CN110713496A - Thiazole medicine molecule used in hospital and gynecology and preparation method and application thereof - Google Patents
Thiazole medicine molecule used in hospital and gynecology and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses thiazole medicine molecules used in hospital and gynecology, a preparation method and application thereof, and belongs to the technical field of synthesis of antitumor medicines. The technical scheme provided by the invention has the key points that: the thiazole drug molecule has a structure
The invention also discloses a preparation method of the benzothiazole compound, which takes low-cost 2-iodine-4-methoxyphenol as an initial raw material, and the low-cost 2-iodine-4-methoxyphenol is reacted with thiourea, bromomethyl biphenyl, dipropyl sulfate, hydrazine hydrate, N-bromosuccinimide and other compounds in sequence through six steps to obtain a target compound.
Description
Technical Field
The invention belongs to the technical field of antineoplastic drug synthesis, and particularly relates to thiazole drug molecules used in hospitals and gynecology, and a preparation method and application thereof.
Background
In modern society, the incidence of cancer is higher and higher, and the mortality rate is always high. According to statistical data, the number of new cancer cases is 429 ten thousand per year, which accounts for 20% of new cases in China, and 281 ten thousand of cases of death bring great hidden troubles to the sustainable development of the society in China. Cancer is often difficult to diagnose early in onset, and most patients are already in an advanced stage when they are diagnosed, which is one of the reasons for high mortality. Drug therapy is currently the most dominant treatment modality over physical and surgical therapy, as it is relatively less restrictive than other approaches, and can be prescribed for early, intermediate, and late stages of cancer. However, most of the current anticancer drugs have more or less side effects on human body, so the development and research of new anticancer drugs with less side effects are still hot spots of research.
The heterocyclic compounds are particularly abundant, widely distributed in nature, and play a large role in the development, growth and the like of organisms. In the early nineteenth century, the heterocyclic compounds are mostly extracted from natural products, but the obtained compounds have low yield, low purity and high price; with the development of organic synthesis technology, in order to fully utilize heterocyclic compounds, chemists have begun to artificially synthesize heterocyclic compounds on a large scale, so that the heterocyclic compounds are widely applied, including biological medicines, energy storage materials, biological simulation materials, high-performance dyes and the like. The nitrogen-containing heterocyclic compound is an important heterocyclic compound, has broad-spectrum biological activity and pharmacological activity due to a unique structure, has biological activity such as sterilization, antivirus, antitumor and the like, and can be used as a lead compound framework of a plurality of medicines and has important function in the field of medicine creation.
Thiazole rings are an important five-membered aromatic nitrogen-containing heterocyclic ring. The skeleton of the thiazole ring contains sulfur and nitrogen, and the introduction of sulfur atoms causes the thiazole ring to show a plurality of characteristics superior to other heterocyclic compounds; for example, it has an abundant electron cloud density, readily forming hydrogen bonds with other compounds; and the thiazole also shows aromaticity, for example, the hydrogen on the 2-position has strong activity, and the characteristics enable the compound of the thiazole skeleton to have special biological performance, can form strong acting force with amino acid residues in tumor cell target protein, and has wide application in research and development of new drugs and total synthesis of natural products. For example, in recent years, many studies on the synthesis of benzothiazole derivatives have been reported, and benzothiazole compounds exist in various natural products with biomedical activity, and have great application prospects in treating diseases such as tumors, diabetes, parkinsonism, tuberculosis drugs and the like. The benzothiazole and the derivatives thereof can also be used as design, synthesis, biological evaluation and other functions of cyclooxygenase inhibitors, the optimized compounds can form a new anti-cancer drug, and the compounds are worthy of further research, for example, an anti-cancer compound containing thiazole rings discovered in the second people hospital of Shenzhen city has better inhibitory activity on cervical cancer cell Hela and lung cancer cell A549.
In recent thirty years, the fluorescent probe technology has attracted extensive attention in the fields of environmental science, biology, medicine and the like by virtue of the advantages of low cost, fast response, good sensitivity, high resolution and the like, and the design and synthesis of the probe can be referred to by various fluorescence control mechanisms, such as Excited State Intramolecular Proton Transfer (ESIPT), and the unique excited state intramolecular proton transfer effect is widely researched, so that the development of fluorescent materials is promoted. In recent years, a great deal of research shows that the benzothiazole has a very remarkable light-emitting effect due to a special skeleton structure, and the compound can be applied to the fields of fluorescent probes, optical functional materials and the like.
Therefore, in view of the very wide application value of thiazole compounds, the benzothiazole compounds with novel structures are prepared by taking 2-iodine-4-methoxyphenol and thiourea as raw materials through a novel green and efficient synthesis method, and antitumor activity tests show that the compounds have good inhibition effect on cervical cancer cells Hela and have potential for being used as hospital gynecological medicines.
Disclosure of Invention
The invention aims to provide thiazole medicine molecules used in hospital and gynecology, and a preparation method and application thereof.
