℃ under nitrogen atmosphere, reacting for 16h, monitoring the reaction of 3, 4-bis (2-methoxyethoxy) aniline by TLC, cooling to room temperature, adding 800mL of ethyl acetate and 600mL of water into the reaction solution, stirring for 1h, separating out an organic phase, extracting the aqueous phase for multiple times by 200mL of ethyl acetate, combining the organic phases, washing twice by 300mL of saturated sodium chloride solution, drying by anhydrous magnesium sulfate, and concentrating under vacuum to obtain 22.09g of 3, 4-bis (2-methoxyethoxy) benzamidine; LC-MS (ESI) m/z 269[ M+H ] +.
Example 3
Adding 27g of 3, 4-bis (2-methoxyethoxy) benzamidine into 500mL of chloroform in a reaction bottle with nitrogen protection and a temperature control device, uniformly stirring and then cooling to 0 ℃, slowly dropwise adding 300mL of chloroform in which 36g of triphosgene is dissolved, keeping the temperature stable, stirring for 1h after the dropwise addition, concentrating the reaction solution, continuously stirring for 1h after the dropwise addition by repeatedly adding 200mL of a mixed solution of cyclohexane and acetonitrile (volume ratio is 2:1), vacuum evaporating to remove residual water and triphosgene byproducts in the reaction system, finally adding 400mL of mixed solution of tetrahydrofuran and 200mL of diethyl ether into the concentrated reaction system, stirring uniformly and then keeping the nitrogen environment at 0-10 ℃, slowly dropwise adding 100mL of diethyl ether solution in which 20g of boron trifluoride is dissolved, stirring and reacting for 1h after the dropwise addition is complete, adding 2.4g of boron chloride into the reaction system and keeping the nitrogen atmosphere, continuously stirring for 1h after the dropwise addition, heating to room temperature, filtering and then removing residual water and the byproducts of the triphosgene in the reaction system, finally adding 400mL of tetrahydrofuran and 200mL of diethyl ether into the mixed solution after the vacuum distillation and the mixed solution is cooled to 1:6, refluxing to obtain solid after the mixed solution is distilled to 1:1-6, and the mixed solution is cooled to 1:1, and distilled to be separated under the conditions of the reflux, and distilled solution is cooled to 4:1:1, and distilled to the solid is heated to obtain solid after the solid 19.58g;LC-MS(ESI):m/z 295[M+H]+;1H NMR(400MHz,DMSO-d6):δ7.97(s,1H),7.47(s,1H),7.16(s,1H),4.27-4.19(m,4H),3.74-3.70(m,4H),3.37-3.35(m,6H).
Example 4
Adding 30g of 6, 7-dimethoxyethoxyquinazolin-4-one and 100g of phosphorus oxychloride into 600mL of N, N-dimethylformamide in a reaction bottle with stirring, uniformly stirring, slowly heating to 110 ℃, stirring for 4.5h, adding 800mL of saturated sodium bicarbonate solution at 0-10 ℃, stirring for 20min, extracting for multiple times with 300mL of dichloromethane, merging organic phases, washing once with 200mL of saturated saline solution, washing for multiple times with 100mL of water, drying with anhydrous sodium sulfate, and concentrating to obtain 26.43g of 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline; LC-MS (ESI) m/z 313[ M+H ] +.
