Preparation method of deuterated ibrutinib

A technology of ibrutinib and deuteration, which is applied in the field of preparation of deuterated ibrutinib, can solve the problems of poor selectivity of deuterated sites, highly toxic raw materials, low deuterated rate, etc., and achieve good catalytic effect and simple operation , good selective effect

Active Publication Date: 2021-06-01
绍兴舜邦医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the formula (I), each Y is independently selected from hydrogen or deuterium, and the corresponding commercially available deuterated intermediates are used to synthesize deuterated ibrutinib, but in the above-mentioned route for synthesizing deuterated ibrutinib, there are many steps , complex operation, expensive raw materials and other disadvantages, as well as problems such as dangerous use and highly toxic raw materials
Hydrogen-deuterium exchange method: poor deuterium site selectivity, excessive deuterium reagent is required, and the deuterium rate is low

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Under the protection of an inert gas, 4CzIPN (63.04mg, 0.08mmol, 0.02eq), ibrutinib (1.76g, 4.0mmol, 1.0eq), Li 2 CO 3 (355mg, 4.8mmol, 1.2eq), NMP (30mL), triisopropylsilanethiol (228mg, 1.2mmol, 0.3eq) and D 2 O (4 mL, 200 mmol, 50 equiv). The reaction mixture was irradiated with a 25W 395nm blue LED light setting for 24 hours at room temperature. The crude product was purified by flash chromatography to give a white solid (1.2501 g, 70.2% yield).

Embodiment 2

[0036] Under the protection of inert gas, add Cu[(BCP)(Xantphos)]PF in sequence 6 (34.2mg, 0.03mmol, 0.03eq), ibrutinib (0.44g, 1mmol, 1.0eq), Li 2 CO 3 (74mg, 1.0mmol, 1.0eq), NMP (10mL), triphenylsilanethiol (87.7mg, 0.3mmol, 0.3eq) and D 2 O (0.2 mL, 10 mmol, 10 equiv). The reaction mixture was irradiated for 1 hour at 150°C with a 25W 395nm blue LED light setting. The crude product was purified by flash chromatography to give a white solid (0.056 g, 12.73% yield).

Embodiment 3

[0038] Under the protection of inert gas, add Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (33.6mg, 0.03mmol, 0.03eq), ibrutinib (0.44g, 1mmol, 1.0eq), Li 2 CO 3 (88.7mg, 1.2mmol, 1.2eq), NMP (5mL), triisopropylsilanethiol (57.1mg, 0.3mmol, 0.3eq) and D 2 O (1 mL, 50 mmol, 50 equiv). The reaction mixture was irradiated for 36 hours at 30°C with a 25W 395nm blue LED light setting. The crude product was purified by flash chromatography to give a white solid (0.268 g, 60.22% yield).

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Abstract

The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of deuterated ibrutinib. The preparation method of the deuterated ibrutinib provided by the invention comprises the following step of: synthesizing the positioned deuterated ibrutinib from the raw material ibrutinib under the illumination condition under the catalysis of a photosensitizer. The method provided by the invention has the characteristics of simple operation, mild conditions, high yield, good selectivity, environmental protection and the like, and the synthesized deuterated ibrutinib significantly increases the absorption degree of the drug, thereby providing a new process route for the synthesis of selective deuterated ibrutinib.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a preparation method of deuterated ibrutinib. Background technique [0002] Many drugs have poor absorption, distribution, metabolism, and / or excretion properties, known as toxic pharmacokinetics (ADME), that hinder their widespread use or limit their use in certain indications. In order to expand the application of drugs, it is necessary to improve their ADME properties, among which, in addition to formulation technology and prodrug strategy, deuterium modification is also a feasible method to improve the ADME properties of drugs. On the one hand, since the shape and volume of deuterium in the drug molecule are basically the same as hydrogen, if the hydrogen in the drug molecule is selectively replaced by deuterium, the deuterated drug will basically retain the original biopharmaceutical activity. On the other hand, since the carbon-deuterium bond has a lower vibrat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P35/00A61P35/02
CPCC07D487/04A61P35/00A61P35/02C07B2200/05
Inventor 罗书平徐丹丹刘晓庆王天琦
Owner 绍兴舜邦医药科技有限公司
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