Preparation method of cefazolin acid three-position intermediate TDA

Abstract

The invention relates to preparation of a cefazolin compound, in particular to a preparation method of a cefazolin acid three-position intermediate TDA. The preparation method comprises the following steps: carrying out condensation reaction on 7-ACA and MMTD serving as raw materials, dimethyl carbonate serving as a solvent and a boron trifluoride dimethyl carbonate complex and glacial acetic acid serving as catalysts to obtain condensation reaction liquid; adding EDTA (Ethylene Diamine Tetraacetic Acid) and sodium pyrosulfite into water, carrying out stirring reaction, transferring the condensation reaction liquid into water, and continuously carrying out heat-preservation stirring, so as to obtain a hydrolysis reaction liquid; and adding a sodium carbonate solution into the hydrolysis reaction solution while stirring, adjusting the pH value, growing crystals, and then performing suction filtration, washing and drying to obtain a finished product. A boron trifluoride dimethyl carbonate complex-glacial acetic acid catalysis method is adopted, the product quality and yield are guaranteed in industrial production, meanwhile, the reagent usage amount and the waste liquid generation amount are reduced, the production cost and the environment pressure are reduced, normal reaction is maintained at normal pressure, and the reaction is prevented from being too severe.

Description

Technical Field

[0001] The invention relates to the preparation of cefazolin compounds, and in particular to a method for preparing a three-terminal intermediate TDA of cefazolinic acid. Background Art

[0002] Cefazolinic acid, chemically known as (6R,7R)-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-8-oxo-7-[[2-(tetrazolyl-1-yl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, is a semi-synthetic cephalosporin with a broad-spectrum antibacterial effect that can inhibit the synthesis of bacterial cell walls. It is widely used clinically for sensitive bacterial infections of organs and tissues such as the liver, kidney, heart, spleen, lung, and muscle.

[0003] The preparation of the three-terminal intermediate TDA of cefazolinic acid usually starts with 7-ACA, which directly reacts with MMTD in the presence of a catalyst to obtain the intermediate 3-(2-methyl-1,3,4-thiodiazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid (TDA). In the previous method, the reaction of 7-ACA and MMTD must be carried out under pressure or nitrogen protection conditions to ensure the safety of the reaction and promote the normal progress of the reaction. There are many types of catalysts for this reaction. Patent CN105646537A provides a solution using concentrated sulfuric acid as a catalyst. However, in industrial production, the concentrated sulfuric acid catalytic method consumes a large amount of reagents, produces a lot of waste liquid, and increases the workload for subsequent waste liquid treatment and reagent storage. In terms of physical and chemical properties, concentrated sulfuric acid releases heat when dissolved, which is not conducive to temperature control during production. In addition, concentrated sulfuric acid is highly corrosive to metals, and has certain damage to production equipment such as production kettles and storage tanks, increasing production pressure. In addition, patent CN102633813A proposes to introduce boron trifluoride gas to catalyze the reaction. However, boron trifluoride gas is highly toxic and difficult to control during transportation, transfer and industrial production. It is more likely to cause leakage accidents, posing a threat to production safety.

[0004] Therefore, it is urgent to explore a more economical, safe and high-yield catalytic method. Summary of the invention

[0005] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a method for preparing a three-terminal intermediate TDA of cefazolinic acid, which is intended to reduce reagent consumption and production risks, ensure product yield and reduce production costs.

[0006] The preparation method of the three-terminal intermediate TDA of cefazolinic acid of the present invention is prepared by the following steps: (1) Condensation reaction: 7-aminocephalosporanic acid (7-ACA) and 2-mercapto-5-methyl-1,3,4-thiadiazole (MMTD) are used as raw materials, dimethyl carbonate is used as solvent, boron trifluoride carbonate dimethyl ester complex and glacial acetic acid are used as catalysts to carry out condensation reaction to obtain a condensation reaction liquid; (2) Hydrolysis reaction: Add edetate disodium (EDTA) and sodium metabisulfite to water and stir to react, transfer the condensation reaction solution to water, control the addition time to 20-30 min, then continue to keep warm and stir to obtain a hydrolysis reaction solution; (3) Adding sodium carbonate solution to the hydrolysis reaction solution with stirring for 40-60 min, adjusting the pH, growing crystals, and then filtering, washing, and drying to obtain the finished product of the three-terminal intermediate of cefazolinic acid TDA; In the step (1), the order of adding materials is dimethyl carbonate, boron trifluoride dimethyl carbonate complex, glacial acetic acid, 7-ACA, and MMTD.

