Method for preparing cephapirin benzathine

Abstract

The invention relates to a method for preparing cephapirin benzathine, which is used for chemical medicine synthesis. The method comprises the following steps of: reacting 7-ACA (acetic acid) with 4-pyridylmercaptoacetyl chloride in a weight ratio of 1:0.80-1:5 at the temperature of between 0 and 30 DEG C for 0.5 to 15 hours in alkali to generate cephapirin acid; and reacting the cephapirin acid with dibenzylethylene diamine acetate or dibenzylethylenediamine in a weight ratio of 1:0.65-1:2.6 at the temperature of between 0 and 50DEG C for 0.1 to 20 hours, filtering, washing, and drying to obtain white solid cephapirin benzathine. The solvent in the solution is one or more of acetone, ethanol, water, methanol, benzene, methylbenzene, dimethylbenzene, isopropanol, dichloromethane, ethyl acetate, cyclohexane, methyl acetate and butyl acetate; and the alkali is triethylamine, sodium acetate or sodium isooctanoate. The method has the advantages that: raw materials are readily available and cheap; a few production technological processes are simple; and the method is suitable for industrial production.

Description

technical field

[0001] The invention relates to the field of synthesis of cephalosporin chemical drugs, and more specifically relates to a new method for preparing benzathine cefapirin. Background technique

[0002] Cephapirin Benzathine (Cephapirin Benzathine), its structural formula is as follows:

[0003]

[0004] Benzathine cefapirin is an amine salt complex of cefapirin, which belongs to the first generation of cephalosporin antibiotics. Benzathine cefapirin is effective against many Gram-positive and some Gram-negative bacteria and is highly effective against pneumococci and enterococci. It is mainly used for the treatment of urinary system infection, respiratory system infection and soft tissue infection caused by sensitive bacteria, such as the treatment of pyelitis, cystitis, osteomyelitis, sepsis, meningitis, endocarditis, etc. In addition to the efficacy of cefapirin, benzathine cefapirin has the advantage of long-acting effect, and is currently mainly used t...

Examples

Embodiment 1

[0024] Add 100 grams of 7-ACA into a mixed solvent of 2500 milliliters of acetone and 250 milliliters of water, cool down to 0-5° C., add 190 milliliters of triethylamine to dissolve the solid, pH=8-9. Add 200 grams of 4-pyridylthioacetyl chloride hydrochloride and react at 10° C. for 3 hours. After the reaction is complete, add 8 grams of activated carbon for decolorization and filter. Add 1,500 milliliters of water, add 100 grams of DBED at room temperature, react at 37 to 40° C. for 6 hours, filter, wash the product with 3×300 milliliters of water, and dry in vacuo to obtain white solid cefepirin benzathine. Molar yield is 94~97%, adopts Agilent 1200 liquid chromatographs to measure and contain cefapirin acid 79% (USP31 standard is 71.5~82.0%), adopts titration method to measure and contain benzathine 22% (USP31 standard is 20.0%) ~24.0%).

Embodiment 2

[0026] 100 grams of 7-ACA was added to a mixed solvent of 2500 milliliters of acetone and 100 milliliters of water, the temperature was lowered to 0-5 ° C, and 190 milliliters of triethylamine was added to dissolve the solid. Add 200 grams of 4-pyridylthioacetyl chloride hydrochloride and react at 10° C. for 3 hours. After the reaction is complete, add 8 grams of activated carbon for decolorization and filter. Add 1,500 milliliters of water, add 100 grams of DBED at room temperature, react at 37 to 40° C. for 6 hours, filter, wash the product with 3×300 milliliters of water, and dry in vacuo to obtain white solid cefepirin benzathine. The molar yield was 86%.

Embodiment 3

[0028] 100 grams of 7-ACA was added to a mixed solvent of 1000 milliliters of acetone and 250 milliliters of water, the temperature was lowered to 0-5° C., and 190 milliliters of triethylamine was added to dissolve the solid. Add 200 grams of 4-pyridylthioacetyl chloride hydrochloride and react at 10° C. for 3 hours. After the reaction is complete, add 8 grams of activated carbon for decolorization and filter. Add 1,500 milliliters of water, add 100 grams of DBED at room temperature, react at 37 to 40° C. for 6 hours, filter, wash the product with 3×300 milliliters of water, and dry in vacuo to obtain white solid cefepirin benzathine. The molar yield was 75%.

technical field

[0001] The invention relates to the field of synthesis of cephalosporin chemical drugs, and more specifically relates to a new method for preparing benzathine cefapirin. Background technique

[0002] Cephapirin Benzathine (Cephapirin Benzathine), its structural formula is as follows:

[0003]

[0004] Benzathine cefapirin is an amine salt complex of cefapirin, which belongs to the first generation of cephalosporin antibiotics. Benzathine cefapirin is effective against many Gram-positive and some Gram-negative bacteria and is highly effective against pneumococci and enterococci. It is mainly used for the treatment of urinary system infection, respiratory system infection and soft tissue infection caused by sensitive bacteria, such as the treatment of pyelitis, cystitis, osteomyelitis, sepsis, meningitis, endocarditis, etc. In addition to the efficacy of cefapirin, benzathine cefapirin has the advantage of long-acting effect, and is currently mainly used t...

Examples

Embodiment 1

[0024] Add 100 grams of 7-ACA into a mixed solvent of 2500 milliliters of acetone and 250 milliliters of water, cool down to 0-5° C., add 190 milliliters of triethylamine to dissolve the solid, pH=8-9. Add 200 grams of 4-pyridylthioacetyl chloride hydrochloride and react at 10° C. for 3 hours. After the reaction is complete, add 8 grams of activated carbon for decolorization and filter. Add 1,500 milliliters of water, add 100 grams of DBED at room temperature, react at 37 to 40° C. for 6 hours, filter, wash the product with 3×300 milliliters of water, and dry in vacuo to obtain white solid cefepirin benzathine. Molar yield is 94~97%, adopts Agilent 1200 liquid chromatographs to measure and contain cefapirin acid 79% (USP31 standard is 71.5~82.0%), adopts titration method to measure and contain benzathine 22% (USP31 standard is 20.0%) ~24.0%).

Embodiment 2

[0026] 100 grams of 7-ACA was added to a mixed solvent of 2500 milliliters of acetone and 100 milliliters of water, the temperature was lowered to 0-5 ° C, and 190 milliliters of triethylamine was added to dissolve the solid. Add 200 grams of 4-pyridylthioacetyl chloride hydrochloride and react at 10° C. for 3 hours. After the reaction is complete, add 8 grams of activated carbon for decolorization and filter. Add 1,500 milliliters of water, add 100 grams of DBED at room temperature, react at 37 to 40° C. for 6 hours, filter, wash the product with 3×300 milliliters of water, and dry in vacuo to obtain white solid cefepirin benzathine. The molar yield was 86%.

Embodiment 3

[0028] 100 grams of 7-ACA was added to a mixed solvent of 1000 milliliters of acetone and 250 milliliters of water, the temperature was lowered to 0-5° C., and 190 milliliters of triethylamine was added to dissolve the solid. Add 200 grams of 4-pyridylthioacetyl chloride hydrochloride and react at 10° C. for 3 hours. After the reaction is complete, add 8 grams of activated carbon for decolorization and filter. Add 1,500 milliliters of water, add 100 grams of DBED at room temperature, react at 37 to 40° C. for 6 hours, filter, wash the product with 3×300 milliliters of water, and dry in vacuo to obtain white solid cefepirin benzathine. The molar yield was 75%.

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