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Preparation method of ceftriaxone sodium compound

A technology of ceftriaxone sodium and chloromethylation, applied in the direction of organic chemistry, etc., can solve the problems of low color grade, many impurities or by-products, etc.

Pending Publication Date: 2022-02-18
上海欣峰制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The molar yield of the condensation process is 93.5%; but the color grade of the unrefined PEG product is lower than yellow grade 7, indicating that there are still more impurities or by-products in the crude product of ceftriaxone sodium

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: the preparation of supported phase transfer catalyst

[0049] Chloromethylated polystyrene resin pretreatment: wash with tap water first, until chloromethylated polystyrene resin (DVB cross-linking degree 2%, chlorine content 22.2%, particle size 100~200 mesh) to chlorine-free ether odor, and then washed with deionized water until there is no chloride ion, then rinsed with ethanol, and dried in vacuum at 40°C for later use.

[0050] The preparation of the supported phase transfer catalyst is as follows: take 20g of pretreated chloromethylated polystyrene resin, swell it with 50mL of toluene for 24h, then add 100m1 of toluene, 60g of PEG-400 and 80g of 50wt% sodium hydroxide solution in Reflux reaction at 80°C for 12h, after cooling, filter with suction, wash with ethanol, tap water and deionized water in sequence until no chloride ions are present, rinse with ethanol, and dry under vacuum at 40°C.

Embodiment 2

[0052] At 2°C, add 100 mL of a volume ratio of 3:2 dichloromethane-water mixed solvent, 32 g of the aforementioned supported phase transfer catalyst, 37 g (0.1 mol) of 7-ACT, 35g (0.1mol) of AE active ester and 25g of tetramethylguanidine were stirred for 3h. After the reaction was completed, the supported phase transfer catalyst was removed by filtration, and the filtrate was retained; and washed three times with a dichloromethane-water mixed solvent with a volume ratio of 3:2, and the washing liquid was combined with the filtrate. Add 20mL of 1mol / L hydrochloric acid solution, stir for 15min, and let stand to separate the layers to obtain the aqueous phase.

[0053] Add 50mL of 0.3g / mL sodium acetate aqueous solution dropwise to the water phase, stir to mix evenly; then add 5g of activated carbon for decolorization for 30min. At 5°C, slowly add 1mol / L hydrochloric acid dropwise to adjust the pH of the solution to 3. Stir at 200 rpm for 3 h under heat preservation condition...

Embodiment 3

[0056] Dissolve 20 g of the aforementioned white crystal powder in 60 mL of acetone-water mixed solvent with a volume ratio of 2:1, add dilute NaOH solution to pH = 7, and add it to a constant temperature ice machine. Turn on the constant temperature ice machine, and add isopropanol dropwise when the temperature of the solution reaches 15°C at a rate of 0.1ml / min; add 0.2g of seed crystals (Livzon Pharmaceutical Group Co., Ltd., injection grade ceftriaxone sodium) after 90 minutes of adding ; Cultivate the crystal for 30 minutes; then adjust the isopropanol dropping rate to 2ml / min, and continue dropping for 120 minutes. The stirring speed was controlled at 200 rpm throughout the crystallization process. After the dissolution and crystallization, vacuum filtration was performed, the filter cake was washed twice with acetone, and dried in vacuum to obtain a white crystal powder. The color grade of the product is grade 1, the ceftriaxone polymer content is 0.13%, and the pH val...

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Abstract

The invention discloses a preparation method of a ceftriaxone sodium compound. The preparation method comprises the following steps: stirring 7-ACT, AE active ester and tetramethylguanidine in the presence of a loaded phase transfer catalyst and a dichloromethane-water mixed solvent to react; standing and layering the mixture to obtain a water phase; adding a sodium acetate aqueous solution into the water phase, and decolorizing the aqueous solution with activated carbon; under the condition of 0-10 DEG C, adjusting the pH value to 2-4, and keeping the temperature for 1-5 hours; and carrying out vacuum filtration and drying to obtain white crystal powder. The invention also discloses the ceftriaxone sodium obtained by the method. According to the method, the yield and the color grade of the ceftriaxone sodium are improved, and ceftriaxone polymer impurities are reduced.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy and relates to a preparation method of ceftriaxone sodium compound. Background technique [0002] The chemical name of ceftriaxone sodium is [6R[6α,7β(Z)]]-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1 ,2,4-triazin-3-yl)thio]methyl]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo- 5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt triple hemihydrate, molecular weight 661.6, belongs to the third generation of β-lactam cephalosporins. [0003] Ceftriaxone sodium is a long-acting antibiotic created by Roche, Switzerland. It has a long half-life, is stable to β-lactamase, has strong tissue penetration ability, and has bactericidal activity by inhibiting the synthesis of bacterial cell walls. Bactericidal effect on Gram-negative and Gram-positive bacteria. This is the only type of cephalosporin injection that successfully introduces an acidic group into the 3-position side...

Claims

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Application Information

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IPC IPC(8): C07D501/36C07D501/12C07D501/04
CPCC07D501/36C07D501/12C07D501/04
Inventor 卢平平魏天琪崔嘉鸣蔡东霖
Owner 上海欣峰制药有限公司
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