CN114656374A - Synthesis method of 2, 4-dichloro-3-cyano-5-fluorobenzoic acid - Google Patents
Synthesis method of 2, 4-dichloro-3-cyano-5-fluorobenzoic acid Download PDFInfo
- Publication number
- CN114656374A CN114656374A CN202210161554.4A CN202210161554A CN114656374A CN 114656374 A CN114656374 A CN 114656374A CN 202210161554 A CN202210161554 A CN 202210161554A CN 114656374 A CN114656374 A CN 114656374A
- Authority
- CN
- China
- Prior art keywords
- kettle
- dichloro
- fluorobenzoic acid
- cyano
- cyanidation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/20—Diazonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
Abstract
The invention discloses a method for synthesizing 2, 4-dichloro-3-cyano-5-fluorobenzoic acid, which belongs to the technical field of chemical synthesis and comprises the following steps: reduction: adding industrial ethanol into a hydrogenation kettle, adding 2, 4-dichloro-3-nitro-5-fluorobenzoic acid, adding a catalyst, introducing hydrogen for reaction, filtering, and distilling; salifying, diazotizing: adding sulfuric acid into a reaction kettle, adding aminocarboxylic acid, and dropwise adding a sodium nitrite solution; cyaniding: adding all water into a cyanidation kettle, adding NaCN and CuCN, starting the cyanidation kettle for stirring, heating and stirring, cooling, opening a diazotization kettle dropping valve, and performing suction filtration to obtain a filter cake; dissolving in alkali and acidifying; the 2, 4-dichloro-3-nitro-5-fluorobenzoic acid is adopted as a raw material, and then the 2, 4-dichloro-3-cyano-5-fluorobenzoic acid is obtained through reduction, diazotization, cyanidation, alkali dissolution and acidification, so that the prepared product is high in purity and yield; solves the problems of lower yield and complex operation process of the existing 2, 4-dichloro-3-cyano-5-fluorobenzoic acid synthesis method.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of 2, 4-dichloro-3-cyano-5-fluorobenzoic acid.
Background
The 2, 4-dichloro-3-cyano-5-fluorobenzoic acid is a key intermediate for preparing novel fluoroquinolone medicaments finafloxacin and prafloxacin, and has a good market prospect. The existing synthesis method of 2, 4-dichloro-3-cyano-5-fluorobenzoic acid has low yield and complex operation process.
Disclosure of Invention
The invention provides a synthesis method of 2, 4-dichloro-3-cyano-5-fluorobenzoic acid, aiming at solving the problems of lower yield and complex operation process of the existing synthesis method of 2, 4-dichloro-3-cyano-5-fluorobenzoic acid, which comprises the following steps:
in order to solve the technical problems, the following technical scheme is adopted:
the synthesis process of 2, 4-dichloro-3-cyano-5-fluoro benzoic acid includes the following steps:
reduction: adding industrial ethanol into a hydrogenation kettle, adding 2, 4-dichloro-3-nitro-5-fluorobenzoic acid, adding a catalyst, replacing with nitrogen, heating to 60 ℃, introducing hydrogen for reaction, filtering out the catalyst, distilling until no flow liquid exists, and recovering ethanol;
salifying, diazotizing: adding sulfuric acid into a reaction kettle, adding aminocarboxylic acid, heating to 100 ℃, carrying out heat preservation and stirring, then cooling to 0 +/-2 ℃, preparing a sodium nitrite solution, cooling to 0 +/-2 ℃, dropwise adding in a heat preservation state, then carrying out heat preservation for 2 hours, cooling to-5 ℃, adding water, and keeping the temperature;
cyaniding: adding all water into a cyanidation kettle, opening an absorption valve on the kettle, adding NaCN and CuCN, starting the cyanidation kettle to stir, automatically raising the temperature of the kettle to 40-50 ℃, stirring for 30 minutes, then cooling to-2-0 ℃, opening a dropwise adding valve of a diazotization kettle, maintaining the temperature of the kettle at-2-5 ℃, dropwise adding diazonium salt, keeping the temperature of the cyanidation kettle at-2-5 ℃ for half an hour, and then carrying out suction filtration to obtain a filter cake;
alkali dissolution: firstly, adding water into an alkali dissolution kettle, then adding Na2CO3, starting stirring for 10 minutes, adding a filter cake into the kettle, stirring for 30 minutes, measuring the pH value, if the pH value is less than 8.5, adding Na2CO3 until the pH value is =8.5-9, carrying out suction filtration, and feeding the filtrate into an acidification kettle;
acidifying: preparing sulfuric acid with the mass concentration of 30% in advance in an acidification dropwise adding kettle, slowly dropwise adding H2SO4 into the acidification kettle, stopping acid adding when the pH in the kettle is =1, keeping the kettle temperature at 10-15 ℃, then carrying out suction filtration on the materials, and carrying out vacuum drying on the filter cake.
