Synthetic Process for RET Kinase Inhibitor via Segmentation
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Solution Overview
Problem
There is a need for alternative synthetic procedures for the preparation of the compound of Formula I, which exhibits RET kinase inhibition, as existing methods are not adequately addressed.
Innovation Solution
A multi-step process involving various chemical reactions such as treating compounds with 6-methoxynicotinaldehyde, reducing agents, deprotecting agents, and catalysts to form the compound of Formula I or its pharmaceutically acceptable salts, utilizing specific reagents and conditions to achieve the desired structure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing synthetic procedures are used for preparing the compound of Formula I, then the compound can be obtained, but the synthetic procedure is not optimal in terms of efficiency, yield, or complexity
Solution Approach 1:
The synthesis is divided into distinct modular steps: (i) preparation of compound 16 from compound 15 using deprotecting agents, (ii) condensation of compound 16 with 6-methoxynicotinaldehyde and reducing agents to form compound I. Each step uses specific reagents and conditions that can be independently optimized, improving overall synthetic efficiency while maintaining clarity in the procedure.
Solution Approach 2:
The patent employs specific parameter optimizations including pH control during deprotection, temperature control during condensation reactions, and selection of specific reducing agents (e.g., sodium borohydride, lithium aluminum hydride) to optimize yield and reduce side reactions. These parameter changes enhance productivity while streamlining the synthetic procedure.
2Reliability
If existing synthetic procedures are used for preparing the compound of Formula I, then the compound can be obtained, but the yield or purity may not be optimal
Solution Approach 1:
Compound 16 serves as a key intermediary that is prepared in high purity through controlled deprotection of compound 15. This intermediate is then used in the condensation reaction with 6-methoxynicotinaldehyde, ensuring high purity of the final product. The use of purified intermediates at each step enhances both reliability and manufacturing precision.
Solution Approach 2:
The patent replaces traditional purification methods with more efficient techniques such as selective crystallization, filtration, and use of high-performance liquid chromatography (HPLC) for final purification. These substitutions improve both the reliability of obtaining the desired compound and the manufacturing precision in terms of purity.
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 provides a reliable and efficient method for preparing the compound, enabling its use in pharmaceutical applications for RET kinase inhibition.
Implementation Method 1
treating a compound of formula 16 or a salt thereof with 6-methoxynicotinaldehyde and a reducing agent to form the compound of Formula I or a pharmaceutically acceptable salt thereof
Implementation Method 2
treating a compound of formula 15 or a salt thereof, wherein R1 is an amine protecting group, with a deprotecting agent to form the compound of formula 16 or a salt thereof
Implementation Method 3
treating a compound of formula 13 or a salt thereof, wherein X represents a halogen or a sulfonate, with a compound of formula 21 in the presence of 2,2-dimethyloxirane, a first catalyst comprising a metal, and a first weak base to form the compound of formula 13 or a salt thereof
Implementation Method 4
treating the compound of formula 22 or a salt thereof with a first strong base and hydrogen peroxide to form a compound of formula 23 or a salt thereof
Data Source
AI summary
In some embodiments, provided herein is a process for preparing a compound of Formula Ior a pharmaceutically acceptable salt thereof, as disclosed herein.