Method for preparing cefozopran hydrochloride, cefozopran hydrochloride powder injection and preparation method thereof

A technology for cefazolam hydrochloride and injection, which is applied in the field of drug synthesis and its preparation, can solve the problems of complicated process, difficult preparation dissolution, poor stability and the like, and achieves the effects of high reaction yield, good fluidity and good stability

Active Publication Date: 2008-09-17
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In addition, the products marketed in Japan are cefzoram hydrochloride as raw material and ceftizolan hydrochloride for injection as the preparation. The raw material is non-sterile preparation. Blue and commonly used solvents all produce solvation, and it is very difficult to remove these solvents. It is reported in the literature that supercritical extraction is used to remove the solvent, which will make the process complicated, and it is also impossible to prepare sterile raw materials. If the solvent is removed by heating, for The acetone test proves that vacuum drying at 80°C is required to remove it. The test also proves that the acetone cannot be washed away with a low-boiling solvent such as ether. If the solvent is removed with high-humidity air, the water content will be high. Bacteria raw materials, complex process, the prepared preparation is difficult to dissolve after mixing with sodium carbonate, strong shaking is required, and the clarity of the product is usually unqualified
[0011] Japanese Patent Publication No. 62-149682 discloses ceftizolam and its method, and the ceftizolam prepared by it is an amorphous and solvated compound with poor stability; Chinese patent CN88108305.4 discloses a kind of ceftizole hydrochloride The preparation method of blue
The method is to prepare solvated crystallized cefzoram hydrochloride, and also discloses the use of supercritical technology to remove residual solvents. In this patent, the researcher has prepared crystallized cefozopran hydrochloride, but due to poor solubility, thus Prepared crystalline cefozopran hydrochloride
But because the cefozolam of its preparation and cefozolam hydrochloride are solvate and can't remove solvent to a satisfactory degree by ordinary vacuum drying, thereby adopt supercritical extraction to remove solvent, because supercritical extraction is very important when making cephalosporin See the equipment, and can not control the sterile conditions, etc., so that its application still cannot meet the demand
In addition, after preparing ceftozolam hydrochloride, as adopting freeze-drying method to prepare cefazolam sodium dissolved in water for clinical injection, the product still has problems such as poor stability
[0012] In summary, the synthesis of cefozopran hydrochloride i.e. the compound of formula (I) all has problems such as starting material is difficult to obtain, yield is too low

Method used

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  • Method for preparing cefozopran hydrochloride, cefozopran hydrochloride powder injection and preparation method thereof
  • Method for preparing cefozopran hydrochloride, cefozopran hydrochloride powder injection and preparation method thereof
  • Method for preparing cefozopran hydrochloride, cefozopran hydrochloride powder injection and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0050] [Example 1] Preparation of Cefozopran Hydrochloride

[0051] (1) Put 1.93Kg (7.6mol) of 7-ACA, 180ml of HMDS, 12L of dichloromethane and 0.1L of iodotrimethylsilane into a 100L reactor, heat and reflux for 8 hours, cool down to 0°C, and add iodotrimethylsilane 1.16L (14.5mol) was stirred for 8 hours, 2.9kg (27.1mol) of the compound of formula (II) was added with 1H-imidazol[1,2-b]pyridazine, stirred at room temperature for 8 hours, methanol was added dropwise, and the filter cake was dichloromethane Washing, washing with methanol, and drying in vacuo to give 7-amino--3-(1H-imidazo[1,2-b]pyridazin-4-ium-1-yl)methyl-8-oxo-5-thio- 1-azabicyclo[4.2.0]octyl-2-enyl-2-carboxylic acid.hydriodide is formula (III) compound ( figure 1 ) 3.1kg (yield = 85.6%), TLC inspection impurity spot is no more than 5% (developing agent: acetonitrile: water = 4: 1);

[0052] (2) Take the 7-amino-3-(1H-imidazo[1,2-b]pyridazin-4-ium-1-yl)methyl-8-oxo-5-thio- 1-Azabicyclo[4.2.0]octyl-2-enyl-2-...