The invention adopts the following technical scheme for solving the technical problems, and the thiazole medicine molecule used in the hospital and the gynecology and the preparation method and the application thereof have the following structure:
the invention adopts the following technical scheme for solving the technical problems, and the preparation method of thiazole medicine molecules used in hospital and gynecology is characterized by comprising the following specific steps:
(1) adding a certain amount of toluene solvent into a reaction bottle with a water separator, adding a certain amount of 2-iodine-4-methoxyphenol and palladium/calcium carbonate (the palladium content is 5 percent), slowly heating to reflux under the protection of argon, removing water in a reaction system through the water separator, reacting for a period of time, cooling to 50 ℃, quickly adding a certain amount of thiourea, keeping the state of argon protection, stirring and reacting for a period of time at 50 ℃, observing that the solution is light yellow, heating to reflux, removing the water generated in the reaction system in time, keeping the reaction under the reflux state until the raw materials react completely, allowing the reaction solution to be dark red, reducing the temperature to 50 ℃, filtering the reaction solution while hot, recovering the catalyst palladium/calcium carbonate, removing the toluene in a vacuum manner, concentrating, adding a sodium chloride saturated solution into the reaction solution, and stirring uniformly, extracting the reaction solution with chloroform for multiple times, mixing organic phases, concentrating, adding the concentrate into tetrahydrofuran, and stirring under argon protection; then rapidly adding anhydrous lithium bromide, stirring uniformly, slowly raising the temperature to 60 ℃, gradually precipitating white solids in a reaction system, stopping heating after the reaction is finished, cooling to room temperature, adding water, stirring for a period of time, carrying out reduced pressure rotary evaporation under a vacuum condition to remove most tetrahydrofuran, adding a certain amount of dichloromethane, adjusting the pH of a reaction solution to 4 by using dilute hydrochloric acid under room temperature stirring, separating out an organic phase, extracting a water phase by using dichloromethane for multiple times, combining the organic phases, drying the organic phase by using anhydrous magnesium sulfate, concentrating, and finally carrying out silica gel column chromatography separation to obtain 2-amino-6-hydroxybenzothiazole; the mass ratio of the 2-iodine-4-methoxyphenol to the palladium/calcium carbonate is 10: 1; the catalyst palladium/calcium carbonate can be recycled for many times; the feeding amount molar ratio of the 2-iodine-4-methoxyphenol to the thiourea is 1: 1.5-2; the feeding amount molar ratio of the 2-iodine-4-methoxyphenol to the anhydrous lithium bromide is 1: 1.2 to 1.5;
(2) adding a certain amount of 2-amino-6-hydroxybenzothiazole and an alkaline compound into acetone, slowly dropwise adding an acetone solution in which bromomethylbiphenyl is dissolved at room temperature, gradually heating to reflux after dropwise adding, continuously reacting until raw materials react completely, concentrating the reaction liquid, then pouring into water, adjusting the pH of the reaction liquid to be neutral by using dilute hydrochloric acid, evaporating to remove the acetone solvent under a vacuum condition, extracting the reaction liquid for multiple times by using dichloromethane, combining organic phases, and concentrating to obtain 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole-2-amine; the alkaline compound is triethylamine or potassium carbonate; the feeding amount molar ratio of the 2-amino-6-hydroxybenzothiazole to the alkaline compound is 1:1 to 1.5; the feeding amount molar ratio of the 2-amino-6-hydroxybenzothiazole to the bromomethyl biphenyl is 1: 1;
(3) adding a certain amount of 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole-2-amine and calcium carbonate into chloroform, heating to reflux, dissolving the raw materials completely, dissolving calcium carbonate partially, stirring for a period of time, filtering the reaction solution while the solution is hot, adding a certain amount of calcium oxide into the reaction solution, heating to 40 deg.C again, under the protection of nitrogen, slowly dropwise adding a chloroform solution dissolved with dipropyl sulfate, heating to reflux after dropwise adding, reacting until the raw materials completely react, cooling the reaction liquid to room temperature, adding water into the reaction liquid, stirring for a period of time, separating out an organic phase, drying the organic phase with anhydrous magnesium sulfate, performing suction filtration, and concentrating to obtain N-propyl 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole-2-imine; the feeding amount molar ratio of the 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole-2-amine to the calcium oxide to the dipropyl sulfate is 1: 0.5-1.2: 1 to 1.1;
(4) adding a certain amount of N-propyl 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole-2-imine and propylamine into N, N-dimethylformamide in a high-pressure reaction kettle, adding a certain amount of hydrazine hydrate with the content of 65%, closing the high-pressure reaction kettle, checking the sealing condition, then removing the air in the reaction kettle by vacuum, introducing ammonia gas into the reaction kettle after stirring for a period of time at room temperature, slowly heating to a certain temperature, keeping the pressure in the reaction kettle at 0.12MPa, reducing the pressure in the reaction kettle after reacting for a period of time, continuously introducing ammonia gas to keep the pressure in the reaction kettle at more than 0.1MPa, keeping the pressure in the reaction kettle at more than 0.05MPa for a continuous period of time, reducing to the room temperature after the reaction is finished, extracting unreacted alkaline gas in the reaction kettle under the vacuum condition, then cooling to 10 ℃, slowly dropwise adding dilute hydrochloric acid to adjust the pH of the reaction solution to be alkalescent (the pH is about 9), then adding saturated sodium chloride solution for washing, extracting the reaction solution for multiple times by using ethyl acetate, combining organic phases, drying and concentrating to obtain N-propyl 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole hydrazone; the feeding amount molar ratio of the N-propyl 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole-2-imine to the propylamine to the hydrazine hydrate is 1: 1: 3; the reaction temperature is 80 ℃;
(5) adding a certain amount of N-propyl 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole hydrazone into a reaction bottle, replacing the solution with nitrogen for three times, dissolving the solution with dry dichloromethane under the protection of nitrogen, dropwise adding a dichloromethane solution in which bromoacetyl chloride is dissolved into the system at 10 ℃, after dropwise adding, finding that obvious turbidity appears in the system, gradually returning to room temperature, adding a saturated sodium bicarbonate solution after the reaction is finished, then separating out an organic phase, extracting a water phase with dichloromethane, combining the organic phases, concentrating, and then separating and purifying by silica gel column chromatography to obtain a brominated compound; the feeding amount molar ratio of the N-propyl 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole hydrazone to the bromoacetyl chloride is 1: 1.2;
(6) under the protection of nitrogen, a certain amount of magnesium powder, potassium iodide and iodine are put into a reaction bottle, adding into a certain amount of completely dehydrated mixed solvent, slightly heating to 40 deg.C to initiate reaction, slowly dropwise adding tetrahydrofuran solution dissolved with bromo-compound, heating to 60 deg.C for reaction for a period of time, cooling to room temperature, then adding a certain amount of N-bromosuccinimide and 1, 3-bis (diphenylphosphinopropane) nickel dichloride, vacuumizing, replacing with nitrogen for many times to ensure that the reaction system is completely in the nitrogen atmosphere, then stirring the mixture for reaction at room temperature, monitoring the reaction of the raw materials by TLC, adding saturated sodium chloride solution into the reaction solution for washing, removing solvent tetrahydrofuran under vacuum condition, extracting reaction system with ethyl acetate for several times, collecting organic phase, drying with anhydrous magnesium sulfate, and separating with silica gel column chromatography to obtain target compound; the feeding amount molar ratio of the magnesium powder to the potassium iodide to the brominated compound is 2: 0.2: 1; the feeding amount molar ratio of the brominated compound to the 1, 3-bis (diphenylphosphinopropane) nickel dichloride is 100: 1; the feeding amount molar ratio of the brominated compound to the N-bromosuccinimide is 1: 0.5 to 1.2; the mass ratio of the potassium iodide to the iodine is 10: 0.045; the mixed solvent is tetrahydrofuran and 1, 2-dibromoethane; the feeding volume ratio of the tetrahydrofuran to the 1, 2-dibromoethane is 2: 1.
