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Method for preparing btk inhibitor

A solvent and reaction mixture technology, applied in the field of preparation of BTK inhibitors, can solve the problem of low total yield of starting materials

Active Publication Date: 2022-08-02
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Multi-step method requires two chromatographic purification steps and lower overall yields based on starting material

Method used

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  • Method for preparing btk inhibitor
  • Method for preparing btk inhibitor
  • Method for preparing btk inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0147] Preparation of compound 400

[0148] In some aspects of the invention, tricyclic lactam compound 400, its stereoisomers, its geometric isomers, its tautomers, and its salts can be prepared from compounds 300 and 310 according to the following reaction schemes:

[0149]

[0150] The method of preparing compound 400 includes forming a reaction mixture comprising an organic solvent, an organic base, and compounds 300 and 310, and reacting the reaction mixture to form a reaction product mixture comprising the tricyclic lactam of compound 400.

[0151] R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b independently selected from H and C 1-6 alkyl. R 5 selected from H, C 1-6 Alkyl, cycloalkyl, aryl, substituted aryl, benzyl, substituted benzyl, heteroaryl, substituted heteroaryl. In some respects, R 1a , R 1b , R 3a , R 3b , R 4a , R 4b and R 5 is H, and R 2a and R 2b yes-ch 3 .

[0152] Halogen is as described elsewhere herein. In some aspect...

Embodiment

[0224] The figures and examples provide exemplary methods for preparing the disclosed compounds; those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds. Although particular starting materials and reagents are described and discussed in the Figures and Examples, other starting materials and reagents can be substituted to provide various derivatives and / or reaction conditions. In addition, many of the described and exemplary methods can be further modified in light of the present disclosure using conventional chemical methods well known to those skilled in the art.

[0225] In the examples, equivalent weights and equivalent ratios are based on reference starting materials for each reaction. Volume per weight value, eg, L / kg and mL / g, refers to the volume of liquid components based on the weight of the reference starting material for each reaction.

[0226] Analytical method

[0227] High pressure liquid chromatography (HPLC...

Embodiment 5 to 8

[0229] Examples 5 to 8. Column: Waters Atlantis T3 (4.6*150mm 3μm). Mobile phase A: 10 mM ammonium formate pH 3.7. Mobile phase B: CH 3 EN. Flow rate: 1.0 mL / min. Injection volume: 2.0uL. Column temperature: 45°C. UV detection wavelength: 315nm. Thinner: CAN.

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Abstract

Provided is the preparation of the Bruton tyrosine kinase ("BTK") inhibitor compound 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxa Cyclobutane-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4']bipyridin-2'-yl} of -7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-1-one method. Also provided are methods of preparing the tricyclic lactam compounds.

Description

[0001] Background of the Invention [0002] The field of the invention relates generally to the preparation of the Bruton tyrosine kinase ("BTK") inhibitor compound 2-{3'-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl- 4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4']bipyridine-2 '-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazine- 1-keto method. The field of the invention also generally relates to methods of preparing tricyclic lactam compounds. [0003] A BTK inhibitor compound having the structure 2-{3'-Hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl- Piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4']bipyridin-2'-yl}-7,7-dimethyl -3,4,7,8-Tetrahydro-2H,6H-cyclopentadieno[4,5]pyrrolo[1,2-a]pyrazin-1-one: [0004] [0005] Known from US Published US 2013 / 0116235 A1, it is a BTK inhibitor useful for the treatment of diseases or conditions selected from immune disorders, cancer, cardiovascular diseases...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04B01J31/2414B01J31/2409C07B2200/09B01J2531/824B01J2231/40
Inventor D·博德里T·克拉维林F·戈瑟兰N-K·利姆S·马尔霍特拉田清平张海明A·格姆林A·费蒂斯S·巴赫曼
Owner F HOFFMANN LA ROCHE & CO AG
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