CN112321444A - Synthesis method of 4-bromo-3-oxo-N-phenylbutanamide - Google Patents
Synthesis method of 4-bromo-3-oxo-N-phenylbutanamide Download PDFInfo
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- CN112321444A CN112321444A CN202010982705.3A CN202010982705A CN112321444A CN 112321444 A CN112321444 A CN 112321444A CN 202010982705 A CN202010982705 A CN 202010982705A CN 112321444 A CN112321444 A CN 112321444A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
Abstract
The invention is applicable to the field of chemical synthesis, and provides a synthesis method of 4-bromo-3-oxo-N-phenylbutanamide, which comprises the following steps: putting diketene in an organic solvent, and dropwise adding bromine at the temperature of-15-50 ℃ for reaction to obtain a reaction solution; and adding alkali and aniline into the reaction solution for heat preservation reaction, and filtering to obtain the 4-bromo-3-oxo-N-phenylbutyramide. The method uses diketene to react with bromine and then condenses with aniline to generate 4-bromo-3-oxo-N-phenyl butyramide, the reaction condition is mild, the purpose of generating high-content 4-bromo-3-oxo-N-phenyl butyramide by a one-step method can be realized, and the product obtained by production can reach the content required by subsequent production without refining, so that the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a synthesis method of 4-bromo-3-oxo-N-phenylbutanamide.
Background
4-bromomethylquinolinone is a key intermediate for producing rebamipide, rebamipide is a novel anti-ulcer drug, is firstly marketed in Japan as a drug for gastric ulcer and acute and chronic gastritis in 1990, and is a gastric mucosa protective agent in rebamipide, so that the gastric mucosa blood flow, the synthesis of prostaglandin E2 and the secretion of gastric mucosa can be increased, the expression of epidermal growth factor and a receptor thereof can be promoted, and the effects of preventing ulcer and promoting ulcer healing can be achieved. Research shows that the pharmaceutical composition is effective on various experimental gastric ulcers, can promote the generation of prostaglandin on gastric mucosa and protect the gastric mucosa from being damaged by various ulcer-causing factors, is suitable for treating gastric ulcer, acute gastritis and acute exacerbation of chronic gastritis and gastric mucosa lesion, and has high clinical application value.
The key intermediate for synthesizing the 4-bromomethylquinolinone is 4-bromo-3-oxo-N-phenylbutanamide. The intermediate is usually prepared by reacting acetoacetanilide with bromine, and the reaction equation is as follows:
in the production process, more dibromide and bromine byproducts on a benzene ring can be generated; the content of the obtained crude product is not high, the requirement of the next cyclization reaction can be met only by refining, the production process is complex, and the yield is not high due to large refining loss.
Disclosure of Invention
The embodiment of the invention aims to provide a synthesis method of 4-bromo-3-oxo-N-phenylbutanamide, aiming at solving the problems in the background art.
The embodiment of the invention is realized by a method for synthesizing 4-bromo-3-oxo-N-phenylbutanamide, which comprises the following steps:
putting diketene in an organic solvent, and dropwise adding bromine at the temperature of-15-50 ℃ for reaction to obtain a reaction solution;
and adding alkali and aniline into the reaction solution for heat preservation reaction, and filtering to obtain the 4-bromo-3-oxo-N-phenylbutyramide.
The reaction equation of the above synthesis method is as follows:
in the step, the temperature of the dropwise adding bromine is controlled to be 10-30 ℃.
In another preferable scheme of the embodiment of the invention, in the step, the temperature of the heat preservation reaction is controlled to be 30-60 ℃.
As another preferable scheme of the embodiment of the invention, in the step, the mass ratio of the diketene, the bromine and the organic solvent is 1 (1-5) to (1-15).
In another preferred embodiment of the present invention, the organic solvent is at least one of an alkane, a chlorinated hydrocarbon and an aromatic hydrocarbon, such as N-hexane, dichloromethane, chloroform, acetonitrile, 1, 2-dichloroethane, benzene, toluene, N-dimethylformamide and chlorobenzene.
As another preferable scheme of the embodiment of the invention, in the step, the reaction time is kept for 1-4 h.
As another preferable aspect of the embodiment of the present invention, the base is an inorganic base or an organic base.
In another preferred embodiment of the present invention, the inorganic base is at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and sodium acetate.
As another preferable mode of the embodiment of the present invention, the organic base is at least one of triethylamine, aniline, pyridine, 4-dimethylaminopyridine, and N, N-diisopropylethylamine.