the invention adopts the following technical scheme for solving the technical problems, and the thiazole medicine molecule for hospital and gynecology and the preparation method thereof are characterized by comprising the following specific steps:
the technical advantages are as follows: the thiazole drug molecule with a novel structure is designed and synthesized, biphenyl has lipophilicity, and hydrazine amide has hydrophilicity, so the drug molecule has good organism permeability; the invention completes two alkylation reactions by using the cheap calcium catalyst and the common nickel catalyst respectively, and has the advantages of high reaction yield and simple operation; the thiazole drug molecule obtained by the invention has good inhibition effect on the cervical cancer cell Hela.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 2-amino-6-hydroxybenzothiazole prepared in example 1;
FIG. 2 is a nuclear magnetic hydrogen spectrum of 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazol-2-amine prepared in example 4;
FIG. 3 is a nuclear magnetic hydrogen spectrum of the objective compound produced in example 12.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
Adding 180mL of toluene into a 500mL reaction bottle with a water separator, adding 25g of 2-iodine-4-methoxyphenol and 2.5g of palladium/calcium carbonate (the palladium content is 5 percent), slowly heating to reflux under the protection of argon, removing water in a reaction system through the water separator, separating out 30mL of a mixed solution of toluene and water after 50min, cooling to 50 ℃, quickly adding 15g of thiourea, keeping the argon protection state,stirring and reacting for 30min at 50 ℃, observing that the solution is light yellow, then heating to reflux, removing water generated in a reaction system in time, controlling the amount of the removed toluene to be 50mL, keeping the reaction for 1.5h under the reflux state, monitoring the complete reaction of the raw materials by TLC, enabling the reaction solution to be dark red, then reducing the temperature to 50 ℃, filtering the reaction solution while the reaction solution is hot, recovering a catalyst palladium/calcium carbonate, then removing the toluene in a vacuum manner, adding 100mL of saturated solution of sodium chloride into the reaction solution after concentration, extracting the reaction solution for four times by using 50mL of chloroform, merging organic phases, concentrating, adding the concentrate into 150mL of tetrahydrofuran, and stirring uniformly under the protection of argon; then, 13g of anhydrous lithium bromide is quickly added, after stirring for a few minutes, the temperature is slowly raised to 60 ℃, and white solids are gradually separated out from the reaction system; keeping the temperature and stirring for 1.5h, generating a large amount of solid, stopping heating, cooling to room temperature, adding 80mL of water, stirring for 20min, carrying out reduced pressure rotary evaporation under vacuum conditions to remove most of tetrahydrofuran, adding 60mL of dichloromethane, adjusting the pH of a reaction solution to 4 by using dilute hydrochloric acid under room temperature stirring, separating out an organic phase, extracting a water phase by using dichloromethane for multiple times, combining the organic phases, drying the organic phase by using anhydrous magnesium sulfate, concentrating, and finally carrying out silica gel column chromatography to obtain 13.9g of 2-amino-6-hydroxybenzothiazole;1H NMR(400MHZ,DMSO-d6)δ9.09(s,1H),7.13(d,J＝12.0Hz,1H),7.09(s,2H),7.03(d,J＝4.0Hz,1H),6.65(dd,J1＝4.0Hz,J2＝4.0Hz,1H)。
example 2
Adding 180mL of toluene into a 500mL reaction bottle with a water separator, adding 25g of 2-iodine-4-methoxyphenol and 2.5g of palladium/calcium carbonate (the palladium content is 5%) (recovering for the first time), slowly heating to reflux under the protection of argon, removing water in a reaction system through the water separator, separating out about 30mL of a toluene and water mixed solution after 50min, cooling to 50 ℃, quickly adding 15g of thiourea, keeping the argon protection state, stirring and reacting at 50 ℃ for 30min, observing that the solution is light yellow, heating to reflux, removing the water generated in the reaction system in time, controlling the amount of the removed toluene to be 50mL, keeping the reaction for 3.5h under the reflux state, and monitoring by TLC that the raw material reaction is completely carried outReducing the temperature to 50 ℃, filtering the reaction solution while the reaction solution is hot, recovering the catalyst palladium/calcium carbonate again, removing toluene in vacuum, adding 100mL of saturated sodium chloride solution into the reaction solution after concentration, extracting the reaction solution for four times by using 50mL of chloroform, merging organic phases, concentrating, adding the concentrate into 150mL of tetrahydrofuran, and stirring uniformly under the protection of argon; then, 13g of anhydrous lithium bromide is quickly added, after stirring for a few minutes, the temperature is slowly raised to 60 ℃, and white solids are gradually separated out from the reaction system; keeping the temperature and stirring for 1.5h, generating a large amount of solid, stopping heating, cooling to room temperature, adding 80mL of water, stirring for 20min, carrying out reduced pressure rotary evaporation under vacuum conditions to remove most of tetrahydrofuran, adding 60mL of dichloromethane, adjusting the pH of a reaction solution to 4 by using dilute hydrochloric acid under room temperature stirring, separating out an organic phase, extracting a water phase by using dichloromethane for multiple times, combining the organic phases, drying the organic phase by using anhydrous magnesium sulfate, concentrating, and finally carrying out silica gel column chromatography to obtain 11.4g of 2-amino-6-hydroxybenzothiazole;1H NMR(400MHZ,DMSO-d6)δ9.09(s,1H),7.13(d,J＝12.0Hz,1H),7.09(s,2H),7.03(d,J＝4.0Hz,1H),6.65(dd,J1＝4.0Hz,J2＝4.0Hz,1H)。
