Preparation method of difloxacin key intermediate
By improving the difloxacin synthesis route, using acid binding agents and organic solvents to avoid low temperature and dangerous raw materials, the problems of harsh reaction conditions and low yields in the prior art are solved, and efficient preparation of key difloxacin intermediates are achieved.
Patent Information
- Application Number
- CN202510617571.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-14
- Publication Date
- 2025-08-19
AI Technical Summary
The reaction conditions in the existing difloxacin synthesis route are harsh, and dangerous raw materials such as butyl lithium are used. The reaction time is long and the yield is not high, making it difficult to adapt to industrial production.
In the presence of acid binding agent, 2,3,4,5-tetrafluorobenzoyl chloride and N,N-dimethylaminoacrylate react in an organic solvent. After adding p-fluoroaniline, the ring is closed, and then the aqueous alkali solution is added to hydrolyze and acidify to avoid low temperature conditions and dangerous raw materials, and control the limit of reaction impurities.
It achieves mild reaction conditions, simplifies operating steps, improves yield, is suitable for industrial production, and reduces impurity content.
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Figure CN120504632A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of difloxacin synthesis, and in particular to a method for preparing a key intermediate of difloxacin. Background Art
[0002] Difloxacin is a latest-generation fluoroquinolone drug with a broad antimicrobial spectrum and strong bactericidal activity. It is highly effective against most Gram-negative and Gram-positive bacteria, mycoplasmas, and anaerobic infections of the digestive tract, respiratory tract, urinary tract, and skin. Difloxacin is primarily used to prevent and treat sensitive bacterial infections in dogs and chickens. It can also treat contagious pleuropneumonia, swine plague, and swine asthma in pigs. It has the structure shown in Formula I.
[0003]
[0004] The key intermediate for synthesizing difloxacin is shown in Formula II.
[0005]
[0006] In the prior art, the synthetic route of formula II is as follows:
[0007]
[0008] However, in this synthetic route, butyl lithium and monoethyl malonate react at -35°C to generate lithium monoethyl malonate, which then reacts with 2,3,4,5-tetrafluorobenzoyl chloride at -78°C to obtain Formula II. On the one hand, the reaction conditions are harsh and the industrial production value is low; on the other hand, the reaction time is long and the yield is not high. Summary of the Invention
[0009] The present application provides a method for preparing a key intermediate of difloxacin to solve the problems mentioned in the background technology.
[0010] To achieve the above objectives, the present application provides a method for preparing a key intermediate of difloxacin, which comprises the following steps:
[0011] In the presence of an acid-binding agent, 2,3,4,5-tetrafluorobenzoyl chloride and ethyl N,N-dimethylaminoacrylate are placed in an organic solvent to react;
[0012] After adding p-fluoroaniline, heat at 95-100°C in the presence of an acid-binding agent to close the ring;
[0013] Add an aqueous base solution for hydrolysis, and finally acidify to obtain the key intermediate of difloxacin.
[0014] Preferably, the organic solvent is tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, dioxane, ethyl acetate, toluene, xylene, chlorobenzene or a mixture thereof.
[0015] Preferably, the acid binding agent is triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine, pyridine or a mixture thereof.
[0016] Preferably, the reaction temperature of the 2,3,4,5-tetrafluorobenzoyl chloride and N,N-ethyl dimethacrylate is 40-110° C., and the reaction time is 0-10 h.
[0017] Preferably, in S1, it includes: adding 2,3,4,5-tetrafluorobenzoyl chloride and an acid binding agent to an organic solvent, and dropwise adding N,N-dimethylaminoethyl acrylate at 10-20° C., heating to 65-70° C. and reacting for 2-8 hours.
[0018] Preferably, the molar ratio of 2,3,4,5-tetrafluorobenzoyl chloride to N,N,-ethyl dimethacrylate is 1:1.
[0019] Preferably, the reaction temperature after the addition of p-fluoroaniline is 30-50° C., and the reaction time is 0-6 h.
[0020] Preferably, in the aqueous alkali solution, the alkali is one of sodium hydroxide, potassium hydroxide, and lithium hydroxide, and the solvent is at least one of water, methanol, and ethanol.
[0021] Preferably, when the hydrolysis is completed and acidification is performed, the pH value adjusted by acidification is 2 to 3, and the acid used is one of hydrochloric acid and dilute sulfuric acid.
