CN113307740A - Preparation method of 2-amino-4-fluorobenzoic acid - Google Patents
Preparation method of 2-amino-4-fluorobenzoic acid Download PDFInfo
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- CN113307740A CN113307740A CN202110583859.XA CN202110583859A CN113307740A CN 113307740 A CN113307740 A CN 113307740A CN 202110583859 A CN202110583859 A CN 202110583859A CN 113307740 A CN113307740 A CN 113307740A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
Abstract
The invention relates to a preparation method of 2-amino-4-fluorobenzoic acid, which comprises the steps of taking 4-fluorobenzyl alcohol which is cheap and easy to obtain as a raw material, carrying out nitration reaction to obtain a nitro substituent, carrying out oxidation reaction on the nitro substituent to obtain a benzoic acid oxide, and finally carrying out reduction reaction on the benzoic acid oxide to finally obtain the 2-amino-4-fluorobenzoic acid with high purity and high yield. The preparation method has the characteristics of cheap and easily obtained raw materials, short reaction route, conventional reaction, mild reaction conditions, high yield and easy industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of 2-amino-4-fluorobenzoic acid.
Background
2-amino-4-fluorobenzoic acid, also known as 4-fluoroanthranilic acid, is an important medical intermediate, is applied to the preparation of various medicaments and is used as a raw material of other important medical intermediates, and is particularly applied to the preparation of second-generation EGFR (epidermal growth factor receptor) targeted new medicament afatinib.
Afatinib is an aniline quinazoline compound, is an irreversible EGFR-HER2 dual tyrosine kinase receptor inhibitor, can irreversibly combine with EGFR-HER2 tyrosine kinase to inhibit the tyrosine kinase activity thereof, further blocks EGFR-HER 2-guided tumor cell signal conduction, inhibits the metastasis and proliferation of tumor cells, and promotes the apoptosis of the tumor cells.
The existing method for synthesizing afatinib has the defects that the intermediate is expensive, and the impurity content of the synthesized final product is high, so that the search for a more economic and practical route for synthesizing afatinib is very necessary.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of 2-amino-4-fluorobenzoic acid, which has the advantages of mild reaction conditions and high product yield. According to the preparation method, 4-fluorobenzyl alcohol which is cheap and easy to obtain is used as a raw material, and the 2-amino-4-fluorobenzoic acid is prepared through three steps of nitration reaction, oxidation and reduction reaction, so that the purity and the yield are high. The preparation method has the characteristics of cheap and easily obtained raw materials, short reaction route, conventional reaction, mild reaction conditions, high yield and easy industrial production.
The technical scheme adopted by the invention is as follows:
a preparation method of 2-amino-4-fluorobenzoic acid comprises the following steps:
(1) adding 4-fluorobenzyl alcohol into concentrated sulfuric acid, cooling, stirring for dissolving, adding a nitration reagent under stirring for reacting after cooling, and obtaining a nitro substituent;
(2) adding the nitro substituent in the step (1) into an organic solvent, adding an oxidant, heating, and reacting under stirring to obtain benzoic acid oxide;
(3) and (3) dissolving the benzoic acid oxide obtained in the step (2) in an organic solvent, and then adding a reducing agent for reaction to obtain a target product 2-amino-4-fluorobenzoic acid.
The nitrating reagent is any one or more of concentrated nitric acid, fuming nitric acid and nitrate. Concentrated nitric acid is preferred.
In the step (1), the nitrate is potassium nitrate, sodium nitrate or other nitrates.
In the step (1), the reaction temperature is-20-40 ℃, preferably 10-20 ℃, and the reaction time is 1-6 hours, preferably 4-5 hours.
In the step (2), the organic solvent is one or more of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, 1, 2-dichloroethane, dimethyl sulfoxide and DMF, preferably dimethyl sulfoxide.
The oxidant is one or more of hydrogen peroxide, sodium hypochlorite, TEMPO, hexavalent chromium reagent, potassium permanganate, chromium trioxide, potassium dichromate, ruthenium tetroxide, dimethyl sulfoxide oxidation method and high-valence iodine compounds. Hydrogen peroxide is preferred.
In the step (2), the reaction temperature is-20-90 ℃, preferably 50-60 ℃, and the reaction time is 2-12 hours, preferably 5-6 hours.
