Carfilzomib Synthesis: Optimized Coupling Agent Stoichiometry
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Solution Overview
Problem
Current processes for preparing carfilzomib are inefficient due to the use of excess coupling agents and solvents, leading to impurities, increased reaction times, and reduced yield, making them unsuitable for large-scale manufacturing.
Innovation Solution
A process involving the reaction of specific compounds with optimized amounts of coupling agents and additives in suitable solvents, followed by purification steps to minimize impurities and enhance yield, resulting in higher purity and efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If excess quantity of coupling agents and additives are used in amide coupling reactions, then the reaction completeness is improved, but the formation of impurities increases and requires separate purification techniques
Solution Approach 1:
The patent changes the parameters of coupling agent usage from excess quantity to optimized amounts (equivalent to or slightly more than stoichiometric amount), and adjusts reaction conditions (temperature, time, solvent) to achieve complete reaction without forming excessive impurities, thus resolving the contradiction between reaction completeness and impurity formation
Solution Approach 2:
The patent employs alternative coupling methods that replicate the amide coupling function using different mechanisms (such as using activated esters or other activated compounds instead of traditional coupling agents), achieving the same reaction outcome with fewer impurities
2Productivity
If excess quantity of coupling agents and solvents are used, then the reaction efficiency is improved, but the manufacturing cycle time increases
Solution Approach 1:
The patent optimizes reaction parameters including coupling agent amount, temperature, and time to achieve efficient reactions with shorter durations, eliminating the need for excessive solvents and reducing overall manufacturing cycle time while maintaining high productivity
Solution Approach 2:
The patent extracts and eliminates unnecessary excess solvents and coupling agents from the reaction system, using only the minimum required amounts, which reduces the time needed for purification and drying steps, thereby shortening the manufacturing cycle
3Reliability
If excess quantity of coupling agents are used, then the reaction completeness is improved, but the final yield and purity are reduced
Solution Approach 1:
The patent changes the quantity parameter of coupling agents from excess to optimized amounts and adjusts other reaction parameters (temperature, time, catalysts) to ensure complete reaction and high yield without compromising purity, thus resolving the contradiction between reaction completeness and final yield
4Manufacturing precision
If solvent extractions are used for isolation of intermediates and final product, then the purification is improved, but additional purifications are required to separate unwanted coupling agents
Solution Approach 1:
The patent extracts and eliminates the need for multiple purification steps by using coupling agents and reaction conditions that do not leave behind unwanted byproducts, achieving purification through the reaction process itself rather than requiring separate extraction and purification operations
Solution Approach 2:
The patent converts the potential harm of coupling agent byproducts into a benefit by using coupling agents that decompose into harmless or easily removable substances, or by designing the reaction to produce only desired products, thus simplifying the purification process
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 achieves higher yields and purities of carfilzomib, reducing impurities and reaction times, making it more viable for commercial production.
Implementation Method 1
coupling of N-boc-leucine of Formula II with phenyl alanine benzyl ester of Formula III in presence of excess quantity of coupling agents such as PyBOP
Implementation Method 2
reacting a compound of Formula V or a salt thereof with a compound of Formula VI in presence of a coupling agent (C2), an additive (A2) and a base (B2)
Data Source
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AI summary
The present invention relates to an improved process for the preparation of carfilzomib or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for the preparation of amorphous form of carfilzomib.