example 3
Adding 180mL of toluene into a 500mL reaction bottle with a water separator, adding 25g of 2-iodine-4-methoxyphenol and 2.5g of palladium/calcium carbonate (palladium content is 5 percent) into the reaction bottle, slowly heating the mixture to reflux under the protection of argon, removing water in a reaction system through the water separator, separating out about 30mL of a mixed solution of the toluene and the water after 50min, cooling the mixed solution to 50 ℃, quickly adding 11.3g of thiourea, keeping the argon protection state, stirring the mixed solution at 50 ℃ for reaction for 30min, observing that the solution is light yellow, heating the mixed solution to reflux, removing the water generated in the reaction system in time, controlling the amount of the removed toluene to be 50mL, keeping the reaction for about 1.5h under the reflux state, monitoring by TLC that the raw materials are completely reacted, enabling the reaction solution to be dark red, then reducing the temperature to 50 ℃, filtering the reaction solution while the reaction solution is hot, and recovering the catalyst palladium/calcium, then toluene is removed in vacuum, 100mL of saturated solution of sodium chloride is added into the reaction solution after concentration, 50mL of chloroform is used for extracting the reaction solution for four times, and the reaction solution is combinedConcentrating the organic phase, adding the concentrate into 150mL of tetrahydrofuran, and stirring uniformly under the protection of argon; then, 13g of anhydrous lithium bromide is quickly added, after stirring for a few minutes, the temperature is slowly raised to 60 ℃, and white solids are gradually separated out from the reaction system; keeping the temperature and stirring for 1.5h, generating a large amount of solid, stopping heating, cooling to room temperature, adding 80mL of water, stirring for 20min, carrying out reduced pressure rotary evaporation under vacuum conditions to remove most of tetrahydrofuran, adding 60mL of dichloromethane, adjusting the pH of a reaction solution to 4 by using dilute hydrochloric acid under room temperature stirring, separating out an organic phase, extracting a water phase by using dichloromethane for multiple times, combining the organic phases, drying the organic phase by using anhydrous magnesium sulfate, concentrating, and finally carrying out silica gel column chromatography to obtain 9.2g of 2-amino-6-hydroxybenzothiazole;1H NMR(400MHZ,DMSO-d6)δ9.09(s,1H),7.13(d,J＝12.0Hz,1H),7.09(s,2H),7.03(d,J＝4.0Hz,1H),6.65(dd,J1＝4.0Hz,J2＝4.0Hz,1H)。
example 4
Adding 17g of 2-amino-6-hydroxybenzothiazole and 10g of triethylamine into 200mL of acetone in a reaction bottle, slowly dropwise adding 150mL of acetone solution dissolved with 25g of bromomethyl biphenyl at room temperature, gradually heating to reflux after dropwise adding, continuing to react for 4h, concentrating the reaction solution, pouring into 200mL of water, adjusting the pH of the reaction solution to be neutral by using dilute hydrochloric acid, evaporating the solvent acetone under vacuum condition, extracting the reaction solution for multiple times by using 50mL of dichloromethane, combining organic phases, and concentrating to obtain 6- ([1, 1' -biphenyl)]-3 yl-methoxy) -benzo [ d]27g of thiazol-2-amine;1H NMR(400MHZ,DMSO-d6)δ7.79(s,1H),7.73(d,J＝8.0Hz,2H),7.68(d,J＝8.0Hz,1H),7.57-7.50(m,4H),7.44(dd,J1＝4.0Hz,J2＝4.0Hz,2H),7.30(t,J1＝12.0Hz,J2＝4.0Hz,3H),7.00(dd,J1＝4.0Hz,J2＝4.0Hz,1H),5.22(s,2H)。
example 5
In a reaction bottle, 2-amino-6-hydroxybenzeneAdding 17g of benzothiazole and 14g of potassium carbonate into 200mL of acetone, slowly and dropwise adding 150mL of acetone solution dissolved with 25g of bromomethylbiphenyl into the mixture at room temperature, gradually heating to reflux after dropwise adding, continuing to react for 1.5h, concentrating the reaction solution, pouring the reaction solution into 200mL of water, adjusting the pH of the reaction solution to be neutral by using dilute hydrochloric acid, evaporating the solvent acetone under vacuum condition, extracting the reaction solution for multiple times by using 50mL of dichloromethane, combining organic phases, and concentrating to obtain 6- ([1, 1' -biphenyl)]-3 yl-methoxy) -benzo [ d]24.8g of thiazol-2-amine;1H NMR(400MHZ,DMSO-d6)δ7.79(s,1H),7.73(d,J＝8.0Hz,2H),7.68(d,J＝8.0Hz,1H),7.57-7.50(m,4H),7.44(dd,J1＝4.0Hz,J2＝4.0Hz,2H),7.30(t,J1＝12.0Hz,J2＝4.0Hz,3H),7.00(dd,J1＝4.0Hz,J2＝4.0Hz,1H),5.22(s,2H)。
example 6
Adding 17g of 2-amino-6-hydroxybenzothiazole and 20g of potassium carbonate into 200mL of acetone in a reaction bottle, slowly dropwise adding 150mL of acetone solution dissolved with 25g of bromomethyl biphenyl at room temperature, gradually heating to reflux after dropwise adding, continuing to react for 1h, concentrating the reaction solution, pouring into 200mL of water, adjusting the pH of the reaction solution to be neutral by using dilute hydrochloric acid, evaporating the solvent acetone under vacuum condition, extracting the reaction solution for multiple times by using 50mL of dichloromethane, combining organic phases, and concentrating to obtain 6- ([1, 1' -biphenyl)]-3 yl-methoxy) -benzo [ d]29.6g of thiazol-2-amine;1H NMR(400MHZ,DMSO-d6)δ7.79(s,1H),7.73(d,J＝8.0Hz,2H),7.68(d,J＝8.0Hz,1H),7.57-7.50(m,4H),7.44(dd,J1＝4.0Hz,J2＝4.0Hz,2H),7.30(t,J1＝12.0Hz,J2＝4.0Hz,3H),7.00(dd,J1＝4.0Hz,J2＝4.0Hz,1H),5.22(s,2H)。
example 7
