Method for synthesizing intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib

A technology of phenoxyphenyl and ibrutinib, which is applied in the field of organic preparation, can solve the problems of unavailable raw materials, complicated operation, and high production cost, and achieve the effects of cheap reagents, simple operation, and high overall yield

Inactive Publication Date: 2014-08-06
HUAIHAI INST OF TECH
View PDF4 Cites 16 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by this invention is to overcome the technical problem of existing preparation formula (I) compound 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine Raw materials are not easy to get, the production cost is high, the operation is complicated, and it is not conducive to the defects of large-scale industrial production, and an effective method for preparing 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3, 4-d] the method of pyrimidine, the raw material of this method is cheap and easy to get, reaction condition mild, production cost is lower, is 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
  • Method for synthesizing intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib
  • Method for synthesizing intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib
  • Method for synthesizing intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 15

[0024] The preparation of embodiment 15-amino-4-cyanopyrazole

[0025] Add 100mmol malononitrile and 200mmol acetic anhydride into a three-necked flask, stir at 100°C-105°C for 1 hour, then add 100mmol triethyl orthoformate, and keep stirring at 100°C-105°C for 0.5h. The low-boiling raw material was evaporated to obtain an oily residue. Add 15mL of 85% hydrazine hydrate, raise the temperature of the system to 90-95°C, and reflux at this temperature for 2h. Heating was stopped, and 20 mL of water was added to the reaction flask, stirred, and a solid was precipitated. Suction filtration, washing with ice water 2 to 3 times, and drying to obtain a solid with a yield of 90%.

Embodiment 2

[0026] The preparation of embodiment 2 formula (II) compound 4-amino-1H-pyrazolo [3,4-d] pyrimidine

[0027] Add 50mmol of 5-amino-4-cyanopyrazole, 50mmol of formamide, 2mL of anhydrous tin tetrachloride and 100mL of toluene into the reaction flask, heat to reflux for 4h, cool to room temperature, add 50mL of saturated aqueous sodium carbonate solution, and stir until no longer Bubbles escaped. Separate the organic layer, extract the aqueous phase with toluene (100mL×3), combine the organic layers, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and recrystallize the residue with ethyl acetate to obtain the compound of formula (II). The rate is 83%.

Embodiment 3

[0028] The preparation of embodiment 3 formula (III) compound 4-amino-3-bromo-1H-pyrazolo[3,4-d]pyrimidine

[0029] Add 50mmol of 1H-pyrazolo[3,4-d]pyrimidin-4-amine, 3 drops of DMF and 50mL of thionyl chloride into the reaction flask, stir and react at room temperature for 1h, then add 65mmol of bromine dropwise, and remove the system The temperature was raised to 60-70°C, and the reaction was stirred at this temperature for 3h. Stop heating, add 150mL of toluene to the reaction bottle, after stirring, evaporate toluene, unreacted thionyl chloride and bromine under reduced pressure, then add 100mL of toluene and stir, add 150mL of distilled water, separate the organic layer, and wash with distilled water for 3 times , dried with anhydrous sodium sulfate and distilled off the solvent under reduced pressure to obtain the compound of formula (III) with a yield of 80%.

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 synthesizing an important intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib. The method comprises the following steps: step one, condensing malononitrile and triethyl orthoformate and then carrying out a one-pot reaction with hydrazine hydrate to obtain 5-amino-4-cyano-pyrazole; step two, condensing the 5-amino-4-cyano-pyrazole with formamide to prepare a compound of formula (II) 4-amino-1H-pyrazolo[3,4-d]pyrimidine; step three, carrying out a bromination reaction of the compound of formula (II) and brominating agent to obtain a compound of formula (III) 4-amino-3-bromine-1H-pyrazolo[3,4-d]pyrimidine; step four, carrying out a Stille reaction on the compound of formula (III) and trimethyl p-phenoxy phenyltin under the catalyst effect of metal palladium to prepare a compound of formula (I) 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine. According to the method for synthesizing the important intermediate 4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine of Ibrutinib provided by the invention, raw materials are low in price and easily obtained, the reaction conditions are moderate, the operation is simple and convenient, the method is suitable for industrial production, and a new way is provided for preparing Ibrutinib and intermediate.

Description

technical field [0001] The invention belongs to the technical field of organic preparation, in particular to a method for synthesizing ibrutinib intermediate 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine . Background technique [0002] Ibrutinib (Formula A), chemical name 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d] Pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one, which was jointly developed by Pharmacyclics and Johnson & Johnson, was first listed in November 2013 with the accelerated approval of the US Food and Drug Administration. The trade name is Imbruvica . Ibrutinib is an oral first-in-class drug called a Bruton's tyrosine kinase (BTK) inhibitor, which is mainly used to treat a rare and aggressive blood cancer called mantle cell lymphoma (MCL). The drug irreversibly inhibits BTK by selectively covalently binding to cysteine ​​residues in the active site of the target protein Btk, thereby effectively preventing tumor migration from B cells to ly...

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): C07D487/04
CPCC07D487/04
Inventor 程青芳周菲菲林敏王启发
Owner HUAIHAI INST OF TECH
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