Preparation method of cefquinome

Abstract

The invention discloses a preparation method of cefquinome sulfate, which comprises the following steps: reacting 7-ACA with tetrahydroquinoline under the action of trimethyliodosilane, and oxidizing with hydrogen peroxide to obtain an intermediate 7-ACQ; enabling the 7-ACQ to react with AE-active ester, and performing post-treatment to obtain the cefquinome. The cefquinome is prepared by adopting a new synthesis route, the conditions are mild, the process is stable, and the operation is easy.

Description

Technical Field

[0001] The present application belongs to the technical field of drug synthesis, and specifically relates to a method for preparing cefquinome. Background Art

[0002] Cefquinome is a fourth-generation cephalosporin antibiotic, which is now mainly used as a veterinary antibiotic. There are not many literature reports on the preparation process of this variety. The main method is: using 7-aminocephalosporanic acid (7-ACA) as the raw material and dichloromethane as the reaction solvent, the important intermediate of cefquinome sulfate, 7-aminocefquinome (7-ACQ) hydroiodide, is obtained through a "one-pot method" through silylation reaction, iodination reaction, nucleophilic substitution reaction and deprotection steps; using acetone and water as condensation reaction solvents, the intermediate reacts with AE-active ester under the action of triethylamine, and cefquinome sulfate is obtained after acidification with sulfuric acid. This application designs a process route for the purpose of reducing costs, improving yields, and saving energy and protecting the environment. Summary of the invention

[0003] The present application discloses a method for preparing cefquinome, comprising the following steps: 1) 7-ACA and tetrahydroquinoline were reacted with trimethylsilyl iodide to prepare 7-ACQ; 2) 7-ACQ and AE-active ester are salified with sulfuric acid to obtain cefquinome sulfate; 3) Cefquinome sulfate is dissolved in water, and the pH is adjusted with an organic base to precipitate cefquinome crystals.

[0004] Compared with the prior art, the present application can obtain the following technical effects: 1) In the synthesis process involved in the present application, the key intermediate 7-ACQ is first prepared from 7-ACA, and the product color can be well controlled during the process. In this way, the product color can also be kept good in the subsequent condensation, and high temperature heating can be avoided.

[0005] 2) After the condensation reaction between 7-ACQ and AE-active ester, the product is crystallized in the form of sulfate, which ensures the purity and quality of the product. After that, the sulfate is dissolved in water (or methanol, ethanol) and purified to further improve the quality of the product.

[0006] 3) The process of the present application is stable and feasible, and it is easy to realize industrialization in industry, with high product yield and good quality.

[0007] Of course, any product implementing this application does not necessarily need to achieve all of the technical effects described above at the same time.

[0008] In the above-mentioned synthetic method of the present invention, the addition amount, concentration, reactant ratio of various reactants and solvents etc. can be determined by those skilled in the art according to various factors such as calculation of chemical reaction formula, production scale, etc., and can also be adjusted and optimized by limited tests according to existing in the art. This is within the capabilities of those skilled in the art and is not critical to the realization of the excellent effects of the present invention. Their exemplary quantitative values ​​are provided in the embodiments of the present invention, but this is not meant to limit the scope of the present invention. DETAILED DESCRIPTION

[0009] The following will be used in conjunction with examples to describe the implementation methods of the present application in detail, so that the implementation process of how the present application uses technical means to solve technical problems and achieve technical effects can be fully understood and implemented accordingly. However, the following examples are only used to illustrate the principles of the present invention and provide proof of the feasibility of the present invention, and do not constitute a limitation on the scope of the present invention. All technologies that can be implemented based on the above content of the present invention belong to the scope of the present invention.

