Preparation method of Ibrutinib

A technology of ibrutinib and cyclization reaction, which is applied in the field of preparation of ibrutinib, can solve the problems of manufacturing cost and unsatisfactory reaction conditions, and achieve the effects of promoting development, easy availability of raw materials, and environmentally friendly and economical process

Active Publication Date: 2014-03-12
TONGLING WANGYANTANG BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since the preparation of the parent ring 1H-pyrazolo[3,4-d]pyrimidin-4-amine is not involved, and the preparation process will use reactions such as halogenation, Suzuki coupling, and Mitsunobu coupling, the manufacturing cost and reaction conditions are low. not ideal

Method used

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  • Preparation method of Ibrutinib
  • Preparation method of Ibrutinib
  • Preparation method of Ibrutinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Add malononitrile (6.6g, 0.1mol), sodium hydride (4.8g, 0.2mol, 80% dispersed in paraffin) and freshly treated anhydrous tetrahydrofuran 100mL in a three-necked reaction flask, and add 4- A solution of phenoxybenzoyl chloride (II) (23.2 g, 0.1 mol) in 50 mL tetrahydrofuran. After keeping the reaction at room temperature for 2 hours, 250 mL of 1M dilute hydrochloric acid was added, stirred and reacted for 30 minutes, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and the resulting solid was concentrated and dissolved in 150 mL of dioxane and 50 mL of saturated sodium bicarbonate solution. Dimethyl sulfate (37.8 g, 0.3 mol) was added, the temperature was raised to 80-90° C., the reaction was stirred for 3 hours, and the reaction was detected by TLC. Add 400 mL of deionized solution, extract 3 times with methyl tert-butyl ether, combine the organic phases, and dry over anhydrous sodium sulfate. The ...

Embodiment 2

[0027] Add 4-phenoxyphenyl (methoxy)vinylidene dicyanomethane (III) (13.8g, 50mmol), 1-(3R-hydrazino-1-piperidinyl)- 2-propen-1-one (IV) (8.5g, 50mmol) and ethanol 200mL were added dropwise with triethylamine (5g, 50mmol) while stirring. The temperature was raised to reflux, and the reaction was stirred for 5 hours, and the reaction was detected by TLC. Concentrate under reduced pressure, add deionized water to the residue, stir and crystallize at room temperature. Filtration, the obtained solid ethanol and water (1:1) were recrystallized to obtain off-white solid 1-[(3R)-[3-(4-phenoxyphenyl)-4-cyano-5-amino-1H- Pyrazolyl]-1-piperidinyl]-2-propen-1-one (V) 16.6 g, yield 80.4%.

Embodiment 3

[0029] Add 1-[(3R)-[3-(4-phenoxyphenyl)-4-cyano-5-amino-1H-pyrazolyl]-1-piperidinyl]-2 to the three-necked reaction flask -propen-1-one (V) (4.13g, 10mmol), N,N-dimethylformamide dimethyl acetal (1.19g, 15mmol) and toluene 50mL, add acetic acid 3mL under stirring, heat up to 105- 110°C, use an oil-water separator to separate the produced methanol, keep it warm for 3 hours, and detect the reaction by TLC. Concentrate under reduced pressure to remove toluene, add 30% concentrated ammonia water to the residue, and a solid precipitates out. The temperature was raised to reflux under stirring, and the reaction was detected by TLC after 3 hours. When the temperature was lowered to room temperature, solids were precipitated, and crystallized under slow stirring for 12 hours. After filtration, the crude product was recrystallized from ethanol to obtain 3.2 g of ibrutinib (I), with a yield of 72.7%.

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Abstract

The invention discloses a preparation method of Ibrutinib (I). The preparation method comprises the following steps: performing condensation and methyl oxidization reaction on 4-phenoxyl benzoyl chloride (II) serving as a raw material and methylene cyanide and dimethyl sulfate to generate 4-phenoxyl phenyl (methoxyl) ethenylidene dicyan methane (III); performing pyrazol cyclization reaction between the intermediate (III) and 1-(3R-diazanyl-1-piperidyl)-2-propylene-1-ketone(IV) to obtain 1-[(3R)-[3-(4-phenoxyl phenyl)-4-nitrile-5-amino-1H-pyrazolyl]-1-piperidyl]-2-propylene-1-ketone(V). The pyrimidine cyclization reaction between the intermediate (V) and a cyclization agent is performed to prepare the Ibrutinib (I). The preparation method has easily-available raw materials, and is simple in process, economical and environment-friendly, and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a preparation method of ibrutinib. Background technique [0002] Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor jointly developed by Johnson & Johnson and Pharmacyclics Inc., because the compound does not yet have a standard Chinese translation, so this application People here transliterate it as "Irutinib". In February 2013, the drug obtained the "Breakthrough Therapy" qualification from the US Food and Drug Administration (FDA), and was approved for marketing on November 13, 2013. It is applicable as a single treatment for mantle cell lymphoma. For patients with mantle cell lymphoma who have been treated by other means before, the brand name is Imbruvca (Imbruvca). Ibrutinib is the first marketed drug targeting Bruton's tyrosine kinase inhibitor. [0003] The chemical name of Ibruti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 许学农
Owner TONGLING WANGYANTANG BIOTECHNOLOGY CO LTD
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