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
View PDF5 Cites 6 Cited by
  • 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

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of Ibrutinib intermediate
  • Preparation method of Ibrutinib intermediate
  • Preparation method of Ibrutinib intermediate

Examples

Experimental program
Comparison scheme
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).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07D487/04
Inventor 孙辉周伟澄黄浩刘珍仁
Owner SHANGHAI INST OF PHARMA IND
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap