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Synthesis method of ibrutinib intermediate

A technology of ibrutinib and intermediates, applied in the field of medicine, can solve the problems of harsh synthesis conditions, unsuitable for industrial production, expensive and the like, and achieve the effects of short synthesis steps and simple operation

Active Publication Date: 2019-11-29
HANGZHOU ZHONGMEI HUADONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This synthesis route is relatively simple, but requires the use of more expensive noble metal catalysts and boric acid compounds, and the synthesis conditions are harsh, so it is not suitable for industrial production. At present, the route with longer reaction steps is generally selected for scale-up production.

Method used

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  • Synthesis method of ibrutinib intermediate
  • Synthesis method of ibrutinib intermediate
  • Synthesis method of ibrutinib intermediate

Examples

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Effect test

Embodiment 1

[0035] Add N,N-dimethylformamide (50mL) to the reaction flask, add 4-phenoxybenzoic acid (II) (4.37g, 0.02mol) under nitrogen protection, 3-chloro-4-amino-1H-pyridine Azolo[3,4,d]pyrimidine(III) (5.19g, 0.03mol), potassium phosphate (17.14g, 0.08mol), CuI (0.38g, 0.002mol) and pyridine (0.65g, 0.008mol). The temperature was raised to 150° C. for reflux reaction for 12 hours, and the reaction was detected by HPLC to be complete (the content of 4-phenoxybenzoic acid was less than 1%). Cool down to room temperature, slowly add water to precipitate a solid, filter, and dry to obtain a solid product (3.89 g, yield: 64.1%).

Embodiment 2

[0037] N,N-dimethylacetamide (50mL) was added to the reaction flask, and 4-phenoxybenzoic acid (II) (4.81g, 0.022mol), 3-bromo-4-amino-1H- Pyrazolo[3,4,d]pyrimidine (III) (4.37g, 0.02mol), sodium carbonate (8.74g, 0.1mol), CuBr (0.43g, 0.003mol), 1,10-phenanthroline (0.73 g, 0.004mol). The temperature was raised to 150°C for 24h. Cool down to room temperature, slowly add water to precipitate a solid, filter, and dry to obtain a solid product (4.95 g, yield: 81.5%).

Embodiment 3

[0039] Dimethylsulfoxide (50mL) was added into the there-necked flask, and 4-phenoxybenzoic acid (II) (8.74g, 0.04mol) was added under nitrogen protection, 3-iodo-4-amino-1H-pyrazolo[ 3,4,d] pyrimidine(III) (5.33g, 0.02mol), cesium carbonate (7.87g, 0.04mol), CuOAc (0.49g, 0.004mol) and 2,2'-bipyridine (0.32g, 0.002mol ). The temperature was raised to 140°C for 10 hours. Cool down to room temperature, slowly add water to precipitate a solid, filter, and dry to obtain a solid product (5.08 g, yield: 83.7%).

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Abstract

The invention provides a preparation method of an ibrutinib intermediate (I). According to the method, 4-phenoxy benzoic acid (II) and 3-substituted-4-amino-1H-pyrazolo [3, 4, d] pyrimidine (III) aretaken as raw materials, a copper catalyzed decarboxylation coupling reaction is carried out, and the ibrutinib key intermediate 3-(4-phenoxy phenyl)-4-amino-1H-pyrazolo [3, 4-d] pyrimidine (I) is prepared. The synthetic route is novel, the operation is simple, the raw materials are cheap and easy to obtain, and large-scale amplification and industrial production are facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a synthetic method of an ibrutinib intermediate, in particular to an ibrutinib intermediate 3-(4-phenoxyphenyl)-4-amino-1H-pyrazolo[ 3,4-d] Synthetic method of pyrimidine (I). Background technique [0002] Ibrutinib, chemical name 1-[(3R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine- 1-yl)-1-piperidinyl)-2-propen-1-one is a kind of oral Bruton's tyrosine kinase (BTK) inhibitor jointly developed and listed by American Pharmacyclics and Johnson & Johnson First-in-class drug. Since it was approved for marketing by the FDA on November 13, 2013, ibrutinib has been used in 5 indications including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). gradually gained approval in the United States. The drug irreversibly inhibits BTK by selectively covalently binding to the cysteine ​​residue (Cys-481) in the active site of ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04Y02P20/55
Inventor 余睿陈禹吴鸿辉胡海文叶凯
Owner HANGZHOU ZHONGMEI HUADONG PHARMA
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