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A kind of synthetic method of ibrutinib

A synthetic method, the technology of ibrutinib, applied in the field of drug synthesis, can solve the problems of waste of raw materials, industrial production costs, low purity affecting product quality, and insufficient purity and yield of ibrutinib, so as to reduce waste of raw materials and industrial production. Production cost, high purity and yield, and the effect of high yield

Active Publication Date: 2022-05-13
扬子江药业集团江苏紫龙药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Aiming at the problems existing in the prior art, the technical problem to be solved in the present invention is: the purity and the yield of synthesizing ibrutinib in the prior art are not high enough, the low purity affects the product quality, and the low yield leads to waste of raw materials and industrial higher production costs

Method used

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  • A kind of synthetic method of ibrutinib
  • A kind of synthetic method of ibrutinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Intermediate M3 was prepared according to the following steps:

[0030] (1) Mix and stir 25g 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo(3,4-d)pyrimidine, 250mLTHF and 43.2g triphenylphosphine to dissolve, add 35g (S)-tert-butyloxycarbonyl-3-hydroxypiperidine, stirred for 10min;

[0031] (2) Protect from light, control the temperature at 10°C, start adding diisopropyl azodicarboxylate dropwise, and stir for 2 hours; cool the reaction down to 0°C, add concentrated hydrochloric acid, adjust the pH of the reaction system to 1, and then raise the temperature to 40°C Reaction 3h;

[0032] (3) Add 500ml of purified water, wash with 500ml of ethyl acetate for 5 times to remove impurities;

[0033] (4) Add NaOH aqueous solution with a mass fraction of 25% dropwise in the impurity-removed system, adjust the pH=9-10, and obtain the light yellow powder intermediate M3 after desalting and crystallizing for 2 hours. figure 1 It is the HPLC spectrogram of the intermediate M3 prepared ...

Embodiment 2

[0039] Intermediate M3 was prepared according to the following steps:

[0040] (1) Mix and stir 25g 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo(3,4-d)pyrimidine, 250mLTHF and 43.2g triphenylphosphine to dissolve, add 35g (S)-tert-butyloxycarbonyl-3-hydroxypiperidine, stirred for 30min;

[0041] (2) Protect from light, control the temperature at 15°C, start adding diisopropyl azodicarboxylate dropwise, and stir for 4 hours; cool the reaction down to 0°C, add concentrated hydrochloric acid, adjust the pH of the reaction system to 1.5, and then raise the temperature to 45°C Reaction 5h,

[0042] (3) Add 750mL of purified water, wash 5 times with 600ml of ethyl acetate to remove impurities,

[0043] (4) Add NaOH aqueous solution with a mass fraction of 25% dropwise to the impurity-removed system, adjust the pH=10, desalt and crystallize for 2 hours to obtain a light yellow powder intermediate M3 with a purity of 99.011%

[0044] Ibrutinib is prepared according to the following step...

Embodiment 3

[0049] Intermediate M3 was prepared according to the following steps:

[0050] (1) Mix and stir 25g 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo(3,4-d)pyrimidine, 250mLTHF and 43.2g triphenylphosphine to dissolve, add 35g (S)-tert-butyloxycarbonyl-3-hydroxypiperidine, stirred for 20min;

[0051] (2) Protect from light, control the temperature at 10-15°C, start adding diisopropyl azodicarboxylate dropwise, and stir for 2 hours; cool the reaction down to 0°C, add concentrated hydrochloric acid, adjust the pH of the reaction system to 1, and then raise the temperature to React at 42°C for 4h,

[0052] (3) Add 600mL of purified water, wash 5 times with 550ml of ethyl acetate to remove impurities,

[0053] (4) Add NaOH aqueous solution with a mass fraction of 25% dropwise to the impurity-removed system, adjust the pH=10, desalt and crystallize for 2 hours to obtain a light yellow powder intermediate M3 with a purity of 99.101%

[0054] Ibrutinib is prepared according to the following...

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Abstract

The invention relates to the technical field of drug synthesis, in particular to a synthesis method of ibrutinib. The purity and yield of synthetic ibrutinib in the prior art are not high enough, low purity affects product quality, and low yield leads to waste of raw materials and high industrial production costs. Based on the above problems, the present invention provides a synthetic method of ibrutinib. First, a high-purity intermediate M3 is prepared, and the high-purity intermediate M3 is acylated with acryloyl chloride under alkaline conditions, and then through a series of The purification step obtains high-purity and high-yield ibrutinib, improves product quality, and greatly reduces waste of raw materials and industrial production costs.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a synthesis method of ibrutinib. Background technique [0002] Ibrutinib, chemical name: 1-{(3R)-3-[4-amino-3-(4-phenoxyphenol)-1H-pyrazol[3,4-d]pyrimidin-1-yl] Piperidin-1-yl}prop-2-en-1-one, molecular formula: C25H24N6O2, its relative molecular mass is 440.50, and its chemical structural formula is as follows: [0003] , [0004] The product name of Ibrutinib is Imbruvica, which was first approved by the US FDA on November 13, 2013, for the treatment of relapsed or refractory mantle cell lymphoma (MCL), and has been approved in the European Union, Japan, and China. marketing authorization. At present, a large number of documents have reported the synthesis technology of this drug, and there are many synthetic routes involved. The purity and yield of the obtained product are not high enough. Low purity affects product quality, and low yield will directly lead to was...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 郭守雷姜威张娟
Owner 扬子江药业集团江苏紫龙药业有限公司
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