Example 5
Adding 24g of 3, 4-bis (2-methoxyethoxy) aniline into 400mL of dichloroethane in a reaction bottle, adding 15g of N-chlorosuccinimide, heating to reflux for 5h, concentrating the reaction solution, adding 500mL of N, N-dimethylformamide, adding 5g of formamide, 17g of barium hydroxide and 14g of potassium dihydrogen phosphate, slowly heating to 100 ℃, stirring for reacting for 5h, cooling to 50 ℃, adding 10g of formamide, 2.4g of bis (triphenylphosphine) palladium dichloride, 8.5g of potassium iodide and 200mL of tetrahydrofuran, slowly heating to 90 ℃ under nitrogen atmosphere, stirring for reacting for 7h, vacuum evaporating tetrahydrofuran, pouring the rest reaction system into 800mL of water, stirring and filtering, adding 800mL of ethyl acetate into the filtrate, stirring for 30min, separating an organic phase, washing the organic phase with 300mL of saturated sodium chloride solution twice, drying with anhydrous magnesium sulfate, concentrating under vacuum condition, and obtaining 27.11g of 4-amino-6, 7-bis (2-methoxyethoxy) quinazoline; LC-MS (ESI) M/z294[ M+H ] +.
Example 6
Adding 31g of 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline into 1000mL of N, N-dimethylformamide, adding 22g of 4-iodoaniline, heating to 80 ℃, reacting for 5h, cooling to room temperature, adding 3.4g of palladium acetate, 13g of triphenylphosphine and 10g of triethylamine, slowly dropwise adding 200mL of dimethyl sulfoxide solution dissolved with 17.5g of vinyloxy trimethylsilane under the protection of nitrogen at room temperature, keeping the room temperature, slowly dropwise adding, heating to 90 ℃ under the protection of nitrogen for reacting for 5h after the dropwise adding is completed, cooling to room temperature again, filtering the reaction solution, adding 1000mL of water into the filtrate, stirring, extracting with 400mL of dichloromethane for multiple times, combining organic phases, concentrating in vacuum, evaporating the organic solvent, separating by silica gel column chromatography to obtain N- (4-ketophenyl) -6, 7-bis (2-methoxyethoxy) -4-quinolinamine 31.17g;1H NMR(600MHz,CDCl3):11.43(s,1H),8.89(s,1H),8.41(s,1H),8.09-8.07(m,2H),7.95(d,J＝12.0Hz,2H),7.40(s,1H),4.41-4.36(m,4H),3.80-3.76(m,4H),3.39(s,3H),3.36(s,3H),2.65(s,3H).
Example 7
Adding 30g of 4-amino-6, 7-bis (2-methoxyethoxy) quinazoline into 1200mL of N, N-dimethylformamide in a reaction bottle, adding 33g of 1, 4-diiodobenzene, heating to 70 ℃, adding 3.4g of palladium acetate, 13g of triphenylphosphine and 10g of triethylamine after reacting for 1.5h, slowly dropwise adding 250mL of dimethyl sulfoxide solution dissolved with 20g of vinyl butyl ether under the protection of nitrogen at room temperature, keeping the room temperature, slowly dropwise adding, heating to 90 ℃ under the protection of nitrogen for reacting for 7.5h, cooling to room temperature again, filtering the reaction solution, adding 1400mL of water into the filtrate, extracting for multiple times with 500mL of dichloromethane, merging organic phases, vacuum concentrating, evaporating the organic solvent, and separating by silica gel column chromatography to obtain N- (4-ketophenyl) -6, 7-bis (2-methoxyethoxy) -4-quinolinamine 24.93g;1H NMR(600MHz,CDCl3):11.43(s,1H),8.89(s,1H),8.41(s,1H),8.09-8.07(m,2H),7.95(d,J＝12.0Hz,2H),7.40(s,1H),4.41-4.36(m,4H),3.80-3.76(m,4H),3.39(s,3H),3.36(s,3H),2.65(s,3H).
