Method for preparing 7-amino-3-sulfotetrazolthiomethylcephalosporanic acid

Abstract

The invention discloses a method for preparing 7-amino-3-sulfotetrazolthiomethylcephalosporanic acid, which comprises: adding solution of boron trifluoride and dimethyl carbonate in a dimethyl carbonate solvent, stirring the solution, adding 7-aminocephalosporanic acid and 5-mercapto-1H-tetrazole-1-methanesulfonic acid disodium salt in turn to perform an reaction; when reactant residue is less than or equal to 0.5 percent, adding purified water to continue the reaction; cooling the reaction solution, filtering the reaction solution, and washing the product obtained by filtration to obtain a coarse crystal product; and dissolving the coarse crystal product, adding an organic solvent, adjusting the pH value, stirring the solution, cooling and standing the solution, filtering the solution, washing the product obtained after filtration and drying the product to obtain the finished product. Compared with the traditional process, the method has the advantages of mild and simple reaction conditions, easy solvent recovery and recycling, reaction yield up to 90 to 91.2 percent, purity up to 98.0 percent and light color as the solution of boron trifluoride and dimethyl carbonate is used as a catalyst. The method is suitable for large-scale production and overcomes the drawbacks of high price, difficult recovery, low yield, low purity and high production cost of the process using solution of boron trifluoride and acetonitrile as a catalyst.

Description

technical field

[0001] The present invention relates to the synthesis of the important intermediate of cephalosporins second-generation broad-spectrum, long-acting antibiotic cefnixin sodium, i.e. 7-amino-3-sulfonic acid tetrazolethiomethyl cephalosporanic acid (abbreviated 7-ACA- 3-SMT) preparation method. Background technique

[0002] At present, at home and abroad, the intermediate of preparing cefnixin sodium, namely the method of 7-amino-3-sulfonic acid tetrazolium thiomethyl cephalosporanic acid is mainly by using 7-amino cephalosporanic acid (hereinafter referred to as 7-ACA) As the starting material, it is formed by condensation reaction with 5-mercapto-1 sulfonic acid methyl tetrazolium disodium salt under the catalysis of the catalyst. The reaction conditions have the following situations: 1. Use boron trifluoride (BF 3 )-acetonitrile or boron trifluoride-ether solution as a catalyst reaction; 2. Add a weak base, such as sodium bicarbonate, to react; 3. Use a hexa...

Examples

Embodiment 1

[0020] a. adding 230kg boron trifluoride concentration in 250kg dimethyl carbonate solvent is 35% dimethyl carbonate solution, after stirring evenly, add 45kg of 7-ACA and 43kg of 5-mercapto-1 sulfonic acid Methyl tetrazolium disodium salt, then reacted at 21°C under stirring;

[0021] b. Stop the reaction when the 7-ACA residue in the above reaction is ≤0.5%, then add 60kg of purified water, and continue the reaction at 25°C;

[0022] c. After the above reaction was carried out for 0.5 to 1 hour, the temperature was lowered to 12°C, and after stirring for 30 minutes, the crude product of 7-amino-3-sulfonic acid tetrazolium thiomethyl cephalosporanic acid crystals was obtained by filtering and washing;

[0023] d. After adding the crude crystalline product above to 200kg of purified water to dissolve, add 15kg of acetone solvent at room temperature 20-25°C, adjust the pH value of the reaction solution to 1.9 with sodium bicarbonate solution or ammonia solution and fully stir i...

Embodiment 2

[0025] Embodiment 2: the difference between this embodiment and embodiment 1 is that

[0026] a. Add 100kg boron trifluoride concentration in 350kg dimethyl carbonate solvent and be 18% dimethyl carbonate solution, after stirring evenly, add 20kg of 7-ACA and 19kg of 5-mercapto-1 sulfonic acid Methyl tetrazolium disodium salt, then reacted at 12°C under stirring;

[0027] b. Stop the reaction when the 7-ACA residue in the above reaction is ≤0.5%, then add 30kg of purified water and continue the reaction at 40°C;

[0028] c. After the above reaction was carried out for 0.5 to 1 hour, the temperature was lowered to 5° C., and after stirring for 30 minutes, filtered and washed to obtain the crude 7-amino-3-sulfonic acid tetrazolium thiomethyl cephalosporanic acid crystal;

[0029] d. After dissolving the crude crystalline product above in 350kg of purified water, add 10kg of tetrahydrofuran solvent at room temperature 20-25°C, adjust the pH value of the reaction solution to 0.9 ...