Embodiment 2

[0054] [Embodiment 2] Preparation of Cefozopran Hydrochloride

[0055] (1) Put 1.93Kg (7.6mol) of 7-ACA, 180ml of HMDS, 12L of dichloromethane and 0.1L of iodotrimethylsilane into a 100L reactor, heat and reflux for 6 hours, cool down to 5°C, and add iodotrimethylsilane 1.16 L (14.5 mol) was stirred for 6 hours, 2.9 kg (27.1 mol) of the compound of formula (II) was added with 1H-imidazol[1,2-b] pyridazine, stirred at room temperature for 6 hours, methanol was added dropwise, and the filter cake was dichloromethane Washing, washing with methanol, and drying in vacuo to give 7-amino--3-(1H-imidazo[1,2-b]pyridazin-4-ium-1-yl)methyl-8-oxo-5-thio- 1-azabicyclo[4.2.0]octyl-2-enyl-2-carboxylic acid.hydriodide is formula (III) compound ( figure 1 ) 3.1kg (yield = 85.6%), TLC inspection impurity spot is no more than 5% (developing agent: acetonitrile: water = 4: 1);

[0056] (2) Take the 7-amino-3-(1H-imidazo[1,2-b]pyridazin-4-ium-1-yl)methyl-8-oxo-5-thio- 1-Azabicyclo[4.2.0]octyl-2...

Embodiment 3

[0058] [Example 3] Preparation of Cefozopran Hydrochloride

[0059](1) Put 1.93Kg (7.6mol) of 7-ACA, 180ml of HMDS, 12L of dichloromethane and 0.1L of iodotrimethylsilane into a 100L reactor, heat and reflux for 10 hours, cool down to 8°C, and add iodotrimethylsilane 1.16L (14.5mol) was stirred for 10 hours, 2.9kg (27.1mol) of the compound of formula (II) was added with 1H-imidazol[1,2-b]pyridazine, stirred at room temperature for 10 hours, methanol was added dropwise, and the filter cake was dichloromethane Washing, washing with methanol, and drying in vacuo to give 7-amino--3-(1H-imidazo[1,2-b]pyridazin-4-ium-1-yl)methyl-8-oxo-5-thio- 1-azabicyclo[4.2.0]octyl-2-enyl-2-carboxylic acid.hydriodide is formula (III) compound ( figure 1 ) 3.1kg (yield = 85.6%), TLC inspection impurity spot is no more than 5% (developing agent: acetonitrile: water = 4: 1);

[0060] (2) Take the 7-amino-3-(1H-imidazo[1,2-b]pyridazin-4-ium-1-yl)methyl-8-oxo-5-thio- 1-Azabicyclo[4.2.0]octyl-2-enyl-...

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Abstract

The invention relates to a preparation method of Cefozopran Hydrochloric acid, Cefozopran Hydrochloric acid powder for injection and preparation method thereof. The preparation method includes allowing 7-ACA as raw material and compound in the formula (II) to react in the presence of solvent such as dichloromethane, HMDS and TMSI, and post-treating to obtain compound in the formula (III); condensing with the compound in the formula (IV), post-treating to obtain the Cefozopran, salifying with hydrochloric acid to obtain product, centrifuging, water washing, and drying to obtain Cefozopran Hydrochloric acid crude product; and refining to obtain Cefozopran Hydrochloric acid refined product. The preparation method of the Cefozopran Hydrochloric acid provided by the invention has easily available raw material, high yield, and suitability for industrialized production. The Cefozopran Hydrochloric acid is mixed with anhydrous sodium carbonate and sodium chloride, and sub-packaged to obtain powder for injection having good stability. The obtained powder for injection can be used together with 5% glucose injection, and 0.9% sodium chloride injection.

Description

technical field [0001] The invention belongs to the field of drug synthesis and preparation thereof, and in particular relates to a preparation method of cefozopran hydrochloride, cefozopran hydrochloride powder injection and a preparation method thereof. Background technique [0002] Cefozopran hydrochloride (cafozopran hydrochloride) was developed by Japan's Takeda Pharmaceutical Co., Ltd. and was launched in Japan in 1995 under the trade name Firstcin. Cefazolam hydrochloride has antibacterial effects on Gram-positive bacteria including Staphylococcus and Gram-negative bacteria including Pseudomonas aeruginosa, and is the fourth-generation cephalosporin for injection. [0003] Cefozopran Hydrochloride (Cefozopran Hydrochloride) molecular formula: C 19 h 17 N 9 o 5 S 2 HCl, molecular weight: 551.99, chemical name: (6R,7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxy Iminoacetamido]-3-(1H-imidazo[1,2-b]pyridazin-4-ium-1-yl)methyl-8-oxo-5-thio-1-azabicyclo[ 4.2....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/06A61K9/14A61K31/546A61P31/04
Inventor 刘保起李明华孙松
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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