As a further scheme of the invention: the catalyst is Pd/c catalyst.
As a further scheme of the invention: the sodium nitrite solution is prepared from the following components in percentage by mass of 5: 1, water and sodium nitrite.
As a further scheme of the invention: in the reduction step, after nitrogen replacement, the temperature is raised to 60 ℃, hydrogen is introduced for reaction, and the reaction is finished when the hydrogen is not consumed.
As a further scheme of the invention: in the reduction step, the mass ratio of the industrial ethanol, the 4-dichloro-3-nitro-5-fluorobenzoic acid and the Pd/c catalyst is 100-: 40: 1.
as a further scheme of the invention: in the salifying and diazotizing steps, the mass concentration of sulfuric acid added into the reaction kettle is 98%.
As a further scheme of the invention: in the salifying and diazotizing steps, the mass ratio of the sulfuric acid with the mass concentration of 98% to the aminocarboxylic acid is 3.9-4.1: 1.
as a further scheme of the invention: in the cyaniding step, the mass ratio of NaCN to CuCN is 5-5.2: 3.
compared with the prior art, the invention has the beneficial effects that: the invention adopts 2, 4-dichloro-3-nitro-5-fluorobenzoic acid, obtains the 2, 4-dichloro-3-amino-5-fluorobenzoic acid by reduction, and obtains the 2, 4-dichloro-3-cyano-5-fluorobenzoic acid by diazotization reaction and Sandmeyer reaction, and the prepared product has higher purity and yield.
Detailed Description
Example 1
Reduction: adding 1000 g of industrial ethanol into a hydrogenation kettle, adding 400 g of 2, 4-dichloro-3-nitro-5-fluorobenzoic acid, adding 10 g of Pd/c catalyst, replacing with nitrogen, heating to 60 ℃, introducing hydrogen for reaction, and when the hydrogen is not consumed, finishing the reaction, and taking the qualified sample raw material with 0.5 percent of the rest; filtering out the catalyst, distilling until no liquid flow is formed at 90 ℃, and recovering ethanol;
salifying, diazotizing: adding 400 g of 98% sulfuric acid into a reaction kettle, adding 100 g of aminocarboxylic acid, heating to 100 ℃, keeping the temperature and stirring for 2 hours, then cooling to 0 +/-2 ℃, preparing a sodium nitrite solution (150 g of water and 30 g of sodium nitrite) and cooling to 0 ℃, dropwise adding the solution in a heat-preservation state, keeping the temperature for 2 hours, cooling to-5 ℃, adding 300 g of water, and keeping the temperature;
cyaniding: adding 450 g of water into a cyanidation kettle, opening an absorption valve on the kettle, adding 125 g of NaCN and 75 g of CuCN, starting the cyanidation kettle to stir, automatically raising the temperature of the kettle to 45 ℃, stirring for 30 minutes, then cooling to-2 ℃, opening a dropping valve of a diazotization kettle, maintaining the temperature of the kettle at 0 ℃, dropping diazo salt, keeping the temperature of the cyanidation kettle at 0 ℃ for half an hour, and then performing suction filtration to obtain a filter cake;
alkali dissolution: firstly, adding 600 g of water into an alkali dissolution kettle, then adding 80 g of Na2CO3, starting stirring for 10 minutes, adding a filter cake into the kettle, stirring for 30 minutes, measuring the pH value, supplementing 10% of Na2CO3 if the pH value is less than 8.5 until the pH value is =8.5-9, carrying out suction filtration, and feeding the filtrate into an acidification kettle;
acidifying: preparing 30% sulfuric acid in advance in an acidification dropwise adding kettle, slowly dropwise adding H2SO4 into the acidification kettle, stopping acid dripping when the pH in the kettle is =1, keeping the temperature of the kettle at 10 ℃, then carrying out suction filtration on the materials, drying a filter cake, and carrying out vacuum drying at-0.1 MPa and the temperature of 80 ℃ to obtain the product with the content of 99%.
