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Preparation method of ibrutinib

A technology of ibrutinib and compound, applied in the field of preparation of ibrutinib, can solve the problems of unfavorable industrial scale, inconvenient operation, high price, etc., achieve stable and controllable synthesis process, easy storage, shorten separation and purification effect of steps

Active Publication Date: 2016-10-12
BIOCOMPOUNDS PHARMACEUTICAL INC +1
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0012] This method uses 4-halogenated diphenyl ethers (IX) as raw materials, through Suzuki coupling and Kumada coupling reactions, without separation to obtain intermediate (R)-3-[4-amino-3-(4-phenoxy Phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (IV), and then remove the Boc protecting group to obtain intermediate (V), and then Acylation of mixed anhydrides formed from acrylic acid with acid chlorides and sulfonyl chlorides using the more expensive palladium catalyst (Pd(dppf) 2 Cl 2 and Pd 2 (dba) 3 ), inconvenient to operate, not conducive to industrial scale-up

Method used

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  • Preparation method of ibrutinib
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  • Preparation method of ibrutinib

Examples

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Embodiment 1

[0061] Synthesis of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo(3,4-d)pyrimidin-4-amine (5)

[0062] Add 20 g (66 mmol) of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine into a 1L three-necked flask; S-1-tert-butoxycarbonyl-3- Hydroxypiperidine 13.3g (66mmol); triphenylphosphine 34.6g (132mmol), add dry tetrahydrofuran 300mL, cool to 5-10°C. Under nitrogen protection, 26.7 g (132 mmol) of diisopropyl azodicarboxylate was slowly added dropwise into the bottle, and the reaction was carried out at 30° C. for 10 hours after the drop was completed. The reaction solution was re-cooled to 0-10°C, 13.4g (132mmol) of 36% hydrochloric acid was added dropwise, and the temperature was raised to 40°C for 1 hour after the dropwise completion. Add water, stir, extract 3 times with dichloromethane, collect the water phase, adjust the water phase to be alkaline (pH>10) with sodium hydroxide solution, precipitate the solid, filter, collect the solid, and bake at 50°C for 8...

Embodiment 2

[0064] Synthesis of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo(3,4-d)pyrimidin-4-amine (5)

[0065] Add 20 g (66 mmol) of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine into a 1L three-necked flask; S-1-tert-butoxycarbonyl-3- Hydroxypiperidine 26.6g (132mmol); triphenylphosphine 51.9g (198mmol), add dry tetrahydrofuran 400mL, cool to 5-10°C. Under nitrogen protection, 40 g (198 mmol) of diisopropyl azodicarboxylate was slowly added dropwise to the bottle, and the reaction was carried out at 30° C. for 12 hours after the drop was completed. The reaction solution was re-cooled to 0-10°C, 20 g (198 mmol) of 36% hydrochloric acid was added dropwise, and the temperature was raised to 40°C for 1 hour after the dropwise completion. Add water, stir, extract 3 times with dichloromethane, collect the water phase, adjust the water phase to be alkaline (pH>10) with sodium hydroxide solution, precipitate the solid, filter, collect the solid, and bake at 50°C for 12 h...

Embodiment 3

[0067] Synthesis of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo(3,4-d)pyrimidin-4-amine (5)

[0068] Add 20 g (66 mmol) of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine into a 1L three-necked flask; S-1-tert-butoxycarbonyl-3- Hydroxypiperidine 26.6g (132mmol); triphenylphosphine 51.9g (198mmol), add dry tetrahydrofuran 400mL, cool to 5-10°C. Under nitrogen protection, 40 g (198 mmol) of diisopropyl azodicarboxylate was slowly added dropwise to the bottle, and the reaction was carried out at 30° C. for 12 hours after the drop was completed. The reaction solution was re-cooled to 0-10°C, 22.5 g (198 mmol) of trifluoroacetic acid was added dropwise, and the temperature was raised to 40°C for 1 hour after the dropwise completion. TLC monitored the end of the reaction. Add water, stir, extract 3 times with dichloromethane, collect the water phase, adjust the water phase to be alkaline (pH>10) with sodium hydroxide solution, precipitate the solid, filter, col...

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Abstract

The invention relates to the technical field of medicine, in particular to a preparation method of ibrutinib. The preparation method of ibrutinib comprises the following steps that 4-amino-3-(4-phenoxy phenyl)-1H-pyrazol[3,4-d]pyrimidine and S-1-tert-butyloxycarbonyl-3-hydroxyl piperidine are prepared into a compound shown in the formula IV (please see the formula in the description) through a Mitsunobu reaction, and a Boc protecting group of the compound shown in the formula IV is removed to prepare a compound shown in the formula V (please see the formula in the description); the compound shown in the formula V and acrylic ester are prepared into a compound shown in the formula I (please see the formula in the description) in the presence of a catalyst and an activating agent. According to the preparation method, the reaction process is mild in condition, few reaction steps are needed, high temperature and copious cooling are not needed, no high-toxicity reagent is adopted, and the whole synthesizing process is stable and controllable; ibrutinib prepared through the method is high in yield and quality and has the advantages of being good in stability, high in purity, convenient to store and the like.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of ibrutinib. Background technique [0002] Ibrutinib (English name Ibrutinib, trade name Imbruvica, molecular formula C 25 h 24 N 6 o 2 , molecular weight 440.50) has the structure shown in formula I, and its chemical name is 1-[(3R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 -d] pyrimidin-1-yl)-1-piperidinyl)-2-propen-1-one. Ibrutinib is a first-in-class oral Bruton's tyrosine kinase (BTK) inhibitor jointly developed and marketed by Pharmacyclics and Johnson & Johnson. The drug binds to the active site of the target protein Btk. The cysteine ​​residue (Cys-481) selectively binds covalently and irreversibly inhibits BTK, thereby effectively preventing tumor migration from B cells to lymphoid tissues adapted to the tumor growth environment. Since it was approved by the FDA on November 13, 2013, ibrutinib has been used in 5 indications including man...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCY02P20/55C07D487/04
Inventor 杨世琼李倩康立涛
Owner BIOCOMPOUNDS PHARMACEUTICAL INC
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