CN110938061A - Synthesis of 2- (2-benzofuranyl) -2-quinoxalinecarboxylic acid derivatives - Google Patents
Synthesis of 2- (2-benzofuranyl) -2-quinoxalinecarboxylic acid derivatives Download PDFInfo
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- CN110938061A CN110938061A CN201911178507.5A CN201911178507A CN110938061A CN 110938061 A CN110938061 A CN 110938061A CN 201911178507 A CN201911178507 A CN 201911178507A CN 110938061 A CN110938061 A CN 110938061A
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to the technical field of quinoxalinecarboxylic acid synthesis, in particular to synthesis of a 2- (2-benzofuranyl) -2-quinoxalinecarboxylic acid derivative, which comprises the following steps of dissolving a raw material in acetonitrile, adding anhydrous potassium carbonate, salicylaldehyde and substituted salicylaldehyde thereof, adding PEG-400, performing reflux reaction, adding an ethanol water solution, heating and refluxing, pouring a mixture into water, placing ice blocks for cooling, adjusting the pH value, crystallizing to obtain a compound, performing reflux reaction on the anhydrous potassium carbonate, salicylaldehyde and substituted salicylaldehyde thereof to obtain an intermediate product, acidifying to separate out a solid, performing suction filtration, washing with water, and drying to obtain the 2- (2-benzofuranyl) -2-quinoxalinecarboxylic acid derivative. The preparation method has the advantages of cheap and easily obtained raw materials and reagents, short synthetic route, simple and convenient operation and the like, and preliminary antitumor activity tests show that the novel compounds have good tumor cell inhibitory activity and have important reference significance for developing novel heterocyclic small molecule antitumor medicines.
Description
Technical Field
The invention relates to the technical field of synthesis of quinoxalinecarboxylic acid, in particular to synthesis of a 2- (2-benzofuranyl) -2-quinoxalinecarboxylic acid derivative.
Background
Quinoxaline-2-carboxylic acids are an organic chemical, CAS number: 879-65-2, which is a tan powder in appearance and property, and 3-bromomethyl-2-quinoxalinecarboxylic acid ethyl ester is the above derivative. The tumor is a new organism formed by local tissue cell proliferation under the action of various tumorigenic factors, and the new organism mostly presents space-occupying blocky bulges, also called neoplasms, and researches show that the tumor cells can generate metabolic changes different from normal cells, and can adapt to the change of metabolic environment through the conversion between glycolysis and oxidative phosphorylation. The organic micromolecules containing benzofuran structures widely exist in natural products, are very important oxygen-containing heterocyclic compounds, have various biological and pharmacological activities such as anti-tumor, antibacterial and antiviral activities and the like, and are one of important lead structures in the field of research and development of new drugs.
Reaction sites suitable for modification and reconstruction exist in the 3-bromomethyl-2-quinoxaline ethyl formate, so that a benzofuran ring and quinoxaline-2-carboxylic acid can be constructed in the same molecular structure, and a 2- (2-benzofuranyl) -2-quinoxaline formic acid derivative with anti-tumor activity is synthesized.
Disclosure of Invention
The invention aims to solve the defects in the prior art and provides a synthesis method of a 2- (2-benzofuranyl) -3-quinoxalinecarboxylic acid derivative with antitumor activity.
In order to achieve the purpose, the invention adopts the following technical scheme:
the synthesis of 2- (2-benzofuranyl) -3-quinoxalinecarboxylic acid derivatives comprises the following steps:
s1, dissolving 2-bromomethyl-3-quinoxaline ethyl formate in acetonitrile in a reaction kettle, continuously stirring for 10-15 min, then respectively adding anhydrous potassium carbonate, salicylaldehyde and substituted salicylaldehyde thereof, wherein the mass ratio of the anhydrous potassium carbonate, the salicylaldehyde and the substituted salicylaldehyde thereof is 1:1:2, stirring for 15-20 min, finally adding PEG-400, and carrying out heating reflux reaction through an oil bath kettle;
s2, after the reaction is completed, evaporating acetonitrile in a rotary mode, cooling to room temperature, then adding 60% ethanol water solution dissolved with KOH, and continuing to use an oil bath pot to heat and reflux to obtain a mixture;
and S3, pouring the mixture obtained in the step S2 into water, putting ice blocks into the water for cooling, cooling the mixture to 10-15 ℃, then adjusting the pH value to 3-4 by using 1mol/L hydrochloric acid, continuously stirring the mixture for 1-2 hours until the mixture is completely acidified to separate out solids, performing suction filtration, washing the mixture by using water, and drying the mixture to obtain a crude product, wherein the crude product is recrystallized by using absolute ethyl alcohol to obtain a pure product.