[0010] Example 1 Preparation of 7-ACQ In a 500mL three-necked flask, add 85mL of dichloromethane and 19.5g of hexamethyldisilazane, and stir. Add 25g of 7-ACA and 0.1mL of trimethylsilyl iodide, stir, and reflux for 4 hours. Cool down to 0-10℃, add 25mL of N, N-diethylaniline, and stir evenly. Add 20mL of trimethylsilyl iodide, heat to 15-20℃, and stir. After the reaction is completed, cool down to 0-10℃, add 26g of 5, 6, 7, 8-tetrahydroquinoline and 45mL of N, N-dimethylacetamide, stir and react for 2 hours, and the reaction is completed. Add 150mL of dichloromethane, add 28mL of methanol dropwise, and then add 60mL of 6MHCl, stir and separate the phases, cool the aqueous phase to 0-10℃, add 10 mL of 7% hydrogen peroxide dropwise, and add within 30 minutes. Stir for 10 minutes. Filter. Add 3 g of activated carbon, stir and decolorize for 30 min, filter and remove the activated carbon. Stir the aqueous phase, add 30 mL of acetone, stir and grow crystals at 0-10°C for 1 hour, filter, wash the filter with acetone / water (1 / 1) mixed solution, and then wash three times with 30 mL of acetone. Dry under vacuum at below 40°C, vacuum ≤-0.08Mpa, and obtain about 30 g of light yellow solid 7-ACQ.

[0011] Example 2 Preparation of 7-ACQ In a 500mL three-necked flask, add 85mL of dichloromethane and 19.5g of hexamethyldisilazane, and stir. Add 25g of 7-ACA and 0.1mL of trimethylsilyl iodide, stir, and reflux for 4 hours. Cool down to 0-10℃, add 25mL of N, N-diethylaniline, and stir evenly. Add 20mL of trimethylsilyl iodide, heat to 15-20℃, and stir. After the reaction is completed, cool down to 0-10℃, add 26g of 5, 6, 7, 8-tetrahydroquinoline and 45mL of N, N-dimethylacetamide, stir and react for 2 hours, and the reaction is completed. Add 150mL of dichloromethane, add 28mL of methanol dropwise, and then add 60mL of 6MHCl, stir and separate the phases, cool the aqueous phase to 0-10℃, add 5mL of 7% hydrogen peroxide dropwise, and add within 30 minutes. Stir for 10 minutes. Filter. Add 3 g of activated carbon, stir and decolorize for 30 min, filter and remove the activated carbon. Stir the aqueous phase, add 30 mL of acetone, stir and grow crystals at 0-10°C for 1 hour, filter, wash the filter with acetone / water (1 / 1) mixed solution, and then wash three times with 30 mL of acetone. Dry under vacuum at below 40°C, vacuum ≤-0.08Mpa, and obtain about 30 g of light yellow solid 7-ACQ.

[0012] Example 3 Preparation of 7-ACQ In a 500mL three-necked flask, add 85mL of dichloromethane and 19.5g of hexamethyldisilazane, and stir. Add 25g of 7-ACA and 0.1mL of trimethylsilyl iodide, stir, and reflux for 4 hours. Cool down to 0-10℃, add 25mL of N, N-diethylaniline, and stir evenly. Add 20mL of trimethylsilyl iodide, heat to 15-20℃, and stir. After the reaction is completed, cool down to 0-10℃, add 26g of 5, 6, 7, 8-tetrahydroquinoline and 45mL of N, N-dimethylacetamide, stir and react for 2 hours, and the reaction is completed. Add 150mL of dichloromethane, add 28mL of methanol dropwise, and then add 60mL of 6MHCl, stir and separate the phases, cool the aqueous phase to 0-10℃, add 20mL of 3% hydrogen peroxide dropwise, and add within 30 minutes. Stir for 10 minutes. Filter. Add 3 g of activated carbon, stir and decolorize for 30 min, filter and remove the activated carbon. Stir the aqueous phase, add 30 mL of acetone, stir and grow crystals at 0-10°C for 1 hour, filter, wash the filter with acetone / water (1 / 1) mixed solution, and then wash three times with 30 mL of acetone. Dry under vacuum at below 40°C, vacuum ≤-0.08Mpa, and obtain about 30 g of light yellow solid 7-ACQ.