Example 8
In a reaction bottle with stirring, 41g of N- (4-ethyl ketophenyl) -6, 7-bis (2-methoxyethoxy) -4-quinolinamine is added into 1400mL of a mixed solution of glacial acetic acid and acetic anhydride (volume ratio is 1:1), 33g of iodobenzene diacetate is added after stirring for 20min, 18g of copper triflate is added after stirring for 10min, the reaction is heated to 80 ℃, reaction is carried out for 5h, then the reaction solution is filtered, the filtrate is concentrated by an oil pump in vacuum to remove most of the solvent, then the filtrate is poured into 1000mL of dichloromethane, the pH of the system is regulated to be neutral by saturated solution of sodium carbonate under stirring, the organic phase is separated out, the organic phase is washed for a plurality of times by water, then concentrated and then added into 1000mL of dimethyl sulfoxide, 19g of p-toluenesulfonyl hydrazine, 22.5g of 1-aminopyridine iodine and 17g of iodine are added, the mixture is heated to 100 ℃ for stirring reaction for 1h, then the reaction solution is poured into 1200mL of water for a plurality of times, the organic phase is combined, and the organic phase is concentrated and separated and purified by a silica gel column chromatography to obtain the phenyl triazole target compound 22.67g;LC-MS(ESI):m/z435[M+H]+;1H NMR(600MHz,CDCl3)δ11.73(s,1H),9.79-9.76(m,1H),9.05(s,1H),8.46(s,1H),8.09-8.07(m,1H),7.86(s,1H),7.55(s,1H),7.49(t,J1＝6.0Hz,J2＝6.0Hz,1H),4.35-4.32(m,4H),3.79-3.76(m,4H),3.38(s,3H),3.36(s,3H).
Example 9
Adding 41g of N- (4-ethyl ketophenyl) -6, 7-bis (2-methoxyethoxy) -4-quinolinamine and 17g of potassium iodide into 1000mL of benzene in a reaction bottle with a stirring and water knockout drum, adding 18g of copper triflate into the mixture after stirring for 10min, slowly dropwise adding 200mL of benzene solution dissolved with 19g of phosphorus oxychloride into the mixture after stirring for 10min, heating to reflux, removing water in the reaction system through the water knockout drum, reacting for 8.5h, filtering the reaction solution, removing most of the solvent by vacuum concentration, pouring into 1000mL of dichloromethane, regulating the pH of the system to be neutral by using a saturated solution of sodium carbonate under stirring, separating an organic phase, washing the organic phase with water for a plurality of times, adding 1000mL of dimethyl sulfoxide after concentration, adding 19g of p-toluenesulfonyl hydrazine, 22.5g of 1-aminopyridine iodine and 17g of iodine into 1000mL of dimethyl sulfoxide, heating to 100 ℃ for stirring for 1h, adding the reaction solution into 1200mL of water, extracting for a plurality of times by using 500mL of dichloromethane, merging the organic phase, concentrating, and separating and purifying by silica gel column chromatography to obtain the target compound of phenyl triazole 37.82g;LC-MS(ESI):m/z 435[M+H]+;1H NMR(600MHz,CDCl3)δ11.73(s,1H),9.79-9.76(m,1H),9.05(s,1H),8.46(s,1H),8.09-8.07(m,1H),7.86(s,1H),7.55(s,1H),7.49(t,J1＝6.0Hz,J2＝6.0Hz,1H),4.35-4.32(m,4H),3.79-3.76(m,4H),3.38(s,3H),3.36(s,3H).
Example 10
Adding 30g of 4-amino-6, 7-bis (2-methoxyethoxy) quinazoline and 14g of potassium carbonate into 1200mL of benzene in a reaction bottle with a stirring and water knockout drum, adding 26g of 2, 4-bis (trifluoromethyl) phenylacetaldehyde, heating to 100 ℃, adding 3.4g of potassium iodide and 18g of copper triflate after reacting for 1h, slowly dropwise adding 200mL of benzene solution dissolved with 19g of phosphorus oxychloride under the protection of nitrogen at room temperature, heating to reflux under the protection of nitrogen, removing water in a reaction system by the water knockout drum, reacting for 7.5h to room temperature, filtering the reaction solution, adding 1400mL of water into the filtrate, extracting for multiple times by using 500mL of dichloromethane, merging organic phases, concentrating in vacuum, evaporating the organic solvent, separating by silica gel column chromatography to obtain the 2, 4-bis (trifluoromethyl) phenyl target compound 32.18g;LC-MS(ESI):m/z 530[M+H]+;1H NMR(600MHz,CDCl3)δ9.27(s,1H),7.99(s,1H),7.67-7.64(m,2H),7.56(s,1H),7.48(d,J＝6.0Hz,1H),7.45(s,1H),4.36-4.32(m,4H),3.77-3.74(m,4H),3.39(s,3H),3.37(s,3H).