Preferably, in both S1 and S2, the progress of the reaction is monitored by TLC.
Preferably, in the S1, the heating reflux time is 2-4 h, the mass ratio of the 2-bromomethyl-3-quinoxaline ethyl formate to the acetonitrile is 1:2, the mass ratio of the acetonitrile to the anhydrous potassium carbonate is 0.5:1, and the mass ratio of the PEG-400 to the anhydrous potassium carbonate is 1: 1.
Preferably, in S2, the mass ratio of the ethanol aqueous solution to the acetonitrile is 1: 2.
Preferably, in S3, the mixture in S2 is poured into water, ice blocks are added for cooling, then the pH value is adjusted to 3 by using 1mol/L hydrochloric acid, and stirring is continued for 1h until the solid is completely precipitated by acidification.
Preferably, in the S3, the mass ratio of the hydrochloric acid to the acetonitrile is 0.2:1, and the mass ratio of the absolute ethyl alcohol to the hydrochloric acid is 1: 1.
Compared with the prior art, the 2- (2-benzofuranyl) -3-quinoxalinecarboxylic acid derivative with antitumor activity is obtained by carrying out a reaction on the basis of 2-bromomethyl-3-quinoxalinecarboxylic acid ethyl ester, further carrying out anhydrous potassium carbonate, salicylaldehyde and substituted salicylaldehyde thereof, and further carrying out a reflux reaction to obtain an intermediate product in a matching manner, then adjusting the pH value, acidifying to separate out a solid, carrying out suction filtration, washing with water, and drying.
Drawings
FIG. 1 is a flow chart of the synthesis of a 2- (2-benzofuranyl) -3-quinoxalinecarboxylic acid derivative according to the invention;
FIG. 2 is a NMR spectrum of 3a in the present invention;
FIG. 3 is a NMR carbon spectrum of 3a in the present invention;
FIG. 4 is a NMR spectrum of 3b in the present invention;
FIG. 5 is a NMR carbon spectrum of 3b in the present invention;
FIG. 6 is a NMR spectrum of 3c in the present invention;
FIG. 7 is a NMR carbon spectrum of 3c in the present invention;
FIG. 8 is a NMR chart of 3d in the present invention;
FIG. 9 is a NMR carbon spectrum of 3d in accordance with the present invention;
FIG. 10 is a NMR spectrum of 3e in the present invention;
FIG. 11 is a NMR carbon spectrum of 3e in the present invention;
FIG. 12 is a NMR chart of 3f in the present invention;
FIG. 13 is a NMR carbon spectrum of 3f in the present invention;
FIG. 14 is a NMR chart of 3g in the present invention;
FIG. 15 is a NMR carbon spectrum of 3g in the present invention;
FIG. 16 is a NMR spectrum of 3h in accordance with the present invention;
FIG. 17 is a NMR carbon spectrum of 3h in the present invention.
Detailed Description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control. When "mass, concentration, temperature, time, or other value or parameter is expressed as a range, preferred range, or as a range defined by a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. For example, a range of 1 to 50 should be understood to include any number, combination of numbers, or subrange selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, and all fractional values between the above integers, e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, specifically consider "nested sub-ranges" that extend from any endpoint within the range. For example, nested sub-ranges of exemplary ranges 1-50 may include 1-10, 1-20, 1-30, and 1-40 in one direction, or 50-40, 50-30, 50-20, and 50-10 in another direction. "
The present invention will be further illustrated with reference to the following specific examples.