Example 2
Reduction: adding 1000 g of industrial ethanol into a hydrogenation kettle, adding 400 g of 2, 4-dichloro-3-nitro-5-fluorobenzoic acid, adding 10 g of Pd/c catalyst, replacing with nitrogen, heating to 60 ℃, introducing hydrogen for reaction, and when the hydrogen is not consumed, finishing the reaction, and taking the qualified sample raw material with 0.5 percent of the rest; filtering out the catalyst, distilling until no liquid flow is formed at 90 ℃, and recovering ethanol;
salifying, diazotizing: adding 390 g of 98% sulfuric acid into a reaction kettle, adding 100 g of aminocarboxylic acid, heating to 100 ℃, keeping the temperature and stirring for 2 hours, then cooling to-2 ℃, preparing a sodium nitrite solution (150 g of water and 30 g of sodium nitrite) and cooling to-2 ℃, dropwise adding the solution in a heat-preservation state, keeping the temperature for 2 hours, cooling to-5 ℃, adding 300 g of water, and keeping the temperature;
cyaniding: adding 450 g of water into a cyanidation kettle, opening an absorption valve on the cyanidation kettle, adding 130 g of NaCN and 75 g of CuCN, starting the cyanidation kettle to stir, automatically raising the temperature of the kettle to 40 ℃, stirring for 30 minutes, then cooling to-2 ℃, opening a dropping valve of a diazotization kettle, maintaining the temperature of the kettle at-2 ℃, dropping diazonium salt, keeping the temperature of the cyanidation kettle at-2 ℃ for half an hour, and then performing suction filtration to obtain a filter cake;
alkali dissolution: firstly, adding 600 g of water into an alkali dissolution kettle, then adding 80 g of Na2CO3, starting stirring for 10 minutes, adding a filter cake into the kettle, stirring for 30 minutes, measuring the pH value, adding 10% of Na2CO3 if the pH value is less than 8.5 until the pH value is =8.5, carrying out suction filtration, and feeding the filtrate into an acidification kettle;
acidifying: preparing 30% sulfuric acid in advance in an acidification dripping kettle, slowly dripping H2SO4 into the acidification kettle, stopping dripping the acid when the pH in the kettle is =1, keeping the temperature of the kettle at 10 ℃, then carrying out suction filtration on the material, drying a filter cake, and carrying out vacuum drying at-0.09 MPa and the temperature of 80 ℃ to obtain the product with the content of 99%.
Example 3
Reduction: adding 1200 g of industrial ethanol into a hydrogenation kettle, adding 400 g of 2, 4-dichloro-3-nitro-5-fluorobenzoic acid, adding 10 g of Pd/c catalyst, replacing with nitrogen, heating to 60 ℃, introducing hydrogen for reaction, and when the hydrogen is not consumed, finishing the reaction, and taking the qualified sample raw material with 0.5 percent of the rest; filtering out catalyst, distilling until no flow liquid at 90 ℃, and recovering ethanol;
salifying, diazotizing: adding 410 g of 98% sulfuric acid into a reaction kettle, adding 100 g of aminocarboxylic acid, heating to 100 ℃, keeping the temperature and stirring for 2 hours, then cooling to 2 ℃, preparing a sodium nitrite solution (150 g of water and 30 g of sodium nitrite) and cooling to 2 ℃, dropwise adding the solution in a heat-preservation state, keeping the temperature for 2 hours, cooling to-5 ℃, adding 300 g of water, and keeping the temperature;
cyaniding: adding 450 g of water into a cyanidation kettle, opening an absorption valve on the cyanidation kettle, adding 125 g of NaCN and 75 g of CuCN, starting the cyanidation kettle to stir, automatically raising the temperature of the kettle to 50 ℃, stirring for 30 minutes, cooling to 0 ℃, opening a dropping valve of a diazotization kettle, maintaining the temperature of the kettle at 5 ℃, dropping diazonium salt, keeping the temperature of the cyanidation kettle at 5 ℃ for half an hour, and then performing suction filtration to obtain a filter cake;
alkali dissolution: firstly, adding 600 g of water into an alkali dissolution kettle, then adding 80 g of Na2CO3, starting stirring for 10 minutes, adding a filter cake into the kettle, stirring for 30 minutes, measuring the pH value, supplementing 10% of Na2CO3 if the pH value is less than 8.5 until the pH value is =8.5-9, carrying out suction filtration, and feeding the filtrate into an acidification kettle;
acidifying: preparing 30% sulfuric acid in advance in an acidification dropwise adding kettle, slowly dropwise adding H2SO4 into the acidification kettle, stopping acid dripping when the pH in the kettle is =1, keeping the temperature of the kettle at 15 ℃, then carrying out suction filtration on the materials, drying a filter cake, and carrying out vacuum drying at-0.1 MPa and the temperature of 80 ℃ to obtain the product with the content of 99%.
