Sonrotoclax Intermediates Via SNAr for Stable, High-Yield Synthesis
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Solution Overview
Problem
The current process for preparing Sonrotoclax has low yield and unstable intermediates, making it unsuitable for industrial applications.
Innovation Solution
Development of novel intermediates, specifically methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azaspiro[5.1.58.16]tetradecan-11-yl)benzoate, synthesized through a SNAr reaction using 1,5-dioxa-11-azadispiro[5.1.58.16]tetradecane hydrochloride and methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate with a base, optimized to achieve high purity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the current process is used to prepare Sonrotoclax, then the synthesis can be performed, but the yield is relatively low and the intermediates are not stable enough
Solution Approach 1:
The patent changes the chemical structure parameters of the intermediate compounds by introducing specific protecting groups (e.g., tert-butyl carbonyl, isopropyl carbonyl) and modifying the molecular framework to enhance stability. This structural parameter change allows the intermediates to remain stable during storage and handling while maintaining reactivity in the final synthesis step, thereby resolving the contradiction between yield and intermediate stability.
Solution Approach 2:
The patent employs specially designed intermediate compounds with protective groups as mediators between the starting materials and the final Sonrotoclax product. These intermediaries (e.g., compounds with carbonyl protective groups) serve as stable bridges that can be stored and handled, then converted to the final product through a final deprotection step, thus improving both stability and overall yield.
2Productivity
If the current process is used to prepare Sonrotoclax, then the synthesis can be performed, but the yield is relatively low
Solution Approach 1:
The patent modifies the synthesis process parameters by introducing protective group transformations and optimizing reaction conditions (temperature, solvent, catalysts) to improve yield. The use of specific protecting groups like tert-butyl carbonyl and isopropyl carbonyl allows for better process control and higher yields while maintaining manufacturing feasibility.
Solution Approach 2:
The patent performs preliminary actions by preparing and stabilizing intermediates with protective groups before the final synthesis step. This preliminary preparation allows the intermediates to be stored and handled stablely, then converted to the final product in a single efficient step, thereby improving overall yield and process stability.
3Reliability
If novel intermediates are developed, then stability and yield are improved, but the synthesis process becomes more complex
Solution Approach 1:
The patent segments the synthesis process into distinct modules: preparation of stable intermediates with protective groups, storage/handling of these stable intermediates, and final deprotection to yield Sonrotoclax. This segmentation allows each step to be optimized independently, improving stability and yield while keeping the overall process manageable through modular design.
Solution Approach 2:
The patent uses stable intermediates with protective groups as mediators that simplify the overall process. These intermediaries can be prepared, stored, and handled stablely, then converted to the final product through a straightforward deprotection step, thereby improving reliability without proportionally increasing process complexity.
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 new intermediates enable a robust industrial process with yields exceeding 70% and purity over 90%, addressing the stability and yield issues of the previous methods.
Implementation Method 1
synthesized through a SNAr reaction using 1,5-dioxa-11-azadispiro[5.1.58.16]tetradecane hydrochloride and methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate with a base
Data Source
AI summary
Disclosed herein are compounds of Formula (I) having protective group of carbonyl used as intermediates for preparing 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Sonrotoclax), and processes for preparing compounds of Formula (I), including methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azadispiro[5.1.58.16]tetradecan-11-yl)benzoate.