Example one
The invention provides a synthetic method of a 2- (2-benzofuranyl) -3-quinoxalinecarboxylic acid derivative, which comprises the following steps:
s1, dissolving 2-bromomethyl-3-quinoxaline ethyl formate in acetonitrile in a reaction kettle, continuously stirring for 10min, then respectively adding anhydrous potassium carbonate, salicylaldehyde and substituted salicylaldehyde thereof, wherein the mass ratio of the anhydrous potassium carbonate, the salicylaldehyde and the substituted salicylaldehyde thereof is 1:1:2, stirring for 15min, finally adding PEG-400, heating and refluxing the mixture in an oil bath kettle for reaction for 2h, and monitoring the reaction process by TLC;
s2, after the reaction is completed, evaporating acetonitrile in a rotary mode, cooling to room temperature, then adding 60% ethanol water solution dissolved with KOH, continuously heating and refluxing by using an oil bath pot to obtain a mixture, and monitoring the reaction process by TLC;
and S3, pouring the mixture in the S2 into water, adding ice blocks for cooling, cooling to 10 ℃, then adjusting the pH value to 3 by using 1mol/L hydrochloric acid, continuing stirring for 1 hour until the mixture is completely acidified to precipitate solids, performing suction filtration, washing by using water, and drying to obtain a crude product, and recrystallizing the crude product by using absolute ethyl alcohol to obtain a pure product.
Wherein in S1, the mass ratio of ethyl 2-bromomethyl-3-quinoxalinecarboxylate to acetonitrile is 1:2, the mass ratio of acetonitrile to anhydrous potassium carbonate is 0.5:1, the mass ratio of PEG-400 to anhydrous potassium carbonate is 1:1, in S2, the mass ratio of aqueous ethanol to acetonitrile is 1:2, in S3, the mass ratio of hydrochloric acid to acetonitrile is 0.2:1, and the mass ratio of anhydrous ethanol to hydrochloric acid is 1: 1.
Example two
The invention provides a synthetic method of a 2- (2-benzofuranyl) -3-quinoxalinecarboxylic acid derivative with antitumor activity, which comprises the following steps:
s1, dissolving 2-bromomethyl-3-quinoxaline ethyl formate in acetonitrile in a reaction kettle, continuously stirring for 12min, then respectively adding anhydrous potassium carbonate, salicylaldehyde and substituted salicylaldehyde thereof, wherein the mass ratio of the anhydrous potassium carbonate, the salicylaldehyde and the substituted salicylaldehyde thereof is 1:1:2, stirring for 17min, finally adding PEG-400, heating and refluxing the mixture in an oil bath kettle for reaction for 3h, and monitoring the reaction process by TLC;
s2, after the reaction is completed, evaporating acetonitrile in a rotary mode, cooling to room temperature, then adding 60% ethanol water solution dissolved with KOH, continuously heating and refluxing by using an oil bath pot to obtain a mixture, and monitoring the reaction process by TLC;
and S3, pouring the mixture in the S2 into water, adding ice blocks for cooling, cooling to 10-15 ℃, then adjusting the pH value to 3 by using 1mol/L hydrochloric acid, continuing stirring for 1.5 hours until the mixture is completely acidified to separate out solids, performing suction filtration, washing with water, and drying to obtain a crude product, and recrystallizing the crude product by using absolute ethyl alcohol to obtain a pure product.
Wherein in S1, the mass ratio of ethyl 2-bromomethyl-3-quinoxalinecarboxylate to acetonitrile is 1:2, the mass ratio of acetonitrile to anhydrous potassium carbonate is 0.5:1, the mass ratio of PEG-400 to anhydrous potassium carbonate is 1:1, in S2, the mass ratio of aqueous ethanol to acetonitrile is 1:2, in S3, the mass ratio of hydrochloric acid to acetonitrile is 0.2:1, and the mass ratio of anhydrous ethanol to hydrochloric acid is 1: 1.
