Palladium removal method for crizotinib intermediate

A technology for crizotinib and intermediates, which is applied in the field of palladium removal for crizotinib intermediates, can solve problems such as not being suitable for industrial production, and achieve the effects of meeting industrial production requirements, saving organic solvents, and being simple and easy to operate

Pending Publication Date: 2020-06-30
JIANGSU WANBANG BIOPHARMLS +1
View PDF0 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method will use a large amount of organic solvents and is not suitable for industrial 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
  • Palladium removal method for crizotinib intermediate
  • Palladium removal method for crizotinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 1kg toluene, 238g (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (TM4) and 4-(4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert Butyl ester (SM2), 1.5g tetrabutylammonium bromide, 240g cesium carbonate and 3.8g Pd(dppf)Cl 2 Add to the reaction bottle in turn, start stirring and add 1200g of purified water, replace with nitrogen for 3 times before adding, heat to 80-90°C under the protection of nitrogen, and keep stirring at 65-95°C for 3-6 hours.

[0033] After the reaction was completed, the temperature was lowered after the reaction was completed, the liquids were separated, the organic phase was washed once with 1000 L of water, and the aqueous phase was discarded.

[0034] Add 42.8g of N-acetyl-L-cysteine ​​to the organic phase, stir at 50-70°C for 10-16h, add 1000L of potassium carbonate aqueous solution, wash, separate the liquid, and discard the aqueous phase; then use 1000L of potassium carb...

Embodiment 2

[0039] 1kg toluene, 238g (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (TM4) and 4-(4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert Butyl ester (SM2), 1.5g tetrabutylammonium bromide, 240g cesium carbonate and 3.8g Pd(dppf)Cl 2 Add to the reaction bottle in turn, start stirring and add 1200g of purified water, replace with nitrogen for 3 times before adding, heat to 80-90°C under nitrogen protection, and keep stirring at 650-95°C for 3-6 hours.

[0040] After the reaction was completed, the temperature was lowered after the reaction was completed, the liquids were separated, the organic phase was washed once with 1000 L of water, and the aqueous phase was discarded.

[0041]Add 60 g of 1.3.5-triazine-2.4.6-trithiol trisodium salt to the organic phase, stir at 50-70°C for 3-10 hours, filter with suction, and discard the filter cake.

[0042] Heat the organic phase to 50-80°C, add 2000g of n-heptane, coo...

Embodiment 3

[0046] 1kg toluene, 238g (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (TM4) and 4-(4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert Butyl ester (SM2), 1.5g tetrabutylammonium bromide, 240g cesium carbonate and 3.8g Pd(dppf)Cl 2 Add to the reaction bottle in turn, start stirring and add 1200g of purified water, replace with nitrogen for 3 times before adding, heat to 80-90°C under nitrogen protection, and keep stirring at 650-95°C for 3-6 hours.

[0047] After the reaction was completed, the temperature was lowered after the reaction was completed, the liquids were separated, the organic phase was washed once with 1000 L of water, and the aqueous phase was discarded.

[0048] Add 60g of mercapto silica gel to the organic phase, stir at 50-70°C for 3-10h, filter with suction, and discard the filter cake.

[0049] Heat the organic phase to 50-80°C, add 2000g of n-heptane, cool down to 5-25°C after additio...

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 method for removing palladium from a crizotinib intermediate. The method comprises the following steps: adding a heavy metal ion remover into a palladium-containing reactionsolution; after the remover is separated, a solid is separated out from an organic phase, and the crizotinib intermediate (R)-4-(4-(6-amino-5-(1-(2, 6-dichloro-3-fluorophenyl) ethoxy) pyridine-3-yl)-1H-pyrazol-1-yl) tert-butyl ester piperidine-1- carboxylate tert-butyl ester with the palladium content as low as 10 ppm is obtained. The method is simple to operate, saves an organic solvent and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a method for removing palladium of a crizotinib intermediate. Background technique [0002] Crizotinib is a white crystalline powder and a chemical raw material. [0003] Crizotinib is a new drug developed by Pfizer in the United States for the treatment of lung cancer. It is the first drug targeting anaplastic lymphoma kinase (ALK) and can be used to treat locally advanced and metastatic anaplastic lymphoma kinase (ALK) positive of non-small cell lung cancer (NSCLC). Its chemical name is: (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyridine Azol-4-yl)pyridin-2-amine [0004] The structural formula is: [0005] [0006] The synthetic route of existing reported crizotinib is: [0007] With 2,6-dichloro-3-fluorophenylethyl alcohol (SM1) as the starting material, 1-(2,6-dichloro-3-fluorophenyl)ethanol is obtained through reduction reaction; race...

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): C07D401/14
CPCC07D401/14
Inventor 王克艳姚浩
Owner JIANGSU WANBANG BIOPHARMLS
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