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Preparation method of Ibrutinib intermediate

An intermediate and volumetric technology, which is applied in the field of preparation of ibrutinib intermediates, can solve the problems of complex reaction operation, high cost, and excessive production of three wastes

Active Publication Date: 2016-08-03
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved in the present invention is to overcome the ibrutinib intermediate (R)-1-tert-butoxycarbonyl-3-(4-amino-3-(4-phenoxyphenyl)- The preparation method of 1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine has high cost, large amount of reagents, more wastes, complex reaction operation, cumbersome post-treatment, low yield and low optical purity , Not suitable for industrialized production defects, and provides a preparation method of ibrutinib intermediates

Method used

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  • Preparation method of Ibrutinib intermediate
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  • Preparation method of Ibrutinib intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0061] Into a 100ml reaction flask, add (S)-1-Boc-3-hydroxypiperidine (5.0g, 24.9mmol) and 20ml of pyridine, cool to about 5°C in an ice bath, add p-toluenesulfonyl chloride (5.2g , 27.4mmol), stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, the organic phase was washed with water, dilute hydrochloric acid (3M), and brine successively, concentrated under reduced pressure, and the residue was added with 20 ml of petroleum ether, stirred for 2.0 h, filtered, washed with petroleum ether, and dried at 60°C to obtain White crystal product (S)-1-tert-butoxycarbonyl-piperidin-3-yl-4-methyl-1-benzenesulfonate (8.5g), yield 96%, specific rotation: [α] 20 D =-24.6° (c=1.0, EtOH).

Embodiment 2

[0063] To a 100ml reaction flask, add (S)-1-Boc-3-hydroxypiperidine (5.0g, 24.9mmol), triethylamine (5.0g, 49.5mmol) and 50ml of dichloromethane, and cool to 5°C in an ice bath Around, methanesulfonyl chloride (3.15 g, 27.4 mmol) was added dropwise to the reaction liquid, and stirred overnight at room temperature. The organic phase was washed with salt water, concentrated under reduced pressure, and the residue was added to 20ml of petroleum ether, stirred for 2.0h, filtered, washed with petroleum ether, and dried at 60°C to obtain the white crystal product (S)-1-tert-butoxycarbonyl-piperidine -3-yl-mesylate (6.4g), yield 92%, specific rotation: [α] 20 D =-16.3° (c=1.0, EtOH).

Embodiment 3

[0065] To a 100ml reaction flask, add (S)-1-Boc-3-hydroxypiperidine (5.0g, 24.9mmol), diisopropylethylamine (6.4g, 49.5mmol) and 50ml of ethyl acetate, and cool in an ice bath To about 5°C, methanesulfonyl chloride (3.15g, 27.4mmol) was added dropwise to the reaction liquid, and stirred overnight at room temperature. The organic phase was washed with salt water, concentrated under reduced pressure, and the residue was added to 20ml of petroleum ether, stirred for 2.0h, filtered, washed with petroleum ether, and dried at 60°C to obtain the white crystal product (S)-1-tert-butoxycarbonyl-piperidine -3-yl-mesylate (6.6g), yield 95% Specific rotation: [α] 20 D =-16.4° (c=1.0, EtOH).

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Abstract

The invention discloses a preparation method of an Ibrutinib intermediate shown as a formula 4. The method comprises the following steps: in a organic solvent, under effect of an acid-binding agent, a compound shown as a formula 2 and a compound shown as a formula 3 are subjected to a nucleophilic substitution reaction, and the Ibrutinib intermediate shown as the formula 4 is prepared. The acid-binding agent is one or more of sodium carbonate, potash and sodium hydride; wherein, Y is C1-C6 alkyl, phenyl or C1-C6 alkyl-substituted phenyl; and Z is halogen, or 4-phenoxyl-phenyl. The preparation method has the advantages of simple operation, low cost, less reagent amount, less three wastes, environmental pollution, simple post-treatment, high yield, and high optical purity, and is suitable for industrial production.

Description

technical field [0001] The present invention specifically relates to a preparation method of an ibrutinib intermediate. Background technique [0002] Antineoplastic drug Ibrutinib (Ibrutinib), 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, the molecular formula is C 25 h 24 N 6 o 2 , the indications are mantle cell lymphoma and chronic lymphocytic leukemia, the structural formula is as follows: [0003] [0004] ibrutinib [0005] US Patent US20080108636 discloses ibrutinib and its preparation method. The synthetic route is as follows: [0006] [0007] This patent discloses an ibrutinib intermediate (R)-1-tert-butoxycarbonyl-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3, 4-d] The preparation method of pyrimidin-1-yl)piperidine: take intermediate (3) and (S)-1-Boc-3-hydroxypiperidine as raw materials, and undergo Mitsunobu reaction to obtain the intermediate (4), the yield is only 34...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 孙辉周伟澄黄浩刘珍仁
Owner SHANGHAI INST OF PHARMA IND
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