According to the synthesis method of 4-bromo-3-oxo-N-phenylbutanamide provided by the embodiment of the invention, diketene is used for reacting with bromine, and then the diketene is condensed with aniline to generate 4-bromo-3-oxo-N-phenylbutanamide, the reaction conditions are mild, the purpose of generating high-content 4-bromo-3-oxo-N-phenylbutanamide by a one-step method can be realized, the one-pot production can be realized, and the product obtained by the production can reach the content required by the subsequent production without refining, so that the synthesis method is suitable for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
This example provides a method of synthesizing 4-bromo-3-oxo-N-phenylbutanamide, comprising the steps of:
s1, adding 84g of diketene and 600g of organic solvent into a reaction bottle, cooling to 5 ℃, stirring and mixing, controlling the system temperature to 15 ℃, and simultaneously dropwise adding 160g of bromine for reaction to obtain a reaction solution. Wherein the organic solvent is dichloromethane;
s2, stirring the reaction solution for 1h, adding 120g of alkali for mixing, controlling the temperature of the system at 30 ℃, gradually dripping a proper amount of aniline for reaction, and after dripping, placing at 35 ℃ for heat preservation reaction for 3h to obtain a reaction product. Wherein the base is triethylamine;
s3, cooling the reaction product to 3 ℃, filtering, leaching a filter cake with 50g of dichloromethane, and drying the filter cake to obtain 238.2g of 4-bromo-3-oxo-N-phenyl butyramide.
Example 2
This example provides a method of synthesizing 4-bromo-3-oxo-N-phenylbutanamide, comprising the steps of:
s1, adding 84g of diketene and 600g of organic solvent into a reaction bottle, cooling to 5 ℃, stirring and mixing, controlling the system temperature to 15 ℃, and simultaneously dropwise adding 160g of bromine for reaction to obtain a reaction solution. Wherein the organic solvent is dichloromethane;
s2, stirring the reaction solution for 1h, adding 100g of alkali for mixing, controlling the temperature of the system at 30 ℃, gradually dripping a proper amount of aniline for reaction, and after dripping, placing at 35 ℃ for heat preservation reaction for 3h to obtain a reaction product. Wherein the alkali is sodium bicarbonate;
s3, adding the reaction product into 1000g of water, cooling to 3 ℃, stirring for 40min, filtering, leaching the filter cake with 100g of water, and drying the filter cake to obtain 187g of 4-bromo-3-oxo-N-phenyl butyramide.
Example 3
This example provides a method of synthesizing 4-bromo-3-oxo-N-phenylbutanamide, comprising the steps of:
s1, adding 84g of diketene and 800g of organic solvent into a reaction bottle, cooling to 5 ℃, stirring and mixing, controlling the system temperature to 15 ℃, and simultaneously dropwise adding 180g of bromine for reaction to obtain a reaction solution. Wherein the organic solvent is 1, 2-dichloroethane;
s2, stirring the reaction solution for 0.5h, distilling under vacuum reduced pressure to evaporate about 200g of organic solvent, adding 200g of alkali for mixing, controlling the temperature of the system at 30 ℃, gradually adding a proper amount of aniline dropwise for reaction, and after dropwise addition, placing at 35 ℃ for heat preservation reaction for 3h to obtain a reaction product. Wherein the base is aniline;
s3, cooling the reaction product to 3 ℃, filtering, leaching a filter cake with 200g of 1, 2-dichloroethane, and drying the filter cake to obtain 220.0g of 4-bromo-3-oxo-N-phenylbutanamide.
Example 4
This example provides a method of synthesizing 4-bromo-3-oxo-N-phenylbutanamide, comprising the steps of:
s1, adding 84g of diketene and 800g of organic solvent into a reaction bottle, cooling to 5 ℃, stirring and mixing, controlling the system temperature to 35 ℃, and simultaneously dropwise adding 180g of bromine for reaction to obtain a reaction solution. Wherein the organic solvent is 1, 2-dichloroethane;
s2, stirring the reaction solution for 0.5h, distilling under vacuum reduced pressure to evaporate about 200g of organic solvent, adding 200g of alkali for mixing, controlling the temperature of the system at 20 ℃, gradually adding a proper amount of aniline dropwise for reaction, and after dropwise addition, placing at 55 ℃ for heat preservation reaction for 3h to obtain a reaction product. Wherein the base is aniline;
s3, cooling the reaction product to 3 ℃, filtering, leaching a filter cake with 200g of 1, 2-dichloroethane, and drying the filter cake to obtain 205.7g of 4-bromo-3-oxo-N-phenylbutanamide.