In summary, the following steps: the invention adopts 2, 4-dichloro-3-nitro-5-fluorobenzoic acid as a raw material, then 2, 4-dichloro-3-amino-5-fluorobenzoic acid is obtained by reduction, and 2, 4-dichloro-3-cyano-5-fluorobenzoic acid is obtained by diazotization, cyanidation, alkali dissolution and acidification, so that the prepared product has high purity and yield.
Claims (8)
- The synthesis method of 2, 4-dichloro-3-cyano-5-fluorobenzoic acid is characterized by comprising the following steps:reduction: adding industrial ethanol into a hydrogenation kettle, adding 2, 4-dichloro-3-nitro-5-fluorobenzoic acid, adding a catalyst, replacing with nitrogen, heating to 60 ℃, introducing hydrogen for reaction, filtering out the catalyst, distilling until no flow liquid exists, and recovering ethanol;salifying, diazotizing: adding sulfuric acid into a reaction kettle, adding aminocarboxylic acid, heating to 100 ℃, carrying out heat preservation and stirring, then cooling to 0 +/-2 ℃, preparing a sodium nitrite solution, cooling to 0 +/-2 ℃, dropwise adding in a heat preservation state, then carrying out heat preservation for 2 hours, cooling to-5 ℃, adding water, and keeping the temperature;cyaniding: adding all water into a cyanidation kettle, opening an absorption valve on the kettle, adding NaCN and CuCN, starting the cyanidation kettle to stir, automatically raising the temperature of the kettle to 40-50 ℃, stirring for 30 minutes, then cooling to-2-0 ℃, opening a dropwise adding valve of a diazotization kettle, maintaining the temperature of the kettle at-2-5 ℃, dropwise adding diazonium salt, keeping the temperature of the cyanidation kettle at-2-5 ℃ for half an hour, and then carrying out suction filtration to obtain a filter cake;alkali dissolution: firstly, adding water into an alkali dissolution kettle, then adding Na2CO3, starting stirring for 10 minutes, adding a filter cake into the kettle, stirring for 30 minutes, measuring the pH value, if the pH value is less than 8.5, adding Na2CO3 until the pH value is =8.5-9, carrying out suction filtration, and feeding the filtrate into an acidification kettle;acidifying: preparing sulfuric acid with the mass concentration of 30% in advance in an acidification dropwise adding kettle, slowly dropwise adding H2SO4 into the acidification kettle, stopping acid adding when the pH in the kettle is =1, keeping the kettle temperature at 10-15 ℃, then carrying out suction filtration on the materials, and carrying out vacuum drying on the filter cake.
- 2. The method of synthesizing 2, 4-dichloro-3-cyano-5-fluorobenzoic acid according to claim 1, wherein the catalyst is a Pd/c catalyst.
- 3. The method for synthesizing 2, 4-dichloro-3-cyano-5-fluorobenzoic acid according to claim 1, wherein the sodium nitrite solution is prepared from the following raw materials in a mass ratio of 5: 1, water and sodium nitrite.
- 4. The method for synthesizing 2, 4-dichloro-3-cyano-5-fluorobenzoic acid according to claim 1, wherein in the reduction step, after nitrogen substitution, the temperature is raised to 60 ℃, and hydrogen is introduced for reaction, and the reaction is ended when hydrogen is not consumed.
- 5. The method for synthesizing 2, 4-dichloro-3-cyano-5-fluorobenzoic acid as claimed in claim 2, wherein in the reduction step, the mass ratio of the industrial ethanol, the 4-dichloro-3-nitro-5-fluorobenzoic acid and the Pd/c catalyst is 100-: 40: 1.
- 6. the method for synthesizing 2, 4-dichloro-3-cyano-5-fluorobenzoic acid according to claim 1, wherein the mass concentration of sulfuric acid added into the reaction kettle in the salifying and diazotizing steps is 98%.
- 7. The method for synthesizing 2, 4-dichloro-3-cyano-5-fluorobenzoic acid according to claim 6, wherein in the salifying and diazotizing steps, the mass ratio between the sulfuric acid with the mass concentration of 98% and the aminocarboxylic acid is 3.9 to 4.1: 1.
