Aficamten Synthesis Route for Chiral Purity and Cardiac Selectivity
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Solution Overview
Problem
Current agents targeting the cardiac sarcomere for treating cardiac diseases like hypertrophic cardiomyopathy and heart failure with preserved ejection fraction are poorly selective, leading to adverse effects such as cell damage and arrhythmogenic side effects, necessitating improved methods for preparing selective cardiac myosin inhibitors with better safety and pharmacokinetics.
Innovation Solution
A multi-step process involving conversions of specific compounds using reagents like (R)-tert-butanesulfinamide, sodium borohydride, and hydroxylamine, with conditions optimized for high yield and purity, including the use of Lewis acids and water scavengers, to synthesize (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current agents (inotropes) are used to target the cardiac sarcomere, then contractility is increased, but selectivity for cardiac tissue is poor leading to adverse effects
Solution Approach 1:
The patent applies local quality by designing a compound with specific molecular features that confer cardiac selectivity. The compound structure includes a pyrazole carboxamide moiety coupled to a chiral indane skeleton with specific substituents, creating local chemical properties that enable selective binding to cardiac myosin while sparing smooth muscle and other tissues, thereby resolving the contradiction between achieving contractility enhancement and maintaining tissue selectivity
2Reliability
If current inotropic agents are used to increase contractility, then cardiac function is improved, but therapeutic index is narrow due to adverse effects
Solution Approach 1:
The patent employs parameter changes by establishing specific stereochemical parameters through asymmetric synthesis using chiral catalysts and reagents. The compound is synthesized as a single enantiomer ((R)-configuration) rather than a racemic mixture, and specific stereochemical configurations are maintained throughout the synthesis pathway. This parameter control achieves superior pharmacological selectivity and a wider therapeutic index by eliminating the adverse effects associated with racemic mixtures of current inotropes
3Productivity
If conventional synthesis methods are used for preparing the compound, then the process is simpler, but yield and purity are insufficient
Solution Approach 1:
The patent applies segmentation by dividing the synthesis into distinct modular steps: (1) asymmetric synthesis of the chiral indane intermediate using chiral catalysts, (2) conversion to the pyrazole carboxamide compound through controlled chemical transformations, and (3) purification by chiral HPLC. Each step is optimized independently to maximize yield and purity at each stage, resolving the contradiction between process simplicity and overall efficiency
4Reliability
If the compound is synthesized with high selectivity and purity, then safety and therapeutic index are improved, but the synthesis process becomes more complex
Solution Approach 1:
The patent applies preliminary action by performing asymmetric synthesis in the early stages to establish the correct stereochemistry before subsequent transformations. The chiral indane intermediate is prepared with high enantiomeric excess using chiral catalysts, and this stereochemical information is carried forward through the synthesis. This preliminary establishment of chirality simplifies later steps and ensures safety through consistent stereochemical configuration throughout the molecule
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 method provides a compound with a wider therapeutic index, less impact on cardiac relaxation, and improved safety, addressing the limitations of current agents by enhancing selectivity and reducing adverse effects.
Implementation Method 1
reacting the compound of Formula (7) with (R)-tert-butanesulfinamide is performed in the presence of a Lewis acid
Implementation Method 2
reacting the compound of Formula (6) with a reducing agent is performed in the presence of tetrahydrofuran at a temperature of between about -15 °C and about -5 °C. In some embodiments, the reducing agent is sodium borohydride
Implementation Method 3
converting the compound of Formula (5) or salt thereof to the compound of Formula (1) or a salt thereof comprises converting the compound of Formula (5) or salt thereof to the compound of Formula (4) or salt thereof
Data Source
AI summary
Provided herein is a process for the preparation of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, intermediates thereof, and salts of the foregoing.