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Preparation method of high-purity cefathiamidine

A technology of cefathiamidine and diisopropylthiourea, which is applied in the field of preparation of high-purity cefathiamidine, can solve problems such as thermal instability, and achieve the effects of simple and controllable operation, reduced residue, and high production yield

Active Publication Date: 2012-05-16
GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, cefathiamidine has an internal salt structure, is unstable when exposed to heat, and is prone to degradation during production and storage.

Method used

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  • Preparation method of high-purity cefathiamidine
  • Preparation method of high-purity cefathiamidine
  • Preparation method of high-purity cefathiamidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036]At 40°C, add 10g bromoacetyl-7-ACA, 80ml dichloromethane and 8mL methanol to a 250ml three-neck flask, add triethylamine dropwise until bromoacetyl-7-ACA just dissolves; add N,N'-diiso Propylthiourea 4.5g, reacted for 3 hours. Cool down to 6-8°C, and add 100ml of acetone dropwise. After the addition, continue to stir for 30 minutes, filter with suction, wash with acetone, drain, and vacuum-dry at room temperature to obtain 9.2 g of off-white solid with a yield of 92%.

[0037] Adopt high performance liquid chromatography instrument, according to the chromatographic condition of relevant impurity item method in 2010 edition " Chinese Pharmacopoeia " cefathiamidine, the cefathiamidine that makes is carried out HPLC analysis, collection of illustrative plates is as follows figure 2 As shown in B, the peak at 5.5 minutes represents cefathiamidine, and the peak at 4.1 minutes represents bromoacetyl-7-ACA. Calculated according to the area percentage, bromoacetyl-7-ACA accoun...

Embodiment 2

[0044] At 25°C, add 10g bromoacetyl-7-ACA, 80ml dichloromethane and 5mL methanol to a 250ml three-neck flask, add triethylamine dropwise until bromoacetyl-7-ACA just dissolves; add N,N'-diiso Propylthiourea 4.2g, reacted for 4 hours. The temperature was lowered to 0-3°C, and 80 ml of dichloromethane was added dropwise. After the addition, continue to stir for 30 minutes, filter with suction, wash with acetone, drain, and dry in vacuum at room temperature to obtain 8.5 g of white solid, with a yield of 85%.

[0045] Using a high-performance liquid chromatography instrument, according to the chromatographic conditions of the method for the impurity item in the 2010 edition of "Chinese Pharmacopoeia" cefathiamidine, the prepared cefathiamidine was analyzed by HPLC (the map is omitted), calculated according to the area percentage, bromoacetyl-7 -ACA accounts for 0.20%, and the purity of cefathiamidine is 98.31%.

Embodiment 3

[0047] At 30°C, add 10g bromoacetyl-7-ACA, 110ml dichloromethane and 10mL ethanol to a 250ml three-neck flask, add triethylamine dropwise until bromoacetyl-7-ACA just dissolves; add N,N'-diiso Propylthiourea 4.3g, reacted for 4 hours. Cool down to 3-6°C, and add 80ml of acetone dropwise. After the addition, continue to stir for 30 minutes, filter with suction, wash with acetone, drain, and dry in vacuum at room temperature to obtain 9.0 g of white solid with a yield of 90%.

[0048] Using a high-performance liquid chromatography instrument, according to the chromatographic conditions of the method for the impurity item in the 2010 edition of "Chinese Pharmacopoeia" cefathiamidine, the prepared cefathiamidine was analyzed by HPLC (the map is omitted), calculated according to the area percentage, bromoacetyl-7 -ACA accounts for 0.18%, and the purity of cefathiamidine is 98.20%.

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Abstract

The invention relates to a preparation method of cefathiamidine, in particular to a preparation method of high-purity cefathiamidine with low content of impurity acetyl bromide-7-ACA (acetic acid). The preparation method comprises the following steps: adding acetyl bromide-7-ACA, a reaction solvent and less auxiliary solvent into a reactor, and adding alkali to completely dissolve the acetyl bromide-7-ACA; adding N,N'-di-isopropyl thiourea, reacting for 0.5 to 8.0 hours at the temperature between 0 and 40 DEG C; regulating the system temperature to be between 0 and 35 DEG C, dripping a crystallization solvent, then continuing to stir, filtering, cleaning, and drying to obtain the cefathiamidine. According to the preparation method in the invention, residues of the reactant acetyl bromide-7-ACA in cefathiamidine can be effectively reduced, the content of the acetyl bromide-7-ACA in the cefathiamidine is reduced to 0.2 percent or lower, and the content of the acetyl bromide-7-ACA can be reduced to lower than 0.1 percent or completely removed by virtue of further refining, so that the safety of the cefathiamidine is further improved.

Description

technical field [0001] The invention relates to a preparation method of cefathiamidine, in particular to a preparation method of high-purity cefathiamidine with low content of impurity bromoacetyl-7-ACA. Background technique [0002] Cefathiamidine, chemical name is (6R,7R)-3-[(acetyloxy)methyl]-7-[α-(N,N'-diisopropylamidinothio)-acetamido]- 8-Oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-ene-2-carboxylate betaine, molecular formula C 19 h 28 N 4 o 6 S 2 , its structural formula is as follows: [0003] [0004] Cefathiamidine structural formula [0005] Cefathiamidine is a first-generation b-lactam antibiotic with a similar antibacterial spectrum to cephalothin. It has antibacterial activity against Gram-positive bacteria and some negative bacteria, especially against Gram-positive cocci. It has good antibacterial effect on Streptococcus viridans, Hemolytic Streptococcus, Non-hemolytic Streptococcus, Bacillus diphtheriae, Clostridium perfringens, Bacillus tetani and Bacill...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/28C07D501/04
Inventor 陈矛冯胜昔姚柳端朱少璇郑丽真刘晓红刘丹青王锋波卢丹胡海容
Owner GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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