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Preparation method of ibrutinib

A technology of ibrutinib and phenoxyphenyl, which is applied in the field of bulk drug preparation, can solve problems such as unfavorable industrialized production, lower product purity, lower yield, etc., and achieves the advantages of promoting development, environmental protection and economy, and easy availability of raw materials. Effect

Inactive Publication Date: 2015-04-29
王立强 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this route introduces the propenyl structure and carries out pyrimidine cyclization at high temperature, which is likely to cause side reactions, resulting in reduced product purity and yield, which is not conducive to industrial production

Method used

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  • Preparation method of ibrutinib
  • Preparation method of ibrutinib
  • Preparation method of ibrutinib

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Under nitrogen atmosphere, take 30.3g 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine and 78.6g triphenylphosphine into 1000mL tetrahydrofuran, Add 31gl-[3(S)-hydroxyl-1-piperidinyl]-2-propene-1-one to the mixture, then add dropwise 60.6g diisopropyl azodicarboxylate (DIAD), and the reaction solution is at room temperature Stir overnight. After the reaction, the reaction solution was concentrated under reduced pressure by a rotary evaporator, dissolved in dichloromethane, washed with saturated sodium chloride solution, dried, filtered, and the filtrate was concentrated and recrystallized with isopropanol to obtain an off-white solid, ibrutinib 33.2 g, yield 75.4%.

Embodiment 2

[0030] Take 10.1g of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine and 17.5g of polymer supported triphenylphosphine into 200mL THF, Add 10.4g (1-[3(S)-hydroxyl-1-piperidinyl]-2-propene-1-one) to the mixture, then add 13.4g diethyl azodicarboxylate dropwise, and the reaction solution is heated at 30°C After the reaction was completed, the reaction system was filtered, the filtrate was concentrated under reduced pressure by a rotary evaporator, dissolved in ethyl acetate, washed with saturated sodium chloride solution, dried, filtered, and the filtrate was concentrated and recrystallized by ethanol to obtain Irutidine Nitride 7.1g, yield 48.3%.

Embodiment 3

[0032] Add 4.4g of triphenylphosphine to 100mL of dichloromethane, add 6.8g of diphenyl azodicarboxylate dropwise, stir for half an hour, then add 5.1g of 4-amino-3-(4-phenoxyphenyl)- 1H-pyrazolo[3,4-d]pyrimidine and 3.9g (1-[3(S)-hydroxyl-1-piperidinyl]-2-propene-1-one, then the reaction solution was stirred at 0°C Overnight, the reaction solution was washed with saturated sodium chloride solution, dried, filtered, and the filtrate was concentrated and then recrystallized with isopropanol to obtain 2.7 g of ibrutinib with a yield of 37.0%.

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Abstract

The invention relates to a preparation method of ibrutinib. The preparation method comprises the following steps: allowing 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidine, 1-[3(S)-hydroxy-1-piperidinyl]-2-propen-1-one, and triphenylphosphine to be dissolved in tetrahydrofuran as a reaction solvent at a temperature of -20 to 100 DEG C, and then slowly adding diisopropyl azodicarboxylate, and stirring until the reaction is finished to obtain the ibrutinib. The preparation method provided by the invention has the advantages of easy availability of raw materials, mild conditions, simple process, economy and environmental protection, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of preparation of raw materials, in particular to a preparation method of Ibrutinib. Background technique [0002] Ibrutinib (English name Ibrutinib, trade name IMBRUVICA) is a Bruton's tyrosine kinase (BTK) inhibitor jointly developed by Johnson&Johnson and Pharmacyclics Inc. of the United States. The drug was approved for marketing on November 13, 2013, and is used for the treatment of mantle cell lymphoma (MCL). The chemical name of Ibrutinib is: 1-[3(R)-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine -1-yl]-1-piperidinyl]-2-propene-1-one, its structural formula is: [0003] [0004] Document ChemMedChem.2007, 2 (1): 58-61 reports the synthetic method of ibrutinib, [0005] [0006] The method takes 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine as raw material, and 3(S)-hydroxypiperidine-1-formic acid tert-butyl Ibrutinib was prepared from the ester through Mitsunobu reactio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 王立强邱飞
Owner 王立强
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