EXAMPLE III
The invention provides a synthetic method of a 2- (2-benzofuranyl) -3-quinoxalinecarboxylic acid derivative with antitumor activity, which comprises the following steps:
s1, dissolving 2-bromomethyl-3-quinoxaline ethyl formate in acetonitrile in a reaction kettle, continuously stirring for 15min, then respectively adding anhydrous potassium carbonate, salicylaldehyde and substituted salicylaldehyde thereof, wherein the mass ratio of the anhydrous potassium carbonate, the salicylaldehyde and the substituted salicylaldehyde thereof is 1:1:2, stirring for 20min, finally adding PEG-400, heating and refluxing the mixture in an oil bath kettle for reaction for 4h, and monitoring the reaction process by TLC;
s2, after the reaction is completed, evaporating acetonitrile in a rotary mode, cooling to room temperature, then adding 60% ethanol water solution dissolved with KOH, continuously heating and refluxing by using an oil bath pot to obtain a mixture, and monitoring the reaction process by TLC;
and S3, pouring the mixture in the S2 into water, adding ice blocks for cooling, cooling to 15 ℃, then adjusting the pH value to 4 by using 1mol/L hydrochloric acid, continuing stirring for 2 hours until the mixture is completely acidified to precipitate solids, performing suction filtration, washing by using water, and drying to obtain a crude product, and recrystallizing the crude product by using absolute ethyl alcohol to obtain a pure product.
Wherein in S1, the mass ratio of ethyl 2-bromomethyl-3-quinoxalinecarboxylate to acetonitrile is 1:2, the mass ratio of acetonitrile to anhydrous potassium carbonate is 0.5:1, the mass ratio of PEG-400 to anhydrous potassium carbonate is 1:1, in S2, the mass ratio of aqueous ethanol to acetonitrile is 1:2, in S3, the mass ratio of hydrochloric acid to acetonitrile is 0.2:1, and the mass ratio of anhydrous ethanol to hydrochloric acid is 1: 1.
The results of the tests performed in the first to third embodiments are as follows:
TABLE 12 yield and melting Point of (3 b-3 l) quinoxaline-3-carboxylic acid Compounds
Activity of target compound against A549 and HT-29 of tumor cells
Physiological activity test method:
culturing A549 and HT-29 cells in RPMI1640 complete culture solution, culturing at 37 deg.C in 5% CO2 incubator, digesting logarithmic phase cells with pancreatin/EDTA digestive juice, centrifuging, and blowing with complete culture solution to obtain single cell suspension. The concentration was adjusted to 5X 104 cells/mL. Accurately inoculating 100 uL of cell suspension into each hole of a 96-hole plate, culturing for 24 hours, discarding culture solution, adding 100 uL of 5 tested substances with different concentrations into each hole, wherein the final concentration is ug/mL and each concentration is 3 multiple holes. After culturing for 48 or 72 hours, the old solution was discarded, each well was washed with 200. mu.L of physiological saline and discarded, the MTT stock solution was diluted 10 times with the culture solution, 100. mu.L of MTT was added to each well to the final concentration of 0.5 mg/mL, and the culture was continued for 4 hours. Discard old solution, add 100 uLDMSO per well, shake culture plate for 3 min. The absorbance of each well was measured with a microplate reader, the A1 well was zeroed, and the test wavelength was 490, 630 nm. After averaging the OD values of each group, percent inhibition was calculated. IC50 values were calculated using nonlinear regression with GraphPad Prism 6 software.
Cell inhibition = (1-absorbance for experimental group/absorbance for control group) × 100%
Table 2 lists the IC50 values of the target compounds against the activity of a549 and HT29 in tumor cells.
