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Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation

A technology of cefathiamidine and compounds, applied in medical preparations containing active ingredients, organic chemistry, organic active ingredients, etc., can solve the problem of poor stability of conventional crystal forms of cefathiamidine, poor selection of solvent systems, and poor color grades And other issues

Inactive Publication Date: 2016-06-08
HAINAN LINGKANG PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, in the condensation reaction, the solvent system is not well selected, and it is not easy to remove impurities, resulting in low crude product content
The cefathiamidine compound currently on the domestic market has poor purity, poor color grade, and poor stability, thereby affecting the quality of its preparations
[0006] The conventional crystalline form of cefathiamidine has poor stability, and is unstable to heat, acidic environment, and alkaline environment. It is manifested in problems such as easy discoloration of appearance, decrease in content, and occurrence of degradation products.

Method used

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  • Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation
  • Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation
  • Novel-crystal-form cefathiamidine compound adopting crystal product molecular assembly and form optimization technology in particle process and preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment 1: Preparation of Cefathiamidine New Crystal Form Compound

[0024] (1) Add 5.0 g of N,N'-diisopropylsulfur into 120 mL of dichloromethane, stir to dissolve, add 10.1 g of bromoacetamidocephalosporanic acid and 3 g of triethylamine, and keep the reaction at 45°C for 1.5 h. The reaction temperature was lowered to 5° C. and crystallization was carried out for 1 h to form a crystallization solution. Suction filtration, washing with acetone twice, 20ml each time, and vacuum drying at 40°C gave 9.4g of crude cefathiamidine.

[0025] (2) Add 50ml of water for injection and 5.0g of cefathiamidine into the reactor, stir to dissolve, add 0.1g of medicinal charcoal, stir and decolorize for 30min, filter the decolorization solution with a sterilizing filter, and adjust the pH value of the filtrate with hydrochloric acid 4.1. Add 200ml of isopropanol to the filtrate, cool to 0-5°C, stir for 1 hour, crystallize out, wash with acetone twice, 50ml each time, use ethanol as...

Embodiment 2

[0032] Example 2: Preparation of Cefathiamidine New Crystal Form Compound

[0033] (1) Add 10.2g of N,N'-diisopropylsulfur into 120mL of dichloromethane, stir to dissolve, add 10.1g of bromoacetamidocephalosporanic acid and 3.1g of triethylamine, and keep the reaction at 50°C for 1.5h , the reaction temperature was lowered to 0° C. for 1 h, and the crystallization liquid was formed. Suction filtration, washing with acetone twice, 20ml each time, and vacuum drying at 40°C to obtain 10.5g of crude cefathiamidine.

[0034] (2) Add 50ml of water for injection and 5.5g of cefathiamidine into the reactor, stir to dissolve, add 0.1g of medicinal charcoal, stir and decolorize for 30min, filter the decolorizing solution with a sterilizing filter, and adjust the pH value of the filtrate with hydrochloric acid 3.5. Add 200ml of isopropanol to the filtrate, lower the temperature to 0-5°C, stir for 1 hour, precipitate crystals, wash with acetone twice, 50ml each time, use ethanol as solve...

Embodiment 3

[0036] Example 3: Preparation of Cefathiamidine New Crystal Form Compound

[0037] (1) Add 5.4g of N,N'-diisopropylsulfur into 120mL of dichloromethane, stir to dissolve, add 15.3g of bromoacetamidocephalosporanic acid and 4.0g of triethylamine, and keep it at 50°C for 1.5h , the reaction temperature was lowered to 0° C. for 1 h, and the crystallization liquid was formed. Suction filtration, washing with acetone twice, 20ml each time, and vacuum drying at 40°C gave 5.4g of crude cefathiamidine.

[0038] (2) Add 50ml of water for injection and 5.1g of cefathiamidine into the reactor, stir and dissolve, add 0.1g of medicinal charcoal, stir and decolorize for 30min, filter the decolorizing solution with a sterilizing filter, and adjust the pH value of the filtrate with hydrochloric acid 5.5. Add 200ml of isopropanol to the filtrate, cool down to 0-5°C, stir for 1 hour, crystallize out, wash with acetone twice, 50ml each time, use ethanol as solvent, and recrystallize to obtain 4...

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PUM

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Abstract

The invention discloses a novel-crystal-form cefathiamidine compound and a crystallization preparation method thereof. The novel-crystal-form cefathiamidine compound is prepared with a crystal product molecular assembly and form optimization technology in a particle process. The novel-crystal-form cefathiamidine compound has the characteristics of high purity, low impurity content, good flowability and good stability. Meanwhile, the invention further discloses cefathiamidine for a preparation, namely, cefathiamidine for injection, prepared from the cefathiamidine.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a new crystal form compound of cefathiamidine and a preparation using particle process crystal product molecular assembly and shape optimization technology. Background technique [0002] Cefathiamidine, also known as cephalosporin 18, has a chemical name of (6R,7R)-3[(acetoxy)methyl]-7-[α-(N,N'-diisopropylamidinesulfur base)-acetylamino]8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate betaine, the molecular formula is C 19 h 28 N 4 o 6 S 2 , the molecular weight is 472.59, and its chemical structural formula is: [0003] [0004] Cefathiamidine is a β-lactam antibiotic independently developed by Shanghai Institute of Pharmaceutical Industry and Guangzhou Baiyunshan Pharmaceutical Co., Ltd. It has a strong antibacterial effect on Gram-positive bacteria, especially has a unique effect on enterococci. It is widely used clinically. [0005] Cefathiamidin...

Claims

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Application Information

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IPC IPC(8): C07D501/28C07D501/04C07D501/12A61K31/545A61P31/04
CPCA61K31/545C07D501/04C07D501/12C07D501/28C07B2200/13
Inventor 陶灵刚王静康尹秋响郝红勋
Owner HAINAN LINGKANG PHARMA CO LTD
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