Example 11
Adding 31g of 4-chloro-6, 7-di (2-methoxyethoxy) quinazoline into 1000mL of ethanol in a reaction bottle with a stirring and water knockout drum, slowly dropwise adding 50g of hydrazine hydrate at 0 ℃, keeping the temperature at not more than 10 ℃ after the dropwise adding is completed, reacting for 1.5h, placing at 0 ℃ for stirring and filtering, adding 1000mL of ethanol, adding 20g of triethylamine 10g and 20g of 2-fluoro-4-bromo-benzaldehyde, heating to reflux under the protection of nitrogen, reacting for 5h, vacuum concentrating, adding 1000mL of benzene, adding 3.4g of potassium iodide and 18g of copper triflate, slowly dropwise adding 200mL of benzene solution dissolved with 19g of phosphorus oxychloride at room temperature under the protection of nitrogen, heating to reflux under the protection of nitrogen, removing water in a reaction system by the water knockout drum, cooling to room temperature for 7.5h, filtering the reaction liquid, adding 1400mL of water, extracting for multiple times by using 500mL of dichloromethane, merging organic phases, vacuum concentrating, evaporating organic solvent, separating by a silica gel column chromatography to obtain 2-fluoro-4-phenyl target compound 41.07g;LC-MS(ESI):m/z 491[M+H]+;1H NMR(600MHz,CDCl3)δ9.25(s,1H),7.64(d,J＝12.0Hz,2H),7.57(s,1H),7.43(d,J＝6.0Hz,1H),7.38-7.36(m,1H),4.35-4.31(m,4H),3.78-3.75(m,4H),3.38(s,3H),3.37(s,3H).
Example 12
Taking out viable human cervical cancer Hela cell culture dishes from the CO 2 incubator, and respectively performing the following operations: and (3) performing aseptic operation beside the alcohol lamp, opening a dish cover, sucking out the culture solution in a waste liquid jar, washing the culture solution in the culture bottle with 2mL of PBS twice, performing digestion with 0.25% trypsin, stopping digestion when the increase of cell gaps and the change of cells into a small circle shape are observed, blowing the bottom of the culture bottle by using a pipetting gun to make the cells fall off, transferring the obtained cell suspension into an aseptic centrifuge tube, setting the centrifuge to be 1000r/min, centrifuging for 3min, slowly pouring the supernatant in the centrifuge tube, adding 2-5 mL of culture solution, and performing cell counting under an inverted microscope. According to the counting result, viable human cervical cancer HeLa cells grown in logarithmic phase were plated in 96-well cell culture plates at 50000 cells per well, cultured for 5 to 6 hours with RPMI1640 containing 10% fetal bovine serum, 100. Mu.L of the test compound diluted with the medium (0.2. Mu.M, 0.4. Mu.M, 0.8. Mu.M, 1.6. Mu.M, 3.2. Mu.M, 6.4. Mu.M, 12.8. Mu.M, 25.6. Mu.M) and recombinant human interferon gamma (final concentration 100 ng/mg) were added to activate IDO1 expression in HeLa cells. After the completion of the operation, the 96-well cell culture plate was placed in a 37℃cell culture incubator rich in 5% carbon dioxide for 18 hours, and the reaction was terminated with a certain amount of 3.05N trichloroacetic acid, followed by incubation at 50℃for 30 minutes. After the cell culture solution is precipitated, supernatant is taken, and after the supernatant is developed by (N, N-dimethyl) benzaldehyde, absorbance at 480nm is detected by a multifunctional enzyme-labeled instrument. The group treated with IFNγ medium alone without drug was taken as 100% (At), and the group treated with DMSO medium alone At 0.1% was taken as blank 0% (Ab); the absorbance at different conditions was calculated according to the following formula: absorbance% = (a-Ab)/(At-Ab), a: drug treatment +100ng/mL ifnγ, ab: blank, at: no drug contained only 100ng/mL IFNγ; a suppression curve with IC 50 values was generated according to using GRAPH PAD PRISM 8.0.0 software. As can be seen from the following table, the compoundsThe inhibitory activity against IDO1 is best consistent with the predicted outcome.