Example 5
This example provides a method of synthesizing 4-bromo-3-oxo-N-phenylbutanamide, comprising the steps of:
s1, adding 80g of diketene and 80g of organic solvent into a reaction bottle, cooling to 5 ℃, stirring and mixing, controlling the system temperature at-15 ℃, and simultaneously dropwise adding 80g of bromine for reaction to obtain a reaction solution. Wherein the organic solvent is n-hexane;
s2, stirring the reaction solution for 1 hour, adding 120g of alkali for mixing, controlling the temperature of the system at 20 ℃, gradually dripping a proper amount of aniline for reaction, and after dripping, placing at 30 ℃ for heat preservation reaction for 1 hour to obtain a reaction product. Wherein the alkali is a mixture of sodium carbonate, potassium carbonate and sodium acetate;
s3, cooling the reaction product to 0 ℃, filtering, leaching a filter cake with 50g of N-hexane, and drying the filter cake to obtain the 4-bromo-3-oxo-N-phenylbutanamide.
Example 6
This example provides a method of synthesizing 4-bromo-3-oxo-N-phenylbutanamide, comprising the steps of:
s1, adding 80g of diketene and 1200g of organic solvent into a reaction bottle, cooling to 5 ℃, stirring and mixing, controlling the system temperature at 50 ℃, and simultaneously dropwise adding 400g of bromine for reaction to obtain a reaction solution. Wherein the organic solvent is a mixture of trichloromethane and acetonitrile;
and S2, stirring the reaction solution for 4 hours, adding 120g of alkali for mixing, controlling the temperature of the system at 40 ℃, gradually dropwise adding a proper amount of aniline for reaction, and after dropwise adding, placing at 60 ℃ for heat preservation reaction for 4 hours to obtain a reaction product. Wherein the alkali is a mixture of sodium hydroxide and potassium hydroxide;
s3, cooling the reaction product to 5 ℃, filtering, leaching a filter cake with 50g of dichloromethane, and drying the filter cake to obtain the 4-bromo-3-oxo-N-phenyl butyramide.
Example 7
This example provides a method of synthesizing 4-bromo-3-oxo-N-phenylbutanamide, comprising the steps of:
s1, adding 84g of diketene and 600g of organic solvent into a reaction bottle, cooling to 5 ℃, stirring and mixing, controlling the system temperature to 10 ℃, and simultaneously dropwise adding 160g of bromine for reaction to obtain a reaction solution. Wherein the organic solvent is a mixture of benzene and toluene;
and S2, stirring the reaction solution for 2 hours, adding 120g of alkali for mixing, controlling the temperature of the system at 30 ℃, gradually dropwise adding a proper amount of aniline for reaction, and after dropwise adding, placing at 40 ℃ for heat preservation reaction for 3 hours to obtain a reaction product. Wherein the alkali is a mixture of triethylamine and pyridine;
s3, cooling the reaction product to 5 ℃, filtering, leaching a filter cake with 50g of benzene, and drying the filter cake to obtain the 4-bromo-3-oxo-N-phenyl butyramide.
Example 8
This example provides a method of synthesizing 4-bromo-3-oxo-N-phenylbutanamide, comprising the steps of:
s1, adding 84g of diketene and 600g of organic solvent into a reaction bottle, cooling to 5 ℃, stirring and mixing, controlling the system temperature at 30 ℃, and simultaneously dropwise adding 160g of bromine for reaction to obtain a reaction solution. Wherein the organic solvent is N, N-dimethylformamide;
and S2, stirring the reaction solution for 3 hours, adding 120g of alkali for mixing, controlling the temperature of the system at 30 ℃, gradually dropwise adding a proper amount of aniline for reaction, and after dropwise adding, placing at 50 ℃ for heat preservation reaction for 3 hours to obtain a reaction product. Wherein the base is C4-dimethylaminopyridine;
s3, cooling the reaction product to 2 ℃, filtering, leaching the filter cake with 50g of N, N-dimethylformamide, and drying the filter cake to obtain the 4-bromo-3-oxo-N-phenylbutanamide.