In the step (3), the organic solvent is one or more of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform and 1, 2-dichloroethane. Methanol is preferred.
In the step (3), the reducing agent is one or more of palladium carbon, hydrazine hydrate, iron powder, zinc powder and stannous chloride. Palladium on carbon is preferred.
In the step (3), the reaction temperature is 20-90 ℃, preferably 50-60 ℃, and the reaction time is 2-10 hours, preferably 5-6 hours.
The invention has the following beneficial effects:
according to the preparation method of the 2-amino-4-fluorobenzoic acid, 4-fluorobenzol which is cheap and easy to obtain is used as a raw material, nitration reaction is firstly carried out to obtain a nitro substituent, then oxidation reaction is carried out on the nitro substituent to obtain a benzoic acid oxide, and finally reduction reaction is carried out on the benzoic acid oxide, so that the 2-amino-4-fluorobenzoic acid prepared finally is high in purity and yield. The preparation method has the characteristics of cheap and easily obtained raw materials, short reaction route, conventional reaction, mild reaction conditions, high yield and easy industrial production.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIGS. 1A to 1B are an HPLC chromatogram and a mass chromatogram, respectively, of 4-fluoro-2-nitrobenzol obtained in example 1 of the present invention;
FIG. 1C is an IR spectrum of 4-fluoro-2-nitrobenzol obtained in example 1 of the present invention;
FIGS. 2A to 2B are an HPLC chromatogram and a mass chromatogram, respectively, of 4-fluoro-2-nitrobenzoic acid obtained in example 1 of the present invention;
FIG. 2C is an IR spectrum of 4-fluoro-2-nitrobenzoic acid obtained in example 1 of the present invention;
FIGS. 3A to 3B are an HPLC chromatogram and a mass chromatogram, respectively, of 2-amino-4-fluorobenzoic acid obtained in example 1 of the present invention;
FIG. 3C is an IR spectrum of 2-amino-4-fluorobenzoic acid obtained in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the embodiments described are merely exemplary of the invention, and not of the invention in its entirety. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.
Example 1
This example provides a method for preparing 2-amino-4-fluorobenzoic acid, which comprises the following steps:
the method specifically comprises the following steps:
(1) adding 4-fluorobenzyl alcohol into a reaction bottle, adding concentrated sulfuric acid with the volume being 5 times that of the reaction bottle, cooling, stirring and dissolving, cooling to 10 ℃, adding concentrated nitric acid to react for 4 hours under the condition of heat preservation and stirring, detecting that the 4-fluorobenzyl alcohol disappears by TLC, slowly adding the 4-fluorobenzyl alcohol into water under the condition of cooling and stirring, performing suction filtration, and performing forced air drying and drying at 50 ℃ to obtain a brown yellow solid intermediate 4-fluoro-2-nitrobenzyl alcohol (shown in figures 1A-1C), wherein the molar yield is 81%;
(2) adding the 4-fluoro-2-nitrobenzol obtained in the step (1) into a reaction bottle, adding dimethyl sulfoxide with the volume 5 times that of the 4-fluoro-2-nitrobenzol, heating to 50 ℃, slowly adding hydrogen peroxide under the stirring condition, reacting for 5 hours under the heat preservation stirring condition, detecting the disappearance of the 4-fluoro-2-nitrobenzol by TLC, stirring, cooling, adding water, performing suction filtration to obtain a light yellow solid intermediate 4-fluoro-2-nitrobenzoic acid (shown in figures 2A-2C), and performing forced air drying and drying at 50 ℃ to obtain the molar yield of 79%;
(3) adding the 4-fluoro-2-nitrobenzoic acid obtained in the step (2) into a reaction bottle, adding 5 times of methanol, adding palladium-carbon for reaction, performing nitrogen displacement three times, pressurizing hydrogen to 5 atmospheric pressures, heating to 50 ℃, preserving heat for reaction for 5 hours, detecting the disappearance of the 4-fluoro-2-nitrobenzoic acid by TLC, stirring, cooling, performing suction filtration, and performing spin drying on an organic phase to obtain a light yellow solid, namely the target product 2-amino-4-fluorobenzoic acid (shown in figures 3A-3C), wherein the molar yield is 89%.