Example 13
In vitro urease inhibition assay
After feeding for 1h, 400mL of rumen fluid is collected by a special rumen fluid collector through an artificial rumen fistula, and is filtered through 4 layers of gauze for later use. After adding the corresponding reagents according to the amounts in the table, 4 drops of liquid paraffin are added dropwise, and the mixture is placed on a constant-temperature water bath oscillator at the temperature of (39.0+/-0.5) DEG C for light shaking. At 1,2,4,6 and 8 hours of incubation, respectively, a portion of the incubation tube was removed from each group, and 4 drops of saturated mercuric chloride solution were immediately added with a dropping tube and shaken well to terminate the reaction. The ammonia nitrogen content in each test tube was determined by Kaiser semi-micro-saturated magnesium oxide distillation. We can find that the designed compound has high inhibition activity to urease with time and good inhibition effect.
Inhibition (%) = (control group ammonia content-test group ammonia content)/(control group ammonia content x 100%)
Time (h) Inhibition rate of control group Test 1 group inhibition ratio Test group 2 inhibition ratio Test 3 group inhibition ratio
1 0％ 1.17％ 3.04％ 6.25％
2 0％ 2.91％ 5.89％ 7.34％
4 0％ 5.94％ 10.62％ 16.09％
6 0％ 14.73％ 19.28％ 28.33％
8 0％ 18.85％ 29.97％ 44.83％
While the basic principles, principal features and advantages of the present invention have been described in the foregoing examples, it will be appreciated by those skilled in the art that the present invention is not limited by the foregoing examples, but is merely illustrative of the principles of the invention, and various changes and modifications can be made without departing from the scope of the invention, which is defined by the appended claims.

Claims (5)

1. A quinoline feed additive is characterized in that the structure of the feed additive is as follows:。
2. A process for preparing the quinoline feed additive of claim 1, comprising the steps of: adding a certain amount of 4-amino-6, 7-bis (2-methoxyethoxy) quinazoline and potassium carbonate into benzene, adding a certain amount of 2, 4-bis (trifluoromethyl) phenylacetaldehyde, heating to 100 ℃, adding potassium iodide and copper triflate after reacting for a period of time, slowly dropwise adding a benzene solution dissolved with phosphorus oxychloride under the protection of nitrogen at room temperature, heating to reflux under the protection of nitrogen, removing water in a reaction system through a water separator, reacting for a period of time to room temperature, filtering a reaction solution, adding water into filtrate, extracting for a plurality of times by using dichloromethane, merging organic phases, vacuum concentrating, evaporating an organic solvent, and separating by silica gel column chromatography to obtain a target compound; the feeding amount molar ratio of the 4-amino-6, 7-bis (2-methoxyethoxy) quinazoline to the 2, 4-bis (trifluoromethyl) phenylacetaldehyde is 1: 1-1.1; the feeding amount molar ratio of the 4-amino-6, 7-bis (2-methoxyethoxy) quinazoline to the potassium iodide to the copper triflate is 1:0.2:0.5; the feeding amount molar ratio of the 4-amino-6, 7-di (2-methoxyethoxy) quinazoline to the phosphorus oxychloride is 1:1 to 1.2.