[0013] Example 4 Preparation of crude cefquinome sulfate In a 500mL three-necked flask, add 160mL of anhydrous ethanol, then add 220mL of dichloromethane, stir, then add 30g of 7-ACQ, and continue stirring. Cool to 3-7℃, add 1.5mL of triethylamine dropwise, and stir. Add 25.5g of AE-active ester and 0.2g of sodium sulfite, and stir for 3 hours. Filter, wash the filter cake with a mixture of 50mL of dichloromethane and 80mL of ethanol, add the combined filtrate to a 500mL three-necked flask, add 80mL of purified water, stir for 10 minutes, stand for stratification, discard the dichloromethane phase, and add 60mL of ethyl acetate to the aqueous phase for extraction. Stand for stratification, take the aqueous phase, add 10mL of water to the ethyl acetate phase for extraction, stand for stratification, and discard the ethyl acetate phase. Combine the aqueous phase and add it to a 500mL three-necked flask, cool it to 3-7℃, stir, add 120mL acetone, adjust the pH to 4.0, add 4g activated carbon, stir and decolorize for 20 minutes, filter, and wash the filter cake with a mixture of 30mL acetone and 10mL water. Add the filtrate to a 500mL three-necked flask, heat it to 25℃, stir, add sulfuric acid dropwise, adjust the pH to 2.0, cool it to 20-15℃, stir and crystallize for 1 hour. Add acetone dropwise, cool it to 7-10℃, adjust the pH to about 1.8, stir and crystallize for 30 minutes, filter, wash the filter cake with 100mL acetone three times, and filter it. Put it in a dryer, keep the vacuum degree ≤-0.08Mpa, and vacuum dry it below 40℃ to a moisture content of ≤4.0%. The dry product is about 18-20g, and the yield is 72-80%.

[0014] Example 5 Cefquinome Sulfate Recrystallization Add 175mL of purified water, 59.8mL of ethyl acetate, and 0.2g of sodium pyrosulfite to a 500mL three-necked flask, stir and cool to 3-7℃. Add 25.5g of crude cefquinome sulfate, stir for 10 minutes, and turn off. Slowly add 12.5mL of triethylamine, stir for 30 minutes to dissolve all, stop stirring, and let it stand for stratification. Take the aqueous phase, add 10mL of ethyl acetate to the aqueous phase, extract for 10 minutes, and let it stand for stratification. Combine the aqueous phases, add 30.5mL of ethanol, cool to 3-7℃, add 120mL of acetone, adjust the pH to 4.0 with sulfuric acid, add 3g of activated carbon, and stir for 20 minutes. Filter, wash the cake with 30mL of acetone and 10mL of water mixture. Control the temperature at 15-20℃, drop 6.5mL of sulfuric acid to adjust the pH to 2±0.1, form salt, and add a little seed crystal, grow the crystal for 1 hour, and the crystal growing is complete. Add 200mL of acetone and sulfuric acid to adjust the pH to 1.8, and then cool to 3-7℃. Cultivate the crystal for 1 hour. Filter and wash, and wash the filter cake with 38mL of acetone three times. Keep the wet product in vacuum degree ≥-0.08Mpa, temperature 45-50℃, and dry to moisture ≤4.0%. Get the dry product. After the test is qualified, unload the dry product, weigh about 20.4g of dry product, and the molar yield of dry product is 97.14±2%.

[0015] The process for synthesizing cefquinome by adopting the method is stable and feasible, and it is easy to realize industrialization in industry, and the product yield is high and the quality is good.

[0016] The above description shows and describes several preferred embodiments of the invention, but as mentioned above, it should be understood that the invention is not limited to the form disclosed herein, and should not be regarded as excluding other embodiments, but can be used in various other combinations, modifications and environments, and can be modified within the scope of the invention concept described herein through the above teachings or the technology or knowledge of the relevant field. Changes and modifications made by those skilled in the art should be within the scope of protection of the claims attached to the invention without departing from the spirit and scope of the invention.

Claims

1. A method for preparing cefquinome, characterized in that: The following steps are involved: 7-ACA reacts with tetrahydroquinoline under the action of trimethylsilyl iodide, and then oxidizes with hydrogen peroxide to prepare 7-ACQ; then condenses with AE-active ester in a solvent, and uses a base to maintain the pH value during the process. After the reaction is completed, an inorganic acid is added to precipitate cefquinome inorganic acid salt; the cefquinome inorganic acid salt is dissolved in water, an organic base is added, the pH is adjusted, the mixture is fully stirred, and the cefquinome inorganic acid salt is filtered to obtain cefquinome.

2. As described in claim 1, the condensation of 7-ACA and tetrahydroquinoline is carried out under the action of trimethylsilyl iodide, and then oxidized with hydrogen peroxide, wherein the concentration of hydrogen peroxide is 3% to 7%, and the amount added is 20% to 40% of 7-ACA.

3. As described in claim 1, in the process of recrystallization of cefquinome sulfate, the crystal growing step should be carried out under controlled pH and temperature conditions, wherein the pH is 2±0.1 and the temperature is 3-7°C.