[0022] The beneficial effects of the technical solution provided by this application include:
[0023] This application provides a method for preparing a key intermediate of difloxacin. This method utilizes a one-pot process, using ethyl dimethylaminoacrylate as a raw material to react with 2,3,4,5-tetrafluorobenzoyl chloride, followed by reaction with p-fluoroaniline, and then ring closure to obtain the key intermediate of difloxacin. The reaction process is simple, requires few steps, and operates under mild conditions, avoiding low temperatures of -78°C and the use of hazardous raw materials such as butyl lithium. The required raw materials are gradually added throughout the process, and the intermediate does not require purification during the reaction. The reaction process controls the degree of reaction, keeping the impurity limit at a low level, resulting in a high yield and being suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.
[0025] Figure 1 This is a flow chart of the preparation method of the key intermediate of difloxacin provided in this application. DETAILED DESCRIPTION
[0026] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.
[0027] See also Figure 1 As shown, the present application provides a method for preparing a key intermediate of difloxacin, which comprises the following steps:
[0028] In the presence of an acid-binding agent, 2,3,4,5-tetrafluorobenzoyl chloride and N,N-dimethylaminoethyl acrylate are placed in an organic solvent to react;
[0029] After adding p-fluoroaniline, heat at 95-100°C in the presence of an acid-binding agent to close the ring;
[0030] Add an aqueous base solution for hydrolysis, and finally acidify to obtain the key intermediate of difloxacin.
[0031] Furthermore, after acidification, the process further includes filtering or centrifuging to obtain a primary product, and then drying at 90-95° C. to obtain a key intermediate of difloxacin.
[0032] In some optional embodiments, the organic solvent is tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, dioxane, ethyl acetate, toluene, xylene, chlorobenzene or a mixture thereof.
[0033] In some optional embodiments, the acid binding agent is triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine, pyridine or a mixture thereof.
[0034] In some optional embodiments, the reaction temperature of 2,3,4,5-tetrafluorobenzoyl chloride and N,N-ethyl dimethacrylate is 40-110° C., and the reaction time is 0-10 h.
[0035] In some optional embodiments, S1 specifically includes: adding 2,3,4,5-tetrafluorobenzoyl chloride and an acid binding agent to an organic solvent, and dropwise adding N,N-dimethylamino ethyl acrylate at 10-20° C., heating to 65-70° C. and reacting for 2-8 hours.
[0036] In some optional embodiments, the ratio of 2,3,4,5-tetrafluorobenzoyl chloride to N,N,-ethyl dimethacrylate is 1:1.
[0037] In some optional embodiments, the reaction temperature after adding p-fluoroaniline is 30-50° C., and the reaction time is 0-6 h.
[0038] In some optional embodiments, in the aqueous alkali solution, the alkali is one of sodium hydroxide, potassium hydroxide, and lithium hydroxide, and the solvent is at least one of water, methanol, and ethanol.
[0039] In some optional embodiments, when the hydrolysis is completed and acidification is performed, the specific pH value of the acidification adjustment is 2-3, and the acid used is one of hydrochloric acid and dilute sulfuric acid.
[0040] Example 1
[0041] S1. Add 300 mL of toluene, 100 g of 2,3,4,5-tetrafluorobenzoyl chloride, and 90 g of tri-n-butylamine to a 1 L three-necked flask. Maintain the temperature at 15°C, add 80.5 g of ethyl N,N-dimethylaminoacrylate dropwise, raise the temperature to 70°C, and react for 2 h.
[0042] S2. After cooling to 40°C, add 51.3g of p-fluoroaniline, control the temperature to 30°C and react for 2h;
[0043] After cooling to room temperature, add 200 mL of water and adjust the pH to 4 with hydrochloric acid. Separate the aqueous layer and add 170 g of toluene to the toluene layer. Remove the water from the organic layer. Maintain the temperature at 95°C and add 66 g of anhydrous potassium carbonate. Maintain the temperature at 95°C after addition and react for 1 hour. Remove the toluene by distillation and recycle.
[0044] S3. Add 500 g of an aqueous solution containing 15 g of sodium hydroxide, heat to 95 ° C, stir for 1.5 h, cool to 25 ° C, add hydrochloric acid to adjust the pH to 2, stir for 30 min, filter, and dry to obtain 150 g of the product with a total yield of 93.8%, HPLC>98.5%.
[0045] Example 2
[0046] S1. Add 300 mL of dioxane, 100 g of 2,3,4,5-tetrafluorobenzoyl chloride, and 96 g of triethylamine to a 1 L three-necked flask. Maintain the temperature at 15°C, add 80.5 g of ethyl N,N-dimethylaminoacrylate dropwise, raise the temperature to 65°C, and react for 4 h.
