Aficamten Synthesis via Segmented Reaction Steps
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Solution Overview
Problem
There is a need for cost-effective, novel processes for the preparation of Aficamten that result in high overall yield and purity, as existing disclosures are limited.
Innovation Solution
A new process for preparing Aficamten involving the conversion of intermediate compounds through a series of reactions, including condensation, reduction, and cyclization, using specific reagents and solvents to obtain high purity Aficamten.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If existing disclosed processes are used for preparation of Aficamten, then the process is known and documented, but the cost is high and overall yield and purity are limited
Solution Approach 1:
The synthesis process is divided into distinct modular steps: condensation of compound (I) to form (II), reduction to (III), conversion to (IV), coupling with (V) to form (VI), cyanation to (VII), hydroxylamine reaction to (VIII), and final cyclization to Aficamten. Each step is optimized independently with specific reagents and conditions to maximize yield and purity at each stage, resolving the contradiction between manufacturing precision and productivity.
Solution Approach 2:
The patent optimizes reaction parameters including temperature ranges (e.g., 0-50°C for condensation, 60-80°C for cyclization), solvent types (DCM, MeOH, EtOAc, toluene), reagent equivalents (1.1-2.0 eq), and reaction times to achieve high purity (>98%) and high overall yield (60-70%). These parameter changes enable simultaneous improvement of both manufacturing precision and productivity.
2Reliability
If existing disclosed processes are used for preparation of Aficamten, then the process is established, but the cost is high
Solution Approach 1:
The patent employs cost-effective, readily available reagents and solvents such as EDC·HCl, HOBt, NaBH4, SnCl2·2H2O, CuCN, K4Fe(CN)6·3H2O, and common solvents (DCM, MeOH, EtOAc, toluene). These inexpensive reagents replace costly alternatives while maintaining process reliability and producing high purity Aficamten, thereby reducing manufacturing cost without sacrificing reliability.
Solution Approach 2:
The process uses straightforward workup and purification procedures where crude products are directly purified by filtration and standard chromatographic techniques. The reaction conditions are designed to minimize side products and simplify isolation, reducing the need for complex, costly purification steps while maintaining high purity and reliable results.
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 Aficamten with a purity of about 98% or more and chiral purity of about 98% or more, effectively addressing the need for high yield and purity.
Implementation Method 1
reacting a compound of Formula (IV) or a salt, an isomer or a mixture thereof with a compound of Formula (V) to obtain compound of Formula (VI)
Implementation Method 2
converting compound of Formula (VI) or a salt, an isomer or a mixture thereof to compound of Formula (VII)
Implementation Method 3
converting compound of Formula (VII) or a salt, an isomer or a mixture thereof to compound of Formula (VIII)
Implementation Method 4
converting compound of Formula (VIII) or a salt, an isomer or a mixture thereof to Aficamten
Data Source
AI summary
The present disclosure provides a new process for preparation of Aficamten. The present disclosure also provides t a novel intermediate compound or a salt, isomer or mixture thereof. Further, the present disclosure also provides a process for preparation of novel intermediate compound or a salt, an isomer or a mixture thereof. Furthermore, the provides a method of using of novel intermediate compound for preparation of Aficamten.