Preparation method of cefozopran hydrochloride intermediate

A technology for cefozopram hydrochloride and its intermediates, which is applied in the field of preparation formula (I), can solve the problems of complicated operation, high cost of raw materials, long production cycle, etc., and achieve the effect of high yield and few adverse reactions

Inactive Publication Date: 2012-02-01
SHANDONG CHENGCHUANG PHARMA R&D
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Problems solved by technology

Yet the intermediate of this medicine is the key material of preparation medicine, and the preparation of this intermediate that has already disclosed all exists deficiency, for example: adopt 7β-amino-3-(3-oxobutyryloxymethyl)-3- Cephem-4-carboxylic acid (7-AACA) is the preparation method of raw material, and the cost of raw material is extremely high, and product needs chromatographic separation; In addition, in the preparation method that adopts 7-ACA as starting material, need silanization to protect amino group and Carboxyl, such as hexamethyldisilazane, trimethyl iodosilane, prepared by deprotection reaction, this method is complicated to operate, the reaction conditions are relatively high, and the production cycle is long; The preparation method of amido-3-chloromethyl cephalosporanic acid methoxybenzyl ester as a starting material requires hydrolysis to remove the C-4 protective group, and enzymatic detachment to remove the C-7 protective group. The method used The enzyme must maintain high activity, and the production cost of maintaining high enzyme activity is greatly increased

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  • Preparation method of cefozopran hydrochloride intermediate
  • Preparation method of cefozopran hydrochloride intermediate
  • Preparation method of cefozopran hydrochloride intermediate

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preparation example Construction

[0030] A kind of preparation method of cefozopram hydrochloride intermediate of the present invention, comprises the steps:

[0031] ① The chemical name of the intermediate of cefazolam hydrochloride: 7-amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl] Methyl]imidazo[1,2-b]pyridazinium salt, represented by the following general formula (I):

[0032]

[0033] Formula (I), wherein HX represents HI, HCl, H 2 SO 4 Wait;

[0034] ② Using formula (II) 7-phenylacetamido-3-chloromethyl cephalosporanate (GCLE) as the starting material, first activate the C-3 position with iodine, potassium iodide or sodium iodide hydrate and then combine with the formula ( Ⅲ) Imidazo[1,2-b]pyridazine is reacted, and after post-treatment, the compound of formula (Ⅳ) is obtained;

[0035]

[0036] Formula (II); wherein R is p-methoxybenzyl or benzhydryl; Ph is phenyl;

[0037]

[0038] Formula (Ⅲ);

[0039]

[0040] Formula (Ⅳ);

[0041] ③ The compou...

Embodiment 1

[0049] step:

[0050] ①Under nitrogen protection, dissolve 97g of potassium iodide in 50ml of deionized water, add 500ml of acetone, stir, cool down to 5°C in an ice-water bath, add 47g of 7-phenylacetamido-3-chloromethyl cephalosporanic acid benzyl, Avoid light reaction, keep temperature 5-8 o C was reacted for 10 hours; acetone was evaporated under reduced pressure, 100ml of deionized water was added, extracted with dichloromethane, and the organic layer was washed with 1mol / L sodium thiosulfate solution, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 57g of light yellow oil, dissolve the oil in dichloromethane, stir, add 15g of imidazopyridazine, 25-28 o C reaction for 10 hours, concentrated dichloromethane under reduced pressure to the end, added anhydrous methanol, precipitated solid, filtered, washed and dried. Obtain light yellow solid 7-phenylacetamido-2-methoxybenzyl carboxylate-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3...

Embodiment 2

[0054] ① Under the protection of nitrogen, dissolve 25g of sodium iodide in 20ml of water, add to 480ml of acetone, stir, cool the ice water to 0°C, add 50g of 7-phenylacetamido-3-chloromethyl cephalosporanic acid methoxybenzyl ester , Avoid light reaction, keep warm at 0-5°C for 6 hours. Evaporate acetone under reduced pressure, then add dichloromethane, 25g imidazopyridazine at 25-28 o C was reacted for 8 hours, washed with 1mol / L sodium thiosulfate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, added anhydrous methanol, precipitated solid, filtered, washed, dried to obtain a light yellow solid 7 -Phenylacetylamino-2-methoxybenzyl carboxylate-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]imidazo [1,2-b]Pyridazinium iodide (Formula II) 66.3g, HPLC detection purity 99%.

[0055] ② Put 63g of phosphorus pentachloride and 1000ml of dichloromethane into the reaction bottle, cool down the reaction solution to -10°C, con...

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Abstract

The invention discloses a preparation method of cefozopran hydrochloride intermediate, which comprises the following steps: (1) the chemical name of the cefozopran hydrochloride intermediate is 7-amino-2-carboxy-8-oxo-5-thia-1-aza-bicyclo[4.2.0]octyl-2-alkenyl-3-yl]methyl]imidazo-[1,2-b]pyridazine onium salt; (2) by using 7-phenylacetamido-3-chloromethylcephalosporanate (GCLE) as the initial raw material, activating C-3 site with iodine, potassium iodide or sodium iodide hydrate, reacting with imidazo-[1,2-b]pyridazine disclosed as Formula (III), and carrying out after-treatment to obtain a compound; and (3) hydrolyzing the compound obtained in the step (2) under the action of phosphorous pentachloride to remove C-7 site protective group, hydrolyzing under the action of phenol to remove C-4 site phenylacetyl protective group, and carrying out after-treatment to obtain the cefozopran hydrochloride intermediate. The invention has the advantages of cheap and accessible raw materials, mild and manageable reaction conditions, high production safety and low production cost.

Description

technical field [0001] The present invention relates to medicines and provides a method for preparing formula (I). [0002] [0003] Formula (Ⅰ). [0004] It is an important intermediate in the preparation of cefazolam hydrochloride (Ⅴ). [0005] Formula (Ⅴ). Background technique [0006] The intermediate for making the fourth-generation cephalosporin antibiotic is called cefazolam hydrochloride intermediate, and its chemical name is: 7-amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[ 4.2.0] Oct-2-en-3-yl]methyl]imidazo[1,2-b]pyridazinium salt. Because the fourth-generation cephalosporins have good antibacterial effects and the human body has low drug resistance, they are gradually being produced in various countries. Yet the intermediate of this medicine is the key material of preparation medicine, and the preparation of this intermediate that has already disclosed all exists deficiency, for example: adopt 7β-amino-3-(3-oxobutyryloxymethyl)-3- Cephem-4-carboxylic acid ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/06
CPCY02P20/55
Inventor 王延斌谢鸿霞赵殿东
Owner SHANDONG CHENGCHUANG PHARMA R&D
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