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Method for using zinc chloride to separate and purify ibrutinib intermediate

A technology of separation and purification, ibrutinib, applied in the direction of organic chemistry, etc., can solve the problems of difficult removal and insufficient complexation, and achieve the effect of improving efficiency

Inactive Publication Date: 2019-01-18
FUJIAN INST OF MICROBIOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But MgCl 2 All equivalents need to be 2.5, and repeated concentration and crystallization are required, and it is difficult to remove all at one time (up to less than 1.0%), which may be due to MgCl 2 with Ph 3 The complexation of PO is not strong enough

Method used

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  • Method for using zinc chloride to separate and purify ibrutinib intermediate
  • Method for using zinc chloride to separate and purify ibrutinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Under nitrogen protection, Ph 3 P (58.0g, 224mmol), (3 S )-Hydroxy-1-tert-butoxycarbonylpiperidine (36.0g, 179mmol) was dissolved in 300ml of tetrahydrofuran, cooled to 0°C, and the temperature was controlled not to exceed 5°C, and DIAD (50.0g, 250mmol) was added within 20-30min Tetrahydrofuran (80ml) solution was added, and the yellow solution was stirred for 10 minutes. Add 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (56.0g, 184mmol) in tetrahydrofuran (300ml) at 0~5°C , Added, stirred at room temperature for 5h. Add 7ml of water, then add zinc chloride (30.5g, 224mmol), stir and warm to 30-40°C for 2.5h, cool to 0°C, filter, and wash with tetrahydrofuran (100ml×2), remove the solvent by rotary evaporation, and the residual The oily matter was slurried with ethyl acetate (600ml), added n-hexane (100ml), filtered, and the filter residue was washed with ethyl acetate (60ml×2), and the filtrate was washed with water (200ml×2) and saturated brine (300ml), ...

Embodiment 2

[0027] Under nitrogen protection, Ph 3 P (29.2g, 112mmol), (3 S )-Hydroxy-1-tert-butoxycarbonylpiperidine (18.0g, 89.3mmol) was dissolved in 150ml of tetrahydrofuran, cooled to 0°C, and the temperature was controlled not to exceed 5°C, and DIAD (25.3g, 125mmol) was added within 20-30min ) 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) in tetrahydrofuran (150ml) at 0~5°C The solution was added and stirred at room temperature for 5h. Add 3.2ml of water, then add zinc chloride (18.2g, 134mmol), stir and warm to 30-40°C for 2.5h, cool to 0°C~-5, filter, wash with tetrahydrofuran (50ml×2), and remove the solvent by rotary evaporation , beat the residual oil with ethyl acetate (300ml), add n-hexane (50ml), filter, wash the filter residue with ethyl acetate (30ml×2), and wash the filtrate with water (100ml×2), saturated saline (150ml ) washe...

Embodiment 3

[0029] Under nitrogen protection, Ph 3 P (29.0g, 112mmol), (3 S )-Hydroxy-1-tert-butoxycarbonylpiperidine (18.0g, 89.3mmol) was dissolved in 150ml of tetrahydrofuran, cooled to 0°C, and the temperature was controlled not to exceed 5°C, and DIAD (25.1g, 125mmol) was added within 20-30min ) 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) in tetrahydrofuran (150ml) at 0~5°C The solution was added and stirred at room temperature for 5h. Add 3.5ml of water, then add zinc chloride (22.8g, 168mmol, 1.5eq), stir and warm to 30-40°C for 2.5h, cool to 0°C, filter, wash with tetrahydrofuran, and remove the solvent by rotary evaporation. The product was beaten with ethyl acetate, added n-hexane, filtered, washed the filter residue with ethyl acetate, the filtrate was washed with water and saturated brine, dried with anhydrous sodium sulfate, the fi...

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Abstract

The invention discloses a method for using zinc chloride to separate and purify an ibrutinib intermediate, and particularly relates to a separation and purification method of the ibrutinib intermediate (3R)-4-amido-3-(4-phenoxy phenyl)-1-(1-tert-butoxy carbonyl piperidine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine. After Mitsunobu reaction for preparing the intermediate is terminated, zinc chloride is added into a mixture, heated and cooled, composition sediment of zinc chloride and triphenylphosphine oxide is removed by filtering, and the intermediate with good purity is obtained. The process omits column chromatography, and is an efficient and low-cost separation and purification method.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for separating and purifying an ibrutinib intermediate with zinc chloride. Background technique [0002] 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) selectively binds covalently and irreversibly inhibits 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). [0003] Studies have shown that ibrut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 赵学清成佳威林燕琴范琳陈忠徐敏华易铭艳
Owner FUJIAN INST OF MICROBIOLOGY
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