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Ceftezole sodium powder injection and synthesizing method thereof

A technology of ceftezole sodium and its synthesis method, which is applied in the field of medicine and can solve problems such as low yield, temperature and light instability, and high price

Active Publication Date: 2009-07-01
SHANDONG LUOXIN PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In summary, the existing ceftezole sodium sterile powder injection has disadvantages such as poor stability, temperature and light instability.
This has great limitations on the clinical application of the drug
In addition, the yield of the preparation method of ceftezole sodium is very low at present, and the higher cost has caused the price of the pharmaceutical preparation to be expensive, increasing the economic burden of the patient, and using highly polluting chemical reagents in its synthesis, which is harmful to the environment. greater damage

Method used

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  • Ceftezole sodium powder injection and synthesizing method thereof
  • Ceftezole sodium powder injection and synthesizing method thereof
  • Ceftezole sodium powder injection and synthesizing method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0077] Embodiment 1: the synthesis of 7-(1H-1-tetrazolyl) acetamide-cephalosporanic acid (I)

[0078] Add 1412g (11.03mol) tetrazoleacetic acid, 1609g (8.75mol) N, N'-dicyclohexylcarbodiimide (DCC), and 50L dimethyl sulfoxide into a 100L reactor, and stir to dissolve completely. Mix and dissolve 2000g (7.35mol) of 7-amino-cephalosporanic acid, 2227g (22.05mol) of triethylamine, and 30L of ethyl acetate. After dissolving, add dropwise to the above tetrazoleacetic acid solution, and control the reaction temperature at -5 to 0 Between ℃, 1.5h added. After the dropwise addition, react at -5~0°C for 1h, at 0~5°C for 1h, and at room temperature for 3h. The precipitate was filtered off, 70L of water was added to the filtrate, and the water layer was separated. The aqueous layer was washed twice with 10 L of ethyl acetate. Use 10% hydrochloric acid to adjust the pH<2, and a large amount of precipitate precipitates out. Add 45L of ethyl acetate, and extract twice. The extracts wer...

Embodiment 2

[0079] Example 2: 7-(1H-1-tetrazolyl)acetamido-3-[2-(1,3,4-thiadiazolyl)]thiomethyl-3-cephem-4-carboxylic acid ( Synthesis of Ceftezole)

[0080] 2043g (5.35mol) compound (III) was dissolved in an appropriate amount of 10% NaHCO 3The solution was dissolved (about 4300ml), and then this solution and 755g (6.40mol) 1,3,4-thiadiazole-2-thiol (IV) were added to 80L of phosphate buffer solution with a pH value of 6.4, and heated to 60°C , Stir the reaction for 6h. It was then washed with ether until the solution became clear. The aqueous layer was acidified with 10% hydrochloric acid to pH<2.0, and a large amount of precipitate was deposited. Extracted twice with 70L ethyl acetate, combined extracts, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, crystallized, and suction filtered to obtain 2028 g of crude product.

Embodiment 3

[0081] Example 3: 7-(1H-1-tetrazolyl)acetamido-3-[2-(1,3,4-thiadiazolyl)]thiomethyl-3-cephem-4-carboxylic acid ( Refining of ceftezole)

[0082] 2028g crude ceftezole was heated to 60°C with 6 times of acetone to dissolve completely. Then let cool and crystallize for 2 hours, filter with suction, wash with a little ethanol, and dry under reduced pressure at 40°C for 4 hours to obtain 1834 g of product, yield: 94.8%.

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Abstract

The invention provides a ceftezole sodium powder injection and a synthesis method thereof. The powder injection is composed of more stable ceftezole sodium crystals. The method reacts tetrazoleacetic acid, N, N'-dicyclohexylcarbodiimide and 7-aminocephalosporanic acid in a ratio of 1.4~1.7:1~1.3:1 in dimethyl sulfoxide, and then The reaction intermediate is reacted with 1.1-1.3 times of thiadiazole mercaptan to prepare ceftezole, and after recrystallization with acetone, ceftezole sodium is prepared in aqueous sodium bicarbonate solution. The method is simple and easy, and the total yield is as high as 55.5%.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a cephalosporin drug and a synthesis method thereof, more specifically a ceftezole sodium powder injection and a synthesis method thereof. Background technique [0002] Ceftezole Sodium (Ceftezole Sodium, molecular weight 462.47, molecular formula C 13 h 11 N 8 NaO 4 S 3 ), the chemical name is (6R,7R)-3-[[(1,3,4-thiadiazol-2-yl)sulfur]methyl]-7-[(1H-tetrazol-1-yl)acetyl Amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt. Its chemical structural formula is as follows: [0003] [0004] The substance is white to light yellow crystalline powder, odorless and hygroscopic. [0005] Ceftezole sodium is the first generation of cephalosporin antibiotics for injection. It is a semi-synthetic cephalosporin derivative. Its mechanism of action is to exert antibacterial activity by inhibiting the synthesis of bacterial cell walls. Gram-positive bacteria,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/14A61K31/546A61P31/04C07D501/34
Inventor 刘保起李明华孙松
Owner SHANDONG LUOXIN PHARMA GRP CO LTD
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