Example 2
This example provides a method for preparing 2-amino-4-fluorobenzoic acid, which includes the following steps:
(1) adding 4-fluorobenzyl alcohol into a reaction bottle, adding concentrated sulfuric acid with the volume being 5 times that of the reaction bottle, cooling, stirring and dissolving, cooling to-20 ℃, adding fuming nitric acid to react for 6 hours under the condition of heat preservation and stirring, detecting that the 4-fluorobenzyl alcohol disappears by TLC, slowly adding the mixture into water under the condition of cooling and stirring, performing suction filtration, and performing forced air drying and drying at 50 ℃ to obtain a brown-yellow solid intermediate 4-fluoro-2-nitrobenzyl alcohol with the molar yield of 75%;
(2) adding the 4-fluoro-2-nitrobenzol obtained in the step (1) into a reaction bottle, adding 5 times of DMF (dimethyl formamide) in volume, heating to 20 ℃, slowly adding sodium hypochlorite under stirring, reacting for 12 hours under heat preservation and stirring conditions, detecting the disappearance of the 4-fluoro-2-nitrobenzol by TLC (thin layer chromatography), stirring, cooling, adding water, performing suction filtration to obtain a light yellow solid intermediate 4-fluoro-2-nitrobenzoic acid, and performing forced air drying and drying at 50 ℃ to obtain a molar yield of 75%;
(3) adding the 4-fluoro-2-nitrobenzoic acid obtained in the step (2) into a reaction bottle, adding tetrahydrofuran with the volume being 5 times that of the reaction bottle, adding hydrazine hydrate for reaction, replacing the mixture with nitrogen for three times, pressurizing hydrogen to 5 atmospheric pressures, heating to 60 ℃, preserving the temperature for reaction for 10 hours, detecting the disappearance of the 4-fluoro-2-nitrobenzoic acid by TLC, stirring, cooling, performing suction filtration, and spin-drying an organic phase to obtain a light yellow solid, namely the target product 2-amino-4-fluorobenzoic acid, wherein the molar yield is 82%.
Example 3
This example provides a method for preparing 2-amino-4-fluorobenzoic acid, which includes the following steps:
(1) adding 4-fluorobenzyl alcohol into a reaction bottle, adding concentrated sulfuric acid with the volume being 5 times that of the reaction bottle, cooling, stirring and dissolving, cooling to 40 ℃, adding potassium nitrate to react for 1 hour under the condition of heat preservation and stirring, detecting that the 4-fluorobenzyl alcohol disappears by TLC, slowly adding the mixture into water under the condition of cooling and stirring, performing suction filtration, and drying by blowing at 50 ℃ to obtain a brown solid intermediate 4-fluoro-2-nitrobenzyl alcohol with the molar yield of 73%;
(2) adding the 4-fluoro-2-nitrobenzol obtained in the step (1) into a reaction bottle, adding 5 times of DMF (dimethyl formamide) in volume, heating to 60 ℃, slowly adding TEMPO (TEMPO) under stirring, reacting for 2 hours under heat preservation and stirring conditions, detecting the disappearance of the 4-fluoro-2-nitrobenzol by TLC (thin layer chromatography), stirring, cooling, adding water, performing suction filtration to obtain a light yellow solid intermediate 4-fluoro-2-nitrobenzoic acid, and performing forced air drying and drying at 50 ℃ to obtain a light yellow solid intermediate 4-fluoro-2-nitrobenzoic acid with a molar yield of 67%;
(3) adding the 4-fluoro-2-nitrobenzoic acid obtained in the step (2) into a reaction bottle, adding 5 times of 1, 2-dichloroethane in volume, adding iron powder for reaction, replacing nitrogen for three times, pressurizing hydrogen to 5 atmospheric pressures, heating to 90 ℃, preserving heat for reaction for 2 hours, detecting by TLC that the 4-fluoro-2-nitrobenzoic acid disappears, stirring, cooling, carrying out suction filtration, and carrying out spin drying on an organic phase to obtain a light yellow solid, namely the target product 2-amino-4-fluorobenzoic acid, wherein the molar yield is 81%.