[0047] S2. After cooling to 40°C, add 51.3g of p-fluoroaniline and control the temperature to 40°C for 2h;
[0048] After cooling to room temperature, add 250 mL of water, separate the aqueous layer, add 170 g of toluene to the toluene layer, and remove the water from the organic layer. Maintain the temperature at 98°C and add 66 g of anhydrous potassium carbonate. Maintain the temperature at 98°C after addition and react for 1 hour. Distill to remove the toluene and recover it for reuse.
[0049] S3. Add 500 g of an aqueous solution containing 15 g of sodium hydroxide, heat to 95 ° C, stir for 1.5 h, cool to 25 ° C, add hydrochloric acid to adjust the pH to 2, stir for 30 min, filter and dry to obtain 145 g of product with a total yield of 90.6%, HPLC>98.8%.
[0050] Example 3
[0051] S1. Add 200 mL of tetrahydrofuran, 100 mL of methyltetrahydrofuran, 100 g of 2,3,4,5-tetrafluorobenzoyl chloride, and 96 g of a mixture of tri-n-propylamine and diisopropylethylamine (the mass ratio of tri-n-propylamine to diisopropylethylamine is 2:1) to a 1 L three-necked flask. Maintain the temperature at 20° C., add 80.5 g of ethyl N,N-dimethylaminoacrylate dropwise, raise the temperature to 70° C., and react for 8 h.
[0052] S2. After cooling to 35°C, add 51.3g of p-fluoroaniline, control the temperature to 50°C and react for 3h;
[0053] After cooling to room temperature, add 200 mL of water and adjust the pH to 4 with hydrochloric acid. Separate the aqueous layer and add 170 g of toluene to the toluene layer. Remove the water from the organic layer. Maintain the temperature at 100°C and add 66 g of anhydrous potassium carbonate. Maintain the temperature at 100°C for 1 hour. Remove the toluene by distillation and recycle.
[0054] Add 500 g of an aqueous solution containing 15 g of sodium hydroxide, heat to 95 ° C, stir for 1.5 h, cool to 25 ° C, add dilute sulfuric acid to adjust the pH to 3, stir for 30 min, filter and dry to obtain 142 g of product with a total yield of 88.7%, HPLC>97.7%.
[0055] It can be seen that the key intermediate of difloxacin obtained in the example has a low impurity limit in the reaction and a high yield, and is suitable for industrial production.
[0056] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.
Claims
1. A method for preparing a key intermediate of difloxacin, characterized in that: It includes the following steps: S1. In the presence of an acid binding agent, reacting 2,3,4,5-tetrafluorobenzoyl chloride and ethyl N,N-dimethylaminoacrylate in an organic solvent; S2. After adding p-fluoroaniline, heat at 95-100°C in the presence of an acid binding agent to close the ring; S3. Add an aqueous base solution for hydrolysis, and finally acidify to obtain the key intermediate of difloxacin.
2. The method for preparing a key intermediate of difloxacin as claimed in claim 1, wherein: The organic solvent is tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, dioxane, ethyl acetate, toluene, xylene, chlorobenzene or a mixture thereof.
3. The method for preparing the key intermediate of difloxacin as claimed in claim 1, wherein: The acid binding agent is triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine, pyridine or a mixture thereof.
4. The method for preparing a key intermediate of difloxacin as claimed in claim 1, wherein: The reaction temperature of the 2,3,4,5-tetrafluorobenzoyl chloride and N,N-ethyl dimethacrylate is 40-110° C., and the reaction time is 0-10 hours.
5. The method for preparing the key intermediate of difloxacin according to claim 1 or 4, wherein: In the above-mentioned S1, it comprises: adding 2,3,4,5-tetrafluorobenzoyl chloride and an acid binding agent to an organic solvent, and dropwise adding N,N-dimethylaminoethyl acrylate at 10-20° C., raising the temperature to 65-70° C. and reacting for 2-8 hours.
6. The method for preparing the key intermediate of difloxacin as claimed in claim 1, wherein: The molar ratio of the 2,3,4,5-tetrafluorobenzoyl chloride to N,N,-ethyl dimethacrylate is 1:
1.
7. The method for preparing the key intermediate of difloxacin as claimed in claim 1, wherein: The reaction temperature after the addition of the p-fluoroaniline is 30-50° C., and the reaction time is 0-6 hours.
8. The method for preparing the key intermediate of difloxacin as claimed in claim 1, wherein: In the aqueous alkali solution, the alkali is one of sodium hydroxide, potassium hydroxide, and lithium hydroxide, and the solvent is at least one of water, methanol, and ethanol.
9. The method for preparing the key intermediate of difloxacin as claimed in claim 1, wherein: When the hydrolysis is completed and acidification is carried out, the pH value of the acidification adjustment is 2 to 3, and the acid used is one of hydrochloric acid and dilute sulfuric acid.