(6R, 7R)-3-hydroxymethyl-7-[alpha-(N, N'-diisopropylamidino thio)-acetamido]-8-oxo-5-thia-1-azabicycle [4, 2, 0]-oct-2-ene-2-carboxylic acid

An azabicycle and acetamido technology, which is applied in the field of chemical pharmacy, can solve the problems such as the compound structure not being prepared, and achieve the effect of small drug dosage

Active Publication Date: 2013-01-09
GUANGZHOU BAIYUNSHAN PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The above report is only the analysis and inference of the researchers based on the LC-MS i

Method used

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  • (6R, 7R)-3-hydroxymethyl-7-[alpha-(N, N'-diisopropylamidino thio)-acetamido]-8-oxo-5-thia-1-azabicycle [4, 2, 0]-oct-2-ene-2-carboxylic acid
  • (6R, 7R)-3-hydroxymethyl-7-[alpha-(N, N'-diisopropylamidino thio)-acetamido]-8-oxo-5-thia-1-azabicycle [4, 2, 0]-oct-2-ene-2-carboxylic acid
  • (6R, 7R)-3-hydroxymethyl-7-[alpha-(N, N'-diisopropylamidino thio)-acetamido]-8-oxo-5-thia-1-azabicycle [4, 2, 0]-oct-2-ene-2-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] At room temperature, add 30 g (0.13 mol) of D-7-ACA to 300 ml of water, and slowly add triethylamine dropwise under stirring at 120 rpm until D-7-ACA dissolves to obtain a clear solution. To the above clear solution, add 50ml of toluene, adjust the temperature to 0-5°C, add dropwise sodium bicarbonate solution (24g dissolved in 250ml of water) and 15ml of bromoacetyl bromide (0.17mol). Insulate and react for 30-60 minutes, let stand to separate the layers, separate the water layer, slowly add 3mol / L sulfuric acid dropwise to the water layer, keep the temperature at 0-5°C, add until the pH is about 1.0-1.5, and continue to grow crystals for 1 hour . Then, it was suction filtered, and the filter residue was washed three times with water, and dried in vacuum to obtain about 40 g of Intermediate A.

Embodiment 2

[0031] At room temperature, in 500ml water, add D-7-ACA 30g (0.13mol), under stirring at 120 rpm, add dropwise sodium bicarbonate solution (27.6g dissolved in 250ml water) until D-7-ACA is dissolved , a clear solution was obtained. Add 100ml of dichloromethane to the above clear solution, adjust the temperature to 30-35°C, add dropwise the remaining sodium bicarbonate solution and 25ml (0.29mol) bromoacetyl bromide, keep the reaction for 30-60min, let stand to separate layers, separate Remove the water layer, adjust the temperature to room temperature, slowly add 3 mol / L hydrochloric acid dropwise to the water layer until the pH is about 2.0-2.5, and continue to grow crystals for 1 hour. Then suction filtered, the filter residue was washed three times with water, and vacuum-dried to obtain about 38 g of Intermediate A.

[0032] Step 2: Preparation of Compound I

Embodiment 3

[0034] Adjust the temperature of 500ml of dichloromethane: acetone (3:1 by volume) mixed solvent to 15-20°C, add 25g (0.058mol) of intermediate A, slowly add triethylamine dropwise until dissolved, add N,N- Diisopropylthiourea 14g (0.0875mol), slowly adjust the temperature to 20-25°C. After reacting for 2h, suction filtered, and the filter residue was washed 3 times with dichloromethane. After vacuum drying at room temperature, about 19 g of compound I white powder was obtained. 98.3% purity.

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Abstract

The invention belongs to the field of chemical pharmaceuticals, and relates to (6R, 7R)-3-hydroxymethyl-7-[alpha-(N, N'-diisopropylamidino thio)-acetamido]-8-oxo-5-thia-1-azabicycle [4, 2, 0]-oct-2-ene-2-carboxylic acid, a preparation method and application thereof. With the adoption of a two-phase process, 7-amino-3-hydroxymethyl-8-oxo-5-thia-1-azabicycle[4.2.0]-oct-2-ene-2-formic acid and bromoacetyl bromide are reacted to obtain an intermediate A; and the intermediate A and N',N-diisopropylthiourea are reacted to obtain the compound provided by the invention. The compound provided by the invention has the antibacterial effects on staphylococcus aureus, streptococcus pneumoniae, enterococcus hirae and enterococcus faecalis etc., especially, the antimicrobial activity on staphylococcus aureus is very strong and is 10 folds stronger than cefathiamidine, the activity on enterococcus faecalis is 15 folds stronger than cefathiamidine, and the activity on streptococcus pneumoniae is strong as well, so that the compound is a potential antibacterial agent.

Description

technical field [0001] The present invention belongs to the field of chemical pharmacy, and more specifically, relates to a cephalosporin compound and its preparation method and application, especially (6R, 7R)-3-hydroxymethyl-7-[α-(N, N' -Diisopropylamidinothio)-acetylamino]-8-oxo-5-thia-1-azabicyclo[4,2,0]-oct-2-ene-2-carboxylic acid betaine and Its preparation method and use. Background technique [0002] Hu Min and Hu Changqin analyzed the degradation products of cefathiamidine using LC-MS method (Hu Min, Hu Changqin, "LC-MS analysis of cefathiamidine degradation products", Acta Pharmaceutica Sinica 2006, 41(10): 1015-1019) , deduce that 2 main degradation products are the hydrolysis products of cefathiamidine, respectively deacetyl cefathiamidine (hereinafter referred to as compound I) and cefathiamidine lactone, its structural formula is as follows: [0003] [0004] Ye Fang et al. also used LC-MS to analyze the degradation products of cefathiamidine (Ye Fang et a...

Claims

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Application Information

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IPC IPC(8): C07D501/28C07D501/04A61K31/545A61P31/04
Inventor 冯胜昔姚柳端陈矛朱少璇刘丹青郑丽珍王锋波卢茂君刘晓红
Owner GUANGZHOU BAIYUNSHAN PHARM CO LTD
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