Example 4
This example provides a method for preparing 2-amino-4-fluorobenzoic acid, which includes the following steps:
(1) adding 4-fluorobenzyl alcohol into a reaction bottle, adding concentrated sulfuric acid with the volume being 5 times that of the reaction bottle, cooling, stirring and dissolving, cooling to 20 ℃, adding sodium nitrate to react for 3 hours under the condition of heat preservation and stirring, detecting that the 4-fluorobenzyl alcohol disappears by TLC, slowly adding the mixture into water under the condition of cooling and stirring, performing suction filtration, and performing forced air drying and drying at 50 ℃ to obtain a brown solid intermediate 4-fluoro-2-nitrobenzyl alcohol, wherein the molar yield is 72%;
(2) adding the 4-fluoro-2-nitrobenzol obtained in the step (1) into a reaction bottle, adding dichloromethane with the volume 5 times that of the 4-fluoro-2-nitrobenzol, heating to 60 ℃, slowly adding potassium dichromate under stirring, reacting for 10 hours under heat preservation and stirring conditions, detecting the disappearance of the 4-fluoro-2-nitrobenzol by TLC, stirring, cooling, adding water, performing suction filtration to obtain a light yellow solid intermediate 4-fluoro-2-nitrobenzoic acid, and performing forced air drying and drying at 50 ℃ to obtain the light yellow solid intermediate 4-fluoro-2-nitrobenzoic acid with the molar yield of 69%;
(3) adding the 4-fluoro-2-nitrobenzoic acid obtained in the step (2) into a reaction bottle, adding 5 times of isopropanol, adding zinc powder for reaction, performing nitrogen displacement for three times, pressurizing hydrogen to 5 atmospheric pressures, heating to 75 ℃, preserving heat for reaction for 2 hours, detecting the disappearance of the 4-fluoro-2-nitrobenzoic acid by TLC, stirring, cooling, performing suction filtration, and performing spin drying on an organic phase to obtain a light yellow solid, namely the target product 2-amino-4-fluorobenzoic acid, wherein the molar yield is 78%.
Example 5
This example provides a method for preparing 2-amino-4-fluorobenzoic acid, which includes the following steps:
(1) adding 4-fluorobenzyl alcohol into a reaction bottle, adding concentrated sulfuric acid with the volume being 5 times that of the reaction bottle, cooling, stirring and dissolving, cooling to 20 ℃, adding sodium nitrate to react for 5 hours under the condition of heat preservation and stirring, detecting that the 4-fluorobenzyl alcohol disappears by TLC, slowly adding the mixture into water under the condition of cooling and stirring, performing suction filtration, and performing forced air drying and drying at 50 ℃ to obtain a brown solid intermediate 4-fluoro-2-nitrobenzyl alcohol, wherein the molar yield is 69%;
(2) adding the 4-fluoro-2-nitrobenzol obtained in the step (1) into a reaction bottle, adding ethyl acetate with the volume of 5 times, heating to 60 ℃, slowly adding ruthenium tetroxide under the stirring condition, reacting for 6 hours under the heat preservation and stirring conditions, detecting the disappearance of the 4-fluoro-2-nitrobenzol by TLC (thin layer chromatography), stirring, cooling, adding water, and performing suction filtration to obtain a light yellow solid intermediate 4-fluoro-2-nitrobenzoic acid, and performing forced air drying and drying at 50 ℃ to obtain the molecular yield of 68%;
(3) adding the 4-fluoro-2-nitrobenzoic acid obtained in the step (2) into a reaction bottle, adding 5 times of volume of tert-butyl alcohol, adding stannous chloride for reaction, performing nitrogen displacement for three times, pressurizing hydrogen to 5 atmospheric pressures, heating to 60 ℃, preserving heat for reaction for 6 hours, detecting the disappearance of the 4-fluoro-2-nitrobenzoic acid by TLC, stirring, cooling, performing suction filtration, and performing spin drying on an organic phase to obtain a light yellow solid, namely the target product 2-amino-4-fluorobenzoic acid, wherein the molar yield is 84%.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. A preparation method of 2-amino-4-fluorobenzoic acid is characterized by comprising the following steps:
(1) adding 4-fluorobenzyl alcohol into concentrated sulfuric acid, cooling, stirring for dissolving, adding a nitration reagent under stirring for reacting after cooling, and obtaining a nitro substituent;
(2) adding the nitro substituent in the step (1) into an organic solvent, adding an oxidant, heating, and reacting under stirring to obtain benzoic acid oxide;
(3) and (3) dissolving the benzoic acid oxide obtained in the step (2) in an organic solvent, and then adding a reducing agent to react to obtain the target product 2-amino-4-fluorobenzoic acid.
