Preparation methods of cefpirome intermediate and cefpirome

A technology for cefpirome and aminocephalosporanic acid, which is applied in the field of drug synthesis, can solve the problems of difficult treatment and recovery of three wastes, cumbersome post-processing operations, waste of iodine cost, and the like, achieves simplified treatment and recovery, saves cumbersome processes and waste of raw materials, The effect of saving crystallization solvent

Active Publication Date: 2013-09-18
QILU ANTIBIOTICS PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] 1, the iodine used in production is finally dispersed in the waste liquid of each step in the form of iodide ions, making the three wastes in production difficult to process and reclaim, and the expensive iodine accounts for a large proportion in the production cost of intermediate formula 1 ( 15-20%), if the iodine-containing waste liquid is discharged randomly, it will not only cause a large amount of waste of iodine and greatly increase the cost, but also cause serious environmental pollution
[0010] 2. The post-treatment operations of the reactants such as deprotection, dissolution, extraction and crystallization are cumbersome, and have been subjected to conditions such as strong acid, resulting in a loss of yield. A large amount of solvent is required for crystallization, and the production cost is high. Therefore, it is necessary to find a Easier and more optimized crystallization conditions are important

Method used

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  • Preparation methods of cefpirome intermediate and cefpirome
  • Preparation methods of cefpirome intermediate and cefpirome
  • Preparation methods of cefpirome intermediate and cefpirome

Examples

Experimental program
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Effect test

Embodiment 1

[0050] [embodiment 1] the preparation of cefpirome intermediate (formula 1, wherein HX is HCl) monohydrate

[0051] (1) 40g (0.147mol) of 7-aminocephalosporanic acid (formula 4), 150ml of dichloromethane, and 48ml (0.23mol) of hexamethyldisilazane (HMDS) were placed in a reaction flask, heated to reflux for 8 hours, Add 29ml (0.18mol) of N,N-diethylaniline (0.18mol) and TMSI (40.8g, 0.204mol) under ice-cooling, react at room temperature for 3 hours, cool down to 0-5°C, add 24ml of 2,3-cyclopentenopyridine ( 0.182mol), temperature controlled at 5-10°C and stirred for 5hr to obtain a solution of the compound of formula 5;

[0052] (2) Add 40ml of methanol dropwise to the solution of the compound of formula 5 prepared above, react for 10mins, add 10ml (0.21mol) of hydrogen peroxide with a concentration of 50wt%, 120ml of concentrated hydrochloric acid, and 120ml of water, stir until the solids are all dissolved, and let stand for stratification. Add 550ml of acetone to the water...

Embodiment 2

[0053] [embodiment 2] the preparation of cefpirome sulfate

[0054] N, N-dimethylformamide 350ml (DMF), water 125ml, cefpirome intermediate monohydrochloride monohydrate 40g (prepared by Example 1), AE-active ester 42g is placed in the reaction flask, cooling To 0~5℃, add 13.5ml of triethylamine dropwise, keep stirring for 4hr after adding, add 480ml of dichloromethane, stir for 30mins, let it stand for stratification, add 10g of activated carbon to the water phase for decolorization, filter, and the concentration of the filtrate is 40wt% Adjust the pH to 1.2-1.5 with sulfuric acid, add 2500ml of acetone at room temperature, cool to 0-5°C and stir for 1 hr, filter, wash the filter cake with 200ml of acetone, and dry in vacuo to obtain 56.6g of white solid, content 86.4%, HPLC purity > 99%, That is cefpirome sulfate, the molar yield is 92.5%.

Embodiment 3

[0055] [embodiment 3] the synthesis of cefpirome intermediate (formula 1, wherein HX is HI) monohydrate

[0056] Step (1) is as described in Example 1, the difference is: add methanol 120ml and water 80ml dropwise to the solution of the compound of formula 5, stir for 2hr after adding, filter, filter cake is washed with methanol 150ml, and vacuum-dried to obtain a White product 64.9g (molar yield 92.1%), content 69.1%, purity > 98% (HPLC), KF: 3.9%, iodide ion content: 26.9%, be cefpirome intermediate hydroiodide monohydrate .

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Abstract

The invention relates to preparation methods of cefpirome intermediate and cefpirome; 7-amino cephalsporanic acid is used as a raw material; a silanization reaction, an iodination reaction, and a pyridine reaction are performed; the obtained product is added with an oxidant, and hydrochloric acid or is added into a mixed solvent of an organic solvent and water to prepare a halogen acid salt of the cefpirome intermediate (6R, 7R)-7-amino-3-[(2,3-cyclopentene-pyridine)methyl]ceph-3-ene-4-carboxylic acid. The invention also provides a method for preparing cefpirome sulfates by using the obtained intermediate halogen acid salt. The cefpirome intermediate and cefpirome prepared by the methods have high yield, and low production cost; the operation is simple; the discharge of three wastes is less; treatment and recovery are easy, and the methods are applicable to industrial production.

Description

technical field [0001] The invention relates to a high-purity hydrohalide salt of cefpirome intermediate and a synthesis method of cefpirome, belonging to the technical field of medicine synthesis. Background technique [0002] Cephalosporins are a series of semi-synthetic antibiotics obtained by modifying the side chain of cephalosporin C extracted from crown cephalosporin culture solution. Its advantages are: wide antibacterial spectrum, relatively stable to acid and β-lactamase produced by various bacteria. Among several listed cephalosporins, onium salt cephalosporin compounds (ceftazidime, cefepime, cefpirome) occupy a pivotal position. Cefpirome sulfate belongs to the fourth-generation cephalosporins. It has the advantages of broad antibacterial spectrum, strong antibacterial effect, high stability to β-lactamase, and good drug tolerance. It is a promising antibiotic. [0003] The key intermediate for the synthesis of cefpirome sulfate is (6R, 7R)-7-amino 3-{(2,3-cyc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/18C07D501/04C07D501/46
Inventor 王晓艳李凤侠王欣王勇进时米超翟长均徐畅言
Owner QILU ANTIBIOTICS PHARMA
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