[0007] When adding materials in step (1), the order of solvent-catalyst-reactant is followed, and the reactant is added after the solvent and catalyst are evenly stirred. After adding glacial acetic acid to the solvent, acidic conditions are created for the reaction, and the acetic acid molecules can form hydrogen bonds with the surface of the trifluoroboron carbonate dimethyl ester complex, thereby promoting the reaction; in the reaction of 7-ACA and MMTD, 7-ACA removes the acid radical ion and condenses with MMTD to produce acetic acid, and the addition of glacial acetic acid can balance this reaction and prevent the reaction rate from being too fast, thereby making the two react more fully.

[0008] The temperature of the condensation reaction in step (1) is 15-30° C., and the reaction time is 0.5-1 h.

[0009] The weight ratio of the amount of glacial acetic acid used in step (1) to 2-mercapto-5-methyl-1,3,4-thiadiazole is 1:(3.5-4.5); the weight ratio of the amount of glacial acetic acid used to the dimethyl boron trifluoride carbonate complex is (1-1.5):10.

[0010] The residual amount of 7-ACA in the condensation reaction liquid of step (1) is ≤1wt.%.

[0011] The weight ratio of dimethyl carbonate to glacial acetic acid in step (1) is 10:(1-1.5), the weight ratio of 7-aminocephalosporanic acid (7-ACA) to glacial acetic acid is 5:(1-1.2), and the stirring speed is 300-350 rpm.

[0012] The temperature of the stirring reaction in step (2) is 20-35°C, and the time of the stirring reaction is 1-1.5h. The temperature of the heat preservation stirring is 20-35°C, and the time of the heat preservation stirring is 30-40min.

[0013] The transfer of the condensation reaction liquid in step (2) is carried out under normal pressure, and the stirring speed is controlled to be 300-350 rpm.

[0014] The weight ratio of disodium edetate, sodium metabisulfite and water in step (2) is 1:1:1000, and the weight ratio of water to dimethyl carbonate in step (2) is 20:1.

[0015] The pH adjustment in step (3) is to adjust the pH to 3.95-4.05.

[0016] The crystal growing time in step (3) is 1.5-2 hours, the crystal growing temperature is 20-28°C, and the crystal growing stirring speed is 200-220 rpm.

[0017] The concentration of the sodium carbonate solution in step (3) is 15-20 wt.%.

[0018] The washing in step (3) is to fully wash the filter cake obtained by filtration with pure water for 2 to 3 times, and then wash it with acetone for 1 to 2 times. The filter cake drying temperature is 60°C.

[0019] Compared with the prior art, the present invention has the following beneficial effects: (1) The boron trifluoride dimethyl carbonate complex-glacial acetic acid catalysis method proposed in the present invention can maintain the normal reaction under normal pressure and prevent excessive reaction.

[0020] (2) The present invention adopts the boron trifluoride dimethyl carbonate complex-glacial acetic acid catalysis method, which reduces the amount of reagents used and the amount of waste liquid generated while ensuring product quality and yield in industrial production, thereby reducing production costs and environmental pressure. The three-terminal intermediate of cefazolinic acid obtained by this method has a high content and purity, and can be used for the subsequent production of products such as cefazolinic acid. DETAILED DESCRIPTION

[0021] The present invention will be further described below with reference to the embodiments.

[0022] Unless otherwise specified, all raw materials used in the examples are commercially available.

[0023] Example 1 The preparation method of the three-terminal intermediate TDA of cefazolinic acid is prepared by the following steps: (1) Condensation reaction: 300 kg of dimethyl carbonate, 300 kg of boron trifluoride dimethyl carbonate complex, and 30 kg of glacial acetic acid were added to the reaction tank in sequence. After the temperature was controlled at 15°C, 150 kg of 7-ACA and 105 kg of MMTD were added. The stirring speed was controlled at 300 rpm. The reaction was stirred for 0.5 h to obtain a condensation reaction liquid. (2) Hydrolysis reaction: add 6000 kg of purified water to the hydrolysis tank, raise the temperature to 20°C, add 6 kg of EDTA and 6 kg of sodium pyrosulfite, stir and dissolve for 1 hour, transfer the reaction solution obtained in step (1) to the tank under normal pressure, and control the addition time to 20 min; keep warm and stir for 30 min to obtain the hydrolysis reaction solution; (3) Crystallization: Add 15 wt.% sodium carbonate solution to the reaction solution obtained in step (2) with stirring, control the addition time to 40 min, adjust the pH of the hydrolysis reaction solution to 4.01, stop dropping, control the temperature to 20°C, the stirring speed to 200 rpm, and grow the crystals for 1.5 h. The obtained crystals are dried and filtered in a centrifuge, and the filter cake is washed twice with 2000 kg of purified water and once with 1000 kg of acetone. After the filter cake is dried, it is dried at 60°C, and the moisture content is less than 2.0% after detection.