Example 9
This example provides a method of synthesizing 4-bromo-3-oxo-N-phenylbutanamide, comprising the steps of:
s1, adding 84g of diketene and 800g of organic solvent into a reaction bottle, cooling to 5 ℃, stirring and mixing, controlling the system temperature at 20 ℃, and simultaneously dropwise adding 150g of bromine for reaction to obtain a reaction solution. Wherein the organic solvent is chlorobenzene;
and S2, stirring the reaction solution for 3 hours, adding 100g of alkali for mixing, controlling the temperature of the system at 30 ℃, gradually dropwise adding a proper amount of aniline for reaction, and after dropwise adding, placing at 40 ℃ for heat preservation reaction for 3 hours to obtain a reaction product. Wherein the base is N, N-diisopropylethylamine;
s3, cooling the reaction product to 2 ℃, filtering, leaching the filter cake with 50g of aromatic hydrocarbon, and drying the filter cake to obtain the 4-bromo-3-oxo-N-phenyl butyramide.
Example 10
This example provides a method of synthesizing 4-bromo-3-oxo-N-phenylbutanamide, comprising the steps of:
s1, adding 84g of diketene and 500g of organic solvent into a reaction bottle, cooling to 5 ℃, stirring and mixing, controlling the system temperature at 30 ℃, and simultaneously dropwise adding 150g of bromine for reaction to obtain a reaction solution. Wherein the organic solvent is dichloromethane;
s2, stirring the reaction solution for 2 hours, adding 100g of alkali for mixing, controlling the temperature of the system at 30 ℃, gradually dripping a proper amount of aniline for reaction, and after dripping, placing at 50 ℃ for heat preservation reaction for 3 hours to obtain a reaction product. Wherein the alkali is sodium carbonate;
s3, cooling the reaction product to 3 ℃, filtering, leaching a filter cake with 50g of dichloromethane, and drying the filter cake to obtain the 4-bromo-3-oxo-N-phenyl butyramide.
The content and yield of 4-bromo-3-oxo-N-phenylbutanamide synthesized in examples 1 to 4 were measured, and the measurement results are shown in table 1.
TABLE 1
| Synthesis method | Product content | Yield of product |
| Example 1 | 99.1% | 93.0% |
| Example 2 | 96.5% | 73.0% |
| Example 3 | 98.1% | 85.9% |
| Example 4 | 95.1% | 80.3% |
In summary, in the synthesis method provided by the embodiment of the present invention, diketene is reacted with bromine, and then the reaction product is condensed with aniline to generate 4-bromo-3-oxo-N-phenylbutanamide, the reaction conditions are mild, and the purpose of generating high content of 4-bromo-3-oxo-N-phenylbutanamide by a one-step method can be achieved.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (9)
1. A synthetic method of 4-bromo-3-oxo-N-phenylbutanamide is characterized by comprising the following steps:
putting diketene in an organic solvent, and dropwise adding bromine at the temperature of-15-50 ℃ for reaction to obtain a reaction solution;
and adding alkali and aniline into the reaction solution for heat preservation reaction, and filtering to obtain the 4-bromo-3-oxo-N-phenylbutyramide.
2. The method for synthesizing 4-bromo-3-oxo-N-phenylbutanamide according to claim 1, wherein in the step, the temperature for adding bromine dropwise is controlled to be 10-30 ℃.
3. The method for synthesizing 4-bromo-3-oxo-N-phenylbutanamide according to claim 1, wherein in the step, the temperature of the heat preservation reaction is controlled to be 30-60 ℃.
4. The method for synthesizing 4-bromo-3-oxo-N-phenylbutanamide according to claim 1, wherein in the step (A), the mass ratio of the diketene to the bromine to the organic solvent is 1 (1-5) to (1-15).
5. The method for synthesizing 4-bromo-3-oxo-N-phenylbutanamide according to claim 1 or 4, wherein the organic solvent is at least one of N-hexane, dichloromethane, chloroform, acetonitrile, 1, 2-dichloroethane, benzene, toluene, N-dimethylformamide, and chlorobenzene.
6. The method for synthesizing 4-bromo-3-oxo-N-phenylbutanamide according to claim 1, wherein in the step, the reaction is carried out for 1-4 hours under heat preservation.
7. The method for synthesizing 4-bromo-3-oxo-N-phenylbutanamide according to claim 1, wherein the base is an inorganic base or an organic base.
8. The method for synthesizing 4-bromo-3-oxo-N-phenylbutanamide according to claim 7, wherein the inorganic base is at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and sodium acetate.
9. The method for synthesizing 4-bromo-3-oxo-N-phenylbutanamide according to claim 7, wherein the organic base is at least one of triethylamine, aniline, pyridine, 4-dimethylaminopyridine, and N, N-diisopropylethylamine.
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