In a multi-mouth reaction bottle with stirring, 6- ([1, 1' -biphenyl ] is added]-3 yl-methoxy) -benzo [ d]33g of thiazol-2-amine and 10g of calcium carbonate were added to chloroformHeating to reflux in 200mL, completely dissolving the raw material, partially dissolving calcium carbonate, stirring for 2h, filtering the reaction solution while the solution is hot, then adding 5.5g of calcium oxide into the reaction solution, heating to 40 ℃ again, slowly dropwise adding 70mL of chloroform solution dissolved with 18g of dipropyl sulfate under the protection of nitrogen, heating to reflux after dropwise adding, reacting for 5h, monitoring the complete reaction of the raw material by TLC, cooling the reaction solution to room temperature, adding 200mL of water into the reaction solution, stirring for 30min, separating out an organic phase, drying the organic phase for 20min by using 50g of anhydrous magnesium sulfate, filtering, and concentrating to obtain N-propyl 6- ([1, 1' -diphenyl-ether)]-3 yl-methoxy) -benzo [ d]31.7g of thiazole-2-imine;1H NMR(400MHZ,CDCl3)δ7.83(s,1H),7.76-7.73(m,2H),7.65(d,J＝16.0Hz,1H),7.61-7.57(m,2H),7.55-7.52(m,2H),7.45(d,J＝8.0Hz,2H),7.33-7.29(m,1H),6.98(dd,J1＝4.0Hz,J2＝4.0Hz,1H),5.26(s,2H),4.39(d,J＝8.0Hz,2H),1.89-1.86(m,2H),1.07(t,J1＝8.0Hz,J2＝8.0Hz,3H)。
example 8
In a multi-mouth reaction bottle with stirring, 6- ([1, 1' -biphenyl ] is added]-3 yl-methoxy) -benzo [ d]Adding 33g of thiazole-2-amine and 10g of calcium carbonate into 200mL of chloroform, heating to reflux, completely dissolving the raw materials, partially dissolving the calcium carbonate, filtering the reaction solution while the solution is hot after stirring for 2 hours, then adding 2.8g of calcium oxide into the reaction solution, heating to 40 ℃ again, slowly dropwise adding 70mL of a chloroform solution dissolved with 18g of dipropyl sulfate under the protection of nitrogen, heating to reflux after dropwise adding, cooling the reaction solution to room temperature after reaction for 9 hours, adding 200mL of water into the reaction solution, stirring for 30 minutes, separating out an organic phase, drying the organic phase for 20 minutes by using 50g of anhydrous magnesium sulfate, filtering, concentrating, and separating by silica gel column chromatography to obtain N-propyl 6- ([1, 1' -diphenyl)]-3 yl-methoxy) -benzo [ d]22.5g of thiazole-2-imine;1H NMR(400MHZ,CDCl3)δ7.83(s,1H),7.76-7.73(m,2H),7.65(d,J＝16.0Hz,1H),7.61-7.57(m,2H),7.55-7.52(m,2H),7.45(d,J＝8.0Hz,2H),7.33-7.29(m,1H),6.98(dd,J1＝4.0Hz,J2＝4.0Hz,1H),5.26(s,2H),4.39(d,J＝8.0Hz,2H),1.89-1.86(m,2H),1.07(t,J1＝8.0Hz,J2＝8.0Hz,3H)。
example 9
In a multi-mouth reaction bottle with stirring, 6- ([1, 1' -biphenyl ] is added]-3 yl-methoxy) -benzo [ d]Adding 33g of thiazole-2-amine and 10g of calcium carbonate into 200mL of chloroform, heating to reflux, completely dissolving raw materials, partially dissolving the calcium carbonate, filtering the reaction solution while the solution is hot after stirring for 2 hours, then adding 6.6g of calcium oxide into the reaction solution, heating to 40 ℃ again, slowly dropwise adding 70mL of a chloroform solution dissolved with 20g of dipropyl sulfate under the protection of nitrogen, heating to reflux after dropwise adding, monitoring the complete reaction of the raw materials by TLC after reacting for 4 hours, cooling the reaction solution to room temperature, adding 200mL of water into the reaction solution, stirring for 30 minutes, separating out an organic phase, drying the organic phase for 20 minutes by using 50g of anhydrous magnesium sulfate, filtering, and concentrating to obtain N-propyl 6- ([1, 1' -biphenyl)]-3 yl-methoxy) -benzo [ d]29.3g of thiazole-2-imine;1H NMR(400MHZ,CDCl3)δ7.83(s,1H),7.76-7.73(m,2H),7.65(d,J＝16.0Hz,1H),7.61-7.57(m,2H),7.55-7.52(m,2H),7.45(d,J＝8.0Hz,2H),7.33-7.29(m,1H),6.98(dd,J1＝4.0Hz,J2＝4.0Hz,1H),5.26(s,2H),4.39(d,J＝8.0Hz,2H),1.89-1.86(m,2H),1.07(t,J1＝8.0Hz,J2＝8.0Hz,3H)。
example 10
In a high-pressure reaction kettle, adding N-propyl 6- ([1, 1' -biphenyl)]-3 yl-methoxy) -benzo [ d]Adding 38g of thiazole-2-imine and 6g of propylamine into 150mL of N, N-dimethylformamide, adding 25g of 65% hydrazine hydrate, closing a high-pressure reaction kettle, checking the sealing condition, removing air in the reaction kettle through vacuum, stirring for 30min at room temperature, introducing ammonia gas into the reaction kettle, slowly heating to 80 ℃, keeping the pressure of the reaction kettle at 0.12MPa, reducing the pressure of the reaction kettle after 20min of reaction, continuously introducing ammonia gas to keep the pressure in the reaction kettle at more than 0.1MPa, continuously reacting for 1.5h, keeping the pressure in the reaction kettle at more than 0.05MPa, continuously reacting for 1h, sampling TLC (thin-layer chromatography) to monitor the complete reaction of raw materials, reducing the temperature to room temperature, and extracting the raw materials in the reaction kettle under the vacuum condition without reactionCooling the reacted alkaline gas to 10 ℃, slowly dropwise adding dilute hydrochloric acid to adjust the pH of the reaction solution to be alkalescent (about pH 9), then adding 500mL of saturated sodium chloride solution, extracting the reaction solution for multiple times by using 100mL of ethyl acetate, merging organic phases, drying and concentrating to obtain N-propyl 6- ([1, 1' -biphenyl)]-3 yl-methoxy) -benzo [ d]35g of thiazole hydrazone; HR-MS (ESI)+)m/z：390.5128[M+H]+。
Example 11
In a multi-mouth reaction bottle with stirring, the product is called N-propyl 6- ([1, 1' -biphenyl)]-3 yl-methoxy) -benzo [ d]Adding 40g of thiazole hydrazone into a bottle, replacing the thiazole hydrazone with nitrogen for three times, dissolving the thiazole hydrazone with 180mL of dry dichloromethane under the protection of nitrogen, placing the system at 10 ℃ and dropwise adding 50mL of dichloromethane solution in which 19g of bromoacetyl chloride is dissolved, after the dropwise addition, finding that the system is obviously turbid, gradually returning to the room temperature, finishing TLC detection reaction, adding 160mL of saturated sodium bicarbonate solution into the reaction solution, separating out an organic phase, extracting an aqueous phase with dichloromethane, combining the organic phases, concentrating, and separating and purifying by silica gel column chromatography (V petroleum ether: V ethyl acetate 1:1) to obtain 42.7g of a brominated compound; HR-MS (ESI)+)m/z：511.4517[M+H]+。