[0024] The weight yield of the product obtained by the preparation method is 99.74%, the purity of the obtained TDA is 99.17%, the residual content of 7-ACA is 0.016%, and the residual content of MMTD is 0.017%.

[0025] Example 2 The preparation method of the three-terminal intermediate TDA of cefazolinic acid is prepared by the following steps: (1) Condensation reaction: 300 kg of dimethyl carbonate, 300 kg of boron trifluoride dimethyl carbonate complex, and 37.5 kg of glacial acetic acid were added to the reaction tank in sequence. After the temperature was controlled at 23°C, 170 kg of 7-ACA and 150 kg of MMTD were added. The stirring speed was controlled at 325 rpm. The mixture was stirred for 45 min to obtain a condensation reaction liquid. (2) Hydrolysis reaction: add 6000 kg of purified water to the hydrolysis tank, raise the temperature to 28 °C, add 6 kg of EDTA and 6 kg of sodium pyrosulfite, stir and dissolve for 75 min, transfer the reaction solution obtained in step (1) to the tank under normal pressure, and control the addition time to 25 min; keep the temperature and stir for 35 min to obtain the hydrolysis reaction solution; (3) Crystallization: Add 17 wt.% sodium carbonate solution to the reaction solution obtained in step (2) with stirring, control the addition time to 50 min, adjust the pH of the hydrolysis reaction solution to 4.03, stop dropping, control the temperature to 24 °C, the stirring speed to 210 rpm, and grow the crystals for 110 min. The obtained crystals are dried and filtered in a centrifuge, and the filter cake is washed 3 times with 2000 kg of purified water and then washed 2 times with 1000 kg of acetone. After drying the filter cake, dry it at 60 °C, and collect the material if the moisture content is less than 2.0% after testing.

[0026] The weight yield of the product obtained by the preparation method is 99.63%, the purity of the obtained TDA is 99.43%, the residual content of 7-ACA is 0.011%, and the residual content of MMTD is 0.016%.

[0027] Example 3 The preparation method of the three-terminal intermediate TDA of cefazolinic acid is prepared by the following steps: (1) Condensation reaction: 300 kg of dimethyl carbonate, 300 kg of boron trifluoride dimethyl carbonate complex, and 45 kg of glacial acetic acid were added to the reaction tank in sequence. After the temperature was controlled at 30°C, 187.5 kg of 7-ACA and 202.5 kg of MMTD were added. The stirring speed was controlled at 350 rpm. The reaction was stirred for 1 hour to obtain a condensation reaction liquid. (2) Hydrolysis reaction: add 6000 kg of purified water to the hydrolysis tank, raise the temperature to 35°C, add 6 kg of EDTA and 6 kg of sodium pyrosulfite, stir and dissolve for 90 min, transfer the reaction solution obtained in step (1) to the tank under normal pressure, and control the addition time to 30 min; keep the temperature and stir for 40 min to obtain the hydrolysis reaction solution; (3) Crystallization: Stir and add 20 wt.% sodium carbonate solution to the reaction solution obtained in step (2), control the addition time to 60 min, adjust the pH of the hydrolysis reaction solution to 3.97, stop dropping, control the temperature to 28 °C, and the stirring speed to 220 rpm, and grow the crystals for 2 h. The obtained crystals are dried and filtered in a centrifuge, and the filter cake is washed twice with 2000 kg of purified water and once with 1000 kg of acetone. After drying, the filter cake is dried at 60 °C, and the moisture content is less than 2.0% after detection.

[0028] The weight yield of the product obtained by the preparation method is 99.89%, the purity of the obtained TDA is 99.68%, the residual content of 7-ACA is 0.069%, and the residual content of MMTD is 0.012%.

[0029] Comparative Example 1 Except that glacial acetic acid was not added, other conditions were the same as those in Example 1. Under the same reaction time conditions, the reaction solution had a darker color and a lower clarity during the condensation of the reactants. The TDA obtained by this method was a light yellow powder with a weight yield of 83%, a purity of 78%, a 7-ACA residue of 0.433%, and a MMTD residue of 0.28%.

[0030] Comparative Example 2 The boron trifluoride gas catalysis method was used to prepare the three-terminal intermediate TDA of cefazolinic acid. The amount of solvent dimethyl carbonate input was 300 kg, and 100 kg of boron trifluoride gas was introduced when the temperature was raised to 30°C. The introduction time was controlled to be 70 minutes. The reaction raw materials 7-ACA were input 50 kg and MMTD was input 11 kg. The weight yield of the product obtained by this method was 98.74%, the purity of the obtained TDA was 98.36%, the residual 7-ACA was 0.11%, and the residual MMTD was 0.16%.

