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New method for preparing ibrutinib and key intermediate of ibrutinib

A technology for ibrutinib and its intermediates, which is applied in the field of preparation of ibrutinib and its intermediates, and can solve the problems of expensive coupling catalysts, harsh Suzuki coupling reaction conditions, and high cost

Inactive Publication Date: 2018-01-30
南京亿华药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] 1. Route 1 uses trimethylsilyldiazomethane (TMSCH 2 N 2 ), this product has a certain degree of danger, and it is difficult to industrialize (Ye Feng, CN201210310343.9); and the operation of this route is relatively cumbersome
[0008] 2. The conditions of route 2 Suzuki coupling reaction are relatively harsh, requiring strict anhydrous and anaerobic operation; and compound 5 and the coupling catalyst used are expensive and costly

Method used

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  • New method for preparing ibrutinib and key intermediate of ibrutinib
  • New method for preparing ibrutinib and key intermediate of ibrutinib
  • New method for preparing ibrutinib and key intermediate of ibrutinib

Examples

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Embodiment 1

[0019] Example 1 Preparation of ibrutinib and its key intermediates

[0020] (1) Add IM1 (15.3 g, 0.066 mol), malononitrile (4.4 g, 0.066 mol), 60 mL tetrahydrofuran into a 250 mL three-neck flask, and cool in an ice bath to an internal temperature of -5-5 o C, slowly add triethylamine (6.7 g, 0.066 mol) dropwise under stirring, and control the internal temperature not to exceed 5 o C, continue to stir for 1 h after dropping.

[0021] (2) Slowly add phosphorus oxychloride (15.2 g, 0.099 mol) dropwise to the above reaction solution, and control the internal temperature not to exceed 5 o C, continue to stir for 1 h after dropping.

[0022] (3) Slowly add 25%-28% ammonia water (47 mL) dropwise to the above reaction solution, and control the internal temperature not to exceed 20 o C, continue stirring for 1 h after dropping, then add water (100 mL) dropwise, continue stirring for 0.5 h after dropping, filter with suction, wash with water (30 ml x 3), and dry in vacuum (45 o C,...

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Abstract

The invention relates to a new method for preparing ibrutinib and a key intermediate of the ibrutinib. According to the new method, rigorous reaction conditions and expensive initial materials and reagents are avoided in an existing synthesis process; through the adoption of a one-pot method for the synthesis of the key intermediate, tedious post-processing operation is simplified, and the cost isreduced; the purity of the prepared intermediate is 99% or above, the yield is high, and the operation is simple, so that the method for preparing the ibrutinib and the key intermediate of the ibrutinib is suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of ibrutinib and an intermediate thereof, belonging to the technical field of pharmacy. Background technique [0002] The chemical name of Ibrutinib is 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1- yl]prop-2-en-1-one, CAS No. 936563-96-1, is a Bruton's tyrosine kinase (BTK) inhibitor, which was granted breakthrough drug designation by FDA in February 2013. It was approved as a treatment for mantle cell lymphoma (MCL) and leukemia (CLL) on November 13, 2013 and February 12, 2014, respectively. [0003] The synthetic route of ibrutinib is relatively long, and the routes reported in the current literature mainly include the following two routes: [0004] 1. The effect of 4-phenoxybenzoyl chloride and malononitrile to obtain the intermediate IM2. Intermediates IM2 and TMSCH 2 N 2 The reaction affords intermediate 3, which reacts with hydrazine hydrate to yield the imi...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D231/38C07C253/30C07C255/43C07C253/16C07C255/37
Inventor 袁静刘武张霞
Owner 南京亿华药业有限公司
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