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Preparation method of ibrutinib

A technology of ibrutinib and compounds, applied in the field of preparation of ibrutinib, can solve the problems of long reaction route, not environmental protection, and many wastes, etc.

Inactive Publication Date: 2021-08-03
湖南华腾制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Aiming at the above-mentioned preparation method of ibrutinib and its intermediates, there are long reaction routes, low yield, poor selectivity due to the Mitsunobu reaction, many wastes produced, and the technical problems that are not environmentally friendly. One aspect of the present invention is to provide A preparation method of ibrutinib and its intermediates, the method has the characteristics of mild reaction conditions, low cost, high yield, good optical purity, less waste and is suitable for industrial scale-up

Method used

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  • Preparation method of ibrutinib
  • Preparation method of ibrutinib
  • Preparation method of ibrutinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] The preparation of embodiment 1 compound C

[0083]

[0084] Add 0.61kg of compound A, 0.1L of absolute ethanol, and 1.08kg of compound B into the reaction kettle at room temperature, and heat up to 90°C for reflux reaction after the addition. After 5 hours, the HPLC results show that the raw materials have reacted completely, stop the reaction, and cool to room temperature , the reaction solution was filtered, and the filter cake was dried at 80° C. for 14.0 h to obtain 1.32 kg of solid, with a yield of 87.1% and a purity of 99.5%.

[0085] After testing: MS: [M+1] = 304.2, NMR 1 H NMR(400MHz,DMSO-d6)δ8.23(s,1H),6.31(m,2H),3.85-3.91(m,2H),3.96(t,1H),3.52-3.56(m,2H), 1.87-2.12(m,2H),1.58-1.68(m,2H),1.39(s,9H).

Embodiment 2

[0086] The preparation of embodiment 2 compound C

[0087] Add 0.30kg of compound A, 50mL of absolute ethanol, 0.54kg of compound B to the reaction kettle at room temperature, add 0.505kg of triethylamine, and heat up to 90°C for reflux reaction after the addition. After 4 hours, the HPLC results show that the raw materials are completely reacted. Stop the reaction, cool to room temperature, filter the reaction solution, and dry the filter cake at 80° C. for 14.0 h to obtain Compound C, 0.69 kg in total, with a yield of 91.2% and a purity of 99.3%.

Embodiment 3

[0088] The preparation of embodiment 3 compound D

[0089]

[0090] Add 0.43 kg of compound C and 5 mL of formamide to the reaction bottle at room temperature, heat up to 80°C to 85°C for reflux reaction after addition, and react for 12 hours. After the HPLC results show that the raw materials are completely reacted, stop the reaction, cool to room temperature, and add water After stirring, filtering, the filter cake was dissolved in chloroform, concentrated, and purified by methanol-chloroform gradient silica gel chromatography to obtain compound D, 0.29 kg in total, with a yield of 64.5% and a purity of 98.4%.

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Abstract

The invention relates to a preparation method of ibrutinib and an intermediate thereof, belonging to the field of medicinal chemistry. According to the preparation method, the ibrutinib can be obtained through condensation, condensation, substitution, substitution and Suzuki reaction by taking a low-cost material flow as a starting material; and the method is low in cost, free of light delay reaction, high in yield, good in selectivity, short in route, few in generated three wastes and suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of ibrutinib. Background technique [0002] Ibrutinib, an oral Bruton's tyrosine kinase (BTK) inhibitor, was first launched in the United States in November 2013 for the treatment of mantle cell lymphoma that has received previous treatment (MCL), which has recently been approved for the treatment of chronic lymphocytic leukemia (CLL) that has received previous treatment and chronic lymphocytic leukemia (CLL) carrying a del17p deletion mutation; its chemical structure is shown in formula G below: [0003] [0004] At present, a large number of documents have reported the synthesis technology of the drug, and there are many synthetic routes involved, and the purity and yield of the obtained product are not high. [0005] WO2014022390 reported the preparation of intermediate 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine by iodolation using 4-aminopyrazolo[3,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D401/04
CPCC07D487/04C07D401/04
Inventor 许慧王芳芳赵思纯邓泽平
Owner 湖南华腾制药有限公司
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