[0031] Comparative Example 3 The three-terminal intermediate TDA of cefazolinic acid was prepared by concentrated sulfuric acid catalysis. The catalyst concentrated sulfuric acid input amount was 300 kg, the reaction raw materials 7-ACA input was 100 kg, and MMTD input was 50 kg. The product weight yield obtained by this method was 98.23%, the purity of TDA was 98.26%, the residual amount of 7-ACA was 0.13%, and the residual amount of MMTD was 0.12%.

[0032] The boron trifluoride dimethyl carbonate complex-glacial acetic acid catalysis method of the present invention for preparing the three-terminal intermediate TDA of cefazolinic acid has higher product quality and yield than the previous method; in addition, the method produces less wastewater, has less environmental pressure, and has a simpler and safer process, which is suitable for large-scale industrial production.

Claims

1. A method for preparing a three-terminal intermediate of cefazolinic acid, TDA, characterized in that: Prepared by the following steps: (1) Condensation reaction: 7-aminocephalosporanic acid and 2-mercapto-5-methyl-1,3,4-thiadiazole are used as raw materials, dimethyl carbonate is used as solvent, boron trifluoride carbonate dimethyl ester complex and glacial acetic acid are used as catalysts, and a condensation reaction is carried out to obtain a condensation reaction liquid; (2) Hydrolysis reaction: add disodium edetate and sodium metabisulfite to water and stir to react, transfer the condensation reaction liquid to water, then continue to keep warm and stir to obtain a hydrolysis reaction liquid; (3) adding sodium carbonate solution to the hydrolysis reaction solution with stirring, adjusting the pH, growing crystals, and then filtering, washing, and drying to obtain the finished product of the three-terminal intermediate TDA of cefazolinic acid; In the step (1), the order of adding materials is dimethyl carbonate, boron trifluoride dimethyl carbonate complex, glacial acetic acid, 7-aminocephalosporanic acid, and 2-mercapto-5-methyl-1,3,4-thiadiazole.

2. The method for preparing the three-terminal intermediate TDA of cefazolinic acid according to claim 1, characterized in that: The temperature of the condensation reaction in step (1) is 15-30° C., and the reaction time is 0.5-1 h.

3. The method for preparing the three-terminal intermediate TDA of cefazolinic acid according to claim 1, characterized in that: The weight ratio of the amount of glacial acetic acid used in step (1) to 2-mercapto-5-methyl-1,3,4-thiadiazole is 1:(3.5-4.5); the weight ratio of the amount of glacial acetic acid used to the dimethyl boron trifluoride carbonate complex is (1-1.5):

10.

4. The method for preparing the three-terminal intermediate TDA of cefazolinic acid according to claim 1, characterized in that: The weight ratio of dimethyl carbonate to glacial acetic acid in step (1) is 10:(1-1.5), and the weight ratio of 7-aminocephalosporanic acid (7-ACA) to glacial acetic acid is 5:(1-1.2).

5. The method for preparing the three-terminal intermediate TDA of cefazolinic acid according to claim 1, characterized in that: The temperature of the stirring reaction in step (2) is 20-35°C, and the time of the stirring reaction is 1-1.5 hours. The temperature of the heat preservation stirring is 20-35°C, and the time of the heat preservation stirring is 30-40 minutes.

6. The method for preparing the three-terminal intermediate TDA of cefazolinic acid according to claim 1, characterized in that: In step (2), the condensation reaction solution is transferred into water, and the addition time is controlled to be 20-30 min.

7. The method for preparing the three-terminal intermediate TDA of cefazolinic acid according to claim 1, characterized in that: The pH adjustment in step (3) is to adjust the pH to 3.95-4.05; the sodium carbonate solution is added to the hydrolysis reaction solution with stirring, and the addition time is controlled to be 40-60 min.

8. The method for preparing the three-terminal intermediate TDA of cefazolinic acid according to claim 1, characterized in that: The crystal growing time in step (3) is 1.5-2 hours, the crystal growing temperature is 20-28°C, and the crystal growing stirring speed is 200-220 rpm.

9. The method for preparing the three-terminal intermediate TDA of cefazolinic acid according to claim 1, characterized in that: The concentration of the sodium carbonate solution in step (3) is 15-20 wt.%.

10. The method for preparing the three-terminal intermediate TDA of cefazolinic acid according to claim 1, characterized in that: The washing in step (3) is to fully wash the filter cake obtained by filtration with pure water for 2 to 3 times, and then wash it with acetone for 1 to 2 times.