3. The method of claim 2, wherein the preparation of 4-amino-6, 7-bis (2-methoxyethoxy) quinazoline is as follows: adding a certain amount of 3, 4-bis (2-methoxyethoxy) aniline into dichloroethane, adding N-chlorosuccinimide, heating to reflux for a period of time, concentrating the reaction solution, adding the reaction solution into N, N-dimethylformamide, adding a certain amount of formamide, barium hydroxide and potassium dihydrogen phosphate, stirring for reaction, adding a certain amount of formamide, bis (triphenylphosphine) palladium dichloride, potassium iodide and tetrahydrofuran, slowly heating to a certain temperature in a nitrogen atmosphere, reacting for a period of time, vacuum evaporating tetrahydrofuran, pouring the rest reaction system into water, stirring and filtering, adding ethyl acetate into the reaction solution, stirring, separating an organic phase, washing the organic phase twice with saturated sodium chloride solution, drying with anhydrous magnesium sulfate, concentrating under a vacuum condition, and obtaining 4-amino-6, 7-bis (2-methoxyethoxy) quinazoline; the feeding amount molar ratio of the 3, 4-bis (2-methoxyethoxy) aniline to the N-chlorosuccinimide is 1: 1.1-1.5; the molar ratio of the 3, 4-di (2-methoxyethoxy) aniline to the formamide to the barium hydroxide to the potassium dihydrogen phosphate is 1: 2-4: 1-1.1: 1-1.1; the mass ratio of the 3, 4-bis (2-methoxyethoxy) aniline to the bis (triphenylphosphine) palladium dichloride is 10: 1-1.1; the mass ratio of the 3, 4-di (2-methoxyethoxy) aniline to the potassium iodide is 1:0.5 to 0.6; the certain temperature is 80-100 ℃.
4. A process according to claim 3, wherein the 3, 4-bis (2-methoxyethoxy) aniline is prepared by: adding a certain amount of N-Boc-3, 4-dihydroxyaniline and potassium carbonate into N, N-dimethylformamide, heating to a certain temperature under the protection of nitrogen, stirring for a period of time, slowly adding an N, N-dimethylformamide solution dissolved with 2-chloroethyl methyl ether, keeping the temperature until the raw materials react completely, concentrating a reaction system, adding the concentrate into dichloromethane, stirring uniformly, adding 2N hydrochloric acid at 0-10 ℃, stirring, reacting, separating out an organic phase, regulating the pH value of the organic phase to 8 by using a sodium hydroxide saturated solution, separating out an organic phase, and concentrating the organic phase to obtain 3, 4-bis (2-methoxyethoxy) aniline; the molar ratio of the N-Boc-3, 4-dihydroxyaniline to the potassium carbonate to the 2-chloroethyl methyl ether is 1:1: 2-2.5; the certain temperature is 80-100 ℃.
5. The use of a quinoline feed additive according to claim 1 for the preparation of a medicament for inhibiting IDO1 enzyme and urease activity.
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Publication number Priority date Publication date Assignee Title
WO2009051801A2 (en) * 2007-10-16 2009-04-23 Angiogenex Chemical inhibitors of inhibitors of differentiation
WO2021028382A1 (en) * 2019-08-12 2021-02-18 Bayer Aktiengesellschaft [1,2,4]triazolo[1,5-c]quinazolin-5-amines

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SI1549652T1 (en) * 2002-09-30 2009-04-30 Bayer Healthcare Ag Fused azole-pyrimidine derivatives
CN110857291B (en) * 2018-08-24 2021-01-26 中国农业科学院北京畜牧兽医研究所 Natural compound for slowing rumen microorganism from decomposing amino acid and urea and application thereof

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WO2009051801A2 (en) * 2007-10-16 2009-04-23 Angiogenex Chemical inhibitors of inhibitors of differentiation
WO2021028382A1 (en) * 2019-08-12 2021-02-18 Bayer Aktiengesellschaft [1,2,4]triazolo[1,5-c]quinazolin-5-amines

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