2. The method for preparing 2-amino-4-fluorobenzoic acid according to claim 1, wherein in the step (1), the nitrating reagent is any one or more of concentrated nitric acid, fuming nitric acid and nitrate.
3. The process for producing 2-amino-4-fluorobenzoic acid according to claim 2, wherein in the step (1), the nitrate is potassium nitrate or sodium nitrate.
4. The method for preparing 2-amino-4-fluorobenzoic acid according to claim 1, wherein the reaction temperature in the step (1) is-20 to 40 ℃ and the reaction time is 1 to 6 hours.
5. The method according to claim 1, wherein in the step (2), the organic solvent is one or more selected from methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, 1, 2-dichloroethane, dimethyl sulfoxide, and DMF.
6. The method of claim 1, wherein the oxidizing agent is one or more of hydrogen peroxide, sodium hypochlorite, TEMPO, a hexavalent chromium reagent, potassium permanganate, chromium trioxide, potassium dichromate, ruthenium tetroxide, dimethyl sulfoxide oxidation, and a high-valent iodine compound.
7. The method according to claim 1, wherein the reaction temperature in step (2) is-20 to 90 ℃ and the reaction time is 2 to 12 hours.
8. The method according to claim 1, wherein in the step (3), the organic solvent is one or more selected from methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, and 1, 2-dichloroethane.
9. The method for preparing 2-amino-4-fluorobenzoic acid according to claim 1, wherein in the step (3), the reducing agent is one or more of palladium carbon, hydrazine hydrate, iron powder, zinc powder and stannous chloride.
10. The method according to claim 1, wherein the reaction temperature in step (3) is 20 to 90 ℃ and the reaction time is 2 to 10 hours.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0586000A (en) * | 1991-09-27 | 1993-04-06 | Asahi Glass Co Ltd | Production of 2-amino-4-fluorobenzoic acid |
| WO2003095417A1 (en) * | 2002-05-09 | 2003-11-20 | Miteni S.P.A. | Process for the manufacture of 4-fluoro-anthranilic acid |
| CN107556214A (en) * | 2017-09-15 | 2018-01-09 | 大连奇凯医药科技有限公司 | A kind of preparation method of paracyanobenzoic acid |
| CN108467342A (en) * | 2018-04-08 | 2018-08-31 | 中南大学 | A kind of method of ultrasonic wave assisted oxidation benzyl alcohol class compound synthesis benzoic acid derivative |
| CN112778147A (en) * | 2020-12-30 | 2021-05-11 | 锦州三丰科技有限公司 | Preparation method of 2-amino-3-methyl-5-chlorobenzoic acid |
-
2021
- 2021-05-27 CN CN202110583859.XA patent/CN113307740A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0586000A (en) * | 1991-09-27 | 1993-04-06 | Asahi Glass Co Ltd | Production of 2-amino-4-fluorobenzoic acid |
| WO2003095417A1 (en) * | 2002-05-09 | 2003-11-20 | Miteni S.P.A. | Process for the manufacture of 4-fluoro-anthranilic acid |
| CN107556214A (en) * | 2017-09-15 | 2018-01-09 | 大连奇凯医药科技有限公司 | A kind of preparation method of paracyanobenzoic acid |
| CN108467342A (en) * | 2018-04-08 | 2018-08-31 | 中南大学 | A kind of method of ultrasonic wave assisted oxidation benzyl alcohol class compound synthesis benzoic acid derivative |
| CN112778147A (en) * | 2020-12-30 | 2021-05-11 | 锦州三丰科技有限公司 | Preparation method of 2-amino-3-methyl-5-chlorobenzoic acid |
Non-Patent Citations (1)
| Title |
|---|
| 朱小飞: "2-甲基-3-硝基苯乙酸的合成", 《山东化工》 * |
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Application publication date: 20210827 |