Example 12
Under the protection of nitrogen, putting 4.8g of magnesium powder, 3.3g of potassium iodide and 0.015g of iodine into a three-mouth reaction bottle, adding 100mL of tetrahydrofuran and 50mL of 1, 2-dibromoethane which are completely dehydrated, slightly heating to 40 ℃ to initiate reaction, slowly dropwise adding 300mL of tetrahydrofuran solution dissolved with 50g of bromo-compound, heating to 60 ℃ to react for 12h, cooling to room temperature, then adding 18g of N-bromosuccinimide and 0.5g of 1, 3-bis (diphenylphosphinopropane) nickel dichloride, vacuumizing, and then replacing with nitrogen for at least 3 times to ensure that the reaction system is completely in the nitrogen atmosphere,then stirring and reacting at room temperature, monitoring by TLC that the raw materials are completely reacted, adding 300mL of saturated sodium chloride solution into the reaction solution, completely removing 200mL of tetrahydrofuran as a solvent under a vacuum condition, extracting the reaction system for 5 times by using 100mL of ethyl acetate, collecting an organic phase, drying by using anhydrous magnesium sulfate, and finally separating by silica gel column chromatography to obtain 33.1g of a target compound;1H NMR(400MHZ,CDCl3)δ7.68(s,1H),7.59(dd,J1＝8.0Hz,J2＝4.0Hz,4H),7.48-7.43(m,4H),7.37(t,J1＝8.0Hz,J2＝4.0Hz,2H),7.14(d,J＝8.0Hz,1H),5.18(s,2H),3.54-3.52(m,2H),2.76(d,J＝8.0Hz,1H),1.28-1.25(m,2H),1.17(t,J1＝8.0Hz,J2＝4.0Hz,3H)；HR-MS(ESI+)m/z：430.5329[M+H]+。
example 13
Under the protection of nitrogen, putting 4.8g of magnesium powder, 3.3g of potassium iodide and 0.015g of iodine into a three-mouth reaction bottle, adding 100mL of tetrahydrofuran and 50mL of 1, 2-dibromoethane which are completely dehydrated, slightly heating to 40 ℃ to initiate reaction, slowly dropwise adding 300mL of tetrahydrofuran solution dissolved with 50g of bromo-compound, heating to 60 ℃ to react for 12 hours, cooling to room temperature, then adding 9g of N-bromosuccinimide and 0.5g of 1, 3-bis (diphenylphosphinopropane) nickel dichloride, vacuumizing, replacing with nitrogen for at least 3 times to ensure that the reaction system is completely in the nitrogen atmosphere, stirring and reacting at room temperature, monitoring the reaction of raw materials by TLC, adding 300mL of saturated sodium chloride solution into the reaction solution, completely removing 200mL of tetrahydrofuran solvent under the vacuum condition, extracting the reaction system for 5 times by using 100mL of ethyl acetate, collecting an organic phase, and drying by using anhydrous magnesium sulfate, finally, the target compound 21.4g is obtained by silica gel column chromatography separation;1H NMR(400MHZ,CDCl3)δ7.68(s,1H),7.59(dd,J1＝8.0Hz,J2＝4.0Hz,4H),7.48-7.43(m,4H),7.37(t,J1＝8.0Hz,J2＝4.0Hz,2H),7.14(d,J＝8.0Hz,1H),5.18(s,2H),3.54-3.52(m,2H),2.76(d,J＝8.0Hz,1H),1.28-1.25(m,2H),1.17(t,J1＝8.0Hz,J2＝4.0Hz,3H)；HR-MS(ESI+)m/z：430.5329[M+H]+。
example 14
Under the protection of nitrogen, putting 4.8g of magnesium powder, 3.3g of potassium iodide and 0.015g of iodine into a three-mouth reaction bottle, adding 100mL of tetrahydrofuran and 50mL of 1, 2-dibromoethane which are completely dehydrated, slightly heating to 40 ℃ to initiate reaction, slowly dropwise adding 300mL of tetrahydrofuran solution dissolved with 50g of bromo-compound, heating to 60 ℃ to react for 12 hours, cooling to room temperature, then adding 21.5g of N-bromosuccinimide and 0.5g of 1, 3-bis (diphenylphosphinopropane) nickel dichloride, vacuumizing, replacing with nitrogen for at least 3 times to ensure that the reaction system is completely in nitrogen atmosphere, stirring and reacting at room temperature, monitoring the reaction of raw materials by TLC, adding 300mL of saturated sodium chloride solution into the reaction solution, completely removing 200mL of tetrahydrofuran solvent under vacuum condition, extracting the reaction system for 5 times with 100mL of ethyl acetate, collecting an organic phase, and drying with anhydrous magnesium sulfate, finally, separating by silica gel column chromatography to obtain 28.3g of a target compound;1H NMR(400MHZ,CDCl3)δ7.68(s,1H),7.59(dd,J1＝8.0Hz,J2＝4.0Hz,4H),7.48-7.43(m,4H),7.37(t,J1＝8.0Hz,J2＝4.0Hz,2H),7.14(d,J＝8.0Hz,1H),5.18(s,2H),3.54-3.52(m,2H),2.76(d,J＝8.0Hz,1H),1.28-1.25(m,2H),1.17(t,J1＝8.0Hz,J2＝4.0Hz,3H)；HR-MS(ESI+)m/z：430.5329[M+H]+。
example 15
From CO2And taking out cell culture flasks of the cervical cancer cell Hela, the lung cancer cell A549 and the lung cancer cell H1985 from the incubator, and respectively carrying out the following operations: unscrewing a bottle cap, pouring out a culture solution into a waste liquid cylinder, performing aseptic operation beside an alcohol lamp, washing the culture solution in a culture bottle twice by using 2mL PBS, digesting by using 0.25% trypsin, stopping digestion when observing that the cell gap is increased and the cell becomes a small circle shape, blowing the bottom of the culture bottle by using a liquid transfer gun to enable the cell to fall off, transferring the obtained cell suspension into an aseptic centrifuge tube, setting a centrifuge at 800r/min for 3min, centrifuging, slowly pouring a supernatant in the centrifuge tube, adding 2-5 mL culture solution, and counting the cells under an inverted microscope. According to the counting result, the obtained product is prepared into 5X 10 culture solution4cells/mL of single cell suspension, then seeded in 96-well plates, and 100 μ L per well. The 96-well plate was placed at 37 ℃ in 5% CO2Culturing in an incubator for 24 h.
