Method for synthesizing antibiotic cefpirome sulfate

A technology of cefpirome sulfate and synthetic method, applied in the direction of antibacterial drugs, organic chemistry, etc., can solve the problems of harsh reaction conditions, high cost of raw materials, long reaction time, etc., and achieve simple process conditions, stable product quality, and product yield. high rate effect

Inactive Publication Date: 2011-02-02
国药集团致君(苏州)制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The synthetic method of cefpirome sulfate, existing some patent document reports at home and abroad, as US4609653, CN1587267A and EP62321, GB2195334A and CN1772754, AEP64740,, in these known synthetic methods, there is the shortcoming that raw material cost is high and difficult to obtain, The reaction conditions are harsh and the reaction time is long, which is not conducive to continuous and large-scale industrial production
The synthesis technology of cefpirome sulfate is relatively difficult, although some progress has been made in domestic research on its synthesis technology, but the cost is still high and the quality is not good

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  • Method for synthesizing antibiotic cefpirome sulfate

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Comparison scheme
Effect test

Embodiment 1

[0013] Synthesis of Example 1 7-ACP

[0014] In the flask, add 40g (0.14mol) 7-aminocephalosporanic acid (7-ACA), 27.4g (0.17mol) hexamethyldisilazane amine, N,N-dimethylformamide (DMF) 1ml, three Methyl iodosilane 1ml, dichloromethane 300mL, stirred at 20-25°C for 6-10 hours. Then the temperature was lowered to 0° C., 27 mL of tetrahydrofuran was added, and 63 g (0.3 mol) of iodotrimethylsilane was added dropwise, and then, the reaction was stirred for 4-5 hours.

[0015] Then, 30 g (0.24 mol) of 2,3-cyclopentenopyridine was added dropwise. After the dropwise addition was completed, the mixture was incubated for 3 hours, and then naturally raised to room temperature for overnight reaction.

[0016] After the reaction, dropwise add methanol 50mL + concentrated hydrochloric acid 160mL + deionized water 200mL mixed solution, control the temperature of the feed liquid during the dropwise addition to not exceed 10°C, and fully stir at this temperature for 10 minutes. Then the li...

Embodiment 2

[0019] The preparation of embodiment 2 cefpirome sulfate

[0020] In the flask, add 550mL of deionized water, 250mL of DMF, 150ml of isopropanol, add 40g of 7-ACP and 80g of AE active ester, then cool to -10°C, and add 30mL of diethylamine dropwise. During the dropwise addition, the temperature does not exceed 0 ℃. After the dropwise addition was complete, stirring was continued for 2 hours. Then the temperature was raised to 15-20° C. for 3 hours, and the reaction solution was extracted three times with 500 mL of dichloromethane. The organic phase was back-extracted with 300 mL of deionized water, and the aqueous phase was combined. The aqueous phase was decolorized with activated carbon, and then quickly filtered through an aluminum oxide column.

[0021] Then add 80 mL of 6mol / L sulfuric acid to control PH=1.5, stir at room temperature for 1 hour, then add 3 L of acetone, stir for 2 hours, filter, wash the filter cake with acetone, and dry to obtain 57 grams of cefpirome ...

Embodiment 3

[0025] 7-ACA is placed in an organic solvent, and the weight ratio of the 7-ACA to the organic solvent N, N-dimethylformamide (DMF) or N, N-dimethylacetamide (DMAC) is 1: 1; Add hexamethyldisilazane and iodotrimethylsilane or trimethylchlorosilane with 1 times the dosage of 7-ACA, and reflux for 2 hours to obtain a brown reaction solution, cool to room temperature, and add 7-ACA dosage dropwise 1 times of trimethyl iodosilane, then dropwise adding 2,3-cyclopentenopyridine of 1 times the amount of 7-ACA, and then acidolysis to obtain 7-ACP;

[0026] The resulting 7-ACP and AE active ester weight ratio are mixed at 1:1 and placed in a mixed solvent where the volume ratio of organic solvent and water is mixed at 1:30, and the pH is adjusted to 1:30 with alkali sodium hydroxide or potassium hydroxide. 7.0, dissolved and acylation reaction occurred, the temperature of acylation reaction was -10°C.

[0027] The obtained cefpirome solution is added into a sulfuric acid solution to c...

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Abstract

The invention relates to a synthesis method of cefpirome sulfate that is a bacteriophage. 7-amin cethalosporanic acid (7-ACA) is used as starting material and reacts with hexamethyldisilane amine (HMDS) and iodotrimethylsilane (TMSI) first to obtain 7-ACA for protecting amino and carboxyl; then 7-ACA, amino and carboxyl of which are protected, reacts with iodotrimethylsilane and 2, 3-cyclopenopyridine to synthesize an intermediate 7-ACP through a one-pot method; then 7-ACP reacts with active ester to prepare a product of cefpirome sulfate through acidylation reaction and salifying reaction. Compared with the existing technical route, the synthesis method has the advantages that the process conditions are simple, the operation is convenient, the product yield is high, the product quality is stable, the method is suitable for the large-scale industrialized production, etc.

Description

technical field [0001] The invention relates to a synthesis method of the fourth-generation cephalosporin antibiotic cefpirome sulfate, which belongs to the technical field of medicine preparation Background technique [0002] Cefpirome, developed by the German company Hoechst, was first launched in Sweden under the trade name of Cefrom in 1992, and then in Switzerland, Finland, the United Kingdom, France, Germany and other countries. As the fourth-generation cephalosporin for injection, cefpirome shows broad-spectrum antibacterial activity against Gram-positive bacteria, negative bacteria and anaerobic bacteria, and is the third- and fourth-generation cephalosporin known to be effective against Gram The antibiotic with the strongest antibacterial activity against positive bacteria, especially the activity against Streptococcus and Streptococcus pneumoniae is greatly enhanced. The effect on Pseudomonas aeruginosa is similar to that of ceftazidime, and it is effective agains...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/46A61P31/04
Inventor 史利军孙元强陈德华
Owner 国药集团致君(苏州)制药有限公司
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