Embodiment 3

[0031] Embodiment 3: the difference between this embodiment and embodiment 1 is,

[0032] a. in 500kg dimethyl carbonate solvent, add the weight percent concentration of 250kg boron trifluoride to be 50% dimethyl carbonate solution, after stirring, add successively 5-mercapto-1 sulfonic acid of 50kg of 7-ACA and 47kg Methyl tetrazolium disodium salt, then react at 40°C under stirring;

[0033] b. Stop the reaction when the 7-ACA residue in the above reaction is ≤0.5%, then add 60kg of purified water and continue the reaction at 30°C;

[0034] c. After the above reaction was carried out for 0.5 to 1 hour, the temperature was lowered to 15° C., stirred for 30 minutes, filtered and washed to obtain the crude 7-amino-3-sulfonic acid tetrazolium thiomethyl cephalosporanic acid crystal;

[0035] d. After adding the crude crystalline product above to 500kg of purified water for dissolution, add 30kg of isopropanol solvent at room temperature 20-25°C, adjust the pH value of the react...

technical field

[0001] The present invention relates to the synthesis of the important intermediate of cephalosporins second-generation broad-spectrum, long-acting antibiotic cefnixin sodium, i.e. 7-amino-3-sulfonic acid tetrazolethiomethyl cephalosporanic acid (abbreviated 7-ACA- 3-SMT) preparation method. Background technique

[0002] At present, at home and abroad, the intermediate of preparing cefnixin sodium, namely the method of 7-amino-3-sulfonic acid tetrazolium thiomethyl cephalosporanic acid is mainly by using 7-amino cephalosporanic acid (hereinafter referred to as 7-ACA) As the starting material, it is formed by condensation reaction with 5-mercapto-1 sulfonic acid methyl tetrazolium disodium salt under the catalysis of the catalyst. The reaction conditions have the following situations: 1. Use boron trifluoride (BF 3 )-acetonitrile or boron trifluoride-ether solution as a catalyst reaction; 2. Add a weak base, such as sodium bicarbonate, to react; 3. Use a hexa...

Examples

Embodiment 1

[0020] a. adding 230kg boron trifluoride concentration in 250kg dimethyl carbonate solvent is 35% dimethyl carbonate solution, after stirring evenly, add 45kg of 7-ACA and 43kg of 5-mercapto-1 sulfonic acid Methyl tetrazolium disodium salt, then reacted at 21°C under stirring;

[0021] b. Stop the reaction when the 7-ACA residue in the above reaction is ≤0.5%, then add 60kg of purified water, and continue the reaction at 25°C;

[0022] c. After the above reaction was carried out for 0.5 to 1 hour, the temperature was lowered to 12°C, and after stirring for 30 minutes, the crude product of 7-amino-3-sulfonic acid tetrazolium thiomethyl cephalosporanic acid crystals was obtained by filtering and washing;

[0023] d. After adding the crude crystalline product above to 200kg of purified water to dissolve, add 15kg of acetone solvent at room temperature 20-25°C, adjust the pH value of the reaction solution to 1.9 with sodium bicarbonate solution or ammonia solution and fully stir i...

Embodiment 2

[0025] Embodiment 2: the difference between this embodiment and embodiment 1 is that

[0026] a. Add 100kg boron trifluoride concentration in 350kg dimethyl carbonate solvent and be 18% dimethyl carbonate solution, after stirring evenly, add 20kg of 7-ACA and 19kg of 5-mercapto-1 sulfonic acid Methyl tetrazolium disodium salt, then reacted at 12°C under stirring;

[0027] b. Stop the reaction when the 7-ACA residue in the above reaction is ≤0.5%, then add 30kg of purified water and continue the reaction at 40°C;

[0028] c. After the above reaction was carried out for 0.5 to 1 hour, the temperature was lowered to 5° C., and after stirring for 30 minutes, filtered and washed to obtain the crude 7-amino-3-sulfonic acid tetrazolium thiomethyl cephalosporanic acid crystal;

[0029] d. After dissolving the crude crystalline product above in 350kg of purified water, add 10kg of tetrahydrofuran solvent at room temperature 20-25°C, adjust the pH value of the reaction solution to 0.9 ...

Embodiment 3

[0031] Embodiment 3: the difference between this embodiment and embodiment 1 is,

[0032] a. in 500kg dimethyl carbonate solvent, add the weight percent concentration of 250kg boron trifluoride to be 50% dimethyl carbonate solution, after stirring, add successively 5-mercapto-1 sulfonic acid of 50kg of 7-ACA and 47kg Methyl tetrazolium disodium salt, then react at 40°C under stirring;

[0033] b. Stop the reaction when the 7-ACA residue in the above reaction is ≤0.5%, then add 60kg of purified water and continue the reaction at 30°C;

[0034] c. After the above reaction was carried out for 0.5 to 1 hour, the temperature was lowered to 15° C., stirred for 30 minutes, filtered and washed to obtain the crude 7-amino-3-sulfonic acid tetrazolium thiomethyl cephalosporanic acid crystal;

[0035] d. After adding the crude crystalline product above to 500kg of purified water for dissolution, add 30kg of isopropanol solvent at room temperature 20-25°C, adjust the pH value of the react...

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