Thiazole drug molecules were formulated to the desired concentrations: 0.16. mu. mol/L, 0.8. mu. mol/L, 4.0. mu. mol/L, 20.0. mu. mol/L, 100. mu. mol/L. From CO2The 96-well plate is taken out from the incubator, 100 mu L of drug-containing culture medium is added into each well, and 3 multiple wells are simultaneously arranged for each concentration of drug. As a blank well, an equal volume of the corresponding culture medium was added. Placing it at 37 ℃ and 5% CO2Culturing for 72h in an incubator. Docetaxel was used as a positive control in this experiment, and each drug was run in triplicate using the same batch of cells at different passage numbers. After 72 hours, 20. mu.L of MTT solution (5 mg/mL) was added to each well in the dark, and CO addition was continued2Culturing for 4h in an incubator, absorbing supernatant by using a pipette gun, adding 150 mu L DMSO into each hole, placing a shaking table for 5min to mix uniformly, measuring the absorbance OD value of the mixture at the wavelength of 562nm by using a microplate reader, and calculating the cell proliferation inhibition rate by the following method: inhibition rate of cell proliferation [ OD ]Control-ODExperiment of]/ODControlX is 100%; the tested target compound has the inhibition rate IC on Hela cells and A549 and H1985 cells50Respectively reaches 0.47 mu mol/L, 2.96 mu mol/L and 14.38 mu mol/L, and the thiazole drug molecules found by the inventor have good inhibition effect on Hela cells and certain inhibition effect on A549 cells.
The foregoing embodiments illustrate the principles, principal features and advantages of the invention, and it will be understood by those skilled in the art that the invention is not limited to the foregoing embodiments, which are merely illustrative of the principles of the invention, and that various changes and modifications may be made therein without departing from the scope of the principles of the invention.
Claims (9)
1. A thiazole medicine molecule used in hospital and gynecology and a preparation method and application thereof are characterized in that the structure of the benzothiazole compound is as follows:
2. a thiazole drug molecule according to claim 1, which is prepared by the following steps:
(1) adding a certain amount of toluene solvent into a reaction bottle with a water separator, adding a certain amount of 2-iodine-4-methoxyphenol and palladium/calcium carbonate (the palladium content is 5 percent), slowly heating to reflux under the protection of argon, removing water in a reaction system through the water separator, reacting for a period of time, cooling to 50 ℃, quickly adding a certain amount of thiourea, keeping the state of argon protection, stirring and reacting for a period of time at 50 ℃, observing that the solution is light yellow, heating to reflux, removing the water generated in the reaction system in time, keeping the reaction under the reflux state until the raw materials react completely, allowing the reaction solution to be dark red, reducing the temperature to 50 ℃, filtering the reaction solution while hot, recovering the catalyst palladium/calcium carbonate, removing the toluene in a vacuum manner, concentrating, adding a sodium chloride saturated solution into the reaction solution, and stirring uniformly, extracting the reaction solution with chloroform for multiple times, mixing organic phases, concentrating, adding the concentrate into tetrahydrofuran, and stirring under argon protection; then rapidly adding anhydrous lithium bromide, stirring uniformly, slowly raising the temperature to 60 ℃, gradually precipitating white solids in a reaction system, stopping heating after the reaction is finished, cooling to room temperature, adding water, stirring for a period of time, carrying out reduced pressure rotary evaporation under a vacuum condition to remove most tetrahydrofuran, adding a certain amount of dichloromethane, adjusting the pH of a reaction solution to 4 by using dilute hydrochloric acid under room temperature stirring, separating out an organic phase, extracting a water phase by using dichloromethane for multiple times, combining the organic phases, drying the organic phase by using anhydrous magnesium sulfate, concentrating, and finally carrying out silica gel column chromatography separation to obtain 2-amino-6-hydroxybenzothiazole;
(2) adding a certain amount of 2-amino-6-hydroxybenzothiazole and an alkaline compound into acetone, slowly dropwise adding an acetone solution in which bromomethylbiphenyl is dissolved at room temperature, gradually heating to reflux after dropwise adding, continuously reacting until raw materials react completely, concentrating the reaction liquid, then pouring into water, adjusting the pH of the reaction liquid to be neutral by using dilute hydrochloric acid, evaporating to remove the acetone solvent under a vacuum condition, extracting the reaction liquid for multiple times by using dichloromethane, combining organic phases, and concentrating to obtain 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole-2-amine;
(3) adding a certain amount of 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole-2-amine and calcium carbonate into chloroform, heating to reflux, dissolving the raw materials completely, dissolving calcium carbonate partially, stirring for a period of time, filtering the reaction solution while the solution is hot, adding a certain amount of calcium oxide into the reaction solution, heating to 40 deg.C again, under the protection of nitrogen, slowly dropwise adding a chloroform solution dissolved with dipropyl sulfate, heating to reflux after dropwise adding, reacting until the raw materials completely react, cooling the reaction liquid to room temperature, adding water into the reaction liquid, stirring for a period of time, separating out an organic phase, drying the organic phase with anhydrous magnesium sulfate, performing suction filtration, and concentrating to obtain N-propyl 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole-2-imine;
