Remibrutinib Drug Substance Synthesis for Nitrosamine Reduction
Solution Overview
Problem
Existing processes for preparing remibrutinib, a potent Bruton's tyrosine kinase inhibitor, result in the formation of nitrosamine impurities, which are potentially carcinogenic and require stringent regulatory compliance, necessitating a new synthesis route to minimize their presence.
Innovation Solution
A new process for preparing remibrutinib that avoids the use of undesirable intermediates and includes crystallization steps to reduce nitrosamine impurities to levels below 1000 ppb, utilizing crystalline forms of solvates or salts to achieve substantial purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If existing synthesis processes are used to prepare remibrutinib, then the production process is straightforward, but nitrosamine impurities are formed at levels around 1.6 ppm which are potentially carcinogenic
Solution Approach 1:
The patent removes the problematic N-methylacrylamide intermediate from the synthesis pathway entirely. By using alternative starting materials (5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and appropriate pyrimidine building blocks) and avoiding the nitrosation-prone N-methylacrylamide group, the process eliminates the source of nitrosamine impurity formation while maintaining the desired remibrutinib product
Solution Approach 2:
The patent changes the chemical parameters of the synthesis pathway by modifying the intermediate structures and reaction conditions. Specifically, it alters the acrylamide synthesis step to avoid N-methylacrylamide formation, thereby changing the chemical composition parameters to prevent nitrosamine generation while still achieving the target molecule
2Object-affected harmful factors
If crystallization steps are added to reduce nitrosamine impurities to below 1000 ppb, then nitrosamine levels are reduced significantly, but the process complexity increases
Solution Approach 1:
The patent performs preliminary purification actions during the synthesis process itself. By incorporating crystallization steps at strategic points (such as isolating intermediate compounds or the final product), the process proactively removes nitrosamine impurities before they can accumulate to problematic levels, thereby reducing the need for more complex post-processing purification techniques
Solution Approach 2:
The patent utilizes phase transition (crystallization) as a purification mechanism. By controlling the crystallization conditions of remibrutinib or intermediate compounds, the process exploits the differential solubility and crystal lattice formation to exclude nitrosamine impurities from the crystal structure, achieving purification through solid-liquid phase transition
3Reliability
If alternative synthesis routes avoiding mutagenic intermediates are used, then patient safety is improved, but the manufacturing process becomes more complex
Solution Approach 1:
The patent introduces alternative intermediate compounds that serve as safe mediators in the synthesis pathway. Instead of using the mutagenic N-methylacrylamide intermediate, the process employs different chemical intermediates (such as protected amine derivatives or alternative coupling intermediates) that achieve the same synthetic transformation without posing mutagenic risks, thereby maintaining patient safety while enabling the synthesis
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The process effectively reduces nitrosamine impurities to low levels, ensuring compliance with regulatory standards and patient safety by minimizing mutagenic risks.
Implementation Method 1
The invention further relates to a crystalline form of a solvate of LOU064 or a crystalline form of a salt of LOU064 used in the process
Data Source
AI summary
This invention relates to a new process for preparing N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (LOU064) drug substance substantially free of nitrosamine impurities as well as new crystalline forms of salt and solvate of LOU064 used in the process. The invention further relates to pharmaceutical composition comprising N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, wherein the composition is substantially free of a nitrosamine impurity, e.g. the nitrosamine impurity N-(3-(6-amino-5-(2(methyl)(nitroso)amino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide. Pharmaceutical products containing said drug substance and compositions are also disclosed, as well as methods for preparing said drug substance, pharmaceutical compositions and products.