Method for synthesizing parent nucleus of cefroxadine

A technology of ceftoxadine and a synthesis method, which is applied in the field of synthesis of ceftoxadine parent nucleus, can solve problems such as unfavorable safety production, metal aluminum solid waste, unfavorable safety management, etc., and achieves environmental protection, good quality, and operation The effect of high safety

Active Publication Date: 2017-05-10
YANCHENG KAIYUAN MEDICINE CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The disadvantage of this technique is that the methylating reagent dimethyl sulfate is a highly toxic compound, which is not conducive to the safety management of production. In addition, the removal of the 4-position carboxyl protecting group adopts the aluminum chloride / anisole method, which requires Using a large amount of aluminum trichloride will produce a large amount of solid waste containing metallic aluminum, which is not conducive to environmental protection
[0012] In summary, due to the difficulty in synthesizing the existing cefoxadine core, the methylation reagents used are prone to explosion or highly toxic compounds, which is not conducive to safe production

Method used

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  • Method for synthesizing parent nucleus of cefroxadine
  • Method for synthesizing parent nucleus of cefroxadine
  • Method for synthesizing parent nucleus of cefroxadine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Synthesis of BH:

[0031] Add 3-hydroxycephalosporin (50.06g, 0.10mol), methanol (100mL), CHCl 3 (200mL), HC(OMe) 3 (11.67g, 0.11mol), stirred to dissolve, added anhydrous p-toluenesulfonic acid (TsOH) (0.86g, 0.005mol) and stirred to reflux for 8h, sampling, HPLC detection of 3-hydroxycephalosporin residual less than 1%, the reaction was completed. Cool down to 0-5°C, add 50mL of pure water, stir for 10min, separate the layers, and wash the water layer with CHCl 3 Extract twice, 50 mL each time, combine the organic layers, add 5 g of anhydrous magnesium sulfate and stir for 10 min, then add 5 g of activated carbon and stir for 10 min, filter with suction, and collect the filtrate.

[0032] Control the internal temperature of the filtrate to less than 30°C and distill to dryness under reduced pressure, add CH 2 Cl 2 (300mL), cooled to -10~-5℃, added pyridine (11.87g, 0.15mol), CBr 4 (36.48g, 0.11mol), triphenylphosphine (28.85g, 0.11mol), temperature controlled at ...

Embodiment 2

[0036] Synthesis of BH:

[0037] Add 3-hydroxycephalosporin (50.06g, 0.10mol), methanol (150mL), CHCl 3 (150mL), HC(OMe) 3 (10.61g, 0.10mol), stirred and dissolved, added anhydrous p-toluenesulfonic acid (TsOH) (0.86g, 0.005mol) and stirred and refluxed for 8h, sampling, HPLC detection of 3-hydroxycephalosporin residual less than 1%, the reaction was completed. Cool down to 0-5°C, add 50mL of pure water, stir for 10min, separate the layers, and wash the water layer with CHCl 3 (50 mL / time) extracted twice, combined the organic layers, added 5 g of anhydrous magnesium sulfate and stirred for 10 min, then added 5 g of activated carbon and stirred for 10 min, filtered with suction, and collected the filtrate.

[0038] Control the internal temperature of the filtrate to less than 30°C and distill to dryness under reduced pressure, add CH2 Cl 2 (300mL), cooled to -10~-5℃, added pyridine (7.91g, 0.10mol), CBr 4 (33.16g, 0.10mol), triphenylphosphine (26.23g, 0.10mol), temperature...

Embodiment 3

[0042] Synthesis of BH:

[0043] Add 3-hydroxycephalosporin (50.06g, 0.10mol), methanol (75mL), CHCl 3 (225mL), HC(OMe) 3 (12.73g, 0.12mol), stirred and dissolved, added anhydrous p-toluenesulfonic acid (TsOH) (0.86g, 0.005mol) and stirred and refluxed for 8h, sampling, HPLC detection of 3-hydroxycephalosporin residual less than 1%, the reaction was completed. Cool down to 0-5°C, add 50mL of pure water, stir for 10min, separate the layers, and wash the water layer with CHCl 3 (50 mL / time) extracted twice, combined the organic layers, added 5 g of anhydrous magnesium sulfate and stirred for 10 min, then added 5 g of activated carbon and stirred for 10 min, filtered with suction, and collected the filtrate.

[0044] Control the internal temperature of the filtrate to less than 30°C and distill to dryness under reduced pressure, add CH 2 Cl 2 (300mL), cooled to -10~-5℃, added pyridine (15.83g, 0.20mol), CBr 4 (39.80g, 0.12mol), triphenylphosphine (31.47g, 0.12mol), temperatu...

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Abstract

The invention discloses a method for synthesizing a parent nucleus of cefroxadine. The method includes taking 3-hydroxy-cepham as a starting material, and conducting methylation reaction and removal of an amino-protecting group-phenylacetic group at the 7 position and a protecting group-benzhydryl on the carboxyl at the 4 position sequentially so as to obtain the parent nucleus of the cefroxadine, wherein trimethyl orthoformate serves as a methylation reagent during the methylation reaction. The method has the advantages that the method is simple and safe to implement; during removal of the protecting group on the carboxyl at the 4 position, a scandium trifluoromethanesulfonate catalyst is reusable after being activated, and accordingly environmental protection is benefited; the method is high in product quality and suitable for industrial production. The parent nucleus of the cefroxadine produced by the method is white solid powder with the purity above 99.0%.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, in particular to a method for synthesizing cefoxadine nuclei. Background technique [0002] The English abbreviation of cefoxadine parent nucleus is 7-AMOCA, molecular formula: C 8 h 10 N 2 o 4 S, molecular weight: 230.24, appearance is white or off-white solid powder, CAS: 51803-38-4, the structure is as follows: [0003] [0004] As an oral cephalosporin antibiotic, cefoxadin has a spectrum antibacterial effect on Gram-positive and negative bacteria, and its antibacterial spectrum is similar to that of cefaclor. Its antibacterial activity is stronger than cephalexin. It is clinically used for infections of the respiratory tract, urinary tract, skin and soft tissues, reproductive organs, etc., and is also commonly used for otitis media. This product is well absorbed orally, the serum is 1 hour, and most of it is excreted in urine within 12 hours. It ha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/59C07D501/04
CPCY02P20/55C07D501/59C07D501/04
Inventor 徐波丁清杰刘悉承邱国华汪前胜
Owner YANCHENG KAIYUAN MEDICINE CHEM
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