CN112409192A - Purification method of 4-fluoro-2-methoxyaniline - Google Patents
Purification method of 4-fluoro-2-methoxyaniline Download PDFInfo
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- CN112409192A CN112409192A CN202011346034.8A CN202011346034A CN112409192A CN 112409192 A CN112409192 A CN 112409192A CN 202011346034 A CN202011346034 A CN 202011346034A CN 112409192 A CN112409192 A CN 112409192A
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- fluoro
- methoxyaniline
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- pressure evaporation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
Abstract
The invention discloses a method for purifying 4-fluoro-2-methoxyaniline, which comprises the steps of carrying out reduction reaction on 4-fluoro-2-methoxynitrobenzene to obtain reaction liquid of the 4-fluoro-2-methoxyaniline, carrying out azeotropic distillation on a product by adopting steam distillation, and extracting and removing a solvent by using the solvent to obtain the faint yellow high-purity 4-fluoro-2-methoxyaniline. The method is simple and convenient, is easy to operate, and has high product yield and good quality, wherein the yield is more than 95 percent, and the GC content is more than 99.0 percent.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, and particularly relates to a purification method of 4-fluoro-2-methoxyaniline.
Background
The fluoro-2-methoxyaniline is an important intermediate of an anti-lung cancer drug ocitinib. The 4-fluoro-2-methoxyaniline is generally obtained by reducing 4-fluoro-2-methoxynitrobenzene according to the following reaction principle:
the literature reports 2 reduction methods:
1. carrying out catalytic hydrogenation reduction on palladium and carbon;
2. and reducing iron powder.
By adopting the two reduction modes, some impurities, especially reduction intermediate products, are inevitably generated, and the reaction color is dark and blackened. Since palladium carbon is expensive and used in high-pressure reaction equipment, the production cost is high, and currently, an iron powder reduction method is mainly used industrially. In the review of the literature and patents, the post-treatment method is to filter and then concentrate to remove the solvent (CN104844580), or to filter, extract the solvent and then remove the solvent (CN 104860941). The purity of the obtained product is only 90-92% (CN104860941, CN104974140, CN105001208 and CN 10647860). After-treatment is carried out according to the method, and the product with the color close to brownish black is obtained.
Disclosure of Invention
The invention aims to provide a method for purifying 4-fluoro-2-methoxyaniline, which has high product yield and good quality.
The technical solution of the invention is as follows:
a method for purifying 4-fluoro-2-methoxyaniline is characterized by comprising the following steps: reducing 4-fluoro-2-methoxynitrobenzene to obtain reaction liquid of 4-fluoro-2-methoxyaniline, carrying out steam distillation to carry out azeotropic distillation on the product, and extracting by using a solvent to remove the solvent to obtain the faint yellow high-purity 4-fluoro-2-methoxyaniline.
The water vapor is generated by directly introducing steam or heating tap water added into the reaction kettle.
The solvent is dichloromethane, chloroform or dichloroethane. When the solvent is removed, normal pressure evaporation or reduced pressure evaporation is adopted; the vacuum degree of reduced pressure evaporation is 0.08-0.1 MPa.
The method is simple and convenient, is easy to operate, and has high product yield and good quality, wherein the yield is more than 95 percent, and the GC content is more than 99.0 percent.
The present invention will be further described with reference to the following examples.
Detailed Description
Example 1:
650mL of tap water, 13.2g of acetic acid and 147.3g of iron powder are put into a 1000mL clean and dry three-mouth bottle, and after the materials are put into the three-mouth bottle, the temperature is raised to 70 ℃, and the temperature is kept for 30 min. Then controlling the temperature to be 70-90 ℃, slowly adding 132g of 4-fluoro-2-methoxynitrobenzene, keeping the temperature and stirring for 2 hours after adding, adding 300g of water at 40 ℃, adjusting the pH value to be 8-9 by using 30% liquid caustic soda, evaporating the water at normal pressure until the evaporated liquid is clear, and stopping evaporation (about 2000mL of water is required to be evaporated). The aqueous phase was evaporated and 250g of dichloromethane were added and the phases were extracted. Separating out oil phase, controlling the temperature to be 60 ℃, concentrating dichloromethane under reduced pressure, cooling to below 40 ℃ under the vacuum degree of 0.08-0.1MPa at the end of evaporation, and obtaining light yellow liquid, namely 103.4 g of 4-fluoro-2-methoxyaniline, with the yield of 96% and the purity of 99.2%.
Example 2:
650mL of tap water, 13.2g of acetic acid and 147.3g of iron powder are put into a 1000mL clean and dry three-mouth bottle, and after the materials are put into the three-mouth bottle, the temperature is raised to 70 ℃, and the temperature is kept for 30 min. Then controlling the temperature to be 70-90 ℃, slowly adding 132g of 4-fluoro-2-methoxynitrobenzene, keeping the temperature and stirring for 2 hours after adding, adding 300g of water at 40 ℃, adjusting the pH value to be 8-9 by using 30% liquid caustic soda, evaporating the water at normal pressure until the evaporated liquid is clear, and stopping evaporation (about 2000mL of water is required to be evaporated). The aqueous phase was evaporated and 250g of dichloroethane were added and the phases were separated by extraction. Separating out oil phase, controlling the temperature to be 70 ℃, concentrating dichloroethane under reduced pressure, controlling the vacuum degree at the end of evaporation to be 0.08-0.1MPa, and cooling to be below 40 ℃ to obtain yellow liquid 4-fluoro-2-methoxyaniline of 101.2 g, the yield is 98%, and the purity is 99.0%.
Claims (4)
1. A method for purifying 4-fluoro-2-methoxyaniline is characterized by comprising the following steps: reducing 4-fluoro-2-methoxynitrobenzene to obtain reaction liquid of 4-fluoro-2-methoxyaniline, carrying out steam distillation to carry out azeotropic distillation on the product, and extracting by using a solvent to remove the solvent to obtain the faint yellow high-purity 4-fluoro-2-methoxyaniline.
2. The method for purifying 4-fluoro-2-methoxyaniline according to claim 1, wherein: the water vapor is generated by directly introducing steam or heating tap water added into the reaction kettle.
3. The method for purifying 4-fluoro-2-methoxyaniline according to claim 1, wherein: the solvent is dichloromethane, chloroform or dichloroethane.
4. The method for purifying 4-fluoro-2-methoxyaniline according to claim 1, wherein: when the solvent is removed, normal pressure evaporation or reduced pressure evaporation is adopted; the vacuum degree of reduced pressure evaporation is 0.08-0.1 MPa.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202011346034.8A CN112409192A (en) | 2020-11-26 | 2020-11-26 | Purification method of 4-fluoro-2-methoxyaniline |
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| CN202011346034.8A CN112409192A (en) | 2020-11-26 | 2020-11-26 | Purification method of 4-fluoro-2-methoxyaniline |
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| CN202011346034.8A Pending CN112409192A (en) | 2020-11-26 | 2020-11-26 | Purification method of 4-fluoro-2-methoxyaniline |
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