Results of the activity of the compounds of Table 2 against tumor cells A549 and HT29
In conclusion, the invention carries out reaction on the basis of 2-bromomethyl-3-quinoxaline ethyl formate, and further carries out anhydrous potassium carbonate, salicylaldehyde and substituted salicylaldehyde thereof, and further carries out reflux reaction to obtain an intermediate product in a matching way, and then obtains the 2- (2-benzofuranyl) -3-quinoxaline formic acid derivative with antitumor activity by adjusting the pH value, acidifying and separating out a solid, carrying out suction filtration, washing with water and drying.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (6)
- A method for synthesizing a 2- (2-benzofuranyl) -2-quinoxalinecarboxylic acid derivative, comprising the steps of:s1, dissolving 3-bromomethyl-2-quinoxaline ethyl formate in acetonitrile in a reaction kettle, continuously stirring for 10-15 min, then respectively adding anhydrous potassium carbonate, salicylaldehyde and substituted salicylaldehyde thereof, wherein the mass ratio of the anhydrous potassium carbonate, the salicylaldehyde and the substituted salicylaldehyde thereof is 1:1:2, stirring for 15-20 min, finally adding PEG-400, and carrying out heating reflux reaction through an oil bath kettle;s2, after the reaction is completed, evaporating acetonitrile in a rotary mode, cooling to room temperature, then adding 60% ethanol water solution dissolved with KOH, and continuing to use an oil bath pot to heat and reflux to obtain a mixture;and S3, pouring the mixture obtained in the step S2 into water, putting ice blocks into the water for cooling, cooling the mixture to 10-15 ℃, then adjusting the pH value to 3-4 by using 1mol/L hydrochloric acid, continuously stirring the mixture for 1-2 hours until the mixture is completely acidified to separate out solids, performing suction filtration, washing the mixture by using water, and drying the mixture to obtain a crude product, wherein the crude product is recrystallized by using absolute ethyl alcohol to obtain a pure product.
- 2. The method for synthesizing 2- (2-benzofuranyl) -2-quinoxalinecarboxylic acid derivatives according to claim 1, wherein in both of S1 and S2, the progress of the reaction is monitored by TLC.
- 3. The method for synthesizing a 2- (2-benzofuranyl) -2-quinoxalinecarboxylic acid derivative according to claim 1, wherein in S1, the heating reflux time is 2-4 h, the mass ratio of ethyl 3-bromomethyl-2-quinoxalinecarboxylate to acetonitrile is 1:2, the mass ratio of acetonitrile to anhydrous potassium carbonate is 0.5:1, and the mass ratio of PEG-400 to anhydrous potassium carbonate is 1: 1.
- 4. The method for synthesizing 2- (2-benzofuranyl) -2-quinoxalinecarboxylic acid derivatives according to claim 1, wherein the mass ratio of the ethanol aqueous solution to the acetonitrile in S2 is 1: 2.
- 5. The method for synthesizing 2- (2-benzofuranyl) -2-quinoxalinecarboxylic acid derivatives according to claim 1, wherein in S3, the mixture in S2 is poured into water, ice is put into the water for cooling, then 1mol/L hydrochloric acid is used for adjusting the pH value to 3, and stirring is continued for 1h until the acidification is completed to precipitate solids.
- 6. The method for synthesizing 2- (2-benzofuranyl) -2-quinoxalinecarboxylic acid derivatives according to claim 1, wherein in S3, the mass ratio of hydrochloric acid to acetonitrile is 0.2:1, and the mass ratio of absolute ethyl alcohol to hydrochloric acid is 1: 1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102656163A (en) * | 2009-09-03 | 2012-09-05 | 拜奥埃内杰尼克斯公司 | Heterocyclic compounds for the inhibition of PASK |
| CN104817535A (en) * | 2015-03-19 | 2015-08-05 | 广西师范大学 | Quinolinone derivative, and synthetic method and application thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102656163A (en) * | 2009-09-03 | 2012-09-05 | 拜奥埃内杰尼克斯公司 | Heterocyclic compounds for the inhibition of PASK |
| CN104817535A (en) * | 2015-03-19 | 2015-08-05 | 广西师范大学 | Quinolinone derivative, and synthetic method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 孟繁浩等: "《药物化学》", 31 January 2016, 中国医药科技出版社 * |
| 高文涛等: "2-(2-苯并呋喃基)-6-氯-3-喹啉甲酸衍生物的简便合成", 《有机化学》 * |
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