Ceftolozane sulfate and preparation method and application thereof

A technology of ceftolozax and sulfuric acid, which is applied in the field of pharmaceutical chemical synthesis, can solve problems such as harsh reaction conditions, low safety, and environmental pollution, and achieve the effects of controllable reaction, less pollutant generation, and simplified and optimized reaction conditions

Active Publication Date: 2021-02-05
湖南润星制药有限公司
View PDF14 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] There are various drawbacks such as severe reaction conditions, high cost, low safety and environmental pollution in the above-mentioned preparation of ceftolozaxa sulfate technology, so it is necessary to explore a method for preparing ceftolozaxa sulfate with low process cost, simplicity and efficiency, and suitable for industrialized production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Ceftolozane sulfate and preparation method and application thereof
  • Ceftolozane sulfate and preparation method and application thereof
  • Ceftolozane sulfate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Embodiment 1 provides a kind of preparation method of ceftolozax sulfate, comprises the steps:

[0061] A) Preparation of Intermediate II

[0062] Intermediate I (20.0g, 54mmol) was dissolved in dichloromethane (250mL), 10% sodium bicarbonate (70g, 83mmol) solution was added, cooled in an ice bath, fluorenylmethoxycarbonyl chloride (16.0g, 62mmol) was added slowly, 0 Reaction at ℃ for 6 h, rotary evaporation to dryness under reduced pressure, extraction with dichloromethane, washing with brine, drying over anhydrous sodium sulfate, rotary evaporation to dryness under reduced pressure, the obtained crude product was recrystallized from a mixed solvent of ethyl acetate-petroleum ether, Intermediate II was obtained as an off-white to solid (31.5 g), with a yield of 98%.

[0063] B) Preparation of Intermediate III

[0064] {2-[3-(1-Methyl-5-(tritylamino)-1H-pyrazol-4-yl)ureido]ethyl}carbamate tert-butyl ester (30.0g, 55mmol) was dissolved in N,N-Dimethylformamide (500mL)...

Embodiment 2

[0070] Embodiment 2 provides a kind of preparation method of ceftolozax sulfate, comprises the steps:

[0071] A) Preparation of Intermediate II

[0072] Intermediate I (25.0g, 68mmol) was dissolved in 1,2-dichloroethane (300mL), added 10% sodium carbonate (122g, 115mmol) solution, cooled in an ice bath, and slowly added fluorenylmethoxycarbonyl chloride (23.0g, 89mmol), reacted at 5°C for 3h, evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Crystallization gave Intermediate II as an off-white to solid (39.0 g), yield 97%.

[0073] B) Preparation of Intermediate III

[0074] {2-[3-(1-Methyl-5-(tritylamino)-1H-pyrazol-4-yl)ureido]ethyl}carbamate tert-butyl ester (43.0g, 80mmol) was dissolved in N, N-dimethylformamide (600mL), add hexamethyldisilazide (47.0g, 0.23mol), then add intermediate II (39.0g, 66mmol) and potassium iodide (20.0g, 0.12m...

Embodiment 3

[0080] Embodiment 3 provides a kind of preparation method of ceftriaxone sulfate, comprises the steps:

[0081] A) Preparation of Intermediate II

[0082] Intermediate I (85.0g, 0.23mol) was dissolved in chloroform (1000mL), 10% potassium carbonate (630.0g, 0.46mol) solution was added, cooled in an ice bath, fluorenylmethoxycarbonyl chloride (88.0g, 0.34mol) was added slowly, Reaction at 15°C for 2 h, rotary evaporation to dryness under reduced pressure, extraction with dichloromethane, washing with brine, drying over anhydrous sodium sulfate, rotary evaporation to dryness under reduced pressure, the obtained crude product was recrystallized from a mixed solvent of ethyl acetate-petroleum ether to obtain Intermediate II, off-white to solid (130.0 g), yield 95%.

[0083] B) Preparation of Intermediate III

[0084] {2-[3-(1-methyl-5-(tritylamino)-1H-pyrazol-4-yl)ureido]ethyl}carbamate tert-butyl ester (155.0g, 0.29mol) In N,N-dimethylformamide (2000mL), add hexamethyldisilazi...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention provides ceftazidime sulfate and a preparation method and application thereof, and the method comprises the following steps: making an intermediate I (p-methoxybenzyl 7-amino-3-chloromethyl-3-cefazolin-4-carboxylate) with fluorenylmethoxycarbonyl chloride to obtain an intermediate II, making the intermediate II react with tert-butyl {2-[3-(1-methyl-5-(triphenylmethylamino)-1H-pyrazole-4-yl)ureido]ethyl}carbamate to obtain an intermediate III, carrying out amino deprotection reaction on the intermediate III in a second alkaline solvent system to obtain an intermediate IV, and making the intermediate IV react with the intermediate V in an acid-binding agent alkali solvent system to obtain ceftazidime sulfate. According to the preparation method of ceftazidime sulfate, mild reaction types and reaction conditions are adopted, the reaction conditions are simplified and optimized, the impurities in each step of reaction are few, the reaction is controllable, less pollutants aregenerated, the yield is high, and the preparation method has a green and environment-friendly effect.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a cefolozaxa sulfate and a preparation method and application thereof. Background technique [0002] Cefolozane is a fifth-generation cephalosporin antibacterial drug invented and developed by Astellas Pharma for the treatment of infections caused by Gram-negative bacteria. The medicinal form of ceftolozane is the sulfate salt, namely ceftolozane sulfate (Cefolozane sulfate), its chemical name is (6R,7R)-7-((Z)-2-(5-amino-1,2, 4-thiadiazol-3-yl)-2-(((2-carboxyprop-2-yl)oxy)imino)acetamido)-3-((5-amino-4-(3-(2 -Aminoethyl)ureido)-1-methyl-1H-pyrazol-2-ium-2-yl)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0 ] Oct-2-ene-2-carboxysulfate, its chemical structural formula is as follows: [0003] [0004] According to published patents and bibliographical reports, there are mainly the following synthetic routes for the preparation of ceftolozax sulfate, which ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/46C07D501/06C07D501/18C07D501/38C07D501/24A61K31/546A61P31/04A23L33/10
CPCC07D501/46C07D501/06C07D501/18C07D501/38C07D501/24A61P31/04A23L33/127A23V2002/00A23V2200/30
Inventor 张瑜黄艳陈健
Owner 湖南润星制药有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap