Preparation methods for impurities of escitalopram oxalate

A technology of escitalopram oxalate and citalopram amide, which is applied in the field of preparation of impurities of escitalopram oxalate

Inactive Publication Date: 2013-10-23
CHINA PHARM UNIV
View PDF8 Cites 7 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are very few reports on the synthesis of citalopram impurities at home and abroad, especially for citalopram amide impurities (II), citalopram lactone impurities (III) and citalopram N-oxidized impurities (IV) (structural formula is as follows) The synthesis of the three impurities has not been reported in the literature

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 methods for impurities of escitalopram oxalate
  • Preparation methods for impurities of escitalopram oxalate
  • Preparation methods for impurities of escitalopram oxalate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 11

[0039] Preparation of Example 11-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carboxamide (II)

[0040] Add 2.0g of citalopram (I) into a 100ml three-necked bottle, add 80ml of methanol and stir to dissolve at 0-5°C, adjust the pH to 10 with dilute sodium hydroxide solution, add 0.6ml of 30% hydrogen peroxide dropwise , and then added 0.2ml of 30% hydrogen peroxide every 30min until the TCL tracking reaction was complete. Add an appropriate amount of saturated sodium bisulfite solution and stir until the starch potassium iodide test paper does not change color, then adjust the pH to alkaline with dilute aqueous sodium hydroxide solution, extract with n-butanol / ethyl acetate (15ml×3), combine the organic layers, and anhydrous Dry over sodium sulfate and concentrate under reduced pressure to obtain crude product (II). Silica gel column chromatography (methanol / dichloromethane=1 / 3) gave 0.9 g of pure white solid (II), with a yield of 42.6%.

[0041] I...

Embodiment 21

[0044] Example 2 Preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (III)

[0045] Add 8.0 g of citalopram and 80 ml of acetone into a 250 ml three-necked bottle, stir and dissolve at 0-5°C, add 30 ml of Jones reagent dropwise, stir for 30 min, and move to room temperature to react overnight. Add an appropriate amount of isopropanol, stir for 30 minutes, filter with diatomaceous earth, adjust the pH of the filtrate to 13 in an ice-water bath, extract with ethyl acetate (20ml×3), combine the organic layers, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure. The isopropanol was dissolved, and oxalic acid was added to form a salt, and the isopropanol was recrystallized to obtain 6.0 g of pure light yellow oil (III), with a yield of 75.8%.

[0046] Its structural identification data are as follows:

[0047] 1 H-NMR (DMSO-d 6 )δ: 8.45(s, 1H), 8.28(d, 1H), 8.08(d, 1H), 7.6...

Embodiment 31

[0049] Example 3 Preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisopropylfuran-5-carbonitrile-N-oxide (IV)

[0050] Add 2.34g citalopram base (I) in the 250ml three-necked bottle, dichloromethane 50ml, stirring and dissolving under ice-salt bath condition, add dropwise the dichloromethane solution 50ml that contains m-chloroperoxybenzoic acid 1.72g, dropwise Finished and continued to stir for 2h. The reaction solution was quenched with sodium bisulfite solution, concentrated under reduced pressure, added an appropriate amount of water to the residue, added dilute sodium hydroxide solution to adjust the pH to alkaline, extracted with n-butanol / ethyl acetate (20ml×3), anhydrous sulfuric acid Dry over sodium, concentrate under reduced pressure to obtain the crude product (IV), and perform silica gel column chromatography (n-butanol / ethyl acetate=1 / 3) to obtain 0.13 g of pure light yellow oil (IV), with a yield of 5.6%.

[0051] Its structural identific...

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 relates to novel synthetic methods for three impurities of escitalopram oxalate. The methods have great significance for synthesis of the escitalopram oxalate with high purity. The invention mainly study syntheses of a citalopram amide impurity 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran-5-formamide (II), a citalopram lactone impurity 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile (III) and a citalopram-N-oxide impurity 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran-5-cyano-N-oxide (IV). Specific synthetic routes of the impurities are showed as follows.

Description

technical field [0001] The invention relates to a preparation method of escitalopram oxalate impurity. Background technique [0002] Escitalopram Oxalate, chemical name: S-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro Isobenzofuran-5-nitrile oxalate, a serotonin reuptake inhibitor (SSRI), is the S-isomer of citalopram (I) (structural formula below) (trade name Lexapro). Studies have shown that escitalopram oxalate has a unique serotonin isomeric site binding mechanism and is highly selective for serotonin receptors. Jointly developed by Forest Laboratories of the United States and Lundbeck of Denmark, escitalopram oxalate was first launched in Switzerland and other European and American countries in March 2002, and was approved by the FDA in August for use in severe cases. Treatment of depression and maintenance treatment of depression. [0003] [0004] The synthetic main reaction route of escitalopram oxalate and citalopram (I) is as follows: [000...

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): C07D307/87C07D307/88
Inventor 陈国华李明叶郭祥昌
Owner CHINA PHARM UNIV
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