SHP2 Inhibitor Synthesis via B3′ Intermediate and Thiosulfate
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Solution Overview
Problem
Existing synthesis methods for the compound (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine require large quantities of materials and pose thermo safety risks, especially due to the use of excessive hydroxylamine hydrochloride and pyrophoric reagents like anhydrous Na2S.
Innovation Solution
A new synthesis route using a novel intermediate B3′ and sodium thiosulfate instead of sodium sulfide, along with optimized reaction conditions, reduces material requirements and eliminates thermo safety hazards, improving the efficiency and safety of the manufacturing process.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If equivalent amounts of lactone B2 are used to synthesize B3, then the reaction can proceed, but large quantities of material are required which is inefficient for commercial manufacture
Solution Approach 1:
The patent changes the stoichiometric parameters of the reaction by using a different synthetic route that requires only 0.5 equivalents of lactone B2 instead of 1 equivalent, thereby reducing material consumption while maintaining productivity
2Reliability
If at least five fold molar excess of hydroxylamine hydrochloride is used to achieve good conversion from B3 to B4, then the reaction converts well, but this poses thermo safety risks for large scale synthesis
Solution Approach 1:
The patent extracts and removes the problematic step requiring 5-fold excess of hydroxylamine hydrochloride by using an alternative synthetic route that avoids this high-risk condition while maintaining good conversion efficiency
Solution Approach 2:
The patent converts the harmful thermo safety risk into a benefit by selecting a reaction pathway that inherently requires fewer reagents, thus transforming a potentially dangerous process into a safe one while maintaining or improving conversion efficiency
3Ease of manufacture
If anhydrous Na2S is used in the synthesis, then the reaction can proceed, but the reagent is pyrophoric and poses safety hazards
Solution Approach 1:
The patent replaces the dangerous pyrophoric reagent anhydrous Na2S with sodium thiosulfate, which is safer, commercially available in large scale, and equally effective for the synthesis, eliminating the need to handle hazardous materials
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 method requires less material and safer reagents, enhancing the scalability and environmental friendliness of the synthesis, while maintaining the effectiveness of producing the compound for inhibiting SHP2 activity.
Implementation Method 1
reacting a compound of the formula V with sodium thiosulfate to yield the intermediate B3′
Implementation Method 2
cyclized with hydroxylamine, or a salt thereof, to yield a hydroxylamine compound of the formula VII
Implementation Method 3
hydrogenated to yield an amino compound of the formula VIII
Data Source
AI summary
The present invention relates to a method for the manufacture of a compound of Formula I or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof, said method comprising reacting a compound of the formula II with a compound of the formula III according to the following reaction scheme: wherein LG, A, n, m and p are as defined in the Summary of the Invention, said manufacture including the manufacture and use of a compound of the formula VI; wherein R1 is a secondary amino protecting group and R5 is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted aryl.