(4) adding a certain amount of N-propyl 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole-2-imine and propylamine into N, N-dimethylformamide in a high-pressure reaction kettle, adding a certain amount of hydrazine hydrate with the content of 65%, closing the high-pressure reaction kettle, checking the sealing condition, then removing the air in the reaction kettle by vacuum, introducing ammonia gas into the reaction kettle after stirring for a period of time at room temperature, slowly heating to a certain temperature, keeping the pressure in the reaction kettle at 0.12MPa, reducing the pressure in the reaction kettle after reacting for a period of time, continuously introducing ammonia gas to keep the pressure in the reaction kettle at more than 0.1MPa, keeping the pressure in the reaction kettle at more than 0.05MPa for a continuous period of time, reducing to the room temperature after the reaction is finished, extracting unreacted alkaline gas in the reaction kettle under the vacuum condition, then cooling to 10 ℃, slowly dropwise adding dilute hydrochloric acid to adjust the pH of the reaction solution to be alkalescent (the pH is about 9), then adding saturated sodium chloride solution for washing, extracting the reaction solution for multiple times by using ethyl acetate, combining organic phases, drying and concentrating to obtain N-propyl 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole hydrazone;
(5) adding a certain amount of N-propyl 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole hydrazone into a reaction bottle, replacing the mixture with nitrogen for three times, dissolving the mixture with dry dichloromethane under the protection of nitrogen, dropwise adding a dichloromethane solution in which bromoacetyl chloride is dissolved into the system at 10 ℃, after dropwise adding, finding that obvious turbidity appears in the system, gradually returning to room temperature, detecting by TLC (thin layer chromatography), finishing the reaction, adding a saturated sodium bicarbonate solution into the reaction solution, separating out an organic phase, extracting a water phase with dichloromethane, combining the organic phases, concentrating, and separating and purifying by silica gel column chromatography to obtain a brominated compound;
(6) under the protection of nitrogen, adding a certain amount of magnesium powder, potassium iodide and iodine powder into a reaction bottle, adding into a certain amount of completely dehydrated mixed solvent, slightly heating to 40 deg.C to initiate reaction, slowly dropwise adding tetrahydrofuran solution dissolved with bromo-compound, heating to 60 deg.C for reaction for a period of time, cooling to room temperature, then adding a certain amount of N-bromosuccinimide and 1, 3-bis (diphenylphosphinopropane) nickel dichloride, vacuumizing, replacing with nitrogen for many times to ensure that the reaction system is completely in the nitrogen atmosphere, then stirring the mixture for reaction at room temperature, monitoring the reaction of the raw materials by TLC, adding saturated sodium chloride solution into the reaction solution for washing, the solvent tetrahydrofuran is removed completely under vacuum condition, the reaction system is extracted for a plurality of times by ethyl acetate, the organic phase is collected and dried by anhydrous magnesium sulfate, and finally the target compound is obtained by silica gel column chromatography separation.
3. The preparation method of thiazole medicine molecules for hospital and gynecology according to claim 2, wherein the feeding amount mass ratio of the 2-iodo-4-methoxyphenol to the palladium/calcium carbonate in the step (1) is 10: 1 to 1.2; the catalyst palladium/calcium carbonate can be recycled for many times; the feeding amount molar ratio of the 2-iodine-4-methoxyphenol to the thiourea is 1: 1.5-2; the feeding amount molar ratio of the 2-iodine-4-methoxyphenol to the anhydrous lithium bromide is 1: 1.2 to 1.5.
4. The method for preparing thiazole drug molecules for hospital and gynecology according to claim 2, wherein the basic compound in step (2) is triethylamine or potassium carbonate; the feeding amount molar ratio of the 2-amino-6-hydroxybenzothiazole to the alkaline compound is 1:1 to 1.5; the feeding amount molar ratio of the 2-amino-6-hydroxybenzothiazole to the bromomethyl biphenyl is 1:1 to 1.1.
5. The method for preparing thiazole medicine molecules for hospital gynecology according to claim 2, wherein the feeding amount molar ratio of the 6- ([1, 1' -biphenyl ] -3 yl-methoxy) -benzo [ d ] thiazol-2-amine to the calcium oxide and the dipropyl sulfate in the step (3) is 1: 0.5-1.2: 1 to 1.1.
6. The method for preparing thiazole medicine molecules for hospital gynecology according to claim 2, wherein the molar ratio of the N-propyl 6- ([1, 1' -biphenyl ] -3-yl-methoxy) -benzo [ d ] thiazole-2-imine to the input amount of propylamine to hydrazine hydrate in step (4) is 1: 1-1.1: 3 to 3.5; the reaction temperature was 80 ℃.
7. The preparation method of thiazole medicine molecules for hospital and gynecology according to claim 2, wherein the molar ratio of the N-propyl 6- ([1, 1' -biphenyl ] -3 yl-methoxy) -benzo [ d ] thiazole hydrazone to the bromoacetyl chloride in the feeding amount in the step (5) is 1:1 to 1.2.
8. The method for preparing thiazole medicine molecules for hospital and gynecology according to claim 2, wherein the molar ratio of the magnesium powder to the potassium iodide to the brominated compounds in step (6) is 2: 0.2: 1; the feeding amount molar ratio of the brominated compound to the 1, 3-bis (diphenylphosphinopropane) nickel dichloride is 100: 1; the feeding amount molar ratio of the brominated compound to the N-bromosuccinimide is 1: 0.5 to 1.2; the mass ratio of the potassium iodide to the iodine is 10: 0.045; the mixed solvent is tetrahydrofuran and 1, 2-dibromoethane; the feeding volume ratio of the tetrahydrofuran to the 1, 2-dibromoethane is 2: 1.
9. the thiazole molecules of claim 1 for their anti-tumor activity.
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| HUE054822T2 (en) * | 2017-02-23 | 2021-10-28 | Fujian Cosunter Pharmaceutical Co Ltd | Tri-cycle compound and applications thereof |
| CN107903244B (en) * | 2017-11-29 | 2019-06-14 | 武汉珈创生物技术股份有限公司 | 2- amido with anti-tumor activity replaces Benzodiazepine compound and preparation method thereof |
| CN107759606B (en) * | 2017-11-29 | 2018-12-21 | 南京诺希生物科技有限公司 | Azepine cycloolefin with anti-tumor activity and phenodiazine Zhuo drug molecule and preparation method thereof |
-
2019
- 2019-06-05 CN CN201910485061.4A patent/CN110172068A/en active Pending
- 2019-11-28 CN CN201911187181.2A patent/CN110713496A/en not_active Withdrawn
- 2019-12-26 CN CN201911366472.8A patent/CN110872307B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN110872307A (en) | 2020-03-10 |
| CN110172068A (en) | 2019-08-27 |
| CN110872307B (en) | 2020-07-10 |
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