Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method of celecoxib impurity B

A technology for celecoxib and impurities, which is applied in the field of preparation of impurities B in the celecoxib process, and can solve the problems of increasing production costs, being unsuitable for practical production applications, and having low yields.

Active Publication Date: 2018-03-06
YANGTZE RIVER PHARMA GRP BEIJING HAIYAN PHARMA +1
View PDF2 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield of compound B obtained by this method is relatively low, and use reversed-phase chromatographic separation and purification, the boiling point of the mixed solvent of the collected distillate water and acetonitrile is higher, follow-up processing needs a lot of time even freeze-drying processing, greatly increased Production cost, not suitable for practical production application

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
  • Preparation method of celecoxib impurity B
  • Preparation method of celecoxib impurity B
  • Preparation method of celecoxib impurity B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Synthesis of 4,4,4-trifluoro-1-(4-methylphenyl)butane-1,3-dione

[0034] Under nitrogen protection, methyl tert-butyl ether (3.0 L) and 20% by weight sodium ethoxide ethanol solution (3.55 kg, 10.43 mol) were added respectively, and the nitrogen was replaced three times. Control the temperature not to exceed 25±5°C, stir mechanically, and add ethyl trifluoroacetate (3) (1.27kg, 8.94mol) and p-methylacetophenone (4) (1.0kg, 7.45mol) in batches in sequence. Under nitrogen protection, the reaction temperature was controlled at 25±5° C., and mechanically stirred for 24 hours. It was detected by TLC that the raw materials disappeared and the reaction was completed (developing solvent: petroleum ether / ethyl acetate, volume ratio: 1 / 1).

[0035] Stop the reaction, add 5% by weight hydrochloric acid solution (6.5L) to the reaction solution to adjust the pH to 7.0-8.0, let stand for 15min, separate layers, collect the organic phase, extract the aqueous phase with eth...

Embodiment 2

[0036] Embodiment 2: Preparation of celecoxib impurity B

[0037] Add absolute ethanol (19.2L), purified water (4.8L) and 4,4,4-trifluoro-1-(4-methylphenyl)butane-1,3-dione (1.6 kg, 6.84mol), dissolved completely, added 4-hydrazinobenzenesulfonamide hydrochloride (1.61kg, 7.18mol), stirred mechanically, raised the temperature to reflux, reacted for 20h, compound 1 disappeared as detected by HPLC, and stopped heating. The reaction mixture was cooled and crystallized. When the temperature reached 20°C, the temperature was kept and stirred for 3h. Centrifuge, wash the filter cake with a small amount of mixed solvent (absolute ethanol / water: 1 / 1), collect the solid wet product, and dry the wet product at 45°C for 16 hours to obtain the crude product. The content of impurity B in the crude product is 32.8% as detected by HPLC (attached figure 1 ).

Embodiment 3

[0038] Embodiment 3: Preparation of celecoxib impurity B

[0039]Take 10g of 4,4,4-trifluoro-1-(4-methylphenyl)butane-1,3-dione, add ethanol (120mL) to dissolve completely, measure its pH value to 7~8, then add Purified water (30mL) and 4-hydrazinobenzenesulfonamide hydrochloride (10.2g, 46.0mmol) were stirred, heated up, and refluxed for 20h. After sampling, HPLC detected that the content of impurity B reached 26.1%. The reaction was stopped, and concentrated to dryness under reduced pressure. .

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 discloses a preparation method of celecoxib impurity B. According to the method, the content of the impurity B is increased to be more than 25% through a synthetic method, and then the impurity is purified until the purity is more than 99% through the application of a supercritical fluid chromatography separation technology.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a preparation method of celecoxib process impurity B. The method not only increases the content of the celecoxib impurity B, but also improves the purification yield and the purity of the product. Background technique [0002] Patent US5760068 describes the synthesis method of celecoxib, 4,4,4-trifluoro-1-(4-methylphenyl)butane-1,3-dione and 4-hydrazinobenzenesulfonamide hydrochloride The salt is synthesized into celecoxib through addition and ring-closing reaction; certain by-product impurity B will be produced during the reaction process. During this reaction step, 1,3-diketone compound has two electrophilic sites, and 4-hydrazinobenzenesulfonamide hydrochloride has two nucleophilic sites. According to the activity of the sites, firstly the highly active sites Nu1 and E1 condense, and then Nu2 and E2 ring-close to generate celecoxib; conversely, Nu1 and E2 condense, Nu2 and ...

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
IPC IPC(8): C07D231/12
CPCC07D231/12Y02P20/54
Inventor 褚立军王建耀陈东齐源韩硕
Owner YANGTZE RIVER PHARMA GRP BEIJING HAIYAN PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com