High-efficiency preparation method for ibrutinib

A high-efficiency technology for ibrutinib, applied in the field of high-efficiency preparation of ibrutinib, to achieve mild reaction conditions, simple operation, and environment-friendly effects

Active Publication Date: 2017-11-24
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The object of the present invention is to provide an Yilu compound that is easy to operate, mild in reaction conditions, low in cost, high in optical purity, easy to purify and suitable for industrial production, aiming at the defects of low optical purity and high cost of synthetic products in the prior art. Efficient preparation method of Tini

Method used

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  • High-efficiency preparation method for ibrutinib
  • High-efficiency preparation method for ibrutinib

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Preparation of nitroso compound III

[0025]Mix 20.0g (200mmol) of racemic 3-aminopiperidine and 160mL of absolute ethanol in a 500mL reaction flask, add 26.0g (200mmol) of D-pyroglutamic acid, and reflux for 2 hours. At room temperature, a white solid was precipitated, filtered, and the resulting solid R-3-aminopiperidine pyroglutamate was mixed with 52.4g (240mmol) (Boc) 2 O was added to 200mL of dichloromethane, then 50.6g (500mmol) of triethylamine was added, and the reaction was stirred at room temperature for 5h. After the reaction, the solvent was concentrated, diluted with water, and then extracted with ethyl acetate. The organic phase was washed three times with a saturated NaCl solution. Concentrate under reduced pressure to obtain 29.4g product, this product, 34.2g (150mmol) periodic acid, 10g wet SiO 2 and 10.3g (150mol) of sodium nitrite were added to 200mL of dichloromethane, stirred and reacted at room temperature for 3h, after the reaction was completed...

Embodiment 2

[0027] Preparation of 3R-hydrazino-1-piperidine compound IV

[0028] Dissolve 29.6g (90mmol) of nitroso compound III in 200mL of dichloromethane, add 50mL of glacial acetic acid and 117.0g of zinc powder, and react at room temperature for 15min. After the reaction, add saturated NaCO 3 The solution adjusts the pH of the reaction system to be alkaline, adding ethyl acetate for extraction, standing still, layering, pouring out the lower aqueous phase, and then refilling the organic phase with saturated NaCO 3 The solution was washed once, and finally washed three times with a saturated NaCl solution, the organic phase was concentrated, and 23.6 g of a hydrazine-based intermediate was obtained through chromatography column purification, and then the hydrazine-based intermediate was added to 90 mL of 4M hydrogen chloride in methanol solution, and the reaction was stirred at room temperature for 0.5 h. The solvent was evaporated to dryness to obtain 13.5 g of 3R-hydrazino-1-piperid...

Embodiment 3

[0030] Preparation of 3R-hydrazino-1-piperidine compound IV

[0031] Dissolve 29.6g (90mmol) of nitroso compound III in 200mL of dichloromethane, add 50mL of glacial acetic acid and 117.0g of zinc powder, and react at room temperature for 10min. After the reaction, add saturated NaCO 3 The solution adjusts the pH of the reaction system to be alkaline, adding ethyl acetate for extraction, standing still, layering, pouring out the lower aqueous phase, and then refilling the organic phase with saturated NaCO 3 The solution was washed once, and finally washed three times with saturated NaCl solution, the organic phase was concentrated, and 23.6 g of hydrazine-based intermediates were obtained through chromatography column purification, and then the hydrazine-based intermediates were added to 180 mL of 4M hydrogen chloride in methanol solution, and the reaction was stirred at 10 ° C After 2 hours, the solvent was evaporated to dryness to obtain 10.2 g of 3R-hydrazino-1-piperidine c...

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Abstract

The invention discloses a high-efficiency preparation method for ibrutinib, which belongs to the technical field of organic synthesis. A concrete synthetic route is shown in a specification. The method has the advantages of mild reaction condition, simple operation, low cost, convenient purifying, friendly environment, and high product optical purity, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of organic compounds and their raw materials and intermediates, and specifically relates to an efficient preparation method of ibrutinib. Background technique [0002] Ibrutinib (common name: Ibrutinib) is a drug for the treatment of B-lymphocyte malignant proliferation diseases. It is an irreversible inhibitor of Btk kinase and was approved by the US Food and Drug Administration in 2013 for the treatment of Mantle cell lymphoma (MCL). In December 2013, the FDA granted the drug the title of Breakthrough Therapy, which is the second drug approved by the FDA to enjoy this treatment since the launch of the New Deal for Breakthrough New Drugs. Its indications were subsequently extended by the FDA to treat chronic lymphocytic leukemia (CLL) and Waldenstrom's macroglobulinemia (WM). The drug has a huge market prospect. Evaluate pharma predicts that the global annual sales will approach US$6 billion ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04Y02P20/55
Inventor 马春华毛龙飞苗玉淇丁清杰朱虹李伟
Owner HENAN NORMAL UNIV
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