Radioisotope carbon-14 labeled ibrutinib and synthesis method thereof

A radioactive isotope and ibrutinib technology, applied in the field of radiochemical synthesis, can solve the problem of high cost of labeling and synthesis, and achieve the effect of low raw material cost and high operational safety

Active Publication Date: 2021-06-25
浙江爱索拓标记医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, a large excess of [ 14 C] formamide, the cost of labeling synthesis is high, and [ 14 C] the preparation process of formamide involves volatile [ 14 C] Formic acid, which is harmful to the operator 14 C Potential risks of internal exposure

Method used

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  • Radioisotope carbon-14 labeled ibrutinib and synthesis method thereof
  • Radioisotope carbon-14 labeled ibrutinib and synthesis method thereof
  • Radioisotope carbon-14 labeled ibrutinib and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] S1: Slowly drop concentrated sulfuric acid (5mL, 18.4M) into the radioactive material under argon protection at -78°C[ 14 C] In barium carbonate (28.8μCi, 0.5mmol), escape [ 14 C]CO 2 A solution (5 mL) of the metal reagent 4-phenoxyphenyllithium (0.55 mmol) in tetrahydrofuran was introduced through a thin glass tube. After stirring for 30 minutes, the reaction was completed. The system was slowly raised to room temperature, and water (5 mL) was added to quench the reaction under ice-water bath cooling. The aqueous phase was extracted with dichloromethane, and the remaining aqueous phase was adjusted to pH 4 with dilute hydrochloric acid (1M). Methane (4mL) was extracted 5 times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, and dried to obtain 4-phenoxybenzene[ 14 C] Formic acid (2, 25.9 μCi, 96 mg, radiochemical yield 90%). 1 H NMR (400MHz, DMSO-d 6 )δ: 12.82(s, 1H), 7.94(d, J=8.7H...

Embodiment 2

[0053] S1: Slowly drop concentrated sulfuric acid (5mL, 18.4M) into the radioactive material under the protection of argon at room temperature[ 14 C] In barium carbonate (28.8μCi, 0.5mmol), escape [ 14 C]CO 2 A solution (5 mL) of the metal reagent 4-phenoxyphenylmagnesium iodide (0.55 mmol) in tetrahydrofuran was introduced through a thin glass tube. After stirring for 30 min, the reaction was completed. The system was slowly raised to room temperature, and water (5 mL) was added to quench the reaction under cooling in an ice-water bath. The aqueous phase was extracted with dichloromethane, and the remaining aqueous phase was adjusted to pH 4 with dilute hydrochloric acid (1M). Methane (4mL) was extracted 5 times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, and dried to obtain 4-phenoxybenzene[ 14 C] formic acid (2, 24.7μCi, radiochemical yield 86%). 1 H NMR (400MHz, DMSO-d 6 )δ: 12.82(s...

Embodiment 3

[0062] S1: Slowly drop concentrated sulfuric acid (5mL, 18.4M) into the radioactive material under the protection of argon at room temperature[ 14 C] In barium carbonate (28.8μCi, 0.5mmol), escape [ 14 C]CO 2A solution (5 mL) of the metal reagent 4-phenoxyphenylmagnesium bromide (0.55 mmol) in tetrahydrofuran was introduced through a thin glass tube. After stirring for 30 minutes, the reaction was completed. The system was slowly raised to room temperature, and water (5 mL) was added to quench the reaction under ice-water bath cooling. The aqueous phase was extracted with dichloromethane, and the remaining aqueous phase was adjusted to pH 4 with dilute hydrochloric acid (1M). Methane (4mL) was extracted 5 times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, and dried to obtain 4-phenoxybenzene[ 14 C] formic acid (2,27.4μCi, radiochemical yield 95%). 1 H NMR (400MHz, DMSO-d 6 )δ: 12.82(s, 1...

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Abstract

The invention provides radioisotope carbon-14 labeled ibrutinib and a preparation method and application thereof. The preparation method comprises the steps that [14C] barium carbonate serves as an initial radioisotope raw material, and the carbon-14 labeled ibrutinib is obtained through [14C] carbon dioxide preparation, carboxylation, halogenation, condensation, methylation, two times of cyclization, Mitsunobu reaction, protecting group removal and the like; a feasible, economical and safe method is provided for the preparation of the 3-site carbon-14 marker in the pyrazolo [3, 4-d] pyrimidine fragment of the ibrutinib molecule for the first time. Furthermore, the related carbon-14 labeled ibrutinib can be used as a radioactive tracer, is mainly used for the fundamental research of the environmental safety problem of the medicine ibrutinib, and can also be used for the fundamental research of the radiopharmacokinetics of the tissue distribution, metabolite structure identification, mass balance and the like of the medicine. Meanwhile, the method provides a reference for the preparation of the carbon-14-containing synthetic building block.

Description

technical field [0001] The invention belongs to the field of radiochemical synthesis, in particular to a radioactive isotope carbon-14 labeled ibrutinib ((R)-1-(3-(4-amino-3-(4-phenoxyphenyl)- 1H-[3- 14 C] a preparation method of pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one). Background technique [0002] At present, medicine is one of the important living materials necessary for human health care and disease treatment. For a long time, people often rely on medicines for their own health care diseases and the treatment of diseases, so medicines have been used in large quantities for a long time in people's daily life. Studies have found that residues of various drugs have been detected in wastewater and sludge (including biomass entrapped therein) discharged from many municipal sewage pipes around the world. In order to save water resources and protect the environment, these waste water are often recycled and reused by people (such as irrigation), and the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04C07B2200/05Y02P20/55
Inventor 杨征敏王国通李琳港李书琰
Owner 浙江爱索拓标记医药科技有限公司
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