Separation and purification method of ibrutinib intermediate

A technology of separation and purification, ibrutinib, applied in the direction of organic chemistry, etc., can solve the problems of high cost, cumbersome, difficult to remove triphenylphosphine, etc., to achieve the effect of improving efficiency

Inactive Publication Date: 2017-07-21
FUJIAN INST OF MICROBIOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] When the Mitsunobu reaction is applied industrially, its biggest defect is its by-product triphenylphosphine (Ph 3 PO) are difficult to remove and usually require tedious and costly column chromatographic separations

Method used

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  • Separation and purification method of ibrutinib intermediate
  • Separation and purification method of ibrutinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Under nitrogen protection, Ph 3 P (29.2g, 112mmol, 1.25eq), (3 S )-Hydroxy-1-tert-butoxycarbonylpiperidine (18.0g, 89.3mmol, 1.0eq) was dissolved in 150ml of tetrahydrofuran, cooled to 0°C, and the temperature was controlled not to exceed 5°C, and DIAD (25.3 g, 125mmol, 1.4eq) in tetrahydrofuran (40ml), after the addition was complete, the yellow solution continued to stir for 10min. Add 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (28.4g, 93.8mmol, 1.05eq) in tetrahydrofuran at 0~5°C (150ml) solution, after addition, stirred at room temperature for 5h. Add 3.2ml of water, warm to 50-60°C for 30min, then add magnesium chloride (10.6g, 112mmol, 1.25eq), stir and warm to 50-60°C for 2.5h, cool to 0°C, filter, and wash with tetrahydrofuran (50ml×2 ), and the solvent was removed by rotary evaporation, the residual oil was slurried with ethyl acetate (300ml), added n-hexane (50ml), filtered, and the filter residue was washed with ethyl acetate (30ml×2), and th...

Embodiment 2

[0026] Under nitrogen protection, Ph 3 P (29.0g, 112mmol, 1.25eq), (3 S )-Hydroxy-1-tert-butoxycarbonylpiperidine (18.0g, 89.3mmol, 1.0eq) was dissolved in 150ml of tetrahydrofuran, cooled to 0°C, and the temperature was controlled not to exceed 5°C, and DIAD (25.1 g, 125mmol, 1.4eq) in tetrahydrofuran (40ml), after the addition was complete, the yellow solution continued to stir for 10min. Add 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (28.4g, 93.9mmol, 1.05eq) in tetrahydrofuran at 0~5°C (150ml) solution, after addition, stirred at room temperature for 5h. Add 3.2ml of water, warm to 50-60°C for 30min, then add magnesium chloride (14.3g, 168mmol, 1.5eq), stir and warm to 50-60°C for 2.5h, cool to 0°C, filter, and wash with tetrahydrofuran (50ml×2 ), and the solvent was removed by rotary evaporation, the residual oil was slurried with ethyl acetate (300ml), added n-hexane (50ml), filtered, and the filter residue was washed with ethyl acetate (30ml×2), and the...

Embodiment 3

[0028] Under nitrogen protection, Ph 3 P (29.0g, 112mmol, 1.25eq), (3 S )-Hydroxy-1-tert-butoxycarbonylpiperidine (18.0g, 89.3mmol, 1.0eq) was dissolved in 150ml of tetrahydrofuran, cooled to 0°C, and the temperature was controlled not to exceed 5°C, and DIAD (25.1 g, 125mmol, 1.4eq) in tetrahydrofuran (40ml), after the addition was complete, the yellow solution continued to stir for 10min. Add 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (28.2g, 93.9mmol, 1.05eq) in tetrahydrofuran at 0~5°C (150ml) solution, after addition, stirred at room temperature for 5h. Add 3.2ml of water, warm to 50-60°C for 30min, then add magnesium chloride (21.3g, 224mmol, 2.0eq), stir and warm to 50-60°C for 2.5h, cool to 0°C, filter, and wash with tetrahydrofuran (50ml×2 ), and the solvent was removed by rotary evaporation, the residual oil was slurried with ethyl acetate (300ml), added n-hexane (50ml), filtered, and the filter residue was washed with ethyl acetate (30ml×2), and the...

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Abstract

The invention discloses a separation and purification method of an ibrutinib intermediate-(3R)-4-amino-3-(4-phenoxyphenyl)-1-(1-tert-butoxycarbonylpiperidine-3-group)-1-1H-pyrazole [3, 4-d] pyrimidine. The separation and purification method includes: after Mitsunobu reaction for preparing the intermediate stops, adding magnesium chloride into a mixture; cooling after back-flowing; filtering to remove compound precipitate of magnesium chloride and triphenyl phosphine oxide to obtain the intermediate high in purity. Column chromatography is omitted in the process, so that the separation and purification method is high in efficiency and low in cost.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a separation and purification method of an ibrutinib intermediate. [0002] technical background [0003] Ibrutinib is a new targeted anti-cancer drug jointly developed by Johnson Johnson and Pharmacyclics. It is a first-in-class oral Bruton's tyrosine kinase (BTK) inhibitor. The site cysteine ​​residue (Cys-481) is selectively covalently bound to irreversibly inhibit BTK, thereby effectively preventing tumor migration from B cells to lymphoid tissues adapted to the tumor growth environment. It was granted breakthrough drug designation by the FDA in February 2013, and was launched in the United States in December 2013 and in Europe in October 2014, and was approved for chronic lymphocytic leukemia (chronic lymphocyticleukemia, CLL) and mantle cell Drugs for the treatment of lymphoma (mantle celllymphoma, MCL). [0004] Studies have shown that ibrutinib has...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 赵学清林燕琴黄杨威陈忠徐敏华
Owner FUJIAN INST OF MICROBIOLOGY
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