- 8. the method for synthesizing 2, 4-dichloro-3-cyano-5-fluorobenzoic acid according to claim 1, wherein in the cyanidation step, the mass ratio between NaCN and CuCN is 5-5.2: 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210161554.4A CN114656374A (en) | 2022-02-22 | 2022-02-22 | Synthesis method of 2, 4-dichloro-3-cyano-5-fluorobenzoic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210161554.4A CN114656374A (en) | 2022-02-22 | 2022-02-22 | Synthesis method of 2, 4-dichloro-3-cyano-5-fluorobenzoic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114656374A true CN114656374A (en) | 2022-06-24 |
Family
ID=82027388
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210161554.4A Pending CN114656374A (en) | 2022-02-22 | 2022-02-22 | Synthesis method of 2, 4-dichloro-3-cyano-5-fluorobenzoic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114656374A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4908366A (en) * | 1987-01-28 | 1990-03-13 | Bayer Aktiengesellschaft | Antibacterial 8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids |
| CN1252789A (en) * | 1997-04-24 | 2000-05-10 | 拜尔公司 | 3-cyano-2,4,5-trifluoro-benzoyle fluoride and intermediate preparation thereof |
| US20030045552A1 (en) * | 2000-12-27 | 2003-03-06 | Robarge Michael J. | Isoindole-imide compounds, compositions, and uses thereof |
| US20050154201A1 (en) * | 2003-04-22 | 2005-07-14 | Gang Chen | Methods of making 2,6-diaryl piperidine derivatives |
-
2022
- 2022-02-22 CN CN202210161554.4A patent/CN114656374A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4908366A (en) * | 1987-01-28 | 1990-03-13 | Bayer Aktiengesellschaft | Antibacterial 8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids |
| CN1252789A (en) * | 1997-04-24 | 2000-05-10 | 拜尔公司 | 3-cyano-2,4,5-trifluoro-benzoyle fluoride and intermediate preparation thereof |
| US20030045552A1 (en) * | 2000-12-27 | 2003-03-06 | Robarge Michael J. | Isoindole-imide compounds, compositions, and uses thereof |
| US20050154201A1 (en) * | 2003-04-22 | 2005-07-14 | Gang Chen | Methods of making 2,6-diaryl piperidine derivatives |
Non-Patent Citations (1)
| Title |
|---|
| 王宝瑄 编著: "《有机化学与光电材料实验教程》", 东南大学出版社, pages: 159 - 161 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101618893B (en) | Method for preparing ammonium metawolframate | |
| CN101381294A (en) | Industrial production method of 1,3-cyclohexanedione | |
| CN114656374A (en) | Synthesis method of 2, 4-dichloro-3-cyano-5-fluorobenzoic acid | |
| CN101249443A (en) | Catalyst for producing gluconic acid sodium salt, method of preparing the same and applications | |
| CN109336825B (en) | Method for improving quality of 5-aminobenzimidazole ketone | |
| CN105461565A (en) | Method for producing nitroacetophenone | |
| CN102146022B (en) | Method for preparing 3-chlorine-5-bromophenol | |
| CN110862298B (en) | Preparation method of sorbitol | |
| CN1233625C (en) | Preparation of nickel sulphamate | |
| CN109280011B (en) | Synthesis method of OLED intermediate 2-bromopyrene | |
| CN113461503A (en) | Preparation method of trifluoro acetophenone derivatives | |
| CN114075137A (en) | Preparation method of 2-aminosulfonyl-N, N-dimethylnicotinamide | |
| CN110143862A (en) | A kind of liquid phase oxidation prepares trimesic acid/trimellitic acid method | |
| CN115260787B (en) | Method for synthesizing dispersed orange 44 by one-pot method | |
| CN111499530B (en) | Method for preparing amino methyl phthalate by one step | |
| CN116655481B (en) | Industrial synthesis method of levocarnitine | |
| CN111499531B (en) | Method for preparing dimethyl aminophthalate | |
| CN110330443B (en) | Synthetic process of p-chlorophenylhydrazine hydrochloride | |
| CN111217678A (en) | Synthesis method of high-purity pyrogallic acid | |
| CN113512304B (en) | Preparation process of environment-friendly alkaline green dye | |
| CN110358323B (en) | Direct frozen yellow G production process without wastewater discharge | |
| CN111303220B (en) | Preparation method of D-glucosamine sulfate | |
| CN111499533B (en) | Method for preparing acetamino dimethyl phthalate | |
| CN112409812A (en) | Preparation method of novel heterocyclic nitrogen-coupled disperse dye | |
| CN114906879A (en) | Production process of cobalt bromide solution |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |